Conditions: Neoplasms
Keywords: Adoptive T-cell therapy Advanced synovial sarcoma Advanced Myxoid/Round Cell Liposarcoma Advanced tumors GSK3845097 T cell receptor Leukapheresis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 5
Healthy volunteers: no

Brief summary:
To assess the safety, tolerability and determine recommended phase 2 dose (RP2D) of GSK3845097 in HLA-A\*02:01, HLA-A\*02:05 and/or HLA-A\*02:06 positive participants with New York esophageal squamous cell carcinoma (NY-ESO)-1 and/or Cancer testis antigen 2 (LAGE-1a) positive, previously treated, advanced (metastatic or unresectable) Synovial Sarcoma (SS) and Myxoid/Round Cell Liposarcoma (MRCLS).

Detailed description:
This study is a substudy of the Master record - (209012) NCT04526509.

Arms:
arm 1: Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive high dose of GSK3845097 after completing lymphodepleting chemotherapy. The first study participant receiving GSK3845097 will receive the total assigned dose as 2 separate infusions 7 days apart, in aliquots of 30% (first infusion) and 70% (second infusion) of the total target dose , respectively. Based on the dose limiting toxicities reported in the first participant, then all subsequent participants treated with GSK3845097 will receive the full dose as a single, i.e., one-time, infusion.

Interventions: intervention 1: GSK3845097 intervention 2: Cyclophosphamide intervention 3: Fludarabine
Intervention descriptions: intervention 1: GSK3845097 was administered. intervention 2: Cyclophosphamide was administered as lymphodepleting chemotherapy. intervention 3: Fludarabine was administered as lymphodepleting chemotherapy.

Protocol document:
Prot_000.pdf: 
Protocol Amendment 4
Study ID:  209012 Substudy 2
Sub-study Official Title: Assessment of Safety and Recommended Phase 2 
Dose of Autologous T cells Engineered with an Affinity-enhanced TCR 
Targeting NY-ESO-1 and LAGE-1a, and co-expressing the dnTGF-βRII 
(GSK3845097) in Participants with NY-ESO-1 and/or LAGE-1a Positive 
Previously Treated Advanced (Metastatic or Unresectable) Synovial 
Sarcoma and Myxoid/Round Cell Liposarcoma 
NCT ID for sub-study: NCT05943990
Date of Document: 27-MAY-2022


TMF-14682598 
CONFIDENTIAL 
GlaxoSmithKline group of companies 
209012 
Protocol Amd 04 
1 
Substudy 2 
TITLE PAGE 
Protocol Title: Master Protocol to Assess the Safety and Recommended Phase 2 Dose of 
Next Generations of Autologous Enhanced NY-ESO-1/ LAGE-1a TCR Engineered 
T cells, alone or in combination with other agents, in Participants with Advanced Tumors 
Protocol Number: 209012/Amendment 04 Substudy 2 
Compound Number: GSK3845097 
Short Title: Master Protocol of Autologous Enhanced T Cells in Advanced Tumors 
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline LLC 
5 Crescent Drive 
Philadelphia, PA 19112 
US 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual 
Sponsor Signatory 
Laura Pearce 
Group Sr. Director, Clinical Development Lead 
Oncology, Cell and Gene Therapy 
GlaxoSmithKline 
Nitin Patel, BM BCh MA 
Senior Medical Director 
Oncology, Cell and Gene Therapy 
GlaxoSmithKline 
Regulatory Agency Identifying Number(s): 
IND Number: 19751 
EudraCT Number: 2019-004446-14 
Approval Date:  27 May 2022 
©2022 GSK group of companies or its licensor. All rights reserved. Unauthorized 
copying or use of this information is prohibited.


TMF-14682598 
CONFIDENTIAL 
209012 
Protocol Amd 04 
2 
Substudy 2 
Substudy 2:  GSK3845097 in Previously Treated Advanced Synovial Sarcoma and 
Myxoid/Round Cell Liposarcoma  
Substudy title:  Assessment of Safety and Recommended Phase 2 Dose of Autologous 
T cells Engineered with an Affinity-enhanced TCR Targeting NY-ESO-1 and LAGE-1a, 
and co-expressing the dnTGF-βRII (GSK3845097) in Participants with NY-ESO-1 
and/or LAGE-1a Positive Previously Treated Advanced (Metastatic or Unresectable) 
Synovial Sarcoma and Myxoid/Round Cell Liposarcoma 
This document contains substudy 2 specific details. Refer to the body of the Core 
Section of the Master Protocol Amendment 04 for all other information. 


TMF-14682598 
CONFIDENTIAL 
209012 
Protocol Amd 04 
3 
Substudy 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY SUBSTUDY 2 
Document 
Date 
DNG Number 
Amendment 04 
27 May 2022 
TMF-14682598 
Amendment 03 
20 December 2021 
TMF-14357930 
Amendment 02 
04 November 2021 
TMF-14137790 
Amendment 01 
21 May 2021 
TMF-13779299 
Original Protocol 
02 December 2019 
2019N419717_00 
Amendment 04 - 27 May 2022 
The primary reasons for Amendment 04 are as follows: 
•
Changes to correct text inadvertently modified during the publication of
Amendment 02. Edits in Amendment 04 reflect intended language
•
Updated eligibility criteria on prior therapies for synovial sarcoma and
myxoid/round cell liposarcoma participants to incorporate standard of care
practice and investigator’s discretion
•
Minor changes to Substudies 1, 2, and 3 to ensure alignment of design and
procedures across the 3 substudies
Section # and Name 
Description of Change 
Brief Rationale 
Substudy 2 
Throughout the protocol 
Made administrative changes and corrected 
clerical errors. 
Removed mentions of NSCLC relevant only 
to Substudy 1 
For clarity and consistency 
Clarified language on lower dose range to 
“0.1-0.8 x109“ instead of “1-8x108“  
Section 2 – Schedule of 
Activities – Table 1 
Added footnote (#13): If leukapheresis is 
rescheduled, existing brain MRI results will 
be accepted if obtained within 2 months 
prior to the rescheduled procedure and the 
participant has no new neurological 
symptoms 
For flexibilty 
Section 2 – Schedule of 
Activities – Table 2 
Day 64 was added next to Days “78, 120, 
162.” It was inadvertently deleted in PA02 
Day 64 was inadvertently deleted in 
PA02  
Section 2 – Schedule of 
Activities – Table 2 and 
Table 4 
Removed requirement for creatinine 
clearance assessments originally 
scheduled at Months 18 and 30  
Serum creatinine test has been 
maintained at these timepoints as 
part of chemistry panel and can still 


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Section # and Name 
Description of Change 
Brief Rationale 
provide an estimation of creatinine 
clearance 
 
Transgene Copies (persistence for safety) 
and
 
 to be collected every 6 months from 
Month 12 and onwards, while the patient is 
in follow-up 
In alignment with GSK Long-Term 
Follow Up study 208750 
 
Modified existing language (footnote #17) 
on Brain MRI at baseline to clarify that it 
should be obtained among participants with 
no history of CNS metastasis if more than 3 
months have elapsed between the last 
brain MRI and the start of lymphodepletion 
or if they show neurological symptoms 
consistent with CNS metastasis. Brain MRI 
at baseline should be obtained for all 
participants with a history of brain 
metastasis. 
To clarify assessment window and for 
safety purposes 
 
Added footnote #6 to indicate that Day -7 
visit is not required for participants who 
initiate lymphodepletion on Day -6. 
Complete physical exam must occur on 
Day -6 for these participants. 
To clarify visit requirements for 
participants who initiate 
lymphodepletion on Day -6 
 
Modified existing language (footnote #14) 
on CT/MRI for clarity 
For clarity 
Section 2 – Schedule of 
Activities – Table 3 and 
Table 5 
Week 8 sample collection for all parameters 
except biopsies was added, as these were 
inadvertently deleted in PA02 
Week 8 sample collection was 
inadvertently deleted in PA02 
 
Footnote #7 was revised to clarify that an 
archived FFPE block from a biopsy taken 
preferably after completion of the 
participant’s last line of therapy, preferably 
within 90 days prior to initiating 
lymphodepleting chemotherapy, may be 
accepted at the discretion of the Medical 
Monitor (or designee) 
Language edited for clarity 
Section 2 – Schedule of 
Activities – Table 6 
Footnote #9 was revised to align text with 
changes incorporated in Protocol 
Amendment 01.  
To align text with changes 
incorporated in Protocol Amendment 
01 
Section 5.1.1.2  
Modified footnote for “U” in Table 9 to 
include action to “de-escalate to the lower 
dose if applicable” 
For clarity 
 
Modified language on analyses for the dose 
de-escalation or RP2D confirmation 
decision 
In alignment with DSC plan 
CCI


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
5 
Substudy 2 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1.2 – Dose 
Expansion Phase  
Removed language related to primary 
analysis 
Listed in Section 10.5.2 
Section 5.1.4 – Tumor 
Biopsies 
An archived FFPE block from a biopsy 
taken preferably after completion of the 
participant’s last line of therapy, preferably 
within 90 days prior to initiating 
lymphodepleting chemotherapy, may be 
accepted at the discretion of the Medical 
Monitor (or designee) 
Archived biopsy (even if not from 
screening period) may be accepted at 
the discretion of the Medical Monitor 
 
Removed details discussed within the 
Laboratory Manual 
To eliminate redundancy 
Section 5.3.1 – End of 
Substudy for Individual 
Participants  
Removed inaccurate AE follow-up 
requirements and referred to the relevant 
section of the Core protocol 
For clarity and to eliminate repetitive 
language 
Section 6.1.1 – Inclusion 
Criteria – Target Expression 
Screening 
Criterion #2 was revised to add that 
participants must weigh ≥40 kg to proceed 
with target expression screening 
For participant safety and in line with 
current product manufacturing 
capabilities  
 
Criteron #5 was revised to include MRCLS 
For accuracy 
Section 6.1.2 - Inclusion 
Criteria - Leukapheresis 
Eligibility Screening  
Aligned language on measurable disease 
between eligibility criterion #9 and eligibility 
criterion #20 
Aligned language on LAGE-1a testing 
between eligibility criterion #8 and 
corresponding note 
For consistency 
Modified language on criterion #12 on prior 
lines of therapy to align with Substudy #3 
To align across substudies 
 
 
In Table 10 for Criterion #17,  text was 
added to clarify that acceptable hemoglobin 
values for eligibility may not be achieved by 
transfusion 
For patient fitness and in alignment 
with Substudy 1 
Section 6.1.3 – Inclusion 
Criteria – Treatment 
Eligibility Screening 
The note below criterion #20 was revised to 
include previously biopsied lesions  
For clarity 
 
Added language on eligibility criterion #21 
(baseline biopsy) for single measurable 
lesions 
For clarity 
Section 6.2.2 - Exclusion 
Criteria – Leukapheresis 
Eligibility Screening 
Criterion #6 was revised to clarify that no 
central nervous system metastases are 
permitted 
For clarity 
 
Criterion #14 was corrected to accurately 
reflect that active Epstein Barr virus 
infection or cytomegalovirus infection are 
For clarity 


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Section # and Name 
Description of Change 
Brief Rationale 
exclusion criteria. Redundant language was 
removed.  
Section 10.2 – Sample Size 
Determination 
Additional information (i.e., use of 
uninformative Beta) was added to sample 
size determination  
For clarity 
 
Corrected language to indicate that 5 of 
more confirmed responses (not 4) out of 10 
evaluable participants at RP2D may 
provide sufficient efficacy evidence to 
expand and enroll additional participants 
To align with Section 5.1.2 
Section 10.5.1 – Interim 
Analysis 
Correction to number of subjects required 
for early interim analysis 
For accuracy 

CCI


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
7 
Substudy 2 
 
TABLE OF CONTENTS 
PAGE 
1 
SYNOPSIS ............................................................................................................. 10 
2 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 11 
3 
INTRODUCTION .................................................................................................... 30 
3.1 
Background and Rationale .......................................................................... 30 
3.1.1 
GSK3845097 ............................................................................... 30 
3.1.2 
Synovial Sarcoma ........................................................................ 34 
3.1.3 
Myxoid/Round Cell Liposarcoma (MRCLS) .................................. 35 
3.2 
Benefit/Risk Assessment ............................................................................ 36 
3.2.1 
Risk Assessment ......................................................................... 36 
3.2.2 
Benefit Assessment ..................................................................... 41 
3.2.3 
Overall Benefit: Risk Conclusion .................................................. 42 
4 
OBJECTIVES AND ENDPOINTS ........................................................................... 43 
5 
SUBSTUDY DESIGN ............................................................................................. 45 
5.1 
Overall Design ............................................................................................ 45 
5.1.1 
Dose Confirmation Phase ............................................................ 45 
5.1.1.1 
Split Dosing and Staggered Treatment ....................... 46 
5.1.1.2 
Determining the RP2D ................................................ 46 
5.1.2 
Dose Expansion Phase ................................................................ 48 
5.1.3 
Participant Journey ...................................................................... 48 
5.1.4 
Tumor Biopsies ............................................................................ 51 
5.2 
Number of Participants ............................................................................... 52 
5.3 
End of Study Definition ............................................................................... 52 
5.3.1 
End of Substudy for Individual Participants .................................. 52 
5.3.2 
End of Substudy .......................................................................... 53 
5.4 
Justification for Population .......................................................................... 53 
5.5 
Justification for Dose .................................................................................. 53 
5.5.1 
Dosing Rationale ......................................................................... 53 
5.5.2 
Justification of Lymphodepleting Regimen ................................... 55 
6 
STUDY POPULATION ........................................................................................... 56 
6.1 
Inclusion Criteria ......................................................................................... 56 
6.1.1 
Target Expression Screening ....................................................... 56 
6.1.2 
Leukapheresis Eligibility Screening .............................................. 56 
6.1.3 
Treatment Eligibility Screening ..................................................... 60 
6.1.3.1 
Treatment Fitness (for Safety) .................................... 61 
6.2 
Exclusion Criteria ........................................................................................ 61 
6.2.1 
Target Expression Screening ....................................................... 61 
6.2.2 
Leukapheresis Eligibility Screening .............................................. 62 
6.2.3 
Treatment Eligibility Screening ..................................................... 64 
6.2.3.1 
Treatment Fitness (for Safety) .................................... 65 
6.3 
Lifestyle Considerations .............................................................................. 66 
6.3.1 
Meals and Dietary Restrictions .................................................... 66 
6.3.2 
Activity ......................................................................................... 66 
6.3.3 
Screen Failures............................................................................ 66 
6.3.4 
Screening under Other GSK Studies ........................................... 66 


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CCI
CCI


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
10 
Substudy 2 
 
1 
SYNOPSIS 
GSK3845097 belongs to the second generation of NY-ESO-1 TCR engineered T cells 
that incorporate additional sequences on the lentiviral vector construct to encode genes 
for molecules that would enhance T-cell function within the tumor micro-environment 
(TME). 
GSK3845097 is modified by multi-component engineering to enable co-expression, 
alongside the NY-ESO-1c259 TCR, of the dnTGF-βRII receptor to decrease the potential 
inhibition of T-cell function by the TME. 
This is a first time in human (FTIH) non-randomized, open-label substudy to investigate 
GSK3845097 in previously treated participants with advanced (metastatic or 
unresectable) synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS). This 
substudy will consist of two phases: Dose Confirmation Phase and Dose Expansion Phase 
as follows: 
Substudy 2 Design 
 
NOTE:  Participants included in different substudies may have the same eligibility criteria.  
Sponsor will inform Investigators of the participant assignments between substudies and indicate if the 
participant is a sentinel participant and the number of remaining slots.  
LTFU = long-term follow-up; MRCLS = myxoid/round cell liposarcoma; PD = progressive disease; 
RP2D = recommended phase 2 dose; SS = synovial sarcoma 
 
See Section 1 Synopsis in the Core Protocol for overall study summary. 


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CCI


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
12 
Substudy 2 
 
Table 1 
Substudy 2 Schedule of Activities – Screening and Leukapheresis 
Substudy 2:  Screening and Leukapheresis 
 
Screening 
Phase1 
Leukapheresis 
Notes 
Target 
Expression 
Screening2 
Leukapheresis 
Eligibility 
Screening, 
within 28 days 
prior to 
leukapheresis3 
Informed Consent for Screening1 
X 
 
 
1. 
Written informed consent must be obtained prior to performing any study 
assessments or procedures, except as stated in footnote 10. Informed 
Consent for Leukapheresis and Treatment must be repeated if given more 
than 90 days prior to leukapheresis procedure. 
2. This visit may be performed under a separate protocol when it is introduced. 
3. Participants must be 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 tumor prior to 
conducting leukapheresis eligibility screening procedures. 
4. Only collect this sample if optional Genetics Research Consent has been 
signed by the participant. Sample may be collected any time from signature of 
optional consent until leukapheresis. Liquid biopsy is a blood sample from 
which circulating cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and 
exosomes may be extracted.  
5. Medical history and tobacco use will be recorded in the eCRF at 
Leukapheresis Eligibility Screening and at Treatment Fitness and 
Eligibility/Baseline visits; however, any changes in medical history must be 
recorded in source documents throughout the conduct of the study. 
6. Includes all prescription, over-the-counter medications, and herbal remedies. 
Any use of mutagenic agents or investigational agents must also be reported. 
7. Can be performed at any time within 7 days prior to the day of leukapheresis. 
8. CD3 count prior to leukapheresis should be preferably performed within 
24 hours prior to leukapheresis procedure. 
9. Includes temperature, blood pressure (in triplicate), pulse rate, respiratory 
rate, and pulse oximetry. 
Informed Consent for Leukapheresis 
and Treatment1 
 
X 
 
Inclusion/Exclusion for Screening 
X 
 
 
Inclusion/Exclusion for Leukapheresis 
 
X 
 
Demographics 
X 
 
 
Central Laboratory HLA -A*02:01, 
A*02:05, or A*02:06 genotyping3 
X 
 
 
Tumor expression of NY-ESO- 1 and/or 
LAGE-1a3 
X 
 
 
Liquid biopsy (blood)4 
X 
 
 
Medical History and Tobacco use5 
 
X 
 
Prior/Concomitant Medications6 
 
X 
X 
Height and Weight 
 
X 
 
Physical Exam (complete) 
 
X 
X7 
ECOG  
 
X 
 
12-lead ECG (in triplicate) 
 
XXX 
XXX7 
Vital Signs9 
 
X 
X7 
ECHO/MUGA 
 
X10 
 


TMF-14682598 
CONFIDENTIAL 
 
 
 
209012 
 
 
Protocol Amd 04 
 
13 
Substudy 2 
 
Substudy 2:  Screening and Leukapheresis 
 
Screening 
Phase1 
Leukapheresis 
Notes 
Target 
Expression 
Screening2 
Leukapheresis 
Eligibility 
Screening, 
within 28 days 
prior to 
leukapheresis3 
CT / MRI 
 
X11 
 
10. ECHO/MUGA, brain MRI and laboratory assessments performed as standard 
of care prior to study consent will be acceptable as long as assessment is 
done within 28 days before leukapheresis.  
11. CT/MRI scan confirming disease progression can be performed at any time 
following participant’s last round of prior treatment. Any FDG PET/CT 
performed as part of clinical routine at the same time will also be collected. 
12. In addition to the Brain MRI, MRI of the spine will be performed when clinically 
indicated.  
13. If leukapheresis is rescheduled, existing brain MRI results will be accepted if 
obtained within 2 months prior to the rescheduled procedure and the 
participant has no new neurological symptoms. 
14. PFTs will include FEV1, FVC, TLC, and DLCO will be measured to determine 
eligibility. PFTs may be assessed at other time points if medically necessary. 
15. WOCBP must have a highly sensitive negative urine or serum pregnancy test 
at Screening for leukapheresis and within 24 h prior to leukapheresis.  
16. Includes HIV, HBV, HCV, HTLV, EBV, CMV, and syphilis (spirochete 
bacterium). 
17. See Section 6.1 Table 10 of this substudy for specifics on renal assessment. 
18. SAEs and AEs assessed as related to study participation (e.g., study 
intervention, protocol-mandated procedures, invasive tests, or change in 
existing therapy) or leading to study withdrawal will be collected from signing 
informed consent for target expression screening. All SAEs and AEs will be 
collected starting at leukapheresis. 
Brain MRI12 
 
X10 
 
Hematology 
 
X10 
X7 
Clinical Chemistry 
 
X10 
X7 
Coagulation Tests 
 
X10 
X7 
Lymphocyte Subset (CD3/CD4/CD8) 
 
X 
X7,8 
Pulmonary function test (PFTs)14 
 
X 
 
FSH, if needed to determine CBP 
 
X 
 
Pregnancy Test15 
 
X15 
X15 
Urinalysis 
 
X10 
X7 
Infectious disease markers16 
 
X10 
 
Creatinine clearance by eGFR or 24h 
urine17 
 
X 
 
Adverse Events and Serious Adverse 
Events 
X18 
X18 
X 
Leukapheresis 
 
 
X 
AE = Adverse event; CBP=child-bearing potential; CMV = Cytomegalovirus; CT = computerized tomography; DLCO = diffusing capacity of the lung for carbon monoxide; 
EBV = Epstein Barr virus; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; FDG = Fluorodeoxyglucose; FEV1= Forced expiratory 
volume in 1 second; FSH = follicle-stimulating hormone; FVC = Forced vital capacity; GFR = glomerular filtration rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 


TMF-14682598 
CONFIDENTIAL 
 
 
 
209012 
 
 
Protocol Amd 04 
 
14 
Substudy 2 
 
immunodeficiency virus; HTLV = human T-lymphotropic virus; MRI = magnetic resonance imaging; MUGA = multigated acquisition; PD = progressive disease; PFT = pulmonary 
function test; SAE = Serious adverse event; TLC = total lung capacity; WOCBP = Women of childbearing potential. 


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
15 
Substudy 2 
 
Table 2 
Substudy 2 Schedule of Activities – Interventional Phase (Lymphodepletion, Treatment, and Follow-up)  
Substudy 2:  Interventional Phase (Lymphodepletion, Treatment and Follow-up) 
 
Treatment 
Fitness & 
Eligibility / 
Baseline 
Lymphodepletion 
T-cell 
Infusion1 
Post T-cell Infusion 
Month 
(1 month = 4 weeks) 
-1 
1 
2 
3-6 
9, then Q3M until 
confirmed PD or 
phase end, 2 
whichever is sooner 
Week 
(Week N visit for N≥1 
is scheduled on 1st day of 
the week = Day 7N-6) 
-3 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
10, 12, 18, 24 or 
until confirmed 
PD, whichever is 
sooner 
 
Day 
-17 to -8 
-7 
-6 
-5 
 -4 
1 
2 
3 
4 
6 
8 
15 
22 
29 
36 
43 
50 
64, 78, 120, 
162  
 
Visit Window 
N/A 
±1 day 
±3 days 
±7 days   
±1 month  
Admission to hospital 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from hospital 
 
 
 
 
 
 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
Treatment Fitness and 
Inclusion/Exclusion for 
Treatment Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Request GSK3845097 
shipment 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med. History & Tobacco 
use5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Physical Exam 
(Complete)6 
X 
X6 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
 Physical Exam 
(Dedicated) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
Prior/Con Meds 7 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Vital Signs 8 and weight 
X 
X6 
X 
X 
X 
X 9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHO/MUGA 20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telemetry 10 
 
 
 
 
 
X 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oximetry 11 
 
 
 
 
 
X 11 
X 
X 
X 
X 
X 
X 12 
X 
X 12 
X 
X 
X 
X 
 


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
16 
Substudy 2 
 
Substudy 2:  Interventional Phase (Lymphodepletion, Treatment and Follow-up) 
 
Treatment 
Fitness & 
Eligibility / 
Baseline 
Lymphodepletion 
T-cell 
Infusion1 
Post T-cell Infusion 
Month 
(1 month = 4 weeks) 
-1 
1 
2 
3-6 
9, then Q3M until 
confirmed PD or 
phase end, 2 
whichever is sooner 
Week 
(Week N visit for N≥1 
is scheduled on 1st day of 
the week = Day 7N-6) 
-3 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
10, 12, 18, 24 or 
until confirmed 
PD, whichever is 
sooner 
 
Day 
-17 to -8 
-7 
-6 
-5 
 -4 
1 
2 
3 
4 
6 
8 
15 
22 
29 
36 
43 
50 
64, 78, 120, 
162  
 
Visit Window 
N/A 
±1 day 
±3 days 
±7 days   
±1 month  
12-lead ECG 13 
XXX 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
CT/MRI 14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 15 
 
 
X 16 
X 
Brain MRI 17 
X 17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICE 18 
 
 
 
 
 
X 19 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Chest X-Ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 21 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry 21 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Uric acid 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Creatinine clearance by 
GFR or 24 h urine 21 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Tests 20, 22 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Ferritin 20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponin and  
NT-proBNP/BNP 20, 23 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
X 
 
 
 
 
X 24 
 
 
 
 
 
 
X 
 
 
 
X 
X 25 
X 25 
Urinalysis 26 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious disease 
markers 27 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV IgG and PCR 28 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Thyroid function tests 29 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP 20 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Substudy 2:  Interventional Phase (Lymphodepletion, Treatment and Follow-up) 
 
Treatment 
Fitness & 
Eligibility / 
Baseline 
Lymphodepletion 
T-cell 
Infusion1 
Post T-cell Infusion 
Month 
(1 month = 4 weeks) 
-1 
1 
2 
3-6 
9, then Q3M until 
confirmed PD or 
phase end, 2 
whichever is sooner 
Week 
(Week N visit for N≥1 
is scheduled on 1st day of 
the week = Day 7N-6) 
-3 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
10, 12, 18, 24 or 
until confirmed 
PD, whichever is 
sooner 
 
Day 
-17 to -8 
-7 
-6 
-5 
 -4 
1 
2 
3 
4 
6 
8 
15 
22 
29 
36 
43 
50 
64, 78, 120, 
162  
 
Visit Window 
N/A 
±1 day 
±3 days 
±7 days   
±1 month  
Adverse Events and 
Serious Adverse Events 30 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transgene Copies 
(Persistence for Safety)  31 
and
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks 12 and 
24 
Month 12 and 
Q6M 32 
Genetic sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphodepletion 
Fludarabine 
 
X6,33 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP Administration 
GSK3845097  
 
 
 
 
 
X 34 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.
On Day 1, all samples will be collected and assessments performed prior to T-cell infusion (within 24 h), unless otherwise specified.  
2.
See Section 5.3.1  of this substudy for the definition of the end of Interventional phase. 
3.
After all of the procedures are complete and participant is deemed ready for discharge by the Investigator. 
4.
As GSK3845097 needs to be on site prior to lymphodepletion, request GSK3845097 no later than 4 working days prior to the day of lymphodepletion. The mechanism of 
request will be provided in Drug Product and Infusion Manual. 
5.
Medical history and tobacco use will be recorded in the eCRF at Screening and Baseline visits; however, any changes in medical history and tobacco use must be recorded 
in source documents throughout the conduct of the study. 
6.
For participants who initiate lymphodepletion on Day -6, the Day -7 visit is not required. A complete physical exam for these participants must occur on Day -6. 
7.
Includes all prescription, over-the-counter medications, and herbal remedies. Any use of mutagenic agents or investigational agents must also be reported. 
8.
Vital signs include temperature, blood pressure, pulse rate, and respiratory rate. 
CCI


