Clinical trial NCT04526509
Conditions: Neoplasms
Keywords: Adoptive T-cell therapy Advanced synovial sarcoma Advanced non-small cell lung cancer Advanced tumors GSK3845097 GSK3901961 GSK4427296 T cell receptors Leukapheresis Advanced myxoid/round cell liposarcoma
Sponsor: Adaptimmune
Start date: 2020-12-21; Completion date: 2023-06-08
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial will evaluate the safety and efficacy of first time in human engineered T-cell therapies, in participants with advanced tumors.

Detailed description:
This study is a master protocol. It has two sub studies registered as 209012 Sub Study 1 (NCT06048705) and 209012 Sub Study 2 (NCT05943990).

Arms: arm 1: Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3901961, as intravenous (IV) infusion after completing lymphodepleting chemotherapy. arm 2: Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3901961, as IV infusion after completing lymphodepleting chemotherapy. arm 3: Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK3845097, as IV infusion after completing lymphodepleting chemotherapy. arm 4: Eligible participants will be leukapheresed to manufacture engineered T-cells. Participants will then receive GSK4427296, as IV infusion after completing lymphodepleting chemotherapy.
Interventions: intervention 1: GSK3901961 intervention 2: GSK3845097 intervention 3: GSK4427296 intervention 4: Cyclophosphamide intervention 5: Fludarabine
Intervention descriptions: intervention 1: GSK3901961 as an IV infusion. intervention 2: GSK3845097 as an IV infusion. intervention 3: GSK4427296 as an IV infusion. intervention 4: Cyclophosphamide will be used as lymphodepleting chemotherapy and will be administered via IV route. intervention 5: Fludarabine will be used as lymphodepleting chemotherapy and will be administered via IV route.

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 4
Study ID:  209012 Core
Official Title of Study: 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
NCTID: NCT04526509
Date of Document: 27 May 2022


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s  
2 0 9 0 1 2  
Pr ot o c ol A m d 0 4  
1  
C or e  
TI T L E P A G E  
Pr ot oc ol Title:  M aster Pr ot oc ol t o Assess t he Safet y a n d Rec o m me n de d P hase 2 D ose of 
Ne xt Ge nerati o n s of A ut ol o g o us E n ha n ce d  N Y -E S O -1/ L A G E -1 a T C R E n gi neere d  
T  cells, al o ne or i n c o m bi nati o n wit h ot her a ge nts, i n Partici pa nts  wit h A d va nce d T u m ors  
Pr ot oc ol N u m ber : 2 0 9 0 1 2/ A me n d me nt 0 4  
C o m p o u n d N u m ber: G S K 3 9 0 1 9 6 1, G S K 3 8 4 5 0 9 7, G S K 4 4 2 7 2 9 6  
S h ort Title : Master Pr ot oc ol of A ut ol o g o us E n h a nce d  T  Cells i n A d va nce d T u m ors  
S p o ns or N a me a n d Le g al Re gistere d A d dress: 
Gla x o S mit h Kli ne L L C  
5 Cresce nt Dri v e  
P hila del p hia, P A 1 9 1 1 2  
U S  
Me dic al M o nit or N a me a n d C o nt act I nf or m ati o n  ca n be f o u n d i n t he St u d y Refere n ce 
Ma n ual  
Cli nical De v el o p me nt Lea d 
O nc ol o g y , C ell a n d Ge ne T hera p y 
Gla x o S mit h Kli ne  
, B M B C h M A 
 
O nc ol o g y , C ell a n d Ge ne T hera p y 
Gla x o S mit h Kli ne   
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s):  
I N D N u m ber: 1 9 7 5 1  
E u dr a C T N u m ber : 2 0 1 9 -0 0 4 4 4 6 -1 4  
A p pr o v al D ate:  2 7 Ma y 2 0 2 2  
© 2 0 2 2  G S K gr o u p of c o m p a nies or its lice ns or . All ri g hts res er ve d. U na ut h orize d 
c o p yi n g or use of t his i nf or mati o n is pr o hi bite d
P P D
P P D
P P D


TMF-14682560 
CONFIDENTIAL 
 
209012 
 
Protocol Amd 04 
 
2 
Core 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
GSK Document Number  
Amendment 04 
27 May 2022 
 
TMF-14682560 
Amendment 03 
20 December 2021 
TMF-14357914 
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 
 
Overall Rationale for Amendment 04: 
The primary reasons for Amendment 04 are as follows: 
• Changes to correct text inadvertently modified during the publication of 
Amendment 2. Edits in Amendment 04 reflect intended language 
• Updated eligibility criteria on prior therapies across indications 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 
Core Section 
Throughout the protocol 
Made administrative changes and corrected 
clerical errors. Added mentions of MRCLS 
where missing. 
For clarity and consistency 
 
The designation number of the planned 
Long-term Follow-up Study (i.e., 208750) 
was added. 
Update information 
Section 5.2 – Participant 
Journey (Part 3) 
 
Section 9.10.1 – Tumor 
Biopsy 
If it is not feasible to obtain a fresh biopsy, 
an archival tumor biopsy (FFPE block) 
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). 
Text edited to ensure clarity 


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S e cti o n # a n d N a m e  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
S ecti o n 5. 2 –  P artici p a nt 
J o ur n ey ( P art 4) 
A s e nt e nc e w as a d d e d t o cl arify t h at t h e 
tr a nsf er of a ny i n divi d u al p artici p a nt t o t h e 
L o n g -T er m F oll o w -U p ( L T F U ) pr ot oc ol 
2 0 8 7 5 0 s h o ul d n ot exc e e d 6  m o nt hs of 
c o m pl eti n g t h e i nt erv e nti o n al p orti o n of a 
s u bst u dy. 
F or cl arity a n d t o ali g n t ext wit h 
Su bst u di es’ t ext  
S ecti o n 6. 3 –  
R escr e e ni n g/ Tr a nsf er  
M o difi e d s e nt e nc e t o i n dic at e t h at 
r escr e e ni n g f or a nti g e n ex pr essi on  m ay n ot 
b e r e q uir e d d e p e n di n g o n t h e t est 
pl atf or m(s) us e d a n d w h et h er t h ey m e et 
st u dy r e q uir e m e nts 
F or cl arity  
S ecti o n 9. 1. 8 –  M o nit ori n g 
f or I m m u n e Eff ect or C ell-
Ass oci at e d N e ur ot oxicity 
Sy n dr o m e  
a n d  
S ecti o n 1 2. 7. 8. 2 –  
M a n a g e m e nt of I m m u n e 
Eff ect or C ell -Ass oci at e d 
N e ur ot oxicity Sy n dr o m e 
(I C A N S) 
M o difi e d existi n g l a n g u a g e o n Br ai n M RI at 
b as eli n e t o cl arify t h at it s h o ul d b e o bt ai n e d  
a m o n g p artici p a nts wit h n o hist ory of C N S 
m est ast asis if m or e t h a n 3 m o nt hs h av e 
el a ps e d b et w e e n t h e l ast br ai n M RI a n d t h e 
st art of ly m p h o d e pl eti o n or if t h ey  s h o w 
n e ur ol o gic al sy m pt o ms c o nsist e nt wit h 
C N S m et ast asis . Br ai n M RI at b as eli n e 
s h o ul d b e o bt ai n e d f or all  p artici p a nts wit h 
a hist ory of br ai n m et ast asis . 
T o cl arify ass ess m e nt wi n d o w  a n d f or 
s af ety p ur p os es 
Ali g n e d t h e l a n g u a g e b et w e e n t h e t w o 
s ecti o ns 
F or c o nsist e ncy  
S ecti o n 9. 2. 1 - Ti m e P eri o d 
a n d Fr e q u e ncy f or 
C oll ecti n g A E a n d S A E 
I nf or m ati o n (i ncl u di n g 
Fi g ur e 4)  
T ext c o nc er ni n g t h e A E/ S A E c oll ecti o n 
p eri o ds w as m o difi e d t o diff er e nti at e 
b et w e e n t h e e n d of t h e i nt erv e nti o n al p h as e 
a n d t h e e n d of t h e st u dy, a n d f or cl arity 
p ur p os es.  
T ext e dit e d t o e ns ur e cl arity  
S ecti o n 9. 2. 7 –  A dv ers e 
Ev e nts of S p eci al I nt er est 
( A E SIs) 
S plit  existi n g A E SI of p a ncyt o p e ni a / a pl astic 
a n e mi a  i nt o 2 s e p ar at e A E SIs  t o av oi d 
c o nf usi o n 
T o  e ns ur e cl arity  
 
M o difi e d A E SI of p n e u m o nitis/ p n e u m o ni a 
t o acc ur at ely r efl ect i nt e nt t o c o m m u nic at e 
ev e nts of p n e u m o nitis, n ot p n e u m o ni a, as 
s o o n as s us p ect e d 
T o ali g n wit h A E SI i nt e nt  
 
A d d e d l a n g u a g e t o A E SI of I C A N S t o n ot e 
t h at ev e nts t h at ar e Gr a d e 3 or hi g h er 
s h o ul d b e r e p ort e d as S A E wit hi n 2 4 h o urs 
A d d e d l a n g u a g e t o A E SI of a pl astic a n e mi a  
t o n ot e all ev e nts of a pl astic a n e mi a  s h o ul d 
b e r e p ort e d as S A E wit hi n 2 4 h o urs  
T o ali g n wit h s af ety m o nit ori n g i nt e nt  
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TMF-14682560 
CONFIDENTIAL 
 
209012 
 
Protocol Amd 04 
 
4 
Core 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 9.3.1 – Evaluation 
of Anti-Cancer Activity 
Minor changes in language on acceptable 
imaging modalities for the study 
For clarity 
 
Added statement to clarify that confirmation 
of progression is only required in 
participants who are clinically stable after 
criteria for progression were first met 
For clarity and consistency with 
language in Substudies 1-3 
Section 9.10.1 
General Guidance on Biopsies: Added 
language on biopsy of single measurable 
lesions if non-target lesions are absent or 
not accessible 
Post T-Cell Infusion Biopsies: removed 
“non-target lesion” to align with change 
above 
For clarity 
Section 12.3.2 – Definition 
of SAE 
Added language to SAE definition to 
indicate that all events of aplastic anemia 
and Grade ≥3 events of ICANS or GVHD 
must be reported as SAEs within 24 hours 
To align with Section 9.2.7 
Section 12.3.5 – Reporting 
of SAE to GSK 
Added language to SAE reporting 
requirements to clarify that email 
notifications do not replace the need for the 
Investigator to complete and sign the SAE 
CRF pages 
For clarity 
Section 12.5 – Appendix 5 
– Genetics  
Deleted mention of stool sample 
Removed because sample is no 
longer collected, as of PA02 
Section 12.6.1 – RECIST 
v1.1 Assessment 
Guidelines 
Added definitions of target and non-target 
lesions 
For clarity 
Section 12.7.2.3 - 
Cytomegalovirus 
Added language to clarify that participants 
will be screened for CMV IgG seropositivity 
at baseline, following the Schedule of 
Activities 
For clarity 
 


TMF-14682560 
CONFIDENTIAL 
 
209012 
 
Protocol Amd 04 
 
5 
Core 
 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
1. 
SYNOPSIS ............................................................................................................. 11 
2. 
SCHEDULE OF ACTIVITIES (SOA) ....................................................................... 18 
3. 
INTRODUCTION .................................................................................................... 19 
3.1. 
Study Rationale .......................................................................................... 19 
3.2. 
Background ................................................................................................ 20 
3.2.1. 
Adoptive cell therapies and NY-ESO-1/LAGE-1a ......................... 20 
3.2.2. 
GSK3377794 (letetresgene autoleucel, lete-cel) .......................... 21 
3.2.3. 
Next Generation Engineering ....................................................... 22 
4. 
OBJECTIVES AND ENDPOINTS ........................................................................... 23 
5. 
STUDY DESIGN .................................................................................................... 24 
5.1. 
Overall Design ............................................................................................ 24 
5.1.1. 
Dose Confirmation Phase ............................................................ 25 
5.1.2. 
Dose Expansion Phase ................................................................ 25 
5.2. 
Participant Journey ..................................................................................... 25 
5.3. 
Number of Participants ............................................................................... 29 
5.4. 
Scientific Rationale for Protocol Design ...................................................... 29 
5.4.1. 
Data Monitoring Committee ......................................................... 29 
5.5. 
End of Study Definition ............................................................................... 30 
5.5.1. 
End of Study for Individual Participants ........................................ 30 
5.5.2. 
End of Master Protocol ................................................................ 30 
6. 
PROTOCOL POPULATION ................................................................................... 31 
6.1. 
Screen Failures........................................................................................... 31 
6.2. 
Screening under Other GSK Studies .......................................................... 31 
6.3. 
Rescreening/Transfer ................................................................................. 31 
7. 
STUDY INTERVENTION ........................................................................................ 33 
8. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 34 
8.1. 
Discontinuation of Study Intervention .......................................................... 34 
8.1.1. 
Single Dose Administration .......................................................... 34 
8.1.2. 
Split Dose Administration ............................................................. 34 
8.2. 
Dose Limiting Toxicity ................................................................................. 35 
8.2.1. 
Liver Chemistry Stopping and Increased Monitoring 
Criteria ......................................................................................... 37 
8.2.1.1. 
Stopping Criteria ......................................................... 37 
8.2.1.2. 
Level 1 Monitoring ...................................................... 37 
8.2.1.3. 
Level 2 Monitoring ...................................................... 38 
8.2.1.4. 
Administration of Subsequent T Cell Dose(s) 
after Liver Stopping Criteria Met ................................. 39 
8.2.2. 
QTc Stopping Criteria .................................................................. 39 
8.2.3. 
Temporary Discontinuation .......................................................... 40 


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8. 3.  
P arti ci p a nt Di s c o nti n u ati o n/ Wit h dr a w al fr o m t h e St u d y  ............................... 4 0  
8. 4.  
L o st t o F oll o w U p  ........................................................................................ 4 1  
8. 5.  
St u d y St o p pi n g a n d P a u si n g R ul e s  ............................................................. 4 2  
9.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ..................................................... 4 3  
9. 1.  
S af et y A s s e s s m e nt s  ................................................................................... 4 3  
9. 1. 1.  
D o s e S el e cti o n C o m mitt e e  .......................................................... 4 3  
9. 1. 2.  
G S K S af et y R e vi e w T e a m  ........................................................... 4 4  
9. 1. 3.  
P h y si c al E x a mi n ati o n s  ................................................................. 4 4  
9. 1. 4.  
E C O G P erf or m a n c e St at u s  .......................................................... 4 4  
9. 1. 5.  
Vit al Si g n s  .................................................................................... 4 4  
9. 1. 6.  
C ar di a c A s s e s s m e nt s  .................................................................. 4 4  
9. 1. 7.  
P ul m o n ar y A s s e s s m e nt s  ............................................................. 4 5  
9. 1. 8.  
M o nit ori n g f or I m m u n e Eff e ct or C ell -A s s o ci at e d 
N e ur ot o xi cit y  S y n dr o m e  ............................................................... 4 6  
9. 1. 9.  
M o nit ori n g f or D e m y eli n ati n g N e ur o p at h y a n d  ot h er 
N e ur ol o gi c al E v e nt s  ..................................................................... 4 7  
9. 1. 1 0.  
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s  ...................................... 4 7  
9. 2.  
A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  ............................................. 5 0  
9. 2. 1.  
Ti m e P eri o d a n d Fr e q u e n c y f or C oll e cti n g A E a n d S A E 
I nf or m ati o n ................................................................................... 5 1  
9. 2. 2.  
M et h o d of D et e cti n g A E s a n d S A E s  ............................................. 5 2  
9. 2. 3.  
F oll o w -u p of A E s a n d S A E s  ......................................................... 5 3  
9. 2. 4.  
R e g ul at or y R e p orti n g R e q uir e m e nt s f or S A E s  ............................. 5 3  
9. 2. 5.  
C ar di o v a s c ul ar E v e nt s a n d D e at h  ................................................ 5 3  
9. 2. 6.  
Pr o gr e s si o n of U n d erl yi n g M ali g n a n c y  ......................................... 5 4  
9. 2. 7.  
A d v er s e E v e nt s of S p e ci al I nt er e st ( A E SI s)  ................................. 5 4  
9. 3.  
Effi c a c y A s s e s s m e nt s  ................................................................................. 5 5  
9. 3. 1.  
E v al u ati o n of A nti -C a n c er A cti vit y  ................................................ 5 5  
9. 3. 2.  
L o n g -T er m F oll o w -u p  ................................................................... 5 6  
9. 4.  
P ati e nt R e p ort e d O ut c o m e s  ........................................................................ 5 6  
9. 5.  
Tr e at m e nt of O v er d o s e  ............................................................................... 5 6  
9. 6.  
P h ar m a c o ki n eti c s  ....................................................................................... 5 7  
9. 7.  
P h ar m a c o d y n a mi c s  .................................................................................... 5 7  
9. 8.  
G e n eti c s  ..................................................................................................... 5 7  
9. 9.  
I m m u n o g e ni cit y A s s e s s m e nt s ..................................................................... 5 8  
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1 0.  S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................ 6 4  
1 0. 1.  St ati sti c al H y p ot h e s e s ................................................................................. 6 4  
1 0. 2.  S a m pl e Si z e D et er mi n ati o n  ........................................................................ 6 4  
1 0. 3.  D at a A n al y si s C o n si d er ati o n s  ..................................................................... 6 4  
1 0. 4.  P o p ul ati o n s f or A n al y s e s  ............................................................................ 6 4  
1 0. 5.  St ati sti c al A n al y s e s  ..................................................................................... 6 5  
1 0. 5. 1.  
I nt eri m A n al y s e s .......................................................................... 6 5  
1 0. 5 . 2. 
K e y El e m e nt s of A n al y si s Pl a n  .................................................... 6 5  
1 0. 5. 2. 1.  S af et y A n al y s e s  .......................................................... 6 5  
1 0. 5. 2. 2.  Effi c a c y A n al y s e s  ....................................................... 6 6  
1 1.  R E F E R E N C E S  ....................................................................................................... 6 7  
1 2.  S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L  
C O N SI D E R A TI O N S  ............................................................................................... 7 1  
1 2. 1.  A p p e n di x 1: R e g ul at or y, Et hi c al, a n d St u d y O v er si g ht 
C o n si d er ati o n s  ............................................................................................ 7 1  
1 2. 1. 1.  
R e g ul at or y a n d Et hi c al C o n si d er ati o n s  ........................................ 7 1  
1 2. 1. 2.  
Fi n a n ci al Di s cl o s ur e  ..................................................................... 7 1  
1 2. 1. 3.  
I nf or m e d C o n s e nt Pr o c e s s .......................................................... 7 2  
1 2. 1. 4.  
D at a Pr ot e cti o n  ............................................................................ 7 2  
1 2. 1 . 5. 
Di s s e mi n ati o n of Cli ni c al St u d y D at a  ........................................... 7 3  
1 2. 1. 6.  
D at a Q u alit y A s s ur a n c e  ............................................................... 7 3  
1 2. 1. 7.  
S o ur c e D o c u m e nt s  ...................................................................... 7 4  
1 2. 1. 8.  
St u d y a n d Sit e Cl o s ur e  ................................................................ 7 4  
1 2. 1. 9.  
R e m ot e M o nit ori n g a n d S o ur c e D at a V erifi c ati o n  ......................... 7 5  
1 2. 2.  A p p e n di x  2: Cli ni c al L a b or at or y T e st s  ......................................................... 7 6  
1 2. 3.  A p p e n di x 3: A d v er s e E v e nt s: D efi niti o n s a n d Pr o c e d ur e s f or 
R e c or di n g, E v al u ati n g, F oll o w -u p, a n d R e p orti n g  ....................................... 7 8  
1 2. 3. 1.  
D efi niti o n of A E  ............................................................................ 7 8  
1 2. 3. 2.  
D efi niti o n  of S A E  .......................................................................... 7 9  
1 2. 3. 3.  
D efi niti o n of C ar di o v a s c ul ar E v e nt s  ............................................. 8 0  
1 2. 3. 4.  
R e c or di n g a n d F oll o w -U p of A E a n d S A E  .................................... 8 0  
1 2. 3. 5.  
R e p orti n g of S A E t o G S K  ............................................................. 8 2  
1 2. 4.  A p p e n di x 4: C o ntr a c e pti v e G ui d a n c e a n d C oll e cti o n of Pr e g n a n c y 
I nf or m ati o n .................................................................................................. 8 4  
1 2. 4. 1.  
D efi niti o n s  .................................................................................... 8 4  
1 2. 4. 2.  
C o ntr a c e pti o n G ui d a n c e  .............................................................. 8 5  
1 2. 4. 3.  
C oll e cti o n of Pr e g n a n c y I nf or m ati o n:  ........................................... 8 6  
1 2. 5.  A p p e n di x  5: G e n eti c s  .................................................................................. 8 8  
1 2. 5. 1.  
C o m p a ni o n Di a g n o sti c s  ............................................................... 8 8  
1 2. 6.  A p p e n di x 6: G ui d eli n e s f or A s s e s s m e nt of Di s e a s e, Di s e a s e 
Pr o gr e s si o n, a n d R e s p o n s e Crit eri a  ........................................................... 9 0  
1 2. 6. 1.  
R E CI S T v 1. 1 A s s e s s m e nt G ui d eli n e s  .......................................... 9 0  
1 2. 6. 2.  
i R E CI ST G ui d eli n e s  ..................................................................... 9 5  
1 2. 7.  A p p e n di x 7: S u p p orti v e C ar e G ui d a n c e  .................................................... 1 0 2  
1 2. 7. 1.  
T -C ell I nf u si o n S y m pt o m M a n a g e m e nt  ...................................... 1 0 2  
1 2. 7. 2.  
I nf e cti o n ..................................................................................... 1 0 2  
1 2. 7. 2. 1.  P n e u m o c y sti s c ari nii  P n e u m o ni a ( P C P)  ................... 1 0 3  
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1 2. 7. 2. 2.  H er p e s Si m pl e x, V ari c ell a Z o st er a n d E p st ei n 
B arr vir u s ( E B V)  ....................................................... 1 0 3  
1 2. 7. 2. 3.  C yt o m e g al o vir u s  ....................................................... 1 0 3  
1 2 . 7. 2. 4. H e p atiti s B Pr o p h yl a xi s  ............................................. 1 0 3  
1 2. 7. 2. 5.  S y p hili s  ..................................................................... 1 0 3  
1 2. 7. 2. 6.  Ot h er A nti -Mi cr o bi al Pr o p h yl a xi s  ............................... 1 0 4  
1 2. 7. 3.  
H e m at ol o gi c a n d Bl o o d Pr o d u ct S u p p ort  ................................... 1 0 4  
1 2. 7. 3. 1.  Irr a di at e d Bl o o d Pr o d u ct ........................................... 1 0 4  
1 2. 7. 3. 2.  C M V S cr e e n e d Bl o o d Pr o d u ct s  ................................ 1 0 4  
1 2. 7. 4.  
M a n a g e m e nt of A ut oi m m u nit y  ................................................... 1 0 5  
1 2. 7. 5.  
M a n a g e m e nt of C yt o ki n e R el e a s e S y n dr o m e  ............................ 1 0 5  
1 2. 7. 6.  
M a n a g e m e nt of Gr aft -v er s u s -H o st Di s e a s e ( G v H D)  .................. 1 0 8  
1 2. 7. 6. 1.  Di a g n o si s of G v H D  ................................................... 1 0 9  
1 2. 7. 6. 2.  Gr a di n g of G v H D  ...................................................... 1 1 0  
1 2. 7. 6. 3.  M a n a g e m e nt of G v H D  .............................................. 1 1 0  
1 2. 7. 7.  
M a n a g e m e nt of P a n c yt o p e ni a wit h B o n e M arr o w 
F ail ur e/ A pl a sti c A n e mi a  ............................................................. 1 1 2  
1 2. 7. 8.  
M a n a g e m e nt of I m m u n e Eff e ct or C ell -A s s o ci at e d 
N e ur ot o xi cit y S y n dr o m e (I C A N S)  ............................................... 1 1 3  
1 2. 7. 8. 1.  Gr a di n g of I C A N S  ..................................................... 1 1 3  
1 2. 7. 8. 2.  M o nit ori n g f or I m m u n e Eff e ct or C ell -A s s o ci at e d 
N e ur ot o xi cit y S y n dr o m e (I C A N S)  ............................. 1 1 5  
1 2. 7. 8. 3.  M a n a g e m e nt of I C A N S  ............................................. 1 1 5  
1 2. 7. 9.  
C h e m ot h er a p y S y m pt o m M a n a g e m e nt  ...................................... 1 1 7  
1 2. 7. 9. 1.  M a n a g e m e nt of N e utr o p e ni a  .................................... 1 1 7  
1 2. 7. 1 0.  M a n a g e m e nt of G uill a n -B arr é S y n dr o m e ( G B S)  ........................ 1 1 8  
1 2. 7. 1 0. 1.  N e ur ol o gi c al S y m pt o m s  ............................................ 1 1 9  
1 2. 7. 1 0. 2.  Bri g ht o n K e y Di a g n o sti c Crit eri a  ............................... 1 1 9  
1 2. 7. 1 0. 3.  Er a s m u s R e s pir at or y I n s uffi ci e n c y S c or e 
( E G RI S) .................................................................... 1 1 9  
1 2. 7. 1 0. 4.  M o difi e d Er a s m u s G B S O ut c o m e s S c or e 
( m E G O S) ................................................................. 1 1 9  
1 2. 7. 1 0. 5.  S u m m ar y of Di a g n o si s a n d Tr e at m e nt f or G B S  ........ 1 2 0  
1 2. 8.  A p p e n di x 8: N e ur ol o g y C o n s ult ati o n –  F urt h er G ui d eli n e s f or Si g n s 
a n d S y m pt o m s S u g g e sti v e of G uill ai n -B arr é S y n dr o m e  ............................ 1 2 1  
1 2. 8. 1.  
A d diti o n al A s s e s s m e nt s f or S u s p e ct e d G B S at H o s pit al 
A d mi s si o n  .................................................................................. 1 2 1  
1 2. 8. 1. 1.  Ri s k of R e s pir at or y I n s uffi ci e n c y A s s e s s m e nt  ........... 1 2 1  
1 2. 8. 1. 2.  Pr o g n o sti c T o ol f or A s s e s s m e nt of G B S 
O ut c o m e at H o s pit al A d mi s si o n  ................................ 1 2 2  
1 2. 8. 2.  
A s s e s s m e nt s P o st H o s pit al A d mi s si o n f or G B S  ......................... 1 2 2  
1 2. 8. 2. 1.  Bri g ht o n Crit eri a  ....................................................... 1 2 2  
1 2. 8. 2. 2.  Pr o g n o sti c T o ol f or A s s e s s m e nt of G B S 
1 2. 1 0.  A p p e n di x 1 0: m T PI -2 D e si g n Si m ul ati o n R e s ult s  ...................................... 1 2 5  
1 2. 1 1.  A p p e n di x 1 1: A b br e vi ati o n s a n d Tr a d e m ar k s  ............................................ 1 2 6  
1 2. 1 2.  A p p e n di x 1 2: Li st of S u b st u di e s  ................................................................ 1 3 2  
1 2. 1 3.  A p p e n di x 1 3: M a st er Pr ot o c ol D o c u m e nt Hi st or y  ...................................... 1 3 3  
1 3.  P R O T O C O L A M E N D M E N T H I S T O R Y ................................................................. 1 3 4  
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d 
b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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13.1. 
Amendment 1 (21 May 2021) .................................................................... 134 
13.2. 
Amendment 2 (04 November 2021) .......................................................... 156 
13.3. 
Amendment 3 (20 December 2021) .......................................................... 160 
 
LIST OF TABLES 
PAGE 
Table 1 
Protocol-Required Safety Laboratory Assessments ............................... 77 
Table 2 
Time Periods for Contraception Usage ................................................... 86 
Table 3 
Evaluation of Overall Response for Participants with Measurable 
Disease at Baseline ............................................................................... 94 
Table 4 
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease ............................................................................ 100 
Table 5 
Management Guidelines for Cytokine Release Syndrome .................... 107 
Table 6 
Overview of Clinical Findings/Symptoms of GvHD ............................... 109 
Table 7 
Staging of Dermal, Gastrointestinal and Hepatic Involvement with 
Acute GvHD ......................................................................................... 110 
Table 8 
Grading of Acute GvHD ........................................................................ 110 
Table 9 
Management Guidelines for GvHD ....................................................... 111 
Table 10 
ICE-Encephalopathy Assessment Tool for Grading of ICANS .............. 114 
Table 11 
Grading of Immune Effector Cell-Associated Neurotoxicity 
Syndrome (ICANS) .............................................................................. 114 
Table 12 
Management of ICANS ........................................................................ 116 
Table 13 
Brighton Diagnostic Criteria .................................................................. 121 
Table 14 
Design Simulation Results ................................................................... 125 
 
LIST OF FIGURES 
PAGE 
Figure 1 
Participant Journey Schema................................................................... 17 
Figure 2 
Study Design .......................................................................................... 24 
Figure 3 
Patient Journey Schema ........................................................................ 25 
Figure 4 
 Time Period for Collecting AE and SAE Information .............................. 52 


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Figure 5 
Imaging and Treatment for Clinically Stable Participants after 
First Radiologic Evidence of PD Assessed by the Investigator ............. 101 
Figure 6 
Diagnosis and Treatment of Guillain-Barré Syndrome (GBS) ............... 120 
 


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1. 
SYNOPSIS 
Protocol Title: Master Protocol to Assess the Safety and Recommended Phase 2 Dose of 
Next Generations of Autologous Enhanced NYESO-1/ LAGE-1a TCR engineered 
T cells, alone or in combination with other agents, in Participants with Advanced Tumors  
Short Title: Master Protocol of Autologous Enhanced T Cells in Advanced Tumors  
Rationale:  
This master protocol will investigate a series of next generations of NY-ESO-1/LAGE-1a 
TCR engineered T cells that are efficacy enhanced using advances in technology, 
including (1) multi-component engineering (MCE, an approach in which more than one 
gene-product is introduced into T cells to modify the pharmacological activity of the 
engineered T cell), and/or (2) innovative ways of manufacturing for potentially fitter 
T cells.  These T cells may be evaluated alone or in combination with other agents.  
Adoptive T-cell therapy (ACT) is a therapeutic approach that uses autologous (cancer 
patient’s own) or allogeneic T lymphocytes obtained by leukapheresis, that are 
subsequently genetically engineered to express a tumor-targeting receptor, such as a 
T-cell receptor (TCR) or a chimeric antigen receptor (CAR), expanded in vitro and 
re-infused into the participant, with the aim of generating and propagating an anti-tumor 
T-cell immune response. 
NY-ESO-1 and LAGE-1a are members of the cancer-testis antigen (CTA) family of 
tumor-associated antigens.  These are cytoplasmic proteins detectable in multiple cancer 
types including synovial sarcoma (SS), myxoid/round cell liposarcoma (MRCLS), 
multiple myeloma, non-small cell lung cancer (NSCLC), bladder cancer, melanoma, 
gastric cancer, liver cancer, and many others.  Specific peptide epitopes of the NY-ESO-1 
or LAGE-1a protein are processed and presented on the surface of the tumor cell in 
complex with an HLA molecule, which can be recognized by T cells.  An HLA-A*02 
binding peptide (SLLMWITQC aa 157-165) that is common to both NY-ESO-1 and 
LAGE-1a antigens has been identified that can be recognized by NY-ESO-1 reactive 
T cells.   
GSK is currently developing an NY-ESO-1 TCR-T cell product (letetresgene autoleucel, 
lete-cel, GSK3377794, IND 14603 and IND 18944) that is one of the most advanced 
TCR-T engineered cell therapies in clinical trials for solid tumors.  The retained 
optimized TCR clone (called NY-ESO-1c259 or c259) used to manufacture GSK3377794 
targets the SLLMWITQC peptide bound to HLA-A*02.  As of 27 January 2021, 
125 patients covering six different NY-ESO-1 and/or LAGE-1a-positive malignancies 
have been treated with GSK3377794, with demonstration of a manageable safety profile 
and initial evidence of encouraging clinical activity in patients with metastatic synovial 
sarcoma (SS) and MRCLS. (Please refer to the most recent IB for up-to-date information 
regarding lete-cel).  Based on this early demonstration of positive risk-benefit in SS, the 
FDA has granted breakthrough designation and the EMA has granted PRIME status, thus, 
a pivotal trial (study 208467) has been initiated with GSK3377794 (lete-cel) in SS and 
MRCLS.  Other studies are ongoing, with early observations of clinical activity in other 
tumor types. 


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Despite the encouraging clinical activity of this first generation TCR-T, there is a need to 
further improve the activity and duration of response, as a proportion of patients 
receiving GSK3377794 (lete-cel) do not respond to treatment, and some of the patients 
that initially show tumor responses eventually relapse with their disease.  There are 
several proposed mechanisms for these observations, including the immunosuppressive 
tumor microenvironment (TME) and limited functional activity of CD4+ T cells within 
the T-cell product.  In order to further improve upon the clinical response rate and 
durability of response, next generations of engineered T-cell products are being 
developed that use the same affinity-enhanced TCR and in addition use (1) 
multi-component engineering (MCE) to incorporate within the lentiviral vector construct 
additional genes encoding molecules expected to enhance T-cell function and survival 
and/or (2) innovative ways of manufacturing for potentially fitter T cells.  
Study 209012 is a master protocol to assess the initial safety, tolerability, and 
recommended Phase 2 dose (RP2D) of such next-generations of NY-ESO-1 and 
LAGE-1a specific T cells, alone or in combination with other anticancer agents, in 
HLA-A*02 positive participants with NY-ESO-1 and/or LAGE-1a positive advanced 
tumors.  
Objectives and Endpoints: 
In general, the objectives and endpoints below will apply to all substudies unless 
otherwise specified.  Discrepancies between those stated here and those in the substudies 
will not require amendment and those stated in the substudies will apply.  
Exploratory objectives and endpoints, if any, will be provided in the substudy specific 
sections.  


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Objectives 
Endpoints 
Primary 
To assess the safety, tolerability, and determine 
recommended phase 2 dose (RP2D) of 
NY-ESO-1 and LAGE-1a specific T cells, alone 
or in combination with other agents, in HLA-A*02 
positive participants with NY-ESO-1 and/or 
LAGE-1a positive advanced tumors 
• 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 efficacy NY-ESO-1 and 
LAGE-1a specific T cells, alone or in 
combination with other agents, in HLA-A*02 
positive participants with NY-ESO-1 and/or 
LAGE-1a positive advanced tumors 
• Overall Response Rate (ORR) 
(investigator assessed according to 
RECIST v1.1) 
• Duration of Response (DoR) 
Secondary - Pharmacokinetics 
To characterize in vivo cellular PK profile (levels, 
expansion, persistence) of NY-ESO-1 and 
LAGE-1a specific T cells, alone or in 
combination with other agents, over time 
• Maximum transgene expansion (Cmax) 
• Time to Cmax (Tmax) 
• Area under the time curve from zero to 
time t AUC(0-t), as data permit 
AE = adverse event; AESI = AE of special interest; DLTs = dose-limiting toxicities; DoR = duration of response; 
HLA = human leukocyte antigen;  NY-ESO-1 = New York esophageal antigen-1; ORR = overall response rate; 
RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended phase 2 dose; SAE = serious AE. 
Overall Design:  
This is a master protocol investigating the safety, tolerability, RP2D and early efficacy of 
autologous, next-generation, NY-ESO-1 and LAGE-1a specific T cells, alone or in 
combination with other agents, in HLA-A*02 positive participants with NY-ESO-1 
and/or LAGE-1a positive advanced tumors.  
This protocol consists of a core protocol with multiple independent substudies.  For 
further details outlining each substudy, please refer to the List of Substudies in 
Section 12.12. 
The protocol may be amended at a later time to add additional substudies to investigate 
other NY-ESO-1 and/or LAGE-1a positive tumor types and other NY-ESO-1 and 
LAGE-1a specific T cells, potentially in combination with other agents.  Details of 
treatment will be provided in the substudy specific sections. 
Unless otherwise specified in a substudy-specific section, participants will receive 
NY-ESO-1 and LAGE-1a specific T cells after Screening, fulfilling eligibility criteria and 
completing lymphodepleting chemotherapy. 


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Study Schema  
 
 
NOTE:  Schema will not be updated for any additional substudies - please refer to Core Section 12.12 for 
the complete list of substudies. Participants with LAGE-1a positive tumors will be eligible if identified 
under a designated central laboratory test when available. 
 
Disclosure Statement: This is an open-label treatment master protocol with no masking.  
Number of Participants: 
This is a master protocol consisting of multiple substudies, the overall sample size is not 
fixed.  For details regarding planned participant numbers for each substudy, as well as for 
an up-to-date projected overall sample size, please refer to the List of Substudies in 
Section 12.12.  
Any further expansion of the substudies or additional substudies will be added by 
amendment subject to regulatory review.  
Sample size for each substudy will be documented in the substudy specific sections. 
Methodology and Study Duration: 
Each substudy in this Master Protocol will consist of two phases: Dose Confirmation 
Phase and Dose Expansion Phase.   
Dose Confirmation Phase 
In this phase, each next-generation NY-ESO-1/LAGE-1a specific T-cell product will be 
evaluated to assess/confirm the RP2D to be used in further clinical investigations. 
Dose Expansion Phase 
After RP2D has been determined for a given T-cell product, the dose expansion phase 
will begin.  In this phase, additional participants will be enrolled as necessary to meet the 
substudy requirements for the number of evaluable participants treated at the RP2D. Each 
     
     
       
        
                 
                
                      
                      
     
                    
                
          
Substudy 1:  GSK3901961 [CD8α_NY-ESO-1(c259)T]
in previously treated HLA-A*02 positive participants with 
• NY-ESO-1/LAGE-1a positive metastatic NSCLC  (Cohort 1)
• NY-ESO-1/LAGE-1a positive metastatic or unresectable 
SS/MRCLS (Cohort 2)
                38  09  [       _NY     1    9   
                                                          
•                                                      
        
Potential additional substudies:  
Next generations enhanced NY-ESO-1 specific T cells, alone 
or in combination with other agents, in NY-ESO-1/LAGE-1a 
positive advanced tumors 


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substudy will define the maximal number of participants for this phase in the substudy 
specific section. 
If supported by safety and efficacy results, additional participants may be enrolled to 
confirm the safety and efficacy in further cohort expansions via a protocol amendment. 
Additional details will be provided in each substudy specific section. 
Participant Journey 
For each individual participant, the study will consist of the following (see Figure 1 
Participant Journey schema below):  
Part 1: Screening 
1) Target expression Screening for tumor expression of NY-ESO-1 and/or 
LAGE-1a. For further details regarding HLA testing, please refer to the specific 
substudies.  
Note: Participants screened or enrolled in other GSK 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 positivity and/or 
NY-ESO-1/LAGE-1a expression under a different GSK-sponsored protocol, 
retesting 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 
and substudy requirements. If the 209012 requirements are not met, repeat testing 
may be required and may or may not require new sample collection. 
2) Leukapheresis eligibility screening phase to determine eligibility for undergoing 
leukapheresis beginning up to 28 days prior to leukapheresis. 
Part 2: Leukapheresis/Manufacture 
3) Leukapheresis procedure  
Note: leukapheresis may have been performed under another GSK-sponsored 
protocol or substudy of this protocol.  
Part 3: Lymphodepletion/Treatment 
4) Treatment fitness assessment and eligibility confirmation 
5) Interventional phase including Lymphodepletion from Days -7 to -4, TCR 
engineered T-cell infusion on Day 1, and follow-up as defined in each specific 
substudy.  
Note: TCR engineered T cells may have been manufactured under another 
GSK-sponsored protocol or substudy of this protocol. 
Part 4: Long-Term Follow-Up (LTFU) 
6) Long-term follow-up phase for up to 15 years from the date of TCR engineered 
T-cell infusion.  


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Following Screening (Target Expression Screening and Leukapheresis Eligibility 
Screening), participants who meet substudy entry criteria will be eligible to the study. 
Eligible participants will undergo Leukapheresis to collect autologous T cells; these will 
undergo MCE transduction to manufacture the IP, as specified in each substudy specific 
section.  The successful initiation of leukapheresis procedure constitutes enrollment to the 
study. 
In order to maximize patient benefit, participants who have failed screening or withdrawn 
before T-cell infusion, may rescreen in the same substudy or be screened for another 
substudy.  
Interventional Phase (Lymphodepletion/Treatment) 
Once the T-cell product has been successfully manufactured, released, and is available 
for infusion at the site, and once participant’s fitness for lymphodepletion has been 
assessed and additional eligibility criteria for treatment are met, participants will receive 
lymphodepleting chemotherapy as specified within each substudy specific section.  
Lymphodepleting chemotherapy may be given as outpatient treatment per institutional 
guidelines. 
Participants will receive growth factor support with G-CSF from ~24 hours following 
lymphodepleting chemotherapy until neutrophil count recovery in accordance with 
ASCO guidelines [Smith, 2015] or institutional practice.   
The IP will be administered as a single intravenous (IV) infusion on Day 1, unless 
otherwise indicated in a substudy specific section.  Information on T-cell infusion, 
hospitalization, and follow-up guidelines is provided in the substudy specific sections.   
After NY-ESO-1-specific T-cell infusion, participants are followed in the interventional 
portion of a given substudy until confirmed disease progression or for a minimal duration 
defined in each substudy specific section, at which time the participants enter the 
long-term follow up phase.   
Long-Term Follow-Up  
Upon completing the interventional portion of a given substudy, but no sooner than 90 
days post T-cell infusion, participants will be entered into a separate long-term follow-up 
(LTFU) protocol (GSK study 208750), where they will be followed for up to 15 years 
after T-cell infusion for gene therapy related adverse events per health authority 
guidance.  If LTFU protocol is not yet available at the particular clinical site, participants 
can be followed per LTFU schedules in substudy specific sections until LTFU protocol 
becomes available. 


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Figure 1 
Participant Journey Schema 
 
 
Data Monitoring Committee: 
A dose selection committee (DSC) will be in place to periodically evaluate safety of the 
dose levels and to make dose level (de/re)-escalation decisions.   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.  Additional details on the DSC will be presented in the substudy 
specific sections. 


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2. 
SCHEDULE OF ACTIVITIES (SOA) 
The SOA will be documented in each substudy specific section. 


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3. 
INTRODUCTION 
This is a master protocol investigating the safety, tolerability, recommended Phase 2 dose 
(RP2D) and early efficacy of enhanced autologous NY-ESO-1 and LAGE-1a specific 
T cells, alone or in combination with other agents, in HLA-A*02 positive participants 
with NY-ESO-1 and/or LAGE-1a positive advanced tumors.  This master protocol 
consists of a core protocol with multiple substudies. 
The protocol will initially include two monotherapy substudies as described in the Study 
Design (Section 5). Please refer to Section 12.12 for details outlining any additional 
substudies. 
The protocol may be amended at a later time to add additional substudies to investigate 
other NY-ESO-1 and/or LAGE-1a positive tumor types and other enhanced autologous 
NY-ESO-1 and LAGE-1a specific T cells, as monotherapy or in in combination with 
other anticancer agents.   
3.1. 
Study Rationale 
Adoptive T-cell therapy (ACT) is a therapeutic approach that uses autologous (cancer 
patient’s own) or allogeneic (donor’s own) T lymphocytes obtained by leukapheresis, that 
are subsequently genetically engineered to express a tumor-targeting receptor, such as a 
T-cell receptor (TCR) or a chimeric antigen receptor (CAR), expanded in vitro and 
re-infused into the participant, with the aim of generating and propagating an anti-tumor 
T-cell immune response.  
NY-ESO-1 and LAGE-1a are members of the cancer-testis antigen (CTA) family of 
tumor-associated antigens.  These are cytoplasmic proteins detectable in multiple cancer 
types including non-small cell lung cancer (NSCLC), bladder cancer, melanoma, liver 
cancer, synovial sarcoma (SS), myxoid/round cell liposarcoma (MRCLS), multiple 
myeloma and many others. Specific peptide epitopes of the NY-ESO-1 or LAGE-1a 
protein are processed and presented on the surface of the tumor cell in complex with an 
HLA molecule, which can be recognized by T cells.  An HLA-A*02 binding peptide 
(SLLMWITQC aa 157-165) that is common to both NY-ESO-1 and LAGE-1a antigens 
has been identified that can be recognized by NY-ESO-1 reactive T cells.   
GSK3377794 (lete-cel) T-cell product consists of autologous T cells transduced with a 
self-inactivating lentiviral vector encoding an affinity-enhanced TCR (c259) targeting the 
SLLMWITQC peptide bound to HLA-A*02.  In previous clinical trials using 
GSK3377794 (lete-cel), objective responses have been observed in 40 to 60% of treated 
participants who are HLA-A*02 positive and have NY-ESO-1+ SS [Robbins, 2011; 
Robbins, 2015; D’Angelo, 2018a].  Similar or higher response rates have been observed 
with this treatment in metastatic melanoma [Robbins, 2011], and multiple myeloma post 
autologous stem cell transplant (ASCT) [Rapoport, 2009].  GSK3377794 (lete-cel) is 
currently being investigated in ongoing GlaxoSmithKline (GSK) sponsored pilot clinical 
trials in HLA-A*02 positive participants with multiple types of tumors that are 
NY-ESO-1 and/or LAGE-1a positive.  A summary of the clinical data obtained to date 


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with GSK3377794 (lete-cel) is presented in the Benefit/Risk Assessment Sections of the 
substudy specific sections.   
Despite this encouraging clinical activity, not all patients receiving GSK3377794 
(lete-cel) or other ACTs have experienced a clinical benefit. Additionally, some patients 
who achieved responses have eventually relapsed with their disease [Error! Reference s
ource not found., 2018b].  The likely mechanisms for the limited efficacy observed in 
some patients include the immunosuppressive effects of the tumor microenvironment 
(TME; e.g. by secretion of cytokines that suppress T-cell activity [Anderson, 2017]) or 
limited CD4+ T-cell activation, thereby limiting the persistence of infused T cells and 
cytotoxic activity [D'Angelo, 2018b].  Furthermore, in tumors with limited expression of 
the targeted antigen, the efficacy is predicted to be lower.  Therefore, next generations of 
engineered T-cell products are being developed that use the same affinity-enhanced TCR 
and in addition use (1) multi-component engineering (MCE) to incorporate within the 
lentiviral vector construct additional genes encoding molecules expected to enhance 
T-cell function and survival and/or (2) innovative ways of manufacturing for potentially 
fitter T cells.  
In this protocol, we will investigate such autologous T cells that have been genetically 
engineered to (a) encode the same affinity-enhanced TCR (c259) as GSK3377794 
(lete-cel), and thus recognize with high affinity NY-ESO-1 and LAGE-1a tumor antigens, 
and at the same time (b) co-express molecules that should enhance T-cell function and 
survival and/or use other innovative ways of manufacturing for potentially fitter T cells.  
The aim of these studies will be to develop engineered T-cell products that will allow to 
further enhance clinical responses, with a goal to achieve long-term remissions of cancer.  
Given the encouraging early clinical activity of GSK3377794 (lete-cel), and in 
consideration of additional potential advantages provided by MCE, a clinical 
investigation of the next-generation products is justified to achieve maximum efficacy 
across NY-ESO-1 and /or LAGE-1a expressing tumors.   
3.2. 
Background 
3.2.1. 
Adoptive cell therapies and NY-ESO-1/LAGE-1a 
Genetic modification of autologous T cells targeting specific tumor antigens has been 
developed to overcome immune tolerance and to empower the immune system of the 
cancer patient with lasting anti-tumor immunity permitting long term remission of 
disease.  The TCR approach to engineered T-cell therapy is attractive because TCRs can 
recognize not only cell surface proteins (as is the case with CAR T cells) but also any 
intracellular proteins, since TCRs recognize peptide fragments of these intracellular 
proteins that are processed and presented on the cell surface in the context of HLA. The 
TCR-modified T-cell approach is also particularly suited for solid tumors due to their 
ability to recognize low concentrations of these intracellular cognate antigens.  In 
addition, the TCR approach mimics the natural function of the T cell by recruiting the 
endogenous signalling molecules and adhering to correct spatial orientation between the 
T cell and its target.  These aspects may contribute to a manageable safety profile, high 
anti-tumor activity and enhanced persistence of the infused TCR engineered T cells, 
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Morgan et al. first demonstrated tumor regression in 2 of 17 patients after adoptive 
transfer of genetically engineered T cells expressing a TCR specific for a 
melanocyte-differentiating antigen (MART-1) [Morgan, 2006].  Responding patients 
demonstrated long term persistence of infused T cells. Identification and sequencing of 
TCRs able to recognize epitopes expressed by human tumors together with improvements 
in TCR gene transfer technology has allowed for rapid redirection of T cells and targeting 
of a variety of tumor antigens, including gp100, carcinoembryonic antigen (CEA) 
[Johnson, 2009], p53 [Kuball, 2005], cancer testis antigen (CTA) family members such 
as NY-ESO-1 [Robbins, 2011] as well as melanoma associated antigens (MAGE)-A3 
[Morgan, 2013], MAGE-A4 [Kageyama, 2015] and MAGE-A10 [Border, 2018]. 
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 3- and 
5-year survival rates for patients with SS were 38% and 14%, respectively [Robbins, 
2015]. No toxicity attributed to the modified cells was reported in these studies. 
Most clinical protocols with TCR gene therapy have incorporated preconditioning of the 
patient with a lymphodepleting chemotherapy regimen prior to T-cell infusion [Rohaan, 
2019].  Lymphodepletion prior to ACT may enhance immune reconstitution by the 
transferred cells and increase tumor-specific responses. Immune reconstitution is 
enhanced through homeostatic mechanisms that facilitate expansion of T lymphocytes 
[Baccala, 2005], facilitate trafficking of the engineered T cells [Pinthus, 2004], and also 
improve the persistence of infused T cells. Lymphodepletion can also enhance the 
activity of the adoptively transferred cells via the removal of inhibitory factors such as 
regulatory T cells [Wolf, 2003] and can activate antigen presenting cells through release 
of inflammatory cytokines and induction of tumor apoptosis with resulting cross 
presentation of tumor antigens to T cells.  Therefore, a lymphodepleting regimen 
containing cyclophosphamide and fludarabine will be used in this study; details will be 
provided in the substudy specific sections. 
GSK is currently developing a therapy consisting of autologous CD4+ and CD8+ T cells 
expressing the affinity-enhanced NY-ESO-1c259 TCR (GSK3377794, lete-cel), that is 
capable of recognizing the SLLMWITQC peptide, which is derived from CTA family 
members NY-ESO-1 and LAGE-1a, upon presentation on HLA-A*02:01, *02:05 or 
*02:06. GSK3377794 has been infused into more than 125 patients with various 
malignancies. Treatment with GSK3377794 has demonstrated unprecedented clinical 
responses in patients with SS, inducing a clinical response in 50% of treated SS patients 
with a manageable safety profile [D'Angelo, 2018b]. This therapy is currently being 
explored in other tumors including NSCLC, Myxoid round cell liposarcoma (MRCLS), 
and multiple myeloma.  Details are provided in Section 3.2.2. 
3.2.2. 
GSK3377794 (letetresgene autoleucel, lete-cel) 
All next-generation T-cell therapies anticipated to be tested in this master protocol 
encode the same affinity-enhanced TCR (c259) as GSK3377794 (lete-cel), and thus 
recognize NY-ESO-1 and LAGE-1a tumor antigens with high affinity.  Therefore, prior 


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observations and outcomes of clinical trials investigating GSK3377794 (lete-cel) provide 
relevant information for the development of these next-generation therapies.  
As of 27 January 2021, 125 participants have received GSK3377794 infusions in clinical 
studies. For the most up to date information regarding lete-cel, please refer to the current 
IB. The clinical development program for GSK3377794 consists of 11 studies in 6 tumor 
types, including the studies that were started by Adaptimmune and taken over by GSK 
and studies started by GSK since the transfer.  An observational long-term follow-up 
study 208750 is also being conducted in participants exposed to GSK adoptive cell 
therapies in a previous clinical trial. 
Additional information about GSK3377794 (lete-cel), including a review of existing data 
in the context of the benefit/risk assessment of the next-generation products, is provided 
in the relevant substudy specific sections. 
3.2.3. 
Next Generation Engineering 
Despite the encouraging early efficacy results, not all patients receiving GSK3377794 
have experienced a clinical benefit. Additionally, some patients who achieved responses 
have eventually relapsed with their disease [D'Angelo, 2018b].  
Enhanced efficacy of tumor-specific T cells against solid tumors, aiming to increase the 
response rate of TCR T-cell therapy, requires strategies levering their 
immunosuppressive microenvironment. Therefore, GSK has been developing 
enhancement technologies and the first wave of these enhancements includes using MCE 
to enable co-expression of additional components alongside the NY-ESO-1c259 TCR. The 
first two assets to be investigated are GSK3901961 and GSK3845097 as described in 
Substudy 1 and Substudy 2.  Other NY-ESO-1 specific T cells may be introduced into 
this protocol and will be described in additional substudy specific modules. For more 
details regarding additional substudies, please refer to the List of Substudies in 
Section 12.12.  


