Conditions: Neoplasms
Keywords: Bintrafusp Alfa Platinum Agent Response Evaluation Criteria in Solid Tumors Urothelial Cancer M7824
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate bintrafusp alfa in participants with metastatic or locally advanced urothelial cancer. This trial provides the first evaluation of bintrafusp alfa in participants with urothelial cancer that has progressed following platinum therapy.

Detailed description:

Arms:
arm 1: Participants will receive bintrafusp alfa.

Interventions: intervention 1: Bintrafusp alfa
Intervention descriptions: intervention 1: Participants will receive bintrafusp alfa.

Protocol document:
Prot_000.pdf: 
TMF-14396625 
CONFIDENTIAL 
GlaxoSmithKline group of companies 
213152 
Protocol Amd 02 
1 
TITLE PAGE 
Protocol Title: A Phase Ib Trial to Evaluate the Efficacy and Safety of Bintrafusp Alfa 
Monotherapy in Metastatic or Locally Advanced/Unresectable Urothelial Cancer with 
Disease Progression or Recurrence Following Treatment with a Platinum Agent 
Protocol Number: 213152/Amendment 02 
Compound 
Number or Name: 
GSK4045154 bintrafusp alfa (M7824) 
Brief Title: A Phase Ib trial to evaluate the efficacy and safety of bintrafusp alfa 
monotherapy in metastatic or locally advanced urothelial cancer 
Study Phase: Phase Ib 
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
Manufacturer: Merck KGaA 
Regulatory Agency Identifying Number(s): 
IND 
145828 
EudraCT 
2020-000416-29 
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual. 
Sponsor Signatory: 
Rachael M. Easton, MD, PhD 
Medical Director, Oncology Clinical Development 
Approval Date: 03 Mar 2022 
©2022 GSK group of companies or its licensor. All rights reserved. Unauthorized 
copying or use of this information is prohibited.


TMF-14396625 
CONFIDENTIAL 
 
 
 
213152 
Protocol Amd 02 
 
 
 
 
2 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Document Identifier 
Amendment 2 
03 Mar 2022 
TMF-14396625 
Amendment 1 
28 May 2020 
2019N411039_01 
Original Protocol 
30 Jan 2020 
2019N411039_00 
 
Amendment 02: 03 Mar 2022 
This amendment is considered to be substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment: 
Based on the lack of efficacy of bintrafusp alfa in clinical studies in other tumor types, 
and improved efficacy of other therapies for urothelial cancer, the study sponsor has 
decided to cease enrollment into the study. In line with the sponsor’s decision, this 
protocol has been amended to provide updated instructions for continued study conduct. 
A summary of significant changes from Amendment 1 is provided in the table below 
together with a brief rationale for the changes: 
Section # and Name 
Description of Change 
Brief Rationale 
Full document 
 
Editorial changes have 
been made throughout 
document to increase 
clarity/consistency, adjust 
abbreviation usage, align 
with current template 
requirements, and correct 
minor typographical errors. 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
Pr ot o c ol A m d 0 2  
 
 
 
 
3  
 
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 ecti o n 1 Pr ot ocol S u m m ary  
T ext h as b e en a d d ed  
pr ovi di n g a n ov ervi e w of th e 
d ecisi o n to st op e nr oll m ent 
a n d t h e c orr esp o n din g 
i m p acts o n st u dy c on d uct 
a n d d at a c oll ecti o n . 
A d diti o n h as b e e n m a d e to 
r efl ect th e ov er all r ati on al e 
f or A m e n d m e nt 02. 
S p ecific ally, bas e d o n t h e 
l ack of effic acy of bi ntr afus p 
alf a i n cli nical stu di es i n 
ot h er t u mor ty pes a nd 
i m pr ove d effic acy of ot h er 
t h er a pi es f or urot h eli al 
c a nc er, t h e st u dy s p o ns or 
h as d eci d ed t o ce as e 
e nr oll m e nt int o t h e st u dy. I n 
li n e wit h t h e sp o nsor’s 
d ecisi o n, this pr ot oco l h as 
b e e n a me n d e d t o pr ovi d e 
u p d at e d i nstructi ons f or 
c o nti nu e d st u dy c o n duct. 
S ecti o n 1. 1 Sy no psis  
S ecti o n 3 O bj ectiv es a n d E ndp oi nts  
S ev er al s ec on d ary 
o bj ectiv es a n d e n d p oi nts 
h av e b ee n u pd at e d an d 
E nr oll m ent i nto t h e st u dy 
h as b e en disc o nti n u ed; 
st u dy o bj ectives an d 
e n d p oi nts h av e b ee n 
u p d at e d to r efl ect ch a n g e i n 
st u dy sc op e. 
S ecti o n 1. 1 Sy no psis  
S ecti o n 1. 3 Sc he d ul e of Activiti es  
S ecti o ns 3 O bj ectives a nd E nd p oi nts  
S ecti o n 8. 3 Ev al u atio n of A nti -C a nc er 
Activity  
S ecti o n 9. 6  I n d ep e n d ent R a diol o gy 
Co m mitt ee  
T ext h as b e en m o difi e d t o 
r efl ect th at a n
 
will n ot b e utilize d f or th e 
ev al u ati o n of a ntit u m or 
activity.  
M o dific atio ns h av e b e e n 
m a d e t o refl ect t h e 
s p o nsor’s d ecisi on t o ce as e 
e nr oll m e nt int o t h e st u dy 
a n d t h e c orr esp o n din g 
u p d at e of st u dy o bj ectiv es 
a n d st udy co n d uct.  
S ecti o n 1. 1 Sy no psis  
S ecti o n 1. 3 Sc he d ul e of Activiti es  
D et ails h av e b e e n ad d e d 
r e g ar di n g d at a c ollectio n t o 
b e c o n duct ed f oll o wi n g th e 
d at a c ut -off ( D C O) d ate.  
A d diti o n w as m ad e t o 
pr ovi d e i nstr ucti o n 
r e g ar di n g d at a c ollectio n 
f oll o wi ng t h e D C O dat e. 
S ecti o n 1. 1 Sy no psis  
S ecti o n 4. 1 Ov er all D esi g n  
S ecti o n 4. 6 N u m ber of P artici pa nts  
S ecti o n 9. 2 S a mpl e Siz e D et er mi n atio n  
T h e s a m pl e siz e h as  b e e n 
r evis ed fr o m 4 0 t o 
2 5  p artici p ants w h o will 
r ec eive bi ntr af usp alf a. 
M o dific atio n h as b e en 
m a d e b as e d o n t h e 
s p o nsor’s d ecisi on t o ce as e 
e nr oll m e nt.  
S ecti o n 1. 3 Sc he d ul e of Activiti es  
T ext i ndic ati n g th at ‘( unl ess 
n ot e d i n ass ess m e nt 
“ Not es”)’ w as a d d e d 
r e g ar di n g ti mi n g of” D 1 
ass ess me nts.  
M o dific atio n w as m a d e f or 
cl arity. 
C CI
C CI
C CI


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Pr ot o c ol A m d 0 2  
 
 
 
 
4  
 
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 ecti o n 1. 3 Sc he d ul e of Activiti es  
S ecti o n 6. 1 St u dy I nt erv e ntio n(s) 
A d mi nist er e d  
T ext h as b e en a d d ed 
s p ecifyi ng t h at st u dy 
i nt erv enti o n a d mi nistrati o n 
d ur ati o n c a n b e c onti n ue d  
f or u p t o 2 y e ars fr o m t h e 
ti m e of a c onfir m ed c o m pl et e 
r es p o ns e ( C R). 
M o dific atio n w as m a d e f or 
c o nsist e ncy with t h e 
tr e at m e nt d ur atio n li mit 
pr es e nt ed t hr o ug h o ut th e 
r est of t he pr ot oc ol. 
S ecti o n 1. 3 Sc he d ul e of Activiti es  
S a m pl es f or bintr af us p alfa 
a n alysis will n o l o n ger b e 
c oll ect e d. 
I n li g ht of t h e 
disc onti n uati o n of 
e nr oll m e nt, r e m oval of 
t h es e s a m pl es will r e duc e 
t h e b ur d en f or o ng oi n g 
p articip a nts.  
S ecti o n 1. 3 Sc he d ul e of Activiti es  
I n li g ht of t h e 
disc onti n uati o n of 
e nr oll m e nt, r e m oval of 
t h es e s a m pl es will r e duc e 
t h e b ur d en f or o ng oi n g 
p articip a nts.  
S ecti o n 1. 3 Sc he d ul e of Activiti es  
I n li g ht of t h e 
disc onti n uati o n of 
e nr oll m e nt, r e m oval of 
t h es e s a m pl es will r e duc e 
t h e b ur d en f or o ng oi n g 
p articip a nts.  
S ecti o n 1. 3 Sc he d ul e of Activiti es  
S a m pl es f or ass ess me nt of 
bi ntr af us p
will 
n o l o n ger b e c oll ect e d.  
I n li g ht of t h e 
disc onti n uati o n of 
e nr oll m e nt, r e m oval of 
t h es e s a m pl es will r e duc e 
t h e b ur d en f or o ng oi n g 
p articip a nts.  
S ecti o n 2. 2. 5 Risk Ass ess m ent  
T ext h as b e en a d d ed 
r e g ar di n g pl a nn e d 
h e m at ol o gy s urveill a nc e. 
M o dific atio n w as m a d e t o 
c orr ect a n i n adv erte nt 
o missi o n fr o m previ ous 
v ersi ons of t h e pr ot oc ol. 
S ecti o n 2. 2. 7 Ov er all B e nefit -Risk 
Ass ess m e nt  
T ext h as b e en a d d ed 
r e g ar di n g t h e co nti nu o us 
ev al u ati o n of t h e be n efit -risk 
pr ofil e for bi ntraf usp  alf a. 
M o dific atio n w as m a d e t o 
r efl ect th e e mer gi ng d at a 
fr o m ot h er st u di es i n t h e 
c o nsid er atio n of th e 
b e n efit -risk assess m e nt. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


TMF-14396625 
CONFIDENTIAL 
 
 
 
213152 
Protocol Amd 02 
 
 
 
 
5 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 4 Study Design 
Text has been added 
regarding the sponsor’s 
decision to cease enrollment 
into the study. 
Addition was made to 
reflect the discontinuation 
of enrollment for this study. 
Section 4.1 Overall Design 
Text regarding the 
secondary objectives of the 
study has been modified. 
Modifications were made to 
correspond to changes in 
the objectives and 
endpoints sections of the 
protocol. 
Section 4.1 Overall Design 
Text has been added 
regarding data collection and 
participant follow-up after the 
DCO date. 
Addition was made to 
provide instruction 
regarding data collection 
and study conduct following 
the DCO date. 
Section 4.4, Archival Tumor Biopsy PD-L1 
Status 
Section 5.1 Inclusion Criteria 
(Criterion #10) 
Section 8.11.2 Tumor Tissue 
Language regarding 
prospective and/or 
retrospective assessment of 
PD-L1 status has been 
removed from the protocol. 
Text has been updated in 
line with ceasing enrollment 
into the study and the 
update of study conduct. 
Section 4.7 Oversight 
Section 4.7.1 Independent Radiology 
(Review) Committee (IRC) 
Sections have been 
removed. 
Sections were deleted to 
reflect the sponsor’s 
decision to cease 
enrollment into the study 
and the corresponding 
updates to study objectives 
and study conduct. 
Section 4.7 End of Study Definition 
(formerly Section 4.8) 
The end of study (EOS) 
definition has been revised 
to be the last participant’s 
last visit. 
Modification was made to 
reflect the discontinuation 
of study enrollment. 
Section 5.2 Exclusion Criteria (Exclusion 
Criterion #24) 
The duration of 5 half-lives 
has been updated from 
30 days to 35 days. 
Modification was made for 
alignment with the 
Investigator’s Brochure. 
Section 6.7 Dose Modification 
Text has been added to 
allow for dose modifications 
in response to bleeding 
events. 
Addition was made to 
reflect new language 
regarding bleeding events 
in Section 6.8.5.1. 
Section 6.8.5.1 Bleeding Events 
Language regarding 
appropriate follow-up for 
bleeding events has been 
updated with additional 
detail. 
Language has been 
updated to be consistent 
with the Investigator’s 
Brochure. 


TMF-14396625 
CONFIDENTIAL 
 
 
 
213152 
Protocol Amd 02 
 
 
 
 
6 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.9 Intervention After the End of 
the Study 
Text has been added 
1) relating to the potential for 
study participants to roll over 
to a continuation study has 
been deleted, and 
2) specifying that 
participants with continued 
benefit from study 
intervention will have access 
to study intervention until 
EOS. 
Modifications were made to 
reflect the discontinuation 
of enrollment into the study 
and the corresponding 
updates to study conduct. 
Section 6.10 Continued Access to Study 
Intervention after Data Cut-off  
(new section) 
Text has been added to 
describe the availability of 
study intervention after the 
DCO date. 
Modifications were made to 
reflect the discontinuation 
of enrollment into the study 
and the corresponding 
updates to study conduct. 
Section 7.1 Discontinuation of Study 
Intervention 
Text has been added 
regarding management of 
participants who discontinue 
study intervention after the 
DCO date. 
Addition was made to 
provide instruction 
regarding study visits and 
data collection following the 
DCO date. 
Section 7.2 Participant 
Discontinuation/Withdrawal from the Study 
Text has been added 
specifying that the maximum 
duration of study treatment is 
2 years from first dose or 
from the time of confirmed 
CR. 
Modification was made for 
consistency with the 
treatment duration limit 
presented throughout the 
rest of the protocol. 
Section 7.2 Participant 
Discontinuation/Withdrawal from the Study 
Text regarding continuation 
of survival follow-up until 
67% of randomized 
participants have died or 
withdrawn consent (to a 
maximum of 3 years) has 
been deleted. 
Modification was made to 
reflect the change the EOS 
definition (Section 4.7).  
Section 7.4 Participant and Study 
Completion 
Text regarding the definition 
of a participant’s completion 
of the study has been 
modified. 
The definition of participant 
completion has been 
revised to reflect the 
definition applicable to 
participants receiving study 
intervention at the time of 
Amendment 02. 


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7  
 
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 ecti o n 8. 2 F oll o w -u p Ass ess m e nts  
T ext h as b e en a d d ed t o 
d escrib e t h e i m pl e m ent atio n 
of t h e D C O d at e, cli nic al 
st u dy d at a b as e lock, cli nic al 
m a n a g e m e nt  of p artici pa nts, 
a n d p h ar m ac ovi gil a nc e 
pr oc e d ures t o b e c on d uct e d 
aft er t h e D C O  d at e. 
A d diti o n w as m ad e t o 
pr ovi d e i nstr ucti o n 
r e g ar di n g d at a c ollectio n 
f oll o wi ng t h e D C O dat e a nd 
t o e ns ure t h e nec ess ary 
s p o nsor ov ersi g ht of 
p articip a nts w h o c onti n ue 
t o rec eiv e st u dy 
i nt erv enti o n aft er t he D C O 
d at e. 
S ecti o n 8. 3 Ev al u atio n of A nti -C a nc er 
Activity  
All r ef er e nc es t o 
i m m u ne-r el ate d R E CI S T 
(ir R E CI S T) a n d all of 
S ecti o n  8. 3. 1. 2 h av e b e e n 
d el et e d.  
ir R E CI S T h as b e e n 
r e m ov ed fr o m th e stu dy 
e n d p oi nts; c orr es po n din g 
t ext r elati n g t o t h es e 
ev al u ati o n crit eri a h av e 
t h er ef or e be e n d el et e d. 
S ecti o n 8. 4. 1 P hysic al Ex a minati o ns  
Ass ess m e nt of i nf usio n sit e 
r e acti ons h as b e en m ov e d 
fr o m Scr e eni n g (i e, co m pl et e 
p hysic al ex a mi n ati o n) t o t h e 
s u bs eq u e nt visits (i e, brief 
p hysic al ex a mi n ati o ns).  
M o dific atio n w as m a d e t o 
c orr ecti o n a n err or i n 
pr evi o us versi on (i e, 
m o nit ori n g of i nf usi o n sit e 
r e acti ons is n ot rel eva nt f or 
t h e Scr e e ni n g peri o d) an d 
t o ali gn wit h t he S o A. 
S ecti o n 8. 5. 2 C oll ecti o n of S afety 
I nf or m ati o n Aft er Data C ut-off 
( n e w s ecti o n) 
A n e w s ecti o n h as b ee n 
a d d e d r e gar di n g t h e 
c oll ecti on of saf ety 
i nf or m ati o n aft er t h e D C O 
d at e. 
A d diti o n w as m ad e t o 
pr ovi d e i nstr ucti o n 
r e g ar di n g d at a c ollectio n 
f oll o wi ng t h e D C O date a nd 
t o e ns ure t h e nec ess ary 
s p o nsor ov ersi g ht of 
p articip a nts w h o c onti n ue 
t o r ec eiv e st u dy 
i nt erv enti o n aft er t he D C O 
d at e. 
S ecti o n 8. 5. 3 M et h o d of D et ecti n g A Es 
a n d S A Es  
T ext h as b e en a d d ed t o 
s p ecify t hat d et ecti on of A Es 
a n d S A Es als o a ppli ed t o 
t h os e ev e nts occ urri ng aft er 
t h e D C O d at e. 
A d diti o n w as m ad e t o 
e ns ur e ap pr o priat e A E a n d 
S A E c oll ecti o n fro m 
p articip a nts w h o c onti n ue 
t o r ec eiv e st u dy 
i nt erv enti o n aft er t he D C O 
d at e. 
S ecti o n 8. 6 P artici p ant S p ecific D os e 
A dj ust me nts Crit eri a  
T ext h as b e en  a d d ed t o 
hi g hlig ht t he exc e ptio ns for 
w hic h d os e r e ductio ns of 
st u dy i nt erv e ntio n ar e 
all o w e d, as d etail ed i n 
S ecti o n  6. 8. 
A d diti o n w as m ad e f or 
c o nsist e ncy with 
m o dific atio ns m a d e i n 
S ecti o n 6. 7 a n d 
S ecti o n  6. 8. 5. 1.  
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Pr ot o c ol A m d 0 2  
 
 
 
 
8  
 
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 ecti o n 9 St atistical C o nsi d er ati o ns  
T ext h as b e en a d d ed 
r e g ar di n g pl a ns f or 
a b br eviat e d r ep orti ng of 
st u dy d at a an d t h e re m ov al 
of t h e pr evi o usly pl a nn e d 
i nt eri m a n alysis. 
M o dific atio n h as b e en 
m a d e b as e d o n t h e 
s p o nsor’s d ecisi on t o ce as e 
e nr oll m e nt.  
S ecti o n 9. 1 St atistic al Hyp ot h esis  
S ect i o n 9. 4 St atistic al A nalys es 
S ecti o n 9. 4. 2 Pri m ary E nd p oint  
I nst a nc es r ef erri n g t o t h e 
fi n al an alysis or t h e E O S 
a n alysis h av e b e e n c h a ng e d 
t o r ef er t o th e pri m ary 
a n alysis.  
T h es e m o dific ati o n s w ere 
m a d e t o m or e acc urat ely 
d escrib e t h e a n alysis of th e 
pri m ary e n d p oi nt.  
S ecti o n 9. 4. 3 S ec o n d ary E n d poi nts  
C o nt e nt h as b e e n m o difi e d 
t o r efl ect 1) t h e d el eti o n of 
t h e a n alysis r e gar di n g
M o dific atio ns w er e m a d e t o 
c orr es po n d t o c h a ng es 
m a d e t o st u dy o bjectiv es 
a n d e n d poi nts.  
S ecti o n 1 0. 3. 5 R ep orti n g of S A Es t o G S K  
T ext r e g ardi n g th e r e p orti n g 
of S A E s a n d A Es l e a di n g t o 
disc onti n uati o n h as b e e n 
u p d at e d.  
M o dific atio n w as m a d e t o 
pr ovi d e i nstr ucti o ns 
r e g ar di n g t h e saf ety 
r e p orti n g re q uir e m e nts f or 
p articip a nts r ec eivin g stu dy 
i nt erv enti o n aft er t he D C O 
d at e. 
S ecti o n 1 0. 4. 2 C ontr ac eptive G ui d anc e  
A st at e me nt h as b e en a d d ed 
t h at t h e prot oc ol’s 
c o ntr ace ptiv e g ui d a nc e will 
als o ap ply t o p articip a nts 
w h o c o ntin u e t o rec eiv e 
st u dy i nt erv e ntio n aft er t h e 
D C O d at e.  
A d diti o n w as m ad e f or 
cl arity. 
S ecti o n 1 0. 4. 3 C oll ecti o n of Pre g n a ncy 
I nf or m ati o n 
A st at e me nt h as b e en a d d ed 
t h at c oll ecti o n of pr e g na ncy 
i nf or m ati o n r eq uir e m e nts will 
als o ap ply t o p articip a nts 
w h o c o ntin u e t o rec eiv e 
st u dy i nt erv e ntio n aft er t h e 
D C O d at e.  
A d diti o n w as m ad e f or 
cl arity. 
S ecti o n 1 1 R ef er e nc es  
R ef er e nc es n o lo n g er cit e d 
i n t h e prot oc ol h av e b e en 
d el et e d.  
M o dific atio ns w er e m a d e t o 
c orr es po n d t o d el eti o ns 
m a d e t o t ext i n t h e b o dy of 
t h e pr ot oc ol. 
 
 
C CI
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9  
 
T A B L E O F C O N T E N T S  
P A G E  
TI T L E P A G E  ................................................................................................................... 1  
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E  ..................................... 2  
T A B L E O F C O N T E N T S  .................................................................................................. 9  
1.  
P R O T O C O L S U M M A R Y  ........................................................................................ 1 3  
1. 1.  
S y n o p si s  ..................................................................................................... 1 3  
1. 2.  
St u d y S c h e m a  ............................................................................................ 1 8  
1. 3.  
S c h e d ul e of A cti viti e s  .................................................................................. 1 8  
2.  
I N T R O D U C TI O N .................................................................................................... 2 6  
2. 1.  
St u d y R ati o n al e  .......................................................................................... 2 6  
2. 2.  
B a c k gr o u n d  ................................................................................................ 2 6  
2. 2. 1.  
Ur ot h eli al C a n c er  ......................................................................... 2 6  
2. 2. 2.  
R ol e of T G F -β  i n Ur ot h eli al C a n c er P at h o g e n e si s a n d 
Cli ni c al O ut c o m e  .......................................................................... 2 7  
2. 2. 3.  
M e c h a ni s m of A cti o n of Bi ntr af u s p Alf a  ........................................ 2 7  
2. 2. 4.  
Cli ni c al E x p eri e n c e wit h Bi ntr af u s p Alf a  ....................................... 2 8  
2. 2. 5.  
Ri s k A s s e s s m e nt  ......................................................................... 2 8  
2. 2. 6.  
B e n efit A s s e s s m e nt  ..................................................................... 3 0  
2. 2. 7.  
O v er all B e n efit -Ri s k A s s e s s m e nt  ................................................. 3 1  
3.  
O B J E C TI V E S A N D E N D P O I N T S ........................................................................... 3 2  
4.  
S T U D Y D E SI G N  .................................................................................................... 3 4  
4. 1.  
O v er all D e si g n  ............................................................................................ 3 4  
4. 2.  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  .......................................................... 3 5  
4. 3.  
J u stifi c ati o n f or D o s e  .................................................................................. 3 5  
4. 5.  
Fr e s h T u m or Bi o p s y  ................................................................................... 3 5  
4. 6.  
N u m b er of P arti ci p a nt s  ............................................................................... 3 5  
4. 7.  
E n d of St u d y D efi niti o n  ............................................................................... 3 6  
5.  
S T U D Y P O P U L A TI O N  ........................................................................................... 3 7  
5. 1.  
I n cl u si o n Crit eri a ......................................................................................... 3 7  
5. 2.  
E x cl u si o n Crit eri a  ........................................................................................ 3 9  
5. 3.  
Lif e st yl e C o n si d er ati o n s  .............................................................................. 4 2  
5. 3. 1.  
M e al s a n d Di et ar y R e stri cti o n s  .................................................... 4 2  
5. 3. 2.  
Al c o h ol a n d T o b a c c o U s e  ............................................................ 4 2  
5. 3. 3.  
A cti vit y  ......................................................................................... 4 2  
5. 4.  
S cr e e n F ail ur e s ........................................................................................... 4 2  
6.  
S T U D Y I N T E R V E N TI O N  ........................................................................................ 4 3  
6. 1.  
St u d y I nt er v e nti o n( s) A d mi ni st er e d  ............................................................. 4 3  
6. 2.  
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y  .............................................. 4 3  
6. 3.  
M e a s ur e s t o Mi ni mi z e Bi a s: R a n d o mi z ati o n a n d Bli n di n g  ........................... 4 4  
6. 4.  
St or a g e  ....................................................................................................... 4 4  
6. 5.  
Tr e at m e nt C o m pli a n c e  ................................................................................ 4 4  
6. 6.  
C o n c o mit a nt M e di c ati o n s a n d N o n -Dr u g T h er a pi e s  .................................... 4 4  
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
1 0  
 
6. 6. 1.  
Pr o hi bit e d M e di ci n e s  ................................................................... 4 5  
6. 7.  
D o s e M o difi c ati o n  ....................................................................................... 4 5  
6. 8.  
M a n a g e m e nt of A d v er s e E v e nt s of I nt er e st  ................................................ 4 5  
6. 8. 1.  
I m m u n e-r el at e d A d v er s e E v e nt s .................................................. 4 5  
6. 8. 2.  
P ot e nti al T G F -β  M e di at e d D er m at ol o gi c A d v er s e E v e nt s  ............ 4 6  
6. 8. 3.  
I nf u si o n-r el at e d R e a cti o n s I n cl u di n g I m m e di at e 
H y p er s e n siti vit y ............................................................................ 4 7  
6. 8. 4.  
Tr e at m e nt -r el at e d A n e mi a ........................................................... 4 9  
6. 8. 5.  
A d diti o n al Ri s k s  ........................................................................... 5 0  
6. 9.  
I nt er v e nti o n Aft er t h e E n d of t h e St u d y ....................................................... 5 2  
6. 1 0.  C o nti n u e d A c c e s s t o St u d y I nt er v e nti o n Aft er D at a C ut -off  ......................... 5 2  
7.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ..................................................................... 5 3  
7. 1.  
Di s c o nti n u ati o n of St u d y I nt er v e nti o n  .......................................................... 5 3  
7. 1. 1.  
Di s e a s e Pr o gr e s si o n  .................................................................... 5 4  
7. 1. 2.  
Li v er C h e mi str y St o p pi n g Crit eri a  ................................................ 5 4  
7. 1. 3.  
Q T c St o p pi n g Crit eri a  .................................................................. 5 5  
7. 1. 4.  
A d v er s e Dr u g R e a cti o n St o p pi n g Crit eri a ..................................... 5 6  
7. 2.  
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  ............................... 5 7  
7. 3.  
L o st t o F oll o w U p  ........................................................................................ 5 8  
7. 4.  
P arti ci p a nt a n d St u d y C o m pl eti o n  ............................................................... 5 8  
8.  
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  ..................................................... 5 9  
8. 1.  
S cr e e ni n g A s s e s s m e nt s  ............................................................................. 5 9  
8. 2.  
F oll o w -u p A s s e s s m e nt s  .............................................................................. 6 1  
8. 3.  
E v al u ati o n of A nti -C a n c er A cti vit y  ............................................................... 6 2  
8. 3. 1.  
Di s e a s e R e s p o n s e A s s e s s m e nt s  ................................................. 6 3  
8. 4.  
S af et y A s s e s s m e nt s  ................................................................................... 6 4  
8. 4. 1.  
P h y si c al E x a mi n ati o n s  ................................................................. 6 4  
8. 4. 2.  
E C O G P erf or m a n c e St at u s  .......................................................... 6 5  
8. 4. 3.  
Vit al Si g n s  .................................................................................... 6 5  
8. 4. 4.  
El e ctr o c ar di o gr a m s  ...................................................................... 6 5  
8. 4. 5.  
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  ...................................... 6 5  
8. 5.  
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  ............................................. 6 6  
8. 5. 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 ................................................................................... 6 6  
8. 5. 2.  
C oll e cti o n of S af et y I nf or m ati o n Aft er D at a C ut -off  ....................... 6 6  
8. 5. 3.  
M et h o d of D et e cti n g A E s a n d S A E s  ............................................. 6 7  
8. 5. 4.  
F oll o w -u p of A E s a n d S A E s  ......................................................... 6 7  
8. 5. 5.  
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  ............................. 6 7  
8. 5. 6.  
Pr e g n a n c y  ................................................................................... 6 7  
8. 5. 7.  
C ar di o v a s c ul ar a n d D e at h E v e nt s  ................................................ 6 8  
8. 5. 8.  
Di s e a s e -R el at e d E v e nt s a n d/ or Di s e a s e -R el at e d 
O ut c o m e s N ot Q u alif yi n g a s S A E s ............................................... 6 8  
8. 6.  
P arti ci p a nt S p e cifi c D o s e A dj u st m e nt s Crit eri a  ........................................... 6 8  
8. 7.  
Tr e at m e nt of O v er d o s e  ............................................................................... 6 9  
C CI
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C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
1 1  
 
8. 1 3.  H e alt h E c o n o mi c s  ....................................................................................... 7 4  
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................ 7 5  
9. 1.  
St ati sti c al H y p ot h e s e s ................................................................................. 7 5  
9. 2.  
S a m pl e Si z e D et er mi n ati o n  ........................................................................ 7 5  
9. 3.  
P o p ul ati o n s f or A n al y s e s  ............................................................................ 7 5  
9. 4.  
St ati sti c al A n al y s e s  ..................................................................................... 7 6  
9. 4. 1.  
G e n er al C o n si d er ati o n s  ............................................................... 7 6  
9. 4. 2.  
Pri m ar y E n d p oi nt  ......................................................................... 7 6  
9. 4. 3.  
S e c o n d ar y E n d p oi nt s  ................................................................... 7 7  
9. 4. 5.  
Ot h er S af et y A n al y s e s  ................................................................. 7 9  
9. 4. 6.  
Ot h er A n al y s e s  ............................................................................ 7 9  
9. 6.  
I n d e p e n d e nt R a di ol o g y C o m mitt e e ............................................................. 8 0  
1 0.  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  ............................................................................................... 8 1  
1 0. 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  ............................................................................................ 8 1  
1 0. 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  ........................................ 8 1  
1 0. 1. 2.  
I nf or m e d C o n s e nt Pr o c e s s .......................................................... 8 1  
1 0. 1. 3.  
D at a Pr ot e cti o n  ............................................................................ 8 2  
1 0. 1. 4.  
Di s s e mi n ati o n of Cli ni c al St u d y D at a  ........................................... 8 2  
1 0. 1. 5.  
D at a Q u alit y A s s ur a n c e  ............................................................... 8 3  
1 0. 1. 6.  
S o ur c e D o c u m e nt s  ...................................................................... 8 3  
1 0. 1. 7.  
St u d y a n d Sit e St art a n d Cl o s ur e  ................................................. 8 4  
1 0. 1. 8.  
P u bli c ati o n P oli c y  ......................................................................... 8 4  
1 0. 2.  A p p e n di x 2: Cli ni c al L a b or at or y T e st s  ......................................................... 8 5  
1 0. 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  ....................................... 8 8  
1 0. 3. 1.  
D efi niti o n of A E  ............................................................................ 8 8  
1 0. 3. 2.  
D efi niti o n of S A E  .......................................................................... 8 9  
1 0. 3. 3.  
D efi niti o n of C ar di o v a s c ul ar E v e nt s  ............................................. 9 0  
1 0. 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  .................................... 9 0  
1 0. 3. 5.  
R e p orti n g of S A E t o G S K  ............................................................. 9 2  
1 0 . 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 .................................................................................................. 9 4  
1 0. 4. 1.  
D efi niti o n s  .................................................................................... 9 4  
1 0. 4. 2.  
C o ntr a c e pti o n G ui d a n c e  .............................................................. 9 5  
1 0. 4. 3.  
C oll e cti o n of Pr e g n a n c y I nf or m ati o n  ............................................ 9 6  
1 0. 6.  A p p e n di x 6: Li v er S af et y: R e q uir e d A cti o n s a n d F oll o w -u p 
A s s e s s m e nt s  .............................................................................................. 9 9  
1 0. 7.  A p p e n di x 7: C o u ntr y -s p e cifi c r e q uir e m e nt s  ............................................... 1 0 2  
C CI
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1 2  
 
1 0. 8.  A p p e n di x 8: A b br e vi ati o n s a n d Tr a d e m ar k s  .............................................. 1 0 3  
1 0. 9.  A p p e n di x 9: T h e R e c o m m e n d ati o n s f or ir A E M a n a g e m e nt, i n 
A c c or d a n c e wit h t h e J oi nt A m eri c a n S o ci et y of Cli ni c al O n c ol o g y 
Cli ni c al Pr a cti c e G ui d eli n e s a n d N ati o n al C o m pr e h e n si v e C a n c er 
N et w or k  .................................................................................................... 1 0 6  
1 0. 1 0.  A p p e n di x 1 0: E C O G P erf or m a n c e St at u s  ................................................. 1 5 0  
1 0. 1 1.  A p p e n di x 1 1: R e n al F u n cti o n M e a s ur e s  ................................................... 1 5 1  
1 0. 1 2.  A p p e n di x 1 2: Pr ot o c ol A m e n d m e nt Hi st or y  ............................................... 1 5 3  
1 1.  R E F E R E N C E S  ..................................................................................................... 1 5 5  
 
LI S T O F T A B L E S  
P A G E  
T a bl e  1  
S c h e d ul e of A cti viti e s  ............................................................................. 1 9  
T a bl e  2  
B e n efit/ Ri s k A s s e s s m e nt  ........................................................................ 2 8  
T a bl e  3  
Tr e at m e nt M o difi c ati o n f or S y m pt o m s of I nf u si o n -R el at e d 
R e a cti o n s  ............................................................................................... 4 8  
T a bl e  4  
E v al u ati o n G ui d a n c e of S u s p e ct e d Tr e at m e nt -r el at e d A n e mi a 
A d v er s e E v e nt s  ...................................................................................... 5 0  
T a bl e  6  
Pr ot o c ol -R e q uir e d S af et y L a b or at or y A s s e s s m e nt s  ............................... 8 6  
T a bl e  7  
Hi g hl y Eff e cti v e C o ntr a c e pti v e M et h o d s  ................................................. 9 5  
 
LI S T O F FI G U R E S  
P A G E  
Fi g ur e  1  
St u d y S c h e m a  ........................................................................................ 1 8  
Fi g ur e  2  
P h a s e I/II Li v er C h e mi str y St o p pi n g a n d I n cr e a s e d M o nit ori n g 
Al g orit h m i n cl u di n g P arti ci p a nt s WI T H d o c u m e nt e d li v er 
m et a st a s e s/t u m or i nfiltr ati o n at b a s eli n e A N D e ntr y crit eri a A L T 
> 2. 5 x U L N b ut 5 x U L N  ......................................................................... 5 5  
C CI


TMF-14396625 
CONFIDENTIAL 
 
 
 
213152 
 
Protocol Amd 02 
 
13 
 
1. 
PROTOCOL SUMMARY 
The study sponsor has decided to cease enrollment based on a rapidly evolving treatment 
landscape in urothelial carcinoma, in addition to recent data showing lack of efficacy of 
bintrafusp alfa in studies in other tumor types. 
In line with the sponsor’s decision, this protocol has been amended to provide updated 
instructions for study conduct. 
At the time of writing this protocol amendment, 25 participants have been treated with 
bintrafusp alfa, and no new safety signals were identified.  
In summary, participants still on treatment at the time of the final data cut-off (DCO) date 
and who the study investigator in agreement with the GSK medical monitor considers are 
deriving benefit from bintrafusp alfa and do not meet any protocol-defined treatment 
discontinuation criteria may continue to receive study intervention per the 
protocol-defined time period after the DCO date, as follows: 
• 
Participants who decide to continue with study intervention are re-consented. 
• 
Participants will be managed in accordance with the local institutional standard of 
care. 
• 
Serious Adverse Events (SAEs), adverse events (AEs) leading to treatment/study 
discontinuation, overdoses, and pregnancies will be reported through a paper-based 
pharmacovigilance (PV) process (see Study Reference Manual) and captured in asset 
PV database. 
A DCO date will be specified that represents the end of data collection for the planned 
final analysis described in the Reporting and Analysis Plan (RAP). The DCO date will be 
communicated to the study sites in a letter. Once the final DCO for this study has been 
reached, no new data will be entered into the clinical study database and the database will 
be locked for final analysis. At the time of final DCO, participants in follow-up will no 
longer be followed for survival and will be considered to have completed the study. 
Although the clinical study database(s) will be closed at the time of the final DCO date, 
the study remains open until all participants discontinue study treatment and the end of 
study (EOS) is reached. The EOS is defined as the date of the last visit of the last 
participant in the study. 
The reporting of this study will focus on the primary and secondary objectives only. 
1.1. 
Synopsis 
Protocol Title: A Phase Ib Trial to Evaluate the Efficacy and Safety of Bintrafusp Alfa 
Monotherapy in Metastatic or Locally Advanced/Unresectable Urothelial Cancer with 
Disease Progression or Recurrence Following Treatment with a Platinum Agent 
 
Short Title: A Phase Ib single-arm clinical trial of bintrafusp alfa monotherapy in 
metastatic or locally advanced/unresectable urothelial cancer 


TMF-14396625 
CONFIDENTIAL 
 
 
 
213152 
 
Protocol Amd 02 
 
14 
 
Background and Rationale: 
Worldwide 549,393 new cases of bladder cancer are diagnosed each year. Urothelial 
cancer is the most common histological type of bladder cancer, accounting for 90% of 
diagnoses in the United States (US) and Europe. In addition to the bladder, urothelial 
cancers can also be diagnosed in the urethra, ureters, and renal pelvis. Approximately 
25% of urothelial cancer patients, at diagnosis, will have disease that invades the detrusor 
muscle (muscle-invasive bladder cancer; MIBC) or is metastatic. Cisplatin-containing 
chemotherapy remains the first-line standard-of-care for those patients able to tolerate it, 
but most patients will eventually progress. Given the success of checkpoint inhibitor 
therapy in patients with urothelial cancers, numerous immunomodulatory combinations 
are under development to counteract resistance to single agent anti-programmed 
death-1/programmed death-ligand 1 (anti-PD-1/PD-L1) agent; such resistance can be 
multifactorial and may be related to immunosuppressive signal in the tumor 
stroma/microenvironment. 
While bintrafusp alfa is a bifunctional fusion protein designed to target 2 negative 
regulatory pathways of immunosuppression in the tumor microenvironment: the cell 
intrinsic pathway mediated by a tumor cell-immune cell interaction, in which PD-L1 
plays a major role, and the cell extrinsic pathway mediated by immunosuppressive 
cytokines, of which transforming growth factor- (TGF-β) is a prominent member. The 
anti-PD-L1 moiety of bintrafusp alfa is identical to the monoclonal antibody (mAb) 
avelumab (Bavencio), except for 3 amino acid substitutions in the heavy chain constant 
regions that result in a different human immunoglobulin (Ig) G1 allotype, and 1 amino 
acid substitution in the heavy chain for antibody fusion protein stability. Avelumab is 
approved in the US for the treatment of platinum-experienced, locally advanced or 
metastatic urothelial cancers that have disease progression during or following 
platinum-containing chemotherapy or have disease progression within 12 months of 
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. TGF-β 
functions predominantly as an autocrine and a paracrine factor in the local tumor 
microenvironment, and the TGF-RII component of bintrafusp alfa functions as a TGF-β 
neutralizing “trap.” Therefore, a novel design such as bintrafusp alfa, which blocks both 
the cell intrinsic PD-L1/PD-1 interaction and the immunosuppressive TGF-β, could be 
more effective than agents that target only a single pathway. 
Bintrafusp alfa has been administered to approximately 700 participants in Phase I 
development (EMR200647-001 and EMR200647-0008) and is currently in Phase II and 
III development for multiple indications. Bintrafusp alfa has a favorable safety profile 
with known risks consistent with the bifunctional mechanism of action. In Phase I, 
bintrafusp alfa has shown encouraging efficacy outcomes, in particular, for participants 
with non-small cell lung cancer (NSCLC) and biliary tract cancer (BTC). The Phase I 
studies of bintrafusp alfa did not include participants with urothelial cancers. 
Bintrafusp alfa is well-suited for therapeutic evaluation in urothelial cancer due to its 
ability to interfere with both PD-1/L1 and TGF-β pathways. Preclinical experiments 
demonstrate that bintrafusp alfa strongly enhances antitumor activity and prolongs 
survival in mouse tumor models above the effect of either the anti-PD-1/L1 antibody or 
the TGF-β Trap control alone (at the same molarity as bintrafusp alfa). Therefore, we 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
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1 5  
 
h y p ot hesize t hat it is m ore effi caci o us  t ha n c urre ntl y a p pr o ve d c h ec k p oi nt i n hi bit ors. T his 
trial pr o vi des t he first e v al uati o n of bi ntraf us p alf a i n partici pa nts wit h ur ot helial ca ncer 
t hat has pr o gress e d f oll o wi n g plati n u m t hera p y. 
O bjecti ves a n d E n d p oi nts : 
O bjecti ves  
E n d p oi nts  
P ri m ar y  
 
•  
E val uate t he a ntit u m or acti vit y per 
R E CI S T 1. 1.i n partici pa nts wit h 
metastatic or l ocall y 
a d va nce d/ u nresecta ble ur ot helial ca ncer 
treate d wit h bi ntraf us p alfa. 
•  
C o nfir me d O verall Res p o nse per 
R E CI S T 1. 1 assesse d  b y i n vesti gat or. 
Sec o n d ar y  
  
•  
E val uate t he safet y a n d t olera bilit y of 
bi ntraf us p alfa i n partici pa nts wit h 
ur ot helial ca ncer.  
•  
Fre q ue nc y a n d se verit y of A Es usi n g 
N CI -C T C A E  v 5 . 
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C O N FI D E N TI A L  
 
 
 
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1 6  
 
O bjecti ves  
E n d p oi nts  
N CI -C T C A E  v 5 =  N ati o n al C a nc er I nstit ut e -C o m m o n T er mi n ol o gy Crit eri a f or A dv ers e Ev e nts , versi o n 5 ; 
 O R R  =  ov er all r es p o ns e r at e;
P D  =  pr o gr essiv e dis e as e;
 P R =  p arti al r es p o ns e;  
R E CI S T 1. 1 = R es p o ns e Ev al u ati o n Crit eri a i n S oli d T u m ors Versi o n 1. 1
; S D =  st a bl e 
dis e as e; T G F - =  tr a nsf or mi n g gro wt h f act or b et a. 
C CI
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TMF-14396625 
CONFIDENTIAL 
 
 
 
213152 
 
Protocol Amd 02 
 
17 
 
Overall Design: 
This is a Phase Ib open label, single arm study of bintrafusp alfa in participants with 
metastatic or locally advanced/unresectable urothelial cancer with disease progression or 
recurrence following treatment with a platinum agent. 
Bintrafusp alfa will be administered intravenously (IV) at a dose of 1200 mg once every 
2 weeks (Q2W) until confirmed disease progression, death, unacceptable toxicity, study 
withdrawal, for up to 24 months after a confirmed complete response (CR). 
Number of Participants: 
Approximately 25 participants will be treated in this study. 
Intervention Groups and Duration: 
The study comprises three periods: screening, treatment, and follow-up. The total 
duration of study participation begins with the signing of the informed consent form 
(ICF) through the final protocol-defined follow-up assessment for survival. 
• During the 45-day Screening period, participants will be evaluated for study 
eligibility per protocol as defined in the Inclusion/Exclusion criteria. Eligible 
participants must have confirmed diagnosis of metastatic or locally 
advanced/unresectable urothelial cancer with disease progression or recurrence 
following treatment with a platinum agent.  
• During the Treatment Period, safety and disease assessments will be performed 
regularly according to the Schedule of Activities (SoA). Treatment will continue until 
disease progression as determined by RECIST 1.1, death, unacceptable toxicity, 
sponsor decision to terminate the study, or other protocol-defined criteria are met, for 
up to 2 years or up to 2 years from confirmed complete response. Note: participants 
receiving treatment may continue past PD if the participant’s ECOG PS has remained 
at least stable, and if in the opinion of the investigator and in consultation with the 
GSK medical monitor, the participant will benefit from continued treatment. 
• For participants who discontinue study intervention for reasons other than or in the 
absence of PD, disease evaluation will continue to be performed until confirmed PD 
(documented), death, start of a new anti-cancer therapy, or withdrawal of consent. 
After the DCO date, it is expected that disease evaluation will be performed per 
institutional practice, but these data will not be collected by the sponsor. 
• After study treatment is permanently discontinued, participants will be followed for 
survival and subsequent anti-cancer therapy once every 12 weeks (Q12W) for a 
maximum of 3 years from the date of enrollment. At DCO, survival and subsequent 
anti-cancer therapy in participants in follow-up will no longer be collected by the 
sponsor and participants will be considered to have exited the study. 
• After study treatment is permanently discontinued, all SAEs, nonserious 
treatment-related AEs, and AEs of interest will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up. 
Related AE of all other AEs will be followed until the last follow up visit. At the 


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DCO, participants still receiving study intervention will be followed as outlined in 
Section 8.2. 
Participants who permanently discontinue study treatment will enter the follow-up period 
of the study and undergo the assessments as described in the SoA until the DCO date. 
1.2. 
Study Schema 
Figure 1 
Study Schema 
 
1.3. 
Schedule of Activities 
• Study participants who continue to receive study intervention after the DCO date (see 
Section 6.10) will be monitored and receive follow-up care in accordance with 
standard local clinical practice. Assessments will revert to the standard of care at a 
participant’s study site and only SAEs, AEs leading to treatment/study 
discontinuation, overdoses, and pregnancies will be reported directly to the sponsor 
via paper forms (see Section 8.5.2). 
• The SoA is presented in Table 1. 
 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
1 9  
 
T a bl e  1  
S c h e d ul e of A cti viti e s  
 
S cr e e ni n g  I nter v e nti o n (tr e at m e nt) P eri o d 
 
S afet y F oll o w -u p  
L o n g T er m 
F oll o w -u p  
N ote s  
As se ss m e nt a n d 
Pr o c e d ur e s  
4 5 Da y - t o 
fir st d o s e 
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7  
U ntil P D  
E O T  
2 8 Da y s 
( ± 5 D a y s) 
Aft er L a st 
Tr e at m e nt  
1 2 W e e ks  
 ( ± 2 
W e e k s) 
Aft er L a st 
Tr e at m e nt  
E v er y 1 2 
W e e ks  
( ± 2 W e e ks) 
D1: All a ss e ss m e nts m u st b e p erf or m e d o n 
d a y i n di c ate d ( u nl e s s n ote d i n a s s e ss m e nt 
" N ote s”). 
Da y 1 5 t hr o u g h P D: Vi sits c a n b e p erf or m e d 
3 d a ys.  
E O T: O n d a y of or wit hi n 7 d a ys of d e ci si o n 
t o di s c o nti n u e. 
F oll o w u p: Vi sits c a n b e p erf or m e d 
2  W e e ks.  
W 1  
W 3  
W 5  
W 7  
W 9  
W 1 1  
W 1 3  
D 1  
D 1 5  
D 2 9  
D 4 3  
D 5 7  
D 7 1  
D 8 5  
I nf or m e d c o ns e nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
I C F c a n b e si g ne d u p t o 4 5 d ays b ef ore st art of 
i nt erv e nti o n. 
I ncl usi o n a n d 
excl usi o n crit eri a  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
Co nfir m ati o n of all eli gi bility is re quir e d pri or t o 
d osi n g o n W 1 D1. S e e S R M f or m ore d et ails  
De mo gra phy  
X  
 
 
 
 
 
 
 
 
 
 
 
 
S ec S ecti o n 8 .  
F ull p hysic al 
ex a mi n ati o n ( P E) 
i ncl u di n g h ei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
Q 2 W  
X  
X  
 
 
Co mpl et e P E at Scre e ni n g; Bri ef P Es s h oul d be 
p erf or m e d at s u bs e qu e nt cli nic al visits a n d 
s h oul d i ncl u de inf usi o n sit e re acti o n 
ass ess m e nts.  
Ref er t o S ecti o n 8. 4. 1 . 
Hei g ht is re quire d at scre eni n g o nly.  
W ei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
Q 2 W  
 
 
 
 
W ei g ht is re quir e d at ev ery tr e at m e nt visit.  
M e dic al hist ory 
(i ncl u des s u bst a nc e 
us a ge,
wit hi n 
6 0  d ays.  
X  
 
 
 
 
 
 
 
 
 
 
 
 
S u bst a nc es: alc o hol a nd t o bacc o us e,
 wit hi n 
6 0  d ays pri or t o st u dy i nt erv e nti o n.  
Dis e as e 
Ch aract eristics  
X  
 
 
 
 
 
 
 
 
 
 
 
 
Ref er t o S ecti o n 8. 1  
Pri or a nti -c a nc er 
dru g/ra di ot h era py/  
proc e dures  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI


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Screening Intervention (treatment) Period 
 
Safety Follow-up 
Long Term 
Follow-up 
Notes 
Assessment and 
Procedures 
45 Day- to 
first dose 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Until PD 
EOT 
28 Days 
(±5 Days) 
After Last 
Treatment 
12 Weeks  
 (± 2 
Weeks) 
After Last 
Treatment 
Every 12 
Weeks  
(± 2 Weeks) 
D1: All assessments must be performed on 
day indicated (unless noted in assessment 
"Notes”). 
Day 15 through PD: Visits can be performed 
3 days. 
EOT: On day of or within 7 days of decision 
to discontinue. 
Follow up: Visits can be performed 
2 Weeks. 
W1 
W3 
W5 
W7 
W9 
W11 
W13 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
Serum or Urine 
Pregnancy Test 
(WOCBP only) 
X 
 
 
X 
 
X 
 
X 
Q4W 
 
X 
 
 
Serum pregnancy test only required 24 hours 
prior to first dose. Monthly urine/serum 
(preference) pregnancy testing will be 
performed as consistent with local standards 
however if a urine test is positive or borderline, 
or in the event of a missed menstrual period or 
suspicion of pregnancy, a serum β-hCG test will 
be required. 
HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV testing is not required, only known status 
will be collected at baseline. 
TST, QuantiFERON-
TB-Gold, or T-SPOT  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Performed if positive history of tuberculosis 
exposure.  
Safety Assessments 
Skin Assessment 
X 
 
 
 
X 
 
 
X 
Q6W 
X 
X 
 
 
Refer to Section 8.4.1. 
12-lead ECG 
X 
As clinically indicated 
 
 
 
 
 
ECHO 
X 
 
 
 
 
 
MUGA is acceptable if ECHO is not available; 
for each participant the same modality must be 
used for all subsequent evaluations. 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Q2W 
X 
X 
 
 
Vital signs will be measured after 5 minutes of 
rest and will include temperature, systolic and 
diastolic blood pressure, pulse rate and oxygen 
saturation (measured by pulse oximetry). Blood 
pressure should be taken in the same position 
throughout the study and captured in the eCRF. 
ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
Q2W 
X 
X 
 
 
ECOG PS 0 or 1 is required at W1D1. Review 
Predose.  


