First-in-human, Open-label, Dose-escalation Trial With Expansion Cohorts to Evaluate Safety of Axl-specific Antibody-drug Conjugate (Enapotamab Vedotin, HuMax®-AXL-ADC) in Patients With Solid Tumors
Phase: PHASE1
Conditions: Ovarian Cancer, Cervical Cancer, Endometrial Cancer, Non Small Cell Lung Cancer (NSCLC), Thyroid Cancer, Melanoma, Sarcoma, Solid Tumors
Sponsor: Genmab

Document Name: GCT1021-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
1 
PROTOCOL AND SUMMARY OF PROTOCOL 
AMENDMENTS 
First-in-human, open-label, dose-escalation trial with 
expansion cohorts to evaluate safety of Axl-specific antibody-
drug conjugate (enapotamab vedotin, HuMax®-AXL-ADC) in 
patients with solid tumors 
 
Protocol No.: 
GCT1021-01 
IND No.: 
129620 
EudraCT No.: 
2016-002243-42 
NCT No.: 
NCT02988817 
Sponsor: 
Genmab A/S 
Kalvebod Brygge 43 
DK-1560 Copenhagen V, Denmark 
Medical Monitor: 
 
 
 
 United Kingdom 
 
 

Document Name: GCT1021-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
1 
OVERVIEW OF PROTOCOL AMENDMENTS .................................................. 3 
2 
SUMMARY OF PROTOCOL AMENDMENTS .................................................... 4 
3 
REDACTED PROTOCOL VERSION 11.0, LATEST VERSION ....................... 7 
 
 
 

Document Name: GCT1021-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
3 
1 OVERVIEW OF PROTOCOL AMENDMENTS 
 
Protocol/Amendment No; Version  
Issue Date 
Version 11.0 (incorporating Protocol Amendment 10) 
30 June 2021 
Version 10.0 (incorporating Protocol Amendment 9) 
09-dec-19 
Version 9.0 (incorporating Protocol Amendment 8) 
21 October 2019 
Version 8.0 (incorporating Protocol Amendment 7) 
18 June 2019 
Version 7.0 (incorporating Protocol Amendment 6) 
07-dec-18 
Version 6.0 (incorporating Protocol Amendment 5) 
11 October 2018 (internal version only) 
Version 5.0 (incorporating Protocol Amendment 4) 
12-apr-18 
Version 4.0 (incorporating Protocol Amendment 3) 
25-sep-17 
Version 3.0 (incorporating Protocol Amendment 2) 
10 August 2017 (internal version only) 
Version 2.0 (incorporating Protocol Amendment 1) 
16-dec-16 
Version 1.0 (original protocol) 
07 June 2016 
 
 

Document Name: GCT1021-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
4 
2 SUMMARY OF PROTOCOL AMENDMENTS 
A total of 10 amendments were made to the protocol Table 1; of these, Amendment 2 (protocol 
v3.0) was only an internal Genmab document and never distributed to sites or submitted to any 
health authorities.  
Table 1 
Protocol Amendments 
Amendment Number/ 
Protocol Version and Date 
Key Changes 
Global Amendment 10 
(Protocol v11.0) 
30 June 2021 
• To allow analysis and reporting of the trial, while permitting the 3 remaining subjects to stay on 
treatment and be followed per protocol.  
• At the time of this Amendment, the Dose Escalation part and the enrollment of the Expansion 
part of trial had been completed; 3 subjects remained on treatment. The 3 subjects had been on 
treatment for at least 7 months, which was considered sufficient to evaluate efficacy and safety.  
• With this amendment, the 3 subjects still on treatment will continue treatment and be followed 
with reduced procedures and visits. (Refer to the protocol Appendix VI and Table 31 for 
applicable procedures and assessments as of Amendment 10.) 
• Sections 10 Statistical Analysis, 10.7 Interim Analyses, and 10.8 Clinical Trial Reporting were 
revised to reflect the analysis of efficacy and safety per data cut-off date and clinical trial 
reporting plans. The plan to present QTc analyses in a separate report was removed.  
Note: Amendment 10 (protocol v11.0) did not have any impact on the current reporting, since this 
amendment was generated after the data cut-off date for this CSR. 
Global Amendment 9 
(Protocol v10.0) 
09 December 2019  
• 
Added Cohort 8 to further explore, in the same subject population as Cohort 2, the 1.0 mg/kg 
3Q4W schedule adding up to 37 subjects to be treated. 
• 
Added a rationale for the subgroup of the subjects in Cohort 2 at a dose of 1.8 mg/kg, which was 
not included in Amendment 8. 
• 
Excluded subjects who experienced hyper-progressive disease during prior checkpoint inhibitor 
therapy. 
• 
Reduced number of visits as visits are a burden for subjects. 
• 
Clarified pharmacokinetic (PK) assessments – Expansion. 
• 
Added peripheral neuropathy reporting requirements to enhance data collection and facilitate the 
understanding and characterization of the event. 
• 
Clarified data summarized for subjects with NSCLC without epidermal growth factor receptor 
(EGFR)/ALK mutations. 
• 
Removed interim analysis for futility for Cohorts 6 and 8. 
Global Amendment 8 
(Protocol v9.0)  
21 October 2019 
• Implemented more stringent dose modification guidance for treatment-emergent adverse events 
(TEAEs) of peripheral neuropathy. 
• Modified PK sampling. 
• In an attempt to improve the observed tolerability profile and expand the possible therapeutic 
window for enapotamab vedotin, a limited number of subjects could be enrolled in Cohort 2 on a 
starting dose of 1.8 mg/kg. 
• In order to obtain 25 fresh biopsies from Cohort 6, up to 15 additional subjects could be 
recruited. 
• Implemented to further explore the potential of the maximum tolerated dose (MTD) of the 3Q4W 
schedule.  
• Clarified that adjuvant or maintenance treatment would be counted as 1 regimen, together with 
the relevant surgery or primary treatment.  
• Revised inclusion criteria. The reference to adjuvant and maintenance treatment was no longer 
relevant for the inclusion criterion. 
• Relaxed the restriction criteria, as the restriction of up to 3 lines of prior treatment proved to be 
challenging for enrolment as many subjects failed more than 3 lines. 

Document Name: GCT1021-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
5 
Amendment Number/ 
Protocol Version and Date 
Key Changes 
• Clarified how long dosing could be delayed for and how the resumption of dosing should be 
handled for the 3Q4W dosing schedule. 
• Spain was included as a country in the trial. 
Global Amendment 7  
(Protocol v8.0)  
18 June 2019 
• 
Excluded subjects with ongoing pneumonitis at Screening or with a history of non-infectious 
pneumonitis that required steroids. The protocol was amended to allow for inclusion of subjects 
who had pneumonitis in the past if more than 6 months prior to enrollment, if subjects were 
asymptomatic, did not require any steroid treatment, and had no radiologic evidence of 
pneumonitis. 
• 
In order to maximize the clinical benefit for subjects, the treatment interruption window was not 
limited to 2 weeks but allowed for a longer period of recovery prior to re-starting treatment. 
• 
Figure was deleted as details in dose reduction were clear enough in Table 5 and text.  
• 
Clarified that every effort should be made to document disease progression by radiological 
imaging and response evaluation criteria in solid tumors (RECIST) even though subject was 
discontinued from trial treatment, eg, due to an adverse event (AE). 
• 
 
 
• 
Clarified text around confirmation of response according to RECIST and guidance added around 
scans in case of discontinuation due to an AE, ie, that scans should continue until progression, 
start of new cancer therapy, withdrawal of consent or death, even though trial treatment was 
prematurely withdrawn. 
• 
Clarified timing of scans, ie, that they need to be calendar based, regardless of trial drug 
administration delay.  
• 
Clarified that unscheduled scans should be performed if clinically indicated and all additional 
scans should be submitted to the Independent Review Committee (IRC) for independent review 
for subjects in the Expansion part.  
• 
Clarified that both investigator disease assessments as well as IRC assessment would be used for 
analysis. 
• 
Added clarification on expectations where bronchoscopy-guided biopsies may be allowed. 
• 
Noted that the information on investigator assessment of the clinical significance of lab values 
was not included in the Study Data Tabulation Model (SDTM) dataset and therefore could not be 
extracted for inclusion in listings.  
• 
The treatment algorithm was changed from a limited number of cycles to treatment until 
progression of the underlying disease per RECIST was detected.  
Global Amendment 6  
(Protocol v7.0)  
07 December 2018 
• 
Modified some of the inclusion criteria for the expansion cohorts to further define the exact 
target subject population and to guard subject safety during the trial.  
• 
Due to emerging safety data, a new subsection on dose modifications for immune-related AEs 
was introduced for optimal management of these events.  
• 
The possibility to conduct further safety review after 36 and 100 subjects in the Expansion part 
was added. 

Document Name: GCT1021-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
6 
Amendment Number/ 
Protocol Version and Date 
Key Changes 
Global Amendment 5  
(Protocol v6.0)  
11 October 2018 
• 
Additional subjects to be enrolled in Cohort 2 were added due to observation of an efficacy 
signal in subjects without drug-sensitizing mutations treated for NSCLC. Clarified that in Cohort 
2, only subjects with wild-type EGFR should be enrolled ie, not only subjects without the 
classical sensitizing EGFR mutations but also without the resistance mutations such as T790M, 
targeted by third generation TKIs. This wording was also added to the last part of inclusion 
criterion #1.  
• 
Newly identified risks, including peripheral neuropathy and neutropenia, were described for 
enapotamab vedotin in Version 4.0 of the Investigator’s Brochure (IB). Based on this IB update, 
new subsections were added describing the relevant safety findings.  
• 
Throughout the protocol, changed the INN name for HuMax-AXL-ADC to enapotamab vedotin. 
• 
Expansion part: cohort(s) used throughout the protocol instead of arm(s). 
Global Amendment 4  
(Protocol v5.0)  
12 April 2018 
• 
A 7th arm with platinum-resistant ovarian cancer subjects was added to the Expansion part of the 
trial. By adding this arm, the planned number of subjects also increased. 
• 
An interim analysis for futility for all cohorts was introduced. This provided a mechanism to 
reduce the number of subjects exposed to a potentially inefficient experimental therapy. 
• 
Subjects who benefit from the treatment were offered continued treatment within the scope of the 
protocol until their disease progressed or until they experienced unacceptable toxicity. 
• 
A subject diary was introduced in order to capture information on prophylactic use of stool 
softeners to prevent constipation. The diary also captured changes in stool frequency and 
consistency. 
Global Amendment 3 
(Protocol v4.0) 
25 September 2017  
 
 
• 
Introduced the updated mitigation plan for handling of constipation as well as introducing safety 
blood samples to be collected locally 24 hours prior to each investigational medicinal product 
administration. 
• 
Clarified the visit window of Cycle 2 Visit 1 in order to ensure that the DLT evaluation period 
during Cycle 1 completed as planned before initiation of Cycle 2. 
• 
Updated time windows for some of the assessments of vital signs in order to allow for practical 
and safe assessments. 
Amendment 2 
(Protocol v3.0) 
10 August 2017 
Amendment 2 (protocol v3.0) was never distributed; only internal document at Genmab. 
 
Global Amendment 1 
(Protocol v2.0)  
16 December 2016 
• 
Included melanoma cancer as an additional indication in the trial.  
• 
Inclusion/exclusion criteria were updated. 
• 
Genetic and proteomic analyses were removed.  
• 
Updated and clarified the sampling, timing, specification, handling and methods of the 
exploratory analyses.  
• 
Storage of the biological samples in the trial was clarified. 
Original Protocol v1.0 
07 June 2016  
Original Protocol 
 
 
 

Document Name: GCT1021-01 Redacted Protocol and Summary of Protocol Amendments 
Genmab 
 
 
7 
3 REDACTED PROTOCOL VERSION 11.0, LATEST VERSION 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 1 of 259 
TRIAL PROTOCOL 
First-in-human, open-label, dose-escalation trial with expansion cohorts to evaluate safety 
of Axl-specific antibody-drug conjugate (enapotamab vedotin, HuMax®-AXL-ADC) in 
patients with solid tumors 
Protocol No.: 
GCT1021-01 
IND No.: 
129620 
EudraCT No.: 
2016-002243-42 
 
 
Coordinating 
Investigator: 
Prof. Dr. 
 
 
 
 
, Belgium 
 
 
Sponsor: 
Genmab A/S 
Kalvebod Brygge 43 
DK-1560 Copenhagen V, Denmark 
 
 
Medical 
Monitor: 
 
 
 
 
 United Kingdom 
 
Version and 
Date: 
Version 11.0 (incorporating Protocol Amendment 10), 30 June 2021 
Version 10.0 (incorporating Protocol Amendment 9), 09 December 2019 
Version 9.0 (incorporating Protocol Amendment 8), 21 October 2019 
Version 8.0 (incorporating Protocol Amendment 7), 18 June 2019 
Version 7.0 (incorporating Protocol Amendment 6), 07 December 2018 
Version 6.0 (incorporating Protocol Amendment 5), 11 October 2018 
(internal version only) 
Version 5.0 (incorporating Protocol Amendment 4), 12 April 2018 
Version 4.0 (incorporating Protocol Amendment 3), 25 September 2017 
Version 3.0 (incorporating Protocol Amendment 2), 10 August 2017 
(internal version only) 
Version 2.0 (incorporating Protocol Amendment 1), 16 December 2016 
Version 1.0 (original protocol), 07 June 2016 
 This document contains strictly confidential information and cannot be 
disclosed or used, unless authorized in writing by Genmab A/S and 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 2 of 259 
INVESTIGATOR AGREEMENT 
I have read this protocol and agree that it contains all necessary details for carrying out this trial. I will 
conduct the trial as outlined herein and will complete the trial within the time designated. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this trial. I will discuss this material with them to ensure that they are fully informed 
regarding the trial drug, the conduct of the trial, and the obligations of confidentiality. 
NOTE: The Coordinating Investigator section below is applicable only to the country-specific coordinating 
investigators within the EU, where applicable. 
Coordinating Investigator (where required): 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Signature: 
 
Date: 
 
 
 
 
(DD-Mmm-YYYY) 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(DD-Mmm-YYYY) 
 
Note: If the address or telephone number of the investigator changes during the course of the trial, 
written notification will be provided by the investigator to the sponsor, and a protocol amendment will not 
be required. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 3 of 259 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................3 
CLINICAL TRIAL SYNOPSIS ....................................................................14 
PROTOCOL AMENDMENTS .....................................................................31 
1. 
GENERAL INFORMATION .......................................................34 
1.1 
Protocol Number and Title of the Trial ............................................34 
1.2 
Sponsor .............................................................................................34 
1.3 
Clinical Research Organization (CRO) ............................................34 
1.4 
Signature Authorization ...................................................................34 
2. 
BACKGROUND INFORMATION ..............................................35 
2.1 
Introduction ......................................................................................35 
2.2 
Non-Clinical Safety ..........................................................................36 
2.3 
Summary of Known and Potential Risks to Human Patients ...........38 
2.3.1 
Implications of Non-Clinical Safety Results for Monitoring of 
Patients/Mitigation Plans ..................................................................38 
2.3.2 
Implications of Clinical Safety Results for Monitoring of 
Patients/Mitigation Plans ..................................................................39 
3. 
TRIAL DESCRIPTION .................................................................40 
3.1 
Patient Population .............................................................................40 
3.2 
Trial Design Rationale ......................................................................40 
3.2.1 
Rationale for PK Sampling ...............................................................42 
3.2.2 
Rationale for Biomarker Analyses ...................................................42 
3.3 
Dose Rationale .................................................................................42 
3.3.1 
Rationale for Dose Frequency ..........................................................43 
3.4 
Number of Patients and Sites ...........................................................43 
3.5 
Duration of Treatment ......................................................................46 
3.6 
Characteristics of a Well-Conducted Trial .......................................46 
4. 
TRIAL OBJECTIVES AND PURPOSE ......................................47 
4.1 
Primary Objective .............................................................................47 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 4 of 259 
4.2 
Secondary Objectives .......................................................................47 
4.3 
Exploratory Objective ......................................................................47 
4.4 
Primary Endpoints ............................................................................47 
4.5 
Secondary Endpoints ........................................................................47 
4.6 
Exploratory Endpoints ......................................................................48 
5. 
TRIAL DESIGN .............................................................................49 
5.1 
Overview of Trial Design .................................................................49 
5.2 
Dose Escalation, 1Q3W ...................................................................51 
5.3 
Dose Escalation, 3Q4W ...................................................................53 
5.4 
Expansion Part ..................................................................................54 
5.5 
Data Monitoring Committee ............................................................55 
5.6 
Trial Overview .................................................................................56 
5.6.1 
Screening Phase (Visit 0) .................................................................56 
5.6.2 
Treatment Phase ...............................................................................56 
5.6.2.1 
Dose Escalation Part .........................................................................56 
5.6.2.2 
Expansion Part ..................................................................................57 
5.6.3 
Unscheduled visit .............................................................................57 
5.6.4 
End of Treatment visit ......................................................................57 
5.6.5 
Safety Follow-up ..............................................................................57 
5.6.6 
Follow-up Contact ............................................................................57 
5.6.7 
Lost to Follow-up .............................................................................58 
5.6.8 
End of Trial ......................................................................................58 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ...............59 
6.1 
Inclusion Criteria ..............................................................................59 
6.2 
Exclusion Criteria .............................................................................63 
6.3 
Withdrawal Criteria ..........................................................................66 
6.3.1 
Criteria for Patient Withdrawal from Treatment ..............................67 
6.3.2 
Criteria for Patient Withdrawal from the Trial .................................67 
6.4 
Noncompliance .................................................................................67 
6.5 
Trial Stopping Criteria ......................................................................67 
6.6 
Definition of End of Trial .................................................................68 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 5 of 259 
7. 
TREATMENT OF PATIENTS .....................................................68 
7.1 
Investigational Medicinal Product - Enapotamab Vedotin ..............68 
7.1.1 
Treatment Administration ................................................................68 
7.1.2 
Treatment Preparation ......................................................................69 
7.2 
Dose-limiting Toxicity .....................................................................69 
7.3 
Dose Modifications ..........................................................................70 
7.3.1 
Dose Delay, Dose Modification and Stopping Rules during Dose 
Escalation .........................................................................................70 
7.3.2 
Dose Modifications and Dose Delays for Patients Experiencing 
Adverse Events during Expansion ...................................................72 
7.3.3 
Immune-related Adverse Events ......................................................76 
7.4 
Limitation in Concomitant Medication ............................................82 
7.4.1 
Prophylactic Concomitant Medications ...........................................82 
7.4.2 
Permitted Concomitant Medications ................................................83 
7.4.3 
Excluded Concomitant Therapy .......................................................84 
7.5 
Infusion-Related Reactions ..............................................................85 
8. 
TRIAL EVALUATION .................................................................86 
8.1 
Table of Assessments .......................................................................86 
8.2 
PK Sampling (Enapotamab Vedotin, HuMax-AXL and MMAE) ...95 
8.3 
Exploratory Biomarker Analyses .....................................................96 
8.4 
Clinical Assessments ........................................................................99 
8.4.1 
Demographics ...................................................................................99 
8.4.2 
Disease Status ...................................................................................99 
8.4.3 
Medical History ..............................................................................100 
8.4.4 
Height and Weight ..........................................................................100 
8.4.5 
Physical Examination .....................................................................100 
8.4.6 
Electrocardiogram ..........................................................................100 
8.4.6.1 
ECG Assessment ............................................................................101 
8.4.7 
Imaging/Computed Tomography ...................................................102 
8.4.8 
Vital Signs ......................................................................................103 
8.4.9 
ECOG Performance Status .............................................................105 
8.4.10 
Concomitant Medication ................................................................105 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 6 of 259 
8.4.11 
Prior Cancer Therapy and Surgery .................................................105 
8.4.12 
Adverse Events ...............................................................................106 
8.4.13 
Patient Diary ...................................................................................106 
8.5 
Laboratory Assessments .................................................................107 
8.5.1 
Biochemistry ..................................................................................108 
8.5.2 
Hematology ....................................................................................109 
8.5.3 
CA 125 ...........................................................................................109 
8.5.4 
Urinalysis ........................................................................................109 
8.5.5 
Enapotamab Vedotin, HuMax-AXL and MMAE in Serum ...........109 
8.5.6 
Hepatitis B, C and Cytomegalovirus Serology ..............................109 
8.5.7 
Pregnancy Test ...............................................................................110 
8.5.8 
Immunogenicity of Enapotamab Vedotin ......................................110 
8.5.9 
Tumor Biopsy .................................................................................110 
8.5.9.1 
Axl Expression ...............................................................................110 
8.5.10 
Exploratory Biomarker Analyses ...................................................111 
8.5.11 
Biological Sample Handling ..........................................................112 
8.5.12 
Chain of Custody of Biological Samples .......................................112 
9. 
REPORTING OF ADVERSE EVENTS ....................................114 
9.1 
Recording Instructions ...................................................................114 
9.1.1 
Definition of Adverse Events of Special Interest (AESI) ..............115 
9.1.2 
Diagnosis ........................................................................................115 
9.1.3 
Intensity ..........................................................................................115 
9.1.4 
Relatedness to Investigational Medicinal Product .........................115 
9.1.5 
Start Date and Time ........................................................................115 
9.1.6 
Outcome .........................................................................................116 
9.1.7 
Action Taken with Investigational Medicinal Product ...................116 
9.1.8 
End Date and Time .........................................................................116 
9.1.9 
Adverse Events of Special Interest .................................................117 
9.1.9.1 
Constipation ....................................................................................117 
9.1.9.2 
Neutropenia ....................................................................................117 
9.1.9.3 
Peripheral Neuropathy ....................................................................117 
9.1.9.4 
Immune-related Adverse Events ....................................................118 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 7 of 259 
9.1.10 
Information about Infusion Related Reactions ...............................118 
9.1.11 
Serious Adverse Event ...................................................................118 
9.2 
Definition of Serious Adverse Events ............................................118 
9.3 
Events Requiring Immediate Reporting .........................................119 
9.3.1 
Serious Adverse Events and Non-serious Grade 3 Adverse Events
 ........................................................................................................119 
9.3.2 
Peripheral Neuropathy Adverse Events ≥ Grade 2 or Leading to 
Permanent Discontinuation of Enapotamab Vedotin Treatment ....119 
9.3.3 
Overdose and Medication Errors ....................................................119 
9.3.4 
Pregnancy .......................................................................................119 
9.4 
Timelines for Reporting .................................................................120 
9.5 
Suspected Unexpected Serious Adverse Reactions ........................121 
9.6 
Follow-Up on Adverse Events .......................................................121 
9.7 
Safety Management Plan ................................................................121 
10. 
STATISTICAL ANALYSIS ........................................................123 
10.1 
Analysis Sets ...................................................................................123 
10.1.1 
Full Analysis Set .............................................................................123 
10.1.2 
Safety Set ........................................................................................124 
10.1.3 
Per-Protocol Set ..............................................................................124 
10.1.4 
Dose-Determining Set .....................................................................124 
10.2 
Statistical Methodology for Primary Endpoint ..............................124 
10.2.1 
Dose Escalation, 1Q3W .................................................................125 
10.2.2 
Dose Escalation, 3Q4W .................................................................126 
10.2.3 
Expansion Part ................................................................................126 
10.3 
Statistical Methodology for other Endpoints ..................................127 
10.3.1 
Patient Disposition .........................................................................127 
10.3.2 
Demographics and Baseline Characteristics ..................................127 
10.3.3 
Medical History ..............................................................................127 
10.3.4 
Prior Cancer Therapies ...................................................................127 
10.3.5 
Treatments (Enapotamab Vedotin, Concomitant Therapies, 
Compliance) ...................................................................................128 
10.3.6 
Clinical Safety Data ........................................................................128 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 8 of 259 
10.3.6.1 Adverse Events ...............................................................................128 
10.3.6.2 Patient diary ....................................................................................128 
10.3.6.3 Other Clinical Safety Data .............................................................129 
10.3.7 
Safety Laboratory Parameters ........................................................129 
10.3.8 
Hepatitis B, C and Cytomegalovirus Serology ..............................129 
10.3.9 
Pregnancy Test ...............................................................................129 
10.3.10 
Immunogenicity of Enapotamab Vedotin ......................................129 
10.3.11 
Axl Expression ...............................................................................130 
10.3.12 
Exploratory Analyses .....................................................................130 
10.3.13 
Anti-tumor Activity ........................................................................130 
10.4 
Response .........................................................................................130 
10.4.1 
Response Evaluation and Reporting of Results .............................133 
10.4.2 
Progression-Free Survival ..............................................................133 
10.4.3 
Duration of Response .....................................................................133 
10.4.4 
Overall Survival .............................................................................134 
10.4.5 
Tumor Shrinkage ............................................................................134 
10.4.6 
Statistical Methodology for Pharmacokinetics Data ......................134 
10.5 
Handling of Missing Data or Outliers ............................................134 
10.6 
Subgroups and Site Effects .............................................................134 
10.7 
Interim Analyses .............................................................................135 
10.8 
Clinical Trial Reporting ..................................................................135 
10.9 
Sample Size Estimation ..................................................................135 
10.9.1 
Dose Escalation ..............................................................................136 
10.9.2 
Expansion .......................................................................................137 
10.9.3 
Statistical Power in Exploratory Analyses in the Expansion .........139 
11. 
TRIAL OPERATIONS ................................................................140 
11.1 
Countries ........................................................................................140 
11.2 
Number of Sites ..............................................................................140 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
PROCEDURES ............................................................................140 
12.1 
Monitoring of the Trial and Regulatory Compliance .....................140 
12.2 
Curricula Vitae of Investigators .....................................................141 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 9 of 259 
12.3 
Protocol Modification .....................................................................141 
12.4 
Publication Policy ...........................................................................141 
13. 
ETHICAL CONSIDERATIONS ................................................142 
13.1 
Informed Consent ...........................................................................142 
13.2 
Institutional Review Board/Independent Ethics 
Committee/Regulatory ...................................................................143 
13.3 
Patient Privacy/Data Protection ......................................................143 
13.4 
Finance and Insurance ....................................................................144 
14. 
DATA HANDLING AND RECORD KEEPING ......................145 
14.1 
Data Flow .......................................................................................145 
14.2 
Data to be Recorded Directly in the Case Report Form .................145 
14.3 
Recording of Data ..........................................................................146 
14.4 
Data Security ..................................................................................146 
14.5 
Trial Records ..................................................................................146 
15. 
REFERENCES .............................................................................147 
 
Appendix I: Scientific Background About Patient Population................. 149 
 
 
 
 
 
 
 
Appendix V: Recommendations Related to Contraception and Pregnancy 
Testing in Clinical Trials .............................................................................. 231 
 
Appendix VI: Trial Procedures and Assessments Applicable per 
Amendment 10 .............................................................................................. 244 
16. 
TRIAL EVALUATION AS OF AMENDMENT 10 .................246 
16.1 
Table of Assessments .....................................................................246 
16.2 
Clinical Assessments ......................................................................249 
16.2.1 
Demographics .................................................................................249 
16.2.2 
Disease Status .................................................................................249 
16.2.3 
Medical History ..............................................................................249 
16.2.4 
Height and Weight ..........................................................................249 
16.2.5 
Physical Examination .....................................................................249 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 10 of 259 
16.2.6 
Electrocardiogram ..........................................................................249 
16.2.7 
Imaging/Computed Tomography ...................................................250 
16.2.8 
Vital Signs ......................................................................................251 
16.2.9 
ECOG Performance Status .............................................................251 
16.2.10 
Concomitant Medication ................................................................251 
16.2.11 
Prior Cancer Therapy and Surgery .................................................252 
16.2.12 
Adverse Events ...............................................................................252 
16.2.13 
Patient Diary ...................................................................................252 
16.3 
Laboratory Assessments .................................................................252 
16.3.1 
Biochemistry ..................................................................................253 
16.3.2 
Hematology ....................................................................................253 
16.3.3 
CA 125 ...........................................................................................253 
16.3.4 
Urinalysis ........................................................................................254 
16.3.5 
Enapotamab Vedotin, HuMax-AXL and MMAE in Serum ...........254 
16.3.6 
Hepatitis B, C and Cytomegalovirus Serology ..............................254 
16.3.7 
Pregnancy Test ...............................................................................254 
16.3.8 
Immunogenicity of Enapotamab Vedotin ......................................254 
16.3.9 
Tumor Biopsy .................................................................................254 
16.3.9.1 Axl Expression ...............................................................................254 
16.3.10 
Exploratory Biomarker Analyses ...................................................254 
16.3.11 
Biological Sample Handling ..........................................................255 
16.3.12 
Chain of Custody of Biological Samples .......................................255 
17. 
REPORTING OF ADVERSE EVENTS AS OF AMENDMENT 
10 ....................................................................................................255 
17.1 
Recording Instructions ...................................................................255 
17.1.1 
Definition of Adverse Events of Special Interest (AESI) ..............255 
17.1.2 
Diagnosis ........................................................................................256 
17.1.3 
Intensity ..........................................................................................256 
17.1.4 
Relatedness to Investigational Medicinal Product .........................256 
17.1.5 
Start Date and Time ........................................................................256 
17.1.6 
Outcome .........................................................................................256 
17.1.7 
Action Taken with Investigational Medicinal Product ...................256 
17.1.8 
End Date and Time .........................................................................256 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 11 of 259 
17.1.9 
Adverse Events of Special Interest .................................................256 
17.1.10 
Information about Infusion Related Reactions ...............................256 
17.1.11 
Serious Adverse Event ...................................................................256 
17.2 
Definition of Serious Adverse Events ............................................257 
17.3 
Events Requiring Immediate Reporting .........................................257 
17.3.1 
Serious Adverse Events ..................................................................257 
17.3.2 
Overdose and Medication Errors ....................................................257 
17.3.3 
Pregnancy .......................................................................................257 
17.4 
Timelines for Reporting .................................................................257 
17.5 
Suspected Unexpected Serious Adverse Reactions ........................258 
17.6 
Follow-Up on Adverse Events .......................................................258 
17.7 
Safety Management Plan ................................................................259 
 
LIST OF FIGURES 
Figure 1. Overview of trial design .................................................................................. 49 
Figure 2. Trial flow for the 1Q3W dose escalation. ....................................................... 51 
Figure 3. Trial Flow of the 3Q4W dose escalation. ........................................................ 53 
Figure 4. Overview of the classic 3+3 design in the 3Q4W dose escalation .................. 54 
Figure 5. Statistical power in exploratory analyses ...................................................... 139 
Figure 6. Outline of data flow ....................................................................................... 145 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 12 of 259 
LIST OF TABLES 
Table 1. Overview of sample sizes in the expansion part cohorts .................................. 45 
Table 2. Instructions for dose interruptions and reductions for enapotamab vedotin 
related hematologic toxicity occurring during a cycle ..................................... 72 
Table 3. Dose Modification for enapotamab vedotin related Non-Hematologic toxicity 
occurring during a cycle ................................................................................... 73 
Table 4. 
Table 5.
Table 6.
Table 7. 
Table 8. Dose Modification and Management of immune-related AEs ......................... 76 
Table 9. Table of Assessments – Dose Escalation 1Q3W .............................................. 86 
Table 10. Table of Assessments – Dose Escalation 3Q4W ............................................ 89 
Table 11. Table of Assessments – Expansion ................................................................. 92 
Table 12. PK Sampling Dose Escalation, 1Q3W ........................................................... 95 
Table 13. PK Sampling Dose Escalation, 3Q4W ........................................................... 95 
Table 14. PK Sampling Expansion ................................................................................. 96 
Table 15.
 
Table 16. 
 
Table 17. ECG Assessments Dose Escalation, 1Q3W ................................................. 101 
Table 18. ECG Assessments Dose Escalation, 3Q4W ................................................. 101 
Table 19. ECG Assessments Expansion Part ................................................................ 102 
Table 20. Vital Signs during the Dose Escalation Part, 1Q3W .................................... 104 
Table 21. Vital Signs during the Dose Escalation Part, 3Q4W .................................... 104 
Table 22. Vital Signs during the Expansion Part .......................................................... 104 
Table 23. ECOG Performance Status ........................................................................... 105 
Table 24. Timeframes for Reporting SAEs, Grade 3 AEs, Peripheral Neuropathy, 
Overdose and Medication Errors and Pregnancies ......................................... 120 
Table 25. Minimum Exposure for Inclusion in DDS Set.............................................. 124 
Table 26. Definition of Response (RECIST Criteria v1.1) ........................................... 131 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 13 of 259 
Table 27. Impact of Sample Size on Descriptive and Inferential Statistics for 
Dose-Escalation 3Q4W .................................................................................. 136 
Table 28. Impact of Sample Size on Descriptive and Inferential Statistics for Endpoints 
in the Expansion Part ...................................................................................... 137 
Table 29. Power Analysis of the Expansion Part .......................................................... 138 
Table 30. Operating characteristics in the futility analyses (stop recruiting if ≤ 2/22 or 
≤ 3/22 responders) ........................................................................................... 138 
Table 31. Table of Assessments – Expansion ............................................................... 246 
Table 32. Timeframes for Reporting SAEs, Grade 3 AEs, Peripheral Neuropathy, 
Overdose and Medication Errors and Pregnancies ......................................... 258 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 14 of 259 
CLINICAL TRIAL SYNOPSIS 
 
Name of Sponsor: Genmab A/S 
 
 
Name of Monitor: 
 
 
Name of finished product: Enapotamab vedotin 
 
Name of active ingredient: Enapotamab vedotin 
 
Title of the trial: First-in-human, open-label, dose-escalation trial with expansion cohorts to 
evaluate 
safety 
of 
Axl-specific 
antibody-drug 
conjugate 
(enapotamab 
vedotin, 
HuMax®-AXL-ADC) in patients with solid tumors. 
 
Investigators and trial sites: Please refer to the Trial Operations Manual  
 
Publication (reference): Not applicable  
 
Clinical phase: I/IIa 
 
Objectives: 
Primary Objective 
• To determine the maximum tolerated dose (MTD) and to establish the safety profile of 
enapotamab vedotin in a mixed population of patients with specified solid tumors.  
Secondary Objective 
• To evaluate the safety laboratory parameters of enapotamab vedotin in a mixed 
population of patients with specified solid tumors. 
• To establish the pharmacokinetic (PK) profile and evaluate immunogenicity of 
enapotamab vedotin after single and multiple infusions. 
• To evaluate the antitumor activity of enapotamab vedotin in a mixed population of 
patients with specified solid tumors.  
• To evaluate Axl expression in tumor biopsies from a mixed population of patients with 
specified solid tumors. 
Exploratory Objective 
To explore biomarkers predictive of response and resistance to enapotamab vedotin. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 15 of 259 
 
Methodology: 
This is an open-label, multi-center Phase I/IIa safety trial of enapotamab vedotin in a mixed 
population of patients with solid tumors known from the literature to overexpress Axl and 
where the use of systemic tubulin inhibitors is part of Standard of Care (SoC). The trial consists 
of two parts; a dose escalation part (phase I, first-in-human [FIH]) and an expansion part (phase 
IIa). The dose escalation part has two dose escalation arms: the first one investigates a once 
every 3 weeks (1Q3W) dose schedule and the second one investigates a three administrations 
over 4 weeks (3Q4W) dose schedule.  
When a minimum of 8 patients have been treated and evaluated for Dose Limiting Toxicities 
(DLTs), the 1.5 mg/kg cohort has been declared safe on the 1Q3W arm, and the predicted AUC 
on the starting dose in 3Q4W arm is below pre-defined limits, the 3Q4W arm will be initiated. 
In November 2020, Genmab decided to discontinue development of enapotamab vedotin 
but continue to offer treatment to patients who are deriving clinical benefit in the present 
trial. With Amendment 10, procedures and visits are reduced for the 3 remaining patients 
active on trial treatment.   
 
Number of Patients: 
In total, approximately 426 patients can be enrolled in this trial. Assuming an anticipated screen 
failure rate of 30%, up to 609 patients can be screened.  
Up to 41 patients will be enrolled in the 1Q3W dose escalation.  
Between 15 and 36 patients will be enrolled in the 3Q4W dose escalation depending on the 
number of dose levels during the dose escalation. 
In the expansion part, approximately 349 patients can be enrolled in 8 cohorts.  
In Cohorts 1, 3, 4, 5, and 7, the aim is to enroll 22 patients per cohort. However, in order to 
obtain evaluable fresh tumor biopsies from at least 15 patients per cohort, up to 15 patients may 
be additionally recruited per cohort leading to a maximum of 37 patients enrolled per cohort 
except for Cohort 2, where up to 60 additional patients will be enrolled in order to further 
understand the safety, tolerability, efficacy, and biomarker findings of enapotamab vedotin as 
an efficacy signal has been observed in this population of non-small cell lung cancer (NSCLC) 
patients without EGFR/ALK mutations. 
A sub-group of the patients in Cohort 2 (up to 30 patients), may be enrolled on a dose of 
1.8 mg/kg to further understand the tolerability profile and to extend the therapeutic window of 
enapotamab vedotin. 
Furthermore, if considered necessary (as assessed by the Data Monitoring Committee [DMC] 
and the sponsor Safety Committee [SC]) selected arm(s) might be explored on both dosing 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 16 of 259 
schedules from the dose escalation without increasing the total number of patients to be 
included in the trial.  
In Cohort 6, 30 patients with solid tumors (except for NSCLC, melanoma, sarcoma, and ovarian 
cancer patients, unless having a known AXL gene amplification) who have failed a PD-1/PD-
L1 inhibitor and are able to provide the required fresh tumor biopsy will be enrolled.  
For further exploration of the safety and efficacy profile of the 3Q4W schedule, patients in 
Cohort 6 will be enrolled on a dose of 1.0 mg/kg administered 3Q4W, which was determined 
to be the MTD for this schedule in the dose escalation part of the trial. Preferably, no more than 
8 patients should be recruited for one tumor type in this cohort.  
In order to obtain sufficient evaluable fresh tumor biopsies, up to 15 additional patients may be 
recruited in Cohort 6 to ensure that 25 fresh biopsies are acquired. A maximum of 45 patients 
may therefore be enrolled in Cohort 6. A higher number of biopsies are required in this cohort 
due to the mixture of tumor types being enrolled. 
Cohort 8 will further explore the safety and efficacy of the 1.0 mg/kg 3Q4W schedule in 
NSCLC patients without EGFR/ALK mutations. This is the same patient population as Cohort 
2 where a preliminary efficacy signal was observed for the 1Q3W schedule. Cohort 8 will 
include up to 37 patients with the aim to collect evaluable fresh tumor biopsies from 15 patients. 
Recruitment is not linked to the number of biopsies collected and may continue up to a 
maximum of 37 patients even if 15 fresh tumor biopsies have already been obtained. The 
benefit/risk balance will be evaluated on an ongoing basis in this cohort. 
An interim analysis for futility will be performed after 22 patients per cohort (minus Cohorts 6 
and 8) if there are < 15 patients with evaluable fresh biopsies in the corresponding cohort. Based 
on the results, further recruitment to the corresponding cohort may be stopped. 
 