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
18 
Substudy 2 
 
9. 
Vital signs on 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 the infusion has started.  
10. Inpatient telemetry must be done for participants with Baseline tumor masses in close proximity to the cardiac muscle for a minimum of three and up to seven days post 
T-cell infusion. 
11. On T-cell infusion day, pulse oximetry should be taken pre-infusion, and at 5, 15 and 30 minutes, and 1, 1.5, 2, and 4 hours after the infusion has started.  
12. Pulse oximetry at these visits will be performed if medically indicated.  
13. ECG can also be performed at other time points if medically indicated. Triplicate ECG will be collected at Baseline and single ECGs at other timepoints. Participants with 
clinically significant cardiovascular risk factors (as per Core Section 9.3.6) will undergo evaluation by a cardiologist prior to lymphodepletion 
14. See Section 9.3.1 in the Core Protocol for scan description and areas to scan. If a participant is found to have a tumor response or PD by imaging and considered to be 
clinically stable by iRECIST criteria (see Section 12.6 in the Core Protocol), a follow-up confirmation scan must be done no earlier than 4 weeks and no later than 8 weeks 
following the scan when response or PD first seen. Any FDG PET/CT or other scans used for tumor assessment performed as per clinical routine will be collected centrally.  
15. CT/MRI at this visit has a window of  7 days. 
16. CT/MRI will not be performed at Week 10. CT/MRI assessments only need to continue until confirmed PD. 
17. Brain MRI should be performed at Baseline in all participants with a history of CNS metastasis. It should be performed at Baseline in participants with no history of CNS 
metastasis if more than 3 months have elapsed between the last brain MRI and the start of lymphodepletion or if they show neurological symptoms consistent with CNS 
metastasis. Brain MRI will be performed at other time points, if clinically indicated. MRI of the spine will be performed, if clinically indicated. 
18. All participants will be monitored as shown in the SOA. Participants with known brain metastases should be monitored at least twice per day for the first 5 days following 
GSK3845097 infusion. If a participant is found to have ICANS, the ICE neurological assessment tool should be used at least twice per day until ICANS is resolved or stable 
(See Section 12.7.8 in the Core Protocol). It can also be used at later visits if indicated.  
19. To be administered prior to T-cell infusion. 
20. If CRS and/or ICANS is suspected, chemistry, hematology, ferritin, coagulation and CRP tests should be performed locally every day for the first week and every other day 
thereafter until symptoms are improving or an alternative diagnosis is confirmed. In addition, if CRS is suspected, cytokine samples will be collected for central analysis 
following same scheduled (per SOA Table 3 footnote 4). In addition, troponin, and N-terminal pro B-type natriuretic peptide (NT-proBNP) / BNP tests should be monitored for 
participants with CRS Grade ≥2 as clinically indicated.  If suspected CRS Grade ≥2, an ECHO/MUGA is required at onset of Grade ≥2 CRS. Additional monitoring must be 
conducted (including inpatient continuous cardiac telemetry monitoring) for a minimum of 3 days post onset and as long as deemed necessary by the Investigator (refer to 
Core Section 12.7.5).   
21. See Section 6.1 Table 10 for specifics on renal assessment.  
22. Coagulation tests include INR, PTT or aPTT, and fibrinogen. Coagulation tests should be taken at baseline, Day 1, 2, 3, 4, 6, 8, and 15. 
23. Troponin and NT-proBNP/BNP tests should be assessed prior to initiation of lymphodepletion. 
24. WOCBP must have a negative urine or serum pregnancy test within 24 h prior to GSK3845097 infusion. If a urine test cannot be confirmed as negative (e.g., an ambiguous 
result), a serum pregnancy test is required.  
25. WOCBP will need to have pregnancy tests performed at all visits indicated in the table for the duration of the contraception period. 
26. In addition to the specified time points, urinalysis will be done at other timepoints if warranted by the symptoms. 
27. Includes HIV, HBV, HCV, HTLV, EBV, and syphilis (spirochete bacterium). 
28. Only participants who are CMV IgG seropositive at Baseline will continue to be monitored for CMV viremia by CMV DNA PCR post Baseline. CMV will also be assessed if 
GBS is suspected. 
29. Thyroid function tests will also be performed at other time points, if clinically indicated. 
30. In all cases of SAE that occur after T-cell infusion, a transgene copy (persistence) sample must be obtained if feasible. 


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31. If possible, this sample also needs to be obtained in case of any SAE that occurs after T-cell infusion. 
32. If no gene modified cells are detected for 2 consecutive assessments post-infusion and the participant is ≥2 years post T-cell infusion, samples for 
 and 
persistence of gene modified cells will be discontinued (Section 9.1.12 of the Core Protocol). 
33. On this day, fludarabine will not be administered to participants t60 years old. 
34. For participants who receive GSK3845097 as split doses of ~30% and ~70%, please see Table 4 and Table 5. 
 
AE = Adverse event; aPTT = Activated PTT; BNP = B-type natriuretic peptide; CMV = Cytomegalovirus; Con Meds = concomitant medications; CRP = C-reactive protein; 
CRS = cytokine release syndrome; CT = computerized tomography; EBV = Epstein Barr virus; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; GBS = Guillain Barre syndrome; GFR = glomerular filtration rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
HTLV = human T-lymphotropic virus; ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-Associated Encephalopathy; INR = International 
Normalized Ratio; Med history=medical history; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NT-proBNP = N-terminal pro-BNP; PCR = Polymerase chain 
reaction; PD = progressive disease; PK = Pharmacokinetics; PTT = partial thromboplastin time; Q3M = every 3 months; Q6M = every 6 months; 
; 
SAE = Serious adverse event; TSH = Thyroid stimulating hormone; VSV-G =vesicular stomatitis virus G protein; WOCBP = Women of childbearing potential. 

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Substudy 2:  PK, Immunogenicity, and 
- Interventional Phase (Treatment and Follow-up) 
 
Sample Type Baseline 
T-cell infusion 
Post T-cell infusion 
Month 
(1 month = 4 weeks) 
 
-1 
1 
2 
3-6  
9, then Q3M until confirmed 
PD or phase end, whichever 
is sooner1,2 
Week 
 
-3 to -2 
1 
2 
3 
4 
6 
8 
12, 18, 24 or until 
confirmed PD, 
whichever is sooner1  
 
Day 
 
-17 to -8 
13 
2 
3 
4 
6 
8 
15 
22 
36 
50 
78, 120, 162  
 
Visit Window 
 
N/A 
±1 day 
±3 days 
±7 days 
±1 month 
Cell phenotype and Functional Assays 
PBMC 
X 



X 

X 
X 
X 
X 
X 
X 
X 
Transgene Copies (Pharmacokinetics)  
PBMC 
X 

X 

X 

X 
X 
X 
X 
X 
X 
X 
dnTGF-βRII Expression Analyses 
Whole Blood 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Cytokine Analyses4 
Serum 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TGF-β analyses 
Plasma 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Serum 

X 




 
X 

X 
X 
Weeks 12 and 24 
X 
Liquid biopsy (blood)5 
Whole blood 
X 
 
 
 
 
 
X 
 
X 
X 
 
X 
X 
Tumor Biopsy6 
Biopsy 
X7 
 
 
 
 
 
 
 
X8 
 
 
X9 
1.
All assessments need to be performed at all visits specified in the Table, up to and including the visit establishing confirmed PD or study withdrawal or discontinuation. There are 
no assessments that need to be performed at Weeks 5, 7, and 10; therefore, Weeks 5, 7, and 10 are not present in this table.  
2.
See Section 5.3.1  of this substudy for the definition of the end of Interventional phase. 
3.
All assessments to be performed prior to T-cell infusions. 
4.
If CRS is suspected, cytokine samples should be collected every day for the first week and approximately every other day thereafter until symptoms are improving or an 
alternative diagnosis is confirmed. 
Notes:   
- For scheduled visits where a cytokine sample collection is already requested, there is no need to collect an additional sample from the CRS collection kit that day.  
- Chemistry, hematology, ferritin, coagulation and CRP tests should also be performed locally following same schedule (per SOA Table 2 footnote 20). 
5.
Blood sample from which circulating cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and exosomes may be extracted should match tumor biopsy visits and imaging (Body 
CT/MRI) visits as well as be taken on Day 8 and Day 22. 
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TMF-14682598 
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Protocol Amd 04 
 
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Substudy 2 
 
6. 
Biopsies for research are at Baseline, at Week 4, and at disease progression, with the exception of participants for whom there is no safely accessible tumor tissue. In addition to 
the indicated collection times, tumor biopsies can be obtained at any time during the study execution if clinically indicated.  
7. 
The Baseline biopsy should be collected anytime within 28 days prior to the start of lymphodepleting chemotherapy. An archived FFPE block from a biopsy taken preferably after 
completion of the participant’s last line of therapy, preferably within 90 days prior to initiating lymphodepleting chemotherapy, may be accepted at the discretion of the Medical 
Monitor (or designee). For participants who already provided a fresh screening biopsy and did not receive any subsequent bridging or standard of care anti-cancer therapy, this 
may be used as the Baseline sample if obtained preferably within 90 days prior to initiating lymphodepleting chemotherapy. 
8. 
Week 4 biopsy must be taken preferably between Days 21-23 if medically feasible, but window for collection is extended until Week 6 visit (Day 39). 
9. 
Must be taken once at confirmed disease progression if medically feasible. 
 
BL = Baseline; PBMC = peripheral blood mononuclear cell; PD = progressive disease; Q3M = every 3 months. 
 


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
22 
Substudy 2 
 
Table 4 
Substudy 2 Schedule of Activities – Interventional Phase (Lymphodepletion, Treatment and Follow-up) for Split 
Dosing 
Substudy 2:  Interventional Phase (Lymphodepletion, Treatment and Follow-up) for Split Dosing 
 
TFE / BL 
Lymphodepletion 
T-cell infusion1 
Post T-cell Infusion 
Month 
(1 month = 4 weeks) 
-1 
1 
2 
3 
3-6 
9, then Q3M until 
confirmed PD or 
phase end2, 
whichever is 
sooner 
Week 
(Week N visit for N≥1 
is scheduled on 1st day of 
the week = Day 7 N-6) 
-3 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10, 12, 18, 24, or 
until confirmed 
PD, whichever 
is sooner 
 
Day 
-17 to -8 
-76 
-66 
-5 
-4 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
13 
15 
22 
29 
36 
43 
50 
57 64, 78, 120, 162 
 
Visit Window 
N/A 
±1 days   
±3 days   
±7 days 
±1 month  
Admission to hospital 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge from hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
 
 
 
 
 
 
 
 
 
 
Treatment Fitness and 
Inclusion/Exclusion for 
Treatment Eligibility 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Request GSK3845097 
shipment 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med. History5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam (complete)6 
X 
X6 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
X 
X 
X 
X 
X 
Physical Exam (dedicated) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
Prior/Con Meds7 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Vital Signs8 and weight 
X 
X6 
X 
X 
X 
X9 
X 
X 
X 
X 
X 
X 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECHO/MUGA20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telemetry 
 
 
 
 
 
X10 
 
 
 
 
 
 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oximetry 
 
 
 
 
 
X11 
X 
X 
X 
X 
X 
X 
X11 
X 
X 
X 
X 
X12 
X 
X12 
 
X 
X 
X 
X 
 
12-lead ECG13 
XXX 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
CT/MRI14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
 
 
 
X16 
X 
Brain MRI17 
X17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICE18 
 
 
 
 
 
X19 
X 
X 
X 
X 
X 
X 
X19 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Chest X-Ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Chemistry20 
X 
X6 
X 
X 
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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Substudy 2:  Interventional Phase (Lymphodepletion, Treatment and Follow-up) for Split Dosing 
 
TFE / BL 
Lymphodepletion 
T-cell infusion1 
Post T-cell Infusion 
Month 
(1 month = 4 weeks) 
-1 
1 
2 
3 
3-6 
9, then Q3M until 
confirmed PD or 
phase end2, 
whichever is 
sooner 
Week 
(Week N visit for N≥1 
is scheduled on 1st day of 
the week = Day 7 N-6) 
-3 to -2 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10, 12, 18, 24, or 
until confirmed 
PD, whichever 
is sooner 
 
Day 
-17 to -8 
-76 
-66 
-5 
-4 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
13 
15 
22 
29 
36 
43 
50 
57 64, 78, 120, 162 
 
Visit Window 
N/A 
±1 days   
±3 days   
±7 days 
±1 month  
Uric acid 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Creatinine clearance by 
GFR or 24 h urine21 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation Tests20,22 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Ferritin20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponin and  
NT-proBNP / BNP20,23 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
X 
 
 
 
 
X24 
 
 
 
 
 
 
X24 
 
 
 
 
 
X 
 
 
 
X 
 
X25 
X25 
Urinalysis26 
X 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious disease 
markers27 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV IgG and PCR28 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Thyroid function tests29 
X25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CRP20 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs and SAEs30 
X 
X6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transgene Copies 
(Persistence for Safety)31 
and 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks 12 and 
24 
Month 12 and 
Q6M32  
Genetic sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphodepletion 
Fludarabine 
 
X6,33 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cyclophosphamide 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IP Administration 
GSK3845097  
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.
On Day 1 and Day 8, all samples will be collected and assessments performed prior to T-cell infusion (within 24 hours), unless otherwise specified.  
2.
See Section 5.3.1  of this substudy for the definition of the end of Interventional phase. 
CCI


TMF-14682598 
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209012 
 
 
Protocol Amd 04 
 
24 
Substudy 2 
 
3. 
After all of the procedures are complete and participant is deemed ready for discharge by the Investigator. 
4. 
As GSK3845097 needs to be on site prior to lymphodepletion, request GSK3845097 no later than 4 working days prior to the day of lymphodepletion. The mechanism of request 
will be provided in Drug Product and Infusion Manual. 
5. 
Medical history will be recorded in the eCRF at Screening and Baseline visits; however, any changes in medical history and tobacco use must be recorded in source documents 
throughout the conduct of the study. 
6. 
For participants who initiate lymphodepletion on Day -6, the Day -7 visit is not required. A complete physical exam for these participants must occur on Day -6. 
7. 
Includes all prescription, over-the-counter medications, and herbal remedies. Any use of mutagenic agents or investigational agents must also be reported. 
8. 
Vital signs include temperature, blood pressure, pulse rate, and respiratory rate. 
9. 
Vital signs on days 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 the infusion has started.  
10. Inpatient telemetry must be done for participants with Baseline tumor masses in close proximity to the cardiac muscle for a minimum of three and up to seven days post T-cell 
infusion. 
11. On T-cell infusion days, pulse oximetry should be taken pre-infusion, and at 5, 15 and 30 minutes, and 1, 1.5, 2, and 4 hours after the infusion has started.  
12. Pulse oximetry at these visits will be performed if medically indicated.  
13. ECG can also be performed at other time points if medically indicated. Triplicate ECG will be collected at Baseline and single ECGs at other timepoints.  Participants with clinically 
significant cardiovascular risk factors (as per Core Section 9.1.6) will undergo evaluation by a cardiologist prior to lymphodepletion. 
14. See Core Section 9.3.1 for scan description and areas to scan. If a participant is found to have a tumor response or PD by imaging and considered to be clinically stable by 
iRECIST criteria (see Section 12.6 in the Core Protocol), a follow-up confirmation scan must be done no earlier than 4 weeks and no later than 8 weeks following the scan when 
response or PD first seen. Any FDG PET/CT or other scans used for tumor assessment performed as per clinical routine will be collected centrally.  
15. CT/MRI at this visit has a window of  7 days. 
16. CT/MRI will not be performed at Week 10. CT/MRI assessments only need to continue until confirmed PD. 
17. Brain MRI should be performed at Baseline in all participants with a history of CNS metastasis. It should be performed at Baseline in participants with no history of CNS 
metastasis if more than 3 months have elapsed between the last brain MRI and the start of lymphodepletion or if they show neurological symptoms consistent with CNS 
metastasis. Brain MRI will be performed at other time points, if clinically indicated. MRI of the spine will be performed, if clinically indicated. 
18. All participants will be monitored as shown in the SOA. Participants with known brain metastases should be monitored at least twice per day for the first 5 days following 
GSK3845097 infusion. If a participant is found to have ICANS, the ICE neurological assessment tool should be used at least twice per day until ICANS is resolved or stable (See 
Section 12.7.8 in the Core Protocol). It can also be used at later visits if indicated.  
19. To be administered prior to T-cell infusion. 
20. If CRS and/or ICANS is suspected, chemistry, hematology, ferritin, coagulation and CRP tests should be performed locally every day for the first week and every other day 
thereafter until symptoms are improving or an alternative diagnosis is confirmed. In addition, if CRS is suspected, cytokine samples will be collected for central analysis following 
same schedule (as per SOA Table 5 footnote 4). In addition, troponin and N-terminal pro-B type natriuretic peptide (NT-proBNP) / BNP tests should be monitored for participants 
with CRS Grade ≥2 as clinically indicated.  If suspected CRS Grade ≥2, an ECHO/MUGA is required at onset of Grade ≥2 CRS. Additional monitoring must be conducted 
(including inpatient continuous cardiac telemetry monitoring) for a minimum of 3 days post onset and as long as deemed necessary by the Investigator (refer to Core 
Section 12.7.5).   
21. See Section 6.1 Table 10 for specifics on renal assessment. 
22. Coagulation tests include INR, PTT or aPTT and fibrinogen. Coagulation tests should be taken at baseline, Day 1 thru 11, 13, and 15. 
23. Troponin, and NT-proBNP / BNP tests should be assessed prior to initiation of lymphodepletion. 


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24. WOCBP must have a negative urine or serum pregnancy test within 24 h prior to each GSK3845097 infusion. If a urine test cannot be confirmed as negative (e.g., an ambiguous 
result), a serum pregnancy test is required.  
25. WOCBP will need to have pregnancy tests performed at all visits indicated in the table for the duration of the contraception period. 
26. In addition to the specified time points, urinalysis will be done at other timepoints if warranted by the symptoms. 
27. Includes HIV, HBV, HCV, HTLV, EBV, and syphilis (spirochete bacterium). 
28. Only participants who are CMV IgG seropositive at Baseline will continue to be monitored for CMV viremia by CMV DNA PCR post Baseline. CMV will also be assessed if GBS is 
suspected. 
29. Thyroid function tests will also be performed at other time points, if clinically indicated. 
30. In all cases of SAE that occur after T-cell infusion, a transgene copy (persistence) sample must be obtained if feasible. 
31. If possible, this sample also needs to be obtained in case of any SAE that occurs after T-cell infusion. 
32. If no gene modified cells are detected for 2 consecutive assessments post-infusion and the participant is ≥2 years post T-cell infusion, samples for 
) and 
persistence of gene modified cells will be discontinued (Section 9.1.12 of the Core Protocol). 
33. On this day (Day -7), fludarabine will not be administered to participants t60 years old. 
 
AE = adverse event; aPTT = Activated PTT; BNP = B-type natriuretic peptide;  CMV = Cytomegalovirus; Con Meds = concomitant medications; CRP = C-reactive protein; 
CRS = cytokine release syndrome; CT = computerized tomography; EBV = Epstein Barr virus; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; GBS = Guillain Barre syndrome; eGFR = estimated glomerular filtration rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
HTLV = human T-lymphotropic virus; ICANS = immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-Associated Encephalopathy; INR = International 
Normalized Ratio; Med history = medical history; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NT-proBNP = N-terminal pro-BNP; PCR = Polymerase chain 
reaction; PD = progressive disease; PK = Pharmacokinetics; PTT = partial thromboplastin time;  Q3M = every 3 months; Q6M = every 6 months; 
; 
SAE = serious adverse event; TFE / BL = Treatment Fitness & Eligibility / Baseline; TSH = Thyroid stimulating hormone; VSV-G = vesicular stomatitis virus G protein; 
WOCBP = Women of childbearing potential. 
CCI
CCI


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Substudy 2:  PK, Immunogenicity, and
 - Interventional Phase (Treatment and Follow-up) for Split Dosing 
 
Sample Type 
BL 
T-cell infusion 
Post T-cell Infusion 
Month 
(1 month = 4 weeks) 
 
1 
2 
3-6 
9, then Q3M until 
confirmed PD or 
phase end, 
whichever is 
sooner1,2  
Week 
 
-3 to -2 
1 
2 
3 
4 
6 
8 
12, 18, 24 or until 
confirmed PD, 
whichever is sooner1 
 
Day 
 
-17 to -8 
13 
2 
3 
4 
6 
7 
83 
9 
10 
11 
13 
15 
22 
36 
50 
78, 120, 162 
 
Visit Window 
 
N/A 
N/A 
±1 days   
±3 days   
±7 days   
±1 month  
Cell phenotype and Functional 
Assays 
PBMC 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
 
Transgene Copies 
(Pharmacokinetics)  
PBMC 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
dnTGF-βRII Expression Analyses Whole Blood 
X 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Cytokine Analyses4 
Serum 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TGF-β analyses 
Plasma 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
Serum 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
Weeks 12 and 24 
X 
Liquid biopsy (blood)5 
Whole blood 
X 
 
 
 
 
 
 
X 
 
 
 
 
X 
X 
X 
 
X 
X 
Tumor Biopsy6 
Biopsy 
X7 
 
 
 
 
 
 
 
 
 
 
 
 
X8 
 
 
X9 
1.
All assessments need to be performed at all visits specified in the Table, up to and including the visit establishing confirmed PD or study withdrawal or discontinuation. There are 
no assessments that need to be performed at Weeks 5, 7, 9, and 10; therefore, Weeks 5, 7, 9, and 10 are not present in this table. 
2.
See Section 5.3.1  of this substudy for the definition of the end of Interventional phase  
3.
All assessments to be performed prior to Tcell infusions. 
4.
If CRS is suspected, cytokine samples should be collected every day for the first week and approximately every other day thereafter until symptoms are improving or an alternative 
diagnosis is confirmed. 
Notes:   
- For scheduled visits where a cytokine sample collection is already requested, there is no need to collect an additional sample from the CRS collection kit that day.  
- Chemistry, hematology, ferritin, coagulation and CRP tests should also be performed locally following same schedule (as per SOA Table 4 footnote 20). In addition, troponin 
and N-terminal pro B-type natriuretic peptide (NT-proBNP) / BNP tests should be monitored for participants with CRS Grade ≥2 as clinically indicated.  
CCI
CCI
CCI


TMF-14682598 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
27 
Substudy 2 
 
5. 
Blood sample from which circulating cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), and exosomes may be extracted should match tumor biopsy visits and imaging (Body 
CT/MRI) visits as well as be taken on Day 8 and Day 22. 
6. 
Biopsies for research are at Baseline, at Week 4, and at disease progression, with the exception of participants for whom there is no safely accessible tumor tissue. In addition to 
the indicated collection times, tumor biopsies can be obtained at any time during the study execution if clinically indicated.  
7. 
The Baseline biopsy should be collected anytime within 28 days prior to the start of lymphodepleting chemotherapy. An archived FFPE block from a biopsy taken preferably after 
completion of the participant’s last line of therapy, preferably within 90 days prior to initiating lymphodepleting chemotherapy, may be accepted at the discretion of the Medical 
Monitor (or designee). For participants who already provided a fresh screening biopsy and did not receive any subsequent bridging or standard of care anti-cancer therapy, this 
may be used as the Baseline sample if obtained preferably within 90 days prior to initiating lymphodepleting chemotherapy. 
8. 
Week 4 biopsy must be taken preferably between Days 21-23 if medically feasible, but window for collection is extended until Week 6 visit (Day 39). 
9. 
Must be taken once at confirmed disease progression if medically feasible. 
BL = Baseline; PBMC = peripheral blood mononuclear cell; PD = progressive disease; Q3M = every 3 months. 


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Substudy 2:  Follow-up after Disease Progression or after Completion of Interventional Phase Follow-up1 
Time post GSK3845097 infusion
Year 12 
Year 2  
Year 3  
Year 4  
Year 5  
Years 6-153  
Months (1 month = 4 weeks) 
3 
6 
12 
18 
24 
30 
36 
42 
48 
54 
60 
Annually 
Visit window 
± 2 weeks 
± 3 months 
± 6 months 
Safety Assessments 
Medical History, Tobacco Use, and Physical Exam4 

X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mutagenic agents, other investigational agents or 
anti-cancer therapies  

X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events and Serious Adverse Events5 

X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X,6 
Pregnancy test for WOCBP7 
<===========================X7===========================> 
Haematology8 

X 
X 
 
X 
 
X 
 
X 
 
X 

Serum chemistry8 

X 
X 
 
X 
 
X 
 
X 
 
X 

Laboratory Assessments 
Transgene Copies (Persistence) for safety association 
) for safety8,9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Assessments 
Survival Status10 

X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1.
If a site visit is not feasible, then medical evaluation of participants may take place via telemedicine (e.g. phone call or video conferences) where country and/or local 
regulations allow. Where applicable country and local regulations and infrastructure for home healthcare allow, upon approval by the sponsor, home healthcare may take 
place at a location other than the clinical trial site to perform study assessments, which may include medical history, physical exam, collection of blood samples, 
measurement of height and weight. Remote visits may be performed upon approval by the sponsor at the participant’s home by qualified study personnel or at a local medical 
facility, unless the Investigator deems that a site visit is necessary. 
2.
Participants will continue with all interventional phase assessments until disease progression when they will transfer to the follow-up portion of the study. To ensure adequate 
collection of safety information, participants must remain in the interventional portion of the study for at least 90 days post T-cell infusion. 
3.
Participants who do not have persistence of gene modified cells may be followed remotely during years 6-15. 
4.
New medical history/medications/chemotherapies. 
5.
Adverse Event and Serious Adverse Event collection is limited to: 
a.
New malignancies 
b.
New incidence or exacerbation of a pre-existing neurologic disorder 
c.
New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder 
CCI


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d.
New incidence of a hematologic disorder 
e.
New incidence of infection (potentially related to gene-modified cell therapy) 
f.
Unanticipated illness and/or hospitalization deemed related to gene modified cell therapy 
6.
During years 6-15 of annual follow-up period, AEs and SAEs will be entered in the CRF if reported by the participant or investigator. 
7.
For Women of child-bearing potential (WOCBP), pregnancy testing should be conducted during contraception period only. When pregnancy testing is performed at visits 
where hematology sample is collected, blood pregnancy testing will be done. At visits where hematology sample is not collected, urine pregnancy test is acceptable unless 
serum testing is required by local regulation or IRB/IEC. 
8.
If a visit for medical evaluation is conducted via telemedicine, a site visit to collect a blood samples should be performed as soon as practicable. 
9.
If no gene modified cells are detected for 2 consecutive assessments post infusion and the participant is ≥2 years post T-cell infusion, samples for 
 and 
persistence of gene modified cells will be discontinued (Section 9.1.12 of the Core Protocol). 
10. If a participant is contacted between the scheduled visits, the date of last contact should be recorded as an unscheduled visit.  
 
