Conditions: Malignant Melanoma
Keywords: Uveal melanoma Cutaneous melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
IMCgp100-401 is a rollover study that is designed to provide continued access to IMCgp100 for eligible participants with advanced melanoma who have previously participated in an IMCgp100 study (parent study).

Detailed description:
IMCgp100-401 is a rollover study that is designed to provide continued access to IMCgp100 for eligible participants with advanced melanoma who have previously participated in an IMCgp100 study (parent study). Parent studies that are eligible for participants to continue to receive IMCgp100 in this rollover study must have completed and satisfied its primary endpoints or have been terminated by the Sponsor for reasons other than safety.

Eligible participants will have tolerated IMCgp100 for a minimum of 4 weeks of dosing without significant toxicities that would preclude further dosing in the opinion of the principal investigator or Sponsor.

Arms:
arm 1: IMCgp100 (77 kDa bi-specific protein) weekly dosing regimen (QW)

Interventions: intervention 1: IMCgp100
Intervention descriptions: intervention 1: Bispecific soluble human leukocyte antigen-A2 (HLA-A2) restricted gp100-specific TCR fused to anti-CD3

Protocol document:
Prot_001.pdf: 
PROTOCOL NUMBER: IMCgp100-401
Investigational Product: IMCgp100  
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Clinical Study Protocol IMCgp100-401
An Open-label, Multi-Center, Rollover Study in Patients with Advanced 
Melanoma After Completing an IMCgp100 Clinical Study 
Sponsor:  Immunocore, Ltd.  
EUDRACT Number:  2016-002236-32
Protocol Version: 3.0
Release Date:  07 November 2016
Sponsor Emergency Contact:  
 
 
 
This document contains confidential and proprietary information which is the property of Immunocore Ltd, 
United Kingdom, and therefore is provided in confidence for your review. It is understood that this 
information will not be disclosed to others without written approval from Immunocore Ltd.
This study will be conducted in compliance with the Declaration of Helsinki (with amendments), and in 
accordance with local legal and regulatory requirements.


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AMENDMENT 2
Amendment Rationale
The pattern of clinical response to immunotherapeutic agents differs from that observed with cytotoxic 
therapies. There is accumulating evidence that a proportion of patients with advanced melanoma treated 
with immunotherapy agents, including IMCgp100, may develop initial radiographic progression of the 
tumor before demonstrating meaningful clinical benefit. This delayed response to therapy or immune-
mediated tumor flare have been coined as “pseudo-progression” that can then be followed by prolonged 
periods of disease stabilization or objective tumor responses. To allow for patients to continue therapy 
beyond an initial assessment of progressive disease according to RECIST v1.1, this amendment provides 
additional detail delineating criteria for treatment beyond progression. Patients must meet specific 
clinical criteria and provide additional informed consent to continue therapy beyond an initial assessment 
of disease progression. 
 Changes to the Protocol
1.
Added criteria for treatment beyond progression (Section 6.6.1) and rationale (Section 2.4) and 
treatment discontinuation in the setting of treatment beyond progression 
2.
Clarified that the dose and regimen of IMCgp100 will be determined based upon the dose and 
schedule utilized in the parent study 
3.
Extended the safety follow-up period from 30 days to 90 days 
4.
Minor edits to clarify language, improve content flow and readability 
 
Institutional Review Board/Independent Ethics Committee
A copy of this amended protocol will be sent to the Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) and Health Authorities.  The changes described in this amended protocol require IRB or 
IEC approval.  Changes herein affect the Informed Consent, and sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in this amended 
protocol. The revised informed consent form will replace the previous informed consent form. 
AMENDMENT 1 
Amendment Rationale
Amendment 1 for this protocol serves to clarify the required hospitalizations for treatment with 
IMCgp100.   
Changes to the Protocol
1.
Hospitalization requirements are clarified
2.
Minor editss to clarify language, improve content flow and readability 


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TABLE OF CONTENTS
Amendment 2 ...............................................................................................................................................2
Amendment 1 ............................................................................................................................................... 2 
Table of Contents .......................................................................................................................................... 3 
List of Tables ................................................................................................................................................. 8 
Protocol Signatures ....................................................................................................................................... 9 
Protocol Synopsis ........................................................................................................................................ 11 
List of Abbreviations and Definitions of Terms ........................................................................................... 15 
1 
Background......................................................................................................................................... 17 
1.1 
Overview of Disease Setting ....................................................................................................... 17 
1.2 
Overview of IMCgp100 ............................................................................................................... 17 
1.3 
Non-clinical Experience with IMCgp100 ..................................................................................... 18 
1.3.1 
Pre-clinical Pharmacology Summary ................................................................................... 18 
1.3.2 
Non-clinical Toxicology Summary ....................................................................................... 18 
1.4 
Clinical Program and Safety Summary ........................................................................................ 19 
1.4.1 
Weekly Dosing:  Dose Escalation Results ............................................................................ 19 
1.4.2 
Weekly Dosing:  Recommended Phase II Dosing of the Weekly Regimen (RP2D-QW) Cohort 
Results 20 
1.4.3 
Daily Dosing:  Dose Escalation Results ................................................................................ 21 
1.4.4 
Preliminary Pharmacokinetic Data from First-in-human IMCgp100-01 Study ................... 21 
2 
Rationale ............................................................................................................................................ 23 
2.1 
Study Rationale and Purpose ...................................................................................................... 23 
2.2 
Rationale for Study Design .......................................................................................................... 23 
2.3 
Rationale for Treatment Dose and Regimen .............................................................................. 23 
2.4 
Rationale for Treatment Beyond Initial Progression in Select Settings ...................................... 24 
3 
Study Design ....................................................................................................................................... 25 
3.1 
Description of Study Design and Populations ............................................................................. 25 
3.2 
Definition of Study Periods ......................................................................................................... 25 
3.3 
Definition of End of Treatment ................................................................................................... 26 


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3.4 
Definition of End of Study ........................................................................................................... 26 
3.5 
Early Study Termination .............................................................................................................. 26 
4 
Study Objectives and Endpoints ......................................................................................................... 28 
4.1 
Primary Objective........................................................................................................................ 28 
4.2 
Secondary Objectives .................................................................................................................. 28 
4.3 
Primary Endpoint ........................................................................................................................ 28 
4.4 
Secondary Endpoints .................................................................................................................. 28 
5 
Population Selection Criteria.............................................................................................................. 30 
5.1 
Patient Population ...................................................................................................................... 30 
5.2 
Inclusion Criteria ......................................................................................................................... 30 
5.3 
Exclusion Criteria ......................................................................................................................... 30 
6 
Study Treatments and Administration ............................................................................................... 32 
6.1 
Study Treatment ......................................................................................................................... 32 
6.2 
Concomitant Therapy ................................................................................................................. 33 
6.2.1 
Permitted Concomitant Therapy ........................................................................................ 33 
6.2.2 
Permitted Concomitant Therapy Requiring Caution .......................................................... 33 
6.2.3 
Prohibited Concomitant Therapy ........................................................................................ 34 
6.3 
Patient Numbering and Treatment Assignment ......................................................................... 34 
6.3.1 
Patient Numbering .............................................................................................................. 34 
6.3.2 
Treatment Assignment  ....................................................................................................... 34 
6.4 
Study Drug Preparation and Dispensation .................................................................................. 34 
6.4.1 
Packaging and Labeling of Study Drug(s) ............................................................................ 35 
6.4.2 
Study Drug Compliance and Accountability ........................................................................ 35 
6.4.3 
Drug Supply, Storage, and Disposal .................................................................................... 35 
6.5 
Management and Follow-up of Toxicity ..................................................................................... 35 
6.6 
Treatment Discontinuation ......................................................................................................... 39 
6.6.1 
Criteria for Treatment Beyond Initial RECIST v.1.1 Disease Progression ............................ 39 
6.7 
Contraception ............................................................................................................................. 40
7 
Study Schedule and Assessments ...................................................................................................... 42


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7.1 
Screening Procedures and Assessments ..................................................................................... 42 
7.1.1 
Screening Assessments ....................................................................................................... 45 
7.2 
Treatment, Treatment Discontinuation, and Follow-up Phases ................................................. 45 
7.2.1 
Treatment Period ................................................................................................................ 45 
7.2.2 
Discontinuation of Study Treatment ................................................................................... 45 
7.2.3 
90-day Safety Follow-up Period .......................................................................................... 46 
7.2.4 
Survival Follow-up Period ................................................................................................... 46 
7.2.5 
Lost to Follow-up ................................................................................................................ 46 
7.3 
Safety and Tolerability Assessments ........................................................................................... 47 
7.3.1 
Physical Examination ........................................................................................................... 47 
7.3.2 
Vital Signs ............................................................................................................................ 47 
7.3.3 
Height and Weight .............................................................................................................. 48 
7.3.4 
Laboratory Evaluations ....................................................................................................... 48 
7.3.5 
Immunogenicity Assessments ............................................................................................. 49 
8 
Adverse Events and Safety Reporting ................................................................................................ 50 
8.1 
Assessment of Safety .................................................................................................................. 50 
8.1.1 
Definitions ........................................................................................................................... 50 
8.2 
Criteria for Expectedness ............................................................................................................ 51 
8.3 
Assessment of Causality .............................................................................................................. 52 
8.3.1 
Causality Assessment Required for All Adverse Events ...................................................... 52 
8.4 
Adverse Event Reporting ............................................................................................................ 52 
8.4.1 
Expedited Reporting ........................................................................................................... 52 
8.4.2 
Standards for Expedited Reporting ..................................................................................... 53 
8.4.3 
Reporting of Out-of-range Laboratory Test Results as Adverse Events.............................. 53 
8.4.4 
Reporting Guidelines for Other Observations .................................................................... 53 
8.4.5 
Pregnancy Reporting ........................................................................................................... 54 
8.5 
Investigator’s Responsibilities ..................................................................................................... 54
8.6
Sponsor and Clinical Research Organization’s Responsibilities .................................................. 55
9 
Statistical Methods and Data Analyses .............................................................................................. 56 


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9.1 
General Principles ....................................................................................................................... 56 
9.2 
Analysis Sets ................................................................................................................................ 56 
9.2.1 
Full Analysis Set ................................................................................................................... 56 
9.2.2 
Safety Analysis Set .............................................................................................................. 56 
9.3 
Patient Demographics and Other Baseline Characteristics ........................................................ 56 
9.4 
Treatment Data ........................................................................................................................... 56 
9.5 
Primary Analysis .......................................................................................................................... 57 
9.5.1 
Variables .............................................................................................................................. 57 
9.6 
Secondary Analyses ..................................................................................................................... 57 
9.6.1 
Safety .................................................................................................................................. 57 
9.7 
Exploratory Analyses ................................................................................................................... 58 
9.7.1 
Overall Survival ................................................................................................................... 58 
9.7.2 
Immunogenicity—Exposure and/or Adverse Event Relationship ....................................... 58 
9.8 
Interim Analysis ........................................................................................................................... 58 
9.9 
Sample Size Calculation .............................................................................................................. 59 
10 
Data Handling and Management ....................................................................................................... 60 
10.1 
Data Confidentiality .................................................................................................................... 60 
10.2 
Site Monitoring ........................................................................................................................... 60 
10.3 
Data Collection ............................................................................................................................ 60 
10.4 
Database Management ............................................................................................................... 61 
11 
Ethical Considerations and Administrative Procedures ..................................................................... 62 
11.1 
Regulatory and Ethical Compliance ............................................................................................ 62 
11.2 
Responsibilities of the Investigator and Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board ......................................................................................................... 62 
11.3 
Informed Consent Procedures .................................................................................................... 63 
11.4 
Discontinuation of the Study ...................................................................................................... 63 
11.5 
Publication of Study Protocol and Results .................................................................................. 63 
11.6 
Study Documentation, Record Keeping, and Retention of DocumentsError! 
Bookmark 
not 
defined. 


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11.7 
Confidentiality of Study Documents and Patient Records .......................................................... 63 
11.8 
Audits and Inspections ................................................................................................................ 63 
11.9 
Financial Disclosures ................................................................................................................... 63 
12 
References .......................................................................................................................................... 64 
 


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LIST OF TABLES
Table 2-1 
Maximum Dose and Schedule of Administration Based Upon Parent Study..........................23
Table 4-1     Objectives and Related Endpoints ........................................................................................... 28 
Table 6-1 
Dose and Treatment Schedule ................................................................................................ 32 
Table 6-2 
Recommended Dose Modifications by Toxicity Grade for Study Medications ...................... 36 
Table 7-1      Schedule of Study Assessments ............................................................................................. 43 
Table 7-3 
Local Clinical Laboratory Parameters Collection Plan ............................................................. 48 




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Principal Investigator Signature
I, the undersigned, have reviewed the amended protocol, including the appendices, and I will conduct the 
clinical study as described and will adhere to the tripartite International Conference on Harmonization 
guideline E6 (R1): Guideline for Clinical Practice and all the ethical and regulatory considerations stated.  
I have read and understood the contents of the Investigator’s Brochure for IMCgp100. 
 