Inclusion Criteria: 
Patients must meet all of the following inclusion criteria before they will be allowed to 
participate in the trial: 
1. For the dose escalation part: Patients with relapsed or refractory cancer of the ovary, cervix, 
endometrium, thyroid, NSCLC, or melanoma (cutaneous, mucosal, acral or uveal 
melanoma) who have failed available standard therapy or who are not candidates for 
standard therapy, and for whom, in the opinion of the investigator, experimental therapy 
with enapotamab vedotin may be beneficial.  
For the expansion part: Patients with advanced and/or metastatic cancer who are not 
candidates for standard therapy, and for whom, in the opinion of the investigator, 
experimental therapy with enapotamab vedotin may be beneficial, who have failed the 
following anticancer therapy as follows: 
Expansion Cohort 1 (NSCLC patients with classical sensitizing EGFR mutations and/or 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 17 of 259 
other EGFR mutations targeted by third generation TKIs [e.g., T790M for osimertinib]):  
• NSCLC patients after failure of up to 4 prior treatment regimens containing systemic 
therapy for metastatic disease.  
o adjuvant and maintenance treatment is considered being part of one treatment 
regimen 
• Documented progressive disease on last prior treatment  
• Last prior treatment to enrolment to GCT1021-01 should have been 
o an EGFR inhibitor (e.g. Erlotinib, Osimertinib, etc.),  
o or a PD-1/PD-L1 inhibitor 
o or a platinum-based doublet chemotherapy 
 
Expansion Cohorts 2 and 8 (NSCLC patients without activating EGFR mutations or ALK 
rearrangements) 
• NSCLC patients after failure of no more than 2 lines of therapy which should include 
a platinum based chemotherapy and PD-1/PDL1 inhibitor treatment for advanced 
(Stage IIIA or IIIB) or metastatic disease (Stage IV) either in combination or 
sequentially. 
• Documented progressive disease on last prior treatment 
• Last prior treatment to enrolment to GCT1021-01 should have been (either in 
combination or sequentially) 
o a platinum based chemotherapy 
o or a PD-1/PD-L1 inhibitor 
 
Expansion Cohort 3 (Melanoma patients with BRAF V600 mutation):  
• Cutaneous, acral, or mucosal melanoma patients after failure of up to 4 prior treatment 
regimens containing systemic therapy for metastatic disease 
o adjuvant and maintenance treatment is considered being part of one treatment 
regimen 
• Documented progressive disease on last prior treatment 
• Last prior treatment to enrolment to GCT1021-01 should have been  
o a BRAF inhibitor (+/- Mek inhibitor)  
o or a checkpoint inhibitor  
 
Expansion Cohort 4 (Melanoma patients with BRAF V600 wild-type) 
• Cutaneous, acral, or mucosal melanoma patients after failure of up to 3 prior treatment 
regimens containing systemic therapy for metastatic disease 
o adjuvant and maintenance treatment is considered being part of one treatment 
regimen 
• Documented progressive disease on last prior treatment 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 18 of 259 
• Last prior treatment to enrolment to GCT1021-01 should have been  
o a checkpoint inhibitor  
 
Expansion Cohort 5 (Sarcoma patients) 
• Sarcoma patients after failure of up to 3 prior treatment regimens containing systemic 
therapy for metastatic disease  
o Limited to undifferentiated pleomorphic sarcoma, lipo-, leiomyosarcoma, 
synovial sarcoma, Ewing’s sarcoma, osteo-, and chondrosarcoma  
o adjuvant and maintenance treatment is considered being part of one treatment 
regimen 
• Documented progressive disease on last prior treatment 
 
Expansion Cohort 6 (patients with solid tumors, excluding NSCLC, melanoma, sarcoma, 
and ovarian cancer patients unless having a known AXL gene amplification; preferably 
no more than 8 patients should be recruited for one tumor type) 
• Patients with solid tumors (except for NSCLC, melanoma, ovarian cancer, and 
sarcoma patients unless having a known AXL gene amplification) that have failed a 
PD-1/PD-L1 inhibitor for metastatic disease 
• Documented progressive disease on last prior treatment 
• Last prior treatment to enrolment to GCT1021-01 should have been 
o An immune-checkpoint inhibitor 
 
Expansion Cohort 7 (Platinum-resistant ovarian cancer patients) 
• Ovarian cancer patients with resistance to at least one platinum-based therapy defined 
according to GCIG. Disease progression during or within 6 months of previous 
platinum-based chemotherapy include the following 2 categories:  
• Primary platinum-resistant: Previously untreated patients who have achieved at 
least a partial response to platinum-based chemotherapy, but experience a 
relapse within a period of >1 and <6 months following treatment completion  
• Secondary platinum-resistant: Previously treated patients who have achieved at 
least a partial response with platinum-based therapy as 2nd line treatment, but 
experience a relapse within a period of >1 and <6 months following treatment 
completion.  
• Ovarian cancer patients after failure of at least 2 prior treatment regimens containing 
systemic therapy but not more than 5 for recurrent disease  
o Limited to invasive epithelial tubo-ovarian carcinoma including malignant 
serous (restricted to high-grade serous ovarian cancer (HGSOC), 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 19 of 259 
carcinosarcoma, and High Grade (or ≥ Grade 3) clear cell / endometrioid / 
mixed epithelial carcinoma 
o Maintenance treatment (e.g., with bevacizumab, PARPi, PD-1/PD-L1 
inhibitor, etc.) is considered being part of one treatment regimen  
▪ Treatments that had to be changed to a similar drug due to toxicity 
count as one regimen (e.g., change from carboplatin to cisplatinum 
because of allergy, etc.) 
• Documented progressive disease on or after last prior treatment  
o Start of screening must be within 60 days after documented progression  
o Isolated GCIG CA 125 progression does NOT qualify for trial entry 
• Albumin levels should be > 25 g/L (‘CTCAE G2 intermediate’) to allow inclusion 
 
For the following conditions in Expansion Cohorts 1-8, the sponsor medical officer’s 
approval of enrolment is needed: 
➢ if documented progression has not been on measurable disease (i.e. symptomatic 
progression) 
 
2. Patients must have measurable disease according to RECIST (Response Evaluation Criteria 
In Solid Tumors) version 1.1.  
o A minimum of one lesion ≥ 10 mm (or twice the slice thickness if slices are not 5 mm 
thick) in the longest diameter (LD) from a non-irradiated area 
o Lymph nodes lesion ≥ 15 mm in the shortest diameter from a non-irradiated area 
o If target lesion(s) are located within previously irradiated area patients can be 
enrolled if: 
• target lesions have not been irradiated within the last 3 months 
• there has been demonstrated progression in the “in field” target lesion and 
after sponsor acceptance 
o In the dose escalation part, patients with ovarian cancer can be included based on CA 125 
positivity according to the Gynecologic Cancer Intergroup Guideline1,2; only if they have 
a pretreatment sample that is at least twice the upper limit of the reference range and 
within 2 weeks before starting the treatment. 
Note: Patients are not evaluable by CA 125 if they have received mouse antibodies 
(unless the assay used has been shown not to be influenced by human anti-mouse 
antibody) or if there has been medical and/or surgical interference with their peritoneum 
or pleura during the previous 28 days (e.g., paracentesis). 
3. A) In the dose escalation part all patients must provide a tumor tissue sample (Formalin 
Fixed Paraffin Embedded (FFPE) blocks / slides) from archival tissue or fresh biopsy 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 20 of 259 
collected before Cycle 1 Visit 1, preferably derived from advanced disease stage. 
B) In the expansion part all patients must provide a mandatory fresh biopsy (FFPE tissue 
blocks/slides) at screening (aspirates are not acceptable) which contains tumor tissue and is 
taken after failure/stop of last prior treatment. Documentation of the fresh FFPE biopsy 
shipment must be submitted to the Sponsor as a part of eligibility package prior to 
administration of first dose of enapotamab vedotin. In case it is not feasible to meet the 
required criteria for a fresh tumor biopsy, the sponsor medical officer’s approval of 
enrollment is needed. Furthermore the latest available archival tumor tissue sample should 
be collected if available.  
4. Age ≥ 18 years. 
5. Have an acceptable renal function defined as: 
o Glomerular filtration rate (GFR)  40 mL/min/1.73 m² – e.g., according to the 
abbreviated 
Modification 
of 
Diet 
in 
Renal 
Disease 
(MDRD) 
equation: 
 GFR = 186 × (SCr-1.154) × (age-0.203)(where SCr, the serum creatinine level, is expressed 
in mg/dL; multiply it by 0.742 if the patient is female; multiply it by 1.212, if the patient 
is African-American3). 
o Not being on dialysis 
6. Have an acceptable liver function defined as: 
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the 
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 
7. Have an acceptable hematological status 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. 
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
9. Life expectancy of at least 3 months. 
10. 
Patients, both females and males, of childbearing/reproductive potential must agree to 
use adequate contraception while included in the trial and for 6 months after the last 
infusion of enapotamab vedotin (see Appendix V). 
11. 
Patients must provide signed informed consent form. 
 
Exclusion Criteria: 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 21 of 259 
If any of the following applies, the patient MUST NOT enter the trial: 
Hematological 
1. Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for 
at least 4 weeks prior to first enapotamab vedotin administration. 
2. Patient has a history of thromboembolic event(s) and is not willing to take 
thromboembolic prophylaxis.  
Cardiovascular 
3. Have clinically significant cardiac disease, including: 
o Onset of unstable angina within 6 months of signing the Informed Consent Form 
(ICF). 
o Acute myocardial infarction within 6 months of the signing the ICF. 
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% and/or 
baseline QT interval as corrected by Fridericia’s formula (QTcF) > 480 msec or 
uncontrolled atrial fibrillation. 
o Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or 
diastolic blood pressure ≥ 100 mmHg, despite optimal medical management. 
Immunological 
4. Ongoing or recent (within 1 year) evidence of significant autoimmune disease that 
required treatment with systemic immunosuppressive treatments, which may suggest 
risk for immune related adverse events. 
5. Patients with a history of Grade 3 or higher immune related adverse events should be 
excluded (adverse events below Grade 3 should be discussed with the sponsor).   
6. Patients with a history of non-infections pneumonitis related to prior systemic treatment 
and that required treatment with steroids within the last 6 months prior to enrolment. 
o If an event of pneumonitis is considered fully resolved more than 6 months prior 
to trial start, i.e., patient has no radiologic evidence of pneumonitis, is 
asymptomatic and does not require any steroid treatment, patient can be 
enrolled. 
Excluded medications or treatment regimens 
7. Have 
received 
granulocyte 
colony 
stimulating 
factor 
(G-CSF) 
or 
granulocyte/macrophage colony stimulating factor support 3 weeks prior to first 
enapotamab vedotin administration.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 22 of 259 
8. Have received a cumulative dose of corticosteroid > 150 mg prednisone (or equivalent 
doses of corticosteroids) within two weeks before the first enapotamab vedotin 
administration. 
9. History of ≥ Grade 3 allergic reactions to monoclonal antibody therapy as well as known 
or suspected allergy or intolerance to any agent given in the course of this trial. 
Surgery/procedures 
10. Major surgery within 4 weeks before first enapotamab vedotin administration. 
Central nervous system  
11. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain 
metastases or stroke. 
o Transient ischemic attack ≥ 6 months prior to screening is allowed. 
o Patients with known or suspected central nervous system metastases must 
undergo a Computed Tomography (CT) scan or Magnetic Resonance Imaging 
(MRI) of the brain and/or spinal cord for documentation of baseline disease 
status. Spinal cord metastasis is acceptable. However, patients with known 
spinal cord compression that is symptomatic or patients who have not undergone 
definitive treatment for the spinal cord compression and subsequently do not 
have evidence of clinically stable disease (SD) for at least 28 days should be 
excluded. 
o In the expansion cohorts the enrolment of patients with stable brain metastases, 
i.e. being asymptomatic for the last 14 days prior to treatment initiation, is 
allowed (use of corticosteroids and radiotherapy are described in exclusion 
criterion 7) 
o Symptomatic uncontrolled brain or leptomeningeal metastases. (To be 
considered “controlled,” central nervous system [CNS] disease must have 
undergone treatment [e.g., radiation or chemotherapy] at least 2 weeks prior to 
first enapotamab vedotin administration. The patient must not have any new or 
progressive signs or symptoms related to the CNS disease and must be taking 
< 10mg of prednisone or equivalent per day or no steroids). Patients who have 
untreated brain metastases and who are not symptomatic may enroll if the 
investigator feels that treatment of these metastases is not indicated. Patients 
with spinal cord compression may be considered for enrolment if they have 
received definitive treatment for this and evidence of clinically stable disease 
(SD) for at least 28 days. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 23 of 259 
Prior therapy 
12. Any anticancer therapy including; small molecules, immunotherapy, chemotherapy 
monoclonal antibodies or any other experimental drug within 5 half-lives but maximum 
4 weeks before first infusion. Accepted exceptions are bisphosphonates, denosumab and 
gonadotropin-releasing hormone agonist or antagonist, which can be continued 
throughout the trial. 
o Toxic effects of prior anti-cancer therapy considered as chronic, such as 
chemotherapy-induced fatigue, alopecia, or anorexia of  Grade 2, where no 
more resolution is expected, does not prevent the patient from participation in 
the trial. 
13. Any prior therapy with a conjugated or unconjugated auristatin derivative/vinca-binding 
site targeting payload. (Previous treatment with vinca alkaloids is allowed in line with 
inclusion criterion #1.) 
14. Radiotherapy within 14 days prior to first enapotamab vedotin administration (Palliative 
radiotherapy will be allowed). 
15. Patients who discontinued treatment due to disease progression within the first 6 weeks 
of commencing a prior immune checkpoint inhibitor containing treatment 
Other cancer/metastases 
16. 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 > 2 years duration. 
Other 
17. Melanoma patients with an LDH ≥ 3 x ULN. 
18. Ongoing significant, uncontrolled medical condition including: 
o Serious, non-healing wound, skin ulcer (of any grade), or bone fracture. 
19. Presence of ≥ Grade 2 peripheral neuropathy. 
20. Clinically significant active viral, bacterial or fungal infection requiring: 
o Intravenous treatment with anti-infective therapy that has been administered less 
than two weeks prior to first dose, or 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 24 of 259 
o Oral treatment with anti-infective therapy that has been administered less than 
one week prior to first dose. 
o Prophylactic anti-infective therapy, which is given without clinical symptomatic 
is allowed (e.g., antibiotic prophylaxis prior to dental extraction, etc.). 
21. Known human immunodeficiency virus seropositivity. 
22. Known history / positive serology for hepatitis B (unless immune due to vaccination or 
resolved natural infection or unless passive immunization due to immunoglobulin 
therapy): 
o Positive test for antibodies to hepatitis B core antigens (anti-HBc) 
and 
o Negative test for antibodies to hepatitis B surface antigens (anti-HBs). 
23. Known positive serology for hepatitis C (unless due to immunoglobulin therapy or 
completely resolved natural infection). 
24. Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the trial or evaluation of the trial result. 
25. History of organ allograft (except for corneal transplant) or autologous or allogeneic 
bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of 
enapotamab vedotin. 
26. Body weight < 40 kg. 
27. Women who are pregnant or breast feeding.  
28. Patients are not allowed to take part in any other interventional trial while participating 
in current trial.  
Specifically for NSCLC 
29. Pulmonary hemorrhage or hemoptysis > 2.5 mL blood within 6 weeks unless cause has 
been addressed and is medically resolved. 
 
Dose and Mode of Administration: 
Treatment Preparation 
The dose of enapotamab vedotin for administration must be prepared by the site pharmacy using 
aseptic technique. Please refer to the IMP manual (Preparation and Administration of 
enapotamab vedotin) for details on the preparation of the infusion. Enapotamab vedotin will be 
supplied to the site/pharmacy as bulk supply cartons. Labelling of enapotamab vedotin will be 
done in accordance with local standards and regulations. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 25 of 259 
Enapotamab vedotin will be supplied in vials containing 40 mg of enapotamab vedotin as 
lyophilized powder. The powder should be reconstituted with 4 mL water for injection leading 
to a 10 mg/mL solution.  
The reconstituted enapotamab vedotin should be diluted into 0.9% NaCl 100 mL infusion bag 
according to the dose assigned to the patient. 
Enapotamab vedotin (lyophilized vials) should be stored in a refrigerator at 2°C to 8°C.  
The infusion must be completed within 24 hours after the enapotamab vedotin vials have been 
reconstituted. An in-line filter 0.2 µm must be used for the infusion. The entire infusion volume 
from the prepared infusion bag needs to be administered. No dead volume is provided. 
 
Treatment Administration 
Enapotamab vedotin will be administered as an intravenous infusion. Each patient’s dose will 
be calculated based on the patient’s weight 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) (where x denotes the dose level) 
Enapotamab vedotin will be administered over a minimum of 30 minutes and the infusion must 
be completed within 4 hours. The infusion is complete when the infusion line has been flushed 
with saline. 
In the dose-escalation part, there will be a minimum of 2 nights between the first and second 
patient in each dose cohort to account for any safety concerns in each new dose. 
 
Data Monitoring Committee: 
A Data Monitoring Committee (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 intermediate level, halted altogether or include more patients at the same dose level to 
evaluate safety.  
Following each DMC meeting, a sponsor SC meeting will be held to discuss and confirm 
actions recommended by the DMC. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 26 of 259 
 
Duration of Treatment: 
Dependent on which dose-escalation arm the patient is recruited to, enapotamab vedotin will 
be administered either 1Q3W or 3Q4W. The patients will receive treatment with enapotamab 
vedotin until disease progression or unacceptable toxicity has been observed. Patients will be 
followed for 52 weeks after end of treatment. In the expansion part of the trial, up to 
349 patients will receive enapotamab vedotin at the MTD/RP2Ds found in either 1Q3W or 
3Q4W schedule as recommended by the DMC and confirmed by the internal sponsor SC.  
When a patient completes or withdraws from treatment, they should come for an end of 
treatment visit as soon as possible.  
 
Criteria for Evaluation: 
Primary Endpoints 
• Dose Limiting Toxicities (DLTs) 
• Adverse events (AEs): incidences of AEs, serious adverse events (SAEs), infusion-
related AEs, ≥ Grade 3 AEs, and AEs related to enapotamab vedotin during the trial. 
Secondary Endpoints 
• Safety laboratory parameters (hematology and biochemistry). 
• 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 enapotamab vedotin and free toxin monomethyl 
auristatin E [MMAE]). 
• Immunogenicity of enapotamab vedotin (anti-drug antibodies). 
• Anti-tumor activity measured by tumor shrinkage (based on computerized tomography 
[CT]-scan evaluations), as well as change in CA 125 in patients with ovarian cancer and 
change in prostate specific antigen (PSA) in patients with castration-resistant prostate 
cancer (CRPC). 
• Objective Response, Progression-Free Survival (PFS), Duration of Response (DoR) and 
Overall survival (OS). 
• Axl expression in the tumor biopsy.  
 
Exploratory Endpoints 
Biomarkers predictive of response or resistance to enapotamab vedotin 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 27 of 259 
 
Statistical Methods: 
The statistical analyses will be performed by a Contract Research Organization (CRO) 
, 
under the direction of sponsor personnel. Any data analysis carried out independently by the 
investigator should be submitted to the sponsor prior to publication or presentation. 
All data will be listed. Also, data will be summarized using descriptive statistics (continuous 
data) and/or contingency tables (categorical data) for demographic and baseline characteristics, 
efficacy measurements, safety measurements, and all relevant pharmacokinetic measurements. 
The results will be presented by the 1Q3W and 3Q4W dose escalation and expansion parts 
separately. Also, the results will be presented by groups and total. In the dose-escalation 1Q3W 
and 3Q4W arms of the trial, groups are defined by dose-levels. In the expansion part, groups are 
defined by solid tumor indication. The results from the patients in the expansion part will be 
presented 2 times: by indication and in total. In addition, for NSCLC patients without 
EGFR/ALK mutations, data will be summarized based on different dosing regimens, e.g., 1.8 
mg/kg 1Q3W, 2.2 mg/kg 1Q3W. The final analysis of trial data will be based on all patient data 
of the escalation and expansion phases. 
For the sake of the statistical analyses and summaries, baseline is defined as the available data 
from the latest recorded measurement made before the first enapotamab vedotin administration. 
Details of statistical analysis and data reporting will be provided in a Statistical Analysis Plan 
(SAP) document finalized prior to database lock. Additional analyses may be added in the SAP 
and tables, listings and figures shells will also be provided. 
In November 2020, Genmab decided to discontinue development of enapotamab vedotin 
but continue to offer treatment to patients who are deriving clinical benefit in the present 
trial. With Amendment 10, the dose escalation part and the enrollment of the dose 
expansion part of trial have been completed. Three patients remain on treatment. The 3 
patients have been on treatment for at least 7 months, which is considered sufficient to 
evaluate efficacy and safety. An analysis is therefore planned, i.e. data collected up to and 
including the data cutoff date will be included in the CSR. Furthermore, limited AE and 
SAE data from data cutoff to the time of database lock for the three active patients will 
be included. Data collected after the data cutoff date until the end of trial will be reported 
in an addendum to the CSR, once the trial is completed. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 28 of 259 
LIST OF ABBREVIATIONS 
ADA 
 
Anti-drug antibody 
ADC 
 
Antibody-drug conjugate 
  
 
AE 
 
Adverse Event 
ALK 
 
Anaplastic lymphoma kinase 
ALT 
 
Alanine aminotransferase 
ANC 
 
Absolute neutrophil count 
anti-HBc 
Antibodies to hepatitis B core antigens 
anti-HBs 
Antibodies to hepatitis B surface antigens 
AST 
 
Aspartate aminotransferase 
ATC 
 
Anatomical therapeutic chemical 
AUC 
 
Area Under the Curve 
BID 
 
Twice a day (bis in die) 
BLRM   
Bayesian logistic regression model 
BMI 
 
Body mass index 
BRCA1  
Breast Cancer 1 
BRCA2  
Breast Cancer 2 
CA 
 
Competent Authority 
CA 125  
Cancer Antigen 125 
  
 
CFR 
 
Code of Federal Regulations 
CHX 
 
Chemotherapy 
Cmax 
 
maximum Concentration 
CMV 
 
Cytomegalovirus 
CR 
 
Complete response 
CRM 
 
Continual Reassessment Method 
CRO 
 
Contract Research Organisation 
CRPC  
Castration-resistant prostate cancer 
CT 
 
Computed Tomography 
CTCAE  
Common Terminology Criteria for Adverse Events 
  
 
DDS 
 
Dose-Determining Set 
DLT 
 
Dose limiting toxicity 
DMC 
 
Data Monitoring Committee 
 
 
 
DoR 
 
Duration of Response 
 
 
  
ECG 
 
Electrocardiogram 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 29 of 259 
ECOG  
Eastern Cooperative Oncology Group 
eCRF 
 
Electronic Case Report Form 
EGFR  
Epidermal growth factor receptor 
EWOC  
Escalation With Overdose Control 
FAS 
 
Full Analysis Set 
FDA 
 
U.S. Food and Drug Administration 
F 
 
Female 
FIH 
 
First-in-human 
 
 
 
Gas6 
 
Growth arrest-specific 6 
G-CSF  
Granulocyte Colony Stimulating Factor 
GCP 
 
Good Clinical Practice 
GFR 
 
Glomerular filtration rate 
 
 
 
HBsAg  
Hepatitis B surface antigen 
 
 
 
  
 
HuMax®- 
AXL-ADC 
Enapotamab vedotin 
ICH 
 
International Conference on Harmonization 
ICF 
 
Informed Consent form 
IEC 
 
Independent Ethics Committee 
IB 
 
Investigator’s Brochure 
IHC 
 
Immunohistochemistry 
IMP 
 
Investigational Medicinal Product (enapotamab vedotin) 
IRB 
 
Institutional Review Board 
i.v. 
 
Intravenous 
 
 
LD 
Longest Diameter 
LDH 
Lactate Dehydrogenase 
M 
 Male 
mCRM  
Modified Bayesian Continual Reassessment Method 
MDRD  
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMAE  
Monomethyl auristatin E 
MRI 
 
Magnetic Resonance Imaging  
MTD 
 
Maximum tolerated dose 
NCCN  
National Comprehensive Cancer Network 
NCI 
 
National Cancer Institute 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 30 of 259 
NGS 
 
Next generation sequencing 
NS 
 
Non serious 
NSCLC  
Non-small cell lung cancer 
PAP 
 
Papanicolaou 
  
 
PD 
 
Progressive disease 
P-gp 
 
P-glycoprotein 
PK 
 
Pharmacokinetic 
PFS 
 
Progression-free survival 
PR 
 
Partial response 
PSA 
 
Prostate specific antigen 
QD 
 
Every day (quaque die) 
RECIST  
Response Evaluation Criteria In Solid Tumors 
RDFD  
Recommended Dose for Further Development 
RNA 
 
Ribonucleic acid 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SC 
 
Safety Committee 
SCC 
 
Squamous cell carcinoma 
SD 
 
Stable disease 
SoC 
 
Standard of Care 
SUSAR  
Suspected Unexpected Serious Adverse Reactions 
 
 
 
TID 
 
Three times a day (ter in die) 
TLS 
 
Tumor lysis syndrome 
TNM 
 
Tumor Nodes Metastasis 
TSH 
 
Thyroid Stimulating Hormone 
T3 
 
Triiodothyronine 
T4 
 
Thyroxine 
ULN 
 
Upper Limit of Normal 
vc 
 
Valine-citrulline 
VEGF   
Vascular Endothelial Growth Factor 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 31 of 259 
PROTOCOL AMENDMENTS 
Protocol/Amendment No; Version  
Issue Date 
Original Protocol; Version 1.0 
07 June 2016 
Amendment 1; Version 2.0 
16 December 2016 
Amendment 2; Version 3.0 
10 August 2017 (internal version only) 
Amendment 3; Version 4.0 
25 September 2017 
Amendment 4; Version 5.0 
12 April 2018 
Amendment 5; Version 6.0 
11 October 2018 (internal version only) 
Amendment 6; Version 7.0 
07 December 2018 
Amendment 7; Version 8.0 
18 June 2019 
Amendment 8; Version 9.0 
21 October 2019 
Amendment 9; Version 10.0 
09 December 2019 
Amendment 10; Version 11.0 
30 June 2021 
 
Amendment 10 (30 June 2021) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
To allow analysis and reporting of the trial, while permitting the 3 remaining patients to stay on treatment 
and be followed per protocol.   
At the time of this Amendment, the dose escalation part and the enrollment of the dose expansion part of 
trial have been completed. Three patients remain on treatment. The 3 patients have been on treatment for 
at least 7 months, which is considered sufficient to evaluate efficacy and safety.  
With this amendment, the 3 patients still on treatment will continue treatment and be followed with reduced 
procedures and visits. Refer to Appendix VI and Table 31 for applicable procedures and assessments as 
of Amendment 10.  
The amendment changes are summarized below. As applicable, changes included in the Summary of 
Changes table are incorporated in the Trial Synopsis. Section numbers are as per Amendment 10. 
Section # and Name 
Description of Change 
Brief Rationale 
3.2 Trial Design Rationale; 
3.5 Duration of Treatment; 
5.6 Trial Overview; 
5.6.6 Follow-up Contact; 
6.3 Withdrawal Criteria; 
8.1 Table of Assessments; 
8.2 PK Sampling (Enapotamab 
Vedotin, HuMax-AXL and 
MMAE); 
Inclusion of text boxes referring to Appendix VI, Table 
31 and/or Sections 16 and 17 for applicable procedures 
and assessments as of Amendment 10. 
Clarification 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 32 of 259 
Section # and Name 
Description of Change 
Brief Rationale 
8.3 Exploratory Biomarker 
Analyses; 
8.4 Clinical Assessments; 
8.5 Laboratory Assessments;  
9 Reporting of Adverse Events  
10 Statistical Analysis; 
10.7 Interim Analyses; 
10.8 Clinical Trial Reporting 
Sections were revised to reflect the analysis of efficacy 
and safety per data cutoff date and clinical trial reporting 
plans.  
The plan to present QTc analyses in a separate report 
was removed.   
To clarify and 
describe the 
current analysis 
and reporting 
plans for the trial, 
following the 
decision to 
discontinue 
development of 
enapotumab 
vedotin. 
Appendix VI; 
16 Trial Evaluation as of 
Amendment 10; 
17 Reporting of Adverse Events 
as of Amendment 10 
Updated assessment table and descriptions of procedures 
and assessments as per Amendment 10 were included. In 
summary:  
• The duration of treatment for each patient in this trial 
will be until disease progression or unacceptable 
toxicity (Section 3.5). 
• Follow-up contact every 12 weeks post trial treatment 
is no longer applicable (Section 5.6.6). 
• Sampling and assessment of PK and biomarkers are 
no longer applicable.   
• Height, weight and physical examination outcome are 
no longer to be recorded in the eCRF.   
• ECGs will be taken locally.  
• Any irregularity observed or occurring during the 
ECGs should either induce a repeat of the ECG or be 
annotated in the medical journal. 
• New or worsened clinically significant abnormalities 
should be recorded as AEs on the AE form.  
• Post-baseline CT-scans are to be performed every 12 
weeks (±7 days) and are not to be sent for central 
reading. 
• Vital signs should be measured if deemed necessary 
by the investigator, but are not to be recorded in the 
eCRF. 
• Any medication or therapy other than enapotamab 
vedotin that is related to an AE or is considered 
prophylactic treatment is considered concomitant 
medication.  
• Patient diary data are not to be recorded in the eCRF.    
• All laboratory samples will be analysed locally.   
Clarification of 
procedures and 
assessments 
applicable from 
implementation of 
Amendment 10 
until end of trial. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 33 of 259 
Section # and Name 
Description of Change 
Brief Rationale 
• Urinalysis is only to be performed if deemed 
necessary by the investigator and not to be entered in 
the eCRF.  
• New or worsened clinically significant laboratory 
abnormalities should be recorded as AEs on the AE 
form. 
• Assessments for CA 125, enapotamab vedotin, 
MMAE, hepatitis B and C, cytomegalovirus serology, 
immunogenicity and Axl expression are no longer 
applicable.  
• Collection and assessment of tumor biopsies is no 
longer applicable. 
• Exploratory biomarker analyses are no longer 
applicable. 
• Non-serious Grade 3 AEs, peripheral neuropathy AEs 
≥ Grade 2 and peripheral neuropathy AEs leading to 
permanent treatment discontinuation are no longer to 
be reported on the Safety Reporting form. 
Throughout protocol 
Minor clarifications, formatting, or spelling changes 
were made.  
Improve clarity 
and correct minor 
errors. 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 34 of 259 
1. 
GENERAL INFORMATION 
1.1 
Protocol Number and Title of the Trial 
GCT1021-01 
First-in-human, open-label, dose-escalation trial with expansion cohorts to evaluate safety of Axl-
specific antibody-drug conjugate (enapotamab vedotin, HuMax-AXL-ADC) in patients with solid 
tumors. 
1.2 
Sponsor 
Genmab A/S  
 
 
 
Sponsor Medical Officer: 
Kalvebod Brygge 43  
 
 
, MD, PhD 
DK-1560 Copenhagen V 
 
 
 
Denmark 
 
 
 
 
 
 
 
 
 
 
 
E-mail: 
 
1.3 
Clinical Research Organization (CRO) 
  
 
CRO Medical Officer: 
 
 
 
, MD, PhD 
  
 
 
 
 
 
 
Phone: 
 
United Kingdom 
 
 
 
Mobile: 
 
 
 
 
 
 
Fax: 
 
 
E-mail: 
 
 
A complete list of all relevant vendors will be provided in the Trial Operations Manual. 
1.4 
Signature Authorization 
 will act as the Sponsor representative.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 35 of 259 
2. 
BACKGROUND INFORMATION 
2.1 
Introduction 
Axl (also named Ark, Ufo, Tyro 7) is a transmembrane receptor tyrosine kinase. Human Axl 
consists of 894 amino acids and is a single chain glycoprotein. Together with Tyro-3 and Mer, Axl 
forms the TAM family of receptor tyrosine kinases, which is characterized by two 
immunoglobulin-like domains (Ig1 and Ig2) and two fibronectin type III domains (FN1 and FN2) 
in the extracellular domain. Furthermore, these receptors have an intracellular tyrosine kinase 
domain that is activated upon ligand stimulation. Growth arrest-specific 6 (Gas6) is the 
physiological ligand of Axl that binds to the Axl Ig1- and Ig2-domains, resulting in activation of 
the intracellular kinase domain. Generally, Axl is expressed in various tumor types. Axl expression 
is thought to functionally contribute to tumor development. Enhanced tumor cell motility, 
adherence and migration, epithelial-to-mesenchymal transition, angiogenesis and resistance to 
targeted therapy and chemotherapy have been linked to Axl expression. Gas6, the physiological 
ligand of Axl, is also expressed in some cancers, potentially contributing to Axl activation through 
an Axl-Gas6 autocrine loop4. 
Enapotamab vedotin is a human IgG1 antibody that is generated by conjugation of an Axl-specific 
antibody with the microtubule disrupting agent monomethyl auristatin E (MMAE) through the 
protease cleavable valine-citrulline (vc) linker5-7. Enapotamab vedotin binds to the Ig1 domain of 
Axl and does not compete with Gas6 for receptor binding. This is particularly relevant in tumors 
that co-express Axl and Gas6, in which enapotamab vedotin is still able to bind in the presence of 
Gas68.  
The dominant mechanism of action for enapotamab vedotin is tumor cell killing by 
MMAE-mediated interference with cell division. Upon binding of enapotamab vedotin to Axl 
expressed on the cell surface of tumor cells, the complex is rapidly internalized and targeted to the 
lysosomes. Proteolytic cleavage of the vc peptide linker in the lysosomes subsequently releases 
MMAE from the complex. Free MMAE can diffuse within the cell where it directly binds to 
microtubules and inhibits tubulin polymerization. Thereby MMAE interferes with proper 
assembly of the mitotic spindle during cell division resulting in cell cycle arrest and eventually 
cell death. Tubulin inhibitors primarily induce cytotoxicity in proliferating cells and not in 
quiescent cells. Therefore, proliferating tumor cells are preferentially targeted over normal cells, 
which are generally quiescent. Due to its membrane permeability, MMAE can also cause a 
bystander effect, e.g., cell death of proliferating Axl-negative tumor cells that surround 
Axl-positive tumor cells5. 
 
 
 
 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 36 of 259 
For more comprehensive information regarding enapotamab vedotin, refer to the current version 
of the Investigator's Brochure (IB) for enapotamab vedotin. 
2.2 
Non-Clinical Safety 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 37 of 259 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 38 of 259 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.3 
Summary of Known and Potential Risks to Human Patients 
2.3.1 
Implications of Non-Clinical Safety Results for Monitoring of Patients/Mitigation 
Plans 
Although there is limited clinical experience with enapotamab vedotin as this is a first-in-human 
(FIH) trial, while there is substantial experience with MMAE-based ADCs as described in 
Investigator’s Brochure, the following notable observations in the toxicology studies with 
enapotamab vedotin pointing to potential risks in human should be kept in mind. 
• During infusion of enapotamab vedotin in non-clinical toxicology studies in cynomolgus 
monkeys, infusion-related reactions with swelling of the eye lids, decreased muscle tone, 
labored breathing, or brief loss of consciousness was observed during the second treatment in 
2 out of a total of 30 monkeys treated with enapotamab vedotin (1Q3W x 3). Infusion-related 
clinical signs did not occur or were milder during the third infusion in the monkeys when the 
infusion time was prolonged from 30 to 60 min. Infusion-related reactions have also been 
observed with related ADC compounds using MMAE as the toxin. Patients should be 
monitored closely during infusion of enapotamab vedotin.  
• Bone marrow suppression has been observed in non-clinical studies of enapotamab vedotin 
and this adverse effect is expected during treatment with MMAE-ADCs and is a common 
adverse finding for other MMAE-ADCs. Low neutrophil count with increased risk of 
infections as well as anemia, lymphocytopenia and thrombocytopenia might occur and 
hematological parameters should be monitored during treatment. 
• Enapotamab vedotin caused dose-related, reversible changes in the male reproductive system 
(reduced sperm motility, lower testes and epididymides weights, and degenerative changes in 
the sperm-producing epithelium in testes). As risk mitigation, it is recommended that fertile 
males consider having semen specimen obtained for storage for potential future conception. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 39 of 259 
• MMAE is metabolized mainly via the CYP3A4 pathway and is capable of inhibiting human 
CYP3A4/5 enzymatic activity in vitro, although at concentrations that are substantially 
higher than clinically relevant plasma concentrations. MMAE is a substrate for the 
transmembrane transporter protein P-gp. Patients who are receiving strong CYP3A4 or P-
gp inhibitors concomitantly with enapotamab vedotin should be closely monitored for 
adverse reactions. 
Peripheral neuropathy has been observed frequently in patients receiving MMAE-ADCs. 
2.3.2 
Implications of Clinical Safety Results for Monitoring of Patients/Mitigation Plans 
Important newly identified risks for enapotamab vedotin include constipation, peripheral 
neuropathy and neutropenia.  
In particular, events of constipation (≤ Grade 3), some of them leading to hospitalization, have 
been observed. The use of prophylactic concomitant medication to avoid and manage constipation 
is described in Section 7.4.1. 
The peripheral neuropathy assessment through physical examination will be performed at the 
baseline and at End of Treatment visit, and the assessment will continue through the treatment 
period where indicated. Pausing of dosing or dose adjustment of enapotamab vedotin in case of 
neutropenia or peripheral neuropathy is required (please refer to Section 7.3.2). Specific safety 
reporting requirements are in place for AEs of peripheral neuropathy (please refer to 
Section 9.3.2). 
Please refer to the IB for the benefit-risk of enapotamab vedotin.  
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 40 of 259 
3. 
TRIAL DESCRIPTION 
3.1 
Patient Population 
Aberrant expression and activation of Axl has been reported in solid and hematological cancers 
and is associated with poor clinical prognosis in a number of cancer types4. Indication selection 
for the FIH trial of enapotamab vedotin is based on expression analysis of Axl in a broad variety 
of tumors evaluated by sponsor’s immunohistochemistry (IHC) staining of tumor tissue, which is 
supported by literature and the use of tubulin inhibitors according to current treatment guidelines. 
The preferred front line treatment for localized solid tumors is surgery, which can also be used to 
decrease tumor burden for larger invasive carcinomas. In addition, irradiation is used for local and 
locally advanced carcinomas, either alone or in combination with chemotherapy (CHX). For 
recurrent, advanced and/or metastatic carcinomas, CHX is the main treatment modality. For the 
selected indications, except for thyroid cancer and melanoma, first line CHX often includes 
platinum-based regimens. Tubulin inhibitors (including vinca alkaloids and taxanes) are often 
added to platinum in the chosen indications, except for iodine-refractory thyroid cancers where 
small molecular kinase inhibitors as well as taxanes, carboplatin and doxorubicin are the standard 
of care (SoC). For melanoma, tubulin inhibitors are also a recommended alternative as second-line 
or subsequent therapy for metastatic disease. For sarcoma, tubulin inhibitors are also used for 
several subtypes. Tubulin inhibitors are widely used for relapsed disease and for patients ineligible 
for platinum-based CHX, either as part of multi-agent CHX regimens or as single agent. Thus, the 
rationale for using tubulin inhibition in oncology is evident. 
Based on the criteria described above, ovarian cancer, cervical cancer, endometrial cancer, thyroid 
cancer, non-small cell lung cancer (NSCLC), melanoma, and sarcoma have been selected to be 
explored in this trial. These tumor types and the treatment modalities are described in Appendix I. 
For more information, please also refer to the IB. 
AXL expression has been associated with innate and acquired resistance to a range of therapeutic 
agents across multiple solid tumor types, including kinase inhibitors, chemotherapy and more 
recently immune checkpoint inhibitors. In a cohort of malignant melanoma patients, resistance to 
anti-PD-1 antibody treatment was linked to concurrent enhanced expression of a number of genes, 
including AXL.9 Furthermore, preclinical studies in murine breast cancer models suggested that 
AXL expression in tumor cells is directly associated with an immunosuppressive phenotype, that 
results in reduced sensitivity to radiotherapy and/or PD-1 blockade.10 Since there is a high medical 
need for patients that have failed PD-1/PD-L1 inhibitors, it is the aim to explore the hypothesis 
that this failure is linked to aberrant expression of Axl and that these patients may benefit from 
treatment with enapotamab vedotin. Therefore, it is intended to evaluate this hypothesis across 
multiple solid tumors in the expansion part of this trial. 
3.2 
Trial Design Rationale 
In November 2020, Genmab decided to discontinue development of enapotamab vedotin but 
continue to offer treatment to patients already recruited in the present trial. In March 2021 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 41 of 259 
all but 3 patients had discontinued treatment. The patients still on treatment have been on 
treatment for at least 7 months, which is considered sufficient time to evaluate efficacy and 
safety. It was therefore agreed to amend the present protocol (Amendment 10) to reduce data 
collection going forward. Refer to Appendix VI and Table 31 for applicable procedures and 
assessments as of Amendment 10. 
The trial consists of a dose-escalation part with two arms (part I) and a dose expansion part 
(part II).  
Part I of this trial is a FIH, open-label, dose-escalation, safety trial of Axl-specific ADC 
enapotamab vedotin in a mixed patient population with solid tumors to determine the MTD and 
the safety profile of enapotamab vedotin. 
Part I of this trial includes two arms for identification of the most optimal dosing regimen: 
• 1Q3W: Dosing once every 3 weeks.  
o There is broad experience with 1Q3W dosing of ADCs11 and brentuximab vedotin 
has received market authorization using this schedule (see Investigator’s Brochure).  
• 3Q4W: Weekly dosing for 3 weeks followed by one treatment-free week.   
 