; VSV-G =vesicular stomatitis virus G protein.
CCI
CCI


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3 
INTRODUCTION 
3.1 
Background and Rationale  
Core Protocol Section 3.1 describes the rationale for investigating second generation 
T-cell therapy. Core Protocol Section 3.2 provides background information on TCR 
approach, NY-ESO-1, and GSK3377794 (letetresgene autoleucel, lete-cel).  
The background and rationale for investigating the specific second-generation product, 
GSK3845097 in SS and MRCLS are provided in this section.  
3.1.1 
GSK3845097  
GSK3845097 is a second-generation T-cell therapy product based on GSK3377794 
(lete-cel). Both products are autologous CD4+ and CD8+ T cells that have been 
transduced with a SIN lentiviral vector expressing the identical affinity-enhanced 
NY-ESO-1 and/or LAGE-1a specific TCR. In addition to the antigen-specific TCR, 
GSK3845097 co-expresses dnTGF-βRII (a mutant, truncated non-signaling TGF-βRII), 
aiming to resist T-cell inhibitory effects of TGF-β in the TME.  
Tumor cells can evade an immune attack by creating an immunosuppressive TME 
(e.g., by secretion of cytokines that suppress T-cell activity) [Anderson, 2017]. 
Transforming growth factor beta (TGF-β) is a soluble cytokine, which has been found at 
high levels in solid tumors and contributes to their resistance to immunotherapies 
including T-cell therapy [Ganesh, 2018]. TGF-β promotes cancer progression by directly 
promoting metastasis, as well as suppressing anti-tumor immunity. Binding of TGF-β to 
its cognate receptor on the T-cell surface initiates intracellular signaling pathways, 
leading to decreased T-cell activation or even apoptosis. This inhibitory TGF-β signaling 
can be prevented by overexpression of a dominant-negative TGF-β receptor type II 
(dnTGF-βRII), which has been mutated to be incapable of inducing this T-cell inhibitory 
signaling pathway. The expression of dnTGFβ-RII by transduced T cells has been shown 
to enhance the in vitro proliferative potential and in vivo expansion of CAR-T cells in 
xenograft mouse models of solid cancer [Kloss, 2018]. 
In clinical trials investigating safety and tolerability of adoptively transferred virus 
specific T cells [Bollard, 2018] or PSMA CAR-T cells [Narayan, 2018] co-expressing 
dnTGF-βRs, to date there have not been any concerning toxicities above those that are 
typically observed with T-cell therapies. More than 40 patients have been treated with 
such engineered or native immune-receptor cell products that express dnTGF-R without 
revealing any signs of toxicity caused by expression of dnTGF-βRs on autologous 
T cells. Clinical trials that have published results, indicate an acceptable safety profile 
[Amaria, 2018; Bollard, 2018; Narayan, 2018]. More information on the targets, 
indications, dosing regimens, lymphodepleting regimens etc. for these studies is provided 
in Table 7. 
In presence of TGF-, GSK3845097 has demonstrated enhanced efficiency against 
NY-ESO-1/LAGE-1a positive tumor cell lines compared to first generation GSK3377794, 
which is lacking the dnTGF-RII component. Pre-clinical assessment of GSK3845097 is 
described in IB [GlaxoSmithKline Document Number RPS-CLIN-015260].  


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Table 7 
Clinical Studies Investigating Autologous T Cells Expressing dnTGF-βRs 
Product and 
Sponsor 
Target 
NCT# 
Phase and 
Study status 
(Ongoing, 
Closed) 
Indication 
Dose 
LD regimen 
# pts 
Planned/ 
Dosed 
Safety data, with a 
focus on (a) pulmonary 
events; (b) 
neurotoxicity; (c) CRS. 
Reference 
CAR T cells 
 
University of 
Pennsylvania 
PSMA 
NCT03089203 
I 
(recruiting) 
Advanced 
Castrate 
Resistant 
Prostate 
Cancer 
Cohort 1: 1-3 × 107 (10-30 million)/m2 
cells on day 0 
 
Cohort 2: 1-3 × 108 (100-300 
million)/m2 cells on day 0 
 
Cohort 3: MTD on day 0 
Cohort 1 and 2: no 
LD 
 
Cohort 3: 
Cyclophosphamide 
300 mg/m2 and 
fludarabine 30 
mg/m2 on Day -3 
18 / 6 
ASCO 2019: no DLT in 
Cohorts 1/2 
6 patients received CAR-T 
PSMA dnTGFβR cell 
infusions at the specified 
dose levels 
2 patients had Grade 2 
CRS responsive to 
tocilizumab 
1 patient had Grade 3 
neurotoxicity requiring 
corticosteroids 
Johnson, 
2009, 
Kloss, 2018,  
Narayan, 2018 
Autologous/ 
syngeneic or 
allogeneic 
EBV(LMP)-
specific CTLs  
 
Baylor College 
of Medicine 
LMP-1, 
-2a 
NCT00368082 
I 
(active, not 
recruiting) 
Lymphoma, 
Hodgkin's 
Disease, 
Relapsed 
Lymphoma, 
Non-
Hodgkin 
Lymphoma 
Each patient received 2 T-cell 
infusions 14 days apart, according to 
the following dosing schedules: 
 
Group 1: Day 0 & Day 14 = 2 × 107 
(20 million) cells/m2 
 
Group 2: Day 0 & Day 14 = 6 × 107 
(60 million) cells/m2 
 
Group 3: Day 0 & Day 14 = 1.5 × 108 
(150 million) cells/m2 
None 
8 / 8 
No immediate toxicity was 
observed. 
Bollard, 2018 


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Product and 
Sponsor 
Target 
NCT# 
Phase and 
Study status 
(Ongoing, 
Closed) 
Indication 
Dose 
LD regimen 
# pts 
Planned/ 
Dosed 
Safety data, with a 
focus on (a) pulmonary 
events; (b) 
neurotoxicity; (c) CRS. 
Reference 
TGFβdnRII-
transduced 
Autologous TILs 
+ high dose IL-2 
 
M.D. Anderson 
Cancer Center 
general TIL 
increase, 
NGFR 
NCT01955460 
I 
(recruiting) 
Metastatic 
Melanoma 
TGFb DNRII-transduced autologous 
TIL on day 0.  
NGFR-transduced autologous T 
lymphocytes on day 0. 
High-dose Interleukin-2 on days 1-5 
(up to 15 doses) and 22-26 (up to 15 
doses). 
Cyclophosphamide 
on days -7 and -6,  
Fludarabine 
phosphate daily on 
days -5 to -1 
15 / 15 No added toxicity from the 
gene modified TIL  
Toxicities attributed to LD 
and IL-2 
Amaria, 2018 
CAR T cells  
 
Baylor College 
of Medicine 
EBV/ 
Her2 
NCT00889954 
I 
(completed) 
Breast, CNS, 
Glioblastom
a, 
Colorectal, 
Esophageal, 
Gastric, 
Head/Neck, 
NSCLC, 
Pancreas, 
Prostate 
TGFBeta resistant HER2/EBV-
specific CTLs. Each pt will be 
followed for 6 weeks after the CTL 
infusion for evaluation of dose 
limiting toxicity (DLT). 
Up to six additional doses at 6 to 12 
weeks intervals 
None 
20 
No results 
N/A 
EBV-specific 
CTL  
 
Baylor College 
of Medicine 
EBV 
NCT02065362 
I 
(active, not 
recruiting) 
Nasopharyn
geal 
Carcinoma 
Dose Level 1: Day 0 & Day 14 = 
2 × 107 (20 million) total T cells/m2 
Dose Level 2: Day 0, Day 1 or Day 2 
= 4 × 107 (40 million) total T cells/m2 
Dose Level 3: Day 0, Day 1 or Day 2 
= 1 × 108 (100 million) total T cells/m2 
Dose Level 1: None 
Dose Level 2: 
Cy/Flu on Days -4 
to -2  
Dose Level 3: 
Cy/Flu on Days -4 
to -2 
14 
No results 
N/A 


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Product and 
Sponsor 
Target 
NCT# 
Phase and 
Study status 
(Ongoing, 
Closed) 
Indication 
Dose 
LD regimen 
# pts 
Planned/ 
Dosed 
Safety data, with a 
focus on (a) pulmonary 
events; (b) 
neurotoxicity; (c) CRS. 
Reference 
HPV-specific 
CTL 
 
Baylor College 
of Medicine 
HPV-16/18; 
E6/E7 
NCT02379520 
I 
(recruiting) 
Relapsed 
HPV-
associated 
cancers 
Dose Level 1: 1 × 107 (10 million) 
cells/m2 
Dose Level 2: 3 × 107 (30 million) 
cells/m2 
Dose Level 3: 1 × 108 (100 million) 
cells/m2 
If patients have clinical benefit (as 
determined by symptoms, physical 
exam or radiological studies) & no 
significant toxicities, they may get up 
to 5 repeat infusions (for max total of 
6 infusions) of HPVSTs at or below 
the same dose level. 
 
Group A -HPVST cells only 
Group B -lymphodepletion & 
nivolumab & HPVST cells. 
 
Nivolumab (Group B) : 240mg every 
2 weeks (3 days) starting on day -1 
Groupe A: 
None 
 
Groupe B: 
Cyclophosphamide: 
500mg/m2/day × 3 
days (on days -4, -3 
and -2) 
Fludarabine: 
30mg/m2/day × 3 
days (on 
days -4, -3, and -2) 
32 
No results 
N/A 
TCR T cells 
 
Roswell Park 
Cancer Institute 
NY-ESO-1 NCT02650986 
I/IIa 
(recruiting) 
Locally 
advanced or 
stage IV 
solid tumors 
NY-ESO-1 reactive TCR retroviral 
vector transduced autologous PBL 
with TGFbDNRII-transduced 
autologous TILs infusion on day 0. 
Cyclophosphamide 
on days -5 and -4. 
24 
No results 
N/A 
 


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3.1.2 
Synovial Sarcoma 
Soft Tissue Sarcomas (STS) are a heterogeneous group of connective tissue cancers 
originating from mesenchymal cells and their precursors [Blay, 2014] representing ~1% 
of all cancers in adults worldwide each year and accounting for ~2% of cancer related 
mortality [Singer, 2000; Amankwah, 2013]. STS consists of approximately 50 
histological subtypes [Amankwah, 2013], each with distinct specific characteristics, 
including differential chemo-sensitivity.  
SS is a rare malignancy accounting for approximately 5–10% of all STS [Riedel, 2018; 
Noone, 2018; Brennan, 2016; Honoré, 2015]. The estimated incidence of SS is 0.15 per 
100,000 in the United Stated (U.S.) and 0.14 per 100,000 in the UK [Wang, 2017; 
Stacchiotti, 2018; Brennan, 2016].  
SS is a life-threatening disease with a 5-year overall and cancer-specific survival of 
50-60% in adult patients [Spillane, 2000; Lewis, 2000; Singer, 2000]. For patients 
presenting with localized disease, standard treatment consists of a wide surgical excision 
or radical surgery of the primary tumor, combined with adjuvant radiotherapy for 
intermediate-high grade tumors and deep tumors >5 cm in diameter. There is no clear 
role of neoadjuvant and adjuvant chemotherapy in high risk patients. Approximately 50% 
of patients with SS will develop metastatic disease [Ten Heuvel, 2009; Krieg, 2011], and 
the survival for patients developing metastatic disease is approximately 12-15 months. 
These rates have not improved over the last 2 decades.  
Standard first-line treatment in patients with advanced, unresectable, or metastatic SS 
consists of anthracycline chemotherapy as single agent or as part of combination 
regimens (e.g., doxorubicin with ifosfamide), which induces responses in 18-30% 
[Spurrell, 2005; Sleijfer, 2010; Vlenterie, 2016]. Dacarbazine is also authorized in some 
countries in the EU for the advanced soft tissue sarcoma as a part of combination 
chemotherapy and dacarbazine monotherapy response rates range from 4% to 6% in 
prospective studies [Dacarbazine SmPC, 2020].  
After failure of anthracycline-based chemotherapy, few options exist for patients to be 
treated in second-line setting. These patients have poor clinical outcomes with currently 
available treatments.  
Pazopanib (Votrient) is authorized by EMA and by FDA for treatment of patients with 
metastatic STS who have failed prior chemotherapy. However, response rates in SS are 
low, ranging from 4% to 13%, and this offers no improvement in overall survival 
[Votrient SmPC, 2018; Votrient USPI, 2017]. Trabectedin (Yondelis) is approved in the 
EU for patients with advanced soft tissue sarcoma, after failure of anthracyclines and 
ifosfamide, or who are unsuited to receive these agents. Trabectedin (Yondelis) is also 
approved in the U.S. for select histological subtypes of STS (liposarcoma and 
leiomyosarcoma). Efficacy data are based mainly on liposarcoma and leiomyosarcoma 
and demonstrated overall response rates of <10% in Phase 3 studies [Yondelis SmPC, 
2012; Yondelis USPI, 2015]. While the registration studies with trabectedin did not 
include SS patients, in a Phase 2 study, SS patients treated with trabectedin demonstrated 


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an ORR of about 10% [Sanfilippoa, 2015]. Trabectedin has also not been shown to 
improve survival in any sarcoma population.  
It has been recognized that a proportion of patients with soft tissue sarcomas, and up to 
76% of SS, express high levels of the cancer testis antigen NY-ESO-1 [Lai, 2012] and 
GSK3377794 (lete-cel) has demonstrated clinical activity in SS (See Section 3.2 of this 
Substudy).  This warrants investigation in SS.  
3.1.3 
Myxoid/Round Cell Liposarcoma (MRCLS) 
Liposarcomas (LPS) are the most common type of STS in adults and, as such, arise from 
mesenchymal cells and express adipose features [Moreau, 2012; Haniball, 2011]. 
MRCLS is the second-most common histologic subtype-comprised of both myxoid 
liposarcoma (MLS) and round cell liposarcoma (RCLS)-with the chromosomal 
translocation t(12;16)(q13;q11) found in >90% of tumors [Moreau, 2012; Haniball, 2011; 
Manji, 2016]. RCLS is a poorly differentiated, high-grade variant of MLS defined by 
>5% round cell component in the tumor [Moreau, 2012; Smith, 1996; Fiore, 2007]. In a 
retrospective study comparing MLS and RCLS in 29 patients, MLS was generallyfound 
to be low-grade and responds well to chemotherapy [Amer, 2020]. Whereas, RCLS is 
usually more aggressive, has higher rates of metastasis, poorer prognosis, and a poorer 
response to chemotherapy relative to MLS, though response to chemotherapy is better 
overall compared to other STS histologic subtypes [Amer, 2020; Smith, 1996; Fiore, 
2007].  
MRCLS accounts for approximately 40% of LPS and 10% of all STS [Pollack, 2012]. 
MRCLS is a rare disease with an incidence rate of approximately 0.21 per 100,000 
[Bock, 2020].  
Predicting MRCLS prognosis is challenging in that tumor site, grade, depth, necrosis, and 
potentially patient age are used to determine outcome at the time of diagnosis [Moreau, 
2012; Haniball, 2011]. Unlike most sarcomas, MRCLS has a propensity for 
extrapulmonary metastasis to soft tissue and bone, occurring in 14-38% of patients 
[Moreau, 2012; Gouin, 2019]. Consequently, metastases during staging and follow-up are 
sometimes missed [Moreau, 2012]. In general, the 5-year overall survival is 76.4-91% for 
MLS and 54.9-79% for RCLS [Moreau, 2012; Amer, 2020]. However, diagnosis of bone 
metastases is an indicator of poor survival, which is reflected in the drastic decline of the 
5-year overall survival to 16%, with median survival ranging from 8.5 to 21.9 months 
indicating metastatic MRCLS is a life-threatening disease [Gouin, 2019].  
Patients with locally recurrent, unresectable, or metastatic disease are treated with 
chemotherapy [Amankwah, 2013]. First-line therapy utilizes an anthracycline-based 
regimen (i.e., doxorubicin either as a monotherapy or in combination with ifosfamide) 
and has a 48% response to treatment [Manji, 2016; Amankwah, 2013]. Both trabectedin 
and eribulin are approved for use in patients treated with a prior anthracycline-containing 
regimen [Manji, 2016]. Trabectedin demonstrates a median PFS of 5.6 months in 
MRCLS and eribulin has a median OS of 13.5 months for all LPS [Manji, 2016].  


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Given the lack of treatment options and low response rates in unresectable/metastatic 
disease, there is a clear unmet medical need. Furthermore, in one study evaluating 
NY-ESO-1 expression in MRCLS, 100% stained positive for NY-ESO-1, with 23 of the 
25 samples staining at least 2+ [Pollack, 2012]. This indicates that MRCLS patients may 
be good candidates for NY-ESO-1 TCR T cells. 
3.2 
Benefit/Risk Assessment 
3.2.1 
Risk Assessment 
GSK3845097 has not been tested in humans prior to this study; therefore, the known 
safety profile of this IP comes primarily from the nonclinical information obtained to date 
(see GSK3845097 Investigator’s Brochure [IB GlaxoSmithKline Document 
Number RPS-CLIN-015260; Smith, 2015]) and the safety profile of GSK3377794 
(letetresgene autoleucel, lete-cel). For the most up-to-date safety and benefit/risk 
assessment information on GSK3901961 [IB GlaxoSmithKline Document Number RPS-
CLIN-015261] and GSK3377794 [IB GlaxoSmithKline Document Number RPS-CLIN-
015027] please refer to the most recent versions of their respective Investigator’s 
Brochures. 
Clinical Safety Profile of GSK3377794 (lete-cel) 
The known safety profile of GSK3377794 (lete-cel) is based on 166 enrolled and 
125 treated participants as of 27 January 2021 (see GSK3377794 IBv13, 
GlaxoSmithKline Document Number RPS-CLIN-015027). The most commonly reported 
treatment-emergent adverse events which occurred in 50% of participants following 
lymphodepleting chemotherapy and GSK3377794 (lete-cel) infusion were 
leukopenia/WBC decreased (81%), neutropenia/neutrophil count decreased (80%), 
nausea (78%), anemia/RBC decreased (78%), thrombocytopenia/platelet count decreased 
(77%), fatigue (70%), pyrexia (66%), diarrhea (57%), and lymphopenia/lymphocyte 
count decreased (54%).   The most common Grade 3 and 4 AEs which occurred in 50% 
of participants following lymphodepleting chemotherapy and GSK3377794 infusion were 
leukopenia/WBC decreased (78%), neutropenia/neutrophil count decreased (74%), 
thrombocytopenia/platelet count decreased (62%), anemia/RBC decreased (58%), and 
lymphopenia/lymphocyte count decreased (52%). These AEs are consistent with 
expected immediate adverse events after lymphodepletion chemotherapy. These events 
are also consistent with those observed after the first infusion with lete-cel. 
Across all studies, 47 (38%) participants had SAEs considered by the Investigator to be 
related to study treatment. The most common treatment-related SAEs occurring in more 
than 2 subjects were as follow: CRS (15%), pyrexia (6%), neutropenia/neutrophil count 
decreased (5%), rash/rash maculo-papular (4%), thrombocytopenia/platelet count 
decreased (4%), and febrile neutropenia (3%).  
Among the adverse events of special interest are the following:  
• 
CRS was reported in 52 cases (of 125) as of 27 January 2021 across all 
GSK3377794 (lete-cel) clinical trials. Of these, there was 1 participant with Grade 
4, 9 with Grade 3, 21 with Grade 2, and 19 with Grade 1. Twelve  cases were 


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treated with tocilizumab. Median duration of all CRS events was 8-9 days (range 
1-28 days).  
• 
A total of 7 cases (of 125) 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 participants with reported GvHD were from Study 209393 (formerly ADP-01411) 
which required an allogeneic stem cell transplant prior to the T-cell infusion.  
• 
Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported as an 
SAE in 1 case with multiple brain metastasis; this case  was transient and resolved in 
2 days with supportive care. A second case of ICANS (Grade 1) was reported for a 
second participant. This second case was not serious and resolved after 2 days.  
• 
Five (4%) participants had reported treatment-emergent AE of pancytopenia 
(5 participants: 3 with Grade 4, and 1 with Grade 3) or bone marrow failure 
(2 participants: 1 with Grade 5 fatal, and 1 with Grade 3). 
• 
GBS has been reported in 2 participants, both of which completely recovered with 
standard immune-globulin treatment. 
 
To date, none of the analyses for insertional oncogenesis and replication competent 
lentivirus are positive for insertional oncogenesis or replication competent lentivirus. 
Non-Clinical Safety Profile of GSK3845097  
Because of the human specificity, standard toxicology studies cannot be conducted. 
GSK3845097 demonstrated the same potent activity against NY-ESO-1 and/or LAGE-1a 
expressing tumor cell lines as observed with GSK3377794, with no relevant off-target 
responses noted. However, weak normal cell recognition response (IFN release) was 
detected against one tonsil cell line, one liver stellate, and one activated B cell line. These 
weak responses were subsequently shown to be due to recognition of low levels of target 
antigen or unidentified EBV peptides. Of note, a similar weak response with the same 
cell line was noted with GSK3377794 (lete-cel, investigated in ongoing clinical trials). 
In clinical studies with GSK3377794 (lete-cel), there are no findings indicative of 
GSK3377794 recognition and engagement with these cell types.  
No changes in cytokine levels, indicative of acute cytokine release following infusion of 
GSK3845097 were observed in the in vitro whole blood assay. The in vitro alanine scan 
and cellular assay ‘X‐scan’ (amino acid scanning enabling the determination of peptide 
residues critical for TCR engagement) assays did not identify any potential off target 
cross reactivity that would be indicative of potential safety concern in the proposed 
clinical trials. Finally, the in vitro alloreactivity assays showed that GSK3845097 did not 
recognize a different peptide on another HLA class I allele. Furthermore, the findings in 
this in vitro nonclinical safety package are comparable to those noted with GSK3377794 
(lete-cel).  
The potential for carcinogenicity of TCR therapies is considered low because terminally 
differentiated cells are transduced (rather than pluripotent T cells) and the persistence of 
the transduced cells is unlikely to be durable [Conlon, 2018]. Additional safety 
modifications in the vectors used to generate GSK3845097 include SIN LTR sequences 


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and an internal human housekeeping gene (EF-1α) promoter, so the vector does not 
contain enhancer elements that were linked to transactivation of oncogenes in early 
(-retroviral vector mediated) gene therapy clinical trials [Hacein Bey-Abina, 2008]. 
The risk of potential for on- or off-target recognition and engagement on peripheral 
nerves is low based on lack of NY-ESO-1 and LAGE-1a mRNA expression, NY-ESO-1 
protein expression and the reported absence of HLA expression by normal Schwann cells 
and neurons. Pre-clinical assessment of GSK3845097 is described in the IB 
[GlaxoSmithKline Document Number RPS-CLIN-015260]. 
Table 8 
Risk Mitigation Strategy 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Lymphodepleting Chemotherapy (Fludarabine/Cyclophosphamide) 
• Myelosuppression 
• Immunosuppression 
• Bone marrow failure and 
infection 
• Cardiotoxicity 
• Pulmonary toxicity 
• Urinary tract and renal toxicity 
• Veno-occlusive disease 
• Secondary malignancy 
• Hyponatremia 
• Neurotoxicity 
Cases were reported with both 
drugs. 
Please refer to the prescribing 
information of fludarabine and 
cyclophosphamide and Core 
Section 12.7. 
• Autoimmune hemolytic anemia 
• Autoimmune thrombocytopenia  
• Visual impairment 
• Decreased vision 
• Peripheral neuropathy 
Cases were reported with 
fludarabine 
Please refer to the prescribing 
information of fludarabine. 
IP GSK3845097 
Fatal Cardiac arrest 
Potential risk associated with 
lymphodepletion chemotherapy and 
TCR T-cell infusion. There have 
been 2 reports of unexpected 
cardiac arrest. The first occurred 
5 months after T-cell infusion and 
was confounded by hypotension 
due to poor oral intake and 
concurrent renal insufficiency. The 
second occurred approximately 
1 week after T-cell infusion in the 
setting of a recent fungal catheter 
line infection, concurrent treatment 
with caspofungin and multifocal 
pneumonia / edema seen on chest 
CT 
Participants with significant cardiac risk 
factors or with CRS ≥ Grade 2 will 
receive close cardiac monitoring (Core 
Section 9.1.6 and Core Section 12.7.5).  
Participants with lung metastases 
should be considered for pulmonary 
consultation prior to lymphodepletion; 
participants deemed at high risk of 
pulmonary complications should be 
monitored closely (Core Section 9.1.7). 
Central lines should be closely 
monitored for infection (Core 
Section 12.7.2). 
Systemic fungal infections are excluded 
(Exclusions 9) 
Monitoring of risk of increased cardiac 
toxicity with the use of anti-microbials 
(Core Section 12.7.2.6) 
Cytokine Release Syndrome (CRS) 
Identified risk due to TCR T-cell 
infusion, considered an adverse 
event of special interest (AESI) 
I/E criteria exclude participants with 
pre-existing autoimmune disorders 
(Section 6.2 of this substudy). See 
management for CRS, Core 


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Substudy 2 
 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
Section 12.7.5. Events Grade ≥3 must 
be reported as SAEs and submitted to 
GSK within 24 hours. 
Graft vs. Host disease (GVHD) 
Identified risk associated with TCR 
T cells reacting against normal 
tissues and organs, considered an 
AESI  
I/E criteria exclude participants with 
pre-existing autoimmune disorders 
(Section 6.2). See management for 
GVHD, (Core Section 12.7.6) 
Hematopoietic cytopenias  
(including Pancytopenia with bone 
marrow failure/Aplastic Anemia) 
Identified risk associated with 
lymphodepletion chemotherapy, 
considered an AESI 
I/E criteria exclude participants with 
hematologic imbalance. See 
management for pancytopenia, Core 
Section 12.7.7 
Hemorrhage secondary to 
thrombocytopenia 
Identified risk associated with 
lymphodepletion chemotherapy and 
TCR T-cell infusion. There have 
been reports of haemorrhage 
(including intracranial and 
pulmonary) in participants with 
severe, prolonged 
thrombocytopenia 
Protocol guidance on Blood product 
support provides recommendation on 
platelets levels to be maintained in the 
in-patient setting and the out-patient 
setting, as per Core Section 12.7.3 
Hypersensitivity 
Identified risk associated with 
lymphodepletion chemotherapy and 
TCR T-cell infusion, considered an 
AESI 
Participants with history of allergic 
reactions to any agents used in the 
study are excluded. See Section 6.2 for 
details. 
Participants will be premedicated 
against potential infusion reactions with 
antihistamines on the day of TCR T-cell 
infusion. See Section 7.1.4 for details. 
Reactivation of previous viral 
infections after prolonged 
leukopenia 
Identified risk associated with 
lymphodepletion chemotherapy and 
TCR T-cell infusion 
Participants who have received 
radiation to bone marrow that would 
predispose them to prolonged 
cytopenia after lymphodepletion (in the 
investigator’s opinion) are excluded. 
See Section 6.2 for details. 
Lymphodepletion dose will be modified 
in participants with potentially reduced 
bone marrow reserve. See 
Section 7.1.3 for details. 
Participants with active infection are 
excluded. Participants with CMV 
seropositivity will be monitored 
regularly for viral reactivation. For 
HSV/VZV prophylaxis, participants will 
receive acyclovir or valacyclovir for one 
year from LD. Prophylaxis will be given 
to those with HBV seropositivity. See 
Section 6.2 and Core Section 12.7.2 for 
details. 
Neutropenia (including fatal 
neutropenia) 
Identified risk associated with 
lymphodepletion chemotherapy and 
TCR T-cell infusion 
Patients are excluded based on 
absolute neutrophil counts 
(Section 6.1.2). Investigator must 
discuss with Medical Monitor or 
designee to determine the need for 
dose modification of the 
lymphodepletion regimen in 
participants at risk (Section 7.1.3). 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
G-CSF to be administered in 
accordance with ASCO guidelines or 
institutional practice (Section 7.1.3).  
Dose modifications are included for 
fludarabine and cyclophosphamide 
(Section 7.1.3) 
Grade 4 Neutropenia events lasting 
≥28 days must be submitted to GSK 
within 24 hours (Core Section 9.2.7). 
Visual impairment  
Potential risk: There was a report of 
decreased vision in a participant 
who received TCR-T infusion 
following lymphodepletion with 
fludarabine and cyclophosphamide. 
Dose reductions for fludarabine for 
renal impairment are included 
(Section 7.1.3). Investigator must 
discuss with Medical Monitor or 
designee to determine the need for 
dose modification of the 
lymphodepletion regimen in patients at 
risk (Section 7.1.3) 
Guillain-Barré Syndrome 
(GBS)/Acute inflammatory 
demyelinating polyneuropathy 
Potential risk associated with TCR 
T-cell infusion. Two participants 
who received GSK3377794 
developed GBS. 
Participants with prior or active 
demyelinating disease will be excluded 
(Section 6.2). Neurologic consultation 
is required for participants with 
Grade 2 or higher neurologic events of 
a ≥7-day duration. Any potential future 
recurrence of GBS will lead to a pause 
in study enrolment until further 
investigation. 
Treatment-related inflammatory 
response at tumor site(s) 
Identified risk associated with TCR 
T-cell infusion 
Routine monitoring and testing as 
clinically required. 
Immune effector cell-associated 
neurotoxicity syndrome (ICANS) 
Theoretical risk associated with 
inflammation in the brain following 
TCR infusion.  There have been 
reports of ICANS in participants 
who received lete-cel. 
Participants with brain metastases with 
features associated with increased risk 
of ICAN are excluded (Section 6.2). 
Monitoring criteria for ICAN are 
described in Core Section 12.7.8.  
Risk to Females of Reproductive 
Potential 
Safety during pregnancy has not 
been established. It is not known 
whether antigens are excreted in 
human milk and safety during 
lactation has not been established. 
Participants who are pregnant, 
intending to become pregnant, or 
are breastfeeding are excluded 
from TCR-T studies. Preclinical 
reproductive toxicity studies were 
Pregnant and breastfeeding women are 
excluded from study participation. 
Study incorporate specific 
contraception requirements for male 
and female participants 
Pregnancy testing is conducted during 
participation in the study. 
CCI


