Study of GSK2241658A Antigen-Specific Cancer Immunotherapeutic in Patients With Unresectable and Progressive Metastatic Cutaneous Melanoma
Phase: PHASE1
Conditions: Melanoma
Sponsor: GlaxoSmithKline

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Clinical Study Protocol
Sponsor:
GlaxoSmithKline Biologicals
Rue de l’Institut, 89
1330 Rixensart, Belgium
Primary Study product and 
number
Recombinant His/NY-ESO-1 protein combined with 
the AS15 immunological Adjuvant System
(GSK2241658A)
eTrack study number and 
Abbreviated Title
112406 (NYESO1-AS15-MEL-001 (MET))
Investigational New Drug 
(IND) number
14313
EudraCT number
2010-020663-20
Date of protocol
Final - 22 February 2010
Date of protocol 
amendment/administrative 
change
Amendment 1 Final: 18 April 2011
Administrative Change 1 Final: 17 January 2013
Amendment 2 Final: 27 November 2013
Amendment 3 Final: 03 September 2014
Title
Study of GSK2241658A Antigen-Specific Cancer 
Immunotherapeutic in patients with unresectable and 
progressive metastatic cutaneous melanoma
Detailed Title
An open Phase I Study of immunization with the 
recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic in patients with NY-ESO-1-
positive unresectable and progressive metastatic 
cutaneous melanoma
Co-ordinating author
, MSc, Scientific writer
Contributing authors
, MD, (Vice President, Head of 
Immunotherapeutics Cancer Incubator)
, MD, (Director, Early Clinical 
Development, Cancer Immunotherapeutics)
, MSc, (Study Delivery Lead, Clinical 
Operations, Cancer Immunotherapeutics)
, PhD, (Clinical Scientist, Early 
Clinical Development, Cancer Immunotherapeutics)
, (Safety Scientist, Clinical Safety and 
Pharmacovigilance)
, MD, (Senior Manager, Clinical Safety 
and Pharmacovigilance)
, (Biostatistician, Clinical Operations)
, PhD, (Clinical Data Management, 
Cancer Immunotherapeutics)
(Amended 03 September 2014)
 
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eTrack study number and 
Abbreviated Title
112406 (NYESO1-AS15-MEL-001 (MET))
Investigational New Drug 
(IND) number
14313
EudraCT number
2010-020663-20
Detailed Title
An open Phase I Study of immunization with the 
recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic in patients with NY-ESO-1-
positive unresectable and progressive metastatic 
cutaneous melanoma
Contributing authors
, PhD, (Director, Head of R&D, Cancer 
Immunotherapeutics)
, (Clinical Data Management, 
Cancer Immunotherapeutics)
GSK Biologicals’ Immunotherapeutic Protocol Template v 13.0 based on GSK 
Biologicals Protocol DS v 13.0
Copyright 2010-2014 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised 
copying or use of this information is prohibited.
 
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Protocol Amendment 3 Sponsor Signatory Approval
eTrack study number and 
Abbreviated Title
112406 (NYESO1-AS15-MEL-001 (MET))
IND number
14313
EudraCT number
2010-020663-20
Date of protocol amendment
Amendment 3 Final: 03 September 2014
Detailed Title
An open Phase I Study of immunization with the 
recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic in patients with NY-ESO-1-
positive unresectable and progressive metastatic 
cutaneous melanoma
Sponsor signatory
Frédéric Lehmann, MD
Vice President, Head of Immunotherapeutics 
Cancer Incubator (Amended 03 September 2014)
Signature
Date
 
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Protocol Amendment 3 Rationale
Amendment number:
Amendment 3
Rationale/background for changes: 
The enrolment of new patients in the study, the follow-up of the patients who 
discontinued the study treatment due to disease progression or due to other 
reasons, or patients in the 1 year follow-up following the completion of the study 
treatment will be stopped given the fact that:

the detailed analysis of the MAGRIT study (A double-blind, randomized, placebo-
controlled Phase III study to assess the efficacy of recMAGE-A3 + AS15 Antigen-
Specific Cancer immunotherapeutic as adjuvant therapy in patients with resected 
MAGE-A3-positive Non-Small Cell Lung Cancer) showed the absence of 
treatment effect in any of the primary, secondary, or exploratory analyses1. All 
aspects of the MAGRIT study have been carefully assessed, and unfortunately 
these investigations failed to identify a root cause for the lack of efficacy of the 
MAGE-A3 ASCI in NSCLC.

a comprehensive review of the MAGE-A3 ASCI Phase III results, together with all 
other available clinical and laboratory data in early clinical studies with various 
recombinant proteins, including NY-ESO-1, tested in different diseases and 
settings suggests that the anticancer activity of these ASCI, all based on the 
recombinant protein combined with adjuvant system AS15 technology may well 
be very limited.

the balance of anticipated benefits and apparent risks associated with NY-ESO-1 + 
AS15 ASCI continues to be acceptable following the ongoing systematic review of 
safety data. Also, no additional safety data will be collected, except for patients 
who continue treatment.
By stopping the active follow-up, the patients will not be further exposed to 
unnecessary study related procedures. 
Although GSK has no reasonable expectation of a population benefit from the 
treatment, GSK cannot exclude that some patients in the NYES01-AS15-MEL-001 
study may benefit from this treatment on an individual basis. Therefore, patients in the 
study and who are currently still receiving the study treatment, will be offered the 
option to continue treatment if they wish to do so, following discussion with their 
treating physician. 
                                                
1 GSK. (April 2 2014). Update on phase III clinical trial of investigational MAGE-A3 antigen-specific cancer 
immunotherapeutic in non-small cell lung cancer [Press release]. Retrieved from http://www.gsk.com/media/press-
releases/2014/update-on-phase-III-clinical-trial-of-investigational-MAGE-A3-antigen-specific-cancer-
immunotherapeutic-in-non-small-cell-lung-cancer.html. The data will be presented at the European Society For 
Medical Oncology Annual Congress 2014.
 
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In the best interest of patients, blood drawings which were planned for protocol 
research purposes (i.e. PBMCs, serum collection) will not be performed anymore. 
Blood drawing for safety monitoring as per protocol will continue.
By default, for each biological sample already collected in the scope of this study and 
not tested yet, testing will not be performed except if a scientific rationale remains 
relevant. In this case, testing will be done in compliance with the protocol and ICF 
signed by the patient.
The main changes in this Protocol Amendment are:

Addition of a subsection in the introduction and rationale explaining the results of 
the Phase III trials with the MAGE-A3 ASCI

Removal of all active follow-up visits and procedures,

Addition of a statement regarding the decision not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant, and that no further blood samples for protocol research 
purposes will be collected.

A clarification about the concentration in CpG7909 in different lots used in the 
study was added

The list of AEs to be recorded as pIMDs was updated

Additional clarifications were added to:

the study procedures 

the hematology, serum chemistry and urine tests 

the criteria for postponement of ASCI administrations

the evaluation of the overall response
In the main body of the protocol, changed text is indicated in bold italics. Appendix D
contains deleted text (marked with strikethrough) along with changed text. Throughout, 
the date of ALL deleted and/or changed text is 03 September 2014.
 
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Protocol Amendment 3 Investigator Agreement
I agree:

To conduct the study in compliance with this protocol, any mutually agreed future 
protocol amendments or protocol administrative changes, and with any other study 
conduct procedures and/or study conduct documents provided by GlaxoSmithKline 
Biologicals (GSK Biologicals).

To assume responsibility for the proper conduct of the study at this site.

That I am aware of, and will comply with, ‘Good Clinical Practice’ (GCP) and all 
applicable regulatory requirements.

To ensure that all persons assisting me with the study are adequately informed about 
the GSK Biologicals investigational product(s) and other study-related duties and 
functions as described in the protocol.

To acquire the reference ranges for laboratory tests performed locally and, if required 
by local regulations, obtain the laboratory’s current certification or Quality Assurance 
procedure manual.

To ensure that no clinical samples (including serum samples) are retained onsite or 
elsewhere without the approval of GSK Biologicals and the express written informed 
consent of the patient.

To perform no other biological assays on the clinical samples except those described 
in the protocol or its amendment(s).

To co-operate with a representative of GSK Biologicals in the monitoring process of 
the study and in resolution of queries about the data.

That I have been informed that certain regulatory authorities require the sponsor to 
obtain and supply, as necessary, details about the investigator’s ownership interest in 
the sponsor or the investigational product, and more generally about his/her financial 
ties with the sponsor. GSK Biologicals will use and disclose the information solely 
for the purpose of complying with regulatory requirements.
Hence I:

Agree to supply GSK Biologicals with any necessary information regarding 
ownership interest and financial ties (including those of my spouse and dependent 
children).

Agree to promptly update this information if any relevant changes occur during the 
course of the study and for 1 year following completion of the study. 

Agree that GSK Biologicals may disclose any information it has about such 
ownership interests and financial ties to regulatory authorities.

Agree to provide GSK Biologicals with an updated Curriculum Vitae and other 
documents required by regulatory agencies for this study.
 
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eTrack study number and 
Abbreviated Title
112406 (NYESO1-AS15-MEL-001 (MET))
IND number
14313
EudraCT number
2010-020663-20
Date of protocol amendment
Amendment 3 Final: 03 September 2014
Detailed Title
An open Phase I Study of immunization with the 
recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic in patients with NY-ESO-1-
positive unresectable and progressive metastatic 
cutaneous melanoma
Investigator name
Signature
Date
 
(LKP) name:
Signature
Date
 
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SYNOPSIS
Detailed 
Title
An open Phase I Study of immunization with the recNY-ESO-1 + AS15 
Antigen-Specific Cancer Immunotherapeutic in patients with NY-ESO-
1-positive unresectable and progressive metastatic cutaneous melanoma
Indication
Patients with NY-ESO-1-positive unresectable and progressive 
metastatic cutaneous melanoma (Stage III or Stage IV M1a; not Stage 
IV M1b or IV M1c)
Rationale 
for the 
study and 
study 
design
1. Need for new therapeutic approaches for metastatic melanoma
Patients with Stage III and IV M1a cutaneous malignant melanoma 
without visceral lesions have an unfavorable prognosis and there is 
currently no treatment able to extend survival.
The NY-ESO-1 gene is not expressed in normal adult tissues except 
testis, and is expressed during embryogenesis as well as in 
spermatogonia and placenta as an intracellular protein. It should be 
noted that these normal adult cells expressing NY-ESO-1 protein do not 
bear Human Leukocyte Antigen (HLA) molecules on their surface and 
therefore do not present any NY-ESO-1-derived peptides to T-cells. By 
consequence, spontaneous and induced NY-ESO-1-specific immune 
response is unlikely to be associated with immune-related toxicities.
Because of this particular expression pattern, those genes are also called 
“Cancer-Testis (CT) genes”. NY-ESO-1 is an example of a CT gene. The 
MAGE-A3 gene is another example of a CT gene.
The NY-ESO-1 gene has been shown to be expressed (by Reverse 
Transcription Polymerase Chain Reaction; RT-PCR) in 20% to 40% of 
several tumor types, including breast cancer, lung cancer, prostate 
cancer, bladder cancer, esophageal cancer, and melanoma. The overall 
NY-ESO-1 gene expression in melanoma patients is 29-43% when 
measured by RT-PCR, a similar range (24-45%) is determined using 
immunohistochemistry (IHC) in the total melanoma population, and 27-
36% in the metastatic melanoma population.
NY-ESO-1 as proteins, peptides, viral vectors or plasmid DNA have 
been combined with a variety of immunological adjuvants in 29 clinical 
studies involving cancer patients with e.g. melanoma, breast, 
esophageal, bladder and ovarian cancers. In the large majority of these 
studies, a NY-ESO-1-specific CD4+ and CD8+ T-cell immune response 
has been induced, and in some patients a clinical response has been 
observed without major safety signal.
 
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In a Phase II trial, recMAGE-A3 + AS15 ASCI (Antigen-Specific 
Cancer Immunotherapeutic) was administered to melanoma patients 
with early metastatic disease (GSK Study 249553/008). Objective 
clinical response was observed for 4 of the 36 patients, which met the 
criteria for proof-of-concept.
The Final Container (per human dose) is composed of 420 g of 
CpG7909 oligonucleotide (see note below), which will be co-
lyophilized with the 300 g recNY-ESO-1 protein and the liquid 
AS01B-4 adjuvant, which contains 50 g of QS21 (a saponin molecule) 
and 50 g of Monophosphoryl lipid A (MPL®), in a liposome 
formulation.
[Note: The concentration in CpG7909 depends on the lot used –
Certain lots are labeled as containing 420 µg CpG, whereas other lots 
will be labeled as 380 µg CpG. This difference in how the CpG content 
is noted is due to the fact that a different analytical method to 
determine the content of the CpG was applied to more recent lots and 
the change in the content designation from 420 to 380 µg is a result of 
a recalculation. The actual content of the CpG in the lots is the same
(within the allowable assay variation).] (Amended 03 September 
2014).
In this proposed study, recNY-ESO-1 + AS15 ASCI will be tested at the 
same dose schedule, in the same patient population and with the same 
Adjuvant System (AS15), as recMAGE A3 + AS15 ASCI in the GSK 
249553/008 Study.
2. Rationale for using recNY-ESO-1 protein combined with AS15 
Adjuvant System
There are two advantages in immunizing patients using the recNY-ESO-
1 protein instead of peptides.  First, a full protein carries multiple 
potential epitopes therefore targeting a broader patient population.
Second, the recNY-ESO-1 protein is also expected to carry epitopes 
specific for CD4+ T-helper lymphocytes of the Th1 type, whose 
activation could significantly enhance the strength of the anti-tumor 
immune response.
The selection of the AS15 Adjuvant System is based on the expected 
benefits from a combination of immunological adjuvants, a favorable 
safety profile in toxicity studies evaluating the safety profile of AS15 
and its individual components, and improved immunogenicity because 
AS15 is a strong immunostimulant in mice, monkeys and humans, and 
is able to induce a more powerful Th1 response and subsequently to 
better protect against tumor challenge than AS02B Adjuvant System.
 
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GSK recently reported the negative results of the MAGRIT study. The 
detailed analysis of MAGRIT showed the absence of treatment effect 
in any of the primary, secondary, or exploratory analyses. All aspects 
of the MAGRIT study have been carefully assessed, and unfortunately 
these investigations failed to identify a root cause for the lack of 
efficacy of the MAGE-A3 ASCI  in NSCLC. 
Furthermore, a comprehensive review of the MAGE-A3 ASCI Phase 
III results, together with all other available clinical and laboratory 
data in early clinical studies with various recombinant proteins, 
including NY-ESO-1,  tested in different diseases and settings suggests 
that the anticancer activity of these ASCI, all based on the 
recombinant protein combined with adjuvant system AS15 technology 
may well be very limited. 
In light of this, GSK has decided to stop further development of the 
recombinant protein adjuvanted portfolio as a standalone treatment 
for cancer patients (Amended 03 September 2014).
3. NY-ESO-1 dose and schedule of administration
GSK will evaluate the safety and immunogenicity of recNY-ESO-1 + 
AS15 ASCI at a fixed dose of AS15 and antigen.  GSK Biologicals will 
capitalize on the previous MAGE-A3 experience in melanoma through 
using the same dose of the tumor antigen (300 g), the same schedule of 
immunization, in the same patient population and with the same AS15 
Adjuvant System as the ones used for the GSK 249553/008 Study.  The 
recMAGE-A3 + AS15 ASCI has demonstrated clinical activity in this 
metastatic melanoma population and this study will enable a further 
validation of the MAGE-A3 predictive gene signature and provide the 
potential to define a specific NY-ESO-1 predictive gene signature.
Objectives
Co-primary: The two co-primary objectives of this study are to 
document and to characterize the severe toxicity and clinical activity of 
the recNY-ESO-1 + AS15 ASCI in patients with NY-ESO-1-positive 
metastatic cutaneous melanoma.
Secondary: The secondary objectives of this study are to document and 
characterize:
1. Additional clinical indicators of clinical activity in the overall 
population and in the population of patients who present the 
predictive MAGE-A3 gene signature.
2. Additional indicators of safety.
3. The specific humoral and cellular immune response induced by 
recNY-ESO-1 + AS15 ASCI.
 
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Translational: The exploratory objectives of this study are to document 
and characterize:
1. Expression testing for other tumor antigens (such as MAGE-A3, 
MAGE-C2, LAGE-1, PRAME and WT1) on the presenting 
lesion(s) and on any new lesion(s) and NY-ESO-1 expression 
testing on any new lesion(s).
2. The gene profiling on the tumor resected at baseline and any 
relapsed tumor (if available).
3. The “antigen spreading” in both the humoral and cellular immune 
responses elicited by the recNY-ESO-1 + AS15 ASCI.
4. The gene profiling of the immunological response elicited by the 
recNY-ESO-1 + AS15 ASCI.
5. Proteomics profiling of the immunological response elicited by the 
recNY-ESO-1 + AS15 ASCI.
6. Tumor immune infiltration assessment and characterization.
7. DNA promoter methylation analysis of NY-ESO-1, other tumor 
antigens and candidate genes that might be predictive to NY-ESO-1 
ASCI clinical efficacy, in addition to immunoregulatory genes.
8. Pharmacogenetics analyses.
These different exploratory tests will only be performed on biological 
samples from patients who voluntarily gave their consent for these 
specific assessments in the Informed Consent Form.
Note that, as of Amendment 3, the decision was taken not to perform 
further testing on biological samples already collected in this study by 
default, except if a scientific rationale remains relevant. No further 
blood samples for protocol research purposes will be collected. 
(Amended 03 September 2014)
Study 
design

Experimental design: Single-arm, Phase I multicenter study.

Treatment allocation: Sequential.

Blinding: No blinding, open-label.
Treatment Groups: Single treatment study
recNY-ESO-1 + AS15 ASCI).

Treatment administration schedule(s): patients may receive up to 4 
cycles of ASCI administration (maximum of 24 ASCI 
administrations), provided that at each tumor evaluation time point, 
the clinical criteria to continue the treatment are met, including 
patients having a clinical response of either CR, PR, SD, or SPD.
Cycle 1: 6 ASCI administrations given at 2-week intervals
(Weeks 0, 2, 4, 6, 8, 10)
 
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Cycle 2: 6 ASCI administrations given at 3-week intervals
(Weeks 14, 17, 20, 23, 26, 29)
Cycle 3: 4 ASCI administrations given at 6-week intervals
(Weeks 33, 39, 45, 51)
Cycle 4: 4 ASCI administrations given at 3-month intervals
followed by 4 ASCI administrations given at 6-month intervals

Control: None.

Type of study: Self-contained.

Data collection: Remote Data Entry (RDE) on electronic Case 
Report Forms (eCRF).

Duration of the study:  The duration of the ASCI treatment period 
(from first visit to the concluding visit) will not last longer than 49 
months for any patient, comprising the entire period of 
immunization and the concluding visit.  The duration of the follow-
up will be one year after the concluding visit.  The total duration 
including follow-up is approximately 5 years.
As of Amendment 3, all active follow-up visits and procedures will 
be stopped. Post-study AEs/SAEs will continue to be reported as 
described in Section 9.3.1. (Amended 03 September 2014).
Number of 
patients
It is planned to recruit 34 patients with metastatic melanoma 
(unresectable Stage III melanoma, Stage III in-transit metastasis with 
(N3) or without (N2c) nodal metastasis or Stage IV M1a).
Endpoints
Co-primary
Safety endpoint

Occurrence of severe toxicities during the study treatment phase 
and follow-up.
Defined according to CTCAE (Version 4.0) as follows:
1.
An ASCI-related or possibly ASCI-related Grade 3 or higher 
toxicity.  Grade 3 myalgia, arthralgia, headache, fever, rigors/chills 
and fatigue (including lethargy, malaise and asthenia) should 
persist for 48 hours despite therapy in order to be taken into 
account.
2.
An ASCI-related or possibly ASCI-related Grade 2 or higher 
allergic reaction occurring within 24 hours following the ASCI 
administration.
Note: Any severe toxicity event must be entered in the patient’s eCRF 
within 24 hours of the event becoming known to the investigator.
 
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Clinical activity endpoint

The induction of objective clinical response (Complete Response 
(CR) or Partial Response (PR)) in the overall population.
Secondary
Clinical activity endpoints
The secondary clinical activity endpoints will include:
1. Occurrence of objective clinical response (CR or PR) in the 
population of patients who present the predictive MAGE-A3 gene 
signature.
2. In the overall population and in the population of patients presenting 
the predictive MAGE-A3 gene signature:

Occurrence of stable disease (SD).

Occurrence of mixed response (MR).

Time to Treatment Failure (TTF).
TTF is defined as the time from first treatment until the date of the last 
treatment administration, irrespective of the reason for study treatment 
discontinuation.

Progression-free survival (PFS).
PFS is defined as the time from first treatment to either the date of first 
disease progression (PD or SPD) or the date of death (for whatever 
reason), whichever comes first. Patients alive and without disease 
progression are censored at the date of the last visit/contact. (Amended 
03 September 2014)

Overall survival (OS).
OS is defined as the time from first treatment until death. Patients alive 
at the time of analysis are censored at the time of the last visit/contact.

The duration of response for patients with CR, PR or Stable 
Disease (SD) status.
The duration of the response is defined as time from first objective 
response or SD evaluation to first PD assessment or death. (Amended 
03 September 2014)
 
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Safety endpoints
The secondary safety endpoints will include:

Occurrence of adverse events (AEs) and serious adverse events 
(SAEs) during the study treatment period and ending 30 days after 
the last study treatment administration.
Note: The occurrence of SAEs (possibly) related to the recNY-ESO-1 + 
AS15 ASCI will be captured during the entire study duration.
Immunogenicity endpoints
Note that, as of Amendment 3, the decision was taken not to perform 
further testing on biological samples already collected in this study by 
default, except if a scientific rationale remains relevant. No further 
blood samples for protocol research purposes will be collected.
(Amended 03 September 2014).

Immunogenicity of the NY-ESO-1 ASCI treatment will be 
evaluated at different timepoints.
On the basis of:
1.
The anti-NY-ESO-1 humoral antibody concentration and response.
(Amended 03 September 2014)
2.
The anti-NY-ESO-1 cellular (T-cell) response.
 
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TABLE OF CONTENTS
PAGE
SYNOPSIS......................................................................................................................8
LIST OF ABBREVIATIONS...........................................................................................23
GLOSSARY OF TERMS ...............................................................................................26
1.
INTRODUCTION....................................................................................................29
1.1.
Background ................................................................................................29
1.1.1.
Background on malignant cutaneous melanoma..........................29
1.1.2.
Background on NY-ESO-1...........................................................30
1.2.
The recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic.....................................................................................31
1.2.1.
The recNY-ESO-1 antigen ...........................................................31
1.2.2.
The AS15 Adjuvant System .........................................................32
1.2.3.
Pre-clinical safety and toxicology tests with NY-ESO-1 + 
AS15 ASCI ..................................................................................32
1.2.4.
Previous clinical studies with NY-ESO-1......................................32
1.3.
Rationale for the study and study design ....................................................33
1.3.1.
Need for new therapeutic approaches for metastatic 
melanoma....................................................................................33
1.3.2.
Rationale for using NY-ESO-1 recombinant protein 
combined with AS15 Adjuvant System.........................................34
1.3.2.1.
recNY-ESO-1 protein..................................................34
1.3.2.2.
AS15 Adjuvant System...............................................34
1.3.3.
NY-ESO-1 dose and schedule of administration ..........................36
1.3.4.
Rationale for translational research..............................................37
2.
OBJECTIVES.........................................................................................................38
2.1.
Co-primary objectives .................................................................................38
2.2.
Secondary objectives..................................................................................38
2.3.
Translational research objectives................................................................38
3.
STUDY DESIGN OVERVIEW ................................................................................39
3.1.
General outline of study design...................................................................39
3.2.
Study Treatment Schedule .........................................................................40
3.3.
Duration of study participation.....................................................................40
4.
STUDY POPULATION...........................................................................................42
4.1.
Number of patients/centers.........................................................................42
4.1.1.
Overview of the recruitment plan .................................................42
4.1.2.
Replacement ...............................................................................42
4.2.
Inclusion criteria..........................................................................................42
4.3.
Exclusion criteria for enrolment...................................................................44
5.
STUDY PRODUCT AND ADMINISTRATION.........................................................45
5.1.
Description of study product........................................................................45
5.2.
Storage and handling of study product........................................................46
5.3.
Dosage and administration of study product ...............................................46
 
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5.3.1.
Dosage........................................................................................46
5.3.2.
Administration..............................................................................47
5.4.
Replacement of unusable study product doses...........................................47
5.5.
Contraindications to subsequent study product administration....................48
5.5.1.
Criteria for postponement of ASCI administration ........................48
5.5.2.
Criteria for permanent stopping of ASCI administration................49
5.6.
Concomitant medication and non-drug therapies........................................50
5.6.1.
Permitted medication ...................................................................50
5.6.2.
Medications, vaccines and non-drug therapies that may 
lead to the elimination of a patient from ATP analyses.................51
5.6.2.1.
Prohibited medications or non-drug therapies.............51
5.6.2.2.
Elimination criteria for analysis ...................................52
5.6.3.
Time window for concomitant vaccination....................................52
5.6.4.
Time window for recording concomitant medication and 
non-drug therapies in the eCRF...................................................53
5.7.
Intercurrent medical conditions that may lead to elimination from the 
ATP cohort for analysis...............................................................................53
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................53
6.1.
Patient identification and randomization of treatment..................................53
6.1.1.
Patient identification.....................................................................53
6.1.2.
Randomization / treatment assignment........................................54
6.2.
Method of blinding ......................................................................................54
6.3.
General study aspects ................................................................................54
6.3.1.
Attendance of study visits ............................................................54
6.3.2.
Staggered enrolment of patients..................................................56
6.3.3.
Temporary or permanent stopping of the entire study..................56
6.4.
Outline of study procedures ........................................................................57
6.5.
Detailed description of study procedures ....................................................63
6.5.1.
Procedures prior to study participation.........................................63
6.5.1.1.
Informed consent........................................................63
6.5.2.
Procedures during screening phase/prior to the first ASCI 
administration ..............................................................................63
6.5.2.1.
NY-ESO-1 expression screening of tumor 
lesion(s)......................................................................63
6.5.2.2.
Check inclusion and exclusion criteria ........................64
6.5.2.3.
Collect demographic data...........................................64
6.5.2.4.
Medical history ...........................................................64
6.5.2.5.
Physical examination..................................................64
6.5.2.6.
Tumor imaging and assessment.................................64
6.5.2.7.
Urine and blood collection ..........................................65
6.5.2.8.
Pregnancy test ...........................................................65
6.5.2.9.
HIV status...................................................................65
6.5.2.10.
Recording SAEs.........................................................66
6.5.3.
Procedures during ASCI administration phase.............................66
6.5.3.1.
Check inclusion and exclusion criteria ........................66
6.5.3.2.
Check and record concomitant medication.................66
6.5.3.3.
Check contraindications to ASCI administration .........66
6.5.3.4.
Blood sampling for safety or immune response 
assessments ..............................................................67
6.5.3.5.
Sampling of other body fluids .....................................67
6.5.3.6.
Additional tumor biopsy or tumor resection.................67
 
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6.5.3.7.
Treatment number assignment...................................67
6.5.3.8.
ASCI administration....................................................67
6.5.3.9.
Recording of non-serious AEs, SAEs, potential 
immune-mediated diseases (pIMDs) and 
pregnancy ..................................................................68
6.5.3.10.
Tumor response assessment .....................................68
6.5.3.11.
Clinical response criteria for continuing ASCI 
administration.............................................................68
6.5.4.
Concluding visit............................................................................69
6.5.4.1.
Patients who received all the scheduled doses...........69
6.5.4.2.
Patients withdrawn before the end of the 
scheduled doses ........................................................69
6.5.4.3.
Study conclusion ........................................................70
6.6.
Response criteria........................................................................................70
6.6.1.
Response criteria for patients with all target lesions ≥ 20.0 
mm ..............................................................................................71
6.6.1.1.
Measurability of tumor lesions ....................................71
6.6.1.1.1.
Definitions...............................................71
6.6.1.1.2.
Methods of measurement .......................71
6.6.1.2.
Tumor response evaluation ........................................72
6.6.1.2.1.
Baseline documentation of target 
and non-target lesions ............................72
6.6.1.2.2.
Response criteria....................................73
6.6.1.2.3.
Evaluation of best overall 
response.................................................73
6.6.2.
Tumor response for cutaneous/subcutaneous/lymph node 
disease with target lesions of less than 20.0 mm .........................74
6.6.2.1.
Measurability of 
cutaneous/subcutaneous/lymph node tumor 
lesions at baseline......................................................75
6.6.2.1.1.
Definitions...............................................75
6.6.2.1.2.
Methods of measurement .......................75
6.6.2.2.
Tumor response evaluation ........................................76
6.6.2.2.1.
Baseline documentation of target 
and non-target lesions ............................76
6.6.2.2.2.
Response criteria....................................76
6.6.2.2.3.
Evaluation of best overall 
response.................................................77
6.6.3.
Response criteria for patients with both target lesion(s) ≥ 
20 mm and target lesion(s) < 20 mm ...........................................77
6.6.3.1.
Evaluation of best overall response............................78
6.6.4.
Confirmation measurements and duration of response................78
6.6.4.1.
Confirmation...............................................................78
6.6.4.2.
Duration of overall response.......................................78
6.6.4.3.
Duration of stable disease ..........................................78
6.6.5.
Definition of mixed response........................................................79
6.6.5.1.
Mixed response adapted from the RECIST 
criteria ........................................................................79
6.6.5.2.
Mixed response for disease not evaluable 
according to RECIST criteria ......................................79
6.6.6.
Definition of Slow Progressive Disease status .............................80
6.7.
Biological sample handling and analysis.....................................................81
 
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6.7.1.
Use of specified study materials ..................................................82
6.7.2.
Hematology, Serum Chemistry and Urine tests............................82
6.7.3.
Molecular, immunological and translational research read-
outs..............................................................................................84
6.7.3.1.
NY-ESO-1 expression screening of the tumor ............87
6.7.3.2.
Immunological read-outs ............................................87
6.7.3.2.1.
Antibody response to the ASCI 
antigens..................................................87
6.7.3.2.2.
Cellular immune response to the 
ASCI antigens.........................................88
7.
TRANSLATIONAL RESEARCH .............................................................................90
7.1.
Analysis of expression of NY-ESO-1 and other tumor antigens on 
presenting lesion and on any new lesions...................................................90
7.2.
Gene profiling research...............................................................................91
7.2.1.
Gene profiling on the baseline tumor lesion .................................91
7.2.2.
Gene profiling and NY-ESO-1 expression testing on 
additional lesions .........................................................................92
7.3.
Natural immunity and antigen spreading induced by the recNY-
ESO-1 + AS15 ASCI (Amended 03 September 2014) ................................92
7.4.
Gene profiling of immunological response to the recNY-ESO-1 + 
AS15 ASCI .................................................................................................93
7.5.
Proteomic profiling......................................................................................93
7.6.
Analysis of tumor immune infiltration...........................................................94
7.7.
DNA promoter methylation analysis of NY-ESO-1 and other tumor 
antigens......................................................................................................94
7.8.
Pharmacogenetics analyses .......................................................................96
8.
HEALTH ECONOMICS ..........................................................................................97
9.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS.....................................97
9.1.
Safety definitions ........................................................................................97
9.1.1.
Definition of an adverse event......................................................97
9.1.2.
Definition of a serious adverse event ...........................................98
9.1.3.
Potential immune mediated diseases...........................................99
9.1.4.
Clinical laboratory parameters and other abnormal 
assessments qualifying as adverse events or serious 
adverse events ..........................................................................102
9.2.
Events or outcomes not qualifying as adverse events or serious 
adverse events .........................................................................................102
9.2.1.
Progression of the melanoma ....................................................102
9.2.2.
Pregnancy .................................................................................102
9.3.
Detecting and recording adverse events, serious adverse events 
and pregnancies .......................................................................................103
9.3.1.
Time period for detecting and recording adverse events, 
serious adverse events and pregnancies...................................103
9.3.2.
Evaluation of adverse events and serious adverse events.........105
9.3.2.1.
Active questioning to detect adverse events 
and serious adverse events......................................105
9.3.2.2.
Assessment of adverse events.................................105
9.3.2.2.1.
Assessment of intensity........................105
9.3.2.2.2.
Assessment of causality .......................106
 
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9.3.2.3.
Assessment of outcomes..........................................107
9.4.
Reporting and follow-up of adverse events, serious adverse events 
and pregnancies .......................................................................................107
9.4.1.
Prompt reporting of serious adverse events and other 
events to GSK Biologicals..........................................................107
9.4.2.
Regulatory reporting requirements for serious adverse 
events........................................................................................108
9.4.3.
Completion and transmission of SAEs reports to GSK 
Biologicals .................................................................................108
9.4.3.1.
Back-up system in case the electronic SAE 
reporting system does not work................................109
9.4.3.2.
Back-up system in case the electronic system 
for reporting of severe toxicities does not work.........109
9.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals .................................................................................110
9.4.5.
Reporting of pIMDs to GSK Biologicals......................................110
9.4.6.
Follow-up of adverse events and serious adverse events..........111
9.5.
Treatment of adverse events ....................................................................111
9.6.
Unblinding.................................................................................................111
9.7.
Emergency unblinding ..............................................................................112
9.8.
Patient card ..............................................................................................112
10. PATIENT COMPLETION AND WITHDRAWAL....................................................112
10.1.
Patient completion ....................................................................................112
10.1.1.
Patient completion of ASCI administration .................................112
10.1.2.
Patient completion of study........................................................112
10.2.
Patient withdrawal.....................................................................................113
10.2.1.
Patient withdrawal from ASCI administration .............................113
10.2.2.
Patient withdrawal from the study ..............................................114
10.3.
Screen and baseline failures.....................................................................114
11. DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES.............115
11.1.
Co-primary endpoint .................................................................................115
11.1.1.
Safety endpoint..........................................................................115
11.1.2.
Clinical activity endpoint.............................................................115
11.2.
Secondary endpoints ................................................................................115
11.2.1.
Clinical activity endpoints...........................................................115
11.2.2.
Safety endpoints........................................................................116
11.2.3.
Immunogenicity endpoints .........................................................116
11.3.
Estimated sample size..............................................................................117
11.3.1.
Definitions..................................................................................117
11.3.2.
Statistical errors will be ..............................................................117
11.3.3.
Study success criteria................................................................118
11.4.
Study cohorts to be evaluated...................................................................119
11.4.1.
Total treated cohort....................................................................119
11.4.2.
According-to-protocol (ATP) cohort for analysis of 
immunogenicity..........................................................................119
11.5.
Derived and transformed data...................................................................119
11.5.1.
Humoral immunogenicity ...........................................................119
11.5.2.
Cellular Immunogenicity.............................................................120
11.5.3.
Safety ........................................................................................120
11.6.
Conduct of analyses .................................................................................120
 
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11.6.1.
Sequence of analyses................................................................120
11.6.2.
Statistical considerations for interim analyses............................120
11.7.
Statistical methods....................................................................................120
11.7.1.
Analysis of demographics/baseline characteristics ....................121
11.7.2.
Analysis of clinical activity..........................................................121
11.7.3.
Analysis of immunogenicity........................................................122
11.7.4.
Analysis of safety.......................................................................122
12. ADMINISTRATIVE MATTERS .............................................................................123
12.1.
Remote data entry instructions .................................................................123
12.2.
Regulatory and ethical considerations, including the informed 
consent process........................................................................................124
12.3.
Data Safety Monitoring Committee ...........................................................125
12.4.
GSK Biologicals’ Safety Review Team......................................................126
12.5.
Monitoring by or on behalf of GSK Biologicals ..........................................126
12.6.
Archiving of data at study sites .................................................................127
12.7.
Audits .......................................................................................................127
12.8.
Ownership, confidentiality and publication ................................................128
12.8.1.
Ownership .................................................................................128
12.8.2.
Confidentiality ............................................................................128
12.8.3.
Publication.................................................................................128
13. COUNTRY SPECIFIC REQUIREMENTS.............................................................129
13.1.
French administrative considerations........................................................129
13.2.
Germany specific requirements ................................................................132
14. REFERENCES.....................................................................................................133
 
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LIST OF TABLES
PAGE
Table 1
Overview of ASCI administrations, tumor and immunological 
evaluations 1...........................................................................................41
Table 2
Dosage and administration.....................................................................47
Table 3
Permitted deviations from stipulated dates of visits ................................55
Table 4
Example of postponement of study treatment dose for 3 weeks 
during Cycle 1 and the delay of the schedule induced............................55
Table 5
Example of postponement of ASCI treatment for more than 4 
weeks leading to withdrawal of patient from the study treatment............56
Table 6
List of study procedures for Cycle 1 (including screening)......................58
Table 7
List of study procedures for Cycle 2 .......................................................60
Table 8
List of study procedures for Cycle 3 .......................................................61
Table 9
List of study procedures for Cycle 4 .......................................................62
Table 10
Hematology, Serum Chemistry, Urine tests............................................83
Table 11
Overview of molecular and immunological read-outs and 
translational research.............................................................................85
Table 12
Examples of AEs to be recorded as pIMDs (amended 3 
September 2014) .................................................................................100
Table 13
Reporting periods for AEs, SAEs, pIMDs and pregnancies ..................104
Table 14
Time frames for submitting SAEs and other events reports to 
GSK Biologicals ...................................................................................108
Table 15
Outcome of simulations with both safety and clinical response ............118
LIST OF FIGURES
PAGE
Figure 1
Estimated survival curves for melanoma patients according to 
disease stage.........................................................................................30
 
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LIST OF APPENDICES
PAGE
Appendix A
TNM classification for melanoma .........................................................139
Appendix B
Common Terminology Criteria for Adverse Events, Version 4.0...........142
Appendix C
Eastern Cooperative Oncology Group (ECOG) performance 
status ...................................................................................................143
Appendix D
Amendments and administrative changes to the protocol.....................144
 
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LIST OF ABBREVIATIONS
Ab
Antibody
AE
Adverse Event
AJCC
American Joint Committee on Cancer
ALAT
ALanine AminoTransferase
ANA
Anti-Nuclear Antibody
APC
Antigen Presenting Cells
APTT
Activated Partial Thromboplastin Time
ASAT
ASparate AminoTransferase
ASCI
Antigen-Specific Cancer Immunotherapeutic
ATP
According-To-Protocol
HCG
Beta Human Chorionic Gonadotropin
BCG
Bacillus Calmette-Guérin
B-RAF
B-raf murine sarcoma viral oncogene homolog B1
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CHP
Cholesterol-bearing Hydrophobized Pullulan
CK
Creatine Kinase
CMI
Cell-Mediated Immune
CpG7909
24-nucleotide immunostimulatory oligonucleotide
CR
Complete Response
CRA
Clinical Research Associate
CT
Computer Tomography
CT gene
Cancer-Testis gene
CTA
Cancer-Testis Antigen
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Cytotoxic T Lymphocyte
DERMA
ADjuvant ImmunothERapy with MAGE-A3 in melanoMA
DNA
DeoxyriboNucleic Acid
DSMC
Data Safety Monitoring Committee
DTIC
Dacarbazine
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
ELISA
Enzyme-Linked Immunosorbent Assay
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FACS
Fluorescence-Activated Cell Sorting
FDA
Food and Drug Administration, United States
 
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FFPE
Formalin-Fixed Paraffin Embedded
GT
Gamma-Glutamyl Transpeptidase
GCP
Good Clinical Practice
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
GMT
Geometric Mean Titer
GSK
GlaxoSmithKline 
GSM
Global Study Manager
HIV
Human Immunodeficiency Virus
HLA
Human Leukocyte Antigen
IB
Investigator Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDDM
Insulin-Dependent Diabetes Mellitus
IEC
Independent Ethics Committee
IFN
Interferon alpha
IFN-
Interferon-gamma
IHC
ImmunoHistoChemistry
IL-2
Interleukin-2
i.m.
IntraMuscular
IMAC
Ion Metal Affinity Chromatography
IND
Investigational New Drug
IRB
Institutional Review Board
IUD
IntraUterine Device
IUS
IntraUterine System
KM
Kaplan-Meier
LICR
Ludwig Institute for Cancer Research
LD
Longest Diameter
LDH
Lactate DeHydrogenase
MAGE
Melanoma AntiGEn
MAGRIT
MAGE-A3 as Adjuvant Non-Small Cell LunG CanceR
ImmunoTherapy
MedDRA
Medical Dictionary for Regulatory Activities
MET
Metastatic
MHC
Major Histocompatibility Complex
MPL
MonoPhosphoryl Lipid A
MR
Mixed Response
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
 
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NCI
National Cancer Institute
NK
Natural Killer
NSCLC
Non-Small Cell Lung Cancer
NY-ESO-1
Cancer-Testis gene: New York-ESOphageal cancer-1
OS
Overall Survival
PBMC
Peripheral Blood Mononuclear Cells
PD
Progressive Disease
PFS
Progression-Free Survival
pIMD
potential immune mediated disease
PR
Partial Response
PREDICT
Predictive gene signature for REsponse to recMAGE-A3 in 
unresecteD metastatIc CuTaneous melanoma
PT
Prothrombin Time
QS21
Saponin extracted from the tree bark of Quillaja saponaria Molina
RDE
Remote Data Entry
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
RiboNucleic Acid
RT-PCR
Reverse Transcription Polymerase Chain Reaction
SAE
Serious Adverse Event
SBIR
Simply the Best Internet Randomization
(GSK Biologicals’ system for treatment allocation using the 
internet)
SD
Stable Disease
SDV
Source Document Verification
SOP
Standard Operating Procedure
SPD
Slow Progressive Disease
SPM
Study Procedures Manual
SRT
Safety Review Team
SSSS
Site Staff Signature Sheet
TE
Tumor Evaluation
Th1
T-helper-1
TLR9
Toll-Like Receptor 9
TNM
The TNM staging system is based on the extent of the tumor (T), 
spread to lymph nodes (N), and metastasis (spread to other parts of 
the body) (M)
TSH
Thyroid Stimulating Hormone
TTF
Time to Treatment Failure
US
Ultrasound
USA
United States of America
 
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GLOSSARY OF TERMS
Adequate contraception:
Adequate contraception is defined as a contraceptive 
method with failure rate of less than 1% per year when 
used consistently and correctly (when applicable, as 
mentioned in the product label) for example abstinence, 
combined or progestogen oral contraceptives, injectable 
progestogen, implants of levonorgestrel, oestrogenic 
vaginal ring, percutaneous contraceptive patches or 
intrauterine device (IUD) or intrauterine system (IUS), 
vasectomy with documented azoospermia of the sole 
male partner or double barrier method (condom or 
occlusive cap plus spermicidal agent).
For azoospermia, ‘documented’ refers to the laboratory 
report of azoospermia, required for acceptable 
documentation of successful vasectomy in the patient’s 
male partner.
Adverse event:
Any untoward medical occurrence in a patient or clinical 
investigation patient, temporally associated with the use 
of a medicinal product, whether or not considered related 
to the medicinal product.
An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For 
marketed medicinal products, this also includes failure to 
produce expected benefits (i.e. lack of efficacy), abuse or 
misuse.
Eligible:
Qualified for enrolment into the study based upon strict 
adherence to inclusion/exclusion criteria.
eTrack:
GSK’s tracking tool for clinical trials.
Evaluable:
Meeting all eligibility criteria, complying with the 
procedures defined in the protocol, and, therefore, 
included in the according-to-protocol (ATP) analysis (see 
Sections 5.6.2 and 11.4 for details on criteria for 
evaluability).
 
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Global Study Manager:
An individual assigned by GSK Biologicals Headquarters 
who is responsible for assuring the co-ordination of the 
operational aspects and proper conduct of a clinical study, 
including compliance with International Conference on 
Harmonization (ICH) Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP) and GSK policies and 
standard operating procedures.
Investigational study 
product/product:
(Synonym of 
Investigational Medicinal 
Product)
A pharmaceutical form of an active ingredient or placebo 
being tested or used as a reference in a clinical trial, 
including a product with a marketing authorization when 
used in a way different from the approved form, or when 
used for an unapproved indication, or when used to gain 
further information about an approved use. 
Medical Monitor:
An individual medically qualified to assume the 
responsibilities of the sponsor (GSK Biologicals) 
especially in regards to the ethics, clinical safety of a 
study and the assessment of adverse events.
Month
One month is defined as four weeks i.e. 28 days during 
the treatment phase.  One year is equal to 12 months.
Menarche:
Menarche is the onset of menses for the first time in a 
young female and is preceded by several changes 
associated with puberty including breast development and 
pubic hair growth. Menarche usually occurs within 1-2 
years of breast development, thelarche. However, a 
young female can become pregnant before her first 
menses. Thus, a conservative definition of non-
childbearing potential in a pre-menarcheal female is a 
young female who has not yet entered puberty as 
evidenced by lack of breast development (palpable 
glandular breast tissue).
Menopause:
Menopause is the age associated with complete cessation 
of menstrual cycles, menses, and implies the loss of 
reproductive potential by ovarian failure. A practical 
definition accepts menopause after 1 year without menses 
with an appropriate clinical profile at the appropriate age 
e.g. > 45 years.
Patient:
Term used throughout the protocol to denote an 
individual who has been contacted in order to participate 
or participates in the clinical study, either as a recipient of 
the product(s) or as a control.
 
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Patient number:
A unique number identifying a patient, assigned to each 
patient consenting to participate in the study/as soon as 
they sign the first informed consent.
Protocol amendment:
ICH defines a protocol amendment as: ‘A written 
description of a change(s) to or formal clarification of a 
protocol.’ GSK Biologicals further details this to include 
a change to an approved protocol that affects the safety of 
patients, scope of the investigation, study design, or 
scientific integrity of the study.
Protocol administrative 
change:
A protocol administrative change addresses changes to 
only logistical or administrative aspects of the study.
NB Any change that falls under the definition of a 
protocol amendment (e.g. a change that affects the safety 
of patients, scope of the investigation, study design, or 
scientific integrity of the study) MUST be prepared as an 
amendment to the protocol. 
Site Monitor:
An individual assigned by the sponsor who is responsible 
for assuring proper conduct of clinical studies at one or 
more investigational sites.
Study procedures manual 
(SPM):
Manual that provides the investigator and the site 
personnel with administrative and detailed technical 
information that does not impact the safety of the 
patients.
Sub-population:
A group of patients for whom specific data are collected 
compared to other patients.
Treatment:
Term used throughout the clinical study to denote a set of 
investigational product(s) or marketed product(s) or 
placebo intended to be administered to a patient, 
identified by a unique number, according to the study 
randomization or treatment allocation.
Treatment number:
A number identifying a treatment to a patient, according 
to the study randomization or treatment allocation.
 