 
 
The less frequent dosing-arm (1Q3W) is designed as a Modified Bayesian Continuous 
Reassessment Method (mCRM) incorporating Escalation with Overdose Control (EWOC). This 
design is considered appropriate as the Bayesian mCRM in general better estimates the MTD with 
less bias and more precision than a classic 3+3 design12. A comprehensive comparison of the 
Continual Reassessment Method (CRM) to the standard 3+3 dose escalation scheme in phase I 
dose-finding studies has been described by Iasonos et. al12. 
The properties of MMAE-based ADCs have been studied comprehensively and based on the 
overview provided by Deslandes11 (in particular Table 1 of the article), an U.S. Food and Drug 
Administration (FDA) analysis of ADCs, in combination with sponsor’s own development 
experience with tisotumab vedotin (HuMax-TF-ADC) it is assumed that the MTD will be between 
1.8 mg/kg – 2.5 mg/kg for the 1Q3W dose schedule. 
The design provides flexibility in terms of cohort sizes (allowed to vary in CRM but not in classic 
3+3 design).  
In contrast, the more frequent dosing-arm (3Q4W) will be conducted as a classic 3+3 design as it 
consists of fewer dose-levels 5-6 and will include fewer patients (15-36, 17 expected as compared 
to 28 in the 1Q3W-arm). The CRM would need at least ~20-25 patients in order to work properly12.  
The 3Q4W-arm will follow the 1Q3W-arm. Decisions in this arm will be supplemented by 
information from the 1Q3W-arm which at all times will have exposed patients at higher dose-
levels than the 3Q4W-arm. 
The aim of the expansion part is to provide further data on the safety, tolerability, pharmacokinetic 
(PK) and anti-tumor activity of the selected dose(s)/treatment regimen(s).  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 42 of 259 
3.2.1 
Rationale for PK Sampling 
The PK sampling described in Section 8.2 is designed so that an adequate estimation of the PK 
profile, including population PK modelling and non-compartmental estimation of PK parameters, 
can be performed. It is based on the predicted PK-profiles presented in 
 where more 
details can be found.  
In the escalation part PK assessments are made only on odd-numbered cycles (please refer to Table 
12 and Table 13): a more frequent sampling scheme every two cycles can be more efficient and 
informative than a less frequent sampling scheme performed every cycle. Performing the current 
sampling scheme every cycle would not provide additional significantly valuable information 
compared to the current design. 
In the expansion part PK assessments are collected as outlined in Table 14. Of particular interest 
are the assessments made on Days 1 and 4 in order to obtain samples near the expected Cmax for 
the ADC and MMAE in the 1Q3W arm. In the 3Q4W arm, the corresponding assessments are 
made on Days 15 and 17. 
3.2.2 
Rationale for Biomarker Analyses 
Biomarker samples will be collected to correlate Axl expression as measured by IHC  
 
 to clinical response to enapotamab vedotin.  
 
 
 
 
3.3 
Dose Rationale 
 
 
 
  
  
 
 
 
 
 
Data from cleavable MMAE-based ADC described in literature, including brentuximab vedotin, 
glembatumumab vedotin, ASG-5ME-ADC, PSMA-ADC, pinatuzumab vedotin, polatuzumab 
vedotin and the sponsor compound tisotumab vedotin (HuMax-TF-ADC) have indicated the MTD 
and/or Recommended Phase 2 Dose (RP2D) are within the range of 1.8 mg/kg to 2.5 mg/kg across 
the molecules when three-weekly dose schedules were used, for more details please refer to the 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 43 of 259 
Investigator’s Brochure.  
The 1Q3W dose escalation part of this trial includes 7 main dose levels: 0.3, 0.6, 1.0, 1.5, 2.0, 2.4 
and 2.8 mg/kg, corresponding to the following dose increments: 100%, 67%, 50%, 33%, 20% and 
17%. For the 1Q3W schedule, the MTD and RP2D were determined to be 2.2 mg/kg. 
The 3Q4W dose escalation part of the trial is expected to include 5 to 6 dose levels: (0.45), 0.6, 
0.8, 1.0, 1.2 and 1.4 mg/kg, corresponding to the following dose increments: (33%), 33%, 25%, 
20%, and 17%. The dose level 0.45 mg/kg may be added as described in Section 5.1. There are at 
least two ADCs containing MMAE as toxin, ASG-5ME13 and brentuximab vedotin14 for which a 
MTD of 1.2 mg/kg has been reported for 3Q4W dosing, for more details please refer to the 
Investigator’s Brochure. Therefore, it is considered safe to apply dose increments higher than 20% 
(but no more than 33%) for dose levels below this reported MTD for 3Q4W dosing. The 
increments of the dose escalation steps in the 3Q4W-arm below 1.2 mg/kg are in the range of 33%-
20% based on a modified Fibonacci approach and beyond 1.2 mg/kg not higher than 20%. As an 
additional precaution, the Data Monitoring Committee (DMC) can recommend intermediate dose 
levels at any step during dose escalation. For the 3Q4W schedule, the MTD was determined to be 
1.0 mg/kg. 
3.3.1 
Rationale for Dose Frequency 
In the dose escalation part, enapotamab vedotin will be administered 1Q3W in the first dose 
escalation arm and 3Q4W in the second dose escalation arm; for further details see Section 3.2. 
The dosing frequency is based on toxicokinetic and toxicology data obtained in cynomolgus 
monkeys, suggesting adequate recovery of neutrophils, thrombocytes and red blood cell 
parameters and otherwise an acceptable safety profile. No relevant accumulation of enapotamab 
vedotin or MMAE between cycles is anticipated based on the proposed dose intervals and non-
clinical population PK model (see 
. 
3.4 
Number of Patients and Sites 
In total, approximately 426 patients can be enrolled in this trial. Assuming an anticipated screen 
failure rate of 30%, up to 609 patients can be screened. 
 
Up to 41 patients are planned to be enrolled in the 1Q3W dose escalation. 
 
Between 15 and 36 patients are planned to be enrolled in the 3Q4W dose escalation depending on 
the number of dose levels during the dose escalation.  
 
In the expansion part, approximately 349 patients can be enrolled in 8 cohorts:  
 
In Cohorts 1, 3, 4, 5 and 7, the aim is to enroll 22 patients per cohort; however, in order to obtain 
evaluable fresh tumor biopsies from at least 15 patients per cohort, up to 15 patients may be 
additionally recruited per cohort leading to a maximum of 37 patients enrolled per cohort.  
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 44 of 259 
An efficacy signal has been observed in NSCLC patients without EGFR/ALK mutations, therefore 
up to 60 additional patients will be enrolled into the NSCLC Cohort 2 (Table 1) to further 
understand the safety, tolerability, efficacy and biomarker findings of enapotamab vedotin in this 
population of patients; the aim is therefore to enroll a total of up to 82 patients in Cohort 2. 
 
 
 
A sub-group of the patients in Cohort 2 (up to 30 patients), may be enrolled on a dose of 1.8 mg/kg 
to further understand the tolerability profile and to extend the therapeutic window of enapotamab 
vedotin. Enapotamab vedotin belongs to valine-citrulline-monomethyl auristatin E (vc-MMAE) 
class of ADC, and peripheral neuropathy is a known side-effect of MMAE and a potential dose 
limiting toxicity (DLT). It has been shown in a pooled time-to-event analysis across eight vc-
MMAE ADCs, that peripheral neuropathy events (Grade ≥2) were higher in patients with higher 
ADC exposure15. The MTD/RP2D in ADC-vc-MMAE ranges from 1.8 mg/kg to 2.4 mg/kg16. 
Given the identical cytotoxic payload of MMAE and the similar safety profile observed for 
enapotamab vedotin as compared to other ADC-vc-MMAEs, 1.8 mg/kg dose is expected to have 
a better tolerability profile. 
 
 
 
 
 
 
 
 
 
Furthermore, if considered necessary (as assessed by the DMC and the sponsor safety committee) 
selected cohort(s) might be explored on both dosing schedules from the dose escalation without 
increasing the total number of patients to be included in the trial. 
 
In Cohort 6, 30 patients with solid tumors (except for NSCLC, melanoma, sarcoma, and ovarian 
cancer patients, unless having a known AXL gene amplification) who have failed a PD-1/PD-L1 
inhibitor and are able to provide the required fresh tumor biopsy will be enrolled. 
For further exploration of the safety and efficacy profile of the 3Q4W schedule, patients in Cohort 
6 will be enrolled on a dose of 1.0 mg/kg administered 3Q4W, which was determined to be the 
MTD for this schedule in the dose escalation part of the trial. Preferably, no more than 8 patients 
should be recruited for one tumor type in this cohort 
In order to obtain sufficient evaluable fresh tumor biopsies up to 15 additional patients may be 
recruited to Cohort 6 to ensure that 25 fresh biopsies are acquired. A maximum of 45 patients may 
therefore be enrolled into Cohort 6. A higher number of biopsies are required in this cohort due to 
the mixture of tumor types being enrolled. 
 
Cohort 8 will further explore the safety and efficacy of the 1.0 mg/kg 3Q4W schedule in NSCLC 
patients without EGFR/ALK mutations. 
 
 Cohort 8 will include up to 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 45 of 259 
37 patients with the aim to collect evaluable fresh tumor biopsies from 15 patients. Recruitment is 
not linked to the number of biopsies collected and may continue up to a maximum of 37 patients 
even if 15 fresh tumor biopsies have already been obtained. The benefit/risk balance will be 
evaluated on an ongoing basis in this cohort. An enapotamab vedotin dose of 1.0 mg/kg 
administered 3Q4W was well tolerated in the dose escalation part of this trial and was determined 
to be the 3Q4W MTD. Emerging data indicates that more frequent dosing has the potential to be 
efficacious when used for ADCs. For example, enfortumab vedotin 1.25 mg/kg 3Q4W 
demonstrated a clinically meaningful response rate (ORR of 44%) with a manageable and tolerable 
safety profile in patients with locally advanced or metastatic urothelial carcinoma who were 
previously treated with platinum and anti–PD-1/L1 therapies17. In addition, a phase I/II study of 
glembatumumab vedotin in patients with advanced melanoma showed a modest improvement in 
ORR with more frequent dosing schedules compared to the 1Q3W schedule although the number 
of patients treated was small and no improvement in PFS was observed18. 
 
 
 Overall, the 1.0 mg/kg 3Q4W 
schedule is anticipated to provide a favorable balance of anti-tumor activity with an acceptable 
safety profile. 
 
An interim analysis for futility will be performed after 22 patients per cohort (minus Cohorts 6 and 
8) if there are < 15 patients with evaluable fresh biopsies in the corresponding cohort. If too few 
responders are observed, further recruitment to the corresponding cohort may be stopped, refer to 
Section 10.7 for more details. However, if the required number of biopsies as well as responders 
(see Table 1) have been observed before the futility analysis in the corresponding cohort, the 
futility analysis can be cancelled. 
Table 1. Overview of sample sizes in the expansion part cohorts 
Cohort 
number 
Minimum 
number of 
patients 
Stop for futility if 
≤ n responders/ 
N patients 
Extra patients if not 15** evaluable 
fresh biopsies from the first 22 patients 
and no stopping due to futility 
Maximum 
number of 
patients 
1 
22 
2/22 
Up to 15 
37 
2 
22 
2/22 
Up to 60* 
82 
3 
22 
2/22 
Up to 15 
37 
4 
22 
2/22 
Up to 15 
37 
5 
22 
2/22 
Up to 15 
37 
6 
30 
- 
Up to 15 
45 
7 
22 
3/22 
Up to 15 
37 
8 
- 
- 
- 
37 
Total 
162 
- 
- 
349 
* Enrolment will continue until sufficient data have been generated to confirm initial efficacy, safety, and biomarker 
findings.  
** For Cohort 6: up to 15 extra patients if not 25 evaluable fresh biopsies from first 30 patients. 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 46 of 259 
For the dose escalation part 1Q3W, 3 sites will be opened and when the 3Q4W dose escalation is 
to be initiated, 3 additional sites may be opened. A communication plan for information sharing 
between sites as well as sponsor will be completed before trial start.  
 
For the expansion part of the trial, up to 60 sites can be opened. 
3.5 
Duration of Treatment 
As of Amendment 10, the duration of treatment for each patient in this trial will be until 
disease progression or unacceptable toxicity (See Sections 6.5, 6.6, and 6.3). 
The duration of treatment for each patient in this trial will be until disease progression or 
unacceptable toxicity followed by data collection every 12 weeks on disease/survival status and 
start of new anti-cancer treatment.   
3.6 
Characteristics of a Well-Conducted Trial 
The following characteristics of an adequate and well-conducted trial will be implemented: 
1. 
The Investigators will be well qualified by scientific training and experience. 
2. 
Detailed electronic Case Report Forms (eCRFs) will be completed for every patient. 
3. 
Requirements for institutional ethics review as set forth by the appropriate Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), Title 21 Code of Federal 
Regulations (CFR) Part 56, the European Union Directive 2001/20/EC and its associated 
Detailed Guidelines, European Union GCP Directive 2005/28/EC, the ICH Guideline for 
Good Clinical Practice (GCP) E6(R2), Sections 3 and 4, and the terms of the Declaration 
of Helsinki (2013), will be followed. 
4. 
Requirements for informed consent in accordance with institutional guidelines, FDA 
requirements as specified in Title 21 CFR, Part 50, the European Union Directive 
2001/20/EC and its associated Detailed Guidelines, European Union GCP Directive 
2005/28/EC, the ICH Guideline for GCP, Section 4.8, and the terms of the Declaration of 
Helsinki (2013), will be followed. 
5. 
Safety data will be recorded and evaluated. 
6. 
Routine monitoring visits will be conducted by the Sponsor’s representative 
 
to ensure data accuracy. 
7. 
Drug accountability will be strictly maintained. 
8. 
This trial will be conducted according to GCP, the protocol and applicable regulatory 
requirements. 
9.  
Exploratory analysis will be exempted from the GCP compliance statement as the data 
from the exploratory analysis will be used for internal knowledge and decision making. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 47 of 259 
4. 
TRIAL OBJECTIVES AND PURPOSE 
4.1 
Primary Objective 
• To determine the MTD and to establish the safety profile of enapotamab vedotin in a mixed 
population of patients with specified solid tumors.  
4.2 
Secondary Objectives 
• To evaluate the safety laboratory parameters of enapotamab vedotin in a mixed 
population of patients with specified solid tumors. 
• To establish the PK profile and evaluate immunogenicity of enapotamab vedotin after 
single and multiple infusions. 
• To evaluate the antitumor activity of enapotamab vedotin in a mixed population of 
patients with specified solid tumors.  
• To evaluate Axl expression in tumor biopsies from a mixed population of patients with 
specified solid tumors. 
4.3 
Exploratory Objective 
• To explore biomarkers predictive of response and resistance to enapotamab vedotin. 
4.4 
Primary Endpoints 
• Dose Limiting Toxicities (DLTs). 
• Adverse events AEs: incidences of AEs, serious adverse events (SAEs), infusion-related 
AEs ≥ Grade 3 AEs, and AEs related to enapotamab vedotin during the trial. 
4.5 
Secondary Endpoints 
• Safety laboratory parameters (hematology and biochemistry). 
• 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 enapotamab vedotin and free toxin [MMAE]). 
• Immunogenicity of enapotamab vedotin (anti-drug antibodies). 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 48 of 259 
• Anti-tumor activity measured by tumor shrinkage (based on computerized tomography 
[CT]-scan evaluations), as well as change in CA 125 in patients with ovarian cancer and 
change in prostate specific antigen (PSA) in patients with castration-resistant prostate 
cancer (CRPC). 
• Objective Response, Progression-Free Survival (PFS), Duration of Response (DoR) and 
Overall survival (OS). 
• Axl expression in the tumor biopsy.  
4.6 
Exploratory Endpoints 
• Biomarkers predictive of response or resistance to enapotamab vedotin 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 49 of 259 
5. 
TRIAL DESIGN 
5.1 
Overview of Trial Design 
This is an open-label, multi-center Phase I/IIa safety trial of enapotamab vedotin in a mixed 
population of patients with solid tumors known from the literature to overexpress Axl and where 
the use of systemic tubulin inhibitors is part of Standard of Care (SoC). The trial consists of two 
parts; a dose-escalation part (phase I, FIH) and an expansion part (phase IIa). The dose escalation 
part has two dose escalation arms: the first one investigates a 1Q3W dose schedule and the second 
one investigates a 3Q4W dose schedule (see Figure 1).   
 
 
Figure 1. Overview of trial design 
(description of A, B and C can be found in the following text) 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 50 of 259 
The 3Q4W arm will only be allowed to start once: 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Although the two arms formally run independently (e.g. reaching the MTD at a dose-level in one 
arm will not automatically disallow patient allocation to correspondingly higher dose-levels in the 
other), safety signals identified in one arm will be taken into consideration for the other arm during 
ongoing safety surveillance, see Section 9.7.  
 
The expansion part is planned to consist of 8 parallel cohorts (Figure 1), mainly to provide 
additional safety and initial efficacy information. Interim analyses for futility may be performed 
(Cohorts 1, 2, 3, 4, 5, and 7) and, based on the results of these analyses, further recruitment in an 
individual cohort may be stopped, see Section 10.7. 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 51 of 259 
5.2 
Dose Escalation, 1Q3W 
In the 1Q3W dose escalation the patients will receive 1 infusion of enapotamab vedotin every three 
weeks as according to Figure 2. Patients will be treated until disease progression or unacceptable 
toxicity is observed. 
 
Screening 
Period
Trial entry
Treatment Period
 Enapotamab vedotin infusion on Day 1 of 21- day cycle. 
Follow-up 
visits
End of Treatment
End of 
Trial
Safety FU 
visit 
 
Figure 2. Trial flow for the 1Q3W dose escalation. 
 
The 1Q3W dose-escalation will be conducted as a mCRM design. The defining property of a CRM 
is a model relating dose to the probability of a DLT. The mCRM chooses the dose for the next 
cohort by estimating the MTD with the currently available data, and then selecting a dose that is 
as close to the MTD as possible while obeying certain modifying constraints (such as not escalating 
too fast). 
After each cohort, patients are assessed for a DLT during the DLT period, the model parameters 
will be updated and a next dose suggested based on the posterior probability of DLT at each dose. 
The DLT period will include the safety data obtained from patients in the respective cohort during 
their first treatment cycle (21 days). 
The 1Q3W dose escalation will potentially (dependent on data collected during the trial) evaluate 
enapotamab vedotin at 7 main dose levels: 0.3, 0.6, 1.0, 1.5, 2.0, 2.4 and 2.8 mg/kg, and 4 optional 
intermediate dose levels 1.25, 1.8, 2.2 and 2.6 mg/kg. Further escalation with steps of 0.4 mg/kg 
and de-escalation by 0.2 mg/kg is allowed, if the MTD has not been declared at a dose level up to 
2.8 mg/kg.  
 
 
 
 
 
 
The following provides a description of the procedure for patient accrual and provisions for dose 
escalation/de-escalation decisions in the 1Q3W schedule. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 52 of 259 
1. After completion of Cycle 1 of each cohort, based on the safety data and the Bayesian 
logistic regression model (BLRM), the DMC will recommend the dose-level for the next 
cohort of patients. 
2. In order to limit patients being treated at a possibly non-efficacious dose (i.e. < 1.0 mg/kg, 
1Q3W schedule), this trial will begin by evaluating enapotamab vedotin in cohorts of at 
least one evaluable patient at each of the first two dose levels. If patients in one of these 
cohorts have experienced a DLT or ≥ Grade 3 toxicity (at least possibly drug-related), the 
cohort size will be increased to at least 3 evaluable patients for the current and subsequent 
cohorts.  
3. At least 3 patients should be enrolled to the 1.0 mg/kg or higher dose-levels.  
4. A patient will be considered as evaluable for dose determination if they experience a DLT 
during Cycle 1 or meet the minimum treatment and safety evaluation requirements for the 
first cycle (see Section 10.1.4). 
5. A two-parameter BLRM with overdose control principle will be used to support 
recommendations on the next dose level, with the following three exceptions: 
 
 
 
 
 
 
 
 
 
 
 
 
6. Following the principle of EWOC, the BLRM model only allows escalation to dose levels 
which are likely to be safe.  
7. For further understanding of the safety, tolerability and PK of enapotamab vedotin, 
additional cohorts of patients may be enrolled at preceding dose levels, or to intermediate 
dose levels before or while proceeding with further dose escalation or even thereafter. 
8. 
 
 
 
 
 
 
9. After repeating the above steps, the MTD is declared when at least 9 patients have been 
evaluated at a dose level and the BLRM recommends allocating an additional cohort to the 
same dose level. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 53 of 259 
10. The dose escalation stops when either the MTD has been declared, no doses are considered safe, 
or the maximum number of patients (Nmax=41) has been enrolled.  
More details on the CRM and criteria for overdose control (when a dose is considered safe) 
can be found in Section 10.2.1 and 
 
 
5.3 
Dose Escalation, 3Q4W 
In the 3Q4W dose escalation the patients will receive weekly dosing for 3 weeks followed by one 
treatment-free week according to Figure 3. Patients will be treated until disease progression or 
unacceptable toxicity is observed. 
 
 
Figure 3. Trial Flow of the 3Q4W dose escalation. 
 
The 3Q4W dose escalation will be conducted as a standard 3 (+3) design which will evaluate 
enapotamab vedotin at doses of (0.45), 0.6, 0.8, 1.0, 1.2 and 1.4 mg/kg. If the 1.4 mg/kg is reached 
without significant safety concerns and it is considered safe to escalate above 1.4 mg/kg, the 
escalation may continue to higher dose levels with increments up to 20% using the standard 3+3 
rules. The starting dose is expected to be 0.6 mg/kg (a dose level of 0.45 mg/kg may be added, see 
Section 5.1). 
The 3Q4W part is initiated based on the criteria described in Section 5.1. The DLT period will 
include the safety data obtained from patients of the respective cohort during their first treatment 
cycle (28 days). The DMC can recommend and the sponsor safety committee may decide to 
implement intermediate dose levels at any step during dose escalation to ensure patient safety and 
better define the MTD. 
Decisions to escalate the dose of enapotamab vedotin for the next cohort will be based on the safety 
data obtained from the 3 (+3) patients during their first treatment cycle (28 days). Before escalating 
from the first dose level to the second dose level in the 3Q4W-arm, PK data must be available for 
DMC review.  
Each cohort will include 3 patients. If during the evaluation period insufficient safety information 
is collected from a patient, the patient will be replaced (see Section 10.1.4). Patients who 
Screening 
Period 
Trial entry
Treatment Period
Enapotamab
-
vedotin infusion on Day 1,8 and 15 of 28- day cycle . 
Follow- up 
visits 
End of treatment visit End of Trial
safety FU visit 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 54 of 259 
discontinue the trial during the first cycle for reasons other than a DLT can be replaced. 
The classic 3+3 design is implemented as follows: 3 patients are allocated per new dose level until 
a DLT is observed. If a DLT is observed within the first cycle, the cohort on the corresponding 
dose level is expanded with 3 more patients. If one additional patient with DLT (i.e., ≥ 2 patients 
with DLTs in total within the 6 patients) is observed on the same dose level, de-escalation will 
take place until a dose-level where 6 patients have been treated at that level with ≤ one patient with 
DLT is observed; this dose level is then the MTD. However, if no other DLTs are observed the 
trial will continue escalation to next dose level. Intermediate dose levels may be implemented to 
ensure patient safety and better define the MTD. After the MTD of the 3Q4W-arm has been 
determined the sponsor may decide to recruit additional  6 patients on the MTD level and the 
level below. 
 
 
New cohort at a new 
dose: Enroll 3 patients
Go to next lower level and 
enroll 3 additional patients 
or declare MTD at next 
lower level if already 6 
patients
Go to next higher 
untested level or declare 
MTD
Go to next lower level and 
enroll 3 additional patients 
or declare MTD at next 
lower level if already 6 
patients
Enroll 3 additional 
patients on same level
Go to next higher 
untested level or enroll 3 
additional patients at 
same level if max level
DLT = 0/3
DLT = 1/3
DLT = 1/6
DLT ≥ 2/6
DLT ≥ 2/3
 
Figure 4. Overview of the classic 3+3 design in the 3Q4W dose escalation 
5.4 
Expansion Part 
The aim of the expansion part is to provide further data on the safety, tolerability, PK, and 
anti-tumor activity of the selected dose(s)/treatment regimen(s).  
Recruitment will be initiated in up to 8 cohorts primarily encompassing cancer types treated in the 
dose escalation part (see cohorts in Figure 1 and Section 6.1). Based on a safety review of data 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 55 of 259 
from the first 12 patients recruited and followed for at least one cycle (regardless of indication), 
the DMC and the sponsor SC will evaluate the safety profile with particular emphasis on any safety 
signals. Additional safety reviews will be performed after 36 and 100 patients have been recruited 
and followed for at least one cycle (regardless of indication) or as needed to ensure the safety of 
patients participating in the trial. 
Patients will be treated with the dose and dose schedule from the dose escalation part 
recommended by the DMC and confirmed by the sponsor SC based on benefit-risk assessment. If 
deemed appropriate, based on data available, the expansion part may be initiated before the MTD 
has been reached in both arms. However, expansion cohort 6 will be opened when sufficient data 
on the benefit-risk ratio derived from both dosing schedules as well as the impact of prior exposure 
to a PD-1/PD-L1 inhibitor have become available, i.e. when at least 10 patients with previous 
exposure to a PD-1/PD-L1 inhibitor have been exposed to enapotamab vedotin and from whom 
safety and biologic activity data have been analyzed. Furthermore, different doses and schedules 
might be explored in the expansion cohorts, without increasing the total number of patients to be 
included in the trial. 
The trial flow as illustrated in either Figure 2 or Figure 3 will be applicable for the expansion part. 
5.5 
Data Monitoring Committee 
A DMC will be established and have its first meeting before trial start (first patient screened). The 
DMC will include medical experts within the disease to be treated, and at least one with DMC 
experience. At the first meeting, the DMC will decide the future format and the degree of the 
information it needs in order to evaluate the patients at each dose level. The functions and 
responsibilities of the DMC will be described in the DMC Charter, which will be approved by the 
DMC.  
Patients will be enrolled in cohorts of 1-3 patients per dose level in the dose escalation part (1Q3W 
and 3Q4W arms as listed above). For each cohort, the DMC will evaluate aggregate safety data 
for the number of patients required in the respective treatment arms in order to recommend whether 
it is safe to escalate to the next dose level. Before the DMC review of safety data, 1-3 patients in 
a cohort must complete the first treatment cycle or have withdrawn from treatment due to a DLT 
(see Section 10.1.4). 
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 intermediate level, halted altogether 
or more patients are required at the same dose level to evaluate safety. In addition cumulative 
safety data for all cohorts will be evaluated at each DMC meeting. 
The DMC meetings will be divided into an open and a closed session. During the open sessions 
representatives from the sponsor, and if deemed relevant one or more investigators involved in the 
trial, will participate together with the DMC members. During the closed session, only DMC 
members will participate.  
The conclusion of the DMC meeting will be documented in meeting minutes.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 56 of 259 
Following each DMC meeting, a sponsor SC meeting will be held to discuss and confirm actions 
recommended by the DMC. The sponsor SC may decide to implement intermediate dose levels to 
ensure patient safety and better define the MTD. 
 
 
 
 
 
 
The DMC will, as a minimum, during the course of the escalation phase, receive reports of any 
SAEs reported in patients treated with enapotamab vedotin, non-serious Grade 3 related AEs and 
DLTs immediately after review of the event by the sponsor.  
5.6 
Trial Overview 
As of Amendment 10, follow-up contact is no longer applicable. Refer to applicable 
assessments in Table 31. 
5.6.1 
Screening Phase (Visit 0) 
No trial-related activities, including any screening procedures, may be performed before written 
informed consent form (ICF) from the patient has been obtained. 
Patients will provide written informed consent. 
All screening assessments must be performed ≤ 21days prior first dose (Visit C1V1) except for 
CT imaging that can be performed up to 28 days prior to first dose (Visit C1V1). If the patient has 
not had a CT scan performed within 28 days prior to first dose a CT scan must be performed within 
14 days prior to first dose. 
A patient can be re-screened once only. The rescreening must be approved by the sponsor to ensure 
that the safety of the patient is not compromised.  
Upon re-screening a new informed consent form must be signed and the patient must complete a 
full new screening visit and all eligibility criteria must be re-assessed at the re-screening visit. An 
exception to this is in cases where re-screening is done within the initial screening period in which 
case only the assessment(s) that did not meet the eligibility criteria must be re-assessed. A new 
screening number will not be allocated to the patient at re-screening.  
5.6.2 
Treatment Phase 
The investigator must have evaluated the patient’s eligibility before the patient’s first infusion. 
5.6.2.1 
Dose Escalation Part 
Dependent on which dose escalation arm the patient is recruited to enapotamab vedotin will be 
administered either 1Q3W or 3Q4W. Patients can be allocated to either the 1Q3W or the 3Q4W 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 57 of 259 
treatment arms by sponsor.  
The patients will receive treatment with enapotamab vedotin at three-week or four-week intervals 
until disease progression or unacceptable toxicity. 
There will be a minimum of 2 nights between the first and second patient in each dose cohort to 
account for any safety concerns in each new dose. Furthermore no other patients within a dose 
cohort will receive their first treatment simultaneously, i.e., on the same day, at different sites 
during the dose escalation part of the trial. 
For visit schedule and windows see Table 9 and Table 10 for 1Q3W and 3Q4W dose schedules 
respectively. 
5.6.2.2 
Expansion Part 
In the expansion part of the trial up to 349 patients will be enrolled and treated with enapotamab 
vedotin at the MTD/RP2Ds in either 1Q3W or 3Q4W as recommended by the DMC and confirmed 
by the sponsor safety committee. The patients will be treated until disease progression or 
unacceptable toxicity.  
The expansion part will recruit patients to each of the cohorts in parallel, without any delay 
between administrations. 
For visit schedule and windows see Table 11. 
5.6.3 
Unscheduled visit 
If deemed necessary by the investigator the patient may be called in for an unscheduled visit(s). 
During the visit the investigator can perform any clinical or laboratory assessment necessary. The 
visit date and reason for the visit must be recorded in the eCRF. 
5.6.4 
End of Treatment visit 
If a patient withdraws from treatment or experiences disease progression they should come for an 
end of treatment visit as soon as possible. 
5.6.5 
Safety Follow-up 
A safety follow-up visit must be performed 30 days after last treatment (according to tables of 
assessments) to collect information about AEs, disease status and new treatment. If the end of 
treatment visit is performed 30 days or more after the last dosing, the safety follow-up visit can be 
omitted. 
5.6.6 
Follow-up Contact  
As of Amendment 10, follow-up contact is no longer applicable.  
After last administration of enapotamab vedotin, every 12 weeks, data will be collected regarding 
patient disease/survival status and new anti-cancer treatment (including date of starting and 
stopping). Also suspected enapotamab vedotin related AEs will be collected until start of new anti-
cancer treatment. Data will be collected until trial termination (see Section 6.6). 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 58 of 259 
5.6.7 
Lost to Follow-up 
For patients whose status is unclear because they fail to appear for trial visits without stating an 
intention to withdraw consent, the investigator should show "due diligence" by contacting the 
subject, family or family physician as agreed in the informed consent form and by documenting in 
the source documents steps taken to contact the subject, e.g., dates of telephone calls, registered 
letters, etc. A patient should not be considered lost to follow-up until due diligence has been 
completed (as a minimum 3 documented attempts). Patients lost to follow-up should be recorded 
as such on the appropriate disposition eCRF. 
5.6.8 
End of Trial 
The end of trial page must be completed after the last contact with the patient (Section 5.6.5).  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 59 of 259 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Investigators should ensure that all trial eligibility criteria are fulfilled at screening. If a patient's 
status changes (including laboratory results or receipt of additional medical records) after 
screening but before the first dose of enapotamab vedotin is given meaning that they no longer 
fulfil all eligibility criteria, they should not be included in the trial. 
6.1 
Inclusion Criteria 
Patients MUST meet all of the following inclusion criteria before they will be allowed to 
participate in the trial: 
1. For the dose escalation part: Patients with relapsed or refractory cancer of the ovary, cervix, 
endometrium, thyroid, NSCLC, or melanoma (cutaneous, mucosal, acral or uveal melanoma) 
who have failed available standard therapy or who are not candidates for standard therapy, and 
for whom, in the opinion of the investigator, experimental therapy with enapotamab vedotin 
may be beneficial. 
For the expansion part: Patients with advanced and/or metastatic cancer who are not 
candidates for standard therapy, and for whom, in the opinion of the investigator, experimental 
therapy with enapotamab vedotin may be beneficial, who have failed the following anticancer 
therapy as follows: 
 
Expansion Cohort 1 (NSCLC patients with classical sensitizing EGFR mutations and/or 
EGFR mutations targeted by third generation TKIs [e.g., T790M for osimertinib]):  
• NSCLC patients after failure of up to 4 prior treatment regimens containing systemic 
therapy for metastatic disease 
o adjuvant and maintenance treatment is considered being part of one treatment 
regimen  
• Documented progressive disease on last prior treatment  
• Last prior treatment to enrolment to GCT1021-01 should have been 
o an EGFR inhibitor (e.g., Erlotinib, Osimertinib, etc.)  
o or a PD-1/PD-L1 inhibitor 
o or a platinum-based doublet chemotherapy 
 
Expansion Cohorts 2 and 8 (NSCLC patients without activating EGFR mutations or ALK 
rearrangements) 
• NSCLC patients after failure of no more than 2 lines of therapy which should include a 
platinum based chemotherapy and PD-1/PD-L1 inhibitor treatment for advanced (Stage 
IIIA or IIIB) or metastatic disease (Stage IV) either in combination or sequentially 
• Documented progressive disease on last prior treatment 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 60 of 259 
• Last prior treatment to enrolment to GCT1021-01 should have been (either in 
combination or sequentially) 
o a platinum based chemotherapy 
o or a PD-1/PD-L1 inhibitor 
 
Expansion Cohort 3 (Melanoma patients with BRAF V600 mutation):  
• Cutaneous, acral, or mucosal melanoma patients after failure of up to 4 prior treatment 
regimens containing systemic therapy for metastatic disease 
o adjuvant and maintenance treatment is considered being part of one treatment 
regimen 
• Documented progressive disease on last prior treatment 
• Last prior treatment to enrolment to GCT1021-01 should have been  
o a BRAF inhibitor (+/- Mek inhibitor) 
o or a checkpoint inhibitor 
 
Expansion Cohort 4 (Melanoma patients with BRAF V600 wild-type) 
• Cutaneous, acral, or mucosal melanoma patients after failure of up to 3 prior treatment 
regimens containing systemic therapy for metastatic disease  
o adjuvant and maintenance treatment is considered being part of one treatment 
regimen 
• Documented progressive disease on last prior treatment 
• Last prior treatment to enrolment to GCT1021-01 should have been  
o a checkpoint inhibitor 
 
