A Multicenter, Double Blind, Randomized, Controlled Study of M7824 With Concurrent Chemoradiation Followed by M7824 Versus Concurrent Chemoradiation Plus Placebo Followed by Durvalumab in Participants With Unresectable Stage III Non-small Cell Lung Cancer
Phase: PHASE2
Conditions: Non-small Cell Lung Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 1 5 5
Cli nic al St u d y Pr ot oc ol
Title P a ge
Cli nic al St u d y Pr ot oc ol Title:
A  
M ultice nter,  
D o u ble  
Bli n d,  
Ra n d o mize d, 
C o ntr olle d 
St u d y  
of M 7 8 2 4  
wit h 
C o nc urre nt 
C he m ora diati o n  
F oll o we d 
b y   
M7 8 2 4 
vers us 
C o nc urre nt
C he m ora diati o n
Pl us Place b o F oll o we d 
b y  Dur val u ma b i n Partici pa nts wit h U nresecta ble 
Sta ge III N o n -s mall Cell L u n g Ca ncer
St u d y N u m ber:
M S 2 0 0 6 4 7 _ 0 0 0 5
Merc k C o m p o u n d:
M 7 8 2 4
Merc k Re gistere d C o m p o u n d N a me i n 
J a p a n:
N ot A p plica ble
St u d y P h ase:
P hase II
S h ort Title:
M 7 8 2 4 wit h c C R T
i n U nresecta ble Sta ge III N S C L C
C o or di n ati n g I n vesti g at or:
S p o ns or N a me a n d Le g al Re gistere d 
A d dress:
F or all c o u ntries, e xce pt t he U S a n d Ja pa n:
Merc k K Ga A
Fra n kf urter Str. 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
Affiliates of Merc k K Ga A, Dar msta dt, Ger ma n y:
I n t he U S:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, 
I nc.
4 5 A Mi d dlese x T ur n pi ke
Billerica, M A, 0 1 8 2 1, U S A
L ocal S p o ns or f or Sites i n Ja pa n:
Merc k Bi o p har ma C o., Lt d. Ja pa n
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma ny
Arc o T o wer, 1 - 8-1 S hi m o me g ur o
Me g ur o -k u, T o k y o 1 5 3 -8 9 2 6, Ja pa n
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
E u dra C T 2 0 1 8- 0 0 3 2 6 5- 3 4
Pr ot oc ol Versi o n:
2 2 J u ne 2 0 2 1 / Versi o n 4. 0
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
P P D
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 1 5 5
Me dic al 
M o nit or 
N a me a n d C o nt act 
I nf or m ati o n:
P h o ne: 
E- mail: 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
P P D
P P D
P P D
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 1 5 5
Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges
Pr ot oc ol Hist or y
V er si o n N u m b er
T y p e
V er si o n D at e
1. 0
Ori gi n al pr ot o c ol
0 7 -D e c -2 0 1 8
2. 0
Gl o b al A m e n d m e nt
0 5- M ar -2 0 1 9
2. 1
L o c al A m e n d m e nt ( C hi n a)
0 8 -M a y -2 0 1 9
2. 2
L o c al A m e n d m e nt 
( E U c o u ntri e s p arti ci p ati n g i n V H P) 
2 1 -M a y -2 0 1 9
3. 0
Gl o b al A m e n d m e nt 
0 5- J u l-2 0 1 9
3. 1 
L o c al A m e n d m e nt ( K or e a )
0 5 -N o v -2 0 1 9
4. 0
Gl o b al A m e n d m e nt
2 2- J u n -2 0 2 1
Pr ot oc ol Versi o n [ 4. 0 ] (2 2- J U N -2 0 2 1)
O ver all R ati o n ale f or t he A me n d me nt
T he t w o ke y  rati o nales f or t his a me n d me nt are: t o re d uce t he sa m ple size fr o m 3 5 0 partici pa nts t o 
a p pr o xi matel y 16 0 partici pa nts t o pr o vi de a n earlier res ult fr o m t he pri mar y  anal y sis t o gi ve i nsi g ht 
i nt o t he p ote ntial be nefit of M 7 8 2 4 i n patie nts wit h u nresecta ble Sta ge III N S C L C , a n d t o u p date 
t he ris k classificati o n a n d mi ni mizati o n meas ures.
T his a me n d me nt is s u bsta ntial base d o n criteria i n Article 1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of t he 
E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.
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
Titl e p a g e
R e m o v al of d et ail s of m e di c al 
r e s p o n si bl e a n d a p pr o v al d at e .
U p d at e d f or c o n si st e n c y wit h M er c k 
pr ot o c ol st a n d ar d s.
Titl e p a g e
C h a n g e of M e di c al M o nit or d et ail s . 
T o r efl e ct c h a n g e i n M e di c al M o nit or .
1. 1 S y n o p si s ( O bj e cti v e 
a n d e n d p oi nt s)
3 O bj e cti v e s a n d 
E n d p oi nt s
 
P F S a n d o bj e cti v e r e s p o n s e 
c h a n g e d fr o m i n d e p e n d e nt 
c e ntr al r e vi e w t o I n v e sti g at or
a s s e s s m e nt .
 
 
S e e c h a n g e t o effi c a c y e n d p oi nt s b el o w. 

 
 
.

 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C
C
I
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 1 5 5
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
1. 1 S y n o p si s 
1. 2 S c h e m a
4. 1 O v er all d e si g n
4. 1. 1. 5 Str atifi c ati o n
6. 3. 2 Bli n di n g
 
 
 
 
 
 
 
 
 
 
 
 
1. 1 S y n o p si s
3. O bj e cti v e s a n d 
E n d p oi nt s
8. 1 Effi c a c y A s s e s s m e nt s 
a n d Pr o c e d ur e s
9. 4. 1 Effi c a c y A n al y s e s
9. 4. 1. 1 T u m or A s s e s s m e nt 
b y I R C ( n e w s e cti o n)
A p p e n di x 8 R e s p o n s e 
E v al u ati o n Crit eri a i n S oli d 
T u m or s V er si o n 1. 1 
( R E CI S T 1. 1)
T h e m ai n a n al y si s of e ffi c a c y 
e n d p oi nt s b a s e d o n r a di o gr a p hi c 
s c a n d at a will b e b a s e d o n
I n v e sti g at or a s s e s s m e nt , a n d n ot 
I R C. A p p e n di x 8 , R e s p o n s e 
E v al u ati o n Crit eri a i n S oli d T u m or s 
V er si o n 1. 1 ( R E CI S T 1. 1), h a s b e e n 
a d d e d f or g ui d a n c e.
T h e I n v e sti g at or a s s e s s m e nt i s a p pr o pri at e 
gi v e n t h e d o u bl e -bli n d n at ur e of t h e st u d y 
wit h l o w s u s c e pti bilit y t o bi a s i n i m a gi n g 
a s s e s s m e nt. C e ntr ali z e d i m a gi n g c oll e cti o n 
will c o nti n u e t o all o w f urt h er a n al y s e s, a s 
a p pli c a bl e .
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 1)
4. 1 O v er all D e si g n
 
S cr e e ni n g h a s b e e n e xt e n d e d t o 
u p t o 2 8 d a y s f or s el e ct e d 
a s s e s s m e nt s. 
 
A d diti o n all y, t h e s cr e e ni n g 
p eri o d h a s b e e n c h a n g e d fr o m a 
s p e cifi c n u m b er of d a y s t o “ u p 
t o” 2 1 or 2 8 d a y s.
 
T o all o w f or s cr e e ni n g a s s e s s m e nt s t h at 
h a v e b e e n f o u n d t o r e q uir e m or e ti m e t o 
p erf or m pri or t o D a y 1.
 
T h e a d diti o n of “ u p t o” h a s b e e n m a d e 
t o all o w fl e xi bilit y i n d ur ati o n of t h e 
s cr e e ni n g p eri o d u p t o a m a xi m u m 
n u m b er of d a y s. 
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 1)
8. 1 Effi c a c y A s s e s s m e nt s 
a n d Pr o c e d ur e s
 
 
F or cl arifi c ati o n.
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 1)
T h e W e e k 1 D a y 1 c o nfir m ati o n of 
eli gi bilit y c h e c kli st pri or t o d o si n g 
h a s b e e n r e m o v e d .
I n t hi s r a n d o mi z e d cli ni c al st u d y, t h e 
c o nfir m ati o n of eli gi bilit y i s p erf or m e d 
d uri n g s cr e e ni n g, pri or t o r a n d o mi z ati o n.
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 1)
A n ot e st ati n g t h at s cr e e ni n g t e st s 
p erf or m e d pri or t o i nf or m e d c o n s e nt 
ar e a c c e pt a bl e if wit hi n t h e 
s cr e e ni n g p eri o d h a s b e e n 
r e m o v e d.
T h e s cr e e ni n g wi n d o w i s e xt e n d e d fr o m 
2 1 t o 2 8 d a y s f or m o st of s cr e e ni n g 
a s s e s s m e nt s.
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 2)
6. 1 St u d y I nt er v e nti o n( s) 
A d mi ni str ati o n
T h e r o w f or M 7 8 2 4/ pl a c e b o 
pr e m e di c ati o n i n T a bl e 2 h a s b e e n 
r e m o v e d a n d pr e m e di c ati o n f or 
M 7 8 2 4/ pl a c e b o h a s b e e n m a d e 
o pti o n al.
F or c o n si st e n c y wit h c urr e nt m a n a g e m e nt 
g ui d eli n e s f or M 7 8 2 4. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5/ 1 5 5
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
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 1 a n d T a bl e 3)
 
 
 
 
 
 
 
 
 
 
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 1, T a bl e 3 a n d 
T a bl e 4)
N ot e d e s cri bi n g d o c u m e nt ati o n of 
a d v er s e e v e nt s h a s b e e n r e pl a c e d 
wit h r ef er e n c e t o A p p e n di x 4.
T o si m plif y t h e s c h e d ul e of a cti viti e s a n d 
r ef er e n c e t h e a p p e n di x d e s cri bi n g s af et y 
r e c or di n g a n d r e p orti n g. 
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 3)
 
 
F or cl arifi c ati o n.
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 3)
 
 
 
 
.
 
 
1. 3 S c h e d ul e of A cti viti e s 
( T a bl e 4)
8. 1 Effi c a c y A s s e s s m e nt s 
a n d Pr o c e d ur e s
R e m o v al of p arti ci p a nt c o nt a ct pri or 
t o i nt eri m a n al y si s. 
T h e i nt eri m a n al y si s h a s b e e n r e m o v e d.
2. 2 B a c k gr o u n d
A r ef er e n c e t o t h e I n v e sti g at or’ s 
Br o c h ur e h a s b e e n a d d e d.
T o pr o vi d e a r ef er e n c e t o t h e c urr e nt st at u s 
of t h e cli ni c al e v al u ati o n of M 7 8 2 4. 
2. 3 B e n efit/ Ri s k 
A s s e s s m e nt
U p d at e of d et ail s of i d e ntifi e d a n d 
p ot e nti al ri s k s f or M 7 8 2 4.
F or c o n si st e n c y wit h c urr e nt k n o wl e d g e of 
M 7 8 2 4
a n d t h e l at e st v er si o n of t h e 
I n v e sti g at or’ s Br o c h ur e. 
3 O bj e cti v e s a n d 
E n d p oi nt s
 
 
 
 
 
 
 
 
 
3 O bj e cti v e s a n d 
E n d p oi nt s
A n ot e h a s b e e n a d d e d t o T a bl e 6 
st ati n g t h at a n al y si s of 
 e n d p oi nt s will b e 
c o nti n g e nt o n t h e o ut c o m e s of 
pri m ar y a n d s e c o n d ar y e n d p oi nt s.
T o pr o vi d e fl e xi bilit y i n a n al y si s of 
 e n d p oi nt s.
4. 3 J u stifi c ati o n f or D o s e 
D et ail o n d o s e j u stifi c ati o n h a s b e e n 
r e m o v e d, a n d a r ef er e n c e t o t h e I B 
a d d e d.
T o str e a mli n e t h e s e cti o n a n d e n s ur e 
r e a d er s ar e dir e ct e d t o c urr e nt d et ail s. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 1 5 5
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
4. 1. O v er all D e si g n
4. 3 J u stifi c ati o n f or D o s e
6. 1 St u d y I nt er v e nti o n( s) 
A d mi ni str ati o n
6. 3. 2 Bli n di n g
6. 4 St u d y I nt er v e nti o n 
C o m pli a n c e
6. 6 D o s e S el e cti o n a n d 
M o difi c ati o n
6. 9. 5 Bl e e di n g A d v er s e 
E v e nt s
7. 1. 1 P er m a n e nt 
Di s c o nti n u ati o n
S e cti o n 6. 9. 5: a d diti o n of 
i nf or m ati o n of M 7 8 2 4 d o s e 
m o difi c ati o n s i n c a s e of bl e e di n g 
e v e nt s. S e cti o n 6. 3. 2 pr o vi d e s 
d et ail s of pr e p ar ati o n of r e d u c e d 
d o s e s i n a d o u bl e -bli n d m a n n er.
T o f a cilit at e pr o p er m a n a g e m e nt of 
bl e e di n g e v e nt s a n d all o w bli n di n g t o b e 
m ai nt ai n e d.
4. 1. 1. 1 P F S a s t h e Pri m ar y 
E n d p oi nt
T h e I T T s et h a s b e e n u p d at e d t o 
t h e F A S.
F or c o n si st e n c y wit h M er c k st a n d ar d s.
4. 4 E n d of St u d y D efi niti o n  
T h e d efi niti o n of e n d of st u d y h a s 
b e e n u p d at e d t o eit h er t h e d at e of 
pri m ar y a n al y si s or w h e n all 
p arti ci p a nt s h a v e c o m pl et e d 
m ai nt e n a n c e t h er a p y a n d s af et y 
f oll o w-u p, w hi c h e v er o c c ur s l at er .
F or c o n si st e n c y wit h t h e c h a n g e s i n st u d y 
d e si g n a n d o bj e cti v e s.
5 St u d y P o p ul ati o n
A p p e n di x 2
T e xt o n t h e p arti ci p a nt’ s l e g al 
r e pr e s e nt ati v e h a s b e e n a d d e d.
T o cl arif y t h at l e g al r e pr e s e nt ati v e s c a n 
o nl y pr o vi d e i nf or m e d c o n s e nt w h er e 
all o w e d b y l o c al l a w s a n d r e g ul ati o n s.
5. 2 E x cl u si o n Crit eri a 
E x cl u si o n crit eri o n 7 h a s b e e n s plit 
i nt o t w o s e p ar at e crit eri a: o n e 
r ef erri n g t o u n c o ntr oll e d i nt er c urr e nt 
ill n e s s e s ( crit eri o n 7 a ), a n d o n e 
r ef erri n g t o bl e e di n g di at h e si s a n d 
r e c e nt m aj or bl e e di n g e v e nt s 
( crit eri o n 7 b ). 
A d diti o n all y, cli ni c all y r el e v a nt 
bl e e di n g e v e nt s of h e m o pt y si s 
Gr a d e ≥ 2 wit hi n t h e l a st m o nt h
w er e a d d e d t o t h e n e w crit eri o n 7 b .
T h e crit eri o n w a s s plit at t h e r e q u e st of a 
h e alt h a ut h orit y. 
T h e a d diti o n of h e m o pt y si s w a s f or 
c o n si st e n c y wit h a si mil ar M 7 8 2 4 st u d y i n 
w hi c h t hi s r e q u e st w a s m a d e b y t h e I D M C . 
5. 2 E x cl u si o n Crit eri a 
A d diti o n of e x cl u si o n crit eri o n 2 4 : 
pri or r a di ot h er a p y if d eli v er e d i n 
a dj u v a nt/ n e o -a dj u v a nt r e gi m e n.
T o f urt h er cl arif y n e e d t o e x cl u d e 
p arti ci p a nt s w h o u n d er w e nt pri or 
r a di ot h er a p y if d eli v er e d i n a dj u v a nt/ n e o-
a dj u v a nt r e gi m e n.
5. 4 S cr e e n F ail ur e s 
L a n g u a g e o n e xt e n si o n of 
s cr e e ni n g wi n d o w i n c a s e s of 
a b n or m al s cr e e ni n g l a b or at or y 
v al u e or t e st t h at m a y c orr e ct h a s 
b e e n r e m o v e d.
T h e s cr e e ni n g wi n d o w i s e xt e n d e d fr o m 
2 1 t o 2 8 d a y s f or s o m e s cr e e ni n g 
a s s e s s m e nt s.
6. 1 St u d y I nt er v e nti o n( s) 
A d mi ni str ati o n 
U p d at e s t o d et ail s of pr o vi si o n of 
M 7 8 2 4, d ur v al u m a b, a n d 
c h e m ot h er a p y .
T o all o w a p pr o pri at e pr o vi si o n of st u d y 
i nt er v e nti o ns a cr o s s all sit e s.
6. 1. 1 R a di ati o n
D ail y u s e of i m a g e g ui d a n c e h a s 
b e e n c h a n g e d fr o m r e q uir e d t o 
r e c o m m e n d e d. 
R e c o m m e n d ati o n c o n si d er e d m or e 
a p pr o pri at e i n a b s e n c e of m et h o d of 
r e c o n cili ati o n. 
6. 1. 2 C h e m ot h er a p y 
O pti o n t o d eli v er et o p o si d e 
a c c or di n g t o l o c al pr a cti c e a d d e d. 
T o all o w d el i v er y of c h e m ot h er a p y b y l o c al 
pr a cti c e. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 1 5 5
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
6. 2. 3 D ur v al u m a b
U p d at e of c h ar a ct eri sti c s a n d 
g ui d a n c e of u s e f or d ur v al u m a b.
T o pr o vi d e m o st r e c e nt d et ail s o n 
d ur v al u m a b.
6. 3. 2 Bli n di n g
D el et e d m e nti o n of i nt eri m a n al y si s 
a n d st at e d t h at I D M C will r e c ei v e 
u n bli n d e d d at a t o p erf or m t h eir 
o n g oi n g s af et y a n al y s e s. 
T o u p d at e aft er r e m o v al of i nt eri m a n al y si s, 
a n d f or cl arit y of bli n di n g st at u s of I D M C. 
6. 3. 3 E m er g e n c y 
U n bli n di n g
L a n g u a g e w a s a d d e d t o st at e t h at i f 
e m er g e n c y u n bli n di n g i s r e q uir e d, 
t h e p arti ci p a nt c a n c o nti n u e st u d y 
tr e at m e nt u nl e s s t h er e ar e ot h er 
cir c u m st a n c e s t h at r e q uir e 
p arti ci p a nt di s c o nti n u ati o n.
T o cl arif y t h e st at u s of p arti ci p a nt s aft er 
e m er g e n c y u n bi n di n g.
6. 5. 2 Pr o hi bit e d M e di ci n e s 
L a n g u a g e o n v a c ci n e s h a s b e e n 
u p d at e d t o s p e cifi c all y all o w 
a p pr o v e d S A R S -C o V -2 v a c ci n e s at 
a n y p oi nt .
T o all o w p arti ci p a nt s t o b e pr ot e ct e d 
a g ai n st C O VI D -1 9 di s e a s e. 
6. 8 S p e ci al Pr e c a uti o n s
6. 9 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
S e cti o n s h a v e b e e n si m plifi e d f or 
cl arit y a n d t o r e d u c e r e p etiti o n, a n d 
ar e n o w or g a ni z e d a s f oll o w s:
 
6. 8 S p e ci al Pr e c a uti o n s
 
6. 9 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
 
6. 1 0 Ri s k M a n a g e m e nt f or 
C h e m or a di ati o n
6. 1 1 A d v er s e Dr u g R e a cti o n s 
R e q uiri n g Tr e at m e nt 
Di s c o nti n u ati o n
Pri m aril y t o str e a mli n e a n d si m plif y t h e s e 
s e cti o n s, r e d u ci n g r e p etiti o n a n d i m pr o vi n g 
cl arit y. A d diti o n all y, ri s k cl a s sifi c ati o n w a s 
u p d at e d a c c or di n g t o c urr e nt pr ofil e of 
M 7 8 2 4, a n d d et ail s o n m a n a g e m e nt of 
bl e e di n g e v e nt s w er e a d d e d t o all o w 
a p pr o pri at e m a n a g e m e nt.
6. 8 S p e ci al Pr e c a uti o n s
A p p e n di x 5 ( d el et e d)
G e n er al g ui d a n c e pr e vi o u sl y i n 
S e cti o n 6. 9. 2 ( A d v er s e Dr u g 
R e a cti o n s R e q uiri n g Tr e at m e nt 
Di s c o nti n u ati o n) h a s b e e n r el o c at e d 
t o 6. 8 t o r e d u c e r e p etiti o n a n d 
e n s ur e all i n f or m ati o n i s e a sil y 
a c c e s si bl e. N o si g nifi c a nt c h a n g e s 
h a v e b e e n m a d e t o g e n er al 
g ui d a n c e f or m a n a g e m e nt of A D R s. 
R ef er e n c e s t o t h e c urr e nt N C C N 
g ui d eli n e s h a v e b e e n a d d e d. 
6. 9. 1 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
G ui d eli n e s f or m a n a g e m e nt h a v e 
b e e n si m plifi e d , a n d ri s k 
r e cl a s sifi c ati o n fr o m “i m p ort a nt 
i d e ntifi e d” t o “i d e ntifi e d” ri s k h a s 
b e e n d o n e . 
6. 9. 2 I m m u n e-r el at e d 
A d v er s e E v e nt s
Ri s k r e cl a s sifi c ati o n h a s b e e n d o n e 
a n d t h e li st of e v e nt s h a s b e e n 
u p d at e d a c c or di n gl y
6. 9. 5 Bl e e di n g A d v er s e 
E v e nt s
Bl e e di n g e v e nt s ar e r e cl a s sifi e d 
fr o m “p ot e nti al ri s k ” t o “i m p ort a nt 
i d e ntifi e d ri s k” f or M 7 8 2 4.
D et ail s of d o s e r e d u cti o n s f or 
m a n a g e m e nt of bl e e di n g e v e nt s 
h a v e b e e n a d d e d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8/ 1 5 5
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
6. 9. 6 Ot h er I m p ort a nt 
P ot e nti al Ri s k s
T h e ri s k n a m e “ Alt er ati o n s i n 
W o u n d H e ali n g or R e p air of Ti s s u e 
D a m a g e” h a s b e e n c h a n g e d t o 
“I m p air e d W o u n d H e ali n g”.
6. 1 0 Ri s k M a n a g e m e nt f or 
C h e m or a di ati o n
T h e f oll o wi n g t e xt w a s d el et e d: 
T h er e will b e n o d o s e m o difi c ati o n s 
f or c ar b o pl ati n a n d p a clit a x el e x c e pt 
c ar b o pl ati n d o s e m o difi c ati o n s f or 
r e n al t o xi cit y.
T e xt c o nfli ct e d wit h ot h er d et ail s i n s e cti o n. 
6. 1 0 Ri s k M a n a g e m e nt f or 
C h e m or a di ati o n
( c ar b o pl ati n/ p a clit a x el)
T h e f oll o wi n g t e xt w a s a d d e d: If a 
Gr a d e 2 a n e mi a d o e s n ot r e s ol v e t o 
Gr a d e ≤ 1 b y t h e l a st d a y of t h e 
c urr e nt c y cl e b ut i s m a n a g e a bl e 
a n d/ or n ot cli ni c all y r el e v a nt, t h e 
M e di c al M o nit or s h o ul d b e 
c o n s ult e d t o a s s e s s if it i s cli ni c all y 
r e a s o n a bl e t o a d mi ni st er t h e 
f oll o wi n g i nf u si o n.
T o pr o vi d e fl e xi bilit y f or m a n a g e m e nt of 
a n e mi a w h e n a p pr o pri at e. 
7. 2 P arti ci p a nt 
Di s c o nti n u ati o n/ Wi t h dr a w al 
fr o m t h e St u d y
D et ail s o n di s c o nti n u ati o n h a v e 
b e e n u p d at e d.
F or cl arit y.
8. 1 Effi c a c y A s s e s s m e nt s 
a n d Pr o c e d ur e s
L a n g u a g e h a s b e e n a d d e d st ati n g 
t h at C T of t h e p el vi s m a y b e o mitt e d 
if it i s n ot p art of t h e st a n d ar d of 
c ar e a n d C T of t h e a b d o m e n 
i n cl u d e s t h e e ntir et y of t h e li v er a n d 
b ot h a dr e n al gl a n d s, a s w ell a s all 
ot h er k n o w n sit e s of di s e a s e .
F or r a di ati o n pr ot e cti o n r e a s o n s.
8. 1 Eff i c a c y A s s e s s m e nt s 
a n d Pr o c e d ur e s
L a n g u a g e h a s al s o b e e n a d d e d 
st ati n g t h at r a di o mi c a n al y si s of 
i m a g e s f or di git al f e at ur e s 
p ot e nti all y pr e di cti v e of pr o g n o si s 
a n d/ or f ut ur e tr e at m e nt b e n efit will 
o nl y b e p erf or m e d r etr o s p e cti v el y if 
d e e m e d a p pr o pri at e.
T o cl arif y t h at r a di o mi c a n al y s e s will o nl y b e 
p erf or m e d if d e e m e d a p pr o pri at e.
8. 1 Effi c a c y A s s e s s m e nt s 
a n d Pr o c e d ur e s
T e xt h a s b e e n a d d e d st arti n g 
hi g h -r e s ol uti o n C T s c a n s m a y b e 
e v al u at e d f or r a di ati o n i n d u c e d 
p ul m o n ar y fi br o si s b y a n 
i n d e p e n d e nt r e vi e w c o m mitt e e.
T o cl arif y st at u s of a n al y si s of 
hi g h -r e s ol uti o n C T s c a n i m a g e s.
8. 1 Effi c a c y A s s e s s m e nt s 
a n d Pr o c e d ur e s
L a n g u a g e h a s b e e n a d d e d st ati n g 
di a g n o si s of di s e a s e pr o gr e s si o n 
b a s e d s ol el y o n n o d al e nl ar g e m e nt 
wit hi n 8 w e e k s of c or o n a vir u s 
v a c ci n ati o n s h o ul d b e m a d e wit h 
e xtr e m e c a uti o n .
C O VI D -1 9 v a c ci n ati o n c a n mi mi c P D b ut 
r e s ol v e s wit h ti m e.
8. 5 P h ar m a c o ki n eti c s  
L a n g u a g e h a s b e e n a d d e d st ati n g 
t h at P K a n d A D A s a m pl e s c oll e ct e d 
at t h e s a m e ti m e p oi nt s m a y b e 
u s e d i nt er c h a n g e a bl y if t h e 
d e di c at e d s a m pl e h a s i n s uffi ci e nt 
q u a ntit y.
T o all o w fl e xi bilit y i n c a s e of i s s u e wit h 
eit h er s a m pl e c oll e cti o n. T h e p arti ci p a nt s 
will h a v e c o n s e nt e d t o all c oll e cti o n s a n d 
t e st s h a s b e e n a d d e d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 1 5 5
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
 
T h e I T T s et h a s b e e n u p d at e d 
t o t h e F A S.
 
D et ail s of effi c a c y h y p ot h e si s 
a n d a n al y s e s h a v e b e e n 
u p d at e d i n S e cti o n s 9. 1, 9. 2 a n d 
9. 4. 1 .
 
T hr e e -ti er a p pr o a c h t o a n al y si s 
of a d v er s e e v e nt s h a s b e e n 
r e m o v e d fr o m T a bl e 2 5.
 
T h e s e q u e n c e s of a n al y s e s 
( S e cti o n 9. 4. 4) h a s b e e n 
u p d at e d.
 
F or c o n si st e n c y wit h M er c k st a n d ar d s.
 
T o r efl e ct c h a n g e s i n r e cl a s sifi c ati o n of 
s o m e s e c o n d ar y effi c a c y e n d p oi nt s t o 
e x pl or at or y e n d p oi nt s.
C h a n g e s t o t h e tri al s a m pl e si z e n o 
l o n g er s u p p ort t hi s a n al y si s a p pr o a c h.
 
T o r efl e ct t h e r e m o v al of t h e i nt eri m 
a n al y si s a n d t h e s e p ar at e O S pri m ar y 
a n al y si s .
A p p e n di x 2 St u d y 
G o v er n a n c e
A d diti o n of l a n g u a g e o n st u d y a n d 
sit e cl o s ur e 
F or cl arifi c ati o n a n d c o n si st e n c y wit h 
c urr e nt M er c k b e st pr a cti c e. 
A p p e n di x 4 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
A d diti o n of bl e e di n g e v e nt s a s a n 
A E SI
F or c o n si st e n c y wit h I B v er si o n 7. 
T hr o u g h o ut pr ot o c ol   
Mi n or u p d at e s t o f or m atti n g, 
p hr a si n g, et c.
F or cl arit y, t o c orr e ct t y p o s a n d f or m atti n g 
i s s u e s, a n d f or c o n si st e n c y wit h M er c k 
c urr e nt pr a cti c e s. 
- C o nfi d e nti al -
T hi s d o c u m e nt i s t h e pr o p ert y of M er c k K G a A, D ar m st a dt, G er m a n y, or o n e of it s s u b si di ari e s. It i s i nt e n d e d f or 
r e stri ct e d u s e o nl y a n d m a y n ot – i n f ull or p art – b e p a s s e d o n, r e pr o d u c e d, p u bli s h e d or u s e d wit h o ut e x pr e s s 
p er mi s si o n of M er c k K G a A, D ar m st a dt, G er m a n y, or it s s u b si di ar y. C o p yri g ht © 2 0 2 1 b y M er c k K G a A, D ar m st a dt , 
G er m a n y, or it s s u b si di ar y. All ri g ht s r e s er v e d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 / 1 5 5
T a ble of C o nte nts
Title Pa ge 
.............................................................................................................. 1
Ta ble of C o nte nts
............................................................................................................ 1 0
Ta ble of Ta ble s 
............................................................................................................ 1 4
Ta ble of Fi g ures 
............................................................................................................ 1 5
1
Pr ot oc ol S u m mar y .............................................................................. 1 6
1. 1
S y n o psis ..............................................................................................1 6
1. 2
Sc he ma ................................................................................................ 1 8
1. 3
Sc he d ule of Acti vi ties......................................................................... 2 0
2
I ntr o d ucti o n......................................................................................... 3 8
............................. 3 8
2. 2
Bac k gr o u n d ......................................................................................... 4 0
2. 3
Be nefit/ Ris k Assess me nt .................................................................... 4 2
3
O bje cti ves a n d E n d p oi nts ................................................................... 4 3
4
St u d y  Desi g n....................................................................................... 4 5
4. 1
O verall Desi g n .................................................................................... 4 5
4. 1. 1
St u d y  Inter ve nti o n Be y o n d Pr o gressi o n ............................................. 4 8
4. 1. 1. 1
P F S as t he Pri mar y  E n d p oi nt..............................................................4 9
4. 1. 1. 2
C he m ot hera p y Re gi me ns a n d Ra di ot hera p y ...................................... 4 9
4. 1. 1. 3
D ur val u ma b as C o m parat or ................................................................ 5 0
4. 1. 1. 4
D o u ble Bli n d Desi g n .......................................................................... 5 1
4. 1. 1. 5
Stratificati o n ....................................................................................... 5 1
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................ 5 1
4. 3
J ustificati o n f or D ose .......................................................................... 5 1
4. 4
E n d of St u d y  Defi niti o n...................................................................... 5 2
5
St u d y  P o p ulati o n.................................................................................5 2
5. 1
I ncl usi o n Criteria................................................................................ 5 3
5. 2
E xcl usi o n Criteria ...............................................................................5 6
5. 3
Lifest y le C o nsi derati o ns.....................................................................5 9
5. 4
Scree n Fail ures ....................................................................................5 9
6
St u d y  Inter ve nti o n(s) ..........................................................................5 9
6. 1
St u d y  I nter ve nti o n(s) A d mi nistrati o n.................................................5 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 / 1 5 5
6. 1. 1
Ra diati o n .............................................................................................6 1
6. 1. 2
C he m ot hera p y..................................................................................... 6 1
6. 2
St u d y  Inter ve nti o n(s) Pre parati o n, Ha n dli n g, St ora ge, a n d 
Acc o u nta bilit y ..................................................................................... 6 3
6. 2. 1
M 7 8 2 4 ................................................................................................. 6 3
6. 2. 2
Place b o ................................................................................................ 6 4
6. 2. 3
D ur val u ma b ........................................................................................ 6 4
6. 2. 4
C he m ot hera p y a ge nts .......................................................................... 6 4
6. 3
Meas ures t o Mi ni mize Bias: St u d y  Inter ve nti o n Assi g n me nt a n d 
Bli n di n g ..............................................................................................6 4
6. 3. 1
St u d y  Inter ve nti o n Assi g n me nt .......................................................... 6 4
6. 3. 2
Bli n di n g ..............................................................................................6 5
6. 3. 3
E mer ge nc y  U n bli n di n g....................................................................... 6 6
6. 4
St u d y  Inter ve nti o n C o m plia nce .......................................................... 6 7
6. 5
C o nc o mita nt T hera p y ......................................................................... 6 7
6. 5. 1
Per m itte d Me dici nes........................................................................... 6 7
6. 5. 2
Pr o hi bite d Me dici nes .......................................................................... 6 8
6. 5. 2. 1
Me dici nes t o Use wit h Ca uti o n ........................................................... 6 8
6. 5. 3
Per mitte d/ Pr o hi bite d Pr oce d ures ........................................................ 7 0
6. 5. 4
Ot her I nter ve nti o ns ............................................................................. 7 0
6. 6
D ose Selecti o n a n d M o dificati o n ........................................................ 7 0
6. 7
St u d y  Inter ve nti o n after t he E n d of t he St u d y .................................... 7 0
6. 8
S pecial Preca uti o ns ............................................................................. 7 0
6. 9
Ma na ge me nt of A d verse E ve nts of I nterest ........................................ 7 3
6. 9. 1
I nf usi o n-relate d Reacti o ns Incl u di n g I m me diate H y perse nsiti vit y ....7 3
6. 9. 2
I m m u ne-relate d A d verse E ve nts.........................................................7 6
6. 9. 3
T G F -β i n hi biti o n me diate d S ki n Reacti o ns ........................................ 7 7
6. 9. 4
A ne mia ................................................................................................7 8
6. 9. 5
Blee di n g A d verse E ve nts ....................................................................8 0
6. 9. 6
Ot her I m p orta nt P ote ntial Ris ks ......................................................... 8 1
6. 9. 6. 1
I m paire d w o u n d heali n g .....................................................................8 1
6. 9. 6. 2
E m br y ofetal T o xicit y ..........................................................................8 1
6. 1 0
Ris k Ma na ge me nt f or C he m ora diati o n ............................................... 8 1
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 / 1 5 5
6. 1 1
A d verse Dr u g Reacti o ns Re q uiri n g Treat me nt Disc o nti n uati o n........ 9 4
7
Disc o nti n uati o n of St u d y I nter ve nti o n a n d Partici pa nt 
Disc o nti n uati o n/ Wit h dra wal ...............................................................9 4
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................ 9 4
7. 1. 1
Per ma ne nt Disc o nti n uati o n ................................................................. 9 4
7. 1. 2
Rec halle n ge ......................................................................................... 9 5
7. 2
Partici pa nt Disc o nti n uati o n/ Wit h dra wal fr o m t he St u d y ................... 9 5
7. 3
L ost t o F oll o w -U p ............................................................................... 9 6
8
St u d y  Assess me nts a n d Pr oce d ures.................................................... 9 7
8. 1
Efficac y  Assess me nts a n d Pr oce d ures................................................ 9 7
8. 2
Safet y  Assess me nts a n d Pr oce d ures................................................... 9 9
8. 2. 1
P h y sical E xa mi nati o ns ........................................................................ 9 9
8. 2. 2
Vital Si g ns ........................................................................................ 1 0 0
8. 2. 3
Electr ocar di o gra ms ........................................................................... 1 0 0
8. 2. 4
Cli nical Safet y  La b orat or y Assess me nts.......................................... 1 0 0
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts ................................... 1 0 0
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y  f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or mati o n .................................................. 1 0 0
8. 3. 2
Met h o d of Detecti n g A d verse E ve nts a n d Seri o us A d verse E ve nts . 1 0 1
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o u s A d verse E ve nts ............. 1 0 1
8. 3. 4
Re g ulat or y  Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ... 1 0 1
8. 3. 5
Pre g na nc y ......................................................................................... 1 0 2
8. 4
Treat me nt of O ver d ose ..................................................................... 1 0 3
8. 5
P har mac o ki netics .............................................................................. 1 0 3
...................................1 0 4
...................................1 0 5
8. 8
I m m u n o ge nicity Assess me nts .......................................................... 1 0 6
............................................1 0 6
............................................1 0 7
............................................1 0 7
............................................1 0 8
9. 3
P o p ulati o ns f or A nal y ses .................................................................. 1 0 8
9. 4
Statistical A nal y ses ...........................................................................1 0 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 / 1 5 5
9. 4. 1
Efficac y  A nalys es .............................................................................1 0 9
9. 4. 1. 1
T u m or Assess me nt b y  IR C ...............................................................1 1 1
9. 4. 2
Safet y  A nalys es ................................................................................ 1 1 1
9. 4. 3
Ot her A nal ys es .................................................................................. 1 1 1
9. 4. 4
Se q ue nce of A nal ys es ....................................................................... 1 1 2
1 0
Refere nces ......................................................................................... 1 1 3
1 1
A p pe n dices ....................................................................................... 1 1 8
A p pe n di x 1 
A b bre vi ati o ns .................................................................................... 1 1 9
A p pe n di x 2 
St u d y  G o ver na nce............................................................................. 1 2 3
A p pe n di x 3 
C o ntrace pti o n .................................................................................... 1 2 9
A p pe n di x 4 
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g .............................................. 1 3 1
A p pe n di x 5 
Cli nical L a b orat or y Tests ................................................................. 1 3 5
............................... 1 3 7
A p pe n di x 7 
Pr o hi bite d Tra dit i o nal C hi nese Me dici ne......................................... 1 3 8
A p pe n di x 8 
Res p o nse E val uati o n Criteria i n S oli d T u m ors Versi o n 1. 1 
( R E CIS T 1. 1) ....................................................................................1 4 0
A p pe n di x 9 
Pr ot oc ol A me n d me nt Hist or y ........................................................... 1 4 9
A p pe n di x 1 0 
S p o ns or Si g nat ure Pa ge .................................................................... 1 5 3
A p pe n di x 1 1 
C o or di nati n g I n vesti gat or Si g nat ure Pa ge ........................................ 1 5 4
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 / 1 5 5
T a ble of T a bles
...... 2 0
...... 2 7
...... 2 9
Ta ble 4
Sc he d ule of Assess me nts f or Safet y a n d L o n g -ter m F oll o w-u p ........ 3 5
Ta ble 5
Acti vit y  of D ur val u ma b i n P A CIFI C St u d y ....................................... 4 1
Ta ble 6
St u d y  O bjecti ves a n d E n d p oi nts......................................................... 4 3
Ta ble 7
A d mi nistrati o n of M 7 8 2 4, Place b o, or D ur val u ma b .......................... 6 0
Ta ble 8
Treat me nt M o dificati o n G ui da nce f or S y m pt o ms of I nf usi o n -
Rel ate d Reacti o ns I ncl u di n g I m me diate H y perse nsiti vit y ................. 7 5
Ta ble 9
E val uati o n G ui da nce of S us pecte d A ne mia ....................................... 7 9
Ta ble 1 0 
Gra di n g a n d G ui deli nes f or D ose M o dificati o ns of 
Car b o plati n/ Paclita xel Relate d He mat ol o gic A d verse E ve nts ........... 8 3
Ta ble 1 1 
D ose M o dificati o ns of Car b o plati n/ Paclita xel Relate d Mai n 
N o n he mat ol o gic A d verse E ve nts ....................................................... 8 4
Ta ble 1 2 
Pre d osi n g C o nsi derati o n f or Cis plati n ................................................ 8 5
Ta ble 1 3 
D ose Re d u cti o ns f or Cis plati n/ Et o p osi de-relate d He mat ol o gic 
A d verse E ve nts ................................................................................... 8 6
Ta ble 1 4 
D ose Re d ucti o ns f or Cis plati n/ Et o p osi de -relate d N o n he mat ol o gic 
A d verse E ve nts ................................................................................... 8 6
Ta ble 1 5 
D ose M o dificati o ns f or Pe metre xe d a n d Cis plati n Base d o n 
He mat ol o gic T o xicities ....................................................................... 8 7
Ta ble 1 6 
D ose M o dificati o ns f or Pe metre xe d a n d Cis plati n Base d o n 
N o n he mat ol o gic T o xicities ................................................................. 8 8
Ta ble 1 7 
D ose M o dificati o ns f or Cis plati n Base d o n Ne ur ot o xicit y ................. 8 9
Ta ble 1 8 
Treat me nt M o dificati o ns f or N o n he mat ol o gic A d verse E ve nts i n 
R T -Fiel d ..............................................................................................9 0
Ta ble 1 9 
Dia g n osis a n d Gra di n g of Es o p ha gitis ...............................................9 1
Ta ble 2 0 
Dia g n osis a n d Gra di n g f or P ne u m o nitis................................ .............9 2
Ta ble 2 1 
Dia g n osis a n d Gra di n g f or P ul m o nar y  Fi br osis ................................. 9 3
Ta ble 2 2 
P osteri or Pr o ba bilit y  f or t he Tr ue H R Gi ve n Differe nt O bser ve d 
H R Val ues ......................................................................................... 1 0 8
Ta ble 2 3 
A nal y sis P o p ulati o ns ........................................................................ 1 0 9
Ta ble 2 4 
Efficac y  E n d p oi nts a n d Statistical A nal ysis Met h o ds ......................1 1 0
Ta ble 2 5 
Safet y  E n d p oi nts a n d Statistical A nal ysis Met h o ds ......................... 1 1 1
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 / 1 5 5
Ta ble 2 6 
Pr ot oc ol -Re q uire d Cli nical La b orat or y  Assess me nts....................... 1 3 5
T a ble of Fi g ures
Fi g ure 1 
Dia gra m of St u d y Desi g n ................................................................... 1 9
Fi g ure 2 
Effects of M 7 8 2 4 o n L u n g Fi br osis i n Precli nical M o del .................. 4 0
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 / 1 5 5
1
Pr ot oc ol S u m m ar y
1. 1
S y n o psis
Pr ot oc ol Title: A M ultice nter, D o u ble Bli n d, Ra n d o mize d, C o ntr olle d St u d y  of M 7 8 2 4 wit h 
C o nc urre nt C he m ora diati o n F oll o we d b y  M7 8 2 4 vers us C o nc urre nt C he m ora diati o n Pl us Place b o 
F oll o we d b y  D ur val u ma b i n Partici pa nts wit h U nresecta ble Sta ge III N o n-s mall Cell L u n g Ca ncer
S h ort Title: M 7 8 2 4 wit h c C R T i n U nresecta ble Sta ge III N S C L C
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 / 1 5 5
O bjecti ves a n d E n d p oi nts:
Pri m ar y  O bj e cti v e
Pri m ar y  E n d p oi nt
T o e v al u at e P F S i n p arti ci p a nt s tr e at e d wit h c C R T pl u s M 7 8 2 4 
f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o f oll o w e d b y 
d ur v al u m a b 
P F S a c c or di n g t o R E CI S T 1. 1 a s s e s s e d b y 
I n v e sti g at or
S e c o n d ar y  O bj e cti v e s
S e c o n d ar y  E n d p oi nt s
T o e v al u at e t h e s af et y i n p arti ci p a nt s tr e at e d wit h c C R T pl u s 
M 7 8 2 4 f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o f oll o w e d b y 
d ur v al u m a b
O c c urr e n c e of T E A E s a n d tr e at m e nt -r el at e d 
A E s 
T o e v al u at e O S i n p arti ci p a nt s tr e at e d wit h c C R T pl u s M 7 8 2 4 
f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o f oll ow e d b y 
d ur v al u m a b
O S
T o e v al u at e o bj e cti v e t u m or r e s p o n s e i n p arti ci p a nt s tr e at e d wit h 
c C R T pl u s M 7 8 2 4 f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o 
f oll o w e d b y d ur v al u m a b
O bj e cti v e r e s p o n s e a c c or di n g t o R E CI S T 1. 1 
a s s e s s e d b y I n v e sti g at or
T o e v al u at e d ur ati o n of r e s p o n s e i n p arti ci p a nt s tr e at e d wit h 
c C R T pl u s M 7 8 2 4 f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o 
f oll o w e d b y d ur v al u m a b
D ur ati o n of r e s p o n s e a s s e s s e d fr o m C R or P R 
u ntil P D, d e at h, or l a st t u m or a s s e s s m e nt
T o c h ar a ct eri z e P K pr ofil e of M 7 8 2 4 pl u s c C R T a n d aft er c C R T 
P K pr ofil e of M 7 8 2 4 i n t er m s of C e oi a n d C tr o u g h
d uri n g tr e at m e nt a n d S af et y f oll o w - u p vi sit.
T o c h ar a ct eri z e t h e i m m u n o g e ni cit y of M 7 8 2 4 pl u s c C R T a n d 
aft er c C R T
I m m u n o g e ni cit y of M 7 8 2 4 a s m e a s ur e d b y A D A 
a s s a y s fr o m S cr e e ni n g t hr o u g h l a st S af et y 
F oll o w -u p vi sit.
A E = a d v er s e e v e nt, A D A = a nti dr u g a nti b o d y, c C R T = c o n c o mit a nt c h e m or a di ati o n t h er a p y; C e oi = c o n c e ntr ati o n 
i m m e di at el y at t h e e n d of i nf u si o n, C R = c o m pl et e r e s p o n s e, ct D N A = cir c ul ati n g t u m or D N A, Ctr o u g h= c o n c e ntr ati o n 
i m m e di at el y b ef or e n ext d o si n g , O S = o v er all s ur vi v al, P D = pr o gr e s si v e di s e a s e, P F S = pr o gr e s si o n -fr e e s ur vi v al,
P K = p h ar m a c o ki n eti c s, P R = p arti al r e s p o n s e, R E CI S T 1. 1 = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s V er si o n 
1. 1, T E A E =tr e at m e nt -e m er g e nt a d v er s e e v e nt.
O ver all Desi g n: T his is a gl o bal, m ultice nter, ra n d o mize d, d o u ble -bli n d, c o ntr olle d st u d y in 
u nresecta ble Sta ge III N S C L C. T his st u d y  has 2 ar ms:  