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1.
INTRODUCTION
1.1.
Background
1.1.1.
Background on malignant cutaneous melanoma
The incidence of malignant cutaneous melanoma is increasing rapidly having doubled in 
the last 10 years. The worldwide yearly incidence of melanoma is over 160,000 cases 
[Ferlay, 2004]. Currently, over 90% of the patients present with only primary melanoma 
at first diagnosis [Garbe, 2001].
Although resection of the primary tumor is curative in many cases, some 20 - 30% of the 
patients will eventually die of their malignant melanoma (Figure 1). Patients with distant 
metastases, Stage IV disease, have a very poor prognosis with a median survival of 8 
months and a 2-year survival rate of 11% [Balch, 2001].
The currently most used (and to date, the only cytotoxic approved for this indication by 
the United States Food and Drug Administration (US-FDA)) chemotherapy in the 
treatment of metastatic melanoma is the tetrazine alkylating agent dacarbazine (DTIC). 
The response rates for single-agent dacarbazine are 10 - 20% with complete remission 
being rare and a median length of remission of approximately 6 months [Khayat, 2002]. 
Several other single-agent chemotherapies lead to similar response rates but none results 
in better overall survival. Combination chemotherapies with 2 - 5 drug regimens may 
increase response rates up to 40% but do not result in a survival advantage [Chapman, 
1999]. High dose interleukin-2 (IL-2) has been licensed for use in metastatic melanoma 
following Phase II studies in which approximately 5% of the patients achieved long-term 
remissions. This regimen is, however, associated with significant toxicity and is not 
widely applicable [Tarhini, 2007]. Combination bio-chemotherapy interleukin-2 (IL-2) 
and interferon-alpha (INF) has in several Phase II studies been demonstrated to have 
high response rates of 20 - 50% with a small proportion, 5 - 10%, of long-term survivors 
[Legha, 1998]. Disappointingly, however, Phase III studies have shown that bio-
chemotherapy does not result in a survival advantage over chemotherapy in advanced 
melanoma [Keilholz, 2005]. Targeted therapies are also evaluated in the treatment of 
advanced metastatic melanoma patients. Since B-RAF (B-raf murine sarcoma viral 
oncogene homolog B1) has been found to be mutated in approximately 50% of 
melanoma patients, B-RAF inhibitors were investigated in advanced melanoma. 
Whereas sorafenib, a tyrosine kinase inhibitor targeting VEGFR, B-RAF and other 
tyrosine kinases, in combination with carboplatin and paclitaxel did not provide any 
advantage over placebo treatment in Phase III [Hauschild, 2009], a mutant B-RAF 
V600E specific inhibitor showed promising results in early clinical development [Hersey, 
2009]. In a Phase II clinical study in patients with metastatic melanoma, bevacizumab, a 
monoclonal antibody targeting VEGF and inhibiting angiogenesis, demonstrated clinical 
benefit in combination with carboplatin and paclitaxel [O’Day, 2009; Perez, 2009].
 
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Figure 1
Estimated survival curves for melanoma patients according to 
disease stage
Survival curves over a follow-up period of 15 years comparing localized melanoma (Stages I and II), regional 
metastases (Stage III), and distant metastases (Stage IV). The numbers in parentheses are patients from the AJCC 
melanoma staging database used to calculate the survival rates. The differences between the curves are significant (P 
< 0.0001).  Adapted from [Balch, 2001].
1.1.2.
Background on NY-ESO-1
The NY-ESO-1 gene is not expressed in normal adult tissues except testis [Scanlan, 
2004]. The NY-ESO-1 gene is expressed during embryogenesis as well as in 
spermatogonia and placenta [Jungbluth, 2007] as an intracellular protein. It is expressed 
primarily in the cytoplasm although nuclear expression can be seen in some 
spermatogonia [Jungbluth, 2001]. It should be noted that these normal adult cells 
expressing NY-ESO-1 protein do not bear Human Leukocyte Antigen (HLA) molecules 
on their surface and therefore do not present any NY-ESO-1-derived peptides to the T-
cells [Jungbluth, 2007; Guillaudeux, 1996; Simpson, 2005]. By consequence, 
spontaneous and induced NY-ESO-1-specific immune response is unlikely to be 
associated with immune-related toxicities.
Because of this particular expression pattern, those genes are also called “Cancer-Testis 
(CT) genes”. NY-ESO-1 is an example of a CT gene. The MAGE-A3 gene is another 
example of a CT gene [Gnjatic, 2006].
 
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The NY-ESO-1 gene has been shown to be expressed (by Reverse Transcription 
Polymerase Chain Reaction; RT-PCR) in 20% to 40% of several tumor types, including 
breast cancer, lung cancer, prostate cancer, bladder cancer, esophageal cancer and 
melanoma. The overall NY-ESO-1 gene expression in melanoma patients is 29-43% 
when measured by RT-PCR [Lethé, 1998; Sahin, 1998; Sahin, 2000], a similar range (24-
45%) is determined using immunohistochemistry (IHC) in the total melanoma population
[Jungbluth, 2001; Prasad, 2004; Vaughan, 2004], and 27-36% in the metastatic 
melanoma population [Jungbluth, 2001; Prasad, 2004].
NY-ESO-1 is a very immunogenic antigen as shown by its capacity to elicit spontaneous 
antibody and T-cell responses in a proportion of cancer patients. Approximately 5-10% 
of the melanoma, ovarian or breast cancer patients and 10% of operable Non-Small Cell 
Lung Cancer (NSCLC) patients appear to spontaneously develop NY-ESO-1 antibodies 
[Stockert, 1998; Scanlan, 2002; Chapman, 2007]. The presence of spontaneous CD4+
and CD8+ T-cells specific for NY-ESO-1 and restricted to different HLA, have also been 
found in the blood of some cancer patients.
Therefore, NY-ESO-1 is a good candidate for specific immune recognition of cancer due 
to its restricted pattern of expression in normal tissues, but frequent occurrence in various 
cancers.
Please refer to the current Investigator Brochure for a review of the pre-clinical and 
clinical studies of the recNY-ESO-1 + AS15 ASCI.
1.2.
The recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic
GSK Biologicals’ candidate recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic (ASCI) comprises the recombinant His/NY-ESO-1 antigen
(abbreviated as recNY-ESO-1 in the rest of this document) in combination with GSK 
Biologicals’ proprietary immunostimulant Adjuvant System AS15.
1.2.1.
The recNY-ESO-1 antigen
The recombinant NY-ESO-1-derived fusion protein (192-aa long) contains the full-length 
NY-ESO-1 sequence (amino acids 13-192) preceded by a 12-aa stretch comprising:

an N-terminal tetra peptide containing the translator initiator Met: MRGS.

a hexahistidine tag enabling the purification of the protein.

a dipeptide linker: GS.
The fusion protein is produced in E.coli by employing the DNA recombinant technology. 
One human dose of the candidate recNY-ESO-1 + AS15 ASCI contains 300 g of 
His/NY-ESO-1 antigen.
For details of this recombinant protein, see the Investigator's Brochure.
 
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1.2.2.
The AS15 Adjuvant System
The AS15 Adjuvant System consists of the Adjuvant System AS01B-4 and the 
immunostimulatory nucleotide CpG7909 (which is co-lyophilized with the His/NY-ESO-
1 protein).
Per 0.5 mL dose, the liquid Adjuvant System AS01B-4 contains 50 g of QS21 and 50 
g of Monophosphoryl lipid A (MPL®), in a liposome formulation.  The 
immunostimulatory nucleotide CpG7909 is included [420 g per dose (see note in 
Section 5.1)] to enhance the immune response (Amended 03 September 2014).
For details on this Adjuvant System, please see the Investigator’s Brochure.
1.2.3.
Pre-clinical safety and toxicology tests with NY-ESO-1 + AS15 
ASCI
The expression of the NY-ESO-1 gene in humans is restricted only to tissues 
characterized by their inability to present any sort of antigens to specialized cells of the 
immune system, thus suggesting a lack of toxicity for humans immunized with the NY-
ESO-1 protein.
No homolog close to the human NY-ESO-1 gene could be found by mining available 
genomic sequences from mouse, rat, and rabbit species. Immune reactions elicited 
through hyper-immunization of animals might be irrelevant and of no extrapolative value 
to the assessment of risk to humans. Finally, no significant related or possible-related 
adverse events have been reported in over 3550 recorded immunizations in over 600 
patients in 29 non-GSK clinical trials involving either NY-ESO-1 protein, peptides, viral 
vectors or plasmid DNA. The results of these trials indicated that this therapeutic 
approach in humans is a safe one.
Please refer to the current Investigator’s Brochure for a review of the pre-clinical and 
clinical studies, and the potential risks and benefits of the recNY-ESO-1 + AS15 ASCI.
1.2.4.
Previous clinical studies with NY-ESO-1
A large number of academic clinical trials targeting the NY-ESO-1 tumor antigen have 
been performed using many different immunotherapy approaches including NY-ESO-1-
derived peptides or non-GSK recombinant protein combined with a non-GSK 
immunological adjuvant, as well as recombinant DNA or live vectors.
NY-ESO-1 recombinant protein immunotherapy have been tested in trials that involve 
patients with the following cancers: melanoma, breast, transitional cell carcinoma of the 
bladder, esophageal, prostate, sarcoma, synovial sarcoma and ovarian cancer. Other 
studies have involved various NY-ESO-1-derived peptide immunotherapies, NY-ESO-1 
viral vector immunotherapies or a NY-ESO-1 plasmid DNA immunotherapy in patients 
with similar types of cancer. A variety of immunological adjuvants have been used in 
these studies including ISCOMATRIX®, Cholesterol-bearing Hydrophobized Pullulan 
(CHP), Bacillus Calmette-Guérin (BCG), Granulocyte Macrophage Colony-Stimulating 
 
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Factor (GM-CSF), CpG7909, Montanide ISA®-51, polyarginine, and the topical 
application of imiquimod.
No significant related or possibly-related adverse events has been reported in over 3500 
recorded immunizations in over 600 patients all within the context of an anti-NY-ESO-1 
immune response induced with different immunotherapy approaches and using several 
administration schedules and different immunological adjuvants. In the large majority of 
studies where immunological data is available, NY-ESO-1-specific antibodies have been 
detected together with a NY-ESO-1-specific CD4+ and CD8+ T-cell response. Some of 
these immunological responses have been associated with clinical activity including 
objective responses or long lasting disease stabilization in distinct cancer diseases.
Interestingly, in a recently reported case, a complete clinical response has been obtained 
in a patient with recurrent metastatic melanoma [Hunder, 2008] by adoptive transfer of in 
vitro amplified autologous CD4+ T cells (3.3 x 109) specific for the DPB1*0401 restricted 
epitope of NY-ESO-1. The patient remained disease-free for more than 2 years with no 
major safety concern.
The immunological adjuvant AS15 has been administered in combination with other 
antigens (MAGE-A3 in NSCLC and melanoma patients, dHER2 in breast cancer 
patients, P501 in prostate cancer patients), showing that it is well tolerated even in the 
context of long-term treatment and even in older patients.
For more details on previous clinical trials targeting NY-ESO-1 tumor antigen and 
clinical studies with AS15 combined with other tumor antigens e.g. dHER2, P501 and 
recMAGE-A3 recombinant proteins, refer to the Investigator’s Brochure.
1.3.
Rationale for the study and study design
1.3.1.
Need for new therapeutic approaches for metastatic melanoma
Patients with Stage III or IV cutaneous malignant melanoma have an unfavorable 
prognosis and there is currently no treatment able to extend survival. New approaches to 
improve the life expectancy for these patients are thus needed. Active immunization 
against tumor antigens is certainly one of these approaches.
NY-ESO-1 as proteins, peptides, viral vectors or plasmid DNA have been combined with 
a variety of immunological adjuvants in 29 clinical studies involving cancer patients with 
e.g. melanoma, breast, esophageal, bladder and ovarian cancers. In the large majority of 
these studies, a NY-ESO-1-specific CD4+ and CD8+ T-cell immune response has been 
induced, and in some patients a clinical response has been observed without major safety 
signal (see Section 1.2.4). In the same approach, several clinical teams have 
administered MAGE-A3 antigens, another tumor antigen encoded by a CT gene, to 
metastatic melanoma patients, using various modalities [Boon, 2006]. Again, these early 
clinical trials demonstrated the possibility of inducing long-term objective responses in 
15% of the patients without safety signal. More specifically, in a Phase II trial, 
recMAGE A3 + AS15 ASCI was administered to melanoma patients with early 
metastatic disease (GSK Study 249553/008). Objective clinical response was observed 
 
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for 4 of the 36 patients, which met the criteria for proof-of-concept (PoC). The ASCI 
treatments had an acceptable safety profile and the recMAGE-A3 + AS15 ASCI is now 
being tested in a Phase III trial as adjuvant therapy in patients with resected melanoma 
(DERMA Study). In this proposed study, recNY-ESO-1 + AS15 ASCI will be tested at 
the same dose schedule, in the same patient population and with the same Adjuvant 
System (AS15), as recMAGE-A3 + AS15 ASCI in the GSK 249553/008 study. The 
same dose schedule is utilized in two ongoing trials: PREDICT (Predictive gene signature 
for REsponse to recMAGE-A3 in unresecteD metastatIc CuTaneous melanoma) and 
Study 111473 MAGE3-AS15-MEL-004 (MET), that are both targeting the same patient 
population.  The patients enrolled will have Stage III or Stage IV M1a cutaneous 
malignant melanoma without visceral lesions.
1.3.2.
Rationale for using NY-ESO-1 recombinant protein combined 
with AS15 Adjuvant System
1.3.2.1.
recNY-ESO-1 protein
There are two advantages in immunizing patients using the recNY-ESO-1 protein instead 
of peptides. First, a full protein carries multiple potential epitopes therefore allowing to 
target a broader patient population. The eligibility of patients can be extended to all NY-
ESO-1 expressing melanoma, regardless of the HLA alleles, since it may be assumed that 
the NY-ESO-1 protein carries additional epitopes with binding motifs specific for other 
HLA molecules.
Second, the recNY-ESO-1 protein is also expected to carry epitopes specific for CD4+ T-
helper lymphocytes of the Th1 type, whose activation could significantly enhance the 
strength of the anti-tumor immune response. In this regard, CD4+ melanoma infiltrating 
lymphocytes have been shown to recognize MHC Class II-restricted tumor epitopes on 
human melanoma cells [Le Drean, 1995].
1.3.2.2.
AS15 Adjuvant System
The immunological Adjuvant System AS15 has been selected for clinical development of 
the recNY-ESO-1 + AS15 ASCI.  AS15 is the same immunological Adjuvant System 
that is included in the GSK candidate recMAGE-A3 + AS15 ASCI, which is currently 
under development in the Phase III pivotal studies in NSCLC (MAGE-A3 as Adjuvant 
Non-Small Cell LunG CanceR ImmunoTherapy or MAGRIT) and melanoma (ADjuvant 
immunothERapy with MAGE-A3 in melanoMA or DERMA), based on previous positive 
PoC Phase II studies (please refer to the Investigator’s Brochure for further details of the 
AS15 Adjuvant System).
 
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This selection is based on:

Benefits expected from a combination of immunological adjuvants
The AS02B adjuvant contains a Toll-like Receptor 4 (TLR4) agonist (Monophosphoryl 
lipid A or MPL®) and a purified saponin molecule (QS21) in a GSK proprietary
oil-in-water emulsion.  It has been shown to induce both humoral and T-cell-mediated 
immune responses and to lead to the induction of a systemic anti-tumor response [Gerard, 
2001; Moore, 1999].  Several preclinical and clinical data support the fact that the 
addition of CpG to MPL® and QS21 (in a liposome formulation to form the AS15
Adjuvant System) can induce stronger immune and anti-tumor responses [Krieg, 2001; 
Meidenbauer, 2004; Ren, 2004]. CpG is a Toll-like Receptor 9 (TLR9) agonist and 
therefore triggers the activation of distinct sub-populations of immune cells [Akira, 2006;
Pulendran, 2004; Seya, 2006], therefore eliciting broader immune responses when 
combined with other immunostimulants (GSK Biologicals data and [Speiser, 2005]).

Favorable safety profile
Toxicity studies evaluating the safety profile of AS15 and its individual components have 
been conducted and no safety concern was raised.
When recMAGE-A3 + AS15 ASCI and recMAGE-A3 + AS02B ASCI were evaluated in 
parallel in a melanoma trial (Phase II GSK Study 249553/008), no difference in safety 
was observed. In addition, the AS15 immunological adjuvant has been administered in 
combination with ASCI antigens other than MAGE-A3 (dHER2 in breast cancer patients 
and P501 in prostate cancer patients) showing that it is well tolerated in the various target 
populations. These previous studies with AS15 also support good tolerability in long-
term treatment and in elderly patients.

Improved immunogenicity
AS15 is a strong immunostimulant in mice, monkeys and humans, and is able to induce a 
more powerful Th1 response and subsequently to better protect against tumor challenge 
than AS02B ([Speiser, 2005] and unpublished GSK Biologicals data).
Moreover, in the melanoma trial (Phase II GSK Study 249553/008), the combination of 
recMAGE-A3 + AS15 ASCI compared to recMAGE-A3 + AS02B ASCI yielded higher 
specific antibody titers, increased CD4+ T-cell induction and a significant benefit to 
overall survival of patients.
 
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GSK recently reported the negative results of the MAGRIT study. The detailed analysis 
of MAGRIT showed the absence of treatment effect in any of the primary, secondary, 
or exploratory analyses2. All aspects of the MAGRIT study have been carefully 
assessed, and unfortunately these investigations failed to identify a root cause for the 
lack of efficacy of the MAGE-A3 ASCI  in NSCLC. 
Furthermore, a comprehensive review of the MAGE-A3 ASCI Phase III results, 
together with all other available clinical and laboratory data in early clinical studies 
with various recombinant proteins, including NY-ESO-1,  tested in different diseases 
and settings suggests that the anticancer activity of these ASCI, all based on the 
recombinant protein combined with adjuvant system AS15 technology may well be very 
limited. 
In light of this, GSK has decided to stop further development of the recombinant 
protein adjuvanted portfolio as a standalone treatment for cancer patients (Amended 
03 September 2014). 
1.3.3.
NY-ESO-1 dose and schedule of administration
GSK will evaluate the safety and immunogenicity of recNY-ESO-1 + AS15 ASCI at a 
fixed dose of AS15 and antigen. The same dose of AS15 has been combined with the 
other ASCI antigens under development, including MAGE-A3, dHER-2/Neu and 
PRAME.  The amount of the recombinant NY-ESO-1 protein will be 300 g. The dose 
proposed for NY-ESO-1 (i.e. 300 g) is within the range of or equal to antigen doses 
used in GSK clinical trials of dHER-2/Neu and recMAGE-A3 and is also based on two 
previous clinical studies using NY-ESO-1 recombinant protein combined with different 
immunoadjuvants [Davis, 2004; Valmori, 2007].
For details of these previous clinical trials, refer to the Investigator's Brochure.
The disease is considered aggressive, given the high rate of progression. Therefore, a 
sustained schedule of treatment administration is proposed for these patients. The dose of 
the tumor antigen (300 g) and the schedule of immunization will be exactly the same as 
the ones used for the GSK 249553/008 proof of concept study with the recMAGE-A3 + 
AS15 ASCI in patients with metastatic cutaneous melanoma.
In the proposed Phase I study, the endpoints will not be evaluated according to a dose 
escalation study design. It is acknowledged that the requirement to determine the 
maximum tolerated dose (MTD) is based on the design of conventional Phase I dose-
escalation trials used for cytotoxic drugs. It is supported by the assumption that 
                                                
2 GSK. (April 2 2014). Update on phase III clinical trial of investigational MAGE-A3 antigen-specific cancer 
immunotherapeutic in non-small cell lung cancer [Press release]. Retrieved from http://www.gsk.com/media/press-
releases/2014/update-on-phase-III-clinical-trial-of-investigational-MAGE-A3-antigen-specific-cancer-
immunotherapeutic-in-non-small-cell-lung-cancer.html. The data will be presented at the European Society For 
Medical Oncology Annual Congress 2014.
 
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maximizing dose should maximize clinical efficacy and that the anti-tumor activity of a 
non-specific cytotoxic agent is inevitably connected to toxicity risks. However, antigen-
specific cancer immunotherapeutics are generally believed to be safe relative to cytotoxic 
agents.  In addition, the NY-ESO-1 CT gene is only expressed in cancer cells, 
spermatogonia, placenta tissue and during embryogenesis.  The spermatogonia and 
placenta tissues expressing NY-ESO-1 protein do not bear HLA molecules on their 
surface and therefore do not present any NY-ESO-1-derived peptides to the T-cells 
[Jungbluth, 2007; Guillaudeux, 1996; Simpson, 2005].  By consequence, and considering 
this specific pattern of expression, spontaneous and induced NY-ESO-1-specific immune 
responses are unlikely to be associated with immune-related toxicities.
1.3.4.
Rationale for translational research
Previous clinical studies performed with the adjuvanted recombinant MAGE-A3 protein 
in metastatic melanoma patients have led to encouraging sign of clinical activity, leading 
to long-term objective clinical responses and stable disease. In parallel, we showed that 
antibodies and T-cell responses specific to the MAGE-A3 antigen can be measured in the 
immunized patients [Kruit, 2008].
However, so far it has been difficult to establish a true correlation between one of the 
immune parameters as measured on peripheral blood samples from the patients and the 
clinical benefit to the patients. Obtaining access to tissues other than blood (tumor 
samples taken at different moments during or after treatment) to explore other new 
immune read-outs or other ways to assess the immune response using genomics or 
proteomics could be very informative.
In parallel to the monitoring of the immune response induced in the patients by MAGE-
A3 ASCI, in a previous study the gene profile of tumors before immunization using an 
Affymetrix microarray platform was analyzed. This allowed the definition of a gene 
signature which is associated with clinical benefit (including objective response, mixed 
response, and long-term disease stabilization). Estimated Kaplan-Meier curves of the 
Time to Treatment Failure (TTF) for the recMAGE-A3 + AS15 ASCI group of patients 
from the GSK 249553/008 melanoma trial also suggest that the presence of the gene 
signature correlates with a favorable clinical outcome in response to the recMAGE-A3 + 
AS15 ASCI therapy [Louahed, 2008]. This set of genes differentially expressed in 
MAGE-A3 positive melanoma patients with clinical benefit in response to the MAGE-A3 
ASCI treatment will in this protocol be referred to as the predictive MAGE-A3 gene 
signature. It will be interesting to evaluate if the MAGE-A3 gene signature can predict 
clinical benefit in patients that receive the recNY-ESO-1 + AS15 ASCI. In addition, it 
would also be interesting to explore if a specific predictive NY-ESO-1 gene signature 
exists, that is different to the predictive MAGE-A3 gene signature.
These measurements are described in detail in Section 7, and their objectives are 
delineated in the corresponding sections. Each of them is essential for an understanding 
of the induction of an immune response, as together they allow insight into the “cross-
talk” between the tumor and its environment and ultimately the regulation by the immune 
system of its anti-tumor response.
 
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These different translational and additional exploratory tests will only be performed on 
biological samples from patients who voluntarily gave their consent for these specific 
assessments on the Informed Consent Form (ICF).
2.
OBJECTIVES
2.1.
Co-primary objectives
The two co-primary objectives of this study are to document and to characterize the
severe toxicity and clinical activity of the recNY-ESO-1 + AS15 ASCI in patients with 
NY-ESO-1-positive metastatic cutaneous melanoma.
Refer to Section 11.1 for the definition of the primary endpoints.
2.2.
Secondary objectives
Note that, as of Amendment 3, the decision was taken not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant. No further blood samples for protocol research purposes 
will be collected.(Amended 03 September 2014).
The secondary objectives of this study are to document and characterize:
1. Additional clinical indicators of clinical activity in the overall population and in 
the population of patients who present the predictive MAGE-A3 gene signature.
2. Additional indicators of safety.
3. The specific humoral and cellular immune response induced by recNY-ESO-1 +
AS15 ASCI.
Refer to Section 11.2 for the definition of the secondary endpoints.
2.3.
Translational research objectives
Note that, as of Amendment 3, the decision was taken not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant. No further blood samples for protocol research purposes 
will be collected.(Amended 03 September 2014).
The exploratory objectives of this study are to document and characterize:
1. Expression testing for other tumor antigens (such as MAGE-A3, MAGE-C2,
LAGE-1, PRAME and WT1) on the presenting lesion(s) and on any new lesion(s) 
and NY-ESO-1 expression testing on any new lesion(s).
2. The gene profiling on the tumor resected at baseline and any relapsed tumor (if 
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3. The “antigen spreading” in both the humoral and cellular immune responses 
elicited by the recNY-ESO-1 + AS15 ASCI.
4. The gene profiling of the immunological response elicited by the recNY-ESO-1 + 
AS15 ASCI.
5. Proteomics profiling of the immunological response elicited by the recNY-ESO-1 
+ AS15 ASCI.
6. Tumor immune infiltration assessment and characterization.
7. DNA promoter methylation analysis of NY-ESO-1, other tumor antigens and 
candidate genes that might be predictive to NY-ESO-1 ASCI clinical efficacy, in 
addition to immunoregulatory genes.
8. Pharmacogenetics analyses.
These different exploratory tests will only be performed on biological samples from 
patients who voluntarily gave their consent for these specific assessments in the ICF.
3.
STUDY DESIGN OVERVIEW
3.1.
General outline of study design
This will be an open-label, single-group, multicenter Phase I study, planned to be 
conducted at approximately 20 centers.
Approximately 34 patients with metastatic melanoma (unresectable Stage III melanoma, 
Stage III in-transit metastasis with (N3) or without (N2c) nodal metastasis or Stage IV 
M1a) will be enrolled. All patients will be treated as out-patients and will receive the 
same treatment. Withdrawals will not be replaced in this study.
Data collection will be conducted by using Remote Data Entry (RDE) on electronic case 
report forms (eCRF).
Adverse events, including severe toxicity as defined in Section 11.1.1, will be monitored 
throughout this Phase I study.
The first five patients will be enrolled in a staggered manner controlled by a central 
process such that they will receive their first ASCI administration on different days.  For 
example, one patient immunized per day until five patients have been immunized.  The 
other patients can receive their first ASCI administration at any time starting from one 
day after the fifth patient has received his/her first ASCI administration.
A centralized process is in place to ensure that all the investigators are informed about 
any serious adverse event (SAE) considered as related or possibly related to the ASCI, 
i.e., when an investigator becomes aware of such an SAE in one of his patients the 
Sponsor should be notified immediately (within 24 hours, refer also to Section 9.4.3).  
 
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3.2.
Study Treatment Schedule
Patients may receive up to four cycles of ASCI administration (maximum of 24 ASCI 
administrations), provided that at each tumor evaluation time point, the clinical criteria to 
continue the treatment are met:
Cycle 1:
6 ASCI administrations, each given at 2-week intervals
(Weeks 0, 2, 4, 6, 8, 10)
Cycle 2:
6 ASCI administrations, each given at 3-week intervals
(Weeks 14, 17, 20, 23, 26, 29)
Cycle 3:
4 ASCI administrations, each given at 6-week intervals
(Weeks 33, 39, 45, 51)
Cycle 4:
4 ASCI administrations, each given at 3-month intervals
4 ASCI administrations, each given at 6-month intervals
The patient’s clinical response to the treatment will be assessed regularly (for details, see 
Section 6.6), because this will determine, whether (s)he may continue receiving the study 
treatment. The clinical responses qualifying for a continuation of the study treatment are 
set out in Section 6.5.3.11.
3.3.
Duration of study participation
For each patient, the maximal duration of the study treatment period will be 
approximately 4 years (49 months) from the first administration of the study treatment 
until the concluding visit (Table 1).The duration of active follow-up for survival, disease 
progression and serious adverse events (SAEs) related to study participation or related to 
concurrent use of GSK medications will be one year after the concluding visit. During 
the follow-up period, the patient will have to come for follow-up visits every 3 months. 
Patients withdrawn from study treatment because of disease progression will not be asked 
to come for such follow-up visits but will be followed for survival by means of bi-annual 
contacts (e.g., by phone or during standard visits of the patient to the institution). All 
patients should be followed up for survival for a minimum of 5 years after the first study 
treatment administration, regardless of disease progression and of when they cease to 
receive the study treatment. For patients having completed (part of) the follow-up visits, 
the further follow-up for survival up to 5 years after the first study treatment 
administration will be done by bi-annual contacts, e.g., by phone or during the patient’s 
standard visits to the institution. Patients withdrawn from the study because they 
withdraw their consent to participate in the study will not be contacted in this way.
As of Amendment 3, all active follow-up visits and procedures will be stopped. Post-
study AEs/SAEs will continue to be reported as described in Section 9.3.1. (Amended 
03 September 2014.)
 
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Table 1
Overview of ASCI administrations, tumor and immunological evaluations 1
Cycle no.
Cycle 1
Cycle 2
Interval between ASCI 
administrations (admin.)
2 weeks
3 weeks
Continue treatment if CR or PR or SD or SPD at each TE
Visit no.
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Weeks after first ASCI admin. (w)
w-6 to w-1
0
2
4
6
8
10
12
14
17
20
22
23
26
29
31
recNY-ESO-1 + AS15 admin no.
1
2
3
4
5
6
7
8
9
10
11
12
Tumor evaluation (TE)
x
x
x
x
Anti-NY-ESO-1 Ab response
x
x
x
x
x
x
Anti-NY-ESO-1 T cell responses
x
x
x
Cycle no.
Cycle 3
Cycle 4
Interval between ASCI admin.
6 weeks
3 months
6 months
Concluding
Continue treatment if CR or PR or SD or SPD at each TE
Visit
Visit no.
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Week (w), month (m) or year (y) 
after first ASCI admin.
33w
39w
45w
51w
54w
V19 
+3m
V21 
+3m
V22 
+3m
V23 
+3m
V24 
+6m
V25 
+6m
V26 
+6m
V27 
+6m
V28 + 30 days
recNY-ESO-1 + AS15 admin no.
13
14
15
16
17
18
19
20
21
22
23
24
Tumor evaluation (TE)
x
x
x
x
x
x
x
Anti-NY-ESO-1 Ab response
x
x
x
x
x
x
x
Anti-NY-ESO-1 T cell responses
x
x
x
x
x
x
x
1.
Abbreviations: Ab - Antibody; Admin - Administration; CR - Complete Response; m = Month (Month, as calculation convention: 1 month is defined as 4 weeks i.e. 28 days during 
the treatment phase);  PR - Partial Response; SD - Stable Disease; SPD - Slow Progressive Disease; TE - Tumor Evaluation; w - Week; y - Year.
2.
In case a study visit needs to be delayed for any reason, the date for the visits following the delayed visit will be determined by the “intervals between study treatment 
administration” rather than by the “weeks after first study treatment administration”.
(Amended 03 September 2014)
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4.
STUDY POPULATION
4.1.
Number of patients/centers
It is planned that recruitment will stop when 34 patients have been enrolled into the 
study. Patients who have entered the screening phase and signed the ICF at the time, 
when the targeted number of patients has been reached, will be allowed to enroll in the 
study.
4.1.1.
Overview of the recruitment plan
The recruitment of patients will include the following essential aspects:

Approximately 20 study centers will participate.

Enrolment will take place by these centers in parallel and be competitive. No limit 
will be placed on the number of patients that can be recruited by any center.

Recruitment is expected to start in February 2011 and is expected to be completed 
within approximately 1 year, i.e., by the end of the 1st quarter of 2012. If this target 
cannot be met, the recruitment period may be extended as required.

Recruitment tracking will be performed centrally by GSK Biologicals. Monitoring 
will include supervision of adherence to the recruitment plan and will be carried out 
by qualified and authorized people who work for or with GSK Biologicals. A 
screening log will be kept at each site. All patients screened will be entered into the 
screening log.
4.1.2.
Replacement
Patients withdrawn after having received the first dose of study treatment will not be 
replaced. Any patient withdrawn before receiving the first ASCI dose will be replaced.
4.2.
Inclusion criteria
The following criteria should be checked during the screening procedures and again just 
before the first ASCI dose. The patient may only be included in the study if ALL the 
following inclusion criteria are fulfilled:
1. Male or female patient with histologically proven, measurable metastatic 
cutaneous melanoma, and with documented progressive disease within the 12 
weeks before the first administration of study treatment.
According to the [American Joint Committee on Cancer], 2002 classification, all 
melanoma patients with measurable, unresectable Stage III melanoma, Stage III in-transit 
metastasis with (N3) or without (N2c) nodal metastasis and Stage IV M1a melanoma are 
candidates for inclusion, whereas patients with resected Stage IV and Stage IV M1b or 
IV M1c disease cannot be included in the study (for the TNM classification, see
Appendix A).
 
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2. Written informed consent for NY-ESO-1 expression screening and gene profiling 
on resected tumor tissue and for the complete study has been obtained from the 
patient prior to shipment of the sample for expression testing and prior to the 
performance of any other protocol-specific procedure.
Note: Procedures performed before obtaining the patient’s informed consent as part of
standard institution practices or in the context of another research study (see Section 6.4) 
are accepted as study procedures provided the time intervals stipulated in the protocol are 
observed.
3. Patient is 18 years of age at the time of signature of the informed consent.
4. The patient’s tumor shows expression of NY-ESO-1, as determined by real-time 
quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis or 
any updated technique on fresh tissue sample(s).
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. The patient has normal organ functions as shown by all of the following:

Hemoglobin 12 g/dL

Absolute leukocytes count 3.0 x 109/L

Absolute lymphocytes count 1.0 x 109/L

Platelets 100 x 109/L

Serum creatinine Upper Limit of Normal (ULN)

Serum total bilirubin 1.5 x ULN (except for patients with Gilbert’s 
syndrome for whom the limit is 2 x ULN)

Lactate dehydrogenase (LDH) ULN

Aspartate aminotransferase (ASAT) 2 x ULN

Alanine aminotransferase (ALAT) 2 x ULN
These tests musts be done no more than 3 weeks before the first ASCI 
administration.
7.
Female patients of non-childbearing potential may be enrolled in the study. Non-
childbearing potential is defined as current tubal-ligation, hysterectomy, 
ovariectomy or post-menopause. 
Please refer to the glossary of terms for the definition of menopause.
8.
Female patient of childbearing potential may be enrolled in the study, if the 
patient:

has practiced adequate contraception for 30 days prior to first ASCI
administration, and

has a negative pregnancy test at the specified study visits, and
 
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
has agreed to continue adequate contraception during the entire treatment 
period and for 2 months after completion of the ASCI administration series.
Please refer to the glossary of terms for the definition of adequate contraception.
A pregnancy test must be done no more than one week before the first ASCI 
administration.
9.
In the view of the investigator, the patient can and will comply with the 
requirements of this protocol.
4.3.
Exclusion criteria for enrolment
The following criteria should be checked during the screening procedures and again just 
before the first ASCI administration. If ANY exclusion criterion applies, the patient must 
not be included in the study:
1. The patient has at any time received systemic chemotherapy, biochemotherapy, 
small molecules or anti-CTLA-4 monoclonal antibody for metastatic disease.
Note: Isolated limb perfusion or local electrochemotherapy, as long as this was 
performed at least 4 weeks before first ASCI administration is authorized. (Amended 03 
September 2014).
2. The patient is scheduled to receive any other anticancer treatments than those 
specified in the protocol, including but not limited to (bio-)chemotherapeutic, 
immunomodulating agents and radiotherapy.
3. The patient received any cancer immunotherapy containing a NY-ESO-1 antigen 
or any cancer immunotherapy for his/her metastatic disease.
Note: Previous adjuvant treatment with interferon, anti-CTLA-4 monoclonal antibody or 
a cancer immunotherapeutic (“vaccine”) containing a tumor antigen other than NY-ESO-
1 or radiotherapy is allowed, if the last administration took place at least 8 weeks before 
the first ASCI administration. (Amended 03 September 2014).
4. The patient requires concomitant treatment (more than 7 consecutive days) with 
systemic corticosteroids, or any other immunosuppressive agents.
Exception: The use of prednisone, or equivalent, at a dose 0.125 mg/kg/day (absolute 
maximum 10 mg/day) for more than 7 consecutive days or at a dose > 0.125 mg/kg/day 
but for less than 7 consecutive days is allowed. The use of inhaled corticosteroids or 
topical steroids is also permitted.
5. Use of any investigational or non-registered product (drug or vaccine) other than 
the ASCI within 30 days preceding the first ASCI administration, or planned use 
during the study period.
6. The patient has (had) previous or concomitant malignancies at other sites 
(including carcinoma in situ), except effectively treated non-melanoma skin 
cancers or carcinoma in situ of the cervix or effectively treated malignancy that 
has been in remission for over 5 years and is highly likely to have been cured.
 
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The patient has an allergy to any component of the study investigational product or has a 
history of previous allergic reactions to vaccinations.
7. The patient has an autoimmune disease such as, but not limited to, multiple 
sclerosis, lupus, and inflammatory bowel disease. Patients with vitiligo are not 
excluded.
8. The patient has a family history of congenital or hereditary immunodeficiency.
9. The patient is known to be positive for the Human Immunodeficiency Virus 
(HIV).
Specification for Germany: Please, refer to Section 13.2.
10.
The patient has an uncontrolled bleeding disorder.
11. The patient has psychiatric or addictive disorders that may compromise his/her 
ability to give informed consent, or to comply with the trial procedures.
12.
The patient has concurrent severe medical problems, unrelated to the 
malignancy, that would significantly limit full compliance with the study or 
expose the patient to unacceptable risk.
13. For female patients: the patient is pregnant or lactating.
5.
STUDY PRODUCT AND ADMINISTRATION
5.1.
Description of study product
The recNY-ESO-1 + AS15 ASCI to be used has been developed and manufactured by 
GSK Biologicals.
The Quality Control Standards and Requirements for this candidate ASCI are described 
in separate Quality Assurance documents (e.g. release protocols, certificate of analysis) 
and the required approvals have been obtained.
The ASCI is labeled and packed according to applicable regulatory requirements.
In this study, the recNY-ESO-1 + AS15 ASCI will be administered by using a sterile 
two-vials set comprising:

One vial containing 300 g of the recNY-ESO-1 protein co-lyophilized with 420 g 
of CpG7909;
[Note: The concentration in CpG7909 depends on the lot used –Certain lots are labeled 
as containing 420 µg CpG, whereas other lots will be labeled as 380 µg CpG. This 
difference in how the CpG content is noted is due to the fact that a different analytical 
method to determine the content of the CpG was applied to more recent lots and the 
change in the content designation from 420 to 380 µg is a result of a recalculation. The 
actual content of the CpG in the lots is the same (within the allowable assay 
variation).] (Amended 03 September 2014).
 
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
One vial with liquid Adjuvant System AS01B-4 (0.5 mL; liposomes containing 50 
g of monophosphoryl lipid A (MPL®), 1000 g of dioleylphosphatidylcholine 
(DOPC), 250 g of cholesterol and 50 g of QS21 (QS21 is a natural saponin 
molecule extracted from bark of the South-American tree Quillaja saponaria molin) 
in phosphate-buffered saline, making up the remainder of the Adjuvant System 
AS15).
The final recNY-ESO-1 + AS15 ASCI for administration is obtained by reconstitution of 
the lyophilized preparation with the adjuvant diluent. A recNY-ESO-1 + AS15 ASCI 
dose consists of 0.5 mL.
The recNY-ESO-1 + AS15 ASCI will be administered by intramuscular injection (i.m.).
5.2.
Storage and handling of study product
All ASCI products to be administered to the patients must be stored in a safe and locked 
place with no access by unauthorized personnel.
The ASCI product must be stored at the defined temperature range (i.e., 2 to 8°C/36F to 
46F).  Please refer to the Study Procedures Manual (SPM) for more details on storage of 
the ASCI.  The storage temperature of the ASCI will be monitored daily with validated 
temperature monitoring device(s) (at the minimum calibrated) and will be recorded as 
specified in the SPM.
The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact.
Any temperature deviation outside the range (0-8C/36-46F), must be reported to the 
Sponsor as soon as detected. Following an exposure to such a temperature deviation, 
ASCI will not be used until approval has been given by the Sponsor. In case of 
temperature deviation between 0 and +2C/32 and 36F, the impacted study products can 
still be administered, but the site must take adequate actions to go back to the defined 
range +2 to +8C/36 to 46F and avoid re-occurrence of such a temperature deviation.
Refer to the SPM for details and instructions on the temperature deviation process, 
packaging and accountability of the ASCI.
5.3.
Dosage and administration of study product
5.3.1.
Dosage
A standard dose of recNY-ESO-1 protein (300 g) and of AS15 will be used, irrespective 
of the patient's body weight or body surface area (BSA).
No modification of the dose of the study product is permitted for any individual patient, 
irrespective of the patient’s weight or BSA.
 
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5.3.2.
Administration
The needles used for study treatment administration should be suitable for intramuscular 
(i.m.) injection. The entire liquid content of the diluent vial is to be transferred 
aseptically into the vial containing the lyophilized preparation. The vial is to be shaken 
gently until complete dissolution of the pellet. The reconstituted mixture must be at a 
suitable temperature (i.e., no longer chilled) when it is administered.  The final 
preparation is to be injected immediately or, if not possible, no later than 4 hours after 
reconstitution and provided that the final preparation has been kept at a temperature 
between 4°C (39°F) and 30°C (86°F).
The investigator or designate will subsequently withdraw the reconstituted mixture, 
change the needle, and inject the dose slowly (over approximately 30 seconds) i.m. into 
thigh or deltoid.  The site of injections should be alternated to prevent the patient’s 
discomfort.  The injections may not be administered in anatomical regions where lymph 
nodes have been excised.
The patients will be observed closely for at least 30 minutes following the administration 
of the ASCI treatment, with appropriate medical treatment readily available in case of a 
rare anaphylactic reaction.
For treatment schedules, see the in-text table in Section 3.1. For exact specification of the 
visits and for calculation of the duration of treatment, see Section 6.
Table 2
Dosage and administration
Treatment
Dose
Administration
Timing
Route and site
recNY-ESO-1 + AS15 ASCI
1 dose corresponding to
300 g of recNY-ESO-1 
protein and 380 g CpG, 
reconstituted in AS01B-4
(Amended 03 September 
2014)
Cycle 1: q2w x 6
Cycle 2: q3w x 6
Cycle 3: q6w x 4
Cycle 4: q3m x 4 
then q6m x 4
i.m.
Deltoid or lateral region of 
the thigh, preferably with 
alternation on right or left 
side at each succeeding 
injection
5.4.
Replacement of unusable study product doses
Additional ASCI doses will be provided to replace those that are unusable (see SBIR 
manual for details).
The Investigator or delegate will request a new treatment number from GSK Biologicals 
(SBIR system) via the Internet. He/she will access the allocation system and enter the 
patient’s ID number and date of birth. The allocation system will then determine the 
treatment number to be used for the immunization of that patient.
The actual treatment number used for the study treatment administration of the patient 
must be recorded in the eCRF (treatment allocation section).
 
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5.5.
Contraindications to subsequent study product 
administration
The criteria in the following subsections should be checked at each visit. If any of these 
events occurs during the study, this will require appropriate action, i.e. postponement or 
permanent stopping of the ASCI administration (See Sections 5.5.1 and 5.5.2).
5.5.1.
Criteria for postponement of ASCI administration
If one of the following conditions is present at the time scheduled for administration of 
the recNY-ESO-1 + AS15 ASCI, the patient may be treated at a later date (i.e. the entire 
program of study visits and ASCI administrations is interrupted), within the time window 
specified in Section 6.3.1, or as soon as the patient’s condition allows it, or withdrawn at 
the discretion of the investigator.
1. Acute disease is defined as the presence of a moderate or severe illness with or 
without fever. All ASCIs can be administered to persons with a minor illness such 
as diarrhea or mild upper respiratory infection without fever. The patient must be 
followed until resolution of the event, as with any adverse event (AE) (see Section 
9.3).
2. Fever, defined as an oral, axillary or tympanic temperature of 38°C/100°F or 
above.
3. Any other medical reason that would expose the patient to an unacceptable risk, 
at the investigator’s discretion (Amended 03 September 2014).
For these three conditions, the entire program of study visits and ASCI administrations 
will be resumed as soon as the patient’s condition allows or at the investigator’s 
discretion (see Section 6.3.1). If the re-treatment criteria are not met within 4 weeks (3 
months during and after Cycle 4) after the scheduled treatment date, the patient must be 
withdrawn from the study treatment and the procedures detailed for the Concluding Visit 
are to be carried out (see Section 6.5.4). (Amended 03 September 2014).
In the framework of an imposed vaccination program, the ASCI administration may be 
postponed in order to administer the influenza vaccine on the fixed day.  The ASCI 
administration should be given as close in time as possible to the time scheduled in the 
original administration schedule.  However, a 6 day interval should be maintained 
between the influenza vaccine and the ASCI administration (see also Section 5.6.3 on 
time window for prophylactic vaccination).
 
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5.5.2.
Criteria for permanent stopping of ASCI administration
If any of the following criteria becomes applicable during the study, the patient will be 
required to discontinue the study ASCI administration.
1. Evidence of disease progression that does not correspond to the Slow Progressive 
Disease (SPD) (See Section 6.6.6 and Section 6.5.3.11 Clinical response criteria 
for continuing ASCI administration).
2. Treatment with one of the following:

Investigational or non-registered product other than the study recNY-ESO-1 + 
AS15 ASCI.

