Clinical trial NCT02001623
Conditions: Ovary Cancer Cervix Cancer Endometrium Cancer Bladder Cancer Prostate Cancer (CRPC) Esophagus Cancer Lung Cancer(NSCLC) Squamous Cell Carcinoma of the Head and Neck (SCCHN)
Keywords: ovary cancer cervix cancer endometrium cancer bladder cancer prostate cancer (CRPC) esophagus cancer lung cancer(NSCLC) Squamous cell carcinoma of the head and neck (SCCHN)
Sponsor: Seagen Inc.
Start date: 2013-11-30; Completion date: 2019-05-02
Enrollment: 195 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The purpose of the trial is to establish the tolerability of HuMax-TF-ADC in a mixed population of patients with specified solid tumors.

Detailed description:
The study is conducted in two parts. The dose escalation portion of the trial subjects are enrolled into cohorts at increasing dose levels of HuMax-TF-ADC in 21 day treatment cycles.

In the Cohort Expansion part of the trial, will further explore the recommended phase 2 dose of HuMax-TF-ADC as determined in Part 1

Arms: arm 1: All arms of the trial (borh in escalation and expansion phase) will be administered tisotumab vedotin (HuMax-TF-ADC)
Interventions: intervention 1: Tisotumab Vedotin (HuMax-TF-ADC)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Document Name: GEN701 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
1 
PROTOCOL AND SUMMARY OF PROTOCOL 
AMENDMENTS 
First-In-Human, Dose Escalating Safety Study 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 
Protocol no.: 
GEN701 
Trial name 
innovaTV 201 
ClinicalTrials.gov Identifier 
NCT02001623 
Sponsor: 
Genmab A/S 
Collaborators: 
Seattle Genetics, Inc. 
EudraCT No.: 
2013-001074-15 
IND No.: 
115906 
IMP Name: 
Tisotumab vedotin (HuMax®-TF-ADC) 
Development Phase: 
1/2 
 
 
 
 
 
*Genmab is a global organization that operates through different legal entities in various countries. 
Therefore, the legal entity acting as the sponsor for Genmab trials may vary, such as, but not limited to 
Genmab Holding B.V.; Genmab A/S; or Genmab US, Inc. The term “sponsor” is used throughout the 
protocol to represent these various legal entities; the sponsor is identified on the following sponsor 
information page. 
The information in this document is confidential and is proprietary to Genmab. It is understood that information in this 
document shall not be disclosed to any third party, in any form, without prior written consent of an authorized officer of 
Genmab 


Document Name: GEN701 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
1 
OVERVIEW OF PROTOCOL AMENDMENTS .................................................. 3 
2 
SUMMARY OF PROTOCOL AMENDMENTS .................................................... 4 
3 
REDACTED PROTOCOL VERSION 16.0, LATEST VERSION ....................... 6 
 
 
 


Document Name: GEN701 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
3 
1 OVERVIEW OF PROTOCOL AMENDMENTS 
 
Protocol Version  
Issue Date 
Final 1.0 
 21 June 2013 
Final 2.0 (incorporating Protocol Amendment 1) 
 05 September 2013 
Final 3.0 (incorporating Protocol Amendment 2) 
 28 January 2014 
Final 4.0 (incorporating Protocol Amendment 3) 
 03 April 2014 
Final 5.0 (incorporating Protocol Amendment 4) 
 05 May 2014 
Final 6.0 (incorporating Protocol Amendment 5) 
 12 September 2014 
Final 7.0 (incorporating Protocol Amendment 6) 
 29 May 2015 
Final 8.0 (incorporating Protocol Amendment 7) 
 23 November 2015 
Final 9.0 (incorporating Protocol Amendment 8) 
 17 March 2016 
Final 10.0 (incorporating Protocol Amendment 9) 
 03 June 2016 
Final 11.0 (incorporating Protocol Amendment 10) 
 07 July 2016 
Final 12.0 (incorporating Protocol Amendment 11) 
 27 October 2016 
Final 13.0 (incorporating Protocol Amendment 12) 
 22 December 2016 
Final 14.0 (incorporating Protocol Amendment 13) 
 26 September 2017 
Final 15.0 (incorporating Protocol Amendment 14) 
 05 October 2017 
Final 16.0 (incorporating Protocol Administrative change 3) 
 18 July 2018 
 
 
 






Document Name: GEN701 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
Confidential 
6 
3 REDACTED PROTOCOL VERSION 16.0, LATEST VERSION 






Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
 18 Jul 2018 
Page 3 of 130 
Coordinating Investigator 
I have read and agree to the protocol GEN701 (innovaTV 201), entitled ‘First-in-human, 
dose-escalating safety study 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’, Version 16.0 Incorporating Administrative change 3 (18 July 
2018). I am aware of my responsibilities as an Investigator under the guidelines of GCP, 
local regulations (as applicable) and the study protocol. I agree to conduct the study 
according to these responsibilities and to appropriately direct and assist the staff under my 
control, who will be involved in the study. 
Coordinating Investigator Signature: 
 
Professor Section of Medicine 
Institute of Cancer Research 
Name 
Title 
/United Kingdom 
In
Si
Date 


Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
 18 Jul 2018 
Page 4 of 130 
1.
SYNOPSIS
NAME OF SPONSOR: Genmab A/S 
PROTOCOL No.: GEN701 
STUDY NAME: innovaTV 201 
NAME OF STUDY TREATMENT: Tisotumab vedotin (HuMax®-TF-ADC) 
TITLE OF STUDY: First-in-human, dose-escalating safety study 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   
STUDY CENTERS: The Dose Escalation part is planned to be performed in a maximum of five sites in 
Denmark, United Kingdom and the United States (US), with up to 30 additional sites to be included in 
Europe and the US for the Cohort Expansion part.  
STUDY PERIOD: A Dose Escalation part will be followed by a Cohort 
Expansion part. The study will be stopped when the last patient included in 
the Cohort Expansion part completes the study or when the last ongoing 
patient has discontinued treatment and attended the Safety Follow-up Visit, 
whichever occurs first.  
PHASE OF 
DEVELOPMENT: 
Phase I/II 
PLANNED STUDY DATES: Enrolment period in the Dose Escalation part is planned to last 
approximately 21 months. Enrolment period in the Cohort Expansion part is planned to last approximately 
30 months. 
OBJECTIVES:  
Primary Objective: To establish the tolerability of tisotumab vedotin (HuMax-TF-ADC) in a mixed 
population of patients with specified solid tumors. 
Secondary Objective(s): 
• To establish the long term tolerability of tisotumab vedotin (HuMax-TF-ADC) in a mixed population of
patients with specified solid tumors.
• To determine the maximum tolerated dose and the recommended dose for phase II studies with
tisotumab vedotin (HuMax-TF-ADC).
• To establish the pharmacokinetic (PK) profile of tisotumab vedotin (HuMax-TF-ADC) after single and
multiple infusions.
• To evaluate the anti-tumor activity of tisotumab vedotin (HuMax-TF-ADC) in a mixed population of
patients with specified solid tumors.
STUDY DESIGN AND METHODOLOGY: 
This is a dose-escalating, open-label, multicenter phase I/II safety study of tisotumab vedotin 
(HuMax-TF-ADC) 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 
study consists of two parts: a Dose Escalation part followed by a Cohort Expansion part. The Dose 
Escalation part is considered first in human and the Cohort Expansion part a phase II. A Data Monitoring 
Committee (DMC) will evaluate safety data during the study. 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 eight dose levels is anticipated (not including potential intermediate dose cohorts). The Cohort 
Expansion part will enroll approximately 169 patients who will be treated with a regimen based on the data 
obtained from the Dose Escalation part. The aim of the Cohort Expansion part is to provide further safety, 
tolerability, PK and anti-tumor activity data from patients with cancer types that express TF. Recruitment 
will be initiated in five arms. Based on a safety review of data from the first ten patients recruited and 
followed for at least one cycle (regardless of indication), the DMC and an internal sponsor’s Safety 
committee will evaluate the safety profile and, if deemed safe, the DMC and the sponsor’s Safety 
committee will approve the recruitment of the three remaining arms, esophagus, non-small cell lung cancer 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
 18 Jul 2018 
 
 
Page 5 of 130 
(NSCLC), and squamous cell carcinoma of the head and neck (SCCHN). A minimum of 14 and maximum 
of 30 patients will be recruited each to the cervix and endometrial indications (if one of these two 
indications does not appear promising while another indication shows promising efficacy, it may be 
decided to expand this other indication instead). After implementation of Protocol Amendment 13 
(Protocol version 14.0), up to 25 additional patients will be recruited to the cervix indication, for a 
maximum of approximately 55 patients. In the remaining indications (ovary, bladder, castration-resistant 
prostate cancer [CRPC], NSCLC, esophagus and SCCHN), 14 patients will be recruited.  
STUDY 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 (CRPC), 
esophagus or lung (NSCLC) who have failed available standard treatments or who are not candidates for 
standard therapy.  
The patient population in the Cohort Expansion part will encompass patients with advanced (locally 
advanced and/or metastatic) cancer of the ovary, cervix, endometrium, bladder, prostate (CRPC), 
esophagus, NSCLC SCCHN who have failed available standard treatments as specified in the inclusion 
criteria. 
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: Patients with relapsed, advanced and/or metastatic cancer of the ovary, 
cervix, endometrium, bladder, prostate, head and neck (SCCHN), esophagus or lung (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 study 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 (GEJ) 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 (ALK) mutations should have been treated with appropriate 
targeted therapy before study entry. Patients must have received no more than four (five allowed for 
patients with EGFR mutated adenocarcinomas) prior treatment regimens for advanced disease. 
o SCCHN: refractory to platinum-based therapy, also failing an anti-EGFR-based therapy if patient is 
eligible and if anti-EGFR therapy is part of the established SoC therapy. Patients must have 
received no more than one prior platinum-based and in total three prior treatment regimens for 
advanced disease. 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
 18 Jul 2018 
 
 
Page 6 of 130 
• 
Patients must have measurable disease according to RECIST (Response Evaluation Criteria In 
Solid Tumors) version. 1.1. A minimum of one 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. 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. 
Patients with ovarian cancer can be included based on CA 125 positivity according to the 
Gynecologic Cancer Intergroup Guideline in the Dose Escalation part only. 
• 
Age ≥ 18 years. 
• 
Acceptable renal function: Glomerular filtration rate (Cockcroft-Gault) > 45 mL/ min. 
• 
Acceptable liver function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 3 times the upper limit of normal (ULN) (if liver tumor/ metastases are present, then ≤ 5 × ULN 
is allowed); bilirubin ≤ 1.5 × ULN, except in patients diagnosed with Gilbert’s syndrome, direct 
bilirubin ≤ 2 × ULN. 
• 
Acceptable hematological status (hematologic support is allowed if administered at least one week 
before Cycle 1 Day 1): 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: International normalized ratio (INR) ≤ 1.2 (without 
anticoagulant therapy), and activated partial thromboplastin time (aPTT) ≤ 1.25 
ULN; patients on stable doses of therapeutic anti-coagulative treatment for ≥ 8 
weeks (e.g., warfarin) must have an INR < 3. 
• 
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). 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. 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 study, patients must provide signed 
informed consent before any study-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 study 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: have received granulocyte colony stimulating factor 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
 18 Jul 2018 
 
 
Page 7 of 130 
(G-CSF) or granulocyte/macrophage colony stimulating factor support within one week or 
pegylated G-CSF within two weeks before the Screening Visit; have received a cumulative dose of 
corticosteroid ≥ 150 mg (prednisone, or equivalent doses of corticosteroids) within two weeks 
before the first infusion. 
• 
Surgery/procedures: major surgery within six weeks or open biopsy within seven days before drug 
infusion; plan for any major surgery during treatment period; patients not willing or able to have a 
pre-study tumor biopsy taken (in the Dose Escalation part the screening biopsy can be omitted if 
archived material is available; in the Cohort Expansion part the most recent available archived 
sample can be used, if no biopsies are available a new biopsy must be obtained before dosing); 
presence or anticipated requirement of epidural catheter in relation to infusions (within 48 hours 
before and after dose of study drug). 
• 
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 five half-lives before first infusion 
(for anti-cancer therapies with half-lives > 8 days, a washout period of at least 28 days is 
acceptable); prior treatment with bevacizumab within twelve weeks before the first infusion; 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 adjacent to (Dose Escalation part only) or invading (both parts) any 
large blood vessel, unless approved by the sponsor Medical Officer should also be excluded. 
• 
Other: ongoing significant, uncontrolled medical condition; presence of CTCAE (Common 
Toxicity 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 HBsAg (hepatitis B surface antigen) and/or positive test for anti-HBs 
and anti-HBc (antibodies to hepatitis B surface and core antigens); 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 SUBJECTS: Approximately 310 patients will be screened to ensure that up to 217 patients 
(anticipated screen failure rate of 30%) are enrolled in the study.  
A maximum of 48 patients are planned to be enrolled in the Dose Escalation part: three to six patients per 
dose level for eight dose levels. Approximately 169 patients will be enrolled in the Cohort Expansion part. 
STUDY TREATMENT(S): In the Dose Escalation part, tisotumab vedotin (HuMax-TF-ADC) will be 
administered as an intravenous infusion over one hour on Day 1 of each cycle; in the Cohort Expansion 
part, tisotumab vedotin (HuMax-TF-ADC) will be administered as an intravenous infusion over 30 minutes 
on Day 1 of each (1 treatment cycle is 21 days). Preventive eye therapy should be administered in relation 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
 18 Jul 2018 
 
 
Page 8 of 130 
to infusions. 
The Dose Escalation part is a standard 3 (+3) design which will evaluate tisotumab vedotin 
(HuMax-TF-ADC) at doses of 0.30 mg/kg and up (0.3, 0.6, 0.9, 1.2, 1.5, 1.8, 2.2 and 2.6 mg/kg). The 
maximum tested dose will be 2.6 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 (21 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. The DMC 
and the sponsor’s Safety committee will, based on the Dose Escalation part, determine the dose level to be 
used in the Cohort Expansion part. At the conclusion of the Dose Escalation part, the dose level selected for 
the Cohort Expansion part is 2.0 mg/kg. 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.  
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 benefitting from 
treatment, at the discretion of the treating physician after agreement with Genmab on the patient status, 
there is an option to continue in the study for up to a maximum of eight additional cycles (24 weeks) or 
until unacceptable toxicity according to protocol is observed. The treatment period will have a maximum 
duration of 36 weeks. 
In the Cohort Expansion part, the patients will be treated with the dose identified from the Dose Escalation 
part by the DMC and the sponsor’s Safety committee for four cycles or until unacceptable toxicity. 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 study for up to a maximum of eight additional cycles 
(24 weeks) or until unacceptable toxicity is observed. The treatment period will have a maximum duration 
of 36 weeks. 
At the end of the planned number of cycles in both parts, 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. 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
 18 Jul 2018 
 
 
Page 9 of 130 
STUDY EVALUATIONS:  
Primary Endpoint:  
• AEs during the study: incidences of AEs, SAEs, infusion-related AEs, CTCAE grade ≥ 3 AEs, and AEs 
related to study 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 [MMAE]). 
• Immunogenicity (anti-drug antibodies) of tisotumab vedotin (HuMax-TF-ADC). 
• 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) after 6, 12, 24 and 
36 weeks, Progression-Free Survival (PFS) and Duration of Response (DoR). 
Exploratory Endpoints: 
• TF expression in tumor biopsies. 
• Circulating TF. 
• Protein biomarker. 
• Circulating cell-free deoxyribonucleic acid (cfDNA). 
STATISTICAL METHODS: The presentations will be done separately for the Dose Escalation and 
Cohort Expansion parts. 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 study drug and will be 
used for evaluation of all endpoints. 
Further details will be given in a separate Statistical Analysis Plan. 
DATE AND VERSION:  Final 16.0 incorporating Protocol Administrative change 3, 18 July 2018 


 
 
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Final 16.0 (incorporating Protocol Admin. Ch. 3) 
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Page 10 of 130 
2. 
TABLE OF CONTENTS 
1. 
SYNOPSIS .................................................................................................................. 4 
2. 
TABLE OF CONTENTS ........................................................................................ 10 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS......................... 17 
4. 
ETHICS .................................................................................................................... 20 
4.1 
Ethics Committee ...................................................................................................... 20 
4.2 
Ethical Conduct of the Study ..................................................................................... 20 
4.3 
Patient Information and Consent ............................................................................... 20 
5. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ........... 22 
6. 
INTRODUCTION ................................................................................................... 24 
6.1 
Key Background and Rationale ................................................................................. 24 
6.1.1 
Rationale for Indications ........................................................................................... 26 
6.1.1.1 
Selected Indications ................................................................................................... 26 
6.1.1.2 
Gynecological cancers ............................................................................................... 26 
6.1.1.3 
Genito-urethral Cancers ............................................................................................. 27 
6.1.1.4 
Lung Cancers ............................................................................................................. 28 
6.1.1.5 
Gastrointestinal Cancers ............................................................................................ 28 
6.1.1.6 
Head and Neck Cancer .............................................................................................. 29 
6.1.2 
Indications for the Cohort Expansion Part ................................................................ 29 
6.2 
Compound Review .................................................................................................... 30 
6.2.1 
Non-Clinical Studies ................................................................................................. 30 
6.2.2 
Previous Clinical Experience with MMAE-based ADCs .......................................... 32 
6.2.3 
Clinical Experience.................................................................................................... 34 
6.2.4 
Summary of Known and Potential Risks to Human Subjects ................................... 36 
6.3 
Clinical Study Rationale ............................................................................................ 38 
6.3.1 
Patient Population ...................................................................................................... 38 
6.3.2 
Study Design ............................................................................................................. 38 
6.3.3 
Dose Rationale ........................................................................................................... 39 
6.4 
Immunogenicity Assay Strategy for tisotumab vedotin (HuMax-TF-ADC) ............. 40 
6.5 
Rationale for Exploratory Endpoints ......................................................................... 40 
6.5.1 
Tumor Biopsy ............................................................................................................ 40 
6.5.2 
Biomarkers ................................................................................................................ 41 
6.5.2.1 
Circulating Tissue Factor in Plasma .......................................................................... 41 
6.5.2.2 
Protein Biomarkers .................................................................................................... 41 
6.5.2.3 
Circulating Free DNA ............................................................................................... 41 
7. 
STUDY OBJECTIVES AND ENDPOINTS ......................................................... 42 


 
 
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7.1 
Study Objectives ........................................................................................................ 42 
7.1.1 
Primary Study Objective ........................................................................................... 42 
7.1.2 
Secondary Study Objectives ...................................................................................... 42 
7.2 
Study Endpoints ......................................................................................................... 42 
7.2.1 
Primary Endpoint ....................................................................................................... 42 
7.2.2 
Secondary Endpoints ................................................................................................. 42 
7.2.3 
Exploratory Endpoints ............................................................................................... 43 
8. 
INVESTIGATIONAL PLAN ................................................................................. 44 
8.1 
Overall Study Design and Plan .................................................................................. 44 
8.1.1 
Dose Escalation Part .................................................................................................. 44 
8.1.2 
Cohort Expansion Part ............................................................................................... 44 
8.1.3 
Study Overview ......................................................................................................... 46 
8.1.3.1 
Screening Phase (Visit 0) .......................................................................................... 46 
8.1.3.2 
Treatment Phase (C1 to CX) ..................................................................................... 46 
8.1.3.3 
Unscheduled Visit (U1 to UX) .................................................................................. 47 
8.1.3.4 
Follow-up Phase (FU1 to FU4) ................................................................................. 47 
8.1.3.5 
End of Study Visit (EOS) .......................................................................................... 47 
8.1.3.6 
Safety Follow-up Visit (SFU).................................................................................... 47 
8.2 
Study Duration and End of Study .............................................................................. 56 
8.2.1 
Study Stopping Criteria ............................................................................................. 56 
8.3 
Study Population ....................................................................................................... 57 
8.3.1 
Inclusion Criteria ....................................................................................................... 57 
8.3.2 
Exclusion Criteria ...................................................................................................... 60 
8.3.3 
Patient Allocation Procedure ..................................................................................... 62 
8.3.4 
Withdrawal and Replacement of Patients .................................................................. 62 
8.3.4.1 
Criteria for Patient Withdrawal from Treatment ....................................................... 62 
8.3.4.2 
Criteria for Patient Withdrawal from the Study ........................................................ 64 
8.3.4.3 
Evaluations at Withdrawal from Treatment .............................................................. 64 
8.3.4.4 
Evaluations at Withdrawal from the Study ................................................................ 64 
8.3.4.5 
Replacement of Patients ............................................................................................ 65 
8.4 
Treatment ................................................................................................................... 65 
8.4.1 
Treatments Administered .......................................................................................... 65 
8.4.2 
Study Treatment Preparation ..................................................................................... 66 
8.4.3 
Study Treatment Storage and Accountability ............................................................ 66 
8.4.3.1 
Study Treatment Storage ........................................................................................... 66 
8.4.3.2 
Study Treatment Accountability ................................................................................ 66 
8.4.4 
Treatment of Infusion-Related Reactions .................................................................. 67 


 
 
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8.4.5 
Dose Modification and Mitigation Plan for Skin Toxicity ........................................ 67 
8.4.6 
Mitigation Plan for Mucositis .................................................................................... 68 
8.4.7 
Dose Modification for Peripheral Neuropathy and Neutropenia ............................... 68 
8.4.8 
Dose Modification and Mitigation Plan for Ocular Adverse Events ......................... 69 
8.4.9 
Dose Modification for QTcF Changes in the Electrocardiogram .............................. 72 
8.4.10 
Dose Modification for Increased Liver Enzymes ...................................................... 73 
8.4.11 
Precautions ................................................................................................................ 73 
8.4.12 
Dose Escalation ......................................................................................................... 73 
8.4.12.1 
Dose Escalation Overview......................................................................................... 73 
8.4.12.2 
Dose-escalation Rules................................................................................................ 74 
8.4.13 
Dose Limiting Toxicities for the Dose Escalation Part of the Study ......................... 75 
8.4.14 
Data Evaluation for the Cohort Expansion Part ........................................................ 76 
8.4.15 
Prior and Concomitant Therapy ................................................................................ 76 
8.4.15.1 
Prior Therapy ............................................................................................................. 76 
8.4.15.2 
Permitted Concomitant Medications ......................................................................... 77 
8.4.15.3 
Excluded Concomitant Medications .......................................................................... 77 
8.4.15.4 
Treatment Compliance .............................................................................................. 77 
8.4.15.5 
Assignment to Treatment........................................................................................... 77 
9. 
STUDY EVALUATIONS ....................................................................................... 78 
9.1 
Dose Escalation Part .................................................................................................. 78 
9.1.1 
Dose Escalation: Screening (Visit 0) ......................................................................... 78 
9.1.2 
Dose Escalation: Treatment ....................................................................................... 78 
9.1.2.1 
Dose Escalation Cycles 1 and 2 ................................................................................. 79 
9.1.2.2 
Dose Escalation Cycles 3 and 4 ................................................................................. 79 
9.1.2.3 
Dose Escalation Cycles 5 to 12 ................................................................................. 79 
9.1.3 
Dose Escalation Follow-up Visits (FU1 to FU4) ...................................................... 79 
9.1.4 
Dose Escalation Unscheduled Visit (U1 to UX) ....................................................... 79 
9.1.5 
Dose Escalation End of Study Visit (EOS) ............................................................... 80 
9.1.6 
Dose Escalation Safety Follow-up Visit (SFU) ......................................................... 80 
9.2 
Cohort Expansion Part ............................................................................................... 80 
9.2.1 
Cohort Expansion: Screening (Visit 0) ...................................................................... 80 
9.2.2 
Cohort Expansion: Treatment .................................................................................... 80 
9.2.2.1 
Cohort Expansion Cycles 1 to 4 ................................................................................ 81 
9.2.2.2 
Cohort Expansion Cycles 5 to 12 .............................................................................. 81 
9.2.3 
Cohort Expansion Follow-up Visits (FU1 to FU4) ................................................... 81 
9.2.4 
Cohort Expansion Unscheduled Visit (U1 to UX) .................................................... 81 
9.2.5 
Cohort Expansion End of Study Visit (EOS) ............................................................ 81 


 
 
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9.2.6 
Cohort Expansion Safety Follow-up Visit (SFU) ...................................................... 82 
10. 
METHODS OF ASSESSMENT ............................................................................. 83 
10.1 
Demographics ............................................................................................................ 83 
10.2 
Medical History ......................................................................................................... 83 
10.3 
Height and Weight ..................................................................................................... 83 
10.4 
Physical Examination ................................................................................................ 83 
10.5 
Vital Signs ................................................................................................................. 83 
10.6 
Electrocardiogram ..................................................................................................... 84 
10.7 
Computerized Tomography ....................................................................................... 85 
10.8 
ECOG Performance Status ........................................................................................ 85 
10.9 
Adverse Events .......................................................................................................... 85 
10.10 
Concomitant Medication ........................................................................................... 86 
10.11 
Bleeding Assessments ............................................................................................... 86 
10.12 
Skin Assessments ...................................................................................................... 86 
10.13 
Neuropathy Assessment ............................................................................................ 87 
10.14 
Ophthalmological Evaluation .................................................................................... 87 
10.15 
Radionuclide Bone Scan ............................................................................................ 87 
10.16 
Laboratory Assessments ............................................................................................ 88 
10.16.1 
Hematology ............................................................................................................... 88 
10.16.2 
Biochemistry .............................................................................................................. 89 
10.16.3 
Coagulation Factors ................................................................................................... 89 
10.16.4 
PSA and CA 125 ....................................................................................................... 89 
10.16.5 
Flow Cytometry ......................................................................................................... 89 
10.16.6 
Pregnancy Test .......................................................................................................... 89 
10.16.7 
Immunogenicity of Tisotumab Vedotin (HuMax-TF-ADC) ..................................... 89 
10.16.8 
Hepatitis B, C, HPV and Cytomegalovirus Serology ................................................ 90 
10.17 
PK Assessments ......................................................................................................... 90 
10.18 
Tumor Biopsy ............................................................................................................ 90 
10.19 
Exploratory Biomarkers ............................................................................................ 91 
10.19.1 
Circulating TF ........................................................................................................... 91 
10.19.2 
Protein Biomarkers .................................................................................................... 91 
10.19.3 
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 Serious Adverse Events ....................................................................... 92 
11.1.1 
Definition of Infusion-Related Reaction ................................................................... 93 


 
 
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11.1.2 
Adverse Events of Special Interest ............................................................................ 93 
11.2 
Adverse Event Reporting........................................................................................... 93 
11.2.1 
Study Disease ............................................................................................................ 94 
11.2.1.1 
Pre-existing Conditions ............................................................................................. 94 
11.2.2 
Procedures ................................................................................................................. 94 
11.3 
Recording Instructions ............................................................................................... 94 
11.3.1 
Diagnosis ................................................................................................................... 94 
11.3.2 
Intensity ..................................................................................................................... 94 
11.3.3 
Relationship to Study Drug ....................................................................................... 94 
11.3.4 
Time of Onset ............................................................................................................ 94 
11.3.5 
Outcome .................................................................................................................... 95 
11.3.6 
Events Requiring Immediate Reporting .................................................................... 95 
11.3.6.1 
Serious Adverse Events, Non-serious Grade 3 Adverse Events and Non-serious Grade 2 
Ocular Adverse Events .............................................................................................. 95 
11.3.6.2 
Overdose and Medication Errors ............................................................................... 95 
11.3.6.3 
Pregnancy .................................................................................................................. 95 
11.3.7 
Reporting of Serious Adverse Events, Grade 3 Adverse Events, Grade 2 Ocular Adverse 
Events and Pregnancies ............................................................................................. 96 
11.3.8 
Suspected Unexpected Serious Adverse Reactions ................................................... 97 
11.4 
Follow-Up on Adverse Events .................................................................................. 97 
11.5 
Safety Communication Plan for Information to Site ................................................. 97 
11.6 
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 
Disease Control After 6, 12, 24 and 36 Weeks........................................................ 104 
12.5.3.6 
Patients with Tumor Shrinkage ............................................................................... 104 


 
 
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12.5.4 
Changes in PSA and CA 125 ................................................................................... 104 
12.5.5 
Exploratory Endpoints ............................................................................................. 104 
12.5.6 
Host Immune Response ........................................................................................... 104 
12.5.7 
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 Study Reporting ......................................................................................... 106 
13. 
MONITORING PROCEDURES/QUALITY ASSURANCE ............................ 107 
13.1 
Data Collection ........................................................................................................ 107 
13.2 
Data Management .................................................................................................... 107 
13.3 
Study Monitoring ..................................................................................................... 108 
13.4 
Inspections and Auditing Procedures ...................................................................... 109 
14. 
STUDY MANAGEMENT AND MATERIALS .................................................. 110 
14.1 
Data Collection ........................................................................................................ 110 
14.2 
Source Documents Maintenance ............................................................................. 110 
14.3 
Record Maintenance ................................................................................................ 111 
14.4 
Confidentiality ......................................................................................................... 111 
15. 
ADMINISTRATION PROCEDURES ................................................................ 113 
15.1 
Regulatory Approval ............................................................................................... 113 
15.2 
Protocol Amendments ............................................................................................. 113 
15.3 
Protocol Adherence and Deviations ........................................................................ 113 
15.4 
Publication Policy .................................................................................................... 114 
15.5 
Contractual and Financial Details ............................................................................ 114 
15.6 
Insurance, Indemnity and Compensation ................................................................ 114 
15.7 
Discontinuation of the Study ................................................................................... 115 
15.8 
Study Center File Management ............................................................................... 115 
16. 
REFERENCE LIST .............................................................................................. 116 
17. 
APPENDICES ........................................................................................................ 121 
17.1 
Appendix 1: ECOG Performance Status Scale ........................................................ 121 
17.2 
Appendix 2: Highly Effective Methods of Contraception ....................................... 122 
17.3 
Appendix 3: Declaration of Helsinki ....................................................................... 124 
 
 
LIST OF TABLES 
 
No table of contents entries found. 


 
 
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LIST OF FIGURES 
 
No table of contents entries found. 


 
 
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3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
3q4w 
Three times every four weeks  
ADA 
Anti-drug antibody 
ADC 
Antibody drug conjugate 
AE 
Adverse event  
ALK 
Anaplastic lymphoma kinase  
ALT  
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
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 
CI 
Confidence interval 
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 Toxicity 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  
EOS 
End of Study  
FVII, FIX, FX 
Factor VII, factor IX, factor X 


 
 
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FVIIa, FIXa, FXa 
Activated factor VII/factor IX/factor X 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
GAPDH 
Glyceraldehyde 3-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GEJ 
Gastro-esophageal junction 
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 Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G1 
IHC 
Immunohistochemistry  
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Independent Review Board 
IRR 
Infusion-related reaction 
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 
PAR-2 
Protease activated receptor 2 
PCR 
Polymerase chain reaction  
PD 
Progressive disease 


 
 
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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 
US/USA 
United States/United States of America 
Vc 
Valine citrulline  
VEGF 
Vascular endothelial growth factor  
WMA 
World Medical Association 


 
 
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4. 
ETHICS 
4.1 Ethics Committee 
This study will be conducted in compliance with independent ethics committee 
(IEC)/institutional review board (IRB) and International Conference on 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 study will adhere to all local regulatory requirements, and requirements 
for data protection. 
Before initiating a trial/study, the investigator/institution must have written and dated 
approval/favorable opinion from the IEC/IRB for the study 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 Study 
This study will be conducted in accordance with the Note for Guidance on GCP (ICH 
Harmonized Tripartite Guideline E6 (R2); FDA CFR (21 CFR § 50, 56, 312)), Declaration of 
Helsinki (Fortaleza 2013) (Appendix 3) and all applicable regulatory requirements. 
It is possible that the exploratory endpoint analysis of protein biomarkers may not fulfill the 
above GCP compliance statement. Best efforts to make sure that the research laboratory 
follows the principles of GCP will be set in place. 
4.3 Patient Information and Consent 
The investigator will explain the benefits and risks of participation in the study to each 
patient and will obtain written informed consent. Written informed consent must be obtained 
prior to the patient entering the study and before initiation of any study-related procedure 
(including administration of study 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 study should important new information 
become available that may be relevant to the safety and procedures of the patient. In this 


 
 
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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 study. 