c C R T pl us M 7 8 2 4 f oll o we d b y M 7 8 2 4 ( Ar m 1)

c C R T pl us place b o f oll o we d b y d ur val u ma b ( Ar m 2)  
D uri n g t he safety r u n-i n, t he first 4 2 partici pa nts ( 1 2 Ja pa nese, a n d 3 0 n o n- Ja pa nese) will be 
ra n d o mize d i n 1: 1 rati o bet wee n Ar m 1 a n d Ar m 2. Ja pa nese partici pa nts are defi ne d b y et h nicity 
o nl y  an d n ot b y  co u ntr y . Et h nicit y  will be t he stratificati o n fact or d uri n g t he safety r u n- i n t o e ns ure
a 1: 1 treat me nt ar m all ocati o n f or b ot h Ja pa nese a n d n o n- Ja pa nese partici pa nts d uri n g t he safety 
r u n-i n. 
 at baseli ne will be deter mi ne d retr os pecti vely i n t hese 
partici pa nts.
A p pr o xi matel y  11 8 a d diti o nal partici pa nts will be ra n d o mize d i n 1: 1 rati o bet wee n Ar m 1 a n d 
Ar m 2. T he I nde pe n de nt data M o nit ori n g C o m mittee (I D M C) will peri o dicall y  re vie w t he safety 
data d uri n g t he safety r u n-i n as well as e x pa nsi o n part of t he st u d y. D uri n g t he safety r u n-i n, 
I D M C will assess t he safet y of t he c o m bi nati o n of c C R T a n d M 7 8 2 4 i n n o n-Ja pa nese partici pa nts 
a n d ma y  als o deci de u p o n c o nti n u o us e nr oll me nt s u bse q ue nt t o t he safety r u n-i n base d o n 
pres pecifie d r ules i n t he I D M C c harter. I D M C will ma ke se parate assess me nt f or Ja pa nese 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 / 1 5 5
par tici pa nts a n d deter mi ne if a d diti o nal Ja pa nese partici pa nts ca n be e nr olle d i n t he e x pa nsi o n part 
of t he st u d y  as part of t he a p pr o xi matel y 1 1 8 a d diti o nal partici pa nts. 
C he m ot hera p y re gi me n a n d P D -L 1 e x pressi o n i n t u m or cells ( < 1 % vers us ≥1 %) will be t he 
stratificati o n fact ors i n t he e x pa nsi o n part of t he st u d y.
N u m ber of P artici p a nts: A sa m ple size of a p pr o xi matel y 16 0 ra n d o mize d partici pa nts (c o nsisti n g 
of 4 2 partici pa nts i n t he safety r u n -i n as well as 1 1 8 i n t he e x pa nsi o n p hase ) is pla n ne d i n or der t o 
o bser ve 7 0 pr o gressi o n -free s ur vi val (P F S ) e ve nts at t he pri mar y a nalys is.
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: T he st u d y i nter ve nti o n c o nsists of 6 0 G y  of ra diati o n 
t hera py c o nc urre nt wit h sta n dar d c he m ot hera p y pl us M 7 8 2 4 i n A r m 1 or place b o i n Ar m 2, 
f oll o we d by u p t o 2 6 d oses of M 7 8 2 4 ( Ar m 1) or d ur val u ma b ( Ar m 2) .
I n v ol ve me nt of S peci al C o m mittee(s): Yes 
I D M C: T he I D M C will peri o dicall y re vie w t he safety data d uri n g t he safet y ru n -i n as well as 
e x pa nsi o n part of t he st u d y. I n de pe n de nt data M o nit ori n g C o m mittee r oles a n d res p o nsi bilities are 
detaile d i n t he I D M C c harter.
I n de pe n de nt Re vie w C o m mittee (I RC) : Assess me nt of ra di o gra p hic sca ns will be perf or me d b y  
t he I nvesti gat or i n t his st u d y. Sca ns will be c ollecte d a n d hel d f or a n y p ote ntial later i n de pe n de nt 
rea d. If a cli nically r ele va nt P F S treat me nt effect acc or di n g t o I n vesti gat or assess me nt is o bser ve d
at t he pri mar y  anal ys is, a n I RC m a y  be esta blis he d t o i n de pe n de ntl y assess t he i ma ges a n d ce ntrall y 
e xcl u de I nvesti gat or bias.
1. 2
Sc he m a
T he o verall st u d y d esi g n is s h o w n i n  Fi g u re 1 . Detaile d sc he d ule of st u dy pr oce d ures/assess me nts 
is pr o vi de d i n Secti o n 1. 3.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 /1 5 5
Fi g u re 1
Di a gr a m of St u d y Desi g n
C R = c o m pl et e r e s p o n s e, P F S = pr o gr e s si o n -fr e e s ur vi v al, P R = p arti al r e s p o n s e, S D = st a bl e di s e a s e
*: I n t h e s af et y r u n-i n, 4 2 p arti ci p a nt s ( 1 2 J a p a n e s e a n d 3 0 n o n -J a p a n e s e) will b e r a n d o mi z e d i n 1: 1 r ati o w it h 
str atifi c ati o n b a s e d o n et h ni cit y t o e n s ur e a 1: 1 tr e at m e nt ar m all o c ati o n f or b ot h J a p a n e s e a n d n o n -J a p a n e s e 
p arti ci p a nt s d uri n g t h e s af et y r u n -i n. J a p a n e s e p arti ci p a nt s ar e d efi n e d b y et h ni cit y o nl y a n d n ot b y c o u ntr y.
**: I n t h e e x p a n si o n p h a s e, a p pr o xi m at el y 1 1 8 a d diti o n al p arti ci p a nt s will b e r a n d o mi z e d i n a 1: 1 r ati o i n Ar m 1 a n d 
Ar m 2 . T h e str atifi c ati o n i n t h e e x p a n si o n p art i s b a s e d o n c h e m ot h er a p y r e gi m e n a n d P D -L 1 e x pr e s si o n i n t u m or c ell s 
( < 1 % v er s u s ≥1 %) .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 / 1 5 5
1. 3
Sc he d ule of Acti vities
T a ble 1
Sc he d ule of Acti vitie s f or c C R T-b ase d Tre at me nt
c C R T -b a s e d 
Tr e at m e nt
S cr e e ni n g
c C R T -b a s e d Tr e at m e nt ( ± 3 d a y s)
E n d -of -c C R T
Vi sit 
( + 5 d a ys)
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h 
W e e k 9 d o si n g vi sit. O v erl a p pi n g 
a s s e s s m e nt s o nl y n e e d t o b e p erf or m e d 
o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s). S e e  T a bl e 3 a n d 
S e cti o n  4. 1 f or a d diti o n al d et ail s.
U p t o 
D a y - 2 8 t o 
R a n d o m -
i z ati o n
U p t o 
D a y - 2 1 t o 
R a n d o m -
i z ati o n
V 1  
V 6 
V 1 1  
V 1 6  
V 2 1  
V 2 6  
V 3 1
W 1   
W 2   
W 3   
W 4   
W 5   
W 6   
W 7
D 1   
D 8 
D 1 5   
D 2 2   
D 2 9   
D 3 6   
D 4 3   
D 5 7
A d mi ni str ati v e Pr o c e d ur e s
Wr itt e n i nf or m e d 
c o n s e nt
X
I n cl u si o n/ e x cl u si o n/ 
E nr oll m e nt (if eli gi bl e)
X
D e m o gr a p hi c d at a
X
M e di c al hi st or y 
X
M e di c al hi st or y i n cl u d e s s u b st a n c e u s a g e 
(t o b a c c o a n d ni c oti n e).
D o c u m e nt ati o n 
c o n c o mit a nt m e di c ati o n 
a n d pr o c e d ur e s
X  
X  
X  
X  
X  
X  
X  
X  
X
Pri or a nti c a n c er 
dr u g/r a di ot h er a p y/ pr o c e
d ur e s
X
Vir al s er ol o g y 
( H B V, H C V)
X
A s cli ni c all y i n di c at e d i n p arti ci p a nt s wit h a hi st or y of H B V or H C V 
i nf e cti o n.
HI V t e sti n g i s n ot m a n d at e d f or st u d y 
i n cl u si o n; h o w e v er, if it i s p erf or m e d at a n y 
p oi nt i n S cr e e ni n g or w hil e o n st u d y, a sit e 
m u st c o n s e nt t h e p arti ci p a nt f or HI V 
t e sti n g a s p er l o c al st a n d ar d g ui d a n c e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 / 1 5 5
c C R T -b a s e d 
Tr e at m e nt
S cr e e ni n g
c C R T -b a s e d Tr e at m e nt ( ± 3 d a y s)
E n d -of -c C R T
Vi sit 
( + 5 d a ys)
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h 
W e e k 9 d o si n g vi sit. O v erl a p pi n g 
a s s e s s m e nt s o nl y n e e d t o b e p erf or m e d 
o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s). S e e  T a bl e 3 a n d 
S e cti o n  4. 1 f or a d diti o n al d et ail s.
U p t o 
D a y - 2 8 t o 
R a n d o m -
i z ati o n
U p t o 
D a y - 2 1 t o 
R a n d o m -
i z ati o n
V 1  
V 6 
V 1 1  
V 1 6  
V 2 1  
V 2 6  
V 3 1
W 1   
W 2   
W 3   
W 4   
W 5   
W 6   
W 7
D 1   
D 8 
D 1 5   
D 2 2   
D 2 9   
D 3 6   
D 4 3   
D 5 7
Dr u g A d mi ni str ati o n D uri n g C R T -b a s e d Tr e at m e nt (S e e  T a bl e 2)
T u m or E v al u ati o n / St a gi n g
T h or a x A b d o m e n P el vi s 
C T ( pr ef err e d)/ M RI
X a
X b
a : i d e all y wit hi n 1 4 d a y s pri or t o 
r a n d o mi z ati o n.
b : C T s c a n s m u st b e a c q uir e d pri or t o fir st 
d o s e of M 7 8 2 4 or d ur v al u m a b aft er c C R T
(t h e + 5 d a y s e n d of c C R T vi sit wi n d o w 
d o e s n ot a p pl y t o t h e t u m or a s s e s s m e nt) .
S e e S e cti o n  8. 1
Br ai n M RI 
( pr ef err e d)/ C T
X c
X d
c : i d e all y wit hi n 1 4 d a y s pri or t o 
r a n d o mi z ati o n.
d: Br ai n s c a n s m u st b e d o n e pri or t o fir st 
d o s e of M 7 8 2 4 or d ur v al u m a b aft er c C R T.
S e e S e cti o n  8. 1
F D G -P E T S c a n
X
S af et y  As s e s s m e nt s
D o c u m e nt ati o n of A E s  
X  
X  
X e
X e
X e
X e
X e
X e
X e
X
e : P erf or m e d at e a c h vi sit a c c or di n g t o 
T a bl e 2 . S e e  A p p e n di x 4 f or s af et y 
r e c or di n g a n d r e p orti n g.
P h y si c al e x a mi n ati o n
X  
X  
X  
X  
X  
X  
X  
X  
X
C o m pl et e P E at S cr e e ni n g . S u b s e q u e nt 
f o c u s e d P E s t o b e p erf or m e d a s p er l o c al 
st a n d ar d pr a cti c e a n d a s cli ni c all y 
i n di c at e d. T h or a x e x a m at e a c h vi sit a n d 
fi n di n g s m u st b e r e p ort e d i n t h e e C R F.  
S ki n A s s e s s m e nt
X
X
S e e S e cti o n  6. 9. 3 f or p arti ci p a nt s 
e x p eri e n ci n g a d er m at ol o gi c -r el at e d A E.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 / 1 5 5
c C R T -b a s e d 
Tr e at m e nt
S cr e e ni n g
c C R T -b a s e d Tr e at m e nt ( ± 3 d a y s)
E n d -of -c C R T
Vi sit 
( + 5 d a ys)
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h 
W e e k 9 d o si n g vi sit. O v erl a p pi n g 
a s s e s s m e nt s o nl y n e e d t o b e p erf or m e d 
o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s). S e e  T a bl e 3 a n d 
S e cti o n  4. 1 f or a d diti o n al d et ail s.
U p t o 
D a y - 2 8 t o 
R a n d o m -
i z ati o n
U p t o 
D a y - 2 1 t o 
R a n d o m -
i z ati o n
V 1  
V 6 
V 1 1  
V 1 6  
V 2 1  
V 2 6  
V 3 1
W 1   
W 2   
W 3   
W 4   
W 5   
W 6   
W 7
D 1   
D 8 
D 1 5   
D 2 2   
D 2 9   
D 3 6   
D 4 3   
D 5 7
Vit al si g n s   
X  
X  
X  
X  
X  
X  
X  
X  
X
I n cl u di n g w ei g ht a n d h ei g ht ( h ei g ht at 
S cr e e ni n g o nl y). T e m p er at ur e, p ul s e r at e, 
r e s pir at or y r at e, bl o o d pr e s s ur e, a n d 
re sti n g p ul s e o xi m etr y m u st b e d o n e at 
e a c h vi sit a n d m u st b e r e p ort e d i n t h e 
e C R F. S e e S e cti o n  8. 2. 2 f or a d diti o n al 
d et ail s.
E C O G P S
X  
X  
X  
X  
X  
X  
X  
X  
X
1 2 -l e a d E C G
X
S pir o m etr y
X f
X g
V C m a x, F E V1 , F V C, F E V1 / F V C r ati o, m u st 
b e r e p ort e d
f: D at a s h o ul d b e e nt er e d t o t h e v e n d or 
p ort al pri or t o r a n d o mi z ati o n.
g : D a y 5 7 (± 7 d a y s)
Hi g h r e s ol uti o n C T 
S c a n
X
P erf or m o nl y if p arti ci p a nt m e et s all t h e 
i n cl u si o n crit eri a f or t h e st u d y 
6- mi n w al ki n g t e st
X
X h
Di st a n c e a n d O 2 s at ur ati o n m u st b e 
r e p ort e d 
h : D a y 5 7 (± 7 d a y s)
L a b or at or y  As s e s s m e nt s
H e m o st a s e ol o g y
X  
X k
X
X
X
k : W1 D 1 m u st b e d o n e if t e st at S cr e e ni n g 
i s p erf or m e d m or e t h a n 2 w e e k s pri or t o 
W 1 D 1.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 3 / 1 5 5
c C R T -b a s e d 
Tr e at m e nt
S cr e e ni n g
c C R T -b a s e d Tr e at m e nt ( ± 3 d a y s)
E n d -of -c C R T
Vi sit 
( + 5 d a ys)
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h 
W e e k 9 d o si n g vi sit. O v erl a p pi n g 
a s s e s s m e nt s o nl y n e e d t o b e p erf or m e d 
o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s). S e e  T a bl e 3 a n d 
S e cti o n  4. 1 f or a d diti o n al d et ail s.
U p t o 
D a y - 2 8 t o 
R a n d o m -
i z ati o n
U p t o 
D a y - 2 1 t o 
R a n d o m -
i z ati o n
V 1  
V 6 
V 1 1  
V 1 6  
V 2 1  
V 2 6  
V 3 1
W 1   
W 2   
W 3   
W 4   
W 5   
W 6   
W 7
D 1   
D 8 
D 1 5   
D 2 2   
D 2 9   
D 3 6   
D 4 3   
D 5 7
H e m at ol o g y 
X  
X  
X  
X  
X  
X  
X  
X  
X
S e e A p p e n di x 5 for i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el. 
S a m pl e s m u st al s o b e dr a w n wit hi n 3 d a y s
a n d r e s ult s t o b e r e vi e w e d pri or t o d o s e 
a d mi ni str ati o n. L a b t e st t o b e r e p e at e d i n 
c a s e of t o xi cit y a s cli ni c all y i n di c at e d.  All 
L a b t e st s m u st b e r e p ort e d o n e C R F.
C or e s er u m c h e mi str y 
X l
X
X
X
S e e A p p e n di x 5 for i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el. 
l: O nl y n e e d e d if f ull c h e mi str y i s t a k e n 
m or e t h a n 7 d a y s pri or D 1 or cli ni c all y 
i n di c at e d. S a m pl e s m u st al s o b e dr a w n 
wit hi n 3 d a y s a n d r e s ult s t o b e r e vi e w e d 
pri or t o d o s e a d mi ni str ati o n. L a b t e st t o b e 
r e p e at e d i n c a s e of t o xi cit y a s cli ni c all y 
i n di c at ed.  All L a b t e st s m u st b e r e p ort e d 
o n e C R F.
F ull s er u m c h e mi str y 
P a n el A 
X
X
X
X  
X
S e e  A p p e n di x 5 f or i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el. S a m pl e s m u st al s o b e 
dr a w n wit hi n 3 d a y s a n d r e s ult s t o b e 
r e vi e w e d pri or t o d o s e a d mi ni str ati o n. L a b 
t e st t o b e r e p e at e d i n c a s e of t o xi cit y a s 
cli ni c all y i n di c at e d.  All L a b t e st s m u st b e 
r e p ort e d o n e C R F. 
F ull s er u m c h e mi str y 
P a n el B 
X
S e e  A p p e n di x 5 f or i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el. L a b t e st t o b e r e p e at e d 
a s cli ni c all y i n di c at e d. All L a b t e st s m u st 
b e r e p ort e d o n e C R F.
Uri n al y si s
X
A s cli ni c all y i n di c at e d
F ull uri n al y si s ( di p sti c k pl u s mi cr o s c o pi c 
e v al u ati o n) at t h e S cr e e ni n g vi sit . If t h e 
uri n al y si s i s a b n or m al, t h e n a c ult ur e 
s h o ul d b e p erf or m e d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 4 / 1 5 5
c C R T -b a s e d 
Tr e at m e nt
S cr e e ni n g
c C R T -b a s e d Tr e at m e nt ( ± 3 d a y s)
E n d -of -c C R T
Vi sit 
( + 5 d a ys)
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h 
W e e k 9 d o si n g vi sit. O v erl a p pi n g 
a s s e s s m e nt s o nl y n e e d t o b e p erf or m e d 
o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s). S e e  T a bl e 3 a n d 
S e cti o n  4. 1 f or a d diti o n al d et ail s.
U p t o 
D a y - 2 8 t o 
R a n d o m -
i z ati o n
U p t o 
D a y - 2 1 t o 
R a n d o m -
i z ati o n
V 1  
V 6 
V 1 1  
V 1 6  
V 2 1  
V 2 6  
V 3 1
W 1   
W 2   
W 3   
W 4   
W 5   
W 6   
W 7
D 1   
D 8 
D 1 5   
D 2 2   
D 2 9   
D 3 6   
D 4 3   
D 5 7
β- H C G pr e g n a n c y t e st 
( o nl y a p pli c a bl e t o 
W O C B P)
X  
X
X
β- H C G m u st b e d et er mi n e d fr o m s er u m at 
S cr e e ni n g a n d fr o m a uri n e or s er u m 
s a m pl e t h er e aft er e v er y 4 w e e k s. R e s ult s 
of t h e m o st r e c e nt pr e g n a n c y t e st ar e t o b e 
a v ail a bl e pri or t o d o si n g of st u d y 
i nt er v e nti o n.
T 4 a n d T S H
X
X
S er u m K L -6, S P - A a n d 
S P - D
X m
X m
X m
X m
X m
m : T e st s r e q uir e d i n J a p a n e s e p arti ci p a nt s 
e nr oll e d i n J a p a n. 
P ati e nt R e p ort e d O ut c o m e s
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 / 1 5 5
c C R T -b a s e d 
Tr e at m e nt
S cr e e ni n g
c C R T -b a s e d Tr e at m e nt ( ± 3 d a y s)
E n d -of -c C R T
Vi sit 
( + 5 d a ys)
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h 
W e e k 9 d o si n g vi sit. O v erl a p pi n g 
a s s e s s m e nt s o nl y n e e d t o b e p erf or m e d 
o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s). S e e  T a bl e 3 a n d 
S e cti o n  4. 1 f or a d diti o n al d et ail s.
U p t o 
D a y - 2 8 t o 
R a n d o m -
i z ati o n
U p t o 
D a y - 2 1 t o 
R a n d o m -
i z ati o n
V 1  
V 6 
V 1 1  
V 1 6  
V 2 1  
V 2 6  
V 3 1
W 1   
W 2   
W 3   
W 4   
W 5   
W 6   
W 7
D 1   
D 8 
D 1 5   
D 2 2   
D 2 9   
D 3 6   
D 4 3   
D 5 7
P K, A D A, Bi o m ar k er 
Bl o o d s a m pl e f or P K
X/ X
( pr e/ e oi
)
X/ X
( pr e/ e oi
)
X/ -
( pr e/ e
oi)
X/ -
( pr e/ e oi)o
S a m pl e s f or P K a n al y si s t o b e t a k e n 
b ef or e ( pr e) i nf u si o n ( a s cl o s e t o t h e st art 
of t h e i nf u si o n a s p o s si bl e, pri or t o M 7 8 2 4 
or pl a c e b o a d mi ni str ati o n o n t h e s a m e 
d a y), i m m e di at el y aft er t h e e n d of M 7 8 2 4 
or pl a c e b o i nf u si o n ( e oi, a s cl o s e t o t h e 
c o m pl eti o n a s p o s si bl e b ut n o l at er t h a n 
3 0 mi n ut e s p o st e n d of i nf u si o n). T h e 
pr e d o s e s a m pl e s h o ul d still b e dr a w n e v e n 
if d o si n g i s ulti m at el y d ef err e d at t h e st u d y 
vi sit. T h e e x a ct ti m e of e a c h dr a w m u st b e 
r e c or d e d. A pr ot o c ol d e vi ati o n i s d efi n e d 
b y a s a m pl e n o t b ei n g dr a w n.
o : If E n d-of -c C R T a n d D a y 5 7 tr e at m e nt 
ar e o n t h e s a m e d a y, s a m pl e t o b e 
c oll e ct e d b ef or e d o si n g. If diff er e nt d a y, 
s a m pl e t o b e c oll e ct e d at E n d -of -c C R T .
Bl o o d s a m pl e f or A D A 
X
X/ -
( pr e/ e oi
)
X/ -
( pr e/ e
oi)
X/ -
( pr e/ e oi)p
S a m pl e s will b e c oll e ct e d pri or t o M 7 8 2 4 or 
pl a c e b o a d mi ni str ati o n. 
p : If E n d-of -c C R T a n d D a y 5 7 tr e at m e nt 
ar e o n t h e s a m e d a y, s a m pl e t o b e 
c oll e ct e d b ef or e d o si n g. If diff er e nt d a y, 
s a m pl e t o b e c oll e ct e d at E n d -of -c C R T .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
6 8
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 / 1 5 5
c C R T -b a s e d 
Tr e at m e nt
S cr e e ni n g
c C R T -b a s e d Tr e at m e nt ( ± 3 d a y s)
E n d -of -c C R T
Vi sit 
( + 5 d a ys)
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h 
W e e k 9 d o si n g vi sit. O v erl a p pi n g 
a s s e s s m e nt s o nl y n e e d t o b e p erf or m e d 
o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s). S e e  T a bl e 3 a n d 
S e cti o n  4. 1 f or a d diti o n al d et ail s.
U p t o 
D a y - 2 8 t o 
R a n d o m -
i z ati o n
U p t o 
D a y - 2 1 t o 
R a n d o m -
i z ati o n
V 1  
V 6 
V 1 1  
V 1 6  
V 2 1  
V 2 6  
V 3 1
W 1   
W 2   
W 3   
W 4   
W 5   
W 6   
W 7
D 1   
D 8 
D 1 5   
D 2 2   
D 2 9   
D 3 6   
D 4 3   
D 5 7
A D A = a nti -dr u g a nti b o d y, A E = a d v er s e e v e nt s, β H C G = β -h u m a n c h ori o ni c g o n a d otr o pi n , c C R T = c o n c o mit a nt c h e m or a di ati o n t h er a p y , C T = c o m p ut e d t o m o gr a p h y , 
, D = D a y,
, E C G = el e ctr o c ar di o gr a m, E C O G P S = E a st er n C o o p er ati v e 
O n c ol o g y Gr o u p P erf or m a n c e St at u s,
r e,
e oi = e n d of i nf u si o n ,
 
H B V = h e p atiti s B vir u s, H C V = h e p atiti s C vir u s, HI V = H u m a n i m m u n o d efi ci e n c y vir u s , M RI = m a g n eti c r e s o n a n c e i m a gi n g, N S C L C -S A Q = n o n - s m all c ell l u n g c a n c er 
S y m pt o m A s s e s s m e nt Q u e sti o n n air e ,
, P K = p h ar m a c o ki n eti c s,
, T4 =fr e e t h yr o xi n e ,
, T S H =t h yr oi d -sti m ul ati n g h or m o n e , V = vi sit , W = W e e k , W O C B P = W o m a n of 
c hil d b e ari n g p ot e nti al .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 / 1 5 5
T a ble 2
Dr u g A d mi nistr ati o n Sc he d ule D uri n g cC R T -b ase d Tre at me nt
c C R T -b a s e d 
Tr e at m e nt
V
1
V
2
V
3
V
4
V
5
V
6
V
7
V
8
V
9
V
1 0
V
1 1
V
1 2
V
1 3
V
1 4
V
1 5
V
1 6
V
1 7
V
1 8
V
1 9
V
2 0
V
2 1
V
2 2
V
2 3
V
2 4
V
2 5
V
2 6
V
2 7
V
2 8
V
2 9
V
3 0
V
3 1
V
3 2
V
3 3
V
3 4
V
3 5
N ot e s
V 3 2, V 3 3, V 3 4, a n d V 3 5 
ar e o pti o n al i n c a s e 
p arti ci p a nt h a s n ot 
c o m pl et e d c C R T . S e e 
S e cti o n  4. 1 f or a d diti o n al 
d et ail s
W
1
W
2
W
3
W
4
W
5
W
6
W
7
D
1
D
2
D
3
D
4
D
5
D
8
D
9
D
1 0
D
1 1
D
1 2
D
1 5
D
1 6
D
1 7
D
1 8
D
1 9
D
2 2
D
2 3
D
2 4
D
2 5
D
2 6
D
2 9
D
3 0
D
3 1
D
3 2
D
3 3
D
3 6
D
3 7
D
3 8
D
3 9
D
4 0
D
4 3
D
4 4
D
4 5
D
4 6
D
4 7
Ci s pl ati n / Et o p o si d e
(all o w e d wi n d o w f or a d mi ni str ati o n ± 3 d a y s u nl e s s d o s e d el a y i s r e q uir e d d u e t o A E s -s e e S e cti o n  6. 1 0 )
Ci s pl ati n 5 0 
m g/ m 2 d a y 
( d o s e f or 
ci s pl ati n/ et o p o s
i d e r e gi m e n)
X
X
X
X
Et o p o si d e 5 0 
m g/ m 2 d a y
X 
X 
X 
X 
X
X 
X 
X 
X 
X
H y dr ati o n 
X
X
X
X
I n p arti ci p a nt s r e c ei vi n g 
ci s pl ati n/ et o p o si d e 
e n s ur e a d e q u at e 
h y dr ati o n. All t h e 
m e di c ati o n s u s e d a s 
h y dr ati o n ( dr u g s a n d 
fl ui d s) m u st b e r e p ort e d i n 
t h e e C R F.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 / 1 5 5
c C R T -b a s e d 
Tr e at m e nt
V
1
V
2
V
3
V
4
V
5
V
6
V
7
V
8
V
9
V
1 0
V
1 1
V
1 2
V
1 3
V
1 4
V
1 5
V
1 6
V
1 7
V
1 8
V
1 9
V
2 0
V
2 1
V
2 2
V
2 3
V
2 4
V
2 5
V
2 6
V
2 7
V
2 8
V
2 9
V
3 0
V
3 1
V
3 2
V
3 3
V
3 4
V
3 5
N ot e s
V 3 2, V 3 3, V 3 4, a n d V 3 5 
ar e o pti o n al i n c a s e 
p arti ci p a nt h a s n ot 
c o m pl et e d c C R T . S e e 
S e cti o n  4. 1 f or a d diti o n al 
d et ail s
W
1
W
2
W
3
W
4
W
5
W
6
W
7
D
1
D
2
D
3
D
4
D
5
D
8
D
9
D
1 0
D
1 1
D
1 2
D
1 5
D
1 6
D
1 7
D
1 8
D
1 9
D
2 2
D
2 3
D
2 4
D
2 5
D
2 6
D
2 9
D
3 0
D
3 1
D
3 2
D
3 3
D
3 6
D
3 7
D
3 8
D
3 9
D
4 0
D
4 3
D
4 4
D
4 5
D
4 6
D
4 7
P a clit a x el/ C a rb o pl ati n
( all o w e d wi n d o w f or a d mi ni str ati o n ± 3 d a y s u nl e s s d o s e d el a y i s r e q uir e d d u e t o A E s -s e e S e cti o n  6. 1 0 )
P a clit a x el 4 5 
m g/ m 2
X
X
X
X
X
X
X
C ar b o pl ati n 
A U C 2 
X
X
X
X
X
X
X
P e m etr e x e d/ Ci s pl ati n
( all o w e d wi n d o w f or a d mi ni str ati o n ± 3 d a y s u nl e s s d o s e d el a y i s r e q uir e d d u e t o A E s -s e e S e cti o n  6. 1 0 )
Ci s pl ati n 7 5 
m g/ m 2 d a y 
( d o s e f or 
ci s pl ati n/ p e m et
r e x e d r e gi m e n)
X
X
X
P e m etr e x e d 
5 0 0 m g/ m 2
X
X
X
F oli c a ci d 3 5 0 -
1 0 0 0 µ g
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
St arti n g at D a y -5 a n d 
c o nti n ui n g 2 1 d a y s aft er 
t h e l a st d o s e of 
p e m etr e x e d
Vit a mi n B 1 2
1 0 0 0 µ g
D uri n g t h e w e e k b ef or e t h e fir st d o s e of p e m etr e x e d a n d at t h e e n d of c C R T
Pr e m e di c ati o n 
f or all 
c h e m ot h er a p y 
r e gi m e n s
All p arti ci p a nt s s h o ul d b e pr e m e di c at e d wit h or al or i nj e ct a bl e st er oi d s a c c or di n g t o t h e a p pr o v e d pr o d u ct l a b el a n d/ or st a n d ar d pr a cti c e. 
A d diti o n al pr e m e di c ati o n s h o ul d b e a d mi ni st er e d a s p er st a n d ar d pr a cti c e. A c orti c o st er oi d - s p ari n g a p pr o a c h f or a nti e m eti c pr o p h yl a xi s s h o ul d 
b e pr ef err e d a n d e v al u at e d o n a c a s e b y c a s e a n d c h e m ot h er a p y r e gi m e n b a si s . Dr u g s u s e d i n pr e m e di c ati o n m u st b e r e p ort e d i n t h e e C R F.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 / 1 5 5
T a ble 3
Sc he d ule of Assess me nts f or Tre at me nt after cC R T
Tr e at m e nt aft er 
c C R T
Tr e at m e nt aft er c C R T
( ± 3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h W e e k 9 d o si n g 
vi sit. O v erl a p pi n g a s s e s s m e nt s o nl y n e e d t o b e 
p erf or m e d o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s) . S e e S e cti o n 4. 1 f or a d diti o n al 
d et ail s.
V 3
6
V 3 7 
V 3 8  
V 3 9 
V 4 0 
V 4 1 
V 4 2
U ntil 
E n d -of -
Tr e at m e nt 
O n t h e D a y  of 
or Wit hi n 
7 D a y s of 
D e ci si o n t o 
E n d 
Tr e at m e nt
W 9   W 1 1 
W 1 3 
W 1 5 
W 1 7 
W 1 9   
W 2 1
D 5
7
D 7 1 
D 8 5 
D 9 9 
D 1 1 3 
D 1 2 7 
D 1 4 1
A d mi ni str ati v e Pr o c e d ur e s
D o c u m e nt ati o n 
c o n c o mit a nt 
m e di c ati o n a n d 
pr o c e d ur e s
X  
X  
X  
X  
X  
X  
X
O n c e e v er y 
2 w e e k s
X
Vir al tit er ( H B V, H C V) 
A s cli ni c all y i n di c at e d i n p arti ci p a nt s wit h a hi st or y of H B V or H C V i nf e cti o n
HI V 
t e sti n g i s n ot m a n d at e d  f or st u d y i n cl u si o n; 
h o w e v er, if it i s p erf or m e d at a n y p oi nt i n S cr e e ni n g or 
w hil e o n st u d y, a sit e m u st c o n s e nt t h e p arti ci p a nt f or 
HI V t e sti n g a s p er l o c al st a n d ar d g ui d a n c e.
M 7 8 2 4
a n d d ur v al u m a b A d mi ni str ati o n
M 7 8 2 4 or d ur v al u m a b 
X a
X  
X  
X  
X  
X  
X
O n c e e v er y 
2 w e e k s b
a: If cli ni c all y i n di c at e d, t h e fir st d o s e of d ur v al u m a b 
or M 7 8 2 4 aft er t h e e n d of c C R T s h o ul d b e 
a d mi ni st er e d o n D a y 5 7 b ut n ot b ef or e 1 4 d a y s fr o m 
t h e pr e vi o u s d o s e of M 7 8 2 4 or pl a c e b o
b : O n c e e v er y 2 w e e k s f or a m a xi m u m of 2 6 d o s e s 
of st u d y i nt er v e nti o n aft er c C R T .
All o w e d wi n d o w f or a d mi ni str ati o n ( ± 3 d a y s )
S af et y  As s e s s m e nt s
D o c u m e nt ati o n of A E s  X  
X  
X  
X  
X  
X  
X
O n c e e v er y 
2 w e e k s
X 
S e e  A p p e n di x 4 f or s af et y r e c or di n g a n d r e p orti n g. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 / 1 5 5
Tr e at m e nt aft er 
c C R T
Tr e at m e nt aft er c C R T
( ± 3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h W e e k 9 d o si n g 
vi sit. O v erl a p pi n g a s s e s s m e nt s o nl y n e e d t o b e 
p erf or m e d o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s) . S e e S e cti o n 4. 1 f or a d diti o n al 
d et ail s.
V 3
6
V 3 7 
V 3 8  
V 3 9 
V 4 0 
V 4 1 
V 4 2
U ntil 
E n d -of -
Tr e at m e nt 
O n t h e D a y  of 
or Wit hi n 
7 D a y s of 
D e ci si o n t o 
E n d 
Tr e at m e nt
W 9   W 1 1 
W 1 3 
W 1 5 
W 1 7 
W 1 9   
W 2 1
D 5
7
D 7 1 
D 8 5 
D 9 9 
D 1 1 3 
D 1 2 7 
D 1 4 1
P h y si c al e x a mi n ati o n 
X  
X  
X  
X  
X  
X  
X
O n c e e v er y 
2 w e e k s
X
C o m pl et e P E at S cr e e ni n g . S u b s e q u e nt f o c u s e d P E s 
t o b e p erf or m e d a s p er l o c al st a n d ar d pr a cti c e a n d 
a s cli ni c all y i n di c at e d T h or a x e x a m at e a c h vi sit a n d 
fi n di n g s m u st b e r e p ort e d i n t h e e C R F.  
S ki n A s s e s s m e nt
X
X
O n c e e v er y 
6 w e e k s
X
S e e S e cti o n  6. 9. 3 f or p arti ci p a nt s e x p eri e n ci n g a 
d er m at ol o gi c -r el at e d A E.
Vit al si g n s
X  
X  
X  
X  
X  
X  
X
O n c e e v er y 
2 w e e k s
X
I n cl u di n g w ei g ht a n d h ei g ht ( h ei g ht at S cr e e ni n g
o nl y). T e m p er at ur e, p ul s e r at e, r e s pir at or y r at e, 
bl o o d pr e s s ur e, a n d r e sti n g p ul s e o xi m etr y m u st b e 
d o n e at e a c h vi sit a n d m u st b e r e p ort e d i n t h e e C R F. 
E C O G P S
X  
X  
X  
X  
X  
X  
X
O n c e e v er y 
2 w e e k s
X
S pir o m etr y
O n c e e v er y 1 2 w e e k s ( ± 7 d a y s) u ntil E o T
X c
V C m a x, F E V1 , F V C, F E V1 / F V C r ati o m u st b e r e p ort e d. 
c : D o e s n ot n e e d t o b e p erf or m e d at E n d -of -
Tr e at m e nt if p erf or m e d wit hi n 7 d a y s of E o T Vi sit .
6- mi n W al ki n g T e st
O n c e e v er y 1 2 w e e k s ( ± 7 d a y s) u ntil E o T
X c
Di st a n c e a n d O 2 s at ur ati o n m u st b e r e p ort e d .
c : D o e s n ot n e e d t o b e p erf or m e d at E n d -of -
Tr e at m e nt if p erf or m e d wit hi n 7 d a y s of E o T Vi sit .
Hi g h r e s ol uti o n C T 
s c a n
At W e e k 3 3 a n d W e e k 5 7 ( ± 7 d a y s)
C a n b e p erf or m e d wit hi n ± 7 d a y s of t h e t ar g et vi sit s 
a n d if p o s si bl e, s h o ul d c oi n ci d e wit h C T s c a n .
L a b or at or y  As s e s s m e nt s
H e m o st a s e ol o g y
A s cli ni c all y i n di c at e d
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 / 1 5 5
Tr e at m e nt aft er 
c C R T
Tr e at m e nt aft er c C R T
( ± 3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h W e e k 9 d o si n g 
vi sit. O v erl a p pi n g a s s e s s m e nt s o nl y n e e d t o b e 
p erf or m e d o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s) . S e e S e cti o n 4. 1 f or a d diti o n al 
d et ail s.
V 3
6
V 3 7 
V 3 8  
V 3 9 
V 4 0 
V 4 1 
V 4 2
U ntil 
E n d -of -
Tr e at m e nt 
O n t h e D a y  of 
or Wit hi n 
7 D a y s of 
D e ci si o n t o 
E n d 
Tr e at m e nt
W 9   W 1 1 
W 1 3 
W 1 5 
W 1 7 
W 1 9   
W 2 1
D 5
7
D 7 1 
D 8 5 
D 9 9 
D 1 1 3 
D 1 2 7 
D 1 4 1
H e m at ol o g y
X
O n c e e v er y 2 w e e k s
X
S e e  A p p e n di x 5 f or i n di vi d u al t e st s i n e a c h l a b or at or y 
p a n el. S a m pl e s m u st al s o b e dr a w n wit hi n 3 d a y s 
a n d r e s ult s t o b e r e vi e w e d pri or t o d o s e 
a d mi ni str ati o n. 
C or e s er u m c h e mi str y 
X d
X
X
X
O n c e e v er y 
2 w e e k s
C or e s er u m c h e mi str y ar e li st e d i n A p p e n di x 5
S a m pl e s m u st al s o b e dr a w n wit hi n 3 d a y s a n d 
r e s ult s t o b e r e vi e w e d pri or t o d o s e a d mi ni str ati o n.
d: C or e s er u m c h e mi str y n ot n e e d e d if e n d of c C R T 
vi sit a n d D 5 7 W 9 tr e at m e nt vi sit s o v erl a p. F or s u c h 
o v erl a p pi n g vi sit s, o nl y p a n el A c h e mi str y m u st b e 
d o n e.
F ull s er u m c h e mi str y 
P a n el A
X
X
X
X
S e e A p p e n di x 5 f or i n di vi d u al t e st s i n e a c h l a b or at or y 
p a n el. S a m pl e s m u st al s o b e dr a w n wit hi n 3 d a y s
a n d r e s ult s t o b e r e vi e w e d pri or t o d o s e 
a d mi ni str ati o n . Aft er W e e k 1 9, r e p e at f ull s er u m 
c h e mi str y p a n el A a s cli ni c all y i n di c at e d .
Uri n al y si s
A s cli ni c all y i n di c at e d
If t h e uri n al y si s i s a b n or m al, t h e n a c ult ur e s h o ul d b e 
p erf or m e d.
β- H C G pr e g n a n c y t e st 
( o nl y a p pli c a bl e t o 
W O C B P)
O n c e e v er y 4 w e e k s
β- H C G t o b e d et er mi n e d fr o m a uri n e or s er u m 
s a m pl e o n c e e v er y 4 w e e k s. R e s ult s of t h e m o st 
r e c e nt pr e g n a n c y t e st s h o ul d b e a v ail a bl e pri or t o 
d o si n g of st u d y i nt er v e nti o n.
T 4 a n d T S H
X
X
O n c e e v er y
6 w e e k s
S er u m K L -6, S P -A a n d 
S P - D
E v er y 2 w e e k s f or J a p a n e s e p arti ci p a nt s e nr oll e d i n J a p a n f or t h e fir st 1 2 w e e k s 
aft er c C R T f oll o w e d b y e v er y 4 w e e k s u ntil E o T
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 / 1 5 5
Tr e at m e nt aft er 
c C R T
Tr e at m e nt aft er c C R T
( ± 3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h W e e k 9 d o si n g 
vi sit. O v erl a p pi n g a s s e s s m e nt s o nl y n e e d t o b e 
p erf or m e d o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s) . S e e S e cti o n 4. 1 f or a d diti o n al 
d et ail s.
V 3
6
V 3 7 
V 3 8  
V 3 9 
V 4 0 
V 4 1 
V 4 2
U ntil 
E n d -of -
Tr e at m e nt 
O n t h e D a y  of 
or Wit hi n 
7 D a y s of 
D e ci si o n t o 
E n d 
Tr e at m e nt
W 9   W 1 1 
W 1 3 
W 1 5 
W 1 7 
W 1 9   
W 2 1
D 5
7
D 7 1 
D 8 5 
D 9 9 
D 1 1 3 
D 1 2 7 
D 1 4 1
P ati e nt R e p ort e d O ut c o m e s
T u m or A s s e s s m e nt s
T h or a x A b d o m e n 
P el vi s C T 
( pr ef err e d)/ M RI
X ( ± 7 
d a y s)
E v er y 
8 w e e k s
( ± 7 d a y s)
C o nfir m ati o n of C R or P R s h o ul d b e p erf or m e d 
pr ef er a bl y at t h e r e g ul arl y s c h e d ul e d 8 w e e kl y 
a s s e s s m e nt i nt er v al s, b ut n o s o o n er t h a n 4 w e e k s 
aft er t h e i niti al d o c u m e nt ati o n. C o nfir m ati o n of P D i s 
al s o r e q uir e d a n d s h o ul d b e p erf or m e d pr ef er a bl y 
a n d if cl i ni c all y f e a si bl e, at t h e r e g ul arl y s c h e d ul e d 8 
w e e kl y a s s e s s m e nt i nt er v al s, b ut n o s o o n er t h a n 4 
w e e k s aft er t h e i niti al d o c u m e nt ati o n. T h e s c h e d ul e 
of C T s c a n ( e v er y 8 w e e k s ± 7 d a y s) s h o ul d b e 
m ai nt ai n e d r e g ar dl e s s of d o si n g.
A b o n e s c a n will b e d o n e a s cli ni c all y i n di c at e d. 
S e e S e cti o n  8. 1
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 / 1 5 5
Tr e at m e nt aft er 
c C R T
Tr e at m e nt aft er c C R T
( ± 3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h W e e k 9 d o si n g 
vi sit. O v erl a p pi n g a s s e s s m e nt s o nl y n e e d t o b e 
p erf or m e d o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s) . S e e S e cti o n 4. 1 f or a d diti o n al 
d et ail s.
V 3
6
V 3 7 
V 3 8  
V 3 9 
V 4 0 
V 4 1 
V 4 2
U ntil 
E n d -of -
Tr e at m e nt 
O n t h e D a y  of 
or Wit hi n 
7 D a y s of 
D e ci si o n t o 
E n d 
Tr e at m e nt
W 9   W 1 1 
W 1 3 
W 1 5 
W 1 7 
W 1 9   
W 2 1
D 5
7
D 7 1 
D 8 5 
D 9 9 
D 1 1 3 
D 1 2 7 
D 1 4 1
Br ai n M RI
( pr ef err e d)/ C T
O n c e e v er y 1 2 w e e k s ( ± 7 d a y s)
T h e s c h e d ul e of Br ai n M RI / C T s c a n ( e v er y 1 2 w e e k s
± 7 d a y s) s h o ul d b e m ai nt ai n e d r e g ar dl e s s of d o si n g. 
S e e S e cti o n  8. 1
P K, A D A, P D a n d Bi o m ar k er 
Bl o o d s a m pl e f or P K
X/ -
( pr e/
e oi)
X/ -
( pr e/
e oi)
Pr e- i nf u si o n 
s a m pl e s 
e v er y 6 
w e e k s u p t o 
W e e k 2 5. 
P r e- a n d 
p o sti nf u si o n 
s a m pl e s 
e v er y 1 2 
w e e k s u ntil 
W e e k 4 9
X/ -
( pr e/ eoi)
S a m pl e s f or P K a n al y si s t o b e t a k e n b ef or e ( pr e) 
i nf u si o n ( a s cl o s e t o t h e st art of t h e i nf u si o n a s 
p o s si bl e), i m m e di at el y aft er t h e c o m pl eti o n of 
i nf u si o n (e oi, a s cl o s e t o t h e c o m pl eti o n a s p o s si bl e 
b ut n o l at er t h a n 3 0 mi n p o st e n d of i nf u si o n). T h e 
pr e d o s e s a m pl e will still b e dr a w n e v e n if d o si n g i s 
ulti m at el y d ef err e d at t h e st u d y vi sit. T h e e x a ct ti m e 
of e a c h dr a w m u st b e r e c or d e d. A pr ot o c ol d e vi ati o n 
will b e d efi n e d b y a s a m pl e n ot b ei n g dr a w n.
Bl o o d s a m pl e f or A D A 
X/ -
( pr e/
e oi)
X/ -
( pr e/
e oi)
E v er y 6 
w e e k s u p t o 
W e e k 2 5 
(i n cl u d e d), 
t h e n e v er y 
1 2 w e e k s 
u ntil 
W e e k 4 9
X/ -
( pr e/
e oi)
S a m pl e s will b e c oll e ct e d pri or t o M 7 8 2 4 or 
d ur v al u m a b a d mi ni str ati o n. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 / 1 5 5
Tr e at m e nt aft er 
c C R T
Tr e at m e nt aft er c C R T
( ± 3 d a y s)
E n d -of -
Tr e at m e nt
Vi sit
N ot e s
E n d of c C R T vi sit m a y c oi n ci d e wit h W e e k 9 d o si n g 
vi sit. O v erl a p pi n g a s s e s s m e nt s o nl y n e e d t o b e 
p erf or m e d o n c e a n d s h o ul d f oll o w W e e k 9 vi sit 
wi n d o w ( ± 3 d a y s) . S e e S e cti o n 4. 1 f or a d diti o n al 
d et ail s.
V 3
6
V 3 7 
V 3 8  
V 3 9 
V 4 0 
V 4 1 
V 4 2
U ntil 
E n d -of -
Tr e at m e nt 
O n t h e D a y  of 
or Wit hi n 
7 D a y s of 
D e ci si o n t o 
E n d 
Tr e at m e nt
W 9   W 1 1 
W 1 3 
W 1 5 
W 1 7 
W 1 9   
W 2 1
D 5
7
D 7 1 
D 8 5 
D 9 9 
D 1 1 3 
D 1 2 7 
D 1 4 1
A D A = a nti -dr u g a nti b o d y, A E = a d v er s e e v e nt s, β H C G = β -h u m a n c h ori o ni c g o n a d otr o pi n, c C R T = c o n c o mit a nt c h e m or a di ati o n t h er a p y , C T = c o m p ut e d 
t o m o gr a p h y, 
, D = D a y,
, E C G = el e ctr o c ar di o gr a m, E C O G P S = E a st er n 
C o o p er ati v e O n c ol o g y Gr o u p P erf or m a n c e St at u s,
 