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4. 
OBJECTIVES AND ENDPOINTS 
In general, the objectives and endpoints below will apply to all substudies unless 
otherwise specified.  Discrepancies between those stated here and those in the substudy 
specific sections will not require amendment and those stated in the substudy specific 
sections will apply. 
Exploratory objectives and endpoints, if any, will be provided in the substudy specific 
sections.  
Objectives 
Endpoints 
Primary 
To assess the safety, tolerability and determine 
recommended phase 2 dose (RP2D) of 
NY-ESO-1 and LAGE-1a specific T cells, alone 
or in combination with other agents, in HLA-A*02 
positive participants with NY-ESO-1 and/or 
LAGE-1a positive advanced tumors 
• 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 efficacy of NY-ESO-1 and 
LAGE-1a specific T cells, alone or in 
combination with other agents, in HLA-A*02 
positive participants with NY-ESO-1 and/or 
LAGE-1a positive advanced tumors 
• Overall Response Rate (ORR) 
(investigator assessed according to 
RECIST v1.1) 
• Duration of Response (DoR) 
Secondary – Pharmacokinetics 
To characterize in vivo cellular PK profile (levels, 
expansion, persistence) of NY-ESO-1 and 
LAGE-1a specific T cells, alone or in 
combination with other agents, over time 
• Maximum transgene expansion (Cmax) 
• Time to Cmax (Tmax) 
• Area under the time curve from zero to 
time t AUC(0-t), as data permit 
AE = adverse event; AESI = AE of special interest; DLTs = dose-limiting toxicities; DoR = duration of response; 
HLA = human leukocyte antigen; NY-ESO-1 = New York esophageal antigen-1; ORR = overall response rate; 
RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended phase 2 dose; SAE = serious AE. 
 


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5. 
STUDY DESIGN 
5.1. 
Overall Design 
This is a master protocol investigating the safety, tolerability, RP2D and early efficacy of 
autologous, next-generation, NY-ESO-1 and LAGE-1a specific T cells, alone or in 
combination with other agents, in HLA-A*02 positive participants with NY-ESO-1 
and/or LAGE-1a positive advanced tumors.  
This protocol consists of a core protocol with multiple independent substudies.  The 
protocol will initially include two substudies to investigate (a) GSK3901961 (NY-ESO-1 
TCR engineered T cells co-expressing the α-chain of the CD8 co-receptor) in previously 
treated (2L+) HLA-A*02+ participants with NY-ESO-1+ advanced SS, MRCLS, or 
NSCLC (Substudy 1) and (b) GSK3845097 (NY-ESO-1 TCR engineered T cells 
co-expressing, the dnTGF-βRII receptor) in previously treated (2L+) HLA-A*02+ 
participants with NY-ESO-1+ advanced SS or MRCLS (Substudy 2). For more details 
regarding additional substudies and indications, please refer to the list in Section 12.12.  
The protocol may be amended at a later time to add additional substudies to investigate 
other NY-ESO-1 and/or LAGE-1a positive tumor types and other NY-ESO-1 and 
LAGE-1a specific T cells, potentially in combination with other agents (see Figure 2 
Study Design schematic below).  Details of treatment are provided in the substudy 
specific sections. 
Unless otherwise specified in a substudy specific section, participants will receive 
NY-ESO-1 and LAGE-1a specific T-cells after Screening, fulfilling eligibility criteria 
and completing lymphodepleting chemotherapy. 
Figure 2 
Study Design 
 
Note:   Schema will not be updated for any additional substudies - please refer to Core Section 12.12. for 
the complete list of substudies. Participants with LAGE-1a positive tumors will be eligible if identified 
under a designated central laboratory test when available. 
Participants included in different substudies may have the same eligibility criteria.   
Long-
Term 
Follow-
Up Study
Next Generations 
Enhanced NY-ESO-
1/LAGE_1a Specific  T 
Cells in participants 
with 
relapsed/refractory 
advanced tumors
Substudies
Substudy 1:  GSK3901961 [CD8α_NY-ESO-1(c259)T]
in previously treated HLA-A*02 positive participants with 
• NY-ESO-1/LAGE-1a positive metastatic NSCLC  (Cohort 1)
• NY-ESO-1/LAGE-1a positive metastatic or unresectable 
SS/MRCLS (Cohort 2)
                38  09  [       _NY     1    9   
                                                          
•                                                      
        
                                  
                                                           
                                                         
                         


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Sponsor will inform Investigators of the participant assignments between substudies and 
indicate if the participant is to receive a split dose as a sentinel participant (see 
Section 8.1.2 for details) and the number of remaining slots. 
Each substudy in this Master Protocol will consist of two phases: Dose Confirmation 
Phase and Dose Expansion Phase. 
5.1.1. 
Dose Confirmation Phase 
In this phase, each next-generation NY-ESO-1 and LAGE-1a T-cell product will be 
evaluated to assess/confirm the RP2D to be used in further clinical investigations. 
5.1.2. 
Dose Expansion Phase 
After RP2D has been determined for a given T-cell product, the dose expansion phase 
will begin.  In this phase, additional participants will be enrolled as necessary to meet the 
substudy requirements for the number of evaluable participants treated at the RP2D.  
Each substudy will define the maximal number of participants for this phase in the 
substudy specific section. 
If supported by safety and efficacy results, additional participants may be enrolled to 
confirm the safety and efficacy in further cohort expansions via a protocol amendment.  
Additional details will be provided in each substudy specific section. 
5.2. 
Participant Journey  
Unless otherwise specified in a given substudy specific section, participants will undergo 
stepwise enrolment followed by treatment according to defined phases within each 
substudy (See Patient Journey Schema Figure 3).  
Figure 3 
Patient Journey Schema 
 
 


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Part 1: Screening 
1) Target expression Screening for tumor expression of NY-ESO-1 and/or LAGE-1a.  For further 
details regarding HLA testing, please refer to the specific substudies. 
Note: 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 positivity, 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 testing may be required and may or may not require new sample collection. 
2) Leukapheresis screening phase to determine eligibility for undergoing leukapheresis beginning up 
to 28 days prior to leukapheresis. 
 
Part 2: Leukapheresis/Manufacture 
3) Leukapheresis procedure  
Note: leukapheresis may have been performed under another GSK-sponsored protocol or substudy 
of this protocol.  
 
Part 3: Lymphodepletion, Treatment, and Follow-up 
4) Treatment fitness assessment and eligibility confirmation,  
5) Interventional phase including Lymphodepletion from Days -7 to -4, TCR engineered T-cell 
infusion on Day 1, and follow-up as defined in each specific substudy.  
Note: TCR engineered T cells may have been manufactured under another GSK-sponsored 
protocol or substudy of this protocol. 
 
Part 4: Long-Term Follow-Up (LTFU) 
6) Long-term follow-up phase for up to 15 years from the date of TCR engineered T-cell infusion.    
 
Part 1: Screening 
Screening will consist of two phases:  Target Expression Screening and Leukapheresis 
eligibility Screening. 
Participant Target Expression Screening may start at any time after diagnosis of advanced 
disease; either prior to or during ongoing line of prior therapy, subject to any substudy 
specific requirements; also consult the substudy requirements for specific mandates on 
the presence of radiographic and/or clinical disease progression at the time of 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.  HLA-typing and tumor antigen expression 
testing should be performed sequentially (considering the expected >50% attrition with 
HLA) but may also be performed in parallel at the discretion of the Investigator. 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.  Participants with the 
HLA-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 alleles and whose tumor expresses 


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the NYESO-1 and/or LAGE1a antigen, as measured using validated testing at a 
designated central laboratory, are eligible to undergo further Screening under this 
protocol.  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 another GSK-sponsored NY-ESO-1 and/or LAGE-1a targeting T-cell 
protocol or substudy of this protocol. 
Once participants are deemed HLA positive and tumor antigen expression positive, 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. 
Part 2: Leukapheresis/Manufacture 
Following completion of Screening, participants who meet substudy entry criteria will be 
eligible to the study. Eligible participants will undergo leukapheresis to collect 
autologous T cells. 
The initiation of leukapheresis procedure constitutes enrollment to the study. 
The collected T cells will undergo MCE transduction to manufacture the investigational 
product (IP), as specified in each substudy specific section. 
Unless otherwise specified in a substudy specific section, bridging therapies 
(e.g., chemotherapy, local therapy [e.g. radiotherapy, cryoablation, surgical resection]) 
may be administered between leukapheresis and the start of lymphodepletion, if a 
participant cannot be treatment-free. The following conditions must be met: 
1. Mandatory washout periods prior to start of T-cell infusion must be respected (see 
substudy specific sections) 
AND 
2. Indicated based on benefit/risk assessment and/or local regulatory requirements and 
following agreement with Sponsor’s Medical Monitor (or designee) 
AND 
3. Treatments, AEs and other clinical observations are reported into the current study 
database 
 
Participants who failed screening or withdrew before T-cell infusion, may rescreen in the 
same substudy or consider entering screening for another substudy (see Section 6.3 for 
further details). 
Part 3: Lymphodepletion, Treatment, and Follow-up 
The following conditions need to be satisfied prior to initiating lymphodepletion and 
T-cell treatment: 
1. Treatment fitness assessment and confirmation of additional inclusion/exclusion 
criteria for treatment must be completed from 1 to 10 days prior to initiating 
lymphodepleting chemotherapy. 
2. Baseline radiological tumor assessment is obtained from 1 to 10 days prior to 
lymphodepletion.  
3. T cell product availability verified by site for each criterion below:  


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
2 8  
C or e  
 
a. C o nfir mati o n of s uccessf ul ma n ufact ur e of T -cell pr o d uct  
b.  T -cell pr o d uct s atisfies all release criteria  as state d o n Certificate of 
A nal ysis  
c. T -cell pr o d uct a vaila ble f or i nf usi o n at t he site per criteria s pecifie d i n t he 
Dr u g  Pr o d uct a n d I nf usi o n Ma n ual  
4.  Pre -treat me nt t u m or bi o ps y c ollecte d wit hi n 2 8 da ys  pri or t o  i nitiati n g 
l y m p h o de pleti o n is re q uire d. T his bi o ps y will be use d as t he Baseli ne sa mpl e  f or 
a n al ys es . If it is n ot feasi ble t o o btai n a fres h bi o ps y, a n arc hi val t u m or 
bi o ps y  ( F F P E bl oc k) t a k e n prefera bl y after c o m pleti o n of t he partici pa nt’s last 
li ne of t hera p y, prefera bl y wit hi n 9 0 da ys pri or t o i nitiati n g l y m p h o de pleti n g 
c he m ot hera p y,  m a y be acce pte d at t he discreti o n of t he Me dical M o nit or ( or 
desi g nee) . F or partici pa nts w h o alrea d y pr o vi de d a fres h bi o ps y f or a nti ge n 
e x pressi o n a n d di d n ot recei ve a n y s u bs e q ue nt bri d gi n g  or sta n d ar d of care li ne of 
a nti ca ncer t hera p y, t h is scree ni n g bi o ps y ma y b e use d as t he B aseli ne sa m ple 
pr o vi de d t he scree ni n g bi o ps y was ta ke n prefera bl y wit hi n 9 0  da ys pri or t o 
i nitiati n g l y m p h o de pleti n g c h e m ot hera p y. 
 
F oll o wi n g l y m p h o de pleti o n, after ~ 2 4 h o urs of c o m pleti n g l y m p h o d e pleti n g 
c he m ot herap y, p artici pa nts m ust recei ve Gra n ul oc yt e-C ol o n y Sti m ulati n g Fact or 
( G-C S F) s u p p ort .  T h e f or m ulati o n of G -C S F t o be use d ca n b e deci de d b y t he 
I n v esti gat or base d o n t h e i nstit uti o nal practice.  
Refer t o s u bst u d y s pecifi c secti o ns f or i nf or mati o n o n T-cell i nf usi o n, h os pitalizati o n a n d 
f oll o w-u p g ui d eli nes . A d diti o nal cl ose m o nit ori n g or h os pitalizati o n ma y b e warra nte d 
base d u p o n cli nical ne e d a n d is at I n vesti gat or’s discreti o n ( pleas e refer t o S ecti o n 9. 1  f or 
safet y assess me nts a n d m o nit ori n g; Secti o n 9. 2  f or re p orti n g of a d v erse e ve nts; a n d 
Sect i o n 1 2. 7  f or s u p p orti ve care g ui da nce o n T-cell i nf usi o n, C R S a n d ot her p ote ntial 
ris ks). 
If a d diti o nal treat me nts are c o m bi ne d wit h T-cell treat me nt  i n f ut ure s u bst u dies, t he 
details of t h ose treat me nts will be gi ve n i n t he s u bst u d y s pecific secti o ns . 
Partici pa nts will be fre q u e ntl y m o nit ore d f or a n y u ne x pecte d Gra d e ≥3 A E a n d a n y 
S A Es , acc or di n g t o t he S o A i n t he s u bst u dy s pecific secti o ns. 
Partici pa nts w h o are n ot eli gi ble f or st u d y i nter ve nti o n b y t he ti me T  Cells e x pire, will be 
wit h dra w n fr o m t he st u d y a n d will n ot u n der g o l y m p h o de pleti o n wit hi n t his st u d y.  
A n y re mai ni n g ma n ufact ure d T  cells fr o m eac h partici pa nt ( w het her or n ot eli gi ble f or 
st u d y i nter ve nti o n) will b e st ore d b y t he S p o ns or f or t he c urre nt s helf life of t he cells aft er 
ma n ufact ur e is c o m plete d.  After e x pir y of t he s h elf life, t he st ore d T  cells ca n be 
destr o ye d or, if c o nse nte d  b y t he p artici pa nt , use d f or scie ntific researc h at the S p o ns or’s 
discreti o n f or a p eri o d of u p t o 1 5 years de p e n di n g o n l ocal re g ulati o ns .  
P art 4:  L o n g -T er m F oll o w -U p ( L T F U ) 
U p o n c o m pleti n g t he i nter ve nti o nal p orti o n of a gi ve n s u bst u d y (as defi n e d f or eac h 
s u bst u d y s pecifi c secti o n), b ut n o s o o ner t ha n 9 0 da ys  p ost T -cell i nf usi o n  (i n or der t o 
ca pt ure e n o u g h safet y i nf or mati o n), partici pa nts will be e ntere d i nt o a se p arate l o n g -ter m 
C CI


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follow-up (LTFU) protocol (GSK Study 208750) and will be monitored for 15 years. If 
the LTFU protocol is not yet available at the particular clinical site, participants can be 
followed per LTFU schedules in substudy specific sections until the LTFU protocol 
becomes available. The transfer of any participant to the LTFU study (Study 208750) 
should occur within 6 months of completing the interventional portion of a substudy. 
5.3. 
Number of Participants 
This is a master protocol consisting of multiple substudies, the overall sample size is not 
fixed. For details regarding participant numbers for each substudy, please refer to the List 
of Substudies in Section 12.12. 
Any further expansions of individual substudies or additional new substudies will be 
added via protocol amendments with specification of number of participants for each 
expansion and/or substudy. Any additional sub-studies will be added by amendment 
subject to regulatory review.   
Refer to the substudy specific sections for additional details on sample size 
determinations. 
5.4. 
Scientific Rationale for Protocol Design 
This is a master protocol to assess, via multiple independent substudies, the safety, 
tolerability and RP2D of multiple autologous next-generation NYESO-1 and/or LAGE1a 
specific T cells, alone or in combination with other agents, in HLA-A*02 positive 
participants with NYESO-1 and/or LAGE1a positive advanced tumors. GSK seeks to test 
these next-generation agents in the clinic, relying on the currently available nonclinical 
models and the first-generation GSK3377794 (lete-cel) clinical and nonclinical data, with 
an optimal strategy to enable rapid establishment of tolerability and proof of concept for 
efficient further development decisions and early access to patients. 
This master protocol design provides the flexibility to conduct multiple substudies, 
thereby permitting an efficient evaluation of agents in multiple indications compared with 
separate clinical trials (either by indication or by product). This mechanism provides an 
opportunity to optimize the choice of candidates to advance into mid/late-stage product 
development by permitting efficient generation of clinical data that cannot be gained 
using currently available nonclinical models [FOCR, 2019]. 
The scientific rationale for the design of each substudy, including rationales for the 
participant population and dose selection, are provided in each substudy specific section.  
5.4.1. 
Data Monitoring Committee  
A dose selection committee (DSC) will be in place (see substudy specific sections for 
descriptions) to periodically evaluate safety of the dose levels and to make dose level 
(de/re)-escalation decisions.  Further details on the DSC will be provided in the Dose 
Selection Plan.  Further data review committees may be put in place as cohort expansions 
and new substudies may require it.  


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5.5. 
End of Study Definition 
5.5.1. 
End of Study for Individual Participants 
Refer to the substudy specific sections for end of substudy definitions for individual 
participants. 
5.5.2. 
End of Master Protocol  
This Master Protocol will end as of the last visit of the last participant in the last 
substudy, or when all participants have met their respective substudy end criteria 
including those who have died, withdrawn consent, are lost to follow-up, or have 
transferred to the separate long-term follow up protocol (GSK study 208750) for 
observation of delayed AEs and survival for a duration of 15 years post-T-cell infusion in 
accordance with Food and Drug Administration (FDA) [FDA, 2020b] and European 
Medicines Agency (EMA) guidance [EMA, 2009].  


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6. 
PROTOCOL POPULATION 
The protocol will enroll participants with advanced tumors to independent substudies. 
Initially, the protocol will enroll participants with advanced SS or MRCLS (Substudies 1 
and 2) and advanced NSCLC (Substudy 1).  Any additional substudy may include SS, 
MRCLS, NSCLC or other tumor types – please refer to Core Section 12.12 for the 
complete list of substudies. The rationale for the chosen tumor settings will be discussed 
in the substudy specific sections. 
The full detailed inclusion and exclusion criteria and lifestyle considerations are 
presented in the substudy specific section.  Prospective approval of protocol deviations 
relating to enrolment criteria for the purpose of recruiting participants, also known as 
protocol waivers or exemptions, is not permitted. 
6.1. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical 
protocol but are not subsequently enrolled into a substudy. 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, disease 
characteristics, prior line of anti-cancer treatments and any serious adverse events 
(SAEs). 
6.2. 
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 NYESO1/LAGE-1a 
expression under a different GSK-sponsored protocol, testing of HLA and/or 
NYESO1/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 testing may be required and may or may not require 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 Medical Monitor.  
6.3. 
Rescreening/Transfer 
Individuals who do not meet the criteria for participation in a given substudy at any stage 
(screen failure for reasons other than HLA negative and/or NY-ESO-1 and LAGE-1a 
negative diagnostic status) or who were withdrawn prior to T-cell administration may be 
rescreened or transferred to any applicable GSK-sponsored study or substudy of this 
protocol.  HLA typing may not need to be repeated (Section 6.2). Rescreening for the 


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NY-ESO-1 and/or LAGE-1a antigen expression of a recent tumor sample may not be 
required depending on the test platform(s) used and whether they meet the 209012 
protocol requirements (Section 6.2). For participants who were withdrawn after 
leukapheresis but before T-cell administration and for whom suitable leukapheresis or 
manufactured product is available, the requirement for leukapheresis and/or 
remanufacture may be waived after consultation with the Sponsor. 


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7. 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
Details of study interventions and guidelines, including dose, administration, and 
concomitant medications are specified in each substudy specific section.  
In general, however, study intervention will follow the steps outlined in Section 5.2 of the 
Core Protocol and in the intervention schema included there.   


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8. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
The guidelines and criteria below apply to all protocol participants except where 
otherwise indicated in substudy specific sections.  
8.1. 
Discontinuation of Study Intervention 
8.1.1. 
Single Dose Administration 
As the T-cell intervention is expected to be administered as a single dose for all 
autologous next-generation NY-ESO-1 and LAGE-1a specific T cells to be tested in this 
master protocol, there is no possibility of discontinuation of study intervention.  In the 
event of severe reactions during infusion, the infusion may be interrupted. 
Please refer to the current Drug Product and Infusion Manual for details of dose 
administration. Please refer to Section 9.1 for safety assessments and monitoring; Section 
9.2 for reporting of adverse events; and Section 12.7 for supportive care guidance on 
T-cell infusion, CRS and other potential risks.  
Infusion-related reactions Grade 3 or higher during infusion should be reported to 
Sponsor promptly : 
• GSK CGT Patient Supply Co-ordinator by e-mail (GSK.CELL@gsk.com) or by 
phone +1-833-GSK-CELL (+1 833-475-2355) or +44 800-026-6295 (for 
European countries);  
• Medical Monitor or designee (contact information provided in SRM).  
 
In participants with infusion-related reaction Grade ≤2, infusion may be restarted once 
resolved to Grade <1. The bag of cells that was being infused prior to reaction, cannot be 
used beyond 45 minutes after thawing.  
Should other agents be added in future either as monotherapy or combination therapy, 
any additional details will be added via amendment to this core or via additional 
substudies, as applicable. 
8.1.2. 
Split Dose Administration 
While dosing is described in Section 8.1.1, please refer to each substudy for 
substudy-specific details outlining if there is a requirement for the T cells to be 
administered as split dosing (i.e., in two aliquots) to the first (‘sentinel’) participant; such 
split dosing may be extended to additional participants based on the safety and 
tolerability profile. Split dosing may also be required in other substudies if appropriate.  
Additionally, future next-generation NY-ESO-1 and LAGE-1a specific T cells may be 
administered by repeat dosing, or as single doses as well as in combination with other 
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As such, individual stopping rules described below apply only to those participants 
receiving multiple administrations of the T cells and/or other anticancer agents used in 
combination.   
For such participants: 
• The subsequent dose of the agent will be administered as described in the 
respective substudy specific section, unless one of the following events occurs:  
– Clinical deterioration that in the opinion of the Investigator in consultation 
with the Sponsor warrants interrupting or stopping the dosing;  
– Unacceptable toxicity, whether meeting the definition of DLT or not, and 
including meeting the standard GSK stopping criteria for liver chemistry 
and QTc prolongation (see below);  
– Death;  
– Any other substudy-specific event requiring IP interruption or 
discontinuation; 
• Even if the dosing was interrupted or stopped for any of the reasons above, 
participants will continue to be followed according to the SOA, as discontinuation 
of dosing does not represent withdrawal from the study. 
 
In the event of severe reactions during the T-cell infusion, the infusion may be 
interrupted. 
8.2. 
Dose Limiting Toxicity 
The toxicities listed below are considered to be dose limiting toxicities (DLTs) if: 
• They are considered at least possibly related to transduced T cells; AND 
• They occur within the DLT-assessment period of 28 days after the initial dosing 
of T cells.  For participants receiving T cells as split dose, DLT assessment period 
will begin at the start of the first infusion and continue for 28 days after 
completion of the last infusion.   
Of Note:  
• Toxicities related to lymphodepletion will be evaluated by the Sponsor and DSC 
on a case-by-case basis.  
• Attribution of relatedness to treatment for DLT will be discussed between the 
Investigator, the Sponsor, DSC, and any other substudy-specific review 
committee; where attribution varies, the most conservative assessment will be 
retained. 
• Additional toxicities which occur following the DLT assessment period of 
28 days may be declared DLTs, after consultation between the Sponsor, DSC, and 
any other substudy-specific review committee based on the emerging safety 
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• Individual substudies may expand the list below to include additional defined 
DLTs as appropriate based on the mechanism of action of the specific transduced 
T cells. 
 
The following will be considered DLTs: 
1. Grade 4 or greater toxicities (including death), that are at least possibly related to 
the investigational agent.  
2. Grade 3 toxicities that are at least possibly related to the investigational agent and 
do not resolve to Grade 1 (or Baseline) within 7 days from the onset of the event.  
3. CTCAE Grade ≥3 non-infectious pneumonitis not responding to oxygen 
supplementation and systemic steroid treatment.  
4. Any Grade 3 cytokine release syndrome (CRS) at least possibly related to study 
agent that does not improve to Grade <2 toxicity within 7 days with or without 
dexamethasone 10 mg q12hr IV (or an equivalent corticosteroid dose).  
5. Any Grade 4 CRS at least possibly related to study product that does not improve 
to Grade ≤2 (or Baseline) within 7 days.  
6. Any Grade 3 or greater neurotoxicity that does not resolve to Grade ≤2 within 
72 hours.  
7. Any Grade ≥3 organ toxicity (exclusive of CRS toxicity) involving major organ 
systems that persists for >72 hours and occurs within 28 days of infusion.  
 
The following constitutes exceptions from DLTs: 
• Laboratory abnormalities CTCAE Grade 3 or 4 not considered clinically 
significant by the investigator 
• Electrolyte abnormalities CTCAE Grade 3 or 4 responding to best supportive care 
per institutional guidelines 
• Hypoalbuminemia CTCAE Grade 3 or 4 responding to best supportive care per 
institutional guidelines 
• Fever and chills CTCAE Grade 3 or 4 clinically stable with best supportive care 
per institutional guidelines 
• AE related to the cancer or its progression 
• Thrombocytopenia CTCAE Grade 3 or 4 not associated with significant bleeding 
• Anemia CTCAE Grade 3 or 4 responding to best supportive care per institutional 
guidelines 
• Lymphocytopenia CTCAE Grade 3 or 4 
• Leukopenia CTCAE Grade 3 or 4  
 
For any additional DLT criteria based on asset, please refer to the substudy.  


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8.2.1. 
Liver Chemistry Stopping and Increased Monitoring Criteria 
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology.  
8.2.1.1. 
Stopping Criteria 
The next dose or the second aliquot of a split dose will not be administered to a 
participant if: 
• A participant meets one of the conditions outlined in the algorithm below 
OR 
• When in the presence of abnormal liver chemistries not meeting 
protocol-specified stopping rules, the investigator believes study intervention 
discontinuation is in the best interest of the participant. 
 
 
The following Level 1 and Level 2 monitoring are required for all participants.  
8.2.1.2. 
Level 1 Monitoring 
In the event that a participant develops elevations in liver function test (LFT) parameter 
values as defined below, an increase to liver chemistry monitoring i.e., at weekly 
intervals, will apply.  


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Liver Chemistry Monitoring Criteria Level 1 
Criteria 
Actions 
ALT 3x ULN and 1.5x Baseline value but 
ALT <5x ULN and <2x Baseline value and 
bilirubin <2xULN, without symptoms believed 
to be related to liver injury, or hypersensitivity 
• 
Notify the GSK Medical Monitor within 24 hours of learning 
of the abnormality to discuss participant safety.  
• 
Participant must return weekly for repeat liver chemistries 
(ALT, AST, alkaline phosphatase, bilirubin) until they 
resolve, stabilise or return to within Baseline  
• 
If, during monitoring, ALT increases to 5xULN and 2x 
Baseline value or remains 3x ULN and 1.5x Baseline 
value for 4 weeks, or if total bilirubin increases to 2xULN, 
refer to Level 2 monitoring guidance below. 
• 
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin 
<2xULN, monitor participants twice monthly until liver 
chemistries normalize or return to within Baseline. 
ALT = alanine aminotransferase; ULN = upper limit of normal; AST = aspartate aminotransferase. 
8.2.1.3. 
Level 2 Monitoring 
In the event that the participant develops elevations in LFT parameters as defined below, 
an increase to liver chemistry monitoring at more frequent intervals (i.e., twice weekly) 
will apply.  
Liver Chemistry Monitoring Criteria Level 2 
ALT Absolute 
Both ALT 5xULN and 2x Baseline value 
ALT Increase 
Both ALT 3xULN and ≥1.5x Baseline value that persists for 4 weeks 
Bilirubin1, 2 
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2  
ALT 3xULN and INR >1.5 
Symptomatic3 
ALT 3xULN and 1.5x Baseline value associated with symptoms (new or worsening) 
believed to be related to liver injury or hypersensitivity 
 
Required Actions and Follow-Up Assessments  
Actions 
Follow-Up Assessments 
• 
Report the event to GSK within 24 hours 
• 
Complete the liver event CRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2 
• 
Perform liver event follow-up assessments  
• 
Monitor the participant until liver chemistries 
resolve, stabilize, or return to within Baseline 
(pre-gene therapy) 
MONITORING: 
For bilirubin or INR criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin, INR) and 
perform liver event follow-up assessments 
within 24 hrs 
• Viral hepatitis serology4 
• Obtain INR and recheck with each liver chemistry 
assessment until the transaminases values show 
downward trend 
• Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin 2xULN 
• If possible, obtain peripheral blood for persistence of 
genetically modified cells. 
• Obtain complete blood count with differential to assess 
eosinophilia 
• Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the AE 
report form 


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• 
Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to within 
Baseline (pre-gene therapy) 
• 
A specialist or hepatology consultation is 
recommended 
For all other criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin, INR) and 
perform liver event follow-up assessments 
within 24-72 hrs  
• 
Monitor participants at least weekly until liver 
chemistries resolve, stabilize or return to within 
Baseline (pre-Gene Therapy) 
• Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications. 
• Record alcohol use on the liver event alcohol intake 
case report form 
For bilirubin or INR criteria: 
• Anti-nuclear antibody, anti-smooth muscle antibody, 
Type 1 anti-liver kidney microsomal antibodies, and 
quantitative total immunoglobulin G (IgG) or gamma 
globulins. 
• Liver imaging (ultrasound, magnetic resonance, or 
computed tomography) and /or liver biopsy to evaluate 
liver disease; complete Liver Imaging and/or Liver 
Biopsy CRFs. 
1. 
Serum bilirubin fractionation should be performed if testing is available. Additionally, if serum bilirubin fractionation 
testing is unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury.  
2. 
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR >1.5, which may 
indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); The INR threshold value stated will not apply to participants receiving anticoagulants. 
3. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).  
4. 
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing); Hepatitis E IgM antibody. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; CRF = Case 
Report Form; LDH = lactate dehydrogenase; INR = International normalized ratio; ULN = upper limit of normal. 
 
8.2.1.4. 
Administration of Subsequent T Cell Dose(s) after Liver Stopping 
Criteria Met 
If participant meets liver chemistry stopping criteria and subsequently the liver event 
resolves, any planned subsequent T cell dose(s) may be administered, provided: 
• 
GSK Medical Governance approval is granted 
• 
Ethics and/or Institutional review board (IRB) approval is obtained, if required, and 
• 
Separate consent for intervention restart/rechallenge is signed by the participant 
 
If GSK Medical Governance approval to administer subsequent dose(s) is not granted, 
then participant will continue in the study for protocol-specified follow up assessments. 
8.2.2. 
QTc Stopping Criteria 
The following QTc stopping criteria will apply: 
• 
QTc >500 msec  
OR 
• 
Change from Baseline of QTc >60 msec 
 


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For participants with underlying bundle branch block, follow the discontinuation 
criteria listed below: 
Baseline QTc with Bundle Branch Block 
Discontinuation QTc with Bundle Branch Block 
<450 msec 
>500 msec 
450 – 480 msec 
≥530 msec 
 
Notes: 
• 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from further study treatment.  This 
formula may not be changed or substituted once the participant has been enrolled. 
– For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well. 
– Once the QT correction formula has been chosen for a participant’s eligibility, 
the same formula must continue to be used for that participant for all QTc data 
being collected for data analysis.  Safety electrocardiograms (ECGs) and other 
non-protocol specified ECGs are an exception.   
• The QTc should be based on the average of triplicate ECG readings obtained over a 
brief (e.g., 5-10 minute) recording period. 
 
8.2.3. 
Temporary Discontinuation 
Infusion of the IP can be stopped for any adverse events experienced by the participant or 
observed by the treating physician.  Refer to the Drug Product and Infusion Manual for 
details of dose administration.  
NY-ESO-1 specific TCR engineered T cells intervention is typically administered as a 
single dose via IV infusion, except for sentinel participants who will receive a split dose 
(Section 8.1.2).  In the event of severe reactions associated with liver toxicities during or 
in between the 2 doses, the infusion may be interrupted or delayed.  Please refer to 
Section 8.1 for guidance on discontinuation of intervention and restarting of infusion.  
Should other agents be added in future either as monotherapy or combination therapy, 
any additional details will be added via amendment to this core or via additional 
substudies, as applicable. 
8.3. 
Participant Discontinuation/Withdrawal from the Study 
• 
A participant may withdraw from the substudy to which he/she is enrolled at any 
time at his/her own request or at the discretion of the Investigator for safety, 
behavioral, compliance or administrative reasons. No further assessments will be 
required, and the Investigator must document this in the site study records.  
• 
Treatment follow-up may be permanently discontinued for any of the following 
reasons: 
– Significant deviation(s) from the protocol 


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– Withdrawal of consent by participant (or proxy) 
– Participant is lost to follow-up 
– Closure or termination of the study by the sponsor 
• 
Participants for whom treatment follow-up has been permanently discontinued will 
continue into the LTFU phase of the protocol or, if consent was given, into the LTFU 
study GSK 208750.   
• 
If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• 
If a participant withdraws from the substudy to which he/she is enrolled after 
providing study samples, GSK will retain those samples and any results generated 
from testing prior to participant withdrawal, as described in the informed consent.  If 
the participant specifically requested destruction of their samples at the time of 
withdrawal, the Investigator should notify GSK, and document this in the site study 
records. Once notified, GSK will not perform any further testing, and will destroy 
the sample.  
• 
A participant will be considered to have withdrawn from the substudy to which 
he/she is enrolled if the participant has not died and is lost to follow-up (Section 8.4 
of the core protocol). 
• 
Refer to the SoA in each substudy specific section for data to be collected at the time 
of study discontinuation and for any further evaluations that need to be completed.  
 
8.4. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to and/or should 
continue in the substudy to which he/she is enrolled. 
• 
Before a participant is deemed lost to follow up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the substudy to which he/she is enrolled.  
 
Discontinuation of specific sites or of the study as a whole is handled as part of 
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8.5. 
Study Stopping and Pausing Rules  
The study will pause enrolment and stop treatment for all participants if any of the 
following events occur pending submission to Regulatory Agencies and review by any 
substudy-specific safety review committees (e.g., DSC), IRBs/ECs, and the Sponsor.   
• 
Uncontrolled clonal T-cell proliferation felt to be attributable to the next-generation 
NY-ESO-1 and LAGE-1a specific T cells  
• 
A case of documented symptomatic progressive cerebral edema confirmed by an 
expert neurological examination and computed tomography (CT)/ magnetic 
resonance imaging (MRI), that is not responding to treatment. 
• 
A biologically functional positive Replication Competent Lentivirus (RCL) after 2 
confirmed positive tests by polymerase chain reaction (PCR). 
• 
Death directly attributed to the investigational agent by the Investigator and DSC. 
• 
Any event of Guillain-Barre syndrome (GBS) as diagnosed by a neurologist 
according to diagnostic guidance for GBS [Fokke, 2014]. 
 
Premature termination of individual substudies or the entire study may occur if: 
• 
Sponsor, in consultation with any safety review committees (e.g., DSC), decides for 
any reason that participant safety may be compromised by continuing the study. 
• 
The Sponsor decides to discontinue the development of the intervention to be used in 
this study.  
 
It is expected that AEs will occur frequently in these patient populations based on the 
underlying advanced malignancies in the initial and future substudies and these can be 
SAEs.  A review of individual significant safety events across all substudies in 
conjunction with the cumulative review of safety data by the sponsor, any 
substudy-specific safety review committees (e.g., DSC), and Investigators, will inform 
decisions for premature termination of individual substudies or the entire study.  SAEs 
that are related to the direct effects of T-cell therapy may be considered as stopping 
criteria.  Interruption or premature termination of individual substudies or the entire 
clinical study may also occur because of a regulatory authority decision.  
Please refer to specific substudies for any additional substudy-specific assessments.  


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9. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures and their timings are summarized in the SoA tables 
within each substudy specific section.  
Unless otherwise stated in a substudy specific section and its SoA, the descriptions and 
guidelines in this section and subsections will apply.  Where there is a discrepancy 
between this core protocol and the relevant substudy specific section, the substudy 
specific section should be followed.  
Adherence to the substudy design requirements, including those specified in the SoA, is 
essential and required for study conduct. Protocol waivers or exemptions are not allowed 
except for immediate safety concerns.  
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.  
All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a Screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
Screening failure, as applicable.  
Informed consent must be signed by a participant before any study required procedures 
are performed. However, procedures conducted as part of the routine clinical 
management (e.g., imaging studies) and conducted prior to signing of the study informed 
consent may be used for Screening/Baseline assessments provided the procedure fulfills 
the protocol defined specifications and has been performed within the protocol indicated 
timeframe.  
If assessments are scheduled for the same nominal time, then the assessments should 
occur in the following order:  
1. 12-lead ECG  
2. Vital signs  
3. Blood draws  
 
9.1. 
Safety Assessments 
Please refer to the individual substudies for any additional substudy-specific monitoring.  
9.1.1. 
Dose Selection Committee  
Dose selection committee (DSC) will be established for making dose recommendations 
for each investigational agent, i.e. substudy, 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(s) will be tasked to determine 


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whether the same dose can be given to additional participants; or decide to move to a 
lower dose level for any of the investigational agents as guided by the appropriate 
statistical model (described in the substudy specific section).  The membership, meeting 
structure and frequency, data to be reviewed, and recommendations to be made by the 
committee will be described in the Dose Selection Plan.  
9.1.2. 
GSK Safety Review Team 
For substudies where a DSC is not implemented or once DSC is no longer required when 
dose confirmation phase has completed for a particular substudy, an internal GSK Safety 
review team will be put in place, consisting of a cross functional team of the appropriate 
disciplines required to ensure holistic evaluation of the safety profile of the T-cell product 
under evaluation. The Safety review team will conduct systematic, periodic and 
documented reviews of available safety data and address the safety issues pertinent to the 
medicine.   
9.1.3. 
Physical Examinations 
A complete physical examination will include, at a minimum, weight and assessments of 
the Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height 
will be assessed at timepoints indicated in the SoA in each substudy specific section. 
A dedicated physical examination will include assessments based on specific concerns of 
the Investigator. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses or tumor sites.  
9.1.4. 
ECOG Performance Status 
The performance status will be assessed using Eastern Cooperative Oncology Group 
(ECOG) scale (Section 12.8) at the time points specified in the SoA in each substudy 
specific section.   
9.1.5. 
Vital Signs 
Blood pressure, pulse measurements (rate and oximetry), respiratory rate, and body 
temperature should be assessed per institutional standards.  The same methods should be 
used throughout the course of the study.  Manual techniques will be used only if an 
automated device is not available. 
Where vital signs and blood collection for laboratory tests are performed on the same 
day, vital signs should be taken before blood collection for laboratory tests. 
9.1.6. 
Cardiac Assessments 
All cardiac assessments will be performed locally at the site. 
The following assessments will be conducted in order to monitor participant safety: 


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An echocardiography (ECHO) or multigated acquisition scan (MUGA) scan is required 
to determine eligibility. Additional scans may be performed as clinically indicated.  
NOTE: the same method of cardiac evaluation should be used consistently for all 
follow-up scans. 
Single or triplicate 12-lead ECG (as indicated in the SOA) will be obtained using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT 
intervals corrected for heart rate by Fridericia’s formula (QTcF) or QT duration corrected 
for heart rate by Bazzetts’s formula (QTcB) intervals.  The replicate ECG tracings should 
be obtained as closely as possible in succession.  The full set of triplicates should be 
completed within approximately 4 minutes.   
Serum troponin and NT-proBNP / BNP as markers for cardiac health will be assessed 
prior to initiation of lymphodepletion. 
Participants with clinically significant cardiovascular risk factors, such as but not limited to: 
• Prior cardiac insult (ie, prior myocardial infarct and prior coronary 
revascularization)  
• Significant valvular disease  
• Low ejection fraction  
• Cardiomyopathy  
• History of heart failure  
• Significant cardiac arrhythmias  
• History of cardiac toxicity from prior therapies 
• Baseline tumor masses in close proximity to the cardiac muscle 
 
Must: 
• Undergo evaluation by a cardiologist prior to lymphodepletion 
• Be monitored by inpatient continuous cardiac telemetry for a minimum of 3 days 
post Tcell infusion and as long as deemed necessary by the Investigator.  
 
In these participants with clinically significant cardiovascular risk factors, all reports of 
cardiac events following T-cell infusion will be monitored through proactive 
pharmacovigilance to determine causality.  Supportive treatment for these participants 
will be provided per standard clinical practice guidelines. 
9.1.7. 
Pulmonary Assessments 
Participants with known lung metastases (active or previously treated with surgical 
resection or radiotherapy) should be considered for pulmonary consultation prior to 
lymphodepletion, which may include pulmonary function tests. 


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Participants deemed at high risk for pulmonary complications per the pulmonologist 
should have closer post-infusion monitoring during the following periods:  
• Post T-cell infusion, for a minimum of 3 days and for as long as deemed 
necessary by the Investigator 
• If CRS is suspected, for the first week and until symptoms are improving or an 
alternative diagnosis is confirmed 
 
And should include:  
• Close monitoring of chest imaging, as clinically indicated 
• Close monitoring of fluid balance 
• Continuous cardiac telemetry monitoring 
 
Participants who have an airway that may be compromised should be assessed prior to 
lymphodepletion, including considerations such as speech and swallow evaluation, 
anaesthesia consultation, or consideration for closer post-infusion monitoring (as above) 
in the event their airway may be compromised due to tumor inflammation, prior 
surgery/radiation, decreased consciousness, infection, or other cause. 
9.1.8. 
Monitoring for Immune Effector Cell-Associated Neurotoxicity 
Syndrome 
Brain MRI (or CT scan if an MRI is not feasible) must be obtained for all participants as 
part of leukapheresis eligibility Screening. This should be repeated at Baseline prior to 
lymphodepletion in the following: 
• All participants with a history of CNS metastasis, and 
• Participants with no history of brain 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 may be performed as clinically indicated thereafter.  
Immune Effector Cell-Associated Encephalopathy (ICE) (see Section 12.7.8 for 
definition) must be measured immediately prior to T-cell infusion on the day of infusion, 
and then according to each substudy SoA. Participants with known brain metastases must 
be monitored at least twice per day for the first 5 days following T-cell infusion. If a 
participant is found to have Immune Effector Cell-Associated Neurotoxicity Syndrome 
(ICANS), the ICE neurological assessment tool should be used at least twice per day until 
ICANS is resolved or stable and may be measured at follow up visits if indicated. 
For management of ICANS, refer to Section 12.7.8. 


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9. 1. 9.  
M o nit ori n g f or D e m y eli n ati n g N e ur o p at h y a n d ot h er N e ur ol o gi c al 
E v e nt s  
O btai n a ne ur ol o gic al c o ns ultati o n f or partici pa nts wit h Gra de 2  or hi g h er ne ur ol o gi c 
e ve nts of a ≥7 da y d urati o n.  Partici pa nts w h o de v el o p si g ns a n d s y m pt o ms c o nsiste nt 
wit h G B S m ust be e val uate d b y a ne ur ol o gist acc or di n g t o dia g n ostic g ui da nce f or G B S 
[F o k ke , 2 0 1 4] t o pr o vi de e x pert rec o m me n dati o ns t o g ui de a p pr o priate di a g n ostic 
w or k u p s uc h as electr o m y o gra p h y ( E M G ), l u m bar p u nct ure, i nf ecti o us pa n el t o g ui de 
ma na ge me nt a n d f oll o w u p  ( See Secti o n 1 2. 7. 1 0 ). 
A n y a d diti o nal m o nit ori n g re q uire me nts or m o difi cati o ns t o t hese re q uir e m e nts as well as 
a n y m a na g e m e nt g ui d eli nes will be a d dress e d i n t he s u bst u dy s pecific secti o ns . 
9. 1. 1 0.  
Cli ni c al S af et y L a b or at or y A s s e s s m e nt s  
Refer t o Secti o n  1 2. 2  f or t he list of cli nical la b orat or y tests t o be p erf or me d.  
T he I n vesti gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri ng t he st u d y i n t he A E s ecti o n of t he C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d o c u me nts. Cli nicall y si g nifica nt 
a b n or mal la b orat or y fi n di n gs are t h ose w hic h are n ot ass ociate d wit h t he u n derl yi n g 
disease, u nless j u d ge d b y t he I n v esti gat or t o be m ore se vere t ha n e x pecte d f or t he 
partici pa nt's c o n diti o n.  
All a b n or mal la b orat or y val ues c o nsi dere d cli nicall y si g nifi ca nt occ urri n g  d uri n g  
partici pati o n i n t he st u d y or wit hi n 3 0 da ys after t h e last d ose of st u d y treat me nt s h o ul d 
be re peate d u ntil t he val u es ret ur n t o n or mal or B aseli ne. If s uc h v al ues d o n ot ret ur n t o 
n or mal/ B aseli ne wit hi n a peri o d of ti me j u d ge d reas o na ble b y t he I n v esti gat or, t he 
eti ol o g y s h o ul d be i de ntifie d a n d t he s p o ns or n otifie d.  
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n Secti o n 1 2. 2  m ust be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he S o A  i n eac h s u bst u d y 
s pecific secti o n. Refere n ce ra n ges f or all safet y p ara meters m ust be pr o vi d e d t o t he site 
b y t he la b orat or y res p o nsi ble f or t he assess me nts.  
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9.2. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Section 12.3. 
The Investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE.  The Investigator or 
designee is responsible for following up AEs that are serious, considered related to the 
study intervention or the study, or that caused the participant to discontinue the study 
intervention or the study.  
In the absence of a clear alternative etiology (e.g., chemotherapy, concomitant 
medications, disease progression, infections, etc.), AEs should be considered potentially 
immune-related. Immune-related AEs may include diarrhea/colitis, rash, hepatitis, Graft 
versus host disease (GVHD), cytokine release syndrome (CRS), secondary pancytopenia, 
pneumonitis, endocrinopathies, nephritis, and any other manifestations that may indicate 
an immune-related phenomenon. 
Adverse events of special interest (AESIs) in this study are defined in Section 9.2.7. They 
need to be reported to Sponsor (Medical Monitor or designee) within 24 hours via 
e-mail (see SRM for further instructions).  
Certain events in this protocol are identified as delayed AEs and should be marked as 
delayed AEs in the eCRF. 
Delayed AEs are defined as those events that fall into one or more of the 6 categories 
listed below and which occur either after disease progression or last Interventional Phase 
visit, whichever occurs first.  Delayed AEs will be collected as part of the LTFU phase of 
the substudy or in the LTFU Study 208750, contingent upon formal transfer of participant 
to Study 208750. 
Delayed AEs will be collected until 5 years have elapsed from last T-cell infusion, or 
until patient dies, withdraws consent or is deemed lost to follow-up. Delayed AEs will be 
recorded in the CRF if reported by the patient or investigator between years 6 – 15. Any 
AE collected on-study may also be indicated as a delayed AE by the Investigator at their 
discretion.  
The 6 categories for delayed AEs are as follows: 
• New malignancies 
• New incidence or exacerbation of a pre-existing neurological disorder 
• New incidence or exacerbation of a prior rheumatologic or other autoimmune 
disorder 
• New incidence of hematologic disorder 
• New incidence of an infection (potentially related to gene modified cell therapy) 
• Unanticipated illness or hospitalization deemed related to gene modified cell 
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Time period for designating an event from the above categories as delayed AE in the 
eCRF will be provided in the SRM.  If a participant is monitored in this protocol post 
disease progression (i.e., for LTFU phase), the only AEs that will be assessed are delayed 
AEs. 
9.2.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
Collection of AEs and SAEs starts from the timing of signing the ICF for target 
expression screening, and will be performed as follows: 
• All AEs/SAEs will be collected from the start of leukapheresis until the end of the 
interventional phase, or through 90 days following T-cell infusion, whichever is 
later, unless a new anticancer therapy is initiated. 
– If the new anticancer therapy is initated within 30 days following T-cell 
infusion, AEs/SAEs will be collected through 30 days following T-cell 
infusion. 
– If the new anticancer therapy is initated beyond the 30 days following T-cell 
infusion, AEs/SAEs will be collected until the new anticancer therapy is 
initiated.  
• Additionally, any AEs or SAEs assessed as related to study participation (e.g., 
study intervention, protocol-mandated procedures, invasive tests, or change in 
existing therapy) or leading to early withdrawal will be collected in the AE 
section of the CRF from the time a participant signs the informed consent for 
target expression Screening.  All other relevant events that begin before the start 
of leukapheresis but after obtaining informed consent will be recorded on the 
Medical History/Current Medical Conditions section of the CRF not the AE 
section. 
 
Figure 4 displays the AE/SAE collection time periods in relationship to the 4 phases of a 
substudy intervention. 


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Figure 4 
 Time Period for Collecting AE and SAE Information 
 
• All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in Section 
12.3. The Investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
• Events of special interest (AESIs) (Section 9.2.7) will be reported to the Sponsor 
(Medical Monitor or designee) within 24 hours via e-mail (see SRM for further 
instructions): AESIs should be communicated as soon as suspected, and any 
confirmed diagnosis must be reported immediately. 
• Events occurring after the end of the interventional phase and before the 
participant enrolls onto the LTFU Study 208750 will be collected and reported as 
indicated in the SoA for Part 4 in each substudy specific section.  
• Events occurring after the participant enrolls onto the LTFU Study 208750 will be 
collected and reported in the LTFU protocol database. 
• Any SAE, including death, brought to the attention of an Investigator at any time 
outside of the time period specified above must be reported immediately to the 
Sponsor if the event is considered to be related to investigational product. 
 