Expansion Cohort 5 (Sarcoma patients) 
• Sarcoma patients after failure of up to 3 prior treatment regimens containing systemic 
therapy for metastatic disease  
o Limited to undifferentiated pleomorphic sarcoma, lipo-, leiomyosarcoma, synovial 
sarcoma, Ewing’s sarcoma, osteo-, and chondrosarcoma  
o adjuvant and maintenance treatment is considered being part of one treatment 
regimen 
• Documented progressive disease on last prior treatment 
 
Expansion Cohort 6 (patients with solid tumors, excluding NSCLC, melanoma, ovarian 
cancer, and sarcoma patients unless having a known AXL gene amplification; preferably 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 61 of 259 
no more than 8 patients should be recruited for one tumor type) 
• Patients with solid tumors (except for NSCLC, melanoma, ovarian cancer, and sarcoma 
patients unless having a known AXL gene amplification) that have failed a PD-1/PD-L1 
inhibitor for metastatic disease 
• Documented progressive disease on last prior treatment 
• Last prior treatment to enrolment to GCT1021-01 should have been 
o An immune- checkpoint inhibitor 
 
Expansion Cohort 7 (Platinum-resistant ovarian cancer patients) 
• Ovarian cancer patients with resistance to at least one platinum-based therapy defined 
according to GCIG. Disease progression during or within 6 months of previous platinum-
based chemotherapy include the following 2 categories:  
• Primary platinum-resistant: Previously untreated patients who have achieved at 
least a partial response to platinum-based chemotherapy, but experience a relapse 
within a period of > 1 and < 6 months following treatment completion  
• Secondary platinum-resistant: Previously treated patients who have achieved at 
least a partial response with platinum-based therapy as 2nd line treatment, but 
experience a relapse within a period of > 1 and < 6 months following treatment 
completion.  
• Ovarian cancer patients after failure of at least 2 prior treatment regimens containing 
systemic therapy but not more than 5 for recurrent disease  
o Limited to invasive epithelial tubo-ovarian carcinoma including malignant serous 
(restricted to high-grade serous ovarian cancer (HGSOC), carcinosarcoma, and 
High Grade (or ≥ Grade 3) clear cell / endometrioid / mixed epithelial carcinoma 
o Maintenance treatment (e.g., with bevacizumab, PARPi, PD-1/PD-L1 inhibitor, 
etc.) is considered being part of one treatment regimen  
▪ Treatments that had to be changed to a similar drug due to toxicity count 
as one regimen (e.g. change from carboplatin to cisplatinum because of 
allergy, etc.) 
• Documented progressive disease on or after last prior treatment  
o Start of screening must be within 60 days after documented progression  
o Isolated GCIG CA 125 progression does NOT qualify for trial entry 
• Albumin levels should be > 25 g/L (‘CTCAE G2 intermediate’) to allow inclusion 
 
For the following conditions in Expansion Cohorts 1-8, the sponsor medical officer’s 
approval of enrolment is needed: 
➢ if documented progression has not been on measurable disease (i.e., symptomatic 
progression) 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 62 of 259 
2. Patients must have measurable disease according to Response Evaluation Criteria In Solid 
Tumors (RECIST) version 1.1.  
• 
A minimum of one lesion ≥ 10 mm (or twice the slice thickness if slices are not 5 mm thick) 
in the longest diameter (LD) from a non-irradiated area.  
o Lymph nodes lesion ≥ 15 mm in the shortest diameter from a non-irradiated area. 
o If target lesion(s) are located within previously irradiated area patients can be 
enrolled if: 
▪ target lesions have not been irradiated within the last 3 months 
▪ there has been demonstrated progression in the “in field” target lesion and 
after sponsor acceptance 
• 
In the dose escalation part, patients with ovarian cancer can be included based on CA 125 
positivity according to the Gynecologic Cancer Intergroup Guideline1,2; only if they have 
a pretreatment sample that is at least twice the upper limit of the reference range and within 
2 weeks before starting the treatment.  
Note: Patients are not evaluable by CA 125 if they have received mouse antibodies 
(unless the assay used has been shown not to be influenced by human anti-mouse 
antibody) or if there has been medical and/or surgical interference with their 
peritoneum or pleura during the previous 28 days (e.g., paracentesis). 
3. A) In the dose escalation part all patients must provide a tumor tissue sample (Formalin Fixed 
Paraffin Embedded (FFPE) blocks / slides) from archival tissue or fresh biopsy collected 
before 
Cycle 1, 
Visit 1, 
preferably 
derived 
from 
advanced 
disease 
stage. 
B) In the expansion part all patients must provide a mandatory fresh biopsy (FFPE tissue 
blocks/slides) at screening (aspirates are not acceptable) which contains tumor tissue and is 
taken after failure/stop of last prior treatment. Documentation of the fresh FFPE biopsy 
shipment must be submitted to the Sponsor as a part of eligibility package prior to 
administration of first dose of enapotamab vedotin. In case it is not feasible to meet the required 
criteria for fresh tumor biopsy, the sponsor medical officer’s approval of enrollment is needed. 
Furthermore, the latest available archival tumor tissue sample must be collected if available.  
4. Age ≥ 18 years. 
5. Have an acceptable renal function defined as: 
• 
Glomerular filtration rate (GFR)  40 mL/min/1.73 m² – e.g., according to the 
abbreviated Modification of Diet in Renal Disease (MDRD) equation: 
GFR = 186 × (SCr-1.154) × (age-0.203) 
(where SCr, the serum creatinine level, is expressed in mg/dL; multiply it by 0.742 if the 
patient is female; multiply it by 1.212, if the patient is African-American3). 
• 
Not being on dialysis 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 63 of 259 
6. Have an acceptable liver function defined as: 
• 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the 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 
7. Have an acceptable hematological status defined as: 
• 
Hemoglobin ≥ 5.6 mmol/L (~ 9 g/dL).  
• 
Absolute neutrophil count (ANC) ≥ 1500/µL (1.5  109/L). 
• 
Platelet count ≥ 100 109/L. 
8. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
9. Life expectancy of at least 3 months. 
10. Patients, both females and males, of childbearing/reproductive potential must agree to use 
adequate contraception while included in the trial and for 6 months after the last infusion of 
enapotamab vedotin (see Appendix V). 
11. Patients must provide signed ICF. 
6.2 
Exclusion Criteria 
If any of the following applies, the patient MUST NOT enter the trial: 
Hematological 
1. Acute deep vein thrombosis or clinically relevant pulmonary embolism, not stable for at least 
4 weeks prior to first enapotamab vedotin administration.  
2. Patient has a history of thromboembolic event(s) and is not willing to take thromboembolic 
prophylaxis.  
Cardiovascular 
3. Have clinically significant cardiac disease, including: 
o 
Onset of unstable angina within 6 months of signing the ICF. 
o 
Acute myocardial infarction within 6 months of the signing the ICF. 
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% and/or 
baseline QT interval as corrected by Fridericia’s formula (QTcF) > 480 msec or 
uncontrolled atrial fibrillation. 
o 
Uncontrolled hypertension defined as systolic blood pressure ≥ 160 mmHg and/or 
diastolic blood pressure ≥ 100 mmHg, despite optimal medical management. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 64 of 259 
Immunological 
4. Ongoing or recent (within 1 year) evidence of significant autoimmune disease that required 
treatment with systemic immunosuppressive treatments, which may suggest risk for immune 
related adverse events. 
5. Patients with a history of Grade 3 or higher immune related adverse events should be excluded 
(adverse events below Grade 3 should be discussed with the sponsor).  
6. Patients with a history of non-infectious pneumonitis related to prior systemic treatment and 
that required treatment with steroids within the last 6 months prior to enrolment.  
o If an event of pneumonitis is considered fully resolved more than 6 months prior to trial 
start, i.e., patient has no radiologic evidence of pneumonitis, is asymptomatic and does 
not require any steroid treatment, patient can be enrolled. 
 
Excluded medications or treatment regimens 
7. Have received granulocyte colony stimulating factor (G-CSF) or granulocyte/macrophage 
colony stimulating factor support 3 weeks prior to first enapotamab vedotin administration.  
8. Have received a cumulative dose of corticosteroid > 150 mg prednisone (or equivalent doses 
of corticosteroids) within two weeks before the first enapotamab vedotin administration. 
9. History of ≥ Grade 3 allergic reactions to monoclonal antibody therapy as well as known or 
suspected allergy or intolerance to any agent given in the course of this trial. 
Surgery/procedures 
10. Major surgery within 4 weeks before first enapotamab vedotin administration. 
Central nervous system  
11. Any history of intracerebral arteriovenous malformation, cerebral aneurysm, brain metastases 
or stroke. 
o Transient ischemic attack ≥ 6 months prior to screening is allowed. 
o Patients with known or suspected central nervous system metastases must undergo a 
Computed Tomography (CT) scan or Magnetic Resonance Imaging (MRI) of the brain 
and/or spinal cord for documentation of baseline disease status. Spinal cord metastasis 
is acceptable. However, patients with known spinal cord compression that is 
symptomatic or patients who have not undergone definitive treatment for the spinal 
cord compression and subsequently do not have evidence of clinically stable disease 
(SD) for at least 28 days should be excluded. 
o In the expansion cohorts the enrolment of patients with stable brain metastases, i.e., 
being asymptomatic for the last 14 days prior to treatment initiation, is allowed (use of 
corticosteroids and radiotherapy are described in exclusion criterion 7 and  
Section 7.4.2) 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 65 of 259 
o Symptomatic uncontrolled brain or leptomeningeal metastases. (To be considered 
“controlled”, central nervous system [CNS] disease must have undergone treatment 
[e.g., radiation or chemotherapy] at least 2 weeks prior to first enapotamab vedotin 
administration. The patient must not have any new or progressive signs or symptoms 
related to the CNS disease and must be taking < 10 mg of prednisone or equivalent per 
day or no steroids). Patients who have untreated brain metastases and who are not 
symptomatic may enroll if the investigator feels that treatment of these metastases is 
not indicated. Patients with spinal cord compression may be considered for enrolment 
if they have received definitive treatment for this and evidence of clinically stable 
disease (SD) for at least 28 days. 
Prior therapy 
12. Any anticancer therapy including; small molecules, immunotherapy, chemotherapy 
monoclonal antibodies or any other experimental drug within 5 half-lives but maximum 4 
weeks before first infusion. Accepted exceptions are bisphosphonates, denosumab and 
gonadotropin-releasing hormone agonist or antagonist, which can be continued throughout the 
trial. 
o Toxic effects of prior anti-cancer therapy considered as chronic, such as chemotherapy-
induced fatigue, alopecia, or anorexia of  Grade 2, where no more resolution is 
expected, does not prevent the patient from participation in the trial. 
13. Any prior therapy with a conjugated or unconjugated auristatin derivative/vinca-binding site 
targeting payload. (Previous treatment with vinca alkaloids is allowed in line with inclusion 
criterion #1). 
14. Radiotherapy within 14 days prior to first enapotamab vedotin administration. (Palliative 
radiotherapy will be allowed as described in Section 7.4.2). 
15. Patients who discontinued treatment due to disease progression within the first 6 weeks of 
commencing a prior immune checkpoint inhibitor containing treatment. 
Other cancer/metastases 
16. 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 > 2 years duration. 
Other 
17. Melanoma patients with an LDH ≥ 3 x ULN. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 66 of 259 
18. Ongoing significant, uncontrolled medical condition including: 
o Serious, non-healing wound, skin ulcer (of any grade), or bone fracture. 
19. Presence of ≥ Grade 2 peripheral neuropathy. 
20. Clinically significant active viral, bacterial or fungal infection requiring: 
o I.v. treatment with anti-infective therapy that has been administered less than two 
weeks prior to first dose, or 
o Oral treatment with anti-infective therapy that has been administered less than one 
week prior to first dose. 
o Prophylactic anti-infective therapy, which is given without clinical symptomatic is 
allowed (e.g. antibiotic prophylaxis prior to dental extraction, etc.). 
21. Known human immunodeficiency virus seropositivity. 
22. Known history / positive serology for hepatitis B (unless immune due to vaccination or 
resolved natural infection or unless passive immunization due to immunoglobulin therapy): 
o Positive test for antibodies to hepatitis B core antigens (anti-HBc) 
           and 
o Negative test for antibodies to hepatitis B surface antigens (anti-HBs).  
23. Known positive serology for hepatitis C (unless due to immunoglobulin therapy or completely 
resolved natural infection)  
24. Substance abuse, medical, psychological or social conditions that may interfere with the 
patient’s participation in the trial or evaluation of the trial result 
25. History of organ allograft (except for corneal transplant) or autologous or allogeneic bone 
marrow transplant, or stem cell rescue within 3 months prior to the first dose of enapotamab 
vedotin 
26. Body weight < 40 kg 
27. Women who are pregnant or breast feeding.  
28. Patients are not allowed to take part in any other interventional trial while participating in 
current trial.  
Specifically for NSCLC  
29. Pulmonary hemorrhage or hemoptysis > 2.5 mL blood within 6 weeks unless cause has been 
addressed and is medically resolved. 
6.3 
Withdrawal Criteria 
As of Amendment 10, follow-up every 12 weeks is no longer applicable. Refer to applicable 
assessments in Table 31. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 67 of 259 
6.3.1 
Criteria for Patient Withdrawal from Treatment 
Patients can be withdrawn from treatment for the following reasons: 
• Unacceptable toxicity reported as AEs (see Section 7.3 for specifications, exceptions and dose 
modifications)  
• Pregnancy 
• Withdrawal of consent 
• Investigator or sponsor decision due to individual patient safety issues not covered by other 
withdrawal criteria 
• Disease progression according to RECIST 1.1 or clinical disease progression 
Patients should, whenever possible, irrespective of the reason for withdrawal, be examined as soon 
as possible at the end of treatment visit. 
Patients being withdrawn from treatment for any reason will have a safety follow-up visit 30 days 
after last treatment as well as follow-up contacts every 12 weeks after last dose. 
6.3.2 
Criteria for Patient Withdrawal from the Trial 
The sponsor will make any effort to ensure patients are followed up for completion of safety 
assessment in the trial. Patients will be withdrawn from the trial (dose escalation or expansion 
parts), including safety follow-up and follow-up contact, for the following reasons: 
• Withdrawal of informed consent 
• Lost to follow-up (see Section 5.6.7) 
• Patient died 
• Trial closure (see Section 6.5) 
6.4 
Noncompliance 
All instances of noncompliance and all resulting protocol deviations will be documented. 
6.5 
Trial Stopping Criteria 
If any of the following occur, administration of the enapotamab vedotin will be stopped and no 
additional patients will be included into the trial: 
1)  
Events that, in the judgment of the sponsor Safety department and Medical officer, are 
deemed serious enough to warrant immediate review by the DMC. 
2)  
Any other safety finding assessed as related to enapotamab vedotin that, in the opinion of 
the sponsor, contraindicates further dosing of trial patients. 
If any of the above-listed events occurs, a prompt cumulative review of safety data and the 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 68 of 259 
circumstances of the event in question will be conducted by the DMC to ascertain whether dosing 
and trial entry should be resumed, whether the protocol should be modified, or whether the trial 
should be discontinued permanently. Review and approval by the sponsor safety committee is 
required for resumption of the trial in the event that the trial is interrupted because of one of the 
above-listed events. Where applicable, regulatory authorities IECs/IRBs will be notified of any 
actions taken with the trial. 
Any patients who have already received enapotamab vedotin and are currently in the trial at the 
time trial stopping criteria are met will continue to be followed by the investigator. 
6.6 
Definition of End of Trial 
The trial is considered completed with the last safety follow-up visit of the last patient in the trial. 
The trial will run for a maximum of 3 years after the last patient’s first treatment. 
7. 
TREATMENT OF PATIENTS 
The dose escalation part of this FIH trial must be run in phase I units with cardiopulmonary 
resuscitation equipment available at bedside and fast access to Emergency units. The expansion 
part must be run at hospital wards with access to Emergency units. Throughout the infusion, 
patients will be under surveillance by trial personnel. The physician supervising the enapotamab 
vedotin infusion must be readily accessible for assistance during the day of the infusion. 
7.1 
Investigational Medicinal Product - Enapotamab Vedotin 
Enapotamab vedotin (HuMax-AXL antibody-drug conjugate) is an ADC composed of an IgG1 
human monoclonal antibody (HuMax-AXL) chemically conjugated via a protease cleavable vc 
linker to the drug MMAE. 
7.1.1 
Treatment Administration 
Enapotamab vedotin will be administered as an i.v. infusion. Each patient’s dose will be calculated 
based on the patient’s weight 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 to be administered to the patient 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) (where x denotes the dose level) 
 
Enapotamab vedotin will be administered over a minimum of 30 minutes and the infusion must be 
completed within 4 hours. The infusion is complete when the infusion line has been flushed with 
saline. For further details please refer to the IMP manual (Preparation and Administration of 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 69 of 259 
enapotamab vedotin). 
7.1.2 
Treatment Preparation 
The dose of enapotamab vedotin for administration must be prepared by the site pharmacy using 
aseptic technique. Please refer to the IMP manual (Preparation and Administration of enapotamab 
vedotin) for details on the preparation of the infusion. 
Enapotamab vedotin will be supplied to the site/pharmacy as bulk supply cartons. Labelling of the 
enapotamab vedotin will be done in accordance with local standards and regulations. 
Enapotamab vedotin will be supplied in vials containing 40 mg of enapotamab vedotin as 
lyophilized powder. The powder should be reconstituted with 4 mL water for injection leading to 
a 10 mg/mL solution. 
Enapotamab vedotin (lyophilized vials) should be stored in a refrigerator at 2°C to 8°C.  
The reconstituted enapotamab vedotin should be diluted into 0.9% NaCl 100 mL infusion bag 
according to the dose assigned to the patient. 
The infusion must be completed within 24 hours after the enapotamab vedotin vials have been 
reconstituted. An in-line filter 0.2 µm must be used for the infusion. The entire infusion volume 
from the prepared infusion bag needs to be administered. No dead volume is provided. 
7.2 
Dose-limiting Toxicity 
For the purpose of dose-escalation, SAEs, non-serious (NS) ≥ Grade 3 AEs and clinically 
significant abnormal lab values at least possibly related to enapotamab vedotin will be collected 
and assessed by the DMC for DLTs (in each cohort during the first cycle; 21 days for the 1Q3W 
schedule and 28 days for the 3Q4W schedule). National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v.4.03 will be used to assess severity of 
toxicities/AEs. 
 
DLTs are defined as follows: 
Hematological 
• Grade 4 neutropenia (i.e., ANC < 0.5  109 cells/L) for minimal duration of 7 days.  
• Grade 3 and 4 febrile neutropenia (i.e., ANC < 1.0  109 cells/L with a single temperature of 
> 38.3°C or a sustained temperature of ≥ 38°C for more than one hour). 
• Grade 4 thrombocytopenia (≤ 25.0  109 platelets/L) for minimal duration of 7 days. 
• ≥ Grade 3 hemorrhage associated with thrombocytopenia of ≥ Grade 3. 
• Grade 4 anemia. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 70 of 259 
Non-hematological 
• Stevens Johnson syndrome, Toxic Epidermal Necrolysis, ≥ Grade 3 cutaneous vasculitis. 
• Grade 3 neuropathy (not improving to Grade 1 within 3 weeks following pausing of dosing) 
and Grade 4 neuropathy. 
• Grade 3 infusion-related reactions that do not resolve to Grade 1 or baseline within 24 hours. 
• Grade 4 infusion-related reactions or events of Grade 4 anaphylaxis. 
• Diarrhea and/or vomiting ≥ Grade 3 persisting for more than 48 hours (despite optimal medical 
management).  
• Nausea ≥ Grade 3 (not disease-related) lasting 7 days (despite optimal medical management). 
• Any ≥ Grade 3 related non-hematological AEs, which occur during the first treatment cycle 
and regarded as medically important as assessed by the DMC. 
o Excluding Grade 3 fatigue,  72 hours.  
o Excluding non-hematological laboratory abnormalities that have no clinical 
consequences and resolve within 7 days (this includes electrolyte abnormalities that 
respond to medical intervention). 
In the event of a potential DLT the sponsor will notify the DMC promptly. Depending on the 
nature of the DLT and patient status, the DMC and the sponsor may, if requested by the 
investigator upon thorough benefit-risk assessment of the individual patient, allow a patient with 
a DLT to continue in the trial on a reduced dose (see Section 7.3.1 for further details). 
At the DMC meetings which follow each cohort, safety data for the specific cohort as well as 
cumulative safety data (SAEs, AE and laboratory data, and DLTs where applicable) for all cohorts 
will be evaluated for identification of safety signals, and actions will be recommended by the 
DMC. A sponsor SC meeting will be held following each DMC meeting, to discuss and confirm 
actions recommended by the DMC. 
7.3 
Dose Modifications 
7.3.1 
Dose Delay, Dose Modification and Stopping Rules during Dose Escalation 
 
 
 
  
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 71 of 259 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 72 of 259 
7.3.2 
Dose Modifications and Dose Delays for Patients Experiencing Adverse Events 
during Expansion 
For patients who do not tolerate the protocol-specified dosing schedule, dose reductions are 
permitted in order to allow the patient to continue treatment with enapotamab vedotin.  
Specific instructions on dose interruptions and reductions for different toxicities are provided in 
Table 2, Table 3 and Table 8. These instructions are applicable for both the 1Q3W and 3Q4W 
dosing schedules and should be applied in association with the relevant dose modification scheme 
described in Table 4 to Table 7. 
Table 2. Instructions for dose interruptions and reductions for enapotamab vedotin related hematologic 
toxicity occurring during a cycle 
Hematologic Toxicity 
Enapotamab Vedotin Dose Modification 
Grade 4 neutropenia (ANC < 0.5 x 109/L) 
or  
Febrile neutropenia (fever ≥ 38.5 C and ANC 
< 1 x 109/L) 
Enapotamab vedotin dosing should be interrupted 
until recovery to ≤ grade 2. 
G-CSF therapy should be initiated and/or 
maintained, if already started, at the discretion of 
the treating physician. 
On Day 1 of the next cycle, the dose of 
enapotamab vedotin may be maintained if 
neutropenia was the only AE, G-CSF treatments 
are continued or if event has normalized to grade 
0 or baseline. Otherwise, decrease by one dose 
level at the start of the next cycle (see Table 4, 
Table 6 and Table 7). 
Grade 3 afebrile neutropenia  
Repeat CBC with differential count weekly, 
consider dose interruption until recovery to 
≤ grade 2, and G-CSF prophylaxis in case of 
worsening or delayed recovery beyond 2 weeks. 
Grade 4 thrombocytopenia 
Enapotamab vedotin dosing should be interrupted. 
Decrease by one dose level when dosing is 
resumed (see Table 4, Table 6 and Table 7). 
To restart enapotamab vedotin treatment 
following a dose interruption, the platelets count 
must be ≥ 50 x 109/L. 
Other enapotamab vedotin related AEs (excluding 
neutropenia, febrile neutropenia, and 
thrombocytopenia) ≥ Grade 3 
Enapotamab vedotin dosing should be interrupted. 
Decrease by one dose level when dosing is 
resumed (see Table 4, Table 6 and Table 7). 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 73 of 259 
Table 3. Dose Modification for enapotamab vedotin related Non-Hematologic toxicity occurring during a 
cycle 
Non-Hematologic Toxicity 
Enapotamab Vedotin Dose Modification 
Thrombosis/embolism ≥ Grade 2 
If the event occurred without or during inadequate 
anticoagulation, initiate adequate anticoagulation 
treatment. Enapotamab vedotin dosing may 
continue without interruption at the discretion of 
the treating physician. Dose level may be 
maintained at the discretion of the treating 
physician. 
If the event occurred during adequate 
anticoagulation treatment (prophylactic dose of 
anticoagulation therapy with LMW heparin, 
heparin or Coumadin), discontinue enapotamab 
vedotin. 
Peripheral Neuropathy = Grade 1 (only worsening 
from G0 to G1) 
Enapotamab vedotin dosing should be reduced to 
a lower dose level as indicated in Table 5, Table 6 
and Table 7 without dose interruption. 
Peripheral Neuropathy = Grade 2 or 3 
Enapotamab vedotin dosing should be interrupted. 
Decrease dose (as indicated in Table 5, Table 6 or 
Table 7 depending on dose and schedule 
(neuropathy must resolve to ≤ Grade 1). 
Peripheral Neuropathy = Grade 4 
Permanently discontinue enapotamab vedotin. 
Other enapotamab vedotin related AEs ≥ Grade 3  
Enapotamab vedotin dosing should be interrupted. 
Decrease by one dose level when dosing is 
resumed (see Table 4, Table 6 and Table 7) (AEs 
must resolve to ≤ Grade 2). 
 
For AEs and grades not addressed above, any dose modification must be discussed with the 
medical monitor.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 74 of 259 
In case dose reduction is required due to AE as per protocol (see Table 2, Table 3 and Table 8), 
the dose must be reduced according to the guidelines provided in Table 4 to Table 7 depending on 
the dose and dosing schedule as follows:  
 
 
  
Table 4. 
 
 
 
 
 
Table 5. 
 
 
 
 
  
Table 6. 
 
 
 
If 1.0 mg/kg dose cannot be tolerated by patient on the 1Q3W schedule (independent of type of 
AE), enapotamab vedotin should be permanently discontinued. 
 
  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 75 of 259 
Table 7. 
 
 
 
If 0.6 mg/kg dose cannot be tolerated by a patient on the 3Q4W schedule (independent of type of 
AE), enapotamab vedotin should be permanently discontinued. 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 76 of 259 
7.3.3 
Immune-related Adverse Events 
Guidance for dose modification and management of immune-related AEs is provided in Table 8. For Grade 1 immune-related AEs, 
enapotamab vedotin treatment should be continued with close monitoring. Corticosteroids taper should be initiated over the course of 
at least 4 to 6 weeks when the immune-related AE improves to ≤ Grade 1. Trial treatment should be permanently discontinued for any 
serious Grade 3 immune-related AE that recurs and for any Grade 4 immune-related AE, with the exception of endocrinopathies that 
have been controlled by hormone replacement. For additional guidance on the recommended management of immune-related AEs, 
please refer to the Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: 
American Society of Clinical Oncology Practice Guideline19. 
 
Table 8. Dose Modification and Management of immune-related AEs 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 77 of 259 
Immune-related 
AEs 
Toxicity grade 
(CTCAE v4.03) 
Dose Modification 
Guidance for Management of Immune-related AEs 
Hepatitis (Elevated 
Liver Function Tests 
[LFTs]) 
Infliximab should 
not be used for 
management of 
Immune Related 
Hepatitis 
Any Grade 
- 
- 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
- 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications). 
Grade 1 
(AST or ALT > ULN 
to 3 x ULN and/or 
total bilirubin (TB) 
> ULN to 1.5 x ULN) 
No dose modification 
If it worsens to Grade 2, 
refer to guidance for 
treatment of Grade 2 event  
For Grade 1 AST or ALT and/or TB elevation: 
- 
Continue LFT monitoring per protocol. 
Grade 2 
(AST or ALT > 3 to 5 
x ULN or TB > 1.5-
3.0 x ULN) 
Hold trial drug resolution 
to ≤ Grade 1 
• 
If toxicity 
worsens to Grade 
3 or 4, refer to 
guidance for 
treatment of 
Grade 3 or Grade 
4 event 
• 
If improves to 
baseline, then 
treat at next 
scheduled 
treatment date 
For Grade 2 AST or ALT and or TB elevation: 
- 
Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved. 
- 
If no resolution to ≤ Grade 1 in 1-2 days, discuss with study 
physician. 
- 
If event is persistent (> 3-5 days or worsens, promptly start 
prednisone 1-2 mg/kg/day or IV equivalent. 
- 
If still no improvement within 3-5 days despite 1-2 mg/kg/day 
of prednisone or IV equivalent, consider additional workup and 
prompt treatment with IV methylprednisolone 2-4 mg/kg/day 
started. 
- 
If still no improvement within 3-5 days 2-4 mg/kg/day despite 
IV methylprednisolone, promptly start immunosuppressive 
(mycophenolate mofetil at 500 mg every 12 hours). Discuss 
with study physician if mycophenolate mofetil is not available. 
Infliximab should not be used. 
- 
Once improving, gradually taper steroids over ≥ 4 weeks and 
consider prophylactic antibiotics, antifungals and anti PPCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer related infections [Category 2B 
recommendations]). 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 78 of 259 
Grade 3 
(AST or ALT > 5 - 20 
x ULN and /or TB > 
3.0-10 x ULN 
For elevations in 
transaminases ≤ 8 x ULN, 
or elevations in bilirubin 
≤ 5 x ULN  
- 
Hold trial drug 
until resolution to 
≤ Grade 1 or 
baseline 
- 
Resume trial drug 
administration at 
the next 
scheduled dose if 
elevations resolve 
to ≤ Grade 1 or 
baseline within 
14 days 
Permanently discontinue 
trial drug/ if the elevations 
do not resolve to ≤ Grade 1 
or baseline within 14 days. 
 
For elevations in 
transaminases > 8 x ULN 
or elevations in bilirubin 
> 5 x ULN, permanently 
discontinue trial drug. 
 
Permanently discontinue 
trial drug for any case 
meeting Hy’s law criteria 
(ALT > 3 x ULN + 
bilirubin > 2 x ULN 
without initial findings of 
cholestasis (i.e., elevated 
alkaline P04) and in the 
absence of any alternative 
For Grade 3 or 4 AST or ALT and/or TB elevation: 
- 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
- 
If still no improvement within 3 – 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy 
(mycophenolate mofetil at 500 mg every 12 hours). Discuss 
with study physician if mycophenolate is not available. 
Infliximab should not be used. 
- 
Hepatology consult, abdominal workup, and imaging as 
appropriate. 
- 
Once improving, gradually taper steroids over ≥ 4 weeks and 
consider prophylactic antibiotics, antifungals and anti PCP 
treatment (please refer to current NCCN guidelines for 
treatment of cancer related infections [Category 2B 
recommendations]). 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 79 of 259 
cause  
Grade 4 
(AST or ALT > 20 x 
ULN and/or TB > 10 x 
ULN 
Permanently discontinue 
trial drug 
Pneumonitis 
Grade 1-2 
1st occurrence 
If there is radiographic 
evidence of pneumonitis 
progression, hold treatment 
until there is evidence of 
improvement/resolution to 
Grade 1 or less1 
2nd occurrence 
Permanently discontinue 
Monitor for signs and symptoms of pneumonitis. 
Evaluate for pneumonitis with radiographic imaging. 
For ≥ Grade 2: 
Consider initiation of corticosteroid treatment (initial dose of 1-2 mg/kg 
prednisone or equivalent followed by taper). Corticosteroid taper should 
be initiated when the immune-related AE improves to ≤ Grade 1.  
Grade 3 or 4 
Permanently discontinue 
Colitis 
Grade 2 
Continue treatment at the 
discretion of the 
investigator 
Monitor for signs and symptoms of colitis. Consider gastroenterology 
consultation and confirm diagnosis of colitis. 
Consider administration of corticosteroids (initial dose of 1-2 mg/kg 
prednisone or equivalent) followed by taper.  
Corticosteroid taper should be initiated when the immune-related AE 
improves to ≤ Grade 1.  
Grade 3  
Refer to text below  
Grade 4 
Permanently discontinue 
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia 
Newly diagnosed 
T1DM or Grade 3-4 
hyperglycemia 
Refer to text below  
Monitor for hyperglycemia or other signs and symptoms of diabetes. 
Consider endocrinology consultation.  
Consider administration of insulin for type 1 diabetes. 
Consider administration of anti-hyperglycemic in subjects with 
hyperglycemia. 
Hypophysitis 
Grade 2 
Continue treatment at the 
discretion of the 
investigator 
Monitor for signs and symptoms of hypophysitis. Consider 
endocrinology consultation. 
Consider administration of corticosteroids and initiate hormonal 
replacements as clinically indicated. Corticosteroid taper should be 
initiated upon immune-related AE improving to Grade 1 or less.  
Grade 3 or 4 
Refer to text below 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 80 of 259 
Hyperthyroidism  
Grade 2 
Continue treatment at the 
discretion of the 
investigator 
Monitor for signs and symptoms of thyroid disorders.  
Consider management with thionamides and beta-blockers as 
appropriate. 
Grade 3-4  
Refer to text below 
Hypothyroidism 
Grade 2 
Continue treatment at the 
discretion of the 
investigator 
Monitor for signs and symptoms of thyroid disorders. Consider 
endocrinology consultation. 
Consider initiation of thyroid replacement hormones per standard of care. 
Grade 3-4 
Refer to text below  
Nephritis and Renal 
dysfunction 
Grade 1 
Consider temporary hold 
pending consideration of 
baseline renal function and 
to confirm etiology1 
Monitor for changes in creatinine levels. 
For ≥ Grade 2: 
If worsening or no improvement, consider administration of 
corticosteroids (prednisone 1-2 mg/kg or equivalent) followed by taper. 
Corticosteroid taper should be initiated upon immune-related AE 
improving to Grade 1 or less.  
Grade 2 
Hold treatment until 
resolved to baseline1 
Grade 3-4  
Permanently discontinue 
Skin Toxicities 
Grade 1-2 
Continue treatment at the 
discretion of the 
investigator 
Based on the severity of the adverse reaction, consider administration of 
corticosteroids. Corticosteroid taper should be initiated upon immune-
related AE improving to Grade 1 or less.  
 
For signs or symptoms of Steven Johnsons Syndrome (SJS) or Toxic 
Epidermal Necrolysis (TEN), withhold and refer the subjects for 
specialized care. If SJS or TEN is confirmed, permanently discontinue. 
Grade 3 
Refer to text below 
Grade 4 
Permanently discontinue 
All other immune-
related AEs 
Grade 2 
Continue treatment at the 
discretion of the 
investigator 
Based on type and severity of AE, consider administration of 
corticosteroids. Permanently discontinue for any Grade 3 immune-related 
AE that recurs and for any life-threatening immune-related AEs. 
Grade 3 
Refer to text below or 
discontinue based on the 
type of event. 
Grade 4  
Permanently discontinue 
1 20  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 81 of 259 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 82 of 259 
Dose Delays 
1Q3W and 3Q4W Schedule 
For immune-related AEs, please refer to Section 7.3.3 regarding dose delays. 
For all other AEs/Toxicities, enapotamab vedotin administration can be delayed for up to a 
maximum of 12 weeks. Radiological assessments should be continued during this period, as 
per protocol Section 8.4.7 and as clinically indicated, to monitor for disease progression.  
Patients should be withdrawn from treatment if the treatment delay exceeds 12 weeks or if 
disease progression is observed while treatment is interrupted. 
3Q4W Schedule Only 
If a patient has to delay a dose for more than 14 days and the toxicity has resolved by that time, 
the patient should start with a new regular cycle upon resuming treatment. 
 