, e oi = e n d of i nf u si o n , 
 
, H B V = h e p atiti s B v ir u s, H C V = h e p atiti s C vir u s, HI V = H u m a n i m m u n o d efi ci e n c y vir u s , M RI = m a g n eti c r e s o n a n c e i m a gi n g ,
N S C L C -S A Q = n o n - s m all c ell l u n g c a n c er Sy m pt o m A s s e s s m e nt Q u e sti o n n air e ,
 
 P K = p h ar m a c o ki n eti c s,
, T4 =fr e e t h yr o xi n e ,
r d e n, T S H =t h yr oi d -sti m ul ati n g h or m o n e ,
V = vi sit , W = W e e k , W O C B P = W o m a n of c hil d b e ari n g p ot e nti al .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
8 5 6 8
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 / 1 5 5
T a ble 4
Sc he d ule of Assess me nts f or S afet y a n d L o n g -ter m F oll o w-u p
S af et y  a n d L o n g-t er m F oll o w-u p
S af et y  F oll o w -u p Vi sit 
L o n g -t er m F oll o w-u p a
N ot e s
2 8 D a y s 
( ± 5 d a ys) aft er 
L a st Tr e at m e nt
1 2 W e e k s 
( ± 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 k s
( ± 2 w e e k s) st arti n g 2 4 
w e e k s aft er L a st 
Tr e at m e nt
a : L o n g t er m f oll o w -u p will b e c o n d u ct e d b y  
p h o n e or m a y  b e c o n d u ct e d d uri n g a cli ni c vi sit
D o c u m e nt ati o n c o n c o mit a nt t h er a p y
X
X
X b
b : M a y b e c o n d u ct e d vi a p h o n e c all i n L o n g -t er m 
F oll o w -u p p h a s e.
D o c u m e nt ati o n of A E s 
X
X c
X c
S e e  A p p e n di x 4 f or s af et y r e c or di n g a n d r e p orti n g.
c : T h e 1 2- w e e k S af et y F oll o w-u p a n d L o n g -t er m 
F oll o w -u p m a y b e c o n d u ct e d vi a t el e p h o n e c all s or
p ati e nt c h art r e vi e w s a s n e c e s s ar y u nl e s s t h er e i s 
m e di c al n e c e s sit y r e q uiri n g a cli ni c al vi sit.
P h y si c al e x a mi n ati o n
X
X d
F o c u s e d P E s t o b e p erf or m e d a s p er l o c al st a n d ar d 
pr a cti c e.
d: N ot m a n d at or y, o nl y p erf or m if cli ni c all y i n di c at e d
S ki n a s s e s s m e nt
X
Vit al si g n s
X
I n cl u di n g w ei g ht. T e m p er at ur e, p ul s e r at e, 
r e s pir at or y r at e, bl o o d pr e s s ur e, a n d r e sti n g p ul s e 
o xi m etr y m u st b e m e a s ur e d.
E C O G P S
X
1 2 -l e a d E C G
X
H e m at ol o g y 
X
D et ail s o n bl o o d t e st s u n d er t hi s c at e g or y ar e li st e d 
i n A p p e n di x 5 .
F ull s er u m c h e mi str y P a n el A
X
S e e  A p p e n di x 5 f or i n di vi d u al t e st s i n e a c h 
l a b or at or y p a n el. 
Uri n al y si s
X
β- h C G pr e g n a n c y t e st
X
β- h C G m u st b e d et er mi n e d fr o m uri n e or s er u m.
T 4 a n d T S H
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 / 1 5 5
S af et y  a n d L o n g-t er m F oll o w-u p
S af et y  F oll o w -u p Vi sit 
L o n g -t er m F oll o w-u p a
N ot e s
2 8 D a y s 
( ± 5 d a ys) aft er 
L a st Tr e at m e nt
1 2 W e e k s 
( ± 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 k s
( ± 2 w e e k s) st arti n g 2 4 
w e e k s aft er L a st 
Tr e at m e nt
a : L o n g t er m f oll o w -u p will b e c o n d u ct e d b y  
p h o n e or m a y  b e c o n d u ct e d d uri n g a cli ni c vi sit
S u b s e q u e nt a nti c a n c er t h er a p y ( a n y li n e)
X
X
X
S ur vi v al f oll o w -u p
X
P arti ci p a nt s will b e c o nt a ct e d s h ortl y b ef or e t h e 
d at a c ut -off f or t h e pri m ar y a n al y si s t o pr o vi d e 
c o m pl et e s ur vi v al d at a .
T u m or e v al u ati o n/ st a gi n g ( C T S c a n of T h or a x , 
a b d o m e n a n d p el vi s / M RI/ ot h er e st a bli s h e d 
m et h o d s) d uri n g f oll o w -u p
F or p arti ci p a nt s w h o di d 
n ot e x p eri e n c e P D: C T 
s c a n e v er y 8 w e e k s u p t o 
2 4 m o nt h s a n d t h e n e v er y 
8- 1 2 w e e k s u p t o 
pr o gr e s si o n, st art of n e w 
tr e at m e nt or d e at h. Br ai n 
M RI e v er y 1 2
w e e k s u p t o 
2 4 m o nt h s a n d t h e n 
a c c or di n g t o l o c al 
pr a cti c e.
F or p arti ci p a nt s w h o 
e x p eri e n c e d P D: i m a gi n g 
f or t u m or e v al u ati o n will 
b e e v al u at e d a s p art of 
P F S 2 a s s e s s m e nt u si n g 
R E CI S T 1. 1 . 
R e s p o n s e a n d pr o gr e s si o n o n s u b s e q u e nt 
tr e at m e nt
X
X
X
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 7 / 1 5 5
S af et y  a n d L o n g-t er m F oll o w-u p
S af et y  F oll o w -u p Vi sit 
L o n g -t er m F oll o w-u p a
N ot e s
2 8 D a y s 
( ± 5 d a ys) aft er 
L a st Tr e at m e nt
1 2 W e e k s 
( ± 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 k s
( ± 2 w e e k s) st arti n g 2 4 
w e e k s aft er L a st 
Tr e at m e nt
a : L o n g t er m f oll o w -u p will b e c o n d u ct e d b y  
p h o n e or m a y  b e c o n d u ct e d d uri n g a cli ni c vi sit
A E = a d v er s e e v e nt , β-h C G = b et a -h u m a n c h ori o ni c g o n a d otr o pi n , C T = c o m p ut e d t o m o gr a p h y , E C G = el e ctr o c ar di o gr a m ,
 
e ,
, M RI = m a g n eti c r e s o n a n c e i m a gi n g , N S C L C -S A Q = n o n -s m all c ell l u n g c a n c er S y m pt o m 
A s s e s s m e nt Q u e sti o n n air e , O S = O v er all s ur vi v al , P D = Pr o gr e s si v e di s e a s e , P E = p h y si c al e x a mi n ati o n , P F S = Pr o gr e s si o n -fr e e s ur vi v al,
 
,
S A E = s eri o u s a d v er s e e v e nt , T4 =fr e e t h yr o xi n e , T S H =t h yr oi d -sti m ul ati n g h or m o n e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 8 / 1 5 5
2
I ntr o d ucti o n
M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C, bi ntraf us p alfa) is an i n n o vati ve first-i n-class bif u ncti o nal f usi o n pr otei n 
c o m p ose d of t he e xtracell ular d o mai n of T G F-β rece pt or II ( T G F-β RII or T G F - β Tra p ) c o vale ntl y 
li n ke d via a fle xi ble li n ker t o t he C- ter mi n us of eac h hea v y  chai n of a n i m m u n o gl o b uli n (I g G 1) 
a nti b o d y bl oc ki n g pr o gra m me d deat h -li ga n d 1 (a nti-P D -L 1). Bi ntraf us p alfa is t he pr o p ose d 
i nter nati o nal n o n pr o prietar y na me f or M 7 8 2 4.
C o m plete i nf or mati o n o n t he c he mistr y, p har mac ol o g y , efficac y, a n d safet y of M 7 8 2 4
is i n t he
I n vesti gat or’s Br oc h ure.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 / 1 5 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 /1 5 5
2. 2
B ac k gr o u n d
A p pr o xi matel y  one t hir d of patie nts wit h N S C L C ha ve Sta ge III, l ocall y ad va nce d disease at 
dia g n osis (A u péri n 2 0 1 0 ). Alt h o u g h s ur ger y is a p pr o priate f or s o me of t hese patie nts, m ost of t he 
patie nts are c o nsi dere d t o be i n o pera ble.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 / 1 5 5
U ntil t he a p pr o val of d ur val u ma b, t he sta n dar d of care f or u nresecta ble Sta ge III N S C LC patie nts 
wit h a g o o d perf or ma nce stat us has bee n plati n u m -base d d o u blet c he m ot hera p y c o nc urre nt wit h 
ra di ot hera py (c he m ora di ot hera py, c C R T) f oll o we d b y  obser vati o n u ntil e vi de nce of disease 
pr o gressi o n ( P D) (Y o o n
2 0 1 7 ). H o we ver, t he me dia n P F S ( m P F S) a m o n g patie nts w h o ha ve 
recei ve d c C R T was p o or (a p pr o xi matel y 8 t o 1 0 m o nt hs), a n d o nl y  15 % of patie nts were ali ve at 
5 y ears (A u péri n 2 0 1 0, A h n 2 0 1 6 ). 
D ur val u ma b (I M FI N ZI® ) is a P D -L 1  bl oc ki n g a nti b o d y an d has bee n a p pr o ve d b y  FD A i n 
Fe br uar y  2 0 1 8 i n patie nts wit h disease c o ntr ol after c o nc urre nt plati n u m-base d c he m ot hera p y a n d 
ra diati o n t hera py. P A CI FI C st u d y de m o nstrate d t hat, i n patie nts wit h disease c o ntr ol after c C R T, 
d ur val u ma b i ncrease d m P F S b y  11. 2 m o nt hs c o m pare d t o place b o c o ntr ol (A nt o nia 2 0 1 7) a n d 
m O S has n ot bee n reac he d c o m pare d t o 2 8. 7 m o nt hs i n t he place b o c o ntr ol ar m (A nt o nia 2 0 1 8)
M ore o ver, as s u m marize d i n Ta ble 5, d ur val u ma b s h o we d i m pr o ve me nt i n all sec o n dar y en d p oi nts 
as p u blis he d s o far. 
T a ble 5
Acti vit y of D ur v al u m a b i n P A CI FI C St u d y 
St u d y  
I nt er v e nti o n
m P F S
( m o nt h)a
1 2 m 
P F S
( %)a
1 8 m 
P F S
( %)a
M e di a n 
Ti m e t o 
D e at h or 
Di st a nt 
M et a st a si s
( m o nt h s)a
Fr e q u e n c y  
of N e w 
L e si o n 
( %)a
O R R
( %)a
P D
( %)a
1 2 m 
D o R
( %)a
1 8 m 
D o R
( %)a
m O S
( m o nt h)b
D ur v al u m a b 
1 6. 8  
5 5. 9  
4 4. 2  
2 3. 2  
2 0. 4  
2 8. 4  
1 6. 5  
7 2. 8  
7 2. 8 
N R
Pl a c e b o
5. 6 
3 5. 3  
2 7. 0  
1 4. 6  
3 2. 1  
1 6. 0  
2 7. 7  
5 6. 1  
4 6. 8  
2 8. 7
O R R = o bj e cti v e r e s p o n s e r at e, m P F S = m e di a n pr o gr e s si o n -fr e e s ur vi v al, P D = pr o gr e s si o n di s e a s e, 
D o R = d ur ati o n of r e s p o n s e, m O S = m e di a n o v er all s ur vi v al, N R = n ot r e a c h e d .
S o ur c e: a A nt o ni a, 2 0 1 7 ; b A nt o ni a 2 0 1 8 .
M 7 8 2 4 is a bif u ncti o nal f usi o n pr otei n t hat c o m bi nes a n a nti-P D -L 1 a nti b o d y a n d t he e xtracell ular 
d o mai n of T G -F β rece pt or II ( T G F-β RII) as a T G F -β ne utralizi n g ‘tra p’, i nt o a si n gle m olec ule. 
C o m plete i nf or mati o n o n t he c he mistr y, p har mac ol o g y , efficac y, a n d safet y of M 7 8 2 4 is i n t he 
M 7 8 2 4 I nvesti gat or ’s Br oc h ure ( M 7 8 2 4 I B).
T he n o vel desi g n of M 7 8 2 4, w hic h ne utralizes T G F -β a n d si m ulta ne o usl y i n hi bits t he a nti -P D -L 1  
pat h wa y  i n t he t u m or micr oe n vir o n me nt, ma y be m ore effecti ve t ha n a ge nts tar geti n g P D -L 1 a n d 
T G F -β se parately. 
 
 
 
 
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 / 1 5 5
T he e val uati o n of t he cli nical pr ofile of M 7 8 2 4 is o n g oi n g; refer t o t he c urre nt I B f or f urt her details .
M 7 8 2 4 has de m o nstrate d a ma na gea ble safety pr ofile t o date ( See Secti o n 4. 3 ) a n d pr o misi n g 
cli nical acti vit y in par tici pa nts wit h 2 L  NS C L C acr oss P D -L 1  e xpressi o n le vels i n t u m or cells (see 
Secti o n  2. 1).
T he mec ha nis m of acti o n of M 7 8 2 4, t o get her wit h its e nc o ura gi n g P hase I cli nical acti vit y in 
N S C L C, al o n g wit h cli nical be nefit de m o nstrate d b y  dur val u ma b f oll o wi n g c C R T i n P A CI FI C 
st u d y su p p ort t he st u d y of M 7 8 2 4 c o nc o mita nt wit h c C R T f oll o we d b y  M7 8 2 4 i n u nresecta ble 
Sta ge III N S C L C.
2. 3
Be nefit/ Ris k  Assess me nt
M o re detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bly 
e x pecte d a d verse e ve nts of M 7 8 2 4
or d ur val u ma b or a n y ot her st u d y i nter ve nti o n a d mi nistere d i n 
t his st u d y m a y  be f o u n d i n Secti o n  2. 1 a n d t he I nvesti gat or’s Br oc h ure, Partici pa nt I nf or mati o n 
Leaflet, 
Pac ka ge 
I nsert, De vel o p me nt 
Safet y 
U p date 
Re p ort 
or S u m mar y  of Pr o d uct 
C haracteristics.
Base d o n t he a v aila ble
a n d cli nical data t o date, t he c o n d uct of t he st u d y,  as s pecifie d 
i n t his pr ot oc ol, is c o nsi dere d j ustifia ble.
T he be nefit a n d ris k assess me nt t o c o n d uct t his st u d y in Sta ge III u nresecta ble N S C L C is base d o n 
a str o n g scie ntific rati onale o bser ve d d uri n g precli nical st u dies wit h M 7 8 2 4. I n ad diti o n , i n 2 L  
N S C L C patie nts, M 7 8 2 4 s h o we d pr o misi n g cli nical acti vit y a n d a ma na gea ble safet y pr ofile 
c o nsiste nt wit h o verall safet y of a nti-P D -( L) 1 a n d T G F -β a ge nts. Acce pta ble safety pr ofiles ha v e 
als o bee n o bser ve d i n o n g oi n g cli nical st u dies wit h ot her c hec k p oi nt i n hi bit ors i n c o m bi nati o n 
wit h C R T (Peters 2 0 1 8 ). 
P D -L 1  ex pressi o n is o bser ve d t o be u pre g ulate d i n t he t u m or micr oe n vir o n me nt after ra diati o n 
t hera py a n d c he m ot hera pe utic a ge nts i n m ulti ple h u ma n ca ncer cell li nes (Li n 2 0 1 7, Sa ma nta 2 0 1 8 ,
Gra b osc h , 2 0 1 5 ) a n d m uri ne t u m or m o dels (De n g 2 0 1 4 , D o ve di 2 0 1 4 ). N ota bl y , s uc h u pre g ulati o n 
of P D -L 1 e x pressi o n b y i rra diati o n ca n be f urt her e n ha nce d b y T G F-bl oc ka de (Va n p o uille- B o x 
2 0 1 5 ), s u p p orti n g t he h y p ot hesis t hat c o m bi ni n g M 7 8 2 4 wit h ra di ot hera p y will li kel y pr o vi de 
be neficial effect i n partici pa nts re gar dless of t he i nitial P D -L 1  stat us of t he t u m or.
Im p orta nt 
i de ntifie d ris ks f or M 7 8 2 4 
are i m m u ne-relate d a d verse e ve nts (im m u ne -relate d 
p ne u m o nitis , im m u ne -relate d he patitis, im m u ne -relate d c olitis, im m u ne -relate d ne p hritis a n d re nal 
d y sf u ncti o n, im m u ne -relate d e n d ocri n o pat hies [t h yr oi d dis or ders, a dre nal i ns ufficie nc y, Ty p e 1 
D ia betes mellit us, 
pit uitar y  dis or ders], i m m u ne-relate d ras h a n d ot her ir A Es [m y ositis, 
m y ocar ditis, e nce p halitis ]), T G F -β i n hi biti o n me diate d s ki n reacti o ns, a ne mia, a n d blee di n g 
a d verse e ve nts (refer t o I B f or f ull safet y details).
I nf usi o n-relate d reacti o ns are a n i de ntifie d ris k of M 7 8 2 4.
I n p o ole d data fr o m 7 6 5 partici pa nts 
w h o recei ve d bi ntraf us p alfa m o n ot hera p y at 1 2 0 0 m g q 2 w, inf usi o n -relate d reacti o ns were 
re p orte d i n 6. 3 % of partici pa nts . The maj orit y  of I R Rs were Gra de 1 or 2 , i ncl u di n g 2. 9 % w h o 
e x perie nce d I R Rs d uri n g t he first i nf usi o n. Per ma ne nt disc o nti n uati o n a n d i nterr u pti o ns d ue t o 
I R Rs occ urre d i n l o w fre q ue nc y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 / 1 5 5
I m p orta nt p ote ntial ris ks are f urt her im m u ne -relate d a d verse e ve nts ( G uillai n-Barré s yn dr o me, 
u veitis, pa ncreatitis, m y ast he nia gra vis/ m y ast he nic s yn dr o me) , im paire d w o u n d heali n g , a nd 
e m br yofetal t o xicit y .
I nf usi o n-relate d reacti o ns are i m p orta nt i de ntifie d ris ks f or d ur val u ma b . T he i m m u ne -relate d A Es 
i m m u ne me diate d c olitis or diarr hea, he patitis, p ne u m o nitis, h y p o p h y sitis or h y p o pit uitaris m, 
ne p hritis, h y pert h y r oi dis m, h y p ot h y r oi dism, T y pe I dia betes, a dre nal i ns ufficie nc y, ras h or 
der matitis, a n d m y ocar ditis are i m p orta nt i de ntifie d ris ks f or d ur val u ma b.
T he rati o nale f or c o m bi ni n g c C R T wit h M 7 8 2 4 at 1 2 0 0 m g flat d ose fr o m t he P hase I st u dies is 
base d o n n o pr ojecte d ris k of P K i nteracti o ns d ue t o differe nt cleara nce mec ha nis ms f or 
c he m ot hera p y ( cis plati n/et o p osi de, cis plati n/ pe metre xe d or car b o plati n/ paclita xel) vers us M 7 8 2 4. 
Alt h o u g h ra di ot hera p y is e x pecte d t o i ncrease e x pressi o n of P D -L 1 a n d/ or T G F - β i n t he t u m ors 
(see Secti o n  2. 1), c o ntri b uti o n of tar get-me diate d cleara nce mec ha nis ms t o t he cleara nce of M 7 8 2 4 
is n ot pr ojecte d at 1 2 0 0 m g o nce e ver y  t w o wee ks (q 2 w) d ose re gi me n. I n ad diti o n, base d o n t he 
mec ha nis ms of acti o n of M 7 8 2 4 or C R T, t here is n o pr ojecti o n of e xa g gerate d i m m u ne res p o nse 
(e. g., c yt o ki ne release) i n M 7 8 2 4/ C R T c o m bi nati o n. T o date, c yt o ki ne data a nal ys is i n partici pa nts 
of t he P hase I st u d y, s h o we d a tra nsie nt mil d effect of M 7 8 2 4 
(at 1 2 0 0 m g q 2 w d ose) o n 
i nfla m mat or y cyt o ki nes i n bl o o d. T heref ore, n o a dj ust me nt i n t he d ose of cisplati n/et o p osi de, 
cis plati n/ pe metre xe d, car b o plati n/ paclita xel or M 7 8 2 4 is c o nsi dere d necessar y  f or t his st u d y.
I n c o ncl usi o n, t he d ual m o de of acti o n of bi- f u ncti o nal M 7 8 2 4 
i n t u m or micr oe n vir o n me nt, 
t o get her wit h its e nc o ura gi n g n o ncli nical data wit h c he m ot hera p y a n d ra diati o n, a n d P hase I 
cli nical acti vit y in a d va nce d N S C L C, s u p p ort t he i n vesti gati o n of M 7 8 2 4 
wit h c C R T i n 
u nresecta ble Sta ge III N S C L C. I ncrease d cli nical be nefit i n ter ms of i m pr o ve d P F S, O S al o n g wit h 
a n i m pr o ve d Q o L is a ntici pate d wit h a d mi nistrati o n of M 7 8 2 4 wit h c C R T f oll o we d b y  M7 8 2 4 
treat me nt i n t his patie nt p o p ulati o n . T he o verall be nefit/ris k assess me nt a p pears fa v ora ble t o 
c o n d uct t his gl o bal st u d y. A d diti o nall y , t he safety of M 7 8 2 4 pl us c C R T will be m o nit ore d b y  t he 
I D M C peri o dic all y duri n g t he safety r u n-i n a n d t he c o nti n uati o n of t he st u d y is base d o n t heir 
assess me nt of t he ris k-be nefit relati o ns hi p o n a n o n g oi n g basis. 
3
O bjecti ves a n d E n d p oi nts
T a ble 6
St u d y O bjecti ves a n d E n d p oi nts
Pri m ar y  O bj e cti v e
Pr i m ar y E n d p oi nt
T o e v al u at e P F S i n p arti ci p a nt s tr e at e d wit h c C R T pl u s M 7 8 2 4 
f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o f oll o w e d b y 
d ur v al u m a b 
P F S a c c or di n g t o R E CI S T 1. 1 a s s e s s e d b y 
I n v e sti g at or
S e c o n d ar y  O bj e cti v e s
S e c o n d ar y  E n d p oi nt s
T o e v al u at e t h e s af et y i n p arti ci p a nt s tr e at e d wit h c C R T pl u s 
M 7 8 2 4 f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o f oll o w e d b y 
d ur v al u m a b
O c c urr e n c e of T E A E s a n d tr e at m e nt -r el at e d 
A E s 
T o e v al u at e O S i n p arti ci p a nt s tr e at e d wit h c C R T pl u s M 7 8 2 4 
f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl ac e b o f oll o w e d b y 
d ur v al u m a b
O S
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 / 1 5 5
T o e v al u at e o bj e cti v e t u m or r e s p o n s e i n p arti ci p a nt s tr e at e d wit h 
c C R T pl u s M 7 8 2 4 f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o 
f oll o w e d b y d ur v al u m a b
O bj e cti v e r e s p o n s e a c c or di n g t o R E CI S T 1. 1 
a s s e s s e d b y I n v e sti g at or
T o e v al u at e d ur ati o n of r e s p o n s e i n p arti ci p a nt s tr e at e d wit h 
c C R T pl u s M 7 8 2 4 f oll o w e d b y M 7 8 2 4 or c C R T pl u s pl a c e b o 
f oll o w e d b y d ur v al u m a b
D ur ati o n of r e s p o n s e a s s e s s e d fr o m C R or P R 
u ntil P D, d e at h, or l a st t u m or a s s e s s m e nt
T o c h ar a ct eri z e P K pr ofil e of M 7 8 2 4 pl u s c C R T a n d aft er c C R T 
P K pr ofil e of M 7 8 2 4 i n t er m s of C e oi a n d C tr o u g h
d uri n g tr e at m e nt a n d S af et y f oll o w - u p vi sit.
T o c h ar a ct eri z e t h e i m m u n o g e ni cit y of M 7 8 2 4 pl u s c C R T a n d 
aft er c C R T
I m m u n o g e ni cit y of M 7 8 2 4 a s m e a s ur e d b y A D A 
a s s a y s fr o m S cr e e ni n g t hr o u g h l a st S af et y 
F oll o w -u p vi sit.
A E = a d v er s e e v e nt, 
, A D A = a nti dr u g a nti b o d y, c C R T = c o n c o mit a nt c h e m or a di ati o n 
t h er a p y; Ce oi = c o n c e ntr ati o n i m m e di at el y at t h e e n d of i nf u si o n, C R = c o m pl et e r e s p o n s e, 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 / 1 5 5
, Ctr o u g h= c o n c e ntr ati o n i m m e di at el y b ef or e n e xt d o si n g;
 
 
 
, H R C T = hi g h r e s ol uti o n C T, I H C =im m u n o hi st o c h e mi str y, 
N S C L C -S A Q = N o n – S m all C ell L u n g C a n c er S y m pt o m A s s e s s m e nt Q u e sti o n n air e, O S = o v er all s ur vi v al, 
P D = pr o gr e s si v e di s e a s e,
 P F S = pr o gr e s si o n-fr e e s ur vi v al,
 
, 
 
, P K = p h ar m a c o ki n eti c s, P R = p arti al r e s p o n s e,
, R E CI S T 
1. 1 = R e s p o n s e E v al u ati o n Crit eri a i n S oli d T u m or s V er si o n 1. 1, T E A E =tr e at m e nt -e m er g e nt a d v er s e e v e nt, 
.
N ot e: a n al y si s of 
 e n d p oi nt s will b e c o nti n g e nt o n t h e o ut c o m e s of pri m ar y a n d s e c o n d ar y 
e n d p oi nt s.
4
S t u d y Desi g n
4. 1
O ver all Desi g n
T his is a gl o bal, m ultice nter, ra n d o mize d, d o u ble -bli n d, c o ntr olle d P hase II st u d y i n u nresecta ble 
Sta ge III N S C L C. T his st u d y  has 2 ar ms:  

c C R T pl us M 7 8 2 4 f oll o we d by M 7 8 2 4 ( Ar m 1)

c C R T pl us place b o f oll o we d b y d ur val u ma b ( Ar m 2)  
A sa m ple size of a p pr o xi matel y 1 6 0 ra n d o mize d partici pa nts (c o nsisti n g of 4 2 partici pa nts i n t he 
safety r u n-i n as well as a p pr o xi matel y 1 1 8 i n t he e x pa nsi o n p hase) is pla n ne d i n or der t o o bser ve 
7 0 P F S e ve nts at t he pri mar y a nalys is. 
D uri n g t he safety r u n-i n, t he first 4 2 partici pa nts ( 1 2 Ja pa nese a n d 3 0 n o n- Ja pa nese) will be 
ra n d o mize d i n 1: 1 rati o be t wee n Ar m 1 a n d Ar m 2. Ja pa nese is defi ne d b y  et h nicity a n d n ot b y  
c o u ntr y. Et h nicit y w ill be t he stratificati o n fact or d uri n g t he safety r u n -i n t o e ns ure a 1: 1 treat me nt 
ar m all ocati o n f or b ot h Ja pa nese a n d n o n- Ja pa nese partici pa nts . T he safety of M 7 8 2 4 
i n 
c o m bi nati o n wit h c C R T will be e val uate d i n t hese 2 s u b gr o u ps ( 1 2 Ja pa nese a n d 3 0 n o n- Ja pa nese) 
b y  ID M C se parately a n d i n parallel. P D -L 1  ex pressi o n i n t u m or cells at baseli ne will be deter mi ne d 
retr os pecti vely i n t hese partici pa nts.
I n de pe n de nt Data M o ni t ori n g C o m mittee (I D M C) will peri o dicall y  re vie w t he safet y data d uri n g 
t he safet y ru n -i n  as well as e x pa nsi o n part of t he st u d y. D uri n g t he safety r u n -i n, I DM C
will assess 
t he safety of t he c o m bi nati o n of c C R T a n d M 7 8 2 4 i n n o n- Ja pa nese partici pa nts a n d m a y als o 
deci de u p o n c o nti n u o us e nr oll me nt s u bse q ue nt t o t he safet y  ru n -i n base d o n pres pecifie d r ules i n 
t he I D M C c harter. I D M C will ma ke se parate assess me nt f or Ja pa nese partici pa nts a n d deter mi ne 
if a d diti o nal Ja pa nese partici pa nts ca n be e nr olle d i n t he e x pa nsi o n part of t he st u d y as part of t he 
a p pr o xi matel y 1 1 8 a d diti o nal partici pa nts.
Partici pa nts e nr olle d i n t he safety r u n -i n will c o nti n ue t o recei ve st u d y inter ve nti o n as per sc he d ule 
d uri n g t he safet y e val uati o n b y  ID M C.
Safet y  eval uati o n will i ncl u de b ut is n ot li mite d t o t he assess me nt of t he n u m bers of a d verse e ve nts 
lea di n g t o per ma ne nt disc o nti n uati o n of st u d y inter ve nti o n i n Ar m 1 a n d Ar m 2, j u d ge d b y  the 
I n vesti gat or a n d I D M C me m bers as relate d or n ot relate d t o t he st u d y dr u gs. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 / 1 5 5
A n a p pr o xi matel y 1 18 a d diti o nal partici pa nts will be ra n d o mize d i n 1: 1 rati o bet wee n Ar m 1 a n d 
Ar m 2 after t he safet y  of M 7 8 2 4 wit h C R T is cleare d b y ID M C. C he m ot hera p y  re gi me n a n d P D-
L 1 e x pressi o n i n t u m or cells ( < 1 % vers us ≥1 %) will be stratificati o n fact ors i n t he e x pa nsi o n part 
of t he st u d y. P D -L 1 e x pressi o n will be deter mi ne d pr os pecti vel y  b y the Ve nta na P D -L 1 ( S P 2 6 3) 
i n vesti gati o nal use o nl y (I U O) assa y i n ce ntral la b orat ories.
T he c he m ot hera p y re gi me ns all o we d are t he f oll o wi n g:

cis plati n/et o p osi de f or partici pa nts wit h s q ua m o us or n o ns q ua m o us Sta ge III N S C L C

car b o plati n/ paclita xel f or partici pa nts wit h s q ua m o us or n o ns q ua m o us Sta ge III N S C LC

cis plati n/ pe metre xe d f or partici pa nts wit h n o ns q ua m o us Sta ge III N S C L C 
C he m ot hera p y re gime n 
will 
be 
deci de d 
b y  the 
I nvesti gat or
pri or 
t o ra n d o mizati o n. 
I nte nsity- m o d ulate d ra diati o n t hera py (I M R T) will be use d i n t his st u d y as f urt her descri be d i n 
Secti o n  4. 1. 1. 2 .
T he d osi n g sc he d ule of st u d y  i nter ve nti o ns is as descri be d i n Ta ble 2.
Partici pa nts w h o e x perie nce t o xicities fr o m t he se lecte d c he m ot hera py r e gi me n (i.e., a na p h yl actic 
reacti o n t o paclita xel), will be all o we d t o s witc h t o t he ot her c he m ot hera p y re gi me ns if cli nicall y 
i n dicate d.
T his st u d y  i ncl u des: 

Scree ni n g peri o d of u p t o 2 8 d a y s pri or t o ra n d o mizati o n. M ost of t he e val uati o ns s h o ul d be 
perf or me d wit hi n 2 1 da ys pri or t o ra n d o mizati o n (see  Ta ble 1 f or details). 

c C R T-base d treat me nt is c o nsi dere d fr o m t he first d ose of ra diati o n t o t he last d ose of ra diati o n 
or c he m ot hera p y, w hic he ver occ urs last. c C R T ca n be e xte n de d u p t o 5 b usi ness da y s i n case 
of tec h nical a n d l o gistic iss ues. T he 5 b usi ness da y  peri o d ca n be e xten de d if partici pa nts re q uire 
wit h h ol di n g of t he st u d y inter ve nti o n d ue t o t o xicities. I n s uc h cases, treat me nt s h o ul d be 
a d mi nistere d as descri be d i n Secti o n  6. 1 0.  Disc ussi o n wit h Me dical M o nit or s h o ul d occ ur o n 
case b y case bas is.

St u d y  inter ve nti o n s h o ul d be disc o nti n ue d if t here is c o nfir me d P D d uri n g or at t he e n d of 
c C R T
u nless partici pa nt meets 
t he criteria f or treat me nt b e y o n d pr o gressi o n (see 
Secti o n 4. 1. 1 ).

