Conditions: Neoplasms
Keywords: Relapsed and Refractory Multiple Myeloma T Cell Receptor Immuno-oncology NY-ESO-1 Leukapheresis Adoptive TCR T-cell therapy Letetresgene autoleucel
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This trial will evaluate safety, tolerability, and efficacy of letetresgene autoleucel (GSK3377794) with or without pembrolizumab in participants with relapsed and refractory multiple myeloma.

Detailed description:

Arms:
arm 1: Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive letetresgene autoleucel (GSK3377794), as a single intravenous (IV) infusion after completing lymphodepleting chemotherapy. arm 2: Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive letetresgene autoleucel (GSK3377794), as a single intravenous (IV) infusion after completing lymphodepleting chemotherapy, followed by pembrolizumab 200 mg every 3 weeks.

Interventions: intervention 1: Letetresgene autoleucel intervention 2: Letetresgene autoleucel with pembrolizumab intervention 3: Fludarabine intervention 4: Cyclophosphamide intervention 5: Pembrolizumab
Intervention descriptions: intervention 1: Letetresgene autoleucel (GSK3377794) as an IV infusion intervention 2: Letetresgene autoleucel (GSK3377794) as an IV infusion, followed by pembrolizumab every 3 weeks intervention 3: Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route. intervention 4: Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route. intervention 5: Pembrolizumab is available as an IV infusion

Protocol document:
Prot_000.pdf: 
GSK208470 (ADP-0011-008)
CONFIDENTIAL
GlaxoSmithKline group of companies
208470
Protocol Number: GSK208470 
(ADP-0011-008)
Version: 6.0
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Date:  24-FEB-2020
Page 1 of 182
TITLE PAGE
Protocol Title: Open-Label Pilot Study to Assess the Safety, Tolerability and Antitumor 
Activity of Genetically Engineered NY-ESO-1 Specific (c259) T Cells Alone or in 
Combination with Pembrolizumab in HLA-A2+ Subjects with NY-ESO-1 and/or LAGE-
1a Positive Relapsed and Refractory Multiple Myeloma
Protocol Number: 208470/05
Short Title: NY-ESO-1c259 T alone and in combination with pembrolizumab for multiple 
myeloma
Compound 
Number:
GSK3377794 (also known as NY-ESO-1c259T)
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline
5 Crescent Drive
Philadelphia, PA 19112
US
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Regulatory Agency Identifying Number(s):
Investigational New Drug Number: 014603
Approval Date: 24-FEB-2020.
Copyright 2020 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorized copying or use of this information is prohibited.


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol Title: Open-Label Pilot Study to Assess the Safety, Tolerability and Antitumor Activity 
of Genetically Engineered NY-ESO-1 Specific (c259) T Cells Alone or in Combination with 
Pembrolizumab in HLA-A2+ Subjects with NY-ESO-1 and/or LAGE-1a Positive Relapsed and 
Refractory Multiple Myeloma
I, the undersigned, have reviewed the protocol, including the appendices, and I will conduct the 
clinical study as described and will adhere to the International Conference on Harmonization 
(ICH) tripartite guideline E6 (R1): Guideline for Good Clinical Practice (GCP) and all the ethical 
and regulatory considerations stated. I have read and understood the contents of the 
NY-ESO-1c259T Investigator’s Brochure.
Investigator Name
Investigator Title
Investigator Site and Address
Investigator Signature
Date


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CLINICAL STUDY PROTOCOL
Title: Open-Label Pilot Study to Assess the Safety, Tolerability and Antitumor Activity of 
Genetically Engineered NY-ESO-1 Specific (c259) T Cells Alone or in Combination with 
Pembrolizumab in HLA-A2+ Subjects with NY-ESO-1 and/or LAGE-1a Positive Relapsed and 
Refractory Multiple Myeloma
Product Name: NY-ESO-1c259T
Protocol Number:  GSK208470 (ADP-0011-008) 
Regulatory Agency identifying Number:  IND 014603
DATE OF ORIGINAL PROTOCOL        19-DEC-2016
Amendment Number
Date
Reason for Change
Amendment 1
13-Mar-2017
Integration of the Screening tests of ADP-0000-001 for HLA-
genotyping and NY-ESO-1/LAGE-1a antigen expression levels 
in the Interventional protocol
Amendment 2
24-Jul-2018
Subsequent to the licensing of Adaptimmune product NY-ESO 
by GSK, the purpose of this protocol amendment is to:
-
Delete or replace references to Adaptimmune or its staff 
with that of GlaxoSmithKline (GSK) and its authorized agents to 
align with the change of sponsorship;
-
Make administrative changes to align with GSK 
processes and procedures;
-
Changes to lymphodepletion regimen throughout.
Amendment 3
17-Oct-2018
Changes made to the protocol were requested by the FDA as a 
result of safety events which included 2 reports of Guillain-Barré 
syndrome in subjects who have received chemotherapy and 
NY-ESO-1c259T during clinical trials.
Amendment 4
19-Sep-2019
Changes related to FDA requests were made, including 
changes to Inclusion Criteria #5, the addition of study stopping 
rules, and the Encephalopathy (now Immune Effector Cell-
Associated Neurotoxicity or ICANS) and the CRS grading and 
management criteria were updated. Also, changes were made 
to the lymphodepletion regimen for older subjects, and the 
randomization scheme was removed to enroll Arm1 (NY-ESO-
1c259T single infusion) subjects first.


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Amendment Number
Date
Reason for Change
Amendment 5
Protocol was amended to allow subjects who undergo 
leukapheresis as part of Study 208470 to subsequently receive 
a full line of therapy with an agent targeting BCMA– potentially 
in a study run by another sponsor.  The subject would then 
receive NY-ESO-1c259T, after progressive disease from this 
intermediate BCMA-targeted therapy.  The protocol was also 
amended to update several eligibility criteria, clarify the intent of 
Section 3.3.1 – study activities following lymphodepletion of 
third Arm 2 subject, update risk language for NY-ESO-1c259and 
pembrolizumab, update plans for statistical analyses, and 
update version of International Myeloma Working Group 
Uniform Response Criteria for Multiple Myeloma used in efficacy 
determination from 2011 version to 2016 version.
CONFIDENTIALITY STATEMENT
This document contains information which is the property of GlaxoSmithKline (GSK), and 
therefore is provided in confidence for your review. It is understood that this information will not 
be disclosed to others without written approval from GSK.
DECLARATION
This study will be conducted in compliance with ICH GCP, all applicable subject privacy 
requirements, and the guiding principles of the current version of the Declaration of Helsinki 
(with amendments), and in accordance with local legal and regulatory requirements.


PPD
PPD


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SYNOPSIS
Title Open-Label Pilot Study to Assess the Safety, Tolerability and Antitumor Activity of Genetically 
Engineered NY-ESO-1 Specific (c259) T Cells Alone or in Combination with Pembrolizumab in 
HLA-A2+ Subjects with NY-ESO-1 and/or LAGE-1a Positive Relapsed and Refractory Multiple 
Myeloma
Short Title
NY-ESO-1c259 T alone and in combination with pembrolizumab for multiple 
myeloma
Protocol Number
GSK208470 (ADP-0011-008)
Phase
This is a pilot study.
Methodology
Subjects will undergo screening for HLA-type and for the presence of NY-
ESO-1 and/or LAGE-1a antigen in their bone marrow. Only subjects who are 
selected after HLA-genotyping and determination of antigen expression will be 
considered for the eligibility screening.
Subjects meeting all eligibility criteria will be assigned to a treatment Arm: 
NY-ESO-1c259T alone (Arm 1) or NY-ESO-1c259T in combination with 
pembrolizumab (Arm 2). Enrollment of Arm 1 will be completed before 
continuing enrolling subjects to Arm 2.
Subjects will then undergo leukapheresis to obtain cells for the manufacture of 
autologous NY-ESO-1c259 SPEAR T cells™ (Specific Peptide Enhanced 
Affinity Receptor T cells).  Anticancer therapy may be administered between 
screening and leukapheresis, and between leukapheresis and the start of 
lymphodepletion (bridging or intermediate therapy), if a subject has 
progressive disease and cannot be treatment-free, but mandatory washout 
periods (see exclusion criterion 3) must be respected.  When the 
NY-ESO-1c259T product is available, subjects who have been confirmed 
eligible during baseline assessments period (Day -14 until Day -8) will 
undergo lymphodepleting chemotherapy with fludarabine on Day -8, Day -7, 
Day -6, and Day -5, and cyclophosphamide on Day -7, Day -6, and Day -5, 
followed by granulocyte-colony stimulating factor (G-CSF) support starting on 
Day -4 then receive the single infusion of NY-ESO-1c259T (transduced cell 
range: 1 × 109 to 8 × 109) that will be administered on Day 1. Eligible subjects 
who do not receive the NY-ESO-1c259T infusion for any reason may be 
replaced.
In Arm 1, the single infusion of NY-ESO-1c259T on Day 1 will be the only 
Investigational Product (IP) administered.  
In Arm 2, 3 weeks after the infusion of NY-ESO-1c259T on Day 1, an initial 
dose of the other IP pembrolizumab will be administered on Day 22 (Week 3).  
The second dose of pembrolizumab will be administered three (3) weeks later 
at Week 6, and subsequent doses of pembrolizumab will be administered every 
3 weeks thereafter up to Week 108 post T-cell infusion.  If toxicities that 
preclude pembrolizumab treatment (such as CRS Grade ≥2) are observed at 
Day 22 (Week 3), infusion of pembrolizumab will start on Week 6.  If 
toxicities have not resolved by Week 6, pembrolizumab will not be 
administered and the subject will be followed for visits as a subject in Arm 1.


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Safety will be assessed at each clinic visit.  This is the first study investigating 
the safety and efficacy of the combination of NY-ESO-1c259T and 
pembrolizumab.  Treatment Limiting Toxicities (TLTs) will be evaluated for 
subjects in the combination arm (Arm 2).  A Safety Review Team (SRT)will 
review safety data in both Arm 1 and Arm 2 at any time.  Enrollment in Arm 2 
will be paused after the third subject in Arm 2 has initiated lymphodepletion. A 
complete safety review of the first 3 subjects dosed with T-cells and 
pembrolizumab on Arm 2 will be conducted before enrollment may resume.  
The study may be paused to evaluate safety at any time or if at an interim 
assessment the predictive probability that the TLT rate at the end of the trial 
exceeds 33%, is greater than 50%.  The SRT may recommend closing an arm 
of the trial at any time.
Efficacy will be assessed using International Myeloma Working Group 
(IMWG) Uniform Response Criteria (2016) 
Subjects will complete the study once they have met one of the criteria to be 
transferred into the Long-Term Follow-Up (LTFU) protocol:subjects never 
dosed with pembrolizumab will be transferred once their disease progression is 
confirmed or 108 weeks after NY-ESO-1c259- cell infusion, whichever is 
sooner; subjects who received pembrolizumab will in addition require to be 
followed for a minimum of 24 months past their last dose of pembrolizumab 
and monitored for 18 months for complications of post allogeneic stem cell 
transplant (allo-SCT) when applicable if transplant were to occur during the 
24 month follow-up.
Study Duration
It is anticipated that study enrollment would be completed in approximately 
18 months. The primary data analysis will be conducted after all treated 
subjects have been followed up for at least 6 months after NY-ESO-1c259T 
infusion or have progressed or died or were withdrawn from the study. A 
subject will complete the treatment phase upon disease progression (subject to 
9 weeks minimum follow-up for safety), or 108 weeks after NY-ESO-1c259T-
cell infusion, whichever is sooner.  All subjects, completing the treatment 
phase, will enter a LTFU protocol. Study completion occurs when all subjects 
in the treatment phase of the study have been rolled over to the Long-Term 
Follow-Up (LTFU) protocol GSK208750 (ADP-0000-002) or died or were 
withdrawn from the study. The final analysis will be conducted after all 
subjects have completed the study or died or withdrawn.  If it is believed the 
primary analysis will occur within 6 months of the final analysis, the primary 
analysis may not be performed such that there will only be the final analysis.  
Monitoring for adverse events (AEs) of gene therapy and overall survival will 
last 15 years from the time of the T-cell infusion.  In addition, subjects who 
received pembrolizumab and undergo an allogeneic stem cell transplant within 
24 months from their last pembrolizumab dose, will be followed for 
complications of post allo-SCT (defined in Section 9.5) for 18 months.
Study Centers
This is a multicenter study, including approximately 10 sites.  Additional sites 
may be added at the discretion of the Sponsor.


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Objectives: 
Endpoints:
Primary
To describe the safety and tolerability of 
autologous genetically modified T cells 
(NY-ESO-1c259T) alone (Arm 1) or in 
combination with pembrolizumab 
(Arm 2) in subjects who are human 
leukocyte antigen HLA-A*02:01, 
HLA-A*02:05, and/or HLA-A*02:06 
positive and have NY-ESO-1 and/or 
LAGE-1a positive relapsed refractory 
multiple myeloma.
Adverse events (TLT rate and AEs), including serious 
adverse events (SAEs); laboratory assessments including 
chemistry, hematology and coagulation; and cardiac 
assessments by electrocardiogram (ECG).
Secondary
To describe the antitumor activity of 
autologous genetically modified T cells 
(NY-ESO-1c259T) alone (Arm 1) or in 
combination with pembrolizumab 
(Arm 2) in subjects who are 
HLA-A*02:01, HLA-A*02:05, and/or 
HLA-A*02:06 positive and have 
NY-ESO-1 and/or LAGE-1a positive 
relapsed refractory multiple myeloma
To describe the persistence of autologous 
genetically modified T cells (NY-ESO-
1c259T) over time

Overall Response Rate (ORR)

Time to Response (TTR)

Duration of Response (DOR) for all subjects who 
achieve at least PR

Progression-free survival (PFS)

Maximum persistence (Cmax), time to Cmax 
(Tmax), and area under the time curve from zero to 
time t AUC(0-t), as data permit 
Exploratory
To describe the antitumor activity of 
autologous genetically modified T cells 
(NY-ESO-1c259T) alone (Arm 1) or in 
combination with pembrolizumab 
(Arm 2) in subjects who are 
HLA-A*02:01, HLA-A*02:05, and/or 
HLA-A*02:06 positive and have 
NY-ESO-1 and/or LAGE-1a positive 
relapsed refractory multiple myeloma.
Overall survival (OS).
To evaluate minimal residual disease 
(MRD) at 4 months post T-cell infusion 
(Week 15).
MRD rate at Week 15.
To evaluate the persistence, phenotype, 
and functionality of NY-ESO-1c259
positive T cells.
Correlate persistence, phenotype, and functionality of 
NY-ESO-1c259T in the peripheral blood and/or bone marrow 
with response to treatment and safety.


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To understand mechanisms of resistance 
to NY-ESO-1c259T.
Determine whether loss of NY-ESO-1 and/or LAGE-1a 
expression in myeloma cells is a resistance mechanism.
Correlate apparition of anti-NY-ESO-1c259TCR antibodies 
with efficacy and safety.
Correlate expression of PD-L1 in the tumor 
microenvironment and PD-1 expression on T cells with 
response to treatment.
Correlate frequency of immune cell subsets in peripheral 
blood and/or bone marrow with treatment response.
Correlate frequency of immune cell subsets in peripheral 
blood and in bone marrow.
To evaluate antigen spreading as a 
mechanism of response.
Correlate clonal outgrowth of T-cell populations with tumor 
response following T-cell infusion.
To evaluate cytokine levels pre- and 
post-infusion on cytokine release 
syndrome (CRS).
Correlate cytokine levels with incidence and severity of CRS 
or other safety events.
To evaluate the impact of germline 
polymorphisms in IL-6, TNF-α, IL-10, 
IFN-γ and TGF-β on CRS
Polymorphisms in germline deoxyribonucleic acid (DNA) 
will be correlated with CRS.
Number of subjects
The target enrollment for this study is approximately 24 subjects treated with 
NY-ESO-1c259T: 12 in Arm 1 and 12 in Arm 2.  Eligible subjects who do not 
receive the NY-ESO-1c259T infusion for any reason may be replaced.
Inclusion /Exclusion 
Criteria
Subject Inclusion Criteria
A subject must meet the following inclusion criteria to be eligible for 
participation in this study:
Screening (Part 1):
1.
Subject has voluntarily agreed to participate by giving written 
informed consent for the screening process in accordance with 
ICH GCP Guidelines and applicable local regulations.
2.
Subject has voluntarily agreed to abide by all protocol required 
procedures including study related assessments, and 


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management by the treating institution for the duration of the 
study and long-term follow-up. 
3.
Subjects must be 18 years of age or older at the date of 
consent.
4.
Histologically confirmed diagnosis of secretory multiple 
myeloma (must have measurable M protein in serum or urine) 
with at least one of the following:

Serum M- protein ≥0.5 g/dL (≥5 g/L) for IgG, IgM, IgA, 
or ≥0.05 g/dL for IgD; or

Urine M-protein ≥200 mg/24 hours ; or

Serum free light chain (FLC) assay: 
involved FLC level ≥10 mg/dL (100 mg/L) and an 
abnormal serum FLC ratio (<0.26 or >1.65).
5.
Subject must have documented diagnosis of relapsed and 
refractory multiple myeloma (RRMM) as described below:

subjects who have received at least 3 prior regimens and, 

were responsive to at least 1 or more prior regimens (as 
defined by IMWG criteria), and 

are refractory to their most recent therapy (≤ 25% 
response or progression during therapy or within 60 days 
after completion of therapy).
Prior therapies for subjects with RRMM must have contained 
at least one drug from each of the following drug classes: an 
immunomodulatory imide drug (IMiD), proteasome inhibitor, 
alkylator (unless the subject is ineligible or contraindicated to 
receive an alkylator), CD38 monoclonal antibody, and 
glucocorticoid as separate lines or a combined line of therapy. 
If prior therapy includes autologous stem cell transplantation 
(ASCT), then induction/ASCT/maintenance therapies will be 
considered as one line of therapy altogether. 
Subjects who have relapsed after ASCT or are unable to 
receive ASCT are eligible.  The interval from ASCT to entry 
in the study must be ≥12 weeks.
6.
Left ventricular ejection fraction (LVEF) ≥50%.  A lower 
LVEF (≥40%) is permissible if a formal cardiologic evaluation 
reveals no evidence for clinically significant functional 
impairment, otherwise the subject may not enter the study.
7.
For subjects who have received prior checkpoint inhibitors or 
other immuno-oncology agents like T-cell receptor agonists:


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
Subjects with endocrine AE of any grade are permitted to 
enroll if they are stably maintained on appropriate 
replacement therapy and are asymptomatic.

Must not have experienced any ≥ Grade 3 AE nor any 
neurologic AE of any grade while receiving prior 
checkpoint inhibitors.

Must not have required the use of additional 
immunosuppression other than corticosteroids for the 
management of an AE related to checkpoint inhibitors, 
not have experienced recurrence of an AE related to 
checkpoint inhibitors if re-challenged, and not currently 
require maintenance doses of corticosteroids.
8.
Subject has Eastern Cooperative Oncology Group (ECOG) 
Performance Status 0 or 1.
Leukapheresis/Manufacturing (Part 2):
All screening criteria must be reviewed and fulfilled along with all of the 
following criteria prior to leukapheresis.  Leukapheresis may not be necessary 
for subject for whom NY-ESO-1c259T-cell product is already manufactured.
9.
Subject is HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 
positive as determined by a central laboratory. (This 
determination will be made under a pre-enrollment screening 
informed consent form [ICF].  There are no restrictions on the 
timing of HLA typing for screening and data can be taken from 
subjects’ records..
10. Subject has confirmed sufficient expression of NY-ESO-1 and/or 
LAGE-1a by reverse transcription polymerase chain reaction 
(RT-PCR) as determined by a central laboratory contracted by the 
Sponsor (this determination will be made under a pre-enrollment 
screening ICF).
11. Subject has voluntarily agreed to participate by giving written 
informed consent for treatment in accordance with International 
Council on Harmonisation (ICH) Good Clinical Practice (GCP) 
Guidelines and applicable local regulations.
12. In the Investigator’s opinion, the subject is fit for cell collection.
13. The subject has the following laboratory parameters determined 
prior to leukapheresis according to timelines in the Apheresis 
Manual and which meet the requirements in the table below:


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Absolute neutrophil count (ANC)
1.0 x 109/L
CD3 count
≥200/μL
Lymphocyte count
≥0.5 x 109/L
Lymphodepletion / Treatment (Part 3)
All prior inclusion criteria described for Screening and Leukapheresis must be 
reviewed and fulfilled along with the following criteria prior to 
lymphodepletion.
14. Subject has adequate vital organ function as indicated by the 
following laboratory values in the table below. Specimens must 
be collected no more than 7 days prior to start of 
lymphodepletion.
System
Laboratory Value
Hematological
Absolute Neutrophil count (ANC)
≥1.0 × 109/L (without G-CSF support)
Plateletsa
≥50 × 109/L
Hemoglobin
>80 g/L (8 g/dL) (without transfusion 
support within 7 days from start of 
leukapheresis)
Coagulation
Prothrombin time (PT)b
or International Normalized Ratio 
(INR)
≤1.5 × upper limit of normal (ULN) 
Partial thromboplastin time (PTT)b
≤1.5 × ULN
Renal
Measured or calculatedc creatinine 
clearance
≥30 mL/min and not on dialysis
Hepatic
Serum total bilirubin
≤1.5 × ULN (unless subject has 
documented Gilbert’s Syndrome with 
direct bilirubin <35% of total 
bilirubin)
Aspartate aminotransferase (AST)/ 
serum glutamic oxaloacetic 
transaminase (SGOT)
≤2.5× ULN 


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Alanine aminotransferase (ALT)/ 
serum glutamic pyruvic 
transaminase (SGPT)
a.
Subjects should not have received platelet transfusion within 2 weeks of 
screening blood count.
b.
Unless receiving therapeutic anticoagulation, in which case PT or PTT 
should be within therapeutic range of intended use of anticoagulants.
c.
Subjects who are >18 or <65 years of age can be assessed using estimated 
creatinine clearance calculated using the Chronic kidney disease 
Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009]:
GFR = 141 x min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if 
female] × 1.159 [if black] where, Scr is serum creatinine in mg/dL, κ is 0.7 for 
females and 0.9 for males, is -0.329 for females and -0.411 for males, min 
(Scr /κ, 1) indicates the minimum of Scr /κ or 1, and max (Scr /κ, 1) indicates 
the maximum of Scr /κ or 1.
Subjects ≥65 of age must have renal function measured either by 24-hour urine 
creatinine collection or by nuclear medicine EDTA GFR measurement, 
according to standard practice at the treating institution.
15. Subject previously treated with BCMA therapy (BCMA CAR-T, 
ADC, or other type of BCMA-targeted therapy) must have 
progressed from this therapy prior to attending the Baseline visit 
prior to beginning lymphodepletion.
16. Contraception used by men or women should be consistent with 
local regulations regarding the methods of contraception for those 
participating in clinical studies. 

Male subjects:
Male subjects are eligible to participate if they agree to the 
following during the period starting at the first dose of 
chemotherapy for at least 12 months after receiving the T-
cell infusion, or 4 months after there is no evidence of 
persistence/ gene modified cells in the subject’s blood, 
whichever is longer.
o
Refrain from donating sperm
Plus either: 
o
Be abstinent from heterosexual or homosexual intercourse 
as their preferred and usual lifestyle (abstinent on a long 
term and persistent basis) and agree to remain abstinent 
OR
o
Must agree to use contraception/barrier as detailed below
o
Agree to use a male condom and should also be advised of 
the benefit for a female partner to use a highly effective 
method of contraception, as a condom may break or leak 
when having sexual intercourse with a woman of 


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childbearing potential (WOCBP) who is not currently 
pregnant.
o
Agree to use male condom when engaging in any activity 
that allows for passage of ejaculate to another person.

Female subjects: 
A female subject is eligible to participate if she is not 
pregnant or breastfeeding, and at least one of the following 
conditions applies:
o
Is not a WOCBP as defined in Section 6.3.3
OR
o
Is a WOCBP (as defined in Section 6.3.3) and using a 
contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency, 
as described in Section 6.3.3 during the period starting at 
the Baseline Visit, for at least 12 months after receiving 
the T-cell infusion, or 4 months after there is no evidence 
of persistence/ gene modified cells in the subject’s blood, 
whichever is longer.  If assigned to Arm 2 must use 
effective contraception for at least 4 months after the last 
dose of pembrolizumab if this time frame is longer than
the duration of contraception required in the context of 
chemotherapy and gene modified cells.  WOCBP should 
also agree not to donate eggs (ova, oocytes) for the 
purpose of reproduction during this period. The 
investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of 
study intervention.
o
A WOCBP must have a negative highly sensitive 
pregnancy test (urine or serum as required by local 
regulations) within 24 hours before the first dose of study 
intervention. 
If a urine test cannot be confirmed as negative (e.g., an 
ambiguous result), a serum pregnancy test is required. In 
such cases, the subject must be excluded from 
participation if the serum pregnancy result is positive.
The investigator is responsible for review of medical 
history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a woman with an early 
undetected pregnancy.


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Subject Exclusion Criteria
A subject meeting any of the following criteria is not eligible for participation 
in the study.
Screening (Part 1):
1.
Subjects with only plasmacytomas, plasma cell leukemia, 
monoclonal gammopathy of undetermined significance 
(MGUS), smoldering multiple myeloma (SMM), non-
secretory myeloma or primarily amyloidosis.
2.
Subject has already received one of the following 
therapy/treatment: anti-PD-1, anti-PD-L1, or anti-PD-L2 
inhibitor. Note: this exclusion only applies to subjects that 
would be assigned to Arm 2.
3.
Subjects who have previously participated in Merck pivotal 
trial NCT02576977: Study of Pomalidomide and Low Dose 
Dexamethasone With or Without Pembrolizumab (MK-3475) 
in Refractory or Relapsed and Refractory Multiple Myeloma 
(RRMM) (MK-3475-183/KEYNOTE-183). 
4.
Subject has received a prior allogeneic stem cell transplant.
5.
Subject has toxicity from previous anticancer therapy that has 
not recovered to ≤Grade 1 or to their baseline level of organ 
function (as outlined in Subject Inclusion Criteria 14) prior to 
enrollment (except for non-clinically significant toxicities, 
e.g., alopecia, vitiligo).  Subjects with Grade 2 toxicities that 
are deemed stable or irreversible (e.g. peripheral neuropathy) 
can be enrolled on a case-by-case basis with prior consultation 
and agreement with the Sponsor Study Physician.
6.
Subject had major surgery within 4 weeks prior to enrollment 
(kyphoplasty is not considered major surgery); subjects should 
have been fully recovered from any surgical related toxicities.
7.
Subject has history of allergic reactions attributed to 
fludarabine, cyclophosphamide, or agents similar in 
chemical or biologic composition to fludarabine, 
cyclophosphamide or other agents used in the study.
8.
Known history of myelodysplasia.
9.
Current active liver or biliary disease (with the exception of 
Gilbert's syndrome or asymptomatic gallstones, liver 
metastases or otherwise stable chronic liver disease per 
investigator assessment).


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NOTE: Stable chronic liver disease should generally be 
defined by the absence of ascites, encephalopathy, 
coagulopathy, hypoalbuminaemia, oesophageal or gastric 
varices, persistent jaundice or cirrhosis.
10. Known history of chronic active hepatitis or liver cirrhosis (if 
suspected by laboratory studies, should be confirmed by liver 
biopsy).
11. Subject has an active infection with human immunodeficiency 
virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), 
or human T-lymphotropic virus (HTLV) as defined below:

Positive serology for HIV.

Presence of hepatitis B surface antigen (HBsAg),
positive hepatitis C antibody test result at screening or 
within 3 months prior to first dose of chemotheraphy.

Active hepatitis C subjects as demonstrated by test for 
hepatitis C ribonucleic acid (RNA).  Subjects who are 
HCV antibody positive will be screened for HCV RNA 
by any RT-PCR or by DNA assay. If HCV antibody is 
positive, eligibility will be determined based on a 
negative screening RNA value.

Positive serology for HTLV 1 or 2.
Re-screening for infection disease markers is not 
required at baseline (prior to lymphodepleting 
chemotherapy)
12. History of severe immune disease, including non-infectious 
pneumonitis, requiring steroids or other immunosuppressive 
treatments.
13. Active immune-mediated diseases including: 
a.
Connective tissue diseases, uveitis, sarcoidosis, 
inflammatory bowel disease, multiple sclerosis, (non-
infectious) pneumonitis.
b.
Prior or active demyelinating disease.
14. Evidence or history of significant cardiac disease (such as, but 
not limited to, unstable angina pectoris, myocardial infarction 
within the prior 6 months, heart failure within 6 months, 
symptomatic congestive heart failure, symptomatic or 
uncontrolled arrhythmias, severe aortic stenosis, symptomatic 
mitral stenosis).
15. QTc > 450 msec or QTc > 480 msec for patients with bundle 
branch block. 
NOTES: 


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
The QTc is the QT interval corrected for heart rate 
according to Bazett's formula (QTcB), Fridericia's 
formula (QTcF), and/or another method, machine-read or 
manually over-read.

The specific formula that will be used to determine 
eligibility and discontinuation for an individual subject 
should be determined prior to initiation of the study. In 
other words, several different formulae cannot be used to 
calculate the QTc for an individual subject and then the 
lowest QTc value used to include or discontinue the 
subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT 
correction formula, or a composite of available values of 
QTc will be used as specified in the Reporting and 
Analysis Plan (RAP).  
16. Evidence or history of other significant, hepatic, renal, 
ophthalmologic, psychiatric, or gastrointestinal disease which 
would likely increase the risks of participating in the study.
17. Subjects with concomitant second malignancies (except 
adequately treated non-melanomatous skin cancers, carcinoma 
in situ of the breast, treated superficial bladder cancer or 
prostate cancer, or in situ cervical cancers) are excluded unless 
a complete remission was achieved at least 2 years prior to 
study entry and no additional therapy is required or anticipated 
to be required during the study period.  Long-term adjuvant 
therapy (example: breast cancer) is acceptable.
18. Known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis. Subjects with previously treated 
brain metastases may participate provided they are 
radiologically stable, i.e., without evidence of progression for 
at least 4 weeks by repeat imaging (note that the repeat 
imaging should be performed during study screening), 
clinically stable, and without requirement of steroid treatment 
for at least 14 days prior to first dose of study treatment.
19. Active bacterial or systemic viral or fungal infections
20. Pregnant or breastfeeding. 
Leukapheresis/Manufacturing (Part 2)
21. The subject has received or plans to receive the following 
treatment regimens and does not or cannot meet the specified 
time frames prior to leukapheresis or lymphodepleting 
chemotherapy: 


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Treatment/Therapy
Required Wash-out
Cytotoxic chemotherapy
2 weeks
Immune therapy (including 
monoclonal antibody therapy)
No wash-out
Immunomodulator imide therapy 
(IMiD e.g. lenalidomide or 
pomalidomide)
No wash-out
Proteasome inhibitor therapy (e.g. 
bortezomib or carfilzomib)
2 weeks
Anticancer Vaccine
4 weeks
The subject should be excluded if the 
Investigator considers their disease is 
responding to an experimental vaccine 
given within 6 months
Live-virus vaccination. NOTE: 
Seasonal flu vaccines that do not 
contain live virus are not an 
exclusion.
4 weeks
Allogeneic hematopoietic stem cell 
transplant at any time
Not permitted
Corticosteroids or any other 
immunosuppressive therapy. 
NOTE:  Use of inhaled or topical 
steroids, or of physiologic 
corticosteroid replacement therapy 
for adrenal or pituitary 
insufficiency is permitted. 
2 weeks
Genetically engineered cell 
therapy
12 weeks
Investigational treatment 
4 weeks or 5 half-lives, whichever is 
longer
Radiotherapy
2 weeks
NOTE: Duration of any other anticancer therapies must be discussed with 
the Sponsor Study Physician
Lymphodepletion/Treatment (Part 3):
A subject is not eligible for lymphodepletion if any of exclusion criteria for 
screening or leukapheresis or any of the following parameters apply:
22. More than two years have passed since the last leukapheresis 
collection. 


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Study Product, Dose, 
Route, Regimen
The two IPs in this study are:

NY-ESO-1c259T, an autologous T cell transduced with a self-
inactivating lentivirus encoding for a high affinity NY-ESO-1/LAGE-
1a-specific T-cell receptor (TCR).  The “c259” designation refers to 
the optimized affinity clone.

Pembrolizumab [Keytruda USPI, 2020], a humanized monoclonal 
antibody against the PD-1 protein.
Fludarabine 30 mg/m2/day on Days -8, -7, -6, and -5 over 30 minutes, and 
cyclophosphamide 900 mg/m2/day on Days -7, -6, and -5 intravenously (over 1 
hour) will be used for lymphodepletion prior to the study treatment (see dose 
modification for patients over 60 years of age).  G-CSF will be given to all 
subjects 24 hours after the last dose of cyclophosphamide.  
Arm 1: Subjects will receive NY-ESO-1c259T alone.  A single infusion of 
NY-ESO-1c259T will be administered on Day 1, which is 4 days after 
completing the cyclophosphamide and fludarabine (there is no Day 0 for this 
study). 
Arm 2: Subjects will receive NY-ESO-1c259T in combination with 
pembrolizumab.  A single infusion of NY-ESO-1c259T will be administered on 
Day 1, which is 4 days after completing the cyclophosphamide and fludarabine 
(there is no Day 0 for this study). The first dose of pembrolizumab will be 
administered on Day 22, 3 weeks later.  The second dose of pembrolizumab 
will be administered at Week 6 and subsequent doses of pembrolizumab will 
be administered every 3 weeks thereafter, up to Week 108 post-infusion.  If 
toxicities that preclude pembrolizumab treatment (such as CRS Grade ≥2) are 
observed at Day 22 (Week 3), infusion of pembrolizumab will start on Week 6.  
If toxicities have not resolved by Week 6, pembrolizumab will not be 
administered and the subject will be followed for visits as a subject in Arm 1.  
Pembrolizumab (200 mg) is administered as an intravenous infusion over 
30 min.
NY-ESO-1c259T is administered as a transduced cell dose in the range of 
1 x 109 to 8 x 109 transduced cells.  If the transduced cell dose is less than the 
minimum dose, manufacturing of additional transduced T cells from excess 
banked leukapheresis product will be undertaken to achieve a total dose in the 
target range.  In the event that no banked leukapheresis product is available a 
second leukapheresis may be performed.
Comparator therapy
None
Statistical 
Methodology
Eligible subjects will be assigned to either Arm 1 or Arm 2.  Subjects who do 
not receive the NY-ESO-1c259T infusion for any reason may be replaced.  
Safety will be summarized using descriptive statistics and listings and 
reviewed throughout the trial.  As subjects are accrued and at n≥3 treated with 
both NY-ESO-1c259T and pembrolizumab, Bayesian predictive probabilities 
will be used to evaluate TLTs for the combination. If (at n < Nmax=10) the 
probability that the TLT rate exceeds 0.33 at the end of the trial is greater than 


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0.50, the SRT may recommend to pause the study to review safety and if 
warranted, to stop an arm or the trial for safety.
Summary statistics will be provided for each arm.  The study is not powered to 
compare safety or efficacy between the arms and therefore no formal statistical 
comparisons between arms is planned.  95% two-sided confidence intervals 
may be calculated for selected endpoints for estimation purposes.  Descriptive 
statistics on continuous data will include means, medians, standard deviations, 
and ranges, while categorical data will be summarized using frequency counts 
and proportions.  Graphical summaries of the data may be presented.
Interim analyses to inform internal decision making may be performed for each 
arm after enrollment to the arm is complete and all the enrolled subjects in that 
arm who will receive NY-ESO-1c259T have done so and of those: all have 
completed at least three disease assessments since infusion or have progressed 
(and if progressed prior to the Week 9 visit, have been followed up for safety 
for a minimum of 9 weeks following T-cell infusion) or have died or were 
withdrawn from the study. A further analysis once all Arm 1 subjects satisfy 
the criteria for the primary analysis may also be undertaken.


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TABLE OF CONTENTS
1.
BACKGROUND AND STUDY RATIONALE........................................................... 28
1.1.
Adoptive T-cell Therapy.............................................................................. 28
1.2.
Adoptive Immunotherapy with NY-ESO-1 (c259) Specific T Cells............... 29
1.3.
Multiple Myeloma........................................................................................ 30
1.4.
NY-ESO-1c259T in Multiple Myeloma ........................................................... 32
1.5.
Rationale for Combination of NY-ESO-1c259T with Pembrolizumab for 
Multiple Myeloma........................................................................................ 33
1.5.1.
Pembrolizumab Pharmaceutical and Therapeutic Background.... 34
1.5.2.
Rationale for the Pilot Study ........................................................ 35
2.
TRIAL OBJECTIVES AND ENDPOINTS................................................................ 36
3.
INVESTIGATIONAL PLAN..................................................................................... 37
3.1.
Overall Study Design.................................................................................. 37
3.1.1.
Part 1: Eligibility Screening .......................................................... 40
3.1.2.
Part 2: Leukapheresis/Manufacture ............................................. 40
3.1.2.1.
Bridging Therapy........................................................ 40
3.1.2.2.
Intermediate Line of Therapy...................................... 40
3.1.3.
Part 3: Lymphodepletion/Treatment............................................. 41
3.2.
Rationale for Components of Study Design ................................................ 42
3.2.1.
Screening for HLA and for expression of NY-ESO-1 and LAGE-1a 
antigens in the Context of NY-ESO-1c259T ................................... 42
3.2.2.
T-cell Manufacturing .................................................................... 42
3.2.3.
Lymphodepletion ......................................................................... 43
3.2.4.
T-Cell Infusion ............................................................................. 43
3.2.5.
Rationale for NY-ESO-1c259T Dose .............................................. 43
3.2.6.
Rationale for Pembrolizumab Dose and Timing of the First Dose 44
3.2.6.1.
Rationale for Pembrolizumab Dose............................ 44
3.2.6.2.
Rationale for Timing of First Dose .............................. 45
3.3.
Assessment of Safety and Treatment Limiting Toxicities ............................ 46
3.3.1.
Pause of Enrollment in Arm 2 After the Third Subject in Arm 2 
Begins Lymphodepletion ............................................................. 46
3.3.2.
Scope of Reviews by the SRT ..................................................... 47
3.3.3.
Complete Safety Review before Resuming Enrollment................ 47
3.3.4.
Frequency of SRT meetings........................................................ 47
3.3.5.
Treatment Limiting Toxicities (TLTs)............................................ 48
3.3.5.1.
Three-Week Assessment Period................................ 48
3.3.5.2.
TLT Definition............................................................. 48
3.4.
Number of Subjects and Duration of Study................................................. 49
3.5.
Sites ........................................................................................................... 49
3.6.
Benefit:Risk Assessment............................................................................ 49
3.6.1.
Benefit Assessment..................................................................... 50
3.6.2.
Risk Assessment......................................................................... 51
3.6.3.
Overall Benefit: Risk Conclusion.................................................. 54


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4.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA............. 54
4.1.
Subject Inclusion Criteria............................................................................ 54
4.1.1.
Screening (Part 1) ....................................................................... 54
4.1.2.
Leukapheresis (Part 2) ................................................................ 55
4.1.3.
Lymphodepletion/treatment (Part 3) ............................................ 56
4.2.
Subject Exclusion Criteria........................................................................... 59
4.2.1.
Screening (Part 1) ....................................................................... 59
4.2.2.
Leukapheresis/Manufacturing (Part 2)......................................... 61
4.2.3.
Lymphodepletion/Treatment (Part 3) ........................................... 62
4.3.
Completion of the Treatment Phase ........................................................... 62
4.4.
Conditions for Transfer to the LTFU Protocol – Study Completion.............. 63
4.5.
Study Withdrawal........................................................................................ 63
4.6.
Discontinuation of Pembrolizumab Treatment (Arm 2 subjects).................. 64
4.7.
Considerations for Temporary Suspension of Enrollment ........................... 65
4.8.
Liver Chemistry Stopping Criteria ............................................................... 65
4.9.
QTc Stopping Criteria ................................................................................. 67
5.
STUDY TREATMENTS.......................................................................................... 68
5.1.
Leukapheresis............................................................................................ 68
5.2.
Lymphodepleting Chemotherapy................................................................ 68
5.2.1.
Lymphodepletion Dose Modification ............................................ 70
5.2.2.
Fludarabine Dose Adjustment for Renal Impairment.................... 70
5.2.3.
Mesna ......................................................................................... 70
5.3.
T-cell Infusion............................................................................................. 70
5.3.1.
Premedication ............................................................................. 71
5.3.2.
Cell Infusion................................................................................. 71
5.4.
Pembrolizumab (Arm 2) Infusion ................................................................ 71
5.4.1.
Schedule Modification Guidelines for Pembrolizumab (Arm 2)..... 72
6.
CONCOMITANT MEDICATION AND TREATMENT .............................................. 77
6.1.
Prohibited Concomitant Medication and Treatment .................................... 77
6.2.
Permitted Concomitant Medication and Treatment ..................................... 78
6.3.
Restrictions................................................................................................. 78
6.3.1.
Corticosteroids ............................................................................ 78
6.3.2.
Diet.............................................................................................. 78
6.3.3.
Contraception.............................................................................. 78
6.3.4.
Use in Pregnancy ........................................................................ 81
6.3.5.
Use in Nursing Women................................................................ 82
7.
SCHEDULE OF ASSESSMENTS AND PROCEDURES........................................ 82
7.1.
HLA and Antigen Screening ....................................................................... 84
7.1.1.
Blood sample for HLA subtyping.................................................. 84
7.1.2.
Bone marrow aspirate for antigen testing by RT-PCR ................. 84
7.1.3.
Bone Marrow Sample Banking and Storage ................................ 84
7.1.4.
Companion Diagnostic Development........................................... 85
7.2.
Screen Failures .......................................................................................... 85
7.3.
Schedule of Procedures ............................................................................. 86
7.4.
Clinical Assessments and Procedures........................................................ 93
7.4.1.
Medical History............................................................................ 93


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7.4.2.
Physical Examination and Measurement of Vital Signs................ 93
7.4.3.
Performance Status..................................................................... 93
7.4.4.
Clinical Safety Assessments........................................................ 93
7.4.5.
Laboratory Assessments ............................................................. 94
7.4.6.
Cardiac Assessments.................................................................. 94
7.4.7.
Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)....................................................................................... 94
7.4.8.
Disease Response Assessments ................................................ 95
7.4.9.
Long-Term Follow-up .................................................................. 95
7.4.10.
Allogeneic Stem Cell Transplantation and Follow-up................... 95
7.5.
Correlative Studies and Research Assessments ........................................ 95
7.5.1.
Pharmacogenetics Sample.......................................................... 96
7.5.2.
Cytokine and Soluble Factors Analysis........................................ 97
7.5.3.
Bone Marrow Aspirates ............................................................... 97
7.5.4.
NY-ESO-1c259 T-cell Persistence ................................................. 98
7.5.5.
NY-ESO-1c259 T-Cell Phenotype and Activity ............................... 99
7.5.6.
Peripheral Blood Collection and Analysis .................................... 99
7.5.7.
Request for Autopsy for Death Following Administration of Gene 
Transfer Agents........................................................................... 99
8.
SUPPORTIVE CARE GUIDANCE ....................................................................... 100
8.1.
T-cell Infusion Symptom Management...................................................... 100
8.2.
Infection.................................................................................................... 100
8.2.1.
Pneumocystis carinii Pneumonia (PCP) .................................... 100
8.2.2.
Herpes Simplex and Varicella Zoster......................................... 100
8.2.3.
Cytomegalovirus........................................................................ 101
8.2.4.
Hepatitis B Prophylaxis.............................................................. 101
8.2.5.
Syphilis...................................................................................... 101
8.2.6.
Other Anti-Microbial Prophylaxis................................................ 101
8.3.
Hematologic and Blood Product Support .................................................. 101
8.3.1.
Irradiated Blood Product............................................................ 101
8.3.2.
Cytomegalovirus Screened Blood Products............................... 102
8.4.
Management of Autoimmunity .................................................................. 102
8.5.
Management of Cytokine Release Syndrome........................................... 102
8.6.
Management of Graft-versus-Host Disease (GVHD) ................................ 105
8.6.1.
Diagnosis of GVHD ................................................................... 105
8.6.2.
Grading of GVHD ...................................................................... 106
8.6.3.
Management of GVHD .............................................................. 107
8.7.
Management of Pancytopenia with Bone Marrow Failure / Aplastic Anemia109
8.8.
Chemotherapy Symptom Management .................................................... 110
8.8.1.
Management of Neutropenia ..................................................... 110
8.9.
Dose Modification and Toxicity Management of Infusion-Reactions Related 
to Pembrolizumab..................................................................................... 110
8.10.
Management of ICANS............................................................................. 112
8.10.1.
Grading of ICANS...................................................................... 112
8.10.2.
Monitoring for ICANS................................................................. 114
8.10.3.
Management of ICANS.............................................................. 114
8.11.
Management of Guillain-Barré Syndrome (GBS) ...................................... 117
8.11.1.
Neurological Symptoms............................................................. 118


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8.11.2.
Brighton Key Diagnostic Criteria................................................ 118
8.11.3.
Erasmus GBS Respiratory Insufficiency Score (EGRIS)............ 118
8.11.4.
Modified Erasmus GBS Outcomes Score (mEGOS).................. 118
8.11.5.
Summary of diagnosis and treatment for GBS........................... 119
9.
RECORDING ADVERSE EVENTS...................................................................... 119
9.1.
Time Period for Collecting Adverse Event and Serious Adverse Event 
Information ............................................................................................... 120
9.2.
Definition of Adverse Event ...................................................................... 121
9.2.1.
Assessment of Intensity............................................................. 121
9.2.2.
Assessment of Causality ........................................................... 122
9.3.
Reporting Serious Adverse Events (SAEs)............................................... 123
9.4.
Reporting Criteria during Long-Term Follow-Up (Years 1-15)................... 124
9.5.
Follow-up post Allogenic Stem Cell Transplantation for Subjects Who 
Received Pembrolizumab......................................................................... 125
9.6.
Progression of Underlying Malignancy...................................................... 126
9.7.
Regulatory Reporting Requirements for Serious Adverse Events............. 126
9.8.
Cardiovascular and Death Events ............................................................ 126
9.9.
Pregnancy ................................................................................................ 127
9.10.
Preexisting Condition................................................................................ 127
9.11.
Laboratory Test Abnormalities as Adverse Events.................................... 127
9.12.
Overdose.................................................................................................. 128
9.13.
Adverse Events of Special Interest........................................................... 128
9.14.
Timelines for Safety Reporting.................................................................. 129
10. SAFETY MONITORING....................................................................................... 130
10.1.
Monitoring and Management of Replication-Competent Lentivirus (RCL). 130
10.1.1.
Testing for RCL in Clinical Studies ............................................ 131
10.1.2.
Safety Monitoring Results.......................................................... 131
10.1.3.
Persistence Testing and Monitoring for Insertional Oncogenesis132
10.1.3.1.
Testing for Persistence of Gene Marked Cells in 
Clinical Studies......................................................... 132
10.1.3.2.
Testing for Insertional Oncogenesis ......................... 132
10.2.
Management and Monitoring for Demyelinating Neuropathy and other 
Neurological events.................................................................................. 133
10.3.
Safety Review Team ................................................................................ 133
10.3.1.
Mandated Study Pause Due to GBS.......................................... 133
11. STATISTICAL AND DATA ANALYSIS ................................................................. 133
11.1.
Study Populations..................................................................................... 134
11.2.
Interim Analysis ........................................................................................ 134
11.3.
Sample Size and Assignment of Study Arms............................................ 135
11.4.
Statistical Methods for Safety Parameters ................................................ 135
11.4.1.
TLT Evaluation for Arm 2........................................................... 136
11.4.1.1.
TLT Rate Definition .................................................. 136
11.4.1.2.
Bayesian Predictive Probabilities for Nmax = 10......... 136
11.4.2.
Statistical Methods for Safety Parameters ................................. 137
11.5.
Statistical Methods for Antitumor Activity Endpoints ................................. 138


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12. CLINICAL SUPPLIES .......................................................................................... 139
12.1.
Packaging and Labelling........................................................................... 139
12.1.1.
NY-ESO-1c259T-cell Product....................................................... 139
12.1.2.
Pembrolizumab ......................................................................... 139
12.2.
Standard Policies and Product Return...................................................... 139
12.3.
Storage and Handling............................................................................... 140
12.4.
Product Accountability .............................................................................. 140
13. DATA HANDLING AND RECORD KEEPING....................................................... 140
13.1.
Data Management.................................................................................... 140
13.2.
Case Report Forms .................................................................................. 141
13.3.
Site Documentation and Source Data....................................................... 141
13.4.
Data Retention and Availability................................................................. 142
14. STUDY MONITORING......................................................................................... 142
14.1.
Audits and Inspections.............................................................................. 142
15. REGULATORY AND ETHICAL CONSIDERATIONS ........................................... 143
15.1.
Competent Authority Submissions............................................................ 143
15.2.
Independent Ethics Committees............................................................... 143
15.3.
Local Regulations/Declaration of Helsinki................................................. 143
15.4.
Informed Consent..................................................................................... 143
15.5.
Confidentiality........................................................................................... 144
15.6.
Protocol Adherence.................................................................................. 144
15.7.
Study Suspension, Study Termination and Study Completion .................. 144
15.8.
Public Posting of Study Information .......................................................... 144
15.9.
Clinical Study Report ................................................................................ 144
15.10. Publication Policy ..................................................................................... 145
16. APPENDICES...................................................................................................... 146
16.1.
List of Abbreviations and Definitions of Terms.......................................... 146
16.2.
ECOG Performance Status ...................................................................... 153
16.3.
Laboratory Tests and ECG....................................................................... 154
16.4.
International Myeloma Working Group (IMWG) Criteria for the Diagnosis of 
Multiple Myeloma...................................................................................... 155
16.5.
Response Rates in Subjects with Relapsed and Refractory Multiple 
Myeloma................................................................................................... 156
16.6.
Liver Safety Required Actions and Follow up Assessments...................... 158
17. LIST OF REFERENCES ...................................................................................... 160
18. CHANGE HISTORY............................................................................................. 171


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LIST OF TABLES
Table 1
Lymphodepleting Chemotherapy ........................................................... 69
Table 2
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab ......................................... 73
Table 3
Schedule of Procedures......................................................................... 86
Table 4
Schedule of Procedures in Long-Term Follow-up Phase Prior to Transfer 
to LTFU Protocol.................................................................................... 92
Table 5
Management Guidelines for Cytokine Release Syndrome ................... 103
Table 6
Diagnosis of GVHD.............................................................................. 106
Table 7
Stage of GVHD.................................................................................... 107
Table 8
Grading of GVHD................................................................................. 107
Table 9
Management of GVHD......................................................................... 108
Table 10
Infusion Reaction Treatment Guidelines for Pembrolizumab................ 110
Table 11
Immune Effector Cell-Associated Encephalopathy (ICE) assessment tool113
Table 12
Grading of Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) ............................................................................................... 113
Table 13
Management of ICANS ........................................................................ 115
Table 14
Grading of AEs not specified in NCI-CTCAE v4.0 ................................ 122
Table 15
Predictive Probabilities for Nmax = 10.................................................... 137
Table 16
Pembrolizumab Product Description .................................................... 139


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LIST OF FIGURES
Figure 1
Subject Flow .......................................................................................... 39
Figure 2
Schematic for Study GSK208470 (ADP-0011-008)................................ 83
Figure 3
Case assessment for possible Guillain Barre Syndrome using diagnostic 
and prognostic tools supported by medical diagnosis and/or medical 
treatment ............................................................................................. 117
Figure 4
Diagnosis and Treatment of Guillain-Barré Syndrome (GBS)............... 119


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1.
BACKGROUND AND STUDY RATIONALE
1.1.
Adoptive T-cell Therapy
Adoptive T-cell therapy (ACT) is a treatment that uses a cancer subject’s own T lymphocytes 
with antitumor activity, expanded in vitro and re-infused into the subject.  The ultimate objective 
of the process is the stimulation and expansion of potent and antigen-specific T-cell immunity.  
There are numerous recent publications and reviews of ACT [Kalos, 2013; Klebanoff, 2016; 
Maus, 2014; Morgan, 2010; Robbins, 2011; Rosenberg, 2008].
The first observations that immune system engagement can lead to antitumor effects are often 
attributed to William Coley, who observed regression of sarcoma following severe bacterial 
infections in the 1890s.  Further observations of the spontaneous regression of malignant 
melanoma lesions initially led to the use of T cells isolated from tumor-infiltrating lymphocytes 
(TILs).  Cell therapy using tumor-reactive TILs has resulted in approximately 50% objective 
clinical regression in melanoma subjects [Dudley, 2005; Besser, 2010].  This therapy, however, 
has been limited by the requisite surgery to procure tumor-reactive TILs, by ex vivo
identification and expansion of these cells (TILs could be generated from only 50% of resected 
samples), and by the failure to reproducibly isolate similar cells from other cancer types.
Adoptive transfer of bulk T lymphocytes, obtained from the periphery and expanded ex vivo to 
generate large numbers of cells prior to reinfusion into subjects, is an alternative strategy for 
ACT [Rapoport, 2005].  However, tumor cells are well known to be immunologically selected 
for low antigen presentation and the majority of tumor antigens are normally expressed 
self-antigens.  Hence, the natural T-cell receptors (TCRs) that recognize self-tumor antigens may 
be of low affinity.  The high tolerance to tumor antigens with normal and/or developmental 
expression combined with the potent immunosuppressive microenvironment often present at the 
tumor site is manifest in most cases by suboptimal activation in terms of antitumor activity such 
that “native” T cells may not be sufficient to induce tumor cell death in most subjects with 
advanced malignancy.  Higher affinity TCRs allow T cells to respond to lower levels of antigen; 
this is important for tumor immunotherapy where the tumor microenvironment has adapted itself 
to reduce expression of antigen and also decrease expression of major histocompatibility 
complex (MHC) class I molecules [Marincola, 2000; Baccala, 2005; Barrett, 2009].
Gene-transfer-based strategies have therefore been developed to overcome the consequences of 
immune tolerance on the tumor-specific T-cell repertoire.  These approaches provide the 
potential to redirect T cells to effectively target tumors by the transfer of antigen-specific 
affinity-optimized T-cell receptors.  The majority of clinical approaches have employed T cells 
engineered to stably express transgenes via virus-based transduction.  Virus-mediated gene 
transfer approaches typically employ vectors that are derived from gamma retroviruses or more 
recently lentiviruses. 
Rational high-throughput genetic mutagenesis approaches have resulted in the ability to 
molecularly engineer TCRs with substantially higher affinities for target antigens.  TCR-based 
engineering approaches have certain inherent biological advantages, most notably that essentially 
all cellular proteins can be targeted because the approach is not limited to the targeting of cell 


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surface epitopes, and the primary T-cell activation signal is delivered in a physiological context, 
which may be relevant for optimal functionality of the infused T cells.  Additional details are 
provided in the current NY-ESO-1c259T Investigators’ Brochure (IB) for GSK3377794 [GSK 
Document Number 2018N369930_03].
1.2.
Adoptive Immunotherapy with NY-ESO-1 (c259) Specific T Cells 
NY-ESO-1 and LAGE-1a are members of the cancer-testis family of tumor antigens (CTAs).  
NY-ESO-1 gene expression was detected in 7-36% of multiple myeloma (MM) patients tested 
[Evans, 2001; van Baren, 1999] and has been shown to be highly expressed in poor prognosis 
MM [van Rhee, 2005].  
LAGE-1 mRNA was detected in 49% of MM patients [Andrade, 2008] and its expression in 
relapsed MM cases has been associated with shorter progression-free survival (PFS) [van Duin, 
2011]. LAGE-1a is among the genes whose expressions in MM patients have been shown to be 
correlated with resistance to proteasome inhibitor bortezomib [Richardson, 2003].
LAGE-1 encodes for two alternative splicing isoforms (a and b) and the corresponding encoded 
proteins are largely identical in the first 134 amino acids with 95% similarity between the two 
isoforms (LAGE-1a: 180 amino acids and LAGE-1b: 210 amino acids) [Matsui, 2008].  LAGE-1 
amino acid sequence is also highly similar to NY-ESO-1 [Andrade, 2008].  Its expression has 
been frequently detected in a selection of MM patients, despite the notably lower expression of 
its close homologue NY-ESO-1.  It has been suggested that because of the high sequence 
homology, LAGE-1 may also induce an immune response against NY-ESO-1. Moreover, the 
concomitant expression of LAGE-1 and NY-ESO-1 has been detected in 23% of the advanced 
stage MM patients [Condomines, 2007].
An HLA-A2 binding peptide (SLLMWITQC) corresponding to an amino acid sequence (157 to 
165) that is common to both NY-ESO-1 and LAGE-1a antigens has been identified that can be 
recognized by NY-ESO-1 reactive T cells. NY-ESO-1 epitopes are also recognized in the context 
of multiple HLA class II restriction elements.  Several studies have demonstrated antibodies 
against NY-ESO-1 in patients with cancer.  NY-ESO-1 may be particularly immunogenic.
T cells recognizing the immunodominant class I restricted HLA-A*02 binding peptide have been 
used to clone a specific T-cell receptor capable of recognizing this MHC restricted antigen.  
Further genetic engineering enhanced the affinity of this T-cell receptor toward the 
SLLMWITQC peptide bound to HLA-A*02.  The result is an enhanced affinity T-cell receptor 
designated as 1G4α95:LY TCR (c259 TCR), which shows preclinical activity in vitro and 
in vivo against NY-ESO-1/LAGE-1a expressing HLA-A*02+ tumors.  The 1G4α95:LY TCR 
mediates efficient recognition by CD8+ T cells of the HLA-A*02 bound peptide 157-165 and 
also mediates sufficient avidity to render CD4+ T cells capable of recognizing the 157-165 
peptide in the context of HLA-A*02.  This co-receptor independent recognition implies high 
avidity of the 1G4α95:LY TCR, a potentially important property of clinically active T-cell 
receptors.  The enhanced TCR binds with similar affinity to HLA-A2 subtypes HLA-A*02:01, 
HLA-A*02:05, and HLA-A*02:06. 


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As of 27 January 2019, 100 subjects have received NY-ESO-1c259T in (engineered using a 
lentiviral vector) in clinical trials in the indications of multiple myeloma, synovial sarcoma, 
melanoma, and ovarian cancer.  A total of 27 of these subjects had MM; 25 were treated with 
NY-ESO-1c259T in a post-transplant setting following myeloablative chemotherapy with high-
dose melphalan and stem cell rescue [Rapoport, 2015].  The remaining 2 subjects were treated 
with NY-ESO-1c259T with cyclophosphamide conditioning at a dose of 1500 mg/m2 x 1 day.  In 
the solid tumor (synovial sarcoma, melanoma, ovarian cancer) studies, the lymphodepleting 
regimens have consisted of cyclophosphamide with or without fludarabine.  Refer to the NY-
ESO-1c259T IB [GSK Document Number 2018N369930_03] for further details.  
1.3.
Multiple Myeloma
MM is a cytogenetically heterogeneous clonal plasma cell proliferative disorder [Rajkumar, 
2014]. It is characterized by several features as a result of the abnormal accumulation of 
myeloma cells within the bone marrow.  These features include: skeletal destruction, bone 
marrow failure with resultant anemia, thrombocytopenia and neutropenia; increased plasma 
viscosity and impaired renal function due to the secretion of M protein from myeloma cells into 
the blood and urine; and suppression of normal immunoglobulin production. 
The lifetime risk of getting MM is 1 in 143 (0.7%).  The average annual incidence of MM is 3-4 
per 100,000 persons representing 1.3% of all types of cancer.  An estimated 32,110 people in the 
US will be diagnosed annually and an estimated 12,960 will die from the disease [American 
Cancer Society, 2019].  On a worldwide scale, it is estimated that about 86,000 incident cases of 
MM occur annually, accounting for about 0.8% of all new cancer cases [Becker, 2011].  About 
63,000 subjects are reported to die from the disease each year, accounting for 0.9% of all cancer 
deaths.  Geographically, the frequency is very unevenly distributed in the world with the highest 
incidence in the industrialized regions of Australia/New Zealand, Europe, and North America.
There have been multiple advances for the treatment of MM that have revolutionized the 
treatment of this disease leading to increase in survival.  High-dose chemotherapy followed by 
autologous stem cell transplantation (ASCT) first introduced in the 1970s was shown in 
randomized trials versus chemotherapy to improve survival [Attal, 1996].  
Although high-dose chemotherapy using alkylating agents such as melphalan followed by 
autologous hematopoietic cell transplantation (HCT) remains a core component of aggressive 
treatment armamentarium in younger and fit selected group of myeloma patients, relapse or 
progression of the underlying disease after autologous HCT and subsequent maintenance therapy 
remains inevitable [Palumbo, 2014; McCarthy, 2012; Attal, 2012].  Treatment strategies for MM 
have evolved over time from non-specific conventional combination chemotherapy approach to 
more biologically targeted therapies including proteasome inhibitors, immunomodulatory agents, 
histone deacetylase inhibitors and monoclonal antibodies against either myeloma or bone 
marrow microenvironment target antigens. 
Immunomodulatory imide drugs (IMiDs, e.g., lenalidomide, pomalidomide) are approved for the 
treatment of patients with MM.  Two randomized, double-blind, placebo-controlled studies 
compared lenalidomide/dexamethasone to dexamethasone alone in patients with relapsed or 
refractory multiple myeloma (RRMM) who had received at least one prior treatment 


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[Dimopoulos, 2007; Weber, 2007; Rajkumar, 2005; Zonder, 2007].  In the study by Dimopoulos
et al, the median time to progression (TTP) was 11.3 months in the lenalidomide group and 
4.7 months in the placebo group (P<.001).  The hazard ratio for TTP was 2.85 (95% CI, 2.16-
3.76; P<.001) in favor of the lenalidomide group.  The median survival time in each study was 
similar and favored the combination arm [39.4 months (95% CI: 32.9, 47.4) 
lenalidomide/dexamethasone vs 31.6 months (95% CI: 24.1, 40.9) placebo/dexamethasone; 37.5 
months (95% CI: 29.9, 46.6) lenalidomide/dexamethasone vs 30.8 months (95% CI: 23.5, 40.3) 
placebo/dexamethasone] [Revlimid USPI, 2015].  Similarly, a phase 2, randomized open-label 
study of pomalidomide/dexamethasone vs pomalidomide in patients with RRMM (had 
previously received lenalidomide and bortezomib), the efficacy favored the combination 
[Richardson, 2014].  The median PFS for the combination vs single agent pomalidomide was 
4.2 and 2.7 months (HR = 0.68, 95% CI = 0.51-0.90, P = .003), overall response rates (ORRs) 
were 33% and 18% (P = .013), median response duration was 8.3 and 10.7 months, and median 
overall survival (OS) was 16.5 and 13.6 months (HR = 0.94, 95%, CI = 0.70-1.28, P = .709), 
respectively.
Proteasome inhibitors (e.g. bortezomib, carfilzomib) have also shown efficacy in subjects with 
RRMM.  In a randomized study of bortezomib versus dexamethasone in subjects with 
progressive multiple myeloma following 1 to 3 prior therapies, the ORR for bortezomib treated 
subjects was 38% and median TTP was 6.2 months as compared to the ORR of 18% and median 
TTP of 3.5 months in the dexamethasone treated subjects [Richardson, 2005].  In a single arm 
Phase 2 study of carfilzomib in subjects who had received a median of 5 prior lines of therapy 
including bortezomib, lenalidomide, and thalidomide, the ORR was 23.7% with a median 
duration of response (DOR) of 7.8 months [Siegel, 2012].  The ORR of 52.2% was achieved 
when carfilzomib was given to subjects who were bortezomib naïve further supporting its 
activity in RRMM [Vij, 2012].  Further study of carfilzomib in combination therapy 
demonstrated the efficacy of carfilzomib plus lenalidomide and dexamethasone vs lenalidomide 
and dexamethasone for relapsed MM.  PFS was significantly improved with the addition of 
carfilzomib: median PFS was 26.3 months, vs. 17.6 months in the lenalidomide+dexamethasone 
group (HR = 0.69; 95% CI = 0.57-0.83, P = .0001). 24-month OS rates were 73.3% and 65.0% 
in the carfilzomib+lenalidomide+dexamethasone and lenalidomide+ dexamethasone groups 
respectively (HR = 0.79; 95% CI = 0.63-0.99, P=.04).  ORR was also improved to 87.1% with 
the addition of carfilzomib, vs. 66.7% in the dexamethasone +lenalidomide group (P<.001) 
[Stewart, 2015].
The HDAC inhibitor panobinostat has been approved in combination with bortezomib and 
dexamethasone, for the treatment of subjects with MM who have received at least 2 prior 
regimens, including bortezomib and an IMiD.  A PFS advantage was shown in the panobinostat, 
bortezomib, and dexamethasone treated subjects compared with bortezomib and dexamethasone 
[12 months vs. 8.1 months; 0.63 (95% 0.52, 0.76); P < 0.0001] but the ORR did not differ 
(60.7% vs 54.6%) [San-Miguel, 2014].  In the final OS analysis the median OS in the 
panobinostat arm was 40.3 months and in the placebo arm 35.8 months (HR=0.94, 95% CI, 0.78-
1.14, P=.5435) [Richardson, 2016].