7.4 
Limitation in Concomitant Medication 
7.4.1 
Prophylactic Concomitant Medications 
Constipation (≤ Grade 3) has been the most frequently reported clinically significant adverse event. 
The events seem to be treatment-related and dose-dependent. In order to prevent constipation, oral 
bisacodyl should primarily be administered as prophylactic treatment. If bisacodyl is not available, 
ducosate sodium for oral administration should be used.  
For each cycle, prophylactic treatment should be initiated on Day 5 following the administration 
of enapotamab vedotin, or earlier if the patient experiences signs or symptoms of constipation 
before Day 5. Treatment should continue until Day 21 for the 1Q3W dose schedule and until 
Day 28 for the 3Q4W dose schedule, with dose adjustments as required.   
The doses to be used are as follows:  
 
Preferred: 
Bisacodyl, 5 mg (orally) 
Alternative: 
Ducosate sodium 100 mg 
(orally) 
High dose 
2 tablets QD at bedtime 
1 capsule TID 
Mid dose (starting dose) 
1 tablet QD at bedtime 
1 capsules BID 
Low dose 
1 tablet every other day at bedtime 
1 capsule QD 
 
The Investigator may adjust the starting dose, taking the patient’s medical history and use of 
concomitant opioid medications into consideration.  
The investigator should advise patients how to avoid constipation by a diet high in bulk fiber, fruits 
and vegetables, adequate fluid intake, if possible physical activity and adequate time for toilet 
visits.  
The patient will be given a patient diary for recording of their stool frequency and consistency and 
use of prophylactic treatment, and be instructed how to complete it and to bring it to every visit.  
The site personnel should record the name of the prophylactic treatment and a high dose, mid dose 
(which is the dose to start with on day 5 of a cycle) and a low dose in the patient’s diary.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 83 of 259 
The diary will contain guidance on how to modify the dosing of the prophylactic treatment as 
needed:  
• In case of signs and symptoms of constipation, the patient should increase the dose of the 
prophylactic treatment to the next dose level, indicated in the patient diary. In case the 
highest dose level is already in use, the patient should contact the trial site for advice. 
Patients should also be advised to contact the site if they go for more than 48 hours without 
bowel movements. 
• In case of signs and symptoms of diarrhea, the administration of the prophylactic treatment 
should be interrupted. When diarrhea has resolved, treatment should be reintroduced at a 
dose level lower than the previous dose taken prior to the development of diarrhea. In case 
the previous dose was the lowest dose, then the low dose should be used.   
Additional treatments, such as senna, milk of magnesia, magnesium citrate, and lactulose should 
be administered for ≥ Grade 2 constipation and may be considered for ≤ Grade 1 constipation. If 
not given as primary prophylactic medication to avoid constipation, docusate sodium or bisacodyl 
may be given in addition. 
Any occurrence of diarrhea or constipation should be recorded as an adverse event. Investigators 
should assess further patients for any evidence of autonomic neuropathy, e.g. postural hypotension 
in patients with constipation. 
Investigators should assess further patients for any evidence of autonomic neuropathy, e.g. 
postural hypotension in patients with constipation. 
Investigators should pay particular attention to the definition of the NCI CTCAE Grade 3 
constipation and may well consider that hospital admission equates to “limiting self-care ADL”. 
7.4.2 
Permitted Concomitant Medications 
Investigators may prescribe concomitant medications or treatments deemed necessary to provide 
adequate supportive care except for those medications identified as “excluded”. Administration of 
concomitant medications must be reported in the appropriate section of the eCRF along with dates 
of administration and reasons for use.   
• 
Palliative radiotherapy during the trial will be allowed for local pain control provided that: 
(i) in the opinion of the investigator, the patient does not have known progressive disease 
(PD) and (ii) no more than 10% of the patient’s bone marrow is irradiated and (iii) the 
radiation field does not encompass a target lesion. 
• 
G-CSF and other hematopoietic growth factors may be used in the management of acute 
toxicity (see Section 7.3.2), such as febrile neutropenia, when clinically indicated or at the 
investigator’s discretion. Patients are permitted to be taking chronic erythropoietin provided 
that no dose adjustment was made within two months before the first dose of enapotamab 
vedotin. 
• 
Blood-cell transfusion is allowed if clinically indicated.  
• 
Chronic steroid therapy is acceptable provided that the dose was stable for at least 2 weeks 
before the first administration of enapotamab vedotin and remains stable thereafter. The 
cumulative dose of corticosteroid within two weeks before the first infusion should not have 
been ≥ 150 mg prednisone (or equivalent doses of corticosteroids). Short-term steroid 
treatment is permitted at the discretion of the investigator. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 84 of 259 
• 
Tumor lysis syndrome (TLS): For patients at risk of developing a TLS, prophylaxis according 
to standard local practice with (aggressive) hydration, allopurinol, and/or rasburicase is 
recommended. 
• 
Bisphosphonates, denosumab and gonadotropin-releasing hormone are allowed as according 
to exclusion criteria 10. 
• 
Treatment for constipation, as described in Section 7.4.1, is allowed. 
• Over the course of this trial, additional medications may be required to manage aspects of 
the disease state of the patient, including side effects from trial treatments or disease 
progression. Supportive care may be administrated at the discretion of the investigator. Use 
of immunosuppressive medications for the management of enapotamab vedotin related 
AEs or in patients with contrast allergies is acceptable. In addition, use of inhaled, topical 
and intranasal corticosteroids for concurrent illness (e.g., food allergies and CT scan 
contrast hypersensitivity) are acceptable upon discussion and agreement with the medical 
monitor. 
7.4.3 
Excluded Concomitant Therapy 
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
The following medications and substances are prohibited during the trial.  
• Any other investigational anticancer therapy. Drugs and substances known to be strong 
CYP3A4 and/or P-gp inhibitors (e.g., amiodarone, boceprevir, clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, 
verapamil, voriconazole) should not be administered during the trial period. 
• Drugs and substances known to be strong CYP3A4 inducers (e.g, avasimibe, carbamazepine, 
phenytoin, rifampin, St. John’s wort) should not be administered during the trial period. 
• No dietary supplements are allowed during the trial period, except vitamins, calcium, and 
supplements in prevention of weight loss. The administration of non-approved, herbal and/or 
natural remedies used in folk medicine to prevent or treat disease and symptoms should be 
avoided with the exception of Senna that can be used as required. 
• Vaccinations with live, attenuated vaccines are prohibited during the trial and until 30 days 
after the last dose.  
If a patient receives any of these during the trial, the sponsor must be notified for evaluation of 
whether the patient can continue treatment or not. 
Patients receiving drugs and substances known to be strong CYP3A4 and/or P-gp inhibitors up to 
three weeks after the last treatment with enapotamab vedotin should be monitored closely for 
adverse reactions. 
Please refer to most recent list of CYP3A4 inhibitors and inducers at the FDA website: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 85 of 259 
7.5 
Infusion-Related Reactions 
Infusion-related reactions have been observed in two animals during the non-clinical studies and 
with other cleavable MMAE based ADCs. Patients should therefore be monitored during infusion.  
Pre-medication to prevent injection-related reactions may be administered, at the investigator's 
discretion according to local institutional standards (antihistamine and/or acetaminophen and/or 
corticosteroid). 
• If an infusion-related reaction Grade 1 occurs, the infusion does not need to be interrupted and 
can be continued at the investigator’s discretion at half the infusion rate under close medical 
supervision.  
• If an infusion-related reaction Grade 2 or 3 occurs, the infusion should be interrupted and 
appropriate medical management instituted. The infusions may be restarted at the 
investigator’s discretion at half the infusion rate under close medical supervision if symptoms 
have resolved to  Grade 1 within an hour. 
• Patients who have experienced prior infusion-related Grade 2 or 3 reactions in the trial should 
be pre-medicated.  
• If the patient has a second infusion-related reaction of ≥ Grade 3 with concomitant 
medication, the infusion should be stopped and the patient should be withdrawn from 
treatment. 
• If anaphylaxis or Grade 4 infusion related reaction occurs, administration of enapotamab 
vedotin should be discontinued immediately and permanently and appropriate medical therapy 
should be administered. 
As a routine precaution, patients enrolled in this trial must be observed for at least 1 hour after 
each infusion, in an area with resuscitation equipment and emergency agents. 
At all times during enapotamab vedotin infusion, immediate emergency treatment of an 
anaphylactic reaction according to institutional standards must be assured. In order to treat 
possible anaphylactic reactions, for instance, dexamethasone 10 mg and epinephrine in a 1:1000 
dilution or equivalents should always be available along with equipment for assisted ventilation. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 86 of 259 
8. 
TRIAL EVALUATION 
8.1 
Table of Assessments 
As of Amendment 10, trial assessments are reduced. Refer to Table 31 for applicable assessments. 
Table 9. Table of Assessments – Dose Escalation 1Q3W 
Treatment Cycle 
Screening 
Cycle 1 and 3 
Cycle 2, 4-16 
Cycle 17 to PD22 
End of 
treatment1 
Safety Follow-
up 
Patient follow-up End of trial Unscheduled 
Visit Number 
0 
1 
2 
3 
4 
5 
1 
2 
3 
1 
- 
- 
1-X 
- 
1-X 
Day/Week 
≤ 21 days prior 
to Visit C1V1 
1d 
2d 
4d 
8d 
15d 
1d 
8d 
15d 
1d 
- 
30 days after 
last dosing 
Every 12 weeks 
after last dosing 
 
- 
- 
Visit window2 
 
±3d3 
- 
- 
±1d 
±1d 
±3d3 
±1d 
±1d 
±3d 
- 
+14d 
±14d 
- 
- 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight5 
X 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
Physical Examination25 
X17 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
 
X15 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X15 
ECG 
Please refer to Section 8.4.6.1 for details of ECG assessments 
Imaging 
X7 
X8 
X9 
 
 
 
X15 
ECOG Performance Status X 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
 
X15 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X18 
 
X15 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
 
X15 
Prophylactic concomitant 
medication21 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Enapotamab vedotin 
administration 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
End of treatment/trial 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 87 of 259 
Treatment Cycle 
Screening 
Cycle 1 and 3 
Cycle 2, 4-16 
Cycle 17 to PD22 
End of 
treatment1 
Safety Follow-
up 
Patient follow-up End of trial Unscheduled 
Visit Number 
0 
1 
2 
3 
4 
5 
1 
2 
3 
1 
- 
- 
1-X 
- 
1-X 
Day/Week 
≤ 21 days prior 
to Visit C1V1 
1d 
2d 
4d 
8d 
15d 
1d 
8d 
15d 
1d 
- 
30 days after 
last dosing 
Every 12 weeks 
after last dosing 
 
- 
- 
Visit window2 
 
±3d3 
- 
- 
±1d 
±1d 
±3d3 
±1d 
±1d 
±3d 
- 
+14d 
±14d 
- 
- 
LABORATORY ASSESSMENTS 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X15 
Biochemistry10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X15 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X15 
CA 12511 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
X15 
Pregnancy Test 
X 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
X15 
ADA (Immunogenicity) 
 
X19 
 
 
 
 
X19 
 
 
 
X 
X 
 
 
X15 
Hepatitis B, C, CMV12 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X15 
PK Sampling 
Please refer to Section 8.2 for details of PK samplings 
Tumor biopsy 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
Biomarkers 
X 
 
 
 
X20 
 
 
 
X14 
 
X 
 
 
 
 
Patient diary handout  
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Patient diary collection 
 
X23 
 
 
 
 
X 
 
 
X24 
X 
 
 
 
 
Review of patient diary 
data 
 
X23 
X 
X 
X 
X 
X 
X 
X 
X24 
X 
 
 
 
 
 
Footnotes to Trial Flowchart – Dose Escalation 1Q3W 
1 If the patient shows PD, is to start new anti-cancer treatment or withdraws from treatment due to another reason the End of treatment visit should be performed as soon as possible after decision of 
withdrawal. 
2 The visit windows relate to the day of the previous visit. Visit 1 of Cycle 3 and onwards should be performed 7 days ±3 days after Day 15 of the previous cycle. 
3 Visit window not applicable for C1V1 and C2V1. 
4 Signs, symptoms and diagnosis occurring between Screening Visit and C1V1 should be recorded as medical history (see Section 8.4 for details). SAEs should be reported as of the signing of the informed 
consent. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 88 of 259 
Footnotes to Trial Flowchart – Dose Escalation 1Q3W 
5 Body weight will be 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 weight can be used to calculate dose and is the weight 
recorded in the eCRF. 
6 Temperature, blood pressure and heart rate as according to Section 8.4.8. 
7 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 28 days prior to visit C1V1 as part of standard procedure, it 
is acceptable as screening CT-scan for the trial. If there is suggestion of brain metastases/tumors, a CT-scan of the head will be performed before inclusion.  
8 Radiological assessments to be performed every 6 weeks from C1D1. 
9 To be completed as indicated to confirm response, new symptoms, end of treatment visit or at the physician discretion, see Section 8.4.7. 
10 TSH, T3 and T4 will only be measured at screening and on Visit 1 of every even cycle. 
11 For patients with ovarian cancer CA 125. The screening sample should be taken within 2 weeks before starting the treatment. 
12 As according to Section 8.5.6.  
13 The latest archived biopsy can be used preferably derived from advance disease stage. If no sample is available, a new tumor biopsy must be obtained. 
14 Sample to be taken at last visit of Cycle 2, 4 and 8. 
15 Only if relevant. 
16 Only New Anticancer treatment. 
17 Including a baseline visual acuity assessment at the screening visit. 
18 Suspected enapotamab vedotin related AEs only. 
19 ADA will be drawn before infusion at Visit 1 of each cycle. 
20 Sample only to be taken in Cycle 1. 
21 Please refer to Section 7.4.1 on prophylactic concomitant medications. 
22 The patients will receive treatment until progressive disease (PD) or unacceptable toxicity. 
23 Except at Cycle 1 Day 1. 
24 The last diary will be collected and reviewed at Cycle 17 Day 1. After that, no additional diaries will be handed out. 
25 A complete, general physical examination will be done at the screening and C1D1 visit. At subsequent visits and as clinically indicated, limited symptom-directed physical examinations should be performed. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 89 of 259 
Table 10. Table of Assessments – Dose Escalation 3Q4W 
Treatment Cycle 
Screening 
Cycle 1 and 3 
Cycle 2, 4-12 
Cycle 13 to PD22 
End of 
treatment1 
Safety Follow-up Patient follow-up End of trial Unscheduled 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4 
1 
2 
3 
- 
- 
1-X 
- 
1-X 
Day 
≤21 days prior 
to Visit C1V1 
1d 
8d 
15d 16d 17d 22d 
1d 
8d 
15d 22d 1d 
8d 
15d 
- 
30 days after last 
dosing 
Every 12 weeks 
after last dosing 
 
- 
- 
Visit window2 
 
±3d
3 
±1d ±1d  
 
±1d 
±3d3 ±1d 
±1d ±1d ±3d ±1d 
- 
+14d 
±14d 
- 
- 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight5 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
 
Physical Examination25 
X17 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
 
 
X15 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X15 
ECG 
Please refer to Section 8.4.6.1 for details of ECG assessments 
Imaging 
X7 
X8 
X9 
 
 
 
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 
X 
X 
X18 
 
X15 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X16 
 
X15 
Prophylactic concomitant 
medication21 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Enapotamab vedotin 
administration 
 
X 
X 
X 
 
 
 
X 
X 
X 
 
X 
X 
 
 
 
 
 
End of treatment/trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
LABORATORY ASSESSMENTS 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X15 
Biochemistry10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X15 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 90 of 259 
Treatment Cycle 
Screening 
Cycle 1 and 3 
Cycle 2, 4-12 
Cycle 13 to PD22 
End of 
treatment1 
Safety Follow-up Patient follow-up End of trial Unscheduled 
Visit Number 
0 
1 
2 
3 
4 
5 
6 
1 
2 
3 
4 
1 
2 
3 
- 
- 
1-X 
- 
1-X 
Day 
≤21 days prior 
to Visit C1V1 
1d 
8d 
15d 16d 17d 22d 
1d 
8d 
15d 22d 1d 
8d 
15d 
- 
30 days after last 
dosing 
Every 12 weeks 
after last dosing 
 
- 
- 
Visit window2 
 
±3d
3 
±1d ±1d  
 
±1d 
±3d3 ±1d 
±1d ±1d ±3d ±1d 
- 
+14d 
±14d 
- 
- 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X15 
CA 12511 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X15 
Pregnancy Test 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
 
X 
X 
 
 
X15 
ADA (Immunogenicity) 
 
X19 
 
 
 
 
 
X19 
 
 
 
 
 
X 
X 
 
 
X15 
Hepatitis B, C, CMV12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X15 
PK Sampling 
Please refer to Section 8.2 for details of PK samplings 
Tumor biopsy 
X13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
Biomarkers 
X 
 
X20 
 
 
 
 
 
 
 
X14 
 
 
X 
 
 
 
 
Patient diary handout  
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Patient diary collection 
 
X23 
 
 
 
 
 
X 
 
 
 
X24 
 
X 
 
 
 
 
Review of patient diary 
data 
 
X23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X24 
 
X 
 
 
 
 
 
Footnotes to Trial Flowchart – Dose Escalation 3Q4W 
1 If the patient shows PD, is to start new anti-cancer treatment or withdraws from treatment due to another reason the End of treatment visit should be performed as soon as possible after decision of 
withdrawal. 
2 The visit windows relate to the day of the previous visit. Visit 1 of Cycle 3 and onwards should be performed 7 days ±3 days after Day 22 of the previous cycle. 
3 Visit window not applicable for C1V1 and C2V1. 
4 Signs, symptoms and diagnosis occurring between Visit 0 and first infusion should be recorded as medical history (see Section 8.4 for details). SAEs should be reported as of the signing of the informed consent. 
5 Body weight will be measured on the first dosing day in a cycle, as part of the dose calculation. If body weight is assessed ≤ 7 days before the first day of the planned dosing in a cycle, this weight can be used to 
calculate dose and is the weight recorded in the eCRF. 
6 Temperature, blood pressure and heart rate as according to Section 8.4.8. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 91 of 259 
Footnotes to Trial Flowchart – Dose Escalation 3Q4W 
7 All patients will have a CT-scan with contrast of thorax, abdomen, and pelvis performed as part of the screening procedure. If a CT-scan has been performed within 28 days prior to visit C1V1 as part of 
standard procedure, it is acceptable as screening CT-scan for the trial. If there is suggestion of brain metastases/tumors, a CT-scan of the head will be performed before inclusion.  
8 Radiological assessments are to be performed every 8 weeks from C1D1. See Section 8.4.7. 
9 To be completed as indicated to confirm response, new symptoms, end of treatment visit or at the physician discretion see Section 8.4.7. 
10 TSH, T3 and T4 will only be measured at screening and on Visit 1 of every even cycle. 
11 For patients with ovarian cancer CA 125. The screening sample should be taken within 2 weeks before starting the treatment 
12 As according to Section 8.5.6. 
13 The latest archived biopsy can be used preferably derived from advance disease stage. If no sample is available, a new tumor biopsy must be obtained. 
14 Sample to be taken at last visit of Cycle 2, 4 and 8. 
15 Only if relevant. 
16 Only New Anticancer treatment. 
17 Including a baseline visual acuity assessment at the screening visit. 
18 Suspected enapotamab vedotin related AEs only. 
19 ADA will be drawn before infusion Visit 1 of each cycle.  
20 Sample only to be taken in cycle 1. 
21 Please refer to Section 7.4.1 on prophylactic concomitant medications. 
22 The patients will receive treatment until progressive disease (PD) or unacceptable toxicity 
23 Except at Cycle 1 Day 1. 
24 The last diary will be collected and reviewed at Cycle 13 day 1. After that, no additional diaries will be handed out. 
25 A complete, general physical examination will be done at the screening and C1D1 visit. At subsequent visits and as clinically indicated, limited symptom-directed physical examinations should be performed. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 92 of 259 
 
Table 11. Table of Assessments – Expansion 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-12 or 16 
Cycle 13 or 17 to PD19 
End of 
Treatment1 
Safety Follow-
up 
Patient follow-up End of trial 
Unscheduled 
1Q3W  
Visit 
≤21 days prior 
to Visit C1V1 
1 
- 
2 
3 
1 
- 
2 
3 
1 
- 
- 
- 
1-X 
 
1-X 
Day 
1d 
- 
8d 15d 1d 
- 
8d22 
15d22 
1d 
- 
- 
30 days after 
last dosing 
Every 12 weeks 
after last dosing 
- 
 
3Q4W  
Visit 
≤21 days prior 
to Visit C1V1 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
Day 
1d 8d 15d 
22d 
1d 8d 15d 
22d23 
1d 
8d 
15d 
Visit window2 
 
- 
±1d 
±1d 
±3d 
±1d 
±1d 
±3d 
±1d 
- 
+14d 
±14d 
 
- 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight4 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
Physical Examination 21 
X16 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X14 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X14 
ECG 
Please refer to Section 8.4.6.1 for details of ECG assessments 
Imaging 
X6 
 
 
 
X7 
X8 
 
 
 
X14 
ECOG Performance Status 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
X14 
Adverse Events 
X24 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X17 
 
X14 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X15 
 
X14 
Prophylactic concomitant 
medication18 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Enapotamab vedotin 
administration 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
End of treatment/trial 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
LABORATORY ASSESSMENTS 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X14 
Biochemistry9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X14 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
 
X14 
CA 125 /PSA10 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X14 
Pregnancy Test 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X14 
ADA (Immunogenicity)  
 
X11 
 
 
X11 
 
 
X11 
 
X 
X 
 
 
X14 
Hepatitis B, C, CMV12 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X14 
PK Sampling 
Please refer to Section 8.2 for details of PK samplings 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 93 of 259 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-12 or 16 
Cycle 13 or 17 to PD19 
End of 
Treatment1 
Safety Follow-
up 
Patient follow-up End of trial 
Unscheduled 
1Q3W  
Visit 
≤21 days prior 
to Visit C1V1 
1 
- 
2 
3 
1 
- 
2 
3 
1 
- 
- 
- 
1-X 
 
1-X 
Day 
1d 
- 
8d 15d 1d 
- 
8d22 
15d22 
1d 
- 
- 
30 days after 
last dosing 
Every 12 weeks 
after last dosing 
- 
 
3Q4W  
Visit 
≤21 days prior 
to Visit C1V1 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
Day 
1d 8d 15d 
22d 
1d 8d 15d 
22d23 
1d 
8d 
15d 
Visit window2 
 
- 
±1d 
±1d 
±3d 
±1d 
±1d 
±3d 
±1d 
- 
+14d 
±14d 
 
- 
Tumor biopsy and 
biomarkers 
Please refer to Section 8.3 for details of tumor biopsy and biomarker samplings  
Patient diary handout 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Patient diary collection 
 
 
 
 
X 
 
 
X20 
 
X 
 
 
 
 
Review of patient diary data 
 
 
X 
X 
X 
X 
X 
X20 
 
X 
 
 
 
 
 
Footnotes to Trial Flowchart – Expansion 
1 If the patient shows PD, is to start new anti-cancer treatment or withdraws from treatment due to another reason the End of treatment visit should be performed as soon as possible after decision of withdrawal. 
2 The visit windows relate to the day of the previous visit. Visit 1 of Cycle 2 and onwards should be performed 7 days ±3 days after Day 15/22 of the previous cycle. 
3 Signs, symptoms and diagnosis occurring between Visit 0 and first infusion should be recorded as medical history (see Section 8.4 for details). SAEs should be reported as of the signing of the informed consent. 
4 Body weight will be measured on the first dosing day in a cycle, as part of the dose calculation. If body weight is assessed ≤ 7 days before the first day of the planned dosing in a cycle, this weight can be used to calculate dose 
and is the weight recorded in the eCRF. 
5 Temperature, blood pressure and heart rate as according to Section 8.4.8. 
6 All patients will have a CT-scan with contrast of thorax, abdomen, and pelvis performed as part of the screening procedure. If a CT-scan has been performed within 28 days prior to visit C1V1 as part of standard procedure, 
it is acceptable as screening CT-scan for the trial. If there is suggestion of brain metastases/tumors, a CT-scan of the head will be performed before inclusion. Clinical measurement in case of superficial cutaneous lesions should 
be performed within 28 days prior to visit C1V1 as part of standard procedure. For further details on imaging please refer to Section 8.4.7. 
7 Radiological assessments and clinical measurements of superficial cutaneous lesions are to be performed every 6 (1Q3W and Cohort 8 3Q4W) or 8 (Cohort 6 3Q4W) weeks (±7days) from C1D1 until disease progression. If 
treatment is discontinued prematurely, prior to detection of disease progression (e.g., due to an adverse event), every effort should be made that scans continue according to the protocol until disease progression, start of a new 
anti-cancer treatment, withdrawal of consent or death (see Section 8.4.7 for details). 
8 To be completed as indicated to confirm response or new symptoms at the end of treatment visit or at the physician discretion. 
9 TSH, T3 and T4 will only be measured at screening and on Visit 1 of every even cycle. 
10 For patients with ovarian cancer CA 125 and for patients with prostate cancer PSA. The screening sample should be taken within 2 weeks before starting the treatment 
11 ADA will be drawn before infusion at Visit 1 of Cycle 1-5, then every 4th Cycle until PD, at the end of treatment visit and the safety follow-up visit.  
12 As according to Section 8.5.6. 
13 Not applicable. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 94 of 259 
Footnotes to Trial Flowchart – Expansion 
14 Only if relevant. 
15 Only new anticancer treatment. 
16 Including a baseline visual acuity assessment at the screening visit. 
17 Suspected enapotamab vedotin related AEs only. 
18 Please refer to Section 7.4.1 on prophylactic concomitant medications. 
19 The patients will receive treatment until progressive disease (PD) or unacceptable toxicity. 
20 The last diary will be collected and reviewed at Cycle 13 Day 1 (patients on 3Q4W regimen) or at Cycle 17 Day 1 (patients on 1Q3W regimen). After that, no additional diaries will be handed out. 
21 A complete, general physical examination will be done at the screening and C1D1 visit including peripheral neuropathy assessment, such as checking of tendon reflexes, muscle strength and tone, sensitivity, co-ordination 
and balance. At subsequent visits and as clinically indicated, limited symptom-directed physical examinations should be performed (Section 8.4.5). The peripheral neuropathy assessment should also be performed at the End of 
Treatment visit. 
22 The Day 8/15 visit can be omitted if there have been no AEs fulfilling the DLT criteria in the previous 2 cycles as assessed by investigator. Please note that biomarker samples need to be taken on Cycle 4 Day 15 and Cycle 
8 Day15. 
23 The Day 22 visit can be omitted if there have been no AEs fulfilling the DLT criteria in the previous 2 cycles as assessed by investigator . Please note that biomarker samples need to be taken on Cycle 4 Day 22 and Cycle 8 
Day 22. 
24 Only SAEs 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 95 of 259 
8.2 
PK Sampling (Enapotamab Vedotin, HuMax-AXL and MMAE) 
As of Amendment 10, sampling and assessment of PK is no longer applicable. Refer to Table 
31 for applicable assessments. 
Table 12. PK Sampling Dose Escalation, 1Q3W 
Treatment Cycle 
Cycle 1 and 3 
Cycle 51 - 15 
Cycle 17 and 
every uneven 
cycle until 
PD 
Unscheduled 
Visit Number 
1 
2 
3 
4 
5 
1 
2 
1 
1-X 
Day 
1d 2d 4d 
8d 15d 
1d 
8d 
1d 
- 
Before Infusion (on infusion days) 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
End of infusion (+15 minutes)2 
X 
 
 
 
 
X 
 
X 
 
+2 hours (±15 minutes) after end of 
infusion2 
X 
 
 
 
 
 
 
 
 
+5 hours (±30 minutes) after end of 
infusion2 
X 
 
 
 
 
 
 
 
 
1 Every uneven cycle. 
2 Allowed time windows are indicated in parentheses.   
3 Optional. 
Table 13. PK Sampling Dose Escalation, 3Q4W 
Treatment Cycle 
Cycle 1 and 3 
Cycle 51 - 11 
Cycle 13 and every 
uneven Cycle until PD 
Unschedule
d 
Visit Number 
1 
2 
3 
4 
5 
6 
1 
3 
4 
1 
2 
3 
1-X 
Day 
1d 
8d 15d 16d 17d 22d 1d 15d 22d 
1d 
8d 
15d 
- 
Before Infusion 
(on infusion days) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
End of infusion (+15 minutes) 2 
X 
X 
X 
 
 
 
X 
X 
 
X 
X 
X 
 
+2 hours (±15 minutes) 
after end of infusion 2 
 
 
X 
 
 
 
 
 
 
 
 
 
 
+5 hours (±30 minutes) after 
end of infusion2 
 
 
X 
 
 
 
 
 
 
 
 
 
 
1 Every uneven cycle. 
2 Allowed time windows are indicated in parentheses.  
3 Optional. 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 96 of 259 
Table 14. PK Sampling Expansion 
Treatment Cycle 
1 cycle = 3 weeks 
Cycle 1 - 4  
Cycle 53 - 
PD 
End of Treatment Safety Follow-up 
Unscheduled 
1Q3W  
Visit 
1 
1 
- 
- 
1-X 
 
Day 
1d 
 
 
30 days after last 
dosing 
 
Before Infusion 
[on infusion days] 
X 
X 
X 
X 
X2 
End of infusion 
(+15 minutes)1 
X 
 
 
 
 
 
Treatment Cycle 
1 cycle = 4 weeks 
Cycle 1 - 4 
Cycle 53 - PD 
End of 
Treatment Safety Follow-up 
Unscheduled 
3Q4W  
Visit 
1 
2 
3 
44 
1 
- 
- 
1-X 
Day 
1d 8d 15d 22d 
1d 
 
30 days after last 
dosing 
 
Before Infusion 
[on infusion days] 
X X 
X 
X 
X 
X 
X 
X2 
End of infusion 
(+15 minutes)1 
X X 
X 
 
X 
 
 
 
1 Allowed time windows are indicated in parentheses.   
2 Optional. 
3 Every 4th cycle. 
4 For Cycle 1 and 2 only 
8.3 
Exploratory Biomarker Analyses 
 
 
Table 15. 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 97 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 98 of 259 
Table 16. 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 99 of 259 
8.4 
Clinical Assessments 
 
8.4.1 
Demographics 
Date of birth, race, ethnic origin, gender and smoking and drinking habits will be recorded at 
screening in the eCRF. 
8.4.2 
Disease Status 
Primary site of cancer and initial and current disease stage [Tumor Nodes Metastasis (TNM) 
staging system]21 will be recorded at screening in the eCRF. 
For patients with NSCLC, the patients’ mutational tumor status with respect to EGFR mutations 
and ALK rearrangement and for patients with melanoma with respect to BRAF and NRAS 
mutations will be also recorded (incl. date of the assessment). In addition, for patients with NSCLC 
who have previously been treated with PD-1 or PD-L1 inhibitors, the PD-L1 expression level at 
the time of initiation of prior PD-1/PD-L1 inhibitor treatment will be recorded.  
As of Amendment 10: 
• Height, weight, and physical examination outcome are no longer to be recorded in the 
eCRF.   
• ECGs will be taken locally.  
o Any irregularity observed or occurring during the ECGs should either induce 
a repeat of the ECG or be annotated in the medical journal. 
o New or worsened clinically significant abnormalities should be recorded as 
AEs on the AE form.  
• Post-baseline CT-scans are to be performed every 12 weeks (±7 days) and are not to 
be sent for central reading. 
• Vital signs should be measured if deemed necessary by the investigator, but are not 
to be recorded in the eCRF. 
• Any medication or therapy other than enapotamab vedotin that is related to an AE 
or is considered prophylactic treatment is considered concomitant medication.  
• Patient diary data are not to be recorded in the eCRF.     
Refer to Appendix VI, Table 31 and Section 16.2 for applicable clinical assessments as of 
Amendment 10. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 100 of 259 
8.4.3 
Medical History 
Past and all current diseases will be recorded at screening in the eCRF. Non-serious AEs (signs, 
symptoms and diagnosis) occurring between visit 0 (Screening) and C1V1 should be recorded as 
medical history.  
8.4.4 
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 visit 1 of 
each cycle, as part of the dose calculation, and at end of treatment visit, and will be recorded in the 
eCRF. If body weight is assessed 7 days or less (on the site weight) before the day of the planned 
dosing, this weight can be used and is the weight recorded in the eCRF.  
8.4.5 
Physical Examination 
A complete general physical examination will be done at the screening and C1D1 visit including 
peripheral neuropathy assessment, such as checking of tendon reflexes, muscle strength and tone, 
sensitivity, co-ordination and balance. A baseline visual acuity assessment will be performed at 
the screening visit using the Snellen chart.  
At subsequent visits (or as clinically indicated), limited symptom-directed physical examinations 
should be performed and the outcome of the physical examination must be recorded in the eCRF. 
Changes from baseline abnormalities should be recorded in patient’s notes. New or worsened 
clinically significant abnormalities should be recorded as AEs on the AE form. The peripheral 
neuropathy assessment should also be performed at the End of Treatment visit. 
An unscheduled general physical examination should always be considered, if a significant clinical 
finding is observed. 
8.4.6 
Electrocardiogram 
The electrocardiograms (ECGs) will be recorded digitally at the sites by using the standard 12 
leads. ECGs will be performed in accordance with the ECG manual issued by the vendor and as 
described below. 
The digital ECGs will be transmitted from the sites electronically to a central laboratory for a 
treatment blinded measurement of the cardiac intervals and morphologic assessment by a central 
cardiologist.  
An overall interpretation of the ECGs must be performed by the investigator (the investigator may 
delegate this task to a cardiologist or other qualified staff member, if applicable) before each dosing 
for use of treatment decision (with the exception of evaluation of patient eligibility which must be 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 101 of 259 
evaluated based on the central ECG reading). The investigator ECG interpretation must be done 
using the paper ECG reading from the ECG machine by signing and dating the print out. In case 
of discrepancy between central and the investigator ECG readings, the central reading will be used 
for trial analysis purposes. For the ECG recordings, the patients must be resting and in a horizontal 
or half laid-back position for at least 10 minutes (the position should not change for following 
ECGs). 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. 
Date of the ECG and the overall interpretation of the ECGs will be recorded in the eCRF. 
ECGs will be taken as single or triplicate ECGs according to the tables below. 
8.4.6.1 
ECG Assessment 
Table 17. ECG Assessments Dose Escalation, 1Q3W 
Treatment Cycle 
Screening 
Cycles 1 and 3 Cycle 2, 
4-16 
Cycle 17 
to PD  
End of 
treatment Unscheduled 
Visit Number 
0 
1 
3 
4 
5 
1 
1 
- 
1-X 
Day/Week 
≤ 21 days prior to 
Visit C1V1 
1d 4d 8d 15d 
1d 
1d 
- 
- 
Before infusion (on infusion days) 
1 
3 
3 
3 
3 
3 
1 
1 
1a 
End of infusion (+15 minutes)  
 
3 
 
 
 
 
 
 
 
End of infusion + 2 hours (± 15 minutes)  
 
3 
 
 
 
 
 
 
 
End of infusion + 5 hours (± 30 minutes)  
 
3 
 
 
 
 
 
 
 
1 = Single ECG assessment; 3= Triplicate ECG assessments 
aECG assessed if relevant  
Table 18. ECG Assessments Dose Escalation, 3Q4W 
Treatment Cycle 
Screening 
Cycles 1 and 3 
Cycle 
2, 4-12 
Cycle 13 
to PD  
End of 
treatment 
Unschedule
d 
Visit Number 
0 
1 
3 
5 
6 
1 
1 
- 
1-X 
Day 
≤21 days prior to 
Visit C1V1 
1d 
15
d 
17
d 
22d 
1d 
1d 
- 
- 
Before infusion (on infusion days) 
1 
3 
3 
3 
3 
3 
1 
1 
1a 
End of infusion (+15 minutes)  
 
 
3 
 
 
 
 
 
 
End of infusion + 2 hours (± 15 min)  
 
 
3 
 
 
 
 
 
 
End of infusion + 5 hours (± 30 min)  
 
 
3 
 
 
 
 
 
 
1 = Single ECG assessment; 3 = Triplicate ECG assessments 
aECG assessed if relevant  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 102 of 259 
Table 19. ECG Assessments Expansion Part 
Treatment Cycle 
Screening 
Cycle 1 to PD 
End of Treatment 
Unscheduled 
1Q3W  
Visit 
≤21 days prior to 
Visit C1V1 
1 
- 
1-X 
Day 
1d 
- 
- 
Before infusion 
(on infusion days) 
1 
3 
1 
1a 
 
Treatment Cycle 
Screening 
Cycle 1 to PD 
End of Treatment 
Unscheduled 
3Q4W  
Visit 
≤21 days prior to 
Visit C1V1 
1 
- 
1-X 
Day 
1d 
- 
Before infusion 
(on infusion days) 
1 
3 
1 
1a 
1 = Single ECG assessment; 3 = Triplicate ECG assessments 
aECG assessed if relevant  
8.4.7 
Imaging/Computed Tomography 
All patients will have a CT-scan with contrast of thorax, abdomen and pelvis performed during 
screening. If there is suspicion of brain metastases/tumors, a CT-scan of the head will be performed 
before inclusion. For patients with stable brain metastases enrolled in the expansion part, the CT-
scan must include the head and neck. 
For patients with superficial cutaneous lesions that are not measurable by a CT-scan, measurement 
using calipers can be performed, using photographs as documentation.  
All sites of metastatic disease should be reported at baseline and followed throughout the trial. Up 
to 5 target lesions (maximum two per organ) will be defined at screening. A lesion from which a 
fresh biopsy has been taken during the trial cannot be a target lesion.  
Baseline imaging assessments will be performed during the screening period. Any imaging 
assessments already completed for regular radiographic evaluation of the patient’s cancer can be 
considered as the baseline images for this trial, as long as they are of sufficient diagnostic quality 
and have been obtained ≤ 28 days prior to C1D1. 
 
Post-baseline scans will be performed every 6 weeks (1Q3W and Cohort 8 3Q4W) or 8 weeks 
(Cohort 6 3Q4W) (±7 days) from C1D1 until investigator assessed disease progression according 
to RECIST v1.1. Time points for radiographic evaluation should be calendar based and do not 
depend on cycle visits i.e. radiological evaluation should be performed regardless of IMP 
administration delays. For patients who permanently discontinue IMP for other reasons than 
disease progression (e.g., adverse events), every effort should be made to continue on-trial 
radiological evaluation according to protocol until disease progression, start of a new anti-cancer 
treatment, withdrawal of consent or death (see Table 11). 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 103 of 259 
 
If reduction of target lesions ≥ 30% in size is observed a repeat CT-scan will be performed after 
4 (in particular for the 3Q4W-arm) to 6 weeks (in particular for the 1Q3W-arm) to confirm the 
response.  
Unscheduled imaging may be performed at the investigators discretion to confirm response 
(intervals should not be shorter than 4 weeks). In case of suspicion of disease progression on the 
basis of clinical or laboratory findings, imaging should be performed as soon as possible before 
the next scheduled evaluation. In this case the investigator must choose the imaging technology 
based on the clinical indication. For patients in the expansion part, all supplemental images must 
be submitted for central reading.  
 