 
 
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6. 
INTRODUCTION 
6.1 Key Background and Rationale 
Tisotumab vedotin (HuMax®-TF-ADC) is an antibody drug conjugate (ADC) composed of a 
human monoclonal immunoglobulin G1 ([IgG1] subtype κ) targeting tissue factor (TF; 
HuMax-TF) conjugated via a protease cleavable valine citrulline (vc) linker to the drug 
monomethyl auristatin E (MMAE), a dolastatin 10 analog (Doronina et al., 2003; Hamblett et 
al., 2004; Sun et al., 2005). Dolastatins and auristatins belong to a class of chemotherapies 
that act as microtubule disrupting agents. 
Human TF (thromboplastin, CD142 or coagulation factor III) is a 43-47 kDa, single chain, 
transmembrane glycoprotein. TF is the main initiator of the extrinsic pathway of blood 
coagulation, which starts when TF binds to serine protease factor VII (FVII) or activated 
FVIIa. The TF:FVIIa complex initiates blood coagulation by proteolytic cleavage of factor X 
(FX) to FXa, and factor IX (FIX) to FIXa, eventually leading to thrombin generation and the 
formation of a clot. In addition, the TF:FVIIa complex can initiate an intracellular signaling 
cascade by proteolytic activation of protease activated receptor 2 (PAR-2), resulting in 
release of pro-angiogenic factors and pro-inflammatory mediators such as vascular 
endothelial growth factor (VEGF) and interleukin-8. 
Under pathological conditions, membranous TF can be aberrantly expressed. TF is present on 
neoplastic cells as well as tumor-associated endothelial cells in a variety of solid cancers. 
Indications where tumor cells are known to express TF include gynecological and 
genito-urethral tumors, squamous cell carcinoma of head and neck (SCCHN), lung cancers, 
tumors in the gastrointestinal (GI) tract, breast cancer, malignant melanoma and pancreatic 
cancer (Ohta et al., 2002; Akashi et al., 2003; Khorana et al., 2007; Uno et al., 2007; Patry et 
al., 2008; Yokota et al., 2009; Cocco et al., 2011). For most of these indications, high TF 
expression in tumor biopsies was confirmed using in house immunohistochemistry (IHC) 
studies. However, the high incidence of TF-positive tumors that was previously described in 
breast cancer and malignant melanoma could not be confirmed. To select the indications to 
be included in tisotumab vedotin (HuMax-TF-ADC) first-in-human (FIH) clinical study, 
significant expression of the target (TF) in tumor biopsy material as well as thorough 
information on efficacy of tubulin inhibition as part of standard of care (SoC) were used as 
selection criteria. The indications to be included in this FIH study are gynecological (ovarian, 
endometrial and cervical), genito-urethral (bladder and castration-resistant prostate [CRPC]), 
head and neck (SCCHN), esophagus and non-small cell lung cancer (NSCLC) cancers. In 
these indications, TF expression is variable and IHC data derived from the literature and 
Genmab studies have shown TF expression in up to 75%-100% of the tumors (Akashi et al., 
2003; Chen et al., 2010; Cocco et al., 2010; Cocco et al., 2011a; Cocco et al., 2011b; Patry et 
al., 2008; Sawada et al., 1999; Uno et al., 2007; Yao et al., 2009; Wojtukiewicz et al., 1999). 
Expression of TF on tumor cells has been associated with negative overall survival or disease 
free survival as described in several indications, including ovarian, bladder and pancreatic 
cancer (Nitori et al., 2005; Han et al., 2006; Patry et al., 2008). Experimental studies suggest 
that tumor cells may benefit from both TF procoagulant activity and TF-induced PAR-2 


 
 
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signaling, for example through enhanced metastatic potential, angiogenesis and cell survival 
(Ruf and Mueller, 1996; Kasthuri et al., 2009). Furthermore, monoclonal antibodies that 
inhibited either TF:FVIIa intracellular signaling or TF procoagulant capacity could reduce 
tumor growth in vivo (Versteeg et al., 2008).  
Constitutive TF expression is mostly restricted to sub endothelial cells (such as pericytes, 
smooth muscle cells and fibroblasts,) that only interact with blood borne FVIIa when 
vascular integrity is compromised (Drake et al., 1989). TF is expressed in the vessel walls of 
a wide range of organs, with moderate to high levels observed in the brain, heart, intestine, 
kidney, lung, placenta, uterus, and testes. The expression pattern suggests that TF provides 
additional hemostatic protection to these organs. In addition, TF expression has been 
described in epithelial cells in a number of organs including the skin, kidney and lung 
(Flössel al., 1994; Drake et al., 1989; Imokawa et al., 1997). Under pathological, 
inflammatory conditions TF is aberrantly expressed, including but not limited to bullous 
pemphigoid, urticaria (primarily on eosinophils, Marzano et al., 2009; Marzano et al., 2011; 
Cugno et al., 2009), inflammatory GI diseases including Crohn’s disease and ulcerative 
colitis (More et al., 1993) and lung diseases including acute respiratory distress syndrome 
(Bastarache et al., 2007). 
Broad expression of TF was confirmed in a tissue cross-reactivity study. Binding of 
HuMax-TF-ADC was observed on e.g. epithelial cells in organs, including but not limited to 
skin, breast, lungs, GI tract, kidney, liver and eye. Staining in glomeruli, islet cells in 
pancreas, peripheral nerves, cardiomyocytes, smooth myocytes (esophagus, stomach and 
prostate) and processes of glial cells in grey matter was also observed 
. 
In the clinic, systemic tubulin inhibitors are used in many indications within solid tumor 
oncology, approved by authorities or used as part of SoC. Indications include cancer of the 
ovaries, endometrium, cervix, bladder, prostate, esophagus, stomach, head and neck 
(SCCHN), breast, and NSCLC, all of which are described to express TF. 
HuMax-TF-ADC shows excellent anti-tumor activity in vitro and in vivo. Efficient tumor cell 
killing is thought to rely on HuMax-TF-ADC binding to TF on the cell surface of tumor cells 
followed by rapid internalization and lysosomal processing of MMAE (GMB1015-087 
available upon request). Subsequent intracellular release of MMAE results in tumor cell 
killing by disruption of the microtubule network. In addition, MMAE can exert so-called 
bystander toxicity by diffusion to neighboring tumor cells or tumor stromal cells. The 
cytotoxic effect mediated via MMAE release in target cells is believed to be the main 
mechanism of action of HuMax-TF-ADC. In vitro studies demonstrated that 
HuMax-TF-ADC 
and 
unconjugated 
HuMax-TF 
also 
induce 
antibody-dependent, 
cell-mediated cytotoxicity and inhibition of TF:FVIIa signaling. The contribution of these 
mechanisms to tumor cell killing remains unknown. 
Despite efficient TF binding, HuMax-TF-ADC and unconjugated HuMax-TF showed 
minimal interference with TF procoagulant activity in vitro and in vivo, as was previously 
described for other TF-specific antibodies (unpublished data; Kirchhofer et al., 2000; 
Versteeg et al., 2008). Thus, HuMax-TF-ADC provides efficient targeting of TF-positive 
tumor cells, without a major impact on coagulation.  


 
 
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In summary, HuMax-TF-ADC is an attractive molecule for anti-cancer therapy in solid 
tumors. 
Based on known TF expression and usage of tubulin inhibition as part of treatment 
paradigms, indications to be included in the FIH clinical study of HuMax-TF-ADC 
encompass ovarian, endometrial, cervical, prostate (CRPC), bladder, NSCLC, esophageal 
and SCCHN carcinomas. 
6.1.1 Rationale for Indications 
6.1.1.1 Selected Indications 
To select the indications to be included in this tisotumab vedotin (HuMax-TF-ADC) FIH 
clinical study, significant expression of the target (TF) as well as thorough information on 
efficacy of tubulin inhibition as part of SoC were used as selection criteria.  
Tissue factor is a transmembrane glycoprotein, aberrantly expressed under pathological 
conditions. Tissue factor has been described on neoplastic cells as well as tumor-associated 
endothelial cells in a variety of solid cancers. Indications where tumor cells are known to 
express TF include, but are not limited to, gynecological and genito-urethral tumors, 
SCCHN, lung cancers and tumors in the GI tract (Ohta et al., 2002; Akashi et al., 2003; 
Khorana et al., 2007; Uno et al., 2007; Patry et al., 2008; Yokota et al., 2009; Cocco et al., 
2011). Knowledge about expression of TF mostly derives from IHC staining. In this section, 
available data on TF expression derived from literature, as well as results on a study of TF 
expression and incidence in multiple tumor tissue micro arrays performed by Genmab (Study 
report: SR1015-091) are summarized below. Information on indications is derived from the 
Cancer Facts & Figures 2012, SEER database, combined with the advice of key opinion 
leaders. Treatment algorithms involving tubulin inhibition are obtained from the National 
Comprehensive Cancer Network (NCCN) guidelines. 
Indications to be included in the FIH clinical study of tisotumab vedotin (HuMax-TF-ADC) 
encompass ovarian, endometrial, cervical, prostate (CRPC), bladder, NSCLC, esophageal 
and SCCHN carcinomas. 
The DMC has recommended the exclusion of patients with SCCHN carcinomas in the Dose 
Escalation part of the study due to an event of pharyngeal tumor hemorrhage with fatal 
outcome in the 0.6 mg/kg cohort. The DMC underlined that the event was most likely related 
to the disease itself and the natural course of disease for some of these patients; however, a 
causal relationship cannot be completely excluded, and further experience from other tumors 
is to be warranted before re-exposure to this cancer type. SCCHN carcinomas have therefore 
been removed from the Dose Escalation phase with the implementation of Amendment 4. 
6.1.1.2 Gynecological cancers 
In gynecological tumors, TF expression has been described predominantly in ovarian, 
endometrial as well as cervical cancers.   
6.1.1.2.1 Ovarian Cancer 
In US, 22,000 new cases and 15,500 deaths are estimated each year. Approximately 70% of 
patients will manifest with advanced disease, and five year survival is reported to be 30-40% 


 
 
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for stage III, decreasing to 20% for stage IV. As frontline chemotherapy for treatment of 
advanced disease, tubulin inhibition is used in combination with cisplatin. Tubulin inhibition 
is also used as second line in the platin resistant population as well as in later lines of 
therapy. In ovarian cancer, Uno et al reported expression of TF in 31 of 36 (86%) 
consecutive patients. In this paper, correlation with high TF expression and venous 
thromboembolism was indicated (Uno et al., 2007). Cocco et al reported TF expression in 24 
of 25 (96%) ovarian cancer samples tested and no positive staining in normal ovarian tissue; 
these data were further supported by increased expression in tumor cell lines analyzed by 
real-time quantitative polymerase chain reaction (qRT-PCR, Cocco et al., 2011b). In report 
SR1015-091, 40% of the tested samples were found to be positive for TF expression.  
6.1.1.2.2 Endometrial Cancer 
In US, 47,000 new cases and 8,000 deaths are estimated each year. Approximately 33% of 
patients manifest with advanced disease, and five year survival is reported to be 47-58% for 
stage III, decreasing to 15-17% for stage IV. As frontline chemotherapy treatment, tubulin 
inhibition is used in combination with platin and also as single agent therapy in a relapsed 
setting. In endometrium cancer, Cocco et al reported cytoplasmatic and/or membranous 
staining in all tumor samples tested by IHC (n=16); these findings were supported by 
increased mRNA expression in all six endometrial tumor derived cell lines tested (Cocco et 
al., 2010). In report SR-1015-003, positive staining for TF expression was found in 59% of 
the tested samples.  
6.1.1.2.3 Cervical Cancer 
In US, 12,000 new cases and 4,200 deaths are estimated each year. Approximately 50% of 
patients manifest with advanced disease; however, this figure might decrease with 
availability of human papilloma virus (HPV) screening programs. Anticipated five year 
survival is reported to be approximately 40% for stage III, decreasing to 15% for stage IV. 
As frontline chemotherapy treatment, tubulin inhibition is used in combination with platin 
and also as single agent therapy in a relapsed setting. For cervical cancers, Cocco et al 
reported positive staining in eight of eight tumor samples analyzed as well as increased 
expression detected by qRT-PCR in 11 of 11 cervical carcinoma cell lines tested (Cocco et 
al., 2011a). In report SR1015-091, 86% of the tested tumor samples were found positive for 
TF expression.  
6.1.1.3 Genito-urethral Cancers 
In genito-urethral tumors, TF expression has been described predominantly in cancers of the 
prostate and bladder.  
6.1.1.3.1 Prostate Cancer (Metastatic, CRPC) 
In US, 241,000 new cases and 28,200 deaths are estimated each year. Approximately 10-20% 
of patients manifest with advanced disease. For metastatic disease, an estimated survival of 
24-36 months is reported, decreasing to 12-18 months in metastatic CRPC. In metastatic, 
CRPC, frontline chemotherapy includes tubulin inhibition – where docetaxel is SoC in 
combination with steroid. In prostate cancer, Akasi et al reported positive TF expression in 
75% of tumors from 73 patients with metastatic prostate cancers (Akashi et al., 2003). These 


 
 
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data were consistent with those published by Abdulkadir et al, where most of the prostate 
carcinoma specimens examined (73%; 49 of 67 samples) were found to express high levels 
of TF (Abdulkadir et al., 2000). In a study analyzing archived tissue microarrays (TMAs) 
from both benign prostate, intraepithelial neoplasia and carcinoma, positive staining was seen 
predominantly in carcinoma (47% of 43 tested samples), and it was significantly lower both 
in intraepithelial neoplasia and in benign tissues, where only 9% of samples tested were 
positive for TF staining (Yao et al., 2009). In report SR1015-091, 60% of the tested tumor 
samples expressed TF.  
6.1.1.3.2 Bladder Cancer 
In US, 73,500 new cases and 14,900 deaths are estimated each year. Approximately 30% of 
patients manifest with advanced disease. Anticipated five year survival is reported to be 
approximately 40-50% for stage III, decreasing to 15% for stage IV. As frontline 
chemotherapy treatment, tubulin inhibition is used in combination with platin and also as 
single agent therapy in a relapsed setting. In muscle invasive bladder cancer, Patry et al 
reported positive staining for TF in 78% of TMAs obtained from 218 patients (Patry et al., 
2008). In report SR1015-091, positive staining was observed in 45% of tested samples.  
6.1.1.4 Lung Cancers 
In lung tumors, most data on TF expression derives from NSCLC. In US, 226,000 new cases 
and 160,300 deaths are estimated each year. NSCLC accounts for approximately 2/3 of cases. 
Approximately 50-78% of patients manifest with advanced disease hereof 40% with 
metastatic disease. Anticipated five year survival is reported to 10-25% for stage IIIb, 
decreasing to 4% for stage IV. As frontline chemotherapy treatment of metastatic disease, 
tubulin inhibition is used in combination with cisplatin and as single agent after 
chemotherapy failure. Sawada et al reported positive TF expression in 84% of 55 tumor 
samples obtained from patients with NSCLC; of interest, more intense staining was described 
in patients with metastatic disease (Sawada et al., 1999). Comparable data were generated in 
report SR1015-091, where TF positivity was found in 62% (adenocarcinoma) and 86% 
(squamous cell carcinomas) of tested tumor samples, respectively.  
6.1.1.5 Gastrointestinal Cancers 
In GI tumors, significant TF expression is predominantly described in esophageal as well as 
in colorectal tumors. However, as colorectal cancer is described to be resistant to tubulin 
inhibition, only esophageal cancer will be described. 
6.1.1.5.1 Esophageal Cancer 
In US, 17,500 new cases and 15,000 deaths are estimated each year. Approximately 65% of 
patients manifest with advanced disease. Anticipated five year survival is reported to be 
20-25% for stage III, decreasing to 4% for stage IV. Frontline chemotherapy includes tubulin 
inhibition in combination with platin plus 5-fluorouracil or irinotecan (mostly used in a 
relapsed setting). In a relapsed population, single agent tubulin inhibition can be used. In 
esophageal cancers, Chen et al described positive TF expression in 91% of tumors obtained 
from 103 patients with esophageal squamous cell carcinomas, while normal esophageal 


 
 
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tissue was found to be immunoreactive negative (Chen et al., 2010). No data on TF 
expression in esophageal cancer are available in the SR1015-091 report. 
6.1.1.6 Head and Neck Cancer 
Head and neck cancer comprise tumors of the nasal cavity, tongue, oral cavity, larynx and 
pharynx. TF expression has predominantly been described for SCCHN. 
6.1.1.6.1 SCCHN 
In US, 39,800 new cases and 9,500 deaths are estimated each year. Approximately 60% of 
patients manifest with advanced disease. Anticipated five year survival reported to be 
10-40% for stage III, decreasing to 0-30% for stage IV. Patients with tumors positive for 
HPV seem to have a more favorable prognosis than patients with HPV negative tumors. 
Frontline chemotherapy contains platin. Use of tubulin inhibition has involved combination 
with cisplatin and 5-fluorouracil. In SCCHN, Wojtukiewicz et al reported expression of TF 
on SCCHN tumor cells samples from squamous cell carcinomas of the larynx obtained after 
surgical resection (Wojtukiewicz et al., 1999). In report SR1015-091, positive staining for TF 
was observed in 84% of the tested samples. 
Thus, for all mentioned indications, significant information on expression of TF is available. 
However, it should be noted that variable TF expression has been described. Differences in 
methodology as well as different monoclonal antibody used for detection are likely to 
account for these observations. The extent of TF expression on cancer cells necessary for 
anti-tumor efficacy of tisotumab vedotin (HuMax-TF-ADC) in vivo is also unknown, and as 
such no cut-off limit can be enforced at present. It should be noted that TF expression on 
tumor vessels may also contribute to anti-tumor efficacy. Expression of TF on tumor cells 
has been associated with negative overall survival or disease free survival as described in 
several indications, including ovarian and, bladder cancer (Han et al., 2006; Patry et al., 
2008). In addition, for the selected indications, systemic tubulin inhibition is part of SoC for 
both frontline treatment as well as treatment in relapsed patient populations with advanced 
and/or metastatic disease. 
6.1.2 Indications for the Cohort Expansion Part 
The Cohort Expansion part of the study is designed to gather additional safety, tolerability, 
PK, and anti-tumor activity data by exposing patients at the maximum tolerated dose (MTD) 
found in the Dose Escalation part or at the dose level recommended by the sponsor, in 
collaboration with the DMC, for further development. Approximately 169 patients will be 
enrolled in the Cohort Expansion part, which is considered sufficient to provide the basis for 
the planning and design of further studies. The Cohort Expansion part has a parallel group 
design, with a minimum of 14 and maximum of 30 patients in the cervix and in the 
endometrial indications, and 14 patients in the remaining indications (see Section 6.1.1.1). If 
after 14 patients treated for four cycles in the cervix or endometrial indications no responders 
have been observed, a DMC will evaluate whether it is reasonable to expand the particular 
indication up to 30 patients. If one of these two indications does not appear promising while 
there is another indication that shows promising efficacy, it may be decided to expand the 
other indication instead. After implementation of Protocol Amendment 13 (Protocol version 


 
 
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14.0), up to 25 additional patients will be recruited to the cervix indication for a maximum of 
approximately 55 patients. 
Recruitment will be initiated in five arms encompassing ovary, cervix, endometrium, bladder 
and prostate (CRPC) cancer. Based on a safety review of data from the ten first patients 
recruited and followed for at least one cycle (regardless of indication), the DMC and internal 
sponsor’s Safety committee will evaluate the safety profile with particular emphasis on 
coagulation status and possible cases of hemorrhages. If safety profile is deemed safe, the 
DMC and sponsor’s Safety committee will approve the recruitment of the three remaining 
arms, esophageal cancer, NSCLC and SCCHN. 
6.2 Compound Review 
Tisotumab vedotin (HuMax-TF-ADC) is an ADC composed of a human monoclonal IgG1κ 
targeting TF (HuMax-TF) conjugated via a protease cleavable linker to MMAE, a dolastatin 
10 analog. Dolastatins and auristatins belong to a class of chemotherapies that act as 
microtubule disrupting agents. Each monoclonal antibody molecule carries an average of 
four drug moieties. 
The IMP is a powder for solution for infusion. 
6.2.1 Non-Clinical Studies 
Due to restricted species cross-reactivity, the only relevant species for non-clinical safety 
assessment of HuMax-TF and tisotumab vedotin (HuMax-TF-ADC) was the monkey.  
The pre-clinical toxicity of unconjugated HuMax-TF in cynomolgus monkeys at doses up to 
and including 100 mg/kg showed a decrease in erythrocytes, hemoglobin, hematocrit and an 
increase in reticulocyte counts, assessed as probably related to blood sampling. An increase 
in neutrophil and leucocyte counts was observed, assessed as probably due to stress. No 
adverse effects on coagulation and thromboelastography (TEG) were observed. Urine tests 
were unaffected. There was a decrease in alkaline phosphatase and gamma-glutamyl 
transferase. B- and T- lymphocyte, monocyte and platelet counts were increased, whereas 
natural-killer cell counts decreased initially after dosing, but quickly recovered. No effect 
was seen on inflammatory cytokines and complement factors and Coombs test was negative. 
Functional bleeding time (Surgicutt™) on Day 22 was marginally increased following 
administration of 100 mg/kg HuMax-TF. 
It was concluded that no major toxicity was observed for unconjugated HuMax-TF. A 
marginally prolonged bleeding time was found; however, no adverse effects on general 
coagulation parameters including TEG were seen. 
In a pilot toxicology study in cynomolgus moneys, employing various anti-TF ADCs 
including HuMax-TF-ADC, dose levels up to and including 5 mg/kg were administered 
weekly for four cycles. Decreases in erythrocytes, hemoglobin and hematocrit, and increases 
in reticulocyte counts and a marked decrease in neutrophil counts were assessed as probably 
due to an impact of MMAE on the bone marrow. This was confirmed histopathologically by 
a decrease in bone marrow cellularity. High serum iron was observed. Liver and kidney 
examinations were normal. Urine tests were normal. 


 
 
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In a dose range finding study HuMax-TF-ADC was dosed at 1, 3 and 6 mg/kg once every 
three weeks (q3wk). Severe neutropenia in high dose animals (6 mg/kg) was observed and, in 
some animals, associated with clinical signs indicative of sepsis. One animal was sacrificed 
due to sepsis-related adverse findings, most likely arising due to the low neutrophil count. 
The highest dose was decreased to 5 mg/kg and prophylactic antibiotics implemented. 
Reddening and flaky skin was observed at 3 and 5-6 mg/kg and was most prominent after the 
first dose administration.  
In the 3 mg/kg group, neutropenia was moderate and not associated with the clinical signs 
observed at 6 mg/kg. In the 1 mg/kg group, no neutropenia was observed. 
It was concluded that HuMax-TF-ADC is well tolerated at doses up to and including 
3 mg/kg.  
In the pivotal 13-week repeat dose toxicology study, employing dose levels of 1, 3 and 
5 mg/kg using a once per three-week dosing schedule, similar findings as described above 
were evident. Severe neutropenia was observed at 5 mg/kg, a moderate effect at 3 mg/kg and 
no effect at 1 mg/kg. Decreases in red cell parameters, platelets and lymphocytes were also 
evident occasionally and the effect was most pronounced at the high dose level. No major or 
consistent alterations of kidney or liver related clinical chemistry parameters were evident.  
The coagulation parameters prothrombin time (PT) and activated partial thromboplastin time 
(aPTT) were unaffected by treatment with HuMax-TF-ADC. Occasionally, high fibrinogen 
concentrations were observed in some high dose animals, when compared with control and 
pre-study values.  
High haptoglobin concentrations were observed throughout the treatment period in males and 
females at 5 mg/kg HuMax-TF-ADC, occasionally attaining statistical significance. 
Haptoglobin concentrations during the recovery period were considered similar to control 
and pre-study values. 
Urine analysis was normal and no blood was evident in either urine or stool. 
Assessment of ECG and respiratory rate did not indicate any effect of treatment. 
Skin reactions were seen at both 3 and 5 mg/kg with good recovery in most animals. Due to 
severe skin reactions, four animals (one male and three females) in the high dose group were 
sacrificed based on welfare grounds. The effect on the skin may be target-related and may 
have been aggravated further due to a low neutrophil count and the presence of bacteria.  
These skin reactions were evaluated by a dermato-pathologist who described the findings as 
follows: “Cutaneous toxicity occurred at about 3-9 days after first dose in the mid to high 
range doses (3, 4, or 5 mg/kg). These animals displayed initially flexural erythema, scaling 
and erosions leading to ulceration in high dose animals (4 and 5 mg/kg). Follow-up studies 
with biopsies at the time of initial erythema (sample obtained at Day 6-8 post-dosing) 
revealed basal layer vacuolization, keratinocyte dysmaturation, dyskeratosis and a superficial 
lymphocytic infiltrate. The findings were seen diffusely, but were most severe in clinically 
involved skin of the femoral and neck. Thrombosis of blood vessels and vasculitis were not 
seen. The histologic picture is consistent with chemotherapeutic effect as described with 


 
 
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multiple different chemotherapeutic agents (Cady et al., 2006; Degen et al., 2010, 
Chalermchai et al., 2010; Benghiat and Al-Niaimi, 2011).” 
Daily assessment of vaginal smears for the monitoring of ovarian cycle did not indicate any 
effect of treatment with HuMax-TF-ADC on the menstrual cycle. 
Following administration of HuMax-TF-ADC, once q3wk for thirteen weeks (five doses in 
total), histopathological changes characterized by seminiferous tubular atrophy were 
observed in the testis and were associated with administration of 1, 3, and 5 mg/kg of 
HuMax-TF-ADC. In the epididymis findings included absence of sperm/decreased sperm 
content and epithelial vacuolation 
. At 3 and 5 mg/kg mean testes and 
epididymis weights were also lower compared to controls but statistical significance was not 
attained. Associated sperm count also tended to be reduced and sperm motility was absent or 
reduced in some animals at 1, 3 and 5 mg/kg. Full recovery of the testicular/epididymal 
findings was evident at 1 mg/kg and partial recovery was observed at 3 and 5 mg/kg 
HuMax-TF-ADC.  
Ophthalmoscopy data, obtained during week 12 of treatment, indicated a very mild effect on 
the fundus, which appeared glassy, in all male monkeys at 5 mg/kg HuMax-TF-ADC and at 
25 mg/kg HuMax-TF. No effects were observed after the fifth dose administration in either 
group. No similar effect was seen in female monkeys treated with either test item. This 
finding was not deemed treatment-related. 
During efficacy studies in mice, high dose treatment (50 mg/kg) with unconjugated 
HuMax-TF induced intratumoral hemorrhages in one out of five xenograft models. 
Hemorrhages were not observed after treatment with a lower dose of HuMax-TF (15 mg/kg). 
Treatment with HuMax-TF-ADC was associated with intratumoral hemorrhages in one out 
of fifteen xenograft models. This particular model, NCI-H441 xenograft model, was prone to 
intratumoral hemorrhages even without treatment but the frequency was enhanced after 
treatment with 4.5 mg/kg HuMax-TF-ADC. A similar dose of HuMax-TF did not induce 
intratumoral hemorrhages. It was concluded that the occurrence of intra-tumoral 
hemorrhages upon treatment with HuMax-TF or HuMax-TF-ADC is rare, and largely related 
to the inherent characteristics of the tumor model. At dose levels relevant for ADCs, 
antibody-mediated interference with TF function was not associated with intratumoral 
hemorrhages, although the toxin part of the ADC may induce intratumoral hemorrhages in 
xenograft models that are prone to bleeding.  
The safety monitoring for the FIH study of HuMax-TF-ADC will be based on the pre-clinical 
findings, the class effects of the anti-microtubule agent MMAE and experience with other 
anti-TF-antibodies. 
Further information can be found in the Investigator’s Brochure. 
6.2.2 Previous Clinical Experience with MMAE-based ADCs 
Tisotumab vedotin (HuMax-TF-ADC) is an ADC consisting of three components: 
• The human monoclonal antibody (IgG1κ) targeting TF 
• A protease-cleavable valine-citrulline linker 


 
 
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• The microtubule disrupting agent MMAE 
Literature data from cleavable MMAE-based ADCs include, but are not limited to, 
CD30-ADC (Younes et al., 2010; Adcetris® Prescribing Information, 2014), CR011-ADC 
(Hwu et al., 2008), ASG-5ME-ADC (Morris et al., 2012; Coveler et al., 2012), PSMA-ADC 
(Mega et al., 2012), CD22-ADC (Advani et al., 2012) and CD79b-ADC (Palanca-Wessels et 
al., 2012). Major toxicities commonly seen with MMAE-based ADCs include peripheral 
blood neutropenia and late peripheral neuropathies. In general, no major toxicities have been 
observed below 1 mg/kg when MMAE-based ADCs were administered at a three-weekly 
regimen. 
Data from CD30- ADC dose-escalation trial in Hodgkin’s Lymphoma showed no appearance 
of dose limiting toxicities (DLTs) up to and including 1.5 mg/kg. Furthermore, no grade 3 
skin reactions were reported (Younes et al., 2010). In the package insert, skin rash is reported 
in 27%-31% of patients, none of which were grade 3 or above. An MTD of 1.8 mg/kg was 
found and the main safety findings of CD30-ADC included peripheral neuropathy, 
myelosuppression and infusion-related reactions (IRRs). Myelosuppression was also 
observed during the pre-clinical toxicity studies with dose-related hematological toxicity 
especially neutropenia and hypocellularity of the bone marrow. 
The most common adverse reactions (≥ 20%) reported during treatment with CD30-ADC 
(brentuximab vedotin [Adcetris® Prescribing Information, 2014]) regardless of causality, 
were neutropenia, thrombocytopenia, peripheral sensory neuropathy, fatigue, pyrexia, upper 
respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, rash and cough. 
Two cases of anaphylaxis were reported during infusion of CD30-ADC in phase I trials. 
There were no grade 3 or 4 IRRs reported in the phase II trials. However, grade 1 or 2 IRRs 
were reported for 19 patients (12%). Serious adverse events (SAEs) regardless of causality 
were reported in 31% of patients receiving Adcetris. The most common SAEs in patients 
with Hodgkin’s lymphoma were neuropathy (4%), abdominal pain (3%), pulmonary 
embolism (2%), pneumothorax (2%), pyelonephritis (2%) and pyrexia (2%). 
In the CR011-ADC trial targeting the protein known as GPNMB, at doses ≤ 0.96 mg/kg, only 
grade 1 and 2 adverse events (AEs) were recorded, including fatigue, diarrhea, nausea and 
grade 1 neuropathy and skin rash. At higher doses, grade 3 AEs including, peripheral 
neuropathy and skin disorders and grade 4 neutropenia were observed. Using a three-weekly 
approach, grade 3 skin rash was described in the 1.88 mg/kg dose cohort. Dose limiting 
toxicities were described at 2.63 mg/kg including exfoliative rash in one patient and 
erythematous, blistering rash in another patient. The latter patient was dose reduced and 
continued in the trial. At MTD (1.88 mg/kg q3wk), skin rashes are described in 70% of 
patients with 26% being grade ≥ 3 (Hamid et al., 2010). When more dose intense 
dose-schedules were introduced (dosing weekly, two of three weeks) a grade 5 toxic 
epidermal necrolysis (TEN) was observed. Using a weekly dosing regimen, a grade 5 acute 
renal failure and grade 4 skin rash were observed. 
In the ASG-5ME-ADC trials, DLTs were reported as grade 3 troponin elevation and 
maculo-papular rash when dosed as 3 mg/kg q3wk. Other grade 3 events included fatigue, 
peripheral neuropathy, anorexia, dyspnea and nausea. When a more dose intense regimen 
was used, grade 3-4 vomiting and abdominal pain were reported. 


 
 
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In the PSMA-ADC trial, DLTs were described as primarily neutropenia and MTD was 
determined at 2.5 mg/kg.  
During clinical phase II development, two fatal cases of sepsis were observed and dosing was 
reduced to 2.3 mg/kg going forward. In the CD22-ADC and CD79b-ADC trials, grade 3 AEs 
occurring in ≥ 10% of patients included neutropenia (CD22) and neutropenia, and leukopenia 
(CD79b). Both studies reported a recommended phase II dose (RP2D) at 2.4 mg/kg. Grade 3 
or 4 AEs observed in more than one patient at RP2D included neutropenia (CD22), 
neutropenia, anemia, leukopenia and fatigue (CD79b).  
The mechanism of action of the antibody-based TF antagonist ALT-836 is binding to TF or 
the TF-FVIIa complex thereby preventing the association and activation of FX and inhibiting 
thrombin generation. HuMax-TF inhibits FVIIa binding to human TF and inhibits TF:FVIIa 
signaling; however HuMax-TF did not inhibit FXa generation. 
The main safety issues during treatment with the antibody-based TF antagonist ALT-836 
were hematuria and worsening of hematuria of grade 1 and 2. On average the hematuria 
started 6.7 hours after initiation of treatment and resolved within 29.1 hours without need of 
medical intervention. No major bleeding or other spontaneous minor bleeding was observed. 
There were no effects on PT, platelet count, aPTT or plasma levels of D-dimer, prothrombin, 
fragment 1+2 or fibrinogen at any ALT-836 dose level. 
Overall, data on other monoclonal antibodies targeting TF include minor bleeding 
(hematuria; [ALT-836]). Currently, two other anti-TF monoclonal antibodies are in clinical 
development within solid tumors (ALT-836 and MORAb-066); no data are available from 
those studies. 
The class effects of the anti-microtubule agents primarily include peripheral neuropathy and 
myelosuppression. 
6.2.3 Clinical Experience 
Tisotumab vedotin is being investigated in two clinical trials; GEN701 and GEN702. Each 
trial consists of two parts; a Dose Escalation part and a Cohort Expansion part. The Dose 
Escalation part for GEN701 and GEN702 has been finalized. The Cohort Expansion part is 
ongoing for both trials. As of 16 Aug 2017, 207 patients have been treated with tisotumab 
vedotin. 
GEN701 
As of 16 Aug 2017, 147 patients have been dosed with tisotumab vedotin (HuMax-TF-ADC) 
2.0 mg/kg once q3w in the GEN701 Cohort Expansion part. 
Summary of Clinical Safety Data from GEN701 Part II (Cohort Expansion part) 
Across all indications in the Cohort Expansion part, the most commonly reported AEs 
observed in at least 29 patients (> 20%) were epistaxis (64%), fatigue (53%), nausea (47%), 
alopecia (42%), conjunctivitis (42%), constipation (33%), decreased appetite (32%), diarrhea 
(27%), vomiting (26%) and peripheral neuropathy (26%).  