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Monoclonal antibodies such as elotuzumab (anti-SLAMF-7) and daratumumab (anti-CD38) are 
the most recently approved agents.  A study of elotuzumab plus lenalidomide and 
dexamethasone vs. lenalidomide and dexamethasone alone showed an ORR of 79% and 1-year 
PFS of 68% in elotuzumab treated subjects compared to ORR of 66% and 1 year PFS of 57% for 
lenalidomide and dexamethasone alone [Lonial, 2015].  A single agent study of daratumumab in 
subjects with RRMM who had received at least 3 lines of therapy showed an ORR of 29.2% with 
a median DOR of 7.4 months [Lokhorst, 2015].
Exploratory approaches with chimeric antigen receptor (CAR-T) targeting the anti-B-cell 
maturation antigen (BCMA) have shown promising results in early phase clinical studies [Raje, 
2019].  For example, bb2121 has been evaluated in patients who had received at least three 
previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or 
were refractory to both drug classes, with 85% ORR and median progression-free survival (PFS) 
of 11.8 months. Other promising BCMA-based immune-therapies, including bispecific T-cell 
engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of 
next generation CAR T cells, also demonstrate high anti-multiple myeloma activity in preclinical 
and early clinical studies. Among these, a recent early phase study with the anti-BCMA 
antibody-drug conjugate (ADC) GSK2857916 showed preliminary results from 35 patients with 
relapsed or refractory multiple myeloma, who received the recommended dose of the drug 
[Trudel, 2019]. In this study, 21 (60.0%) of 35 patients achieved PR or better, including two sCR 
and three CR. The mPFS was 12 months and mDOR was 14.3 month. 
Despite the number of therapies available to patients with RRMM, the majority of patients 
progress or relapse and die of their disease.  New therapies are needed to further improve 
outcomes in this patient population.
1.4.
NY-ESO-1c259T in Multiple Myeloma
Twenty-five (25) subjects with MM received NY-ESO-1c259T in the context of ASCT with 
melphalan as the conditioning regimen [study ADP-01411/NTC01352286].  The results on the 
first 20 MM subjects were reported [Rapoport, 2015].  All 25 subjects had active disease; 36% 
had undergone prior ASCT and 48% had high risk cytogenetic abnormalities (13q deletion, 17p 
deletion or >1 abnormality).  The most common treatment-emergent, related adverse events 
(AEs) occurring in >20% of subjects were diarrhea, rash, pyrexia, and fatigue.  Several subjects 
experienced a transient skin rash with lymphocytosis and others had a diarrheal syndrome that 
occurred later than expected for melphalan-induced mucositis, and which was later diagnosed as 
autologous graft versus host disease (aGVHD).  Autologous GVHD has been reported in the post 
ASCT MM population and has been characterized by diarrhea, colitis, and rash.  Liver chemistry 
elevations were low grade (Grade 1 or 2) and were of no clinical consequence.  No bilirubin 
elevations have been observed.  Most toxicities have occurred in the immediate post-treatment 
period (conditioning therapy and T-cell infusion) and usually resolved by Day 28 post-T-cell 
infusion.  Other than fatigue, the vast majority of AEs resolved by Day 42.  
Long-term follow-up including the analysis on the complete population of 25 enrolled MM 
subjects has now been reported [Rapoport, 2017].  T-cell expansion was detected in all subjects 
and persistence at Day 100 was observed in all but 1 subject.  Clinical responses were observed 


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in 20 of 25 subjects (80%) with active disease, with 10 of 25 subjects (40%) having very good 
partial response (VGPR) or complete response (CR) or stringent complete response (sCR) by 
Year 1.  The median PFS was 13.5 months (95% CI, 8.9-31.1), and the median OS was 
35.1 months (95% CI, 22.7-NR).  At study completion, 3 treated patients had remained disease 
progression-free for 60.6, 59.3, and 38.6 months, respectively.
1.5.
Rationale for Combination of NY-ESO-1c259T with Pembrolizumab 
for Multiple Myeloma
T cells are activated when the TCR binds specific antigen peptides presented by MHC on antigen 
presenting cells.  Additional costimulatory signals through CD28 binding to B7-1 and B7-2 are 
essential for proliferation and effector function.  The existence of a number of different 
immunosuppressive pathways can restrict the full potential of ACT.  Increased expression of 
inhibitory immune receptors, such as PD-1, on T cells can limit the adaptive immune response.  
The physiologic role of PD-1 is to maintain T-cell homeostasis by limiting T-cell activation and 
proliferation by ligation of PD-L1 to PD-1 which transmits an inhibitory signal reducing 
cytokine production and limiting T-cell proliferation.  PD-L1/PD-1 axis exerts its function as 
inhibitory mechanism counterbalancing the T-cell stimulatory signals.  PD-1 is also involved in 
the maintenance of peripheral self-tolerance via suppression of autoreactive T cells. 
Although PD-L1 is absent from normal plasma cells [Liu, 2007; Hallett, 2011] it has been shown 
to be present on myeloma cell lines and primary myeloma samples [Liu, 2007; Benson, 2010; 
Kuranda, 2010; Rosenblatt, 2011].  In a syngeneic PD-1 deficient mouse model, Iwai et al. first 
described that myeloma cell growth can be suppressed and also can be inhibited in normal 
syngeneic mice with an anti-PD-1 antibody [Iwai, 2002]. 
In a phase 1 study of single agent nivolumab (a fully human IgG4 monoclonal PD-1 receptor 
blocking antibody) in relapsed or refractory lymphoid malignancies, 27 subjects with MM were 
treated [Lesokhin, 2014].  There were no objective responses in the myeloma subjects with 67% 
stable disease rate.  Nivolumab was given in a dose escalating design at 1 mg/kg and 3 mg/kg 
administered every 2 weeks up to 2 years. 
San Miguel et al. reported the initial results of a phase 1 multicenter dose-escalation study of 
pembrolizumab (a humanized IgG4 anti-PD-1 monoclonal antibody) in 34 relapsed/refractory 
MM subjects (Keynote-023) with data on 17 subjects in the dose determination phase being 
provided in an abstract form [San Miguel, 2015].  Pembrolizumab was administered at 2 mg/kg 
to 200 mg/kg every 2 weeks in combination with 10 mg or 25 mg of lenalidomide on days 1-21 
and 40 mg of dexamethasone weekly, to be repeated every 28 days.  The objective response rate 
(ORR) was 76% with 4 of 17 subjects achieving very good partial response (VGPR) and 9 of 17 
subjects achieving partial response (PR).  ORR was observed in subjects with 
immunomodulatory-refractory and double-refractory disease [San Miguel, 2015]. 
These early results of anti-PD-1 antibody therapy especially in combination therapy are 
promising and many studies in MM using the strategy to target PD-1/PD-L1 axis are ongoing. 


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These results suggest that the combination of a targeted T-cell therapy with PD-1 blockage could 
result in improved efficacy.
1.5.1.
Pembrolizumab Pharmaceutical and Therapeutic Background
Pembrolizumab [Keytruda USPI, 2020] is a potent humanized immunoglobulin G4 (IgG4) 
monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 
(PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy 
for advanced malignancies.  Keytruda™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications.  For more details on specific indications refer to the 
pembrolizumab IB [Pembrolizumab, 2019].
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010].  Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma [Dudley, 2005; Hunder, 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene PDCD1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald, 2005; Okazaki, 
2001].
The structure of murine PD-1 has been resolved [Zhang, 2004].  PD-1 and its family members 
are type I transmembrane glycoproteins containing an Ig-variable–type (IgV type) domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch 
motif.  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, 
to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade [Okazaki, 2001; Chemnitz, 2004; Sheppard, 2004; and Riley, 2009].  The 
mechanism by which PD-1 down-modulates T cell responses is similar to, but distinct from, that 


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of CTLA-4, because both molecules regulate an overlapping set of signaling proteins [Parry, 
2005; Francisco, 2010].
Pembrolizumab has demonstrated initial clinical efficacy in combination with pomalidomide and 
dexamethasone in patients with relapsed/refractory myeloma and showed promising therapeutic 
activity [ORR was 50% in 11 of 22 evaluable subjects] and an acceptable safety profile in 
heavily treated RRMM patients [Badros, 2015].
Data from the on-going KEYNOTE-023 [Mateos, 2016] Phase 1 trial of pembrolizumab in 
combination with Revlimid and dexamethasone in patients with RRMM, has shown that of 40 
patients evaluable for response, 50% responded, with 1 of 40 (3%) achieving a stringent 
complete response (sCR), 5 of 40 (13%) a VGPR, 14 of 40 (35%) a partial response. An 
additional 19 of 40 (48%) achieved stable disease, which is generally viewed as a positive 
outcome in later-stage patients.  Among the patients who were refractory to Revlimid, 38% 
responded to combination therapy.  With a median follow-up time of 9 months (range 1-25), the 
median DOR was 11.3 months and the median time to achieve the first objective response was 
1.5 months (range 1.0-6.6). 75% of patients were still alive at time of clinical cut-off.  The data 
also suggests that this treatment combination has an acceptable safety and tolerability profile that 
is consistent with AEs reported for pembrolizumab used in slide tumors.
Certain AEs observed with checkpoint inhibitors have been termed immune-related AEs (irAEs).  
Immune-related AEs reported with pembrolizumab include pneumonitis (~3%), enterocolitis 
(~1%), hepatitis (~0.5%), nephritis, rash, and endocrinopathies (hypothyroidism [7-8%], 
hyperthyroidism [1-2%], pancreatitis, adrenal insufficiency, hypopituitarism [0.2-0.5%]).  
Exfoliative dermatitis, rash, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial 
seizures arising in a patient with inflammatory foci in brain parenchyma, and myasthenia gravis 
have been reported in less than 1% of patients.
Refer to the pembrolizumab IB and approved label for pembrolizumab for detailed background 
information [Pembrolizumab, 2019 and Keytruda USPI, 2020 respectively].
1.5.2.
Rationale for the Pilot Study
In this 2-arm pilot study, the safety, tolerability, and antitumor activity of NY-ESO-1c259T in 
subjects with RRMM in the context of a lymphodepleting preparative regimen of 
cyclophosphamide and fludarabine will be evaluated.  Arm 1 will evaluate NY-ESO-1c259T 
alone.  The antitumor activity demonstrated in study ADP-01411/NTC01352286 was in the 
context of ASCT.  Arm 1 of this study will assess antitumor activity of NY-ESO-1c259T in a non-
ASCT setting, isolating the efficacy and safety of NY-ESO-1c259T alone in patients with RRMM.
Arm 2 will evaluate NY-ESO-1c259T in combination with the PD-1 inhibitor pembrolizumab.  
The immunomodulatory molecule PD-L1 is expressed on malignant plasma cells, myeloma-
propagating pre-plasma cells and dendritic cells in the bone marrow of MM patients [Yousef, 
2015; Sponaas, 2015].  However, single agent PD-1 inhibition has not yet proven to be effective 


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in treating patients with RRMM.  The KEYNOTE-23 study early reports have already 
demonstrated the potential efficacy of combination therapy for these patients (see Section 1.5.1).
Additionally, PD-L1 expression on tumor cells and PD-1 on T cells can limit the adaptive 
immune response and promote resistance.  Internal data on PBMC or BM samples collected at 
various time points, post-infusion, for the 25 patients from study ADP-01411/NTC01352286 
show that CD8 T-cells that are either pentamer-positive or pentamer-negative (i.e. transduced or 
not respectively) express the exhaustion marker PD-1.  
Therefore, the combination of NY-ESO-1c259T and pembrolizumab could, not only result in an 
additive treatment effect from therapies with different mechanisms of action, but also may result 
in a synergistic effect due to the inhibition of PD-1 on the NY-ESO-1c259T cells.
Preliminary safety and efficacy data on each individual component as well as the mechanistic 
rationale around the potential synergies support the investigation of this combination.
Recent early clinical studies using anti- BCMA regimens have shown promising results in the 
RRMM therapeutic setting. Patients who have failed anti-BCMA therapies may potentially 
benefit from receiving the NY-ESO-1c259T cells because of the possible anti-tumor activity of 
targeting a non-redundant myeloma antigen [Raje, 2019; Trudel, 2019]. With this rationale, this 
study would include patients with RRMM in the post-BCMA failure setting [Timmers, 2019].
2.
TRIAL OBJECTIVES AND ENDPOINTS
Objectives and Endpoints:
Objective
Endpoint
Primary

To describe the safety and tolerability of 
autologous genetically modified T cells (NY-ESO-
1c259T) alone (Arm 1) or in combination with 
pembrolizumab (Arm 2) in subjects who are HLA-
A*02:01, HLA A*02:05, and/or HLA-A*02:06 
positive and have NY-ESO-1 and/or LAGE-1a 
positive relapsed refractory multiple myeloma.

Adverse events (treatment-limiting toxicities [TLT] 
and AEs), including serious adverse events (SAEs); 
laboratory assessments including chemistry, 
hematology and coagulation; and cardiac 
assessments by electrocardiogram (ECG).
Secondary

To evaluate the antitumor activity of autologous 
genetically modified T cells (NY ESO-1c259T) 
alone (Arm 1) or in combination with 
pembrolizumab (Arm 2) in subjects who are HLA-
A*02:01, HLA A*02:05, and/or HLA-A*02:06 
positive and have NY-ESO-1 and/or LAGE-1a 
positive relapsed refractory multiple myeloma

To describe the persistence of autologous 
genetically modified T cells (NY-ESO-1c259T) over 
time

Overall response Rate (ORR)

Time to Response (TTR)

Duration of Response (DOR) for subjects who 
achieve at least PR

Progression-free survival (PFS)

Maximum persistence (Cmax), time to Cmax 
(Tmax), and area under the time curve from zero to 
time t AUC(0-t), as data permit


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Objective
Endpoint
Exploratory

To describe the antitumor activity of autologous 
genetically modified T cells (NY-ESO-1c259T) 
alone (Arm 1) or in combination with 
pembrolizumab (Arm 2) in subjects who are HLA 
A*02:01, HLA-A*02:05, and/or HLA A*02:06 
positive and have NY ESO-1 and/or LAGE-1a 
positive relapsed refractory multiple myeloma.

Overall survival (OS).

To evaluate minimal residual disease (MRD) at 4 
months post T-cell infusion (Week 15).

MRD rate at Week 15.

To evaluate the persistence, phenotype, and 
functionality of NY-ESO-1c259 positive T cells.

Correlate persistence, phenotype, and functionality 
of NY ESO-1c259T in the peripheral blood and/or 
bone marrow with response to treatment and safety.

To understand mechanisms of resistance to NY-
ESO-1c259T.

Determine whether loss of NY-ESO-1 and/or LAGE-
1a expression in myeloma cells is a resistance 
mechanism.

Correlate apparition of anti-NY-ESO-1c259T 
antibodies with efficacy and safety.

Correlate expression of PD-L1 in the tumor 
microenvironment and PD-1 expression on T cells 
with response to treatment.

Correlate frequency of immune cell subsets in 
peripheral blood and/or bone marrow with treatment 
response.

Correlate frequency of immune cell subsets in 
peripheral blood and in bone marrow.

To evaluate antigen spreading as a mechanism of 
response.

Correlate clonal outgrowth of T-cell populations with 
tumor response following T-cell infusion.

To evaluate cytokine levels pre- and post-infusion 
on cytokine release syndrome (CRS).

Correlate cytokine levels with incidence and severity 
of CRS or other safety events.

To evaluate the impact of germline 
polymorphisms in IL-6, TNF-α, IL-10, INF-γ, and 
TGF-β on CRS.

Polymorphisms in germline DNA will be correlated 
with CRS.
3.
INVESTIGATIONAL PLAN
3.1.
Overall Study Design
This is a pilot study of genetically engineered NY-ESO-1c259T in HLA-A*02:01, HLA-A*02:05, 
and/or HLA-A*02:06 subjects with NY-ESO-1/LAGE-1a positive relapsed and refractory 
multiple myeloma (MM). Enrollment will continue in this study to ensure there are at least 10 
subjects in each arm who have received treatment (with NY-ESO-1c259T therapy for Arm 1 and, 
for Arm 2, NY-ESO-1c259T therapy and pembrolizumab), with at least 6 treated subjects per arm 
who have previously received and failed a BCMA-based therapy (CAR-T, ADC, or other types 


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of BCMA-targeted therapies). Assignment to one of two arms will proceed as outlined below. 
Per Protocol Amendment 4, a total of at least ten subjects are to be enrolled into Arm 1 prior to 
restart of enrollment into Arm 2.  Additional subjects may be enrolled if eligible subjects do not 
receive the NY-ESO-1c259T infusion for Arm 1 or, for Arm 2, the NY-ESO-1c259T infusion and 
pembrolizumab for any reason. It is anticipated that subject participation in this study will take 
approximately 42 months to complete (refer to Section 3.4). Figure 1 summarizes the subject 
flow in the study.

Part 1 – Eligibility Screening: Subjects will sign the Screening Informed Consent Form 
and will be screened for the presence of HLA-A*02:01, HLA-A*02:05, and/or HLA-
A*02:06 and for NY-ESO-1/LAGE-1a expression levels in the bone marrow 
(Section 3.2.1).  Subjects who screen positive for the relevant HLA alleles and for the 
NY-ESO-1 and/or LAGE-1a tumor antigen(s) will sign the Treatment Informed Consent 
Form and enter the Eligibility Phase of the study.  

Part 2 – Leukapheresis/Manufacture: If the subject meets the study eligibility criteria 
(Section 4), the subject begins the leukapheresis/manufacture part of the study. During 
this part, subjects can receive bridging therapy or a full line of another experimental 
regimen like a BCMA-targeted agent (Section 3.1.2.1 and Section 3.1.2.2). 
Note:  A subject is considered to be enrolled once the subject has undergone 
leukapheresis.

Part 3 – Lymphodepletion/Treatment:  Once NY-ESO-1c259T cells are released and the 
subject is eligible for the Treatment Phase of this study, lymphodepletion may begin, 
followed by NY-ESO-1c259T-cell infusion. Part 3 runs from the first day of 
lymphodepletion until disease progression or 108 weeks after NY-ESO-1c259T-cell 
infusion, whichever is sooner (completion of the Treatment Phase, see Section 4.2.2).

NOTE: Subjects who complete the Treatment Phase will transfer to the Long-Term 
Follow-Up (LTFU) protocol (GSK208750 [ADP-0000-002]) to continue long-term safety 
monitoring of subjects.  If the LTFU protocol is not available, subjects will be followed 
per the LTFU schedule of assessments detailed in Table 4 until the LTFU protocol 
becomes available.


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Figure 1
Subject Flow
* For subjects aged ≥60 years, lymphodepleting chemotherapy doses can be adjusted after consulting with the sponsor, as per Section 5.2.1.
**Subjects receiving an experimental line of therapy between leukapheresis and lymphodepletion must have progressive disease from this intermediate line of 
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3.1.1.
Part 1: Eligibility Screening
Subjects meeting all eligibility criteria will be assigned prior to leukapheresis into one of the 2 
treatment Arms:
Arm 1: Subjects will receive NY-ESO-1c259T alone as a single infusion.  
Arm 2: Subjects will receive NY-ESO-1c259T as a single infusion, in combination with 
pembrolizumab administered every 3 weeks.  In Arm 2, 3 weeks after the infusion of NY-ESO-
1c259T on Day 1, an initial dose of pembrolizumab will be administered on Day 22 (Week 3).  
The second dose of pembrolizumab will be administered three (3) weeks later, at Week 6, and 
subsequent doses of pembrolizumab will be administered every 3 weeks thereafter up to Week 
108 post T-cell infusion.  If toxicities that preclude pembrolizumab treatment (such as CRS 
Grade ≥2) are observed at Day 22 (Week 3), infusion of pembrolizumab will start on Week 6.  If 
toxicities have not resolved by Week 6, pembrolizumab will not be administered and the subject 
will be followed for visits as a subject in Arm 1.
Enrollment of Arm 1 will be completed before continuing enrolling subjects to Arm 2. 
Anticancer therapy may be administered between screening and leukapheresis, if a subject has 
progressive disease and cannot be treatment-free. The appropriate wash-out period (17) prior to 
leukapheresis should be applied.
3.1.2.
Part 2: Leukapheresis/Manufacture
Following assignment to either Arm 1 or 2, all subjects will undergo leukapheresis to obtain cells 
for the manufacture of autologous NY-ESO-1c259 bearing T cells.  Leukapheresis should be 
performed as soon as possible after the subject is determined to be eligible for study participation 
and assigned to a treatment Arm.  
3.1.2.1.
Bridging Therapy
During Part 2, supportive therapy can be administered to “bridge” the subject to the treatment 
part of this study (Part 3).Anticancer therapy (bridging therapy), may be administered between 
leukapheresis and the start of lymphodepletion if a subject has progressive disease and cannot be 
treatment-free, but mandatory washout periods (see exclusion criterion 21) must be respected.
Bridging therapy may consist of an experimental regimen under another study protocol, 
including with another Sponsor.
Adverse event collection for subjects receiving bridging therapy is described in Section 9.1
3.1.2.2.
Intermediate Line of Therapy
Between leukapheresis and lymphodepletion, an experimental line of therapy may be given (such 
as a BCMA-targeted agent) under another study protocol, including with another Sponsor. In this 


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case, subjects receiving an experimental line of therapy between leukapheresis and 
lymphodepletion must have progressive disease from this intermediate line of therapy before 
receiving lymphodepletion in Study 208470.
3.1.3.
Part 3: Lymphodepletion/Treatment
The subject must begin lymphodepletion within two years after leukapheresis. 
Less than or equal to 7 days before initiating the lymphodepleting chemotherapy, baseline 
eligibility criteria will be re-confirmed, and baseline multiple myeloma tumor assessment 
obtained.  Once the manufactured NY-ESO-1c259T product has been received and the integrity of 
the bag(s) has been verified by the site, each subject will undergo lymphodepletion with 
cyclophosphamide and fludarabine (Section 5.2) in preparation for infusion of NY-ESO-1c259T 
on Day 1 (Section 5.3).  Subjects will receive Granulocyte-Colony Stimulating Factor (G-CSF) 
support starting 24 hours after lymphodepleting chemotherapy.  Refer to Section 8 for supportive 
care guidance on T-cell infusion.
For subjects treated in Arm 2 with pembrolizumab (200 mg IV, every 3 weeks), the initial dose 
of pembrolizumab will be administered on Week 3 (on Day 22, 21 days after the T-cell infusion 
on Day 1).  The second dose of pembrolizumab will be administered three (3) weeks later, at 
Week 6, and subsequent doses of pembrolizumab will be administered every 3 weeks thereafter 
up to Week 108 post T-cell infusion.  If toxicities that preclude pembrolizumab treatment (such 
as CRS Grade ≥2) are observed at Day 22 (Week 3), infusion of pembrolizumab will start on 
Week 6.  If toxicities have not resolved by Week 6, pembrolizumab will not be administered and 
the subject will be followed for visits as a subject in Arm 1.
Subjects will be frequently monitored for any unexpected ≥Grade 3 AE and any SAE; subjects 
treated in the combination Arm 2 will also be monitored for TLTs as outlined in Section 3.3.5.
Efficacy, safety, and biomarker assessments to be conducted at each visit are outlined in the 
Schedule of Procedures (Table 3).  The efficacy will be assessed using the International 
Myeloma Working Group (IMWG) Response Criteria [Kumar, 2016].
Subjects will complete the Treatment Phase of the study upon diagnosis of their disease 
progression or 108 weeks after NY-ESO-1c259 T-cell infusion, whichever is sooner (refer to 
Figure 1).  If disease progression occurred prior to the Week 12 visit, subjects should remain on 
the treatment phase schedule to ensure collection of safety following T-cell infusion for a 
minimum of 9 weeks. 
All subjects will ultimately enter a LTFU protocol once they meet one of the criteria for the 
transfer (Section 4.4).


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Passage to the Long-Term Follow-Up (LTFU) Study 
Subjects will be followed for observation of delayed AEs for up to 15 years from the time of the 
T-cell infusion in accordance with FDA [FDA, 2020] and EMA [EMA, 2009] requirements for 
gene therapy clinical trials.  All subjects will continue to be followed for OS during the LTFU 
phase. 
3.2.
Rationale for Components of Study Design
3.2.1.
Screening for HLA and for expression of NY-ESO-1 and LAGE-1a 
antigens in the Context of NY-ESO-1c259T
The prevalence of HLA sub-types varies from population to population, the most common in the 
Western world being HLA-A*02, thus HLA-A*02 is extensively studied structurally and 
functionally. 
The NY-ESO-1c259T specifically recognizes the HLA-A*02:01, HLA-A*02:05, and 
HLA-A*02:06-restricted NY-ESO-1/LAGE-1a peptide antigen HLA-A*02-SLLMWITQC; 
therefore, this protocol will select for subjects with these three most common HLA-A*02 allelic 
variants.  Further information on prevalence is available at www.allelefrequencies.net.  It is 
recommended that Investigators review the database for HLA-A2 allelic variants relevant to the 
study population at their site.
3.2.2.
T-cell Manufacturing
NY-ESO-1c259T is one of the two Investigational Products (IPs) in this study; NY-ESO-1c259T is 
comprised of autologous CD4 and CD8 T cells that have been transduced with a self-inactivating 
(SIN) lentiviral vector expressing an affinity enhanced NY-ESO-1/LAGE-1a specific TCR.  The 
product of this transduction is polyclonal T cells which are designed to target NY-ESO-1/LAGE-
1a in tissue.  The transfer vector is a SIN lentiviral vector which has been meticulously designed 
to contain only the minimal genetic elements required for function, and no vector proteins for 
maximum biosafety [Dull, 1998].  Lentiviral vectors are a subset of retroviral vectors thought to 
have an enhanced safety profile.  Many reports provide evidence supporting the relative 
biosafety of SIN lentiviral vectors in terms of genotoxicity, resulting primarily from the lack of 
enhancer activity in the lentivirus long terminal repeat (LTR) in comparison to the γ retroviral 
vectors [Montini, 2006; Maruggi, 2009; Modlich, 2009; Montini, 2009]. 
Selected qualified manufacturing sites will prepare NY-ESO-1c259T for subjects enrolled at all 
sites. Utilizing anti-CD3/CD28 monoclonal antibody (mAb) coated magnetic beads, T cells are 
enriched, activated and expanded (for at least 13 days). Cell product typically is ready to be 
returned to the site within less than three months after subject apheresis and will be available for 
shipment approximately one week prior to the scheduled infusion and before the start of 
chemotherapy.


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After the ex vivo activation and expansion, the final cellular product is typically >90% T 
lymphocytes since the culture conditions do not support the growth of macrophages, natural 
killer (NK) or B cells.  By the end of the culture period, B cells comprise approximately <2%, 
NK cells approximately <2%, and macrophages approximately <1% of the total culture. 
Additional details are provided in the NY-ESO-1c259T IB [GSK Document Number 
2018N369930_03].
3.2.3.
Lymphodepletion
The incorporation of lymphodepletion prior to ACT may enhance immune reconstitution by the 
transferred cells and increase tumor specific responses.  Immune reconstitution is enhanced 
through homeostatic mechanisms that facilitate expansion of T lymphocytes [Baccala, 2005] and 
facilitate trafficking of the engineered T cells [Pinthus, 2004].  Lymphodepletion also enhances 
the activity of the adoptively transferred cells via the removal of inhibitory factors such as 
regulatory T cells [Wolf, 2003] and can activate antigen presenting cells through the induction of 
inflammatory cytokines and induction of tumor apoptosis with resulting cross presentation of 
tumor antigens to T cells.
Recent evidence suggests that preparation for successful engraftment and expansion of gene 
modified adoptive cellular therapy depends not just on the depth of cytoreduction but 
additionally on the specific action of some cytotoxic drugs.  Recent studies in lymphoma, 
chronic leukemia, and acute leukemia using adoptive cellular therapy including a chimeric 
antigen receptor showed increased T-cell expansion, persistence, and disease-free survival when 
fludarabine was added to a previously cyclophosphamide-only preparative regimen [Turtle, 
2016].
Based on the results from our previous clinical research using combination fludarabine-
cyclophosphamide lymphodepleting chemotherapy and the increasing evidence that fludarabine 
may be a necessary component, the lymphodepleting regimen in this study consists of 
fludarabine 30 mg/m2/day and cyclophosphamide 900 mg/m2/day intravenously for 4 and 3 
consecutive days, respectively (see dose modification for patients over 60 years of age in Section 
5.2).
3.2.4.
T-Cell Infusion
One of the IPs in this study is the infusion of autologous T cells transduced with lentivirus 
encoding enhanced TCR specific for NY-ESO-1c259T (see Section 5.3 for administration details).
3.2.5.
Rationale for NY-ESO-1c259T Dose
Activity of NY-ESO-1c259T seems to be indirectly related to dose administered (depending also 
on cell expansion and persistence).  Total T-cell doses up to ~100 × 109 cells (median of 5 × 1010
transduced T cells with an anti-NY-ESO-1 TCR range of 1.6 to 130 ×109) [Robbins, 2011] have 
been used although the actual products may differ depending on manufacturing methods.  


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Conversely, doses of CAR-T cells as low as 1.5 × 105 CD19 may also be effective [Porter, 
2011].
Current experience with NY-ESO-1c259T (n=100 subjects treated as of January 2019) is with total 
cell doses in the range of 0.4 × 109 to 3.47 × 1010 with a transduction level of ~18 to 75% 
(transduced cell dose range of 0.23 × 109 to 14.36 × 109).  No identifiable increase in AEs has 
been observed in subjects who received higher transduced cell doses (>5 × 109 cells).  Of the 
5 subjects who received <1 × 109 transduced cells, 3 subjects had poor expansion and persistence 
of transduced cells; meaningful clinical responses were not observed in 4 of the 5 subjects.  No 
clear dose response relationship has been observed to-date.
Based on this data, a range of 1 × 109 to 8 × 109 transduced cells will be administered by a single 
intravenous (IV) infusion on Day 1.  If the transduced cell dose is less than the minimum dose of 
1 × 109, manufacturing of additional transduced T cells from excess banked leukapheresis 
product will be undertaken to achieve a total dose in the target range.  In the event that no banked 
leukapheresis product is available a second leukapheresis may be performed to achieve a dose in 
the target range.
3.2.6.
Rationale for Pembrolizumab Dose and Timing of the First Dose
3.2.6.1.
Rationale for Pembrolizumab Dose
Pembrolizumab is the other IP in this study and will only be given to subjects in Arm 2.  The 
dose of pembrolizumab planned to be studied in this trial is 200 mg administered Q3W from 
Week 3 (or Week 6) until Week 108.
Based on the totality of data generated in the Keytruda development program, 200 mg every 
three weeks (Q3W) is the appropriate dose of pembrolizumab for adults across all indications 
and regardless of tumor type.  As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including OS at 
200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [PBPK] analysis) at 200 mg Q3W.
Among the 8-randomized dose-comparison studies, a total of 2262 subjects were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 


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KN001 Cohort F2 and KN006).  All of these studies demonstrated flat dose- and exposure-
response relationships across the doses studied representing an approximate 5- to 7.5-fold 
difference in exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to 
the highest doses studied.  Subsequently, flat dose-exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer and 
classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of 
the tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other subject covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported 
by these PK characteristics and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols.
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage.  The existing data suggest 200 mg 
Q3W as the appropriate dose for pembrolizumab.
3.2.6.2.
Rationale for Timing of First Dose
Timing of the first dose of pembrolizumab takes into account the mechanism of action of both 
agents as well as their safety profiles.   The lymphocyte nadir induced by the lymphodepleting 
chemotherapy coincides with the NY-ESO-1c259T-cell infusion at study Day 1.  As T cells 
expand, they express exhaustion markers including PD-1 (internal data) therefore 
pembrolizumab should be administered when the AEs of lymphodepleting chemotherapy and T-
cell infusion have begun to subside and expanding PD-1 expressing T-cells are present.  The 
contraction phase of the T cells begins by Week 3, however there is persistence of the PD-1 
expressing transduced NY-ESO-1c259T cells at this point in time.  A review of the treatment-
emergent toxicities in the first 53 patients treated with NY-ESO-1c259T in GSK clinical trials 
shows that while 41 of 53 (77%) subjects experienced ≥Grade 2 AEs in the first week post T-cell 
infusion, these AEs resolved to an acceptable level by Week 3 and that only one (1) subject (2%) 
has experienced a Grade 2 AE of elevated alanine aminotransferase (ALT) that would have 
precluded from receiving the first dose of pembrolizumab at Week 3.


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The first dose of pembrolizumab in this study will be given 3 weeks after T-cell infusion 
(Day 22).  The separation of the T-cell infusion and the first dose of pembrolizumab will allow 
for the checkpoint inhibitor administration when PD-1 expressing T cells persist while 
minimizing the potential for overlapping toxicities.
3.3.
Assessment of Safety and Treatment Limiting Toxicities
Safety will be assessed in a continuous manner (See Section 8 for general considerations on 
supportive care).  
The Sponsor will review the safety throughout the conduct of the study and share the data on a 
frequent basis with the Investigators (Investigator teleconference) and a Safety Review Team 
(SRT).  Refer to Section 10.3 for a description of the SRT.
Safety data will be proactively reviewed for each subject and/or summarized by subject and in 
aggregate across subjects by arm.  The toxicities observed will be reviewed in the context of the 
known safety profiles of NY-ESO-1c259T and pembrolizumab.  
Most toxicities associated with lymphodepleting chemotherapy and NY-ESO-1c259T occur in the 
first 4 weeks of therapy.  Resolution of these toxicities is generally observed by Week 4 post 
T-cell infusion (approximately 5 weeks after the initiation of lymphodepleting chemotherapy).  
Toxicities associated with pembrolizumab have variable times to onset.  When pembrolizumab is 
administered with NY-ESO-1c259T, it is expected that the checkpoint blockade will activate the 
immune system.  This could lead to enhanced antitumor activity as well as toxicity, hence, the 
pause of enrollment in Arm 2 combination arm described in Section 3.3.1 below. 
In the absence of a clear alternative etiology (e.g., chemotherapy and concomitant medications, 
disease progression, infections, etc.), AEs should be considered potentially immune-related.  
Immune-related AEs may include diarrhea/colitis, rash, hepatitis, graft versus host disease 
(GVHD), cytokine release syndrome (CRS), secondary pancytopenia, pneumonitis, 
endocrinopathies, nephritis, and any other manifestations that may indicate an immune-related 
phenomenon.
Additional criteria for possible suspension of treatment/enrollment are also provided in 
Section 4.7.  
3.3.1.
Pause of Enrollment in Arm 2 After the Third Subject in Arm 2 Begins 
Lymphodepletion 
Study enrollment to Arm 2 will be paused after the third subject enrolled in Arm 2 has started 
lymphodepletion, in order to allow for a complete safety review to be conducted by the Sponsor 
and the SRT, and before a decision to resume enrollment in Arm 2 can be made (see 
Section 3.3.3 for the scope and timing of the safety review).  
If one or more of the first three (3) subjects who receive lymphodepletion in Arm 2 fails to 
receive NY-ESO-1c259T or fails to initiate pembrolizumab by Week 6 due to unresolved 


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toxicities, the enrollment may be re-opened temporarily and paused again each time a new 
subject begins lymphodepletion in Arm 2.  This will ensure accrual of the 3 subjects needed for 
the initial safety evaluation (3 subjects treated with NY-ESO-1c259T and who have initiated 
pembrolizumab), without over enrolling prior to the conclusion of the complete safety review of 
the first 3 subjects.  Per Section 3.3.4, the SRT may recommend that enrollment should not be 
temporarily re-opened before the safety evaluation is complete.  If more than 3 subjects enrolled 
in Arm 2 are apheresed and have cells manufactured before completion of the evaluation, the 
SRT will determine in terms of benefit:risk if the safety data available at the time supports 
proceeding with treatment of any of the additional subjects while the data from the first 
3 subjects treated is being reviewed.
3.3.2.
Scope of Reviews by the SRT
All serious adverse events (SAEs) and AEs ≥Grade 3 will be reviewed for both arms. 
This is the first time NY-ESO-1c259T is being administered in combination with pembrolizumab.  
To ensure that the toxicities observed with the combination are consistent with the known safety 
profiles of each individual therapy not only in terms of their type, but also of their incidence and 
their severity, subjects in Arm 2 will additionally be monitored for:

treatment limiting toxicities as defined in Section 3.3.5

any AE that led to treatment discontinuation of pembrolizumab
After the first 3 subjects on Arm 2 who have been dosed with NY-ESO-1c259T and initiated 
pembrolizumab with at least 3 weeks of follow-up after the first dose, a complete safety review 
will be conducted (see Section 3.3.3).  During this review and from that point on, considerations 
should also be given by the SRT to the clinical/statistical guidance in Section 11.4.1.2.
3.3.3.
Complete Safety Review before Resuming Enrollment
The complete safety review will require TLT assessment of the first three (3) subjects assigned 
to Arm 2 who have been infused with NY-ESO-1c259T, received their first dose of 
pembrolizumab and cleared the TLT 3-week assessment period.
3.3.4.
Frequency of SRT meetings
SRT will meet to conduct the safety review described in Section 3.3.3; meeting frequency will be 
determined in the SRT charter.
The SRT may at any time recommend pausing/delaying/stopping/resuming enrollment in either 
arm of the study.


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3.3.5.
Treatment Limiting Toxicities (TLTs)
3.3.5.1.
Three-Week Assessment Period
To evaluate the feasibility of the combination in Arm 2, TLTs will be assessed for the 3-week 
period as follows:

from Week 3-Week 6 for subjects who initiated pembrolizumab on Week 3, or 

from Week 6-Week 9 for subjects who initiated pembrolizumab on Week 6.

from Week 3-Week 6 for subjects who have been permanently precluded from 
initiating pembrolizumab due to unresolved toxicities after 6 weeks post T-cell 
infusion.
3.3.5.2.
TLT Definition

The following toxicities are considered to be TLTs:

Any ≥ Grade 4 AE except for the exclusions listed below.

Grade 3 non-infectious pneumonitis.

Any other Grade 3 AE (excluding pneumonitis), that does not improve to Grade 2 
within 7 days after onset despite medical management and supportive care.

The following toxicities are NOT considered to be TLTs:

Grade 3 or 4 leukopenia, lymphopenia, neutropenia, or febrile neutropenia;

Grade 3 or 4 thrombocytopenia not associated with significant bleeding; 

Grade 3 anemia;

Grade 4 cytokine release syndrome (CRS) or toxicities related to CRS resolving to 
Grade ≤ 2 within 7 days;

Other Grade 3 laboratory abnormality determined to be not clinically significant by the 
Investigator;

Grade 3 or 4 fever and chills; 

Grade 3 or 4 hypoalbuminemia or abnormal electrolytes that are responding to 
supplementation/correction; 

AE related to the cancer or its progression.
Any AE that prevents dosing of pembrolizumab at Week 3, has not resolved to acceptable level 
by Week 6, and consequently precludes a subject assigned to Arm 2 from initiating 
pembrolizumab will be counted as a TLT.
An AE not listed above may be defined as a TLT after consultation with the Sponsor, the 
Investigators, and the SRT based on the emerging safety profile.  


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3.4.
Number of Subjects and Duration of Study
Enrollment will continue in this study to ensure there are at least 10 subjects in each arm who
have received treatment (with NY-ESO-1c259T therapy for Arm 1, and, for Arm 2, NY-ESO-
1c259T therapy and pembrolizumab), with at least 6 treated subjects per arm who have previously 
received and failed a BCMA-based therapy (CAR-T, ADC, or other types of BCMA-targeted 
therapies). For these post-BCMA subjects, BCMA-targeted therapies may have been received 
prior to enrollment in this study or as an intermediate line of therapy between leukapheresis and 
lymphodepletion while on this study. 
If 10 subjects have been enrolled into Arm 1 but fewer than 6 of those 10 subjects have or will 
receive some type of BCMA therapy, then any eligible subject who has or will receive BCMA 
therapy will be enrolled into Arm 1 until the target enrollment of 6 post-BCMA subjects in Arm 
1 has been reached.  Until enrollment into Arm 1 is complete, subjects who have not or will not 
receive any BCMA therapy will be enrolled into Arm 2.
Once at least 10 subjects overall and at least 6 post-BCMA subjects have been enrolled into Arm 
1, then all subsequent subjects regardless of BCMA therapy status will be enrolled into Arm 2.  
In both arms, subjects who do not receive NY-ESO-1c259T therapy may be replaced.
In Arm 2, in case of subjects who do not receive pembrolizumab (perhaps due to incompatible 
toxicity after NY-ESO-1c259T-cell infusion), enrollment may be further extended to ensure at 
least 10 subjects will receive pembrolizumab.
It is assumed that approximately 20% of the subjects will discontinue from the study prior to 
NY-ESO-1c259T cell infusion.
Study enrollment is expected to require approximately 18 months. It is anticipated that the final 
analysis would be conducted approximately 24 months after the last subject has been enrolled, or 
shortly after the last subject has disease progression, whichever is sooner. The study will be 
considered complete once the last enrolled subject has transitioned to the LTFU protocol 
GSK208750 (ADP-0000-002).
3.5.
Sites
The protocol will be conducted in approximately 10 sites in North America and Europe.  The 
number of centers is necessary to ensure recruitment in this targeted population.  Additional 
centers may be added at the discretion of the Sponsor.
3.6.
Benefit:Risk Assessment
The results of Clinical and Non-Clinical studies conducted with NY-ESO-1c259T are summarized 
in the IB [GSK Document Number 2018N369930_03].  Similarly, results of studies conducted 
with pembrolizumab are summarized in the pembrolizumab IB [Pembrolizumab, 2019].  It 
cannot be guaranteed that subjects in clinical trials will directly benefit from treatment during 


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participation as these studies are designed to provide information about the safety and 
effectiveness of investigational medicines.  This section outlines the potential benefits, risks and 
the mitigation strategy for this study.
3.6.1.
Benefit Assessment
NY-ESO-1 and LAGE-1a are highly expressed (based on gene expression profiling) in patients 
with MM. Increased expression of NY-ESO-1 antigen has been observed in patients with 
cytogenetic abnormalities compared to those with normal cytogenetics (60% versus 31%, 
P=.004) and in relapsing patients especially those with cytogenetic abnormalities (100% 
relapsing patients versus approximately 60% at diagnosis, P <.001) [van Rhee, 2005].  NY-ESO-
1 and LAGE-1a antigens are ideal tumor targets for immunotherapies.
This clinical trial is designed to evaluate the safety, tolerability and antitumor activity of 
NY-ESO-1c259T in subjects with RRMM whose tumors express NY-ESO-1 and/or LAGE-1a. 
Despite the many advances in treatment for MM, including promising clinical data from early 
studies testing anti-BCMA targeted therapies in RRMM [Raje,2019; Trudel, 2019], patients with 
RRMM ultimately die from their disease and more effective therapies are needed.  In this study, 
enrollment is allowed to subjects who have received and failed an anti-BCMA targeted therapy. 
These subjects may potentially benefit from receiving the NY-ESO-1c259T cells because of the 
possible anti-tumor activity of targeting a non-redundant myeloma antigen [Timmers, 2019]. 
Safety and antitumor activity of NY-ESO-1c259T in patients with multiple myeloma has been 
demonstrated in the context of ASCT [Rapoport, 2015].  Twenty-five (25) subjects with MM 
have received NY-ESO-1c259T in conjunction with ASCT on study ADP-01411/NTC01352286.  
Clinical responses for this group were observed in 16 of the first 20 myeloma subjects (80%) 
with active disease, with 14 of 20 subjects (70%) having near complete response (nCR) or CR by 
Day 100 [Rapoport, 2015].  At final analysis, three patients remained disease progression-free at 
38.6, 59.2, and 60.6 months post-NY-ESO-1c259T. Median progression-free survival was 13.5 
months (range, 3.2-60.6 months); median overall survival was 35.1 months (range, 6.4-66.7 
months) [Stadtmauer, 2019].  
Pembrolizumab is a potent and highly selective humanized anti–PD-1 monoclonal antibody that 
directly blocks the interaction between PD-1 and its ligands.  Pembrolizumab is approved for 
advanced melanoma and non–small cell lung cancer and has demonstrated robust antitumor 
activity in multiple cancers.
As a single agent, anti-PD-1 antibodies have shown minimal activity in relapsed MM: nivolumab 
alone could only demonstrate a stable disease rate of 67 percent in a phase I trial; partial 
responses or better were not seen [Lesokhin, 2014].  However, high response rates have been 
observed when anti–PD-1 antibodies and IMiDs are used in combination. Preliminary findings 
from the phase I KEYNOTE-023 (NCT02036502) [San Miguel, 2015] study of pembrolizumab 
in combination with the established lenalidomide+dexamethasone regimen (ORR 76%, median 
DOR 9.7 months) and early reports of a phase II study combining pembrolizumab with 
pomalidomide (Pomalyst) and dexamethasone (NCT02289222) [Badros, 2015] (ORR 60%, 75%
PFS at 6 months) both show early signs of activity in heavily pretreated patients with MM.  


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This evidence supports the potential therapeutic benefit of NY-ESO-1c259T in combination with 
pembrolizumab in patients with MM.
3.6.2.
Risk Assessment
The known safety profile of GSK3377794 is based on 119 enrolled and 100 treated subjects as of 
27 January 2019 (IB [GSK Document Number 2018N369930_03]). The most commonly 
reported treatment-emergent adverse events which occurred in 50% of subjects following 
GSK3377794 infusion were nausea (82%), anemia (79%), neutropenia (79%), leukopenia (78%), 
thrombocytopenia (75%), pyrexia (73%), fatigue (72%), diarrhoea (58%) and lymphopenia 
(50%).    The most common Grade 3 and 4 AEs which occurred in 50% of subjects following 
lymphodepleting chemotherapy and GSK3377794 infusion were leukopenia (76%), neutropenia 
(71%), thrombocytopenia (60%), and anemia (57%). These AEs are consistent with expected 
immediate adverse events after lymphodepletion chemotherapy. 
Across all studies, 34 (34%) subjects had SAEs considered by the Investigator to be related to 
study treatment.  The most common treatment-related SAEs were: CRS (12%), pyrexia (7%), 
febrile neutropenia (3%), neutropenia (3%), rash (3%), dehydration (2%), diarrhea (2%), 
Guillain-Barré syndrome (2%), hypotension (2%), thrombocytopenia (2%), and unspecified 
GvHD (2%).  For the 15 subjects who received a second infusion, five treatment related SAEs 
were reported after second T-cell infusion, which included 1 case each of CRS, cytomegalovirus 
infection, thromboembolism, febrile neutropenia, and rash.
Among the adverse events of special interest, 
1. CRS was reported in 29 cases (of 100) as of 27 January 2019 across all GSK3377794 
clinical trials.  Of these, there was 1 subject with Grade 4, 6 with Grade 3, 11 with Grade 
2, and 11 with Grade 1.  Five cases were treated with tocilizumab.  Median duration of 
the CRS events was 8 (after first infusion) and 9 days (after second infusion (range across 
first or second infusion 2-28 days). 
2. A total of 7 cases (of 100) of GvHD have been reported of which 3 cases were reported 
as an SAE.  All cases were Grade 1-3, occurred in patients with multiple myeloma, and 
completely recovered with supportive treatment.  Six (6) out of 7 subjects with reported 
GvHD were from Study 209393 (formerly ADP-01411) which required an allogeneic 
stem cell transplant prior to the T-cell infusion.  
3. Encephalopathy was reported in 1 case with multiple brain metastasis, that was transient, 
and resolved in 2 days with supportive care.
4. Five (5%) subjects had reported treatment-emergent AE of pancytopenia (3 subjects: 2 
with Grade 3, and 1 with Grade 1) or bone marrow failure (2 subjects: 1 with Grade 5 
fatal, and 1 with Grade 2) (refer to IB [GSK Document Number 2018N369930_03] for 
details).
5. Guillain Barre Syndrome (GBS) has been reported in 2 subjects, both of which 
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To date, none of the analyses for Insertional oncogenesis and Replication competent lentivirus 
are positive for insertional oncogenesis or replication competent lentivirus. The potential risks of 
replication competent lentivirus (RCL) and insertional oncogenesis are being monitored in 
accordance with FDA guidance [FDA, 2006]. With the advent of replication incompetent 
lentivirus and the use of fully differentiated human T cells, there have not been any oncogenic 
integration events reported in any patient treated with T-cell gene therapy. 
To date, on all samples assessed for evidence of insertional oncogenesis and replication 
competent lentivirus, the reported findings have been negative.
For those subjects who are enrolled in Study 208470 after having failed other gene and cell 
therapies (e.g. anti-BCMA CAR-T cell treatment) the risk of insertional oncogenesis following 
two separate gene transduction events using lentivirus technologies is nonetheless, considered 
extremely unlikely.
Guidance for the management of CRS, GVHD and pancytopenia with bone marrow failure 
following initial bone marrow recovery is provided in the protocol.  The guidance is based on 
published literature (see Section 8).  There are no published treatment guidelines for autologous 
GVHD, therefore guidance for treatment of allogeneic GVHD is used.  Study sites are expected 
to have access to physicians with expertise in bone marrow transplant, and infectious diseases for 
consultation in the event of a subject developing either CRS or GVHD-like symptomatology.  
Electronic case report forms have been created to specifically capture information on these 
toxicities.  
GSK are also monitoring reports of recurrent pancytopenia after initial bone marrow recovery 
following lymphodepleting chemotherapy and NY-ESO-1c259T-cell infusion.  In order to manage 
this risk, the Sponsor have developed standard protocol guidance on the management of 
pancytopenia with bone marrow failure following initial bone marrow recovery.  Management of 
bone marrow failure (aplastic anemia) and related cytopenias is challenging, with no clearly 
established guidelines regarding immunosuppression.  Therefore, treatment is largely supportive, 
including transfusions and treatment of infections.  Guidance includes a recommendation to 
consult with physicians with expertise in the management of aplastic anemia and infectious 
diseases.
The goal of the risk management measures is to maximize the chance of therapeutic benefit 
while mitigating and better understanding the risks of treatment with NY-ESO-1c259T-cell 
therapy.
The overall safety profile of pembrolizumab is derived primarily from the Merck’s Reference 
Safety Dataset (RSD) (n=2799) which is a locked and verified dataset with pooled data from 
monotherapy clinical trials in melanoma and NSCLC.  The majority of subjects, 2727 or 97.4%, 
experienced 1 or more AEs, and 2062 (73.7%) experienced 1 or more AEs reported as drug-
related by the investigator.  The percentage of subjects who experienced SAEs was lower; 1042 
(37.2%) of subjects experienced 1 or more SAEs; 334 (11.9%) subjects discontinued due to an 
AE, and 282 (10.1%) subjects experienced a drug-related SAE, as determined by the 
investigator.  The 5 most frequently reported AEs were: fatigue (37.3%), nausea (24.5%), 


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decreased appetite (22.5%), diarrhea (22.3%), and cough (22%).  The 5 most frequently reported 
SAEs were pneumonia (3.0%), pleural effusion (1.7%), pneumonitis (1.6%), dyspnea (1.6%) and 
pulmonary embolism (1.5%).  The 5 most frequently reported AEs considered drug related by 
the investigator were fatigue (24.2%), pruritus (16.7%), rash (13.8%), diarrhea (12.3%), and 
nausea (10.9%). The 5 most frequently reported SAEs considered drug-related by the 
investigator were pneumonitis (1.6%), colitis (0.9%), diarrhea (0.6%), pyrexia (0.4%), and 
autoimmune hepatitis, pneumonia, adrenal insufficiency, and hyponatremia, all reported at an 
incidence of (0.3%).  Pembrolizumab has a positive benefit-risk profile and is well tolerated in 
the approved indications, as evidenced by a low rate of toxicity Grade 3 to 5 drug-related AEs 
(13.8%), discontinuations due to AEs (11.9%), and deaths due to drug-related AEs (0.4%).  
Furthermore, the frequency of immune-mediated AEs is low, and these events are readily 
managed in the clinical setting.
Patients who receive allo-SCT following treatment with checkpoint inhibitors may be at 
increased risk for certain adverse effects including GVHD, veno-occlusive disease, febrile 
syndrome, and encephalitis.
Multiple myeloma is not an approved indication for pembrolizumab but numerous studies in 
patients with multiple myeloma are ongoing.  Toxicity profile of pembrolizumab in multiple 
myeloma patients observed so far had been similar to studies in other tumor types, but important 
safety and efficacy information have now been reported on 2 Merck-sponsored trials that 
combined (1) pembrolizumab with pomalidomide and dexamethasone (KN183, NCT02576977) 
in subjects with refractory or relapsed and refractory multiple myeloma and (2) pembrolizumab 
with lenalidomide and dexamethasone (KN185, NCT02579863) in subjects with newly 
diagnosed and treatment naïve multiple myeloma.  The US FDA placed studies KN183, KN185 
and a cohort of KN023 (subjects with refractory or relapsed and refractory multiple myeloma on 
pembrolizumab+lenalidomide+dexamethasone) on full clinical hold based on an excess number 
of deaths in the investigational arms of both KN183 and KN185.  For KN183 the OS HR of the 
pembrolizumab containing investigational arm compared to the control arm was 1.61 (95% CI: 
0.91, 2.85), increasing the relative risk of death by more than 50% compared to the control arm. 
In KN185, the OS HR of the pembrolizumab-containing investigational arm compared to the 
control arm was 2.06 (95% CI: 0.93, 4.55), more than doubling the relative risk of death 
compared to the control arm.   These studies are closed due to the unfavorable benefit-risk 
profile for the combination of pembrolizumab, pomalidomide, and dexamethasone in relapsed 
refractory multiple myeloma, and the combination of pembrolizumab, lenalidomide, and 
dexamethasone in newly diagnosed treatment -naive multiple myeloma [Mateos, 2019; Usmani,
2019]..  While these studies that combine IMiDs with pembrolizumab have been stopped for 
safety reasons, other studies investigating the use of pembrolizumab in combination with other 
treatments for MM are ongoing.  IMiDs will not be used in this combination study.
The potential risk of the combination of NY-ESO-1c259T-cell therapy and pembrolizumab will be 
carefully monitored through a frequent follow-up visit schedule, pause of enrollment after the 
first three (3) subjects treated with the combination, and monitoring of all AEs.


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3.6.3.
Overall Benefit: Risk Conclusion
Data from preclinical studies support the specificity and safety of NY-ESO-1c259T cells (IB 
[GSK Document Number 2018N369930_03]).  Data from the clinical trial ADP-
01411/NTC01352286 [Rapoport, 2015] demonstrate the safety and antitumor activity of NY-
ESO-1c259T in patients with MM sufficiently to support further clinical investigation of this 
product in MM.  Based on the potentially complimentary mechanisms of action of 
NY-ESO-1c259T cells and pembrolizumab, and the ongoing unmet need for better therapies for 
patients with RRMM, including those cases of subjects in the post-BCMA setting, the overall 
benefit:risk of this combination supports an initial clinical study.  Additional details regarding 
specific benefits and risks for subjects participating in this clinical trial may be found in the 
accompanying informed consent documents.
4.
SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA
Subjects will be assessed for and must meet eligibility for study participation prior to 
leukapheresis AND prior to lymphodepleting chemotherapy.
4.1.
Subject Inclusion Criteria
A subject must meet the following inclusion criteria to be eligible for participation in this study:
4.1.1.
Screening (Part 1)
1. Subject has voluntarily agreed to participate by giving written informed consent for the 
screening process in accordance with International Council on Harmonisation (ICH) Good 
Clinical Practice (GCP) Guidelines and applicable local regulations.
2. Subject has voluntarily agreed to abide by all protocol required procedures including study 
related assessments, and management by the treating institution for the duration of the study 
and long-term follow-up. 
3. Subjects must be 18 years of age or older at the date of consent.
4. Histologically confirmed diagnosis of secretory multiple myeloma (must have measurable M 
protein in serum or urine) with at least one of the following:

Serum M- protein ≥0.5 g/dL (≥5 g/L) for IgG, IgM, IgA or ≥0.05 g/dL for IgD; or

Urine M-protein ≥200 mg/24 hours; or

Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (100 mg/L) and an 
abnormal serum FLC ratio (<0.26 or >1.65).
5. Subject must have documented diagnosis of relapsed and refractory multiple myeloma 
(RRMM) as described below:

subjects who have received at least 3 prior regimens and, 


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
were responsive to at least 1 or more prior regimens (as defined by IMWG criteria), 
and 

are refractory to their most recent therapy (≤ 25% response or progression during 
therapy or within 60 days after completion of therapy).
Prior therapies for subjects with RRMM must have contained at least one drug from each of 
the following drug classes: an immunomodulatory imide drug (IMiD), proteasome inhibitor, 
alkylator (unless the subject is ineligible or contraindicated to receive an alkylator), CD38 
monoclonal antibody, and glucocorticoid as separate lines or a combined line of therapy. If 
prior therapy includes autologous stem cell transplantation (ASCT), then 
induction/ASCT/maintenance therapies will be considered as one line of therapy altogether.
Subjects who have relapsed after ASCT or are unable to receive ASCT are eligible.  The 
interval from ASCT to entry in the study must be ≥12 weeks.
6. Left ventricular ejection fraction (LVEF) ≥50%.  A lower LVEF (≥40%) is permissible if a 
formal cardiologic evaluation reveals no evidence for clinically significant functional 
impairment, otherwise the subject may not enter the study.
7. For subjects who have received prior checkpoint inhibitors or other immuno-oncology agents 
like T-cell receptor agonists:

Subjects with endocrine AE of any grade are permitted to enroll if they are stably 
maintained on appropriate replacement therapy and are asymptomatic.

Must not have experienced any ≥Grade 3 AE nor any neurologic AE of any grade 
while receiving prior checkpoint inhibitors.

Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE related to checkpoint inhibitors, not have 
experienced recurrence of an AE related to checkpoint inhibitors if re challenged, and 
not currently require maintenance doses of corticosteroids.
NOTE: see Exclusion Criterion 2 (prior PD-1/PD-L1 checkpoint blockade therapy for 
enrollment in Arm 2).
8. Subject has Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
4.1.2.
Leukapheresis (Part 2)
All screening criteria described in Section 4.1.1 must be reviewed and fulfilled along with all the 
following criteria prior to leukapheresis. Leukapheresis process may not be necessary for 
subjects for which NY-ESO-1c259T-cell product is already manufactured.
9. Subject is HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive as determined by a
central laboratory.  (This determination will be made under a pre enrollment screening ICF.  


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There are no restrictions on the timing of HLA typing for screening and data can be taken 
from subjects’ records [see Section 3.2.1]).
10. Subject has confirmed sufficient expression of NY-ESO-1 and/or LAGE-1a by reverse 
transcription polymerase chain reaction (RT-PCR) as determined by a central laboratory 
contracted by the Sponsor (This determination will be made under a pre-enrollment screening 
ICF).
11. Subject has voluntarily agreed to participate by giving written informed consent for treatment 
in accordance with International Council on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines and applicable local regulations.
12. In the Investigator’s opinion, the subject is fit for cell collection.  
13. The subject has the following laboratory parameters determined prior to leukapheresis 
according to timelines in the Apheresis Manual and which meet the requirements in the table 
below:
Absolute neutrophil count (ANC)
1.0 x 109/L
CD3 count
≥200/μL
Lymphocyte count
≥0.5 x 109/L
4.1.3.
Lymphodepletion/treatment (Part 3)
All prior inclusion criteria described in Section 4.1.1 and Section 4.1.2 must be reviewed and 
fulfilled along with all the following criteria prior to lymphodepletion.
14. Subject has adequate vital organ function as indicated by the following laboratory values in 
the table below. Specimens must be collected no more than 7 days prior to start of 
lymphodepletion.
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1.0 × 109/L (without G-CSF support)
Plateletsa
≥50 × 109/L
Hemoglobin
>80 g/L (8 g/dL) (without transfusion support within 
7 days from start of leukapheresis)
Coagulation
Prothrombin time (PT)b
or International normalized ratio (INR)
≤1.5 × upper limit of normal (ULN) 
Partial thromboplastin time (PTT)b
≤1.5 × ULN
Renal


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System
Laboratory Value
Measured or calculatedc creatinine 
clearance
≥30 mL/min and not on dialysis
Hepatic
Serum total bilirubin
≤1.5 × ULN (unless subject has documented 
Gilbert’s Syndrome with direct bilirubin <35% of total 
bilirubin)
Aspartate aminotransferase (AST)/ Serum 
Glutamic Oxaloacetic Transaminase (SGOT)
Alanine aminotransferase (ALT)/ Serum 
Glutamic Pyruvic Transaminase (SGPT)
≤2.5 × ULN 
a Subjects should not have received platelet transfusion within 2 weeks of screening blood count.
b Unless receiving therapeutic anticoagulation, in which case PT or PTT should be within therapeutic range of intended 
use of anticoagulants.
c Subjects who are >18 or <65 years of age can be assessed using estimated creatinine clearance calculated using the 
Chronic kidney disease Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009]:
GFR = 141 x min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where, Scr is 
serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, is -0.329 for females and -0.411 for males, min 
(Scr /κ, 1) indicates the minimum of Scr /κ or 1, and max (Scr /κ, 1) indicates the maximum of Scr /κ or 1.
Subjects ≥65 of age must have renal function measured either by 24-hour urine creatinine collection or by nuclear 
medicine EDTA GFR measurement, according to standard practice at the treating institution.
15. Subject previously treated with BCMA therapy (BCMA CAR-T, ADC, or other type of 
BCMA-targeted therapy) must have progressed from this therapy prior to attending the 
Baseline visit prior to beginning lymphodepletion.  
16. Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 

Male subjects:
Male subjects are eligible to participate if they agree to the following during the 
period starting at the first dose of chemotherapy for at least 12 months after receiving 
the T-cell infusion, or 4 months after there is no evidence of persistence/ gene 
modified cells in the subject’s blood, whichever is longer.


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o
Refrain from donating sperm
Plus either: 
o
Be abstinent from heterosexual or homosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent 
OR
o
Must agree to use contraception/barrier as detailed below:
o
Agree to use a male condom and should also be advised of the benefit for a 
female partner to use a highly effective method of contraception as a condom 
may break or leak when having sexual intercourse with a woman of 
childbearing (WOCBP) potential who is not currently pregnant.
o
Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 

Female subjects: 
A female subject is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
o
Is not a WOCBP as defined in Section 6.3.3
OR
o
Is a WOCBP (as defined in Section 6.3.3) who will agree to use a barrier 
method (male condom) and use a contraceptive method that is highly effective 
(with a failure rate of <1% per year), as described in Section 6.3.3 during the 
period starting at the Baseline Visit , for at least 12 months after receiving the 
T-cell infusion, or 4 months after there is no evidence of persistence/ gene 
modified cells in the subject’s blood, whichever is longer. If assigned to 
Arm 2 must use a barrier method (male condom) and a highly effective 
contraception (with a failure rate of <1% per year) for at least 4 months after 
the last dose of pembrolizumab if this time frame is longer than the duration 
of contraception required in the context of chemotherapy and gene modified 
cells. WOCBP should also agree not to donate eggs (ova, oocytes) for the 
purpose of reproduction during this period.  The investigator should evaluate 


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the effectiveness of the contraceptive method in relationship to the first dose 
of study intervention.
o
A WOCBP must have a negative highly sensitive pregnancy test (urine or 
serum as required by local regulations) within 24 hours before the first dose of 
study intervention. 
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required.  In such cases, the subject must be excluded from 
participation if the serum pregnancy result is positive.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
4.2.
Subject Exclusion Criteria
A subject meeting any of the following criteria is not eligible for participation in the study.
4.2.1.
Screening (Part 1)
1.
Subjects with only plasmacytomas, plasma cell leukemia, monoclonal gammopathy of 
undetermined significance (MGUS), smoldering multiple myeloma (SMM), non-secretory 
myeloma or primarily amyloidosis.
2.
Subject has already received one of the following therapy/treatment: anti-PD-1, anti-PD-L1, 
or anti-PD-L2 inhibitor. Note: this exclusion only applies to subjects who would be assigned 
to Arm 2.
3.
Subjects who have previously participated in Merck pivotal trial NCT02576977: Study of 
Pomalidomide and Low Dose Dexamethasone With or Without Pembrolizumab (MK-3475) 
in Refractory or Relapsed and Refractory Multiple Myeloma (RRMM) (MK-3475-
183/KEYNOTE-183).
4.
Subject has received a prior allogeneic stem cell transplant.
5.
Subject has toxicity from previous anticancer therapy that has not recovered to ≤Grade 1 or 
to their baseline level of organ function (as outlined in inclusion criteria 14) prior to 
enrollment (except for non-clinically significant toxicities, e.g., alopecia, vitiligo).  Subjects 
with Grade 2 toxicities that are deemed stable or irreversible (e.g. peripheral neuropathy) 
can be enrolled on a case-by-case basis with prior consultation and agreement with the 
Sponsor Study Physician.
6.
Subject had major surgery within 4 weeks prior to enrollment (kyphoplasty is not considered 
major surgery); subjects should have been fully recovered from any surgical related 
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7.
Subject has history of allergic reactions to fludarabine, cyclophosphamide, or agents similar 
in chemical or biologic composition to fludarabine, cyclophosphamide or other agents used 
in the study.
8.
Known history of myelodysplasia.
9.
Current active liver or biliary disease (with the exception of Gilbert's syndrome or 
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per 
investigator assessment).
NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, 
persistent jaundice or cirrhosis.
10. Known history of chronic active hepatitis or liver cirrhosis (if suspected by laboratory 
studies, should be confirmed by liver biopsy).
11. Subject has an active infection with human immunodeficiency virus (HIV), hepatitis B virus 
(HBV), hepatitis C virus (HCV), or human T-lymphotropic virus (HTLV) as defined below:

Positive serology for HIV.

Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at screening or within 3 months prior to first dose of chemotherapy.

Active hepatitis C subjects as demonstrated by test for hepatitis C ribonucleic acid 
(RNA). Subjects who are HCV antibody positive will be screened for HCV RNA by 
any RT-PCR or by DNA assay.  If HCV antibody is positive, eligibility will be 
determined based on a negative screening RNA value.

Positive serology for HTLV 1 or 2.
Re-screening for infection disease markers is not required at Baseline (prior to 
lymphodepleting chemotherapy). 
12. History of severe immune disease, including non-infectious pneumonitis, requiring steroids 
or other immunosuppressive treatments.
13. Active immune-mediated diseases including: 
a.
Connective tissue diseases, uveitis, sarcoidosis, inflammatory bowel disease, 
multiple sclerosis, (non-infectious) pneumonitis.
b. Prior or active demyelinating disease
14. Evidence or history of significant cardiac disease (such as, but not limited to, unstable angina 
pectoris, myocardial infarction within the prior 6 months, heart failure within 6 months, 
symptomatic congestive heart failure, symptomatic or uncontrolled arrhythmias, severe 
aortic stenosis, symptomatic mitral stenosis).
15. QTc > 450 msec or QTc > 480 msec for patients with bundle branch block.


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NOTES: 

The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB), 
Fridericia's formula (QTcF), and/or another method, machine-read or manually over-read.

The specific formula that will be used to determine eligibility and discontinuation for an 
individual subject should be determined prior to initiation of the study. In other words, 
several different formulae cannot be used to calculate the QTc for an individual subject 
and then the lowest QTc value used to include or discontinue the subject from the trial.

For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting and 
Analysis Plan (RAP). 
16. Evidence or history of other significant hepatic, renal, ophthalmologic, psychiatric, or GI 
disease which would likely increase the risks of participating in the study.
17. Subjects with concomitant second malignancies (except adequately treated non-
melanomatous skin cancers, carcinoma in situ of the breast, treated superficial bladder 
cancer or prostate cancer, or in situ cervical cancers) are excluded unless a complete 
remission was achieved at least 2 years prior to study entry and no additional therapy is 
required or anticipated to be required during the study period.  Long-term adjuvant therapy 
(example: breast cancer) is acceptable.
18. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.  
Subjects with previously treated brain metastases may participate provided they are 
radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat 
imaging (note that the repeat imaging should be performed during study screening), 
clinically stable, and without requirement of steroid treatment for at least 14 days prior to 
first dose of study treatment.
19. Active bacterial or systemic viral or fungal infections.
20. Pregnant or breastfeeding.
4.2.2.
Leukapheresis/Manufacturing (Part 2)
A subject is not eligible for leukapheresis if any of the screening exclusion criteria described in 
Section 4.2.1 and any of the following criteria apply:
21. The subject has received or plans to receive the following treatment regimens and does not or 
cannot meet specified time frames prior to leukapheresis or lymphodepleting chemotherapy:


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Treatment/Therapy
Required Wash-out
Cytotoxic chemotherapy
2 weeks
Immune therapy (including monoclonal 
antibody therapy)
No wash-out
Immunomodulator imide therapy (IMiD e.g. 
lenalidomide or pomalidomide) 
No wash-out 
Proteasome inhibitor therapy (e.g. 
bortezomib or carfilzomib)
2 weeks
Anticancer Vaccine
4 weeks
The subject should be excluded if the Investigator 
considers their disease is responding to an experimental 
vaccine given within 6 months
Live-virus vaccination. NOTE: Seasonal flu 
vaccines that do not contain live virus are not 
an exclusion.
4 weeks
Allogeneic hematopoietic stem cell transplant 
at any time
Not permitted
Corticosteroids or any other 
immunosuppressive therapy.  Note:  Use of 
inhaled or topical corticosteroids, or of 
physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency is 
permitted.
2 weeks
Genetically engineered cell therapy
12 weeks
Investigational treatment (other than 
genetically engineered cell therapies) 
4 weeks or 5 half-lives, whichever is longer
Radiotherapy
2 weeks
NOTE: Duration of any other anticancer therapies must be discussed with the Sponsor Study Physician
4.2.3.
Lymphodepletion/Treatment (Part 3)
A subject is not eligible for lymphodepletion if any of the screening or leukapheresis exclusion 
criteria described in Section 4.2.1 and 4.2.2, and any of the following criteria apply:
22. More than two years have passed since the last leukapheresis collection.
4.3.
Completion of the Treatment Phase
A subject will be considered to have completed the treatment phase of the study when he/she has 
progression of disease or 108 weeks after NY-ESO-1c259T-cell infusion, whichever is sooner (see 
Section 7.4.8 for disease response assessments) in order to allow for the primary analysis to 
occur.  


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All subjects completing the treatment phase will continue to be followed for observation of 
delayed AEs during the 15 years post-infusion in accordance with FDA [FDA, 2020] and EMA 
[EMA, 2009] regulations (see Section 7.4.9).  While the follow-up including collection of 
delayed AEs (see Section 9.4) may start in this investigational protocol, subjects will ultimately 
be transferred to the LTFU protocol GSK208750 (ADP-0000-002) once meeting the conditions 
defined in Section 4.4.  If the LTFU protocol is not available, subjects will be followed per the 
LTFU schedule of assessments detailed in Table 4 until the LTFU protocol becomes available.  
Once the LTFU protocol is available, if a subject declines to consent to the LTFU protocol, the 
subject will be considered completed in this study.
4.4.
Conditions for Transfer to the LTFU Protocol – Study Completion
Subjects may be transferred to the LTFU as soon as their disease progression is confirmed and 
no later than 108 weeks after NY-ESO-1c259T-cell infusion.  If disease progression occurred prior 
to the Week 9 visit, subjects should remain on the treatment phase schedule to ensure collection 
of safety following T-cell infusion for a minimum of 9 weeks.  If the LTFU protocol is not 
available, follow-up will start per guidelines detailed in Table 4 until the LTFU protocol 
becomes available.
Subjects who have been dosed with pembrolizumab will be followed for 24 months after their 
last dose of pembrolizumab, to ascertain if they are candidates to receive an allo-SCT transplant.
Subjects who received an allo-SCT within the 24-month follow-up period will be monitored for 
18 months for post allo-SCT complications as defined in Section 9.5.  This follow-up can be 
carried out under the current protocol or under the LTFU protocol.
This study will be considered complete when the last subject has been rolled over into the LTFU 
protocol.
4.5.
Study Withdrawal
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or institution.  However, the Investigator must make every 
reasonable effort to keep each subject on study for the whole duration of the trial.  In cases where 
the subject is deemed ‘lost to follow-up’, the Investigator or designee must make every effort to 
regain contact with the subject (where possible, 3 telephone calls and, if necessary, a certified 
letter to the subject’s last known mailing address or local equivalent methods).  These contact 
attempts should be documented in the subject’s medical records.  Should the subject continue to 
be unreachable, only then will he/she be considered to have withdrawn from the study with the 
primary reason as ‘Lost to Follow-up’.
If the subject withdraws consent for further participation in the study, all final End-of-Study 
assessments should be performed, if possible on the day the decision is made to take the subject 
off-study or as soon as possible thereafter.  All of the results of the evaluations and observations, 
together with a description of the reasons for study withdrawal, must be recorded in the medical 
records and electronic Case Report Form (eCRF).  


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The following are some of the justifiable reasons for the Investigator to withdraw a subject from 
study:

Withdrawal of consent.

Did not receive any T cells (refer to Section 9.1 and Section 9.2 for continued 
monitoring of AEs/SAEs following study procedures).
If a subject who has consented to participate in pharmacogenetics research withdraws from the 
clinical study for any reason other than lost to follow-up, the subject will be given the following 
options concerning the pharmacogenetics sample, if already collected:

Pharmacogenetics research continues as per the subject’s consent; or,

Any remaining sample is destroyed
If a subject withdraws consent from the pharmacogenetics research or requests sample 
destruction, the Investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in the site 
study records.  In either case, GSK will only keep study information collected/generated up and 
until that point.
Once a subject has permanently discontinued from study treatment, the subject will not be 
allowed to be retreated. 
All subjects who discontinue from study treatment will have safety assessments at the time of 
discontinuation and during post-study treatment follow-up as specified in the Schedule of 
Assessments Table (see Section 8).
4.6.
Discontinuation of Pembrolizumab Treatment (Arm 2 subjects)
A subject may discontinue pembrolizumab treatment prior to Week 108 per protocol-defined 
duration. The following are justifiable reasons for the Investigator to discontinue pembrolizumab 
permanently:  

disease progression

toxicity criteria are met (according to Section 5.4.1) that require permanent 
discontinuation of pembrolizumab; or,

subject’s own decision due to unacceptable toxicities; or,

subject who has attained negative minimal residual disease (MRD) status, who has 
been treated for at least 24 weeks with pembrolizumab and had at least 2 treatments 
with pembrolizumab beyond the date when the initial CR was declared.
Once a subject discontinues pembrolizumab treatment, all assessments for the pembrolizumab 
treatment discontinuation visit should be performed, if possible on the day the decision is made 
to take the subject off-treatment or as soon as possible thereafter.  Such subjects will be 
maintained in the interventional study until disease progression or 108 weeks after NY-ESO-


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1c259T-cell infusion, whichever is sooner, as for subjects in Arm 1, and will be following the 
same schedule for safety and disease assessment as Arm 1.
4.7.
Considerations for Temporary Suspension of Enrollment
Throughout the conduct of the study, all safety data including SAEs and grade ≥3 AEs possibly 
associated with any of the 2 treatments (TCR or pembrolizumab) will be closely monitored and 
reviewed at each of the SRT meetings.  The frequency of TLTs for Arm 2 subjects will also be 
assessed in a continuous manner (See Section 3.3).  Based on the severity of the toxicities, 
indicators of potential antitumor activity, and other factors, a recommendation whether to 
suspend the treatment, or continue enrollment will be made with input from the SRT, Sponsor, 
and Investigators.  Final decisions to halt or modify the study will be made by the Sponsor.
Furthermore, temporary suspension of enrollment or dosing will take place and regulatory 
authorities will be notified if any of the following events occur:

Any event of Guillain-Barre syndrome (GBS) as diagnosed by a neurologist according 
to diagnostic guidance for GBS [Fokke, 2014] (refer to Section 10.3.1).

A case of documented symptomatic progressive cerebral edema confirmed by an 
expert neurological examination and CT/MRI, that is not responding to treatment.

Any death occurs that is deemed to be at least probably related to NY-ESO-1c259T or 
the combination of NY-ESO-1c259T and pembrolizumab; or

Two (2) or more Grade 4 immune events are deemed at least probably related to 
NY-ESO-1c259T or the combination of NY-ESO-1c259T and pembrolizumab; or

A subject has a positive test for replication competent lentivirus (RCL):
o
Confirmed positive PBMC RCL test and no other vector lot is available (refer to 
Section 10.1), or
o
Positive biological RCL test – all NY-ESO-1c259T-cell infusions are halted (refer 
to Section 10.1).
Premature study termination may occur if:

The Sponsor decides for any reason that subject safety may be compromised by 
continuing the study.

The Sponsor decides to discontinue the development of the intervention to be used in this 
study. 
Following assessment by the Sponsor, enrollment and dosing may resume if agreed upon by the 
Sponsor and Regulatory authorities, if applicable.  
4.8.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure subject 
safety and evaluate liver event etiology.


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Discontinuation of study intervention for abnormal liver tests is required when:

a subject meets one of the conditions outlined in the algorithm
OR

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study intervention discontinuation is in the 
best interest of the subject. 
Phase I/II Liver Chemistry Stopping and Increased Monitoring Algorithm
Liver Safety Required Actions and Follow up Assessments Section can be found in Section 16.6.
Study Intervention Restart after liver stopping criteria met
If subject meets liver chemistry stopping criteria do not restart subject with study intervention 
unless:

GSK Medical Governance approval is granted

Ethics and/or IRB approval is obtained, if required, and

Separate consent for intervention restart is signed by the subject
If GSK Medical Governance approval to restart subject with study treatment is not granted, then 
subject must permanently discontinue study treatment and may continue in the study for 
protocol-specified follow up assessments.


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Restart Following Transient Resolving Liver Stopping Events NOT Related to Study 
Treatment
Restart refers to resuming study treatment following liver stopping events in which there is a 
clear underlying cause (other than drug-induced liver injury [DILI]) of the liver event (e.g. 
biliary obstruction, pancreatic events, hypotension, acute viral hepatitis). Furthermore, there 
should be no evidence of alcoholic hepatitis or hypersensitivity.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries have 
a clear underlying cause (e.g., biliary obstruction, hypotension and liver chemistries 
have improved to normal or are within 1.5 x baseline and ALT <3xULN).

Possible study DILI has been excluded by the investigator and the study team. This 
includes the absence of markers of hypersensitivity (otherwise unexplained fever, rash, 
eosinophilia). Where a study treatment has an identified genetic marker associated 
with liver injury (e.g. lapatinib, abacavir, amoxicillin/clavulanate), the presence of the 
marker should be excluded. 

There is no evidence of alcoholic hepatitis.

RC/IRB approval of study treatment restart must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

Medical Monitor, and the RC/IRB as required, must be informed of the subject’s 
outcome following study treatment restart. 

GSK to be notified of any adverse events, as per Section 8.10.
4.9.
QTc Stopping Criteria

QTc > 500 msec 
OR


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
Change from baseline of QTc > 60 msec
For subjects with underlying bundle branch block, follow the discontinuation criteria listed 
below:
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch 
Block
< 450 msec
> 500 msec
450 – 480 msec
≥ 530 msec
5.
STUDY TREATMENTS
5.1.
Leukapheresis
Subjects who complete screening procedures defined in Section 7 and who meet all eligibility 
criteria defined in Section 4 will be eligible to undergo leukapheresis to obtain starting material 
for the manufacture of autologous NY-ESO-1c259T.
For collection of starting material, a large-volume non-mobilized PBMC collection should be 
performed according to institutional standard procedures. The goal of the procedure is to collect 
a satisfactory cell count in the apheresis material prior to drug product manufacture. The target 
CD3+ cell count for drug product manufacture is 2.4x109 CD3+ cells.
In cases where the minimum number of CD3+ is not collected or the T cells are not able to be 
infused back to the subject, a second apheresis may be performed. Additional aphereses may be 
performed in a case by case basis evaluation between the investigator and the Sponsor. Citrate 
anticoagulant should be used.  Prophylaxis and treatment of adverse effects of the citrate 
anticoagulant (e.g. Ca gluconate, CaCl2 or MgSO4 infusions) may be administered at the 
discretion of the Investigator.  The collected apheresis product will then be transported for 
manufacture as detailed in the Study Procedures Manual (SPM).
Once NY-ESO-1c259T product has been manufactured, eligible subjects will proceed to have 
lymphodepleting chemotherapy and infusion of the study therapy as detailed in Section 5.2 and 
Section 5.3.
5.2.
Lymphodepleting Chemotherapy
Prior to the administration of lymphodepleting chemotherapy baseline eligibility criteria will be 
re-confirmed and baseline tumor assessment obtained. 
When the manufactured NY-ESO-1c259T product has been received, the integrity of the bag(s) 
has been checked by the site, and the subject has been assigned to Arm 1 or Arm 2, fludarabine 
and cyclophosphamide will be used as lymphodepleting chemotherapy prior to administration of 
the study treatment as described in Table 1.  For subjects with documented history of severe and 
prolonged cytopenia (anemia, thrombocytopenia, or leukopenia), the investigator should discuss 
with the sponsor’s medical monitor or designee to determine the need for dose modification of 
the lymphodepletion regimen.


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Appropriate IV hydration should be administered and Mesna given to prevent neurotoxicity 
while cyclophosphamide is administered, as described below.  Other premedication (e.g., 
antiemetics) may also be provided in accordance with institutional standards.  Steroids may be 
used as antiemetics for cyclophosphamide but must be discontinued no later than Day -3.  G-CSF 
will be given to all subjects from 24 hours after the last dose of cyclophosphamide until 
resolution of neutropenia in accordance with American Society of Clinical Oncology (ASCO) 
guidelines or institutional practice (see Section 8.8.1).   
On admission for lymphodepleting chemotherapy, subjects will commence antimicrobial and 
antifungal prophylaxis in line with institutional standard practice (see Section 8.2).
Table 1
Lymphodepleting Chemotherapy
Treatment schedule
Recommended 
Prophylaxis and 
Supportive Medication
Daya
Drug
Dose
Route
Administration
Infection: on admission 
for lymphodepleting 
chemotherapy, 
commence antimicrobial 
and antifungal prophylaxis 
(see Section 8.2), or in 
line with institutional 
guidelines.
Hydration: Ensure 
adequate hydration and 
antiemetic provision prior 
to commencing 
cyclophosphamide 
infusions
Mesna: may be given per 
institutional guidelines or 
as recommended in 
Section 5.2.3.
G-CSF: start 24 hours 
post final 
cyclophosphamide until 
resolution of neutropeniae 
Cell therapy 
premedicationf: 
the premedication with 
acetaminophen 
and diphenhydramine 
should be given 
approximately 30 minutes 
prior to the 
-8
Fludarabineb, c
30 mg/m2
IV
in 50-100 mL 
(concentration 
≤1 mg/mL) of 0.9% 
NaCl over 30 ming
-7
Fludarabineb
30 mg/m2
IV
in 50-100 mL 
(concentration 
≤1 mg/mL) of 0.9% 
NaCl over 30 ming
Cyclophosphamidec
900 
mg/m2
IV
in 100-250 mL 0.9% 
NaCl over 1 hourg
-6
Fludarabineb
30 mg/m2
IV
in 50-100 mL 
(concentration ≤1 
mg/mL) of 0.9% NaCl
over 30 ming
Cyclophosphamidec
900 
mg/m2
IV
in 100-250 mL 0.9% 
NaCl over 1 hourg
-5
Fludarabineb
30 mg/m2
IV
in 50-100 mL 
(concentration 
≤1 mg/mL) of 0.9% 
NaCl over 30 ming
Cyclophosphamidec
900 
mg/m2
IV
in 100-250 mL 0.9% 
NaCl over 1 hourg
-4
start G-CSF
-3
-2
-1
1
NY-ESO-1c259T infusiond


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Treatment schedule
Recommended 
Prophylaxis and 
Supportive Medication
NY-ESO-1c259T infusion 
according to institutional 
practice
IV = intravenous; G-CSF= Granulocyte-colony stimulating factor
Notes:
a There is no Day 0 in this study.
b Fludarabine dose will be adjusted in renal impairment (see Section 5.2.2).
c For subjects ≥ 60 years of age, 3 doses of fludarabine (30 mg/m2 on Days -7 to -5) and 600 mg/m2 cyclophosphamide dose will 
be administered after consulting with the sponsor.
d Administration of NY-ESO-1c259T is described in Section 5.3.
e Long-acting (pegylated) G-CSF may be given instead of short acting G-CSF according to institutional standard practice. If 
pegylated G-CSF is administered, give one dose 24 hours after the last chemotherapy administered.
f Doses of supportive medications per institutional practice.
g Or per institutional standards.
5.2.1.
Lymphodepletion Dose Modification
For participants ≥ 60 years old, the recommended lymphodepleting regimen will be as follows:

Fludarabine at 30mg/m2 for 3 days (Day -7 to Day -5)

Cyclophosphamide at 600mg/m2 (Day -7 to Day -5)
In case of participants with documented history of severe and prolonged cytopenia (anemia, 
thrombocytopenia, or leukopenia), the investigator should discuss with the sponsor’s medical 
monitor or designee the opportunity for potential lymphodepletion dose adjustment
5.2.2.
Fludarabine Dose Adjustment for Renal Impairment
The dose of fludarabine will be adjusted for subjects with renal dysfunction as follows:
Creatinine clearance
Fludarabine dose
>80 mL/min
30 mg/m2
30 – 80 mL/min
20 mg/m2
5.2.3.
Mesna
Mesna will be given to cover the duration of cyclophosphamide chemotherapy according to 
institutional practice or the following recommendation: 
20% cyclophosphamide dose (i.e., 180 mg/m2) as an IV bolus pre-infusion and 3 h, 6 h, and 9 h 
on each day of cyclophosphamide administration.
5.3.
T-cell Infusion
The autologous T cell transduced with lentivirus encoding enhanced TCR specific for 
NY-ESO-1c259 is one of the IPs in this study.


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Subjects will receive transduced T cells in the range of 1 × 109 to 8 × 109 cells.  If the transduced 
cell dose is less than the minimum dose of 1 × 109, manufacturing of additional transduced T-
cells from excess banked leukapheresis product will be undertaken to achieve a total dose in the 
range 1 × 109 to 8 × 109.  In the event that no banked leukapheresis product is available a second 
leukapheresis may be performed.  The cells will be pooled and administered by a single IV 
infusion on Day 1.
5.3.1.
Premedication
Premedication with antihistamine and acetaminophen can help prevent infusion reactions and 
should be administered prior to the T-cell infusion as per institutional standards.  Steroids should 
not be administered because they are cytotoxic and inhibitory to the T-cell product.
5.3.2.
Cell Infusion
Vital signs will be recorded prior to infusion (Table 3).
On Day 1, the participant will receive thawed GSK3377794 by IV infusion. Prior to
infusion, two clinical personnel will independently verify and confirm in the presence of
the subject that the information on the infusion bag is correctly matched to the
subject, as per the Sponsor’s and clinical site’s procedures.
The specific instructions for the preparation and administration of GSK3377794 are
found in the Drug Product and Infusion Manual. Any deviations from the procedure
detailed in the Drug Product and Infusion Manual should be recorded and reported
accordingly.
In the event of adverse reaction to the cell infusion, the infusion rate should be reduced and the 
reaction managed according to institutional standard procedures.  Steroid treatment should be 
avoided unless medically required.  In the event a subject develops a febrile episode following 
the infusion, appropriate cultures and medical management should be initiated, with attention to 
the initiation of empirical antibiotic treatment in the case of febrile neutropenia (see Section 8).
The day of T-cell infusion may be delayed in subjects with significant complications of 
chemotherapy if, according to the Investigator, it is in the best interest of the subject.  The timing 
of all assessments and procedures post-infusion will be calculated with reference to the T-cell 
infusion date (Day 1).  Eligible subjects who do not receive the NY-ESO-1c259T infusion for any 
reason may be replaced.  Cytopenias alone should not be a reason to delay T-cell infusion unless 
complications are present.
Vital signs will be recorded prior to the infusion; and 5, 15, 30 minutes, 1, 1.5, 2 and 4 hours 
after the infusion has started.
5.4.
Pembrolizumab (Arm 2) Infusion
Pembrolizumab will be administered on Day 22, 21 days after the T-cell infusion (the day when 
NY-ESO-1c259T is infused, is considered Day 1, there is no Day 0 in this study), and every 
3 weeks thereafter up to Week 108.  If subject is experiencing toxicities preventing dosing of 


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pembrolizumab at Week 3, the first dose of pembrolizumab may be administered on Week 6 
instead. If subject is still experiencing toxicities preventing starting pembrolizumab dosing at 
Week 6, this subject will not be administered pembrolizumab and will be followed for visits as a 
subject in Arm 1.
Pembrolizumab will be administered as a fixed dose of 200 mg using a 30-minute IV infusion.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes -5 min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of infusion solution.
When pembrolizumab is administered with NY-ESO-1c259T, it is expected that the checkpoint 
blockade will activate the immune system.  This may lead to enhanced antitumor activity as well 
as toxicity (refer to Section 3.1.2).  
5.4.1.
Schedule Modification Guidelines for Pembrolizumab (Arm 2)
AEs (both non-serious and serious) associated with pembrolizumab exposure may represent an 
immunologic etiology.  These irAEs may occur shortly after the first dose or several months after 
the last dose of treatment and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications.  Based on 
existing clinical study data, most irAEs were reversible and could be managed with interruptions 
of pembrolizumab, administration of corticosteroids and/or other supportive care.  For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes.  Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the 
evaluation.  
Table 2 below lists severe or life-threatening AEs and conditions where pembrolizumab 
treatment must not be started or must be withheld for drug-related toxicities.  If pembrolizumab 
cannot be started at Week 3 due to an AE, subjects in Arm 2 may receive their first dose of 
pembrolizumab on Week 6.  See Section 8.9 for supportive care guidelines for management of 
pembrolizumab toxicities.
In special situations not specified below, Sponsor must be contacted.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, and/or 
holidays).  Subjects should be placed back on study therapy by the next scheduled infusion 3 
weeks later, unless otherwise discussed with the Sponsor.  The reason for interruption should be 
documented in the subject's study record.


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Table 2
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 
Pembrolizumab
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor subjects for signs and 
symptoms of pneumonitis
Evaluate subjects with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment
Add prophylactic antibiotics for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Monitor subjects for signs and 
symptoms of enterocolitis (i.e., 
diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) 
and of bowel perforation 
(i.e., peritoneal signs and ileus).


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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up
Grade 4
Permanently discontinue
Subjects with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing 
endoscopy to rule out colitis. 
Subjects with diarrhea/colitis should 
be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be substituted via 
IV infusion.
AST / ALT 
elevation or 
Increased bilirubin
Grade 2
Withhold
Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone 
or equivalent) followed by taper
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable
Grade 3 or 4 
Permanently discontinue
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia
Newly onset 
T1DM or Grade 3 
or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold
Initiate insulin replacement 
therapy for subjects with T1DM 
Administer anti-hyperglycemic in 
subjects with hyperglycemia 
Monitor subjects for hyperglycemia or 
other signs and symptoms of 
diabetes.
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated.  
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or permanently 
discontinue1


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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up
Hyperthyroidism 
Grade 2
Continue 
Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate 
Monitor for signs and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold or 
permanently discontinue1
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of 
care
Monitor for signs and symptoms of 
thyroid disorders. 
Nephritis and 
Renal dysfunction
Grade 2
Withhold 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.
Monitor changes of renal function
Grade 3 or 4 
Permanently discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes
Grade 3 or 4
Permanently discontinue
All other immune-
related AEs
Intolerable/ 
persistent Grade 2
Withhold
Based on type and severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude other 
causes
Grade 3
Withhold or discontinue 
based on the type of 
event.  Events that 
require discontinuation 
include and not limited to:  
Guillain-Barre Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently discontinue


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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up
1Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 
and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  


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6.
CONCOMITANT MEDICATION AND TREATMENT
6.1.
Prohibited Concomitant Medication and Treatment
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phases of this trial:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be considered on an exceptional case-by-case basis after consultation 
with the Sponsor.  Subjects receiving any of palliative radiation therapy 
that could be foreseen impacting disease course or disease assessments 
will be censored for the purposes of determining PFS.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited 
to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, 
Bacillus Calmette-Guérin, and typhoid (oral) vaccine.  Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed.  
However, intranasal influenza vaccines (e.g. Flu - Mist™) are live attenuated 
vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to treat an event of 
suspected immunologic etiology (see Section 8).  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.  
According to local standard of care or ASCO guidelines [Basch, 2011], 
steroids may be used as antiemetics with cyclophosphamide but must be 
discontinued no later than 3 days prior to infusion of NY-ESO-1c259T.  Topical 
steroids for cutaneous application, orally non-absorbable and inhaled steroidal 
treatments are permitted.  

Herbal remedies.
Subjects who undergo any active anticancer therapy other than the protocol-defined IP(s) 
will be considered as having met the progressive disease (PD) criterion for efficacy and 
will be rolled over to the LTFU protocol GSK208750 (ADP-0000-002).
Subjects may receive other medications that the Investigator deems to be medically 
necessary.
See Section 4.2 for washout and excluded treatments prior to leukapheresis or 
lymphodepleting chemotherapy 


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There are no prohibited therapies during the LTFU phase.
6.2.
Permitted Concomitant Medication and Treatment
Lesion sites previously requiring radiotherapy should be recorded prior to 
lymphodepletion.  
Other treatment that the Investigator considers necessary for a subject’s welfare may be 
administered during the treatment phase of the study at the discretion of the Investigator 
in keeping with community standards of medical care and in adherence to the protocol.  
Before immunizing a subject at high risk for vaccine-preventable disease (or member of 
the subject’s household), consult an Infectious Disease specialist or a guidance such as 
the CDC Clinical Practice Guideline for Vaccination of the Immunocompromised Host.
All concomitant medications will be recorded, including all prescription and over-the-
counter (OTC) medications and herbal remedies including dose and frequency.  Any 
changes to concomitant medication regimens should be recorded throughout the study in 
the eCRF.
6.3.
Restrictions
6.3.1.
Corticosteroids
Corticosteroids may diminish the antitumor activity effects of the NY-ESO-1-c259T 
product.  Consider alternatives to steroid therapy when possible.  However, for symptom 
management as indicated in Section 8  or in case of any life-threatening conditions, 
steroids should not be withheld.
6.3.2.
Diet
Subjects should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
6.3.3.
Contraception
Both IPs, NY-ESO-1c259T and pembrolizumab may have adverse effects on a fetus in 
utero.  Furthermore, it is not known if NY-ESO-1c259T and pembrolizumab have transient 
adverse effects on the composition of sperm.  
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.


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Woman in the following categories are not considered WOCBP
1. Premenarchal
Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., mullerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the subject’s 
medical records, medical examination, or medical history interview.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
(as per laboratory parameters for postmenopausal range) may be used to 
confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT) when postmenopausal status is in doubt.  
However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement is required. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
Contraception
Male subjects:
Male subjects must agree to the following during the intervention period starting at the 
first dose of chemotherapy for at least 12 months after receiving the T-cell infusion, or 4 
months after there is no evidence of persistence/ gene modified cells in the subject’s 
blood, whichever is longer.  

Refrain from donating sperm
Plus either: 

Be abstinent from heterosexual or homosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long term and persistent basis) and agree to 
remain abstinent 


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OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom and should also be advised of the benefit 
for a female partner to use a highly effective method of contraception as 
a condom may break or leak, when having sexual intercourse with a 
woman of childbearing potential who is not currently pregnant.

Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person.
Female subjects:
WOCBP must agree to the following during the intervention period starting at the 
Baseline Visit for at least 12 months after receiving the T-cell infusion, or 4 months after 
there is no evidence of persistence/ gene modified cells in the subject’s blood, whichever 
is longer. If assigned to Arm 2, must use effective contraception for at least 4 months 
after the last dose of pembrolizumab if this time frame is longer than the duration of 
contraception required in the context of chemotherapy and gene modified cells. 
For contraception, subjects who are WOCBP, must use a barrier method (male condom) 
and should comply with one of the following:
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year 
when used consistently and correctly.
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc
Intrauterine device
Intrauterine hormone-releasing system
Bilateral tubal occlusion
Vasectomized partner
Note: Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the absence of 
sperm has been confirmed.  If not, an additional highly effective method of contraception 
should be used. Spermatogenesis cycle is approximately 90 days.
Highly Effective Methods b That Are User Dependent Failure rate of <1% per year when 
used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc


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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE:
oral
intravaginal
transdermal
injectable
Progestogen-only hormone contraception associated with inhibition of ovulationc
oral
injectable
Sexual abstinence
Note: Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
intervention.  The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the subjectt
a.
Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for those participating in clinical studies.
b.
Failure rate of <1% per year when used consistently and correctly.  Typical use failure 
rates differ from those when used consistently and correctly.
c.
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the 
primary mode of action.
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method are not acceptable 
methods of contraception.  Male condom and female condom should not be used together (due 
to risk of failure with friction).
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study, subjects of childbearing potential must adhere to the 
contraception requirement (described above) from the Baseline Visit throughout the study 
period up to 12 months after receiving T-cell infusion, or up to 4 months after there is no 
evidence of persistence/gene modified cells in the subjects’ blood, whichever is longer.  
Subjects in Arm 2 must also use effective contraception for at least 4 months after the last 
dose of pembrolizumab.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not 
be entered into the study.
6.3.4.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed 
or terminated.  The outcome of the pregnancy will be reported to the Sponsor without 


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delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The Study Investigator will make every effort to obtain permission 
to follow the outcome of the pregnancy and report the condition of the fetus or newborn 
to the Sponsor.  Any pregnancy complication or elective termination of a pregnancy will 
be reported as an AE or SAE.
6.3.5.
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breastfeeding are not eligible for enrollment.
7.
SCHEDULE OF ASSESSMENTS AND PROCEDURES
The Schedule of Procedures for this study is provided in Table 3.
Subjects will be assigned a unique subject number upon signing the Screening ICF.  
Upon qualification based on HLA and antigen profile (Section 7.1), subjects will be 
asked to sign the Treatment ICF to be further assessed for eligibility.  The number 
assigned at screening will serve as the subject ID as well as for the enrollment, post-
qualification, into the treatment phase of this study.  Study procedures performed as part 
of standard of care prior to signing informed consent can be used for screening if they 
were performed within 7 days prior to leukapheresis for laboratory tests, pregnancy , and 
infectious disease screen, and within 4 weeks prior to leukapheresis for ECHO/MUGA, 
brain MRI, and ECG (including cardiac stress test) (see Section 7.3). Please follow 
guidance in Apheresis Manual for timing of lab tests for CD3 counts, ANC, and 
lymphocyte counts prior to leukapheresis.
Figure 2 presents the overall patient journey from pre-enrollment screening through study 
completion or withdrawal.


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Figure 2
Schematic for Study GSK208470 (ADP-0011-008)  
Between leukapheresis and lymphodepletion, in the place of bridging therapy, an experimental line of therapy can be given (such as a BCMA-targeted agent) under another study 
protocol, including with another Sponsor. 
Subjects receiving an experimental line of therapy between leukapheresis and lymphodepletion must have progressive disease from this intermediate line of therapy before receiving 
lymphodepletion in this study.
1
2


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7.1.
HLA and Antigen Screening 
Subjects who are identified by the Investigator as possible candidates for the trial must be tested 
for their HLA-genotype and for expression of NY-ESO-1 and/or LAGE-1a antigens.  The HLA 
and antigen screening tests must be positive prior to conducting the remaining study screening 
procedures for eligibility.  
7.1.1.
Blood sample for HLA subtyping 
HLA-genotyping at the allelic level (4-digit) will be carried out on a blood sample by a central 
laboratory using a high-resolution Sequence-Based Typing assay.  
7.1.2.
Bone marrow aspirate for antigen testing by RT-PCR
Determination of NY-ESO-1 and/or LAGE-1a expression will be carried out using quantitative 
reverse transcription-polymerase chain reaction (PCR) on RNA isolated from fresh bone marrow 
aspirate samples obtained in accordance with routine clinical practice.
The requirements for the aspiration procedure, processing of the bone marrow aspirate sample, 
as well as quantity and quality are outlined fully within the SPM.  Briefly, to ensure the highest 
quality of the sample, and to ensure sufficient quantity for multiple biomarker analyses, bone 
marrow samples must be collected in PAXgene tubes, processed and submitted directly to the 
reference laboratory for analysis of antigen expression as outlined within the SPM.
Additional assay platforms which may be utilized include but are not limited to: Ribonucleic 
Acid Sequencing (RNA-Sequencing) and RNA expression analysis.
In the event that the bone marrow sample submitted for diagnostic analysis is of insufficient 
quantity or quality (e.g. low plasma cell content) to conduct the testing and determine the 
subject’s antigen expression profile, additional bone marrow sample(s), obtained in accordance 
with routine clinical practice, may be submitted to the central laboratory.
7.1.3.
Bone Marrow Sample Banking and Storage 
Following diagnostic analysis of a subject’s bone marrow specimen at the central reference 
laboratory, remaining sample (residual RNA) will be banked and stored at a GSK-specified 
biorepository for the validation of single- and/or multiple-biomarker companion diagnostic 
assay(s) (Refer to Section 7.1.4).  The central reference laboratory will forward the remaining 
samples directly to the biorepository.  The central reference laboratory will enclose a copy of the 
pathology report or the pathological description of the specimen with each sample along with a 
Sample Transmittal Form.  Residual bone marrow RNA samples will be assigned a unique 
tracking number, will be logged into the biorepository’s Laboratory Information Management 
System, and will be stored at -80°C.  Samples will be retained for up to 15 years after the study 
is closed, after which time the samples will be either returned to the site or disposed of.


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7.1.4.
Companion Diagnostic Development 
Following screening for the antigen expression, remaining screening sample may be used for the 
purpose of developing and validating single- and/or multiple-marker IVD assays for antigen 
screening for regulatory approval of a therapeutic new product indication.  Bone marrow samples 
may be used for the analytical validation (which includes testing for efficiency, sensitivity, 
specificity, exclusivity, accuracy and precision), as well as the clinical validation of such 
diagnostic assays.  Validated and regulatory approved companion diagnostic assays may be used 
in the future to precisely determine subjects’ antigen expression profile so as to determine the 
most appropriate targeted T-cell therapy treatment.
7.2.
Screen Failures
A screen failure log documenting the Investigators assessment of each screened subject with 
regard to the protocol’s inclusion and exclusion criteria is to be maintained by the Investigator.
Screen Failure data including demographics, SAEs, and reason for failing screening will be 
collected in the eCRF.


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7.3.
Schedule of Procedures
Table 3
Schedule of Procedures
Screeninga
Phase
/ 
Eligibility
Phase
Treatment Phase
DC of 
Pem-
broli-
zumab 
Txc
Comple-
tion of 
Treatment 
Phase or 
WDd
Leuk
aphe
resis
Baseline 
≤7 days 
prior to 
chemo
Lymphodepleting 
Chemotherapyb
T-cell 
infu-
sion
Study Day Scr
n
Elig
D -14 to
D -8
D -8
D -
7
D -6 D -5 D -4
D 1
D2
D3
D4
D5
Wk 
1
Wk
2
Wk 
3
Wk 
4
Wk 
6
Wk 
15
Wk 24 
&
Q12wks
Window
±1D ±1D ±1D ±3D ±3D ±3D
±7D
Informed consenta
X
X
Demographics
X
HLA-genotyping
X
NY-ESO-1 and 
LAGE-1a levels
on BM aspirate 
X
Inclusions/
Exclusions 
X
X
Baseline 
characteristicse
X
Medical Historyf
X
Physical Examg
X
X
X
Prior/Concomitant 
medicationh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG PS 
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs / 
Weight
X
X
Xi
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulse oximetry
X
X
ECG
Xj
Xj
X
X
X
Echo / MUGA
Xa,k
Brain MRIl
X
See footnote ‘l’
ICEm
See footnote ‘m’
Chest X-ray 
(if indicated)
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation testsn
X
X


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Screeninga
Phase
/ 
Eligibility
Phase
Treatment Phase
DC of 
Pem-
broli-
zumab 
Txc
Comple-
tion of 
Treatment 
Phase or 
WDd
Leuk
aphe
resis
Baseline 
≤7 days 
prior to 
chemo
Lymphodepleting 
Chemotherapyb
T-cell 
infu-
sion
Study Day Scr
n
Elig
D -14 to
D -8
D -8
D -
7
D -6 D -5 D -4
D 1
D2
D3
D4
D5
Wk 
1
Wk
2
Wk 
3
Wk 
4
Wk 
6
Wk 
15
Wk 24 
&
Q12wks
Window
±1D ±1D ±1D ±3D ±3D ±3D
±7D
Pregnancy testo
X
X
X
X
X
X
X
X
X
X
Urinalysisn
X
X
Infectious Disease 
screenp
X
X
X
CMV PCRq
X
X
X
X
X
X
Thyroid Function 
Testsn
X
X
  X  then Q6wks (Arm 2 only)
C-Reactive 
Proteinr
X
X
X
X
X
Uric acid
X
X
GFR or 24h urine 
creatinines
X
X
Adverse Eventst
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vector Copies 
(Persistence for 
safety)u
X
X
Xu
VSV-G DNA 
(RCL) for safetyu
X
X
Xu
Leukapheresis, Lymphodepleting Chemotherapy
Leukapheresisv
X
Fludarabine
X
X
X
X
Cyclophosphamid
e
X
X
X
G-CSFw
X
Administration of Investigational Products 
NY-ESO-1c259T  
infusion
X
Pembrolizumab  
(Arm 2 only)x
  X  then Q3wks up to Wk108 


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Screeninga
Phase
/ 
Eligibility
Phase
Treatment Phase
DC of 
Pem-
broli-
zumab 
Txc
Comple-
tion of 
Treatment 
Phase or 
WDd
Leuk
aphe
resis
Baseline 
≤7 days 
prior to 
chemo
Lymphodepleting 
Chemotherapyb
T-cell 
infu-
sion
Study Day Scr
n
Elig
D -14 to
D -8
D -8
D -
7
D -6 D -5 D -4
D 1
D2
D3
D4
D5
Wk 
1
Wk
2
Wk 
3
Wk 
4
Wk 
6
Wk 
15
Wk 24 
&
Q12wks
Window
±1D ±1D ±1D ±3D ±3D ±3D
±7D
Multiple Myeloma Disease Assessments 
Myeloma markers 
(labs)y
X
X
X
X then Q3wks until Wk24,                                     X
Q6wks until Wk72, Q12wks thereafter until confirmed 
PD
Bone marrow 
sampleaa, ab
Xz
X
X
X
X
X
Bone imagingac
X
X
X
Research Assessments
Pharmaco-genetic 
- Whole Blood 
Sample
Xad
Bone marrow 
(bone marrow 
mononuclear 
cells)ae
X
X
X
X
X
Cell pheno-typing 
& Functional 
assays - PBMC
X
X
X
X
X
X
X
X
X
X
X
Vector Copies 
(Persistence for 
Research)
X
X
X
X
X
X
X
X
X
Cytokine analyses 
& Anti-TCR 
antibodiesr
X
Xr
X
X
X
X
X
X
Xr
X
Xr
X
X
Soluble BCMA 
(sBCMA)
X
X
X
X
X
X
X
X
X
X
X
X
X
cfDNA and 
exosomes
X
X
X
X
X
X
BM = bone marrow; CBC = complete blood count; CMV = cytomegalovirus; CRP = C-reactive protein; DC = discontinuation; DNA = deoxyribonucleic acid; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; Elig = Eligibility; G-CSF = granulocyte-colony stimulating factor; HBV = hepatitis 


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B virus; HCV = hepatitis C virus; HLA = human leukocyte antigen; HTLV = human T-lymphotropic virus; IMWG = International Myeloma Working Group; 
MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition scan; PBMC = peripheral blood mononuclear cell; PET = positron emission 
tomography; PS = Performance Status; RCL = replication competent lentivirus; Scrn = Screening; Tx = treatment; VSV-G = vesicular stomatitis virus envelope 
glycoprotein; WD = study withdrawal
a. Written subject informed consent (and subject assent as applicable) must be obtained prior to performing any protocol procedures.  An initial Screening 
informed consent must be signed prior to obtaining a blood sample for HLA-testing and bone marrow aspirate for antigen testing.  The Treatment informed 
consent must be signed prior to all other screening procedures.  ECHO/MUGA scans, brain MRI, and ECG (including cardiac stress test) must be completed 
within 4 weeks prior to leukapheresis.  Hematology, chemistry, coagulation tests, urinalysis, GFR or 24-hour urine creatinine as appropriate, and the infectious 
disease panel [HIV, HBV, HCV, HTLV, EBV, CMV, and syphilis (spirochete bacterium)] must be completed no more than 7 days prior to leukapheresis. 
Absolute neutrophil count, absolute lymphocyte count, and CD3+ count must be completed prior to leukapheresis according to timelines in the Apheresis 
Manual.  Laboratory tests performed as standard of care and within the specified time frames will be accepted.
b. Lymphodepleting chemotherapy may only be initiated after the manufactured NY-ESO-1c259T-cell product has been received at the site and the bag(s) have 
passed inspection by site personnel (see further details in study procedures manual [SPM]).  
c. Only for subjects enrolled on Arm 2: if subject discontinues from pembrolizumab treatment prior to relapse/progression, this treatment discontinuation visit 
must be performed including all indicated procedures and assessments listed, unless already recently performed within 30 days.  Subject will be maintained in 
the interventional protocol until disease progression or 108 weeks after NY-ESO-1c259T-cell infusion, whichever is sooner, following the same schedule for 
safety and disease assessment as Arm 1, and will be transferred to the LTFU protocol GSK208750 (ADP-0000-002) as soon as they meet conditions defined 
under Section 4.4. If the LTFU protocol is not available, follow-up will start per guidelines detailed in Table 4 until the LTFU protocol becomes available.
d. If subject withdraws from the treatment phase prior to disease progression, a completion/withdrawal visit must be performed including all procedures and 
assessments listed indicated, unless already recently performed within 30 days.  All subjects will be transferred to the LTFU protocol GSK208750 
(ADP-0000-002) upon completion/withdrawal from treatment phase as soon as they meet conditions defined under Section 4.4.  If the LTFU protocol is not 
available, follow-up will start per guidelines detailed in Table 4.
e. Baseline characteristics include recording time from initial diagnosis and time from last therapy.
f. Includes prior lines of therapy.
g. Physical examination will only be collected at screening and baseline and every 6 months – any abnormal findings outside these time points will be reported as 
an AE.
h. Includes concomitant medication since last visit. 
i. Vital signs (temperature, pulse, respirations and blood pressure) on the day of T-cell infusion should be taken pre-infusion; and at 5, 15 and 30 minutes, and 1, 
1.5, 2, and 4 hours after infusion has started.
j. Cardiac stress test is performed for subjects who are 55 years of age or over (specificity of the test will be at Investigator’s discretion).
k. MUGA and/or ECHO are required at screening.  May also be performed post-lymphodepleting chemotherapy if clinically indicated at the discretion of the 
Investigator.  For subjects with cardiac or pericardial disease at baseline, inpatient telemetry monitoring will be carried out for a minimum of three and up to 
seven days post NY-ESO-1c259T infusion.
l. Brain MRI (or CT Scan if MRI not feasible) should be obtained in all subjects at the time of screening within 4 weeks prior to leukapheresis.  Baseline brain 
MRI should be repeated if more than 4 months have elapsed prior to lymphodepletion.
m. Immune Effector Cell-Associated Encephalopathy (ICE) should be measured on the day of NY-ESO-1c259T-cell infusion prior to receiving treatment and then 
at least through Day 8 according to the schedule of procedures. Subjects with known brain metastases should be monitored at least twice per day for the first 5 


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days following NY-ESO-1c259T-cell infusion.  If a subject is found to have Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), the ICE 
neurological assessment tool should be used at least twice per day until resolution or stable.  It can also be used at later visits if indicated.
n. Additional tests may be performed at any time if clinically indicated.
o. Pregnancy test for women of childbearing potential (WOCBP) only.  Urine or serum pregnancy test (highly sensitive) is to be performed and confirmed 
negative at screening, prior to lymphodepleting therapy, prior to NY-ESO-1c259T-cell infusion, prior to each dose of pembrolizumab, at discontinuation of 
pembrolizumab, and at the completion/withdrawal visit.
p. Testing for infectious disease markers [HIV, HBV, HCV, HTLV, EBV, CMV, and syphilis (spirochete bacterium)] is required at screening, within 7 days prior 
to leukapheresis, and at Baseline. Subjects who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable 
hepatitis B DNA.   Subjects who are HCV antibody positive will be screened for HCV RNA by any RT-PCR or bDNA assay.
q. CMV seropositive subjects will continue to be monitored at least every 3 weeks for CMV viremia by CMV DNA PCR until 9 weeks post T-cell infusion 
(Section 8.2.3) 
r. Sample for cytokine levels at Day 1 will be collected pre-infusion.  If cytokine release syndrome (CRS) is suspected, cytokine levels as well C-reactive protein 
levels should be measured approximately every other day until symptoms are improving or an alternative diagnosis is confirmed. Anti-TCR antibodies will be 
assessed from the same collection as for cytokines but only at Baseline, Week 6 and Week 24.
s. Only for subjects ≥65 years of age.
t. Refer to Section 9.1 for instructions and details of AE collection and periods.
u. Vector Copies (Persistence) and VSV-G DNA (RCL) are Central Labs.  Vector copies for safety samples are collected Day1 (pre-infusion) and at Week 15, 
Week 24, and Week 48 post T-cell infusion, then every 6 months post T-cell infusion from year 2-5, and annually from year 6-15.  RCL samples are collected 
Day1 (pre-infusion), and at Week 15, Week 24, and Week 48 post T-cell infusion, and then annually.
v. Testing of subject leukapheresis will meet regional legislative requirements. In the EU this may include screening for Treponema pallidum (syphilis), details 
will be defined in the SPM.
w. G-CSF will be given from 24 hours after the last dose of cyclophosphamide until resolution of neutropenia in accordance with American Society of Clinical 
Oncology (ASCO) guidelines or institutional practice.  Long-acting (pegylated) G-CSF may be substituted according to institutional practice as described in 
Section 8.8.1.
x. Subjects in Arm 2 will receive 200 mg pembrolizumab IV for the first time on Week 3.  The second dose of pembrolizumab will be administered three (3) 
weeks later, at Week 6, and subsequent doses of pembrolizumab will be administered every 3 weeks thereafter up to Week 108 post T-cell infusion.  If toxicities 
that preclude pembrolizumab treatment (such as CRS Grade ≥2) are observed at Day 22 (Week 3), infusion of pembrolizumab will start on Week 6.  If toxicities 
have not resolved by Week 6, pembrolizumab will not be administered and the subject will be followed for visits as a subject in Arm 1. Schedule adjustments are 
outlined in the protocol (Section 5.4.1).
y. SPEP + immunofixation; quantitative IgG, IgM, IgA; UPEP + immunofixation based on 24-hour urine collection; serum free κ and λ light chain levels and κ/λ
ratio determination; beta-2-microgobulin.
z. The BM sample is optional for eligibility if subject had prior histological confirmation of the disease. 
aa. BM sampling should be preferably a fresh aspirate; aspirates are required at Screening, Baseline, Week 3 (before pembrolizumab infusion in Arm 2) as well 
as for MRD analysis. 
ab. BM samples will be obtained at Baseline, at Week 15 and at Disease Progression (before starting a new treatment) per standard of care and at the time of a 
complete response assessment (per IMWG response criteria [Kumar, 2016]).  If the subject received systemic anticancer therapy between leukapheresis and 
lymphodepleting chemotherapy for disease control, then the timing of the BM sample at baseline is critical and must respect the wash-out periods of Exclusion 
criterion # (Section 4.2).  A BM sample will also be collected at Week 3 or at Week 6 if the scheduled Week 3 infusion of pembrolizumab is delayed to Week 


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6. Any BM sampling at Week 24 and subsequent Q12wks visits are up to PI’s discretion if not required for response assessment per IMWG criteria [Kumar,
2016].  A BM sampling should also be analyzed at the time of a complete response (CR) assessment as per IMWG criteria [Kumar, 2016], in order to confirm 
CR.  Additional BM samples for research purposes semi-annually (optional) or whenever follow-up marrow collection may be performed at PI’s discretion.  
The BM sample obtained at the time point believed to be the closest to maximum response will be analyzed for Minimal Residual Disease (MRD).  Refer to 
Section 7.5.3 for further specific details.  For subjects in Arm 2, the bone marrow aspirate must be taken prior to the pembrolizumab infusion on those 
visits at which both are scheduled.  
ac. Bone imaging (CT, MRI, PET, or bone survey) is required at baseline..  Additional imaging, only if clinically indicated, is scheduled at Week 15 and Week 
24 then every 12 weeks.
ad. If pharmacogenetics sample collection is not done at baseline, it may be done at any other subsequent visit while the subject is in the treatment phase of the 
study.  Collection of pharmacogenetics sample is optional and all subjects who participate must provide consent for pharmacogenetics blood sample collection.
ae. Will be conducted every time a BM sample is obtained.  Research includes tumor antigen, gene marked T cells, T-cell clones and cytokines.  Cytogenetics 
should be performed at least at baseline and at relapse.


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Table 4
Schedule of Procedures in Long-Term Follow-up Phase
Prior to Transfer to LTFU Protocol 
Time post-infusion
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Years 6-15 
Months
3
6
12
18
24
30
36
42
48
54
60
Annually 
Visit window
± 2 
weeks
± 3 month
± 6 months
Safety 
Assessments
Medical History 
and Physical Exam1
X
X
X
X
X
X
X
X
X
X
X
X
Mutagenic agents, 
other 
investigational 
agents or anti-
cancer therapies1
X
X
X
X
X
X
X
X
X
X
X
X
Delayed adverse 
events and serious 
adverse events2
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X3
Serum chemistry
X
X
X
X
X
X
X
X3
Pregnancy test (for 
WOCBP)4
<===========================X4==========================>
Monitor for allo-
SCT5
X
X
X
X
X
X
X
X
X
Central Lab
VSV-G DNA 
(RCL) for safety6
X
X
X
X
X
X
X
X
Vector copies 
(persistence) for 
safety7
X
X
X
X
X
X
X
X
X
X
X
X3
Other 
Assessments
Survival Status
X
X
X
X
X
X
X
X
X
X
X
X
1.
New medical history/medications/chemotherapies.
2.
Delayed adverse event collection is limited to: 
o
New malignancies
o
New incidence or exacerbation of a pre-existing neurologic disorder
o
New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder
o
New incidence of an immune-related hematologic disorder


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o
Serious infections (including opportunistic)
o
Unanticipated illness and/or hospitalization deemed related to gene modified cell therapy
o
Specific events outlined in Section 9.5 for subjects who received pembrolizumab and had 
allo-SCT
3.
In year 6-15, laboratory assessments are performed for as long as persistence is analyzed.  If 
persistence samples are discontinued (Section 10.1.3.1 and Section 10.1.3.2) then laboratory 
assessments are discontinued. 
4.
For WOCBP, pregnancy testing should be conducted during contraception period only as defined 
in Section 4.1, Inclusion Criteria.  When pregnancy testing is performed at visits where 
hematology sample is collected, blood pregnancy testing will be done.  At visits where 
hematology testing is not performed, urine pregnancy test is acceptable unless serum testing is 
required by local regulation or IRB/IEC.
5.
All subjects who received pembrolizumab will be followed for a potential allo-SCT for 2 years 
following the last dose of pembrolizumab.  Subjects who receive an allo-SCT within the 24-month 
follow-up period will be monitored for 18 months for post-allo-SCT complications as stated in 
Section 9.5.
6.
Samples for RCL (VSV-G copies) are collected as described in Section 10.1.1.
7.
Samples for persistence are collected as described in Section 10.1.3.1, and Section 10.1.3.2.
7.4.
Clinical Assessments and Procedures
7.4.1.
Medical History
A complete medical history (including demographics) will be recorded at screening in the 
subject’s medical record and eCRF.
7.4.2.
Physical Examination and Measurement of Vital Signs
At screening for eligibility and baseline, subjects will undergo a physical examination 
including weight, height (collected only once), and measurement of their vital signs 
(temperature, pulse, respirations, and blood pressure [BP]).  The frequency of physical 
examination, weight and vital signs assessments at subsequent visits is specified in the 
Schedule of Procedures (Section 7.3).
7.4.3.
Performance Status
At screening for eligibility and baseline, performance status will be measured using the 
ECOG performance scale (see Section 16.2).  It is recommended, where possible, that a 
subject’s ECOG be assessed by the same person throughout the study.  The frequency of 
the ECOG assessment is specified in the Schedule of Procedures (Section 7.3).
7.4.4.
Clinical Safety Assessments
Subjects will be assessed for AEs throughout the study.  AEs are to be graded by 
National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) Version 4.0 unless specified otherwise in this protocol (see Table 5 in 
Section 8.5 for grading of CRS and Section 8.6.2 for grading of GVHD).  All AEs must 
be recorded in the eCRF. 
Details on assessing and reporting AEs and SAEs are described in Section 8.10.


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7.4.5.
Laboratory Assessments
All laboratory assessments will be performed locally at the site, and laboratory test 
reference ranges must be provided to GSK before the study initiates at site. 
Refer to Section 16.3 for listings of laboratory tests to monitor subject safety.
Women of childbearing potential (WOCBP) must have a negative pregnancy test at 
screening, prior to starting lymphodepleting chemotherapy, prior to NY-ESO-1c259T-cell 
infusion, prior to each dose of pembrolizumab, at discontinuation of pembrolizumab, and 
at the completion/withdrawal visit. 
Please refer to Schedule of Procedures (Section 7.3) for additional information regarding 
the frequency of these assessments.
7.4.6.
Cardiac Assessments
All cardiac assessments will be performed locally at the site.
The following assessments will be conducted in order to monitor subject safety:

An ECHO or MUGA scan will be performed at screening to determine 
eligibility. Additional scans will be performed only if clinically indicated.  
NOTE: the same method of cardiac evaluation must be used consistently for 
any follow-up scans.

ECGs refer to Section 16.3 for the ECG parameters required.
Please refer to Schedule of Procedures (Section 7.3) for information regarding the 
frequency of these assessments.  For subjects with cardiac or pericardial disease at 
baseline, inpatient telemetry monitoring will be carried out for a minimum of three and 
up to seven days post NY-ESO-1c259T infusion.  Reports of cardiac events in subjects 
with cardiac or pericardial masses following treatment with NY-ESO-1c259T will continue 
to be monitored through normal proactive pharmacovigilance.
7.4.7.
Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS)
Please refer to Section 8.10 for information related to the grading and management of 
ICANS.  Brain MRI (or CT Scan if MRI not feasible) should be obtained in all subjects at 
the time of screening.  Baseline brain MRI should be repeated if more than 4 months 
have elapsed prior to lymphodepletion.
Immune Effector Cell-Associated Encephalopathy (ICE) should be measured on the day 
of NY-ESO-1c259T infusion prior to receiving treatment and then at least through Day 8 
according to the schedule of procedures.  Subjects with known brain metastases should be 
monitored at least twice per day for the first 5 days following NY-ESO-1c259T infusion.  
If a subject is found to have ICANS, the ICE tool should be used at least twice per day 
until resolution or stable.  It can also be used at later visits if indicated.


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7.4.8.
Disease Response Assessments
Assessments for response and progression will be evaluated at baseline and throughout 
the study (refer to the Schedule of Procedures; Section 7.3) according to the IMWG 
Uniform Response Criteria for Multiple Myeloma [Kumar, 2016].
Diagnosis criteria will be as described in the IMWG Criteria for the Diagnosis of 
Multiple Myeloma (see Section 16.4).  
7.4.9.
Long-Term Follow-up
All subjects will be followed for survival, and for 15 years from time of T-cell infusion 
for observation of delayed AEs in accordance with FDA and EMA requirements for gene 
therapy clinical trials [FDA; 2020; FDA, 2010; EMA, 2009].  These assessments may be 
collected in the Interventional Phase of the study and will be collected thereafter in the 
LTFU protocol (GSK208750 [ADP-0000-002]).
Reporting criteria for AEs related to gene therapy during LTFU are described in 
Section 9.4. 
7.4.10.
Allogeneic Stem Cell Transplantation and Follow-up 
For subjects who received pembrolizumab and who have an allogeneic stem cell 
transplant (allo-SCT) within 24 months of last dose of pembrolizumab, transplant 
parameters will be collected, and specific and medically important adverse events post-
allo-SCT will be collected for 18 months from the date of the allogeneic transplant (see 
Section 9.5).  This follow-up can be carried out under the current protocol or under the 
LTFU protocol.
If available and relevant to an event post- allo-SCT, concomitant medications and/or 
laboratory results may also be reported. 
7.5.
Correlative Studies and Research Assessments
Correlative studies and research assays will be performed during the trial with the aim of 
monitoring the biological parameters that influence treatment outcome, such as T-cell 
phenotype, function and persistence of the engineered infused cells as well as evaluation 
of candidate biomarkers and their correlation with clinical response to treatment.  Data 
from such studies will be correlated to clinical outcome.  These studies will be performed 
on bone marrow aspirates, serum and fractionated PBMC samples collected according to 
the Schedule of Procedures.  All samples will be processed and/or frozen and analyzed 
either by central laboratory facilities contracted by the Sponsor, or by the Sponsor at the 
Sponsor’s facilities.  
Research studies conducted on blood samples may include:

DNA analysis (qPCR) on PBMCs for engineered T-cell persistence and its 
association with response

Flow cytometry on PBMCs to analyze immune cell subsets and persistence of 
engineered T-cells and their association with response


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
Genomic sequencing to assess T-cell clonality through TCR Vbeta and Valpha 
sequencing and integration site analysis

Determination of serum cytokine levels and their association with response

Determination of soluble BCMA (sBCMA) in serum may be performed as a 
surrogate of disease burden 

As new technologies and data emerge, other assays relevant to the study 
objectives may be performed.
Bone marrow aspirate research studies may include:

Flow cytometry on BMMCs to assess the frequency of immune cell subsets in 
tumor microenvironment and their correlation with treatment response. These 
data may be compared to frequency of immune cells in the blood with respect 
to treatment response 

DNA analysis of bone marrow aspirate (qPCR) to measure persistence of 
infused T-cells 

Assessment of mRNA levels of (RT-PCR, Next-Gen sequencing of RNA or 
Nanostring) of target antigens (NY-ESO-1 and LAGE-1a), other genes and 
immune cell markers including PD-1/PD-L1, and to associate their expression 
with response/resistance

Genomic sequencing to assess T-cell clonality through TCR Vbeta and/or 
Valpha sequencing 

Analysis for target antigen (NY-ESO-1 and LAGE-1a) and immune cell 
infiltrates (by IHC/MultiOmyx) in relation to treatment response

Next-Gen sequencing analyses to determine the evolution of the mutation 
profile of the tumor over the course of the therapy 

As new technologies and data emerge, other assays relevant to the study 
objectives may be performed.
If subjects have an ongoing clinical event, additional biopsy (for example skin, GI tract, 
BM) or blood (serum and PBMC) samples may be requested with the research objective 
of better understanding the etiology of the ongoing clinical event.  For this purpose, the 
above described research tests may be performed on these samples.
7.5.1.
Pharmacogenetics Sample
Understanding genetic determinants of drug response is an important endeavor during 
medical research.  This research will evaluate whether genetic variation within a clinical 
trial population correlates with response to the treatment(s) under evaluation.  If genetic 
variation is found to predict efficacy or AEs, the data might inform optimal use of 
therapies in the patient population. This research contributes to understanding genetic 
determinants of efficacy and safety associated with the treatments in this study.


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A whole blood sample for pharmacogenetics research may be obtained at any time 
throughout the study after eligibility is confirmed (refer to Table 3) in addition to any 
blood samples taken for the clinical study.  The blood sample will be taken on a single 
occasion unless a duplicate sample is required due to inability to utilize the original 
sample.  The blood sample can be taken at baseline or at any point during the treatment 
phase of the study providing the subject has given written informed consent for 
pharmacogenetics research.  Details regarding sample collection are provided in the 
SPM.
Specific genes will be selected from areas of the genome (e.g., candidate genes) including 
areas associated with mechanisms underlying AEs.  The candidate genes that may be 
investigated in this study include TGF-beta, TNF-alpha, IL-6, IL-10, and IFN-gamma.
7.5.2.
Cytokine and Soluble Factors Analysis
Serum is collected at baseline, and at each visit post T-cell infusion (refer to the Schedule 
of Procedures in Section 7.3), to allow for measurement of cytokines in the blood.  Serum 
is also collected from subjects with suspected CRS, samples being taken approximately 
every other day until symptoms are improving or an alternative diagnosis is confirmed 
(see Section 8.2).  Details regarding serum collection are provided in the SPM.
Cytokines, growth factors and soluble receptors including but not limited to IL-6, IFN-γ, 
TNF-α, IL-2Rα, IL-10, IL-13, IL-1Ra, IL-8, IL-12, IL-15, IL-2, and GM-CSF are 
measured.
Serum samples may also be used to investigate anti-TCR antibodies and soluble BCMA 
(sBCMA).
7.5.3.
Bone Marrow Aspirates
A bone marrow (BM) aspirate is required during screening for confirmation of the NY-
ESO-1 and/or LAGE-1a antigen expression.  
As long as the multiple myeloma diagnosis has been histologically confirmed at an 
earlier date, no additional BM sampling will be mandated for eligibility screening.
Bone marrow samples (aspirates) are also required at baseline, Week 3 (or at Week 6 if 
the scheduled Week 3 infusion of pembrolizumab is delayed to Week 6 in Arm 2), Week 
15, and at disease progression/end of treatment phase. In case of dry-tap, an aspirate must 
be repeated in another area for an appropriate bone marrow sample. 
If the subject received systemic anticancer therapy between leukapheresis and 
lymphodepleting chemotherapy for disease control, then the timing of the BM sample at 
the baseline visit prior to lymphodepletion must also respect the wash-out periods of 
Exclusion criterion #21 (Section 4.2.2). 
An aspirate is required at Week 3 (or at Week 6 if the scheduled Week 3 infusion of 
pembrolizumab is delayed to Week 6) to evaluate the infiltration of NY-ESO-1c259T into 
the BM and for evaluation of the tumor microenvironment in relationship to baseline.