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Screening Intervention (treatment) Period 
 
Safety Follow-up 
Long Term 
Follow-up 
Notes 
Assessment and 
Procedures 
45 Day- to 
first dose 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Until PD 
EOT 
28 Days 
(±5 Days) 
After Last 
Treatment 
12 Weeks  
 (± 2 
Weeks) 
After Last 
Treatment 
Every 12 
Weeks  
(± 2 Weeks) 
D1: All assessments must be performed on 
day indicated (unless noted in assessment 
"Notes”). 
Day 15 through PD: Visits can be performed 
3 days. 
EOT: On day of or within 7 days of decision 
to discontinue. 
Follow up: Visits can be performed 
2 Weeks. 
W1 
W3 
W5 
W7 
W9 
W11 
W13 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
Hematology and 
hemostaseology 
X 
X 
X 
X 
X 
X 
X 
X 
Q4W 
X 
X 
 
 
Details on blood tests under this category is 
listed in Table 6. At visits where blood tests are 
required, results should be reviewed prior to 
dosing. Hematology should be repeated if not 
performed within 24 hours of D1. 
Clinical chemistry 
X 
X 
X 
X 
X 
X 
 
X 
Q4W 
X 
X 
 
 
Clinical chemistries are listed in Table 6. At 
visits where blood tests are required, results 
should be reviewed prior to dosing. Chemistry 
should be repeated if not performed within 
24 hours of D1. 
Free T4 and TSH 
X 
 
 
 
X 
 
 
X 
Q6W 
 
X 
 
 
See Appendix 2 
Urinalysis 
X 
As clinically indicated 
 
 
See Appendix 2 
AE review 
See notes 
X 
X 
X 
Start at Consent. See Section 8.5.1. The 
12-week Safety Follow-up and Long-term 
Follow-up may be conducted via telephone calls 
or patient chart reviews as necessary unless 
there is medical necessity requiring a clinical 
visit. All nonserious related AEs and AEs of 
interest will be followed until the event is 
resolved, stabilized, otherwise explained, or the 
participant is lost to follow-up (as defined in 
Section 7.3) All other AEs will be followed until 
the last follow up visit. 


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Screening Intervention (treatment) Period 
 
Safety Follow-up 
Long Term 
Follow-up 
Notes 
Assessment and 
Procedures 
45 Day- to 
first dose 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Until PD 
EOT 
28 Days 
(±5 Days) 
After Last 
Treatment 
12 Weeks  
 (± 2 
Weeks) 
After Last 
Treatment 
Every 12 
Weeks  
(± 2 Weeks) 
D1: All assessments must be performed on 
day indicated (unless noted in assessment 
"Notes”). 
Day 15 through PD: Visits can be performed 
3 days. 
EOT: On day of or within 7 days of decision 
to discontinue. 
Follow up: Visits can be performed 
2 Weeks. 
W1 
W3 
W5 
W7 
W9 
W11 
W13 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
SAE review 
See notes 
X 
X 
X 
Start at Consent. For ongoing SAEs see 
Section 8.5.1. The 12-week Safety Follow-up 
and Long-term Follow-up may be conducted via 
telephone calls or patient chart reviews as 
necessary unless there is medical necessity 
requiring a clinical visit. All SAEs, will be 
followed until the event is resolved, stabilized, 
otherwise explained, or the participant is lost to 
follow-up (as defined in Section 7.3). 
Concomitant 
medication review 
X 
X 
ongoing 
X 
X 
X 
X 
X 
 
Study Intervention and Pretreatment 
Bintrafusp alfa 
administration 
 
X 
X 
X 
X 
X 
X 
X 
Q2W 
 
 
 
 
Bintrafusp alfa is administered as a 1200 mg IV 
infusion over 1 hour (-10 minutes/+20 minutes; 
ie, over 50 to 80 minutes) Q2W for up to 2 years 
(or up to 2 years from confirmed CR). See 
Section 6.1 for information. 


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Screening Intervention (treatment) Period 
 
Safety Follow-up 
Long Term 
Follow-up 
Notes 
Assessment and 
Procedures 
45 Day- to 
first dose 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
Until PD 
EOT 
28 Days 
(±5 Days) 
After Last 
Treatment 
12 Weeks  
 (± 2 
Weeks) 
After Last 
Treatment 
Every 12 
Weeks  
(± 2 Weeks) 
D1: All assessments must be performed on 
day indicated (unless noted in assessment 
"Notes”). 
Day 15 through PD: Visits can be performed 
3 days. 
EOT: On day of or within 7 days of decision 
to discontinue. 
Follow up: Visits can be performed 
2 Weeks. 
W1 
W3 
W5 
W7 
W9 
W11 
W13 
D1 
D15 
D29 
D43 
D57 
D71 
D85 
Response Assessments 
Tumor evaluation/ 
staging 
(CT Scan/MRI/ other 
established methods) 
X 
 
 
 
 
X 
 
 
Q8W up to 6 
months., then 
Q12W 
X 
X 
 
 
CT scan with contrast of the chest, abdomen, 
and pelvis is required.  
Screening scans for lesion assessments are 
required within 28 days of first dose.  
See Section 8.3 for additional information 
Q8W for the first 6 months (mos.) and Q12W 
thereafter, and at the final study visit.  
Schedule should not be affected by dose 
interruptions/delays.  
Confirmation of CR and/or PR should be 
performed at the next scheduled assessment 
but no sooner than 4 weeks.  
Before stopping the treatment, progressive 
disease should be confirmed by imaging at least 
4 weeks after progression. See Section 7.1.1. 
If discontinued intervention without documented 
progression, then continue imaging Q8W for the 
first 6 months followed by Q12W until 
documented PD, or the start of any new 
anti-cancer therapy.  
A bone scan should be done as clinically 
indicated at screening and beyond. TA brain 
CT/MRI scan should be performed as clinically 
indicated 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
2 4  
 
 
S cr e e ni n g  I nter v e nti o n (tr e at m e nt) P eri o d 
 
S afet y F oll o w -u p  
L o n g T er m 
F oll o w -u p  
N ote s  
As se ss m e nt a n d 
Pr o c e d ur e s  
4 5 Da y - t o 
fir st d o s e 
V 1  
V 2  
V 3  
V 4  
V 5  
V 6  
V 7  
U ntil P D  
E O T  
2 8 Da y s 
( ± 5 D a y s) 
Aft er L a st 
Tr e at m e nt  
1 2 W e e ks  
 ( ± 2 
W e e k s) 
Aft er L a st 
Tr e at m e nt  
E v er y 1 2 
W e e ks  
( ± 2 W e e ks) 
D1: All a ss e ss m e nts m u st b e p erf or m e d o n 
d a y i n di c ate d ( u nl e s s n ote d i n a s s e ss m e nt 
" N ote s”). 
Da y 1 5 t hr o u g h P D: Vi sits c a n b e p erf or m e d 
3 d a ys.  
E O T: O n d a y of or wit hi n 7 d a ys of d e ci si o n 
t o di s c o nti n u e. 
F oll o w u p: Vi sits c a n b e p erf or m e d 
2  W e e ks.  
W 1  
W 3  
W 5  
W 7  
W 9  
W 1 1  
W 1 3  
D 1  
D 1 5  
D 2 9  
D 4 3  
D 5 7  
D 7 1  
D 8 5  
F oll o w -u p  
F oll o w u p t el e ph on e 
c all 
 
 
 
 
 
 
 
 
 
 
 
X  
X  
S urviv al st at us. P artici p ants wh o p er m a ne ntly 
disc o nti n ue st u dy tre at m e nt d ue t o dis e as e 
pro gressi o n (r ef er t o S ecti o n 7. 2 ), will b e 
f oll o we d f or s urviv al a nd n e w a nti-c a nc er 
t h era py (i ncl u di n g ra di ot her a py) Q 1 2 W until 
d eat h or wit h dra w al of c o ns e nt. Aft er t h e D C O 
d at e, partici p ants o n goi n g i n t h e st u dy will b e 
f oll o we d acc ordi n g t o S ecti o n 8. 2 . 
S u bs e qu ent 
a nti -c a nc er t h er a py 
(a ny li n e) 
 
 
 
 
 
 
 
 
 
 
X  
X  
X  
Aft er D C O, s u bs e qu e nt anti -c a nc er t h era py will 
n ot be c oll ect e d. 
A b br evi ati o ns: A E = a dv ers e ev e nt; C B C = c o m pl et e bl o o d c o u nt;
;C R = c o m pl et e r es p o ns e; C T = c o m p ut e d t o m o gr a p hy; D = d ay; D C O  =  d at a c ut -off; 
 E C H O  =  ec h oc ar di o gr a m;  E C G = el ectr oc ar di o gr a m; e C R F  =  e l ectr o nic c as e r e p ort f or m; E O T =  e n d -of -tr e at m e nt; H B V = h e p atitis B vir us; 
β -h C G  =  b et a h u m a n c h ori o nic g o n a d otr o pi n;  H C V = h e p atitis C vir us I C F  =  i nf or m e d c o ns e nt f or m; I V =  i ntr av e n o us; M RI =  m a g n etic r es o n a nc e i m a gi n g; M U G A = M ulti g at e d 
Ac q uis iti o n Sc a n;
 P D = dis e as e pr o gr essi o n; P E = p hysic al ex a mi n ati o n;
P R  =  p arti al r es p o ns e; Q 2 W = ev ery 
2  w e eks; Q 4 W = ev ery 4 w e eks; Q 6 W  =  ev ery 6 w e eks; Q 8 W  =  ev er y 8 w e eks; Q 1 2 W = ev ery 1 2  w e ek s;
S A E  =  s eri o us a dv ers e ev e nt; S R M  =  St u dy 
r ef er e nc e m a n u al; T S H  =  t hyr oi d-sti m ul ati n g h or m o n e, V  =  visit; W =  w e ek; W O C B P  =  w o m e n of c hil d b e ari n g p ot e nti al . 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
2 5  
 
•  
T he ti mi n g a n d n u m ber of pla n ne d st u d y assess me nts, i ncl u di n g  b ut n ot li mite d t o  safet y,
assess me nts ma y 
be altere d d uri n g t he c o urse of t he st u d y base d o n ne wl y a vaila ble data (e. g., t o o btai n data cl oser t o t he ti me of
 t o e ns ure 
a p pr o priate  m o nit ori n g.  
•  
A n y c ha n ges i n t he ti mi n g or a d diti o n of ti me p oi nts f or a n y pla n ne d st u d y assess me nts as t he res ult of e mer gi n g
 d ata fr o m 
t his st u d y m ust b e d oc u me nte d a n d a p pr o ve d b y t he rele va nt st u d y tea m me m ber a n d t he n arc hi ve d i n t he s p o ns or a n d site st u d y files b ut will n ot c o nstit ute a 
pr ot oc ol a me n d me nt. T he C o m pete nt A ut h orit y ( C A) a n d et hics c o m mittee ( E C) will be i nf or me d of a n y safet y iss ues t hat c o nstit ute a s u bsta ntial a me n d me nt 
a n d re q uire alterati o n of t he saf et y m o nit ori n g sc he me or a me n d me nt of t he i nf or me d c o ns e nt f or m (I C F). T he c ha n ges will b e a p pr o ve d b y t he C A a n d t he E C 
bef ore i m ple me ntati o n.  
C CI
C CI
C CI


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2. 
INTRODUCTION 
Bintrafusp alfa (MSB0011359C) is a first-in-class bifunctional fusion protein that 
combines an anti-programmed cell death-ligand 1 (PD-L1) receptor monoclonal antibody 
(mAb) and transforming growth factor beta (TGF-β) receptor II as a TGF-β neutralizing 
‘trap’ into a single molecule. Bintrafusp alfa is designed to neutralize the clinically 
validated PD-L1 target as well as the novel TGF-β target. The approach is supported by 
preclinical data showing that bintrafusp alfa enhances antitumor activity and prolongs 
survival in mouse tumor models above the effect of either the anti-PD-L1 mAb or the 
TGF-β Trap control alone (at the same molarity as bintrafusp alfa). The purpose of this 
study is to evaluate bintrafusp alfa in participants with metastatic or locally advanced 
urothelial cancer.  
This trial provides the first evaluation of bintrafusp alfa in participants with urothelial 
cancer that has progressed following platinum therapy. 
Complete information on the chemistry, pharmacology, efficacy, and safety of bintrafusp 
alfa can be found in the bintrafusp alfa Investigator’s Brochure (IB). 
2.1. 
Study Rationale 
The bifunctional activity of bintrafusp alfa is well-suited for evaluation in urothelial 
cancer. Anti-programmed cell death 1/ligand 1 (PD-1/L1) receptor antibodies are 
approved for the treatment of locally advanced and metastatic urothelial cancers. 
However, TGF-β pathways are implicated in blunting the activity of these antibodies in 
this setting. See Section 2.2.2 for additional details. Bintrafusp alfa interferes with both 
PD-1/L1 and TGF-β pathways, and therefore, has the potential to be more active than 
currently approved checkpoint modulators. 
2.2. 
Background 
2.2.1. 
Urothelial Cancer 
Worldwide 549,393 new cases of bladder cancer are diagnosed each year [Bray, 2018] 
Urothelial cancer is the most common histological type of bladder cancer, accounting for 
90% of diagnoses in the United States (US) and Europe. In addition to the bladder, 
urothelial cancers can be diagnosed in the urethra, ureters, and renal pelvis. 
Approximately 25% of urothelial cancer patients, at diagnosis, will have disease that 
invades the detrusor muscle (muscle-invasive bladder cancer; MIBC) or is metastatic. 
Patients with MIBC and metastatic disease are typically treated with surgery, radiation, 
and/or chemotherapy as determined by the stage of disease. Prognosis declines with more 
advanced disease [Sanli, 2017]. Gemcitabine plus cisplatin (GC) and methotrexate, 
vinblastine, doxorubicin, and cisplatin (MVAC) are common chemotherapy regimens 
with median OS outcomes of 13.8 and 14.8 months, respectively, for previously untreated 
patients with locally advanced (T4b, N2, N3) or metastatic (M1) disease [Von der Maase, 
2000]. Fifty percent of patients may be unsuitable for cisplatin-containing therapy based 
on Eastern Cooperative Oncology Group performance status (ECOG PS), hearing loss, 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
2 7  
 
ne ur o pat h y, or  re nal or car diac f u ncti o n  [Balar , 2 0 1 7] . T hese patie nts s o meti mes recei ve 
car b o plati n a n d ge mcita bi ne, wit h me dia n O S of o nl y 9. 3 m o nt hs  [De Sa ntis , 2 0 1 2]. 
C is plati n-c o ntai ni n g c he m ot hera p y re m ai ns t he first-li ne sta n dar d-of -care f or t h ose 
patie nts a ble t o t olerate i t, b ut m ost patie nts will e ve nt uall y pr o gress. 
T he de vel o p me nt of i m m u ne c hec k p oi nt i n hi bit ors has c ha n ge d t h e treat me nt la n dsca pe 
a n d is i m pr o vi n g t he o utl o o k f or patie nts t hat ha ve pr o gresse d after or are i neli gi ble f or 
cis plati n-base d t hera p y. Si nce 2 0 1 6, 5 a nti b o dies bl oc ki n g P D -1 or P D -L 1 (i.e., 
p e m br oliz u ma b, ni v ol u ma b, atez oliz u ma b, d ur val u ma b, a n d a vel u ma b) ha ve recei ve d 
a p pr o val f or t h e treat me nt of ur ot helial ca n cer, i n t he U S, E ur o pea n U ni o n ( E U), a n d 
ot her c o u ntries.  A p pr o ve d i n dicati o ns, de pe n di n g u p o n t he s pecific c hec k p oi nt i n hi bit or, 
i ncl u de patie nts t hat ha ve recei v e d or are n ot eli gi ble f or cis plati n-bas e d c h e m ot hera p y.  
O verall res p o nse rates ha ve ra n ge d fr o m 1 4 % t o 2 1 % f or patie nts t hat ha ve recei v e d 
cis plati n t o 2 3 % t o 2 9 % f or u ntreate d p atie nts  i neli gi ble f or cis plati n. I n si n gle-ar m trials, 
s u p p orti n g accel erate d/ c o n diti o nal a p pr o val, 1 2 -m o nt h s ur vi val o utc o mes f or partici pa nts 
t hat recei v e d a nti-P D -1/ L 1 c hec k p oi nt m o d ulat ors after cis plati n -base d c h e m ot hera p y 
ha ve ra n ge d fr o m 3 9 % t o 5 4 %.  I n K E Y N O T E-0 4 5  [Bell m u nt , 2 0 1 7] , a ra n d o mize d trial 
of pe m br oliz u ma b vers us c he m ot hera p y i n p artici pa nts t hat ha d recei ve d pri or cis plati n 
t hera p y, s u p p orti n g sta n d ar d a p pr o val, t he me dia n o verall s ur vi val ( O S) was 1 0. 4 m o nt hs 
vers us 7. 3 m o nt hs, res pecti vel y, a n d t he O S hazar d rati o ( H R) was 0. 7.  Gi ve n t he s uccess 
of c hec k p oi nt i n hi bit or t hera p y i n patie nts wit h ur ot helial ca ncers, n u mer o us 
i m m u n o m o d ulat or y c o m bi nati o ns are u n der de vel o p me nt t o c o u nteract resista nce t o 
si n gle a ge nt a nti-P D -1/ P D -L 1 a ge nts; s uc h resista nce ca n be m ultifact orial a n d ma y be 
relate d t o i m m u n os u p pressi ve si g nal i n t he t u m or str o ma/ micr oe n vir o n me nt. 
2. 2. 2.  
R ol e of T G F -β  i n Ur ot h eli al C a n c er P at h o g e n e si s a n d Cli ni c al 
O ut c o m e  
Alt h o u g h a nti -P D -1/ L 1 a nti b o dies ca n ac hie ve re mar ka ble a ntit u m or effects i n patie nts 
wit h ur ot helial ca ncers, t he ma g nit u de of t he cli ni cal be nefit ma y b e li mite d b y ot her 
fact ors i n t he t u m or micr oe n vir o n me nt, s uc h as T G F-. T he I M vi g or 2 1 0 st u d y was a 
P h ase II trial e v al uati n g atez oliz u ma b after plati n u m -base d c h e m ot hera p y  [Mariat hasa n , 
2 0 1 8 ]. A ssess me nts of pre-treat me nt t u m or sa m ples usi n g R N A se q u e nci n g 
tra nscri pt o me a n al ysis re veale d a T G F- si g nat ur e t hat pre dicte d l o w er res p o nse rates 
a n d di mi nis he d O S f oll o wi n g treat me nt wit h atez oliz u ma b. N o ncli nical m o dels s u g gest e d 
t hat T G F- restricts t he i nfiltrati o n of t u m ors b y T -cells, a n effect re verse d b y 
coa d mi nistrati o n of a nti -P D -L 1 a n d a nti -T G F - a nti b o dies. Si milarl y, a n e x pl orat or y 
R N A se q ue nci n g a n al ysis of t u m or sa m ples fr o m K E Y N O T E -0 5 2  [G o u die , 2 0 1 1; Gri vas , 
2 0 1 9] a st u d y of pe m br oliz u ma b m o n ot hera p y i n partici pa nts  wit h cis plati n -i neli gi ble 
ca ncer, i de ntifie d a str o mal/ T G F -/ E M T si g nat ure t hat pre dicte d a l ess fa v ora ble efficac y 
o utc o me.  C ollecti v el y, t h ese data s u g gest t hat o utc o mes of patie nts wit h ur ot helial ca ncer 
c o ul d be i nfl ue nce d b y T G F - pat h wa ys i n de pe n d e nt of P D -1/ L 1.  
2. 2. 3.  
Bi ntraf us p alfa is bif u ncti o nal f usi o n pr otei n  desi g ne d t o tar get 2 ne gati ve re g ul at or y 
pat h wa ys of i m m u n os u p pressi o n i n t he t u m or micr oe n vir o n me nt: t he cell i ntri nsic  
pat h wa y  me diate d b y a t u m or cell -i m m u ne cell i nteracti o n, i n w hic h P D-L 1 pla ys a m aj or 
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role, and the cell extrinsic pathway mediated by immunosuppressive cytokines, of which 
TGF-β is a prominent member. The anti-PD-L1 moiety of bintrafusp alfa is identical to 
the mAb avelumab (Bavencio), except for 3 amino acid substitutions in the heavy chain 
constant regions that result in a different human immunoglobulin (Ig) G1 allotype, and 
1 amino acid substitution in the heavy chain for antibody fusion protein stability. 
Avelumab is approved in the US for the treatment of platinum-experienced, locally 
advanced or metastatic urothelial cancer that have disease progression during or 
following platinum-containing chemotherapy or have disease progression within 
12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. 
TGF-β functions predominantly as an autocrine and a paracrine factor in the local tumor 
microenvironment, and the TGF-RII component of bintrafusp alfa functions as a TGF-β 
neutralizing “trap.” Therefore, a novel design such as bintrafusp alfa, which blocks both 
the cell intrinsic PD-L1/1 interaction and the immunosuppressive TGF-β, could be more 
effective than agents that target only a single pathway. 
Bintrafusp alfa was shown to have full biological activity in vitro including the ability to 
block PD-L1 and neutralize TGF-β simultaneously. Experiments demonstrated that 
bintrafusp alfa strongly enhances antitumor activity and prolongs survival in mouse 
tumor models above the effect of either the anti-PD-1/L1 antibody or the TGF-β Trap 
control alone (at the same molarity as bintrafusp alfa). Details are discussed in the current 
IB. 
2.2.4. 
Clinical Experience with Bintrafusp Alfa 
Bintrafusp alfa has been administered to approximately 700 participants in Phase I 
development (EMR200647-001 and MS200647-0008) and is currently in Phase II and III 
development for multiple indications. Bintrafusp alfa has a favorable safety profile with 
known risks consistent with the bifunctional mechanism of action. In Phase I, bintrafusp 
alfa has shown encouraging efficacy outcomes, in particular, for participants with 
non-small cell lung cancer (NSCLC) and biliary tract cancer (BTC). The Phase I studies 
of bintrafusp alfa did not include participants with urothelial cancers. Details are 
discussed in the current IB. 
2.2.5. 
Risk Assessment 
Table 2 
Benefit/Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of 
Data/Rationale for Risk 
Mitigation Strategy 
Intervention Product: Bintrafusp alfa  
irAEs 
Immune-related AEs have 
occurred, in Phase I and 
ongoing studies, at a 
frequency and severity 
similar to other checkpoint 
inhibitors.  
• Eligibility criteria exclude 
participants with history of 
autoimmune disease. 
• irAE management 
guidelines are provided in 
Appendix 9.  


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Potential Risk of Clinical 
Significance 
Summary of 
Data/Rationale for Risk 
Mitigation Strategy 
Infusion-related reactions 
Infusion-related reactions 
have been of mild to 
moderate severity in Phase I 
and ongoing studies. 
• Eligibility criteria exclude 
participants with history of 
severe hypersensitivity 
reactions to monoclonal 
antibodies or any 
ingredient used in the 
study treatment 
formulation. 
• Participants who 
experience infusion related 
reactions may be 
premedicated with an 
antihistamine and with 
paracetamol 
(acetaminophen) (for 
example, 25 to 50 mg 
diphenhydramine and 
500 to 650 mg 
paracetamol 
[acetaminophen] IV or oral 
equivalent) approximately 
30 to 60 minutes prior to 
each dose of bintrafusp 
alfa. Steroids as 
premedication are not 
permitted. 
• Infusion reaction 
management guidelines 
are provided in Section 
6.8.3. 
Dermatologic adverse events 
(attributable to TGF-β-
inhibition)  
Dermatologic AEs attributed 
to TGF--inhibition 
(including hyperkeratosis, 
KA, and cSCC) were 
observed in ~11% of 
participants in Phase I and 
ongoing studies. These 
lesions were previously 
observed in individuals with 
genetic mutations in the 
TGF- receptor (ie, 
Ferguson-Smith Syndrome), 
and participants treated with 
the TGF--targeting agent, 
fresolimumab. (Goudie, 
2011; Morris, 2014)  
• AE surveillance 
instructions are provided 
in Appendix 9. 
• Skin AE management 
guidelines are provided in 
Section 6.8.2. KA and 
cSCC were managed in 
Phase I with simple 
excision and did not 
require any participant to 
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Potential Risk of Clinical 
Significance 
Summary of 
Data/Rationale for Risk 
Mitigation Strategy 
Anemia 
Anemia is considered a 
potential risk based on 
toxicological findings with 
bintrafusp alfa in 
cynomolgus monkeys 
indicating a decrease in Hgb, 
RBC, and hematocrit which 
was fully reversible or 
showed a substantial trend 
toward recovery. 
• Eligibility criteria include 
minimum hemoglobin 
requirements. 
• AE and CBC surveillance 
instructions are provided 
in Section 6.8.4. 
• Hematology surveillance, 
see SoA, Section 1.3, 
Table 1. 
Mucosal bleeding 
Mucosal bleeding is 
considered a potential risk 
based on clinical 
observations of epistaxis, 
hemoptysis, gingival 
bleeding, or hematuria of 
mild to moderate severity in 
Phase I studies EMR200647-
001 and MS200647-0008. 
• Eligibility criteria include 
minimum platelet and 
coagulation requirements. 
• AE surveillance 
instructions are provided 
in Appendix 9 In general, 
these reactions resolve 
without discontinuation of 
treatment. 
Bleeding Events 
Bleeding events are a 
potential risk.  
• Eligibility criteria include 
an exclusion for bleeding 
diathesis or recent major 
bleeding. 
• AE surveillance/dose 
modification instructions 
are provided in 
Section 6.8.5.1. 
Alterations of wound healing 
or repair of tissue damage 
Alterations in wound healing 
or repair of tissue damage is 
considered a potential risk 
because TGF-β pathways 
have been implicated in 
repair of skin and other tissue 
injuries.  
• AE surveillance 
instructions are provided 
in Appendix 9. 
Embryofetal toxicities 
Embryo-fetal toxicities are a 
known risk of the PD-1/ 
PD-L1 targeting class. 
• Eligibility criteria include 
contraception 
requirements. 
Abbreviations: KA=keratoacanthoma; cSCC= cutaneous squamous-cell carcinoma 
 
2.2.6. 
Benefit Assessment 
The anti-PD-L1 moiety of bintrafusp alfa is identical to the anti-PD-L1 monoclonal 
antibody avelumab (Bavencio), except for 3 amino acid substitutions in the heavy chain 
constant regions that result in a different human immunoglobulin (Ig) G1 allotype, and 
1 amino acid substitution in the heavy chain for antibody fusion protein stability. 
Avelumab has been approved for the treatment of platinum-experienced, locally 
advanced or metastatic urothelial carcinoma in the USA based on a response rate of 


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16.1% and a 12-month OS of 54.3%. Bintrafusp alfa is a bifunctional biologic that 
combines anti-PD-L1 activity with transforming growth factor beta (TGF-) receptor II 
as a TGF- neutralizing ‘trap’ into a single molecule. Preclinical models have shown 
bintrafusp alfa that bintrafusp alfa enhances antitumor activity and prolongs survival in 
mouse tumor models above the effect of either the anti-PD-L1 mAb or the TGF- Trap 
control alone. In Phase I, bintrafusp alfa has shown encouraging efficacy outcomes in 
selected indications.  
Bintrafusp alfa is well-suited for therapeutic evaluation in urothelial cancer due to its 
ability to interfere with both PD-1/L1 and TGF-β pathways. Preclinical experiments 
demonstrate that bintrafusp alfa strongly enhances antitumor activity and prolongs 
survival in mouse tumor models above the effect of either the anti-PD-1/L1 antibody or 
the TGF-β Trap control alone (at the same molarity as bintrafusp alfa). Therefore, we 
hypothesize that it is more efficacious than currently approved checkpoint inhibitors. 
2.2.7. 
Overall Benefit-Risk Assessment 
Anti-PD-1/PD-L1 antibodies are standard therapies in patients that have progressed after 
platinum-based chemotherapy. Bintrafusp alfa includes anti-PD-L1 function as well as an 
anti-TGF- Trap function. Given the manageable safety profile of bintrafusp alfa in 
ongoing studies and the evidence for activity in Phase I, the benefit-risk assessment for 
this study remains favorable. The benefit-risk for bintrafusp alfa will be continuously 
evaluated based on emerging data from the current and other studies of the study 
intervention. 
Additional information about the known and expected benefits and risks and reasonably 
expected AEs of bintrafusp alfa are found in Section 2.2.5 and Section 2.2.6, and the 
current version of the IB. See Section 2.2.5 and Section 6.8 for special precautions and 
management of AEs, respectively. 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
3 2  
 
3.  
O B J E C TI V E S A N D E N D P O I N T S 
O bjecti ves  
E n d p oi nts  
P ri m ar y  
 
•  
E val uate t he a ntit u m or acti vit y per 
R E CI S T 1. 1.i n partici pa nts wit h 
metastatic or l ocall y 
a d va nce d/ u nresecta ble ur ot helial ca ncer 
treate d wit h bi ntraf us p alfa . 
•  
C o nfir me d O verall Res p o nse per 
R E CI S T 1. 1 assesse d b y i n vesti gat or.  
Sec o n d ar y  
  
•  
E val uate t he safet y a n d t olera bilit y of 
bi ntraf us p alfa i n partici pa nts wit h 
ur ot helial ca ncer.  
•  
Fre q ue nc y a n d se verit y of A Es usi n g 
N CI -C T C A E  v 5 . 
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
3 3  
 
O bjecti ves  
E n d p oi nts  
;
N CI -C T C A E  v 5 =  N ati o n al C a nc er I nst it ut e-C o m m o n T er mi n ol o gy Crit eri a f or A dv ers e Ev e nts, v ersi o n 5; 
 O R R =  ov er all r es p o ns e r at e;
P D  =  pr o gr essiv e dis e as e;
 
P R  =  p arti al r es p o ns e; 
R E CI S T 1. 1 = R es p o ns e Ev al u ati o n Crit eri a i n S oli d T u m ors Versi o n 1. 1;
S D  = st a bl e 
dis e as e; T G F - =  tr a nsf or mi n g gro wt h f act or b et a. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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4. 
STUDY DESIGN 
Based on the lack of efficacy of bintrafusp alfa in clinical studies in other tumor types, 
and a rapidly evolving treatment landscape for urothelial cancer, the study sponsor has 
decided to cease enrollment into the study. In line with the sponsor’s decision, this 
protocol has been amended to provide updated instructions for continued study conduct. 
4.1. 
Overall Design 
This is a Phase Ib open-label, global, multicenter, single-arm trial of bintrafusp alfa 
administered to participants with metastatic or locally advanced/unresectable urothelial 
cancer with disease progression or recurrence following treatment with a platinum agent. 
The primary study objective is to evaluate the objective response rate (ORR) per 
RECIST v1.1. Secondary objectives include evaluation of safety and tolerability of 
bintrafusp alfa.  
Participants who permanently discontinue study treatment will enter the follow-up period 
of the study and undergo the assessments as indicated in Section 8. 
Approximately 25 participants will be treated in this study. 
The study includes: 
• 
45-day screening period  
• 
Treatment with bintrafusp alfa 1200 mg as an IV infusion Q2W until disease 
progression as determined by the investigator using RECIST v1.1 [Eisenhauer, 2009] 
death, unacceptable toxicity, study withdrawal, or up to 2 years (see Section 7). 
• 
Participants who have experienced a confirmed complete response (CR) can 
continue treatment for a maximum of 24 months after confirmation of response (at 
the discretion of the investigator). If the investigator believes that a participant with 
confirmed CR may benefit from treatment beyond 24 months, it may be permissible 
to continue treatment after discussion with the GSK medical monitor. 
• 
Participants with SD or PR should continue treatment up to a period of 24 months 
from first dose until disease progression, or any other discontinuation criterion is 
met. 
• 
Safety Follow-up: will continue until 12 weeks after the last dose of bintrafusp alfa. 
The 12-week Safety Follow-up can be conducted via telephone calls or patient chart 
reviews unless there is medical necessity requiring a clinical visit. 
• 
Long-term Follow-up: should be performed every 12 weeks after the Safety 
Follow-up according to the Schedule of Activities (SoA; see Table 1). Long-term 
Follow-up should be performed by chart reviews or telephone calls. 
• 
Once the DCO date for the final analysis for this study has been reached, the clinical 
study database will be closed to new data and any participants that continue to 
receive study intervention at this time will be followed as described in Section 8.2. 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
3 5  
 
Bi o psies pri or t o st u d y treat me nt are re q uir e d, as descri be d i n eli gi bilit y criteria 
( Secti o n 5. 1 ).
 
T he o verall st u d y desi g n is s h o w n i n  t he St u d y Sc he ma [Fi g ure  1 ]. A detail e d S o A is 
l ocate d in Ta ble  1 . 
4. 2.  
S ci e ntifi c R ati o n al e f or St u d y D e si g n  
T he bif u ncti o nal a cti vit y of bi ntraf us p alf a  is well-s uite d f or e val uati o n i n ur ot helial 
ca ncer. A nti -P D -1/ P D -L 1 a nti b o dies are a p pr o ve d f or t he treat me nt of l ocall y a d v a nce d 
a n d metastatic ur ot helial ca ncers. H o we ver, Tra nsf or mi n g G r o wt h F act or  (T G F -) 
pat h wa ys are i m plicate d i n bl u nti n g t he acti vit y of t hese a nti b o dies i n ur ot helial ca ncers.  
Bi ntraf us p alfa i nterferes wit h b ot h P D -1/ P D -L 1 a n d T G F -β p at h wa ys, a n d t heref ore, has 
t he p ote ntial t o be m ore acti ve t ha n c urre ntl y a p pr o ve d c hec k p oi nt m o d ulat ors. 
4. 3.  
J u stifi c ati o n f or D o s e  
T he rec o m me n de d P hase II d ose ( R P 2 D) f or bi ntraf us p alfa is 1 2 0 0 m g 
as 
a n I V i nf usi o n Q 2 W . T he selecti o n of R P 2 D is base d o n t he a vaila ble cli nical data fr o m 
t he P hase I St u dies E M R 2 0 0 6 4 7-0 0 1 a n d M S 2 0 0 6 4 7 -0 0 0 8, i ncl u di n g safet y/t olera bilit y, 
P K, a n d p har mac o d y na mics ( P D L 1 t ar get occ u pa nc y i n p eri p heral bl o o d m o n o n uclear 
cell a n d T G F-β plas ma c o nce ntrati o ns), as well as efficac y i n sec o n d-li ne N S C L C 
c o h orts fr o m t he E M R 2 0 0 6 4 7 -0 0 1 st u d y. T h e selecti o n of R P 2 D is als o s u p p orte d b y 
p o p ulati o n p har mac o ki netic ( P o p P K) a n d e x p os ure res p o nse m o d eli n g a n d si m ulati o n. 
T he d ose is bei n g i n vesti gat e d i n o n g oi n g P hase II/III st u dies of  bi ntraf us p alfa . 
Refer t o t he I B f or detail e d data a n d a nal yses s u p p orti n g t he R P 2 D.  
4. 4.  
Ar c hi v al T u m or Bi o p s y : P D -L 1 S t at u s 
Arc hi val tiss ue will be s u b mitte d t o a ce ntral la b orat or y t o c o nfir m e x pressi o n of P D -L 1 
at t he ti me of scree ni n g. ( T he m ost rece ntl y c ollect e d arc hi v al t u m or tiss ue is re q ueste d). 
A nal ys es will be perf or m e d retr os pecti vel y, usi n g t he S P 2 6 3 P D -L 1 assa y . 
4. 5.  
Fr e s h T u m or Bi o p s y  
Baseli ne  t u m or bi o ps y ( d uri n g 4 5-d a y scree ni n g p eri o d) is re q uir e d f or e nr oll me nt i nt o 
t his st u d y ( See Secti o n 8. 1 1. 2 ) ( See Secti o n 5. 1 , I n cl usi o n Criteri o n #5 ). A li mite d 
n u m ber of partici p a nts  ( ma xi m u m 1 0) t hat are u ns uita ble f or bi o ps y (e. g., u nacce pta ble 
ris k, t u m or c haracteristics are li kel y t o yi el d i na de q uate s peci me ns, etc.) m a y b e 
c o nsi dere d f or e nr oll me nt f oll o wi n g disc ussi o n wit h t he s p o ns or.   
Bi o p sies o n treat me nt a n d at disease pr o gressi o n are  o pti o nal . 
4. 6.  
N u m b er of P arti ci p a nt s  
A p pr o xi matel y 2 5  p artici pa nts will be treate d i n t his st u d y.  Partici pa nts w h o disc o nti n ue 
will n ot be re place d. See Secti o n 9. 3  f or defi niti o ns of t he p o p ulati o ns f or a nal yses. 
C CI
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Pending evidence for favorable benefit:risk as compared to standard therapies, the trial 
may be expanded, following amendment. 
4.7. 
End of Study Definition 
A participant has completed the study if he or she has completed all study parts, including 
the last visit or the last scheduled procedure shown in Table 1. 
The end of the study (EOS) is defined as when the last participant’s last visit has been 
reached. Note that any serious adverse events (SAEs) ongoing at the EOS will be 
followed as outlined in Section 8.5.2. 
The sponsor will initiate final study reporting following the DCO date. 


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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Can give signed informed consent/assent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol 
2. At least eighteen (18) years of age at the time of signing the informed consent. 
3. Histologically confirmed locally advanced or metastatic or locally 
advanced/unresectable urothelial carcinoma (including renal pelvis, ureter, urinary 
bladder, urethra). Mixed histologies are acceptable provided transitional cell 
carcinoma is the predominant histology.  
a) Measurable disease per RECIST v1.1 criteria. 
b) Experienced disease progression or recurrence either (1) following platinum-
containing chemotherapy for metastatic or locally advanced/unresectable 
urothelial cancer or (2) within 12 months from completion of neo-adjuvant or 
adjuvant platinum-containing chemotherapy for localized muscle-invasive 
urothelial cancer.  
4. Able to provide, a tumor tissue sample collected during screening and prior to 
administration of bintrafusp alfa (see Study Reference Manual [SRM] for details). 
See Section 4.5  
5. Able to provide an archival tumor sample (preferably from the most recent biopsy). 
Archival material is formalin fixed tumor tissue sample from a biopsy of a tumor 
lesion. See SRM and Section 8.11.2 for further details on tumor tissue requirements. 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. See 
Appendix 10. 
7. Adequate organ system functions as defined by the laboratory assessments listed in 
Appendix 2. 


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System 
Laboratory Values 
Hematologica 
ANC 
1.5 x 109/L 
Hemoglobin 
9 g/dL 
Platelets 
100 x 109/L 
INR or PTb 
1.5 x ULN 
Hepatic 
Albumin 
2.5 g/dL 
ALT and AST 
2.5 x ULN or ≤5 x ULN for participants 
with documented liver metastases 
Total bilirubin 
Bilirubin 1.5 x ULN (isolated bilirubin 
>1.5 x ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%) 
Renal 
Calculated CrClc 
30 mL/min 
Cardiac 
Ejection Fractiond 
50% 
Abbreviations: ANC = Absolute neutrophil count; ALT = alanine aminotransferase; CrCl = creatinine clearance; 
ECHO=echocardiogram; eGFR=estimated glomerular filtration rate; MUGA= multigated acquisition scan; ULN 
= upper limit of normal; WNL = within normal limits 
a. 
Participants may be transfused or receive growth factor treatment to meet minimum hematologic 
values up to 10 days prior to determining eligibility. 
b. Participants receiving anticoagulant therapy exempt. 
c. 
Estimated CrCl/eGFR is required to be calculated using the Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) or Cockcroft-Gault formula; either formula is acceptable and must be 
consistently used for each participant throughout the study. Alternatively, investigators may use 
24-hour urine to determine CrCl (refer to Appendix 11). 
d. MUGA is acceptable if ECHO is not available; for each participant the same modality must be used 
for all subsequent evaluations. 
 
8. Life expectancy of at least 12 weeks. 
9. A female is eligible if she is not pregnant or breastfeeding, and at least one of the 
following conditions applies: 
• Not a woman of childbearing potential (WOCBP) as defined in Appendix 4. 
OR 
• If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate 
of <1% per year), preferably with low user dependency, as described in Appendix 
4 for the following time periods: 
o Before the first dose of the study intervention(s), if using hormonal 
contraception:  
▪ Has completed at least one 4-week cycle of an oral contraception 
pill and either had or has begun her menses. 
OR  
▪ Has used a depot contraceptive or extended-cycle oral 
contraceptive for least 28 days and has a documented negative 
pregnancy test using a highly sensitive assay.  


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o During the intervention period 
o After the study intervention period (i.e., after the last dose of study 
intervention is administered) for at least 2 months. 
The investigator evaluates the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention. 
Has a negative serum or highly sensitive urine pregnancy test, as required by local 
regulations, within 24 hours before the first dose of study intervention. If a urine test 
cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is 
required. 
Additional requirements for pregnancy testing during and after study intervention are in 
Appendix 2. 
The investigator reviews the medical history, menstrual history, and recent sexual activity 
to decrease the risk for inclusion of a female with an early undetected pregnancy. 
Male participants:  
• Contraceptive use by men should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies.  
• Male participants are eligible to participate if they agree to the following 
from the time of first dose of study until 125 days after the last dose of study 
treatment to allow for clearance of any altered sperm:  
o Refrain from donating sperm. 
PLUS, either: 
• Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on long term and persistent basis) and agree to 
remain abstinent. 
OR 
• Must agree to use contraception/barrier as detailed below. 
• Agree to use a male condom and female partner to use an additional highly 
effective contraceptive method with a failure rate of <1% per year as 
described in Section 10.4.2 when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Active brain and/or leptomeningeal disease that is symptomatic or requires 
therapeutic intervention. Participants with asymptomatic CNS metastases who are 


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clinically stable as demonstrated by serial brain images and have no requirement for 
corticosteroids for at least 14 days prior to enrollment are eligible. 
2. History of malignancy other than urothelial cancer within the last 3 years except for 
localized tumors that have been treated with curative intent or have not required 
therapy in the past 2 years. (e.g., resected non-melanoma skin cancer, etc.).  
3.  No more than 2 lines of systemic therapy for the treatment of metastatic disease. If 
the most recent therapy was not a platinum-based regimen, the participant must have 
progressed on or after that therapy. 
4. Cirrhosis or current unstable liver or biliary disease per investigator assessment 
defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, 
esophageal or gastric varices, or persistent jaundice. 
NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or 
asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria. 
5. Current pneumonitis or history of non-infectious pneumonitis that required systemic 
immunosuppressive treatment. 
6. Active autoimmune disease that required systemic immunosuppressive treatment 
within the past 2 years. 
7. Received prior allogeneic/autologous bone marrow or solid organ transplant.  
8. Receiving systemic corticosteroids (>10 mg daily oral prednisone or equivalent) or 
other immunosuppressive agent within 7 days prior to study treatment. Inhaled or 
topical steroids are permitted. 
Note:  
a) Physiologic doses of corticosteroids for treatment of endocrinopathies or 
steroids with minimal systemic absorption, including (e.g., topical, 
inhaled, intra-articular, ophthalmic, intranasal); corticosteroids may be 
continued if the participant is on a stable dose  
b) Steroids as premedication for hypersensitivity reactions (e.g., computed 
tomography [CT] scan premedication) are permitted. 
9. Known severe hypersensitivity reactions to monoclonal antibodies or any ingredient 
used in the study treatment formulation (Grade 3 according to National Cancer 
Institute-Common Terminology Criteria for Adverse Events, version 5 
[NCI-CTCAE v5]). 
10. Active infection requiring systemic therapy. 
11. Received any live vaccine within 30 days prior first dose of intervention. 
12. Known history of positive test for human immunodeficiency virus (HIV) with the 
exception of participants with CD4+ T-cell (CD4+) counts 350 cells/L and no 
history of AIDS-defining opportunistic infections. 
13. Active hepatitis B virus (HBV) (HBV surface antigen-positive). 
14. Active hepatitis C virus (HCV) infection, or positive HCV antibody, with the 
exception of participants that (1) have HCV viral load below the limits of 


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quantitation and (2) completed curative antiviral therapy or are receiving and 
compliant with antiviral therapy 
15. History or evidence of cardiac abnormalities within the 6 months prior to first dose 
of intervention which include: 
a. Serious, uncontrolled cardiac arrhythmia or clinically significant 
electrocardiogram abnormalities including second degree (Type II) or 
third-degree atrioventricular block or QTcF interval >450 msec (or QTcF 
>480 msec for participants with bundle branch block). 
b. Cardiomyopathy, myocardial infarction, acute coronary syndromes 
(including unstable angina pectoris), coronary angioplasty, stenting or 
bypass grafting 
c. Congestive heart failure (Class II, III, or IV) as defined by the New York 
Heart Association functional classification system 
d. Symptomatic pericarditis 
16. Participants with history of bleeding diathesis or recent major bleeding events 
considered by the investigator as high risk for investigational drug treatment are also 
excluded. 
17. Any other serious or uncontrolled medical disorder that, in the opinion of the 
investigator, may increase the risk associated with study participation or study drug 
administration, impair the ability of the participant to receive protocol therapy, or 
interfere with the interpretation of study results.  
Prior/Concomitant Therapy 
18. Received prior systemic anti-cancer therapy within 2 weeks prior to study treatment. 
19. Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways). 
20. Received prior therapy targeting TGF- (e.g., Galunistertib, etc.). 
21. Received radiation therapy (or other non-systemic disease therapy) within 2 weeks 
prior to study treatment. 
22. Undergone major surgery within 4 weeks prior to administration of study treatment. 
23. Residual toxicities attributed to prior anti-cancer therapy that are clinically 
significant or unmanaged and > Grade 1 or previous baseline other than neuropathy 
( Grade 2), alopecia, and fatigue. 
24. The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 35 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 


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25. Exposure to more than 2 investigational anti-cancer medicinal products within 
12 months prior to the first dosing day. 
Other Exclusions 
26. Is known to abuse alcohol or drugs. 
27. Has any psychiatric condition that would prohibit the understanding or rendering of 
informed consent or consistent participation in study procedures? 
28. Has legal incapacity or limited legal capacity. 
5.3. 
Lifestyle Considerations 
No lifestyle restrictions are planned for this study; however, male participants with 
partners of childbearing potential and women of childbearing potential must utilize 
appropriate contraception as described in Appendix 4. 
5.3.1. 
Meals and Dietary Restrictions 
Not applicable. 
5.3.2. 
Alcohol and Tobacco Use 
Alcohol and tobacco use will be collected in the eCRF. See Table 1.  
5.3.3. 
Activity 
Participants will provide one or more biopsies during the study and are expected to limit 
activity according to institutional protocols relevant to the biopsy site. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, any protocol deviations and any 
SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. Participants should be assigned a new participant number. 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
4 3  
 
6.  
S T U D Y I N T E R V E N TI O N  
St u d y i nter ve nti o n is defi ne d as a n y i n vesti gati o nal i nter ve nti o n i nte n de d t o be 
a d mi nistere d t o a st u d y p artici pa nt acc or di n g t o t he st u d y pr ot o c ol.  
6. 1.  
St u d y I nt er v e nti o n(s ) A d mi ni st er e d  
Bi ntraf us p alfa is a d mi nistere d as a 1 2 0 0 m g I V i nf usi o n o ver 1  h o ur  (-1 0 mi n utes/  
+ 2 0  mi n utes; i .e., o ver 5 0 t o 8 0 mi n utes) Q 2 W  f or u p t o 2 years fr o m first d ose or 2 years 
fr o m t he ti me of c o nfir m e d C R. 
I nt erv e nti o n 
Na m e  
Bi ntraf u s p al fa  
D o s a g e  F or m   
S ol uti o n f or i nfusi on  
U nit D o s e 
Stre n gt h( s) / D o s e 
L e v el  
1 0 m g/ m L i n si n gl e -us e glass vi als.  
R o ut e of 
A d mi ni strati o n  
I ntr av e no us i nf usi o n 
D o si n g 
I n str u cti o n s 
1 2 0 0 m g ov er 1 h o ur ( -10  minut es/ + 2 0 mi nut es; i e, ov er 5 0  to 8 0 min ut es) o nce 
ev ery 2  w e eks.  
S e e S ecti on  6. 8. 3 f or s pecial pr ec a utio ns an d m an a g e m e nt of a dv ers e eve nts .  
S u p pli er 
I nf or m ati o n  
Bi ntr af usp al fa  will be s u ppli ed by t h e sp o ns or a nd p ack a g ed, l a b ell e d, an d 
distri but e d for cli nical st u di es by a suit a bl e servic e pr ovi d er a n d fi n ally r el e as e d by a 
S p o ns or q ualifi e d pers o n accor di n g t o G o o d M a n uf act uri n g Pr actic es.  
P a c k a gi n g a n d 
L a b eli n g  
Bi ntr af usp al fa  is for m ulat e d as a 1 0 m g/ m L s oluti o n a n d is su p pli ed  by th e sp o ns or 
i n U S P/ P h E ur ty p e I vials filled t o allo w a n extr acta bl e v ol u m e of 6 0 m L 
( 6 0 0 m g/6 0  m L) a n d cl ose d wit h r u b b er st o p p ers i n s er u m f or m at c o m plyi n g wit h 
U S P a n d P h E ur wit h a n al u min u m cri m p s e al cl os ur e.  
E ac h vial will b e packa g e d a nd l a b ele d p er all ap plic a bl e r e gul at ory re q uir e m e nts 
a n d G oo d M an uf act uri n g Pr actic e G ui d eli n es.  
 