9.2.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 12.3. 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
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9.2.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 9.2.7), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up. Further information 
on follow-up procedures is given in Section 12.3. 
In all cases of SAE that occur after T-cell infusion, a transgene copy (persistence) sample 
must be obtained if feasible. 
9.2.4. 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/ IEC, and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
• Should female participant or female partner of male participant become pregnant, 
collect details of pregnancy and report per guidelines in Section 12.4.   
• The Investigator should inform GSK within 24 hours of learning of any 
pregnancy and should follow the procedures outlined in Section 12.4. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE. 
• If appropriate, the investigator should advise fertile male participants to consider 
collecting and storing viable sperm prior to undergoing lymphodepletion, given 
that cyclophosphamide may result in partial (oligospermia) or total (azoospermia) 
sterility. 
 
9.2.5. 
Cardiovascular Events and Death 
For any cardiovascular events detailed in Section 12.3.3 and all deaths including those 
attributed to progression of malignant disease, whether or not they are considered SAEs, 
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completed. These sections include questions regarding cardiovascular (including sudden 
cardiac death) and non-cardiovascular death.  
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
dictionary for regulatory activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion.  
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
9.2.6. 
Progression of Underlying Malignancy 
Progression of underlying malignancy and related symptoms are not reported as an AE if 
it is clearly consistent with the suspected progression of the underlying cancer. Clinical 
symptoms of progression may be reported as AEs if the symptoms cannot be determined 
as exclusively due to the progression of the underlying malignancy or does not fit the 
expected pattern of progression for the disease under study. 
If there is any uncertainty about an AE being due only to the disease under study, it 
should be reported as an AE or SAE. 
9.2.7. 
Adverse Events of Special Interest (AESIs) 
Adverse events of special interest for this trial should be communicated to Sponsor 
(Medical Monitor or designee) as soon as suspected, and any confirmed diagnosis must 
be reported to GSK within 24 hours via email to the Sponsor (Medical Monitor or 
designee) (see SRM for further instructions). The AESIs for this study are as follows:  
• Cytokine release syndrome [Note: Grade 3 or higher should be reported as SAE 
within 24 hours.] 
• Graft vs host disease [Note: Grade 3 or higher should be reported as an SAE 
within 24 hours.] 
• Immune Effector Cell-Associated Neurotoxicity Syndrome Grade 1 persisting 
beyond 24 hrs or associated with concurrent CRS; or Grade 2 or higher 
[Note: Grade 3 or higher should be reported as SAE within 24 hours.] 
• Guillain Barre syndrome including acute inflammatory demyelinating 
polyneuropathy (AIDP) [Note: All cases must be reported as SAEs within 24 
hours.] 
• 
Pancytopenia with at least 1 cell line Grade ≥3, present on or after Day 28 after 
the T-cell infusion  
• Aplastic anemia [Note: All cases must be reported as SAEs within 24 hours.] 
• Pneumonitis  
• Neutropenia Grade 4 lasting ≥28 days 
 


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A d diti o nal A E SI t hat d oes n ot nee d t o be re p orte d wit hi n 2 4 h o urs  is: 
•  Treat me nt -relate d i nfl a m mat or y res p o nse at t u m or site(s) 
 
Eac h s u bst u d y s pecific s ecti o n ma y defi ne a d diti o nal A E SIs. F or a n y a d diti o nal 
s u bst u d y-s pecific A E SIs, refer t o t he s u bst u d y (see Secti o n  1 2. 1 2  f or a list of t he 
s u bst u dies). 
9. 3.  
Effi c a c y A s s e s s m e nt s  
See s u bst u d y s pecific secti o ns f or a n y a d diti o nal assess me nts.  
9. 3. 1.  
E v al u ati o n of A nti -C a n c er A cti vit y  
T u m or assess me nts f or res p o nse a n d pr o gressi o n will be e val uate d acc or di n g t o 
R E CI S T  v 1. 1 [ Eise n ha uer , 2 0 0 9] a n d i R E CI S T (s ee Secti o n 1 2. 6 ): 
•  R E CI S T v 1. 1 will be use d i n t he assess me nt of disease b ur de n (tar get a n d n o n -
tar get lesi o ns deter mi nati o n ) at B aseline a n d as t he pri mar y meas ure of t u m or 
res p o nse e n d p oi nts.   
•
 
See t he S o A wit hi n eac h s u bst u d y s pecifi c secti o n f or t he sc he d ule of ass ess me nts of 
a nti-ca ncer acti vi t y. A cce pta ble i ma gi n g m o dalities f or t his st u d y i ncl u de: 
•  I V (i o di ne bas e d) c o ntr ast e n ha nce d C T sca n +/ - oral c o ntrast of t h e c hest a n d 
a b d o me n/ pel vis ( C T is t he preferre d m o dalit y f or t u m or assess me nts). E xtre mities  
a n d/ or s ki n lesi o ns will be assesse d if re q uir e d.  
•  I n cases w here c o ntrast e n ha nce d C T is c o ntrai n dicate d : 
o  F or t he a b d o me n/ pel vis, a M RI (wit h a n d wit h o ut ga d oli ni u m c o ntrast ) is 
acce pta ble;   
o  F or t he c hest, a n o n -c o ntrast e n ha n ce d C T or a M RI ( wit h a n d wit h o ut 
ga d oli ni u m c o ntrast) is acce pta bl e . 
•  M RI  of t he e xtre mities  or brai n wit h a n d wit h o ut ga d oli ni u m c o ntrast, or per site 
sta n dar d of care if c o ntr a i n dicate d. 
•  Di gital  p h ot o gra p hs  of s ki n lesi o ns i ncl u di n g a r ul er f or esti mati n g t he size of t he 
lesi o n. 
•  Fl u or o de o x y gl uc os e  ( F D G)-P E T is ge nerall y n ot s uita ble f or o n g oi n g assess me nts 
of disease.   F D G -P E T/ C T will be c ollecte d ce ntrall y if perf or me d as part of t he 
site’s r o uti ne disease ma na ge me nt, at Scree ni n g a n d w hilst o n st u d y.  
 
T hr o u g h o ut t he st u d y, t h e sa me i ma gi n g m o dalit y a n d i ma ge -ac q uisiti o n pr ot oc ol 
(i ncl u di n g t he us e of I V c o ntrast) s h o ul d be use d c o nsiste ntl y acr oss all ti me p oi nts f or a n 
i n di vi d ual partici pa nt t o all o w u nif or m c o m paris o n of lesi o ns.   
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Tumor measurements for each participant should be performed by the same Investigator 
or radiologist (to the extent that this is feasible). 
To allow time for the immune response to become apparent and for potential transient 
inflammatory reaction of the disease to the treatment (‘tumor flare’), response will not be 
assessed before 4 weeks post infusion of the next-generation NY-ESO-1 and LAGE-1a 
specific T cells, unless there is unequivocal clinical evidence of deterioration.  Response 
or progression is to be confirmed by repeat imaging scan performed not earlier than 
4 weeks and not later than 8 weeks after the criteria for response or progression were first 
met (confirmation of progression is only required in participants who are clinically stable 
after criteria for progression were first met).  For post-Baseline assessments, a window is 
permitted to allow for flexible scheduling as defined in the SoA within each substudy 
specific section.  
Tumor images will be obtained by the site and transmitted to a central imaging vendor for 
potential central review. The process for tumor imaging and transmission to the central 
imaging vendor are detailed in the Imaging Manual. 
9.3.2. 
Long-Term Follow-up 
Upon the end of the applicable substudy for each participant, they will be entered into a 
separate LTFU protocol (GSK study 208750) and will be monitored for up to 15 years 
post T-cell infusion for observation of delayed AEs (defined in Section 8.3) in 
accordance with FDA requirements for gene therapy clinical trials [FDA, 2020b; FDA, 
2010].  If the LTFU protocol is not yet available at the particular clinical site, participants 
can be followed per LTFU schedule under this protocol (See SOAs in substudy specific 
sections) until the LTFU protocol becomes available.   
9.4. 
Patient Reported Outcomes 
Patient reported outcomes may be assessed in some of the substudies.  If patient reported 
outcomes are included, specifics regarding these measures will be outlined in the 
substudy specific sections. 
9.5. 
Treatment of Overdose 
Next-generation NY-ESO-1 and LAGE-1a specific T cells must be administered as 
specified in the substudy specific section by trained personnel at the investigational sites 
in this study.  Infusion guidelines provided in the Drug Product and Infusion Manual 
must be strictly followed, including dosing amounts, premedication, duration of infusion, 
and vital sign monitoring. 
In the event of an allergic reaction, the infusion must be immediately stopped, and 
anti-histamine treatment initiated.  Please refer to Section 12.7 for further supportive care 
guidance.  Acute mild respiratory distress developing during or immediately after (within 
48 hours) T-cell infusion can be managed with supportive care, as detailed in 
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S h o ul d a n y s u bst u d y of t he pr ot oc ol i ncl u de a ge nts ot her t ha n t he T  cells, a n y a d diti o nal 
o ver d ose c o nsi d erati o ns will be pr o vi de d i n t he a p plica ble s u bst u d y s pecific secti o n. 
9. 6.  
P h ar m a c o ki n eti c s  
P har mac o ki netics of T  cells (als o k n o w n as T -cell  e x pa nsi o n or persiste nce ) i n t he 
peri p heral bl o o d will be meas ure d i n t he p artici pa nts t o esta blis h t he relati o ns hi p bet wee n 
T -cell e x pa nsi o n a n d res p o nse t o I P.  Persiste n ce of T cells  is als o m o nit ore d as a 
l o n g-ter m safet y me as ure.   
W h ole bl o o d sa m ples of a p pr o xi matel y 8 m L will be c ollecte d f or meas ure me nt of 
tra ns d uce d cell q ua ntities as descri be d i n t he S O A; sa m ples will be pr ocesse d t o P B M C. 
D N A will be is olate d fr o m t hese P B M Cs t o q ua ntif y t he tra ns d uce d cells usi n g P C R of 
t he Psi tra ns ge n e as des cri be d i n Secti o n  9. 1. 1 2 . Sa m ples ma y b e c ollecte d at a d diti o nal 
ti me p oi nts d uri n g t he st u d y if warra nte d a n d a gree d u p o n bet wee n t he I n vesti gat or a n d 
t he S p o ns or. I nstr u cti o ns f or t he c ollecti o n a n d ha n dli n g of bi olo gi cal sa m pl es will be 
pr o vi de d b y t he S p o ns or. T he act ual d ate a n d ti me ( 2 4 -h o ur cl oc k ti me) of eac h sa m ple 
will be rec or de d.  
T he f oll o wi n g P K p ara m eters will be c o m p ute d, as data per mit:  
•  C ma x: ma xi m u m  c o nce ntrati o n/ T -cell e x pa nsi o n  
•  T ma x , ti me of C ma x  
•  A U C( 0 -t), area u n d er  t he c o nce ntr ati o n/T -cell e x pa nsi o n ti me c ur ve fr o m 0 t o 
ti me t. 
 
Sa m ples c ollecte d f or a n al yses of tra ns d u ce d T  C ells i n bl o o d ma y als o be use d t o 
e val uate safet y or effic ac y as p ects t hat ma y arise d uri n g or after t he st u d y.  
9. 7.  
P h ar m a c o d y n a mi c s  
Ser u m c yt o ki ne l e vels a n d ot her 
 m eas ure d f or researc h p ur p oses (see 
Secti o n  9. 1 0 ) ma y b e e v al uate d f or p har mac o d y n a mic relati o ns hi ps wit h i n vesti gati o nal 
a ge nt a d mi nistrati o n.   
9. 8.  
G e n eti c s  
Ge netics r esearc h ma y b e c o n d ucte d o n a ge n etics bl o o d sa m ple, plas ma, a n d o n t u m or 
sa mples c ollecte d i n t he st u d y  as i n dicat e d i n Secti o n 9. 1 0 . C o nse nt f or Le u ka p heresis 
a n d Treat me nt e nc o m passes c o nse nt f or ge netics researc h.  
See Sec ti o n 1 2. 5  f or I nf or mati o n re gar di n g ge neti c researc h. Details o n pr ocesses f or 
c ollecti o n a n d s hi p me nt a n d destr ucti o n of t hes e sa m ples ca n be f o u n d i n t he St u d y 
refere nce ma n ual ( S R M) or La b orat or y Ma n ual. 
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9. 9.  
I m m u n o g e ni cit y A s s e s s m e nt s 
Ser u m sa m ples f or deter mi nati o n of a nti b o dies a gai nst  N Y -E S O -1  s pecific (c 2 5 9) T  cells 
will be ta ke n fr o m all partici pa nts f or a nti -dr u g a nti b o d y ( A D A) testi n g.   
Ser u m sa m ples will be teste d f or a nti b o dies a gai nst N Y -E S O -1  (c 2 5 9) specific T  cells 
usi n g a v ali date d assa y a n d a tiere d -t esti n g sc h e m e (e. g., S cree ni n g, c o nfir mati o n, a n d 
titer assa ys). Briefl y, all sa m ples will be teste d i n a S cree ni n g ass a y t o i de ntif y p ote ntial 
p ositi ves. Ne xt, all p ote ntiall y p ositi ve sa m ples will be teste d i n a c o nfir mati o n assa y t o 
deter mi ne t he s pecificit y of t he res p o nse. Fi nall y, titer val ues will be deter mi ne d f or all 
c o nfir me d p ositi ve sa m pl es. F or eac h p artici pa nt, i m m u n o ge nic it y res ults (e. g., p ositi ve 
or ne gati ve) a n d titer val ues will be re p orte d. Ot her a nal ys es (e. g., n e utrali zi n g a nti b o d y 
assa y) ma y be perf or me d t o f urt her c h aracterize t h e a nti b o dies, if necessar y.  
All sa m ples c ollecte d f or detecti o n of a nti b o dies t o st u d y i nter ve nti o n(s) m a y als o be 
e val uate d t o e n a ble i nter pretati o n of t he a nti b o d y data.  
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
5 9  
C or e  
 
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
6 0  
C or e  
 
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
6 1  
C or e  
 
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
6 2  
C or e  
 
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
6 3  
C or e  
 
9. 1 1.  
R e q u e st f or A ut o p s y i n c a s e of D e at h F oll o wi n g 
A d mi ni str ati o n of G e n e Tr a n sf er A g e nt s  
I n acc or da n ce wit h t he F D A g ui d a nce [F D A , 2 0 2 0a], a ut o psies will be re q ueste d of t he 
fa milies f or all partici p a nts w h o die d ue t o a n a d verse e ve nt p ote ntiall y or directl y rel ate d 
t o t he T-cell i nf usi o n . T o ass ure c o m plia nce, g ui d eli nes f or perf or mi n g a n a ut o ps y are 
pr o vi de d i n t he S R M . 
C CI


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10. 
STATISTICAL CONSIDERATIONS 
Each substudy will be analysed and reported separately. 
The following statistical considerations apply to all substudies. Substudy specific 
considerations are detailed in the individual substudy specific section. 
10.1. 
Statistical Hypotheses 
The primary and secondary objectives of this study are described overall in Section 4 and 
detailed in the individual substudy specific sections.   
Hypotheses for individual substudies are detailed in the substudy specific sections. 
All analyses will be descriptive. 
10.2. 
Sample Size Determination 
Sample size determination is detailed separately for each substudy. 
10.3. 
Data Analysis Considerations 
Data will be listed and summarized according to GSK reporting standards, where 
applicable. Complete details will be documented in the Statistical Analysis Plan (SAP). 
Any deviations from, or additions to, the original analysis plan described in this protocol 
will be documented in the SAP and final study report.  
Other data analysis considerations are detailed in the substudy specific sections. 
10.4. 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screened Population 
All participants who signed an ICF to participate in the study. 
Enrolled Population 
All participants who started leukapheresis procedure. 
Intent-To-Treat (ITT) 
Population  
All participants who started leukapheresis procedure. 
Modified ITT (mITT) 
Population  
All participants who received any dose of NY-ESO-1 specific 
T cells. 
Evaluable Population 
All participants who received T--cell infusion and completed at 
least 2 disease assessments after infusion or progressed or died 
or were withdrawn or lost to follow-up from the substudy 
 


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10.5. 
Statistical Analyses 
10.5.1. 
Interim Analyses 
Interim analyses are detailed separately for each substudy. 
10.5.2. 
Key Elements of Analysis Plan 
10.5.2.1. Safety Analyses 
All safety analyses will be performed on the ITT and mITT Populations.  
Endpoint 
Statistical Analysis Methods 
Primary 
DLTs/AEs/SAEs/AESIs will be summarized using frequencies and proportions. 
 
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively by dose and study cohort. No formal analysis will be conducted comparing 
substudies or cohorts. 
All serially collected safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be 
summarized according to the scheduled, nominal visit at which they were collected and 
across all on-treatment time points using a “worst-case” analysis. Complete details of the 
safety analyses will be provided in the SAP. 
Extent of Exposure 
The number of subjects administered study treatment will be summarized. 
Adverse Events 
Adverse events will be coded using the standard MedDRA and grouped by system organ 
class. AEs will be graded by the investigator according to the National Cancer Institute- 
Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0. 
Events will be summarized by frequency and proportion of total participants, by system 
organ class and preferred term. Separate summaries will be given for all AEs, treatment-
related AEs, SAEs, and AEs leading to discontinuation of study intervention. In addition, 
AEs, if listed in the NCI-CTCAE v5.0, will be summarized by the maximum grade. 
Characteristics (e.g., number of occurrences, action taken, grade) of the AEs of special 
interest (specified in Section 9.2.7) will be summarized separately. 
The incidence of deaths and the primary cause of death will be summarized. 
Dose-limiting toxicities (DLTs, specified in Section 8.2) will be listed for each subject 
and summarized by dose cohort according to International Data Standards Library 
(IDSL) standards. 


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Clinical Laboratory Evaluations 
Haematology and clinical chemistry data will be summarized using frequencies and 
proportions according to National Cancer Institute-Common Toxicity Criteria for 
Adverse Events (NCI-CTCAE), version 5.0. Laboratory test results outside the reference 
ranges that do not have an associated NCI-CTCAE criteria will be summarized using 
proportions. Further details will be provided in the SAP. 
Other Safety Measures 
Data for vital signs, ECGs, and ECHOs will be summarized based on predetermined 
criteria identified to be of potential clinical concern (PCI). Further details will be 
provided in the SAP. 
10.5.2.2. Efficacy Analyses 
Endpoint 
Statistical Analysis Methods 
Secondary 
Overall response rate (ORR), which includes confirmed complete or partial response as 
determined by investigator assessment per RECIST 1.1 will be reported along with 
Clopper-Pearson exact 95% CI. 
Duration of response (DOR) will be summarized using Kaplan-Meier quantile estimates along 
with 2-sided 95% CIs at the time of final analysis, if data warrant.  
Maximum expansion/persistence (Cmax), time to Cmax (Tmax), and area under the time curve 
from zero to time t AUC(0-t) will be presented in tabular or graphical form, if data permit.  
 
Secondary Efficacy Endpoints 
ORR: Overall response rate is defined as the percentage of participants with a confirmed 
CR or a confirmed PR relative to the total number of participants within the analysis 
population at any time per RECIST v1.1 as determined by the local investigators.  
ORR will be reported in the ITT and mITT populations by cohort at the time of primary 
analysis.  
Participants with unknown or missing response will be treated as non-responders, i.e., 
these participants will be included in the denominator when calculating the percentage. 
The number and types of responses, as defined by RECIST v1.1, will be listed and 
summarized separately, as appropriate. 
The observed confirmed ORR will be reported by cohort at the primary analysis along 
with 95% Clopper-Pearson exact confidence interval (CI). 
DOR: Duration of response (DOR) is defined as, in the subset of participants who show a 
confirmed CR or PR as assessed by local investigators, the time from first documented 
evidence of CR or PR until the first documented sign of disease progression or death. 
Duration of response will be summarized descriptively, if data warrant, using Kaplan-
Meier medians and quartiles. Details on rules for censoring will be provided in the SAP. 
Response assessment and DOR will be listed for participants in the mITT population. 


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11. 
REFERENCES 
 
Anderson KG, Stromnes IM, Greenberg PD. Obstacles posed by the tumor 
microenvironment to T cell activity: A case for synergistic therapies. A Cancer Cell. 
2017; 31:311-325. 
Baccala R, Gonzalez-Quintial R, Dummer W, et al. Tumor immunity via homeostatic T 
cell proliferation: mechanistic aspects and clinical perspectives. Springer Semin 
Immunopathol. 2005; 27: 75-85. 
Border EC, Sanderson JP, Weissensteiner T et al. Affinity-enhanced T-cell receptors for 
adoptive T-cell therapy targeting MAGE-A10: strategy for selection of an optimal 
candidate. Oncoimmunology. 2018;8:e1532759.  
D’Angelo SP, Druta M, Liebner DA et al.  Pilot study of NY-ESO-1c259 T cells in 
advanced myxoid/round cell liposarcoma. J Clin Onc 2018a; 36 suppl: 3005-3005. 
D'Angelo SP, Melchiori L, Merchant MS et al. Antitumor Activity Associated with 
Prolonged Persistence of Adoptively Transferred NY-ESO-1 (c259)T Cells in Synovial 
Sarcoma. Cancer Discov. 2018b; 8:944-957. 
Davila ML, Riviere I, Wang X et al. Efficacy and toxicity management of 19-28z CAR T 
cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6:224ra2. 
Dignan FL, Clark A, Amrolia P et al. Diagnosis and Management of acute graft-versus-
host disease. Br J Haematol. 2012;158:30-45. 
Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247. 
EMA Guideline on Follow-Up of Patients Administered with Gene Therapy Medical 
Products (October 2009). 
FDA (2020a). Guidance for Industry, Long Term Follow-Up After Administration Of 
Human Gene Therapy Products (January 2020). 
FDA (2020b) Guidance for Industry, Testing of Retroviral Vector-Based Human Gene 
Therapy Products for Replication Competent Retrovirus During Product Manufacture and 
Patient Follow-up (January 2020). 
FDA Briefing Document – Testing for Replication Competent Retrovirus 
(RCR)/Lentivirus (RCL) in RCR/RCL based gene therapy products (November 2010). 
Fidler C, Klumpp T, Mangan K at al. Spontaneous graft versus host disease occurring in 
a patient with multiple myeloma after autologous stem cell transplant. Am J Hematol. 
2012;87:2-21. 


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Fokke C, van den Berg B, Drenthen J et al. Diagnosis of Guillain-Barre´ syndrome and 
validation of Brighton criteria. Brain. 2014;137:33-43. 
Friends of Cancer Research (FOCR), Designing the Future of Cell Therapies. White 
Paper (2019). 
Garfall A, Kalos M, Furth EE et al. Autologous aGVHD associated with infusion of T 
cells with engineered specificity for NY-ESO-1 and LAGE-1 following high-dose 
melphalan and ASCT in patients with multiple myeloma. Biol Blood Marrow Transplant. 
2013;19:S134. 
Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease 
in human recipients of marrow from HL-A- matched sibling donors. Transplantation. 
1974; 18:295–304. 
Johnson LA, Morgan RA, Dudley ME et al. Gene therapy with human and mouse T-cell 
receptors mediates cancer regression and targets normal tissues expressing cognate 
antigen. Blood. 2009; 114:535-546. 
Kageyama S, Ikeda H, Miyahara Y Imai N et al.  Adoptive transfer of MAGE-A4 T-cell 
receptor gene-transduced lymphocytes in patients with recurrent esophageal cancer. Clin 
Cancer Res. 2015; 21:2268-2277. 
Kaufman RM, Djulbegovic B, Gernsheimer T et al. Platelet transfusion: a clinical 
practice guideline from the AABB. Ann Intern Med. 2015; 162:205-213. 
Kline J, Subbiah S, Lazarus HM et al. Autologous graft-versus-host disease: harnessing 
anti-tumor immunity through impaired self-tolerance. Bone Marrow Transplant. 2008; 
41:505-513. 
Kuball J, Schmitz FW, Voss RH et al. Cooperation of human tumor-reactive CD4(+) and 
CD8(+) T cells after redirection of their specificity by a high-affinity p53A2.1-specific 
TCR. Immunity. 2005; 22:117–129. 
Lee DW, Gardner R, Porter DL et al. Current concepts in the diagnosis and management 
of cytokine release syndrome. Blood. 2014; 124:188-195. 
Lee DW, Santomasso BD, Locke FL et al. ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells. Biol 
Blood Marrow Transplant. 2019;25:625-638. 
Manilla P, Rebello T, Afable C et al. Regulatory Considerations for Novel Gene Therapy 
Products: A Review of the Process Leading to the First Clinical Lentiviral Vector. 
Human Gene Therapy. 2005; 16:17–25. 
Maus MV, Alexander S, Bishop MR, et al. Society for Immunotherapy of Cancer (SITC) 
clinical practice guideline on immune effector cell-related adverse events. Journal for 
ImmunoTherapy of Cancer 2020;8:e001511. 


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Miller AD. Retrovirus packaging cells. Human Gene Therapy. 1990; 1:5-14. 
Morgan RA, Chinnasamy N, Abate-Daga D, et al. Cancer regression and neurological 
toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013;36:133-151.  
Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after 
transfer of genetically engineered lymphocytes. Science. 2006; 314:126-129. 
Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T cell therapy-
assessment and management of toxicities. Nat Rev Clin Oncol. 2018; 15:47-62. 
Pinthus JH, Waks T, Malina V, et al. Adoptive immunotherapy of prostate cancer bone 
lesions using redirected effector lymphocytes. J Clin Invest. 2004; 114:1774-1781. 
Raje N, Berdeja J, Lin Y, et al.  Anti-BCMA CAR T-Cell Therapy bb2121 in Relapsed or 
Refractory Multiple Myeloma. N Engl J Med. 2019; 380:1726-1737.  
Rapoport AP, Stadtmauer EA, Aqui N, et al. Rapid immune recovery and graft-versus-
host disease-like engraftment syndrome following adoptive transfer of costimulated 
autologous T cells. Clin Cancer Res. 2009; 15:4499-4507. 
Robbins PF, Kassim SH, Tran TL, et al. A pilot trial using lymphocytes genetically 
engineered with an NY-ESO-1–Reactive T cell receptor: long-term follow-up and 
correlates with response. Clin Cancer Res. 2015;21:1019-1027. 
Robbins PF, Morgan RA, Feldman SA, et al. Tumor regression in patients with 
metastatic synovial cell sarcoma and melanoma using genetically engineered 
lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011; 29: 917-924. 
Rohaan MW, Wilgenhof S and Haanen JBHG. Adoptive cellular therapies: the current 
landscape. Virchows Arch. 2019; 474:449-461. 
Seymour L, Bogaerts J, Perrone A, et al.  iRECIST: guidelines for response criteria for 
use in trials testing immunotherapeutics. Lancet Oncology. 2017;18:143-152.  
Smith TJ, Bohlke K, Lyman GH, et al. Recommendations for the use of WBC growth 
factors: American society of clinical oncology clinical practice guideline update. J Clin 
Oncol. 2015; 33:3199-3212. 
Tocilizumab SmPC 2020. https://www.ema.europa.eu/en/documents/product-
information/roactemra-epar-product-information_en.pdf 
Tocilizumab USPI 2020. https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/2e5365ff- 
cb2a-4b16-b2c7-e35c6bf2de13/spl-doc?hl=tocilizumab 
Van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical prognostic scoring 
system for Guillain-Barré syndrome. Lancet Neurol. 2007 Jul;6(7):589-94. 
Walgaard C, Lingsma HF, Ruts L, et al. Early recognition of poor prognosis in Guillain-
Barre syndrome. Neurology. 2011; 76:968-975. 


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Walgaard C, Lingsma HF, Ruts L, et al. Prediction of Respiratory Insufficiency in 
Guillain-Barre´ Syndrome. Ann Neurol. 2010; 67:781–787. 
Willison HJ, Jacobs BC, van Doom PA. Guillain-Barre Syndrome. Lancet. 2016; 
388:717-727. 
Wolf AM, Wolf D, Steurer M, et al. Increase of regulatory T cells in the peripheral blood 
of cancer patients. Clin Cancer Res. 2003;9:606-12. 


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12. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
12.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
12.1.1. 
Regulatory and Ethical Considerations 
• 
This study will be conducted in accordance with the protocol and with: 
– Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
– Applicable ICH Good Clinical Practice (GCP) Guidelines 
– Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.  
• 
Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants.  
• 
The Investigator will be responsible for the following: 
– Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
– Notifying the IRB/IEC of SAE or other significant safety findings as required by 
IRB/IEC procedures 
– Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
 
12.1.2. 
Financial Disclosure 
Investigators and sub-Investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


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12.1.3. 
Informed Consent Process 
• 
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
• 
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
• 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant.  
• 
Participants who are rescreened are required to sign a new ICF. 
 
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
Investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature. 
12.1.4. 
Data Protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.  
• 
The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant.  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• 
Publication Policy 
• 
The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 


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sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.  
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 
12.1.5. 
Dissemination of Clinical Study Data 
• 
Where required by applicable regulatory requirements, an Investigator signatory will 
be identified for the approval of the clinical study report. The Investigator will be 
provided reasonable access to statistical tables, figures, and relevant reports and will 
have the opportunity to review the complete study results at a GSK site or other 
mutually-agreeable location. 
• 
GSK will also provide the Investigator with the full summary of the study results. 
The Investigator is encouraged to share the summary results with the study 
participants, as appropriate. 
• 
The procedures and timing for public disclosure of the protocol and results summary 
and for development of a manuscript for publication for this study will be in 
accordance with GSK Policy. 
• 
GSK intends to make anonymized participant-level data from this trial available to 
external researchers for scientific analyses or to conduct further research that can 
help advance medical science or improve patient care. This helps ensure the data 
provided by trial participants are used to maximum effect in the creation of 
knowledge and understanding. 
 
12.1.6. 
Data Quality Assurance 
• 
All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., laboratory 
data). The Investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF.  
• 
The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF.  
• 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical 
Risk-Based Monitoring), methods, responsibilities and requirements, including 


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handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan. 
• 
The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• 
The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• 
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for 30 years from the issue of the final Clinical 
Study Report (CSR)/equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor.  
 
12.1.7. 
Source Documents 
• 
Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
• 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must 
be explained. The Investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be 
available. 
 
12.1.8. 
Study and Site Closure 
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or Investigator may include 
but are not limited to: 
• 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 


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• 
Inadequate recruitment of participants by the Investigator 
• 
Discontinuation of further study intervention development. 
 
12.1.9. 
Remote Monitoring and Source Data Verification  
209012 First Trial In Human (FTIH) study requires close, ongoing monitoring of patient 
data to ensure treatments are safe and tolerated by study participants. When onsite 
monitoring is not permissible due to site/local restrictions (such as with epidemic and/or 
pandemic), remote monitoring may be employed that ensures all of the following 
requirements are met: 
• 
Monitoring plan and execution details [remote source data monitoring (rSDV) 
method and scope of activities] are outlined in the Study Monitoring Plan 
• 
Remote monitoring method to be employed as permitted by local regulations, agreed 
upon by study site and approved by IRB/IEC 
• 
Appropriate security systems/provisions are in place to ensure protection of patient 
data and shared information 
• 
Participants sign ICF including disclosure of remote monitoring for 
(redacted/anonymized) patient data with security provisions in place 
 


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12.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 1 will be performed by the local laboratory. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in the substudies. 
• 
Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations. 
• 
Pregnancy testing:  
– Refer to Inclusion Criteria in the substudy specific sections for Screening 
pregnancy criteria. 
– Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at all times indicated in the SOA. 
– Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the Investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant’s participation in the 
study. 
 


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Table 1 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
• MCV 
• MCH 
• Reticulocytes 
WBC count with 
Differential: 
• Neutrophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Flow cytometry 
CD3/CD4/CD8 
 
 
 
Clinical Chemistrya 
BUNb 
Potassium 
AST (SGOT) 
Total & direct bilirubin 
Creatinine 
Sodium 
ALT (SGPT) 
Total protein 
Glucose [nonfasting] 
Calcium 
Alkaline phosphatase Chloride 
Albumin 
Phosphorus 
LDH 
Urea 
Magnesium 
Bicarbonate 
 
Coagulation 
INR, PT, and aPTT, Fibrinogen 
 
 
 
Routine Urinalysis 
• Specific gravity 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Other Tests 
• CMV IgG and PCR 
• TSH with free T4 
• CRP 
• Uric acid 
• GFR or 24 hour Urine 
• Follicle-stimulating hormone (as needed in women of non-childbearing potential only) 
• Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)b 
• HIV, HBV, HCV, HTLV, EBV, and syphilis (spirochete bacterium). 
• Ferritin 
• Serum troponin 
• NT-proBNP / BNP 
a. 
Details of liver chemistry monitoring criteria and required actions and follow-up assessments after liver monitoring 
event are given in Section 8.2.1. All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 
3 × ULN and INR >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be 
reported as an SAE. 
b. 
Either BUN or UREA tests are acceptable. 
c. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Note: All study-required laboratory safety assessments will be performed by a local laboratory with the exception of 
alleles HLA-A*02:01, A*02:05, or A*02:06 and NY-ESO-1/LAGE-1a expression. The results of the HLA and NY-ESO-
1/LAGE-1a tests must be entered into the eCRF. 
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = Aspartate aminotransferase; 
BNB = B-type natriuretic peptide; BUN = blood urea nitrogen; CMV = cytomegalovirus; CRP = C-reactive protein; EBV 
= Epstein Barr virus; GFR = glomerular filtration rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; HTLV = human T-lymphotropic virus; INR = international normalized ratio; LDH = lactate 
dehydrogenase; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; NT-proBNP = N-terminal 
group pro-BNP; PCR = polymerase chain reaction; PT = prothrombin time; RBC = red blood cells; SGOT = serum 
glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase; T4 = thyroxine; TSH = thyroid 
stimulating hormone; WBC = white blood cells. 
 


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12.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
12.3.1. 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study intervention, whether or not 
considered related to the study intervention. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a study intervention. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from Baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition. 


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• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
 
12.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met. 
A SAE is defined as any untoward medical occurrence that, at any dose: 
Results in death 
Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from Baseline is not considered an AE. 
Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 


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Is a congenital anomaly/birth defect 
Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
• Grade ≥3 CRS, ICANS, or GVHD, all cases of aplastic anemia, and all cases of 
GBS or other demyelinating neuropathies must be reported within 24 hours as 
SAEs. 
 
12.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs: 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep venous thrombosis/pulmonary embolism 
• 
Revascularization 
 
12.3.4. 
Recording and Follow-Up of AE and SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 


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• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign a grade according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE), v5.0, except for the 
following: 
• CRS grading will be based on [Lee, 2019] and include Fever, Hypoxia and 
Hypotension. Organ toxicities associated with CRS will be graded according to 
NCI-CTCAE v5.0 and do not influence CRS grading. 
• ICANS grading will be based on [Lee, 2019]. Organ toxicities associated with 
ICANS will be graded according to NCI-CTCAE v5.0 and do not influence ICANS 
grading. 
 
Assessment of Causality 
• The Investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has 
minimal information to include in the initial report to GSK. However, it is very 


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important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK. 
• The Investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of AE and SAE 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized 
follow-up period, the Investigator will provide GSK with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
 
12.3.5. 
Reporting of SAE to GSK 
SAE Reporting to GSK via Electronic Data Collection Tool 
• The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor/SAE coordinator by telephone. 
• 
Contacts for SAE reporting can be found in the SRM. 
 
 


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SAE Reporting to GSK via Paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor/SAE coordinator. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone or email does not replace the need for the 
Investigator to complete and sign the SAE CRF pages within the designated 
reporting time frames. 
• Contacts for SAE reporting can be found in the SRM. 
 
 


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12.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
12.4.1. 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered. 
Women in the following categories are not considered WOCBP 
• 
Premenarchal 
• 
Premenopausal female with 1 of the following: 
– Documented hysterectomy 
– Documented bilateral salpingectomy 
– Documented bilateral oophorectomy 
 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), Investigator discretion should be 
applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
• 
Postmenopausal female 
– A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
– A high follicle stimulating hormone (FSH) level in the postmenopausal range (as 
per laboratory parameters for postmenopausal range) may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT) when postmenopausal status is in doubt. However, in 
the absence of 12 months of amenorrhea, confirmation with more than one FSH 
measurement is required. 
– Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
 


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12.4.2. 
Contraception Guidance 
Participants should be informed that treatment with fludarabine, cyclophosphamide 
and/or genetically engineered T cells may have adverse effects on a fetus in utero. 
Furthermore, while it is not known if such treatment has transient adverse effects on the 
composition of sperm, the investigator should advise fertile male participants to consider 
collecting and storing viable sperm prior to undergoing lymphodepletion, given that 
cyclophosphamide may result in partial (oligospermia) or total (azoospermia) sterility. 
Participants who are WOCBP must use a barrier method (male condom) and should 
comply with one of the methods in the table below.  Male participants should use a male 
condom and should also be advised of the benefit for a female partner to use one of the 
methods in the table below. 
CONTRACEPTIVES a ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods That Have Low User Dependency Failure rate of <1% per year when used consistently 
and correctly. 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation b 
Intrauterine device (IUD) 
Intrauterine hormone-releasing system (IUS) b 
Bilateral tubal occlusion 
Vasectomized partner 
Note: Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual 
partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. Spermatogenesis cycle is approximately 
90 days. 
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used consistently and 
correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationb 
oral 
intravaginal 
transdermal 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulation b 
oral 
injectable 
Sexual abstinence 
Note: Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. Periodic 
abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception. 
a. 
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b. 
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical 
Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
Note: Male condom and female condom should not be used together (due to risk of failure with friction). 
 


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Participants should be informed that taking the study medication may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study.  
The IB and Informed consent also contain language describing the risks and 
contraceptive guidelines described above. 
Contraception is mandated from the start of study intervention and for the period defined 
in Table 2, based on the study treatments received 
Table 2 
Time Periods for Contraception Usage 
Study Intervention Received 
Contraception to continue from start of study intervention through 
longest of all intervals defined below based on all treatments received  
Fludarabine 
6 months after last dose of fludarabine 
Cyclophosphamide 
Time after last dose of cyclophosphamide: 
Females – 12 months 
Males – 6 months 
NY-ESO-1 specific T cell infusion 
A minimum of 12 months after NY-ESO-1 specific T-cell infusion. 
In the event that there is still evidence of persistence of gene modified cells 
in the participant’s blood beyond 12 months, contraception to continue until 
notification by Sponsor that NY-ESO-1 specific T cells  are not detected in 
blood for 2 consecutive times. 
 
The Sponsor will notify the site once the participants’ persistence is below the level of 
detection for 2 consecutive times.  
12.4.3. 
Collection of Pregnancy Information: 
Male participants with partners who are or become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who is or becomes pregnant while the male participant is participating 
in this study. This applies only to male participants who receive study intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the Investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy.  
• 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK. 
• 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.  
 
Female participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  


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• 
Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy.  
• 
Participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date.  
• 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.  
• 
A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
• 
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study intervention by the Investigator, will be reported to 
GSK as described in Section 12.3. While the Investigator is not obligated to actively 
seek this information in former study participants, he or she may learn of an SAE 
through spontaneous reporting.  
 
Any female participant who becomes pregnant while participating will discontinue study 
intervention if possible. 


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12.5. 
 Appendix 5: Genetics 
USE/ANALYSIS OF DNA 
• 
Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; disease 
etiology; and/or molecular subtype of the disease being treated. Therefore, DNA 
analysis will be conducted on blood, plasma, and tumor biopsies per local 
regulations and IRB/IEC. 
• 
DNA samples will be used for research related to NY-ESO-1 specific TCR 
engineered T cells or cancer indication(s) under study and related diseases. They 
may also be used to develop tests/assays including diagnostic tests related to 
NY-ESO-1 specific TCR engineered T cells and cancer indications under study. 
Genetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome, 
as appropriate. 
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to NY-ESO-1 specific TCR engineered T cells. The results 
of genetic analyses may be reported in the clinical study report or in a separate study 
summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• 
The samples will be retained while research on NY-ESO-1 specific TCR engineered 
T cells (or study interventions of this class) or indications under study continues but 
no longer than 15 years after the last participant last visit or other period as per local 
requirements. 
 
12.5.1. 
Companion Diagnostics 
US Food and Drug Administration states that an in vitro companion diagnostic device 
(IVD) could be essential for the safe and effective use of a corresponding therapeutic 
product to: 
• 
Identify participants who are most likely to benefit from a particular therapeutic 
product; 
• 
Identify participants likely to be at increased risk for serious adverse reactions as a 
result of treatment with a particular therapeutic product; 
• 
Monitor response to treatment for the purpose of adjusting treatment (e.g., schedule, 
dose, discontinuation) to achieve improved safety or effectiveness; 
• 
Identify participants in the population for whom the therapeutic product has been 
adequately studied, and found safe and effective, i.e., there is insufficient 
information about the safety and effectiveness of the therapeutic product in any other 
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Global regulatory requirements for IVD companion diagnostic tests are evolving. If a 
DNA-based IVD companion diagnostic device might be needed to identify participants 
who are appropriate for the GSK medicinal product(s) under investigation in this 
protocol, then GSK should collect and retain DNA samples from participants who carry 
the genetic variant of interest as well as DNA samples from participants who do not carry 
the genetic variants of interest to validate the performance of the companion diagnostic. 
Therefore, where local regulations and IRB/IEC allow, a sample will be collected for 
DNA analysis. Any IVD companion diagnostic research objectives should be described 
in participant ICFs. 


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12.6. 
Appendix 6: Guidelines for Assessment of Disease, Disease 
Progression, and Response Criteria 
12.6.1. 
RECIST v1.1 Assessment Guidelines 
Please note the following: 
• 
The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion. Contrast agents must be used in 
accordance with the Image Acquisition Guidelines. 
• 
All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers. 
• 
Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required. 
• 
Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments of 
disease. However, FDG-PET can be useful in confirming new sites of disease where 
a positive FDG-PET scans correlates with the new site of disease present on CT/MRI 
or when a Baseline FDG-PET was previously negative for the site of the new lesion. 
FDG-PET may also be used in lieu of a standard bone scan providing coverage 
allows interrogation of all likely sites of bone disease and FDG-PET is performed at 
all assessments. 
• 
If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the required 
anatomical coverage and prescribed use of contrast. The method of assessment 
should be noted as CT on the CRF. 
 
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler/callipers to measure the size of the lesion, is 
required [Eisenhauer, 2009].  
CT and MRI: Contrast enhanced CT with 5 mm contiguous slices is recommended. 
Minimum size of a measurable Baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimized for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible the same 
scanner should be used [Eisenhauer, 2009]. 
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however, chest CT is preferred over 
chest X-ray [Eisenhauer, 2009]. 
Brain Scan:  If brain scans are required, then contrast-enhanced MRI is preferable to 
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Bone Scan (typically bone scintigraphy):  If a bone scan is performed and a new 
lesion(s) is equivocal, then correlative imaging (i.e., X-ray, CT, or MRI) is required to 
demonstrate malignant characteristics of the lesion(s).  
Note:  PET [FDG or fluoride] may be used in lieu of a standard bone scan providing 
coverage allows interrogation of all likely sites of bone disease and PET is performed at 
all assessments. 
Guidelines for Evaluation of Disease 
Measurable and Non-measurable Definitions 
Measurable lesion: 
A non-nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of the following: 
• 
10 mm with MRI or CT when the scan slice thickness is no greater than 5 mm. If 
the slice thickness is greater than 5 mm, the minimum size of a measurable lesion 
must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a 
measurable lesion must be 20 mm). 
• 
10 mm caliper/ruler measurement by clinical exam or medical photography.  
• 
20 mm by chest x-ray. 
• 
Additionally, lymph nodes can be considered pathologically enlarged and 
measurable if 15 mm in the short axis when assessed by CT or MRI (slice thickness 
recommended to be no more than 5 mm). At Baseline and follow-up, only the short 
axis will be measured [Eisenhauer, 2009]. 
 
Non-measurable lesion:  
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009]. 
Measurable disease:  
The presence of at least one measurable lesion. Palpable lesions that are not measurable 
by radiologic or photographic evaluations may not be utilized as the only measurable 
lesion. 
Non-measurable only disease:  
The presence of only non-measurable lesions.  
Note: non-measurable only disease is not allowed per protocol. 
 


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Baseline Definition of Target Lesions (TLs) and Non-Target Lesions (NTLs) 
Measurable lesions (see definition above) up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions, and recorded and measured at baseline. These lesions should be selected based 
on their size (measurable diameters) and their suitability for accurate repeated 
measurements.  
All other lesions or sites of disease should be recorded as non-target lesions at 
screening/baseline and should be followed qualitatively. Non-target lesions will be 
grouped by organ. Measurements are not required, rather the status of non-target lesions 
should be determined as “present,” “absent,” or in rare cases “unequivocal progression” 
during follow up. 
Additional guidance for selection of target and non-target lesions at screening/baseline: 
• 
For selection of target lesions, paired organs such as the lungs or kidneys are each 
considered together as a single organ, and no more than 2 lesions should be recorded 
as target lesions within the pair. The skin and all lymph nodes are each considered a 
single organ for purposes of target lesion selection. 
• 
Lymph nodes of pathological size with short-axis diameters of 10 mm to <15 mm 
should be recorded as non-target lesions. 
• 
Lesions identified by clinical assessment (superficial skin lesions) only should be 
followed as non-target lesions when other suitable target lesions are available. 
• 
Cystic lesions thought to represent cystic metastases should not be selected as target 
lesions when other suitable target lesions are available. 
• 
Lesions that have been previously irradiated and have since progressed may be 
considered as target lesions. 
• 
Lesions which are biopsied at baseline should be considered non-target lesions. If 
there is only 1 measurable lesion and non-target lesions are absent or not accessible, 
Medical Monitor (or designee) must be consulted and biopsy may be performed if 
there is no anticipated risk of interfering with measurement of single lesion. 
• 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by CT or MRI can be considered measurable (soft 
tissue component).  Bone scans, FDG-PET scans or X-rays are not considered 
adequate imaging techniques to measure bone lesions. 
 
Response Criteria 
Evaluation of target lesions: 
Definitions for assessment of response for target lesion(s) are as follows: 
• 
Complete Response (CR):  Disappearance of all target lesions. Any pathological 
lymph nodes must be <10 mm in the short axis. 
• 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the Baseline sum of the diameters (e.g. percent change 
from Baseline). 


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• 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease. 
• 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 5 mm. 
• 
Not Applicable (NA): No target lesions at Baseline. 
• 
Not Evaluable (NE): Cannot be classified by one of the five preceding definitions. 
 
Note: 
• 
If lymph nodes are documented as target lesions the short axis is added into the sum 
of the diameters (e.g. sum of diameters is the sum of the longest diameters for 
non-nodal lesions and the short axis for nodal lesions). When lymph nodes decrease 
to non-pathological size (short axis <10 mm) they should still have a measurement 
reported in order not to overstate progression. 
• 
If at a given assessment time point all target lesions identified at Baseline are not 
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, 
PR, or SD, or for use as the nadir for future assessments. However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented. If an assessment of 
PD cannot be made, the response assessment should be NE. 
• 
All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g. 2 mm). If lesions are present but too small to measure, 5 mm 
should be recorded and should contribute to the sum of the diameters, unless it is 
likely that the lesion has disappeared in which case 0 mm should be reported. 
• 
If a lesion disappears and reappears at a subsequent time point it should continue to 
be measured. The response at the time when the lesion reappears will depend upon 
the status of the other lesions. For example, if the disease had reached a CR status 
then PD would be documented at the time of reappearance. However, if the response 
status was PR or SD, the diameter of the reappearing lesion should be added to the 
remaining diameters and response determined based on percent change from 
Baseline and percent change from nadir. 
 
Evaluation of non-target lesions: 
Definitions for assessment of response for non-target lesions are as follows: 
• 
Complete Response (CR):  The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at Baseline must be non-pathological 
(e.g., <10 mm short axis). 
• 
Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at Baseline ≥10 mm short axis. 
• 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  


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• 
Not Applicable (NA):  No non-target lesions at Baseline. 
• 
Not Evaluable (NE):  Cannot be classified by one of the four preceding definitions. 
 
Note: 
• 
In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
• 
Sites of non-target lesions, which are not assessed at a particular timepoint based on 
the assessment schedule, should be excluded from the response determination 
(e.g., non-target response does not have to be "Not Evaluable").  
 
New lesions 
New malignancies denoting disease progression must be unequivocal. Lesions identified 
in follow-up in an anatomical location not scanned at Baseline are considered new 
lesions. 
Any equivocal new lesions should continue to be followed. Treatment can continue at the 
discretion of the Investigator until the next scheduled assessment. If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented. 
Evaluation of overall response 
Table 3 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for participants with measurable disease at Baseline. 
Table 3 
Evaluation of Overall Response for Participants with Measurable 
Disease at Baseline 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR or NA 
No 
CR 
CR 
Non-CR/Non-PD or NE 
No 
PR 
PR 
Non-PD or NA or NE 
No 
PR 
SD 
Non-PD or NA or NE 
No 
SD 
NE 
Non-PD or NA or NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease, NA=Not applicable, 
and NE=Not Evaluable 
 
Note: Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration." Objective response status is determined 


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by evaluations of disease burden. Every effort should be made to document the objective 
progression even after discontinuation of treatment.  
In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of CR depends on this determination, it is recommended that 
the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the Investigators assessment of response at each time point.  
• 
To be assigned a status of SD, follow-up disease assessment must have met the SD 
criteria at least once after first dose at a minimum interval of 28 days.  
• 
If the minimum time for SD is not met, best response will depend on the subsequent 
assessments. For example, if an assessment of PD follows the assessment of SD and 
SD does not meet the minimum time requirement the best response will be PD. 
Alternatively, participants lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable. 
 
Confirmation Criteria: 
• 
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met. 
 
12.6.2. 
iRECIST Guidelines 
iRECIST is based on RECIST v1.1 but adapted to account for the unique tumor response 
seen with immunotherapeutic drugs. iRECIST will be used to assess tumor response and 
progression and make treatment decisions. When clinically stable, participants should not 
be discontinued until progression is confirmed according to the rules described below. This 
allowance to continue treatment despite initial radiologic PD takes into account the 
observation that some participants can have a transient tumor flare in the first few months 
after the start of immunotherapy, and then experience subsequent disease response. These 
data will be captured in the clinical database. 
Clinical stability is defined as meeting all of the following:  
• 
Absence of symptoms and signs indicating clinically significant progression of 
disease 
• 
No decline in ECOG performance status  
• 
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care 
 
Any participant deemed clinically unstable may be discontinued from study intervention 
at site-assessed first radiologic evidence of PD. It is strongly preferred to obtain the 
repeat tumor imaging, when feasible, for confirmation of PD by iRECIST.  