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For subjects in Arm 2, the bone marrow aspirate must be taken prior to the 
pembrolizumab infusion on those visits at which both are scheduled.  
Any bone marrow sampling at Week 24 and subsequent Q12wks visits are up to PI’s 
discretion if not required for response assessment per IMWG criteria [Kumar, 2016]. A 
BM sampling is also required at the time of a CR to confirm the response per IMWG 
response criteria [Kumar, 2016].  The BM sample obtained at the time point believed to 
be the closest to maximum response will be analyzed for MRD.  Whenever follow-up 
marrow collection is performed at physician discretion, sample may be obtained for 
research studies.
Additional details regarding the bone marrow aspirate collection are provided in the 
SPM.
BM aspirates may be used in particular to assess:

target antigen expression (NY-ESO-1 and LAGE-1a)

frequency of immune cells in the bone marrow microenvironment 

NY-ESO-1c259T-cell persistence in the marrow (as described in Section 7.5.4),

NY-ESO-1c259T-cell clonality, and 

the depth of the clinical response by testing the presence of any MRD.
Assessment of MRD will employ a molecular method based on Next-Gen Sequencing 
(NGS) in which the specific immunoglobulin gene rearrangement present in the 
malignant plasma cell (PC) clone is identified in genomic DNA from a pre-therapy BM 
sample, then later tracked and quantified in post-therapy samples.  That assay is the most 
sensitive known to date and is capable of detecting residual malignant PCs down to a 
frequency of 10-6.  MRD will be assessed at Week 15 (if relevant for subjects diagnosed 
with CR) the time of best clinical response.
The diversity of the T cell clones infiltrating the BM will also be investigated by NGS.  
Genomic DNA from BMMC or sorted NY-ESO-1c259T cells will be used to measure the 
number and size of T-cell clones (V beta or V alpha) in relation to clinical response.
7.5.4.
NY-ESO-1c259 T-cell Persistence
The primary research assays for the trial involve monitoring the persistence of infused 
engineered cells in the subjects in order to establish a correlation with potential 
therapeutic effect.  Persistence is also monitored as a long-term safety measure 
(Section 10.1.3).  Two well established methodologies will be used to measure the 
presence of transduced T-cells.

Quantitation of NY-ESO-1c259 TCR+ cells by PCR of a vector-specific 
sequence in DNA extracted from PBMC

Quantitation of NY-ESO-1c259 TCR expressing cells by flow cytometry (FCM) 
on frozen PBMC


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7.5.5.
NY-ESO-1c259 T-Cell Phenotype and Activity
A range of assays will be performed to further elucidate the phenotype and activity of the 
infused cells.  The assays performed will depend upon availability of sample and 
clinical/scientific significance.  The following assays may be performed (although 
analysis may not be limited to these assays; additional assays may be added as they 
become available).

Phenotype analysis for determination of T-cell lineages

Quantitation of the exhaustion and activation status of immune subsets from 
PBMC 

Quantitation of soluble factors reflecting in vivo function of NY-ESO-1c259
TCR+ T cells 

Anti-gene modified T-cell immune responses (tertiary assay)

Ex vivo activity of transduced cells at different time points to assess potential 
anergy and/or exhaustion of those cells

Analysis of gene expression profile to reflect activity of the cells.
7.5.6.
Peripheral Blood Collection and Analysis
Recognizing that BM aspirates and biopsies cannot always be obtained, we set out to 
investigate whether alternative approaches can provide similarly valuable information.  
Therefore, in addition to BM aspirates, peripheral blood plasma will be collected in order 
to investigate both cell-free DNA (cfDNA) and exosomes.
Exosomes (source of stable mRNA, produced by all cells, including tumor cells and 
immune cells) and cfDNA, produced by dying tumor cells will be used to monitor both 
the molecular signature of the tumor burden (including the expression of the target 
antigen) and the immune response.  The analysis of exosomes and cfDNA will allow:

Estimation and genetic profiling of the global tumor burden (including 
expression of NY-ESO-1c259 mRNA and mutational profiling) from exosomes 
and cfDNA.

Systemic assessment of the immune response (gene expression by cytotoxic 
and regulatory immune cells) from exosomes.
7.5.7.
Request for Autopsy for Death Following Administration of Gene 
Transfer Agents
In accordance with FDA and EMA Guidances [FDA, 2020; EMA, 2009], all subjects 
enrolled in this trial are asked to consent to autopsy, and autopsies will be requested of 
the families for all subjects who die during participation in studies after administration of 
gene transfer agents.  To ensure compliance, guidelines for performing an autopsy are 
provided in the SPM.


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8.
SUPPORTIVE CARE GUIDANCE
It is recommended subjects are treated under the care of a specialist with experience in 
the administration of hematopoietic stem cell transplant and/ or other cell and gene 
therapy.  Subjects should be hospitalized for the T-cell infusion and for approximately 1 
week of follow-up or until stable for discharge in a unit with staff experienced in the 
acute care of post-transplant subjects and the management of associated toxicities (e.g., 
cytopenias, CRS, aGVHD).
Subjects are at risk for the development of certain AEs for which recommended 
management strategies have been developed.  Adverse effects are most likely to occur 
within the first month following T-cell infusion, but may occur at later time points. 
8.1.
T-cell Infusion Symptom Management
Mild transient symptoms have been observed following infusion of engineered T cells.  
The management of these symptoms is suggested but should not necessarily be confined 
to the below:

Fever, chills, headache, and temperature elevations will be managed with 
acetaminophen.  It is recommended all subjects who develop fever or chills 
have a blood culture drawn.

Nausea and vomiting may be treated with a non-steroidal antiemetic of choice.

Hypotension will initially be managed by IV fluid administration and further 
measures as dictated by standard medical practice.

Hypoxemia will initially be managed with supplemental oxygen and further 
measures as dictated by standard medical practice.
8.2.
Infection
Additional measures to treat and prevent infection are outlined below. In particular, fever 
and neutropenia should be aggressively managed as well as pre-emptive influenza 
therapy and other standard therapies for immunocompromised hosts, in accordance with 
institutional guidelines.
8.2.1.
Pneumocystis carinii Pneumonia (PCP)
Subjects should receive prophylaxis against PCP with drug, dose and duration according 
to institutional guidelines. Single strength trimethoprim sulfamethoxazole daily is the 
recommended first-line agent, starting at Day 28 post T-cell infusion for one year. Other 
regimens, including atovaquone (1500 mg daily with food) or aerosolized pentamidine 
(300 mg every four weeks) are also acceptable (e.g., if sulfonamide allergy).
8.2.2.
Herpes Simplex and Varicella Zoster
All subjects should receive prophylaxis with acyclovir (800 mg twice daily) or 
valacyclovir (500 mg twice daily) for one year, or in accordance with institutional 
guidelines.


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8.2.3.
Cytomegalovirus
All subjects will be screened for cytomegalovirus (CMV) seropositivity at study entry. If 
CMV viremia is detected at Baseline, treatment should be initiated with evidence of viral 
clearance prior to lymphodepleting chemotherapy. All CMV IgG seropositive subjects 
will continue to be monitored for CMV viremia by CMV DNA PCR until 60 days post 
infusion of cell therapy. In the event CMV viremia is observed, an infectious diseases 
specialist should be consulted and treatment initiated if necessary according to 
institutional practice. Recommended regimens include ganciclovir-based therapy if ANC 
≥1000, and foscarnet if ANC <1000. 
If a subject experiences prolonged or secondary pancytopenia or lymphopenia, additional 
monitoring for viral reactivation should be considered and treatment for viral infection 
initiated if necessary. A strategy for management of pancytopenia or bone marrow failure 
is described in Section 8.7.
8.2.4.
Hepatitis B Prophylaxis
Subjects will be screened for hepatitis B virus (HBV) at study entry. Subjects who are 
hepatitis B core antibody positive must receive prophylaxis against viral reactivation 
using institutional protocols. Prophylaxis should be initiated prior to lymphodepleting 
chemotherapy and continued for 6 months. Acceptable regimens include lamivudine (300 
mg daily), entecavir (0.5 mg daily), or tenofovir (300 mg daily).
8.2.5.
Syphilis
Subjects will be screened for syphilis at study entry. Subjects with positive screening 
results should be evaluated by an infectious diseases consultant. If determined to have 
syphilis infection, the subject should be treated before leukapheresis.
8.2.6.
Other Anti-Microbial Prophylaxis
Antibacterial and antifungal prophylaxis should follow institutional standards for 
autologous bone marrow transplants.
8.3.
Hematologic and Blood Product Support
Blood product support should be provided to maintain platelets >10 × 109/L, hemoglobin 
>8.0 g/dL (or in accordance with the institutional practices), and as clinically indicated.  
See AABB Guideline on platelet transfusion [Kaufman, 2015].
8.3.1.
Irradiated Blood Product
Bone marrow suppression can be a consequence of transfusion associated GVHD.  To 
minimize the possibility of transfusion associated GVHD, all blood products transfused 
within 4 weeks prior to leukapheresis, within 4 weeks prior to initiation of 
lymphodepleting chemotherapy and following lymphodepleting chemotherapy until at 
least 6 months following IP infusion or until lymphocyte count returns to ≥1.0 x109/L 
(whichever is longer) must be irradiated.  In addition, if a subject requires systemic 


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steroids or immunosuppression for the treatment of toxicity, irradiated blood products 
must be given until recovery of immune function.
8.3.2.
Cytomegalovirus Screened Blood Products
Subjects will be screened for CMV seropositivity on study entry.  In order to reduce the 
risk of primary CMV infection all subjects (i.e. both CMV-positive and -negative 
subjects) should receive leukoreduced blood products where possible (excluding the IP 
infusion).  Where leukoreduced blood is not available, CMV negative subjects must only 
receive blood products from CMV-seronegative donors from study entry to study 
completion.
8.4.
Management of Autoimmunity
Subjects should be monitored throughout the trial for potential autoimmune reactions in 
response to the genetically engineered T cells that could include skin toxicity, liver 
toxicity, colitis, eye toxicity etc.  If autoimmunity is suspected, the PI should be contacted 
and every attempt should be made to biopsy the affected organ to clarify whether the 
symptoms are related to the NY-ESO-1c259T-cell therapy.  If the subject sustains 
persistent Grade 2, or Grade 3 or 4 autoimmunity, consideration should be given to 
administration of corticosteroid therapy, either topically (e.g. skin, eyes) or systemically 
as clinically indicated.
8.5.
Management of Cytokine Release Syndrome
CRS is a potentially life-threatening toxicity that has been observed following 
administration of antibodies and adoptive T-cell therapies for cancer.  It is defined 
clinically by symptoms many of which mimic infection including pyrexia, nausea, 
diarrhea, headache, fatigue, tachycardia, hypotension, transaminitis, rash and dyspnea.  It 
is important to evaluate the subject for concurrent infections.  Potentially life-threatening 
complications of CRS include cardiac dysfunction, adult respiratory distress syndrome, 
neurologic toxicity, renal and/or hepatic failure and disseminated intravascular 
coagulation.  CRS may also be associated with findings of macrophage activation 
syndrome or occur coincident with tumor lysis syndrome.
CRS causes a rapid rise in serum cytokine levels under conditions of immune activation 
and although cytokines will be assayed serially throughout the study, results of the assays 
will not be available in real time; therefore CRS, should be graded and managed with 
supportive and immunosuppressive interventions according to the severity of symptoms 
[Lee, 2019].
Table 5 provides the recommended management of CRS according to grade, which has 
been further adapted from CTCAE for use with immunotherapy and should be 
implemented in accordance with institutional guidelines.  Symptoms can mimic those 
seen with infection.  The diagnosis of CRS is clinical and is supported by the exclusion of 
infection as well as the presence of increased cytokine levels and other biomarkers.  
Assessment and treatment guidelines are provided below.  If CRS is suspected, in 
addition to assessment for infection, cytokine levels as described Section 7.5.2 as well 


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CRP levels should be measured approximately every other day until symptoms are 
improving or an alternative diagnosis is confirmed.
Table 5
Management Guidelines for Cytokine Release Syndrome
Grade
Clinical Presentation for Grading 
Assessment1,2
Management Guidelines
1
Temperature ≥38.0 °C
Vigilant supportive care4
Assess for infection and treat5
2
Temperature ≥38.0 °C with 
hypotension not requiring 
vasopressors and/or hypoxia requiring 
the use of oxygen delivered by low-
flow nasal cannula (≤6 L/minute) or 
blow-by
Monitor cardiac and other organ 
function
Vigilant supportive care4
Assess for infection and treat5
Treat hypotension with fluid and 
pressors6
Administer O2 for hypoxia
Consider administering tocilizumab ± 
corticosteroids7
3
Temperature ≥38.0 °C with 
hypotension requiring a vasopressor 
with or without vasopressin and/or 
hypoxia requiring high-flow nasal 
cannula (>6 L/minute), facemask, non-
rebreather mask, or venturi mask not 
attributable to any other cause3
Monitor subject very closely for cardiac 
and other organ dysfunction.  Most likely 
will require monitoring in an intensive 
care unit (ICU).
Vigilant supportive care4
Assess for infection and treat5
Treat hypotension with fluid and 
pressors6  
Administer O2 for hypoxia
Administer tocilizumab ± 
corticosteroids7
4
Temperature ≥38.0 °C with 
hypotension requiring multiple 
vasopressors (excluding vasopressin) 
and/or hypoxia requiring positive 
pressure (eg: CPAP, BiPAP, intubation 
and mechanical ventilation)
Manage subject in ICU
Intensive supportive care including 
mechanical ventilation, fluids, pressors, 
antibiotics and other measures as 
required6
Administer tocilizumab ± 
corticosteroids7
5
Death
1.
Fever is defined as temperature 38°C not attributable to any other cause. In subjects who have 
CRS then receive antipyretic or anti-cytokine therapy such as tocilizumab or steroids, fever is no 
longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia.
2.
CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any 
other cause. For example, a subject with temperature of 39.5°C, hypotension requiring 1 
vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS. 
3.
Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes 
blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as 
oxygen delivered at >6 L/minute.
4.
Supportive care includes:  monitor fluid balance, maintain adequate hydration and blood pressure.


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5.
Assessment and treatment to include history and physical, blood and urine cultures, imaging 
studies, administration of antimicrobial agents for concurrent bacterial infections, and for 
treatment of fever and neutropenia as per institutional practice; and antipyretics, analgesics as 
needed. 
6.
Given that prolonged fluid resuscitation without pressor use is associated with worse outcome and 
because early and aggressive supportive care, early use of vasopressors, and timely anti-cytokine 
therapy are paramount to mitigating life-threatening CRS.
7.
Other immunosuppressor agents may be used, including TNFα and IL-1R inhibitors. 
Source: [Lee, 2019]
Grade 1 CRS is defined as fever (≥38.0°C) with or without constitutional symptoms 
(Table 5). The constitutional symptoms of CRS, such as myalgia, arthralgia, and malaise, 
are by themselves nonspecific; however, when coincident with fever in the expected 
timeframe, the etiology of CRS is more likely. 
Grade 2 CRS is defined as fever (≥38.0°C) with hypotension not requiring vasopressors 
and/or hypoxia requiring the use of oxygen delivered by low-flow nasal cannula (≤6 
L/minute) or blow-by (Table 5). 
Grade 3 CRS is defined as fever (≥38.0°C) with hypotension requiring 1 vasopressor with 
or without vasopressin and/or hypoxia requiring high-flow nasal cannula (>6 L/minute), 
facemask, nonrebreather mask, or venturi mask not attributable to any other cause (Table 
5). 
Grade 4 CRS is defined as fever (≥38.0°C) with hypotension requiring multiple 
vasopressors (excluding vasopressin) and/ or hypoxia requiring positive pressure [eg, 
Continuous airway positive pressure (CPAP), bilevel positive airway pressure, intubation, 
mechanical ventilation] not attributable to any other cause. Outside of vasopressin, 
adding a second agent is a strong indication that the patient remains hemodynamically 
unstable after the first intervention. Such a scenario would be consistent with grade 4 
CRS. Any use of positive-pressure ventilation constitutes a grade 4 CRS. Intubation of a 
patient without hypoxia for the possible neurologic compromise of a patent airway alone 
or for a procedure is not, by definition, grade 4 CRS. By extension, a patient experiencing 
seizures in which a compromised airway affects oxygenation and intubation reverses 
such deficits is not considered to have grade 4 CRS, because the seizure rather than CRS 
is the cause of the hypoxia. Furthermore, a patient who remains intubated for a 
neurologic cause is not considered to have CRS when the other signs of CRS have 
resolved. 
By convention, grade 5 CRS is defined as death due to CRS in which another cause is not 
the principle factor leading to this outcome.
Subjects requiring immunosuppressive intervention may receive tocilizumab, steroids, or 
both [Davila, 2014; Lee, 2014; Lee, 2019].  Tocilizumab is a humanized anti-IL-6 
receptor antibody that has been used to manage severe CRS (although it is not approved 
for this indication).  Anecdotally, tocilizumab has produced rapid and complete 
correction of CRS with single doses [Maude, 2014]. Lee et al. [Lee, 2014; Lee, 2019] 
recommend administration of tocilizumab 4 mg/kg administered over 1 hour in adult 
subjects as the first-line treatment of severe CRS.  Subjects may receive a repeat dose if 
clinical signs and symptoms do not improve within 24-48 hours.


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Side effects attributed to chronic use of tocilizumab in rheumatologic disease include 
transaminitis, thrombocytopenia, elevated cholesterol and low-density lipoproteins, 
neutropenia and increased infections but acute infusional toxicities have not been 
reported in CRS use [Lee  2014; Lee, 2019].
Subjects unresponsive to tocilizumab or experiencing severe neurological symptoms (e.g. 
confusion, delirium, seizure) may require treatment with steroids. Lee et al. [Lee  2014; 
Lee, 2019] recommend steroids as second-line therapy for CRS as the response to 
tocilizumab may be more rapid and owing to the potential of steroids to attenuate the 
antitumor effects of the ACT.  However, in subjects with Grade 3 or 4 CRS associated 
with neurologic dysfunction without significant hemodynamic instability or other life-
threatening symptomatology, consideration may be given to the use of corticosteroids as 
a preferred first-line immunosuppressive therapy.  High doses (e.g. 2 mg/kg/day 
prednisone equivalent) may be required.
If CRS is suspected, a physician with expertise in the management of subjects following 
bone marrow transplant should be consulted.  If high-dose corticosteroids are required, 
treatment should generally be continued for at least 5 days followed by tapering doses 
over several weeks.
Please refer to the most recent version of the product label for tocilizumab.
8.6.
Management of Graft-versus-Host Disease (GVHD)
Autologous GVHD has been described in association with adoptive transfer of ex vivo
expanded/co-stimulated autologous T-cells [Rapoport, 2009], as well as infusion of T-
cells with engineered specificity for NY-ESO-1 and LAGE-1a [Garfall, 2013], following 
high-dose chemotherapy and ASCT in subjects with MM.  There is the potential for 
subjects who receive lymphodepleting therapy followed by engineered autologous T-Cell 
infusion to experience GVHD and/or autoimmune GVHD-like symptomatology.  
Autologous GVHD is typically milder than classic (allogeneic) GVHD [Kline, 2008], and 
is usually manageable with treatment.  However, severe cases (including fatalities) have 
been reported [Fidler, 2012].  There are no published guidelines for the management of 
autologous GVHD.  However, lessons can be drawn from published cases reports and 
guidelines for the diagnosis and management of acute GVHD following allogeneic 
transplant [Dignan, 2012].
8.6.1.
Diagnosis of GVHD
The diagnosis of GVHD is predominantly based on clinical findings and is often one of 
exclusion.  Many of these symptoms can also occur in the setting of the preparative 
regimen, high-dose cyclophosphamide as well as with CRS.  Any of these conditions 
including GVHD can be associated with fever.  The skin is the most commonly involved 
organ, followed by the GI tract and liver.  A constellation of symptoms involving these 
organ systems may be helpful in establishing the diagnosis of GVHD.  Diarrhea, rash, 
fever, and pancytopenia are common toxicities in the NY-ESO-1c259T program where we 
have the most clinical experience.  Mild (Grade 1 or 2) transient transaminitis without 
cholestasis has been observed.


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Table 6
Diagnosis of GVHD
Organ
Findings/Symptoms
Differential Diagnosis
Histopathology
Skin
Maculopapular rash 
involving the neck and 
shoulders as well as the 
palms and soles that 
spreads to include the rest of 
the body.
Drug reactions, viral 
exanthems, cytokine 
release syndrome, and 
effects of chemotherapy 
or radiation
Apoptosis at base of 
epidermal rete pegs, 
dyskeratosis, exocytosis of 
lymphocytes, satellite 
lymphocytes adjacent to 
dyskeratotic epidermal 
keratinocytes and 
perivascular lymphocytic 
infiltration in the dermis.
GI
Secretory diarrhea is most 
common but nausea, 
vomiting, anorexia, weight 
loss and abdominal pain can 
also occur.  Diarrhea can be 
copious.  Bleeding may 
result from mucosal 
ulceration and ileus may 
ensue.
Side effects of 
chemotherapy or other 
drugs and infection of 
the GI tract
Patchy ulcerations, 
apoptotic bodies at crypt 
bases, crypt ulceration and
flattening of surface 
epithelium
Liver
Cholestatic pattern of liver 
injury including elevated 
conjugated bilirubin, alkaline 
phosphatase and gamma-
glutamyl transpeptidase 
(GGTP).  Subjects may 
present with jaundice, with 
pruritus in more severe 
cases.
Veno-occlusive disease 
of the liver, viral 
infections, drug toxicity 
and sepsis.
Endothelialitis, lymphocytic 
infiltration of the portal 
areas, pericholangitis and 
bile-duct destruction.
Of Note: Bone marrow suppression and related cytopenias have been described in the 
setting of acute GVHD.  Management of this complication is challenging, with no clearly 
established guidelines regarding immunosuppression.  Treatment may be largely 
supportive, including transfusions and treatment of infections.
Management should include consultation with a physician with expertise in the 
management of subjects following bone marrow transplant.
Bone marrow suppression is also a feature of transfusion-related GVHD.  To minimize 
the possibility of transfusion-related GVHD, see Section 8.3.1 for guidance on irradiated 
blood products.
8.6.2.
Grading of GVHD
Grading of acute GVHD is based on the stage of dermal, GI, and hepatic involvement as 
described in the Table below.  Careful measurement of stool volume and assessment of 
percentage of body area covered by rash are important for proper grading and treatment.


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Table 7
Stage of GVHD
Stag
e
Skin
Gut
Liver
1
Maculopapular rash <25% of body 
area
Diarrhea >500 mL/day
Bilirubin 2-3 mg/dL
2
Maculopapular rash 25%-50% of 
body area
Diarrhea >1,000 mL/day
Bilirubin 3-6 mg/dL
3
Generalized erythroderma
Diarrhea>1,500 mL/day
Bilirubin 6-15 mg/dL
4
Desquamation and bullae
Diarrhea>2,000 mL/day 
or pain or ileus
Bilirubin >15 mg/dL
With the addition of assessment of functional impairment, grading can be determined 
using the Table 8 [Glucksberg, 1974].
Table 8
Grading of GVHD
Grade
Skina
Guta
Livera
Functional statusb
I
1-2
0
0
0
II
1-3
1
1
1
III
2-3
2-3
2-3
2
IV
1-4
2-4
2-4
3
aStaging is described above
bMild, moderate, or severe decrease in performance status
8.6.3.
Management of GVHD
Although the diagnosis of GVHD is predominantly based on clinical grounds, biopsy of 
affected organs can be helpful in excluding other causes and supporting the diagnosis of 
GVHD with consistent histopathologic findings.  However, awaiting biopsy results 
should not delay the institution of appropriate therapy.
If GVHD is suspected:

A physician with expertise in the management of subjects following BM 
transplant should be consulted

Consider biopsy of the affected organ(s)
Corticosteroids have been used as the standard first-line treatment for GVHD for several 
decades.  Their effect is likely to be due to lympholytic effects and anti-inflammatory 
properties.  In general, intestinal and liver GVHD require more prolonged steroid therapy 
than skin disease although response times vary.
Diarrhea should be managed with volume replacement, dietary restriction, and 
antidiarrheal agents including the consideration of somatostatin for secretory diarrhea.  
Agents that slow motility should be used cautiously, ensuring that there is no evidence of 
ileus or toxic megacolon, and infectious causes of diarrhea should be excluded.


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General guidelines for first-line treatment based on grade are provided below and should 
be considered in conjunction with input from the consulting physician with BM 
transplant expertise.
Table 9
Management of GVHD
Grade
Management Strategy
I
Subjects with grade I disease are not likely to require systemic treatment.  
Cutaneous GVHD may respond to topical steroid creams.  Antihistamines may be 
helpful in subjects with pruritus.  Subjects should be reviewed frequently for other 
organ manifestations of GVHD.
II
Treat skin symptoms with topical steroids.  For GI symptoms - optimize 
antidiarrheal regimen, dietary restrictions, volume replacement and consider 
initiation of non-absorbable steroids.  For refractory or progressive symptoms 
consider systemic steroids as outlined below.
III
For more severe or progressive symptoms consider systemic corticosteroids (e.g., 
methylprednisolone one (1) mg/kg per day*)
IV
Methylprednisolone two (2) mg/kg per day*
* The use of ‘nonabsorbable’ steroids (budesonide and beclomethasone) can be considered for 
acute intestinal GVHD in order to reduce the dose of systemic steroids
If high-dose corticosteroids are required, treatment should generally be continued for at 
least 5 days followed by tapering doses over several weeks.  A physician with expertise 
in infectious diseases in immunocompromised hosts should be consulted, and 
prophylactic antimicrobials should be considered.
Second-line treatment can be considered for subjects who have failed to respond for 5 
days or have progressive symptoms after 3 days.  There is no clear second-line agent that 
is preferred for steroid refractory GVHD.  General guidelines for second-line treatment 
based on grade are provided below, and should be considered in conjunction with input 
from the consulting physician with BM transplant expertise.
For steroid refractory skin rash, topical tacrolimus may also be useful.
Most of the allogeneic transplant subjects are concurrently receiving calcineurin 
inhibitors in part as prophylaxis against GVHD.  Therefore, for grade II-IV disease 
refractory to high-dose steroids, the addition of a calcineurin inhibitor can be considered.
Otherwise, there are several additional second-line treatment options for which there is 
currently limited and/or evolving supporting data.  Treating physicians can refer to the 
Haemato-oncology Task Force of the British Committee for Standards in Haematology 
and the British Society for Blood and Marrow Transplantation guideline for diagnosis 
and management of acute GVHD [Dignan, 2012].


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8.7.
Management of Pancytopenia with Bone Marrow Failure / 
Aplastic Anemia
Pancytopenia with BM failure / aplastic anemia has been reported after initial BM 
recovery from high-dose chemotherapy followed by infusion of NY-ESO-1c259 T-cells.  
BM recovery following lymphodepletion will be defined as:

Absolute neutrophil count ≥1,000/μL for 2 consecutive measurements 
approximately seven days apart, and

Platelet count ≥20,000/μL without transfusion support for one week.
Aplastic anemia is a rare hematological disorder characterized by pancytopenia and a 
hypocellular marrow.  Subjects are usually symptomatic on presentation, but some are 
detected incidentally when unexpected cytopenias are found on a routine blood count.  
The diagnosis of severe aplastic anemia is made in the setting of a hypocellular bone 
marrow when 2 of the following 3 blood counts are met: absolute neutrophil count 
<500/μL, absolute reticulocyte count <60,000/μL, and platelet count <20,000/μL, and 
myelodysplastic syndrome is ruled out.  The clinical consequences of aplastic anemia are 
life-threatening bleeding from thrombocytopenia, and infection as a result of neutropenia.  
Bacterial and fungal infections are common and a significant cause of morbidity and 
mortality.
Management of BM suppression and related cytopenias in aplastic anemia is challenging, 
with no clearly established guidelines regarding immunosuppression.  Treatment is 
largely supportive, including transfusions and treatment of infections.  If there is evidence 
of, or concern for the development of pancytopenia (decreasing hemoglobin, platelets or 
neutrophils, or increasing transfusion requirements) following initial BM recovery, the 
following measures should be implemented:

Consult a physician with expertise in the management of aplastic anemia.

Increase the frequency of CBCs as clinically indicated.

Exclude other alternative etiologies such as other drugs, viral causes, etc.

An early BM biopsy is recommended for clinical diagnosis, with a sample to be 
provided to the Sponsor for study.  Refer to Section 7.4.10 (Correlative Studies 
and Research Assessments).  Details on tissue collections, kit use and shipment 
information can be found in the SPM.

A matched peripheral blood sample should be collected in parallel with the BM 
sample and provided to the Sponsor (refer to Section 7.4.10)

Initiate treatment with G-CSF

Consult an Infectious Diseases expert

Once alternative etiologies have been excluded, strongly consider 
immunosuppression (e.g. methylprednisolone 2 mg/kg initial dose) or more 
aggressive regimens (e.g. antithymocyte globulin (ATG), cyclosporine, 
eltrombopag) as well as antimicrobial prophylaxis/therapy with the advice of your 


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hematology/ID consultant(s).  If high-dose corticosteroids are initiated, continue 
for a minimum of 5 days and taper gradually with advice from expert consultants.
Refer to Section 8.6 (Management of Graft-versus-Host Disease) regarding bone marrow 
suppression as a feature of GVHD.
8.8.
Chemotherapy Symptom Management
Cyclophosphamide and fludarabine are used as pre-conditioning lymphodepletion 
chemotherapy in this study.  Symptoms associated with the use of cyclophosphamide and 
fludarabine are included in the respective product labels.  Refer to the most current 
product label and Section 1 for details of prohibited medications.
8.8.1.
Management of Neutropenia
The cyclophosphamide and fludarabine chemotherapy is intended to cause 
lymphodepletion.  However, neutropenia is also common.  Prophylactic use of G-CSF is 
recommended in all subjects.  Filgrastim (G-CSF) should be used for management of 
neutropenia according to ASCO guidelines.  G-CSF should be given 24 hours after the 
administration of chemotherapy and continued until reaching an absolute neutrophil 
count (ANC) of at least 2 to 3 × 109/L.
Long-acting (pegylated) G-CSF may be given in preference to short acting daily G-CSF 
in accordance with institutional standard practice.  Pegylated G-CSF will be given as one 
dose 24 hours after the final dose of cyclophosphamide.
8.9.
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab 
associated infusion reaction are provided in Table 10.
Table 10
Infusion Reaction Treatment Guidelines for Pembrolizumab
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
Investigator.
None
Grade 2
Requires therapy or 
infusion interruption 
but responds 
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Subject may be 
premedicated 1.5 h (± 
30 minutes) prior to 
infusion of 


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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDS, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for < =24 h
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
Investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g., from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until symptoms 
resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from further 
trial treatment administration.
pembrolizumab (MK-
3475) with:
Diphenhydramine 50 mg 
po (or equivalent dose 
of antihistamine).
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antianalgesic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae 
(e.g., renal 
impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine*
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
Investigator.
Hospitalization may be indicated.
* In cases of anaphylaxis, epinephrine should 
be used immediately.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration.
Abbreviations: NCI-CTCAE: National Cancer Institute-Common Terminology Criteria for Adverse 
Events; NSAID = nonsteroidal anti-inflammatory drug


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8.10.
Management of ICANS
Encephalopathy has been described in association with chimeric antigen receptor (CAR) 
T therapy and termed (CAR) T-cell-related encephalopathy syndrome, or CRES 
[Neelapu, 2018].  CRES typically manifests as a toxic encephalopathy which is generally 
reversible.  Early signs include diminished attention, language disturbance and impaired 
handwriting.  Other signs/symptoms include confusion, disorientation, agitation, aphasia, 
somnolence, and tremors.  In severe cases of CRES (defined as grade >2), seizures, motor 
weakness, incontinence, mental obtundation, increased intracranial pressure, papilledema, 
and cerebral edema may also occur.
CRES occurring within the first 5 days after immunotherapy may be concurrent with high 
fever and CRS symptoms.  This form of CRES tends to be of shorter duration, lower 
grade (Grade 1–2, see Table 12), and is generally reversible with anti-IL-6 therapy.  
CRES presenting as delayed neurotoxicity with seizures or episodes of confusion can 
occur three or four weeks after CART cell therapy, after the initial fever and CRS 
subside.
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is a disorder 
characterized by a pathologic process involving the central nervous system following any 
immune therapy that results in the activation or engagement of endogenous or infused T cells 
and/or other immune effector cells. Symptoms or signs can be progressive and may include 
aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, 
seizures, and cerebral edema. ICANS may occur with other cancer immunotherapies, 
including TCRs.  Cancer patients may also be at risk for ICANS symptoms due to other 
causes ranging from mild to moderate somnolence and confusion as a result of sedating 
medications, to seizures in relation to brain metastases.  The possible contribution of 
other medications, underlying disease and/or co-morbidities should be evaluated when 
considering a diagnosis of ICANS in relation to T-cell therapy.
8.10.1.
Grading of ICANS
[Lee, 2019] have developed a new grading system for ICANS which incorporates use of 
a modified version of the CARTOX 10-point neurological assessment tool termed 
Immune Effector Cell-Associated Encephalopathy (ICE) (Table 11).  Points are assigned 
for each of the tasks in the table which are performed correctly.  Normal cognitive 
function is defined by an overall score of 10. The ICE should be used to monitor all 
subjects for ICANS.


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Table 11
Immune Effector Cell-Associated Encephalopathy (ICE) assessment 
tool
Task
ICE Points
Scoring: 10, no impairment; 7-9; grade 1 ICANS; 3-6, grade 2 ICANS; 0-2, grade 3 ICANS; 0 due to 
patient unarousable and unable to perform ICE assessment, grade 4 ICANS
The ICE score is used in grading of ICANS as presented in Table 12.
Table 12
Grading of Immune Effector Cell-Associated Neurotoxicity 
Syndrome (ICANS)
Neurotoxicity 
Domain
Grade 1
Grade 2
Grade 3
Grade 4
ICE score1
Depressed level 
of consiousness2
Elevated ICP/ 
cerebral edema
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected 
by third party copyright laws and therefore have been excluded.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.


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Neurotoxicity 
Domain
Grade 1
Grade 2
Grade 3
Grade 4
Motor findings5
Seizure
ICANS= Immune Effector Cell-Associated Neurotoxicity Syndrome; ICE = Immune Effector Cell-Associated Encephalopathy; ICP = Intracranial 
Pressure; N/A = not applicable.
1. See Table 11 for ICE. A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global 
aphasia, but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable.
2. Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication)
3. Papilloedema grading is performed according to the modified Frisén scale.
4. Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading. 
5. Tremors and myoclonus associated with immune effector cell therapies do not influence ICANS grading.
This table is based on Lee, 2019.
8.10.2.
Monitoring for ICANS
Brain MRI (or CT Scan if MRI not feasible) should be obtained for all subjects at the 
time of screening.  Baseline brain MRI should be obtained within 4 weeks prior to 
lymphodepletion.
ICE should be measured on the day of NY-ESO-1c259T infusion prior to receiving 
treatment and then at least through Day 8 according to the schedule of procedures.  If a 
subject is found to have ICANS, the ICE should be used at least twice per day until 
resolution or stable.  It can also be used at later visits if indicated.
8.10.3.
Management of ICANS
The recommended management of ICANS should be based on toxicity grade.  Table 13
provides guidance on the management of ICANS and should be implemented in 
accordance with institutional guidelines.  
Grade 1 ICANS is primarily managed with supportive care as outlined below.  For 
subjects requiring intervention beyond supportive measures, anti-IL-6 therapy should be 
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or 
indices, which are protected by third party copyright laws and therefore have been excluded.


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the first line treatment of for ICANS in the setting of CRS. In the setting of concurrent 
CRS, for Grades 1-3 ICANS additional doses of anti-IL-6 therapy should be considered 
before instituting corticosteroids since the use of systemic steroids may abrogate the 
effects of the T-cell therapy.  For subjects with neurologic symptoms refractory to an 
initial dose of anti-IL-6 therapy, consider siltuximab for the second dose based on its 
mechanism of action directly against IL-6.  
A neurology consultation should be obtained for all subjects with ICANS for thorough 
neurological evaluation, and recommendations for further testing such as EEG and 
neuroimaging as indicated in Table 13.
Table 13
Management of ICANS
Grade
Treatment
1
• Vigilant supportive care; aspiration precautions; intravenous (IV) hydration
• Withhold oral intake of food, medicines, and fluids, and assess swallowing
• Convert all oral medications and/or nutrition to IV or enteral tube if swallowing is impaired
• Avoid medications that cause central nervous system (CNS) depression
• Evaluate for other contributing causes and treat accordingly
• Neurology consultation including fundoscopic exam to assess for papilloedema
• MRI of the brain with and without contrast (CT scan of the brain if MRI is not feasible).  
Further testing if indicated such as diagnostic lumbar puncture with measurement of opening 
pressure if increased intracranial pressure is suspected, or MRI of the spine if the subject has 
focal peripheral neurological deficits
• Institute levetiracetam therapy and consider EEG if seizure activity is suspected
• Consider anti-IL-6 therapy with tocilizumab 8 mg/kg1 IVor siltuximab 11 mg/kg IV, if Grade 1 
persists beyond 24 hours, or worsening and associated with concurrent CRS
2
• Supportive care and neurological work-up as described for grade 1 ICANS
• Anti-IL-6 therapy if associated with concurrent CRS
• Consider Dexamethasone 10 mg IV every 6 h or methylprednisolone 1 mg/kg IV every 12 h if 
refractory to anti-IL-6 therapy, or for ICANS without concurrent CRS; once initiated continue 
corticosteroids until improvement to grade 1 ICANS and then taper
• Consider transferring patient to intensive-care unit (ICU) if ICANS associated with grade ≥2 
CRS
3
• Supportive care and neurological work-up as indicated for grade 1 ICANS
• ICU transfer is recommended
• Anti-IL-6 therapy if associated with concurrent CRS if not administered previously
• Corticosteroids as outlined for grade 2 ICANS if symptoms worsen despite anti-IL-6 therapy, 
or for ICANS without concurrent CRS; continue corticosteroids until improvement to grade 1 
ICANS and then taper
• Stage 1 or 2 papilloedema with cerebrospinal fluid (CSF) opening pressure <20 mmHg 
should be treated corticosteroid regimen as per Grade 4 below.
• Consider repeat neuroimaging (CT or MRI) every 2–3 days if patient has persistent grade ≥3 
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Grade
Treatment
4
• Supportive care and neurological work-up as indicated for grade 1 ICANS
• Consider neurosurgical consultation for patients with evidence of increased intracranial 
pressure
• ICU monitoring; consider mechanical ventilation for airway protection
• Anti-IL-6 therapy and repeat neuroimaging as described for grade 3 ICANS
• High-dose corticosteroids continued until improvement to grade 1 ICANS and then taper; for 
example, methylprednisolone IV 1 g/day for 3 days, followed by rapid taper at 250 mg every 12 
h for 2 days, 125 mg every 12 h for 2 days, and 60 mg every 12 h for 2 days
1
Maximum amount of tocilizumab per dose is 800 mg
Grade 1 ICANS. Grade 1 ICANS is defined as a score of 7-9 on the ICE assessment 
(Table 12). A patient with grade 1 ICANS may have a delay in responses or 
disorientation to time or place, mild inattention with difficulty in counting numbers 
backwards, or impairment of handwriting. There may be drowsiness, but patients awaken 
spontaneously, and when prompted, the patient should be able to complete most of the 
ICE assessment. Grade 1 ICANS may be seen during CRS waxing and waning with 
febrile episodes.
Grade 2 ICANS. Grade 2 ICANS is defined as a score of 3-6 on the ICE assessment 
(Table 12).  Expressive aphasia is the most specific first sign of severe neurotoxicity and 
early signs during grade 2 include paraphasic errors (the production of unintended 
syllables and words during attempts to speak) and verbal perseveration with patients 
repeating the same words over and over. Patients with grade 2 ICANS are able to 
communicate their needs but it is effortful. Patients may have depressed level of 
consciousness but are arousable to voice and the responses may be slowed.
Grade 3 ICANS. Grade 3 ICANS is defined as a score of 0-2 on the ICE assessment 
(Table 12).  Patients with grade 3 ICANS have severe global aphasia and are not 
speaking or following commands even when wide awake and therefore may be unable to 
complete any of the ICE questions. Alternatively, they may have excessive drowsiness 
and need tactile stimulus to attend to examiner. Any clinical seizure whether simple 
partial, complex partial or generalized, and any electrographic seizures would also meet 
criteria for grade 3 ICANS (Table 12, Table 13). If neuroimaging shows new focal or 
local edema this would also be categorized as grade 3 ICANS (Table 12, Table 13). 
However, intracranial hemorrhage due to coagulopathy or other causes with or without 
associated edema is not considered a neurotoxicity feature and is excluded from ICANS 
grading.
Grade 4 ICANS.  Grade 4 ICANS is defined as patients who have a score of 0 on the 
ICE assessment (Table 12) due to being unarousable and unable to perform the ICE 
assessment.  Stupor and coma may be seen; the stuporous patient only responds by 
grimacing or drawing away from vigorous or repetitive tactile stimuli and the comatose 
patient is unarousable and/or unresponsive. This depressed level of consciousness should 
be attributable to no other cause (e.g. no sedating medication), which is often a 
complicating factor in sick patients with CRS. Some patients may require intubation for 


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airway protection. In addition, any patient having prolonged or repetitive clinical or 
subclinical electrographic seizures without return to baseline in between, or deep focal 
motor weakness such as hemiparesis or paraparesis would be considered to have Grade 4 
ICANS. Patients with symptoms and signs of elevated ICP such as projectile vomiting 
with headache, depressed consciousness, cranial nerve VI palsies, papilledema, Cushing's 
triad of bradycardia, hypertension and respiratory depression, decerebrate or decorticate 
posturing, or diffuse cerebral edema on head imaging would also be considered to have 
grade 4 ICANS. 
Grade 5 ICANS. By convention, Grade 5 ICANS is defined as death due to ICANS 
where another cause is not the principle factor leading to this outcome.
8.11.
Management of Guillain-Barré Syndrome (GBS)
Please obtain a neurology consultation for all subjects with signs or symptoms suggestive 
of GBS for thorough neurological evaluation, and for expert recommendations on further 
diagnostic workup including EMG, lumbar puncture, infectious panel to guide 
management and follow up.
Figure 3
Case assessment for possible Guillain Barre Syndrome using 
diagnostic and prognostic tools supported by medical diagnosis 
and/or medical treatment
*Please refer to algorithm for treatment described in Figure 4.
Peripheral 
neuropathy
Symptoms 
suggestive of 
GBS/AIDP
Treatment according 
to guidelines/clinical 
practice
GBS Diagnostic tool:
Brighton Criteria
At hospital admission
Indicator of prognosis
EGRIS tool
At hospital 
admission*
mEGOS tool
At hospital admission and Day 7
Yes
Confirmatory assessment 
targeted within 7 days from 
hospital admission
Suspected 
GBS
Strength of diagnosis includes 
clinical assessment and CSF and 
NCV measures. Some tests may not 
be available until several days after 
hospital admission.

Confirmed GBS required to 
implement mEGOS. 

At hospital admission (data 
that supports Brighton level 1 
or 2) may not be available. 

Level 1 or 2 assessment 
required before mEGOS 
assessment i.e. Day 7
Neurology 
consultation


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8.11.1.
Neurological Symptoms
The following features should be considered as suggestive of a GBS diagnosis in clinical 
practice and the use of the Brighton criteria [Fokke, 2014] together with further 
neurological evaluation will be the basis for confirmation of diagnosis:
Progressive weakness in legs and arms (sometimes initially only in legs)
• 
Areflexia (or decreased tendon reflexes) in weak limbs
Additional symptoms
• 
Progressive weakness phase lasts 2 to 4 weeks (often 2 weeks)
• 
Relative symmetry of weakness
• 
Cranial nerve involvement, especially bilateral weakness of facial muscles
• 
Autonomic dysfunction
• 
Pain
8.11.2.
Brighton Key Diagnostic Criteria
At admission and confirmation within 7 days of admission:
•
Bilateral and flaccid weakness of limbs
•
Decreased or absent deep tendon reflexes in weak limbs
•
Monophasic course and time between onset – nadir 12 hours to 28 days
•
CSF cell count < 50/µl
•
CSF protein concentration > normal value
•
Nerve conduction studies’ findings consistent with one of the subtypes of GBS
•
Absence of alternative diagnosis for weakness
8.11.3.
Erasmus GBS Respiratory Insufficiency Score (EGRIS)
Probability of acute risk first week following hospital admission of respiratory 
insufficiency [Walgaard, 2010]. 
Parameters required at hospital admission:
•
Days between onset of weakness and admission
•
Facial and/or bulbar weakness at admission
•
Medical Research Council sum score
8.11.4.
Modified Erasmus GBS Outcomes Score (mEGOS)
Parameters required at hospital admission and 7 days later [Walgaard, 2011]: 
•
Age at onset
•
Preceding diarrhoea (in 4 weeks preceding onset of weakness)


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•
Medical Research Council sum score
8.11.5.
Summary of diagnosis and treatment for GBS
Additional information on the diagnosis and management of GBS (Figure 4) can be 
found in a review article on GBS [Willison, 2016].
Figure 4
Diagnosis and Treatment of Guillain-Barré Syndrome (GBS) 
Abbreviations: EGRIS = Erasmus GBS Respiratory Insufficiency Score; GBS = Guillain-Barré Syndrome; 
ICU = intensive care unit; IVIg = intravenous immunoglobulin; TRF = treatment related fluctuation.
Source:Willison, 2016 (with permission from Willison, H.).
9.
RECORDING ADVERSE EVENTS
Timely, accurate, and complete reporting and analysis of safety information from clinical 
studies are crucial for the protection of subjects and is mandated by regulatory agencies 
worldwide.  The Sponsor has established standard operating procedures in conformity 
with regulatory requirements worldwide to ensure appropriate reporting of all safety 
information; all clinical studies conducted by the Sponsor or its affiliates will be 
conducted in accordance with those procedures.  The Investigator and their designees are 
responsible for detecting, documenting, and reporting events that meet the definition of 
an AE or SAE.  Individual AEs should be evaluated by the Investigator and reported to 


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the Sponsor as appropriate. This includes the evaluation of its intensity, the causality 
between the IP and/or concomitant therapy and the AE, and seriousness. 
The Sponsor has to keep detailed records of all AEs reported by the Investigator(s) and to 
perform an evaluation with respect to causality, seriousness, and expectedness.  
9.1.
Time Period for Collecting Adverse Event and Serious 
Adverse Event Information
AEs and SAEs will be collected at the time points specified in Table 3 for the treatment 
phase of the study.

During Part 1 of the study: Any SAEs or AEs assessed as related to study 
participation (e.g., study intervention, protocol-mandated procedures, invasive 
tests, or change in existing therapy) or leading to early withdrawal, will be 
collected in the AE section of the CRF from the time a subject signs the 
informed consent for target expression screening.  All other relevant events 
that begin before the start of leukapheresis but after obtaining informed consent 
will be recorded on the Medical History/Current Medical Conditions section of 
the CRF, not the AE section.

During Part 2 of the study: Any SAEs or AEs assessed as related to study 
participation (e.g., leukapheresis, other study intervention, protocol-mandated 
procedures, invasive tests, or change in existing therapy) or leading to early 
withdrawal, will be collected in the AE section of the CRF. All other relevant 
events experienced or occurring while the subject was undergoing bridging or 
intermediate therapy (i.e., anti-cancer therapy, including experimental 
regimens under another study protocol, even if with another Sponsor) will be 
recorded on the Medical History/Current Medical Conditions section of the 
CRF, not the AE section, at the time of the evaluation of study eligibility for 
part 3 (lymphodepletion/treatment). 

During Part 3 Arm 1 of the study: All SAEs will be collected from the Baseline 
Visit until the end of study. Regardless of study end for a subject, all SAEs 
must be collected through 90 days following T-cell infusion, or 30 days 
following T-cell infusion if the subject initiates new anticancer therapy, 
whichever is earlier. All AEs will be collected from the Baseline Visit until 30 
days following cessation of study treatment OR the end of study, whichever is 
later

During Part 3 Arm 2 of the study: All AEs and SAEs will be collected as for 
Arm 1 or until 30 days for AEs and 90 days for SAEs following cessation of 
pembrolizumab treatment (30 days only if subject initiates new anticancer 
therapy), whichever is the longest period of collection.  For subjects who 
received pembrolizumab and who have an allo-SCT within 24 months of last 
dose of pembrolizumab, specific and medically important adverse events will 
be collected for 18 months from the date of the transplant (see Section 9.5).


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
During LTFU (15 years post T-cell infusion) subjects will only be monitored 
for potential gene therapy-related delayed adverse events (see Section 9.4 and 
the LTFU protocol GSK208750 [ADP-0000-002]).

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours. The Investigator will 
submit any updated SAE data to the sponsor within 24 hours of it being 
available. Any SAE, including death, brought to the attention of an Investigator 
at any time outside of the time period specified above must be reported 
immediately to the Sponsor if the event is considered to be drug-related.

Events of special interest (Section 9.13) will be reported to the Sponsor (or 
designee) immediately and under no circumstance should this exceed 24 hours.
9.2.
Definition of Adverse Event
In accordance with the ICH, an AE is any untoward medical occurrence in a subject or 
clinical investigation subject who receives a pharmaceutical product.  The event does not 
necessarily have a causal relationship with study treatment to be an AE.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an IP, whether or not 
considered related to the IP.  Pre-existing conditions which worsen during the study are 
to be reported as AEs.  Progression of the cancer under study is not considered an AE 
unless it is considered to be drug-related by the Investigator (see Section 9.5). 
AEs or abnormal laboratory findings should be recorded in the eCRF using a diagnosis or 
possible diagnosis, and rated for intensity, causality, and seriousness.  In the absence of a 
diagnosis, individual symptoms or findings may be recorded and the eCRF updated to 
reflect a final diagnosis once additional information becomes available.  If photographs 
are requested by the Sponsor of, e.g., a rash AE, the subject will sign a Medical 
Photograph Release prior to any photographs being taken.
All AEs should be followed until: 

Resolved or improved to baseline.

Investigator confirms no further improvement can be expected.

Death.
On completion of the subject from the treatment portion of the study, or withdrawal from 
the study, serious or severe AEs will be followed until one of the above criteria is met.  
SAEs related to IP will continue to be recorded and monitored into LTFU at any time 
(Section 9.4).
9.2.1.
Assessment of Intensity
Adverse events will be graded according to the NCI-CTCAE v 4.0. Refer to Section 8.5
and Section 8.6.2 for specific grading of CRS and GVHD respectively.
The Investigator will assess intensity of all AEs using this five-point scale (Grade 1-5) 
and record on the eCRF.


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AEs not specifically listed on the NCI-CTCAE should be graded according to Table 14 :
Table 14
Grading of AEs not specified in NCI-CTCAE v4.0
NCI-CTCAE 
Grade
Equivalent to
Definition
Grade 1
Mild
Discomfort noticed but no disruption of normal daily 
activity.
Grade 2
Moderate
Discomfort sufficient to reduce or affect daily activity; 
minimal medical intervention is indicated.
Grade 3
Severe
Incapacitating with inability to work or perform normal 
daily activity; treatment or medical intervention is 
indicated in order to improve the overall well-being or 
symptoms; delaying the onset of treatment is not 
putting the survival of the subject at direct risk.
Grade 4
Life-threatening/ 
disabling
An immediate threat to life that requires urgent medical 
intervention.
Grade 5
Death
AE resulting in death.
Abbreviations: AE = adverse event; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Events
9.2.2.
Assessment of Causality
The Investigator will assess the causal relationship between the AE and IP according to 
his/her best clinical judgement.  An assessment of possibly/probably/definitely related is 
meant to convey there is evidence of a causal relationship, not that a relationship cannot 
be ruled out.  The Investigator should consider alternative causes such as natural history 
of the underlying disease, lymphodepleting chemotherapy, concomitant medications, and 
other risk factors when making an assessment.  The following scale will be used as 
guidance:

Not related – The subject did not receive the IP; the temporal sequence of the 
AE onset relative to administration of the IP is not reasonable; or there is 
another obvious cause of the AE.

Possibly related – There is evidence of exposure to the IP; the temporal 
sequence of the AE onset relative to T-cell infusion is plausible; or the AE 
could have been due to another equally likely cause.

Probably related – There is evidence of exposure to the IP; the temporal 
sequence of the AE onset relative to T-cell infusion is plausible; the AE shows 
a pattern consistent with previous knowledge of the IP; or the AE is more 
likely explained by the IP than any other cause.

Certainly related – There is evidence of exposure to the IP; the temporal 
sequence of the AE onset relative to T-cell infusion is plausible; the AE shows 
a pattern consistent with previous knowledge of the IP, or the AE is most likely 
explained by the IP and any other cause is improbable.


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The Investigator may change his/her opinion of causality if additional information is 
received and amend the AE eCRF accordingly.  The Investigator causality assessment is 
one of the criteria GSK use to determine regulatory reporting requirements for an SAE.
9.3.
Reporting Serious Adverse Events (SAEs)
An SAE is any adverse event that:

Results in death (results in death; NOTE: death is the outcome, not the event).

Is life-threatening; (NOTE: the term “Life-threatening” refers to an event in 
which the subject was at immediate risk of death at the time of the event; it 
does not refer to an event which could hypothetically have caused a death had 
it been more severe).

Requires hospitalization or prolongation of existing hospitalization.

Results in a persistent or significant disability.

Is a congenital anomaly/birth defect.

Is clinically significant or requires intervention to prevent one or the outcomes 
listed above.
Medical and scientific judgment should be exercised in deciding if an AE is of significant 
enough medical importance to be classified as serious outside the above definitions.  
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above.  For example, drug overdose or 
abuse, a seizure that did not result in inpatient hospitalization, or intensive treatment of 
bronchospasm in an emergency department, would typically be considered serious.  In 
this case event will be reported using the serious criteria of clinically significant or 
requires intervention.
Additional protocol-defined criteria

Any Grade ≥3 CRS or GVHD, and all cases of Guillain-Barré syndrome or 
acute inflammatory demyelinating polyneuropathy must be reported as an SAE 
within 24 hours.
The study will comply with all local regulatory requirements and adhere to the full 
requirements of the ICH Guideline for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2. 
An SAE must be reported to GSK within 24 hours of the study personnel’s discovery of 
the event by completing an SAE Worksheet and submitting by e-mail to both mailboxes: 
and 
, or by fax:
.  The SAE eCRF form within the electronic data capture (EDC) system must also be 
completed.
PPD
PPD
PPD
PPD


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For the time period beginning at signature of Screening ICF through 90 days following 
cessation of pembrolizumab, or 30 days following cessation of pembrolizumab if the 
subject initiates new anticancer therapy, whichever is earlier, any SAE, or follow-up to an 
SAE, including death due to any cause other than progression of the cancer under study, 
whether or not related to the Sponsor's product, must be reported to the Sponsor.
The SAE eCRF must be completed by the Investigator with as much information as is 
available.  The minimum reporting criteria for an SAE include:

Identifiable subject (Subject ID)

Event that is identified as serious (SAE term)

Suspect medicinal product

Relationship to IPs

Identifiable reporting source (PI acknowledgment of the report and his/her 
signature is required).
The Investigator will assess the causal relationship between the SAE and IP(s) according 
to his/her best clinical judgement.  The Investigator will also assess the causal 
relationship between the SAE and the lymphodepleting chemotherapy.
Further details can be found in the SPM.
9.4.
Reporting Criteria during Long-Term Follow-Up (Years 1-15)
Due to the nature of the treatment, subjects are required to be followed for up to 15 years 
after treatment with genetically modified T cells according to FDA and EMA guidance 
[FDA; 2020; EMA, 2009].  Subjects will be followed according to the schedule outlined 
in the LTFU protocol GSK208750 (ADP-0000-002).  Certain events in this protocol are 
identified as delayed AEs and should be marked as delayed AEs in the eCRF.
Delayed AEs are defined as those events that fall into one or more of the 6 categories 
listed below and which occur either more than 108 weeks following NY-ESO-1c259T cell 
infusion or after disease progression, whichever occurs first.  In the event a subject has 
not progressed by 108 weeks following GSK3377794 infusion, delayed AEs will be 
collected in Interventional Phase of study.  Delayed AEs which occur post progression 
will be collected as part of the LTFU phase of the current study or in the LTFU Study 
(208750), contingent upon formal transfer of subject to Study 208750.

New malignancies

New incidence or exacerbation of a preexisting neurological disorder

New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder

New incidence of an immune-related hematologic disorder

Serious infections (including opportunistic)


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
Unanticipated illness or hospitalization deemed related to gene modified cell 
therapy

Specific events outlined in Section 9.5 for subjects who received 
pembrolizumab and had allo-SCT
A detailed narrative description of the event should include the date of diagnosis and the 
nature of the diagnosis for all AEs.  If the diagnosis is cancer, record the type and stage of 
the cancer.  If the cancer is metastatic, list the metastatic sites.  If a new malignancy is 
recorded in a vector target cell type, tumor cells will be evaluated for vector sequences.  
If the tumor is positive for vector sequences or the surrogate sample is positive for vector 
sequences and is confirmed in accordance to this protocol, clonality analysis will be 
performed.  If no evidence of oligo-or monoclonality is observed, a summary report of 
any and all analysis for the pattern of vector integration will be assembled and submitted 
within the annual report of the INDs listed on this protocol under which the subject(s) 
evaluated originally received their treatment.  If evidence of oligo- or monoclonality is 
observed, an information amendment will be submitted within 30 days to the INDs listed 
on this protocol under which the subject(s) evaluated originally received their treatment.  
Adverse events should be recorded in the eCRF using a diagnosis or possible diagnosis, 
and rated for intensity, causality and seriousness.  If photographs are requested by the 
Sponsor of e.g. a rash AE, the subject will sign a Medical Photograph Release prior to 
any photographs being taken.  Suspected unexpected serious adverse reactions (SUSARs) 
deemed related to the gene modified cells will be reported to the Regulatory Agencies 
and shared with Investigators as necessary in the form of Investigational new drug safety 
reports (INDSRs).
All AEs should be followed until:

Resolved or improved to baseline.

Investigator confirms no further improvement can be expected.

Death
9.5.
Follow-up post Allogenic Stem Cell Transplantation for 
Subjects Who Received Pembrolizumab
For subjects who received pembrolizumab and who have an allogeneic stem cell 
transplant (allo-SCT) within 24 months of last dose of pembrolizumab, specific events 
(all grades, and regardless of relationship to study drug) will be collected for 18 months 
from the date of the transplant, to include:

Graft-versus-host-disease (acute and/or chronic) 

Veno-occlusive disease 

Febrile syndrome (a steroid-requiring febrile illness without an infectious 
cause)

Encephalitis 


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Additional medically important adverse events post- allo-SCT may be reported at the 
investigator’s discretion.  This follow-up can be carried out under the current protocol or 
under the LTFU protocol.
9.6.
Progression of Underlying Malignancy
Progression of underlying malignancy and related symptoms are not reported as an AE if 
they are clearly consistent with the suspected progression of the underlying cancer.  
Clinical symptoms of progression may be reported as AEs if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy or does 
not fit the expected pattern of progression for the disease under study.
If there is any uncertainty about an AE being due only to the disease under study, it 
should be reported as an AE or SAE.
9.7.
Regulatory Reporting Requirements for Serious Adverse 
Events
The Sponsor has legal obligations for expedited reporting of certain events to Regulatory 
Authorities, IRBs/ Research Committees (RC), and other study subjects.  GSK will 
comply with all GCP and country specific regulatory requirements relating to safety 
reporting to the Regulatory Authorities, IRBs/RCs, and Investigators.
Investigator safety reports for suspected unexpected serious adverse reactions (SUSARs) 
are prepared and distributed according to local regulatory requirements and GSK policy.  
These safety reports are forwarded to Investigators as necessary in the form of INDSRs.
An Investigator who receives an INDSR describing a SAE(s) or other specific safety 
information (e.g., summary or listing of SAEs) from GSK will file it with the IB and 
notify their IRB/RC if appropriate, in accordance with local requirements.
On request of a competent authority in whose territory the clinical trial is being 
conducted, the Sponsor will submit detailed records of all AEs which are reported to him 
by the relevant Investigator(s).
9.8.
Cardiovascular and Death Events
For any cardiovascular events detailed below and all deaths, whether or not they are 
considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will be 
required to be completed. These sections include questions regarding CV (including 
sudden cardiac death) and non-CV death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion. 
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.


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Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the following 
AEs and SAEs:
Myocardial infarction/unstable angina
Congestive heart failure
Arrhythmias
Valvulopathy
Pulmonary hypertension
Cerebrovascular events/stroke and transient ischemic attack
Peripheral arterial thromboembolism
Deep venous thrombosis/pulmonary embolism
Revascularization
9.9.
Pregnancy
There is no preclinical or clinical trial data of NY-ESO-1c259T in pregnant women; 
however, there is a reasonable but unproven likelihood that this intervention may be 
significantly embryotoxic or even an abortifacient given the underlying biology of the 
target.  The effects on breast milk are unknown; therefore, breastfeeding should be 
discontinued for the duration of the study, starting at the first dose of chemotherapy and 
for at least 12 months after receiving the T-cell infusion, or 4 months after there is no 
evidence of persistence/gene modified cells in the subject’s blood, whichever is longer.
Pregnancy (or pregnancy of a male subject’s partner) is not considered an AE/SAE unless 
there is reason to believe that the pregnancy may be the result of failure of the 
contraceptive being used due to interaction with any of the IPs.  However, the 
Investigator shall report all pregnancies immediately to the Sponsor.  A woman who 
becomes and remains pregnant during the study will be discontinued from the treatment 
phase as exposure to radiation from imaging studies would be contraindicated in this 
setting.  The subject would enter into LTFU.  The outcome of the pregnancy must also be 
reported to the Sponsor.  The contraception and pregnancy guidelines in Section 6.3.3
should continue to be followed during LTFU.
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy.
9.10.
Preexisting Condition
A preexisting condition is one that is present at the start of the study during screening.  A 
preexisting condition should be recorded as an AE if the frequency, intensity, or the 
character of the condition worsens during the treatment phase.
9.11.
Laboratory Test Abnormalities as Adverse Events
Out of range laboratory test results which meet any of the following criteria should be 
reported as AEs:


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
Any CTCAE lab value ≥ Grade 3 should be recorded as an AE.  Grade 1 and 2 
laboratory abnormalities do not require reporting unless the Investigator 
considers the event is clinically significant.

Any Grade 4 CTCAE lab value based solely on numerical criteria (e.g. WBC 
decreased) should be reviewed to determine whether it should be reported as a 
serious adverse event.
9.12.
Overdose
For this trial, an overdose will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab.  No specific information is available on the treatment of overdose of 
pembrolizumab.  In the event of overdose, the subject should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated.
9.13.
Adverse Events of Special Interest
Selected non-serious and serious AEs are also known as events of special interest (ESI) 
and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until enrollment, any ESI , 
or follow-up to an ESI, that occurs to any subject must be reported within 24 hours to the 
Sponsor if it causes the subject to be excluded from the trial, or that is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment, or a procedure.
Following enrollment, ESIs will be reported to sponsor within 24 hours for the same 
period as AEs and SAEs (see Section 9.1).  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the SPM.
ESI for this trial include:

Cytokine release syndrome (CRS) [Note: Grade 3 or higher should be reported as SAE within 
24 hours]

Graft vs host disease (GvHD) 

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Grade 1 persisting 
beyond 24 hrs or associated with concurrent CRS; or Grade 2 or higher

Guillain Barre syndrome (GBS) including acute inflammatory demyelinating polyneuropathy 
(AIDP) [Note: all cases must be reported as SAEs within 24 hours]

Pancytopenia/aplastic anemia if any of the below events occur:
–
Occurs after the bone marrow reconstitution following the lymphodepletion regimen
–
Any Grade 3 or 4 cytopenia following lymphodepletion lasting more than 2 weeks 
with G-CSF support
–
Requiring transfusion support (e.g. platelets or RBC) lasting more than 2 weeks 
following lymphodepletion

Treatment-related inflammatory response at tumor site(s)


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
An overdose of pembrolizumab, as defined in Section 9.12, that is not associated with 
clinical symptoms or abnormal laboratory results. 

An elevated AST or ALT laboratory value that is greater than or equal to 3× the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or equal to 
2× the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2× the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing.
*Note:  These criteria are based upon available regulatory guidance documents.  The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow-up of these criteria can be found in the SPM.
9.14.
Timelines for Safety Reporting
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
Investigator will 
submit any 
updated SAE 
data to GSK 
within 24 hours of 
receipt of the 
information
Updated SAE 
data collection 
tool 
“CV events” and/or 
“death”
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the 
cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
24 Hours
Pregnancy 
Notification Form
2 Weeks
Pregnancy 
Followup- Form
AESI
24 hours
AESI data 
collection tool 
(plus SAE if 
applicable – see 
Section 9.13.)
Update AESI date 
collection tool


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10.
SAFETY MONITORING
10.1.
Monitoring and Management of Replication-Competent 
Lentivirus (RCL)
Replication Competent Lentivirus (RCL) is a theoretical risk associated with the use of 
lentiviral vectors; no RCL has ever been detected in vitro or in vivo.  The risk is derived 
from the detection of replication competent retrovirus (RCR) during the use of early γ 
retroviral vector packaging systems which were inadequately designed to avoid 
recombination events between the vector and packaging components [Miller, 1990].  
Updated γ retroviral packaging systems have not been associated with RCR.  However, in 
a study with Rhesus monkeys, three out of 10 animals died of lymphomas at around 6 
months after transplantation of vector transduced bone marrow cells contaminated with 
replication-competent virus [Donahue, 1992]. Therefore, RCR/L must continue to be 
rigorously evaluated in vector and cell lots, and in subjects post T-cell infusion with any 
product involving a retrovirus [FDA, 2006; FDA; 2020; FDA, 2010; EMA, 2009].
A RCL may be generated during the production phase or subsequently after introduction 
of vector transduced cells into the subject.  RCL may be generated between homologous 
or non-homologous recombination between the transfer vector and packaging elements, 
or endogenous retroviral elements [Chong, 1998; Garrett, 2000].  A RCL resulting from 
the production phase of the lentivirus used in this trial is highly unlikely since elements 
are incorporated in the design of the vector system that minimize vector recombination 
and generation of RCL.  Nevertheless, generation of an RCL by recombination with an 
endogenous virus (i.e., HIV) in the subject following infusion of the vector product 
remains a theoretical possibility.  The consequences of such recombination events could 
be neutral, could reduce the replication rate or pathogenicity of the subject's endogenous 
virus, or could increase the replication rate or pathogenicity of the subject's endogenous 
virus.  Since the development of a strain with increased pathogenicity would pose greater 
risk to both the subject and their close contact(s), periodic monitoring for RCL is 
conducted during the course of the trial and during the 15-year follow-up.
Regulatory agencies and the gene therapy community have previously discussed 
measures to be taken should an RCL be confirmed in a subject [FDA, 2006; FDA; 2020;
EMA, 2009].  However, because the probability and characteristics of an RCL are 
unknown, no concrete plans have been put in place.  As of the writing of this protocol it 
is agreed the subject must be isolated until an understanding of how to manage the 
concern becomes clear.
The following approaches have been discussed for subject management:

Provide targeted antiretroviral therapies based on genotyping of the RCL.