Other anticancer treatments, including but not limited to (bio-)chemotherapeutic
or immunomodulating agents and radiotherapy.
However, any progression of some tumor sites or symptoms can be controlled by surgery 
or radiotherapy (20 Grays); see Section 5.6.1 for further details.
3. ASCI-related or possibly ASCI-related Grade 2 (or higher, according to Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.0) allergic 
reaction/hypersensitivity toxicity (i.e. rash, flushing, urticaria and dyspnea). Drug 
fever will not be part of this definition.
4. Grade 2 (or higher, according to CTCAE, Version 4.0) autoimmune reaction (i.e. 
evidence of autoimmune reaction involving a non-essential organ or function such 
as hypothyroidism).
5. Grade 3 (or higher, according to CTCAE, Version 4.0) injection site reaction (i.e. 
ulceration or necrosis that is severe; operative intervention indicated).
6. Any intolerable AE, at the investigator’s discretion.
7. Appearance of any confirmed or suspected immunosuppressive or 
immunodeficient condition, including HIV infection, or any medical condition 
requiring chronic treatment (more than 7 consecutive days) with systemic 
corticosteroids or any other immunosuppressive agents.
[Note: The use of prednisone, or equivalent, at a dose 0.125 mg/kg/day (absolute 
maximum 10 mg/day) for more than 7 consecutive days or at a dose > 0.125 mg/kg/day 
but for less than 7 consecutive days is allowed. The use of inhaled corticosteroids or 
topical steroids is also permitted.]
8. The patient develops other conditions for which, in the investigator’s opinion, the 
patient’s best interest is to be withdrawn from the study treatment.
9. Inability of the patient to complete the study evaluations/visits because of 
unforeseen circumstances.
10. If in case of postponement of study treatment the re-treatment criteria are not met 
within 4 weeks (3 months during and after Cycle 4) after the scheduled treatment 
date, the patient must be withdrawn from the study treatment (see Section 5.5.1).
 
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11. The patient requests to be withdrawn from the study treatment.
12. For female patients, pregnancy or decision to become pregnant (see Section
9.2.2).
For patients whose treatment is discontinued prematurely during the study, the 
procedures of the Concluding Visit (see Section 6.5.4) will be carried out a minimum of 
30 days after the last ASCI administration and - if possible - before the initiation of any 
other treatment.(Amended 03 September 2014).
After disease progression, the choice of subsequent treatment will be at the discretion of 
the treating physician; the patient will be taken off study treatment and the investigator 
will document any further anti-cancer treatment administered. (Amended 03 September 
2014)
5.6.
Concomitant medication and non-drug therapies
Patients should receive medication appropriate to their health condition during the whole 
study.
At each study visit/contact, the investigator should question the patient about any 
medication(s) taken and treatment received by the patient.
All concomitant medication, including changes in chronic medication, with the exception 
of vitamins and/or dietary supplements, are to be recorded in the eCRF. This also applies 
to any medication intended to treat an AE. Chronic medication is defined as medication 
taken by the patient for a minimum of 6 months before the study start.
Similarly, concomitant medication administered for the treatment of a SAE, at any time, 
must be recorded on the SAE screens in the eCRF, as applicable. Refer to Section 9.1.2
for the definition of a SAE.
5.6.1.
Permitted medication
During the period starting with administration of each dose of study treatment and ending 
30 days after each dose of study treatment, concomitant medication administered for the 
treatment of an AE must be recorded in the eCRF with generic name of the medication 
(trade names are allowed for combination drugs only), medical indication (including 
which AE), total daily dose, route of administration, start and end dates of treatment.
The following palliative melanoma treatments (of tumor sites or symptoms) are allowed 
in addition to the study treatment:

Surgery.
Note: If surgery is performed, sample(s) of the resected tumor lesion(s) will be sent to 
GSK Biologicals or a laboratory contracted for this by GSK Biologicals (see Sections 7.1
and 7.2.2). For patients who have given their specific informed consent to the optional 
translational research, such tumor tissue(s) may also be used to conduct this specific 
testing (see Sections 7.3, 7.6, 7.7, and 7.8).
 
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
Radiotherapy.
However, these treatments may not be applied to more than 20% of the number of all 
target lesions and must always be discussed in advance with, and agreed to, by the 
Sponsor.  The applied radiotherapy dose must be 20 Grays.
The patients who are presenting a progression by (adapted) RECIST (Response 
Evaluation Criteria In Solid Tumors, see Sections 6.6.1, 6.6.2, and 6.6.3) and are 
receiving such treatments will be considered in Progressive Disease (PD) for the purpose 
of response evaluation.
5.6.2.
Medications, vaccines and non-drug therapies that may lead to 
the elimination of a patient from ATP analyses
5.6.2.1.
Prohibited medications or non-drug therapies
Patients may not receive concomitant treatment during the study with any of the 
following:
a.
Other anticancer treatments, including but not exclusively, chemotherapeutic, 
immunomodulating agents and radiotherapy.
However, any progression of some tumor sites or symptoms can be controlled by surgery 
or radiotherapy (20 Grays); see Section 5.6.1 for further details.
b.
Administration of immunosuppressants or other immune-modifying drugs during the 
study period. The use of prednisone, or equivalent, at a dose 0.125 mg/kg/day 
(absolute maximum 10 mg/day) for more than 7 consecutive days or at a dose > 
0.125 mg/kg/day but for less than 7 consecutive days is allowed. The use of inhaled 
corticosteroids or topical steroids is also permitted.
c.
Administration of any commercial anti-infectious vaccine not foreseen by the study 
protocol during the period within the prohibited time as specified in Section 5.6.3.
d.
Administration of immunoglobulins and/or any blood products during the study 
period.
Any of these specifically contraindicated treatments and/or medications administered at 
any time during the study period are to be recorded in the eCRF with generic name of the 
medication (trade names are allowed for combination drugs only), medical indication, 
total daily dose, route of administration, start and end dates of treatment.
If any of these is taken, it will require either permanent discontinuation of study treatment 
(see Section 5.5.2) or may determine a patient evaluability in the according to protocol 
(ATP) analysis (see Section 5.6.2.2).
 
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5.6.2.2.
Elimination criteria for analysis
The following criteria should be checked at each visit subsequent to the first ASCI
administration. If any become applicable during the study, it will not require withdrawal 
of the patient from the study but may determine a patient’s evaluability in the according-
to-protocol (ATP) analysis. See Section 11.4 for definition of study cohorts to be 
evaluated.

Use of any investigational or non-registered product (drug or vaccine) other than the 
ASCI during the study period. This includes other anticancer medications e.g. 
chemotherapeutic agents, immunomodulating agents and radiotherapy (See Section 
5.6.1).

Administration of more than 7 days of immunosuppressants or other immune-
modifying drugs during the study period. For corticosteroids, this will mean 
prednisone > 0.125 mg/kg/day (maximum 10 mg/day) or equivalent. Inhaled and 
topical steroids are allowed.

Any progression of some tumor sites or symptoms which is controlled by surgery or 
by local radiotherapy. If this conventional treatment (surgery or local radiotherapy) 
is applied to > 20% of the total target lesions, this will not require patient withdrawal 
but may affect the patient’s evaluability in the according to protocol (ATP) analysis.

Administration of a product not foreseen by the study protocol during the time period 
specified in Section 5.6.3.

Administration of immunoglobulins and/or any blood products during the study 
period.
A detailed, comprehensive list of reasons for elimination from ATP analyses will be 
established at the time of data cleaning.
5.6.3.
Time window for concomitant vaccination
Immunization with any commercial anti-infectious vaccine may be performed during the 
study. However, this may not take place during the period from six days before any 
ASCI administration to six days after. Thus, if the ASCI is to be administered on a 
notional Day 0, then the vaccination may be performed on or before Day 7, and on or 
after Day 7.  In the framework of an imposed vaccination program, the ASCI 
administration may be postponed in order to administer the influenza vaccine on the fixed 
day.  The ASCI administration should be given as close in time as possible to the time 
scheduled in the original administration schedule.  However, a 6 day interval should be 
maintained between the influenza vaccine and the ASCI administration.  The entire 
program of study visits and ASCI administrations will then be resumed (see Section 
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5.6.4.
Time window for recording concomitant medication and non-
drug therapies in the eCRF
All concomitant medications, including changes in chronic medication with the exception 
of vitamins and/or dietary supplements, administered at ANY time during the period 
starting with the administration of each dose of ASCI and ending 30 days after each dose 
of ASCI are to be recorded in the eCRF.
Any product not foreseen in the study protocol administered in the period beginning 30 
days preceding each dose of ASCI and ending 30 days after each dose of ASCI is to be 
recorded in the eCRF.
Any investigational medication or vaccine administered throughout the study (i.e. from 
first ASCI administration through to 30 days after the last ASCI) must be recorded in the 
eCRF.
Chronic medication will be recorded at the first study visit (Visit 1). Chronic medication
is defined as medication taken by the patient for a minimum of 6 months before the study 
start.
5.7.
Intercurrent medical conditions that may lead to elimination 
from the ATP cohort for analysis
Patients may be eliminated from the ATP cohort for analysis of immunogenicity if, 
during the study, they incur a condition that may alter their immune response.
6.
STUDY ASSESSMENTS AND PROCEDURES
6.1.
Patient identification and randomization of treatment
6.1.1.
Patient identification
Patient numbers will be assigned sequentially to patients consenting to participate in the 
study, and according to the range of patient numbers allocated to each study center.
At the beginning of the study each investigation site will be given a range of patient 
numbers for that site. Patient numbers will be allocated consecutively at the site, from 
the range provided, in ascending order from the time of signing the informed consent. 
After signing the ICF, the investigator will enter the patient into the screening section of 
the eCRF. General demographic details and tumor characteristics will be entered in the 
screening section for each patient for whom a tumor sample is sent for analysis of NY-
ESO-1 expression. When a patient is eligible (i.e., meets all the inclusion criteria and 
does not meet any of the exclusion criteria), the investigator or an authorized site staff 
member will continue with the actual eCRF for this patient.
 
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6.1.2.
Randomization / treatment assignment
This is a single treatment group study, so patients will not be randomized.
The treatment block lists will be prepared at GSK Biologicals, Rixensart, using MATEX, 
a program developed for use in SAS® (Cary, NC, USA) by GSK Biologicals.
The study product doses will be distributed to the study centers within pre-defined 
blocks.
The treatment allocation at the investigational site will be performed using a central 
allocation system on internet (SBIR; available 24hrs/day, 7 days/week). 
Please refer to the SBIR user guide for specific instructions.
After having checked the eligibility of the patient, the site staff in charge of the ASCI 
administration will access the allocation system on internet. Upon providing the patient 
identification number and date of birth, the allocation system will determine the treatment 
numbers to be used for the patient. Each treatment number must be recorded in the eCRF 
on the Study Treatment Administration screen.
This procedure will be repeated for each subsequent dose allocation.
The treatment of the first five patients will occur in a staggered manner as described in 
Section 6.3.2.
6.2.
Method of blinding
This study is an open-label single-group Phase I study, therefore, there will be no study 
blind.
6.3.
General study aspects
6.3.1.
Attendance of study visits
Patients will be required to attend for ASCI administrations and supplementary 
assessments according to the schedules shown in Section 6.4.
It is the investigator’s responsibility to ensure that the stipulated intervals between study 
visits are strictly adhered to.  Permitted deviation from the stipulated date of each visit 
(due e.g. to week-ends or public holidays) will be as follows:
 
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Table 3
Permitted deviations from stipulated dates of visits
Cycle 1:
3 calendar days
Cycle 2:
3 calendar days
Cycle 3:
4 calendar days
Cycle 4:
7 calendar days
(Amended 03 September 2014)
Any deviation greater than this will be regarded as a protocol violation to be recorded in 
the eCRF.
In each case, the Sponsor will decide whether the violation is to be regarded as:

A minor violation (i.e., without consequence),

A major violation (resulting in exclusion of the patient from the population of 
patients evaluable according to protocol),

A violation necessitating immediate exclusion of the patient from the study.
When the permitted deviations are applied or when a ASCI treatment has to be postponed 
(refer to Section 5.5.1 for details on postponement of study treatment), the entire program 
of study visits and ASCI administrations will be resumed as soon as the patient’s 
condition allows or at the investigator’s discretion.  The visits following the first visit 
after a deviation or a postponement must be rescheduled on the basis of the actual date of 
this first visit, while respecting the stipulated time periods between study visits.  Table 4
shows an example of how such a postponement causes a delay, which will be propagated 
to the schedule of visits and dose administrations throughout the entire study period.
Table 4
Example of postponement of study treatment dose for 3 weeks 
during Cycle 1 and the delay of the schedule induced
Week
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Initial schedule
Visit
1
2
3
4
5
6
7
Dose
1
2
3
4
5
6
Actual 
schedule due 
to 
postponement
Visit
1
2
X
3
4
5
6
7
Dose
1
2
X
3
4
5
6
Dose postponed for 
3 weeks
All following visits and doses
delayed for 3 weeks
Note: This postponement will have a similar impact on the complete schedule of visits and dose administrations 
throughout the entire study treatment period. Any further postponement(s) will induce additional delay(s) that must be 
added. (Amended 03 September 2014)
 
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If the re-treatment criteria are not met within 4 weeks after the scheduled treatment date 
(3 months during treatment Cycle 4), the patient must be withdrawn from the ASCI
treatment and the procedures detailed for the Concluding Visit have to be carried out (see 
Section 6.5.4). Such patients will also be followed for survival for 5 years after the first 
ASCI administration (see Section 3.1). Table 5 illustrates this possibility.
Table 5
Example of postponement of ASCI treatment for more than 4 weeks 
leading to withdrawal of patient from the study treatment
Week
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Initial 
schedule
Visit
1
2
3
4
5
6
7
Dose
1
2
3
4
5
6
Actual 
schedule due 
to 
postponement
Visit
1
2
X
3
Dose
1
2
X
X
Patient withdrawn from 
study treatment and 
procedures of 
Concluding visit 
performed at Visit 3
Postponement of dose 
for more than 4 weeks

Note: During Cycle 4 the maximum allowed postponement of a scheduled dose is 3 months and not the 4 weeks 
applicable to Cycles 1 – 3. If the re-treatment criteria are not met before the end of this period, the patient must be 
withdrawn from the study treatment.
6.3.2.
Staggered enrolment of patients
The first five patients will be enrolled in a staggered manner controlled by a central 
process such that they will receive their first ASCI administration on different days. For 
example, one patient immunized per day until five patients have been immunized. The 
other patients can receive their first ASCI administration at any time starting from one 
day after the fifth patient has received his/her first ASCI administration.
6.3.3.
Temporary or permanent stopping of the entire study
Further enrolment will be discussed between the Data Safety Monitoring Committee 
(DSMC; see Section 12.3) and GSK Biologicals’ Safety Review Team (SRT; see Section 
12.4) if:

4 patients develop severe toxicity (See Section 11.1.1 for the definition);
or

2 or more Grade 4 SAEs or death occur that are definitely, probably or possibly 
related to NY-ESO-1 ASCI in 2 separate patients.
The respective National Competent Authorities and Institutional Review Boards (IRBs) 
will be notified of the outcome of this review.
 
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6.4.
Outline of study procedures
Study participation starts with a screening procedure. Signature of the ICF for testing of 
tumor tissue for NY-ESO-1 expression, gene profiling and for study participation will 
take place at the start of this screening procedure.  The patient will also be proposed to 
sign a part of the Informed Consent Form allowing optional translational research on 
biological tissues sampled as part of the mandatory procedures of the trial.
The timing of scheduled assessments for the 4 ASCI administration cycles is shown in 
Table 6 to Table 9. (Amended 03 September 2014).
All chest and complete-abdomen CT scans should be performed so that the results are 
available at the actual visit as per the tables below.
 
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Table 6
List of study procedures for Cycle 1 (including screening)
Visit no.
Screening a 1
2
3
4
5
6
7
Intervals between study 
treatment administrations h
2 weeks
Weeks after first ASCI 
administration
-
0
2
4
6
8
10
12
NY-ESO-1 ASCI admin no.
-
1
2
3
4
5
6
Informed consent
●
Addendum to informed consenti
●
●
●
●
●
●
●
Biopsy for NY-ESO-1 expression
●
Inclusion/exclusion criteria
●
●
Medical history
●
Clinical evaluations
Physical examination b
●
●
●
●
●
●
●
Imaging procedures
●c
●c
Tumor response assessment
●
Safety assessments
(Serious) Adverse Events 
recordedd
●
●
●
●
●
●
●
●
Potential immune-mediated 
diseases (pIMDs) recorded
●
●
●
●
●
●
●
Laboratory assessments
Pregnancy test e
●
●
●
●
●
Urine chemistry tests f
●
●
HIV status g
●
Hematological tests f
●
●
●
●
Blood chemistry tests f
●
●
●
●
Autoimmunity tests f
●
●
Coagulation tests f
●
●
●
●
Criteria for permanent stopping or 
postponement of study treatment
●
●
●
●
●
Recording of concomitant 
medication
●
●
●
●
●
●
●
Note: For patients who are found to be NY-ESO-1 negative, only the following procedures need to be performed for 
this protocol: Informed consent, tumor biopsy, NY-ESO-1 expression testing, inclusion and exclusion criteria. All other 
procedures should only be performed if clinically indicated and do not need to be recorded on the eCRF.
a.
Screening visit/period is to take place a maximum of 6 weeks before the first ASCI administration. However:
1.
Urine and blood chemistry, hematological, coagulation and autoimmunity tests, within 3 weeks before the 
first study treatment administration;
2.
Negative pregnancy test must be obtained within 1 week before the first study treatment administration for 
women of child-bearing potential;
3.
Tumor biopsy can be obtained within 12 weeks before the first ASCI administration; in the rare case the 
analysis of the sample would give an inconclusive result, the patient may be asked to allow a new sample to 
be collected or to allow the use of an already preserved sample to repeat the test. A tumor biopsy performed 
in the context of institution standard practice or another research study may be used for the NY-ESO-1 
testing after obtaining the Sponsor’s agreement, provided this biopsy was preserved in RNAlater® and was 
taken no more than 12 weeks before the first administration of the study treatment.
 
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4.
Tumor imaging no more than 6 weeks before first ASCI administration. Imaging performed as part of 
institution standard clinical practice or in relation to another research study does not need to be repeated, 
provided this imaging was performed no more than 6 weeks before the first administration of the study 
treatment. 
5.
HIV test within 3 weeks before the first ASCI administration, mandatory in Germany only (refer to Section 
13.2).
b.
Complete physical examination. Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers (only during the tumor assessment visit). Recording of all changes in the patient’s medical condition 
including all adverse events.
c.
Chest computer tomography (CT) scan, complete-abdomen CT scan and any other examination medically 
indicated to assess tumor dissemination. A contrast-enhanced CT scan or magnetic resonance imaging (MRI) of 
the brain is mandatory at the Screening Visit; while at subsequent visits it should only be performed in case of 
evocative neurological symptoms. Color photography or ultrasound of skin/node/subcutaneous lesions must also 
be performed if applicable. If a photography presents a characteristic area rending possible the patient 
identification, photography will not be loaded and will need to be sent to the site according to GSK PII 
management procedure.
d.
Refer to Section 9.3. At the screening visit only SAEs related to study participation and GSK concomitant 
medication will be recorded.
e.
For women of child-bearing potential only; urine or blood test according to local practice; a negative result must be 
obtained at screening, before the first ASCI administration and after 2, 6 and 10 weeks of treatment (at Visits 1, 2, 
4 and 6) to allow continued recNY-ESO-1 + AS15 administrations.
f.
Refer to Section 6.7.2.
g.
HIV test is mandatory to determine the HIV status (positive - negative) of patients in Germany only. Patients with 
known HIV-positive status do not need to be re-tested. Patients tested for HIV prior to signature of the ICF for 
study participation do not need to repeat the test, given that it was performed within three weeks of enrolment
(refer to Section 13.2).
h.
In case a study visit needs to be delayed for any reason, the date for the visits following the delayed visit 
will be determined by the “intervals between study treatment administrations” rather than by the “weeks 
after first study treatment administration”.
i.
Signature of the ICF addendum must be the first procedure performed for patients returning for their first 
study visit after approval of Protocol Amendment 3. This only has to be done once. The study will 
continue only with patients from the active treatment group who will decide to stay in the study. Signature 
of the ICF addendum will be documented in the eCRF. 
(Amended 03 September 2014)
 
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Table 7
List of study procedures for Cycle 2
Visit no.
8
9
10
11
12
13
14
15
Intervals between study treatment 
administrationsf
3 weeks
Weeks after first ASCI administrationf
14
17
20
22
23
26
29
31
NY-ESO-1 ASCI admin no.
7
8
9
10
11
12
Addendum to informed consentg
●
●
●
●
●
●
●
●
Clinical evaluations
Physical examination a
●
●
●
●
●
●
Imaging procedures b
●
●
Tumor response assessment
●
●
Safety assessments
(Serious) Adverse Events recorded c
●
●
●
●
●
●
●
●
pIMDs recorded
●
●
●
●
●
●
●
●
Laboratory assessments
Pregnancy test d
●
●
●
●
●
●
Urine chemistry tests e
●
●
●
Hematological tests e
●
●
●
Blood chemistry tests e
●
●
●
Autoimmunity tests e
●
Coagulation tests e
●
●
●
Criteria for permanent stopping or 
postponement of study treatment
●
●
●
●
●
●
Recording of concomitant medication
●
●
●
●
●
●
●
●
a.
Complete physical examination. Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers (only during the tumor assessment visit). Recording of all changes in the patient’s medical condition 
including all adverse events.
b.
At Visits 11 and 15: chest, complete-abdomen CT scans, and any other examination medically indicated to assess 
tumor dissemination are mandatory. Brain contrast-enhanced CT scan (or MRI) should be performed only in case 
of evocative neurological symptoms. Color photography or ultrasound of skin / node / subcutaneous lesions must 
also be performed if applicable. If a photography presents a characteristic area rending possible the 
patient identification, photography will not be loaded and will be sent to the site according to GSK PII 
management procedure.
c.
Refer to Section 9.3.
d.
For women of child-bearing potential only; urine or blood test according to local practice; a negative result must be 
obtained before each ASCI treatment (at Visits 8-10 and 12-14) to allow continued recNY-ESO-1 + AS15 
administrations.
e.
Refer to Section 6.7.2.
f.
In case a study visit needs to be delayed for any reason, the date for the visits following the delayed visit 
will be determined by the “intervals between study treatment administrations” rather than by the “weeks 
after first study treatment administration”.
g.
Signature of the ICF addendum must be the first procedure performed for patients returning for their first 
study visit after approval of Protocol Amendment 3. This only has to be done once. The study will 
continue only with patients from the active treatment group who will decide to stay in the study. Signature 
of the ICF addendum will be documented in the eCRF. 
(Amended 03 September 2014)
 
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Table 8
List of study procedures for Cycle 3
Visit no.
16
17
18
19
20
Intervals between study treatment 
administrations g
6 weeks
Weeks after first ASCI administration g
33
39
45
51
54
NY-ESO-1 ASCI admin no.
13
14
15
16
Addendum to informed consenth
●
●
●
●
●
Clinical evaluations
Physical examination a
●
●
●
●
Imaging procedures b
●
Tumor response assessment
●
Safety assessments
(Serious) Adverse Events recorded c
●
●
●
●
●
pIMDs recorded
●
●
●
●
●
Laboratory assessments
Pregnancy test d
●
●
●
●
Urine chemistry tests e
●
●
●
●
Hematological tests e
●
●
●
●
Blood chemistry tests e
●
●
●
●
Autoimmunity tests e
●
Coagulation tests e
●
●
●
●
Criteria for permanent stopping or 
postponement of study treatment
●
●
●
●
Recording of concomitant medication
●
●
●
●
●
Conclusions for main analysisf
●
a.
Complete physical examination. Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers (only during the tumor assessment visit). Recording of all changes in the patient’s medical condition 
including all adverse events.
b.
At Visit 20: chest, complete-abdomen CT scans, and any other examination medically indicated to assess tumor 
dissemination are mandatory.  Brain contrast-enhanced CT scan (or MRI) should be performed only in case of 
evocative neurological symptoms. Color photography or ultrasound of skin / node / subcutaneous lesions must 
also be performed if applicable. If a photography presents a characteristic area rending possible the 
patient identification, photography will not be loaded and will be sent to the site according to GSK PII 
management procedure.
c.
Refer to Section 9.3.
d.
For women of child-bearing potential only; urine or blood test according to local practice; a negative result must be 
obtained before each ASCI treatment (at Visits 16-19) to allow continued recNY-ESO-1 + AS15 administrations.
e.
Refer to Section 6.7.2.
f.
Main analysis will be performed when all patients have either completed the treatment up to Cycle 3 or have 
withdrawn from study treatment.
g.
In case a study visit needs to be delayed for any reason, the date for the visits following the delayed visit 
will be determined by the “intervals between study treatment administrations” rather than by the “weeks 
after first study treatment administration”.
h.
Signature of the ICF addendum must be the first procedure performed for patients returning for their first 
study visit after approval of Protocol Amendment 3. This only has to be done once. The study will 
continue only with patients from the active treatment group who will decide to stay in the study. Signature 
of the ICF addendum will be documented in the eCRF. 
(Amended 03 September 2014)
 
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Table 9
List of study procedures for Cycle 4
Visit no.
21
22
23
24
25
26
27
28
29
Date of Visit
V 19 
+ 3 m
V 21 
+ 3 m
V 22 
+ 3 m
V 23 
+ 3 m
V 24 
+ 6 m
V 25 
+ 6 m
V 26 
+ 6 m
V 27 
+ 6 m
V 28 + 30 
days a
NY-ESO-1 ASCI admin 
no.
17
18
19
20
21
22
23
24
Concluding 
visit b
Addendum to informed 
consenth
●
●
●
●
●
●
●
●
Clinical evaluations
Physical examination c
●
●
●
●
●
●
●
●
●
Imaging procedures d
●
●
●
●
●
●
Tumor response 
assessment
●
●
●
●
●
●
Safety assessments
(Serious) Adverse Events 
recorded e
●
●
●
●
●
●
●
●
●
pIMDs recorded
●
●
●
●
●
●
●
●
●
Laboratory assessments
Pregnancy test f
●
●
●
●
●
●
●
●
Urine chemistry tests g
●
●
●
●
●
●
●
Hematological tests g
●
●
●
●
●
●
●
●
●
Blood chemistry tests g
●
●
●
●
●
●
●
●
Autoimmunity tests g
●
●
●
●
●
●
●
Coagulation tests g
●
●
●
●
●
●
●
Criteria for permanent 
stopping or postponement 
of study treatment
●
●
●
●
●
●
●
●
Recording of concomitant 
medication
●
●
●
●
●
●
●
●
●
Study conclusion
●
m = month, as calculation convention: 1 month is defined as 4 weeks i.e. 28 days during the treatment phase.
a.
The procedures of the concluding visit are also to be carried out when a patient is withdrawn from study treatment.
b.
For patients who have withdrawn because of disease progression, any resected tumor can be sent to GSK for 
analysis of the gene profile and other appropriate tests upon signature of the adequate ICF by the patient (refer to 
Section 12.2).
c.
Complete physical examination. Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers (only during the tumor assessment visit). Recording of all changes in the patient’s medical condition 
including all adverse events.
d.
At Visits 22, 24, 25, 26, 27 and 29: Chest, complete-abdomen CT scans, and any other examination medically 
indicated to assess tumor dissemination are mandatory and must be performed within 2 weeks before the 
corresponding ASCI administration/visit. Brain contrast-enhanced CT scan (or MRI) should be performed only in 
case of evocative neurological symptoms. Color photography or ultrasound of skin / node / subcutaneous lesions 
mustalso be performed if applicable. If a photography presents a characteristic area rending possible the 
patient identification, photography will not be loaded and will be sent to the site according to GSK PII 
management procedure.
e.
Refer to Section 9.3.
f.
For women of child-bearing potential only; urine or blood test according to local practice; a negative result must be 
obtained before each ASCI treatment (at Visits 21-28) to allow continued recNY-ESO-1 + AS15 administrations.
g.
Refer to Section 6.7.2.
 
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h.
Signature of the ICF addendum must be the first procedure performed for patients returning for their first 
study visit after approval of Protocol Amendment 3. This only has to be done once. The study will 
continue only with patients from the active treatment group who will decide to stay in the study. Signature 
of the ICF addendum will be documented in the eCRF. 
(Amended 03 September 2014)
6.5.
Detailed description of study procedures
6.5.1.
Procedures prior to study participation
6.5.1.1.
Informed consent
Before performing any other study procedure, the signed informed consent of the patient
needs to be obtained. Refer to Section 12.2 for information on how to obtain informed 
consent.
The patient will also be proposed to sign the declaration of informed consent for 
translational and additional research (tick boxes on the informed consent form). This 
research is optional and the patient’s decision to consent or not to allow translational 
research to be performed on his/her biological samples does not influence the eligibility 
of the patient for the study.
6.5.2.
Procedures during screening phase/prior to the first ASCI 
administration
6.5.2.1.
NY-ESO-1 expression screening of tumor lesion(s)
A tumor biopsy will be performed on the day of the patient’s signature of the ICF or as 
soon as possible thereafter.
A tumor sample will be immediately stored in RNAlater® or equivalent RNA stabilizing 
solution (provided by GSK) and shipped as explained in the SPM to GSK Biologicals for 
the analysis of the expression of the NY-ESO-1 gene (see Section 6.7.3.1).
Note: In patients with sufficient tumor material (from the same lesion), another part of 
the tumor tissue will be formalin-fixed and paraffin-embedded (FFPE sample; a 
minimum of 4 mm3 tumor sample must be preserved in RNAlater® and a minimum of 7 
mm3 is needed for the FFPE sample).
The tumor biopsy could have been done previously in the context of local routine 
practices or as part of another research study. This tumor material may be used for the 
NY-ESO-1 expression analysis if and only if:

The patient signs the study ICF before the tumor sample is sent to GSK Biologicals 
for analysis, and;

The first ASCI administration is to take place no more than 12 weeks after this tumor 
biopsy.
 
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
The Sponsor’s permission to use this tissue has been obtained in advance.

The tumor tissue has been preserved in RNAlater® immediately after the surgery 
and the amount of tissue available must comply with the protocol requirements (see 
the SPM). (Amended 03 September 2014).
In the rare case the analysis of the tumor sample gives an inconclusive result, the patient 
may be asked to allow a new sample to be collected or to allow the use of an already 
preserved sample to repeat the test.
The patient will also be proposed to sign the declaration of informed consent for 
translational and additional research on the initial biopsy (tick box on the ICF for study 
participation). Refusal to participate in this optional research will involve no penalty or 
loss of benefits to which the patient would otherwise be entitled.
6.5.2.2.
Check inclusion and exclusion criteria
Check all applicable inclusion and exclusion criteria as described in Sections 4.2 and 4.3
before enrolment.
If a patient is enrolled while not meeting all inclusion criteria or while meeting any of the 
exclusion criteria, this must be reported in the eCRF as a protocol deviation.
6.5.2.3.
Collect demographic data
Record the patient’s demographic data such as date of birth, gender and race in the eCRF.
6.5.2.4.
Medical history
Perform a history-directed medical examination and record any pre-existing conditions 
and signs and/or symptoms present in a patient prior to the start of the study in the eCRF.
Treatment of any abnormality observed during this examination has to be performed 
outside this study according to local medical practice or by referral to an appropriate 
health care provider.
6.5.2.5.
Physical examination
Perform a physical examination of the patient, including assessment of the ECOG 
performance status, body temperature and resting systolic/diastolic blood pressure.
6.5.2.6.
Tumor imaging and assessment
No more than 6 weeks before the administration of the first ASCI dose: Chest CT scan, 
complete-abdomen CT scan, and contrast-enhanced CT scan or MRI of the brain, as well 
as any other examination medically indicated to assess the dissemination of the tumor. 
 
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Note: Tumor imaging performed as part of standard clinical practice or in relation to 
another research study does not need to be repeated, provided this imaging was done no 
more than 6 weeks before the first administration of the study treatment.
In order to enroll a patient in the trial, this tumor imaging should confirm that the patient 
is not presenting visceral metastasis. Color photography or ultrasound of 
skin/node/subcutaneous lesions must also be performed if applicable. (Amended 03 
September 2014).
A complete assessment of all target lesions will be conducted. Superficial cutaneous 
lesions must be documented by photography in metric notation by use of a millimeter 
ruler or calipers. (Amended 03 September 2014)
6.5.2.7.
Urine and blood collection
No more than 3 weeks before the administration of the first ASCI dose:

Collect a urine sample for urine chemistry tests including microalbuminuria. A 
validated quantitative test can be used according to local practice; for each individual 
patient the same test method must be used for all assessments.

Collect a blood sample for hematological tests, blood chemistry tests, autoimmunity
tests, blood urea nitrogen (BUN) and coagulation tests:
a.
Hematological tests: complete blood counts should be performed to include 
hemoglobin, hematocrit, total and differential white blood cells and platelets.
b.
Complete blood chemistry survey including LDH, CK, total protein and albumin, 
creatinine, serum bilirubin, direct bilirubin, ASAT, ALAT, alkaline phosphatase, and 
gamma-glutamyl transpeptidase.
c.
Autoimmunity tests: anti-nuclear antibody (ANA).
d.
Coagulation tests: prothrombin time (PT), activated partial thromboplastin time 
(APTT).
Further details of analysis are provided in Section 6.7.2.
6.5.2.8.
Pregnancy test
Female patients of childbearing potential are to have a pregnancy test at screening and 
visits 1, 2, 4 and 6 during Cycle 1. Subsequently, a pregnancy test must be made prior to 
any ASCI administration. The ASCI may only be administered if the pregnancy test is 
negative. Pregnancy tests should be performed according to current practice at the 
center.
6.5.2.9.
HIV status
HIV test is mandatory in Germany only. Please, refer to Section 13.2.
 
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6.5.2.10.
Recording SAEs
Any fatal SAEs and SAEs related to study participation or to concomitant use of GSK 
medication(s) are to be recorded (see Section 9.3.1).
6.5.3.
Procedures during ASCI administration phase
Note that some of the procedures to be performed during the ASCI administration period
(such as the physical examination, tumor imaging and assessment, taking urine samples, 
taking blood samples for hematological tests, blood chemistry tests, autoimmunity tests 
and coagulation tests, and pregnancy tests) are also performed during screening and are 
described in Section 6.5.2.
All chest CT scans, complete-abdomen CT scans, and any other examinations medically 
indicated to assess tumor dissemination should be performed so that the results are 
available at the actual visit.
Please refer to Table 6 to Table 9 for the timing of the study procedures in Cycles 1 to 4
(Section 6.4).
6.5.3.1.
Check inclusion and exclusion criteria
At Visit 1 only, check all inclusion and exclusion criteria as described in Sections 4.2 and 
4.3. If the patient at this point in time no longer meets all of the inclusion criteria or 
meets any of the exclusion criteria, he/she must not be administered the study treatment 
and must be withdrawn from the study.
6.5.3.2.
Check and record concomitant medication
Concomitant medication must be recorded in the eCRF as described in Section 5.6.2. 
Refer also to Section 5.6.2.1 for details on the medication forbidden and/or allowed 
during the study.
At each study visit subsequent to the first study product administration, it must be 
verified if the patient has experienced or is experiencing any concurrent medical 
condition(s) mentioned in Section 5.7. If this is the case, the condition(s) must be 
recorded in the eCRF.
6.5.3.3.
Check contraindications to ASCI administration
Contraindications to ASCI administration and possible reasons for postponing the 
treatment are to be checked at the beginning of each study product administration visit. 
Refer to Section 5.5.
 
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6.5.3.4.
Blood sampling for safety or immune response assessments
As specified in the lists of study procedures in Section 6.4, blood samples are to be taken 
during certain study visits. Refer to the Module on Biospecimen Management in the SPM 
for general handling of blood samples.
As of Protocol Amendment 3, no more blood samples will be collected for research 
purpose, i.e. blood samples taken for humoral immunological response and PBMC 
collection. For each blood sample already collected in the scope of this study and not 
tested yet, testing will not be performed by default, except if a scientific rationale 
remains relevant. Blood samples for safety assessment will continue to be collected and 
analysed. (Amended 03 September 2014).
6.5.3.5.
Sampling of other body fluids
Urine sample: a volume of 5 mL is required for pH, protein, glucose, blood cells and 
densitometric examination of the urinary sediment for microalbuminuria.
6.5.3.6.
Additional tumor biopsy or tumor resection
In case the investigator performs an additional tumor biopsy or tumor resection during 
the ASCI administration phase (see Section 5.6.1), sample(s) of the resected tumor 
lesion(s) will be sent to GSK Biologicals or a laboratory contracted for this by GSK 
Biologicals (see Sections 7.1 and 7.2.2). For patients who have given their specific 
informed consent to the optional translational research, such tumor tissue(s) may also be 
used to conduct these specific tests (see Sections 7.3, 7.6, 7.7, and 7.8).
Information will be provided regarding the additional resected/biopsied lesion(s). This 
will include the nature of the lesion (skin, lymph node, other), if the lesion is new or not, 
if the lesion is part of the target lesions or not, if the lesion is inflammatory or not, if 
vitiligo is present around the lesion or not and the status of the lesion when 
resected/biopsied (progressive, stable or regressive).
6.5.3.7.
Treatment number assignment
At each ASCI administration visit, the patient will be assigned a treatment number 
defining the treatment he/she will be receiving. The treatment number must be recorded 
in the eCRF at each ASCI administration visit.
6.5.3.8.
ASCI administration
The patient will receive the ASCI (i.m in the deltoid or the lateral region of the thigh; see 
Section 5.3.2). If the investigator or delegate decides that the patient’s health on the day 
of ASCI administration temporarily precludes ASCI administration, the visit will be 
rescheduled within the postponement interval for this visit (Section 6.3.1).
 
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The patient will be observed closely for at least 30 minutes, with appropriate medical 
treatment readily available in case of anaphylaxis following the administration of the 
ASCI.
6.5.3.9.
Recording of non-serious AEs, SAEs, potential immune-mediated 
diseases (pIMDs) and pregnancy
Refer to Section 9.3 for procedures for the investigator to record AEs and SAEs and to 
Section 9.4 for guidelines on how to report these AEs/SAEs to GSK Biologicals. Refer 
to Section 9.4.5 for instructions on reporting of pIMDs.
The patients will be instructed to contact the investigator immediately should they
manifest any signs or symptoms they perceive as serious.
6.5.3.10.
Tumor response assessment
Based on the tumor imaging and (adapted) RECIST criteria (as described in Section 6.6), 
the tumor response will be assessed and recorded.
6.5.3.11.
Clinical response criteria for continuing ASCI administration
Unlike chemotherapy that may cause prompt clinical tumor shrinkage already after 2 to 4 
weeks by exerting a direct cytotoxic effect on tumor cells, ASCIs function indirectly by 
eliciting a cellular and humoral immune response, which takes time to develop and is
maximal only several weeks after the initial immunizations. In accordance with this, in 
previous and ongoing trials with cancer immunotherapeutics most clinical responses were 
observed several weeks after the beginning of the immunizations. Moreover, long-term 
maintenance treatment with immunizations was followed in some patients, who initially 
showed stable disease or mixed response, by long-term complete tumor response. 
Therefore, in the present study, the patient’s response to treatment will be assessed during 
and after each cycle to determine whether to continue treatment.
The overall tumor responses to treatment qualifying patients to receive up to a maximum 
of 24 ASCI administrations are:

Objective responses: Complete Response (CR) and Partial Response (PR).

Stable Disease (SD).

Slow Progressive Disease (SPD).
SPD (defined in Section 6.6.6) corresponds to a protocol-specific convention allowing 
the continuation of ASCI administrations even in the event of a Progressive Disease 
(PD).
Only patients with CR, PR, SD and SPD at the first tumor response evaluation at the end 
of Cycle 1 (Visit 7) may continue to receive study treatment. All the other patients will 
not be admitted to treatment in Cycle 2. Refer to Section 6.6 for the definitions of tumor 
response.
 
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The patients will be assessed midway through Cycle 2 (Visit 11). Patients showing CR, 
PR, SD and SPD may continue to receive study treatment, while all the other patients 
must discontinue the treatment.
Patients showing CR, PR, SD and SPD at the third tumor response evaluation at the end 
of Cycle 2 (Visit 15) may continue to receive study treatment in Cycle 3. All the other 
patients will not be admitted to treatment in Cycle 3.
Patients showing CR, PR, SD and SPD at the end of Cycle 3 (Visit 20), will be admitted 
to treatment in Cycle 4. All the other patients must discontinue treatment.
Patients showing CR, PR, SD and SPD at Visits 22, 24, 25, 26 and 27 (Section 6.6) will 
be allowed to continue Cycle 4.
6.5.4.
Concluding visit
6.5.4.1.
Patients who received all the scheduled doses
The concluding visit will take place 30 days after Visit 28 (for patients withdrawn from 
the study treatment before completion, see Section 6.5.4.2).
The following procedures will be performed within 2 weeks of this visit:
Chest CT scan, complete-abdomen CT scan, and any other examination medically 
indicated to assess tumor dissemination. A contrast-enhanced CT scan or MRI of the 
brain should only be performed in case of evocative neurological symptoms. Color 
photography or ultrasound of skin/node/subcutaneous lesions must also be performed if 
applicable. (Amended 03 September 2014).
Based on the tumor imaging and RECIST criteria (as described in Section 6.6), the 
overall tumor response will be assessed.
At the visit, the following procedures described above will be performed: physical 
examination; recording any AEs and SAEs, pIMDs, and concomitant medications; taking
a urine sample for urine chemistry tests; taking a blood sample for hematological tests, 
blood chemistry tests, autoimmunity tests, coagulation tests. (Amended 03 September 
2014).
6.5.4.2.
Patients withdrawn before the end of the scheduled doses
The patients are free to withdraw from the study at any time and for any reason without 
this having any prejudicial impact on their further treatment. All patients who have 
received any dose of the study treatment should be followed for toxicity assessment.
For patients whose participation in the study is discontinued - for whatever reason -
before all the scheduled ASCI treatments have been administered, the concluding visit is 
to be carried out at least 30 days after the patient's last dose of ASCI.
 
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The following procedures will be performed no more than two weeks before this visit. If 
imaging has been performed less than 6 weeks before, this need not be repeated
(Amended 03 September 2014):

Chest CT scan, complete-abdomen CT scan, and any other examination medically 
indicated to assess tumor dissemination.  A contrast-enhanced CT scan or MRI of the 
brain should only be performed in case of evocative neurological symptoms.
During the visit, the following procedures described above will be performed: physical 
examination including the recording of the ECOG performance status; recording any 
(serious) AEs, pIMDs and concomitant medications; taking a urine sample for urine 
chemistry tests; taking a blood sample for hematological tests, blood chemistry tests, 
autoimmunity tests, coagulation tests. (Amended 03 September 2014).
The urine and blood sampling associated with the concluding visit must be performed 
before initiation of any other new systemic anticancer treatment. If necessary, these
samplings will therefore be performed separately from the other procedures of this
concluding visit.
For patients who have withdrawn because of progression of the disease, any resected 
tumor can be sent to GSK for analysis of NY-ESO-1 expression and gene profile upon 
signature of the adequate ICF by the patient (refer to Section 12.2); for patients who have 
given their specific consent to this, such tumor tissue(s) may also be used for optional 
translational research.
6.5.4.3.
Study conclusion
The study conclusion will be made at the Concluding Visit. (Amended 03 September 
2014).
6.6.
Response criteria
Some patients may present an objective tumor response that may be evaluated according 
to the RECIST criteria [Therasse, 2000] as the primary endpoint of this study (see 
Section 6.6.1).
Nevertheless, the majority of the patients of the study population will present a cutaneous 
and/or sub-cutaneous and/or lymph node disease which may not be assessed according to 
the RECIST criteria, because all target lesions will have a longest diameter < 20 mm (in-
transit metastasis, Stage IV M1a disease). Specific measurability and response criteria 
must therefore be defined for this particular subgroup of patients (see Section 6.6.2).
A third category of patients may present both target lesion(s) ≥ 20 mm and target 
lesion(s) < 20 mm. Specific measurability and response criteria must also be defined for 
this subgroup of patients (see Section 6.6.3).
 
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6.6.1.
Response criteria for patients with all target lesions ≥20.0 mm
Objective tumor response is assessed according to the RECIST criteria as a primary 
endpoint of this study.
The response assessment is essentially based on a set of measurable lesions identified at 
baseline as target lesions, and followed until disease progression.
The following paragraphs contain a brief summary of the RECIST criteria [Therasse, 
2000] as appropriate to this study. The complete criteria are available at
http://www.eortc.be/recist/documents/RECISTGuidelines.pdf.
6.6.1.1.
Measurability of tumor lesions
6.6.1.1.1.
Definitions
Measurable disease: the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.
Measurable lesions: lesions that can be accurately measured in at least one dimension 
with longest diameter 20 mm. With spiral CT-scan, the lesion must be 10 mm in at 
least one dimension.
Non-measurable lesions: all other lesions, including small lesions (longest diameter < 20 
mm with conventional techniques or < 10 mm with spiral CT scan) and other non-
measurable lesions. These include: bone lesions; leptomeningeal disease; ascites; pleural 
/ pericardial effusion; inflammatory breast disease; lymphangitis cutis / pulmonis; 
abdominal masses that are not confirmed and followed by imaging techniques; and cystic 
lesions.
All measurements should be recorded in metric notation by use of a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the start of treatment 
and never more than 6 weeks before the start of the treatment.
6.6.1.1.2.
Methods of measurement
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline. (Amended 03 September 2014).

Clinically detected lesions will only be considered measurable when they are 
superficial (e.g. skin nodules, palpable lymph nodes). For the case of skin lesions, 
documentation by color photography - including a ruler to estimate the size of the 
lesion - is required.
 
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
CT-scan and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment. Conventional CT-scan and 
MRI should be performed with contiguous cuts of 10 mm or less in slice thickness. 
Spiral CT-scan should be performed using a 5 mm contiguous reconstruction 
algorithm; this specification applies to the tumors of the chest, abdomen and pelvis 
while head and neck tumors and those of the extremities usually require specific 
protocols.