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Substudy 2 
 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for 
Risk 
Mitigation Strategy 
not conducted because of the 
human specificity of TCR therapy. 
Pulmonary Toxicity 
Theoretical risk. Activation of T cells 
could result in respiratory 
distress/pulmonary toxicity. Severe 
CRS can also be associated with 
pulmonary toxicity. Theoretical risk 
exists for a systemic 
proinflammatory response in 
response to dnTGFβR TCR the 
lung based on observations in 
TGFβ knock out animals. Activation 
of T cells bearing the dnTGFβR 
would predominantly occur due to 
TCR engagement, resulting in local 
anti-tumor effects but minimizing 
systemic impact.  
Participants with insufficient pulmonary 
function are excluded (See Section 6.2 
of this Substudy). Symptoms 
associated with respiratory distress will 
be evaluated during routine safety 
assessments and timely assessments 
by a critical care expert and standard 
supportive care will be given if required 
(e.g., oxygen, intubation).  
On/Off-Target Off-Tumor Risks 
Potential risk associated with use of 
TCR T-cell therapy 
To be monitored in this protocol and in 
the LTFU Protocol. Protocol includes 
eligibility criteria (Section 6.1 and 
Section 6.2), routine PV, and 
management strategies as appropriate 
to limit, diagnose, characterize and 
treat toxicities related to potential risks 
(Core Section 12.7). 
Study Procedures  
Tumor biopsy 
Bleeding, pain, swelling associated 
with the procedure 
Biopsies are performed by trained 
personnel. Image-guided when 
necessary, and performed only if 
deemed safe 
Leukapheresis 
Electrolyte imbalance and bleeding 
at the site of phlebotomy 
Refer to local site procedures and 
guidelines. 
 
3.2.2 
Benefit Assessment  
No clinical studies have been conducted to date with GSK3845097. The clinical benefit 
expected from this IP is based on the clinical benefit observed with GSK3377794 
(lete-cel) and on the considerations of additional advantages provided by the 
multi-component engineering. 
As of 27 January 2021, 125 participants have been treated with GSK3377794. Objective 
responses have been observed in the completed  SS study (208466/ADP-04511) and in 
multiple myeloma post-autologous transplant study (209393/ADP-01411). In Cohort 1 of 
study 208466 (which is similar to the treatment regimen proposed for this protocol), a 
single infusion of GSK3377794 (lete-cel) demonstrated an encouraging response rate of 
50% (6/12 participants, 95% CI: 0.21-0.79), with an encouraging durability of response 
of 30.9 weeks (95% CI: 14-72) and one participant demonstrating a complete response. 
Importantly, the responses induced after T-cell infusion were associated with a median 
survival of approximately 24 months, which represents a marked improvement over a 
median survival of 12 months in relapsed metastatic SS.  


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Objective responses have been observed in 21 (84%) out of 25 of participants in multiple 
myeloma after autologous transplant (study 209393/ADP-01411) [GlaxoSmithKline 
Document Number RPS-CLIN-015027]. 
Additionally, studies conducted by the NCI Surgery Branch have demonstrated that 
adoptive immunotherapy using T cells genetically engineered to recognize NY-ESO-1 
following lymphodepletion led to objective antitumor responses in 4 of 6 patients (67%) 
[Robbins, 2011] and 11 of 18 patients (61%) [Robbins, 2015] with SS. The estimated 
overall three and five-year survival rates for these patients with SS were 38% and 14%, 
respectively [Robbins, 2015]. 
More recently, responses have also been observed in patients with myxoid round cell 
liposarcoma (MRCLS, study 208469) [D'Angelo, 2021]. Nine of 10 patients in Cohort 2 
experienced tumor shrinkage, and 4 of these 10 participants had a confirmed partial 
response. These collective results thereby demonstrated encouraging clinical activity of 
GSK3377794 (lete-cel) across multiple NY-ESO-1 and LAGE-1a expressing tumor 
types.  
3.2.3 
Overall Benefit: Risk Conclusion 
GSK3845097 has not been tested in humans prior to this study. Clinical data initially 
demonstrate the safety and activity of the related product GSK3377794 (lete-cel). The 
typical risks associated with T-cell therapies, such as CRS and neurotoxicity (ICANS), 
have been observed in 42% and 1% of 125 patients treated, respectively, and resolved 
with appropriate management. As GSK3845097 has the same target as GSK3377794 
(lete-cel), their TCR-related safety profile is expected to be similar and acceptable. Any 
additional safety events related to multi-component engineering will be monitored and 
managed in this study; some potential events are also incorporated in the DLT criteria. 
Additionally, the pre-clinical data support target specificity of GSK3845097.  
From the benefit standpoint, enhanced efficacy over lete-cel is expected as a result of 
multi-component engineering. In view of the clinical responses observed in relapsed, 
refractory patients, and as per the risk assessment presented above, the benefit / risk ratio 
supports a FTIH clinical investigation of GSK3845097 in participants with relapsed 
refractory metastatic SS or MRCLS. 


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Objectives 
Endpoints 
Primary 
To assess the safety, tolerability and determine 
recommended phase 2 dose (RP2D) of 
GSK3845097 in HLA-A*02:01, HLA-A*02:05 
and/or HLA-A*02:06 positive participants with 
NY-ESO-1 and/or LAGE-1a positive, previously 
treated, advanced (metastatic or unresectable) 
SS and MRCLS  
x Frequency of dose-limiting toxicities (DLTs)  
x Frequency and severity of adverse events 
(AEs), serious adverse events (SAEs) and 
AEs of special interest (AESI; as defined in 
the core protocol) 
Secondary - Efficacy 
To investigate the anti-tumor activity of 
GSK3845097 in HLA-A*02:01, HLA-A*02:05 
and/or HLA-A*02:06 positive participants with 
NY-ESO-1 and/or LAGE-1a positive, previously 
treated, advanced (metastatic or unresectable) 
SS and MRCLS 
x Overall Response Rate (ORR) (investigator 
assessed according to RECIST v1.1) 
x Duration of Response (DoR) 
 
Secondary - Pharmacokinetics 
To characterize in vivo cellular PK profile (levels, 
expansion, persistence) of GSK3845097over 
time 
x Maximum transgene expansion (Cmax) 
x Time to Cmax (Tmax) 
x Area under the time curve from zero to time 
t AUC(0-t), as data permit 
Exploratory 
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Objectives 
Endpoints 
AE = adverse event/s; AESI = adverse event/s of special interest; AUC (0-t) = area under the time curve from zero to 
time t; Cmax = maximum concentration; CRS = Cytokine Release Syndrome; DLTs = dose-limiting toxicities; 
DNA = deoxyribonucleic acid ; DOR = duration of response; ECG = Electrocardiogram; 
 
; HLA = human leukocyte antigen; 
; 
MRCLS = myxoid/round cell liposarcoma; NY-ESO-1 = New York esophageal antigen-1; ORR = overall response rate; 
; 
; 
 ; RECIST = Response 
Evaluation Criteria In Solid Tumors; RNA = ribonucleic acid; RP2D = recommended phase 2 dose; SAE = serious 
adverse event; SS = synovial sarcoma; Tmax = Time to Cmax; 
; 
 
 
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TMF-14682598 
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Substudy 2 
 
5 
SUBSTUDY DESIGN 
5.1 
Overall Design  
This is a first time in human (FTIH) single cohort, non-randomized, open-label substudy 
to investigate GSK3845097 in previously treated participants with advanced (metastatic 
or unresectable) SS and MRCLS. This substudy will consist of two phases: Dose 
Confirmation Phase and Dose Expansion Phase (Figure 1).  
Figure 1 
Substudy 2 Design 
 
NOTE:  Participants included in different substudies may have the same eligibility criteria.  
Sponsor will inform Investigators of the participant assignments between substudies and indicate if the participant is a 
sentinel participant and the number of remaining slots.  
LTFU = long-term follow-up; MRCLS = myxoid/round cell liposarcoma; PD = progressive disease; 
RP2D = recommended phase 2 dose; SS = synovial sarcoma. 
 
5.1.1 
Dose Confirmation Phase 
Dose confirmation phase will commence first. Sponsor will inform Investigators of the 
participant assignments within this phase and indicate if the participant is a sentinel 
participant (see Core protocol Section 8.1.2 for definition) and the number of remaining 
slots for dose confirmation phase. Once all participants needed for dose confirmation 
(n=6-15) have been assigned, participants will be assigned to dose expansion phase. 
The primary objective of the dose confirmation phase is to identify the recommended 
phase 2 dose (RP2D) of GSK3845097. RP2D will be determined as the maximum 
tolerated dose (MTD) or lower that provides adequate biologic activity with superior 
tolerability. The MTD is defined as the dose that maximizes the probability of target 
toxicity of 30% while controlling the probability of excessive or unacceptable toxicity. 
Dose Selection Committee review will occur after the DLT period in every 3 participants 
to enable dose decision until the final dose selection is achieved (6 to 15 participants). 
The starting dose will be the RP2D of GSK3377794 (lete-cel); that is, the initial group of 
3 participants will receive a dose in the range of 1 × 109 -8 × 109 transduced T cells. If 


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Substudy 2 
 
DLTs are reported that require dose de-escalation according to the mTPI-2 model, then a 
lower dose range of 0.1 × 109 –0.8 × 109 transduced T cells will be explored, with the 
possibility to re-escalate if the model supports such action. Alternative doses may be 
investigated if warranted by the emerging safety profile.  
5.1.1.1 
Split Dosing and Staggered Treatment 
The first study participant receiving GSK3845097 will receive the total assigned dose 
(1 × 109 -8 × 109 transduced T cells) as 2 separate infusions, 7 days apart, in aliquots of 
~30% (first infusion) and ~70% (second infusion) of the total manufactured dose, 
respectively. After the first infusion, participant will remain hospitalized for 7 days and 
be monitored per SOA. If no dose-limiting toxicities (DLTs defined in Section 8.2 of the 
Core Protocol) are reported during this time, participant will receive the second dose and 
be hospitalized for an additional 3 days. If no DLTs are reported for the participant 
receiving split dosing during the stagger period defined in the next paragraph, then all 
subsequent participants treated with the particular investigational agent will receive the 
full dose as a single, i.e. one-time, infusion. If DLTs are reported for the participants 
receiving split doses, additional participants may be treated with a split dose regimen at 
the discretion of the sponsor in consultation with the participating Investigators and the 
DSC.  
At each dose level, dose administration in the first 3 participants will be staggered. 
Initiation of the lymphodepleting regimen in the 2nd and 3rd participant will be separated 
by a minimum of 2 weeks from the complete dose administered to the prior participant to 
enable close monitoring of toxicities in each participant and DSC consultation if needed. 
Once the first 3 participants have received the dose successfully per DSC agreement, 
subsequent participants will receive lymphodepletion and the IP without any delays. 
5.1.1.2 
Determining the RP2D 
To find the RP2D, modified toxicity probability interval 2 (mTPI-2) design will be 
implemented (Table 9) [Guo, 2017]. Participants will be recruited and treated in blocks of 
three.  
The design aims to identify a dose with a true underlying toxicity rate of 30, with a range 
of 25% to 35%. The monitoring rules guiding dose escalation are provided in Table 9. 
Columns provide the numbers of participants treated at the current dose level, and rows 
provide the corresponding numbers of participants experiencing DLTs. The entries of the 
table are dose-finding decisions (i.e., R, S, and D) representing re-escalating the dose, 
staying at the same dose, and de-escalating the dose. In addition, decision U means that 
the current dose level is unacceptable because of high toxicity and should be excluded 
from the trial. For example, when one of three participants experiences toxicity, the 
decision can be located at row 1 and column 3, which is S –to stay at the current dose 
level. Consequently, the next block of participants will be treated at the same dose level 
currently being used. If zero of three participants experience toxicity, the decision is at 
row 0 and column 3, which is R –to re-escalate. Thus, the next block of participants will 
be treated at the higher dose level, if available. If three of three participants experience 


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Substudy 2 
 
toxicity, the decision is U –to de-escalate to the lower dose level and exclude the current 
dose from the trial, because the toxicity level is unacceptable. 
The final determination of RP2D will be based on the mTPI-2 recommended dose, as 
defined as 6 participants treated at this dose and an observed toxicity rate closest to the 
targeted toxicity rate at 30% after isotonic regression , in addition to considering the 
clinical response rate and available PK and PD data generated from all participants.  
Table 9 
DLT De-Escalation/Re-Escalation Rules 
 
Number of participants who received study drug at the current 
dose 
Number of participants with Dose Limiting 
Toxicities (DLTs)  
at the current dose 
 
3 
6 
9 
12 
15 
0 
R  
R 
R 
R 
R 
1 
S 
R 
R 
R 
R 
2 
D 
S 
R 
R 
R 
3 
U 
D 
S 
S 
R 
4 
 
U 
D 
S 
S 
5 
 
U 
U 
D 
S 
6 
 
U 
U 
D 
D 
7 
 
 
U 
U 
D 
8 
 
 
U 
U 
U 
9 
 
 
U 
U 
U 
10 
 
 
 
U 
U 
11 
 
 
 
U 
U 
12 
 
 
 
U 
U 
13 
 
 
 
 
U 
14 
 
 
 
 
U 
15 
 
 
 
 
U 
R=Re-escalate to the higher dose if applicable OR Stay at the current dose otherwise 
S=Stay at the current dose 
D=De-escalate to the lower dose if applicable OR Stay at the current dose otherwise 
U=The current dose is unacceptably toxic; de-escalate to the lower dose if applicable 
 
MTD=30% 
Epsilon1=Epsison2=0.05 
 
For example, in the scenario depicted in Figure 2 below, if there are 2 participants with 
DLTs out of the first 3 dosed at the full dose of 1 × 109 – 8 × 109 transduced cells, the 
dose will be  de-escalated and  the next 3 participants will be treated at the reduced dose 
of 0.1 × 109 – 0.8 × 109 transduced cells. At the low dose, if there are 0 participants with 
DLT out of 3 participants, the dose will be re-escalated and the next 3 participants will be 
treated at the full dose. If 0 participants have DLTs out of these 3 additional participants, 
the full lete-cel dose will be suggested as the RP2D for GSK3845097.  


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Figure 3 
Participant Journey 
 
1. Screening, including HLA typing and antigen testing, may be done in this study or as part of a separate Pre-screening protocol. 
2. Sponsor will inform Investigators of the participant assignments between substudies and indicate if the participant is a sentinel participant and the number of remaining slots. 
3. The first participant to be dosed will receive the total dose in 2 separate infusions as aliquots of ~30% and ~70% of the total manufactured dose, administered 7 days apart. The 
second infusion will only be administered if no acute toxicities preventing full dosing are observed. If no DLTs are reported for the participants receiving split doses, then all 
subsequent participants administered the particular product will receive the full dose as a single, i.e. one-time, infusion.  
4. See Section 5.3.1 of this substudy for definition of the end of interventional phase for a participant.  
5. The LTFU assessments and procedures may be done in this study or under a separate LTFU protocol. 
 
EOT = end of treatment (i.e., interventional) portion of the trial; HLA = human leukocyte antigen; ICF = informed consent form; LTFU = long-term follow-up; MRCLS = myxoid/round cell 
liposarcoma; SS = synovial sarcoma.  
 
Target expression screening 
criteria met
                             
                          
         
Treatment and
Follow-up 
EOT4
Synovial 
Sarcoma 
/MRCLS 
2L+
Participant
Signed 
Screening 
ICF
Leukapheresis
Treatment  eligibility criteria still met
      
  s    
         
s    
Lympho
depletion
         
Interventional Phase
LTFU
End of study participation 
LTFU for 
total of 15 
years5
HLA typing
A*02:01
A*02:05
A*02:06
        
     ss    
  s    
  
    
   
      
       
Leukapheresis & Treatment 
criteria met
            
        s  
       
             
Follow
up
Leukapheresis and Manufacture
GSK3845097 
manufacture
SS/MRCLS 
participant 
enrolled in 
Substudy 22


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Substudy 2 
 
Screening  
See inclusion / exclusion criteria in Section 6 of this Substudy for complete details of 
Screening approach. 
This study will enroll participants with previously treated advanced (metastatic or 
unresectable) SS and MRCLS. 
Target expression Screening will be conducted in participants who have evidence of 
advanced disease and may still be undergoing a prior line of therapy.  
For target expression Screening, once informed consent has been obtained, a blood 
sample will be collected from each participant for testing the presence of HLA-A*02:01, 
HLA-A*02:05 and/or HLA-A*02:06. NY-ESO-1 and/or LAGE-1a expression will also 
be evaluated on representative tumor tissue from a formalin-fixed and paraffin-embedded 
(FFPE) archival (most recent preferred) or fresh biopsy. Central laboratory HLA-typing 
is frequently performed first, followed by tumor antigen expression testing (considering 
the expected >50% attrition with HLA). This testing may also be performed in parallel. If 
an Investigator is aware of a participant’s positive HLA status (the presence of 
HLA-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 based on high resolution local 
testing), the Investigator may provide tumor tissue for antigen testing either at the same 
time as or before a confirmatory HLA test by the central laboratory. The use of the HLA 
and the NY-ESO-1 and/or LAGE-1a tests in this substudy is investigational. 
NOTE: target expression Screening may also be performed under a separate Screening 
protocol such as the GSK molecular disease characterization initiative (MDCI) study 
(213299), or under another GSK-sponsored NY-ESO-1 and/or LAGE-1a targeting T-cell 
protocol or substudy of this protocol, if the tests are identical to the tests in this study and 
performed under the same procedure by the same laboratories. 
Once participants are deemed positive for HLA and tumor antigen expression, they will 
sign the main study informed consent to undergo screening for leukapheresis eligibility 
within 28 days prior to the day of the scheduled leukapheresis procedure. 
Leukapheresis and Manufacture 
Eligible participants, upon study enrollment, will undergo leukapheresis. Leukapheresis 
procedure requires that participant has completed prior line of therapy and has 
radiographic evidence of disease progression. 
The initiation of leukapheresis procedure constitutes enrollment in the study. 
The collected T cells will be sent for manufacturing. 
See Section 5.2 in the Core Protocol and Section 7.1.2 of this Substudy for supportive 
chemo- or radio-therapy administration. 
Interventional Phase 
See Section 5.2 in the Core Protocol. T-cell administration will be performed as follows. 


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who already provided a fresh biopsy for antigen expression screening and did not receive 
any subsequent bridging or standard of care anti-cancer therapy, this screening biopsy 
may be used as the Baseline sample, if the screening biopsy was obtained preferably 
within 90 days prior to initiating lymphodepleting chemotherapy. 
Additional biopsies will also be collected at Week 4, and at disease progression. In 
exceptional cases, where such biopsies cannot be collected, these may be deferred in 
consultation with the sponsor. These cases include participants for whom there is no 
safely accessible tumor tissue; or if conducting such a biopsy would compromise the 
medical condition of the participant; or if other clinical considerations preclude conduct 
of the biopsy procedure. In addition to the indicated collection times, tumor biopsies may 
be obtained at any time during the study execution. 
Refer to Core Section 9.10.1 and the SRM for additional details for tumor biopsies.  
5.2 
Number of Participants 
Up to 10 evaluable participants treated with RP2D are needed for dose expansion phase. 
Up to 9 additional participants may be needed during the dose confirmation phase to 
determine RP2D. Thus, the total expected maximal number of participants is 
approximately 19. 
Any participant who does not receive T-cell infusion will be replaced by additional 
participant(s) assigned to the same dose level.  
Additional participants or additional cohorts may be added to perform further evaluation 
of the efficacy and safety of GSK3845097. 
5.3 
End of Study Definition 
5.3.1 
End of Substudy for Individual Participants 
a) End of Interventional phase for individual participants: 
A participant is considered to have completed the Interventional phase of the substudy 
when one of the following occurs (whichever is sooner): 
• Participant has confirmed disease progression;  
• Participant dies; 
• Interventional phase of the substudy ends (see Section 5.3.2 of this substudy).  
 
If participant withdraws consent or is withdrawn for other reasons prior to substudy 
completion, they will be considered early withdrawal. See Core Section 9.2.1 for AE 
follow-up requirements during the interventional phase. 
All participants alive after the Interventional phase, will be followed in a separate long 
term follow up (LTFU) protocol (GSK study 208750) for observation of delayed AEs and 
survival for a duration of 15 years post–T-cell infusion in accordance with FDA [FDA, 
2020b] and EMA guidance [EMA, 2009]. If LTFU protocol is not yet available at the 


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particular clinical site, participants may be temporarily followed per LTFU schedule 
under this protocol (Section 2 of this Substudy) until LTFU protocol becomes available. 
The transfer of any individual participant to the LTFU protocol 208750 should occur 
within 6 months of completing the interventional portion of the study.  
b) End of substudy for individual participants 
The substudy ends for an enrolled participant when they have transferred to the separate 
LTFU protocol (GSK study 208750), declined consenting to the separate LTFU protocol, 
completed LTFU requirement in this study, have been lost to follow-up, or withdrawn, or 
died. 
5.3.2 
End of Substudy  
a) End of interventional phase 
• The Interventional phase of the substudy ends when 80% of the total number of 
participants dosed with RP2D have confirmed disease progression or died or have 
been lost to follow-up or withdrew early. and all the remaining dosed participants 
(including any treated at doses other than the RP2D) have been followed for at 
least 1-year post infusion or have confirmed disease progression or died or were 
withdrawn or lost to follow-up from the substudy.  
b) End of substudy 
• This substudy ends when all enrolled participants have moved to the separate 
LTFU protocol (GSK study 208750), declined consenting the LTFU protocol, 
completed LTFU requirement in this study, have been lost to follow-up, or 
withdrawn early, or died.  
 
5.4 
Justification for Population 
The target population for treatment with GSK3845097 of previously treated, advanced 
(metastatic or unresectable) SS and MRCLS patients has taken into consideration the 
high unmet medical need for this population. Additionally, inclusion of participants with 
SS enables GSK to seek early signals of efficacy improvements of GSK3845097 over 
GSK3377794 (lete-cel), given that data from pilot Study 208466 and 208469 suggest that 
GSK3377794 provides clinical benefit in the 2L+ setting.  
5.5 
Justification for Dose 
5.5.1 
Dosing Rationale 
The proposed starting dose range is 1 × 109 -8 × 109 transduced T cells, which is also the 
RP2D for GSK3377794 (lete-cel) and is within the range used in other TCR-T or more 
generally ACT studies, and also the range that is currently being used for GSK3377794 
(lete-cel) clinical trials. If required by the observed DLT rate, the dose range will be 
lowered to 0.1 × 109 – 0.8 × 109 transduced T cells 


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This proposal to start at RP2D for GSK3377794 (lete-cel) is based on a detailed 
assessment of the structure and properties of GSK3845097 and its expected mechanism 
of action, taking into account existing data with GSK3377794 and other ACTs as well as 
similarities and differences between GSK3377794 and GSK3845097, as described in 
Section 3.2 of this Substudy and with a few additional points as follows:  
• Clinical data from TCR T-cell products targeting NY-ESO-1 or other ACTs 
suggest that the proposed dose range should be safe:   
− GSK3377794 (lete-cel) has been administered at doses as high as 14 × 109 
(14 billion) transduced T cells and has demonstrated an AE profile that has 
generally been manageable and acceptable at all doses administered.  
− In the GSK analysis of clinical data from GSK3377794 (lete-cel), there was no 
identified dose-vs-toxicity relationship, and an extensive correlative analysis for 
CRS events did not demonstrate any dose effect. 
− T-cell therapies with the same NYESO1 TCR but using a different viral vector 
have been found to be well-tolerated at up to 1011 (100 billion) cells, without 
doselimiting toxicity [Robbins, 2015]. To date no DLTs have been reported for 
any TCR T-cell product targeting NYESO1. 
− Furthermore, the proposed dose is within the range used in other TCR-T or CART 
studies [Morgan, 2006; Johnson, 2009; Hartmann, 2017; Pettitt, 2018]. 
• The TCR has shown no cross-reactivity in nonclinical or clinical studies  
• Efficacy has been demonstrated with doses in the proposed target dose range:   
− In clinical trials higher doses of NY-ESO-1 TCR-engineered T cells were 
associated with a higher likelihood of clinical responses [Robbins, 2015];  
− In pilot studies with GSK3377794, clinical activity was observed in SS with 
infusion of 1-8 × 109 transduced T cells. and peak expansion was correlated with 
efficacy. The proposed dose range was also associated with higher peak expansion 
of the infused T cells and T-cell persistence, which appear to correlate with 
efficacy in internal GSK analyses of GSK3377794 data (results not shown) and 
similarly for CD19 CAR-T studies [Porter, 2015].  
 