     
 
 
 
 
 
 
  
 
 
Institution Name 


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PROTOCOL SYNOPSIS
Study Number
IMCgp100-401
Title 
An Open-label, Multi-center, Rollover Study in Patients with Advanced 
Melanoma After Completing an IMCgp100 Clinical Study 
Brief Title 
IMCgp100-401 Rollover Study 
Sponsor 
Immunocore, Ltd. 
Investigational Agents 
IMCgp100 administered on a weekly (QW) basis. 
Study Type 
Interventional 
Study Purpose and 
Rationale 
IMCgp100-401 is a rollover study that is designed to provide continued 
access to IMCgp100 for eligible patients with advanced melanoma who 
have previously participated in an IMCgp100 study (parent study). 
Parent studies that are eligible for patients to continue to receive 
IMCgp100 in this rollover study must have completed and satisfied its 
primary endpoints or have been terminated by the Sponsor for reasons 
other than safety.   
Eligible patients will have tolerated IMCgp100 for a minimum of 4 weeks 
of dosing without significant toxicities that would preclude further 
dosing in the opinion of the principal investigator or Sponsor and have 
no evidence of unequivocal progressive disease.   
The rollover study will provide continued access to IMCgp100 for all 
patients treated on a completed IMCgp100 clinical study for whom 
there is evidence of continued benefit from treatment with IMCgp100 
and for whom alternative therapies are not available. Patients will enroll 
in the IMCgp100 rollover study and the principal investigator and 
Sponsor will determine the regimen and dose for patients to receive in 
the rollover using guidance from the previous (parent study).   
Primary Objective 
The primary objective is to determine the number of patients with 
adverse events (AEs) associated with IMCgp100 treatment. 


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Secondary Objectives
To characterize the long-term safety (> 1 year dosing) and 
tolerability profile associated with treatment with IMCgp100 
To evaluate the incidence of anti-IMCgp100 antibody formation 
following multiple infusions of IMCgp100 
To estimate the overall survival (OS) in patients treated with 
IMCgp100 
Study Design 
This rollover study will enroll patients who are currently receiving 
IMCgp100 treatment and for whom the parent IMCgp100 clinical study 
completes.  At the time of parent study completion, the rollover study 
will enroll all patients actively receiving IMCgp100 treatment in the 
parent study in order to continue to provide patient access to 
treatment.  Patients who enroll in the rollover study will, in the opinion 
of the investigator, continue to receive clinical benefit from treatment 
with IMCgp100.  Patients who are receiving treatment as part of an 
ongoing and not yet completed study, are not eligible to participate in 
the rollover study until the time of study completion. 
At the time of rollover study entry, patients can continue to receive the 
current dose from the parent study or an alternative dose can be 
implemented with written agreement from the Sponsor.  Doses higher 
than that in the parent in study will not be permitted.  
For patients from the IMCgp100-01 parent study the maximum 
dose will be the recommended Phase II dose (50 mcg flat dose)  
All patients must sign the rollover study consent form and be enrolled 
in the new study.  All assessments will commence with Rollover Cycle 1.  
Safety assessments (physical examinations, clinical laboratory, 
electrocardiogram (ECG) assessments, and continuous monitoring of 
AEs) will continue throughout the study at the described intervals.  
Patients will continue to receive IMCgp100 until loss of clinical benefit 
for the individual patient (as per local imaging with a minimum  interval 
of 12 weeks and the protocol-specified response criteria), unacceptable 
toxicity as defined by the principal investigator or Sponsor, withdrawal 
of consent, loss to follow up, or death. 
No efficacy or biomarker endpoints will be collected as part of the 
rollover study.  Date of death will be collected to assess overall survival 
(OS) only. Imaging of disease will continue as described in the study 


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protocol using modified immune-related Response Evaluation Criteria 
in Solid Tumors (irRECIST).  
Population Under 
Study 
The rollover study will enroll patients who have been treated as part of 
an IMCgp100 clinical study that has completed.  At the time of rollover 
study entry, patients must be continuing to receive IMCgp100 as part of 
the active parent study and for whom the study is completing.  Patients 
must not have any ongoing, serious IMCgp100-related toxicities at the 
time of rollover study entry that would preclude further dosing in the 
opinion of the investigator or the Sponsor.     
Inclusion Criteria 
1.
Patient is currently participating in an Immunocore-sponsored 
study of IMCgp100 and is actively receiving IMCgp100. Patient must 
have fulfilled all required assessments in the parent study (unless 
the study is being terminated) 
2.
Patient is currently receiving clinical benefit from the treatment 
with IMCgp100, as determined by the principal investigator from 
the parent study 
3.
Patient has demonstrated compliance with the parent study 
requirements, as assessed by the principal investigator and patient 
is able to comply with the necessary visits and assessments as part 
of the rollover study  
4.
Written informed consent must be obtained prior to enrolling in the 
roll-over study and receiving study treatment. If consent cannot be 
expressed in writing, it must be formally documented and 
witnessed, ideally via an independent trusted witness 
Exclusion Criteria 
1.
Patient has been permanently discontinued from any IMCgp100 
study or from IMCgp100 treatment in the parent study due to  
unequivocal progressive disease, unacceptable toxicity, non-
compliance to study procedures, withdrawal of consent, or any 
other reason 
2.
Pregnant or nursing (lactating) women, where pregnancy is defined 
as the state of a female after conception and until the termination 
of gestation, confirmed by a positive human chorionic gonadotropin 
laboratory test 
3.
Women of child-bearing potential who are sexually active with a 
non-sterilized male partner, defined as all women physiologically 
capable of becoming pregnant, unless they are using 2 methods of 


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highly effective contraception from Screening, and must agree to 
continue using such precautions for 6 months after the final dose of 
investigational product; cessation of birth control after this point 
should be discussed with a responsible physician.  Highly effective 
methods include barrier methods, intrauterine devices,
or 
hormonal methods. Periodic abstinence, the rhythm method, and 
the withdrawal method are not acceptable methods of birth 
control.  Women of child-bearing potential must have a negative 
serum pregnancy test at Screening.  Otherwise, female patients 
must be post-menopausal (no menstrual period for at least 12 
months prior to Screening), or surgically sterile
4.
Male patients who are not surgically sterile unless they are using a 
double barrier contraception method from enrollment through 
treatment and for 6 months following administration of the last 
dose of study drug 
Efficacy Assessments 
No efficacy assessments will be collected in this rollover study.  Patients 
will be assessed for tumor progression using protocol-specified 
modified irRECIST criteria at a minimum of every 12 weeks.    
Safety Assessments 
Safety will be monitored by assessing physical examination, vital signs, 
body height and weight, hematology, chemistry, pregnancy, ECG, 
cytokine testing, as well as collecting of the AEs at every visit. 
Keywords 
IMCgp100, melanoma, gp100, rollover 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation 
Term
AE
Adverse event
AESI 
Adverse event of special interest 
Anti-CD3 
Anti-cluster of differentiation 3
C#D# 
Cycle # day # 
CD3 
Cluster of differentiation 3 
Cmax 
Maximum observed concentration 
CRO 
Contract research organization 
CTL 
Cytotoxic T lymphocyte 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOT 
End of treatment 
FAS 
Full analysis set 
GCP 
Good clinical practice
HLA-A2
Human leukocyte antigen-A2 
ICF
Informed consent form
ICH 
International Conference on Harmonization 
IEC
Independent Ethics Committee
IMCgp100 
77 kDa bi-specific protein 
IRB 
Institutional Review Board 
irRECIST
Immune-related response evaluation criteria in solid tumors
IV 
Intravenous 
kD
Binding affinity
MTD 
Maximum tolerated dose 
nM 
Nanomolar 
NCI CTCAE 
National Cancer Institute common terminology criteria for adverse events 
NSAID 
Non-steroidal anti-inflammatory drug. 
OS
Overall survival 
PD 
Progressive disease 
PK
Pharmacokinetics
pM 
Picomolar 
QD 
Every day 
QW 
Every week 
RC# 
Rollover cycle # 


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REB
Research ethics board
RECIST
Response evaluation criteria in solid tumors
RP2D
Recommended Phase II dose
RP2D-QD 
Recommended Phase II dose – daily 
RP2D-QW 
Recommended Phase II dose — weekly 
SAE 
Serious adverse event 
SUSAR 
Suspected, unexpected, serious adverse reaction 
t½
Distribution and elimination half-life 
T½
Terminal binding half-life 
UM 
Uveal melanoma


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1
BACKGROUND
1.1
Overview of Disease Setting
Melanoma arises from pigment containing cells (melanocytes) present in the skin, eye, and mucus 
membranes.  Melanoma most frequently occurs in the skin; however, ocular melanoma arises from 
pigmented cells in the eye. The primary cause of melanoma is thought to be radiation-induced 
deoxyribonucleic acid damage from ultraviolet light exposure.  Melanoma is the most deadly of skin 
cancers.  Globally, in 2012, melanoma occurred in 232,000 people and resulted in 55,000 deaths. It is 
estimated that almost 76,000 new diagnoses of melanoma will be made in 2016 in the United States, and 
approximately 10,000 people are expected to die of melanoma (American Cancer Society, 2016).  In 
addition, the rate of diagnosis of melanoma continues to rise at a significant rate; according to 2013 
Surveillance, Epidemiology, and End Results data, the average incidence rate rose 1.4% each year for the 
last decade, and melanoma is now the sixth most common cancer diagnosis in the United States 
(Surveillance, Epidemiology, and End Results, 2015).  Cutaneous and uveal melanoma (UM) is more 
common in men than women.  UM is a rare type of melanoma where the incidence has ranged from 5.3 
to 10.9 cases per million (Singh, 2003). 
1.2
Overview of IMCgp100
IMCgp100 is a 77 kDa bi-specific protein with targeting and effector moieties which is manufactured in 
Escherichia coli, E coli.  The targeting portion of IMCgp100 (the T cell receptor) functions to bind to the 
gp100 antigen as presented by major histocompatibility complex Class I on the surface of melanoma cells.  
The targeted gp100 peptide is presented by a subset of the population that express a specific variant of 
the major histocompatibility complex Class I complex known as human leukocyte antigen-A2 (HLA-A2).  
This variant is carried by approximately 50% of the population in the Western World (Middleton, 2003). 
The effector function (anti-cluster of differentiation 3 [anti-CD3]) works by binding and activating T cells 
via cluster of differentiation 3 (CD3).  These T cells can be tumor-specific cells which are already resident 
in the tumor (tumor infiltrating lymphocytes), 
 
 
 
 
 
 
 
  


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1.3
Non-clinical Experience with IMCgp100
1.3.1
Pre-clinical Pharmacology Summary
IMCgp100 has been shown to induce the full repertoire of cytotoxic T lymphocyte (CTL) activation events 
in a dose-dependent manner in vitro when combined with target melanoma cells.  
 
 
 
 
he activation of CD4 T cells has also been demonstrated at similar concentrations and with similar 
kinetics.  Such activation would be expected to augment the CTL-mediated immune response through the 
recruitment of other inflammatory cells.  
Using peripheral blood mononuclear cells from melanoma patients, IMCgp100 has been shown to 
augment an already present anti-tumoral response. Finally, the tumor infiltrating T cells that would be the 
first line of attack in a clinical situation would be expected to be outnumbered by melanoma targets; 
therefore, a single T cell is capable of serial killing in vitro.  
These data demonstrate that IMCgp100 is a potent tumor-killing agent. 
1.3.2
Non-clinical Toxicology Summary
Both the gp100-specific soluble T cell receptor and the CD3 targeting ends of IMCgp100 have been 
demonstrated to have high specificity for the human HLA-A2-gp100 peptide complex and human CD3.  
Therefore, binding and activation of IMCgp100 cannot be demonstrated in non-human primates, which 
show a relatively high degree of sequence homology to human CD3.  In addition, both the T cell receptor 
targeting end and CD3 activation arm do not interact at any level in any other species.  Given the 
limitations in binding of IMCgp100 and activation of any T cell subsets in any standard toxicology species, 
there is no relevant toxicology species in which IMCgp100 can be tested. 
Tissue cross-reactivity studies with IMCgp100 and published gp100 immunohistochemistry demonstrate 
gp100 expression in human melanocytes, and expression levels have been demonstrated directly in the 
retina, melanocytes, the substantia nigra, and the thymus (Takase, 2005; Wagner, 1997).  
 
 
 
 
 
 
 
 


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1.4
Clinical Program and Safety Summary
IMCgp100 is being studied in an ongoing first-in-human, open-label, dose escalation study (IMCgp100-
01).  Patients with advanced melanoma were enrolled into 2 separate dose escalation cohorts: (1) a 
weekly (QW) dosing regimen cohort, and (2) a daily (QD) dose x 4 days repeated every 3 weeks dosing 
regimen cohort.  The study was designed to identify the maximum tolerated dose (MTD) or recommended 
Phase II dose (RP2D) of IMCgp100 in the 2 repeat dosing regimens: (1) weekly dosing (the RP2D-QW) and 
(2) daily dosing x 4 days (the RP2D-QD).   
1.4.1
Weekly Dosing:  Dose Escalation Results
The weekly dosing regimen dose escalation included dose levels from 5 ng/kg up to 900 ng/kg, and the 
MTD for this dosing regimen was identified at 600 ng/kg QW (Middleton, 2015).  In the review of the 
safety and pharmacokinetic (PK) data for the weekly dosing regimen, the RP2D-QW was initially identified 
as a flat dose of 50 mcg administered intravenously (IV) on a weekly basis; 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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Cytokine analyses of the peripheral circulation combined with clinical findings in patients treated with 
weekly dosing revealed rare cases of severe, systemic cytokine release syndrome. As a consequence of 
on-target skin or tumor activity, with consequential cytokines permeating into the periphery, many 
patients showed modest, drug-induced levels of 1 or more inflammatory cytokines 
 
 
 
   
Please refer to the current IMCgp100 Investigator’s Brochure for details.   
1.4.2
Weekly Dosing:  Recommended Phase II Dosing of the Weekly Regimen (RP2D-QW) 
Cohort Results
A review of the PK and safety data from the QW dose escalation cohorts suggested that the more severe 
toxicities and higher drug exposures of IMCgp100 were associated with the higher absolute doses 
administered.  Based on these data and the range of absolute doses administered at the MTD of 600 ng/kg 
(n=5 pts, range 34–66 mcg QW, median dose of 54 mcg), the RP2D-QW was initially determined to be a 
flat dose of 50 mcg administered on a weekly basis.  
 