Ultrasound (US) should not be used to measure tumor lesions that are clinically not 
easily accessible. It may be used as a possible alternative to clinical measurements 
of superficial palpable nodes, subcutaneous lesions. US might also be useful to 
confirm the complete disappearance of superficial lesions usually assessed by 
clinical examination. US should preferentially be performed by the same 
investigator.
6.6.1.2.
Tumor response evaluation
6.6.1.2.1.
Baseline documentation of target and non-target lesions
All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and will be 
recorded and measured at baseline.
Target lesions should be selected on the basis of their size (those with the longest 
diameter) and their suitability for accurate repetitive measurements (either by imaging 
techniques or clinically).
A sum of the longest diameter (LD) for all target lesions will be calculated and reported 
as the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor response.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded and measured at baseline. Measurements are not required but the 
presence or absence of each should be noted throughout follow-up.
 
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6.6.1.2.2.
Response criteria
Evaluation of target lesions
Complete Response (CR) Disappearance of all target lesions.
Partial Response (PR)
At least a 30% decrease in the sum of LD of target lesions 
taking as reference the baseline sum LD.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest 
sum LD since the treatment started.
Progressive Disease (PD)
At least a 20% increase in the sum of LD of target lesions 
taking as references the smallest sum LD recorded since the 
treatment started OR the appearance of one or more new 
lesions OR both of these.
Evaluation of non-target lesions
Complete Response (CR) Disappearance of all non-target lesions.
Incomplete Response / 
Stable Disease
Persistence of one or more non-target lesion(s).
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. (Although a 
clear progression of “non-target” lesions only is 
exceptional, in such circumstances the opinion of the 
treating physician should prevail.)
6.6.1.2.3.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). In general the patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status.
 
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Summary for evaluation of overall response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR (or NA)
No
CR
CR
Incomplete response / SD
No
PR
PR
Any response other than PD
No
PR
SD
Any response other than PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Not all 
evaluated
Any response other than PD
No
NE
Any response 
other than PD
Not all evaluated
No
NE
Any
Any
Yes
PD
Abbreviations: CR: complete response; PR: partial response; SD: stable disease; PD : progressive 
disease; NA: not applicable; NE: non-evaluable.
(Amended 03 September 2014).
6.6.2.
Tumor response for cutaneous/subcutaneous/lymph node 
disease with target lesions of less than 20.0 mm
Some patients of this protocol will present a cutaneous and/or sub-cutaneous and/or 
lymph node disease that could not be evaluable according to RECIST criteria because all 
target lesions will have a longest diameter < 20 mm (in transit metastasis, Stage IV M1a).
Specific measurability and response criteria must therefore be defined for this particular
subset of patient.
Similarly to the standard RECIST criteria, the response assessment for patients with 
cutaneous and/or subcutaneous and/or lymph node disease with target lesions of less than 
20 mm are essentially based on a set of measurable lesions identified as target lesions at 
baseline, and followed until disease progression.
 
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6.6.2.1.
Measurability of cutaneous/subcutaneous/lymph node tumor lesions at 
baseline
6.6.2.1.1.
Definitions
Measurable disease: the presence of at least one cutaneous or subcutaneous or lymph 
node measurable lesion.
Measurable cutaneous/subcutaneous/lymph node lesions: lesions that can be accurately 
measured in at least one dimension.
Minimal longest diameter required for one target lesion is:
Clinical detection
(color photography)
Ultrasound
Cutaneous lesion
Lesion must be 5 mm
–
Subcutaneous lesion
–
Lesion must be 5 mm
Lymph-node lesion
–
Lesion must be 5 mm
Measurable cutaneous confluent lesion: if cutaneous lesions are too numerous and too 
small (< 5 mm) but are confluent, they can be recorded as a specific measurable confluent 
lesion.
Non-measurable lesion: all other lesions, including small lesions (longest diameter < 5 
mm).
All measurements should be recorded in metric notation by use of a ruler or calipers. 
Baseline evaluations should be performed as closely as possible to the start of treatment 
(could be performed at Visit 1) and never more than 6 weeks before the start of the 
treatment. (Amended 03 September 2014).
6.6.2.1.2.
Methods of measurement
The same method of assessment and the same technique should be used to characterize 
each identified and reported (confluent) lesion at baseline and during follow-up.
For patients presenting a cutaneous disease with all lesions having a longest diameter of 
< 20 mm (measurable cutaneous lesions, measurable cutaneous confluent lesions and 
non-measurable lesions), the lesions must be documented/recorded by color photography 
- including a ruler to estimate the size of the lesion.
For patients presenting a subcutaneous or lymph node disease with all lesions having a 
longest diameter of < 20 mm, lesions must be documented/recorded by ultrasound (US)
or CT scan.  Note: US may also be useful to confirm the complete disappearance of 
cutaneous lesions usually assessed by clinical examination.
 
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6.6.2.2.
Tumor response evaluation
6.6.2.2.1.
Baseline documentation of target and non-target lesions
All measurable cutaneous/subcutaneous/lymph node lesions and measurable cutaneous 
confluent lesion up to a maximum of 5 lesions per site (skin, subcutaneous or lymph 
node) should be identified as target lesions and will be recorded and measured at 
baseline.
Target lesions should be selected on the basis of their size (those with the longest 
diameter) and their suitability for accurate repetitive measurements (either by US or 
clinically).
All other lesions should be identified as non-target lesions and should also be recorded 
and evaluated at baseline as well as at each further visit including a tumor response 
assessment. They should be followed as “present” or “absent” at baseline and followed 
using the RECIST criteria at further visits. Independently to this follow-up assessment, 
any new lesion will be recorded as non-target lesion. (Amended 03 September 2014).
6.6.2.2.2.
Response criteria
Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions.
Partial Response (PR) / 
Stable Disease (SD)
Neither sufficient shrinkage to qualify for CR nor 
sufficient increase to qualify for PD taking as 
references the smallest sum LD since the treatment 
started.
Progressive Disease (PD)
According to investigator, clear increase of diameters of 
target lesions taking as references the smallest 
diameters recorded since the treatment started OR the 
appearance of one or more new target lesions OR both 
of these.
Evaluation of non-target lesions
Complete Response (CR)
Disappearance of all non-target lesion.
Incomplete Response / Stable 
Disease
Persistence of one or more non-target lesion(s).
Progressive Disease (PD)
Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  
(Although a clear progression of “non-target” lesions 
only is exceptional, in such circumstances the opinion 
of the treating physician should prevail.)
 
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6.6.2.2.3.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for PD the smallest 
measurements recorded since the treatment started). In general the patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria.
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.
6.6.3.
Response criteria for patients with both target lesion(s) ≥20 mm 
and target lesion(s) < 20 mm
The present guidelines prevent the consideration of a patient with good responding 
lesions 20 mm as progressive based on progression of some small lesions (< 20 mm) or 
to consider a patient with one large stable lesion (20 mm) as stable disease while all the 
other target lesions (< 20 mm) show progression.
The advice for response evaluation in this patient category is to take the sum of the 
longest diameters for all target lesions (< and 20 mm) and to use the response criteria as 
defined below.
The definitions for complete response (CR), partial response (PR) and stable disease (SD) 
remain the same.
Progressive disease can be defined as either an increase of at least 20% in the sum of the 
longest diameters of the target lesions OR if at least half of the target lesions show at 
least a doubling of diameters OR the appearance of one or more new lesions.
Evaluation of target lesions
Complete Response (CR) Disappearance of all target lesions.
Partial Response (PR)
At least a 30% decrease in the sum of LD of target lesions 
taking as reference the baseline sum LD.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as references the smallest 
sum LD since the treatment started.
Progressive Disease (PD)
At least a 20% increase in the sum of LD of target lesions 
taking as references the smallest sum LD recorded since the 
treatment started OR the appearance of one or more new 
lesions OR both of these.
 
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Evaluation of non-target lesions
Complete Response (CR) Disappearance of all non-target lesions.
Incomplete Response / 
Stable Disease
Persistence of one or more non-target lesion(s).
Progressive Disease (PD)
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. (Although a clear 
progression of “non-target” lesions only is exceptional, in 
such circumstances the opinion of the treating physician 
should prevail.)
6.6.3.1.
Evaluation of best overall response
See corresponding part of Section 6.6.1.2.2.
6.6.4.
Confirmation measurements and duration of response
6.6.4.1.
Confirmation
The main goal of confirmation of objective response is to minimize the risk of 
overestimation of the response rate. In cases where confirmation of response is not 
feasible, it should be made clear when reporting the outcome of such studies that the 
responses are not confirmed. In the present study, responses always need to be 
confirmed.
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeated assessments that should be performed no less than 4 weeks after the criteria 
for response are first met.
6.6.4.2.
Duration of overall response
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is recorded first) until the first date that recurrence or PD is 
objectively documented (taking as reference for PD the smallest measurements recorded 
since the treatment started).
6.6.4.3.
Duration of stable disease
Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD taking as references the sum of LD of target lesions 
recorded previously but not necessarily at baseline.
The minimal time interval required between two measurements for determination of SD 
is at least 16 weeks.
 
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6.6.5.
Definition of mixed response
The concept of a Mixed Response (MR) is based on the observation that some melanoma 
patients present with tumor lesions that indubitably regress after ASCI administration, 
whereas other lesions remain unchanged or progress or with new lesions appearing.
As one example, consider a case with the complete regression of all initial target lesions 
but with the appearance of one new lesion - this must certainly be considered as a PD. 
However, it is important that the detailed information about such a case is recorded in an 
early clinical study as a MR, because such a situation could be explained by an adequate 
biological activity of the ASCI but with a resistance of the new tumor lesion to the 
immune response induced by the ASCI (i.e., HLA Class I loss, NY-ESO-1 negative 
metastasis).
Cases of MR will NOT be considered as meeting the criteria of the definition of an 
objective response (for assessment of the primary endpoint), as all MR are either a stable 
disease (SD) or a progressive disease (PD). However, the recorded information about 
MRs will be useful in the descriptive assessment of the biological activity of the ASCI 
treatment.
6.6.5.1.
Mixed response adapted from the RECIST criteria
Some patients will present an objective tumor response that may be measured according 
to the RECIST criteria.  For these patients, the MR criteria are defined as follows:

At least 30% decrease in the longest diameter (LD) occurring in at least one target 
lesion recorded and measured at baseline. Such response occurring in otherwise SD 
or PD status of the LD of target lesions and without the appearance of one or more 
new lesions will be classified as “SD with target lesion regression” or “PD with 
target lesion regression”, respectively.

The appearance of new lesions in otherwise PR status of the LD of target lesions will 
be classified as “PR with new lesion.
6.6.5.2.
Mixed response for disease not evaluable according to RECIST criteria
Some patients of the target population of this study will present cutaneous and/or sub-
cutaneous and/or lymph node lesion(s) that cannot be evaluated according to the RECIST 
criteria because all target lesions will have a longest diameter < 20 mm as in transit 
metastasis, (i.e., patients with Stage IV M1a disease).
For these patients, the MR criteria are defined as follows:

A clear decrease of diameters occurring in at least one target lesion recorded and 
measured at baseline. Such response occurring in otherwise SD or PD status of the 
LD of (baseline) target lesions and without the appearance of one or more new 
lesions will be classified as “SD with target lesion regression” or “PD with target 
lesion regression”, respectively.
 
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
The appearance of new lesions in otherwise PR status of the LD of target lesions will 
be classified as “PR with new lesion.(Amended 03 September 2014).
6.6.6.
Definition of Slow Progressive Disease status
Unlike chemotherapy, which may prompt tumor shrinkage within 2 - 4 weeks of 
treatment start by exerting a direct cytotoxic effect on the tumor cells, ASCI therapies 
function indirectly by eliciting an immune response (humoral and cellular), which 
requires time and repeated immunizations to be established and hence becomes maximal 
only several weeks after the initiation of the ASCI injections. Thus, in previous and 
ongoing cancer immunotherapeutic trials, most clinical responses were recorded several 
weeks after the start of the immunizations. Moreover, in some patients with otherwise 
stable disease or a mixed response, long-term maintenance treatment with ASCI 
injections has been followed by a complete tumor response.
The concept Slow Progressive Disease (SPD) has been defined to allow for the time 
required for eliciting a stable and effective immune response and to avoid premature 
withdrawal from the study treatment of some patients who might benefit from continued 
immunization. For patients meeting the criteria for SPD status, disease progression is 
therefore not to be considered as a criterion for withdrawal from the study treatment.
It is to be noted that SPD is not to be considered as a success criterion of the study, and 
time to progression will be determined as the time of first evidence of disease progression 
notwithstanding that the patient may have been allowed to continue the study treatment 
because of having SPD status.
The SPD status is defined below:
Slow 
Progressive 
Disease
All of the following criteria must be met:
1.
The patient's ECOG performance status is 0 or 1.
2.
The patient's LDH value is not greater than twice the normal
upper limit.
3.
There is no appearance of visceral metastases other than in the 
lung.
4.
The patient does not meet any of the criteria for permanent 
stopping of study treatment (Section 5.5.2).
 
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6.7.
Biological sample handling and analysis
As of Protocol Amendment 3, no more biological samples will be collected for research 
purpose. For each biological sample already collected in the scope of this study and not 
tested yet, testing will not be performed by default, except if a scientific rationale 
remains relevant. In this case, testing will be done in compliance with the protocol and 
the ICF signed by the patient as described in the sub-sections below. (Amended 03 
September 2014).
Please refer to the SPM for details of biospecimen management (handling, storage and 
shipment).
Samples will not be labeled with information that directly identifies the patients but will 
be coded with the identification number for the patient (patient number).
Collected samples may also be used for purposes related to the quality assurance of the 
laboratory tests described in this protocol. This may include the management of the 
quality of these current tests, the maintenance or improvement of these current tests, the 
development of new test methods for the markers described in this protocol, as well as 
making sure that new tests are comparable to previous methods and work reliably.
It may be that any findings in the present study or in other studies necessitate further 
investigation by GSK Biologicals into the efficacy or immunogenicity of the recNY-
ESO-1 + AS15 ASCI and its constituents or further research in the disease under study. 
Therefore, all patients in countries where this is allowed, will be invited to give their 
separate agreement (tick box in the Informed Consent Form) to allow GSK to perform, 
under these circumstances, additional testing outside the scope of this protocol on the 
samples.
It is also possible that future findings may make it desirable to use the samples acquired 
in this study for tests that are not related to the disease under study. Therefore, all 
patients in countries where this is allowed, will be invited to give their separate 
agreement (tick box in the Informed Consent Form) to allow GSK to perform such 
additional testing.
The decision to accept or reject translational and/or additional testing will not affect the 
ability of the patient to enter the study. Any sample testing will be done strictly in line 
with the consent of the individual patient and will be subject to the laws and regulations 
concerning such testing in the respective countries. This additional research will only be 
performed once the relevant Ethics Committee(s) has/have been informed and has/have 
reviewed the tests to be performed, and has/have had the possibility of deciding to obtain 
the specific informed consent of the patient for this/these test(s).
Any sample testing will be done in line with the consent of the individual patient.
Any human pharmacogenetic testing will require specific consent from the individual 
patients and the ethics committee approval.
 
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Refer also to the Investigator Agreement, where it is noted that the Investigator cannot 
perform any other biological assays except those described in the protocol or its 
amendment(s).
Collected samples will be stored for up to 15 years (counting from when the last patient 
performed the last study visit), unless local rules, regulations or guidelines require 
different timeframes or different procedures, which will then be in line with the patient 
consent. These extra requirements need to be communicated formally to and discussed 
and agreed with GSK Biologicals.
6.7.1.
Use of specified study materials
When materials are provided by GSK Biologicals or central laboratories contracted by 
GSK Biologicals, it is MANDATORY that all clinical samples be collected and stored 
exclusively using those materials in the appropriate manner. The use of other materials 
could result in the exclusion of the patient from the ATP analysis (See Section 11.4 for 
the definition of study populations to be evaluated). The investigator must ensure that 
his/her personnel and the laboratory(ies) under his/her supervision comply with this 
requirement. However, when GSK Biologicals does not provide material for collecting 
and storing clinical samples, then appropriate materials from the investigator’s site are to 
be used. Refer to the Module on Clinical Trial Supplies in the SPM or biospecimen 
management for more details.
6.7.2.
Hematology, Serum Chemistry and Urine tests
Sampling for the various laboratory tests will be performed as shown in Table 10.  For 
details of the blood sampling (volumes in each tube), information will be supplied to the 
study sites as necessary. These assays will be conducted at each investigational site's 
local laboratory; samples will be handled according to the site's standard procedures. If a 
clinically significant laboratory abnormality is detected at one of these assessments, it 
should be followed up as adequate until it has returned to normal or a satisfactory 
explanation has been provided.
Specification for Germany: An additional blood sample might be required for HIV test. 
Collect of the sample will be performed according to standard local practice. For more 
information, please refer to Section 13.2.
 
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Table 10
Hematology, Serum Chemistry, Urine tests
Sample type
System
Component
Scale
Timing
HEMATOLOGY
Blood (5 mL)
Whole 
blood
Hemoglobin
Quantitative
During screening
Cycle 1: Visits 1, 3 and 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 21 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment
Hematocrit
Complete blood cell count
Total and differential white 
blood cell count
Platelets
BIOCHEMICAL VALUES
Blood (5 mL)
Serum
Sodium
Quantitative
During screening
Cycle 1: Visits 1, 3 and 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 21, 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment
Potassium
Calcium
Lactate dehydrogenase 
(LDH)
Creatine kinase (CK)
Total protein4
Albumin4
HEPATIC FUNCTION
Blood (5 mL)
Serum
Aspartate aminotransferase 
(ASAT)
Quantitative
During screening
Cycle 1: Visits 1, 3 and 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 21, 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment
Alanine aminotransferase 
(ALAT)
Alkaline phosphatase
Gamma-glutamyl 
transpeptidase (GT)
Serum bilirubin4
Direct bilirubin3,4
RENAL FUNCTION
Blood (5 mL)
Serum
Blood urea nitrogen (BUN)5
Quantitative
During screening
Cycle 1: Visit 6
Cycle 2: Visits 10 and 14
Cycle 3: Visits 17 and 19
Cycle 4: Visits 22, 25, and 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment
Creatinine
COAGULATION
Blood (5 mL)
Serum
Prothrombin Time (PT)
Quantitative
During screening
Cycle 1: Visits 1, 3 and 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment(s)
Activated Partial 
Thromboplastin Time
(APTT)
 
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Sample type
System
Component
Scale
Timing
AUTOIMMUNITY
Blood (5 mL)
Serum
Anti-nuclear antibody (ANA)
1
Quantitative
During screening
Cycle 1: Visit 6
Cycle 2: Visit 14
Cycle 3: Visit 19
Cycle 4: Visits 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment(s)
Follow-up Visits: F2, F4
PREGNANCY TESTING (MANDATORY) 2
Blood (5 ml) 
or urine 
according to 
local practice
Serum or 
urine
According to local practice
Ordinal
During screening
Cycle 1: Visits 1, 2, 4, and 6
Cycles 2 - 4: prior to each ASCI 
administration
URINALYSIS
Urine
Urine
Protein (test strip)
Ordinal
During screening
Cycle 1: Visit 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment(s)
Glucose (test strip)
pH (test strip)
Quantitative
Erythrocyte (Red Blood Cells 
- test strip)
Microalbuminuria3,4
(densitometric evaluation of 
urinary sediment)
1.
ANA test will be carried out by immunofluorescence on HEPG2 cells. In case anti-nuclear antibodies are detected, 
further analysis will be performed by immunodot and/or enzyme-linked immunosorbent Assay (ELISA) to identify 
the auto-target antigen.
2.
For women of child-bearing potential only.
3.
It is mandatory to measure direct bilirubin/microalbuminurea, only when bilirubin/albumin  testing reveals 
abnormal results. 
4.
A quantitative or qualitative test can be performed at the investigator’s  discretion. In cases where 
positivea qualitative results are received, test a quantitative test also needs to be performed. It is 
sufficient to do only one test for protein in Urine, if this test is sensitive enough.  
5.
Measurement of serum urea (azotemia) is allowed instead of measurement of BUN. The choice between 
these tests is left at the investigator’s discretion. If measurements are in serum urea, they need to be 
converted to BUN. The conversion has to made according to the following formula: Urea [mg/dL]= BUN 
[mg/dL] * 2.14. BUN can be expressed in either in mg/dL or in mmol/L. If Serum Urea has been expressed 
in mmol/L, the conversion factor is 1 and as the formula is: SU (mmol/L) = BUN (mmol/L).
(Amended 03 September 2014)
6.7.3.
Molecular, immunological and translational research read-outs
Note that, as of Amendment 3, the decision was taken not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant. No further blood samples for protocol research purposes 
will be collected. (Amended 03 September 2014).
Table 11 summarizes the molecular and immunological read-outs that have to be 
performed during the study as well as translational research and provides the time points 
for performance of these tests. For a more detailed description of the read-outs and 
research refer to Sections 6.7.3.1, 6.7.3.2 and 7.  The tests will be performed by GSK 
SK Biologicals or a validated laboratory designated by GSK Biologicals.
 
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The GSK Biologicals’ clinical laboratories have established a Quality System supported 
by procedures.  The activities of GSK Biologicals’ clinical laboratories are audited 
regularly for quality assessment by an internal (Sponsor-dependent) but laboratory-
independent Quality Department.
Table 11
Overview of molecular and immunological read-outs and 
translational research
NY-ESO-1 SCREENING (MANDATORY)
Test
Sample Type
Laboratory
Timing
NY-ESO-1 expression testing
(see also Section 6.7.3.1)
Fresh tissue
sample (in 
RNAlater® or 
equivalent)
GSK Biologicals or 
contracted lab a
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection.
IMMUNOLOGICAL READ-OUTS (MANDATORY)
Test
Sample Type Laboratory
Timing
Humoral immunity
(see Section 6.7.3.2.1)
Serum
(2 x 5 ml) b
GSK Biologicals or 
contracted lab a
Cycle 1: Visits 1, 3, 5 to 7
Cycle 2: Visit 14
Cycle 3: Visit 19
Cycle 4: Visits 22, 24 to 27
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn from 
study treatment(s)
Follow-up Visits: F1 to F4
Anti-NY-ESO-1 antibody response
Cellular immunity
(see Section 6.7.3.2.2)
Blood
(150 ml) c
Cycle 1: Visits 1 and 6
Cycle 2: Visit 14
Cycle 3: Visit 19
Cycle 4: Visits 22, 24 to 27
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn from 
study treatment(s)
Follow-up Visits: F2, F4
Cellular (T-cell) response (including 
regulatory T-cell responses)
MANDATORY TRANSLATIONAL RESEARCH (SEE SECTION 7.2.1)
Test
Sample Type Laboratory
Timing
Gene profiling of the tumor
Fresh tissue
sample (in 
RNAlater® or 
equivalent)
and FFPE 
tissue
(if available) d
GSK Biologicals or 
contracted lab a
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection.
 
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OPTIONAL TRANSLATIONAL RESEARCH (SEE SECTION 7 EXCEPT 7.2.1)
Test
Sample Type
Laboratory
Timing
Expression analysis of
NY-ESO-1 and other tumor
antigens (e.g., MAGE-A3, 
PRAME, LAGE-1, MAGE-C2 and 
WT1)
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue
(if available) d
GSK 
Biologicals or 
contracted
lab a
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection.
Natural immunogenicity and
Antigen spreading
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue
(if available) d,
serum and blood
b, c
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection.
May be performed on any of the blood 
samples taken for the humoral and cellular 
immunity tests
Gene profiling of the immune 
response
Blood
(150 ml) c
May be performed on any of the blood 
samples taken for the cellular immunity tests 
(PBMC collection)
Proteomic profiling
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue (if 
available) d,
serum and blood 
b, c
During screening (initial biopsy) or on any of 
the blood samples taken for the humoral and 
cellular immunity tests
infiltrating lymphocytes 
(including T regulatory cells and 
other immune cellular entities)
Either fresh 
tissue sample (in 
RNAlater® or 
equivalent) or
FFPE tissue
(if available) d
During screening (initial biopsy). In case of 
additional tumor biopsy or tumor resection
DNA methylation status of NY-
ESO-1, other antigens and 
predictive genes, in addition to 
immunoregulatory genes
Either fresh 
tissue sample (in 
RNAlater® or 
equivalent) or
FFPE tissue (if 
available) d,
serum and blood
b, c
During screening (initial biopsy) or in case of 
additional tumor biopsy or tumor resection 
(disease progression), or on any of the blood 
samples taken for the humoral and cellular 
immunity tests
Pharmacogenetics analyses
Tumor samples 
and blood
Preferably on blood collected at Visit 1. On 
tumor cells from screening or from additional 
lesions
a.
GSK Biologicals laboratory or a validated laboratory designated by GSK Biologicals.
b.
2 x 5 ml of blood will be used for both anti-NY-ESO-1 antibody responses; and for the optional translational
research (as applicable).
c.
A total of 150 ml of blood will be used for cellular immunological read-outs; and for the optional translational
research (as applicable).
d.
FFPE tissue is only to be collected from patients with sufficient tumor material from the same lesion to provide a
fresh sample and a FFPE sample. GSK Biologicals or a contracted laboratory will require a block of at least 7 
mm3 or 15 slides of 10 m each.
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6.7.3.1.
NY-ESO-1 expression screening of the tumor
This test will be performed on fresh tumor tissue. The tumor sample will be processed as 
described in the SPM.
Note that in the rare case that the analysis of the sample would give an inconclusive 
result, the patient may be asked to allow a new sample to be collected to repeat the test 
or, if available, to allow the use of an already preserved sample to repeat the test.
This test will be performed at GSK Biologicals or at another laboratory or laboratories 
chosen and contracted for this task by GSK Biologicals.
NY-ESO-1 expression screening of the tumor will be carried out using a real-time 
quantitative PCR test developed and validated by GSK or any updated technique at the 
time of analysis.
NY-ESO-1 transcript will be amplified in parallel with one or more control genes (e.g. -
actin), used for normalization and relative quantification of NY-ESO-1 transcript levels. 
Commercial RNA or RNA from cell lines expressing NY-ESO-1 is used as a positive 
control and commercial RNA or RNA from cell lines that do not express NY-ESO-1 is 
used as negative control.
A sample will be defined as NY-ESO-1 positive if NY-ESO-1 transcript level in 
extracted RNA (normalized to one or more control genes) is above a fixed cut-off level.
6.7.3.2.
Immunological read-outs
As the immunotherapy proposed for this study is designed to activate both B- and T-cell 
compartments of the immune system, both the serology and the cellular immune 
responses induced by the immunization will be measured.
As this study is the first time in human study with the recNY-ESO-1 + AS15 ASCI, no 
serum or PBMC samples of immunized patients have been available so far to optimize 
the assays and to determine cut-off values to define the immunological responders. The 
optimal assays and cut-off values will be established during the course of this clinical 
study.
These tests will be performed at GSK Biologicals or at another laboratory or laboratories
chosen and contracted for this task by GSK Biologicals.
6.7.3.2.1.
Antibody response to the ASCI antigens
Currently, testing of serum to assess antibody mediated immune responses has been 
performed for a subset of samples collected in this study. Further testing will only be 
performed if a scientific rationale remains relevant in compliance with the protocol 
and the ICF signed by the patient as described in the sub-sections below. (Amended 03 
September 2014).
 
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The antibody response to the NY-ESO-1 antigen will be assessed for all patients enrolled 
into the study. (Amended 03 September 2014)
Specific anti-NY-ESO-1 antibodies pre-existing and induced by the recNY-ESO-1 + 
AS15 ASCI will be measured by ELISA or upgraded techniques, and the results will be 
provided in EU/mL or other appropriate units. This can be done using either the NY-
ESO-1 recombinant protein or NY-ESO-1-derived peptides spanning the entire NY-ESO-
1 sequence as coating antigen. A patient will be considered as seropositive if the
antibody titer is superior or equal to the assay cut-off value and at least twice the patient’s 
value at baseline. (Amended 03 September 2014).
These tests will be performed at GSK Biologicals or at another laboratory chosen and 
contracted for this task by GSK Biologicals.
At each planned visit (as defined in Section 6.4), the amount of blood to be drawn for the 
analysis of antibody response will be 2 x 5 mL blood in appropriate tubes. Time points 
for serum collections are described in Section 6.4.
6.7.3.2.2.
Cellular immune response to the ASCI antigens
Currently, testing of PBMCs to assess cell-mediated immune responses has been 
performed for a subset of samples collected in this study. Further testing will only be 
performed if a scientific rationale remains relevant in compliance with the protocol 
and the ICF signed by the patient as described in the sub-sections below. (Amended 03 
September 2014).
1. PBMC processing and analysis
The cell-mediated immune (CMI) response pre-existing or induced by the ASCI 
administrations will be assessed for all patients enrolled into the study(Amended 03 
September 2014).
The technique used for assessing CMI responses may be updated to the best available 
approved procedure at the time of analysis.  These analyses will be completed (or 
performed again with an updated technique) at GSK Biologicals or at another laboratory 
chosen and contracted for this task by GSK Biologicals.
In order to obtain a more precise picture of the patient’s CMI response, a Human 
Leukocyte Antigen (HLA) typing could be needed, but this would not require additional 
blood sampling.
Peripheral blood mononuclear cells (PBMC), to be drawn for the CMI response analysis 
at certain planned visits, will be obtained from 150 mL of venous blood. Time points for 
collection of blood for PBMC isolation are indicated in Section 6.4.
To ensure that the PBMC samples taken are usable, these visits must take place according 
to the schedule provided in the SPM. For details, please refer to the SPM.
 
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PBMC processing will be performed centrally at a chosen external laboratory contracted 
for this purpose by GSK Biologicals.
2. Cellular response to the recNY-ESO-1 + AS15 ASCI
So far, in contrast to serology, there is no standard or validated technique available to 
monitor the T-cell response induced by immunization with a recombinant protein in 
cancer patients. The techniques described in this section may be updated to the best 
available at the time of analysis.  Dependent on the immunogenicity of the tumor-antigen 
targeted, the T-cell responses can either be measured directly ex vivo or will require a 
step of specific in vitro re-stimulation of the T-cells. The presence of specific cells may
be documented by measuring the production of cytokines, by measuring a cytolytic 
activity (e.g. by detection of Granzyme, Perforin or CD107a marker), specific activation 
markers upon antigen encounter or by tetramer staining using known T cell-epitopes 
using appropriate assays. The percentage of those T-cells can then be determined by 
ELISPOT or by Fluorescence-Activated Cell Sorter (FACS), after surface and/or 
intracellular cytokine staining(Amended 03 September 2014).
Briefly, the characterization of the T-cell response may be performed as 
follows(Amended 03 September 2014):

The detection and functionality of the T-cell response will be assessed by stimulating 
PBMCs with pools of peptides spanning the entire NY-ESO-1 protein (after in vitro
stimulation in order to amplify specific CD4+ and CD8+ T-cell populations if 
necessary). This will be measured by FACS, including their capacity to produce 
cytokines and to present other markers of lytic capacity such as Perforin and 
Granzyme, or activation such as CD107a, CD40L or CD137.

Depending on the ex vivo frequency of NY-ESO-1 specific T-cells and the 
availability of antigen-specific tetramers, the phenotype of cells can be analyzed in 
order to evaluate the nature of the specific response elicited (effector/memory). For 
this, expression of several surface markers such as CCR7, CD45RA, CD27 and 
CD28 can be measured by FACS or by another updated technology and markers.
In order to obtain a more precise picture of the patient’s CMI response, tetramer assays 
could be carried out depending on the patient’s HLA typing. Several tetramers are 
already available which would allow monitoring of the evolution of NY-ESO-1 specific 
CD4+ and CD8+ T-cell responses in patients after immunization.
The NY-ESO-1 cellular response will be assessed before immunization (to determine 
baseline values) and at several time points in each cycle of immunization (see Table 6 to
Table 9).(Amended 03 September 2014)
 
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7.
TRANSLATIONAL RESEARCH
As of Amendment 3, the decision was taken not to perform further testing on biological 
samples already collected in this study by default, except if a scientific rationale 
remains relevant. In case testing would be performed in the future, testing will be done 
in compliance with the protocol and the ICF signed by the patient as described in the 
sub-sections below. (Amended 03 September 2014).
This section provides details on the translational research that may be done on the 
biological samples collected during this study. These different tests may only be 
performed on biological samples from patients who voluntarily gave their consent to
these specific assessments on the ICF, unless specified as mandatory for participation in 
the clinical study (see Section 7.2.1). (Amended 03 September 2014).
Refusal to participate in the optional translational research procedures will involve no 
penalty or loss of benefits to which the patient would otherwise be entitled. These tests 
will be performed at GSK Biologicals or a validated laboratory designated by GSK 
Biologicals. Based on the data generated in the study and in other studies, not all samples 
from patients consenting to this optional research may be processed.
7.1.
Analysis of expression of NY-ESO-1 and other tumor 
antigens on presenting lesion and on any new lesions
The presenting lesion will also be tested for the expression of other tumor antigens such 
as MAGE-A3, MAGE-C2, LAGE-1, PRAME and WT1. Any new lesions will be tested 
for NY-ESO-1 expression and also for expression of the other tumor antigens just 
mentioned.
These tests will be performed on fresh tumor tissue and on formalin-fixed paraffin-
embedded (FFPE) tissue (if available). The tumor samples will be processed as described 
in the SPM.
The tumor antigen mRNA expression levels in tumor samples will be determined using a 
GSK qualified assay based on quantitative RT-PCR or any updated technique at the time 
of the analysis. The level will be calculated relative to normalization controls. A patient 
will be defined as having a tumor antigen-positive tumor if the tumor antigen transcript 
level in the tumor is above an arbitrarily fixed cut-off level.  Additional analysis of tumor 
antigen protein expression might be performed by using an appropriate technique such as 
immunohistochemistry (IHC) or any updated technology.
These tests will be performed at GSK Biologicals or at another laboratory or laboratories 
chosen and contracted for this task by GSK Biologicals.
 
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7.2.
Gene profiling research
7.2.1.
Gene profiling on the baseline tumor lesion
The research to evaluate the possible existence of a specific predictive NY-ESO-1 gene 
profile that would be different from the “predictive MAGE-A3 gene profile” will be very 
informative and is therefore mandatory. It is worth noting that this will not require any 
other tumor tissue sample than the one used for the mandatory NY-ESO-1 expression 
screening (inclusion criteria for the study). In addition, the clinical benefit induced by the 
recNY-ESO-1 + AS15 ASCI will also be evaluated in the subgroup of patients who 
present the predictive MAGE-A3 gene signature.  Moreover the incidence of expression 
of these two gene profiles will be evaluated in all patients who provided the ICF consent 
(e.g. screening failure patients).  Cancer is a heterogeneous disease, including its 
cellularity, different genetic alterations and diverse clinical behavior patterns. Many 
analytical techniques have been used to study human tumors and to classify them into 
groups that can predict clinical behavior.
DNA microarrays have made significant contributions to this field by detecting 
similarities and differences amongst tumors by the simultaneous analysis of the 
expression of thousands of genes. DNA microarrays have allowed investigators to 
develop expression-based classification of tumors. Efforts aimed at discovering 
independent predictors of clinical outcome have identified molecular subsets of cancer 
based on these gene expression profiles. Subcategories of lymphoma, breast carcinoma 
and sarcomas with distinct prognosis and/or clinical behavior were recognized. Recently, 
two subgroups of metastatic melanoma lesions were identified; however, these had no 
predictive correlation with clinical outcome [Bittner, 2000; Wang, 2002].
Despite significant efforts to identify independent predictors of melanoma outcome, no 
generally accepted histopathological or molecular marker defines disease subsets with 
clinically different outcomes [Byers, 1998; Weyers, 1999; Busam, 2004]. But analyses 
of gene expression have shed new light on the progression from local to metastatic 
disease as well as on melanoma immune responsiveness [Carr, 2003; Wang, 2002; Haqq, 
2005]. In a previous GSK Phase II study with MAGE-A3 ASCI, 75 patients with 
progressive, unresectable Stage III or Stage IV M1a MAGE-A3 (+) melanomas, were 
randomized to receive recMAGE-A3 + AS15 ASCI or recMAGE-A3 + AS02B ASCI. 
Gene expression profiling was performed on tumor biopsies taken prior to any 
immunotherapy. Two clusters of genes or gene signatures were identified that were 
either associated with clinical benefit - MAGE-A3 positive gene signature, or progressive 
disease - MAGE-A3 negative gene signature [Louahed, 2008].
Total RNA will be extracted from the fresh tumor tissue samples using an appropriate 
extraction kit. A fraction of the extracted RNA (e.g. 50 ng) will be used to hybridize a 
gene expression chip with a locked set of genes (e.g. Affymetrix or other commercial 
chips). Further gene expression profiling and validation of differentially expressed genes 
associated with clinical response might be performed by quantitative polymerase chain 
reaction (Q-PCR) on remaining or newly extracted total RNA from the tumor samples. 
 
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FFPE tumor tissue samples, when available, might also be used for gene expression 
profiling and validation of differentially expressed genes by using appropriate techniques 
such as Q-PCR, immunohistochemistry (IHC) or proteomic analysis.
7.2.2.
Gene profiling and NY-ESO-1 expression testing on additional 
lesions
These tests will be performed in case the investigator plans to perform or has performed
an additional tumor biopsy or a tumor resection during the study (e.g. palliative surgery, 
see Section 5.6.1) or because of disease progression. If the procedure occurs in the 
context of disease progression, the patients will be proposed to sign a separate ICF to 
allow a sample of this lesion to be sent to GSK Biologicals or a validated laboratory 
designated by GSK Biologicals for the optional research on gene profiling.
The details of this research are the same as for the gene profiling research on a fresh 
tissue sample from the initial tumor lesion at baseline (see Section 7.2.1).
7.3.
Natural immunity and antigen spreading induced by the 
recNY-ESO-1 + AS15 ASCI (Amended 03 September 2014)
The aim of a cancer immunotherapeutic is to stimulate the patient’s cellular and humoral 
immune response in order to eliminate the cancer cells. Although such immune 
responses can be detected upon administration of a cancer immunotherapeutic, the direct 
impact of this response, especially the T-cell response, on the clinical activity has not yet 
been demonstrated; some patients who show evidence of tumor regression upon 
administration of a cancer immunotherapeutic have very low T-cells directed against the 
target antigen of the immunotherapeutic [Lurquin, 2005]. It has now been shown that in 
melanoma patients who have been immunized against MAGE-A3, T-cells directed 
against other tumor antigens (i.e. tumor antigens not present in the immunotherapeutic) 
were enriched after anti-MAGE-A3 immunization [Germeau, 2005]. Moreover, these 
anti-tumor T-cells were found to be more frequent inside metastases than anti-MAGE-A3 
T-cells, suggesting that they could have a role in the effective tumor destruction 
[Lurquin, 2005].
On the basis of these findings, we will assess whether administration of the recNY-ESO-
1 + AS15 ASCI is able to induce antibodies and T-cells against other tumor antigens that 
are co-expressed by the patient's tumor (e.g. MAGE-C2, MAGE-A3, LAGE-1, WT1, 
PRAME) in addition to tissue differentiation or overexpressed tumor antigens such as, for 
instance, Melan-A/MART-1 or gp100.  The expression of these tumor antigens in the 
tumor presenting at baseline or in any progressive lesion(s) may be assessed as well by 
quantitative RT-PCR or any updated technique at the time of the analysis. Validation of 
tumor antigen expression (including NY-ESO-1) at the protein level may also be 
performed by IHC or other proteomic analytical method. (Amended 03 September 2014).
The analyses will be performed on fresh tissue put in RNAlater® immediately and used 
for the mandatory NY-ESO-1 expression screening (inclusion criterion for the study) or 
additional lesions excised during the study, and on serum and blood samples collected for 
 
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analysis of the immune responses to these other tumor antigens elicited by the recNY-
ESO-1 + AS15 ASCI administrations (see Table 11).
7.4.
Gene profiling of immunological response to the recNY-
ESO-1 + AS15 ASCI
This will allow investigation of the patient’s immunological response status prior to the 
start of the ASCI immunizations. This general gene expression profile will be used to 
identify genes that may be involved in the immunological response to the recNY-ESO-1
+ AS15 ASCI. We will assess the kinetics of the immune response induced by the study 
treatment to get insight into the adaptive and the innate immune response that may 
correlate with clinical benefit.
If enough material is available, the cellular response to the recNY-ESO-1 protein will be 
examined upon in vitro re-stimulation. Total PBMCs harvested before and after ASCI 
administration will be stimulated twice in vitro with NY-ESO-1 or other cancer antigen -
peptide pool. The general gene expression profile will be determined from unstimulated 
and stimulated PBMCs.
No additional blood sampling is needed as this gene profiling of the immune response 
may be performed on any of the blood samples collected for the analysis of the humoral 
or cellular immune response to the ASCI .  Gene expression profiling will be performed 
on total RNA extracted from whole blood or from purified populations (CD4+ T-cells, 
CD8+ T-cells, antigen-presenting cells) from PBMC by hybridization to a gene 
expression chip with a locked set of genes (e.g., Affymetrix or other commercial chips)
or by the use of epigenetic markers (e.g. methylation). Further gene expression profiling 
and validation may be performed by Q-RT-PCR. (Amended 03 September 2014).
7.5.
Proteomic profiling
Protein rather than mRNA regulate and mediate cellular function. Studies comparing 
mRNA and protein levels often showed a weak correlation between them. Thus it would 
be highly beneficial to have proteomic information along with gene profiling.
Proteomics has been shown in the literature to be a good technique to study patients' 
prognosis and response to therapy [Pusztai, 2004]. There has been little proteomic 
information to date on the serum or tumor proteomics of patients responding or not to the 
ASCI.
Using appropriate techniques the serum or tumor proteome may be analyzed .This will 
identify useful bio-markers for responsiveness to the NY-ESO-1 antigen. (Amended 03 
September 2014).
This optional proteomic profiling may be performed on any of the blood samples 
collected for analyses of the humoral and cellular immune responses to the ASCI or on 
the tumor tissue sample used for the mandatory NY-ESO-1 expression test during 
screening, including FFPE samples.
 
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7.6.
Analysis of tumor immune infiltration
Immunotherapeutics are designed to boost tumor-specific T-cell responses in cancer 
patients.  Nevertheless, the presence of tumor antigen-specific T-cells in peripheral blood 
of immunized patients does not always demonstrate a clear correlation with the clinical 
outcome, leaving the open question whether changes in tumor T-cell infiltration 
following immunotherapy could correlate better with clinical outcome.  Moreover, the 
predictive gene signature identified in melanoma and NSCLC (refer to Section 1.3.4) 
indicates that the capacity of the tumor to be infiltrated by lymphocytes may be a key 
factor to support immunotherapy approaches.
To address the correlation of tumor T-cell infiltration before and after immunotherapy 
with clinical outcome, suitable markers to assess immune infiltration will be evaluated.  
The markers, as well as the techniques used for assessing immune infiltration may be 
updated at the time of analysis.
This analysis will be done using either fresh tumor tissue or FFPE tumor samples if 
available at screening and later biopsies collected during the study and at disease 
progression.
7.7.
DNA promoter methylation analysis of NY-ESO-1 and other 
tumor antigens
Gene methylation (i.e., addition of a methyl group to a cytosine residue) is a control 
mechanism that regulates gene expression. Methylation of DNA occurs at CpG sites, 
where cytosine (C) is attached next to guanine (G) by a phosphate atom (p). Such CpG 
sites, located at the promoter and first exon of genes, are known as CpG islands (or CpG 
dinucleotide-rich region).  In several diseases, these regions can be aberrantly methylated.  
When promoter regions are hypo-methylated, abnormally high levels of protein can be 
produced. Aberrant methylation of specific genes has been shown to be associated with 
the presence and development of some cancer types.  The pattern of gene methylation in 
tumor cells is often specific to the tissue of origin and could be used to improve cancer 
detection, assess cancer aggressiveness, and predict a tumor’s response to therapy 
[Baylin, 2006; Jones, 2005].  The correlation of mRNA expression levels of genes in the 
ASCI predictive gene signature or other genes that could be predictive with their 
methylation status will be performed for the genes for which methylation assays are 
available.
 
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It has been shown that expression of cancer-testis antigens (CTAs) is re-activated during 
tumorigenesis and experimentally following demethylation of their promoter region 
[Simpson, 2005].  Even though, different studies have shown that pharmacological 
demethylation of tumor cell lines causes NY-ESO-1 re-expression in vitro [Weiser, 2001; 
Natsume, 2008; Woloszynska-Read, 2008], only one study has shown that the 
heterogeneous expression of NY-ESO-1 in ovarian tumor cells by IHC might be 
correlated with promoter demethylation in the NY-ESO-1-positive cell population 
[Woloszynska-Read, 2008].  It is then important to corroborate these findings and study 
their possible association with NY-ESO-1 ASCI efficacy and its implication for the 
development of a non-invasive screening test based on circulating tumor cells or 
circulating tumor cells DNA detection by NY-ESO-1 promoter methylation status.
Tumor cell DNA can be detected from the blood of melanoma patients even in early 
disease [Kounalakis, 2005].  This DNA can for instance originate from the primary
tumor, where some cells are lyzed releasing DNA material in the blood or from 
circulating tumor cells. The presence of NY-ESO-1 expressing tumor cells should 
therefore be anticipated if the presence of demethylated NY-ESO-1 promoter DNA is 
detected in the patient’s blood.  The detection of NY-ESO-1 specific demethylated DNA 
from the blood could lead to the development of non-invasive methods to identify the 
presence of NY-ESO-1 expressing tumor cells. It could also potentially be used to 
anticipate the efficacy of the treatment, if the level of the circulating tumor DNA is 
increased over time.  Practically, this approach could broaden the patient population for a 
treatment with NY-ESO-1 ASCI compared to the traditional methods of NY-ESO-1 
detection by RT-PCR on a tumor sample.
This part of the translational research aims to analyze whether the methylation status of 
the NY-ESO-1 gene in tumor tissue, as assessed by using DNA from tumor tissue or 
blood, can be correlated with NY-ESO-1 mRNA and protein expression in the tumor.
The methylation status of regulatory regions of genes encoding other tumor antigens 
(e.g., MAGE-C2, PRAME, LAGE-1, MAGE-A3 and WT1) will also be assessed in the 
cases for which a methylation assay is available.  It will be analyzed to what extent 
specific DNA methylation as detected in blood and tumor lesions correlates with gene 
expression.  DNA methylation analysis will be performed based on the availability of 
methylation assays.
In addition, methylation status of regulatory regions of genes encoding transcriptional 
factors relevant in the regulation of immune response (such as Foxp3, GATA-3, T-bet, 
ROR-T expressed by helper CD4 + T cells) might be analyzed. In the case of Foxp3
evaluation, the presence and characterization of circulating T regulatory cells may be 
evaluated in parallel or independently of the realization of these transcriptional 
profiling. (Amended 03 September 2014).
A fraction of the stored serum and blood collected over time for the immunological 
analyses will be used for the methylation analysis. DNA methylation will also be 
assessed either on fresh tumor tissue or FFPE tumor sections used for NY-ESO-1
detection and additional biopsies taken during the study and at disease progression.
 