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.  
Localized CT with contrast or MRI (with or without contrast; for sarcomas with contrast) must be 
acquired for assessment of lesions of the skeleton/extremities and head and neck if not visible on 
other images. At the discretion of the investigators, combined PET/CT (e.g., FDG-PET) may be 
performed for tumor assessments as per RECIST 1.1, but only if the CT portion is of similar 
diagnostic quality to CT alone. Chest x-rays and ultrasound should not be used to measure tumor 
lesions. 
The same imaging modality and ideally the same scanner should be used throughout the trial to 
optimize the reproducibility of the assessment and preserve the accuracy of the assessment of 
response or progression.  
In the dose escalation part the reading of the scans will be done by a local radiologist. Sites should 
attempt to maintain the same radiologist throughout the trial. The overall interpretation of the 
evaluation shall be recorded in the eCRF and a copy of the evaluation reports should be kept in the 
patient’s file. 
In the expansion part the scans will be read by the local radiologist and subsequently sent for 
central reading and archiving.  
8.4.8 
Vital Signs 
Vital signs should be measured and recorded in the eCRF including temperature, blood pressure 
and heart rate. Vital signs will be measured as according to the schedules outlined in Table 9, Table 
10 and Table 11. Within each visit, preferably the same equipment shall be used for vital sign 
measurements. On infusion days, vital signs should be assessed just before and no longer than 30 
minutes before infusion start, during and after the infusions until 4 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 20, Table 21 and Table 22 for the dose escalation and expansion parts. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 104 of 259 
Table 20. Vital Signs during the Dose Escalation Part, 1Q3W 
Cycle 1 and cycle 2 treatment days 
Cycle 3 until PD (treatment days) 
Pre-infusion  
Pre-infusion  
15 min after start of infusion (±5 min) 
15 min after start of infusion (±5 min) 
At the end of infusion (±5 min)  
At the end of infusion (±5 min) 
15 min after end of infusion (±5 min) 
*15 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 (±15 min) 
1 hour after end of infusion (±15 min) 
4 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 15 minutes (±5 minutes) for the remaining duration 
of the infusion.  
* These assessments can be skipped for the 1Q3W schedule from Cycle 7 onwards, if no infusion reaction has been observed during 
previous enapotamab vedotin administrations.  
Table 21. Vital Signs during the Dose Escalation Part, 3Q4W 
Cycle 1 treatment days 
Cycle 2 until PD (treatment days) 
Pre-infusion  
Pre-infusion  
15 min after start of infusion (±5 min) 
15 min after start of infusion (±5 min) 
At the end of infusion (±5 min)  
At the end of infusion (±5 min) 
15 min after end of infusion (±5 min) 
*15 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 (±15 min) 
1 hour after end of infusion (±15 min) 
4 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 15 minutes (±5 minutes) for the remaining duration 
of the infusion.  
* These assessments can be skipped for the 3Q4W schedule from Cycle 3 onwards, if no infusion reaction has been observed during 
previous enapotamab vedotin administrations.  
Table 22. Vital Signs during the Expansion Part 
Treatment days 
Pre-infusion  
At the end of infusion (±10 min)  
1 hour 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. 
* These assessments can be skipped for the 1Q3W/3Q4W schedule from Cycle 7/3 onwards, if no infusion reaction has been 
observed during previous enapotamab vedotin administrations.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 105 of 259 
8.4.9 
ECOG Performance Status 
The eastern cooperative oncology group (ECOG) performance status will be assessed by the 
investigator at screening, on Visit 1 of each cycle, and at the end of treatment visit. Performance 
status will be scored using the ECOG performance status scale index. 
Table 23. ECOG Performance Status 
Score 
Performance status 
0 
Fully active, able to carry out all normal activity without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature, 
e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair. 
5 
Dead 
8.4.10 
Concomitant Medication 
Any medication or therapy other than enapotamab vedotin is considered concomitant medication 
and should be recorded in the eCRF with the following information: 
Start date  
Route of administration 
Stop date of administration or ongoing at trial termination 
Indication / reason for use. 
The total daily dose should be filled in whenever possible. 
Relevant prior concomitant medication given within one month prior to screening and all 
medication given from visit 0 (Screening) until the 30-day safety follow-up must be recorded. 
During the patient follow-up period only new anti-cancer treatment will be collected. 
8.4.11 
Prior Cancer Therapy and Surgery 
Administration of prior anti-cancer therapies and surgeries must be reported in the appropriate 
section of the eCRF. Number of cycles, response and stop reason along with dates of 
administration and progression should be reported. Radiotherapy should be recorded if the 
indication is cancer. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 106 of 259 
8.4.12 
Adverse Events 
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 30 day safety follow-up visit. Any non-serious AEs (signs, symptoms and diagnosis) 
occurring between screening and the day of first treatment administration should be recorded as 
medical history. 
SAEs should be reported from the time the patient signs the ICF (both on the eCRF AE form and 
the SAE reporting form) and until the 30 day safety follow-up visit. All deaths should be reported 
as an SAE. In relation to the follow up visits conducted every 12 weeks after end of treatment, 
only suspected enapotamab vedotin related AEs should be reported. 
For further details regarding reporting of AEs, please see Section 9. 
8.4.13 
Patient Diary 
Patients will receive a patient diary at the start of each treatment cycle. The diary will capture 
changes in stool frequency and consistency as well as prophylactic treatment for constipation.  
The patient should complete the diary daily, and bring the diary to each visit. The principal 
investigator or sub-investigator will review the diary and discuss the stool pattern and dose and 
effect of the prophylactic treatment with the patient. The data will be recorded as is in the eCRF 
by the trial staff. In case of missing data in the diary, this will be recorded as ‘not done’ in the 
eCRF. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 107 of 259 
8.5 
Laboratory Assessments 
 
Blood sampling will be collected for assessment of laboratory parameters. All laboratory samples 
will be drawn and shipped for centralized testing. The central laboratory automatically provides 
test results graded according to NCI-CTCAE. 
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 may provide standard analyses not requested in the protocol but produced 
automatically in connection with the requested analyses. Such data will not be included in the 
database, but must be reported to the investigator. 
The tests detailed in Table 9, Table 10 and Table 11 will be drawn and shipped for centralized 
testing and results will be reported to the investigators by the central laboratory as described in the 
laboratory manual.  
Local laboratory values for biochemistry (Section 8.5.1) and hematology (Section 8.5.2) must be 
obtained the day before or on the day of each enapotamab vedotin administration and reviewed by 
the investigator prior to each enapotamab vedotin administration to ensure the patient can be dosed 
as defined in the protocol.  
As of Amendment 10: 
• All laboratory samples will be analysed locally.   
• Urinalysis is only to be performed if deemed necessary by the investigator and not 
to be entered in the eCRF.  
• New or worsened clinically significant abnormalities should be recorded as AEs on 
the AE form. 
• Assessments for CA 125, enapotamab vedotin, MMAE, hepatitis B and C, 
cytomegalovirus serology, immunogenicity and Axl expression are no longer 
applicable.  
• Collection and assessment of tumor biopsies is no longer applicable. 
• Exploratory biomarker analyses are no longer applicable. 
Refer to Appendix VI, Table 31 and Section 16.3 for applicable laboratory assessments as 
of Amendment 10. 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 108 of 259 
Patient eligibility must always be evaluated based on central laboratory values, however, local 
safety laboratory values (glomerular filtration rate (GFR), ALT/AST/bilirubin, hemoglobin, 
neutrophil count, platelet count, LDH [melanoma patients]) must be obtained the day before or on 
the day of C1D1 to confirm patient eligibility.  
Furthermore, local laboratory values may be obtained at the discretion of the investigator and used 
for other clinical treatment decisions of the patient. 
For clinical treatment decisions, e.g. enapotamab vedotin administration or safety reasons, for an 
individual patient, local laboratory values take precedence over central laboratory values. Local 
laboratory values must be recorded in the eCRF if they are assessed by the investigator to be 
clinically significant or lead to dose modifications/delays of enapotamab vedotin. In case local or 
central laboratory values are assessed as clinically significant by the investigator, a corresponding 
adverse event must be reported on an AE form (Section 9.1). Furthermore local labs will be 
assessed for the evaluation of DLT.  
 
For the analyses and reporting of the trial results, the central laboratory values will be used. All 
recorded local laboratory values will be listed. 
Urinalysis is taken locally and the result will be entered in the eCRF.  
8.5.1 
Biochemistry 
Blood samples will be drawn in accordance with Table 9, Table 10 and Table 11.  
A full panel of biochemistry parameters for this trial will be analyzed centrally while some 
biochemistry parameters will also be analyzed locally. 
The following Biochemistry parameters will be analyzed centrally:  
Sodium, potassium, magnesium, creatinine, calcium, blood urea nitrogen, AST, ALT, alkaline 
phosphatase, albumin, glucose, total bilirubin, LDH, uric acid, C-reactive protein, lipase, amylase, 
gamma-glutamyl transferase, glycosylated hemoglobin, chloride, cholesterol, triglycerides, high-
density lipoprotein and low density lipoprotein (calculated).  
Thyroid stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) will only be 
measured at screening and on visit 1 of every even cycle (i.e., C2V1).  
The following Biochemistry parameters will be analyzed locally the day before or on the day of 
each enapotamab vedotin administration: 
Sodium, potassium, magnesium, creatinine, calcium, blood urea nitrogen, AST, ALT, alkaline 
phosphatase, albumin, glucose, total bilirubin, uric acid, cholesterol, triglycerides, lipase, amylase, 
and gamma-glutamyl transferase. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 109 of 259 
8.5.2 
Hematology 
Blood samples will be drawn as according to Table 9, Table 10 and Table 11. 
The following hematology parameters will be analyzed centrally, as well as locally at site (the day 
before or on the day of each enapotamab vedotin administration): 
Red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, white blood cell count with differential, 
platelet count, reticulocyte count and coagulation factors (prothrombin time, international 
normalized ratio and activated partial thromboplastin time). 
8.5.3 
CA 125 
For patients with ovarian cancer, blood samples for CA 125 assessment will be analyzed as 
according to Table 9, Table 10 and Table 11. 
8.5.4 
Urinalysis 
Site will perform a urinalysis (dipstick) as according to Table 9, Table 10 and Table 11, measuring 
pH, density, nitrite, protein, glucose, blood, leukocytes, bilirubin, urobilinogen and ketones. 
Based on the results from the dipstick urinalysis a microscopic analysis of the urine sediment for 
white blood cell count, red blood cell count, epithelial cells, and bacteria may be performed at the 
discretion of the investigator. 
8.5.5 
Enapotamab Vedotin, HuMax-AXL and MMAE in Serum 
Blood samples for assessment of enapotamab vedotin and MMAE will be drawn for central 
analysis in accordance with the PK flowcharts (see Section 8.2). Two assays will be used for 
enapotamab vedotin, one detecting enapotamab vedotin only and one detecting enapotamab 
vedotin and non-conjugated HuMax-AXL. In addition a third assay will be used to determine free 
MMAE in circulation. 
8.5.6 
Hepatitis B, C and Cytomegalovirus Serology 
A blood sample will be drawn at screening for central 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. 
For hepatitis C virus, anti-IgG will be assessed and, if positive, it will be confirmed with hepatitis 
C virus PCR. 
Blood samples will be drawn for assessment of antibodies to CMV antigen after the end of 
enapotamab vedotin administration (at the end of treatment visit).  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 110 of 259 
8.5.7 
Pregnancy Test 
Pregnancy testing will be performed as scheduled in Table 9, Table 10 and Table 11 from all 
women of childbearing potential and will be analyzed centrally. Pregnant women may not take 
part in this trial 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 (see Appendix V). 
8.5.8 
Immunogenicity of Enapotamab Vedotin 
Blood samples will be drawn for central analysis of ADA at the time points shown in Table 9, 
Table 10 and Table 11. Analysis of ADA will be done in batches of several samples. ADA 
assessment is performed according to a tiered approach: Firstly samples are screened for an ADA 
response. Positively screened samples will be analysed in a confirmation method. Subsequently 
confirmed positive samples will be analysed for titre and the presence of neutralizing antibodies.  
8.5.9 
Tumor Biopsy 
Tumor biopsies will be collected at screening from each patient as according to inclusion 
criterion 3 and must be in accordance with the collection and processing guidance provided in the 
laboratory manual. To ensure sufficient tumor tissue, it is mandatory to collect core needle 
biopsies, which should be CT or ultrasound-guided for internal solid tumor lesions and performed 
by experienced interventionists. Biopsies which are collected using bronchoscopy are only allowed 
in cases where a core needle biopsy is not clinically feasible as assessed and documented by the 
investigator and when significant tumor sample can be collected during the bronchoscopy 
procedure. 
For the expansion part additional biopsies will be collected during treatment and at the end of 
treatment, as specified in Section 8.3 and preferably from the same lesion biopsied at screening.  
It should be noted that it is not allowed to take biopsies from target lesions during treatment. 
Archival biopsies should be formalin fixed, paraffin embedded (FFPE). Fresh biopsies should be 
collected as both mandatory FFPE tissue (blocks/slides) and optional fresh frozen tissue. 
8.5.9.1 
Axl Expression 
The IHC-assay to measure Axl expression (in all indications) on an automated staining platform 
will be evaluated at a central laboratory. Tumor sections will be scored for Axl expression by a 
certified pathologist.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 111 of 259 
Digital images will be made from Axl stained tumor sections and used for exploratory digital 
pathology analyses of Axl expression.  
8.5.10 
Exploratory Biomarker Analyses 
Axl expression in tumor tissue is one of the major determinants of response to enapotamab vedotin 
in pre-clinical models and will accordingly be evaluated as patient selection biomarker. Axl 
expression is however known to be dynamic and heterogeneous. IHC methods may therefore be 
suboptimal to measure Axl expression, and additional methods may be utilized to assess molecular 
Axl expression. In addition, the exploratory biomarker analyses will also investigate 
pharmacodynamic markers and explore the relationship to efficacy and/or mechanism of action. 
In later cycles, assessments will be performed on visits with a planned CT scan in order to enable 
correlation analyses with response to treatment or disease progression.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 112 of 259 
 
 
 
 
 
 
 
 
 
 
 
 
  
8.5.11 
Biological Sample Handling 
Details of sample collection, processing, shipping and storage will be described in the laboratory 
manual. Samples will be stored and batched for logistical reasons before analysis. 
Each sample for exploratory research will be identified with the trial number and patient enrolment 
number. In this way exploratory biomarker and genetic data may be correlated with clinical data. 
Samples will be destroyed in the case of withdrawal of consent.  
8.5.12 
Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their lifecycle. The Principal 
Investigator, at each site, keeps full traceability of collected biological samples from the patients 
while in storage at the site until shipment or disposal (where appropriate) and keeps documentation 
of receipt of arrival. The Principal Investigator will also ensure that access to the samples while in 
storage at the trial site will be limited only to those people for whom access is required. The sample 
receiver keeps full traceability of the samples while in storage and during use, until used or 
disposed of or until further shipment and keeps documentation of receipt of arrival. The sponsor 
keeps oversight of the entire life cycle through internal procedures, monitoring of trial sites and 
auditing of external laboratory providers.  
All samples collected during the trial will be destroyed at the latest 5 years after last patient last 
visit in the trial if not analyzed before then.  
 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 113 of 259 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 114 of 259 
9. 
REPORTING OF ADVERSE EVENTS 
 
9.1 
Recording Instructions 
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial are 
provided in the instructions that accompany the AE eCRFs.  
All AEs, regardless of relatedness or cause, should be reported as an AE in the eCRF. When an 
AE becomes Grade 3 or results in an SAE, it should be reported both in the eCRF and on the Safety 
Reporting form, as applicable. Events of neuropathy Grade 2 and neuropathy leading to 
discontinuation should also be reported both in the eCRF and on the Safety Reporting form, as 
applicable; see also Section 9.3.2. 
All AEs with an outcome of death (including disease progression) should be reported as an AE (in 
the eCRF) and as an SAE from the time patients sign the ICF until 30 days after the last enapotamab 
vedotin dosing.  
All AEs in the 30 day safety follow-up visit including laboratory findings considered to be 
clinically significant should be reported accordingly. After the 30 days safety follow-up visit, 
should the investigator become aware of an SAE possibly related to enapotamab vedotin, this 
should be reported accordingly. 
Laboratory assessments 
If a central laboratory value indicates dose modification/delay, but the local laboratory value does 
not, the sponsor medical officer and/or CRO Medical Monitor should be contacted and the site 
will be asked to retrospectively record the corresponding local laboratory value in the eCRF. Any 
local or central laboratory values leading to a dose modification/delay or are assessed by the 
investigator to be clinically significant should be recorded as an AE (Section 8.5). 
Pre-existing Conditions 
In this trial, a pre-existing conditions (i.e., a disorder present before the AE reporting period started 
As of Amendment 10: 
• Non-serious Grade 3 AEs, peripheral neuropathy AEs ≥ Grade 2, and peripheral 
neuropathy AEs leading to permanent treatment discontinuation are no longer to 
be reported on the Safety Reporting form.  
• All laboratory samples will be analysed locally.   
Refer to Section 17 for applicable safety reporting as of Amendment 10. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 115 of 259 
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. 
9.1.1 
Definition of Adverse Events of Special Interest (AESI) 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which are 
of scientific and medical concern specific to the sponsor’s product or program, for which ongoing 
monitoring and rapid communication by the investigator to the sponsor may be appropriate. Such 
events may require further investigation in order to characterize and understand them.  
AESIs are defined on the basis of an ongoing review of the safety data. AESIs are discussed further 
in Section 9.1.9 and in the IB. 
9.1.2 
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.  
9.1.3 
Intensity 
The investigator will use the NCI-CTCAE version 4.03 to describe the severity of the AE (NCI-
CTCAE v4.03, 2010).  
A persistent AE is one that extends continuously between patient evaluation timepoints without 
resolution. Such events should only be recorded once on the AE eCRF. Changes in intensity of an 
ongoing AE should be assessed at each visit or more frequent if deemed necessary. In case of a 
change in NCI-CTCAE grading, the new grading and date of change should be reported on the 
relevant Adverse Event eCRF (please refer to the instructions that accompany the AE eCRF for 
more information).  
A recurrent AE is one that resolves between patient evaluation timepoints and subsequently recurs. 
Each recurrence of an AE should be recorded as a separate event on the AE eCRF.  
9.1.4 
Relatedness to Investigational Medicinal Product 
The relatedness of the event to enapotamab vedotin must be assessed by a physician. If relatedness 
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.  
9.1.5 
Start Date and Time 
Start date for (S)AEs is the date of occurrence of the first symptom of the disease, e.g., if chest 
pain occurs on 01 April 2016 and the patient is hospitalized with myocardial infarction on 04 April 
2016, the onset date of the SAE myocardial infarction is 01 April 2016. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 116 of 259 
For laboratory AE’s, the start date is the date the sample was taken.  
Time should be filled in if event starts on a dosing day or if the duration of the event is less than 
24 hours.  
9.1.6 
Outcome 
Outcome of the AE must be judged by investigator by the following terms:  
• 
Fatal 
• 
Not recovered/not resolved 
• 
Recovered/resolved 
• 
Recovered/resolved with sequelae 
• 
Recovering/resolving  
• 
Unknown 
9.1.7 
Action Taken with Investigational Medicinal Product 
Action taken with enapotamab vedotin should be measured as: 
• 
Dose increased 
• 
Dose not changed 
• 
Dose reduced 
• 
Dose interrupted 
• 
Drug withdrawn 
• 
Not applicable 
• 
Unknown 
Not applicable should only be used if the AE occurs before first treatment or in the follow-up 
period. 
9.1.8 
End Date and Time 
End date should be filled in if the outcome of an event is fatal, recovered/resolved, 
recovered/resolved with sequelae, recovering/resolving. 
For laboratory AE’s, the end date is the date a sample is taken, which shows a decrease in the NCI-
CTCAE grade and is no longer considered clinically significant. 
In case the local and central laboratory assessments of a sample taken on the same day differ with 
respect to AE resolution/grade change, the AE end date is determined by the central laboratory 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 117 of 259 
assessment. 
In case a sample is taken for local assessment, without a central assessment, and it shows that the 
laboratory AE has resolved, the end date will be the date the sample was taken. In case a central 
laboratory assessment taken after this date shows that the laboratory AE is not resolved, and it is 
considered clinical significant, then a new laboratory AE should be recorded, with start date 
entered as the date the sample for the central assessment was taken.  
Time should be filled in if event starts on a treatment/dosing day or if the duration of the event is 
less than 24 hours. 
9.1.9 
Adverse Events of Special Interest 
9.1.9.1 
Constipation 
Constipation (≤ Grade 3) has been the most frequently reported clinically significant adverse 
event. The event seems to be treatment-related and dose-dependent. 
Measures for handling AEs of constipation have been implemented in order to prevent severe 
toxicity of patients with constipation enrolled with mild gastrointestinal disorders and to minimize 
the risk of constipation evolving in patients enrolled without similar symptoms (please refer to 
Section 7.4.1 for prophylactic concomitant medications). 
9.1.9.2 
Neutropenia 
Neutropenia has been reported in > 20% of patients at any dose/cohort. The majority of events was 
treatment-related, was reported in patients receiving dose of 2.0 mg/kg or more, and was from the 
1Q3W arm, and recovered without dose change.  
Measures for handling AEs of neutropenia include dose delays and dose reductions, please refer 
to Section 7.3.2. 
9.1.9.3 
Peripheral Neuropathy 
Peripheral neuropathy has been reported in > 20% of patients at any dose/cohort. Although 
considered as treatment-related, onset latency and a deducible pattern based on dose-strength of 
enapotamab vedotin are unclear. The peripheral neuropathy will be assessed at the baseline and 
throughout the trial, when clinically indicated, to better understand its clinical course 
(Section 8.4.5). 
Measures for handling AEs of peripheral neuropathy include dose delays and dose reductions, 
please refer to Section 7.3.2. Specific safety reporting requirements are in place for peripheral 
neuropathy (see Section 9.3.2) 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 118 of 259 
9.1.9.4 
Immune-related Adverse Events 
Measures for handling immune-related AEs please refer to Section 7.3.3. 
9.1.10 
Information about Infusion Related Reactions 
Information on whether AEs are infusion related or not must be reported in the eCRF. 
9.1.11 
Serious Adverse Event 
Indicate whether or not the AE is determined to be “serious” based on what is defined in  
Section 9.2. 
9.2 
Definition of Serious Adverse Events 
The classification of the seriousness of the event determines the reporting procedures to be 
followed.  
 
An AE that meets one or more of the following criteria/outcomes is classified as serious:  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
Is a congenital anomaly/birth defect 
• 
Medically important 
• 
Results in death 
• 
Is life-threatening 
 
The term "life-threatening" in the definition of "serious" refers to an event in which the patient 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe.  
Elective surgery, overnight for convenience or other scheduled hospitalization periods that were 
planned before the patient was included in this trial 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. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 119 of 259 
9.3 
Events Requiring Immediate Reporting 
9.3.1 
Serious Adverse Events and Non-serious Grade 3 Adverse Events  
SAEs and non-serious Grade 3 AEs must be reported from the investigational site to the Safety 
CRO no later than 24 hours following a) the patient visit at which such AE was reported, noted or 
recognized; or b) the principal investigator’s or any investigator personnel’s receipt of the test 
results or other information at, or from which, such development was reported, noted or 
recognized. Grade 3 and 4 abnormal lab test results must be reported as AEs when these are 
assessed as clinically significant by the reporting investigator.  
9.3.2 
Peripheral Neuropathy Adverse Events ≥ Grade 2 or Leading to Permanent 
Discontinuation of Enapotamab Vedotin Treatment  
All events of peripheral neuropathy ≥ Grade 2 or leading to permanent discontinuation of 
enapotamab vedotin (regardless of grade) must be reported from the investigational site to the 
sponsor within 24 hours of knowledge of the event. 
9.3.3 
Overdose and Medication Errors 
An overdose is defined as a patient receiving a dose of enapotamab vedotin in excess 10% of that 
specified in this protocol. All cases of overdose of enapotamab vedotin whether it resulted in an 
AE or not must be reported to the sponsor as protocol deviations and Safety CRO within 24 hours 
of knowledge of the event. It should also be recorded on the eCRF AE page.  
Medication errors and uses outside what is foreseen in the protocol, including misuse and abuse 
of enapotamab vedotin must be reported to the sponsor as protocol deviations and Safety CRO 
within 24 hours of knowledge of the event. It should also be recorded on the eCRF AE page. 
Furthermore, AEs fulfilling the criteria in Section 9.2 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.  
9.3.4 
Pregnancy 
Any pregnancy that occurs during trial participation must be reported. Pregnant trial patients must 
be withdrawn from treatment immediately, whereas male patients may continue in the trial should 
pregnancy of female partners occur. In this case, a separate informed consent will be obtained from 
the female partner for collection of information regarding the pregnancy. 
Each pregnancy must be reported to the Safety CRO 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. The child must be followed at least to the age of one month.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 120 of 259 
Pregnancy complications and elective terminations for medical reasons must be reported as an AE 
or SAE. Spontaneous abortions must be reported as an SAE. Any SAE occurring in association 
with a pregnancy brought to the investigator’s attention after the patient has completed the trial 
and considered by the investigator as possibly related to the enapotamab vedotin, must be promptly 
reported to sponsor or designee. 
9.4 
Timelines for Reporting 
The required timeframes and reporting forms for reporting SAEs, non-serious Grade 3 AEs, 
neuropathy Grade 2 AEs, neuropathy AEs leading to discontinuation, overdose, medication errors, 
and pregnancies are presented in Table 24. 
All new information regarding SAEs (initial and follow-up) must be reported from sites to sponsor 
within 24 hours. The final SAE report must be signed by a physician. Sites must respond to follow-
up queries from sponsor within 3 days. 
Table 24. Timeframes for Reporting SAEs, Grade 3 AEs, Peripheral Neuropathy, Overdose and Medication 
Errors and Pregnancies 
  
Initial Reports  
Follow-up Information on a Previous 
Report  
Type of Event  
Time 
Frame  
Documents  
Time 
Frame  
Documents 
All SAEs, Grade 3 
AEs, neuropathy 
Grade 2 AEs, 
neuropathy AEs 
leading to 
discontinuation 
24 hours*  Safety Reporting 
Form  
3 days * 
24 hours*  
CDS SAE DCF  
Site SAE DCF  
Overdose and 
Medication Errors  
24 hours*  Safety Reporting 
Form  
3 days * 
24 hours*  
CDS SAE DCF  
Site SAE DCF  
Pregnancy  
24 hours*  Pregnancy Form  
3 days  
Updated Pregnancy Form  
AE=adverse event; DCF=Data Clarification Form; CDS=Corporate Drug Safety; SAE=serious adverse 
event  
*no later than 24 hours/3 days following a) the patient visit at which such AE was reported, noted or 
recognized; or b) the principal investigator’s or any investigator personnel’s receipt of the test results or 
other information at, or from which, such development was reported, noted or recognized. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 121 of 259 
Completed safety report forms or pregnancy forms must immediately be forwarded to Safety CRO: 
If you have access to a secured email you may forward completed forms to 
 
If you do not have access to a secured email, please forward completed forms to: 
Fax: 
 
Any suspected enapotamab vedotin related SAE, occurring at any time after the patient has 
terminated trial participation, should be faxed to 
 
9.5 
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 7 days) of first knowledge by the 
sponsor or designee, to the competent regulatory authorities and/or to the Ethics Committee 
according to the applicable local regulatory requirements. Relevant follow-up information of fatal 
or life-threatening SUSARs will be communicated subsequently within an additional eight days.   
The investigator should be aware of local reporting regulations to the IEC/IRB. The Clinical 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.  
9.6 
Follow-Up on Adverse Events 
All AEs should be followed until they are resolved or until the Safety Follow-Up visit, whichever 
comes first. Related non-serious ≥ Grade 3 AEs and AEs meeting one of the serious criteria, and 
still ongoing after ended trial participation should be followed on a regular basis, according to the 
investigator’s clinical judgment, until the event has been resolved or until the investigator assesses 
it as chronic and all queries have been resolved..  
9.7 
Safety Management Plan 
In order to secure full transparency regarding patient safety-related questions to sites participating 
in the trial, frequent communication of observations at the different sites will be required. The 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 122 of 259 
communication set-up will include the following components: 
• 
SAEs and non-serious Grade 3 AEs must be reported from the investigational site to the 
sponsor via the Safety CRO within 24 hours and medically evaluated following receipt. 
During the dose escalation part of the trial, at least biweekly safety/medical meetings to 
discuss AEs and laboratory data will be held with the participation of at least Drug Safety, 
sponsor medical officer and CRO Medical Monitor; and the safety data will be evaluated for 
individual treatment arms as well as across treatment arms. If safety signals warranting actions 
are identified in one treatment arm, actions will be implemented in the other treatment arm if 
deemed relevant for the specific signal in question.  
• 
Monthly telephone conferences between all participating Investigators, CRO Medical 
Monitor and sponsor 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 
 Medical Monitor.  
• 
Direct telephone link from investigator to sponsor medical officer.  
• 
DMC meetings following each cohort and ad hoc as needed. Ad-hoc DMC meetings may be 
called for by both the DMC and Sponsor any time during the escalation and expansion phases 
of the trial if new safety data warrants immediate action to the conduct of the trial. The 
outcome of the DMC meeting will be discussed and confirmed by the sponsor safety 
committee and ultimately communicated to the investigators following each meeting. 
• 
Investigators or their representative(s) may participate in the open part of the DMC meetings 
if deemed relevant.   
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 123 of 259 
10. 
STATISTICAL ANALYSIS 
All statistical analysis will be performed by a Contract Research Organization (CRO) 
 
under the direction of sponsor personnel. Any data analysis carried out independently by the 
investigator should be submitted to the sponsor prior to publication or presentation. 
All data will be listed. Also, data will be summarized using descriptive statistics (continuous 
data) and/or contingency tables (categorical data) for demographic and baseline characteristics, 
efficacy measurements, safety measurements, and all relevant pharmacokinetic measurements. 
The results will be presented by the 1Q3W, 3Q4W dose escalation and expansion parts separately. 
Also, the results will be presented by groups and total. In the dose-escalation 1Q3W and 3Q4W 
arms of the trial, groups are defined by dose-levels. In the expansion part, groups are defined by 
arm and dosing regimen. The results from the patients in the expansion part will be presented 2 
times: by cohort and in total. In addition, for NSCLC patients without EGFR/ALK mutations, data 
will be summarized based on different dosing regimens, e.g., 1.8 mg/kg 1Q3W, 2.2 mg/kg 1Q3W.  
For the sake of the statistical analyses and summaries, baseline is defined as the available data 
from the latest recorded measurement made before the first enapotamab vedotin administration. 
In general, in plots where patient data are grouped together (e.g., plots of means), the ticks on the 
time-axis will denote the nominal visit numbers (e.g., 0, C1V1, C1V2 , C1V3 etc.) separated with 
distances proportionate to the difference between the time points of the corresponding visits in the 
relevant dose schedule (cf. the Visit Number and Day/Week rows of the assessment tables in 
Section 8). In plots where individual patient data are plotted vs. time, the time on the horizontal 
axis will denote the actual time since C1V1.  
Details of statistical analysis and data reporting will be provided in a Statistical Analysis Plan 
(SAP) document finalized prior to database lock. Additional analyses may be added in the SAP 
and tables, listings and figures shells will also be provided. 
10.1 Analysis Sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) consists of all patients who have been exposed to enapotamab 
vedotin. Patients will be classified according to the assigned treatment/dose (dose- level and 
schedule planned). Patients who were screened but never started treatment will be listed. 
Screening failures will not be included in any of the analyses and summary tables. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 124 of 259 
10.1.2 
Safety Set 
The Safety Set consists of all patients who receive at least one dose of enapotamab vedotin and 
have at least one valid post-baseline safety assessment. Patients will be classified according to 
actual treatment received. 
10.1.3 
Per-Protocol Set 
Not applicable. 
10.1.4 
Dose-Determining Set 
The Dose-Determining Set (DDS) consists of all patients from the safety set who either meet the 
minimum exposure criterion and have completed the DLT observation period, or have 
experienced a DLT during cycle 1. This constitutes an evaluable patient for the determination of 
MTD. 
A patient is considered to have met the minimum exposure criterion at a dose level if enapotamab 
vedotin has been administered for at least 90% of the planned dose in each of the infusions. Patients 
who do not experience DLT during the first cycle are considered to have sufficient safety 
evaluations if they have been observed for a minimum length following the first dose defined in 
Table 25 below, and are considered by both the Sponsor and the DMC to have enough safety data 
to conclude that a DLT did not occur. 
Table 25. Minimum Exposure for Inclusion in DDS Set 
Trial part 
Number of 
infusions 
Number of 
observation days in 
Cycle 1 
Dose-escalation 
1Q3W 
1 
21 
Dose-escalation 
3Q4W 
3 
28 
 
10.2 Statistical Methodology for Primary Endpoint 
The primary objective of the escalation phase is to determine the MTD of enapotamab vedotin 
when administered as a single agent i.v. to adult patients with solid tumors. The MTD in the 
1Q3W-arm is defined as the dose that has an estimated DLT rate nearest to 22% and that is also 
considered safe. In the 3Q4W-arm, the MTD is defined as the highest dose-level where 
< 1/6 patients have DLT. Estimation of the MTD during the dose escalation phase of the trial will 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 125 of 259 
be based upon observed DLTs in Cycle 1 in patients in the DDS. 
After the expansion phase of the trial, the final recommended dose for future development will be 
based on considerations of the MTDs estimated in the two dose-escalation arms, and on an overall 
clinical assessment of all available safety, tolerability, anti-tumor activity, and PK data from all 
cycles at all different dose levels tested, in both the dose escalation and expansion parts of the 
trial. This final recommended dose will be referred to as the Recommended Dose for Further 
Development (RDFD). If it is determined that treatment at a dose of enapotamab vedotin lower 
than the MTDs established during the dose escalation parts of the trial is better tolerated, or has 
a better efficacy profile based on clinical considerations, then that dose may be the RDFD. 
The FAS will be used for the corresponding summaries and listings. The dose-escalation/de-
escalation decisions described below will be based on DDS. Patients excluded from the DDS and 
reasons therefore will be listed. 
10.2.1 
Dose Escalation, 1Q3W 
The primary analysis for the determination of the MTD is based on a modified Continuous 
Reassessment Method using BLRM guided by the EWOC principle. The MTD will be further 
evaluated for preliminary efficacy and overall tolerability during the expansion phase of the trial.  
An adaptive BLRM (with 2 parameters) guided by the EWOC principle will be used to make 
dose recommendations and estimate the MTD during the escalation phase of the trial. 
For each available dose level, including intermediate doses (d = 1….11), the DLT rate is modelled 
(πd) on the log odds scale: 
qd = log
p d
1-p d
æ 
è 
ç 
ö 
ø 
÷ . 
A two parameter model is used relating the log odds to standardized doses xd, 
d
d
x
1
0



+
=
, 
where the standardized dose is computed by subtracting the median dose strength from each dose. 
Prior distributions are placed on each of the  terms and after each cohort is treated and assessed 
for DLT, the distributions of these parameters are updated, resulting in a posterior distribution used 
to estimate the MTD and select the dose for the next cohort. 
For this trial a bivariate normal prior distribution is placed on (
0
,log(
1
)), with 
0
 marginally 
N(-1,1.5), log(
1
) marginally N(0,0.5), and a correlation of 0. The prior distribution is selected to 
achieve good operating characteristics while also maintaining a similar dose-toxicity relationship 
to that shown for a similar antibody-MMAE. Generally, the prior anticipates the lower doses have 
a good chance of being safe while the higher doses are a priori likely to be unsafe.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 126 of 259 
Each dosing frequency will be continuously monitored for safety. A dose level is considered to be 
safe to escalate to if there is at least a 40% probability that the DLT rate on the corresponding dose 
level during the first cycle is less than 22%. That is,  
Pr(πd < 22%) > 40%. 
As fairly common in Bayesian statistics, the above is a probability of a probability and should be 
interpreted with due caution. E.g. it does not mean that there is 60% probability of having a DLT 
rate of ≥22% on a dose level.  
The target toxicity level (here 22%) in the CRM-design has no corresponding equivalent measure 
in the 3+3 design. In a 3+3 design, the observable DLT-rates in a 3-patients cohort are 0%, 33%, 
67% and 100%. The “≥2/6 patients with DLT triggers a de-escalation”-rule implies that the target 
toxicity level is <33% in the 3+3 design. Hence, even if the 3+3 design targets a DLT-rate <33%, 
during the trial it is possible to observe higher DLT-rates on a dose-level.  
In the same way, in a CRM-design during the trial it is possible to observe higher DLT-rates on a 
dose-level than the target toxicity level (here 22%). 
For detailed illustrations of the effect of this and the other design features, cf. 
. These 
sample realizations demonstrate that the mCRM-model is expected to be well-behaved in terms of 
safe-guarding the patients’ safety by being sensitive to observed DLTs and recommend dose-levels 
accordingly.  
At any time during the trial, the method can recommend patient allocation to a dose that is not safe 
by this definition. If all dose levels are considered unsafe, the trial will stop early, with the MTD 
estimated to be below the experimental dose range. 
The MTD will be the dose that has an estimated DLT rate nearest to 22% and that is also 
considered safe by the above definition.   
The dose recommended by the adaptive Bayesian logistic model may be regarded as guidance 
and information to be integrated with a clinical assessment of the toxicity profiles observed at the 
time of the analysis in determining the next dose level to be investigated. 
Further details of the statistical methodology and operating characteristics of the mCRM are given 
in the report prepared by 
 in 
 
10.2.2 
Dose Escalation, 3Q4W 
In the dose escalation 3Q4W-arm, the trial design will follow a standard traditional 3+3 design. 
See Section 5.3 for more details.  
The results will be described using descriptive statistics. 
10.2.3 
Expansion Part 
The results from the expansion phase will be presented using summary statistics. For each cohort, 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 127 of 259 
the number of responders will be evaluated. Let 𝜋𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒,𝑖 denote the proportion of responders in 
cohort i, where i=1, 2, 3, 4, 5 or 6. The null hypothesis 𝐻0,𝑖: 𝜋𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒,𝑖≤0.10 will be tested 
against the one-sided alternative hypothesis 𝐻𝑎𝑙𝑡,𝑖: 𝜋𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒,𝑖> 0.10, for Cohorts 1-6 and Cohort 
8, using the exact binomial test on the 5% significance level, for both confirmed as well as 
unconfirmed response. The null hypothesis for the platinum-resistant ovarian cancer patients in 
Cohort 7 𝐻0,7: 𝜋𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒,7 ≤0.15 will be tested against the one-sided alternative hypothesis 
𝐻𝑎𝑙𝑡,7: 𝜋𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒,𝑖> 0.15. Patients receiving different dosing regimens will be analyzed separately 
from each other. 
With a minimum follow up of at least 7 months for all patients, the analysis per CSR cutoff is 
considered the full efficacy results. Any data collected after the CSR cutoff will be presented in 
data listings in the CSR addendum. 
10.3 Statistical Methodology for other Endpoints 
The FAS will be used for the corresponding summaries and listings, unless otherwise specified. 
10.3.1 
Patient Disposition 
Patient dispositions will be presented in flow diagrams in accordance with the current CONSORT 
statement22. 
10.3.2 
Demographics and Baseline Characteristics 
Age (including age<65 and age ≥65), race, ethnic origins, gender, weight, height, BMI, ECOG 
performance score, smoking and drinking history, stage, primary site of cancer, details of tumor 
histology histological grade, disease stage (TNM) at initial diagnosis and at screening, NSCLC 
and melanoma patients’ mutational tumor status, time (in months) from initial diagnosis of 
primary site to start date of enapotamab vedotin, time (in months) since most recent 
recurrence/relapse or progression to start date of enapotamab vedotin, current stage of cancer 
and types of lesions (target and non-target lesions) at baseline will be summarized using 
appropriate descriptive statistics. 
10.3.3 
Medical History 
Medical history will be listed and summarized using descriptive statistics.  
10.3.4 
Prior Cancer Therapies 
All prior cancer therapies, except for surgeries, will be listed and tabulated by anatomical 
therapeutic chemical (ATC) code and preferred term. Surgeries will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and presented accordingly. The response to the 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 128 of 259 
latest prior cancer therapies will be tabulated. The number and percentage of patients will be 
summarized in the tabulations.  
10.3.5 
Treatments (Enapotamab Vedotin, Concomitant Therapies, Compliance) 
The actual dose and duration in days of enapotamab vedotin will be listed and summarized by 
means of descriptive statistics.  
Concomitant medications and significant non-drug therapies prior to and after the start of the 
enapotamab vedotin will be, respectively, listed by patient and summarized by ATC term by 
means of contingency tables.  
The number of patients who received and completed trial treatment will be presented by cycle, 
summarized in a table and presented in bar charts. Also, the number of patients who, per treatment cycle 
completed, withdrew due to AE, withdrew due to PD, and withdrew due to other reason will be presented 
in bar charts. Also, the number of patient days (total number of days in trial) will be presented for 
each dose group. 
10.3.6 
Clinical Safety Data 
These data will be presented for the safety set. 
10.3.6.1 Adverse Events 
AEs will be coded using the latest version of MedDRA available prior to clinical database 
lock and will be graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03. All AE summaries will be summarized (frequency counts and percentages) by system 
organ class and/or preferred term, and maximum severity grades, except where otherwise noted. 
Additional summaries of AEs will be specified in the SAP. A patient with multiple Common 
Terminology Criteria (CTC) grades for an AE will be summarized under the maximum CTC grade 
recorded for the event. 
All AEs will be listed, and any other information collected (e.g., start/end dates and duration of 
AE, severity or relatedness to trial medication) will be listed as appropriate.  
A safety overview table will be provided for all AEs collected during the entire trial. 
10.3.6.2 Patient diary 
The information from the patient diaries recorded in the eCRFs (cf. Section 8.4.13) will be listed 
and summarized addressing the following questions: is the diary used as planned and do the 
constipation measures work? 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 129 of 259 
10.3.6.3 Other Clinical Safety Data 
Abnormal findings in physical examination, visual acuity, ECG measurements and body weight 
will be summarized and listed. Vital signs will be listed. 
10.3.7 
Safety Laboratory Parameters 
Safety laboratory assessments (biochemistry, hematology and urinalysis) will be graded using NCI 
CTCAE. All laboratory assessments will be converted to the corresponding international system 
of unit and plotted and/or listed. The following summaries will be produced for laboratory data 
(by laboratory parameter): 
Shift tables using CTC grades to compare baseline to the worst post-baseline value for laboratory 
parameters with CTC grades. 
The following patient data listings will be produced for all laboratory parameters where CTCAE 
grades are defined: 
Listing of patients with laboratory abnormalities of CTC Grade 3 or 4. 
Listing of all laboratory data including CTC grades and values that are below or above the 
corresponding laboratory reference range. 
All other laboratory parameters will be listed by laboratory parameter and patient. Laboratory 
values outside normal range will be listed. Percentage change in laboratory safety parameters from 
baseline to subsequent visits (scheduled or unscheduled) will be derived and presented in listings. 
These data will be presented for the safety set. 
10.3.8 
Hepatitis B, C and Cytomegalovirus Serology 
All hepatitis B, C, and CMV serology data will be summarized and listed.   
10.3.9 
Pregnancy Test 
All pregnancy data will be summarized and listed. 
10.3.10 
Immunogenicity of Enapotamab Vedotin 
Titers of enapotamab vedotin will be listed and positive/negative host immune response to 
enapotamab vedotin and presence of neutralizing antibodies will be summarized 
(positive/negative). Presence of PK-concentrations above a certain threshold, that depends on the 
drug tolerance of the ADA assay, at the same time as the ADA sample may make the ADA 
undetectable and hence render non-conclusive. The association between positive/non-positive 
ADA and PK (pre-dose, AUC, Cmax), major safety signals (CTCAE ≥ Grade 3) and efficacy 
information (change in tumor size by CT scan) will be explored.    