 


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1.4.3
Daily Dosing:  Dose Escalation Results
The dose escalation in the daily dosing regimen Phase I arm (Arm 2) is complete with the dosing regimen 
identified as a flat dose of 50 mcg QDx4 administered every 3 weeks (n=15 patients across 5 dose levels 
ranging from 10 mcg to 50 mcg).  
 
   
For further details refer to the most recent version of the IMCgp100 Investigator’s Brochure. 
1.4.4
Preliminary Pharmacokinetic Data from First-in-human IMCgp100-01 Study
 
 
 
 
 
 
  
 
 
   


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. 
For detailed information regarding PK data of IMCgp100, refer to the IMCgp100 Investigator’s Brochure. 
 


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2
RATIONALE
2.1
Study Rationale and Purpose
IMCgp100-401 is a rollover study that is designed to provide continued access to IMCgp100 for eligible 
patients with advanced melanoma who have previously participated in an IMCgp100 study (parent study).  
Parent studies that are eligible for patients to continue to receive IMCgp100 in this rollover study must 
have completed and satisfied its primary endpoints or have been terminated by the Sponsor for reasons 
other than safety.   
Eligible patients for the rollover study will have tolerated IMCgp100 for a minimum of 4 weeks of dosing 
without significant toxicities that would preclude further dosing in the opinion of the principal investigator 
or of the Sponsor and have no evidence of unequivocal progressive disease (PD).      
2.2
Rationale for Study Design
The rollover study will provide continued access to IMCgp100 for all patients treated on a completed 
IMCgp100 clinical study for whom there is evidence of continued benefit from treatment with IMCgp100 
and for whom alternative therapies are not available.  Patients will enroll in the IMCgp100 rollover study 
and the principal investigator and Sponsor will determine the regimen and dose for patients to receive in 
the rollover using guidance from the previous (parent study).   
Please see Section 2.3 below for dose and regimen details.   
2.3
Rationale for Treatment Dose and Regimen 
Patients enrolled in this rollover study will enter this study with a defined dose and regimen from the 
parent study.  Patients can continue to receive the current dose and regimen from the parent study (Table 
2-1) or an alternative dose can be implemented with written agreement from the Sponsor.  Doses higher 
than that administered in the parent in study will not be permitted.  
For patients from the IMCgp100-01 parent study the maximum dose will be the RP2D flat dose 
(50 mcg) 
Table 2-1 Maximum Dose and Schedule of Administration Based Upon Parent 
Study
Study Protocol
Maximum IMCgp100 Dose and Frequency of 
Administration
IMCgp100-01
50 mcg IV weekly (QW)


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2.4
Rationale for Treatment Beyond Initial Progression in Select Settings
There is accumulating evidence in the field of immune-oncology that some patients treated with immune 
therapy agents, such as IMCgp100, may develop initial progression of the tumor, as evidenced on 
computed tomography (CT) or magnetic resonance imaging (MRI), before demonstrating meaningful 
clinical benefit from the treatment with disease stabilization or subsequent objective response after the 
initial progression is noted (Hodi, 2016).  Such cases were noted in the Phase I development of IMCgp100 
(Middleton, 2015; Middleton, 2016). In light of these data, patients who demonstrate an initial 
progression by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 may continue to receive study 
treatment with IMCgp100 until further progression under the management principles of immune-related 
response criteria (irRECIST) criteria (where a second, confirmatory scan is required for confirmation of 
progression) provided that such patients are assessed by the investigator as deriving clinical benefit from, 
and tolerating treatment with IMCgp100 (Eisenhauer, 2009; Wolchok, 2009).  See Section 6.6.1 for details 
regarding criteria for treatment with IMCgp100 beyond initial progression by RECIST v1.1.   


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3
STUDY DESIGN
3.1
Description of Study Design and Populations
This is a study of IMCgp100 conducted to provide continued access to IMCgp100 treatment for patients 
enrolled in a completed clinical study of IMCgp100.  Patients enrolled in the rollover study must be 
currently receiving IMCgp100 within an IMCgp100 clinical study that has completed.  Patients must meet 
all selection criteria defined in this rollover study Section 5.  Patients do not need to be re-assessed against 
the parent study entry criteria at the time of enrollment in the rollover study.  
This rollover study will enroll patients who are currently receiving IMCgp100 treatment and for whom the 
parent IMCgp100 clinical study completes.  At the time of parent study completion, the rollover study will 
enroll all patients actively receiving IMCgp100 treatment in the parent study in order to continue to 
provide patient access to treatment.  Patients who enroll in the rollover study will, in the opinion of the 
investigator, continue to receive clinical benefit from treatment with IMCgp100.  Patients who are 
receiving treatment as part of an ongoing, and not yet completed, study are not eligible to participate in 
the rollover study until the time of study completion. 
At the time of rollover study entry, patients can continue to receive the current dose from the parent 
study or an alternative dose can be implemented with written agreement from the Sponsor.  Doses higher 
than that in the parent in study will not be permitted.  
For patients from the IMCgp100-01 parent study the maximum dose will be the RP2D flat dose 
(50 mcg)  
See Table 6-1 in Section 6.1 Study Treatment details in the rollover study.  All patients must sign the 
rollover study consent form and be enrolled in the new study.  All assessments will commence with 
Rollover Cycle 1.  Safety assessments (physical examinations, clinical laboratory, and electrocardiogram 
[ECG] assessments, as well as continuous monitoring of AEs) will continue throughout the study at the 
described intervals.  Patients will continue to receive IMCgp100 until loss of clinical benefit for the 
individual patient (Section 6.6.1), unacceptable toxicity as defined by the principal investigator or Sponsor, 
withdrawal of consent, loss to follow-up, or death.  
No efficacy or biomarker assessments will be collected as part of the rollover study.  Date of death will be 
collected to assess overall survival (OS) only.  Patients will be assessed for tumor progression using 
protocol-specified modified immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) with  
a minimum interval of imaging of every 12 weeks.    
3.2
Definition of Study Periods
The Screening Period will begin once a patient has signed the consent form and concludes with either a 
screen failure decision or initiation of study dosing on Rollover C1D1 (RC1D1).  During the Screening 


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Period, patients are evaluated against the study inclusion and exclusion criteria (see Section 5 Population 
Selection Criteria). The screening window for all procedures will be up to 21 days.  Please note, if the last 
dose of IMCgp100 on the parent study and the first dose of IMCgp100 on the rollover study are separated 
by more than 21 days, the first dose of IMCgp100 must be administered with overnight inpatient 
monitoring; given the risk of severe infusion-related toxicity and potential for hypotension (refer to 
Section 1.4 for details of clinical experience with IMCgp100).
The Treatment Period will begin with the first treatment in the first cycle with RC1D1.  For the purpose of 
treatment scheduling, a cycle consists of 4 weeks.   The Treatment Period consists of the time from RC1D1 
until the end of study treatment.  
The 90-day Safety Follow-up Period consists of the time from the last dose of study medication for a 
period of 90 days.  Safety observations during this 90-day Follow-up Period are outlined in Section 7.2.3
and include reporting of all AEs and all serious AEs (SAEs) in the same manner as the Treatment Period. 
The Survival Follow-up Period will initiate after the 90-day Follow-up Period and continue until death.  As 
applicable, all patients will be followed for survival until the end of the study is reached.   
3.3
Definition of End of Treatment
In all patients in this study, IMCgp100 will be administered IV according to the defined regimen.  Patients 
will continue to receive IMCgp100 until loss of clinical benefit for the individual patient (as per local 
imaging standard of care and the appropriate response criteria, as defined by the principal investigator), 
unacceptable toxicity as defined by the principal investigator or Sponsor, withdrawal of consent, loss to 
follow-up, or death. 
3.4
Definition of End of Study
The end of the study will be when all patients enrolled have completed IMCgp100 treatment or the study 
is terminated by the Sponsor.   
3.5
Early Study Termination
The study can be terminated at any time for any reason by the Sponsor.  Should this be necessary, any 
ongoing patient should be seen as soon as possible for end of treatment (EOT) visit and the assessments 
should be performed as described in Table 7-1.  
The investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. Under guidance of the 
Sponsor, the investigator will be responsible for informing the Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) of the termination of the trial. 


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4
STUDY OBJECTIVES AND ENDPOINTS
4.1
Primary Objective
The primary objective is to determine the number of patients with AEs associated with IMCgp100 
treatment.  
4.2
Secondary Objectives
To characterize the long-term safety (> 1 year dosing) and tolerability profile associated with 
treatment with IMCgp100 
To evaluate the incidence of anti-IMCgp100 antibody formation following multiple infusions of 
IMCgp100 
To estimate the OS of patients treated with IMCgp100 
4.3
Primary Endpoint
The primary endpoint is incidence of AEs associated with IMCgp100. 
4.4
Secondary Endpoints
Tolerability:  Dose interruptions, reductions, and dose intensity of IMCgp100 
Assessments of anti-IMCgp100 antibody formation 
Date of death in all patients treated with IMCgp100 
 
Table 4-1 Objectives and Related Endpoints
Objective(s)
Endpoint(s)
Primary
To determine the number of patients with 
adverse events associated with IMCgp100 
treatment
Incidence of adverse events
Secondary 
To characterize the long-term safety (> 1 year 
dosing) and tolerability of IMCgp100   
Tolerability: Dose interruptions, reductions, and 
dose intensity of IMCgp100


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Table 4-1 Objectives and Related Endpoints
Objective(s)
Endpoint(s)
To evaluate the incidence of anti-IMCgp100 
antibody formation following multiple infusions 
of IMCgp100
Assessments of anti-IMCgp100 antibody 
formation
To estimate the overall survival in patients 
treated with IMCgp100
Date of death in all patients treated with 
IMCgp100


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5
POPULATION SELECTION CRITERIA
5.1
Patient Population
This rollover study will enroll patients who have been treated as part of an IMCgp100 clinical study that 
has completed.  At the time of rollover study entry, patients must be continuing to receive IMCgp100 as 
part of the active parent study and for whom the study is completing.  Patients must not have any ongoing, 
serious IMCgp100-related toxicities at the time of rollover study entry that would preclude further dosing 
in the opinion of the investigator or the Sponsor.   
5.2
Inclusion Criteria
Patients eligible for inclusion in this study must meet all of the following criteria: 
1.
Patient is currently participating in an Immunocore-sponsored study of IMCgp100 and is actively 
receiving IMCgp100.  Patient must have fulfilled all required assessments in the parent study 
(unless the study is being terminated) 
2.
Patient is currently receiving clinical benefit from the treatment with IMCgp100, as determined 
by the principal investigator from the parent study 
3.
Patient has demonstrated compliance with the parent study requirements, as assessed by the 
principal investigator and patient is able to comply with the necessary visits and assessments as 
part of the rollover study 
4.
Written informed consent must be obtained prior to enrolling in the rollover study and receiving 
the study treatment. If consent cannot be expressed in writing, then the consent must be formally 
documented and witnessed, ideally via an independent trusted witness 
5.3
Exclusion Criteria
Patients eligible for this study must not meet any of the following criteria: 
1.
Patient has been permanently discontinued from any IMCgp100 study or from IMCgp100 
treatment in the parent study due to  unequivocal PD, unacceptable toxicity, non-compliance to 
study procedures, withdrawal of consent, or any other reason 
2.
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human chorionic 
gonadotropin laboratory test 


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3.
Women of child-bearing potential who are sexually active with a non-sterilized male partner, 
defined as all women physiologically capable of becoming pregnant, unless they are using 2 
methods of highly effective contraception from Screening, and must agree to continue using such 
precautions for 6 months after the final dose of investigational product; cessation of birth control 
after this point should be discussed with a responsible physician.  Highly effective methods include 
barrier methods, intrauterine devices or hormonal methods. Periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of birth control.  Women of 
child-bearing potential must have a negative serum pregnancy test at Screening.  Otherwise, 
female patients must be post-menopausal (no menstrual period for at least 12 months prior to 
Screening), or surgically sterile 
4.
Male patients who are not surgically sterile unless they are using a double barrier contraception 
method from enrollment through treatment and for 6 months following administration of the last 
dose of study drug 
 


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6
STUDY TREATMENTS AND ADMINISTRATION
6.1
Study Treatment
For this study, the investigational drug refers to IMCgp100. Study drug will be supplied by the Sponsor, 
Immunocore. 
All dosages prescribed and dispensed to patients and all dose changes during the study must be recorded 
on the Dosage Administration Record electronic case report form (eCRF). 
 