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7.8.
Pharmacogenetics analyses
Pharmacogenetics (PGx) (also referred to as pharmacogenomics) is the study of 
variability in response to a treatment due to hereditary factors in different individuals.  
There is increasing evidence that an individual's genetic composition (i.e., genotype) may 
impact clinical outcome to treatment with therapy, in terms of efficacy and/or safety and 
tolerability.  Besides individual genetic variability, it has been shown that changes in 
DNA sequences occurring in cancer cells might also correlate with response to a given 
treatment [Goetz, 2007; Schroth, 2007; Higgins, 2009; Coate, 2009; Ding, 2008].
In this study, PGx will, next to the analysis of the patient’s genotype, include studying 
whether changes in the genes of the tumoral cells might correlate with treatment 
response. The goal of the PGx research is thus to find genomic biomarkers that correlate 
with treatment efficacy, safety or tolerability. This analysis could be done at the DNA 
and/or RNA level.
Two types of material will therefore be used:

For the individual genetic variability: a fraction of the stored blood collected over 
time for the immunological analysis (cellular immunity tests) will be used from the 
patients who consent to PGx research. It is recommended that the sample used for 
this analysis should be the one taken at Visit 1. However, any study sample 
collected while the patient is participating in the clinical study may be used.

For the tumor genetic variability: this analysis might be performed on the tumor 
sample collected for screening, on tumor tissue samples from additional resected
lesions or on tumor invaded lymph node when material is available and of 
appropriate quality. Of note, this investigation of the tumoral cells will not require 
additional material.
The specific type of genetic investigation to be applied will be dependent on the most 
scientifically feasible approach available to address understanding of the response of the 
recNY-ESO-1 + AS15 ASCI.
Generally, two approaches to explore genetic variation in response to medicine may be 
applied:
1. Search and analysis of candidate genes, which would have been shown or 
hypothesized to be associated with the effects of ASCI or that have been shown or 
hypothesized to play a role in melanoma development or progression.  These 
analyses could aim at determining DNA sequence variation (mutations) in the 
regulatory or coding region of these genes, translocations and copy number 
variation using appropriate techniques that might involve whole genome 
interrogation.
 
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2. Genome-wide single nucleotide polymorphisms (SNP) scanning: through the 
evaluation of large numbers of polymorphic markers, such as SNPs, throughout 
the genome, sets of markers may be identified that associate with differential 
response to medicine (safety and efficacy).  These whole genome scans provide a 
hypothesis free approach, where there is limited mechanistic insight.  Whole 
genome scans could be performed using standardized SNP arrays, for example 
commercially available Affymetrix or Illumina SNP chips targeting either 
100,000 or 500,000 SNP coverage of the genome or any updated technology 
including other techniques that interrogate the whole genome.  Validation of the 
findings might require the use of alternative approaches to detect SNPs for 
example genotyping PCR.  These investigations will be limited to the response of 
study NY-ESO-1 ASCI.
DNA extracted from the blood or tumor samples may be subjected to sample quality 
control analysis.  This analysis might involve the genotyping of several genetic markers 
to confirm the integrity of individual samples.
PGx analyses will be carried out at GSK Biologicals laboratories, laboratories approved 
by GSK Biologicals and/or associated with GSK Biologicals.
8.
HEALTH ECONOMICS
Not applicable.
9.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The investigator or site staff is/are responsible during the study for the detection and 
documentation of events meeting the criteria and definition of an adverse event (AE) or 
serious adverse event (SAE) as provided in this protocol.
Each patient will be instructed to contact the investigator immediately should the patient 
manifest any signs or symptoms they perceive as serious.
9.1.
Safety definitions
9.1.1.
Definition of an adverse event
An AE is any untoward medical occurrence in a clinical investigation patient, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product. For marketed medicinal products, this also includes 
failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse. 
 
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Examples of AEs to include:

Significant or unexpected worsening or exacerbation of the condition/indication 
under study.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after investigational product administration 
even though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concurrent medication (overdose per se should not be 
reported as an AE/SAE).

Signs, symptoms temporally associated with ASCI treatment administration.

Significant failure of expected pharmacological or biological action.
Examples of AEs to NOT include:

Medical or surgical procedures (e.g. endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (e.g. social and/or 
convenience admission to a hospital, admission for routine examination).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

For therapeutic studies, the disease/disorder being studied, or expected progression, 
signs, or symptoms of the disease/disorder being studied, unless more severe than 
expected for the patient’s condition.
AEs may include pre- or post-treatment events that occur as a result of protocol-
mandated procedures (i.e. invasive procedures, modification of patient’s previous 
therapeutic regimen).
Example of events to be recorded in the medical history section of the eCRF:

Pre-existing conditions or signs and/or symptoms present in a patient prior to the 
start of the study (i.e. prior to the first ASCI administration).
9.1.2.
Definition of a serious adverse event
A serious adverse event (SAE) is any untoward medical occurrence that:
a.
Results in death.
b.
Is life-threatening.
 
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NB: The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which 
the patient was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, had it been more severe.
c.
Requires hospitalization or prolongation of existing hospitalization.
NB: In general, hospitalization signifies that the patient has been admitted at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate 
in the physician’s office or out-patient setting. Complications that occur during 
hospitalization are also considered AEs. If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event will also be considered serious. When in 
doubt as to whether ‘hospitalization’ occurred or was necessary, the AE should be 
considered serious.
Hospitalization for elective treatment of a pre-existing condition (known/diagnosed prior 
to informed consent signature) that did not worsen from baseline is NOT considered an 
AE.
d.
Results in disability/incapacity, or
NB: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect in the offspring of a study patient
f.
Is a Grade 4 AE according to the Common Terminology Criteria for Adverse Events 
(CTCAE, Version 4.0).
g.
In addition, in this study, Grade 3 or higher pIMDs will be considered as medically 
significant and will therefore be notified as SAE.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization.
9.1.3.
Potential immune mediated diseases
Potential immune mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune etiology. AEs that need to be recorded and 
reported as pIMDs include those listed in the table below.
 
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Table 12
Examples of AEs to be recorded as pIMDs (amended 3 September 
2014)
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve disorders, 
including paralyses/paresis 
(e.g. Bell’s palsy)

Optic neuritis

Multiple sclerosis 

Transverse myelitis

Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other variants

Acute disseminated 
encephalomyelitis, including 
site specific variants: e.g. 
non-infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis

Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome 

Immune-mediated peripheral 
neuropathies and 
plexopathies,  (including 
chronic inflammatory 
demyelinating 
polyneuropathy, multifocal 
motor neuropathy and 
polyneuropathies associated 
with monoclonal 
gammopathy).

Narcolepsy

Systemic lupus 
erythematosus  and 
associated conditions

Systemic Scleroderma 
(Systemic sclerosis), 
including diffuse systemic 
form and CREST syndrome

Idiopathic inflammatory 
myopathies, including 
Dermatomyositis, 
Polymyositis,

Antisynthetase syndrome

Rheumatoid arthritis and 
associated conditions 
including Juvenile chronic 
arthritis and Still’s disease)

Polymyalgia rheumatica 

Spondyloarthritis, including 
ankylosing spondylitis, 
reactive arthritis (Reiter's 
Syndrome) and  
undifferentiated 
spondyloarthritis

Psoriatic arthropathy

Relapsing polychondritis

Mixed connective tissue 
disorder

Psoriasis

Vitiligo

Erythema nodosum

Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis)

Alopecia areata

Lichen planus

Sweet’s syndrome

Localised Scleroderma 
(Morphoea)
Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis

Primary biliary cirrhosis

Primary sclerosing 
cholangitis

Autoimmune cholangitis.

Inflammatory Bowel 
disease, including Crohn’s 
disease, ulcerative colitis, 
microscopic colitis, 
ulcerative proctitis

Celiac disease

Autoimmune pancreatitis

Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis)

Grave's or Basedow’s 
disease

Diabetes mellitus type I

Addison’s disease

Polyglandular autoimmune 
syndrome

Autoimmune hypophysitis
 
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Vasculitides
Blood disorders
Others

Large vessels vasculitis 
including: giant cell arteritis 
such as Takayasu's arteritis 
and temporal arteritis. 

Medium sized and/or small 
vessels vasculitis including: 
polyarteritis nodosa, 
Kawasaki's disease, 
microscopic polyangiitis, 
Wegener's granulomatosis, 
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis), Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and 
anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified), 
Henoch-Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic vasculitis.

Autoimmune hemolytic 
anemia

Autoimmune 
thrombocytopenia

Antiphospholipid syndrome

Pernicious anemia

Autoimmune aplastic 
anaemia

Autoimmune neutropenia 

Autoimmune pancytopenia

Autoimmune 
glomerulonephritis 
(including IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis)

Ocular autoimmune 
diseases (including 
autoimmune uveitis and 
autoimmune retinopathy)

Autoimmune 
myocarditis/cardiomyopathy

Sarcoidosis

Stevens-Johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary 
fibrosis

Goodpasture syndrome

Raynaud’s phenomenon
However, the investigator will exercise his/her medical and scientific judgment in 
deciding whether other immune-mediated diseases have an autoimmune origin (i.e. 
pathophysiology involving systemic or organ-specific pathogenic autoantibodies) and 
should also be recorded as a pIMD. 
When there is enough evidence to make any of the diagnoses listed in Table 12, the AE 
must be reported as a pIMD. Symptoms, signs or conditions which might (or might not) 
represent one of these diagnoses, should be recorded and reported as AEs but not as a 
pIMDs until the final or definitive diagnosis has been determined, and alternative 
diagnoses have been eliminated or shown to be less likely.
In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to these 
diagnoses will be available to the investigators at the study start.
 
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9.1.4.
Clinical laboratory parameters and other abnormal assessments 
qualifying as adverse events or serious adverse events 
Abnormal laboratory findings (e.g. clinical chemistry, hematology, urinalysis) or other 
abnormal assessments that are judged by the investigator to be clinically significant will 
be recorded as AEs or SAEs if they meet the definition of an AE, as defined in Section 
9.1.1 or of a SAE, as defined in Section 9.1.2. Clinically significant abnormal laboratory 
findings or other abnormal assessments that are detected during the study or are present at 
baseline and significantly worsen following the start of the study will be reported as AEs 
or SAEs.
The investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant.
9.2.
Events or outcomes not qualifying as adverse events or 
serious adverse events
9.2.1.
Progression of the melanoma
An event which is part of the natural course of the disease under study (i.e., disease 
progression), is captured as an efficacy measure. Therefore it does not need to be 
reported as an SAE.
Progression of the tumor will be recorded in the clinical assessments in the eCRF. Death 
due to progressive disease is to be recorded on a specific form in the eCRF but not as an 
SAE.
However, if the investigator considers that there was a causal relationship between the 
administration of the ASCI or protocol design/procedures and the disease progression, 
then this must be reported as an SAE.
Any new primary cancer (non-related to the cancer under study) must be reported as an 
SAE.
9.2.2.
Pregnancy
Any female patients that are pregnant or lactating at the time of ASCI administration
must not receive additional doses of the ASCI but may continue other study procedures at 
the discretion of the investigator.
The investigator, or his/her designee, will collect pregnancy information on any patient 
who becomes pregnant while participating in this study from the first ASCI 
administration until the Concluding Visit. (Amended 03 September 2014).
The investigator, or his/her designee, will record pregnancy information on the 
Pregnancy Report Form and submit it to GSK within 24 hours of learning of a patient's 
 
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pregnancy.  The patient will be followed to determine the outcome of the pregnancy.  At 
the end of the pregnancy, whether that be full-term or prematurely, information on the 
status of the mother and child will be forwarded to GSK.  Generally, follow-up will be no 
longer than six to eight weeks following the estimated delivery date.
While pregnancy itself is not considered an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or a 
SAE, as described in Sections 9.1.1 and 9.1.2, and will be followed as described in 
Section 9.4.4.
A spontaneous abortion is always considered to be a SAE and will be reported as 
described in Section 9.4. Furthermore, any SAE occurring as a result of a post-study 
pregnancy AND considered by the investigator to be reasonably related in time to the 
receipt of the investigational product will be reported to GSK Biologicals as described in 
Section 9.4. While the investigator is not obligated to actively seek this information from 
former study participants, he/she may learn of a pregnancy through spontaneous 
reporting.
Information on pregnancies identified during screening/prior to ASCI administration is 
not required to be collected and communicated to safety.
9.3.
Detecting and recording adverse events, serious adverse 
events and pregnancies
9.3.1.
Time period for detecting and recording adverse events, serious 
adverse events and pregnancies
All AEs (except AEs categorized as pIMDs - see Section 9.1.3) starting from first dose to 
30 days after the last dose of the ASCI must be recorded into the Adverse Event screen in 
the patient’s eCRF, irrespective of intensity or whether or not they are considered ASCI
administration-related.
The standard time period for collecting and recording SAEs (except SAEs categorized as 
pIMDs - see Section 9.1.3) will begin at the first receipt of ASCI and will end 30 days
following administration of the last dose of ASCI for each patient. See Section 9.4 for 
instructions on reporting and recording SAEs.
The standard time period for collecting and recording severe toxicity events, pIMDs and 
pregnancy will begin at the first receipt of the product and last until the end of the study 
(Table 13).
In addition to the above-mentioned reporting requirements and in order to fulfill
international reporting obligations, SAEs that are related to study participation (e.g. 
protocol-mandated procedures, invasive tests, a change from existing therapy) or are 
related to a concurrent GSK medication/vaccine or any fatal SAE will be collected and 
recorded from the time the patient consents to participate in the study until she/he is 
discharged.
 
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Table 13
Reporting periods for AEs, SAEs, pIMDs and pregnancies
Study activity
Screening 
phase
Treatment phase
Concluding 
visit 1
ICF signature 
to Visit 1
Visit 1
Visit X
(X= 2 to 28)
30 days after 
last ASCI 
administration
Visit 29
Reporting of AEs and 
SAEs 
Reporting of severe 
toxicity events
Reporting of pIMDs and 
pregnancy
Reporting of SAEs 
related to the study 
treatment
Reporting of SAEs 
related to study 
participation and 
concurrent GSK 
medications, and 
reporting of any fatal 
SAEs, not due to 
disease progression
1.
Or the concluding visit for patients withdrawn from study treatment(s).
(Amended 03 September 2014).
A post-study AE/SAE is defined as any event that occurs outside of the AE/SAE 
reporting period defined in Table 13. Investigators are not obligated to actively seek AEs 
or SAEs in former study participants. However, if the investigator learns of any SAE, 
including a death, at any time after a patient has been discharged from the study, and 
he/she considers the event reasonably related to the investigational product, the 
investigator will promptly notify the Study Contact for Reporting SAEs.
 
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9.3.2.
Evaluation of adverse events and serious adverse events
9.3.2.1.
Active questioning to detect adverse events and serious adverse 
events
As a consistent method of soliciting AEs, the patient should be asked a non-leading 
question such as:
‘Have you felt different in any way since receiving the ASCI or since the previous visit?’
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g. hospital progress notes, laboratory, and diagnostics reports) relative 
to the event. The investigator will then record all relevant information regarding an 
AE/SAE on the eCRF screens as applicable. It is not acceptable for the investigator to 
send photocopies of the patient’s medical records to GSK Biologicals instead of the 
appropriate completed AE/SAE screens in the eCRF. However, there may be instances 
when copies of medical records for certain cases are requested by GSK Biologicals. In 
this instance, all patient identifiers will be blinded on the copies of the medical records 
prior to submission to GSK Biologicals.
The investigator will attempt to establish a diagnosis pertaining to the event based on 
signs, symptoms, and/or other clinical information. In such cases, the diagnosis should 
be documented as the AE/SAE and not the individual signs/symptoms.
9.3.2.2.
Assessment of adverse events
9.3.2.2.1.
Assessment of intensity
Severity of AEs will be assessed according to the CTCAE; Version 4.0.
The investigator will assess the maximum intensity that occurred over the duration of the 
event for all AEs, including SAEs reported during the study. The assessment will be 
based on the investigator’s clinical judgment.
The intensity of each AE and SAE recorded in the eCRF or SAE Report screens, as 
applicable, should be assigned according to the table given in the CTCAE (Version 4.0).
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE. Grade 3 
is a category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3. An event is defined as ‘serious’ when it meets the definition in 
Section 9.1.2.
 
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9.3.2.2.2.
Assessment of causality
The investigator is obligated to assess the relationship between the ASCI and the 
occurrence of each AE/SAE. The investigator will use clinical judgment to determine the 
relationship. Alternative plausible causes, based on the natural history of the underlying 
diseases, concomitant therapy, other risk factors and the temporal relationship of the 
event to the ASCI treatment will be considered and investigated. The investigator will 
also consult the Investigator Brochure (IB) in the determination of his/her assessment.
There may be situations when a SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK Biologicals. However, it is very 
important that the investigator always makes an assessment of causality for every event 
prior to submission of the SAE to GSK Biologicals. The investigator may change his/her
opinion of causality in light of follow-up information, amending the SAE information 
accordingly. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements.
In case of concomitant administration of multiple products, it may not be possible to 
determine the causal relationship of AEs to the individual product administered. The 
investigator should, therefore, assess whether the AE could be causally related to the 
ASCI administration rather than to the individual products.
Causality of all other AEs should be assessed by the investigator using the following 
question:
Can we eliminate the fact that the AE is unambiguously explained by a cause other than 
the study product (e.g. progressive tumor, accident, infection, natural history of a pre-
existing disorder, etc.)?
YES
:
The AE will be considered as at least possibly related to the study 
product.
NO
:
The AE is not related to the study product. There are other, more 
likely causes and the study product is not suspected to have 
contributed to the AE.
Non-serious and serious AEs will be evaluated as two distinct events. If an event meets 
criteria to be determined ‘serious’ (see Section 9.1.2 for definition of serious adverse 
event), additional examinations/tests will be performed by the investigator in order to 
determine ALL possible contributing factors applicable to each SAE.
 
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Possible contributing factors include:

Medical history.

Other medication.

Protocol required procedure.

Other procedure not required by the protocol.

Lack of efficacy of the ASCI, if applicable.

Erroneous administration.

Other cause (specify).
9.3.2.3.
Assessment of outcomes
Outcome of any non-serious AE occurring within 30 days post-ASCI administration or 
any SAE reported during the entire study will be assessed as:

Recovered/resolved.

Not recovered/not resolved.

Recovering/resolving.

Recovered with sequelae/resolved with sequelae.

Fatal (SAEs only).
9.4.
Reporting and follow-up of adverse events, serious adverse 
events and pregnancies
9.4.1.
Prompt reporting of serious adverse events and other events to 
GSK Biologicals
SAEs will be reported promptly to GSK as described in Table 14 once the investigator 
determines that the event meets the protocol definition of an SAE.
Pregnancies will be reported promptly to GSK as described in Table 14 once the 
investigator becomes aware of a pregnancy in the time period defined in Section 9.3. The 
patient will be followed to determine the outcome of the pregnancy. At the end of the 
pregnancy, whether that be full-term or premature, information on the status of the 
mother and child will be forwarded to GSK. Generally, follow-up should be no longer 
than 6 to 8 weeks following the estimated delivery date.
 
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Table 14
Time frames for submitting SAEs and other events reports to GSK 
Biologicals
Type of Event
Initial Reports
Follow-up Information
on a Previous Report
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours*
SAE screen
24 hours*
SAE screen
Severe toxicities 
24 hours*
eCRF
24 hours
eCRF
pIMDs 
24 hours
SAE screen
24 hours
SAE screen
Pregnancy
24 hours*
Pregnancy Report 
Form
24 hours*
Pregnancy Report Form
* Time frame allowed after receipt or awareness of the information.
In case the electronic reporting system is temporarily unavailable, a back-up system is in 
place. Please refer to Section 9.4.3 for a detailed description. Please see the Sponsor 
Information Sheet for contact details.
Back-up Study Contact for Reporting SAEs and severe toxicities
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: +
 or +
24/24 hour and 7/7 day availability
9.4.2.
Regulatory reporting requirements for serious adverse events
The investigator will promptly report all SAEs to GSK Biologicals in accordance with 
the procedures detailed in Section 9.4.1. GSK Biologicals has a legal responsibility to 
promptly notify, as appropriate, both the local regulatory authorities and other regulatory 
agencies about the safety of a product under clinical investigation. Prompt notification of 
SAEs by the investigator to the Study Contact for Reporting SAEs is essential so that 
legal obligations and ethical responsibilities towards the safety of other patients are met.
Investigator safety reports are prepared according to the current GSK Biologicals policy 
and are forwarded to investigators as necessary. An investigator safety report is prepared 
for a SAE(s) that is both attributable to the investigational product and unexpected. The 
purpose of the report is to fulfill specific regulatory and Good Clinical Practice (GCP) 
requirements, regarding the product under investigation.
9.4.3.
Completion and transmission of SAEs reports to GSK Biologicals
Once an investigator becomes aware that a SAE has occurred in a study patient, the 
investigator will complete and submit the information in the SAE screens in eCRF within
24 hours. The SAE screens in eCRF will always be completed as thoroughly as possible 
with all available details of the event and will be submitted by the investigator. If the 
investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying GSK Biologicals of the event and 
completing the SAE screens in eCRF. The SAE screens in eCRF should be updated 
when additional relevant information is received WITHIN 24 HOURS.
 
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The investigator will always provide an assessment of causality at the time of the initial 
report.
Upon notification, GSK Biologicals will in turn inform all investigators by fax or email 
(within 24 hours) about any SAE considered as related or possibly related to the ASCI 
administration.  The investigators will acknowledge receipt of this information.
Any severe toxicity event must be entered in the patient’s eCRF within 24 hours of the 
event becoming known to the investigator.
9.4.3.1.
Back-up system in case the electronic SAE reporting system does not 
work
If the SAE reporting system has been down for 24 hours, the investigator or his/her 
delegate should fax an SAE report form directly to the GSK Biologicals Central Safety 
department (please refer to Section 9.4.1) within 24 hours. The maximum timeline for 
reporting SAEs to central safety is therefore 48 hours.
NB. This back-up system should only be used if the electronic reporting system is not 
working and NOT if the system is slow.
As soon as the electronic reporting system is working again, the investigator or delegate 
must update the SAE screens in the eCRF within 24 hours.
The final valid information for regulatory reporting will be the information reported
through the electronic system.
When additional information is received on a SAE after freezing of the patient’s eCRF, 
new or updated information is to be recorded on the paper SAE Report Form, with all 
changes signed and dated by the investigator. The updated SAE Report Form should be 
resent to GSK Biologicals WITHIN 24 HOURS of receipt of the follow-up information.
9.4.3.2.
Back-up system in case the electronic system for reporting of severe 
toxicities does not work
If the electronic system for severe toxicity reporting has been down for 24 hours, the 
investigator or his/her delegate should fax a severe toxicity form directly to the GSK 
Biologicals Central Safety Department (please refer to Section 9.4.1) within 24 hours. 
The maximum timeline for reporting severe toxicities is therefore 48 hours.
As soon as the electronic reporting system is working again, the investigator or delegate
must update the severe toxicity screen in the eCRF within 24 hours.
The final valid information for regulatory reporting will be the information reported 
through the electronic system.
 
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9.4.4.
Completion and transmission of pregnancy reports to GSK 
Biologicals
Once the investigator becomes aware that a patient is pregnant, the investigator (or 
designate) must complete a Pregnancy Report Form and fax it to the Study Contact for 
Reporting SAEs (refer to the Sponsor Information Sheet) WITHIN 24 HOURS. 
The Pregnancy Report Form will always be completed as thoroughly as possible with all 
available details and then dated and signed by the investigator (or designate). Even if the 
investigator does not have all information regarding the pregnancy, the form should still 
be completed and forwarded to GSK within 24 hours. Once additional relevant 
information is received, the form will be updated and forwarded to GSK WITHIN 24 
HOURS. 
In absence/dysfunction of facsimile equipment, the Study Contact for Reporting SAEs 
should be notified by telephone within 24 hours. As soon as the facsimile equipment is 
working again, the investigator (or designate) must fax the Pregnancy Report Form to the 
Study Contact for Reporting SAEs (refer to the Sponsor Information Sheet) within 24 
hours. 
9.4.5.
Reporting of pIMDs to GSK Biologicals
Once onset of a new pIMD or exacerbation of a pre-existing pIMD is diagnosed (serious 
or non-serious) in a study patient, the investigator (or designate) must complete the 
information in the SAE screens of the eCRF WITHIN 24 HOURS after he/she becomes 
aware of the diagnosis. A field on the SAE screen allows to specify that the event is a 
pIMD and whether it is serious or non serious. The SAE screens will always be 
completed as thoroughly as possible with all available details of the event, in accordance 
with the pIMD standard questionnaire provided. Even if the investigator does not have all 
information regarding a pIMD, the SAE screens should still be completed within 24 
hours. Once additional relevant information is received, the SAE screens in the eCRF 
should be updated WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report.
Refer to Section 9.4.3.1 for back-up system and updating of SAE information after 
freezing of the patient’s eCRF.
 
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9.4.6.
Follow-up of adverse events and serious adverse events
After the initial AE/SAE report, the investigator is required to proactively follow each 
patient and provide further information to GSK Biologicals on the patient’s condition.
All SAEs documented at a previous visit/contact and designated as not recovered/not 
resolved or recovering/resolving will be reviewed at subsequent visits/contacts until the 
end of the study.
All AEs and pIMDs documented at a previous visit/contact and designated as not 
recovered/not resolved or recovering/resolving will be reviewed at subsequent 
visits/contacts until 30 days after the last ASCI administration.
All severe toxicities and pIMDs documented at a previous visit/contact and designated as 
not recovered/not resolved or recovering / resolving will be reviewed at subsequent 
visits/contacts until the end of the study.
Investigators will follow-up patients:

With SAEs or patients withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilized, disappeared, or until the event is otherwise 
explained, or the patient is lost to follow-up.

Or, in the case of other non-serious AEs and pIMDs until they complete the study or 
they are lost to follow-up.
Clinically significant laboratory abnormalities will be followed up until they have 
returned to normal, or a satisfactory explanation has been provided. Additional 
information (including but not limited to laboratory results) relative to the subsequent 
course of such abnormalities noted for any patient must be made available to the Site 
Monitor.
GSK Biologicals may request that the investigator perform or arrange for the conduct of 
additional clinical examinations/tests and/or evaluations to elucidate as fully as possible 
the nature and/or causality of the AE or SAE. The investigator is obliged to assist. If a 
patient dies during participation in the study or during a recognized follow-up period, 
GSK Biologicals will be provided with a copy of any available post-mortem findings, 
including histopathology.
9.5.
Treatment of adverse events
Treatment of any adverse event is at the sole discretion of the investigator and according 
to current good medical practice. Any medication administered for the treatment of an 
AE should be recorded in the patient’s eCRF. Refer to Section 9.4.
9.6.
Unblinding
Not applicable.
 
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9.7.
Emergency unblinding
Not applicable.
9.8.
Patient card
Study patients must be provided with the address and telephone number of the main
contact for information about the trial.
Investigator/delegate should therefore provide a “patient card” to each patient. The aim 
of this card is to inform any physician having to deal with a patient in an emergency 
situation that the patient is in a clinical trial and that he/she can contact the trial 
investigator for more relevant information.
Patients must be instructed to keep these cards in their possession at all times.
10.
PATIENT COMPLETION AND WITHDRAWAL
10.1.
Patient completion
10.1.1.
Patient completion of ASCI administration
A patient will be considered to have completed the study treatment when he/she has 
received injection number 24 with the ASCI.
Administration of the ASCI should continue until documented disease progression
(except for SPD (Section 6.6.6)), or withdrawal due to contraindications for subsequent 
ASCI administration (see Section 5.5.2).
Once the patient has been withdrawn from the ASCI, the reason must be documented in 
the patient’s medical records and eCRF.
10.1.2.
Patient completion of study
A patient will be considered to have completed the study when he/she has reached the 
end of all scheduled study visits. 
Once the patient has been withdrawn from the study, the reason must be documented in 
the patient’s medical records and eCRF. (Amended 03 September 2014).
 
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10.2.
Patient withdrawal
Patients who are withdrawn because of AEs must be clearly distinguished from patients 
who are withdrawn for other reasons. Investigators will follow patients who are 
withdrawn as result of a SAE/AE until resolution of the event (see Section 9.4).
Once the patient has been withdrawn, the reason must be documented in the patient’s 
medical records and eCRF. Withdrawals will not be replaced.
10.2.1.
Patient withdrawal from ASCI administration
A ‘withdrawal’ from the ASCI refers to any patient who does not receive the complete 
treatment, i.e. when no further planned dose is administered from the date of withdrawal. 
A patient withdrawn from the ASCI may not necessarily be withdrawn from the study as 
further study procedures or follow-up may be performed, if planned in the study protocol.
The investigator will document whether the decision to discontinue further ASCI
administration was made by the patient themselves, or by the investigator, as well as 
which of the following possible reasons was responsible for withdrawal:

(Serious) adverse event (including concurrent illness, unacceptable toxicity),

Disease progression/recurrence,

Consent withdrawal

Protocol violation,

Other (specify).
In this case, a concluding visit will be performed with procedures described in Section 
6.5.4. (Amended 03 September 2014).
If the patient refuses or cannot undergo these study procedures, he/she will be considered 
as withdrawn from study (Section 10.2.2). Patients who withdraw, or are withdrawn, 
from the study will not be replaced.
 
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10.2.2.
Patient withdrawal from the study
A patient will be considered as being withdrawn from the study when he/she does not 
undergo any further planned study visit after the date of withdrawal.
A patient may voluntarily discontinue participation in this study at any time. The 
investigator may also, at his/her discretion, discontinue the patient from participating in 
this study at any time. In addition, if the sponsor decides to discontinue the study, no 
further study procedures (including administration of the ASCI) will occur.
Information relative to the withdrawal will be documented in the eCRF. The investigator 
will document whether the decision to withdraw from the study was made by the patient 
or the investigator and which of the following reason applies:

Death (any cause).

(Serious) adverse event (including intercurrent illness, unacceptable toxicity).

Disease progression/recurrence.

Consent withdrawal, not due to an adverse event.

Lost to follow-up.

Protocol violation.

Moved from study area.

Other (specify).
All data collected until the date of withdrawal/last contact of the patient will be used for 
the analysis.
10.3.
Screen and baseline failures
A patient is considered to be a screen or baseline failure if he/she signs the ICF, but 
withdraws before receiving the first dose of ASCI treatment.
All patients having given consent to undergo NY-ESO-1 expression screening upon 
resection of their tumor will be referenced into a screening section of the eCRF.
In addition to NY-ESO-1 expression screening, translational research will be performed 
on the tumor tissue sample of patients having given their specific consent for this 
research. For details on the translational research, refer to Section 7.
 
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11.
DATA EVALUATION: CRITERIA FOR EVALUATION OF 
OBJECTIVES
This section describes the criteria for evaluation of objectives as initially planned. 
However, due to the Protocol Amendment 3, not all analyses described in this section 
will be performed. A detailed description of the analyses that will be done will be given 
in the Statistical Analysis Plan. The final analysis will occur when all patients have 
performed their Concluding Visit or have withdrawn from the study. (Amended 03 
September 2014)
11.1.
Co-primary endpoint
11.1.1.
Safety endpoint

Occurrence of severe toxicities during the study treatment phase and follow-up.
Defined according to CTCAE (Version 4.0) as follows:
1.
An ASCI-related or possibly ASCI-related Grade 3 or higher toxicity. Grade 3 
myalgia, arthralgia, headache, fever, rigors/chills and fatigue (including lethargy, 
malaise and asthenia) should persist for 48 hours despite therapy in order to be taken 
into account.
2.
An ASCI-related or possibly ASCI-related Grade 2 or higher allergic reaction 
occurring within 24 hours following the ASCI administration.
Note: Any severe toxicity event must be entered in the patient’s eCRF within 24 
hours of the event becoming known to the investigator.
11.1.2.
Clinical activity endpoint

The induction of objective clinical response (CR or PR) in the overall population.
Defined in Section 6.6.
11.2.
Secondary endpoints
11.2.1.
Clinical activity endpoints
The secondary clinical activity endpoints will include:
1. Occurrence of objective clinical response (CR or PR) in the population of patients 
who present the predictive MAGE-A3 gene signature.
2. In the overall population and in the population of patients presenting the predictive 
MAGE-A3 gene signature:

Occurrence of stable disease (SD).
 
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
Occurrence of mixed response (MR).

Time to Treatment Failure (TTF).
TTF is defined as the time from first treatment until the date of the last treatment 
administration, irrespective of the reason for study treatment discontinuation.

Progression-free survival (PFS).
PFS is defined as the time from first treatment to either the date of first disease 
progression (PD or SPD) or the date of death (for whatever reason), whichever comes 
first. Patients alive and without disease progression are censored at the date of the last 
visit/contact. (Amended 03 September 2014)

Overall survival (OS).
OS is defined as the time from first treatment until death. Patients alive at the time of 
analysis are censored at the time of the last visit/contact.

The duration of response for patients with CR, PR or SD status.
The duration of the response is defined as time from first objective response or SD
evaluation to first PD assessment or death. (Amended 03 September 2014).
11.2.2.
Safety endpoints
The secondary safety endpoints will include:

Occurrence of AEs and SAEs during the study treatment period and ending 30 days 
after the last study treatment administration.
Note: The occurrence of SAEs (possibly) related to the recNY-ESO-1 + AS15 ASCI will 
be captured during the entire study duration, as described in Table 13.
11.2.3.
Immunogenicity endpoints

Immunogenicity of the NY-ESO-1 ASCI treatment will be evaluated at different 
timepoints.
This is explained in Section 6 and is on the basis of:
1. The anti-NY-ESO-1 humoral antibody concentration and response. (Amended 03 
September 2014)
2. The anti-NY-ESO-1 specific cellular (T-cell) response. (Amended 03 September 
2014)
 
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11.3.
Estimated sample size
The study will require a planned sample size of 34 patients having received at least one 
ASCI injection.

Alpha: 0.10

Beta: 0.10

Levels: P0 = 0.05, P1 = 0.20, 1 – T0 = 0.75, 1 – T1 = 0.95
11.3.1.
Definitions

P0 is the unacceptable response probability which, if true, implies that the 
therapeutic activity does not warrant further investigation of the regimen. In the 
present trial, P0 has been taken as 5%.

P1 is the lowest acceptable response probability which, if true, implies that the 
therapeutic activity does warrant further investigation of the regimen, provided that 
the incidence of severe toxicity is acceptable. In the present trial, P1 has been taken 
as 20%.

(1 – T0) is the unacceptable non-severe toxicity probability which, if true, implies 
that the regimen does not warrant further investigation. In the present trial, (1 – T0) 
has been taken as 75%.

(1 – T1) is the acceptable non-severe toxicity probability which, if true, implies that 
the regimen does warrant further investigation, provided that the response rate is 
acceptable. In the present trial, (1 – T1) has been taken as 95%.
11.3.2.
Statistical errors will be

Beta is the probability of rejecting from further trials a regimen with a true response 
rate at least equal to P1 and a true non-severe toxicity rate equal to or higher than (1 -
T1). In the present trial, beta has been taken as 0.10.

Alpha is the accepted probability of recommending for further investigation a 
regimen with a true response rate lower than P0. It is also the accepted probability of 
recommending for further trials a regimen with a true non-severe toxicity rate lower 
than (1 – T0). In the present trial, the two alphas have been taken as 0.10.

A total of 34 patients will be enrolled and assessed for overall response and severe 
toxicity.
 
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11.3.3.
Study success criteria

If 4 (4/34 = 11.8%) objective clinical responses are observed, then the treatment 
regimen will be considered as active.

If 4 (4/34 = 11.8%) severe toxicities (see Section 11.1.1) are observed, then the 
treatment regimen will be considered as feasible from a safety point of view.
If these two conditions are met, the conclusion will be that the given regimen is active 
and feasible, and should be investigated further in this patient population.
If 1 (1/34 = 3%) clinical responses are observed or if 5 patients (5/34 = 14.7%) have 
severe toxicity, the conclusion will be that the recNY-ESO-1 + AS15 ASCI is not active 
enough or is too toxic and that it should not be investigated further in this patient 
population.
If 2 or 3 clinical responses are observed and 4 patients have severe toxicity, the study 
will be unconclusive (neither success nor failure).
Simulations (5000 repetitions, binomial distribution for the risk that one patient does 
develop a severe toxicity and for the objective clinical response) have been used to 
determine the percentage of trials that satisfy the criteria for further development, fail or 
be unconclusive, considering the different criteria defined above, and assuming different 
values for the severe toxicity and the clinical response probabilities on a patient level 
(Table 15).
For example, if the true clinical response rate is 20% and the true toxicity rate 2.5%, we 
have 93% probability to conclude on a success, 0.5% probability to conclude on a failure 
and 6.4% probability where more investigation will be needed before final conclusion; if 
the true clinical response rate is 5% and the true toxicity rate 20%, we have 1.5%, 91% 
and 7.3% probabilities, respectively.
Table 15
Outcome of simulations with both safety and clinical response
True
Toxicity
rate
True Clinical response rate 1
5%
10%
15%
20%
F
U
S
F
U
S
F
U
S
F
U
S
2.5%
49%
42%
9.0%
13%
42%
45%
3.1%
20%
77%
0.5%
6.4%
93%
5.0%
50%
41%
9.0%
15%
41%
44%
5.3%
19%
75%
3.0%
6.4%
91%
10.0%
61%
32%
6.5%
35%
32%
33%
27%
15%
58%
25%
5.0%
70%
20.0%
91%
7.3%
1.5%
86%
6.6%
7.7%
84%
3.3%
12%
84%
1.1%
15%
1.
F = % failure, U = % inconclusive, S = % success
 
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11.4.
Study cohorts to be evaluated
11.4.1.
Total treated cohort
The total treated cohort will include all the enrolled patients who have received at least 
one dose of the ASCI.
11.4.2.
According-to-protocol (ATP) cohort for analysis of 
immunogenicity
The ATP cohort for analysis of immunogenicity will include all evaluable patients (i.e., 
those meeting all eligibility criteria, who did not report major protocol deviation, who 
have complied with all the procedures defined in the protocol, who have received at 
least the first four study treatment administrations and have provided a result for 
immunogenicity evaluation within the 4 weeks following dose no. 4 and completed Visit 
5). For each non-compliant patient, all data collected after protocol violation (i.e. 
treatment administered or blood sample collected too early or too late, concomitant 
medication, medical condition,…) will be eliminated from the ATP immunogenicity 
analyses. (Amended 03 September 2014)
11.5.
Derived and transformed data
11.5.1.
Humoral immunogenicity
1. The cut-off value of the Enzyme-Linked Immunosorbent Assay (ELISA) assay will 
be defined by the laboratory before the analysis.
2. A seropositive patient is a patient whose anti-NY-ESO-1 antibody titer is higher than 
or equal to the cut-off value. (Amended 03 September 2014)
3. Seroconversion in a patient is defined by the increase in antibodies (anti-NY-ESO-1) 
from a titer below the cut-off level before the treatment to a titer above the cut-off 
level following treatment. (Amended 03 September 2014)
4. An ASCI humoral response is defined as:

For an initially seronegative patient: an increase in the anti-NY-ESO-1 antibody 
titer to above the cut-off level (i.e seroconversion).

For an initially seropositive patient: an increase in anti-NY-ESO-1 antibody titer 
to a level at least two times higher than the pre-treatment titer.
5. The geometric mean titer (GMT) is calculated by taking the anti-logarithm of the 
mean of the log 10 transformations. Antibody titers below the cut-off of the assay 
will be given an arbitrary value of half of the cut-off for the purpose of the 
calculation.
6. For a given patient and given immunogenicity measurement, results of missing or 
non-evaluable measurements will not be replaced. Therefore, an analysis will 
exclude patients with missing or non-evaluable measurements.
 
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11.5.2.
Cellular Immunogenicity
A patient will be considered as a cellular-mediated immune responder if there is an 
increased amount of NY-ESO-1-specific T-cells after immunization as compared to the 
patient’s baseline value
The cut-off above which a patient will be considered to present NY-ESO-1 cellular 
immunogenicity will be determined and specified in the Statistical Analysis plan.
(Amended 03 September 2014)
11.5.3.
Safety
For analysis of serious adverse events or adverse events by primary MedDRA term, all 
patients treated will be considered. Patients who did not report an event will be 
considered as patients without the event.
11.6.
Conduct of analyses
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the statistical analysis plan and/or final study report.
(Amended 03 September 2014)
11.6.1.
Sequence of analyses
Safety data will be reviewed according to the safety rules (Section 6.3.3) and the DSMC 
charter, by the DSMC and GSK Biologicals.
The final analysis will be performed when all patients have done their concluding visit 
or have withdrawn from the study. Due to Protocol Amendment 3, not all analyses 
described in this section will be performed. A detailed description of the analyses that 
will be done will be given in the statistical analysis plan.. A full clinical study report 
will be written including individual data listings.
(Amended 03 September 2014)
11.6.2.
Statistical considerations for interim analyses
Not applicable.
11.7.
Statistical methods
All statistical analyses will be performed using SAS software and/or StatXact.
Due to Protocol Amendment 3, not all analyses described in this section will be 
performed. A detailed description of the analyses that will be done will be given in the 
statistical analysis plan. (Amended 03 September 2014)
 
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11.7.1.
Analysis of demographics/baseline characteristics
Demographic characteristics (age, gender, race, etc.) and baseline tumor characteristics 
such as stage or gene expression will be tabulated and analyzed by appropriate 
descriptive statistics:

Frequency tables will be generated for categorical variable such as gender.

Mean, median, standard error will be provided for continuous data such as age.

The total number of ASCI doses administered to each patient and the length of 
follow-up will be summarized.
These descriptive analyses will be performed on the total treated cohort.
11.7.2.
Analysis of clinical activity

Disease progression, including death, during the study will be described in detail by 
patient narratives.

Estimates of the rates of best clinical response and their 95% confidence interval (CI)
will be reported.

Kaplan-Meier curves will be estimated for TTF, PFS and OS. If study treatment 
failure does not occur before the patient's last study visit, then the time to study 
treatment failure will be censored at the date of the last visit. If progression does not 
occur before the patient's last study visit, then the time to progression will be 
censored at the date of the last visit. If the patient is withdrawn from the study 
treatment for other reasons than progression, then the time to study treatment failure 
or progression will be censored at the date of the last assessment of the patient. For 
OS, patients who are still alive at the time of the analysis will be censored at the 
date last known to be alive(Amended 03 September 2014)

In addition, other exploratory analyses may be performed if necessary.
The analysis of clinical activity will be performed on the total treated cohort.
 
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11.7.3.
Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for immunogenicity. Humoral and 
cellular responses will also be analyzed for the total treated cohort if more than 3 patients 
are excluded from the ATP cohort for immunogenicity.
For each cohort, at each blood sampling time point for which results are available:

Anti-NY-ESO-1 antibody seropositivity rate, humoral response rate and antibody 
geometric mean titers (GMTs) with 95% CIs will be measured or calculated;

Percentages of patients presenting NY-ESO-1 immunogenicity scores above cut-off
and cellular T-cell responses to NY-ESO-1 with exact 95% CIs will be given.
Estimations of the cellular T cell precursor frequencies will be given if available.

In addition, individual data over time will be displayed graphically
(Amended 03 September 2014).
11.7.4.
Analysis of safety
The verbatim reports of AEs will be reviewed by a physician and coded according to the 
MedDRA Dictionary for Adverse Reaction Terminology.
All patients who received at least one ASCI injection will be included in overall toxicity 
analyses (total treated cohort). Patients who have discontinued treatment because of 
toxicity will always be included in the toxicity analyses. Toxicity and AEs occurring in 
ineligible patients will be reported separately.
A summary of AEs by maximum grade and cohort will be displayed. The same 
tabulation will be presented for events with a suspected relationship to the study 
treatment.  A summary of AEs by maximum grade and cohort will also be provided 
separately for the four treatment cycles.
SAEs will be described in detail by patient narratives.
Non-hematological, acute side effects will be assessed and reported separately for each 
ASCI administration, and graded according to the CTCAE version 4.0 criteria.
 
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12.
ADMINISTRATIVE MATTERS
To comply with ICH GCP administrative obligations relating to data collection, 
monitoring, archiving data, audits, confidentiality and publications must be fulfilled.
12.1.
Remote data entry instructions
Prior to screening and/or enrolling the first potential participant, the investigator will 
provide the Site Monitor with a list (Site Staff Signature Sheet (SSSS)) showing the name 
and title, signature and initials of all site staff who have a role in the study and to whom 
the investigator has delegated significant study related duties such as entering data in the 
eCRF or changing entries in the eCRFs. If the authorized individuals change during the 
study, the investigator is to inform GSK Biologicals’ representative of the specific 
change(s). The SSSS needs to be updated accordingly in order to reflect the current 
situation at all times.
Remote Data Entry (RDE), a validated computer application, will be used as the method 
for data collection.
In all cases, patient initials will not be collected nor transmitted to GSK. Patient data 
necessary for analysis and reporting will be entered/transmitted into a validated database 
or data system. Clinical data management will be performed in accordance with 
applicable GSK standards and data cleaning procedures.
The patient information will be entered into a computer at the investigational site 
preferably within 5 working days of becoming available. The site will be able to modify 
the data to assure accuracy with source documentation. All new/updated information will 
be reviewed and verified by a GSK Biologicals' Site Monitor. This information will 
finally be stored in a central database maintained by GSK Biologicals. At the conclusion 
of the study, GSK Biologicals will archive the study data in accordance with internal 
procedures.
While completed eCRFs are reviewed by a GSK Biologicals’ Site Monitor at the study 
site, omissions or inconsistencies detected by subsequent eCRF review may necessitate 
clarification or correction of omissions or inconsistencies with documentation and 
approval by the investigator or appropriately qualified designee. In all cases, the 
investigator remains accountable for the study data.
The investigator will be provided with a CD-ROM of the final version of the data 
generated at the investigational site once the database is archived and the clinical study 
report is complete and approved by all parties.
 