In this substudy, GSK will implement specific safety measures to mitigate risk including 
split dosing and staggered treatment as described in Study Design, Section 5.1 of this 
Substudy.  
The approach of split-dosing has previously been utilized in initial CAR-T studies in an 
effort to avert acute severe CRS when the diagnosis and management of these 
complications was not well defined. Administering a reduced (30%) dose aliquot initially 
is expected to achieve a more controlled T-cell expansion and limited cytokine release 
from the infused T cells. The 7-day gap permits immediate action (including possibly 
delaying, or not administering at all, the second aliquot) in case of early acute toxicities.  
Severe acute toxicities associated with ACT typically occur within the first 7 to 15 days. 
Therefore, initiation of the lymphodepleting regimen in the 2nd and 3rd participant  will be 


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separated by a minimum of 2 weeks from the complete dose administered to the prior 
participant. 
5.5.2 Justification of Lymphodepleting Regimen 
Based on prior experience with GSK3377794 in participants with synovial sarcoma and 
melanoma, where a similar lymphodepletion regimen was associated with optimal 
responses [Mackall, 2016; D’Angelo, 2018], the previously used lymphodepletion 
regimen was fludarabine, 30 mg/m2/day × 4 days (Day -7 to -4) and cyclophosphamide, 
1800 mg/m2/day × 2 days (Day -5 to -4), with GSK3377794 infusion on Day 1. 
Based on additional safety data (prolonged neutropenia; fatal neutropenia [see 
GSK3377794 IBv13, GlaxoSmithKline Document Number RPS-CLIN-015027, 2021]) 
and modelling data, to further optimize lymphodepletion and reduce potential for acute 
and prolonged cytopenias while also minimizing impact on efficacy, the 
cyclophosphamide cumulative dose is modified from 3600 to 2700 mg/m2. The 
fludarabine dose remains unchanged.  
This regimen was previously used in Study 208469 (Cohort 2) in MRCLS and the dosing 
regimen is currently in use for NSCLC participants in Study 208471 (slightly different 
schedule).  
The refined lymphodepleting regimen for participants treated as of protocol amendment 
02 is as follows: 
• Fludarabine, 30 mg/m2/day × 4 days (Day -7 to -4) and cyclophosphamide, 
900 mg/m2/day × 3 days (Day-6 to -4), with GSK3377794 infusion on Day 1.  
 
Rules for further dose reductions on cyclophosphamide are also adapted by applying the 
same 33% reduction as previously used in Protocol Amendment 01 as follows: 
• As of protocol amendment 02, a standard reduction for cyclophosphamide dose 
(in mg/m2) of 2700 = 900 × 3 days is to use 1800 = 600 × 3 days 


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6 
STUDY POPULATION 
Inclusion/Exclusion criteria are grouped into 3 parts and eligibility Screening will take 
place in the following 3 steps: 
• Target expression screening: A set of criteria permitting participants’ blood to be 
screened for HLA status and archival or fresh tumor samples to be screened for the 
expression of NY-ESO-1/LAGE-1a. 
• Leukapheresis eligibility screening:  To be fulfilled prior to performing 
leukapheresis procedure. 
• Treatment eligibility screening: To be fulfilled prior to starting lymphodepletion. 
o Treatment fitness (for safety): To be evaluated prior to commencing 
lymphodepleting chemotherapy and administration of GSK3845097. 
 
6.1 
Inclusion Criteria 
6.1.1 Target Expression Screening 
Participant is eligible to be screened for target expression (HLA-A*02:01, A*02:05, or 
A*02:06 and NY-ESO-1 and/or LAGE-1a) only if all of the following criteria apply: 
1. Capable of giving signed informed consent for the Screening process including 
compliance with the requirements and restrictions listed in the Screening informed 
consent form and in the protocol.  
2. Is ≥18 years of age and weighs ≥40 kg on the day of signing informed consent form. 
3. A representative tumor tissue specimen [archived or fresh biopsy] with associated 
pathology report should be available to perform NYESO1/LAGE-1a (when a 
designated central laboratory test is available) antigen expression analysis unless the 
result of a recent test performed under a different GSK-sponsored protocol or 
substudy, and on a platform(s) that meets the 209012 protocol requirements is 
available. For guidance on acceptable specimen material see Tumor Biopsies under 
Section 5.1.4.  
4. Has a diagnosis of SS or MRCLS as confirmed by local histopathology with evidence 
of disease-specific translocation.  Note:  Evidence of a relevant disease-specific 
translocation is required at latest prior to leukapheresis (Inclusion Criterion 11). 
5. Has advanced (metastatic or unresectable) SS or MRCLS. Unresectable refers to a 
tumor lesion in which clear surgical excision margins cannot be obtained without 
leading to significant functional compromise. 
 
6.1.2 Leukapheresis Eligibility Screening 
Prior to finalizing participant treatment plan, please note that bridging/standard of care 
anti-cancer therapy is allowed under Section 7.1.2 conditions but that there are washout 
requirements prior to leukapheresis and prior to lymphodepletion. Additional 
considerations should be given to accumulated radiotherapy prior to lymphodepletion. 
The Inclusion Criteria in Section 6.1.1 must apply. In addition, the following criteria 
must also be met prior to leukapheresis: 


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6. Is capable of giving signed informed consent for the trial (including the potentially 
15-year-long LTFU phase) including compliance with the requirements and 
restrictions listed in the informed consent form and in the protocol. 
7. Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 
alleles by a validated test in a designated central laboratory prior to leukapheresis. 
NOTE: The result of an HLA test performed under a different GSK-sponsored 
protocol or substudy, and on a platform(s) that meets the 209012 protocol 
requirements, is acceptable. 
8. Participant's tumor (either the most recent archival specimen or a fresh biopsy) must 
have tested positive for NY-ESO-1 and/or LAGE-1a expression (when LAGE-1a 
testing is available) by a GSK designated laboratory (and meets the threshold criteria 
defined for the specific tumor type).  
NOTE: The result of a recent NY-ESO-1 and/or LAGE-1a expression test (when 
LAGE-1a testing is available) performed under a different GSK-sponsored 
protocol or substudy, and on a platform(s) that meets the 209012 protocol 
requirements, is acceptable in place of the result from a new test performed as part 
Target Expression Screening for Substudy 2 (Section 6.3.4).   
9. Has measurable disease according to RECIST v1.1.  
NOTE: Lesions situated in a previously irradiated area are considered measurable 
if progression has been demonstrated in such lesions. 
10. Has evidence of radiographic or clinical disease progression. 
11. Participant has confirmed evidence of a relevant disease-specific translocation per 
below: 
• For synovial sarcoma, presence of a translocation involving chromosome 18 
(SYT gene) and/or chromosome X (SSX1, SSX2 or SSX4 genes); 
• For myxoid/round cell liposarcoma, presence of a translocation involving 
chromosome 12 (DDIT3 gene) and/or chromosome 16 (FUS gene) and/or 
chromosome 22 (EWSR1 gene). 
Note: Methods, such as, but not limited to, fluorescence in situ hybridization 
(FISH) assay or Next Generation Sequencing (NGS) or immunohistochemistry 
(IHC) using fusion-specific antibody are commonly used to detect translocations. 
12. Participant has completed at least one standard of care treatment including 
anthracycline containing regimen unless intolerant to or ineligible to receive the 
therapy. Participants who are not candidates to receive anthracycline should have 
received ifosfamide unless also intolerant to or ineligible to receive ifosfamide. 
Participants who received neoadjuvant/adjuvant anthracycline or ifosfamide based 
therapy and progressed will be eligible.  
OR 
NOTE: Participants "intolerant" to a therapy include but are not limited to those 
who are ineligible to receive therapy due to poor functional status, or have 
developed Grade ≥ 3 toxicity necessitating discontinuation, dose modification or 
unplanned hospitalization to alleviate effects of toxicity [van Abbema, 2019]. 


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13. Performance status: Eastern Cooperative Oncology Group (ECOG) of 0-1.  
14. Predicted life expectancy that is ≥6 months. 
15. Left ventricular ejection fraction ≥45% with no evidence of clinically significant 
pericardial effusion or as per institution’s guidelines. 
16. In the Investigator’s opinion, the participant is fit for leukapheresis and has adequate 
venous access for the cell collection. 
17. Participant must have adequate organ function and blood cell counts within 7 days 
prior to the day of leukapheresis (and prior to first day of lymphodepletion during 
Treatment Fitness Assessment), as indicated by the laboratory values in Table 10. 
 
Table 10 
Definitions of Adequate Organ Function 
System 
Laboratory Value 
Hematological a, b, c 
Absolute Neutrophil count (ANC) 
1.5 x109/L (without granulocyte colony-stimulating support) 
Absolute Lymphocyte count (ALC) 
0.5 × 109/L 
Hemoglobin 
8 g/dL or 5.0 mmol/L (not achieved by transfusion) a 
Platelets 
100 x109/L (not achieved by transfusion) b 
Renal 
Creatinine clearance 40 mL/min  
• 
Participants who are 18 and <65 years of age must be assessed either:  
a. 
by 24-hour urine creatinine collection   OR  
b. 
by using Serum Creatinine (Scr) via an estimated creatinine clearance (CrCl) calculated as outlined 
below by using the CKD-EPI equation and adjusting the result by multiplying with (BSA/1.73) to 
obtain CrCl in mL/min:  
Step 1: estimated glomerular filtration rate (GFR) to be obtained from the Chronic kidney disease 
Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009]:  
Estimated GFR (mL/min/1.73m2) =  
                141 × 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,  
max(Scr/κ,1) indicates the maximum of Scr/κ or 1, and  
Age is in years. 
Step 2: correction factor to be applied per the American National Kidney Foundation in order to 
obtain the estimated creatine clearance in mL/min 
Estimated CrCl (mL/min) = Estimated GFR (mL/min/1.73 m2) × BSA (m2) / 1.73 
To calculate the BSA for fludarabine dosing, use actual body weight. An adjusted body weight 
(ABW) may be required for cyclophosphamide, see Section 7.1.3 for further details. 
• 
Participants 65 years 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. 


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System 
Laboratory Value 
Hepatic 
Albumin 
3.5 g/dL 
Total bilirubin 
Participants with Gilbert’s Syndrome (only if 
direct bilirubin 35%) 
1.5 × ULN (isolated bilirubin 1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
ALT 
2.5 × ULN (or 5 × ULN if documented history of liver metastases)  
Coagulation d 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
1.5 × ULN unless participant is receiving anticoagulant therapy as 
long as PT or aPTT is within therapeutic range of intended use of 
anticoagulants 
a. 
No red blood cell transfusions to meet minimum hematologic values for eligibility 
b. 
No platelet transfusions within 14 days. 
c. 
Organ function will be reassessed prior to lymphodepletion: if, upon consultation with the Medical Monitor, there is 
evidence from laboratory values that recovery from last anti-cancer treatment is underway, hematology labs may 
be considered acceptable and requirements waived to proceed with lymphodepletion 
d. 
Prior to lymphodepletion, please refer to Substudy 2 Section 7.5.2 for guideline on use of anticoagulant 
medication. 
 
18. Male or female. Contraceptive use by men or women should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical 
studies.  
a. Male Participants: 
Male participants are eligible to participate if they agree to the following 
starting at the first dose of chemotherapy during lymphodepletion and for at 
least 12 months after receiving the T-cell infusion, or until persistence of gene 
modified cells in the participant’s blood is below the level of detection for 2 
consecutive assessments, 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  
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 described 
in Core Section 12.4 when having sexual intercourse with a woman of 
childbearing potential (WOCBP) who is not currently pregnant (as a 
condom may break or leak) 
• Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person  


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there is no anticipated risk of interfering with measurement of single lesion. If it is not 
feasible to obtain a fresh biopsy, other options including an archival tumor tissue 
(FFPE block) preferably taken after completion of the participant’s last line of 
therapy, preferably within 90 days prior to initiating lymphodepleting chemotherapy, 
may be accepted at the discretion of the Medical Monitor (or designee). For 
participants who already provided a fresh biopsy for antigen expression and did not 
receive any bridging or standard of care anti-cancer therapy, the screening biopsy will 
be used for baseline. 
22. A hematologist has been consulted prior to lymphodepletion in participants who have 
had a serious/significant bleeding/thrombosis history. 
 
6.1.3.1 
Treatment Fitness (for Safety) 
Given potential changes in clinical status between screening/enrollment and the start of 
lymphodepleting chemotherapy, safety assessments from Section 6.1.1 and Section 6.1.2 
will be reassessed prior to lymphodepletion. If the results of any assessments or 
procedure are outside of the eligibility criteria, please consult with the GSK Medical 
Monitor prior to proceeding with lymphodepletion. 
6.2 
Exclusion Criteria 
6.2.1 
Target Expression Screening 
Participants are not eligible to be screened for target expression (HLA-A*02:01, 
A*02:05, or A*02:06 and NY-ESO-1 and/or LAGE-1a) if any of the following criteria 
apply: 
1. Any other prior malignancy that is not in complete remission.  
Exceptions include: 
a. Completely resected non-melanoma skin cancer, or successfully treated in situ 
carcinoma (melanoma in situ, basal cell carcinoma, prostate ca in-situ, 
periosteal osteosarcoma) 
b. Previous malignancies that have been definitively treated, and have been in 
remission for 5 years may be enrolled upon consultation with sponsor Medical 
Monitor or designee 
2. Clinically significant systemic illness: 
a. serious active infections or significant cardiac, pulmonary, hepatic or other 
organ dysfunction, that in the judgment of the Investigator would compromise 
the participant’s ability to tolerate protocol therapy or significantly increase 
the risk of complications  
OR 
b. prior or active demyelinating disease 
3. Previous treatment with genetically engineered NY-ESO-1-specific T cells, 
NY-ESO-1 vaccine, or NY-ESO-1 targeting antibody. 


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Exception: Participants who achieved a confirmed RECIST v1.1 response of CR or 
PR or SD 3 months following treatment with letetresgene autoleucel 
(GSK3377794, lete-cel) on another GSK sponsored study/substudy may be 
considered for eligibility to Study 209012 following discussion with the Sponsor 
Medical Monitor. 
4. Prior gene therapy using an integrating vector. 
Exception: Participants who achieved a confirmed RECIST v1.1 response of CR or 
PR or SD 3 months following treatment with letetresgene autoleucel 
(GSK3377794, lete-cel on another GSK sponsored study/substudy may be 
considered for eligibility to Study 209012 following discussion with the Sponsor 
Medical Monitor.  
5. Previous allogeneic hematopoietic stem cell transplant within the last 5 years or solid 
organ transplant. 
 
6.2.2 
Leukapheresis Eligibility Screening 
Participants are not eligible for leukapheresis if any of the Exclusion criteria from 
Section 6.2.1 apply. Please note in particular that mandatory washout period restrictions 
must be respected (Table 11) before starting leukapheresis. In addition, participants are 
not eligible for leukapheresis if any of the following criteria apply: 
6. Participant has central nervous system (CNS) metastases. 
7. Participant has a history of chronic or recurrent (within the last year prior to 
leukapheresis) severe autoimmune or immune mediated disease (e.g. Crohn’s disease, 
systemic lupus) requiring steroids or other immunosuppressive treatments.  
8. Participant has a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to cyclophosphamide, fludarabine, other agents 
used in the study.  
9. Uncontrolled intercurrent illness including, but not limited to: 
a. Ongoing or active infection (including, but not limited to, systemic fungal 
infection)  
b. Clinically significant cardiac disease defined by congestive heart failure New 
York Heart Association (NYHA) Class 3 or Class 4 
c. Uncontrolled clinically significant arrhythmia  
d. Acute coronary syndrome (angina or myocardial infarction) in last 6 months 
e. Severe aortic stenosis, symptomatic mitral stenosis 
f. Interstitial lung disease (participants with existing pneumonitis as a result of 
radiation are not excluded; however, participants cannot be oxygen dependent)  
10. Insufficient pulmonary function with mechanical parameters <40% predicted (forced 
expiratory volume in 1 second [FEV1], forced vital capacity [FVC], total lung 
capacity [TLC], pulmonary diffusing capacity for carbon monoxide [DLCO]) 


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11. 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. 
12. QTc >480 msec  
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 according to 
the site practices, machine-read or manually over-read. 
Only one preferred formula should be used to calculate the QTc for an individual 
participant; multiple formulae should not be used. 
For purposes of data analysis, either QTcB, QTcF, another QT correction formula, 
or a composite of available values of QTc will be used as specified in the SAP. 
13. Participant has known psychiatric or substance abuse disorders that would interfere 
with cooperating with the requirements of the study. 
14. Participant has active infection with HIV, HBV, HCV, EBV, CMV, syphilis, or 
HTLV as defined below: 
• Positive serology for human immunodeficiency virus (HIV). 
• Active hepatitis B infection as demonstrated by test for hepatitis B surface 
antigen. Participants who are hepatitis B surface antigen negative but are hepatitis 
B core antibody positive must have undetectable hepatitis B DNA and receive 
prophylaxis against viral reactivation. 
• Active hepatitis C infection as demonstrated by hepatitis C RNA test. Participants 
who are HCV antibody positive will be screened for HCV RNA by any RT PCR 
or bDNA assay. If HCV antibody is positive, eligibility will be determined based 
on a negative Screening RNA value. 
• Active Epstein-Barr virus (EBV) infection. Participants with positive EBV 
serology will undergo additional tests/assessments in order to rule out active 
infection. 
• Active cytomegalovirus virus (CMV) infection. Participants with positive CMV 
serology will undergo additional tests/assessments in order to rule out active 
infection. 
• Positive test for syphilis (spirochete bacterium). 
• Positive serology for human T lymphotropic virus 1 or 2 (HTLV 1 or 2). 
15. Pregnant or breastfeeding females (due to risk to fetus or newborn). 
16. Prior/Concomitant Therapy: 
a. Any prior treatment-related toxicities must be CTCAE (Version 5.0) Grade ≤1 at 
the time of initiating study intervention (except for non-clinically significant 
toxicities e.g., alopecia, vitiligo). Participants with Grade 2 toxicities that are 


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deemed stable or irreversible (e.g. chemotherapy related arthritis or tendinitis, 
skin discoloration or erythema) can be enrolled. 
b. Bridging or intermediate standard of care anti-cancer treatment is allowed but 
washout periods in Table 11 should be followed. 
17. Investigational treatment within 4 weeks or 5 half-lives (whichever is shorter) prior to 
leukapheresis. Investigational vaccines (other than NYESO1 vaccines that are not 
allowed) must follow the washout period specified in Washout Period Table 11 
below. Exceptions to this rule must be evaluated by the Investigator in agreement 
with the Sponsor’s Medical Monitor (or designee).  
NOTE: Investigational treatment is not allowed between leukapheresis and study 
intervention. 
 
6.2.3 
Treatment Eligibility Screening 
Please note that mandatory washout period restrictions must be respected (Table 11) 
before starting lymphodepletion. In addition to confirming Treatment fitness per 
Section 6.2.3.1, participants are not eligible for lymphodepletion or treatment if any of 
the following criteria apply: 
18. Participant has received cytotoxic therapy within 3 weeks prior to lymphodepleting 
chemotherapy. 
19. Participant has received systemic corticosteroids or any other immunosuppressive 
therapy within 2 weeks prior to lymphodepleting chemotherapy.  
NOTE: Isolated doses of systemic corticosteroids are permitted to manage acute 
allergic reactions. Use of inhaled or topical steroids is not exclusionary  
20. Participant has received ≥50 Gy to a significant volume of the pelvis, long bones or 
spine, or a cumulative dose of radiation that, in the investigator’s opinion would 
predispose patients to prolonged cytopenia after lymphodepletion. 
21. All of the participant’s target lesions have been irradiated within 3 months prior to 
lymphodepletion. A lesion with unequivocal progression may be considered a target 
lesion regardless of time from last radiotherapy dose.  
22. Radiotherapy that involves the lung (V20 exceeding 30% lung volume or mean heart 
dose >20Gy) within 3 months OR radiotherapy (including but not limited to palliative 
radiotherapy) to lung/mediastinum with V20 less than 30% lung volume and with 
mean heart dose ≤20Gy within 4 weeks (3 days): 
NOTE: 
a. Electron beam radiotherapy to superficial structures in the chest is permitted.  
b. There is no wash-out period for palliative radiation to non-target organs other than 
the lung and mediastinum  
23. Participant has received an anti-cancer vaccine within 2 months of lymphodepletion 
in the absence of tumor response. The participant should be excluded if their disease 
is responding to an experimental vaccine given within 6 months of lymphodepletion. 


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24. Participant has received live vaccine within 4 weeks prior to lymphodepletion. 
25. Participant has received immune therapy (monoclonal antibody therapy, checkpoint 
inhibitors) within 4 weeks of lymphodepletion. 
26. Participant had major surgery within 4 weeks prior to lymphodepletion. 
 
Table 11 
Washout Periods 
Treatment/Therapy a 
Required Washout 
Prior to Leukapheresis 
Required Washout 
Prior to Lymphodepletion 
Cytotoxic chemotherapy 
3 weeks 
Immune therapy (including monoclonal 
antibody therapy) 
4 weeks 
Anticancer Vaccine 
• 2 months in the absence of tumor response 
• The participant should be excluded if the Investigator considers 
their disease is responding to an experimental vaccine given 
within 6 months 
Live-virus vaccination (there is no required 
washout for seasonal flu vaccines that do not 
contain live virus). 
4 weeks 
Systemic corticosteroids or any other 
immunosuppressive therapy (there is no 
washout required for inhaled or topical steroids 
as they are allowed during the study) 
2 weeks 
Investigational treatment  
4 weeks or 5 half-lives 
(whichever is shorter) 
Not allowed 
Radiotherapy 
None 
To the target lesions within 3 months 
prior to lymphodepletion b  
NOTE: There is no washout period for 
palliative radiation to non-target 
lesions with the exception of 
non-target lesions in the lung and 
mediastinum for which the washout 
period prior to lymphodepletion is 
4 weeks. 
Tyrosine kinase inhibitors 
1 week 
a. 
Permission and washout for any other anticancer therapies must be discussed with the Sponsor’s Medical Monitor 
(or designee). 
b. 
A lesion with unequivocal progression may be considered a target lesion regardless of time from last radiotherapy 
dose. 
6.2.3.1 
Treatment Fitness (for Safety) 
Given potential changes in clinical status between screening/enrollment and the start of 
lymphodepleting chemotherapy, safety assessments from Section 6.2.1 and Section 6.2.2 
will be reassessed prior to lymphodepletion. If the results of any assessments or 
procedure are outside of the eligibility criteria, please consult with the GSK Medical 
Monitor prior to proceeding with lymphodepletion. 


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6.3 
Lifestyle Considerations 
6.3.1 
Meals and Dietary Restrictions 
Participants should maintain the current/regular diet unless modifications are required to 
manage an AE such as diarrhea, nausea, or vomiting. 
6.3.2 
Activity 
Participants will abstain from extraordinarily strenuous athletic activity for 24 hours 
before each blood collection for clinical laboratory tests. Participants may participate in 
light recreational activities during studies (e.g., watching television, reading). 
6.3.3 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse 
events (SAEs). 
6.3.4 
Screening under Other GSK Studies 
Participants screened or enrolled in other GSK treatment  studies may be considered for 
enrollment to this study, where it is IRB/IEC approved, on a case-by-case scenario 
following risk/benefit evaluation between the Investigator and Sponsor Medical Monitor 
(or designee).  
Where a participant was previously tested for HLA and/or NY-ESO-1/LAGE-1a 
expression under a different GSK-sponsored protocol, testing of HLA and/or 
NY-ESO-1/LAGE-1a for 209012 may not be required dependent on the test platform(s) 
used and whether they meet the 209012 protocol requirements. If the 209012 
requirements are not met, repeat test(s) may be required. The repeat test(s) may be 
possible without requiring new sample collection. Other screening/baseline assessments 
or procedures (e.g., biopsy collection, imaging) performed under a separate GSK 
sponsored protocol may be accepted, in consultation with the Sponsor. 
6.3.5 
Rescreening/Transfer 
Individuals who do not meet the criteria for participation in this study or another 
GSK-sponsored similar study or substudy of this protocol (screen failure for reasons 
other than NY-ESO-1 or HLA status) may be rescreened or transferred.  
For each rescreened/transferred participant, the Sponsor will review the following on 
evaluation of eligibility to Substudy 2 and before initiating leukapheresis or 
manufacturing of the T cells: 


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• Participant will be considered HLA positive if already tested positive for 
HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a validated test in a 
designated central laboratory under this substudy or under another GSK-sponsored 
study or substudy of this protocol;  
• Participant’s tumor antigen expression will be considered positive if previously 
pathologically reviewed by a GSK designated laboratory under this substudy or under 
another GSK-sponsored study or substudy of this protocol, with confirmed positive 
NY-ESO-1/LAGE-1a expression for the indication;   
• If participant has previously completed Sponsor protocol-specified leukapheresis 
under this substudy or under another GSK-sponsored study or substudy of this 
protocol:  
− Already banked cryopreserved T cells under an applicable process may be used in 
the manufacturing of GSK3845097 if within shelf-life specifications;  
− Already stored manufactured GSK3845097 product under an applicable process 
may be used for the T-cell infusion if within shelf-life specifications. 
 
6.3.6 
Potential Eligibility of Participants Who Have Previously 
Received Letetresgene Autoleucel (Lete-Cel) 
Participants who achieved a confirmed RECIST v1.1 response of CR or PR or SD 
≥3 months following treatment with letetresgene autoleucel (GSK3377794, lete-cel) on 
another GSK sponsored study may be considered for eligibility to this substudy.  
6.3.7 
Conditions for Inclusion of Participants Who Have Previously 
Received Letetresgene Autoleucel (Lete-Cel)  
Consideration for eligibility on a case by case basis will include the following conditions, 
in addition to meeting eligibility criteria in the relevant substudy (Section 6.1 and 
Section 6.1.3.1): 
• Participant had a confirmed CR or PR or SD ≥3 months following treatment with 
letetresgene autoleucel on a GSK sponsored study; 
• Participant’s disease subsequently progressed no earlier than 12 weeks after infusion 
of letetresgene autoleucel; 
• Participant has not received systemic anti-cancer therapy for the treatment of their 
disease with the exception of bridging therapy which is permitted; 
• Eligibility based on NY-ESO-1/LAGE-1a target expression from fresh biopsy is 
confirmed (from 1st infusion progression biopsy optimally obtained prior to receipt of 
any additional systemic anti-cancer therapy). If acquisition of a post-progression 
biopsy sample is not feasible, alternatives may be discussed with the Medical Monitor 
or designee; 
• Participant meets the substudy eligibility criteria with the exception of  
− Exclusion criterion #3: “Previous treatment with genetically engineered 
NY-ESO-1-specific T cells, NY-ESO-1 vaccine, or NY-ESO-1 targeting 
antibody.” 
− Exclusion criterion #4: “Prior gene therapy using an integrating vector” 


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• Participant did not experience a Grade 4 CRS event or Grade 4 neurologic toxicity 
after the first NY-ESO-1 specific T-cell infusion;  
• Toxicities related to conditioning chemotherapy and infusion of letetresgene 
autoleucel with the exception of alopecia, have resolved to Grade ≤1 or returned to 
baseline prior to initiation of lymphodepletion for treatment with next generation 
NYESO1 specific T cells. 
 