For all study medication administration, a physician must be present at the site or immediately available 
to respond to emergencies during all administrations of all study medications. Fully functional 
resuscitation facilities should be available.  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Table 6-1 
Dose and Treatment Schedule
Study
Treatment
Pharmaceutical Form 
and Route of 
Administration
Dose
Frequency and/or 
Regimen
IMCgp100
Weekly


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. 
6.2
Concomitant Therapy
6.2.1
Permitted Concomitant Therapy
Concomitant medications and therapies deemed necessary for the supportive care and safety of the 
patient are allowed in general.  Examples include anti-diarrheal medications, anti-emetics, or electrolyte 
supplementation.   
Patients must be told to notify the investigational site staff about any new medications, herbal remedies, 
or dietary supplements that he or she takes after the start of the study treatment, regardless of treatment 
duration. All concomitant medications and significant non-drug therapies (including physical therapy, 
herbal or natural medications, and blood transfusions) administered during the study must be listed on 
the Concomitant Medications or other relevant eCRF.  
IV hydration required to manage toxicity associated with any of the study treatments (eg, hypotension) 
should be recorded in the Concomitant Medications eCRF.  IV hydration prior to administration of study 
treatments does not need to be recorded in the eCRF unless fluids are prescribed to manage toxicity. 
6.2.2
Permitted Concomitant Therapy Requiring Caution
Anti-coagulant therapy is permitted if the patients are already at stable doses of warfarin or stable doses 
of low molecular weight heparin for > 2 weeks at time of first dose.  International normalized ratio should 
be monitored as clinically indicated per investigator’s discretion.  
Anti-hypertensives are allowed as concomitant medications; however, because transient hypotension has 
previously occurred during infusions of IMCgp100 and monoclonal antibodies, 
 
  


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6.2.3
Prohibited Concomitant Therapy
During the course of the study, patients may not receive other additional investigational drugs, agents, 
devices, anti-neoplastic therapy, or any other therapies that may be active against cancer. Additionally, 
no other therapeutic monoclonal antibodies and no immunosuppressive medication may be administered 
while on this study.  
 
  
 
 
 
 
 
6.3
Patient Numbering and Treatment Assignment
6.3.1
Patient Numbering
Each patient is identified in the study by a number that is assigned when the patient is first enrolled for 
Screening. The patient number is retained as the primary identifier for the patient throughout 
participation in the trial. The patient number consists of the center number assigned by the Sponsor and 
a sequential patient number suffix so that each patient is numbered uniquely across the entire database. 
Patient numbers will be assigned by the Sponsor at the time of Screening.  
The subject number, patient ID along, with the last IMCgp100 dose and date of last dose from the parent 
study will be captured in the relevant eCRF for the rollover study. 
6.3.2
Treatment Assignment 
Patients enrolled in the rollover study will be assigned to the dosing regimen (please refer to Table 6-1, 
Section 6.1 Study Treatment) based upon the parent protocol in which the patient was enrolled and 
treated.  
6.4
Study Drug Preparation and Dispensation
Further instructions for the preparation and dispensation of IMCgp100 are described in the Study 
Pharmacy Manual.  See Section 6.1 Study Treatment for details.   
All dosages prescribed to the patient and all dose changes during the study must be recorded on the 
Dosage Administration Record eCRF. 


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6.4.1
Packaging and Labeling of Study Drug(s)
Further instructions for the preparation and dispensation of IMCgp100 are described in the Study 
Pharmacy Manual.  See Section 6.1 Study Treatment for details.  
All dosages prescribed to the patient and all dose changes during the study must be recorded on the 
Dosage Administration Record eCRF. 
6.4.2
Study Drug Compliance and Accountability
Study treatment will be administered to the patient by the trained study site staff at the study sites. 
Compliance with the prescribed regimen will be assured by administration of the study treatment under 
the supervision of investigator or his/her designee. 
The investigator or designee must maintain an accurate record of the shipment and dispensing of study 
treatment according to local institutional drug accountability processes. Drug accountability will be noted 
by the field monitor during site visits and at the completion of the study. At study close-out, and, as 
appropriate during the course of the study, the investigator will return all used and unused study 
treatment, packaging, drug labels, and a copy of the completed drug accountability log to the site study 
monitor.   
6.4.3
Drug Supply, Storage, and Disposal
Study treatments must be received by designated personnel at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated site personnel 
have access. Upon receipt, IMCgp100 supply should be recorded and stored according to the instructions 
specified on the drug labels. 
All IMCgp100 supply remaining at the end of the study, following appropriate drug accountability 
procedures at each site can be destroyed per local institutional practice at the study site or at a third party 
vendor as appropriate and agreed with Sponsor.  Used vials can be discarded according to local procedures 
and recorded in the accountability log.  Unused vials (after expiry or at the end of study) must be disposed 
of only after agreement from Sponsor and a certificate of destruction must be retained within the 
pharmacy binder.   
6.5
Management and Follow-up of Toxicity
Patients whose study treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed-up at least once a week (or more if clinically indicated) for 
4 weeks, and subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first.  Appropriate clinical experts should be consulted as deemed necessary for any AEs 


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observed in the course of the trial. In the case of a toxicity suspected to be related to a cytokine release 
syndrome, the immunologic assessments outlined in Section 7.3.4 should be performed.  
Guidelines for management of AE and dose modifications are presented below in Table 6-2 (below). 
Institutional protocols for management of immune-related AEs should be implemented in cases of 
immune-related AEs and will take precedence over guidance in Table 6-2.  All patients must be followed 
up for the occurrence of AEs and SAEs for 90 days following the last dose of IMCgp100.   
 
 
 
 
 
 
 
 
   
.  
Table 6-2 
Recommended Dose Modifications by Toxicity Grade for Study 
Medications
Worst Toxicity NCI 
CTCAE v4.03 Grade
Recommended Dose Modifications
Skin Toxicity
Rash/Photosensitivity
Grade 1
Continue dosing.  If symptomatic, consider systemic antihistamine regimen  
Grade 2
Hold all doses of study IMCgp100 until returned to NCI CTCAE grade 
1.
Use local skin management and systemic antihistamine regimen as indicated.  
Anti-pruritic regimen:  Can include antihistamine therapy.  In patients where 
antihistamine therapy does not provide adequate relief, gabapentin or 
aprepitant may be considered.  
Topical corticosteroid regimens:  Preparation of recommended regimens
For face and/or intertriginous areas (including genitalia) recommend 
alclometasone 0.05% or hydrocortisone 2.5% creams  
For other body areas (ie, trunk and extremities) recommend clobetasol 
or betamethasone 0.05% creams.  Consider spray preparation for 
ease of application on trunk.  For scalp involvement, consider a foam 
preparation
Grade 3
Hold all doses of IMCgp100 until 


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Table 6-2
Recommended Dose Modifications by Toxicity Grade for Study 
Medications
Worst Toxicity NCI 
CTCAE v4.03 Grade
Recommended Dose Modifications
Management: Treat according to institutional practice which generally includes
an anti-pruritic regimen (see grade 2 management above).  In addition, 
corticosteroid treatment (oral or topical) can be considered for symptomatic rash 
that does not respond to anti-pruritic regimen. For topical regimens, refer to 
grade 2 management above).
Dose adjustments:  If grade 3 rash observed with IMCgp100 resolves to NCI 
1 within 7 days, restart at the same dose.  If grade 3 rash 
–21 days, restart with a reduction in the 
dose of IMCgp100, as discussed with the medical monitor.
Grade 4
Any grade 4 rash, permanently discontinue IMCgp100.  
Manage according to institutional practice, consultation with a dermatologist is 
recommended.  
All study medications must be permanently discontinued.
Infusion Reactions
Grade 1
Administer medications for symptomatic relief as needed. Infusion interruption 
may be considered until resolution of the event (up to 4 hours).  The infusion 
rate of the study medication may be decreased by 50%. If resolved with 
decreased rate of infusion, any subsequent infusions can be administered at the 
reduced rate. 
Grade 2
Stop infusion and keep intravenous line open. Treat according to institutional 
practice.  Provide all supportive measures as indicated.  Provide supplemental 
oxygen and fluids, as needed. 
Monitor vital signs (eg, blood pressure, pulse, and temperature) until resolution. 
Administer medications for symptomatic relief as needed. Antihistamines, 
acetaminophen (paracetamol), or corticosteroids may be administered, as 
needed at the discretion of the investigator.
Restart infusion only once infusion reaction resolves (within 4 hours of initial 
start of infusion). Administer oral pre-medication (eg, 1000 mg of 
acetaminophen or paracetamol, 50–100 mg diphenhydramine hydrochloride or 
alternative antihistamine), within 60 minutes of restarting the infusion.
Restart infusion at 50% of previous rate under continuous observation. Ensure 
that there is a minimum observation period of 1 hour prior to restarting the 
infusion. If the adverse event recurs at the reinitiated slow rate of infusion, and 
despite oral pre-medication, then permanently discontinue the patient from
study treatment.
Grade 3 or 4
Discontinue infusion immediately, and permanently discontinue patient from 
study treatment.
Manage severe infusion-related reactions per institutional standards. Provide 
supplemental oxygen, fluids, and other resuscitative measures as needed. 
Monitor vital signs (eg, blood pressure, pulse, respiration, and temperature) 
until resolution.
Hypotension


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Table 6-2
Recommended Dose Modifications by Toxicity Grade for Study 
Medications
Worst Toxicity NCI 
CTCAE v4.03 Grade
Recommended Dose Modifications
Grade 2
Intravenous fluid support and other supportive measures for additional AE as 
needed.  
Grade 3 or 4
Hold all doses of
fluid support and other supportive measures for additional adverse events.  In 
cases of hypotension where fluid support is not adequate, consider systemic 
corticosteroid therapy as needed for hypotension.   
In case of hypotension not responding to intravenous corticosteroid, inotropic 
pressor support may be indicated.  
Cytokine Release Syndrome
Grade 2
Interrupt infusion of IMCgp100.  Supportive measures for symptoms of 
cytokine release, ie, intravenous fluid support, non-steroidal anti-inflammatory 
drug (NSAID), antihistamine.   
If resolves within 4 hours, may restart infusion of IMCgp100.  If recurs with 
restarting infusion, hold the dose of IMCgp100 and institute supportive 
measures as indicated.  
Grade 3
Discontinue infusion immediately.  Supportive measures for symptoms of 
cytokine release, ie, intravenous fluid support, NSAID, antihistamine.  To 
consider intravenous corticosteroid (eg, methylprednisolone or hydrocortisone) 
for severe symptoms and management of sequelae.  
If symptoms resolve to NCI CTCAE grade 1 within 7 days, may consider 
restarting IMCgp100 after written approval of Sponsor Medical Monitor.  
Grade 4
Discontinue infusion immediately.  Supportive measures for symptoms of 
cytokine release.  In addition to supportive measures, intravenous 
corticosteroid dosing (eg, methylprednisolone or hydrocortisone) should be 
administered.  If symptoms do not resolve with intravenous corticosteroid 
dosing consider anti-IL6 (tocilizumab) therapy.  
If symptoms resolve to NCI CTCAE grade 1 within 7 days, may consider 
restarting IMCgp100 after written approval of Sponsor Medical Monitor.  
Other Adverse Events
In patients experiencing adverse events (not meeting the specific criteria above) of grade 
3, study 
drugs should be omitted until resolved to grade 
1. 
Treat according to institutional practice and for immune-related adverse events of grade 3 or greater, 
treatment with corticosteroids should be considered.  Consult Sponsor Medical Monitor for further 
guidance as needed.
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NSAID = 
non-steroidal anti-inflammatory drug.
All dose modifications should be based on the worst preceding toxicity. Once a dose has been reduced it 
will not be increased at a later time even if there is no toxicity. Patients who require more than 2 dose 
reductions should discontinue treatment.