6. 2.  
Pr e p ar ati o n/ H a n dli n g/ St or a g e/ A c c o u nt a bilit y  
F urt her g ui d a nce a n d i nf or mati o n f or t he pre parati o n, ha n dli n g, a n d st ora ge of st u d y 
i nter ve nti o n(s) are pr o vi d e d i n t he P har mac y M a n ual. 
1.  T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve 
bee n mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o n recei v e d a n d a n y 
discre pa n cies are re p orte d a n d res ol ve d b ef ore use of t he st u d y i nter ve nti o n.  
2.  O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y i nter ve nti o n a n d o nl y 
a ut h orize d site staff ma y s u p pl y or a d mi nister st u d y i nter ve nti o n . All st u d y 
i nter ve nti o ns m ust be st ore d i n a sec ure, e n vir o n m e ntall y c o ntr olle d, a n d m o nit ore d 
( ma n ual or aut o mat e d) area i n acc or da n ce wit h t he la bele d st ora ge c o n diti o ns wit h 
access li mite d t o t he i n vesti gat or a n d a ut h orize d site staff . F urt her g ui da nce a n d 
i nf or mati o n f or fi nal dis p ositi o n of u n use d st u d y tr eat me nt are pr o vi de d i n S P M. 
C CI


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3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the SRM and Pharmacy Manual.  
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and generation of aerosols and mists. In case of 
unintentional occupational exposure notify the monitor, medical monitor, and/or 
GSK study contact. 
• 
A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK. 
Precaution will be taken to avoid direct contact with the study intervention. A Material 
Safety Data Sheet (MSDS) describing occupational hazards and recommended handling 
precautions will be provided to the investigator. In the case of unintentional occupational 
exposure notify the monitor, medical monitor and/or GSK study contact. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This study is a single arm, non-blinded or randomized trial. 
6.4. 
Storage 
Bintrafusp alfa drug product should be stored in a refrigerator (2°C to 8°C) until use. 
Bintrafusp alfa must not be frozen and should be stored in the original packaging. 
Additional instructions for the preparation, handling, storage, and disposal of bintrafusp 
alfa will be provided in the Pharmacy Manual. 
6.5. 
Treatment Compliance 
Study treatments will be intravenously administered to participants at the site. 
Administration will be documented in the source documents and reported in the eCRF. 
6.6. 
Concomitant Medications and Non-Drug Therapies 
Participants should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate. Participants will be instructed to inform the investigator prior 
to starting any new medications from the time of first dose of study treatment until the 
end of the study (Final Study Visit). Any concomitant medication(s), including non-
prescription medication(s) and herbal product(s), taken during the study will be recorded 
in the electronic case report form (eCRF). The minimum requirement is that drug name, 
dose and the dates of administration are to be recorded. Additionally, a complete list of 
all prior anti-cancer therapies will be recorded in the eCRF.  


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Palliative radiotherapy may be administered to non-target lesions during the study 
following discussion with the medical monitor. The indication, dose and dates of 
administration are to be recorded in the eCRF. 
Questions regarding concomitant medications should be directed to the GSK medical 
monitor for clarification. 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter. 
6.6.1. 
Prohibited Medicines 
Anti-cancer therapy other than bintrafusp alfa (e.g., chemotherapy, radiotherapy, 
immunotherapy, investigational, etc.) is prohibited except as noted in Section 6.6. 
Systemic immunosuppressive drugs are prohibited except as required for the short-term 
treatment of allergic reactions or immune-related AEs. 
Live vaccines should not be administered. 
6.7. 
Dose Modification 
Bintrafusp alfa will be administered according to Table 1. Dose modifications are not 
permitted with the exception of the allowance for bleeding events noted in Section 6.8.5. 
Dose interruptions are allowed as described Table 3. If there is a dose delay, efficacy 
assessments must be performed on a calendar schedule and should not be affected by 
dose interruptions/delays. 
6.8. 
Management of Adverse Events of Interest 
Adverse events of interest are serious or nonserious AEs specific to the known 
mechanism of action of the study intervention that are of clinical interest requiring 
ongoing monitoring. 
6.8.1. 
Immune-related Adverse Events 
Immune-related AEs are specific to immunotherapies and vary by organ system. 
Immune-related AEs are important identified risks for bintrafusp alfa. 
General management by NCI-CTCAE v5 grading, as per ASCO guidelines, is listed 
below: 
• 
Grade 1: study treatment should be continued with close monitoring, with the 
exception of some neurologic, hematologic, and cardiac toxicities.  
• 
Grade 2: study treatment may be suspended for most Grade 2 toxicities, with 
consideration of resuming when symptoms revert to Grade 1 or less. 
Corticosteroids may be administered (initial dose of 0.5 to 1 mg/kg/d of 
prednisone or equivalent).  


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• 
Grade 3: study treatment is generally suspended and the high-dose 
corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 
2 mg/kg/d) treatment should be initiated. Corticosteroids should be tapered 
over the course of at least 4 to 6 weeks. Some refractory cases may require 
infliximab or other immunosuppressive therapy.  
• 
Grade 4: in general, permanent discontinuation of study treatment is 
recommended, with the exception of endocrinopathies that have been 
controlled by hormone replacement. 
Detailed recommendations for irAE management of specific organ systems as per 
published guidelines are provided in Appendix 9 . These recommendations are in 
accordance with ASCO Clinical Practice Guidelines in collaboration with NCCN 
guidelines (Brahmer, 2018).  
6.8.2. 
Potential TGF-β Mediated Dermatologic Adverse Events 
Management guidelines for potential TGF-β-mediated dermatologic AEs: 
• 
Discontinuation or interruption of study treatment is generally not required. 
Continuation of treatment should be evaluated by the investigator. 
• 
Emollients may continue to be used. Diagnostic and treatment plan should be 
developed in collaboration between investigator and dermatologist. In general, 
treatment of TGF-β-mediated dermatologic lesions such as hyperkeratosis, KA and 
cSCC should be based on local guidelines/standard of care. Lesion evaluation should 
include excision biopsy of one representative lesion to confirm diagnosis. 
• 
Treatment and follow-up for KA and cSCC will depend on number and localization 
of lesions.  
o For single lesions: Full excision may be recommended. 
o For multiple lesions or location not suitable for full excision other 
treatment options may be offered by the dermatologist, such as Mohs 
surgery, cryotherapy, or other standard treatment options depending on the 
pathology. Use of retinoids if recommended by dermatologist, may be 
considered after discussion with medical monitor.  
• 
Close clinical follow-up for re-evaluation, resolution, or potential recurrence should 
be implemented. Spontaneous resolution of KA lesions without surgical intervention 
has been observed, typically occurring within weeks after discontinuing bintrafusp 
alfa. 
The number and localization of lesions, diagnosis (including histopathological diagnosis), 
treatment, and outcome should be appropriately documented in the eCRF. Consult with 
study medical monitor as needed for management of TGF--mediated dermatologic 
lesions. 


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6.8.3. 
Infusion-related Reactions Including Immediate Hypersensitivity 
Infusion-related reactions (IRRs) including immediate hypersensitivity are important 
identified risks for bintrafusp alfa. 
Infusion reactions may vary in manifestation and timing, and signs and symptoms usually 
develop during or shortly after drug infusion which generally resolves completely within 
24 hours of completion of infusion.  
Further information regarding mitigation of IRRs are detailed in Table 2. 
As a routine precaution, for the first 2 infusions, all participants enrolled in this study 
must be observed for 2 hours post end of infusion, in an area with resuscitation 
equipment and emergency agents. 
At all times during bintrafusp alfa study treatment, immediate emergency treatment of an 
IRR or a severe hypersensitivity reaction according to institutional standards must be 
assured. To treat possible hypersensitivity reactions like anaphylactic reactions, for 
instance, dexamethasone 10 mg and epinephrine in a 1:1000 dilution or equivalents 
should always be available along with equipment for assisted ventilation. 


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Table 3 
Treatment Modification for Symptoms of Infusion-Related Reactions 
NCI-CTCAE v5 Grade 
Treatment Modification 
Grade 1 – mild 
• Mild transient reaction; infusion 
interruption not indicated; intervention not 
indicated. 
• 
Increased monitoring of vital signs as 
medically indicated, presuming these 
participants are deemed medically stable. 
Grade 2 – moderate 
• 
Therapy or infusion interruption indicated 
but if responds promptly to symptomatic 
treatment (for example, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for 24 hours. 
• Stop bintrafusp alfa infusion. 
Increased monitoring of vital signs as 
medically indicated as participants are 
deemed medically stable by attending 
investigator.  
If symptoms resolve quickly or decreased 
to Grade 1, resume infusion at 50% of 
original rate with close monitoring of any 
worsening otherwise dosing held until 
resolution of symptoms with mandated 
premedication for the next schedule.  
If worsens to Grade 3 or 4, follow 
treatment modification guidelines 
accordingly. 
Grade 3 or Grade 4 – severe or life-
threatening 
• Grade 3: Prolonged (for example, not 
rapidly responsive to symptomatic 
medication and/or brief interruption of 
infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for clinical 
sequelae. 
• 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
• Stop the bintrafusp alfa infusion 
immediately and disconnect infusion 
tubing from the participant with additional 
appropriate medical measures and close 
monitoring until deemed medically stable 
by attending investigator. Hospitalization 
may be indicated. 
• Participants will be permanently withdrawn 
immediately from bintrafusp alfa treatment 
and must not receive any further 
bintrafusp alfa treatment 
IV = intravenous; NCI-CTCAE v5= National Cancer Institute-Common Terminology Criteria for Adverse Events, 
version 5; NSAIDs = nonsteroidal anti-inflammatory drugs.  
For Grade 3 or 4 infusion-related reactions, bintrafusp alfa discontinuation is mandated.  
For all types and grades of infusion reactions, details about drug physical constitution, method of preparation and 
infusion must be recorded. 
In the event of a Grade 2 IRR that does not improve or worsens after implementation of 
the dose modifications indicated in Table 3 (including reducing the infusion rate by 
50%), the investigator may consider treatment with corticosteroids and the infusion 
should be stopped for that day. At the next infusion, the investigator may consider the 
addition of H2 blocker antihistamines (for example, famotidine or ranitidine), in addition 


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to premedication, for select participants. However, prophylactic steroids are NOT 
permitted. At next dose, if the participant has a second IRR Grade 2 on the slower 
infusion rate, with the addition of further medication to premedication, the infusion 
should be stopped, and the participant removed from treatment. 
If a severe hypersensitivity reaction occurs, the participant must be treated according to 
the best available medical practice. Management of hypersensitivity may include:  
1. Epinephrine injection and IV dexamethasone 
2. Cardiac, blood pressure, heart rate, and oxygen saturation monitoring 
3. Intensive care unit transfer if required. 
Participants should be instructed to report any delayed reactions to the investigator. 
6.8.4. 
Treatment-related Anemia 
A thorough investigation of new anemia cases of unspecified etiology is expected. For 
new anemia events assessed as treatment-related, items queried may include, but are not 
limited to, detailed relevant past medical and treatment history, bruising tendency, history 
of blood transfusions and/or dependency, and a request for an updated eCRF including 
details such as concomitant medications, all laboratory data, updated dosing information 
and recent tumor evaluation scans. 
General guidance for anemia management and evaluation: 
1. Participants must enter the study with hemoglobin values at least 9 g/dL; routine 
blood test parameters are specified in Appendix 2. 
2. Transfusion should be performed at the discretion of the investigator. 
3. Relevant hematologic testing for treatment-related anemias should be done prior 
to blood transfusion, if clinically feasible. Guidance for evaluation of suspected 
treatment-related anemias is provided in Table 4. 
4. Discuss further management with medical monitor for clinically significant 
treatment-related anemias.  
Guidance for evaluation of suspected treatment-related anemias is provided in Table 4. 


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Table 4 
Evaluation Guidance of Suspected Treatment-related Anemia 
Adverse Events 
Baseline anemia evaluation (prior to transfusion, if feasible) 
Hb and CBC with differential (eg, MCV, RDW, ANC, hematocrit, reticulocytes counts) 
Peripheral blood smear for cell morphological assessment 
Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, and serum folate, 
B12 values and other chemistries 
Coagulation factors (PT, PTT, INR) 
Urinalysis including culture 
Iron panel (TIBC, ferritin, iron) 
TSH/hormonal panel 
Fecal-occult blood testing 
Erythropoietin 
Haptoglobin 
Further recommendation based on suspected etiology (in addition to Baseline anemia testing) 
Unknown etiology, 
suspect possible 
hemolysis 
Coombs test, fibrinogen, d-dimer 
Consider hematology consultation. 
Consider blood transfusion at clinical discretion. 
Unknown etiology, 
suspect possible 
bleeding 
Consider blood transfusion at clinical discretion. 
Consider surgical/interventional radiology consultation. 
Consider imaging, as clinically indicated (eg, FAST scan, CT scan, MRI, 
angiography). 
Consider endoscopy (upper/lower)  
Unknown etiology 
despite above work-up 
Hematology consultation 
Consider bone marrow aspiration/morphologic evaluation 
ANC = absolute neutrophil count; CBC = complete blood count; CT = computed tomography; FAST = focused 
assessment with sonography for trauma; Hb = hemoglobin; INR = international normalized ratio; LDH = lactate 
dehydrogenase; LFT = liver function test; MCV = mean corpuscular volume; MRI = magnetic resonance 
imaging; PT =prothrombin time; PTT = partial thromboplastin time; RDW = red cell distribution width; 
TIBC = total iron-binding capacity; TSH = thyroid-stimulating hormone.  
6.8.5. 
Additional Risks 
6.8.5.1. 
Bleeding Events 
Bleeding events are a potential risk for bintrafusp alfa (refer to IB). 
For all participants: 
For Grade 2 tumor bleeding, study treatment must be held until the event recovers to 
Grade 1. If a Grade 3 tumor bleeding event has been observed, regardless of causality 
with the study intervention, upon resumption of the study intervention the bintrafusp alfa 
dose should be reduced to 600 mg Q2W. Once there is stable resolution and no 
recurrence of bleeding on the reduced dose, the investigator is encouraged to 
communicate with the medical monitor regarding a potential dose re-escalation after 
careful benefit-risk assessment. Treatment should be permanently discontinued if the 
investigator considers the participant to be at risk for additional severe bleeding. In case 
of a rapid decrease of hemoglobin (Hgb), see Table A8 (Management of Hematologic 
irAEs in Patients Treated with ICPis) in Section 10.9. 


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If a Grade 3 non-tumor bleeding event is observed, study treatment must be 
permanently discontinued unless an alternative explanation can be identified (such as 
concomitant use of antithrombotic agents, traumatic event, etc.). In case of alternative 
explanations for the Grade 3 bleeding event, study treatment should be held until the 
event recovers to Grade 1. If a Grade 3 bleeding event is observed, regardless of 
causality with the study intervention, upon resumption of study intervention, the 
bintrafusp alfa dose should be reduced to 600 mg Q2W. Once a Hgb decrease recovers to 
Grade 1 or there is stable resolution and no recurrence of bleeding on the reduced dose, 
the investigator is encouraged to communicate with the medical monitor regarding a 
potential dose re-escalation after careful benefit-risk assessment. The dose of bintrafusp 
alfa may be re-escalated to full dose (1200 mg Q2W) once Hgb is stabilized without 
further need for blood transfusion in the subsequent cycles. The timing of re-escalation 
will be determined on a case-by-case basis. See Section 6.8.4 regarding the stabilization 
of anemia. 
For Grade 4 non-tumor bleeding, treatment must be permanently discontinued if no 
alternative explanation is identified. In case of rapid decrease of Hgb, such as a decrease 
greater than 2.0 g/dL across a 2-week period, withhold the subsequent cycles of study 
intervention until HgB is stabilized and do a thorough assessment of bleeding (for 
example, upper and lower gastrointestinal [GI] endoscopy, contrast-enhanced CT scan, 
etc.). If Grade 1 bleeding is observed or suspected, withhold the bintrafusp alfa until the 
bleeding is resolved/controlled and resume the dose of bintrafusp alfa, decreased to 
600 mg Q2W. The dose of bintrafusp alfa may be re-escalated to full dose (1200 mg 
Q2W) once Hgb is stabilized to Grade 1 or baseline without further need for blood 
transfusion in the subsequent cycles; the investigator is encouraged to communicate with 
the medical monitor to re-escalate the dose. The timing of re-escalation will be 
determined on a case-by-case basis. See Section 6.8.4 regarding stabilization of anemia. 
6.8.5.2. 
Alterations in Wound Healing or Repair of Tissue Damage 
Due to the involvement of TGF-β in tissue and skin repair, alterations in wound healing 
or repair of tissue damage is considered an important potential risk. No relevant event is 
reported in the ongoing bintrafusp alfa clinical studies. Monitoring of any surgical 
wounds while on study is recommended. In general, a 2-week delay from treatment is 
recommend following minor surgery and 4-week delay for major surgery, but cases 
should be discussed with the medical monitor. 
6.8.5.3. 
Embryofetal Toxicity 
Embryo-fetal toxicities are a known risk of the PD-1/L1 targeting class. Animal models 
link the PD-1/L1 signaling pathway with maintenance of pregnancy through induction of 
maternal immune tolerance to fetal tissue. Embryo-fetal and reproductive toxicities have 
also been investigated in animal models for a humanized monoclonal antibody targeting 
TGF-β1. At doses as high as 30 mg/kg, no maternal reproductive toxicity or embryo-fetal 
lethality were observed in rabbits (Hilbish, 2016). To mitigate these potential risks, 
pregnant participants are excluded from the study, and all participants of 
childbearing/conceiving potential must use highly-effective contraception. 


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6.9. 
Intervention After the End of the Study 
Study participants that continue to benefit from study intervention beyond the DCO date 
will continue to have access to study intervention until the EOS as defined in Section 4.7. 
There is no planned intervention following the EOS. 
The investigator is responsible for ensuring that consideration has been given to the 
post-study care of the participant’s medical condition. 
Refer to the SoA (Table 1) for follow-up assessments of participants who are to be 
followed for disease progression and survival after they permanently discontinue from 
bintrafusp alfa until the DCO date and from the DCO date to the EOS. 
6.10. 
Continued Access to Study Intervention After Data Cut-off  
Participants who are considered to be deriving benefit from study intervention by the 
investigator, with agreement with the GSK medical monitor, and who do not meet any 
protocol-defined treatment discontinuation criteria may continue to receive study 
intervention after the DCO date for up to 2 years after their first dose or up to 2 years 
from time of confirmed CR. Please see the SRM for details regarding drug resupply. 
Drug accountability data will also be collected at site visits. 


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7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Intervention 
In some instances, it may be necessary for a participant to permanently discontinue study 
intervention for any of the following reasons:  
• A participant may discontinue from the study intervention at any time at his/her 
own request (i.e., withdrawal of consent), and without giving a reason. 
• Occurrence of an exclusion criterion, which is clinically relevant and affects the 
participant's safety, if discontinuation is considered necessary by the investigator 
and/or sponsor. 
• A participant may be discontinued at any time at the discretion of the investigator 
for safety, behavioral, compliance, or administrative reasons (See Section 6.8 for 
TEAEs and AEs of Interest that require treatment discontinuation). 
• Confirmed PD per RECIST 1.1, with the exception that participants receiving 
treatment may continue past PD if the participant’s ECOG PS has remained at 
least stable, and if in the opinion of the investigator, the participant will benefit 
from continued treatment (See Section 7.1.1). 
• Unacceptable toxicity. 
• Some TEAEs and AEs of Interest require withdrawal from treatment 
(Section 6.8). 
• Drug must not be given to a known pregnant participant (refer to Appendix 4). 
• Use of a prohibited concomitant drug, as defined in Section 6.6.1, where the 
predefined consequence is withdrawal from the study intervention. 
The SoA (Table 1) specifies the data to collect at study intervention discontinuation, 
28-day safety follow-up, follow-up, and any additional evaluations that need to be 
completed. 
In case of discontinuation from the study intervention: 
• The day of End-of-Treatment will correspond to the day of withdrawal (or within 
7 days). 
• An attempt should be made to perform all assessments scheduled for the 
End-of-Treatment visit if possible. If not possible, the most clinically relevant 
assessments and appropriate eCRFs for the End-of-Treatment visit should be 
prioritized as feasible. 
• Participants will be asked to continue Safety and Survival Follow-up, which 
includes the collection of data on survival, and subsequent anti-cancer therapy. 
After completion of the follow-up period or after the End-of-Treatment visit, 
whichever is applicable, the appropriate eCRF section for Study Termination 
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• If the participant is enrolled into a new study or any new therapy post-withdrawal 
from study intervention, the Safety Follow-up visit should be scheduled prior to 
the start of the new treatment irrespective of the 28-day Safety Follow-up period. 
• For participants discontinuing from study treatment after the DCO date for final 
analysis, no study-specific visits or eCRF completion will be required per 
Section 8.2. 
7.1.1. 
Disease Progression 
Disease progression must be assessed by the investigator and documented in the 
participants CRF. Before stopping the treatment, progressive disease should be confirmed 
by imaging at least 4 weeks after progression according to RECIST v1.1 unless: 
• Study intervention is not tolerated, or 
• ECOG PS is declining, or 
• The investigator considers an alternative intervention to be in the best interest of 
the study participant. 
The decision to continue treatment beyond confirmed PD should be discussed with the 
medical monitor and documented in the study records if the investigator believes that the 
participant would continue to benefit according to Table 1. 
Participants who continue beyond progression will be evaluated for further tumor 
response as per the protocol schedule. Treatment should be discontinued upon 
documentation of further, unequivocal, disease progression or upon meeting any other 
criteria for discontinuation.  
7.1.2. 
Liver Chemistry Stopping Criteria 
Liver chemistry stopping, and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology. 
Discontinuation of study intervention for abnormal liver tests is required when:  
• a participant meets one of the conditions outlined in Appendix 6.  
• 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.  


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Figure 2 
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm including Participants WITH documented liver 
metastases/tumor infiltration at baseline AND entry criteria ALT 
>2.5x ULN but 5x ULN 
 
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.  
7.1.2.1. 
Study Intervention Restart or Rechallenge after liver stopping criteria 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed. 
7.1.3. 
QTc Stopping Criteria 
• 
The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the participant has been enrolled. 
o For example, if a participant is eligible for the protocol based on QTcF, then 
QTcF must be used for discontinuation of this individual participant as well. 
o 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 ECGs and other non-protocol specified 
ECGs are an exception. 


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• 
The scheduled QTc evaluations should be based on single ECG readings. 
• 
Withdrawal of participants is to be based on an average QTcF value of triplicate 
ECGs. If a single ECG demonstrates a prolonged QTcF interval, then obtain 2 more 
ECGs over a brief period (e.g., 5-10 minutes) and then use the averaged QTcF values 
of the 3 ECGs to determine whether the participant should be discontinued from the 
study. 
o If a participant meets either of the following criteria, they must be discontinued 
from study treatment: QTcF >500 msec OR Change from baseline of QTcF 
>60 msec. 
o For participants with underlying bundle branch block and baseline QTcF 
<450 msec, discontinue if QTcF is >500 msec. For participants with baseline 
QTcF 450-480 msec, discontinue if QTcF is >530 msec. 
o QTcF = QT duration corrected for heart rate by Fridericia’s formula. See the SoA 
(Table 1) for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.1.4. 
Adverse Drug Reaction Stopping Criteria 
Adverse drug reactions are defined in this study as any AEs related to study intervention 
assessed by the investigator and/or sponsor.  
Management guidelines for AEs of Interest (Immune-related AEs, TGF-β-mediated 
dermatologic AEs, Infusion-related reactions, and treatment-related anemia) as described 
in Section 6.8 supersede the general guidelines below.  
Adverse Drug Reactions (ADRs) requiring discontinuation of study treatment 
include: 
• 
Any Grade 4 ADRs. 
• 
Persistent Grade 3 non-hematologic ADRs that do not recover to Grade 0 or 1 within 
6 weeks after dose of treatment Recurrent Grade 3 ADRs (after recovery to Grade 0 
or 1) that last more than 72 hours, with optimal medical management, also require 
discontinuation. 
• 
Any ADR requiring treatment with corticosteroids beyond 12 weeks at doses greater 
than 10 mg prednisone (or equivalent) per day. 
Exceptions to the criteria for discontinuation: 
• 
Fatigue. 
• 
Isolated laboratory values out of normal range that do not have any clinical 
correlation. 
• 
Endocrinopathies controlled with hormone replacement therapy.  
• 
Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of 
known or suspected tumor. 
• 
Keratoacanthomas and/or cSCC (see Section 6.8.2). 


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7.2. 
Participant Discontinuation/Withdrawal from the Study 
Participants will receive study treatment for a maximum of approximately 2 years (from 
first dose or from the time of confirmed CR), or until the occurrence of disease 
progression (See Section 7.1), death or unacceptable toxicity, including meeting stopping 
criteria for liver chemistry defined in Section 7.1.2. In addition, study treatment may be 
permanently discontinued for any of the following reasons: 
• 
deviation(s) from the protocol 
• 
request of the participant or proxy (withdrawal of consent by participant or 
proxy) 
• 
investigator’s discretion 
• 
participant is lost to follow-up  
• 
study is closed or terminated. 
• 
3 consecutive missed doses unless the GSK medical monitor agrees that further 
treatment may benefit the participant 
The primary reason study treatment was permanently discontinued must be documented 
in the participant’s medical records and electronic case report form (eCRF). 
All participants who permanently discontinue study treatment without disease 
progression will be followed for progression according to the protocol schedule until: 
a. 
new anti-cancer therapy is initiated 
b. progression 
c. 
death, or 
d. study has completed 
All participants who permanently discontinue study treatment will be followed Q12W 
(±2 weeks) for survival and the start of new anti-cancer therapy to a maximum of 3 years, 
unless otherwise indicated (see Section 8.2). If participants are unable or unwilling to 
attend clinic visits during follow-up, contact to assess survival may be made via another 
form of communication (e.g., phone, email, etc.). 
If the participant voluntarily discontinues from treatment due to toxicity, ‘adverse event 
(AE)’ will be recorded as the primary reason for permanently discontinuation on the 
electronic case report form (eCRF). 
All participants who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post-study treatment follow-up as specified in Table 1. 
• 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. 


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• If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records. 
7.3. 
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 study. 
• 
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 study.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1. 
7.4. 
Participant and Study Completion 
A participant will be considered to have completed the study if the participant dies or 
otherwise progresses during the treatment or follow-up period or has been in follow-up 
for a maximum of 3 years or until the DCO date is reached, whichever is sooner. 
Document the cause of death in the CRF. A participant will be considered to have 
withdrawn from the study if the participant has not died or progressed and is lost to 
follow-up, has withdrawn consent, or at the investigator’s discretion is no longer being 
followed.  


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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in Table 1. 
• 
Protocol waivers or exemptions are not allowed  
• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
Adherence to the study design requirements, including those specified in Table 1, is 
essential and required for study conduct. 
• 
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. 
• 
Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in Table 1. 
• 
Note: Repeat or unscheduled samples may be taken for safety reasons, based 
on emerging data or for technical issues with the samples. 
8.1. 
Screening Assessments 
All screening assessments must be performed within 45 days prior to the first dose unless 
otherwise specified. Screening scans for lesion assessments are required within 28 days 
of the first dose. The ICF may be signed within 45 days prior to enrollment; tumor tissue 
biopsy procedure must be performed during the screening period after participant ICF 
obtained. An archived tumor sample is mandatory and will be used for PD-L1 testing. 
The term ‘baseline’ refers to the assessment performed during the screening period prior 
to first dose of study treatment that serves as a comparison or control. For example, the 
baseline laboratory assessment is the laboratory assessment performed prior to first dose. 
Refer to Table 1 for additional details on assessments required at Screening and prior to 
the start of study intervention. 
The following assessments are required during screening: 
• 
Informed Consent 
• 
Demographic parameters such as year of birth and sex will be captured 
• 
Medical history including cardiovascular medical history, tobacco use, prior use 
of probiotics and antibiotics within (60 of first dose) and other risk factors will 
be assessed as related to the inclusion/exclusion criteria. 
• 
Complete physical examination. 


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
6 0  
 
•  
S ki n assess me nts are perf or me d at Baseli ne o n all partici pa nts ( refer t o Ta ble  1  
a n d Secti o n 8. 4. 1 ). A det aile d me dical hist or y of ge netic or iatr o ge nic 
der mat ol o gi c  co n diti o ns, s ki n t y pe, ge o gra p hical l ocati o n, occ u p ati o nal or 
e n vir o n me ntal e x p os ure t o ra diati o n or c h e micals will be q uerie d.  
•  
Disease c h aracteristics i n cl u di n g me dical, s ur gical, a n d treat me nt hist or y ( best 
res p o nse t o pri or t hera p y [ra di ot hera p y a n d s yste mic] will be rec or de d), dat e of 
i nitial dia g n osis, pri mar y t u m or l ocati o n, sta ge at i nitial dia g n osis, hist ol o g y, 
a n d c urre nt sites of disease will be ta ke n as p art of t he disease hist or y/stat us.  I n 
a d diti o n, m olec ular c haracterizat i o n of ca ncer, i ncl u di n g P D-L 1 e x pressi o n b y 
I H C will be rec or de d. If P D-L 1 e x pressi o n has bee n pre vi o usl y deter mi ne d , 
res ults a n d t y p e of ass a y utilize d (e. g., Ve nta na S P 2 6 3 , Ve nta na S P 1 4 2, Da k o 
2 8 -8, or Da k o 2 2 C 3) m ust be rec or de d i n e C R F.  
•  
A brai n C T/ M R T  sca n perf or me d as cli nicall y i n dicate d.  
•  
E C O G Perf or ma n ce Stat us.  
•  
Vital Si g ns (refer t o Secti o n 8. 4. 3 ). 
•  
C o nc o mita nt me dicati o n  
o  Rec or de d starti n g fr o m scree ni n g t hr o u g h p ost -st u d y treat me nt f oll o w-u p.  
o  Rec or d all me dicati o ns t he partici pa nt is ta ki n g i ncl u di n g prescri pti o n 
me dicati o ns, o ver -t he-c o u nter dr u gs or pre parati o ns, a n d her bal pre parati o ns 
i ncl u di n g a n y ca n na bi n oi ds a n d/ or recreati o nal dr u gs use d. 
o  At a mi ni m u m, t he dr u g na me, r o ute of a d mi nistrati o n, d ose, a n d fre q ue nc y 
of d osi n g, al o n g wit h start a n d st o p dates m ust be rec or de d.  
•  
Electr ocar di o gra m  ( E C G; refer t o Secti o n 8. 4. 4 ). 
•  
E c h ocar di o gra m at scree ni n g.  M U G A is acce pta ble if E C H O is n ot a vaila ble; 
f or eac h partici p a nt t he s a me m o dalit y m ust be us e d f or all s u bse q ue nt 
e val uati o ns . 
•  
La b orat or y assess me nts ( he mat ol o g y, c h e mistr y, uri nal ysis T 4, T S H, a n d s er u m 
pre g na nc y as a p pr o priate). (refer t o A p pe n di x 2  f or re q uire m e nts). 
•  
Ne wl y c ollect e d t u m or tiss ue se nt t o ce ntral la b orat or y (refer t o t he S R M f or 
re q uire me nts). M a n dat or y.  
•  
Arc hi v al T u m or sa m ple o btai ne d a n d will  be se nt t o ce ntral la b (refer t o t h e 
S R M f or re q uire me nts). 
•  
H B V a n d H B C testi n g  
•  
HI V k n o w n stat us.  
•  
T S T, Q ua nti F E R O N -T B -G ol d, or T -S P O T (if p ositi ve hist or y of t u berc ul osis 
e x p os ure). 
C CI


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Baseline scans for lesion assessments per RECIST v1.1 guideline [Eisenhauer, 2009] are 
required within 28 days of enrollment and include:  
• 
CT scan with contrast of the chest, abdomen, and pelvis is required. 
o Note: Contrast-enhanced computed tomography (CT) of 
chest/abdomen/pelvis covering the area from the superior extent of the 
thoracic inlet to the symphysis pubis is the first choice of imaging modality. 
If a participant cannot receive iodinated contrast, or if regional radiation 
regulations prevent full CT scan, magnetic resonance imaging (MRI) of the 
abdomen and pelvis, using gadolinium enhancement (according to local 
protocol) is permitted, and should be acquired in conjunction with the 
unenhanced CT of the chest. The same modality, and preferably the same 
scanner, should be used per participant throughout the study.  
• 
Other areas should be evaluated as indicated by the participant’s underlying 
disease prior to screening.  
• 
Refer to RECIST version 1.1 guidelines for use of FDG-PET/CT [Eisenhauer, 
2009]. 
• 
Note: Measurable lesions that have been previously irradiated and have not been 
shown to be progressing following irradiation should not be considered as target 
lesions.  
8.2. 
Follow-up Assessments 
Participants who permanently discontinue study treatment for any reason, except 
withdrawal of consent (refer to Section 7.2), will be followed for survival and new 
anti-cancer therapy (including radiotherapy) Q12W until death or the DCO date, 
whichever is sooner. A DCO date will be specified that will represent the end of data 
collection for the planned final analysis described in the Reporting and Analysis Plan 
(RAP). Refer to the SoA in Table 1 for the follow-up schedule. 
Once the final DCO date for this study has been reached, no new data will be entered into 
the clinical study database and the database will be locked for final analysis. Participants 
who are considered to be deriving benefit from study intervention in the opinion of the 
investigator, with agreement from the GSK medical monitor, and do not meet any 
protocol-defined treatment discontinuation criteria may continue to receive study 
intervention for a defined period after the DCO date, as follows: 
o Participants will be managed in accordance with the local institutional 
standard of care. 
o SAEs, AEs leading to treatment/study discontinuation, overdoses, and 
pregnancies will be reported through a paper-based pharmacovigilance (PV) 
process and captured in the asset PV database. Investigators will report all 
SAEs, overdoses, and pregnancy cases until 35 days (5 half-lives) after receipt 
of a given participant’s last dose of study intervention or start of subsequent 
anti-cancer therapy. Any SAE will be followed until resolution unless the 
event is considered by the investigator to be unlikely to resolve, or the 
participant is lost to follow-up. 


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Participants in survival follow-up at the time of the final DCO date will be considered to 
have completed the study. 
Although the clinical study database will be closed at the time of the final DCO date, the 
study will remain open until all participants discontinue study intervention and the EOS 
definition is reached. 
8.3. 
Evaluation of Anti-Cancer Activity 
RECIST version 1.1 guidelines will be used to determine the overall tumor burden at 
baseline, select target and non-target lesions, and in the disease assessments throughout 
the duration of the study. The primary measure of response-based efficacy endpoints is 
according to RECIST v1.1 definition as assessed by the investigator [Eisenhauer, 2009]. 
• 
Response assessments will be performed Q8W for the first 6 months and Q12W 
thereafter, until end of treatment, and at the final study visit (refer to Table 1). 
• 
If bintrafusp alfa is discontinued without documented progression, then continue 
imaging Q8W for the first 6 months from first dose of bintrafusp alfa followed 
by Q12W until documented PD, or the start of any new anti-cancer therapy. 
• 
For post-baseline assessments, a window of [3 days] is permitted to allow for 
flexible scheduling. 
Assessments must be performed on a calendar schedule and should not be affected by 
dose interruptions/delays. 
If the last radiographic assessment was 6 weeks or more prior to the participant’s 
withdrawal from study treatment and PD has not been documented, a disease assessment 
should be obtained at the time of withdrawal from study treatment. See Table 1 for the 
schedule of assessments of anti-cancer activity. 
• 
All the scans performed during screening need to be repeated at subsequent 
visits for tumor assessment. 
• 
To ensure comparability between the baseline and subsequent assessments, the 
same method of assessment and the same technique must be used when 
assessing response. 
Refer to the imaging manual for details on imaging/clinical assessment requirements and 
submission guidelines. 
Tumor responses to treatment will be assigned based on the evaluation of the response of 
target, non-target, and new lesions according to RECIST v1.1. 
Treatment decisions will be made by the treating investigator based on RECIST v1.1. 
Study intervention should continue until disease progression, unacceptable toxicity, or 
any criterion for withdrawal from the trial or study intervention occurs (see Section 7). 
Before stopping the treatment, progressive disease should be confirmed by imaging at 
least 4 weeks after initial progression according to RECIST v1.1. 


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See Section 7.1 for more information about continued study intervention after disease 
progression. 
The intervention should be stopped immediately if the participant does not tolerate 
bintrafusp alfa or if therapeutic failure occurs that requires urgent treatment with an 
additional drug or results in clinically significant progression/deterioration. 
8.3.1. 
Disease Response Assessments  
8.3.1.1. 
RECIST v1.1 
RECIST v1.1 guidelines will be used to determine the overall tumor burden at screening, 
select target and non-target lesions, and in the disease assessments through the duration 
of the study [Eisenhauer, 2009]. See the SRM for additional information. 
• 
As indicated in RECIST version 1.1 guidelines: 
o Lymph nodes that have a short axis of <10 mm are considered non-pathological 
and must not be recorded or followed. 
o Pathological lymph nodes with <15 mm but 10 mm short axis are considered 
non-measurable. 
o Pathological lymph nodes with 15 mm short axis are considered measurable and 
can be selected as target lesions; however, lymph nodes should not be selected as 
target lesions when other suitable target lesions are available. 
o Measurable lesions up to a maximum of two 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 (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).  
Note: Cystic lesions thought to represent cystic metastases must not be selected as target 
lesions when other suitable target lesions are available. 
Note: Measurable lesions that have been previously irradiated and have not been shown 
to be progressing following irradiation must not be considered as target lesions. 
• 
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. 
Bone scans, FDG-PET scans or X-rays are not considered adequate imaging 
techniques to measure bone lesions. 
• 
All other lesions (or sites of disease) must be identified as non-target and must 
also be recorded at baseline. Non-target lesions will be grouped by organ. 
Measurements of these lesions are not required, but the presence or absence of 
each must be noted throughout follow-up. 
Disease assessment modalities may include imaging (e.g., CT scan, MRI, bone scan) and 
physical examination (as indicated for palpable/superficial lesions). 
At each post-baseline assessment, evaluation of the sites of disease (all target and 
non-target lesions) identified by the baseline scans is required. CT scans with contrast of 
the chest, abdomen and pelvis, or if contra-indicated (more details will be available in the 


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SRM/imaging manual), MRI, is required at each post-baseline assessment. To ensure 
comparability between the baseline and subsequent assessments, the same method of 
assessment and the same technique will be used when assessing response. 
Refer to Table 1 for the frequency of disease assessment. Assessments must be performed 
on a calendar schedule and should not be affected by dose interruptions/delays. 
Participants whose disease responds (either CR or PR) should have a confirmatory 
disease assessment performed at least 4 weeks after the date of assessment during which 
the response was demonstrated. More frequent disease assessments may be performed at 
the discretion of the investigator. 
If study treatment is resumed upon disease progression and following consultation with 
the investigator and GSK medical monitor, imaging scans which indicated progression 
will serve as the baseline scans. Representative new lesions, if measurable, may be 
incorporated into the evaluation of disease burden.  
The foreseen treatment duration is until disease progression verified by a scan subsequent 
to the initial documentation of PD, unacceptable toxicity, or any criterion for withdrawal 
from the trial or study intervention occurs (see Section 7.1.1).  
8.4. 
Safety Assessments 
Planned time points for all safety assessments are provided in Table 1. 
8.4.1. 
Physical Examinations 
• A complete physical examination performed at Screening will include, at a 
minimum, assessment of the cardiovascular, respiratory, gastrointestinal, and 
neurological systems. 
• A brief physical examination performed at each subsequent visit will include, at a 
minimum, assessments of the skin, lungs, cardiovascular system, and abdomen 
(liver and spleen), and infusion site reaction assessments. 
• Skin assessments are performed at Baseline and every 6 weeks for all participants. 
A detailed medical history of genetic or iatrogenic dermatologic conditions, skin 
type, geographical location, occupational or environmental exposure to radiation 
or chemicals will be queried. For participants experiencing a dermatologic-related 
AE (hyperkeratosis, KA, or cSCC), initial biopsy with pathology report of initial 
AE is expected. Additional excisional biopsies of suspicious lesions should occur, 
and management discussed with the medical monitor as indicated. Dermatology 
consultation is encouraged for diagnosis, outcome and follow-up. Skin biopsy 
pathology testing is performed locally.  
• Investigators should pay special attention to clinical signs related to previous 
serious illnesses. 
• Abnormal findings are to be reassessed at subsequent visits. 


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8.4.2. 
ECOG Performance Status 
Performance status will be assessed using the ECOG scale at each visit; refer to 
Appendix 10. 
8.4.3. 
Vital Signs 
• Vital signs will be measured after 5 minutes of rest in a semi-recumbent or 
supine position, and will include temperature, systolic and diastolic blood 
pressure, pulse rate, and oxygen saturation (measured by pulse oximetry). Blood 
pressure should be taken in the same position throughout the study and captured 
in the eCRF. 
• Vital signs will be measured more frequently if warranted by clinical condition 
of the participant. 
• Height will be recorded at Screening only. 
• Weight will be measured and recorded (in kilograms) at baseline and at every 
treatment visit. 
8.4.4. 
Electrocardiograms 
A single 12-lead ECG will be obtained as outlined in Table 1 using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
8.4.5. 
Clinical Safety Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to Table 1 
for the timing and frequency. 
• 
The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition. 
• 
All laboratory tests with values considered clinically significantly abnormal and 
related to study intervention during participation in the study or within 28 days 
after the last dose of study intervention should be repeated until the values return 
to normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 
• 
If such values do not return to normal/baseline within a period judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
• 
Urine or serum pregnancy test according to local standards. Refer to Table 1, 
and Table 6. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2 must be 
conducted in accordance with the laboratory manual and Table 1. 


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8.5. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain 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 (see Section 7). 
8.5.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
All SAEs will be collected from the signing of the ICF at the time points specified in the 
Table 1. Any SAEs assessed as related to study participation (e.g., study intervention, 
protocol-mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product will be recorded from the time a participant consents to participate in the 
study. 
All AEs will be collected from the signing of the ICF at the time points specified in 
Table 1. Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the case report form (CRF) not the AE section. 
• 
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 
Appendix 3. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
• 
Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor. 
8.5.2. 
Collection of Safety Information After Data Cut-off 
After the DCO for the final analysis, in alignment with Section 6.10, participants still 
deriving benefit will continue to receive bintrafusp alfa. For these participants, GSK will 
continue to collect safety information, including SAEs, AEs leading to treatment/study 
discontinuation, overdoses, and pregnancy cases via paper forms (refer to the SRM) that 
will be submitted directly to GSK per defined time frames as follows: 
• 
SAEs, AEs leading to treatment/study discontinuation, overdoses, and pregnancy 
cases will be reported until 35 days (5 half-lives) after last dose or the start of 
subsequent anti-cancer therapy, whichever comes first. 
• 
An SAE will be followed until resolution unless the event is considered by the 
investigator to be unlikely to resolve, or the patient is lost to follow-up. 


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Reporting of these events (SAEs, AEs leading to discontinuation of study intervention, 
overdoses, and pregnancies) will continue to be in accordance with the protocol. The 
sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the time of the DCO date for the final analyses, if judged 
necessary. 
8.5.3. 
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, including after 
DCO date, are provided in Appendix 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 AE occurrence.  
8.5.4. 
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 nonserious AEs of 
interest (as defined in Section 6.8) will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3. 
8.5.5. 
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, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators. 
• 
For all studies except those utilizing medical devices 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 IB and will notify the 
IRB/IEC, if appropriate according to local requirements. 
8.5.6. 
Pregnancy 
• 
Details of all pregnancies in female participants will be collected after the start 
of study intervention and until 2 months after the last dose of bintrafusp alfa. 


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• 
If a pregnancy is reported, the investigator should inform GSK within 24 hours 
of learning of the pregnancy and should follow the procedures outlined in 
Appendix 4. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAE. 
8.5.7. 
Cardiovascular and Death Events 
For any cardiovascular events detailed in Appendix 3 and all deaths, whether they are 
considered SAEs, must be recorded in the CRF within one week of occurrence. 
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. 
8.5.8. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE. 
Death due to disease under study is to be recorded on the death eCRF form. 
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the participant, or if the investigator considers that there was a 
causal relationship between treatment with study treatment(s) or protocol 
design/procedures and the disease progression, then this must be reported as an SAE. 
NOTE: If either of the following conditions apply, then the event must be recorded and 
reported as a SAE (instead of a disease-related event): 
• The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or 
• The investigator considers that there is a reasonable possibility that the event was 
related to treatment with study treatment(s). 
8.6. 
Participant Specific Dose Adjustments Criteria 
Dose reductions for bintrafusp alfa are not permitted while participant is being treated 
on-study, except as described in Section 6.8. Dosing may be held in the event of an AE 
that is deemed related to treatment. If 3 or more consecutive doses are held, the 
investigator must discuss the case with the GSK medical monitor to confirm that further 
treatment with bintrafusp alfa may benefit the participant. 