Intensive follow-up of subject in consultation with gene therapy experts, Study 
Investigators, HIV physicians, FDA, other regulatory agencies, and NIH.


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10.1.1.
Testing for RCL in Clinical Studies
RCL will be monitored using a PCR-based assay that detects and measures copies of the 
gene coding for the vector’s envelope protein, namely Vesicular Stomatitis Virus G 
protein (VSV-G) that is necessary for the assembly of pseudotyped infectious lentiviral 
particles but absent from the vector’s backbone.  RCL testing and monitoring will take 
place on:

The cell product, whereby RCL testing will be performed by or under the 
direction of the manufacturing facility responsible for manufacturing and 
release of the vector.

Subject PBMCs will be collected prior to infusion of transduced T cells and 
then at 3, 6, and 12 months post treatment.  If these tests are negative at all 
time points during the first year, PBMC samples will be collected annually and 
archived for up to 15 years post T-cell infusion or until assessments for 
persistence have ended (Section 10.1.3.1); however, if VSV-G DNA copies are 
detected at any time point in the first year post-infusion, the safety monitoring 
protocol (Section 10.1.2) will be triggered.  Subject samples will continue to be 
tested for VSV-G DNA copies until VSV-G DNA copies are not detected for 3 
consecutive annual assessments, then subject samples will be collected 
annually until 15 years post-infusion and archived at GSK’s centralized 
biorepository or until assessments for persistence have ended 
(Section 10.1.3.1).
10.1.2.
Safety Monitoring Results
If a positive VSV-G DNA signal is obtained, the Investigator will be informed and the 
subject scheduled for a retest as soon as possible and no later than one month after the 
initial positive result was reported to the Sponsor.  A review by the Sponsor will take 
place.
Response to potential outcome of second VSV-G DNA test:

If the second test is negative, then subject samples will continue to be tested for 
VSV-G DNA copies until VSV-G DNA copies are not detected for 3 
consecutive annual assessments, at which time the subject samples will be 
collected and archived annually until year 15.

If the second test is positive, infusions for all subjects receiving T cells 
modified with the same vector lot will be postponed.  The subject with the 
confirmed positive VSV-G signal will be scheduled for leukapheresis and a 
biological RCL test will be performed on the leukapheresis product.  The 
biological RCL test assesses whether there is active production of infectious 
viral particles from the leukapheresis product [Manilla, 2005].
If the biological RCL test is positive, all infusions using NY-ESO-1c259T in the 
interventional protocol(s) will be halted.  An action plan will be discussed with FDA and 
other regulatory authorities and experts as appropriate.  Additional subjects will not be 


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treated with NY-ESO-1c259T cells until such time as a plan is completed, reviewed, and 
agreed upon.
If the biological RCL test is negative, infusions for all subjects can resume.
10.1.3.
Persistence Testing and Monitoring for Insertional Oncogenesis
Monitoring for insertional oncogenesis follows the recommendations set forth in the FDA 
and EMA guidances [FDA, 2006; FDA; 2020; EMA, 2009]. Insertional oncogenesis is a 
theoretical risk in T cells transduced with a lentiviral vector.  T cells appear resistant to 
transformation by integrating viruses [Cattoglio, 2010; Newrzela, 2008].  However, there 
are cases of oncogenesis with γ-retroviral transduced stem cells.  Four of nine subjects 
with X-linked severe combined immunodeficiency (SCID-X1) treated with retrovirus 
transduced stem cells were found to have insertion near the LMO2 proto-oncogene 
promoter, leading to aberrant transcription and expression of LMO2 which resulted in 
acute T-cell lymphoblastic leukemia [Hacein-Bey-Abina, 2003; Hacein-Bey-Abina, 
2014].  Additionally, two subjects treated for X-linked chronic granulomatous disease 
(X-CGD) with retroviral transduced stem cells demonstrated insertional activation of the 
EVI1 transcription factor which resulted in genetic instability, monosomy 7 and clonal 
progression toward myelodysplasia [Stein, 2010].  
10.1.3.1.
Testing for Persistence of Gene Marked Cells in Clinical Studies
PBMC samples will be collected and used as the “surrogate sample” for monitoring 
persistence of gene modified cells in subjects prior to infusion of transduced T cells and 
then at 3, 6 and 12 months post-infusion, then every 6 months until 5 years post-infusion 
and every year from year 6 post infusion in accordance with the FDA and EMA 
guidances [FDA, 2006; FDA; 2020; EMA, 2009].  The samples will be tested using a 
PCR-based method to detect the presence of the WPRE or the Psi gene, both of which are 
part of the lentiviral vector used to transduce T cells.  Detection of Psi DNA copies 
reflects persistence of the genetically modified T cells.  If at 1 year or beyond post-
infusion greater than 1% PBMCs test positive for vector sequences, the subject’s PBMCs 
will be evaluated for integration site analysis (see Section 10.1.3.2).  If no gene modified 
cells are detected for three consecutive assessments post-infusion, and the subject is more 
than 5 years post-infusion, no further monitoring of PBMCs is required and collection of 
samples for persistence may be discontinued.  NOTE: Samples for RCL must continue to 
be collected and archived up to 15 years post-infusion.  Hematology and chemistry 
assessments may also be discontinued. The subject will continue to be followed by the 
Investigator for up to 15 years post-infusion.  The Investigator will be the primary 
physician responsible for continued follow up of the subject for the duration of LTFU 
whenever possible.  If contact with the investigator becomes no longer feasible, follow up 
can be transitioned to a local physician, preferably an oncologist.
10.1.3.2.
Testing for Insertional Oncogenesis
If persistence, as detected by the presence of a vector sequence (Psi DNA copies), is 
present in >1% of PBMC at 1 year or beyond post-infusion, DNA from the subject’s 


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PBMCs will be sent for integration site analysis.  Integration site analysis will also assess 
the possibility of insertional oncogenesis.
If there is clonal dominance in the genetically modified T-cell population (either 
monoclonality or oligoclonality) the persistence assessment will be repeated within 3 
months on a new sample.  If the repeated analysis demonstrates: 1) persistent 
monoclonality, 2) evidence of insertional oncogenesis or 3) clonal expansion (an increase 
in percent predominance of a clone), there will be a review by the Sponsor to develop a 
monitoring plan specific to the health care risk, and/or strategies to inform appropriate 
subjects, Investigators, and regulators of the findings.  If the integration site analysis 
indicates polyclonality of the genetically modified T-cell population, then screening will 
continue as scheduled.
10.2.
Management and Monitoring for Demyelinating Neuropathy 
and other Neurological events
Obtain a neurological consultation for subjects with Grade 2 or higher neurologic events 
of a ≥ 7-day duration.  Subjects who develop signs and symptoms consistent with GBS 
must be evaluated by a neurologist according to diagnostic guidance for GBS [Fokke, 
2014] to provide expert recommendations to guide appropriate diagnostic workup such as 
EMG, lumbar puncture, infectious panel to guide management and follow up.
10.3.
Safety Review Team
A SRT will be implemented in this study.  In line with routine pharmacovigilance, a GSK 
SRT will review safety data, including clinical laboratory parameters and AEs, at 
appropriate intervals during the period of study conduct.  Recommendations on study 
modification, halting the study and/or pausing enrollment will be provided by the SRT.  
An SRT charter, defining roles and accountabilities and the process for safety review and 
meeting frequency, will be available.
10.3.1.
Mandated Study Pause Due to GBS
The occurrence of any event of GBS will mandate a pause in enrollment and stopping 
treatment for all subjects within the GSK3377794 studies.  The case must be diagnosed 
by a neurologist as GBS according to diagnostic guidance for GBS [Fokke, 2014].
11.
STATISTICAL AND DATA ANALYSIS
The objective and endpoints for this study are described in Section 2.  This section 
focuses on key aspects for the analysis and reporting of the primary and secondary 
efficacy and safety endpoints.  Details for the analysis of all endpoints will be provided in
the RAP.  
For this pilot study the objective is to describe the safety/tolerability and antitumor 
activity of monotherapy (NY-ESO-1c259T alone; Arm 1) and combination therapy (NY-
ESO-1c259T plus pembrolizumab; Arm 2).  The study is not powered to compare efficacy 
or safety between the arms and therefore no formal statistical comparisons between arms 
is planned.


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Key endpoints for safety include all AEs, AEs of special interest, clinical and laboratory 
assessments, long-term safety follow-up, and subject disposition.
Key endpoints for antitumor activity include ORR and DOR, as well as PFS and OS.
The primary analysis will be performed after enrollment is complete and all the enrolled 
subjects that will receive NY-ESO-1c259T have done so and of those: all have been 
followed up for at least 6 months after NY-ESO-1c259T infusion or have progressed or 
died or were withdrawn from the study.
The final analysis will be conducted after enrollment is complete and all the enrolled 
subjects that will receive NY-ESO-1c259T have done so and of those: all have completed 
the study (as defined in Section 4.4) or died or were withdrawn from the study.
If it is believed the primary analysis will occur within 6 months of the final analysis, the 
primary analysis may not be performed such that there will only be the final analysis.
A description of the key safety and efficacy analyses follows.  The details for the safety 
and efficacy analyses will be described prospectively in the RAP.  Analysis of 
exploratory endpoints, sensitivity analyses, and the handling of missing values including 
censoring rules will be described in the RAP.
11.1.
Study Populations
To ensure robustness and a more comprehensive understanding of the data, the following 
populations will be evaluated using descriptive statistics for safety and anti-tumor 
activity: 
Screened Population:  All subjects who were screened for eligibility.  
Intent-to-Treat (ITT) population: All subjects who underwent leukapheresis. The ITT 
population will be the primary analysis population for safety endpoints.
Modified ITT (mITT) population: All subjects who received NY-ESO-1c259T. The 
mITT population will be the primary analysis population for efficacy endpoints.
As-Treated (AT) population:  All ITT subjects per the actual treatment received. This 
population will only be assessed if subjects do not receive the assigned therapy.
Additional analysis populations may be defined in the RAP.  
If the ITT and mITT populations are identical at the end of the trial, then only the ITT 
population will be summarized.  TLTs will only be evaluated for eligible subjects 
assigned to Arm 2.
All data analyses will be conducted within arm, unless otherwise noted.
Analyses grouped by use of BCMA as prior intermediate therapy may be presented if 
there are sufficient subjects.
11.2.
Interim Analysis
Interim analyses to inform internal decision making may be performed for each arm after 
enrollment to the arm is complete and all the enrolled subjects in that arm who will 


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receive NY-ESO-1c259T have done so and of those: all have completed at least three 
disease assessments since infusion or have progressed (and if progressed prior to the 
Week 9 visit have been followed up for safety for a minimum of 9 weeks following T-
cell infusion) or have died or were withdrawn from the study.
The sponsor will do period data looks to inform internal decision making. This may 
include an analysis once all Arm 1 subjects satisfy the criteria for the primary analysis.
11.3.
Sample Size and Assignment of Study Arms
Sample size is based on clinical judgement.  Based on the known safety profile of 
NY-ESO-1c259T, a sample size of 10 subjects per arm is considered clinically sufficient 
for evaluation of safety and tolerability of each arm in this pilot study.  The study is not 
powered to compare efficacy or safety between the treatment arms.  Eligible subjects will 
be assigned to either Arm 1 or Arm 2 prior to leukapheresis.  Enrollment of Arm 1 will 
be completed before continuing enrollment of subjects to Arm 2.  Subjects who do not 
receive NY-ESO-1c259T for any reason may be replaced.  Enrollment to Arm 2 will be 
paused after the third subject enrolled in Arm 2 has started lymphodepletion 
(Section 3.3.1).  Enrollment may be paused again later in the trial if a potential safety 
finding emerges in either arm at any time (Section 4.7).
The overall response rates (ORR) in subjects with RRMM who have received a median 
of 5 prior therapies ranges from 23.7% to 33% where the midpoint is 28.35% (see 
Section 16.5).  Further development of NY-ESO-1c259T for RRMM in monotherapy or in 
combination with pembrolizumab may be stopped due to futility if there is sufficient 
evidence from the corresponding arm that the true ORR is less than 40%. 
The hypothesis for ORR is H0: 20% vs. H1: 40%. The sample size of 10 subjects treated 
per arm allows for early stopping of further development of that arm due to futility if the 
posterior probability that the ORR is less than 40% is >99%. This is equivalent to 
observing 0 or 1 responders out of the 10 treated subjects. Additionally, if the true ORR 
is 20%, the probability of observing 1 or 0 responders out of 10 treated subjects is 38% 
and if the true ORR is 40% the probability of observing 1 or 0 responders out of 10 
treated subjects is 5%. These decision rules are for guidance only and the final decision 
for stop for futility will be determined on totality of data.
If supported by safety and efficacy results, additional subjects may be enrolled to confirm 
the safety and efficacy via a protocol amendment or as part of a separate protocol.  Two 
or more confirmed responses (CR or PR) out of 10 treated subjects may provide 
sufficient efficacy evidence to expand and enroll additional participants.  This will serve 
as guidance for final decisions regarding enrollment of additional subjects, which will be 
based on a review of the totality of the data.
11.4.
Statistical Methods for Safety Parameters
Safety will be evaluated both during the trial and at the planned analyses.


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11.4.1.
TLT Evaluation for Arm 2
Bayesian methods will be employed to assess safety throughout the study.  The 
advantages of a Bayesian framework in a small safety-oriented study is that in addition to 
being able to incorporate prior information, it also allows one to make evaluations 
without relying on large sample theory.
11.4.1.1.
TLT Rate Definition
The TLT rate is defined as the proportion of subjects at any time during the study who 
have at least one TLT.  The TLT rate, p, will be evaluated in the combination arm only, 
in an ongoing manner.  Statistical evaluations for the TLT rate will be made after a 
minimum of n=3 subjects have been infused with NY-ESO-1c259T, received their first 
dose of pembrolizumab and cleared the TLT 3-week assessment period (as described in 
Section 3.3.2). TLT rates in excess of 0.33 have been identified as clinically concerning. 
Bayesian methods are used to continually evaluate the strength of evidence that the 
subjects will experience a TLT rate > 0.33 if the arm were to proceed to treat Nmax=10 
subjects.
The number of subjects with at least one TLT, X, in n subjects at any time during the trial 
is assumed to follow a binomial distribution, B(n, p). Further, assuming a fairly non-
informative prior distribution, i.e., a beta(0.18, 0.82) for the TLT rate, the posterior of the 
TLT rate follows a beta(0.18+x, 0.82+n-x) distribution. This then means that the future 
number of TLTs, Y in m = Nmax - n follows a beta-binomial (m, 0.18+x, 0.82+n-x) 
distribution. Using the methods described by Lee and Liu [Lee, 2008] (with θ=0.9), the 
predictive probability that the TLT rate exceeds 0.33 at Nmax, can be computed as 
subjects accrue.  This probability will be assessed at a threshold of 0.50.
11.4.1.2.
Bayesian Predictive Probabilities for Nmax = 10
As described in Section 3.3.5, only the combination arm will be evaluated for TLTs.  
Given n and Nmax, the above predictive probabilities can be computed as X varies from 0 
to n, and the threshold for safety considerations corresponds to the first time the 
predictive probability exceeds 0.5.  The corresponding values of X subjects with TLTs 
out of n (≥3) are described below.
Table 15 below provides the predictive probabilities where the gray shaded blocks are the 
smallest X for a given n where the predictive probability exceeds 0.50.


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Table 15
Predictive Probabilities for Nmax = 10
X=0
X=1
X=2
X=3
X=4
X=5
X=6
X=7
X=8
X=9
n=3
0.0017
0.115
0.566
0.9426
NA
NA
NA
NA
NA
NA
n=4
0.0002
0.0341
0.3083
0.7812
0.9842
NA
NA
NA
NA
NA
n=5
0
0.0059
0.1255
0.5447
0.9165
0.9974
NA
NA
NA
NA
n=6
0
0
0.0298
0.2932
0.7678
0.9813
1
NA
NA
NA
n=7
0
0
0
0.0956
0.5305
0.9279
1
1
NA
NA
n=8
0
0
0
0
0.2406
0.7954
1
1
1
NA
n=9
0
0
0
0
0
0.518
1
1
1
1
For example, when n=3, the first time the predictive probability exceeds 0.50 is when 2 
subjects out of 3 experience at least one TLT.  The predictive probability in this situation 
that the TLT rate exceeds 0.33 at Nmax = 10, is 0.5660, which exceeds 0.5. Clearly if 3 of 
3 subjects experience TLTs, this would also lead to pausing enrolment.  Therefore, if at 
least 2 out of 3 subjects experience a TLT, the trial should be paused to evaluate safety 
further.  Similarly, the trial may be paused for safety evaluation if (at least) 3 out of 4 or 
5, 4 out of 6 or 7, or 5 out of 8 or 9 subjects have at least 1 TLT.
Further, if the threshold exceeds 0.5 as described above, other supportive information 
may be computed.  For example, the predictive probability distribution may also be 
evaluated to calculate the probabilities associated with specific outcomes.  For e.g., if 4 
subjects have TLTs out of 7, then the beta-binomial (3, 4.18, 3.82) will be used to 
compute the probability that one would observe 1 or more subjects with TLTs out of the 
remaining 3, the average number subjects with at least one TLT, the variability around 
these estimates, etc. In addition, the 95% credible interval for the TLT rate will be 
derived from the posterior distribution.  These and other characteristics of the posterior 
distribution and posterior predictive distribution may aid in the evaluation of TLT rates. 
11.4.2.
Statistical Methods for Safety Parameters
Descriptive statistics will be provided for demography, safety and disease assessments 
within each Arm by dose and time as appropriate.  Descriptive statistics on continuous 
data will include means, medians, standard deviations, and ranges, while categorical data 
will be summarized using frequency counts and percentages.  Graphical summaries of the 
data may be presented.
The safety profile will be based on AEs reported including TLTs (Arm 2), AEs of special 
interest, vital signs measurements, clinical laboratory measurements, ECG recordings, 
and physical examination results.
Adverse Events – All AEs will be listed and coded by the MedDRA.  Subjects with at 
least one TLT (Arm 2) will be listed.  The number and percent of subjects reporting any 
treatment-emergent AEs will be tabulated by system organ class and preferred term and 


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categorized by dose.  AEs with missing date of onset will be considered treatment-
emergent.  AEs will be tabulated by severity, relationship to treatment, and seriousness.  
Tables and/or narratives of any on study death, or serious or significant AE, including 
early withdrawals because of AEs, will be provided should they occur.
Vital Signs – Vital signs will be listed and reviewed for each subject.  Depending on the 
size and the scope of changes, summaries of vital signs data over time and/or changes 
from pre-dose value over time may be provided.
Electrocardiogram – ECG data will be listed and reviewed for each subject. Fridercia’s 
and Bazett’s correction will be used to adjust QT for RR.  Summaries of ECG intervals 
and/or the change from baseline will be provided.  Baseline ECG parameters will be 
based on the mean of the screening and pre-dose ECG assessments.
T-cell Phenotype and Cytokines – The results will be listed.
Clinical Laboratory Tests – Clinical chemistry, hematology, and urinalysis data will be 
listed for each subject.  Values outside the normal laboratory reference ranges will be 
flagged as high or low on the listings.  Laboratory abnormalities will be graded using 
NCI-CTCAE v 4.0.  Each subject’s maximum post-baseline grade will be computed for 
each laboratory parameter and referred to as their worst grade for that laboratory 
parameter.  For each parameter shift tables from baseline to worst grade may be 
presented.
11.5.
Statistical Methods for Antitumor Activity Endpoints
ORR is defined as the proportion of subjects with a confirmed sCR, CR, VGPR and PR 
using IMWG uniform response criteria for MM [Kumar, 2016].  ORR is the key clinical 
endpoint for assessing antitumor activity.
ORR will be estimated for each arm using two-sided 95% Wilson and exact based 
confidence intervals (CIs).  The study is not powered to conduct statistical comparisons 
of the observed ORR to a historical control rate.  Bayesian posterior probabilities for the 
ORR within each arm may be calculated with a range of assumptions that will be outlined 
in the RAP.
Other endpoints such as TTR, DOR, PFS and OS, will be summarized descriptively if 
data warrant.
Definitions:

TTR, defined as the time from T-cell infusion to initial date of response of the 
subjects who achieved confirmed sCR, CR, VGPR or PR.

DOR, defined as the time from the initial date of response of the subjects who 
achieved confirmed sCR, CR, VGPR or PR to the date of progressive disease or 
death.

PFS, defined as the interval between the date of T-cell infusion and the earliest 
date of disease progression or death due to any cause.


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
OS, defined as the time from T-cell infusion to death due to any cause. Subjects 
who are alive will be censored at the date of last contact.
Time to event endpoints will be summarized and displayed graphically using Kaplan-
Meier methodology to estimate the 25th, 50th (median), and 75th percentiles with 
associated 2-sided 95% CIs, as well as the proportion of censored observations if data 
warrant.  OS will also be assessed descriptively at fixed time points such as 1 year and 2 
years using proportions and Kaplan-Meier methods if data warrant.
12.
CLINICAL SUPPLIES
12.1.
Packaging and Labelling
12.1.1.
NY-ESO-1c259T-cell Product
Selected, qualified manufacturing sites will manufacture, package and label cell product 
for each individual subject in accordance with applicable regulatory requirements.
Labels will include batch number, protocol number, number of transduced cells, the 
subject’s unique study identification number.
12.1.2.
Pembrolizumab
Clinical supplies of pembrolizumab will be provided by the Sponsor as summarized in 
Table 16.
Table 16
Pembrolizumab Product Description
Product Name & Potency
Dosage Form
MK-3475 100 mg/4 mL
Solution for Injection
12.2.
Standard Policies and Product Return
IPs must be received by a designated person at the site, handled and stored safely and 
properly, and kept in a secure location to which only the Investigator and designated 
assistants have access.  IPs are to be dispensed only in accordance with the protocol.  The 
Investigator is responsible for keeping accurate records of the IPs received from the 
Sponsor, the amount dispensed, and the unused IPs remaining or destroyed at the 
conclusion of the study.  The Sponsor or designee should be contacted regarding any 
questions concerning both IPs.  At the end of the study or as dictated by protocol or 
process, all clinical supplies will be returned or destroyed as indicated.
All sites should contact the Sponsor or designee for specific instructions for IP returns or 
destruction and appropriate documentation for drug accountability.


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12.3.
Storage and Handling
The subject’s T-cell product that is received at the site will be stored below -135°C. The 
cell product will be thawed and infused as specified in Section 5.3.
12.4.
Product Accountability
The two IPs provided for this study are for use only as directed in the protocol.  It is the 
Investigator/institution’s responsibility to establish a system for handling both IPs as to 
ensure that:

Deliveries of IPs are correctly received by a responsible person.

Such deliveries are recorded.

IPs are handled and stored safely and properly as stated on their respective 
label.

IPs are only dispensed to study subjects in accordance with the protocol.

Any unused NY-ESO-1c259T product is returned to the Commercial 
Manufacturing Location (CML) and accounted for in the site records.

Any unused pembrolizumab product is destroyed per institution practice and 
accounted for in the site records.
At the end of the study, it must be possible to reconcile delivery records with records of 
usage and destroyed stock.  Records of usage should include the bag number (for 
NY-ESO-1c259T) or the container number (for pembrolizumab), the identification 
of the person (subject ID) to whom the IP(s) were dispensed and the quantity and 
date of dispensing.  This record is in addition to any IP information recorded on 
the eCRF.  Any discrepancies must be accounted for on the appropriate forms.  
All unused IP should be returned or destroyed once appropriate IP accountability 
procedures are performed by the Monitor or clinical research associate (CRA). 
Refer to SPM for further details.
13.
DATA HANDLING AND RECORD KEEPING
13.1.
Data Management
An EDC system will be used to collect data pertaining to this trial.  Trial data will be 
captured through an eCRF.  Within the EDC system the eCRF data will be entered by the 
site staff and all source document verification and data cleaning will be performed by the 
Sponsor or designee (e.g., contract research organization [CRO]). 
The specifications for the EDC system will be documented and approved before the EDC 
system is released for live use.  The validation of the eCRF data will be defined in a Data 
Management Plan.  As data are entered into the eCRF, the validation checks will be 
performed and where necessary, queries will be raised.  All queries raised will be held in 
the EDC database.


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The EDC system is a validated software program that has been designed to comply with 
21 CFR Part 11 requirements.  All users will access the system via unique user name and 
password.  A full audit history of all actions performed within the system is maintained.  
User accounts ensure that each user can only perform the tasks applicable to their role 
and only have access to the data applicable to their role. Standard coding dictionaries, 
WHO Drug and MedDRA, will be used to code medications and AEs.
When all data have been entered and all data cleaning is complete the data will be locked 
and made available for analysis and reporting.
On completion of the study all eCRF data, including all associated queries and audit 
history, will be made available in PDF format to both the study Sponsor and the sites.
13.2.
Case Report Forms
For each subject enrolled, an eCRF must be completed and signed by the principal 
Investigator or authorized delegate.  If a subject withdraws from the study, the reason 
must be noted on the eCRF.  If a subject is withdrawn from the study because of a 
treatment limiting AE, thorough efforts should be made to clearly document the outcome.
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported to the Sponsor in the eCRFs and in all required reports.
13.3.
Site Documentation and Source Data
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents are classified into two different categories: (1) Investigator Site File (ISF) and 
(2) subject specific source documents.
The Investigator is responsible for maintaining a complete and accurate ISF containing 
essential documents as required by ICH GCP.
Source documents contain the results of original observations and activities of a clinical 
investigation.  Source documents include, but are not limited to, subject medical 
records/progress notes, appointment book, original laboratory reports, ECG printouts, 
CT/MRI scans, pathology and special assessment reports, and signed informed consents 
forms.  In no circumstances is the eCRF to be considered as source data.
The Investigator must ensure the availability of source documents from which the 
information on the eCRF was derived.
The Investigator must permit authorized representatives of the Sponsor, the respective 
national, local or foreign regulatory authorities, the IRB/IEC and auditors to inspect 
facilities and to have direct access to the ISF and all source documents relevant to this 
study regardless of the type of media.


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13.4.
Data Retention and Availability
The Investigator must keep all essential study documents including source data on file for 
at least 25 years after completion or discontinuation of the Study.  After that period of 
time the documents may be destroyed, subject to local regulations.
The Investigator will not dispose of any records relevant to this study without written 
permission from the Sponsor.  If the Investigator cannot guarantee the archiving 
requirement at the investigational site for any or all of the documents, such study records 
may be transferred upon request to the Sponsor or its designee.
Should the Investigator wish to assign the study records to another party or move them to 
another location, the Sponsor must be notified in writing in advance.
Study documentation is subject to inspection by the Sponsor, its representatives and 
regulatory agencies and must be stored in such a way that it can be accessed/retrieved 
within a reasonable timeframe at a later date.
14.
STUDY MONITORING
Study Monitoring will be conducted by the Sponsor or designated CRO.
It is understood the responsible monitor will contact and visit the Investigator regularly 
and will be allowed, on request, to inspect all records of the trial (e.g. eCRFs, ISF, and 
source documents) provided that subject confidentiality is maintained in accordance with 
local requirements.
It will be the monitors’ responsibility to inspect the eCRFs at regular intervals throughout 
the study, to verify adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered.  The monitor should have direct access to subject 
source documents to verify the entries on the eCRF.  The Investigator (or designee) 
agrees to cooperate with the monitor to ensure any discrepancies detected are resolved.
14.1.
Audits and Inspections
The Sponsor or its representatives may conduct audits at investigative sites including, but 
not limited to, facilities where the study is being conducted, IP handling and 
accountability, presence of required documents, the informed consent process and 
comparison of eCRFs with source documents.
All study documentation including source data must be available for audit.
The Investigator agrees to cooperate fully with audits conducted at a convenient time in a 
reasonable manner.
Regulatory agencies may also inspect investigative sites during or after the study.  The 
Investigator (or designee) should contact the Sponsor immediately if this occurs, and 
provide copies of correspondence relating to requests for an inspection of the site 
facilities.


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15.
REGULATORY AND ETHICAL CONSIDERATIONS
15.1.
Competent Authority Submissions
GSK or its authorized representatives will be responsible for ensuring that appropriate 
competent authority approvals are obtained according to local country requirements.  
Competent authority approval (or notification as applicable) will be obtained before 
initiation of the study.
15.2.
Independent Ethics Committees
The final study protocol and subject informed consent documentation will be approved 
by the IRB/IEC and any other site level committee deemed appropriate by the Institution.  
Approval from each applicable committee will be received in writing before initiation of 
the study.
Protocol amendments must also be approved by the IRB/IEC (and other committees as 
applicable) before implementation, except in the case of changes made to protect subjects 
from immediate hazard, which may be implemented immediately.
15.3.
Local Regulations/Declaration of Helsinki
The Investigator will ensure this study is conducted in full compliance with the principles 
of the “Declaration of Helsinki” or with the laws and regulations of the country in which 
the research is conducted, whichever affords the greater protection to the subject.  The 
study must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” ICH Tripartite Guideline (January 1997) or with local law if it affords greater 
protection to the subject.
15.4.
Informed Consent
It is the responsibility of the Investigator to obtain written informed consent from all 
study subjects prior to any study related procedures being performed.  All consent 
documentation must be in accordance with applicable regulations and ICH GCP.  
Documentation must include the dated signature of both the subject (or the subject’s 
parents or legally authorized representative as applicable) and the person conducting the 
consent discussion.  If the subject is illiterate, an impartial witness should be present 
during the consent discussion, and the consent signed and dated by the witness, the 
subject, and the person conducting the consent discussion.  The consent form should be 
translated and communicated to the subject in a language that is understandable to the 
subject.  Certified translations of the informed consent documentation will be provided as 
applicable.
A copy of the signed and dated informed consent should be provided to the subject before 
participation in the study.
Tests performed as standard of care prior to documentation of consent may be used for 
screening results as appropriate.


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15.5.
Confidentiality
The confidentiality of records that may identify subjects will be protected in accordance 
with applicable laws, regulation and guidelines.
The Investigator must ensure that each subject’s anonymity is maintained and protected 
from unauthorized parties.  On eCRFs or other documents submitted to the Sponsor, 
subjects must not be identified by their names, but by a unique identification code 
allocated to them to ensure confidentiality on all study documentation.  Subjects will 
retain this unique number throughout the study.
The Investigator will keep a subject enrollment log showing subject unique identification 
codes, names and addresses in the ISF.
The Sponsor and/or its representatives accessing subject records and data at site will take 
all reasonable precautions to maintain subject confidentiality.
15.6.
Protocol Adherence
The Investigator must sign the protocol to confirm acceptance and willingness to comply 
with the study protocol.
The Investigator or designee will not deviate from the protocol unless necessary to 
eliminate an apparent immediate hazard to the safety, rights or welfare of any study 
subject.  In the event of a protocol deviation for any reason, the Investigator will 
promptly report the deviation to the Sponsor in writing.
15.7.
Study Suspension, Study Termination and Study 
Completion
The Sponsor may suspend or terminate the study at any time for any reason.  If the study 
is suspended or terminated the Sponsor will ensure applicable sites, regulatory agencies 
and IRBs/IECs are notified as appropriate.
If the Investigator stops/terminates the study at their site, the Sponsor must be notified.  
The Sponsor will ensure Regulatory Agencies and IRBs/IECs are notified as appropriate.
The Sponsor will ensure End of Study declarations are made to the relevant Regulatory 
Agencies/IECs in accordance with local regulations.
15.8.
Public Posting of Study Information
The Sponsor is responsible for posting appropriate study information on applicable 
clinical study registry websites.  Information included in clinical study registries may 
include participating Investigator’s names and contact information.
15.9.
Clinical Study Report
The results of the study will be presented in an integrated Clinical Study Report (CSR) 
according to ICH guideline E3: Structure and Content of Clinical Study Reports.


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15.10.
Publication Policy
The Investigator may not submit the results of the study for publication or present the 
results of the study without the prior written agreement of the Sponsor in accordance with 
the Clinical Trial Agreement.  The results of this study will be published as a whole once 
all subjects have completed the study and the study results have been analyzed.  Interim 
publications of data from the study may be made if mutually agreed between the Sponsor 
and the Investigators.  Agreement will not be provided by the Sponsor where in the 
Sponsor’s view interim publications would introduce bias or lead to any 
misrepresentation or inaccuracies in data.
Authorship will be determined in conformance with the International Committee of 
Medical Journal Editors (ICMJE) guidelines and/or publication guidelines if applicable.


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16.
APPENDICES
16.1.
List of Abbreviations and Definitions of Terms
The following abbreviations and specialist terms are used in this study protocol.  
Abbreviations and Specialist Terms
ACT
ADC
AE
aGVHD
ALK
allo-SCT
ALT
ANC
ASCO
ASCT
AST
BBB
BCMA
BM
BP
CAR
CBC
CDC
cfDNA
CFR
Adoptive cell therapy
Antibody-drug conjugate
Adverse event
Autologous graft versus host disease
Anaplastic lymphoma kinase
Allogeneic stem cell transplant
Alanine aminotransferase
Absolute neutrophil count
American Society of Clinical Oncology
Autologous stem cell transplant
Aspartate aminotransferase
Bundle branch block
B cell maturation antigen
Bone marrow
Blood pressure
Chimeric antigen receptor
Complete blood count
Centers for Disease Control and Prevention
Cell-free DNA
Code of Federal Regulations


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CHMP
CI
CMLCMV
CNS
CR
CRA
CRAB
CRES
CRO
CRP
CRS
CSR
CTA
CTCAE
CTLA-4
CV
DC
DILI
DKA
DNA
DOR
EBV
EC
ECG
Committee for Medicinal Products for Human Use
Confidence interval
Commercial Manufacturing LocationCytomegalovirus
Central nervous system
Complete response
Clinical research associate
Calcium elevation, renal insufficiency, anemia, and bone 
abnormalities
Cell-related encephalopathy syndrome
Contract research organization
C-reactive protein
Cytokine release syndrome
Clinical study report
Cancer testes antigen
Common Terminology Criteria for Adverse Events
Cytotoxic T lymphocyte-associated antigen 4
Cardiovascular
Discontinuation
Drug-induced liver injury
Diabetic ketoacidosis
Deoxyribonucleic acid
Duration of response
Epstein-Barr virus
Ethics Committee
Electrocardiogram


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ECHO
ECOG
eCRF
EDC
EEA
EEG
EGFR
EMG
ES
ESI
EU
FCM
FDA
FLC
FSH
GBS
GCP
G-CSF
GFR
GGTP
GI
GLP
GMP
GVHD
Echocardiogram
Eastern Cooperative Oncology Group
Electronic Case Report Form
Electronic data capture
European Economic Area
Electroencephalogram
Epidermal growth factor receptor
Electromyography
Encephalopathy syndrome
Events of Special Interest
European Union
Flow cytometry
Food and Drug Administration
Free light chain
Follicle-stimulating hormone
Guillain-Barré Syndrome
Good clinical practice
Granulocyte-colony stimulating factor
Glomerular filtration rate
Gamma-glutamyl transpeptidase
Gastrointestinal
Good laboratory practice
Good manufacturing practice
Graft-versus-host disease


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HBsAg
HBV
HCT
HCV
HIV
HLA
HRT
HTLV
IB
ICANS
ICE
ICF
ICH
ICMJE
ICU
IEC
IHC
IMiD
IMWG
IND
INDSR
INL
INR
IP
Hepatitis B surface antigen
Hepatitis B virus
Hematopoietic cell transplantation
Hepatitis C virus
Human immunodeficiency virus
Human leukocyte antigen
Hormonal replacement therapy
Human T-lymphotropic virus
Investigator’s Brochure
Immune Effector Cell-Associated Neurotoxicity Syndrome
Immune Effector Cell-Associated Encephalopathy
Informed Consent Form
International Council on Harmonisation
International Committee of Medical Journal Editors
Intensive care unit
Independent Ethics Committee
Immunohistochemistry
Immunomodulatory imide drug
International Myeloma Working Group
Investigational New Drug application
Investigational new drug safety reports
Investigator Notification Letter
International normalised ratio
Investigational Product


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irAE
IRB
ISF
ITIM
ITSM
ITT
IV
LDH
LTFU
LTR
LVEF
MedDRA
MGUS
MHC
MHRA
mITT
MM
MR
MRD
MRI
MTD
MUGA
NCI
nCR
Immune-related adverse event
Institutional Review Board
Investigator Site File
Immunoreceptor tyrosine-based inhibition motif
Immunoreceptor tyrosine-based switch motif
Intent-to-treat population
Intravenous
Lactic acid dehydrogenase
Long-term follow-up
Long terminal repeat
Left ventricular ejection fraction
Medical Dictionary for Regulatory Activities
Monoclonal gammopathy of undetermined significance
Major histocompatibility complex
Medicines and Healthcare Products Regulatory Agency
Modified intent-to-treat population
Multiple myeloma
Minimal response
Minimal residual disease
Magnetic resonance imaging
Maximum tolerated dose
Multiple-gated acquisition scan
National Cancer Institute
Near complete response


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NCI
NGS
NIH
NK
NR
NSAID
NSCLC
ORR
OS
OTC
PBMC
PBPK
PCR
PD
PD-1
PD-L1
PD-L2
PET
PFS
PK
PR
PT
PTT
Q2W
National Cancer Institute
Next-Gen Sequencing
National Institutes of Health
Natural killer
Not reached
Nonsteroidal anti-inflammatory drug
Non-small cell lung cancer
Overall response rate
Overall survival
Over-the-counter
Peripheral blood mononuclear cell
Physiologically-based pharmacokinetic
Polymerase chain reaction
Progressive disease
Programmed cell death 1
Programmed cell death ligand 1
Programmed cell death ligand 2
Positron emission tomography
Progression-free survival
Pharmacokinetic
Partial response
Prothrombin time
Partial thromboplastin time
Every 2 weeks


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Q3W
QTcB
QTcF
RAC
RAP
RC
RCL
RCR
RSD
RN
RNA
RRMM
RT-PCR
SAE
SC
sCR
Scrn
SD
SEER
SGOT
SGPT
SIN
SMM
SOP
Every 3 weeks
QT interval corrected for heart rate according to Bazett's formula
QT interval corrected for heart rate according to Fridericia's 
formula
Recombinant DNA Advisory Committee
Reporting and Analysis Plan
Research Committee
Replication competent lentivirus
Replication competent retrovirus
Reference Safety Dataset
Registered nurse
Ribonucleic acid
Relapsed and refractory multiple myeloma
Reverse transcription polymerase chain reaction
Serious adverse event
Subcutaneous
Stringent complete response
Screening
Stable disease
Surveillance, Epidemiology, and End Results
Serum glutamic oxaloacetic transaminase
Serum glutamic pyruvic transaminase
Self-inactivating
Smoldering multiple myeloma
Standard operating procedure


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SPM
SRT
SUSAR
T1DM
TCR
TILs
TLT
TSH
TTP
Tx
ULN
USPI
VGPR
VSV-G
V-type
WBC
WOCBP
WPRE
Study procedures manual
Safety Review Team
Suspected unexpected serious adverse reaction
Type 1 diabetes mellitus
T-cell receptors
Tumor-infiltrating lymphocytes
Treatment-limiting toxicities 
Thyroid stimulating hormone
Time to progression
Treatment
Upper limits of normal
United States Prescribing Information
Very good partial response
Vesicular stomatitis virus envelope glycoprotein
Variable type
White blood cell
Women of childbearing potential
Woodchuck hepatitis post-transcriptional regulatory element
16.2.
ECOG Performance Status
Grade ECOG
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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[Oken, 1982]
16.3.
Laboratory Tests and ECG
Hematology, Chemistry and Urinalysis Variables
Clinical Chemistry:
Calcium
Phosphorus
Magnesium
Albumin
Bilirubin
Alanine aminotransferase
Aspartate aminotransferase
Alkaline phosphatase
Lactate dehydrogenaase
Sodium
Potassium
Bicarbonate
Creatinine*
Chloride
Glucose
BUN or Urea
* In subjects ≥65 years add GFR
Hematology:
Red cell count
Hemoglobin
Hematocrit
Mean cell volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin concentration
Platelet count
White blood cell count & differential count 
(percent & absolute)
Coagulation Screen:
Prothrombin time or International Normalized 
Ratio
Activated partial thromboplastin time
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.


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Hematology, Chemistry and Urinalysis Variables
Microbiology:
Infectious disease screen:
HIV 1+2 antibody
Hepatitis B surface antigen
Hepatitis B core antibody – if positive, test for 
HBV DNA
Hepatitis C antibody – if positive, test for HCV 
RNA
HTLV 1+2 IgG
CMV IgG 
EBV (EBNA)
Syphilis (RPR)
Viral reactivation:
CMV DNA PCR – peripheral blood for 
detection of reactivation.
Pregnancy Test:
Serum beta-HCG or Urine test
Thyroid Function Tests:
TSH
Other Tests:
Uric Acid
C-reactive protein
ECG Parameters:
Heart Rate
Heart Rhythm
PR Interval 
RR Interval
QRS Interval
QTc Interval (Fridericia’s or Bazett’s 
correction)
Urinalysis:
Glucose
Ketones
Specific gravity
Protein
Blood
Microscopy
Bilirubin
pH
16.4.
International Myeloma Working Group (IMWG) Criteria for 
the Diagnosis of Multiple Myeloma
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma and any one or more of the following CRAB features and myeloma-
defining events:

Evidence of end organ damage that can be attributed to the underlying plasma 
cell proliferative disorder, specifically: 


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o
Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the 
upper limit of normal or >2.75 mmol/L (>11 mg/dL)
o
Renal insufficiency: creatinine clearance <40 mL per minute or serum 
creatinine >177µmol/L (>2 mg/dL)
o
Anemia: hemoglobin value of >20 g/L below the lowest limit of normal, 
or a hemoglobin value <100 g/L
o
Bone lesions: one or more osteolytic lesion on skeletal radiography, CT, 
or PET/CT. If bone marrow has <10% clonal plasma cells, more than one 
bone lesion is required to distinguish from solitary plasmacytoma with 
minimal marrow involvement

Any one or more of the following biomarkers of malignancy (MDEs): 
o
60% or greater clonal plasma cells on bone marrow examination
o
Serum involved / uninvolved free light chain ratio of 100 or greater, 
provided the absolute level of the involved light chain is at least 100 mg/L 
(a patient’s “involved” free light chain—either kappa or lambda—is the 
one that is above the normal reference range; the “uninvolved” free light 
chain is the one that is typically in, or below, the normal range)
o
More than one focal lesion on MRI that is at least 5 mm or greater in size.
Abbreviations: CR, complete response; FLC, free light chain; M, monoclonal; MR, minimal response; PD, 
progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, 
very good partial response.
16.5.
Response Rates in Subjects with Relapsed and Refractory 
Multiple Myeloma
The response rates in subjects with RRMM are shown in the table below.  In subjects 
who have received a median of 5 prior therapies, the response rates range from 23.7% 
with single agent carfilzomib [Siegel, 2012] to 33% with pomalidomide/dexamethasone 
[Richardson, 2014].  Higher response rates in excess of 50% are observed in subjects who 
have received a median of 2 prior therapies [San-Miguel, 2014; Garderet, 2012; 
Stadtmauer, 2013; Dimopoulos, 2013; Lonial, 2015; Stewart, 2015].  These subjects 
appear to have less refractory disease. The study population based on the eligibility 
criteria in our study will be a relapsed and refractory population and it is estimated that 
the historic response rate would be ~25%.  A response rate of 45% with a median DOR in 
excess of 6 would be of clinical significance.


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Author/Study/Subjects
Regimen
ORR
Median PFS/OS
Richardson, 2014
Phase 2 (N=221)
Median 5 prior therapies
Pom/Dex vs. Pom
33% vs. 
18%
PFS: 4.2 m vs. 2.7 m
OS: 16.5 m vs. 13.6 m
San-Miguel, 2014 
Phase 3 (N=387)
Pano/Vel/Dex vs. 
Vel/Dex
60.7% vs. 
54.6%
PFS: 11.99 m vs. 8.08 
m
OS: 33.64 m vs. 30.39 
m
Siegel, 2012 
Phase 2 (N=266)
Median of 5 lines of therapy
Single agent 
carfilzomib
23.7%
Median duration of 
response: 7.8 m
OS: 15.6 m
Garderet, 2012 
Phase 3 (N=269)
MM patients progressing or 
relapsing after autologous 
HCT
Vel/Thal/Dex vs. 
Thal/Dex
88% vs. 
72%
Median duration of 
response: 17.9 vs 13.4 
m
2-year OS: 71% vs. 
65%
Stadtmauer, 2013 
Phase 2 (N=72)
Median 6 prior regimens
Car/Pom/Dex
64%
PFS:12 m
OS: 16.3 m
Dimopoulos, 2013 
Phase 3 (N=637)
Median 2 prior regimens
Vorinostat + Vel vs. 
Vel
56.2% vs. 
40.6%
PFS: 7.63 m vs. 6.83 m
Lonial, 2015 
Phase 3 (N=646)
Median 2 prior regimens
Elotuzumab + 
Rev/Dex vs. Rev/Dex
79% vs. 
66%
1-year PFS: 68% vs. 
57%
PFS: 19.4 m vs. 14.9 m
Stewart, 2015 
Phase 3 (N=792)
Median 2 prior regimens
Car/Rev/Dex (KRD) 
vs. Rev/Dex
87.1% vs. 
66.7%
PFS: 26.3 m vs. 17.6 m
24-m OS: 73.3% vs. 
65%
FDA label
Study 1
Phase 1 (N=106)
At least 3 prior regimens
Study 2 (N=42)
Median 4 prior regimens
Daratumumab
Study 1: 
29%
Study 2: 
36%
Abbreviations: car, carfilzomib; dex, dexamethasone; pano, panobinostat; PFS, progression-free survival; 
pom, pomalidomide; ORR, overall response rate; OS, overall survival; rev, lenalidomide; thal, 
thalidomide; vel, bortezomib


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16.6.
Liver Safety Required Actions and Follow up Assessments
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Phase I/II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot 
Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT  3xULN associated with symptoms (new or worsening) 
believed to be related to  liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping 
Event
Actions
Follow Up Assessments

Immediately discontinue study 
treatment 

Report the event to GSK within 24 
hours

Complete the CRF and complete an 
SAE data collection tool if the event 
also meets the criteria for an SAE2

Perform liver event follow up 
assessments 

Monitor the subject until liver 
chemistries resolve, stabilize, or 

Viral hepatitis serology4

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN, obtain NY-ESO 
peripheral blood cell level assessment

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form


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return to within baseline (see 
MONITORING below)

Do not restart subject with study 
treatment unless allowed per 
protocol and GSK Medical 
Governance approval is granted
(refer to Section 4.8)
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries (include 
ALT, AST, alkaline phosphatase, 
bilirubin) and perform liver event 
follow up assessments within 24 hrs

Monitor subjects twice weekly until 
liver chemistries resolve, stabilize or 
return to within baseline

A specialist or hepatology
consultation is recommended
For All other criteria: 

Repeat liver chemistries (include 
ALT, AST, alkaline phosphatase, 
bilirubin) and perform liver event 
follow up assessments within 24-72 
hrs 

Monitor subjects weekly until liver 
chemistries resolve, stabilize or 
return to within baseline

Record use of concomitant medications 
on the concomitant medications report 
form including acetaminophen, herbal 
remedies, other over the counter 
medications

Record alcohol use on the liver event 
alcohol intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that subject if ALT 
3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations 
and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and
INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is 
not required and the threshold value stated will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be related to
hypersensitivity (such as fever, rash or eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody 
(IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM 
antibody 


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5.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D 
RNA virus (where needed) [Le Gal F, 2005].
Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN but <5xULN and 
bilirubin <2xULN, without symptoms 
believed to be related to liver injury or 
hypersensitivity and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours
of learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment 

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to 
within baseline.
17.
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18.
CHANGE HISTORY
Protocol v2.0 (Amendment 1)
1- Integration of the sequential screening tests for HLA-genotyping and NY-ESO-
1/LAGE-1a antigen expression level determination by RT-PCR into the investigational 
protocol
Relevant sections amended:
Study design: 

Section 3.1; Figure 1; Section 3.2.1
Procedures:

Sections 7; 7.1; 7.1.1; 7.1.2; 7.1.3; 7.1.4; 7.2; 7.3; 7.5.3
2- Update to Pembrolizumab background 
Relevant section amended:

Section 1.5.1
3- Miscellaneous minor corrections/clarifications  
Relevant section amended:

Section 3.6.2- Risk assessment : 

Clarification that enrolment will not be staggered but rather paused after 
first 3 subjects randomized on pembrolizumab to just match with all the 
other sections of the protocol. 

Section 7.3- Schedule of procedures and footnotes:

Clarifying that ‘virology’ should actually be ‘infectious disease screen’

Clarifying that ‘Vector Copies (Persistence)’ and ‘VSV-G DNA (RCL)’ are 
Central Labs.

Correcting that Q12wks schedule from Week 24 falls on Week 48,
not Week 52 as initially indicated

Section 7.5.2- Cytokine and soluble factor analysis:

updated with new standard wording 

Section 7.5.4- NY-ESO-1c259 T-Cell Persistence

updated with new standard wording

Section 16.3- Laboratory Test and ECG

Clarified wording for microbiology tests to match with Section 7.3


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Protocol v3.0 (Amendment 2)
Primary Reason for Amendment
Protocol Amendment No. 01, dated 13 March 2017 is replaced by Protocol Amendment 
No. 02.
Subsequent to the licensing of Adaptimmune product NY-ESO by GSK, the purpose of 
this protocol amendment is to:
-
Delete or replace references to Adaptimmune or its staff with that of 
GlaxoSmithKline (GSK) and its authorized agents to align with the change of 
sponsorship;
-
Make administrative changes to align with GSK processes and procedures;
-
Update of lymphodepletion regimen throughout.
Section of Amendment No. 2.0
Change
Throughout the document
•
GSK study numbers added to former Adaptimmune 
study numbers
•
Adaptimmune replaced by GSK / “the Sponsor” 
where appropriate
•
“Adaptimmune’s Safety Review Team and Safety 
Governance Board” replaced with “the Sponsor” 
where appropriate.
•
Update of lymphodepleting regimen
Objectives
Primary, secondary and exploratory objectives updated.
Section 1.2 Adoptive 
Immunotherapy with NY-ESO-1c259
Specific T Cells
Number of subjects treated with study drug to date 
updated.
Section 1.4 NY-ESO-1c259 T in 
Multiple Myeloma
Text updated with currently available information.
Section 1.5.1 Pembrolizumab 
Pharmaceutical and Therapeutic 
Background
Text updated with currently available information.
Section 3.1 Overall Study Design
Study design amended to update screening requirements, 
and definition of interventional phase completion, and to 
describe follow-up of subjects. 
Section 3.2.6.1 Rationale for 
Pembrolizumab Dose
Rationale for pembrolizumab dose updated.


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Section of Amendment No. 2.0
Change
Section 3.3 Assessment of Safety 
and TLT
Change Safety Review Committee (SRC) to Safety 
Review Team (SRT)
Section 3.3.4 Frequency of SRT 
Meetings
Set timing of SRT meetings removed. Timing will be 
specified in the SRT charter.
Section 3.3.5.2 TLT Definition
Minor revision of definition of toxicities not considered 
TLTs.
Section 3.6.2 Risk Assessment
Information on known safety profile updated. 
Section 4.2.1 Inclusion Criteria 
Minor revision to contraceptive requirements.
Section 4.2.2, Exclusion Criteria
Exclusion of subjects with active liver or biliary disease 
added, exclusion of subjects with CNS metastases added, 
and QTc criteria and details of hepatitis B and C tests 
amended.
Section 4.3 Completion of the 
Treatment Phase
Definition of completion of the treatment phase 
amended.
Section 4.4 Condition for Transfer to 
the LFTU Protocol – Study 
Completion
Definition of study completion and conditions for 
transfer to LFTU protocol updated.
Section 4.5 Study Withdrawal
Clarification of Investigator or designee on regaining 
contact with subjects to avoid loss of follow-up.  Text 
regarding subject voluntarily withdrawing from treatment 
due to toxicity to be recorded as an AE, has been 
removed.
Section 4.6, Subject Withdrawal
Details of follow-up attempts amended, and information 
with regards to subjects who voluntarily discontinued 
added.
Section 4.7 Considerations for 
Temporary Suspension of 
Enrollment
Updated to accommodate GSK common practice.
Section 4.8 Liver Chemistry 
Stopping Criteria
Updated to include liver chemistry stopping and 
increased monitoring criteria.
Section 4.9 QTc Stopping Criteria
Updated to include QTc stopping criteria.
Section 5.2 Lymphodepleting 
Chemotherapy
Lymphodepleting chemotherapy regimen for the study 
updated.
Section 5.2.3 Cell Infusion
Details of cell infusion revised.


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Version: 6.0
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Date:  24-FEB-2020
Page 174 of 182
Section of Amendment No. 2.0
Change
Section 5.4.1 Schedule Modification 
Guidelines for Pembrolizumab (Arm 
2)
Schedule modification guidelines for pembrolizumab 
(Arm 2) revised and details of irAEs added. Removal of 
AST, ALT, or increased bilirubin as replaced with liver 
chemistry stopping criteria.
Section 6.1 Prohibited concomitant 
medication and treatment
Minor revision to note on subjects receiving radiation 
therapy.
Section 6.3 Contraception
New contraceptive requirements added.
Section 6.3.4 Use in Pregnancy
Clarification of pregnancy complication or elective 
termination of pregnancy to be reported as AE or SAE.
Section 7.1.4 Companion Diagnostic 
Test
Clarification of text to allow for flexibility in 
methodology for assays.
Section 7.2 Screen Failures
Updated to include SAEs.
Section 7.3 Schedule of Procedures
Minor revisions to schedule of procedures to reflect 
changes throughout the protocol, including addition of 
Brain MRI and CARTOX 10. Schedule of procedures for 
LFTU protocol updated.
Section 7.4.5 Laboratory 
Assessments
Clarification of pregnancy test assessments.
Section 7.4.6 Cardiac Assessments
Requirement for inpatient telemetry monitoring for
subjects with cardiac or pericardial disease added. Minor 
amendments to infusion reaction treatment guidelines for 
pembrolizumab.
Section 7.4.7 Monitoring for 
Encephalopathy Syndrome
New section added to describe monitoring for 
encephalopathy syndrome
Section 8.9 Pembrolizumab 
Symptom Management
Requirement for monitoring of subjects with pneumonitis 
added.  Management of myocarditis added.
Section 8.10 Management of 
Encephalopathy Syndrome
New section added to describe management of 
encephalopathy syndrome
Section 9.1 Time Period for 
Collecting Adverse Event and 
Serious Adverse Event Information
Clarification to ensure AEs and SAEs are collected until 
the end of the study in all subjects.
Section 9.2 Definition of AEs
Clarification of definition of AEs.
Section 9.3 Reporting Serious 
Adverse Events
Reporting requirements of SAEs to GSK added.


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Protocol Number: GSK208470 
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Date:  24-FEB-2020
Page 175 of 182
Section of Amendment No. 2.0
Change
Section 9.4 Reporting Criteria 
During Long-Term Follow-up (Years 
1 to 15)
Reporting criteria amended.  Clarification that SUSARs 
to be shared in the form of INDSRs.
Section 9.7 Regulatory Reporting 
Requirements for Serious Adverse 
Events
Clarification that SUSARs to be shared in the form of 
INDSRs.
Section 9.8 Cardiovascular and 
Death Events
Updated to include CV and death sections of the CRF to 
be completed.
Section 9.9 Pregnancy
Clarification for pregnancy reporting.
Section 9.13 Events of Clinical 
Interest
Clarification for ECI reporting.
Section 9.14 Timelines for Safety 
Reporting
Updated to include timelines for safety reporting for 
initial reports and follow-up information on previous 
reports.
Section 10.2 Safety Review Team
Minor revision to description of SRT to align with GSK 
terminology.
Section 16.1 List of Abbreviations 
and Definitions of Terms
Updated abbreviation list
Protocol v4.0 (Amendment 3)
Primary Reason for Amendment
Changes made to the protocol were requested by the FDA as a result of safety events 
which included 2 reports of Guillain-Barré syndrome in subjects who have received 
chemotherapy and NY-ESO-1c259T during clinical trials.
Section of Amendment No. 3.0
Change
Synopsis
Key Inclusion/Exclusion Criteria
Addition of ‘Prior or active demyelinating disease as an 
exclusion criterion’.
3.6.2
Update to risk assessment to add additional risk of 
Guillain-Barré syndrome and other demyelinating 
neuropathies.
4.2
Addition of Prior or active demyelinating disease as an 
exclusion criterion.


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Section of Amendment No. 3.0
Change
9.3
Addition of all cases of Guillain-Barré syndrome or 
acute demyelinating neuropathy as a reportable SAE 
within 24 hours.
10.2
Addition of Management and Monitoring for 
Demyelinating Neuropathy and other Neurological 
events
10.3.1
Addition of Mandated Study Pause due to GBS
Protocol v5.0 (Amendment 4)
Primary Reason for Amendment
Several changes related to FDA requests were made, including changes to Inclusion 
Criteria #5, the addition of study stopping rules, and the Encephalopathy (now Immune 
Effector Cell-Associated Neurotoxicity or ICANS) and the CRS grading and 
management criteria were updated. Also, changes were made to the lymphodepletion 
regimen for older subjects, and the randomization scheme was removed to enroll Arm1 
(NY-ESO-1c259T single infusion) subjects first.
Section of Amendment No. 4.0
Change
Synopsis and Section 3.1 and 
Throughout
Removal of subject randomization. Enrollment of Arm 
1 will be completed before continuing enrolling 
subjects to Arm 2
Synopsis and Section 4.1
Updated Inclusion Criteria #5; removed PRMM and 
modified RRMM to only include subjects who have 
received at least 3 prior regimens. List of prior 
therapies has also been modified
Updated Inclusion Criteria #10. Modified calculation 
for creatinine clearance
Synopsis and Section 4.2
Updated Exclusion Criteria #2 to note that it only 
applies to subjects that would be assigned to Arm 2
Updated Exclusion Criteria #3 for clarity
Added new Exclusion Criteria #5
Updated Exclusion Criteria #13 to include GvHD 


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Page 177 of 182
Section of Amendment No. 4.0
Change
occurring post ASCT
Synopsis and Section 2
Updated subject population to those with relapsed 
refractory disease only
Synopsis, Section 11
Plans for statistical analyses extensively updated; 
futility analysis incorporated.
Section 4.1
Clarified Inclusion Criterion 5 with respect to prior 
therapy requirements
Section 4.2
Updated Exclusion Criterion 3 and corrected Exclusion 
Criterion 13
Section 4.7 
Updated study stopping and pausing rules
Section 3.6.1
Updated section with final analysis data and reference
Section 5.4.1
Table 2 updated with currently available information.
Section 5.2
Added lymphodepleting regimen adjustments for 
subjects 60 years old history and for those with 
history of severe and prolonged cytopenia to improve 
subject safety
Section 7.1 and 7.5.3
Removed sequential sample collection for screening 
and clarified language regarding sample collection for 
consistency across study documents
Section 7.3 and 7.5.3
Updated scheduled bone marrow sampling from Week 
6 to Week 3, unless the scheduled Week 3 infusion of 
pembrolizumab is delayed to Week 6
Section 8.2
Revised language according to GSK Safety Panel 
recommendations to align with other study protocols
Section 8.5
Revised management guidelines to utilize the American 
Society for Transplantation and Cellular Therapy 
updated grading system


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Protocol Number: GSK208470 
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Date:  24-FEB-2020
Page 178 of 182
Section of Amendment No. 4.0
Change
Section 8. 9
Text updated with currently available information.
Section 8.10
Revised management guidelines to utilize the American 
Society for Transplantation and Cellular Therapy 
updated grading system [Lee, 2019]
Section 8.11
Added section for management of Guillain-Barré 
Syndrome (GBS)
Section 9.1 and Section 9.4
Modified AE and SAE collection times for the study; 
added delayed AE definition
Section 9.13
Additional ECIs were included to align with other 
study protocols as per GSK Safety Panel 
recommendations
Section 10.1.3.2
Removed the definition of clonality in relation to 
testing for insertional oncogenesis
Section 11.2
Added section regarding interim analysis
Protocol v6.0 (Amendment 5)
Primary Reason for Amendment
This amendment restructures the protocol for a clearer presentation of the 3-part study 
design.  This amendment also introduces the intent to enroll, treat, and monitor for safety 
and efficacy subjects who have previously received a BCMA-targeted therapy as a 
separate line of therapy potentially in a separate clinical trial. In addition to other changes 
listed in the table below, this amendment updates several eligibility criteria and clarifies 
Section 3.3.1 to indicate that enrollment into Arm 2 only rather than enrollment into both 
arms would be paused following start of lymphodepletion of the third Arm 2 subject. 
The following changes were implemented in Protocol Amendment 5.
Section of Amendment No. 5.0
Change
Change history, Section 3.1, Section 
3.1 Figure 1 footnote, Section 
3.1.2.2, Section 7 Figure 2 footnotes
Clarified that subjects may receive BCMA-targeted 
therapy as a distinct line of therapy between 
leukapheresis and lymphodepletion and that this 
therapy may be in a separate clinical trial.  The subject 
must progress from this BCMA-targeted therapy prior 


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Section of Amendment No. 5.0
Change
to receiving NY-ESO-1c259 T cell therapy.  
Synopsis, Section 2
Added secondary endpoint to monitor persistence of 
NY-ESO-1c259T cells and to evaluate potential 
correlation with safety, clinical response and phenotype 
of the infused T-cells.
Synopsis, Section 4.1.1
Modified Inclusion Criterion 5 to indicate that subjects 
must have received an alkylator as prior anti-cancer 
therapy unless the subject was ineligible to receive an 
alkylator or unless receipt of an alkylator was 
contraindicated for the given subject. 
Synopsis, Section 4.1.1
Updated Inclusion Criterion 7 to include immuno-
oncology agents overall in addition to checkpoint 
inhibitors
Synopsis, Section 4.1.3, Section 
6.3.3
Updated Inclusion Criterion 16 to remove requirement 
for male subjects that contraception continue to be used 
for at least 4 months following last dose of 
pembrolizumab.  This change brings this inclusion 
criterion into alignment with the current United States 
Prescribing Information for pembrolizumab.
Synopsis and numerous other points 
in the protocol where 
pembrolizumab dosing schedule 
discussed 
Clarified pembrolizumab dosing schedule in the event 
of ongoing toxicities that would impact pembrolizumab 
treatment 
Synopsis, Section 11
Clarified timing of primary data analysis from at least 6 
months after last subject treated with NY-ESO-1c259T 
to after the last subject treated with NY-ESO-1c259T had 
undergone 3 disease assessments 
Section 3.1
Clarified plan by which future subjects would be 
enrolled following removal of randomization in 
Protocol Amendment 4.  
Synopsis, Section 3.4
Updated number of subjects enrolled per arm to permit 
adequate enrollment to support results analysis and 
clarified the types of subjects to be enrolled
Synopsis
Grouped inclusion criteria and exclusion criteria into 
Screening (Part 1), Leukapheresis (Part 2) and 


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Version: 6.0
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Date:  24-FEB-2020
Page 180 of 182
Section of Amendment No. 5.0
Change
Lymphodepletion and Treatment (Part 3) to correspond 
with three key portions of study 
Synopsis, Section 4.1
Added inclusion criterion (13) for absolute neutrophil 
count (ANC), CD3 count, and lymphocyte count prior 
to leukapheresis
Synopsis, Section 4.1
Updated ANC and haemoglobin requirements 
(Inclusion criterion 14). 
Synopsis, Section 4.1
Clarified contraception start times for males and 
females (Inclusion criterion 15)
Synopsis, Section 4.2
Clarified exclusion criterion 7 to be applicable not only 
to drugs similar to fludarabine or cyclophosphamide 
but to be applicable also to fludarabine and 
cyclophosphamide
Synopsis, Section 4.2
Add exclusion criterion 22 to impose a time limit for 
start of lymphodepletion relative to leukapheresis
Section 1.3
Added information about therapies targeting the anti-B 
cell maturation antigen (BCMA)
Section 1.5.2
Added rationale for treating patients previously treated 
with agent(s) targeting BCMA
Section 3.1
Clarified study’s 3-part composition (screening, 
leukapheresis/manufacturing, and 
lymphodepletion/treatment) and added description of 
activities associated with each part
Section 3.1
Added clear definition of “enrolled”
Section 3.1
Added figure showing 3 key parts to study and subject 
path through study 
Section 3.1 and Section 3.4
Clarified numbers of patients to be enrolled per arm 
and enrollment plan
Section 3.1.2.2
Added description of intermediate therapy, including 
timing and potential that intermediate therapy could be 
received while enrolled in an alternative study with 
another sponsor


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Protocol Number: GSK208470 
(ADP-0011-008)
Version: 6.0
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Date:  24-FEB-2020
Page 181 of 182
Section of Amendment No. 5.0
Change
Section 3.3.1
Clarified that, after the third subject in Arm 2 has 
begun lymphodepletion, enrollment into Arm 2 would 
be paused until completion of the safety analysis for 
Arm 2 or unless a subject required replacement
Section 3.6.2
Updated risk information for NY-ESO-1c259T, 
including information for adverse events of special 
interest
Section 3.6.2
Updated risk information for pembrolizumab interest
Synopsis, Section 4.1.3
Updated requirements for male contraception for Arm 2 
subjects following last dose of pembrolizumab.  
Section 4.6
Added “progressive disease” as a reason for 
discontinuing pembrolizumab.  
Section 5.1
Clarified guidance on target apheresis collection and on 
potential for additional aphereses.
Section 5.2.1
Added new section with dose modification guidance 
for lymphodepletion of subjects ≥60 years of age
Section 5.3.2
Updated and streamlined cell infusion guidance, 
referring sites to Drug Product and Infusion Manual for 
details
Section 7
Moved study schematic from Section 3 to Section 7 to 
be closer to description of study procedures
Section 7.3 Table 3, and footnotes 
“a” and “ac” in Table 3
Updated “bone survey” to “bone imaging” to include 
not only bone survey, but also CT, PET, and MRI.  
Section 7.3
Footnote “a”- clarified timing of test completion and 
sample collections
Section 7.3 Table 3, Section 7.5, 
Section 7.5.2
Added text describing sample collection purpose and 
schedule for soluble BCMA analysis to support 
predictions of patient outcomes
Section 7.5
Clarified that correlative studies would be performed 
on bone marrow aspirates – not from material collected 
by biopsy


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Version: 6.0
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Section of Amendment No. 5.0
Change
Section 7.5.3
Added additional guidance for collection of bone 
marrow aspirates
Section 9.1
Updated to clarify timing of AE/SAE collection and 
types of AE/SAE that are to be collected in Part 1, Part 
2, and Part 3 and to specify how any safety event 
occurring during bridging therapy is to be recorded 
Section 9.13
Updated categories / descriptions of Adverse Events of 
Special Interest (AESI)
Section 9.14
Updated safety reporting table to include guidance for 
reporting of AESI
Section 11
Updated data analysis approach and response 
assumptions
Section 11.1
Clarified all population definitions to make consistent 
with program definitions.
Section 11.2
Added conditions for conduct of interim analyses.
Section 11.3
Statistical section was re-evaluated and refocused on 
overall subject population (10 subjects per arm) rather 
than also on BCMA-treated subjects.  Decision rules 
for futility determination were redefined.  Conditions 
for study expansion were added
Section 7.4.8 and Appendix 16.5
Updated version of International Myeloma Working 
Group (IMWG) Uniform Response Criteria for 
Multiple Myeloma from Rajkumar,2011 to Kumar,
2016 in Section 7.4.8.  Deleted former Appendix 16.5 
which included full IMWG Uniform Response Criteria 
for Multiple Myeloma, 2011. Deleted Rajkumar 
reference for 2011 version and added Kumar, 2016 
reference.

SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
208470 
 
1 
 
Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for Open-Label Pilot Study to 
Assess the Safety, Tolerability and Antitumor Activity of 
Genetically Engineered NY-ESO-1 Specific (c259) T-cells 
Alone or in Combination with Pembrolizumab in HLA-A2+ 
Subjects with NY-ESO-1 and/or LAGE-1a Positive 
Relapsed and Refractory Multiple Myeloma 
Compound Number  : GSK3377794 
Effective Date  
: 23-APR-2021 
 
Description: 
• 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the abbreviated Clinical Study Report for Protocol 208470. 
• 
This RAP is intended to describe the planned safety, tolerability and efficacy 
analyses required for the study. 
• 
This RAP will be provided to study team members to convey the planned content 
of the Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author(s): 
Author 
Date 
 
25-MAR-2021 
Principal Biostatistician, PAREXEL employee on behalf of 
GlaxoSmithKline 
 
Copyright 2021 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
208470 | Statistical Analysis Plan  RAP 23 Apr 2021 | TMF-13337917 | 1.0
PPD


 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
208470 
 
2 
 
RAP Team Reviewer (Method: Email): 
Approver 
Date 
 
Statistician (Contingent Worker), 
GlaxoSmithKline 
29-MAR-2021 
 
Principal Programmer (Oncology Clinical 
Programming), GlaxoSmithKline 
29-MAR-2021 
  
Principal Statistical Programmer, 
PAREXEL 
31-MAR-2021 
 
Clinical Scientist (Oncology Clinical 
Development), GlaxoSmithKline 
31-MAR-2021 
 
Quantitative Clinical Pharmacology 
Director (Oncology CPMS), 
GlaxoSmithKline 
08-APR-2021 
 
Clinical Biomarker Lead (Oncology Cell 
Therapy, EMU), GlaxoSmithKline 
06-APR-2021 
Clinical Statistics and Clinical Programming Line Approvals (Method: Email): 
Approver 
Date 
 
23-APR-2021 
Statistics, Director, Oncology Clinical 
Statistics, GlaxoSmithKline  
 
 
22-APR-2021 
Director, Oncology Clinical 
Programming, GlaxoSmithKline 
 
 
 
 
 
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CONFIDENTIAL 
 
 
 
208470 
 
3 
 
 
TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 9 
2.1. 
Change to Protocol Specified Statistical Analysis Plan ................................. 9 
2.2. 
Study Objective(s) and Endpoint(s)............................................................. 10 
2.3. 
Study Design .............................................................................................. 12 
2.4. 
Statistical Analyses ..................................................................................... 15 
3. 
PLANNED ANALYSES .......................................................................................... 16 
3.1. 
Safety Monitoring Review for TLTs ............................................................. 16 
3.1.1. 
Predictive Probabilities ................................................................. 16 
3.2. 
Interim Analyses ......................................................................................... 17 
3.3. 
Final Analysis ............................................................................................. 18 
4. 
ANALYSIS POPULATIONS ................................................................................... 19 
4.1. 
Protocol Deviations ..................................................................................... 19 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 20 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 20 
5.2. 
Baseline Definitions .................................................................................... 20 
5.3. 
Multicentre Studies ..................................................................................... 21 
5.4. 
Examination of Covariates, Other Strata and Subgroups ............................ 21 
5.5. 
Multiple Comparisons and Multiplicity ......................................................... 21 
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 21 
6. 
STUDY POPULATION ANALYSES ....................................................................... 22 
6.1. 
Overview of Planned Study Population Analyses ........................................ 22 
6.2. 
Disposition of Participants ........................................................................... 22 
6.3. 
Protocol Deviations ..................................................................................... 22 
6.4. 
Demographic and Baseline Characteristics ................................................. 23 
6.5. 
Prior and Concomitant Medications ............................................................ 23 
6.6. 
Study Treatment Exposure ......................................................................... 24 
6.7. 
Anti-Cancer Therapies ................................................................................ 24 
6.7.1. 
Prior Anti-Cancer Therapies......................................................... 24 
6.7.2. 
On-Study Anti-Cancer Therapies ................................................. 25 
7. 
EFFICACY ANALYSES .......................................................................................... 27 
7.1. 
Primary Efficacy Analyses .......................................................................... 27 
7.1.1. 
Primary Endpoint/Variable: Overall Response Rate (ORR) .......... 27 
7.1.1.1. 
Best Overall Response ............................................... 27 
7.1.1.2. 
Overall Response Rate .............................................. 27 
7.1.1.3. 
Definition of Adequate Assessment ............................ 27 
7.1.1.4. 
Date Associated with Response ................................. 27 
7.1.1.5. 
Confirmed Response .................................................. 28 
7.1.2. 
Summary Measurement ............................................................... 29 
7.1.3. 
Population of Interest ................................................................... 30 
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7.1.4. 
Strategy for Intercurrent Events ................................................... 30 
7.1.5. 
Statistical Analyses / Methods ..................................................... 30 
7.2. 
Secondary Efficacy Analyses ...................................................................... 31 
7.2.1. 
Endpoints/Variables ..................................................................... 31 
7.2.1.1. 
Time to Response (TTR) ............................................ 31 
7.2.1.2. 
Duration of Response (DoR) ...................................... 31 
7.2.1.3. 
Progression Free Survival (PFS) ................................ 33 
7.2.2. 
Summary Measure ...................................................................... 35 
7.2.2.1. 
Time to Response (TTR) ............................................ 35 
7.2.2.2. 
Duration of Response ................................................. 36 
7.2.2.3. 
Progression Free Survival .......................................... 36 
7.2.3. 
Population of Interest ................................................................... 36 
7.2.4. 
Statistical Analyses / Methods ..................................................... 36 
7.3. 
Exploratory Efficacy Analyses ..................................................................... 36 
7.3.1. 
Endpoints/Variables ..................................................................... 36 
7.3.1.1. 
Overall Survival (OS) .................................................. 36 
7.3.2. 
Summary Measure ...................................................................... 36 
7.3.3. 
Population of Interest ................................................................... 36 
7.3.4. 
Statistical Analyses / Methods ..................................................... 36 
8. 
SAFETY ANALYSES ............................................................................................. 38 
8.1. 
Adverse Events Analyses ........................................................................... 38 
8.2. 
Adverse Events of Special Interest (AESI) Analyses ................................... 40 
8.2.1. 
Cytokine Release Syndrome (CRS) and Graft versus Host 
Disease (GvHD) ........................................................................... 41 
8.3. 
Clinical Laboratory Analyses ....................................................................... 42 
8.3.1. 
Analyses of Liver Function Tests (LFT) ........................................ 44 
8.4. 
Other Safety Analyses ................................................................................ 44 
8.4.1. 
Performance Status ..................................................................... 44 
8.4.2. 
ECG ............................................................................................. 45 
8.4.3. 
Pregnancies ................................................................................. 45 
8.4.4. 
Vital Signs .................................................................................... 45 
8.4.5. 
Replication Competent Lentivirus (RCL) and Persistence 
of NY-ESO-1c259T ......................................................................... 46 
8.4.6. 
COVID-19 .................................................................................... 46 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 46 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 46 
9.1.1. 
Endpoint / Variables ..................................................................... 46 
9.1.1.1. 
Drug Concentration Measures .................................... 46 
9.1.1.2. 
Derived Pharmacokinetic Parameters......................... 47 
9.1.2. 
Summary Measure ...................................................................... 47 
9.1.3. 
Population of Interest ................................................................... 48 
10. BIOMARKER ANALYSES ...................................................................................... 49 
10.1. 
Biomarker Analyses .................................................................................... 49 
10.1.1. 
Endpoint / Variables ..................................................................... 49 
10.1.2. 
Summary Measure ...................................................................... 49 
10.1.2.1. Anti-NYESO-1 Antibody Formation ............................. 49 
10.1.3. 
Population of Interest ................................................................... 49 
10.1.4. 
Statistical Analyses / Methods ..................................................... 49 
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11. POPULATION PHARMACOKINETIC (POPPK) ANALYSES .................................. 49 
12. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 49 
13. REFERENCES ....................................................................................................... 50 
14. APPENDICES ........................................................................................................ 51 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 51 
14.2. 
Appendix 2: Schedule of Activities .............................................................. 52 
14.2.1. 
Protocol Defined Schedule of Events ........................................... 52 
14.2.2. 
Schedule of Procedures in Long-Term Follow-up prior to 
Transfer to LTFU Protocol ........................................................... 59 
14.3. 
Appendix 3: Assessment Windows ............................................................. 61 
14.3.1. 
Definitions of Assessment Windows for Analyses ........................ 61 
14.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 62 
14.4.1. 
Study Phase ................................................................................ 62 
14.4.1.1. Study Phases for Concomitant Medication ................. 62 
14.4.1.2. Study Phases for Anti-Cancer Therapy/Surgery ......... 62 
14.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 62 
14.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 63 
14.5.1. 
Reporting Process ....................................................................... 63 
14.5.2. 
Reporting Standards .................................................................... 63 
14.5.3. 
Reporting Standards for Pharmacokinetic Data ........................... 64 
14.6. 
Appendix 6: Derived and Transformed Data ............................................... 65 
14.6.1. 
General ........................................................................................ 65 
14.6.2. 
Study Population .......................................................................... 65 
14.6.3. 
Safety .......................................................................................... 66 
14.6.4. 
Efficacy ........................................................................................ 67 
14.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 68 
14.7.1. 
Premature Withdrawals ................................................................ 68 
14.7.2. 
Handling of Missing Data ............................................................. 68 
14.7.2.1. Handling of Missing and Partial Dates ........................ 68 
14.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 71 
14.8.1. 
Laboratory Values ........................................................................ 71 
14.8.2. 
ECG ............................................................................................. 71 
14.8.3. 
Vital Signs .................................................................................... 72 
14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 73 
14.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 74 
14.11. Appendix 11: Abbreviations & Trademarks ................................................. 75 
14.11.1. Abbreviations ............................................................................... 75 
14.11.2. Trademarks ................................................................................. 76 
14.12. Appendix 12: List of Data Displays.............................................................. 77 
14.12.1. Data Display Numbering .............................................................. 77 
14.12.2. Mock Example Shell Referencing ................................................ 77 
14.12.3. Deliverables ................................................................................. 77 
14.12.4. Study Population Tables .............................................................. 78 
14.12.5. Efficacy Tables ............................................................................ 86 
14.12.6. Efficacy Figures ........................................................................... 87 
14.12.7. Safety Tables ............................................................................... 89 
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14.12.8. Safety Figures ........................................................................... 108 
14.12.9. Biomarkers Tables ..................................................................... 112 
14.12.10. Pharmacokinetic Tables ............................................................. 113 
14.12.11. Pharmacokinetic Figures ........................................................... 114 
14.12.12. ICH Listings ............................................................................... 115 
14.12.13. Non-ICH Listings ........................................................................ 126 
14.13. Appendix 13: Example Mock Shells for Data Displays .............................. 131 
14.14. Appendix 14: Combined Preferred Terms ................................................. 132 
14.15. Appendix 15: Adverse Event Collapsing Rules ......................................... 134 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 208470: 
Protocol Revision Chronology: 
Version 01 
19-Dec-2016 
Original 
Version 02 
(Amendment 1) 
13-Mar-2017 
Changes included: 
- Integration of the sequential screening tests for 
HLA-genotyping and NY-ESO-1/LAGE-1a 
antigen expression level determination by RT-PCR. 
- Update to Pembrolizumab background. 
- Miscellaneous minor corrections/clarifications. 
Version 03 
(Amendment 2) 
24-Jul-2018 
Subsequent to the licensing of Adaptimmune 
product NY-ESO by GlaxoSmithKline (GSK), the 
purpose of this protocol amendment was to: 
- Delete or replace references to Adaptimmune or 
its staff with that of GSK and its authorized agents 
to align with the change of sponsorship. 
- Make administrative changes to align with GSK 
processes and procedures. 
- Make changes to lymphodepletion regimen. 
Version 04 
(Amendment 3) 
17-Oct-2018 
Changes made to the protocol were requested by 
the FDA as a result of safety events which included 
2 reports of Guillain-Barré Syndrome in subjects 
who received chemotherapy and GSK3377794 
during clinical trials. 
Version 05 
(Amendment 4) 
19-Sep-2019 
Several changes were made related to FDA 
requests, including updating Inclusion Criterion #5, 
adding study stopping rules, and updating 
Encephalopathy (now Immune Effector Cell-
Associated Neurotoxicity or ICANS) and CRS 
grading and management criteria based upon 
American Society for Transplantation and Cellular 
Therapy, Lee, 2019 guidance. Also, changes were 
made to the lymphodepletion regimen for older 
subjects, and the randomization scheme was 
removed to first enrol subjects into Arm 1 (NY-
ESO-1c259 T single infusion). 
Version 06 
(Amendment 5) 
24-Feb-2020 
This amendment restructured the protocol for a 
clearer presentation of the 3-part study design. The 
amendment also introduced the intent to enrol, 
treat, and monitor for safety and efficacy subjects 
who have previously received a BCMA-targeted 
therapy as a separate line of therapy potentially in a 
separate clinical trial. Additionally, several 
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Protocol Revision Chronology: 
eligibility criteria were updated, clarification was 
made that enrolment into Arm 2 only (versus both 
arms) would be paused following start of 
lymphodepletion of the third subject, and the 
version of International Myeloma Working Group 
(IMWG) Uniform Response Criteria for Multiple 
Myeloma used in efficacy determination was 
updated from 2011 to 2016. 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Change to Protocol Specified Statistical Analysis Plan 
In this RAP, there are no changes or deviations to the statistical analysis from that 
described in the latest amended protocol (dated 24-Feb-2020) other than the following: 
• Definitions of analysis populations, removing the As-Treated Population. 
• Explicit instruction to summarize data for the Modified Intent-to-Treat (mITT) 
Population (instead of Intent-to-Treat [ITT] Population), when the two populations 
are identical. 
• Efficacy endpoints described in the Efficacy Analyses section (Section 7) as Primary 
and Secondary Efficacy Endpoints, rather than overall Secondary Endpoints. 
• Protocol Section 11.2 states that “Interim analyses to inform internal decision making 
may be performed for each arm after enrolment to the arm is complete and all 
enrolled subjects in that arm who will receive NY-ESO-1c259T have done so and of 
those: all have completed at least three disease assessments since infusion or have 
progressed (And if progressed prior to the Week 9 visit have been followed up for 
safety for a minimum of 9 weeks following T-cell infusion) or have died or were 
withdrawn from the study.” As accrual to the study was halted prior to completing 
enrolment in either arm, the interim analysis was not conducted. Thus, references to 
the interim analysis and the evaluable population have been removed from the RAP. 
• Protocol Section 3.1.3 and Section 4.3 state that “A subject will be considered to have 
completed the treatment phase of the study when he/she has progression of disease or 
108 weeks after NYESO-1c259T-cell infusion, whichever is sooner”. In this RAP, death 
is also considered a criterion for completion of the treatment phase. 
• Protocol Section 4.4 states that “This study will be considered complete when the last 
subject has been rolled over into the LTFU protocol.” This RAP notes that study 
completion can also occur in the case that one or more patients have withdrawn from 
the parent study (including lost to follow-up), completed long-term follow-up in this 
study, or expired prior to rolling over into the LTFU protocol. 
• Protocol Section 6.1 states that “Subjects receiving any of palliative radiation therapy 
that could be foreseen impacting disease course or disease assessments will be 
censored for the purposes of determining PFS.” In this RAP, new anti-cancer therapy 
that would result in censoring PFS only includes systemic therapy. 
• This study was terminated early; thus, only analyses relevant to these limited data are 
presented.  
• Due to early termination of the study, only a final analysis will be performed. Thus, a 
primary analysis has been removed from Section 3. 
• According to GSK standards, Listing of Race (DM9) is required per ICH E3. Due to 
differences in Adaptimmune data collection, only Listing of Demographic 
Characteristics (DM2) will be displayed which will include race information. 
 
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2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
• To describe the safety and tolerability 
of autologous genetically modified T-
cells (NY-ESO-1c259T) alone (Arm 1) 
or in combination with pembrolizumab 
(Arm 2) in participants who are human 
leukocyte antigen HLA-A*02:01, 
HLA-A*02:05, and/or HLA-A*02:06 
positive and have NY-ESO-1 and/or 
LAGE-1a positive relapsed refractory 
multiple myeloma (RRMM). 
• Adverse events (AEs and Treatment 
Limiting Toxicity (TLT) rate), 
including serious adverse events 
(SAEs); laboratory assessments, 
including chemistry, hematology, 
and coagulation; and cardiac 
assessments by electrocardiogram 
(ECG). 
Secondary Objectives 
Secondary Endpoints 
• To describe the antitumor activity of 
autologous genetically modified T-cells 
(NY-ESO-1c259T) alone (Arm 1) or in 
combination with pembrolizumab (Arm 
2) in participants who are HLA-
A*02:01, HLA-A*02:05, and/or HLA-
A*02:06 positive and have NY-ESO-1 
and/or LAGE-1a positive RRMM. 
• Overall Response Rate (ORR). 
• Time to Response (TTR). 
• Duration of Response (DoR) for 
participants who achieve at least a 
Partial Response (PR). 
• Progression-free survival (PFS). 
• To describe persistence of autologous 
genetically modified T-cells (NY-ESO-
1c259T) over time. 
• Maximum persistence (Cmax), time 
to Cmax (Tmax), and area under the 
time curve from zero to time t 
(AUC(0-t)), as data permit. 
 
 
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Exploratory Objectives 
Exploratory Endpoints 
• To describe the antitumor activity of 
autologous genetically modified T-cells 
(NY-ESO-1c259T) alone (Arm 1) or in 
combination with pembrolizumab (Arm 
2) in participants who are HLA-
A*02:01, HLA-A*02:05, and/or HLA-
A*02:06 positive and have NY-ESO-1 
and/or LAGE-1a positive RRMM. 
• Overall survival (OS). 
• To evaluate minimal residual disease 
(MRD) at 4 months post T-cell infusion 
(Week 15). 
• MRD Rate at Week 15. 
• To evaluate the persistence, phenotype, 
and functionality of NY-ESO-1c259 
positive T-cells. 
• Correlate persistence, phenotype, and 
functionality of NY-ESO-1c259T in 
the peripheral blood and/or bone 
marrow with response to treatment 
and safety. 
• To understand mechanisms of 
resistance to NY-ESO-1c259T. 
• Determine whether loss of NY-ESO-
1 and/or LAGE-1a expression in 
myeloma cells is a resistance 
mechanism. 
• Correlate apparition of anti-NY-
ESO-1c259T antibodies with efficacy 
and safety. 
• Correlate expression of PD-L1 in the 
tumor microenvironment and PD-1 
expression on T-cells with response 
to treatment.  
• Correlate frequency of immune cell 
subsets in peripheral blood and/or 
bone marrow with treatment 
response. 
• Correlate frequency of immune cell 
subsets in peripheral blood and in 
bone marrow. 
• To evaluate antigen spreading as a 
mechanism of response. 
• Correlate clonal outgrowth of T-cell 
populations with tumor response 
following T-cell infusion. 
• To evaluate cytokine levels pre- and 
post-infusion on cytokine release 
syndrome (CRS). 
• Correlate cytokine levels with 
incidence and severity of CRS or 
other safety events. 
• To evaluate the impact of germline 
polymorphisms in IL-6, TNF-α, IL-10, 
IFN-γ and TGF-β on CRS. 
• Correlate polymorphisms in germline 
deoxyribonucleic acid (DNA) with 
CRS. 
 
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2.3. 
Study Design 
Overview of Study Design and Key Features 
 
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Overview of Study Design and Key Features 
Design 
Features 
• This is a 2-arm, open-label, pilot study, with 3 distinct parts: (1) 
Eligibility Screening, (2) Leukapheresis/Manufacturing, and (3) 
Lymphodepletion/Treatment, with Parts 2 and 3 collectively 
representing the Treatment Phase.  
• Participants will first undergo screening for HLA-type (HLA-
A*02:01, HLA-A*02:05, and/or HLA-A*02:06) and presence of 
antigen NY-ESO-1 and/or LAGE-1a in their bone marrow. Only 
participants who are selected after HLA-genotyping and 
determination of antigen expression will be considered for further 
eligibility screening. 
• In the initial study design, participants meeting all eligibility criteria 
were assigned to 1 of 2 treatment arms: NY-ESO-1c259T alone (Arm 
1) or NY-ESO-1c259T in combination with pembrolizumab (Arm 2). 
Following protocol amendment 5, the enrolment of participants in 
Arm 1 will be completed before the enrolment of participants in 
Arm 2 continues. 
• Following enrolment, participants will undergo leukapheresis to 
obtain cells for the manufacture of autologous NY-ESO-1c259 
bearing T-cells. 
• When NY-ESO-1c259T-cells are available, participants will undergo 
lymphodepleting chemotherapy with fludarabine and 
cyclophosphamide and receive granulocyte-colony stimulating 
factor (G-CSF) support before undergoing infusion of NY-ESO-
1c259T-cells.  
• Re-confirmation of eligibility and baseline assessments will occur 
during the 7 days preceding lymphodepleting chemotherapy. 
• Participants may receive anticancer therapy between screening and 
leukapheresis and between leukapheresis and lymphodepletion, with 
mandatory wash-out periods respected. 
• Ten participants per arm (20 participants in total) are targeted to be 
enrolled in the study and receive the NY-ESO-1c259T infusion, with 
at least 6 participants per arm having received and failed BCMA-
based therapy (CAR-T, ADC, or other types of BCMA-targeted 
therapies) between screening and leukapheresis and/or between 
leukapheresis and lymphodepletion. 
• Eligible participants who do not receive the NY-ESO-1c259T infusion 
for any reason will be replaced, and infused participants in Arm 2 
who do not receive pembrolizumab will be included in Arm 1 for 
purposes of analysis and replaced within Arm 2. Analyses describing 
the Intent-to-Treat (ITT) population will summarize by the treatment 
group to which the participant was assigned. 
• A participant will be considered to have completed the treatment 
part of the study at the earliest of confirmed disease progression 
(with minimum 9 weeks of follow-up for safety), 108 weeks after 
NY-ESO-1c259T-cell infusion, or death.  
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Overview of Study Design and Key Features 
• After treatment, participants will be rolled into a long-term follow-
up (LTFU) study under a separate protocol and followed at month 3, 
6, and 12, then every 6 months for 5 years, and then yearly for up to 
15 years. If the LTFU protocol is not available, follow-up will start 
on this protocol following the guidelines listing above until the 
LTFU becomes available. 
Dosing 
• The 2 investigational products (IPs) in this study are: 
• NY-ESO-1c259T: An autologous T-cell transduced with a self-
inactivating lentivirus encoding for a high affinity NY-ESO-
1/LAGE-1a-specific T-cell receptor (TCR), administered 
through a single IV infusion (cell range: 1 × 109 to 8 × 109 
transduced cells) in both treatment arms.  
• Pembrolizumab: A humanized monoclonal antibody, 
administered as a fixed dose of 200 mg through a 30-minute IV 
infusion in Arm 2. 
• Participants in both arms who have been re-confirmed as eligible 
during the baseline assessment period (Day -14 to -8) will undergo 
lymphodepleting chemotherapy with fludarabine (30 mg/m2/day) on 
Days -8, -7, -6, and -5 and cyclophosphamide (900 mg/m2/day) on 
Days -7, -6, and -5, followed by G-CSF support on Day -4 and 
infusion of NY-ESO-1c259T-cells on Day 1.  
• For participants in Arm 2, pembrolizumab will be administered on 
Day 22 (Week 3; 21 days after NY-ESO-1c259T infusion) and then 
every 3 weeks thereafter up to Week 108. If the participant 
experiences toxicity preventing Week-3 dosing of pembrolizumab, 
the first dose of pembrolizumab may be administered on Week 6 
instead. If toxicity still prevents starting pembrolizumab dosing at 
Week 6, the participant will not be administered pembrolizumab and 
will be followed as a participant in Arm 1.  
Time & 
Events 
• Refer to Appendix 2: Schedule of Activities 
Treatment 
Assignment 
• Participants meeting all eligibility criteria will be treated in one of 
two treatment arms:  
• Arm 1: Participants will receive NY-ESO-1c259T alone as a 
single infusion on Day 1, 4 days after completing fludarabine, 
cyclophosphamide, and G-CSF (there is no Day 0 for this study). 
• Arm 2: Participants will receive NY-ESO-1c259T in combination 
with pembrolizumab. NY-ESO-1c259T will be administered as a 
single infusion on Day 1, 4 days after completing fludarabine, 
cyclophosphamide, and G-CSF. Pembrolizumab will be 
administered first on Day 22 (Week 3) and then every 3 weeks 
thereafter up to Week 108.   
• Eligible participants who do not receive the NY-ESO-1c259T infusion 
for any reason will be replaced, and infused participants in Arm 2 
who do not receive pembrolizumab will be included in Arm 1 for 
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Overview of Study Design and Key Features 
purposes of analysis and replaced within Arm 2. Analyses describing 
the Intent-to-Treat (ITT) population will summarize by the treatment 
group to which the participant was assigned. 
• The study initially was initially designed to randomize participants 
to the two arms. Following protocol amendment 5, the enrolment of 
participants in Arm 1 will be completed before the enrolment of 
participants in Arm 2 continues.  
Safety 
Monitoring 
Review for 
TLTs 
• Safety will be assessed at each clinic visit. A Safety Review Team 
(SRT) may review safety data in both treatment arms at any time. 
• TLTs will be evaluated for participants in Arm 2 only. 
• Enrolment in Arm 2 will be paused after the third enrolled 
participant has initiated lymphodepleting chemotherapy. A complete 
safety review of the first 3 Arm 2 participants will be conducted 
before enrolment resumes. 
• The SRT may recommend pausing the study at any time to evaluate 
safety and, if warranted, to close an arm of the trial (e.g., in Arm 2, 
if at an interim assessment the predictive probability that the TLT 
rate for participants exceeds 33%, is greater than 50%).  
• Interim analyses to inform internal decision-making may be 
performed for each arm after enrolment to the arm is complete and 
all enrolled participants in that arm who will receive NY-ESO-1c259T 
have done so and have completed at least 3 disease assessments 
since infusion, progressed (if progressed prior to Week 9, then have 
been followed for safety for at least 9 weeks following infusion), 
died, or withdrawn from the study. Additional analyses may be 
undertaken when all participants in Arm 1 satisfy the criteria for 
primary analysis. Given accrual to the study was stopped prior to 
completing enrolment to either arm, this interim analysis will not 
occur. 
 
 
2.4. 
Statistical Analyses 
This study is not powered to compare safety or efficacy between the 2 treatment arms. 
Therefore, no hypothesis testing or formal statistical comparisons are planned. All 
analyses will be descriptive in nature. Continuous data will be summarized, minimally, 
using n, means, medians, standard deviations, and ranges, while categorical data will be 
summarized using frequency counts and percentages or proportions. Graphical 
summaries of the data will be presented, as appropriate. Time-to-event endpoints will be 
summarized as the median and 25th and 75th percentiles and displayed graphically using 
Kaplan-Meier (product-limit) curves, if the data warrant. 
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3. 
PLANNED ANALYSES 
3.1. 
Safety Monitoring Review for TLTs 
After the third participant in Arm 2 has initiated lymphodepleting chemotherapy, 
enrolment will be paused. Enrolment may resume after these participants have received 
both T-cells and pembrolizumab and a complete safety review by the SRT of Treatment-
Limiting Toxicities (TLT) has been conducted.  
Additionally, safety review for the assessment of TLTs may be carried out at any time in 
Arm 2. The SRT may recommend pausing the study to evaluate safety and, if warranted, 
stopping the trial (e.g., if the predictive probability of the TLT rate exceeding 33% is 
greater than 50%). 
3.1.1. 
Predictive Probabilities  
Predictive probabilities will be estimated for participants in Arm 2 only. 
As participants are accrued and at n≥3 participants, Bayesian predictive probabilities will 
be used to evaluate TLTs in Arm 2. If , the probability of the end-of-trial TLT rate 
exceeding 0.33 is greater than 0.50 at an interim assessment (i.e., when n < [Nmax = 
10]), then the SRT may recommend to pause the study for safety review and, if 
warranted, to stop the trial for safety. 
To evaluate the TLT rate using a Bayesian framework, let p denote the TLT rate for Arm 
2, and let X denote the number of TLTs in n≥3 participants. X is assumed to follow a 
binomial distribution B(n, p). Assuming a non-informative prior distribution of beta 
(0.18, 0.82) for the TLT rate, the posterior of the TLT rate will follow a beta (0.18+x, 
0.82+n-x) distribution.  
Let Y represent the number of TLTs in m (equal to Nmax – n) future participants. With 
the aforementioned prior and likelihood, Y follows a beta-binomial (m, 0.18+x, 0.82+n-
x) distribution. This distribution will be explored to better estimate the probability of 
observing y (0 [zero] to m) TLTs in the m future participants.  
Let the predictive probability (PP) equal the probability of the end-of-trial TLT rate 
exceeding 0.33, given the maximum planned sample size (Nmax) of 10. Using results 
from the first n participants, a defined θ=0.9, and methods described by Lee and Liu 
(Lee, 2008), PP will be computed as the weighted average (i.e., weighted by the 
probability of the realization of each Y) as? the indicator of a positive trial (i.e., at each Y, 
the probability of TLT rate > 0.33 is greater than 90%), should the current trend continue 
and the trial be conducted until the end of the study. 
Refer to Table 1 below for the calculated PP associated with n < Nmax. If at least 2 of the 
first 3 participants experience a TLT, the trial should be paused to further evaluate safety. 
Similarly, the trial may be paused for safety evaluation if at least 3 of the first 4 or 5 
participants, at least 4 of the first 6 or 7 participants, or at least 5 of the first 8 or 9 
participants experience a TLT. 
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Table 1 
Predictive Probabilities for Nmax = 10 
  
X=0 
X=1 
X=2 
X=3 
X=4 
X=5 
X=6 
X=7 
X=8 
X=9 
n=3 
0.0017 0.115 
0.566 
0.9426 NA 
NA 
NA 
NA 
NA 
NA 
n=4 
0.0002 0.0341 0.3083 0.7812 0.9842 NA 
NA 
NA 
NA 
NA 
n=5 
0 
0.0059 0.1255 0.5447 0.9165 0.9974 NA 
NA 
NA 
NA 
n=6 
0 
0 
0.0298 0.2932 0.7678 0.9813 1 
NA 
NA 
NA 
n=7 
0 
0 
0 
0.0956 0.5305 0.9279 1 
1 
NA 
NA 
n=8 
0 
0 
0 
0 
0.2406 0.7954 1 
1 
1 
NA 
n=9 
0 
0 
0 
0 
0 
0.518 
1 
1 
1 
1 
Furthermore, if the threshold exceeds 0.5, as described above, other supportive 
information may be computed. For example, the PP distribution may also be evaluated to 
calculate the probabilities associated with specific outcomes. For instance, if 4 of 7 
participants experience a TLT, then the beta-binomial (3, 4.18, 3.82) will be used to 
compute the probability of observing TLTs in 1 or more of the remaining 3 participants, 
the average number participants with at least one TLT, the variability around these 
estimates, etc. In addition, the 95% credible interval for the TLT rate will be derived from 
the posterior distribution. These and other characteristics of the posterior distribution and 
posterior predictive distribution may aid in the evaluation of TLT rates. 
3.2. 
Interim Analyses 
Protocol Section 11.2 states that interim analyses to inform internal decision-making may 
be performed for each arm after enrolment to the arm is complete and all enrolled 
participants in that arm who will receive NY-ESO-1c259T have done so and have 
completed at least 3 disease assessments since infusion, progressed (if progressed prior to 
Week 9, then have been followed for safety for at least 9 weeks following infusion), died, 
or withdrawn from the study. Additional analyses may be undertaken when all 
participants in Arm 1 satisfy the criteria for primary analysis. 
 
Note that such an interim analysis is not planned and thus is not listed as a deliverable in 
Appendix 12: List of Data Displays. 
 
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3.3. 
Final Analysis 
The final analyses will be performed after the completion of the following sequential 
steps: 
1. All participants have completed the study or have withdrawn from the study for any 
reason. A participant will complete the treatment phase of the study upon disease 
progression, death, or 108 weeks after NY-ESO-1c259T-cell infusion, whichever is 
sooner. All infused participants will enter a LTFU protocol. Study completion occurs 
when all participants in the treatment phase of the study have rolled over to the 
LTFU protocol GSK208750 (ADP-0000-002), completed long-term follow-up in this 
study, expired,  or withdrawn (including lost to follow-up) from the parent study 
before rollover to the LTFU protocol 
2. All required database cleaning activities have been completed and final DBR and 
DBF has been declared by Data Management. 
 
 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
Screened 
• All participants who signed the 
screening informed consent form. 
• Screen failures 
Enrolled 
• All participants who underwent 
leukapheresis, with treatment arm 
identified as the assigned 
(planned) arm. 
• Required study 
population displays 
(see Appendix 12: 
List of Data Displays 
for specific displays) 
Intent-To-
Treat (ITT) 
• All participants who underwent 
leukapheresis, with treatment arm 
identified as the assigned 
(planned) arm. 
• Study population 
• Primary safety (where 
appropriate) 
 
Modified 
Intent-To-
Treat (mITT) 
• All participants in the ITT 
Population who received the NY-
ESO-1c259T infusion, with 
treatment arm identified as the 
arm of actual treatment received.   
• Efficacy 
• Primary safety (where 
appropriate) 
 
Refer to Appendix 12: List of Data Displays, which details the population to be used for each display. Note that, if an 
analysis is planned for both the mITT and ITT Population and these populations contain the same participants in the 
same arms, then results will be reported for the mITT Population only. 
 
4.1. 
Protocol Deviations 
Protocol deviations will be tracked in accordance with the Protocol Deviation 
Specification Form by the study team throughout the conduct of the study and sent to the 
Data Manger and Biostatistics Lead in a spreadsheet. Protocol deviations will not be 
identified programmatically. 
Inclusion/exclusion criteria deviations will be based on data as recorded on the 
inclusion/exclusion page of the eCRF. 
 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
Data will be listed and summarized according to GSK reporting standards, as applicable.  
5.1. 
Study Treatment & Sub-group Display Descriptors 
Two treatment arms are included in this study (Arm 1: Participants who receive NY-
ESO-1c259T alone; Arm 2: Participants who receive NY-ESO-1c259T in combination with 
pembrolizumab). As data will be displayed within summaries and listings principally by 
treatment arm, the table below provides an example of the treatment descriptors to be 
used for distinguishing the treatment arms within the displays. Actual treatment doses 
may differ (e.g., in the case of modified pembrolizumab dosage) but will follow the same 
format. 
Treatment Group Descriptions 
Data Displays for Reporting 
Description 
Order in TLF 
GSK794 
1 
GSK794+PEMBRO 
2 
Total 
3 
 
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects 
CDISC and GSK Data Display Standards terminology. 
5.2. 
Baseline Definitions 
Unless otherwise specified, baseline values will be represented by the latest non-missing 
measurements (including unscheduled visits) prior to the start of lymphodepleting 
chemotherapy. Per protocol, baseline assessments should occur within the 7 days 
preceding lymphodepletion. If an assessment is not performed within the 7-day window, 
then the latest assessment prior to the 7-day window will be used. If an assessment is 
performed on the same date as the start of lymphodepletion and the time of assessment is 
not recorded, then the assessment will be assumed to have occurred prior to 
lymphodepletion and used as baseline.  
For ECG parameters, if baseline values are missing (given the aforementioned baseline 
definition of latest record within the 7 days preceding lymphodepletion), then baseline 
values will be represented by the mean of values recorded during the screening and Day 1 
pre-dose assessments. 
For participants who do not receive lymphodepleting chemotherapy during the study, 
baseline values will be represented by the latest, non-missing measurements recorded. If 
baseline data is missing, then no derivation will be performed, and baseline will be set to 
missing. 
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5.3. 
Multicentre Studies 
Data from all participating centres will be pooled prior to analyses. 
It is anticipated that participant accrual will be spread thinly across centres. 
Consequently, data summaries by centre are unlikely to be informative and will not be 
provided.  
5.4. 
Examination of Covariates, Other Strata and Subgroups 
No covariates or strata will be incorporated into analyses, and no subgroup analyses will 
be performed in this study. 
5.5. 
Multiple Comparisons and Multiplicity 
No formal statistical testing will be performed; therefore, no adjustments for multiple 
comparisons or multiplicity are planned.  
5.6. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
following appendices: 
Section 
Component 
14.3 
Appendix 3: Assessment Windows 
14.4 
Appendix 4: Study Phases and Treatment Emergent Adverse Events 
14.5 
Appendix 5: Data Display Standards & Handling Conventions 
14.6 
Appendix 6: Derived and Transformed Data 
14.7 
Appendix 7: Reporting Standards for Missing Data 
14.8 
Appendix 8: Values of Potential Clinical Importance 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
Study population analyses will be based on the ITT Population, unless otherwise 
specified. Some study population analyses will be repeated in the mITT population. If the 
mITT and ITT Populations contain the same participants in the same arms, then results 
planned for both the ITT & mITT populations will only be reported for the mITT 
Population. 
 
Based on GSK Core and Oncology Data Standards, study population analyses will 
include summaries and listings of participant disposition, protocol deviations, 
demographic and other baseline characteristics, prior and concomitant medications, study 
treatment exposure, disease characteristics at initial diagnosis and screening, and prior 
and on-study anti-cancer therapies, prior anti-cancer radiotherapy, and prior and on-study 
surgical procedures. Details of the planned displays are presented in Appendix 12: List of 
Data Displays. 
6.2. 
Disposition of Participants 
Using the Screened Population, a summary and a listing of screening status and reasons 
for screen failure will be provided. A summary of the number of participants in each 
analysis population (see Section 4 for definitions) and a listing of participants excluded 
from each population will also be provided detailing reason for exclusion.  
Overall study disposition, including transfer to the separate LTFU protocol GSK208750, 
will be summarized. 
Treatment phase status for both arms will be summarized with reasons for non-
completion as captured in the eCRF. 
Listings of data describing reasons for study withdrawal and study treatment status will 
be produced, with the latter including dates and times, associated with leukapheresis, 
lymphodepletion, and T-cell infusion, dose level of T-cell infusion, indicators of 
treatment phase completion (vs. discontinuation), end of study status, and reasons for 
treatment phase discontinuation. 
A summary and listing of pembrolizumab treatment status and reasons for 
discontinuation will be generated for participants in Arm 2.  
Lastly, the number of participants in the Enrolled Population will be listed by country and 
study site ID.  
6.3. 
Protocol Deviations 
Important protocol deviations will be summarized and listed. 
A separate listing of inclusion/exclusion deviations will also be provided. 
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6.4. 
Demographic and Baseline Characteristics 
Demographic characteristics, including race, age, ethnicity, sex, height, baseline body 
weight, body mass index (BMI), and body surface area (BSA) as per the Mosteller 
formula, will be both summarized and listed. Age, height, weight, BMI, and BSA will be 
summarized as continuous variables, while age, sex, race, and ethnicity will be 
summarized as categorical variables. Age will be categorized and summarized using the 
GSK IDSL standard (≤18, 19-64, and ≥65 years), and in a separate summary, using 
EudraCT (18-64, 65-84 and ≥85 years). Age will be derived per Section 14.6.2. 
Separate summaries and listings of disease characteristics at initial diagnosis and at 
screening will be provided. Disease characteristics including time from initial diagnosis 
to screening ICF signed (in months), stage at diagnosis, histologic type, percent clonal 
bone marrow plasma cells, presence and type of end organ damage, presence and type of 
plasmacytoma, presence of bone lesion(s), and chromosomal aberrations will be 
summarized and listed. Disease characteristics at screening will include type of multiple 
myeloma, HLA-A status, NY-ESO-1 status, LAGE-1a status, number of systemic therapy 
regimens prior to leukapheresis, number of  radiotherapy regimens prior to leukapheresis, 
receipt of stem-cell transplant prior to leukapheresis (Y/N), and subtype of stem-cell 
transplant received (autologous or allogeneic). Listings will additionally disclose relevant 
dates (e.g., diagnosis date, dates of antigen testing). Derivation of the number of prior 
systemic therapy regimens should include therapies recorded as systemic therapy, as well 
as stem cell therapy and associated conditioning chemotherapy as a prior line. Time from 
initial diagnosis to screening ICF signed (in months) will be calculated as detailed in 
Appendix 6. 
Medical conditions (history and ongoing) at screening will be listed and summarized. 
6.5. 
Prior and Concomitant Medications 
All concomitant medications will be summarized (for the mITT Population only), and all 
prior and concomitant medications will be included in a single listing. The definitions of 
prior and concomitant medications are provided in Appendix 4: Study Phases and 
Treatment Emergent Events. 
Medications will be coded using GSK Drug coding dictionary. The summary of 
concomitant medications will show the number and percentage of participants taking 
concomitant medication by Ingredient. Multi-ingredient products will be summarized by 
their separate ingredients rather than as a combination of ingredients. Anatomical 
Therapeutic Chemical (ATC) classification Level 1 (Body System) information will be 
included in the dataset created but will not appear on the listing or summary.  
In the summary of concomitant medications, each participant will be counted once per 
unique ingredient. For example, if a participant takes Amoxycillin on 2 separate 
occasions, the participant will be counted only once under the ingredient “Amoxycillin”. 
In the summary of concomitant medications, ingredients will be summarized by the base 
only. 
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Data describing concomitant receipt of blood products will be both summarized and 
provided in a listing. 
6.6. 
Study Treatment Exposure 
Study treatments – described in Section 5 of the protocol – are leukapheresis, 
lymphodepleting chemotherapy, NY-ESO-1c259T cell infusion, and pembrolizumab. 
The number and percentage of participants having undergone leukapheresis, 
lymphodepleting chemotherapy, T-cell infusion (overall and given the minimum dose of 
1 x 109 transduced cells), and pembrolizumab infusion will be summarized.  
The total number of transduced T-cells will be summarized as both a continuous variable 
and categorical variable. Categories will include <1, 1 to ≤8, and >8 (x 109 cells) and <1, 
1 to ≤3, >3 to ≤8, and >8 (x 109 cells). An associated listing will provide T-cell infusion 
start/stop dates/times (over all bags), average vector copy number per cell in cell product, 
total number of transduced cells, and percentage of cells transduced. 
For participants in Arm 2, pembrolizumab dose intensity (mg/3 weeks) and number of 
pembrolizumab cycles received will be listed. A listing, disclosing the details of 
pembrolizumab exposure, will also be generated. Additionally, a listing will be provided 
for all dose delays experienced on the study and duration of delay. Duration of delays is 
defined as period from the expected start date of dose to actual start date of current dose. 
The calculation of duration of delay is actual start date of current dose - expected start 
date of dose. Expected start date of dose = actual start date of previous dose + 21. Note 
that the expected start date of the first dose of pembrolizumab is 21 days after T-cell 
infusion. Thus, if this dose is not received, this will be considered a dose delay.  
Dose administration data for lymphodepleting chemotherapy, including fludarabine and 
cyclophosphamide, will be presented in a single data listing. Lastly, a single participant-
level data listing will be dedicated to disclosing dates of leukapheresis, lymphodepleting 
chemotherapy, T-cell infusion, and pembrolizumab infusion. 
6.7. 
Anti-Cancer Therapies 
Number and percentage of participants who receive any anti-cancer therapy (including 
systemic therapy and radiotherapy) or cancer-specific surgery will be provided in 
separate summaries. Systemic therapy drugs will be coded using the GSK Drug coding 
dictionary, then summarized by ingredient. Participant-level data describing all anti-
cancer therapies and cancer-specific surgeries will be provided in separate listings. 
6.7.1. 
Prior Anti-Cancer Therapies 
Anti-cancer therapies will be classified into prior and on-study phases as described in 
Appendix 4. Note that only therapies initiated on or after the first day of lymphodepletion 
chemotherapy are considered on-study. Prior therapies will be further classified into 
subphases at date of leukapheresis.  
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Prior therapy types will include systemic therapy (including stem cell therapy), 
radiotherapy, and cancer-related surgery, with systemic therapies other than stem cell 
therapy coded using the GSK Drug coding dictionary. While all therapy types will be 
described within each of the aforementioned summaries, the details of each therapy type 
will be provided in separate listings. 
Summaries of the numbers of radiotherapy and systemic anti-cancer regimens received 
prior to leukapheresis will be presented as part of the summary of disease characteristics 
at screening. 
Systemic anti-cancer therapy regimens initiated between leukapheresis and 
lymphodepletion (as defined in Appendix 4) will be categorized as either bridging 
(regimens administered to maintain/stabilize the participant until T-cell infusion) or full 
lines (regimens administered with the intent of disease effect) by GSK physician review. 
Bridging therapies will be excluded from summaries of prior anti-cancer therapy. 
Thus, unless otherwise stated, summaries of prior systemic anti-cancer therapies will 
include all therapies before lymphodepletion except those in the leukapheresis to 
lymphodepletion period identified as bridging therapies. (Note that this is equivalent to 
all therapies prior to leukapheresis plus therapies initiated between leukapheresis and 
lymphodepletion identified as full lines.)  
A breakdown of the number of participants who received each type of prior anti-cancer 
therapy will be presented. 
Anti-cancer therapy will be coded using GSK Drug coding dictionary. The number of 
participants receiving prior anti-cancer therapies will be summarized by ATC Level 1 and 
ingredient. Bridging therapies will be similarly summarized. 
A summary of the number of overall systemic prior anti-cancer therapy regimens and 
radiotherapies prior to lymphodepletion will also be produced. Systemic therapy 
regimens will not be broken down by type of systemic therapy since different types of 
therapies are expected within a regimen. 
All prior anti-cancer therapy will be listed with subphase indicated and bridging therapies 
flagged. 
All anti-cancer radiotherapy (including on-study) will be listed, with phase and subphase 
indicated. 
All prior cancer related surgical procedures will be listed, with subphase indicated. Those 
before lymphodepletion will be summarized by intent and site.  
6.7.2. 
On-Study Anti-Cancer Therapies 
The number and percentage of participants who receive any anti-cancer therapy 
(including systemic therapy, radiotherapy, and stem cell therapy) or cancer-specific 
surgery will be provided in separate summaries. Systemic therapy drugs will be coded 
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using the GSK Drug coding dictionary, then summarized by ingredient. Participant-level 
data describing all anti-cancer therapies and cancer-specific surgeries will be provided in 
separate listings. 
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7. 
EFFICACY ANALYSES 
7.1. 
Primary Efficacy Analyses 
All efficacy analyses are planned to be performed by treatment arm and overall. Efficacy 
Analyses will be conducted according to International Myeloma Working Group 
(IMWG) (2016) Criteria [Kumar 2016, Section 13]. 
7.1.1. 
Primary Endpoint/Variable: Overall Response Rate (ORR) 
With minimal exception (see description of Confirmed Response below), only disease 
assessments occurring from the start of NY-ESO-1c259T infusion to the earlier of 
confirmed progressive disease (PD) or initiation of new anti-cancer therapy (including 
only systemic therapy) will be considered. Note that while considered a primary endpoint 
for the purposes of efficacy analysis in this RAP, ORR is defined as a secondary 
objective in the protocol.  
7.1.1.1. 
Best Overall Response 
The BOR is defined as the best confirmed response (stringent Complete Response [sCR] 
> Complete Response [CR] > Very Good Partial Response [VGPR] > Partial Response 
[PR] > Minimal Response [MR] > Stable Disease [SD] > Progressive Disease [PD] > Not 
Evaluable [NE]) from treatment start date until disease progression or initiation of new 
anti-cancer therapy (including only systemic therapy), whichever is earlier, as assessed 
per IMWG (2016). Participants with only assessments of not evaluable (NE) or missing 
response will be treated as non-responders (i.e., they will be included in the denominator 
when calculating BOR percentages and the proportion representing ORR). 
7.1.1.2. 
Overall Response Rate 
The primary efficacy endpoint is ORR, defined as the percentage of participants with a 
best overall response (BOR) of confirmed stringent complete response (sCR), complete 
response (CR), very good partial response (VGPR), or partial response (PR) per IMWG 
(2016). Details regarding derivation of confirmed response are provided in Table 2. 
7.1.1.3. 
Definition of Adequate Assessment 
An adequate assessment for purposes of identifying BOR and computing ORR is defined 
as a disease assessment with Investigator-assessed response of sCR, CR, VGPR, PR, MR, 
SD, or PD per IMWG (2016). This definition of adequate assessment differs from that 
used for time-to-event endpoints (see Section 7.2, Secondary Efficacy Analyses). 
7.1.1.4. 
Date Associated with Response 
A disease assessment may occur at a scheduled or unscheduled visit. While the date of 
assessment recorded on the Disease Assessment eCRF may or may not exactly match the 
dates of all procedures supporting the assessment and associated with the visit, it will be 
used to represent the date of response.  
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7.1.1.5. 
Confirmed Response 
An individual Investigator-assessed response must be confirmed at a subsequent disease 
assessment. Details describing the derivation of a confirmed response are provided below 
and in Table 2. 
Pertaining to the responses of sCR, CR, VGPR, PR, and MR, a confirmed response is an 
Investigator-assessed response that has been documented at the confirmed response level 
or better across 2 consecutive adequate disease assessments (referred to as “first 
assessment” and “subsequent assessment”). First and subsequent disease assessments are 
consecutive, representing a dual-assessment scenario. The subsequent assessment is 
defined as the next adequate assessment (i.e., not missing or with NE response) following 
the first assessment, before (or on the same date of) start of new anti-cancer therapy 
(except for confirmation of PD, for which PD or death due to disease under study after 
new anti-cancer therapy may be confirmation of PD). No minimal time interval is 
required for the subsequent disease assessment, but a different sample is required for 
confirmation. If 2 consecutive assessments are performed on different dates, the 
assumption will be made that the 2 assessments are based on different samples. 
• Note that, for participants who receive subsequent anti-cancer therapy, no imputation 
will be performed for completely missing start dates. However, if the start date of the 
anti-cancer therapy is partial (i.e., either missing the day but has the month and year 
available or missing both day and month), then the imputation rules described in 
Section 14.7.2.1, Handling of Missing and Partial Dates, will be applied. 
Table 2 
Response Confirmation Algorithm 
Response Documented at 
the First Assessment[1] 
Response Documented at the 
Subsequent Assessment 
Confirmed 
Response 
Associated with the 
First Assessment[1] 
sCR 
sCR 
sCR 
sCR 
CR 
CR 
CR 
sCR/CR 
sCR/CR 
VGPR 
VGPR 
VGPR 
sCR/CR/VGPR 
sCR/CR/VGPR 
PR 
PR 
PR 
sCR/CR/VGPR/PR 
sCR/CR/VGPR/PR 
MR 
MR 
MR 
sCR/CR/VGPR/PR/MR 
sCR/CR/VGPR/PR/MR/SD SD/PD/NE 
OR 
No subsequent disease assessment prior 
to new anti-cancer therapy, if any 
(participant may or may not still be on 
study) 
SD 
PD (due to reasons other 
than imaging, i.e., 
plasmacytoma or bone 
lesion) 
PD (any reason), including PD after 
initiation of new anti-cancer therapy 
OR 
PD 
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Response Documented at 
the First Assessment[1] 
Response Documented at the 
Subsequent Assessment 
Confirmed 
Response 
Associated with the 
First Assessment[1] 
No subsequent disease assessment: 
participant died due to disease under 
study before further adequate 
assessment could be performed 
(including death due to disease under 
study after initiation of new anti-cancer 
therapy) 
PD due to imaging (i.e., 
plasmacytoma or bone 
lesion) 
Any 
OR 
No subsequent disease assessment 
PD (due to reasons other 
than imaging, i.e., 
plasmacytoma or bone 
lesion) 
sCR/CR/VGPR/PR/MR/SD 
OR 
No subsequent disease assessment 
NE 
NE or missing 
Any 
OR 
No subsequent disease assessment 
1  The date of confirmed response for all scenarios equals the date associated with the first disease 
assessment. 
 
7.1.2. 
Summary Measurement 
The number and percentage of participants in the following best confirmed response 
categories will be summarized: sCR, CR, VGPR, PR, overall response 
(sCR+CR+VGPR+PR), MR, SD, PD, and NE. Corresponding 2-sided exact (Clopper-
Pearson) 95% CIs for ORR will also be provided for each arm and total. Participants with 
unknown or missing responses will be considered NE. 
A participant-level data listing of Investigator-assessed responses per assessment 
timepoint, visit level response, and BOR will be provided, including the name of the 
corresponding visit, date of the response assessment, study day, and observed response.  
A spider plot for the change from baseline over time and a waterfall plot showing the 
maximum percent reduction from baseline will be produced for Serum M-protein, Urine 
M-protein and Serum free light chain (FLC), if data warrant. The maximum percent 
reduction will be plotted in the following hierarchical order:  
(1) Plot Serum M-protein maximum percent reduction from baseline, if data are 
available; 
(2) If (1) is not feasible, plot Urine M-protein maximum percent reduction from baseline, 
if data are available; 
(3) If both (1) and (2) are not feasible, plot maximum percent reduction from baseline for 
difference between 2 types of Serum FLC, if data are available. 
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Difference between 2 types of Serum FLC  
The percent change from baseline for difference between 2 types of Serum FLC is 
defined as:  
(post-baseline difference – baseline difference) / baseline difference x 100. 
To calculate the difference, the “involved” and “non-involved” light chains must be 
determined first, based on the ratio of non-missing values for Serum Kappa FLC protein 
and Serum Lambda FLC protein at baseline. 
The detailed algorithm is provided as below: 
• If the baseline ratio of (Kappa FLC/Lambda FLC) > 1.65, then Kappa FLC is defined 
as involved FLC, and Lambda FLC is defined as non-involved FLC. Then: 
o Difference between involved and uninvolved = Kappa FLC – Lambda FLC. 
• If the baseline ratio of (Kappa FLC/Lambda FLC) < 0.26, then Lambda FLC is 
defined as involved FLC, and Kappa FLC is defined as non-involved FLC. Then: 
o Difference between involved and uninvolved = Lambda FLC – Kappa FLC. 
• If the baseline ratio of (Kappa FLC/Lambda FLC) ≥ 0.26 and ≤ 1.65, then “involved” 
and “non-involved” FLC cannot be determined (ratio is normal), and calculation of 
the maximum percent reduction from baseline for the difference between 2 types of 
Serum FLC will not be possible. 
7.1.3. 
Population of Interest  
The mITT Population will support the primary efficacy analyses, while the ITT 
Population will be used for sensitivity analysis of the primary efficacy endpoint. If the 
mITT and ITT Populations are identical, then only the results associated with the mITT 
Population will be reported. 
7.1.4. 
Strategy for Intercurrent Events 
A composite strategy will be followed for participants who are not evaluable or have 
missing BOR who will be treated as non-responders; i.e., they will be included in the 
denominator when calculating the percentage. 
7.1.5. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
based on GSK data standards and statistical principles.  
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7.2. 
Secondary Efficacy Analyses 
7.2.1. 
Endpoints/Variables 
7.2.1.1. 
Time to Response (TTR) 
TTR is defined as the time interval (in months) from T-cell infusion to initial date of 
documented confirmed response (PR or better) in the subset of participants who showed a 
confirmed BOR of PR or better by Investigator assessment per IMWG (2016). 
7.2.1.2. 
Duration of Response (DoR) 
DoR is defined as the time interval (in months) from initial date of documented 
confirmed response (PR or better) to the date of confirmed PD or death due to disease 
under study for participants who showed a confirmed BOR of PR or better IMWG 
(2016).   
Although documentation of responses of PR and better requires a confirmatory 
measurement, the start time for DoR will be the first date on which response was noted 
(i.e., the date of “first assessment”, as described in Section 7.1.1, Primary 
Endpoint/Variable: Overall Response Rate (ORR)). Determination of event/censoring for 
DoR events and associated dates are described in Table 3. 
Note that, for participants who receive subsequent anti-cancer therapy, no imputation will 
be performed for completely missing start dates. However, if the start date of the anti-
cancer therapy is partial (i.e., either missing the day but has the month and year available 
or missing both day and month), then the imputation rules described in Section 14.7.2.1, 
Handling of Missing and Partial Dates, will be applied. 
Table 3 
Assignments for Progression/Death and Censoring Dates for DoR 
Analysis 
Scenario 
Date of Event or Censoring 
Event or Censored 
No (or inadequate) baseline 
assessment[1] and the participant 
has not died (if the participant 
has died, follow the rules for 
death at the bottom of this 
table). 
Date of T-cell infusion 
Censored 
No post-baseline assessments 
and the participant has not died 
(if the participant has died, 
follow the rules for death at the 
bottom of this table). 
Date of T-cell infusion 
Censored 
New anti-cancer therapy started 
on or after lymphodepletion and 
prior to T-cell infusion 
Date of T-cell infusion 
Censored 
PD documented at or between 
scheduled visits. 
Date of documented PD[3] 
Event 
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Scenario 
Date of Event or Censoring 
Event or Censored 
With post-baseline assessment 
but no PD or death. 
Date of last adequate disease 
assessment[2]  
Censored 
New anti-cancer therapy started 
prior to documented PD or 
death[3]. 
Date of last adequate disease 
assessment[2] on or prior to starting 
anti-cancer therapy  
Censored 
Death due to disease under 
study without extended loss to 
follow-up. 
Date of death  
Event 
Death from causes other than 
disease under study without 
extended loss to follow-up. 
Date of death  
Censored 
Death or PD after extended loss 
to follow-up of 2 or more 
cycles + 1/3/7-day window.  
As the schedule of assessments 
(Myeloma markers labs) changes 
through the course of the protocol 
(i.e., starting on Week 1 and then 
every 3 weeks from Week 3 until 
Week 24 and then every 6 weeks 
until Week 72, then every 12 weeks 
until PD), the following rules will be 
used for identifying extended loss to 
follow-up or extended time without 
an adequate assessment (i.e., 2 or 
more missed assessments + window). 
• If death or PD is on or prior to 
Day 45 (= Week 6 + 3-day 
window), then participant status 
will be labelled “extended loss to 
follow-up” if the participant did 
not have an adequate assessment 
during the period of 37 days (= 2 
weeks + 3 weeks + 1-day window 
+ 1-day window) prior to death or 
PD;  
•  Else if death or PD is after Day 45 
(= Week 6 + 3-day window) and 
on or prior to Day 175 (= Week 24 
+ 7-day window), then participant 
status will be labelled “extended 
loss to follow-up” if the 
participant did not have an 
adequate assessment during the 
period of 48 days (= 3 weeks + 3 
weeks + 3-day window + 3-day 
window) prior to death or PD; 
• Else if death or PD is after Day 
175 (= Week 24 + 7-day window) 
and on or prior to Day 504 (= 
Week 72 + 7-day window), then 
Censored 
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Scenario 
Date of Event or Censoring 
Event or Censored 
participant status will be labelled 
“extended loss to follow-up” if the 
participant did not have an 
adequate assessment during the 
period of 98 days (= 6 weeks + 6 
weeks + 7-day window + 7-day 
window) prior to death or PD; 
• Else if death or PD is after Day 
504 (= Week 72 + 7-day window), 
then participant status will be 
labelled “extended loss to follow-
up” if the participant did not have 
an adequate assessment during the 
period of 182 days (= 12 weeks + 
12 weeks + 7-day window + 7-day 
window) prior to death or PD. 
DoR will be censored on the date of 
last adequate disease assessment 
prior to PD/death.[2] 
1 Adequate baseline assessment is defined as a baseline assessment with at least one serum protein 
electrophoresis (SPEP), urine protein electrophoresis (UPEP), or involved FLC result available for 
analysis. 
2   Adequate disease assessment is defined as a disease assessment with Investigator-assessed response of 
sCR, CR, VGPR, PR, MR, or SD per IMWG (2016). The date of response will be recorded on the 
Disease Assessment eCRF. 
3  If PD (or death) and new anti-cancer therapy occur on the same day, the assumption will be made that PD 
(or death) was documented first (i.e., PD would equal the outcome and the relevant date would be the 
date of documented PD). If anti-cancer therapy is started prior to any adequate disease assessments (but 
after lymphodepleting chemotherapy), the censoring date will equal the date of T-cell infusion. 
7.2.1.3. 
Progression Free Survival (PFS) 
PFS is defined as the time interval (in months) between the date of T-cell infusion and the 
initial assessment date of confirmed PD as assessed by the investigator per IMWG (2016) 
or date of death due to any cause. Determination of dates of PFS events and dates for 
censoring are described in Table 4. 
Table 4 
Assignments for Progression and Censoring Dates for PFS Analysis 
Scenario 
Date of Event (Progression/Death) 
or Censoring 
Event 
(Progression/Death) 
Or Censored 
No (or inadequate) baseline 
assessment[1] and the 
participant has not died (if the 
participant has died, follow the 
rules for death at the bottom of 
this table). 
Date of T-cell infusion 
Censored 
No post-baseline assessments 
and the participant has not 
Date of T-cell infusion 
Censored 
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Scenario 
Date of Event (Progression/Death) 
or Censoring 
Event 
(Progression/Death) 
Or Censored 
died (if the participant has 
died, follow the rules for death 
at the bottom of this table). 
PD documented between 
scheduled visits, without 
extended loss to follow-up. 
Date of documented PD[3] 
Event 
With post-baseline assessment 
but no documented PD or 
death.  
Date of last adequate disease 
assessment[2] 
Censored 
No adequate post-baseline 
assessment before start of new 
anti-cancer therapy. 
Date of T-cell infusion 
Censored 
With adequate post-baseline 
assessment and new anti-
cancer therapy started prior to 
documented PD or death[3]. 
Date of last adequate disease 
assessment[2] on or prior to starting 
anti-cancer therapy  
Censored 
Death before first scheduled 
assessment, or death at 
baseline without adequate 
baseline assessment, or death 
following a post-baseline 
assessment (i.e., “between 
assessments”) without 
extended loss to follow-up. 
Date of death 
Event 
Death or PD after extended 
loss to follow-up or time 
without adequate disease 
assessment of 2 or more cycles 
+ 1/3/7-day window  
As the schedule of assessments 
(Myeloma markers labs) changes 
through the course of the protocol 
(i.e., starting on Week 1 and then 
every 3 weeks starting from Week 3 
until Week 24 and then every 6 
weeks until Week 72, then every 12 
weeks until PD), the following rules 
will be used for identifying extended 
loss to follow-up or extended time 
without an adequate assessment (i.e., 
2 or more missed assessments + 
window). 
• If death or PD is after Day 45 (= 
Week 6 + 3-day window) and on 
or prior to Day 175 (= Week 24 + 
7-day window), then participant 
status will be labelled “extended 
loss to follow-up” if the participant 
did not have an adequate 
assessment during the period of 48 
days (= 3 weeks + 3 weeks + 3-day 
Censored 
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Scenario 
Date of Event (Progression/Death) 
or Censoring 
Event 
(Progression/Death) 
Or Censored 
window + 3-day window) prior to 
death or PD;  
•  Else if death or PD is after Day 
175 (= Week 24 + 7-day window) 
and on or prior to Day 504 (= 
Week 72 + 7-day window), then 
participant status will be labelled 
“extended loss to follow-up” if the 
participant did not have an 
adequate assessment during the 
period of 98 days (= 6 weeks + 6 
weeks + 7-day window + 7-day 
window) prior to death or PD; 
• Else if death or PD is after Day 
504 (Week 72 + 7-day window), 
then participant status will be 
labelled “extended loss to follow-
up” if the participant did not have 
an adequate assessment during the 
period of 182 days (12 weeks + 12 
weeks + 7-day window + 7-day 
window) prior to death or PD. 
PFS will be censored on the date of 
last adequate disease assessment (or 
T-cell infusion, if no adequate disease 
assessment) prior to PD/death.[2]  
1 Adequate baseline assessment is defined as a baseline assessment with at least one serum protein 
electrophoresis (SPEP), urine protein electrophoresis (UPEP), or involved FLC result available for 
analysis. 
2   Adequate disease assessment is defined as a disease assessment with Investigator-assessed response of 
sCR, CR, VGPR, PR, MR, or SD per IMWG (2016). The date of response will be recorded on the 
Disease Assessment eCRF. 
3  If PD (or death) and new anti-cancer therapy occur on the same day, the assumption will be made that PD 
(or death) was documented first (i.e., PD would equal the outcome and the relevant date would be the 
date of documented PD). If anti-cancer therapy is started prior to any adequate disease assessments (but 
after starting lymphodepleting chemotherapy), the censoring date will equal the date of T-cell infusion. 
 