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6.6
Treatment Discontinuation
Reasons for discontinuation of study treatment will include: 
Unequivocal PD, see Section 6.6.1
Loss of clinical benefit from treatment with IMCgp100 in the opinion of the principal investigator 
or the initiation of alternative anti-cancer therapy (including another investigational agent) 
Unacceptable toxicity defined as an AE that, in the opinion of the investigator or the Sponsor, 
 
Withdrawal of consent from further treatment with investigational product by the patient or the 
investigator or lost to follow-up 
Patient is determined to have failed to meet selection criteria for the study AND continuing to 
receive investigational product might constitute a safety risk.  Patients who fall into this category 
and for whom continuation of study treatment is not thought to pose a safety risk in the opinion 
of the investigator may continue to receive study treatment after discussion with the Sponsor  
Pregnancy or intent to become pregnant  
At the time patients discontinue study treatment, the EOT visit should be scheduled in the appropriate 
window of 14 days after the last dose was administered.  At this visit, all of the assessments listed for the 
EOT visit will be performed (see Table 7-1).  If the decision to withdraw the patient occurs at a regularly 
scheduled visit, that visit may become the EOT visit rather than having the patient return for an additional 
visit (EOT follow-up will still continue for the full 14-day observation period, see Section 7.2 for details of 
assessments required).  An End of Treatment eCRF page should be completed at the EOT visit, giving the 
date and reason for stopping the study treatment.  End of treatment/premature withdrawal visit is not 
considered as the end of the study.   
6.6.1
Criteria for Treatment Beyond Initial RECIST v.1.1 Disease Progression 
Imaging studies will be performed on all patients to monitor for disease progression using RECIST v1.1 
criteria.  Upon disease progression by standard RECIST v.1.1 criteria, treatment beyond progression is an 
option.   
Clinical evidence suggests that a minority of patients treated with immunotherapies, including IMCgp100, 
will derive clinical benefit after an initial assessment of PD. For patients in the IMCgp100 arm, if PD based 
on RECIST v.1.1 occurs, treatment may continue according to the protocol-specified regimen until 1 of the 
following criteria is met: 


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1.
Unequivocal, confirmed PD based on immune-related Response Evaluation Criteria in Solid 
Tumors (irRECIST) (guidelines based on Wolchok, 2009; Nishino, 2013; and Bohnsack, 2014): An 
initial assessment of PD by RECIST v.1.1 (initial PD assessment) will be confirmed with a repeat 
radiologic evaluation will be performed at least 4 but no more than 12 weeks later as scheduled 
per protocol. For patients who continue IMCgp100 therapy beyond initial PD, unequivocal, 
confirmed PD is defined as an additional 20% increase in tumor burden (sum of diameters of both 
target and new lesions) from the initial PD assessment 
2.
Meets any of the investigational product discontinuation criteria (Section 6.6 above) 
3.
Clinical symptoms or signs indicating clinically significant PD (not meeting radiologic PD) such as 
decline in ECOG performance status or the benefit-risk ratio of continuing therapy is no longer 
justified 
4.
Rapid PD or threat to vital organs/critical anatomical sites (eg, spinal cord compression) requiring 
urgent alternative medical intervention, and/or continuation of study therapy would prevent 
institution of such intervention 
Once unequivocal, confirmed PD is recognized, treatment with IMCgp100 must be discontinued. 
Patients continuing treatment beyond the protocol-specified RECIST v.1.1 progression must provide 
separate consent to continue treatment after an initial assessment of PD. Treatment and 
assessments after an initial assessment of PD will continue to follow the treatment regimen of weekly 
IMCgp100. 
6.7
Contraception 
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, 
unless they are using highly effective methods of contraception during dosing and for 6 months after the 
last dose of IMCgp100.  
Highly effective contraception methods include and of the following: 
Total abstinence from sexual relations for the duration of the treatment when applicable to the 
lifestyle of the patient.  Periodic abstinence (eg, calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or 
tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow-up hormone level 
assessment 


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Male sterilization (at least 6 months prior to screening). For female patients on the study the 
vasectomized male partner should be the sole partner for that patient 
The combination of any 2 of the following methods as long as they are both used simultaneously: 
a.
Use of oral, injected, or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception 
b.
Placement of an intrauterine device or intrauterine system 
c.
Barrier methods of contraception:  condom or occlusive cap (diaphragm or cervical/vault 
caps) when used with spermicidal foam, gel, film, cream, or used of a spermicidal vaginal 
suppository 
In case of use of oral contraception women should have been stable on the same oral contraceptive pill 
for a minimum of 3 months before beginning treatment on this study. 
Women are considered post-menopausal and not of child bearing potential if they have had 12 months 
of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age appropriate, history of 
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or 
tubal ligation at least 6 weeks ago. In the case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow-up hormone level assessment is she considered not of child 
bearing potential. 
 


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7
STUDY SCHEDULE AND ASSESSMENTS
7.1
Screening Procedures and Assessments
All of the assessments required as part of the study are indicated in Table 7-1 organized by visit date, with 
assessments required indicated with an “X” at the specific visits when they should be performed. 
Laboratory and radiological assessments performed as part of the parent study and/or standard of care 
prior to signing the rollover informed consent may be used if performed within the screening time window 
(21 days for laboratory assessments). No radiologic assessments will be collected as part of the rollover 
study. Assessments performed as part of the parent study should be included in the parent study 
database. Please note, if the last dose of IMCgp100 on the parent study and the first dose of IMCgp100 
on the rollover study are separated by more than 21 days, the first dose of IMCgp100 must be 
administered with overnight inpatient monitoring; given the risk of severe infusion-related toxicity and 
potential for hypotension (refer to Section 1.4 for details of clinical experience with IMCgp100).  
During the course of the study visits, test and/or procedures should occur on schedule whenever possible. 
A visit window of ± 7 days is allowed unless otherwise indicated in the protocol.


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Table 7-1 Schedule of Study Assessments
Screening 
Phase
Treatment Phase
Follow-up Phase
Procedure 
Protocol 
Section
Screeninga
Rollover Cycle 1
Rollover Cycle 2
End of 
Treatment
90-day 
Safety 
Follow Up
Survival 
Follow 
Up
Day 
1a
Day 
8
Day 
15
Day 
22
Day 
1
Day 
8
Day 
15
Day 
22
Informed Consent
7.1.1
X
Demography
7.1.1.2
X
Inclusion/exclusion criteria
5.2/5.3
X
Medical history
7.1.1.2
X
Diagnosis and extent of cancer
7.1.1.2
X
Prior/concomitant medications
7.1.1.2
X
Continually assessed
Physical examinationb
7.3.1
X
X
X
X
X
X
X
X
X
X
Height
7.3.3
X
Weight
7.3.3
X
X
X
X
Vital signsc
7.3.2
X
X
X
X
X
X
X
X
X
X
Hematology paneld
7.3.4
X
X
X
X
X
X
X
X
X
X
Chemistry panele
7.3.4
X
X
X
X
X
X
X
X
X
X
Cytokine panelf
7.3.4
In case of a suspected cytokine release syndrome
Pregnancy testg
7.3.4
X
X
X
12-lead electrocardiogram
7.3.4
X
X
IMCgp100 administrationh
6.1
X
X
X
X
X
X
X
X
Immunogenicity samplingi
7.3.5
X
X
Adverse events
8
Continually assessed
Tumor evaluation per
RECISTv.1.1 and modified 
irRECIST (Refer to Section 
6.6.1)
6.6.1
X
Assessed at a minimum of 12 week intervals
Survival contact
7.2.4
X


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Table 7-1 Schedule of Study Assessments
Screening 
Phase
Treatment Phase
Follow-up Phase
Procedure 
Protocol 
Section
Screeninga
Rollover Cycle 1
Rollover Cycle 2
End of 
Treatment
90-day 
Safety 
Follow Up
Survival 
Follow 
Up
Day 
1a
Day 
8
Day 
15
Day 
22
Day 
1
Day 
8
Day 
15
Day 
22
irRECIST = immune-related Response Evaluation Criteria in Solid Tumors.
a.
Screening and Rollover Cycle 1 Day 1 (RC1D1) may be the same day, no procedures or events need to be repeated.
b.
At Screening (or RC1D1), prior to IMCgp100 infusion, a complete physical examination will be performed. From RC1D8 onwards, a short physical examination 
will be performed. See Section 7.3.1.
c.
Frequent vital signs, as per institutional standard, should be implemented during any required inpatient observations at a minimum of every 4 hours.  (Refer to
Section 7.3.2 for additional details).
d.
Hematology panel should be obtained at Screening, before every IMCgp100 dose, and at the End of Treatment visit as well.
e.
Chemistry panel should be obtained at Screening, before every dose of IMCgp100, and at the End of Treatment visit.
f.
Cytokine panel should be obtained in all patients with a suspected occurrence of cytokine release syndrome. See Section 7.3.4.
g.
Pregnancy testing is required in all females of childbearing potential. At Screening, a serum pregnancy test must be performed within 72 hours before the first 
dose of IMCgp100. During the study (Day 1 of each cycle starting with Cycle 2) a serum or urine pregnancy test must be performed. At End of Treatment, a 
serum or urine pregnancy test must also be performed.
h.
Please refer to Section 6.1 Study Treatment for details of weekly IMCgp100 administration.
i.
Immunogenicity samples are to be taken at Day 1 of all odd-numbered cycles and at End of Treatment. All samples are to be collected immediately before 
IMCgp100 infusion.
j.
Target and non-target tumors to be assessed for radiographic disease progression by modified irRECIST criteria (refer to Section 7.3.5). Disease assessment to 
be performed at a minimum of 12 week intervals.


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7.1.1
Screening Assessments
The study IRB/IEC-approved informed consent form (ICF) must be signed and dated before IMCgp100 
administration per the rollover study. 
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments 
required at Baseline will be performed.  For details of all screening assessments, refer to Table 7-1. 
Screening assessments must be repeated if performed outside of the specified screening window.   
7.1.1.1
Information to be Collected on Screening Failures 
The demographic information, informed consent, and screening pages (with reason for screen fail) 
must also be completed for screen failure patients. No other data will be entered into the clinical 
database for patients who are screen failures, unless the patient experienced a SAE during Screening, 
which would be reported in the usual manner via eCRF AE page (See Section 8.4).  If the patient is still 
enrolled in the parent study at the time of Screening and experiences an SAE, this SAE must be 
reported to both this rollover study, as well as the initial parent study (see Section 8.1 Assessment of 
Safety).   
A patient who signed the Main Study ICF but failed to be started on study treatment for any reason 
will be considered a screen failure. If patients are found not eligible after signing the main study 
consent, the patients will be considered as screening failures, and data will be handled in the same 
manner. 
7.1.1.2
Patient Demographics and Other Baseline Characteristics 
Data to be collected will include general patient demographics, relevant medical history and current 
medical conditions, diagnosis and extent of cancer, prior/concomitant medications, prior procedures, 
significant non-drug therapies, and any other assessments that are done for the purpose of 
determining eligibility for inclusion in the study.  Prior anti-neoplastic therapies including medications, 
radiotherapy, and surgery are to be recorded on the separate Prior Anti-neoplastic Therapy eCRF 
during Screening. 
7.2
Treatment, Treatment Discontinuation, and Follow-up Phases
7.2.1
Treatment Period
A treatment cycle is defined as 4 weeks for the purposes of scheduling procedures and evaluations. 
Please refer to Table 7-1 for details of the timing of required assessments and visit windows.   
7.2.2
Discontinuation of Study Treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a patient 
decides to discontinue from the study treatment, the investigator should make every effort to 
determine the primary reason for this decision and record this information in the patient’s chart and 


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on the appropriate eCRF pages.  Other reasons for discontinuation of study treatment are outlined in 
Section 6.6.  
Patients will be considered withdrawn from treatment if they state an intention to withdraw, fail to 
return for visits, or become lost to follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being. 
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible, 
within 14 days of the last dose of study drug or within 14 days of the decision to permanently 
discontinue study treatment, at which time all of the assessments listed for the EOT visit will be 
performed (Table 7-1). If the decision to withdraw the patient occurs at a regularly scheduled visit, 
that visit may become the EOT visit rather than having the patient return for an additional visit. An 
end of treatment eCRF page should be completed, giving the date and reason for stopping the study 
treatment. End of treatment/premature withdrawal visit is not considered as the end of the study. 
Patients who discontinue study treatment should NOT be considered withdrawn from the study. They 
should return for the assessments indicated in Section 7 and Table 7-1 and be followed for the 90-day 
Safety Follow-up Period at a minimum. If they fail to return for these assessments for unknown 
reasons, every effort (eg, telephone, email, postal letter) should be made to contact them.  At this 
time, the reason for study completion should be recorded on the Study Disposition eCRF page. 
7.2.3
90-day Safety Follow-up Period
All patients must have safety evaluations 90 days after the last dose of study treatment. Information 
related to all AEs (including concomitant medication taken for ongoing AEs) will be collected for 90 
days after the last dose of study drug. All AEs suspected to be related to study treatment should be 
followed up weekly or as clinically indicated until resolution or stabilization.   
7.2.4
Survival Follow-up Period
Upon completion of the 90-day follow-up, patients will be followed for survival every 3 months (can 
be done by telephone call) until death or until the end of the study is reached, unless they withdraw 
consent or are lost to follow-up. 
7.2.5
Lost to Follow-up
For patients whose status is unclear because they fail to appear for study visits without stating an 
intention to withdraw consent, the investigator should show "due diligence" by contacting the patient, 
family, or family physician as agreed in the informed consent and by documenting in the source 
documents steps taken to contact the patient, eg, dates of telephone calls, registered letters, etc, a 
patient should not be considered lost to follow-up until due diligence has been completed. Patients 
lost to follow-up should be recorded as such on the appropriate Patient Disposition eCRF. 