T M F -1 4 3 9 6 6 2 5  
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2 1 3 1 5 2  
 
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6 9  
 
8. 7.  
Tr e at m e nt  of O v er d o s e  
F or t his st u d y, a n y d ose of bi ntraf us p alf a g reater t ha n 2 ti mes m ore (ie, >2 4 0 0  m g) t ha n 
t he pla n ne d d ose a d mi nistere d wit hi n a 2 4-h o ur ti me peri o d will  be c o nsi d ere d a n 
o ver d ose . T his is base d o n d ose -escalati o n st u d y d ata i n w hic h partici p a nts safel y 
recei v e d u p t o 3 0 m g/ k g bi ntraf us p alfa Q 2 W (i ncl u di n g wit h d oses > 2 4 0 0  m g) wit h n o 
o bser ve d ma xi m u m t olerate d d oses  (refer t o t he I B). Safet y at si g nifi ca ntl y hi g her d oses 
has  n ot bee n cli nicall y e v al uate d.  
I n case of o ver d os e wit h cli nical c orrelati o n, s y m pt o matic treat me nt m ust be use d; t here 
are n o k no w n a nti d otes f or t he c o m p o u n d.  
I n e ve nt of o v er d ose, i nf usi o n s h o ul d be disc o nti n ue d,  a n d partici p a nts s h o ul d be 
o bser ve d cl os el y f or a n y si g ns of t o xicit y . S u p p orti ve treat me nt s h o ul d be pr o vi de d if 
cli nicall y i n dicat e d . If a n A E occ urs res ulti n g fr o m o ver d ose, it s h o ul d f oll o w S A E 
re p orti n g criteria as i n dicate d i n A p pe n di x 3 . 
If a n i nci de n ce of o ver d ose occ urs meeti n g t h e pr ot oc ol-defi ne d d efi niti o n wit h o ut a n y 
ass ociati o n of s y m pt o ms or la b orat or y a b n or malities, t he n it m ust be tra ns mitte d b y t he 
sa me pr ocess s pecifie d f or S A E re p orti n g i n A p pe n di x 3 , secti o n o n Re p orti n g Seri o us 
A d verse E v e nts, usi n g t h e ter mi n ol o g y ”acci de ntal or i nte nti o nal o ver d ose” wit h o ut 
a d verse effects.  
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 0  
 
C CI
C CI
C CI
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 1  
 
8. 1 1. 2.  
T u m or Ti s s u e  
St u d y p artici pa nts are re q uire d, as des cri be d i n eli gi bilit y criteria, t o pr o vi de a fres h 
t u m or bi o ps y a n d a n arc hi val t u m or tiss ue sa m ple.  
Arc hi val tiss ue will be s u b mitte d t o a ce ntral la b orat or y f or e x pressi o n of P D -L 1 at t he 
ti me of scree ni n g. A n al yses will be perf or me d retr os pecti vel y.  Ot her bi o m ar kers ma y b e 
e val uate d as deter mi ne d b y a d diti o nal researc h a n d data . Details f or s a m ple c ollecti o n, 
st ora ge, a n d s hi p me nt will be pr o vi de d i n t he S R M . 
8. 1 1. 3.  
St o ol C oll e cti o n f or Mi cr o bi o m e A n al y si s  
St o ol s peci me ns offer accessi bl e mea ns of e val uati n g t he g ut micr o bial c o m m u nit y . 
Ass ociati o n of t he st o ol micr o bi o me c o m p ositi o n wit h p h ysi ol o gical a n d me dical 
c o n diti o ns a n d res p o nse t o treat me nts has bee n re p orte d f or n u mer o us i n dicati o ns . T he 
relati o ns hi p bet wee n a nti bi otic/ pr o bi otic use pri or t o treat me nt a n d a ntit u m or acti vit y 
ma y als o be e val u ate d.  R efer t o T a ble  1  f or t h e sc he d ule.  
C CI
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 2  
 
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 3  
 
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 4  
 
8. 1 3.  
H e alt h E c o n o mi c s  
Healt h Ec o n o mics/ Me dic al Res o urce Utilizati o n a n d Healt h Ec o n o mics para meters are 
n ot e val uate d i n t his st u d y.  
C CI


T M F -1 4 3 9 6 6 2 5  
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2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 5  
 
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
As of Pr ot oc ol A me n d me nt 0 2, t he i nteri m a n al ysis descri be d herei n will n o l o n ger 
be c o n d ucte d.   
T he fi nal a n al ysis will i ncl u de all data c ollecte d t hr o u g h t he D C O date . A n a b bre viate d 
re p orti n g (t o i ncl u de o nl y t he pri mar y a n d sec o n d ar y e n d p oi nts i n Secti o n 3 ) of t he data 
will be  perf or me d a n d a d diti o nal details will be  descri be d i n t he R A P . 
9. 1.  
St ati sti c al H y p ot h e s e s  
T he pri mar y e n d p oi nt of t he st u d y is t he o bjecti ve res p o nse acc or di n g t o R E CI S T 1. 1, 
base d o n t he t u m or assess me nt res ults fr o m i n vesti gat or.  
9. 2.  
S a m pl e Si z e D et er mi n ati o n  
A t otal of 2 5  partici pa nts wil l recei ve bi ntraf us p alfa . 
9. 3.  
P o p ul ati o n s f or A n al y s e s  
T he  f oll o wi n g p o p ul ati o ns are defi ne d: 
P o p ul ati o n  
Descri pti o n  
Scree ne d  
All partici pa nts w h o si g n t he I C F . 
Safet y/ Treat e d  
All partici pa nts w h o were a d mi nistere d at least 1 i nf usi o n 
of bi ntraf us p alf a. T his is t he pri mar y a n al ysis  p o p ulati o n 
f or re p orti n g efficac y a n d safet y.  
C CI
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 6  
 
9. 4.  
St ati sti c al A n al y s e s  
T he R A P  f or pri mar y a nal ysis re p orti n g will be fi n alize d pri or t o database l oc k a n d it will 
i ncl u de a m ore te c h nical a n d detaile d des cri pti o n of t he statistical a nal yses descri be d i n 
t his secti o n. T his secti o n is a s u m mar y of t he pla n ne d statistical a nal yses of t he m ost 
i m p orta nt e n d p oi nts, i ncl u di n g pri mar y a n d ke y sec o n dar y e n d p oi nts. 
9. 4. 1.  
G e n er al C o n si d er ati o n s  
I n ge neral, c o nti n u o us varia bles will be s u m marize d usi n g n u m ber ( n), mea n, me dia n, 
sta n dar d de viati o n, mi ni m u m, a n d ma xi m u m. Cate g orical varia bles will be s u m marize d 
usi n g fre q ue n c y c o u nts a n d per ce nt a ges.  Pr o p orti o ns are calc ulate d base d o n t he n u m ber 
of partici pa nts i n t he a n al ysis set of i nterest.  
9. 4. 2.  
Pri m ar y  E n d p oi nt  
T he pri mar y effic ac y e n d p oi nt  is o bjecti ve res p o nse b y t h e i n vesti gat or assess me nt ,
T he pri mar y effic ac y e n d p oi nt  will be a nal yze d  base d o n t he Safet y/ Treate d p o p ulati o n 
u nless ot her wise s pecifie d.  
T he O R R is defi ne d as t h e perce nta ge ( %) of parti ci pa nts wit h a P R or C R as assesse d b y 
i n vesti gat or usi n g R E CI S T 1. 1. T he c orres p o n di n g 9 5 % CI f or O R R will als o be 
calc ulate d usi n g t he Cl o p per -Pears o n (e x act) met h o d.  
C CI
C CI
C CI
C CI
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 7  
 
9. 4. 3.  
S e c o n d ar y E n d p oi nt s  
T he sec o n d ar y e n d p oi nts will be a nal yze d  b ase d o n t he Safet y/ Treate d p o p ulati o n u nless 
ot her wise s pecifie d.  
E n d p oi nts  
Ke y St atistic al A n al ysis / Re p orti n g  
Fre q ue nc y a n d 
se verit y of A Es 
T he n u m ber a n d perce nt of partici pa nts wit h A Es will be s u m marize d.  
 
C CI
C CI
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
7 8  
 
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
7 9  
 
9. 4. 5.  
Ot h er S af et y A n al y s e s  
All safet y a nal yses will be  perf or me d  o n t he Safet y / Treate d p o p ulati o n.  
Safet y e n d p oi nts i ncl u de A Es, A Es  of Interest , cli nical la b orat or y assess me nts, vital 
si g ns, p h ysical e x a mi nati o n, a n d E C O G P S.  
T E A Es are t h os e e ve nts wit h o nset dates occ urri n g d uri n g t he o n -treat me nt peri o d or if 
t he w orse ni n g of a n e ve nt is d uri n g t he o n-tr eat me nt peri o d. 
A d diti o nal a nal ys es of A Es (e. g., A Es of I nterest, Se verit y, Rel ati o ns hi p t o St u d y  
I nter ve nti o n) a n d ot h er S afet y E n d p oi nts will be descri be d i n m ore d etails i n t he R A P. 
All safet y a nal yses will be ma de o n t he Safet y P o p ulati o n . 
C CI
C CI
C CI


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
 
8 0  
 
C CI


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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
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, IB, 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 
10.1.2. 
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. 


T M F -1 4 3 9 6 6 2 5  
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8 2  
 
•  
T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was 
o btai ne d bef ore t he partici pa nt was e nr olle d i n t he s t u d y a n d t he date t he writte n 
c o nse nt was o btai ne d . T h e a ut h orize d pers o n o btai ni n g t he i nf or m e d c o nse nt 
m ust als o si g n t he I C F.  
•  
Partici pa nts m ust be re -c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) 
d uri n g t heir p artici pati o n i n t he st u d y.  
•  
A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt’s 
le gall y a ut h orize d re pres e ntati ve.  
1 0. 1. 3.  
D at a Pr ot e cti o n  
•  
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or . A n y partici pa nt 
rec or ds or datasets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de ntifier 
o nl y; partici pa nt n a mes or a n y i nf or mati o n w hic h w o ul d ma ke t he partici p a nt 
i de ntifia ble will n ot be tra nsferre d.  
•  
T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d d ata will be 
use d b y t h e s p o ns or i n acc or da nce wit h l ocal dat a pr otecti o n la w . T he l e vel of 
discl os ure m ust als o be e x plai ne d t o t he partici pa nt  w h o will be re q uire d t o gi ve 
c o nse nt f or t heir d ata t o be use d as des cri be d i n t he i nf or me d c o ns e nt .  
•  
T he partici pa nt m ust be i nf or me d t hat his/ her me dica l rec or ds ma y be e x a mi ne d 
b y Cli nical Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d 
b y t he s p o ns or, b y a p pr o priate I R B/I E C me m b ers, a n d b y i ns p ect ors fr o m 
re g ulat or y a ut h orities. 
1 0. 1. 4.  
Di s s e mi n ati o n of Cli ni c al St u d y D at a  
•  
W here re q uir e d b y a p plica ble re g ulat or y re q uir e m e nts, a n i n vesti gat or si g n at or y 
will be i de ntifie d f or t he a p pr o val of t he cli nical st u d y re p ort.  T he i n vesti gat or 
will be pr o vi de d reas o na ble access t o statistical ta bles, fi g ures, a n d rele va nt 
re p orts a n d will ha ve t h e o p p ort u nit y t o re vie w t he c o m plete st u d y res ults at a 
G S K site or ot her m ut uall y -a greea ble l ocati o n.  
•  
G S K will als o pr o vi de t he i n vesti gat or wit h t he f ull s u m mar y of t he st u d y 
res ults. T he i n vesti gat or is e nc o ura ge d t o s hare t he s u m mar y res ults wit h t he 
st u d y pa rtici p a nts, as a p pr o priate. 
•  
T he pr oce d ures a n d ti mi n g f or p u blic discl os ure of t he pr ot oc ol a n d res ults 
s u m mar y a n d f or de vel o p me nt of a ma n uscri pt f or p u blicati o n f or t his st u d y will 
be i n acc or da nce wit h G S K P olic y.  
•  
G S K i nte n ds t o ma ke a n o n y mize d patie nt -le vel d ata fr o m t his trial a vaila ble t o 
e xter nal researc h ers f or s cie ntific a nal yses or t o c o n d uct f urt her researc h t h at 
ca n hel p a d v a nce me dical scie nce or i m pr o ve pati e nt care . T his hel ps e ns ure t he 
data pr o vi de d b y trial p artici pa nts are use d t o ma xi m u m effect i n t he creati o n of 
k n o wle d ge a n d u n d ersta n di n g  
•  
A ma n uscri pt will be pr o gresse d f or p u blicati o n i n 
literat ur e if t he 
res ults pr o vi de i m p orta nt scie ntific or me dical k n o wle d ge. 
C CI


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10.1.5. 
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 
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 25 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.  
10.1.6. 
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. 


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• 
Definition of what constitutes source data can be found in the SRM and 
Monitoring Plan. 
10.1.7. 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
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 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified 
by the applicable regulatory requirements. The investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up 
10.1.8. 
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 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. 


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10.2. 
Appendix 2: Clinical Laboratory Tests 
• 
The tests detailed in Table 6 will be performed by the local laboratory unless 
otherwise specified. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
• 
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 Section 5.1 Inclusion Criteria for screening pregnancy criteria. 
• 
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention. Refer to Table 1 for the 
schedule. 
• 
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure plus an additional 28 days 
and correspond with the time frame for female participant contraception in 
Section 5.1, Inclusion Criteria. 
• 
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure. 
• 
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 6 
Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments1 
Parameters 
All parameters are performed locally 
Hematology5 
• Platelet Count  
• RBC Count 
• Hemoglobin 
• Hematocrit 
• %Reticulocytes 
• Absolute 
lymphocyte 
count 
• Absolute 
neutrophil 
count 
• RBC 
Indices: 
• MCV 
• MCHC 
• RDW 
• aPTT 
• Prothrombin 
time 
• aINR 
WBC count with Differential: 
• Neutrophils (ANC) 
• Lymphocytes 
• Monocytes 
• Eosinophils 
• Basophils 
Clinical 
Chemistry  
Panel5 
• Blood Urea 
Nitrogen/total 
urea 
• Creatinine 
• Glucose 
• Lipase 
• C-reactive 
protein 
• Potassium 
• Sodium 
• Calcium 
• Chloride 
• Amylase 
• Aspartate 
Aminotransferase2 
(AST) 
• Alanine 
Aminotransferase 
(ALT) 2 
• Alkaline 
phosphatase2 
• Albumin2 
• Bilirubin (total 
indirect/direct2) 
• Total Protein2 
• GGT2 
 
 
Routine 
Urinalysis3 
• Specific gravity, physical appearance, color 
• pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase, by dipstick 
• Microscopic examination (if blood or protein is abnormal) 
Thyroid Panel 
• Free T4, TSH 


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Laboratory 
Assessments1 
Parameters 
All parameters are performed locally 
Other 
Screening 
Tests 
• Follicle-stimulating hormone and estradiol (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)4 
• Hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody. 
• TST, QuantiFERON-TB-Gold, or T-SPOT (if positive history of tuberculosis 
exposure)6 
The results of each test must be entered into the CRF. 
NOTES : ALT = alanine aminotransferase; ANC = absolute neutrophil count; aPTT = activated partial 
thromboplastin time; AST = aspartate aminotransferase; β-hCG = beta-human chorionic gonadotropin; 
BUN = blood urea nitrogen; CRP = C reactive protein; GGT = gamma-glutamyltransferase; HBV = hepatitis B 
virus; HCV = hepatitis C virus; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; 
MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood 
cell; RDW = red cell distribution width; T4 = free thyroxine; TSH = thyroid-stimulating hormone; 
TST = tuberculin skin test; WBC = white blood cell. 
1. Performed as indicated in Section 1.3 (Schedule of Activities). 
2. Details of liver chemistry stopping criteria and required actions and follow-up assessments after 
liver stopping or monitoring event are given in Section 7.1.2 and Section 10.6. All events of 
ALT 3 × upper limit of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or 
ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured, which may 
indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis). 
3. Routine urinalysis performed at Screening and as clinically indicated thereafter. 
4. Local urine or serum pregnancy testing, as required by local regulation or IRB/IEC. 
5. Chemistry and Hematology should be repeated if not performed within 24 hours of Day 1. 
6. Performed at Screening if positive history. Discuss with medical monitor if another test not listed is 
standard of care for your institution. 
 
 


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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
10.3.1. 
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 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. 
 
10.3.2. 
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 (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
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 or significant 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. 
 
10.3.3. 
Definition of Cardiovascular Events 
Cardiovascular Events (CV) Definition: 
Investigators will be required to record the CV in the CRF within one week of 
occurrence 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 
 
10.3.4. 
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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• 
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 assign it to 1 of the following categories:  
• 
Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AE and SAE can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined 
outcomes as described in the definition of an SAE, NOT when it is rated as severe. 
Other measures to evaluate AE and SAE may be utilized (e.g., NCI-CTCAE v5). 
 
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 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. 


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• 
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 
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. 
• 
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. 
 
10.3.5. 
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. 
• 
The investigator or medically-qualified sub-investigator must show evidence 
within the eCRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to IP/study participation (causality) within 
72 hours of SAE entry into the eCRF. 
• 
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 by telephone. 


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• 
Contacts for SAE reporting can be found in SRM. 
 
SAE and AEs Leading to Study Discontinuation Reporting to GSK via Paper CRF 
• 
If the electronic system is unavailable for greater than 24 hours, the site will use 
the paper SAE data collection tool and email to OAX37649@gsk.com or fax to 
+44 (0) 208 754 7822. Site will enter the SAE or AE data into the electronic 
system as soon as it becomes available unless paper SAEs and AEs leading to 
study discontinuation (where indicated) are being collected after DCO (below). 
• 
The paper SAE/AE data collection tool will also be utilized for SAE and AE 
(where indicated) reporting after the DCO for final analysis, at which time no 
entry into the eCRF will be required, as the clinical database will be closed. 
• 
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 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 SRM. 


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10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information 
10.4.1. 
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 
1. Premenarchal 
2. 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., Müllerian 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. 
3. 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 may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). 
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 
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10.4.2. 
Contraception Guidance 
Male participants 
• 
Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined 
time frame in Section 5.1.  
• Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent  
• Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 7 when having 
penile-vaginal intercourse with a woman of childbearing potential  
• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration for the duration of the study and for at least 120 days after the 
last dose of study treatment. 
Female participants 
Table 7 
Highly Effective Contraceptive Methods 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per 
year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• 
Intrauterine device (IUD)  
• 
Intrauterine hormone-releasing system (IUS)c 
• 
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 Methodsb That Are User Dependent Failure rate of <1% per year 
when used consistently and correctly. 


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Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationc 
• 
oral 
• 
intravaginal 
• 
transdermal 
• 
injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
oral 
• 
injectable 
Sexual abstinence 
• 
Note: Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
a. Contraceptive use by men or women should be consistent with local regulations regarding 
the use of contraceptive methods for those participating in clinical studies. 
b. Failure rate of <1% per year when used consistently and correctly. Typical use failure rates 
differ from those when used consistently and correctly. 
c. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the 
primary mode of action. 
Note: Periodic abstinence (calendar, sympto-thermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not 
acceptable methods of contraception. Male condom and female condom should not be used 
together (due to risk of failure with friction) 
Note: This contraceptive guidance will also apply to participants who continue to receive 
study intervention after the DCO date. 
10.4.3. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• 
Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to male participants who receive bintrafusp alfa. 
• 
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. 


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Female participants who become pregnant 
• 
Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study.  
• 
The initial 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 for medical reasons will be 
reported as an AE or SAE.  
• 
A spontaneous abortion (occurring at <22 weeks gestational age) or still birth 
(occurring at >22 weeks gestational age) 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 Appendix 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.  
Note: The collection of pregnancy information will also apply to participants who 
continue to receive study intervention after the DCO date until last visit. 


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10.6. 
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments  
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure participant safety and evaluate liver event etiology (in alignment with 
the FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf. 
Phase I/II Liver Chemistry Stopping Criteria and Required Follow up Assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event 
Including participants with documented liver metastases/tumor infiltration at baseline AND 
entry criteria ALT >2.5 x ULN but 5 x ULN 
ALT-absolute 
Both ALT 5 x ULN and 2 x baseline value 
ALT Increase 
Both ALT 3 x ULN and 1.5 x baseline value that persists for 4 weeks 
Bilirubin1, 2 
ALT 3 x ULN and bilirubin 2 x ULN (>35% direct bilirubin)  
INR2  
ALT 3 x ULN and INR >1.5, if INR measured 
Cannot Monitor 
Both ALT 3 x ULN and 1.5 x baseline value that cannot be monitored for 
4 weeks 
Symptomatic3 
Both ALT 3 x ULN and 1.5 x baseline value associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity 
Required Actions and Follow up Assessments following ANY Liver Stopping Event 
Actions 
Follow Up Assessments 
• 
Immediately discontinue study treatment  
• 
Report the event to GSK within 24 hours 
• 
Complete the CRF within one week of 
occurrence 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 
(see MONITORING below) 
• 
Do not restart/rechallenge participant  
• 
If restart/rechallenge not allowed per 
protocol or not granted, permanently 
• 
Viral hepatitis serology4 
• 
Obtain INR and recheck with each liver chemistry 
assessment until the transaminases values show 
downward trend. 
• 
Only in those with underlying chronic hepatitis B at 
study entry (identified by positive hepatitis B 
surface antigen) quantitative hepatitis B DNA and 
hepatitis delta antibody5.  
• 
Blood sample for pharmacokinetic (PK) analysis, 
obtained approximately 48hrs after last dose6 
• 
Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH). 
• 
Fractionate bilirubin, if total bilirubin2xULN 


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discontinue study treatment and may 
continue as a participant in the study for any 
protocol specified follow up assessments  
MONITORING: 
For bilirubin or INR criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs 
• 
Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• 
A specialist or hepatology consultation is 
recommended 
For All other criteria:  
• 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs  
• 
Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
• 
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 
• 
Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications 
• 
Record alcohol use in the SAE form if reported as 
an SAE  
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). 
• 
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution to 
liver injury in participants with definite or likely 
acetaminophen use in the preceding week [James, 
2009]. NOTE: not required in China  
• 
Liver imaging (ultrasound, magnetic resonance, or 
computerized tomography) and /or liver biopsy to 
evaluate liver disease. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT  3xULN and bilirubin  2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT 3 x ULN and bilirubin 2 x ULN (>35% direct bilirubin) or ALT 3 x ULN and INR >1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to 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 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  
5. PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM. 
 


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Phase I/II Oncology Liver Chemistry Increased Monitoring Criteria With 
Continued Therapy 
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event 
Criteria 
Actions 
Participant with entry criteria ALT 
2.5 x ULN 
ALT 3 x ULN but <5 x ULN and 
 bilirubin <2 x ULN, without symptoms 
believed to be related to liver injury or 
hypersensitivity and who can be monitored 
weekly for 4 weeks 
Participant with documented liver 
metastases/tumor infiltration at baseline 
AND entry criteria ALT>2.5 x ULN but 5 x 
ULN 
ALT 3 x ULN and 1.5 x baseline value but 
ALT <5 x ULN and 2 x baseline value and 
bilirubin <2 x ULN, without symptoms believed 
to be related to liver injury, or hypersensitivity 
and who can be monitored weekly for 4 weeks 
• 
Notify the GSK medical monitor within 24 hours 
of learning of the abnormality to discuss 
participant safety.  
• 
Participant must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to 
within baseline  
• 
If at any time participant meets the liver chemistry 
stopping criteria, proceed as described above 
For participants with entry criteria ALT 2.5 x ULN 
• 
If, after 4 weeks of monitoring, ALT <3 x ULN and 
bilirubin <2 x ULN, monitor participants twice 
monthly until liver chemistries normalize or return 
to within baseline. 
For participants with documented liver 
metastases/tumor infiltration at baseline AND entry 
criteria ALT >2.5 x ULN but 5 x ULN 
• 
If, after 4 weeks of monitoring, ALT <3 x ULN and 
<1.5 x baseline value, and bilirubin <2 x ULN, 
monitor participants twice monthly until liver 
chemistries normalize or return to within baseline 
Reference: 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of 
Acetaminophen-Adduct in Adults with Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 
2009;37:1779-1784. 


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10.7. 
Appendix 7: Country-specific requirements 
There are no country specific requirements.  


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1 0. 8.  
A p p e n di x 8 : A b br e vi ati o n s a n d Tr a d e m ar k s 
A b br e vi ati o n s  
A D R  
A d verse Dr u g Reacti o n  
A E  
A d verse E v e nt  
A L T  
Ala ni ne A mi n otra nsferas e  
A N C  
A bs ol ute Ne utr o p hil C o u nt  
A S T  
As partate A mi n otra nsferase  
A S C O  
T he A merica n S ociet y of Cli nical O nc ol o g y  
-h C G  
Beta -h u ma n C h ori o nic G o na d otr o pi n  
CI  
C o nfi de nce I nter val  
C N S  
Ce ntral Ner v o us S yste m  
C R  
C o m plete Res p o nse  
Cr Cl  
Creati ni ne Cleara nce  
C R P  
C Reacti ve Pr otei n  
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 L A -4  
C yt ot o xic T -L y m p h oc yte -Ass ociate d Pr otei n 4  
c S C C 
c uta ne o us S q ua m o us -cell C arci n o ma  
C V  
Car di o vasc ular  
D C O  
Data C ut -o ff 
E C H O  
Ec h ocar di o gra m  
E CI  
E ve nts of Cli nical I nt erest 
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 Cas e Re p ort F or m  
E U  
E ur o pea n U ni o n  
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 TI H  
First -Ti me -i n-H u m a n  
GI  
Gastr oi ntesti nal  
G S K  
Gla x o S mit h Kli ne  
H g b  
He m o gl o bi n  
H R T  
H or m o ne Re place me nt T hera p y  
H y p ot hesis  
H  
I B 
I n v esti gat or’s Br oc h ure 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil o n Har m o nizati o n of Tec h ni cal 
Re q uire me nts f or Re gistrati o n of P har mace uticals f or 
H u ma n Use  
C CI
C CI
C CI
C CI
C CI
C CI


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I E C 
I n d e pe n de nt Et hics C o m mittees 
I g 
I m m u n o gl o b uli n 
I L 
I nterle u ki n 
I N R 
I nter nati o nal N or m alize d Rati o 
ir A E 
I m m u ne-relat e d A d verse E ve nt 
I R B 
I nstit uti o nal Re vie w B oar d  
I R R 
I nf usi o n-relat e d Reacti o n 
I V 
I ntr a ve n o us 
K A  
Kerat oaca nt h o ma  
k g  
Kil o gra m(s)  
L V E F  
Left Ve ntric ul ar Ejecti o n Fracti o n  
m A b  
M o n ocl o nal A nti b o d y  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
MI B C  
M uscle -I n vasi v e Bla d der Ca ncer 
g  
Micr o gra m(s)  
m g  
Milli gra m(s)  
m L  
Milliliter(s)  
M RI  
Ma g n etic Res o na nce I ma gi n g  
M S D S  
Material Safet y Data S heet  
M S E C  
Millisec o n d(s)  
M U G A  
M ulti gate d Ac q uisiti o n Sca n  
N CI -C T C A E  v 5  
Nati o nal Ca ncer I nstit ute - C o m m o n Ter mi n ol o g y  Criteria 
f or A d verse E ve nts, versi o n 5 
O R R  
O verall Res p o nse Rate  
P D  
Pr o gressi ve Diseas e  
P D -1  
Pr o gra m me d Deat h  1  
P D -L 1  
Pr o gra m me d Deat h -Li ga n d 1  
P R  
Partial Res p o nse  
P S  
Perf or ma nce Stat us  
P V  
P har mac o vi gila nce  
Q 2 W  
E ver y 2 Wee ks  
Q 3 W  
E ver y 3 Wee ks  
Q 6 W  
E ver y 6 Wee ks  
Q 1 2 W  
E ver y 1 2 Wee ks  
Q Tc  
Q T i nter val d urati o n c orrecte d  
Q Tc F  
Q T i nter val d urati o n c orrecte d b y Fre d ericia f or m ula  
R A P  
Re p orti n g a n d A nal ysis P la n 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
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RP2D 
Recommended Phase 2 Dose 
SCC 
Squamous-cell Carcinoma  
SD 
Stable Disease 
SoA 
Schedule of Activities 
SRM 
Study Reference Manual 
TCR 
T Cell Receptor 
TGF-β 
Transforming Growth Factor β 
TEAE 
Treatment Emergent Adverse Event 
TNF 
Tumor Necrosis Factor, alpha 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States 
WOCBP 
Woman of Childbearing Potential 
 
Trademark Information 
Trademarks of the GlaxoSmithKline 
group of companies 
 
Trademarks not owned by the 
GlaxoSmithKline group of companies 
NONE 
 
Bavencio 
 


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10.9. 
Appendix 9: The Recommendations for irAE Management, in 
Accordance with the Joint American Society of Clinical 
Oncology Clinical Practice Guidelines and National 
Comprehensive Cancer Network 
Adapted from: 
Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor 
Therapy: American Society of Clinical Oncology Clinical Practice Guideline [Brahmer, 2018]. 
 
Table of Tables 
Table A1 
Management of Skin irAEs in Patients Treated With ICPis ................... 107 
Table A2 
Management of GI irAEs in Patients Treated With ICPis ...................... 113 
Table A3 
Management of Lung irAEs in Patients Treated with ICPis ................... 118 
Table A4 
Management of Endocrine irAEs in Patients Treated with ICPis ........... 120 
Table A5 
Management of Musculoskeletal irAEs in Patients Treated With 
ICPis .................................................................................................... 126 
Table A6 
Management of Renal irAEs in Patients Treated With ICPis ................ 130 
Table A7 
Management of Nervous System irAEs in Patients Treated With 
ICPis .................................................................................................... 132 
Table A8 
Management of Hematologic irAEs in Patients Treated With 
ICPis .................................................................................................... 138 
Table A9 
Management of Cardiovascular irAEs in Patients Treated With 
ICPis .................................................................................................... 145 
Table A10 
Management of Ocular irAEs in Patients Treated With ICPis ............... 148 
 


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Table A1 
Management of Skin irAEs in Patients Treated With ICPis 
1.0 Skin Toxicities 
1.1 Rash/inﬂammatory dermatitis 
Deﬁnition: Erythema multiforme minor (a targetoid reaction in the skin and mucous membranes usually 
triggered by infections, such as herpes simplex viruses, but can be associated with an immune-related 
drug eruption and if progresses to erythema multiforme major, it and can be a harbinger of SCAR, such 
as SJS), lichenoid (resembling the ﬂat-topped, polygonal, and sometimes scaly or hypertrophic lesions of 
lichen-planus), eczematous (inﬂammatory dermatitis characterized by pruritic, erythematous, scaly, or 
crusted papules or plaques on the skin, which is vulnerable to superinfection, psoriasiform [resembling 
the well-demarcated, erythematous, and scaly papules and plaques of psoriasis], morbilliform [a 
nonpustular, nonbullous measles-like exanthematous rash of the skin often referred to as 
“maculopapular” and without systemic symptoms or laboratory abnormalities, excluding occasional 
isolated peripheral eosinophilia, palmoplantar erythrodysesthesia [hand-foot syndrome; redness, 
numbness, burning, itching, and superﬁcial desquamation of the palms and soles], neutrophilic 
dermatoses [eg, Sweet syndrome], and others) 
Diagnostic work-up 
 
Pertinent history and physical examination 
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin 
condition linked to another systemic disease or unrelated primary skin disorder 
If needed, a biologic checkup, including a blood cell count and liver and kidney tests 
Directed serologic studies if an autoimmune condition is suspected, such as lupus or dermatomyositis: a 
screening antinuclear antibody test, SS-A/Anti-Ro, SS-B/Anti-La if predominantly 
photodistributed/photosensitivity, antihistone, double-stranded DNA, and other relevant serologies. 
Consider expanding serologic studies or diagnostic work-up if other autoimmune conditions are 
considered based on signs, symptoms Skin biopsy 
Consider clinical monitoring with use of serial clinical photography 
Review full list of patient medications to rule out other drug-induced cause for photosensitivity 
Grading 
Management 
Grading according to CTCAE is a challenge for 
skin. Instead, severity may be based on BSA, 
tolerability, morbidity, and duration. 
 
G1: Symptoms do not affect the quality of life or 
controlled with topical regimen and/or oral 
antipruritic 
Continue ICPi 
Treat with topical emollients and/or mild-moderate 
potency topical corticosteroids 
Counsel patients to avoid skin irritants and sun 
exposure 
G2: Inﬂammatory reaction that affects quality of 
life and requires intervention based on diagnosis 
Consider holding ICPi and monitor weekly for 
improvement. If not resolved, interrupt treatment 
until skin AE has reverted to Grade 1 
Consider initiating prednisone (or equivalent) at 
dosing 1 mg/kg, tapering over at least 4 weeks 
In addition, treat with topical emollients, oral 
antihistamines, and medium- to high-potency 
topical corticosteroids 
G3: As G2 but with failure to respond to indicated 
interventions for a G 2 dermatitis 
Hold ICPi therapy and consult with dermatology to 
determine appropriateness of resuming 
Treat with topical emollients, oral antihistamines, 
and high-potency topical corticosteroids 
Initiate (methyl)prednisolone (or equivalent) 1-2 
mg/kg, tapering over at least 4 weeks 


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1.0 Skin Toxicities 
G4: All severe rashes unmanageable with prior 
interventions and intolerable 
Immediately hold ICPi and consult dermatology to 
determine appropriateness of resuming ICPi 
therapy upon resolution of skin toxicity and once 
corticosteroids are reduced to prednisone (or 
equivalent) 10 mg 
Systemic corticosteroids: IV (methyl)prednisolone 
(or equivalent) dosed at 1-2 mg/kg with slow 
tapering when the toxicity resolves 
Monitor closely for progression to severe 
cutaneous adverse reaction 
Should admit patient immediately with direct 
oncology involvement and with an urgent consult 
by dermatology 
Consider alternative antineoplastic therapy over 
resuming ICPis if the skin irAE does not resolve to 
G1 or less; if ICPIs are the patient’s only option, 
consider restarting once these adverse effects have 
resolved to a G1 level 
1.2 Bullous dermatoses 
Deﬁnition: Including bullous pemphigoid or other autoimmune bullous dermatoses, bullous drug 
reaction 
Diagnostic work-up 
Physical examination 
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin 
condition linked to another systemic disease 
If needed, a biologic check-up, including a blood cell count, liver, and kidney tests; consider serum 
antibody tests to rule out bullous pemphigoid or, under the guidance of dermatology, sending patient 
serum for indirect immunoﬂuorescent testing to rule out other autoimmune blistering diseases 
Referral to dermatology for blisters that are not explained by infectious or transient other causes (eg, 
herpes simplex, herpes zoster, bullous impetigo, bullous insect bite, friction or pressure blister) 
Consider skin biopsy (both hematoxylin and eosin evaluation of lesional skin and direct 
immunoﬂuorescence evaluation of perilesional skin) 
Grading 
Management 
G1: Asymptomatic, blisters covering <10% BSA 
and no associated erythema 
If blisters are <10% BSA, asymptomatic, and 
noninﬂammatory (such as the case with friction 
blisters or pressure blisters), cessation of ICPi is 
not necessary, and only observation and/or local 
wound care is warranted. 
When symptomatic bullae or erosions, which are 
deroofed vesicles or bullae, are observed on the 
skin or mucosal surfaces, the cutaneous irAE is by 
deﬁnition considered at least G2 
See G2 management recommendations 
G2: Blistering that affects quality of life and 
requires intervention based on diagnosis not 
meeting criteria for Grade >2 
Blisters covering 10%-30% BSA 
Hold ICPi therapy and consult with dermatology 
for work-up and to determine appropriateness of 
resuming 


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1.0 Skin Toxicities 
Attention given to general local wound care, which 
includes plain petrolatum ointment and bandages 
or plain petrolatum ointment gauze and bandage 
over any open erosions, which are left over on the 
skin after the blister has popped or if the roof of 
the blister easily sloughs off 
Counsel patients to avoid skin irritants and 
overexposure to sun, wear protective clothing, use 
sunscreens 
Work-up for autoimmune bullous disease as above 
Initiate Class 1 high-potency topical corticosteroid 
(eg, clobetasol, betamethasone or equivalent) and 
reassess every 3 days for progression or 
improvement 
Low threshold to initiate treatment with prednisone 
(or equivalent) at 0.5-1 mg/kg dosing and taper 
over at least 4 weeks 
Monitor patients with G2 irAEs closely for 
progression to involvement of greater BSA and/or 
mucous membrane involvement. Consider 
following patients closely using serial photography 
Primer on monitoring for complicated cutaneous 
adverse drug reactions: 
 
Review of systems: Skin pain (like a sunburn), 
fevers, malaise, myalgias, arthralgias, 
abdominal pain, ocular discomfort or 
photophobia, sores or discomfort in the nares, 
sores or discomfort in the oropharynx, 
odynophagia, hoarseness, dysuria, sores or 
discomfort in the vaginal area for women or 
involving the meatus of the penis for men, 
sores in the perianal area, or pain with bowel 
movements 
 
Physical examination: Include vital signs and a full 
skin examination speciﬁcally evaluating all 
skin surfaces and mucous membranes (eyes, 
nares, oropharynx, genitals, and perianal area). 
Assess for lymphadenopathy, facial or distal 
extremity swelling (may be signs of 
DIHS/DRESS). Assess for pustules or blisters 
or erosions in addition to areas of “dusky 
erythema,” which may feel painful to 
palpation. To assess for a positive Nikolsky 
sign, place a gloved ﬁnger tangentially over 
erythematous skin and apply friction parallel to 
the skin surface. Nikolsky sign is positive if 
this results in detached or sloughing epidermis 
demonstrating poor attachment of the 
epidermis to the dermis, which is the case in 
some autoimmune disorders (eg, pemphigus) 
and SJS/TEN 
G3: Skin sloughing covering >30% BSA with 
associated pain and limiting self-care ADL 
Hold ICPi therapy and consult with dermatology to 
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1.0 Skin Toxicities 
Administer IV (methyl)prednisolone (or 
equivalent) 1-2 mg/kg, tapering over at least 4 
weeks 
If bullous pemphigoid is diagnosed, it may be 
possible to avoid long-term use of systemic 
corticosteroids and treat with rituximab, as an 
alternative approach to treating the irAE 
Seek infectious disease consultation if patient 
might have secondary cellulitis or if patient has 
other infection risk factors, such as neutropenia, 
etc. 
G4: Blisters covering >30% BSA with associated 
ﬂuid or electrolyte abnormalities 
Permanently discontinue ICPi 
Admit patient immediately and place under 
supervision of a dermatologist 
Administer IV (methyl)prednisolone (or 
equivalent) 1-2 mg/kg with tapering over at least 4 
weeks when the toxicity resolves 
If bullous pemphigoid is diagnosed, it may be 
possible to avoid long-term use of systemic 
corticosteroids and treat with rituximab as an 
alternative approach to treating the irAE 
Seek infectious disease consultation if patient 
might have secondary cellulitis or if patient has 
other infection risk factors, such as neutropenia, 
etc 
1.3 SCARs, including SJS, TEN, acute generalized exanthematous pustulosis, and DRESS/DIHS 
Deﬁnition: Severe changes in either structure or functions of skin, the appendages or the mucous 
membranes due to a drug 
Diagnostic work-up 
Total body skin examination with attention to examining all mucous membranes as well as complete 
review of systems 
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin 
condition linked to another systemic disease 
A biologic checkup, including a CBC with differential test, and liver and kidney function tests, including 
urinalysis, in addition to the blood work; if the patient is febrile, blood cultures should be considered as 
well 
Skin biopsies to assess for full-thickness epidermal necrosis, as is seen in SJS/TEN, as well as other 
possible etiologies like paraneoplastic pemphigus or other autoimmune blistering dermatoses or other 
drug reactions, such as acute generalized exanthematous pusulosis 
Consider following patients closely using serial clinical photography 
If mucous membrane involvement or blistering is observed on the skin, consider early admission to a 
burn center for further monitoring and management Primer on monitoring for complicated cutaneous 
adverse drug reactions: 
Review of systems: Skin pain (like a sunburn), fevers, malaise, myalgias, arthralgias, abdominal pain, 
ocular discomfort or photophobia, sores or discomfort in the nares, sores or discomfort in the 
oropharynx, odynophagia, hoarseness, dysuria, sores or discomfort in the vaginal area for women or 
involving the meatus of the penis for men, sores in the perianal area, or pain with bowel movements 


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Physical examination: Include vital signs and a full skin examination speciﬁcally evaluating all skin 
surfaces and mucous membranes (eyes, nares, oropharynx, genitals, and perianal area). Assess for 
lymphadenopathy, facial or distal extremity swelling (may be signs of DIHS/DRESS). Assess for 
pustules or blisters or erosions in addition to areas of “dusky erythema,” which may feel painful to 
palpation. To assess for a positive Nikolsky sign, place a gloved ﬁnger tangentially over erythematous 
skin and apply friction parallel to the skin surface. Nikolsky sign is positive if this results in detached or 
sloughing epidermis demonstrating poor attachment of the epidermis to the dermis, which is the case in 
some autoimmune disorders (eg, pemphigus) and SJS/TEN 
Grading 
Management 
All Grades 
In cases of suspected SJS or any mucous 
membrane involvement, discontinue ICPi 
treatment and monitor closely for improvement, 
regardless of grade 
G1: NA 
For SCARs, there is no G1 category; if lower BSA 
is involved with bullae or erosions, there should 
remain a high concern that this reaction will 
progress to G3 or G4 
G2: Morbilliform (“maculopapular”) exanthem 
covering 10%-30% BSA with systemic symptoms, 
lymphadenopathy, or facial swelling 
Hold ICPi and monitor patients closely every 3 
days with G2 irAEs for progression to involvement 
of greater BSA and/or mucous membrane 
involvement 
Consider following patients closely using serial 
photography 
Initiate therapy with topical emollients, oral 
antihistamines, and medium- to high-strength 
topical corticosteroids 
Consider initiation of prednisone (or equivalent) 
0.5-1 mg/kg tapered over at least 4 weeks 
G3: Skin sloughing covering <10% BSA with 
mucosal involvement associated signs (eg, 
erythema, purpura, epidermal detachment, mucous 
membrane detachment) 
Hold ICPi therapy and consult with dermatology 
Treat skin with topical emollients and other 
petrolatum emollients, oral antihistamines, and 
high-strength topical corticosteroids; dimethicone 
may also be offered as an alternative to petrolatum 
Administer IV (methyl)prednisolone (or 
equivalent) 0.5-1 mg/kg and convert to oral 
corticosteroids on response, wean over at least 4 
weeks 
Admit to burn and/or consult wound services with 
attention to supportive care, including ﬂuid and 
electrolyte balance, minimizing insensible water 
losses, and preventing infection 
Given the immune mechanism of action of these 
medicines, use of immune suppression is 
warranted and should be offered 
For mucous membrane involvement of SJS or 
TEN, appropriate consulting services should be 
offered to guide management in preventing 
sequelae from scarring (eg, ophthalmology; ear, 
nose, and throat; urology; gynecology; etc, as 
appropriate) 


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G4: Skin erythema and blistering/sloughing 
covering 10% to >30% BSA with associated 
signs (eg, erythema, purpura, epidermal 
detachment, mucous membrane detachment) 
and/or systemic symptoms and concerning 
associated blood work abnormalities (eg, liver 
function test elevations in the setting of 
DRESS/DIHS) 
Permanently discontinue ICPi 
Admit patient immediately to a burn unit or ICU 
with consulted dermatology and wound care 
services 
Consider further consultations based on 
management of mucosal surfaces 
(eg, ophthalmology; urology; gynecology; ear, 
nose, and throat surgery; etc) Initiate IV 
(methyl)prednisolone (or equivalent) 1-2 mg/kg, 
tapering when toxicity resolves to normal 
IVIG or cyclosporine may also be considered in 
severe or corticosteroid-unresponsive cases 
Consider pain/palliative consultation and/or 
admission in patients presenting with DRESS 
manifestations 
Additional considerations: The usual prohibition of corticosteroids for SJS is not relevant here, as the 
underlying mechanism is a T-cell immunodirected toxicity 
Adequate suppression is necessary with corticosteroids or other agents and may be prolonged in cases of 
DRESS/DIHS 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate 
Abbreviations: ADL = activities of daily living; AE = adverse event; BSA = body surface area; CBC = complete blood 
count; CTCAE = Common Terminology Criteria for Adverse Events; DIHS = drug-induced hypersensitivity 
syndrome; DRESS = drug reaction with eosinophilia and systemic symptoms; G = Grade; ICPi = immune 
checkpoint inhibitor; ICU = intensive care unit; irAE = immune-related adverse event; IV = intravenous; 
IVIG = intravenous immunoglobulin; NA = not applicable; SCAR = severe cutaneous adverse reactions; 
SJS = Stevens-Johnson syndrome; TENS = toxic epidermal necrolysis. 
 


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Table A2 
Management of GI irAEs in Patients Treated With ICPis 
2.0 GI Toxicities 
2.1 Colitis 
Deﬁnition: A disorder characterized by inﬂammation of the colon 
Diagnostic work-up 
G2 
Work-up of blood (CBC, comprehensive metabolic panel, TSH, ESR, CRP), stool (culture, Clostridium 
difficile, parasite, CMV or other viral etiology, ova and parasite) should be performed 
Consider testing for lactoferrin (for patient stratiﬁcation to determine who needs more urgent 
endoscopy) and calprotectin (to follow-up on disease activity) 
Screening laboratories (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients to start 
inﬂiximab should be routinely done in patients at high risk for those infections and appropriately 
selected patients based on infectious disease expert’s evaluation 
Imaging (eg, CT scan of abdomen and pelvis and GI endoscopy with biopsy) should be considered as 
there is evidence showing that the presence of ulceration in the colon can predict a corticosteroid-
refractory course, which may require early inﬂiximab 
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating 
endoscopy for disease monitoring can be considered when clinically indicated and when planning to 
resume therapy 
G3-4 
All the work-up listed for G2 (blood, stool, imaging, and scope with biopsy) should be completed 
immediately 
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating 
endoscopy for disease monitoring should only be considered when clinically indicated and when 
planning to resume ICPi 
Grading (based on CTCAE for diarrhea, as most 
often used clinically) 
Management 
All patients 
Counsel all patients to be aware of and inform their 
health care provider immediately if they 
experience: 
Abdominal pain, nausea, cramping, blood or 
mucus in stool or changes in bowel habits, fever, 
abdominal distention, obstipation, constipation 
For G2 or higher, consider permanently 
discontinuing CTLA-4 agents and may restart PD-
1, PD-L1 agents if patient can recover to G1 or 
less; concurrent immunosuppressant maintenance 
therapy should be considered only if clinically 
indicated in individual cases 
G1: Increase of fewer than four stools per day 
over baseline; mild increase in ostomy output 
compared with baseline 
Continue ICPi; alternatively, ICPi may be held 
temporarily and resumed if toxicity does not 
exceed 
G1 
Monitor for dehydration and recommend dietary 
changes Facilitate expedited phone contact with 
patient/caregiver May obtain gastroenterology 
consult for prolonged G1 cases 
G2: Increase of four to six stools per day over 
baseline; moderate increase in ostomy output 
compared with baseline 
Should hold ICPi temporarily until patient’s 
symptoms recover to G1; can consider 
permanently 


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discontinuing CTLA-4 agents and may restart PD-
1, PD-L1 agents if patient can recover to G1 or less 
Concurrent immunosuppressant maintenance 
therapy (10 mg prednisone equivalent dose) may 
be offered only if clinically indicated in individual 
cases 
May also include supportive care with medications 
such as Imodium if infection has been ruled out 
Should consult with gastroenterology for G2 or 
higher 
Administer corticosteroids, unless diarrhea is 
transient, starting with initial dose of 1 mg/kg/day 
prednisone or equivalent 
When symptoms improve to G1 or less, taper 
corticosteroids over at least 4-6 weeks before 
resuming treatment, although resuming treatment 
while on low-dose corticosteroid may also be an 
option after an evaluation of the risks and beneﬁts 
EGD/colonoscopy, endoscopy evaluation should 
be highly recommended for cases Grade 2 to 
stratify patients for early treatment with inﬂiximab 
based on the endoscopic ﬁndings and to determine 
the safety of resuming PD-1, PD-L1 therapy 
Stool inﬂammatory markers can be considered 
(lactoferrin and calprotectin) in cases of G2 or 
higher to differentiate functional versus 
inﬂammatory diarrhea, and use calprotectin to 
monitor treatment response if provider prefers 
Repeat colonoscopy is optional for cases of G2 or 
higher for disease activity monitoring to achieve 
complete remission, especially if there is a plan to 
resume ICPi 
G3: Increase of seven or more stools per day over 
baseline, incontinence, hospitalization indicated, 
severe increase in ostomy output compared with 
baseline, limiting self-care ADL 
Should consider permanently discontinuing CTLA-
4 agents and may restart PD-1, PD-L1 agents if 
patient can recover to G1 or less. 
Administer corticosteroids (initial dose of 1-2 
mg/kg/d prednisone or equivalent) 
Consider hospitalization or outpatient facility for 
patients with dehydration or electrolyte imbalance 
If symptoms persist 3-5 days or recur after 
improvement, consider administering IV 
corticosteroid or noncorticosteroid (eg, inﬂiximab) 
Consider colonoscopy in cases where patients have 
been on immunosuppression and may be at risk for 
opportunistic infections as an independent cause 
for diarrhea (ie, CMV colitis) and for those who 
are anti-TNF or corticosteroid refractory 
G4: Life-threatening consequences; urgent 
intervention indicated 
Permanently discontinue treatment 
Should admit patient when clinically indicated; 
patients managed as outpatients should be very 
closely monitored 


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2.0 GI Toxicities 
Administer 1-2 mg/kg/d methylprednisolone or 
equivalent until symptoms improve to G1, and then 
start taper over 4-6 weeks 
Consider early inﬂiximab 5-10 mg/kg if symptoms 
refractory to corticosteroid within 2-3 days 
Consider lower GI endoscopy if symptoms are 
refractory despite treatment or there is concern of 
new infections 
Additional considerations 
The use of vedolizumab (not approved in Japan) may be considered in patients refractory to inﬂiximab 
and/or contraindicated to TNF-a blocker. The decision should be made on an individual basis from 
gastroenterology and oncology evaluation. This is based on case series showing promising results 
Patients with hepatitis and irAE colitis are rare, and management should include permanently 
discontinuing ICPi and offering other immunosuppressant agents that work systemically for both 
conditions 
Currently, enteritis alone as the cause of diarrhea is uncommon and requires small bowel biopsy as the 
evaluation tool. It may be managed similar as colitis, including corticosteroid and/or inﬂiximab, etc 
2.2 Hepatitis (management based on guidelines by Brahmer et al., 2018, with modifications) 
Deﬁnition: A disorder characterized by a viral pathologic process involving the liver parenchyma 
Diagnostic work-up 
Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin prior to each infusion and/or 
weekly if G1 liver function test elevations. No treatment is recommended for G1 liver function test 
abnormality 
For G2 or higher: 
Work-up for other causes of elevated liver enzymes should be tested, viral hepatitis, alcohol history, iron 
study, thromboembolic event, liver ultrasound, cross-sectional imaging for potential liver metastasis 
from primary malignancy. If suspicion for primary autoimmune hepatitis is high, can consider ANAs, 
antismooth muscle antibodies, antineutrophil cytoplasmic antibodies. If patients with elevated alkaline 
phosphatase alone, g-glutamyl transferase should be tested. For isolated elevation of transaminases, 
consider checking CK for other etiologies 
Grading 
Management 
All patients 
Counsel all patients to be aware of and inform their 
health care provider immediately if they 
experience: 
Yellowing of skin or whites of the eyes Severe 
nausea or vomiting 
Pain on the right side of the abdomen Drowsiness 
Dark urine (tea colored) 
Bleeding or bruising more easily than normal 
Feeling less hungry than usual 
G1: Asymptomatic (AST or ALT > ULN to 
3.0 x ULN and/or total bilirubin > ULN to 
1.5 x ULN) 
Continue ICPi with close monitoring; consider 
alternate etiologies 
Monitor laboratories one to two times weekly 
Manage with supportive care for symptom control 
G2: Asymptomatic (AST or ALT >3.0 to 5 x 
ULN and/or total bilirubin >1.5 to 3 x ULN). For 
participants with metastatic disease to liver and 
elevated transaminases at baseline, see Appendix 
6 for grading that accommodates baseline liver 
chemistry values. 
Permanently discontinue ICPi if: 
- 
ALT 3 x ULN persists for 4 weeks 
- 
ALT 3 x ULN and bilirubin 2 x ULN 
(>35% direct bilirubin) 
- 
ALT 3 x ULN and INR >1.5, if INR 
measured 


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- 
ALT 3 x ULN and cannot be monitored 
weekly for 4 weeks 
In the absence of criteria above, hold ICPi 
temporarily. Consider corticosteroid 0.5-1 mg/kg/d 
prednisone or equivalent if the abnormal elevation 
persists. Increase frequency of monitoring. See 
Appendix 6 for additional details.  
May resume ICPi treatment followed by taper only 
when symptoms improve to G1 or less and 
corticosteroid 10 mg/d; taper over at least 1 
month 
Participants should be advised to stop unnecessary 
medications and any known hepatotoxic drugs. 
Inﬂiximab might not be the most appropriate 
treatment option in the situation of immune-
mediated hepatitis given the potential risk of 
idiosyncratic liver failure (Note: No clear evidence 
shows the liver toxicity from inﬂiximab from other 
studies) 
Participants should be advised to stop unnecessary 
medications and any known hepatotoxic drugs 
G3: Symptomatic liver dysfunction, ﬁbrosis by 
biopsy, compensated cirrhosis, reactivation of 
chronic hepatitis (AST or ALT 5-20 x ULN and/or 
total bilirubin 3-10 x ULN). For participants with 
metastatic disease to liver and elevated 
transaminases at baseline, see Appendix 6 for 
grading that accommodates baseline liver 
chemistry values. 
Permanently discontinue ICPi 
Immediately start corticosteroid 1-2 mg/kg 
methylprednisolone or equivalent 
If corticosteroid refractory or no improvement after 
3 days, consider mycophenolate mofetil or 
azathioprine (if using azathioprine should test for 
thiopurine methyltransferase deﬁciency) 
Laboratories at daily or every other day; consider 
inpatient monitoring for patients with AST/ALT 
>8 x ULN and/or elevated TB 3 x ULN 
Increase frequency of monitoring to every 1-2 days 
Inﬂiximab might not be the most appropriate 
treatment option in the situation of immune-
mediated hepatitis given the potential risk of liver 
failure (Note: No clear evidence shows that the 
liver toxicity from inﬂiximab from other studies); 
alternatives include non–TNF-a agents as systemic 
immunosuppressants If no improvement is 
achieved with corticosteroids or for patients on 
combination therapy with a novel agent, with 
standard chemotherapy, or with targeted therapy, 
refer to hepatologist for further pathologic 
evaluation of hepatitis 
Corticosteroid taper can be attempted around 4-6 
weeks; re-escalate if needed; optimal duration 
unclear 
G4: Decompensated liver function (eg, ascites, 
coagulopathy, encephalopathy, coma; AST or 
ALT > 20 x ULN and/or total bilirubin > 10 x 
ULN) 
Permanently discontinue ICPi 
Administer 2 mg/kg/d methylprednisolone 
equivalents 
If corticosteroid refractory or no improvement after 
3 days, consider mycophenolate mofetil 


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2.0 GI Toxicities 
Monitor laboratories daily; consider inpatient 
monitoring 
Avoid the use of inﬂiximab in the situation of 
immune-mediated hepatitis 
Hepatology consult if no improvement was 
achieved with corticosteroid 
Corticosteroid taper can be attempted around 4-6 
weeks when symptoms improve to G1 or less; re-
escalate if needed; optimal duration unclear 
Consider transfer to tertiary care facility if 
necessary 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations is moderate. 
*not approved in Japan.  
Abbreviations: ADL = activities of daily living; ALT = alanine aminotransferase; ANA = antinuclear antibody; 
AST = aspartate aminotransferase; CBC = complete blood count, CK = creatine kinase; CMV = cytomegalovirus; 
CRP = C-reactive protein; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; CTLA-4 = cytotoxic T-cell lymphocyte-4; EGD = esophagogastroduodenoscopy; ESR = erythrocyte 
sedimentation rate; G = Grade; GI = gastrointestinal; HIV = human immunodeficiency virus; ICPi = immune 
checkpoint inhibitor; irAE = immune-related adverse event; IV = intravenous; PD-1 = programmed death 1; 
PD-L1 = programmed death ligand 1; TB = tuberculosis; TNF = tumor necrosis factor; TSH = thyroid-stimulating 
hormone; ULN = upper limit of normal. 
 