Consideration of such participant for eligibility assessment to this trial must first be 
agreed with Sponsor taking into account benefit-risk for the specific patient. 
No such participants will be permitted on this substudy until at least the dose 
confirmation phase is complete.  
No more than 3 participants who were previously treated with letetresgene autoleucel will 
be permitted in this substudy.  
6.3.7.1 
Benefit:Risk Assessment for Inclusion of Participants Who Have 
Previously Received Letetresgene Autoleucel (Lete-Cel)  
Prior clinical experience of retreatment with the same T-cell product across multiple 
studies of CAR and TCRs, including GSK3377794 (lete-cel), supports the considerations 
of enrolling participants who have previously received GSK3377794 into the substudy 
with a next generation T-cell product which targets the same NY-ESO-1 epitope as 
GSK3377794. 
In 2 studies conducted at the pediatric [Lee, 2015] and Surgery Branch [Kochenderfer, 
2015] of the National Cancer Institute (NCI) 6 subjects were re-treated upon progression. 
Three of the re-treated subjects (indolent lymphoma/leukemia) experienced durable 
responses to retreatment after an initial response and disease progression. Gauthier et al, 
[Gauthier, 2021] demonstrated that second infusions of CAR-T therapy were both 
feasible and induced responses in 39% of subjects, including CRs in 20%. Evidence of 
tumor regression post disease progression following a second infusion of TILs was 
demonstrated by Tran el al, [Tran, 2014] in a subject with cholangiocarcinoma. Similarly 
Hegde et al [Hegde, 2020] reported a second remission (CR) in a child with 
rhabdomyosarcoma following retreatment with HER2 CAR T cells following progression 
6 months post first CAR T infusion.  
In GSK sponsored trials, a total of sixteen (16) subjects [11 subjects in Study 208466 
(SS) (formerly ADP-04511), 4 subjects in Study 209393 (multiple myeloma) (formerly 
ADP-01411), and 1 subject in Study 208749 (NSCLC) have received a second infusion 
of GSK3377794 (lete-cel) after progressive disease following response (or prolonged 
stable disease) to their initial infusion. There were no fatal SAEs reported among subjects 
who received a second infusion of GSK3377794. Although the data is limited, the safety 
profile following a second infusion of GSK3377794 is consistent with that of all subjects 
infused.  
In Study 208466, many of the subjects who underwent initial treatment with 
GSK3377794 (lete-cel) demonstrated clinical benefit, with measurable tumor regression 
by RECIST 1.1 and investigator assessment observed in one third (33%) of subjects. On 
retreatment (11 participants), 1 CR, 1 PR, and multiple SD were observed. In Study 
208749, 1 subject received a second infusion post progression and achieved SD.  


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Ultimately, the benefit:risk has been maintained in participants who received 
GSK3377794 (lete-cel) for a second time. 
Enrollment of participants who have received GSK3377794 (lete-cel) will only be 
permitted once the dose confirmation phase is complete, when early safety and efficacy 
data on GSK3845097 is available. A limited number of participants will be permitted and 
only following agreement between Sponsor and Investigator.  Participants will be 
assessed on a case-by-case basis, including evidence of acceptable safety and evidence of 
efficacy demonstrated by a confirmed CR or PR or SD ≥3 months following initial 
infusion of GSK3377794 (see Section 6.3.7 for details).  
The risk of receiving GSK3845097 after GSK3377794 (lete-cel) is considered similar to 
that of treating a participant with GSK3845097 for the first time. On this basis, in the 
context of patients with limited alternative treatment options, the benefit:risk for enrolling 
participants who have received GSK3377794 is considered acceptable. 
7 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s) described below 
intended to be administered to a study participant according to the study protocol. 
7.1 
Study Intervention(s) Administered 
7.1.1 
Leukapheresis 
Participants will undergo leukapheresis to obtain starting material for the manufacture of 
GSK3845097.  
Investigators will follow institutional guidelines and the minimum requirements as 
outlined in the Apheresis Manual. 
A CD3 count of at least 200/L prior to leukapheresis is recommended to ensure an 
adequate T-cell collection for manufacture of GSK3377794. If the laboratory test returns 
a value lower than 200, there is the potential that more than one collection will be needed 
to reach the T-cell target. The laboratory test should be repeated, and the Sponsor alerted 
as soon as possible. Should there be any manufacturing issues, such as failure, additional 
collection(s) may be required. 
7.1.2 
Bridging Therapy and/or Standard of Care Intermediate 
Anti-Cancer Therapy before Lymphodepletion 
Since HLA-typing and NY-ESO-1 expression testing are required prior to treatment, 
bridging or standard of care systemic chemotherapy, experimental therapy and/or local 
therapy (e.g., radiotherapy, cryoablation, surgical resection) may be administered 
between Target Expression Screening and Leukapheresis. Mandatory washout periods 
prior to Leukapheresis (see Section 6.2 Table 11) must be respected when planning 
treatment or procedure. 


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Additionally, systemic chemotherapy may be administered between Leukapheresis and 
the start of Lymphodepletion, if a participant has progressive disease and cannot be 
treatment-free. Mandatory washout periods prior to lymphodepletion (see Section 6.2 
Table 11) must be respected when planning treatment or procedure. 
At the discretion of the Investigator and after discussion with the Medical Monitor, 
bridging or standard of care intermediate anti-cancer therapy may be considered for any 
participant, particularly those with high disease burden or disease-related symptoms at 
screening. 
Administration will be based on Investigator’s evaluation of risk/benefits, in accordance 
with local regulatory requirements and standards, and in agreement with the Sponsor’s 
Medical Monitor (or designee).  
7.1.3 
Lymphodepleting Chemotherapy 
Prior to the administration of lymphodepleting chemotherapy, participant’s fitness for 
lymphodepletion will be assessed, treatment eligibility criteria will be confirmed and 
Baseline tumor assessment CT/MRI obtained per Section 9.1 in the Core Protocol and the 
SOA in this Substudy. Disease progression after prior line of treatment needs to be 
documented prior to performing lymphodepletion. 
When the GSK3845097 has been manufactured, has fulfilled release criteria, and is 
available for infusion at the site, lymphodepleting fludarabine and cyclophosphamide can 
be administered as described in Table 12. Cyclophosphamide and fludarabine will be 
supplied by the pharmacy of the participating Institution.  
Dose and regimen for lymphodepleting chemotherapy is adjusted for participants 
60 years of age, as specified in Table 12. The investigator must discuss with the 
Sponsor’s Medical Monitor (or designee) to determine the need for dose modification of 
the lymphodepletion regimen in situations such as but not limited to the following: 
• 
Participants with documented history of severe and prolonged cytopenia (anemia, 
thrombocytopenia, or leukopenia),  
• 
Participants with 3 or more prior lines of therapies, 
• Participants with documented extensive prior radiation of the pelvis, long bones or 
spine 
• 
Participants with documented history of intensive chemotherapy that could reduce the 
bone marrow reserve. 
• 
Participants with documented low albumin (≤3.5 g/dL). 
 
For Investigators with patients approaching lymphodepletion, Sponsor requires that site 
review creatinine clearance (CrCl) and lymphodepleting chemotherapy dose calculations 
with the Medical monitor or designee. Before lymphodepletion, site must provide 
Sponsor with intended doses (in mg/day) of fludarabine and cyclophosphamide, patient’s 
height, weight, gender, ethnicity, baseline serum creatinine(s) and creatinine clearance 


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(estimated or measured). Any significant discrepancy that would lead to a change in dose 
will be discussed with Medical monitor prior to commencing lymphodepletion. 
• Calculations methods are provided in Section 6.1 Table 10 Definitions of Adequate 
Organ Function, Renal for CKD-EPI using BSA (e.g. DuBois), but institutions may 
use their own BSA calculator (e.g., Mosteller), if required per local institutional 
practice.  
• If there is variability in pre-leukapheresis and pre-lymphodepletion serum creatinine 
by ±30%, institution must consider more formal/accurate measure rather than rely on 
estimation of creatinine clearance. 
 
If the infusion of GSK3845097 is delayed >2 weeks, in general lymphodepleting 
chemotherapy should be repeated. The Investigator is expected to discuss the 
participant’s condition and the treatment plan with the Medical Monitor. 
Supportive therapy guidelines are provided in Core Section 12.7. 
Table 12 
Lymphodepleting Chemotherapy  
 
Lymphodepleting chemotherapy 
Recommended prophylaxis 
and supportive medication 
Day 
Drug 
Dose, 
mg/m2 
Dose for 
participants 
60 years 
old, mg/m2 
Route 
Administration 
Infection: On admission for 
lymphodepleting 
chemotherapy, commence 
anti-microbial and anti-fungal 
prophylaxis as recommended 
in Core Section 12.7 or in line 
with institutional standard 
practice. 
 
Hydration:  Ensure adequate 
hydration and antiemetic 
provision prior to commencing 
cyclophosphamide infusions 
 
Mesna: May be given to 
prevent urotoxicity per 
institutional guidelines or as 
recommended in this Section 
below. 
 
G-CSF: must start ~24 hours 
after the last 
cyclophosphamide infusion. 
G-CSF support to continue 
until resolution of neutropenia 
in accordance with ASCO 
guidelines [Smith, 2015] or 
institutional practice. 
-7 
Fludarabine1 
30 
none 
IV 
in 50 – 100 mL 
0.9% NaCl over 
30 mins2 
-6 
Fludarabine1 
30 
30 
IV 
in 50 – 100 mL 
0.9% NaCl over 
30 mins2 
Cyclophosphamide3 
900 
600 
IV 
in 200 – 500 mL 
0.9% NaCl over 
1 hour2 
-5 
Fludarabine1 
30 
30 
IV 
in 50 – 100 mL 
0.9% NaCl over 
30 mins2 
Cyclophosphamide3 
900 
600 
IV 
in 200 – 500 mL 
0.9% NaCl over 
1 hour2 
-4 
Fludarabine1 
30 
30 
IV 
in 50 – 100 mL 
0.9% NaCl over 
30 mins2 
Cyclophosphamide3 
900 
600 
IV 
in 200 – 500 mL 
0.9% NaCl over 
1hour2 
-3 
start G-CSF4 
-2, -1 There is no day 0 on this study 
+1 
GSK3845097 
1. 
Fludarabine dose will be adjusted in renal impairment as described in this section. This adjustment needs to be 
applied to all doses, on top of the age-related and weight-related modifications. Fludarabine dose will not be 
adjusted by body weight per ASBMT guidelines that recommend dosing based upon body surface area (BSA) 
using actual body weight [Bubalo, 2014], unless required otherwise by institutional guidelines. 


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2. 
Or per institutional guidelines. 
3. 
Cyclophosphamide dose will be adjusted in obese participants as described in this section. This adjustment needs 
to be applied to all doses, on top of the age-related and renal impairment modification. 
4. 
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. 
 
ASCO = American Society of Clinical Oncology; IV = intravenous; NaCl = sodium chloride; G-CSF = granulocyte-colony 
stimulating factor. 
Fludarabine Dose Adjustment for Renal Impairment 
This adjustment needs to be applied to all doses, on top of the age-related modifications. 
The dose of fludarabine will be adjusted for participants with renal dysfunction as 
follows: 
Creatinine clearance (CrCl) 
Fludarabine dose 
>80 mL/min 
30 mg/m2 
>50 – 80 mL/min 
20 mg/m2 
30 – 50 mL/min 
15 mg/m2 
Note:  To estimate CrCl (in mL/min), please see Section 6.1, Table 10 for calculation steps before comparing to the 
thresholds given above. 
If estimating CrCl using the CKD-EPI equation, adjust the result by multiplying by (BSA/1.73) to obtain a CrCl in 
mL/min. For fludarabine dosing for this BSA calculation, use actual body weight. 
Creatinine clearance must be reassessed prior to lymphodepletion for use in these calculations. 
 
Cyclophosphamide Dose Adjustments 
This adjustment needs to be applied to all doses, on top of the age-related modification. If 
the participant’s weight is greater than 175% Ideal Body Weight (IBW), then calculate 
cyclophosphamide dose based on Body Surface Area (BSA) calculated using the 
Adjusted Body Weight (ABW). 
Calculating Ideal Body Weight 
 
Estimated ideal body weight (IBW) in kg 
Males 
IBW = (0.9 × height in cm) −88 
Females 
IBW = (0.9 × height in cm) −92 
Estimation of Ideal Body Weight may be performed per local institutional guidelines instead. 
 
Calculating Adjusted Body Weight 
If the actual body weight is greater than 175% of the calculated IBW, calculate the ABW:  
ABW = IBW + 0.4 × (actual weight −IBW) 
Estimation of Adjusted Body Weight may be performed per local institutional guidelines 
instead. 


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The IBW and ABW are used to calculate medication dosages when the participant is 
obese. This formula only applies to persons 152 cm or taller. Use ABW in the calculation 
for body surface area. 
Mesna 
Mesna should be administered per institutional guidelines or as recommended below: 
50% of cyclophosphamide daily dose (450 mg/ or 300 mg/m2) divided into 4 doses at 
times 0 (start of cyclophosphamide infusion) and then 3 hours, 6 hours, and 9 hours after 
the start of each cyclophosphamide infusion. 
7.1.4 
GSK3845097 Infusion 
Refer to the current version of the IB regarding GSK3845097 and related clinical 
experience. Refer to the Drug Product and Infusion Manual for details and instructions on 
storage and administration of GSK3845097. 
Participants will receive GSK3845097 after completing the lymphodepleting 
chemotherapy. This is considered Day 1 and all procedures and assessments to be 
performed are listed in the SOA. Supportive care guidelines are provided in Section 12.7 
of the Core Protocol. 
Tocilizumab availability in institution’s local pharmacy 
A minimum of 2 doses of tocilizumab available for each participant will be required for 
administration within 2 hours after T-cell infusion, if needed for treatment of Cytokine 
Release Syndrome (CRS). 
Premedication 
Thirty to sixty (30 to 60) minutes prior to T-cell infusion, participants will be 
premedicated against potential infusion reactions with antihistamines and acetaminophen 
(paracetamol). Follow institutional practice for dosage and specific medications. Steroids 
should not be administered as premedication for T-cell infusion because they are 
lymphotoxic and inhibitory to the T-cell product. 
GSK3845097 Dose 
The intended dose of GSK3845097 will be within the range of 1 × 109 – 8 × 109 
transduced T cells, which will be administered by a single intravenous infusion on Day 1 
unless the participant is a sentinel participant who will receive split dosing (see 
Section 5.1.1 of this Substudy). The minimum transduced cell dose for meeting release 
criteria is 1 × 109.  
In the event dose de-escalation is required, the dose range will be lowered 10-fold to 
0.1 × 109 – 0.8 × 109 transduced T cells. The minimum transduced cell dose for meeting 
release criteria in case of dose de-escalation is 0.1 × 109. 
If the transduced cell dose is less than the minimum dose required, manufacturing of 
additional transduced T cells from excess banked leukapheresis product will be 


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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. 
Additional Dosing Considerations  
See Study Design Section 5.1 in this Substudy for split dosing and staggered dosing in 
the sentinel participants.  
GSK3845097 Administration 
Participants will be admitted into the hospital on the day of T-cell infusion and will be 
hospitalized for follow-up care post T-cell infusion for at least 3 days after receiving 
T-cell infusion and at the discretion of the Investigator thereafter. Participants will 
maintain close follow up with the Investigator for 2 weeks following T-cell infusion. 
On Day 1, the participant will receive thawed T cells by intravenous infusion. Prior to 
infusion, two clinical personnel in the presence of the participant, will independently 
verify and confirm that the information on the infusion bag is correctly matched to the 
participant, as per the sponsor’s and clinical site’s procedures. 
Dosing and follow-up for sentinel participant(s) is described in Section 5.1.1 of this 
Substudy. 
The specific instructions for preparation and administration are found in Drug Product 
and Infusion Manual.  
Any deviation from the procedures 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 or 
stopped, and the reaction managed according to institutional standard procedures (Core 
Section 12.7). Steroid treatment should be avoided unless medically required. In the 
event a participant 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. 
The day of T-cell infusion may be delayed in participants with significant complications 
of lymphodepleting chemotherapy if according to the Investigator it is in the best interest 
of the participant. The timing of all assessments post-infusion will be calculated with 
reference to the T-cell infusion date. Participants who have undergone leukapheresis but 
do not receive the T-cell infusion will be replaced. Cytopenias alone should not be a 
reason to delay T-cell infusion unless complications are present (see Core Section 12.7 
for guidance).  
Vital signs will be recorded prior to the infusion (see SOA). 


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7.2 
Preparation / Handling / Storage / Accountability  
1. Deliveries of the IP are correctly received by a responsible person. Deliveries are 
recorded. 
2. The Investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
3. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the Investigator and authorized site staff. 
4. The participant’s T-cell product received at the site from the manufacturer will be 
stored below -130°C until ordered by the Investigator (or designee) to be infused. 
5. The Investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
6. Further guidance and information for the preparation, handling, storage, 
accountability and final disposition of unused study intervention will be provided in 
the Study Reference Manual or Drug Product and Infusion Manual.  
 
Precaution will be taken to avoid direct contact with the IP. A Material Safety Data Sheet 
(MSDS) describing occupational hazards and recommended handling precautions will be 
provided to the Investigator. In the case of unintentional occupational exposure notify the 
monitor, Medical Monitor, and/or GSK study contact. 
7.3 
Measures to Minimize Bias: Randomization and Blinding  
Not applicable to this open-label study. 
7.4 
Study Intervention Compliance 
GSK3845097 will be intravenously administered to participants at the site per guidelines 
specified in the Drug Product and Infusion Manual. Other study interventions will be 
administered as described in this protocol and per institutional guidelines. 
Administration will be documented in the source documents and reported in the eCRF. 
7.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving starting at the time 
of Screening for leukapheresis or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 


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• Dosage information including dose and frequency 
 
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
All concomitant medications including all prescription, over-the-counter medications, 
and herbal remedies, will be recorded, including dose and frequency. The following will 
be recorded on the appropriate eCRF pages: 
1. 
All prescription and non-prescription medication, vitamins, herbal and nutritional 
supplements taken by the participant during the 30 days prior to Screening for 
leukapheresis will be recorded at the Screening Phase visit. 
2. 
All prior anti-cancer treatments taken by the participant must be recorded regardless 
of time. 
3. 
All concomitant medications taken by the participant while in the Interventional 
Phase.  
4. 
Use of any mutagenic agents or investigational agents must be reported. 
5. 
Concomitant medications administered after the Interventional phase of the study 
will be recorded for SAEs and adverse events of special interest (AESIs). 
 
Any changes to concomitant medication regimens must be recorded throughout the study 
in the eCRF. 
7.5.1 
Prohibited Concomitant Medication and Treatment 
The following anti-cancer treatments are prohibited from the timepoints specified in the 
washout Table 11 before the start of study intervention and until PD is confirmed: non-
protocol chemotherapy, immune therapy, biological therapy (including targeted therapies 
with tyrosine kinase inhibitors or monoclonal antibodies), or investigational anti-cancer 
therapy. 
Once PD has been confirmed following T-cell infusion, participants can receive therapy 
at the discretion of their healthcare provider while they remain in this study. This 
includes participation in other clinical studies as needed. 
During the Interventional Phase of the study until PD is confirmed participants should 
also not undergo other anticancer locoregional therapies, such as surgical resection, 
excisional biopsies or non-palliative radiation. Procedures intended for palliative care or 
symptomatic relieve on non-target lesions are permitted.  
Systemic steroids may abrogate the effects of the T-cell therapy and therefore are 
discouraged unless required to manage CRS (refer to Core Section 12.7 for CRS 
management) or other significant immune-mediated AEs. According to local standard of 
care or American Society of Clinical Oncology (ASCO) guidelines [Smith, 2015], 
steroids may be used as anti-emetics before cyclophosphamide but must be discontinued 
no later than 3 days prior to infusion of the IP. Topical steroids for cutaneous application 
and inhaled steroidal treatments are permitted. 


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Recommendations for participants on therapeutic anticoagulants: [Maus, 2020] 
• Before proceeding with lymphodepletion, participants on therapeutic anticoagulants 
should be switched from long-acting to short-acting formulations, wherever possible. 
Long-acting anticoagulants can significantly potentiate bleeding risk during CRS. 
• If platelet counts drop below 100,000/μL in participants undergoing study treatment, 
dual-acting anticoagulants should be discontinued. 
• If platelet counts drop below 50,000/μL in participants undergoing study treatment, 
all anticoagulants should be discontinued unless a patient has a recent thrombosis. 
• If platelet counts drop below 50,000/μL in participants undergoing study treatment 
and the patient has a recent thrombosis, anticoagulants may be continued, but the 
dose should be reduced, or the platelet transfusions should be administered. 
 
7.5.3 
Rescue Medications and Supportive Care 
Anti-IL-6 drugs such as Tocilizumab may be administered to participants experiencing 
cytokine release syndrome (Core Section 12.7.5 for details). Steroids may be used for 
emergent medical conditions. For all non-emergent conditions, consult with the 
Sponsor’s Medical Monitor. Guidelines for management of complications are provided 
separately in the appendices. 
See Core Section 12.7 for details on general supportive care that can be given during the 
study. 
7.6 
Dose Modification 
See Section 5.1 of this Substudy for split dosing and staggered treatment for the sentinel 
participants. Once dose confirmation phase is complete, dose modification is not 
applicable to T cells. The entire dose of T cells that has been received by the site for the 
participant needs to be administered as a single dose or as otherwise instructed. If a 
reaction occurs that does not allow safe administration of the full dose, the dose 
administered needs to be recorded. 
If the transduced cell dose is less than the minimum dose required, 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.  
7.7 
Intervention after the End of the Study 
No therapeutic intervention will be provided by the sponsor after the end of the study. 
Participants may receive any necessary treatment interventions from their oncologist. 


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8 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION / WITHDRAWAL 
Definitions and procedures for discontinuation of study intervention and participant 
discontinuation / withdrawal should follow the SoA in this Substudy and details outlined 
in Core Protocol Section 8. 
In this substudy, Liver chemistry and QTc stopping criteria described in Core Protocol 
Section 8 will apply only to the participants who receive study intervention dose as a split 
infusion (sentinel participants). 
9 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures should be performed per the SoA and as defined in the 
Core Protocol Section 9.  
There are no substudy-specific assessments in this Substudy. Dose selection committee 
will be engaged in this substudy. 
9.1 
Dose Selection Committee  
In this Substudy, the DSC will be established for making dose recommendations based on 
a review of all relevant data. The DSC will include participating investigators as well as 
GSK representatives from functional groups including safety, clinical, statistics and may 
also include external experts that are not involved in the study. The committee will be 
tasked to determine whether the same dose can be given to additional participants; or 
decide to move to a lower dose level or to a higher dose level by the mTPI-2 model 
(described in Section 5.1.1 of this Substudy). In absence of DLTs, DSC will meet after 
every 3 participants have received the dose and been followed for a minimum of 4 weeks. 
Ad hoc DSC meetings may also be held at other time points if deemed necessary (i.e., for 
DLT discussion). DSC will be in place until the end of Dose Confirmation Phase. 
Additional details on the DSC will be provided in a charter or plan. 
10 
STATISTICAL CONSIDERATIONS  
The following substudy-specific considerations are in addition to those specified in the 
Core Protocol Section 10. 
10.1 
Statistical Hypotheses 
The primary objectives of this study are safety, tolerability and determining the RP2D of 
GSK3845097. All analyses will be descriptive. 
10.1.1 
Modified Toxicity Probability Interval 2 (mTPI-2) Based Dose 
Confirmation Design 
The dose confirmation phase of this study is based on an mTPI-2 [Guo, 2017] design. 
mTPI-2 is implemented within a formal Bayesian decision frame work and is extension 
of the modified toxicity probability interval method (mTPI) [Ji, 2010]. mTPI-2 was 


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chosen over mTPI because it is more preventative against overdosing and non-intuitive 
decision making, resulting in an improved decision table that uses the same estimation 
procedure for the maximum tolerated dose as mTPI. Additionally, mTPI-2 preserves the 
simple and transparent nature of mTPI with Bayesian statistical modifications. 
The choice of this design is validated by simulation results found in Core Section 12.10.  
The three dosing intervals are associated with three different dose-escalation decisions. 
The under-dosing interval corresponds to a dose re-escalation (R), overdosing 
corresponds to a dose de-escalation (D), and proper dosing corresponds to staying at the 
current dose (S), found in Table 9 of Section 5.1.1.2 of this Substudy. Similar to mTPI, 
mTPI-2 employs a simple beta-binomial hierarchic model. Decision rules are based on 
calculating the unit probability mass (UPM) of three classifications of intervals 
corresponding to under dosing, proper dosing, and overdosing in terms of toxicity. We 
assume the target toxicity is defined as pT. The unit interval (0,1) is divided into equal 
length subintervals of size (e1+e2), such that the proper dosing interval is (pT – e1, pT + 
e2), the under-dosing intervals are all intervals contained in (0, pT – e1),  and the 
overdosing intervals are all intervals contained in  (pT + e2, 1), where e1 and e2 are small 
fractions to account for the uncertainty around the true target toxicity. If the proper 
dosing interval has the highest UPM, it is chosen as the winning model and the dosing 
decision is to stay at the current dose. If any interval contained in the under-dosing 
interval has the highest UPM, it will be chosen as the winning model and the decision is 
to escalate the next cohort to a higher dose. If any interval contained in the over-dosing 
interval has the highest UPM, it will be chosen as the winning model and the decision is 
to deescalate the next cohort to a lower dose. Guo et al. [Guo, 2017] shows that the 
decision based on the UPM is optimal in that it minimizes a subsequent expected loss. 
Under the mTPI-2 design, a dose confirmation phase is terminated when either the lowest 
dose is above the MTD or a prespecified maximum sample size is reached. The phase 
will also be terminated if ≥6 subjects are treated, and the observed toxicity is ≤1/3. For 
this study, pT, the target toxicity level, is 0.3 and the uncertainty values are set at 
e1=e2=0.05. 
10.2 
Sample Size Determination 
Once the RP2D has been established, the substudy will expand to up to n=10 participants 
treated at that dose. The hypothesis is H0: 40% v. H1: 60%. This substudy size was 
chosen to allow for early stopping of further development due to futility if the posterior 
probability that the ORR is less than 60% is >90%. This is equivalent to observing 4 or 
fewer responders out of 10 treated participants. An uninformative Beta(a=0.02, b=0.08) 
prior was used. Additionally, if the true ORR is 40%, the probability of observing 4 or 
fewer responders out of 10 treated participants is 63% and if the true ORR is 60% the 
probability of observing 4 or fewer responders out of 10 treated participants is 17%. 
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 participants may be enrolled to 
confirm the safety and efficacy via a protocol amendment or as part of a separate 
protocol. Five or more confirmed responses (CR or PR) out of 10 evaluable participants 


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software. All calculations of non-compartmental parameters will be based on actual 
sampling times. PK data from this study may be combined with PK data from other 
studies and analyzed using population PK approaches, with descriptive statistics 
presented by treatment, dose and population.  
If performed, the population PK analysis and pharmacodynamic analyses will be 
presented separately from the main clinical study report. 