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 130 of 259 
10.3.11 
Axl Expression 
Axl expression measurements will be listed and summarized. Furthermore, association between 
degree and intensity of Axl expression and biologic activity as measured by tumor burden, CA 125 
and response will be investigated using correlation and logistic regression analysis 
correspondingly.  
10.3.12 
Exploratory Analyses 
Results of biomarker and pharmacodynamic analyses will be presented in a separate report. 
Planned analyses are based on the availability of qualified assays and may be deferred if emerging 
trial data show no likelihood of providing useful scientific information. 
10.3.13 
Anti-tumor Activity 
Anti-tumor activity measured by tumor shrinkage including change in CA 125 for patients with 
ovarian cancer and PSA for patients with CRPC will be described by descriptive statistics, 
graphical plots (including waterfall plots) and patient data listings. 
10.4 Response 
Response in solid tumor cancers will be assessed in accordance with the RECIST criteria version 
1.123 and for patients with ovarian cancer according to RECIST 1.1 in combination with CA 125 
as defined by the Gynecological Cancer Intergroup2.    
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 131 of 259 
Table 26. Definition of Response (RECIST Criteria v1.1) 
 
Category 
Criteria 
Based on target 
lesions 
Complete 
Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes must have reduction in short axis to < 10 mm. 
Partial 
Response 
(PR) 
≥ 30% decrease in the sum of the LD of target lesions, 
taking as reference the baseline sum LD. 
Stable Disease  
(SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum of LDs since the treatment started. 
Progressive 
Disease (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. 
 
 
Evaluation of best overall response (RECIST Criteria v1.1) 
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. 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 132 of 259 
Confirmation 
PR and CR: changes in tumor measurements that are confirmed by repeat assessments performed 
no less than 4 weeks after the criteria for response are first met are called confirmed responses. 
Onset of PR or CR without such confirmation is called unconfirmed.   
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. 
Patients with ovarian cancer will also be evaluated according to CA 125. 
A CA 125 response is defined as 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 
upper limit of the reference range and within 2 weeks before starting the treatment. 
To calculate CA 125 responses accurately, the following rules apply: 
Intervening samples and the 28-day confirmatory sample must be less than or equal to (within an 
assay variability of 10%) the previous sample. 
Variations within the reference range of CA 125 levels will not interfere with the response 
definition. 
For each patient, the same assay method must be used, and the assay must be tested in a quality 
control scheme. 
Patients are not evaluable by CA 125 if they have received mouse antibodies or if there has been 
medical and/or surgical interference with their peritoneum or pleura during the previous 28 days 
(e.g., paracentesis).  
The date when the CA 125 level is first reduced by 50% is the date of the CA 125 response. To 
calculate response, an analysis should be used that includes all patients with an initial CA 125 level 
of at least twice the upper limit of the reference range as eligible and evaluable. In addition, as a 
separate analysis, those patients who have a CA 125 response and whose CA 125 level falls to 
within the reference range can be classified as CA 125 complete responders. Patients who have a 
fall of CA 125 to within the reference range but whose initial CA 125 was less than twice the upper 
limit of the reference range have not had a CA 125 response and cannot therefore be classified as 
a CA 125 complete responder. 
CA 125 will be presented graphically in plots. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 133 of 259 
10.4.1 
Response Evaluation and Reporting of Results 
In the dose escalation, response evaluation will be performed by the investigator and sponsor. 
In the expansion, response evaluation will be performed by the investigator and sponsor as well as 
a group of external medical experts. 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. 
Individual patient data listings and summaries of objective response, best overall tumor response 
(based primarily on confirmed but also on unconfirmed response) and disease control will be 
presented.  
For patients with ovarian cancer, responses will be evaluated and reported as per RECIST 1.123, 
CA 125 and the combination of the two sets of response criteria in accordance with the 
Gynecological Cancer Intergroup definitions2. 
For patients with prostate cancer, responses will be evaluated and reported as per RECIST 1.123 
and PSA according to the Updated Recommendations from the Prostate Cancer Clinical Trials 
Working Group 3.24  
10.4.2 
Progression-Free Survival 
PFS is defined as the number of days from Visit 1 in Cycle 1 to first PD or death. If no death is 
observed within this period, PFS will be censored at the last progression assessment. PFS will be 
derived for all patients and presented graphically as well as summarized using survival analysis 
methods: distribution functions will be estimated using Kaplan-Meier technique and times will be 
censored in accordance with Table A in Appendix 3 in the FDA Guidance for Industry: Clinical 
Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007).   
10.4.3 
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. DoR will be analyzed using the same statistical 
methodology as PFS. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 134 of 259 
10.4.4 
Overall Survival 
Overall survival (OS) is defined as the number of days from Visit 1 in Cycle 1 to death. OS will 
be analyzed using the same statistical methodology as PFS and DoR except that censoring will not 
be applied neither when visits are skipped nor when new anti-cancer therapies are given. 
10.4.5 
Tumor Shrinkage 
Tumor shrinkage (based on CT-scan evaluations) will be listed and summarized, per source 
(radiologist, central read). 
10.4.6 
Statistical Methodology for Pharmacokinetics Data 
Individual curves of plasma/serum concentration of enapotamab vedotin, HuMax-AXL 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 values, and half-
life. The PK parameters will be calculated separately per treatment cycle.  
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 modelling approaches to parameter estimation will be 
applied.  
Furthermore, a population PK model will be developed before starting the 3Q4W-arm. The model 
will be updated during the trial. Details of these analyses are provided in a separate population PK 
analysis plan (
). 
Further exploratory analyses of PK data may be performed. 
10.5 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. 
10.6 Subgroups and Site Effects 
Subgroup analyses for the following factors are planned: 
• Cancer type 
• ADA-positivity (only for ≥ Grade 3 AEs and tumor shrinkage endpoints) 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 135 of 259 
Other sub-group analyses may be performed post hoc. Due to the low expected number of patients 
per site no investigation of side effects are planned. 
10.7 Interim Analyses 
Protocol Amendment 9 (v 10.0) allowed for exploratory analysis of subsets of data.  
In November 2020, Genmab decided to discontinue development of enapotamab vedotin but 
continue to offer treatment to patients who are deriving clinical benefit in the present trial. At the 
time of this amendment (Amendment 10), the dose escalation part and the enrollment of the dose 
expansion part of the trial have been completed with only 3 patients active on trial treatment. The 
3 patients have been on treatment for at least 7 months, which is considered sufficient time to 
evaluate efficacy and safety. An analysis is therefore planned, i.e. data collected up to and 
including the data cutoff date will be included in the CSR. Furthermore, limited AE and SAE data 
from data cutoff to the time of database lock for the three active patients will be included. Data 
collected after the data cutoff date until the end of trial will be reported in an addendum to the 
CSR, once the trial is completed.  
From time of approval of this protocol amendment to end of trial no further information is being 
collected for patients in patient follow-up.  
The reporting of the trial will be based on a locked database with clean data up to the cutoff point.  
Final lock will be done at end of trial.  
10.8 Clinical Trial Reporting 
Data collected up to and including the data cutoff date will be included in the CSR. Data collected 
after the data cutoff date until the end of trial will be reported in an addendum to the CSR, once 
the trial is completed. 
10.9 Sample Size Estimation 
The estimates and calculations in this section are all performed in SAS V9.4. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 136 of 259 
10.9.1 
Dose Escalation 
In the dose-escalation 1Q3W-arm, 28 patients are expected and the maximum number of patients 
is set to 41. The dose-escalation 3Q4W–arm will be including 15-36 patients. The expansion 
cohorts will include up to 349 patients. The information obtained from the above patients is 
considered adequate to provide sufficient basis for the planning and design of further trials.  
For the dose escalation part, no formal sample size calculation has been performed. For the 1Q3W-
arm, the operating characteristics of the mCRM-design are described in details in 
 
and 
. For the 3Q4W-arm, effect of the 3+3 design on estimates-precision is presented 
below: 
The probability of making at least 1 observation of an event with rare incidence. 
The widths of two-sided 95% confidence intervals for incidences of AEs, based on an exact 
binomial distribution. 
Table 27. Impact of Sample Size on Descriptive and Inferential Statistics for Dose-Escalation 3Q4W 
Probability of at least one 
observation of a rare event 
Width of two-sided 95% exact confidence interval  
for estimate of proportions 
 
 
 
 
Probability 
of rare 
event 
Probability of ≥ 1 observation 
of the rare event 
 
N=3 
 
N=6 
 
N=12 
 
N=18 
10% 
27% 
47% 
72% 
85% 
5% 
14% 
26% 
46% 
60% 
2% 
6% 
11% 
22% 
30% 
1% 
3% 
6% 
11% 
17% 
0.1% 
0% 
1% 
1% 
2% 
-75
-70
-65
-60
-55
-50
-45
-40
-35
-30
-25
-20
-15
-10
-505
10
15
20
25
30
35
40
45
50
55
60
65
70
75
Proportion of patients with event (%)
0
10
20
30
40
50
60
70
80
90
100
Probability of observing a rare event at least once
upper limits 
lower limits 
(N=3)
(N=6)
(N=12)
(N=18)

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 137 of 259 
10.9.2 
Expansion 
Table 28. Impact of Sample Size on Descriptive and Inferential Statistics for Endpoints in the Expansion Part 
Probability of at least one 
observation of a rare event 
Width of two-sided 95% exact confidence interval  
for estimate of proportions 
 
 
 
 
 
 
 
 
  
 
 
 
The widths of the confidence intervals apply to binary endpoints of both safety (e.g., AE) and 
efficacy (e.g., response) nature. 
 
For the test of the null hypotheses (cf. Section 10.2.3): e.g., assuming 𝜋𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒=30%, the 
probability of rejecting the null hypothesis 𝐻0: 𝜋𝑟𝑒𝑠𝑝𝑜𝑛𝑠𝑒≤0.10 is 69% when N=22.  
 
The sample size in this exploratory trial has not been determined based on a formal power analysis. 
A power analysis of various assumptions of 𝐻0,𝑖 and 𝐻𝑎𝑙𝑡 is presented in Table 29. 
 
Probability 
of rare  
event 
Probability of ≥ 1 observation           
of the rare event 
 
N=22 
 
N=37 
 
N=82 
 
N=202 
 
N=297 
10% 
90% 
98% 
100% 
100% 
100% 
5% 
68% 
85% 
99% 
100% 
100% 
2% 
36% 
53% 
81% 
98% 
100% 
1% 
20% 
31% 
56% 
87% 
95% 
0.1% 
2% 
4% 
8% 
18% 
26% 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 138 of 259 
Table 29. Power Analysis of the Expansion Part 
 
𝑯𝟎 
 
𝑯𝒂𝒍𝒕 
Power 
N=22 
Power 
N=30 
Power 
N=37 
Power 
N=45 
Power 
N=82 
Power 
N=202 
Power 
N=349 
0.10 
0.25 
48% 
65% 
74% 
83% 
97% 
100% 
100% 
0.30 
69% 
84% 
91% 
95% 
100% 
 
0.35 
84% 
94% 
97% 
99% 
100% 
 
0.40 
93% 
98% 
99% 
100% 
100% 
 
0.15 
0.25 
30% 
33% 
45% 
45% 
69% 
97% 
0.30 
51% 
57% 
71% 
74% 
93% 
100% 
0.35 
70% 
78% 
88% 
91% 
99% 
 
0.40 
84% 
91% 
97% 
98% 
100% 
 
Power= P(reject 𝑯𝟎|𝑯𝒂𝒍𝒕), no stopping in interim analysis, calculated using PROC POWER. 
 
 
Table 30. Operating characteristics in the futility analyses (stop recruiting if ≤ 2/22 or ≤ 3/22 responders) 
 
ORR to 
beat 
(𝐻0) 
 
 
𝑯𝒂𝒍𝒕 
P[Stop 
early | 𝐻0] 
(N=22) 
P[Stop 
early | 𝐻𝑎𝑙𝑡] 
(N=22) 
Statistical 
Power 
(N=22+8) 
Statistical 
Power 
(N=22+15) 
Statistical 
Power 
(N=22+60) 
 
Stop if ≤ 2/22 responders 
0.10 
0.25 
0.62 
0.06 
65% 
73% 
92% 
0.10 
0.35 
0.62 
0.006 
94% 
97% 
99% 
0.15 
0.25 
0.34 
0.06 
33% 
45% 
67% 
0.15 
0.35 
0.34 
0.006 
77% 
88% 
99% 
0.20 
0.25 
0.15 
0.06 
11% 
11% 
22% 
0.20 
0.35 
0.15 
0.006 
49% 
55% 
88% 
 
Stop if ≤ 3/22 responders 
0.15 
0.25 
0.57 
0.16 
33% 
44% 
63% 
0.15 
0.35 
0.57 
0.025 
77% 
88% 
97% 
0.20 
0.25 
0.33 
0.16 
11% 
11% 
21% 
0.20 
0.35 
0.33 
0.025 
49% 
56% 
87% 
 
The estimates in Table 30 are based on 120000 simulations of clinical trials with the corresponding 
stopping rule for futility incorporated in the interim analysis. The one-sided test in the final analysis 
is performed on the 5% significance level. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 139 of 259 
10.9.3 
Statistical Power in Exploratory Analyses in the Expansion 
The power estimates (Figure 5) are based on 4000 simulations of exploratory analyses, with e.g., 
the ones in Section 10.3.11 in mind. The simulations estimate the power in detecting a relation 
between two uniformly distributed variables (%response and biomarker expression both ranging 
from 0% to 100% to in general represent any kind of response and expression) with correlation 
ρPearson between them, either by correlation analysis or logistic regression. The analyses are 
performed on the 5% significance level. For the logistic regression, the responder-variable is 
based on a dichotomization of the %response-variable: responder = yes if the %response > 30% 
and responder = no if the %response < 30%.  
 
Power in correlation analysis 
Power in logistic regression, response 
rate=30% 
 
 
Figure 5. Statistical power in exploratory analyses 
 
E.g., if data from 202 patients are available, the power in detecting a correlation between % tumor 
reduction and Axl-expression would be ≈79% if the correlation between them is = 0.20. And when 
the correlation = 0.30 and the (objective) response rate is 30%, the power in finding a relationship 
between (objective) response and Axl-expression by means of logistic regression is approximately 
88%. 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 140 of 259 
11. 
TRIAL OPERATIONS 
11.1 Countries 
The trial is expected to be conducted in Denmark, Belgium, UK, US, the Netherlands and Spain. 
More countries may be added. 
11.2 Number of Sites 
In the dose escalation part 3-6 sites will participate and the number of sites will be increased up to 
60 sites for the expansion part. Please refer to Section 3.4. 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
12.1 Monitoring of the Trial and Regulatory Compliance 
The CRO project manager, or designee, will make a site initiation visit at each site to review the 
protocol and its requirements with the Investigator(s), inspect the enapotamab vedotin storage area, 
and fully inform the Principal Investigator of his/her responsibilities and the procedures for 
assuring adequate and correct documentation. During the site initiation visit the eCRFs will be 
reviewed. Other pertinent trial materials will also be reviewed with the Investigator’s research 
staff.   
During the course of the trial, the monitor will make regular site visits in order to review protocol 
compliance, examine eCRFs, and individual patient’s medical records and assure that the trial is 
being conducted according to pertinent regulatory requirements as well as GCP. All eCRF entries 
will be verified with source documentation. The review of medical records will be done in a 
manner to assure that patient confidentiality is maintained. In accordance with applicable national 
and local regulations, monitors, investigators and the sponsor’s (or their designee’s) will only have 
access to information relevant to the trial. 
Representatives of the sponsor's clinical quality assurance department may visit the trial site at any 
time during or after completion of the trial to conduct an audit of the trial in compliance with 
regulatory guidelines and company policy. These audits will require access to all trial records, 
including source documents, for inspection and comparison with the eCRFs. Patient privacy must, 
however, be respected. The investigator and trial-site personnel are responsible for being present 
and available for consultation during routinely scheduled trial-site audit visits conducted by the 
sponsor or its designees.  
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 141 of 259 
of a national GCP compliance program or to review the results of this trial in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection. 
12.2 Curricula Vitae of Investigators 
All Principal Investigators and Sub-investigators will be required to provide a current signed and 
dated curriculum vitae and evidence of GCP training to sponsor and 
  
12.3 Protocol Modification 
No modification of the protocol should be implemented without the prior written approval of the 
sponsor or the sponsor’s representative 
. Any such changes which may affect a 
patient’s treatment or informed consent, especially those increasing potential risks, must receive 
prior approval by the IRB/IEC and regulatory authorities. The exception to this is where 
modifications are necessary to eliminate an immediate hazard to trial patients, or when the change 
involves only logistical or administrative aspects of the trial (e.g., change in monitor, change in 
telephone number). Other administrative revisions which may impact the clinical portion of a trial 
will be duly reported to the IRB/IEC by the Principal Investigator. 
12.4 Publication Policy 
The sponsor acknowledges the investigator’s right to publish the entire results of the trial, 
regardless of the outcome, in accordance with the Uniform Requirements for Manuscripts 
Submitted to Biomedical Journals of the International Committee of Medical Journal Editors 
(http://www.icmje.org/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 trial or the writing and presentation of 
results. The sponsor will have representation in the list of authors.  
Publications are subject to the following conditions: 
 
• No publication before the completion of the trial at all participating sites without written 
agreement with the sponsor. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 142 of 259 
• All proposed publications and presentations, including any modifications or 
amendments, shall be submitted to the sponsor for its review at least 30 days before such 
presentation or publication is submitted to any third party. 
• Publications shall not disclose any sponsor confidential information and property (not 
including the trial results, which can be published as described elsewhere in this section). 
 
Results of exploratory biomarker analyses performed after the Clinical Trial Report has been 
issued will be reported in a separate report and will not require a revision of the Clinical Trial 
Report. Patient identifiers will not be used in publication of results. Any work created in 
connection with performance of the trial and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for above) shall be the property 
of the Sponsor as author and owner of copyright in such work. 
13. 
ETHICAL CONSIDERATIONS 
13.1 Informed Consent  
The Investigator will obtain written informed consent from each patient participating in the trial. 
The form must be signed, witnessed and dated prior to any trial-specific procedures, including any 
screening procedures, being performed. It is the personal responsibility of the investigator to obtain 
written informed consent from the patient. Part of the informed consent process may be delegated 
to other trial team members by the investigator. If this is done the requirements for the delegates 
must be documented prior to start of the trial. National laws must always be adhered to when 
allowing potential delegation. Any delegation must be documented in the site delegation log.  
Prior to obtaining written informed consent the investigator or a designee must explain to the 
potential patient the aims, the methods and the potential hazards of the trial and any discomfort it 
may entail. Patients must be informed that their participation in the trial is voluntary and that they 
are free to withdraw from the trial at any time without justifying their decision. Patients must be 
informed of the possibility of withdrawing consent. Patients must be given ample time and 
opportunity to inquire about details of the trial prior to deciding whether to participate in the trial.  
It is the responsibility of the investigator to ensure that all questions about the trial are answered 
to the satisfaction of the patients.  
The ICF will contain all the essential elements of Informed Consent set forth in 21 CFR, Part 50, 
the European Union Directive 2001/20/EC and its associated Detailed Guidances, European Union 
GCP Directive 2005/28/EC, the ICH Guideline for GCP, Section 4.8, and the terms of the 
Declaration of Helsinki (2013). Copies of the signed informed consent form will be given to the 
patient and filed in the Investigator’s site file, as well as the patient’s medical record if in 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 143 of 259 
conformance with the institution’s Standard Operating Procedures.  
13.2 Institutional Review Board/Independent Ethics Committee/Regulatory 
The trial will not be initiated without approval of the appropriate IRB/IEC and compliance with 
all administrative requirements of the governing body of the institution as well as the national 
Competent Authority (CA) in each country.  
This protocol, consent procedures, and any amendments must be approved by the IRB/IEC/CA in 
compliance with current regulations of the FDA and the European Union as applicable and in 
accordance with ICH/GCPs. A letter of approval will be sent to the Sponsor prior to initiation of 
the trial and when any subsequent modifications are made. The IRB/IEC/CA will be kept informed 
by the Investigator, 
 or the sponsor, as required by national regulations, as to the 
progress of the trial as well as to any serious and unexpected AEs.  
13.3 Patient Privacy/Data Protection 
The collection and processing of personal data from patients enrolled in this trial will be limited 
to those data that are necessary to fulfill the objectives and purposes of the trial and as specifically 
defined in the protocol. 
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place, 
see Section 14.4. Sponsor personnel whose responsibilities require access to personal data agree 
to keep the identity of patients confidential. 
The informed consent obtained from the patient (or his or her legally acceptable representative) 
includes explicit consent for the processing of personal data for the purpose of the trial and for the 
investigator/institution to allow direct access to his or her original medical records (source 
data/documents) for trial-related monitoring, audit, IEC/IRB review, and regulatory inspection. 
This consent also addresses the transfer of the data to other entities and to other countries, as 
specified in the ICF. 
The patient has the right to request access to his or her personal data and the right to request 
rectification of any data that are not correct or complete by contacting the investigator. Reasonable 
steps will be taken by the investigator to respond to such a request, taking into consideration the 
nature of the request, the conditions of the trial, the clinical trial agreement including the data 
processor agreement and applicable laws and regulations. The investigator will inform and work 
together with the sponsor when handling such requests. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 144 of 259 
Exploratory research is not conducted under standards appropriate for the return of data to patients. 
In addition, the sponsor cannot make decisions as to the significance of any findings resulting from 
exploratory research. Therefore, exploratory research data will not be returned to patients or 
investigators, unless required by law or local regulations. Privacy and confidentiality of data 
generated in the future on stored samples will be protected by the same standards applicable to all 
other clinical data. 
13.4 Finance and Insurance 
This trial is initiated and funded by sponsor, who will cover all costs for the procedures in the trial 
not part of standard care.  
A Clinical Trial Agreement (CTA) outlining overall sponsor and investigator responsibilities as 
well as all financial aspects of the work conducted by the investigators will be completed and 
signed between sponsor and the investigators and/or the institution involved as required. The 
remuneration of the Investigator shall be exclusively a matter between Investigator and his/her 
institution. The Investigator and other personnel receive no other payment than outlined in the 
CTA from sponsor for conducting this trial. The investigators are obliged to disclose their financial 
ties to sponsor by signing a financial disclosure form when working on the trial.  
The trial is covered under the sponsor’s liability insurance policy. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 145 of 259 
14. 
DATA HANDLING AND RECORD KEEPING 
14.1 Data Flow 
Figure 6 illustrates the flow of data collected for this trial. 
electronic
CRF
Investigators
External
Database(1)
External
Database(2)
Clinical study Database
Coding
Sponsor
Queries
Generation
Edit checks
Queries
       Data
reconciliation
Database
    lock
Listings
Progress
reports
 
Figure 6. Outline of data flow 
External databases are laboratory data, ECG data and CT-scan data 
14.2 Data to be Recorded Directly in the Case Report Form 
Not applicable. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 146 of 259 
14.3 Recording of Data 
Data collected during the trial will be recorded in the patient’s eCRF by the investigational site 
staff. The staff will keep records of the patient’s visit in the files considered as source documents 
for the site, e.g., hospital chart, research chart. The Investigator will be responsible for the 
recording of all data on the eCRF in a timely manner.  
The Investigator will provide access to his/her original records to permit a representative from the 
sponsor to verify the proper transcription of data.   
14.4 Data Security 
In relation to the collection and handling of data, including any personal data, potential risks to the 
patients have been assessed and adequate technical and organizational measures have been 
implemented to ensure a level of security appropriate to the risk. The security measures 
implemented entail among other things that: 
• Access to data has been restricted so that access is only granted to authorized individuals. 
• Data is only stored on IT systems and networks that are protected against virus, malware 
and unauthorized access. 
• Data is backed-up at regular intervals. In case of a data breach, a clear allocation of roles 
and responsibilities for managing the data breach, including notifying affected patients and 
authorities, has been established in order to mitigate any adverse impact on the patients. 
Additional technical security measures implemented include that: 
• All data is encrypted when at rest. 
• Data has been pseudonymized to the effect that only authorized individuals can link data 
to identified individuals. 
• A data breach response plan has been established. 
14.5 Trial Records 
The investigator must maintain all trial records (excluding the patient’s medical files) for at least 
25 years after the end of the clinical trial. 
Patient’s medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 147 of 259 
15. 
REFERENCES 
1. 
Rustin GJ, Bast RC, Jr., Kelloff GJ, et al. Use of CA-125 in clinical trial evaluation of new 
therapeutic drugs for ovarian cancer. Clinical cancer research : an official journal of the 
American Association for Cancer Research. 2004;10(11):3919-3926. 
2. 
Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in 
ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the 
Gynecological Cancer Intergroup (GCIG). International journal of gynecological cancer : 
official journal of the International Gynecological Cancer Society. 2011;21(2):419-423. 
3. 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Annals of internal medicine. 
1999;130(6):461-470. 
4. 
Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine 
sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014;14(12):769-
785. 
5. 
Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody 
auristatin conjugates for cancer therapy. Nat Biotechnol. 2003;21(7):778-784. 
6. 
Hamblett KJ, Senter PD, Chace DF, et al. Effects of drug loading on the antitumor activity 
of a monoclonal antibody drug conjugate. Clin Cancer Res. 2004;10(20):7063-7070. 
7. 
Sun MM, Beam KS, Cerveny CG, et al. Reduction-alkylation strategies for the 
modification 
of 
specific 
monoclonal 
antibody 
disulfides. 
Bioconjug 
Chem. 
2005;16(5):1282-1290. 
8. 
Esther CW Breij SV, Andreas Lingnau, Edward N van den Brink, Maarten, Janmaat MH, 
Wim Bleeker, David Satijn, Paul Parren. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 2015;33((suppl; abstr 3066)). 
9. 
Hugo W, Zaretsky JM, Sun L, et al. Genomic and Transcriptomic Features of Response to 
Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 2016;165(1):35-44. 
10. 
Aguilera TA, Rafat M, Castellini L, et al. Reprogramming the immunological 
microenvironment through radiation and targeting Axl. Nat Commun. 2016;7:13898. 
11. 
Deslandes A. Comparative clinical pharmacokinetics of antibody-drug conjugates in first-
in-human Phase 1 studies. MAbs. 2014;6(4):859-870. 
12. 
Iasonos A, Wilton AS, Riedel ER, Seshan VE, Spriggs DR. A comprehensive comparison 
of the continual reassessment method to the standard 3 + 3 dose escalation scheme in Phase 
I dose-finding studies. Clinical trials (London, England). 2008;5(5):465-477. 
13. 
Coveler AL, Ko AH, Catenacci DV, et al. A phase 1 clinical trial of ASG-5ME, a novel 
drug-antibody conjugate targeting SLC44A4, in patients with advanced pancreatic and 
gastric cancers. Invest New Drugs. 2016;34(3):319-328. 
14. 
Fanale MA, Forero-Torres A, Rosenblatt JD, et al. A phase I weekly dosing study of 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 148 of 259 
brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic 
malignancies. Clin Cancer Res. 2012;18(1):248-255. 
15. 
Kagedal M, Samineni D, Gillespie WR, et al. Time-to-Event Modeling of Peripheral 
Neuropathy: Platform Analysis of Eight Valine-Citrulline-Monomethylauristatin E 
Antibody-Drug Conjugates. CPT Pharmacometrics Syst Pharmacol. 2019;8(8):606-615. 
16. 
Nejadmoghaddam MR, Minai-Tehrani A, Ghahremanzadeh R, Mahmoudi M, Dinarvand 
R, Zarnani AH. Antibody-Drug Conjugates: Possibilities and Challenges. Avicenna J Med 
Biotechnol. 2019;11(1):3-23. 
17. 
Rosenberg JE, O'Donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin in 
Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death 
Ligand 1 Therapy. J Clin Oncol. 2019;37(29):2592-2600. 
18. 
Ott PA, Hamid O, Pavlick AC, et al. Phase I/II study of the antibody-drug conjugate 
glembatumumab vedotin in patients with advanced melanoma. J Clin Oncol. 
2014;32(32):3659-3666. 
19. 
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse 
Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society 
of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768. 
20. 
Postow MA. Managing immune checkpoint-blocking antibody side effects. Am Soc Clin 
Oncol Educ Book. 2015:76-83. 
21. 
AJCC. AJCC cancer staging manual. 7th ed. Chicago, IL: Springer; 2010. 
22. 
Hong J, Belkhiri A. AXL mediates TRAIL resistance in esophageal adenocarcinoma. 
Neoplasia. 2013;15(3):296-304. 
23. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
24. 
Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-
Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical 
Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-1418. 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 149 of 259 
Appendix I: Scientific Background About Patient Population 
 
Disease and Treatments 
Lung Cancer 
Lung cancer is the most frequently diagnosed cancer and also the most common cause of cancer 
mortality. Lung cancer is classified according to the World Health Organization depending on its 
origin. The majority of lung cancers arise from the bronchial epithelium and include Non-small 
cell lung cancer (NSCLC) and Small-cell lung cancer and account for approximately 90% of all 
lung cancers, whereas the remaining are of different origin, e.g., mesotheliomas, lymphomas and 
stromal tumors1. 
NSCLC 
NSCLC represents approximately 80% of lung cancer and includes adenocarcinomas which 
account for approximately 50% of lung cancers, squamous cell carcinomas (SCC) which account 
for approximately 20% and large cell carcinomas which account for approximately 10% of lung 
cancers1.   
In the US, 133,703 new cases of NSCLC were diagnosed in 20142 and 211,401 patients were 
diagnosed in the EU in 20123. Sixty-six percent of the patients had advanced or metastatic disease 
(stage IIIA, IIIB or IV) at the time of diagnosis and the 5-years overall survival was 17% in 20142. 
Several drugs are approved for treatment of NSCLC including alkylators, antimetabolites, tubulin 
inhibitors and monoclonal antibodies. Bevacizumab (anti-Vascular Endothelial Growth Factor 
(VEGF)), ramucirumab (anti-VEGFR-2) and tyrosine kinase inhibitors are reserved for patients 
who are EGFR or ALK positive. Recently the immune checkpoint inhibitor nivolumab and 
pembrolizumab (a human and humanized IgG4 monoclonal antibodies, respectively) that target 
PD-1 have both gained approval as 2nd line therapy for SCCs and as subsequent therapy for patients 
with metastatic non-squamous NSCLC which has progressed on or after first-line chemotherapy4. 
For patients diagnosed in NSCLC early stages I and II, surgical resection with or without 
neoadjuvants is 1st line treatment. For those patients not eligible for surgery, chemotherapy or 
chemoradiation is 1st line treatment4. 
For patients diagnosed with NSCLC stage III or IV, chemotherapy is 1st line treatment and tubulin 
inhibitors, paclitaxel, docetaxel, vinorelbine and nab-paclitaxel, in combination with platinum 
based chemotherapy is standard of care (SoC) treatment. Tubulin inhibitors in combination with 
non-platinum agents is an option, when data on activity or toxicity are available e.g. docetaxel in 
combination with gemcitabine4.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 150 of 259 
In patients with sensitizing EGFR mutations, erlotinib is recommended as 1st line treatment 
(gefitinib and afatinib are also indicated in this patient population); and for patients with an ALK 
mutation crizotinib is 1st line therapy4. 
Initiation of docetaxel as maintenance therapy after 1st line platinum-doublet chemotherapy is 
recommended in patients with SCCs and pemetrexed is indicated as maintenance therapy in non-
squamous cell carcinomas. However, systemic immune checkpoint inhibitors are preferred, and 
docetaxel may be used subsequently4. 
The tubulin inhibitor docetaxel is recommended as monotherapy in 2nd and subsequent lines of 
therapy due to its superiority to vinorelbine or ifosfamide. However, the combination of docetaxel 
and ramucirumab is recommended due to improved survival compared to docetaxel as single agent 
treatment4. 
Gynecological cancers 
Axl expression has been shown in the literature as well as in sponsor IHC staining studies in 
ovarian, endometrial and cervical cancers.  
Ovarian cancer  
The incidence of ovarian cancer was 20,651 in the US2 and 44,149 in the EU3 in 2014 and 2012, 
respectively. Approximately 69% of the patients had advanced disease at the time of diagnosis2. 
The 5-year overall survival was 42% in 2014 with shortest survival observed in the advanced 
stages; stage I: 85%, II: 67%, III: 37% and IV:16%2.  
The risk factors for ovarian cancer are nulli- or low parity, family history and heritable mutations. 
There are three different types of primary ovarian cancer; epithelial (65-70%), germ cell (15-20%) 
and sex cord-stroma (5-10%). Metastasis to the ovaries account for 5% of ovarian tumor masses. 
Epithelial carcinomas are the most frequent ovarian cancer and represent 90% of the malignant 
cases.  
The most prominent genetic risk factors are BRCA1 and BRCA2 mutations. Bearing one of those 
mutations increases the risk of ovarian cancer by 20% to 60% by 70 years of age. The majority of 
these malignancies are cystadenomas whereas approximately 30% of ACs express Human 
epidermal growth factor receptor 2/neu oncogenes, while p53 is found in more than 50% of ovarian 
carcinomas5.  
First line treatment for epithelial ovarian cancer is taxanes in combination with carboplatin in all 
stages of the disease but it is recommended to treat patients with advanced disease with 2 cycles 
more than those with early stage disease. Bevacizumab is approved by the European Medicines 
Agency for late stage disease epithelial ovarian cancer, IIIB, IIIC and IV in combination with 
paclitaxel and carboplatin6. In the US, paclitaxel is recommended in combination with carboplatin 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 151 of 259 
or cisplatin as 1st line treatment in patients with advanced disease. Other combinations include 
carboplatin, doxorubicin or docetaxel. Intraperitoneal chemotherapy is an option in patients, who 
underwent debulking surgery, and it is administrated in combination with systemic chemotherapy, 
however such combinations can lead to severe toxicity7. 
For patients who need 2nd and subsequent treatment lines 1st line has to be taken in consideration. 
For example, for those who are platinum-resistant or have recurrent epithelial ovarian, fallopian 
tube or primary peritoneal cancer, bevacizumab in combination with paclitaxel, pegylated 
liposomal doxorubicin or topotecan is recommended7.  
Olaparib is approved for maintenance treatment of adult patients with platinum-sensitive BRCA-
mutated ovarian cancer achieving complete response (CR) or partial response (PR) to platinum-
based chemotherapy6 and it is approved in the US for treatment of patients with a BRCA mutation 
who have failed 3 or more prior treatment lines7.  
Endometrial cancer  
The number of new cases of endometrial cancer was 50,182 in US in 20142 and 98,919 new cases 
in EU in 20123. Twenty-two percent of the patients had advanced or metastatic disease at 
diagnosis2; the 5-year overall survival was 75% in 20142 however, it varies widely between the 
stages of the disease; 98%, 76%, 59% and 17% in stage I, II, III and IV, respectively2.  
Risk factors of endometrial cancer are prolonged estrogen stimulation and endometrial 
hyperplasia. The disease is more frequently seen in women treated with estrogen replacement 
therapy. Also, synthesis of estrogens in body fat from adrenal and ovarian androgens may explain 
that endometrial cancer is frequently seen in elderly obese patients. Also women with diabetes 
(abnormal glucose intolerance in the majority), hypertension, and infertility have a higher 
incidence of endometrial cancer5. 
For newly diagnosed late stage diseases including metastatic or recurrent disease, hormone therapy 
is the preferred first line systemic therapy for patients with receptor positive tumor in the absence 
of rapidly progressive disease. Multi-agent treatment is used for patients not suitable for hormonal 
therapy, with anthracyclines, platins and taxanes being preferred. Based on a response rate of > 
60% for paclitaxel combined with carboplatin or cisplatin, this regimen is preferred as 1st line 
treatment for advanced endometrial cancer or recurrent disease. If multi-agent chemotherapy is 
not tolerated single agent treatment is an option and paclitaxel is the recommended 1st choice as 
single agent and docetaxel is used if paclitaxel is contraindicated. There is no SoC for second-line 
chemotherapy8.  
Cervical cancer 
The incidence of cervical cancer was 11,669 in US2 in 2014 and 33,354 in EU3 in 2012. Thirty-