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In a clinically unstable participant, if the Investigator decides to continue treatment, 
following consultation with the Sponsor medical monitor, the participant may continue to 
receive study intervention. The tumor assessment should be repeated at least 4 weeks and 
up to 12 weeks later to confirm PD by iRECIST. Images should continue to be sent in to 
the central imaging vendor for potential central review.  
If repeat imaging does not confirm PD per iRECIST and the participant continues to be 
clinically stable, study intervention may continue and follow the regular imaging 
schedule. If PD is confirmed, participants will be discontinued from study intervention. 
If a participant has confirmed radiographic progression (iCPD) as defined below, study 
intervention phase should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, continuation of study intervention may be considered 
following consultation with the Sponsor. In this case, if study intervention is continued, 
tumor imaging should continue to be performed following the intervals as outlined in the 
SOA and submitted to the central imaging vendor.  
Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST v1.1 Progression 
Until radiographic disease progression based on RECIST v1.1, there is no distinct iRECIST 
assessment. 
Assessment and Decision at RECIST v1.1 Progression 
For participants who show evidence of radiological PD by RECIST v1.1, the Investigator 
will decide whether to continue a participant on study intervention until repeat imaging is 
obtained (using iRECIST for participant management [see Table 4]). This decision should 
be based on the participant’s overall clinical condition. (See discussion of clinical stability 
above).  
Tumor flare may manifest as any factor causing radiographic progression per RECIST 
v1.1, including: 
• 
Increase in the sum of diameters of target lesion(s) identified at Baseline to ≥20% 
and ≥5 mm from nadir 
– Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST v1.1 terminology. 
• 
Unequivocal progression of non-target lesion(s) identified at Baseline 
• 
Development of new lesion(s) 
 
iRECIST defines response categories, including iUPD (unconfirmed progressive disease) 
and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, the first 
visit showing progression according to RECIST v1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 


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At this visit, target and non-target lesions identified at Baseline by RECIST v1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for Baseline lesion assessment in RECIST v1.1. From measurable 
new lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – 
Target. The sum of diameters of these lesions will be calculated and kept distinct from 
the sum of diameters for target lesions at Baseline. All other new lesions will be followed 
qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
At the confirmatory imaging visit assessment, the participant will be classified as 
progression confirmed (with an overall response of iCPD), or as showing persistent 
unconfirmed progression (with an overall response of iUPD), or as showing disease 
stability or response (iSD/iPR/iCR).  
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• 
Any of the factors that were the basis for the initial iUPD show worsening 
– For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point 
– For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST v1.1 
– For new lesions, worsening is any of these: 
▪ An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point  
▪ Visible growth of new non-target lesions  
▪ The appearance of additional new lesions 
• 
Any new factor appears that would have triggered PD by RECIST v1.1 
 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• 
None of the progression-confirming factors identified above occurs AND 
• 
The target lesion sum of diameters (initial target lesions) remains above the initial 
PD threshold (by RECIST v1.1) 
 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging 
on which iUPD is seen (see Figure 5). This may correspond to the next visit in the 
original visit schedule. The assessment of the subsequent confirmation imaging proceeds 
in an identical manner, with possible outcomes of iCPD, iUPD, and iSD/iPR/iCR. 


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Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, 
if: 
• 
None of the progression-confirming factors identified above occurs, AND 
• 
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows 
radiographic progression, whenever it occurs, is again classified as iUPD by iRECIST, 
and the confirmation process is repeated before a response of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and 
the participant continues to be clinically stable, study intervention may continue and 
follow the regular imaging schedule. If PD is confirmed, participants will be discontinued 
from study intervention. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, 
but the participant is achieving a clinically meaningful benefit, continuation of study 
intervention may be considered following consultation with the Sponsor. In this case, if 
study intervention is continued, tumor imaging should continue to be performed 
following the intervals as outlined in the SOA and submitted to the central imaging 
vendor. 
Detection of Progression at Visits after Pseudo-Progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is 
indicated by any of the following events: 
• 
Target lesions 
– Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression. 
• 
Non-target lesions 
– If non-target lesions have never shown unequivocal progression, doing so for the 
first-time results in iUPD. 
– If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions. 
• 
New lesions 


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– New lesions appear for the first time 
– Additional new lesions appear 
– Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum 
– Previously identified non-target lesions show any significant growth 
 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the 
confirmatory imaging the burden of new lesions has increased from its smallest value (for 
new target lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD 
cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the new lesion 
burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication [Seymour, 
2017]. 


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Table 4 
Imaging and Treatment after First Radiologic Evidence of 
Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD by 
RECIST v1.1  
Repeat imaging at 
4 to 8 weeks to 
confirm PD. 
May continue study 
intervention at the 
Investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging by site 
by iRECIST. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
Investigator 
assessment 
No additional 
imaging required. 
Discontinue treatment 
(exception is possible 
upon consultation with 
Sponsor). 
No additional 
imaging required. 
Not applicable 
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment 
Repeat imaging at 
4 to 8 weeks to 
confirm PD. May 
occur at next 
regularly 
scheduled 
imaging visit. 
Continue study 
intervention at the 
Investigator’s 
discretion. 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
Investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor 
imaging shows 
iSD, iPR, or iCR by 
iRECIST per 
Investigator 
assessment. 
Continue regularly 
scheduled 
imaging 
assessments. 
Continue study 
intervention at the 
Investigator’s 
discretion. 
Continue regularly 
scheduled 
imaging 
assessments. 
May restart study 
intervention if condition 
has improved and/or 
clinically stable per 
Investigator’s discretion. 
Next tumor imaging 
should occur according 
to the regular imaging 
schedule. 
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = 
iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST v1.1 = Response Evaluation Criteria in 
Solid Tumors v1.1. 
 


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Figure 5 
Imaging and Treatment for Clinically Stable Participants after First 
Radiologic Evidence of PD Assessed by the Investigator 
 
iRECIST = Modified RECIST 1.1; PD = progressive disease. 


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12.7. 
Appendix 7: Supportive Care Guidance  
It is recommended that a specialist with experience in the administration of hematopoietic 
stem cell transplant and/or other cell and gene therapy be involved in the care of study 
participants. During lymphodepletion, supportive care should be provided to participants 
as per local institutional guidelines, based on established oncology practice guidelines for 
chemotherapy administration and supportive care. 
All participants should be hospitalized for at least 3 days after the T-cell infusion. Staff 
treating trial participants should be experienced in acute post-transplant care and the 
management of associated toxicities (e.g., cytopenias, cytokine release syndrome (CRS), 
autologous graft versus host disease). 
Participants are at risk for the development of certain adverse effects for which 
recommended management strategies have been developed. Adverse events are most 
likely to occur within the first month following T-cell infusion but may occur at later 
time points. 
Supportive care treatments recommended herein, including tocilizumab, will be supplied 
by the pharmacy of the participating institution. 
See additional supportive guidance in corresponding section within the substudy for 
substudy specific details, when applicable. 
12.7.1. 
T-Cell Infusion Symptom Management 
Mild transient symptoms have been observed following infusion of engineered T cells. 
The management of these symptoms is suggested but should not necessarily be confined 
to the below. 
• 
Fever, chills, headache and temperature elevations will be managed with 
acetaminophen or an alternative per institutional practice. It is recommended all 
participants that develop fever or chills have a blood culture drawn. 
• 
Nausea and vomiting may be treated with a non-steroidal anti-emetic of choice. 
• 
Hypotension will initially be managed by intravenous fluid administration and 
further measures as dictated by standard medical practice. 
• 
Hypoxemia will initially be managed with supplemental oxygen and further 
measures as dictated by standard medical practice. 
 
In participants with infusion-related reaction Grade ≤2, infusion may be restarted once 
resolved to Grade <1. The bag of cells that was being infused prior to reaction, cannot be 
used beyond 45 min after thawing. Infusion-related reactions Grade 3 or higher during 
infusion should be reported to Sponsor promptly. 
12.7.2. 
Infection 
Additional measures to treat and prevent infection are outlined below. In particular, fever 
and neutropenia should be aggressively managed as well as pre-emptive influenza 


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therapy and other standard therapies for immunocompromised hosts, in accordance with 
institutional guidelines.  For participants with indwelling central lines, consider increased 
surveillance to monitor for catheter-associated infections. 
12.7.2.1. 
Pneumocystis carinii Pneumonia (PCP) 
Participants should receive prophylaxis against PCP with drug, dose and duration 
according to institutional guidelines. Single strength trimethoprim sulfamethoxazole daily 
is the recommended first-line agent, starting at Day 28 post T-cell infusion for one year. 
Other regimens, including atovaquone (1500 mg daily with food) or aerosolized 
pentamidine (300 mg every four weeks) are also acceptable (e.g., if sulfonamide allergy). 
12.7.2.2. 
Herpes Simplex, Varicella Zoster and Epstein Barr virus (EBV) 
All participants should receive prophylaxis with acyclovir (800 mg twice daily) or 
valacyclovir (500 mg twice daily) for one year initiated prior to lymphodepletion, or in 
accordance with institutional guidelines and labels. 
12.7.2.3. 
Cytomegalovirus 
All participants will be screened for cytomegalovirus (CMV) IgG seropositivity at study 
entry and baseline. If CMV viremia is detected at Baseline, treatment should be initiated 
with evidence of viral clearance prior to lymphodepleting chemotherapy. All CMV IgG 
seropositive participants will continue to be monitored for CMV viremia by CMV DNA 
PCR until 60 days post infusion of cell therapy. In the event CMV viremia is observed, 
an infectious diseases specialist should be consulted and treatment initiated if necessary 
according to institutional practice. Recommended regimens include ganciclovir-based 
therapy if ANC ≥1000, and foscarnet if ANC <1000. 
If a participant experiences prolonged or secondary pancytopenia or lymphopenia, 
additional monitoring for viral reactivation should be considered and treatment for viral 
infection initiated if necessary. A strategy for management of pancytopenia or bone 
marrow failure is described in Section 12.7.7. 
12.7.2.4. 
Hepatitis B Prophylaxis 
Participants will be screened for hepatitis B virus (HBV) at study entry. Participants who 
are hepatitis B core antibody positive must receive prophylaxis against viral reactivation 
using institutional protocols. Prophylaxis should be initiated prior to lymphodepleting 
chemotherapy and continued for 6 months. Acceptable regimens include lamivudine 
(300 mg daily), entecavir (0.5 mg daily), or tenofovir (300 mg daily). 
Additional considerations will be left to the Investigator’s discretion in accordance with 
label recommendations and institutional guidelines. 
12.7.2.5. 
Syphilis 
Participants will be screened for syphilis before leukapheresis and before 
lymphodepletion. Participants with positive Screening results should be evaluated by an 


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infectious diseases consultant. If determined to have syphilis infection, the participant 
should be treated as needed before the study procedure. 
12.7.2.6. 
Other Anti-Microbial Prophylaxis 
Antibacterial and antifungal prophylaxis should follow institutional standards for 
autologous bone marrow transplants. 
If patient has prolonged leukopenia, consider vigilance for latent viral infections. 
If a participant presents with severe or gross hematuria, consider checking for BK viruria 
and viremia. 
If a participant requires anti-microbial treatment associated with risk of cardiac toxicity, 
consider close monitoring of cardiac function (Section 9.1.6). 
12.7.3. 
Hematologic and Blood Product Support 
Blood product support should be provided to maintain the following: 
• 
Platelets >10 × 109/L in the in-patient setting and platelets >20 x 109/L in the 
out-patient setting 
• 
Hb >8.0 g/dL 
or as clinically indicated in the judgment of the Investigator, in accordance with 
institutional practice.  
See American Association of Blood Banks Guideline on platelet transfusion 
[Kaufman, 2015]. 
12.7.3.1. 
Irradiated Blood Product 
Bone marrow suppression can be a consequence of transfusion associated GvHD. To 
minimize the possibility of transfusion associated GvHD, all blood products transfused 
within 4 weeks prior to leukapheresis, within 4 weeks prior to initiation of 
lymphodepleting chemotherapy and following lymphodepleting chemotherapy until at 
least 6 months following IP infusion or until lymphocyte count returns to 1.0 × 109/L 
(whichever is longer) must be irradiated. In addition, if a participant requires systemic 
steroids or immunosuppression for the treatment of toxicity, irradiated blood products 
must be given until recovery of immune function. 
12.7.3.2. 
CMV Screened Blood Products 
Participants will be screened for CMV seropositivity at study entry. In order to reduce the 
risk of primary CMV infection, all participants (i.e., both CMV-positive and -negative 
participants) should receive leukoreduced blood products where possible (excluding the 
IP infusion). Where leukoreduced blood is not available, CMV negative participants must 
only receive blood products from CMV-seronegative donors from study entry to study 
completion. 


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 0 5  
C or e  
 
1 2. 7. 4.  
M a n a g e m e nt of A ut oi m m u nit y  
Partici pa nts s h o ul d be m o nit ore d t hr o u g h o u t t he trial f or p ote ntial a ut oi m m u ne reacti o ns 
i n res p o nse t o t he ge neticall y e n gi n eere d T cells t h at c o ul d i ncl u de s ki n t o xicit y, li ver 
t o xicit y, c olitis, e ye t o xicit y etc. If a ut oi m m u nit y is s us pecte d, t he I n v esti gat or s h o ul d be 
c o ntacte d, a n d e ver y atte m pt s h o ul d be ma de t o bi o ps y t he affecte d or ga n t o clarif y 
w het her t he s y m pt o ms are relate d t o t he a d mi nistere d T -cell t hera p y. If t he partici pa nt 
s ustai ns persiste nt Gra de 2, or Gra d e 3 or 4 a ut oi m m u nit y, c o nsi derati o n s h o ul d be gi ve n 
t o a d mi nistrati o n of c ortic oster oi d t hera p y, eit her l ocall y (e. g., s ki n, e yes) or s yste mic all y 
as cli nicall y i n dicate d.  
1 2. 7. 5.  
M a n a g e m e nt of C yt o ki n e R el e a s e S y n dr o m e  
C R S is a p ote ntiall y life -t hreate ni n g t o xicit y t hat h as bee n o bser ve d f oll o wi n g 
a d mi nistrati o n of a nti b o dies a n d A C T s f or ca ncer. It is defi n e d cli nicall y b y s y m pt o ms 
ma n y of w hic h mi mic i nf ecti o n, i ncl u di n g p yre xia, na usea, diarr hea, hea d ac he, fati g ue, 
tac h ycar dia, h y p ote nsi o n, tra nsa mi nitis, ras h, a n d d ys p nea. It is i m p orta nt t o e val uate t he 
partici pa nt f or c o nc urre nt  i nfecti o ns. P ote ntiall y life-t hreate ni n g c o m plicati o ns of C R S 
i ncl u de car di ac d ysf u n cti o n, a d ult res pirat or y distress s y n dr o m e, ne ur ol o gic t o xicit y, 
re nal a n d/ or h e patic fail ure, a n d disse mi nate d i ntr a vasc ular c oa g ul ati o n. C R S ma y als o be 
ass ociate d wit h fi n di n gs of macr o p ha ge acti vati o n s y n dr o me or occ ur c oi nci de nt wit h 
t u m or l ysis s y n dr o me. 
C R S ca uses a ra pi d rise i n ser u m c yt o ki ne le vels u n der c o n diti o ns of i m m u ne acti vati o n 
a n d alt h o u g h c yt o ki nes will be assa ye d seriall y t hr o u g h o ut t he st u d y, res ults o f t he assa ys 
will n ot be a vaila ble i n real ti me; t heref ore, C R S s h o ul d be gra de d a n d ma na ge d wit h 
s u p p orti ve a n d i m m u n os u p pressi ve i nter ve nti o ns acc or di n g t o t he s e verit y of s y m pt o ms 
[Lee , 2 0 1 9]. C R S gra di n g will i ncl u de Fe ver, H y p o xia a n d H y p ote nsi o n. Or ga n t o xicities 
ass ociate d wit h C R S will be gra de d acc or di n g t o N CI -C T C A E v 5. 0 a n d d o n ot i nfl ue nce 
C R S gra di n g [ Lee , 2 0 1 9]. 
Ta ble 5  pr o vi des t he rec o m me n de d ma na ge m e nt of C R S acc or di n g t o gra de, w hic h has 
bee n f urt h er a d a pte d fr o m C T C A E f or use wit h i m m u n ot hera p y a n d s h o ul d be 
i m ple me nte d i n acc or da n ce wit h i nstit uti o nal gui deli nes. S y m pt o ms ca n mi mic t h ose 
see n wit h i nfecti o n. T he dia g n osis of C R S is cli nical a n d is s u p p orte d b y t he e x cl usi o n of 
i nfecti o n as well as t he prese nce of i ncreas e d c yt o ki ne le vels a n d ot her  
 
Assess me nt a n d treat me nt g ui deli nes are pr o v i de d bel o w i n ali g n me nt wit h (t he S ociet y 
f or I m m u n ot hera p y of Ca ncer SI T C) g ui deli nes [Ma us , 2 0 2 0] a n d s h o ul d be f oll o we d i n 
c o nj u ncti o n wit h a n y l o cal g ui deli n es w h ere a vail a ble .  
If C R S is s us pecte d, a p h ysicia n wit h e x pertise i n t he ma na ge me nt of p artici pa nts 
f oll o wi n g b o ne marr o w tra ns pla nt s h o ul d be c o ns ulte d. 
If C R S is s us pecte d, i n a d diti o n t o assess me nt f or i nfecti o n, per t he Sc h e d ule of 
Assess me nt ( S O A) i n i n di vi d ual s u bst u dies, t he f oll o wi n g tests s h o ul d be c o n d ucte d 
C CI


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every day for the first week and approximately every other day thereafter until symptoms 
are improving or an alternative diagnosis is confirmed: 
• 
Local tests: 
– Chemistry, hematology, ferritin and coagulation, as well as C-reactive protein 
(CRP) labs; 
• 
Central tests: 
– Cytokine-profiling as described in Section 9.10.3. 
 
If CRS is suspected, participants deemed to have significant cardiovascular risk factors 
(per Section 9.1.6) should be considered for earlier intervention with tocilizumab and/or 
steroids at the onset of CRS. 
If CRS Grade ≥2 is suspected, an ECHO/MUGA is required at onset of Grade ≥2 CRS. 
Additional monitoring must be conducted for a minimum of 3 days post onset of 
Grade ≥2 CRS and as long as deemed necessary by the Investigator: 
• 
Continuous cardiac telemetry monitoring  
• 
ECHO/MUGA as clinically indicated 
• 
Local tests: 
– Daily troponin and N-terminal pro B-type natriuretic peptide (NT-proBNP) or 
BNP tests. 
 
If, in the opinion of the Investigator, a participant develops any clinically significant new 
or worsening cardiovascular symptoms or abnormal cardiac labs / imaging finding, a 
cardiology consult should be conducted for urgent evaluation. 


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Table 5 
Management Guidelines for Cytokine Release Syndrome 
Grade 
Clinical Presentation for Grading 
Assessment1,2 
Management Guidelines 
1 
Temperature 38.0 °C 
Vigilant supportive care4 
Assess for infection and treat5 
2 
Temperature 38.0 °C with hypotension not 
requiring vasopressors and/or hypoxia requiring 
the use of oxygen delivered by low-flow nasal 
cannula (≤6 L/minute) or blow-by. 
Monitor cardiac and other organ function 
Vigilant supportive care4 
Assess for infection and treat5 
Treat hypotension with fluid and pressors 
Administer O2 for hypoxia6 
Consider administering tocilizumab ± 
corticosteroids7  
3 
Temperature 38.0 °C with hypotension requiring 
a vasopressor with or without vasopressin and/or 
hypoxia requiring high-flow nasal cannula (>6 
L/minute), facemask, non-rebreather mask, or 
venturi mask not attributable to any other cause3 
Monitor participant very closely for cardiac and 
other organ dysfunction. Most likely will require 
monitoring in an intensive care unit (ICU). 
Vigilant supportive care4 
Assess for infection and treat5 
Treat hypotension with fluid and pressors6. 
Administer O2 for hypoxia. 
Administer tocilizumab ± corticosteroids7 
4 
Temperature ≥38.0 °C with hypotension requiring 
multiple vasopressors (excluding vasopressin) 
and/or hypoxia requiring positive pressure (eg: 
CPAP, BiPAP, intubation and mechanical 
ventilation) 8 
Manage participant in ICU 
Intensive supportive care including mechanical 
ventilation, fluids, pressors, antibiotics and other 
measures as required6 
Administer tocilizumab ± corticosteroids7 
5 
Death9 
 
1. 
Fever is defined as temperature ≥38°C not attributable to any other cause. The constitutional symptoms of CRS, 
such as myalgia, arthralgia, and malaise, are by themselves nonspecific; however, when coincident with fever in 
the expected timeframe, the etiology of CRS is more likely. In patients who have CRS then receive antipyretic or 
anticytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS 
severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
2. 
CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. 
For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring 
low-flow nasal cannula is classified as grade 3 CRS. 
3. 
Low-flow nasal cannula is defined as oxygen delivered at 6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
4. 
Supportive care includes:  monitor fluid balance, maintain adequate hydration and blood pressure  
5. 
Assessment and treatment to include history and physical, blood and urine cultures, imaging studies, 
administration of antimicrobial agents for concurrent bacterial infections, and for treatment of fever and 
neutropenia as per institutional practice; and antipyretics, analgesics as needed.  
6. 
Given that prolonged fluid resuscitation without pressor use is associated with worse outcome and because early 
and aggressive supportive care, early use of vasopressors, and timely anti-cytokine therapy are paramount to 
mitigating life-threatening CRS. 
7. 
Other immunosuppressor agents may be used, including TNFα and IL-1R inhibitors.  
8. 
Intubation of a patient without hypoxia for the possible neurologic compromise of a patent airway alone or for a 
procedure is not, by definition, grade 4 CRS. By extension, a patient experiencing seizures in which a 
compromised airway affects oxygenation and intubation reverses such deficits is not considered to have grade 4 
CRS, because the seizure rather than CRS is the cause of the hypoxia. Furthermore, a patient who remains 
intubated for a neurologic cause is not considered to have CRS when the other signs of CRS have resolved. 
9. 
Grade 5 CRS is defined as death due to CRS in which another cause is not the principle factor leading to this 
outcome. 
Source: [Lee, 2019] 


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Participants requiring immunosuppressive intervention may receive tocilizumab, steroids, 
or both [Davila, 2014; Lee, 2014; Lee, 2019]. Tocilizumab is a humanized anti-IL-6 
receptor antibody that has been approved for the management of severe or 
life-threatening CRS induced by chimeric antigen receptor (CAR) T cell therapy 
[Tocilizumab USPI, 2020; Tocilizumab SmPC, 2020].  
Per the package insert, the recommended dose of tocilizumab for patients with severe or 
life-threatening CRS who weigh 30 kg or above is 8 mg/kg, administered intravenously 
over 1 hour with a total dose not exceeding 800 mg per infusion. If no clinical 
improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 
additional doses of tocilizumab may be administered. The interval between consecutive 
doses should be at least 8 hours. 
Side effects attributed to chronic use of tocilizumab in rheumatologic disease include 
transaminitis, thrombocytopenia, elevated cholesterol and low-density lipoproteins, 
neutropenia and increased infections but acute infusional toxicities have not been 
reported in CRS use [Lee, 2014; Lee, 2019]. 
Per SITC 2020 guidelines: 
If CRS does not improve after one dose of tocilizumab, then steroids should be 
administered with a second dose tocilizumab (e.g. methylprednisolone 2 mg/kg/day or 
dexamethasone 0.5 mg/kg up to 10 mg/dose). If CRS does not improve after 2 doses of 
tocilizumab (and steroids), third-line agents, including anakinra, siltuximab, and 
high-dose methylprednisolone, should be considered. If steroids are used in the 
management of CRS, a rapid taper should be used once symptoms begin to improve 
[Maus, 2020].  
Use of myeloid growth factors, particularly Granulocyte-Macrophage Colony Stimulating 
Factor (GM-CSF) is not recommended because GM-CSF may theoretically aggravate 
CRS [Raje, 2019]. Consider holding G-CSF during CRS [Maus, 2020]. 
Assessment and management of neurological signs and symptoms associated with CRS 
should include consideration of concurrent occurrence of Immune-effector cell-associated 
neurotoxicity syndrome (ICANS). See Section 12.7.8 for further details. 
12.7.6. 
Management of Graft-versus-Host Disease (GvHD) 
Autologous GvHD has been described in association with adoptive transfer of ex-vivo 
expanded/co-stimulated autologous T cells [Rapoport, 2009], as well as infusion of 
T cells with engineered specificity for NY-ESO-1 and LAGE-1a [Garfall, 2013], 
following high-dose chemotherapy and ASCT in participants with multiple myeloma. 
There is the potential for participants who receive lymphodepleting therapy followed by 
engineered autologous T-cell infusion to experience GvHD and/or autoimmune 
GvHD-like symptomatology. Autologous GvHD is typically milder than classic 
(allogeneic) GvHD [Kline, 2008], and is usually manageable with treatment. However, 
severe cases (including fatalities) have been reported [Fidler, 2012].  There are no 
published guidelines for the management of autologous GvHD. However, lessons can be 


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drawn from published case reports and guidelines for the diagnosis and management of 
acute GvHD following allogeneic transplant [Dignan, 2012]. 
12.7.6.1. 
Diagnosis of GvHD 
The diagnosis of GvHD is predominantly based on clinical findings and is often one of 
exclusion (Table 6). Many of these symptoms can also occur in the setting of the 
preparative regimen, high dose cyclophosphamide, as well as with CRS. Any of these 
conditions including GvHD can be associated with fever. The skin is the most commonly 
involved organ, followed by the GI tract and liver. A constellation of symptoms 
involving these organ systems may be helpful in establishing the diagnosis of GvHD. 
Diarrhea, rash, fever, and pancytopenia are common toxicities in the GSK3377794 
(lete-cel) program where we have the most clinical experience. Mild (Grade 1 or 2) 
transient transaminitis without cholestasis has been observed. 
Table 6 
Overview of Clinical Findings/Symptoms of GvHD 
Organ 
Findings/Symptoms 
Differential Diagnosis 
Histopathology 
Skin 
Maculopapular rash involving the 
neck and shoulders as well as the 
palms and soles that spreads to 
include the rest of the body. 
Drug reactions, viral 
exanthems, CRS, and effects 
of chemotherapy or radiation 
Apoptosis at base of epidermal 
rete pegs, dyskeratosis, 
exocytosis of lymphocytes, 
satellite lymphocytes adjacent to 
dyskeratotic epidermal 
keratinocytes and perivascular 
lymphocytic infiltration in the 
dermis. 
GI 
Secretory diarrhea is most 
common but nausea, vomiting, 
anorexia, weight loss and 
abdominal pain can also occur. 
Diarrhea can be copious. 
Bleeding may result from mucosal 
ulceration and ileus may ensue. 
Side effects of chemotherapy 
or other drugs and infection of 
the GI tract 
Patchy ulcerations, apoptotic 
bodies at crypt bases, crypt 
ulceration and flattening of 
surface epithelium 
Liver 
Cholestatic pattern of liver injury 
including elevated conjugated 
bilirubin, alkaline phosphatase 
and GGTP. Participants may 
present with jaundice, with pruritis 
in more severe cases. 
Veno-occlusive disease of the 
liver, viral infections, drug 
toxicity and sepsis. 
Endothelialitis, lymphocytic 
infiltration of the portal areas, 
pericholangitis and bile-duct 
destruction. 
 
NOTE:  Bone marrow suppression and related cytopenias have been described in the 
setting of acute GvHD. Management of this complication is challenging, with no clearly 
established guidelines regarding immunosuppression. Treatment may be largely 
supportive, including transfusions and treatment of infections. 
Management should include consultation with a physician with expertise in the 
management of participants following bone marrow transplant. 


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Bone marrow suppression is also a feature of transfusion-related GvHD. To minimize the 
possibility of transfusion-related GvHD, refer to Section 12.7.3.1 for guidance on 
irradiated blood products.  
12.7.6.2. 
Grading of GvHD 
Grading of acute GvHD is based on the stage of dermal, gastrointestinal, and hepatic 
involvement as described in Table 7. Careful measurement of stool volume and 
assessment of percentage of body area covered by rash are important for proper grading 
and treatment. 
Table 7 
Staging of Dermal, Gastrointestinal and Hepatic Involvement with 
Acute GvHD 
Stage 
Skin 
Gut 
Liver 
1 
Maculopapular rash <25% of body area 
Diarrhea >500 mL/day 
Bilirubin 2-3 mg/dL 
2 
Maculopapular rash 25%-50% of body area 
Diarrhea >1,000 mL/day 
Bilirubin 3-6 mg/dL 
3 
Generalized erythroderma 
Diarrhea>1,500 mL/day 
Bilirubin 6-15 mg/dL 
4 
Desquamation and bullae 
Diarrhea>2,000 mL/day or pain or 
ileus 
Bilirubin >15 mg/dL 
 
With the addition of assessment of functional impairment, grading can be determined 
using Table 8 [Glucksberg, 1974]. 
Table 8 
Grading of Acute GvHD 
Grade 
Skin 1 
Gut 1 
Liver 1 
Functional status 2 
I 
1-2 
0 
0 
0 
II 
1-3 
1 
1 
1 
III 
2-3 
2-3 
2-3 
2 
IV 
1-4 
2-4 
2-4 
3 
1. 
Staging is described in Table 7. 
2. 
Mild, moderate, or severe decrease in performance status 
 
12.7.6.3. 
Management of GvHD 
Although the diagnosis of GvHD is predominantly based on clinical grounds, biopsy of 
affected organs can be helpful in excluding other causes and supporting the diagnosis of 
GvHD with consistent histopathologic findings. However, awaiting biopsy results should 
not delay the start of appropriate therapy. 
If GvHD is suspected: 
• 
A physician with expertise in the management of participants following bone 
marrow transplant should be consulted 
• 
Biopsy of the affected organ(s) should be considered 
 


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Corticosteroids have been used as the standard first-line treatment for GvHD for several 
decades. Their effect is likely to be due to lympholytic effects and anti-inflammatory 
properties. In general, intestinal and liver GvHD require more prolonged steroid therapy 
than skin disease although response times vary. 
Diarrhea should be managed with volume replacement, dietary restriction, and anti-
diarrheal agents including the consideration of somatostatin for secretory diarrhea. 
Agents that slow motility should be used cautiously, ensuring that there is no evidence of 
ileus or toxic megacolon, and infectious causes of diarrhea should be excluded. 
General guidelines for first-line treatment based on grade are provided in Table 9 and 
should be considered in conjunction with input from the consulting physician with bone 
marrow transplant expertise. 
Table 9 
Management Guidelines for GvHD 
Grade 
Management Strategy 
I 
Participants with Grade I disease are not likely to require systemic treatment. Cutaneous GvHD 
may respond to topical steroid creams. Antihistamines may be helpful in participants with pruritis. 
Participants should be reviewed frequently for other organ manifestations of GvHD. 
II 
Treat skin symptoms with topical steroids. For GI symptoms - optimize anti-diarrheal regimen, 
dietary restrictions, volume replacement and consider initiation of non-absorbable steroids. For 
refractory or progressive symptoms consider systemic steroids as outlined below. 
III 
For more severe or progressive symptoms consider systemic corticosteroids (e.g., 
methylprednisolone one (1) mg/kg per day1) 
IV 
Methylprednisolone two (2) mg/kg per day1 
1. 
The use of ‘nonabsorbable’ steroids (budesonide and beclomethasone) can be considered for acute intestinal 
GvHD in order to reduce the dose of systemic steroids 
 
If high-dose corticosteroids are required, treatment should generally be continued for at 
least 5 days followed by tapering doses over several weeks. A physician with expertise in 
infectious diseases in immunocompromised hosts should be consulted, and prophylactic 
antimicrobials should be considered. 
Second-line treatment can be considered for participants who have failed to respond for 
5 days or have progressive symptoms after 3 days. There is no clear second-line agent 
that is preferred for steroid refractory GvHD. General guidelines for second-line 
treatment based on grade are provided below and should be considered in conjunction 
with input from the consulting physician with bone marrow transplant expertise. 
For steroid refractory skin rash, topical tacrolimus may also be useful. 
Most of the allogeneic transplant participants are concurrently receiving calcineurin 
inhibitors in part as prophylaxis against GvHD. Therefore, for Grade II-IV disease 
refractory to high dose steroids, the addition of a calcineurin inhibitor can be considered. 


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Otherwise, there are several additional second-line treatment options for which there is 
currently limited and/or evolving supporting data. Treating physicians can refer to the 
Haemato-oncology Task Force of the British Committee for Standards in Hematology 
and the British Society for Blood and Marrow Transplantation guideline for diagnosis 
and management of acute graft-versus-host disease [Dignan, 2012]. 
12.7.7. 
Management of Pancytopenia with Bone Marrow Failure/Aplastic 
Anemia 
Pancytopenia with bone marrow failure / aplastic anemia has been reported after initial 
bone marrow recovery from high-dose chemotherapy followed by infusion of NY-ESO-1 
specific T cells. Bone marrow recovery following lymphodepletion will be defined as: 
• 
ANC 1,000/μL for 2 consecutive measurements approximately 7 days apart, and 
• 
Platelet count 20,000/μL without transfusion support for 1 week. 
 
Aplastic anemia is a rare hematological disorder characterized by pancytopenia and a 
hypocellular marrow. Participants are usually symptomatic on presentation, but some are 
detected incidentally when unexpected cytopenias are found on a routine blood count. 
The diagnosis of severe aplastic anemia is made in the setting of a hypocellular bone 
marrow when 2 of the following 3 blood counts are met: ANC <500/μL, absolute 
reticulocyte count <60,000/μL, and platelet count <20,000/μL, and myelodysplastic 
syndrome is ruled out. The clinical consequences of aplastic anemia are life-threatening 
bleeding from thrombocytopenia, and infection as a result of neutropenia. Bacterial and 
fungal infections are common and a significant cause of morbidity and mortality. 
Management of bone marrow suppression and related cytopenias in aplastic anemia is 
challenging, with no clearly established guidelines regarding immunosuppression. 
Treatment is largely supportive, including transfusions and treatment of infections. If 
there is evidence of, or concern for the development of pancytopenia (decreasing 
hemoglobin, platelets or neutrophils, or increasing transfusion requirements) following 
initial bone marrow recovery the following measures should be implemented: 
• 
Consult a physician with expertise in the management of aplastic anemia 
• 
Increase the frequency of complete blood counts (CBCs) as clinically indicated. 
• 
Exclude other alternative etiologies such as other drugs, viral causes, etc. 
• 
An early bone marrow biopsy is recommended for clinical diagnosis, with a sample 
to be provided to the Sponsor for study. Details on tissue collections, kit use, and 
shipment information can be found in the SRM.  
• 
A matched peripheral blood sample should be collected in parallel with the bone 
marrow sample and provided to the Sponsor.  
• 
Initiate treatment with G-CSF 
• 
Consult an Infectious Diseases expert 
• 
Once alternative etiologies have been excluded, strongly consider 
immunosuppression (e.g. methylprednisolone 2mg/kg initial dose) or more 


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aggressive regimens (e.g. antithymocyte globulin (ATG), cyclosporine, eltrombopag) 
as well as antimicrobial prophylaxis/therapy with the advice of your 
hematology/Infectious Diseases consultant(s). If high dose corticosteroids are 
initiated, continue for a minimum of 5 days and taper gradually with advice from 
expert consultants. 
 
Refer to Section 12.7.6 regarding bone marrow suppression as a feature of GvHD. 
12.7.8. 
Management of Immune Effector Cell-Associated Neurotoxicity 
Syndrome (ICANS) 
Encephalopathy has been described in association with chimeric antigen receptor (CAR) 
T therapy and termed CAR T cell related encephalopathy syndrome, or CRES [Neelapu, 
2018]. CRES typically manifests as a toxic encephalopathy which is generally reversible. 
Early signs include diminished attention, language disturbance and impaired handwriting. 
Other signs/symptoms include confusion, disorientation, agitation, aphasia, somnolence, 
and tremors. In severe cases of CRES (defined as Grade >2), seizures, motor weakness, 
incontinence, mental obtundation, increased intracranial pressure, papilledema, and 
cerebral edema may also occur. 
CRES occurring within the first 5 days after immunotherapy may be concurrent with high 
fever and CRS symptoms. This form of CRES tends to be of shorter duration, lower 
grade (Grade 1–2), and the CRS is generally reversible with anti-IL-6 therapy. CRES 
presenting as delayed neurotoxicity with seizures or episodes of confusion can occur 
three or four weeks after CAR T-cell therapy, after the initial fever and CRS subside. 
Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is a disorder 
characterized by a pathologic process involving the central nervous system following any 
immune therapy that results in the activation or engagement of endogenous or infused 
T cells and/or other immune effector cells. Symptoms or signs can be progressive and 
may include aphasia, altered level of consciousness, impairment of cognitive skills, motor 
weakness, seizures, and cerebral edema. ICANS may occur with other cancer 
immunotherapies, including ACT. Cancer patients may also be at risk for ICANS 
symptoms due to other causes ranging from mild to moderate somnolence and confusion 
as a result of sedating medications, to seizures in relation to CNS tumors. The possible 
contribution of other medications, underlying disease and/or co-morbidities should be 
evaluated when considering a diagnosis of ICANS in relation to T-cell therapy. 
12.7.8.1. 
Grading of ICANS 
Lee et al. [Lee, 2019] have developed a new grading system for ICANS which 
incorporates the use of a modified version of the CARTOX 10-point neurological 
assessment tool termed Immune Effector Cell-Associated Encephalopathy (ICE) (Table 
10). Points are assigned for each of the tasks in Table 10, which are performed correctly. 
Normal cognitive function is defined by an overall score of 10. The ICE should be used 
to monitor all participants for ICANS. 


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Table 10 
ICE-Encephalopathy Assessment Tool for Grading of ICANS 
Task 
ICE Points 
Orientation to: year, month, city, hospital 
Total of 4 points (one point for each) 
Name three objects, for example point to: clock, pen, button 
Total of 3 points (one point for each) 
Follow simple commands (for example, “Show me 2 fingers” or “Close 
your eyes and stick out your tongue” 
1 point 
Write a standard sentence, e.g., ‘our national bird is the bald eagle’ 
1 point 
Count backwards from 100 in tens 
1 point 
Abbreviation:ICE = Immune Effector Cell-Associated Encephalopathy; ICANS= Immune Effector Cell-Associated 
Neurotoxicity Syndrome. 
Scoring: 10, no impairment; 7-9; grade 1 ICANS; 3-6, grade 2 ICANS; 0-2, grade 3 ICANS; 0 due to patient 
unarousable and unable to perform ICE assessment, grade 4 ICANS. 
 
The ICE score is used in grading of ICANS in adults as presented in Table 11.   
Table 11 
Grading of Immune Effector Cell-Associated Neurotoxicity 
Syndrome (ICANS)  
Neurotoxicity 
Domain  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE score 1 
7 to 9 
3 to 6 
0 to 2 
0 (Participant is unarousable 
and unable to perform ICE) 
Depressed level of 
consiousness 2 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to tactile 
stimulus 
Patient is unarousable or 
requires vigorous or repetitive 
tactile stimuli to arouse. Stupor 
or coma 
Elevated 
ICP/cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimaging 4 
Diffuse cerebral edema on 
neuroimaging; decerebrate 
or decorticate posturing; or 
cranial nerve VI 
palsy; or papilledema 3; or 
Cushing's triad 
Motor findings 5 
N/A 
N/A 
N/A 
Deep focal motor weakness 
such as hemiparesis or 
paraparesis 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves rapidly or 
nonconvulsive seizures 
on EEG 
that resolve with 
intervention 
Life-threatening prolonged 
seizure (>5 min); or 
Repetitive clinical or electrical 
seizures without 
return to Baseline in between 
1. See Table 10 for ICE. A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global 
aphasia, but a patient with an ICE score of 0 may be classified as grade 4 ICANS if unarousable. 
2. Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication) 
3. Papilloedema grading is performed according to the modified Frisén scale. 
4. Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded 
from ICANS grading.  
5. Tremors and myoclonus associated with immune effector cell therapies do not influence ICANS grading 
This table is based on Lee, 2019. 
ICANS= Immune Effector Cell-Associated Neurotoxicity Syndrome; ICE = Immune Effector Cell-Associated 
Encephalopathy; CSF = cerebrospinal fluid; ICP = Intracranial Pressure; N/A = not applicable. 
 


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12.7.8.2. 
Monitoring for Immune Effector Cell-Associated Neurotoxicity 
Syndrome (ICANS) 
Brain MRI (or CT Scan if MRI not feasible) must be obtained for all participants as part 
of leukapheresis eligibility screening. This should be repeated at Baseline prior to 
lymphodepletion in: 
• 
All participants with a history of CNS metastasis, and 
• 
In participants with no history of CNS metastasisif more than 3 months have elapsed 
between last brain MRI and the start of lymphodepletion or if they show neurological 
symptoms consistent with CNS metastasis. 
 
Brain MRI may be performed at other time points, if clinically indicated. 
ICE should be measured on the day of T-cell infusion prior to receiving treatment and 
then at least through Day 8 according to the SOA in individual substudies. If a participant 
is found to have ICANS, the ICE should be used at least twice per day until resolution or 
stable.  It can also be used at later visits if indicated. 
12.7.8.3. 
Management of ICANS 
The recommended management of ICANS should be based on toxicity grade. Table 12 
provides guidance on the management of ICANS and should be implemented in 
accordance with institutional guidelines.  
A neurology consultation should be obtained for all participants with ICANS for 
thorough neurological evaluation, and recommendations for further testing such as 
electroencephalogram (EEG) and neuroimaging as indicated.  
The following tests should be conducted every day for the first week and approximately 
every other day thereafter until symptoms are improving or an alternative diagnosis is 
confirmed: 
• 
Local tests: 
– Chemistry, hematology, ferritin, and coagulation, as well as C-reative protein 
(CRP) labs 
 
Per SITC 2020 guidelines: 
Across several trials, tocilizumab has failed to resolve symptoms of ICANS, despite 
alleviating severe CRS [Maus, 2020]. It remains to be determined whether targeting 
IL-6R in isolation during established CRS is insufficient to prevent subsequent 
neurotoxicity or if the lack of efficacy is due to tocilizumab’s inability to cross the 
blood-brain barrier. It has been postulated that tocilizumab may worsen ICANS and 
therefore an assessment of treatment priority may be required between the severity of 
CRS and ICANS. Alternative IL-6 blockade such as siltuximab or the IL-1 antagonist, 
anakinra, have been proposed as potential alternatives, but data are lacking on their safety 
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Corticosteroids have been successfully used for the management of ICANS and seizure 
prophylaxis has been implemented in some studies, but the ideal dose and duration have 
not yet been determined [Maus, 2020].  
Table 12 
Management of ICANS 
ICANS 
Grade 
Treatment 
1 
• Vigilant supportive care; aspiration precautions; IV hydration 
• Withhold oral intake of food, medicines, and fluids, and assess swallowing 
• Convert all oral medications and/or nutrition to IV or enteral tube if swallowing is impaired 
• Avoid medications that cause central nervous system depression 
• Evaluate for other contributing causes and treat accordingly 
• Neurology consultation including fundoscopic exam to assess for papilloedema 
• MRI of the brain with and without contrast (CT scan of the brain if MRI is not feasible).  Further testing 
if indicated and appropriate such as diagnostic lumbar puncture with measurement of opening 
pressure if increased intracranial pressure is suspected, or MRI of the spine if the participant has focal 
peripheral neurological deficits 
• Consider levetiracetam therapy and EEG if seizure activity is suspected 
• Consider anti‑IL‑6 therapy. Tocilizumab1 may worsen neurotoxicity. Management of neurotoxicity may 
take precedence over the management of low-grade CRS, but this does not apply to high-grade CRS. 
Alternative IL-6 blockade may be considered (e.g. siltuximab) or the IL-1 antagonist, anakinra. 
2 
• As described for Grade 1 PLUS 
• Consider ICU transfer 
• Consider corticosteroids2 
3 
• As described for Grade 1 & 2 PLUS 
• Corticosteroids are recommended 
• Stage 1 or 2 papilloedema with CSF opening pressure <20 mmHg should be treated corticosteroid 
regimen as per Grade 4 below. 
• Consider repeat neuroimaging (CT or MRI) every 2 to 3 days if participant has persistent Grade 3 
ICANS 
4 
• As described for Grade 1 & 2 & 3 PLUS 
• Consider neurosurgical consultation for participants with evidence of increased intracranial pressure 
• ICU monitoring; consider mechanical ventilation for airway protection 
1. Tocilizumab: 8mg/kg iv for patients weighing 30kg or above, administered over 1 hr, max dose 800 mg, doses at 
least 8 hrs apart. 
2. Consider dexamethasone 10 mg IV every 6 hrs (Grade ≤3 ICANS), or methylprednisolone 1 mg/kg IV every 24 hrs 
for 3 days (Grade 4 ICANS), if refractory to anti‑IL‑6 therapy, or for ICANS without concurrent CRS; once initiated 
continue corticosteroids for at least two doses until improvement to Grade 1 ICANS and then taper. 
Source: [Maus, 2020]. 
CRS = cytokine release syndrome; CSF = cerebrospinal fluid; CT = computed tomography; 
EEG = electroencephalogram; hrs = hours; ICANS = Immune Effector Cell-Associated Neurotoxicity Syndrome; 
ICU = intensive care unit; IL-6 = interleukin-6; IV = intravenous; MRI = magnetic resonance imaging. 
 
Grade 1 ICANS. Grade 1 ICANS is defined as a score of 7 to 9 on the ICE assessment in 
Table 11. A patient with grade 1 ICANS may have a delay in responses or disorientation 
to time or place, mild inattention with difficulty in counting numbers backwards, or 
impairment of handwriting. There may be drowsiness but patients awaken spontaneously, 
and when prompted, the patient should be able to complete most of the ICE assessment. 
Grade 1 ICANS may be seen during CRS waxing and waning with febrile episodes. 
Grade 2 ICANS. Grade 2 ICANS is defined as a score of 3 to 6 on the ICE assessment 
as presented in Table 11. Expressive aphasia is the most specific first sign of severe 


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neurotoxicity and early signs during grade 2 include paraphasic errors (the production of 
unintended syllables and words during attempts to speak) and verbal perseveration with 
patients repeating the same words over and over. Patients with grade 2 ICANS are able to 
communicate their needs but it is effortful. Patients may have depressed level of 
consciousness but are arousable to voice and the responses may be slowed. 
Grade 3 ICANS. Grade 3 ICANS is defined as a score of 0 to 2 on the ICE assessment 
as presented in Table 11. Patients with grade 3 ICANS have severe global aphasia and are 
not speaking or following commands even when wide awake and therefore may be 
unable to complete any of the ICE questions. Alternatively, they may have excessive 
drowsiness and need tactile stimulus to attend to examiner. Any clinical seizure whether 
simple partial, complex partial or generalized, and any electrographic seizures would also 
meet criteria for grade 3 ICANS. If neuroimaging shows new focal or local edema this 
would also be categorized as grade 3 ICANS. However, intracranial hemorrhage due to 
coagulopathy or other causes with or without associated edema is not considered a 
neurotoxicity feature and is excluded from ICANS grading. 
Grade 4 ICANS.  Grade 4 ICANS is defined as patients who have a score of 0 on the 
ICE assessment due to being unarousable and unable to perform the ICE assessment as 
presented in Table 11. Stupor and coma may be seen; the stuporous patient only responds 
by grimacing or drawing away from vigorous or repetitive tactile stimuli and the 
comatose patient is unarousable and/or unresponsive. This depressed level of 
consciousness should be attributable to no other cause (e.g., no sedating medication), 
which is often a complicating factor in sick patients with CRS. Some patients may 
require intubation for airway protection. In addition, any patient having prolonged or 
repetitive clinical or subclinical electrographic seizures without return to Baseline in 
between, or deep focal motor weakness such as hemiparesis or paraparesis would be 
considered to have Grade 4 ICANS. Patients with symptoms and signs of elevated ICP 
such as projectile vomiting with headache, depressed consciousness, cranial nerve VI 
palsies, papilledema, Cushing's triad of bradycardia, hypertension and respiratory 
depression, decerebrate or decorticate posturing, or diffuse cerebral edema on head 
imaging would also be considered to have grade 4 ICANS.  
Grade 5 ICANS. By convention, Grade 5 ICANS is defined as death due to ICANS 
where another cause is not the principle factor leading to this outcome. 
12.7.9. 
Chemotherapy Symptom Management 
Cyclophosphamide and fludarabine are used as conditioning chemotherapy in this study 
to cause lymphodepletion and facilitate expansion of the infused T cells. Symptoms 
associated with the use of cyclophosphamide and fludarabine are included in the product 
labels. Refer to the most current product labels, and substudy specific sections for details 
of prohibited medications. 
12.7.9.1. 
Management of Neutropenia 
The conditioning chemotherapy is intended to cause lymphodepletion. However, 
neutropenia is also common. Prophylactic use of G-CSF is recommended in all 
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according to ASCO guidelines [Smith, 2015]. G-CSF should be given starting ~24 hours 
after the administration of chemotherapy until resolution of neutropenia (reaching an 
ANC of at least 2 × 109/L to 3 × 109/L or as per institutional practice).  
Long-acting (pegylated) G-CSF may be given in preference to short acting daily G-CSF 
in accordance with institutional standard practice. Pegylated G-CSF will be given as one 
dose ~24 hours post the final dose of cyclophosphamide. 
12.7.10. 
Management of Guillan-Barré Syndrome (GBS) 
Please obtain a neurology consultation for all participants with signs or symptoms 
suggestive of GBS for thorough neurological evaluation, and for expert recommendations 
on further diagnostic workup including EMG, lumbar puncture, infectious panel to guide 
management and follow up. 
Case assessment for possible Guillain Barre Syndrome using diagnostic and 
prognostic tools supported by medical diagnosis and/or medical treatment 
 
*Please refer to algorithm for treatment described in Figure 6. 
Additional details specific to the neurology consultation are included in Appendix 8 
(Section 12.8). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral 
neuropathy 
Symptoms 
suggestive of 
GBS/AIDP 
Treatment according 
to guidelines/clinical 
practice 
GBS Diagnostic tool: 
Brighton Criteria 
At hospital admission 
Indicator of prognosis 
EGRIS tool 
At hospital 
admission* 
mEGOS tool 
At hospital admission and Day 7 
Yes 
Confirmatory assessment 
targeted within 7 days from 
hospital admission 
Suspected 
GBS 
Strength of diagnosis includes 
clinical assessment and CSF and 
NCV measures. Some tests may not 
be available until several days after 
hospital admission. 
• 
Confirmed GBS required to 
implement mEGOS.  
• 
At hospital admission (data 
that supports Brighton level 1 
or 2) may not be available.  
• 
Level 1 or 2 assessment 
required before mEGOS 
assessment i.e. Day 7 
Neurology 
consultation 


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


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• 
Age at onset 
• 
Preceding diarrhoea (in 4 weeks preceding onset of weakness) 
• 
Medical Research Council sum score 
 
12.7.10.5. Summary of Diagnosis and Treatment for GBS 
Additional information on the diagnosis and management of GBS (Figure 6) can be 
found in a review article on GBS [Willison, 2016].  
Figure 6 
Diagnosis and Treatment of Guillain-Barré Syndrome (GBS)  
 
Abbreviations: EGRIS = Erasmus GBS Respiratory Insufficiency Score; GBS = Guillain-Barré Syndrome; 
ICU = intensive care unit; IVIg = intravenous immunoglobulin; TRF = treatment related fluctuation. 
Source with permission: Willison, 2016. 
 