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11 
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Immunohistochem Mol Morphol. 2009;17(3):189–195. 
van Abbema DL, den Akker M, Janssen-Heijnen ML, et al. Patient- and tumor-related 
predictors of chemotherapy intolerance in older patients with cancer: A systematic 
review. J Geriatric Oncology. 2019;10:31–41. 
Vlenterie M, Litie`re S, Rizzo E, et al. Outcome of chemotherapy in advanced synovial 
sarcoma patients: Review of 15 clinical trials from the European Organisation for 
Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group; setting a new 
landmark for studies in this entity. Eur J Cancer. 2016;58:62–72. 
Votrient SmPC 2018 https://www.medicines.org.uk/emc/product/7861/smpc. 
Votrient USPI. May 2017. 
Wang S, Song R, Sun T, et al. Survival changes in patients with synovial sarcoma, 1983–
2012. J Cancer. 2017;8:1759–1768.  
Yondelis SmPC. August 2012 https://www.ema.europa.eu/documents/product-
information/yondelis-epar-product-information_en.pdf 
Yondelis USPI. October 2015. 


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12 
PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). Below is history of prior protocol 
amendments. 
12.1 
Amendment 01 (21 May 2021) 
Overall Rationale for Amendment 01: 
The primary rationale for protocol Amendment 01 is . 
1. Changes to Substudy 1 and 2 Inclusion criteria relative to disease status requirements 
to allow participants with advanced disease diagnosis to undergo target expression 
screening; participants with evidence of radiological or clinical disease progression 
will be able to undergo leukapheresis; initiation of lymphodepletion will require 
evidence of disease progression from prior line of therapy by RECIST v1.1.  
2. Changes to Substudy 1 Inclusion and Exclusion criteria language relative to prior 
lines of treatments for NSCLC participants to allow those who have received any 
PD-1/PD-L1 checkpoint blockade therapy and, in the same or different line of 
treatment, any platinum containing chemotherapy. NSCLC participants with 
actionable genetic aberrations may also be included if they have exhausted the 
targeted standard of care therapy. 
3. Clarifications to Substudy 1 and 2 lymphodepleting chemotherapy dose adjustments 
to ensure adequate consideration given to prior anti-cancer therapies (systemic and 
radiation exposure), renal function (for fludarabine) as well as use of adjusted body 
weight (for cyclophosphamide when necessary).   
4. Protocol language optimization to harmonize with program.  
5. Allowing potential future inclusion of a limited number of patients who progressed 
following clinical benefit (PR, CR, SD >/= 3 months) from infusion with letetresgene 
autoleucel (GSK3377794, lete-cel) on a GSK sponsored trial. 
 


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Section # and Name 
Description of Change 
Brief Rationale 
Substudy 2 
 
 
2.  Schedule of activities 
Table 1. Substudy 2 
Schedule of Activities – 
Screening and 
Leukapheresis 
Footnote #1 (Table 1) has been amended 
to state that consent for Leukapheresis and 
Treatment must be repeated if given more 
than 90 days prior to leukapheresis 
procedure. 
Minor wording clarifications for footnotes 
#3, 5 and 7. 
Footnote #4 clarifies that optional Genetics 
sample “may be collected any time from 
signature of optional consent until 
leukapheresis”. 
Footnote #8 clarifies that “CD3 count prior 
to leukapheresis should preferably be 
performed within 24 hours prior to 
leukapheresis procedure”. 
Footnote #9 aligns with Core Protocol 
Section 9.1.5 on Vital Signs collection, 
allowing institutional standard methods for 
collection. 
Footnote #16 added to reference details of 
renal assessment in Substudy 2 Section 
6.1 Table 10. 
Clarification and alignment of SOA 
with other section changes 
2.  Schedule of activities 
Table 2. Substudy 2 
Schedule of Activities – 
Interventional Phase 
(Lymphodepletion, 
Treatment and Follow-up) 
And  
Table 4. Substudy 2 
Schedule of Activities – 
Interventional Phase 
(Lymphodepletion, 
Treatment and Follow-up) 
for Split Dosing 
Added standard method of conversion for 
calendar visit scheduling between month to 
week, and week to day. 
Combined Transgene Copies (Persistence 
for Safety) and
) rows 
into one as only one sample will be 
collected to perform both tests. 
Footnote #15 clarified to instruct that 
“CT/MRI assessments only need to 
continue until confirmed PD”.  
Added requirement for ferritin, troponin and 
NT-proBNP / BNP test prior to 
Lymphodepletion (Table 2) 
Added Coagulation assessments for 
baseline, Day 1 thru 4, Day 6, Day 8, and 
Day 15 (Table 2) 
-
Included requirement for suspected 
CRS or ICANS to monitor chemistry, 
hematology, ferritin, coagulation and C 
reactive protein labs, daily for a week 
then every other day until symptoms 
are improving or an alternative 
diagnosis is confirmed. Included 
monitoring of troponin and NT-proBNP 
Clarification and alignment of SOA 
with other section changes 
 
 
 
 
 
 
 
 
Addition of 
 and 
coagulation tests. 
 
 
 
 
Clarification of schedule of 
assessment for suspected CRS or 
ICANS. 
 
 
 
 
 
. 
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Section # and Name 
Description of Change 
Brief Rationale 
/ BNP labs for CRS grade ≥2 as 
clinically indicated.  
2.  Schedule of activities 
Table 3. Substudy 2 
Schedule of Activities – PK, 
Immunogenicity, and 
 - Interventional 
Phase (Treatment and 
Follow-up) 
And 
Table 5. Substudy 2 
Schedule of Activities – PK, 
Immunogenicity, and 
 - Interventional 
Phase (Treatment and 
Follow-up) for Split Dosing 
Clarified that Sample Type for dnTGF-ERII 
should be “whole blood” instead of PBMC. 
Removal of Day 64 since Week 10 visit is 
not showing on the table (per footnote #1). 
Updated Requirement for on-study biopsy 
at Week 4 instead of Week 6 (Footnote #8 
specifies that the window of collection for 
the Week 4 biopsy is extended from Day 21 
to Day 39). 
Corrected schedule of collection for 
Cytokine Analyses (removal of Week 5, 7 
and 9 collections) 
Updated footnote related to collection of 
cytokines when CRS is suspected to 
reference local laboratory monitoring 
Clarification and alignment of SOA 
with other section changes 
2.  Schedule of activities 
Table 6. Substudy 2 
Schedule of Activities – 
Follow-up after Disease 
Progression or after 
Completion of Interventional 
Phase Follow-up 
Combined Transgene Copies (Persistence 
for Safety) and 
 rows 
into one as only one sample will be 
collected to perform both tests. 
Clarified language to align with Long-term 
Follow-up Study 208750, including:   
-
Discontinuation of persistence/
 
 at  ≥2 year post T-cell 
infusion  for participants whose 
transduced T cells are undetected for 2 
consecutive visit assessments 
-
Allow medical evaluations to take place 
via telemedicine (e.g. phone call or 
video conferences) and/or home 
healthcare where country and/or local 
regulations allow 
Added option of remote visits for years 6-15 
Clarification and alignment of SOA 
with other section changes 
3.2.1 Risk Assessment 
Table 7. Risk Mitigation 
Strategy 
Corrected reference to IP as GSK3845097 
for Substudy 2.  
Updated risk assessment table: 
-
To include risks of decreased vision 
and peripheral neuropathy for 
lymphodepleting chemotherapy 
(fludarabine/cyclophosphamide);  
To include/amend risks of haematopoietic 
cytopenias, hypersensitivity, reactivation of 
previous viral infections after prolonged 
leukopenia, neutropenia (including fatal 
neutropenia) decreased vision, to TCR-T 
infusion. 
Update to risk mitigation.  
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Section # and Name 
Description of Change 
Brief Rationale 
4. Objectives and Endpoints 
 
Reformatted Secondary Objectives and 
Endpoints into “Secondary – Efficacy” and 
“Secondary – Pharmacokinetics”. 
Recategorized “
 as 
Exploratory objective instead of secondary 
objective. 
Combined Frequency and severity of 
Adverse Events (AEs), Serious AEs (SAEs) 
and AEs of Special Interest (AESIs) as one 
single endpoint. 
Optimized description of Secondary – 
Pharmacokinetics objectives and 
endpoints. 
Updated list of abbreviations.  
To clarify subcategories of secondary 
objectives. 
 
 
 
Update to 
 plan. 
 
Standardization of reporting. 
 
 
 
Clarification of Pharmacokinetics 
plan. 
 
Finalization of table. 
5.1.1.1 Determining the 
R2PD 
Minor clarification to the RP2D suggested 
dose which will have ≥6 participants treated 
at this dose and an observed toxicity rate 
≤1/3.  
Clarification of threshold for 
suggested RP2D dose. 
5.1.3 Participant Journey 
Optimization of wording to Participant 
journey description to align with equivalent 
Core Protocol Section 5.2.  
Alignment of wording with equivalent 
Core protocol section 
5.1.4 Tumor Biopsies (new 
section added)And  
6.1 Former Inclusion 
Criterion #5 (now Inclusion 
Criterion #4) 
6.1. Former Inclusion 
criterion # 21 (now inclusion 
Criterion #24) 
Added requirements for on-study tumor 
biopsies 
 
A representative tumor tissue specimen 
[archived or fresh biopsy] with associated 
pathology report should be available to 
perform NY ESO 1 antigen expression 
analysis unless an appropriate recent 
NY-ESO-1 expression result is already 
available.  
Clarification of requirements for baseline 
biopsy. 
Clarification. 
5.3 End of Substudy 
definition 
Clarification of end of Interventional Phase 
and end of substudy for individual 
participants as well as for the entire 
substudy/cohort  
Clarification of patient disposition 
5.1 Overall Design 
6.1 Inclusion Criteria 
6.2 Exclusion Criteria 
Optimization of Treatment Fitness and 
Eligibility criteria prior to Lymphodepletion 
Removed requirement for repetition 
of all assessments for eligibility 
criteria that were already met prior to 
leukapheresis. Replaced by a 
Treatment Fitness assessment of the 
safety criteria in consultation with 
Medical Monitor.  
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Section # and Name 
Description of Change 
Brief Rationale 
6.1 Former Inclusion #3 
moved to Inclusion #9   
And 
Former Inclusion #4 moved 
to Inclusion #10   
And 
6.1 Former Inclusion #12 
(now Inclusion #19) 
Participants must have measurable disease 
by RECIST v1.1 (Inclusion #9) and 
evidence of radiographic or clinical disease 
progression only prior to leukapheresis 
(Inclusion #10).  
Participants must have documented 
radiographic evidence of disease 
progression from prior line of therapy prior 
to lymphodepletion (Inclusion #19). 
Clarification on disease requirements 
to allow for participants who have not 
progressed to undergo Target 
Expression Screening.. 
6.1 Former Inclusion #6 
moved to Inclusion #4   
Clarification on translocation requirement 
for inclusion of SS participants: Methods, 
such as, but not limited to, Fluorescence in 
situ hybridization (FISH) assay or Next 
Generation Sequencing (NGS) are 
commonly used to detect translocations. 
Facilitate inclusion of SS participants 
on the basis of confirmed histology 
only. 
6.1 Former Inclusion #8 
(deleted)  
And 
6.1 Former Inclusion #13 
(now Inclusion #11) 
Advanced (metastatic or unresectable) SS 
participants must have completed at least 
one standard of care treatment including 
anthracycline containing regimen OR is 
intolerant to the therapy.  Participants who 
are not candidates to receive doxorubicin 
should have received ifosfamide unless 
also intolerant to or ineligible to receive 
ifosfamide.  Participants who received 
neoadjuvant/adjuvant anthracycline or 
ifosfamide based therapy and progressed 
within 6 months with metastatic disease will 
be eligible. 
Clarification on disease 
characteristics for inclusion of  
Cohort 2 SS participants. 
6.1 Former Inclusion #15 
(now Inclusion #13)  
- 
Participants must have a predicted life 
expectancy that is ≥6 months 
(Inclusion #13). 
Extension of projected life 
expectancy requirement because 
leukapheresis can now be performed 
earlier in treatment plan. 
6.1 Former Inclusion #16 
(now Inclusion #14)  
Participants must have a Left ventricular 
ejection fraction ≥45% with no evidence of 
clinically significant pericardial effusion or 
as per institution’s guidelines (Inclusion 
#14). 
Clarification. 
6.1 Former Inclusion #18 
(now Inclusion #16)  
Table 10. 
Participant must have adequate organ 
function and blood cell counts within 7 days 
prior to the day of leukapheresis, (or first 
day of lymphodepletion during Treatment 
fitness assessment), as indicated by the 
laboratory values in Table 10 (Inclusion #16 
Clarification of Definitions of Adequate 
Organ Function: 
- 
ANC (must be obtained without G-CSF 
support) 
Clarification. 


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Section # and Name 
Description of Change 
Brief Rationale 
- 
CD3 count is no more an eligibility 
criterion 
- 
Platelets must be ≥100 x109/L 
- 
Renal function has been clarified 
based on participant age, and method 
- 
Albumin must be ≥3.5 g/dL 
- 
Footnote a) prohibits platelet 
transfusions accepted within 14 days 
from testing 
- 
Footnote b) prohibits red blood cell 
transfusions to meet minimum 
hematologic values for eligibility 
- 
Footnote c) clarifies reassessment 
conditions prior to lymphodepletion 
Footnote d) references guideline on 
anticoagulant medication prior to 
lymphodepletion 
6.1 Former Inclusion 
Criterion #19 (now Inclusion 
#17) 
Clarify that contraception for male and 
female participants must be followed during 
the intervention period starting at the first 
dose of chemotherapy for at least 12 
months after receiving the T-cell infusion, or 
until persistence of gene modified cells in 
the participant’s blood is below the level of 
detection for 2 consecutive assessments, 
whichever is longer.   
Clarification. 
6.2 Exclusion Criteria 
6.2.2 Leukapheresis 
Eligibility Screening 
And 
6.2.3 Treatment 
And 
Table 11 – Washout 
periods 
Clarification of washout periods 
requirements prior to leukapheresis and 
prior to lymphodepletion. 
Alignment with cell gene therapy 
program.  
6.2 Exclusion Criteria 
Former Exclusion Criterion 
#1 (now Exclusion criterion 
#6) 
Move CNS metastases requirement to prior 
Leukapheresis 
  
Optimization of screening for 
eligibility 
6.2 Exclusion Criteria #3 
and 4 
 
Per Section 6.3.5: 
- 
Added exception to exclusion of 
participants who have received prior 
genetically engineered NY-ESO-1 
specific T cells, NY-ESO-1 vaccine or 
targeting antibody.  
Allow participants who have benefited 
from GSK3377794 (lete-cel) to be 
considered for treatment with 
GSK3901961 under conditions 
defined in Section 6.3.5. 


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Section # and Name 
Description of Change 
Brief Rationale 
Added exception to participants who have 
received prior gene therapy using an 
integration vector.   
6.3.4. Rescreening/Transfer 
(new section added)  
Participants who were 
screenfailure/withdrawn prior to T-cell 
administration may be rescreened in the 
same study/substudy or transferred to any 
applicable GSK-sponsored study or 
substudy of this protocol. 
- 
Rescreening, leukapheresis procedure 
or manufacture process may be waived 
after consultation with Sponsor. 
To allow for re-allocation of 
participants onto other suited 
protocols/substudies when available, 
and for the possibility of skipping 
steps that have already been 
completed under the original 
comparable protocol, after 
consultation with Sponsor. 
6.3.5. Potential eligibility of 
participants who have 
previously received 
letetresgene autoleucel 
Participants who achieved a confirmed 
response of CR or PR or SD ≥3 months 
following first infusion of GSK3377794 
(lete-cel) could possibly benefit post 
progression from receiving a second course 
of treatment with next generation 
NY-ESO-1 specific T cells (such as 
GSK38445097). 
Considerations will be made on a case by 
case basis. Rationale and minimal 
requirements are laid out in this section 
To allow for possible future inclusion 
of prior lete-cel treated participants.  
7.1.2 Bridging Therapy 
and/or Intermediate 
Standard of Care Anti-
Cancer of Therapy before 
Lymphodepletion 
Clarified that bridging or standard of care 
systemic chemotherapy, experimental 
therapy and/or local therapy may be 
administered between Target Expression 
Screening and Leukapheresis; and 
systemic chemotherapy may be 
administered, between Leukapheresis and 
the start of Lymphodepletion, if a participant 
has progressive disease and cannot be 
treatment-free.   
Added clarification. 
7.1.3 Lymphodepleting 
Chemotherapy 
Clarified situations where Medical Monitor 
must be consulted to discuss 
Lymphodepleting regimen dose 
adjustments. 
Clarified that if creatine clearance is 
estimated that the same method as for 
adequate organ function should be used to 
consider fludarabine dose adjustments 
Clarified requirement for timing of G-CSF 
start post last chemotherapy dose. 
Added safety oversight and 
precautions. 
 
Added clarification. 
7.5.1 Prohibited 
Concomitant Medication 
and Treatment 
Removal of redundant sentence prohibiting 
use of any non-protocol antineoplastic 
therapy.  
Added clarifications. 


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Section # and Name 
Description of Change 
Brief Rationale 
7.5.2 Permitted 
Concomitant Medication 
and Treatment 
Added recommendations for participants on 
therapeutic anticoagulants 
Added clarification. 
7.5.3 Rescue Medications 
and Supportive Care 
Minor optimization of language  
Added clarifications. 
7.6 Dose Modification 
Addition of standard language on provision 
for additional manufacturing from excess 
banked leukapheresis product or for a 
second leukapheresis if the transduced cell 
dose does not meet the minimum dose 
required.  
Added clarifications. 
9.1 Dose Selection 
Committee 
Addition of language to cover situation 
where DLTs are observed  
Added clarifications. 
10.1.1 Modified Toxicity 
Probability Interval 2 (mTPI-
2) Based Dose 
Confirmation Design 
Minor clarification to the RP2D suggested 
dose which will have ≥6 participants treated 
at this dose and an observed toxicity rate 
≤1/3. 
Added clarifications. 
Throughout document 
Minor edits and typo corrections done 
Editorial changes 
 


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12.2 
Amendment 02 (04 November 2021) 
Amendment 02 - Date 04 November 2021 
Overall Rationale for Amendment 2:  
1. Implementation of additional safety monitoring measures in accordance with a 
recent Dear Investigator Letter and safety events. 
2. For participants treated as of protocol amendment 02, the cyclophosphamide dose 
in the lymphodepleting chemotherapy was reduced on Day -7 thru Day -4 to 
further optimize and reduce potential for acute and prolonged cytopenias while 
also minimizing impact on efficacy. 
3. For NSCLC participants in Substudy 1 Cohort 2 treated as of Protocol 
Amendment 02, the lymphodepleting chemotherapy schedule was changed from 
Day -8 through Day -5 to Day -7 through Day -4 to align with the schedule for the 
sarcoma participant cohort. 
4. Inclusion of myxoid/round cell liposarcoma (MRCLS) as a second translation-
related sarcoma indication.   
Section # and Name 
Description of Change 
Brief Rationale 
1 Synopsis – Rationale 
Updated IB cutoff date and number of 
patients treated with lete-cel 
Added most recent IB data 
1 Synopsis - Overall design 
Description of substudies moved to Section 
12.12, Reference to Section 12.12 for 
further details regarding additional 
substudies.  
In anticipation of additional 
substudies, enables administrative 
changes to document.  
Synopsis Screening and 
Section 5.2 Screening 
Addition of LAGE-1a as potential antigen 
assay 
Inclusion of LAGE-1a as potential 
screen for antigen testing to expand 
potential participant eligibility 
3 Introduction 
Reference to Secction 12.12 for details 
regarding substudies 
In anticipation of additional 
substudies, enables administrative 
changes to document. 
3.2.2 GSK3377794 
(letetresgene autoleucel, 
lete-cel) (lete-cel) 
Updated lete-cel IB details 
Added most recent IB data 
3.2.2 GSK3377794 
(letetresgene autoleucel, 
lete-cel) (lete-cel) 
Updated LTFU study 208750 details  
Study 208570 is not product specific 
3.2.3  Next Generation 
Engineering 
Reference to Section 12.12 for details 
regarding substudies 
In anticipation of additional 
substudies, enables administrative 
changes to document. 
1 Synopsis  Next 
Generation Engineering 
Added MRCLS to figure for Substudy 1 and 
Substudy 2 
Inclusion ofMRCLS in both 
substudies 
5.1 Overall design 
Updated study schema 
Inclusion of MRCLS in both 
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Section # and Name 
Description of Change 
Brief Rationale 
5.1 Overall design 
Reference to Section 12.12 for details 
regarding substudies 
In anticipation of additional 
substudies, enables administrative 
changes to document. 
5.2 Participant Journey 
Included reference to substudies for HLA 
testing substudy specific details 
HLA testing is substudy specific – 
details are not provided in Core but in 
individual substudy sections. 
5.2 Participant Journey Part 
1 Screening 
Included third option of target expression 
screening 
Added option of proceeding with 
tumor sample collection based on a 
positive local HLA result.. 
5.3  Number of Participants 
Reference to Section 12.12 for details 
regarding substudies 
In anticipation of additional 
substudies, enables administrative 
changes to document. 
6.2 Screening Under Other 
GSK Studies 
Updated to indicate acceptability of LAGE-
1a positive participants  
In order to accommodate participants 
from other studies whose tumor was 
positive for LAGE-1a and to facilitate 
study-to-study transfer of these 
participants 
6. Protocol population 
Added sentence to refer to substudies for 
protocol population details relevant to each 
substudy.  
Transition to modular format.  
8.1.2 Split Dose 
Administration 
Updated language to refer to substudies for 
split dosing  
Transition to modular format 
8.2 Dose Limiting Toxicity 
Updated timing for DLT window for point 7 
to harmonize 
Typo correction 
8.2 Dose Limiting Toxicity 
Included reference to substudies for any 
substudy specific DLTs 
In the event DLTs specific to a 
substudy arise, these will be added to 
the substudy via amendment  
8.5 Study Stopping and 
Pausing Rules 
Added reference to substudy for any 
specific safety assessments 
In the event substudy specific safety 
assessments arise, these will be 
added to the substudy via 
amendment 
9.1.6 Cardiac assessments 
Added text to define specific cardiovascular 
risk factors and steps necessary to 
evaluate and monitor participant 
Implementation of additional safety 
monitoring measures in accordance 
with a recent Dear Investigator Letter 
(21 Oct 2021)and safety events.. 
9.1.7 Pulmonary 
Assessments 
Added new section on participant 
pulmonary function assessment prior to 
lymphodepletion 
Implementation of additional safety 
monitoring measures in accordance 
with a recent Dear Investigator Letter 
(21 Oct 2021) and safety events.   
9.1.8 Monitoring for 
Immune Effector Cell-
Associated Neurotoxicity 
Syndrome 
Added reference to substudy for any 
specific assessments 
Added language in the event there 
are additional assessments specific 
to a substudy.  
9.1.9 Monitoring for 
Demyelinating Neuropathy 
and other Neurological 
Events 
Added reference to substudy for any 
specific assessments 
Added language in the event there 
are additional assessments specific 
to a substudy.  
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Section # and Name 
Description of Change 
Brief Rationale 
9.2.1 Time Period and 
Frequency for Collecting AE 
and SAE Information 
Updated timing for AE and SAE collection 
Clarified AE and SAE reporting 
guidance 
9.2.5 Pregnancy 
Moved table of contraception use timings to 
Appendix 12.4 Contraception Guidance and 
Collection of Pregnancy Information 
Added table of contraception use 
timings to appendix pertaining to 
contraceptive guidance rather than 
retain in the Pregnancy section  
9.2.7 Adverse Events of 
Special Interest (AESIs) 
Added reference to substudy for any 
specific assessments 
Added language in the event there 
are additional assessments specific 
to a substudy.  
9.8 Genetics 
Clarified language and cross referenced 
Section 9.10 
Streamlined language 
9.10
 
Updated list of possible tumor biopsy 
research studies 
Updated list to reflect tumor tests to 
be conducted under Protocol 
Amendment 02 
9.10
 
Removal of stool samples and cfRNA,  
Stool samples and cfRNA no longer 
planned to be conducted in Study 
209012.  
9.10.1 Tumor Biopsy 
Removal of time limitations and reference 
to substudy for archival tissue time 
limitations 
Formatted section by time of biopsy  
Included requirements on sample suitability  
Indications vary by substudy 
Divided text into Screening, Baseline 
and On-study sampling times to 
enhance reader understanding 
Added guidance on type of biopsy 
that is acceptable per protocol 
9.10.2 Liquid Bopsies (from 
circulating blood) 
Included additional descriptive text 
Added text to provide more 
background to research purpose of 
liquid biopsies 
9.10.4 Cell Phenotype and 
Functional Activity  
Included text about apheresis product 
Expanded applicability of assays to 
both apheresis and manufactured 
product 
9.10.5 dnTGFbRII Receptor 
Expression Analyses 
Updated language to refer to substudies for 
dnTGFbRII Receptor Expression Analyses 
testing requirements 
dnTGFbRII Receptor Expression 
Analyses are not tested in all 
substudies 
9.10.8 Stool Collection for 
Microbiome Analysis 
Deleted section 
Removed because assay not being 
conducted under Protocol 
Amendment 02 
11. References 
Updated references section 
Updated references to be core-
specific 
12.7 Appendix 7: 
Supportive Care Guidance 
Included language to refer to substudy for 
additional substudy specific guidance, 
when applicable.  
Added language in the event there 
are additional assessments specific 
to a substudy. 
12.7.2 Infection  
Included guidance for participants with 
indwelling central lines 
Added guidance for increased 
monitoring of indwelling catheter lines 
to watch for infection 
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Section # and Name 
Description of Change 
Brief Rationale 
12.7.2.6 Other Anti-
Microbial 
Prophylaxis/Treatment 
Included guidance for participants with 
severe or gross hematuria 
Included guidance for participants requiring 
anti-microbial therapy with cardiac toxicity 
risk 
Added guidance to check for BK 
viruria and viremia.  In adiditon, 
added guidance to raise site’s 
awareness of need to carry out 
increased cardiac monitoring in 
participants receiving any anti-
microbial agent with a recognized 
cardiac toxicity risk.  
12.7.3 Hematologic and 
Blood Product Support 
Included language for management of 
thrombocytopenia in in- and out-patient 
setting 
Clarified out-patient support for 
completeness.  
12.7.5 Management of 
Cytokine Release 
Syndrome 
Included language for additional monitoring 
of participants with cardiac risks 
Provided detailed  guidance for 
monitoring of participants with cardiac 
risk factors who also develop CRS in 
an effort to minimize further risks.   
12.11 Appendix 11: 
Abbreviations and 
Trademarks 
Updated abbreviations list 
Removed abbreviations no longer 
applicable 
12.12. Appendix 12: List of 
substudies 
Table of substudies added 
Transition to modular format to 
enable administrative changes and 
provide overview of all substudies 
13. Protocol Amendment 
History 
Amendment 01 rationale and table moved 
to new section (Appendix 13) 
Introduction of additional amendment.  
Throughout document 
Minor edits and type corrections done 
Editorial changes 
Table of contents  
Udpated to refer only to Core  
In an effort to support future 
modularization of the 209012 
protocol, the Table of Contents was 
updated to reflect only the Core 
section of the protocol. 
Section 11 References 
Updated to include only those references 
relevant to the Core section of the protocol. 
In an effort to support future 
modularization of the 209012 
protocol, reference list was updated 
to include only those references 
relevant to the Core section of the 
protocol. 
 
 
 


TMF-14357930 
CONFIDENTIAL 
 
 
209012 
 
 
Protocol Amd 04 
 
101 
Substudy 2 
 
12.3 
Amendment 03 (20 December 2021) 
Finalize splitting of document from Master protocol Amendment 02 as independent 
Substudy 2 document. Please refer to Core Section 12.13 for Master Protocol Document 
History. 
Minor typo corrections throughout document. 
 