E n d of c C R T visit m ust be perf or me d at D a y 5 7 ( + 5 da y s) e xce pt f or partici pa nts w h o di d n ot 
c o m plete c C R T. I n t his case, t he E n d of c C R T visit m ust occ ur wit hi n 2 wee ks fr o m last d ose 
of M 7 8 2 4 or place b o a n d partici pa nt will :

e nter f oll o w - u p or 

c o nti n ue M 7 8 2 4 i n Ar m 1 or start d ur val u ma b i n Ar m 2.

St u d y  inter ve nti o n
after c C R T u ntil u nacce pta ble t o xicit y, c o nfir me d P D
assesse d b y  
I n vesti gat or ( u nless partici pa nt meets t he criteria f or st u d y inter ve nti o n be y o n d pr o gressi o n) , or 
f or u p t o 2 6 d oses of M 7 8 2 4 or d ur val u ma b , w hic he ver occ urs first (see Secti o n 1. 3) . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 / 1 5 5

T he first d ose of M 7 8 2 4 or d ur val u ma b after c C R T m ust be a d mi nistere d 1 4 da y s fr o m t he 
pre vi o us a d mi nistrati o n of M 7 8 2 4 or place b o a n d n ot bef ore t u m or assess m e nt a n d e n d of 
cC R T visit. 

I n case c C R T is ter mi nate d earl y d ue t o t o xicit y a n d if cli nicall y in dicate d, partici pa nts i n 
Ar m 1 are all o we d t o c o nti n ue M 7 8 2 4
a n d p artici pa nts i n Ar m 2 are all o we d t o start 
d ur val u ma b . St u d y  inter ve nti o n s h o ul d be gi n 1 4 da y s fr o m t he last d ose of M 7 8 2 4 or place b o
a n d n ot bef ore t u m or assess me nt a n d e n d of cC R T visit has bee n perf or me d. 

St u d y  i nter ve nti o n s h o ul d be disc o nti n ue d if t here is c o nfir me d P D u nless partici pa nt meets 
t he criteria f or treat me nt be yo n d pr o gressi o n ( See Secti o n  4. 1. 1 )

Partici pa nts w h o e x perie nce A Es are all o we d t o s ki p u p t o 3 c o nsec uti ve d oses of M 7 8 2 4, 
place b o, or d ur val u ma b at a n y ti me d uri n g t he e ntire st u d y. I n case partici pa nts rec o ver fr o m 
A Es wit hi n t he all o we d ti me ( u p t o 3 d oses of st u d y M 7 8 2 4, place b o , or d ur val u ma b ) a n d are 
a ble t o resu me st u d y inter ve nti o n , t he y will n ot be wit h dra w n fr o m treat me nt. Treat me nt ma y 
be res u me d i n partici pa nts w h o ha ve e x perie nce d a n A E wit h a pr ol o n ge d d ose h ol d ( > 3 
c o nsec uti ve d oses) a n d i n t he o pi ni o n of t he I n vesti gat or wil l be nefit fr o m restarti n g treat me nt. 
S uc h cases m ust be disc usse d wit h t he Me dical M o nit or pri or t o res u mi n g treat me nt. See 
Secti o n  6. 9. 5 f or s pecific g ui da nce o n blee di n g a d verse e ve nts, f or w hic h d ose re d ucti o ns ma y 
be a p pr o priate .

Partici pa nts wit h ra pi d t u m or pr o gressi o n or wit h s y m pt o matic pr o gressi o n t hat re q uires ur ge nt 
me dical i nter ve nti o n (e. g., ce ntral ner v o us s yste m metastasis, res pirat or y fail ure d ue t o t u mor 
c o m pressi o n, s pi nal c or d c o m pressi o n) will n ot be eli gi ble t o c o nti n ue t o recei ve st u d y 
i nter ve nti o n u nless cli nicall y in dicate d a n d after disc ussi o n wit h t he Me dical M o nit or a n d t he 
S p o ns or Me dical Res p o nsi ble.

Partici pa nts w h o ha ve a d ose i nterr u pti o n f or a reas o n differe nt t ha n t o xicit y at a ny t i me d uri n g 
t he st u d y ma y res u me a n d recei ve u p t o 2 6 t otal d oses of M 7 8 2 4 or d ur val u ma b

L o n g -ter m f oll o w- u p 

Partici pa nts w h o e x perie nce P D a n d d o n ot c o nti n ue st u d y inter ve nti o n will e nter f oll o w- u p.

Partici pa nts w h o disc o nti n ue st u d y inter ve nti o n d ue t o reas o n ot her t ha n P D will e nter 
f oll o w- u p.

Partici pa nts w h o ac hie ve a n d mai ntai n disease c o ntr ol ( C R, P R, or S D) t hr o u g h t o t he e n d 
of t he 1 2 -m o nt h st u d y i nter ve nti o n after c C R T will e nter f oll o w - u p.

P artici pa nts w h o start s u bse q ue nt treat me nt s h o ul d be m o nit ore d f or res p o nse t o t hat 
treat me nt acc or di n g t o 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. T u m or 
sca ns s h o ul d be perf or me d f oll o wi n g l ocal cli nical practice f or m o nit ori n g disease stat us o n 
s u bse q ue nt li nes of t hera p y. T he st u d y tea m e nc o ura ges a n d re q uests sca ns t o be perf or me d 
e ver y 8 t o 1 2 wee ks, if feasi ble, i n a d diti o n t o a sca n wit hi n 2 8 d a y s pri or t o starti n g t he 
s u bse q ue nt treat me nt. T hese e val uati o ns s h o ul d be d oc u me nte d b y  t he I nvesti gat or i n t he 
e C R F. Best o verall res p o nse acc or di n g t o R E CI S T 1. 1 t o t he s u bse q ue nt treat me nt after 
pr o gressi ve disease s h o ul d als o be re p orte d. A partici pa nt’s pr o gressi o n ma y  in v ol ve t he 
f oll o wi n g: o bjecti ve ra di ol o gical or deat h d ue t o a d va ncin g disease. T his s h o ul d be 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 / 1 5 5
d oc u me nte d e ver y 8t o 1 2 wee ks u ntil i nitiati o n of t he ne xt s u bse q ue nt treat me nt, wit h dra wal 
of c o nse nt, or deat h.
4. 1. 1
St u d y I nter ve nti o n Be y o n d Pr o gressi o n
St u d y  i nter ve nti o n b e y o n d i nitial pr o gressi o n
Partici pa nts will recei ve M 7 8 2 4 or d ur val u ma b u ntil u nacce pta ble t o xicit y, c o nfir me d P D assesse d 
b y  I n vesti gat or, or f or u p t o 2 6 d oses of M 7 8 2 4 or d ur val u ma b , w hic he ver occ urs first (see Secti o n 
1. 3 ). M 7 8 2 4 or d ur val u ma b ma y  co nti n ue past t he i nitial deter mi nati o n of disease pr o gressi o n 
acc or di n g t o R E CIS T 1. 1 as l o n g as t he f oll o wi n g criteria are met:

I n vesti gat or-assesse d cli nical be ne fit, wit h o ut a n y ra pi d disease pr o gressi o n

N o ne w u nacce pta ble treat me nt or disease -relate d t o xicit y

T olera nce of st u d y i nter ve nti o ns

Sta ble E C O G P S

St u d y  inter ve nti o n b e y o n d pr o gressi o n will n ot dela y  an i m mi ne nt i nter ve nti o n t o pre ve nt 
seri o us c o m plicatio ns of disease pr o gressi o n (f or e xa m ple, ce ntral ner v o us s yste m metastases).
A ra di o gra p hic assess me nt s h o ul d be perf or me d prefera bl y wit hi n 8 wee ks ( b ut n o s o o ner t ha n 
4 wee ks) of ori gi nal P D, at t he ne xt sc he d ule d visit, t o deter mi ne w het her t here has be e n a decrease 
i n t he t u m or b ur de n, or c o nti n ue d P D. T he assess me nt of cli nical be nefit s h o ul d be bala nce d b y  
cli nical j u d g me nt as t o w het her t he partici pa nt is cli nicall y deteri orati n g a n d u nli kel y t o recei ve 
a n y be nefit fr o m c o nti n ue d treat me nt wit h M 7 8 2 4 or d ur val u ma b.
St u d y  i nter ve nti o n b e y o n d c o nfir me d pr o gressi o n
After c o nfir me d P D, if per I n vesti gat or’s assess me nt t he partici pa nt c o nti n ues t o ac hie ve cli nical 
be nefit b y  co nti n ui n g st u d y i nter ve nti o n, t he partici pa nt s h o ul d re mai n o n t he st u d y an d c o nt i n ue 
t o recei ve st u d y inter ve nti o n a n d m o nit ori n g acc or di n g t o t he Sc he d ule of Acti vities. T he decisi o n 
t o c o nti n ue st u d y inter ve nti o n be y o n d c o nfir me d P D s h o ul d be disc usse d wit h t he Me dical M o nit or 
a n d d oc u me nte d i n t he st u d y  rec or ds.
Partici pa nts w h o c o nti n ue be y o n d pr o gressi o n will be e val uate d f or f urt her t u m or res p o nse as per 
t he pr ot oc ol sc he d ule. St u d y  inter ve nti o n s h o ul d be disc o nti n ue d per ma ne ntl y  up o n d oc u me ntati o n 
of f urt her, u ne q ui v ocal, disease pr o gressi o n u nless t here are n o alter nati ve t hera pe utic o pti o ns a n d 
t he be nefit -ris k assess me nt is fa v ora ble i n c o ns ultati o n bet wee n t he I n vesti gat or a n d t he Me dical 
M o nit or. I n case of c o nti n uati o n of st u d y inter ve nti o n be y o n d P D, st u d y inter ve nti o n will be 
disc o nti n ue d o nce a n y ot her criteria f or wit h dra wal are met (see Secti o n  7. 1) .
C o nti n uati o n of st u d y  i nter ve nti o n after l ocal treat me nt of disease pr o gressi o n:
If disease pr o gressi o n is d ue t o brai n metastasis
or b o ne metastasis , partici pa nts ma y  co nti n ue 
st u d y inter ve nti o ns after t he l ocal treat me nt of t he brai n or b o ne lesi o ns (if cli nicall y in dicate d)
a n d disc ussi o n wit h t he Me dical M o nit or pr o vi de d t hat t he a b o ve criteria are met i n a d diti o n t o t he 
f oll o wi n g:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 / 1 5 5

T u m or assess me nt s h o wi n g disease pr o gressi o n has bee n perf or me d a n d was d oc u me nte d 
acc or di n g t o R E C I ST 1. 1. pri or t o t he pr oce d ure

If cli nically i n dicate d, b rai n metastases ha ve bee n treate d l ocall y a n d are cli nicall y sta ble f or at 
least 2 wee ks pri or t o c o nti n uati o n of st u d y i nter ve nti o ns

T here are n o o n g oi n g ne ur ol o gical s ym pt o ms t hat are relate d t o t he brai n l ocalizati o n of t he 
disease (se q uelae t hat are a c o nse q ue nce of t he treat me nt of t he brai n metastases are acce pta ble)

Partici pa nts m ust be eit her off ster oi ds or o n a sta ble or decreasi n g d ose of ≤ 1 0 m g d ail y 
pre d nis o ne ( or e q ui vale nt)  

If cli nicall y in dicate d, b o ne lesi o ns ha ve bee n treate d wit h palliati ve ra di ot hera py at least 
2 wee ks pri or t o c o nti n uati o n of st u d y  i nter ve nti o ns

Be nefit -ris k assess me nt t o c o nti n ue st u d y i nter ve nti o n is fa v ora ble u n der c o nsi derati o n of a n y 
alter nati ve treat me nt o pti o ns as assesse d b y t he I nvesti gat or .
4. 1. 1. 1 
P F S as t he Pri m ar y E n d p oi nt
T his is t he first st u d y eval uati n g t he safety a n d efficac y of c C R T pl us M 7 8 2 4 f oll o we d b y  treat me nt 
wit h M 7 8 2 4. T he pri mar y e n d p oi nt is P F S, w hic h ca n be c o nsi dere d as a pri mar y  en d p oi nt f or 
de m o nstrati o n of efficac y per t he F D A a n d E ur o pea n Me dici nes A ge nc y  (E M A) g ui da nce f or 
N S C L C.
P r o gressi o n-free sur vi val will be e val uate d i n t he f ull a nal ys is set i n t he st u d y. T he se q ue nce of 
a nal ys is is i n Secti o n  9. 4. 4 .
4. 1. 1. 2 
C he m ot her a p y Re gi me ns a n d R a di ot her a p y
Plati n u m -base d d o u blet c he m ot hera p y gi ve n c o nc urre ntl y wit h ra diati o n is t he bac k b o ne of t he 
treat me nt f or patie nts wit h u nresecta ble Sta ge III N S C L C (A u péri n 2 0 1 0 ).
St u dies s u g gesti n g s u peri or efficac y of o ne c he m ot hera p y re gi me n c o m pare d t o t he ot hers re mai n 
c o ntra dict or y a n d t here is n o c o nse ns us f or t he m ost fa v ora ble a n d o pti mal d o u blet. 
Cis plati n/et o p osi de a n d car b o plati n/ paclita xel are t he m ost 
c o m m o nl y use d plati n u m -base d 
d o u blet c he m ot hera p y re gi me ns acr oss se veral c o u ntries (Ste uer 2 0 1 7 ). I n a lar ge retr os pecti ve 
a nal ys is, t here were n o si g nifica nt differe nces i n efficac y, w het her c o m pari n g O R R, P F S, or O S. 
H o we ver, cis plati n-et o p osi de was ass ociate d wit h hi g her rates of a d verse e ve nts, s pecifically 
Gra de 3 na usea a n d/ or v o miti n g a n d he mat ol o gic t o xicities (Ste uer 2 0 1 7, Wa n g 2 0 1 2 ). 
Se veral cli nical st u dies ha ve s h o w n t hat pe metre xe d wit h 
cis plati n ca n be a d mi nistere d 
c o nc urre ntl y wit h t h oracic ra diati o n t hera py wit h o ut i ncreasi n g t he e x pecte d t o xicit y of t his 
c o m bi ne d treat me nt (Bra de 2 0 1 1, G o vi n da n 2 0 0 8, C h o y 2 0 1 5 ). Alt h o u g h t he P R O C L AI M st u d y 
di d n ot s h o w i m pr o ve d O S i n patie nts treate d wit h cis plati n/ pe metre xe d f oll o we d b y  co ns oli dati o n 
wit h pe metre xe d, c o m pare d t o cis plati n/et o p osi de f oll o we d b y c o ns oli dati o n wit h plati n u m- base d 
c he m ot hera p y,  the i nci de nce of p ossi ble treat me nt-relate d Gra de 3 t o 4 e ve nts, was si g nifica ntly 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 / 1 5 5
l o wer i n patie nts treate d wit h cis plati n/ pe metre xe d f oll o we d b y  pe metre xe d i n c o ns oli dati o n 
(Se na n 2 0 1 6 ). 
All t hre e re gi me ns are all o we d i n t his st u d y an d i n di vi d ual st u d y i nter ve nti o n selecti o n s h o ul d be 
ma de b y  the I n vesti gat or f or a gi ve n partici pa nt base d o n s pecific fact ors s uc h as a ge, perf or ma nce 
stat us a n d c o m or bi dities. T he e val uati o n a n d ris k ma na ge me nts are descri be d i n Secti o n 6. 1 0.
F or o ver 3 0 ye ars t he acce pte d d ose of ra di ot hera p y for u nresecta ble Sta ge III N S C L C has bee n 
6 0- 6 6 G y  an d a rece nt ra n d o mize d cli nical s t u d y de m o nstrate d t hat a hi g her d ose of 7 4 G y is n ot 
ass ociate d wit h i ncrease d cli nical be nefit c o m pare d t o t he sta n dar d d osi n g of 6 0 G y  an d is m ore 
t o xic (Bra dle y 2 0 1 5 ). I n t his st u d y t he t otal d ose of ra diati o n all owe d is 6 0 G y .
I M R T uses c o m ple x m o d ulate d ra diati o n bea ms t hat sc ul pt t he ra diati o n d ose t o precisel y  co nf or m 
t o c o m ple x ge o metric tar gets, w hic h creates s har per ra diati o n d ose gra die nts bet wee n t u m or a n d 
n or mal tiss ue. F or t hese reas o ns, I M R T ca n i m pr o ve ra diati o n c o vera ge of t u m ors a n d e n ha nce t he 
t hera pe utic rati o b y  spari n g critical a djace nt str uct ures (W u
2 0 0 4 ; C h u n 2 0 1 7 ). I n a sec o n dar y 
a nal ys is of lar ge pr os pecti ve st u d y ( R T O G 0 6 1 7), des pite si milar efficac y, IM R T was ass ociate d 
wit h a si g nifica nt re d ucti o n of Gra de 3 p ne u m o nitis c o m pare d t o 3 D -C R T (t hree-di me nsi o nal 
c o nf or mal e xter nal bea m ra diati o n t hera py) . M ore o ver, I M R T was s h o w n t o re d uce ra diati o n d oses 
deli vere d t o t he heart a n d preser ve d q ualit y  of life (C h u n 2 0 1 7 ; M o vsas
2 0 1 6 ). I n this st u d y the 
ra diati o n treat me nt will be deli vere d by I M R T.
4. 1. 1. 3 
D ur v al u m a b as C o m p ar at or
D ur val u ma b (I M FI N ZI® ) is a P D -L 1  bl oc ki n g a nti b o d y an d has bee n a p pr o ve d b y  FD A
a n d 
P M D A i n earl y 2 0 1 8 f or t he treat me nt of patie nts wit h u nresecta ble sta ge III N S C L C wit h disease 
c o ntr ol after c he m ot hera p y  a n d ra diati o n t hera p y re gar dless of P D -L 1 e x pressi o n .  
Rece ntl y , E M A gra nte d a p pro val f or d ur val u ma b
f or t he treat me nt of l ocall y ad va nce d, 
u nresecta ble N S C L C i n a d ults w h ose t u m ors e x press P D -L 1 o n ≥ 1 % of t u m or cells a n d w h ose 
disease has n ot pr o gresse d f oll o wi n g plati n u m -base d c he m ora diati o n t hera p y .
All c o mers Sta ge III N S C L C patie nts were e nr olle d i n P A CI FI C st u d y a n d c ollecti o n of t u m or 
tiss ue at Baseli ne or P D -L 1 e x pressi o n stat us were n ot re q uire d f or i ncl usi o n i n t he st u d y.
 
 
 
 
 
 
 
 
 
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 / 1 5 5
 
4. 1. 1. 4 
D o u ble Bli n d Desi g n
T his st u d y will use a d o u ble -bli n d desi g n t o f ull y assess t he safety a n d efficac y of M 7 8 2 4 wit h 
c C R T f oll o we d b y  M7 8 2 4 ( Ar m 1) c o m pare d t o c C R T pl us place b o f oll o we d b y  dur val u ma b 
( Ar m 2). C he m ot hera p y re gi me n will be deci de d b y  the I n vesti gat or pri or ra n d o mizati o n a n d 
t heref ore t he c he m othera p y  will n ot be bli n de d. See Secti o n 6. 1. 2 f or details.
4. 1. 1. 5 
Str atific ati o n
Partici pa nts e nr olle d i n t he safet y ru n- i n will 
be stratifie d f or et h nicit y (Ja pa nese a n d 
n o n- Ja pa nese) t o e ns ure a 1: 1 treat me nt ar m all ocati o n f or b ot h Ja pa nese a n d n o n- Ja pa nese 
partici pa nts . Ja pa nese partici pa nts are defi ne d by et h nicit y o nly a n d n ot b y c o u ntr y.
C he m ot hera p y re gi me n a n d P D -L 1 e x pressi o n i n t u m or cells ( < 1 % vers us ≥ 1 %) will be t he 
stratificati o n fact ors f or t he a p pr o xi matel y 11 8 a d diti o nal partici pa nts . C he m ot hera p y  re gi me n will 
be eit her cis plati n/et o p osi de, cis plati n/ pe metre xe d or car b o plati n/ paclita xel, a n d deci de d b y  the 
I n vesti gat or pri or t o ra n d o mizati o n. P D -L 1  ex pressi o n will be deter mi ne d pr os pecti vel y b y  the 
Ve nta na P D - L 1 ( S P 2 6 3) IU O assa y  i n ce ntral la b orat ories.
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
See Secti o n  2. 1.
4. 3
J ustific ati o n f or D ose
T he R P 2 D f or M 7 8 2 4 is 1 2 0 0 m g a d mi nistere d as a n I V i nf usi o n q 2 w i ncl u di n g c he m ora diati o n 
c o m bi nati o n st u d y. 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 P hase I 
St u d y  
 
a n d 
St u d y  
, 
i ncl u di n g 
safety/ t olera bilit y, 
p har mac o ki netics ( P K), a n d 
 s uc h as  
 tar get occ u pa nc y [ T O] i n P B M Cs 
a n d  
 tra p pi n g i n bl o o d, as well 
as efficac y in 2 L  
NS C L C c o h orts fr o m St u d y  
E M R 2 0 0 6 4 7 - 0 0 1. T he selecti o n of R P 2 D is als o s u p p orte d b y  po p ulati o n P K ( po p P K) a n d 
e x p os ure -res p o nse m o deli n g a n d si mulati o n a n d e val uati o n of p ote ntial o verla p pi n g t o xicities a n d 
P K i nteracti o ns i n M 7 8 2 4/c he m ora diati o n st u d y. Refer t o t he I B f or f urt her details. 
M 7 8 2 4 i n c o m bi nati o n wit h c C R T
Base d  
o n 
differe nt 
cleara nce 
mec ha nis ms  
f or 
c he m ot hera p y 
(cis plati n/et o p osi de , 
cis plati n/ pe metre xe d or car b o plati n/ paclita xel) vers us M 7 8 2 4 , a n d t he o bser ve d safet y pr ofile of 
M 7 8 2 4
m o n ot hera p y, P K i nteracti o ns or o verla p pi n g t o xicities of M 7 8 2 4
a n d c he m ot hera p y are 
c o nsi dere d u nli kel y , e xce pt f or a ne mia. Alt h o u g h ra di ot hera p y is e x pecte d t o i ncrease e x pressi o n 
of 
 i n t he t u m ors (see Secti o n 2. 1), c o ntri b uti o n of tar get-me diate d cleara nce 
mec ha nis ms t o t he c leara nce of M 7 8 2 4 is n ot e x pecte d at 1 2 0 0 m g q 2 w d ose re gi me n. I n a d diti o n, 
base d o n mec ha nis ms of acti o n of M 7 8 2 4 or C R T, t here are n o e x pectati o ns of e xa g gerate d 
i m m u ne res p o nse (e. g., c yt o ki ne release) i n M 7 8 2 4/ C R T c o m bi nati o n. T o date, c yt o ki ne data 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 / 1 5 5
a nal ys is i n partici pa nts of t he P hase I st u dy, s h o we d a tra nsie nt mil d effect of M 7 8 2 4 (at 1 2 0 0 m g 
q 2 w d ose) o n i nfla m mat or y cyt o ki nes i n bl o o d. T heref ore, n o a dj ust me nt i n t he d ose of 
cis plati n/et o p osi de, cis plati n/ pe metre xe d, car b o plati n/ paclita xel or M 7 8 2 4 is c o nsi dere d necessar y 
f or t his st u d y, wit h t he e xce pti o n of d ose re d ucti o ns f or blee di n g e ve nts (see bel o w). I nitial safety 
r u n-i n, as well as t he ris k ma na ge me nt 
f or c he m ot hera p y (i ncl u di n g d ose m o dificati o ns), 
ra di ot hera py, a n d M 7 8 2 4 is i n place t o ad dress p ote ntial ris ks of o verla p pi n g t o xicities bet wee n 
M 7 8 2 4 a n d c C R T. H o we ver, i n t he cases of blee di n g e ve nts, a d ose m o dificati o n mi g ht be 
re q uire d. A 6 0 0 m g  Q2 W M 7 8 2 4
d ose is rec o m me n de d f or t he d ose re d ucti o n i n a partici pa nt wit h 
a blee di n g e ve nt, si nce t his d ose is e x pecte d t o re d uce t he ris k of blee di n g ( base d o n a rece nt 
e x p os ure -safety a nal ys is f or blee di n g A Es c o n d ucte d wit h preli mi nar y  data fr o m P hase I a n d P hase 
II st u dies), w hile mai ntai ni n g p har mac ol o gicall y  rele va nt e x p os ures ass ociate d wi t h P D - L-
1 i n hi biti o n. F or f urt her details o n d ose m o dificati o ns f or ma na ge me nt of blee di n g see Secti o n 
6. 9. 5 a n d Secti o n 6. 3. 2 .
I n s u m mar y, efficac y, safet y/t olera bilit y, P K a n d   
data fr o m t he P hase I st u dies, t he e val uati o n 
of p ote ntial o verla p pi n g t o xicities a n d P K i nteracti o ns of t he M 7 8 2 4/c C R T c o m bi nati on a n d 
pla n ne d miti gati o n meas ures i n t he st u d y (i ncl u di n g d ose i nterr u pti o ns a n d re d ucti o ns), as well as 
preli mi nar y  po p P K a n d e x p os ure-res p o nse m o deli n g of t he data s u p p ort e val uati o n of M 7 8 2 4 at 
1 2 0 0 m g q 2 w wit h c C R T i n t he pr o p ose d gl o bal st u d y in a d va n ce d ca ncer patie nts wit h 
u nresecta ble Sta ge III N S C L C .
4. 4
E n d of St u d y Defi niti o n
T he e n d of t he st u d y is defi ne d as eit her t he date of pri mar y a nal ys is or w he n all partici pa nts ha ve 
c o m plete d mai nte na nce t hera p y an d safety f oll o w- u p (see Secti o n 1. 3 ), w hic he ver occ urs later. 
T he a nal ys is o n t he pri mar y  en d p oi nt P F S is perf or me d w he n 7 0 P F S e ve nts per I nvesti gat or are 
reac he d a n d after a mi ni m u m f oll o w-u p of 1 5 m o nt hs after ra n d o mizati o n of t he last partici pa nt.
After sti p ulate d E n d of S t u d y, s ur vi val f oll o w-u p ma y  c o nti n ue u ntil last partici pa nt has die d or at 
discreti o n of t he S p o ns or.
T he S p o ns or m a y  ter mi nate t he st u d y at a n y ti me o nce access t o M 7 8 2 4 or d ur val u ma b f or 
partici pa nts still be nefitti n g is pr o visi o ne d via a r oll o ver st u d y, e x pa n de d access, mar kete d pr o d uct 
or a n ot her mec ha nis m of access as a p pr o priate. See als o  A p pe n di x 2 f or st u d y a n d site cl os ure.
A partici pa nt has c o m plete d t he st u d y if he/s he has c o m plete d all st u d y parts, i ncl u di n g t he last 
visit or t he last sc he d ule d pr oce d ure s h o w n i n  Ta ble 4.
5
St u d y P o p ul ati o n
T he criteria i n Secti o n  5. 1 (Incl usi o n Criteria) a n d 5. 2 ( E xcl usi o n Criteria) are desi g ne d t o e nr oll 
o nl y  partici pa nts, w h o are a p pr o priate f or t he st u d y; t here b y, e ns uri n g t he st u d y fulfills its 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 / 1 5 5
o bjecti ves. All rele va nt me dical a n d n o n me dical c o n diti o ns s h o ul d be ta ke n i nt o c o nsi derati o n 
w he n deci di n g w het her a partici pa nt is s uita ble f or t his st u d y .
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi o n a n d e xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Bef or e perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne me dical care, 
t he I nvesti gat or will c o nfir m t hat t he partici pa nt or t he partici pa nt’s le gal re prese ntati ve (w here 
all o we d b y  local la ws a n d re g ulati o ns) has pr o vi de d writte n i nf or me d c o nse nt, as i n dicate d i n 
A p pe n di x 2 .
5. 1
I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y:
A ge
1. Are ≥ 1 8 ye ars of a ge at t he ti me of si g ni n g t he i nf or me d c o nse nt. I n Ja pa n, if a patie nt 
is < 2 0 years, t he writte n i nf or me d c o nse nt fr o m his/ her pare nt or g uar dia n will be re q uire d 
i n a d diti o n t o t he patie nt’s writte n c o nse nt.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2.
Partici pa nts m ust ha ve meas u ra ble or n o n- meas ura ble b ut e val ua ble disease assesse d b y  the 
I n vesti gat or. Partici pa nts m ust ha ve hist ol o gicall y d oc u me nte d N S C L C w h o prese nt wit h 
Sta ge III l ocall y a d va nce d, u nresecta ble disease (I nter nati o nal Ass ociati o n f or t he St u d y of 
L u n g Ca ncer Sta gi n g Ma n ual i n T h oracic O nc ol o g y  [I A SL C Sta gi n g Ma n ual i n T h oracic 
O nc ol o g y ], v 8).
3.
A vaila bilit y  of t u m or material ( < 6 m o nt hs ol d) a de q uate f or bi o mar ker a nal ys is is 
ma n dat or y  for all partici pa nts a n d ce ntral la b orat or y co nfir mati o n is re q uire d. F or 
partic i pa nts e nr olle d i n t he safety r u n-i n, P D -L 1 e x pressi o n will be teste d retr os pecti vely 
b y  a ce ntral la b orat or y. F or partici pa nts e nr olle d i n t he e x pa nsi o n part of t he st u d y, P D-L 1  
e x pressi o n m ust 
be teste d b y  the ce ntral la b orat or y an d res ults a vaila ble bef ore 
ra n d o mizati o n. O nl y  res ults fr o m t he ce ntral la b orat or y testi n g will 
be use d f or 
ra n d o mizati o n a n d if P D -L 1  stat us is n o n- e val ua ble, t he partici pa nt is n ot eli gi ble f or t his 
st u d y. T u m or sa m ples o btai ne d b y  en d osc o pic bi o psies, c ore nee dle bi o psies, e x cisi o nal 
bi o psies, p u nc h bi o psies, a n d s ur gical s peci me ns t hat are < 6 m o nt hs ol d a n d a de q uate f or 
bi o mar ker a nal ys is are acce pta ble. Bi o psies o btai ne d b y  fi ne nee dle as pirati o n are n ot 
acce pta ble.
4.
Partici pa nts wit h t u m or har b ori n g a n E G F R se nsitizi n g (acti vati n g) m utati o n, 
A L K 
tra nsl ocati o n, R O S - 1 rearra n ge me nt are eli gi ble. T hese tests are n ot re q uire d f or e nr oll me nt 
i n t he st u d y.
5.
Partici pa nts wit h o n g oi n g p ost -o bstr ucti ve p ne u m o nia d ue t o t he t u m or are eli gi ble .
6.
If a ple ural eff usi o n is prese nt, t he f oll o wi n g criteria m ust be met t o e xcl u de mali g na nt 
i n v ol ve me nt (i nc ura ble T 4 disease):
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 / 1 5 5
a. 
W he n 
ple ural fl ui d is visi ble o n b ot h t he C T sca n a n d o n a c hest x- ra y, a 
t h orace ntesis is re q uire d t o c o nfir m t hat t he ple ural fl ui d is c yt ol o gicall y ne gati ve.
b. 
Partici pa nts wit h e x u dati ve ple ural eff usi o ns are e xcl u de d, re gar dless of c yt ol o g y .
c. 
Partici pa nts wit h eff usi o ns t hat are mi ni mal, i.e., are t o o s mall t o safely ta p are 
eli gi ble.
7.
Partici pa nts m ust be at least 3 wee ks fr o m pri or t h orac ot o m y (if perf or me d) .
8.
Partici p a nts m ust ha ve a de q uate p ul m o nar y f u ncti o n defi ne d as a f orce d e x pirat or y v ol u me 
i n 1 sec o n d ( F E V1) ≥ 1. 2 liters or ≥ 5 0 % of pre dicte d n or mal v ol u me meas ure d wit hi n 
3 wee ks pri or t o ra n d o mizati o n. If partici pa nts d o n ot meet t he a b o ve criteria, treat me nt 
w it h i n hale d ster oi ds a n d br o nc h o dilat ors ca n be i nitiate d if cli nicall y i n dicate d a n d 
eli gi bilit y ca n be reassesse d after 1-2 wee ks.
9.
E C O G perf or ma nce stat us of 0 t o 1 at Scree ni n g a n d o n t he da y  of first d ose.
1 0. Life e x pecta nc y  ≥1 2 wee ks .
1 1. Ha ve a de q uate or ga n f u ncti o n as i n dicate d b y  t he f oll o wi n g la b orat or y val ues
a.
A de q uate 
he mat ol o gical f u ncti o n defi ne d b y  abs ol ute ne utr o p hil c o u nt ( A N C) 
≥1. 5 × 1 0 9/ L, platelet c o u nt ≥1 0 0 × 1 0 9/ L, a n d he m o gl o bi n ≥9 g/ d L .
b.
A de q uate he patic f u ncti o n defi ne d b y  a total bil ir u bi n le vel ≤ 1. 5 × u p per li mit of n or mal 
( U L N), a n as partate a mi n otra nsferase ( A S T) le vel ≤ 
3. 0 × U L N, 
a n ala ni ne 
a mi n otra nsferase ( A L T) le vel ≤ 3. 0 × U L N a n d al kali ne p h os p hatase ≤ 2. 5 U L N .  
c.
A de q uate re nal f u ncti o n defi ne d b y  creati ni ne ≤ 1. 5 × U L N or calc ulate d creati ni ne 
cleara nce ( Cr Cl) ≥ 5 0 m L / mi n f or partici pa nt wit h Cr > 1. 5 × U L N ( G F R ca n als o be 
use d). N ote: Cr Cl s h o ul d be calc ulate d per i nstit uti o nal sta n dar d. If n o l ocal g ui deli ne is 
a vaila ble, Cr Cl s h o ul d be calc ulate d usi n g t he C oc kcr oft -Ga ul t Met h o d:
Cr Cl = (( 1 4 0 -a ge) * wei g ht ( k g) * ( 0. 8 5 f or fe males o nl y )) / ( 7 2 * creati ni ne)
d.
A de q uate c oa g ulati o n f u ncti o n defi ne d as i nter nati o nal n or malize d rati o (I N R) or 
pr ot hr o m bi n ti me ( P T) ≤1. 5 × U L N u nless t he partici pa nt is recei vi n g a ntic oa g ula nt 
t hera p y a n d acti vate d partial t hr o m b o plasti n ti me (a P T T) ≤1. 5 × U L N u nless t he 
partici pa nt is recei vi n g a ntic oa g ula nt t hera p y.
Se x
1 2. C o ntrace pti ve use b y  males or fe males will be c o nsiste nt wit h l ocal re g ulati o ns o n 
c o ntrace pti o n met h o ds f or t h ose partici pati n g i n cli nical st u dies.
a. Male Partici pa nts:
C o ntrace pti ve meas ures s h o ul d be c o nti n ue d as per g ui da nce s pecifie d i n la beli n g 
d oc u me nt f or a p pr o ve d c he m ot hera pies. If n ot s pecifie d, c o nti n ue meas ures si milar t o 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 / 1 5 5
i n vesti gati o nal a ge nt i.e a gree t o the f oll o wi n g d uri n g t he st u d y i nter ve nti o n peri o d a n d 
f or at least 6 m o nt hs after t he last d ose of st u dy i nter ve nti o n

Refrai n fr o m d o nati n g s per m .
P L U S, eit her:

A bstai n fr o m i nterc o urse wit h a W O C B P.
O R

Use a male c o n d o m: W he n ha vi n g se x ual i nterc o urse wit h a W O C B P, w h o is n ot
c urre ntl y pre g na nt, a n d a d vise her t o use a hi g hl y  effecti ve c o ntrace pti ve met h o d 
wit h a fail ure rate of < 1 % per year, as descri be d i n A p pe n di x 3,  si nce a c o n d o m 
ma y  brea k or lea k.
b. Fe male Partici pa nts:
 
Are n ot pre g na nt or breastfee di n g, a n d at least o ne of t he f oll o wi n g c o n diti o ns 
a p plies:
 
N ot a W O C B P .
O R
 
If a W O C B P, use a hi g hl y effecti ve c o ntrace pti ve met h o d (i.e., wit h a fail ure 
rate of < 1 % per y ear), prefera bly wit h l o w user de pe n de nc y, as descri be d i n
A p pe n di x 3 f or t he f oll o wi n g ti me peri o ds:

Bef ore t he first d ose of t he st u d y  i nter ve nti o n(s), if usi n g h or m o nal 
c o ntrace pti o n: 
 
Has c o m plete d at least o ne 4- wee k c y cle of a n oral c o ntrace pti o n pill 
a n d eit her ha d or has be g u n her me nses
O R
 
Has use d a de p ot c o ntrace pti ve or e xte n de d -c ycle oral c o ntrace pti ve 
f or least 2 8 da ys a n d has a d oc u me nte d ne gati ve pre g na nc y test 
usi n g a hi g hl y se nsiti ve assa y.
 
D uri n g t he i nter ve nti o n peri o d.
 
C o ntrace pti ve meas ures s h o ul d be c o nti n ue d as per g ui da nce s pecifie d i n 
la beli n g d oc u me nt f or a p pr o ve d c he m ot hera pies. If n ot s pecifie d, 
c o nti n ue meas ures si milar t o i n vesti gati o nal a ge nt i.e., after t he st u d y 
i nter ve nti o n peri o d (i.e., after t he last d ose of st u d y i nter ve nti o n is 
a d mi nistere d) f or at least 4 m o nt hs after t he last d ose of st u d y  
i nter ve nti o n a n d a gree n ot t o d o nate e g gs ( o va, o oc ytes) f or re pr o d ucti o n 
d uri n g t his peri o d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 / 1 5 5
 
Ha ve a ne gati ve pre g na nc y  test, as re q uire d b y l ocal re g ulati o ns, o n 
W 1 D 1 bef ore t he first d ose of st u d y i nter ve nti o n . 
 
A d diti o nal re q uire me nts f or pre g na nc y  testi n g d uri n g a n d after st u d y inter ve nti o n 
are i n S o A.
 