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12.2.
Regulatory and ethical considerations, including the 
informed consent process
GSK will obtain favorable opinion/approval to conduct the study from the appropriate 
regulatory agency, in accordance with applicable country-specific regulatory 
requirements, prior to a site initiating the study in that country.
The study will be conducted in accordance with all applicable regulatory requirements, 
including a United States Investigational New Drug Application (US IND).
The study will be conducted in accordance with the ICH Guideline for Good Clinical 
Practice (GCP), all applicable patient privacy requirements and the guiding principles of 
the Declaration of Helsinki.
Conduct of the study includes, but is not limited to, the following:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favorable opinion/approval of study protocol and any subsequent amendments.

Patient informed consent.

Investigator reporting requirements as stated in the protocol.
GSK will provide full details of the above procedures to the investigator, either verbally, 
in writing, or both.
Freely given and written informed consent must be obtained from each patient prior to 
participation in the study.
GSK Biologicals will prepare a model Informed Consent Form (ICF) which will embody 
the ICH GCP and GSK Biologicals required elements. While it is strongly recommended 
that this model ICF is to be followed as closely as possible, the informed consent 
requirements given in this document are not intended to pre-empt any local regulations 
which require additional information to be disclosed for informed consent to be legally 
effective. Those sections marked as mandatory must not be modified. Clinical judgment, 
local regulations and requirements should guide the final structure and content of the 
local version of the ICF.
The investigator has the final responsibility for the final presentation of the ICF, 
respecting the mandatory requirements of local regulations. The ICF generated by the 
investigator with the assistance of the sponsor’s representative must be acceptable to 
GSK Biologicals and be approved (along with the protocol, and any other necessary 
documentation) by the IRB/IEC.
 
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12.3.
Data Safety Monitoring Committee
A Data and Safety Monitoring Committee (DSMC) composed of an independent group of 
experts to advise GSK Biologicals and the study investigators will be established by GSK 
Biologicals, and the DSMC will supervise this Phase I study in metastatic melanoma.
The Committee will review the clinical relevance of each severe toxicity event and its 
relationship to the ASCI administration.  The DSMC should provide immediate feedback 
within 3 working days. For each severe toxicity event, GSK will not wait for the 
feedback of the DSMC to continue the dosing of the other patients.
In addition, the DSMC will receive a safety report from GSK Biologicals every 6 months 
(or more frequently, if necessary) for review and will review progress and safety results, 
and will also make recommendations to GSK Biologicals as detailed below. Ad hoc
meetings can be convened on the basis of requests from GSK Biologicals or from any 
member of the DSMC. No member of the Committee may be an investigator in the study 
or an employee of GSK Biologicals. The operating rules of the Committee will be 
established jointly by the Committee and GSK Biologicals within the framework set out 
in the protocol. A detailed statement of the tasks of the DSMC will be given in a separate 
document to be prepared by GSK Biologicals in consultation with the Committee's 
members.
The primary responsibilities of the DSMC will be as follows:

The DSMC will review the study progress reports provided by GSK Biologicals on a 
regular basis, with a view to identifying any findings that could have an effect on the 
conduct or validity of the present study or on the safety of the patients. If safety 
concerns are identified, then GSK Biologicals, the Principal Investigator(s), the 
DSMC and/or the applicable regulatory agencies may recommend that the study be 
suspended, amended, or terminated.

The DSMC will assess the clinical relevance of each severe toxicity event and must 
provide feedback within 3 working days.

On the basis of safety information, the Committee will make recommendations to the 
sponsor concerning the continuation, modification or termination of the trial. As 
soon as one of the criteria for stopping or suspending the entire study (see Section 
6.3.3) is met, the DSMC will be contacted for advice as to whether to continue the 
study or not.
Although the DSMC will advise GSK Biologicals, the authority to suspend, amend or 
terminate the study remains with GSK Biologicals.
Members will be available for expert consultation on any other medical, scientific or 
safety issues that may arise during the trial.
 
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12.4.
GSK Biologicals’ Safety Review Team
The GSK Biologicals’ Safety Review Team (core members include Clinical 
Development Manager, Safety Product Specialist and Biostatistician) will on a regular 
basis review all available safety data related to the investigational product to identify any 
potential safety issues or signals to evaluate and to agree on action plans, if necessary.
12.5.
Monitoring by or on behalf of GSK Biologicals
Monitoring visits by a formal representative of the Sponsor or a GSK Site Monitor are for 
the purpose of confirming that GSK Biologicals’ sponsored studies are being conducted 
in accordance with the ethical principles that have their origins in the Declaration of 
Helsinki and that are consistent with Good Clinical Practice (GCP) and the applicable 
regulatory requirement(s) (verifying continuing compliance with the protocol, 
amendment(s), reviewing the investigational product accountability records, verifying 
that the site staff and facilities continue to be adequate to conduct the study). 
The investigator must ensure provision of reasonable time, space and qualified personnel 
for monitoring visits.
Direct access to all study-site related and source data is mandatory for the purpose of 
monitoring review. The monitor will perform a RDE review and a Source Document 
Verification (SDV). By SDV we understand verifying RDE entries by comparing them 
with the source data that will be made available by the investigator for this purpose.
The Source Documentation Agreement Form describes the source data for the different 
data in the RDE. This document should be completed and signed by the site monitor and 
investigator and should be filed in the monitor’s and investigator’s study file. Any data 
item for which the RDE will serve as the source must be identified, agreed and 
documented in the source documentation agreement form.
For RDE, the monitor will mark completed and approved screens at each visit.
In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors 
will contact the site prior to the start of the study to review with the site staff the protocol, 
study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements. When reviewing data collection procedures, the discussion will also 
include identification, agreement and documentation of data items for which the eCRF 
entries will serve as the source document.
GSK will monitor the study to verify that, amongst others, the: 

Data are authentic, accurate, and complete.

Safety and rights of patients are being protected.

Study is conducted in accordance with the currently approved protocol and any 
amendments, any other study agreements, GCP and all applicable regulatory 
requirements.
 
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The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
Upon completion or premature discontinuation of the study, the monitor will conduct site 
closure activities with the investigator or site staff, as appropriate, in accordance with 
applicable regulations, GCP, and GSK procedures.
12.6.
Archiving of data at study sites
Following closure of the study, the investigator must maintain all site study records in a 
safe and secure location. The records must be maintained to allow easy and timely 
retrieval, when needed (e.g. audit or inspection), and, whenever feasible, to allow any 
subsequent review of data in conjunction with assessment of the facility, supporting 
systems, and staff. Where permitted by applicable laws/regulations or institutional 
policy, some or all of these records can be maintained in a validated format other than 
hard copy (e.g. electronic for studies with an eCRF); however, caution needs to be 
exercised before such action is taken. The investigator must assure that all reproductions 
are legible and are a true and accurate copy of the original and meet accessibility and 
retrieval standards, including re-generating a hard copy, if required. Furthermore, the 
investigator must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.
GSK will inform the investigator/institution of the time period for retaining these records 
to comply with all applicable regulatory requirements. However, the 
investigator/institution should seek the written approval of the sponsor before proceeding 
with the disposal of these records. The minimum retention time will meet the strictest 
standard applicable to that site for the study, as dictated by ICH GCP, any institutional 
requirements or applicable laws or regulations, or GSK standards/procedures; otherwise, 
the minimum retention period will default to 15 years.
The investigator/institution must notify GSK of any changes in the archival 
arrangements, including, but not limited to, the following: archival at an off-site facility, 
transfer of ownership of the records in the event the investigator leaves the site.
12.7.
Audits
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after 
completion of the study. If an audit or inspection occurs, the investigator and institution 
agree to allow the auditor/inspector direct access to all relevant documents and to allocate 
his/her time and the time of his/her staff to the auditor/inspector to discuss findings and 
any relevant issues.
 
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12.8.
Ownership, confidentiality and publication
12.8.1.
Ownership
All information provided by GSK and all data and information generated by the site as 
part of the study (other than a patient’s medical records) are the sole property of GSK.
All rights, title, and interests in any inventions, know-how or other intellectual or 
industrial property rights which are conceived or reduced to practice by site staff during 
the course of or as a result of the study are the sole property of GSK, and are hereby 
assigned to GSK.
If a written contract for the conduct of the study which includes ownership provisions 
inconsistent with this statement is executed between GSK and the study site, that 
contract’s ownership provisions shall apply rather than this statement.
12.8.2.
Confidentiality
Documented evidence that a potential investigator is aware and agrees to the confidential 
nature of the information related to the study must be obtained by means of a 
confidentiality agreement.
All information provided by GSK and all data and information generated by the site as 
part of the study (other than a patient’s medical records) will be kept confidential by the 
investigator and other site staff. This information and data will not be used by the 
investigator or other site personnel for any purpose other than conducting the study. 
These restrictions do not apply to: (i) information which becomes publicly available 
through no fault of the investigator or site staff; (ii) information which it is necessary to 
disclose in confidence to an IEC or IRB solely for the evaluation of the study; (iii) 
information which it is necessary to disclose in order to provide appropriate medical care 
to a study patient; or (iv) study results which may be published as described in the next 
paragraph. If a written contract for the conduct of the study which includes 
confidentiality provisions inconsistent with this statement is executed, that contract’s 
confidentiality provisions shall apply rather than this statement.
12.8.3.
Publication
For multicenter studies, the first publication or disclosure of study results shall be a 
complete, joint multicenter publication or disclosure coordinated by GSK. Thereafter, 
any secondary publications will reference the original publication(s).
Prior to submitting for publication, presentation, use for instructional purposes, or 
otherwise disclosing the study results generated by the site (collectively, a ‘Publication’), 
the investigator shall provide GSK with a copy of the proposed Publication and allow 
GSK a period to review the proposed Publication (at least twenty-one working days, or at 
least fifteen working days for abstracts/posters/presentations). Proposed Publications 
shall not include either GSK confidential information other than the study results or 
personal data on any patient, such as name or initials.
 
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At GSK’s request, the submission or other disclosure of a proposed Publication will be 
delayed a sufficient time to allow GSK to seek patent or similar protection of any 
inventions, know-how or other intellectual or industrial property rights disclosed in the 
proposed Publication.
If a written contract for the conduct of the study, which includes publication provisions 
inconsistent with this statement is executed, that contract’s publication provisions shall 
apply rather than this statement.
13.
COUNTRY SPECIFIC REQUIREMENTS
13.1.
French administrative considerations
This Section includes all the requirements of the French law (n2004-806 of 
09 August 2004), and identifies, item by item, the mandatory modifications or additional 
information to the study protocol.

Concerning the “Study Population”
In line with the local regulatory requirements, the following text in section “OTHER 
STUDY ELIGIBILITY CRITERIA CONSIDERATIONS” is added:
A patient will be eligible for inclusion in this study if he /she is either affiliated to or 
beneficiary of a social security category.
It is the investigator’s responsibility to ensure and to document (in source document -
patient notes) that the patient is either affiliated to or beneficiary of a social security 
category.

Concerning the “Data Evaluation: Criteria for Evaluation of Objectives”
Section on the “ESTIMATED SAMPLE SIZE”
The following text concerning the “sample size assumption” is added:
The expected number of patients to be recruited in France is declared to the French 
Regulatory Authority.

Concerning the “Conduct of the Study”
Section “REGULATORY AND ETHICAL CONSIDERATIONS, INCLUDING 
THE INFORMED CONSENT PROCESS”
The following text concerning “the process for informing the patient or his/her 
legally authorized representative” is added:
French Patient ICF is a document in triplicate which summarizes the main features of 
the study and allows collection of the patient's written consent. It also contains a 
reference to the authorization of ANSM and the approval from the French Ethics 
Committee and the maintenance of confidentiality of the returned consent form by 
GSK France.
 
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In addition, the following text concerning “the process for obtaining the patient's 
informed consent” is added:

When biomedical research is carried out on a minor / on an adult in the care of a 
“tutelle” guardian, consent is given by their legal representative and, if the 
committee mentioned in article L. 1123-1 considers that the research in 
question, because of the gravity of the restraints or the specificity of the medical 
acts involved, entails a serious risk of affecting their private life or the integrity 
of their body, by the family council if it has been instated, or by the judge of 
“tutelle” guardians.

When biomedical research is carried out on an adult in the care of a “curatelle” 
guardian, consent is given by the patient assisted by his guardian. However, if 
the adult in the care of a “curatelle” guardian is invited to participate in research 
which the committee mentioned in article L. 1123-1 considers, because of the 
gravity of the restraints or the specificity of the medical acts involved, to entail a 
serious risk of affecting their private life or the integrity of their body, the matter 
is submitted to the judge of guardians who decides whether the adult is capable 
of giving his consent. In the case of incapacity, the judge will decide whether or 
not to authorize the biomedical research.

When biomedical research, which complies with the conditions laid down in 
article L. 1121-8, is considered for an adult incapable of expressing his consent 
and not under a legal protection order, consent is given by a person of 
confidence as defined in article L. 1111-6 and, failing this, by a person who 
maintains close and stable links with the patient. However, if the committee 
mentioned in article L. 1123-1 considers that the research in question, because 
of the gravity of the restraints or the specificity of the medical acts involved, 
entails a serious risk of affecting their private life or the integrity of their body, 
consent is given by the judge of guardians.

Finally, concerning “the management of the Patient ICFs” the following text is 
added:
The first copy of the Patient ICF is kept by the investigator. The second copy is kept 
by the Director of the Medical Department of GlaxoSmithKline France and the last 
copy is given to the patient or his/her legally authorized representative.
The second copy of all the consent forms will be collected by the investigator at the 
end of the trial under the Clinical Research Assistant’s (CRA's) control, and placed 
in a sealed envelope bearing only:

The study number,

The identification of the Centre: name of the principal investigator and number 
of centre),

The number of informed consents,

The date and,

The principal investigator’s signature.
 
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Then, the CRA hands the sealed envelope over to the Director of the Medical 
Department, for confidential recording, under his responsibility.

In section concerning the “ DEMOGRAPHIC DATA ” the following text is added:
In accordance with the data-processing and freedom French law dated on 6th of 
January 1978 modified on the 6th of August 2004 - article 8, the ethnic origin can 
only be collected if the collection of this data is justified within the framework of this 
study.

In section concerning the “ TESTING OF BIOLOGICAL SAMPLES ” the following 
text is added:
In accordance with Article L1211-2 of the French Public Health Code, a biological 
sample without identified purpose at the time of the sample and patient’s preliminary 
information is not authorized.

Concerning “Administrative matters”
The following text concerning “notification to the hospital director” is added (if 
applicable):
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 
financial disposition, the name of the investigator(s), the number of sites involved in 
his establishment and the estimated time schedule of the trial (R.1123-63).
The following text concerning “information to the hospital pharmacist” is added (if 
applicable):
In accordance with Article R.1123-64 of the Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him to dispense the 
drug(s) of the trial according to the trial methodology), all information concerning 
the product(s) of the trial (e.g. included in the Clinical Investigator's Brochure), the 
name of the investigator(s), the number of sites involved in his establishment and the 
estimated time schedule of the trial.
Finally, the following text concerning “data management” is added:
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, involved in 
this clinical trial, and data regarding the patients recruited in this clinical trial (patient 
number, treatment number, patient status with respect to the clinical trial, dates of 
visit, medical data) will be collected and computerized in GSK Biologicals data 
bases by Laboratoire GlaxoSmithKline or on its behalf, for reasons of follow up, 
clinical trial management and using the results of said clinical trial. According to the 
Act no. 78-17 of 6th January 1978 further modified, each of these people aforesaid 
 
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has a right of access, correction and opposition on their own data through 
Laboratoire GlaxoSmithKline (Clinical Operations Department). 
13.2.
Germany specific requirements
Concerning the HIV test
Upon request from Paul-Ehrlich-Institut (Germany), HIV test is mandatory to assess the 
HIV status (positive - negative) of patients in Germany only. Testing will be performed 
during the screening phase of the study and according to local standard practice. Patients 
with known HIV-positive status or positive for HIV as per testing will not be eligible for 
entry in the study. Patients for which the test is positive will be managed according to 
standard local clinical practice. Patients with known HIV-positive status do not need to 
be retested. Patients tested for HIV prior to signature of the ICF for study participation do 
not need to repeat the test, given that it was performed within three weeks of enrolment.
Patients tested for HIV prior to signature of the ICF for study participation do not need to 
repeat the test, given that it was performed within three weeks of enrolment.
Table 6 “List of study procedures for Cycle 1 (including screening)” has been adapted to 
include this HIV test.
 
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14.
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Appendix A
TNM classification for melanoma
The TNM staging system characterizes melanoma with respect to several factors 
including tumor size, thickness and ulceration, extent of lymphatic invasion, and the 
presence of distant metastasis.
The current version of the staging system used has been published in the Sixth Edition of 
the AJCC Cancer Staging Manual [American Joint Committee on Cancer, 2002].
The definition of TNM is the following [American Joint Committee on Cancer, 2002]:
T – Primary tumor
TX –
Primary tumor cannot be assessed (e.g., shave biopsy or regressed melanoma).
T0 –
No evidence of primary tumor
Tis –
Melanoma in situ
T1 –
Melanoma of 1.0 mm in thickness with or without ulceration
T1a – Melanoma of 1.0 mm in thickness and level II or III, no ulceration
T1b – Melanoma of 1.0 mm in thickness and level IV or V or with ulceration
T2 –
Melanoma 1.01-2.0 mm in thickness with or without ulceration
T2a – Melanoma 1.01-2.0 mm in thickness, no ulceration
T2b – Melanoma 1.01-2.0 mm in thickness, with ulceration
T3 –
Melanoma 2.01-4.0 mm in thickness with or without ulceration
T3a – Melanoma 2.01-4.0 mm in thickness, no ulceration
T3b – Melanoma 2.01-4.0 mm in thickness, with ulceration
T4 –
Melanoma greater than 4.0 mm in thickness with or without ulceration
T4a – Melanoma > 4.0 mm in thickness, no ulceration
T3b – Melanoma > 4.0 mm in thickness, with ulceration
 
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N – Regional lymph nodes
NX –
Regional lymph nodes cannot be assessed
N0 –
No regional lymph node metastasis
N1 –
Metastasis in one lymph node
N1a – Clinically occult (microscopic) metastasis
N1b – Clinically apparent (macroscopic) metastasis
N2 –
Metastasis in two to three regional nodes or intra-lymphatic regional metastasis
without nodal metastases
N2a – Clinically occult (microscopic) metastasis
N2b – Clinically apparent (macroscopic) metastasis
N2c – Satellite or in-transit metastasis without nodal metastasis
N3 –
Metastasis in four or more regional lymph nodes, or mated metastatic nodes, or
in-transit metastasis or satellite(s) with metastasis in regional node(s)
M – Distant metastasis
MX – Distant metastasis cannot be assessed
M0 –
No distant metastasis
M1 –
Distant metastasis
M1a – Metastasis to skin, subcutaneous tissue or distant lymph node
M1b – Metastasis to lung
M1c – Metastasis to all other visceral sites or distant metastasis at any site associated 
with an elevated serum lactate dehydrogenase (LDH)
 
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AJCC pathological stage groupings
Stage 0
Tis, N0, M0
Stage IA
T1a, N0, M0
Stage IB
T1b, N0, M0
T2a, N0, M0
Stage IIA
T2b, N0, M0
T3a, N0, M0
Stage IIB
T3b, N0, M0
T4a, N0, M0
Stage IIC
T4b, N0, M0
Stage IIIA
T1-4a, N1a, M0
T1-4a, N2a, M0
Stage IIIB
T1-4b, N1a, M0
T1-4b, N2a, M0
T1-4a, N1b, M0
T1-4a, N2b, M0
T1-4a/b, N2c, M0
Stage IIIC
T1-4b, N1b, M0
T1-4b, N2b, M0
Any T, N3, M0
Stage IV
Any T, Any N, M1
 
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Appendix B
Common Terminology Criteria for Adverse Events, Version 4.0
The severity of adverse events will be assessed by reference to the Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0 of May 28, 2009. A copy can be 
downloaded from the internet website:
http://evs.nci.nih.gov/ftp1/CTCAE
 
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Appendix C
Eastern Cooperative Oncology Group (ECOG) performance status
0
Fully active, able to carry on all pre-disease performance without 
restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work.
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any selfcare.  Totally confined to 
bed or chair.
5
Dead.
 
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Appendix D
Amendments and administrative changes to the protocol
GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 1
eTrack study number and 
abbreviated title
112406 (NYESO1-AS15-MEL-001 (MET))
EudraCT number
2010-020663-20
Title
Study of GSK2241658A Antigen-Specific Cancer 
Immunotherapeutic in patients with unresectable and 
progressive metastatic cutaneous melanoma
Detailed title:
An open Phase I Study of immunization with the 
recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic in patients with NY-ESO-1-
positive unresectable and progressive metastatic 
cutaneous melanoma
Amendment number:
Amendment 1
Amendment date:
18 April 2011
Co-ordinating author:
 (Scientific writer)
The background and rationale for the changes made to the protocol as a consequence of 
Amendment 1 are described below:

Reduce the interval between Cycle 1 and Cycle 2 by one week with consequent 
changes of dates of ASCI administrations to align with other ASCI studies with the 
same treatment schedule (Synopsis, Sections 3.3 and 6.4)

Ensure that tumor biopsies and imaging done as local standard practice or for 
another research study are not to be repeated if timelines are respected (Sections 
4.2, 6.4, 6.5.2.1, 6.5.2.6)

Specify quantitative limits for hematological variables (Section 4.2)

Allow higher bilirubin values for patients with Gilbert’s syndrome (Section 4.2)

Update section on study product storage according to new protocol exemption 
form (Section 5.2)

Recording of second-line treatment after disease progression and assessment of 
tumor response to this (Sections 5.5.2, 6.6.5)

Specifying that tumor tissue samples from biopsies or resection of additional 
lesions during the ASCI administration period may be used to perform tests of 
NY-ESO-1 antigen expression and gene profile plus for optional translational 
research for patients having given specific informed consent to this (Sections 5.6.1 
and 6.5.3.6)

Clarification that pregnancy tests may be done following standard clinical practice 
using blood or urine test (Sections 6.4, 6.5.2.2.8, 6.5.3, 6.7.2)

Clarification that alternation of ASCI administration side is preferable but not 
mandatory (Section 5.3)
 
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
Reporting of auto-immune diseases has been replaced by reporting of potential 
immune-mediated diseases (pIMDs) and the list of autoimmune disease has been 
replaced by a list of pIMDs. It is specified that all pIMDs will be recorded in the 
eCRF/reported within 24 hours using the SAE screen, regardless of whether the 
pIMDs are AEs or SAEs. In addition, SAEs related to the study treatment are 
introduced as a separate category of adverse events, to be recorded within a 
specific time frame. Instructions for recording and reporting adverse events, 
pIMDs and pregnancies have been reshuffled and grouped for clarity. Referrals to 
autoimmune diseases have been replaced by pIMD throughout

Some inconsistencies in the use of US English spelling have been corrected 
throughout the document
In the following sections, amended text has been included in bold italics, while 
deleted text is marked by strikethrough:
Front page, Protocol amendment 1 Sponsor Signatory Approval and Protocol amendment 
1 Investigator agreement:
IND number: 14313
Eudract Number: 2010-020663-20
, PhD (Project Manager, Science Writing, Clinical Operations
, MSc, Scientific writer
, MSc (Global Study Manager, Clinical Operations, Cancer 
Immunotherapeutics)
, MD, Senior Manager, Clinical Safety and Pharmacovigilance
 (Clinical Data Management, Cancer Immunotherapeutics)
 BSc (Specialist, Clinical Data Management, Cancer 
Immunotherapeutics)
Synopsis, Study design
Cycle 2: 6 ASCI administrations given at 3-week intervals
(Weeks 145, 178, 201, 234, 267, 2930)
Cycle 3: 4 ASCI administrations given at 6-week intervals
(Weeks 334, 3940, 456, 512)
 
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PPD
PPD
PPD
PPD
PPD
PPD

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List of abbreviations
pIMD
potential immune mediate disease
Section 3.1 General outline of study design
This will be an open-label, single-group, multicentreer Phase I study, planned to be 
conducted at approximately 20 centers.
The Sponsor will in turn inform all the investigators within 24 hours by fax or email.  The 
investigators must acknowledge receipt of this information.
Section 3.2 Study treatment schedule
Cycle 2:
6 ASCI administrations, each given at 3-week intervals
(Weeks 145, 178, 201, 234, 267, 2930)
Cycle 3:
4 ASCI administrations, each given at 6-week intervals
(Weeks 334, 3940, 456, 512)
Section 3.3 Duration of study participation
Cycle no.
Cycle 2
Interval between ASCI 
administrations (admin)
3 weeks
Continue treatment if CR or PR or SD or SPD at each TE
Visit no.
Screening
8
9
10
11
12
13
14
15
Weeks after first ASCI injection
w-6 to w-1
154
187
210
232
243
276
3029
321
recNY-ESO-1 + AS15 admin no.
7
8
9
10
11
12
Cycle no.
Cycle 3
Interval between ASCI administrations 
(admin)
6 weeks
Visit
Visit no.
16
17
18
19
20
Time after first ASCI admin
343 w
4039 w
465w
521w
54w
recNY-ESO-1 + AS15 admin no.
13
14
15
16
Section 4.1.1 Overview of the recruitment plan

Recruitment is expected to start in the October  February 20110 and is expected to 
be completed within approximately 1 year, i.e., by the end of the 3rd 1st quarter of 
20121. If this target cannot be met, the recruitment period may be extended as 
required.
Section 4.2 Inclusion criteria
Note: Procedures performed before obtaining the patient’s informed consent as part of 
standard institution practices or in the context of another research study (see 
Section6.4) are accepted as study procedures provided the time intervals stipulated in 
the protocol are observed.
 
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The patient has normal organ functions as shown by all of the following:

Hemoglobin Lower Limit of Normal. 12 g/dL

Absolute leukocytes count Lower Limit of Normal. 3.0 x 109/L

Absolute lymphocytes count Lower Limit of Normal. 1.0 x 109/L

Platelets Lower Limit of Normal. 100 x 109/L

Serum creatinine Upper Normal Limit of Normal (ULN).

Serum total bilirubin 1.5 x Upper Normal Limit ULN (except for patients with 
Gilbert’s syndrome for whom the limit is 2 x ULN).

Lactate dehydrogenase (LDH) Upper Normal Limit. ULN

Aspartate aminotransferase (ASAT) 2 x Upper Normal Limit. ULN

Alanine aminotransferase (ALAT) 2 × Upper Normal Limit. ULN
Section 4.3 Exclusion criteria
The patient has at any time received systemic chemotherapy, biochemotherapy, small 
molecules or anti-CTLA-4 monoclonal antibody for metastatic disease.
12. The patient has a family history of congenital or hereditary immunodeficiency.
Section 5.2 Storage and handling of the study product
All ASCI products to be administered to the patients must be stored in a safe and locked 
place with no access by unauthorized personnel.
The ASCI product must will be stored at the defined temperature range (i.e., 2 to 
8°C/36F to 46F).  Please refer to the Study Procedures Manual (SPM) for more details 
on storage of the ASCI.  The storage temperature of the ASCI will be monitored daily 
with validated temperature monitoring device(s) (at the minimum calibrated) and will be 
recorded as specified in the SPM.
The storage conditions will be assessed during pre-study activities under the 
responsibility of the sponsor study contact.
Any temperature deviation, i.e. temperature outside the defined range (02-8C/36-46F), 
must be reported to the sponsor as soon as detected. Following an exposure to such a 
temperature deviation, ASCI will not be used until written approval has been given by the 
Sponsor. In case of temperature deviation between 0 and +2C/32 and 36F, the 
impacted study products can still be administered, but the site must take adequate 
actions to go back to the defined range +2 to +8C/36 to 46F and avoid re-occurrence 
of such a temperature deviation.
Refer to the SPM for details and instructions on the temperature deviation process, 
packaging and accountability of the ASCI.
 
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Section 5.3.2 Administration
….The final preparation is to be injected immediately or, if not possible, no later than 4 
hours after reconstitution and provided that the final preparation has been kept at a 
temperature between 4°C (39°F) and 3025°C (8677°F).
When reconstituted, the recNY-ESO-1 + AS15 ASCI can be kept between 4°C (39F) 
and 25°C (77F) for a maximum of 4 hours.
Table 2 Dosage and administration
Treatment
Dose
Administration
Timing
Route and site
recNY-ESO-1 + AS15 ASCI
1 dose corresponding to
300 g of recNY-ESO-1 
protein and 420 g CpG, 
reconstituted in AS01B-4
Cycle 1: q2w x 6
Cycle 2: q3w x 6
Cycle 3: q6w x 4
Cycle 4: q3m x 4 
then q6m x 4
i.m.
Deltoid or lateral region of 
the thigh, preferably with 
alternation on right or left 
side at each succeeding 
injection 
Section 5.5.2 Criteria for permanent stopping of ASCI administration
After disease progression, the choice of subsequent treatment will be at the discretion of 
the treating physician; the patient will be taken off study treatment and the investigator 
will document at least the first-line treatment administered after the study. any further 
anti-cancer treatment administered and assess the patient’s best clinical response to 
second-line treatment.
5.6.1 Permitted medication
Treatment of any melanoma progression The following palliative melanoma treatments
(of tumor sites or symptoms) are allowed in addition to the study treatment are

Surgery.
Note: If surgery is performed, sample(s) of the resected tumor lesion(s) will be sent to 
GSK Biologicals or a laboratory contracted for this by GSK Biologicals (see Sections 7.1 
and 7.2.2). For patients who have given their specific informed consent to the optional 
translational research, such tumor tissue(s) may also be used to conduct this specific 
testing (see Sections 7.3, 7.6, 7.7, and 7.8).
Section 6.1.1 Patient identification
Patient numbers will be assigned sequentially to patients consenting to participate in the 
study, and according to the range of patient numbers allocated to each study centerre.
 
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Section 6.4 Outline of study procedures
Table 6. List of study procedures for Cycle 1
Visit no.
Screening a 1
2
3
4
5
6
7
Weeks after first ASCI 
administration
-
0
2
4
6
8
10
12
NY-ESO-1 ASCI admin no.
-
1
2
3
4
5
6
Safety assessments
(Serious) Adverse Events recorded 
d
●
●
●
●
●
●
●
●
Potential immune-mediated 
diseases (pIMDs) recorded
●
●
●
●
●
●
●
Table 7. List of study procedures for Cycle 2
Visit no.
8
9
10
11
12
13
14
15
Weeks after first ASCI administration
145
178
201
223
234
267
2930
312
NY-ESO-1 ASCI admin no.
7
8
9
10
11
12
Table 8: List of study procedures for Cycle 3
Visit no.
16
17
18
19
20
Weeks after first ASCI administration
334
3940
456
512
54
NY-ESO-1 ASCI admin no.
13
14
15
16
Tables 6 - 10 List of study procedures
Safety assessments
Autoimmune diseases pIMDs
recorded
●
●
●
●
●
●
●
Laboratory assessments
Footnotes to Table 6 (only footnotes impacted are retained here)
a.
Screening visit/period is to take place a maximum of 6 weeks before the first ASCI administration. However:
1.
Urine and blood chemistry, hematological, coagulation and autoimmunity-tests within 3 weeks before the first 
ASCI administration;
2.
Negative urine pregnancy test must be obtained within 1 week before the first ASCI administration for women 
of child-bearing potential;
3.
Tumor biopsy can be obtained within 12 weeks before the first ASCI administration; in the rare case the 
analysis of the sample would give an inconclusive result, the patient may be asked to allow a new sample to 
be collected or to allow the use of an already preserved sample to repeat the test. A tumor biopsy 
performed in the context of institution standard practice or another research study may be used for 
the NY-ESO-1 testing after obtaining the Sponsor’s agreement, provided this biopsy was preserved in 
RNAlater and was taken no more than 12 weeks before the first administration of the study treatment.
4.
Tumor imaging no more than 6 weeks before first ASCI administration. Imaging performed as part of 
institution standard clinical practice or in relation to another research study does not need to be 
 
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repeated, provided this imaging was performed no more than 6 weeks before the first administration 
of the study treatment. 
Section 6.5.2.1 NY-ESO-1 expression screening of tumor lesion(s)
The tumor biopsy could have been done previously in the context of local routine 
practices or as part of another research study. This tumor material may be used for the 
NY-ESO-1 expression analysis if and only if:

The patient signs the study ICF before the tumor sample is sent to GSK Biologicals 
for analysis, and;

The first ASCI administration is to take place no more than 12 weeks after this tumor 
biopsy.

The Sponsor’s permission to use this tissue has been obtained in advance.

The tumor tissue has been preserved in RNAlater immediately after the surgery 
and the amount of tissue available must comply with the protocol requirements (see 
the SPM).
Section 6.5.2.6 Tumor imaging and assessment
Note: Tumor imaging performed as part of standard clinical practice or in relation to 
another research study does not need to be repeated, provided this imaging was done 
no more than 6 weeks before the first administration of the study treatment.
Section 6.5.2.7 Urine and blood collection

Collect a urine sample for urine chemistry tests including microalbuminuria. A 
validated quantitative test can be used according to local practice; for each 
individual patient the same test method must be used for all assessments.
Section 6.5.2.8 Pregnancy tests
Female patients of childbearing potential are to have a pregnancy test (urine or blood test 
according to local practice) at screening and visits 1, 2, 4 and 6 during Cycle 1.  
Section 6.5.3 Procedures during ASCI administration phase
Note that some of the procedures to be performed during the ASCI administration period 
(such as the physical examination, tumor imaging and assessment, taking urine samples, 
taking blood samples for hematological tests, blood chemistry tests, autoimmunity tests
tests and coagulation tests, and urine pregnancy tests) are also performed during 
screening and are described in Section 6.5.2.
 
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Section 6.5.3.6 Additional tumor biopsy or tumor resection
If surgery is performed during the ASCI administration phase (see Section 5.6.1), 
sample(s) of the resected tumor lesion(s) will be sent to GSK Biologicals or a laboratory
contracted for this by GSK Biologicals (see Sections 7.1 and 7.2.2). For patients who 
have given their specific informed consent to the optional translational research, such
tumor tissue(s) may also be used to conduct this specific testing (see Sections7.3, 7.6, 
7.7, and 7.8).
Section 6.5.3.9 Recording of non-serious AEs, SAEs, autoimmune diseases potential 
immune-mediated diseases (pIMDs) and pregnancy
Refer to Section 9.3 for procedures for the investigator to record AEs and SAEs and to 
Section 9.4 for guidelines on how to report these AEs/SAEs to GSK Biologicals.  Refer 
to Section 9.4.5 for instructions on reporting of autoimmune diseases pIMDs.
Section 6.5.4.1 Patients who received all the scheduled doses and
Section 6.5.4.2 Patients withdrawn before the end of the scheduled doses
At the visit, the following procedures described above will be performed: physical 
examination; recording any AEs and SAEs, autoimmune diseases pIMDs, and 
concomitant medications; taking a urine sample for urine chemistry tests; taking a blood 
sample for hematological tests, blood chemistry tests, autoimmunity tests, coagulation 
tests, serum sampling for humoral immunity tests and PBMC collection for cellular 
immunity tests.
For patients who have withdrawn because of progression of the disease, any resected 
tumor can be sent to GSK for analysis of NY-ESO-1 expression and gene profile upon 
signature of the adequate ICF by the patient (refer to Section 12.2); for patients who have 
given their specific consent to this, such tumor tissue(s) may also be used for optional 
translational research.
Section 6.5.5 Procedures during follow-up phase

Patients who were withdrawn from study treatment because of disease progression or 
who progressed during the post-treatment study period will not be asked to return for 
complete study follow-up visits.  These patients will be contacted every 6 months 
after the first ASCI injection for survival assessment until 5 years after the first study 
treatment administration. followed for survival by means of bi-annual contacts 
(e.g., by phone). If a second-line anti-cancer treatment is administered, the 
patient’s best clinical response to this will be assessed, e.g., during the patient’s 
standard visits to the institution.
 
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Section 6.7.2 Hematology, serum chemistry, urine tests
Sample type
System
Component
Scale
Timing
PREGNANCY TESTING (MANDATORY)
Blood (5 ml) 
or urine 
according to 
local practice
Serum or 
urine
Choriogonadotropin (urine 
HCG pregnancy test)
According to local 
practice
Ordinal
During screening
Cycle 1: Visits 1, 2, 4, and 6
Cycles 2 - 4: prior to each ASCI 
administration
Section 6.7.3 Molecular, immunological and translational research read-outs
NY-ESO-1 SCREENING (MANDATORY)
Test
Sample Type
Laboratory
Timing
NY-ESO-1 expression testing
(see also Section 6.7.3.1)
Fresh tissue 
sample (in 
RNAlater® or 
equivalent)
GSK Biologicals or 
contracted lab a
During screening (initial biopsy).
In case of additional tumor biopsy or 
tumor resection 
MANDATORY TRANSLATIONAL RESEARCH (SEE SECTION 7.2.1)
Test
Sample Type Laboratory
Timing
Gene profiling of the tumor
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) 
and FFPE 
tissue
(if available) d
GSK Biologicals or 
contracted lab a
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection. (disease progression)
OPTIONAL TRANSLATIONAL RESEARCH (EXCEPT SECTION 7.2.1)
Test
Sample Type
Laboratory
Timing
Expression analysis of
NY-ESO-1 and other tumor 
antigens (e.g., MAGE-A3, 
PRAME, LAGE-1, MAGE-C2 
and WT1)
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue
(if available) d
GSK 
Biologicals or 
contracted
lab a
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection. (disease progression)
Antigen spreading
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue
(if available) d ,
serum and blood
b, c
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection. (disease progression)
May be performed on any of the blood 
samples taken for the humoral and cellular 
immunity tests
Proteomic profiling
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue (if 
available) d,
serum and blood 
b, c
During screening (initial biopsy) or on any of 
the blood samples taken for the humoral and 
cellular immunity tests
Tumor infiltrating lymphocytes 
(including T regulatory cells 
and other immune cellular 
entities)
Either fresh 
tissue sample (in 
RNAlater® or 
equivalent) or 
FFPE tissue
(if available) d
During screening (initial biopsy). In case of 
additional tumor biopsy or tumor resection.
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7.2.2 Gene profiling and NY-ESO-1 expression testing on additional lesions
These tests will be performed Iin case the investigator will plans to perform or has 
performed an additional tumor biopsy or a tumor resection during the study (e.g. 
palliative surgery, see Section 5.6.1) or because of disease progression. If the procedure 
occurs in the context of disease progression, the patients will be proposed to sign a 
separate ICF to allow a sample of this lesion to be sent to GSK Biologicals or a validated 
laboratory designated by GSK Biologicals for the optional research on gene profiling.
7.6 Analysis of tumor immune filtration 
This analysis will be done using either fresh tumor tissue or FFPE tumor samples if 
available at screening and later biopsies collected upon during the study and at disease 
progression.
7.7 DNA promoter methylation analysis
Tumor cell DNA can be detected from the blood of melanoma patients even in early 
disease [Kounalakis, 2005].  This DNA can for instance originate from the primary 
tumor, where some cells are lyzsed releasing DNA material in the blood or from 
circulating tumor cells.
A fraction of the stored serum and blood collected over time for the immunological 
analyses will be used for the methylation analysis.  DNA methylation will also be 
assessed either on fresh tumor tissue or FFPE tumor sections used for NY-ESO-1 
detection and biopsy of any new lesions. additional biopsies taken during the study and
at disease progression.
7.8 Pharmacogenetics analyses

For the tumor genetic variability: this analysis might be performed on the tumor 
sample collected for screening, on tumor tissue samples from additional resected of 
progressive lesions or on tumor invaded lymph node when material is available and 
of appropriate quality.  Of note, this investigation of the tumoral cells will not 
require additional material
Section 9.1.2 Definition of a serious adverse event
c.
Requires hospitalizsation or prolongation of existing hospitalizsation.
NB: In general, hospitalizsation signifies that the patient has been admitted at the hospital 
or emergency ward for observation and/or treatment that would not have been appropriate 
in the physician’s office or out-patient setting.  Complications that occur during 
hospitalizsation are also considered AEs.  If a complication prolongs hospitalizsation or 
fulfills any other serious criteria, the event will also be considered serious.  When in 
doubt as to whether ‘hospitalizsation’ occurred or was necessary, the AE should be 
considered serious.
g.
In addition, in this study, Grade 3 or higher autoimmune disorders pIMDs will be 
considered as medically significant and will therefore be notified as SAE.
 
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h.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalizsation but may 
jeopardizse the patient or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition.  These should also be considered 
serious.  Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalizsation.
Section 9.1.3 Autoimmune diseases Potential immune mediated diseases
Potential immune mediated diseases (pIMDs) are a subset of AEs that include 
autoimmune diseases and other inflammatory and/or neurologic disorders of interest 
which may or may not have an autoimmune etiology. AEs that need to be recorded 
and reported as pIMDs include those listed in the table below.
 
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Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders
Cranial nerve disorders, including 
paralyses/paresis (e.g. Bell’s palsy), 
and neuritis (e.g. optic neuritis)
Multiple sclerosis (including 
variants)
Transverse myelitis
Guillain-Barré syndrome, (including 
Miller Fisher syndrome and other 
variants)
Other demyelinating diseases 
(including acute disseminated 
encephalomyelitis)
Myasthenia gravis (including 
Lambert-Eaton myasthenic 
syndrome)
Non-infectious encephalitis/ 
encephalomyelitis 
Neuritis (including peripheral 
neuropathies)
Systemic lupus erythematosus 
Scleroderma (including, CREST 
syndrome and morphoea)
Systemic sclerosis
Dermatomyositis 
Polymyositis 
Antisynthetase syndrome
Rheumatoid arthritis, 
Juvenile chronic arthritis, 
(including Still’s disease)
Polymyalgia rheumatica 
Reactive arthritis
Psoriatic arthropathy
Ankylosing spondylitis
(including undifferentiated 
spondyloarthritides)
Relapsing polychondritis
Mixed connective tissue disorder
Psoriasis
Vitiligo
Raynaud’s phenomenon
Erythema nodosum
Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid and 
dermatitis herpetiformis)
Cutaneous lupus 
erythematosus
Alopecia areata
Lichen planus
Sweet’s syndrome
Liver disorders
Gastrointestinal disorders
Metabolic diseases
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune cholangitis.
Crohn’s disease 
Ulcerative colitis 
Ulcerative proctitis 
Celiac disease
Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis)
Grave's or Basedow’s disease
Diabetes mellitus type I
Addison’s disease
Vasculitides
Others

Large vessels vasculitis including: giant cell 
arteritis such as Takayasu's arteritis and 
temporal arteritis. 

Medium sized and/or small vessels vasculitis 
including: polyarteritis nodosa, Kawasaki's 
disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg–Strauss syndrome, 
thromboangiitis obliterans (Buerger’s 
disease), necrotizing vasculitis, allergic 
granulomatous angiitis, Henoch-Schonlein 
purpura, anti-neutrophil cytoplasmic antibody 
positive vasculitis, Behcet's syndrome, 
leukocytoclastic vasculitis. 

Vasculitides secondary to other immune 
mediated diseases such as lupus vasculitis 
and rheumatoid vasculitis.

Autoimmune hemolytic anemia

Autoimmune thrombocytopenias

Antiphospholipid syndrome

Pernicious anemia

Autoimmune glomerulonephritis (including IgA 
nephropathy, glomerulonephritis rapidly 
progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis)

Uveitis

Autoimmune myocarditis/cardiomyopathy

Sarcoidosis

Stevens-johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary fibrosis

Goodpasture syndrome
However, the investigator will exercise his/her medical and scientific judgment in 
deciding whether other immune-mediated diseases have an autoimmune origin (i.e. 
pathophysiology involving systemic or organ-specific pathogenic autoantibodies) and 
should also be recorded as a pIMD. 
When there is enough evidence to make any of the diagnoses listed in Table 13, the AE 
must be reported as a pIMD. Symptoms, signs or conditions which might (or might not) 
represent one of these diagnoses, should be recorded and reported as AEs but not as a 
pIMDs until the final or definitive diagnosis has been determined, and alternative 
diagnoses have been eliminated or shown to be less likely.
 