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12.8. 
Appendix 8: Neurology Consultation – Further Guidelines 
for Signs and Symptoms Suggestive of Guillain-Barré 
Syndrome 
For patients presenting with neurological events, a confirmed diagnosis of peripheral 
neuropathy should be treated according to local guidelines and/or clinical practice.  
However, any patient with presenting signs and symptoms suggestive of GBS (see 
protocol, Section 12.7.10.1), must be further evaluated by a neurologist according to 
diagnostic guidance for GBS using the Brighton diagnostic criteria (Fokke, 2014] see 
Table 13 below). The initial assessment at hospital admission should be further verified 
within 7 days of initial assessment, following availability of all test results as listed: 
Table 13 
Brighton Diagnostic Criteria 
Diagnostic Criteria 
Level of Diagnostic Certainty 
1 
2 
3 
4 
Bilateral and flaccid weakness of limbs 
+ 
+ 
+ 
 
Decreased or absent deep tendon reflexes in weak limbs 
+ 
+ 
+ 
 
Monophasic course and time between onset-nadir 12 hours to 
28 days 
+ 
+ 
+ 
 
CSF cell count <50/L 
+ 
+1 
- 
 
CSF protein concentration > normal value 
+ 
1 
- 
 
Nerve conduction study findings consistent with one of the 
subtypes of GBS 
+ 
 
- 
 
Absence of alternative diagnosis for weakness 
+ 
+ 
+ 
+ 
1. 
If CSF not collected or results not available, nerve conduction studies must be consistent with diagnosis of GBS 
(modified from Fokke, 2014). 
+ = present; - = absent;  = present or absent; GBS = Guillain-Barré Syndrome. 
 
12.8.1. 
Additional Assessments for Suspected GBS at Hospital 
Admission 
12.8.1.1. 
Risk of Respiratory Insufficiency Assessment 
An assessment of the probability of risk of respiratory insufficiency during the first week 
following admission of suspected GBS is required using the Erasmus GBS Respiratory 
Insufficiency Score (EGRIS) tool (total score 0 to 7) [Walgaard, 2010]. 
Please access link to assessment tool and record total score in eCRF. 
https://qxmd.com/calculate/calculator_527/erasmus-gbs-respiratory-insufficiency-score-
egris 
Assessment at hospital admission to include: 
• 
Days of onset of weakness and admission  
• 
Facial and/or bulbar weakness at admission  


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• 
Medical Research Council score  
 
The Medical Research Council score includes assessment for 6 muscle groups, 
including shoulder abductors, elbow flexors, wrist extensors, hip flexors, knee extensors, 
and foot dorsiflexors on both sides. The MRC score of an individual muscle group range 
from 0 to 5: 
Assessment 
Score 
No visible contraction 
0 
Visible contraction without movement of the limb 
1 
Active movement of the limb, but not against gravity 
2 
Active movement against gravity over (almost) the full range 
3 
Active movement against gravity and resistance 
4 
Normal 
5 
Source: [Van Koningsveld , 2007]. 
The MRC total scores range from 60 (normal) to 0 (quadriplegic). The total score should 
be included in the eCRF assessment for EGRIS. 
12.8.1.2. 
Prognostic Tool for Assessment of GBS Outcome at Hospital 
Admission 
An assessment of prognosis using the modified Erasmus GBS Outcomes Score 
(mEGOS) (total score 0 to 9) for diagnosed cases of GBS [Walgaard, 2011] should also 
be performed. Early assessment following hospital admission includes assessment of the 
following: 
• 
Age (years) at onset:  ≤ 40, 41 – 60, > 60 
• 
Preceding diarrhoea (in 4 weeks preceding onset of weakness): absent/present 
• 
MRC sum score (see above): 0 – 30, 31 - 40, 41 – 50, 51 – 60 
 
Please access link to assessment tool and record total score in eCRF. 
https://qxmd.com/calculate/calculator_529/modified-erasmus-gbs-outcome-score-egos-
at-day-7-of-admission 
12.8.2. 
Assessments Post Hospital Admission for GBS 
12.8.2.1. 
Brighton Criteria 
The initial assessment at hospital admission should be further verified within 7 days of 
initial assessment, following availability of all test results. 


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12.8.2.2. 
Prognostic Tool for Assessment of GBS Outcome at Day 7 Post 
Hospital Admission 
An assessment of prognosis using the modified Erasmus GBS Outcomes Score 
(mEGOS) (total score 0 to 9) for diagnosed case of GBS [Walgaard, 2011]. Assessment 
following Day 7 hospital admission includes assessment of the following: 
• 
Age (years) at onset:  ≤ 40, 41 – 60, > 60 
• 
Preceding diarrhoea (in 4 weeks preceding onset of weakness): absent/present 
• 
MRC sum score (see above): 0 – 30, 31 - 40, 41 – 50, 51 – 60 
 
Please access link to assessment tool and record total score in eCRF. 
https://qxmd.com/calculate/calculator_529/modified-erasmus-gbs-outcome-score-egos-
at-day-7-of-admission 
• Brighton criteria - the initial assessment at hospital admission should be further 
verified within 7 days of initial assessment, following availability of all test results. 


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
1 2 4  
C or e  
 
 
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y t hir d p art y 
c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


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12.10. 
Appendix 10: mTPI-2 Design Simulation Results 
Simulations on the mTPI-2 design were conducted assuming either a 10% or 20% 
toxicity rate for the low dose (0.1 × 109 – 0.8 × 109 transduced T cells) and a 10%, 20%, 
30%, or 40% toxicity rate for the high dose (1 × 109 – 8 × 109 transduced T cells). The 
maximum tolerated dose is defined as the dose with DLT rate of 30%. The simulation 
results are shown in the tables below which demonstrates that mTPI-2 is a robust study 
design under all scenarios.   
Table 14 shows the results of the simulation. Based on the preclinical evidence and 
observed GSK3337794 toxicity data, we assume the moderate (20%) or borderline (30%) 
high dose toxicities are the most likely scenarios for GSK3901961 & GSK3845097. For 
these scenarios, highlighted in bold, we see that average observed toxicity rate is very 
close to the true underlying rate for the high dose and lower than the true underlying rate 
for the low dose. The average number of participants who experienced DLTs at the high 
dose is less than 2 out of an average of 8 participants when there is a borderline toxicity 
rate and less than 2 out of an average of 7 participants if there is a moderate toxicity rate. 
These results support our claim that the chosen design will be protective against over 
dosing. Additionally, the maximum tolerated dose is chosen >91% of the time when there 
is a moderate toxicity rate in the high dose and >76% of the time when there is a 
borderline toxicity rate in the high dose, which shows that the design is robust in 
correctly choosing the correct MTD under different underlying dose-DLT rate models. 
Table 14 
Design Simulation Results 
True DLT 
rates 
Low: 0.1 
High: 0.1 
Low: 0.1 
High: 0.2 
Low: 0.1 
High: 0.3 
Low: 0.1 
High: 0.4 
Low: 0.2 
High: 0.2 
Low: 0.2 
High: 0.3 
Low: 0.2 
High: 0.4 
Average Observed Toxicity Rate 
Low Dose 
0.07 
0.09 
0.09 
0.09 
0.17 
0.18 
0.18 
High Dose 
0.10 
0.20 
0.30 
0.42 
0.20 
0.31 
0.43 
Average Number of DLTs 
Low Dose 
0.02 
0.08 
0.17 
0.30 
0.17 
0.37 
0.62 
High Dose 
0.60 
1.23 
1.90 
2.55 
1.21 
1.82 
2.42 
Average Sample Size 
Low Dose 
0.15 
0.76 
1.74 
2.94 
0.86 
1.88 
3.14 
High Dose 
6.02 
6.13 
6.30 
6.36 
6.04 
6.07 
6.03 
Total Dosed 
6.17 
6.89 
8.04 
9.29 
6.90 
7.95 
9.17 
Percent picked as Maximum Tolerated Dose (MTD) 
No Dose 
0.00 
0.00 
0.00 
0.00 
0.01 
0.02 
0.02 
Low Dose 
0.01 
0.07 
0.21 
0.42 
0.09 
0.22 
0.42 
High Dose 
0.99 
0.93 
0.79 
0.58 
0.91 
0.76 
0.55 
 


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12.11. 
Appendix 11: Abbreviations and Trademarks 
1L 
First line 
2L 
Second line 
ABW 
Adjusted body weight 
ACT 
Adoptive T-cell therapy 
AE 
Adverse event 
AESI 
Adverse events of special interest 
AIDP 
Acute inflammatory demyelinating polyneuropathy 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATG 
Antithymocyte globulin 
AUC(0-t) 
Area under the concentration-time curve over the dosing interval 
BUN 
Blood urea nitrogen 
CA 
Competent Authority 
CAR 
Chimeric antigen receptor 
CBC 
Complete blood count 
CD3/CD4/CD8 
Cluster of differentiation 3/ cluster of differentiation 4/ cluster of 
differentiation 8 
CDC 
Center for Disease Control 
CFR 
Code of federal regulations 
cfDNA 
Cell-free DNA 
CI 
Confidence Interval 
CIOMS 
Council for international organizations of medical sciences 
CKD-EPI 
Chronic kidney disease epidemiology collaboration 
cm 
Centimetres 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration; 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CONSORT 
Consolidated standards of reporting trials 
CPD 
Confirmed progression 
CPK 
Creatine phosphokinase 
CR 
Complete response 
CRES 
CAR T-cell related encephalopathy syndrome 
CRF 
Case report form 
CRP 
C-reactive protein 
CRS 
Cytokine release syndrome 


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 2 7  
C or e  
 
C S R  
Cli nical st u d y re p ort  
C T  
C o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n ter mi n ol o g y criteria f or a d verse e ve nts  
ct D N A  
Circ ulati n g t u m or D N A  
C T F G  
Cli nical Trial Facilitati o n Gr o u p  
C V  
Car di o vasc ular  
D  
Da y  
d L  
Decilitre  
 
 
D L C O  
Diff usi n g ca p acit y of t he l u n g f or car b o n m o n o xi de  
D N A  
De o x yri b o n ucleic aci d  
D O R  
D urati o n of res p o ns e  
E B V  
E pstei n -Barr vir us  
E C G  
Electr ocar di o gra m(s)  
E C H O  
Ec h ocar di o gra p h y  
e C O A  
electr o nic Cli nical O utc o me Assess me nt  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
Electr o nic case re p ort f or m  
E D T A  
Et h yle ne di a mi netetraacetic aci d  
E M A  
E ur o pea n Me dici nes A ge nc y  
E M G  
Electr o m y o gra p h y  
E O T  
E n d of treat me nt  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F D G -P E T  
Fl u or o de o x y gl uc os e p ositr o n e missi o n t o m o gra p h y  
F E V 1  
F orce d e x pirat or y v ol u me i n 1 sec o n d  
F F P E  
F or mali n -fi x e d paraffi n-e m be d de d  
F S H  
F ollicle sti m ulati n g h or m o ne  
F V C  
F orce d vital ca p acit y  
G B S  
G u illai n-Barr é S y n dr o me  
G C L P  
G o o d cli nical la b orat or y practice  
G C P  
G o o d cli nical practice  
G -C S F  
Gra n ul oc yte c ol o n y -sti m ulati n g fact or 
G F R  
Gl o mer ular filtrati o n rate  
GI  
Gastr oi ntesti nal  
G S K  
Gla x os mit h kli ne  
G v H D  
Graft vers us h ost disease  
H b  
Hae m o gl o bi n  
H B V  
He patitis B vir us  
H Bs A g  
He patitis B s urface a nti ge n  
H bc A b  
He patitis B c ore a nti b o d y  
h C G  
h u ma n c h ori o nic g o na d otr o pi n  
H C V  
He patitis C vir us  
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 2 8  
C or e  
 
HI P A A  
Healt h i ns ura nce p orta bilit y a n d acc o u nta bilit y act  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H L A  
H u ma n le u k oc yte a nti ge n  
hr  
H o ur  
H R T  
H or m o ne re pl ace m e nt t hera p y 
H T L V  
H u ma n T -l y m p h otr o pi c vir us 
I B 
I n v esti gat or’s br oc h ure 
I B W 
I d eal B o d y Wei g ht 
I C A N S 
I m m u ne Effect or Cell-Ass ociate d Ne ur ot o xicit y S y n dr o me  
I C E 
I m m u ne Effect or Cell-Ass ociate d E nce p hal o pat h y  
I C F 
I nf or me d c o ns e nt f or m 
I C H 
I nter nati o nal c o u n cil o n har m o nizati o n of tec h nical re q uire m e nts 
f or re gistrati o n of p h ar m ace uticals f or h u ma n use 
i C P D 
i R E CI S T c o nfir me d pr o gressi ve diseas e 
i C R 
i R E CI S T c o m plete res p o nse 
I E C 
I n d e pe n de nt et hics c o m mittees 
I F N 
I nterfer o n 
I F N 
I nterfer o n, ga m ma 
I g G 
I m m u n o gl o b uli n G 
I L 
I nterle u ki n 
I L-1 R  
I nterle u ki n-1 Rece pt or  
I N R 
I nter nati o nal n or malize d rati o 
 
 
i P R 
i R E CI S T pr o gressi ve dis ease 
ir A Es 
I m m u ne-relat e d A Es 
I R B 
I nstit uti o nal re vie w b o ar d 
i R E CI S T 
M o difie d R E CI S T  1. 1 f or i m m u ne -base d t hera pe utics  
i S D 
i R E CI S T sta ble disease 
I T T 
I nte nt t o treat 
I U D 
I ntr a uteri ne de vice  
i U P D 
i R E CI S T u nc o nfir me d pr o gressi ve diseas e 
I U S 
I ntr a uteri ne h or m o ne-rel easi n g s yst e m 
I V 
I ntr a ve n o us 
I V D 
I n vitr o c o m pa ni o n dia g n ostic de vice 
k g  
Kil o gra ms  
L A M  
Lactati o nal a me n orr h oea met h o d  
L D H  
Lactate d e h y dr o ge n ase  
L T F U  
L o n g -t er m f oll o w-u p  
m 2  
Meters s q uare d  
m A b  
M o n ocl o nal a nti b o d y  
M C H  
Mea n c or p us c ular h ae m o gl o bi n  
M C V  
Mi x e d cell v ol u me  
C C
I


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MCE 
Multi-component engineering 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram 
mITT 
Modified Intent to treat 
mL 
Millilitre 
L 
Microliter 
mm 
Millimetres 
MRCLS 
Myxoid/round cell liposarcoma 
MRI 
Magnetic resonance imaging 
MSDS 
Material Safety Data Sheet 
mTPI-2 
Modified Toxicity Probability Interval 2 
MUGA 
Multigated acquisition scan 
NA 
Not applicable 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NIH 
National Institutes for Health 
NSAIDs 
Nonsteroidal anti-inflammatory drugs 
NSCLC 
Non-small-cell lung cancer 
NSCLC-SAC 
Non-small-cell lung cancer Symptom Assessment Questionnaire 
NY-ESO-1 
New York esophageal antigen-1 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell 
PCI 
Potential clinical importance 
PCP 
Pneumocystis carinii Pneumonia 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD-1 
Programmed death receptor-1 
PD-L1 
Programmed cell death ligand 1 
PD-L2 
Programmed cell death ligand 2 
PFS 
Progression-free survival 
PFT 
Pulmonary function test 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR 
Partial response 
PS 
Performance status 
PT 
Prothrombin time 
QTc 
Corrected QT interval duration 
QTcB 
QT duration corrected for heart rate by Bazzetts’s formula 
QTcF 
QT duration corrected for heart rate by Fridericia’s formula 
RBC 
Red blood cell 


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Pr ot o c ol A m d 0 4  
 
1 3 0  
C or e  
 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R T -q P C R  
Re verse tr a nscri ptase p ol y m erase c hai n reacti o n  
R N A  
Ri b o n ucleic aci d  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical A nal ysis Pla n  
S C T  
Ste m cell tra ns pla nt  
S D  
Sta ble disease  
S G O T  
Ser u m gl uta mic o x al oacetic tra nsa mi nase  
S G P T  
Ser u m gl uta mic p yr u vi c tra nsa mi nase  
S O A  
Sc he d ule of ass ess me nts  
S o C  
Sta n dar d of care  
S R M  
St u d y refere n ce ma n ual  
S R T  
Safet y R e vie w  Tea m  
S S  
S y n o vial sarc o ma  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o ns  
T 4  
T h yr o xi ne 4  
T C R  
T -cell rece pt or  
T G F  
Tra nsf or mi n g gr o wt h fact or  
T L C  
T otal l u n g ca pacit y  
T L Ts  
Treat me nt Li miti n g T o xicities  
T ma x  
Ti me t o ma xi m u m c o nce ntrati o n  
T M B  
T u m or m utati o nal b ur de n  
T M D D  
Tar get -me di ate d dr u g dis p ositi o n  
T M E  
T u m or micr oe n vir o n me nt  
T N F  
T u m or necr osis fact or  
T S H  
T h yr oi d sti m ulati n g h or m o ne  
 
 
U L N  
U p per li mit of n or mal  
U P D  
U nc o nfir me d pr o gressi o n  
 
 
W  
Wee k  
W B C  
W hite bl o o d cell  
W H O  
W orl d healt h or ga nizati o n  
W O C B P  
W o ma n of c hil d beari n g p ote ntial  
 
C CI
C CI
C CI


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Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
ADVAIR 
 
Chiron RIBA 
 
 
MedDRA 
 
 
SAS 
 
 
WinNonlin 
 
 


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12.12. 
Appendix 12: List of Substudies 
Substudy 
Number 
Substudy Title 
GSK number 
Anticipated 
number of 
participants 
Indications 
Countries where substudy 
will be active 
1 
GSK3901961 [NY-ESO-1(c259)TCR engineered T cells co-
expressing the α-chain of the CD8 co-receptor] in previously 
treated (2L+) HLA-A*02+ participants with NY-ESO-1 and/or 
LAGE-1a advanced SS, MRCLS, or NSCLC 
GSK3901961 
29 
SS, NSCLC, MRCLS 
Australia, Canada, 
Germany, Netherlands, 
Sweden, USA,  
2 
GSK3845097 [NYESO-1(c259) TCR engineered T cells co-
expressing the dnTGF-βRII receptor] in previously treated (2L+) 
HLA-A*02+ participants with NYESO-1+ and/or LAGE1a+ advanced 
SS or MRCLS 
GSK3845097 
19 
SS, MRCLS 
Australia, Canada, 
Germany, Netherlands, 
Sweden, USA, 
3 
GSK4427296 [NYESO-1(c259) TCR engineered T cells using the 
Epi-R manufacturing process] in previously treated (2L+) HLA-
A*02+ participants with NYESO-1+ and/or LAGE1a+ advanced SS 
or MRCLS 
GSK4427296 
19 
SS, MRCLS 
USA only 
Overall projected sample size 
67 
SS, NSCLC, MRCLS 
 


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12.13. 
Appendix 13: Master Protocol Document History  
DOCUMENT HISTORY 
Original protocol and all amendments listed in reverse chronological order. 
Master Protocol Format 
Amended Documents* 
Amendment Number 
Date 
Document Number 
Master Protocol  
split into separate documents 
Core Protocol 
Amendment 4 
27 May 2022 
 
TMF-14682560 
Substudy 1 
TMF-14682591 
Substudy 2 
TMF-14682598 
Substudy 3 
TMF-14682622 
Core Protocol 
Amendment 3 
20-December-2021 
TMF-14357914 
Substudy 1 
TMF-14357929 
Substudy 2 
TMF-14357930 
Substudy 3 (new) 
TMF-14357932 
Master Protocol  
as single document 
Master Protocol with 3 sections:  
Core, Substudy 1 and Substudy 2 
Amendment 2 
04-November-2021 
TMF-14137790 
Amendment 1 
21-May-2021 
TMF-13779299 
Original Protocol 
02-December-2019 
2019N419717_00 
*  The most current version of each document is in bold and underlined. 
 


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13. 
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. 
13.1. 
Amendment 1 (21 May 2021) 
Overall Rationale for Amendment 1: 
The primary rationale for protocol Amendment 1 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. 
 


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 3 5  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
C ore pr ot o c ol  
1.  Sy n o psis  
4.  O bj ectiv es a n d E n d p oi nts  
R ef or m att e d S ec o n d ary O bj ectiv es a n d 
E n d p oi nts i nt o “ Sec o n d ary –  Effic acy”, 
“ S ec o n d ary –  Saf ety” a n d “ Sec o n d ary –  
P h ar m ac oki n etics”.  
C o m bi n e d Fr e q u e ncy a n d s ev erity of 
A dv ers e Ev e nts ( A Es), S eri o us A Es ( S A Es) 
a n d A Es of Sp eci al I nt er est ( A E SIs) as o n e 
si n gl e e n d p oi nt. 
O pti miz e d d escri pti o n of Sec o n d ary –  
P h ar m ac oki n etics o bj ectiv es a n d 
e n d p oi nts.  
U p d at e d list of  a b br evi ati o ns.  
T o cl arify s u bc at e g ori es of s ec o n d ary 
o bj ectiv es.  
 
 
St a n d ar diz ati o n of r e p orti n g.  
 
 
 
Cl arific ati o n of Ph ar m ac oki n etics 
pl a n.  
 
Fi n aliz ati o n of t a bl e.  
1.  Sy n o psis  
5.  D esi g n  
 
Mi n or u p d at e t o st u dy sc h e m a:  
- 
T o st a n d ar diz e d esi g n at e d p o p ul ati o ns 
as p artici p a nts wit h r el a ps e d/r efr act ory 
a dv a nc e d t u m ors.  
- 
T o st a n d ar diz e d esi g n at e d S S 
p o p ul ati o n i n S u bst u di es 1 a n d 2 as 
p artici p a nts wit h “ m et ast atic or 
u nr es ect a bl e” S S.  
- 
T o st a n d ar diz e d esi g n at e d  
N S C L C p o p ul ati o n i n Su bst u dy 1 as 
p artici p a nts wit h “ m et ast atic” N S C L C.  
H ar m o niz ati o n of p o p ul ati o n 
d esi g n ati o ns t hr o u g h o ut pr ot oc ol.  
1.  Sy n o psis  
5.  D esi g n  
 
I ncl usi o n of d et ail e d d escri pti o n of 
P artici p a nt J o ur n ey, i n ali g n m e nt wit h 
Fi g ur e 1 P artici p a nt J o ur n ey Sc h e m a.  
I ncl usi o n of pr ovisi o n f or all o wi n g t ar g et 
ex pr essi o n scr e e ni n g t ests, l e uk a p h er esis 
a n d m a n uf act ur e t o b e c o n d uct e d u n d er 
s e p ar at e G S K-s p o ns or e d pr ot oc ol or 
s u bst u dy of t his pr ot oc ol. 
Cl arific ati o n of Partici p a nt J o ur n ey 
st e ps.  
 
T o f acilit at e pr e -scr e e ni n g ( ev e nt u ally 
p erf or m e d i n ot h er pr ot oc ols), a n d t o 
all o w f or r e -all oc ati o n of p artici p a nts 
o nt o ot h er s uit e d 
pr ot oc ols/s u bst u di es w h e n av ail a bl e.  
1.  Sy n o psis  
5.  D esi g n  
O pti miz ati o n of Tr e at m e nt Fit n ess a n d 
Eli gi bility crit eri a pri or t o Ly m p h o d e pl eti o n  
R e m ov e d r e q uir e m e nt f or r e p etiti o n 
of all eli gi bility crit eri a ass ess m e nts 
t h at w er e alr e a dy m et pri or t o 
l e uk a p h er esis. R e pl ac e d by a 
Tr e at m e nt Fit n ess ass ess m e nt of t h e 
s af ety crit eri a i n c o ns ult ati o n wit h 
M e dic al M o nit or.  
3. 2 B ack gr o u n d  
3. 2. 2  G S K 3 3 7 7 7 9 4 
(l et etr es g e n e a ut ol e uc el, 
l et-c ell) 
R e m ov e d t a bl e of G S K3 3 7 7 7 9 4  
Cli nic al st u di es.  
T o r ef oc us b ack gr o u n d s ecti o n a n d 
i m pr ov e r e a d a bility of d oc u m e nt. 
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 3 6  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
5. 1.  Ov er all D esi g n  
I ncl u d e d r ef er e nc e t o d efi niti o n of s e nti n el 
p artici p a nt as t h os e t o r ec eiv e s plit d osi n g 
p er C or e S ecti o n 8. 1. 2.  
T o b ett er i ntr o d uc e w h at a s e nti n el 
p artici p a nt is.  
5. 3.  N u m b er of P artici p a nts  
Cl arific ati o n of pr oj ect e d n u m b er of 
p artici p a nts ( 4 8) ex p ect e d f or d os e 
c o nfir m ati o n a n d ex p a nsi o n i n Su bst u di es 1 
a n d 2 c o m bi n e d.  
Cl arifi e d s a m pl e siz e pr oj ecti o n.  
6. 2.  Scr e e ni n g u n d er ot h er 
G S K st u di es ( n e w s ecti o n 
a d d e d)  
P artici p a nts scr e e n e d or e nr oll e d i n ot h er 
G S K st u di es m ay b e c o nsi d er e d f or 
e nr oll m e nt t o t his st u dy, w h er e it is I R B/I E C 
a p pr ov e d, o n a c as e -by -c as e sc e n ari o. 
T o all o w f or  t ar g et ex pr essi o n 
eli gi bility of p artici p a nts scr e e n e d 
u n d er ot h er G S K st u di es u n d er 
i d e ntic al t esti n g c o n diti o ns 
6. 3.  R escr e e ni n g/ Tr a nsf er 
( n e w s ecti o n a d d e d)  
P artici p a nts w h o w er e scr e e n f ail ur e / 
wit h dr a w n pri or t o T -c ell a d mi nistr ati o n m ay 
b e r escr e e n e d i n t h e s a m e st u dy/s u bst u dy 
or tr a nsf err e d t o a ny a p plic a bl e G S K -
s p o ns or e d st u dy or s u bst u dy of t his 
pr ot oc ol.  
R escr e e ni n g, l e uk a p h er esis pr oc e d ur e or 
m a n uf act ur e pr oc ess m ay b e w aiv e d aft er 
c o ns ult ati o n wit h Sp o ns or. 
T o all o w f or r e -all oc ati o n of 
p art ici p a nts o nt o ot h er s uit e d 
pr ot oc ols/s u bst u di es w h e n av ail a bl e, 
a n d f or t h e p ossi bility of ski p pi n g 
st e ps t h at h av e alr e a dy b e e n 
c o m pl et e d u n d er t h e ori gi n al 
c o m p ar a bl e pr ot oc ol, aft er 
c o ns ult ati o n wit h Sp o ns or. 
8. 1.  Disc o nti n u ati o n of 
St u dy I nt erv e nti o n  
8. 1. 1  Si n gl e D os e 
A d mi nistr ati o n  
I ntr o d uc e d r ef er e nc es f or d os e 
a d mi nistr ati o n, s af ety ass ess m e nt a n d 
m o nit ori n g, f or r e p orti n g of A Es, a n d 
s u p p ortiv e c ar e g ui d a nc e. 
I ncl u d e d i nstr ucti o ns f or r es u mi n g i nf usi o n 
w h e n i nf usi o n -r el at e d r e acti o n Gr a d e ≤2 
r es olve d t o Gr a d e < 1.  
Ad d e d r ef er e nc es f or si n gl e d os e 
a d mi nistr ati o n a n d i nstr ucti o ns f or 
p ot e nti al r es u mi n g c o n diti o ns aft er 
i nf usi o n-r el at e d r e acti o n. 
8. 2. 3.  T e m p or ary 
Disc o nti n u ati o n  
A d dr essi n g s ev er e r e acti o ns ass oci at e d 
wit h liv er t oxiciti es i n b et w e e n t h e 2 s plit 
d os es i nf usi o n.  
Cl arific ati o n of i nstr ucti o ns.  
9. 1. 2.  G S K S af ety R evi e w 
T e a m  
M a n d at e d St u dy P a us e 
D u e t o G B S  
P ar a gr a p h o n M a n d at e d St u dy P a us e D u e 
t o G B S r e m ov e d b ec a us e r e d u n d a nt wit h 
S ecti o n 8. 5.  
R e m ov e d r e d u n d a ncy.  
9.  St u dy Ass ess m e nts a n d 
Pr oc e d ur es  
9. 1. 5.  Vit al Si g ns  
Cl arifi e d t h at bl o o d pr ess ur e, p uls e 
m e as ur e m e nts, r es pir at ory r at e a n d b o dy 
t e m p er at ur e s h o ul d b e ass ess e d by 
i nstit uti o n al st a n d ar ds. 
O pti miz e d w or di n g t o m ak e t h e or d er of 
ass ess m e nts b et w e e n vit al si g ns, E K G a n d 
bl o o d dr a w s a r ec o m m e n d ati o n r at h er t h a n 
a r e q uir e m e nt.  
Will all o w sit es t o us e l oc al 
i nstit uti o n al g ui d a nc e.  
9. 1. 6 C ar di ac Ass ess m e nts  
A d diti o n of s er u m tr o p o ni n a n d N -t er mi n al 
pr o B -ty p e n atri ur etic p e pti d e ( N T-pr o B N P) 
/ B N P t ests 
Ad diti o n of c ar di ac  
 t ests as 
p art of r e q uir e d b as eli n e visit 
ass ess m e nts  
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 3 7  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
9. 2.  A dv ers e Ev e nts a n d 
S eri o us A dv ers e Ev e nts  
U p d at e d d efi niti o n of D el ay e d A Es t o ali g n 
wit h u p d at e d F D A g ui d a nc e [ F D A, 2 0 2 0 a].  
I ncl u d e d Fi g ur e 3 Ti m e P eri o d f or 
C oll ecti n g A E a n d S A E I nf or m ati o n as 
vis u al ai d t o f oll o w A E/ S A E r e p orti n g 
i nstr ucti o ns 
Cl arify t h at A E SIs will b e r e p ort e d t o t h e 
S p o ns or ( M e dic al M o nit or or d es i g n e e) 
wit hi n 2 4 h o urs vi a e -m ail (s e e S R M f or 
f urt h er i nstr ucti o ns. 
U p d at e d d efi niti o ns of 6 c at e g ori es of 
d el ay e d A Es p er F D A.  
H ar m o niz e d c o m m u nic ati o n o n 
A E/ S A E c oll ecti o n.  
 
Cl arific ati o n of A E SI r e p orti n g 
i nstr ucti o ns. 
9. 2. 5.  Pr e g n a ncy  
Cl arifi e d c o ntr ac e pti o n p eri o d d ur ati o n t o 
s p ecify a mi ni m u m of 1 2 m o nt hs fr o m st art 
of T -c ell i nf usi o n. 
I ncl u d e d a d diti o n al c o ntr ac e pti o n 
r e q uir e m e nts a p plic a bl e t o t h e us e of 
fl u d ar a bi n e a n d cycl o p h os p h a mi d e 
c h e m ot h er a pi es. 
A d d e d i nstr ucti o n t o I nv esti g at or t o a dvis e 
p artici p a nts o n t h e c o ns erv ati o n of s p er m 
pri or t o i niti ati n g tr e at m e nt.   
F or p artici p a nts w h o h av e p ersisti n g 
G S K 3 3 7 7 7 9 4 b ey o n d 1 2 m o nt hs p ost 
i nf usi o n: o nc e p ersist e nc e t est r es ults s h o w 
b el o w l ev el of d et ecti o n f or 2 c o ns ec utiv e 
ti m es, S p o ns or will n otify t h e sit e t h at 
c o ntr ac e pti o n p eri o d r e q uir e m e nt is ov er. 
Cl arific ati o n of c o ntr ac e pti o n 
r e q uir e m e nts. 
9. 2. 7   A dv ers e Ev e nts of 
S p eci al I nt er est ( A E SIs)  
A d d e d i nstr ucti o ns f or Gr a d e 3 or hi g h er 
A E SI of Gv H D t o  b e als o r e p ort e d as a n 
S A E wit hi n 2 4 h o urs.  
U p d at e d i nstr ucti o ns.  
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Section # and Name 
Description of Change 
Brief Rationale 
9.3.1 Evaluation of Anti-
Cancer Activity 
Clarification that in cases where contrast 
enhanced CT is contraindicated, a 
Magnetic Resonance Imaging (MRI) of the 
abdomen/pelvis (with and without 
gadolinium contrast), and an MRI (with and 
without gadolinium contrast) or a non-
contrast enhanced CT of the chest is 
acceptable.  
Clarification of imaging modalities.   
9.10.1. Tumor Biopsy 
Clarification of time points for biopsy 
collections (Baseline, Week 4 and 
progression). 
Wording optimization.  
9.10.9. Genetic Blood 
Sample (section added) 
Section added 
Added clarification on genetic 
analysis plan. 
10.4. Populations for 
Analyses 
- 
Screened Population was amended to 
include “All participants who signed an 
ICF to participate in the study” 
- 
Enrolled and Intent-To-Treat (ITT) 
populations were amended to the 
same definition of  “All participants who 
started leukapheresis procedure” 
- 
Modified Intent-To-Treat (mITT) 
population was amended to include  
“All participants who received any dose 
of NY-ESO-1 specific T cells” 
Optimization and harmonization of 
Populations for analyses:at program 
level. 
12.1.10 Remote Monitoring 
and Source Data 
Verification 
Addition of provision that when onsite 
monitoring is not permissible due to 
site/local restrictions (such as with epidemic 
and/or pandemic), remote monitoring may 
be employed that ensures all of the 
following requirements are met 
Clarification on remote monitoring.  
12.2. Appendix 2: Clinical 
Laboratory Tests 
Specified that for Clinical Chemistry BUN, 
both BUN or UREA tests are acceptable. 
Addition of Fibrinogen as part of the 
Coagulation test requirements 
Addition of Ferritin, serum troponin,  
NT-proBNP / BNP as part of the Other 
Tests. 
Clarification of laboratory tests. 
12.4.2 Contraception 
guidance 
Added potential risks to fetus linked to 
treatment with fludarabine and 
cyclophosphamide. 
Added risk that cyclophosphamide 
treatment may result in partial or total 
sterility in male participants.   
To clarify risks to fetus and to male 
sterility linked to treatment with 
lymphodepleting chemotherapy 
regimen in response to regulatory 
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Brief Rationale 
12.7.5. Management of 
Cytokine Release 
Syndrome (CRS) 
Addition of monitoring requirement for 
suspected CRS, with chemistry, 
hematology, ferritin, coagulation, C reactive 
protein, troponin and NT-proBNP / BNP 
labs. 
Addition of monitoring requirement on left 
ventricular ejection fraction for suspected 
CRS. 
Clarified posology for tocilizumab and 
alternative options for participants not 
responding to tocilizumab. 
Additions of monitoring requirements 
for CRS according to SITC 2020 
guideline on immune effector cell-
related adverse events. 
12.7.8. Management of 
Immune Effector Cell-
Associated Neurotoxicity 
Syndrome (ICANS) 
Clarification that Brain MRI must be taken 
at screening and repeated at baseline if 
more than 4 months have elapsed between 
screening MRI and baseline. 
Addition of monitoring requirement for 
suspected ICANS, with chemistry, 
hematology, ferritin, coagulation, and 
C-reactive protein labs. 
Clarification of ICANS management table 
Addition that tocilizumab may worsen 
ICANS in some situations. 
Clarification on Brain MRI 
requirements for reference 
assessments. 
 
Additions of monitoring requirements 
for ICANS according to SITC 2020 
guideline on immune effector cell-
related adverse events. 
12.7.10. Management of 
Guillain-Barré Syndrome 
(GBS) 
12.8 Appendix 8: Neurology 
Consultation – Further 
Guidelines for Signs and 
Symptoms Suggestive of 
Guillain-Barré Syndrome 
(new) 
Added cross reference to new Appendix 8 
for Neurology Consultation. 
Added Appendix 8 for further guidelines for 
Signs and Symptoms Suggestive of 
Guillain-Barré Syndrome (GBS) 
To clarify diagnosis of GBS. 
12.7.2.2 Herpex Simplex 
and Varicella Zoster and 
Epstein Barr virus (EBV) 
 
12.7.2.4 Hepatitis B 
prophylaxis 
Clarified that prophylaxis for herpex simplex 
and varicella zoster should be initiated prior 
to lymphodepletion. 
Clarified that additional considerations on 
Hepatitis B prophylaxis (acceptable 
regimens included) will be left to the 
Investigator’s discretion in accordance with 
label recommendations and institutional 
guidelines. 
To clarify Infection prophylaxis 
language. 


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Description of Change 
Brief Rationale 
Substudy 1 
2.  Schedule of activities 
Table 1. Substudy 1 
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 8. 
Footnote #4 clarifies that optional Genetics 
sample “may be collected any time from 
signature of optional consent until 
leukapheresis”. 
Footnote #9 clarifies that “CD3 count prior 
to leukapheresis should preferably be 
performed with 24 hours prior to 
leukapheresis procedure”. 
Footnote #10 aligns with Core Protocol 
Section 9.1.5 on Vital Signs collection, 
allowing institutional standard methods for 
collection. 
Footnote #17 added to reference details of 
renal assessment in Substudy 1 
Section 6.1 Table 9. 
Clarification and alignment of SOA 
with other section changes 


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 4 1  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
2.   Sc h e d ul e of activiti es  
T a bl e 2.  S u bst u dy 1 
Sc h e d ul e of Activiti es –  
I nt erv e nti o n al P h as e 
( Ly m p h o d e pl eti o n, 
Tr e at m e nt a n d F oll o w -u p) 
A n d  
T a bl e 4.  S u bst u dy 1 
Sc h e d ul e of Activiti es –  
I nt erv e nti o n al P h as e 
( Ly m p h o d e pl eti o n, 
Tr e at m e nt a n d F oll o w -u p) 
f or S plit D osi n g 
A d d e d st a n d ar d m et h o d of c o nv ersi o n f or 
c al e n d ar visit sc h e d uli n g b et w e e n m o nt h t o 
w e ek, a n d w e ek t o d ay.  
C o m bi n e d Tr a ns g e n e C o pi es ( Persist e nc e 
f or S af ety) a n d 
 r o ws 
i nt o o n e as o nly o n e s a m pl e will b e 
c oll ect e d t o p erf or m b ot h t ests. 
F o ot n ot e #1 6 cl arifi e d t o i nstr uct t h at 
“ C T/ M RI ass ess m e nts o nly n e e d t o 
c o nti n u e u ntil c o nfir m e d P D”.  
A d d e d r e q uir e m e nt f or f erriti n, tr o p o ni n a n d 
N T -pr o B N P / B N P t est pri or t o 
Ly m p h o d e pl eti o n ( T a bl e 2)  
A d d e d C o a g ul ati o n ass ess m e nts f or 
b as eli n e, D ay 1 t hr u 4, D ay 6, D ay 8, a n d 
D a y 1 5 ( T a bl e 2) 
I ncl u d e d r e q uir e m e nt f or s us p ect e d C R S or 
I C A N S t o m o nit or c h e mistry, h e m at ol o gy, 
f erriti n, c o a g ul ati o n a n d C r e activ e pr ot ei n 
l a bs, d aily f or a w e ek t h e n ev ery ot h er d ay 
u ntil sy m pt o ms ar e i m pr ovi n g or a n 
alt er n ativ e di a g n osis is c o nfir m e d.  I ncl u d e d 
r e q uir e m e nt f or m o nit ori n g of tr o po ni n a n d 
N T -pr o B N P / B N P l a bs f or C R S gr a d e ≥2 as 
cli nic ally i n dic at e d. 
Mi n or cl arific ati o ns t o f o ot n ot e #3 3 t o 
ext e n d wi n d o w of c oll ecti o n of g e n etic 
s a m pl e u ntil first d ay of ly m p h o d e pl eti o n 
a n d f o ot n ot e #3 4 t o cl e arly i d e ntify st art of 
ly m p h o d e pl eti o n d ay p er i n dic ati o n. 
Cl arific ati o n a n d ali g n m e nt of S O A 
wit h ot h er s ecti o n c h a n g es  
 
 
 
 
 
 
 
 
Ad diti o n of c ar di ac  
 a n d 
c o a g ul ati o n t ests. 
 
 
 
 
Cl arific ati o n of sc h e d ul e of 
ass ess m e nt f or s us p ect e d C R S or 
I C A N S. 
 
 
 
 
 
 
Cl arific ati o n of S O A f o ot n ot es.  
2.   Sc h e d ul e of activiti es  
T a bl e 3.  S u bst u dy 1 
Sc h e d ul e of Activiti es –  P K, 
I m m u n o g e nicity, a n d 
 - I nt erv e nti o n al 
P h as e ( Tr e at m e nt a n d 
F oll o w -u p)  
A n d  
T a bl e 5.  S u bst u dy 1 
Sc h e d ul e of Activiti es –  P K, 
I m m u n o g e nicity, a n d 
 - I nt erv e nti o n al 
P h as e ( Tr e at m e nt a n d 
F oll o w -u p) f or S plit D osi n g  
Cl arifi e d t h at S a m pl e Ty p e f or d n T G F -RII 
s h o ul d b e “ w h ol e bl o o d” i nst e a d of P B M C.  
R e m ov al of D ay 6 4 si nc e W e ek 1 0 visit is 
n ot s h o wi n g o n t h e t a bl e ( p er f o ot n ot e #1).  
U p d at e d R e q uir e m e nt f or o n -st u dy bi o psy 
at W e ek 4 i nst e a d of W e ek 6 ( F o ot n ot e #9 
s p ecifi es t h at t h e wi n d o w of c oll ecti o n f or 
t h e W e ek 4 bi o psy is ext e n d e d fr o m D ay 2 1 
t o D ay 3 9). 
C orr ect e d sc h e d ul e of c oll ecti o n f or 
Cyt oki n e A n alys es (r e m ov al of W e ek 5, 7 
a n d 9 c oll ecti o ns)  
U p d at e d f o ot n ot e #5 r el at e d t o c oll ecti o n of 
cyt oki n es w h e n C R S is s us p ect e d, t o 
r ef er e nc e l oc al l a bor at ory  m o nit ori n g  
Cl arific ati o n a n d ali g n m e nt of S O A 
wit h ot h er s ecti o n c h a n g es  
C CI
C CI
C CI
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 4 2  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
2.   Sc h e d ul e of activiti es  
T a bl e 6.  S u bst u dy 1  
Sc h e d ul e of Activiti es –  
F oll o w -u p aft er Dis e as e 
Pr o gr essi o n or aft er 
C o m pl eti o n of I nt erv e nti o n al 
P h as e F oll o w -u p  
C o m bi n e d Tr a ns g e n e C o pi es ( Persist e nc e 
f or S af ety) a n d 
 r o ws 
i nt o o n e as o nly o n e s a m pl e will b e 
c oll ect e d t o p erf or m b ot h t ests. 
Cl arifi e d l a n g u a g e t o ali g n wit h L o n g -t er m 
F oll o w -u p St u dy 2 0 8 7 5 0, i ncl u di n g:   
- 
D isc o nti n u ati o n of p ersist e nc e 
 
m o nit ori n g at  ≥2 y e ar p ost T -c ell 
i nf usi o n  f or p artici p a nts w h os e 
tr a ns d uc e d T c ells ar e u n d et ect e d f or 2 
c o ns ec utiv e visit ass ess m e nts  
- 
A ll o w m e dic al ev al u ati o ns t o t ak e pl ac e 
vi a t el e m e dici n e ( e. g. p h o n e c all or 
vi d e o c o nf er e nc es) a n d/ or h o m e 
h e alt hc ar e w h er e c o u ntry a n d/ or l oc al 
r e g ul ati o ns all o w 
- 
A d d e d o pti o n of r e m ot e visits f or y e ars 
6 -1 5  
Cl arific ati o n a n d ali g n m e nt of S O A 
wit h ot h er s ecti o n c h a n g es  
3. 2. 1 Risk Ass ess m e nt  
T a bl e 7. Risk Miti g ati o n 
Str at e gy  
C orr ect e d r ef er e nc e t o I P as G S K 3 9 0 1 9 6 1 
f or S u bst u dy 1.  
U p d at e d risk ass ess m e nt t a bl e:  
- 
T o i ncl u d e risks of d ecr e as e d visi o n 
a n d p eri p h er al n e ur o p at hy f or 
ly m p h o d e pl eti n g ch e m ot h er a py 
(fl u d ar a bi n e/cycl o p h os p h a mi d e);  
- 
T o i ncl u d e/ a m e n d risks of 
h a e m at o p oi etic cyt o p e ni as, 
hy p ers e nsitivity, r e activ ati o n of 
pr evi o us vir al i nf ecti o ns aft er pr ol o n g e d 
l e uk o p e ni a, n e utr o p e ni a (i ncl u di n g f at al 
n e utr o p e ni a) d ecr e as e d visi o n, t o T C R -
T i nf usi o n  
- 
T o r e m ov e risk of p ul m o n ary t oxicity as 
it s h o ul d o nly b e s p ecific t o s u bst u dy 2. 
U p d at e t o risk miti g ati o n.  
C CI
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 4 3  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
4. O bj ectiv es a n d E n d p oi nts  
 
R ef or m att e d S ec o n d ary O bj ectiv es a n d 
E n d p oi nts i nt o “ Sec o n d ary –  Effic acy” a n d 
“ S ec o n d ary –  Ph ar m ac oki n etics”.  
C o m bi n e d Fr e q u e ncy a n d s ev erity of 
A dv ers e Ev e nts ( A Es), S eri o us A Es ( S A Es) 
a n d A Es of Sp eci al I nt er est ( A E SIs) as o n e 
si n gl e e n d p oi nt. 
O pti miz e d  d escri pti o n of Sec o n d ary –  
P h ar m ac oki n etics o bj ectiv es a n d 
e n d p oi nts.  
U p d at e d list of a b br evi ati o ns.  
T o cl arify s u bc at e g ori es of s ec o n d ary 
o bj ectiv es.  
 
St a n d ar diz ati o n of r e p orti n g.  
 
 
 
Cl arific ati o n of Ph ar m ac oki n etics 
pl a n.  
F i n aliz ati o n of t a bl e. 
5. 1. 1. D os e C o nfir m ati o n 
P h as e  
A n d  
6. 1 F or m er I ncl usi o n #1 0 
( d el et e d)  
A n d  
6. 1 F or m er I ncl usi o n #1 6 
( n o w I ncl usi o n #1 3)  
A n d  
6. 2 F or m er Excl usi o n #1 
( d el et e d) 
C o h ort 1 m et ast atic N S C L C p artici p a nts 
m ust h av e r ec eiv e d pri or t o 
ly m p h o d e pl eti o n (I ncl usi o n #1 3) a 
P D -1/ P D -L 1 c h eck p oi nt bl ock a d e t h er a py 
“a n d, i n t h e s a m e or diff er e nt li n e of 
tr e at m e nt, a pl ati n u m c o nt ai ni n g 
c h e m ot h er a py, or p artici p a nt is i nt ol er a nt t o 
it”.   
C o h ort 1 m et ast atic N S C L C p artici p a nts 
ar b orri n g a n acti o n a bl e g e n etic a b err ati o n 
( e. g., B R A F, AL K/ R O S 1) p er N C C N 
g ui d eli n es, m ust als o h av e r ec eiv e d pri or t o 
ly m p h o d e pl eti o n (I ncl usi o n #1 3) “t h e 
st a n d ar d of c ar e ( S O C) t ar g et e d t h er a py as 
r ec o m m e n d e d by N C C N or e q uiv al e nt 
c o u ntry-l ev el g ui d eli n es ( e. g., E S M O, 
NI C E)”.  
Cl arific ati o n o n dis e as e 
c h ar act eristics f or i ncl usi o n of 
C o h ort  1 N S C L C p artici p a nts.  
R e m ov al of a ny r e q uir e m e nt of 
s p ecific a nti-c a nc er tr e at m e nt pri or t o 
l e uk a p h er esis. 
5. 1. 1. 1 D et er mi ni n g t h e 
R 2 P D  
 
Mi n or cl arific ati o n t o t h e R P2 D s u g g est e d 
d os e w hic h will h av e ≥6  p artici p a nts tr e at e d 
at t his d os e a n d a n o bs erv e d t oxicity r at e 
≤1/ 3.  
Cl arific ati o n of t hr es h ol d f or 
s u g g est e d R P2 D d os e. 
5. 1. 3 P artici p a nt J o ur n ey  
 
O pti miz ati o n of w or di n g t o Partici p a nt 
j o ur n ey d escri pti o n t o ali g n wit h e q uiv al e nt 
C o r e Pr ot oc ol Secti o n 5. 2.  
Ali g n m e nt of w or di n g wit h e q uiv al e nt 
C or e pr ot oc ol s ecti o n  
C CI


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Description of Change 
Brief Rationale 
5.1.4 Tumor Biopsies (new 
section added) 
And  
6.1 Former Inclusion 
Criterion #5 (now Inclusion 
Criterion #3) 
6.1 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.  
6.1 Former Inclusion #6 
moved to Inclusion #4   
Clarification on translocation requirement 
for inclusion of SS participants (Cohort 2): 
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 #3 
moved to Inclusion #10 
And Former Inclusion #4 
moved to Inclusion #11   
And 
6.1 Former Inclusion #14 
(now Inclusion #23) 
Participants must have measurable disease 
by RECIST v1.1 (Inclusion #10) and 
evidence of radiographic or clinical disease 
progression only prior to leukapheresis 
(Inclusion #11).  
Participants must have documented 
radiographic evidence of disease 
progression from prior line of therapy prior 
to lymphodepletion (Inclusion #23). 
Clarification on disease requirements 
to allow for participants who have not 
progressed to undergo Target 
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Brief Rationale 
6.1 Former Inclusion #8 
(deleted)  
And 
6.1 Former Inclusion #15 
(now Inclusion #12) 
Cohort 2 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  
SS participants.  
6.1 Former Inclusion #18 
(now Inclusion #15)  
Participants must have a predicted life 
expectancy that is ≥6 months (Inclusion 
#15) 
Extension of projected life 
expectancy requirement because 
leukapheresis can now be performed 
earlier in treatment plan. 
6.1 Former Inclusion #19 
(now Inclusion #16)  
Participants must have a Left ventricular 
ejection fraction ≥45% with no evidence of 
clinically significant pericardial effusion or 
as per institution’s guidelines (Inclusion 
#16) 
Clarification. 


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Brief Rationale 
6.1 Former Inclusion #20 
(now Inclusion #18)  
Table 9. 
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 9 (Inclusion #18 
Clarification of Definitions of Adequate 
Organ Function: 
- 
ANC (must be obtained without G-CSF 
support) 
- 
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 
Clarification. 
6.1 Former Inclusion 
Criterion #21 (now Inclusion 
#19) 
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 10 – Washout 
periods 
Clarification of washout periods 
requirements prior to leukapheresis and 
prior to lymphodepletion. 
Alignment with cell gene therapy 
program.  


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Description of Change 
Brief Rationale 
6.2 Exclusion Criteria 
Former Exclusion Criterion 
#2 (now Exclusion criterion 
#6) 
And 
Exclusion criterion #5 
(deleted) 
 
 
Clarification of CNS metastases exceptions 
for NSCLC participants. 
 