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SAP_001.pdf: 
Statistical Analysis Plan Amendment 1
Study ID:  209012 Substudy 2
Sub-study Official Title: Assessment of Safety and Recommended Phase 2 
Dose of Autologous T cells Engineered with an Affinity-enhanced TCR 
Targeting NY-ESO-1 and LAGE-1a, and co-expressing the dnTGF-βRII 
(GSK3845097) in Participants with NY-ESO-1 and/or LAGE-1a Positive 
Previously Treated Advanced (Metastatic or Unresectable) Synovial Sarcoma 
and Myxoid/Round Cell Liposarcoma 
NCT ID for sub-study: NCT05943990
Date of Document: 03-APR-2023


CONFIDENTIAL 
The GlaxoSmithKline group of companies  
209012 
Page 1 of 21 
Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
Master Protocol to Assess the Safety and Recommended Phase 
2 Dose of Next Generations of Autologous Enhanced NY-
ESO-1/ LAGE-1a TCR Engineered T cells, alone or in 
combination with other agents, in Participants with Advanced 
Tumors 
Substudy Title: 
Assessment of Safety and Recommended Phase 2 Dose of 
Autologous T cells Engineered with an Affinity-enhanced TCR 
Targeting NY-ESO-1 and LAGE-1a, and co-expressing the 
dnTGF-βRII (GSK3845097) in Participants with NY-ESO-1 
and/or LAGE-1a Positive Previously Treated Advanced 
(Metastatic or Unresectable) Synovial Sarcoma and 
Myxoid/Round Cell Liposarcoma 
Study Number: 
209012  
Compound Number: GSK3845097 
Abbreviated Title: 
Substudy 2: GSK3845097 in previously treated advanced 
synovial sarcoma and myxoid/round cell liposarcoma 
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s)  
Registry 
ID 
IND Number 
19751 
EudraCT Number 
2019-004446-14 
Clinicaltrials.gov 
NCT04526509 
Copyright 2023 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.


CONFIDENTIAL 
209012 
Page 2 of 21 
TABLE OF CONTENTS 
PAGE 
1.
INTRODUCTION ...................................................................................................... 5
1.1.
Objectives, Estimands, and Endpoints .......................................................... 5
1.1.1. 
Objectives and Endpoints .............................................................. 5
1.2.
Study Design ................................................................................................ 8
2.
STATISTICAL HYPOTHESES ............................................................................... 12
2.1.
Multiplicity Adjustment ................................................................................ 12
3.
ANALYSIS SETS ................................................................................................... 13
4.
STATISTICAL ANALYSES ..................................................................................... 14
4.1.
General Considerations .............................................................................. 14
4.1.1. 
General Methodology .................................................................. 14
4.1.2. 
Baseline Definition ....................................................................... 14
4.2.
Primary Endpoint(s) Analyses ..................................................................... 14
4.3.
Secondary Endpoint(s) Analyses ................................................................ 14
4.4.
Exploratory Endpoint(s) Analyses ............................................................... 14
4.5.
Safety Analyses .......................................................................................... 15
4.6.
Other Analyses ........................................................................................... 15
4.6.1.
Subgroup analyses ...................................................................... 15
4.7.
Interim Analyses ......................................................................................... 15
4.7.1.
Dose Confirmation Phase ............................................................ 15
4.7.2.
Dose Expansion Phase ................................................................ 17
4.7.3.
Primary Analysis .......................................................................... 17
4.7.4.
Final Analysis .............................................................................. 18
4.8. 
Changes to Protocol Defined Analyses ....................................................... 18
5.
SAMPLE SIZE DETERMINATION ......................................................................... 19
6.
SUPPORTING DOCUMENTATION ....................................................................... 20
6.1. 
Appendix 1 Study Population Analyses ....................................................... 20
6.1.1. 
Demographic and Baseline Characteristics .................................. 20
7.
REFERENCES ....................................................................................................... 21


CONFIDENTIAL 
209012 
Page 3 of 21 
Version history 
 SAP 
Version 
Approval Date 
Protocol 
Version (Date) 
on which SAP 
is Based 
Change 
Rationale 
SAP v1 
17 May 2022 
209012/Amend
ment 3 (20-Dec-
2021) 
Not Applicable 
Original 
version 
SAP 
Amendment 
1 
03 Apr 2023 
209012/Amend
ment 4 (27-
May-2022) 
In addition to 
minor 
typographical and 
formatting 
changes, the 
following updates 
have been made 
in relation to the 
reduction in scope 
of original 
planned analyses 
as a result of 
substudy 
termination: 
•
Removal
of
references
to
summaries
based on
RP2D or
the
Evaluable
Analysis
Set
(througho
ut
document)
.
•
Clarificati
on on the
presentati
on of the
safety and
efficacy
analyses


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CONFIDENTIAL 
209012 
Page 5 of 21 
1.
INTRODUCTION
The purpose of this Statistical Analysis Plan (SAP) is to describe the planned analyses to 
be included in the CSR for Sub-study 2 (GSK3845097) 209012. The core SAP covers the 
majority of the analyses for this substudy. However, additional details that are specific to 
this substudy are provided below.  
As described in Core SAP Amendment 2, due to early termination of all substudies only a 
subset of the previously planned analyses are now required. The following key changes to 
previously planned analyses are relevant to this document: 1) since the substudy was 
terminated prior to the establishment of the recommended phase 2 dose (RP2D), no 
related analyses will be provided (e.g., analyses based on the Evaluable analysis set). 2) 
The Interim and Primary analyses described in Substudy 2 Protocol Amendment 4 
Section 10.5 will not be conducted, only the Final Analysis will be undertaken. 3) No 
subgroup analyses will be undertaken as a result of recruiting fewer participants than the 
planned target sample size. 
1.1. 
Objectives, Estimands, and Endpoints 
The full list of objectives and endpoints below is the list given in the Substudy 2 Protocol 
Amendment 4.  
As of Substudy 2 SAP Amendment 1: Due to early termination of this substudy, only a 
subset of the exploratory endpoints will be analysed. 
1.1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the safety, tolerability and determine 
recommended phase 2 dose (RP2D) of 
GSK3845097 in HLA-A*02:01, HLA-A*02:05 
and/or HLA-A*02:06 positive participants with 
NY-ESO-1 and/or LAGE-1a positive, previously 
treated, advanced (metastatic or unresectable) 
SS and MRCLS 
•
Frequency of dose-limiting toxicities
(DLTs)
•
Frequency and severity of adverse
events (AEs), serious adverse events
(SAEs) and AEs of special interest
(AESI; as defined in the core protocol)
Secondary – Efficacy 
To investigate the anti-tumor activity of 
GSK3845097 in HLA-A*02:01, HLA-A*02:05 
and/or HLA-A*02:06 positive participants with 
NY-ESO-1 and/or LAGE-1a positive, previously 
treated, advanced (metastatic or unresectable) 
SS and MRCLS 
•
Overall Response Rate (ORR)
(investigator assessed according to
RECIST v1.1)
•
Duration of Response (DoR)
Secondary – Pharmacokinetics (PK) 
To characterize in vivo cellular PK profile (levels, 
expansion, persistence) of GSK3845097 over 
time 
•
Maximum transgene expansion (Cmax)
•
Time to Cmax (Tmax)


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Objectives 
Endpoints 
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Area under the time curve from zero to 
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Exploratory 
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CONFIDENTIAL 
 
209012 
Page 8 of 21 
1.2. 
Study Design 
Overview of Study Design and Key Features 
EOT = end of treatment (i.e., interventional) portion of the trial; HLA = human leukocyte antigen; ICF = informed consent form; LTFU = long-
term follow-up; MRCLS = myxoid/round cell liposarcoma; SS = synovial sarcoma.  
1. Screening, including HLA typing and antigen testing, may be done in this study or as part of a separate Pre-screening protocol.  
2. Sponsor will inform Investigators of the participant assignments between substudies and indicate if the participant is a sentinel participant 
and the number of remaining slots.  
3. The first participant to be dosed will receive the total dose in 2 separate infusions as aliquots of ~30% and ~70% of the total manufactured 
dose, administered 7 days apart. The second infusion will only be administered if no acute toxicities preventing full dosing are observed. If 
no DLTs are reported for the participants receiving split doses, then all subsequent participants administered the particular product will 
receive the full dose as a single i.e., one-time, infusion.  
4. See Section 5.3.1 of this substudy Protocol for definition of the end of interventional phase for a participant.  
5. The LTFU assessments and procedures may be done in this study or under a separate LTFU protocol.  
 
LTFU = long-term follow-up; MRCLS = myxoid/round cell liposarcoma; PD = progressive disease; RP2D = recommended phase 
2 dose; SS = synovial sarcoma. 
 
Design 
Features 
• 
This is a first time in human (FTIH) non-randomized, open-label substudy to investigate 
GSK3845097 in previously treated participants with advanced (metastatic or unresectable) 
synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCLS). This substudy will 
consist of two phases: Dose Confirmation Phase and Dose Expansion Phase. 
 
• 
Dose Confirmation Phase (n=6-15) 


 
CONFIDENTIAL 
 
209012 
Page 9 of 21 
Overview of Study Design and Key Features 
o The primary objective of the dose confirmation phase is to identify the RP2D of 
GSK3845097. RP2D will be determined as the maximum tolerated dose (MTD) or lower 
that provides adequate biologic activity with superior tolerability. The MTD is defined as 
the dose that maximizes the probability of target toxicity of 30% while controlling the 
probability of excessive or unacceptable toxicity 
o To find the RP2D, modified toxicity probability interval 2 (mTPI-2) design will be 
implemented. Participants will be recruited and treated in blocks of three. The design 
aims to identify a dose with a true underlying toxicity rate of 30, with a range of 25% to 
35%. 
o The dose will be re-escalated/de-escalated based on all available data. The DLT 
information on all participants enrolled in the trial is used to update the estimated dose 
toxicity relationship and provide supportive information in addition to the mTPI-2 design 
in the next re-escalation/de-escalation decision. 
o Dose Selection Committee (DSC) will meet after the DLT period in every 3 participants 
to enable dose decision until the final dose selection is achieved (6 to 15 participants). 
o The final determination of RP2D will be based on the mTPI-2 recommended dose, as 
defined as 6 participants treated at this dose and an observed toxicity rate closest to 
the targeted toxicity rate at 30% after isotonic regression, in addition to considering the 
clinical response rate and available PK and PD data generated from all participants. 
 
• 
Dose Expansion Phase (n = 10) 
o After RP2D has been determined, the cohort will enroll additional participants to ensure 
n=10 participants have become evaluable at the RP2D.  
o Evaluable participants are those who have received T-cell infusion and have completed 
at least 2 post-baseline disease assessments since infusion or have progressed or died 
or were withdrawn from the substudy.  
• 
For each individual participant, the study will consist of the following: 1) Screening, 
2) Leukapheresis and manufacture, 3) Interventional Phase (Lymphodepletion, Treatment and 
Follow-up), 4) Long-term follow-up (LTFU). Part 1: Screening - Target expression screening 
for the presence of HLA- A*02:01, HLA-A*02:05 and/or HLA-A*02:06 positivity and tumour 
expression of NY-ESO-1 and/or LAGE-1a, leukapheresis eligibility screening within 28 days 
prior to the day of the scheduled leukapheresis procedure. Part 2: Leukapheresis and 
Manufacture - Eligible participants, upon study enrollment, will undergo leukapheresis. The 
initiation of leukapheresis procedure constitutes enrollment in the study. The collected T cells 
will be sent for manufacturing. Part 3: Interventional Phase (Lymphodepletion, Treatment and 
Follow-up) - Treatment fitness assessment and eligibility confirmation, Lymphodepletion from 
Days -7 to -4, GSK3845097 intravenous (IV) infusion on Day 1 and follow-up until the end of 
study (as defined in Protocol Section 5.3 of this Substudy). Part 4: Long-Term Follow-Up 
(LTFU) - Long-term follow-up phase for up to 15 years from the date of GSK3845097 infusion. 
 
Study 
intervention 
• 
Leukapheresis  
o Participants will undergo leukapheresis to obtain starting material for the manufacture of 
GSK3845097. 
 
• 
Bridging therapy and/or standard of care intermediate anti-cancer therapy 
o Bridging or standard of care systemic chemotherapy, experimental therapy and/or local 
therapy (e.g., radiotherapy, cryoablation, surgical resection) may be administered 
between Target Expression Screening and Leukapheresis. 
 


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Overview of Study Design and Key Features 
o Systemic chemotherapy may be administered between Leukapheresis and the start of 
Lymphodepletion, if a participant has progressive disease and cannot be treatment-free. 
 
o Mandatory washout periods prior to Leukapheresis or Lymphodepletion are required.  
 
x
Lymphodepletion 
o When the GSK3845097 has been manufactured, has fulfilled release criteria, and is 
available for infusion at the site, lymphodepleting regimen can be administered. The 
lymphodepleting regimen consists of fludarabine 30mg/m2/day x 4 days (Day -7 to -4) 
and cyclophosphamide 900mg/m2/day x 3 days (Day -6 to -4). This regimen is adjusted 
for participants >60 years of age, as specified in Table 12 of the substudy Protocol. 
Lymphodepletion regimen dose modification may also occur as per reasons in Section 
7.1.3 of substudy Protocol. 
 
x
Dose Confirmation Phase 
o The starting dose will be the RP2D of GSK3377794 (lete-cel); that is, the initial group of 
3 participants will receive a dose in the range of 1 × 109 - 8 × 109 transduced T cells 
which will be administered by a single intravenous infusion on Day 1. 
 
o If DLTs are reported that require dose de-escalation according to the mTPI-2 model, 
then a lower dose range of 0.1 × 109 - 0.8 × 109 transduced T cells will be explored, with 
the possibility to re-escalate if the model supports such action. Alternative doses may be 
investigated if warranted by the emerging safety profile. 
 
o Split dosing and staggered treatment will be used: The first study participant receiving 
GSK3845097 will receive the total assigned dose (1 × 109 -8 × 109 transduced T cells) 
as 2 separate infusions, 7 days apart, in aliquots of ~30% (first infusion) and ~70% 
(second infusion) of the total manufactured dose, respectively. If no DLTs are reported 
for the participant receiving split dosing during the stagger period defined in the next 
paragraph, then all subsequent participants treated with the particular investigational 
agent will receive the full dose as a single i.e., one-time, infusion. If DLTs are reported 
for the participants receiving split doses, additional participants may be treated with a 
split dose regimen at the discretion of the sponsor in consultation with the participating 
Investigators and the DSC. 
 
x
Dose Expansion Phase 
o Additional participants will be enrolled to ensure n =10 participants dosed at the RP2D of 
GSK3845097 have become evaluable at the RP2D.  
Study 
intervention 
Assignment 
o This is a non-randomized, single arm open-label substudy. It is planned that all 
participants will receive GSK3845097. 
Interim 
Analysis 
x
Dose Confirmation Phase 
o During the dose confirmation phase, no formal interim analysis is planned. All available 
data (including safety laboratory data, 
 (if applicable), PK data (if applicable) 
and the safety profile) will be reviewed during the DSC meetings to inform dose 
escalation decisions. The mTPI-2 design will be utilised to guide dose re-escalation/de-
escalation and RP2D decisions. 
 
x
Dose Expansion Phase 
CCI


 
CONFIDENTIAL 
 
209012 
Page 11 of 21 
Overview of Study Design and Key Features 
o An interim analysis will be performed for each cohort after 10 participants in the cohort 
are evaluable at the RP2D. These analyses may be performed earlier with fewer than 10 
evaluable participants at the RP2D if it is clear from the accumulated data what the 
decision at 10 evaluable participants treated at RP2D would be. In the event that an 
early futility decision is made for ORR then enrollment to the cohort will be closed. 
 
• 
Primary Analysis 
o The primary analysis for each cohort will be performed after enrollment to the cohort is 
complete and all the enrolled participants in the cohort that will receive T-cell infusion 
have done so and of those: 
▪ 
at least 80% have confirmed disease progression or died, or 
▪ 
were withdrawn or lost to follow-up from the substudy; and  
▪ 
all the remaining infused participants have completed at least 2 post 
baseline disease assessments since infusion. 
o If the primary analysis for a cohort is expected to occur within 9 months of the final 
analyses for the cohort, then the primary analysis may be omitted and only the final 
analyses carried out. 
 
Time & 
Events 
• 
For the schedule of activities refer to Section 2 of the substudy Protocol. 
 


 
CONFIDENTIAL 
 
209012 
Page 12 of 21 
2. 
STATISTICAL HYPOTHESES  
The primary aim is to determine the recommended phase 2 dose, safety profiles and 
pharmacology of GSK3845097. Descriptive methods will be used in analyses of the data 
from this substudy. No inferential statistical hypothesis testing will be conducted.  
The null hypothesis for the secondary endpoint ORR is: p=40% 
The alternative hypothesis is: p=60% 
The assumptions for the secondary endpoint of ORR, as defined in the core SAP Section 
4.3.1.1.1, underlying the design are detailed below: 
 
The null hypothesis for the secondary endpoint ORR is: p=40% 
The alternative hypothesis is: p=60% 
2.1. 
Multiplicity Adjustment 
No formal statistical hypothesis testing will be performed and therefore no multiplicity 
adjustment is required. 


 
CONFIDENTIAL 
 
209012 
Page 13 of 21 
3. 
ANALYSIS SETS 
Refer to Section 3 of the core SAP. 


 
CONFIDENTIAL 
 
209012 
Page 14 of 21 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
No inferential statistical hypothesis testing will be conducted, i.e., no p-values will be 
calculated. Unless otherwise specified, continuous data will be summarized using 
descriptive statistics: number of subjects (n), mean, standard deviation, median, 
minimum, and maximum. Categorical data will be summarized as the number and 
percentage of participants in each category.  
Confidence intervals will use 95% confidence levels unless otherwise specified.  
For safety, data will be summarised by phase. In general, safety data will be displayed by 
actual dose received (total number of transduced T-cells) using the following columns: 
0.1-0.8 x 10^9 vs. 1-8 x 10^9 (mITT population tables). Please refer to Table 1 in the 
core SAP for the applicable tables that are to be displayed by the planned dose. The 
planned dose tables will use the following columns: DL-1 (for 0.1-0.8 x 10^9) and DL1 
(for 1-8 x 10^9). For tables on the ITT population, an additional column of “No 
treatment” will be included consisting of those who did not receive lymphodepletion 
chemotherapy and T-cell infusion. 
 
For efficacy, data will be summarised  by phase. The planned analyses will only include 
the efficacy data from the cohort of interest for the analyses. Data will be displayed by 
actual dose received (total number of transduced T-cells) using the following columns: 
0.1-0.8 x 10^9 vs. 1-8 x 10^9 (mITT population tables only) 
Details of the planned displays are provided in the core and Substudy 2 Output and 
Programming Specification (OPS) and are based on GSK data standards and statistical 
principles. 
4.1.2. 
Baseline Definition 
Refer to Section 4.1.2. of the core SAP. 
4.2. 
Primary Endpoint(s) Analyses 
Refer to Section 4.2. of the core SAP. 
4.3. 
Secondary Endpoint(s) Analyses 
Refer to Section 4.3. of the core SAP. 
4.4. 
 Exploratory Endpoint(s) Analyses 
Refer to Section 4.4. of the core SAP.  


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GSK3845097 falls within the range from 25% to 35% and is centred at 30%. The 
stopping rule threshold for excessive toxicity is 0.95 and the prior probability of toxicity 
at each dose is distributed as Beta(1,1). 
The monitoring rules guiding dose escalation are provided in Table 1. Columns provide 
the numbers of participants treated at the current dose level, and rows provide the 
corresponding numbers of participants experiencing DLTs. The entries of the table are 
dose-finding decisions (i.e., R, S, and D) representing re-escalating the dose, staying at 
the same dose, and de-escalating the dose. In addition, decision U means that the current 
dose level is unacceptable because of high toxicity and should be excluded from the trial. 
For example, when one of three participants experiences toxicity, the decision can be 
located at row 1 and column 3, which is S –to stay at the current dose level. 
Consequently, the next block of participants will be treated at the same dose level 
currently being used. If zero of three participants experience toxicity, the decision is at 
row 0 and column 3, which is R –to re-escalate. Thus, the next block of participants will 
be treated at the higher dose level, if available. If three of three participants experience 
toxicity, the decision is to de-escalate to the lower dose level and exclude the current dose 
from the trial, because the toxicity level is unacceptable. 
The final determination of RP2D will be based on the mTPI-2 recommended dose, as 
defined as 6 participants treated at this dose and an observed toxicity rate closest to the 
targeted toxicity rate at 30% after isotonic regression, in addition to considering the 
clinical response rate and available PK and PD data generated from all participants. 
Table 1 
DLT De-escalation/Re-Escalation Rules 
Number of participants with Dose Limiting 
Toxicities (DLTs)  
at the current dose 
 
3 
6 
9 
12 
15 
0 
R  
R 
R 
R 
R 
1 
S 
R 
R 
R 
R 
2 
D 
S 
R 
R 
R 
3 
U 
D 
S 
S 
R 
4 
 
U 
D 
S 
S 
5 
 
U 
U 
D 
S 
6 
 
U 
U 
D 
D 
7 
 
 
U 
U 
D 
8 
 
 
U 
U 
U 
9 
 
 
U 
U 
U 
10 
 
 
 
U 
U 
11 
 
 
 
U 
U 
12 
 
 
 
U 
U 
13 
 
 
 
 
U 
14 
 
 
 
 
U 
15 
 
 
 
 
U 
R=Re-escalate to the higher dose if applicable OR Stay at the current dose otherwise 
S=Stay at the current dose 
D=De-escalate to the lower dose if applicable OR Stay at the current dose otherwise 
U=The current dose is unacceptably toxic 
 
Target toxicity level=30% 
e1=e2=0.05 
 


 
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4.7.2. 
Dose Expansion Phase 
As of Substudy 2 SAP Amendment 1: Note that this substudy was terminated prior to 
the determination of RP2D. Hence this section of text is no longer applicable. 
 
An interim analysis for futility will be performed for each cohort after 10 participants in 
the cohort are evaluable at the RP2D. Evaluable subjects who received RP2D in the dose 
confirmation phase will be included in the 10 participants. The endpoint assessed for 
futility is the Overall Response Rate (ORR), defined as the proportion of participants 
with an investigator-assessed confirmed complete response (CR) or confirmed partial 
response (PR) per RECIST v1.1. The endpoint assessed for futility is the Overall 
Response Rate (ORR), defined as the proportion of participants with an investigator-
assessed confirmed complete response (CR) or confirmed partial response (PR) per 
RECIST v1.1. 
The interim analysis may be performed earlier with fewer than 10 evaluable participants 
at the RP2D if it is clear from the accumulated data what the decision at 10 evaluable 
participants treated at RP2D would be.  
Futility rules are provided in Table 2 and justification for these rules is provided in 
Section 5. Note that these rules are for guidance only and futility decisions will be made 
based on the totality of the data. In the event that an early futility decision is made then 
enrollment to the cohort will be closed. 
If there are 4 or fewer responders out of 10 evaluable participants, then the substudy may 
stop for futility (see Section 5 for justification). This interim analysis may be performed 
earlier with less than 10 evaluable participants at the RP2D if it is clear from the 
accumulated data what the decision at 10 evaluable participants treated at RP2D would 
be (Table 2). For example, if no responders are observed in the first 6 evaluable 
participants at the RP2D then an early interim analysis may be conducted. 
Table 2 
Interim Analysis Futility Rules 
Interim Analysis 
Early Interim Analysis 
Number of participants 
evaluable at RP2D 
Stop for futility if no. of 
responders is 
Number of participants 
evaluable at RP2D 
Stop for futility if no. of 
responders is 
10 
4 
6 
0 
Abbreviations: RP2D = Recommended Phase 2 Dose. 
Criteria are for guidance only. Final decisions will be based on a review of the totality of the data.  
4.7.3. 
Primary Analysis 
As of Substudy 2 SAP Amendment 1: Protocol-planned analyses include an Interim, 
Primary and Final analysis. However, due to the early termination of all substudies, 
only a final analysis will be conducted. 
 
Refer to Section 4.7.2 in the core SAP and Section 10.5.1.1 in the Substudy 2 Protocol.  


 
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4.7.4. 
Final Analysis 
Refer to Section 4.7.3 in the core SAP. 
4.8. 
Changes to Protocol Defined Analyses 
Any changes from the originally planned statistical analysis specified in the protocol 
amendment 4 (Dated: 27-May-2022) are described in the Core SAP Section 4.8. 


 
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5. 
SAMPLE SIZE DETERMINATION 
The Dose Confirmation phase would need 6-15 participants to establish RP2D (see 
mTPI-2 simulation results in core SAP Section 6.4.1). Thus, the total expected maximal 
number of participants in the Dose Confirmation phase is 15. 
Once the RP2D has been established, the substudy will expand to up to n=10 evaluable 
participants treated at that dose. The null hypothesis is that the true ORR is 40% and the 
alternative hypothesis is that the true ORR is 60%. This substudy size was chosen to 
allow for early stopping of further development due to futility if the posterior probability 
that the ORR is less than 60% is >90%. This is equivalent to observing 4 or fewer 
responders out of 10 treated participants. It was assumed that the prior distribution for the 
response rate follows an uninformative Beta(a=0.02, b=0.08) distribution. Additionally, if 
the true ORR is 40%, the probability of observing 4 or fewer responders out of 10 treated 
participants is 63% and if the true ORR is 60% the probability of observing 4 or fewer 
responders out of 10 treated participants is 17%. These decision rules are for guidance 
only and the final decision for stop for futility will be determined based on the totality of 
the data.  
 
If supported by safety and efficacy results, additional participants may be enrolled to 
confirm the safety and efficacy via a protocol amendment or as part of a separate 
protocol.  
• 
For this substudy, five or more confirmed responses (CR or PR) out of 10 
evaluable participants treated at RP2D may provide sufficient efficacy evidence 
to expand and enroll additional participants. 
This will serve as guidance for final decisions regarding enrollment of additional 
participants, which will be based on a review of the totality of the data. 


 
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6. 
SUPPORTING DOCUMENTATION 
Refer to Section 6 of the core SAP. Any differences or additional analyses are specified 
below. 
6.1. 
Appendix 1 Study Population Analyses 
6.1.1. 
Demographic and Baseline Characteristics 
Disease characteristics at initial diagnosis and screening will be analysed as per Section 
6.1.2 in the core SAP. Presentations will also include the specific disease characteristics 
related to SS and MRCLS that are entered on separate corresponding eCRF pages. For SS 
this will include the extent of the disease at screening (local unresectable or metastatic), 
SYT-SSX translocation (SYT-SSX1, SYT-SSX2, SYT-SSX4 or not applicable or other) 
and histology type (monophasic, biphasic, not available, or other). For MRCLS this will 
include the extent of disease at screening (local unresectable or metastatic), specific 
translocation (FUS-DDIT3, EWSR1-DDIT3, not applicable or other) and percent round 
cell. 


 
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7. 
REFERENCES 
Guo Wang SJ, Yang S, Lynn H, Ji Y. A Bayesian interval dose-finding design addressing 
Ockham's razor: mTPI-2. Contemp Clin Trials. 2017; 58:23-33.