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7.3
Safety and Tolerability Assessments
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
hematology, chemistry, pregnancy, ECG, cytokine testing, as well as collecting of the AEs at every visit. 
For details on AE collection and reporting, refer to Section 8, Adverse Events and Safety Reporting.  
7.3.1
Physical Examination
Physical examination will be performed according to Table 7-1. 
At Screening (or RC1D1), prior to IMCgp100 infusion on the rollover study, a complete physical 
examination will be performed and will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
and neurological system. If indicated based on medical history and/or symptoms, rectal, external 
genitalia, breast, and pelvic exams will be performed. 
From RC1D8 onwards, a short physical examination will be performed as indicated in the Schedule of 
Events, Table 7-1.  A short physical exam will include the examination of general appearance, vital 
signs (body temperature, pulse rate, respiratory rate, and blood pressure) and body sites as directed 
by symptoms. 
Significant findings that were present prior to the signature of the informed consent must be included 
in the Medical History eCRF page. Significant new findings that begin or worsen after informed consent 
must be recorded on the AE eCRF page. 
7.3.2
Vital Signs
Vital signs (body temperature, pulse rate, respiratory rate, and blood pressure) must be performed 
before dosing, and after the IMCgp100 administration (at least twice after administration) as indicated 
in Table 7-1, and as per institutional standards. Clinically significant abnormalities are to be reported 
on the AE eCRF page.
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. More 
frequent examinations may be performed at the discretion of the investigator if medically indicated.  
Frequent vital signs, as per institutional standard, should be implemented during any inpatient 
observations at a minimum of every 4 hours. If the full 21-day screening period is utilized for a patient, 
and the patient has a gap of greater than 21 days between their last dose of IMCgp100 on the parent 
study, and the first dose of IMCgp100 on the rollover study, the first dose of IMCgp100 (RC1D1) must 
be administered with overnight inpatient monitoring.  
Patients experiencing a grade 3 or 4 hypotension event during any dose of IMCgp100 will require 
inpatient hospitalization for the next 2 doses.  Further inpatient hospitalizations are at the discretion 
of the investigator.   


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Patients receiving IMCgp100 as an outpatient, for whom no grade 3 or 4 hypotension event was 
observed, should be monitored in the clinic for a minimum of 1 hour after the IMCgp100 infusion with 
at least 2 post-dose vital signs measurements performed.   
7.3.3
Height and Weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but 
without shoes) will be measured as indicated in Table 7-1. 
7.3.4
Laboratory Evaluations
All laboratory parameters assessed for safety purposes will be evaluated locally. Refer to Table 7-3 for 
a summary of the parameters to be evaluated according to Table 7-1. On dosing days of IMCgp100, 
samples for these parameters will be collected prior to the infusion of IMCgp100. 
More frequent evaluations may be performed at the investigator’s discretion if medically indicated; 
results should be recorded as unscheduled laboratory assessments. 
The Sponsor or the designated contract research organization (CRO) will be provided with a copy of 
the laboratory certification and tabulation of the normal ranges for each parameter required. In 
addition, if at any time a patient has laboratory parameters obtained from a different outside 
laboratory, the Sponsor or the CRO must be provided with a copy of the certification and a tabulation 
of the normal ranges for that laboratory. 
Table 7-3 
Local Clinical Laboratory Parameters Collection Plan
Test Category
Test Name
Hematology
Hematocrit, hemoglobin, platelets, white blood cells with differential 
(basophils, eosinophils, lymphocytes, monocytes, neutrophils)
Chemistry
Albumin, alkaline phosphatase, alanine transaminase, aspartate 
transaminase, bicarbonate, calcium, chloride, creatinine, glucose
magnesium, inorganic phosphate, potassium, sodium, total bilirubin (also
measure direct and indirect bilirubin if total bilirubin is > grade 1), blood 
urea nitrogen or urea, amylase, and lipase
Cytokines
Hematology:  The panels outlined in Table 7-3 will be performed as per the assessment schedule in 
Table 7-1. 
Clinical chemistry:  The panels outlined in Table 7-3 will be performed as per the assessment schedule 
in Table 7-1. 


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Cytokine analysis panel:  The cytokine panel outlined in Table 7-3 will be performed on an as needed 
basis in case a patient has an AE suspected to include cytokine release syndrome. This assessment 
should be performed at the following time points: 
 
 
Pregnancy and assessment of fertility:  Pregnancy tests will be performed for women of child bearing 
potential.  At Screening, a serum pregnancy test must be performed within 72 hours before the first 
dose of IMCgp100. During the study (Day 1 of each cycle starting with Cycle 2), a serum or urine 
pregnancy test must be performed. At EOT, a serum or urine pregnancy test must also be performed. 
Pregnancy will be reported through the Pregnancy Reporting Form (paper) as well as in the eCRF as 
an AE. 
Cardiac assessments:  A standard 12-lead ECG will be performed as per the assessment schedule in 
Table 7-1.  ECG assessment is performed at Screening prior to the first dose and at EOT assessment. 
Clinically significant abnormalities present at Screening should be reported on the Medical History 
eCRF page. New or worsened clinically significant findings occurring after informed consent must be 
recorded on the AE eCRF page.   
7.3.5
Immunogenicity Assessments
The immunogenicity blood samples should be taken according to Table 7-1. Details are also described 
in the laboratory manual for the handling, labelling, and shipment of immunogenicity blood samples. 
The blood samples should be collected immediately before IMCgp100 infusion, and it is essential that 
the actual time and date of collection be recorded on the patient’s eCRF.   


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8
ADVERSE EVENTS AND SAFETY REPORTING
8.1
Assessment of Safety
All patients who receive any treatment with IMCgp100 will be considered evaluable for safety. All AEs, 
regardless of study drug relationship, will be collected through the 90-day Safety Follow-up Period. At 
the time of consent, if any patient has any ongoing AE(s) from the parent IMCgp100 study, the AE(s) 
will be captured on the eCRF page and the “Ongoing at Start of Study” must be answered “Yes”. The 
start date recorded in the eCRF for the rollover study should be equal to the start date of the event as 
recorded in the parent study. Timely, accurate, and complete reporting and analysis of safety 
information from clinical studies are crucial for the protection of patients and is mandated by 
regulatory agencies worldwide. The Sponsor and CRO have established standard operating procedures 
in conformity with regulatory requirements worldwide to ensure appropriate reporting of all safety 
information. All clinical studies conducted by the Sponsor or its affiliates will be conducted in 
accordance with those procedures. 
Individual AEs should be evaluated by the investigator and should be reported to the CRO/Sponsor for 
evaluation. This includes the evaluation of the event’s seriousness and the causality between the 
investigational medicinal product(s) and/or concomitant therapy and the AE. The CRO/Sponsor is 
required to maintain detailed records of all AEs reported by the investigator(s) and to perform an 
evaluation with respect to seriousness, causality, and expectedness. On request of a competent 
authority in whose territory the clinical trial is being conducted, the Sponsor should submit detailed 
records of all AEs which are reported by the relevant investigators. Case report processing concerns 
evaluation of data in individual cases, identification of individual cases requiring specific handling, 
recognition and processing of alerts, and any other data processing of aggregated cases. 
8.1.1
Definitions
Definitions of AEs, adverse drug reactions, SAEs, unexpected adverse drug reactions, and AEs of special 
interest (AESI) are presented below. 
AE:  An AE is defined as the appearance of (or worsening of pre-existing) an undesirable sign, 
symptom, or medical condition that occurs after patient’s signed informed consent has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute AEs only if they 
induce clinical signs or symptoms, are considered clinically significant, require therapy (eg, 
hematologic abnormality that requires transfusion or hematological stem cell support), or require 
changes in study medication. 
Adverse drug reaction:  An adverse drug reaction is an unwanted or harmful reaction which occurs 
after administration of a drug or drugs and is suspected or known to be due to the drug. Adverse drug 
reactions have traditionally been categorized as pharmacologic (predicted based on the pharmacology 
of the drug) or idiosyncratic (not predicted based on pharmacology). 
SAE:  A SAE is any AE that is defined as 1 of the following: 


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Is fatal or life-threatening  
Results in persistent or significant disability or incapacity 
Constitutes a congenital anomaly/birth defect 
Is medically significant, ie, defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent 1 of the outcomes listed above 
Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
o
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
o
Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
Death due to the progression of malignancy should not be reported as a SAE, if documented 
by use of appropriate method (eg, as per Response Evaluation Criteria in Solid Tumors v.1.1).  
Any AE that occurred as a result of the PD should be reported in the appropriate manner 
Unexpected adverse drug reaction: An adverse drug reaction that is not consistent with applicable 
product information or characteristics of the study drug. 
Suspected, unexpected, serious adverse reaction (SUSAR):  A SUSAR is an adverse reaction meeting 
serious criteria (above), the nature or severity of which is not consistent with the reference safety 
information for the investigational drug(s). 
AESI: An AESI (serious or non-serious) is an AE with scientific and/or medical concern specific to the 
Sponsor’s program, for which ongoing monitoring and rapid communication by the investigator to the 
Sponsor can be appropriate.  Refer to the IMCgp100 Investigator’s Brochures for details of the AESI. 
8.2
Criteria for Expectedness
The concept of expectedness refers to events that may or may not have previously been observed and 
documented and not necessarily the known pharmacological properties of the medicine. An AE will 
be unexpected for purposes of regulatory reporting unless it is mentioned in the appropriate 
reference safety information within the current Investigator’s Brochure for the investigational drug, 
even if it is a medical occurrence expected for the disease being treated. 


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8.3
Assessment of Causality
8.3.1
Causality Assessment Required for All Adverse Events
The investigator decides whether he or she interprets the observed AE as either related to disease, to 
the study medication, study procedure, or other concomitant treatment or pathologies.  To assess the 
relationship of the AE to the study drug, the following terms are defined:    
(1) Related:  A direct cause and effect relationship between the study treatment and the AE is 
likely   
(2) Possibly related:  A cause and effect relationship between the study treatment and the AE has 
not been demonstrated at this time and is not probable, but is also not impossible 
(3) Unrelated:  Without question, the AE is definitely not associated with the study treatment 
All “related” and “possibly related” AEs and SAEs will be defined as related to study drug. 
8.4
Adverse Event Reporting
8.4.1
Expedited Reporting
Cases of adverse drug reactions from all sources that are assessed as serious are subject to expedited 
reporting. Expedited reporting of cases will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.  Additionally, any 
safety information from other observations that could change the risk benefit evaluation of the 
product will be communicated in an expedited manner to the regulatory authorities and all 
investigators by the Sponsor.  
The CRO will be responsible for the processing and reporting of SAEs. AEs will be coded by using 
International Conference on Harmonization (ICH) Medical Dictionary for Regulatory Activities. 
Minimum criteria for a valid adverse drug reaction case have been established by ICH and individual 
regulatory agencies and are listed as the following: 
An identifiable reporter
An identifiable patient
A reaction/event
A suspected medicinal product 
Other safety issues that also qualify for expedited reporting by the Sponsor are those that would 
materially alter the current benefit risk assessment of the investigational product (sufficient to 
consider changes in the administration or in the overall conduct of the trial).  Although these events 
will not be reported as SUSARs, they might require other action, such as putting in place urgent safety 


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measures, the generation of substantial amendments, or early termination of the trial.  The Sponsor 
will inform the regulatory authorities and all IEC of safety issues which might materially alter the 
benefit-risk assessment of the investigational agents. 
8.4.2
Standards for Expedited Reporting
Cases of adverse drug reactions from all sources that are assessed as SUSAR are subject to expedited 
reporting. Additionally, any safety information from other observations that could change the risk-
benefit evaluation of the product should be promptly communicated to the regulatory authorities. 
Any other SUSAR associated with the investigational product should be reported as soon as the 
Sponsor becomes aware of them, and this includes SUSAR which occur in another trial conducted by 
the same sponsor or which are identified by spontaneous reports or a publication, or which are 
transmitted to the sponsor by another regulatory authority. 
8.4.3
Reporting of Out-of-range Laboratory Test Results as Adverse Events
Out-of-range laboratory test results should be reported as AEs (not as abnormal laboratory values, ie, 
report as anemia, not low hemoglobin) if, in the opinion of the principal investigator, they are clinically 
significant.  Abnormal laboratory results that are not considered to be clinically significant will not be 
reported as AEs.  Significance of abnormal laboratory results should be documented in the study 
records.   
8.4.4
Reporting Guidelines for Other Observations
Other safety issues that also qualify for expedited reporting where they might materially alter the 
current benefit risk assessment of the investigational product (sufficient to consider changes in the 
administration or in the overall conduct of the trial), for instance include: 
An increase in the rate of occurrence of an expected serious adverse reaction, which is judged 
to be clinically important
A post-study SUSAR that occurs after the patient has completed a clinical trial and is reported 
by the investigator to the Sponsor 
Events which occur during the trial and are relevant in terms of patient safety, but which do not fall 
within the definition of SUSAR (and thus are not subject to the reporting requirements for SUSARs) 
are:  
An SAE which could be associated with the trial procedures and which could modify the 
conduct of the trial 
A significant hazard to the patient population such as lack of efficacy of an investigational 
medicinal product 
A major safety finding from a newly completed animal study (such as carcinogenicity) 


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A temporary halt of a trial for safety reasons if the trial is conducted with the same 
investigational medicinal product in another country by the same Sponsor 
Safety recommendations of the Safety Management Team 
Although these events/observations will not be reported as SUSARs, they might require other action, 
such as putting in place urgent safety measures, the generation of substantial amendments, or early 
termination of the trial.  The Sponsor will inform the regulatory authorities and the IECs of safety 
issues, which might materially alter the benefit-risk assessment of the investigational medicinal 
product. 
Expedited reporting is not usually required for reactions that are serious but expected, or for non-
serious adverse reactions whether expected or not. 
It is usually also inappropriate to report events that are considered unrelated to the investigational 
medicinal product. 
8.4.5
Pregnancy Reporting
Pregnancy will be reported through the Pregnancy Reporting Form (paper) as well as in the eCRF as 
an AE. The Pregnancy form (paper) should be completed and reported as indicated to the CRO 
pharmacovigilance team within 24 hours of being made aware of the event. Women who become 
pregnant during the study will be withdrawn from treatment at the earliest opportunity.  The 
investigator shall report all pregnancies immediately to the CRO.  The CRO will then notify the Sponsor 
within 1 business day of being informed of the event.  Following withdrawal from the study, every 
attempt will be made to follow the patient and any resulting offspring for up to 6-weeks postpartum, 
unless otherwise medically indicated.  Abortion, stillbirth, or any malformation/disease in the 
offspring must be reported as an SAE.  
For men participating in the study who report the pregnancy of a partner, the investigator will ask to 
collect information about the results of the pregnancy/birth using the Pregnant Partner forms.  The 
partner may be asked to sign a consent form giving permission for information to be collected.  This 
health information will become part of the research study records.  It will be shared with the Sponsor. 
8.5
Investigator’s Responsibilities
The investigator is responsible for the collection of AE data. All AEs should be recorded in the eCRF.  
The investigator shall report all SAEs immediately within 24 hours of being made aware of the event 
to Pharmacovigilance via the clinical database by completing as much information as possible and 
checking Yes when prompted whether the event is classified as an SAE in the AEs eCRF. The initial 
reporting can be supplemented by written reports using the SAE report form provided.  
The follow-up reports (if required) shall identify the trial patients by unique code numbers assigned 
to the patient. The investigator shall supply the Sponsor with any additional requested information, 
notably for reported deaths of a patient. 