 
 
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Grade ≥ 3 AEs were reported in 55% of patients. The most frequently reported grade ≥ 3 AEs 
were fatigue (8%), anemia (6%), abdominal pain (4%), vomiting (4%), hypokalemia (4%), 
hyponatremia (3%) and conjunctivitis (3%). All other grade ≥ 3 AEs were reported in one or 
two patients only.  
Serious adverse events were reported in 45% of patients. Vomiting was the most frequently 
reported SAE (4%), followed by abdominal pain (3%), hypokalemia, hyponatremia, general 
physical health deterioration and anemia (2% each). All other SAEs were reported in one 
patient (1%) only. 
Adverse events leading to discontinuation were reported in 44 patients (30%); across all 
indications the most frequently AEs leading to discontinuation were peripheral neuropathy 
(5%), conjunctivitis (4%), peripheral sensory neuropathy (3%) and polyneuropathy (2%). All 
other AEs leading to discontinuation were reported in one patient (1%) each.  
One patient experienced a grade 5 AE possibly related to the IMP (pneumonia preceded by 
neutropenic sepsis observed in a patient with relapsed prostate cancer). 
Two patients experienced an SAE (grade 2 and 3, respectively) of ischemic cerebral stroke, 
and one patient experienced an incidental finding of a pulmonary embolism possibly related 
to the IMP. Cancer patients have a well-known increased risk of both arterial and venous 
thromboembolic events (none of these patients had received anti-coagulant therapy prior to 
the event), and the observed rates are below the expected rates of thromboembolic events in 
this patient population (Lyman, 2011; Navi et al., 2017).  
The above data indicate a manageable toxicity profile, overall in line with what is expected 
for an MMAE-based ADC, with the exception of conjunctivitis. An ocular mitigation plan 
was implemented by Amendment 12 (dated 22 Dec 2016) and has reduced the frequency and 
severity of ocular adverse events including conjunctivitis in GEN701. 
For further details of AEs observed in GEN701 please refer to the Investigator’s Brochure. 
Summary of Efficacy and Concentration Data from GEN701 Part I and II 
Preliminary efficacy results consist of four patients achieving response at some point, of 
which only one was subsequently confirmed. Of the three unconfirmed responses, two were 
observed after the patients had already been withdrawn due to AEs, and one had disease 
progression about four weeks after the response was first observed. 
From the Dose Escalation part of GEN701, the maximum observed maximum concentration 
(Cmax) for TF-ADC was 62700 ng/mL while the maximum area-under-the-concentration-time 
curve (AUC0-t) was 2706325.5 hr*ng/mL. For MMAE, the maximum Cmax was 12100 pg/mL 
while the maximum AUC0-t was 2776657.4 hr*pg/mL. 
GEN702 
In the Cohort Expansion part of GEN702 a more frequent dosing regimen of tisotumab 
vedotin has been tested. As of 16 Aug 2017, 24 patients have been enrolled in the Cohort 
Expansion part. Patients were initially treated with tisotumab vedotin (HuMax TF ADC) 1.2 
mg/kg administered three times every four weeks (3q4w). However, the more frequent 


 
 
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dosing regimen was later discontinued due to severe ocular toxicity despite adherence to the 
ocular mitigation plan (implemented by Amendment 12 dated 22 Dec 2016), and patients 
enrolled have instead been offered tisotumab vedotin (HuMax TF ADC) 2.0 mg/kg once 
q3w, which in GEN701 has been found to be potentially efficacious and safe. The ocular 
mitigation plan has further been updated (implemented by urgent safety measure dated 23 
Jun 2017) in order to specify how to mitigate ocular AEs according to grading and to ensure 
treatment according to ophthalmologist’s guidelines.  
Summary of Clinical Safety Data from GEN702 Part II (Cohort Expansion Part) 
For further details of AEs observed in GEN702 please refer to the Investigator’s Brochure. 
Summary of Efficacy and Concentration Data from GEN702 Part I and II 
Data are too preliminary to be presented. 
6.2.4 Summary of Known and Potential Risks to Human Subjects 
The below section is based on data available as of 16 Aug 2017: 
Tissue cross-reactivity: 
• In both human and cynomolgus monkey tissue, staining was generally observed both on 
the membrane and in the cytosol. The staining was generally consistent with reported 
sites of TF expression, indicating expression in various epithelia; mesothelium, 
endothelium, stromal cells, glial and neuronal cells, peripheral nerves and ganglia, retina, 
adipose tissue, mononuclear cells (including alveolar macrophages), cardiomyocytes, 
smooth muscle, glomerular tuft cells, and islet cells. No literature was available 
describing the observed expression of TF in skeletal muscle, ovarian luteal and thecal 
cells, testicular spermatogenic and Leydig cells. The staining of these tissue elements 
may represent an unreported site of TF expression.  
• The staining pattern was generally similar between the human and cynomolgus monkey 
tissue panels examined, with a few exceptions. HuMax-TF and tisotumab vedotin 
(HuMax-TF-ADC) stained mesothelium in several tissues, endothelium in the spleen, 
and thecal cells in the ovary in the cynomolgus monkey, whereas staining in these cells 
and tissues was not observed in human tissues. HuMax-TF and tisotumab vedotin 
(HuMax-TF-ADC) likewise stained elements in human tissues that were not evident in 
cynomolgus monkey tissues, and included arachnoid cap cells in cerebellum and spinal 
cord, ganglion cells in adrenal, striated skeletal myocytes in the eye, intrinsic smooth 
myocytes in esophagus, stomach, and prostate, islet cells in pancreas, luteal cells in 
ovary, and spermatogenic cells in testis. These differences are likely to be due to other 
variations e.g., section, donor, donor age than species differences; however, toxicity to 
these organs cannot be excluded. 
MMAE metabolism: 
• MMAE is mainly metabolized by cytochrome CYP3A4 and is capable of inhibiting 
human CYP3A4/5 at clinically relevant concentrations. Additionally, MMAE is a 
substrate for the cellular trans-membrane transporter P-glycoprotein (P-gp). 


 
 
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Consequently, as a precaution, patients should not be co-medicated with drugs known to 
be strong inhibitors of CYP3A4 and/or P-gp. 
Specific adverse events: 
• Infusion-related reactions have been observed with other MMAE-ADCs. One IRR, 
including skin rash and swelling of eyes and lips, was observed during non-clinical 
studies in a female monkey following a second dose of tisotumab vedotin 
(HuMax-TF-ADC) 3 mg/kg. No IRRs were observed in this animal following the third 
or fourth dose administration of IMP. Infusion-related reactions have been observed in 
patients treated with tisotumab vedotin (HuMax-TF-ADC), but the majority of reactions 
have been mild to moderate. Please refer to the Investigator’s Brochure for more 
information. 
• Due to mode of action of tisotumab vedotin (HuMax-TF-ADC) its potential impact on 
TF-dependent coagulation was investigated in vitro in a series of coagulation assays 
including an FXa generation assay, the standard PT assay, a clotting assay, TEG and a 
thrombin generation assay. Overall, only relatively minor impact of HuMax-TF on 
TF-mediated coagulation was observed. No bleeding events were observed in 
cynomolgus monkeys and PT and aPTT coagulation parameters were unaffected by 
treatment with tisotumab vedotin (HuMax-TF-ADC) in all repeat-dose toxicology 
studies. In line with pre-clinical findings, no major impact on aPTT or PT has until now 
been found in humans treated with tisotumab vedotin (HuMax-TF-ADC) and despite 
high frequency of mild grade 1 epistaxis (possibly caused by inflammation), no 
clinically relevant increased bleeding risk have been observed. Please refer to 
Investigator’s Brochure for more detailed information. 
• Bone marrow suppression is a common adverse reaction for MMAE-ADCs and was 
observed in cynomolgus monkeys in relation to treatment with tisotumab vedotin 
(HuMax-TF-ADC). The observed bone marrow suppression was reversible and mostly 
reduced total peripheral white cells, notably the neutrophils. In line with these findings, 
adverse reactions of anemia and neutropenia are frequently reported in patients treated 
with tisotumab vedotin (HuMax-TF-ADC). Please refer to the Investigator’s Brochure 
for more detailed information and an overview of expected adverse events (RSI table).  
• Severe skin toxicity was observed in cynomolgus monkeys following treatment with 
tisotumab vedotin (HuMax-TF-ADC). The toxicity was dose-related and reversible and 
characterized by skin reddening and dry flaky skin. In a few animals the skin changes 
deteriorated, possibly in connection with accidental skin wounds that became 
secondarily infected, and three animals had to be terminated for animal welfare reasons. 
Mild events of rash, maculopapular rash and other skin reactions like pruritus have 
frequently been reported in patients treated with tisotumab vedotin (HuMax-TF-ADC), 
but only one serious event of rash (grade 4) has been reported across all trials. Please 
refer to the Investigator’s Brochure for more information. 
• Peripheral neuropathy is a well-known AE of treatment with chemotherapeutic drugs 
including other MMAE-based ADCs. Peripheral neuropathy (including the preferred 
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neuropathy and polyneuropathy) has been observed in patients treated with tisotumab 
vedotin (HuMax-TF-ADC), however only few patients experienced a grade ≥ 3 event. 
This is in line with what is expected for an MMAE-ADC and also reflecting that most 
subjects in GEN701 were heavily pre-treated prior to entering this trial. Please refer to 
the Investigator’s Brochure for more information. 
• Severe events of hepatotoxicity have been observed in relation to treatment with other 
MMAE-based ADCs but pre-clinical studies in cynomolgus monkeys found no 
hepatotoxicity of tisotumab vedotin (HuMax-TF-ADC). Increased liver enzymes have 
been reported in patients treated with tisotumab vedotin, however the majority of the 
events have been grade 1 and 2. Please refer to the Investigator’s Brochure for more 
information. 
• Testicular toxicity was observed in cynomolgus monkeys administered 1, 3 and 5 mg/kg 
of tisotumab vedotin (HuMax-TF-ADC). Full recovery was observed at 1 mg/kg but 
only partial reversibility was observed after 6 weeks recovery at 3 and 5 mg/kg 
tisotumab vedotin (HuMax TF-ADC). Tisotumab vedotin (HuMax-TF-ADC) may have 
an adverse effect on spermatogenesis in man. 
Please refer to Section 6.2.3 for a summary of the safety data obtained in GEN701 part II. 
6.3 Clinical Study Rationale 
6.3.1 Patient Population  
Tissue factor is aberrantly expressed in many solid tumors as well as in the tumor 
vasculature. To retain possible benefit for patients, the patient population will be restricted to 
indications where TF is known to be expressed and where the usage of systemic 
tubulin-inhibition is a part of SoC in the clinic.  
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.  
Based on the safety data of the Dose Escalation part and the DMC and sponsor’s Safety 
committee recommendation, the Cohort Expansion part will encompass patients with 
advanced (locally advanced and/or metastatic) cancer of the ovary, cervix, endometrium, 
bladder, prostate (CRPC), esophagus, lung (NSCLC) or SCCHN who have failed available 
standard treatments as specified in the inclusion criteria. Patients included in the “bladder 
cancer” cohort will encompass patients with urothelial carcinomas (transitional cell 
carcinomas) regardless of the initial site of origin of the tumor (renal pelvis, ureter or bladder 
lumen). 
6.3.2 Study Design 
This is a phase I/II, open-label, dose-escalation, safety study of tisotumab vedotin 
HuMax-TF-ADC) dosed once q3wk in a mixed patient population with solid tumors to 
establish the safety profile. The study consists of two parts: A Dose Escalation part followed 


 
 
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by a Cohort Expansion part. The Dose Escalation part is considered FIH and the Cohort 
Expansion part a phase II. 
The Dose Escalation part will have a standard 3 (+3) design. In each dose cohort, the initial 
three patients must include at least two different cancer types. With eight planned dose 
levels, it is anticipated to include a maximum of 48 patients.  
The Cohort Expansion part will enroll approximately 169 patients who will be treated with a 
regimen based on the data obtained from the Dose Escalation part. The Cohort Expansion 
part will provide further safety, tolerability, PK and anti-tumor activity data from patients 
with cancer types that express TF.   
6.3.3 Dose Rationale 
Based on toxicology data from the 13-week repeat dose toxicology study in cynomolgus 
monkeys the highest non-severely toxic dose (HNSTD) was set at 3 mg/kg in females. A 
safety factor of 10 was then applied to the HNSTD resulting in a starting dose of 0.30 mg/kg.  
Data from cleavable MMAE-based ADC described in literature, including CD30-ADC, 
CR011-ADC, ASG-5ME-ADC, PSMA-ADC, CD22-ADC and CD79b-ADC, have indicated 
that no significant safety signals are observed at doses below or at 1 mg/kg given q3wk and 
MTD and/or RP2D are within the range of 1.8 mg/kg to 2.5 mg/kg across the molecules 
when q3wk dose regiments were used. Based on these literature findings and preclinical data 
of tisotumab vedotin (HuMax-TF-ADC) no major toxicity of tisotumab vedotin is anticipated 
in the clinic at doses below 1 mg/kg. The Dose Escalation part of the study includes eight 
dose cohorts; 0.3, 0.6, 0.9, 1.2, 1.5, 1.8, 2.2 and 2.6 mg/kg, corresponding to the following 
dose increments: 100%, 50%, 33%, 25%, 20%, 22% and 18%. The maximum tested dose 
will be 2.6 mg/kg. 
Tisotumab vedotin (HuMax-TF-ADC) will be administered once q3wk. This dosing 
frequency is based on toxicokinetics and toxicology data obtained in cynomolgus monkeys, 
suggesting adequate recovery of neutrophils, red cell parameters and skin changes over a 
three-week period and otherwise an acceptable safety profile. No accumulation of tisotumab 
vedotin (HuMax-TF-ADC) is anticipated based on the proposed dose interval. Main study 
period will encompass four treatment cycles and allow patients with potential benefit 
(defined as stable disease [SD] or better) to continue for up to eight additional treatment 
cycles (for a maximum of twelve cycles in total). 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 progressive disease (PD) is observed. If a specific safety 
signal is observed in one of the tested indications in the Dose Escalation part, the sponsor 
will retain the possibility to include more patients at the same dose level. Finally, the sponsor 
in collaboration with the DMC has the possibility to add intermediate dose cohorts to better 
define MTD. 
In each dose cohort in the Dose Escalation part, a minimum of ten days between 
administration of first dose in patient 1 and patient 2 and minimum of one day between the 
subsequent patients will be implemented. 


 
 
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The Cohort Expansion Part will recruit patients to each of the indication arms in parallel, 
without any delay between administrations. 
6.4 Immunogenicity Assay Strategy for tisotumab vedotin (HuMax-TF-ADC)  
Patient serum samples will be assessed for the presence of anti-drug antibodies (ADA) 
against tisotumab vedotin (HuMax-TF-ADC) in a screening assay.  
Positive samples will be assessed in a confirmatory assay where samples will be 
pre-incubated with HuMax-TF-ADC. Confirmed positive samples will subsequently be 
titrated to establish an ADA titer.  
To determine the specificity of ADA response of confirmed positive samples, it will be 
assessed whether the response is directed against the toxin or the antibody moiety of the drug 
(binding region assay) and a neutralization assay will be performed.  
The binding region assay will use the format of the confirmatory assay and samples will be 
pre-incubated with HuMax-TF-ADC, HuMax-TF or free MMAE. 
For the neutralization assay, several potentially suitable assay formats are under evaluation. 
Two assays are based on the mechanism of action of HuMax-TF-ADC; a cell-based 
internalization assay of HuMax-TF-ADC and a cell-based killing assay for HuMax-TF-ADC. 
Alternatively, a competitive ligand binding assay; either cell-based or immobilized 
recombinant ligand-based will be considered. 
During study conduct, AEs and laboratory data will be collected to monitor all patients 
closely for potential safety signals. In addition, potential biologic activity determined by 
applied CT scanning, CA 125 and PSA measurements will be assessed. The association 
between positive/non-positive ADA and PK (pre-dose, Cmax), major safety signals (CTCAE 
grade ≥ 3) and efficacy information (change in tumor size by CT-scan) will be explored.   
6.5 Rationale for Exploratory Endpoints 
6.5.1 Tumor Biopsy 
In this clinical study, tumor tissue samples will be collected at screening and TF expression 
will be determined by IHC using a TF-specific antibody. In the Dose Escalation part an 
archived sample may be used as screening sample. The most recent available archived 
sample should be used. In addition to TF-expression analysis, morphological analysis of the 
tumor section will be done using standard histological methods (i.e., hematoxylin-eosin 
staining). The results will be used to explore the clinical utility of such an IHC assay for the 
characterization of TF expression in tumors and to get a first impression on a possible 
correlation between tumor TF expression and clinical safety and/or biological activity of 
tisotumab vedotin (HuMax-TF-ADC). 
In the Cohort Expansion part of the study, tumor biopsies are collected at screening from 
each patient. The most recent available archived sample can be used. If no biopsies are 
available, a new biopsy must be obtained before dosing. In addition, an optional tumor 
biopsy may be obtained three weeks after last dosing (+ 2 weeks). TF expression levels, as 
determined using the IHC assay, will be compared between the two biopsies to evaluate 


 
 
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potential modulation of TF expression due to tisotumab vedotin (HuMax-TF-ADC) 
treatment. 
6.5.2 Biomarkers 
Plasma samples are collected for retrospective analysis in a centralized laboratory of 
i) circulating TF, ii) an array of 1129 different proteins, and iii) total levels of circulating 
cell-free deoxyribonucleic acid (cfDNA). 
6.5.2.1 Circulating Tissue Factor in Plasma 
Enhanced levels of circulating TF have been reported in the plasma of patients with many 
different types of cancer, including cancers evaluated in GEN701 (Strijbos et al., 2010, 
Golding-Lang et al., 2008, Han et al., 2006). Circulating TF may exist as full length TF 
associated with (tumor) cell-derived microvesicles, as the soluble alternative splice variant of 
TF (alternatively spliced TF), or as truncated TF. Levels of circulating TF may correlate with 
the tumor mass of TF expressing tumors. Accordingly, circulating TF may provide an easy 
accessible and sensitive pharmacodynamic marker to monitor patient responses to tisotumab 
vedotin (HuMax-TF-ADC). 
6.5.2.2 Protein Biomarkers 
Although the GEN701 study is primarily setup to evaluate safety and dosing of tisotumab 
vedotin (HuMax-TF-ADC), plasma samples are collected to identify potential markers for 
efficacy of HuMax-TF-ADC. In these samples an array of 1129 proteins is measured using 
the SOMAscan technology™ 
, US) and/or another existing 
platform for protein analyses. 
6.5.2.3 Circulating Free DNA 
Cell-free DNA fragments are commonly observed in plasma of healthy individuals, and are 
thought to originate from dying or apoptotic cells as part of normal tissue turnover. In 
patients with advanced cancer, including NSCLC, ovarian cancer and bladder cancer, 
enhanced levels of cfDNA have been reported (Gautschi, 2004; Ellinger et al, 2008, 
Choudhuri et al., 2014; Spindler et al., 2012). Although the factors that influence changes in 
total cfDNA levels in cancer patients are not fully understood, a substantial portion of 
circulating cfDNA in cancer patients is thought to originate from tumor cells. Importantly, a 
decrease in cfDNA levels was found to be an indicator of response to treatment in ovarian 
cancer, NSCLC and breast cancer (Gautschi, 2004; Choudhuri et al., 2014; Dawson et al., 
2013). Treatment with tisotumab vedotin (HuMax-TF-ADC), if effective, may result in a 
reduction of cfDNA levels. With the purpose of monitoring changes in levels of cfDNA 
during treatment with HuMax-TF-ADC, blood plasma samples will be taken and cfDNA will 
be isolated. 


 
 
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7. 
STUDY OBJECTIVES AND ENDPOINTS  
7.1 Study Objectives 
7.1.1 Primary Study Objective 
• To establish the tolerability of tisotumab vedotin (HuMax-TF-ADC) in a mixed 
population of patients with specified solid tumors. 
7.1.2 Secondary Study Objectives 
• To establish the long term tolerability of tisotumab vedotin (HuMax-TF-ADC) in a 
mixed population of patients with specified solid tumors. 
• To determine the MTD and the recommended dose for phase II studies with tisotumab 
vedotin (HuMax-TF-ADC). 
• To establish the PK profile of tisotumab vedotin (HuMax-TF-ADC) after single and 
multiple infusions. 
• To evaluate the anti-tumor activity of tisotumab vedotin (HuMax-TF-ADC) in a mixed 
population of patients with specified solid tumors. 
7.2 Study 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 study drug during the study. 
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 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 (ADA) of tisotumab vedotin (HuMax-TF-ADC). 
• Anti-tumor activity measured by tumor shrinkage (based on computerized tomography 
[CT]-scan evaluations), change in PSA and CA 125.  
• Objective Response (Complete Response [CR] or Partial Response [PR]), Disease 
Control (CR, PR or SD) after 6, 12, 24 and 36 weeks, Progression-Free Survival (PFS) 
and Duration of Response (DoR).  


 
 
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7.2.3 Exploratory Endpoints 
• TF expression in tumor biopsies. 
• Circulating TF. 
• Protein biomarker. 
• cfDNA. 


 
 
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8. 
INVESTIGATIONAL PLAN 
8.1 Overall Study Design and Plan 
This is a dose-escalating, open-label, multicenter phase I/II safety study of tisotumab vedotin 
(HuMax-TF-ADC) dosed once q3wk in a mixed population of patients with solid tumors 
known to express TF and where the use of systemically administered tubulin inhibitors is part 
of SoC. The study consists of two parts: a Dose Escalation part and Cohort Expansion part. 
The Dose Escalation part is considered FIH and the Cohort Expansion part a phase II. 
8.1.1 Dose Escalation Part 
The Dose Escalation part is a standard 3 (+3) design which will evaluate tisotumab vedotin 
(HuMax-TF-ADC) at doses of 0.30 mg/kg and up (0.3, 0.6, 0.9, 1.2, 1.5, 1.8, 2.2 and 
2.6 mg/kg). 
In the absence of unacceptable first cycle toxicities, doses are escalated in the subsequent 
cohorts, as deemed appropriate by the DMC and confirmed by sponsor. If unacceptable first 
cycle toxicities are observed, cohorts will be expanded from three to six patients. Depending 
on the nature of the observed event, 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 experiencing the event. If a patient withdraws prior to completing the first 
treatment cycle, the sponsor should replace the patient, unless the withdrawal is due to a 
DLT. Further details of the dose-escalation steps are provided in Section 8.4.12. 
In each dose cohort, the initial three patients included must include at least two different 
cancer types. Patients will be treated for four cycles or until unacceptable toxicity is 
observed. Patients showing clinical benefit, defined as SD or better, can receive up to a 
maximum of eight additional treatment cycles (for a maximum of twelve cycles in total). 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.  
See Figure 1 below for illustration. 
Figure 1: Dose Escalation Part: Dose Levels and Cohorts - Dosing Period (Cycles 1-4) 
and Extended Dosing Period (Cycles 5-12) 
 
 
Twelve cycles are expected to correspond to 36 weeks. 
8.1.2 Cohort Expansion Part 
The aim of the Cohort Expansion part is to provide further safety, tolerability, PK and 
anti-tumor activity data from patients with cancer types that express TF. Recruitment will be 


 
 
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initiated in five arms encompassing ovary, cervix, endometrium, bladder, and prostate 
(CRPC). Based on a safety review of data from the first ten patients recruited and followed 
for at least one cycle (regardless of indication), the DMC and the sponsor’s Safety committee 
will evaluate the safety profile with particular emphasis on coagulation status and possible 
cases of hemorrhages. If the safety profile is deemed safe, the DMC and the sponsor’s Safety 
committee will approve the recruitment of the three remaining arms, esophagus, NSCLC, and 
SCCHN. A minimum of 14 and maximum of 30 patients will be recruited each to the cervix 
and endometrial indications. In the remaining indications (ovary, bladder, CRPC, NSCLC, 
esophagus and SCCHN), 14 patients will be recruited. 
Cervical and endometrial indications will be expanded from 14 to 30 patients if, and only if, 
a responder is observed (evaluated after last patient has had four cycles) or, in case of no 
responders, the DMC evaluates whether it is nevertheless meaningful to expand. If one of 
these two indications does not appear promising while there is another indication that shows 
promising efficacy, it may be decided to expand the other indication instead, up to 
30 patients. After implementation of Protocol Amendment 13 (Protocol version 14.0), up to 
25 additional patients will be recruited to the cervix indication, for a maximum of 
approximately 55 patients. 
Patients will be treated with the dose determined from the Dose Escalation part of the study 
by the DMC and the sponsor’s Safety committee. Reduced dose can be administered in 
accordance with the mitigation strategies (Section 8.4.4 to 8.4.10) 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. 
Patients showing clinical benefit, defined as SD or better, can receive up to a maximum of 
eight additional treatment cycles (for a maximum of twelve cycles in total). 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. 
See Figure 2 below for illustration. 


 
 
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Figure 2: Cohort Expansion Part: Dosing Period (Cycles 1-4) and Extended Dosing 
Period (Cycles 5-12) 
 
Twelve cycles are expected to correspond to 36 weeks. 
8.1.3 Study Overview 
A study overview is described below. The study flowchart is in Table 1 for the Dose 
Escalation part and in Table 2 for the Cohort Expansion part. Study evaluations by visit are 
detailed in Section 9.   
8.1.3.1 Screening Phase (Visit 0) 
Subjects 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 study eligibility. The medical history, physical 
examination, potential biopsies, ECG and laboratory studies (including biomarkers) must be 
performed within 21 days before study entry (Visit C1-V1). CT imaging must be performed 
within four weeks before study 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.   
8.1.3.2 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 every 21 days. Dose-escalation 
to MTD is anticipated to involve approximately eight dose levels with an anticipated 
maximum dose level of 2.6 mg/kg (not including potential intermediate dose cohorts). 
Patients will receive four cycles (doses) of tisotumab vedotin (HuMax-TF-ADC) at 21-day 
intervals. Thus, the treatment period will last for twelve weeks, or until disease progression. 


 
 
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After four cycles, if there is evidence of the patient benefitting from treatment, at the 
discretion of the treating physician after agreement with Genmab on the patient status, there 
is an option to continue in the study for up to a maximum of eight additional cycles 
(24 weeks) or until unacceptable toxicity according to protocol is observed.  
The treatment period will have a maximum duration of 36 weeks. 
Cohort Expansion Part 
The investigator must have evaluated the patient’s eligibility and signed the Screening 
Evaluation Form before the patient’s first infusion. 
Tisotumab vedotin (HuMax-TF-ADC) will be administered every 21 days. Approximately 
169 patients will receive four cycles (doses) of tisotumab vedotin (HuMax-TF-ADC) at the 
dose determined by the sponsor in agreement with the DMC based on the Dose Escalation 
part of the study. The treatment period will last for twelve weeks or until disease progression.  
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 study for up to a 
maximum of eight additional cycles (24 weeks) or until unacceptable toxicity is observed.  
The treatment period will have a maximum duration of 36 weeks. 
8.1.3.3 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 study clinical or 
laboratory assessment deemed necessary. The visit date and reason for visit must be recorded 
in the patient’s medical records and electronic case report form (eCRF). 
For the Cohort Expansion part, an unscheduled visit may also be used to collect information 
about the tumor biopsy obtained three weeks after last treatment (optional), or to document a 
repeat CT-scan to confirm response. 
8.1.3.4 Follow-up Phase (FU1 to FU4) 
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 (24 weeks) or until PD, other treatment is initiated or 
the patient withdraws from the study due to other reason, whichever occurs first. After that, 
the patient will return for an End of Study Visit (EOS). 
8.1.3.5 End of Study Visit (EOS)  
If a patient completes all the follow-up visits, the EOS Visit should be performed four weeks 
after Follow-up Visit 4. In case of withdrawal from the study, the EOS Visit will be 
performed as soon as possible. The EOS Visit will include most assessments performed at 
the Screening Visit, and response assessments.  
8.1.3.6 Safety Follow-up Visit (SFU) 
Patients who withdraw from the study before Follow-up Visit 1 will return for a Safety 
Follow-up Visit 30 days after the last IMP dosing. In the Safety Follow-up Visit, only SAEs 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
 18 Jul 2018 
 
 
Page 48 of 130 
will be assessed, as well as any new anti-cancer treatment, if applicable, in the Cohort 
Expansion part. If the patient has died within the 30 days, this should be entered as an AE in 
the eCRF and reported as an SAE. 
 