7.2.2. 
Summary Measure 
7.2.2.1. 
Time to Response (TTR)  
Time to response for each participant with a confirmed response (PR or better) will be 
listed in months. Details are provided in Appendix 12. 
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7.2.2.2. 
Duration of Response 
Duration of response for each participant with a confirmed response (PR or better) will be 
listed in months. Details are provided in Appendix 12. 
7.2.2.3. 
Progression Free Survival  
PFS will be summarized using Kaplan-Meier curves. Median PFS, first and third 
quartiles and 95% CI, will be estimated using the Brookmeyer-Crowley method 
[Brookmeyer, 1982]. A listing of PFS times and associated details will also be provided. 
Details of the planned displays are provided in Appendix 12. 
7.2.3. 
Population of Interest  
Secondary efficacy analyses will be based on the mITT Population.  
7.2.4. 
Statistical Analyses / Methods 
Details of the planned displays will be provided in Appendix 12: List of Data Displays 
and are based on GSK data standards and statistical principles. Unless otherwise 
specified, endpoints / variables defined above in Section 7.2.2 will be summarized by arm 
using descriptive statistics, graphically presented (as appropriate), and listed.  
7.3. 
Exploratory Efficacy Analyses 
MRD will not be analysed at part of this RAP.  
7.3.1. 
Endpoints/Variables 
7.3.1.1. 
Overall Survival (OS) 
OS is defined as the time interval (in months) from the date of T-cell infusion to the date 
of death due to any cause. 
Survival outcomes for subjects who have not died by the point of analysis will be 
censored on the date of last known contact with the participant. 
7.3.2. 
Summary Measure 
OS for each participant will be listed in months. 
7.3.3. 
Population of Interest  
The exploratory efficacy analysis will be based on the mITT Population.  
7.3.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
are based on GSK data standards and statistical principles. Unless otherwise specified, 
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endpoints / variables defined in Section 7.3.1 will be summarized using descriptive 
statistics, graphically presented (if appropriate), and listed. 
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8. 
SAFETY ANALYSES 
The safety analyses will be based on the Intent-to-Treat population except for displays 
that are treatment dependent where the modified Intent-to-Treat population will be used, 
as detailed in Appendix 12. 
Unless otherwise specified, summaries will include descriptive statistics by treatment 
arm, as well as overall (across treatment arms). 
8.1. 
Adverse Events Analyses 
Analysis of AEs, including all AEs, serious AEs (SAEs), and other significant AEs, will 
be based on GSK Core Data Standards. The details of the planned displays are provided 
in Appendix 12: List of Data Displays. 
AEs will be graded according to National Cancer Institute-Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE) version 4.03 unless otherwise specified in the protocol. 
For instance, the grading of AE-related Cytokine Release Syndrome (CRS) will be 
performed using modified NCI-CTCAE guidance developed by Lee (2019, Section 13); 
see protocol Table 5 and Section 8.5. For the grading of Graft versus Host Disease 
(GVHD) associated AEs, see protocol Section 8.6.2. AEs will be coded to the level of 
Preferred Term (PT) using the latest version of the Medical Dictionary for Regulatory 
Affairs (MedDRA). 
In the eCRF for this study Adverse Events for which the grade changes over the course of 
the event are entered as multiple records, one record per grade. (If multiple grades are 
experienced on the same day then the highest grade for that day is reported.) Similarly, 
events where other attributes such as relatedness change over the course of the event will 
also be entered as multiple records. For analyses requiring summaries of numbers or 
characteristics of individual events, these multiple sequential segments will be collapsed 
back into a single event record prior to analysis using the algorithm detailed in Appendix 
15 
AEs related to study treatment, SAEs, SAEs related to any study treatment, fatal AEs, 
and fatal AEs related to any study treatment will be summarized.  
Tables will summarize all AEs for the ITT population and Treatment Emergent AEs for 
the MITT population. 
A summary of common non-serious AEs that occurred strictly in ≥5% of participants will 
be provided, without rounding of the percentage to overcome the 5% threshold (e.g., 
events with 4.9% incidence rate will not be included). This summary will display the 
number and percentage of participants, while a separate summary will present the total 
numbers of occurrences of the common non-serious AEs. Both summary tables will be 
displayed by MedDRA System Organ Class (SOC) and PT.  
The relationship between MedDRA SOC, PT, and Verbatim Text will be listed. 
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A summary of number and percentage of participants with any AEs by maximum grade 
will be produced. AEs will be sorted by combined PT in descending order of total 
incidence. The summary will use the following algorithms for counting the participant: 
• 
Preferred term row: Participants experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade. 
• 
Any event row: Each participant with at least one AE will be counted only once at 
the maximum grade no matter how many events they have. 
In addition, the frequency and percentage of AEs (all grades) will be summarized and 
displayed in 2 ways: 1) in descending order of total incidence by combined PT only and 
2) in descending order of total incidence by SOC and PT. In the SOC row, the number of 
participants with multiple events under the same SOC label will be counted once.  
A study treatment-related AE is defined as an AE for which the investigator classifies the 
relationship to lymphodepleting chemotherapy, T-cell infusion, and/or pembrolizumab as 
“Yes”, which includes “Definitely Related”, “Probably Related”, and “Possibly Related”. 
Summary of study treatment related AEs by combined PT and maximum grade will also 
be provided separately for relatedness to each study treatment. A worst-case scenario 
approach will be taken to handle missing relatedness data (i.e., the summary table will 
include events with the relationship to study treatment as ‘Yes’ or missing).   
In addition to the summaries and listings described above, listings will be provided for all 
AEs, AEs leading to pembrolizumab dose interruption (in Arm 2), AEs leading to 
pembrolizumab dose reduction (in Arm 2), AEs leading to pembrolizumab dose 
discontinuation (in Arm 2), delayed AEs as adjudicated by GSK (provided from external 
data source), and participant IDs per individual AE. 
Tables that summarize AEs by SOC and PT will use MedDRA preferred terms, as well as 
any adverse event tables required for disclosure. This will be detailed in the programming 
notes in Appendix 12: List of Data Displays. Most other AE tables will summarize AEs 
by using the combined terms defined in Appendix 14: Combined Preferred Terms, as 
detailed in the programming notes in Appendix 12: List of Data Displays. 
In the event that a participant has withdrawn consent, no data after the withdrawal of 
consent date from this participant including death should appear in the database, which 
should be part of the data cleaning process. All deaths will be summarised based on the 
number and percentage of participants. This summary will classify participants by time of 
death relative to the date of T-cell infusion (>30 days or 30 days) and primary cause of 
death (disease under study, treatment related toxicity, or other). A supportive listing will 
be generated to provide participant-specific details on participants who died.  
AEs deemed serious are those events leading to death, life-threatening circumstance, or 
new/prolonged hospitalization or, given appropriate medical judgement, requires medical 
or surgical intervention to prevent one or more of the aforementioned outcomes (see 
protocol Section 9.3 for more detail). Separate summaries will be provided for AEs (and 
SAEs) related to study treatments: one for lymphodepleting chemotherapy-related 
(S)AEs, one for T-cell infusion-related (S)AEs, and one for all study treatment related 
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(S)AEs. Summaries of fatal AEs, and fatal AEs related to any study treatment will be 
produced. Fatal AEs will only be summarized if there are at least 5 participants with fatal 
AEs. 
SAEs will be included in the listing of all AEs, but also separate supportive listings with 
participant-level details will be generated for: 
• 
Non-fatal SAEs 
• 
Reasons for considering AE as serious 
A summary of total incidence and frequency and percentage of grade 3, 4, and 5 events 
will be presented by study arm and total for the following: all AEs, all treatment 
emergent AEs, all study-treatment related AEs, all T-cell related AEs, all 
lymphodepletion related AEs, all serious AEs, and all study-treatment related, T-cell 
related, and lymphodepletion related serious AEs. 
A plot of study duration including study days of any SAE, death, progression, and 
response will be produced. 
8.2. 
Adverse Events of Special Interest (AESI) Analyses 
AESIs include: 
• 
Cytokine Release Syndrome 
• 
Haematopoietic cytopenias (including pancytopenia and aplastic anaemia) 
• 
Graft versus Host Disease (GvHD) 
• 
Immune Effector-Cell Associated Neurotoxicity Syndrome (ICANS) 
• 
Guillain-Barre Syndrome (GBS) 
A focused list of MedDRA terms based on clinical review will be used to identify each 
type of event. In addition, all potential haematopoietic cytopenias will be identified using 
a comprehensive list of MedDRA terms. Changes to the MedDRA dictionary may occur 
between the start of the study and the time of reporting, and emerging data from on-going 
studies may highlight additional AEs of special interest (AESIs). Therefore, the list of 
terms to be used for each event of interest and the specific events of interest will be based 
on the SRT agreements in place at the time of reporting. Due to expected small numbers, 
Gullian-Barre Syndrome, Immune Effector-Cell Associated Neurotoxicity Syndrome, 
and Graft versus Host Disease will only be displayed in listings. Details of the planned 
displays are provided in Appendix 12: List of Data Displays. 
AESI tables will be reported for the mITT population.  
The number and percentage of participants with these events will be summarized by 
categories of AESI, combined preferred term, and grade in one table using both the 
comprehensive list and focused list. All additional AESI tables described below will be 
summarized using the focused list and additional Haematopoietic cytopenia AESI tables 
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will also be summarized by cell line, using the specific neutropenia, thrombocytopenia, 
and anemia preferred terms in the focused list. 
Listings of AESIs will be produced for each AESI category using the focused list, which 
will include leukapheresis date, lymphodepletion start date, T cell infusion date, AE start 
date, AE end date, SAE code, grade, relationship to study treatment and outcome of 
event. An additional listing of cytopenias identified in the comprehensive list will also be 
provided. 
The summary of event characteristics for each category of AESI will also be provided, 
including number of participants with any event, number of events, number of 
participants with any event that is serious, number of participants with any event that is 
related to study treatment, the outcome of the event, maximum grade and the action taken 
for the event. The percentage will be calculated in 2 ways, one with number of 
participants with event as the denominator and the other with total number of participants 
as the denominator. The worst-case approach will be applied at participant level for the 
event outcome and maximum grade, i.e. a participant will only be counted once as the 
worst case from all the events experienced by the participant. For action taken to an 
event, participant will be counted once under each action, e.g. if a participant has an 
event leading to both study treatment discontinuation and dose reduction, the participant 
will be counted once under both actions. 
A summary of onset and duration of the first occurrence of all AESIs will be created for 
each AESI separately, and for Haematopietic cytopenias this will include an overall 
analysis of events in the focused list of PTs for this AESI as well as separate analyses for  
cell lines describing events of Neutropenia, Anemia, and Thrombocytopenia. A summary 
of onset and duration of the last occurrence of focused list Haematopoietic cytopenias 
will also be created. In addition, a summary of time to resolution will be created for each 
AESI separately. The time to resolution displays summarize participants with an AESI 
occurring before study day 30. Among all AESIs occurring before study day 30, the 
worst-case study day of resolution will be summarized. Additionally, the worst-case 
AESI duration of all recurrent AESIs will be summarized. Recurrent AESI is defined as 
additional occurrences of AESIs after day 30, after initial occurrence and before study 
day 30. Duration is defined as AESI end date – AESI start date + 1. 
Characteristics, Onset and Duration, and Time to Resolution summaries will not be 
created if there are 0 or 1 AESI in total. 
8.2.1. 
Cytokine Release Syndrome (CRS) and Graft versus Host 
Disease (GvHD)  
Refer to protocol Section 8.5 and Section 8.6 for the definitions and the grading of CRS 
and GvHD. The listing of CRS AESIs will also include time from infusion to first CRS 
(days) and time from infusion to max CRS (days). Listings of symptoms, medications 
and procedures related to CRS and GvHD will be produced separately. The mock-up 
shells are in Appendix 13: Example Mock Shells for Data Displays. 
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8.3. 
Clinical Laboratory Analyses 
Laboratory evaluations including chemistry, hematology, and other laboratory tests, 
including biomarker tests, will be based on GSK Core Data Standards. The details of the 
planned displays are in Appendix 12: List of Data Displays.  
The laboratory assessments to be conducted for monitoring participant safety are listed in 
Table 5, List of Clinical Laboratory Tests.  
Table 5 
List of Clinical Laboratory Tests 
Clinical Chemistry 
Hematology 
Total Calcium 
Calcium corrected for Albumin 
Phosphorus 
Magnesium 
Albumin 
Bilirubin 
Alanine aminotransferase 
Aspartate aminotransferase 
Alkaline phosphatase 
Lactate dehydrogenase 
Sodium 
Potassium 
Bicarbonate 
Creatinine*  
Chloride 
Glucose 
BUN or Urea  
Uric Acid 
C-reactive protein 
* In participants ≥65 years, add GFR 
Red blood cell count 
Hemoglobin 
Hematocrit 
Mean cell volume 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin concentration 
Platelet count 
White blood cell count 
White blood cell differential absolute counts of 
lymphocytes, monocytes, and neutrophils  
White blood cell differential percentages of 
lymphocytes, monocytes, and neutrophils 
 
 
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Other Clinical Lab tests 
Urinalysis:  
Glucose 
Ketones 
Specific gravity 
Protein 
Blood 
Microscopy 
Bilirubin 
pH  
 
Coagulation:  
Prothrombin time or International 
Normalized Ratio 
Activated partial thromboplastin time  
 
Endocrinology: 
Thyroid stimulating hormone 
 
Myeloma markers: 
SPEP 
UPEP 
IgG 
IgM 
IgA 
Serum free Kappa chain 
Serum free Lambda chain 
Kappa/Lambda ratio determination 
Beta-2 microglobulin 
Serum M-protein 
Serum Immunofixation 
Immunology:  
HIV 1+2 antibody 
Hepatitis B surface antigen 
Hepatitis B core antibody – if positive, test for 
HBV DNA 
Hepatitis C antibody – if positive, test for HCV 
RNA 
HTLV 1+2 IgG 
CMV IgG  
EBV (EBNA) 
Syphilis (RPR) 
CMV DNA PCR – peripheral blood for 
detection of reactivation.  
 
 
Pregnancy:  
Serum beta-HCG or urine test  
 
 
Summaries of worst-case grade increase from baseline grade at Week 4, Week 15, and 
across all post-baseline visits will be provided for all the lab tests that are gradable by 
NCI-CTCAE v4.03. The worst grade will be derived based on all post baseline records 
including unscheduled visits. These summaries will display the number and percentage of 
participants with a maximum post-baseline grade increasing from their baseline grade. 
Missing baseline grade will be assumed as grade 0. For laboratory tests that are graded 
for both low and high values, summaries will be done separately and labeled by direction, 
e.g. sodium will be summarized as hyponatremia and hypernatremia. 
For lab tests that are not gradable by NCI-CTCAE v4.03, summaries of worst-case 
changes from baseline with respect to normal range will be generated. Decreases to low, 
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changes to normal or no changes from baseline, and increases to high will be summarized 
at each scheduled visit as well as for the worst-case post-baseline. If a participant has a 
decrease to low and an increase to high during the same time interval, then the participant 
is counted in both the “Decrease to Low” categories and the “Increase to High” 
categories. In addition, the summary will include worst-case changes from baseline with 
respect to normal range for worst cases. 
Separate summary tables for hematology, chemistry, and other laboratory tests will be 
produced. Summary of the change from baseline for hematology, chemistry, and other 
lab tests will be provided by visit using n, mean, median, standard deviation, minimum, 
and maximum. A plot of each subject’s laboratory data over time will be created for the 
following hematologic tests: neutrophils, lymphocytes, platelets, and hemoglobin. 
Additionally, all laboratory values will be provided in a listing. 
Detailed derivation of baseline assessment is specified in Section 5.2, Baseline 
Definitions. Unless otherwise specified, the denominator used in calculating percentage 
at each scheduled visit will equal the number of participants with non-missing values at 
the particular visit. 
8.3.1. 
Analyses of Liver Function Tests (LFT) 
Listings of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above, including listings of liver 
monitoring and stopping events as well as a listing of subjects meeting hepatobiliary 
laboratory criteria post-baseline. 
Possible Hy’s law cases will be defined as any event of either: (a) alanine 
aminotransferase (ALT) ≥3 × the upper limit of normal (ULN) and bilirubin ≥2 × ULN 
(>35% direct bilirubin) or (b) ALT ≥3 × ULN and INR >1.5, if INR is measured. Total 
bilirubin ≥2 × ULN can be within 28 days following the ALT elevation and, if direct 
bilirubin is available on the same day, it must be ≥35% of total bilirubin. Note that INR 
measurement is not required, and the threshold value stated will not apply to participants 
receiving anticoagulants.  
A scatter plot of maximum total bilirubin versus maximum ALT will be generated. Also, 
a scatter plot of maximum vs baseline for ALT will be produced. 
8.4. 
Other Safety Analyses 
The analyses of non-laboratory safety test results, including ECGs and vital signs, will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 12: List of Data Displays. 
8.4.1. 
Performance Status 
Eastern Cooperative Oncology Group (ECOG) performance status at baseline and at the 
participant’s last assessment will be summarized. A summary of change from baseline by 
scheduled visits will also be produced, including the worst-case and best-case post-
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baseline changes during the study (improved, no change, deteriorated). Summaries will 
use frequency and percentage of participants at each planned assessment time. A 
supportive listing will also be provided. 
8.4.2. 
ECG 
A summary of the number and percentage of participants who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by 
scheduled visits as well as for the worst-case post-baseline. The worst case will be chosen 
from all available ECG findings, including scheduled and unscheduled visits.  
A summary of change from baseline in ECG values will be produced. 
A summary of increases in QTc comparing the baseline value to worst-case post baseline 
value will be provided. The worst-case post baseline row is used to summarize the 
participants’ overall worst-case shifts post baseline. The determination of the worst-case 
post baseline takes into account both planned and unscheduled assessments.  In addition, 
the summary also includes a comparison of the worst-case shifts by planned time 
intervals. 
Similarly, the amount of increase from baseline in QTc values will also be summarized. 
Participants with missing baseline values will be excluded from this summary. 
Summaries of QTc values will incorporate corrections based on Friderica’s or Bazett’s 
formula separately (with values referred to as QTcF and QTcB, respectively). 
Listings of abnormal ECG findings and a listing of ECG values will be provided. 
A figure plotting QTc shift from baseline to worst-case post baseline will be produced, 
with separate plots for the 2 correction methods (QTcF and QTcB). Plots within the 
figure will have reference lines at 480 and 500 msec for both the ordinate and abscissa 
axes. There will be diagonal reference lines at equality (i.e., a 45-degree line), at equality 
plus 30 msec, and at equality plus 60 msec. 
8.4.3. 
Pregnancies 
Pregnancy (or pregnancy of a male participant’s partner) is not considered an AE/SAE 
unless there is reason to believe that the pregnancy may be the result of failure of the 
contraceptive being used due to interaction with the study drug. However, the 
investigator shall report all pregnancies immediately to the Sponsor. If participants or 
participants’ partner become pregnant while on the study, the information will be 
included in the narratives and no separate table or listing will be produced. 
8.4.4. 
Vital Signs 
A summary of change from baseline in vital signs will be provided. Also, a summary of 
worst-case vital signs results by Potential Clinical Importance (PCI) criteria post-baseline 
relative to baseline will be generated (see Appendix 8: Values of Potential Clinical 
Importance).  
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A listing of vital signs with values of PCI will be provided. 
8.4.5. 
Replication Competent Lentivirus (RCL) and Persistence of NY-
ESO-1c259T 
The proportion of participants who are RCL positive will be summarized. RCL is 
reported as “Negative” if copies of VSV-G are <50 copies/ug DNA. 
RCL results will also be presented in a data listing. 
The proportion of patients showing >1% gene marked peripheral blood mononuclear 
cells (PBMCs) one-year post-treatment will be summarized if data warrant.  
For any patient who has greater than 1% gene marked PBMCs at 1 year or beyond post-
infusion, integration site analysis will be performed on PBMCs to assess clonality and 
possible insertional oncogenesis. A summary of the number of subjects with any number 
of clones with >7% abundance will be summarized if data warrant. A supporting listing 
will be provided. Two diversity indices, Shannon diversity index and Gini index, will be 
reported in the data listing. These indices can help summarize the composition of a 
population of clones. Shannon diversity is a measurement that represents the uncertainty 
about the identity of a single species within the population [Shannon, 1948, Section 13]. 
The Gini index can help detect the similarity in abundance of different clones across the 
population [Gini, 1914, Section 13] 
Further details of the handling of persistence data and its analysis as a biomarker are 
given in Section 9.1. 
8.4.6. 
COVID-19 
A listing of all COVID-19 assessments, including test date and result, along with 
symptom assessments will be provided. 
9. 
PHARMACOKINETIC ANALYSES 
9.1. 
Primary Pharmacokinetic Analyses 
9.1.1. 
Endpoint / Variables 
Evaluation of persistence of NY-ESO-1c259T cells over time is a secondary objective.  
9.1.1.1. 
Drug Concentration Measures 
Spider plots will be used to graphically summarize persistence over time for each 
participant by responders and non-responders. Spider plots of Bone Marrow 
Mononuclear Cell (BMMC) persistence data will also be produced if data is available. 
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9.1.1.2. 
Derived Pharmacokinetic Parameters 
The PK parameters presented in the table below will be derived during programming. 
This will be the responsibility of the Statistics and Programming group at PAREXEL 
under the direction of the Clinical Pharmacology Modeling and Simulation (CPMS) 
Department at GSK.  
Peak expansion during the study (Cmax), time to peak expansion (Tmax), and as data 
permit, AUC(0-28) will be summarized overall and for responders and non-responders 
using descriptive statistics and dot plots. 
The area under the plasma concentration-time curve to day 28 (AUC(0-28)) will be 
determined using the linear trapezoidal rule for increasing concentrations and the 
logarithmic trapezoidal rule for decreasing concentrations. PK samples intended for day 
28 will be treated as collected on that day provided they are collected within 4 days of 
day 28. 
9.1.2. 
Summary Measure 
For each of these parameters, except Tmax, the following summary statistics will be 
calculated: n, median, minimum, maximum, arithmetic mean, 95% confidence interval 
for the arithmetic mean, standard deviation, coefficient of variation (coefficient of 
variation (CV) = 100*(sqrt (exp(SD2) - 1))) [NOTE: SD = SD of log transformed data]), 
geometric mean, 95% confidence interval for the geometric mean and standard deviation 
of logarithmically transformed data. Data will be summarized by treatment arm and 
overall, and by type of persistence if BMMC persistence data is available. 
 
For Tmax, calculations will include median, maximum, minimum, arithmetic mean, 95% 
confidence interval, and standard deviation. Data will be summarized by treatment arm 
and overall. 
 
A listing of persistence will be provided and will include coefficient of variation, number 
of positive replicates, copies/cell, copies/µg DNA, percent gene marked cells of PBMCs 
(%), interpretive result, duration of detectible persistence, time to loss of 25%/50%/75% 
peak expansion, and AUC(0-28). An identical persistence listing will be created for BMMC 
data. 
Time to loss of 25% of peak expansion will be calculated as the time since T-cell infusion 
corresponding to observing at least 25% loss of peak expansion. If time to 25% loss of 
peak expansion is not observed, the last observed time will be reported with a “+”. The 
same procedure will be followed for 50% and 75%. 
The following calculations will be performed: 
copies/cell is calculated with the following formula: 
copies/cell=(copies/µg) x (0.0000063 µg gDNA/cell) 
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Percent gene-marked cells of peripheral blood mononuclear cells (PBMCs) = 
(copies/cell) x 100 
The final reported result of copies/µg gDNA is calculated as follows: 
copies/µg DNA=copies per well/µg gDNA per well 
For persistence value below LLOQ, the following rules will be applied: 
Reported Copies 
per cell Result 
Reported Copies 
per ug gDNA 
Result 
Reported Result 
Set Value for 
Copies per cell 
Set Value for 
Copies per ug 
gDNA 
<0.0003 
<50.0 
Negative 
0 
0 
<0.0003 
<50.0 
Detectable, 
<LLOQ 
0.0003 
50 
 
Note, sometimes values for copies per cell and copies per ug DNA might be different 
than above as it depends on the input of DNA, but rule would be the same: 
- 
If interpretive reported result is negative, then set values to 0.  
- 
If interpretive reported result is “Detectable, <LLOQ”, set values to LLOQ (If 
<XXX, set at XXX) 
The unit for persistence will be “Copies/ug of gDNA” 
Duration of detectable persistence is defined as time from T-cell infusion until 
persistence is no longer detectable. Persistence above the assay limit of detection but 
below the lower limit of quantitation is considered for the duration determination, i.e. the 
time window from infusion until the first instance persistence falls below the detection 
limit and the interpretive reported result is “Negative.” If persistence for a given 
participant remains detectable (“Positive” or “Detectable, LLOQ”) at their last sample 
collection timepoint, the last observed time is reported and considered as right-censored 
with a “+” appended to the numerical result. Note, transduced T-cells frequently persist 
beyond the follow-up period, and hence, the reported duration is directly influenced by 
length of time the participant is on-study 
9.1.3. 
Population of Interest 
All analyses of persistence will be based on the mITT population, unless otherwise 
specified. 
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10. 
BIOMARKER ANALYSES 
10.1. 
Biomarker Analyses 
10.1.1. 
Endpoint / Variables 
Anti-NYESO antibody formation will be reported if data warrant.  
10.1.2. 
Summary Measure 
10.1.2.1. 
Anti-NYESO-1 Antibody Formation 
The anti-NY-ESO-1 antibody results, including titers, will be reported for all participants 
in a data listing. Additionally, the overall incidence of participants with all negative or 
confirmed positive results at baseline and any post-treatment time point will be 
summarized if data warrant. 
10.1.3. 
Population of Interest 
Biomarker analyses will be based on the mITT Population, unless otherwise specified. 
10.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
are based on GSK data standards and statistical principles. 
11. 
POPULATION PHARMACOKINETIC (POPPK) 
ANALYSES 
Not applicable. 
12. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
Not applicable. 
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13. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41. 
Gini C. Sulla misura della concentrazione e della variabilita dei caratteri. Transactions of 
the Real Istituto Veneto di Scienze. 1914; LIII:1203Appendices 
Kumar S, Pariva B, Anderson KC, et al. International Myeloma Working Group 
consensus criteria for response and minimal residual disease assessment in multiple 
myeloma. The Lancet. 2016;17;e328-e346. 
Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine 
Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. 
Biol. Blood Marrow Transplant. 2019;25:625-638. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin 
Trials. 2008;5(2):93-106. 
Shannon, C. A mathematical theory of communication. Bell Syst. Tech. J. 1948;27:379–
423, 623–656.  
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14. 
APPENDICES 
14.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Specification document. 
 
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14.2. 
Appendix 2: Schedule of Activities 
14.2.1. 
Protocol Defined Schedule of Events 
 
Screeninga 
Phase 
/  
Eligibility 
Phase 
Treatment Phase 
DC of 
Pem-
broli-
zumab 
Txc 
Comple- 
tion of 
Treatment 
Phase or 
WDd 
Leukapheresis 
Baseline 
≤7 days 
prior to 
chemo 
Lymphodepleting 
Chemotherapyb 
T-cell 
infu-
sion 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
Scrn Elig 
 
D -14 to 
 D -8 
D -
8 
D-7 
D -
6 
D -
5 
D -
4 
D 1 
D2 D3 D4 D5 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
6 
Wk 
15 
Wk 24 
& 
Q12wks  
 
Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1D ±1D ±1D ±3D ±3D ±3D ±7D 
 
 
Informed 
consenta 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA-genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NY-ESO-1 and 
LAGE-1a levels 
on BM aspirate  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusions/ 
Exclusions  
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
characteristicse 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examg 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Prior/Concomitant 
medicationh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
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Screeninga 
Phase 
/  
Eligibility 
Phase 
Treatment Phase 
DC of 
Pem-
broli-
zumab 
Txc 
Comple- 
tion of 
Treatment 
Phase or 
WDd 
Leukapheresis 
Baseline 
≤7 days 
prior to 
chemo 
Lymphodepleting 
Chemotherapyb 
T-cell 
infu-
sion 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
Scrn Elig 
 
D -14 to 
 D -8 
D -
8 
D-7 
D -
6 
D -
5 
D -
4 
D 1 
D2 D3 D4 D5 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
6 
Wk 
15 
Wk 24 
& 
Q12wks  
 
Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1D ±1D ±1D ±3D ±3D ±3D ±7D 
 
 
ECOG PS  
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs / 
Weight 
 
X 
 
X 
 
 
 
 
 
Xi  
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Pulse oximetry 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
Xj 
 
Xj 
 
 
 
 
 
X 
 
 
X  
X 
 
 
 
 
 
 
 
 
Echo / MUGA 
 
Xa,k   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray  
(if indicated) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry  
X 
 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation testsl  
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy testm 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisl 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious 
Disease screenn 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV PCRo 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
 
 
 
Thyroid Function 
Testsl 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
  X  then Q6wks (Arm 2 only) 
 
 
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Screeninga 
Phase 
/  
Eligibility 
Phase 
Treatment Phase 
DC of 
Pem-
broli-
zumab 
Txc 
Comple- 
tion of 
Treatment 
Phase or 
WDd 
Leukapheresis 
Baseline 
≤7 days 
prior to 
chemo 
Lymphodepleting 
Chemotherapyb 
T-cell 
infu-
sion 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
Scrn Elig 
 
D -14 to 
 D -8 
D -
8 
D-7 
D -
6 
D -
5 
D -
4 
D 1 
D2 D3 D4 D5 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
6 
Wk 
15 
Wk 24 
& 
Q12wks  
 
Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1D ±1D ±1D ±3D ±3D ±3D ±7D 
 
 
C-Reactive 
Proteinp 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X  
 
X 
 
X 
 
 
 
 
Uric acid 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
GFR or 24h urine 
creatinineq 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Eventsr 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
Vector Copies 
(Persistence for 
safety)s 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Xs 
 
 
VSV-G DNA 
(RCL) for safetys 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Xs 
 
 
Leukapheresis, Lymphodepleting Chemotherapy 
Leukapheresist 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophospha-
mide 
 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
G-CSFu 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screeninga 
Phase 
/  
Eligibility 
Phase 
Treatment Phase 
DC of 
Pem-
broli-
zumab 
Txc 
Comple- 
tion of 
Treatment 
Phase or 
WDd 
Leukapheresis 
Baseline 
≤7 days 
prior to 
chemo 
Lymphodepleting 
Chemotherapyb 
T-cell 
infu-
sion 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
Scrn Elig 
 
D -14 to 
 D -8 
D -
8 
D-7 
D -
6 
D -
5 
D -
4 
D 1 
D2 D3 D4 D5 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
6 
Wk 
15 
Wk 24 
& 
Q12wks  
 
Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1D ±1D ±1D ±3D ±3D ±3D ±7D 
 
 
Administration of Investigational Products  
NY-ESO-1c259T  
infusion 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab  
(Arm 2 only)v  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  X  then Q3wks up to Wk108  
 
Multiple Myeloma Disease assessments  
Myeloma markers 
(labs)w 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 X then Q3wks until Wk24,                                     X 
Q6wks until Wk72, Q12wks thereafter until PD 
Bone marrow 
sampley, z 
 
Xx 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Bone surveyaa 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Research assessments 
Pharmaco-
genetic - Whole 
Blood Sample 
 
 
 
Xab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screeninga 
Phase 
/  
Eligibility 
Phase 
Treatment Phase 
DC of 
Pem-
broli-
zumab 
Txc 
Comple- 
tion of 
Treatment 
Phase or 
WDd 
Leukapheresis 
Baseline 
≤7 days 
prior to 
chemo 
Lymphodepleting 
Chemotherapyb 
T-cell 
infu-
sion 
 
 
 
 
 
 
 
 
 
 
 
Study Day 
Scrn Elig 
 
D -14 to 
 D -8 
D -
8 
D-7 
D -
6 
D -
5 
D -
4 
D 1 
D2 D3 D4 D5 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
6 
Wk 
15 
Wk 24 
& 
Q12wks  
 
Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
±1D ±1D ±1D ±3D ±3D ±3D ±7D 
 
 
Bone marrow 
(bone marrow 
mononuclear 
cells)ac 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
Cell pheno-typing 
& Functional 
assays - PBMC 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X X 
X 
X X 
X 
X 
X 
X 
X 
Vector Copies 
(Persistence for 
Research)  
 
 
 
X 
 
 
 
 
 
 
 
 
 
X X 
X 
X X 
X 
 
 
 
X 
Cytokine 
analyses & Anti-
TCR antibodiesp 
 
 
 
X 
 
 
 
 
 
Xp 
 
X  
X X 
X 
X X 
Xp 
X 
Xp 
X 
X 
cfDNA and 
exosomes 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
BM = bone marrow; CBC = complete blood count; CMV = cytomegalovirus; CRP = C-reactive protein; DC = discontinuation; DNA = deoxyribonucleic acid; ECHO 
= echocardiogram; ECOG = Eastern Cooperative Oncology Group; Elig = Eligibility; G-CSF = granulocyte-colony stimulating factor; HBV = hepatitis B virus; HCV 
= hepatitis C virus;HLA = human leukocyte antigen; HTLV = human T-lymphotropic virus; IMWG = International Myeloma Working Group; MRI = magnetic 
resonance imaging; MUGA = multiple-gated acquisition scan; PBMC = peripheral blood mononuclear cell; PET = positron emission tomography; PS = Performance 
Status; RCL = replication competent lentivirus; Scrn = Screening; Tx = treatment; VSV-G = vesicular stomatitis virus envelope glycoprotein; WD = study 
withdrawal. 
a. Written participant informed consent (and participant assent as applicable) must be obtained prior to performing any protocol procedures.  An initial Screening 
informed consent will have been signed prior to obtaining a blood sample for HLA-testing and bone marrow aspirate for antigen testing. The Treatment informed 
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consent will be signed prior to all other screening procedures. Note: Information regarding ECHO/MUGA scans, and bone surveys which were performed as standard 
of care assessments within 4 weeks prior to study consent will be acceptable. Laboratory test performed as standard of care and prior to study consent but within 10 
days for leukapheresis will be accepted. 
b. Lymphodepleting chemotherapy may only be initiated after the manufactured NY-ESO-1c259T-cell product has been received at the site and the bag(s) have passed 
inspection by site personnel (see further details in study procedures manual [SPM]).   
c. Only for participants enrolled on Arm 2: if participant discontinues from pembrolizumab treatment prior to relapse/progression, this treatment discontinuation visit 
must be performed including all indicated procedures and assessments listed, unless already recently performed within 30 days.  Participant will be maintained in the 
interventional protocol until disease progression, following the same schedule for safety and disease assessment as Arm 1, and will be transferred to the LTFU 
protocol ADP-0000-002 as soon as they meet conditions defined under Protocol Section 4.4..  
d. If participant withdraws from the treatment phase prior to disease progression, a completion/withdrawal visit must be performed including all procedures and 
assessments listed indicated, unless already recently performed within 30 days.  All participants will be transferred to the LTFU protocol ADP-0000-002 upon 
completion/withdrawal from treatment phase as soon as they meet conditions defined under Protocol Section 4.4. . 
e. Baseline characteristics include recording time from initial diagnosis and time from last therapy. 
f. Includes prior lines of therapy. 
g. Physical Exam (PE) will only be collected at screening and baseline and every 6 months – any abnormal findings outside these time points will be reported as an 
AE. 
h. Includes concomitant medication since last visit.  
i. Vital signs (temperature, pulse, respirations and blood pressure) on the day of T-cell infusion should be taken pre-infusion; and at 5, 15 and 30 minutes, and 1, 1.5, 
2, and 4 hours after infusion has started. 
j. Cardiac stress test is performed for participants who are 55 years of age or over (specificity of the test will be at Investigator’s discretion). 
k. MUGA and/or ECHO are required at screening. May also be performed post-lymphodepleting chemotherapy if clinically indicated at the discretion of the 
Investigator. 
l. Additional tests may be performed at any time if clinically indicated. 
m. Pregnancy test for Female Participant of Reproductive Potential (FSRP) only. 
n. Testing for infectious disease markers is required only at screening and does not need to be repeated at Baseline to satisfy the inclusion / exclusion criteria.  
Participants who are hepatitis B surface antigen negative but are hepatitis B core antibody positive must have undetectable hepatitis B DNA. Participants who are 
HCV antibody positive will be screened for HCV RNA by any RT-PCR or bDNA assay. 
o. CMV seropositive participants will continue to be monitored at least every 3 weeks for CMV viremia by CMV DNA PCR until 9 weeks post T-cell infusion 
(Protocol Section 8.2.3)  
p. Sample for Cytokine levels at Day 1 will be collected pre-infusion. If cytokine release syndrome (CRS) is suspected, cytokine levels as well C-reactive protein 
levels should be measured approximately every other day until symptoms are improving or an alternative diagnosis is confirmed. Anti-TCR antibodies will be 
assessed from the same collection as for Cytokines but only at Baseline, Week 6 and Week 24. 
q. Only for participants ≥65 years of age. 
r. Refer to Protocol Section 9.1 for instructions and details of AE collection and periods. 
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s. Vector Copies (Persistence) and VSV-G DNA (RCL) are Central Labs. Vector copies for safety samples are collected Day1 (pre-infusion) and at Week 15, Week 
24, and Week 48 post T-cell infusion, then every 6 months post T-cell infusion from year 2-5, and annually from year 6-15.  RCL samples are collected Day1 (pre-
infusion), and at Week 15, Week 24, and Week 48 post T-cell infusion, and then annually. 
t. Testing of participant leukapheresis will meet regional legislative requirements. In the EU this may include screening for Treponema pallidum (syphilis), details 
will be defined in the SPM. 
u. G-CSF will be given from 24 hours after the last dose of cyclophosphamide until resolution of neutropenia in accordance with American Society of Clinical 
Oncology (ASCO) guidelines or institutional practice. Long-acting (pegylated) G-CSF may be substituted according to institutional practice as described in Protocol 
Section 8.8.1. 
v. Participants in Arm 2 will receive 200 mg pembrolizumab IV for the first time on Week 3 Subsequent doses will be administered every 3 weeks thereafter up to 
Week 108. Schedule adjustments are outlined in the protocol (Protocol Section 5.4.1). 
w. SPEP + immunofixation; quantitative IgG, IgM, IgA; UPEP + immunofixation based on 24 hour urine collection; serum free κ and λ light chain levels and κ/λ 
ratio determination; beta-2-microgobulin. 
x. The BM sample is optional for eligibility if participant had prior histological confirmation of the disease.  
y. Bone marrow (BM) sampling should be preferably an aspirate over a fresh biopsy; aspirates are required at Screening, Baseline, as well as for MRD analysis.  
z. BM samples will be obtained at baseline, at Week 15 and at Disease Progression (before starting a new treatment) per standard of care and at the time of a complete 
response assessment (per IMWG response criteria, see Protocol Section 16.4). If the participant received systemic anticancer therapy between leukapheresis and 
lymphodepleting chemotherapy for disease control, then the timing of the BM sample at baseline is critical and must respect the wash-out periods of Exclusion 
criterion #3 (Protocol Section 4.2). A BM sample will also be collected at Week 6. A BM sampling at Week 24 is strongly recommended but not mandatory (per PI’s 
discretion). A BM sampling should also be analyzed at the time of a complete response (CR) assessment as per IMWG criteria (see Protocol Section 16.4), in order to 
confirm CR. Additional BM samples for research purposes semi-annually (optional) or whenever follow-up marrow collection may be performed at PI’s discretion.  
The BM sample obtained at the time point believed to be the closest to maximum response will be analyzed for Minimal Residual Disease (MRD). Refer to Protocol 
Section 7.5.3 for further specific details. 
aa. MRI and PET scan if clinically indicated. 
ab. If pharmacogenetics sample collection is not done at baseline, it may be done at any other subsequent visit while the participant is in the treatment phase of the 
study. Collection of pharmacogenetics sample is optional and all participants who participate must provide consent for pharmacogenetics blood sample collection. 
ac. Will be conducted every time a BM sample is obtained. Research includes tumor antigen, gene marked T-cells, T-cell clones and cytokines. Cytogenetics should 
be performed at least at baseline and at relapse. 
 
 
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14.2.2. 
Schedule of Procedures in Long-Term Follow-up prior to Transfer to LTFU Protocol 
Time post-infusion 
  
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Years 6-15 
Months 3 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
Annually  
Visit window ± 2 weeks 
± 3 months 
± 6 months 
Safety Assessments 
Medical History and Physical Exam1  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mutagenic agents, other investigational agents or anti-
cancer therapies1  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events2  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X3 
Serum chemistry 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X3 
Central Lab 
 
 
 
 
 
 
 
 
 
 
 
 
VSV-G DNA (RCL) for safety4  
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
Vector Copies (Persistence) for safety5  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X3 
Other Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
Overall Survival 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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1. New medical history/medications/chemotherapies 
2. Adverse event collection is limited to: 
• 
New malignancies 
• 
New incidence or exacerbation of a pre-existing neurologic disorder 
• 
New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder 
• 
New incidence of a hematologic disorder 
• 
Opportunistic and or serious infections 
• 
Unanticipated illness and/or hospitalization deemed related to gene modified cell therapy 
3. In year 6-15, laboratory assessments are performed for as long as persistence is analyzed.  If persistence samples are discontinued (Protocol Section 10.3.1 
and Section 10.3.2) then laboratory assessments are discontinued.  
4. Samples for RCL (VSV-G copies) are collected as described in Protocol Section 10.1.1. 
5. Samples for persistence are collected as described in Protocol Section 10.1.3.1  and Section 10.1.3.2 
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14.3. 
Appendix 3: Assessment Windows 
14.3.1. 
Definitions of Assessment Windows for Analyses 
No assessment windows will be applied. 
 
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14.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
14.4.1. 
Study Phase 
14.4.1.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
End date of medication is not missing and is before the start date of 
lymphodepletion OR lymphodepletion chemotherapy start date is missing 
Concomitant 
Any medication that is not a prior 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
14.4.1.2. Study Phases for Anti-Cancer Therapy/Surgery 
Study Phase 
Definition 
On-Study 
Start date is on or after the first day of lymphodepletion chemotherapy  
(both start date and lymphodepletion chemotherapy start date not missing). 
Prior 
Not classified as On-Study. 
NOTES:  
• 
Please refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
anti-cancer therapy 
The prior phase will be further subdivided as follows: 
Study Phase 
Definition 
Prior to leukapheresis 
If classified as prior and entered on the screening visit 2 eCRF 
Leukapheresis to 
lymphodepletion 
If classified as prior and not entered on the screening visit 2 eCRF. 
NOTES:  
• 
Please refer to Appendix 7 for handling of missing and partial dates for anti-cancer therapy 
 
14.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
• 
If AE onset date is on or after lymphodepletion chemotherapy start date. 
(Lymphodepletion Start Date ≤ AE Start Date) 
• 
If AE onset date is missing and AE end date is before the lymphodepletion 
start date, then the AE will not be classified as Treatment-Emergent. If AE 
onset date is missing and AE end date is either missing or on or after 
lymphodepletion start date, then the AE will be classified as treatment-
emergent  
• 
Partially missing AE onset and end dates will be imputed following rules in 
Section 14.7.2.1 for determining Treatment Emergent AEs 
 
 
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14.5. 
Appendix 5: Data Display Standards & Handling 
Conventions 
14.5.1. 
Reporting Process 
Software 
• 
The currently supported versions of SAS software will be used. 
Reporting Area 
HARP Server 
: US1SALX00259  
HARP Compound 
: arprod\GSK3377794\mid208470 
Analysis Datasets  
• 
Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1). 
Generation of RTF Files 
• 
RTF files will be generated for SAC. 
14.5.2. 
Reporting Standards 
General 
• 
The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx): 
• 
4.03 to 4.23: General Principles 
• 
5.01 to 5.08: Principles Related to Data Listings 
• 
6.01 to 6.11: Principles Related to Summary Tables 
• 
7.01 to 7.13: Principles Related to Graphics  
• 
Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH or non-ICH listings 
• 
While text within this RAP uses the term “participant”, all data displays (Tables, Figures, and 
Listings) will use the term “subject”, reflecting CDISC and GSK Data Display Standards terminology. 
Formats 
• 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected, unless otherwise stated. 
• 
Numeric data will be reported at the precision collected on the eCRF. 
• 
The reported precision from non eCRF sources will follow the IDSL statistical principles but may be 
adjusted to a clinically interpretable number of DP’s.  
Planned and Actual Time 
• 
Reporting for tables, figures and formal statistical analyses: 
• 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
• 
The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate. 
• 
Reporting for Data Listings:  
• 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
• 
Unscheduled or unplanned readings will be presented within the participant’s listings.  
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Unscheduled Visits 
• 
Unscheduled visits will not be included in summary tables and/or figures, except in cases where 
worse-case post-baseline is calculation. 
• 
All unscheduled visits will be included in listings. 
Descriptive Summary Statistics 
Continuous Data 
Refer to IDSL Statistical Principle 6.06.1 
Categorical Data 
N, n, frequency, % 
Graphical Displays 
• 
Refer to IDSL Statistical Principals 7.01 to 7.13. 
 
14.5.3. 
Reporting Standards for Pharmacokinetic Data 
Pharmacokinetic Concentration Data 
PC Windows Non-
Linear (WNL) File 
All PK parameters will be derived by the PK programmer. No WNL file will be 
produced. 
ADPC data file  
Persistence data will be captured in ADBIOMRK, and derived persistence 
parameters will be captured as additional PARAMCD values in ADBIOMRK. No 
ADPC data file will be created. 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Example shells for persistence are provided in Appendix 13. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per rules in the RAP. 
Pharmacokinetic Parameter Derivation 
PK Parameters to be 
Derived by PK 
Programmer 
The following PK parameters will be derived by the PK Programmer: Cmax, 
Tmax, and AUC(0-28). 
Pharmacokinetic Parameter Data 
Is NQ impacted PK 
Parameters Rule 
Being Followed 
No. 
 
 
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14.6. 
Appendix 6: Derived and Transformed Data 
14.6.1. 
General 
Multiple Measurements at One Analysis Time Point 
• 
Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented. 
• 
For character variables, if multiple assessments on different days are reported for the same 
scheduled assessment, then the worst-case assessment for that scheduled assessment will be 
analysed. 
• 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables. 
Study Day 
• 
Calculated as the number of days from T-cell infusion date: 
• 
Ref Date = Missing              → Study Day = Missing  
• 
Ref Date < T-cell infusion Date → Study Day = Ref Date – T-cell infusion Date 
• 
Ref Date ≥ T-cell infusion Date→ Study Day = (Ref Date – T-cell infusion Date) + 1     
Change from Baseline 
• 
Change from Baseline = Post-Baseline Visit Value – Baseline 
• 
% Change from Baseline = 100 x (Post-Baseline Visit Value – Baseline) / Baseline 
• 
Maximum Increase/Decrease from Baseline = maximum (Increase/Decrease from Baseline) 
• 
If either the Baseline or Post-Baseline Visit Value is missing, then both Change from Baseline and % 
Change from Baseline are set to missing 
Date of New on Study Anti-Cancer Therapy 
• 
Derived as the earliest date of new systemic anti-cancer therapy  
• 
Missing or partial dates will be imputed for derivation of new anti-cancer therapy following rules 
specified in Section 14.7.2.1. 
 
14.6.2. 
Study Population 
Age 
• 
For participants with a T-cell infusion date, age is derived using T-cell infusion date as the reference 
date. For ITT participants without a T-cell Infusion date, date of eligibility for apheresis is used as the 
reference date. 
Body Mass Index (BMI) 
• 
Calculated as Weight (kg) / [Height (m)2] 
Time since Initial Diagnosis to Screening ICF signed 
• 
Time (in months) since initial diagnosis to screening will be calculated below: 
• 
Months since initial diagnosis = (Date of Screening Visit (Screening ICF Signed) - Date of Initial 
diagnosis +1) / 30.4375  
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On-study Treatment Follow-up Time 
• 
Time (in months) from T-cell infusion to end of follow-up will be calculated below: 
• 
Months of on-study treatment follow-up = (Date of Death/Last Contact – T-cell Infusion Date+1) / 
30.4375 
Extent of Exposure (Pembrolizumab) 
• 
Number of days of exposure to Pembrolizumab will be calculated based on the formula:   
Duration on study treatment is calculated as the minimum of:  
• 
Last treatment stop date – first treatment start date + 21  
• 
Date of death – first treatment start date + 1 
• 
Participants who did not report a Pembrolizumab start date will be categorised as having zero days 
of exposure.  
• 
The cumulative actual dose in mg for Pembrolizumab will be based on the formula: 
Cumulative Dose (mg) = Sum of (200 mg * % of bag infused at each visit) 
• 
Dose intensity (mg/per 3 weeks) for Pembrolizumab is the cumulative actual dose divided by 
expected duration of exposure in 3 weeks (expected = (last infusion date – first infusion date + 
21)/21) 
14.6.3. 
Safety  
Adverse Events 
Adverse Events of Special Interest (AESIs) 
The events of special interest included from protocol Section 9.13 (Adverse Events of Special Interest). 
This section includes the following events: 
• 
Guillain-Barre Syndrome 
• 
Recurrent Pancytopenia/Aplastic Anaemia 
• 
Immune Effector-Cell Associated Neurotoxicity Syndrome (ICANS) 
• 
Graft versus Host Disease (GVHD) 
• 
Cytokine Release Syndrome (CRS) 
Duration of AE 
• 
Calculated as the number of days from AE Start Date to AE Stop Date: 
o AE Start Date = Missing              → Elapse Time = Missing  
o AE Stop Date = Missing              → Elapse Time = Missing 
Otherwise                                    → Elapsed Time = AE Stop Date – AE Start Date + 1     
Imputed dates will not be used to calculate AE duration. 
 
Laboratory Parameters 
• 
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a 
character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the comment 
field) is present, the following rules will be applied to impute numeric values:  
o If the reported value is “NOT DETECTED” (or some other indicator of such), then impute to 0 
(zero). 
o If the reported value is “OLIGOCLONAL POP” (or some other indicator of such), then no 
imputation of a numeric value will be applied. 
o If the reported value is “TRACE” (or some other indicator of such), then no imputation of a 
numeric value will be applied.    
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14.6.4. 
Efficacy 
Refer to Section 7 for endpoint derivation information. 
Secondary Endpoints 
Date of Last Contact 
• 
Last date in all SDTM domains 
• 
If patient died, the last contact date should be death date. 
• 
Dates after date of death will be excluded. Future dates will be excluded. 
• 
SDTM domain SE will be excluded and SDTM variables DM.BRTHDTC, MH.MHSTDTC, 
SV.SVENDTC, SV.SVSTDTC,  DM.RFPENDTC,  _ALL_.ANALDTC, DV.DVDTC, DV.DVSTDTC, 
and any other external source data dates as necessary will be excluded 
• 
Partial and missing dates will not be imputed for the purpose of deriving date of last contact 
 
 
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14.7. 
Appendix 7: Reporting Standards for Missing Data 
14.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
• 
A participant will be considered to have completed the treatment phase (as specified 
in the protocol) at the earliest point of confirmed progressive disease, 108 weeks 
following NY-ESO-1c259T-cell infusion, or death.  
• 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
14.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
• 
Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument: 
o 
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table.  
o 
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
• 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
Responder 
Analysis 
• 
For endpoints which determine the percentage of responders, participants with 
unknown/not evaluable or missing best overall response will be assumed to be non-
responders and will be included in the denominator when calculating the 
percentages. 
14.7.2.1. 
Handling of Missing and Partial Dates 
Imputed partial dates can be used to derive study day, duration, or elapsed time variables, 
unless otherwise specified. However, imputed dates are not used for deriving the last 
contact date in the overall survival analysis dataset. 
Imputed dates will not be displayed in listings. For listings, use the SDTM character date 
variables and do not show day and duration based on imputed dates. The imputed dates 
can be used for sorting the data for listings. In addition, partial dates may be imputed for 
‘slotting’ data to study phases or for specific analysis purposes, as outlined below.  
The partial date imputation will follow ADaM conventions. The ADaM approach is to 
populate the numeric date variables with the imputed date and add a flag variable to the 
dataset that indicates the level of imputation.  
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The flag variable can contain the values: blank, 'D', 'M', 'Y'.  
blank: indicates that no imputation was done 
D='Day': indicates that the day portion of the date is imputed 
M='Month': indicates that the month and day portions of the date are imputed 
Y='Year': indicates that the entire date (year, month, and day) is imputed 
Example of date variables:  
XYZDTC_ - character date variable 
XYZDT - numeric date variable 
XYZDTFL - flag variable 
Details on imputing partial dates for specific datasets are outlined below. 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays. 
Adverse 
Events 
• 
Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings. 
• 
Partial dates for AE recorded in the eCRF will be imputed using the following 
conventions: 
Missing start day 
• 
If lymphodepletion start date is missing (i.e. participant did not 
start lymphodepletion), then set start date = 1st of month. 
• 
Else if lymphodepletion start date is not missing: 
o 
If month and year of start date = month and year of 
lymphodepletion start date then 
▪ 
If stop date contains a full date and stop date is 
earlier than lymphodepletion start date then set start 
date= 1st of month. 
▪ 
Else set start date = lymphodepletion start date. 
o Else set start date = 1st of month. 
Missing start day 
and month 
• 
If lymphodepletion start date is missing (i.e. participant did not 
start lymphodepletion), then set start date = January 1st. 
• 
Else if lymphodepletion start date is not missing: 
o 
If year of start date = year of lymphodepletion start date 
then 
▪ 
If stop date contains a full date and stop date is 
earlier than lymphodepletion start date then set start 
date = January 1st. 
▪ 
Else set start date = lymphodepletion start date.       
o 
Else set start date = January 1st. 
Missing stop day  
Last day of the month will be used. 
Missing stop day 
and month 
No Imputation 
Completely missing 
start/end date 
No imputation 
Anti-Cancer 
Therapy 
(including 
• 
Completely missing start or end dates will remain missing, with no imputation 
applied. 
• 
If partial start date contains a year only set to January 1st. 
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Element 
Reporting Detail 
stem cell 
transplant) 
and 
Radiotherapy 
• 
If partial start date contains a month and year set to the 1st of the month. 
• 
Partial or missing end dates will not be imputed. 
Concomitant 
Medications/ 
Blood 
Supportive 
Products 
• 
These imputation rules will be used for classifying a medication as prior or 
concomitant. 
• 
Completely missing start dates will not be imputed.  
• 
Partial start dates for any concomitant medications recorded in the eCRF will be 
imputed using the following convention: 
Missing start day 
• 
If lymphodepletion start date is missing (i.e. participant did not 
start lymphodepletion), then set start date = 1st of month. 
• 
Else if lymphodepletion start date is not missing: 
o 
If month and year of start date = month and year of 
lymphodepletion start date then 
▪ 
If stop date contains a full date and stop date is earlier 
than lymphodepletion start date then set start date= 1st 
of month. 
▪ 
Else set start date = lymphodepletion start date. 
o 
Else set start date = 1st of month. 
Missing start day 
and month 
• 
If lymphodepletion start date is missing (i.e. participant did not 
start lymphodepletion), then set start date = January 1st. 
• 
Else if lymphodepletion start date is not missing: 
o 
If year of start date = year of lymphodepletion start date 
then 
▪ 
If stop date contains a full date and stop date is earlier 
than lymphodepletion start date then set start date = 
January 1st. 
▪ 
Else set start date = lymphodepletion start date.       
• 
Else set start date = January 1st. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the month 
and year)  
Missing end day and 
month 
A '31' will be used for the day and 'Dec' will be used for the month. 
Completely missing 
start/end date 
No imputation 
New Anti-
Cancer 
Therapy/ 
Stem cell 
transplants 
for Efficacy 
Evaluation 
(e.g., 
response 
rate, time to 
event) 
• 
Completely missing start dates will remain missing, with no imputation applied; 
• 
Partial start dates will be imputed using the following convention: 
• 
If both month and day are missing, no imputation will be applied; 
• 
If only day is missing:  
o If the month of partial date is the same as the month of T-cell infusion, 
minimum of (date of T-cell infusion date + 1, last day of the month) will be 
used for the day; 
o If the month of partial date is the same as the month of last disease 
assessment and the last disease assessment is PD, minimum of (last date 
of disease assessment + 1, last day of the month) will be used for the day; 
o If both conditions above are met, the later date will be used for the day; 
o Otherwise, a ‘01’ will be used for the day; 
• 
Completely or partial missing end dates will remain missing, with no imputation 
applied; 
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14.8. 
Appendix 8: Values of Potential Clinical Importance 
14.8.1. 
Laboratory Values 
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). Note: a high abnormal 
or low abnormal laboratory value is not necessarily of clinical concern. The laboratory 
reference ranges will be provided on the listings of laboratory data. Clinical laboratory 
test results outside of the reference range will be flagged in the listings. 
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.03) will be used to 
assign grades to the relevant laboratory parameters. NCI-CTCAE v4.03 can be found at 
http://ctep.cancer.gov/reporting/ctc.html.  
For laboratory data which are not listed in the NCI CTCAE v4.03, a summary of values 
outside the normal range will be provided. 
For lab test values that can be graded, values of grade 1 or above are defined as values of 
potential clinical concern. For lab test values that cannot be graded, values out of the 
normal range are defined as values of potential clinical concern. For lab tests reported 
descriptively as ‘Normal’, ‘Abnormal, not clinically significant’, or ‘Abnormal, clinically 
significant’ (such as urinalysis), responses of ‘Abnormal, clinically significant’ will be 
considered as of potential clinical concern. 
14.8.2. 
ECG 
The following criteria will be used to flag electrocardiogram (ECG) values that are values 
of potential clinical importance:  
To identify QTc (Bazett’s or Fridericia’s) values of potential clinical importance, NCI-
CTCAE v4.03 will be used to assign grades (see adverse event ‘Electrocardiogram QT 
corrected interval prolonged’). The eCRF collects either QTcB or QTcF. Note that there 
is a slight inconsistency between CTCAE v4 and ICH E14 (Absolute QTc interval 
prolongation). It was decided to align with CTCAE for the oncology standard categories. 
The following criteria will be used to flag other ECG values that are values of potential 
clinical importance: 
PCI Flag 
Potential Clinical Importance (PCI) Range 
Unit 
High (H) 
Grade 2 or Higher (QTc≥481)  
or  
QTc increase from baseline of >30msec 
Msec 
  
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14.8.3. 
Vital Signs 
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.03 will be 
used to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus 
tachycardia’, ‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’. 
The following criteria will be used to flag vital sign values that are values of potential 
clinical importance: 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Decrease from baseline 
Heart Rate 
Decrease to <60 
bpm 
Increase from baseline Heart 
Rate 
Increase to >100 
bpm 
 
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.03 
will be used to assign categories that align with the grades for ‘Hypertension’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Increase from baseline 
Systolic Blood Pressure 
120 to <140 (Grade 1) 
140 to <160 (Grade 2) 
160 (Grade 3) 
mmHg 
Increase from baseline 
Diastolic Blood Pressure 
80 to <90 (Grade 1) 
90 to <100 (Grade 2) 
100 (Grade 3) 
mmHg 
 
To identify temperature values of potential clinical importance, NCI-CTCAE v4.03 will 
be used to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Increase from baseline 
temperature 
Increase to 38 
Degrees C 
Decrease from baseline 
temperature 
Decrease to 35 
Degrees C 
 
To identify respiratory rate of potential clinical importance, NCI-CTCAE v4.03 will be 
used to assign categories that align with the grades for ‘Respiratory’. 
Vital Sign Parameter 
Potential Clinical Importance (PCI) Range 
Unit 
Increase from baseline 
respiratory rate 
Increase to >30 
Breaths/minute 
 
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14.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Not applicable. 
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14.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
Not applicable. 
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14.11. 
Appendix 11: Abbreviations & Trademarks 
14.11.1. 
Abbreviations 
Abbreviation 
Description 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMMC 
Bone Marrow Mononuclear Cells 
BOR 
Best Overall Response 
CDISC 
Clinical Data Interchange Standards Consortium 
Cmax 
Peak Expansion 
CMV 
Cytomegalovirus  
CPMS 
Clinical Pharmacology Modelling & Simulation 
CR 
Complete Response 
CRP 
C-reactive Protein  
CRS 
Cytokine Release Syndrome  
CSR 
Clinical Study Report 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid  
DBF 
Database Freeze  
DBR 
Database Release  
DoR 
Duration of Response 
DP 
Decimal Places 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Record Form 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Clinical Results Disclosure Requirements 
FLC 
Free Light Chain  
GBS 
Guillain-Barre Syndrome 
G-CSF 
Granulocyte-Colony Stimulating Factor 
GSK 
GlaxoSmithKline 
GvHD 
Graft versus Host Disease  
HLA 
Human Leukocyte Antigen 
IA 
Interim Analysis 
ICANS 
Immune Effector-Cell Associated Neurotoxicity Syndrome 
ICH 
International Conference on Harmonization 
IDSL 
Integrated Data Standards Library 
IMWG 
International Myeloma Working Group 
IP 
Investigational Product 
ITT 
Intent-To-Treat 
LFT 
Liver Function Test 
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Abbreviation 
Description 
LTFU 
Long-Term Follow-Up 
mITT 
Modified Intent-To-Treat 
MR 
Minimal Response 
MRD 
Minimal Residual Disease 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PCI 
Potential Clinical Importance  
PCR 
Polymerase Chain Reaction  
PD 
Progression Disease 
PFS 
Progression-free Survival 
PP 
Predictive Probability  
PR 
Partial Response 
PT 
Preferred Term 
QC 
Quality Control 
QTcF 
Frederica’s QT Interval Corrected for Heart Rate 
QTcB 
Bazett’s QT Interval Corrected for Heart Rate 
RAP 
Reporting & Analysis Plan 
RCL 
Replication Competent Lentivirus  
RRMM 
Relapsed Refractory Multiple Myeloma 
SAC 
Statistical Analysis Complete 
SAE 
Serious Adverse Event 
sCR 
Stringent Complete Response 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
SRT 
Safety Review Team  
TFL 
Tables, Figures & Listings  
TLT 
Treatment Limiting Toxicity 
Tmax 
Time to Peak Expansion 
TTR 
Time to Response  
ULN 
Upper Limit of Normal 
VGPR 
Very Good Partial Response 
14.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
KEYTRUDA 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 
 
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14.12. 
Appendix 12: List of Data Displays 
14.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.0010 to 1.0220 
NA 
Efficacy 
2.0010 to 2.0020 
2.0030 to 2.0070 
Safety 
3.0010 to 3.0620 
3.0630 to 3.0680 
Biomarker 
3.0690 to 3.0690 
NA 
Pharmacokinetic 
4.0010 to 4.0020 
4.0030 to 4.0050 
Section 
Listings 
ICH Listings 
0010 to 0430 
Other Listings 
0440 to 0520 
 
14.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays. 
Section 
Figure 
Table 
Listing 
Study Population 
POP_Fn 
POP_Tn 
POP_Ln 
Efficacy 
EFF_Fn 
EFF_Tn 
EFF_Ln 
Safety 
SAFE_Fn 
SAFE_Tn 
SAFE_Ln 
Biomarker 
BIO_Fn 
BIO_Tn 
BIO_Ln 
Pharmacokinetic 
PK_Fn 
PK_Tn 
PK_Ln 
NOTES:  
• 
Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
14.12.3. 
Deliverables 
Delivery  
Description 
SAC  
Final Statistical Analysis Complete 
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14.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Subject Disposition 
1.0010 
mITT 
[Non-Standard] 
POP_T2 
Summary of Subject Status – Treatment Phase (mITT) 
ICH E3, FDAAA, EudraCT  
Subject Status: Completed, Ongoing, 
Did not complete.  
Use reasons on the EOT CRF (reason 
for early discontinuation) for withdrawal, 
prepopulate all of them in the display. 
Note that progressive disease, death, 
and not progressed at 108 weeks are 
the only reasons for completion of the 
treatment phase. 
Not aligned w/study 208469 (MRCLS). 
SAC 
1.0020 
mITT 
[Non-Standard] 
POP_T3 
Summary of Subject Status – End of Study (mITT) 
ICH E3, FDAAA, EudraCT  
Use logic provided in RAP text to derive 
end-of-study status. 
Subject Status: Completed, Ongoing, 
Withdrawn 
Reason for withdrawal comes from 
treatment phase table above. 
Not aligned w/study 208469 (MRCLS). 
SAC 
1.0030 
Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
Journal Requirements 
Align w/study 208469 (MRCLS). 
SAC 
1.0040 
ITT 
SD4 
Summary of Reasons for Study Treatment Discontinuation 
(Pembrolizumab) 
Only include participants from Arm 2. 
Reasons for discontinuation should 
match the Pembrolizumab disposition 
eCRF in content and order 
Not aligned w/ 208469 (MRCLS) 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.0050 
Enrolled 
NS1 
Summary of Number of Subjects by Country and Site ID 
EudraCT/Clinical Operations 
Align w/study 208469 (MRCLS). 
SAC 
Population Analysed 
1.0060 
Screened 
SP1A 
Summary of Study Populations  
IDSL 
Screened, Enrolled, ITT, mITT only. 
Align w/study 208469 (MRCLS). 
SAC 
Protocol Deviations 
1.0070 
ITT 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
Align w/study 208469 (MRCLS). 
SAC 
Demographic and Baseline Characteristics 
1.0080 
mITT 
DM1 
Summary of Demographic Characteristics (mITT) 
ICH E3, FDAAA, EudraCT 
Report baseline height, weight, BMI, 
and BSA. 
Report Race but not Race Detail. 
Age groups to be presented: <=18, 19-
64, and >=65 years. 
Align w/study 208469 (MRCLS). 
SAC 
1.0090 
Enrolled 
DM11 
Summary of Age Ranges 
EudraCT 
Age groups to be presented: 18-64, 65-
84 and >=85 years. 
Align w/study 208469 (MRCLS). 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Disease Characteristics 
1.0100 
mITT 
DC1 
Summary of Disease Characteristics at Initial Diagnosis (mITT) 
ICH E3 
Time from initial diagnosis to screening 
ICF signed (in months), stage at 
diagnosis, histologic type, % clonal 
bone marrow plasma cells, presence 
and type of end organ damage, 
presence and type of plasmacytoma, 
and chromosomal aberrations 
(previously referred to as karyotype). 
Not aligned w/study 208469 (MRCLS). 
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81 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.0110 
mITT 
DC2 
Summary of Disease Characteristics at Screening (mITT) 
ICH E3 
Type of multiple myeloma (IgA Kappa, 
IgA Lambda, IgG Kappa, etc.), HLA 
status (Allele 1 & Allele 2), NY-ESO-1 
status, LAGE-1a status, number of 
radiotherapy regimens prior to 
leukapheresis, number of systemic 
therapy regimens prior to 
leukapheresis, receipt of stem-cell 
transplant prior to leukapheresis (Y/N), 
bone lesion (Y/N), and subtype of stem-
cell transplant received (autologous or 
allogeneic). 
Break down “Number of Prior Systemic 
Therapy Regimens” into 
{0,1,2,3,4,5,6,>6}.  
Also, use the new derivation of lines of 
systemic therapy (i.e., count systemic 
therapy + conditioning chemo 
associated w/stem cell therapy) – 
please add a footnote that makes this 
clear. 
Not aligned w/study 208469 (MRCLS). 
SAC 
Medical Conditions and Concomitant Medications 
1.0120 
mITT 
MH4 
Summary of Medical Conditions (mITT) 
ICH E3  
Include both past and ongoing medical 
conditions at screening. 
Align w/study 208469 (MRCLS). 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.0130 
mITT 
CM8 
Summary of Concomitant Medications (mITT) 
ICH E3 
Use GSK Drug Coding Dictionary 
Align w/study 208469 (MRCLS). 
SAC 
1.0140 
mITT 
BP1A 
Summary of Blood Products on Treatment (mITT) 
Using the same rule as con meds, 
include only "concomitant blood 
products" in the display and provide a 
footnote that explains this clearly. 
Align w/study 208469 (MRCLS). 
SAC 
Anti-Cancer Therapy 
1.0150 
mITT 
AC1 
Summary of Prior Anti-Cancer Therapy (mITT) 
IDSL 
In addition to prior systemic and 
radiation therapies, please include prior 
stem cell therapy (by subtype: 
autologous or allogeneic) in this 
summary. 
Systemic therapy should include prior 
to leukapheresis + full line of therapy 
starting after leukapheresis, and 
radiotherapy and surgery should 
include prior to lymphodepletion. 
Add footnote: “Note: Includes all anti-
cancer therapy prior to lymphodepletion 
except bridging therapies.” 
With the exception of stem cell being 
included, this display should align 
w/study 208469 (MRCLS). 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.0160 
mITT 
FAC1 
Summary of On-Study Anti-Cancer Therapy (mITT) 
IDSL 
Add time from T-cell infusion to the first 
post-treatment anti-cancer therapy. 
In addition to systemic and radiation 
therapies, please include stem cell 
therapy (by subtype: autologous or 
allogeneic) in this summary. 
With the exception of stem cell being 
included, this display should align 
w/study 208469 (MRCLS). 
SAC 
1.0170 
mITT 
CM1 
Summary of Prior Dictionary Coded Anti-Cancer Therapy (mITT) 
IDSL 
Use GSK Drug Coding Dictionary 
Systemic therapy should include prior 
to leukapheresis + full line of therapy 
starting after leukapheresis, and 
radiotherapy should include prior to 
lymphodepletion. 
Note that while stem cell therapy is not 
included in this summary, conditioning 
chemotherapy for the stem cell therapy 
is included. 
Add footnote: “Note: Includes all anti-
cancer therapy prior to lymphodepletion 
except bridging therapies.” 
Add footnote: “Note: Stem cell therapy 
is not included in this summary.” 
Align w/study 208469 (MRCLS). 
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Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.0180 
mITT 
AC3 
Summary of Number of Prior Anti-Cancer Therapy Regimens 
(mITT) 
IDSL 
Summarize all prior systemic therapy 
and radiotherapy regimens prior to 
lymphodepletion. Do not split out by 
type of systemic regimen as multiple 
types could make up a regimen. 
Add footnote: “Note: Includes all anti-
cancer therapy prior to lymphodepletion 
except bridging therapies.” 
Not aligned w/study 208469 (MRCLS) 
SAC 
1.0190 
mITT 
CM1 
Summary of On-Study Dictionary Coded Anti-Cancer Therapy 
(mITT) 
IDSL 
Use GSK Drug Coding Dictionary 
Note that while stem cell therapy is not 
included in this summary, conditioning 
chemotherapy for the stem cell therapy 
should be included. 
Add footnote: “Note: Stem cell therapy 
is not included in this summary.” 
Align w/study 208469 (MRCLS). 
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85 
 
Study Population Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
1.0200 
mITT 
CM1 
Summary of Bridging Therapy (mITT) 
IDSL 
Summarize all prior therapies identified 
as bridging. 
In addition to systemic and radiation 
therapies, please include prior stem cell 
therapy in this summary. 
With the exception of stem cell being 
included, this display should align 
w/study 208469 (MRCLS). 
Add footnote: “Note: Includes all anti-
cancer therapy initiated between 
leukapheresis and lymphodepletion 
identified as bridging.” 
 