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 152 of 259 
eight percent of the patients had disease stage III or IV at the time of diagnosis2. The 5-year overall 
survival was 66% in 2014 varying from 98% in stage I, 64% in stage II, 50% in stage III to 16% 
in stage IV2. 
Human papilloma virus is considered to be the most important risk factor of cervical cancer and a 
high viral load increases the risk. Other risk factors of cervical cancer are human leukocyte antigen 
and viral subtypes, oral contraception, genital chlamydia infection and nicotine5.  
Chemotherapy for recurrent or metastatic cervical cancer is a combination regimen in the 1st line 
setting. Paclitaxel is the main chemotherapy of different combination treatment options combined 
with either cisplatin or topotecan as the 2nd drug and bevacizumab added as the 3rd drug. If 
multiple-agent treatment is not an option cisplatin is preferred as single-agent but also paclitaxel 
is recommended. Several agents are recommended for 2nd line treatment and include docetaxel and 
vinorelbine9.  
Radiation therapy is a part of treatment in all stages of the disease except for stage IA9.  
Thyroid cancer  
The highest Axl expression has been shown in the literature as well as in sponsor’s IHC staining 
studies in thyroid cancers. 
In the US, 62,450 new cases of thyroid carcinoma were expected to be diagnosed by 2015 and the 
peak incidence is around age 50 years. The histopathological breakdown (based on data from 2008-
2012) is approximately: 89% papillary, 5% follicular, 2% medullary, 2% Hürthle cell and 1% 
anaplastic thyroid carcinoma. Anaplastic thyroid carcinoma is almost uniformly lethal while 
papillary and follicular carcinoma (stages I-III) display 5-year relative survival rates in the range 
of 90-98%. However, most thyroid carcinoma deaths are from papillary, follicular and Hürthle cell 
carcinomas, which account for nearly 95% of all thyroid carcinoma cases. Approximately 1.950 
deaths are estimated each year among patients with thyroid carcinoma in the US. 
No effective therapy exists for anaplastic thyroid carcinoma. The median survival from diagnosis 
is about 5 months and the 1-year survival rate is about 20%. Single-agent doxorubicin is the only 
agent that is approved by the U.S. Food and Drug Administration (FDA) for this patient 
population. Single-agent paclitaxel may benefit some newly diagnosed patients; increased survival 
has been reported in patients with stage IVB disease10-12. The National Comprehensive Cancer 
Network (NCCN) guideline recommends that given the poor outcome all patients should be 
considered for clinical trials13. 
The 5-year survival rate for stage IV medullary thyroid carcinoma is about 28%14. The kinase 
inhibitors vandetanib and cabozantinib are approved by the FDA and may be appropriate for 
patients with recurrent or persistent medullary thyroid carcinoma that is not resectable. Clinical 
trials can be considered as an alternative. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 153 of 259 
Differentiated (i.e., papillary, follicular, Hürthle cell) thyroid carcinoma is usually asymptomatic 
for long periods and the 10-year relative survival rates in the National Cancer Data Base report 
were 93% for papillary carcinomas, 85% for follicular carcinomas and 76% for Hürthle cell 
carcinomas. Lenvatinib and sorafenib are approved by the FDA and may be considered for 
progressive and/or symptomatic differentiated thyroid carcinoma. Clinical trials can be considered 
as an alternative13. 
Melanoma 
In malignant melanoma, Axl expression has been associated with drug-resistance in mutant BRAF 
as well as NRAS melanoma cell lines22. In addition, Axl expression was enhanced in patients with 
metastatic melanoma that did not respond to anti-PD-1 therapy23, suggesting that Axl expression 
also relates to innate anti-PD-1 resistance. In house studies showed no or little expression of Axl 
in tumor tissues from malignant melanoma patients with predominantly early stage disease 
(GMB1021-105). More recent investigations indicated that Axl is expressed in malignant 
melanoma tissue in patients with advanced/metastatic disease. In a cohort of malignant melanoma 
patients that relapsed from or became refractory to treatment with BRAF inhibitors (GMB1021-
121), Axl expression was observed in the majority of tumor tissues. Of note, Axl expression was 
variable between patients, regarding both staining intensity and percentage of Axl positive tumor 
cells.  
Cytotoxicity studies in vitro showed that BRAF mutant melanoma cell lines that had become 
resistant to BRAF inhibitors, as well as NRAS mutant melanoma cell lines, expressed Axl at levels 
sufficient to induce cytotoxicity with enapotamab vedotin. Moreover, enapotamab vedotin was 
able to induce tumor regression in both BRAF mutant, BRAF-inhibitor-resistant melanoma models 
and NRAS mutant melanoma models in vivo.  
In conclusion, Axl expression was observed in malignant melanoma patients with advanced 
disease, and preclinical efficacy studies suggest that Axl expression levels are sufficient to induce 
anti-tumor activity with enapotamab vedotin. This supports the exploration of enapotamab vedotin 
in such patient population. For more details please also refer to the Investigator’s Brochure. 
The incidence of melanoma continues to rise dramatically. Melanoma is increasing in men more 
rapidly than any other malignancy and in women more rapidly than any other malignancy except 
lung cancer. The lifetime risk of developing melanoma for someone born in the U.S. may be as 
high as 1.1% for women and 1.9% for men. The median age at presentation is 55 years. Patients 
who are younger, female, and have melanomas on the extremities generally have a better 
prognosis. The estimated annual incidence for 2016 in the US is 162,981 cases and 63,549 cases 
in Western Europe2,15. 
In general the prognosis is excellent in patients who present with localized disease and primary 
tumors 1.0 mm or less in thickness, with 5-year survival achieved in more than 90% of patients. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 154 of 259 
However, with stage III, 5-year survival rates range from 20% to 70%, depending primarily on the 
nodal tumor burden. Historically, long-term survival in patients with distant metastatic melanoma, 
taken as a whole, has been less than 10%. However, the impact of emerging effective systemic 
therapies on the survival of patients with stage IV melanoma has made long-term remission 
possible for a larger proportion of patients15. Anyhow, there is still a very high unmet medical need 
for patients that do not experience such long-term remission. 
The therapeutic landscape for metastatic melanoma is rapidly changing with the recent 
development of novel agents, which have demonstrated better efficacy than chemotherapy. For 
first-line therapy of unresectable or metastatic disease, recommended treatment options include 
checkpoint immunotherapy, BRAF-targeted therapy for patients with BRAF-mutated disease, or 
clinical trial. For patients with documented BRAF V600 mutations, selection between first-line 
checkpoint immunotherapy and BRAF-targeted therapy can be difficult given the lack of 
comparative phase III clinical trials. BRAF-targeted therapy seems to be preferred in cases where 
disease is symptomatic or rapidly progressing, given that responses to checkpoint immunotherapy 
can take longer to develop15. 
For patients who progress on first-line therapy or achieve maximum clinical benefit from BRAF-
targeted therapy (if BRAF mutated), options for second-line therapy depend on ECOG 
performance status. Patients with poor performance (PS 3-4) should be offered best supportive 
care. Patients with PS 0-2 have a variety of options depending on their BRAF status and treatment 
history: nivolumab, pembrolizumab, nivolumab/ipilumab combination, or BRAF inhibitor / MEK 
inhibitor combination. In addition to the checkpoint immunotherapy regimens recommended for 
first-line, second-line, and subsequent treatment of metastatic disease, single-agent ipilimumab is 
an option for patients who have received prior systemic therapy for metastatic disease15. 
For patients who progressed on checkpoint immunotherapies (and BRAF-targeted therapy if 
BRAF-mutated) additional options to consider for second-line or subsequent therapy include 
among others cytotoxic agents and clinical trials15. Common cytotoxic agents being used in 
patients with metastatic melanoma include dacarbazine, temozolomide, and paclitaxel with or 
without carboplatin15. These have demonstrated modest response rates less than 20% in first line 
and second-line settings. Nab-paclitaxel has yielded response rates of 22% to 26% in phase II trials 
among chemotherapy-naïve patients with metastatic melanoma16,17. 
Sarcoma 
Publicly available RNA data indicate that AXL is highly expressed in osteo- and chondrosarcoma 
derived cell lines (CCLE database, https://portals.broadinstitute.org/ccle/home). Notably, among 
33 tumor types analyzed in The Cancer Genome Atlas, the highest levels of AXL mRNA 
expression were observed in 265 sarcomas representing various soft tissue sarcoma types, 
primarily including undifferentiated pleomorphic sarcoma, lipo-, and leiomyosarcoma.18 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 155 of 259 
Furthermore, in sponsor IHC staining studies, osteosarcoma and chondosarcoma belong to the 
cancer types showing highest Axl expression. In addition, preclinical efficacy could be 
demonstrated in patient-derived osteo- and chondrosarcoma models in vivo. For more details 
please also refer to the Investigator’s Brochure. 
In the US, 12,390 new cases of soft tissue sarcoma (STS) were expected to be diagnosed by 2017 
with approximately 4,990 deaths19 and 3,260 new cases of bone cancers were expected to be 
diagnosed by 2016 with approximately 1,550 deaths19. The peak incidence is below the age of 40 
years. The most common subtypes of STS are undifferentiated pleomorphic sarcoma, 
gastrointestinal stromal tumors (GISTs) liposarcoma, leiomyosarcoma, synovial sarcoma and 
malignant peripheral nerve sheath tumors. The most common subtypes of primary bone cancers 
are osteosarcoma, chondrosarcoma, and Ewing sarcoma. 
Except for GISTs, the approved armamentarium for systemic therapy of sarcomas is currently 
limited primarily to conventional chemotherapy also including vinca alkaloids and taxanes. A few 
targeted therapies such as pazopanib, sorafenib and olaratumab are registered. The National 
Comprehensive Cancer Network (NCCN) guideline recommends that given the unsatisfactory 
outcome all patients should be considered for clinical trials20, 21. 
 
REFERENCES (APPENDIX I)  
 
1. 
Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson L, Loscalzo J. Harrison’s 
Principles of Internal medicine. 18th Edition ed2011. 
2. 
cancermpact.com. 
3. 
EUCAN fact sheet, 2012, European Union 27 (EU + Norway & Switzerland). 
4. 
NCCN guidelines, version 4.2016. Non-small cell lung cancer. 
5. 
Kumar V, Abbas AK, Fausto N, Robbins SL, Cotran RS. Robbins and Cotran pathologic 
basis of disease. Elsevier Saunders; 2005. 
6. 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00058
2/human_med_000663.jsp&mid=WC0b01ac058001d124. 
7. 
Ovarian Cancer, NCCN Guidelines Version 2. 2015. 
8. 
Uterine Neoplasms, NCCN version 2.2015, ESMO-ESGO-ESTRO Endometrial 
Consensus 2015. 
9. 
Cervical cancer NCCN Guidelines Version 2.2015. 
10. 
Higashiyama T, Ito Y, Hirokawa M, et al. Induction chemotherapy with weekly paclitaxel 
administration for anaplastic thyroid carcinoma. Thyroid : official journal of the American 
Thyroid Association. 2010;20(1):7-14. 
11. 
Ain KB. Anaplastic thyroid carcinoma: behavior, biology, and therapeutic approaches. 
Thyroid : official journal of the American Thyroid Association. 1998;8(8):715-726. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 156 of 259 
12. 
Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with 
paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid 
Cancer Health Intervention Trials (CATCHIT) Group. Thyroid : official journal of the 
American Thyroid Association. 2000;10(7):587-594. 
13. 
Thyroid carcinoma NCCN Guidelines Version 2.2015. 
14. 
Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report 
on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments]. 
Cancer. 1998;83(12):2638-2648. 
15.  
NCCN guidelines version 3.2016. Melanoma. 
16. 
Hersh EM, O’Day SJ, Ribas A, Samlowski WE, Gordon MS, Shechter DE, Clawson AA, 
Gonzalez R. A phase 2 clinical trial of nab-paclitaxel in previously treated and 
chemotherapy-naive patients with metastatic melanoma. Cancer 2010; 116(1):155-63. 
17.  
Kottschade LA1, Suman VJ, Amatruda T 3rd, McWilliams RR, Mattar BI, Nikcevich DA, 
Behrens R, Fitch TR, Jaslowski AJ, Markovic SN. A phase II trial of nab-paclitaxel (ABI-
007) and carboplatin in patients with unresectable stage IV melanoma : a North Central 
Cancer Treatment Group Study, N057E(1). Cancer 2011: 117(8):1704-10. 
18. 
http://www.cbioportal.org/study?id=sarc_tcga#summary 
19. 
Siegel RL et al. Cancer statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. doi: 
10.3322/caac.21387. Epub 2017 Jan 5. 
20. 
NCCN guidelines version 2.2017. Bone cancer. 
21.  
NCCN guidelines version 2.2017. Soft tissue sarcoma. 
22. 
Müller J, Krijgsman O, Tsoi J., et al. Low MITF/AXL ratio predicts early resistance to 
multiple targeted drugs in melanoma. Nat Commun. 2014 Dec 15;5:5712. 
23. 
Hugo W., Zaretsky JM., Sun L., et al. Genomic and Transcriptomic Features of Response 
to Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 2016 Mar 24;165(1):35-44. 
 
.
 
 

Section Number 
Title 
Appendix II 
Bayesian Dose Escalation Design for a Phase I Trial 
 
 
Pages 164-192 removed - Out of Scope 
 

Section Number 
Title 
Appendix III 
Preclinical Population PK Model 
 
 
Pages 165-193 removed - Out of Scope 
 

Section Number 
Title 
Appendix IV 
Population Pharmacokinetic Analysis Plan 
 
 
Pages 194-210 removed - Out of Scope 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 231 of 259 
Appendix V: Recommendations Related to Contraception and Pregnancy Testing 
in Clinical Trials 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 232 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 233 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 234 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 235 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 236 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 237 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 238 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 239 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 240 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 241 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 242 of 259 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 243 of 259 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 244 of 259 
Appendix 
VI: Trial Procedures and Assessments Applicable per 
Amendment 10  
 
This Appendix is intended as a supplement to the main trial protocol to describe the procedures 
and assessments applicable from implementation of Amendment 10 until end of trial. It is not 
intended to be a stand-alone document, and rather than repeating unchanged sections of the main 
protocol, cross-references back to the main protocol have been included in this Appendix when 
applicable.   
Refer to Table 31 and Sections 16 through 17 for applicable assessments as of 
Amendment 10. 
 
In summary, as of Amendment 10: 
• The duration of treatment for each patient in this trial will be until disease progression or 
unacceptable toxicity (Section 3.5). 
• Follow-up contact every 12 weeks post trial treatment is no longer applicable (Section 5.6.6). 
• Sampling and assessment of PK and biomarkers are no longer applicable.   
• Height, weight and physical examination outcome are no longer to be recorded in the eCRF.   
• ECGs will be taken locally.  
• Any irregularity observed or occurring during the ECGs should either induce a repeat 
of the ECG or be annotated in the medical journal. 
• New or worsened clinically significant abnormalities should be recorded as AEs on the 
AE form.  
• Post-baseline CT-scans are to be performed every 12 weeks (±7 days) and are not to be sent 
for central reading. 
• Vital signs should be measured if deemed necessary by the investigator, but are not to be 
recorded in the eCRF. 
• Any medication or therapy other than enapotamab vedotin that is related to an AE or is 
considered prophylactic treatment is considered concomitant medication.  
• Patient diary data are not to be recorded in the eCRF.    
• All laboratory samples will be analysed locally.   
• Urinalysis is only to be performed if deemed necessary by the investigator and not to be entered 
in the eCRF.  
• New or worsened clinically significant laboratory abnormalities should be recorded as AEs on 
the AE form. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 245 of 259 
• Assessments for CA 125, enapotamab vedotin, MMAE, hepatitis B and C, cytomegalovirus 
serology, immunogenicity and Axl expression are no longer applicable.  
• Collection and assessment of tumor biopsies is no longer applicable. 
• Exploratory biomarker analyses are no longer applicable. 
• Non-serious Grade 3 AEs, peripheral neuropathy AEs ≥ Grade 2 and peripheral neuropathy 
AEs leading to permanent treatment discontinuation are no longer to be reported on the Safety 
Reporting form.    
 
 
 
 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 246 of 259 
16. 
TRIAL EVALUATION AS OF AMENDMENT 10 
16.1 Table of Assessments 
Table 31. Table of Assessments – Expansion 
Treatment Cycle 
Screening 
Cycle 1 
Cycle 2-12 or 16 
Cycle 13 or 17 to 
PD19 
End of 
Treatment1 
Safety Follow-up 
End of trial Unscheduled 
1Q3W  
Visit 
≤21 days 
prior to Visit 
C1V1 
1 
- 
2 
3 
1 
- 
2 
3 
1 
- 
- 
- 
 
1-X 
Day 
1d 
- 
8d 15d 1d 
- 
8d22 15d22 
1d 
- 
- 
30 days after last 
dosing 
- 
 
3Q4W  
Visit 
≤21 days 
prior to Visit 
C1V1 
1 
2 
3 
4 
1 
2 
3 
4 
1 
2 
3 
Day 
1d 8d 15d 
22d 
1d 8d 15d 
22d23 
1d 
8d 
15d 
Visit window2 
 
- 
±1d 
±1d 
±3d 
±1d 
±1d 
±3d 
±1d 
- 
+14d 
 
- 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight4 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
Physical Examination 21 
X16 
X 
 
 
X 
 
 
X 
 
X 
 
 
X14 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X14 
ECG 
Please refer to Section 16.2.6 for details of ECG assessments 
Imaging 
X6 
 
 
 
X7 
X8 
 
 
X14 
ECOG 
Performance 
Status 
X 
X 
 
 
X 
 
 
X 
 
X 
 
 
X14 
Adverse Events 
X24 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X14 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X14 
Prophylactic 
concomitant 
medication18 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Enapotamab vedotin 
administration 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
End of treatment/trial 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X14 
Biochemistry9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X14 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X14 
Pregnancy Test 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
 
X14 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 247 of 259 
 
Footnotes to Trial Flowchart – Expansion 
1 If the patient shows PD, is to start new anti-cancer treatment or withdraws from treatment due to another reason the End of treatment visit should be performed as soon as possible after 
decision of withdrawal. 
2 The visit windows relate to the day of the previous visit. Visit 1 of Cycle 2 and onwards should be performed 7 days ±3 days after Day 15/22 of the previous cycle. 
3 Signs, symptoms and diagnosis occurring between Visit 0 and first infusion should be recorded as medical history (see Section 8.4 for details). SAEs should be reported as of the signing 
of the informed consent. 
4 Body weight will be measured on the first dosing day in a cycle, as part of the dose calculation. If body weight is assessed ≤ 7 days before the first day of the planned dosing in a cycle, 
this weight can be used to calculate dose. 
5 Temperature, blood pressure and heart rate as according to Section 16.2.8. 
6 All patients will have a CT-scan with contrast of thorax, abdomen, and pelvis performed as part of the screening procedure. If a CT-scan has been performed within 28 days prior to visit 
C1V1 as part of standard procedure, it is acceptable as screening CT-scan for the trial. If there is suggestion of brain metastases/tumors, a CT-scan of the head will be performed before 
inclusion. Clinical measurement in case of superficial cutaneous lesions should be performed within 28 days prior to visit C1V1 as part of standard procedure. For further details on imaging 
please refer to Section 16.2.7. 
7 Radiological assessments and clinical measurements of superficial cutaneous lesions are to be performed every 12 (1Q3W and Cohort 8 3Q4W) or 8 (Cohort 6 3Q4W) weeks (±7days) 
from C1D1 until disease progression. If treatment is discontinued prematurely, prior to detection of disease progression (e.g., due to an adverse event), every effort should be made that scans 
continue according to the protocol until disease progression, start of a new anti-cancer treatment, withdrawal of consent or death (see Section 16.2.7 for details). 
8 To be completed as indicated to confirm response or new symptoms at the end of treatment visit or at the physicians discretion. 
9 TSH, T3 and T4 will only be measured at screening and on Visit 1 of every even cycle. With Amendment 10, only measured locally if clinically indicated. 
10 Not applicable. Deleted as per Amendment 10 
11 Not applicable. Deleted as per Amendment 10 
12 Not applicable. Deleted as per Amendment 10 
13 Not applicable. 
14 Only if relevant. 
15 Not applicable. Deleted as per Amendment 10 
16 Including a baseline visual acuity assessment at the screening visit. 
17 Not applicable. Deleted as per Amendment 10 
18 Please refer to Section 7.4.1 on prophylactic concomitant medications. 
19 The patients will receive treatment until progressive disease (PD) or unacceptable toxicity. 
20 The last diary will be collected and reviewed at Cycle 13 Day 1 (patients on 3Q4W regimen) or at Cycle 17 Day 1 (patients on 1Q3W regimen). 
21 A complete, general physical examination will be done at the screening and C1D1 visit including peripheral neuropathy assessment, such as checking of tendon reflexes, muscle strength 
and tone, sensitivity, co-ordination and balance. At subsequent visits and as clinically indicated, limited symptom-directed physical examinations should be performed (Section 16.2.5). The 
peripheral neuropathy assessment should also be performed at the End of Treatment visit. 
22 The Day 8/15 visit can be omitted if there have been no AEs fulfilling the DLT criteria in the previous 2 cycles as assessed by investigator.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 248 of 259 
Footnotes to Trial Flowchart – Expansion 
23 The Day 22 visit can be omitted if there have been no AEs fulfilling the DLT criteria in the previous 2 cycles as assessed by investigator.  
24 Only SAEs 
 
 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 249 of 259 
16.2 Clinical Assessments 
16.2.1 
Demographics 
Refer to Section 8.4.1 
16.2.2 
Disease Status 
Refer to Section 8.4.2 
16.2.3 
Medical History 
Refer to Section 8.4.3 
16.2.4 
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 visit 1 of 
each cycle, as part of the dose calculation, and at end of treatment visit, but is not to be recorded 
in the eCRF as of Amendment 10. If body weight is assessed 7 days or less (on the site weight) 
before the day of the planned dosing, this weight can be used.   
16.2.5 
Physical Examination 
A complete general physical examination will be done at the screening and C1D1 visit including 
peripheral neuropathy assessment, such as checking of tendon reflexes, muscle strength and tone, 
sensitivity, co-ordination and balance. A baseline visual acuity assessment will be performed at 
the screening visit using the Snellen chart.  
At subsequent visits (or as clinically indicated), limited symptom-directed physical examinations 
should be performed but with Amendment 10, the outcome of the physical examination will not 
be recorded in the eCRF. Abnormal changes from baseline should be recorded in the patient’s 
notes. New or worsened clinically significant abnormalities should be recorded as AEs on the AE 
form. The peripheral neuropathy assessment should also be performed at the End of Treatment 
visit.   
16.2.6 
Electrocardiogram 
The electrocardiograms (ECGs) will be recorded digitally at the sites by using the standard 
12 leads and is to be reviewed by the investigator (or other qualified staff members).  
An overall interpretation of the ECGs must be performed by the investigator (the investigator may 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 250 of 259 
delegate this task to a cardiologist or other qualified staff member, if applicable) before each dosing 
for use of treatment decision (with the exception of evaluation of patient eligibility which must be 
evaluated based on the central ECG reading). The investigator ECG interpretation must be done 
using the paper ECG reading from the ECG machine by signing and dating the print out. For the 
ECG recordings, the patients must be resting and in a horizontal or half laid-back position for at 
least 10 minutes (the position should not change for following ECGs). Any irregularity observed 
or occurring during the ECGs (e.g., vomiting, cough) should either induce a repeat of the ECG or 
be annotated in the medical journal with the description and time of the occurrence.  
Date and overall interpretation of the ECGs is no longer to be recorded in the eCRF. 
ECGs will be taken as single or triplicate ECGs according to Table 19 using local equipment. New 
or worsened clinically significant abnormalities should be recorded as AEs on the AE form. 
16.2.7 
Imaging/Computed Tomography 
All patients will have a CT-scan with contrast of thorax, abdomen and pelvis performed during 
screening. If there is suspicion of brain metastases/tumors, a CT-scan of the head will be performed 
before inclusion. For patients with stable brain metastases enrolled in the expansion part, the CT-
scan must include the head and neck. 
For patients with superficial cutaneous lesions that are not measurable by a CT-scan, measurement 
using calipers can be performed, using photographs as documentation.  
All sites of metastatic disease should be reported at baseline and followed throughout the trial. Up 
to 5 target lesions (maximum two per organ) will be defined at screening. A lesion from which a 
fresh biopsy has been taken during the trial cannot be a target lesion.  
Baseline imaging assessments will be performed during the screening period. Any imaging 
assessments already completed for regular radiographic evaluation of the patient’s cancer can be 
considered as the baseline images for this trial, as long as they are of sufficient diagnostic quality 
and have been obtained ≤ 28 days prior to C1D1. 
 
Post-baseline scans will be performed every 12 weeks (±7 days) (1Q3W and Cohort 8 3Q4W) or 
8 weeks (±7 days) (Cohort 6 3Q4W) from C1D1 until investigator assessed disease progression 
according to RECIST v1.1. Time points for radiographic evaluation should be calendar based 
and do not depend on cycle visits i.e. radiological evaluation should be performed regardless of 
IMP administration delays. 
 
If reduction of target lesions ≥ 30% in size is observed a repeat CT-scan will be performed after 
4 (in particular for the 3Q4W-arm) to 6 weeks (in particular for the 1Q3W-arm) (±7 days) to 
confirm the response.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 251 of 259 
Unscheduled imaging may be performed at the investigators discretion to confirm response 
(intervals should not be shorter than 4 weeks). In case of suspicion of disease progression on the 
basis of clinical or laboratory findings, imaging should be performed as soon as possible before 
the next scheduled evaluation. 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.  
Localized CT with contrast or MRI (with or without contrast; for sarcomas with contrast) must be 
acquired for assessment of lesions of the skeleton/extremities and head and neck if not visible on 
other images. At the discretion of the investigators, combined PET/CT (e.g., FDG-PET) may be 
performed for tumor assessments as per RECIST 1.1, but only if the CT portion is of similar 
diagnostic quality to CT alone. Chest x-rays and ultrasound should not be used to measure tumor 
lesions. 
The same imaging modality and ideally the same scanner should be used throughout the trial to 
optimize the reproducibility of the assessment and preserve the accuracy of the assessment of 
response or progression.  
In the dose escalation part the reading of the scans will be done by a local radiologist. Sites should 
attempt to maintain the same radiologist throughout the trial. The overall interpretation of the 
evaluation shall be recorded in the eCRF and a copy of the evaluation reports should be kept in the 
patient’s file. 
In the expansion part the scans will be read by the local radiologist.  
16.2.8 
Vital Signs 
Vital signs, including temperature, blood pressure and heart rate, should be measured if deemed 
necessary by the investigator, but are not to be recorded in the eCRF as of Amendment 10. New 
or worsened clinically significant abnormalities should be recorded as AEs on the AE form. 
16.2.9 
ECOG Performance Status 
Refer to Section 8.4.9. 
16.2.10 
Concomitant Medication 
Any medication or therapy other than enapotamab vedotin that is related to an AE or is considered 
prophylactic treatment is considered concomitant medication and should be recorded in the eCRF 
with the following information: 
Start date  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 252 of 259 
Route of administration 
Stop date of administration or ongoing at trial termination 
Indication / reason for use. 
The total daily dose should be filled in whenever possible. 
Relevant prior concomitant medication given within one month prior to screening and all 
medication given from visit 0 (Screening) until the 30-day safety follow-up must be recorded. 
16.2.11 
Prior Cancer Therapy and Surgery 
Refer to Section 8.4.11. 
16.2.12 
Adverse Events 
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 30 day safety follow-up visit. Any non-serious AEs (signs, symptoms and diagnosis) 
occurring between screening and the day of first treatment administration should be recorded as 
medical history. 
SAEs should be reported from the time the patient signs the ICF (both on the eCRF AE form and 
the SAE reporting form) and until the 30 day safety follow-up visit. All deaths should be reported 
as an SAE.  
For further details regarding reporting of AEs, please see Section 9. 
16.2.13 
Patient Diary 
As of Amendment 10, patient diary data are not to be recorded in the eCRF.  
16.3 Laboratory Assessments 
Blood sampling will be collected for assessment of laboratory parameters. All laboratory samples 
will be drawn and analysed locally.  
Laboratory equipment may provide standard analyses not requested in the protocol but produced 
automatically in connection with the requested analyses. Such data will not be included in the 
database, but must be reported to the investigator. 
Local laboratory values for biochemistry (Section 16.3.1) and hematology (Section 16.3.2) must 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 253 of 259 
be obtained the day before or on the day of each enapotamab vedotin administration and reviewed 
by the investigator prior to each enapotamab vedotin administration to ensure the patient can be 
dosed as defined in the protocol.  
Patient eligibility must always be evaluated based on central laboratory values, however, local 
safety laboratory values (glomerular filtration rate (GFR), ALT/AST/bilirubin, hemoglobin, 
neutrophil count, platelet count, LDH [melanoma patients]) must be obtained the day before or on 
the day of C1D1 to confirm patient eligibility.  
Furthermore, local laboratory values may be obtained at the discretion of the investigator and used 
for other clinical treatment decisions of the patient. 
Local laboratory values must be recorded in the eCRF if they are assessed by the investigator to 
be clinically significant or lead to dose modifications/delays of enapotamab vedotin. In case local 
laboratory values are assessed as clinically significant by the investigator, a corresponding adverse 
event must be reported on an AE form (Section 9.1). Furthermore local labs will be assessed for 
the evaluation of DLT.  
16.3.1 
Biochemistry 
Blood samples will be drawn in accordance with Table 31.  
The following Biochemistry parameters will be analyzed locally the day before or on the day of 
each enapotamab vedotin administration: 
Sodium, potassium, magnesium, creatinine, calcium, blood urea nitrogen, AST, ALT, alkaline 
phosphatase, albumin, glucose, total bilirubin, uric acid, cholesterol, triglycerides, lipase, amylase, 
and gamma-glutamyl transferase. 
16.3.2 
Hematology 
Blood samples will be drawn as according to Table 31. 
The following hematology parameters will be analyzed locally at site (the day before or on the day 
of each enapotamab vedotin administration): 
Red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular 
hemoglobin, mean corpuscular hemoglobin concentration, white blood cell count with differential, 
platelet count, reticulocyte count and coagulation factors (prothrombin time, international 
normalized ratio and activated partial thromboplastin time). 
16.3.3 
CA 125 
With Amendment 10, collection and analysis of blood samples for CA 125 is no longer applicable. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 254 of 259 
16.3.4 
Urinalysis 
Urinalysis will be performed locally by site if deemed necessary by the investigator. The result is 
not to be entered in the eCRF, however, new or worsened clinically significant abnormalities 
should be recorded as AEs on the AE form.  
16.3.5 
Enapotamab Vedotin, HuMax-AXL and MMAE in Serum 
With Amendment 10, assessment of enapotamab vedotin and MMAE is no longer applicable. 
16.3.6 
Hepatitis B, C and Cytomegalovirus Serology 
With Amendment 10, assessment of hepatitis B, C and cytomegalovirus serology is no longer 
applicable. 
16.3.7 
Pregnancy Test 
Pregnancy testing will be performed as scheduled in Table 31 from all women of childbearing 
potential and will be analyzed locally. Pregnant women may not take part in this trial 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 (see Appendix V). 
16.3.8 
Immunogenicity of Enapotamab Vedotin 
With Amendment 10, assessment of immunogenicity is no longer applicable.  
16.3.9 
Tumor Biopsy 
With Amendment 10, collection and assessment of tumor biopsies is no longer applicable. 
16.3.9.1 Axl Expression 
With Amendment 10, assessment of Axl expression is no longer applicable.  
16.3.10 
Exploratory Biomarker Analyses 
With Amendment 10, exploratory biomarker analyses are no longer applicable.  

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 255 of 259 
16.3.11 
Biological Sample Handling 
Refer to Section 8.5.11. 
16.3.12 
Chain of Custody of Biological Samples 
Refer to Section 8.5.12. 
17. 
REPORTING OF ADVERSE EVENTS AS OF AMENDMENT 10 
17.1 Recording Instructions 
Instructions for reporting changes in an ongoing AE during a patient's participation in the trial are 
provided in the instructions that accompany the AE eCRFs.  
All AEs, regardless of relatedness or cause, should be reported as an AE in the eCRF.  
All AEs with an outcome of death (including disease progression) should be reported as an AE (in 
the eCRF) and as an SAE from the time patients sign the ICF until 30 days after the last enapotamab 
vedotin dosing.  
All AEs in the 30 day safety follow-up visit including laboratory findings considered to be 
clinically significant should be reported accordingly. After the 30-day safety follow-up visit, 
should the investigator become aware of an SAE possibly related to enapotamab vedotin, this 
should be reported accordingly. 
Laboratory assessments 
If a local laboratory value indicates dose modification/delay, the site will be asked to record the 
local laboratory value in the eCRF. Any local laboratory values leading to a dose 
modification/delay or are assessed by the investigator to be clinically significant should be 
recorded as an AE (Section 8.5). 
Pre-existing Conditions 
In this trial, a pre-existing condition (i.e., a disorder present before the AE reporting period started 
and noted on the medical history/physical examination form) should not be reported as an AE. If 
a pre-existing condition worsens during the treatment period the event should be reported as an 
AE. 
17.1.1 
Definition of Adverse Events of Special Interest (AESI) 
Refer to Section 9.1.1. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 256 of 259 
17.1.2 
Diagnosis 
Refer to Section 9.1.2. 
17.1.3 
Intensity 
Refer to Section 9.1.3.  
17.1.4 
Relatedness to Investigational Medicinal Product 
Refer to Section 9.1.4.  
17.1.5 
Start Date and Time 
Refer to Section 9.1.5.  
17.1.6 
Outcome 
Refer to Section 9.1.6 
17.1.7 
Action Taken with Investigational Medicinal Product 
Refer to Section 9.1.7. 
17.1.8 
End Date and Time 
End date should be filled in if the outcome of an event is fatal, recovered/resolved, 
recovered/resolved with sequelae, recovering/resolving. 
For laboratory AEs, the end date is the date a sample is taken, which shows a decrease in the NCI-
CTCAE grade and is no longer considered clinically significant. 
Time should be filled in if event starts on a treatment/dosing day or if the duration of the event is 
less than 24 hours. 
17.1.9 
Adverse Events of Special Interest 
Refer to Section 9.1.9. 
17.1.10 
Information about Infusion Related Reactions 
Refer to Section 9.1.10. 
17.1.11 
Serious Adverse Event 
Refer to Section 9.3.1. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 257 of 259 
17.2 Definition of Serious Adverse Events 
Refer to Section 9.2. 
17.3 Events Requiring Immediate Reporting 
17.3.1 
Serious Adverse Events  
SAEs must be reported from the investigational site to the Safety CRO no later than 24 hours 
following a) the patient visit at which such AE was reported, noted or recognized; or b) the 
principal investigator’s or any investigator personnel’s receipt of the test results or other 
information at, or from which, such development was reported, noted or recognized. Grade 3 and 
4 abnormal lab test results must be reported as AEs when these are assessed as clinically significant 
by the reporting investigator.  
17.3.2 
Overdose and Medication Errors 
Refer to Section 9.3.3.  
17.3.3 
Pregnancy 
Refer to Section 9.3.4. 
17.4 Timelines for Reporting 
The required timeframes and reporting forms for reporting SAEs, overdose, medication errors, and 
pregnancies are presented in Table 32. 
All new information regarding SAEs (initial and follow-up) must be reported from sites to sponsor 
within 24 hours. The final SAE report must be signed by a physician. Sites must respond to follow-
up queries from sponsor within 3 days. 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 258 of 259 
Table 32. Timeframes for Reporting SAEs, Grade 3 AEs, Peripheral Neuropathy, Overdose and Medication 
Errors and Pregnancies 
  
Initial Reports  
Follow-up Information on a Previous 
Report  
Type of Event  
Time 
Frame  
Documents  
Time 
Frame  
Documents 
All SAEs  
24 hours*  Safety Reporting 
Form  
3 days * 
24 hours*  
CDS SAE DCF  
Site SAE DCF  
Overdose and 
Medication Errors  
24 hours*  Safety Reporting 
Form  
3 days * 
24 hours*  
CDS SAE DCF  
Site SAE DCF  
Pregnancy  
24 hours*  Pregnancy Form  
3 days  
Updated Pregnancy Form  
AE=adverse event; DCF=Data Clarification Form; CDS=Corporate Drug Safety; SAE=serious adverse 
event  
*no later than 24 hours/3 days following a) the patient visit at which such AE was reported, noted or 
recognized; or b) the principal investigator’s or any investigator personnel’s receipt of the test results or 
other information at, or from which, such development was reported, noted or recognized. 
Completed safety report forms or pregnancy forms must immediately be forwarded to Safety CRO: 
If you have access to a secured email you may forward completed forms to 
 
If you do not have access to a secured email, please forward completed forms to: 
Fax: 
 
Any suspected enapotamab vedotin related SAE, occurring at any time after the patient has 
terminated trial participation, should be faxed to 
 
17.5 Suspected Unexpected Serious Adverse Reactions 
Refer to Section 9.5.  
17.6 Follow-Up on Adverse Events 
All AEs should be followed until they are resolved or until the Safety Follow-Up visit, whichever 
comes first. Related AEs meeting one of the serious criteria, and still ongoing after ended trial 

 
Genmab 
Document Name: GCT1021-01 Protocol 
Document Number: TMF-03326 
 
Version: 11.0 
Template No.: 07-072 
Template version: 0.1              
Template Date: 03 Feb 2014 
 
 
Page 259 of 259 
participation should be followed on a regular basis, according to the investigator’s clinical 
judgment, until the event has been resolved or until the investigator assesses it as chronic and all 
queries have been resolved.  
17.7 Safety Management Plan 
In order to secure full transparency regarding patient safety-related questions to sites participating 
in the trial, frequent communication of observations at the different sites will be required. The 
communication set-up will include the following components: 
• 
SAEs must be reported from the investigational site to the sponsor via the Safety CRO within 
24 hours and medically evaluated following receipt. During the dose escalation part of the 
trial, at least biweekly safety/medical meetings to discuss AEs and laboratory data will be held 
with the participation of at least Drug Safety, sponsor medical officer and CRO Medical 
Monitor; and the safety data will be evaluated for individual treatment arms as well as across 
treatment arms. If safety signals warranting actions are identified in one treatment arm, actions 
will be implemented in the other treatment arm if deemed relevant for the specific signal in 
question.  
• 
Monthly telephone conferences between all participating Investigators, CRO Medical 
Monitor and sponsor will be arranged when deemed necessary. 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 
 Medical Monitor.  
• 
Direct telephone link from investigator to sponsor medical officer.  
• 
DMC meetings following each cohort and ad hoc as needed. Ad-hoc DMC meetings may be 
called for by both the DMC and Sponsor any time during the escalation and expansion phases 
of the trial if new safety data warrants immediate action to the conduct of the trial. The 
outcome of the DMC meeting will be discussed and confirmed by the sponsor safety 
committee and ultimately communicated to the investigators following each meeting. 
• 
Investigators or their representative(s) may participate in the open part of the DMC meetings 
if deemed relevant.