 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
 Final 16.0 (incorporating Protocol Admin. Ch. 3), 18 Jul 2018 
 
Page 49 of 130 
Table 1: 
Study Flow Chart – Dose Escalation Part 
Treatment 
Cycle 
Screening 
Cycle 1-2 
Cycle 3-4 
Cycle 5-121 
Follow 
Up 
EOS2 
Withdrawal 
Safety 
Follow Up 
Unsched 
Visit Number 
0 
13 
2 
3 
4 
5 
6 
1 
2 
3 
1 
2 
3 
1-4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to 
Visit C1-V1 
1d 
2d 
4d 
8d 
11d 
15d 
1d 
8d 
15d 
1d 
8d 
15d 
6 
weekly 
- 
30 days 
after last 
dosing5 
- 
Visit window4 
 
±1d 
- 
±1d 
±1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±3d 
±1d 
±1d 
±7d 
- 
+14d 
- 
Informed 
Consent 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Body 
Weight8 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Physical 
Examination 
X20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital Signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X16 
ECG10 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X16 
CT-Scan 
X11 
 
 
 
 
 
 
X12 
 
 
X12 
 
 
X 
X12 
 
X16 
ECOG 
Performance 
Status 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
X16 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X16 
Study Drug 
Administration 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
Bleeding 
Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
Skin Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
X16 
Neuropathy 
Assessment 
X 
X 
 
 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
 
X16 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
 Final 16.0 (incorporating Protocol Admin. Ch. 3), 18 Jul 2018 
 
Page 50 of 130 
Treatment 
Cycle 
Screening 
Cycle 1-2 
Cycle 3-4 
Cycle 5-121 
Follow 
Up 
EOS2 
Withdrawal 
Safety 
Follow Up 
Unsched 
Visit Number 
0 
13 
2 
3 
4 
5 
6 
1 
2 
3 
1 
2 
3 
1-4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to 
Visit C1-V1 
1d 
2d 
4d 
8d 
11d 
15d 
1d 
8d 
15d 
1d 
8d 
15d 
6 
weekly 
- 
30 days 
after last 
dosing5 
- 
Visit window4 
 
±1d 
- 
±1d 
±1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±3d 
±1d 
±1d 
±7d 
- 
+14d 
- 
Radionuclide 
Bone Scan13 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X16 
LABORATORY ASSESSMENTS14 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X16 
Biochemistry 
X 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X16 
Coagulation 
factors 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X16 
PSA13 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
X16 
CA 12515 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
X16 
Flow Cytometry 
 
X19 
 
 
 
 
 
 
 
 
X19 
 
 
 
X 
 
X16 
Pregnancy Test 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X16 
ADA 
(Immunogenicity) 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X16 
Hepatitis B, C, 
CMV, HPV17 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X16 
PK Sampling21 
X 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X16 
Tumor biopsy 
X18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X16 
Biomarkers 
X 
 
 
 
 
 
 
 
 
 
X22 
 
 
 
 
 
 
Abbreviations: ADA=anti-drug antibody; CMV=cytomegalovirus; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EOS=End of Study; HCV=hepatitis C virus; HPV= human papilloma virus; PCR=polymerase chain reaction; PK=pharmacokinetic; PSA=prostate specific antigen 
Footnotes to Study Flowchart – Dose Escalation Part 
1 Additional treatment only if patient shows response of SD or better and after approval by Genmab. 
2 If patient is withdrawn from study during treatment or Follow-up period, the EOS Visit should be performed as soon as possible after decision of withdrawal. If 
patient completes all Follow-up visits, the EOS Visit should be performed four weeks after Follow-up Visit 4.  
3 The patient shall stay hospitalized the first 24 hours after the infusion and be discharged the following day after assessments and 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. 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
 Final 16.0 (incorporating Protocol Admin. Ch. 3), 18 Jul 2018 
 
Page 51 of 130 
5 For patients who withdraw from the study before Follow-up Visit 1. Only SAEs will be assessed. 
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 C1-V1 should be recorded as medical history (see Section 10 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 study, only body weight is measured on dosing days, as part of the dose calculation. If body weight is 
assessed ≤ 3 days before the day of the planned dosing, this value can be used and is the weight recorded in the eCRF. 
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 24 hours after end of infusion of the 2 first infusions 
and until 2 hours after the remaining infusions, as indicated in Section 10.5. 
10 One ECG will be performed at screening. Three ECGs should be performed at least 2 minutes apart before each infusion of the study drug, in accordance with 
the ECG Specifications Manual. 
11 Within four weeks prior to Visit C1-V1. All patients will have a CT-scan with contrast of thorax, abdomen, and pelvis performed during screening. If a 
CT-scan has been performed within four weeks prior to Visit C1-V1 as part of standard procedure, it is acceptable as screening CT-scan for the study. 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 2nd cycle, i.e., on Day 1 of Cycles 3, 5, 7, 9 and 11, 21 days (± 3 days) after Day 1 of Cycle 12, and at the EOS Visit. 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. To be completed as indicated to confirm 
response, new symptoms, end of study or physician discretion. If reduction of target lesions ≥ 30% in size is observed, one repeat CT-scan will be performed 
after four weeks to substantiate response. 
13 Radionuclide bone scan and PSA will be performed for CRPC patients. Radionuclide bone scan will be performed at screening, every twelve 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 twelve weeks later. The screening 
radionuclide bone scan can be performed four weeks prior to Visit C1-V1.  
14 Hematology, biochemistry, serology and pregnancy test will be analyzed locally at the sites. All other laboratory parameters will be analyzed centrally. 
15 For patients with ovarian cancer. 
16 Optional. 
17 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 EOS, only antibodies to CMV antigen will be assessed. 
18 Archived biopsy 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. 
19 Flow cytometry only on Cycle 1 and Cycle 5. 
20 Including a baseline visual acuity assessment at screening. 
21 See Table 3 for details of PK samplings. 
22 Only on Cycle 5. 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
 Final 16.0 (incorporating Protocol Admin. Ch. 3), 18 Jul 2018 
 
Page 52 of 130 
Table 2: 
Study Flow Chart – Cohort Expansion Part  
Treatment Cycle 
Screening 
Cycle 1-2 
Cycle 3-4 
Cycle 5-121 
Follow 
Up 
EOS2 
Withdrawal 
Safety 
Follow Up 
Unscheduled 
Visit Number 
0 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1-4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to 
Visit C1-
V1 
1d 
8d 
15d 
1d 
8d 
15d 
1d 
8d 
15d 
6 
weekly 
- 
30 days after 
last dosing4 
- 
Visit window3 
 
±1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±3d 
±1d 
±1d 
±7d 
- 
+14d 
- 
Informed Consent 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and Body weight7 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital Signs8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X15 
ECG9 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X15 
CT-Scan 
X10 
 
 
 
X11 
 
 
X11 
 
 
X 
X11 
 
X15 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
X15 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X15 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X15 
Pre-infusion Medication23 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Study Drug Administration  
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Bleeding Assessment 
X 
X 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
Skin Assessment 
X 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
X15 
Neuropathy Assessment 
X 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
X15 
Ophthalmological 
Evaluation 
X 
 
X20 
 
 
X20 
 
 
X20 
 
 
X20 
 
X20 
Radionuclide Bone Scan12 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X15 
New Anti-cancer 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X15 
LABORATORY ASSESSMENTS13 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X15 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
 Final 16.0 (incorporating Protocol Admin. Ch. 3), 18 Jul 2018 
 
Page 53 of 130 
Treatment Cycle 
Screening 
Cycle 1-2 
Cycle 3-4 
Cycle 5-121 
Follow 
Up 
EOS2 
Withdrawal 
Safety 
Follow Up 
Unscheduled 
Visit Number 
0 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1-4 
- 
- 
1-X 
Day/Week 
≤ 21 days 
prior to 
Visit C1-
V1 
1d 
8d 
15d 
1d 
8d 
15d 
1d 
8d 
15d 
6 
weekly 
- 
30 days after 
last dosing4 
- 
Visit window3 
 
±1d 
±1d 
±1d 
±3d 
±1d 
±1d 
±3d 
±1d 
±1d 
±7d 
- 
+14d 
- 
Biochemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X15 
Coagulation factors 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
X15 
PSA12 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X15 
CA 12514 
X14 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X15 
Flow Cytometry 
 
X16 
 
 
 
 
 
X16 
 
 
 
X 
 
X15 
Pregnancy test17 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X15 
ADA (Immunogenicity) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X15 
Hepatitis B, C, CMV, 
HPV18 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X15 
PK Sampling19 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X15 
Tumor Biopsy 
X21 
 
 
 
 
 
 
 
 
 
 
X21 
 
X15 
Biomarkers 
X 
 
 
 
 
 
X22 
 
 
 
 
 
 
 
Abbreviations: ADA=anti-drug antibody; CMV=cytomegalovirus; CT=computed tomography; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EOS=End of Study; HCV=hepatitis C virus; HPV= human papilloma virus; PCR=polymerase chain reaction; PK=pharmacokinetic; PSA=prostate specific antigen 
Footnotes to Study Flowchart – Cohort Expansion Part 
1 Additional treatment only if patient shows response of SD or better. 
2 If patient is withdrawn from study during treatment or Follow-up period, the EOS Visit should be performed as soon as possible after decision of withdrawal. If 
patient completes all Follow-up visits, the EOS Visit should be performed four weeks after Follow-up Visit 4.  
3 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. 
4 For patients who withdraw from the study before Follow-up Visit 1. Only SAEs will be assessed. 
5 Informed consent can be obtained outside the Screening Visit window, i.e. may be reasonably prior to the screening date. 
6 Signs and symptoms occurring between Visit 0 and Visit C1-V1 should be recorded as medical history (see Section 10 for details). 
7 Height is only assessed at the Screening Visit. During the study, only body weight is measured on dosing days, as part of the dose calculation. If body weight is 
assessed ≤ 7 days before the day of the planned dosing, this value can be used and is the weight recorded in the eCRF. 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
 Final 16.0 (incorporating Protocol Admin. Ch. 3), 18 Jul 2018 
 
Page 54 of 130 
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 infusion, as indicated in 
Section 10.5. 
9 One ECG will be performed at screening. Three ECGs should be performed at least 2 minutes apart before each infusion of the study drug, in accordance with 
the ECG Specifications Manual. 
10 Within four weeks prior to Visit C1-V1. All patients will have a CT-scan with contrast of thorax, abdomen, and pelvis performed during screening. If a 
CT-scan has been performed within four weeks prior to Visit C1-V1 as part of standard procedure, it is acceptable as screening CT-scan for the study. In patients 
with SCCHN additional CT-scan of neck will be performed during screening. If there is suggestion of brain metastases/tumors, a CT-scan of the head will be 
performed before inclusion. 
11 At the end of every 2nd cycle, i.e., on Day 1 of Cycles 3, 5, 7, 9 and 11, 21 days (± 3 days) after Day 1 of Cycle 12, and at the EOS Visit. 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. To be completed as indicated to confirm 
response, new symptoms, end of study or physician discretion. If reduction of target lesions ≥ 30% in size is observed, one repeat CT-scan will be performed 
after four weeks to substantiate response. 
12 Radionuclide bone scan and PSA will be performed for CRPC patients. Radionuclide bone scan will be performed at screening, every twelve weeks, and upon 
clinical indication. If there is suspicion of progression, another bone scan will be performed twelve weeks later. The screening radionuclide bone scan can be 
performed four weeks prior to Visit C1-V1.  
13 All laboratory parameters will be analyzed centrally. 
14 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. 
15 Optional. 
16 Flow cytometry only on Cycle 1 and Cycle 5. 
17 At the screening visit; every second cycle, i.e., on Day 1 of Cycles 1, 3, 5, 7, 9, 11; at the Follow Up visits and at the EOS visit. 
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 SCCHN and cervical cancer. At EOS, only antibodies to CMV antigen will be assessed. 
19 See Table 4 for details of PK samplings. 
20 At screening and at every second cycle, i.e., Day 8 of Cycles 2. 4. 6. , 8, 10 and 12. Patients experiencing ocular symptoms must be referred to an 
ophthalmologist for prompt review (preferably within 72 hours and no later than within one week). 
21 The most recent available archived sample can be used. If no biopsies are available, a new biopsy must be obtained before dosing. In addition, an optional 
sample may be obtained 3 weeks (+ 2 weeks) after last dosing; this should be entered as an unscheduled visit (Section 10.18). 
22 Only on Cycle 4. 
23 Preventive eye therapy to be administered in relation to infusions as detailed in Section 8.4.8. 


 
 
Protocol No.GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) in mixed solid tumors 
 Final 16.0 (incorporating Protocol Admin. Ch. 3), 18 Jul 2018 
 
Page 55 of 130 
Table 3: 
PK Sampling in the Dose Escalation Part 
Treatment Cycle 
Screening 
Cycle 1-2 
Cycle 3-4 
Cycle 5-12 
Follow-Up 
Unscheduled 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
1 
2 
3 
1 
2 
3 
1-4 
1-X 
Day/Week 
- 
1d 
2d 
4d 
8d 
11d 
15d 
1d 
8d 
15d 
1d 
8d 
15d 
6 weekly 
 
Before Infusion 
(on infusion days) 
X 
X 
X1 
 
X 
 
X 
X 
 
 
X 
 
 
X 
X3 
End of infusion 
(+15 minutes) 2 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
+ 2 hours (± 15 minutes) 
after end of infusion 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 5 hours (± 30 minutes) 
after end of infusion 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 12 hours (± 60 minutes) 
after end of infusion 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Time window for the Day 2 sampling in the Dose Escalation Part is 24 hours ± 2 hours after end of infusion on Day 1. 
2 Allowed time windows are indicated in parentheses.   
3 Optional. 
 
 
Table 4: 
PK Sampling in the Cohort Expansion Part 
Treatment Cycle 
Screening 
Cycle 1-2 
Cycle 3-4 
Cycle 5-12 
Follow-Up 
Unscheduled 
Visit Number 
0 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1-4 
1-X 
Day/Week 
- 
1d 
8d 
15d 
1d 
8d 
15d 
1d 
8d 
15d 
6 weekly 
 
Before Infusion       
(on infusion days) 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X2 
End of infusion   
(+15 minutes) 1 
 
X 
 
 
X 
 
 
X 
 
 
 
 
+ 2 hours (± 15 minutes) after 
end of infusion 1 
 
X 
 
 
 
 
 
 
 
 
 
 
1 Allowed time windows are indicated in parentheses.   
2 Optional. 
 


 
 
Protocol No. GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
 Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
18 Jul 2018 
 
 
Page 56 of 130 
8.2 Study Duration and End of Study 
Enrolment period in the Dose Escalation part is planned to last approximately 21 months. 
Enrolment period in the Cohort Expansion part is planned to last approximately 30 months.  
The study will be stopped when the last patient included in the Cohort Expansion part 
completes the study or when the last ongoing patient has discontinued treatment and attended 
the EOS Visit and Safety Follow-up Visit, whichever occurs first. 
The end of study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment for the last patient in the study or the date the study 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 study completion, as directed by the site monitor. The IEC/IRB will be notified when 
the study has been completed. 
Genmab A/S reserves the right to temporarily suspend or prematurely discontinue this study 
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 enrolment with respect to quality or quantity. 
If the study 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 study drug and other materials or supplies provided by the 
sponsor. 
8.2.1 Study Stopping Criteria 
If any of the following occur, administration of the study drug will be stopped and no 
additional patients will be included into the study: 
1) Grade ≥ 3 anaphylactic reaction to tisotumab vedotin (HuMax-TF-ADC) in any patient. 
2) Other events that, in the judgment of the sponsor Medical Officer, are deemed serious 
enough to warrant immediate review 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 study patients. 
If any of the above-listed events occurs, a prompt cumulative review of safety data and the 
circumstances of the event in question will be conducted by the DMC to determine whether 
dosing and study entry should be resumed, whether the protocol will be modified, or whether 
the study will be discontinued permanently. Review and approval by the sponsor’s Safety 
committee is required for resumption of the study in the event that the study 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 study. 


 
 
Protocol No. GEN701 (innovaTV 201) 
Tisotumab vedotin (HuMax®-TF-ADC) 
 Final 16.0 (incorporating Protocol Admin. Ch. 3) 
in mixed solid tumors 
18 Jul 2018 
 
 
Page 57 of 130 
Any patients who have already received the study drug and are currently in the study at the 
time study stopping criteria are met will continue to be followed by the investigator for 
safety. 
Withdrawal criteria for individual patients are provided in Section 8.3.4. 
8.3 Study Population 
The Dose Escalation part is planned to be performed in a maximum of five sites in Denmark, 
United Kingdom and the US, with up to 30 additional sites to be included in Europe and the 
US for the Cohort Expansion part. Approximately 310 patients will be screened to ensure 
that up to 217 patients (anticipated screen failure rate of 30%) are enrolled in the study.  
A maximum of 48 patients are planned to be enrolled in the Dose Escalation part: up to 
six patients per dose level for eight dose levels. Approximately 169 patients will be enrolled 
in the Cohort Expansion part. 
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 NSCLC who have failed available standard treatments or who 
are not candidates for standard therapy.  
The patient population in the Cohort Expansion part will encompass patients with unmet 
medical need as specified under Inclusion Criterion 1 (Section 8.3.1). 
8.3.1 Inclusion Criteria 
Investigators should ensure that all study enrollment criteria have been met at screening. If a 
subject's status changes (including laboratory results or receipt of additional medical records) 
after screening but before the first dose of study drug is given such that they no longer meet 
all eligibility criteria, they should be excluded from participation in the study. 
Patients MUST satisfy all of the following entry criteria before they will be allowed to 
participate in the study: 
 
1. 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: Patients with relapsed, advanced and/or metastatic cancer 
of the ovary, cervix, endometrium, bladder, prostate, head and neck (SCCHN), 
esophagus, or lung (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. 


 
 
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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 study 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 [GEJ] 
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 (ALK) mutations 
should have been treated with appropriate targeted therapy before study entry. 
Patients must have received no more than four (five allowed for patients with 
EGFR mutated adenocarcinomas) prior treatment regimens for advanced disease. 
o SCCHN: refractory to platinum-based therapy, also failing an anti-EGFR-based 
therapy if patient is eligible and if anti-EGFR therapy is part of the established 
SoC therapy. Patients must have received no more than one prior platinum-based 
and in total three prior treatment regimens for advanced disease. 
2. 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 
only, the patient can be enrolled only if there has been demonstrated progression 
in the “in field” lesion and after sponsor acceptance. 
a. 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 (Scher et al., 2008). 
o Patients with ovarian cancer can be included based on CA 125 positivity 
according to the Gynecologic Cancer Intergroup Guideline (Rustin et al., 2004) in 
the Dose Escalation part only. 
3. Age ≥ 18 years. 


 
 
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4. Acceptable renal function defined as: 
o Glomerular filtration rate (Cockcroft-Gault) > 45 mL/min. 
5. 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. 
6. 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. 
7. Acceptable coagulation status defined as: 
o INR ≤ 1.2 (without anticoagulant therapy). 
o aPTT ≤ 1.25ULN. 
o patients on stable doses of therapeutic anti-coagulative treatment for ≥ 8 weeks 
(e.g., warfarin) must have an INR < 3. 
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
9. Life expectancy of at least three months. 
10. 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.   
11. 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 (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 semen 
specimen obtained for storage for potential future conception. 
12. Following receipt of verbal and written information about the study, patients must 
provide signed informed consent before any study-related activity is carried out. 


 
 
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8.3.2 Exclusion Criteria 
If any of the following apply, the patient MUST NOT enter the study: 
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 study 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. (Exclusion criterion removed with Protocol Amendment 14) 
9. Have 
received 
granulocyte 
colony 
stimulating 
factor 
(G-CSF) 
or 
granulocyte/macrophage colony stimulating factor support within one week or pegylated 
G-CSF within two weeks before the Screening Visit. 
10. Have received a cumulative dose of corticosteroid ≥ 150 mg (prednisone or equivalent 
doses of corticosteroids) within two weeks before the first infusion. 
11. (Exclusion criterion removed with Protocol Amendment 13). 
Surgery/procedures 
12. Major surgery within six weeks or open biopsy within seven days before drug infusion. 
13. Plan for any major surgery during treatment period. 


 
 
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14. Patients not willing or able to have a pre-study tumor biopsy taken. In the Dose 
Escalation part, the screening biopsy can be omitted if archived material is available. In 
the Cohort Expansion part, the most recent available archived sample can be used; if no 
biopsies are available a new biopsy must be obtained before dosing. 
15. Presence or anticipated requirement of epidural catheter in relation to infusions (within 
48 hours before and after dose of study drug). 
Central nervous system  
16. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain 
metastases or stroke. 
o Transient ischemic attack > 1 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 five half-lives before first 
infusion. For anti-cancer therapies with half-lives greater than 8 days, a washout period 
of at least 28 days is acceptable. 
18. Prior treatment with bevacizumab within twelve 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. 
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 complete response (CR) of > 5 years duration. 
23. Radiographic evidence of cavitating pulmonary lesions. 
24. For the Dose Escalation part: Tumor adjacent to or invading any large blood vessel, 
unless approved by the sponsor Medical Officer.  
For the Cohort Expansion part: Tumor invading any large blood vessel. 
Other 
25. Ongoing significant, uncontrolled medical condition. 


 
 
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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).  
8.3.3 Patient Allocation Procedure 
Allocation of patients in both Dose Escalation and Cohort Expansion parts 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 8.4.12.2. 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 
Dose Escalation Part: 
Patients will be withdrawn from treatment for the following reasons: 


 
 
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• DLT (see Section 8.4.13 for specification and exception) 
• > 2 dose reductions due to recurrent toxicities possibly related to tisotumab vedotin 
(HuMax-TF-ADC) (see Sections 8.4.5, 8.4.6 and 8.4.8) 
• Dose delay of more than 2 weeks due to toxicity possibly related to tisotumab vedotin 
(HuMax-TF-ADC)  
• Pregnancy 
• Patient choice 
Cohort Expansion Part: 
Patients will be withdrawn from treatment for the following reasons: 
• CTCAE grade ≥ 3 macular-papular skin rash 
• TEN, Steven Johnson and CTCAE grade ≥ 3 cutaneous vasculitis 
• CTCAE grade ≥1 treatment-related bullous dermatitis or skin bullae (blister) ≥ 0.5 cm 
• CTCAE grade 4 peripheral neuropathy  
• CTCAE grade 4 neutropenia for a minimal duration of seven days 
• CTCAE grade 4 febrile neutropenia (with a single temperature of > 38.3°C or a 
sustained temperature of ≥ 38 °C for more than one hour) 
• CTCAE grade 4 thrombocytopenia 
• Major bleeding (as defined in Section 10.11) 
• CTCAE grade 4 IRR 
• 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 8.4.8) 
• Third occurrence of CTCAE grade ≤ 2 keratitis (despite dose reductions, see Section 
8.4.8) 
• 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 following discussion with 
the Genmab Medical Officer 


 
 
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• > 2 dose reductions due to recurrent toxicities possibly related to tisotumab vedotin 
(HuMax-TF-ADC)   
• Dose delay of more than 2 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 
* This exception is due to the fact that decrease to CTCAE grade 1 in intensity for 
neuropathy, skin rash, keratitis and conjunctivitis may last for more than 2 weeks. 
8.3.4.2 Criteria for Patient Withdrawal from the Study 
Patients will be withdrawn from the study (Dose Escalation or Cohort Expansion parts) at 
any time for any of the following reasons: 
• Patient choice 
• Investigator or sponsor decision 
• Disease progression 
• Initiation of new anti-cancer treatment  
• Lost to follow-up 
• Intercurrent illness that precludes further participation or requires a prohibited 
concomitant treatment 
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 Study 
When a patient withdraws from the study, investigators should attempt to obtain information 
and perform an EOS Visit as soon as possible and prior to initiation of new treatment. In 
addition, a Safety Follow-up Visit must be performed at least 30 days following the last dose 
of IMP. The EOS Visit will include most assessments performed at the Screening Visit, and 
response assessments (see Section 9.1.5 for the EOS Visit in the Dose Escalation part and 
Section 9.2.5 for the EOS Visit in the Cohort Expansion part). 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, as well as any new anti-cancer 
treatment, if applicable, in the Cohort Expansion part.  
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 


 
 
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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. 
8.3.4.5 Replacement of Patients 
Patients who discontinue the study during the first cycle (21 days) of the Dose Escalation 
part for reasons other than a DLT should be replaced. Patients in the Cohort Expansion part 
who discontinue the study without receiving dose on first cycle for whatever reason should 
be replaced; patients who withdraw after the first dose of the first cycle in the Cohort 
Expansion will not be replaced. 
Patients who are withdrawn after the first cycle of the Dose Escalation part or during the 
Cohort Expansion part will not be replaced. However, sufficient number of patients will be 
included to ensure the minimum sample size defined (see Section 12.9). 
8.4 Treatment 
The Dose Escalation part is a FIH study and it must be run in phase I units with 
cardiopulmonary resuscitation rescue equipment available and fast access to Emergency 
units. The Cohort Expansion part is considered a phase II study and the sites do not need to 
be phase I units. Throughout the infusion patients will be under surveillance by study 
personnel. The physician supervising the study drug infusion must be readily accessible for 
assistance during the day of infusion. 
Tisotumab vedotin (HuMax-TF-ADC) is an antibody drug conjugate composed of an IgG1 
human monoclonal antibody (HuMax-TF) chemically conjugated via a protease cleavable vc 
linker to the drug MMAE. 
Tisotumab vedotin (HuMax-TF-ADC) is presented as a lyophilized cake for reconstitution in 
water for injection and is intended for dosing by the intravenous route by infusion after 
dilution in physiological saline solution. During the Dose Escalation part the drug product 
(Batch #3C001) will be used. 
8.4.1 Treatments Administered 
The final composition of the drug product after reconstitution is 10 mg/mL tisotumab vedotin 
(HuMax-TF-ADC) formulated in a mixture of histidine, sucrose, mannitol at pH 6.0. 
The investigator must ensure that the study drug will be used only in accordance with the 
protocol. 
Tisotumab vedotin (HuMax-TF-ADC) will be administered as an intravenous infusion on 
Day 1 of each cycle (one treatment cycle is 21 days). Each patient’s dose will be calculated 
based on the patient’s weight (measured at the particular dosing visit; see Section 10.3) 
rounded to the nearest kilogram, i.e., assigned cohort dose in mg/kg × body weight in kg. For 
patients whose body mass index (BMI) is greater than 30 kg/m2, the investigator should use a 
weight that, based on the patient’s height, corresponds to a maximum BMI of 30. 
The dose is calculated according to the following formula if BMI is greater than 30 kg/m2: 
Dose (mg) = x (mg/kg) * 30 (kg/m2)* height (m) * height (m) 


 
 
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Tisotumab vedotin (HuMax-TF-ADC) will be administered over a minimum of one hour in 
the Dose Escalation part and over a minimum of 30 minutes in the Cohort Expansion part. If 
infusion-related events emerge, refer to Section 8.4.4. The infusion is complete when the 
infusion line has been flushed with minimum 15 mL saline. Preventive eye therapy should be 
administered in relation to infusions as detailed in Section 8.4.8. 
8.4.2 Study 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 EU Guidelines to Good Manufacturing Practice, 
Annex 13, Investigational Medicinal Products, and any other applicable local regulatory 
requirements. 
8.4.3 Study 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 Study Treatment Storage 
Tisotumab vedotin (HuMax-TF-ADC) will be stored at 2-8°C in a secure area with restricted 
access. 
8.4.3.2 Study Treatment Accountability 
The study drug must exclusively be used for the investigation specified in this protocol and it 
will only be accessible to authorized staff. The investigator or designee must confirm and 
document the receipt of the study drug. 
Vials must be kept at the pharmacy. Throughout the study, 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 
Infusion-related reactions have been observed with other MMAE-ADCs. One IRR including 
skin rash and swelling of eyes and lips was observed during non-clinical studies in a female 
monkey following a second dose of tisotumab vedotin (HuMax-TF-ADC) 3 mg/kg. No IRRs 
were observed in this animal following the third or fourth dose administration of IMP. 
Infusion-related reactions have been observed in patients treated with tisotumab vedotin 
(HuMax-TF-ADC), but the majority of the reactions have been mild to moderate (data 
cut-off date 16 Aug 2017). Please refer to the Investigator’s Brochure for more information.  
• Patients should be monitored during infusion.  
• If an infusion-related reaction occurs, the infusion should be interrupted and appropriate 
medical management instituted. The infusions may be restarted at the investigator’s 
discretion. 
• Patients who have experienced prior infusion-related CTCAE grade ≥ 3 reactions in the 
study should be pre-medicated before all subsequent infusions with antihistamine and/or 
acetaminophen and/or corticosteroid at the investigator’s discretion.  
• If anaphylaxis occurs, administration of study drug should be discontinued immediately 
and permanently and appropriate medical therapy should be administered. 
8.4.5 Dose Modification and Mitigation Plan for Skin Toxicity 
• Ongoing, acute or chronic inflammatory skin disease is an exclusion criterion in this 
study (see Section 8.3.2). 
• Frequent assessments of skin should be performed during Cycles 1 and 2 of the Dose 
Escalation part: 
o At Days 1, 2, 4, 8, 11, and 15 of each three-week cycle. 
• Assessment of skin during the remaining cycles of the Dose Escalation part will be 
performed on Day 1 in each cycle before dosing. 
• During the Cohort Expansion part, assessments of skin should be performed during 
Cycles 1 and 2: 
o At Days 1 and 15 of each three-week cycle. 
• Assessment of skin during the remaining cycles of the Cohort Expansion part will be 
performed on Day 1 in each cycle before dosing. 
• Patients’ information to include information about potential skin toxicity and, for the 
Dose Escalation part, advise the patients to contact the investigator and/or the site 
dermatologist in case of skin rash, pruritus or bullae. For the Cohort Expansion part, due 
to benign skin toxicity profile observed in the Dose Escalation part, the visit to 
dermatologist is optional. 
• Investigators will be trained in skin monitoring and action to findings. 
• Dose adjustment for skin toxicity should be managed as follows: 


 
 
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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 as planned. Treat the skin rash with a potent topical 
steroid (betamethasone valerate or equivalent) once daily for up to one week; facial 
areas with a moderate topical steroid (Hydrocortisone butyrate 0.1% or equivalent) 
twice daily, followed by dosing once every other day for a maximum of three 
weeks. 
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. 
8.4.6 Mitigation Plan for Mucositis 
From implementation of Protocol Amendment 6: 
• Patients with CTCAE grade 3 mucositis: hold dose until mucositis improves to grade 2 
and treat according to local practice. 
• Withdrawal criteria for mucositis: 
o Patients with CTCAE grade ≥ 4 mucositis: the patient should be withdrawn from 
treatment. 
8.4.7 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 grade ≤ 1, and then restart at 2/3 of the initial dose until end of study 
treatment.  


 
 
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• 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 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 study drug to 2/3 of the initial dose until end of 
study treatment may be considered after discussion with the Genmab Medical Officer. 
8.4.8 Dose Modification 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. 
Preventive measures for all patients: 
• Use of preservative-free lubricating eye drops from the start of study 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. 


 
 
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• 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 the same dose as 
administered prior to the event onset.  
o In case of recurrence of CTCAE grade 2 conjunctivitis, 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 can be resumed at a reduced dose (please refer to dose modification 
scheme below).  
 In case of a third occurrence of CTCAE grade 2 conjunctivitis, 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 can be resumed at a further 
reduced dose (please refer to dose modification scheme below). 
• In case of ≥ fourth occurrence of CTCAE grade 2 conjunctivitis, 
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). 


 
 
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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 third 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. 
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 


 
 
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Ocular symptom  
Treatment guideline  
(The length of treatment should be decided by the local 
ophthalmologist) 
Keratitis: CTCAE grade 2 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative-free 
antibiotic prophylaxis such as chloramphenicol 
Conjunctival ulceration: 
any grade 
The local ophthalmologist should prescribe frequent 
dosing (every 2nd hour) of preservative-free topical 
steroid drops in conjunction with preservative-free 
antibiotic prophylaxis such as chloramphenicol 
 
Dose modification scheme: 
Previous dose of tisotumab vedotin 
Reduced dose of tisotumab vedotin 
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 following discussion with 
the Genmab Medical Officer  
8.4.9 Dose Modification for QTcF Changes in the Electrocardiogram 
Prolongation of QTcF interval during the study 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. 


 
 
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• 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 
substitute until normal levels; ECGs should be performed at least daily; consider to 
obtain cardiology consult. 
8.4.10 Dose Modification for Increased Liver Enzymes  
From implementation of Protocol Amendment 6, in case of CTCAE grade ≥ 3 liver enzymes 
increase is not resolved (decreased to grade 2 or lower) at time of dosing, the site must 
contact Genmab Medical Officer before the next dosing of the patient, in order to decide 
whether there should be any dose adjustment, delay or withdrawal of the patient. 
8.4.11 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 8.4.15.3) like boceprevir, clarithromycin, 
conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole, amiodarone, clarithromycin, verapamil1. 
8.4.12 Dose Escalation 
8.4.12.1 Dose Escalation Overview 
The Dose Escalation part is a standard 3 (+3) design which will evaluate tisotumab vedotin 
(HuMax-TF-ADC) at doses of 0.30 mg/kg and up (0.3, 0.6, 0.9, 1.2, 1.5, 1.8, 2.2 and 
2.6 mg/kg). The maximum tested dose will be 2.6 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 (21 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 three weeks after the first infusion before data are sent to the DMC to review. 
                                                 
1                         http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteract
ionsLabeling/ucm093664.htm 


 
 
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Based on the results presented in these safety profiles, the DMC will recommend whether it 
appears safe to escalate the dose. 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 evaluate at the DMC meetings cumulative data 
obtained during the additional three cycles per cohort.  
Patients who discontinue the study during the first cycle for reasons other than a DLT should 
be replaced. 
For this study, the MTD will be defined as the dose level below the dose at which ≥ 2 DLTs 
within the 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.   
The DMC and the sponsor’s Safety committee will, based on the Dose Escalation part, 
determine the dose level to be used in the Cohort Expansion part including approximately 
169 patients.  
8.4.12.2 Dose-escalation Rules 
Each cohort will start with three patients. If an unacceptable toxicity is observed during the 
first treatment cycle, the cohort for the current dose level will be expanded to include 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 ten days between administration of first dose in patient 1 
and patient 2, and minimum of one day between the subsequent patients will be 
implemented. 
• All patients in a cohort must be observed for at least three 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 DLTs are identified the study will continue escalation to next dose level.   
• If one additional DLT (i.e. ≥ 2 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 study, dose cohorts 
will be partially stratified as follows: 


 
 
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Table 5: 
Number of Different Cancer Types Represented in Each Dose Cohort, 
Depending on Cohort Size (Dose Escalation Part) 
No. of patients in cohort 
Number of different cancer types represented in the cohort 
3 
≥ 2  
6 
≥ 3* 
*Depending on the nature of the safety signal observed, 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. 
8.4.13 Dose Limiting Toxicities for the Dose Escalation Part of the Study 
For the purpose of dose-escalation, DLTs will be collected and assessed for the first cycle 
(21 days) of each cohort. DLTs must be reported to the sponsor within 24 hours. Causality 
for DLTs will be assessed by the sponsor in collaboration with the DMC. 
DLTs include the following AEs at least possibly related to tisotumab vedotin 
(HuMax-TF-ADC): 
• Grade 4 neutropenia (i.e., ANC < 0.5 ×109 cells/L) for minimal duration of seven days.  
• Grade 3 and 4 febrile neutropenia (i.e., ANC < 1.0 ×109 cells/L with a single temperature 
of > 38.3°C or a sustained temperature of ≥ 38°C for more than one hour). 
• Grade 4 thrombocytopenia (≤ 25.0 ×109 platelets/L). 
• Grade 3 thrombocytopenia associated with bleeding episodes. 
• Major bleeding (as defined in Section 10.11). 
• Stevens Johnson syndrome, TEN, grade ≥ 3 cutaneous vasculitis. 
• Grade 3 neuropathy (not improving to grade 1 within 3 weeks following stop of dosing) 
and grade 4 neuropathy. 
• Grade 3 infusion-related AEs that do not resolve to grade 1 or baseline within 24 hours. 
• Grade 4 infusion-related events including anaphylaxis. 
• Any grade ≥ 3 non-hematological AEs which occur during the first treatment cycle and 
are at least possibly study drug related, excluding non-hematological laboratory 
abnormalities that have no clinical consequences and resolve within 48 hours. 
• Grade ≥ 3 diarrhea and/or vomiting persisting for more than 48 hours with optimal 
medical management. 
• Grade ≥ 3 nausea (not disease-related) lasting 3 days or more with optimal medical 
management.  
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 
each DMC meeting, an internal Safety committee meeting will be held comprising Heads of 


 
 
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Drug Safety, Regulatory, Clinical Development and Medical to discuss and confirm actions 
recommended by the DMC. 
From implementation of Protocol Amendment 6, depending on the nature of the DLT and 
patient status, the DMC and sponsor’s Safety committee in agreement with the investigator 
may allow a patient with a DLT to continue on the study on a reduced dose. 
8.4.14 Data Evaluation for the Cohort Expansion Part 
During the Cohort Expansion part, a pre-planned safety evaluation is scheduled after the first 
ten patients (across indications) are followed for at least one cycle. Based on cumulative 
overall safety data, including all reported AEs, SAEs, withdrawals and laboratory data, the 
DMC can propose and the sponsor’s Safety committee can endorse the following actions: 
• whether the protocol should continue unchanged,  
• whether the protocol should be modified,  
• whether the dose be reduced,  
• whether dosing and study entry should be held for already included patients,  
• whether additional patients should be included, or  
• whether the study should be discontinued permanently.  
Also, based on this safety evaluation, opening of the remaining three indications (SCCHN, 
NSCLC and esophageal cancer) can be determined. A second safety evaluation is 
pre-planned when 30 patients have been dosed and followed for at least one cycle.  
In the cervical and endometrial cancer indications, efficacy will be evaluated at an interim 
analysis after enrolling 14 of the pre-planned 30 patients in each of these indications. After a 
minimum of 6 weeks of therapy, if no responder is observed among the first 14 enrolled 
patients, then pending DMC recommendation and approval by the sponsor’s Safety 
committee, no further patients are to be enrolled in the relevant indication. 
Where applicable, regulatory authorities IECs/IRBs will be notified of any actions taken with 
the study.  
8.4.15 Prior and Concomitant Therapy 
8.4.15.1 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. 