T he I n vesti gat or re vie ws t he me dical hist or y, me nstr ual hist or y, a n d rece nt se x ual 
acti vit y to decrease t he ris k f or i ncl usi o n of a fe male wit h a n earl y u n detecte d 
pre g na nc y .
I nf or me d C o nse nt
1 3. Ca n gi ve si g ne d i nf or me d c o nse nt , as i n dicate d i n A p pe n di x 2 , w hic h i ncl u des c o m plia nce 
wit h t he re q uire me nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt f or m (I C F) a n d t his 
pr ot oc ol.
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y  if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1. 
Mi xe d s mall cell wit h n o n- s mall cell l u n g ca ncer hist ol o g y .
2.
Greater t ha n mi ni mal, e x u dati ve, or c y t ol o gically p ositi ve ple ural eff usi o ns .
3.
Rece nt maj or s ur ger y wit hi n 4 wee ks pri or t o e ntr y int o t he st u d y (e xcl u di n g t he place me nt 
of vasc ular access) t hat w o ul d pre ve nt a d mi nistrati o n of st u d y  dr u g.
4.
Acti ve or pri or d oc u me nte d i nfla m mat or y  b o wel disease (e. g., Cr o h n’s disease, ulcerati ve 
c olitis).
5.
Hist or y  of or ga n tra ns pla nt t hat re q uires t hera pe utic i m m u n os u p pressi o n.
6.
Si g nifica nt ac ute or c hr o nic i nfecti o ns i ncl u di n g, a m o n g ot hers:
a. K n o w n hist or y  of p ositi ve test f or h u ma n i m m u n o deficie nc y vir us ( HI V) or k n o w n 
ac q uire d i m m u n o deficie nc y sy n dr o me (testi n g at Scree ni n g is n ot re q uire d). If a n 
I n vesti gat or has a str o n g s us pici o n of HI V i nfecti o n wit h o ut k n o w n hist or y  for a 
partici pa nt i n Scree ni n g, h o we ver partici pa nt ref uses testi n g, disc uss wit h Me dical 
M o nit or t o assess eli gi bilit y. ( N ote: HI V testi n g is n ot ma n date d f or st u d y incl usi o n; 
h o we ver, if it is perf or me d at a n y p oi nt i n Scree ni n g or w hile o n st u d y, a site m ust 
c o nse nt t he partici pa nt f or HI V testi n g a s per l ocal sta n dar d g ui da nce.)
b. Acti ve he patitis B vir us ( H B V) or he patitis C vir us ( H C V) i nfecti o n ( H B V s urface 
a nti ge n p ositi ve a n d H B V c ore a nti b o d y p ositi ve wit h refle x t o p ositi ve H B V D N A, or 
H B V c ore a nti b o d y positi ve al o ne wit h refle x t o p ositi ve H B V D N A, or p ositi ve H C V 
a nti b o d y wit h refle x t o p ositi ve H C V R N A) at Baseli ne. Disc uss wit h t he Me dical 
M o nit or 
if hist or y  of H B V or H C V i nfecti o n is k n o w n. If me dicall y  in dicate d, 
partici pa nts i nfecte d wit h H B V m ust be treate d a n d o n a sta ble d ose of a nti virals (e. g, 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 / 1 5 5
e nteca vir, te n of o vir, or la mi v u di ne; a def o vir or i nterfer o n are n ot all o we d) at st u d y entr y  
a n d wit h pla n ne d m o nit ori n g a n d ma na ge me nt acc or di n g t o a p pr o priate la beli n g 
g ui da nce. Partici pa nts o n acti ve H C V t hera p y at st u d y entr y  must be o n a sta ble d ose 
wit h o ut d oc u me nte d cli nicall y si g nifica nt i m paire d li ver f u ncti o n test or he mat ol o gic 
a b n or malities ( m ust meet criteria a b o ve) a n d wit h pla n ne d m o nit ori n g a n d ma na ge me nt 
acc or di n g t o a p pr o priate la beli n g g ui da nce. H B V a n d/ or H C V viral titers m ust
be 
m o nit ore d acc or di n g t o S o A i n t hese partici pa nts.
c. Partici pa nts wit h acti ve t u berc ul osis ( hist or y of e x p os ure or hist or y of p ositi ve 
t u berc ul osis test; pl us prese nce of cli nical s ym pt o ms, 
p h y sical, or ra di o gra p hic 
fi n di n gs).
7.
a. U nc o ntr olle d i nterc urre nt ill ness i ncl u di n g, b ut n ot li mite d t o, s ym pt o matic c o n gesti ve 
heart fail ure, u nc o ntr olle d h y perte nsi o n, u nsta ble a n gi na pect oris, car diac arr h yt h mia, 
acti ve pe ptic ulcer disease or gastritis, acti ve blee di n g diat heses, acti ve u veitis or 
ps y c hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce wit h st u d y re q uire me nts or 
c o m pr o mise t he a bilit y of t he patie nt t o gi ve writte n i nf or me d c o nse nt.
7.
b. Pa rtici pa nts wit h hist or y of blee di n g diat hesis or rece nt maj or blee di n g e ve nts c o nsi dere d 
b y  t he I n vestigat or as hi g h ris k f or i n vesti gati o nal dr u g treat me nt s uc h as partici pa nts wit h 
cli nicall y rele va nt blee di n g e ve nts of he m o ptys is Gra de ≥ 2 wit hi n t he last m o nt h are als o 
e xcl u de d.
8.
C hr o nic O bstr ucti ve P ul m o nar y Disease e xacer bati o n or ot her res pirat or y ill ness re q uiri n g 
h os pitalizati o n or precl u di n g st u d y t hera p y wit hi n 3 0 da y s bef ore ra n d o mizati o n.
9.
K n o w n cli nical hist or y  of t u berc ul osis, l u n g sarc oi d osis a n d Interstitial L u n g Diseases .
1 0. Hist or y  of a n ot her pri mar y  mali g na nc y wit hi n 3 years pri or t o startin g st u d y dr u g, e xce pt 
f or a de q uatel y treate d basal or s q ua m o us cell carci n o ma of t he s ki n, a de q uatel y treate d 
carci n o ma i n sit u, e. g., ca ncer of t he cer vi x i n sit u, s u perficial bla d der ca ncer. Hist or y  of 
ot her l ocalize d mali g na ncies treate d wit h c urati ve i nte nt nee ds t o be disc usse d wit h t he 
Me dical M o nit or.
1 1. U nc o ntr olle d ne ur o pat h y Gra de 2 or greater re gar dless of ca use .
1 2. Si g nifica nt heari n g l oss a n d partici pa nts u n willi n g t o acce pt p ote ntial f or f urt her heari n g 
l oss (I nvesti gat or s h o ul d c o nsi der treati n g t he partici pa nt wit h car b o plati n/ paclita xel) .
Pri or/ C o nc o mit a nt T her a p y
1 3. A n y  pri or s yste mic c yt ot o xic c he m ot hera p y f or t heir N S C L C or a n y a nti b o d y or dr u g 
tar geti n g T- cell c ore g ulat or y pr otei ns (i m m u ne c hec k p oi nts) s uc h as a nti-P D -( L) 1, or 
a nti-C T L A- 4 a nti b o d y.
1 4. C urre nt or pri or use of i m m u n os u p pressi ve me dicati o n wit hi n 2 8 da ys bef ore t he first d ose 
of st u d y dr u g, wit h t he e xce pti o ns of i ntra nasal a n d i n hale d c ortic oster oi ds or s yste mic 
c ortic oster oi ds at p h y si ol o gical d oses, w hic h are n ot t o e xcee d 1 0 m g/ da y of pre d nis o ne, 
or a n e q ui vale nt c ortic oster oi d. S y ste mic ster oi d a d mi nistrati o n re q uire d t o ma na ge 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 8 / 1 5 5
t o xicities arisi n g fr o m ra diati o n t hera py d eli vere d as part of t he c C R T f or l ocall y a d va nce d 
N S C L C is all o we d.
1 5. Acti ve a ut oi m m u ne disease t hat has re q uire d s yste mic treat me nt i n past 1 ye ar (i.e., wit h 
use of disease -m o dif y i n g a ge nts, c ortic oster oi ds, or i m m u n os u p pressi ve dr u gs), O R is 
recei vi n g s yste mic ster oi d t hera p y < 3 d a ys pri or t o t he first d ose of st u d y inter ve nti o n or 
recei vi n g a n y ot her f or m of
i m m u n os u p pressi ve me dicati o n. 
Partici pa nts re q uiri n g 
h or m o ne re place me nt wit h c ortic oster oi ds are eli gi ble if t he ster oi ds are a d mi nistere d o nl y 
f or t he p ur p ose of h or m o nal re place me nt a n d at l o w d oses (t ypicall y ≤ 1 0 m g  of pre d nis o ne 
or e q ui vale nt per da y). E q ui vale nt h y dr oc ortis o ne d oses are als o per mitte d if a d mi nistere d 
as a re place me nt t hera py. C ortic oster oi d use o n st u d y as a pre me dicati o n f or I V c o ntrast 
aller gies/reacti o ns (relate d t o sca ns) is all o we d a n d m ust be d oc u me nte d. T his m ust be 
disc usse d wit h Me dical M o nit ors f or cli nical i n dicati o ns i n w hic h partici pa nts ma y re q uire 
a hi g her d ose. Acti ve a ut oi m m u ne disease t hat mi g ht deteri orate w he n recei vi n g a n 
i m m u n osti m ulat or y age nt. Partici pa nts wit h dia betes T y pe I, vitili g o, al o pecia, ps oriasis, 
h y p o - or h y pert h yr oi d disease n ot re q uiri n g i m m u n os u p pressi ve treat me nt are eli gi ble. 
C o ns ult Me dical M o nit or f or ot her a ut oi m m u ne diseases.
1 6. Recei pt of li ve atte n uate d vacci nati o n wit hi n 3 0 da y s of recei vi n g st u d y dr u g.
1 7. Use of a pr o hi bite d c o nc o mita nt dr u g, as defi ne d i n Secti o n 6. 5. 2 wit hi n 4 wee ks 
ra n d o mizati o n.
1 8. K n o w n se vere h y perse nsiti vit y  (Gra de ≥ 3 Nati o nal Ca ncer I nstit ute [ N CI] C o m m o n 
Ter mi n ol o g y  Criteria f or A d verse E ve nts [ C T C A E] v 5. 0) t o st u d y inter ve nti o ns or an y  
c o m p o ne nts i n t heir f or m ulati o ns, or u nc o ntr olle d ast h ma (i.e., 3 or m ore feat ures of 
partiall y  c o ntr olle d ast h ma).
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
1 9. Partici pati o n i n a n ot her cli nical st u d y wit h a n i n vesti gati o nal pr o d uct wit hi n t he last 
4 wee k s.
2 0. C o nc urre nt 
e nr olme nt 
i n a n ot her cli nical st u d y, u nless it is a n o bser vati o nal 
( n o n-i nter ve nti o nal) cli nical st u d y or t he f oll o w-u p peri o d of a n i nter ve nti o nal st u d y .
Di a g n ostic Assess me nts
2 1. ≥1 0 % wei g ht l oss wit hi n t he past m o nt h .
2 2. Fe male patie nts w h o 
are
pre g na nt, breast- fee di n g or male 
or fe male patie nts of 
re pr o d ucti ve p ote ntial w h o are n ot e m pl oyi n g a n effecti ve met h o d of birt h c o ntr ol.
Ot her E xcl usi o ns
2 3. A n y  co n diti o n t hat, i n t he o pi ni o n of the I n vesti gat or, w o ul d i nterfere wit h e val uati o n of 
t he st u d y dr u g or i nter pretati o n of partici pa nt safet y or st u d y res ults.
2 4. Pri or ra di ot hera p y if deli vere d i n a dj u va nt/ ne o -a dj u va nt re gi me n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 / 1 5 5
5. 3
Lifest yle C o nsi der ati o ns
N ot A p plica ble .
5. 4
Scree n F ail ures
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his stu d y  (scree n fail ure) m a y  be 
rescree ne d. 
Rescree ne d partici pa nts will be assi g ne d a ne w partici pa nt n u m ber. I n sit uati o ns w he n a partici pa nt 
has bee n scree n-faile d, t he site s h o ul d c o ntact t he Me dical 
M o nit or 
t o disc uss w het her t he 
partici pa nt ma y  be rescree ne d.
6
St u d y I nter ve nti o n(s)
St u d y  inter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), place b o, or me dical 
de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  partici pa nt per t he st u d y pr ot oc ol.
6. 1
St u d y I nter ve nti o n(s) A d mi nistr ati o n
Preferre d se q ue nce of st u d y inter ve nti o n d uri n g cC R T is M 7 8 2 4 or place b o a d mi nistere d first 
f oll o we d b y  2-h o ur i n-h o use safet y mo nit ori n g f or t he first 2 d oses pri or t o c he m ot hera p y w he n 
a d mi nistere d o n t he sa me visit.
W he n t he ra di ot hera py is deli vere d at a se parate l ocati o n, l o gistic c o nsi derati o ns m a y  res ult i n 
ra di ot hera py bei n g deli vere d pri or t o t he a d mi nistrati o n of M 7 8 2 4 or place b o. If ra di ot hera py is 
a d mi nistere d first, M 7 8 2 4 or place b o m ust be f oll o we d wit h 2- h o ur i n-h o use safet y mo nit ori n g 
bef o re a d mi nistrati o n of c he m ot hera p y. R T s h o ul d be deli vere d after c he m ot hera p y w he n 
a d mi nistere d o n t he sa me visit .
After t he first 2 i nf usi o ns of M 7 8 2 4 or place b o , partici pa nts s h o ul d be m o nit ore d f or 1 h o ur bef ore 
a d mi nistrati o n of c he m ot hera p y o n t he sa me da y . If n o I R Rs are o bser ve d d uri n g c C R T t he 
ma n date d p ost i nf usi o n o bser vati o n ti me is n o l o n ger re q uire d f or t he treat me nt after t he e n d of 
cC R T.
M 7 8 2 4,
place b o a n d d ur val u ma b will be a d mi nistere d i n a bli n de d ma n ner
(see 
Secti o n 6. 3. 2 ). F or i nf or mati o n re gar di n g M 7 8 2 4, place b o, a n d d ur val u ma b refer t o  Ta ble 7.  
Refer t o eac h c he m ot hera p y age nt S m P C or pac ka ge i nsert f or m ore i nf or mati o n. De pe n di n g o n 
t he l ocal re g ulati o ns, c he m ot hera p y age nt(s) m a y  be eit her s o urce d fr o m a l ocal h os p ital p har mac y 
or s u p plie d b y  the S p o ns or ( or desi g ne d ser vice pr o vi der) a n d will be pac ka ge d, la bele d, a n d 
distri b ute d f or t his cli nical st u d y  acc or di n g t o l ocal re q uire me nts .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 / 1 5 5
T a ble 7
A d mi nistr ati o n of M 7 8 2 4, P l ace b o, or D ur v al u m a b
St u d y  I nt er v e nti o n 
N a m e:
M 7 8 2 4
( M S B 0 0 1 1 3 5 9 C)
M 7 8 2 4 ( M S B 0 0 1 1 3 5 9 C) 
Pl a c e b o
D ur v al u m a b
D o s e F or m ul ati o n:
St eril e c o n c e ntr at e s ol uti o n 
f or i nf u si o n
St eril e c o n c e ntr at e s ol uti o n 
f or i nf u si o n. T h e c o m p o siti o n 
of t h e pl a c e b o i s i d e nti c al t o 
t h e c o m p o siti o n of M 7 8 2 4 
dr u g pr o d u ct, e x c e pt f or t h e 
pr e s e n c e of M 7 8 2 4
Cl e ar t o o p al e s c e nt, 
c ol orl e s s t o sli g ht y ell o w 
s ol uti o n
U nit D o s e 
Str e n gt h( s)/
D o s a g e L e v el( s):
1 0 m g/ m L i n si n gl e -u s e 
gl a s s vi al s
pl a c e b o s ol uti o n i n a si n gl e -
u s e gl a s s vi al s
 
5 0 0 m g/ 1 0 m L 
( 5 0 m g/ m L) i n a 
si n gl e - d o s e vi al 
 
1 2 0 m g/ 2. 4 m L
( 5 0 m g/ m L) i n a 
si n gl e - d o s e vi al 
R o ut e of 
A d mi ni str ati o n:
I ntr a v e n o u s i nf u si o n
I ntr a v e n o u s i nf u si o n  
I ntr a v e n o u s i nf u si o n
D o si n g 
I n str u cti o n s:
1 2 0 0 m g o v er 1 h o ur 
(- 1 0 mi n ut e s/ + 2 0 mi n ut e s; 
i. e., o v er 5 0 t o 8 0 mi n ut e s) 
q 2 w.
S e e S e cti o n  6. 8 f or s p e ci al 
pr e c a uti o n s a n d S e cti o n 6. 9
f or m a n a g e m e nt of A E SI
O v er 1 h o ur 
(-1 0 mi n ut e s/ + 2 0 mi n ut e s; 
i. e., o v er 5 0 t o 8 0 mi n ut e s) 
q 2 w.
1 0 m g/ K g o v er 1 h o ur 
(- 1 0 mi n ut e s/ + 2 0 mi n ut e s; 
i. e., o v er 5 0 t o 8 0 mi n ut e s) 
q 2 w.
S o ur ci n g
Pr o vi d e d c e ntr all y b y t h e 
S p o n s or
Pr o vi d e d c e ntr all y b y t h e 
S p o n s or
C o m m er ci al pr o d u ct, 
pr o vi d e d c e ntr all y b y t h e 
S p o n s or , sit e p h ar m a c y, or 
b y t h e d e si g n at e d t hir d p art y 
s u p pli er
P a c k a gi n g a n d 
L a b eli n g
E a c h vi al will b e p a c k a g e d 
a n d l a b el e d p er all 
a p pli c a bl e r e g ul at or y 
r e q uir e m e nt s a n d G o o d 
M a n uf a ct uri n g Pr a cti c e 
G ui d eli n e s.
E a c h vi al will b e p a c k a g e d 
a n d l a b el e d p er all a p pli c a bl e 
r e g ul at or y r e q uir e m e nt s a n d 
G o o d M a n uf a ct uri n g Pr a cti c e 
G ui d eli n e s.
C o m m er ci al pr o d u ct:
R ef er t o d ur v al u m a b S m P C 
or P a c k a g e I n s ert f or m or e 
i nf or m ati o n.
I n v e sti g ati o n al M e di ci n al 
Pr o d u ct:
E a c h vi al will b e p a c k a g e d 
a n d l a b el e d p er all 
a p pli c a bl e r e g ul at or y 
r e q uir e m e nt s a n d G o o d 
M a n uf a ct uri n g Pr a cti c e 
G ui d eli n e s.
Pre me dicati o n f or M 7 8 2 4 or place b o is o pti o nal. I n or der t o miti gate i nf usi o n-relate d reacti o ns, 
pre me dicati o n wit h a n a nti hista mi ne a n d wit h paraceta m ol (aceta mi n o p he n) (f or e xa m ple, 2 5 t o 
5 0 m g di p he n h y d ra mi ne a n d 5 0 0 t o 6 5 0 m g  paraceta m ol [aceta mi n o p he n] I V or oral e q ui vale nt
d ose ) a p pr o xi matel y 30 t o 6 0 mi n utes pri or t o M 7 8 2 4
or place b o s h o ul d be a d mi nistere d at t he 
discreti o n of t he I n vesti gat or. Ster oi d s as pre me dicati o n f or M 7 8 2 4, place b o , or d ur val u ma b are 
n ot per mitte d (ster oi ds as pre me dicati o n are all o we d pri or t o c he m ot hera p y, see Secti o n  6. 5. 2 ). 
T here are n o d ose re d ucti o ns f or M 7 8 2 4, place b o, or d ur val u ma b , wit h t he e xce pti o n of d ose 
re d ucti o ns as a res ult of blee di n g e ve nts (see Secti o n 6. 9. 5 ). D osi n g m o dificati o ns ( i.e., c ha n ges 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 1 / 1 5 5
i n i nf usi o n rate) a n d d ose dela y s are descri be d i n Secti o n 6. 6 t o as part of preca uti o ns a n d ris k 
ma na ge me nt. 
D ose 
re d ucti o ns a n d m o dificati o ns 
f or c he m ot hera p y a n d ra di ot hera p y are all o we d (see 
Secti o n 6. 6 ).
6. 1. 1
R a di ati o n
F ull details of pr ot oc ol re q uire me nts f or ra di ot hera p y ca n be f o u n d i n t he Ra di ot hera p y G ui deli nes 
f or t his st u d y pr o vi de d t o t he sites. Pri or t o i nitiati n g R T, t he ra diati o n treat me nt pla n s h o ul d be 
s u b mitte d b y  the I n vesti gat or t o t he ra diati o n o nc ol o g y  ve n d or f or re vie w. A brief s u m mar y of 
re q uire me nts f oll o ws.
Patie nts will 
be treate d wit h 
p h ot o ns t o a prescri pti o n d ose of 6 0 G y  in 3 0 fracti o ns 
( 2 G y /fracti o n). Treat me nt s h o ul d be deli vere d 5 da ys a wee k ( Da y 1 -5, eac h wee k) d uri n g c C R T
as per pr ot oc ol. T he r a diati o n treat me nt pla n m ust be s u b mitte d t o t he ra di ot hera py v e n d or as s o o n 
as it is a p pr o ve d b y t he site. I deally, t he pla n will be s u b mitte d bef ore t he start of treat me nt b ut n o 
later t ha n 7 da y s f oll o wi n g t he i nitiatio n of treat me nt. All st u d y inter ve nti o ns m ust be a d mi nistere d 
o n Wee k 1, Da y 1. It is preferre d t hat ra diati o n is a d mi nistere d after c he m ot hera p y on t he sa me 
da y  of t he sc he d ule d visit . (see Secti o n  1. 3 f or a d diti o nal details ). Ra di ot hera p y si m ulati o n m ust 
c o nsist of creati o n of s o me f or m of i m m o bilizati o n de vice (e. g., al p ha-cra dle, vac u u m ba d, etc.), 
a n d ac q uisiti o n of a pla n ni n g C T. IV c o ntrast s h o ul d be use d, u nless t here is a dia g n ostic C T wit h 
c o ntrast t hat ca n be c o -re gistere d t o t he si m ulati o n C T, or t here is a me dical c o ntrai n dicati o n t o 
c o ntrast. If a vaila ble, t he P E T/ C T s h o ul d be c o-re gistere d as well. A d diti o nall y , s o me f or m of b o t h 
( 1) m oti o n assess me nt (e. g., 4 D -C T, fl u or osc o p y) a n d ( 2) m oti o n ma na ge me nt (e. g., a b d o mi nal 
c o m pressi o n, gati n g, etc.) is re q uire d. 
Deli neati o n of tar gets a n d or ga ns at ris k will f oll o w sta n dar d I C R U 6 2 g ui deli nes wit h m ore 
s pecific details i n t he Ra diot hera p y G ui deli nes . Fi nal tar get v ol u mes will be re prese ntati ve of t he 
m oti o n ma na ge me nt strate g y selecte d. T he use of I M R T a n d me ga v olta ge p h ot o ns f or ra di ot hera py 
treat me nt pla n ni n g is re q uire d. C o m plia nce criteria f or tar get c o vera ge a n d or ga n at ris k d ose will 
be defi ne d i n t he Ra di ot hera p y G ui deli nes .
D ail y use of i ma ge-g ui da nce f or treat me nt deli ver y  is rec o m me n de d t o mi ni mize t he re q uire me nts 
f or P T V e x pa nsi o ns, w hic h ma y incl u de, b ut is n ot li mite d t o o n- b oar d p ortal i ma gi n g, c o ne -bea m 
C T, or ort h o g o nal k V/ M V i ma gi n g.
6. 1. 2
C he m ot her a p y
I n vesti gat ors ca n select t he c he m ot hera p y re gi me n fr o m t he f oll o wi n g 3 sta n dar d o pti o ns
acc or di n g t o N C C N g ui deli nes:
Cis plati n ( 5 0 m g/ m2)/ Et o p osi de ( 5 0 m g/ m2)
Cis plati n/ Et o p osi de ma y  be s o urce d fr o m t he l ocal p har mac y w here all o we d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 / 1 5 5
Cis plati n is a d mi nistere d at a d ose of 5 0 m g / m2 i ntra ve n o usly o ver 6 0 mi n utes or acc or di n g t o 
l ocal sta n dar ds o n Da y s 1, 8, 2 9, 3 6 d uri n g c C R T. Cis plati n s h o ul d n ot be e m pl o ye d i n partici pa nts 
wit h re nal or heari n g i m pair me nt. Ca uti o ns m ust be o bser ve d i n t he case of na usea, v o miti n g, a n d 
de h y drati o n.
Et o p osi de is a d mi nistere d at a d ose of 5 0 m g/ m 2 i ntra ve n o usly o ver a mi ni m u m of 3 0 mi n utes u p 
t o 6 0 mi n utes, or acc or di n g t o l ocal sta n dar ds, dail y  o n Da ys 1- 5, 2 9- 3 3 d uri n g c C R T.
Sta n dar d pre me dicati o n c o nsisti n g of a n H 2
bl oc ker, a ntie metics, de xa met has o ne ( oral or 
i ntra ve n o us) s h o ul d be a d mi nistere d acc or di n g t o l ocal g ui deli nes. A de q uate h y drati o n pre - a n d 
p ost -treat me nt i n partici pa nts recei vi n g cis plati n/et o p osi de m ust be e ns ure d acc or di n g t o t he l ocal 
practice a n d re p orte d i n t he e C R F. 
Car b o plati n ( A U C 2)/ Paclita xel ( 4 5 m g/ m2)
Car b o plati n/ Paclita xel ma y  be s o urce d fr o m t he l ocal p har mac y w here all o we d. 
Car b o plati n is a d mi nistere d i ntra ve n o usl y base d o n A U C 2 o ver 3 0 mi n utes or acc or di n g t o l ocal 
sta n dar ds o n D a y 1, Da y 8, Da y 15, D a y 22, D a y 29, D a y 36, a n d D a y 43 d uri n g c C R T. Car b o plati n 
will be gi ve n wit h sta n dar d a ntie metics after t he paclita xel is a d mi nistere d. 
Paclita xel is a d mi nistere d i ntra ve n o usl y  at a d ose of 4 5 m g/ m2 o ver 6 0 mi n utes o n Da y  1, D a y 8, 
Da y  1 5, Da y 2 2, Da y 2 9, Da y 3 6, a n d Da y 4 3 d uri n g c C R T. Sta n dar d pre me dicati o n c o nsisti n g of 
di p he n h y dra mi ne 2 5 -5 0 m g, a n H 2 bl oc ker, a n d de xa met has o ne ( oral or I V is acce pta ble) s h o ul d 
be a d mi nistere d at least 3 0 mi n utes pri or t o paclita xel or acc or di n g t o l ocal sta n dar ds, a n d re p orte d 
i n t he e C R F.
Cis plati n ( 7 5 m g/ m2)/ Pe metre xe d ( 5 0 0 m g/ m2)
Cis plati n/ Pe metre xe d ma y  be s o urce d fr o m t he l ocal p har mac y w here all o we d.
Cis plati n is a d mi nistere d at a d ose of 7 5 m g / m2 i ntra ve n ousl y o ver 6 0 mi n utes or acc or di n g t o 
l ocal sta n dar ds o n Da ys 1, 2 2, a n d 4 3 d uri n g c C R T. Cis plati n s h o ul d n ot be e m pl o ye d i n 
partici pa nts wit h re nal or heari n g i m pair me nt. Ca uti o ns m ust be o bser ve d i n t he case of na usea, 
v o miti n g, a n d de h y drati o n.
Pe metre xe d is a d mi nistere d after cis plati n at a d ose of 5 0 0 m g/ m 2 i ntra ve n o usl y over 1 0 mi n utes 
or acc or di n g t o l ocal sta n dar ds o n Da y s 1, 2 2, a n d 4 3 d uri n g c C R T.
Partici pa nts treate d wit h t his c he m ot hera p y re gi me n will als o recei ve ma n dat or y s u p ple me ntati o n 
wit h f olic aci d a n d vita mi n B 1 2. F olic aci d a d mi nistere d at d ose 3 5 0-1 0 0 0 μ g oral a d mi nistrati o n 
dail y  f or at least 5 d a ys m ust be ta ke n d uri n g t he 7- da y  peri o d prece di n g t he first d ose of 
pe metre xe d a n d c o nti n ui n g t hr o u g h o ut st u d y inter ve nti o n a n d f or 2 1 da y s after t he last d ose of 
pe metre xe d.
Vita mi n B 1 2 will be a d mi nistere d at 1 0 0 0 μ g i ntra m usc ular i njecti o n o nce d uri n g t he wee k 
prece di n g t he first d ose of pe metre xe d, a n d at t he e n d of c C R T .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 / 1 5 5
6. 2
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y
T he I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is res p o nsi ble 
f or st u d y inter ve nti o n acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce 
(i.e., recei pt, 
rec o nciliati o n, a n d fi nal dis p ositi o n rec ords).

U p o n recei pt of t he st u d y inter ve nti o n(s), t he I nvesti 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 a n d a ny discre pa ncies are re p orte d 
a n d res ol ve d bef ore use. Als o, t he res p o nsi ble pers o n will c hec k f or acc urate deli ver y . F urt her 
g ui da nce a n d i nf or mati o n f or st u d y inter ve nti o n acc o u nta bilit y are pr o vi de d i n t he O perati o ns 
Ma n ual.

O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y inter ve nti o n(s) a n d o nl y  aut h orize d 
site staff m a y  su p pl y or a d mi nister it. All st u d y i nter ve nti o n(s) m ust be st ore d i n a sec ure, 
e n vir o n me ntall y-c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area , i n acc or da nce wit h t he 
la bele d st ora ge c o n diti o ns, a n d 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.

Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u nta bilit y for ms s o t hat acc urate rec or ds 
will be a vaila ble f or verificati o n at e ac h m o nit ori n g visit.

St u d y  i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:

C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge.

T he i n ve nt or y  pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site.

T he d ose(s) eac h partici pa nt use d d uri n g t he st u d y.

T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y  u n use d st u d y i nter ve nti o n(s).

Dates, q ua ntities, batc h n u m bers, c o ntai ner n u m bers, e x pir y dates, f or m ulati o n (f or st u d y 
i nter ve nti o ns pre pare d at t he site), a n d t he partici pa nt n u m bers.

T he I n vesti gat or site will mai ntai n rec or ds, w hic h a de q uately d oc u me nts t hat partici pa nts were 
pr o vi de d t he d oses s pecifie d i n t his pr ot oc ol, a n d all st u d y i nter ve nti o n(s) pr o vi de d were f ully 
rec o ncile d.

U n use d st u d y inter ve nti o n(s) m ust n ot be discar de d or use d f or a n y p ur p ose ot her t ha n t he 
prese nt st u d y. N o st u d y i nter ve nti o n t hat is dis pense d t o a partici pa nt ma y  be redis pe nse d t o a 
differe nt partici pa nt.

A St u d y  M o nit or will peri o dicall y c ollect t he st ud y i nter ve nti o n(s) acc o u nta bilit y  f or ms.

F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y i nter ve nti o n(s) are 
pr o vi de d i n t he P har mac y Ma n ual .
6. 2. 1
M 7 8 2 4
M 7 8 2 4 dr u g pr o d uct s h o ul d be st ore d i n a refri gerat or 
 u ntil use. M 7 82 4 m ust n ot be 
fr oze n a n d s h o ul d be st ore d i n t he ori gi nal pac ka gi n g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 4 / 1 5 5
A d diti o nal i nstr ucti o ns f or t he pre parati o n, ha n dli n g, st ora ge, a n d dis p osal of M 7 8 2 4 will be 
pr o vi de d i n t he P har mac y Ma n ual.
6. 2. 2
Pl ace b o
Place b o s h o ul d be st ore d i n a refri gerat or ( 
 u ntil use. T he c o m p ositi o n of t he place b o 
is i de ntical t o t he c o m p ositi o n of M 7 8 2 4 dr u g pr o d uct (a sterile, clear c o nce ntrate f or s ol uti o n f or 
i nf usi o n), e xce pt f or t he prese nce of M 7 8 2 4 . Place b o m ust n ot be fr oze n a n d s h o ul d be st ore d i n 
t he ori gi nal pac ka gi n g. 
A d diti o nal i nstr ucti o ns f or t he pre parati o n, ha n dli n g, st ora ge, a n d dis p osal of place b o will be 
pr o vi de d i n t he P har mac y Ma n ual.
6. 2. 3
D ur v al u m a b
D ur val u ma b is a clear t o o palesce nt, c olorless t o sli g ht yell o w c o nce ntrate f or s ol uti o n f or i nf usi o n 
pr o vi de d i n a si n gle d ose vial. D ur val u ma b dr u g pr o d uct s h o ul d be st ore d i n a refri gerat or ( 
 
. If n ot use d i m me diatel y after dil uti o n, c he mical a n d p h ysical i n-use sta bilit y  of d ur val uma b 
has bee n de m o nstrate d f or n o m ore t ha n 2 4 h o urs at   
 or 4 h o urs at r o o m te m perat ure u p 
t o 2 5° C fr o m t he ti me of vial p u nct ure t o t he start of a d mi nistrati o n. D ur val u ma b m ust n ot be 
fr oze n a n d s h o ul d be st ore d i n t he ori gi nal pac ka ge i n or der to pr otect fr o m li g ht.
A d diti o nal i nstr ucti o ns f or t he pre parati o n, ha n dli n g, st ora ge, a n d dis p osal of d ur val u ma b will be 
pr o vi de d i n t he P har mac y Ma n ual .
6. 2. 4
C he m ot her a p y a ge nts
C he m ot hera p y a ge nts m ust be st ore d acc or di n g t o t he P har mac y  Ma n ual.
A d diti o nal i nstr ucti o ns f or t he pre parati o n, ha n dli n g, st ora ge, a n d dis p osal of c he m ot hera p y 
a ge nt(s) will be pr o vi de d i n t he P har mac y  Ma n ual.
6. 3
Me as ures t o Mi ni mize Bi as: St u d y I nter ve nti o n Assi g n me nt 
a n d Bli n di n g
6. 3. 1
St u d y I nter ve nti o n Assi g n me nt
P artici pa nts will be ra nd o ml y  assi g ne d t o st u d y inter ve nti o n i n a 1: 1 rati o t o mi ni mize t he bias d ue 
t o c o nf o u n di n g fact ors . T he ra n d o mizati o n will be stratifie d b y  et h nicit y d uri n g t he safet y r u n -i n.
I n vesti gat or selecte d c he m ot hera p y re gi me n a n d P D -L 1  ex pressi o n i n t u m or cells ( < 1 % vers us 
≥1 %) will be stratificati o n fact ors i n t he e x pa nsi o n p hase. O nce a partici pa nt me ets t he eli gi bilit y 
criteria, a n d is e nr olle d, t he partici pa nt will be ra n d o ml y assi g ne d t o a u ni q ue ra n d o mizati o n 
n u m ber t ha t is ass ociate d wit h t he st u d y i nter ve nti o n assi g n me nt per t he ra n d o mizati o n sc he d ule.
Partici pa nt i de ntifiers will c o m prise 1 7 di gits, t he first 1 0 di gits re prese nti n g t he st u d y nu m ber, t he 
f oll o wi n g 3 di gits re prese nti n g t he site n u m ber, a n d t he last 4 d i gits re prese nti n g t he partici pa nt 
n u m ber, w hic h is all ocate d se q ue ntiall y starti n g wit h 0 0 0 1.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 / 1 5 5
After c o nfir mati o n of partici pa nt’s eli gi bilit y an d at t he last practical m o me nt pri or t o st u d y 
i nter ve nti o n a d mi nistrati o n, partici pa nts will be ce ntrall y  all ocate d t o eit her Ar m 1 or Ar m 2 i n a 
1: 1 rati o usi n g a n I nteracti ve We b 
Res p o nse S y ste m (IW R S) 
a n d per a c o m p uter-ge nerate d 
ra n d o mizati o n list.
T he I WR S will be use d t o assi g n u ni q ue partici pa nt n u m bers, all ocate partici pa nts t o st u d y 
i nter ve nti o n gr o u p at the ra n d o mizati o n visit, a n d st u d y i nter ve nti o n t o partici pa nts at eac h st u d y 
i nter ve nti o n visit.
Bef ore t he st u d y is i nitiate d, t he l o g i n i nf or mati o n a n d directi o ns f or t he I W R S will be pr o vi de d 
t o eac h site. T he site will c o ntact t he I WR S pri or t o starti n g st u d y i nter ve nti o n a d mi nistrati o n f or 
eac h partici pa nt.
6. 3. 2
Bli n di n g
Bli n di n g Met h o d
T his is a d o u ble -bli n d st u d y , t h us the partici pa nts a n d all of t he I n vesti gat or or S p o ns or a n d C R O 
staff w h o are i n v ol ve d i n t he treat me nt or cli nical e val uati o n of t he partici pa nts will be bli n de d t o 
st u d y i nter ve nti o n all ocati o n. As t he I MP pac ka gi n g a n d la beli n g is n ot bli n de d, a n u n bli n de d 
st u d y site p har macist is nee de d t o pre pare M 7 8 2 4 or place b o or d ur val u ma b f or a partici pa nt as 
s pecifie d b y  the ra n d o mizati o n sc he me ( o nl y t he u n bli n de d
p har macist will 
k n o w t he 
ra n d o mizati o n/treat me nt all ocati o n details). 
T o e ns ure t he bli n di n g of t he st u d y, u n bli n de d p har macists will be gi ve n s pecific i nstr ucti o ns i n 
t he P har mac y  Ma n ual f or st u d y inter ve nti o n pre parati o n a n d ha n d o ver t o a bli n de d st u d y staff 
me m ber w h o will a d mi nister t he st u d y inter ve nti o n. U n bli n de d p har macists will n ote if t he d o u ble -
bli n d c o n diti o ns ha ve bee n c o m pr o mise d or t he bli n d br o ke n. 
T o e ns ure pr o per st u d y i nter ve nti o n a d mi nistrati o n, I nvesti gat or or st u d y st uff m ust c o m m u nicate 
t o t he u n bli n de d p har macist w he n partici pa nt has c o m plete d c C R T a n d will recei ve M 7 8 2 4 or 
d ur val u ma b. S p o ns or will u n derta ke meas ures t o preser ve t he bli n d of t he st u d y by mas ki n g t he 
i de ntit y of t he st u d y inter ve nti o n(s) na mel y  M7 8 2 4, place b o , a n d d ur val u ma b. Details t o be 
pr o vi de d i n t he P har mac y Ma n ual.
T he I D M C will be pr o vi de d wit h u n bli n de d data t o perf or m o n g oi n g safet y a nal ys es.
T he S p o ns or st u d y tea m is u n bli n de d at t he ti me of t he P F S pri mar y  anal ysis ( data c ut -off w he n 
7 0 P F S e ve nts reac he d a n d a mi ni m u m f oll o w- u p of 1 5 m o nt hs after ra n d o mizati o n of t he last 
partici pa nt has bee n reac he d ), w hile t he I n vesti gat or a n d partici pa nts re mai n bli n d e d u ntil E n d of 
S t u d y.
U n bli n di n g Cli nic al St u dies f or S a m ple A n al ysis of S peci al D a t a
T he bi oa nal yt ical m o nit ors a n d a nal yt ical la b orat or y for meas ure me nt of M 7 8 2 4 c o nce ntrati o ns 
will be u n bli n de d si nce o btai ni n g t he res ult re veals t he st u d y  i nter ve nti o n ar m f or t he partici pa nt. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 / 1 5 5
M 7 8 2 4 c o nce ntrati o n i nf or mati o n t hat m a y u n bli n d t he st u d y will n ot be re p orte d t o st u d y sites or 
bli n de d pers o n nel u ntil t he st u d y  has bee n u n bli n de d.
It is pla n ne d t hat t he bi oa nal yst m a y ha ve access t o t he ra n d o mizati o n list t o fa cilitate a nal ysis of 
t he P K/ a nti dr u g a nti b o d y (A D A ) sa m ples (i.e., t o a v oi d t he u n necessar y  anal y sis of place b o 
sa m ples). H o we ver, t he bi oa nal y st will n ot s hare t he ra n d o mizati o n details t o pre ve nt t he st u d y 
tea m fr o m bei n g u n bli n de d pre mat urel y.
P h ar m acist U n bli n di n g
A n u n bli n de d p har macist is re q uire d t o pre pare a n d ha n dle st u d y i nter ve nti o n(s) t o mai ntai n st u d y 
bli n d.
If t he I n vesti gat or deci des a re d ucti o n i n bli n de d treat me nt is nee de d t o ma na ge t o xicit y per 
Secti o n 6. 9. 5 ( M 7 8 2 4/ place b o i n c C R T treat me nt peri o d, M 7 8 2 4/ d ur val u ma b 
i n mai nte na nce 
treat me nt peri o d), he/s he s h o ul d rec or d it o n t he e C R F. T he u n bli n de d p har macist will:

I n t he c C R T treat me nt peri o d: Pre pare a re d uce d d ose of M 7 8 2 4
or place b o.

I n t he mai nte na nce treat me nt peri o d: Pre pare a re d uce d d ose of M 7 8 2 4 
f or partici pa nts 
recei vi n g M 7 8 2 4, O R pre pare t he us ual d ose of d ur val u ma b.

T he act ual d ose s h o ul d be rec or de d via I WR S b y  t he u n bli n de d p har macist.
Re gar dless of t he d ose, t he i nf usi o n ba g v ol u me s h o ul d be 2 5 0 m L .
6. 3. 3
E mer ge nc y U n bli n di n g
I n a n e mer ge nc y, t he I n vesti gat or is s olely res p o nsi ble f or deter mi ni n g if u n bli n di n g of a 
partici pa nt’s st u d y inter ve nti o n assi g n me nt is warra nte d. Partici pa nt safety m ust al wa ys be t he first 
c o nsi derati o n i n t his decisi o n. If t he I n vesti gat or deci des t hat u n bli n di n g is warra nte d, t he 
I n vesti gat or s h o ul d ma ke e ver y eff ort t o c o ntact t he S p o ns or pri or t o t he u n bli n di n g, u nless t his 
c o ul d dela y e mer ge nc y treat me nt. T he S p o ns or m ust be n otifie d wit hi n 2 4 h o urs after u n bli n di n g.
T he I n vesti gat or m ust pr o vi de t he S p o ns or t he reas o n f or u n bli n di n g wit h o ut re veali n g t he st u d y 
i nter ve nti o n, e xce pt t o t he desi g nate d dr u g safet y re prese ntati ve via t he E mer ge nc y  Un bli n di n g 
N otificati o n F or m. T he date of a n d reas o n f or u n bli n di n g m ust be rec or de d i n t he s o urce d oc u me nts 
a n d C R F.
C o ntact i nf or mati o n f or u n bli n di n g i n a n e mer ge nc y is gi ve n o n t he partici pa nt 
e mer ge nc y car d pr o vi de d t o eac h partici pa nt, as n ote d i n A p pe n di x 2 . If a d ose re d ucti o n is 
warra nte d, refer t o Secti o n 6. 3. 2 . If e mer ge nc y un bli n di n g is re q uire d, t he partici pa nt ca n c o nti n ue 
st u d y treat me nt u nless t here are ot her circ u msta nces t hat re q uire partici pa nt disc o nti n uati o n.
T he S p o ns or’s dr u g safet y de part me nt will s u b mit a n y Sus pecte d U ne x pecte d Seri o us A d verse 
Reacti o ns ( S U S A R) re p orts t o re g ulat or y aut h orities a n d et hics c o m mittees wit h
u n bli n de d 
i nf or mati o n, per a p plica ble re g ulati o ns. O nl y bli n de d i nf or mati o n will be pr o vi de d t o t he st u d y 
tea m.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 / 1 5 5
6. 4
St u d y I nter ve nti o n C o m pli a nce
I n t his st u d y, partici pa nt s will recei ve st u d y inter ve nti o n at t he i n vesti gati o nal site. Well -trai ne d 
me dical staff will m o nit or a n d perf or m t he st u d y i nter ve nti o n a d mi nistrati o n. T he i nf or mati o n of 
eac h st u d y inter ve nti o n a d mi nistrati o n i ncl u di n g t he date, ti me, a n d d o se f or c he m ot hera p y a n d 
R T a n d if patie nt c o mplete d i nf usi o n f or M 7 8 2 4, d ur val u ma b, a n d place b o a n d will be rec or de d 
o n t he e C R F. T he I n vesti gat or will ma ke s ure t hat t he i nf or mati o n e ntere d i nt o t he e C R F re gar di n g 
dr u g a d mi nistrati o n is acc urate f or eac h partici pa nt . D ose re d ucti o ns f or bli n de d trea t me nt d ue t o 
blee di n g e ve nts (see Secti o n 6. 9. 5 ) s h o ul d be rec or de d i n t he e C R F, t he act ual d ose s h o ul d be 
rec or de d b y  I WR S t o mai ntai n bli n di n g (see Secti o n 6. 3. 2 ). A n y reas o n f or n o nc o m plia nce s h o ul d 
be d oc u me nte d.
N o n -c o m plia nce w o ul d be defi ne d as a partici pa nt missi n g > 1 i nf usi o n of st u d y inter ve nti o n f or 
n o n- me dical reas o ns.
6. 5
C o nc o mit a nt T her a p y
Rec or d i n t he eC R F all c o nc o mita nt t hera pies (e. g., me dici nes or n o n dr u g i nter ve nti o ns) use d fr o m 
t he ti me t he partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di n g a n y 
c ha n ges. F or prescri pti o n a n d o ver -t he-c o u nter me dici nes, vita mi ns, a n d her bal s u p ple me nts, 
rec or d t he na me, reas o n f or use, dates a d mi nistere d, a n d d osi n g i nf or mati o n.
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t hera p y.
6. 5. 1
Per mitte d Me dici nes
T he o nl y  per mitte d me dicati o ns are t he f oll o wi n g:
 
A n y  me dicati o ns ( ot her t ha n t h ose e xcl u de d b y  the e xcl usi o n criteria or t he pr o hi bite d 
me dici nes) t hat are c o nsi dere d necessar y  for t he partici pa nts’ welfare a n d will n ot i nterfere 
wit h t he st u d y  dr u g ma y be gi ve n at t he I n vesti gat or’s discreti o n
 
Ot her dr u gs t o be use d f or pr o p h y la xis, treat me nt of h y perse nsiti vit y  reacti o ns, a n d treat me nt 
of fe ver or fl u -li ke sy m pt o ms are de scri be d i n Secti o n 6. 5. 1 as part of preca uti o ns
 
Sec o n dar y  pr o p hyl a xis wit h G- C S F is all o we d if cli nicall y i n dicate d per I n vesti gat or
assess me nt. I n vesti gat ors s h o ul d be a ware t hat G- C S F use i n patie nts wit h N S C L C treate d 
wit h C R T is ass ociate d wit h increase d i nci de nce of se vere t hr o m b oc yt o pe nia a n d a ne mia, 
b ut n ot ass ociate d wit h a n i ncrease d ris k of es o p ha gitis or p ne u m o nitis a n d n ot detri me ntal 
f or P F S a n d O S as re p orte d o n t he C O N V E R T P hase III st u d y (G o mes, E L C C a n d A n nals 
O nc ol o g y , 2 0 1 7)
 
Er y t hr o p oieti n is all o we d if cli nicall y i n dicate d
 
Ster oi ds are all o we d as pre me dicati o n f or c he m ot hera p y. De pe n di n g o n t he c he m ot hera p y 
re gi me n, all partici pa nts s h o ul d recei ve t he a p pr o priate c ortic oster oi d pre me dicati o n as per 
t he l ocal practice a n d a p pr o ve d la bel. A c ortic oster oi d -s pari n g a p pr oac h f or a ntie metic 
pr o p h y la xis s h o ul d be preferre d a n d e val uate d o n a case b y case a n d c he m ot hera p y re gi me n 
bas is (Nati o nal C o m pre he nsi ve Ca ncer Net w or k [ N C C N] Cli nical Practice G ui deli nes i n 
O nc ol o g y [ N C C N G ui deli nes ®] A ntie mesis , 2 0 1 9 ) 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 8 / 1 5 5
T he I n vesti gat or will rec or d all c o nc o mita nt me dicati o ns ta ke n b y  the partici pa nt d uri n g t he st u d y, 
fr o m t he date of si g nat ure of i nf or me d c o nse nt, i n t he a p pr o priate secti o n of t he e C R F. A n y 
a d diti o nal c o nc o mita nt t hera p y that bec o mes necessar y  duri n g t he st u d y a n d a n y c ha n ge t o 
c o nc o mita nt dr u gs m ust be rec or de d i n t he c orres p o n di n g secti o n of t he e C R F, n oti n g t he na me, 
d ose, d urati o n, a n d i n dicati o n of eac h dr u g. A n y m e dici nes t hat are c o nsi dere d necessar y  to pr otect 
t he partici pa nt’s welfare i n e mer ge ncies m a y  be gi ve n at t he I nvesti gat or ’s discreti o n , re gar dless 
if it res ults i n a pr ot oc ol de viati o n.
6. 5. 2
Pr o hi bite d Me dici nes

C y t ore d ucti ve t hera p y

Use of a n y i n vesti gati o nal dr u g wit hi n 4 w ee ks bef ore ra n d o mizati o n 

I m m u n ot hera py, i m m u n os u p pressi ve dr u gs, c he m ot hera p y or s ys te mic c ortic oster oi ds e xce pt:

W he n re q uire d f or treat me nt of aller gic reacti o ns or f or t he treat me nt of ir A Es or i nf usi o n 
relate d reacti o ns/ h yperse nsiti vit y

S ys te mic c ortic oster oi ds f or ma na ge me nt of patie nts wit h aller g y  t o Ra di o gra p hic C o ntrast 
Me dia

S y ste mic c ortic oster oi ds at p h ysi ol o gic d oses ≤ 1 0 m g/ da y  of pre d nis o ne or e q ui vale nt
N ote: 
T he use of s yste mic c ortic oster oi ds f or partici pa nt s ra n d o mize d t o recei ve 
c he m ot hera p y is per I n vesti gat or’s discreti o n a n d is t o be base d o n l ocal a n d i nstit uti o nal 
g ui deli nes. A c ortic oster oi d -s pari n g a p pr oac h f or a ntie metic pr o p h y la xis s h o ul d be preferre d 
a n d e val uate d o n a case b y case a n d c he m ot hera p y re gi me n bas is (N C C N Cli nical Practice 
G ui deli nes i n O nc ol o g y  [ N C C N G ui deli nes ®] - A ntie mesis, 2 0 1 9 )

Vacci ne a d mi nistrati o n wit hi n 4 wee ks bef ore ra n d o mizati o n. Vacci nati o n wit h li ve vacci nes 
w hile o n st u d y is pr o hi bite d. A d mi nistrati o n of i nacti vate d vacci nes (f or e xa m ple, i nacti vate d 
i nfl ue nza vacci nes) is all o we d. A p pr o ve d S A R S - C o V- 2 vacci nes are all o we d at a n y ti me, 
i ncl u di n g bef ore a n d d uri n g scree ni n g.