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Table A3 
Management of Lung irAEs in Patients Treated with ICPis 
3.0 Lung Toxicities 
3.1 Pneumonitis 
Deﬁnition: Focal or diffuse inﬂammation of the lung parenchyma (typically identiﬁed on CT imaging) 
No symptomatic, pathologic, or radiographic features are pathognomonic for pneumonitis 
Diagnostic work-up 
Should include the following: CXR, CT, pulse oximetry 
For G2 or higher, may include the following infectious work-up: nasal swab, sputum culture and 
sensitivity, blood culture and sensitivity, urine culture and sensitivity 
Grading 
Management 
G1: Asymptomatic, conﬁned to one lobe of the 
lung or <25% of lung parenchyma, clinical or 
diagnostic observations only 
Continue ICPi  
if clinically indicated. Monitor participants weekly 
or more frequently as needed with history, physical 
examination and pulse oximetry; may also offer 
CXR. May offer one repeat CT scan in 3-4 weeks; 
in patients who have had baseline testing, may 
offer a repeat spirometry/DLCO in 3-4 weeks 
If symptoms appear and/or changes in the physical 
exam are noted, treat as G2 
G2: Symptomatic, involves more than one lobe of 
the lung or 25%-50% of lung parenchyma, 
medical intervention indicated, limiting 
instrumental ADL 
Hold ICPi until resolution to G1 or less 
Prednisone 1-2 mg/kg/d and taper by 5-10 mg/Wk 
over 4-6 weeks Consider bronchoscopy with BAL 
Consider empirical antibiotics 
Monitor every 3 days with history and physical 
examination and pulse oximetry, consider CXR; no 
clinical improvement after 48-72 hours of 
prednisone, treat as G3 
G3: Severe symptoms, hospitalization required, 
involves all lung lobes or 50% of lung 
parenchyma, limiting self-care 
ADL, oxygen indicated 
G4: Life-threatening respiratory compromise, 
urgent intervention indicated (intubation) 
Permanently discontinue ICPi 
Empirical antibiotics; (methyl)prednisolone IV 
1-2 mg/kg/d; no improvement after 48 hours, may 
add inﬂiximab 5 mg/kg or mycophenolate mofetil 
IV 1 g twice a day or IVIG for 5 days or 
cyclophosphamide; taper corticosteroids over 4-6 
weeks 
Pulmonary and infectious disease consults if 
necessary 
Bronchoscopy with BAL ± transbronchial biopsy 
Patients should be hospitalized for further 
management 
Additional considerations 
GI and Pneumocystis prophylaxis with PPI and Bactrim may be offered to patients on prolonged 
corticosteroid use (>12 weeks), according to institutional guidelines 
Consider calcium and vitamin D supplementation with prolonged corticosteroid use 
The role of prophylactic ﬂuconazole with prolonged corticosteroid use (> 12 weeks) remains unclear, 
and physicians should proceed according to institutional guidelines 
Bronchoscopy + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: ADL = activities of daily living; BAL = bronchoalveolar lavage; CT = computed tomography; CXR = chest 
x-ray; DLCO = diffusing capacity of lung for carbon monoxide; G = Grade; GI = gastrointestinal; ICPi = immune 


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checkpoint inhibitor; irAE = immune-related adverse event; IV = intravenous; IVIG = intravenous immunoglobulin; 
PPI = proton pump inhibitor. 


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Table A4 
Management of Endocrine irAEs in Patients Treated with ICPis 
4.0 Endocrine Toxicity 
Counsel patients to inform their health care provider immediately if they experience any changes in their 
health since their last visit, especially any of the following: 
Headaches that will not go away or unusual 
headache patterns 
Vision changes 
Rapid heartbeat 
Increased sweating 
Extreme tiredness or weakness 
Muscle aches 
Weight gain or weight loss 
Dizziness or fainting 
Feeling more hungry or thirsty than usual 
Hair loss 
Changes in mood or behavior, such as decreased 
sex drive, irritability, or forgetfulness Feeling cold 
Constipation 
Voice gets deeper 
Urinating more often than usual 
Nausea or vomiting 
Abdominal pain 
 
4.1 Thyroid 
4.1.1 Primary hypothyroidism 
Deﬁnition: Elevated TSH, normal or low FT4 
Diagnostic work-up 
TSH and FT4 every 4-6 weeks as part of routine clinical monitoring on therapy or for case detection in 
symptomatic patients 
Grading 
Management 
G1: TSH <10 mIU/L and asymptomatic 
G2: Moderate symptoms; able to perform ADL; 
TSH persistently >10 mIU/L 
Should continue ICPi with close follow-up and 
monitoring of TSH, FT4 May hold ICPi until 
symptoms resolve to baseline 
Consider endocrine consultation 
Prescribe thyroid hormone supplementation in 
symptomatic patients with any degree of TSH 
elevation or in asymptomatic patients with TSH 
levels that persist >10 mIU/L (measured 4 weeks 
apart) 
Monitor TSH every 6-8 weeks while titrating 
hormone replacement to normal TSH FT4 can be 
used in the short term (2 weeks) to ensure 
adequacy of therapy in those with frank 
hypothyroidism where the FT4 was initially low 
Once adequately treated, should monitor thyroid 
function (at least TSH) every 6 weeks while on 
active ICPi therapy or as needed for symptoms to 
ensure appropriate replacement; repeat testing 
annually or as indicated by symptoms once stable 


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4.0 Endocrine Toxicity 
G3-4: Severe symptoms, medically signiﬁcant or 
life-threatening consequences, unable to perform 
ADL 
Hold ICPi until symptoms resolve to baseline with 
appropriate supplementation 
Endocrine consultation 
May admit for IV therapy if signs of myxedema 
(bradycardia, hypothermia) Thyroid 
supplementation and reassessment as in G2 
Additional considerations 
For patients without risk factors, full replacement can be estimated with an ideal body weight–based 
dose of approximately 1.6 µg/kg/d 
For elderly or fragile patients with multiple comorbidities, consider titrating up from low dose, starting 
at 25-50 mg 
Extreme elevations of TSH can be seen in the recovery phase of thyroiditis and can be watched in 
asymptomatic patients to determine whether there is recovery to normal within 3-4 weeks 
Under guidance of endocrinology, consider tapering hormone replacement and retesting in patients with 
a history of thyroiditis (initial thyrotoxic phase) 
Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy is initiated  
4.1.2 Hyperthyroidism 
Deﬁnition: Suppressed TSH and high normal or elevated FT4 and/or triiodothyronine 
Diagnostic work-up 
Monitor TSH, FT4 every 4-6 weeks from the start of therapy or as needed for case detection in 
symptomatic patients 
Consider TSH receptor antibodies if there are clinical features and suspicion of Grave disease (eg, 
ophthalmopathy) 
Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch transition to 
hypothyroidism in patients with thyroiditis and hyperthyroidism 
Grading 
Management 
G1: Asymptomatic or mild symptoms 
Can continue ICPi with close follow-up and 
monitoring of TSH, FT4 every 2-3 weeks until it 
is clear whether there will be persistent 
hyperthyroidism (see below) or hypothyroidism 
(see 4.1.1 of Table A4- Appendix 9) 
Consider holding ICPi until symptoms return to 
baseline 
Consider endocrine consultation 
b-Blocker (eg, atenolol, propranolol) for 
symptomatic relief 
Hydration and supportive care 
Corticosteroids are not usually required to shorten 
duration 
For persistent hyperthyroidism (>6 weeks) or 
clinical suspicion, work-up for Graves disease 
(TSI or TRAb) and consider thionamide 
(methimazole or PTU) Refer to endocrinology for 
Graves disease 
G3-4: Severe symptoms, medically signiﬁcant or 
life-threatening consequences, unable to perform 
ADL 
Hold ICPi until symptoms resolve to baseline with 
appropriate therapy 
Endocrine consultation 
b-Blocker (eg, atenolol, propranolol) for 
symptomatic relief 


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4.0 Endocrine Toxicity 
For severe symptoms or concern for thyroid 
storm, hospitalize patient and initiate prednisone 
1-2 mg/kg/d or equivalent tapered over 1-2 weeks; 
consider also use of SSKI or thionamide 
(methimazole or PTU). 
Additional considerations 
Thyroiditis is transient and resolves in a couple of weeks to primary hypothyroidism or normal. 
Hypothyroidism can be treated as above. Graves disease is generally persistent and is due to increased 
thyroid hormone production that can be treated with antithyroid medical therapy. Physical examination 
ﬁndings of ophthalmopathy or thyroid bruit are diagnostic of Graves and should prompt early endocrine 
referral. 
4.2 Adrenal – primary adrenal insufﬁciency 
Deﬁnition: Adrenal gland failure leading to low morning cortisol, high morning ACTH, as well as 
hyponatremia and hyperkalemia with orthostasis and volume depletion due to loss of aldosterone 
Diagnostic work-up for patients in whom adrenal 
insufﬁciency is suspected: 
Evaluate ACTH (AM), cortisol level (AM) 
Basic metabolic panel (Na, K, CO2, glucose) 
Consider ACTH stimulation test for indeterminate 
results 
If primary adrenal insufﬁciency (high ACTH, low 
cortisol) is found biochemically: 
Evaluate for precipitating cause of crisis such as 
infection Perform an adrenal CT for 
metastasis/hemorrhage 
 
Grading 
Management 
G1: Asymptomatic or mild symptoms 
Consider holding ICPi until patient is stabilized on 
replacement hormone 
Endocrine consultation 
Replacement therapy with prednisone (5-10 mg 
daily) or hydrocortisone (10-20 mg orally every 
morning, 5-10 mg orally in early afternoon) 
May require ﬂudrocortisone (0.1 mg/d) for 
mineralocorticoid replacement in primary adrenal 
insufﬁciency 
Titrate dose up or down as symptoms dictate 
G2: Moderate symptoms, able to perform ADL 
Consider holding ICPi until patient is stabilized on 
replacement hormone 
Endocrine consultation 
Initiate outpatient treatment at two to three times 
maintenance 
(if prednisone, 20 mg daily; if hydrocortisone, 20-
30 mg in the morning, and 10-20 mg in the 
afternoon) to manage acute symptoms. 
Taper stress-dose corticosteroids down to 
maintenance doses over 5-10 days 
Maintenance therapy as in G1. 
G3-4: Severe symptoms, medically signiﬁcant or 
life-threatening consequences, unable to perform 
ADL 
Hold ICPi until patient is stabilized on 
replacement hormone 
Endocrine consultation 


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See in clinic or, for after hours, make an 
emergency department referral for normal saline 
(at least 2 L) and IV stress-dose corticosteroids on 
presentation (hydrocortisone 100 mg or 
dexamethasone 4 mg (if the diagnosis is not clear 
and stimulation testing will be needed) 
Taper stress-dose corticosteroids down to 
maintenance doses over 7-14 days after discharge 
Maintenance therapy as in G1 
Additional considerations 
Primary and secondary adrenal insufﬁciency can be distinguished by the relationship between ACTH 
and cortisol. If the ACTH is low with low cortisol, then management is as per 4.3. 
Patients on corticosteroids for management of other conditions will have low morning cortisol as a result 
of iatrogenic, secondary adrenal insufﬁciency. ACTH will also be low in these patients. A diagnosis of 
adrenal insufﬁciency is challenging to make in these situations (see next section on hypophysitis). 
Emergent therapy for someone with suspected adrenal insufﬁciency is best done with dexamethasone as 
a stimulation test can still be performed. If the diagnosis is already conﬁrmed, can use hydrocortisone 
100 mg. 
All patients need education on stress dosing and a medical alert bracelet for adrenal insufﬁciency to 
trigger stress-dose corticosteroids by EMS. 
Endocrine consultation prior to surgery or any procedure for stress-dose planning. 
4.3 Pituitary - hypophysitis 
Deﬁnition: Inﬂammation of the pituitary with varying effects on hormone function. Most commonly 
presenting with central adrenal insufﬁciency. May also have central hypothyroidism, diabetes insipidus, 
and hypogonadism. Diagnostic work-up 
Diagnosis: Low ACTH with a low cortisol. Low or normal TSH with a low FT4. Hypernatremia and 
volume depletion with diabetes insipidus. Low testosterone or estradiol with low LH and FSH. 
Testing: 
Evaluate ACTH, cortisol (AM), TSH, FT4, electrolytes 
Consider evaluating LH, FSH, and testosterone levels in males or estrogen in premenopausal females 
with fatigue, loss of libido, and mood changes Consider MRI of the brain with or without contrast with 
pituitary/sellar cuts in patients with multiple endocrine abnormalities ± new severe headaches or 
complaints of vision changes 
Grading 
Management 
G1: Asymptomatic or mild symptoms 
Consider holding ICPi until patient is stabilized on 
replacement hormones 
Endocrine consultation 
Hormonal supplementation as in G1 
G3-4: Severe symptoms, medically signiﬁcant or 
life-threatening consequences, unable to perform 
ADL 
Hold ICPi until patient is stabilized on 
replacement hormones 
Endocrine consultation 
Hormonal supplementation as in G1 
Consider initial pulse dose therapy with 
prednisone 1-2 mg/kg oral daily (or equivalent) 
tapered over at least 1-2 weeks 
Additional considerations 
Be aware of the need to start corticosteroids ﬁrst when planning hormone replacement therapy for 
multiple deﬁciencies 
All patients need instruction on doubling doses for illness (stress dosing) and a medical alert bracelet for 
adrenal insufﬁciency to trigger stress-dose corticosteroids by EMS 


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Corticosteroid use can cause isolated central adrenal insufﬁciency 
Work-up cannot be done with a simple AM cortisol in a patient on corticosteroids for other conditions 
Laboratory conﬁrmation of adrenal insufﬁciency should not be attempted until treatment with 
corticosteroids for other disease is ready to be discontinued. For long-term exposure, consult 
endocrinology for recovery and weaning protocol using hydrocortisone. 
4.4 Diabetes 
Deﬁnition: T2DM is a combination of insulin resistance and insufﬁciency that may require oral or 
insulin therapy. It may be new onset or exacerbated during therapy for nonimmunologic reasons, such as 
corticosteroid exposure. 
Autoimmune T1DM results from islet cell destruction and is often acute onset, with ketosis and an 
insulin requirement 
Diagnostic work-up 
Monitor patients for hyperglycemia or other signs and symptoms of new or worsening DM, including 
measuring glucose at baseline and with each treatment cycle during induction for 12 weeks, then every 
3-6 weeks thereafter. To guide the work-up in new-onset hyperglycemia, clinicians should consider a 
patient’s medical background, exposure history, and risk factors for each subtype of DM. 
Laboratory evaluation in suspected T1DM should include testing for ketosis in urine and an assessment 
of the anion gap on a metabolic panel. Anti–glutamic acid decarboxylase, anti–islet cell, or anti–insulin 
antibodies are highly speciﬁc for autoimmune diabetes. Insulin and C-peptide levels can also assist in the 
diagnosis. 
Grading 
Management 
G1: Asymptomatic or mild symptoms; fasting 
glucose value > ULN (160 mg/dL); fasting glucose 
value > ULN (8.9 mmol/L); no evidence of ketosis 
or laboratory evidence of T1DM 
Can continue ICPi with close clinical follow-up 
and laboratory evaluation 
May initiate oral therapy for those with new-onset 
T2DM 
Screen for T1DM if appropriate, for example, 
acute onset with prior normal values or clinical 
concern for ketosis 
G2: Moderate symptoms, able to perform ADL, 
fasting glucose value >160-250 mg/dL; fasting 
glucose value >8.9-13.9 mmol/L, ketosis or 
evidence of T1DM at any glucose level 
May hold ICPi until glucose control is obtained 
Titrate oral therapy or add insulin for worsening 
control in T2DM Should administer insulin for 
T1DM (or as default therapy if there is confusion 
about type) 
Urgent endocrine consultation for any patient with 
T1DM; in the absence of endocrinology, internal 
medicine may sufﬁce 
Consider admission for T1DM if early outpatient 
evaluation is not available or signs of ketoacidosis 
are present 
G3-4: Severe symptoms, medically signiﬁcant or 
life-threatening consequences, unable to perform 
ADL 
G3: >250-500 mg/dL (>13.9-27.8 mmol/L) 
G4: >500 mg/dL (>27.8 mmol/L) 
Hold ICPi until glucose control is obtained on 
therapy with reduction of toxicity to G1 or less 
Urgent endocrine consultation for all participants 
Initiate insulin therapy for all patients 
Admit for inpatient management: Concerns for 
developing DKA, Symptomatic participants 
regardless of diabetes type, New-onset T1DM 
unable to see endocrinology 
Additional considerations 
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Long-acting therapy alone is not usually sufﬁcient for T1DM, where half of daily requirements are 
usually given in divided doses as prandial coverage and half as long acting. 
Insulin doses will be lower in T1DM because of preserved sensitivity (total daily requirement can be 
estimated at 0.3-0.4 units/kg/d). 
In T2DM, sliding-scale coverage with meals over a few days provides data to estimate a patient’s daily 
requirements and can be used to more rapidly titrate basal needs. 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: ACTH = adrenocorticotropic hormone; ADL = activities of daily living; CT = computed tomography; 
DKA = diabetic ketoacidosis; DM = diabetes mellitus; EMS = emergency medical services; 
FSH = follicle-stimulating hormone; FT4 = free thyroxine; G = Grade; ICPi = immune checkpoint inhibitor; 
irAE = immune-related adverse event; LH = luteinizing hormone; MRI = magnetic resonance imaging; 
PTU = propylthiouracil; 2L = second-line; SSKI = potassium iodide; T1DM = type 1 diabetes mellitus; T2DM = type 
2 diabetes mellitus; TRAb = thyroid-stimulating hormone receptor antibody; TSH = thyroid-stimulating hormone; 
TSI = thyroid-stimulating immunoglobulin; ULN = upper limit of normal. 
 


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Table A5 
Management of Musculoskeletal irAEs in Patients Treated With 
ICPis 
5.0 Musculoskeletal Toxicities 
5.1 Inﬂammatory arthritis 
Deﬁnition: A disorder characterized by inﬂammation of the joints 
Clinical symptoms: Joint pain accompanied by joint swelling; inﬂammatory symptoms, such as stiffness 
after inactivity or in the morning, lasting >30 minutes to 1 hour; improvement of symptoms with 
NSAIDs or corticosteroids but not with opioids or other pain medications may also be suggestive of 
inﬂammatory arthritis. 
Diagnostic work-up 
G1 
Complete rheumatologic history and examination of all peripheral joints for tenderness, swelling, and 
range of motion; examination of the spine Consider plain x-ray/imaging to exclude metastases and 
evaluate joint damage (erosions), if appropriate 
Consider autoimmune blood panel including ANA, RF, and anti-CCP, and anti-inﬂammatory markers 
(ESR and CRP) if symptoms persist; if symptoms are suggestive of reactive arthritis or affect the spine, 
consider HLA B27 testing 
G2 
Complete history and examination as above; laboratory tests as above 
Consider US ± MRI of affected joints if clinically indicated (eg, persistent arthritis unresponsive to 
treatment, suspicion for differential diagnoses such as metastatic lesions or septic arthritis) 
Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms of 
arthralgia persist > 4 weeks 
G3-4 
As for G2 
Seek rheumatologist advice and review 
Monitoring: Patients with inﬂammatory arthritis should be monitored with serial rheumatologic 
examinations, including inﬂammatory markers, every 4-6 weeks after treatment is instituted. 
Grading 
Management 
All Grades 
Clinicians should follow reports of new joint pain 
to determine whether inﬂammatory arthritis is 
present; question whether symptom new since 
receiving ICPi 
G1: Mild pain with inﬂammation, erythema, or 
joint swelling 
Continue ICPi 
Initiate analgesia with acetaminophen and/or 
NSAIDs 
G2: Moderate pain associated with signs of 
inﬂammation, erythema, or joint swelling, limiting 
instrumental ADL 
Hold ICPi and resume upon symptom control and 
on prednisone 10 mg/d  
Escalate analgesia and consider higher doses of 
NSAIDS as needed 
If inadequately controlled, initiate prednisone or 
prednisolone 10-20 mg/d or equivalent for 4-6 
weeks 
If improvement, slow taper according to response 
during the next 4-6 weeks; if no improvement after 
initial 4-6 weeks, treat as G3 
If unable to lower corticosteroid dose to <10 mg/d 
after 3 months, consider DMARD 
Consider intra-articular corticosteroid injections for 
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Referral to rheumatology 
G3-4: Severe pain associated with signs of 
inﬂammation, erythema, or joint swelling; 
irreversible joint damage; disabling; limiting self-
care ADL 
For G3: Hold ICPi temporarily and may resume in 
consultation with rheumatology, if recover to G1 
or less 
For G4: permanently discontinue ICPi 
Initiate oral prednisone 0.5-1 mg/kg 
If failure of improvement after 4 weeks or 
worsening in meantime, consider synthetic or 
biologic DMARD 
Synthetic: methotrexate, leﬂunomide 
Biologic: consider anticytokine therapy such as 
TNF-a or IL-6 receptor inhibitors. (Note: As 
caution, IL-6 inhibition can cause intestinal 
perforation; while this is extremely rare, it should 
not be used in patients with colitis.) Test for viral 
hepatitis B, C, and latent/active TB test prior to 
DMARD treatment 
Referral to rheumatology. 
Additional considerations 
Early recognition is critical to avoid erosive joint damage. 
Corticosteroids can be used as part of initial therapy in inﬂammatory arthritis, but due to likely 
prolonged treatment requirements, physicians should consider starting corticosteroid-sparing agents 
earlier than one would with other irAEs 
Oligoarthritis can be treated early on with intra-articular corticosteroids; consider early referral. 
Consider PCP prophylaxis for patients treated with high dose of corticosteroids for 12 weeks, as per 
local guidelines. 
5.2 Myositis 
Deﬁnition: A disorder characterized by muscle inﬂammation with weakness and elevated muscle 
enzymes (CK). Muscle pain can be present in severe cases. Can be life threatening if respiratory muscles 
or myocardium are involved 
Diagnostic work-up 
Complete rheumatologic and neurologic history regarding differential diagnosis; rheumatologic and 
neurologic examination, including muscle strength; and examination of the skin for ﬁndings suggestive 
of dermatomyositis. Muscle weakness is more typical of myositis than pain. Consider preexisting 
conditions that can cause similar symptoms. 
Blood testing to evaluate muscle inﬂammation 
CK, transaminases (AST, ALT), LDH, and aldolase can also be elevated 
Troponin to evaluate myocardial involvement and other cardiac testing, such as echocardiogram, as 
needed 
Inﬂammatory markers (ESR and CRP) 
Consider EMG, imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain and 
overlap with neurologic syndromes, such as myasthenia gravis, is suspected 
Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as myasthenia 
gravis Monitoring: CK, ESR, CRP 
G1: Complete examination and laboratory work-up as above 
G2: Complete history and examination as above; autoimmune myositis blood panel; EMG, MRI of 
affected joints 
Early referral to a rheumatologist or neurologist 
G3-4: As for G2 
Urgent referral to a rheumatologist or neurologist 


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Grading 
Management 
G1: Mild weakness with or without pain 
Continue ICPi 
If CK is elevated and patient has muscle weakness, 
may offer oral corticosteroids, and treat as G2 
Offer analgesia with acetaminophen or NSAIDs if 
there are no contraindications 
G2: Moderate weakness with or without pain, 
limiting age-appropriate instrumental ADL 
Hold ICPi temporarily and may resume upon 
symptom control, if CK is normal and prednisone 
dose 10 mg; if worsens, treat as per G3 
NSAIDs as needed 
Referral to rheumatologist or neurologist 
If CK is elevated three times or more), initiate 
prednisone or equivalent at 0.5-1 mg/kg 
May require permanent discontinuation of ICPi in 
most patients with G2 symptoms and objective 
ﬁndings (elevated enzymes, abnormal EMG, 
abnormal muscle MRI or biopsy) 
G3-4: Severe weakness with or without pain, 
limiting self-care ADL 
For G3: Hold ICPi until G1 or less and 
permanently discontinue if any evidence of 
myocardial involvement 
For G4: permanently discontinue ICPi 
Consider hospitalization for severe weakness 
Referral to rheumatologist or neurologist 
Initiate prednisone 1 mg/kg or equivalent. Consider 
1-2 mg/kg of methylprednisolone IV or higher-
dose bolus if severe compromise (weakness 
severely limiting mobility, cardiac, respiratory, 
dysphagia)  
Consider plasmapheresis 
Consider IVIG therapy 
Consider other immunosuppressant therapy, such 
as methotrexate, azathioprine, or mycophenolate 
mofetil, if symptoms and CK levels do not improve 
or worsen after 4-6 weeks; rituximab is used in 
primary myositis but caution is advised given its 
long biologic duration 
In case of management with rituximab, ICPi 
treatment should be discontinued 
Additional considerations: Caution is advised with rechallenging 
5.3 Polymyalgia-like syndrome 
Deﬁnition: Characterized by marked pain and stiffness in proximal upper and/or lower extremities and 
no signs of true muscle inﬂammation such as CK elevation or EMG ﬁndings of myositis. No true muscle 
weakness, difﬁculty in active motion related to pain 
Diagnostic work-up 
G1 
Complete rheumatologic history regarding differential diagnosis and examination of all joints and skin 
Check for symptoms of temporal arteritis, such as headache or visual disturbances; refer to 
ophthalmologist if present, and consider temporal artery biopsy ANA, RF, anti-CCP 
CK to evaluate differential diagnosis of myositis 
Inﬂammatory markers (ESR, CRP) 


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Monitoring: ESR, CRP 
G2: Complete history and examination as above; autoimmune tests as required for differential diagnosis; 
early referral to a rheumatologist 
G3-4: As for G2; see rheumatologist advice and review 
Grading 
Management 
G1: Mild stiffness and pain 
Continue ICPi 
Initiate analgesia with acetaminophen and/or 
NSAIDs if there are no contraindications 
G2: Moderate stiffness and pain, limiting age-
appropriate instrumental ADL 
Consider holding ICPi and resuming upon 
symptom control, prednisolone <10 mg; if 
worsens, treat as per G3 
Initiate prednisone 20 mg/d or equivalent; if 
symptoms improve, start to taper dose after 3-4 
weeks 
If no improvement or need for higher dosages after 
4 weeks, escalate to G3 Consider referral to 
rheumatology 
G3-4: Severe stiffness and pain, limiting self-care 
ADL 
For G3: Hold ICPi and may resume, in 
consultation with rheumatology, if recover to G1 
or less; however, note that cases of toxicity 
returning upon rechallenge have been reported. 
ICPi should be permanently discontinued in such 
cases 
For G4: permanently discontinue ICPi 
Referral to rheumatology 
Should initiate prednisone 20 mg/d or equivalent. 
If no improvement or need for higher dosages for 
prolonged time, may offer a corticosteroid-sparing 
agent such as methotrexate or IL-6 inhibition with 
tocilizumab 
(Note: As caution, IL-6 inhibition can cause 
intestinal perforation; while this is extremely rare, 
it should not be used in patients with colitis or GI 
metastases). Consider admission for pain control 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: ADL = activities of daily living; ALT = alanine aminotransferase; ANA = antinuclear antibodies; 
AST = aspartate aminotransferase; CCP = citrullinated protein antibody; CK = creatine kinase; CRP = C-reactive 
protein; DMARD = disease-modifying antirheumatic drug; EMG = electromyography; ESR = erythrocyte 
sedimentation rate; G = Grade; HLA = human leukocyte antigen; ICPi = immune checkpoint inhibitor; 
IL = interleukin; irAE = immune-related adverse event; IV = intravenous; IVIG = intravenous immunoglobulin; 
LDH = lactate dehydrogenase; MRI = magnetic resonance imaging, NSAID = nonsteroidal anti-inﬂammatory drug; 
PCP = Pneumocystis pneumonia; RF = rheumatoid factor; TB = tuberculosis; TNF = tumor necrosis factor. 
 


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Table A6 
Management of Renal irAEs in Patients Treated With ICPis 
6.0 Renal Toxicities 
Nephritis and renal dysfunction: diagnosis and monitoring 
For any suspected immune-mediated adverse reactions, exclude other causes 
Monitor patients for elevated serum creatinine prior to every dose 
Routine urinalysis is not necessary, other than to rule out UTIs, etc; nephrology may consider further 
If no potential alternative cause of AKI identiﬁed, then one should forego biopsy and proceed directly 
with immunosuppressive therapy Swift treatment of autoimmune component important 
6.1 Nephritis 
Deﬁnition: Inﬂammation of the kidney affecting the structure 
Grading 
Management 
G1: Creatinine level increase of >0.3 mg/dL; 
creatinine 1.5-2.0 x over baseline 
Consider temporarily holding ICPi, pending 
consideration of potential alternative etiologies 
(recent IV contrast, medications, ﬂuid status) and 
baseline renal function. A change that is still <1.5 x 
ULN could be meaningful 
G2: Creatinine 2-3 x above baseline 
Hold ICPi temporarily 
Consult nephrology 
Evaluate for other causes (recent IV contrast, 
medications, ﬂuid status, etc); if other etiologies 
ruled out, administer 0.5-1 mg/kg/d prednisone 
equivalents 
If worsening or no improvement: 1 to 2 mg/kg/d 
prednisone equivalents and permanently 
discontinue treatment 
If improved to G1 or less, taper corticosteroids 
over 4-6 weeks If no recurrence of chronic renal 
insufﬁciency, discuss resumption of ICPI with 
patient after taking into account the risks and 
beneﬁts. 
G3: Creatinine >3 x baseline or >4.0 mg/dL; 
hospitalization indicated 
Permanently discontinue ICPi 
G4: Life-threatening consequences; dialysis 
indicated 
Consult nephrology 
Evaluate for other causes (recent IV contrast, 
medications, ﬂuid status, etc) 
Administer corticosteroids (initial dose of 1-2 
mg/kg/d prednisone or equivalent) 
Additional considerations 
Monitor creatinine weekly 
Reﬂex kidney biopsy should be discouraged until corticosteroid treatment has been attempted 
6.2 Symptomatic nephritis: follow-up 
Grading 
Management 
G1 
Improved to baseline, resume routine creatinine 
monitoring 
G2 
If improved to G1, taper corticosteroids over at 
least 3 weeks before resuming treatment with 
routine creatinine monitoring If elevations persist 
>7 days or worsen and no other cause found, treat 
as G3 


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G3 
If improved to G1, taper corticosteroids over at 
least 4 weeks  
If elevations persist 3-5 days or worsen, consider 
additional immunosuppression (eg, 
mycophenolate) 
G4 
If improved to G1, taper corticosteroids over at 
least 4 weeks 
If elevations persist 2-3 days or worsen, consider 
additional immunosuppression (eg, 
mycophenolate) 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: AKI = acute kidney injury; G = Grade; ICPi = immune checkpoint inhibitor; irAE = immune-related 
adverse event; IV = intravenous; ULN = upper limit of normal; UTI = urinary tract infection. 
 


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Table A7 
Management of Nervous System irAEs in Patients Treated With 
ICPis 
7.0 Nervous System Toxicities 
7.1 Myasthenia gravis 
Deﬁnition: Fatigable or ﬂuctuating muscle weakness, generally more proximal than distal. Frequently 
has ocular and/or bulbar involvement (ptosis, extraocular movement abnormalities resulting in double 
vision, dysphagia, dysarthria, facial muscle weakness). May have neck and/or respiratory muscle 
weakness. (Note: May occur with myositis and/or myocarditis. Respiratory symptoms may require 
evaluation to rule out pneumonitis, myocarditis. Miller Fisher variant of Guillain-Barré syndrome 
(ophthalmoparesis) and the oculobulbar myositis (ptosis, ophthalmoparesis, dysphagia, neck and 
respiratory weakness) with ICPi may have overlapping symptoms. 
Diagnostic work-up 
AChR and antistriated muscle antibodies in blood; if AChR antibodies are negative, consider muscle 
speciﬁc kinase and lipoprotein-related 4 antibodies in blood Pulmonary function assessment with NIF 
and VC 
CPK, aldolase, ESR, CRP for possible concurrent myositis 
Consider MRI of brain and/or spine, depending on symptoms to rule out CNS involvement by disease or 
alternate diagnosis 
If respiratory insufﬁciency or elevated CPK, troponin T, perform cardiac examination with ECG and 
TTE for possible concomitant myocarditis 
Neurologic consultation 
Electrodiagnositic studies, including neuromuscular junction testing with repetitive stimulation and/or 
jitter studies, NCS to exclude neuropathy, and needle EMG to evaluate for myositis 
Grading 
Management 
All grades 
All grades warrant work-up and intervention given 
potential for progressive myasthenia gravis to lead 
to respiratory compromise 
No G1 
 
G2: Some symptoms interfering with ADL 
MGFA severity class 1 (ocular symptoms and 
ﬁndings only) and MGFA severity class 2 (mild 
generalized weakness) 
Hold ICPi and may resume in G2 patients (MGFA 
1 and 2) only if symptoms resolve  
Should consult neurology 
Pyridostigmine starting at 30 mg orally three times 
a day and gradually increase to maximum of 120 
mg orally four times a day as tolerated and based 
on symptoms Administer corticosteroids 
(prednisone, 1-1.5 mg/kg orally daily) if symptoms 
G2; wean based on symptom improvement 
G3-4: Limiting self-care and aids warranted, 
weakness limiting walking, ANY dysphagia, 
facial weakness, respiratory muscle weakness, or 
rapidly progressive symptoms, or MGFA severity 
class 3-4 moderate to severe generalized 
weakness to myasthenic crisis 
Permanently discontinue ICPi 
Admit patient, may need ICU-level monitoring 
Neurology consult 
Continue corticosteroids and initiate IVIG 2 g/kg 
IV over 5 days (0.4 g/kg/d) or plasmapheresis for 5 
days 
Frequent pulmonary function assessment 
Daily neurologic review 
Additional considerations 
Avoid medications that can worsen myasthenia: β-blockers, IV magnesium, ﬂuoroquinolones, 
aminoglycosides, and macrolides Initially a 5-day course of plasmapheresis or a 2 g/kg course of IVIG 
over 5 days 


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7.0 Nervous System Toxicities 
1-2 mg/kg methylprednisolone daily, wean based on symptom improvement 
Pyridostigmine, wean based on improvement 
ICPi-associated myasthenia gravis may be monophasic, and additional corticosteroid-sparing agents may 
not be required 
7.2 Guillain-Barré syndrome 
Deﬁnition: Progressive, most often symmetrical muscle weakness with absent or reduced deep tendon 
reﬂexes. Often starts with sensory symptoms/neuropathic pain localized to lower back and thighs. May 
involve extremities (typically ascending weakness but not always), facial, respiratory, and bulbar and 
oculomotor nerves. May have dysregulation of autonomic nerves. 
Diagnostic work-up 
Neurologic consultation 
MRI of spine with or without contrast (rule out compressive lesion and evaluate for nerve root 
enhancement/thickening) 
Lumbar puncture: CSF typically has elevated protein and often elevated WBCs; even though this is not 
typically seen in classic Guillain-Barré syndrome, cytology should be sent with any CSF sample from a 
patient with cancer. 
Serum antibody tests for Guillain-Barré syndrome variants (GQ1b for Miller Fisher variant a/w ataxia 
and ophthalmoplegia) Electrodiagnostic studies to evaluate polyneuropathy 
Pulmonary function testing (NIF/VC) 
Frequent neurochecks 
Grading 
Management 
All grades 
Warrant work-up and intervention given potential 
for progressive Guillain-Barré syndrome to lead to 
respiratory compromise 
Note: There is no G1 toxicity 
G1: Mild, none 
NA 
G2: Moderate, some interference with ADL, 
symptoms concerning to patient 
Discontinue ICPi 
G3-4: Severe, limiting self-care and aids 
warranted, weakness, limiting walking, ANY 
dysphagia, facial weakness, respiratory muscle 
weakness, or rapidly progressive symptoms 
Permanently discontinue ICPi. Admission to 
inpatient unit with capability of rapid transfer to 
ICU-level monitoring Start IVIG (0.4 g/kg/d for 5 
days for a total dose of 2 g/kg) or plasmapheresis. 
Corticosteroids are usually not recommended for 
idiopathic Guillain-Barré syndrome; however, in 
ICPi-related forms, a trial is reasonable 
(methylprednisolone 2-4 mg/kg/d), followed by 
slow corticosteroid taper 
Pulse corticosteroid dosing (methylprednisolone 1 
g/d for 5 days) may also be considered for G3-4 
along with IVIG or plasmapheresis 
Frequent neurochecks and pulmonary function 
monitoring 
Monitor for concurrent autonomic dysfunction 
Nonopioid management of neuropathic pain 
Treatment of constipation/ileus 
Additional considerations 
Slow prednisone taper after corticosteroid pulse plus IVIG or plasmapheresis May require repeat IVIG 
courses 
Caution with rechallenging for severe cases 


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7.0 Nervous System Toxicities 
7.3 Peripheral neuropathy 
Deﬁnition: Can present as asymmetric or symmetric sensory, motor, or sensory motor deﬁcit. Focal 
mononeuropathies, including cranial neuropathies (eg, facial neuropathies/Bell palsy) may be present. 
Numbness and paresthesias may be painful or painless. Hypo- or areﬂexia or sensory ataxia may be 
present. 
Diagnostic work-up 
G1 
Screen for reversible neuropathy causes: diabetic screen, B12, folate, TSH, HIV, consider serum protein 
electrophoresis, and other vasculitic and autoimmune screen Neurologic consultation 
Consider MRI of spine with or without contrast 
G2: in addition to above 
MRI spine advised/MRI of brain if cranial nerve Consider EMG/NCS 
Consider neurology consultation 
G3-4: go to Guillain-Barré syndrome algorithm 
Grading 
Management 
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: Any 
cranial nerve problem should be managed as 
moderate 
Low threshold to hold ICPi and monitor symptoms 
for a week If to continue, monitor very closely for 
any symptom progression 
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (ie, pain but no 
weakness or gait limitation) 
Hold ICPi and resume once return to G1 
Initial observation OR initiate prednisone 0.5-1 
mg/kg (if progressing from mild) 
Neurontin, pregabalin, or duloxetine for pain 
G3-4: Severe, limiting self-care and aids 
warranted, weakness limiting walking or 
respiratory problems (ie, leg weakness, foot drop, 
rapidly ascending sensory changes) Severe may 
be Guillain-Barré syndrome and should be 
managed as such 
Permanently discontinue ICPi 
Admit patient 
Neurologic consultation 
Initiate IV methylprednisolone 2-4 mg/kg and 
proceed as per Guillain-Barré syndrome 
management 
7.4 Autonomic neuropathy 
Deﬁnition: Nerves that control involuntary bodily functions are damaged. This may affect blood 
pressure, temperature control, digestion, bladder function, and sexual function. A case of severe enteric 
neuropathy with ICPi has been reported. Can present with GI difﬁculties such as new severe 
constipation, nausea, urinary problems, sexual difﬁculties, sweating abnormalities, sluggish pupil 
reaction, and orthostatic hypertension. 
Diagnostic work-up 
An evaluation by neurologist or relevant specialist, depending on organ system, with testing that may 
include 
Screening for other causes of autonomic dysfunction: diabetic screen, adrenal insufﬁciency, HIV, 
paraproteinemia, amyloidosis, botulism; consider chronic diseases such as Parkinson and other 
autoimmune screening 
AM orthostatic vitals 
Consider electrodiagnostic studies to evaluate for concurrent polyneuropathy 
Consider paraneoplastic Lambert-Eaton myasthenic syndrome, antineutrophil cytoplasmic antibodies, 
and ganglionic AChR antibody testing 


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7.0 Nervous System Toxicities 
Grading 
Management 
G1: Mild, no interference with function and 
symptoms not concerning to patient 
Low threshold to hold ICPi and monitor symptoms 
for a week; if to continue, monitor very closely for 
any symptom progression 
G2: Moderate, some interference with ADL, 
symptoms concerning to patient 
Hold ICPi and resume once return to G1 
Initial observation OR initiate prednisone 0.5-1 
mg/kg (if progressing from mild) 
Neurologic consultation 
G3-4: Severe, limiting self-care and aids 
warranted 
Permanently discontinue ICPi 
Admit patient 
Initiate methylprednisolone 1 g daily for 3 days 
followed by oral corticosteroid taper Neurologic 
consultation 
7.5 Aseptic meningitis 
Deﬁnition: may present with headache, photophobia, and neck stiffness; often afebrile but may be 
febrile. There may be nausea/vomiting. Mental status should be normal (distinguishes from 
encephalitis). 
Diagnostic work-up 
MRI of brain with or without contrast + pituitary protocol 
AM cortisol, ACTH to rule out adrenal insufﬁciency 
Consider lumbar puncture: measure opening pressure; check cell count and protein glucose; and perform 
Gram stain, culture, PCR for HSV, and other viral PCRs depending on suspicion, cytology 
May see elevated WBC count with normal glucose, normal culture, and Gram stain; may see reactive 
lymphocytes or histiocytes on cytology 
Grading 
Management 
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: Any 
cranial nerve problem should be managed as 
moderate. 
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (ie, pain but no 
weakness or gait limitation) 
G3-4: Severe, limiting self-care and aids 
warranted 
For G1-3: Hold ICPi and discuss resumption with 
patient only after taking into account the risks and 
beneﬁts 
For G4: permanently discontinue ICPi. 
In case of any aseptic meningitis events (G1-4), 
consider empirical antiviral (IV acyclovir) and 
antibacterial therapy until CSF results Once 
bacterial and viral infection are negative, may 
closely monitor off corticosteroids or consider oral 
prednisone 0.5-1 mg/kg or IV methylprednisolone 
1 mg/kg if moderate/severe symptoms 
7.6 Encephalitis 
Deﬁnition: As for aseptic meningitis, need to exclude infectious causes, especially viral (ie, HSV). 
Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of 
consciousness, focal weakness, speech abnormality  
Diagnostic work-up 
Neurologic consultation 
MRI of brain with or without contrast may reveal T2/ﬂuid-attenuated inversion recovery changes typical 
of what is seen in autoimmune encephalopathies or limbic encephalitis or may be normal 
Lumbar puncture: check cell count and protein glucose and perform Gram stain, culture, PCR for HSV 
and other viral PCRs depending on suspicion, cytology, oligoclonal bands, autoimmune encephalopathy, 
and paraneoplastic panels. 
May see elevated WBC count with lymphocytic predominance and/or elevated protein 
EEG to evaluate for subclinical seizures 


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7.0 Nervous System Toxicities 
Blood: metabolic, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including TPO 
and thyroglobulin Rule out concurrent anemia/thrombocytopenia, which can present with severe 
headaches and confusion 
Grading 
Management 
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: Any 
cranial nerve problem should be managed as 
moderate. 
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (ie, pain but no 
weakness or gait limitation) 
G3-4: Severe, limiting self-care and aids 
warranted 
For G1, 2, and 3: Hold ICPi and discuss 
resumption with patient only after taking into 
account the risks and beneﬁts 
For G4: permanently discontinue ICPi 
As above for aseptic meningitis, in case of any 
encephalitis events, suggest concurrent IV 
acyclovir until PCR results obtained and negative 
Trial of methylprednisolone 1-2 mg/kg 
If severe or progressing symptoms or oligoclonal 
bands present, consider pulse corticosteroids 
methylprednisolone 1 g IV daily for 3-5 days plus 
IVIG 2 g/kg over 5 days If positive for 
autoimmune encephalopathy antibody and limited 
or no improvement, consider rituximab or 
plasmapheresis in consultation with neurology. 
In case of management with rituximab, ICPi 
treatment should be discontinued 
7.7 Transverse myelitis 
Deﬁnition: Acute or subacute weakness or sensory changes bilateral, often with increased deep tendon 
reﬂexes 
Diagnostic work-up 
Neurologic consultation 
MRI of spine (with thin axial cuts through the region of suspected abnormality) and MRI of brain 
Lumbar puncture: cell count, protein, glucose, oligoclonal bands, viral PCRs, cytology, onconeural 
antibodies Blood: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG 
Evaluation for urinary retention, constipation 
Grading 
Management 
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: Any 
cranial nerve problem should be managed as 
moderate. 
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (ie, pain but no 
weakness or gait limitation) 
G3-4: Severe, limiting self-care and aids 
warranted 
Permanently discontinue ICPi 
Methylprednisolone 2 mg/kg 
Strongly consider higher doses of 1 g/d for 3-5 
days Strongly consider IVIG 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: AChR = acetylcholine receptor; ACTH = adrenocorticotropic hormone; ADL = activities of daily living; 
ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibodies; CBC = complete blood count; 
CNS = central nervous system; CPK = creatine phosphokinase; CRP = C-reactive protein; CSF = cerebrospinal 
fluid; ECG = electrocardiogram; EEG = electroencephalogram; EMG = electromyography; ESR = erythrocyte 
sedimentation rate; G = Grade; GI = gastrointestinal; HIV = human immunodeficiency virus; HSV = herpes 
simplex virus; ICPi = immune checkpoint inhibitor; ICU = intensive care unit; IgG = immunoglobulin G; 
IV = intravenous; IVIG = intravenous immunoglobulin; irAE = immune-related adverse event; MGFA = Myasthenia 
Gravis Foundation of America; MRI = magnetic resonance imaging; NA = not applicable; NCS = nerve conduction 
study; NIF = negative inspiratory force; PCR = polymerase chain reaction; RPR = rapid plasma reagin, 


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TPO = thyroid peroxidase; TSH = thyroid-stimulating hormone; TTE = transthoracic echocardiogram; VC = vital 
capacity; WBC = white blood cell count. 
 