 
 
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8.4.15.2 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 8.4.15.3). Administration of concomitant medications must be reported in the 
appropriate section of the eCRF along with dates of administration and reasons for use.   
8.4.15.3 Excluded Concomitant Medications 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
The following medications are considered exclusionary during the study. The sponsor must 
be notified if a patient receives any of these during the study. 
• Any investigational anti-cancer therapy. 
• 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 study period. 
8.4.15.4 Treatment Compliance 
Tisotumab vedotin (HuMax-TF-ADC) will be administered by study site personnel, who will 
monitor patient compliance. 
8.4.15.5 Assignment to Treatment 
This is an open-label study. Study 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 study number and subsequently a three- or four-digit number that uniquely identifies a 
patient at a screening visit. For example, a screening number in this study could be 
“S701034”. 
Subjects who have complied with all selection criteria will receive a patient number upon 
enrolment in the study. A patient number consists of the study number combined with a 
three-or four-digit number that uniquely identifies a patient during the study. For example, 
patient 12 in this study would be uniquely identified by the combined code “701012”. 
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 study eligibility 
criteria) including the reason for screening failure. 


 
 
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9. 
STUDY EVALUATIONS  
Study evaluations by visit are detailed in the Schedules of study procedures in Table 1 for the 
Dose Escalation part and in Table 2 for the Cohort Expansion part. A description of the 
methods of assessments is provided in Section 10. 
All patients who are assigned a patient number and receive any study 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 study-specific eCRF or 
logs designated for capturing protocol deviations, if applicable for the study. 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 study personnel to report any abnormalities during the 
intervals between study visits and to come to the study 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 study 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: 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: Treatment  
The investigator must have evaluated the patient’s eligibility and 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.  
Tisotumab vedotin (HuMax-TF-ADC) will be administered every 21 days, on Day 1 of each 
treatment cycle. Dose-escalation to MTD is anticipated to involve approximately eight dose 
levels with an anticipated maximal exposure of 2.6 mg/kg. 
The patients will receive four cycles (doses) of tisotumab vedotin (HuMax-TF-ADC) at 
three-week intervals. Thus, the treatment period will last for twelve weeks, or until disease 
progression.  


 
 
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For the first two infusions the patient must stay hospitalized the first 24 hours and be 
monitored including vital signs and general assessment for any reactions 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. 
For all subsequent infusions the patient should be closely monitored including vital signs and 
general assessment for at least 2 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 Cycles 1 and 2 
During Cycles 1 and 2 of the Dose Escalation part, six study visits will be performed on 
Days 1, 2, 4, 8, 11 and 15 of each cycle, with a visit window of ± 1 day (except for the visit 
on Day 2).  
On Cycles 1 and 2, the patient shall stay hospitalized the first 24 hours after the infusion and 
be discharged the following day after assessments and at the discretion of the investigator. 
9.1.2.2 Dose Escalation Cycles 3 and 4 
During Cycles 3 and 4 of the Dose Escalation part, three-weekly study visits will be 
performed on Days 1 (± 3 days), 8 (± 1 day), and 15 (± 1 day) of each cycle. 
After four cycles, if there is evidence of the patient benefitting from treatment, there is an 
option to continue in the study for up to a maximum of eight additional cycles (24 weeks) or 
until unacceptable toxicity according to protocol, at the discretion of the treating physician 
after agreement with Genmab on the patient status. 
9.1.2.3 Dose Escalation Cycles 5 to 12 
For patients who continue in the study for additional cycles in the Dose Escalation part, 
weekly study visits will be performed on Days 1 (± 3 days), 8 (± 1 day), and 15 (± 1 day) of 
each cycle (Cycles 5 to 12). In addition, a CT-scan will be performed 21 days (± 3 days) after 
Day 1 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 Follow-up Visits (FU1 to FU4) 
If the patient withdraws from treatment or completes all twelve cycles, he/she will continue 
follow-up visits every six weeks (± 7 days) until PD, other treatment is initiated or the patient 
withdraws from the study due to other reasons, for a maximum of 24 weeks. 
9.1.4 Dose Escalation 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. 


 
 
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During an unscheduled visit the investigator will assess AEs and record concomitant 
medication. Additional study assessments can be performed at the investigator’s discretion. 
To monitor patient safety the investigator may request additional blood samples. 
9.1.5 Dose Escalation End of Study Visit (EOS)  
If a patient withdraws from the study, the EOS Visit should be performed as soon as possible 
after withdrawal. If a patient completes all the follow-up visits, the EOS Visit should be 
performed four weeks after Follow-up Visit 4.  
9.1.6 Dose Escalation Safety Follow-up Visit (SFU) 
Patients who withdraw from the study before Follow-up Visit 1 will return for a Safety 
Follow-up Visit 30 days (+ 14 days) after the last IMP dosing. In the Safety Follow-up Visit, 
only SAEs will be assessed. 
9.2 Cohort Expansion Part 
9.2.1 Cohort Expansion: 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), unless otherwise specified (see 
Table 2). 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: Treatment  
The investigator must have evaluated the patient’s eligibility and signed the Screening 
Evaluation Form 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. 
In the Cohort Expansion part of the study approximately 169 patients will receive four cycles 
of tisotumab vedotin (HuMax-TF-ADC) once q3wk at the dose determined from the Dose 
Escalation part (2.0 mg/kg). Tisotumab vedotin (HuMax-TF-ADC) will be administered 
every 21 days, on Day 1 of each treatment cycle. Preventive eye therapy should be 
administered in relation to infusions as detailed in Section 8.4.8. 
Extended treatment until disease progression (with a maximum of twelve cycles) or 
unacceptable toxicity will be available according to protocol. As in the Dose Escalation part 
of the study, doses will be given at three-week intervals, and the treatment period will last for 
a maximum of 36 weeks. 
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 access to resuscitation equipment and other agents necessary to treat anaphylaxis 
(e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). 


 
 
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Patients requiring treatment for infusion-related reactions should be monitored until the 
resolution of the event. 
9.2.2.1 Cohort Expansion Cycles 1 to 4 
During Cycles 1 to 4 of the Cohort Expansion part, three-weekly study visits will be 
performed on Days 1, 8 and 15 of each cycle, with a visit window of ± 1 day. 
After four cycles, if there is evidence of the patient benefitting from treatment, extended 
treatment until disease progression (with a maximum of twelve cycles) or unacceptable 
toxicity will be available according to protocol, at the discretion of the treating physician. As 
in the Dose Escalation part of the study, doses will be given at three-week intervals, and the 
treatment period will last for a maximum of 36 weeks. 
9.2.2.2 Cohort Expansion Cycles 5 to 12 
For patients who continue in the study for additional cycles in the Cohort Expansion part, 
three-weekly study visits will be performed on Days 1 (± 3 days), 8 (± 1 day), and 
15 (± 1 day) of each cycle (Cycles 5 to 12). In addition, a CT-scan will be performed 21 days 
(± 3 days) after Day 1 of Cycle 8. 
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. 
9.2.3 Cohort Expansion Follow-up Visits (FU1 to FU4) 
If the patient withdraws from treatment or completes all twelve cycles, he/she will continue 
follow-up visits every six weeks (± 7 days) after last treatment cycle, until PD, other 
treatment is initiated or the patient withdraws from the study due to other reasons, for a 
maximum of 24 weeks. 
9.2.4 Cohort Expansion 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 study assessments can be performed at the investigator’s discretion. 
To monitor patient safety the investigator may request additional blood samples. 
An unscheduled visit may also be used to collect information about the optional tumor biopsy 
obtained three weeks after last dosing (optional) or to document a repeat CT-scan to confirm 
response. 
9.2.5 Cohort Expansion End of Study Visit (EOS)  
If a patient withdraws from the study, the EOS Visit should be performed as soon as possible 
after withdrawal. If a patient completes all the follow-up visits, the EOS Visit should be 
performed four weeks after Follow-up Visit 4. 


 
 
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9.2.6 Cohort Expansion Safety Follow-up Visit (SFU) 
Patients who withdraw from the study before Follow-up Visit 1 will return for a Safety 
Follow-up Visit 30 days (+ 14 days) after the last IMP dosing. In the Safety Follow-up Visit, 
only SAEs, as well as any new anti-cancer treatment, if applicable, will be assessed. 


 
 
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10. 
METHODS OF ASSESSMENT 
Study procedures will be performed on the study dates noted in Table 1 for the Dose 
Escalation part and in Table 2 for the Cohort Expansion part. A description of the different 
assessments is provided below.  
10.1 
Demographics 
Date of birth, 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. 
Non-serious AEs (signs, symptoms and diagnosis) occurring between Visit 0 (Screening) and 
C1-V1 should be recorded as Medical History. For patients with cervical cancer and 
SCCHN, the most recent PAP smear result will be reported. 
SAEs should be reported from signing informed consent both on the eCRF AE and on the 
SAE reporting form (as described in Section 11.3.7). 
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 EOS, and 
will be recorded in the eCRF rounded to nearest kilogram. If body weight is assessed three 
days or less before the day of the planned dosing, this value can be used and is the weight 
recorded in the eCRF. In the Cohort Expansion part, the allowed window for body weight 
assessment is seven days or less before the day of the planned dosing. 
10.4 
Physical Examination 
A general physical examination should include general appearance and the following body 
systems: 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 24 hours after end of infusion of the 
two first infusions (Dose Escalation part only) and until 2 hours after the remaining 
infusions, as indicated in Table 6 and Table 7 for the Dose Escalation and Cohort Expansion 
parts, respectively. 


 
 
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Table 6: 
Vital Signs During the Dose Escalation Part 
Cycle 1 and Cycle 2 Day 1 
Cycle 3 to Cycle 12 Day 1 
Pre-infusion (including weight) 
Pre-infusion (including weight) 
15 min after start of infusion (± 5 min) 
15 min after start of infusion (± 5 min) 
30 min after start of infusion (± 5 min) 
30 min after start of infusion (± 5 min) 
45 min after start of infusion (± 5 min) 
45 min after start of infusion (± 5 min) 
1 hour after start of infusion (± 5 min) 
1 hour after start of infusion (± 5 min) 
At the end of infusion (± 5 min)  
At the end of infusion (± 5 min) 
10 min after end of infusion (± 5 min) 
10 min after end of infusion (± 5 min) 
30 min after end of infusion (± 5 min) 
30 min after end of infusion (± 5 min) 
1 hour 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) 
6 hours after end of infusion (± 30 min) 
 
12 hours after end of infusion (± 1 hour) 
 
24 hours after end of infusion (± 1 hour) 
 
If infusion lasts for more than 1 hour, vital signs should be assessed every 15 minutes 
(± 5 minutes) for the remaining duration of infusion. 
Table 7: 
Vital Signs During the Cohort Expansion Part 
Cycle 1 and Cycle 2 Day 1 
Cycle 3 to Cycle 12 Day 1 
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 infusion lasts for more than 30 minutes, vital signs should be assessed every 30 minutes 
(± 5 minutes) for the remaining duration of infusion. 
10.6 
Electrocardiogram 
ECGs 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 2 minutes apart before 
each infusion of the study drug, 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 and in a supine position for at least 
10 minutes. Any irregularity observed or occurring during the ECGs (e.g., vomiting, cough) 
should either induce a repeat of the ECG or be annotated on the eCRF with the description 
and time of the occurrence. 


 
 
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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. In the Cohort Expansion part only, in patients with 
SCCHN, an additional CT-scan of neck will be performed during screening. 
Up to five target lesions (maximum two per organ) will be defined at screening and these 
must be followed throughout the study. Non-target lesions will also be assessed throughout 
the study. 
Scans will be repeated every six weeks (at the end of every 2nd cycle) during the study 
period. If reduction of target lesions ≥ 30% in size is observed a repeat CT-scan will be 
performed after four weeks to confirm the response. CT-scans can be performed up to seven 
days before Day 1 of the relevant cycle to ensure result to be available before subsequent 
dosing.  
For example, if a patient shows response at C3V1, a repeat CT-scan should be taken four 
weeks later (approximately at C4V2). The protocol next planned CT-scan would be C5V1 
(-1 week), i.e., the repeat CT-scan would be performed one week earlier than the next 
planned CT-scan. In this case, the C5V1 CT-scan can be omitted and the next CT-scan would 
be at C7V1. 
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.  
MRI can be performed instead of CT-scan if the patient is allergic to iodine contrast or at the 
discretion of the investigator, after approval of the sponsor.  
For the Dose Escalation part the reading of the surveys will be done by a radiologist. Sites 
should attempt to maintain the same radiologist throughout the study. 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. 
In the Cohort Expansion part the scans will be sent for central reading and archiving.  
10.8 
ECOG Performance Status 
The ECOG performance status scale will be used and will be assessed by the investigator at 
screening, on Day 1 of each cycle, and at the EOS Visit. 
10.9 
Adverse Events 
AEs will be assessed and reported at each visit. 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. eCRFs will be supplied to ensure 
fast collection of AEs. 


 
 
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Weekly Safety/Medical meetings will be held to evaluate all AEs and laboratory data and 
follow-up information obtained during the previous week. 
Further details on AEs monitoring and reporting are provided in Section 11. 
10.10 
Concomitant Medication 
Any medication or therapy other than the study 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 study termination. 
• Indication/reason for use. 
The total daily dose should be filled in whenever possible. 
Recording period for concomitant medication will start from Visit 0 (Screening) until the 
EOS Visit.  
Pre-infusion medication is entered on a separate eCRF page. 
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 CTCAE grading.  
10.12 
Skin Assessments 
Development of skin reactions will be monitored during the study and registered on a 
separate form. A dermatologist must be available for consulting at each site during the Dose 
Escalation part only.  
Rash should be reported and graded according to the NCI-CTCAE for macular-papular skin 
rash according to Table 8 below: 


 
 
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Table 8: 
Grading of Skin Rash 
SOC 
Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Skin and 
subcutaneous 
tissue 
disorders 
Rash 
maculo-
papular 
Macules/papules 
covering < 10% 
BSA with or 
without 
symptoms (e.g., 
pruritus, 
burning, 
tightness) 
Macules/papules 
covering 
10-30% BSA 
with or without 
symptoms (e.g., 
pruritus, 
burning, 
tightness); 
limiting 
instrumental 
activities of 
daily living 
Macules/papules 
covering > 30% 
BSA with or 
without 
associated 
symptoms; 
limiting 
self-care 
activities of 
daily living 
Life-
threatening 
Death 
BSA = Body Surface Area; SOC=System Organ Class 
In case of bulla/bullae, these should be measured and reported as AEs. 
Patients should be withdrawn if they experience a study 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 
twelve weeks during treatment, and upon clinical indication. If there is suspicion of 
progression, another bone scan will be performed twelve weeks later. The screening 
radionuclide bone scan can be performed four weeks prior to Visit C1-V1. 


 
 
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10.16 
Laboratory Assessments 
Blood sampling will be collected for assessment of laboratory parameters. In the Dose 
Escalation part, some laboratory samples will be tested at the site while others will be drawn 
and shipped for centralized testing. In the Cohort Expansion part, all laboratory samples 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. 
In case of discrepancy between central and local laboratory values, the central laboratory 
value will be used for study analysis purposes and the local laboratory value may be used for 
patient treatment decisions by the investigator (with the exception of evaluation of patient 
eligibility which must be supported by central laboratory data). In case of discrepancies 
leading to protocol deviations, this will be reported, reviewed and discussed with the sponsor 
medical team and documented. 
If a non-serious grade ≥ 3 laboratory abnormality occurs during Cycle 1 and is assessed as 
related or possibly related to the study 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 to confirm or reject the fulfillment of the DLT assessment as defined 
in Section 8.4.13 (Any grade ≥ 3 non-hematological AEs which occur during the first 
treatment cycle and are at least possibly study drug related, excluding non-hematological 
laboratory abnormalities that have no clinical consequences and resolve within 48 hours.)  
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, and a 
sample must be provided to the central laboratory for analysis. 
10.16.1 Hematology 
Hematology parameters will be analyzed at the site laboratory in the Dose Escalation part 
and shipped for centralized analysis in the Cohort Expansion part. 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. 


 
 
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10.16.2 Biochemistry  
Biochemistry parameters will be analyzed at the site laboratory in the Dose Escalation part 
and shipped for centralized analysis in the Cohort Expansion part. 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 
Coagulation factors will be analyzed at the site in the Dose Escalation part and shipped for 
centralized analysis in the Cohort Expansion part. 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, blood samples for PSA assessment will be drawn for local analysis 
in the Dose Escalation part and shipped for centralized analysis in the Cohort Expansion part.  
For patients with ovarian cancer, and also for patients with endometrial cancer in the Cohort 
Expansion part, blood samples for CA 125 assessment will be drawn for local analysis in the 
Dose Escalation part and shipped for centralized analysis in the Cohort Expansion part. 
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 going forward. 
10.16.6 Pregnancy Test 
A blood sample will be drawn at the Screening Visit, at C1-V1 and at the EOS Visit from all 
women of childbearing potential and will be analyzed at the site laboratory in the Dose 
Escalation part. A blood sample will be drawn at the Screening Visit; every second cycle, 
i.e., on Day 1 of Cycles 1, 3, 5, 7, 9, 11; at the Follow Up visits and at the EOS Visit from all 
women of childbearing potential and will be analyzed centrally in the Cohort Expansion part. 
Pregnant women may not take part in this study and will be considered as screening failures. 
In order to be considered as sterilized or infertile, a patient must have undergone surgical 
sterilization (vasectomy/bilateral tubectomy; hysterectomy and bilateral ovariectomy) or be 
postmenopausal (12 months or more with no period prior to enrolment).  
Safe hormonal contraceptives include contraceptive pills, implants, transdermal patches, 
hormonal vaginal devices or injections with prolonged release. 
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.  


 
 
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10.16.8 Hepatitis B, C, HPV and Cytomegalovirus Serology 
Serology parameters will be analyzed at the site in the Dose Escalation part and centrally in 
the Cohort Expansion part. 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 SCCHN (Cohort Expansion part only) and 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 
study drug administration (at the EOS Visit).  
10.17 
PK Assessments 
Blood samples for assessment of tisotumab vedotin (HuMax-TF-ADC) and MMAE will be 
drawn for central analysis in accordance to the timing provided in Table 3 (Section 8.1.3). 
Two assays will be used for HuMax-TF-ADC, one detecting HuMax-TF-ADC only and one 
detecting HuMax-TF-ADC and non-conjugated Humax-TF. 
10.18 
Tumor Biopsy 
A paraffin-embedded tumor tissue or cytology sample will be obtained at screening. This 
biopsy should be performed at least two weeks prior to dosing to ensure healing of wound.  
In the Dose Escalation part an archived sample may be used as screening sample. The most 
recent available archived sample should be used.  
In the Cohort Expansion part, tumor biopsies will be collected at screening from each patient. 
The most recent available archived sample can be used. If no biopsies are available, a new 
biopsy must be obtained before dosing. In addition, an optional tumor biopsy may be 
obtained three weeks (+ 2 weeks) after last dosing.  
All biopsies will be analyzed retrospectively in a centralized CAP/CLIA (College of 
American Pathologists/Clinical Laboratory Improvement Act) certified laboratory. The 
IHC-assay to measure TF expression is developed on an automated staining platform and has 
been analytically validated for reproducibility, specificity, accuracy, range, linearity, and 
robustness in all eight indications evaluated in GEN701. Tumor sections will be scored for 
TF expression by a certified pathologist. 
In addition, digital images of the stained sections will be analyzed using digital pathology 
software. The results will be used to correlate TF expression and clinical responses to 
efficacy observed in in vivo tumor models in rodents or tumor cell lines in vitro. 


 
 
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10.19 
Exploratory Biomarkers 
Plasma samples will be drawn and stored at the central laboratory for later analysis of 
exploratory biomarkers. The exploratory biomarkers may be tested at a non-certified 
laboratory if a certified laboratory is not available for performing the analysis. In this case, 
best efforts to ensure that the research laboratory follows the principles of GCP will be set in 
place. 
The exploratory biomarker analyses are dependent upon the availability of appropriate 
biomarker assays and may be deferred or not performed if, during or at the end of the study, 
it becomes clear that the analysis will have no scientific value, or if there are not enough 
samples or not enough responders to allow for adequate biomarker evaluation. In the event 
the study is terminated early or shows poor clinical efficacy, completion of biomarker 
assessments is based on justification and intended utility of the data. Samples for biomarker 
evaluations will be collected as specified in the Study Flow Charts (Section 8.1.3). 
10.19.1 Circulating TF 
An analytically validated assay, based on detection of TF using TF-specific antibodies, is 
being developed to measure total levels of circulating TF in plasma. Plasma samples are 
collected at screening and at the first visit of Cycle 5 in the Dose Escalation part, and at 
screening and at Day 15 of Cycle 4 in the Cohort Expansion part, to monitor the modulation 
of circulating TF levels. If the analysis method has not been qualified at the end of the study, 
all patient samples will be destroyed. 
10.19.2 Protein Biomarkers 
An array of 1129 proteins is measured using the SOMAscan technology™ 
 
, US) and/or another existing platform for protein analyses. An analytical assay is 
available to measure all 1129 different protein levels in one plasma sample. Plasma samples 
are collected at screening and at the first visit of Cycle 5 in the Dose Escalation part, and at 
screening and at Day 15 of Cycle 4 in the Cohort Expansion part, to monitor the modulation 
of proteins of interest during the course of treatment. 
10.19.3 Circulating cfDNA 
Total cfDNA levels will be determined by quantifying so-called housekeeping genes, i.e., 
genes that are present in all human cells (tumor cells as well as healthy cells). The 
housekeeping genes to be included in this analysis are β-microglobulin, cyclophilin, 
GAPDH, β-actin, Alu-repeats, Ig-Kappa, Ig-Lambda, β-globin and T-cell receptor genes. 
This way, cfDNA analysis can be done in the same way for all patients in GEN701, 
irrespective of the specific type of cancer. Plasma samples are collected at screening and at 
shortly before dosing at Cycle 5 in the Dose Escalation part, and at screening and at Day 15 
of Cycle 4 in the Cohort Expansion part, to monitor the modulation of cfDNA during the 
course of treatment. If the analysis method has not been qualified at the end of the study, all 
patient samples will be destroyed. 


 
 
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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 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. 


 
 
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Elective surgery, overnight for convenience or other scheduled hospitalization periods that 
were planned before the patient was included in this study are not to be considered serious. 
However, the event must be reported on the AE page in the eCRF and commented upon. 
Medical and scientific judgment must be exercised in deciding whether an AE is believed to 
be “medically important”. Medical important events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. 
11.1.1 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 MedDRA (Medical Dictionary for Regulatory Activities) PT 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 study drug by the 
investigator (Section 11.3.3). 
11.1.2 Adverse Events of Special Interest 
Based on the currently available safety profile for tisotumab vedotin (Humax-TF-ADC), the 
below listed events are regarded as events of special interest: 
• Bleeding-related events 
• Neuropathy 
• Ocular events (conjunctivitis, ulceration, keratitis, symblepharon) 
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 EOS 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.  
SAEs should be reported from the time the patient signs the ICF and until EOS or the end of 
the Safety Follow-up period (i.e. 30 days after last IMP dose). If the patient has died within 
the 30 days Safety Follow-up period after last IMP dose, this should be entered as an AE in 
the eCRF and reported as an SAE. 


 
 
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All AEs that occur in patients during the AE reporting period must be reported, whether or 
not the event is treatment-related. 
11.2.1 Study Disease 
Signs and symptoms, which according to the investigator are expected and well known 
consequences of the cancer type, both in intensity and frequency, 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, all AEs with an outcome of death (including disease 
progression) should be reported as an AE (in the eCRF) and as an SAE (as described in 
Section 11.3.6.1), from the time patients sign the ICF until 30 days after the last IMP dosing. 
11.2.1.1 Pre-existing Conditions 
In this study, 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. 
11.2.2 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. 
11.3 
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, which occurred during the 
AE period. 
11.3.3 Relationship to Study Drug 
The investigator must assess whether or not the event is related to tisotumab vedotin 
(HuMax-TF-ADC). If 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. 
11.3.4 Time of Onset 
Time of onset for SAEs is the date of occurrence 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 of the SAE myocardial infarction is 01 April 2015. 


 
 
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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 
study are provided in the instructions that accompany the AE eCRFs. 
11.3.6 Events Requiring Immediate Reporting 
11.3.6.1 Serious Adverse Events, Non-serious Grade 3 Adverse Events and Non-serious 
Grade 2 Ocular Adverse Events 
SAEs and non-serious grade 3 AEs will be reported from the investigational site to the 
sponsor within 24 hours (see Sections 10.9 and 11.3.7). In addition, all non-serious grade 2 
ocular AEs must be reported from the investigational site to the sponsor within 24 hours (see 
Section 11.3.7).  
11.3.6.2 Overdose and Medication Errors 
An overdose is defined as a patient receiving a dose of the study 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 AE/non-serious grade 2 ocular AE it must be reported within 24 hours (see Section 
11.3.7). 
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 11.3.6.1 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. 
11.3.6.3 Pregnancy 
Any pregnancy that occurs during study participation must be reported and the patient will be 
withdrawn from treatment immediately. To ensure patient safety, each pregnancy must be 
reported to sponsor or designee within 24 hours of learning of its occurrence. The pregnancy 
must be followed-up to determine outcome (including premature termination) and status of 
mother and child. Pregnancy complications and elective terminations for medical reasons 




 
 
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The method of detecting, recording, evaluating and follow-up of AEs and SAEs plus 
procedures for completing and transmitting SAE reports to the sponsor or designee are 
provided in the study procedures manual. Procedures for post-study AEs/SAEs handling are 
provided in the study procedures manual. 
11.3.8 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 EU (EMA or local competent authorities) all unexpected SAEs assessed as related to study 
drug by either the investigator or the sponsor will also qualify for expedited reporting. In the 
US (FDA) the causality assessed by the sponsor will determine whether the case requires 
expedited reporting. 
The CRO will supply investigators with individual SUSAR reports in a form of 
CIOMS/MedWatch, and as biannual line listings, as required per country and local 
regulations. 
The investigator should be aware of local reporting regulations to the IEC/IRB. The Safety 
CRO will either supply the investigator with the reports which should be passed on to the 
IEC/IRB or report directly to the IEC/IRB depending on local regulations. 
11.4 
Follow-Up on Adverse Events 
All AEs should be followed until they are resolved or the patient's participation in the study 
ends, whichever comes first. Related non-serious grade ≥ 3 AEs and AEs meeting one of the 
serious criteria, and still ongoing after ended study 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. 
11.5 
Safety Communication Plan for Information to Site 
In order to secure full transparency regarding patient safety-related questions to sites 
participating in the study, frequent communication of observations at the different sites will 
be required. The communication set-up will include the following components: 


 
 
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• SAEs, non-serious grade 3 AEs and non-serious grade 2 ocular AEs will be reported 
from 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. 
• 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.  
11.6 
Review or Safety Boards 
A DMC will be established and have its first meeting before study 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 in the Dose Escalation 
part. 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 one infusion and be 
observed for 21 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 study 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 


 
 
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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.  
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. 
During the Cohort Expansion part, a pre-planned safety evaluation is scheduled after the first 
ten patients (across indications) are followed for at least one cycle. Based on cumulative 
overall safety data, including all reported AEs, SAEs, withdrawals and laboratory data, the 
DMC can propose and the sponsor’s Safety committee endorse whether the protocol should 
continue, be modified, the dose be reduced, whether dosing and study entry should be held 
for already included patients, whether additional patients should be included, or whether the 
study should be discontinued permanently. Also, based on this safety evaluation of the first 
ten patients, opening of remaining three indications (SCCHN, NSCLC and esophageal 
cancer) can be determined.  
A second safety evaluation is pre-planned when 30 patients have been dosed and followed 
for at least one cycle. 
Further details of the constitution and procedures of the DMC meetings will be included in 
the DMC Charter. 


 
 
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12. 
STATISTICAL ANALYSIS 
The statistical analysis of this study 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 study 
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, listing and 
figures shells will also be provided. 
12.2 
Analysis Populations 
The full analysis population will comprise all patients who have been exposed to study 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 and the Cohort Expansion 
parts. 
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 two-sided 95% confidence 
interval (CI) 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 two-sided 95% exact binomial CI. 
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 study when all planned study 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 CIs will be two-sided 95% CIs. 
In the Dose Escalation part, individual patient profiles including information on actual dose 
will also be presented. Also, 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 cancer type – as relevant (all dose cohorts accumulated). 


 
 
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In the Cohort Expansion part, summary statistics will be presented per cancer type and in 
total. 
12.4 
Statistical Analysis of Primary Endpoint 
Incidences of AEs, SAEs, infusion-related AEs, CTCAE grade ≥ 3 AEs, and AEs related to 
study drug during the study will be summarized (by system organ class and preferred term) 
and listed.  
Also, the number of patient days (total number of days in study) 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. Baseline visual acuity assessments in the Dose Escalation part 
and ophthalmological evaluation in the Cohort Expansion part 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 in 
listings. Special listings related to liver, kidney, heart and skin will be generated. 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). In addition, maximal 
reductions in tumor size (as per CT-scan) will be reported separately per dose in the Dose 
Escalation part and per patient/indication in the Cohort Expansion part. 