Pri mar y  pr o p h yla xis wit h G-C S F
A n y  tra diti o nal C hi nese me dicati o n
or her bal s u p ple me nt wit h a p pr o val f or use as a ntica ncer 
treat me nt (re gar dless of t he t ype of ca ncer) will n ot be per mitte d. Tra diti o nal C hi nese me dicati o n 
f or i n dicati o ns ot her t ha n a ntica ncer treat me nt, s uc h as s u p p orti ve care, ma y  be a d mi nistere d at 
t he discreti o n of t he I n vesti gat or (A p pe n di x 7 ).
If t he a d mi nistrati o n of a n o n per mitte d c o nc o mita nt dr u g bec o mes necessar y d uri n g t he st u d y, t he 
partici pa nt will be wit h dra w n fr o m st u d y treat me nt (t he S p o ns or m a y  be c o ntacte d t o disc uss 
w het her t he st u d y i nter ve nti o n m ust be disc o nti n ue d ). T he partici pa nt s h o ul d c o m plete t he 
E n d - of-Treat me nt visit a n d be f oll o we d f or s ur vi val. 
6. 5. 2. 1 
Me dici nes t o U se wit h C a uti o n
Ca uti o n s h o ul d be use d w he n a d mi nisteri n g cis plati n c o nc o mita nt wit h t he f oll o wi n g:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 / 1 5 5

All o p uri n ol, 
c olc hici ne, pr o be neci d, s ulfi n p yr az o ne (i ncrease i n ser u m uric aci d 
c o nce ntrati o n), 

Ce p hal os p ori ns, a mi n o gl yc osi des, a m p h oterici n B (i ncrease ne p hr ot o xic a n d ot ot o xic 
effects of cis plati n i n t hese or ga ns), 

Cic l os p ori ne (e xcessi ve i m m u n os u p pressi o n, wit h ris k of l ym p h o pr oliferati o n), 

C y clizi ne* , p he n ot hiazi nes ( ma y mas k ot ot o xicit y s ym pt o ms), 

F ur ose mi de 
( hi g h 
d oses), 
h y dralazi ne, 
diaz o xi de 
a n d 
pr o pra n ol ol 
(i nte nsif y 
ne p hr ot o xicit y ),

Oral a ntic oa g ula nts t hat re q uire a n i ncrease d fre q ue nc y of t he I N R m o nit ori n g
(e. g., 
vita mi n K a nta g o nists)

Pe nicilla mi ne ( ma y  di mi nis h t he effecti ve ness of cis plati n) 

P he n y t oi n (re d uce d e pile ps y c o ntr ol)

Ne p hr ot o xic dr u gs ( i nte nsif y ne p hr ot o xicit y) 
Ca uti o n s h o ul d be e xercise d w he n a d mi nisteri n g paclita xel c o nc o mita ntl y  wit h k n o w n s u bstrates 
or i n hi bit ors of t he c y t oc hr o me P 4 5 0 is oe nz ymes C Y P 2 C 8 a n d C Y P 3 A 4

K n o w n s u bstrates of C Y P 3 A 4 (e. g., mi daz ola m, b us pir o ne *, fel o di pi ne, l o vastati n* , 
eletri pta n, sil de nafil, si m vastati n, a n d tr iaz ola m)

K n o w n i n hi bit ors of C Y P 3 A 4 (e. g., ataza na vir, clarit hr o m yci n, i n di na vir, itrac o naz ole, 
ket oc o naz ole, nefaz o d o ne * , nelfi na vir, rit o na vir, sa q ui na vir, a n d telit hr o myci n)

K n o w n i n d ucers of C Y P 3 A 4 ( e. g., rifa m pi n a n d car ba maze pi ne) 

K n o w n s u bstrates o f C Y P 2 C 8 (e. g., re pa gli ni de a n d r osi glitaz o ne*)

K n o w n i n hi bit ors of C Y P 2 C 8 ( e. g., ge mfi br ozil *)

K n o w n i n d ucers ( e. g., rifa m pi n) 
* N ot a p pr o ve d i n Ja pa n
Ca uti o n s h o ul d be e xercise d w he n a d mi nisteri n g pe metre xe d c o nc o mita ntl y wit h I b u pr ofe n d ue t o 
i ncreased ris k of pe metre xe d t o xicit y  i n patie nts wit h mil d t o m o derate re nal i m pair me nt.
F or a d diti o nal details, refer t o eac h c he m ot hera p y a ge nt la bel.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 0 / 1 5 5
6. 5. 3
Per mitte d/ Pr o hi bite d Pr oce d ures
Per mitte d Pr oce d ures
S u p p orti ve care a n d pr oce d ures are per mitte d d uri n g c C R T (e. g., fee di n g t u be) if cli nicall y 
i n dicate d. Palliati ve ra di ot hera py m a y  be all o we d i n partici pa nts w h o e x perie nce P D w hile o n 
st u d y after disc ussi o n wit h t he Me dical M o nit or.
Pr o hi bite d Pr oce d ures
T he f oll o wi n g n o n dr u g t hera pies m ust n ot be a d mi nistere d d uri n g t he st u d y inter ve nti o n ( or wit hi n 
2 8 da y s bef ore ra n d o mizati o n):
Maj or s ur ger y (e xcl u di n g pri or dia g n ostic bi o ps y) wit hi n 4 wee ks bef ore t he start of t he st u d y. 
Disc uss wit h M e dical M o nit or if u n pla n ne d maj or s ur ger y  is re q uire d o n st u d y t o pla n f or ti mi n g 
of treat me nt after s ur ger y .
6. 5. 4
Ot her I nter ve nti o ns
T he f oll o wi n g n o n dr u g t hera pies m ust n ot be a d mi nistere d d uri n g t he st u d y ( or wit hi n 2 1 da y s 
bef ore ra n d o mizati o n):

Her bal re me dies wit h i m m u ne-sti m ulati n g pr o perties (f or e xa m ple, mistlet oe e xtract) or 
k n o w n t o p ote ntiall y  i nterfere wit h maj or or ga n f u ncti o n (f or e xa m ple, h y perici n)
6. 6
D ose Selecti o n a n d M o dific ati o n
D ose m o dificati o n of M 7 8 2 4/ place b o 
d ue t o blee di n g e ve nts is descri be d i n Secti o n 6. 9. 5 , 
pre parati o n a n d rec or di n g of re d uce d d oses are descri be d i n Secti o n 6. 3. 2 . T here are n o d ose 
re d uctio ns f or d ur val u ma b . D ose re d ucti o ns a n d m o dificati o ns f or c he m ot hera p y a n d ra di ot hera py 
are all o we d (see Secti o n  6. 1 0 ).
6. 7
St u d y I nter ve nti o n after t he E n d of t he St u d y
T he S p o ns or will n ot pr o vi de a n y a d diti o nal care t o partici pa nts after t he y lea ve t he st u d y b eca use 
s uc h care w o ul d n ot differ fr o m w hat is n or mall y e x pecte d f or patie nts wit h u nresecta ble Sta ge III 
N S C L C.
6. 8
S peci al Prec a uti o ns
A n y  treat me nt-e mer ge nt A E ( T E A E) t hat is assesse d as relate d t o st u d y treat me nt m a y  re q uire 
per ma ne nt or tra nsie nt disc o nti n uati o n of st u d y treat me nt. 
Si n gle la b orat or y val ues o ut of t he n or mal ra n ge t hat d o n ot ha ve a n y cli nical c orrelate d o n ot 
necessaril y  nee d treat me nt i nterr u pti on. Q uesti o ns or c o ncer ns wit h re gar d t o ma na ge me nt a n d/ or 
f oll o w-u p of T E A Es s h o ul d be disc usse d wit h t he Me dical M o nit or.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 / 1 5 5
I m m u ne-relate d A Es, I R Rs, a ne mia, T G F-β i n hi biti o n me diate d s ki n reacti o ns, a n d blee di n g A Es 
are ma na ge d a n d f oll o we d u p i n t heir respecti ve secti o ns as i n dicate d bel o w. Per ma ne nt st u d y 
i nter ve nti o n disc o nti n uati o n ma y be rec o m me n de d, s o t he rele va nt secti o n m ust be re vie we d:

F or s us pecte d ir A Es, ge neral g ui da nce a n d ma na ge me nt 
are pr o vi de d i n Secti o n 6. 9. 2 . 
I m m u ne-relate d A Es are A E SIs f or M 7 8 2 4 a n d d ur val u ma b.

I R R a n d h y perse nsiti vit y  reacti o n ma na ge me nt 
g ui da nce is prese nte d i n Secti o n 6. 9. 1 .
I nf usi o n-relate d reacti o n A Es are A E SIs f or M 7 8 2 4 a n d d ur val u ma b.

A ne mia ma na ge me nt g ui da nce is prese nte d i n Secti o n 6. 9. 4.

T G F -β i n hi biti o n me diate d s ki n reacti o ns ma na ge me nt g ui da nce is pr o vi de d i n Secti o n 6. 9. 3.
S ki n reacti o ns are st u d y s pecific A E SIs f or ra diati o n i n c o m bi nati o n wit h M 7 8 2 4.

A d diti o nall y , ski n reacti o ns are st u d y specific A E SI s f or ra diati o n i n c o m bi nati o n wit h 
M 7 8 2 4. Ra diati o n der matitis is a si g nifica nt ac ute a n d c hr o nic a d verse effect of R T. Ac ute 
reacti o ns ca n ha ve se vere se q uelae t hat i m pact q ualit y  of life a n d ca ncer treat me nt, t h us 
pr o m pt s ym pt o m ma na ge me nt is a d vise d per l ocal sta n dar d practice. C hr o nic s ki n c ha n ges 
are a u ni q ue s u bset of a d verse reacti o ns t o R T t hat ma y de vel o p m o nt hs t o ye ars f oll o wi n g 
treat me nt a n d are ofte n per ma ne nt, pr o gressi ve, a n d p ote ntiall y  irre versi ble, as i n 
ra diati o n-i n d uce d fi br osis, wit h s u bsta ntial i m pact o n q ualit y  of life. See  Ta ble 1 8 f or st u d y 
i nter ve nti o n m o dificati o n acc or di n g t o t he gra de of se verit y an d see Secti o n 6. 1 0 f or 
ma na ge me nt g ui deli nes .

F or g ui da nce a n d ma na ge me nt of blee di n g A Es, see Secti o n 6. 9. 5.
Ge ner al g ui d a nce:

I n all cases , if ≥2 d oses of M 7 8 2 4 or d ur val u ma b are misse d d ue t o A E, t he Me dical M o nit or 
s h o ul d be c o ns ulte d.

I n all cases, if ≥ 2 d oses of c he m ot hera p y are misse d d ue t o A E, t he Me dical M o nit or s h o ul d 
be c o ns ulte d.

Ge nerall y , i na bilit y to re d uce c ortic oster oi d d ose t o 1 0 m g or less of pre d nis o ne or e q ui vale nt 
per d a y  wit hi n 1 2 wee ks is a n i n dicati o n f or per ma ne nt treat me nt disc o nti n uati o n (e xce pt f or 
use of ster oi ds as h or m o ne s u bstit uti o n).

Persiste nt e n d ocri n o pat hies c o ntr olle d wit h h or m o ne re place me nt t hera p y ge nerall y d o n ot 
re q uire 
per ma ne nt 
treat me nt 
disc o nti n uati o n . 
Ho we ver, 
ot her 
persiste nt 
Gra de 2 
treat me nt-relate d A Es t hat eit her d o n ot res ol ve or i m pr o ve t o Gra de 1 wit hi n 1 2 wee ks after 
last d ose of st u d y i nter ve nti o n are a n i n dicati o n f or per ma ne nt treat me nt disc o nti n uati o n. 
I n ge neral, t he f oll o wi n g a p plies f or T E A Es relate d t o M 7 8 2 4 t hat 
are n ot c o vere d b y  the 
rec o m me n dati o ns f or ir A E ma na ge me nt 
i n t he c urre nt N C C N 
g ui deli ne a vaila ble at 
htt p:// w w w. ncc n. or g:
Gr a de 4 tre at me nt -rel ate d T E A Es
1.
A n y  Gra de 4 treat me nt-relate d T E A Es re q uire per ma ne nt treat me nt disc o nti n uati o n, e xce pt:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 / 1 5 5
a.
E n d ocri n o pat hies t hat ha ve bee n c o ntr olle d b y h or m o ne re place me nt,
b.
Is olate d la b orat or y val ues o ut of n or mal ra n ge t hat d o n ot ha ve a n y cli nical 
c orrelati o n. Disc uss wit h Me dical M o nit or re gar di n g w or k -u p, ma na ge me nt, a n d 
treat me nt c o nti n uati o n vers us h ol d vers us disc o nti n uati o n f or is olate d Gra de 4 
la b orat or y a b n or malities,
c.
If a n alter nati ve e x pla nati o n is i de ntifie d f or Gra de 4 n o n-t u m or blee di n g.
Refer t o t he c urre nt N C C N g ui deli ne a vaila ble at htt p:// w w w. ncc n. or g f or g ui da nce o n s pecific 
Gra de 4 ir A Es, as m ost re q uire per ma ne nt treat me nt disc o nti n uati o n.
F or ma na ge me nt of Gra de 4 A Es relate d t o ra di ot hera p y a n d c he m ot hera p y  see Secti o n 6. 1 0.
Gr a de 3 tre at me nt -rel ate d T E A E 
1.
Partici pa nts wit h a n y rec urre nt Gra de 3 treat me nt-relate d A Es t hat rec ur s h o ul d be 
per ma ne ntl y d isc o nti n ue d. E xce pti o ns ma y  be c o nsi dere d f or t he f oll o wi n g after disc ussi o n 
wit h Me dical M o nit or:
a.
Tra nsie nt Gra de 3 fl u-li ke s ym pt o ms or fe ver t hat is c o ntr olle d wit h me dical 
ma na ge me nt
b.
Tra nsie nt Gra de 3 fati g ue, l ocal reacti o ns, hea dac he, na usea, e mesis t hat res ol ves 
t o Gra de ≤1 or baseli ne
c.
T u m or flare p he n o me n o n defi ne d as l ocal pai n, irritati o n, or ras h l ocalize d at sites 
of k n o w n or s us pecte d t u m ors
d.
A n y  Gra de ≥ 3 dr u g -relate d a m ylase or li pase a b n or malit y that is n ot ass ociate d 
wit h s y m pt o ms or cli nical ma nifestati o ns of pa ncreatitis
e.
Gra de 3 he m o gl o bi n decrease ( < 8. 0 g/ d L) t hat is cli nicall y ma na gea ble wit h 
bl o o d tra nsf usi o ns or er yt hr oi d gr o wt h fact or use
f.
I ncreases i n Easter n C o o perati ve O nc ol o g y  Gr o u p perf or ma nce stat us ( E C O G 
P S) ≥ 3 t hat res ol ves t o ≤ 2 b y  Da y 1 of t he ne xt i nf usi o n (i.e., i nf usi o ns s h o ul d 
n ot be gi ve n if t he E C O G P S is ≥ 3 o n t he da y  of treat me nt a n d s h o uld be dela y e d 
u ntil E C O G P S ≤ 2).
g.
Kerat oaca nt h o ma ( K A) a n d c uta ne o us s q ua m o us cell carci n o ma (c S C C)
h.
Gra de 
3 n o n- t u m or blee di n g re q uiri n g i nter ve nti o n or h os pitalizati o n if 
alter nati ve e x pla nati o n ca n be i de ntifie d (s uc h as c o nc o mita nt use of 
a ntit hr o m b otic a ge nts, tra u matic e ve nt, etc.). 
2.
P artici pa nts wit h p ersiste nt Gra de 3 A Es (e xcl u di n g e n d ocri n o pat hies c o ntr olle d wit h 
h or m o ne re place me nt t hera py) t hat eit her d o n ot res ol ve or i m pr o ve t o Gra de 1 wit hi n 
1 2 wee ks after last d ose of treat me nt m ust be per ma ne ntl y  disc o nti n ue d. 
See t he c urre nt N C C N g ui deli ne a vaila ble at htt p:// w w w. ncc n. or g f or g ui da nce o n s pecific Gra de 3 
ir A Es as ma n y re q uire per ma ne nt treat me nt disc o nti n uati o n, i ncl u di n g p ne u m o nitis a n d ne p hritis.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 3 / 1 5 5
F or ma na ge me nt of Gra de 3 A Es relate d t o ra di ot hera p y a n d c he m ot hera p y see Secti o n 6. 1 0.
Gr a de 2 tre at me nt -rel ate d T E A E
1.
If a Gra de 2 treat me nt-relate d T E A E res ol ves t o Gra de ≤ 1 b y  the da y  bef ore t he ne xt 
i nf usi o n, st u d y i nter ve nti o n ma y be c o nti n ue d.
2.
If a Gra de 2 treat me nt-relate d T E A E d oes n ot res ol ve t o Gra de ≤ 1 b y  the da y  bef ore t he 
ne xt i nf usi o n, b ut it is ma na gea ble a n d/ or n ot cli nicall y rele va nt, t he Me dical M o nit or 
s h o ul d be c o ns ulte d t o assess if it is cli nicall y reas o na ble t o a d mi nister t he f oll o wi n g 
i nf usi o n.
N ote t hat treat me nt rec o m me n dati o ns re gar di n g c o nti n uati o n, h ol d, or disc o nti n uati o n b y  gra de 
are differe nt de pe n di n g o n t he s pecific t o xicit y (see t he c urre nt N C C N g ui deli ne a vaila ble at 
htt p:// w w w. ncc n. or g ). T o xicit y  gra di n g is assi g ne d base d o n 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 ( N CI-C T C A E) Versi o n 5. 0.
F or ma na ge me nt of Gra de 2 A Es relate d t o ra di ot hera p y a n d c he m ot hera p y see Secti o n 6. 1 0.
6. 9
M a n a ge me nt of A d verse E ve nts of I nterest
A d verse e ve nts of s pecial i nterest ( A E SIs) are seri o us or n o nseri o us A Es t hat are of cli nical i nterest 
a n d s h o ul d be cl osel y f oll o we d.
F or t his st u d y , A E SIs i ncl u de o nl y t he f oll o wi n g:

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.

I m m u ne-relate d a d verse e ve nts.

T G F -β i n hi biti o n me diate d s ki n reac ti o ns.

A ne mia.

Blee di n g A Es.

P ne u m o nitis.
P ne u m o nitis is a n A E SI f or b ot h c he m ora diati o n a n d i m m u n ot hera py , a n d a n i m p orta nt 
i de ntifie d ris k f or d ur val u ma b . See Secti o n  6. 9. 2 f or i m m u ne-relate d A E ma na ge me nt a n d see 
Secti o n 6. 1 0 f or gra di n g a n d ma na ge me nt of p ne u m o nitis ass ociate d wit h c C R T.
6. 9. 1
I nf usi o n-rel ate d  
Re acti o ns  
I ncl u di n g  
I m me di ate 
H y perse nsiti vit y
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 , are defi ne d i n t his secti o n. 
I nf usi o n-relate d reacti o ns are i de ntifie d ris ks f or M 7 8 2 4 
a n d i m p orta nt i de ntifie d ris ks f or 
d ur val u ma b .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 4 / 1 5 5
I nf usi o n-Rel ate d Re acti o ns
I nf usi o n-relate d reacti o ns are si g ns or s ym pt o ms e x perie nce d b y  partici pa nts d uri n g st u d y 
i nter ve nti o n a d mi nistrati o n or wit hi n 1 da y  thereafter. A n assess me nt f or p ossi ble I RR s h o ul d be 
tri g gere d base d o n t he cli nical pict ure a n d te m p oral relati o ns hi p t o dru g a d mi nistrati o n. 
P ossi ble I RRs are defi ne d base d o n t he f oll o wi n g 2 lists of Me dical Dicti o nar y  for Re g ulat or y  
Acti vities ( Me d D R A) Preferre d Ter ms ( P Ts) a n d te m p oral relati o ns hi p criteria. E ve nts are di vi de d 
i nt o reacti o ns vers us si g ns a n d s ym pt o ms:

Reacti o ns i ncl u de t he P Ts i nf usi o n-relate d reacti o n, d r u g- hy perse nsiti vit y, h y perse nsiti vit y , 
ty pe - 1- hy perse nsiti vit y , a n d ana p h y lactic reacti o n. T hese P Ts s h o ul d be c o nsi dere d w he n o nset 
is d uri n g t he i nf usi o n or wit hi n 1 da y t hereafter (irres pecti ve of res ol uti o n).  

Si g ns a n d s ym pt o ms of i nf usi o n-relate d reacti o ns i ncl u de t he P Ts p yr e xia, chills, fl us hi n g, 
h y p ote nsi o n, d ys p n oea, w heezi n g, b ac k p ai n, ab d o mi nal p ai n, a n d u rticaria. T hese P Ts s h o ul d 
be c o nsi dere d, if t he o nset occ urs d uri n g or wit hi n 1 da y  after a n i nf usi o n a n d res ol ves wit hi n 
2 da y s.
M a n a ge me nt of I nf usi o n -Rel ate d Re acti o ns
C urre nt e x perie nce i n m ore t ha n 7 0 0 st u d y partici pa nts re veale d t hat I R Rs ass ociate d wit h M 7 8 2 4
occ ur sel d o ml y an d are ge nerall y mil d t o m o derate i n se verit y. T heref ore, a d mi nistrati o n of a 
pre me dicati o n is ge nerall y  n ot re q uire d. 
If a n I n vesti gat or dee ms it necessar y  to a d mi nister a pre me dicati o n pri or t o M 7 8 2 4
i nf usi o n t o a 
partic ular partici pa nt , a n a nti hista mi ne (e. g., 2 5 t o 5 0 m g di p he n h y dra mi ne) a n d paraceta m ol 
(aceta mi n o p he n, 5 0 0 t o 6 5 0 m g 
i ntra ve n o usl y or e q ui vale nt oral d ose) is rec o m me n de d. 
Pre me dicati o n s h o ul d be a d mi nistere d base d u p o n cli nical j u d g me nt a n d prese nce/se verit y  of pri or 
i nfusi o n reacti o ns. T his re gi me n m a y  be m o difie d base d o n l ocal treat me nt sta n dar ds a n d 
g ui deli nes as a p pr o priate , pr o vi de d it d oes n ot i ncl u de s y ste mic gl uc oc ortic oi ds.
Ma na ge me nt of s y m pt o ms s h o ul d f oll o w t he g ui deli nes s h o w n i n  Ta ble 8.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 5 / 1 5 5
T a ble 8
Tre at me nt M o dific ati o n 
G ui d a nce f or S y m pt o ms of I nf usi o n-Rel ate d 
Re acti o ns I ncl u di n g I m me di ate H y perse nsiti vit y
N CI - C T C A E v 5. 0 Gr a d e
Tr e at m e nt M o difi c ati o n 
Gr a d e 1 – mil d
Mil d tr a n si e nt r e a cti o n: i n g e n er al, i nf u si o n i nt err u pti o n 
n ot i n di c at e d; i nt er v e nti o n n ot i n di c at e d.
I n cr e a s e m o nit ori n g of vit al si g n s a s m e di c all y i n di c at e d 
a s p arti ci p a nt s ar e d e e m e d m e di c all y st a bl e b y t h e 
att e n di n g I n v e sti g at or.
H ol d i nf u si o n if d e e m e d n e c e s s ar y b y t h e I n v e sti g at or.
Gr a d e 2 – m o d er at e
T h er a p y or i nf u si o n i nt err u pti o n i n di c at e d b ut r e s p o n d s 
pr o m ptl y t o s y m pt o m ati c tr e at m e nt ( e. g., 
a nti hi st a mi n e s, N S AI D s, n ar c oti c s, I V fl ui d s); 
pr o p h yl a cti c m e di c ati o n s i n di c at e d f or 2 4 h o ur s.
St o p t h e i nf u si o n of t h e st u d y i nt er v e nti o n 
I n cr e a s e m o nit ori n g of vit al si g n s a s m e di c all y i n di c at e d 
a s p arti ci p a nt s ar e d e e m e d m e di c all y st a bl e b y t h e 
att e n di n g I n v e sti g at or. 
If s y m pt o m s r e s ol v e q ui c kl y, r e s u m e i nf u si o n at 5 0 % of 
ori gi n al r at e wit h cl o s e m o nit ori n g of a n y w or s e ni n g 
ot h er wi s e d o si n g h el d u ntil r e s ol uti o n of s y m pt o m s wit h 
m a n d at e d pr e m e di c ati o n f or t h e n e xt s c h e d ul e d vi sit. 
If n ot i m pr o vi n g, c o n si d er a d mi ni str ati o n of 
gl u c o c orti c oi d s a n d st o p t h e i nf u si o n f or t h at d a y.
If t h e p arti ci p a nt h a s a s e c o n d I R R Gr a d e ≥2 o n t h e 
sl o w er i nf u si o n r at e d e s pit e pr e m e di c ati o n, t h e i nf u si o n 
s h o ul d b e st o p p e d a n d t h e I n v e sti g at or m a y c o n si d er 
wit h dr a w al of t hi s p arti ci p a nt fr o m t h e st u d y.
Gr a d e 3 or Gr a d e 4 – s e v er e or lif e- t hr e at e ni n g
Gr a d e 3: Pr ol o n g e d ( e. g., n ot r a pi dl y r e s p o n si v e t o 
s y m pt o m ati c m e di c ati o n a n d/ or bri ef i nt err u pti o n of 
i nf u si o n); r e c urr e n c e of s y m pt o m s f oll o wi n g i niti al 
i m pr o v e m e nt; h o s pit ali z ati o n i n di c at e d f or cli ni c al 
s e q u el a e.
Gr a d e 4: Lif e -t hr e at e ni n g c o n s e q u e n c e s; ur g e nt 
i nt er v e nti o n i n di c at e d.
St o p t h e i nf u si o n of st u d y i nt er v e nti o n - i m m e di at el y a n d 
di s c o n n e ct i nf u si o n t u bi n g fr o m t h e p arti ci p a nt wit h 
a d diti o n al a p pr o pri at e m e di c al m e a s ur e s a n d cl o s el y 
m o nit or u ntil d e e m e d m e di c all y st a bl e b y t h e att e n di n g 
I n v e sti g at or. H o s pit ali z ati o n a n d/ or cl o s e m o nit ori n g i s 
r e c o m m e n d e d.
A d mi ni str ati o n of gl u c o c orti c oi d s m a y b e r e q uir e d
F or Gr a d e 3 or 4 I R R s, p er m a n e nt di s c o nti n u ati o n of 
st u d y i nt er v e nti o n i s m a n d at e d.
O n c e t h e i nf u si o n i s i nt err u pt e d or r at e r e d u c e d t o 5 0 % of pr e vi o u s i nf u si o n r at e, it m u st r e m ai n d e cr e a s e d f or all 
s u b s e q u e nt i nf u si o n s. 
F or all t y p e s a n d gr a d e s of i nf u si o n r e a cti o n s, d et ail s a b o ut dr u g p h y si c al c o n stit uti o n, m et h o d of pr e p ar ati o n, a n d 
i nf u si o n m u st b e r e c or d e d.
P arti ci p a nt s s h o ul d b e i n str u ct e d t o r e p ort a n y d el a y e d r e a cti o n i m m e di at el y.
I R R =i nf u si o n-r el at e d r e a cti o n s, I V =i ntr a v e n o u s, N CI-C T C A E = N ati o n al C a n c er I n stit ut e -C o m m o n T er mi n ol o g y 
Crit eri a f or A d v er s e E v e nt, N S AI D s = n o n st er oi d al a nti- i nfl a m m at or y dr u g s. 
I m me di ate H y perse nsiti vit y Re acti o n
H y perse nsiti vit y  reacti o ns ma y  re q uire i m me diate i nte nsi ve care. M 7 8 2 4
s h o ul d be a d mi nistere d 
i n a setti n g t hat all o ws i m me diate access t o a n i nte nsi ve care u nit or e q ui vale nt e n vir o n me nt a n d 
a d mi nistrati o n of t hera p y for a na p h yla xis, s uc h as t he a bilit y to i m ple me nt i m me diate res uscitati o n 
meas ures. 
P ote nt ster oi ds (e. g., d e xa met has o ne), catec h ola mi nes (e. g. e pi ne p hri ne), aller g y 
me dicati o ns (I V a nti hista mi nes), br o nc h o dilat ors, or e q ui vale nts a n d o x y ge n s h o ul d be a vaila ble 
f or i m me diate access.
A c o m plete g ui deli ne f or t he e mer ge nc y treat me nt of a na p h yl actic reacti o ns acc ordi n g t o t he 
W or ki n g  
Gr o u p 
of 
t he Res uscitati o n 
C o u ncil 
U nite d 
Ki n g d o m 
ca n 
be 
f o u n d at 
htt ps:// w w w.res us. or g. u k/ pa ges/reacti o n. p df .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 / 1 5 5
Fl u -Li ke S y m pt o ms
Treat me nt is base d o n cli nical assess me nt a n d at t he discreti o n of t he I n vesti gat or. F or pr o p h yl a xis 
of fl u li ke s ym pt o ms, a n o nster oi dal a nti -i nfla m mat or y dr u g ( N S AI D), e. g., i b u pr ofe n 4 0 0 m g or 
c o m para ble N S AI D d ose, ma y  b e ad mi nistere d 2 h o urs bef ore a n d 8 h o urs after t he start of eac h 
I V i nf usi o n.
6. 9. 2
I m m u ne-rel ate d A d verse E ve nts
I m m u ne-relate d A Es are s pecific t o i m m u n ot hera pies a n d var y b y or ga n s yste m. I m m u ne-relate d 
A Es are A E SI s.
T he f oll o wi n g ir A Es are i m p orta nt i de ntifie d ris ks f or M 7 8 2 4 :

I m m u ne-relate d p ne u m o nitis

I m m u ne-relate d he patitis

I m m u ne-relate d c olitis

I m m u ne-relate d ne p hritis a n d re nal dys f u ncti o n

I m m u ne-relate d e n d ocri n o pat hies (t hyr oi d dis or ders, a dre nal i ns ufficie nc y, T y pe 1 dia betes 
mellit us, a n d pit uitar y  dis or ders)

I m m u ne-relate d ras h

Ot her i m m u ne- relate d e ve nts ( m yositis, m y ocar ditis, e nce p halitis)
T he f oll o wi n g ir A Es are i m p orta nt p ote n tial ris ks f or M 7 8 2 4 :

G uillai n -Barré s y n dr o me

U veitis

Pa ncreatitis

M y ast he nia gra vis/ m yast he nic s y n dr o me
T he list of ir A Es w hic h are i m p orta nt i de ntifie d ris ks f or d ur val u ma b i ncl u des i m m u ne me diate d 
c olitis or 
diarr hea, 
he patitis, 
p ne u m o nitis, 
h y p o p h y sitis or 
h y p o pit uitaris m, 
ne p hritis, 
h y pert h y r oi dis m, h y p ot h y r oi dis m, T y pe I dia betes, a dre nal i ns ufficie nc y, ras h or der matitis, 
m y ocar ditis (refer t o I mfi nzi ® c urre nt Ris k Ma na ge me nt Pla n [ R M P]).
I n ge neral, t he s pectr u m of ir A Es is si milar f or M 7 8 2 4 c o m pare d wit h ot her c hec k p oi nt i n hi bit ors. 
Effecti ve ris k ma na ge me nt of t hese t o xicities (ir A Es) pri maril y ca use d d ue t o i n hi biti o n of P D -L 1  
a n d P D-1 pat h wa y s is base d o n ke y rec o m me n dati o ns (C ha m piat 2 0 1 6 ). Participa nt e d ucati o n f or 
o n- ti me re p orti n g of s ym pt o ms of p ote ntial ir A Es a n d pr o m pt cli nical assess me nt is critical f or 
effecti ve ma na ge me nt a n d q uic ker res ol uti o n of i m m u ne-me diate d t o xicities, t h us pre ve nti n g 
pr o gressi o n i nt o se vere f or ms of t o xicit y  t hat ot her wise ma y bec o me life-t hreate ni n g a n d diffic ult 
t o ma na ge or warra nt per ma ne nt disc o nti n uati o n fr o m t he st u d y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 / 1 5 5
T he Me dical M o nit or ma y  be i n v ol ve d as nee de d f or F oll o w -u p. Details of t he dia g n ostic w or k - u p 
will be re q ueste d b y t he st u d y  tea m. 
Rec o m me n de d g ui da nce a n d ma na ge me nt f or s pecific ir A Es are pr o vi de d i n t he c urre nt N C C N 
g ui deli ne a vaila ble at  htt p:// w w w. ncc n. or g .
Re q uire me nts i n a d diti o n t o N C C N g ui deli nes:

Per ma ne nt treat me nt disc o nti n uati o n is re q uire d i n case of i m m u ne-relate d Gra de 4 
ras h/i nfla m mat or y der matitis, ne p hritis, a ut oi m m u ne he m ol yt ic a ne mia, he m ol y tic ure mic 
s yn dr o me, a plastic a ne mia, i m m u ne t hr o m b oc yt o pe nia, ac q uire d t hr o m b otic t hr o m b oc yt o pe nic 
p ur p ura, i nfla m mat or y  art hritis, m yositis, a n d p o l ym y al gia-li ke sy n dr o me.

F or Gra de 4 i m m u ne-relate d l ym p h o pe nia, per ma ne nt treat me nt disc o nti n uati o n will be 
re q uire d if l ym p h o pe nia 
is c o nsi dere d i m m u ne-relate d i n nat ure, n o clear alter nati ve 
e x pla nati o n e xists f or t he e ve nt, a n d Gra de 4 l ym p h o pe nia d oes n ot res ol ve wit hi n 1 4 da y s. 
Per ma ne nt treat me nt disc o nti n uati o n is n ot re q uire d w he n t he A E is ma nifest e d b y  a si n gle 
la b orat or y val ue o ut of n or mal ra n ge wit h o ut a n y cli nical c orrelates. I n t his case, treat me nt 
s h o ul d be hel d u ntil t he eti ol o g y is deter m i ne d. If t he e ve nt is n ot c o nsi dere d i m m u ne relate d 
a n d res ol ves t o Gra de ≤ 1, restarti n g treat me nt ma y  be c o nsi dere d.

F or Gra de 1 i m m u ne-relate d p ne u m o nitis: c o nti n ue treat me nt. If cli nicall y in dicate d, m o nit or 
partici pa nts wee kl y or m ore fre q ue ntl y as ne e de d wit h hist or y, p hys ical e xa mi nati o n, a n d p ulse 
o xi metr y . If s ym pt o ms a p pear a n d/ or c ha n ges i n t he p h y sical e xa mi nati o n are n ote d, treat as 
Gra de 2.