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Table A8 
Management of Hematologic irAEs in Patients Treated With 
ICPis 
8.0 Hematologic Toxicities 
8.1 Autoimmune hemolytic anemia 
Deﬁnition: A condition in which RBCs are destroyed and removed from the blood stream before their 
normal lifespan is over. Symptoms include weakness, paleness, jaundice, dark-colored urine, fever, 
inability to do physical activity, and heart murmur. 
Diagnostic work-up 
History and physical examination (with special consideration of history of new drugs and insect, spider, 
or snake bites) 
Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral 
smear; LDH, haptoglobin, bilirubin, reticulocyte count, free Hgb DIC panel, which could include PTNIR 
infectious causes 
Autoimmune serology 
Paroxysmal nocturnal hemoglobinuria screening 
Direct and indirect bilirubin; LDH; direct agglutinin test; and if no obvious cause, bone marrow analysis, 
cytogenetic analysis to evaluate for myelodysplastic syndromes 
Evaluation for viral/bacterial (mycoplasma, etc) causes of hemolysis studies 
Protein electrophoresis, cryoglobulin analysis 
Work-up for bone marrow failure syndrome if refractory, including B12, folate, copper, parvovirus, FE, 
thyroid, infection 
Glucose-6-phosphate dehydrogenase 
Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, 
NSAIDs, quinine/quinidine, ﬂudarabine, ciproﬂoxacin, lorazepam, diclofenac, etc) 
Assessment of methemoglobinemia 
Grading 
Management 
G1: Hgb < LLN to 10.0 g/dL; < LLN to 6.2 
mmol/L; < LLN to 100 g/L 
Continue ICPi with close clinical follow-up and 
laboratory evaluation 
G2: Hgb < 10.0 to 8.0 g/dL; < 6.2 to 4.9mmol/L; 
<100 to 80 g/L 
Hold ICPi and strongly consider permanent 
discontinuation 
Administer 0.5-1 mg/kg/d prednisone equivalents 
G3: Hgb <8.0 g/dL; <4.9 mmol/L; <80 g/L; 
transfusion indicated 
Permanently discontinue ICPi 
Should use clinical judgment and consider admitting 
the patient 
Hematology consult 
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms/speed of development) 
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently discontinue 
ICPi treatment 
Consider RBC transfusion per existing guidelines; 
do not transfuse more than the minimum number of 
RBC units necessary to relieve symptoms of anemia 
or to return a patient to a safe Hgb range (7-8 g/dL 
in stable, noncardiac inpatients) 
Should offer patients supplementation with folic 
acid 1 mg once daily 
G4: Life-threatening consequences, urgent 
intervention indicated 
Permanently discontinue ICPi 
Admit patient 


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8.0 Hematologic Toxicities 
Hematology consult 
IV prednisone corticosteroids 1-2 mg/kg/d 
If no improvement or if worsening while on 
corticosteroids or severe symptoms on presentation, 
initiate other immunosuppressive drugs, such as 
rituximab, IVIG, cyclosporin A, and mycophenolate 
mofetil 
RBC transfusion per existing guidelines; discuss 
with blood bank team prior to transfusions that a 
patient with possible ICPi serious AE is in house. 
Additional considerations: Monitor Hgb levels on a weekly basis until the corticosteroid tapering 
process is complete; thereafter, less-frequent testing is needed 
8.2 Acquired TTP 
Deﬁnition: A disorder characterized by the presence of microangiopathic hemolytic anemia, 
thrombocytopenic purpura, fever, renal abnormalities, and neurologic abnormalities, such as seizures, 
hemiplegia, and visual disturbances. It is an acute or subacute condition.  
Diagnostic work-up 
History with speciﬁc questions related to drug exposure (eg, chemotherapy, sirolimus, tacrolimus, opana 
ER antibiotics, quinine) Physical examination, peripheral smear 
ADAMTS13 activity level and inhibitor titer 
LDH, haptoglobin, reticulocyte count, bilirubin, urinalysis to rule out other causes 
PT, activated PTT, ﬁbrinogen 
Blood group and antibody screen, direct antiglobulin test, CMV serology 
Consider CT/MRI brain, echocardiogram, ECG 
Viral studies 
Note: This disorder is usually associated with a severe drop in platelets and hemolysis/anemia 
precipitously 
Grading 
Management 
All grades 
The ﬁrst step in the management of TTP is a high 
index of suspicion for the diagnosis and timely 
recognition; hematology consult should immediately 
be called, as delay in identiﬁcation is associated with 
increased mortality/morbidity. 
Initially, the patient should be stabilized and any 
critical organ dysfunction stabilized 
G1: Evidence of RBC destruction 
(schistocytosis) without anemia, renal 
insufﬁciency, or thrombocytopenia clinically 
G2: Evidence of RBC destruction 
(schistocytosis) without clinical consequence 
with G2 anemia and thrombocytopenia 
Hold ICPi and discuss resumption with patient only 
after taking into account the risks and beneﬁts, 
noting that there are currently no data to recommend 
restarting ICPi therapy Hematology consult 
Administer 0.5-1 mg/kg/d prednisone 
G3: Laboratory ﬁndings with clinical 
consequences (G3 thrombocytopenia, anemia, 
renal insufﬁciency > 2) 
G4: Life-threatening consequences (eg, CNS 
hemorrhage or thrombosis/embolism or renal 
failure) 
For G3: Hold ICPi and discuss resumption with 
patient only after taking into account the risks and 
beneﬁts, noting that there are currently no data to 
recommend restarting ICPi therapy 
For G4: permanently discontinue ICPi 
Hematology consult 
In conjunction with hematology, initiate PEX 
according to existing guidelines with further PEX 
dependent on clinical progress 


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8.0 Hematologic Toxicities 
Administer methylprednisolone 1 g IV daily for 3 
days, with the ﬁrst dose typically administered 
immediately after the ﬁrst PEX 
May offer rituximab 
In case of management with rituximab, ICPi 
treatment will be discontinued 
8.3 Hemolytic uremic syndrome 
Deﬁnition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, 
hemolytic anemia, and severe thrombocytopenia. Signs and symptoms of hemolytic uremic syndrome 
can include: 
Bloody diarrhea 
Decreased urination or blood in the urine 
Abdominal pain, vomiting, and occasionally fever 
Pallor 
Small, unexplained bruises or bleeding from the nose and mouth Fatigue and irritability 
Confusion or seizures 
High blood pressure 
Swelling of the face, hands, feet, or entire body 
Diagnostic work-up 
History and physical examination (special consideration for new history of high-risk drugs, 
hypertension, or cardiac causes) CBC with indices 
Blood smear morphology. Note that the presence of schistocytes on smear is critical for diagnosis. 
Serum creatinine 
ADAMTS13 (to rule out TTP) 
Homocysteine/methylmalonic acid 
Complement testing C3, C4, CH50 (complement inhibitory antibodies for suspected familial) 
Evaluate reticulocyte count and mean corpuscular volume 
Evaluation of infectious cause, including screening for EBV, CMV, HHV6 
Evaluation for nutritional causes of macrocytosis (B12 and folate) 
Pancreatic enzymes 
Evaluation for diarrheal causes, shiga toxin, Escherichia coli 0157, etc 
Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia 
Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, sirolimus, etc) 
Evaluation for concurrent confusion 
Grading 
Management 
G1-2: Evidence of RBC destruction 
(schistocytosis) without clinical consequences of 
anemia, thrombocytopenia Grade 2 
G3: Laboratory ﬁndings with clinical 
consequences (eg, renal insufﬁciency, petechiae) 
G4: Life-threatening consequences (eg, CNS 
thrombosis/ embolism or renal failure) 
For G1 and G2: Continue ICPi with close clinical 
follow-up and laboratory evaluation 
Supportive care  
For G3 and G4: Permanently discontinue ICPi 
Begin therapy with eculizumab therapy 900 mg 
weekly for four doses, 1,200 mg week 5, then 1,200 
mg every 2 weeks 
Red blood transfusion according to existing 
guidelines 
8.4 Aplastic anemia 
Deﬁnition: Condition in which the body stops producing enough new blood cells  
Diagnostic work-up 


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8.0 Hematologic Toxicities 
History and physical examination (close attention to medications, exposure to radiation, toxins, recent 
viral infections) CBC, smear, reticulocyte count 
Viral studies, including CMV, HHV6, EBV, parvovirus 
Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, vitamin D 
Serum LDH, renal function 
Work-up for infectious causes 
Identify marrow hypo/aplasia 
Bone marrow biopsy and aspirate analysis 
Peripheral blood analysis, including neutrophil count, proportion of GPI-negative cells by ﬂow for PNH 
Flow cytometry to evaluate loss of GPI-anchored proteins 
Type and screen patient for transfusions and notify blood bank that all transfusions need to be irradiated 
and ﬁltered 
Grading 
Management 
G1: Nonsevere, <0.5 polymorphonuclear cells x 
109/L hypocellular marrow, with marrow 
cellularity <25%, peripheral platelet count 
>20,000, reticulocyte count <20,000 
Hold ICPi and provide growth factor support and 
close clinical follow-up, and laboratory evaluation  
Supportive transfusions as per local guidelines 
G2: Severe, hypocellular marrow <25% and two 
of the following: ANC < 500, peripheral platelet 
<20,000, and reticulocyte <20,000 
Hold ICPi and provide growth factor support and 
close clinical laboratory evaluations daily 
Administer ATG + cyclosporine; HLA typing and 
evaluation for bone marrow transplantation if patient 
is candidate; all blood products should be irradiated 
and ﬁltered 
Supportive care with granulocyte colony-stimulating 
factor may be added in addition 
G3-4: Very severe, ANC >200, platelet count 
>20,000, reticulocyte count >20,000, plus 
hypocellular marrow >25% 
For G3: Hold ICPi and monitor weekly for 
improvement; if not resolved, discontinue treatment 
until AE has reverted to G1 
For G4: permanently discontinue ICPi 
Hematology consult, growth factor support 
Horse ATG plus cyclosporine 
If no response, repeat immunosuppression with 
rabbit ATG plus cyclosporine, cyclophosphamide 
For refractory patients, consider eltrombopag plus 
supportive care 
8.5 Lymphopenia 
Deﬁnition: An abnormally low level of lymphocytes in PB; for adults, counts of < 1,500/mm3  
Diagnostic work-up 
History and physical examination (special attention for lymphocyte-depleting therapy such as 
ﬂudarabine, ATG, corticosteroids, cytotoxic chemotherapy, radiation exposure, etc, as well as history of 
autoimmune disease, family history of autoimmune disease) Evaluation of nutritional state as cause 
Spleen size 
CBC with differential, peripheral smear and reticulocyte counts 
CXR for evaluation of presence of thymoma 
Bacterial cultures and evaluation for infection (fungal, viral, bacterial speciﬁcally CMV/HIV) 
Grading 
Management 
G1-2: 500-1,000 PB lymphocyte count 
G3: 250-499 PB lymphocyte count 
Continue ICPi 


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8.0 Hematologic Toxicities 
G4: <250 PB lymphocyte count 
Continue ICPi, checking CBC weekly for 
monitoring, initiation of CMV screening Consider 
holding ICPi 
Initiate Mycobacterium avium complex prophylaxis 
and Pneumocystis jirovecii prophylaxis, CMV 
screening. HIV/hepatitis screening if not already 
done 
May consider EBV testing if evidence of 
lymphadenopathy/hepatitis, fevers, hemolysis 
consistent with lymphoproliferative disease 
8.6 Immune thrombocytopenia 
Deﬁnition: An autoimmune disorder characterized by immunologic destruction of otherwise normal 
platelets  
Diagnostic work-up 
History and physical examination (special attention for lymphocyte-depleting therapy, such as 
ﬂudarabine, ATG, corticosteroids, cytotoxic therapy) Family history of autoimmunity or personal history 
of autoimmune disease 
History of viral illness 
CBC 
Peripheral blood smear, reticulocyte count 
Bone marrow evaluation only if abnormalities in the above test results and further investigation is 
necessary for a diagnosis 
Patients with newly diagnosed immune thrombocytopenia should undergo testing for HIV, hepatitis C 
virus, hepatitis B virus, and Helicobacter pylori Direct antigen test should be checked to rule out 
concurrent Evan syndrome 
Nutritional evaluation 
Bone marrow evaluation if other cell lines affected and concern for aplastic anemia 
Grading 
Management 
G1: Platelet count <100/µL 
G2: Platelet count <75/µL 
Continue ICPi with close clinical follow-up and 
laboratory evaluation 
Hold ICPi but monitor for improvement; if not 
resolved, interrupt treatment until AE has reverted to 
G1 
Administer prednisone 1 mg/kg/d (dosage range, 
0.5-2 mg/kg/d) orally for 2-4 weeks after which time 
this medication should be tapered over 4-6 weeks to 
the lowest effective dose IVIG may be used in 
conjunction with corticosteroids if a more-rapid 
increase in platelet count is required. 
G3: Platelet count <50/µL 
Hold ICPi but monitor for improvement; if not 
resolved, interrupt treatment until AE has reverted to 
G1 
G4: Platelet count <25/µL 
Hematology consult 
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms) 
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently discontinue 
treatment 
IVIG used with corticosteroids when a more-rapid 
increase in platelet count is required 


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8.0 Hematologic Toxicities 
If IVIG is used, the dose should initially be 1 g/kg as 
a one-time dose. This dosage may be repeated if 
necessary 
If previous treatment with corticosteroids and/or 
IVIG unsuccessful, subsequent treatment may 
include rituximab, thrombopoietin receptor agonists, 
or more-potent immunosuppression (From American 
Society of Hematology guideline on immune 
thrombocytopenia97; consult for further details) 
8.7 Acquired hemophilia 
Deﬁnition: Disorder caused by the development of autoantibodies (inhibitors) directed against plasma 
coagulation factors  
Diagnostic work-up 
Full blood count to assess platelet number, ﬁbrinogen, PT, PTT, INR; the typical ﬁnding in patients with 
acquired hemophilia A is a prolonged activated PTT with a normal PT 
MRI, CT, and ultrasonography may be indicated to localize, quantify, and serially monitor the location 
and response of bleeding Medication review to assess for alternative causes 
Determination of Bethesda unit level of inhibitor 
Grading 
Management 
G1: Mild, 5%-40% of normal factor activity in 
blood, 0.05-0.4 IU/mL of whole blood 
Hold ICPi and discuss resumption with patient only 
after taking into account the risks and beneﬁts 
Administer 0.5-1 mg/kg/d prednisone 
Transfusion support as required 
Treatment of bleeding disorders with hematology 
consult 
G2: Moderate, 1%-5% of normal factor activity 
in blood, 0.01- 0.05 IU/mL of whole blood 
Hematology consult 
Administration of factor replacement (choice based 
on Bethesda unit of titer) 
Administer 1 mg/kg/d prednisone ± rituximab (dose, 
375 mg/m2 weekly for 4 weeks) and/or 
cyclophosphamide (dose, 1-2 mg/kg/d); choice of 
rituximab v cyclophosphamide is patient speciﬁc 
and should be done with assistance of hematology 
consult; prednisone, rituximab, and 
cyclophosphamide should be given for at least 5 
weeks 
Factors should be provided to increase level during 
bleeding episodes, with choice of factor based on 
presence or absence of inhibitor 
G3-4: Severe, <1% of normal factor activity in 
blood, <0.01 IU/mL of whole blood 
Permanently discontinue ICPi 
Admit patient 
Hematology consult 
Administration of factor replacement, choice based 
on Bethesda unit level of inhibitor Bypassing agents 
may be used (factor VII, factor VIII inhibitor bypass 
activity); caution should be taken in the elderly and 
those with coronary artery disease 
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms) ± rituximab (dose, 375 mg/m2 weekly 
for 4 weeks) and/or cyclophosphamide (dose, 
1-2 mg/kg/d). 


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8.0 Hematologic Toxicities 
Transfusion support as required for bleeding 
If worsening or no improvement add cyclosporine or 
immunosuppression/immunoadsorption 
Additional considerations: The American Heart Association requires specialist clinical and laboratory 
expertise. Consult and/or transfer to a specialist center is often appropriate. If consultation with or 
transfer to a hemophilia center is not immediately possible, then investigation and treatment should be 
initiated while a liaison is being established. 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: AE = adverse event; ANC = absolute neutrophil count; ATG = antithymocyte globulin; CBC = complete 
blood count; CMV = cytomegalovirus; CNS = central nervous system; CT = computed tomography; CXR = chest 
x-ray; DIC = disseminated intravascular coagulation; EBV = Epstein-Barr virus; ECG = electrocardiogram; 
ER = extended release; FE = ferritin; G = Grade; GPI = glycosylphosphatidylinositol; Hgb = hemoglobin; 
HHV6 = human herpesvirus 6; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; 
ICPi = immune checkpoint inhibitor; INR = international normalized ratio; irAE = immune-related adverse event; 
IV = intravenous; IVIG = intravenous immunoglobulin; LDH = lactate dehydrogenase; LLN = lower limit of normal; 
MRI = magnetic resonance imaging; NSAID = nonsteroidal anti-inﬂammatory drug; PB = peripheral blood; 
PEX = plasma ex-change; PNH = paroxismal nocturnal hemoglobinuria; PT = prothrombin time; PTT = partial 
thromboplastin time; RBC = red blood cell count; TTP = thrombotic thrombocytopenic purpura. 
 


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Table A9 
Management of Cardiovascular irAEs in Patients Treated With 
ICPis 
9.0 Cardiovascular Toxicities 
9.1 Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and 
vasculitis 
Deﬁnition: Signs and symptoms may include chest pain, arrhythmia, palpitations, peripheral edema, 
progressive or acute dyspnea, pleural effusion, fatigue 
Diagnostic work-up 
At baseline 
ECG 
Consider troponin, especially in patient treated with combination immune therapies Upon 
signs/symptoms (consider cardiology consult) 
ECG 
Troponin 
BNP Echocardiogram CXR 
Additional testing to be guided by cardiology and may include 
Stress test 
Cardiac catherization Cardiac MRI 
Grading 
Management 
G1: Abnormal cardiac biomarker testing, 
including abnormal ECG 
G2: Abnormal screening tests with mild 
symptoms 
G3: Moderately abnormal testing or symptoms 
with mild activity 
G4: Moderate to severe decompensation, IV 
medication or intervention required, life-
threatening conditions 
All grades warrant work-up and intervention given 
potential for cardiac compromise 
Consider the following: 
For G1: Hold ICPi 
For G2, G3, and G4: Permanently discontinue ICPi 
For G1-G4: High-dose corticosteroids (1-2 mg/kg 
of prednisone) initiated rapidly (oral or IV 
depending on symptoms) 
Admit patient, cardiology consultation 
Immediate transfer to a coronary care unit for 
patients with elevated troponin or conduction 
abnormalities 
In patients without an immediate response to high-
dose corticosteroids, consider early institution of 
cardiac transplant rejection doses of corticosteroids 
(methylprednisolone 1 g every day) and the 
addition of either mycophenolate, inﬂiximab, or 
antithymocyte globulin 
Qualifying statement: Treatment recommendations are based on anecdotal evidence and the life-
threatening nature of cardiovascular complications. The appropriateness of rechallenging remains 
unknown. Note that inﬂiximab has been associated with heart failure and is contraindicated at high doses 
in patients with moderate-severe heart failure. 
9.2 Venous thromboembolism 
Deﬁnition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a 
distal site via the blood stream. Clinical signs and symptoms are variable and may include pain, 
swelling, increased skin vein visibility, erythema, and cyanosis accompanied by unexplained fever for 
DVT and dyspnea, pleuritic pain, cough, wheezing, or hemoptysis for PE 
Diagnostic work-up 
Evaluation of signs and symptoms of PE or DVT may include Clinical prediction rule to stratify patients 
with suspected venous thromboembolism Venous ultrasound for suspected DVT 


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9.0 Cardiovascular Toxicities 
CTPA for suspected PE 
Can also consider D-dimer for low-risk patients based on risk stratiﬁcation by clinical prediction rule for 
DVT/PE when CT or Doppler are not available or appropriate Ventilation/perfusion scan is also an 
option when CTPA is not appropriate 
Consider other testing, including ECG, CXR, BNP and troponin levels, and arterial blood gas 
Grading 
Management 
G1: Venous thrombosis (eg, superﬁcial 
thrombosis) 
Continue ICPi 
Warm compress 
Clinical surveillance 
G2: Venous thrombosis (eg, uncomplicated DVT), 
medical intervention indicated 
Continue ICPi based on benefit-risk assessment of 
individual patient 
Consider consult from cardiology or other relevant 
specialties 
LMWH is suggested over VKA, dabigatran, 
rivaroxaban apixaban, or edoxaban for initial and 
long-term treatment 
IV heparin is an acceptable alternative for initial 
use, and oral anticoagulants are acceptable for the 
long term 
G3: Thrombosis (eg, uncomplicated PE [venous], 
nonembolic cardiac mural [arterial] thrombus), 
medical intervention indicated 
Hold ICPi until AE reverts back to G1 or less. If 
reverts to G2, use benefit-risk assessment for ICPi 
continuation 
Consider consult from cardiology or other relevant 
specialties 
LMWH is suggested over VKA, dabigatran, 
rivaroxaban apixaban, or edoxaban for initial and 
long-term treatment 
IV heparin is an acceptable alternative for initial 
use, and oral anticoagulants are acceptable for the 
long term 
G4: Life-threatening (eg, PE, cerebrovascular 
event, arterial insufﬁciency), hemodynamic or 
neurologic instability, urgent intervention 
indicated 
Permanently discontinue ICPi 
Admit patient consult from cardiology or other 
relevant specialities 
Respiratory and hemodynamic support 
LMWH is suggested over VKA, dabigatran, 
rivaroxaban, apixaban, or edoxaban for initial and 
long-term treatment 
IV heparin is an acceptable alternative for initial 
use, and oral anticoagulants are acceptable for the 
long term 
Further clinical management as indicated based on 
symptoms 
Additional considerations 
While it may be impossible to determine the etiology of thromboembolic disease in patients with 
advanced cancer and the role, if any, that ICPi treatment plays, it is reasonable to permanently 
discontinue the potential inciting agents given the severity and life-threatening potential of G4 
complications. For G3 events, ICPi must be withheld and clinicians are to use clinical judgment and take 
into account the risks and beneﬁts when deciding whether to restart ICPi treatment. 
Anticoagulant therapy duration should continue for a minimum of 9-12 months to indeﬁnitely in the 
setting of active cancer unless patient is asymptomatic, doing well, or in remission. 


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9.0 Cardiovascular Toxicities 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: ACC = American College of Cardiology; AHA = American Heart Association; BNP = brain natriuretic 
peptide; CT = computed tomography; CTPA = computed tomography pulmonary angiography; CXR = chest x-ray; 
DVT = deep vein thrombosis; ECG = electrocardiogram; G = Grade; ICPi = immune checkpoint inhibitor; 
irAE = immune-related adverse event; IV = intravenous; LMWH = low-molecular-weight heparin; MRI = magnetic 
resonance imaging; PE = pulmonary embolism; VKA = vitamin K agonist. 
 


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Table A10 
Management of Ocular irAEs in Patients Treated With ICPis 
10.0 Ocular Toxicities 
Counsel all patients to inform their health care provider immediately if they experience any of the 
following ocular symptoms 
Blurred vision 
Change in color vision Photophobia 
Distortion 
Scotomas 
Visual ﬁeld changes Double vision Tenderness 
Pain with eye movement Eyelid swelling Proptosis 
Evaluation, under the guidance of ophthalmology 
Check vision in each eye separately 
Color vision 
Red reﬂex 
Pupil size, shape, and reactivity 
Fundoscopic examination 
Inspection of anterior part of eye with penlight 
Prior conditions 
Exclude patients with history of active uveitis 
History of recurrent uveitis requiring systemic immunosuppression or continuous local therapy 
Additional considerations 
Ocular irAEs are many times seen in the context of other organ irAEs 
High level of clinical suspicion as symptoms may not always be associated with severity Best to treat 
after ophthalmologist eye examination 
10.1 Uveitis/iritis 
Deﬁnition: Inﬂammation of the middle layer of the eye Diagnostic work-up: as per above 
Grading 
Management 
G1: Asymptomatic 
Continue ICPi 
Refer to ophthalmology within 1 week 
Artiﬁcial tears 
G2: Medical intervention required, anterior 
uveitis 
Hold ICPi temporarily until after ophthalmology 
consult 
Urgent ophthalmology referral 
Topical corticosteroids, cycloplegic agents, 
systemic corticosteroids 
May resume ICPi treatment once off systemic 
corticosteroids, which are purely indicated for 
ocular adverse effects or once corticosteroids for 
other concurrent systemic irAEs are reduced to ≤ 10 
mg; continued topical/ocular corticosteroids are 
permitted when resuming therapy to manage and 
minimize local toxicity Re-treat after return to G1 
or less 
G3: Posterior or panuveitis 
Permanently discontinue ICPi 
Urgent ophthalmology referral. 
Systemic corticosteroids and 
intravitreal/periocular/topical corticosteroids 


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10.0 Ocular Toxicities 
G4: 20/200 or worse 
Permanently discontinue ICPi 
Emergent ophthalmology referral 
Systemic corticosteroids (IV prednisone 1-2 mg/kg 
or methylprednisolone 0.8-1.6 mg/kg) and 
intravitreal/periocular/topical corticosteroids per 
ophthalmologist opinion 
Additional considerations: Consider use of inﬂiximab or other TNF-α blockers in cases that are severe 
and refractory to standard treatment 
10.2 Episcleritis 
Deﬁnition: Inﬂammatory condition affecting the episcleral tissue between the conjunctiva and the sclera 
that occurs in the absence of an infection Diagnostic work-up: As per 10.0 
Grading 
Management 
G1: Asymptomatic 
Continue ICPi 
Refer to ophthalmology within 1 week 
Artiﬁcial tears 
G2: Vision 20/40 or better 
Hold ICPi therapy temporarily until after 
ophthalmology consult 
Urgent ophthalmology referral 
Topical corticosteroids, cycloplegic agents, 
systemic corticosteroids 
G3: Symptomatic and vision worse than 2/40 
Permanently discontinue ICPi 
Urgent ophthalmology referral. 
Systemic corticosteroids and topical corticosteroids 
with cycloplegic agents 
G4: 20/200 or worse 
Permanently discontinue ICPi 
Emergent ophthalmology referral. 
Systemic corticosteroids and topical corticosteroids 
with cycloplegic agents 
Additional considerations: Consider use of inﬂiximab or other TNF-α blockers in cases that are severe 
and refractory to standard treatment 
10.3 Blepharitis 
Deﬁnition: Inﬂammation of the eyelid that affects the eyelashes or tear production Diagnostic work-up: 
As per 10.0 
Grading 
Management 
No formal grading system 
Warm compresses and lubrication drops 
Continue therapy unless persistent and serious 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
Abbreviations: ICPi = immune checkpoint inhibitor; G = Grade; irAE = immune-related adverse event; IV = intravenous, 
TNF = tumor necrosis factor. 


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10.10. 
Appendix 10: ECOG Performance Status 
The performance status is based on the ECOG Scale [Oken, 1982]. 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and Response Criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5:649-655. 
 


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10.11. 
Appendix 11: Renal Function Measures 
CKD-EPI Formula 
Chronic Kidney Disease (CKD) stage: Kidney Disease Outcomes Quality Initiative 
(KDOQI) CKD stages 3/4/5 defined by estimated glomerular filtration rate (eGFR) using 
the CKD Epidemiology Collaboration (CKD-EPI) formula [Levey, 2009]. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
Cockcroft-Gault Formula 
The Cockcroft-Gault formula is a commonly-used surrogate marker for actual creatinine 
clearance (CrCl) and employs creatinine measurements and a participant's weight (kg) to 
predict the clearance [Cockcroft, 1976].  
If the participant is obese (>30% over ideal body weight), use ideal body weight in 
calculation of estimated CrCl. 
If the participant is below ideal body weight, use actual body weight in calculation of 
estimated CrCl. 
Cockcroft-Gault Formula for serum creatinine in mmol/L  
 
 
 
CrCl (mL/min)= 
Q X (140-age [years]) X actual body weight (kg)a 
 
48816 X serum creatinine (mmol/L) 
Q=0.85 for females 
Q=1.0 for males 
OR 
a. Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974] 
Male participants: 
 
 
 
50.0 kg + (2.3 kg X each inch over 5 feet) 
or 
50.0 kg + (0.906 kg X each cm over 152.4 cm) 


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Female 
participants: 
 
 
 
45.5 kg + (2.3 kg X each inch over 5 feet) 
or 
45.5 kg + (0.906 kg X each cm over 152.4 cm) c 
Cockcroft-Gault Formula for serum creatinine in mg/dL 
 
For example: 
For a male participant with actual body weight = 90.0 kg and height = 68 inches, the 
calculation would be as follows: 
Ideal body weight= 50.0 + (2.3) (68-60) = 68.4 kg 
This participant’s actual body weight is >30% over ideal body weight. In this case, the 
participant’s ideal body weight of 68.4 kg should be used in calculating estimated 
creatinine clearance. 
References 
Cockcroft DW, Gault MH. Prediction of Creatinine Clearence from Serum Creatinine 
Nephron 1976; 16: 31-41.  
Devine BJ. Gentamicin therapy. Drug Intell Clin Pharm 1974;8:650–5. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al., CKD‐EPI 
(Chronic Kidney Disease Epidemiology Collaboration). A new equation to estimate 
glomerular filtration rate. Ann Intern Med. 2009 May 5;150:604-12. 


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10.12. 
Appendix 12: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents. 
Amendment 01 28-MAY-2020 
Overall Rationale for the Amendment: Protocol is an administrative amendment to 
clarify wording of inclusion criteria, QTcF text in the protocol, notes in the SoA, and 
other typos in the original protocol. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 SoA 
Clarified that use of ‘intervention’ 
and ‘treatment’ are interchangeable. 
Conmeds are to be collected during 
follow-up period.  
Brain CT/MRI added.  
Administrative changes are made for 
clarity.  
Conmeds will be collected for safety 
follow-up. 
Brain CT/MRI added to align with 
Section 8. 
Section 4.1 Overall 
Design 
Survival Follow-up will continue until 
the end of study as defined in 
Section 4.8 is removed.  
This statement was redundant.  
Section 5.1 
Inclusion 2 
At least eighteen (18) years of age 
at the time of signing the informed 
consent. 
Clarified to indicate years of age.  
Inclusion 3  
Renal, pelvis changed to renal 
pelvis. Uterus changed to ureter.  
Grammar and spelling correction.  
Inclusion 6 
Removed language regarding NCI 
CTACE toxicity. Expanded ECOG 
acronym to full words. 
Redundant to exclusion criterion 23. 
Expanded to full words for first usage. 
Inclusion 7 
Bilirubin 1.5 x ULN (isolated 
bilirubin >1.5 x ULN is acceptable if 
bilirubin is fractionated and direct 
bilirubin <35%). 
Correct the cut-off for bilirubin to less 
than or equal to 1.5 x ULN.  
Section 5.2 
Exclusion 8  
Excluded systemic corticosteroid 
use clarified to doses that are 
greater than 10 mg daily oral dose.  
Standard dosage prescribed would be 
10 mg or less therefore the protocol 
needs to allow for 10 mg. 
Exclusion 15 
F is added to QTc.  
Fridericia’s correction formula is to be 
used for standardization.  
Section 8.1 Study 
Assessments 
Complete is added to Physical 
Examination at screening.  
Align with SoA.  


T M F -1 4 3 9 6 6 2 5  
C O N FI D E N TI A L  
 
 
 
2 1 3 1 5 2  
 
Pr ot o c ol A m d 0 2  
1 5 4  
 
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  
Arc hiv al T u mor s a m pl e is 
m a n d at ory.  
S ecti o n 8. 3. 1 
Dis e as e R es p o ns e 
Ass ess m e nts  
Dis e as e ass ess m e nt cl a rifi e d to 
i ncl ud e p elvis. 
C h est, a b do m e n a n d p elvis are st a n dar d 
f or t his dise as e i n dic atio n. 
S ecti o n 8. 4. 3 Vital 
Si g ns  
Vit al si g ns will be m e as ur e d aft er 
5  mi n utes of r est i n a s e mi -s upi n e 
s e mir ec u mb e nt or s u pi n e p ositi o n, 
a n d will i ncl u d e te m p erat ur e, s yst olic 
a n d di ast olic bl o o d pr ess ur e, puls e 
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( m e as ur ed by p uls e oxi m etry 
C orr ect ty po –  r e mov e d s e mi-s u pi n e 
F ull d oc u me nt  
 
A d mi nistr ativ e ch a n g es m ad e t hr o u g h o ut 
d oc u me nt t o ali g n s ecti o ns f or cl arity a n d 
s p elli n g c orr ecti o ns.  
 
D O C U M E N T HI S T O R Y  
D o c u m e nt  
D at e  
D o c u m e nt I d e ntifi er  
A m e n d m ent 2  
0 3 M ar 20 2 2  
T M F -1 4 3 9 66 2 5  
A m e n d m ent 1  
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2 0 1 9 N 4 1 1 0 39 _ 0 1  
Ori gi nal Pr ot oc ol  
3 0 J a n 2 0 2 0  
2 0 1 9 N 4 1 1 0 39 _ 0 0  
 
 
C CI
C CI


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11. 
REFERENCES 
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pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or 
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Bellmunt J, et al. A. Pembrolizumab as second-line therapy for advanced urothelial 
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer 
statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 
cancers in 185 countries. CA: a cancer journal for clinicians. 2018 Nov;68(6):394-424. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics. 1982;38:29-41. 
De Santis M, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and 
methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are 
unfit for cisplatin-based chemotherapy: EORTC study 30986. Journal of clinical 
oncology. 2012 Jan 10;30(2):191.  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, et al. New response evaluation 
criteria in solid tumours: revised RECIST guidelines (version 1.1). Eur J Cancer. 2009; 
45:228-47. 
Goudie DR, D’Alessandro M, Merriman B, et al., Multiple self-healing squamous 
epithelioma is caused by disease-specific spectrum of mutations in TGFBR1. Nat Genet. 
2011;43(4):365-9.  
Grivas P, Castellano D, O'Donnell P, Cristescu R, Frenkl R, Keefe S, et. al., Association 
between stromal/TGF-β/EMT gene expression signature and response to pembrolizumab 
monotherapy in cisplatin-ineligible patients with locally advanced (unresectable) or 
metastatic urothelial carcinoma. Journal of Clinical Oncology. Journal of Clinical 
Oncology 2019 37:7_suppl, 433-433.  
Hilbish KG, Martin JA, Stauber AJ, et al., TGF-β1 monoclonal antibody: Assessment of 
embryo fetal toxicity in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 
2016;107(4 5):174-84. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials 2008: 5. 93–106. 


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Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang, et. al., TGF-β 
attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. 
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Morris JC, Tan AR, Olencki TE, et al., Phase I study of GC1008 (fresolimumab): a 
human anti-transforming growth factor-beta (TGF-) monoclonal antibody in patients 
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2014;9(3):e90353. 
NCI-CTCAE v5 Common Terminology Criteria for Adverse Events, Version 5. 2017. 
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Powles T, O’Donnell P, Massard C, Arkenau H, Friedlander T, Hoimes C, et. al., 
Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial 
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Sanli et al., Nature Reviews Disease Primers volume 3, Article number: 17022 (2017) 
Von der Maase et al., Journal of Clinical Oncology, Vol 17, No 17 (September), 2000: pp 
3068-3077 
 


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Si g n ifica nt c ha n ges t o ali g n wit h 
Merc k Bi n traf us p Alfa trial a nal ysis 
pla ns. See trac k e d c h a n ges . 
0. 3  
1 1 N O V 2 0 2 0  
U p date d Secti o n  2. 4 f or t a ble of 
e n d p oi nts.  
A d de d details of e x pl orat or y 
e n d p oi nts a nal ysis . 
A d de d details  of missi n g date 
i m p utati o ns a n d m o ve d t o a p pe n di x 
2.  
U p date d details f or C O VI D -1 9 
a nal ys es t o be c o nsiste nt wit h G S K 
c o m pa n y rec o m me n dati o ns . 
0. 4  
0 4J A N 2 0 2 1   
 
0 7J U L 2 0 2 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
U p date d refere nces. 
 
Si g nifica nt c ha n ges t o ali g n wit h 
st u d y sc o pe d u e t o Pr ot oc ol 
A me n d me nt 0 2.  
P P D
P P D
P P D
P P D
P P D
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c ha n ge i n st u d y sc o pe . 
T he f oll o wi n g  pre vi o usl y pla n ne d 
a nal ys es were re m o ve d:  
All a nal ys es relat e d t o I nteri m 
A nal y sis,
a n d 
 
 
P P D
C CI
C CI
C CI
C CI
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
T A B L E O F C O N T E N T S  
1.  
I N T R O D U C TI O N ......................................................................................................... 1 0  
2.  
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  ............................................................... 1 0  
2. 1.  
Pri m ar y O bjecti ve  ......................................................................................................................................... 1 0  
2. 2.  
Sec o n d ar y O bjecti ve  ...................................................................................................................................... 1 0  
2. 4.  
E n d p oi nts  ........................................................................................................................................................ 1 1  
3.  
S T U D Y D E SI G N  ........................................................................................................... 1 3  
3. 1.  
Ge ner al Descri pti o n  ....................................................................................................................................... 1 3  
3. 2.  
Sc he d ule of Acti vities  ..................................................................................................................................... 1 5  
3. 3.  
C h a n ges t o A n al ysis fr o m Pr ot oc ol  .............................................................................................................. 1 5  
4.  
P L A N N E D A N A L Y S E S ................................................................................................ 1 6  
5.  
A N A L Y SI S S E T S  .......................................................................................................... 1 6  
5. 1.  
Scree ne d A n al ysis  [ S C R] Set  ....................................................................................................................... 1 6  
5. 2.  
S afet y/ Tre ate d A n al ysis Set [ S A F]  ............................................................................................................... 1 6  
6.  
G E N E R A L C O N SI D E R A TI O N S  ................................................................................ 1 7  
6. 1.  
Refere nce St a rt D ate a n d St u d y D a y  ........................................................................................................... 1 7  
6. 2.  
B aseli ne  ........................................................................................................................................................... 1 7  
6. 3.  
Deri ve d Ti me p oi nts  ....................................................................................................................................... 1 8  
6. 3. 1.  
O n -Treat me nt P eri o d  ............................................................................................................................... 1 8  
6. 4.  
Retests, U nsc he d ule d Visits a n d E arl y Ter mi n ati o n D at a  ......................................................................... 1 8  
6. 5.  
Wi n d o wi n g C o n ve nti o ns  ............................................................................................................................... 1 9  
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
6. 6.  
St atistic al Tests  .............................................................................................................................................. 1 9  
6. 7.  
C o m m o n C alc ul ati o ns  ................................................................................................................................... 1 9  
6. 8.  
S oft w are Versi o n  ............................................................................................................................................ 2 0  
7.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ......................................................................... 2 0  
7. 1.  
A dj ust me nts f or C o v ari ates a n d F act ors t o be I ncl u de d i n A n al yses  ....................................................... 2 0  
7. 2.  
M ultice nter St u dies  ........................................................................................................................................ 2 0  
7. 3.  
Missi n g d at a  ................................................................................................................................................... 2 0  
7. 4.  
M ulti ple C o m p aris o ns/ M ulti plicit y  ............................................................................................................. 2 1  
7. 5.  
E x a mi n ati o n of S u b gr o u ps  ............................................................................................................................ 2 1  
8.  
O U T P U T P R E S E N T A TI O N S  ...................................................................................... 2 1  
9.  
DI S P O SI TI O N A N D WI T H D R A W A L S ..................................................................... 2 1  
9. 1.  
Dis p ositi o n  ...................................................................................................................................................... 2 1  
9. 2.  
Pr ot oc ol De vi ati o ns  ........................................................................................................................................ 2 3  
1 0.  
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E R I S TI C S ................ 2 3  
1 0. 1.  
De m o gr a p hics  ............................................................................................................................................. 2 3  
1 0. 2.  
Deri v ati o ns  ................................................................................................................................................. 2 4  
1 1.  
M E DI C A TI O N S  ......................................................................................................... 2 4  
1 1. 1.  
Pre vi o us A nti -c a ncer Tre at me nts a n d Pr oce d ures  ................................................................................. 2 4  
1 1. 2.  
Pre me dic ati o ns f or Bi ntr af us p Alf a  ......................................................................................................... 2 5  
1 2.  
S T U D Y T R E A T M E N T E X P O S U R E  ....................................................................... 2 5  
1 2. 1.  
Deri v ati o ns  ................................................................................................................................................. 2 6  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 7  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
1 3.  
E F FI C A C Y A N D E X P L O R A T O R Y O U T C O M E S  ............................................... 2 7  
1 3. 1.  
Pri m ar y Effic ac y  ........................................................................................................................................ 2 7  
1 3. 1. 1 . 
Pri mar y Efficac y Varia ble(s) & Deri vati o n(s)  ......................................................................................... 2 7  
1 3. 1. 2.  
Missi n g Data Met h o ds f or Pri mar y Efficac y Varia ble(s)  ........................................................................ 2 8  
1 3. 1. 3.  
Fi nal  A nal ysis of Pri mar y Efficac y Varia ble(s)  ...................................................................................... 2 8  
1 4.  
S A F E T Y O U T C O M E S  .............................................................................................. 3 5  
1 4. 1.  
A d verse E ve nts  ........................................................................................................................................... 3 5  
1 4. 1. 1.  
All A Es  .................................................................................................................................................... 3 7  
1 4. 1. 1. 1.  
Se verit y  ............................................................................................................................................ 3 7  
1 4. 1. 1. 2.  
Relati o ns hi p t o St u d y Treat me nt  ..................................................................................................... 3 8  
1 4. 1. 2.  
T E A Es Lea di n g t o T e m p orar y Treat me nt I nterr u pti o n a n d Wit h dra wal of St u d y Treat me nt  ................. 3 8  
1 4. 1. 3.  
T E A Es Lea di n g t o St u d y T er mi nati o n  .................................................................................................... 3 9  
1 4. 1. 4.  
Seri o us A d verse E ve nts  ........................................................................................................................... 3 9  
1 4. 1. 5.  
A Es Lea di n g t o Deat h  .............................................................................................................................. 3 9  
1 4. 1. 6.  
A Es Of S pecial I nterest ............................................................................................................................ 3 9  
1 4. 1. 6. 1.  
I nf usi o n-relate d Reacti o ns I ncl u di n g I m me diate H y perse nsiti vit y .................................................. 4 0  
1 4. 1. 6. 2.  
I m m u ne-relate d A Es ........................................................................................................................ 4 0  
1 4. 1. 6. 3.  
P ote ntial T G F β -me diate d S ki n A Es  ................................................................................................. 4 0  
1 4. 1. 6. 4.  
Treat me nt relate d A ne mia ................................................................................................................ 4 0  
1 4. 1. 6. 5.  
Blee di n g E ve nts  ............................................................................................................................... 4 1  
1 4. 1. 6. 6.  
W o u n d Heali n g Dela y  ..................................................................................................................... 4 1  
1 4. 1. 6. 7.  
Sec o n dar y Mali g na ncies  .................................................................................................................. 4 1  
1 4. 1. 6. 8.  
E m br y ofetal T o xicities  .................................................................................................................... 4 1  
1 4. 2.  
De at hs  ......................................................................................................................................................... 4 1  
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 8  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
1 4. 3.  
L a b or at o r y E v al u ati o ns ............................................................................................................................ 4 2  
1 4. 3. 1.  
Refere nce Ra n ges a n d C T C Gra di n g f or La b orat or y Data  ...................................................................... 4 3  
1 4. 3. 1. 1.  
N CI -C T C A E Gra d a ble P ara meters  .................................................................................................. 4 3  
1 4. 3. 1. 2.  
N o n -gra d a ble P ara meters  ................................................................................................................. 4 5  
1 4. 4.  
E C G E v al u ati o ns  ....................................................................................................................................... 4 6  
1 4. 5.  
Vit al Si g ns  ................................................................................................................................................... 4 6  
1 4. 6.  
Ot he r S afet y Assess me nts  ......................................................................................................................... 4 7  
1 4. 6. 1.  
Pre g na nc y T est ......................................................................................................................................... 4 7  
1 4. 6. 2.  
P h ysical E xa m  ......................................................................................................................................... 4 7  
R E F E R E N C E S  ...................................................................................................................... 4 8  
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S  ........................ 4 9  
I Q VI A O ut p ut C o n ve nti o ns...................................................................................................................................... 4 9  
I ntro d ucti o n  ............................................................................................................................................................... 4 9  
O ut p ut File N a mi n g C o n ve nti o ns  ............................................................................................................................. 4 9  
P a per Size, Orie nt ati o n a n d M ar gi ns  ...................................................................................................................... 4 9  
F o nts  ........................................................................................................................................................................... 5 0  
He a der I nf o r m ati o n  ................................................................................................................................................... 5 0  
T a ble a n d Listi n g O ut p ut C o n ve nti o ns  ................................................................................................................... 5 1  
F o ot n ote I nf o r m ati o n  ................................................................................................................................................ 5 4  
Pr o gr a m mi n g I nstr ucti o ns  ........................................................................................................................................ 5 4  
D ate s & Ti mes ............................................................................................................................................................ 5 4  
S pelli n g F or m at .......................................................................................................................................................... 5 5  
Prese nt ati o n of Tre at me nt Gr o u ps  .......................................................................................................................... 5 5  
Prese nt ati o n of Visits  ................................................................................................................................................. 5 5  
Listi n gs  ....................................................................................................................................................................... 5 5  
C o n versi o n f act ors  ..................................................................................................................................................... 5 5  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 9  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
Defi niti o n of d ur ati o n  ................................................................................................................................................ 5 5  
A P P E N DI X 2.  P A R TI A L D A T E C O N V E N T I O N S ....................................................... 5 7  
Missi n g d at a h a n dli n g r ules f or a ge c alc ul ati o n  ...................................................................................................... 5 7  
Missi n g d at a h a n dli n g r ules f or de at h d ate  ............................................................................................................. 5 7  
Missi n g d at a h a n dli n g r ules f or l ast c o nt a ct d ate  ................................................................................................... 5 7  
Missi n g d at a h a n dli n g r ules f or a d verse e v e nts  ...................................................................................................... 5 8  
Missi n g d at a h a n dli n g r ules f or s u bse q ue nt a ntic a ncer t her a p y  ........................................................................... 5 8  
Missi n g d at a h a n dli n g r ules f or pre vi o us me dic ati o ns, c o nc o mit a nt me dic ati o ns a n d pri or a ntic a ncer 
t her a pies or pr oce d ures ............................................................................................................................................. 5 8  
A P P E N DI X 3.  A D V E R S E E V E N T S O F S P E CI A L I N T E R E S T  .................................. 6 0  
A P P E N DI X 4.  C T C A E G R A DI N G C RI T E R I A ............................................................. 6 1  
A P P E N DI X 5.  A B B R E VI A TI O N S  ................................................................................... 6 2  
 
 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 0  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
1.  IN T R O D U C TI O N  
T his d oc u me nt descri bes t he r ules a n d c o n v e nti o ns t o be use d i n t he prese nt ati o n a n d a nal ysis 
of effic ac y  a n d safet y d at a f or Pr ot oc ol 2 1 3 1 5 2.  It descri bes  t he data t o be s u m marize d a n d 
a nal yze d, i n cl u di n g s pecifics of t he statistical a nal ys es t o be p erf or me d.  
 
T his statistical a nal ysis pla n ( S A P) is base d o n P r ot oc ol A me n d me nt 0 2  date d 0 3 -Ma r-2 0 2 2  
a n d e C R F versi o n  2 . 0 date d 1 0 -J u n-2 0 2 0 .  
2.  S T U D Y O B J E C TI V E S  A N D E N D P OI N T S  
2. 1.  P RI M A R Y O B J E C TI V E  
T he pri mar y o bje cti ve is  t o eval uate t he a nti -t u m or acti vit y p er Res p o nse E val uati o n Criteria 
i n S oli d T u m ors (R E CI S T ) 1. 1  i n partici pa nt s wit h metastatic or l ocall y 
a d va nce d/ u nresecta ble ur ot helial ca ncer treate d wit h bi ntraf us p alfa . 
2. 2.  S E C O N D A R Y O B J E C TI V E  
T he sec o n d ar y o bjecti ve is: 
•  
E val uate t he safet y a n d t olera bilit y of bi ntraf us p alfa i n partici pa nt s wit h ur ot helial ca ncer 
 
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 1  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
2. 4.  E N D P OI N T S  
T he pri mar y , sec o n dar y a n d e x pl orat or y en d p oi nts  rele va nt t o a n al ys es t o be perf or me d 
base d o n t his S A P are descri be d i n t he f oll o wi n g ta ble:  
 
P P D
C CI
C
CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 2  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
T a ble A:  
List of E n d p oi nts  
O bjecti ves  
E n d p oi nts  
S A P 
Secti o n  
A n al ysis Set  
V ari a ble  
P ri m ar y  
 
 
 
 
E val uate t he a nti -t u m or acti vit y 
per R E CI S T 1. 1  i n partici pa nts 
wit h metastatic or l ocall y 
a d va nce d/ u nresecta ble ur ot helial 
ca ncer treate d wit h bi ntraf us p 
alfa   
C o nfir me d O verall 
Res p o nse per 
R E CI S T 1. 1 
assesse d b y 
i n vesti gat or.   
1 3. 1  
Safet y/ Treate d  O R R ( b y 
I n vesti gat or) 
Sec o n d ar y  
  
 
 
 
E val uate t he safet y a n d 
t olera bilit y of bi ntraf us p alfa i n 
partici pa nts wit h ur ot helial 
ca ncer. 
Fre q ue nc y a n d 
se verit y of A Es 
usi n g Err or! 
Ref ere nce s o urce 
n ot f o u n d. . 
1 4. 1. 1   
Safet y/ Treate d  Treat me nt 
E mer ge nt 
A d verse 
E ve nts 
( T E A E) 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 3  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
O bjecti ves  
E n d p oi nts  
S A P 
Secti o n  
A n al ysis Set  
V ari a ble  
;  B O R = B est O verall Res p o nse ;  N CI C T C A E = T o xicit y Gra di n g base d o n nati o nal 
Ca ncer I nstit ute-C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts v 5 ;  O R R = o verall res p o nse rate; 
; R E CI S T 1. 1 = Res p o nse E val uati o n Criteria i n S oli d T u m ors Versi o n 1. 1. 
3.  S T U D Y D E SI G N  
3. 1.  G E N E R A L D E S C RI P TI O N  
T his is a P hase I b o pe n -l a bel, gl o bal, m ultice nter, si n gle-ar m trial of bi ntraf us p alfa a d mi nistere d 
t o partici pa nt s wit h metastatic or l ocall y a d va n ce d/ u nresecta bl e ur ot helial ca ncer wit h disease 
pr o gressi o n or rec urre nce f oll o wi n g treat me nt wit h a plati n u m a ge nt.  
 