 
 
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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 
CR 
Disappearance of all target lesions. Any pathological lymph nodes 
must have reduction in short axis to < 10 mm. 
PR 
≥ 30% decrease in the sum of the LD of target lesions, taking as 
reference the baseline sum LD 
SD 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of 
LDs since the treatment started 
PD 
≥ 20% increase in the sum of the LDs of target lesions, taking as 
reference the smallest sum of the LDs recorded since the treatment 
started or the appearance of one 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 one or more non-target lesion(s) or/and maintenance 
of tumor marker level above the normal limits 
PD 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
CR=Complete Response; LD=Longest Diameter; PD= Progressive Disease; PR=Partial Response; 
SD=Stable Disease 
Response will be evaluated after four cycles (twelve 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 
 
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 bone scan compared with a prior 
scan for study entry. There are no validated criteria for response on radionuclide bone scan. 
For control/relieve/eliminate end points, 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 


 
 
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absence of clearly worsening soft-tissue (nodal and visceral) disease or disease-related 
symptoms. In case where visible lesions disappear, this too should be confirmed at the next 
scheduled assessment. 
For patients with ovarian 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 twice the 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 6 weeks (± 7 days) after first treatment. 
PR and CR: responders will be summarized and reported in two ways: 
• Confirmed: the initial response should be confirmed by a subsequent repeat CT-scan 
performed no less than four weeks (± 7 days) (Section 10.7).  
• All responders (i.e. confirmed and unconfirmed) will be reported. 
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 in the Dose 
Escalation part, as well as by study arm and total in the Cohort Expansion part. 
Also, the maximal response (maximal change in the sum of the LD in the target lesions) in 
target lesions at any time on study will be reported using waterfall plots. 
12.5.3.3 Progression-Free Survival 
PFS is defined as the number of days from Day 1 in Cycle 1 to first PD or death. Only deaths 
that occurred within 60 days of the last visit will be considered in the analysis. PFS will be 
derived for all patients and presented graphically as well as summarized using survival 
analysis methods.  
12.5.3.4 Duration of Response 
DoR 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 Disease Control After 6, 12, 24 and 36 Weeks  
Percent of patients without PD after 6, 12, 24 and 36 weeks will be summarized. 
12.5.3.6 Patients with Tumor Shrinkage  
Patients with tumor shrinkage (based on CT-scan evaluations) after four cycles and at end of 
treatment will be summarized in the Cohort Expansion part only. 
12.5.4 Changes in PSA and CA 125  
PSA and CA 125 will be presented graphically: individual patient plots over time and, in the 
Cohort Expansion part, also plots over time per patient indication (mean and median). 
12.5.5 Exploratory Endpoints 
Exploratory endpoints (TF expression based on biopsies, soluble TF, cfDNA and protein 
analyses) will be listed. 
12.5.6 Host Immune Response 
Titers of tisotumab vedotin (HuMax-TF-ADC) will be listed and positive/negative host 
immune response to HuMax-TF-ADC will be summarized (positive/negative). The 
association between positive/non-positive ADA and PK (pre-dose, Cmax), major safety 
signals (CTCAE grade ≥ 3) and efficacy information (change in tumor size by CT-scan) will 
be explored.  
12.5.7 Statistical Analysis of Pharmacokinetics Data 
Individual curves of plasma/serum concentration of 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-Clast and AUC0-∞), Cmax, Tmax, pre-dose 


 
 
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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, 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. 
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: 
• Cancer type 
• TF expression  
• ADA-positivity (only for Grade ≥ 3 AEs and tumor shrinkage endpoints) 
Other subgroup 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 study is 
completed. A final analysis will be performed when the entire study is completed. 
In addition, in the cervical and endometrial cancer indications, efficacy will be evaluated 
after enrolling 14 of the pre-planned 30 patients in each of these indications. After a 
minimum of 6 weeks of therapy, if no responder is observed among the first 14 enrolled 
patients, then pending DMC recommendation and approval by the sponsor’s Safety 
committee, no further patients are to be enrolled in the relevant indication. 
As part of preparations for subsequent studies, further exploratory analysis of subsets of data 
may be performed. 
12.9 
Sample Size Estimation 
Up to 217 patients are planned to be enrolled in the study. Taking into account an anticipated 
screen failure rate of 30%, it is planned that approximately 310 patients are screened for the 
study. 
A maximum of 48 patients are expected in the Dose Escalation part: three to six patients per 
dose level for eight dose levels. Three patients per dose level, with the possibility to expand 




 
 
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13. 
MONITORING PROCEDURES/QUALITY ASSURANCE 
The sponsor has ethical, legal, and scientific obligations to conduct this study in accordance 
with established research principles and ICH GCP guidelines. As such, in order to fulfill 
these obligations and to maintain current of study progress, the sponsor's monitors or 
representatives will visit the investigative sites during study conduct, in addition to 
maintaining telephone and written communication. On-site visits, telephone calls, and regular 
review of the eCRFs will be conducted in order to assess patient enrolment, compliance with 
protocol procedures, completeness and accuracy of data entered on the eCRFs, verification of 
eCRF data against original source documents, and occurrence of AEs. The investigator must 
provide the monitor, sponsor representative and auditors/Inspectors with full access to all 
source and study documents. 
13.1 
Data Collection 
As part of the responsibilities assumed by participating in the study, 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 study, 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), any AEs/SAEs and the date of ICF signature 
may also be collected. 
13.2 
Data Management 
Data management in this study will be performed by 
. 
The study 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 CRF after saving must be accompanied by a reason 
for the change. The investigator must review and approve, by means of an electronic 
signature, all data entered in the eCRF. 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 data entry instructions will be provided in 
the eCRF Completion Guidelines. 
Previous and concomitant medications will be coded using the latest available World Health 
Organization Drug Reference Dictionary. 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. 


 
 
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A Clinical Informatics Plan and Data Quality Plan will be prepared by 
. The process of 
data collection, validation and transmission is illustrated in Figure 3. 
Figure 3: 
 Process of Data Collection, Validation and Transmission 
 
13.3 
Study Monitoring 
Sponsor or sponsor assigned monitors will conduct regular site visits to the investigational 
facilities for the purpose of monitoring various aspects of the study. The investigator must 
agree to sponsor-authorized personnel having direct access to the clinical (or associated) files 
and clinical study supplies (dispensing and storage areas) for all study subjects considered for 
study entry for the purpose of verifying entries made in the eCRF, and assist with their 
activities, if requested. Adequate time and space for monitoring visits should be made 
available by the investigator. 
The site must complete the electronic eCRFs in a timely manner and on an ongoing basis to 
allow regular review by the study monitor. Further instruction will be provided in the eCRF 
Completion Guidelines. 
The monitor will discuss the conduct and progress of the study with the investigator and 
other site staff. The investigator must cooperate with the monitor to ensure that corrective 
action is taken to resolve any problems noted in the course of the monitoring, and that the 
preventive measures are put into place to prevent recurrence of issues. In cases where 
compliance is not achieved, shipment(s) of the study drug to the investigator will be 
discontinued and study participation by that investigator will be terminated. 


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


 
 
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14. 
STUDY MANAGEMENT AND MATERIALS 
14.1 
Data Collection 
All data entered in the eCRF should be documented at the site. During each study visit, a 
physician participating in the study 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 are found eligible for the study (as applicable) 
• The date of the visit and the corresponding day or visit in the study schedule (e.g., 
screening, Day 1, Day 21, 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 study drug-related. 
• Changes in concomitant medications or dosages. 
• A general reference to the procedures completed. 
• The signature or initials of all physicians making an entry in the medical record 
(progress notes). 
In addition, any contact with the patient via telephone or other means that provides 
significant clinical information will also be documented in the medical record (progress 
notes), as described above.  
Information from the medical records (progress notes) and other source documents will be 
promptly transcribed to the appropriate section of the eCRF. 
Changes to information in the medical record (progress notes), and other source documents 
will be initialed and dated on the day the change is made by the investigator or designee. If 
the reason for the change is not apparent, a brief explanation for the change will be written 
adjacent to the change. 
Details on data validation, data transfers, origin and destination on the data, access to the 
transferred data, timing of the transfer and any actions that may be triggered by real-time 
review of those data will be documented in the Data Management Plan. 
14.2 
Source Documents Maintenance 
Source documents contain the results of original observations and activities of a clinical 
investigation. Source documents include, but are not limited to, medical records (progress 
notes), clinical and office charts, laboratory notes, pharmacy dispensing records, recorded 
data from automated instruments, photographic negatives, microfilm or magnetic media, 
x-rays, computer printouts, subject files, and records kept at the pharmacy, at the laboratories 
and at medico-technical departments involved in the clinical study. There should only be one 
source defined at any time for any data element. 
All source documents from this study will be maintained by the investigator and made 
available for inspection by authorized persons. The original signed informed consent for each 


 
 
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patient shall be filed with records kept by the investigator and a copy shall be given to the 
patient. 
14.3 
Record Maintenance 
All data derived from the study will remain the property of Genmab A/S. 
Records must be retained in accordance with the current ICH Guidelines E6 (R2) on GCP. 
All essential study documents including records of patients, source documents, eCRFs and 
study drug inventory must be kept on file. 
US FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining to the 
conduct of this study 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 US 
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 study 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 study. 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 study 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 study documentation. Patients will retain this 
unique number throughout the study. 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 US FDA to review patients’ medical records as they relate to this study. 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. 


 
 
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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 study. 
 


 
 
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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 study 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 (R2) Guideline for GCP the investigator should not 
implement any deviation from, or changes of the protocol without agreement by the sponsor 
and documented approval from the IEC/IRB of a protocol amendment, except where 
necessary to eliminate an immediate hazard(s) to study subjects, or when the change(s) 
involves only logistical or administrative aspects of the study (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 study 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 study before participation continues. 
15.3 
Protocol Adherence and Deviations 
The protocol must be read thoroughly and the instructions must be followed. However, 
exceptions will be made in emergency situations when the protection, safety, and well-being 
of the patient requires immediate intervention based on the judgment of the investigator or a 
responsible, appropriately trained, and credentialed professional(s) designated by the 
investigator as a sub-investigator.  
In the event of a significant protocol deviation due to an emergency, accident, or error, the 
investigator or designee must contact the Medical Monitor at the earliest possible time by 


 
 
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telephone. This allows for an early joint decision to be made as to whether or not the patient 
should continue in the study. The investigator, the sponsor, and the Medical Monitor will 
document this decision. In addition, a potential serious breach must be reported to the 
competent authorities immediately. 
15.4 
Publication Policy 
The sponsor acknowledges the investigator’s right to publish the entire results of the study, 
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/urm_full.pdf, updated April 2010). 
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 study 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 study 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 study 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 study agreement prior to the start of the study, outlining overall 
sponsor and investigator responsibilities in relation to the study. 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 study insurance policy. 
Deviations from the study protocol - especially the prescription of a dose other than that 
scheduled in the study protocol, other modes of administration, other indications, and longer 
treatment periods - are not permitted and shall not be covered by the statutory patient 
insurance scheme. 


 
 
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15.7 
Discontinuation of the Study 
This study may be terminated by the sponsor. The study may also be terminated prematurely 
at any time when agreed to by both the investigators and the sponsor as being in the best 
interests of patients, and justified on either medical or ethical grounds. In terminating the 
study, Genmab A/S, 
 and the investigator will ensure that adequate consideration is 
given to the protection of the patients’ interests. 
15.8 
Study Center File Management 
The investigator is responsible for assuring that the Study Center File is maintained. The 
Study Center 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 photocopy of their 
respective license(s) where required by law; Original US FDA Form 1572 (for all 
studies conducted under US 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 study conduct; 
(9) 
Laboratory certification(s); 
(10) Patient management logs (screening log, etc.); 
(11) Monitoring log; 
(12) Study drug invoices; 
(13) Delegation log; 
(14) Source document location list. 


 
 
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16. 
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Younes A, Bartlett 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 
 
* 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 5:649-55, 1982. 
 
 
 


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


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


 
 
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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. 
 
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  
 


 
 
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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.  
 
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 


 
 
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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 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. 


 
 
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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 
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 


 
 
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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 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. 
 


 
 
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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: 
Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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Statistical Analysis Plan 
Sponsor: 
Genmab A/S 
Protocol No: 
GEN701 
Protocol Version No./ 
Date: 
Version 16.0 / 18 July 2018 
Title 
First-in-human, dose-escalating safety study 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  
CRF Version No./ Date 
5 May 2015 (Dose Escalation Part) 
20 Nov 2017 (Cohort Expansion Part) 
Project Id: 
GNMGEN70-GEN701 
SAP Version No./ Date: 
3.0 / 30 Jul 2019 
 
APPROVALS 
Sponsor 
Sponsor Name: 
Genmab 
Representative/ Title: 
 Associate Director Biostatistics 
Signature /Date: 
 
 
Project Manager/Title: 
 / Project Director 
Signature /Date: 
 
Biostatistician / Title: 
 / Associate Director Biostatistics 
Signature /Date: 
 
(NOTE: Electronic Signatures should only be used if all parties have the ability to eSign.) 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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TABLE OF CONTENTS 
Approvals .............................................................................................................................. 1 
Table of Contents .................................................................................................................. 2 
1. 
Introduction ................................................................................................................... 5 
1.1 
Changes from Protocol ..................................................................................................... 5 
2. 
Study Objectives ............................................................................................................. 5 
2.1 
Primary Study Objective ................................................................................................... 5 
2.2 
Secondary Study Objective .............................................................................................. 5 
3. 
Study Design .................................................................................................................. 5 
3.1 
Sample Size Considerations ............................................................................................. 6 
3.2 
Randomization ................................................................................................................. 7 
4. 
Study Variables and Covariates ....................................................................................... 7 
4.1 
Primary Variable ............................................................................................................... 7 
4.2 
Secondary Variables ......................................................................................................... 7 
4.3 
Exploratory Variables ....................................................................................................... 8 
5. 
Definitions ...................................................................................................................... 8 
5.1 
Baseline ............................................................................................................................ 8 
5.2 
Response .......................................................................................................................... 8 
5.3 
Best Overall Response ...................................................................................................... 9 
5.4 
Progression Free Survival ................................................................................................. 9 
5.5 
Duration of Response ..................................................................................................... 10 
5.6 
Treatment-emergent Adverse Events ............................................................................ 10 
5.7 
Duration of Adverse Events ............................................................................................ 10 
5.8 
Duration of Exposure ..................................................................................................... 11 
5.9 
Age .................................................................................................................................. 11 
5.10 Time Since Diagnosis ...................................................................................................... 11 
5.11 Study Day and Cycle ....................................................................................................... 11 
5.12 Height, Weight and Body Mass Index ............................................................................ 12 
6. 
Analysis Sets ................................................................................................................. 12 
6.1 
Full Analysis Set .............................................................................................................. 12 
6.2 
Pharmacokinetic Analysis Set ......................................................................................... 12 
7. 
Interim Analyses ........................................................................................................... 12 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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8. 
Data Review ................................................................................................................. 13 
8.1 
Data Handling and Transfer ........................................................................................... 13 
8.2 
Data Screening ............................................................................................................... 13 
9. 
Statistical Methods ....................................................................................................... 13 
9.1 
Subject Disposition ......................................................................................................... 14 
9.2 
Protocol Deviations and Violations ................................................................................ 14 
9.3 
Treatments ..................................................................................................................... 15 
9.3.1 
Extent of Study Drug Exposure ................................................................................. 15 
9.3.2 
Concomitant Medications ......................................................................................... 15 
9.4 
Demographic and Baseline Characteristics .................................................................... 15 
9.5 
Safety Analyses ............................................................................................................... 16 
9.5.1 
Adverse Events .......................................................................................................... 16 
9.5.2 
Laboratory Data ........................................................................................................ 19 
9.5.3 
Skin Disorders ........................................................................................................... 22 
9.5.4 
Bleeding Assessment ................................................................................................ 22 
9.5.5 
Peripheral Neuropathy ............................................................................................. 22 
9.5.6 
Ophthalmology ......................................................................................................... 22 
9.5.7 
Other Safety Assessments ........................................................................................ 23 
9.6 
Pharmacokinetic Analyses .............................................................................................. 24 
9.6.1 
Pharmacokinetic Concentrations .............................................................................. 24 
9.6.2 
Pharmacokinetic Parameters .................................................................................... 27 
9.6.3 
Statistical Analysis of Pharmacokinetic Data ............................................................ 29 
9.7 
Immunogenicity ............................................................................................................. 29 
9.8 
Efficacy Analysis ............................................................................................................. 30 
9.8.1 
Response ................................................................................................................... 30 
9.8.2 
Progression Free Survival .......................................................................................... 30 
9.8.3 
Duration of Response ............................................................................................... 31 
9.8.4 
Tumor Shrinkage ....................................................................................................... 31 
9.8.5 
PSA and CA 125 ......................................................................................................... 31 
10. Validation ..................................................................................................................... 31 
11. References ................................................................................................................... 31 
Appendix 1 
Glossary of Abbreviations ............................................................................ 33 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Appendix 2 
List of In-Text Tables, Figures, and Listings ................................................... 35 
Appendix 3 
List of Post-Text Tables, Figures, Listings, and Supportive SAS Output 
Appendices 
36 
Appendix 4 
Shells for In-Text Tables, Figures, and Listings .............................................. 61 
Appendix 5 
Shells for Post-Text Tables, Figures, and Listings ........................................... 62 
LIST OF TABLES 
Table 1: Rules for Progression and Censoring .............................................................................................. 9 
Table 2: List of AEs of Special Interest ...................................................................................................... 17 
Table 3: 
PK Sampling in the Dose Escalation Part ............................................................................... 25 
Table 4: 
PK Sampling in the Cohort Expansion Part ............................................................................ 26 
 
 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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1. INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analyses of data collected under Genmab Protocol GEN701. This SAP will cover 
the analysis of both the Dose Escalation and Cohort Expansion parts of the study. 
This SAP should be read in conjunction with the study protocol and electronic case report form 
(eCRF). This version of the plan has been developed using the protocol Version 16.0 dated 18 
July 2018 and eCRFs dated 5 May 2015 (Dose Escalation part) and 20 Nov 2017 (Cohort 
Expansion part). Any further changes to the protocol or eCRF may necessitate updates to the 
SAP. 
The SAP will be approved prior to programming commencing, and any updated versions of the 
SAP will be approved prior to database lock. 
1.1 
CHANGES FROM PROTOCOL 
There are no planned changes in analysis from those specified in the protocol. 
2. STUDY OBJECTIVES 
2.1 
PRIMARY STUDY OBJECTIVE 
• To establish the tolerability of tisotumab vedotin (HuMax-TF-ADC) in a mixed population 
of patients with specified solid tumors. 
2.2 
SECONDARY STUDY OBJECTIVE 
• To establish the long term tolerability of tisotumab vedotin (HuMax-TF-ADC) in a mixed 
population of patients with specified solid tumors. 
• To determine the maximum tolerated dose and the recommended dose for phase II studies 
with tisotumab vedotin (HuMax-TF-ADC). 
• To establish the PK profile of tisotumab vedotin (HuMax-TF-ADC) after single and multiple 
infusions. 
• To evaluate the anti-tumor activity of tisotumab vedotin (HuMax-TF-ADC) in a mixed 
population of patients with specified solid tumors. 
3. STUDY DESIGN 
This is a dose-escalating, open-label, multicenter phase I/II safety study of tisotumab vedotin 
(HuMax-TF-ADC) dosed once every 3 weeks in a mixed population of patients with solid 
tumors known to express tissue factor and where the use of systemically administered tubulin 
inhibitors is part of standard of care. The study consists of two parts: a Dose Escalation part and 
Cohort Expansion part. The Dose Escalation part is considered first in human, and the Cohort 
Expansion part a phase II. 
The Dose Escalation part is a standard 3 (+3) design which will evaluate tisotumab vedotin 
(HuMax-TF-ADC) at doses of 0.30 mg/kg and up (0.3, 0.6, 0.9, 1.2, 1.5, 1.8, 2.2 and 2.6 mg/kg). 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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In the absence of unacceptable first cycle toxicities, doses are escalated in the subsequent 
cohorts, as deemed appropriate by the Data Monitoring Committee (DMC) and confirmed by 
sponsor. If unacceptable first cycle toxicities are observed, cohorts will be expanded from three 
to six patients. During the course of the study, the 2.6 mg/kg dose was not used, and an 
additional cohort with dose of 2.0 mg/kg was used following the 2.2 mg/kg dose cohort. 
Patients will be treated for four cycles or until unacceptable toxicity is observed. Patients 
showing clinical benefit, defined as stable disease (SD) or better, can receive up to a maximum 
of eight additional treatment cycles (for a maximum of twelve cycles in total, corresponding to 
36 weeks). 
In the Cohort Expansion part, recruitment will be initiated in five arms encompassing ovary, 
cervix, endometrium, bladder, and prostate (CRPC). Based on a safety review of data from the 
first ten patients recruited and followed for at least one cycle (regardless of indication), if the 
safety profile is deemed safe, the DMC and the sponsor’s Safety committee will approve the 
recruitment of the three remaining arms, esophagus, NSCLC and SCCHN. A minimum of 14 and 
maximum of 30 patients will be recruited each to the cervix and endometrial indications. In the 
remaining indications (ovary, bladder, CRPC, NSCLC, esophagus and SCCHN), 14 patients will 
be recruited. 
Cervical and endometrial indications will be expanded from 14 to 30 patients if, and only if, a 
responder is observed (evaluated after last patient has had four cycles) or, in case of no 
responders, the DMC evaluates whether it is nevertheless meaningful to expand. If one of these 
two indications does not appear promising while there is another indication that shows promising 
efficacy, it may be decided to expand the other indication instead, up to 30 patients. After 
implementation of Protocol Amendment 13 (Protocol version 14.0), up to 25 additional patients 
will be recruited to the cervix indication, for a maximum of approximately 55 patients. 
Patients will be treated for four cycles with the dose determined from the Dose Escalation part of 
the study by the DMC and the sponsor’s Safety committee. Patients showing clinical benefit, 
defined as SD or better, can receive up to a maximum of eight additional treatment cycles (for a 
maximum of twelve cycles in total, corresponding to 36 weeks). 
3.1 
SAMPLE SIZE CONSIDERATIONS 
Up to 217 patients are planned to be enrolled in the study. Taking into account an anticipated 
screen failure rate of 30%, it is planned that approximately 310 patients are screened for the 
study. 
A maximum of 48 patients are expected in the Dose Escalation part: three to six patients per dose 
level for eight dose levels. Three patients per dose level, with the possibility to expand to 
six patients, are considered sufficient to establish the safety basis for escalation to the next dose 
level. 
It is estimated that approximately 169 patients will be enrolled in the Cohort Expansion part (if 
the ovarian indication continues on to 30 patients and the cervical indication continues on to 
approximately 55 patients). The information obtained from this number of patients in the Cohort 
Expansion part is considered enough to provide sufficient basis for the planning and design of 
further studies. 




Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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• Anti-tumor activity measured by tumor shrinkage (based on computerized tomography 
[CT]-scan evaluations), change in PSA and CA 125.  
• Objective Response (Complete Response [CR] or Partial Response [PR]), Disease Control 
(CR, PR or SD) after 6, 12, 24 and 36 weeks, Progression-Free Survival (PFS) and Duration 
of Response. 
4.3 
EXPLORATORY VARIABLES 
• TF expression in tumor biopsies. 
• Circulating TF. 
• Protein biomarker 
• Circulating cell-free deoxyribonucleic acid (cfDNA) 
5. DEFINITIONS 
5.1 
BASELINE 
Unless otherwise stated, Baseline is the last available measurement or assessment prior to first 
administration of study drug.  Assessments on Day 1 of Cycle 1 will be assumed to have been 
made prior to administration of study drug unless the time indicates that it was after. 
5.2 
RESPONSE 
Response will be assessed from the results of CT-scans at the Screening Visit, and at the end of 
every second cycle, and any additional CT-scans performed in order to confirm response. 
Response will be categorized as Complete Response (CR), Partial Response (PR), Stable Disease 
(SD) or Progressive Disease (PD) according to the RECIST criteria version 1.1. Patients who 
died or whose response is not evaluable will be classified as PD. Patients with PR or CR will be 
classed as responders. No formal confirmation of 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. For SD, follow-up measurements must have met the SD 
criteria at least once and not less than six weeks (± 7 days) after first treatment. 
For patients with CRPC, response will be assessed additionally by bone scans which will be done 
every twelve weeks, and PD is defined as at least 2 new lesions on the bone scan compared to 
Screening. PD at the first scheduled assessment should be confirmed on a second scan six or 
more weeks later. Bone scan results will be taken into consideration when assessing whether a 
patient has PD. 
In addition, in the Cohort Expansion parts, response will be assessed by a review committee as 
well as by the investigator. 
Additionally, CA 125 is assessed for patients with ovarian cancer and for patients with 
endometrial cancer in the Cohort Expansion part. 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 




Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Treatment discontinuation for undocumented progression 
Date of last visit with adequate 
assessments 
Censored 
Treatment discontinuation for toxicity or other reason 
Date of last visit with adequate 
assessments 
Censored 
New anti-cancer treatment started 
Date of last visit with adequate 
assessments 
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessments visits 
Date of death 
Progressed 
Death or progression more than 90 days after the previous visit 
with adequate assessments 
Date of previous visit with adequate 
assessments 
Censored 
 
In the Cohort Expansion part of the study only, disease progression will also be evaluated by an 
independent review committee. Further details regarding response and progression assessments 
will be provided in a separate response evaluation charter. The group performing the response 
evaluation will follow this charter.  
5.5 
DURATION OF RESPONSE 
Duration of response is defined as the time in weeks from when confirmed response was first 
documented until the first documented PD, or death from any cause, whichever is earliest. The 
date used for the date of confirmed response will be the date of assessment for the first 
assessment where CR or PR was observed and then confirmed at the next assessment. Patients 
who do not have confirmed response will not have a value for duration of response, and will not 
be included in the analysis of this variable. Patients with confirmed response who do not 
subsequently have either disease progression or death from any cause will be censored at the date 
of the last visit with adequate assessment as defined in Section 5.4 above. For the date to use as 
event date and censoring date for the end of response, the same rules apply as those for 
progression free survival given in Section 5.4 above. . 
5.6 
 TREATMENT-EMERGENT ADVERSE EVENTS 
Treatment-emergent AEs are defined as those which first occur or increase in severity or 
relationship to study drug after the first dose of study drug. 
For the purposes of determining whether an AE is treatment-emergent or not, and which Cycle it 
occurs in, any partial or missing dates will be handled as follows. If the date is completely 
missing, then the AE will be regarded as starting on the date of first study medication. If the year 
is present, but the month and day are missing, then if the year is before or after the year of first 
study medication then the day and month will be set to 01Jan, and if it is the same as the year of 
first study medication then the date will be set to the same as the date of first study medication. If 
the year and month are present, but the day is missing, then if the month and year are the same as 
the month and year of the start date of study medication then the date will be set to the same as 
the start date of study medication, and otherwise the day will be set to 01. 
5.7 
DURATION OF ADVERSE EVENTS 
For the AEs where duration is calculated, it will be calculated as the sum of the duration of 
individual AEs of that type. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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The duration of an individual AE is defined as: (End Date of AE – Start Date of AE)+1. When 
calculating the sum of the duration of individual AEs, if more than one AE of the same type 
overlap, then the same day will not be counted twice. 
If the AE is ongoing, then the stop date will be taken as the date of last visit, and in the case of 
incomplete stop dates the following rules will be applied. If the year is present, but the month 
and day are missing, and the year is the same as the year of the date of last visit, then the date 
will be set to the date of last visit, otherwise the day and month will be set to 31Dec. If the year 
and month are present, but the day is missing, then if the month and year are the same as the 
month and year of the date of last visit, then the date will be set to the date of last visit, otherwise 
the day will be set to the last day of the month. In the case of the interim analysis during the 
Cohort Expansion part, if the patient is ongoing in the study at the time of the data cut, then the 
stop date will be set to the date of the data cut. 
5.8 
DURATION OF EXPOSURE 
Duration of exposure is calculated as: 
(Date of last dose of study medication – date of first dose of study medication) + 1 
5.9 
AGE 
Age will be calculated in whole years from the date of birth and the date of signed informed 
consent. 
5.10 
TIME SINCE DIAGNOSIS 
The time since diagnosis in months will be calculated as: 
(Date of Screening Visit – Date of Diagnosis + 1)/30.4 
In case of partial dates for the date of diagnosis, missing days will be set to 01 and missing 
months to Jan. 
5.11 
STUDY DAY AND CYCLE 
Study day will be calculated in relation to the date of first administration of study medication 
(Day 1). For data on or after the date of the first dose of study medication, the study day is 
calculated as: 
(Date of event/assessment – Date of first dose of study medication) + 1 
For data before the day of first dose of study medication, the study day is calculated as: 
(Date of event/assessment – Date of first dose of study medication). 
When assigning events to cycles, a Cycle will be considered to start at the time of administration 
of study medication, and continue until the next time of administration of study medication. For 
the final cycle, this will be considered to end 30 days after the administration of study 
medication. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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5.12 
HEIGHT, WEIGHT AND BODY MASS INDEX 
Height may be recorded in inches or centimeters.  In the tables and listings height will be 
presented in centimeters, and where recorded in inches will be converted to centimeters using the 
following conversion factor: 
Height in cm = Height in inches x 2.54 
Weight may be recorded in pounds and will be converted to kilograms using the following 
conversion factor: 
Weight in kg = Weight in pounds x 0.4536 
Body Mass Index (BMI) will be calculated as: 
Weight (kg) / (Height (m)2) 
6. ANALYSIS SETS 
6.1 
FULL ANALYSIS SET 
The Full Analysis Set 1 (FAS1) is defined as all patients who have been exposed to study drug in 
the Dose Escalation part of the study.  This population will be used for all analyses of data from 
the Dose Escalation part of the study, with the exception of the PK analysis. 
The Full Analysis Set 2 (FAS2) is defined as all patients who have been exposed to study drug in 
the Cohort Expansion part of the study.  This population will be used for all analyses of data 
from the Cohort Expansion part of the study, with the exception of the PK analysis. 
6.2 
PHARMACOKINETIC ANALYSIS SET 
The PK Analysis Set 1 is defined as all patients who have been exposed to study drug and have 
at least one PK assessment after the first dose of study medication in the Dose Escalation part of 
the study. This population will be used for all analyses of PK data from the Dose Escalation part 
of the study. 
The PK Analysis Set 2 is defined as all patients who have been exposed to study drug and have 
at least one PK assessment after the first dose of study medication in the Cohort Expansion part 
of the study. This population will be used for all analyses of PK data from the Cohort Expansion 
part of the study. 
7. INTERIM ANALYSES 
The analysis of the Dose Escalation part of the study will be done when this part of the study is 
completed.   
The final analysis will be performed when all patients have completed the Cohort Expansion 
part. 
This analysis plan covers both analyses.  
During the Dose Escalation part a DMC will review the data from each cohort to determine 
whether the dose will be escalated, and to determine the dose to be used in the Cohort Expansion 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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part. An explanation of this process and the dose escalation rules are given in the protocol, and 
further details will be provided in the DMC charter.  
The DMC will also meet to review safety data during the Cohort Expansion part. During the 
Cohort Expansion part, a pre-planned safety interim review based on cumulative overall safety 
data is scheduled after the first ten patients (across indications) are followed for at least one 
cycle. The DMC can propose and the sponsor’s Safety committee endorse whether the protocol 
should continue unchanged, be modified, the dose be reduced, dosing and study entry held for 
already included patients, additional patients should be included, or whether the study should be 
discontinued permanently. Based on this interim review, the opening of the remaining three 
indications (SCCHN, NSCLC and esophageal cancer) can be determined. 
A second safety interim is pre-planned during the Cohort Expansion part when 30 patients have 
been dosed and followed for at least one cycle. 
8. DATA REVIEW 
8.1 
DATA HANDLING AND TRANSFER 
will be providing the Data management services for this study.  Details of the processes 
followed in order to provide a clean database are specified in the Data Management Plan for the 
study.  This includes details of handling data not stored in the clinical database, such as data 
from the central laboratory.   
8.2 
DATA SCREENING 
Beyond the data screening built into the 
Data Quality Plan, the 
programming of 
analysis datasets, tables, figures, and listings (TFL) provides additional data screening. Presumed 
data issues will be output into SAS logs and extracted from the logs and sent to Data 
Management for resolution. 
Review of a pre-freeze TFL run on clean patients and a post-freeze TFL run on the frozen 
database allow for further data screening prior to lock. The post-freeze TFL will be discussed 
with the sponsor in a data review meeting to identify any final data issues and seek corrections 
prior to database lock. The 
 statistician and the sponsor must approve database lock. 
9. STATISTICAL METHODS 
All analyses will use SAS version 9.4 or higher. 
Unless otherwise noted, categorical variables will be summarized using counts and percentages. 
Percentages will be displayed as whole numbers, and will not be displayed for zero counts.  
Percentages will be calculated from the number of patients with data. 
Continuous variables will be summarized using the number of observations (n), mean, standard 
deviation (Std), median, minimum and maximum. The median, minimum and maximum values 
will be displayed to the same level of precision as the raw data, the mean to a further decimal 
place and the Std to two additional decimal places, up to a maximum of 4 decimal places. 
No formal statistical testing will be done. Where it is specified that confidence intervals will be 
presented, all confidence intervals will be 95% two-sided confidence intervals. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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In the Dose Escalation part, unless otherwise specified, summary statistics will be presented by 
dose cohort and total. 
In the Cohort Expansion part, summary statistics will be presented by cancer type and total. 
Unless otherwise stated, all summaries will be produced both for the Dose Escalation part, and 
for the Cohort Expansion part. 
No imputation of missing data is planned, except in the calculation of derived variables as 
described in Section 5. 
Listings of data will be produced separately for the Dose Escalation and Cohort Expansion parts 
of the study. Listings will be sorted by dose group, patient number and time of assessment 
(where applicable) for the Dose Escalation part of the study.  For the Cohort Expansion part of 
the study, listings will be sorted by cancer type, patient number and time of assessment (where 
applicable). 
9.1 
SUBJECT DISPOSITION 
The number and percentage of patients screened, enrolled, and in the Full Analysis Set will be 
presented, together with the number and percentage of patients who completed four cycles of 
treatment, withdrew from treatment prematurely and withdrew from the study prematurely. A 
breakdown of the corresponding reasons for withdrawal from treatment and study will be 
included in this table. 
The number and percentage of patients enrolled at each site will also be tabulated. 
In addition, the number and percentage of patients remaining on treatment will also be presented 
by cycle. 
Details of whether patients completed or early terminated from treatment and the study including 
the reason, and inclusion in the analysis set will be listed for individual patients. 
9.2 
PROTOCOL DEVIATIONS AND VIOLATIONS 
Protocol deviations and violations (PDV) will be entered into the 
 Clinical Trials 
Management System (CTMS). The study team and the sponsor will conduct on-going reviews of 
the PDV data from CTMS, and these will be categorized and PDVs relevant for the analysis 
identified. 
The list of PDVs will be categorized and finalized prior to database lock, and these will be 
imported into the analysis database for presentation of the significant PDVs in a listing and 
summary table. Significant PDVs are those indicated as major during medical review. 
The categories of PDVs will be documented in a separate document.  
A subset of the listed major/significant PDVs deemed to be important by medical review will be 
presented separately in the body text of the Clinical Study Report. 
 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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9.3 
TREATMENTS 
9.3.1 
Extent of Study Drug Exposure 
The number of infusions given will be presented in summary tables. 
The total duration of exposure in days as defined in Section 5.8 will also be summarized. In 
addition the duration of infusion in minutes for each cycle will be summarized. Plots showing the 
duration of infusions and number of infusions will be summarized. 
Individual patient data listings of data relating to the infusions, including details of any 
interruptions, will be provided. 
9.3.2 
Concomitant Medications 
Medications received concomitantly with study drug will be categorized by medication coded 
term according to WHODRUG dictionary, and in addition coded using the Anatomical 
Therapeutic Chemical (ATC) classification system. The number and percentage of patients using 
any concomitant medication will be displayed together with the number and percentage of 
patients using at least one medication within each medication coded term. The levels of ATC 
categories to be presented will be level 2 (therapeutic main group), level 3 
(therapeutic/pharmacological subgroup) and WHODRUG preferred term.  
Medications will be considered concomitant if the stop date is after the first date of study drug or 
the medication is marked as continuing, and the start date is before the last date of study drug. If 
there is any doubt as to whether a medication is concomitant due to missing or partial start or 
stop dates, then the medication will be considered concomitant. Concomitant medications will be 
listed. 
A separate summary table of those medications with a start date on or after the date of last 
infusion will also be produced. 
For the cohort expansion part, a separate summary of the pre-infusion ocular medication at each 
cycle will be produced, showing the number of patients receiving cooling pads, vasoconstrictor 
and steroid. 
9.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
Demography data consisting of sex, age, race, ethnicity, height, weight and BMI at the Screening 
Visit will be summarized. 
The number and percentage of patients with each type of cancer (location of primary tumor) will 
be presented, and time since diagnosis will also be summarized. 
Medical history will be coded using the MedDRA dictionary, and summarized by the number 
and percentage of patients with at least one medical history in each system organ class and 
preferred term category. 
Prior medications will be summarized in a similar manner to concomitant medications. Prior 
medications will be defined as those with a start date prior to the start date of study drug. Note 
that medications may be considered both prior and concomitant, and in this case they will be 
summarized in both tables. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Prior cancer therapies will be coded using WHODRUG and ATC classification and will be 
summarized by number and percentage of patients receiving any prior cancer therapy by coded 
term in a similar way to the concomitant medications. In addition, the number of prior lines of 
therapies will be summarized. In the cohort expansion part, response to the last prior therapy will 
be summarized. A summary table will be produced of the TNM classification of the disease 
stage, and in addition the number of patients with distant metastases (number of patients with M 
classification of ‘1’) will be summarized. 
All demographic and baseline characteristics data will be listed. Individual tumor biopsy, 
peripheral neuropathy history and baseline visual acuity data will also be listed. 
9.5 
SAFETY ANALYSES 
9.5.1 
Adverse Events 
AEs will be coded using MedDRA. The severity of the AEs will be recorded using the NCI-
CTCAE v4.03 grading system. Only treatment-emergent AEs will be included in the summary 
tables. 
An overall summary of treatment-emergent AEs will be presented, including the number of 
events reported, the number and percentage of patients reporting at least one AE, the number and 
percentage of patients with at least one SAE, the number and percentage of patients with at least 
one infusion-related AE, the number and percentage of patients with at least one grade ≥3 AE, 
the number and percentage of patients with at least one study drug related AE (related or 
possibly related), the number and percentage of patients discontinuing due to an AE, and the 
number and percentage of patients who died. In addition, the number of patient days (total 
number of days in study) will be presented in these tables for each group.  This table will also 
divide AEs into those occurring in Cycle 1 and those occurring any time whilst on treatment (up 
to the end of the last dose + 30 days).  
A breakdown of the number and percentage of patients reporting each AE, and the number of 
events, categorized by system organ class and preferred term coded according to the MedDRA 
dictionary, will be presented. Note that for the counts of patients, patients are only counted once 
within each body system or preferred term. 
This summary will be repeated for AEs occurring in Cycle 1, AEs occurring any time on 
treatment, SAEs, SAEs occurring any time on treatment, infusion-related AEs, grade ≥3 AEs, 
study drug related AEs (related or possibly related), study drug related grade ≥3 AEs, study drug 
related SAEs, AEs leading to dose interruption, AEs leading to dose reduction, and AEs leading 
to discontinuation. AEs occurring any time on treatment are those with an onset date on or before 
the date of last dose + 30 days. 
Further summary tables will be produced by system organ class and preferred term, additionally 
split by NCI-CTC grade and relationship. This will be done for all AEs, all SAEs, and AEs in 
Cycle 1. 
AEs of special interest will be defined as AEs of skin rash, bleeding, neuropathy, neutropenia, 
neutropenic fever, anemia, thrombocytopenia, vomiting, diarrhea and infusion-related AEs.  
These will be identified as described in Table 2 below, where PT=Preferred Term, and 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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HLT=High Level Term.  A separate document, an excel spreadsheet called SMQs for GEN701 
containing a tab for different types of AE of special interest, is referred to in the table below and 
is an appendix to this SAP. 
Table 2: List of AEs of Special Interest 
Skin Rash 
 PT: Drug eruption, Lip ulceration, Rash, Rash maculo-papular, Rash 
pustular 
Bleeding 
Refer to list of terms in Haemorrhage tab of SMQ appendix. 
Neuropathy 
Refer to list of terms in peripheral neuropathy tab of SMQ appendix. 
Neutropenia  
 