 
Removed restriction on maximum lines of 
therapy for NSCLC participants (former 
Exclusion criterion #5).  
Broaden NSCLC patient eligibility 
6.2 Former Exclusion 
Criteria #6 and 7 (now 
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.  
- 
Added exception to participants who 
have received prior gene therapy using 
an integration vector.   
Allow participants who have benefited 
from GSK3377794 (lete-cel) to be 
considered for treatment with 
GSK3901961 under conditions 
defined in Section 6.3.5. 
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 
GSK3901961). 
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. 


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Brief Rationale 
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. 
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. 


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 4 9  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
S u b st u d y 2  
2.   Sc h e d ul e of activiti es  
T a bl e 1.  S u bst u dy 2 
Sc h e d ul e of Activiti es –  
Scr e e ni n g a n d 
L e uk a p h er esis  
F o ot n ot e #1 ( T a bl e 1) h as b e e n a m e n d e d 
t o st at e t h at c o ns e nt f or L e uk a p h er esis a n d 
Tr e at m e nt m ust b e r e p e at e d if giv e n m or e 
t h a n 9 0 d ays pri or t o l e uk a p h er esis 
pr oc e d ur e.  
Mi n or w or di n g cl arific ati o ns f or f o ot n ot es 
#3, 5 a n d 7.  
F o ot n ot e #4 cl arifi es t h at o pti o n al G e n etics 
s a m pl e “ m ay b e c oll ect e d any ti m e fr o m 
si g n at ur e of o pti o n al c o ns e nt u ntil 
l e uk a p h er esis”. 
F o ot n ot e #8 cl arifi es t h at “ C D 3 c o u nt pri or 
t o l e uk a p h er esis s h o ul d pr ef er a bly b e 
p erf or m e d wit hi n 2 4 h o urs pri or t o 
l e uk a p h er esis pr oc e d ur e”. 
F o ot n ot e #9 ali g ns wit h C or e Pr ot oc ol 
S ecti o n 9. 1. 5 o n Vit al Si g ns c oll ecti o n, 
all o wi n g i nstit uti o n al st a n d ar d m et h o ds f or 
c oll ecti o n. 
F o ot n ot e #1 6 a d d e d t o r ef er e nc e d et ails of 
r e n al ass ess m e nt i n Su bst u dy 2 Secti o n 
6. 1 T a bl e 1 0 . 
Cl arific ati o n a n d ali g n m e nt of S O A 
wit h ot h er s ecti o n c h a n g es  
2.   Sc h e d ul e of activiti es  
T a bl e 2.  S u bst u dy 2 
Sc h e d ul e of Activiti es –  
I nt erv e nti o n al P h as e 
( Ly m p h o d e pl eti o n, 
Tr e at m e nt a n d F oll o w -u p) 
A n d  
T a bl e 4.  S u bst u dy 2 
Sc h e d ul e of Activiti es –  
I nt erv e nti o n al P h as e 
( Ly m p h o d e pl eti o n, 
Tr e at m e nt a n d F oll o w -u p) 
f or S plit D osi n g  
A d d e d st a n d ar d m et h o d of c o nv ersi o n f or 
c al e n d ar visit sc h e d uli n g b et w e e n m o nt h t o 
w e ek, a n d w e ek t o d ay.  
C o m bi n e d Tr a ns g e n e C o pi es ( Persist e nc e 
f or S af ety) a n d 
 r o ws 
i nt o o n e as o nly o n e s a m pl e will b e 
c oll ect e d t o p erf or m b ot h t ests. 
F o ot n ot e #1 5 cl arifi e d t o i nstr uct t h at 
“ C T/ M RI ass ess m e nts o nly n e e d t o 
c o nti n u e u ntil c o nfir m e d P D”.  
A d d e d r e q uir e m e nt f or f erriti n, tr o p o ni n a n d 
N T -pr o B N P / B N P t est pri or t o 
Ly m p h o d e pl eti o n ( T a bl e 2)  
A d d e d C o a g ul ati o n ass ess m e nts f or 
b as eli n e, D ay 1  t hr u 4, D ay 6, D ay 8, a n d 
D ay 1 5 ( T a bl e 2)  
I ncl u d e d r e q uir e m e nt f or s us p ect e d C R S or 
I C A N S t o m o nit or c h e mistry, h e m at ol o gy, 
f erriti n, c o a g ul ati o n a n d C r e activ e pr ot ei n 
l a bs, d aily f or a w e ek t h e n ev ery ot h er d ay 
u ntil sy m pt o ms ar e i m pr ovi n g or a n 
alt er n ativ e di a g n osis is c o nfir m e d. I ncl u d e d 
m o nit ori n g of tr o p o ni n a n d N T -pr o B N P / 
B N P l a bs f or C R S gr a d e ≥2 as cli nic ally 
i n dic at e d.  
Cl arific ati o n a n d ali g n m e nt of S O A 
wit h ot h er s ecti o n c h a n g es  
 
 
 
 
 
 
 
 
Ad diti o n of c ar di ac  
a n d 
c o a g ul ati o n t ests. 
 
 
 
 
Cl arific ati o n of sc h e d ul e of 
ass ess m e nt f or s us p ect e d C R S or 
I C A N S. 
 
 
 
 
 
. 
C CI
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 5 0  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
2.   Sc h e d ul e of activiti es  
T a bl e 3.  S u bst u dy 2 
Sc h e d ul e of Activiti es –  P K, 
I m m u n o g e nicity, a n d 
 - I nt erv e nti o n al 
P h as e ( Tr e at m e nt a n d 
F oll o w -u p)  
A n d  
T a bl e 5.  S u bst u dy 2 
Sc h e d ul e of Activiti es –  P K, 
I m m u n o g e nicity, a n d 
 - I nt erv e nti o n al 
P h as e ( Tr e at m e nt a n d 
F oll o w -u p) f or S plit D osi n g  
Cl arifi e d t h at S a m pl e Ty p e f or d n T G F -RII 
s h o ul d b e “ w h ol e bl o o d” i nst e a d of P B M C.  
R e m ov al of D ay 6 4 si nc e W e ek 1 0 visit is 
n ot s h o wi n g o n t h e t a bl e ( p er f o ot n ot e #1).  
U p d at e d R e q uir e m e nt f or o n -st u dy bi o psy 
at W e ek 4 i nst e a d of W e ek 6 ( F o ot n ot e #8 
s p ecifi es t h at t h e wi n d o w of c oll ecti o n f or 
t h e W e ek 4 bi o psy is ext e n d e d fr o m D ay 2 1 
t o D ay 3 9). 
C orr ect e d sc h e d ul e of c oll ecti o n f or 
Cyt oki n e A n alys es (r e m ov al of W e ek 5, 7 
a n d 9 c oll ecti o ns)  
U p d at e d f o ot n ot e r el at e d t o c oll ecti o n of 
cyt oki n es w h e n C R S is s us p ect e d t o 
r ef er e nc e l oc al l a bor at ory  m o nit ori n g  
Cl arific ati o n a n d ali g n m e nt of S O A 
wit h ot h er s ecti o n c h a n g es  
2.   Sc h e d ul e of activiti es  
T a bl e 6.  S u bst u dy 2 
Sc h e d ul e of Activiti es –  
F oll o w -u p aft er Dis e as e 
Pr o gr essi o n or aft er 
C o m pl eti o n of I nt erv e nti o n al 
P h as e F oll o w -u p  
C o m bi n e d Tr a ns g e n e C o pi es ( Persist e nc e 
f or S af ety) a n d
 r o ws 
i nt o o n e as o nly o n e s a m pl e will be 
c oll ect e d t o p erf or m b ot h t ests. 
Cl arifi e d l a n g u a g e t o ali g n wit h L o n g -t er m 
F oll o w -u p St u dy 2 0 8 7 5 0, i ncl u di n g:   
- 
D isc o nti n u ati o n of p ersist e nc e 
 
m o nit ori n g at  ≥2 y e ar p ost T -c ell 
i nf usi o n  f or p artici p a nts w h os e 
tr a ns d uc e d T c ells ar e u n d et ect e d f or 2 
c o ns ec utiv e visit ass ess m e nts  
- 
A ll o w m e dic al ev al u ati o ns t o t ak e pl ac e 
vi a t el e m e dici n e ( e. g. p h o n e c all or 
vi d e o c o nf er e nc es) a n d/ or h o m e 
h e alt hc ar e w h er e c o u ntry a n d/ or l oc al 
r e g ul ati o ns all o w 
- 
A d d e d o pti o n of r e m ot e visits f or 
y e ars 6 -1 5  
Cl arific ati o n a n d ali g n m e nt of S O A 
wit h ot h er s ecti o n c h a n g es  
3. 2. 1 Risk Ass ess m e nt  
T a bl e 7. Risk Miti g ati o n 
Str at e gy  
C orr ect e d r ef er e nc e t o I P as G S K 3 8 4 5 0 9 7 
f or S u bst u dy 2.  
U p d at e d risk ass ess m e nt t a bl e:  
- 
T o i ncl u d e risks of d ecr e as e d visi o n 
a n d p eri p h er al n e ur o p at hy f or 
ly m p h o d e pl eti n g c h e m ot h er a py 
(fl u d ar a bi n e/cycl o p h os p h a mi d e);  
- 
T o i ncl u d e/ a m e n d risks of 
h a e m at o p oi etic cyt o p e ni as, 
hy p ers e nsitivity, r e activ ati o n of 
pr evi o us vir al i nf ecti o ns aft er pr ol o n g e d 
l e uk o p e ni a, n e utr o p e ni a (i ncl u di n g f at al 
n e utr o p e ni a) d ecr e as e d visi o n, t o 
T C R -T i nf usi o n.  
U p d at e t o risk miti g ati o n.  
C CI
C CI
C CI
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 5 1  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
4. O bj ectiv es a n d E n d p oi nts  
 
R ef or m att e d S ec o n d ary O bj ectiv es a n d 
E n d p oi nts i nt o “ Sec o n d ary –  Effic acy” a n d 
“ S ec o n d ary –  Ph ar m ac oki n etics”.  
C o m bi n e d Fr e q u e ncy a n d s ev erity of 
A dv ers e Ev e nts ( A Es), S eri o us A Es ( S A Es) 
a n d A Es of Sp eci al I nt er est ( A E SIs) as o n e 
si n gl e e n d p oi nt. 
O pti miz e d d escri pti o n of Sec o n d ary –  
P h ar m ac oki n etics o bj ectiv es a n d 
e n d p oi nts . 
U p d at e d list of a b br evi ati o ns.  
T o cl arify s u bc at e g ori es of s ec o n d ary 
o bj ectiv es.  
 
St a n d ar diz ati o n of r e p orti n g.  
 
 
 
Cl arific ati o n of Ph ar m ac oki n etics 
pl a n.  
 
Fi n aliz ati o n of t a bl e.  
5. 1. 1. 1 D et er mi ni n g t h e 
R 2 P D  
 
Mi n or cl arific ati o n t o t h e R P2 D s u g g est e d 
d os e w hic h will h av e ≥6  p artici p a nts tr e at e d 
at t his d os e a n d a n o bs erv e d t oxicity r at e 
≤1/ 3.  
Cl arific ati o n of t hr es h ol d f or 
s u g g est e d R P2 D d os e. 
5. 1. 3 P artici p a nt J o ur n ey  
 
O pti miz ati o n of w or di n g t o Partici p a nt 
j o ur n ey d escri pti o n t o ali g n wit h e q uiv al e nt 
C or e Pr ot oc ol S ecti o n 5. 2.  
Ali g n m e nt of w or di n g wit h e q uiv al e nt 
C or e pr ot oc ol s ecti o n  
5. 1. 4 T u m or Bi o psi es ( n e w 
s ecti o n a d d e d) A n d  
6. 1 F or m er I ncl usi o n 
Crit eri o n #5 ( n o w I ncl usi o n 
Crit eri o n #4)  
6. 1. F or m er I nc l usi o n 
crit eri o n # 2 1 ( n o w i ncl usi o n 
Crit eri o n #2 4)  
A d d e d r e q uir e m e nts f or o n -st u dy t u m or 
bi o psi es  
 
A r e pr es e nt ativ e t u m or tiss u e s p eci m e n 
[ arc hiv e d or fr es h bi o psy] wit h ass oci at e d 
p at h ol o gy r e p ort s h o ul d b e av ail a bl e t o 
p erf or m N Y E S O 1 a nti g e n ex pr essi o n 
a n alysis u nl ess a n a p pr o pri at e r ec e nt 
N Y -E S O -1 ex pr essi o n r es ult is alr e a dy 
av ail a bl e.  
Cl arific ati o n of r e q uir e m e nts f or b as eli n e 
bi o psy.  
Cl arific ati o n.  
5. 3 E n d of S u bst u dy 
d efi niti o n  
Cl arific ati o n of e n d of I nt erv e nti o n al P h as e 
a n d e n d of s u bst u dy f or  i n divi d u al 
p artici p a nts as w ell as f or t h e e ntir e 
s u bst u dy/c o h ort  
Cl arific ati o n of p ati e nt dis p ositi o n  
5. 1  Ov er all D esi g n  
6. 1 I ncl usi o n Crit eri a  
6. 2 Excl usi o n Crit eri a  
O pti miz ati o n of Tr e at m e nt Fit n ess a n d 
Eli gi bility crit eri a pri or t o Ly m p h o d e pl eti o n  
R e m ov e d r e q uir e m e nt f or r e p etiti o n 
of all ass ess m e nts f or eli gi bility 
crit eri a t h at w er e alr e a dy m et pri or t o 
l e uk a p h er esis. R e pl ac e d by a 
Tr e at m e nt Fit n ess ass ess m e nt of t h e 
s af ety crit eri a i n c o ns ult ati o n wit h 
M e dic al M o nit or.  
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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. 


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Section # and Name 
Description of Change 
Brief Rationale 
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) 
- 
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 
Clarification. 
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.  


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Section # and Name 
Description of Change 
Brief Rationale 
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.  
- 
Added exception to participants who 
have received prior gene therapy using 
an integration vector.   
Allow participants who have benefited 
from GSK3377794 (lete-cel) to be 
considered for treatment with 
GSK3901961 under conditions 
defined in Section 6.3.5. 
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. 


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Section # and Name 
Description of Change 
Brief Rationale 
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. 
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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13.2. 
Amendment 2 (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 2, 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 2, 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 
Core protocol 
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 
substudies 


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 5 7  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
5. 1 Ov er all d esi g n  
R ef er e nc e t o S ecti o n 1 2. 1 2 f or d et ails 
r e g ar di n g s u bst u di es 
I n a ntici p ati o n of a d diti o n al 
s u bst u di es, e n a bl es a d mi nistr ativ e 
c h a n g es t o d oc u m e nt. 
5. 2 P artici p a nt J o ur n ey  
I ncl u d e d r ef er e nc e t o s u bst u di es f or H L A 
t esti n g s u bst u dy s p ecific d et ails 
H L A t esti n g is s u bst u dy s p ecific –  
d et ails ar e n ot pr ovi d e d i n C or e b ut i n 
i n divi d u al s u bst u dy s ecti o ns. 
5. 2 P artici p a nt J o ur n ey P art 
1 Scr e e ni n g  
I ncl u d e d t hir d o pti o n of t ar g et ex pr essi o n 
scr e e ni n g 
Ad d e d o pti o n of pr oc e e di n g wit h 
t u m or s a m pl e c oll ecti o n b as e d o n a 
p ositiv e l oc al H L A r es ult..  
5. 3  N u m b er of P artici p a nts  
R ef er e nc e t o S ecti o n 1 2. 1 2 f or d et ails 
r e g ar di n g s u bst u di es 
I n a ntici p ati o n of a d diti o n al 
s u bst u di es, e n a bl es a d mi nistr ativ e 
c h a n g es t o d oc u m e nt. 
6 . 2 Scr e e ni n g U n d er Ot h er 
G S K St u di es  
U p d at e d t o i n dic at e acc e pt a bility of L A G E -
1 a p ositiv e p artici p a nts  
I n or d er t o acc o m m o d at e p artici p a nts 
fr o m ot h er st u di es w h os e t u m or w as 
p ositiv e f or L A G E -1 a a n d t o f acilit at e 
st u dy-t o-st u dy tr a nsf er of t h es e 
p artici p a nts  
6. Pr ot oc ol p o p ul ati o n  
A d d e d s e nt e nc e t o r ef er t o s u bst u di es f or 
pr ot oc ol p o p ul ati o n d et ails r el ev a nt t o e ac h 
s u bst u dy.  
Tr a nsiti o n t o m o d ul ar f or m at.  
8. 1. 2 S plit D os e 
A d mi nistr ati o n  
U p d at e d l a n g u a g e t o r ef er t o s u bst u di es f or 
s plit d osi n g  
Tr a nsiti o n t o m o d ul ar f or m at  
8. 2 D os e Li miti n g T oxicity  
U p d at e d ti mi n g f or D L T wi n d o w f or p oi nt 7 
t o h ar m o niz e 
Ty p o c orr ecti o n  
8. 2 D os e Li miti n g T oxicity  
I ncl u d e d r ef er e nc e t o s u bst u di es f or a ny 
s u bst u dy s p ecific D L Ts 
I n t h e ev e nt D L Ts s p ecific t o a 
s u bst u dy aris e, t h es e will b e a d d e d t o 
t h e s u bst u dy vi a a m e n d m e nt  
8. 5 St u dy St o p pi n g a n d 
P a usi n g R ul es  
A d d e d r ef er e nc e t o s u bst u dy f or a ny 
s p ecific s af ety ass ess m e nts 
I n t h e ev e nt s u bst u dy s p ecific s af ety 
ass ess m e nts aris e, t h es e will b e 
a d d e d t o t h e s u bst u d y vi a 
a m e n d m e nt  
9. 1. 6 C ar di ac ass ess m e nts  
A d d e d t ext t o d efi n e s p ecific c ar di ov asc ul ar 
risk f act ors a n d st e ps n ec ess ary t o 
ev al u at e a n d m o nit or p artici p a nt  
I m pl e m e nt ati o n of a d diti o n al s af ety 
m o nit ori n g m e as ur es i n acc or d a nc e 
wit h a r ec e nt D e ar I nv esti g at or L ett er 
( 2 1 Oct 2 0 2 1) a n d s af ety ev e nts.. 
9. 1. 7 P ul m o n ary 
Ass ess m e nts  
A d d e d n e w s ecti o n o n p artici p a nt 
p ul m o n ary f u ncti o n ass ess m e nt pri or t o 
ly m p h o d e pl eti o n 
I m pl e m e nt ati o n of a d diti o n al s af ety 
m o nit ori n g m e as ur es i n acc or d a nc e 
wit h a r ec e nt D e ar I nv esti g at or L ett er 
( 2 1 Oct 2 0 2 1) a n d s af ety ev e nts.   
9. 1. 8 M o nit ori n g f or 
I m m u n e Eff ect or C ell-
Ass oci at e d N e ur ot oxicity 
Sy n dr o m e  
A d d e d r ef er e nc e t o s u bst u dy f or a ny 
s p ecific ass ess m e nts 
Ad d e d l a n g u a g e i n t h e ev e nt t h er e 
ar e a d diti o n al ass ess m e nts s p ecific 
t o a s u bst u dy.  
9. 1. 9 M o nit ori n g f or 
D e my eli n ati n g N e ur o p at hy 
a n d ot h er N e ur ol o gic al 
Ev e nts  
A d d e d r ef er e nc e t o s u bst u dy f or a ny 
s p ecific ass ess m e nts 
Ad d e d l a n g u a g e i n t h e ev e nt t h er e 
ar e a d diti o n al ass ess m e nts s p ecific 
t o a s u bst u dy.  
C
C
I
C CI


T M F -1 4 6 8 2 5 6 0  
C O N FI D E N TI A L  
 
2 0 9 0 1 2  
 
Pr ot o c ol A m d 0 4  
 
1 5 8  
C or e  
 
S e cti o n # a n d N a me  
D e s cri pti o n of C h a n g e  
Bri ef R ati o n al e  
9. 2. 1 Ti m e P eri o d a n d 
Fr e q u e ncy f or C oll ecti n g A E 
a n d S A E I nf or m ati o n  
U p d at e d ti mi n g f or A E a n d S A E c oll ecti o n  
Cl arifi e d A E a n d S A E r e p orti n g 
g ui d a nc e  
9. 2. 5 Pr e g n a ncy  
M ov e d t a bl e of c o ntr ac e pti o n us e ti mi n gs t o 
S ecti o n  1 2. 4 C o ntr ac e pti o n G ui d a nc e a n d 
C oll ecti o n of Pr e g n a ncy I nf or m ati o n  
Ad d e d t a bl e of c o ntr ac e pti o n us e 
ti mi n gs t o a p p e n dix p ert ai ni n g t o 
c o ntr ac e ptiv e g ui d a nc e r at h er t h a n 
r et ai n i n t h e Pr e g n a ncy s ecti o n  
9. 2. 7  A dv ers e Ev e nts of 
S p eci al I nt er est ( A E SIs)  
A d d e d r ef er e nc e t o s u bst u dy f or a ny 
s p ecific ass ess m e nts 
Ad d e d l a n g u a g e  i n t h e ev e nt t h er e 
ar e a d diti o n al ass ess m e nts s p ecific 
t o a s u bst u dy.  
9. 8 G e n etics  
Cl arifi e d l a n g u a g e a n d cr oss r ef er e nc e d 
S ecti o n 9. 1 0  
Str e a mli n e d l a n g u a g e  
9. 1 0. 1 T u m or Bi o psy  
R e m ov al of ti m e li mit ati o ns a n d r ef er e nc e 
t o s u bst u dy f or arc hiv al tiss u e ti m e 
li mit ati o ns 
F or m att e d s ecti o n by ti m e of bi o psy  
I ncl u d e d r e q uir e m e nts o n s a m pl e s uit a bility  
I n dic ati o ns v ary by s u bst u dy 
Divi d e d t ext i nt o Scr e e ni n g, Bas eli n e 
a n d O n -st u dy s a m pli n g ti m es t o 
e n h a nc e r e a d er u n d erst a n di n g  
A d d e d g ui d a nc e o n ty p e of bi o psy 
t h at is acc e pt a bl e p er pr ot oc ol 
9. 1 0. 2 Li q ui d Bo psi es (fr o m 
circ ul ati n g bl o o d) 
I ncl u d e d a d diti o n al d escri ptiv e t ext 
Ad d e d t ext t o pr ovi d e m or e 
b ack gr o u n d t o r es e arc h p ur p os e of 
li q ui d bi o psi es 
9. 1 0. 4 C ell Ph e n oty p e a n d 
F u n cti o n al Activity  
I ncl u d e d t ext a b o ut a p h er esis pr o d uct 
Ex p a n d e d a p plic a bility of ass ays t o 
b ot h a p h er esis a n d m a n uf act ur e d 
pr o d uct  
9. 1 0. 5 d n T G F b RII R ec e pt or 
Ex pr essi o n A n alys es  
U p d at e d l a n g u a g e t o r ef er t o s u bst u di es f or 
d n T G F b RII R ec e pt or Ex pr essi o n An alys es 
t esti n g r e q uir e m e nts 
d n T G F b RII R ec e pt or Ex pr essi o n 
An alys es ar e n ot t est e d i n all 
s u bst u di es 
9. 1 0. 8 St o ol C oll ecti o n f or 
Micr o bi o m e A n alysis  
D el et e d s ecti o n  
R e m ov e d b ec a us e ass ay n ot b ei n g 
c o n d uct e d u n d er Pr ot oc ol 
A m e n d m e nt 2  
1 1. R ef er e nc es  
U p d a t e d r ef er e nc es s ecti o n 
U p d at e d r ef er e nc es t o b e c or e -
s p ecific 
1 2. 7 A p p e n dix 7: 
S u p p ortiv e C ar e G ui d a nc e  
I ncl u d e d l a n g u a g e t o r ef er t o s u bst u dy f or 
a d diti o n al s u bst u dy s p ecific g ui d a nc e, 
w h e n a p plic a bl e.  
Ad d e d l a n g u a g e i n t h e ev e nt t h er e 
ar e a d diti o n al as s ess m e nts s p ecific 
t o a s u bst u dy. 
1 2. 7. 2 I nf ecti o n  
I ncl u d e d g ui d a nc e f or p artici p a nts wit h 
i n d w elli n g c e ntr al li n es 
Ad d e d g ui d a nc e f or i ncr e as e d 
m o nit ori n g of i n d w elli n g c at h et er li n es 
t o w atc h f or i nf ecti o n 
C CI


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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 1 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-14682560 
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Protocol Amd 04 
 
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13.3. 
Amendment 3 (20 December 2021) 
Overall Rationale for Amendment 3: 
The three primary reasons for Amendment 3 are as follows: 
• Substantial: Addition of Substudy 3 as “GSK4427296 [NYESO 1(c259) TCR 
engineered T cells using the Epi-R manufacturing process] in previously treated 
(2L+) HLA-A*02+ participants with NYESO 1+ and/or LAGE1a+ advanced SS 
or MRCLS” with a planned sample size of 19 and to be conducted in the United 
States only. 
• Non-substantial: Splitting of master protocol into individual separate documents 
while organization of the sections does not change:  
1) The Core Master protocol captures the common design and supporting 
documentation, including an updated list of substudies and the history of 
amendments, and 2) Each substudy is included as an individual document. 
• Non-substantial:Minor changes to Substudy 1 and 2 to ensure alignment of design 
and procedures across 3 substudies. 
Section # and Name 
Description of Change 
Brief Rationale 
Core  
1 Synopsis - Overall design 
Reference to Section 12.12 for further 
details regarding additional substudies and 
planned overall sample size.  
Inclusion of reference to master 
protocol planned overall sample size.  
9.9 Immunogenicity 
Assessments 
Specific asset references removed. 
Specific reference removed as 
collections and assessments are 
intended to apply to any assets under 
current and future substudies. 
12.2 Appendix 2: Clinical 
Laboratory Tests 
Updated Note under table of Clinical 
Laboratory Tests mention LAGE-1a 
expression.  
Inclusion of LAGE-1a tests results 
when applicable. 
12.12. Appendix 12: List of 
substudies (updated) 
Included Substudy 3 as “GSK4427296 
[NYESO 1(c259) TCR engineered T cells 
using the Epi-R manufacturing process] in 
previously treated (2L+) HLA-A*02+ 
participants with NYESO 1+ and/or 
LAGE1a+ advanced SS or MRCLS” with a 
planned sample size of 19 and to be 
conducted in the United States only. 
Included master protocol overall planned 
sample size of approximately 67. 
Countries where substudy will be active is 
added for all 3 substudies 
Inclusion of new substudy and update 
of overall estimated sample size. 


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Section # and Name 
Description of Change 
Brief Rationale 
12.13. Appendix 13: Master 
Protocol Document History 
(new) 
Table captures the chronology of each 
amendment, lists the documents that have 
been updated (including their document 
reference numbers), and identifies the 
current version for each individual 
document as component of the master 
protocol.  
T Capture of history of protocol and 
document amendments before and 
after splitting of master protocol into 
individual separate documents (one 
for the core and one for each 
substudy).  
Throughout document 
Minor edits and typo corrections done 
Editorial changes 
 
 


Si g nat ure Pa ge f or  2 0 9 0 1 2 T M F- 1 4 6 8 2 5 6 0 v 1. 0
Si g nat ure Pa ge f or T M F- 1 4 6 8 2 5 6 0 v 1. 0
Reas o n f or si g ni n g: A p pr o ve d
Na me: 
R ole: A
Date of si g nat ure: 2 7- Ma y- 2 0 2 2 1 4: 2 3: 0 1 G M T + 0 0 0 0
Reas o n f or si g ni n g: A p pr o ve d
Na me: 
R ole: A
Date of si g nat ure: 2 7- Ma y- 2 0 2 2 1 4: 4 7: 2 8 G M T + 0 0 0 0
P P D
P P D

SAP_001.pdf: 
Statistical Analysis Plan Amendment 3
Study ID:  209012 Core
Official Title of Study: 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
NCTID: NCT04526509
Date of Document: 10 May 2023


CONFIDENTIAL 
The GlaxoSmithKline group of companies 
 
209012 
 
Page 1 of 1 
 
Analysis 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 
Study Number: 
209012 
Compound Number: 
GSK3901961, GSK3845097, GSK4427296  
Abbreviated Title: 
Master Protocol of Autologous Enhanced T-Cell in Advanced 
Tumors  
 
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. 
 


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 2  of 7 2  
 
T A B L E O F C O N T E N T S  
P A G E  
1.  
I N T R O D U C TI O N ...................................................................................................... 7  
1. 1.  
O bj e cti v e s, E sti m a n d s, a n d E n d p oi nt s  .......................................................... 7  
1. 2.  
St u d y D e si g n  .............................................................................................. 1 0  
1. 2. 1.  
O v er all St u d y D e si g n  ................................................................... 1 0  
1. 2. 2.  
P arti ci p a nt J o ur n e y  ...................................................................... 1 1  
2.  
S T A TI S TI C A L H Y P O T H E S E S  ............................................................................... 1 2  
2. 1.  
M ulti pli cit y A dj u st m e nt  ................................................................................ 1 3  
3.  
A N A L Y SI S S E T S  ................................................................................................... 1 3  
4.  
S T A TI S TI C A L A N A L Y S E S  ..................................................................................... 1 4  
4. 1.  
G e n er al C o n si d er ati o n s  .............................................................................. 1 4  
4. 1. 1.  
G e n er al M et h o d ol o g y  .................................................................. 1 4  
4. 1. 2.  
B a s eli n e D efi niti o n  ....................................................................... 1 5  
4. 1. 3.  
M ulti c e ntr e St u di e s  ...................................................................... 1 6  
4. 1. 4.  
S el e cti o n of R P 2 D  ....................................................................... 1 6  
4. 1. 5.  
S plit -d o s e P arti ci p a nt s  ................................................................. 1 6  
4. 1. 6.  
P arti ci p a nt s R e c ei vi n g Pri or L et etr e s g e n e a ut ol e u c el 
(G S K 3 3 7 7 7 9 4, l et e -c el) T h er a p y  ................................................. 1 7  
4. 2.  
Pri m ar y E n d p oi nt( s) A n al y s e s  ..................................................................... 1 7  
4. 2. 1.  
D efi niti o n of e n d p oi nt( s)  ............................................................... 1 7  
4. 2. 2.  
M ai n a n al yti c al a p pr o a c h  ............................................................. 1 7  
4. 2. 3.  
Str at e g y f or i nt er c urr e nt e v e nt s  .................................................... 1 7  
4. 2. 4.  
S e n siti vit y a n al y s e s  ..................................................................... 1 8  
4. 2. 5.  
A d diti o n al e sti m a n d s  .................................................................... 1 8  
4. 3.  
S e c o n d ar y E n d p oi nt( s) A n al y s e s  ................................................................ 1 8  
4. 3. 1.  
Effi c a c y s e c o n d ar y e n d p oi nt( s)  .................................................... 1 8  
4. 3. 2.  
P h ar m a c o ki n eti c s ( P K) s e c o n d ar y e n d p oi nt( s)  ............................ 2 2  
4. 4.  
E x pl or at or y E n d p oi nt( s) A n al y s e s  ............................................................... 2 4  
4. 4. 1.  
D efi niti o n of e n d p oi nt s  ................................................................. 2 4  
4. 4. 2.  
M ai n a n al yti c al a p pr o a c h  ............................................................. 3 2  
4. 4. 3.  
Str at e g y f or I nt er c urr e nt E v e nt s  ................................................... 3 3  
4. 5.  
S af et y A n al y s e s  .......................................................................................... 3 4  
4. 5. 1.  
A d v er s e E v e nt s ............................................................................ 3 4  
4. 5. 2.  
Cli ni c al L a b or at or y A n al y s e s  ........................................................ 3 9  
4. 5. 3.  
Ot h er S af et y A n al y s e s  ................................................................. 4 1  
4. 5. 4.  
E xt e nt of E x p o s ur e  ...................................................................... 4 3  
4. 5. 6.  
I m m u n o g e ni cit y............................................................................ 4 4  
4. 6.  
Ot h er A n al y s e s  ........................................................................................... 4 4  
4. 6. 1.  
S u b gr o u p a n al y s e s  ...................................................................... 4 4  
4. 6. 2.  
Ot h er v ari a bl e s a n d/ or p ar a m et er s ............................................... 4 4  
4. 7.  
I nt eri m A n al y s e s ......................................................................................... 4 4  
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Page 3 of 72 
 
4.7.1. 
Interim Analysis ........................................................................... 44 
4.7.2. 
Primary Analysis .......................................................................... 44 
4.7.3. 
Final Analysis .............................................................................. 44 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 45 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 45 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 46 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 46 
6.1.1. 
Participant Disposition ................................................................. 46 
6.1.2. 
Demographic and Baseline Characteristics .................................. 46 
6.1.3. 
Protocol Deviations ...................................................................... 47 
6.1.4. 
Prior and Concomitant Medications ............................................. 47 
6.1.5. 
Anti-cancer therapies ................................................................... 48 
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic .................. 49 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 50 
6.2.1. 
Derived and transformed data ...................................................... 50 
6.2.2. 
Criteria for Potential Clinical Importance ...................................... 52 
6.2.3. 
Study Phase ................................................................................ 54 
6.2.4. 
Study Day and Reference Dates .................................................. 57 
6.2.5. 
Assessment Window ................................................................... 57 
6.2.6. 
Multiple measurements at One Analysis Time Point .................... 58 
6.2.7. 
Handling of Partial Dates ............................................................. 58 
6.2.8. 
Example Scenarios of Assignments of Confirmed Best 
Overall Response per iRECIST ................................................... 63 
6.3. 
Appendix 3 Combined list and Focused list ................................................. 64 
6.3.1. 
Combined Preferred Terms.......................................................... 64 
6.3.2. 
Focused list ................................................................................. 65 
6.4. 
Appendix 4 Modified Toxicity Probability Interval 2 (mTPI-2)....................... 68 
6.4.1. 
mTPI-2 Simulation Results .......................................................... 70 
7. 
REFERENCES ....................................................................................................... 72 
 


CONFIDENTIAL 
 
 
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Page 4 of 72 
 
Version history 
SAP Version 
Approval 
Date 
Protocol 
Version 
(Date) on 
which SAP is 
Based 
Change 
Rationale 
SAP v1 
18 
May 
2022 
209012/ 
Amendment 3 
(20-Dec-2021) 
Not Applicable 
Original 
version 
SAP 
Amendment 1 
14 
Sep 
2022 
209012/ 
Amendment 4 
(27-May-2022) 
In addition to minor formatting 
changes, the following updates have 
been made: 
• Revision of the DLT analysis set 
definition to remove text relating to 
AEs leading to withdrawal since 
these are not permitted per 
protocol (SAP Section 3). 
• Updates on which analyses are to 
be presented by planned/actual 
dose (Table 1).  
• Correction to text relating to 
selection of RP2D (Section 4.1.4). 
• Added reverse Kaplan-Meier 
method for Duration of Response 
follow-up summary (Section 4.3.1). 
• Pneumonia was removed as an 
AESI to align with Protocol 
Amendment 4 (Section 4.5.1.7). 
• Additional information on the 
presentation of screen failure 
summaries (Section 6.1.1) as well 
as HLA status, NY-ESO-1 
expression scores and LAGE-1a 
(Section 6.1.2). 
• Additional clarification added to the 
definition of anti-cancer therapy 
phases, and on-study follow-up 
phase now from lymphodepletion 
and not T-cell infusion to match 
lete-cell program (Section 6.1.5). 
Anti-cancer therapy phases table 
removed from Section 6.2 – will 
not be derived programmatically. 
• Revision of the prior and 
concomitant medication definitions 
to incorporate blood cell products 
and align the definition with the 
lete-cell program (Section 6.2.3.2). 
Minor updates 
and 
corrections 


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 5  of 7 2  
 
S A P V ersi o n  
A p pr o v al 
D at e  
Pr ot oc ol 
V ersi o n  
( D at e) o n 
w hic h S A P is 
B as e d  
C h a n g e  
R ati o n al e  
•  C o m bi n e d t er ms a n d foc us e d list 
u p d at e d fro m Me d D R A V ersi on 
2 4. 1 t o 25. 0 ( S ecti o n 6. 3 ) 
•  C h a n g e t o t he d efi nitio n of ‘ U’ i n 
t h e m T PI-2 ta bl e to i n dic ate t hat 
d os e will b e de -esc al ate d if 
p ossibl e, to m atc h t he 
c orr es po n di ng u p d at e i n 2 0 9 01 2 
Pr ot oc ol A m e n d m e nt 4 ( S ecti on 
6. 4 ). 
S A P 
A m e n d m ent 2  
0 3  
A pr  
2 0 2 3  
2 0 9 0 1 2/ 
A m e n d m ent 4 
( 2 7-M ay -20 2 2) 
I n a d diti o n t o mi nor ty po gr a p hic al a nd 
f or m attin g c ha n g es, t h e foll o win g 
u p d at es h ave b e e n m a d e:  
R e d ucti on i n sc o pe of ori gi n al 
pl a n n e d a n alys es as a r esult of st u dy 
t er mi n ati o n i nclu di n g: 
1.  R e m ov al of a n alys es r el at e d to 
R P 2 D or b as e d on t h e Eval u abl e 
A n alysis S et (thr o u g ho ut 
d oc u me nt)  
2.  Cl arificati o n to t h e D ur ati o n of 
R es p o nse e n d poi nt, if t h e 5 
r es p o n der c o nditi on is n ot m et 
t h e n t h e D O R will be 
s u m maris ed usi n g d escri ptiv e 
st atistics i nst e a d of K a pla n-M ei er 
esti mat es ( S ecti on 4. 3. 1 ). 
3.  R e m ov e d rev ers e K a pla n -M eier 
m et h o d for Dur ati on of R esp ons e 
f oll o w-u p s u m m ary ( S ecti on 
4. 3. 1 ) 
4.  Cl arificati o n th at ex pl orat ory 
effic acy en d p oints will n ot b e 
a n alys e d, alt h o ug h Ov er all 
S urviv al will b e list e d f or t h e I T T 
a n alysis s et ( S ecti o n 4. 4 ) 
5.  R e d ucti on i n sc o pe of S af ety 
a n alys es d u e t o e arly st u dy 
t er mi n ati o n as w ell as ad diti o nal 
s af ety a n alys es f or discl osur e 
a n d a n n ual saf ety re p ortin g 
r e q uir e me nts (S ecti on 4. 5 ). The 
m aj ority of s af ety a n alyses 
( excl udi n g a dv ers e ev e nts, 
ex p osur e, d eat hs an d 
 are 
R e d ucti on i n 
sc o p e of 
ori gi n al 
pl a n n e d 
a n alys es as a 
r es ult of st udy 
t er mi n ati o n 
C CI


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SAP Version 
Approval 
Date 
Protocol 
Version 
(Date) on 
which SAP is 
Based 
Change 
Rationale 
to be listed instead of 
summarised  
6. PCI categories for ECGs and 
Vital signs will not be derived 
(Section 4.5.3) 
7. Subgroup analyses removed 
(Section 4.6.1) 
8. Clarification that the protocol-
planned Interim and Primary 
analyses will not be conducted 
(Section 4.7) 
9. Documented changes to protocol 
defined analyses as a result of 
early termination of substudies 
(Section 4.8) 
10. Reduction in scope of study 
population analyses (Section 6.1) 
11. Summaries of anti-cancer 
therapies removed, only listings 
will be provided (Section 6.1.5) 
 
• 
Updated wording of DLT analysis 
set to DLT Evaluable analysis set 
(Section 3) 
• 
Added clarification that DLT rates 
(proportions) to be presented on 
actual treatment only and DLT 
frequency counts to be presented 
by planned and actual treatment. 
(Table 1 & Section 4.5.1.1)  
• 
Added disease characteristics at 
screening summary based on the 
screened population for 
HLA/NYESO results (Section 
6.1.2).  
• 
Updated derivation of treatment 
emergent flag for adverse events 
to clearly classify AEs that occur 
on the same day as T-cell 
infusion (Section 6.2.3.4) 
• 
Combined terms and focused list 
updated from MedDRA Version 
25.0 to 25.1 (Section 6.3) 


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SAP Version 
Approval 
Date 
Protocol 
Version 
(Date) on 
which SAP is 
Based 
Change 
Rationale 
SAP 
Amendment 3 
10 
May 
2023 
209012/ 
Amendment 4 
(27-May-2022) 
Formatting change to re-correct the 
heading titles and numbers 
Administrative 
amendment, 
no changes 
were made to 
the content of 
the SAP 
 
 
 
 
 
1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to describe the planned analyses applicable 
to all substudies for Study 209012, ‘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’. 
Details of the planned analyses are provided.  
The SAP is structured similarly to the protocol, with a core document which covers the common 
endpoints and analyses for all substudies and substudy-specific SAPs which cover the specific 
analyses for the corresponding substudy only. The combination of the analyses specified in this 
main SAP and substudy-specific SAPs will be included in the substudy specific clinical study 
report. However, it should be noted that due to early termination of all substudies, the purpose 
of this SAP is to describe the planned analyses for synoptic clinical study reports (CSRs). As a 
result, only a subset of the previously planned analyses that were to support full CSRs are now 
required. Additionally, some variables that were previously planned to be presented in 
summaries and/or figures will instead be presented in listing format since early termination has 
resulted in fewer participants than planned. Analyses required for synoptic CSRs are clearly 
indicated in this document. In general, exploratory endpoints will not be analysed, with 
exceptions clearly indicated. Additionally, since the substudies were 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). The Interim and Primary analyses described 
in Protocol Amendment 4 Section will not be conducted, only the Final Analysis will be 
undertaken. 
Note that additional details regarding data handling conventions and the specification of data 
displays are provided in the core and substudy-specific Output and Programming Specification 
(OPS) documents. 
1.1. 
Objectives, Estimands, and Endpoints 
The full list of objectives and endpoints below is the list given in the substudy-specific protocols 
(Amendment 4). It should be noted that due to termination of all substudies, only a subset of 
endpoints will be analysed, as detailed in Section 4. Discrepancies between the objectives and 


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 8  of 7 2  
 
e n d p oi nts  st at e d h er e a n d t h os e i n t h e s u bst u dy s p ecific S A P w ill n ot r e q uir e a m e n d m e nt, 
i nst e a d t h os e st at e d i n t h e s u bst u dy-s p ecific S A P will a p pl y a n d t a k e pri orit y .  
A d diti o n al  p h ar m ac o ki n etic ( P K ) a n d  
 ex pl or at ory a n al ys es n ot d escri b e d i n t his S A P  
will b e d et ail e d i n s e p ar at e P K a n d 
 re p orti n g a n d a n al ysis p l a ns. 
D u e t o t h e p h as e of t h e c urr e nt st u dy, e sti m a n d fr a m e w or k will n ot b e us e d  f or t his st u dy.  
 
 
C CI
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 9  of 7 2  
 
O bj e cti ve s  
E n d p oi nt s  
Pri m ar y  
T o assess t h e saf ety, t ol era bility a n d det er mi n e 
r ec o m m e n d e d p h as e 2 dos e ( R P 2 D) of N Y-E S O -1 
a n d L A G E -1 a s p ecific T -cells, al o n e or i n 
c o m bin ati on wit h oth er a g ents, i n H L A-A* 0 2 p ositiv e 
p articip a nts wit h N Y -E S O -1 and/ or L A G E -1 a p ositiv e 
a dv a nc e d t u m ors  
•  Fr e q u e ncy of dos e -li miti n g t oxiciti es ( DL Ts)  
•  Fr e q u e ncy a n d s ev erity of a dvers e eve nts 
( A Es), s eri ous a dv erse ev ents ( S A Es) a n d 
A Es of s p eci al i nt erest ( A E SI; as d efin e d in 
t h e c or e pr ot ocol) 
S e c o n d ar y - Effi c a c y  
T o i nv esti gat e t h e effic acy of N Y -E S O -1 a n d 
L A G E -1 a s pecific T -c ells, al o ne or i n c o m bi n atio n 
wit h ot h er ag e nts, i n H L A -A* 02 p ositiv e p artici p a nts 
wit h N Y -E S O -1 a n d/ or L A G E -1 a p ositiv e a dva nc ed 
t u m ors 
 
•  Ov er all R es po ns e  R at e ( O R R) (i nv esti g ator 
ass ess e d accor di n g t o R E CI S T v 1. 1)  
•  D ur ati o n of R es p o ns e ( Do R)  
S e c o n d ar y –  P h ar m a c o ki n eti c s  ( P K) 
T o c h ar act eriz e i n viv o cell ul ar P K pr ofil e (l ev els, 
ex p a nsi o n, p ersist e nc e) of N Y -E S O -1 a n d L A G E -1 a 
s p ecific T-c ells, al o n e or i n c o m bi n ati o n wit h ot h er 
a g e nts, ov er ti m e  
•  M axi m u m tra ns ge n e ex p a nsi on ( C m ax)  
•  Ti m e t o C m ax ( T m ax)  
•  Ar e a u n d er t he ti m e c urv e fr o m z er o to ti me t 
A U C( 0 -t), as d at a per mit 
E x pl orat ory  
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 1 0  of 7 2  
 
A E = a dv ers e ev e nt/s; A E SI = a dv ers e ev e nt/s of s p eci al i nt er est; A U C ( 0 -t) = ar e a u n d er t h e ti m e c urv e fr o m z er o t o 
ti m e t; C m ax = m axi m u m c o nc e ntr ati o n; C R S = Cyt oki n e R el e as e Sy n dr o m e; D L Ts = d os e -li miti n g t oxiciti es; D N A = 
d e oxyri b o n ucl eic aci d ; D O R = d ur ati o n of r es p o ns e; E C G = El ectr oc ar di o gr a m; 
 
 H L A = h u m a n l e uk ocyt e a nti g e n; 
; N Y-E S O -1 = 
N e w Y ork es o p h a g e al a nti g e n -1; O R R = ov er all r es p o ns e r at e; 
 
 ; R E CI S T = R es p o ns e Ev al u ati o n Crit eri a I n S oli d T u m ors; R N A = ri b o n ucl eic 
aci d; R P2 D  = r ec o m m e n d e d p h as e 2 d os e; S A E = s eri o us a dv ers e ev e nt; T m ax = Ti m e t o C m ax; T C R = T -c ell 
r ec e pt or; 
; † =  P K a n d  
 ex pl or at ory 
e n d p oi nts / a n alys es n ot c ov er e d i n t his S A P will b e d et ail e d i n s e p ar at e P K a n d 
 r e p orti n g a n d a n alysis pl a ns.  
 
1. 2.  
St u d y D e si g n  
1. 2. 1.  
O v er all St u d y D e si g n  
T his is a m ast er pr ot oc ol wit h m ulti pl e s u bst u di es . R ef er t o t h e s u bst u dy-s p ecific S A P f or t h e 
d et ails of t h e d esi g n of  t h e s p ecific s u bst u dy. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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Figure 1 
Overall Study Design 
 
 
Note: Figure 1 is for illustration, for additional substudies please refer to Core Protocol Section 12.12. 
Each substudy will consist of two phases: Dose Confirmation Phase and Dose Expansion Phase.  
Dose Confirmation Phase 
In this phase, each next-generation NY-ESO-1 and LAGE-1a T-cell product will be evaluated to 
assess/confirm the RP2D to be used in further clinical investigations. 
The RP2D will be determined as described in Section 5.1.1 of each substudy protocol.  
Modified Toxicity Probability Interval–2 (mTPI-2) design is used for the dose confirmation phase. 
Details of the design are provided in Section 6.4. 
Dose Expansion Phase 
After RP2D has been determined for a given T-cell product, the dose expansion phase will begin. 
In this phase, additional participants will be enrolled as necessary to meet the substudy 
requirements for the number of evaluable participants treated at the RP2D. Each substudy will 
define the maximal number of participants for this phase in the substudy-specific Section. If 
supported by safety and efficacy results, additional participants may be enrolled to confirm 
safety and efficacy in further cohort expansions. Additional details will be provided in each 
substudy-specific SAP. 
1.2.2. 
Participant Journey 
Participants will undergo stepwise enrolment followed by treatment according to defined 
phases within each substudy. The general patient journey is divided into four distinct parts: 1) 
Screening, 2) Leukapheresis/Manufacture, 3) Lymphodepletion/Treatment and Follow-up, and 
4) Long-term follow-up.  


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Figure 2 
Patient Journey Schema 
 
 
Part 1: Screening 
• 
Target expression Screening for the presence of HLA-A*02 positivity and tumor 
expression of NY-ESO-1 and/or LAGE-1a. For further details regarding HLA testing, 
please refer to the specific substudies. 
• 
Leukapheresis eligibility screening phase to determine eligibility for undergoing 
leukapheresis beginning up to 28 days prior to leukapheresis. 
Part 2: Leukapheresis/Manufacture 
• 
Leukapheresis procedure. 
(Note: leukapheresis may have been performed under another GSK-sponsored protocol 
or substudy of this protocol.) 
Part 3: Lymphodepletion, Treatment, and Follow-up 
• 
Treatment fitness assessment and eligibility confirmation.  
• 
Interventional phase including Lymphodepletion from Days -7 to -4, TCR engineered T-
cell infusion on Day 1, and follow-up as defined in each specific substudy. (Note: TCR 
engineered T-cells may have been manufactured under another GSK-sponsored protocol 
or substudy of this protocol.) 
Part 4: Long-Term Follow-Up (LTFU) 
• 
Long-term follow-up phase for up to 15 years from the date of TCR engineered T-cell 
infusion 
2. 
STATISTICAL HYPOTHESES  
Substudy and, where applicable, cohort-specific null and alternate hypotheses for the overall 
response rate (ORR) during the dose expansion phase will be described in the substudy-specific 
SAP. No inferential statistical hypothesis testing will be conducted i.e., no p-values will be 
calculated. 


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2.1. 
Multiplicity Adjustment 
No formal statistical hypothesis testing will be performed and therefore no multiplicity 
adjustment is required.  
3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Screened  
All participants who signed an ICF to participate in 
the study. 
• Screen Failures 
Enrolled[1]   
All participants who started leukapheresis 
procedure. 
 
Note: this analysis set will include patients that did 
not meet the treatment eligibility criteria prior to 
lymphodepletion or patients that withdrew or died 
prior to lymphodepletion or T-cell infusion. 
• Specific required Study 
Population displays 
ITT  
All participants who started leukapheresis 
procedure. 
 