T he pri mar y st u d y o bjecti ve is t o e val uate t he O R R per R E CI S T v 1. 1. T he s ec o n dar y o bj ecti ve 
is t o e val uate safet y a n d t olera bilit y of bi ntraf us p alfa .  
 
Partici pa nt s w h o per ma n e ntl y disc o nti n ue st u d y tr eat me nt will e nter t he f oll o w-u p peri o d of t he 
st u d y a n d u n d er g o t he assess me nts as i n dicate d i n Secti o n 8 of t he Pr ot oc ol.  
A p pr o xi matel y 2 5 p artici pa nt s will be treate d i n t his st u d y.  
 
T he st u d y i ncl u d es:  
•  
4 5 -da y scree ni n g peri o d  
•  
Treat me nt wit h bi ntraf us p alfa 1 2 0 0 m g as a n I V i nf usi o n Q 2 W u ntil disease pr o gressi o n 
P P D
C CI
C CI
C CI
C CI
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 4  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
as deter mi ne d b y I n v esti gat or usi n g R E CI S T v 1. 1  ( Eise n ha uer E A, 2 0 0 9) d eat h, 
u nacce pta ble t o xicit y, st u d y wit h dr a wal, or u p t o 2 years (s ee Pr ot oc ol, S ecti o n 7) .   
•  
Partici pa nt s w h o ha ve e x perie nce d a c o nfir me d c o m plete res p o nse ( C R) ca n c o nti n ue 
treat me nt f or a ma xi m u m of 2 4 m o nt hs after c o nfir mati o n of res p o nse (at t he discreti o n 
of t he I n vesti gat or). If t h e I n vesti gat or belie v es t h at a partici pa nt  wit h c o nfir me d C R ma y 
be nefi t fr o m treat me nt be y o n d 2 4 m o nt hs, it ma y b e per missi ble t o c o nti n ue treat me nt 
after disc ussi o n wit h t he G S K Me dical M o nit or.  
•  
Partici pa nt s wit h sta ble disease (S D ) or partial r es p o nse ( P R ) s h o ul d c o nti n ue treat me nt 
u p t o a peri o d of 2 4 m o nt hs  fr o m first d ose u ntil disease pr o gressi o n, or a n y ot her 
disc o nti n uati o n criteri o n is met.  
•  
Safet y F oll o w -u p: will c o nti n ue u ntil 1 2 wee ks after t he last a d mi nistrati o n  of bi ntraf us p 
alfa. T he 1 2 -wee k Safet y F oll o w -u p ca n be c o n d u cte d via tele p h o ne calls or partici pa nt  
chart re vie ws u nless t here is me dical necessit y re q uiri n g a cli nical visit.  
•  
L o n g -t er m F oll o w-u p: s h o ul d be perf or m e d e ver y 1 2 wee ks after t he Safet y F oll o w -u p 
acc or di n g t o t he Sc h e d ule of Acti vities (see Secti o n 1. 3 of t he P r ot oc ol). L o n g-ter m 
F oll o w -u p s h o ul d be perf or me d b y c hart re vie ws or tele p h o ne calls.  
•  
O nce t he D ata C ut -Off ( D C O ) date f or t he fi nal a nal ysis f or t his st u d y has bee n reac h e d, 
t he cli nical st u d y d ata bas e will be cl ose d t o ne w data a n d a n y p artici pa nts t hat c o nti n ue t o 
recei v e st u d y i nter ve nti o n at t his ti me will be f oll o we d as des cri be d i n Secti o n 8. 2 of t he 
pr ot oc ol.  
Bi o psies pri or t o st u d y treat me nt are re q uir e d, as descri be d i n eli gi bilit y criteria ( see Pr ot o c ol 
Secti o n  5. 1 ).
 
P P D
C CI
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 5  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
T a ble B:  
S T U D Y S C H E M A  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. 2.  S C H E D U L E O F A C TI VI TI E S  
Sc he d ule of acti vities  ca n be f o u n d i n Secti o n 1. 3  of t he P r ot oc ol. 
3. 3.  C H A N G E S T O A N A L Y SI S F R O M P R O T O C O L  
•  
T he ter m “ A Es ” i n t he  e n d p oi nt “Fre q u e nc y a n d s e verit y of A Es” ass ociat e d wit h t he 
sec o n dar y o bj ecti ve “ E v al uate t he safet y a n d t olera bilit y of bi ntraf us p alfa i n partici pa nts 
wit h ur ot helial ca ncer”  i n t he pr ot oc ol, refers t o a d verse e v e nts t hat be gi n o n or after t h e 
start of t he st u d y tr eat me nt or w orse ne d after t he start of t he st u d y treat me nt a n d t heref ore 
are tr eat me nt-e m er ge nt A Es ( T E A Es). T E A Es will be use d as t he e n d p oi nt t o be re p orte d 
i n t his S A P. 
•  
D ue t o  s pecial cir c u msta nces relati n g t o t he  C O VI D -1 9 pa n d e mic , t he s pecific g ui da nce 
fr o m l ocal p u blic healt h a n d ot her c o m pet e nt a ut h orities re gar di n g t he pr otecti o n of 
i n di vi d uals’ welfare will be a p plie d.  F or t he d urati o n of s uc h s pecial circ u msta nces, t he 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 6  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
f oll o wi n g ma y i m pact t h e data a n d a nal ysis : 
•  
D ela ye d F PI ( First Patie nt I n) 
•  
Pr ot oc ol de via ti o ns d ue t o C O VI D-1 9  
•  
M isse d visits d ue t o C O VI D -1 9  
•  
Misse d or m o difie d assess me nts  
•  
Treat me nt i nterr u pti o ns  or dela ys  
•  
E arl y st u d y disc o nti n uati o n or wit h dra wals d u e t o ha vi n g C O VI D -1 9  or C O VI D -
1 9  relate d iss ues 
•  
A d v erse e ve nts  or S A Es  d ue t o C O VI D -1 9 . 
4.  P L A N N E D A N A L Y S E S  
All pla n ne d a nal yses i de ntifie d i n t his S A P will be perf or me d i n a Fi nal A nal ysis b y I Q VI A 
Bi ostatistics f oll o wi n g S p o ns or A ut h orizati o n of t his Statistical A nal ysis Pl a n  a n d Dat a base 
L oc k.  
5.  A N A L Y SI S S E T S  
Defi niti o ns f or a nal ysis s ets are p r o vi d e d bel o w. 
 
5. 1.  S C R E E N E D A N A L Y SI S  [ S C R] S E T  
T he Scree ne d A n al ysis ( S C R) set will c o ntai n all par tici pa nts w h o si g n t h e I C F. 
5. 2.  S A F E T Y / TR E A T E D  A N A L Y SI S S E T [ S A F] 
T he safet y /treate d a n al ysis set  ( S A F) will  c o ntai n all partici pa nt s w h o were a d mi nistere d at 
least o ne i nf usi o n of bi ntraf us p alf a . 
 
If t here is a n y d o u bt w het her a partici pa nt  was tr eate d or n ot, t he y will be ass u me d  t o ha ve 
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 7  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
bee n treate d f or t h e p ur p oses of a nal ysis. T his is t he pri mar y a n al ysis set f or re p orti n g 
effic ac y a n d s afet y.  
6.  G E N E R A L C O N SI D E R A TI O N S  
6. 1.  R E F E R E N C E S T A R T D A T E A N D S T U D Y D A Y  
St u d y Da y will be calc ul ate d fr o m t he refere n ce st art date a n d  will be use d t o s h o w s tart/st o p 
da y of assess me nts a n d e ve nts .  
 
Refere n ce start date is defi ne d as t he da y of t he first a d mi nistrati o n  of st u d y treat me nt ( Da y 1 
is t he da y of t he first a d mi nis trati o n of st u d y treat me nt). 
•  
If t he date of t he e v e nt is o n or after t h e refere nce date,  t he n:  
St u d y Da y = ( date of e ve nt –  refere nce date) + 1. 
•  
If t he date of t he e v e nt is pri or t o t he refere n ce d ate,  t he n:  
St u d y Da y = ( date of e ve nt –  refere nce date). 
 
I n t he sit uati o n w h ere t he e ve nt date is partial or missi n g, t he date will a p pear partial or 
missi n g i n t he listi n gs, a n d St u d y Da y , a n d a n y c orres p o n di n g d urati o ns will be prese nt e d 
base d o n t he i m p utati o ns s pecifie d i n A p pe n di x 2; Partial Date C o n ve nti o ns . 
6. 2.  B A S E LI N E  
U nless ot her wise s pecifie d, baseli ne is defi ne d as t he last a vaila ble/n o n -missi n g 
meas ure me nt ta k e n pri or t o refere nce start date. 
•  
If a n ass ess me nt is pla n ne d t o be perf or me d pri or t o t he first a d mi nistrati o n of st u d y 
treat me nt i n t he pr ot oc ol a n d t he assess me nt is perf or me d o n t he sa me da y as t he first  
a d mi nistrati o n of st u d y tr eat me nt, it will be ass u me d t hat it was perf or me d pri or t o st u d y 
treat me nt, if assess me nt ti me is n ot c ollecte d or is missi n g.  
•  
If assess me nt ti me is c ollecte d, t he o bser ve d ti me as well as ti me of first d ose of st u d y 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 8  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
treat me nt will be use d t o deter mi ne pre -d ose o n st u d y da y 1 f or bas eli ne calc ulati o n.  
•  
U nsc he d ule d assess me nts will be use d i n t he deter mi nati o n of baseli ne. H o we ver, if ti me 
is missi n g, a n u nsc he d ule d assess me nt o n St u d y Da y 1 will be c o nsi dere d t o ha ve bee n 
o btai ne d after s t u d y tr eat me nt. 
I n t he cas e w here t he last n o n-missi n g meas ure me nt a n d t he refere n ce start date c oi nci de, 
t hat meas ure me nt will be c o nsi dere d pre-b aseli ne, b ut A d verse E v e nts ( A E s) a n d 
me dicati o ns c o m me nci n g o n t he refere n ce start d ate will be c o nsi dere d p ost -baseli ne.  
6. 3.  D E RI V E D T I M E P OI N T S  
6. 3. 1.  
O N -T R E A T M E N T P E RI O D  
T he o n -treat me nt peri o d is defi ne d as t he ti me fr o m first st u d y treat me nt t o t he last st u d y 
treat me nt date pl us 3 0 da ys or t he earliest d ate of s u bse q ue nt a ntica n cer t h era p y mi n us 1 da y, 
w hic he ver occ urs first , u nless ot her wise state d.  
 
F or partici pa nts wit h treat me nt o n g oi n g at c ut -off date, all data fr o m t he first st u d y treat me nt  
u p t o t he c ut -off dat e will be c o nsi dere d u n d er t he o n -treat me nt peri o d. 
 
A n y s yste mic a ntica ncer t hera p y, a n y a ntica ncer s ur ger y a n d a n y a ntica ncer ra di ot hera p y as 
d oc u me nte d i n t he ” A nti -ca ncer treat me nt after disc o nti n uati o n” eC R F pa ge will be 
c o nsi dere d as s u bse q ue nt a ntica ncer t hera p y.  
 
I n t he cas e of treat me nt d ela y, t he defi niti o n f or o n-treat me nt peri o d re mai ns t he sa me.  
6. 4.  R E T E S T S , U N S C H E D U L E D V I SI T S A N D E A R L Y T E R MI N A TI O N 
D A T A  
F or efficac y a n al ys es, u nsc he d ule d ass ess me nts ca n be use d i n t he deter mi nati o n of baseli ne 
acc or di n g t o S ecti o n 6. 2 . U nsc he d ule d visits p ost-baseli ne will be e x cl u de d fr o m ta ble 
s u m maries
 b ut will be i ncl u de d i n listi n gs.  
 
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 1 9  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
Listi n gs will i ncl u de sc h e d ule d , u nsc he d ule d , retest a n d earl y disc o nti n uati o n data . 
 
Re -scree ne d p artici pa nts will o nl y b e c o u nte d o nce i n t he S C R, a n d will c o nsi der o nl y t he 
latest scree ni n g (scree ni n g wit h t he latest i nf or m e d c o nse nt). 
6. 5.  W
I N D O WI N G C O N V E N TI O N S   
N o visit wi n d o wi n g will be perf or me d f or t his st u d y.  
6. 6.  S T A TI S TI C A L T E S T S  
T he defa ult si g nifica nce l e vel will be ( 5 %); c o nfi d e nce i nter vals will be 9 5 % a n d all tests 
will be t w o -si de d, u nless ot her wise s pecifie d i n t he descri pti o n of t he a nal yses. I n ge neral,  
c o nti n u o us varia bles will be s u m marize d usi n g n u m ber  a n d perce nt a ge of partici pa nts , 
n u m ber a n d perce nt a ge of partici pa nts wit h missi n g val u es,  mea n, sta n d ar d de viati o n, 
me dia n, 2 5 t h-7 5 t h perce ntile ( Q 1 -Q 3), mi ni m u m a n d ma xi m u m. If t here are n o missi n g val ues 
t he n u m ber of partici pa nts wit h missi n g val ues will be set t o 0.  
 
Cate g orical varia bles will be s u m marize d usi n g n u m ber of partici p a nts a n d perce nt a ges. 
U nless ot her wise state d p erce nt a ges are calc ulate d base d o n t he n u m ber of partici pa nt s i n t he 
a nal ysis s et of i nterest  a n d c o u nts of missi n g o bser vati o ns will be i ncl u de d i n t he 
de n o mi nat or . C o u nts of missi n g o bser vati o ns will be i ncl u de d as a s e parate cate g or y i n ta ble 
s u m maries. F or b y -visit s u m maries, de n o mi nat ors will i ncl u de t he n u m ber of partici pa nts i n 
t he a nal ysis set of i nterest t hat are still prese nt i n t he st u d y at t hat visit.  
6. 7.  C O M M O N C A L C U L A TI O N S  
F or q ua ntitati ve meas ure me nts, c ha n ge fr o m baseli ne will be calc ulate d as:  
 
•  
C ha n ge fr o m bas eli ne = ti me p oi nt val ue –  baseli ne val ue  
•  
Perce nt C ha n ge fr o m b as eli ne = 1 0 0 * (ti me p oi nt val ue –  baseli ne v al ue) / baseli ne v al ue. 
C ha n ge fr o m bas eli ne will o nl y b e calc ulate d w h e n b ot h t he ti me p oi nt a n d baseli ne val ues 
are n o n-missi n g.  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 0  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
6. 8.  S O F T W A R E V E R SI O N  
All a nal ys es will be c o n d ucte d usi n g S A S versi o n 9. 4  or hi g h er.   
7.  S T A TI S TI C A L C O N SI D E R A TI O N S  
7. 1.  A D J U S T M E N T S F O R C O V A RI A T E S A N D F A C T O R S T O B E 
IN C L U D E D I N A N A L Y S E S  
T he re will be n o a dj ust me nt f or c o v ariates i n t he a nal ysis. I n a d diti o n, as t he st u d y is o pe n-
la bel a n d o nl y i ncl u des o ne ar m, n o a dj ust me nts will be ma de f or ra n d o mizati o n or bli n di n g 
p ur p oses.  
7. 2.  M U L TI C E N T E R S T U DI E S  
T his st u d y will be c o n d u cte d b y m ulti ple i n vesti gat ors at m ulti ple ce nters i nter nati o nall y.   
 
W he n s pecifie d, statistical a nal ysis will be prese nte d b y  ge o gra p hic re gi o n. Ge o gra p hic 
re gi o n will be cate g orize d as f oll o ws: 
 
Ge o g r a p hic Re gi o n  
C o u ntr y  
N ort h A meric a  
U nite d States, Ca na da  
E ur o pe  
U K, S pai n, Net herl a n ds, Fra n ce  
7. 3.  M I S SI N G D A T A 
U nless ot her wise state d, missi n g data will n ot be i m p ute d. Missi n g statistics s h o ul d be 
prese nte d as “ n d”  f or “ n ot deter mi ne d” i n ta bles. 
 
Missi n g dates (i nc o m plet e or partial d ates a n d ha n dli n g of a ge cal c ulati o ns, disease hist or y, 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 1  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
A Es , pri or a n d c o n c o mita nt me dicati o ns, s u bse q ue nt a nti-ca n cer t hera p y a n d deat h date)  will 
be ha n dle d as p er A p p e n di x 2 of t his S A P.  
 
Missi n g effi cac y d ata will be ha n dle d as des cri be d i n S ecti o n 1 3. 1. 2  a n d 1 3. 2. 3  of t his S A P.   
7. 4.  M U L TI P L E C O M P A RI S O N S / M U L TI P LI CI T Y  
As t here is o nl y o ne pri m ar y efficac y e n d p oi nt, n o a dj ust me nts will be ma de f or m ulti ple 
c o m paris o ns.  
7. 5.  E X A MI N A TI O N O F S U B G R O U P S  
T here will be n o s u b gr o u p a nal ys es c o n d u cte d f or t his st u d y.  
8.  O U T P U T P R E S E N T A TI O N S  
A p pe n di x 1 s h o ws c o n ve nti o ns f or prese ntati o n of data i n o ut p uts.  
 
T he te m plates pr o vi de d wit h t his S A P descri be t he prese nt ati o ns f or t his st u d y a n d t h eref ore 
t he f or mat a n d c o nte nt of t he s u m mar y t a bles
 a n d listi n gs t o be pr o vi de d b y I Q VI A 
Bi ostatistics.  
9.  D I S P O SI TI O N A N D W
I T H D R A W A L S 
All partici pa nt s w h o pr o vi de i nf or me d c o nse nt will be acc o u nte d f or i n t his st u d y.  
9. 1.  D I S P O SI TI O N 
Partici pa nt  dis p ositi o n a n d wit h dra wals  (i ncl u di n g t h ose d ue t o C O VI D-1 9) , a n d reas o ns f or 
e x cl usi o n fr o m eac h a n al ysis set , i ncl u di n g i n cl usi o n a n d e x cl usi o n criteria will be prese nte d 
f or t he S C R set. 
 
T he f oll o wi n g i nf or mati o n will be re p o rte d: 
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 2  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
•  
T otal n u m ber of partici pa nts scree n e d (i.e. p artici pa nts w h o ga ve i n f or me d c o nse nt) 
•  
N u m ber of partici pa nts w h o disc o nti n ue d fr o m t he st u d y pri or t o st u d y tr eat me nt o verall 
a n d gr o u pe d b y t he mai n reas o n (e. g. t he faile d s pecific i ncl usi o n or e x cl usi o n criteria, 
a d verse e ve nt, l ost t o f oll o w -u p, pr ot oc ol n o n -c o m plia nce, deat h, pr o gressi v e disease, 
wit h dra wal b y partici pa nt  a n d ot her)  
•  
N u m ber of re -scree n e d p artici pa nts 
•  
N u m ber of partici pa nts w h o recei ve d at least o ne d ose of st u d y tr eat me nt ( S A F) 
•  
N u m ber of partici pa nts wit h treat me nt o n g oi n g at t he data c ut-off  date  
•  
N u m ber of partici pa nts of f st u d y tr eat me nt, gr o u pe d b y m ai n reas o n (treat me nt 
c o m plete d as per pr ot oc ol, a d verse e ve nt, l ost t o f oll o w -u p, pr ot oc ol n o n -c o m plia nce, 
deat h, pr o gressi ve diseas e, wit h dra wal b y p artici p a nt  a n d ot her) 
•  
N u m ber of partici pa nts o n g oi n g o n t he st u d y at t h e data c ut-off dat e  
•  
N u m ber of partici pa nts w h o c o m plete d/ disc o nti n ue d t he st u d y p artici pati o n, wit h t he 
ass ociate d mai n pri mar y reas o n (st u d y c o m plet e d acc or di n g t o pr ot o c ol, a d verse e v e nt, 
l ost t o f oll o w-u p, pr ot oc ol n o n -c o m plia nce, deat h, pr o gressi ve dise as e, wit h dra wal b y 
partici pa nt  a n d ot her ). 
N o perce nta ges will be pr o vi de d f or t he n u m ber of partici pa nts scree n e d a n d re -scree n e d 
i ncl u di n g f or t h e reas o ns partici pa nts disc o nti n ue d fr o m t he st u d y pri or t o st u d y treat me nt.  
All ot her c o u nts will i ncl u de per ce nta ges b ase d o n t he n u m ber of partici pa nts i n t he S A F.  
 
A partici pa nt will be c o nsi dere d t o ha ve c o m plete d t he st u d y if t he p artici p a nt dies or 
ot her wise pr o gresses d uri n g t he treat me nt or f oll o w -u p peri o d or h as bee n i n f oll o w -u p f or a 
ma xi m u m of 3 yea rs or if t he y are i n f oll o w-u p w he n  t he D C O date is reac h e d, w hic he v er is 
s o o ner.  
 
T he n u m ber of partici pa nts i n eac h a nal ysis set will be s u m marize d o verall .  
 
A listi n g of partici pa nt dis p ositi o n will i ncl u de  partici pa nt  i de ntifier, date of i nf or me d 
c o nse nt, i ncl u de d i n t he st u d y, first/last st u d y tr eat me nt date, date  a n d reas o n f or 
disc o nti n uati o n of treat me nt, date a n d reas o n f or disc o nti n uati o n of t he st u d y, p o p ulati o n 
fla gs, rescree n e d partici pa nt I D, date of scree n fail ure a n d reas o n f or scree n fail ure. W he n  t he 
reas o n s uc h as reas o n f or disc o nti n uati o n of treat me nt will be cate g orize d  as “ Ot her, s p ecif y” 
or “ Wit h dr a wal b y s u bject , s pecif y”, t h e ver bati m  te xt as e ntere d i n t he e C R F will  be  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 3  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
i ncl u de d i n t he listi n g. Partici pa nts  w h o are re -s cree ne d will o nl y b e i ncl u de d o nce, wit h t he 
details of  partici pa nt  i de ntifier, date of s cree n fail ure a n d scree n fail ure reas o n. 
9. 2.  P R O T O C O L D E VI A TI O N S  
Details of t he pr ocess f or pr ot oc ol de viati o n c ollecti o n, re vie w a n d fi n alizati o n  a n d defi niti o n 
of i m p orta nt pr ot oc ol de viati o ns  will be prese nte d i n t he Pr ot oc ol De viati o ns Ma na ge me nt 
Pla n.  
 
All pr ot oc ol de viati o ns classifie d as i m p orta nt  will be liste d  i ncl u di n g t h ose d ue t o C O VI D-
1 9 , if a p plica ble, f or t he S A F. T he  listi n g will i ncl u de: partici pa nt  i de ntifier, cate g or y of t he 
de viati o n (e. g. i ncl usi o n/e x cl usi o n  criteria), a n d a descri pti o n of t he de viati o n. 
1 0.  
D E M O G R A P HI C A N D O T H E R  B A S E LI N E C H A R A C T E RI S TI C S  
De m o gra p hic d ata a n d ot her baseli ne c haracteristics will be prese nte d f or t he S A F . 
 
N o statistical testi n g will be carrie d o ut f or d e m o gra p hic or ot her b aseli ne c haract eristics . 
1 0. 1.  D E M O G R A P HI C S  
T he f oll o wi n g d e m o gra p hic c haracteristics will be s u m marize d f or t his st u d y: 
•  
A ge ( years) - calc ul ate d relati ve t o date of c o nse nt  
•  
A ge Cate g ories:  
o  <  6 5 years, ≥ 6 5 years  
o  6 5 -7 4 years, 7 5 -8 4 years, ≥ 8 5 years . 
•  
Se x  ( male, fe male) 
•  
Race  
o  F or partici pa nts re p orti n g o ne race o nl y: W hite, Blac k or Africa n A merica n, 
Asia n, A merica n I n dia n or Alas ka Nati ve, Nati ve Ha waiia n or ot h er Pacifi c 
Isla n d er, N ot c ollecte d at t he site, Ot her. 
o  F or partici pa nts re p orti n g se veral r aces, all c o m bi n ati o ns will be re p orte d u n der 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 4  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
‘ M ore t ha n o n e race” cat e g or y.  
•  
Et h nicit y  ( His pa nic or Lati n o, n ot His pa nic or Lati n o) 
•  
Ge o gra p hic R e gi o n ( E ur o pe, N ort h A meri ca)  
Details o f alc o h ol usa ge a n d nic oti ne c o ns u m pti o n fr o m t he “Alc o h ol C o ns u m pti o n ” a n d 
“Nic ot ine Usa ge ” e C R F f or ms will be c ollecte d at baseli ne a n d will be i ncl u de d i n a listi n g 
of De m o gra p hi c c haract eristics i ncl u di n g se x, race (all re p orte d races i n t he case of m u lti ple 
races a n d details i n t he case of “ ot h er” race), et h nicit y, ge o gra p hic re gi o n, a ge ( years) , a ge 
cate g or y, h ei g ht, w ei g ht a n d B MI  will be prese nte d i n a listi n g.  T he listi n g will als o i ncl u de 
p ositi ve hist or y of T u berc ul osis ( T B) e x p os ure , T B c ollecti o n dat e, assa y a n d res ult.  
1 0. 2.  D E RI V A TI O N S  
•  
A ge ( years) = ( dat e of gi ve n i nf or me d c o ns e nt –  date of birt h + 1) / 3 6 5. 2 5  
•  
Ge o gra p hic R e gi o n will be deter mi ne d fr o m i n vesti gat or site c o d es  
•  
B MI ( k g/ m 2) = wei g ht ( k g)/ hei g ht ( m)2. 
1 1.  
M E DI C A TI O N S  
Me dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y ( W H O-
D D), B 3 .   
See A p pe n di x 2  f or ha n dli n g of partial dates f or m e dicati o ns.  
1 1. 1.  P R E VI O U S A N TI -C A N C E R T R E A T M E N T S A N D P R O C E D U R E S  
Pri or A nti -ca ncer T hera pies  will be ca pt ure d o n t h e “Pri or A nti -ca ncer Dr u g T hera pies ” 
e C R F pa ge  a n d t he f oll o wi n g will be s u m marize d:   
•  
Partici pa nts wit h at least o ne pre vi o us a nti -ca ncer dr u g t hera p y  
•  
N u m ber of a n y pre vi o us a ntica ncer t hera p y re gi m e ns: 0 , 1 , 2,   > 2 . Als o mea n, S D, 
me dia n, Q 1, Q 3, mi n a n d ma x  
•  
I nte nt of t hera p y (i ncl u di n g all treat me nt re gi me ns): Ne oa dj u va nt / A dj u va nt / Metastatic 
or L o call y a d v a nce d  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 5  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
•  
Best res p o ns e of last treat me nt re gi me n: C o m plete Res p o nse ( C R) / Partial Res p o nse 
( P R) / Sta ble Disease ( S D) / Pr o gressi ve Disease ( P D) / N o n-C o m plete Res p o nse/ N o n -
Pr o gressi ve Diseas e ( n o n -C R/ n o n -P D) / N ot Assessa ble / U n k n o w n / N ot a p plica ble  
•  
T he ti me si nce c o m pleti o n of first -li ne ( 1 L) of plati n u m-base d treat me nt will als o be 
s u m marize d. Plati n u m-base d treat me nt will be i de ntifie d f or partici pa nts w h o recei ve d at 
least o ne plati n u m-base d dr u g (cis plati n, o x ali plati n or car b o pl ati n) . T he ti me si nce 
c o m pleti o n wil l be meas ure d usi n g t h e ma xi m u m st o p date wit hi n t he i de ntifie d re gi me n 
( ma xi m u m start date will be use d i n cas e t he st o p date is n ot a vaila ble). 
•  
N u m ber of partici pa nt s p er 1 L re gi me n, e. g., cis pl ati n/ ge mcita bi ne. 
If t here is a plati n u m-bas e d treat me nt wit h a n i nte nt of metastatic/l ocall y a d va nce d, t he n t h e first 
of t hese will be c o nsi dere d as first -li ne.  Ot her wise, t he first plati n u m -b ase d treat me nt ( wit h 
i nte nt of a dj u va nt or ne o a dj u va nt) will be c o nsi dere d first-li ne. 
 
A listi n g of pre vi o us a nti -ca ncer dr u gs will i ncl u de partici pa nt  i de ntifier, a ge, s e x, race, re gi me n 
na me , me dicati o n(s), st art date, e n d date, i nte nt of t hera p y, Li ne N u m b er f or Metastatic/ L ocall y 
A d va nce d,  b est res p o nse , date of pr o gressi o n  a n d w het her Ra di ot hera p y was a d mi nistere d as p art 
of t he thera p y . 
1 1. 2.  P R E M E DI C A TI O N S F O R B I N T R A F U S P A L F A  
Pre me dicati o ns  are me di cati o ns a d mi nistere d per pr ot oc ol o n t he sa me da y as, b ut  pri or t o, 
t he st u d y treat me nt t o mi ni mize p ote ntial i nf usi o n-relate d reacti o ns.  
Pre me dicati o ns will be i ncl u de d i n a listi n g of i nf usi o n -relate d reacti o ns. 
1 2.  
S T U D Y T R E A T M E N T  E X P O S U R E  
E x p os ure t o st u d y tr eat m e nt i n wee ks  will be prese nte d f or t he S A F.  
 
T he date of first st u d y tr eat me nt a d mi nistrati o n will be ta ke n fr o m t he e C R F “Bi ntraf us p Al fa 
A d mi nistrati o n Details ” f or m. T he date of l ast st u d y treat me nt will be ta ke n fr o m t he e C R F 
“Bi ntraf us p Al fa T er mi n ati o n ” f or m. 
 
F or t he a nal ysis of e x p os ure, a d o se is r e gar de d t o be a d mi nistere d if t he act ual d ose recei ve d 
is > 0 m g. 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 6  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
I nterr u pti o ns, c o m plia nce, a n d d ose c h a n ges are n ot ta ke n i nt o acc o u nt f or d urati o n of 
e x p os ure.  
 
S u m maries of e x p os ure will i ncl u de:  
•  
D urati o n of t reat me nt ( wee ks) 
•  
T otal n u m ber of i nf usi o ns recei v e d 
•  
C u m ulati ve d ose ( m g)  
•  
D ose i nte nsit y ( m g/c ycl e)  
•  
Relati ve d ose i nte nsit y ( %)  as a c o nti n u o us varia ble, a n d cat e g orize d as  
o  < 8 0 %  
o  8 0 % -9 0 %  
o  > 9 0 % . 
St u d y treat me nt e x p os ure will be i ncl u de d i n a listi n g of st u d y tr eat me nt w hic h will i ncl u de 
par tici pa nt i de ntifier, a ge, se x, race, visit, i nf usi o n start date a n d ti me, i nf usi o n e n d date a n d 
ti me, i nf usi o n rate ( m L/ hr), act u al d ose ( m g), r o ut e, a d mi nistrati o n m o dificati o n i ncl u di n g 
d ose n ot gi ve n  a n d reas o n f or m o dificati o n . 
1 2. 1.  D E RI V A TI O N S  
D urati o n of treat me nt (w ee ks ) = (date of last d ose  –  date of first d ose  + 1 4 )/7 .  
 
T otal n u m ber of 2 -w ee k  c ycles is defi ne d as t he d urati o n of t hera p y ( wee ks) / 2.  
 
C u m ulati ve d ose ( m g) per partici pa nt  is t he s u m of t he t otal st u d y treat me nt t hat t he 
partici pa nt  receive d (act u al d ose) o ver t h e d urati o n of e x p os ure   (i.e. t otal st u d y treat me nt 
a d mi nistere d ( m g)).  
 
D ose i nte nsit y of treat me nt ( m g/c ycl e) per 2 -wee k c ycle is defi n e d as c u m ulati ve d ose of 
treat me nt di vi de d b y ( d urati o n of treat me nt (i n w ee ks)/ 2) 
 
Relati ve d ose i nte nsit y is defi ne d as t he act ual d os e i nte nsit y di vi de d b y t he pla n ne d d ose 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 7  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
i nte nsit y p er c ycle a n d e x presse d i n a p erce nta ge.  
1 3.  
E F FI C A C Y A N D E X P L O R A T O R Y O U T C O M E S  
1 3. 1.  P RI M A R Y E F FI C A C Y  
T he pri mar y effic ac y a n al ysis will be perf or me d o n t he S A F.  Details o f t u m or assess me nt 
base d o n i ma gi n g will be liste d a n d will i ncl u de: partici pa nt  I D, a ge, se x, race, first a n d last 
bi ntraf us p alfa a d mi nistrati o n date, c o nfir m e d best o verall res p o nse, d ate f or first s u bse q ue nt 
a nti-ca ncer t hera p y, dat e of deat h, visit, date of i m a gi n g (d a y), Lesi o n t y p e , S u m of Lesi o n 
Dia meters ( m m), C ha n ge fr o m baseli ne ( %) a n d o verall res p o ns e .  T he listi n g als o i ncl u des 
lesi o n I D, size, stat us, site, t y p e, met h o d a n d res p o nse f or eac h lesi o n t y pe, as a p plica ble . 
1 3. 1. 1.  
P RI M A R Y E F FI C A C Y V A RI A B L E (S ) &  D E RI V A TI O N (S ) 
T he pri mar y effic ac y e n d p oi nt is t he c o nfir me d o bjecti ve res p o nse b y t h e i n vesti gat or.  
O verall res p o nse rate ( O R R ) is defi ne d as t he perce nta ge ( %) of partici pa nt s wit h a best 
o verall res p o ns e ( B O R) of P R or C R as assesse d b y  t he i n vesti gat or usi n g R E CI S T 1. 1 o ut of 
t he t otal n u m ber of partici pa nts i n t he S A F. T u m or res p o nse i.e., c o m plete res p o nse ( C R), 
partial res p o nse ( P R), a n d sta ble disease ( S D), a n d pr o gressi ve dise ase ( P D) will be base d o n 
t he assess me nts fr o m t he i n vesti gators’ assess me nt of o bjecti ve e vi de nce (e. g., ra di ol o gical 
sca n). O v erall res p o nses will be meas ure d i n acc or da nce wit h t he R E CI S T v 1. 1 ( Eise n ha uer 
E A, 2 0 0 9) . 
 
Lesi o n assess me nt met h o d a n d ti mi n g, e val u ati o n of disease, dise ase pr o gressi o n a n d 
res p o nse criteria will be c o n d ucte d acc or di n g t o R E CI S T ( versi o n 1. 1) as o utli ne d i n Secti o n  
8. 3  of t he pr ot oc ol. If t h ere are m ulti ple sca n dates ass ociate d wit h a n e val u ati o n, t he earliest 
of t he sca n d ates ass ociat e d wit h t he e val uati o n will be use d as t he date of assess me nt . 
 
Best o verall res p o nse  ( B O R) will be assesse d bas e d o n t he t u m or res p o nse deter mi ne d b y t he 
i n vesti gat or at eac h e val u ati o n ti me p oi nt fr o m t he first  st u d y treat me nt u ntil t he first 
d oc u me nte d diseas e pr o gressi o n f or R E CI S T criteri a. O nl y t u m or assess me nts perf or me d 
bef ore t h e start of a n y f urt her a ntica n cer treat me nt will be c o nsi dere d i n t he assess me nt of 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 8  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
B O R. Cli nical deteri orati o n will n ot be c o nsi dere d as d oc u me nte d dise ase pr o gressi o n.  
 
C o nfir me d B O R a cc or di n g t o R E CI S T 1. 1 ( Eise n ha uer E A, 2 0 0 9) will be assesse d acc or di n g 
t o t he f oll o wi n g r ules:  
•  
C R = at least t w o deter mi nati o ns of C R at least 4 wee ks a p art a n d b ef ore pr o gressi o n .  
o  
N ote: It is r eas o na bl e t o c o nsi der C R -N E -C R or C R -P R -C R as C R as l o n g as t he 
sec o n d C R is m ore t ha n 2 8 da ys a wa y fr o m t he first ti me p oi nt. 
•  
P R = at least t w o deter mi nati o ns of P R at least 4 wee ks a part a n d bef ore pr o gressi o n (a n d 
n ot q ualif yi n g f or a C R)  
o  
N ote: It is r eas o na bl e t o c o nsi der P R -N E -P R or P R -S D -P R as P R as l o n g as t he 
sec o n d P R is m ore t ha n 2 8 da ys a wa y fr o m t he first ti me p oi nt. 
•  
S D = at least o ne S D ass ess me nt ( or better) ≥ 6 wee ks aft er first dat e of st u d y treat me nt 
a n d bef ore pr o gressi o n (a n d n ot q ualif yi n g f or C R or P R)  
•  
P D = pr o gressi o n  ≤1 6  wee ks after first date of st u d y treat me nt (a n d n ot q u alif yi n g f or 
C R, P R or S D)  
•  
N E = all assess me nts are N E or partici pa nt  h as a missi n g  ( or n ot e val u a ble) baseli ne 
t u m or assess me nt a n d/ or n o ( or n ot e val ua bl e) t u m or assess me nts o n-treat me nt, or 
partici pa nt d oes n ot c o m plete a n y of t he f oll o wi n g res p o nse a b o v e . 
1 3. 1. 2.  
M
I S SI N G D A T A M
E T H O D S F O R P RI M A R Y  E F FI C A C Y V A RI A B L E (S ) 
•  
Partici pa nts wit h n o ( or n ot e val ua ble)  p ost -b aseli ne data are c o nsi d ere d as ha vi n g a n o n-
e val ua ble res p o nse. N o missi n g dates will be i m p ute d f or t he pri mar y efficac y vari a ble.  
1 3. 1. 3.  
F I N A L  A N A L Y SI S O F P RI M A R Y E F FI C A C Y V A RI A B L E (S ) 
C o nfir me d B O R will be s u m marize d as t he n u m ber a n d perce nta ge of parti ci pa nts wit h 
c o nfir me d C R, P R, S D, P D or  N E.  I n a d diti o n, the n u m ber of p artici pa nt s ac hie vi n g 
o bjecti ve res p o nse will be s u m marize d. T he c orres p o n di n g t w o-si de d 9 5 % C o nfi de nce 
I nter val (CI ) f or O R R will be calc ulate d usi n g t he Cl o p per-Pears o n (e x act) met h o d  ( Cl o p per 
C, 1 9 3 4)  wit h e x act CI f or bi n o mial pr o p orti o n as c o m p ute d b y d efa ult b y t he F R E Q 
pr oce d ure usi n g t he E X A C T o pti o n . T here will be n o a dj ust me nts f or m ulti plicit y.  
 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 2 9  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
•  
T he f oll o wi n g reas o ns f or n o n-e val u a ble c o nfir me d best o verall res p o ns e will als o be 
i ncl u de d i n t he s u m mar y: 
o  N o baseli ne ass ess me nt (if a p plica ble)  
o  N o p ost -baseli ne ass ess me nts d ue t o deat h wit hi n 8 wee ks after t he start of st u d y 
treat me nt 
o  N o p ost -baseli ne ass ess me nts d ue t o ot her reas o ns  
o  All p ost -baseli ne assess me nts ha ve o verall res p o nse “ N o n -e val ua ble”  
o  Ne w a ntica ncer t hera p y starte d bef ore first e val ua ble p ost -baseli ne assess m e nt  
o  S D of i ns ufficie nt d urati o n ( < 6 wee ks aft er t he st art of st u d y treat me nt) 
o  N o e val ua ble t u m or assess me nt > 1 6 wee ks f oll o w e d b y P D  (i.e. t u m or assess me nt 
of P D was > 1 6  w ee ks after start of st u d y treat me nt a n d t here was n o e val u a ble 
t u m or assess me nt i n bet wee n)  
o  N ot deter mi ne d cate g or y  ma y  als o be a d de d if a p plica ble. 
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 0  of 6 5  
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 1  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 2  of 6 5  
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
 
 
 
P P D
C CI
C CI
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 3  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 4  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
P P D
C CI
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 5  of 6 5  
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
 
P P D
C CI
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 6  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
1 4.  
S A F E T Y O U T C O M E S  
All o ut p uts f or safet y o utc o mes will be base d o n t he S A F .  
 
T here will be n o statistical c o m paris o ns of safet y  data, u nless ot her wise s p ecifie d wit hi n t he 
rele va nt S ecti o n.  
1 4. 1.  A D V E R S E E V E N T S  
A d verse E v e nts ( A Es) will be c o de d usi n g  M e d D R A  V 2 3 . 0 or later . 
  
Treat me n t e mer ge nt a d v erse e ve nts ( T E A Es) are d efi ne d as A Es t h at starte d or w orse n e d i n 
se verit y d uri n g t he o n -tr eat me nt peri o d, as defi ne d i n Secti o n 6. 3. 1 . H o we v er, f or t he first 
a d mi nistrati o n of t he st u d y treat me nt, if t he A E Start Date is e q u al t o t hat date, t he n A Es wit h 
t he fiel d “ Ti mi n g relate d t o Bi ntraf us p alf a” fla g ge d as “ Bef ore” o n t he “A d verse E ve nts 
Details ” f or m of t h e e C R F w o ul d n ot be c o nsi dere d a T E A E.   
 
C ha n ges i n t o xicit y gra d e, seri o us ness or o utc o m e of A Es are rec or de d as se parat e e ntries i n 
t he e C R F wit h ass ociate d e n d a n d start dat es (start date is e q ual t o or 1 da y greater t ha n e n d 
date of pre vi o us e ntr y). S uc h e ntries re p orti n g t he sa me e ve nt i n s uc h i m me diatel y 
c o nsec uti ve peri o ds will be c o nsi dere d as o ne e ve nt i n t he a nal ysis. T hes e e ve nts will be ke pt 
as se parate rec or ds i n t he data base a n d t he listi n g i n or der t o mai ntai n t he f ull detaile d hist or y 
of t he e ve nts. F or ta bles, t he start date of t he first treat me nt e mer ge nt rec or d i n t he se q ue nce 
is ta ke n as start date of t he e ntire e v e nt, si milarl y t he e n d date of t he last e v e nt i n t he 
P P D
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 7  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
se q ue nce is ta k e n as e n d date of t he e ntire e ve nt. T he o verall o utc o me of t he a d verse e v e nt is 
t he o utc o me of t he last e ve nt i n t he se q ue nce. D urati o n of t he A E a n d t he T E A E fla g will be 
a dj uste d acc or di n gl y i n t he a nal ysis.   
 
See A p pe n di x 2  f or ha n dli n g of partial dates f or A Es.  I n t h e cas e w here it is n ot p ossi ble t o 
defi ne a n A E as treat me nt e mer ge nt or n ot, t he A E will be classifie d b y t he w orst -cas e; i.e. 
treat me nt e mer ge nt.  
 
A n o verall s u m mar y of n u m ber a n d perce nt a ge of partici pa nt s wit hi n eac h of t he f oll o wi n g 
cate g ories will be pr o vi de d :  
•  
A n y T E A E  
•  
A n y r elate d T E A E  
•  
A n y s eri o us T E A E  
•  
A n y relate d s eri o us T E A E  
•  
A n y gra de > = 3 T E A E  
•  
A n y relate d gra de > = 3 T E A E  
•  
A n y gra de > = 4 T E A E   
•  
A n y relate d gra de > = 4 T E A E  
•  
A n y T E A E Lea di n g t o D eat h  
•  
A n y relate d T E A E Lea di n g t o Deat h  
•  
A n y T E A E Lea di n g t o  st u d y ter mi nati o n  
•  
A n y relate d T E A E Lea di n g t o st u d y ter mi nati o n  
•  
T E A Es a n d rel ate d T E A E s of s pecial i nterest:  
o  I nf usi o n-relat e d reacti o ns (I R Rs) 
o  I m m u ne-relat e d A Es (ir A Es) 
o  P ote ntial T G F β -me diate d s ki n A Es  
o  Treat me nt r elate d  a n e mia  
o  B lee di n g e v e nts 
o  W o u n d hea li n g 
o  Sec o n da ry Mali g na n cies  
I n a d diti o n, s u m mar y ta bles of t he f oll o wi n g T E A E cate g ori es will be pr o vi de d b y S O C 
( or dere d al p ha b eticall y) a n d P T ( or dere d al p ha beticall y): 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 8  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
•  
T E A Es  
•  
Relate d T E A Es  
•  
Seri o us T E A Es  
•  
Relate d Seri o us T E A Es  
•  
T E A Es N CI C T C A E se v erit y gra de ( ≥3)  
•  
Relate d T E A Es N CI C T C A E se verit y gra d e ( ≥3)  
•  
T E A Es lea di n g t o deat h  
•  
Relate d T E A Es lea di n g t o deat h  
•  
T E A Es Lea di n g t o Per m a ne nt Treat me nt Disc o nti n uati o n  
•  
Relate d T E A Es Lea di n g t o Per ma ne nt Treat me nt Disc o nti n uati o n  
T E A Es a n d rel ate d T E A Es b y w orst gra de will  als o be s u m marize d .  
 
All a nal ys es i n t his Secti o n will be base d o n T E A Es if n ot ot her wise s pecifie d.  
 
A listi n g will be pr o vi de d i ncl u di n g all A Es (i.e. T E A Es a n d N o n -T E A Es ) a n d will c o ntai n 
t he f oll o wi n g i nf or m ati o n: partici pa nt i de ntifier, a ge, s e x, race, first a n d last date of st u d y 
treat me nt, preferre d ter m, re p orte d ter m f or t he A E, start date, e n d d ate, d urati o n of A E (i n 
da ys) , da y relati ve t o t he first i nf usi o n, da y relati v e t o t he m ost rece nt i nf usi o n pri or t o A E 
o nset, relatio ns hi p t o st u d y treat me nt, t o xicit y gra de, acti o n(s) ta ke n, o utc o me, seri o us ness  
( Y/ N), A E SI T y p e (as d etaile d i n secti o n 1 4 . 1. 6). A Es o utsi de t he o n-treat me nt peri o d ( pri or 
or after), will be fla g ge d.  A d diti o nall y, if t he A E occ urre d o n t he sa me da y as a n i nf usi o n , a 
fla g of w het h er t he A E w as bef ore, d uri n g or after t he i nf usi o n. 
 
I n a d diti o n a listi n g s u m mar y of S u bject N u m bers f or I n di vi d ual T E A Es, s orte d b y S O C a n d 
P T i n al p ha betical or der will be prese nte d.  
1 4. 1. 1.  
A L L A E S  
I n ci de nce of T E A Es will be prese nt ed i n fre q u e nc y ta bles, s orte d b y S O C a n d P T i n 
al p ha betical or d er a n d, if a p plica ble, br o ke n d o w n f urt her b y ma xi m u m se verit y.   
Eac h partici pa nt will be c o u nte d o nl y o nce wit hi n eac h P T or S O C. If a partici pa nt 
e x perie nces m ore t h a n o ne T E A E wit hi n a P T or  S O C, o nl y t h e T E A E wit h t he str o n gest 
relati o ns hi p or t he w orst se verit y, as a p pr o priate, will be i ncl u de d i n t he s u m maries of 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 3 9  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
relati o ns hi p a n d se verit y.  
1 4. 1. 1. 1.  Se verit y  
Se verit y is cl ass ifie d b y gra de acc o r di n g t o t he i n vesti gat or as gra d e 1  ( mil d)/ gra de 2 
( m o derate)/ gra d e 3 (se v ere)/ gra de 4 (life t hreate ni n g)/ gra de 5 ( deat h r elate d t o 
A E) (i ncreasi n g se v erit y). A Es will be gra de d usi n g t he N CI -C T C A E v 5 gra di n g as per t he 
A merica n S ociet y of Cli nical O nc ol o g y ( A S C O) g ui deli nes  ( N CI-C T C A E v 5, 2 0 1 7) . 
Gra di n g will be rec or de d i n t he “A d verse E ve nts ” f or m of t he e C R F.  
 