SAC 
Exposure 
1.0210 
mITT 
OEX1 
Summary of Total Infused Transduced T-cells 
Report total number of infused 
transduced T-cells in 10^9 cells and 
categorize it into: 
<1, >=1 to <=8, >8 and  
<1, >=1 to <=3, >3 to <=8, >8 
Align w/study 208469 (MRCLS). 
SAC 
1.0220 
mITT 
[Non-Standard] 
POP_T1 
Summary of Leukapheresis, Lymphodepletion, T-cell Infusion, 
and Pembrolizumab Administration 
Add number of subjects infused with 
minimum dose of 1 x 10^9 transduced 
cells (i.e., in addition to the total number 
who underwent infusion). 
Please add a line for Pembro. 
Not aligned w/study 208469 (MRCLS). 
SAC 
 
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14.12.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Overall Response Rate (ORR) 
2.0010 
mITT 
RE1a 
Summary of Investigator-Assessed Best Response with 
Confirmation (IMWG 2016) (mITT) 
Add Total column.  
Add Overall Response (sCR + CR + 
VGPR + PR) and include 95% CI for 
Overall Response Rate. 
Omit all hypothesis testing sections. 
Not aligned w/study 208469 (MRCLS). 
SAC 
Time to Event 
2.0020 
mITT 
TTE1 
Summary of Investigator-Assessed Progression Free Survival 
(IMWG 2016) 
Unit = months. 
Include a Total column. 
Only create if at least 3 subjects in the 
study 
Omit all hypothesis testing sections i.e., 
Hazard Ratio estimate and 95%CI 
(marked as optional in IDSL shell). 
Include footnote: “Note: Progression 
Free Survival is defined as the interval 
between the date of T-cell infusion and 
the date of confirmed progressive 
disease or death per IMWG 2016.” 
Align w/study 208469 (MRCLS). 
SAC 
 
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14.12.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Responses by Myeloma Biomarkers 
2.0030 
mITT  
[Non-Standard] 
EFF_F1 
Percent Change at Maximum Reduction from Baseline in M-
Protein or Serum Free Light Chain (FLC) Measurement 
Waterfall plot. 
Use Serum M-protein, Urine-M-protein 
(if no Serum M-protein) and difference 
between 2 types of Serum FLC (if 
Serum M-protein and Urine M-protein 
not available), as relevant per subject. 
Do not report separately by arm; 
rather, include all subjects on the same 
plot. 
Color the bars by "Type of Myeloma 
Marker" and "Treatment Arm". 
Example: Arm 1 Serum M prot='Solid 
Blue', Arm 2 Serum M prot='Striped 
Blue'.  
Not aligned w/study 208469 (MRCLS). 
SAC 
2.0040 
mITT 
[Non-Standard] 
EFF_F2 
Spider Plot of Percent Change from Baseline in Myeloma 
Biomarkers by Subject 
Create a separate plot for each 
subject, showing on each plot: Serum 
M-protein, Urine-M-protein and 
difference between 2 types of Serum 
FLC. 
Include date of first pembro dose on 
the plot for each subject. 
Not aligned w/study 208469 (MRCLS). 
SAC 
2.0050 
mITT 
[Non-Standard] 
EFF_F2 
Composite Spider Plot of Percent Change from Baseline in 
Myeloma Biomarkers for All Subjects 
Create a composite plot, with all 
subjects included (1 line per subject). 
The line for each subject will represent 
the subject’s “chosen marker” from the 
waterfall plot above. 
Include date of first pembro dose on 
the plot for each subject. 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Not aligned w/study 208469 (MRCLS). 
Time to Event 
2.0060 
mITT 
TTE10 
Graph of Kaplan-Meier Curve of Investigator-Assessed 
Progression Free Survival with 95% Confidence Band by 
Treatment Arm (IMWG 2016) 
Unit = months. 
Create separate KM curves (lines) for 
treatment arms (distinguish lines by 
color or pattern). 
Only create if at least 3 subjects in a 
single arm. 
Similar to the footnote used in DoR 
displays, add a footnote that defines 
PFS as including confirmed 
progressive disease.  
Align w/study 208469 (MRCLS). 
SAC 
2.0070 
mITT 
TTE10 
Graph of Kaplan-Meier Curve of Investigator-Assessed 
Progression Free Survival with 95% Confidence Band for All 
Subjects (IMWG 2016) 
Unit = months. 
Create single KM curve for all subjects. 
Only create if at least 3 subjects 
overall in the study. 
Similar to the footnote used in DoR 
displays, add a footnote that defines 
PFS as including confirmed 
progressive disease.  
Align w/study 208469 (MRCLS). 
SAC 
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14.12.7. 
Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Adverse Events (AEs) 
3.0010  
ITT 
AE1 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
ICH E3 
Add Total column. 
Do not use combined PTs. 
Align w/study 208469 (MRCLS). 
SAC 
3.0020  
mITT 
AE1 
Summary of All Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term 
ICH E3 
Add Total column. 
Do not use combined PTs. 
Treatment emergent only. 
Align w/study 208469 (MRCLS). 
SAC 
3.0030  
ITT 
OAE07 
Summary of All Adverse Events by Maximum Grade 
Separately for Treatment Arms and Overall 
Add total "by group" page (i.e., 
subheading should be “Treatment: Total 
(N=XXX)”). 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
SAC 
3.0040  
ITT 
AE18 
Summary of All Adverse Events by Maximum Grade and 
Treatment Arm    
Include Total column. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
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90 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.0050  
mITT 
OAE07 
Summary of All Treatment Emergent Adverse Events by 
Maximum Grade Separately for Treatment Arms and Overall 
Treatment emergent only. 
Add total "by group" page (i.e., 
subheading should be “Treatment: Total 
(N=XXX)”). 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
SAC 
3.0060  
mITT 
AE18 
Summary of All Treatment Emergent Adverse Events by 
Maximum Grade and Treatment Arm 
Treatment emergent only. 
Include Total column. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
SAC 
3.0070  
mITT 
OAE07 
Summary of All Study-Treatment Related Adverse Events by 
Maximum Grade Separately for Treatment Arms and Overall 
ICH E3 
Treatment emergent only. 
Add total by-group page. 
Treatment related, including 
lymphodepleting chemotherapy, T-cell 
infusion, and pembrolizumab. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.0080  
mITT 
AE18 
Summary of All Study-Treatment Related Adverse Events by 
Maximum Grade and Treatment Arm 
ICH E3 
Treatment emergent only. 
Include Total column. 
Treatment related, including 
lymphodepleting chemotherapy, T-cell 
infusion, and pembrolizumab. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
SAC 
3.0090  
mITT 
OAE07 
Summary of All T-Cell Infusion Related Adverse Events by 
Maximum Grade Separately for Treatment Arm and Overall  
ICH E3 
Treatment emergent only. 
Add total by-group page. 
Treatment related (T-cell infusion). 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
SAC 
3.0100  
mITT 
AE18 
Summary of All T-Cell Infusion Related Adverse Events by 
Maximum Grade and Treatment Arm 
ICH E3 
Treatment emergent only. 
Include Total column. 
Treatment related (T-cell infusion). 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
3.0110  
mITT 
OAE07 
Summary of All Lymphodepletion-Related Adverse Events by 
Maximum Grade Separately for Treatment Arm and Overall  
ICH E3 
Treatment emergent only. 
Add total by-group page. 
Treatment related (lymphodepleting 
chemotherapy). 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
SAC 
3.0120  
mITT 
AE18 
Summary of All Lymphodepletion-Related Adverse Events by 
Maximum Grade and Treatment Arm 
ICH E3 
Treatment emergent only. 
Include Total column. 
Treatment related (lymphodepleting 
chemotherapy). 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
SAC 
3.0130  
ITT 
OAE07 
Summary of All Serious Adverse Events by Maximum Grade 
Separately for Treatment Arm and Overall  
ICH E3 
Treatment emergent only. 
Serious events. 
Add total by-group page. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
3.0140  
ITT 
AE18 
Summary of All Serious Adverse Events by Maximum Grade 
and Treatment Arm 
ICH E3 
Treatment emergent only. 
Serious events. 
Include Total column. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
SAC 
3.0150  
ITT 
AE15 
Summary of All Common (>=5%) Non-serious Adverse Events 
by System Organ Class and Preferred Term (Number of 
Subjects and Occurrences) 
FDAAA, EudraCT 
Add Total column. 
Do not combine Preferred Terms. 
Align w/study 208469 (MRCLS). 
SAC 
3.0160  
ITT 
AE3 
Summary of All Non-Serious Study-Treatment Related AEs by 
Overall Frequency 
Add Total column. 
Do not combine Preferred Terms. 
Align w/study 208469 (MRCLS). 
SAC 
3.0170  
ITT 
AE1 
Summary of Adverse Events Grouped by Similarity of 
Preferred Terms 
Add Total column. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Remove overall “ANY EVENT” and 
synonym level “Any Event” rows. 
SOC from AE1 should be combined PT. 
PT from AE1 should be the MEDDRA 
PT. 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Label column “Synonym/Preferred 
Term” rather than “System Organ 
Class/Preferred Term” (where / indicates 
new line and indent as in AE1). 
If combined AE does not appear then 
include a 0 count. 
Align w/study 208469 (MRCLS). 
Adverse Events of Special Interest (AE of SI) 
3.0180  
mITT 
OAE01 
Summary of Treatment Emergent Adverse Events of Special 
Interest by Maximum Grade (Focused List) 
Treatment emergent only. 
Add total by-group page (i.e., 
subheading should be “Treatment: Total 
(N=XXX)”).  
Use combined PT identified in the 
focused list with footnote “Preferred 
terms are combined”.  
Use “Adverse Event” (rather than 
“Preferred Term”) as column header. 
Replace SOC with AESI category (use 
AESI category names from current SRT 
AESI specification document if these 
differ to those in RAP). 
Align w/study 208469 (MRCLS). 
SAC 
3.0190  
mITT 
OAE01 
Summary of Treatment Emergent Adverse Events of Special 
Interest by Maximum Grade (Comprehensive List) 
Treatment emergent only. 
Add total by-group page (i.e., 
subheading should be “Treatment: Total 
(N=XXX)”).  
Do not use combined PTs.  
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95 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Replace SOC with AESI category (use 
AESI category names from current SRT 
AESI specification document if these 
differ to those in RAP). 
Align w/study 208469 (MRCLS). 
3.0200  
mITT 
ESI1 
Summary of Characteristics of Haematopoietic Cytopenias 
(Focused List) 
Treatment emergent only. 
Add total column. 
Use Focused Scope List. 
Footnote – “Preferred terms identified in 
the Focused list are summarized”. 
Report for all subjects and for all 
subjects with event. 
Report characteristics, outcome, number 
of occurrences and max grade. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
SAC 
3.0210  
mITT 
ESI1 
Summary of Characteristics of Cytokine Release Syndrome 
(CRS) 
Treatment emergent only. 
Add total column. 
Use Focused Scope List. 
Footnote – “Preferred terms identified in 
the Focused list are summarized”. 
Report for all subjects and for all 
subjects with event. 
Report characteristics, outcome, number 
of occurrences and max grade. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
SAC 
3.0220  
mITT 
ESI2a 
Summary of Onset and Duration of the First Occurrence of 
Haematopoietic Cytopenias (Focused List) 
Treatment emergent only. 
Add total column. 
Use Focused Scope List. 
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96 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Footnote – “Preferred terms identified in 
the Focused list are summarized”. 
Time to onset (days) (-8 - -1, 1 -14, 15-
30, 31-60, >60). 
Remove subjects at risk. 
Duration (days) (1-30,31-90, >90). 
Onset from first T-cell infusion. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
Important: The AE collapsing rules of 
MRCLS should be used for all 
onset/duration tables, where applicable. 
3.0230  
mITT 
ESI2a 
Summary of Onset and Duration of the First Occurrence of 
Haematopoietic Cytopenias (Neutropenia) 
Treatment emergent only. 
Add total column. 
Use Focused Scope Neutropenia List. 
Footnote – “Preferred terms identified in 
the Focused neutropenia list are 
summarized”. 
Time to onset (days) (-8 - -1, 1 -14, 15-
30, 31-60, >60). 
Remove subjects at risk. 
Duration (days) (1-30,31-90, >90). 
Onset from first T-cell infusion. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
Important: The AE collapsing rules of 
MRCLS should be used for all 
onset/duration tables, where applicable. 
SAC 
3.0240  
mITT 
ESI2a 
Summary of Onset and Duration of the First Occurrence of 
Haematopoietic Cytopenias (Thrombocytopenia) 
Treatment emergent only. 
Add total column. 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Use Focused Scope Thrombocytopenia 
List. 
Footnote – “Preferred terms identified in 
the Focused Thrombocytopenia list are 
summarized”. 
Time to onset (days) (-8 - -1, 1 -14, 15-
30, 31-60, >60). 
Remove subjects at risk. 
Duration (days) (1-30,31-90, >90). 
Onset from first T-cell infusion. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
Important: The AE collapsing rules of 
MRCLS should be used for all 
onset/duration tables, where applicable. 
3.0250  
mITT 
ESI2a 
Summary of Onset and Duration of the First Occurrence of 
Haematopoietic Cytopenias (Anemia) 
Treatment emergent only. 
Add total column. 
Use Focused Scope Anemia List. 
Footnote – “Preferred terms identified in 
the Focused Anemia list are 
summarized”. 
Time to onset (days) (-8 - -1, 1 -14, 15-
30, 31-60, >60). 
Remove subjects at risk. 
Duration (days) (1-30,31-90, >90). 
Onset from first T-cell infusion. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
Important: The AE collapsing rules of 
MRCLS should be used for all 
onset/duration tables, where applicable. 
SAC 
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208470 
 
98 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.0260  
mITT 
ESI2a 
Summary of Onset and Duration of the First Occurrence of 
Cytokine Release Syndrome (CRS) 
Treatment emergent only. 
Add total column. 
Use Focused Scope List. 
Footnote – “Preferred terms identified in 
the Focused list are summarized”. 
Time to onset (days) (-8 - -1, 1 -14, 15-
30, 31-60, >60). 
Remove subjects at risk. 
Duration (days) (1-30, 31-90, >90). 
Onset from first T-cell infusion. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
Important: The AE collapsing rules of 
MRCLS should be used for all 
onset/duration tables, where applicable. 
SAC 
3.0270  
mITT 
ESI2a 
Summary of Onset and Duration of the Last Occurrence of 
Haematopoietic Cytopenias (Focused List) 
Treatment emergent only. 
Add total column. 
Use Focused Scope List. 
Footnote – “Preferred terms identified in 
the Focused list are summarized”. 
Time to onset (days) (-8 - -1, 1 -14, 15-
30, 31-60, >60).  
Remove subjects at risk. 
Duration (days) (1-30 31-90, >90). 
Onset from first T-cell infusion. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
SAC 
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208470 
 
99 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Important: The AE collapsing rules of 
MRCLS should be used for all 
onset/duration tables, where applicable. 
3.0280  
mITT 
[Non-Standard] 
SAFE_T1 
Summary of Time to Resolution and Recurrence of Grade 3 
and Above Haematopoietic Cytopenias (Focused List) 
Treatment emergent only. 
Use Focused Scope List. 
Footnote – “Preferred terms identified in 
the Focused list are summarized”. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
SAC 
3.0290  
mITT 
[Non-Standard] 
SAFE_T1 
Summary of Time to Resolution and Recurrence of Grade 3 
and Above Haematopoietic Cytopenias (Neutropenia) 
Treatment emergent only. 
Use Comprehensive Scope List. 
Footnote – “Preferred terms identified in 
the Neutropenia focused list are 
summarized”. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
SAC 
3.0300  
mITT 
[Non-Standard] 
SAFE_T1 
Summary of Time to Resolution and Recurrence of Grade 3 
and Above Haematopoietic Cytopenias (Thrombocytopenia) 
Treatment emergent only. 
Use Comprehensive Scope List. 
Footnote – “Preferred terms identified in 
the thrombocytopenia focused list are 
summarized”. 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
SAC 
3.0310  
mITT 
[Non-Standard] 
SAFE_T1 
Summary of Time to Resolution and Recurrence of Grade 3 
and Above Haematopoietic Cytopenias (Anemia) 
Treatment emergent only. 
Use Comprehensive Scope List. 
Footnote – “Preferred terms identified in 
the Anemia focused list are 
summarized”. 
SAC 
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208470 
 
100 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Do not create if 1 or fewer subjects have 
event (default to listing).  
Align w/study 208469 (MRCLS). 
Serious and Other Significant Adverse Events 
3.0320  
ITT 
AE16 
Summary of All Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences)  
FDAAA, EudraCT 
Add Total column. 
Do not use combined PTs. 
Align w/study 208469 (MRCLS). 
SAC 
3.0330  
ITT 
OAE07 
Summary of All Serious Adverse Events by Maximum Grade 
Add total "by group" page. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
SAC 
3.0340  
mITT 
OAE07 
Summary of All Serious Treatment Emergent Adverse Events 
by Maximum Grade Separately for Treatment Arm and Overall 
Treatment emergent only. 
Add total "by group" page. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
SAC 
3.0350  
mITT 
AE18 
Summary of All Serious Treatment Emergent Adverse Events 
by Maximum Grade and Treatment Arm 
Treatment emergent only. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
SAC 
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208470 
 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Use “Adverse Event” (rather than 
“Preferred Term”) as header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
3.0360  
mITT 
OAE07 
Summary of All Study-Treatment Related Serious Adverse 
Events by Maximum Grade 
Treatment emergent only. 
Add total "by group" page. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
SAC 
3.0370  
mITT 
OAE07 
Summary of All T-cell Infusion Serious Adverse Events by 
Maximum Grade 
Treatment emergent only. 
Add total "by group" page. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
SAC 
3.0380  
mITT 
OAE07 
Summary of All Lymphodepletion-Related Serious Adverse 
Events by Maximum Grade 
Treatment emergent only. 
Add total "by group" page. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
SAC 
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208470 
 
102 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Use “Adverse Event” (rather than 
“Preferred Term”) as header. 
Present grades 3+4+5 combined (as in 
OAE01) rather than 3+4. 
Align w/study 208469 (MRCLS). 
3.0390  
ITT 
AE3 
Summary of Fatal Adverse Events by Preferred Term 
Add Total column. 
Do not produce if <5 subjects have fatal 
AE. 
Do not use combined PTs. 
Align w/study 208469 (MRCLS). 
SAC 
3.0400  
mITT 
AE3 
Summary of Study-Treatment Related Fatal Adverse Events  
Treatment emergent only. 
Add Total column. 
Use combined PTs with footnote 
“Preferred terms are combined.”  
Use “Adverse Event” (rather than 
“Preferred Term”) as header. 
Align w/study 208469 (MRCLS). 
SAC 
3.0410  
ITT 
AE3 
Summary of All Serious Study-Treatment Related AEs by 
Overall Frequency 
Add Total column. 
Do not use combined PTs. 
Align w/study 208469 (MRCLS). 
SAC 
Deaths 
3.0420  
mITT 
DD1 
Summary of Deaths 
IDSL 
Add Total column. 
Report time from T-cell infusion to death 
with median, min, max, 1st Q, 3rd Q in 
months, >30 days or <=30 days. 
Only report Alive at Last Contact (do not 
report follow up ongoing/ended). 
SAC 
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208470 
 
103 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Report primary cause of death 
categories corresponding to those 
captured on MM Combo eCRF.  
Align w/study 208469 (MRCLS). 
Laboratory: Chemistry  
3.0430  
mITT 
LB1 
Summary of Chemistry Changes from Baseline  
ICH E3. 
Add total panel.  
Align w/study 208469 (MRCLS). 
SAC 
3.0440  
mITT 
OLB9C 
Summary of Worst-Case Chemistry Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline 
ICH E3 
Include total panel. 
Report Week 4 and Week 15 visits plus 
Worst-case post-baseline only.  
For labs that are gradable by CTCAE 
v4.03.  
Align w/study 208469 (MRCLS). 
SAC 
3.0450  
mITT 
OLB11C 
Summary of Worst-Case Chemistry Results Relative to 
Normal Range Post-Baseline Relative to Baseline 
ICH E3 
Include total panel. 
Do not report by visit. 
For labs that are NOT gradable by 
CTCAE v4.03. 
Add footnote “Only tests that are not 
gradable by CTCAE are summarized.”  
Align w/study 208469 (MRCLS). 
SAC 
Laboratory: Hematology 
3.0460  
mITT 
LB1 
Summary of Hematology Changes from Baseline 
ICH E3.  
Add total panel.  
Align w/study 208469 (MRCLS). 
SAC 
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208470 
 
104 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.0470  
mITT 
OLB9C 
Summary of Worst-Case Hematology Results by Maximum 
Grade Increase Post-Baseline Relative to Baseline 
ICH E3 
Include total panel. 
Report Week 4 and Week 15 visits plus 
Worst-case post-baseline only. 
For labs that are gradable by CTCAE 
v4.03.  
Align w/study 208469 (MRCLS). 
SAC 
3.0480  
mITT 
OLB11C 
Summary of Worst-Case Hematology Results Relative to 
Normal Range Post-Baseline Relative to Baseline 
ICH E3 
Include total panel. 
Report Week 4 and Week 15 visits plus 
Worst-case post-baseline only. For labs 
that are NOT gradable by CTCAE v4.03. 
Add footnote “Only tests that are not 
gradable by CTCAE are summarized.”  
Align w/study 208469 (MRCLS). 
SAC 
Laboratory: Other Tests 
3.0490  
mITT 
LB1 
Summary of Other Laboratory Changes from Baseline  
ICH E3 
Add total panel. 
Include all "other" (non-chemistry, non-
hematology) quantitative lab tests (i.e., 
coagulation, immunology, endocrine, 
urinalysis, and biomarker). 
Align w/study 208469 (MRCLS). 
SAC 
3.0500  
mITT 
OBL9C 
Summary of Worst-Case Other Laboratory Results by 
Maximum Grade Increase Post-Baseline Relative to Baseline 
ICH E3 
Include total panel. 
Report Week 4 and Week 15 visits plus 
Worst-case post-baseline only. 
For labs that are gradable by CTCAE 
v4.03. 
SAC 
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208470 
 
105 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Include all "other" (non-chemistry, non-
hematology) quantitative lab tests (i.e., 
coagulation, immunology, endocrine, 
urinalysis, and biomarker). 
Align w/study 208469 (MRCLS). 
3.0510  
mITT 
OLB11C 
Summary of Worst-Case Other Laboratory Results Relative to 
Normal Range Post-Baseline Relative to Baseline 
ICH E3 
Include total panel. 
Do not report by visit. 
For labs that are NOT gradable by 
CTCAE v4.03. 
Add footnote “Only tests that are not 
gradable by CTCAE are summarized.” 
Include all "other" (non-chemistry, non-
hematology) quantitative lab tests (i.e., 
coagulation, immunology, endocrine, 
urinalysis, and biomarker). 
Align w/study 208469 (MRCLS). 
SAC 
Performance Status 
3.0520  
mITT 
PS1A 
Summary of ECOG Performance Status 
ICH E3 
Add Total column. 
Only summarize baseline and last 
assessment.  
Align w/study 208469 (MRCLS). 
SAC 
3.0530  
mITT 
PS3A 
Summary of Change in ECOG Performance Status from 
Baseline 
ICH E3 
Add Total column. 
Include best and worst case. 
Align w/study 208469 (MRCLS). 
SAC 
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208470 
 
106 
 
Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
ECG 
3.0540  
mITT 
EG1 
Summary of ECG Findings 
IDSL 
Add Total column. 
“Clinically significant change from 
baseline” in this standard shell is not 
collected in this study so cannot be 
reported; drop from the display. 
Align w/study 208469 (MRCLS). 
SAC 
3.0550  
mITT 
OECG1C 
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category 
IDSL 
Include total panel. 
Do not report by visit. 
QTcB and QTcF should be reported in 
this same table but summarized 
separately. 
QTcB and QTcF values should not be 
derived. 
Align w/study 208469 (MRCLS). 
SAC 
3.0560  
mITT 
EG2 
Summary of Change from Baseline in ECG Values by Visit 
IDSL 
Include total panel. 
QTcB and QTcF should be reported in 
this same table but summarized 
separately. 
Align w/study 208469 (MRCLS). 
SAC 
3.0570  
mITT 
OECG2C 
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category 
IDSL 
Include total panel. 
Do not report by visit. 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
QTcB and QTcF should be reported in 
this same table but summarized 
separately. 
Align w/study 208469 (MRCLS). 
Vital Signs 
3.0580  
mITT 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
Include total panel. 
Include weight, temp, DBP, SBP pulse 
rate, respiratory rate. 
Align w/study 208469 (MRCLS). 
SAC 
3.0590  
mITT 
OVT1C 
Summary of Worst-Case Heart Rate Results Relative to 
Normal Range Post-Baseline Relative to Baseline 
IDSL 
Include total panel. 
Do not summarize by visit. 
Align w/study 208469 (MRCLS). 
SAC 
3.0600  
mITT 
OVT2C 
Summary of Worst-Case Blood Pressure Results by 
Maximum Grade Increase Post-Baseline Relative to Baseline 
IDSL 
Include total panel. 
Do not summarize by visit. 
Align w/study 208469 (MRCLS). 
SAC 
Replication Competent Lentivirus (RCL) 
3.0610  
mITT 
[Non-Standard] 
SAFE_T3 
Summary of Replication Competent Lentivirus Positive 
Please produce even if positive counts 
are low or zero. 
Align w/study 208469 (MRCLS). 
SAC 
3.0620  
mITT 
[Non-Standard] 
SAFE_T3 
Summary of Subjects Showing >1% Gene Marked PBMCs 1 
Year Post-Treatment 
Define 1 year conservatively as at least 
360 days since infusion or month 12 
visit. 
Align w/study 208469 (MRCLS). 
SAC 
 
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14.12.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Duration Plots 
3.0630 
mITT 
[Non-Standard] 
SAFE_F2 
Plot of Duration on Treatment Phase 
 (1) Show all subjects on the same 
plot; do not show by treatment arm. 
Instead, add Arm label as an additional 
column to the right of Age/Sex. 
(2) Sort the Subject ID (y-axis) in 
ascending order of Arm, Best Overall 
Response, and Duration on Study. 
(3) Use x-axis label of “Time Since T-
cell Infusion (months)” and begin the 
axis (origin) at the start of 
lymphodepletion.  
(4) Remove all indication of diagnosis 
and prior therapies. 
(5) Show symbols or colored lines for:  
first confirmed response (star), SAE 
(asterisk), progression (diamond or 
other polygon), transfer to LTFU study 
(dot), ongoing participation in the study 
(blue line), date of first pembro 
(triangle), and ongoing status (at the 
time of analysis, arrow pointing to the 
right). 
(6) Show first date of progression, 
even if not confirmed. Please add a 
footnote to explain which subjects did 
not have confirmed progression. 
Not aligned w/study 208469 (MRCLS). 
SAC 
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208470 
 
109 
 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
3.0640 
mITT 
[Non-Standard] 
SAFE_F1 
Plot of Prior Therapy Information by Treatment Arm 
  
(1) Show all subjects on the same plot; 
do not show by treatment arm. Instead, 
add Arm label as an additional column 
to the right of Age/Sex. 
(2) Sort the Subject ID (y-axis) in 
ascending order of Arm, Best Overall 
Response, and Duration on Study. 
(3) Use x-axis label of “Time Since T-
cell Infusion (months)”. Begin the axis 
(origin) at the earliest diagnosis date 
(i.e., make sure the axis is expansive 
enough to show all diagnosis dates). 
End the axis at point of T-cell infusion. 
(4) Show symbols or colored lines for:  
Diagnosis, SAE, Leukapheresis, 
Surgery, Radiotherapy, Stem Cell 
Therapy (note that stem cell therapy + 
conditioning chemo represent a single 
regimen), Systemic Therapy Regimen 
1, Regimen 2, Regimen 3, etc., and 
Lymphodepleting Chemotherapy. 
(5) Consider imputation of prior 
therapy dates in order to show duration 
on therapy. 
Add footnote: “Note: Start and end 
dates of prior therapy are imputed for 
missing day.’ 
Not aligned w/study 208469 (MRCLS). 
SAC 
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208470 
 
110 
 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
Laboratory 
3.0650 
mITT 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin – 
eDISH 
IDSL 
Include both treatment arms on same 
plot (same axes), with arms 
differentiated by color or pattern. 
Align w/study 208469 (MRCLS). 
SAC 
3.0660 
mITT 
LIVER14 
Scatter Plot of Maximum vs. Baseline for ALT 
IDSL  
Include both treatment arms on same 
plot (same axes), with arms 
differentiated by color or pattern. 
Align w/study 208469 (MRCLS). 
SAC 
3.0670 
mITT 
[Non-Standard] 
SAFE_F3 
Plot of Hematology Data Over Time 
Produce a separate plot for 
neutrophils, lymphocytes, platelets, 
and hemoglobin (page-by lab test) 
Legend should list subjects by 
treatment arm, but subjects should not 
be grouped by treatment arm in the 
figure (each subject should have a 
unique color) 
X-axis units should be days starting at 
day -14.and ending at day 90. 
Not aligned w/study 208469 (MRCLS) 
SAC 
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208470 
 
111 
 
Safety: Figures 
No. 
Population 
IDSL / 
Example Shell 
Title  
Programming Notes 
Deliverable 
ECG 
3.0680 
mITT 
OECG4 
QTc Shifts from Baseline to Worst-Case Post Baseline 
IDSL  
Include both treatment arms in same 
plot (same axes), with arms 
differentiated by color or pattern. 
Create separate plots for the 2 QTc 
correction methods (QTcB vs. QTcF). 
Align w/study 208469 (MRCLS). 
SAC 
 
 
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112 
 
14.12.9. 
Biomarkers Tables 
Biomarker: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
Anti-NY-ESO-1 Antibodies 
3.0690 
mITT 
[Non-Standard] 
BIO_T1 
Summary of Anti-NY-ESO-1 TCR(c259) Antibodies (ATA) 
Align w/study 208469 (MRCLS). 
Only if data are available 
SAC 
 
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14.12.10. Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
Persistence of NY-ESO-1c259T 
4.0010 
mITT 
[Non-
Standard] 
PK_T1 
Summary of Derived Persistence Parameters 
Only report peak expansion (i.e. not 
by scheduled visits). 
Report overall and by responders vs. 
non-responders. 
Add total “by group” page. 
Display by type of persistence if 
BMMC data is available. 
Add footnote: “Note: Samples 
collected within 4 days of day 28 are 
treated as day 28 when calculating 
AUC(0-28)” 
Not aligned w/study 208469 
(MRCLS). 
SAC 
4.0020 
 mITT 
[Non-
Standard] 
PK_T2 
Summary of Log-Transformed Derived Persistence Parameters 
Report overall and by responders vs. 
non-responders. 
Add total “by group” page. 
Display by type of persistence if 
BMMC data is available. 
Add footnote: “Note: Samples 
collected within 4 days of day 28 are 
treated as day 28 when calculating 
AUC(0-28)” 
Not aligned w/study 208469 
(MRCLS). 
SAC 
 
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14.12.11. Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
Persistence of NY-ESO-1c259T  
4.0030  
mITT 
[Non-Standard] 
PK_F2 
Distribution of Peak Expansion 
Updated to dot plot. 
Please show both treatment arms on 
the same plot, with different colors for 
each arm. 
Plot by responders vs. non-
responders. 
Page by type of persistence if BMMC 
data is available. 
Not aligned w/study 208469 (MRCLS). 
SAC 
4.0040  
mITT 
[Non-Standard] 
PK_F1 
Persistence Profile by Subject 
Plot by treatment arm. 
Present with x-axis sufficient to see all 
follow-up. 
Add subject numbers into the legend, 
add symbols at analysis timepoints, 
and differentiate subjects with symbols 
and tine types  
X-axis and Y-axis should be same for 
each treatment arm. 
Label X-axis “Study Day” rather than 
“Time from T-cell Infusion (Days)”. 
Not aligned w/study 208469 (MRCLS). 
SAC 
4.0050  
mITT 
[Non-Standard] 
PK_F1 
BMMC Persistence Profile by Subject  
Present with x-axis sufficient to see all 
follow-up. 
Not aligned w/study 208469 (MRCLS). 
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14.12.12. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
Subject Disposition 
0010 
 
Screened 
ES7 
Listing of Reasons for Screen Failure 
Only include subjects that were screen 
failures; do not include “Run-In” elements 
or optional column “Type of Failure” 
Note that rescreened subjects that screen 
fail twice will appear twice in listing. 
Report as captured on CRF 
SAC 
0020 
 
ITT 
ES2 
Listing of Reasons for Study Withdrawal 
ICH E3 
Do not include columns “Reason 
Term(s)”, “Was a follow-up phone contact 
attempted 3 times?” & “ 
Was a follow-up certified letter mailed?” 
from GSK standard mock as not collected 
in this study. 
Align w/study 208469 (MRCLS). 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
0030 
 
ITT 
[Non-Standard] 
POP_L5 
Listing of Study Treatment Status 
ICH E3 
Present this listing by treatment arm. 
Please include:  Leukapheresis date, 
Lymphodepletion, T Cell Infusion Date, 
Time between Leukapheresis and T Cell 
Infusion, Transduced Dose, Completed 
Treatment Phase, Date of 
Discontinuation/Completion of Treatment 
Phase/Duration on Study (days), Reason 
for Discontinuation/Completion of 
Treatment Phase, End of Study Status 
Reason, and Death Date. 
Please insert a footnote:  "Duration on 
Study refers to duration of follow-up on 
treatment phase.” 
Not aligned w/study 208469 (MRCLS). 
SAC 
0040 
 
mITT 
ODMOD12A 
Listing of Dose Delays (Pembrolizumab) 
Do not include ‘Primary reason for 
Delay/Specify’ column 
Insert footnote: “Note: Duration of Delays 
= actual start date of current dose – 
expected start date of dose. Expected 
start date of dose=actual start date of 
previous dose + 21.” 
Not aligned w/study 208469 (MRCLS) 
SAC 
0050 
 
mITT 
SD2 
Listing of Reasons for Study Treatment Discontinuation 
(Pembrolizumab) 
ICH E3 
Arm 2 only 
Not aligned w/study 208469 (MRCLS). 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
Populations Analysed 
0060 
 
Screened  
SP3 
Listing of Subjects Excluded from Any Population 
ICH E3 
Include all subjects in population for 
display. 
Include columns to indicate exclusion (‘Y’) 
from Enrolled, ITT, and mITT populations. 
Drop “Date of Deviation/ Study day” and 
“Category/Coded Term” columns. 
Populate “Criteria” column with reason for 
exclusion from first: “SUBJECT NOT 
ELIGIBLE FOR APHERESIS”, “SUBJECT 
NOT APHERESED”, “SUBJECT NOT 
INFUSED”. 
Align w/study 208469 (MRCLS). 
SAC 
Protocol Deviations 
0070 
 
ITT 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
Align w/study 208469 (MRCLS). 
SAC 
0080 
 
ITT 
IE3 
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
Align w/study 208469 (MRCLS). 
SAC 
Demographic and Baseline Characteristics 
0090 
 
ITT 
DM2 
Listing of Demographic Characteristics 
ICH E3 
Present this listing by treatment arm. 
Add BMI, BSA, and Race. 
Align w/study 208469 (MRCLS). 
SAC 
Prior and Concomitant Medications 
0100 
 
ITT 
BP4 
Listing of Blood Products 
Include all blood products. 
Align w/study 208469 (MRCLS). 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
0110 
 
ITT 
CM3 
Listing of Medications 
IDSL 
Include all collected medications, do not 
subset on concomitant medication study 
phase 
Replace “Started Pre-Trial” column with 
“Prior / Concomitant” (identified per 
Appendix 4) 
SAC 
Exposure 
0120 
 
ITT 
[Non-Standard] 
POP_L3 
Listing of Leukapheresis, Lymphodepletion, T-cell, and 
Pembrolizumab Infusion Dates 
ICH E3 
With the exception of Pembro being 
added, this listing should align w/study 
208469 (MRCLS). 
SAC 
0130 
 
ITT 
[Non-Standard] 
POP_L1 
Listing of Exposure to Lymphodepletion Chemotherapy 
ICH E3 
One column for Fludarabine dose 
Align w/study 208469 (MRCLS). As per 
MRCLS, please remove MESNA. 
SAC 
0140 
 
ITT 
[Non-Standard] 
POP_L2 
Listing of Exposure to T-cell Infusion 
ICH E3 
Align w/study 208469 (MRCLS). 
SAC 
0150 
 
ITT 
OEX8B 
Listing of Exposure to Pembrolizumab 
ICH E3 
For subjects in Arm 2 only. 
Replace Cycle with Visit. 
Not aligned w/study 208469 (MRCLS). 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
Adverse Events 
0160 
 
ITT 
AE8 
Listing of All Adverse Events 
ICH E3 
Present this listing by treatment arm. 
Report time from first T-cell Infusion. 
Use “Time Since T-cell Infusion” instead 
of Time Since First Dose/Time Since Last 
Dose. 
Add MM Combo specific "action taken" 
column. 
With the exception of the added “action 
taken” (specific to MM Combo), this listing 
should align w/study 208469 (MRCLS). 
SAC 
0170 
 
ITT 
AE8 
Listing of Adverse Events Leading to Dose Interruption, 
Dose Reduction, or Permanent Discontinuation of 
Pembrolizumab 
For subjects in Arm 2 only. 
Not aligned w/study 208469 (MRCLS). 
SAC 
0180 
 
ITT 
[Non-Standard] 
SAFE_L1 
Listing of Delayed Adverse Events 
ICH E3 
Report time from first T-cell Infusion. 
Use “Time Since T-cell Infusion” instead 
of Time Since First Dose/Time Since Last 
Dose. 
SAC 
0190 
 
ITT 
AE7 
Listing of Subject Numbers for Individual Adverse 
Events 
ICH E3 
All AEs. 
Align w/study 208469 (MRCLS). 
SAC 
0200 
 
ITT 
AE2 
Listing of Relationship Between Adverse Event System 
Organ Classes, Preferred Terms, and Verbatim Text 
IDSL 
Align w/study 208469 (MRCLS). 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
Adverse Events of Special Interest 
0210 
 
mITT 
[Non-Standard] 
SAFE_L1 
Listing of AESI (Focused List) 
Use Focused Scope List. 
Sort by USUBJID, AEDECOD, ASTDT, 
AENDT. 
Present by treatment arm and by AESI. 
Align w/study 208469 (MRCLS). 
SAC 
0220 
 
mITT 
[Non-Standard] 
SAFE_L1 
Listing of Haematopoietic Cytopenias (Comprehensive 
List) 
Use Comprehensive Scope List. 
Sort by USUBJID, AEDECOD, ASTDT, 
AENDT. 
Present by treatment arm. 
Align w/study 208469 (MRCLS). 
SAC 
0225 
mITT 
[Non-Standard] 
SAFE_L6 
Listing of CARTOX and ICE Score 
Align w/study 208469 (MRCLS) 
SAC 
Serious and Other Significant Adverse Events 
0230 
 
ITT 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
Align w/study 208469 (MRCLS). 
SAC 
0240 
 
ITT 
AE14 
Listing of Reasons for Considering as a Serious 
Adverse Event 
ICH E3 
Add PAN12. 
Align w/study 208469 (MRCLS). 
SAC 
0250 
 
ITT 
PAN12 
Listing of COVID-19 Assessments and Symptom 
Assessments for Subjects with COVID-19 Adverse 
Events 
If data exists 
SAC 
Death 
0260 
 
ITT 
DD3 
Death Profile 
Align w/study 208469 (MRCLS). 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
Hepatobiliary (Liver) 
0270 
 
ITT 
LIVER5 
Listing of Liver Monitoring/Stopping Event Reporting 
IDSL 
Update columns “Time Since First / Last 
Dose (days)” of LIVER5 mock with “Time 
Since First T-cell Infusion” & “Time Since 
Last T-cell Infusion”. 
Align w/study 208469 (MRCLS). 
SAC 
0280 
 
ITT 
LIVER15 
Liver Stopping Event Profile 
IDSL 
Update variables “Time Since First / Last 
Dose (days)” of LIVER15 mock with “Time 
Since First T-cell Infusion” & “Time Since 
Last T-cell Infusion”. 
Align w/study 208469 (MRCLS). 
SAC 
0290 
 
ITT 
LIVER13 
Listing of Subjects Meeting Hepatobiliary Laboratory 
Criteria Post-Baseline 
IDSL 
Please make sure this is derived correctly 
by considering all liver function criteria 
specified in the LIVER IDSL doc. 
Align w/study 208469 (MRCLS). 
SAC 
All Laboratory 
0300 
 
ITT  
LB5A 
Listing of All Laboratory Data  
ICH E3 
Combining all laboratory data (chem, 
hem, etc.) in one listing, including 
biomarker data but NOT including 
urinalysis data. 
Align w/study 208469 (MRCLS). 
SAC 
0310 
 
ITT 
UR2A 
Listing of Urinalysis Data for Subjects with Any Value of 
Potential Clinical Importance 
ICH E3 
Align w/study 208469 (MRCLS). 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
Replication Competent Lentivirus (RCL) 
0320 
 
mITT 
LB5A 
Listing of VSV-G DNA (RCL) Data 
Align w/study 208469 (MRCLS). 
SAC 
0330 
 
mITT 
[Non-Standard] 
SAFE_L2 
Listing of Integration Site Analysis Results 
This is a supplemental display to the table 
summary “Summary of Subjects Showing 
Monoclonality of Genetically Modified T-
cell Population” (which uses SAFE_T3).  
Create only if data are available. 
Align w/study 208469 (MRCLS). 
SAC 
Pharmacokinetic 
0340 
 
mITT 
[Non-Standard] 
PK_L1 
Listing of Persistence Data 
Present this listing by treatment arm. 
Present by persistence type if BMMC data 
are available.  
Show time to loss of 25%, 50% and 75% 
of peak expansion, peak expansion, time 
to peak expansion, and AUC(0-28). 
With the exception of the added AUC(0-
28) parameter, this listing should align 
w/study 208469 (MRCLS). 
SAC 
Biomarkers 
0350 
 
mITT 
[Non-Standard] 
BIO_L1 
Listing of Anti-NY-ESO-1 Antibodies 
Align w/study 208469 (MRCLS). 
Only if data are available 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
ECG 
0360 
 
ITT 
EG3 
Listing of All ECG Values for Subjects with Any Value 
of Potential Clinical Importance 
IDSL 
Update PCI footnote to use oncology 
definition “…Clinical Importance is defined 
as Grade 2 or Higher (QTc>480), or QTc 
increase of >30 msec…” (as in OECG5A). 
Align w/study 208469 (MRCLS). 
SAC 
0370 
 
ITT 
EG5 
Listing of All ECG Findings for Subjects with an 
Abnormal ECG Finding 
IDSL 
“Clinically significant change from 
baseline” and “Clinically Significant 
Abnormality” in this standard shell are not 
collected in this study so cannot be 
reported – drop from display. 
Align w/study 208469 (MRCLS). 
SAC 
Vital Signs 
0380 
 
ITT 
OVT7A  
Listing of Vital Signs with Values of Potential Clinical 
Importance 
IDSL 
Align w/study 208469 (MRCLS). 
SAC 
Response 
0390 
 
ITT 
[Non-Standard] 
EFF_L2 
Listing of Investigator-Assessed Responses (with 
confirmation) (IMWG 2016) 
Present this listing by treatment arm. 
Please ensure that an additional column 
is included to display "by-visit" Confirmed 
Response, to the right of the column of 
"by-visit" responses. 
Not aligned w/study 208469 (MRCLS). 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
Time to Event 
0400 
 
mITT 
TTE9 
Listing of Investigator-Assessed Time to Response 
(IMWG 2016) 
Use T-cell infusion date. 
Include optional “New Anti-Cancer 
Therapy Start Date” column. 
Align w/study 208469 (MRCLS). 
SAC 
0410 
 
mITT 
TTE9 
Listing of Investigator-Assessed Duration of Response 
(IMWG 2016) 
Present this listing by treatment arm. 
Add Initial Confirmed Response. 
Use T-cell infusion date. 
Include optional “New Anti-Cancer 
Therapy Start Date” column. 
Include footnote: “Note: Duration of 
Response is defined as the interval 
between the initial date of the confirmed 
response (sCR, CR, VGPR, or PR) and 
the date of confirmed progressive disease 
or death among subjects with a confirmed 
response per IMWG 2016.” 
Align w/study 208469 (MRCLS). 
SAC 
0420 
 
mITT 
TTE9 
Listing of Investigator-Assessed Progression Free 
Survival (IMWG 2016) 
Present this listing by treatment arm. 
Use T-cell infusion date 
Include optional “New Anti-Cancer 
Therapy Start Date” column. 
Similar to the footnote used in the DoR 
listing above, add a footnote that defines 
PFS as including confirmed progressive 
disease.  
Align w/study 208469 (MRCLS). 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / Example Shell Title  
Programming Notes 
Deliverable 
0430 
 
mITT 
TTE9 
Listing of Overall Survival 
Use T-cell infusion date. 
Exclude optional “New Anti-Cancer 
Therapy Start Date” column. 
Align w/study 208469 (MRCLS). 
SAC 
 
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14.12.13. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / Example Shell 
Title  
Programming Notes 
Deliverable 
Disease Characteristics 
0440 
 
ITT 
DC3 
Listing of Disease Characteristics at Initial Diagnosis 
Present this listing by treatment arm. 
Please report: date of initial diagnosis, 
time from initial diagnosis to screening 
ICF signed (in months), stage at 
diagnosis, histologic type, % clonal bone 
marrow plasma cells, presence and type 
of end organ damage, presence and 
type of plasmacytoma, and 
chromosomal aberrations. 
Remove primary neoplasm type under 
study and study specific category (as 
they are not relevant) and remove 
histologic grade (as it is not collected). 
Not aligned w/study 208469 (MRCLS). 
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Non-ICH: Listings 
No. 
Population 
IDSL / Example Shell 
Title  
Programming Notes 
Deliverable 
0450 
 
ITT 
[Non-Standard] 
POP_L4 
Listing of Disease Characteristics at Screening 
Present this listing by treatment arm. 
Please report:  type of multiple myeloma, 
HLA status (date, allele 1, allele 2), NY-
ESO-1 biopsy date and status, LAGE-1a 
(date, status), number of systemic 
therapy / radiotherapy regimens prior to 
leukapheresis, and receipt of stem cell 
transplant/therapy prior to leukapheresis 
(Y/N) for each of 2 subtypes (autologous 
vs. allogeneic). 
Also, use the new derivation of lines of 
systemic therapy (i.e., count systemic 
therapy + conditioning chemo associated 
w/stem cell therapy) – please add a 
footnote that makes this clear. 
Not aligned w/study 208469 (MRCLS). 
SAC 
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Non-ICH: Listings 
No. 
Population 
IDSL / Example Shell 
Title  
Programming Notes 
Deliverable 
Anti-Cancer Therapies 
0460 
 
ITT 
AC6 
Listing of Prior Systemic Anti-Cancer Therapy 
Present this listing by treatment arm. 
In addition to the Most Recent 
Response, please include “Best 
Response” in the same column (to be 
shown first) and “MRD” (to be shown 
last).  
Remove “Reason for Stopping” (as not 
collected for prior systemic therapy) and 
replace it with “Disease Refractory to 
Regimen (Y/N)”. 
Add "Intent" (i.e., treatment intent). 
Add final column with header of "Started 
after Leukapheresis?/Bridging Therapy?"   
“Note: This listing includes all systemic 
therapy prior to lymphodepletion.” Sort 
by regimen. 
Conditioning chemotherapies 
(associated with stem cell therapy) and 
stem cell therapy should appear in this 
listing 
Not aligned w/study 208469 (MRCLS). 
SAC 
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Non-ICH: Listings 
No. 
Population 
IDSL / Example Shell 
Title  
Programming Notes 
Deliverable 
0470 
 
ITT 
AC7 
Listing of Anti-Cancer Radiotherapy 
List all radiotherapy before 
lymphodepletion and flag the ones 
occurring between leukapheresis and 
lymphodepletion as "Started after 
Leukapheresis". 
Use T-cell infusion date. 
Include optional “New Anti-Cancer 
Therapy Start Date” column. 
Add final column with header of 
"Transition Therapy"   
Add footnotes:  
“Note: This listing includes all 
radiotherapy received by the subject.” 
“Note: Transition therapies include all 
therapy received after leukapheresis and 
before lymphodepletion.” 
Align w/study 208469 (MRCLS). 
SAC 
0480 
 
ITT 
FAC3 
Listing of On-Study Anti-Cancer Therapy 
Include “Time to Progression (Days)” but 
not “Overall Survival (Days)”. 
Use date of "first progression" even if not 
confirmed for TTP column. Footnote any 
subject with unconfirmed PD. 
Includes radiotherapy, systemic therapy, 
and stem cell therapy 
Align w/ study 208469 (MRCLS) 
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Non-ICH: Listings 
No. 
Population 
IDSL / Example Shell 
Title  
Programming Notes 
Deliverable 
Symptoms, Concomitant Medications and Procedures Related to Adverse Events of Special Interest 
0490 
 
ITT 
[Non-Standard] 
SAFE_L4 
Listing of Symptoms, Concomitant Medications, and 
Procedures Related to Cytokine Release Syndrome 
(CRS) 
Present this listing by treatment arm. 
Add column showing list of all 
symptoms.  
Align w/study 208469 (MRCLS). 
SAC 
0500 
 
ITT 
[Non-Standard] 
SAFE_L5 
Listing of Symptoms, Concomitant Medications, and 
Procedures Related to Graft versus Host Disease 
(GvHD) 
Present this listing by treatment arm. 
Add column showing list of all 
symptoms.  
Align w/study 208469 (MRCLS). 
SAC 
Surgical Procedures 
0510 
 
ITT 
OSP3 
Listing of Prior Cancer-Related Surgical Procedures 
List all surgeries before lymphodepletion 
and flag the ones occurring between 
leukapheresis and lymphodepletion as 
"Started after Leukapheresis?" 
List Surgery Intent and Site and Date of 
Surgery. 
Add footnote: “Note: This listing includes 
all cancer-related surgeries prior to T-cell 
infusion.” 
Align w/study 208469 (MRCLS). 
SAC 
0520 
 
ITT 
OSP3 
Listing of On-Study Cancer-Related Surgical Procedures 
List Site and Date of Surgery. 
Align w/study 208469 (MRCLS). 
SAC 
 
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14.13. 
Appendix 13: Example Mock Shells for Data Displays 
Data Display Specification will be made available on request 
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14.14. 
Appendix 14: Combined Preferred Terms 
Combined Term 
MedDRA Preferred term 
PT Code 
 Anemia/RBC decreased  
Anemia  
10002034 PT 
Cytokine Release Syndrome (CRS)  
Cytokine Release Syndrome  
10052015 PT 
Cytokine Storm  
10050685 PT 
Acute GVHD - Skin 
Acute graft versus host disease in skin 
10066262 PT 
Acute GVHD - Gut (Liver and Intestine) 
Acute graft versus host disease in liver 
10066263 PT 
Acute graft versus host disease in intestine 
10066264 PT 
Acute GVHD  - Other (Lung, Bone Marrow, not specified) 
Acute graft versus host disease 
10066260 PT 
Chronic GVHD -  Skin 
Chronic graft versus host disease in skin 
10072159 PT 
Chronic GVHD - Gut (Liver and Intestine) 
Chronic graft versus host disease in liver 
10072160 PT 
Chronic graft versus host disease in intestine 
10072158 PT 
Chronic GVHD Other -  (Lung, Bone Marrow, not specified) 
Chronic graft versus host disease 
10066261 PT 
Unspecified GVHD - Skin 
Graft versus host disease in skin 
10064675 PT 
Unspecified GVHD - Gut (Liver and Intestine) 
Graft versus host disease in liver 
10064676 PT 
Graft versus host disease in gastrointestinal 
tract 
10075160 PT 
Unspecified GVHD - Other (Lung, Bone Marrow, not specified) 
Graft versus host disease 
10018651 PT 
Graft versus host disease in eye 
10074563 PT 
Graft versus host disease in lung 
10067742 PT 
Prophylaxis against graft versus host disease 
10053239 PT 
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Combined Term 
MedDRA Preferred term 
PT Code 
Transfusion associated graft versus host 
disease 
10070895 PT 
Engraftment syndrome  
10050684 PT 
 Leukopenia/WBC decreased  
White blood cell count decreased 
10047942 PT 
Leukopenia 
10024384 PT 
Lymphopenia/Lymphocyte count decreased  
Lymphocyte count decreased 
10025256 PT 
CD4 lymphocytes decreased  
10007839 PT 
CD8 lymphocytes decreased  
10056283 PT 
Neutropenia/Neutrophil count decreased  
Neutrophil count decreased 
10029366 PT 
Neutropenia 
10029354 PT 
Rash/Rash maculo-papular 
Rash maculo-papular 
10037868 PT 
Rash 
10037844 PT 
Rash erythematous 
10037855 PT 
Thrombocytopenia/Platelet count decreased  
Platelet count decreased 
10035528 PT 
Thrombocytopenia 
10043554 PT 
MedDRA version 21.1 for PT codes  
 
 
 
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14.15. 
Appendix 15: Adverse Event Collapsing Rules 
1. Collapsing AE Segments with a Common AE Preferred Term (PT) into Unique Events based on the Start and End Dates  
For each unique subject, the AE records (segments) with the same AE preferred term will be collapsed into one unique AE event based on 
the start and end dates below. 
 
1.1.Multiple AE Segments with Overlapped or Continuous Start/End Dates 
Multiple AE segments with a common preferred term (PT, variable=ADAE.AEDECOD) that occurred around the same time; 
defined as: 
If a segment starts no more than one day (i.e., ≤ 1 day) prior, on, or after the previous segment’s end date, it is considered as an 
‘event’.   
If the gap between the start date of a segment and the end date of previous segment is greater than one complete day (i.e., > 1 day), 
then consider these segments as different events.  
If partial start or end dates for any AE segments, then consider these segments as separate events. 
 
*** NOTE: Handling of partial dates or completely missing dates 
Partial dates or completely missing dates will not be imputed.  
The reason for not using imputed dates is due to the small number of partial / or completely missing dates.  Furthermore, using 
imputed dates might create additional error of up to 30 days off for the AE start or AE end dates, and can be up to 60 days off for 
the duration of AE.  
 
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1.2.Sort Adverse Events (AE)  
For any AE event identified above: 
Sort the AEs segments by study ID (ADAE.STUDYID), unique subject ID (ADAE.USUBJID), AE preferred term 
(ADAE.AEDECOD), AE start date (ADAE.AESTDTC), and AE end date (ADAE.AEENDTC). The sorting will include all AE 
segments with complete or partial start / end dates. 
 
1.3.Create Derived Variables in ADAE ADaM SAS Dataset 
Based on the ADAE dataset sorted above under Section 1.2, for each unique subject, create the following derived variables in the 
ADAE ADaM SAS dataset: 
 
1) 
ANL01FL: Flag for the unique AE 
a) Collapsed AE Segments 
For collapsed AE segments. based on the ADAE dataset sorted above under Section 1.2:  
• derive the flag variable: ANL01FL=”Y” on the first record for each collapsed AE (i.e. the earliest 
segment within each collapsed AE with the same ADAE.AEDECOD) . In case if the AE segment of 
the collapsed AEs started before Lymphodepletion and ending after it, then populate the ANL01FL=’Y’ 
on very first Treatment emergent record. If there is only one record (segment) which started before 
lymphodepletion and ended after lymphodepletion then populate ANL01FL=’Y’ on that record only.  
• Otherwise ANL01FL="" (Missing). 
 
b) AE Events Comprised of a Single Row (No Collapsing Needed) 
• derive the flag variable: ANL01FL=”Y” for each single segment AE event. 
208470 | Statistical Analysis Plan  RAP 23 Apr 2021 | TMF-13337917 | 1.0


 
CONFIDENTIAL 
 
 
 
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2) 
EVTSEQ: Sequence number of each unique AE with the same PT 
Create a sequence number, EVTSEQ, for each unique AE within the same ADAE.AEDECOD. 
For each unique subject within each unique AE preferred term, this variable will be recorded as the sequential 
number to identify all unique adverse events (including both single segment events (i.e., no collapsing 
needed) and collapsed events from multiple segments) based on the sorting order chronologically addressed 
above under Section 1.2.  
a) Collapsed AE Segments 
Each collapsed AE and its corresponding composed segments will have the same sequence numbers (i.e., if 
multiple segments/records are qualified for being collapsed into one unique AE (i.e., all those records will have 
same value for the derived variable EVTSEQ for that corresponding subject within the same collapsed AE). 
b) Single Segment AE Records 
Each single segment AE event (i.e., un-collapsed event) will have different unique sequence number separately  
c) AE Segments with partial start or end dates  
Each AE segment with partial start or end dates will have different unique sequence number starting from 99XXX, 
where XXX=001, 002, ...  
  * NOTE: 
     For those subjects who received 2 T-cell infusions, the sequential number will be based on both infusion periods combined  
     (i.e., the assigned sequential number will be independent of T-cell infusion periods). 
208470 | Statistical Analysis Plan  RAP 23 Apr 2021 | TMF-13337917 | 1.0