Note: this analysis set will include patients that did 
not meet the treatment eligibility criteria prior to 
lymphodepletion or patients that withdrew or died 
prior to lymphodepletion or T-cell infusion. 
• Study Population 
• Safety (where 
appropriate) 
• Sensitivity for Secondary 
Efficacy Endpoint (ORR) 
Lymphodepletion  
All ITT participants who started lymphodepletion 
chemotherapy.  
• Safety – including AEs 
and Exposure 
Modified ITT 
(mITT) 
All ITT participants who received any dose of 
NY-ESO-1 specific T-cells.  
• Safety (where 
appropriate) 
• Efficacy 
DLT Evaluable 
Participants in the mITT analysis set who are part of 
the dose confirmation phase that either had a DLT 
(meeting the definition of a DLT as defined in 
Section 8.2 of the Core Protocol) or have completed 
the DLT assessment period of 28 days since last T-
cell infusion. 
Note: For participants who receive a single dose, 
the DLT assessment period is up to and including 
Day 28, and for participants who receive split dose, 
the DLT assessment period is up to and including 
Day 28 after the second split-dose. 
• Safety – summary of 
DLTs for dose 
confirmation phase 
Modified ITT 90  
(mITT 90)[2] 
Participants in the mITT analysis set who have been 
followed-up for at least 90 days since the last T-cell 
infusion. 
• Safety – summary of 
delayed AEs 


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Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Evaluable[3]  
Participants in the mITT analysis set who received 
the RP2D and have completed at least 2 disease 
assessments after infusion or progressed or died or 
were withdrawn or lost to follow-up from the 
sub-study. 
• Interim Analysis (for 
dose expansion 
participants and dose 
confirmation participants 
who received RP2D) 
Pharmacokinetic 
(PK) 
Participants in the mITT analysis set from whom at 
least one persistence sample was obtained, 
analysed, and was measurable. 
• PK 
AE = adverse event; DLT = dose limiting toxicity; ICF = informed consent form; ITT = intention-to-treat; ORR = 
overall response rate; PK = pharmacokinetics; RP2D = recommended phase 2 dose.  
[1] Enrolled and ITT analysis sets are identical. The enrolled analysis set is required for disclosure reporting by 
EUdraCT.  
[2] Note that mITT 90 analysis set will not be used since summary of delayed AEs will not be produced following 
termination of substudies.  
[3] Note that all substudies were terminated prior to achieving RP2D and therefore the Evaluable Analysis Set is 
not required for analysis purposes. 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
References to T-cell infusion and T-cell infusion dates throughout the SAP documents are in 
reference to Study 209012 TCR T-cell therapies GSK3901961, GSK3845097, GSK4427296 but not 
GSK3377794 (letetresgene autoleucel, lete-cel), unless otherwise stated.  
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 participants (n), mean, standard deviation, median, minimum, and maximum. 
Categorical data will be summarized as the number and percentage of participants in each 
category. 
Details on the presentation of results are included in substudy-specific SAPs and OPS.  
In general, and unless otherwise specified, participant data will be summarized overall and 
according to either the planned dose range, the actual dose range received, or both depending 
on the data type, as indicated in Table 1. See Section 4.1.5 on the handling of split-dose 
participants for summaries by actual treatment. Listings will be presented by actual treatment, 
unless otherwise specified. 
Table 1 
Presentation of Summaries by Planned/Actual Dose 
 
Present by Planned/Actual Treatment 
Analysis Sets 
Planned and Actual 
T-Cell Infusion Status 
Planned 
Demographic and Baseline Characteristics 
Actual 
Exposure  
Planned 


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Present by Planned/Actual Treatment 
Safety 
Actual 
DLT frequency counts 
Actual & Planned 
DLT Rates 
Actual 
Efficacy 
Actual 
PK 
Actual 
 
Confidence intervals (CI) will use 95% confidence levels unless otherwise specified. 
Details of the planned displays, including those that will be presented for the Interim, Primary 
and Final analyses, are provided in the Core and substudy-specific OPS documents and are 
based on GSK data standards and statistical principles.  
4.1.2. 
Baseline Definition 
Among the participants with lymphodepleting chemotherapy, the baseline value is defined as 
the latest assessment with a non-missing value (including unscheduled visits) prior to initiating 
lymphodepletion (except as noted in Table 2). If time is not collected, assessments taken on the 
day of lymphodepleting chemotherapy are assumed to be taken prior to lymphodepletion and 
used as baseline. If a non-missing assessment within 10 days of initiating lymphodepletion is not 
available, then the last assessment with a non-missing value prior to initiating lymphodepletion 
would be used even if it occurred more than 10 days prior to initiating lymphodepletion. 
For laboratory data, baseline will be defined as the most recent, non-missing value from a 
central laboratory prior to initiating lymphodepletion. If there are no central laboratory values 
collected for a substudy or a participant and the laboratory test is prior to lymphodepletion, the 
most recent, non-missing value from a local laboratory prior to initiating lymphodepletion will 
be defined as the baseline value.  
For summaries of laboratory data by NCI-CTCAE v5.0 grade, missing baseline grades will be 
assumed as grade 0.  
For ECG analyses, the participant level baseline is defined as the mean of the triplicate baseline 
assessments. 
Unless otherwise stated, missing baseline data will not be imputed. 
Table 2 
Baseline Considerations 
Parameter 
Study Assessments Considered as Baseline 
Baseline Used in 
Data Display 
Target Expression 
Screening 
Treatment Eligibility 
Screening/ Baseline 
[Efficacy] 
Target and Non-target 
lesions 
 
X 
Prior to 
lymphodepletion 
[Safety] 


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Parameter 
Study Assessments Considered as Baseline 
Baseline Used in 
Data Display 
Target Expression 
Screening 
Treatment Eligibility 
Screening/ Baseline 
Hematology, Chemistry, 
Additional Lab 
Parameters 
 
X 
Prior to 
lymphodepletion 
Vital Signs, Physical 
Exam, ECOG 
 
X 
Prior to 
lymphodepletion 
Electrocardiograms 
 
X 
Prior to 
lymphodepletion 
Immunogenicity 
 
X 
Prior to 
lymphodepletion 
[Demography] 
Demography 
X 
 
Target Expression 
Screening 
[PK] 
T-cell persistence  
 
X 
Prior to 
lymphodepletion 
 
4.1.3. 
Multicentre Studies 
Data from all participating centres will be pooled prior to analysis. 
It is anticipated that participant accrual will be spread thinly across centres and summaries of 
data by centre would be unlikely to be informative and will not, therefore, be provided.  
Enrolment will be summarized by centre.  
4.1.4. 
Selection of RP2D 
As of Core SAP Amendment 2: Note that all substudies were terminated prior to the 
determination of RP2D. Any references to RP2D in the text are not applicable.  
Selection of the RP2D will be based on the mTPI-2 approach described in Section 6.4. The 
Interim Analysis will be based on 10 evaluable participants within a cohort who received a cell 
dose infusion at the RP2D. Additional supplementary analyses may be performed, selecting 
participants based on similarity in PK cell expansion/persistence profile using parameters such 
Cmax and AUC. 
4.1.5. 
Split-dose Participants 
The sentinel participant is the first study participant per substudy (if applicable for substudy) 
receiving NY-ESO-1 and/or LAGE-1a specific T-cells as two separate infusions, 7 days apart, in 
aliquots of ~30% (first infusion) and ~70% (second infusion) of the total manufactured dose, 
respectively. If DLTs are reported for sentinel participants receiving split doses, additional 
participants may be treated with a split-dose regimen. 


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For the purpose of summaries and listings presented by actual dose, split-dose participants will 
be summarised based on the actual cell dose received as follows: 
• 
If both doses are infused, the actual cell dose would be the sum of the two doses. 
• 
If only the first dose was infused, this would be actual cell dose. 
Split-dose participants will be included in the RP2D provided the participant had received a cell 
dose infusion at the RP2D. 
4.1.6. 
Participants Receiving Prior Letetresgene autoleucel 
(GSK3377794, lete-cel) Therapy 
As of Core SAP Amendment 2: Due to early termination of the study during the dose 
confirmation phase this section of text is no longer applicable.  
 
Participants who achieved a confirmed RECIST v1.1 response of complete response (CR) or 
partial response (PR), or stable disease (SD) ≥3 months following treatment with letetresgene 
autoleucel (GSK3377794, lete-cel) on another GSK sponsored study/substudy may be considered 
for eligibility for certain substudies (if applicable) following discussion with the Sponsor Medical 
Monitor. 
For the applicable substudy, there will be no more than 3 participants who were previously 
treated with lete-cel to be permitted. These participants will not be permitted on a substudy 
until at least after the dose confirmation phase is complete, hence will not be included in the 
dose confirmation analyses used to determine the RP2D. These participants may be included in 
the 10 evaluable participants for the Interim Analysis. 
4.2. 
Primary Endpoint(s) Analyses 
4.2.1. 
Definition of endpoint(s) 
The primary endpoints are frequency of dose-limiting toxicities (DLTs), frequency and severity of 
adverse events (AEs) and serious adverse events (SAEs) and frequency and severity of the AEs of 
special interest (AESIs). 
DLTs are toxicities that are considered to be at least possibly related to transduced T-cells and 
that occur within the DLT-assessment period of 28 days after initial dosing of T cells. For 
participants receiving T cells as a split dose, the DLT assessment period will begin at the start of 
the first infusion and continue for 28 days after completion of the last infusion. Refer to Core 
Protocol Section 8.2 for the full definition of a DLT.  
4.2.2. 
Main analytical approach 
Refer to Safety Analyses Section 4.5.  
4.2.3. 
Strategy for intercurrent events 
Not applicable. 


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4.2.4. 
Sensitivity analyses 
Not applicable. 
4.2.5. 
Additional estimands 
Not applicable. 
4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Efficacy secondary endpoint(s) 
4.3.1.1. 
Definition of endpoint(s) 
4.3.1.1.1. 
Overall Response Rate (ORR)  
ORR is defined as the percentage of participants with a confirmed complete response (CR) or a 
confirmed partial response (PR) as the BOR (Best Overall Response) relative to the total number 
of participants within the relevant cohort and analysis population per RECIST v1.1 as determined 
by the local investigators. 
Participants with either no valid post-baseline assessment, or have non-measurable disease at 
baseline, or experience death prior to the first disease assessment will be treated as non-
responders i.e., these participants will be included in the denominator when calculating the ORR 
and best confirmed response will be summarized as Not Evaluable (NE). 
Best Overall Response (BOR) as per RECIST v1.1: 
The investigator reported disease assessment, as assessed by RECIST v1.1, will be considered 
from best to worst in the order of Complete Response (CR) > Partial Response (PR) > Stable 
Disease (SD) > Progressive Disease (PD) > Not Evaluable (NE). The BOR will be derived as the 
best response recorded from the start of the treatment i.e., 1st T-cell infusion date until disease 
progression or initiation of new anti-cancer therapy, whichever is earlier. 
• 
Note: Unconfirmed responses of CR or PR may be included as a supplementary BOR 
derivation and listed, in which case the BOR will be considered from best to worst in the 
order of CR > Unconfirmed CR > PR > Unconfirmed PR > SD > PD > NE. 
Confirmation Criteria:  
A response of CR or PR is confirmed if the criteria for each are met at a subsequent time point at 
least 28 days later but before disease progression or initiation of new anti-cancer therapy, 
excluding assessments that are not evaluable (NE). 
The following additional rules will be followed during the derivation: 
• 
The date of disease progression is defined as the date of radiological disease 
progression based on imaging data per RECIST v1.1. For cases where symptomatic 
progression is documented by the investigator, the derived overall response based on 
RECIST v1.1 tumor assessment data will be utilized. 
• 
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 28 days after the criteria for response are first met.  


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• 
To be assigned a status of stable disease (SD), follow-up disease assessment must have 
met the SD criteria at least once after the start of treatment at a minimum interval of 28 
days (Core Protocol Section 12.6.1). This period includes 1st T-cell infusion and 
assessment day +1.  
• 
If the minimum time of 28 days for SD is not met, best response will depend on the 
subsequent assessments. For example, if an assessment of PD follows the assessment of 
SD, and SD does not meet the minimum time requirement, the best response will be PD. 
Alternatively, participants lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable. 
• 
Responses of CR/PR that do not meet the requirements of confirmed CR/PR are still 
eligible to be considered SD if they have met the SD criteria. 
• 
Assessments that are not done or not evaluable should be disregarded. 
• 
SD responses between two PR responses for a participant will be handled as follows: 
a) If there is one SD response between two PR responses (i.e., PR-SD-PR) then the 
best overall response will be confirmed PR, provided the participant meets the 
requirements of a confirmed PR. 
b) If there are two SD responses between two PR responses (i.e., PR-SD-SD-PR) 
then the best overall response will not be confirmed PR.  
• 
Disease assessments after on-study start of new anti-cancer therapy will not be 
considered when deriving best overall response. On-study anti-cancer therapies are 
defined in Section 6.1.5.2. 
• 
If time is not collected and anti-cancer therapy starts on the same day as the disease 
assessment, it is assumed that the disease assessment occurred first.  
• 
Study inclusion criteria require participants to have measurable disease at baseline 
according to RECIST v1.1. If this is violated and a participant has no measurable disease 
at baseline, then the participant will be treated as a non-responder and included in the 
denominator when calculating the ORR. Participants with no disease assessments on-
study will also treated as non-responders and included in the denominator when 
calculating the ORR.  
Table 3 summarizes the derivation of confirmed response and BOR per RECIST v1.1. 
Table 3 
Best Overall Response per RECIST v1.1 and Additional 
Programming Notes 
Overall response 
first time point 
Overall response 
subsequent time point 
Best overall response 
Additional 
Programming Notes 
CR 
CR 
CR 
Confirmatory response of 
CR is required >=28 days 
after initial CR 
CR 
PR 
SD provided minimum 
criteria for SD duration 
met**, otherwise, PD 
SD (if >=28 days per SD 
criteria); otherwise 
PD  


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Overall response 
first time point 
Overall response 
subsequent time point 
Best overall response 
Additional 
Programming Notes 
CR 
SD 
SD provided minimum 
criteria for SD duration 
met**, otherwise, PD* 
SD (if >= 28 days per SD 
criteria); Otherwise PD 
CR 
PD 
SD provided minimum 
criteria for SD duration 
met**, otherwise, PD 
SD (if >= 28 days per SD 
criteria); Otherwise 
PD 
CR 
NE 
SD provided minimum 
criteria for SD duration 
met**, otherwise NE 
SD (if >= 28 days per SD 
criteria); Otherwise 
NE 
PR 
CR 
PR 
Confirmatory response of 
PR is required >=28 days 
after initial CR 
PR 
PR 
PR 
Confirmatory response of 
PR is required >=28 days 
after initial PR 
PR 
SD 
SD provided minimum 
criteria for SD duration 
met**, otherwise, NE 
SD (if >= 28 days per SD 
criteria); Otherwise 
NE. 
Note: if after SD there is a 
PR (i.e., PR-SD-PR) then 
BOR is PR. 
 
PR 
PD 
SD provided minimum 
criteria for SD duration 
met**, otherwise, PD 
SD (if >= 28 days per SD 
criteria); Otherwise 
PD 
PR 
NE 
SD provided minimum 
criteria for SD duration 
met**, otherwise, NE 
SD (if >= 28 days per SD 
criteria); Otherwise 
NE 
SD 
CR 
SD provided minimum 
criteria for SD duration 
met**, otherwise, NE 
SD (if >= 28 days per SD 
criteria); Otherwise 
NE 
SD 
PR 
SD provided minimum 
criteria for SD duration 
met**, otherwise, NE 
SD (if >= 28 days per SD 
criteria); Otherwise 
NE. 
 
Note: if prior to SD there 
is a PR (i.e., PR-SD-PR) 
then BOR is PR. 


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Overall response 
first time point 
Overall response 
subsequent time point 
Best overall response 
Additional 
Programming Notes 
SD 
SD 
SD provided minimum 
criteria for SD duration 
met**, otherwise, NE 
SD (if >= 28 days per SD 
criteria); Otherwise 
NE 
SD 
PD 
SD provided minimum 
criteria for SD duration 
met**, otherwise, PD 
SD (if >= 28 days per SD 
criteria); Otherwise 
PD 
SD 
NE 
SD provided minimum 
criteria for SD duration 
met**, otherwise, NE 
SD (if >= 28 days per SD 
criteria); Otherwise 
NE 
NE 
NE 
NE 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
not evaluable. 
* If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR). Best response would depend on whether minimum duration for SD was met.  
** Minimum criterion for SD disease duration is at least 4 weeks to qualify SD as BOR. 
Note: If BOR is confirmed CR or PR, the subject is classified as a responder for the ORR analysis. 
4.3.1.1.2. 
Duration of Response (DOR)  
Duration of response (DOR) is defined as the interval of time (in months) from first documented 
evidence of the confirmed response (PR or CR) to the date of disease progression per RECIST 
v1.1 Criteria or death due to any cause, among participants with a confirmed response of PR or 
CR as the BOR.  
Censoring rules for the DOR will follow those for PFS (Section 4.4.1.2) and as specified in Table 4.  
4.3.1.2. 
Main Analytical Approach 
4.3.1.2.1. 
ORR 
The observed confirmed ORR along with the 95% Clopper-Pearson exact confidence intervals, 
will be summarized based on the mITT analysis set.  
In addition, the number and percentage of participants with the BOR in the following response 
categories as per RECIST v1.1 will be summarized: CR, PR, SD, PD, NE, and overall response 
(CR+PR).  
An overall listing of participant response data will be provided for the ITT analysis set. This listing 
will display all the investigator response evaluations, the best confirmed response, whether the 
participant is ongoing in the study, and whether the participant is in the mITT analysis set. All 
supporting lesion data will be listed. 
Change in sum of target lesion diameters from baseline over time for the mITT analysis set will 
be shown in a spider plot where data from all available tumor assessments will be displayed. 
The BOR, disease progression (first PD and confirmed PD, where applicable) and initiation of 
new anti-cancer therapy will be indicated on the plot.   


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4.3.1.2.2. 
DOR 
DOR will be summarized based on the mITT analysis set using the Kaplan-Meier method. The 
median, 25th and 75th percentiles of DOR will be estimated and corresponding 95% confidence 
intervals will be estimated using the (Brookmeyer-Crowley method, 1982) under a log-log 
transformation. The Kaplan-Meier estimates will only be produced for a cohort if there are 5 or 
more confirmed responses within that cohort. If this condition is not met, standard summary 
statistics will be presented. A supportive listing will be provided on the mITT analysis set.  
4.3.1.3. 
Strategy for Intercurrent Events 
For ORR 
A composite strategy will be followed for participants who experience death prior to response 
assessments. These participants will be treated as non-responders (NE) i.e., they will be included 
in the denominator when calculating the ORR. 
The intercurrent event of start of on-study/follow-up anti-cancer therapy is addressed using a 
while-on-treatment strategy, as the interest lies in the treatment effect of the investigational 
treatments before start of new anti-cancer therapy. Only tumor assessments performed before 
initiation on-study/follow-up anti-cancer therapy will be considered for BOR.  
For DOR 
A composite strategy will be followed for participants who experience death prior to response 
assessments. If death occurs it is considered a progression event and the end of response 
duration.  
The intercurrent event of start of on-study/follow-up anti-cancer therapy started before 
documented PD or death is addressed using a hypothetical strategy, because the interest lies in 
the treatment effect attributable to the investigational treatments and not confounded by other 
anti-cancer therapies. Only tumor assessments performed before initiation of on-study/follow-
up anti-cancer therapy will be considered for DOR.  
4.3.2. 
Pharmacokinetics (PK) secondary endpoint(s) 
4.3.2.1. 
Drug persistence 
T-cell vector copies (expansion/persistence) in the peripheral blood will be measured in 
participants by quantitation of transduced cells by polymerase chain reaction (PCR) of transgene 
from DNA extracted from Peripheral blood mononuclear cell (PBMC). Persistence will be 
measured to establish the relationships with response to the study intervention as well as a 
long-term safety measure.  For all PK analyses, expansion/persistence of the engineered T-cells 
will be applied in lieu of “concentration” to derive PK parameters.   
4.3.2.2. 
Definition of endpoints 
Maximum expansion/persistence (Cmax), time to Cmax (Tmax), and area under the time curve from 
1st T-cell infusion to 28 days (AUC0-28d), are secondary pharmacokinetic endpoints that will be 
determined from the persistence-time data, as data permits.  


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Parameter 
Parameter Description 
AUC0-28d 
Area under the persistence-time curve from 1st T-cell infusion to 28 days will be calculated 
using the linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule 
for each decremental trapezoid. 
Cmax 
Peak cell expansion, determined directly from the persistence-time data. 
Tmax 
Time to reach Cmax, determined directly from the persistence-time data. 
NOTES: 
Additional parameters, such as area under the time curve from 1st T cell infusion to time t (AUC0-t) may be 
included as required, as data permit. 
4.3.2.3. 
Main analytical approach 
All pharmacokinetic analyses will be based on the PK population. All raw persistence and derived 
PK parameters will be listed. 
Pharmacokinetic parameters will be calculated using standard non-compartmental analyses 
according to current working practices and using appropriate software. All calculations of non-
compartmental parameters will be based on actual sampling times. 
For each of these parameters, except Tmax, the following summary statistics will be calculated: 
median, minimum, maximum, arithmetic mean, 95% confidence interval for the arithmetic 
mean, standard deviation, coefficient of variation, geometric mean, 95% confidence interval for 
the geometric mean and standard deviation of logarithmically transformed data. 
Note: Coefficient of variation (CV) = 100*(sqrt (exp(SD2) - 1))), where SD = standard deviation of 
log transformed data.  
For Tmax, median, maximum, minimum, arithmetic mean, 95% confidence interval, and standard 
deviation will be calculated.  
Spider plots will be used to graphically summarize persistence (copies/µg gDNA) over time for 
each participant. 
All PK parameters will be reported to at least 3 significant digits, but to no more significant digits 
than the precision of the original data. 
Drug Concentration Measures 
The following calculations will be performed: 
• 
copies/cell=(copies/µg) x (0.0000063 µg gDNA/cell) 
• 
Percent gene marked peripheral blood mononuclear cells (PBMCs) =(copies/cell) *100 
The final reported result of copies/µg gDNA is calculated as follows: 
• 
copies/µg gDNA=copies per well/µg gDNA per well 
For persistence values below LLOQ, the following rules will be applied:  
 
Reported Copies per 
cell Result  
Reported Copies per 
ug DNA Result  
Interpretive 
Reported Result  
Set Value for Copies 
per cell  
Set Value for 
Copies per ug DNA  
<0.0003  
<50.0  
Negative  
0  
0  


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 2 4  of 7 2  
 
< 0. 0 0 0 3   
< 5 0. 0   
D et ect a bl e, <LL O Q   0. 0 0 0 3   
5 0   
  
N ot e, s o m eti m es v al u es f or c o pi es p er c ell a n d c o pi es p er u g D N A mi g ht b e diff er e nt t h a n a b o v e 
as it d e p e n ds o n t h e i n p ut of D N A, b ut r ul e w o ul d b e t h e s a m e:   
•  
If i nt er pr etiv e r e p ort e d r es ult is “ N e g ati v e”, s et v al u es at 0.   
•  
If i nt er pr etiv e r e p ort e d r es ult is “ D et ect a bl e, <LL O Q”, s et v al u es at LL O Q (If < X X X, s et at 
X X X) .  
4. 4.  
 E x pl or at or y E n d p oi nt( s) A n al y s e s  
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 2 5  of 7 2  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 2 6  of 7 2  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 2 7  of 7 2  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 2 8  of 7 2  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 2 9  of 7 2  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 3 0  of 7 2  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 3 1  of 7 2  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 3 2  of 7 2  
 
C CI


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 3 3  of 7 2  
 
C CI


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4.5. 
Safety Analyses 
The primary safety analysis will be based on the modified ITT population. Additional analyses 
will be presented using the DLT Evaluable, ITT and Lymphodepletion populations, as 
appropriate. Adverse events analyses will be based on different analysis sets for different AE 
phases as summarized in Table 7. 
4.5.1. 
Adverse Events 
4.5.1.1. 
Dose Limiting Toxicities 
Dose-limiting toxicities (DLTs) will be listed for each subject and summarized by frequency and 
proportion by actual treatment (see Table 1). Additionally a summary of the frequency of DLTs 
broken down by the actual treatment within each planned treatment cohort will be presented. 
Reported DLTs will be those collected on the eCRF. Summaries will be based on the DLT 
Evaluable population.  
4.5.1.2. 
AE Standards and Grading Criteria 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs), AEs 
related to study-treatment (lymphodepletion chemotherapy and T-cell infusion), SAEs related to 
study-treatment and other significant AEs will be based on GSK Core Data Standards. 
AEs will be graded according to National Cancer Institute-Common Toxicity Criteria for Adverse 
Events (NCI-CTCAE) version 5.0 or higher unless otherwise specified in the protocol. For 
instance, the grading of Cytokine Release Syndrome (CRS) and ICANS will be performed using 
the American Society for Transplantation and Cellular Therapy (ASTCT) grading criteria (Lee, 
2019); see Core Protocol Section 12.7.5 and Section 12.7.8.1. For the grading of Graft versus 
Host Disease (GVHD), see Core Protocol Section 12.7.6.2. AEs will be coded using the latest 
version of the Medical Dictionary for Regulatory Affairs (MedDRA). 
Per GSK standard, AEs that have grade changes over the course of the event are entered in the 
same record within the eCRF, with grade changes indicated within. Other attributes of the event 
(e.g., seriousness, relatedness) are attributed to the overall event.  
For specific AE displays, Preferred Terms are combined and will be reported together as one 
term. The combined terms for MedDRA Version 25.1 are listed in Section 6.3. Changes to the 
MedDRA dictionary may occur between the start of the study and the time of reporting and/or 
emerging data from on-going studies may highlight additional combined terms, therefore the 
list of combined preferred terms will be based on the safety review team (SRT) agreements in 
place at the time of reporting. A table showing the relationship between the combined 
preferred term and contributing preferred terms will be produced. Tables that summarize AEs 
by SOC and PT will use MedDRA preferred terms. Most other Tables will summarize AEs using 
the combined term in Section 6.3, unless otherwise specified. 
4.5.1.3. 
AE Phases 
AEs will be summarized in the following phases amongst participants which have entered the 
phase (Table 7). These phases are defined in more detail in Section 4.5.1.5. The analyses for 
each phase are presented in Section 4.5.1.5. 


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Table 7 
 AE phases 
Phase 
Definition  
Population  
Pre-Lymphodepletion Phase AEs which start prior to lymphodepletion 
chemotherapy  
Intent-to-Treat Population  
Lymphodepletion Phase 
AEs which start or worsen on or after the start 
of lymphodepletion chemotherapy until prior 
to 1st T-cell infusion  
Lymphodepletion Population  
T-cell Phase (Treatment-
Emergent)  
AEs which start or worsen on or after 1st T-
cell infusion  
mITT Population  
 
4.5.1.4. 
General AE summaries 
AEs which start within the phase or worsen after initiation of the phase (maximum grade after 
initiation of the phase is larger than the maximum grade before initiation of the phase) will 
qualify to be summarized in the phase. AEs may be summarized in multiple phases (ex: A Grade 
2 AE after lymphodepletion increases to Grade 3 after T-cell infusion and is therefore 
summarized as a Grade 2 in the lymphodepletion phase and a Grade 3 in the T-cell Phase).  
The primary analysis of AEs will be performed for AEs which started or worsened in the T-cell 
Phase i.e., treatment-emergent AEs. However additional analyses will be performed in the 
phases above. The full definition of treatment emergence by phase are detailed in Section 
6.2.3.4.  
All AEs collected in the ITT population will be listed and the phase assigned to the AE will be 
indicated in the listing. AEs which led to study treatment withdrawal, interruption, delay, or 
reduction of any study treatment (cyclophosphamide, fludarabine, or T-cell infusion) will be 
flagged in the listing as collected in the eCRF. Additionally, a listing of participant IDs for each 
individual AE will be produced.  
SAEs will be included in the listing of all AEs, but also separate supportive listings with 
participant-level details will be generated for: 
• 
Fatal SAEs 
• 
Non-fatal SAEs 
• 
Reasons for considering AE as serious 
AEs will be summarized and displayed in descending order of total incidence by SOC and PT. In 
the SOC row, the number of participants with multiple events under the same system organ 
class will be counted once. 
Summaries of number and percentage of participants with AEs by maximum grade will also be 
produced. AEs will be sorted by combined PT in descending order of total incidence. The 
summary will use the following algorithms for counting the participant: 


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• 
Combined preferred term row: Participants experiencing the same combined preferred 
term several times with different grades will only be counted once with the maximum 
grade. 
• 
Any event row: Each participant with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have. 
Summaries will be provided for lymphodepletion-related and T-cell-related AEs separately. 
These study treatment-related AEs are defined as an AE for which the investigator classifies the 
relationship to study treatment as “Yes”. For example, lymphodepletion-related AEs include 
lymphodepletion or treatment-emergent AEs that are reported as related to fludarabine and/or 
cyclophosphamide per investigators; T-cell-related AEs include AEs that are reported as related 
to T-cell per investigators. A worst case scenario approach will be taken to handle missing 
relatedness data i.e., the summary table will include events with the relationship to study 
treatment as ‘Yes’ or missing. 
A summary of common non-serious AEs that occurred in 5% of the participants or above will be 
provided (no rounding for the percentage will be used in terms of 5% threshold, e.g., events 
with 4.9% incidence rate should not be included in this Table). This summary will contain the 
number of subjects and occurrences of participants with common non-serious AEs. The 
summary table will be displayed by SOC and PT. 
A summary of All Serious Adverse Events by System Organ Class (SOC) and Preferred Term (PT) 
will also be created to detail the number of participants and occurrences of each event. 
4.5.1.5. 
AE summaries by Phase 
In the AE summaries mentioned below, it refers to all AEs including those collected in the non-
serious AE page and SAE page from eCRF. 
Analyses for all AEs:  
o Common non-serious AEs (number of subjects and occurrences) 
o SAEs (number of subjects and number of occurrences of SAEs, T-cell related SAEs, Fatal 
SAEs and T-cell related Fatal SAEs)  
Analyses for AEs in the Pre-Lymphodepletion Phase will include: 
• 
Summary by maximum grade 
o AEs and SAEs 
Analyses for AEs in the Lymphodepletion Phase will include: 
• 
Summary by maximum grade 
o AEs 
o SAEs 
Analyses for treatment-emergent AEs will include: 
• 
Summary of AEs by System Organ Class and Preferred Term (using PT term) 


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o AEs and SAEs 
• 
Summary by maximum grade  
o AEs 
o SAEs 
o T-cell related AEs 
o Lymphodepletion related AEs and SAES 
o T-cell related SAEs 
• 
Descending frequency (using Preferred Term) 
o Non serious T-cell related AEs  
o Serious fatal and non-fatal T-cell related AE 
4.5.1.6. 
Delayed AEs 
Delayed AEs as defined in the FDA 2020 Guidance- Long Term Follow-Up After Administration of 
Human Gene Therapy Products [FDA, 2020a] are identified through sponsor adjudication as the 
primary method of reporting. Sponsor adjudication will focus on AEs starting 90 days after 
administration of T-cell therapy that fall into one of following categories:  
• 
New malignancies 
• 
New incidence or exacerbation of a pre-existing neurological disorder 
• 
New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder 
• 
New incidence of an immune related hematologic disorder 
• 
Serious infections or non-serious pulmonary or opportunistic infections   
• 
Unanticipated illness or hospitalization deemed related to gene modified cell therapy 
Events that meet the criteria above, are study-treatment related events and are serious and/or 
Grade 3 will be the primary focus of sponsor adjudication, although adjudication is not limited 
to these criteria.  
Delayed AEs are also identified by the investigator and captured in the CRF. Delayed AEs as 
adjudicated by the sponsor (provided from external data source) and identified by the 
investigator will be listed separately on the mITT analysis set. 
4.5.1.7. 
Adverse Events of Special Interest 
Adverse events of special interest (AESIs) covered in this SAP include: 
• 
Cytokine Release Syndrome (CRS) 
• 
Haematopoietic cytopenias (including pancytopenia and aplastic anaemia) 
• 
Graft versus Host Disease (GvHD) 
• 
Immune Effector-Cell Associated Neurotoxicity Syndrome (ICANS) 
• 
Guillain-Barre Syndrome (GBS) 
• 
Pneumonitis 
• 
Treatment-related inflammatory response at tumor site(s) 


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All analyses of AESIs will be performed in the T-cell Phase (treatment emergent) using the mITT 
analysis set, unless otherwise stated. Each summary will only be produced if there are ≥3 
corresponding AESIs.    
A focused list of MedDRA terms based on clinical review will be used to identify each type of 
event and will be used for AESI reporting. In addition, a comprehensive list of MedDRA terms 
aligning with MedDRA SMQ list will also be used for AESI reporting (data set only, no tables or 
listings). Changes to the MedDRA dictionary may occur between the start of the study and the 
time of reporting and/or emerging data from on-going studies highlight additional adverse 
events of special interest, therefore the list of terms to be used for each event of interest and 
the specific events of interest will be based on the safety review team (SRT) agreements in place 
at the time of reporting.  
The protocol-identified AESI, treatment-related inflammatory response at tumor site, is non-
specific and will not be identified using the focused or comprehensive list. Investigator identified 
AEs which may be related to this event will be used to characterize this AESI. 
The number and percentage of participants with treatment emergent AESIs and serious 
treatment emergent AESIs will be summarized by categories of AESI, combined preferred term, 
and grade using the focused list . Haematopoietic cytopenias will be summarized using 
the focused list, and presented overall, as well as by cell lines Neutropenia, Thrombocytopenia 
and Anemia.  
Cytokine Release Syndrome 
The following analyses will be provided: 
• 
Among subjects which experienced CRS, a summary of onset and duration of the first 
occurrence of CRS identified using the focused list will be provided.  
A supporting CRS listing profile will be provided to detail the CRS adverse event, display the 
procedures and medications received to treat CRS and display symptoms associated with the 
event. 
Haematopoetic Cytopenias 
The following analyses will be provided: 
• 
Summary of onset and duration of the first occurrence of febrile neutropenia. 
• 
Listing of persistent cytopenias 
o Persistent cytopenias will be based on laboratory values. Please refer to Section 
4.5.2. 
A supporting Pancytopenia listing profile will be provided to detail these events. 
Graft versus Host Disease (GvHD) 
The following analyses will be provided: 
• 
Summary of onset and duration of the first occurrence of GvHD identified using the 
focused list. 


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A supporting GvHD listing profile will be provided to detail these events. 
Immune Effector-Cell Associated Neurotoxicity Syndrome (ICANS) 
The following analyses will be provided: 
• 
Summary of onset and duration of the first occurrence of ICANS identified using the 
focused list. 
A supporting ICANS listing profile will be provided to detail these events. 
Guillain-Barre Syndrome (GBS) 
A supporting GBS listing profile will be provided to detail these events.  
Pneumonitis 
The following analyses will be provided: 
• 
Summary of onset and duration of the first occurrence of Pneumonitis identified using 
the focused list. 
A supporting Pneumonitis listing profile will be provided to detail these events. Note that in 
209012 Protocol Amendment 3, pneumonia was also included as an AESI. Pneumonia will be 
listed in a separate profile listing but will not be summarized as an AESI. 
4.5.1.8. 
COVID-19 Assessment and COVID-19 AEs 
Separate summaries of COVID-19 AEs will not be produced. The incidence of COVID-19 AEs at 
individual PT level can be obtained from the standard AE/SAE summaries and listings. COVID-19 
AEs leading to study drug discontinuation and study withdrawal can be found in the associated 
listing. 
4.5.2. 
Clinical Laboratory Analyses 
The tests detailed below will be performed by the laboratory. 
Laboratory 
Assessments 
Parameters 
Haematology 
Platelet Count  
RBC Indices: 
• 
MCV 
• 
MCH 
• 
Reticulocytes 
WBC count with 
Differential: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Flow cytometry 
CD3/CD4/CD8 
 
 
 
Clinical Chemistrya 
BUNb 
Potassium 
AST (SGOT) 
Total and direct 
bilirubin 
Creatinine 
Sodium 
ALT (SGPT) 
Total Protein 
Glucose [nonfasting] 
Calcium 
Alkaline 
phosphatase 
Chloride 
Albumin 
Phosphorus 
LDH 
Urea 


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Laboratory 
Assessments 
Parameters 
Magnesium 
Bicarbonate 
 
Coagulation 
INR, PT, and aPTT, 
Fibrinogen 
 
 
 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Other Tests 
• 
CMV IgG and PCR 
• 
TSH with free T4 
• 
CRP 
• 
Uric acid 
• 
GFR or 24 hour Urine 
• 
Follicle-stimulating hormone (as needed in women of non-childbearing potential only) 
• 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)c 
• 
HIV, HBV, HCV, HTLV, EBV, and syphilis (spirochete bacterium). 
• 
Ferritin 
• 
Serum troponin 
• 
NT-proBNP / BNP 
a. 
Details of liver chemistry monitoring criteria and required actions and follow-up assessments after liver monitoring 
event are given in Core Protocol Section 8.2.1. All events of ALT 3 × ULN and bilirubin 2 × ULN (>35% direct 
bilirubin) or ALT 3 × ULN and INR >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s 
Law), must be reported as an SAE. 
b. 
Either BUN or UREA tests are acceptable. 
c. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Note: All study-required laboratory safety assessments will be performed by a local laboratory, exception of alleles 
HLA-A*02:01, A*02:05, or A*02:06 and NY-ESO-1/LAGE-1a expression. The results of each test must be entered into 
the eCRF. 
 
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = Aspartate aminotransferase; 
BUN = blood urea nitrogen; CMV = cytomegalovirus; CRP = C-reactive protein; EBV = Epstein Barr virus; GFR = 
glomerular filtration rate; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
HTLV = human T-lymphotropic virus; INR = international normalized ratio; LDH = lactate dehydrogenase; MCH = mean 
corpuscular hemoglobin; MCV = mean corpuscular volume; NT-proBNP = N-terminal group pro-BNP; PCR = 
polymerase chain reaction; PT = prothrombin time; RBC = red blood cells; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic pyruvic transaminase; T4 = thyroxine; TSH = thyroid stimulating hormone; 
WBC = white blood cells. 
 
A listing of all laboratory data and urinalysis data for participants will be provided. All laboratory 
values, including pre-baseline values, will be included in the listing.  
Laboratory grades will be reported using NCI-CTCAE v5.0 or higher. Missing baseline grade will 
be assumed as grade 0. For laboratory tests that are not gradable by NCI-CTCAE v5.0 or higher, 
values outside the normal range will be provided. Missing baseline grade will be assumed to be 
normal. 
 
Spider plots including neutrophils, platelets, and hemoglobin in the same plot will be created by 
participant. 


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Persistent cytopenias 
Persistent cytopenias are defined as neutropenia, thrombocytopenia, or anemia at Grade 3 or 
above at the Week 5 visit (Day 29 ± 3 days). If the subject does not have a Week 5 laboratory 
assessment, the latest assessment before the Week 5 visit will be analysed. The percentage of 
subjects with any cytopenia, as well as any persistent neutropenia, thrombocytopenia, or 
anemia at Week 5 will be provided separately. If a subject has multiple laboratory values within 
the Week 5 visit window, the worst case grade will be used to define persistent cytopenia. 
Unscheduled visits will be incorporated in the analysis. Grading of cytopenias are reported 
according to NCI-CTCAE v5.0 or higher criteria for neutropenia, anemia, and thrombocytopenia. 
Among the subset of subjects with persistent cytopenias defined above, a listing of time to 
resolution to grade 2 or below will be provided. The time from 1st T-cell infusion to the first 
reduction to Grade 2 after Week 5 will be reported. Resolution to Grade 2 may occur within the 
Week 5 visit window if multiple laboratory assessments are collected. If the participant did not 
achieve resolution to grade 2 at the last laboratory assessment, they will be censored at the last 
laboratory assessment. If a subject is censored, the result for unresolved cytopenia will be 
displayed (death, interventional phase follow-up ended, cytopenia ongoing). Cytopenias may 
worsen to Grade 3 again at a later point in time. Recurrences are not captured in this analysis. 
4.5.2.1. 
Analysis of Liver Function Test (LFT) 
A listing of subjects with liver monitoring/stopping event reporting will be provided. 
A listing of subjects meeting hepatobiliary laboratory abnormalities aligned with the Protocol 
liver monitoring criteria will be provided. The intent of this listing is to identify subjects, in 
particular possible Hy’s Law subjects, for clinical review.  
A liver monitoring level 2 event profile will be provided for subjects who met level 2 monitoring 
criteria, and the event did not result in stopping study treatment. An additional liver stopping 
event profile will be provided to facilitate medical review of subjects with liver stopping events. 
4.5.3. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be based on 
GSK Core Data Standards, unless otherwise specified. 
4.5.3.1. 
Deaths 
All deaths will be summarized based on the number and percentage of participants on the ITT 
and mITT analysis sets. This summary will classify participants by time of death relative to the 
date of 1st T-cell infusion as a categorical (>30 days or 30 days) and primary cause of death 
displayed in the order it appears in the CRF.  
An individual subject profile listing for participants who died will be generated, which will 
include fatal SAE(s).  
4.5.3.2. 
ECOG Performance Status 
A listing of the subject’s ECOG score (0,1,2,3,4-5) will be provided. 


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 4 2  of 7 2  
 
4. 5. 3. 3.  
E C G  
A listi n g of p artici p a nts w h o h a d n or m al a n d a b n or m al (cli nic all y si g nific a nt a n d n ot cli nic ally 
si g nific a nt) E C G fi n di n gs will b e pr es e nt e d. A listi n g of E C G v al u es  f or all p artici p a nts will als o b e 
pr es e nt e d.  T h e c at e g ori es of p ot e nti al cli nic al i m p ort a nc e f or E C G v al u es (s e e S ecti o n 6. 2. 2. 2 ) 
will n ot b e pr es e nt e d . Inst e a d , t h es e t hr es h ol ds will b e pr o vi d e d i n t h e listi n g f o ot n ot es f or 
r ef er e nc e.   
4. 5. 3. 4.  
Vit al Si g n s  
A listi n g of all vit al si g ns ( h e art r at e, di ast olic bl o o d pr ess ur e, syst olic bl o o d pr ess ur e, 
t e m p er at ur e, p uls e oxi m etr y) will b e pr es e nt e d. T h e c at e g ori es of p ot e nti al cli nic al i m p ort a nc e 
f or all vit al si g n s (s e e S ecti o n 6. 2. 2. 3 ) will n ot b e  pr es e nt e d . Inst e a d , t h es e t hr es h ol ds will b e 
pr o vi d e d i n t h e listi n g f o ot n ot es f or r ef er e nc e.   
 
Pr e g n a nc y  
T h e i nv esti g at or will r e p ort all pr e g n a nci es i m m e di at ely t o t h e S p o ns or. If p artici p a nts or 
p artici p a nts’ p art n er b ec o m e pr e g n a nt w hil e o n t h e st u dy, t h e i nf or m ati o n will b e i ncl u d e d i n 
t h e n arr ativ es. A  s u p p ortiv e listi n g of t h os e s u bj ects or p art n ers of s u bj ects t h at b ec a m e 
pr e g n a nt d uri n g t h e st u dy will b e pr o d uc e d  t o s u p p ort t h e c as e n arr ati v es. 
4. 5. 3. 5.  
C ar di o v a s c ul ar E v e nt s  
As r e q uir e d b y t h e G S K Gl o b al S af et y B o ar d, pr ofil e dis pl a ys f or t h e f oll o wi n g ni n e  c ar di ov asc ular 
e v e nts will b e pr o d uc e d if a n e v e nt occ urs a n d t h e a p pr o pri at e C V ev e nt f or m h as b e e n 
c o m pl et e d i n t h e C R F.  
•  
Arr yt h mi as  
•  
C o n g estiv e H e art F ail ur e  
•  
C er e br ov asc ul ar E v e nts  Str o k e  ( C V A) a n d Tr a nsi e nt Isc h e mic Att ack  ( TI A) 
•  
D e e p V ei n T hr o m b osis  ( D V T)/ P ul m o n ar y E m b olis m  ( P E) 
•  
U nst a bl e A n gi n a / My oc ar di al I nf arcti o n  
•  
P eri p h er al Art eri al T hr o m b o e m b olis m  
•  
P ul m o n ar y H y p ert e nsi o n  
•  
R e v asc ul aris ati o n  
•  
V alv ul o p at hy  
4. 5. 3. 6.  
 a n d I nt e gr ati o n Sit e A n al y si s 
F or a n y p artici p a nt w h o h as gr e at er t h a n 1 % g e n e m ar k e d P B M Cs at l e ast 1 y e ar or b ey o n d 
p ost -i nf usi o n, Int e gr ati o n Sit e A n al ysis will b e p erf or m e d o n P B M Cs t o ass ess cl o n alit y . 
I ns erti o n al o nc o g e n esis will b e ev al u at e d if a n y cl o n es r e pr es e nt > 2 0 % of t h e t ot al. 
F or s u bj ects t h at u n d er g o Int e gr ati o n S it e A n alysis, a s u p p orti v e listi n g will b e pr ovi d e d t o 
r e p ort, if d at a ar e  av ail a bl e . T w o di v ersity i n dic es, S h a n n o n di v ersit y i n d ex a n d Gi ni i n d ex  ( GI), 
will b e r e p ort e d i n t h e d at a listi n g. S h a n n o n di v ersit y is a m e as ur e m e nt t h at r e pr es e nts t h e 
C CI
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uncertainty about the identity of a single species within a population. Therefore, the greater 
number of unique species within a population, the less certain the measure is of the “identity” 
of any one species, resulting in a higher value of Shannon diversity. Likewise, the less complex 
the population, the lower the value of Shannon diversity. When Shannon diversity is calculated 
it takes into account the number of distinct clones (“species”) as well as the abundance of each 
clone. A low value of Shannon diversity has been previously reported in the literature as being 
associated with clonal expansion and a reduction in overall clonal diversity (Braun, 2014). 
The GI is a measure for detecting inequality in the distribution of clone sizes. A GI value of 0 
indicates complete equality across the population i.e., all clones have the same abundance. A 
value of 1 would indicate complete inequality i.e., one clone is much more abundant than the 
others. Therefore, as GI approaches 1 this indicates that one clone is highly abundant. It has 
previously been used for insertion site analysis (as the oligoclonality index, Gillet, 2011) to 
describe clonal populations where the dominance of a single clone is seen (e.g., leukaemia). 
4.5.4. 
Extent of Exposure 
A listing of study treatment based on mITT population will be provided, including total number 
of T-cell infusion bags, T-cell infusion bag start and stop date, route of synthesis and whether it 
was a split dose, total cell dose, average vector copy number per cell in the cell product, total 
number of transduced cells and percent of cells transduced. The listing will also include 
information pertaining partially infused bag(s) and reason(s) for pausing or discontinuing 
infusion. The total number of transduced T-cells will be summarized for the mITT population 
using mean, standard deviation, median and range.  Also, the total number of transduced T-cells 
will be categorized into: 
• 
<0.1 x 109  
• 
0.1 x 109 to 0.8 x 109 (i.e., lower planned T-cell dose range) 
• 
>0.8 x 109 to <1 x 109  
• 
1 x 109 to 8 x 109 (i.e., higher planned T-cell dose range) 
• 
>8 x 109 
All dose administration data for T-cell therapy and lymphodepletion chemotherapy will be 
presented in a data listing based on the ITT population. Supportive listings to report dose 
reductions, delay, stoppages, interruption, and dose escalation of lymphodepletion 
chemotherapy, as well as reasons for these, may be provided in addition to cumulative dose, if 
appropriate. Additional displays may be provided if several participants require reductions. 
As detailed in the respective substudy Protocol Schedule of Activities, lymphodepletion doses 
are to be delivered on consecutive days -7, -6, -5 and -4. The duration of lymphodepletion dose 
delay will be calculated for lymphodepletion doses subsequent to the first lymphodepletion 
dose. Lymphodepletion dose delay is defined as the difference between the expected start date 
of dose and actual start date of dose (i.e., actual start date of dose - expected start date of 
dose), where the expected start date of dose = actual start date of previous dose + 1. 


C O N FI D E N TI A L  
 
 
2 0 9 0 1 2  
 
P a g e 4 4  of 7 2  
 
4. 5. 6.  
I m m u n o g e ni cit y 
S er u m s a m pl es f or d et er mi n ati o n of a nti b o di es a g ai nst N Y -E S O -1 a n d L A G E -1 a s p ecific T -c ells 
ar e t a k e n fr o m all p artici p a nts f or a nti -dr u g a nti b o dy ( A D A) t esti n g.  
T h e a nti -dr u g a nti b o dy r es ults ( p ositi v e or n e g ativ e), i ncl u di n g tit ers, will b e r e p ort e d f or  all 
p artici p a nts i n a d at a listi n g  if d at a ar e a v ail a bl e.  
4. 6.  
Ot h er A n al y s e s  
4. 6. 1.  
S u b gr o u p a n al y s e s  
As of C or e S A P A m e n d m e nt 2: D u e t o e arl y t er mi n ati o n of all s u bst u di es, s u b gr o u p a n al ys es 
will n ot b e c o n d uct e d.  
4. 6. 2.  
Ot h er v ari a bl e s a n d/ or p ar a m et er s  
N ot A p plic a bl e  
4. 7.  
I nt eri m A n al y s e s 
As of C or e S A P A m e n d m e nt 2: Pr ot oc ol -p l a n n e d a n al ys es i ncl u d e a n I nt eri m, Pri m ar y a n d Fi n al 
a n al ysis. H o w e v er, d u e t o t h e e arl y t er mi n ati o n of all s u bst u di es, o nl y a fi n al a n al ysis will b e 
c o n d uct e d. 
4. 7. 1.  
I nt eri m A n al y si s 
R ef er t o t h e s u bst u dy-s p ecific S A P f or d et ails. 
4. 7. 2.  
Pri m ar y A n al y si s  
T h e pri m ar y a n alys es will b e p erf or m e d f or e ac h c o h ort (i n e ac h s u bst u dy) aft er t h e c o m pl et i o n 
of t h e f oll o wi n g  s e q u e nti al st e ps:  
1.  E nr ol m e nt t o t h e c o h ort is c o m pl et e  a n d all e nr oll e d p artici p a nts h av e r ec eiv e d T -c ell 
i nf usi o n, a n d 
2.  At l e ast 8 0 %  of p artici p a nts d os e d  at t h e R P 2 D  ( p art of t h e mI T T) h a v e c o nfir m e d dis e as e 
pr o gr essi o n or di e d or w er e wit h dr a w n or l ost t o f oll o w -u p fr o m t h e s u bst u dy , a n d 
3.  All r e m ai ni n g  T -c ell i nf us e d p artici p a nts ( mI T T) , i ncl u di n g t h os e tr e at e d at n o n -R P 2 D  d os e  
h a v e c o m pl et e d 2 p ost b as eli n e dis e as e ass ess m e nts si nc e T -c ell i nf usi o n or h av e c o nfir m e d 
dis e as e pr o gr essi o n or di e d or w er e wit h dr a w n or l ost -f oll o w-u p fr o m t h e s u bst u dy.  
4.  All r e q uir e d d at a b as e cl e a ni n g acti viti es h av e b e e n c o m pl et e d a n d d at a b as e r el e as e ( D B R) 
a n d d at a b as e fr e ez e ( D B F) h as b e e n d ecl ar e d b y D at a M a n a g e m e nt.  
M or e d et ails if a p plic a bl e will b e pr o vi d e d i n t h e s u bst u dy -s p ecific S A Ps.  
4. 7. 3.  
Fi n al A n al y si s  
T h e fi n al a n al ys es will b e p erf or m e d  f or e ac h c o h ort (i n e ac h s u bst u dy) aft er t h e c o m pl eti o n of 
t h e f oll o wi n g s e q u e nti al st e ps:  
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1. Enrolment to the cohort is complete and all enrolled participants have received T-cell 
infusion, and 
2. All participants have completed the substudy. 
• 
Completed the substudy for each cohort is defined as when all enrolled participants in 
the cohort have transferred to the separate LTFU protocol, declined consenting to the 
LTFU protocol, completed LTFU requirement in the applicable study, have been lost to 
follow-up, or withdrawn or died.  
3. All required database cleaning activities have been completed and database release 
(DBR) and database lock (DBL) has been declared by Data Management.  
More details if applicable will be provided in the substudy-specific SAPs.  
4.8. 
Changes to Protocol Defined Analyses 
As of Core SAP Amendment 2: As a result of the early termination of all substudies the following 
changes to the protocol defined analyses have been made: 
• 
Due to early termination of all substudies prior to establishing RP2D, the interim 
analyses described in the substudy-specific Protocols (Amendment 4) Section 10.5.1 will 
not be conducted, as described in Section 4.7. The Primary analysis will also not be 
conducted. 
• 
Safety summaries will be based on the DLT Evaluable, Lymphodepletion, ITT and 
mITT as applicable (note that the Core Protocol Amendment 4 Section 10.5.2.1 states 
that all safety analyses will be performed on the ITT and mITT populations). 
• 
Serially collected (exploratory) safety endpoints (e.g., laboratory tests, vital 
signs, ECGs) will in general be listed and not summarised, with full details given in this 
document. 
• 
Summaries of Characteristics of AESIs will not be presented but instead will be 
listed. 
5. 
SAMPLE SIZE DETERMINATION 
Refer to substudy-specific SAPs for the detail. 