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All SAEs that occur between obtaining the patient’s informed consent and 90 days after the last dose 
of study drug must be reported promptly to the CRO not later than 24 hours after the investigators or 
co-investigators become aware of their occurrence using the SAE eCRF in the study database. 
The SAE eCRF is accessed via the study database. The following minimum information is required for 
the report: 
Patient identification (patient number and date of birth)
Trial number
Study treatment (dose, route, form, regime, start date, end date)
Concomitant medication (including dose, route, form, regime, start date where available)
Nature of SAE (overall diagnosis where available or alternatively signs and symptoms)
Date and time of occurrence
Any associated factors (concomitant disease or medication)
Proposed relationship to study treatment
Outcome
Identify the reporter
Action in relation to study (withdrawn from treatment, suspended, none)
The investigators or co-investigators are required to sign the SAE submission electronically in the 
clinical database within 24 hours of awareness of the event, even if the required information is 
incomplete or if the investigators are awaiting laboratory or diagnostic reports.  Investigators may be 
asked for additional information for any reported SAE.  An SAE follow-up report with attached 
documents (if necessary) should be forwarded to CRO Pharmacovigilance as soon as the additional 
information is available by email. The study number IMCgp100-401 must be in the title of any email 
for study identification purposes.   
8.6
Sponsor and Clinical Research Organization’s Responsibilities
The Sponsor is responsible for the ongoing safety evaluation of the investigational drugs being studied. 
The Sponsor and CRO are responsible for ensuring that expedited reports are made to all concerned 
investigators, to the IEC where required, and to all regulatory authorities of all adverse drug reactions 
that are both serious and unexpected, or findings that could adversely affect the health of patients, 
impact on the conduct of the trial, or alter the competent authority’s authorization to continue the 
trial in accordance with local applicable regulations. 


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9
STATISTICAL METHODS AND DATA ANALYSES
9.1
General Principles
Data will be summarized using descriptive statistics.  Categorical data will be presented as frequencies, 
medians, and percentages. For continuous data, mean, standard deviation, median, minimum, and 
maximum will be presented. 
The following rules will be followed for reporting results unless stated otherwise: 
Screen failure patients are those who signed the informed consent, but never started the 
study treatment for any reason. For these patients, the eCRF data collected will not be 
included in analyses, but will be reported in the clinical study report as separate listings 
Baseline is defined as the last assessment prior to the first dose of treatment received (ie, 
RC1D1 pre-dose) 
Additional analyses not described here will be detailed in the statistical analysis plan for the 
study 
9.2
Analysis Sets
9.2.1
Full Analysis Set
The full analysis set (FAS) comprises all patients assigned to treatment, who received at least 1 full or 
partial dose of IMCgp100. The FAS will be used for all demography, baseline characteristics, and OS 
data summaries.  
9.2.2
Safety Analysis Set
The safety analysis set includes all patients who have received at least 1 full or partial dose of 
IMCgp100. Patients will be classified in this set according to initial treatment received.  The safety 
analysis set will be used for the safety summary of the study. 
9.3
Patient Demographics and Other Baseline Characteristics
Demographic data, baseline disease characteristics, and other baseline data will be listed in detail. 
Quantitative data (eg, weight) will be summarized by appropriate descriptive statistics. 
9.4
Treatment Data
Actual dose and duration in days of treatment for IMCgp100, as well as the dose intensity (actual dose 
received/actual duration), and relative dose intensity (the ratio of dose intensity to planned 
dose/planned duration) will be summarized by descriptive statistics  


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Concomitant medications and significant non-drug therapies prior to and after the start of the study 
treatment will be listed by patient and summarized by anatomical therapeutic chemical term. 
The reason for discontinuation from treatment will be summarized and listed, along with dates of first 
and last doses, duration of exposure to each study drug, and date of discontinuation for each patient. 
9.5
Primary Analysis
9.5.1
Variables
The primary variable is the incidence of AEs.   
9.6
Secondary Analyses
9.6.1
Safety 
For all safety analyses, the safety analysis set will be used.  
The overall observation period will be divided into 3 mutually exclusive segments: 
1.
Pre-treatment period:  From day of patient’s informed consent to the day before first dose of 
study treatment 
2.
On-treatment period:  From day of first dose of study treatment to 90 days after last dose of 
study medication 
3.
Post-treatment period:  Starting at Day 31 after last dose of study treatment 
9.6.1.1
Adverse Events 
Summary tables for AEs include only AEs that are new or worsened during the on-treatment period 
(treatment-emergent AEs). However, all safety data (including those from the pre- and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period are to 
be flagged. 
The incidence of treatment-emergent AEs will be summarized by system organ class and/or preferred 
term, severity (based on NCI CTCAE v.4.03 grades), type of AE, and relation to study treatment by 
treatment group. Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated 
by type of AE and treatment group. 
9.6.1.2
Laboratory Abnormalities 
For laboratory tests covered by the NCI CTCAE version 4.03 the study team will grade laboratory data 
accordingly. For laboratory tests covered by NCI CTCAE, a grade 0 will be assigned for all non-missing 
values not graded as 1 or higher.  For laboratory tests where grades are not defined by NCI CTCAE, 
results will be graded by the low/normal/high classifications based on laboratory normal ranges. 


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The following by-treatment summaries will be generated separately for hematology, biochemistry, 
and other laboratory: 
Frequency table for newly occurring on-treatment grades 3 or 4 and all grades 
Shift tables of laboratory and ECG data using NCI CTCAE grades to compare Baseline to the 
worst on-treatment value 
Listing of all clinically relevant laboratory data and relevant ECG data with values flagged to 
show the corresponding NCI CTCAE grades and the classifications relative to the laboratory 
normal ranges 
9.6.1.3
Other Safety Variables 
Vital signs absolute values and changes from Baseline will be summarized. Normal ranges will be 
specified in the statistical analysis plan and shift tables of Baseline to worst on-treatment results 
will be produced 
ECG data:  QTc interval absolute values and changes from Baseline will be summarized. 
Abnormalities will be classified according to NCI CTCAE grades and shift tables of Baseline to worst 
on-treatment results will be presented  
Physical examination data will be listed and abnormalities will be flagged 
9.6.1.4
Tolerability 
Tolerability of study treatment will be assessed by summarizing the number of treatment dose 
interruptions and dose reductions. Reasons for dose interruptions and dose reductions will be listed 
by patient and summarized. 
9.7
Exploratory Analyses
9.7.1
Overall Survival
Date of death will be collected to assess OS only and will be listed according to treatment regimen. 
The OS data will be presented graphically via Kaplan-Meier survival curves. 
9.7.2
Immunogenicity—Exposure and/or Adverse Event Relationship
 
 
 
9.8
Interim Analysis
No formal interim analyses are planned.   


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9.9
Sample Size Calculation
No formal sample sizing will apply to this study. 
 


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10 DATA HANDLING AND MANAGEMENT
10.1 Data Confidentiality
Information about study patients will be kept confidential and managed under the applicable laws and 
regulations. Those regulations require a signed patient authorization informing the patient of the 
protected health information that will be collected and the use or disclosure of that information.  If 
the patient revokes authorization to collect or use this information, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of patient authorization.  To 
protect the health information of study patients, access to the data collection system will be controlled 
by a sequence of individual user identification codes and passwords that are made available only to 
authorized trained personnel. 
10.2 Site Monitoring
Before study initiation at trial sites, Sponsor and/or CRO study team members will review the protocol 
and eCRFs with the investigators and the site study staff. During the study, the field monitor will visit 
the site regularly to check the completeness of patient records, the accuracy of entries on the eCRFs, 
the adherence to the protocol to good clinical practice (GCP), the progress of enrollment, and to 
ensure that study treatments are being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these visits.  
The investigator must assure that the site monitor is allowed access to all study files, including all site 
medical records, case and visit notes, and laboratory reports.    
10.3 Data Collection
The investigator is required to maintain source documents for each patient in the study, consisting of 
case and visit notes (site medical records), containing demographic and medical information, 
laboratory data, ECGs, and the results of any other tests or assessments. All information recorded in 
the eCRF must be traceable to source documents in the patient's file. The investigator must also keep 
the original signed ICF, with 1 signed copy given to the patient. 
This study will use an electronic data capture (EDC) system and the principal investigator and site study 
staff will enter the data required by the protocol into the eCRF. The eCRF have been built using fully 
validated secure web-enabled software that conforms to 21 CFR Part 11 requirements.  The principal 
investigator and all identified site staff will not be given access to the EDC system until they have been 
trained. The principal investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner.  Field monitors will 
review the eCRF data entries and assist site personnel with any required corrections or additions. 
Field monitors will review the eCRF and laboratory paper requisition forms for accuracy and 
completeness and instruct site personnel to make any required corrections or additions. One copy of 
the requisition form will be forwarded to each analytical laboratory with the respective sample by the 
site staff and 1 copy will be retained at the investigational site. 


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10.4 Database Management
Sponsor clinical study personnel and trial field monitors will review the eCRF data entries and assist 
site personnel with any required corrections or additions. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values and 
sent to the investigational site via the EDC system.   
Concomitant treatment and prior medication data in the database will be coded using the WHO Drug 
Reference List, based on the anatomical therapeutic chemical classification. Medical history, current 
medical conditions and AEs in the database will be coded using the Medical Dictionary for Regulatory 
Activities terminology.  After database lock, the investigator will receive a CD-ROM of the patient data 
for archiving at the investigational site. 
 


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11 ETHICAL CONSIDERATIONS AND ADMINISTRATIVE
PROCEDURES
11.1 Study Documentation, Record Keeping, and Retention of Documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements for the 
protection of confidentiality of patients. Each site will permit authorized representatives of the 
Sponsor and regulatory agencies to examine any clinical records for the purposes of quality assurance 
reviews, audits and evaluation of the study safety and progress.  Source data are all information, 
original records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
principal investigator. The study eCRF is the primary data collection instrument for the study. The 
investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported 
in the CRFs and all other required reports. Data reported on the CRF, that are derived from source 
documents, should be consistent with the source documents or the discrepancies should be explained. 
All data requested on the CRF must be recorded.  
The investigator should maintain the trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable regulations and guidelines. 
The investigator should take measures to prevent accidental or premature destruction of these 
documents. Essential documents should be retained for a period of not less than 15 years from the 
completion of the clinical trial unless Sponsor provides written permission to dispose of them or, 
requires their retention for an additional period of time because of applicable laws, regulations and 
guidelines. 
11.2 Regulatory and Ethical Compliance
This clinical study was designed, shall be implemented and reported in accordance with the ICH 
Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local regulations 
(including European Directive 2001/20/EC and Unites States Code of Federal Regulations, CFR Title 
21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.3 Responsibilities of the Investigator and Institutional Review Board/Independent 
Ethics Committee/Research Ethics Board
The protocol and the proposed ICF must be reviewed and approved by a properly constituted IRB or 
IEC or Research Ethics Board (REB) before study start.  Prior to study start, the investigator is required 
to sign a protocol signature page confirming agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access to all 
relevant data and records to field monitors, auditors, CRO representatives, designated agents of the 
Sponsor, the IRB or IEC or REB, and regulatory authorities as required. 