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In order to facilitate the documentation of pIMDs in the eCRF, a pIMD standard 
questionnaire and a list of preferred terms (PTs) and PT codes corresponding to these 
diagnoses will be available to the investigators at the study start.
Section 9.1.4 Clinical laboratory parameters………
Abnormal laboratory findings (e.g. clinical chemistry, haematology, urinalysis) or other 
abnormal assessments that are judged by the investigator to be clinically significant will
Section 9.3.1 Time period for detecting and recording of adverse events.......
All AEs (except autoimmune AEs categorized as pIMDs - see Section 9.1.3) starting 
from first dose to 30 days after the last dose of the ASCI must be recorded into the 
Adverse Event screen in the patient’s eCRF, irrespective of intensity or whether or not 
they are considered ASCI administration-related.
The standard time period for collecting and recording SAEs (except autoimmune SAEs 
categorized as pIMDs - see Section 9.1.3) will begin at the first receipt of ASCI and will 
end 30 days following administration of the last dose of ASCI for each patient. See 
Section 9.4 for instructions on reporting and recording SAEs.
The standard time period for collecting and recording severe toxicity events, autoimmune 
diseases pIMDs and pregnancy will begin at the first receipt of the product and last until 
the end of the study (Table 14).
Table 14 Reporting periods for AEs, autoimmune diseases pIMDs, …….
Study activity
Screening
Treatment period
Concluding visit
Follow-up
From ICF 
signature 
to Visit 1
Visit 1
Visit X
(X=2 to 13)
Visit 14 or 30 days after 
last ASCI administration
1 year after 
concluding visit
Reporting of 
severe toxicity 
events
Reporting of 
pIMDs and 
pregnancy
Reporting of 
SAEs related to 
the study 
treatment 
 
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Section 9.3.2.2.1 Assessment of intensity
An AE that is assessed as Grade 3 (severe) should not be confused with a SAE.  Grade 3 
is a category utilizsed for rating the intensity of an event; and both AEs and SAEs can be 
assessed as Grade 3.  An event is defined as ‘serious’ when it meets the definition in 
Section 9.1.2.
Section 9.4.1 Prompt reporting of serious adverse events and other events to GSK 
Biologicals
Table 15
Type of Event
Initial Reports
Follow-up Information
on a Previous Report
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours*
SAE screen
24 hours*
SAE screen
Severe toxicities
24 hours*
eCRF
24 hours*
eCRF
pIMDs
24 hours
SAE screen
24 hours
SAE screen
Pregnancy
24 hours*
Pregnancy Report 
Form
24 hours*
Pregnancy Report Form
* Time frame allowed after receipt or awareness of the information.
Back-up Study Contact for Reporting SAEs and severe toxicities
GSK Biologicals Clinical Safety & Pharmacovigilance
Fax: +
 or +
24/24 hour and 7/7 day availability
9.4.3.1 Back-up system in case the electronic SAE reporting system does not work
In rare circumstances, if the electronic system for reporting SAEs (including deaths 
determined by the investigator to be related to the ASCI administration) does not work 
and in the absence of facsimile equipment, notification by email is acceptable.  Initial 
notification via email does not replace the need for the investigator to complete and 
submit SAE screens in the eCRF (or complete and sign the SAE Report Form if back-up 
system need to be used).  The email address for reporting purposes is:
9.4.3.2 Back-up system in case the electronic system for reporting of severe toxicities 
does not work 
If the electronic system for severe toxicity reporting has been down for 24 hours, the 
investigator or his/her delegate should fax a severe toxicity form directly to the GSK 
Biologicals Central Safety Department (please refer to Section 9.4.1) within 24 hours. 
The maximum timeline for reporting severe toxicities is therefore 48 hours.
As soon as the electronic reporting system is working again, the investigator or 
delegate must update the severe toxicity screen in the eCRF within 24 hours.
 
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The final valid information for regulatory reporting will be the information reported 
through the electronic system.
9.4.4 Completion and transmission of pregnancy reports to GSK Biologicals
Once the investigator becomes aware that a patient is pregnant, the investigator (or 
designate) must complete a Pregnancy Report Form and fax it to the Study Contact for 
Reporting SAEs (refer to the Sponsor Information Sheet) WITHIN 24 HOURS. 
The Pregnancy Report Form will always be completed as thoroughly as possible with 
all available details and then dated and signed by the investigator (or designate). Even 
if the investigator does not have all information regarding the pregnancy, the form 
should still be completed and forwarded to GSK within 24 hours. Once additional 
relevant information is received, the form will be updated and forwarded to GSK 
WITHIN 24 HOURS. 
In absence/dysfunction of facsimile equipment, the Study Contact for Reporting SAEs 
should be notified by telephone within 24 hours. As soon as the facsimile equipment is 
working again, the investigator (or designate) must fax the Pregnancy Report Form to 
the Study Contact for Reporting SAEs (refer to the Sponsor Information Sheet) within 
24 hours. 
9.4.5 Reporting of pIMDs to GSK Biologicals
Once onset of a new pIMD or exacerbation of a pre-existing pIMD is diagnosed 
(serious or non-serious) in a study patient, the investigator (or designate) must 
complete the information in the SAE screens of the eCRF WITHIN 24 HOURS after 
he/she becomes aware of the diagnosis. A field on the SAE screen allows to specify that 
the event is a pIMD and whether it is serious or non serious. The SAE screens will 
always be completed as thoroughly as possible with all available details of the event, in 
accordance with the pIMD standard questionnaire provided. Even if the investigator 
does not have all information regarding a pIMD, the SAE screens should still be 
completed within 24 hours. Once additional relevant information is received, the SAE 
screens in the eCRF should be updated WITHIN 24 HOURS.
The investigator will always provide an assessment of causality at the time of the initial 
report.
Refer to Section 9.4.3.1  for back-up system and updating of SAE information after 
freezing of the patient’s eCRF.
Section 9.4.6 Follow-up of adverse events and serious adverse events
All AEs and autoimmune diseases pIMDs documented at a previous visit/contact and 
designated as not recovered/not resolved or recovering/resolving will be reviewed at 
subsequent visits/contacts until 30 days after the last ASCI administration.
 
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All severe toxicities and autoimmune diseases pIMDs documented at a previous 
visit/contact and designated as not recovered/not resolved or recovering/resolving will be 
reviewed at subsequent visits/contacts until the end of the study.
Investigators will follow-up patients:

With SAEs or patients withdrawn from the study as a result of an AE, until the event 
has resolved, subsided, stabilizsed, disappeared, or until the event is otherwise 
explained, or the patient is lost to follow-up.

Or, in the case of other non-serious AEs and autoimmune diseases pIMDs until they 
complete the study or they are lost to follow-up.
If a patient dies during participation in the study or during a recognizsed follow-up 
period, GSK Biologicals will be provided with a copy of any available post-mortem 
findings, including histopathology.
Section 12.1 Remote data entry instructions
If the authorizsed individuals change during the study, the investigator is to inform GSK 
Biologicals’ representative of the specific change(s).  The SSSS needs to be updated 
accordingly in order to reflect the current situation at all times.
12.8.3 Publication
For multicentreer studies, , the first publication or disclosure of study results shall be a 
complete, joint multicentreer publication or disclosure coordinated by GSK.  Thereafter, 
any secondary publications will reference the original publication(s).
 
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GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Administrative change 1
eTrack study number(s) 
and abbreviated title(s)
112406 (NYESO1-AS15-MEL-001 (MET))
EudraCT number
2010-020663-20
Title
Study of GSK2241658A Antigen-Specific Cancer 
Immunotherapeutic in patients with unresectable and 
progressive metastatic cutaneous melanoma
Detailed Title
An open Phase I Study of immunization with the 
recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic in patients with NY-ESO-1-
positive unresectable and progressive metastatic 
cutaneous melanoma
Administrative change
date:
Administrative change 1 Final: 17 January 2013
Co-ordinating author:
 Ph.D, (Scientific Writer, Cancer 
Immunotherapeutics)
In the following sections, additions are marked by bold/italic, while deleted text is 
marked by strikethrough:
Cover page
Contributing authors
, MD (Head of Early Clinical 
Development, Cancer Immunotherapeutics)
, MD (Senior 
Manager Director, Early Clinical Development, 
Cancer Immunotherapeutics)
, MSc (Global Study Manager, Clinical 
Operations, Cancer Immunotherapeutics
, MD
, Safety Scientist
enior Manager, Clinical Safety and Pharmacovigilance
, MSc (Biostatistician, 
Clinical Operations)
, PhD (Director, Head of R&D, Cancer 
Immunotherapeutics)
, (Clinical Data 
Management, Cancer Immunotherapeutics) 
Sponsor signatory
Vincent Brichard, MD, PhD (Senior Vice-President,
Head of Immunotherapeutics)
Signature
 
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Protocol Administrative Change 1 Investigator Agreement
Investigator name
Signature
Date
 
(LKP) name:
Signature
Date
Section 13
Not Applicable
13.1
French administrative considerations
This Section includes all the requirements of the French law (n2004-806 of 
09 August 2004), and identifies, item by item, the mandatory modifications or 
additional information to the study protocol.

Concerning the “Study Population”
In line with the local regulatory requirements, the following text in section 
“OTHER STUDY ELIGIBILITY CRITERIA CONSIDERATIONS” is added:
A patient will be eligible for inclusion in this study if he /she is either affiliated to 
or beneficiary of a social security category.
It is the investigator’s responsibility to ensure and to document (in source 
document - patient notes) that the patient is either affiliated to or beneficiary of a 
social security category.
 
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
Concerning the “Data Evaluation: Criteria for Evaluation of Objectives”
Section on the “ESTIMATED SAMPLE SIZE”
The following text concerning the “sample size assumption” is added:
The expected number of patients to be recruited in France is declared to the 
French Regulatory Authority.

Concerning the “Conduct of the Study”
Section “REGULATORY AND ETHICAL CONSIDERATIONS, INCLUDING 
THE INFORMED CONSENT PROCESS”
The following text concerning “the process for informing the patient or his/her 
legally authorized representative” is added:

French Patient ICF is a document in triplicate which summarizes the main 
features of the study and allows collection of the patient's written consent. It 
also contains a reference to the authorization of ANSM and the approval from 
the French Ethics Committee and the maintenance of confidentiality of the 
returned consent form by GSK France.
In addition, the following text concerning “the process for obtaining the patient's 
informed consent” is added:

When biomedical research is carried out on a minor / on an adult in the care 
of a “tutelle” guardian, consent is given by their legal representative and, if 
the committee mentioned in article L. 1123-1 considers that the research in 
question, because of the gravity of the restraints or the specificity of the 
medical acts involved, entails a serious risk of affecting their private life or the 
integrity of their body, by the family council if it has been instated, or by the 
judge of “tutelle” guardians.

When biomedical research is carried out on an adult in the care of a 
“curatelle” guardian, consent is given by the patient assisted by his guardian. 
However, if the adult in the care of a “curatelle” guardian is invited to 
participate in research which the committee mentioned in article L. 1123-1 
considers, because of the gravity of the restraints or the specificity of the 
medical acts involved, to entail a serious risk of affecting their private life or 
the integrity of their body, the matter is submitted to the judge of guardians 
who decides whether the adult is capable of giving his consent. In the case of 
incapacity, the judge will decide whether or not to authorize the biomedical 
research.

When biomedical research, which complies with the conditions laid down in 
article L. 1121-8, is considered for an adult incapable of expressing his 
consent and not under a legal protection order, consent is given by a person of 
confidence as defined in article L. 1111-6 and, failing this, by a person who 
maintains close and stable links with the patient. However, if the committee 
mentioned in article L. 1123-1 considers that the research in question, 
 
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because of the gravity of the restraints or the specificity of the medical acts 
involved, entails a serious risk of affecting their private life or the integrity of 
their body, consent is given by the judge of guardians.

Finally, concerning “the management of the Patient ICFs” the following text is 
added:
The first copy of the Patient ICF is kept by the investigator. The second copy is 
kept by the Director of the Medical Department of GlaxoSmithKline France and 
the last copy is given to the patient or his/her legally authorized representative.
The second copy of all the consent forms will be collected by the investigator at the 
end of the trial under the Clinical Research Assistant’s (CRA's) control, and 
placed in a sealed envelope bearing only:

The study number,

The identification of the Centre: name of the principal investigator and 
number of centre),

The number of informed consents,

The date and,

The principal investigator’s signature.
Then, the CRA hands the sealed envelope over to the Director of the Medical 
Department, for confidential recording, under his responsibility.

In section concerning the “ DEMOGRAPHIC DATA ” the following text is added:
In accordance with the data-processing and freedom French law dated on 6th of 
January 1978 modified on the 6th of August 2004 - article 8, the ethnic origin can 
only be collected if the collection of this data is justified within the framework of 
this study.

In section concerning the “ TESTING OF BIOLOGICAL SAMPLES ” the 
following text is added:
In accordance with Article L1211-2 of the French Public Health Code, a 
biological sample without identified purpose at the time of the sample and patient’s 
preliminary information is not authorized.

Concerning “Administrative matters”
The following text concerning “notification to the hospital director” is added (if 
applicable):
In accordance with Article L1123-13 of the Public Health Code, the Hospital 
Director is informed of the commitment to the trial in his establishment. The 
Hospital Director is supplied with the protocol and any information needed for the 
financial disposition, the name of the investigator(s), the number of sites involved 
in his establishment and the estimated time schedule of the trial (R.1123-63).
 
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The following text concerning “information to the hospital pharmacist” is added 
(if applicable):
In accordance with Article R.1123-64 of the Public Health Code, the Hospital 
Pharmacist is informed of the commitment to the trial in his establishment. The 
Pharmacist is supplied with a copy of the protocol (which allows him to dispense 
the drug(s) of the trial according to the trial methodology), all information 
concerning the product(s) of the trial (e.g. included in the Clinical Investigator's 
Brochure), the name of the investigator(s), the number of sites involved in his 
establishment and the estimated time schedule of the trial.
Finally, the following text concerning “data management” is added:
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, involved 
in this clinical trial, and data regarding the patients recruited in this clinical trial 
(patient number, treatment number, patient status with respect to the clinical trial, 
dates of visit, medical data) will be collected and computerized in GSK Biologicals 
data bases by Laboratoire GlaxoSmithKline or on its behalf, for reasons of follow 
up, clinical trial management and using the results of said clinical trial. According 
to the Act no. 78-17 of 6th January 1978 further modified, each of these people 
aforesaid has a right of access, correction and opposition on their own data 
through Laboratoire GlaxoSmithKline (Clinical Operations Department).
 
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GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 2
eTrack study number and 
abbreviated title
112406 (NYESO1-AS15-MEL-001 (MET))
EudraCT number
2010-020663-20
Title
Study of GSK2241658A Antigen-Specific Cancer 
Immunotherapeutic in patients with unresectable and 
progressive metastatic cutaneous melanoma
Detailed title:
An open Phase I Study of immunization with the 
recNY-ESO-1 + AS15 Antigen-Specific Cancer 
Immunotherapeutic in patients with NY-ESO-1-
positive unresectable and progressive metastatic 
cutaneous melanoma
Amendment number:
Amendment 2
Amendment date:
27 November 2013
Co-ordinating author:
, PhD, (Scientific writer, XPE 
Pharma for GSK Biologicals)
Contributing authors
, MD, (Vice-President, Head of 
Early Clinical Development, Cancer 
Immunotherapeutics)
, MD, (Director, Early Clinical 
Development, Cancer Immunotherapeutics)
, MSc, (Global Study Manager, Clinical 
Operations, Cancer Immunotherapeutics)
, PhD, (Clinical Scientist, Early 
Clinical Development, Cancer Immunotherapeutics)
, MD, (Senior Manager, Clinical Safety 
and Pharmacovigilance)
, (Biostatistician, Cancer 
Immunotherapeutics)
, PhD, (Clinical Data Management, Cancer 
Immunotherapeutics)
 
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The background and rationale for the changes made to the protocol as a consequence of 
Amendment 2 are described below:

Upon request from Paul-Ehrlich-Institut (Germany), testing for HIV has been made 
mandatory before study entry for all patients in German sites. All HIV-positive 
patients will be ineligible to enter the study. On account of this request, the 
following changes have been made in the protocol as part of this amendment.

A note has been added to exclusion criterion 10 in Section 4.3. This note is a 
specification for Germany only.

The HIV test has been included in the study procedures in Section 6.5.2.9, 
Section 6.7.2 and Table 6.

Section 13.2 German specific requirements has been created. This section 
contains a summary information regarding the HIV test.

Administrative changes and minor modifications have been implemented.

The list of contributing authors has been updated.

Wording regarding the use of prednisone or equivalent has been clarified in 
Sections 4.3, 5.5.2 and 5.6.2.1.

Additional information regarding the tumor assessment has been added in 
section 6.5.2.6.

In Section 6.5.3.6, additional information regarding the need to label every 
new tumor biopsy/resection has been added. Information regarding the 
resected/biopsied tumor lesion(s) will be sent along with the lesion(s). This 
will include the nature of the lesion (skin, lymph node or other), if the lesion is 
new or not, if the lesion is part of the target lesions or not, if the lesion is 
inflammatory or not, if vitiligo is present around the lesion or not and the 
status of the lesion when resected/biopsied (progressive, stable or regressive).

The link to RECIST criteria information has been modified in Section 6.6.1. 
The previous link was not accessible on the internet anymore.

In section 11.2.3, the reference to “Section 6” has been changed by “Section 
7”, as it is more convenient.

The following notable errors have been corrected

Table 1 has been corrected to be aligned with Tables 6 to 9.

Orthographic and grammatical typos have been corrected throughout the 
document.
In the following sections, amended text has been included in bold italics, while 
deleted text is marked by strikethrough.
Cover page
, MD, (Vice-President, Head of Early Clinical Development, Cancer 
Immunotherapeutics)
 
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, PhD, (Clinical Scientist, Early Clinical Development, Cancer 
Immunotherapeutics)
, MD, (Senior Manager, Clinical Safety and Pharmacovigilance)
, PhD, (Clinical Data Management, Cancer Immunotherapeutics)
List of abbreviations
DERMA
ADjuvant ImmunothERapy with MAGE-A3 in 
melanoMA
Table 1. Overview of ASCI administrations, tumor and immunological evaluations
Cycle no.
Cycle 1
Cycle 2
Interval between ASCI 
administrations 
(admin.)
2 weeks
3 weeks
Continue treatment if CR or PR or SD or SPD at 
each TE
Visit no.
Scree
ning
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Weeks after first ASCI 
admin (w)
w-3 
w-6 to 
w-1
0
2
4
6
8
1
0
1
2
14
17
20
22
23
26
29
31
recNY-ESO-1 + AS15 
admin no.
1
2
3
4
5
6
7
8
9
10
11
12
Tumor evaluation (TE)
x
x
x
x
Anti-NY-ESO-1 and 
anti-CpG7909 Ab 
response
x
x
x x x
x
Anti-NY-ESO-1 T cell 
responses 
x
x
x
Cycle no.
Cycle 3
Cycle 4
Interval between ASCI 
6 weeks
3 months
6 months
Conc
Continue treatment if CR or PR or SD or SPD at each TE
Visit
Visit no.
1
6
1
7
1
8
1
9
20
21
22
23
24
25
26
27
28
29
Week (w), month (m) 
or year (y) after first 
ASCI admin. 
3
3
w
3
9
w
4
5
w
5
1
w
54
w
1y
3m
V1
9 
+3
m
1y
6m
V21 
+3
m
1y9
m
V2
2 
+3
m
2y
V2
3 + 
3m
2y
6m
V2
4 + 
6m
3y 
V25 
+6m
3y
6m
V26 
+6m
4y 
V27 
+6m
4y1m
V28 + 
30 
days
recNY-ESO-1 + AS15 
admin no.
1
3
1
4
1
5
1
6
17
18
19
20
21
22
23
24
Tumor evaluation (TE)
x
x
x
x
x
x
x
Anti-NY-ESO-1 and 
anti-CpG7909 Ab 
response
x
x
x
x
x
x
x
Anti-NY-ESO-1 T cell 
responses
x
x
x
x
x
x
x
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Section 4.3. Exclusion criteria for enrolment
4. The patient requires concomitant treatment (more than 7 consecutive days) with 
systemic corticoseriooids, or any other immunosuppressive agents.
Exception: The use of prednisone, or equivalent, at a dose of 0.125 mg/kg/day 
(absolute maximum 10 mg/day) for more than 7 consecutive days or at a dose > 0.125 
mg/kg/day but for less than 7 consecutive days is allowed. The use of, inhaled 
corticosteroids or topical steroids is also permitted.
10.
The patient is known to be positive for the Human Immunodeficiency Virus (HIV).
Specification for Germany: Please, refer to Section 13.2.
Section 5.5.2. Criteria for permanent stopping of ASCI administration
7. Appearance of any confirmed or suspected immunosuppressive or 
immunodeficient condition, including HIV infection, or any medical condition 
requiring chronic treatment (more than 7 consecutive days) with systemic 
corticosteroids or any other immunosuppressive agents.
[Note: The use of prednisone, or equivalent, at a dose of 0.125 mg/kg/day (absolute 
maximum 10 mg/day) for more than 7 consecutive days or at a dose > 0.125 mg/kg/day 
but for less than 7 consecutive days is allowed. The use of, or inhaled corticosteroids or 
topical steroids is also permitted.]
Section 5.6.2.1. Prohibited medications or non-drug therapies
b.
Administration of immunosuppressants or other immune-modifying drugs during the 
study period.  The use of prednisone, or equivalent, at a dose of 0.125 mg/kg/day 
(absolute maximum 10 mg/day) for more than 7 consecutive days or at a dose > 
0.125 mg/kg/day but for less than 7 consecutive days is allowed. The use of, 
maximum duration of treatment of one week) or inhaled corticosteroids or topical 
steroids is also permitted
Table 6. List of study procedures for Cycle 1 (including screening)
Visit no.
Screening a 1
2
3
4
5
6
7
Weeks after first ASCI 
administration
-
0
2
4
6
8
10
12
NY-ESO-1 ASCI admin no.
-
1
2
3
4
5
6
Laboratory assessments
HIV status i
●
8.
HIV test within 3 weeks before the first ASCI administration, mandatory in Germany only (refer to Section 
13.2).
i. HIV test is mandatory to determine the HIV status (positive - negative) of patients in Germany only. Patients 
with known HIV-positive status do not need to be re-tested. Patients tested for HIV prior to signature of the ICF 
for study participation do not need to repeat the test, given that it was performed within three weeks of 
enrolment (refer to Section 13.2).
 
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Section 6.5.2.6. Tumor imaging and assessment
Source documentation that is considered necessary by GSK Biologicals for efficacy or 
safety evaluation such as but not limited to pictures, CT-scans, histology, laboratory 
reports will be collected and upon request sent to GSK Biologicals for review, ensuring 
that patient confidentiality is maintained.
Section 6.5.2.9. HIV status (New section)
HIV test is mandatory in Germany only. Please, refer to Section 13.2.
Section 6.5.3.6. Additional tumor biopsy or tumor resection
In case the investigator performs an additional tumor biopsy or tumor resection during 
the ASCI administration phaseIf surgery is performed during the ASCI administration 
phase (see Section 5.6.1), sample(s) of the resected tumor lesion(s) will be sent to GSK 
Biologicals or a laboratory contracted for this by GSK Biologicals (see Sections 7.1 and 
7.2.2). For patients who have given their specific informed consent to the optional 
translational research, such tumor tissue(s) may also be used to conduct this these
specific tests testing (see Sections 7.3, 7.6, 7.7, and 7.8).
Information will be provided regarding the additional resected/biopsied lesion(s). This 
will include the nature of the lesion (skin, lymph node, other), if the lesion is new or 
not, if the lesion is part of the target lesions or not, if the lesion is inflammatory or not,
if vitiligo is present around the lesion or not and the status of the lesion when 
resected/biopsied (progressive, stable or regressive).
Section 6.6.1. Response criteria for patients with all target lesions 20.0 mm
The following paragraphs contain a brief summary of the RECIST criteria [Therasse, 
2000] as appropriate to this study.  The complete criteria are available at 
http://www.eortc.be/recist/documents/RECISTGuidelines.pdfhttp://www3.oup.co.uk/jnc
i/extra/920205.pdf.
Section 6.7.2. Hematology, serum chemistry and urine tests
Specification for Germany: An additional blood sample might be required for HIV test. 
Collect of the sample will be performed according to standard local practice. For more 
information, please refer to Section 13.2.
Section 11.2.3. Immunogenicity endpoints
This is explained in Section 67 and is on the basis of:
 
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Section 13.2. German specific requirements
Concerning the HIV test
Upon request from Paul-Ehrlich-Institut (Germany), HIV test is mandatory to assess 
the HIV status (positive - negative) of patients in Germany only. Testing will be 
performed during the screening phase of the study and according to local standard 
practice. Patients with known HIV-positive status or positive for HIV as per testing will 
not be eligible for entry in the study. Patients for which the test is positive will be 
managed according to standard local clinical practice. Patients with known HIV-
positive status do not need to be retested. Patients tested for HIV prior to signature of 
the ICF for study participation do not need to repeat the test, given that it was
performed within three weeks of enrolment. Patients tested for HIV prior to signature 
of the ICF for study participation do not need to repeat the test, given that it was 
performed within three weeks of enrolment.
Table 6 “List of study procedures for Cycle 1 (including screening)” has been adapted 
to include this HIV test.
Throughout the document
Orthographic and grammatical typos have been corrected. For a better readability, these 
corrections have not been highlighted in the body of the protocol.
 
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GlaxoSmithKline Biologicals
Clinical Research & Development
Protocol Amendment 3
eTrack study 
number and 
abbreviated title
112406 (NYESO1-AS15-MEL-001 (MET))
EudraCT number
2010-020663-20
Title
Study of GSK2241658A Antigen-Specific Cancer 
Immunotherapeutic in patients with unresectable and 
progressive metastatic cutaneous melanoma
Detailed title:
An open Phase I Study of immunization with the recNY-ESO-1 
+ AS15 Antigen-Specific Cancer Immunotherapeutic in 
patients with NY-ESO-1- positive unresectable and progressive 
metastatic cutaneous melanoma
Amendment 
number:
Amendment 3
Amendment date:
03 September 2014
Co-ordinating 
author:
, PhD, (Scientific writer, Cancer 
Immunotherapeutics)
Contributing 
authors
, MD, (Vice-President, Head of 
Immunotherapeutics Cancer Incubator Early Clinical 
Development, Cancer Immunotherapeutics)
, MD, (Director, Early Clinical Development, 
Cancer Immunotherapeutics)
, MSc, (Study Delivery Lead Global Study 
Manager, Clinical Operations, Cancer Immunotherapeutics)
, PhD, (Clinical Scientist, Early Clinical 
Development, Cancer Immunotherapeutics)
, MD, (Senior Manager, Clinical Safety and 
Pharmacovigilance)
, (Biostatistician, Cancer Immunotherapeutics)
, PhD, (Clinical Data Management, Cancer 
Immunotherapeutics)
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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The background and rationale for the changes made to the protocol as a consequence of 
Amendment 3 are described below:
The enrolment of new patients in the study, the follow-up of the patients who 
discontinued the study treatment due to disease progression or due to other 
reasons, or patients in the 1 year follow-up following the completion of the study 
treatment will be stopped given the fact that:

the detailed analysis of the MAGRIT study (A double-blind, randomized, placebo-
controlled Phase III study to assess the efficacy of recMAGE-A3 + AS15 Antigen-
Specific Cancer immunotherapeutic as adjuvant therapy in patients with resected 
MAGE-A3-positive Non-Small Cell Lung Cancer) showed the absence of 
treatment effect in any of the primary, secondary, or exploratory analyses. All 
aspects of the MAGRIT study have been carefully assessed, and unfortunately 
these investigations failed to identify a root cause for the lack of efficacy of the 
MAGE-A3 ASCI  in NSCLC.

a comprehensive review of the MAGE-A3 ASCI Phase III results, together with all 
other available clinical and laboratory data in early clinical studies with various 
recombinant proteins, including NY-ESO-1,  tested in different diseases and 
settings suggests that the anticancer activity of these ASCI, all based on the 
recombinant protein combined with adjuvant system AS15 technology may well 
be very limited.

the balance of anticipated benefits and apparent risks associated with NY-ESO-1 + 
AS15 ASCI continues to be acceptable following the ongoing systematic review of 
safety data. Also, no additional safety data will be collected, except for patients 
who continue treatment.
By stopping the active follow-up, the patients will not be further exposed to 
unnecessary study related procedures. 
Although GSK has no reasonable expectation of a population benefit from the 
treatment, GSK cannot exclude that some patients in the NYES01-AS15-MEL-001 
study may benefit from this treatment on an individual basis. Therefore, patients in the 
study and who are currently still receiving the study treatment, will be offered the 
option to continue treatment if they wish to do so, following discussion with their 
treating physician. 
In the best interest of patients, blood drawings which were planned for protocol 
research purposes (i.e. PBMCs, serum collection) will not be performed anymore. 
Blood drawing for safety monitoring as per protocol will continue.
By default, for each biological sample already collected in the scope of this study and 
not tested yet, testing will not be performed except if a scientific rationale remains 
relevant. In this case, testing will be done in compliance with the protocol and ICF 
signed by the patient.
In the following sections, amended text has been included in bold italics, while 
deleted text is marked by strikethrough.
 
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Sponsor signatory
Frédéric Lehmann, MD
Vice President, Head of Immunotherapeutics 
Cancer Incubator Vincent Brichard, MD, PhD 
(Senior Vice-President,
Head of Immunotherapeutics)
SYNOPSIS
Rationale for the study and study design
1. Need for new therapeutic approaches for metastatic melanoma
The Final Container (per human dose) is composed of 420 g of CpG7909 
oligonucleotide (see note below), which will be co-lyophilized with the 300 g recNY-
ESO-1 protein and the liquid AS01B-4 adjuvant, which contains 50 g of QS21 (a 
saponin molecule) and 50 g of Monophosphoryl lipid A (MPL®), in a liposome 
formulation.
[Note: The concentration in CpG7909 depends on the lot used –Certain lots are labeled 
as containing 420 µg CpG, whereas other lots will be labeled as 380 µg CpG. This 
difference in how the CpG content is noted is due to the fact that a different analytical 
method to determine the content of the CpG was applied to more recent lots and the 
change in the content designation from 420 to 380 µg is a result of a recalculation. The 
actual content of the CpG in the lots is the same (within the allowable assay 
variation).]
2. Rationale for using recNY-ESO-1 protein combined with AS15 Adjuvant System
GSK recently reported the negative results of the MAGRIT study. The detailed analysis 
of MAGRIT showed the absence of treatment effect in any of the primary, secondary, 
or exploratory analyses. All aspects of the MAGRIT study have been carefully assessed, 
and unfortunately these investigations failed to identify a root cause for the lack of 
efficacy of the MAGE-A3 ASCI  in NSCLC. 
Furthermore, a comprehensive review of the MAGE-A3 ASCI Phase III results, 
together with all other available clinical and laboratory data in early clinical studies 
with various recombinant proteins, including NY-ESO-1,  tested in different diseases 
and settings suggests that the anticancer activity of these ASCI, all based on the 
recombinant protein combined with adjuvant system AS15 technology may well be very 
limited. 
In light of this, GSK has decided to stop further development of the recombinant 
protein adjuvanted portfolio as a standalone treatment for cancer patients.
Objectives
Note that, as of Amendment 3, the decision was taken not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant. No further blood samples for protocol research purposes 
will be collected.
 
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Study design

Duration of the study:  The duration of the ASCI treatment period (from first visit to 
the concluding visit) will not last longer than 49 months for any patient, comprising 
the entire period of immunization and the concluding visit.  The duration of the 
follow-up will be one year after the concluding visit.  The total duration including 
follow-up is approximately 5 years.
As of Amendment 3, all active follow-up visits and procedures will be stopped. Post-
study AEs/SAEs will continue to be reported as described in Section 9.3.1.
Endpoints
Secondary

Progression-free survival (PFS).
PFS is defined as the time from first treatment to either the date of first disease 
progression (PD or SPD) or the date of death (for whatever reason), whichever comes 
first.  Patients alive and without disease progression are censored at the date of the last 
visit/contact.

The duration of response for patients with CR, PR or Stable Disease (SD) status.
The duration of the response is defined as time from first objective response or SD 
evaluation to first PD assessment or death.
Immunogenicity endpoints
Note that, as of Amendment 3, the decision was taken not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant. No further blood samples for protocol research purposes 
will be collected.

Immunogenicity of the NY-ESO-1 ASCI treatment will be evaluated at different 
timepoints.
On the basis of:
1. The anti-NY-ESO-1 and anti-CPG7909 humoral antibody concentration and 
response.
2. The anti-NY-ESO-1 cellular (T-cell) response.
 
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1. INTRODUCTION
1.2.2. The AS15 Adjuvant System
Per 0.5 mL dose, the liquid Adjuvant System AS01B-4 contains 50 g of QS21 and 50 
g of Monophosphoryl lipid A (MPL®), in a liposome formulation.  The 
immunostimulatory nucleotide CpG7909 is included [420 g per dose (see note in 
Section 5.1.1)] to enhance the immune response.
1.3.2.2 AS15 Adjuvant System
GSK recently reported the negative results of the MAGRIT study. The detailed analysis 
of MAGRIT showed the absence of treatment effect in any of the primary, secondary, 
or exploratory analyses. All aspects of the MAGRIT study have been carefully assessed, 
and unfortunately these investigations failed to identify a root cause for the lack of 
efficacy of the MAGE-A3 ASCI  in NSCLC. 
Furthermore, a comprehensive review of the MAGE-A3 ASCI Phase III results, 
together with all other available clinical and laboratory data in early clinical studies 
with various recombinant proteins, including NY-ESO-1,  tested in different diseases 
and settings suggests that the anticancer activity of these ASCI, all based on the 
recombinant protein combined with adjuvant system AS15 technology may well be very 
limited. 
In light of this, GSK has decided to stop further development of the recombinant 
protein adjuvanted portfolio as a standalone treatment for cancer patients. 
2. OBJECTIVES
2.2 Secondary Objectives
Note that, as of Amendment 3, the decision was taken not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant. No further blood samples for protocol research purposes 
will be collected.
2.3 Translational research objectives
Note that, as of Amendment 3, the decision was taken not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant. No further blood samples for protocol research purposes 
will be collected.
3. STUDY DESIGN OVERVIEW
3.3 Duration of study participation
As of Amendment 3, all active follow-up visits and procedures will be stopped. Post-
study AEs/SAEs will continue to be reported as described in Section 9.3.1.
 
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Table 1: Overview of ASCI administrations, tumor and immunological evaluations 1 
Cycle no.
Cycle 1
Cycle 2
Interval between ASCI 
administrations (admin.)
2 weeks
3 weeks
Continue treatment if CR or PR or SD or SPD at each TE
Visit no.
Screening
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Weeks after first ASCI admin. (w)
w-6 to w-1
0
2
4
6
8
10
12
14
17
20
22
23
26
29
31
recNY-ESO-1 + AS15 admin no.
1
2
3
4
5
6
7
8
9
10
11
12
Tumor evaluation (TE)
x
x
x
x
Anti-NY-ESO-1 and anti-CpG7909 Ab 
response
x
x
x
x
x
x
Anti-NY-ESO-1 T cell responses 
x
x
x
Cycle no.
Cycle 3
Cycle 4
Interval between ASCI admin.
6 weeks
3 months
6 months
Concluding
Continue treatment if CR or PR or SD or SPD at each TE
Visit
Visit no.
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Week (w), month (m) or year (y) 
after first ASCI admin.
33w
39w
45w
51w
54w
V19 
+3m
V21 
+3m
V22 
+3m
V23 
+3m
V24 
+6m
V25 
+6m
V26 
+6m
V27 
+6m
V28 + 30 days
recNY-ESO-1 + AS15 admin no.
13
14
15
16
17
18
19
20
21
22
23
24
Tumor evaluation (TE)
x
x
x
x
x
x
x
Anti-NY-ESO-1 and anti-CpG7909 Ab 
response
x
x
x
x
x
x
x
Anti-NY-ESO-1 T cell responses
x
x
x
x
x
x
x
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Follow-up
Visit no.
Months (m) after Concluding visit
Tumor evaluation
Anti-NY-ESO-1 and anti-CpG7909 Ab 
response
Anti-NY-ESO-1 T cell responses
1.
Abbreviations: Ab - Antibody; Admin - Administration; CR - Complete Response; m = Month (Month, as calculation convention: 1 month is defined as 4 weeks i.e. 28 days during 
the treatment phase);  PR - Partial Response; SD - Stable Disease; SPD - Slow Progressive Disease; TE - Tumor Evaluation; w - Week; y - Year.
2.
In case a study visit needs to be delayed for any reason, the date for the visits following the delayed visit will be determined by the “intervals between study treatment 
administration” rather than by the “weeks after first study treatment administration”
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4. STUDY POPULATION
4.3 Exclusion criteria for enrolment
1.
The patient has at any time received systemic chemotherapy, biochemotherapy, 
small molecules or anti-CTLA-4 monoclonal antibody for metastatic disease.
Note: Isolated limb perfusion or local electrochemotherapy, as long as this was 
performed at least 4 weeks before first ASCI administration is authorized.
3.
The patient received any cancer immunotherapy containing a NY-ESO-1 antigen 
or any cancer immunotherapy for his/her metastatic disease.
Note: Previous adjuvant treatment with interferon, anti-CTLA-4 monoclonal antibody or 
a cancer immunotherapeutic (“vaccine”) containing a tumor antigen other than NY-ESO-
1 or radiotherapy is allowed, if the last administration took place at least 8 weeks before 
the first ASCI administration.
5. STUDY PRODUCT ADMINISTRATION
5.1.1 Description of study product

One vial containing 300 g of the recNY-ESO-1 protein co-lyophilized with 420 g 
of CpG7909;
[Note: The concentration in CpG7909 depends on the lot used –Certain lots are labeled 
as containing 420 µg CpG, whereas other lots will be labeled as 380 µg CpG. This 
difference in how the CpG content is noted is due to the fact that a different analytical 
method to determine the content of the CpG was applied to more recent lots and the 
change in the content designation from 420 to 380 µg is a result of a recalculation. The 
actual content of the CpG in the lots is the same (within the allowable assay 
variation).] (Amended 03 September 2014).
5.3.2 Administration
Table 2: Dosage and administration
Treatment
Dose
Administration
Timing
Route and site
recNY-ESO-1 + AS15 ASCI
1 dose corresponding to
300 g of recNY-ESO-1 
protein and 380 420 g CpG, 
reconstituted in AS01B-4
Cycle 1: q2w x 6
Cycle 2: q3w x 6
Cycle 3: q6w x 4
Cycle 4: q3m x 4 
then q6m x 4
i.m.
Deltoid or lateral region of 
the thigh, preferably with 
alternation on right or left 
side at each succeeding 
injection
 
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5.5.1 Criteria for postponement of ASCI administration
3. Any other medical reason that would expose the patient to an unacceptable risk, 
at the investigator’s discretion.
For these three two conditions, the entire program of study visits and ASCI 
administrations will be resumed as soon as the patient’s condition allows or at the 
investigator’s discretion (see Section 6.3.1).  If the re-treatment criteria are not met within 
4 weeks (3 months during and after Cycle 4) after the scheduled treatment date, the 
patient must be withdrawn from the study treatment and the procedures detailed for the 
Concluding Visit are to be carried out (see Section 6.5.4).
5.5.2 Criteria for permanent stopping of ASCI administration
For patients whose treatment is discontinued prematurely during the study, the 
procedures of the Concluding Visit (see Section 6.5.4) will be carried out a minimum of 
30 days after the last ASCI administration and - if possible - before the initiation of any 
other treatment.  These patients should enter the follow-up period.
Patients discontinuing therapy prematurely in the absence of progression should not, if 
possible, receive any other cancer treatment before their disease progresses, unless it is 
clearly not in the best interest of the patient.  Every effort will be made by the 
investigator to ensure documentation of the date of progression.
After disease progression, the choice of subsequent treatment will be at the discretion of 
the treating physician; the patient will be taken off study treatment and the investigator 
will document any further anti-cancer treatment administered and assess the patient’s best 
clinical response to second-line treatment.
6. STUDY ASSESSMENT AND PROCEDURES
6.3.1 Attendance of study visits
Table 3 Permitted deviations from stipulated dates of visits
Cycle 1:
3 calendar days
Cycle 2:
3 calendar days
Cycle 3:
4 calendar days
Cycle 4:
7 calendar days
Follow-up period:
14 calendar days
Table 4: Example of postponement of study treatment dose for 3 weeks during 
Cycle 1 and the delay of the schedule induced
Note: This postponement will have a similar impact on the complete schedule of visits and dose administrations 
throughout the entire study treatment period and for the follow-up period.  Any further postponement(s) will induce 
additional delay(s) that must be added.
 
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6.4 Outline of study procedures
The timing of scheduled assessments for the 4 ASCI administration cycles is shown in 
Table 6 to Table 9.  The procedures during follow-up are described in Table 10.
Table 6: List of study procedures for Cycle 1 (including screening)
Visit no.
Screening a 1
2
3
4
5
6
7
Intervals between study 
treatment administrations hj
2 weeks
Weeks after first ASCI 
administration
-
0
2
4
6
8
10
12
NY-ESO-1 ASCI admin no.
-
1
2
3
4
5
6
Informed consent
●
Addendum to informed consenti
●
●
●
●
●
●
●
Biopsy for NY-ESO-1 expression
●
Inclusion/exclusion criteria
●
●
Medical history
●
Clinical evaluations
Physical examination b
●
●
●
●
●
●
●
Imaging procedures
●c
●c
Tumor response assessment
●
Safety assessments
(Serious) Adverse Events recorded 
d
●
●
●
●
●
●
●
●
Potential immune-mediated 
diseases (pIMDs) recorded
●
●
●
●
●
●
●
Laboratory assessments
Pregnancy test e
●
●
●
●
●
Urine chemistry tests f
●
●
HIV status g
●
Hematological tests f
●
●
●
●
Blood chemistry tests f
●
●
●
●
Autoimmunity  tests f
●
●
Coagulation tests f
●
●
●
●
Serum sampling collection g
PBMC collection h
Criteria for permanent stopping or 
postponement of study treatment
●
●
●
●
●
Recording of concomitant 
medication
●
●
●
●
●
●
●
Note: For patients who are found to be NY-ESO-1 negative, only the following procedures need to be performed for 
this protocol: Informed consent, tumor biopsy, NY-ESO-1 expression testing, inclusion and exclusion criteria.  All other 
procedures should only be performed if clinically indicated and do not need to be recorded on the eCRF.
a
Screening visit/period is to take place a maximum of 6 weeks before the first ASCI administration. However:
1
Urine and blood chemistry, hematological, coagulation and autoimmunity tests, within 3 weeks before the first 
study treatment administration;
 
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2
Negative pregnancy test must be obtained within 1 week before the first study treatment administration for women 
of child-bearing potential;
3
Tumor biopsy can be obtained within 12 weeks before the first ASCI administration; in the rare case the analysis 
of the sample would give an inconclusive result, the patient may be asked to allow a new sample to be collected 
or to allow the use of an already preserved sample to repeat the test. A tumor biopsy performed in the context of 
institution standard practice or another research study may be used for the NY-ESO-1 testing after obtaining the 
Sponsor’s agreement, provided this biopsy was preserved in RNAlater® and was taken no more than 12 weeks 
before the first administration of the study treatment. 
4
Tumor imaging no more than 6 weeks before first ASCI administration. Imaging performed as part of institution 
standard clinical practice or in relation to another research study does not need to be repeated, provided this 
imaging was performed no more than 6 weeks before the first administration of the study treatment. 
5
HIV test within 3 weeks before the first ASCI administration, mandatory in Germany only (refer to Section 13.2).
b
Complete physical examination. Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers (only during the tumor assessment visit).  Recording of all changes in the patient’s medical condition 
including all adverse events.
c
Chest computer tomography (CT) scan, complete-abdomen CT scan and any other examination medically 
indicated to assess tumor dissemination.  A contrast-enhanced CT scan or magnetic resonance imaging (MRI) of 
the brain is mandatory at the Screening Visit; while at subsequent visits it should only be performed in case of 
evocative neurological symptoms.  Color photography or ultrasound of skin/node/subcutaneous lesions must also 
be performed if applicable. If a photography presents a characteristic area rending possible the patient 
identification, photography will not be loaded and will need to be sent to the site according to GSK PII 
management procedure.
d
Refer to Section 9.3.  At the screening visit only SAEs related to study participation and GSK concomitant 
medication will be recorded.
e
For women of child-bearing potential only; urine or blood test according to local practice; a negative result must be 
obtained at screening, before the first ASCI administration and after 2, 6 and 10 weeks of treatment (at Visits 1, 2, 
4 and 6) to allow continued recNY-ESO-1 + AS15 administrations.
f
Refer to Section 6.7.2.
g
Serum collection: collect 2 x 5 mL blood in dry tubes.  For anti-NY-ESO-1 and anti-CpG7909 antibody humoral 
immunity response.
h
Whole blood for peripheral blood mononuclear cells (PBMC) collection:  PBMC will be obtained from 150 mL of 
venous blood.  PBMC will be used for the cellular immune response analysis.  Heparinized tubes will be shipped 
to GSK Biologicals or another laboratory, according to the instructions given to the investigation site.
g
HIV test is mandatory to determine the HIV status (positive - negative) of patients in Germany only. Patients with 
known HIV-positive status do not need to be re-tested. Patients tested for HIV prior to signature of the ICF for 
study participation do not need to repeat the test, given that it was performed within three weeks of enrolment 
(refer to Section 13.2).
h
In case a study visit needs to be delayed for any reason, the date for the visits following the delayed visit 
will be determined by the “intervals between study treatment administrations” rather than by the “weeks 
after first study treatment administration”.
I
Signature of the ICF addendum must be the first procedure performed for patients returning for their first 
study visit after approval of Protocol Amendment 3. This only has to be done once. The study will 
continue only with patients from the active treatment group who will decide to stay in the study. Signature 
of the ICF addendum will be documented in the eCRF. 
 