PT: Neutrophil count abnormal  
PT: Neutrophil count decreased  
PT: Neutrophil percentage abnormal  
PT: Neutrophil percentage decreased  
PT: Band neutrophil count decreased 
PT: Band neutrophil percentage decreased 
HLT: Neutropenias 
Neutropenic fever 
PT: Febrile neutropenia  
Anemia  
PT: Anaemia 
PT: Hemorrhagic anaemia 
PT: Anaemia of chronic disease 
PT: Anaemia of malignant disease 
PT: Aplastic anaemia 
PT: Hypoplastic anaemia 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Thrombocytopenia 
PT: Platelet count abnormal 
PT: Platelet count decreased 
PT: Thrombocytopenia 
PT: Thrombocytopenic purpura 
PT: Thrombotic Thrombocytopenic purpura 
Vomiting 
PT: Vomiting 
Diarrhea 
PT: diarrhea 
PT: diarrhea hemorrhagic 
Infusion Related 
Reaction (IRR) 
Any AE with onset date and time between start date and time of 
infusion and end time of infusion plus 24 hours, considered related by 
the investigator, and with preferred term of 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 high level term of ‘Exfoliative conditions’, 
‘Dyspneas’, ‘Dyspnoeas’ or ‘Breathing abnormalities’ or high level 
group term of ‘Allergic conditions’. 
Conjunctival 
disorders 
Refer to list of terms in Conjunctival disorders tab of SMQ appendix. 
Corneal disorders 
Refer to list of terms in Corneal disorders tab of SMQ appendix. 
Scleral disorders 
Refer to list of terms in Scleral disorders tab of SMQ appendix. 
Retinal disorders 
Refer to list of terms in Retinal disorders tab of SMQ appendix. 
Peri orbital and eyelid 
disorders 
Refer to list of terms in Peri orbital and eyelid disorders tab of SMQ 
appendix. 
Ocular infections 
Refer to list of terms in Ocular infections tab of SMQ appendix. 
Optic nerve disorders 
Refer to list of terms in Optic nerve disorders tab of SMQ appendix. 
Any ocular event 
This is any AE in any of the 7 ocular categories above – conjunctival 
disorders, corneal disorders, scleral disorders, retinal disorders, peri 
orbital and eyelid disorders, ocular infections, and optic nerve disorders. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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The number and percentage of patients with AEs in each category will be summarized, and a 
separate summary of AEs of special interest broken down by category and preferred term will be 
provided. Separate tables will be produced for all AEs of special interest, for AEs of special 
interest occurring in Cycle 1, AEs of special interest which are serious, and AEs of special 
interest occurring in Cycle 1 which are serious. For each of these groups of AEs, a further 
summary table will be produced broken down by maximum NCI-CTCAE grade. Finally, a 
summary of the duration of the AEs will be presented separately for skin rash AEs, bleeding AEs 
and neuropathy AEs. The summary of duration of the AEs will present the number of AEs of that 
type, and summary statistics for the duration in days of the individual events.  
For skin rash, bleeding and neuropathy AEs, plots showing the onset day, duration and intensity 
(NCI-CTCAE grade) of individual AEs will be produced. A separate plot will be produced for 
each type of AE and each cohort in the Dose Escalation part, and each cancer type in the Cohort 
Expansion part.  For the bleeding events, separate plots will be produced for minor bleedings, 
major bleedings and all bleedings. 
In the Cohort Expansion part, the ocular events (defined as those in the Any ocular event 
category above) will be additionally be summarized by whether the patient entered the study 
prior to the mitigation plan (first dose of study medication <= 22Dec2016), or after the 
mitigation plan (first dose of study medication > 22Dec2016).  This will be done for all patients 
overall, and then repeated for each cancer type.  
A further figure will be produced which is a bar graph of all adverse events by cycle and dose 
cohort in the Dose Escalation part, and cancer type in the Cohort Expansion part, showing the 
percentage of patients with an AE. This will be further split by maximum CTCAE grade. 
All AEs (including non-treatment-emergent events) recorded in the eCRF will be listed. Separate 
listings of SAEs, AEs leading to death, AEs leading to discontinuation, AEs with CTCAE 
grade≥3, AEs leading to dose interruption, AEs leading to dose reduction, study treatment related 
AEs, AEs occurring in Cycle 1 and AEs of special interest will be produced.  In the Cohort 
Expansion part, a listing of AEs with CTCAE grade>=3 will be produced for those patients 
determined to have a positive ADA result only. 
Where the NCI-CTCAE grade of an AE is missing, it will be assumed to be ≥3, and where the 
relationship is missing it will be assumed to be related. 
9.5.2 
Laboratory Data 
9.5.2.1 HEMATOLOGY, BIOCHEMISTRY AND COAGULATION FACTORS 
Hematology, biochemistry and coagulation factors will be analyzed at the site laboratory and 
results recorded on the eCRF in the Dose Escalation part of the study. In the Cohort Expansion 
part, these will be tested centrally and the data transferred from the vendor. Values will be 
presented in SI units, and where values are recorded in different units in the eCRF, they will be 
converted into SI units prior to the data being summarized and listed. 
The following parameters are assessed: 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Hematology: Red Blood Cell Count; Hemoglobin; Hematocrit; Mean Corpuscular Hemoglobin; 
Mean Corpuscular Hemoglobin Concentration; White Blood Cell Count; Neutrophils, Absolute; 
Neutrophils, Percent; Lymphocytes, Absolute; Lymphocytes, Percent; Monocytes, Absolute; 
Monocytes, Percent; Eosinophils, Absolute; Eosinophils, Percent; Basophils, Absolute; 
Basophils, Percent; Reticulocytes; Platelet Count 
Biochemistry: 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, Glycosylated Hemoglobin. 
Coagulation Factors: Prothrombin time, INR, aPTT, D-dimer, Fibrinogen. 
Summaries of the actual values at baseline and percentage change from baseline at each post-
baseline visit and will be presented at each visit where they are assessed. 
Laboratory values will be assigned an NCI-CTC grade according to the NCI-CTCAE v4.03 
grading system.  The following parameters will be assigned grades: 
Hematology: Hemoglobin; White Blood Cell Count; Lymphocytes, Absolute; Neutrophils, 
Absolute: Platelets. 
Biochemistry: Albumin, Alkaline Phosphatase, ALT, AST, Total Bilirubin, Calcium, Glucose, 
Magnesium, Potassium, Sodium. 
Coagulation Factors: Fibrinogen, INR, aPTT. 
For the other parameters, it is not possible to assign an NCI-CTC grade. 
For parameters where an NCI-CTC grade is defined, a grade will be assigned for each result, and 
the maximum post-baseline grade and shift from baseline will be summarized. 
Unscheduled assessments will be included in the summary statistics when looking across the 
study as a whole. 
Reference ranges from the individual laboratories will be used, and no transformation of the 
results to a single normal range will be applied. 
All laboratory data will be listed, which will include the NCI-CTC grade and investigator’s 
assessment of clinical significance, and in addition a separate listing of Grade ≥3 results will be 
produced. 
Plots of mean laboratory values over time and values for individual patients over time will be 
presented by dose group for the Dose Escalation part and by cancer type for the Cohort 
Expansion part for each parameter. 
Any additional laboratory assessments taken as a result of the bleeding or neuropathy assessment 
will be listed separately.  
Pregnancy test results will also be listed. 
9.5.2.2 FLOW CYTOMETRY 
Peripheral blood samples for assessment by flow cytometry will be collected at  Day 1 of Cycle 
1 and Cycle 5 and at the End of Study Visit.  The following will be measured: 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Total T-cells (CD3+), Helper T-cells (CD3+CD4+), Cytotoxic T-cells (CD3+CD8+), NK-cells 
(CD3-CD56+CD16+) and B-cells (CD45+CD19+). 
Descriptive statistical summaries of each cellular population (percentages and absolute cell 
counts) at each visit will be tabulated for each cohort. The median percentage change from Cycle 
1 Day 1 (baseline) at Cycle5 day 1 and EOS visits will be presented for each cohort.  In addition 
in the Cohort Expansion part, summaries of each cellular population at Cycle1 Day1 and the  
percentage change in each cellular population from Cycle 1 Day 1 to Cycle 5 Day 1 will be 
presented by overall response (PD,SD, PR, CR) rather than cancer type.    
9.5.2.3 SEROLOGY 
For the parameters of HBsAG, Anti-HBs, Anti-HBc, Hepatitis C, CMV IgG, CMV IgM, and 
HPV (for patients with squamous cell carcinoma of the head and neck or cervical cancer only) 
samples will be collected at the Screening and End of Study visits, and analyzed at a central 
laboratory. The results of positive/negative for each parameter for each patient will be listed, and 
the number and percentage of patients with shifts from negative to positive at any time 
post-baseline will be summarized. 
9.5.2.4 BIOMARKERS 
Tissue Factor (TF) expression will be measured by immunohistochemistry (IHC) assay in tumor 
biopsy samples provided at baseline (screening).  TF expression will be reported as cellular 
membrane staining by H-score, which is a composite scoring of the positive TF staining within 
the tissue sample. The score is obtained by the formula: 3 x percentage of strongly staining cells 
+ 2 x percentage of moderately staining cells + percentage of weakly staining cells, giving a 
range of 0 to 300.  Descriptive summary statistics will be provided for TF expression (number of 
patients with biopsies with TF results, mean, median, minimum, maximum, std) at baseline for 
all patients in dose escalation, and by indication in the expansion phase.  In addition, summaries 
of TF expression (membrane H Score) at baseline will be provided by overall response (PD, SD, 
PR, CR) for each indication in the expansion phase. Finally, summaries of TF expression 
(membrane H Score) at baseline will be provided for patients with overall response of SD, PR or 
CR) versus progressive disease (PD) in each indication.  
Circulating tissue factor will be measured from samples taken at Screening and Day 1 of Cycle 5 
in the Dose Escalation part, and at Screening and Day 15 of Cycle 4 in the Cohort Expansion 
part. Descriptive summary statistics (mean, median, max, min, std) of cTF values at each visit 
and changes from screening will be provided per dose cohort in dose escalation and in the 
expansion phase.  In the expansion phase, this summary will be repeated by subgroup for 
patients with overall response of SD, PR or CR, and patients with overall response of PD.  For 
the expansion phase cohorts, median changes in cTF (Cycle 4 Day 15 vs Screening) will be 
plotted per indication.  Median change in cTF (Cycle 4 Day 15 vs Screening) in patients with 
overall response of SD, PR or CR and those with progressive disease (PD) will also be plotted 
per cohort, for all the expansion cohorts.  Association between cTF and TF expression by IHC 
(H-score) will be assessed by plotting change in cTF versus baseline H-score. 
Cell free DNA (cfDNA) will be measured from samples taken at Screening and Cycle 5 Day 1 in 
the Dose Escalation, and at Screening and Cycle 4 Day 15 in the Cohort Expansion phase. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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Descriptive summary statistics (mean, median, max, min, std) of cfDNA values at each visit and 
changes from screening will be provided per dose cohort in dose escalation and in the expansion 
phase.  In the expansion phase, this summary will be repeated by subgroup for patients with 
overall response of SD, PR or CR, and patients with overall response of PD.  For the expansion 
phase cohorts, median changes in cfDNA (Cycle 4 Day 15 vs Screening) will be plotted per 
indication.  Median change in cfDNA (Cycle 4 Day 15 vs Screening) in patients with overall 
response of SD, PR or CR, and patients with progressive disease (PD) will also be plotted per 
cohort, for all the expansion cohorts. 
9.5.3 
Skin Disorders 
The number and percentage of patients with skin rash and the number of individual occurrences 
of skin rashes at any time will be summarized. 
This will be broken down by the maximum percentage of body surface area affected (<10%, 
≥10-30%, and >30%) and whether there are any vesicles.  
The detailed information on skin rashes assessed will be listed individually for each patient. 
9.5.4 
Bleeding Assessment 
The number and percentage of patients with bleeding events and the number of individual 
occurrences of bleeding events at any time will be summarized. This will be repeated for major 
bleeding events. 
A listing presenting the additional detailed information collected on bleeding events including 
location, suspected cause and intensity by individual patient will be produced. 
In addition, summary tables and bar charts will be produced showing the percentage of patients 
with bleeding in each location.  A patient may be included in more than one category, as a 
patient may have bleeding in more than one location.  The summary table and bar chart will be 
presented for all patients overall and by dose level for the Dose Escalation part of the study, and 
cancer type for the Cohort Expansion part.  There will also be separate tables and bar charts for 
bleeding with onset during Cycle 1. 
9.5.5 
Peripheral Neuropathy 
An assessment of neuropathy will be done at every visit.  The number and percentage of patients 
with neuropathy at any time will be summarized. This will be done for all neuropathy overall, 
and then repeated for motor, sensory and autonomic neuropathy separately. 
Details of the results of the neuropathy exam including type (polyneuropathy, mononeuropathy 
or other), symptoms and cause of the neuropathy will be listed for each individual patient. 
9.5.6 
Ophthalmology 
In the Cohort Expansion part, Individual patient data from the ophthalmology assessments will 
be listed.  This includes visual acuity, Schirmer’s tear test, SLIT lamp, interocular pressure, 
fundoscopy, overall evaluation, and treatment initiated/adjusted.   Summaries of visual acuity, 
Schirmer’s tear test, SLIT lamp (hyperemia, conjunctival staining and cornea staining) and 
intraocular pressure and fundoscopy will be produced. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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9.5.7 
Other Safety Assessments 
9.5.7.1 VITAL SIGNS 
Vitals signs of temperature, blood pressure and heart rate will be assessed at each visit. 
Summaries of the actual values at each time point and change from baseline at each post-baseline 
time point will be presented at each scheduled time point where they are assessed. 
A listing of the vital signs data by patient will be produced, including the change from baseline 
value. Weight will be included in the listing at the visits where it is measured. 
In addition, a separate listing of patients with abnormal vital signs values at any time will be 
produced, where an abnormal value is systolic blood pressure >140 mmHg, diastolic blood 
pressure >90 mmHg, heart rate of <60 bpm or >100 bpm, or temperature of >37.5°C. 
9.5.7.2 ECG 
ECG data of HR, PR, QRS, QTcB and QTcF obtained from the central reading, and the 
investigator’s judgment of whether clinically significant, will be collected at Screening and three 
times on Day 1 of each Cycle. 
Summaries of the actual values at each visit and change from baseline at each post-baseline visit 
will be presented at each scheduled visit where they are assessed for the numerical ECG 
parameters. Where multiple assessments are done at the same visit, the average of the values at 
that visit will be used for the calculation of the summary statistics. For calculating baseline 
value, if multiple assessments were taken on the same date as the last measurement prior to IMP 
administration, then the average of all values on that date prior to IMP administration will be 
used as the baseline value. 
All ECG results will be listed, and a separate listing of ECG data for patients who have a 
clinically significant result at any time, as indicated by the investigator, will be provided. 
9.5.7.3 PHYSICAL EXAMINATION 
Physical examination data will be collected at Screening, Day 1 of Cycle 1 and 2 and End of 
Study. Listings of individual physical examination data will be provided for each patient. 
A separate listing of changes from Normal at Screening to Abnormal at any time post-baseline, 
or from Abnormal – not clinically significant at Screening to Abnormal – clinically significant at 
any time post-baseline will be produced. 
9.5.7.4 ECOG 
ECOG data will be collected at Screening, Day 1 of each cycle, and at the End of Study Visit. 
These data will be listed for each patient, and the number and percentage of subjects in each 
category summarized. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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9.6 
PHARMACOKINETIC ANALYSES 
9.6.1 
Pharmacokinetic Concentrations 
Blood samples for assessment of HuMax-TF-ADC, total HuMax-TF (conjugated and non-
conjugated) and MMAE will be drawn for central analysis in accordance to the timing provided 
in the tables below. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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Table 3: 
PK Sampling in the Dose Escalation Part 
Treatment Cycle 
Screening 
Cycle 1-2 
Cycle 3-4 
Cycle 5-12 
Follow-Up 
Unscheduled 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
1 
2 
3 
1 
2 
3 
1-4 
1-X 
Day/Week 
- 
1d 
2d 
4d 
8d 
11d 
15d 
1d 
8d 
15d 
1d 
8d 
15d 
6 weekly 
 
Before Infusion 
(on infusion days) 
X 
X 
X1 
 
X 
 
X 
X 
 
 
X 
 
 
X 
X3 
End of infusion 
(+15 minutes) 2 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
+ 2 hours (± 15 minutes) 
after end of infusion 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 5 hours (± 30 minutes) 
after end of infusion 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 12 hours (± 60 minutes) 
after end of infusion 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Time window for the Day 2 sampling in the Dose Escalation Part is 24 hours ± 2 hours after end of infusion on Day 1. 
2 Allowed time windows are indicated in parentheses.   
3 Optional. 
 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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Table 4: 
PK Sampling in the Cohort Expansion Part 
Treatment Cycle 
Screening 
Cycle 1-2 
Cycle 3-4 
Cycle 5-12 
Follow-Up 
Unscheduled 
Visit Number 
0 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1-4 
1-X 
Day/Week 
- 
1d 
8d 
15d 
1d 
8d 
15d 
1d 
8d 
15d 
6 weekly 
 
Before Infusion       
(on infusion days) 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X2 
End of infusion   
(+15 minutes) 1 
 
X 
 
 
X 
 
 
X 
 
 
 
 
+ 2 hours (± 15 minutes) after 
end of infusion 1 
 
X 
 
 
 
 
 
 
 
 
 
 
1 Allowed time windows are indicated in parentheses.   
2 Optional. 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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The assay to detect Humax-TF-ADC is GNM124EL-131243-A_PK(IgG1 specific), and the 
assay to detect Total Humax-TF is GNM124EL-131243-B_PK(MMAE specific). 
Plasma concentrations will be summarized for HuMax-TF-ADC, total HuMax-TF and MMAE. 
Concentrations below the lower limit of quantitation (LLOQ) will be set to ½LLOQ in the 
computation of all summary statistics for plasma concentrations. 
Descriptive statistics (number of patients, mean, geometric mean, Std, geometric CV, median, 
minimum, and maximum) will be used to summarize the plasma concentrations within a cohort 
by scheduled time. 
The geometric CV is defined as: 
Geometric CV = √(exp[σ2] – 1) 
where σ2 is the variance of the log transformed values. 
Linear and semi-logarithmic plots of the mean plasma concentration by scheduled sampling time 
and individual plasma concentration by scheduled sampling time will be provided for HuMax-
TF-ADC, total HuMax-TF and MMAE. These plots will show time in days post dose and 
concentrations in ug/mL for HuMax-TFADC and total Humax-TF and ng/ml for MMAE. In 
these plots the values below LLOQ values will be set to 1/2 LLOQ. In the Dose Escalation part, 
these plots will be produced separately for cycle 1 and Cycle 2. Linear plots of mean trough level 
with standard deviations will be presented to assess attainment of steady state for HuMax-TF-
ADC, total HuMax-TF and MMAE for expansion cohort. 
All individual patient plasma concentration data will be listed. 
9.6.2 
Pharmacokinetic Parameters  
PK parameters for HuMax-TF-ADC, total HuMax-TF and free toxin (MMAE) will be estimated 
using noncompartmental methods with Phoenix WinNonlin® (WNL) Version 6.3 or higher 
(Pharsight Corp., Mountain View, CA). PK computations may also be performed in SAS® 
Version 9.1 or higher. 
The plasma PK parameters will be estimated from the concentration-time profiles for all PK 
population patients. For the calculation of PK parameters, pre-dose concentration <LLOQ and 
concentration prior to the first quantifiable concentration that are <LLOQ should be set to 0.00. 
An observation that is <LLOQ which occurs between measurable observations should be set to 
“missing” for the purposes of calculating the PK parameters. If there are more than 2 consecutive 
<LLOQ concentrations after Cmax , then all concentrations after that may be treated as missing 
after review of available documentation (eg, bioanalytical report, clinical report) by the project 
pharmacokineticist in consultation with the sponsor.  Actual sampling times will be used in all 
computations involving sampling times. 
Descriptive statistics (number of patients, mean, geometric mean, Std, geometric CV, median, 
minimum, and maximum) will be used to summarize all the relevant PK parameters within 
cohort by dose group. 
For cycles 1 and 2, the following PK parameters will be calculated based on non-compartmental 
(NCA) methods:  
 






Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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For the purposes of the tables and listings by ADA, a patient will be considered ADA positive if 
they have at least one post-baseline confirmed ADA positive sample. 
9.8 
EFFICACY ANALYSIS 
All individual scan data, PSA and CA125 values, and all derived efficacy variables will be listed 
for each patient. 
9.8.1 
Response 
Best Overall Response will be evaluated and summarized.  Number and percentage of patients in 
each category and who are responders/non-responders will be presented, together with a 95% 
confidence interval calculated using the Clopper-Pearson exact method.  We will also repeat this 
table but requiring confirmation for PR and CR. 
For the Cohort Expansion part this summary will also be repeated by response to last prior 
therapy, and number of prior lines of therapy (0-1, 2-3 and >=4).  
In addition, the number and percentage of patients with and without disease control after 6, 12, 
24 and 36 weeks and associated confidence interval calculated using the Clopper-Pearson exact 
methods will be provided. 
These summaries will be presented by indication as well as by dose cohort. 
A separate summary of bone scan data for the subjects with CRPC where this is done will 
present the number and percentage of patients with No new lesions and New Lesions at each 
assessment. 
In the Cohort Expansion part, a swimlane plot showing the overall response at each assessment 
will be produced. 
In the Cohort Expansion part, response will be assessed both by the investigator, and also by an 
independent review committee, and separate summaries and listings will be provided for both 
assessments. 
For the Cohort Expansion part, a separate summary of the best overall response by whether the 
patient had an ADA result that was determined to be positive rather than cancer type will be 
produced. This will be done for both the investigator assessment and the independent review 
committee assessment. 
In addition, for patients with ovarian cancer and those with endometrial cancer in the Cohort 
Expansion part, response according to CA 125 will be assessed, and this will be summarized as 
the number and percentage of patients with a response. 
Finally, for patients with CRPC, response according to PSA will be assessed, and this will also 
be summarized as the number and percentage of patients with a response. 
9.8.2 
Progression Free Survival 
The proportion of patients with PFS will be summarized using Kaplan-Meier estimates and 95% 
confidence intervals at 12, 24, 36, 48 and 60 weeks.  The number and percentage of patients 
experiencing PD or death and the number and percentage of patients who are censored will also 
be presented. In addition, the Kaplan-Meier estimate for the median PFS together with a 95% 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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confidence interval will be provided. The associated Kaplan-Meier plots will be produced to 
display the results graphically for all dose groups combined in the Dose Escalation part, and for 
each cancer type and total in the Cohort Expansion part. 
In the Cohort Expansion part, PFS will be derived based on the investigator’s assessments, based 
on investigator’s assessments including undocumented progression as disease progression, and 
also based on the assessments of the independent review committee. Separate summaries and 
listings will be provided for all three assessments. 
9.8.3 
Duration of Response 
Kaplan-Meier estimates and 95% confidence intervals for duration of response will be presented 
at 12, 24, 36, 48 and 60 weeks. The number and percentage of patients whose response ends, and 
who are still responding (censored) will be presented. The Kaplan-Meier estimate for the median 
duration of response and 95% confidence interval will be provided. The associated Kaplan-Meier 
plots will be produced to display the results graphically for all dose groups combined in the Dose 
Escalation part, and for each cancer type and total in the Cohort Expansion part. 
In the Cohort Expansion part, duration of response will be derived based on the investigator’s 
assessments, and also based on the assessments of the independent review committee, and 
separate summaries and listings will be provided for both assessments. 
9.8.4 
Tumor Shrinkage 
The maximum change from baseline in the sum of the target lesion measurements at any time on 
study will be included in the listings and plotted using waterfall plots. The percent change will be 
plotted in addition to the absolute change. 
In the Cohort Expansion part only, the change from baseline in the sum of the target lesion 
measurements from the CT-scan evaluation at the end of four cycles and at the end of treatment 
will be summarized. 
9.8.5 
PSA and CA 125 
Summary statistics of PSA and CA 125 and actual and percentage change from baseline will be 
presented by cycle, and in addition plots of individual patient data over time (actual values and 
percent change from baseline) will be produced for these parameters. In the Cohort Expansion 
part, plots of mean and median by cancer type over time will also be produced. Note that PSA is 
assessed for subjects with CRPC only, and CA 125 is measured for subjects with ovarian cancer 
only, and in addition patients with endometrial cancer in the Cohort Expansion part. 
10. VALIDATION 
s goal is to ensure that each TFL delivery is submitted to the highest level of quality. 
 
quality control procedures will be documented separately in the study specific quality control 
plan.  
11. REFERENCES 
The NCI-CTCAE v4.03 criteria can be found here: 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
This will be used for assigning Grades to laboratory parameters. 




Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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HPV 
Human papilloma virus 
HuMax®-TF-ADC 
HuMax Tissue Factor antibody drug conjugate 
INR 
International normalized ratio 
LLOQ 
Lower limit of quantitation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE 
Monomethyl auristatin E 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
PD 
Progressive disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PSA 
Prostate specific antigen 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCCHN 
Squamous cell carcinoma of the head and neck 
SD 
Stable Disease 
Std 
Standard deviation 
TF 
Tissue Factor 
WHO 
World Health Organization 
 






Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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Table 14.2.1.1-A 
Summary of HuMax-TF-ADC Plasma 
Concentrations (ug/mL) by Dose Cohort 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.1.2-A 
Summary of Total HuMax-TF Plasma 
Concentrations (ug/mL) by Dose Cohort 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.1.3-A 
Summary of MMAE Plasma 
Concentrations (ng/mL) by Dose Cohort 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.1.4-A 
Summary of HuMax-TF-ADC Plasma 
Pharmacokinetic Parameters by Dose 
Cohort for Cycles 1 & 2 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.1.5-A 
Summary of Total HuMax-TF Plasma 
Pharmacokinetic Parameters by Dose 
Cohort for Cycles 1 & 2 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.1.6-A 
Summary of MMAE Plasma 
Pharmacokinetic Parameters by Dose 
Cohort for Cycles 1 & 2 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.1.7-A 
Analysis of Dose Proportionality of 
Cycle 1 Cmax, Cycle 1 AUClast and Cycle 
1 AUCinf for HuMax-TF-ADC 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.1.8-A 
Analysis of Dose Proportionality of 
Cycle 1 Cmax, Cycle 1 AUClast and Cycle 
1 AUCinf for total HuMax-TF 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.1.9-A 
Analysis of Dose Proportionality of 
Cycle 1 Cmax, Cycle 1 AUClast and Cycle 
1 AUCinf for MMAE 
Dose Escalation Part (PK 
Analysis Set 1) 
Table 14.2.2.1.1-A 
Summary of Best Overall Response 
(Investigator Assessment) by Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.2.1.2-A 
Summary of Best Overall Response 
(Investigator Assessment) Including 
Confirmation by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.2.2-A 
Summary of Best Overall Response 
(Investigator Assessment) by Indication 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.2.3-A 
Summary of Disease Control 
(Investigator Assessment) by Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.2.4-A 
Summary of Disease Control 
(Investigator Assessment) by Indication 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.3-A 
Summary of Bone Scan Results by Dose 
Cohort  
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.4.1-A 
Summary of Response according to 
CA125 by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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Table 14.2.4.2-A 
Summary of Response according to PSA 
by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.5.1-A 
Kaplan-Meier Summary of Progression 
Free Survival (Investigator Assessment) 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.6.1-A 
Kaplan-Meier Summary of Duration of 
Response (Investigator Assessment) 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.7.1-A 
Summary of PSA by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.7.2-A 
Summary of CA 125 by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.7.3-A 
Summary of Circulating TF (cTF) by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.2.7.4-A 
Summary of cfDNA by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.1-A 
Overall Summary of Adverse Events by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.2-A 
Adverse Events by System Organ Class, 
Preferred Term and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.3-A 
Adverse Events on Treatment by 
System Organ Class, Preferred Term 
and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.4.1-A 
Adverse Events in Cycle 1 by System 
Organ Class, Preferred Term and Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.4.2-A 
Non-Serious Adverse Events with 
Frequency >=5% in any Group by 
System Organ Class, Preferred Term 
and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.5-A 
Serious Adverse Events by System 
Organ Class, Preferred Term and Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.6.1-A 
Serious Adverse Events on Treatment 
by System Organ Class, Preferred Term 
and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.6.2-A 
Study Treatment Related Serious 
Adverse Events on Treatment by 
System Organ Class, Preferred Term 
and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.7-A 
Grade ≥ 3 Adverse Events by System 
Organ Class, Preferred Term and Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
    Protocol no:  GEN701                                                                                30 Jul 2019 / Version 3.0 
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Table 14.3.1.8-A 
Study Treatment Related Adverse 
Events by System Organ Class, 
Preferred Term and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.9-A 
Adverse Events Leading to 
Discontinuation by System Organ Class, 
Preferred Term and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.10-A 
Adverse Events by System Organ Class, 
Preferred Term and CTCAE Grade and 
Relationship 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.11-A 
Serious Adverse Events by System 
Organ Class, Preferred Term and CTCAE 
Grade and Relationship 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.12-A 
Adverse Events in Cycle 1 by System 
Organ Class, Preferred Term and CTCAE 
Grade and Relationship 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.13-A 
Adverse Events of Special Interest by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.14-A 
Adverse Events of Special Interest by 
Category, Preferred Term and Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.15-A 
Adverse Events of Special Interest in 
Cycle 1 by Category, Preferred Term 
and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.16-A 
Serious Adverse Events of Special 
Interest by Category, Preferred Term 
and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.17-A 
Serious Adverse Events of Special 
Interest in Cycle 1 by Category, 
Preferred Term and Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.18-A 
Adverse Events of Special Interest by 
Category, Preferred Term and 
Maximum CTCAE Grade 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.19-A 
Adverse Events of Special Interest in 
Cycle 1 by Category, Preferred Term 
and Maximum CTCAE Grade 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.20-A 
Serious Adverse Events of Special 
Interest by Category, Preferred Term 
and Maximum CTCAE Grade 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.1.21-A 
Serious Adverse Events of Special 
Interest in Cycle 1 by Category, 
Preferred Term and Maximum CTCAE 
Grade 
Dose Escalation Part (Full 
Analysis Set 1) 




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Table 14.3.4.1-A 
Summary of Hematology Results by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.2-A 
Shift Summary of Hematology Results 
by Maximum CTCAE Grade and Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.3-A 
Listing of Grade ≥ 3 Hematology Results 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.4-A 
Summary of Biochemistry Results by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.5-A 
Shift Summary of Biochemistry Results 
by Maximum CTCAE Grade and Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.6-A 
Listing of Grade ≥ 3 Biochemistry 
Results 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.7-A 
Summary of Coagulation Factor Results 
by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.8-A 
Listing of Grade ≥ 3 Coagulation Factor 
Results 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.9-A 
Summary of Flow Cytometry Results by 
Dose Cohort  
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.4.10-A 
Summary of Shifts from Negative to 
Positive Serology Results by Dose 
Cohort   
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.5.1-A 
Summary of Vital Sign Values by Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.5.2-A 
Listing of Abnormal Vital Sign Values 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.5.3-A 
Summary of ECG Values by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.5.4-A 
Listing of Abnormal ECG Results 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.5.5-A 
Listing of Abnormal Physical 
Examination Results 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.5.6-A 
Summary of ECOG Performance Status 
by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Table 14.3.5.7-A 
Summary of Immunogenicity Results by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
TABLES 
Cohort Expansion Part 
Table 14.1.1.1-B 
Patient Disposition by Cancer Type 
Cohort Expansion Part (All 
Enrolled Patients) 


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Table 14.1.1.2-B 
Enrollment by Center and Cancer Type 
Cohort Expansion Part (All 
Enrolled Patients) 
Table 14.1.1.3-B 
Significant Protocol Deviations by 
Cancer Type 
Cohort Expansion Part (All 
Enrolled Patients) 
Table 14.1.1.4-B 
Patients Remaining on Treatment by 
Cycle and Cancer Type 
Cohort Expansion Part (All 
Enrolled Patients) 
Table 14.1.2.1-B 
Demographic Characteristics by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.3.1-B 
Medical History by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.3.2-B 
History of Cancer by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.3.3-B 
Disease Stage by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.3.4-B 
Demographics Histology and 
Histological Grade by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.3.5.1-B 
Summary of Membrane H-Score by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.3.5.2-B 
Summary of Membrane H-Score by Best 
Overall Response 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.3.5.3-B 
Summary of Membrane H-Score by Best 
Overall Response of Clinical Benefit 
versus Progressive Disease 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.4.1-B 
Prior Medications by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.4.2-B 
Prior Cancer Therapies by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.4.3-B 
Number of Prior Lines of Cancer 
Therapies by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.4.4-B 
Concomitant Medications by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.4.5-B 
Concomitant Medications After Last 
Infusion by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.4.6-B 
Pre-infusion Ocular Medication by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.4.7-B 
Response to Last Prior Therapy by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.5.1-B 
Extent of Exposure by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.1.5.2-B 
Duration of Infusion (minutes) by Cycle 
and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Table 14.2.1.1-B 
Summary of HuMax-TF-ADC Plasma 
Concentrations (ug/mL)  
Cohort Expansion Part (PK 
Analysis Set 2) 
Table 14.2.1.2-B 
Summary of Total HuMax-TF Plasma 
Concentrations (ug/mL)  
Cohort Expansion Part (PK 
Analysis Set 2) 
Table 14.2.1.3-B 
Summary of MMAE Plasma 
Concentrations (ng/mL)  
Cohort Expansion Part (PK 
Analysis Set 2) 
Table 14.2.1.4-B 
Summary of HuMax-TF-ADC Plasma 
Pharmacokinetic Parameters for Cycles 
1 & 2 
Cohort Expansion Part (PK 
Analysis Set 2) 
Table 14.2.1.5-B 
Summary of Total HuMax-TF Plasma 
Pharmacokinetic Parameters for Cycles 
1 & 2  
Cohort Expansion Part (PK 
Analysis Set 2) 
Table 14.2.1.6-B 
Summary of MMAE Plasma 
Pharmacokinetic Parameters for Cycles 
1 & 2  
Cohort Expansion Part (PK 
Analysis Set 2) 
Table 14.2.2.1-B 
Summary of Best Overall Response 
(Investigator Assessment) by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.2-B 
Summary of Best Overall Response 
(Review committee) by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.3-B 
Summary of Best Overall Response 
(Investigator Assessment) Including 
Confirmation by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.4-B 
Summary of Best Overall Response 
(Review committee) Including 
Confirmation by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.5-B 
Summary of Best Overall Response 
(Investigator Assessment) by ADA 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.6-B 
Summary of Best Overall Response 
(Review committee) by ADA 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.7-B 
Summary of Best Overall Response 
(Investigatory Assessment) by Response 
to Last Prior Therapy 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.8-B 
Summary of Best Overall Response 
(Review committee) by Response to 
Last Prior Therapy 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.9-B 
Summary of Best Overall Response 
(Investigatory Assessment) by Number 
of Prior Lines of Therapy 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.10-B 
Summary of Best Overall Response 
(Review committee) by Number of Prior 
Lines of Therapy 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Table 14.2.2.11-B 
Summary of Disease Control 
(Investigator Assessment) by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.2.12-B 
Summary of Disease Control (Review 
committee) by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.3-B 
Summary of Bone Scan Results by 
Cancer Type  
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.4.1-B 
Summary of Response according to 
CA125 by Caner Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.4.2-B 
Summary of Response according to PSA 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.5-B 
Summary of Change in Sum of Lesion 
Measurements  
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.6.1-B 
Kaplan-Meier Summary of Progression 
Free Survival (Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.6.2-B 
Kaplan-Meier Summary of Progression 
Free Survival – Including 
Undocumented Progression 
(Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.6.3-B 
Kaplan-Meier Summary of Progression 
Free Survival (Review committee 
Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.7.1-B 
Kaplan-Meier Summary of Duration of 
Response (Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.7.2-B 
Kaplan-Meier Summary of Duration of 
Response (Review committee 
Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.8.1-B 
Summary of PSA by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.8.2-B 
Summary of CA 125 by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.8.3-B 
Summary of Circulating TF (cTF) by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.8.4-B 
Summary of Circulating TF (cTF) by Best 
Overall Response of Clinical Benefit 
versus Progressive Disease and Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.8.5-B 
Summary of cfDNA by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.2.8.6-B 
Summary of cfDNA by Best Overall 
Response of Clinical Benefit versus 
Progressive Disease and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 




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Table 14.3.1.13-B 
Adverse Events of Special Interest by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.14-B 
Adverse Events of Special Interest by 
Category, Preferred Term and Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.15-B 
Adverse Events of Special Interest in 
Cycle 1 by Category, Preferred Term 
and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.16-B 
Serious Adverse Events of Special 
Interest by Category, Preferred Term 
and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.17-B 
Serious Adverse Events of Special 
Interest in Cycle 1 by Category, 
Preferred Term and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.18-B 
Adverse Events of Special Interest by 
Category, Preferred Term and 
Maximum CTCAE Grade 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.19-B 
Adverse Events of Special Interest in 
Cycle 1 by Category, Preferred Term 
and Maximum CTCAE Grade 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.20-B 
Serious Adverse Events of Special 
Interest by Category, Preferred Term 
and Maximum CTCAE Grade 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.21-B 
Serious Adverse Events of Special 
Interest in Cycle 1 by Category, 
Preferred Term and Maximum CTCAE 
Grade 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.22-B 
Summary of Skin Rash by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.23-B 
Summary of Skin Rash Occurring in 
Cycle 1 by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.24-B 
Summary of Bleeding by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.25-B 
Summary of Major Bleeding by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.26-B 
Summary of Bleeding Occurring in Cycle 
1 by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.27-B 
Summary of Major Bleeding Occurring 
in Cycle 1 by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.28-B 
Location of Bleeding by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Table 14.3.1.29-B 
Location of Bleeding in Cycle 1 by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.30-B 
Location of Major Bleeding by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.31-B 
Location of Major Bleeding in Cycle 1 by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.32-B 
Summary of Neuropathy by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.33-B 
Summary of Neuropathy Occurring in 
Cycle 1 by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.34-B 
Ocular Adverse Events by System Organ 
Class, Preferred Term and Before or 
After Mitigation Plan  
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.35-B 
Ocular Adverse Events by System Organ 
Class, Preferred Term, Before or After 
Mitigation Plan and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.36-B 
Study Treatment Related Grade >=3 
Adverse Events by System Organ Class, 
Preferred Term and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.37-B 
Adverse Events Leading to Treatment 
Interruption by System Organ Class, 
Preferred Term and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.1.38-B 
Adverse Events Leading to Dose 
Reduction by System Organ Class, 
Preferred Term and Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.2.1-B 
Listing of Adverse Events with Outcome 
of Death 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.2.2-B 
Listing of Serious Adverse Events 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.2.3-B 
Listing of Adverse Events Leading to 
Discontinuation 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.2.4-B 
Listing of Adverse Events of Special 
Interest 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.1-B 
Summary of Hematology Results by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.2-B 
Shift Summary of Hematology Results 
by Maximum CTCAE Grade and Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.3-B 
Listing of Grade ≥ 3 Hematology Results 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.4-B 
Summary of Biochemistry Results by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Table 14.3.4.5-B 
Shift Summary of Biochemistry Results 
by Maximum CTCAE Grade and Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.6-B 
Listing of Grade ≥ 3 Biochemistry 
Results 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.7-B 
Summary of Coagulation Factor Results 
by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.8-B 
Listing of  Grade ≥ 3 Coagulation Factor 
Results 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.9-B 
Summary of Flow Cytometry Results by 
Cancer Type  
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.10-B 
Summary of Flow Cytometry Results by 
Best Overall Response  
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.4.11-B 
Summary of Shifts from Negative to 
Positive Serology Results by Cancer 
Type   
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.1-B 
Summary of Vital Sign Values by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.2-B 
Listing of Abnormal Vital Sign Values 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.3-B 
Summary of ECG Values by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.4-B 
Listing of Abnormal ECG Results 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.5-B 
Listing of Abnormal Physical 
Examination Results 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.6-B 
Summary of ECOG Performance Status 
by Dose Cohort 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.7-B 
Summary of Immunogenicity Results by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.8.1-B 
Summary of Visual Acuity by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.8.2-B 
Summary of Schirmir’s Tear Test by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.8.3-B 
Summary of SLIT lamp - Hyperemia by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.8.4-B 
Summary of SLIT lamp – Conjunctival 
Staining by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.8.5-B 
Summary of SLIT lamp – Cornea 
Staining by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Table 14.3.5.8.6-B 
Summary of Intraocular Pressure by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Table 14.3.5.8.7-B 
Summary of Fundoscopy by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
FIGURES 
Dose Escalation Part  
Figure 14.1.1-A 
Duration of Infusions 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.1.2-A 
Histogram of Number of Infusions 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.1.1-A 
Plot of Mean (+/- SEM) HuMax-TF-ADC 
Plasma Concentrations versus Time on 
a Linear Scale – Cycle 1 only 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.1.2-A 
Plot of Mean (+/- SEM) Total HuMax-TF  
Plasma Concentrations versus Time on 
a Linear Scale – Cycle 1 only 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.1.3-A 
Plot of Mean (+/- SEM) MMAE Plasma 
Concentrations versus Time on a Linear 
Scale – Cycle 1 only 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.1.4-A 
Plot of Mean (+/- SEM) HuMax-TF-ADC 
Plasma Concentrations versus Time on 
a Semi Logarithmic Scale – Cycle 1 only 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.1.5-A 
Plot of Mean (+/- SEM) Total HuMax-TF  
Plasma Concentrations versus Time on 
a Semi Logarithmic Scale – Cycle 1 only 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.1.6-A 
Plot of Mean (+/- SEM) MMAE Plasma 
Concentrations versus Time on a Semi 
Logarithmic Scale – Cycle 1 only 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.1.7-A 
Plot of Dose versus PK Parameter 
Estimates (Cycle 1 Cmax, Cycle 1 AUC 
[0-last] and Cycle 1 AUC[0-inf]) from 
Dose-proportionality Analysis for 
HuMax-TF-ADC 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.1.8-A 
Plot of Dose versus PK Parameter 
Estimates (Cycle 1 Cmax, Cycle 1 AUC 
[0-last] and Cycle 1 AUC[0-inf]) from 
Dose-proportionality Analysis for total 
HuMax-TF 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.1.9-A 
Plot of Dose versus PK Parameter 
Estimates (Cycle 1 Cmax, Cycle 1 AUC 
[0-last] and Cycle 1 AUC[0-inf]) from 
Dose-proportionality Analysis for 
MMAE 
Dose Escalation Part (PK 
Analysis Set 1) 
Figure 14.2.2.1-A 
Best Change in Sum of Lesion 
Measurement 
Dose Escalation Part (Full 
Analysis Set 1) 


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Figure 14.2.2.2-A 
Best Percent Change in Sum of Lesion 
Measurement 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.3.1-A 
Best Change in PSA 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.3.2-A 
Best Percent Change in PSA 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.3.3-A 
Change in PSA after Four Cycles 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.3.4-A 
Plot of Individual PSA Values Over Time 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.3.5-A 
Plot of Percent Change from Baseline 
for Individual PSA Values Over Time 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.4.1-A 
Best Change in CA125 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.4.2-A 
Best Percent Change in CA125 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.4.3-A 
Plot of Individual CA125 Values Over 
Time 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.4.4-A 
Plot of Percent Change from Baseline 
for Individual CA125 Values Over Time 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.5.1-A 
Kaplan-Meier Plot of PFS (Investigator 
Assessment) 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.2.6.1-A 
Kaplan-Meier Plot of Duration of 
Response (Investigator Assessment) 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.1-A 
Bar Chart of Most Intense Adverse 
Events by Cycle 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.2-A 
Intensity and Duration of Skin Rash by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.3.1-A 
Intensity and Duration of Bleeding by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.3.2-A 
Intensity and Duration of Major 
Bleeding by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.3.3-A 
Intensity and Duration of Minor 
Bleeding by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.4-A 
Intensity and Duration of Peripheral 
Neuropathy by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.5.1-A 
Bar Chart of Bleeding Location by Dose 
Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.5.2-A 
Bar Chart of Bleeding Location in Cycle 
1 by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 


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Figure 14.3.5.3-A 
Bar Chart of Major Bleeding Location by 
Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.5.4-A 
Bar Chart of Major Bleeding Location in 
Cycle 1 by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.6-A 
Plots of Mean Laboratory Values over 
Time by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
Figure 14.3.7-A 
Plots of Individual Laboratory Values 
over Time by Dose Cohort 
Dose Escalation Part (Full 
Analysis Set 1) 
FIGURES 
Cohort Expansion Part 
Figure 14.1.1-B 
Duration of Infusions 
Cohort Expansion Part (All 
Enrolled Patients) 
Figure 14.1.2-B 
Histogram of Number of Infusions 
Cohort Expansion Part (All 
Enrolled Patients) 
Figure 14.2.1.1-B 
Plot of Mean (+/- SEM) Humax-TF-ADC 
Plasma Concentrations versus Time on 
a Linear Scale – Cycle 1 only  
Cohort Expansion Part (PK 
Analysis Set 2) 
Figure 14.2.1.2-B 
Plot of Mean (+/- SEM) Total Humax-TF 
(conjugated and non-conjugated) 
Plasma Concentrations versus Time on 
a Linear Scale – Cycle 1 only  
Cohort Expansion Part (PK 
Analysis Set 2) 
Figure 14.2.1.3-B 
Plot of Mean (+/- SEM) MMAE Plasma 
Concentrations versus Time on a Linear 
Scale – Cycle 1 only 
Cohort Expansion Part (PK 
Analysis Set 2) 
Figure 14.2.1.4-B 
Plot of Mean (+/- SEM) HuMax-TF-ADC 
Plasma Concentrations versus Time on 
a Semi-Logarithmic Scale – Cycle 1 only 
Cohort Expansion Part (PK 
Analysis Set 2) 
Figure 14.2.1.5-B 
Plot of Mean (+/- SEM) Non-conjugated 
Total HuMax-TF Plasma Concentrations 
versus Time on a Semi-Logarithmic 
Scale – Cycle 1 only 
Cohort Expansion Part (PK 
Analysis Set 2) 
Figure 14.2.1.6-B 
Plot of Mean (+/- SEM) MMAE Plasma 
Concentrations versus Time on a Semi-
Logarithmic Scale – Cycle 1 only 
Cohort Expansion Part (PK 
Analysis Set 2) 
Figure 14.2.1.7-B 
Plot of Mean (+/- SEM) HuMax-TF-ADC 
Ctrough, Total HuMax-TF Ctrough, 
MMAE Ctrough versus Time in same 
plot  
Cohort Expansion Part (PK 
Analysis Set 2) 
Figure 14.2.1.8-B 
Plot of Mean (+/- SEM) HuMax-TF-ADC, 
Total HuMax-TF, MMAE Concentration 
versus Time profile in same plot  
Cohort Expansion Part (PK 
Analysis Set 2) 
Figure 14.2.2.1-B 
Best Change in Sum of Lesion 
Measurement 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Figure 14.2.2.2-B 
Best Percent Change in Sum of Lesion 
Measurement 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.3.1-B 
Best Change in PSA 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.3.2-B 
Best Percent Change in PSA 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.3.3-B 
Change in PSA after Four Cycles 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.3.4-B 
Plot of Individual PSA Values Over Time 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.3.5-B 
Plot of Percent Change from Baseline 
for Individual PSA Values Over Time 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.4.1-B 
Best Change in CA125 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.4.2-B 
Best Percent Change in CA125 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.4.3-B 
Plot of Individual CA125 Values Over 
Time 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.4.4-B 
Plot of Percent Change from Baseline 
for Individual CA125 Values Over Time 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.5.1-B 
Kaplan-Meier Plot of PFS (Investigator 
Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.5.2-B 
Kaplan-Meier Plot of PFS – Including 
Undocumented Progression 
(Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.5.3-B 
Kaplan-Meier Plot of PFS (Review 
committee Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.6.1-B 
Kaplan-Meier Plot of Duration of 
Response (Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.6.2-B 
Kaplan-Meier Plot of Duration of 
Response ( Review committee 
Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.6.3-B 
Swimlane Plot by Cancer Type 
(Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.6.4-B 
Swimlane Plot by Cancer Type (Review 
committee Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.7.1-B 
Median change in Circulating TF by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.7.2-B 
Median change in Circulating TF by Best 
Overall Response of Clinical Benefit 
versus Progressive Disease and Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Figure 14.2.7.3-B 
Change in Circulating TF by Baseline H-
Membrane Score 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.8.1-B 
Median change in cfDNA by Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.2.8.2-B 
Median change in cfDNA by Best 
Overall Response of Clinical Benefit 
versus Progressive Disease and Cancer 
Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.1-B 
Bar Chart of Most Intense Adverse 
Events by Cycle 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.2-B 
Intensity and Duration of Skin Rash by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.3.1-B 
Intensity and Duration of Bleeding by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.3.2-B 
Intensity and Duration of Major 
Bleeding by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.3.3-B 
Intensity and Duration of Minor 
Bleeding by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.4-B 
Intensity and Duration of Peripheral 
Neuropathy by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.5.1-B 
Bar Chart of Bleeding Location by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.5.2-B 
Bar Chart of Bleeding Location in Cycle 
1 by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.5.3-B 
Bar Chart of Major Bleeding Location by 
Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.5.4-B 
Bar Chart of Major Bleeding Location in 
Cycle 1 by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.6-B 
Plots of Mean Laboratory Values over 
Time by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
Figure 14.3.7-B 
Plots of Individual Laboratory Values 
over Time by Cancer Type 
Cohort Expansion Part (Full 
Analysis Set 2) 
LISTINGS 
Dose Escalation Part 
Listing 16.2.1.1-A 
Withdrawal from/Completion of Study 
Dose Escalation Part (All 
Enrolled Patients) 
Listing 16.2.1.2-A 
Withdrawal/Completion of Treatment 
Dose Escalation Part (All 
Enrolled Patients) 
Listing 16.2.2-A 
Significant Protocol Deviations 
Dose Escalation Part (All 
Enrolled Patients) 


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Listing 16.2.3-A 
Patient Populations 
Dose Escalation Part (All 
Enrolled Patients) 
Listing 16.2.4.1-A 
Demographic and Baseline Data 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.4.2-A 
General Medical History 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.4.3-A 
Primary Disease History 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.4.4-A 
Tumor Biopsy 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.4.5-A 
Tumor TF Expression 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.4.6-A 
Peripheral Neuropathy History 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.4.7-A 
Prior Cancer Therapies 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.4.8-A 
Prior and Concomitant Medications 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.4.9-A 
Visual Acuity 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.5.1-A 
Study Drug Administration 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.5.2-A 
Exposure to Study Drug 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.5.3-A 
Individual HuMax-TF-ADC, Total 
HuMax-TF and MMAE Plasma 
Concentrations 
Dose Escalation Part (PK 
Analysis Set 1) 
Listing 16.2.5.4-A 
HuMax-TF-ADC Plasma 
Pharmacokinetic Parameters 
Dose Escalation Part (PK 
Analysis Set 1) 
Listing 16.2.5.5-A 
Total HuMax-TF  Plasma 
Pharmacokinetic Parameters 
Dose Escalation Part (PK 
Analysis Set 1) 
Listing 16.2.5.6-A 
MMAE Plasma Pharmacokinetic 
Parameters 
Dose Escalation Part (PK 
Analysis Set 1) 
Listing 16.2.6.1-A 
Target, Non-Target and New Lesion 
Assessment 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.6.2-A 
Response Data 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.6.3-A 
Best Overall Response Data 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.6.4-A 
Progression Free Survival and Duration 
of Response 
Dose Escalation Part (Full 
Analysis Set 1) 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Listing 16.2.6.5-A 
Radionuclide Bone Scan 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.6.6-A 
New Anti-Cancer Treatment 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.6.7-A 
PSA Levels 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.6.8-A 
CA-125 Levels 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.6.9-A 
Circulating Tissue Factor (cTF)  Levels 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.6.10-A 
Tumor Marker (cfDNA) 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.1-A 
Adverse Event Listing 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.2-A 
Adverse Events Sorted by Preferred 
Term 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.3-A 
Listing of Study Treatment Related 
Adverse Events 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.4-A 
Listing of Adverse Events with Grade 
>=3 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.5-A 
Listing of Adverse Events Occurring in 
Cycle 1 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.6-A 
Listing of Adverse Events Leading to 
Dose Interruption 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.6.2-A 
Listing of Adverse Events Leading to 
Dose Reduction 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.7-A 
Skin Assessment 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.8-A 
Bleeding Assessment 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.7.9-A 
Peripheral Neuropathy 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.1-A 
Hematology Results and Change from 
Baseline 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.2-A 
Biochemistry Results and Change from 
Baseline 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.3-A 
Coagulation Factor Results and Change 
from Baseline 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.4-A 
Flow Cytometry Results and Change 
from Baseline 
Dose Escalation Part (Full 
Analysis Set 1) 


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Listing 16.2.8.5-A 
Serology Results 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.6.1-A 
Immunogenicity Results and Change 
from Baseline 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.6.2-A 
Immunogenicity Results Matched with 
PK Assessments  
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.7-A 
Serum Pregnancy Test Results  
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.8-A 
Other Blood Test Results 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.9-A 
Physical Examination 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.10-A 
Vital Signs 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.11-A 
ECG – Investigator Assessment 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.12-A 
ECG – Central Reading 
Dose Escalation Part (Full 
Analysis Set 1) 
Listing 16.2.8.13-A 
ECOG Assessment 
Dose Escalation Part (Full 
Analysis Set 1) 
LISTINGS 
Cohort Expansion Part 
Listing 16.2.1.1-B 
Withdrawal from/Completion of Study 
Cohort Expansion Part (All 
Enrolled Patients) 
Listing 16.2.1.2-B 
Withdrawal/Completion of Treatment 
Cohort Expansion Part (All 
Enrolled Patients) 
Listing 16.2.2-B 
Significant Protocol Deviations 
Cohort Expansion Part (All 
Enrolled Patients) 
Listing 16.2.3-B 
Patient Populations 
Cohort Expansion Part (All 
Enrolled Patients) 
Listing 16.2.4.1-B 
Demographic and Baseline Data 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.2-B 
General Medical History 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.3-B 
Primary Disease History 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.4-B 
Tumor Biopsy 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.5-B 
 Tumor TF expression 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Listing 16.2.4.6-B 
Peripheral Neuropathy History 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.7-B 
Prior Cancer Therapies 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.8-B 
Prior and Concomitant Medications 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.9-B 
Visual Acuity 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.10-B 
HPV Historical Sample and PAP Smear 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.11a-B 
Demographics Histology and 
Histological Grade – Part 1 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.4.11b-B 
Demographics Histology and 
Histological Grade – Part 2 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.5.1.1-B 
Pre-infusion Medication 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.5.1-B 
Study Drug Administration 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.5.2-B 
Exposure to Study Drug 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.5.3-B 
Individual HuMax-TF-ADC, Total 
HuMax-TF and MMAE Plasma 
Concentrations 
Cohort Expansion Part (PK 
Analysis Set 2) 
Listing 16.2.5.4-B 
HuMax-TF-ADC Plasma 
Pharmacokinetic Parameters 
Cohort Expansion Part (PK 
Analysis Set 2) 
Listing 16.2.5.5-B 
Total HuMax-TF  Plasma 
Pharmacokinetic Parameters 
Cohort Expansion Part (PK 
Analysis Set 2) 
Listing 16.2.5.6-B 
MMAE Plasma Pharmacokinetic 
Parameters 
Cohort Expansion Part (PK 
Analysis Set 2) 
Listing 16.2.6.1-B 
Target, Non-Target and New Lesion 
Assessment 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.1b-B 
Target, Non-Target and New Lesion 
Assessment – Independent Review 
Committee 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.2-B 
Response Data 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.2b-B 
Response Data – Independent Review 
Committee 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.3-B 
Best Overall Response Data 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.3b-B 
Best Overall Response Data – 
Independent Review Committee 
Cohort Expansion Part (Full 
Analysis Set 2) 


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Listing 16.2.6.4-B 
Progression Free Survival and Duration 
of Response 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.4a-B 
Progression Free Survival – 
Undocumented Progression 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.4b-B 
Progression Free Survival and Duration 
of Response – Independent Review 
Committee 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.5-B 
Radionuclide Bone Scan 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.6-B 
New Anti-Cancer Treatment 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.7-B 
PSA Levels 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.8-B 
CA-125 Levels 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.9-B 
Circulating Tissue Factor (cTF) Levels 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.6.10-B 
Tumor Marker (cfDNA) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.1-B 
Adverse Event Listing 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.2-B 
Adverse Events Sorted by Preferred 
Term 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.3-B 
Listing of Study Treatment Related 
Adverse Events 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.4.1-B 
Listing of Adverse Events with Grade 
>=3 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.4.2-B 
Listing of Adverse Events with Grade 
>=3 for Patients with Positive ADA 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.5-B 
Listing of Adverse Events Occurring in 
Cycle 1 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.6-B 
Listing of Adverse Events Leading to 
Dose Interruption 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.6.2-B 
Listing of Adverse Events Leading to 
Dose Reduction 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.7-B 
Skin Assessment 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.8-B 
Bleeding Assessment 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.7.9-B 
Peripheral Neuropathy 
Cohort Expansion Part (Full 
Analysis Set 2) 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Listing 16.2.8.1-B 
Hematology Results and Change from 
Baseline 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.2-B 
Biochemistry Results and Change from 
Baseline 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.3-B 
Coagulation Factor Results and Change 
from Baseline 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.4-B 
Flow Cytometry Results and Change 
from Baseline 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.5-B 
Serology Results 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.6.1-B 
Immunogenicity Results and Change 
from Baseline 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.6.2-B 
Immunogenicity Results Matched with 
PK Assessments  
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.7-B 
Serum Pregnancy Test Results  
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.8-B 
Other Blood Test Results  
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.9-B 
Physical Examination 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.10-B 
Vital Signs 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.11-B 
ECG – Investigator Assessment 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.12-B 
ECG – Central Reading 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.13-B 
ECOG Assessment 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.14a-B 
Ophthalmology – Part 1 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.14b-B 
Ophthalmology – Part 2 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.14c-B 
Ophthalmology – Part 3 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.14d-B 
Ophthalmology – Part 4 
Cohort Expansion Part (Full 
Analysis Set 2) 
Listing 16.2.8.14e-B 
Ophthalmology – Part 5 
Cohort Expansion Part (Full 
Analysis Set 2) 
Supportive SAS Output Appendices 
Dose Escalation Part 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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Appendix 16.1.9.1-A 
Analysis of Dose Proportionality of 
Cycle 1 Cmax, Cycle 1 AUClast and Cycle 
1 AUCinf for HuMax-TF-ADC 
Dose Escalation Part (PK 
Analysis Set 1) 
Appendix 16.1.9.2-A 
Analysis of Dose Proportionality of 
Cycle 1 Cmax, Cycle 1 AUClast and Cycle 
1 AUCinf for total HuMax-TF 
Dose Escalation Part (PK 
Analysis Set 1) 
Appendix 16.1.9.3-A 
Analysis of Dose Proportionality of 
Cycle 1 Cmax, Cycle 1 AUClast and Cycle 
1 AUCinf for MMAE 
Dose Escalation Part (PK 
Analysis Set 1) 
Appendix 16.1.9.4-A 
Kaplan-Meier Analysis of Progression 
Free Survival (Investigator Assessment) 
Dose Escalation Part (Full 
Analysis Set 1) 
Appendix 16.1.9.5-A 
Kaplan-Meier Analysis of Duration of 
Response (Investigator Assessment) 
Dose Escalation Part (Full 
Analysis Set 2) 
Cohort Expansion Part 
Appendix 16.1.9.1-B 
Kaplan-Meier Analysis of Progression 
Free Survival (Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Appendix 16.1.9.2-B 
Kaplan-Meier Analysis of Progression 
Free Survival – Including 
Undocumented Progression 
(Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Appendix 16.1.9.3-B 
Kaplan-Meier Analysis of Progression 
Free Survival (Review committee 
Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Appendix 16.1.9.4-B 
Kaplan-Meier Analysis of Duration of 
Response (Investigator Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 
Appendix 16.1.9.5-B 
Kaplan-Meier Analysis of Duration of 
Response (Review committee 
Assessment) 
Cohort Expansion Part (Full 
Analysis Set 2) 


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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APPENDIX 4 SHELLS FOR IN-TEXT TABLES, FIGURES, AND 
LISTINGS 
Not applicable  


Sponsor:  Genmab                                                                                                       Statistical Analysis Plan 
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                                     Page 62 of 62 
APPENDIX 5 SHELLS FOR POST-TEXT TABLES, FIGURES, AND 
LISTINGS 
Shells for post-text Tables, Figures and Listings are contained in a separate document.