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6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the analyses specified in this Section will be based on the ITT 
population.  
6.1.1. 
Participant Disposition 
A summary of the number of participants in each of the analysis sets described in Section 3 will 
be provided by both planned and actual treatment (see Table 1). A listing of participants 
excluded from any analysis sets will also be provided, based on the Screened population. 
Number of participants will be summarized by country and study site ID using the enrolled and 
mITT populations. 
A summary and listing of screening status and screen failures will be provided using the 
Screened population and will be summarised separately for target expression screening status 
and leukapheresis eligibility screening status. Target expression screening will be reported for all 
substudies combined i.e., not separately for each substudy. Where applicable, leukapheresis 
eligibility screening failures will be presented by indication. If indication data for target 
expression screening are available then target expression screen failures will also be presented 
by indication, where applicable. An additional summary of screen failures by each subject’s HLA 
or Antigen results will be presented. Per GSK reporting standards, participants who were 
rescreened will appear once in these displays according to their final status. 
A summary of interventional phase status (see Section 6.2.3) will be produced using both the 
Lymphodepletion and mITT analysis sets, with reasons for completion and study withdrawal 
summarized in the order they are displayed in the CRF. Participant status will be displayed with 
the categories and subcategories: Completed study, Ongoing, or Withdrawn (reasons from the 
CRF).  
Overall study disposition, including long term follow up, will also be summarized for the ITT and 
mITT population. An additional table will be created to summarize the number of participants in 
the ITT population who did and did not receive T-cell infusion, as well as the reason for not 
receiving T-cell infusion. A supportive listing of reason for study withdrawal will be created, 
using the ITT population. 
6.1.2. 
Demographic and Baseline Characteristics 
Demographic characteristics including race, age, gender, ethnicity, height, body weight at 
leukapheresis eligibility screening, body mass index (kg/m2), and body surface area (BSA) per the 
DuBois & Dubois formula will be summarized with descriptive statistics. Age, height, weight, BMI 
and BSA will be summarised using mean, standard deviation, minimum, median, and maximum; 
gender, ethnicity and race will be summarized using number and percentage. In addition, age 
will also be categorized and summarized by <18, 18-64, 65-84 and ≥85 using EudraCT and also 
by GSK IDSL standard as ≤18, 19-64, ≥65. The summary of demographic characteristics will be 
produced on the ITT and mITT analysis sets, with the listing on the ITT analysis set.  


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A supportive summary of age ranges on the enrolled analysis set and a listing of race on the ITT 
will also be produced.  
Disease characteristics at initial diagnosis and screening will be listed as collected in the CRF on 
the ITT analysis set. Disease characteristics at screening will be summarized on the mITT analysis 
set.  The summary and listings will include primary tumor type under study, disease stage at 
initial diagnosis and screening, time since initial diagnosis (months), time since last recurrence 
(months), extent of disease at screening, TNM (tumor, node, metastasis) staging, visceral/non-
visceral disease, progression on therapy (yes/no). Also, a summary of HLA status (including the 
number and phenotype of HLA alleles positive) and NY-ESO-1/LAGE-1a status (by indication and 
including a descriptive summary of the NY-ESO-1 Expression H-score and P-score), LAGE-1a 
expression and NY-ESO-1 tumor site and anatomical location will be produced. In addition to 
those stated above, date of initial diagnosis and date of last recurrence for the primary tumor, 
and date of blood collection and biopsy for antigen testing will be listed. For detail on substudy 
specific disease characteristics refer to the substudy SAPs. 
An additional disease characteristics at screening table will be summarized on the Screened 
analysis set, presenting only the HLA status/phenotype and NY-ESO-1 status/expression 
information described above.  
A listing of metastatic disease at screening will be provided based on the ITT analysis set. Refer 
to Section 6.2.1 for time since initial diagnosis, time since last recurrence and time since 
diagnosis of metastatic disease derivation rules.  
Past medical conditions and current medical conditions as of screening will be listed using the 
ITT analysis set. 
6.1.3. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion criteria, 
conduct of the trial, patient management or patient assessment) will be summarized on both 
the ITT and mITT analysis sets and listed on the ITT analysis set. 
Protocol deviations will be tracked by the study team throughout the conduct of the study. 
These protocol deviations will be reviewed to identify those considered as important as follows: 
• 
Data will be reviewed prior to freezing the database to ensure all important deviations 
(where possible without knowing the study intervention details) are captured and 
categorised in the protocol deviations dataset.  
• 
This dataset will be the basis for the summaries of important protocol deviations. 
A separate listing of all inclusion/exclusion criteria deviations will also be provided using the 
Screened population. This listing will be based on data as recorded on the Eligibility page of the 
eCRF. 
6.1.4. 
Prior and Concomitant Medications 
Prior and concomitant medications are as defined in Section 6.2.3.2. 
Concomitant medications will be coded using both the GSK Drug and WHO Drug dictionaries. 
However, the summary (mITT analysis set) and listing (ITT analysis set) will be based on GSK 


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Drug dictionary only. The summary of concomitant medications will be provided by ingredient 
i.e., multi-ingredient medications will be summarized for each individual ingredient rather than 
a combination of ingredients. The summary will be created using ingredient base names, i.e., 
ingredients with the same base name but different salt will appear under one base name in the 
summary. Anatomical Therapeutic Chemical (ATC) classifications will not appear in the 
summary.  
In the summary of concomitant medications, each participant is counted once within each 
unique ingredient. For example, if a participant takes Amoxycillin on two separate occasions, the 
participant is counted only once under the ingredient ‘Amoxycillin’. In the summary of 
concomitant medications, the ingredients will be summarized by the base only. 
Blood products and blood supportive care products will be listed separately from concomitant 
medications .  
6.1.5. 
Anti-cancer therapies 
Anti-cancer therapy includes systemic therapy (coded using the GSK Drug coding dictionary), 
radiotherapy, and cancer-related surgery.  
Anti-cancer therapies will be classified into prior, bridging, and on-study phases as described 
below. Therapies will be identified using the corresponding CRF pages.  
Type of Therapy 
Definition 
Prior 
Prior therapy is defined as any line of systemic therapy, radiotherapy, 
and cancer-related surgeries given before start of lymphodepletion.  
 
Note: Intermediate systemic therapies are included in this definition, 
supportive chemotherapy is excluded from this definition. 
Bridging 
Bridging therapy is defined as prior systemic therapy given between 
leukapheresis and start of lymphodepletion to maintain disease control 
(not considered a line of therapy).  
 
Note: This definition captures supportive chemotherapies as bridging 
therapies. 
On-Study/Follow-
up 
On-study and follow-up therapies are defined as systemic therapy, 
radiotherapy, or cancer related surgery given on or after the start of 
lymphodepletion. 
 
A listing of systemic therapy will be provided and labelled as prior, bridging, or on-study. 
Radiotherapies and cancer-related surgeries will be listed separately and labelled as prior or on-
study. Both listings will be based on the ITT analysis set. 
6.1.5.1. 
Prior Anti-cancer therapy 
A summary of the number of prior systemic anti-cancer therapy regimens in the 
advanced/metastatic setting (as reported in the Intent field of the prior anti-cancer therapy 
eCRF page), the number of prior radiotherapy regimens and the best response to the most 


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recent prior therapy will be provided. Prior therapy and bridging therapy will be coded using the 
GSK Drug coding dictionary. 
Systemic anti-cancer therapy regimens initiated between leukapheresis and lymphodepletion as 
reported in the intermediate and supportive therapy eCRF page are categorized as either 
bridging (supportive chemotherapy regimens administered to maintain/stabilize the participant 
until T-cell infusion) or full lines of therapy (intermediate standard of care regimens 
administered with the intent of disease effect). Full lines are summarized as prior therapies – 
supportive chemotherapies are not considered in the number of prior lines.  
6.1.5.2. 
On-study Anti-cancer therapy 
On-study systemic therapies will be coded using GSK Drug coding dictionary.   
6.1.6. 
Additional Analyses Due to the COVID-19 Pandemic 
6.1.6.1. 
Participant Disposition 
A country level listing of the dates of the COVID-19 Pandemic measures will be produced.  For 
the definition of the phases of the COVID-19 pandemic measures see Section 6.2.3.3. 
The ‘Summary of Subject Status and Subject Disposition for the Study Conclusion Record’ will be 
repeated, with the reason for withdrawal/discontinuation categorized as due to the COVID-19 
pandemic, or non-due to the COVID-19 pandemic based on information collected on the COVID-
19 Pandemic Study Impact form. The summaries will be based on GSK Core Data Standards.  
6.1.6.2. 
Protocol Deviations 
In addition to the overall summary of important protocol deviations, a separate summary will be 
produced for important protocol deviations related to COVID-19 based on the ITT analysis set. 
Non-important PDs due to the COVID-19 pandemic will be listed using the ITT analysis set. 
Visits and assessments missed due to the COVID-19 pandemic, together with visits conducted 
remotely, will be listed using the ITT analysis set. 
6.1.6.3. 
Additional Displays for Participants with COVID-19 Infection 
A participant is defined as having a suspected, probable, or confirmed COVID-19 infection during 
the study if the answer is “Confirmed”, “Probable” or “Suspected” to the case diagnosis 
question from the COVID-19 coronavirus infection assessment eCRF. A comprehensive profile 
listing of COVID-19 assessments, symptom assessments and epidemiological factors (travel to 
high-risk countries, health care contact, etc) for subjects with COVID-19 adverse events will be 
provided.  
 
 


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6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Derived and transformed data 
6.2.1.1. 
General 
Change from Baseline 
Change from Baseline = Post-Baseline Visit Value – Baseline 
% Change from Baseline= 100 x (Post-Baseline Visit Value – Baseline) / Baseline 
Maximum Increase/Decrease from Baseline = maximum (Increase/Decrease from Baseline) 
If either the Baseline or Post-Baseline Visit Value is missing, Change from Baseline and % Change from 
Baseline are set to missing 
Date of Response 
For post-baseline disease assessments, the date of response (PR, CR) is assigned to the latest date of 
tumor assessments; for other response categories (SD, NE, PD), the date of response is assigned to the 
earliest date of disease assessments.    
Date of New Anti-Cancer Therapy 
Derived as the earliest date of new on study anti-cancer therapy, radiotherapy (where applicable, 
excluding palliative radiotherapy) or cancer-related surgical procedure (where applicable). Missing or 
partial dates will be imputed for derivation of new anti-cancer therapy following rules specified in Section 
6.2.7. 


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6.2.1.2. 
Study Population 
Age 
For participants with a T-cell infusion date, age is derived using 1st T-cell infusion date as the reference 
date. For ITT participants without a T-cell Infusion date, date of eligibility for apheresis is used as the 
reference date. 
BMI 
Weight (kg) at baseline / (Height (m) at leukapheresis eligibility screening)2 
Body Surface Area (BSA) (m2) DuBois & DuBois Formula 
0.007184 * Height(cm)0.725 × Weight(kg)0.425 
Time since Initial Diagnosis to Screening 
Calculated as the number of Months from the Date of Initial Diagnosis: 
Leukapheresis Eligibility Screening Visit Date = Missing           → Elapsed Time = Missing  
Date of Initial Diagnosis = Completely/partially Missing       → Elapsed Time = Missing  
Otherwise       → Elapsed Time = (Leukapheresis Eligibility Screening Visit Date – Date of Initial 
Diagnosis + 1) /30.4375            
Time since Last Recurrence to Screening 
Calculated as the number of Months from the Date of Last Recurrence: 
Leukapheresis Eligibility Screening Visit Date = Missing           → Elapsed Time = Missing  
Date of Last Recurrence = Completely/partially Missing           → Elapsed Time = Missing 
Otherwise       → Elapsed Time = (Leukapheresis Eligibility Screening Visit Date – Date of Last 
Recurrence+ 1) /30.4375            
Time since Metastatic Disease to Screening 
Calculated as the number of Months from the Date of Metastatic Disease was first diagnosed: 
Leukapheresis Eligibility Screening Visit Date = Missing           → Elapsed Time = Missing  
Date of Metastatic Disease was first diagnosed = Completely/partially Missing           → Elapsed Time = 
Missing 
Otherwise       → Elapsed Time = (Leukapheresis Eligibility Screening Visit Date – Date of Metastatic 
Disease was first diagnosed + 1) /30.4375            
 
 


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6.2.1.3. 
Safety 
Adverse Events 
Duration of AE 
Calculated as the number of days from AE Start Date to AE Stop Date: 
AE Start Date = Missing              → Elapsed Time = Missing  
AE Stop Date = Missing              → Elapsed Time = Missing 
Otherwise                        → Elapsed Time = AE Stop Date – AE Start Date + 1     
Imputed dates will not be used to calculate AE duration 
Clinical Laboratory Parameters  
If a laboratory value which is expected to have a numeric value for summary purposes, has a non-
detectable level reported in the database, where the numeric value is missing, but typically a character 
value starting with ‘<=’ or ‘=>’ (or indicated as less than x or greater than x in the comment field) is 
present, the number of significant digits in the observed values will be used to determine how much to 
add or subtract in order to impute the corresponding numeric value.  
 
Example 1: 2 significant digits = ‘<= x’ becomes x – 0.01 
 
Example 2: 1 significant digit = ‘=> x’ becomes x + 0.1 
 
Example 3: 0 significant digits = ‘<=x’ becomes x - 1 
 
6.2.1.4. 
Efficacy 
Date of Last Known Contact 
• 
Last date in all SDTM domains 
• 
If a patient died, the last contact date should be the death date.  
• 
Dates after date of death will be excluded.  
• 
Specific SDTM domains and variables will be excluded from the date of last known 
contact derivation. This also includes excluding any other external source data dates 
as seen necessary. For more details refer to the OPS. 
• 
Partial and missing dates will not be imputed for the purpose of deriving date of last 
contact. 
6.2.2. 
Criteria for Potential Clinical Importance 
6.2.2.1. 
Laboratory values 
To identify laboratory values of potential clinical importance, National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE v5.0 or higher) will be used to assign grades 
for laboratory parameters including clinical chemistry, hematology, liver function tests, thyroid 
function tests, pancreatic enzyme tests, QTc (Bazett’s or Fridericia’s) values, and vital signs 
(heart rate, blood pressure, temperature, pulse oximetry).  
Reference ranges for all laboratory parameters collected throughout the study are provided by 
the laboratory. A laboratory value that is outside the reference range is considered either high 
abnormal (value above the upper limit of the reference range) or low abnormal (value below the 
lower limit of the reference range). Note: a high abnormal or low abnormal laboratory value is 
not necessarily of clinical concern. The laboratory reference ranges will be provided on the 


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listings of laboratory data. Clinical laboratory test results outside of the reference range will be 
flagged in the listings. 
To identify laboratory values of potential clinical importance, National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE v5.0 or higher) will be used to assign grades 
to the relevant laboratory parameters. NCI-CTCAE v5.0 can be found at 
http://ctep.cancer.gov/reporting/ctc.html.  
For laboratory data which are not listed in the NCI-CTCAE v5.0 or higher, a summary of values 
outside the normal range will be provided. 
6.2.2.2. 
ECG values 
To identify QTc (Bazett’s or Fridericia’s) values of potential clinical importance, NCI-CTCAE v5.0 
or higher will be used to assign grades (see adverse event ‘Electrocardiogram QT corrected 
interval prolonged’). The eCRF collects either QTcB or QTcF. The clinical concern range for QRS 
Duration is approximately based on the limits determined by Ramirez, 2011. 
The following criteria indicates electrocardiogram (ECG) values that are values of potential 
clinical importance: 
ECG Parameter 
Units 
Potential Clinical Importance (PCI) Range 
Absolute QTcF [QTcB] interval 
Msec 
450 to 480 (Grade 1) 
481 to 500 (Grade 2) 
501 (Grade 3) 
Increase from baseline QTcF 
[QTcB] 
Msec 
Increase of 31 to 60 
Increase of >60 
 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
QRS Duration 
Msec 
<70 
>105 
6.2.2.3. 
Vital Signs 
To identify values of potential clinical importance, NCI-CTCAE v5.0 or higher will be used to 
indicate categories that align with the grades for ‘Hypothermia’, ‘Fever’, ‘Sinus Bradycardia’ / 
‘Sinus Tachycardia’ and ‘Hypoxia’.  
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Heart Rate 
bpm 
<60 
100 
Temperature 
Degrees C 
35 
38 
Pulse Oximetry 
% 
88 
N/A 
 
To identify values of potential clinical importance for Increase from Baseline Systolic and 
Diastolic Blood Pressure, NCI-CTCAE v5.0 or higher will be used, aligning with the grades for 
‘Hypertension’. 
 Vital Sign Parameter 
Units 
Potential Clinical Importance (PCI) Range 


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Increase from baseline 
Systolic Blood Pressure 
mmHg 
120 to <140 (Grade 1) 
140 to <160 (Grade 2) 
160 (Grade 3) 
Increase from baseline 
Diastolic Blood Pressure 
mmHg 
80 to <90 (Grade 1) 
90 to <100 (Grade 2) 
100 (Grade 3) 
 
For Hypotension, decrease from baseline for diastolic and systolic blood pressure will be 
presented using the thresholds defined below. 
Vital Sign Parameter 
Units 
Potential Clinical Importance (PCI) Range 
Decrease from baseline 
Systolic Blood Pressure 
mmHg 
80 to <100 (Low) 
<80 (Very Low) 
Decrease from baseline 
Diastolic Blood Pressure 
mmHg 
60 to <70 (Low) 
<60 (Very Low) 
 
6.2.3. 
Study Phase 
Assessments and events will be classified according to the time of occurrence relative to the 
study intervention period.  
6.2.3.1. 
Study Phases for Disposition 
Study Phase 
Definition 
Leukapheresis 
Phase 
First Day of Leukapheresis ≤ Date < First Day of Lymphodepletion  
Interventional Phase 
- (Lymphodepletion) 
First Day of Lymphodepletion Date < 1st T-cell Infusion (Day 1) 
Interventional Phase 
- (Post T-cell 
Infusion) 
1st T-cell Infusion (Day 1)  Date  Start of Follow-up Phase (Date of Confirmed 
PD / Withdrawal from Interventional Phase) 
Follow-up Phase 
Start of Follow-up Phase (Date of Confirmed PD / Withdrawal from Interventional 
Phase) < Date  
 
6.2.3.2. 
Study Phases for Concomitant Medication and Blood Product 
Study Phase 
Definition 
Prior 
If lymphodepletion start date is missing, i.e., for participants that did not receive 
lymphodepletion. 
Else if end date of medication is not missing and end date < lymphodepletion start 
date.  
Else if start date of blood product is not missing and start date < lymphodepletion 
start date. 
Concomitant 
Any medication or blood product that is not Prior. 
NOTES:  
• 
Please refer to Section 6.2.7: Reporting Standards for Missing Data for handling of missing and partial 


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dates for concomitant medication. Use the rules in this table if concomitant medication date is missing. 
6.2.3.3. 
Phases of COVID-19 Pandemic Measures 
Pandemic measures began in different countries at different times. A dataset containing the 
date when pandemic measures began, as determined by the GSK country Issue Management 
Teams (IMT), and available within the HARP reporting environment (arcomn folder), will be used 
to determine the start date of pandemic measures within each country. A copy of this dataset 
will be taken at the time of database freeze (DBF). 
Adverse events will be summarised according to whether the onset date was before or after the 
start of the COVID-19 pandemic measures. If the AE onset date is missing, then the AE will be 
assumed to be After pandemic measures phase. 
Pandemic Measures 
Phase 
Definition 
Before 
AE onset date < pandemic measures start date 
After 
Pandemic measures start date ≤ AE onset date  
6.2.3.4. Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent (T-cell 
Phase) 
• 
If AE onset date is equal to T-cell infusion start date (AE start date = T-cell 
infusion start date): 
1. If missing AE onset time and missing T-cell infusion time  
2. If non-missing AE onset time and missing T-cell infusion time  
3. If missing AE onset time and non-missing T-cell infusion time: 
a. If AE end date and time are non-missing: 
▪ 
If AE end date = T-cell infusion start date and AE 
end time is on or after T-cell infusion start time 
(AE End Time >= T-cell infusion start time)  
b. If AE end date is non-missing and is after T-cell infusion 
start date 
c. If AE end date and/or time is missing  
4. If non-missing AE onset time and non-missing T-cell infusion time: 
a. If AE onset time >= T-cell infusion time  
• 
Else if AE onset date is not equal to T-cell infusion start date (AE start Date  
T-cell infusion start date) and AE onset date is after T-cell infusion start date 
(AE Start Date  T-cell Infusion Start Date), OR if AE onset date is before T-
cell infusion start date, but the AE increases in grade after T-cell infusion 
(with respect to maximum grade of the AE before T-cell infusion.  
• 
.  
• 
If AE onset date is missing and AE end date is either missing or on or after T-
cell infusion start date.  
o If T-cell infusion date is missing i.e., the patient did not receive T-cell 
infusion, then the AE will not be classified as Treatment Emergent.  
Lymphodepletion 
Emergent 
(Lymphodepletion 
Phase) 
• 
If AE onset date is equal to Lymphodepletion start date (AE Start Date = 
Lymphodepletion Start Date): 
1. If missing AE onset time and missing Lymphodepletion start time  
2. If non-missing AE onset time and missing Lymphodepletion start 


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Flag 
Definition 
time  
3. If missing AE onset time and non-missing Lymphodepletion start 
time: 
a. If AE end date and time are non-missing: 
▪ 
If AE end date = Lymphodepletion start date and 
AE end time is on or after Lymphodepletion start 
time (AE End Time >= Lymphodepletion Start 
Time)  
b. If AE end date is non-missing and is after Lymphodepletion 
start date 
c. If AE end date and/or time is missing  
4. If non-missing AE onset time and non-missing Lymphodepletion 
start time: 
a. If AE Onset Time >= Lymphodepletion Start Time  
• 
Else if AE onset date is not equal to Lymphodepletion start date (AE start 
Date  Lymphodepletion start date) and: 
o AE onset date is after Lymphodepletion start date and before T-cell 
infusion start date (Lymphodepletion Start Date < AE Start Date < 
T-cell Infusion Start Date), OR 
o AE onset date is after Lymphodepletion start date and T-cell infusion 
date is missing i.e., the participant did not receive the T-cell infusion, 
OR 
o AE onset date is before Lymphodepletion start date and before T-
cell infusion start date, but the AE increases in grade after 
Lymphodepletion start date (with respect to maximum grade of the 
AE before Lymphodepletion). 
• 
If AE onset date is missing and AE end date is either missing or after 
lymphodepletion start date. 
o If lymphodepletion date is missing i.e., the participant did not receive 
lymphodepletion, then the AE cannot be classified as 
Lymphodepletion Emergent.  


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Flag 
Definition 
Pre-
Lymphodepletion 
Emergent (Pre-
Lymphodepletion 
Phase) 
• 
If AE onset date is equal to lymphodepletion start date (AE Start Date = 
Lymphodepletion Start Date) 
1. If missing AE onset time and non-missing Lymphodepletion start 
time: 
a. If AE end date and time are non-missing: 
▪ 
If AE end date = Lymphodepletion start date and 
AE end time is before the Lymphodepletion start 
time (AE End Time < Lymphodepletion Start Time)  
2. If non-missing AE onset time and non-missing Lymphodepletion 
start time: 
a. If AE Onset Time < Lymphodepletion Start Time  
• 
Else if AE onset date is not equal to Lymphodepletion start date (AE start 
Date  Lymphodepletion start date) and: 
o AE onset date is before Lymphodepletion start date (AE Start Date 
< Lymphodepletion Start Date), OR 
o Lymphodepletion start date and T-cell infusion start date is missing 
i.e., the participant did not receive Lymphodepletion or T-cell 
infusion.  
• 
If AE onset date is missing and the AE end date is before the 
Lymphodepletion start date.   
• 
If both the AE onset and end date are missing.   
NOTES:  
• 
Time of study treatment dosing and start[/stop] time of AEs should be considered, if collected. 
• 
T-cell infusion start date is in reference to the 1st T-cell infusion throughout these derivations.  
• 
AEs to be used in the derivation is the overall AE event unless the AE grade changes across AE phases 
(as defined in Table 7) in this case the derivation is based on the AE segment (that had the grade 
change) of the same overall AE.  
 
6.2.4. 
Study Day and Reference Dates 
The reference date is the study intervention start date (1st T-cell infusion date) and will be used 
to calculate study day.  
The study day is calculated as below: 
• Assessment Date = Missing              → Study Day = Missing  
• Assessment Date < Reference Date → Study Day = Assessment Date – Ref Date 
• Assessment Date ≥ Reference Date → Study Day = Assessment Date – Ref Date + 1     
6.2.5. 
Assessment Window  
No assessment windows will be applied. 
For data summaries by visit, scheduled visits with nominal visit description as well as the worst 
case post baseline will be displayed. Unscheduled visits will not be displayed or slotted into a 
visit window but will be included in the derivation of worst case post-baseline assessment. All 
unscheduled visits will be displayed in the listing. 


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6.2.6. 
Multiple measurements at One Analysis Time Point 
When multiple assessments are taken at one analysis time point, the mean of the 
measurements will be calculated first, and summary statistics will be based on the calculated 
mean. This will apply to both baseline and post-baseline assessments. 
For character variables, if multiple assessments on different days are reported for the same 
scheduled assessment, then the worst case assessment for that scheduled assessment will be 
analysed. 
For laboratory tests on a study day, if more than one assessment is taken on the same day from 
the same type of lab, the worst case will be used. 
Participants having both High and Low values for normal ranges at any post-baseline visit for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables. 
6.2.7. 
Handling of Partial Dates 
Imputed partial dates may not be used to derive study day, duration, or elapsed time variables. 
In addition, imputed dates are not used for deriving the last contact date in overall survival 
analysis dataset. Refer to the OPS for more details on partial dates. 
Imputed dates will not be displayed in listings. However, where necessary, display macros may 
impute dates as temporary variables for the purpose of sorting data in listings only. In addition, 
partial dates may be imputed for ‘slotting’ data to study time periods or for specific analysis 
purposes as outlined below.  
The partial date imputation will follow ADaM conventions. The ADaM approach is to populate 
the numeric date variables with the imputed date and add a flag variable to the dataset that 
indicates the level of imputation.  
The flag variable can contain the values: blank, 'D', 'M', 'Y'.  
blank: indicates that no imputation was done 
D='Day': indicates that the day portion of the date is imputed 
M='Month': indicates that the month and day portions of the date are imputed 
Y='Year': indicates that the entire date (year, month, and day) is imputed 
Example of date variables:  
XYZD_ - character date variable 
XYZDT - numeric date variable 
XYZDTFL - flag variable 
Details on imputing partial dates for specific datasets are outlined below 


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Element 
Reporting Detail 
Adverse Events 
• 
Imputations in the adverse events dataset are used for slotting events to the 
appropriate study time periods and for sorting in data listings. 
o This includes identifying an AESI as first or last occurrence. 
• 
Partial dates for AE recorded in the CRF will be imputed using the following 
conventions: 
 
Missing AE 
start day 
• 
If lymphodepletion start date is missing (i.e., participant 
did not start lymphodepletion), then set AE start date = 1st 
of month. 
• 
Else if lymphodepletion start date is not missing and T-cell 
infusion date is missing (i.e., participant did not have 
T-cell infusion) 
o If month and year of AE start date = month and 
year of lymphodepletion start date, then 
▪ 
If AE stop date contains a full date and 
AE stop date is earlier than 
lymphodepletion start date, then set AE 
start date= 1st of month. 
▪ 
Else set AE start date = 
lymphodepletion start date. 
o Else set AE start date =1st of the month 
• 
Else if lymphodepletion start date is not missing and T-cell 
infusion date is not missing  
o If month and year of AE start date = month and 
year of both T-cell infusion start date and 
lymphodepletion start date, then 
▪ 
If AE stop date contains a full date and 
stop date is earlier than 
lymphodepletion start date, then set AE 
start date=1st of the month 
▪ 
Else if AE stop date contains a full date 
and stop date is earlier than T-cell start 
date but later than lymphodepletion start 
date, then set AE start 
date=Lymphodepletion start date 
▪ 
Else set AE start date=T-cell infusion 
start date 
o If month and year of AE start date = month of 
only T-cell infusion start date, then 
▪ 
If AE stop date contains a full date and 
AE stop date is earlier than T-cell 
infusion, then set AE start date=1st of 
the month 
▪ 
Else set AE start date=T-cell infusion 
start date 
o If month and year of AE start date = month and 


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Element 
Reporting Detail 
year of only lymphodepletion start date, then 
▪ 
If AE stop date contains a full date and 
AE stop date is earlier than 
lymphodepletion, then set AE start 
date=1st of the month 
▪ 
Else set AE start date=lymphodepletion 
start date 
o Else set AE start date =1st of the month 
 
Missing AE 
start day and 
month 
• 
If lymphodepletion start date is missing (i.e., participant 
did not start lymphodepletion), then set start date = 
January 1st 
• 
Else if lymphodepletion start date is not missing and T-cell 
infusion date is missing (i.e., participant did not have T-
cell infusion) 
o If year of start date = year of lymphodepletion 
start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than lymphodepletion 
start date, then set start date= January 
1st 
▪ 
Else set start date = lymphodepletion 
start date. 
o Else set start date =January 1st  
• 
Else if lymphodepletion start date is not missing and T-cell 
infusion date is not missing  
o If year of start date = year of both T-cell infusion 
start date and lymphodepletion start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than lymphodepletion 
start date, then set start date=January 
1st 
▪ 
Else if stop date contains a full date and 
stop date is earlier than T-cell start date 
but later than lymphodepletion start 
date, then set start 
date=Lymphodepletion start date 
▪ 
Else set start date=T-cell infusion start 
date 
o If year of start date = year of only T-cell infusion 
start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier than T-cell infusion, then 
set start date=January 1st 
▪ 
Else set start date=T-cell infusion start 
date 
o If year of start date = year of only 


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Element 
Reporting Detail 
lymphodepletion start date, then 
▪ 
If stop date contains a full date and stop 
date is earlier lymphodepletion, then set 
start date=January 1st 
▪ 
Else set start date=lymphodepletion 
start date 
o Else set start date =January 1st  
Missing AE 
stop day  
Last day of the month will be used. 
Missing AE 
stop day and 
month 
No Imputation 
Completely 
missing AE 
start/end 
date 
No imputation. Consequently, time to onset and duration of 
such events will be missing. 
Concomitant 
Medications 
(CM)/ Medical 
History (MH) 
• 
These imputation rules will be used for classifying a medication as prior or 
concomitant 
• 
Completely missing start dates will not be imputed 
• 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
 
Missing CM/MH 
start day 
• 
If lymphodepletion start date is missing (i.e., 
participant did not receive lymphodepletion), then 
set CM/MH start date = 1st of month. 
• 
Else if lymphodepletion start date is not missing: 
o If month and year of CM/MH start date = 
month and year of lymphodepletion start 
date, then 
▪ 
If CM/MH stop date contains a 
full date and stop date is earlier 
than lymphodepletion start 
date, then set CM/MH start 
date= 1st of month. 
▪ 
Else set CM/MH start date = 
lymphodepletion start date. 
o Else set CM/MH start date=1st of the 
month. 
Missing CM/MH 
start day and 
month 
• 
If lymphodepletion start date is missing (i.e., 
participant did not receive lymphodepletion), then 
set CM/MH start date = January 1st. 
• 
Else if lymphodepletion start date is not missing: 
o If year of CM/MH start date = year of 
lymphodepletion start date, then 


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Element 
Reporting Detail 
▪ 
If CM/MH stop date contains a 
full date and stop date is earlier 
than lymphodepletion start 
date, then set CM/MH start 
date = January 1st. 
▪ 
Else set CM/MH start date = 
lymphodepletion start date. 
o Else set CM/MH start date=January 1st  
Missing CM/MH 
end day 
A '28/29/30/31' will be used for the day (dependent on the 
month and year)  
Missing CM/MH 
end day and 
month 
Earliest of (Dec 31st, date of last contact) will be used  
Completely 
missing CM/MH 
start/end date 
No imputation 
Surgical 
Procedures/ 
Radiotherapy 
• 
No Imputation for completely missing dates 
• 
If partial date contains a year only set to January 1st. 
• 
If partial date contains a month and year set to the 1st of the month 
New On-Study 
Anti-Cancer 
Therapy/ 
Radiotherapy/ 
Surgical 
Procedures for 
Efficacy 
Evaluation (e.g., 
response rate, 
time to event) 
Start dates for on-study anti-cancer therapy, radiotherapy (where applicable), and 
surgical procedures (where applicable) will be imputed in order to define event and 
censoring rules for progression-free survival, response rate, or duration of response 
(i.e., start date for new anti-cancer therapy). Dates will only be imputed when a 
month and year are available, but the day is missing. The following rules will be used 
to impute the date when partial start dates are present on anti-cancer therapy, 
radiotherapy, and/or surgical procedures dataset[s]: 
• 
Completely missing start dates will remain missing, with no imputation applied 
• 
Partial start dates will be imputed using the following convention: 
• 
If both month and day are missing, no imputation will be applied 
• 
If only day is missing:  
• 
If the month of partial date is the same as the month of last dosing 
date, minimum of (T-cell infusion date + 1, last day of the month) will 
be used for the day 
• 
If the month of partial date is the same as the month of last 
disease assessment and the last disease assessment is PD, minimum 
of (last date of disease assessment + 1, last day of the month) will be 
used for the day 
• 
If both conditions above are met, the later date will be used for the 
day 
• 
Otherwise, a ‘01’ will be used for the day 
• 
Completely or partial missing end dates will remain missing, with no 
imputation applied; 
• 
T-cell infusion start date is in reference to the 1st T-cell infusion throughout these derivations.  


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6.2.8. 
Example Scenarios of Assignments of Confirmed Best Overall 
Response per iRECIST 
Table 8 
Derivation of iBOR when Confirmation is Required 
Overall 
Response first 
timepoint 
Overall Response 
subsequent 
timepoint 
Best Overall Response 
iCR 
iCR 
iCR 
iCR 
iPR 
iSD provided minimum criteria for iSD duration met, 
otherwise, iUPD 
iCR 
iSD 
iSD provided minimum criteria for iSD duration met, 
otherwise, iUPD 
iCR 
iUPD 
iSD provided minimum criteria for iSD duration met, 
otherwise, iUPD 
iCR 
NE 
iSD provided minimum criteria for iSD duration met, 
otherwise, NE 
iPR 
iCR 
iPR 
iPR 
iPR 
iPR 
iPR 
iSD 
iSD provided minimum criteria for iSD duration met, 
otherwise, NE 
 
Note: if after iSD there is an iPR (i.e. iPR-iSD-iPR) then 
iBOR is iPR.   
iPR 
iUPD 
iSD provided minimum criteria for iSD duration met, 
otherwise, iUPD 
iPR 
NE 
iSD provided minimum criteria for iSD duration met, 
otherwise, NE 
iSD 
iCR 
iSD provided minimum criteria for iSD duration met, 
otherwise, NE 
iSD 
iPR 
iSD provided minimum criteria for iSD duration met, 
otherwise, NE 
 
Note: if prior to iSD there is a iPR (i.e. iPR-iSD-iPR) then 
iBOR is iPR.   
iSD 
iSD 
iSD provided minimum criteria for iSD duration met, 
otherwise, NE 
iSD 
iUPD 
iSD provided minimum criteria for iSD duration met, 
otherwise, iUPD 
iSD 
NE 
iSD provided minimum criteria for iSD duration met, 
otherwise, NE 
iUPD 
iUPD 
iUPD 
iUPD 
iCPD 
iCPD 
iUPD 
NE 
iUPD 
NE 
NE 
NE 
Note: For patients with non-target disease only at baseline, only iCR or non-iCR/non-iUPD can be assigned at each 
timepoint response but is not shown in the table for ease of presentation.  


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6.3. 
Appendix 3 Combined list and Focused list 
6.3.1. 
Combined Preferred Terms 
The combined terms for MedDRA Version 25.1 are listed below. Changes to the MedDRA 
dictionary may occur between the start of the study and the time of reporting and/or emerging 
data from on-going studies may highlight additional combined terms, therefore the list of 
combined preferred terms will be based on the safety review team agreements in place at the 
time of reporting. 
List of Preferred Terms to Be Combined  
The following synonyms will be combined under the PT as shown below. The combined term will be used 
when reporting AE data in tables by PT. Synonymous terms will be combined regardless of body system. 
 
Combined Term 
MedDRA Preferred Term (MedDRA 25.1) 
Anaemia/Red blood cell count decreased  
 
Anaemia  
Red blood cell count decreased 
Cytokine Release Syndrome (CRS)  
Cytokine Release Syndrome  
  
Cytokine Storm  
Acute GvHD - Skin 
Acute graft versus host disease in skin 
Acute GvHD - Gut (Liver and Intestine) 
Acute graft versus host disease in liver 
  
Acute graft versus host disease in intestine 
Acute GvHD - Other (Lung, Bone Marrow, not specified) 
Acute graft versus host disease 
 
Acute graft versus host disease oral 
Chronic GvHD - Skin 
Chronic graft versus host disease in skin 
Chronic GvHD - Gut (Liver and Intestine) 
Chronic graft versus host disease in liver 
  
Chronic graft versus host disease in intestine 
Chronic GvHD Other - (Lung, Bone Marrow, not 
specified) 
Chronic graft versus host disease 
 
Chronic graft versus host disease in eye 
 
Chronic graft versus host disease oral 
 
Chronic graft versus host disease in lung 
Unspecified GvHD - Skin 
Graft versus host disease in skin 
Unspecified GvHD - Gut (Liver and Intestine) 
Graft versus host disease in liver 
  
Graft versus host disease in gastrointestinal tract 
Unspecified GvHD - Other (Lung, Bone Marrow, not 
specified) 
Graft versus host disease 
  
Graft versus host disease in eye 


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List of Preferred Terms to Be Combined  
The following synonyms will be combined under the PT as shown below. The combined term will be used 
when reporting AE data in tables by PT. Synonymous terms will be combined regardless of body system. 
 
Combined Term 
MedDRA Preferred Term (MedDRA 25.1) 
  
Graft versus host disease in lung 
  
Prophylaxis against graft versus host disease 
  
Transfusion associated graft versus host disease 
  
Engraftment syndrome  
Leukopenia/White blood cell decreased 
White blood cell count decreased 
  
Leukopenia 
Lymphopenia/Lymphocyte count decreased  
Lymphocyte count decreased 
 
Lymphopenia 
  
CD4 lymphocytes decreased  
  
CD8 lymphocytes decreased  
Neutropenia/Neutrophil count decreased  
Neutrophil count decreased 
  
Neutropenia 
Rash/Rash maculo-papular 
Rash maculo-papular 
  
Rash 
  
Rash erythematous 
Thrombocytopenia/Platelet count decreased  
Platelet count decreased 
  
Thrombocytopenia 
 
 
Immune effector cell-associated neurotoxicity syndrome 
(ICANS) 
Immune effector cell-associated neurotoxicity 
syndrome 
 
Encephalopathy 
 
 
Tachycardia 
Tachycardia 
 
Sinus tachycardia 
 
6.3.2. 
Focused list 
AE of Special Interest (AESI) 
MedDRA Preferred Term (MedDRA 25.1) 
Guillain-Barre syndrome 
(Focused list) 
Demyelinating polyneuropathy 
Guillain-Barre syndrome 
Peripheral sensorimotor neuropathy 
Subacute inflammatory demyelinating polyneuropathy 
Zika virus associated Guillain Barre syndrome 
Source: MedDRA preferred terms from Guillain-Barre syndrome SMQ 


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Graft versus Host Disease 
(Focused list) 
 
Acute graft versus host disease in skin 
Acute graft versus host disease in liver 
Acute graft versus host disease in intestine 
Acute graft versus host disease 
Acute graft versus host disease oral 
Chronic graft versus host disease 
Chronic graft versus host disease in skin 
Chronic graft versus host disease in liver 
Chronic graft versus host disease in eye 
Chronic graft versus host disease oral 
Chronic graft versus host disease in lung 
Graft versus host disease in skin 
Graft versus host disease in liver 
Graft versus host disease in gastrointestinal tract 
Graft versus host disease 
Graft versus host disease in eye 
Graft versus host disease in lung 
Prophylaxis against graft versus host disease 
Transfusion associated graft versus host disease 
Engraftment syndrome 
Source: MedDRA preferred terms considered associated with graft versus host disease 
Cytokine Release Syndrome 
(Focused list) 
Cytokine release syndrome 
Cytokine storm 
Source: MedDRA preferred terms considered associated with Cytokine release syndrome  
 
Immune Effector-Cell Associated 
Neurotoxicity Syndrome (ICANS)  
(Focused list) 
Encephalopathy 
 
Immune effector cell-associated neurotoxicity syndrome 
Sources: MedDRA preferred terms from Noninfectious encephalitis SMQ and Noninfectious 
encephalopathy/delirium (SMQ) 
 
Hematopoietic Cytopenias (including 
Pancytopenia and Aplastic Anemia) 
(Focused List) 
 
Febrile bone marrow aplasia 
Autoimmune aplastic anaemia 
Aplastic anaemia 
Pancytopenia 
Bone marrow failure 
Full blood count abnormal 
Full blood count decreased 
Cytopenia 
Haemoglobin abnormal 
Hypoplastic anaemia 
Red blood cell count abnormal 
Haematocrit decreased 
Normochromic anaemia 
Normochromic normocytic anaemia 
Normocytic anaemia 


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Reticulocyte count decreased 
Reticulocytopenia 
Haematocrit abnormal 
Haemoglobin decreased 
Anaemia macrocytic 
Erythropoiesis abnormal 
Anaemia 
Erythropenia 
Microcytic anaemia 
Red blood cell count decreased 
Neutropenic sepsis 
Band neutrophil percentage decreased 
Febrile neutropenia 
Granulocytopenia 
Neutropenia 
Neutrophil count abnormal 
Neutrophil percentage decreased 
Neutrophil count decreased 
Plateletcrit abnormal 
Plateletcrit decreased 
Acquired amegakaryocytic thrombocytopenia 
Megakaryocytes decreased 
Platelet production decreased 
Platelet count abnormal 
Platelet count decreased 
Platelet disorder 
Thrombocytopenia 
White blood cell count decreased 
Leukopenia 
Lymphocyte count decreased 
Lymphopenia 
CD4 lymphocytes decreased *  
CD8 lymphocytes decreased * 
Sources: MedDRA preferred terms from Hematopoietic cytopenias SMQ  and  
* MedDRA preferred terms considered associated with hematopoietic cytopenia 
 
Pneumonitis 
(Focused list) 
Acute interstial pneumonitis 
Alveolar lung disease 
Alveolar proteinosis 
Alveolitis 
Alveolitis necrotising 
Autoimmune lung disease 
Bronchiolitis 
Brochiolitis obliterans syndrome 
Chronic graft versus host disease in the lung 
Combined pulmonary fibrosis and emphysema 
Confirmed e-cigarette or vaping product use associated lung injury 
Diffuse alveolar damage 
Eosinophilia myalgia syndrome 
Eosinophilic granulomatosis with polyangiitis 


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Eosinophilic pneumonia 
Eosinophilic pneumonia acute 
Eosinophilic pneumonia chronic 
Hypersensitivity pneumonitis 
Idiopathic interstitial pneumonia 
Idiopathic pneumonia syndrome 
Idiopathic pulmonary fibrosis 
Immune-mediated lung disease 
Interstitial lung disease 
Low lung compliance 
Lung infiltration 
Lung opacity 
Necrotising bronchiolitis 
Obliterative bronchiolitis 
Pleuroparenchymal fibroelastosis 
Pneumonitis 
Probable e-cigarette or vaping product use associated lung injury 
Progressive massive fibrosis 
Pulmonary fibrosis 
Pulmonary necrosis 
Pulmonary radiation injury 
Pulmonary septal thickening 
Pulmonary toxicity 
Pulmonary vasculitis 
Radiation alveolitis 
Radiation bronchitis 
Radiation fibrosis - lung 
Radiation pneumonitis 
Rheumatoid arthritis-associated interstitial lung disease 
Small airways disease 
Transfusion-related acute lung injury 
Source: MedDRA preferred terms considered associated with pneumonitis 
 
6.4. 
Appendix 4 Modified Toxicity Probability Interval 2 (mTPI-2) 
As of Core SAP Amendment 2: Note that all substudies were terminated prior to the 
determination of RP2D, and so there will be no RP2D recommended based on the mTPI-2. 
This study will employ an mTPI-2 [Guo, 2017] design.  mTPI-2 is implemented within a formal 
Bayesian decision framework and is extension of the modified toxicity probability interval 
method (mTPI) [Ji, 2010]. mTPI-2 was 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 Section 6.4.1.  
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 


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Table 9. In addition, decision U means that the current dose level is unacceptable because of 
high toxicity and should be excluded from the trial. 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 trial is terminated when either the 
lowest dose is above the maximum tolerated dose (MTD) or a prespecified maximum sample 
size is reached. For this study, pT, the target toxicity level is 0.3, the uncertainty values are set at 
e1=e2=0.05, 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 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 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 


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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. 
 
Target toxicity level=30% 
e1=e2=0.05 
 
6.4.1. 
mTPI-2 Simulation Results 
Simulations on the mTPI-2 design were conducted assuming either a 10% or 20% toxicity rate for 
the low dose (0.1 × 109 – 0.8 × 109 transduced T-cells) and a 10%, 20%, 30%, or 40% toxicity rate 
for the high dose (1 × 109 – 8 × 109 transduced T-cells). 10000 simulations were conducted per 
scenario. The maximum tolerated dose is defined as the dose with DLT rate of 30%. The 
simulation results are shown in the tables below which demonstrates that mTPI-2 is a robust 
study design under all scenarios.   
Table 10 shows the results of the simulation study. Based on the preclinical evidence and 
observed GSK3337794 toxicity data, we assume the moderate (20%) or borderline (30%) high 
dose toxicities are the most likely scenarios for GSK3901961 & GSK3845097. For these scenarios, 
highlighted in bold, we see that average observed toxicity rate is very close to the true 
underlying rate for the high dose and lower than the true underlying rate for the low dose. The 
average number of participants who experienced DLTs at the high dose is less than 2 out of an 
average of 8 participants when there is a borderline toxicity rate and less than 2 out of an 
average of 7 participants if there is a moderate toxicity rate. These results support our claim that 
the chosen design will be protective against overdosing. Additionally, the maximum tolerated 
dose is chosen >91% of the time when there is a moderate toxicity rate in the high dose and 
>76% of the time when there is a borderline toxicity rate in the high dose, which shows that the 
design is robust in correctly choosing the correct MTD under different underlying dose-DLT rate 
models. 
Table 10 
Design Simulation Results 
True DLT 
rates 
Low: 0.1 
High: 0.1 
Low: 0.1 
High: 0.2 
Low: 0.1 
High: 0.3 
Low: 0.1 
High: 0.4 
Low: 0.2 
High: 0.2 
Low: 0.2 
High: 0.3 
Low: 0.2 
High: 0.4 
Average Observed Toxicity Rate 
Low Dose 
0.07 
0.09 
0.09 
0.09 
0.17 
0.18 
0.18 
High Dose 
0.10 
0.20 
0.30 
0.42 
0.20 
0.31 
0.43 
Average Number of DLTs  
Low Dose 
0.02 
0.08 
0.17 
0.30 
0.17 
0.37 
0.62 
High Dose 
0.60 
1.23 
1.90 
2.55 
1.21 
1.82 
2.42 
Average Sample Size 
Low Dose 
0.15 
0.76 
1.74 
2.94 
0.86 
1.88 
3.14 
High Dose 
6.02 
6.13 
6.30 
6.36 
6.04 
6.07 
6.03 
Total Dosed 
6.17 
6.89 
8.04 
9.29 
6.90 
7.95 
9.17 


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True DLT 
rates 
Low: 0.1 
High: 0.1 
Low: 0.1 
High: 0.2 
Low: 0.1 
High: 0.3 
Low: 0.1 
High: 0.4 
Low: 0.2 
High: 0.2 
Low: 0.2 
High: 0.3 
Low: 0.2 
High: 0.4 
Percent picked as Maximum Tolerated Dose (MTD) 
No Dose 
0.00 
0.00 
0.00 
0.00 
0.01 
0.02 
0.02 
Low Dose 
0.01 
0.07 
0.21 
0.42 
0.09 
0.22 
0.42 
High Dose 
0.99 
0.93 
0.79 
0.58 
0.91 
0.76 
0.55 
 
 
 


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7. 
REFERENCES 
Braun CJ, Boztug K, Paruzynski A, Witzel M, Schwarzer A, Rothe M, Modlich U, Beier R, Göhring 
G, Steinemann D, and Fronza R. Gene therapy for Wiskott-Aldrich syndrome—long-term efficacy 
and genotoxicity. Science translational medicine, 2014, 6(227), pp.227ra33-227ra33 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics, 1982; 
38:29-41. 
FDA. (2020, January). Guidance for Industry, Long Term Follow-Up After Administration of 
Human Gene Therapy Products. 
Gillet NA, Malani N, Melamed A, Gormley N, Carter R, Bentley D, Berry C, Bushman FD, Taylor 
GP, and Bangham CR. The host genomic environment of the provirus determines the abundance 
of HTLV-1–infected T-cell clones. Blood, The Journal of the American Society of Hematology, 
2011, 117(11), pp.3113-3122. 
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. 
Ji Y, Liu P, Li Y. A modified toxicity probability interval method for dose-finding trials. Clin Trials. 
2010; 7:653–663. 
Lee DW, Santomasso BD, Locke FL. ASTCT Consensus Grading for Cytokine Release Syndrome 
and Neurologic Toxicity Associated with Immune Effector Cells. Biology of Blood and Marrow 
Transplantation, 2019;25:625-38. 
Ramirez AH, Schildcrout JS, Blakemore DL, Masys DR, Pulley JM, Basford MA, Roden DM, Denny 
JC. Modulators of normal electrocardiographic intervals identified in a large electronic medical 
record. Heart Rhythm. 2011 Feb;8(2):271-7. doi: 10.1016/j.hrthm.2010.10.034. Epub 2010 Oct 
29. PMID: 21044898; PMCID: PMC3057498.