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Table 7: List of study procedures for Cycle 2
Visit no.
8
9
10
11
12
13
14
15
Intervals between study treatment 
administrationsf
3 weeks
Weeks after first ASCI administration
hf
14
17
20
22
23
26
29
31
NY-ESO-1 ASCI admin no.
7
8
9
10
11
12
Addendum to informed consentg
●
●
●
●
●
●
●
●
Clinical evaluations
Physical examination a
●
●
●
●
●
●
Imaging procedures b
●
●
Tumor response assessment
●
●
Safety assessments
(Serious) Adverse Events recorded c
●
●
●
●
●
●
●
●
pIMDs recorded
●
●
●
●
●
●
●
●
Laboratory assessments
Pregnancy test d
●
●
●
●
●
●
Urine chemistry tests e
●
●
●
Hematological tests e
●
●
●
Blood chemistry tests e
●
●
●
Autoimmunity tests e
●
Coagulation tests e
●
●
●
Serum sampling collection f
PBMC collection g
Criteria for permanent stopping or 
postponement of study treatment
●
●
●
●
●
●
Recording of concomitant medication
●
●
●
●
●
●
●
●
a
Complete physical examination.  Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers (only during the tumor assessment visit).  Recording of all changes in the patient’s medical condition 
including all adverse events.
b
At Visits 11 and 15: chest, complete-abdomen CT scans, and any other examination medically indicated to assess 
tumor dissemination are mandatory.  Brain contrast-enhanced CT scan (or MRI) should be performed only in case 
of evocative neurological symptoms.  Color photography or ultrasound of skin / node / subcutaneous lesions must 
also be performed if applicable. If a photography presents a characteristic area rending possible the 
patient identification, photography will not be loaded and will be sent to the site according to GSK PII 
management procedure.
c
Refer to Section 9.3.
d
For women of child-bearing potential only; urine or blood test according to local practice; a negative result must be 
obtained before each ASCI treatment (at Visits 8-10 and 12-14) to allow continued recNY-ESO-1 + AS15 
administrations.
e
Refer to Section 6.7.2.
f
Serum collection: collect 2 x 5 mL blood in dry tubes.  For anti-NY-ESO-1 and anti-CpG7909 antibody humoral 
immunity response.
g
Whole blood for PBMC collection:  PBMC will be obtained from 150 mL of venous blood.  PBMC will be used for 
the cellular immune response analysis.  Heparinized tubes will be shipped to GSK Biologicals or another 
laboratory according to the instructions given to the investigation site.
f
In case a study visit needs to be delayed for any reason, the date for the visits following the delayed visit 
will be determined by the “intervals between study treatment administrations” rather than by the “weeks 
after first study treatment administration”.
 
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g
Signature of the ICF addendum must be the first procedure performed for patients returning for their first 
study visit after approval of Protocol Amendment 3. This only has to be done once. The study will 
continue only with patients from the active treatment group who will decide to stay in the study. Signature 
of the ICF addendum will be documented in the eCRF.
Table 8: List of study procedures for Cycle 3
Visit no.
16
17
18
19
20
Intervals between study treatment 
administrations g
6 weeks
Weeks after first ASCI administration g
33
39
45
51
54
NY-ESO-1 ASCI admin no.
13
14
15
16
Addendum to informed consenth
●
●
●
●
●
Clinical evaluations
Physical examination a
●
●
●
●
Imaging procedures b
●
Tumor response assessment
●
Safety assessments
(Serious) Adverse Events recorded c
●
●
●
●
●
pIMDs recorded
●
●
●
●
●
Laboratory assessments
Pregnancy test d
●
●
●
●
Urine chemistry tests e
●
●
●
●
Hematological tests e
●
●
●
●
Blood chemistry tests e
●
●
●
●
Autoimmunity tests e
●
Coagulation tests e
●
●
●
●
Serum sampling collection f
PBMC collection g
Criteria for permanent stopping or 
postponement of study treatment
●
●
●
●
Recording of concomitant medication
●
●
●
●
●
Conclusions for main analysis i
●
a.
Complete physical examination.  Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers (only during the tumor assessment visit).  Recording of all changes in the patient’s medical condition 
including all adverse events.
b.
At Visit 20: chest, complete-abdomen CT scans, and any other examination medically indicated to assess tumor 
dissemination are mandatory.  Brain contrast-enhanced CT scan (or MRI) should be performed only in case of 
evocative neurological symptoms.  Color photography or ultrasound of skin / node / subcutaneous lesions must 
also be performed if applicable. If a photography presents a characteristic area rending possible the 
patient identification, photography will not be loaded and will be sent to the site according to GSK PII 
management procedure.
c.
Refer to Section 9.3.
d.
For women of child-bearing potential only; urine or blood test according to local practice; a negative result must be 
obtained before each ASCI treatment (at Visits 16-19) to allow continued recNY-ESO-1 + AS15 administrations.
e.
Refer to Section 6.7.2.
f.
Serum collection: collect 2 x 5 mL blood in dry tubes.  For anti-NY-ESO-1 and anti-CpG7909 antibody humoral 
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g.
Whole blood for PBMC collection:  PBMC will be obtained from 150 mL of venous blood. PBMC will be used for 
the cellular immune response analysis.  Heparinized tubes will be shipped to GSK Biologicals or another 
laboratory, according to the instructions given to the investigation site.
f
Main analysis will be performed when all patients have either completed the treatment up to Cycle 3 or have 
withdrawn from study treatment.
g
In case a study visit needs to be delayed for any reason, the date for the visits following the delayed visit 
will be determined by the “intervals between study treatment administrations” rather than by the “weeks 
after first study treatment administration”.
h
Signature of the ICF addendum must be the first procedure performed for patients returning for their first 
study visit after approval of Protocol Amendment 3. This only has to be done once. The study will 
continue only with patients from the active treatment group who will decide to stay in the study. Signature 
of the ICF addendum will be documented in the eCRF. 
(Amended 03 September 2014)
Table 9: List of study procedures for Cycle 4
Visit no.
21
22
23
24
25
26
27
28
29
Date of Visit
V 19 
+ 3 m
V 21 
+ 3 m
V 22 
+ 3 m
V 23 
+ 3 m
V 24 
+ 6 m
V 25 
+ 6 m
V 26 
+ 6 m
V 27 
+ 6 m
V 28 + 30 
days a
NY-ESO-1 ASCI admin 
no.
17
18
19
20
21
22
23
24
Concluding 
visit b
Addendum to informed 
consenth
●
●
●
●
●
●
●
●
Clinical evaluations
Physical examination c
●
●
●
●
●
●
●
●
●
Imaging procedures d
●
●
●
●
●
●
Tumor response 
assessment
●
●
●
●
●
●
Safety assessments
(Serious) Adverse Events 
recorded e
●
●
●
●
●
●
●
●
●
pIMDs recorded
●
●
●
●
●
●
●
●
●
Laboratory assessments
Pregnancy test f
●
●
●
●
●
●
●
●
Urine chemistry tests g
●
●
●
●
●
●
●
Hematological tests g
●
●
●
●
●
●
●
●
●
Blood chemistry tests g
●
●
●
●
●
●
●
●
Autoimmunity tests g
●
●
●
●
●
●
●
Coagulation tests g
●
●
●
●
●
●
●
Serum sampling 
collection h
PBMC collection i
Criteria for permanent 
stopping or postponement 
of study treatment
●
●
●
●
●
●
●
●
Recording of concomitant 
medication
●
●
●
●
●
●
●
●
●
Study conclusion
●
 
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m = month, as calculation convention: 1 month is defined as 4 weeks i.e. 28 days during the treatment phase.
a.
The procedures of the concluding visit are also to be carried out when a patient is withdrawn from study treatment.
b.
For patients who have withdrawn because of disease progression, any resected tumor can be sent to GSK for 
analysis of the gene profile and other appropriate tests upon signature of the adequate ICF by the patient (refer to 
Section 12.2).
c.
Complete physical examination.  Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers (only during the tumor assessment visit).  Recording of all changes in the patient’s medical condition 
including all adverse events.
d.
At Visits 22, 24, 25, 26, 27 and 29: Chest, complete-abdomen CT scans, and any other examination medically 
indicated to assess tumor dissemination are mandatory and must be performed within 2 weeks before the 
corresponding ASCI administration/visit.  Brain contrast-enhanced CT scan (or MRI) should be performed only in 
case of evocative neurological symptoms.  Color photography or ultrasound of skin / node / subcutaneous lesions 
must also be performed if applicable. If a photography presents a characteristic area rending possible the 
patient identification, photography will not be loaded and will be sent to the site according to GSK PII 
management procedure.
e.
Refer to Section 9.3.
f.
For women of child-bearing potential only; urine or blood test according to local practice; a negative result must be 
obtained before each ASCI treatment (at Visits 21-28) to allow continued recNY-ESO-1 + AS15 administrations.
g.
Refer to Section 6.7.2.
h
Serum collection: collect 2 x 5 mL blood in dry tubes.  For anti-NY-ESO-1 and anti-CpG7909 antibody humoral 
immunity response.
i
Whole blood for PBMC collection: PBMC will be obtained from 150 mL of venous blood.  PBMC will be used for 
the cellular immune response analysis.  Heparinized tubes will be shipped to GSK Biologicals or another 
laboratory, according to the instructions given to the investigation site.
h.
Signature of the ICF addendum must be the first procedure performed for patients returning for their first 
study visit after approval of Protocol Amendment 3. This only has to be done once. The study will 
continue only with patients from the active treatment group who will decide to stay in the study. Signature 
of the ICF addendum will be documented in the eCRF. 
 
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Table 10: List of study procedures during follow-up
Visit No.
F1
F2
F3
F4
Months after Concluding Visit a
Clinical evaluations
Physical examination b
Imaging procedures c
Tumor response assessment
Safety assessments
SAE related to study participation and GSK 
concomitant medication d
pIMDs recorded
Recording of pregnancy
Laboratory assessments
Autoimmunity tests e
Serum sampling collection f
PBMC collection g
Study follow-up conclusion
b.
Months are defined here as calendar months.
c.
Complete physical examination.  Superficial cutaneous lesions must be measured by use of a millimeter ruler or 
calipers.  Recording of all changes in the patient’s medical condition including all adverse events.
d.
Chest, complete-abdomen CT scans, and any other examination medically indicated to assess tumor 
dissemination are mandatory and must be performed within 2 weeks before the corresponding ASCI 
administration/visit.  Brain contrast-enhanced CT scan (or MRI) should be performed only in case of evocative 
neurological symptoms.  Color photography or ultrasound of skin / node / subcutaneous lesions must also be 
performed.
e.
Refer to Section 9.3.
f.
Refer to Section 6.7.2.
g.
Serum collection: collect 2 x 5 mL blood in dry tubes.  For anti-NY-ESO-1 and anti-CpG7909 antibody humoral 
immunity response.
h.
Whole blood for PBMC collection: PBMC will be obtained from 150 mL of venous blood. PBMC will be used for 
the cellular immune response analysis.  Heparinized tubes will be shipped to GSK Biologicals or another 
laboratory, according to the instructions given to the investigation site.
6.5.2.1 NY-ES0-1 expression screening of tumor lesions

The tumor tissue has been preserved in RNAlater® RNAlater immediately after the 
surgery and the amount of tissue available must comply with the protocol 
requirements (see the SPM).
6.5.2.6 Tumor imaging and assessment
In order to enroll a patient in the trial, this tumor imaging should confirm that the patient 
is not presenting visceral metastasis.  Color photography or ultrasound of 
skin/node/subcutaneous lesions must also be performed if applicable.
 
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Source documentation that is considered necessary by GSK Biologicals for efficacy or 
safety evaluation such as but not limited to pictures, CT-scans, histology, laboratory 
reports will be collected and upon request sent to GSK Biologicals for review, ensuring 
that patient confidentiality is maintained.
6.5.3.4. Blood sampling for safety or immune response assessments
As specified in the lists of study procedures in Section 6.4, blood samples are to be taken 
during certain study visits. Refer to the Module on Biospecimen Management in the SPM 
for general handling of blood samples.
As of Protocol Amendment 3, no more blood samples will be collected for research 
purpose, i.e. blood samples taken for humoral immunological response and PBMC 
collection. For each blood sample already collected in the scope of this study and not 
tested yet, testing will not be performed by default, except if a scientific rationale 
remains relevant. Blood samples for safety assessments will continue to be collected 
and analysed.

Serum sample - a volume of 2 x 5 mL of whole blood should be drawn from patients 
for anti-NY-ESO-1 and anti-CpG7909 humoral immune response analysis at each 
predefined timepoint.  After centrifugation, serum samples should be kept at –20°C 
until shipment.

A volume of at least 150 mL of whole blood should be drawn from patients for 
PBMC analysis of cell-mediated immune (CMI) response at each predefined time 
point.  The blood should be stored at the investigator’s site at room temperature and 
it must not be centrifuged.  Samples will be shipped at room temperature (20 to 
25°C) to the designated laboratory for cell separation to be performed within 24 
hours.
6.5.4.1 Patients who received all the scheduled doses
Chest CT scan, complete-abdomen CT scan, and any other examination medically 
indicated to assess tumor dissemination.  A contrast-enhanced CT scan or MRI of the 
brain should only be performed in case of evocative neurological symptoms.  Color 
photography or ultrasound of skin/node/subcutaneous lesions must also be performed if 
applicable.
At the visit, the following procedures described above will be performed: physical 
examination; recording any AEs and SAEs, pIMDs, and concomitant medications; taking 
a urine sample for urine chemistry tests; taking a blood sample for hematological tests, 
blood chemistry tests, autoimmunity tests, coagulation tests. , serum sampling for 
humoral immunity tests and PBMC collection for cellular immunity tests.
6.5.4.2. Patients withdrawn before the end of the scheduled doses
The following procedures will be performed no more than two weeks before this visit.  If 
imaging has been performed less than 6 4 weeks before, this need not be repeated:
 
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
Chest CT scan, complete-abdomen CT scan, and any other examination medically 
indicated to assess tumor dissemination.  A contrast-enhanced CT scan or MRI of the 
brain should only be performed in case of evocative neurological symptoms.
During the visit, the following procedures described above will be performed: physical 
examination including the recording of the ECOG performance status; recording any 
(serious) AEs, pIMDs and concomitant medications; taking a urine sample for urine 
chemistry tests; taking a blood sample for hematological tests, blood chemistry tests, 
autoimmunity tests, coagulation tests, serum sampling for humoral immunity tests and 
PBMC collection for cellular immunity tests.
6.5.4.2. Procedures during follow-up phase
Patients, including those having withdrawn prematurely before having received all the 
scheduled ASCI injections, will be requested to attend follow-up visits every 3 months 
for the first year after the concluding visit.  See Table 10 for the list of study procedures 
during the follow-up period and Sections 6.7.2 and 6.7.3 for details of the laboratory 
assays and immunological readouts conducted during the follow-up period.
There are 2 exceptions to this schedule of follow-up visits:

Patients who have withdrawn from the study because of withdrawal of consent will 
not be contacted again;

Patients who were withdrawn from study treatment because of disease progression or 
who progressed during the post-treatment study period will not be asked to return for 
complete study follow-up visits.  These patients will be followed for survival by 
means of bi-annual contacts (e.g., by phone). If a second-line anti-cancer treatment is 
administered, the patient’s best clinical response to this will be assessed, e.g., during 
the patient’s standard visits to the institution.
Note: Patients withdrawn from the study treatment because of disease progression who 
do not receive any other anti-cancer treatment should be followed according to the 3-
monthly follow-up visits schedule.
Also the imaging procedures and response assessments are conducted 2 weeks before 
follow-up visits 2 and 4 rather than at the time of the visit.
6.5.4.3 Study conclusion
The study conclusion will be made at follow-up visit 4 the Concluding Visit. The 
procedures to be performed are the same as those described for the follow-up period 
(Section 6.5.5).
6.6.1.1.2 Methods of measurement
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.
 
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6.6.1.2.3. Evaluation of best overall response
Summary for evaluation of best overall response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR (or NA)
No
CR
CR
Incomplete response / SD
No
PR
PR
Any response other than PD
No
PR
SD
Any response other than PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Not all 
evaluated
Any response other than PD
No
NE
Any response 
other than PD
Not all evaluated
No
NE
Any
Any
Yes
PD
Abbreviations: CR: complete response; PR: partial response; SD: stable disease; PD : progressive 
disease; NA: not applicable; NE: non-evaluable.
6.6.2.1.1. Definitions
All measurements should be recorded in metric notation by use of a ruler or calipers.  
Baseline evaluations should be performed as closely as possible to the start of treatment 
(could be performed at Visit 1) and never more than 6 4 weeks before the start of the 
treatment. (Amended 03 September 2014).
6.6.2.2.1. Baseline documentation of target and non-target lesions
All other lesions should be identified as non-target lesions and should also be recorded 
and evaluated at baseline as well as at each further visit including a tumor response 
assessment. They should be followed as “present” or “absent” at baseline and followed 
using the RECIST criteria at further visits. Independently to this follow-up assessment, 
any new lesion will be recorded as non-target lesion.
6.6.5.2 Mixed response for disease not evaluable according to RECIST criteria

The appearance of new lesions in otherwise PR status of the LD of target lesions will 
be classified as “PR with new lesion or more.
6.7 Biological sample handling and analysis
As of Protocol Amendment 3, no more biological samples will be collected for research 
purpose. For each biological sample already collected in the scope of this study and not 
tested yet, testing will not be performed by default, except if a scientific rationale 
remains relevant. In this case, testing will be done in compliance with the protocol and 
the ICF signed by the patient as described in the sub-sections below.
 
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6.7.2 Hematology, Serum chemistry and urine tests
Table 11: Hematology, Serum Chemistry, Urine tests
Sample type
System
Component
Scale
Timing
HEMATOLOGY
Blood (5 mL)
Whole 
blood
Hemoglobin
Quantitative
During screening
Cycle 1: Visits 1, 3 and 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 21 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment
Hematocrit
Complete blood cell count
Total and differential white 
blood cell count
Platelets
BIOCHEMICAL VALUES
Blood (5 mL)
Serum
Sodium
Quantitative
During screening
Cycle 1: Visits 1, 3 and 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 21, 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment
Potassium
Calcium
Lactate dehydrogenase 
(LDH)
Creatine kinase (CK)
Total protein4
Albumin4
HEPATIC FUNCTION
Blood (5 mL)
Serum
Aspartate aminotransferase 
(ASAT)
Quantitative
During screening
Cycle 1: Visits 1, 3 and 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 21, 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment
Alanine aminotransferase 
(ALAT)
Alkaline phosphatase
Gamma-glutamyl 
transpeptidase (GT)
Serum bilirubin4
Direct bilirubin3,4
RENAL FUNCTION
Blood (5 mL)
Serum
Microalbuminuria4 (cf. 
urinalysis)
Quantitative
During screening
Cycle 1: Visit 6
Cycle 2: Visits 10 and 14
Cycle 3: Visits 17 and 19
Cycle 4: Visits 22, 25, and 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment
Blood urea nitrogen (BUN)5
Creatinine
COAGULATION
Blood (5 mL)
Serum
Prothrombin Time (PT)
Quantitative
During screening
Cycle 1: Visits 1, 3 and 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment(s)
Activated Partial 
Thromboplastin Time 
(APTT)
 
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Sample type
System
Component
Scale
Timing
AUTOIMMUNITY
Blood (5 mL)
Serum
Anti-nuclear antibody (ANA) 
1
Quantitative
During screening
Cycle 1: Visit 6
Cycle 2: Visit 14
Cycle 3: Visit 19
Cycle 4: Visits 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment(s)
Follow-up Visits: F2, F4
PREGNANCY TESTING (MANDATORY) 2
Blood (5 ml) 
or urine 
according to 
local practice
Serum or 
urine
According to local practice
Ordinal
During screening
Cycle 1: Visits 1, 2, 4, and 6
Cycles 2 - 4: prior to each ASCI 
administration
URINALYSIS
Urine
Urine
Protein (test strip)
Ordinal
During screening
Cycle 1: Visit 6
Cycle 2: Visits 8, 10 and 14
Cycle 3: Visits 16 to 19
Cycle 4: Visits 22, 24 to 28
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn 
from study treatment(s)
Glucose (test strip)
pH (test strip)
Quantitative
Erythrocyte (Red Blood Cells 
- test strip)
Microalbuminuria3,4
(densitometric evaluation of 
urinary sediment)
1.
ANA test will be carried out by immunofluorescence on HEPG2 cells. In case anti-nuclear antibodies are detected, 
further analysis will be performed by immunodot and/or enzyme-linked immunosorbent Assay (ELISA) to identify 
the auto-target antigen.
2.
For women of child-bearing potential only.
3.
It is mandatory to measure direct bilirubin/microalbuminurea, only when bilirubin/albumin  testing reveals 
abnormal results. 
4.
A quantitative or qualitative test can be performed at the investigator’s  discretion. In cases where 
positivea qualitative results are received, test a quantitative test also needs to be performed. It is 
sufficient to do only one test for protein in Urine, if this test is sensitive enough.  
5.
Measurement of serum urea (azotemia) is allowed instead of measurement of BUN. The choice between 
these tests is left at the investigator’s discretion. If measurements are in serum urea, they need to be 
converted to BUN. The conversion has to made according to the following formula: Urea [mg/dL]= BUN 
[mg/dL] * 2.14. BUN can be expressed in either in mg/dL or in mmol/L. If Serum Urea has been expressed 
in mmol/L, the conversion factor is 1 and as the formula is: SU (mmol/L) = BUN (mmol/L).
6.7.3 Molecular, immunological and translational research read outs
Note that, as of Amendment 3, the decision was taken not to perform further testing on 
biological samples already collected in this study by default, except if a scientific 
rationale remains relevant. No further blood samples for protocol research purposes 
will be collected.
 
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Table 12 Overview of molecular and immunological read-outs and translational 
research
NY-ESO-1 SCREENING (MANDATORY)
Test
Sample Type
Laboratory
Timing
NY-ESO-1 expression testing
(see also Section 6.7.3.1)
Fresh tissue 
sample (in 
RNAlater® or 
equivalent)
GSK Biologicals or 
contracted lab a
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection.
IMMUNOLOGICAL READ-OUTS (MANDATORY)
Test
Sample Type Laboratory
Timing
Humoral immunity
(see Section 6.7.3.2.1)
Serum
(2 x 5 ml) b
GSK Biologicals or 
contracted lab a
Cycle 1: Visits 1, 3, 5 to 7
Cycle 2: Visit 14
Cycle 3: Visit 19
Cycle 4: Visits 22, 24 to 27
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn from 
study treatment(s)
Follow-up Visits: F1 to F4
Anti-NY-ESO-1 and anti-CpG7909
antibody response
Cellular immunity
(see Section 6.7.3.2.2)
Blood
(150 ml) c
Cycle 1: Visits 1 and 6
Cycle 2: Visit 14
Cycle 3: Visit 19
Cycle 4: Visits 22, 24 to 27
Concluding Visit: Visit 29
Concluding Visit for patients withdrawn from 
study treatment(s)
Follow-up Visits: F2, F4
Cellular (T-cell) response (including 
regulatory T-cell responses)
MANDATORY TRANSLATIONAL RESEARCH (SEE SECTION 7.2.1)
Test
Sample Type Laboratory
Timing
Gene profiling of the tumor
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) 
and FFPE 
tissue
(if available) d
GSK Biologicals or 
contracted lab a
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection.
 
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OPTIONAL TRANSLATIONAL RESEARCH (SEE SECTION 7 EXCEPT 7.2.1)
Test
Sample Type
Laboratory
Timing
Expression analysis of
NY-ESO-1 and other tumor 
antigens (e.g., MAGE-A3, 
PRAME, LAGE-1, MAGE-C2 and 
WT1)
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue
(if available) d
GSK 
Biologicals or 
contracted
lab a
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection.
Natural immunogenicity and
Antigen spreading
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue
(if available) d ,
serum and blood
b, c
During screening (initial biopsy).
In case of additional tumor biopsy or tumor 
resection.
May be performed on any of the blood 
samples taken for the humoral and cellular 
immunity tests
Gene profiling of the immune 
response
Blood
(150 ml) c
May be performed on any of the blood 
samples taken for the cellular immunity tests 
(PBMC collection)
Proteomic profiling
Fresh tissue 
sample (in 
RNAlater® or 
equivalent) and 
FFPE tissue (if 
available) d,
serum and blood 
b, c
During screening (initial biopsy) or on any of 
the blood samples taken for the humoral and 
cellular immunity tests
Tumor infiltrating lymphocytes 
(including T regulatory cells and 
other immune cellular entities)
Either fresh 
tissue sample (in 
RNAlater® or 
equivalent) or 
FFPE tissue
(if available) d
During screening (initial biopsy). In case of 
additional tumor biopsy or tumor resection
DNA methylation status of NY-
ESO-1, other antigens and 
predictive genes, in addition to 
immunoregulatory genes
Either fresh 
tissue sample (in 
RNAlater® or 
equivalent) or 
FFPE tissue (if 
available) d,
serum and blood
b, c
During screening (initial biopsy) or in case of 
additional tumor biopsy or tumor resection 
(disease progression), or on any of the blood 
samples taken for the humoral and cellular 
immunity tests
Pharmacogenetics analyses
Tumor samples 
and blood
Preferably on blood collected at Visit 1. On 
tumor cells from screening or from additional 
lesions
a GSK Biologicals laboratory or a validated laboratory designated by GSK Biologicals.
b 2 x 5 ml of blood will be used for both anti-NY-ESO-1 and anti-CpG7909 antibody responses; and for the 
optional translational research (as applicable).
c A total of 150 ml of blood will be used for cellular immunological read-outs; and for the optional translational
research (as applicable).
d FFPE tissue is only to be collected from patients with sufficient tumor material from the same lesion to provide a
fresh sample and a FFPE sample.  GSK Biologicals or a contracted laboratory will require a block of at least
7 mm3 or 15 slides of 10 m each.
 
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6.7.3.2 Immunological read-outs
6.7.3.2.1. Antibody response to the ASCI antigens
Currently, testing of serum to assess antibody mediated immune responses has been 
performed for a subset of samples collected in this study. Further testing will only be 
performed if a scientific rationale remains relevant in compliance with the protocol 
and the ICF signed by the patient as described in the sub-sections below.
The antibody response to the NY-ESO-1 antigen and to CpG7909 will be assessed for all 
patients enrolled into the study.
Specific anti-NY-ESO-1 and anti-CpG7909 antibodies pre-existing and induced by the 
recNY-ESO-1 + AS15 ASCI will be measured by ELISA or upgraded techniques, and 
the results will be provided in EU/mL or other appropriate units.  This can be done using 
either the NY-ESO-1 recombinant protein or NY-ESO-1-derived peptides spanning the 
entire NY-ESO-1 sequence as coating antigen.  A patient will be considered as 
seropositive if the antibody titer is superior or equal to the assay cut-off value and at least 
twice the patient’s value at baseline.
6.7.3.2.2. Cellular immune response to the ASCI antigens
Currently, testing of PBMCs to assess cell-mediated immune responses has been 
performed for a subset of samples collected in this study. Further testing will only be 
performed if a scientific rationale remains relevant in compliance with the protocol 
and the ICF signed by the patient as described in the sub-sections below.
1. PBMC processing and analysis
The cell-mediated immune (CMI) response pre-existing or induced by the ASCI 
administrations will be assessed for all patients enrolled into the study.
2. Cellular response to the recNY-ES0-1 + AS15 ASCI
So far, in contrast to serology, there is no standard or validated technique available to 
monitor the T-cell response induced by immunization with a recombinant protein in 
cancer patients.  The techniques described in this section may be updated to the best 
available at the time of analysis.  Dependent on the immunogenicity of the tumor-antigen 
targeted, the T-cell responses can either be measured directly ex vivo or will require a 
step of specific in vitro re-stimulation of the T-cells.  The presence of specific cells can 
may be documented by measuring the production of anti-inflammatory cytokines, by 
measuring a cytolytic activity (e.g. by detection of Granzyme, Perforin or CD107a 
marker), specific activation markers upon antigen encounter or by tetramer staining using 
known T cell-epitopes using appropriate assays.  The percentage of those T-cells can then 
be determined by ELISPOT or by Fluorescence-Activated Cell Sorter (FACS), after 
surface and/or intracellular cytokine staining (Amended 03 September 2014).
Regulatory CD4 T-cells (Tregs) that express the transcription factor Foxp3 have been 
shown to accumulate in the intratumoral areas of metastatic melanoma tumors, and may 
play a role in immune suppression of anti-tumor immune responses [Ahmadzadeh, 2008].  
 
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In a separate study, CD4+ Tregs that were stimulated to proliferate by two NY-ESO-1 
peptides, were identified in the blood of patients with metastatic melanoma [Vence, 
2007].  Both NY-ESO-1 peptides could induce IL-10 secretion in these CD4+ Tregs and a 
proportion of these cells also expressed high levels of Foxp3.  The presence of regulatory 
T-cell populations, defined by flow cytometry markers such as CD4+, CD25+ and Foxp3+
and/or the IL10 secreting regulatory T-cells will be assessed in terms of their frequency 
and functionality using PBMCs or whole blood, if available.
Briefly, the characterization of the T-cell response will may be performed as follows:

To assess regulatory T-cells (Tregs), the most updated techniques will be used, e.g. 
enumeration of Tregs using a panel of antibody against e.g. CD3, CD4, CD25, 
Foxp3, CD39, CTLA4, GITR, PD1, ICOS, and OX40; enumeration of antigen-
specific Tregs using activation markers specifically expressed on antigen-specific 
Treg (e.g. CD 69, PD-1) or in association to HLA Class II tetramers.  The antigen 
specificity of Tregs can be assessed with epitopes from the NY-ESO-1 or from 
control antigens such as tetanus toxoid antigen or CMVpp65 (the most immunogenic 
protein of cytomegalovirus).  The impact of Treg depletion on antigen specific 
proliferation and cytokine secretion, as well as IL10 or other suppressive cytokines 
secretion in immune response to various antigens can also be assessed.  The type and 
number of read-outs will depend on the amount of PBMCs available for this.
The NY-ESO-1 cellular response will be assessed before immunization (to determine 
baseline values) and at several time points in each cycle of immunization and twice 
during follow-up (see Table 6 to Table 9).
7. TRANSLATIONAL RESEARCH
As of Amendment 3, the decision was taken not to perform further testing on biological 
samples already collected in this study by default, except if a scientific rationale 
remains relevant. In case testing would be performed in the future, testing will be done 
in compliance with the protocol and the ICF signed by the patient as described in the 
sub-sections below.
This section provides details on the translational research that may be done on the 
biological samples collected during this study.  These different tests may will only be 
performed on biological samples from patients who voluntarily gave their consent to 
these specific assessments on the ICF, unless specified as mandatory for participation in 
the clinical study (see Section 7.2.1).
 
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7.3 Natural immunity and antigen spreading induced by the recNY-ES0-1 + AS15 
ASCI
On the basis of these findings, we will assess whether administration of the recNY-ESO-
1 + AS15 ASCI is able to induce antibodies and T-cells against other tumor antigens that 
are co-expressed by the patient's tumor (e.g. MAGE-C2, MAGE-A3, LAGE-1, WT1, 
PRAME) in addition to tissue differentiation or overexpressed tumor antigens such as, for 
instance, Melan-A/MART-1 or gp100.  The expression of these tumor antigens in the 
tumor presenting at baseline or in any progressive lesion(s) may will be assessed as well
by quantitative RT-PCR or any updated technique at the time of the analysis.  Validation 
of tumor antigen expression (including NY-ESO-1) at the protein level may also be 
performed by IHC or other proteomic analytical method.
7.4 Gene profiling of immunological response to the recNY-ES0-1 + AS15 ASCI
No additional blood sampling is needed as this gene profiling of the immune response 
may be performed on any of the blood samples collected for the analysis of the humoral 
or cellular immune response to the ASCI (PBMC collection).  Gene expression profiling 
will be performed on total RNA extracted from whole blood or from purified populations 
(CD4+ T-cells, CD8+ T-cells, antigen-presenting cells) from PBMC by hybridization to a 
gene expression chip with a locked set of genes (e.g., Affymetrix or other commercial 
chips) or by the use of epigenetic markers (e.g. methylation). Further gene expression 
profiling and validation may be performed by Q-RT-PCR.
7.5 Proteomic profiling
Using appropriate standard techniques the serum or tumor proteome may be analyzed by 
differential proteomics. This will identify useful bio-markers for responsiveness to the 
NY-ESO-1 antigen.
7.7 DNA promoter methylation analysis of NY-ESO-1 and other tumor antigens
In addition, methylation status of regulatory regions of genes encoding transcriptional 
factors relevant in the regulation of immune response (such as Foxp3, GATA-3, T-bet, 
ROR-T expressed by helper CD4 + T cells) might be analyzed. In the case of Foxp3 
evaluation, the presence and characterization of circulating T regulatory cells may be 
evaluated in parallel or independently of the realization of these transcriptional 
profiling.
 
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9 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
9.1.3 Potential immune mediated diseases
Table 13 Examples of AEs to be recorded as pIMDs
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders

Cranial nerve disorders, 
including paralyses/paresis 
(e.g. Bell’s palsy)

Optic neuritis

Multiple sclerosis 

Transverse myelitis

Guillain-Barré syndrome, 
including Miller Fisher 
syndrome and other variants

Acute disseminated 
encephalomyelitis, including 
site specific variants: e.g. 
non-infectious encephalitis, 
encephalomyelitis, myelitis, 
myeloradiculoneuritis

Myasthenia gravis, including 
Lambert-Eaton myasthenic 
syndrome 

Immune-mediated peripheral 
neuropathies and 
plexopathies,  (including 
chronic inflammatory 
demyelinating 
polyneuropathy, multifocal 
motor neuropathy and 
polyneuropathies associated 
with monoclonal 
gammopathy).

Narcolepsy

Systemic lupus 
erythematosus  and 
associated conditions

Systemic Scleroderma 
(Systemic sclerosis), 
including diffuse systemic 
form and CREST syndrome

Idiopathic inflammatory
myopathies, including 
Dermatomyositis, 
Polymyositis,

Antisynthetase syndrome

Rheumatoid arthritis and 
associated conditions 
including Juvenile chronic 
arthritis and Still’s disease)

Polymyalgia rheumatica 

Spondyloarthritis, including 
ankylosing spondylitis, 
reactive arthritis (Reiter's 
Syndrome) and  
undifferentiated 
spondyloarthritis

Psoriatic arthropathy

Relapsing polychondritis

Mixed connective tissue 
disorder

Psoriasis

Vitiligo

Erythema nodosum

Autoimmune bullous skin 
diseases (including 
pemphigus, pemphigoid 
and dermatitis 
herpetiformis)

Alopecia areata

Lichen planus

Sweet’s syndrome

Localised Scleroderma 
(Morphoea)
Liver disorders
Gastrointestinal disorders
Endocrine disorders

Autoimmune hepatitis

Primary biliary cirrhosis

Primary sclerosing 
cholangitis

Autoimmune cholangitis.

Inflammatory Bowel 
disease, including Crohn’s 
disease, ulcerative colitis, 
microscopic colitis, 
ulcerative proctitis

Celiac disease

Autoimmune pancreatitis

Autoimmune thyroiditis 
(including Hashimoto 
thyroiditis)

Grave's or Basedow’s 
disease

Diabetes mellitus type I

Addison’s disease

Polyglandular autoimmune 
syndrome

Autoimmune hypophysitis
 
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Vasculitides
Blood disorders
Others

Large vessels vasculitis 
including: giant cell arteritis 
such as Takayasu's arteritis 
and temporal arteritis. 

Medium sized and/or small 
vessels vasculitis including: 
polyarteritis nodosa, 
Kawasaki's disease, 
microscopic polyangiitis, 
Wegener's granulomatosis, 
Churg–Strauss syndrome 
(allergic granulomatous 
angiitis), Buerger’s disease 
(thromboangiitis obliterans), 
necrotizing vasculitis and 
anti-neutrophil cytoplasmic 
antibody (ANCA) positive 
vasculitis (type unspecified), 
Henoch-Schonlein purpura, 
Behcet's syndrome, 
leukocytoclastic vasculitis.

Autoimmune hemolytic 
anemia

Autoimmune 
thrombocytopenia

Antiphospholipid syndrome

Pernicious anemia

Autoimmune aplastic 
anaemia

Autoimmune neutropenia 

Autoimmune pancytopenia

Autoimmune 
glomerulonephritis 
(including IgA nephropathy, 
glomerulonephritis rapidly 
progressive, membranous 
glomerulonephritis, 
membranoproliferative 
glomerulonephritis, and 
mesangioproliferative 
glomerulonephritis)

Ocular autoimmune 
diseases (including 
autoimmune uveitis and 
autoimmune retinopathy)

Autoimmune 
myocarditis/cardiomyopathy

Sarcoidosis

Stevens-Johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary 
fibrosis

Goodpasture syndrome

Raynaud’s phenomenon
Neuroinflammatory disorders
Musculoskeletal disorders
Skin disorders
Cranial nerve disorders, including 
paralyses/paresis (e.g. Bell’s palsy), 
and neuritis (e.g. optic neuritis)
Multiple sclerosis (including variants)
Transverse myelitis
Guillain-Barré syndrome, (including 
Miller Fisher syndrome and other 
variants)
Other demyelinating diseases 
(including acute disseminated 
encephalomyelitis)
Myasthenia gravis (including Lambert-
Eaton myasthenic syndrome)
Non-infectious encephalitis/ 
encephalomyelitis 
Neuritis (including peripheral 
neuropathies)
Systemic lupus erythematosus 
Scleroderma (including, CREST 
syndrome and morphoea)
Systemic sclerosis
Dermatomyositis 
Polymyositis 
Antisynthetase syndrome
Rheumatoid arthritis, 
Juvenile chronic arthritis, (including 
Still’s disease)
Polymyalgia rheumatica 
Reactive arthritis
Psoriatic arthropathy
Ankylosing spondylitis (including 
undifferentiated spondyloarthritides)
Relapsing polychondritis
Mixed connective tissue disorder
Psoriasis
Vitiligo
Raynaud’s phenomenon
Erythema nodosum
Autoimmune bullous skin 
diseases (including pemphigus, 
pemphigoid and dermatitis 
herpetiformis)
Cutaneous lupus erythematosus
Alopecia areata
Lichen planus
Sweet’s syndrome
Liver disorders
Gastrointestinal disorders
Metabolic diseases
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Autoimmune cholangitis.
Crohn’s disease 
Ulcerative colitis 
Ulcerative proctitis 
Celiac disease
Autoimmune thyroiditis (including 
Hashimoto thyroiditis)
Grave's or Basedow’s disease
Diabetes mellitus type I
Addison’s disease
 
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Vasculitides
Others

Large vessels vasculitis including: giant cell 
arteritis such as Takayasu's arteritis and temporal 
arteritis. 

Medium sized and/or small vessels vasculitis 
including: polyarteritis nodosa, Kawasaki's 
disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg–Strauss syndrome, 
thromboangiitis obliterans (Buerger’s disease), 
necrotizing vasculitis, allergic granulomatous 
angiitis, Henoch-Schonlein purpura, anti-
neutrophil cytoplasmic antibody positive vasculitis,
Behcet's syndrome, leukocytoclastic vasculitis. 

Vasculitides secondary to other immune mediated 
diseases such as lupus vasculitis and rheumatoid 
vasculitis.

Autoimmune hemolytic anemia

Autoimmune thrombocytopenias

Antiphospholipid syndrome

Pernicious anemia

Autoimmune glomerulonephritis (including IgA 
nephropathy, glomerulonephritis rapidly progressive, 
membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and 
mesangioproliferative glomerulonephritis)

Uveitis

Autoimmune myocarditis/cardiomyopathy

Sarcoidosis

Stevens-johnson syndrome

Sjögren’s syndrome

Idiopathic pulmonary fibrosis

Goodpasture syndrome
9.2.2 Pregnancy
The investigator, or his/her designee, will collect pregnancy information on any patient 
who becomes pregnant while participating in this study from the first ASCI 
administration to the end of the follow-up period until the Concluding Visit.
9.3.1 Time period for detecting and recording adverse events, serious adverse events 
and pregnancies.
 
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Study activity
Screening 
phase
Treatment phase
Concluding 
visit 1
Follow up
ICF signature 
to Visit 1
Visit 1
Visit X
(X= 2 to 28)
30 days after 
last ASCI 
administration
Visit 29
Reporting of AEs and 
SAEs 
Reporting of severe 
toxicity events
Reporting of pIMDs and 
pregnancy
Reporting of SAEs 
related to the study 
treatment
Reporting of SAEs 
related to study 
participation and 
concurrent GSK 
medications, and 
reporting of any fatal 
SAEs, not due to 
disease progression
1.
Or the concluding visit for patients withdrawn from study treatment(s).
10 PATIENT COMPLETION AND WITHDRAWAL
10.1.2. Patient completion of the study
A patient will be considered to have completed the study when he/she has reached the 
end of all scheduled study visits.  The term “study activity” refers to physical visits and 
does not include follow-up contacts (i.e. phone contacts).
Follow-up after completion of ASCI administration should continue for 12 months after 
the concluding visit, unless the patient meets one of the criteria for earlier withdrawal 
(See Section 10.2.1). Once the patient has been withdrawn from the study, the reason 
must be documented in the patient’s medical records and eCRF.
10.2.1. Patient withdrawal from ASCI administration
In this case, a concluding visit will be performed with procedures described in Section 
6.5.4 and the patient will enter the follow-up period with follow-up visits for 1 year after 
completing the Concluding Visit (see Section 6.5.5 for a description of the follow-up 
procedures).
 
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11 DATA EVALUATION CRITERIA FOR EVALUATION OF OBJECTIVES
This section describes the criteria for evaluation of objectives as initially planned. 
However, due to the Protocol Amendment 3, not all analyses described in this section 
will be performed. A detailed description of the analyses that will be done will be given 
in the Statistical Analysis Plan. The final analysis will occur when all patients have 
performed their Concluding Visit or have withdrawn from the study.
11.2.1 Clinical activity endpoints

Progression-free survival (PFS).
PFS is defined as the time from first treatment to either the date of first disease 
progression (PD or SPD) or the date of death (for whatever reason), whichever comes 
first. Patients alive and without disease progression are censored at the date of the last 
visit/contact.
OS is defined as the time from first treatment until death.  Patients alive at the time of 
analysis are censored at the time of the last visit/contact.

The duration of response for patients with CR, PR or SD status.
The duration of the response is defined as time from first objective response or SD 
evaluation to first PD assessment or death.
11.2.3 Immunogenicity endpoints
This is explained in Section 6 and is on the basis of:
1. The anti-NY-ESO-1 and anti-CpG7909 humoral antibody concentration and 
response.
2. The anti-NY-ESO-1 specific cellular (T-cell) response.
11.4.2 According to protocol (ATP) cohort for analysis of immunogenicity
The ATP cohort for analysis of immunogenicity will include all evaluable patients (i.e., 
those meeting all eligibility criteria, who did not report major protocol deviation, who 
have complied with all the procedures defined in the protocol, who have received at 
least the first four study treatment administrations and have provided a result for 
immunogenicity evaluation within the 4 weeks following dose no. 4 and completed Visit 
5). The ATP cohort for analysis of immunogenicity will include all evaluable patients 
(i.e., those meeting all eligibility criteria, who have complied with all the procedures 
defined in the protocol, who have received at least the first four ASCI administrations 
and have completed Visit 5).  For each non-compliant patient, all data collected after 
protocol violation (i.e. treatment administered or blood sample collected too early or too 
late, concomitant medication, medical condition,…) will be eliminated from the ATP 
immunogenicity analyses.
 
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11.5.1 Humoral immunogenicity
2. A seropositive patient is a patient whose anti-NY-ESO-1 and anti-CpG7909
antibody titer is higher than or equal to the cut-off value.
3. Seroconversion in a patient is defined by the increase in antibodies (anti-NY-
ESO-1 and anti-CpG7909) from a titer below the cut-off level before the 
treatment to a titer above the cut-off level following treatment.
11.5.2 Cellular immunogenicity
A patient will be considered as a cellular-mediated immune responder if there is an 
increased amount of NY-ESO-1-specific T-cells after immunization as compared to the 
patient’s baseline value.  These specific T-cells include the CD4+ or CD8+ T-cells 
producing cytokines and/or presenting cytolytic activity (or other, following the updated 
method of detection), as well as specific CD4+ or CD8+ T-cells presenting a particular 
phenotype (effector/memory).
The cut-off above which a patient will be considered to present NY-ESO-1 cellular 
immunogenicityas an immune responder will be determined and specified in the 
Statistical Analysis plan.
Data from analysis of regulatory T-cells will be descriptive.
11.6 Conduct of analysis
Any deviation(s) or change(s) from the original statistical plan outlined in this protocol 
will be described and justified in the statistical analysis plan and/or final study report.
11.6.1 Sequence of analysis
The final analysis will be performed when all patients have done their concluding visit 
or have withdrawn from the study. Due to Protocol Amendment 3, not all analyses 
described in this section will be performed. A detailed description of the analyses that 
will be done will be given in the statistical analysis plan.A main analysis will be 
performed when all patients have either completed the treatment up to Cycle 3 (Visit 20; 
week 54) or have withdrawn from study treatment.  A full clinical study report will be 
written including individual data listings.
A final analysis will be performed when all patients have either completed the treatment 
up to Cycle 4 or have withdrawn from study treatment, and will be reported in annexes to 
the study report.
Follow-up analysis will be performed when all patients have either completed the follow 
up or have withdrawn from study, and will be reported in annexes to the study report.
 
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11.7 Statistical methods
Due to Protocol Amendment 3, not all analyses described in this section will be 
performed. A detailed description of the analyses that will be done will be given in the 
statistical analysis plan.
11.7.2 Analysis of clinical activity

Kaplan-Meier curves will be estimated for TTF, PFS and OS.  If study treatment 
failure does not occur before the patient's last study visit, then the time to study 
treatment failure will be censored at the date of the last visit.  If progression does not 
occur before the patient's last study visit, then the time to progression will be 
censored at the date of the last visit.  If the patient is withdrawn from the study 
treatment for other reasons than progression, then the time to study treatment failure 
or progression will be censored at the date of the last assessment of the patient. For 
OS, patients who are still alive at the time of the analysis will be censored at the 
date last known to be alive.
11.7.3 Analysis of immunogenicity
The primary analysis will be based on the ATP cohort for immunogenicity.  Humoral and 
cellular responses will also be analyzed for the total treated cohort if more than 3 patients 
are excluded from the ATP cohort for immunogenicity.  In this total treated cohort 
analysis, patients without immunogenicity measurements after ASCI treatment will be 
treated as non immunological responders.
For each cohort, at each blood sampling time point and for each antibody (anti-NY-ESO-
1 and anti-CpG7909 antibodies) for which results are available:

Anti-NY-ESO-1 antibody seropositivity rate, humoral response rate and antibody 
geometric mean titers (GMTs) with 95% CIs will be measured or calculated;

Percentages of seroconverted patients presenting NY-ESO-1 immunogenicity scores 
above cut-off and cellular (T-cell) responses to NY-ESO-1 responders with exact 
95% CIs will be given. Estimations of the cellular T cell precursor frequencies will 
be given if available.

In addition, individual data over time will be displayed graphically and per 
timepoint.
 
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PPD