If a partici pa nt  re p orts a T E A E m ore t ha n o nce wit hi n t hat S O C/ P T, t he A E wit h t he w orst-
case gra de will be use d i n t he c orres p o n di n g s u m maries.  I n case a p artici p a nt ha d e ve nts wit h 
missi n g a n d n o n -missi n g gra des, t he ma xi m u m of t he n o n -missi n g gra d es will be dis pla ye d.  
1 4. 1. 1. 2.  Relati o ns hi p t o St u d y Treat me nt  
Relati o ns hi p  t o st u d y tr eat me nt is deter mi ne d b y t he i n vesti gat or. T E A Es wit h a missi n g 
relati o ns hi p t o st u d y treat ment will be re gar de d as “ R el ate d ”  t o st u d y tr eat me nt. If a 
partici pa nt  re p orts t he sa me A E m ore t ha n o nce wit hi n t hat S O C/ P T, t he A E wit h t he w orst-
case relati o ns hi p t o st u d y treat me nt will be use d i n t he c orres p o n di n g relati o ns hi p 
s u m maries.  
1 4. 1. 2.  
T E A E S L E A DI N G T O T E M P O R A R Y T R E A T M E N T IN T E R R U P TI O N  A N D W
I T H D R A W A L 
O F S T U D Y T R E A T M E N T  
F or T E A Es l ea di n g t o treat me nt i nterr u pti o n, m o dificati o n or disc o nti n uati o n of st u d y 
treat me nt, t he f oll o wi n g i nci de nce rates (fre q u e nci es a n d perce nta ges) will be s u m marize d i n 
a n o ver vie w t a ble : 
•  
T E A Es lea di n g t o te m p orar y treat me nt i nterr u pti o n 
•  
Relate d T E A Es lea di n g t o te m p orar y treat me nt i nterr u pti o n 
•  
T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n  
•  
Relate d T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n  
•  
T E A Es lea di n g t o i nf usi o n rate re d ucti o n  
•  
Relate d T E A Es lea di n g t o i nf usi o n rate re d u cti o n . 
 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 0  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
T E A Es lea di n g t o te m p orar y treat me nt i nterr u pti o n will be i de ntifie d b y usi n g t he res p o nse 
f or Acti o n Ta k e n of “ Dr u g I nterr u pte d” o n t he “ A d verse E ve nts D etails” p age of t he e C R F. 
T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of st u d y treat me nt will be i de ntifie d b y usi n g 
t he res p o nse f or Acti o n T a ke n of “ Dr u g Wit h dra w n” o n t he “ A d verse E v e nts Details” f or m 
of t he e C R F. T E A Es le a di n g t o i nf usi o n rate re d u cti o n  will be i de ntifie d b y usi n g t he 
res p o nse f or Ot her A cti o n Ta ke n of “ Rate Re d uce d” o n t he “ A d verse E v e nts Details” pa ge of 
t he e C R F. 
1 4. 1. 3.  
T E A E S L E A DI N G T O S T U D Y T E R MI N A TI O N  
T E A Es lea di n g t o st u d y t er mi nati o n will be i de ntifie d b y usi n g t he res p o nse f or Ot her Acti o n 
Ta ke n of “ Le d t o st u d y ter mi nati o n” o n t he “ A d verse E ve nts D etails” pa ge of t he e C R F.  
1 4. 1. 4.  
S E RI O U S A D V E R S E E V E N T S  
Seri o us a d verse e ve nts ( S A Es) are t h ose e ve nts r ec or de d as “Seri o us ” o n t he “A d verse 
E ve nts ” f or m of t he e C R F. T E A Es wit h missi n g s eri o us ness will be c o nsi d ere d as s eri o us.  
1 4. 1. 5.  
A E S  L E A DI N G T O D E A T H  
T E A Es lea di n g t o Deat h are t h ose e ve nts w hic h are rec or de d as c ha n ge i n gra de =” N o” a n d 
o utc o me = “ Fatal ”  or Gra d e =” Gra de 5 or deat h relat e d t o A E” or seri o us a d v erse e v e nt =” Yes” 
a n d seri o us ness criteria i ncl u de “ Re s ults i n deat h” as t he res p o nse f or O utc o me o n t he 
“A d vers e E ve nt  D etails ” f or m of t he e C R F. 
1 4. 1. 6.  
A E S  O F S P E CI A L IN T E R E S T  
A Es  of S pecial I nterest ( A E SI) will be i de ntifie d b y a sta n dar dize d list of Me d D R A preferre d 
ter ms t o be u p date d o n a n o n g oi n g basis d uri n g t h e st u d y. T h e A E SIs defi n e d f or t his st u d y 
are:  
•  
I nf usi o n-relat e d Reacti o ns 
•  
I m m u ne-relat e d A Es  
•  
T G F -β i n hi biti o n me diate d s ki n e ve nts  i ncl u di n g s ki n lesi o ns 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 1  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
•  
Treat me nt r elate d A n e mia  
•  
Blee di n g e v e nts  
•  
W o u n d heali n g dela y  
•  
Sec o n dar y mali g na n cies  
•  
E m br y ofetal t o xicities . 
 
F urt her d etails of t he deri vati o n of t he A E SI  ca n b e f o u n d i n A p pe n di x 3 . 
1 4. 1. 6. 1.  I nf usi o n-relat e d Reacti o ns I n cl u di n g I m me di ate H y p erse nsiti vit y 
 
I nf usi o n-Relate d Reacti o ns (I R R s) are d efine d as A Es  wit h P Ts acc or di n g t o a pre -s pecifie d 
Me d D R A searc h list , a n d are di vi de d i nt o t w o s u b cate g ories: “reacti o ns” a n d “si g ns a n d 
s y m pt o ms” base d o n  crit eria o n t he ti mel y relati o ns hi p as detaile d i n A p pe n di x 3 . 
 
T he listi n g of I R Rs will dis pla y t he st u d y dr u g a d mi nistrati o n m o dificati o n details t o get her 
wit h t he i nf usi o n -relate d a d verse e ve nt i ncl u di n g a d mi nistrati o n date ( da y) /ti me, reas o n f or 
m o dificati o n, t y pe of m o dificati o n, m o dificati o n start ti me, use of pre m e dicati o n, I R R A E 
Preferre d Ter m, I R R A E gra de, I R R A E start da y /st o p da y, I R R A E ti me relate d t o i nf usi o n.  
1 4. 1. 6. 2.  I m m u ne-relat e d A Es  
 
I m m u ne-relat e d a d verse e ve nts (ir A Es) will be i de ntifie d pr o gra m maticall y as d etaile d i n 
A p pe n di x 3 .  
 
T he fre q u e nc y ta bl e of i m m u ne -relate d A Es b y w orst gra de a n d P T will be pr o vi de d.  
1 4. 1. 6. 3.  P ote ntial T G F β -me diate d S ki n A Es  
 
I d e ntificati o n of s ki n A Es p ossi bl y relate d to T G F β i n hi biti o n  is detaile d i n a p pe n di x 3 .  
 
Fre q u e nc y t a bles f or T G F β -me diate d s ki n T E A Es lea di n g t o p er ma ne nt treat me nt 
disc o nti n uati o n  a n d seri o us T G F β -me diat e d s ki n T E A Es will be pr o vi de d b y Me d D R A P T s 
(i ncl u di n g b ot h narr o w a n d br oa d defi niti o n P Ts).  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 2  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
1 4. 1. 6. 4.  Treat me nt  relate d A n e mia 
 
Treat me nt  relate d an e mia A Es  will be i de ntifie d as descri be d i n A p p e n di x 3 .  
1 4. 1. 6. 5.  Blee di n g E v e nts  
 
Blee di n g e v e nts are classifie d b y t he M e d D R A S M Q He m orr h a ge ter ms ( e x cl u di n g 
la b orat or y ter ms) a n d will be s u m marize d se parat el y f or T E A Es a n d relate d T E A Es b y S O C 
a n d P T.  
1 4. 1. 6. 6.  W o u n d Heali n g D ela y  
 
Deri vati o n of w o u n d h eali n g dela y A Es  ca n b e f o u n d i n A p pe n di x 3 ..  
1 4. 1. 6. 7.  Sec o n dar y Mali g na n cies  
 
Details of t he deter mi nati o n of sec o n dar y mali g n a ncies ca n b e f o u n d i n A p pe n di x 3 .  
1 4. 1. 6. 8.  E m br y ofetal T o xicities  
 
E m br y ofetal T o xicities will n ot be deri ve d as t he o cc urre nce of t his A E is n ot c o nsi dere d a 
li kel y e v e nt d ue t o meas ures of c o ntr ace pti o n a n d fe w partici pa nts at a n a ge of c hil d-beari n g 
p ote ntial .   
1 4. 2.  D E A T H S  
All deat hs, deat hs wit hi n 3 0 da ys afte r l ast d ose of st u d y treat me nt, deat h wit hi n 6 0 da ys after 
first d ose of st u d y treat m e nt (f or all partici pa nts, t he first d ose will be t he first d ose of t he 
first treat me nt p hase) as well as t he pri mar y reas o n f or deat h will be ta b ul ate d base d o n 
i nf or matio n fr o m t he “ D eat h” e C R F f or ms. 
 
T he f oll o wi n g s u m maries will be pr o vi de d:  
•  N u m ber of deat hs  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 3  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
•  N u m ber of deat hs wit hi n 3 0 da ys after l ast d ose of st u d y treat me nt  
•  N u m ber of deat hs wit hi n 6 0 da ys after first d ose of st u d y treat me nt  
 
Pri mar y reas o n f or d eat h  will be i ncl u de d i n eac h of t hese secti o ns wit h t he f oll o wi n g reas o ns:   
o  Pr o gressi ve disease a n d/ or disease relate d c o n diti o n  
o  E ve nt u nrelate d t o st u d y treat me nt  
o  E ve nt relate d t o st u d y treat me nt  
o  U n k n o w n . 
I n a d diti o n, date a n d ca use of d eat h will be pr o vi de d i n a n i n di vi d ual p artici pa nt data listi n g 
t o get her wit h f oll o wi n g d osi n g i nf or mati o n: parti ci pa nt i de ntifier, a ge, se x, race, d ate of first/last 
st u d y treat me nt, n u m ber of i nf usi o ns, da y relati ve t o t he first a n d t he last i nf usi o n, pri mar y reas o n, 
a ut o ps y ( Y/ N/ U), A Es wit h fatal o utc o me (list preferre d t er ms of A Es wit h o utc o me = Fatal, as well 
as Gra d e 5 or Seri o us res ulti n g i n deat h), fla g f or deat h wit hi n 3 0 da ys of last d ose of st u d y 
treat me nt a n d fla g f or d eat h wit hi n 6 0 da ys of first d ose of st u d y tr eat me nt. 
1 4. 3.  L A B O R A T O R Y E V A L U A TI O N S  
Res ults fr o m  l ocal la b orat ories will be i ncl u de d i n t he re p orti n g of t his st u d y f or He mat ol o g y, 
Bi oc he mistr y , Uri n al ysis , C oa g ulati o n , T h yr oi d P a nel a n d Scree ni n g Tests a n d will be 
e ntere d i n t he c orres p o n di n g e C R F f or ms .
 A list of la b orat or y ass ess me nts t o be i ncl u de d i n t he 
o ut p uts is  i ncl u de d i n t he P r ot oc ol, S ecti o n 1 0. 2, A p pe n di x 2, Ta ble 6.  
 
A  listi n g of he mat ol o g y, bi oc he mistr y a n d c oa g ul ati o n will be creat e d. T his  listi n g will 
i ncl u de: partici pa nt i de ntifier, a ge, s e x, race, first d ose date, last d ose dat e, la b orat or y 
para meter ( SI u nits), visit, c ollecti o n date /ti me/ da y, I nter nati o nal S yst e m of U nits ( SI) val ue, 
l o wer li mit of n or mal ( L L N), u p per li mit of n or m al ( U L N), i n dicat or of n or mal ra n ge (l o w, 
n or mal, hi g h), t o xicit y ter m/gra de acc or di n g t o N CI -C T C A E ( w he n a p plica ble) a n d 
hi g hest/l o west o n treat me nt val ue fla g. Bas eli ne a n d p ost -baseli ne val ues after t he o n -
treat me nt peri o d will be fla g ge d. T he o n -tr eat me nt peri o d is defi ne d i n Secti o n 6. 3. 1 .  T he 
listi n g will be s orte d b y p artici pa nt i de ntifier, p ara meter a n d la b orat or y meas ure ment dat e.  
 
T 4 a n d T S H will be rec or de d i n t he “H or m o nal T ests ” f or m of t he e C R F. Res ults will be 
P P D
C CI
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 4  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
i ncl u de d i n t he listi n g. Scree ni n g tests i ncl u di n g pre g n a nc y tests, a n d s er ol o g y dat a will als o 
be liste d fr o m t he e C R F. 
1 4. 3. 1.  
R E F E R E N C E R A N G E S A N D C T C  G R A DI N G F O R L A B O R A T O R Y D A T A  
La b orat or y res ults will be classifie d acc or di n g t o t he N CI -C T C A E criteria versi o n 5. 0 a n d as 
s pecifie d i n A p pe n di x 4 . Q ua ntitati ve la b orat or y meas ure me nts n ot part of N CI-C T C A E will 
be c o m pare d wit h t he rel e va nt la b orat or y refere nce ra n ges,  c o n vert e d i nt o t he I nter n ati o nal 
S yste m of U nits ( SI) a n d cate g orize d as:  
•  
L o w: Bel o w t he l o w er li mit of t he la b orat or y refere nce ra n ge  
•  
N or mal: Wit hi n t he la b orat or y refere nce ra n ge ( u p per a n d l o wer li mit i ncl u de d)  
•  
Hi g h: A b o ve t h e u p per li mit of t he la b or at or y refere nce ra n ge.  
1 4. 3. 1. 1.  N CI -C T C A E Gra d a ble Para meters  
Para meter  
Para meter 
c o de  
Na me i n N CI -C T C  
Directi o n 
of 
a b n or malit
y  
Bi oc he mistr y  
 
 
 
Ala ni ne 
A mi n otra nsferas
e 
A L T  
Ala ni ne a mi n otra nsferas e  
i ncreas e d 
Hi g h  
Al b u mi n  
A L B  
H y p o al b u mi ne mia  
L o w  
Al kali ne 
P h os p hatase  
A L P  
Al kali ne p h os p hatase 
i ncreas e d 
Hi g h  
A m ylase  
A M Y L A S E  
Ser u m a m ylas e i ncrease d  
Hi g h  
As partate 
A mi n otra nsferas
e 
A S T  
As partate a mi n otra nsferase  
i ncreas e d 
Hi g h  
Bilir u bi n t otal  
BI LI  
Bl o o d bilir u bi n i ncreas e d  
Hi g h  
Calci u m a 
C A  
H y p ercalce mia/ H y p o calce mia
a 
Hi g h/ L o w  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 5  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
Para meter  
Para meter 
c o de  
Na me i n N CI -C T C  
Directi o n 
of 
a b n or malit
y  
Creati ni ne  
C R E A T  
Creati ni ne i ncrease d  
Hi g h  
Gl uc ose  
G L U C  
H y p o gl yce mia  
L o w  
Li pas e  
LI P A S E T  
Li pas e i ncrease d  
Hi g h  
P otassi u m  
K  
H y p er kale mia/ H y p o k ale mia  
Hi g h/ L o w  
S o di u m  
S O DI U M  
H y p er natr e mia/ H y p o natr e mia  
Hi g h/ L o w  
He mat ol o g y  
 
 
 
A bs ol ute 
l y m p h oc yte  
L Y M  
L y m p h oc yte c o u nt 
decrease d/ L y m p h oc yte c o u nt 
i ncreas e d 
Hi g h/ L o w  
A bs ol ute 
ne utr o p hils  
N E U T  
Ne utr o p hil c o u nt decreas e d  
L o w  
He m o gl o bi n  
H G B  
A ne mia /He m o gl o bi n 
i ncreas e d 
L o w/ Hi g h  
Le u k o c ytes 
( W B C) 
W B C  
Le u k o c yt osis/ W hite bl o o d cell 
decrease d  
Hi g h/ L o w  
Platelets c o u nt  
P L A T  
Platelet c o u nt decrease d  
L o w  
A bs ol ute 
E osi n o p hils  
E O S  
E osi n o p hilia  
Hi g h  
C oa g ulati o n  
 
 
 
Acti vate d Partial 
T hr o m b o plasti n 
Ti me b 
A P T T  
Acti vate d partial 
t hr o m b o plasti n 
ti me pr ol o n ge d 
Hi g h  
Acti vate d 
P T T/ Sta n dar d b 
A P T T S T N
D  
Acti vate d partial 
t hr o m b o plasti n 
ti me pr ol o n ge d 
Hi g h  
Pr ot hr o m bi n 
I nter nati o nal 
N or maliz e d 
I N R 
I N R i ncreas e d 
Hi g h  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 6  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
Para meter  
Para meter 
c o de  
Na me i n N CI -C T C  
Directi o n 
of 
a b n or malit
y  
Rati o b 
a base d o n correcte d calci u m 
b re p orte d o n t he “ C oa g ulati o n” e C R F f or m 
 
F or calci u m, C T C A E gra di n g is base d o n correcte d calci u m. C orrecte d calci u m is calc ulate d 
fr o m al b u mi n a n d cal ci u m as f oll o ws base d o n t h e I nter n ati o nal S yste m of U nits ( SI):  
C orrecte d calci u m ( m m ol/ L) = m eas ure d t otal cal ci u m ( m m ol/ L) + 0. 0 2 ( 4 0 –  ser u m 
al b u mi n ( g/ L)) 
1 4. 3. 1. 2.  N o n -gra d a ble Para meters  
Pa ra meter ( L B T E S T) 
 
Bi oc he m istr y 
 
Bilir u bi n direct  
BI LI DI R  
Bilir u bi n I n direct  
BI LI N DI R  
C hl ori de  
C L  
C -Reacti ve Pr otei n  
C R P  
Ga m ma -gl uta m yl Tra nsf erase  
G G T  
T otal Pr otei n  
P R O T  
Urea Nitr o ge n  
B U N  
H e mat ol o g y 
 
A bs ol ute Bas o p hils  
B A S O  
A bs ol ute M o n oc yt es  
M O N O  
A bs ol ute Retic ul oc yt es  
R E TI  
Bas o p hils/ Le u k oc ytes  
B A S O L E  
E osi n o p hils/ Le u k oc ytes  
E O S L E  
Er yt hr o c ytes ( R B C)  
R B C  
He mat ocrit  
H C T  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 7  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
Pa ra meter ( L B T E S T) 
 
L y m p h oc ytes/ Le u k oc ytes  
L Y M L E  
Mea n C or p usc ular He m o gl o bi n  
M C H  
Mea n C or p usc ular H G B C o nce ntrati o n  
M C H C  
Mea n C or p usc ular V ol u me  
M C V  
M o n oc yt es/ Le u k oc ytes  
M O N O L E  
Ne utr o p hils/ Le u k o c ytes  
N E U T L E  
Retic ul oc ytes/ Er yt hr oc yt es  
R E TI R B C  
C oa g ulati o n  
 
Pr ot hr o m bi n Ti me *  
P T  
Sta n dar d Pr ot hr o m bi n  Ti me *  
P T S  
 
1 4. 4.  E C G  E V A L U A TI O N S  
Res ults a ut o maticall y calc ulate d fr o m t he si n gle 1 2-lea d E C G will be i ncl u de d i n t he 
re p orti n g of t his st u d y.  
 
T he f oll o wi n g E C G p ara meters will be re p orte d f or t his st u d y : 
•  
H R ( b p m)  
•  
P R I nter v al ( ms ec) 
•  
Q R S I nter v al ( ms ec ) 
•  
Q T I nter val ( ms ec) 
•  
Q Tc F I nter val ( ms ec)  
•  
O verall assess m e nt of E C G (I n vesti gat or’s j u d g me nt ): 
o  N or mal  
o  A b n or mal, N ot Cli nicall y Si g nifica nt ( A N C S)  
o  A b n or mal, Cli nicall y Si g nifica nt ( A C S) . 
A listi n g of E C G val ues will be pr o vi de d i ncl u di n g partici pa nt  i de ntifier, a ge, s e x, race, E C G 
para meter a n d u nit, visit, E C G date / da y/ti me, val ue, c ha n ge fr o m bas eli ne a n d o verall 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 8  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
assess me nt base d o n i n vesti gat or’s j u d ge m e nt . Bas eli ne val ues a n d p ost-b as eli ne val ues 
c ollecte d after t he o n -treat me nt peri o d will be fla g ge d. Q ualitati ve E C G res ults will als o be 
pr o vi de d i n t he listi n g.  
1 4. 5.  V I T A L S I G N S 
Vital si g ns will b e meas ure d aft er 5 mi n utes of rest i n a se mi -rec u m be nt or s u pi ne p ositi o n. 
T he f oll o wi n g Vital Si g ns meas ure me nts will be re p orte d f or t his st u d y:  
•  
S yst olic Bl o o d Press ur e  ( mm H g ) 
•  
Diast olic Bl o o d Press ure  ( mm H g ) 
•  
P ulse Rate  (b p m ) 
•  
O x y ge n Sat urati o n  b y P ulse O x i metr y ( %) 
•  
Te m perat ur e ( ⁰C)  
•  
Hei g ht ( cm) [at scree ni n g o nl y]  
•  
Wei g ht ( k g ) 
•  
B MI ( k g/ m 2). 
A listi n g of vital si g ns will be pr o vi de d  i ncl u di n g partici pa nt  i de ntifier, a ge, se x, race, vital si g n 
para meter, visit,  date, ti me, val ue, u nit  a n d c ha n ge fr o m baseli ne. Bas eli ne val ues , p ost -bas eli ne 
val ues c ollect e d aft er t he o n -treat me nt p eri o d a n d p ote ntiall y cli nicall y si g nifica nt a b n or malities  
will be fla g ge d. T he o n -treat me nt peri o d is defi ne d i n Secti o n 6. 3. 1 . 
1 4. 6.  O T H E R S A F E T Y A S S E S S M E N T S  
1 4. 6. 1.  
P R E G N A N C Y T E S T   
R es ults f or pre g na n c y stat us as c ollecte d o n t he “ Pre g na nc y Test” e C R F f or m will  als o be 
i ncl u de d i n t he la b orat or y listi n g: 
•  P re g n a nc y para met er (s er u m or hi g hl y se nsiti ve uri ne h u ma n c h ori o nic g o n a d otr o pi n 
( h C G)) 
1 4. 6. 2.  
P H Y SI C A L E X A M  
P h ysical E x a m data will n ot be s u m marize d or liste d se paratel y. A n y a b n or mal p h ysical 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 4 9  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
e x a m fi n di n gs will be re p orte d as A Es  a n d s u m marize d i n t he A E  secti o n.  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 0  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
R E F E R E N C E S  
 
Br o o k me yer J, C. J. ( 1 9 8 2). A c o nfi de n ce i nter val f or t he me dia n s ur vi v al ti me. Bi o metrics, 3 8 , 2 9-4 1.  
Cl o p per C, P. E. ( 1 9 3 4). T he use of c o nfi de n ce or fi d ucial li mits ill ustrate d i n t he cas e of t he bi n o mial. 
Bi o metri ka, 2 6 ( 4), 4 0 4-4 1 3.  
Eise n ha uer E A, T. P. ( 2 0 0 9). Ne w res p o nse e v al uati o n criteria i n s oli d t u m ors: re vise d R E CI S T g ui deli nes 
( versi o n 1. 1). E ur J Ca ncer, 4 5 , 2 2 8-4 7.  
N CI -C T C A E v 5.  ( 2 0 1 7). Retrie ve d N o v e m ber 2 0, 2 0 1 8, fr o m C o m m o n Ter mi n ol o g y f or A d verse E v e nts, 
Versi o n 
5: 
htt ps://cte p.ca ncer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _a p plicati o ns/ d ocs/ C T C A E _ v 5 _ Q uic k _ R
efere nce _ 8. 5 x 1 1. p df  
 
 
 
 
 
 
 
 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 1  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
A P P E N DI X 1.  P R O G R A M MI N G C O N V E N TI O N S F O R  O U T P U T S  
I Q VI A O U T P U T C O N V E N TI O N S   
IN T R O D U C TI O N  
 
T his  a p pe n di x a p plies t o sta n dar ds use d f or o ut p utti n g ta bles, listi n gs a n d fi g ures. It is i nte n de d 
t o pr o vi de s pecificati o ns t o g ui de t he statisticia n or statistical pr o gra m mer i n setti n g u p 
s pecificati o ns f or pr o gra m mi n g ta bles, listi n gs a n d fi g ures.  
O U T P U T F I L E N A MI N G C O N V E N TI O N S  
 
File na mes s h o ul d o nl y c o nsist of u p percas e letters, l o wercas e letters, di gits ( 0 t o 9) a n d 
u n dersc ores. A peri o d s h o ul d o nl y be use d t o i n di cate a s e parat or bet w ee n t he file na me a n d t h e 
e xte nsi o n. N o s paces, ot her s peci al c haracters or p u nct uati o n mar ks are per mitte d.  
 
As far as p ossi ble, o ut p ut files s h o ul d be i n R T F f or mat, alt h o u g h . D O C files are als o per mitte d.  
 
T he pr o gra m, pr o gra m l o g a n d o ut p ut file n a me s h o ul d reflect t he t y p e a n d n u m ber of t he 
statistical o ut p ut. If t his is n ot p ossi ble, t he n t he o ut p ut na me s h o ul d be at least as descri pti ve as 
p ossi ble. A prefi x ca n be use d t o disti n g uis h bet wee n a Ta ble, Listi n g a n d Fi g ure d o c u me nt (‘ T’ 
f or ta ble, ‘ L’ f or listi n g a n d ‘ F’ f or fi g ure). If t here is o nl y 1 di git i n t he n u m ber of t he ta ble, 
listi n g or fi g ure i n t he pla ce w here 2 di gits are p ossi ble, a lea di n g zer o s h o ul d be a d de d i n t he file 
na me t o ma ke s orti n g c o nsiste nt wit h t he se q ue nce (e g T 1 4 _ 3 _ 0 1 _ 1. R T F)  
 
P A P E R S I Z E, O RI E N T A TI O N A N D M
A R GI N S  
 
T he siz e of pa per will be Letter f or t h e U nite d States, ot her wise A 4.  
All listi n gs a n d ta bles will be  prese nte d i n la n ds ca pe orie ntati o n.   
 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 2  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
T he dis pla y area will be  9 i nc hes ( 2 2. 8 6 c m) b y 6 i nc hes ( 1 5. 2 4 c m).  T his dis pla y area 
c orres p o n ds t o mar gi ns of at least 1. 2 5'' t o p a n d b ott o m a n d 0. 8 7' ' ri g ht a n d left o n a la n dsca pe 
pa ge.  
 
T he li ne siz e (ls) a n d pa ge siz e ( ps) are n ot s p ecifi c, b ut t he tec h nical refere nce ass ur es a fit usi n g  
1 0 pt C o urier f o nt wit h n o a d diti o nal c o m pressi o n.  
  
F O N T S  
 
T he f o nt t y p e ‘ C o urier Ne w’ s h o ul d be use d as a d efa ult f or ta bl es a n d listi n gs, wit h a f o nt size 
of 1 0 . T he f o nt c ol or s h o ul d be blac k. N o b ol di n g , u n derli ni n g it alics or s u bscri pti n g s h o ul d be 
per mitte d. Tr y t o a v oi d usi n g s u per -scri pts, u nless a bs ol utely necessar y. Si n gle s paci n g s h o ul d 
be use d f or all te xt.  
 
H E A D E R IN F O R M A TI O N  
 
Hea ders s h o ul d be defi n e d as f oll o ws:  
• T he hea d er s h o ul d be place d at t he t o p of t h e pa ge (sa me place o n eac h p a ge) re gar dl ess of t he 
siz e or orie ntati o n of t he ta ble or listi n g 
• T he c ust o mer na m e  s h o ul d a p pear i n r o w 1, left-ali g n e d  
• Pa ge X of Y, wit h Y bei n g t he t otal n u m ber of pa ges i n t he o ut p ut, s h o ul d a p pear i n r o w 1, 
ri g ht ali g ne d 
• T he pr ot oc ol n u m ber s h o ul d a p pear i n r o w 2, left -ali g n e d  
• T he data c ut -off dat e s h o ul d ap pear i n r o w 2, ri g ht -ali g ne d  
• T he dr u g na me s h o ul d a p pear i n r o w 3, left -ali g ne d  
•  T he data e xtract date s h o ul d a p pear i n r o w 3, ri g ht -ali g ne d  
• T he o ut p ut i de ntificati o n n u m ber s h o ul d a p pear i n r o w 4 , ce ntere d 
• T he o ut p ut title s h o ul d start i n r o w 5 , ce ntere d  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 3  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
• T he o ut p ut p o p ulati o n s h o ul d a p pear i n r o w 6 , ce ntere d. T h e p o p ulati o n s h o ul d be s pelle d o ut 
i n f ull, e. g. I nt e nti o n-t o-Treat i n prefere nce t o I T T.  
• R o w 7  s h o ul d be a c o nti n u o us r o w of u n dersc ores (‘ _’) (t h e n u m ber of u n dersc ores s h o ul d 
e q ual t he li nesiz e)  
• R o w 8  s h o ul d be a bla n k li ne 
• Mi x e d case s h o ul d be use d f or titles  
• T he o ut p ut titles s h o ul d be desi g ne d s o t hat t he y are arra n ge d c o nsiste ntl y t hr o u g h all o ut p uts. 
F or e x a m ple, c o nte nt (e g Vital Si g ns) f oll o we d b y metric (e g C ha n ge fr o m B aseli ne) e. g. 
Vital Si g ns –  C ha n ge fr o m Baseli ne.  
• Titles s h o ul d n ot c o ntai n q u otati o n mar ks or f o ot n ote refere n ces  
• T he c ol u m n hea di n gs s h o ul d be u n derli ne d wit h a r o w of u n d ersc ores (‘ _’)  
• C ol u m n hea di n gs s pa n ni n g m ore t ha n o ne c ol u m n s h o ul d be u n derli ne d a n d ha ve u n d ersc ores 
o n eit her si de of t he title a n d s h o ul d be ce ntere d  
• C ol u m n hea di n gs c o ntai ni n g n u m bers s h o ul d be ce ntere d  
• C ol u m n hea di n gs s h o ul d be i n se nte nce cas e  
• I n ge neral, t he p o p ulati o n c o u nt s h o ul d a p pear i n t he c ol u m n hea der i n t he f or m “( N = X X X)” 
• As a r ule, all c ol u m ns after t he first c ol u m n s h o ul d ha ve c ol u m n hea di n gs. 
 
T A B L E A N D L I S TI N G O U T P U T C O N V E N TI O N S  
 
Ge neral:  
• T he first r o w i n t he b o d y of t he t a ble or listi n g s h o ul d be bla n k . 
• T he left ha n d c ol u m n s h o ul d start i n c ol u m n 1. N o i n de nti n g or ce nteri n g of t he o ut p ut s h o ul d 
occ ur.  
• R o u n di n g s h o ul d be d o ne wit h t he S A S f u ncti o n R O U N D.  
• N u m bers i n ta bles s h o ul d be r o u n de d, n ot tr u ncate d.  
• Al p ha n u meric o ut p ut s h o ul d be left ali g n e d.  
• N u m bers s h o ul d be deci mal p oi nt ali g ne d.  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 4  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
• W h ole n u m bers s h o ul d be ri g ht ali g n e d.  
• Te xt val ues s h o ul d be left ali g n e d.  
• T he first letter of a te xt e ntr y s h o ul d b e ca pitalize d . 
• Listi n gs of a d verse e v e nts, c o nc o mita nt me dicati o ns, me dical hist ories etc. s h o ul d be s orte d i n    
c hr o n ol o gical or d er, wit h earliest a d v erse e ve nt, m e dicati o n or hist or y c o mi n g first. 
• If p ossi ble, i ncl u de 1 0 0 % fre q u e ncies i n t he ta bl e s hell, s o t hat it is clear w hat t he de n o mi nat or 
is f or perce nta ge calc ulati o ns. 
• All listi n g o ut p uts s h o ul d be s orte d ( prefera bl y b y Treat me nt, Site N u m ber a n d S u bject 
N u m ber).  
• D o n ot use s u perscri pts a n d s u bscri pts . 
• T he wi dt h of t he e ntire o ut p ut s h o ul d matc h t he li nesize . 
 
U ni variate Statistics:  
• Statistics s h o ul d be prese nte d i n t he sa me or d er acr oss ta bles (i. e., n, Mea n, S D, Me dia n, 
Mi ni m u m, Ma xi m u m)  
• If t he ori gi nal data h as N deci mal places, t he n t h e s u m mar y statistics s h o ul d ha ve t he f oll o wi n g 
deci mal places:  
Mi ni m u m a n d ma xi m u m: N  
Mea n, me dia n a n d C V %: N + 1  
S D: N + 2  
• Missi n g statistics, e. g. w he n t he y ca n n ot be cal c ulate d, s h o ul d be prese nt e d as “ n d” f or “ n ot 
deter mi ne d. F or e x a m ple, if n = 1, t he meas ure of varia bilit y [e. g. sta n dar d de viati o n ( S tD)] 
ca n n ot be c o m p ute d a n d s h o ul d be prese nte d as “ n d”.  
 
Fre q u e ncies a n d perce nta ges ( n a n d %):  
• Perce nt val ues s h o ul d be  re p ort e d i nsi de pare nt heses, wit h o ne s pace bet wee n t he c o u nt a n d t he 
left pare nt h esis of t he perce nta ge. Pare nt hes es s h o ul d be j ustifie d t o acce pt a ma xi m u m of 
1 0 0. 0 as a val ue a n d pa d de d wit h bla n k s pace if t he perce nt is less t ha n 1 0 0. 0. A n e x a m ple is 
gi ve n b el o w:  
7 7 ( 1 0 0. 0 %)  
5 0 ( 6 4. 9 %)  
0 ( 0. 0 %)  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 5  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
Perce nta ges ma y be re p orte d t o 0 deci mal places as a p pr o priate (f or e x a m ple, w here t he 
de n o mi nat or is relati vel y s mall).  
 
C o nfi de nce I nter vals:  
• As a r ule c o nfi de nce i nter vals are o ut p ut t o o ne deci mal place m ore t ha n t he ra w dat a, a n d 
sta n dar d de viati o ns a n d sta n dar d err ors t o t w o deci mal  places m ore t ha n t h e ra w data  
• C o nfi de nce i nter vals s h o ul d be j ustifie d s o t hat pare nt hes es dis pla ye d o n c o nsec uti ve li nes of a 
ta ble “li ne u p”. 
• B o u n dar y v al ues of c o nfi d e nce i nter vals s h o ul d be se parate d b y a c o m ma.  
• B o u n dar y v al ues s h o ul d be pa d de d as necessar y t o acce pt n e gati ve val ues a n d t o all o w 
ali g n me nt of t he d eci mal place.  
• A n e x a m ple is gi ve n bel o w:  
(-0. 1 2, -0. 1 0)  
( 9. 5 4, 1 2. 9 1) 
 
P -val ues:  
• P -val ues s h o ul d be  re p orte d t o t hree d eci mal places, e x ce pt val ues < 1. 0 0 0 b ut > 0. 9 9 9 will be 
prese nte d as ‘ > 0. 9 9 9’ (e. g., 0. 9 9 9 8 is pres e nte d as > 0. 9 9 9); a n d val ues < 0. 0 0 1 will be 
prese nte d as ‘ < 0. 0 0 1’ (e. g., 0. 0 0 0 9 is pres e nte d as < 0. 0 0 1). R o u n di n g will be a p plie d aft er t h e 
< 0. 0 0 1 a n d > 0. 9 9 9 r ule  
 
Rati os:  
• Rati os s h o ul d be re p orte d t o o ne m ore deci mal place t ha n t he ori gi n al dat a.  
 
S paci n g:  
• T here m ust be a mi ni m u m of 1 bla n k s pace b et wee n c ol u m ns ( prefera bl y 2) . 
 
 De n o mi nat ors:  
• If a differe nt c o u nt ot her t ha n t he p o p ulati o n c o u nt is use d f or a de n o mi n at or ( wit hi n t he ta ble) 
t o calc ulate perce nta ges, t here s h o ul d be a r o w i n t he ta ble t hat i de ntifies t h at n u m ber “ n”. 
• Alter nati vel y, a f o ot n ot e s h o ul d be i ncl u de d i n eac h ta ble wit h perce nt a ges t o i n dicate t he 
de n o mi nat or f or perce nta ges.  
 
 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 6  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
Missi n g val ues  
• A “ 0” s h o ul d be use d t o i n dicate a zer o fre q ue n c y.  
• A bla n k will be use d t o i n dicate missi n g data i n a n e n d -of -te xt ta ble or s u bject listi n g. 
 
F O O T N O T E IN F O R M A TI O N  
 
F o oters s h o ul d be d efi ne d as f oll o ws:  
• A c o nti n u o us li ne of u n dersc ores (‘ _’) will f oll o w t he b o d y of t he ta ble or listi n g pri or t o a n y 
f o ot n otes at t he b ott o m of t he pa ge 
• Ta ble f o ot n otes s h o ul d be defi ne d usi n g c o m p ut e state me nts i n t he pr oc re p ort, a n d s h o ul d 
a p pear directl y after t he b o d y of  t h e ta ble 
• T he pr o gra m p at h a n d na me a n d versi o n n u m ber (if a p plica bl e)  a n d d ate/ti me sta m p  s h o ul d 
a p pear as fi nal f o ot n ote at t he b ott o m of t he pa ge 
• F o ot n otes s h o ul d be left -ali g ne d.  
• F o ot n otes s h o ul d be i n se nte nce case.  
• O nl y “t y pe writer” s y m b ols are per mitte d –  e g “ *”, “ $”, “ #”, “ @ ”, “ &” a n d “ +”.  
• T he s y m b ols s h o ul d a p pear i n t he sa m e or der as w hat t he y are defi n e d i n t he ta ble or listi n g, 
fr o m left t o ri g ht. 
 
P R O G R A M MI N G IN S T R U C TI O N S  
 
Pr o gra m mi n g i nstr ucti o ns m ust a p pear at t he e n d of eac h t a ble  or listi n g s h ell. Pr o gra m mi n g 
i nstr ucti o ns, w here necessar y, s h o ul d f oll o w t he ta ble or listi n g s hells, be gi n ni n g wit h t he w or ds 
“ pr o gra m mi n g n otes” f oll o we d b y t h e n otes o n a n e w li ne. T hese i n cl u de n otes o n t he o ut p ut, 
re mi n ders of h o w t o h a n dle missi n g val ues, re peat s hells f or si milar ta bles etc.  
D A T E S &  T I M E S 
 All  dates a n d ti mes will ta ke t he f or m  D D M M M Y Y Y Y  a n d H H: M M  res pecti vel y.  
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 7  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
S P E L LI N G F O R M A T  
E n glis h U S .  
P R E S E N T A TI O N O F T R E A T M E N T G R O U P S  
F or ta bles, si nc e t here is j ust o ne treat me nt gr o u p i n t his st u d y, t here will be o ne c ol u m n 
la belle d as O verall dis pla ye d.  
P R E S E N T A TI O N O F V I SI T S 
      F or o ut p uts, visits will be prese nte d as t he y a p pear ( defa ult L o n g Na me) i n t he dataset.  
L I S TI N G S 
All listi n gs will be or dere d b y t he f oll o wi n g ( u nl ess ot her wise i n dicate d i n t he te m plate):  
•  
Site -partici pa nt  I D,  
•  
Date ( w h ere a p plica ble), 
C O N V E R SI O N F A C T O R S  
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o m o nt hs or years :  
•  
1 m o nt h = 3 0. 4 3 7 5 da ys  
•  
1 y ear = 3 6 5. 2 5 da ys  
D E FI NI TI O N O F D U R A TI O N  
D urati o n will be calc ul ate d b y t h e differe nce bet w ee n start a n d st o p dat e + 1 if n ot ot her wise 
s pecifie d. F or e x a m ple, d urati o n of res p o ns e ( da ys) = date of P D/ deat h/ce ns ori n g –  d ate of 
res p o nse + 1. 
 
T he ti me si nce  a n e ve nt ( e. g. ti me si nce i nitial ca n cer dia g n osis) will be cal c ulate d as refere n ce 
date mi n us date of e v e nt  + 1 . I n ge n eral, t he refere nce date will be t he date of first st u d y 
treat me nt. 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 8  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
T he ti me t o a n e ve nt will be calc ul ate d b y t he differe nce bet w ee n t he ti me of e ve nt a n d t he 
refere nce date + 1 if n ot ot her wise s pecifie d. F or e x a m ple, s ur vi val ti me ( da ys) = dat e of deat h - 
date of first st u d y treat me nt + 1.  
 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 5 9  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
A P P E N DI X 2.  P A R TI A L D A T E C O N V E N TI O N S  
U nle ss ot her wise liste d b el o w, Partial dates  will n ot be i m p ute d a n d  will be prese nte d i n t he 
f or mat “ _ _ _ _ _ Y Y Y Y”. Missi n g dates i m p ute d acc or di n g t o t he g ui d eli nes bel o w will be 
fla g ge d a n d i ncl u d e d i n listi n gs. 
M
I S SI N G D A T A H A N D LI N G R U L E S F O R A G E C A L C U L A TI O N  
I n c o m plete dates ( date of i nf or me d c o nse nt, dat e of birt h) f or t he calc ulati o n of a ge will be 
i m p ute d as f oll o ws:  
o  I n case of missi n g da y f or at least o ne d ate, b ut m o nt h a n d year a vaila ble f or b ot h 
dates: t he da y of i nf or me d c o nse nt a n d t he da y of birt h w ill be set t o 1. 
o  I n case of missi n g m o nt h f or at least o ne d ate, b ut year a v aila ble f or b ot h dates, 
t he da y a n d t he m o nt h of i nf or me d c o nse nt a n d t h e da y a n d m o nt h of birt h will be 
set t o 1. 
o  I n all ot her cases, t he i nc o m plete dates will n ot be i m p ute d.  
M
I S SI N G D A T A H A N D LI N G R U L E S F O R D E A T H D A T E  
F or t he p ur p os e of s ur vi v al a nal yses , partiall y missi n g deat h d ates will be i m p ute d as f oll o ws:  
o  If o nl y t h e da y is missi n g, t he deat h date will be i m p ute d t o t he ma xi m u m of t he 
( n o n-i m p ute d) da y after t he date of last k n o w n ali ve date  a n d t h e 1 5 t h da y of t he 
m o nt h  
o  Ot her wise it will n ot be i m p ute d  
M
I S SI N G D A T A H A N D LI N G R U L E S F O R L A S T C O N T A C T  D A T E  
T he date of l ast c o ntact will be deter mi ne d usi n g t he f oll o wi n g dat es ( wit h dates past t he c ut -off 
i g n ore d b y t h e deri v ati o n):  
o  All partici pa nt assess me nt dates  
o  Start a n d e n d dates of a ntica ncer t hera pies a d mi nistere d after st u d y treat me nt 
disc o nti n uati o n.  
o  A E start a n d e n d d ates  
o  Last k n o w n ali ve date c ollecte d o n t he ‘ S u bject Stat us / S ur vi val F oll o w -U p’ 
e C R F f or m ( d o n ot use f oll o w u p date) 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 0  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
o  St u d y dr u g start a n d e n d dates .  
M
I S SI N G D A T A H A N D LI N G R U L E S F O R A D V E R S E E V E N T S  
I n c o m plete A E-relate d d ates will be i m p ute d as f oll o ws:  
o  I n case t h e o nset date is missi n g c o m pletel y or missi n g partiall y b ut t he o nset 
m o nt h a n d year, or t h e o nset year are e q ual t o t he start of st u d y tr eat me nt t he n t he 
o nset date will be i m p ute d b y t he mi ni m u m of start of st u d y treat me nt a n d A E 
res ol uti o n date (if n ot missi n g).  
o  I n all ot her cases, t he missi n g o nset da y or missi n g o nset m o nt h will be i m p ute d 
b y 1.  
o  I n c o m plete st o p dates will be i m p ute d b y t he last da y of t he m o nt h (if da y is 
missi n g o nl y), if n ot res ulti n g i n a date later t ha n t he date of p artici pa nt’s d eat h. I n 
t he latter cas e, t he date of deat h will be use d t o i m p ute t he i nc o m plete st o p date.  
o  I n all ot her cases, t he i nc o m plete st o p date will n ot be i m p ute d.  
M
I S SI N G D A T A H A N D LI N G R U L E S F O R S U B S E Q U E N T A N TI C A N C E R T H E R A P Y  
I n c o m plete dates f or start date of s u bse q ue nt a nti ca ncer t hera p y ( dr u g t hera p y, ra di ot hera p y, 
s ur ger y) will be i mp ute d as f oll o ws a n d will be use d f or deter mi ni n g ce ns ori n g dates f or 
effic ac y a n al ys es a n d i n t he deri vati o n of t he e n d of o n -treat me nt p eri o d: 
o  If o nl y d a y is missi n g, it will be i m p ute d as t he last da y of t h e m o nt h u nless t he 
e n d date of s u bs e q ue nt a ntic a ncer t h era p y is bef ore t hat date. I n t hat case, t he 
i nc o m plete a ntica ncer t h era p y start d ate will be i m p ute d as t he e n d date of t he 
a ntica ncer t hera p y.  
o  If b ot h da y a n d m o nt h are missi n g, n o i m p utati o n will be perf or me d.  
o  If t he date is c o m plet el y missi n g, n o i m p utati o n will be perf or me d.  
M
I S SI N G D A T A H A N D LI N G R U L E S F O R P R E VI O U S M E DI C A TI O N S , C O N C O MI T A N T 
M E DI C A TI O N S  A N D P RI O R A N TI C A N C E R T H E R A PI E S O R P R O C E D U R E S  
I n c o m plete dates f or pre vi o us a n d c o nc o mita nt me dicati o ns will b e i m p ute d as f oll o ws:  
F or start d ate of me dicati o n : 
o  If t he da y is missi n g, it will be i m p ute d t o t he 1st da y of t he m o nt h.  
o  If b ot h da y a n d m o nt h are missi n g, t he m o nt h a n d da y will be i m p ute d as Ja n uar y 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 1  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
1 st.  
o  If t he date is c o m plet el y missi n g, n o i m p utati o n will be perf or me d.  
F or e n d d ate me dic ati o n:  
o  If t he da y is missi n g, it will be i m p ute d t o t he last da y of t he m o nt h.  
o  If b ot h da y a n d m o nt h are missi n g, t he m o nt h a n d da y will be i m p ute d as 
Dece m b er 3 1 st  
o  If t he date is c o m plet el y missi n g, n o i m p utatio n will be perf or me d.  
N ote: I n cas e t he i m p utati o n res ults i n a date later t ha n t he date of pa rtici pa nt's deat h, t he n t he 
date of deat h will be use d t o i m p ute t he i nc o m plete st o p date.  
 
 
P P D


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 2  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
 
A P P E N DI X 3.  A D V E R S E E V E N T S O F S P E CI A L IN T E R E S T  
Details of t he al g orit h ms f or i de ntif yi n g a d verse e ve nts of s pecial i nterest c a n be f o u n d i n t he 
d oc u me nt A E SI al g orit h ms. d oc x.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P P D


GSK 
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Statistical Analysis Plan 
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Author: 
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Version Date:  
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Template No.:  CS_TP_BS016 Revision 6 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 4. CTCAE GRADING CRITERIA 
See document: CTC V5.0 guidance.xlsx 
CTC V5.0 
guidance.xlsx
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 4  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
A P P E N DI X 5.  A B B R E VI A TI O N S  
1 L  
First Li n e  
A C S  
A b n or mal, Cli nicall y Si g nifica nt  
A E  
A d verse E v e nt  
A E SI  
A d verse E v e nt of S pecial I nterest  
A L P  
Al kali ne P h os p hatase  
A N C S  
A b n or mal, N ot Cli nicall y Si g nifica nt  
A P T T  
A d va nce d Partial T hr o m b o plasti n Ti me  
A S C O  
T he A merica n S ociet y of Cli nical O nc ol o g y  
B MI  
B o d y Mass I n d e x  
B O R  
Best O verall Res p o nse  
b p m  
Beats Per Mi n ute  
C  
Celsi us  
CI  
C o nfi de nce I nter val  
C m  
Ce nti met er 
C R  
C o m plete Res p o nse  
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  
E C G  
Electr ocar di o gra m  
e C R F 
electr o nic Cas e Re p ort F or m  
F D A A A  
F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act  
F PI  
First Patie nt I n  
G S K  
Gla x o S mit h Kli ne  
H C G  
H u ma n C h ori o nic G o na d otr o pi n  
H R  
Heart Rate  
I C 
I nf or me d C o nse nt 
I R 
I m m u ne-relat e d 
ir A E 
I m m u ne-relat e d A Es 
I R C 
In d e pe n de nt Re vi e w C o m mittee  
I R R 
I nf usi o n Relate d Reacti o ns 
k g  
Kil o gra m(s)  
L L N  
L o w er Li mit of N or mal  
m  
Metre  
P P D
C CI
C CI
C CI
C CI


 
G S K  
P R O T O C O L 2 1 3 1 5 2  
 
St ati sti c al A n al y si s Pl a n  
P a g e 6 5  of 6 5  
 
D o c u m e nt:  
\\q ui ntil e s. n et \E nt er pri s e \A p p s \s a s d at a \S A S a \s a s \G S K \G S K 4 0 4 5 1 5 4 \P Z A A 7 7 1 5 \Bi o st ati sti c s \D o c u
m e nt ati o n \S A P \G S K _ 2 1 3 1 5 2 _ P Z A A 7 7 1 5 _ S A P _ Fi n al _ v 1. 0 _ 0 7 S E P 2 0 2 2  
A ut h or:  
V er si o n N u m b er:  
1. 0  
 
V er si o n D at e:  
0 7 S E P 2 0 2 2  
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 6  
R ef er e n c e:  C S _ WI _ B S 0 0 5  
Eff e cti v e D at e: 0 2 D e c 2 0 1 9  
 
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al a n d 
pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
m g  
Milli gra m(s)  
m L  
Milliliter(s)  
m m H g  
Milli meters of Merc ur y  
msec  
Milisec o n ds  
N CI -C T C A E  
Nati o nal Ca ncer I nstit ute - C o m m o n T o xicit y Crit eria f or 
A d verse E v e nts  
N D  
N ot Deter mi ne d  or N o Disease  
N E  
N o n E val ua ble  
N R  
N o Res ult  
O R R  
O bjecti ve  Res p o nse Rate  
P D  
Pr o gressi ve Diseas e  
P D -L 1  
Pr o gra m me d Deat h -Li ga n d 1  
P R  
Partial Res p o nse  
P T  
Preferre d Ter m  
Q 2 W  
E ver y 2 Wee ks  
Q T  
Q T I nter val  
Q Tc F  
Q T i nter val d urati o n c orrecte d  Fri deri cia ’s 
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
S A E  
Seri o us A d verse E v e nt  
S A F  
Safet y/ Treat e d A nal ysis Set  
S A P  
Statistical A nal ysis Pla n  
S C R  
Scree ne d A nal ysis set  
S D  
Sta ble Disease  
SI  
I nter nati o nal S yst e m of U nits 
S O C  
S yste m Or ga n Class  
St D  
Sta n dar d De viati o n  
T E A E  
Treat me nt E mer ge nt A d v erse E ve nt  
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 L Q  
U p per Li mit of Q ua ntificati o n  
W B C  
W hite Bl o o d Cell  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 
P P D
C CI
C CI
C CI