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11.4 Informed Consent Procedures
Eligible patients may only be included in the study after providing written (witnessed, where required 
by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of doing so, after such 
consent has been provided by a legally acceptable representative of the patient. In cases where the 
patient’s representative gives consent, the patient should be informed about the study to the extent 
possible given his/her understanding. If the patient is capable of doing so, he or she should indicate 
assent by personally signing and dating the written informed consent document or a separate assent 
form. 
Informed consent must be obtained before conducting any study-specific procedures. The process of 
obtaining informed consent should be documented in the patient source documents. The date when 
a patient’s informed consent was actually obtained will be captured in the eCRF. 
11.5 Discontinuation of the Study
The Sponsor reserves the right to discontinue this study under the conditions specified in the clinical 
study 
agreement. 
Specific 
conditions 
for 
terminating 
the 
study 
are 
outlined 
in  
Section 3.5 Early Study Termination. 
11.6 Publication of Study Protocol and Results
The Sponsor will publish the key design elements of this protocol in a publicly accessible database 
(clinicaltrials.gov).  At the time of study and clinical study report completion, the results of this study 
will be either submitted for publication and/or posted in a publicly accessible database. 
11.7 Confidentiality of Study Documents and Patient Records
The investigator must ensure anonymity of the patients; patients must not be identified by name in 
any documents submitted to the Sponsor or the CRO. Signed ICFs and patient enrollment log must be 
kept strictly confidential to enable patient identification at the site. 
11.8 Audits and Inspections
Source data and all trial documents must be available to inspections by the Sponsor, the CRO or 
designee, or Health Authorities. 
11.9 Financial Disclosures
Financial disclosures should be provided by study personnel who are directly involved in the treatment 
or evaluation of patients at the site, prior to study start. 
 


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12 REFERENCES
American 
Cancer 
Society. 
Cancer 
Facts 
and 
Figures 
2016. 
http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047070.pdf  
Accessed Feb 16, 2016. 
Middleton D, Menchaca L, Rood H, Komerofsky R. New Allele Frequency Database: 
http://www.allelefrequencies.net. Tissue Antigens. 2003;61:403–407. 
Middleton M, Corrie, P, Sznol, M, Infante J, et al.  A phase I/IIa study of IMCgp100: partial and complete 
durable responses with a novel first-in-class immunotherapy for advanced melanoma. American 
Academy for Cancer Research Annual Meeting, Philadelphia, PA. April 2015.   
Middleton M, Corrie P, Sznol M, et al. Safety, pharmacokinetics and efficacy of IMCgp100, a first-in-
class soluble TCR-antiCD3 bispecific T cell redirector with solid tumour activity: results from the FIH 
study in melanoma. American Society for Clinical Oncology, 2016 Annual Meeting, Chicago, IL. June 
2016. 
Singh AD and Topham, A. Incidence of uveal melanoma in the United States: 1973–1997. 
Ophthalmology. 2003;110(5):956–961.   
Surveillance, Epidemiology, and End Results, 2015. http://seer.cancer.gov/statfacts/html/melan.html. 
Accessed 04 March 2016.  
Takase H, Yu CR, Mahdi RM, et al. Thymic expression of peripheral tissue antigens in humans: a 
remarkable variability among individuals. Int Immunol. 2005;17(8):1131–1140. 
Wagner SN, Wagner C, Schultewolter T, et al.  Analysis of Pmel17/gp100 expression in primary human 
tissue specimens: implications for melanoma immuno- and gene-therapy. Cancer Immunol 
Immunother. 1997;44(4):239–247. 

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1. 
INTRODUCTION ................................................................................................................................................................. 8 
2. 
STUDY OBJECTIVES .......................................................................................................................................................... 8 
2.1. 
Primary Objective ........................................................................................................................................8 
2.2. 
Secondary Objectives ..................................................................................................................................8 
3. 
STUDY DESIGN ................................................................................................................................................................... 8 
3.1. 
General Description .....................................................................................................................................8 
3.2. 
Schedule of Events.......................................................................................................................................9 
3.3. 
Changes to Analysis from Protocol ..............................................................................................................9 
4. 
PLANNED ANALYSES ........................................................................................................................................................ 9 
4.1. 
Final Analysis ...............................................................................................................................................9 
5. 
ANALYSIS SETS ................................................................................................................................................................... 9 
5.1. 
All Patients Enrolled Set [ENR] .....................................................................................................................9 
5.2. 
Full Analysis Set ...........................................................................................................................................9 
5.3. 
Safety Analysis Set [SAF] .............................................................................................................................9 
6. 
GENERAL CONSIDERATIONS ....................................................................................................................................... 10 
6.1. 
Reference Start Date and Study Day .......................................................................................................... 10 
6.2. 
Baseline ..................................................................................................................................................... 10 
6.3. 
Retests, Unscheduled Visits and End of Treatment Data ........................................................................... 10 
6.4. 
Windowing Conventions ............................................................................................................................ 11 
6.5. 
Statistical Tests .......................................................................................................................................... 11 
6.6. 
Software Version ....................................................................................................................................... 11 


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7. 
STATISTICAL CONSIDERATIONS ............................................................................................................................... 11 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses .......................................................... 11 
7.2. 
Multicenter Studies ................................................................................................................................... 11 
7.3. 
Missing data .............................................................................................................................................. 11 
7.4. 
Multiple Comparisons/ Multiplicity ........................................................................................................... 11 
7.5. 
Examination of Subgroups ......................................................................................................................... 11 
8. 
OUTPUT PRESENTATIONS ........................................................................................................................................... 11 
9. 
DISPOSITION AND WITHDRAWALS ......................................................................................................................... 12 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................................................................... 12 
10.1. 
Derivations ............................................................................................................................................ 12 
11. 
SURGICAL AND MEDICAL HISTORY ...................................................................................................................... 13 
12. 
CONCOMITANT MEDICATIONS .............................................................................................................................. 14 
12.1. 
Prohibited Concomitant Medications/Therapies ................................................................................... 14 
13. 
STUDY DRUG EXPOSURE .......................................................................................................................................... 14 
13.1. 
Study Drug Exposure Derivations ........................................................................................................... 15 
13.1.1. 
Missing Data Methods For Study Exposure Variables ..............................................................................17 
14. 
EFFICACY OUTCOMES ................................................................................................................................................ 17 
14.1. 
Overall Survival (OS) .............................................................................................................................. 17 
15. 
SAFETY OUTCOMES .................................................................................................................................................... 18 
15.1. 
Adverse Events ...................................................................................................................................... 18 
15.1.1. 
All TEAEs ...................................................................................................................................................19 
15.1.1.1. 
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Grade .........19 
15.1.1.2. 
Relationship to Study Drug (IMCgp100) ...........................................................................................19 
15.1.2. 
TEAEs Leading to Discontinuation of Study Drug .....................................................................................19 


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15.1.3. 
Serious Adverse Events .............................................................................................................................20 
15.1.4. 
Adverse Events Leading to Death .............................................................................................................20 
15.2. 
Deaths ................................................................................................................................................... 20 
15.3. 
Laboratory Evaluations .......................................................................................................................... 20 
15.3.1. 
Laboratory Specific Derivations ................................................................................................................20 
15.3.2. 
Laboratory Reference Ranges and Markedly Abnormal Criteria ..............................................................21 
15.3.3. 
NCI CTCAE Grading for Laboratory Data ...................................................................................................22 
15.4. 
ECG Evaluations ..................................................................................................................................... 23 
15.4.1. 
ECG Specific Derivations ...........................................................................................................................24 
15.4.2. 
ECG Markedly Abnormal Criteria ..............................................................................................................24 
15.5. 
Vital Signs .............................................................................................................................................. 24 
15.5.1. 
Vital Signs Specific Derivations .................................................................................................................24 
15.5.2. 
Vital Signs Markedly Abnormal Criteria ....................................................................................................25 
15.6. 
Physical Examination ............................................................................................................................. 25 
16. 
EXPLORATORY OBJECTIVES ................................................................................................................................... 25 
16.1. 
Immunogenicity ..................................................................................................................................... 25 
17. 
OTHER DATA NOT SUMMARIZED OR PRESENTED ......................................................................................... 25 
18. 
REFERENCES ................................................................................................................................................................. 26 
 
PROGRAMMING CONVENTIONS FOR OUTPUTS ............................................................................. 27 
 
PARTIAL DATE CONVENTIONS ............................................................................................................. 35 


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–
–


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floor ((intck(‘month’,&birth,&date) 
o


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o
o
–
o
cancer therapy for metastatic disease = the “best” best 
response
Prior Anti-Cancer Therapy (PAT) 
o
o
o
o
o
o
o
o


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‘Prior’ medications are medications which started and stopped prior to the first dose of 
‘Concomitant’ medications are medications which: 
o
o
‘Post’ medications are medications which started after the last dose of study drug
During the ‘concomitant’ period of the study (as above), patients may not receive other 


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Number of cycles started
Number of cycles completed 
Total planned dose
Duration of treatment 
–
Duration of treatment from first parent study dose 
–
Duration of interruption (days) 
o
“Date of visit in which interruption started” = ‘date of visit’ from the Date of Visit 
lassified as “not done”. If it is 
Date of Visit 
Administration of Study Drug 
expected 
following last administered dose, may be used instead (=previous ‘start date of 
study drug administration’ + 14 days). See the definition of a dose interruption
o
If a patient does not have a “start date of next 
interruption” then a dose interruption is 
End of Treatment
End of Treatment


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Total actual dose received
Total planned dose 
Administration of Study Drug 
number of cycles started
‘Actual dose administered’ on the eCRF (any dose > 0 units), that occurs in a given 
number of cycles
total planned dose
the ‘
’
applicable, the dose entered in ‘
’ item, 
Parent Study Details -IMCgp100
total actual dose received is based on the ‘Actual dose administered’ entered on 
Administration of Study Drug 
The date of first study drug administration is taken from the earliest ‘Dose start date’ 
n from the latest ‘Dose end date’ 


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Dose interruption –
Administration of Study Drug
eCRF page where the response to ‘Did the patient receive investigational product at this visit?’ 
‘No, reason for dose omission’.
End of Treatment
he “Date of death or Last contact” (for t
alive) on the End of Study eCRF page and (ii) “Date patient last known to be alive” on the 
AE/SAE Prior and 
Concomitant Medication, 
, Administration of Study 
Drug, Vital Signs, Electrocardiogram, 
,
 Physical Examination. 
–


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s ‘Initial Grade’ 
and ‘
rade’ but not the date 
might have 
and the ‘Most Extreme Grade’ is 
than the ‘Initial Grade’, then the AE is 
classified as ‘missing’
values: ‘missing’, ‘mild’, ‘moderate’, ‘severe’, ‘life threatening’, and ‘death related to AE’). 
categories ‘possibly’ related or ‘related’ will be pooled to create the ‘related’ category. TEAEs 
‘missing’
“Action taken with the study drug” variable collected on the eCRF, where the variable is equal 
to ‘Drug permanently discontinued’. These will be flagged in the listing.


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Serious adverse events (SAEs) are those events recorded as ‘Yes’ in response to the “Does 
the Adverse Event meet seriousness criteria?” question on the
AE/SAE) 
‘
rade’
‘Grade 5 Death related to AE’, or Seriousness Criteria has ‘Death’ ticked
Death
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be 
i.e. as “< X” or “> X” in the listings.
–
o


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o
o
–


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Laboratory tests covered by NCI CTCAE are as follows (found under ‘Investigations’ in the link 
–


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Overall assessment of ECG (Investigator’s judgment):
o
o
o


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–
o
o
450 msec (i.e. ‘Normal’)
o
o
o


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 90 mmHg
Grade 3:  160 mmHg
 60 mmHg
Grade 3:  100 mmHg
 20 breaths/min
 100 bpm
C
– 39.0 C
– 40.0 C
: >40.0 C
“NA” in lieu of “Low”, “Normal” or “High” in listings. 
nor High will be represented as “Normal”.


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ICH Steering Committee. (2005). ICH Harmonised Tripartite Guideline: The clinical evaluation of QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs E14. Retrieved from 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guideline.pdf 
Parent X, S. C. (2009). ["Corrected" calcium: calcium status underestimation in non-hypoalbuminemic patients and 
in hypercalcemic patients]. PubMed, 1. doi:10.1684/abc.2009.0348  
Services, U. D. (2010, June 14). National Institute of Health. Retrieved April 2, 2019, from CTCAE: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 


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possible. A prefix can be used to distinguish between a Table, Listing and Figure document (‘t’ 
for table, ‘l’ for listing and ‘f’ for figure). If there is only 1 


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The font type ‘Courier New’ should be used as a default for tables and listings, with a font size of 
Figures should have a default font of “Times Roman”, “Arial”, or “Courier New”.
derscores (‘_’) (the number of underscores 


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–
The column headings should be underlined with a row of underscores (‘_’)
“(N=XXX)”
“Statistic” should be the column header over n, Mean, SE, n (%) etc.


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>99.9% will be presented as ‘>99.9%’ (e.g., 99.99% is pr
< 0.1% will be presented as ‘<0.1%’ (e.g., 0.08% is presented as <0.1%). 


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lines of a table “line up”.
number “n”.
A “0” should be used to indicate a zero frequency.
or ‘ ‘


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A continuous line of underscores (‘_’) will follow the body of the table or listing prior to 
Only “typewriter” symbols are permitted –
“*”, “$”, “#”, “@”, “&” and “+”.
The choice of footnote symbols should be consistent. E.g. if you have the footnote “# 
indicates last observation carried forward” for one table, the same symbol and footnote 


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beginning with the words “Programming Note” followed by a colon. These include notes on the 


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…
…
randomized/actual treatment groups labelled as ‘Screen Failures’.


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Cannot be assigned as ‘post treatment’
Cannot be assigned as ‘post treatment’