F or m y ositis: i n case of ma na ge me nt wit h rit u xi ma b, treat me nt s h o ul d be disc o nti n ue d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 / 1 5 5
6. 9. 4
A ne mi a
A ne mia is a n A E SI a n d i m p orta nt i de ntifie d ris k f or M 7 8 2 4 . N ota bly,  t here are ma n y reas o ns f or 
a ne mia i n patie nts wit h a d va nce d ca ncer, a n d c o m bi nati o n t hera py wit h c C R T, t heref ore a 
t h or o u g h i n vesti gati o n of ne w a ne mia cases of u ns pecifie d eti ol o g y is rec o m me n de d.
F or ne w a ne mia e ve nts, ite ms q uerie d m a y  incl u de, b ut are n ot li mite d t o, detaile d rele va nt past 
me dical a n d treat me nt hist or y , br uisi n g te n de nc y, hist or y  of bl o o d tra nsf usi o ns a n d/ or de pe n de nc y , 
a n d a re q uest f or a n u p date d e C R F i ncl u di n g details s uc h as c o nc o mit a nt me dicati o ns, all 
la b orat or y data, u p date d d osi n g i nf or mati o n, a n d rece nt t u m or e val uati o n sca ns. 
Ge neral g ui da nce f or a ne mia ma na ge me nt a n d e val uati o n:
1.
Partici pa nts m ust e nter t he st u d y wit h H g b val ues ≥9 g/ d L; r o uti ne bl o o d test para meters 
are re q ui re d per t he S o A (see Secti o n 1. 3 ).
2.
All rele va nt he mat ol o gic testi n g f or a ne mias s h o ul d be d o ne pri or t o a bl o o d tra nsf usi o n, if 
cli nicall y feasi ble.
3.
Tra nsf usi o n s h o ul d be perf or me d at t he discreti o n of t he I n vesti gat or base d o n cli nical 
assess me nt a n d c o nsi dere d w he n t he partici pa nt e x perie nces se vere a ne mia. A n atte m pt 
s h o ul d be ma de t o i nitiate w or k - u p (as s pecifie d bel o w) f or t he ca use of a ne mia pri or t o 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 / 1 5 5
tra nsf usi o n, if cli nicall y feasi ble, t o n ot c o nf o u n d t his w or k - u p. I n ge neral, bl o o d 
tra nsf usi o ns a n d er yt hr oi d gr o wt h fact ors are per mitte d as cli nicall y i n dicate d.
G ui da nce f or e val uati o n of s us pecte d a ne mia is pr o vi de d i n  Ta ble 9.
If partici pa nt rec o vers t o Gra de 1 a ne mia wit h a bl o o d tra nsf usi o n, s us pe n d t he ne xt d osi n g u ntil 
sta ble c o ntr ol of a ne mia is c o nfir me d, a n d t he u n derl y i n g ca use of a ne mia is res ol ve d. As g ui da nce, 
t he I nvesti gat or s h o ul d wait f or at least 1 wee k p ost-tra nsf usi o n t o c o nfir m sta bilizati o n. If a ne mia 
is sta bilize d a n d t he d osi n g criteria ( H g b Gra de 1 or baseli ne) are met 1 wee k after t he tra nsf usi o n, 
t he I nvesti gat or ca n procee d t o t he ne xt d osi n g.
T a ble 9
E v al u ati o n G ui d a nce of S us pecte d A ne mi a
B a si c A n e mi a E v al u ati o n
1. 
C B C wit h e m p h a si s o n r e d c ell i n di c e s ( e. g., H g b, h e m at o crit, M C V, R D W,  M C H, M C H C, r eti c ul o c yt e s 
c o u nt s).
2. 
If i n di c at e d a n d at cli ni c al di s cr eti o n, t h e f oll o wi n g s h o ul d b e c o n si d er e d:
a. 
Ir o n st u di e s ( TI B C, F erriti n, F e)
b. 
S er u m F ol at e a n d Vit B 1 2 v al u e s
c. 
C o a g ul ati o n f a ct or s ( P T, P T T, I N R)
d. 
F e c al o c c ult bl o o d t e sti n g
e. 
Uri n al y si s
f. 
H or m o n e p a n el: T S H, Er yt hr o p oi eti n
g. 
P eri p h er al bl o o d s m e ar f o r c ell m or p h ol o gi c al a s s e s s m e nt
F urt h er R e c o m m e n d ati o n B a s e d o n S u s p e ct e d Eti ol o g y  (i n A d diti o n t o B a si c A n e mi a T e sti n g)
S u s p e ct e d h e m ol y si s: 
Bilir u bi n l e v el, L D H, C o o m b s t e st, fi bri n o g e n, h a pt o gl o bi n, d- Di m er
C o n si d er H e m at ol o g y c o n s ult ati o n.
S u s p e ct e d bl e e di n g:
C o n si d er i m a gi n g/i nt er v e nti o n al r a di ol o g y c o n s ult ati o n a s i n di c at e d
C o n si d er e n d o s c o p y, a s cli ni c all y i n di c at e d.
C o n si d er i m a gi n g, a s cli ni c all y i n di c at e d.
S u s p e ct e d a pl a sti c a n e mi a:   
H e m at ol o g y c o n s ult ati o n.
C o n si d er b o n e m arr o w a s pir ati o n/ m or p h ol o gi c e v al u ati o n.
C B C = c o m pl et e bl o o d c o u nt; H g b = h e m o gl o bi n; I N R = i nt er n ati o n al n or m ali z e d r ati o; L D H = l a ct at e d e h y dr o g e n a s e; 
M C H
=
m e a n c or p u s c ul ar h e m o gl o bi n; M C H C = m e a n c or p u s c ul ar h e m o gl o bi n c o n c e ntr ati o n; M C V
= m e a n 
c or p u s c ul ar v ol u m e; P T = pr ot hr o m bi n ti m e; P T T = p arti al t hr o m b o pl a sti n ti m e; R D W = r e d bl o o d c ell di stri b uti o n 
wi dt h; TI B C = t ot al ir o n bi n di n g c a p a cit y; a n d T S H = t h yr oi d-sti m ul ati n g h or m o n e.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 / 1 5 5
6. 9. 5
Blee di n g A d verse E ve nts
Blee di n g A Es are A E SIs a n d c o nsi dere d a n i m p orta nt i de ntifie d ris k f or M 7 8 2 4.
M uc os al/ N o n -t u m or Blee di n g
Partici pa nts treate d wit h M 7 8 2 4
were c o m m o nl y re p orte d wit h mil d t o m o derate m uc osal A Es 
s uc h as e pista xis, he m o pt ysis, gi n gi val blee di n g a n d he mat uria. I n ge neral, t hese reacti o ns res ol ve 
wit h o ut disc o nti n uati o n of treat me nt. 
F or Gra de 
2 n o n- t u m or blee di n g, see Secti o n 6. 8
f or ge neral ma na ge me nt 
of Gra de 2 
treat me nt-relate d T E A Es.
F or Gra de 3 n o n- t u m or blee di n g, st u d y treat me nt m ust be per ma ne ntl y disc o nti n ue d u nless a n 
alter nati ve e x pla nati o n ca n be i de ntifie d (s uc h as c o nc o mita nt use of a ntit hr o m b otic a ge nts, 
tra u matic e ve nt, etc.). I n case of alter nati ve e x pla nati o ns f or t he Gra de 3 blee di n g e ve nt, st u d y 
treat me nt s h o ul d be hel d u ntil t he e ve nt rec o vers t o Gra de ≤ 1. U p o n res u m pti o n of t he st ud y  
i nter ve nti o n d ose s h o ul d be re d uce d t o 6 0 0 m g Q 2 W or c orres p o n di n g v ol u me of matc hi n g 
place b o if Gra de 3 or se vere blee di n g e ve nt is o bser ve d re gar dless of ca usalit y wit h t he st u d y 
i nter ve nti o n.
Pre parati o n a n d rec or di n g of re d uce d M 7 8 2 4/ place b o 
d oses are descri be d i n 
Secti o n 6. 3. 2 . T here are n o d ose re d ucti o ns f or d ur val u ma b.
F or Gra de 4 n o n- t u m or blee di n g, treat me nt m ust be per ma ne ntl y disc o nti n ue d if n o alter nati ve 
e x pla nati o n is i de ntifie d.
I n case of ra pi d decrease of he m o gl o bi n ( H g b), s uc h as a decrease greater t ha n 3. 0 g/ d L acr oss a 
2- wee k peri o d, wit h h ol d t he s u bse q ue nt c ycles of st u d y i nter ve nti o n u ntil H g b is sta bilize d a n d d o 
a t h or o u g h assess me nt of blee di n g (f or e xa m ple, u p per a n d l o wer G I e n d osc o p y, e n ha nce me nt C T 
etc.); if Gra de 1 or greater blee di n g is o bser ve d or s us pecte d, wit h h ol d t he M 7 8 2 4 / place b o u ntil 
t he blee di n g is res ol ve d/c o ntr olle d a n d res u me t he d ose of M 7 8 2 4
re d uce d t o 6 0 0 m g Q 2 W or 
c orres p o n di n g v ol u me of matc hi n g place b o. Pre parati o n a n d rec or di n g of re d uce d M 7 8 2 4/ place b o 
d oses are descri be d i n Secti o n 6. 3. 2.  T here are n o d ose re d ucti o ns f or d ur val u ma b . O nce H g b 
decrease is rec o vere d t o ≤ Gra de 1 or baseli ne a n d sta bl y co ntr olle d, t he I n vesti gat or is e nc o ura ge d 
t o c o m m u nicate wit h Me dical M o nit or t o re-escalate t he d ose. T he d ose of M 7 8 2 4 / place b o ma y 
be re-escalate d t o f ull d ose (M 7 8 2 4
1 2 0 0 m g or c orres p o n di n g v ol u me f or place b o) o nce H g b is 
sta bilize d wit h o ut f urt her nee d f or bl o o d tra nsf usi o n i n t he s u bse q ue nt c ycles. T he ti mi n g of 
re-escalati o n m a y  nee d a case-b y -case decisi o n. S ee Secti o n 6. 9. 4 re gar di n g sta bilizati o n of 
a ne mia.
T u m or Blee di n g
Partici pa nts treate d wit h M 7 8 2 4 were re p orte d i n l o wer fre q ue ncies, wit h Gra de ≥3 he m orr ha ges 
i ncl u di n g t u m or blee di n g. F or Gra de ≥ 2 t u m or blee di n g, st u d y treat me nt m ust be hel d u ntil t he 
e ve nt rec o vers t o Gra de ≤ 1. U p o n res u m pti o n of t he st u d y  i nter ve nti o n dose s h o ul d be re d uce d t o 
6 0 0 m g Q 2 W or c orres p o n di n g v ol u me of matc hi n g place b o if Gra de 3 or se vere blee di n g e ve nt 
is o bser ve d re gar dless of ca usalit y wit h t he st u d y inter ve nti o n. Treat me nt s h o ul d be per ma ne ntl y 
disc o nti n ue d if t he I n vesti gat or c o nsi ders t he partici pa nt t o be at ris k f or a d diti o nal se vere blee di n g.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 / 1 5 5
6. 9. 6
Ot her I m p ort a nt P ote nti al Ris ks
6. 9. 6. 1 
I m p aire d w o u n d he ali n g
I m paire d w o u n d heali n g is c o nsi dere d as a n i m p orta nt p ote ntial ris k (a t he oretical ris k base d o n 
literat ure fi n di n gs) f or M 7 8 2 4 , gi ve n t he r ole of T G F-β i n w o u n d he ali n g. Ma na ge me nt s h o ul d be 
disc usse d wit h t he Me dical M o nit or f or partici pa nts re q uiri n g s ur ger y on st u d y. It is rec o m me n de d 
t o h ol d st u d y inter ve nti o n f or a p pr o xi matel y 4 wee ks p ost maj or s ur ger y for o bser vati o n. 
P ost o perati ve w o u n d heali n g will be cl ose l y m o nit ore d.
6. 9. 6. 2 
E m br y ofet al T o xicit y
E m br y ofetal t o xicity is a k n o w n ris k of t he P D -1/ P D -L 1  tar geti n g class a n d is c o nsi dere d a n 
i m p orta nt p ote ntial ris k f or M 7 8 2 4 . A ni mal m o dels li n k t he P D-1/ P D -L 1  si g nali n g pat h wa y wit h 
mai nte na nce of pre g na nc y  thr o u g h i n ducti o n of mater nal i m m u ne t olera nce t o fetal tiss ue. A n 
a p pr o priate c o ntrace pti o n war ni n g is pr o vi de d as part of t he i ncl usi o n criteria. Pre g na nt a n d 
breastfee di n g w o me n are n ot all o we d i n t he M 7 8 2 4 st u d y, a n d a de q uate c o ntrace pti ve meas ures 
are rec o m me n ded d uri n g t he st u d y to mi ni mize or eli mi nate t he p ote ntial ris k t o t he de vel o pi n g 
fet us.
Res pecti ve safet y meas ures t o miti gate ris ks c o m prise i ncl usi o n/e xcl usi o n criteria f or partici pati o n 
i n cli nical st u dies wit h M 7 8 2 4 , g ui da nce f or pre ve nti o n, m o nit ori n g, a n d me dical ma na ge me nt of 
p ote ntial ris ks, as well as g ui da nce o n st u d y i nter ve nti o n i nterr u pti o n or disc o nti n uati o n.
6. 1 0
Ris k  M a n a ge me nt f or C he m or a di ati o n
T o xicities of c C R T ma y  arise t o differe nt de grees at differe nt ti me p oi nts i n vari o us s u b p o p ulati o ns 
a n d sce nari os. First, wit h re gar ds t o c he m ot hera p y, t he prese nce of i m p orta nt varia bles s uc h as 
a ge, perf or ma nce stat us, a n d pree xisti n g c o m or bi dities pla y s a lar ge r ole i n h o w well t he 
partici pa nts ca n t olerate c C R T. S o me partici pa nts ma y  als o be nefit fr o m c he m ot hera p y alterati o ns 
i n d oses, i nter vals or e ve n s pecific c o m p o u n ds a n d re gi me ns. Sec o n d, fr o m t he R T pers pecti ve, 
beca use a d va nce d ra di ot hera py tec h ni q ues ha ve de vel o pe d, a n d i ma ge-g ui de d R T has n o w bec o me 
t he sta n dar d of care, fe wer R T-relate d t o xicities are e x pecte d (Ver ma 2 0 1 7 ). Ris k ma na ge me nt of 
c he m ora diati o n si de effects mai nl y  incl u des earl y detecti o n, st u d y inter ve nti o n m o dificati o n a n d 
pr o m pt t o xicit y ma na ge me nt. Base d o n N C C N g ui deli nes f or t he treat me nt of Sta ge III N S C L C, 
R T i nterr u pti o ns a n d d ose re d ucti o ns f or ma na gea ble ac ute t o xicities s h o ul d be a v oi de d b y  
e m pl o yi n g s u p p orti ve care.
Ma na ge me nt 
a n d w or k u p m ust be d o ne i n acc or da nce wit h la beli n g i nstr ucti o ns a n d l ocal 
i nstit uti o nal g ui deli nes a n d i n disc ussi o n wit h t he Me dical M o nit or. In case of clear c orrelati o n of 
A Es a n d c C R T, treat me nt wit h eit her M 7 8 2 4 or d ur val u ma b s h o ul d be c o nsi dere d a n d disc usse d 
wit h t he Me dical M o nit or. 
Car b o plati n/ Paclita xel
See  Ta ble 1 0 a n d Ta ble 1 1 f or g ui deli nes f or wit h h ol di n g st u d y  i nter ve nti o n f or he mat ol o gic a n d 
mai n 
n o n he mat ol o gic t o xicities, res pecti vel y. D ose 
m o dificati o ns 
( d ose dela y s a n d d ose 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 / 1 5 5
re d ucti o ns) f or t o xicities n ot liste d bel o w s h o ul d be ma de i n acc or da nce wit h la beli n g i nstr ucti o ns 
a n d l ocal i nstit uti o nal g ui deli nes. Disc o nti n uati o n of c he m ot hera p y d ue t o A Es s h o ul d als o be d o ne 
i n acc or da nce wit h t he c he m ot hera p y la bel a n d l ocal i nstit uti o nal practice a n d disc usse d wit h t he 
S p o ns or.
W he n 
st u d y inter ve nti o n is wit h hel d f or he mat ol o gic t o xicities, re peat C B C wee kl y ( or m ore 
fre q ue ntly if cli nicall y in dicate d) a n d res u me c he m ot hera p y base d o n Ta ble 1 0 . D oses of 
car b o plati n/ paclita xel t hat are misse d will n ot be ma de u p a n d will be d oc u me nte d. If st u d y 
i nter ve nti o n m ust be wit h hel d f or greater t ha n t w o c o nsec uti ve wee ks, c o nsi der wit h h ol di n g 
car b o plati n/ paclita xel per ma ne ntl y  f or t he d urati o n of c o nc urre nt ra di ot hera p y. 
A c ha n ge of > 1 0 % i n t he ser u m creati ni ne, base d o n wee kl y  calc ulate d creati ni ne cleara nce, will 
warra nt a recalc ulati o n of t he car b o plati n d ose. 
If a Gra de 2 a ne mia d oes n ot res ol ve t o Gra de ≤ 1 b y  the last da y  of t he c urre nt c ycle b ut is 
ma na gea ble a n d/ or n ot cli nicall y  rele va nt, t he Me dical M o nit or s h o ul d be c o ns ulte d t o assess if it 
is cli nicall y reas o na ble t o a d mi nister t he f oll o wi n g i nf usi o n.
H y perse nsiti vit y  reacti o ns: A na p h y la xis a n d se vere h y perse nsiti vit y  reacti ons c haracterize d b y  
d y s p nea a n d h y p ote nsi o n re q uiri n g treat me nt. A n gi oe de ma, a n d ge neralize d urticaria ha ve 
occ urre d i n 2 % t o 4 % of patie nts recei vi n g paclita xel i n cli nical st u dies. All partici pa nts recei vi n g 
paclita xel s h o ul d be pretreate d wit h c ortic ost er oi ds, di p he n h ydra mi ne, a n d H 2 a nta g o nists at least 
3 0 mi n utes pri or paclita xel a d mi nistrati o n. Partici pa nts w h o e x perie nce se vere h y perse nsiti vit y  
reacti o ns t o paclita xel s h o ul d n ot be re-c halle n ge d wit h t he dr u g. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 / 1 5 5
T a ble 1 0 
Gr a di n g  
a n d  
G ui deli nes  
f or  
D ose  
M o dific ati o ns  
of 
C ar b o pl ati n/ P aclit a xel Rel ate d He m at ol o gic A d verse E ve nts
C ar b o pl ati n/ P a clit a x el R el at e d H e m at ol o gi c A d v er s e 
E v e nt s ( C T C A E v 5. 0)
P a clit a x el 
C ar b o pl ati n
N e utr o p e ni a
G 1 ( 1 5 0 0 -1 9 9 9/ m m 3 )
N o c h a n g e
N o c h a n g e
G 2 ( 1 0 0 0 -1 4 9 9/ m m 3 )
N o c h a n g e
N o c h a n g e
G 3 ( 5 0 0 -9 9 9/ m m 3 )
Wi t h h ol d t h er a p y 
Wi t h h ol d t h er a p y
G 4 ( < 5 0 0/ m m 3 )
Wi t h h ol d t h er a p y 
Wi t h h ol d t h er a p y
N e utr o p e ni c f e v er 
A N C < 1 0 0 0/ m m 3 wit h a si n gl e t e m p er at ur e of > 3 8. 3° C 
( 1 0 1° F) 
or 
s u st ai n e d t e m p er at ur e of ≥ 3 8° C ( 1 0 0. 4° F) f or m or e t h a n 
o n e h o ur
Wi t h h ol d t h er a p y 
Wi t h h ol d t h er a p y
T hr o m b o c y t o p e ni a
G 1 ( < L L N -7 5, 0 0 0/ m m 3 )
N o c h a n g e
N o c h a n g e
G 2 ( 5 0, 0 0 0 -7 4, 9 9 9/ m m 3 )
Wi t h h ol d t h er a p y 
Wi t h h ol d t h er a p y
G 3 ( 2 5, 0 0 0 -4 9, 9 9 9/ m m 3 )
Wi t h h ol d t h er a p y 
Wi t h h ol d t h er a p y
G 4 ( < 2 5, 0 0 0/ m m 3 )
Wi t h h ol d t h er a p y 
Wi t h h ol d t h er a p y
A N C = a b s ol ut e n e utr o p hil c o u nt
R ef er e n c e:  Br a dl e y 2 0 1 5
Ot h er h e m at ol o gi c t o xi citi e s: T h er e will b e n o d o s e m o difi c ati o n s/r e d u cti o n s f or c h a n g e s i n l e u c o p e ni a a n d 
l y m p h o p e ni a.
If st u d y i nt er v e nti o n i s wit h h el d f or gr e at er t h a n t w o c o n s e c uti v e w e e k s, p er m a n e nt di s c o nti n u ati o n s h o ul d b e 
c o n si d er e d. B e n efit of r e s u mi n g tr e at m e nt aft er wit h h ol di n g > 2 w e e k s m u st b e e v al u at e d o n a c a s e b y c a s e b a si s
a n d di s c u s s e d wit h t h e M e di c al M o nit or
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 / 1 5 5
T a ble 1 1 
D ose  
M o dific ati o ns  
of  
C ar b o pl ati n/ P aclit a xel  
Rel ate d  
M ai n 
N o n he m at ol o gic A d verse E ve nts
C ar b o pl ati n/ P a clit a x el R el at e d M ai n 
N o n h e m at ol o gi c A d v er s e E v e nt s 
( C T C A E v 5. 0)a, b
P a clit a x el 
C ar b o pl ati n
P ar o n y c hi a G 2
N o c h a n g e
N o c h a n g e
N e ur o p at h y
≤ G 1
N o c h a n g e
N o c h a n g e
G 2
H ol d t h er a p y u ntil r e s ol v e t o ≤ G 1. 
R e st art at f ull d o s e
N o c h a n g e
G 3
Di s c o nti n u e t h er a p y
N o c h a n g e
Ot h er n o n h e m at ol o gi c t o xi citi e s 
G 3
H ol d t h er a p y u ntil r e s ol v e t o ≤ G 2
H ol d t h er a p y u ntil r e s ol v e t o 
≤G 2
a M ai nt ai n d o s e f or t h e ≤ G 2 n o n h e m at ol o gi c t o xi citi e s n ot li st e d i n t hi s T a bl e. F oll o w t h e g ui d eli n e s li st e d i n t hi s 
T a bl e f or n e ur o p at h y. 
b R T s h o ul d c o nti n u e t o b e d eli v er e d f or ≤ Gr a d e 3 n o n h e m at ol o gi c t o xi citi e s i n or o ut si d e t h e r a di ati o n tr e at m e nt 
fi el d. R T s h o ul d b e wit h h el d f or all Gr a d e 4 n o n h e m at ol o gi c t o xi cit y i n or o ut si d e t h e tr e at m e nt fi el d a n d r e s u m e d 
o nl y w h e n t o xi cit y i s ≤ Gr a d e 2. If st u d y i nt er v e nti o n i s wit h h el d f or gr e at er t h a n t w o c o n s e c uti v e w e e k s, p er m a n e nt 
di s c o nti n u ati o n s h o ul d b e c o n si d er e d. B e n efit of r e s u mi n g tr e at m e nt aft er wit h h ol di n g > 2 w e e k s m u st b e 
e v al u at e d o n a c a s e b y c a s e b a si s a n d di s c u s s e d wit h t h e M e di c al M o nit or.
Cis plati n/ Et o p osi de
See Ta ble 1 2 f or pre d osi n g c o nsi derati o ns f or cis plati n. A de q uate h y drati o n m ust be e ns ure d 
bef ore a n d after cis plati n i nf usi o n t o re d uce t he ris k of ne p hr ot o xicit y . 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 / 1 5 5
T a ble 1 2 
Pre d osi n g C o nsi der ati o n f or Cis pl ati n
I s s u e/I n di c ati o n
R e c o m m e n d e d St e p s
Pr e- e m e si s
F oll o w c urr e nt M A S C C/ E S M O a or N C C N b g ui d eli n e s f or c h e m ot h er a p y -i n d u c e d 
n a u s e a a n d v o miti n g f or a “ hi g h ri s k” r e gi m e n
H y dr ati o n/
n e p hr ot o xi cit y
P er p a c k a g e i n s ert/ S m P C f o r ci s pl ati nc. Ci s pl ati n c a u s e s s e v er e c u m ul ati v e 
n e p hr ot o xi cit y. A uri n e o ut p ut of 1 0 0 m L/ h o ur or gr e at er will t e n d t o mi ni mi z e 
ci s pl ati n n e p hr ot o xi cit y. A d e q u at e h y dr ati o n m u st t h er ef or e b e m ai nt ai n e d t o 
c a u s e s uffi ci e nt di ur e si s pri or t o, d uri n g a n d aft e r tr e at m e nt wit h ci s pl ati n. N e xt 
t o I V i nf u si o n, f or c e d di ur e si s m a y b e r e q uir e d a n d m or e o v er p arti ci p a nt s ar e t o 
b e r e q u e st e d t o dri n k a p pr o pri at e q u a ntiti e s of li q ui d s f or 2 4 h o ur s aft er ci s pl ati n 
i nf u si o n t o e n s ur e a d e q u at e uri n e s e cr eti o n.
M y el o s u p pr e s si o n/
n e utr o p e ni a
R ef er t o t h e c urr e nt p a c k a g e i n s ert/ S m P C f or m o difi c ati o n s i n d o s e a n d 
s c h e d ul e of ci s pl ati n c. Fir st d o s e of ci s pl ati n s h o ul d b e wit h h el d if pl at el et c o u nt 
i s l e s s t h a n 1 0 0, 0 0 0 c ell s/ m m3 or n e utr o p hil c o u nt i s l e s s t h a n 1 5 0 0 c ell s/ m m 3 . 
D o s e m o difi c ati o n s f or s u b s e q u e nt a d mi ni str ati o n s will b e b a s e d o n t h e 
n e utr o p hil a n d pl at el et n a dir fr o m t h e pr e c e di n g c y cl e ( s e e  T a bl e 1 3 ).
A c c or di n g t o N CI -C T C A E v 5. 0 f e bril e n e utr o p e ni a ( F N) i s d efi n e d a s A N C 
< 1 0 0 0/ m m 3 a n d a si n gl e t e m p er at ur e of > 3 8. 3 d e gr e e s C ( 1 0 1 d e gr e e s F) or a 
s u st ai n e d t e m p er at ur e of ≥3 8 d e gr e e s C ( 1 0 0. 4 d e gr e e s F) f or m or e t h a n o n e 
h o ur. F N tr e at m e nt s h o ul d b e d o n e p er l o c al pr a cti c e a n d r e p ort e d i n e C R F. F N 
Pr o p h yl a xi s: A c c or di n g t o N C C N g ui d eli n e s f or t h e u s e of m y el oi d gr o wt h f a ct or s 
( v 1. 2 0 1 8)d , pri m ar y pr o p h yl a xi s wit h G-C S F i n or d er t o r e d u c e t h e ri s k of F N i s 
n ot r e c o m m e n d e d. S e c o n d ar y pr o p h yl a xi s wit h G -C S F s s h o ul d b e c o n si d er e d 
a n d t h e ri s k b e n efit a s s o ci at e d wit h t h eir u s e m u st b e c ar ef ull y e v al u at e d. 
I n v e sti g at ors m u st b e a w ar e t h at t h e u s e of G -C S F d uri n g c h e m or a di ati o n i s 
a s s o ci at e d wit h i n cr e a s e d i n ci d e n c e of s e v er e t hr o m b o c yt o p e ni a a n d a n e mi a. 
P arti ci p a nt s r e c ei vi n g G -C S F d uri n g c h e m or a di ati o n m u st b e cl o s el y m o nit or e d 
f or t h e s e a d v er s e e v e nt s. T h e d o s a g e i n str u cti o n s s h o ul d f oll o w t h e l o c al 
g ui d eli n e s or t h e N C C N g ui d eli n e s. 
Ot ot o xi cit y/
n e ur ot o xi cit y
P er S m P C f or ci s pl ati n c. Ci s pl ati n i s pr o v e n t o b e c u m ul ati v e ot ot o xi c a n d 
n e ur ot o xi c. N e ur ol o gi c e x a mi n ati o n a n d m o nit ori n g of p ot e nti al ot ot o xi cit y m u st 
b e p erf or m e d pri or t o e a c h ci s pl ati n d o si n g a n d d uri n g t h e st u d y i nt er v e nti o n.
A N C = A b s ol ut e n e utr o p hil c o u nt , C S F = c ol o n y sti m ul ati n g f a ct or, E S M O = E ur o p e a n S o ci et y f or M e di c al 
O n c ol o g y , F N = f e bril e n e utr o p e ni a , G-C S F = gr a n ul o c yt e -c ol o n y sti m ul ati n g f a ct or , I V = i ntr a v e n o u s ,
M A S C C
= M ulti n ati o n al A s s o ci ati o n of S u p p orti v e C ar e i n C a n c er , N C C N = 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 , N CI -C T C A E = N ati o n al C a n c er I n stit ut e C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s , 
S m P C = s u m m ar y of pr o d u ct c h ar a ct eri sti c s.
a A n n al s of O n c ol o g y 2 1 ( S u p pl e m e nt 5): v 2 3 2 – v 2 4 3, 2 0 1 0
b N C C N Cli ni c al Pr a cti c e G ui d eli n e s i n O n c ol o g y [ N C C N G ui d eli n e s ®] - A nti e m e si s , v er si o n 1. 2 0 1 9
c htt p s:// w w w. m e di ci n e s. or g. u k/ e m c/ m e di ci n e/ 2 5 9 4 4 
d N C C N g ui d eli n e s M y el oi d gr o wt h f a ct or s v er si o n 1. 2 0 1 8
See Ta ble 1 3 a n d Ta ble 1 4 f or d ose m o dificati o ns of cis plati n/et o p osi de i n case of he mat ol o gic 
a n d n o n he mat ol o gic a d verse e ve nts, res pecti vel y. F or t o xicities ≥ Gra de 3, treat me nt s h o ul d be 
dela y e d u ntil res ol uti o n t o less t ha n or e q ual t o t he patie nt’s baseli ne val ue bef ore res u m i n g st u d y 
i nter ve nti o n at a d ose re d ucti o n. D ose m o dificati o ns ( d ose dela y s a n d d ose re d ucti o ns) f or 
t o xicities n ot liste d a b o ve s h o ul d be ma de i n acc or da nce wit h la beli n g i nstr ucti o ns a n d l ocal 
i nstit uti o nal g ui deli nes. Disc o nti n uati o n of c he m ot hera p y d ue t o A Es s h o ul d als o be d o ne i n 
acc or da nce wit h t he c he m ot hera p y la bel a n d l ocal i nstit uti o nal practice a n d disc usse d wit h t he 
S p o ns or. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 / 1 5 5
W he n 
st u d y inter ve nti o n is wit h hel d f or he mat ol o gic t o xicities, re peat C B C wee kl y ( or m ore 
fre q ue ntly if cli nicall y i n di cate d) a n d res u me c he m ot hera p y base d o n  Ta ble 1 3 . Treat me nt s h o ul d 
be res u me d if o n t he da y  of t he a d mi nistrati o n platelet c o u nt is ≥ 1 0 0 × 1 0 9/ L a n d ne utr o p hil c o u nt 
is 1. 5 × 1 0 9/ L, per a p pr o ve d pr o d uct la bel or sta n dar d practice . D oses of cis plati n/et o p osi de t hat are 
misse d will n ot be ma de u p a n d will be d oc u me nte d.
T a ble 1 3 
D ose Re d ucti o ns f or Cis pl ati n/ Et o p osi de -rel ate d He m at ol o gic A d verse 
E ve nts  
Ci s pl ati n/ Et o p o si d e -r el at e d H e m at ol o gi c A d v er s e E v e nt s   
Ci s pl ati n 
Et o p o si d e
N e utr o p hil s 
Pl at el et s
> 0. 5 x 1 0 9 / L
> 5 0 x 1 0 9 / L
1 0 0 % of pr e vi o u s 
d o s e
1 0 0 % of pr e vi o u s d o s e
< 0. 5 x 1 0 9 / L
≥ 5 0 x 1 0 9 / L
7 5 % of pr e vi o u s 
d o s e
7 5 % of pr e vi o u s d o s e
< 1. 0 x 1 0 9 / L wit h f e v er 
≥3 8. 5° C
≥ 5 0 x 1 0 9 / L
7 5 % of pr e vi o u s 
d o s e
7 5 % of pr e vi o u s d o s e
A n y c o u nt
< 5 0 x 1 0 9 / L
5 0 % of pr e vi o u s 
d o s e
7 5 % of pr e vi o u s d o s e
A n y c o u nt
≤ 2 5 x 1 0 9 / L < 5 0 x 1 09 / L wit h 
bl e e di n g
5 0 % of pr e vi o u s 
d o s e
5 0 % of pr e vi o u s d o s e
T a ble 1 4 
D ose 
Re d ucti o ns 
f or Cis pl ati n/ Et o p osi de -rel ate d 
N o n he m at ol o gic 
A d verse E ve nts
Ci s pl ati n/ Et o p o si d e -r el at e d N o n h e m at ol o gi c 
A d v er s e E v e nt s ( C T C A E v 5. 0)
Ci s pl ati n
Et o p o si d e
H e p ati c/ Tr a n s a mi n a s e el e v ati o n, G 3 -G 4
7 5 % of pr e vi o u s d o s e
7 5 % of pr e vi o u s d o s e
M u c o siti s, G 3 -G 4
1 0 0 % of pr e vi o u s d o s e
7 5 % of pr e vi o u s d o s e
E s o p h a giti s, G 3 -G 4
S e e  T a bl e 1 8
S e e  T a bl e 1 8
N e ur ot o xi cit y/ Ot ot o xi cit y, G 2
5 0 % of pr e vi o u s d o s e
1 0 0 % of pr e vi o u s d o s e
N e ur ot o xi cit y/ Ot o t o xi cit y, G 3
Di s c o nti n u e
7 5 % of pr e vi o u s d o s e
N e ur ot o xi cit y/ Ot ot o xi cit y, G 4
Di s c o nti n u e
Di s c o nti n u e
Ot h er G 1 -G 2
1 0 0 % of pr e vi o u s d o s e  
1 0 0 % of pr e vi o u s d o s e
Ot h er G 3 -G 4
7 5 % of pr e vi o u s d o s e
7 5 % of pr e vi o u s d o s e
Cis plati n/ Pe metre xe d
See  Ta ble 1 5 t o Ta ble 1 7 f or d ose m o dificati o n of cis plati n/ pe metre xe d i n case of he mat ol o gic a n d 
n o n he mat ol o gic a d verse e ve nts. D ose m o dificati o ns ( d ose dela y s a n d d ose re d ucti o ns) f or 
t o xicities n ot liste d a b o ve s h oul d be ma de i n acc or da nce wit h la beli n g i nstr ucti o ns a n d l ocal 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 / 1 5 5
i nstit uti o nal g ui deli nes. Disc o nti n uati o n of c he m ot hera p y d ue t o A Es s h o ul d als o be d o ne i n 
acc or da nce wit h t he c he m ot hera p y la bel a n d l ocal i nstit uti o nal practice a n d disc usse d wit h t he 
S p o ns o r. W he n st u d y inter ve nti o n is wit h hel d f or he mat ol o gic t o xicities, re peat C B C wee kl y ( or 
m ore fre q ue ntly if cli nicall y in dicate d) a n d res u me c he m ot hera p y base d o n Ta ble 1 5. D oses of 
cis plati n/ pe metre xe d t hat are misse d will n ot be ma de u p a n d will be d oc u me nte d.
T a ble 1 5 
D ose M o dific ati o ns f or Pe metre xe d a n d Cis pl ati n B ase d o n He m at ol o gic 
T o xicities 
D a y
A N C
( x 1 09 / L)
Pl at el et
( x 1 09 / L)
D o s e f or B ot h P e m etr e x e d a n d
Ci s pl ati n ( m g/ m 2 )
O n D a y 1 of t h e
s u b s e q u e nt c y cl e
≥ 1. 5  
a n d 
≥ 1 0 0  
1 0 0 % of pr e vi o u s d o s e
O n D a y 1 of t h e
s u b s e q u e nt c y cl e
< 1. 5  
or  
< 1 0 0  
d el a y 1 w e e k
Aft er 1 -w e e k d el a y  
≥ 1. 5  
a n d  
≥ 1 0 0  
1 0 0 % of pr e vi o u s d o s e
Aft er 1 -w e e k d el a y 
< 1. 5  
or  
< 1 0 0 
n otif y pri n ci p al s y s t e mi c t h er a p y I n v e sti g at or or 
hi s/ h er d e si g n e e t o d et er mi n e if f urt h er 
c h e m ot h er a p y i s p o s si bl e
A n y ti m e 
≥ 0. 5  
a n d  
≥ 5 0 
1 0 0 % of pr e vi o u s d o s e
A n y ti m e 
< 0. 5  
a n d   
≥ 5 0 
7 5 % of pr e vi o u s d o s e
A n y ti m e 
A n y  
a n d  
< 5 0 
7 5 % of pr e vi o u s d o s e
A n y ti m e 
A N C < 1. 0 wit h f e v er d efi n e d a s 
F e v er i s d efi n e d a s t e m p er at ur e 
≥3 8. 5º C o n 1 r e a di n g.
7 5 % of pr e vi o u s d o s e
A n y ti m e 
Pl at el et s < 5 0 wit h bl e e di n g
r e g ar dl e s s of A N C
5 0 % of pr e vi o u s d o s e
R ef er e n c e:  S e n a n 2 0 1 6
A N C = a b s ol ut e n e utr o p hil c o u nt
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 / 1 5 5
T a ble 1 6 
D ose  
M o dific ati o ns  
f or 
Pe metre xe d 
a n d 
Cis pl ati n  
B ase d 
o n 
N o n he m at ol o gic T o xicities
D a y 
E v e nt s 
D o s e of P e m etr e x e d
( m g/ m2 )
D o s e f or Ci s pl ati n
( m g/ m2 )
O n D a y 1 of t h e
s u b s e q u e nt c y cl e
Cr Cl ≥ 4 5 m L/ mi n 
1 0 0 % of pr e vi o u s d o s e  
1 0 0 % of pr e vi o u s d o s e
O n D a y 1 of t h e
s u b s e q u e nt c y cl e
Cr Cl < 4 5 m L/ mi n 
d el a y 1 w e e k 
d el a y 1 w e e k
If aft er 1-w e e k
d el a y
Cr Cl ≥ 4 5 m L/ mi n 
1 0 0 % of pr e vi o u s d o s e  
1 0 0 % of pr e vi o u s d o s e
a n d i n cr e a s e pr e - a n d
p o st -ci s pl ati n h y dr ati o n
If aft er 1-w e e k
d el a y
Cr Cl < 4 5 m L/ mi n 
n otif y pri n ci p al s y st e mi c
t h er a p y I n v e sti g at or or
hi s/ h er d e si g n e e t o
d et er mi n e if f urt h er
c h e m ot h er a p y i s p o s si bl e
n otif y pri n ci p al s y st e mi c
t h er a p y I n v e sti g at or or
hi s/ h er d e si g n e e t o
d et er mi n e if f urt h er
c h e m ot h er a p y i s p o s si bl e
A n y 
C T C A E Gr a d e 3 or 4
n a u s e a a n d/ or v o miti n g
1 0 0 % of pr e vi o u s d o s e
a n d s h o ul d b e m a n a g e d
wit h a p pr o pri at e c h a n g e s
i n a ntie m eti c r e gi m e n
1 0 0 % of pr e vi o u s d o s e
A n y 
C T C A E Gr a d e 3 or 4
m u c o siti s
5 0 % of pr e vi o u s d o s e   
1 0 0 % of pr e vi o u s d o s e
A n y 
C T C A E Gr a d e 3
e s o p h a giti s a
h ol d at t h e p h y si ci a n’ s
di s cr eti o n
h ol d at t h e p h y si ci a n’ s
di s cr eti o n
A n y 
C T C A E Gr a d e 4
e s o p h a giti s b
h ol d p e m etr e x e d 
h ol d ci s pl ati n
A n y 
C T C A E Gr a d e 3 or 4
di arr h e a or a n y gr a d e
r e q uiri n g h o s pit ali z ati o n
7 5 % of pr e vi o u s d o s e  
7 5 % of pr e vi o u s d o s e
A n y 
Ot h er C T C A E Gr a d e 3 or 
4 
7 5 % of pr e vi o u s d o s e  
7 5 % of pr e vi o u s d o s e
R ef er e n c e:  S e n a n 2 0 1 6
Cr Cl = cr e ati ni n e cl e ar a n c e; C T C A E = C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s.
a Gr a d e 3 e s o p h a giti s will o c c ur i n a si g nifi c a nt n u m b er of p ati e nt s t o w ar d t h e e n d of r a di ati o n t h er a p y. F or
p arti ci p a nt s w h o e x p eri e n c e t hi s e v e nt e arli er i n t h e c o ur s e of t h ei r tr e at m e nt t h a n a nti ci p at e d, t h e a d vi c e w o ul d b e 
t o h ol d c h e m ot h er a p y a n d a s s e s s at w e e kl y i nt er v al s. If s y m pt o m s do n ot pr o gr e s s at t h e ti m e of 
a s s e s s m e nt, c h e m ot h er a p y c a n b e r e s u m e d at 7 5 % of pr e vi o u s d o s e f or b ot h dr u g s. If st u d y i nt er v e nti o n i s
wit h h el d f or gr e at er t h a n t w o c o n s e c uti v e w e e k s, p er m a n e nt di s c o nti n u ati o n s h o ul d b e c o n si d er e d. B e n efit of 
r e s u mi n g tr e at m e nt aft er wit h h ol di n g > 2 w e e k s m u st b e e v al u at e d o n a c a s e b y c a s e b a si s a n d di s c u s s e d wit h t h e 
M e di c al M o nit or
b Gr a d e 4 e s o p h a git i s r e s ult s i n h ol di n g c h e m ot h er a p y u ntil t o xi cit y r e s ol v e s t o ≤ Gr a d e 2, a n d t h e n c h e m ot h er a p y
m a y b e r e s u m e d at 7 5 % of pr e vi o u s d o s e f or b ot h dr u g s. If st u d y i nt er v e nti o n i s wit h h el d f or gr e at er t h a n t w o 
c o n s e c uti v e w e e k s, p er m a n e nt di s c o nti n u ati o n s h o ul d b e c o n si d er e d. B e n efit of r e s u mi n g tr e at m e nt aft er 
wit h h ol di n g > 2 w e e k s m u st b e e v al u at e d o n a c a s e b y c a s e b a si s a n d di s c u s s e d wit h t h e M e di c al M o nit or
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
8 9 / 1 5 5
T a ble 1 7 
D ose M o dific ati o ns f or Cis pl ati n B ase d o n Ne ur ot o xicit y
N e ur ot o xi cit y
C T C A E ( v 5. 0) 
D o s e f or P e m etr e x e d
( m g/ m2 )
D o s e f or Ci s pl ati n
( m g/ m2 )
Gr a d e 0 or 1 
1 0 0 % of pr e vi o u s d o s e 
1 0 0 % of pr e vi o u s d o s e
Gr a d e 2 
1 0 0 % of pr e vi o u s d o s e 
5 0 % of pr e vi o u s d o s e
Gr a d e 3 or 4 a 
di s c o nti n u e p e m etr e x e d 
di s c o nti n u e ci s pl ati n
R ef er e n c e: P R O C L AI M pr ot o c ol
C T C A E = C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s.
a At t h e di s cr eti o n of t h e att e n di n g p h y si ci a n, p arti ci p a nt s e x p eri e n ci n g Gr a d e 3 n e ur ol o gi c t o xi cit y a s a tr a n si e nt 
i s c h e mi c att a c k t h at h a s c o m pl et el y r e s ol v e d m a y n ot r e q uir e d o s e r e d u cti o n or di s c o nti n u ati o n.
T h oracic Ra diati o n T hera p y  
I M R T is re p orte d t o be ass ociate d wit h fe wer o bser ve d t o xicities a n d will be use d i n t his st u d y 
(see Secti o n 4. 2 ).
T he e x pecte d ac ute o nset si de effects of ra diati o n t hera py are re versi ble or per ma ne nt al o pecia, 
b o ne marr o w t o xicit y, s ki n pi g me ntati o n, p ne u m o nitis a n d es o p ha gitis (Ver ma 2 0 1 7 ). Pr o m pt 
rec o g niti o n of si g ns/sy m pt o ms & its earl y m a na ge me nt acc or di n gl y to l ocal sta n dar d practice will 
be be neficial.
T he late o nset si de effects ca n be b ut n ot li mite d t o ra diati o n-i n d uce d m y ocar ditis or tra ns verse 
m y elitis, alt h o u g h rarel y occ ur at d oses l o wer t ha n 5 0 G y . Ra di o gra p hic e vi de nce of ra diati o n 
c ha n ges i n or ga ns c o m pactl y sit uate d i n t he t h oracic ca vit y. L u n g wit h s u bse q ue nt l u n g fi br osis 
ca n occ ur i n l u n g tiss ue irra diate d at ≥ 2 0 G y  us uall y wit hi n t he first 6 m o nt hs after i nitiati o n of 
treat me nt. It is esse ntial t o s pare as m uc h n or mal l u n g as p ossi ble t o a v oi d s ym pt o matic l u n g i nj ur y.
Se e Ta ble 1 8 f or st u d y i nter ve nti o n m o dificati o ns f or n o n he mat ol o gic t o xicities i n R T fiel d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 0 / 1 5 5
T a ble 1 8 
Tre at me nt 
M o dific ati o ns 
f or N o n he m at ol o gic 
A d verse 
E ve nts 
i n 
R T -Fiel d
I n fi el d
C T C A E v 5. 0
R T
C h e m ot h er a p y
E s o p h a g u s/ p h ar y n x 
( o n d a y of c h e m ot h er a p y)
Gr a d e 2
N o c h a n g e
N o c h a n g e
E s o p h a g u s/ p h ar y n x 
( o n d a y of c h e m ot h er a p y)
Gr a d e 3
N o c h a n g e or h ol d ≤ 5 
d a y s
H ol d st u d y i nt er v e nti o n 
u ntil ≤ G 2
E s o p h a g u s/ p h ar y n x 
( o n d a y of c h e m ot h er a p y)
Gr a d e 4
H ol d st u d y i nt er v e nti o n 
u ntil ≤ G 2
H ol d st u d y i nt er v e nti o n 
u ntil ≤ G 2
P ul m o n ar y 
Gr a d e 3
H ol d st u d y i nt er v e nti o n 
u ntil ≤ G 2
H ol d st u d y i nt er v e nti o n 
u ntil ≤ G 2
P ul m o n ar y 
Gr a d e 4
Di s c o nti n u e
H ol d st u d y i nt er v e nti o n 
u ntil ≤ G 2
S ki n 
Gr a d e 3
N o c h a n g e
N o c h a n g e
S ki n 
Gr a d e 4
H ol d st u d y i nt er v e nti o n 
u ntil ≤ G 2
H ol d st u d y i nt er v e nti o n 
u ntil ≤ G 2
R ef er e n c e: R O T G 0 6 1 7 pr ot o c ol. 
If st u d y i nt er v e nti o n i s wit h h el d f or gr e at er t h a n t w o c o n s e c uti v e w e e k s, p er m a n e nt di s c o nti n u ati o n s h o ul d b e 
c o n si d er e d. B e n efit of r e s u mi n g tr e at m e nt aft er wit h h ol di n g > 2 w e e k s m u st b e e v al u at e d o n a c a s e b y c a s e b a si s 
a n d di s c u s s e d wit h t h e M e di c al M o nit or
W he n st u d y inter ve nti o n is wit h hel d, partici pa nts s h o ul d be m o nit ore d wee kl y  ( or m ore fre q ue ntly 
if cli nicall y i n dicate d). C he m ot hera p y a n d R T s h o ul d be res u me d base d o n Ta ble 1 8 . 
Detaile d descri pti o n, sta gi n g a n d ma na ge me nt of ac ute es o p ha geal t o xicit y, p ne u m o nitis, l u n g 
fi br osis a n d car di ot o xicit y is pr o vi de d bel o w.
Ac ute es o p h a ge al t o xicities
Ac ute es o p ha geal t o xicities ( A E T) i ncl u de es o p ha gitis, o d yn o p ha gia, a n d d y s p ha gia. Es o p ha geal 
c o m plai nts are c o m m o n wit h c o m bi ne d m o dalit y t hera py.  AE T d oes n ot c o nstit ute a reas o n t o 
i nterr u pt or dela y  ra di ot hera py o r c he m ot hera p y p r o vi de d earl y s y m pt o m ma na ge me nt, oral i nta ke
is s ufficie nt t o mai ntai n h y drati o n a n d n utriti o nal stat us. Partici pa nts s h o ul d be a d vise d t o a v oi d 
alc o h olic, aci dic, or s pic y fo o ds or be vera ges. Ac ute es o p ha gitis ma y  persist f or 4 t o 6 wee ks a n d 
t he se verity s h o ul d be cl osel y m o nit ore d u ntil res ol uti o n a n d disc usse d as dee me d necessar y . 
Refer t o  Ta ble 1 9 f or t he dia g n osis a n d gra di n g of es o p ha gitis. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 / 1 5 5
T a ble 1 9 
Di a g n osis a n d Gr a di n g of Es o p h a g itis
S c al e
Gr a d e 1
Gr a d e 2
Gr a d e 3
Gr a d e 4   
Gr a d e 5
C T C A E 
v 5. 0
A s y m pt o m ati c; 
cli ni c al or di a g n o sti c 
o b s er v ati o n s o nl y; 
i nt er v e nti o n n ot 
i n di c at e d
S y m pt o m ati c; 
alt er e d 
e ati n g/ s w all o wi n g; 
or al s u p pl e m e nt s 
i n di c at e d
S e v er el y alt er e d 
e ati n g/ s w all o wi n g; 
t u b e f e e di n g, T P N 
or h o s pit ali z ati o n 
i n di c at e d
Lif e -t hr e at e ni n g 
c o n s e q u e n c e s; 
ur g e nt 
o p er ati v e 
i nt er v e nti o n 
i n di c at e d
D e at h
C T C A E = C o m m o n T er mi n ol o g y Crit eri a f or A d v er s e E v e nt s , T P N = t ot al p ar e nt er al n utriti o n. 
St u d y  inter ve nti o n s h o ul d be i nterr u pte d f or Gra de 3 or greater d y s p ha gia or o d y n o p ha gia. A E T, 
w hic h t ypicall y ca n occ ur wit hi n 2 wee ks of t he i nitiati o n of st u d y inter ve nti o n a n d ma nifests as 
d y s p ha gia, o d y n o p ha gia, refl u x s ym pt o ms, etc. s h o ul d be p har mac ol o gicall y  ma na ge d wit h t he 
f oll o wi n g a p pr oach a n d s h o ul d be i nitiate d at t he first si g ns or s ym pt o ms of es o p ha geal t o xicit y. 
F or t he p har mac ol o gic ma na ge me nt c o nsi der t he f oll o wi n g:

Ket oc o naz ole 2 0 0 m g  PO * q d a y  OR Fl uc o naz ole 1 0 0 m g  PO q da y  until t he c o m pleti o n of 
ra diati o n
* N o oral f or m ulati o n is a p pr o ve d i n Ja pa n
Mi xt ure of: 2 % visc o us li d ocai ne: 6 0 cc; M y la nta ( n ot a vaila ble i n Ja pa n): 3 0 cc; S ucralfate 
( 1 g m/cc): 1 0 cc.  Ta ke 1 5 - 3 0 cc P O q 3- 4 hrs as nee de d. ( C o ntrai n dicati o ns: patie nts o n Dila nti n 
[pr o d uct na me i n Ja pa n: Ale viat u n ], Ci pr o [ pro d uct na me i n Ja pa n: Ci pr o xa n ], Di g o xi n) . F or m ore 
detaile d i nf or mati o n o n dr u g- dr u g i nteracti o ns wit h s ucralfate, refer t o  S ul oc ha na 2 0 1 6 .

Ra niti di ne 1 5 0 m g P O BI D ( or ot her H 2 bl oc ker or a pr ot o n p u m p i n hi bit or s uc h as o me praz ole) 
u ntil t he c o m pleti o n of ra diati o n

Gra de 4 es o p ha gitis: h ol d R T a n d c he m ot hera p y u ntil Gra de 2 or less. ( See als o  Ta ble 1 8)
P ne u m o nitis
Ac ute a n d late o n set p ne u m o nitis are i m p orta nt si de effects see n wit h c C R T. Ra diati o n 
p ne u m o nitis occ urs as a res ult of t he se nsiti vit y of n or mal l u n g pare nc h y ma t o R T a n d it is t ypicall y 
t h o u g ht t o be treat me nt li miti n g a n d life t hreate ni n g. T he ris k of de vel o pi n g ra diatio n p ne u m o nitis 
is directl y  relate d t o t he v ol u me of irra diate d l u n g, t he a m o u nt of ra diati o n gi ve n, a n d t he use of 
c o nc urre nt c he m ot hera p y. I n a rece nt re vie w i ncl u di n g o ver 6 0 0 0 patie nts fr o m se veral cli nical 
st u dies wit h C R T usi n g eit her cis plati n/et o p osi de or car b o plati n/ paclita xel, t he rate of Gra de 3 t o 
4 p ne u m o nitis was re p orte d t o be si milar bet wee n t he t w o re gi me ns ( 1 2 % vs 9 %; P = 0. 1 2, 
res pecti vely)  (Ste uer 2 0 1 7 ). I n t he P R O C L AI M st u d y, the i nci de nce of Gra de 2 p ne u m o nitis was 
si g nifica ntly hi g her i n patie nts treate d wit h cis plati n/ pe metre xe d f oll o we d b y  pe metre xe d.  Gra de 
3 t o 4 e ve nts were o bser ve d i n less t ha n 3 % of patie nts treate d wit h cis plati n/ pe metre xe d f oll o we d 
b y  pe metre xe d or cis plati n/et o p osi de f oll o we d b y t w o c ycles of c o ns oli dati o n plati n u m -base d 
d o u blet c he m ot hera p y  (Se na n 2 0 1 6 ). A d diti o nal ris k fact ors i ncl u de c o m or bi d l u n g disease, p o or 
baseli ne p ul m o nar y  f u ncti o n testi n g, a n d perf or ma nce stat us. S ym pt o ms of ra diati o n p ne u m o nitis, 
i ncl u di n g l o w-gra de fe ver, c o n gesti o n, dr y  co u g h, ple uritic c hest pai n, a n d a se nsati o n of c hest 
D oc u me nt N o. 0 9 0 0 ba be 8 1 5 2c 7 4e v 1. 0
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 / 1 5 5
f ull ness, us uall y  de vel o p 1 t o 3 m o nt hs after c o m pleti o n of ra diati o n t hera p y. See Ta ble 2 0 f or 
dia g n osis a n d gra di n g.
T a ble 2 0 
Di a g n osis a n d Gr a di n g f or P ne u m o nitis
S c al e
Gr a d e 1
Gr a d e 2
Gr a d e 3
Gr a d e 4   
Gr a d e 5
C T C A E 
v 5. 0
A s y m pt o m ati c; 
cli ni c al or 
di a g n o sti c 
o b s er v ati o n s o nl y; 
i nt er v e nti o n n ot 
i n di c at e d 
S y m pt o m ati c; 
m e di c al 
i nt er v e nti o n 
i n di c at e d; li miti n g 
i n str u m e nt al A D L
S e v er e s y m pt o m s; 
li miti n g s elf-c ar e 
A D L; o x y g e n 
i n di c at e d
Lif e -t hr e at e ni n g 
r e s pir at or y 
c o m pr o mi s e; 
ur g e nt i nt er v e nti o n 
i n di c at e d (e. g.,
tr a c h e ot o m y or 
i nt u b ati o n)
D e at h
A D L = A cti viti e s of D ail y L i vi n g, C T C A E = C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s 
P ne u m o nitis has als o bee n re p orte d i n patie nts treate d wit h a nti-P D -( L) 1 i n hi bit ors, t heref ore, 
p ne u m o nitis occ urri n g d uri n g c C R T m ust be ma na ge d as ir A E acc or di n g t o Secti o n 6. 9. 2 as it 
w o ul d be diffic ult t o i de ntif y the mai n dri ver of t his t o xicit y. T heref ore, p ne u m o nitis is st u d y 
s pecific A E SI d ue t o c o m bi nati o n wit h M 7 8 2 4.
I ncrease d l u n g t o xicit y in Ja pa nese patie nts wit h N S C L C treate d wit h i m m u n ot hera py has bee n 
re p orte d c o m pare d t o n o n -Ja pa nese patie nts (Va nstee n kiste 2 0 1 7 ). T he safety of c C R T pl us 
M 7 8 2 4 i n Ja pa nese partici pa nts will be first i n vesti gate d i n 1 2
Ja pa nese partici pa nts i n t he safet y  
r u n-i n part of t he st u d y.  As a n a d diti o nal safety meas ure, ser u m mar kers i ncl u di n g K L - 6, S P -A 
a n d S P -D will be meas ure d i n Ja pa nese partici pa nts e nr olle d i n Ja pa n f or p ote ntial early detecti o n 
of p ne u m o nitis. I ncreases i n t hese mar kers are n ot necessaril y i n dicat ors of p ne u m o nitis or 
i nterstitial l u n g disease (I L D). T heref ore, if cli nicall y in dicate d, f urt her i n vesti gati o n s uc h as 
re peate d bl o o d tests a n d/ or c hest C T sca n s h o ul d be perf or me d f or c o nfir mat or y dia g n osis. 
Treat me nt decisi o ns s h o ul d be disc usse d wit h M e dical M o nit or a n d base d o n c o nfir mat or y 
dia g n osis. 
P ul m o n ar y Fi br osis
P ul m o nar y  fi br osis is us uall y o bser ve d as a late c o m plicati o n of C R T. I n s u m mar y: 

Ma n y  cases are asy m pt o matic at o nset a n d earl y  fi br otic alterati on i n l u n g tiss ue wit h mi ni mal 
c ha n ges ca n be diffic ult t o disti n g uis h fr o m i nfla m mat or y c ha n ges i n t he l u n g. 

S y m pt o matic cases ofte n i n v ol ve hi g h c hr o nic i nfla m mati o n c haracterize d b y  hi gh le vels of 
circ ulati n g platelet -deri ve d a n d basic fi br o blast gr o wt h fact or e x presse d after i nitial ac ute 
i nfla m mati o n. T his lea ds t o fi br o blast pr oliferati o n a n d mi grati o n, t he release of T G F -β ( maj or 
pr ofi br otic m olec ule), al o n g wit h c olla ge n de p ositi o n i n a n y  hist ol o gic s pace of t he irra diate d 
l u n g, i ncl u di n g vasc ular a n d al ve olar c o m part me nts; t his ca n lea d t o ve ntilati o n -perf usi o n 
mis matc h a n d res ult i n w orse ni n g of p ul m o nar y f u ncti o n ( or e ve n f u ncti o nal stat us) as a 
pri mar y  sy m pt o m. 

Ot her s ym pt o ms ma y  be si milar t o ac ute-ra diati o n p ne u m o nitis, i ncl u di n g n o n pr o d ucti ve
c o u g h a n d d ys p nea, alt h o u g h t hese s ym pt o ms are ge nerall y m ore c hr o nic i n nat ure. O wi n g t o 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 3 / 1 5 5
t he pat h o p h ys i ol o gic ti me c o urse, s ym pt o ms are n ot see n u ntil se veral m o nt hs after R T a n d 
ma y  co nti n ue t o pr o gress f or ye ars after t hera p y. Ra di o gra p hic e vi de nce of ra diati o n-i n d uce d 
c ha n ges a n d s u bse q ue nt fi br osis of t he l u n g m a y  occ ur wit hi n l u n g v ol u mes recei vi n g ≥ 2 0 G y .  
Ra diati o n ca n mai nl y  ca use 2 t ypes of l u n g da ma ge. Ra diati o n p ne u m o nitis t ypicall y occ urs 
2- 6 m o nt hs after c o m pleti o n of R T a n d is fre q ue ntl y foll o we d b y  ra diati o n fi br osis t hat us uall y 
bec o mes e vi de nt bet wee n 6 a n d 1 2 m o nt hs (V ujas k o vic 2 0 0 0 , M or ga n 1 9 9 5 ). De pe n di n g o n t he 
st u d y assess me nts, t he i nci de nce of ra diati o n fi br osis has bee n f o u n d t o be varia ble, ra n gi n g fr o m 
1 t o 4 0 % (K o n g 2 0 0 5, Me hta 2 0 0 5 , Niezi n k 2 0 1 6 ). I nte grate d ra di ol o gical a n d cli nical data are 
u se d f or t he dia g n osis a n d t he se verit y of l u n g da ma ge. It is esse ntial t o s pare as m uc h n or mal l u n g 
as p ossi ble i n or der t o a v oi d ac ute a n d l o n g-ter m s ym pt o matic l u n g i nj ur y. See Ta ble 2 1 f or 
dia g n osis a n d gra di n g. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T a ble 2 1   
Di a g n osis a n d Gr a di n g f or P ul m o n ar y Fi br osis 
S c al e 
Gr a d e 1
Gr a d e 2
Gr a d e 3
Gr a d e 4
Gr a d e 5
C T C A E
v 5. 0
Mil d 
h y p o x e mi a; 
r a di ol o gi c 
p ul m o n ar y 
fi br o si s
M o d er at e h y p o x e mi a; 
e vi d e n c e of p ul m o n ar y 
h y p ert e n si o n; 
r a di o gr a p hi c 
p ul m o n ar y fi br o si s 2 5 –
5 0 %
S e v er e h y p o x e mi a; 
e vi d e n c e of ri g ht -
si d e d h e art f ail ur e; 
r a di o gr a p hi c 
p ul m o n ar y fi br o si s 
> 5 0 – 7 5 %
Lif e -t hr e at e ni n g 
c o n s e q u e n c e s ( e. g.,
h e m o d y n a mi c/ p ul m o n ar y 
c o m pli c ati o n s); 
i nt u b ati o n wit h v e ntil at or y 
s u p p ort i n di c at e d; 
r a di o gr a p hi c p ul m o n ar y 
fi br o si s > 7 5 % wit h 
s e v er e h o n e y c o m bi n g
D e at h
A b br e vi ati o n s: C T C A E = C o m m o n T o xi cit y Crit eri a f or A d v er s e E v e nt s ( V er si o n 5. 0).
C ar di ot o xicit y
T here are ma n y f or ms of R T -i n d uce d car diac t o xicities a n d us uall y  occ ur as late o nset a d verse 
e ve nts. Ra diati o n ca n affect t he pericar di u m, m uscle, t he electrical c o n d ucti o n s yste m, val ves a n d 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 4 / 1 5 5
vasc ulat ure, a m o n g ot her str uct ures. Mec ha nisticall y , t he effects of R T o n vasc ulat ure m a y  be m ost 
i m p orta nt f or pat h o p h y si ol o gic c orrelati o ns of heart t o xicit y. T he effects of R T o n s mall vessels, 
re gar dless of l ocati o n, are t hat of fi br osis ( p ossi bl y prece de d b y  so me le vel of c hr o nic 
i nfla m mati o n) a n d e n d ot helial i nj ur y (p ote ntiall y a partiall y o bliterati ve e n darteritis p h e n ot y pe). 
T his n ot o nl y  ca n pre dis p ose t o arterial disease fr o m pree xisti n g ca uses (e.g. li pi d d y sre g ulati o n 
a n d at her oscler osis), b ut is als o a n i n de pe n de nt ris k fact or f or c hr o nic isc he mia a n d f ut ure car diac 
e ve nts. I n e ve nt of car di ot o xicit y, car di ol o gi st s h o ul d be c o ns ulte d a n d ma na ge d per l ocal 
g ui da nce. 
6. 1 1
A d verse  
Dr u g  
Re acti o ns  
Re q uiri n g  
Tre at me nt 
Disc o nti n u ati o n 
A d verse dr u g reacti o ns ( A D R) are defi ne d i n t his st u d y as a n y A Es relate d t o st u d y treat me nt 
assesse d b y  t he I n vesti gat or a n d / or S p o ns or. Seri o us a d verse reacti o ns ( S A Rs) are A D Rs w hic h 
are assesse d as seri o us. A n y  q uesti o ns or c o ncer ns wit h re gar ds t o ma na ge me nt a n d/ or f oll o w-u p 
of A D Rs s h o ul d be disc usse d wit h t he M e dical M o nit or.
Details of m a na ge me nt of a d verse dr u g reacti o ns i ncl u di n g per ma ne nt treat me nt disc o nti n uati o n 
s h o ul d f oll o w t he f oll o wi n g secti o ns:

F or s us pecte d ir A Es, ir A E ma na ge me nt a n d g ui da nce i n Secti o n  6. 9. 2. 

I nf usi o n-relate d reacti o ns a n d h yperse nsiti vit y  reacti o ns g ui da nce i n Secti o n 6. 9. 1 .

A ne mia g ui da nce i n Secti o n  6. 9. 4

Blee di n g a d verse e ve nt g ui da nce i n Secti o n 6. 9. 5

G ui da nce a n d ma na ge me nt f or p ote ntiall y T G F -β i n hi biti o n me diate d s ki n reacti o ns are 
disc usse d i n Secti o n 6. 9. 3

G ui da nce 
a n d ma na ge me nt 
f or ra di ot hera py a n d c he m ot hera p y A Es 
are disc usse d i n 
Secti o n 6. 1 0.
F or g e neral g ui da nce , refer t o secti o n 6. 8.
7
Disc o nti n u ati o n 
of 
St u d y 
I nter ve nti o n a n d 
P artici p a nt 
Disc o nti n u ati o n/ Wit h dr a w al
7. 1
Disc o nti n u ati o n of St u d y I nter ve nti o n
7. 1. 1
Per m a ne nt Disc o nti n u ati o n
Partici pa nts will be wit h dra w n fr o m st u d y i nter ve nti o n f or a ny of t he f oll o wi n g reas o ns:

Partici pa nts wit h pr o gressi o n per R E CI S T 1. 1 a n d s u bse q ue nt c o nfir mati o n wit h t he e xce pti o n 
t hat partici pa nt ma y  co nti n ue past t he deter mi nati o n of P D if t he E C O G P S has re mai ne d sta ble, 
a n d if i n t he o pi ni o n of t he I n vesti gat or, t he partici pa nt will be nefit fr o m c o nti n ue d treat me nt.
See Secti o n  4. 1. 1 f or st u d y inter ve nti o n be y o n d pr o gressi o n. I n case of pre mat ure wit h dra wal 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 5 / 1 5 5
fr o m t he st u d y i nter ve nti o n f or reas o ns ot her t ha n P D, t he partici pa nts will be as ke d t o atte n d 
sc he d ule d visits i ncl u di n g t u m or assess me nt a n d ot her assess me nts as pla n ne d until c o nfir me d 
P D, E n d o f St u d y or deat h.   

T he partici pa nt m a y  be wit h dra w n at a n y ti me at t he discreti o n of t he I nvesti gat or f or safety,  
be ha vi oral, c o m plia nce, or a d mi nistrati ve reas o ns (e. g., disr u pti o n of o perati o ns d ue t o nat ural 
disasters, i nterr u pti o n of la b orat or y or facilit y accre ditati o n, partici pa nt m o vi n g t o a n ot her 
c o u ntr y, resi g nati o n of ke y staff).

Si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n), defi ne d as ne w sy m pt o ms t hat are 
dee me d b y  the I n vesti gat or t o be cli nicall y si g nifica nt or si g nifica nt w orse ni n g of e xisti n g 
s ym pt o ms.

U nacce pta ble t o xicit y  ( See Secti o n 6. 8 f or a d diti o nal details) 

T hera pe utic fail ure re q uiri n g ur ge nt a d diti o nal or alter nati ve a ntica ncer treat me nt.

Occ urre nce of A Es res ulti n g i n t he per ma ne nt disc o nti n uati o n of t he st u d y i nter ve nti o n bei n g 
desire d or c o nsi dere d necessar y  by t he I n vesti gat or a n d/ or the partici pa nt (see Secti o ns 6. 8, 6. 9,  
a n d 6. 1 0 ). Partici pa nts w h o e x perie nce A Es are all o we d t o s ki p u p t o 3 c o nsec uti ve d oses of 
M 7 8 2 4, place b o, or d ur val u ma b at a n y ti me d uri n g t he e ntire st u d y inter ve nti o n . I n case 
partici pa nts rec o ver fr o m A Es wit hi n t he all o we d ti me ( u p t o 3 d oses of M 7 8 2 4, place b o, or 
d ur val u ma b) a n d are a ble t o res u me st u d y i nter ve nti o n, t he y will n ot be wit h dra w n fr o m st u d y 
i nter ve nti o n. Treat me nt ma y  be res u me d i n partici pa nts w h o ha ve e x perie nce d a n A E wit h a 
pr ol o n ge d d ose h ol d ( > 3 c o nsec uti ve d oses) a n d i n t he o pi ni o n of t he I nvesti gat or will be nefit 
fr o m restarti n g treat me nt. S uc h cases m ust be disc usse d wit h t he Me dical M o nit or pri or t o 
res u mi n g treat me nt. See Secti o n 6. 9. 5 f or s pecific g ui da nce o n blee di n g a d verse e ve nts, f or 
w hic h d ose re d ucti o ns ma y  be a p pr o priate.

Occ urre nce of pre g na nc y i n t he partici pa nt.

Use of a pr o hi bite d c o nc o mita nt dr u g, as defi ne d i n Secti o n 6. 5. 2, w here t he pre defi ne d 
c o nse q ue nce is wit h dra wal fr o m t he st u d y i nter ve nti o n if c o nsi dere d necessar y  by t he 
I n vesti gat or or t he S p o ns or. 

N o nc o m plia nce ( See Secti o n 6. 4)
I n case of wit h dra w al fr o m st u d y inter ve nti o n t he assess me nts sc he d ule d f or t his visit s h o ul d be 
perf or me d, if p ossi ble wit h f oc us o n t he m ost rele va nt assess me nts.
7. 1. 2
Rec h alle n ge
R ec halle n ges i n ter ms of treat me nt re-i nitiati o n (p ost disc o nti n uati o n ) are n ot all o we d i n t his st u d y.
7. 2
P artici p a nt Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y
A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest ( i.e., wit h dra wal of 
c o nse nt) or m a y  be wit h dra w n at a n y ti me at t he discreti o n of t he I nvesti gat or f or safet y, 
be ha vi oral, c o m plia nce, or a d mi nistrati ve reas o ns.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 6 / 1 5 5
At t he ti me of di sc o nti n ui n g fr o m t he st u d y, if p ossi ble, a disc o nti n uati o n visit will be c o n d ucte d, 
as liste d i n t he S o A ( Secti o n 1. 3 ). T he S o A s pecifies t he data t o c ollect at stu d y  disc o nti n uati o n 
a n d f oll o w-u p, a n d a n y  a d diti o nal e val uati o ns t hat nee d t o be c o m plete d.
If t he partici pa nt wit h dra ws c o nse nt f or f ut ure i n v ol ve me nt i n t he st u d y, a n y data c ollecte d u p t o 
t hat p oi nt ma y  still be use d, b ut n o f ut ure data ca n be ge nerate d, a n d a n y bi ol o gical sa m ples 
c ollecte d will be destr o ye d.
A partici pa nt has t he ri g ht at a n y  ti me t o re q uest destr ucti o n of a n y bi ol o gical sa m ples ta ke n. T he 
I n vesti gat or will d oc u me nt t his i n t he site st u d y  rec or ds. 
I n case of partici pa nt disc o nti n uati o n / wit h dra wal fr o m t he st u d y:

T he a p pr o priate electr o nic case re p ort f or ms (e C R Fs) f or t he E n d - of-Treat me nt visit m ust 
be c o m plete d. 

Partici pa nts will be as ke d t o si g n a wit h dra wal c o nse nt t o c o nti n ue safet y an d s ur vi val 
f oll o w- u p, w hic h i ncl u des t he c ollecti o n of data o n s ur vi val, patie nt re p orte d o utc o mes 
q uesti o n naires, a n d s u bse q ue nt a ntica ncer t hera p y. After c o m pleti o n of t he F oll o w -u p 
peri o d or after t he E n d -of -Treat me nt visit, w hate ver is a p plica ble, t he a p pr o priate e C R F 
secti o n f or St u d y Ter mi nati o n m ust be c o m plete d.

If partici pa nt gets e nr olle d i nt o ne w st u d y or a ny n e w t hera p y p ost wit h dra wal fr o m st u d y , 
t he Safet y F oll o w - u p visit s h o ul d be sc he d ule d pri or t o start of t he ne w treat me nt 
irres pecti ve of t he 2 8-d a y  safety f oll o w -u p peri o d. 
7. 3
L ost t o F oll o w -U p
A partici pa nt will be c o nsi dere d l ost t o f oll o w-u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d by t he st u d y  site.
T he f oll o wi n g acti o ns m ust be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:

T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble, c o u nsel t he partici pa nt o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule, a n d ascertai n if t he partici pa nt wa nts t o or s h o ul d c o nti n ue i n t he st u d y.

B ef ore a partici pa nt is dee me d “l ost t o f oll o w-u p”, t he I n vesti gat or or desi g nee m ust ma ke 
e ver y eff ort t o re gai n c o ntact wit h t he partici pa nt: 1) w here p ossi ble, ma ke 3 tele p h o ne calls; 
2) if necessar y, se n d a certifie d letter ( or a n e q ui vale nt l ocal met h o d) t o t he partici pa nt’s last 
k n o w n maili n g a d dress, a n d 3) if a partici pa nt has gi ve n t he a p pr o priate c o nse nt, c o ntact t he 
partici pa nt’s ge neral practiti o ner f or i nf or mati o n. T hese c o ntact atte m pts s h o ul d be 
d oc u me nte d i n t he partici pa nt’s me dical rec or d, 4) if pr o per c o nse nt is o btai ne d, c o nti n ue t o 
c ollect healt h stat us t hr o u g h p u blic data 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 7 / 1 5 5

S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be dee me d l ost t o f oll o w - u p.
8
St u d y Assess me nts a n d Pr oce d ures

St u d y  assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n Secti o n 1. 3.

N o pr ot oc ol wai vers or e xe m pti o ns are all o we d.

I m me diate safety c o ncer ns s h o ul d be disc usse d wit h t he S p o ns or i m me diatel y up o n 
occ urre nce or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y 
i nter ve nti o n.

A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n Secti o n 1. 3,  is 
esse ntial a n d re q uire d f or st u d y  c o n d uct.

All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he I n vesti gator will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nts scree ne d, t o c o nfir m eli gi bilit y, a n d if a p plica ble, rec or d 
reas o ns f or scree ni n g fail ure.

Pri or t o perf or mi n g a n y st u d y assess me nts t hat are n ot part of t he partici pa nt’s r o uti ne 
me dic al care, t he I n vesti gat or will o btai n writte n i nf or me d c o nse nt as s pecifie d i n 
A p pe n di x 2.

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) 
a n d o btai ne d bef ore si g ni n g of t he I CF m a y  be use d f or scree ni n g or Baseli ne p ur p oses 
pr o vi de d t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he 
ti me fra me defi ne d i n Secti o n  1. 3.
8. 1
Effic ac y Assess me nts a n d Pr oce d ures
C o ntrast -e n ha nce d c o m p ute d t o m o gra p hy ( C T) of c hest/a b d o me n a n d pel vis c o veri n g t he area 
fr o m t he s u peri or e xte nt of t he t h oracic i nlet t o t he s ym p h y sis p u bis is t he first c h oice of i ma gi n g 
m o dalit y  to assess treat me nt efficac y. T he C T sca n of t he pel vis m a y be o mitte d f or ra diati o n 
pr otecti o n reas o ns if it is n ot part of t he sta n dar d of care a n d C T of t he a b d o me n i ncl u des t he 
e ntiret y of t he li ver a n d b ot h a dre nal gla n ds, as well as all ot her k n o w n sites of disease. If a 
partici pa nt ca n n ot recei ve i o di nated c o ntrast, or if re gi o nal ra diati o n re g ulati o ns pre ve nt f ull C T 
sca n, ma g netic res o na nce i ma gi n g ( M RI) of t he sa me area, usi n g macr oc y clic ga d oli ni u m 
e n ha nce me nt is per mitte d i n c o nj u ncti o n wit h u ne n ha nce d C T of t he c hest fr o m t he t h oracic i nlet 
t o t he i nferi or c ost o p hre nic recess. T he sa me m o dalit y , a n d prefera bl y  the sa me sca n ner, s h o ul d 
be use d per partici pa nt t hr o u g h o ut t he st u d y. T he + 5 d a y s e n d of c C R T visit wi n d o w d oes n ot 
a p pl y t o t he t u m or assess me nt at t his ti me p oi nt.
A brai n C T/ M RI (M RI preferre d) sca n is re q uire d at Baseli ne , at t he e n d of c C RT a n d d uri n g st u d y 
i nter ve nti o n after c C R T e ver y 1 2 wee ks a n d as cli nicall y i n dicate d i n case of de vel o p me nt of ne w 
s pecific s ym pt o ms. I n case of s us pecte d s ki n metastasis d uri n g st u d y inter ve nti o n a bi o ps y m ust 
be perf or me d t o c o nfir m P D. T he sa me m o dalit y, a n d prefera bl y t he sa me sca n ner, s h o ul d be use d 
per partici pa nt t hr o u g h o ut t he st u d y .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 8 / 1 5 5
I n vesti gat ors will rea d a n d i nter pret s o me or all C T / M RI  data a n d treat me nt decisi o ns will be 
ma de b y  the treati n g I n vesti gat or base d o n I n vesti gat or t u m or assess me nts . T u m or res p o nses t o 
st u d y inter ve nti o n assesse d acc or di n g t o R E CI S T 1. 1 b y  the I n vesti gat or will be d oc u me nte d i n 
t he e C R F (all meas ure me nts s h o ul d be rec or de d i n metric n otati o n). Res p o nse will be defi ne d 
acc or di n g t o R E CI S T 1. 1 (refer t o R E CI S T 1. 1 i nstr ucti o ns i n A p pe n di x 8 ). As per R E CI S T 1. 1 
criteria, t u m or lesi o ns sit uate d i n a pre vi o usl y -irra diate d area, or i n a n area s u bjecte d t o ot her 
l oc o-re gi o nal t hera p y are n ot us uall y  co nsi dere d meas ura ble, h o we ver, e xcl u di n g meas ura ble 
tar get lesi o n(s) wit hi n t he ra diati o n fiel d is n ot j ustifie d f or patie nts wit h Sta ge III N S C L C. I n fact, 
partici pa nts i n t his st u d y will all recei ve c C R T as S o C treat me nt a n d t u m or assess me nts will 
i ncl u de irra diate d lesi o n(s). L o calize d p ost-ra diati o n c ha n ges w hic h affect lesi o n sizes ma y occ ur 
a n d t here m a y  be hi g h le vels of necr osis/fi br osis wit h little or n o acti ve t u m or i n rece ntly i rra diate d 
lesi o ns. H o we ver, acce pti n g t hese li mitati o ns i n t his patie nt p o p ulati o n wit h pri or c urati ve 
ra diati o n treat me nt, irra diate d lesi o ns ma y be c o nsi dere d meas ura ble a n d selecte d as tar get lesi o ns 
pr o vi di n g t he y  f ulfil t he ot her criteria f or meas ura bilit y.
Baseli ne sca ns are ta ke n wit hi n 2 1 da y s (i deall y, wit hi n 1 4 da y s) pri or t o ra n d o mizati o n. All t he 
sca ns perf or me d at Baseli ne, u nless ot her wise s pecifie d i n t he S o A, nee d t o be re peate d at 
s u bse q ue nt visits f or t u m or assess me nt. I n ge neral, lesi o ns detect e d at Baseli ne nee d t o be f oll o we d 
usi n g t he sa me i ma gi n g met h o d ol o g y  an d prefera bl y  the sa me i ma gi n g e q ui p me nt at s u bse q ue nt 
t u m or e val uati o n visits. All sca ns d uri n g -st u d y inter ve nti o n are t o be re peate d usi n g t he sa me 
met h o d at t he s u bse q ue nt assess me nt ti me p oi nts. 
Partici pa nts will be e val uate d e ver y 8 wee ks wit h ra di o gra p hic i ma gi n g of c hest, a b d o me n, a n d 
pel vis , t o assess res p o nse t o st u d y inter ve nti o n f or u p t o 2 4 m o nt hs after t he partici pa nt’s first d ose
u nless pr o gressi o n or wit h dra wal fr o m t he st u dy w hic he ver occ ur s first. S u bse q ue nt sca ns will be 
d o ne e ver y 8 t o 1 2 wee ks u p t o pr o gressi o n, start of ne w treat me nt or deat h. T o e val uate t u m or 
v ol u me s hri n ka ge, a n d ra di o mic feat ures of i ma ges i n partici pa nts, ra di o mics a nal ys is of i ma ges 
for di gital feat ures p ote ntiall y  pre dicti ve of pr o g n osis a n d/ or f ut ure treat me nt be nefit will o nl y be 
perf or me d retr os pecti vel y  if dee me d a p pr o priate. 
I n t he case of a P R or C R, a c o nfir mat or y  C T or M RI  sca n s h o ul d be perf or me d at t he sc he d ule d 
8- wee k i nt er val or n o s o o ner t ha n 4 wee ks fr o m t he assess me nt. After P D, c o nfir mati o n of P D is 
als o re q uire d a n d s h o ul d be perf or me d prefera bl y  an d if cli nicall y feasi ble, at t he re g ularly 
sc he d ule d 8 wee kl y  assess me nt i nter vals, b ut n o s o o ner t ha n 4 wee ks 
after t he i nitial 
d oc u me ntati o n. F or i n vesti gati o nal assess me nts, t he date of pr o gressi o n will be deter mi ne d base d 
o n t he earliest of t he R E CI S T assess me nt/sca n dates of t he c o m p o ne nt t hat i n dicates pr o gressi o n.
Dia g n osis of disease pr o gressi o n base d s olel y on n o da l e nlar ge me nt wit hi n 8 wee ks of c or o na vir us 
vacci nati o n s h o ul d be ma de wit h e xtre me ca uti o n, partic ularl y i f i n a xillar y a n d/ or s u pracla vic ular 
n o des o n t he i psilateral si de t o vacci nati o n, a n d verifie d wit h hi n dsi g ht if p ossi ble. Partici pa nts 
w h o start s ubse q ue nt treat me nt s h o ul d be m o nit ore d f or res p o nse t o t hat treat me nt acc or di n g t o 
R E CI S T 1. 1. T u m or sca ns s h o ul d be perf or me d f oll o wi n g l ocal cli nical practice f or m o nit ori n g 
disease stat us o n s u bse q ue nt li nes of t hera p y.  T he st u d y  tea m e nc o ura ges a n d re q uests sca ns t o be 
perf or me d e ver y 8 to 1 2 wee ks, if feasi ble, i n a d diti o n t o a sca n wit hi n 2 8 da y s pri or t o starti n g 
t he s u bse q ue nt treat me nt. T hese e val uati o ns s h o ul d be d oc u me nte d b y  the I nvesti gat or i n t he 
e C R F. A partic i pa nt’s pr o gressi o n m a y  in v ol ve t he f oll o wi n g: o bjecti ve ra di ol o gical pr o gressi o n 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
9 9 / 1 5 5
or deat h d ue t o a d va nci n g disease. T his s h o ul d be d oc u me nte d e ver y  8 t o 1 2 wee ks u ntil i nitiati o n 
of t he ne xt treat me nt, wit h dra wal of c o nse nt, or deat h.
F or partici pa nts w h o
disc o nti n ue st u d y inter ve nti o n d ue t o t o xicit y or a reas o n ot her t ha n 
ra di ol o gical c o nfir me d P D, o bjecti ve t u m or assess me nts s h o ul d be c o nti n ue d e ver y 8 wee ks f or 
u p t o 2 4 m o nt hs fr o m t he partici pa nt’s first d ose or u ntil pr o gressi o n, start of ne w treat ment or 
deat h , w hic he ver occ urs first.
A d mi nistrati o n of M 7 8 2 4 or d ur val u ma b ca n c o nti n ue be y o n d P D as o utli ne d i n Secti o n  4. 1. 1
Partici pa nts will be m o nit ore d f or s ur vi val e ver y 1 2 wee ks i n t he L o n g -ter m F oll o w -u p peri o d . 
Partici pa nts will be c o ntacte d s h ortly bef ore t he data c ut-off f or t he pri mar y  a nal ys es t o pr o vi de 
c o m plete s ur vi val data.
L u n g fu ncti o n is als o assesse d as desc ri be d i n Secti o n  1. 3 t o e val uate t he p ote ntial c ha n ges i n d uce d 
b y  M7 8 2 4 w he n a d mi nistere d wit h c C R T a n d after c C R T c o m pare d wit h c C R T f oll o we d b y 
d ur val u ma b. Hi g h -res ol uti o n C T sca ns are as sc he d ule d i n Secti o n 1. 3 a n d ma y  be e val uate d f or 
Ra diati o n I n d uce d P ul m o nar y  Fi br osis ( RI P F) by a n I n de pe n de nt re vie w c o m mittee as o utli ne d i n 
t he H R C T C harter.
8. 2
S afet y Assess me nts a n d Pr oce d ures
T he safet y profile of t he st u d y inter ve nti o n will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
a nal ys is of baseli ne me dical c o n diti o ns, a d verse e ve nts ( A Es), p h y sical e xa mi nati o n fi n di n gs, vital 
si g ns, electr ocar di o gra ms, a n d la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y pote ntial t o xicit y ex perie nce d b y  eac h partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he 
I n vesti gat or wil l re p ort a n y A Es, w het her o bser ve d b y  the I n vesti gat or or re p orte d b y  the 
partici pa nt; t he r e p orti n g peri o d is s pecifie d i n Secti o n  8. 3. 1.
8. 2. 1
P h ysic al E x a mi n ati o ns
A c o m plete p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he car di o vasc ular, 
res pirat or y, gastr oi ntesti nal a n d n e ur ol o gical s ys te ms at Scree ni n g. H ei g ht a n d wei g ht will als o be 
meas ure d a n d rec or de d (see Secti o n 1. 3).
S u bse q ue nt f oc use d p h y sical e xa mi nati o ns t o be perf or me d as per l ocal sta n dar d practice a n d as 
cli nicall y in dicate d . D ue t o t he i ncrease d ris k of p ne u m o niti s wit h c C R T a n d M 7 8 2 4 
or 
d ur val u ma b, perf or m i n g th ora x e xa mi nati o n at eac h visit a n d acc or di n g t o t he S o A is re q uire d (see 
Ta ble 1 a n d Ta ble 3) .
I n vesti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us ill nesses.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 0 / 1 5 5
8. 2. 2
Vit al Si g ns
T e m perat ure, p ulse rate, res pirat or y rate, resti n g p ulse o xi metr y , a n d bl o o d press ure will be 
assesse d.
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d i n se mi-s u pi ne p ositi o n wit h a c o m pletel y 
a ut o mate d de vice. Ma n ual tec h ni q ues will be use d o nl y  if a n a ut o mate d de vice is n ot a vaila ble.
Bl o o d press ure a n d p ulse meas ure me nts s h o ul d be prece de d b y  at least 5 mi n utes of rest f or t he 
partici pa nt i n a q uiet setti n g wit h o ut distracti o ns (e. g., tele visi o n, cell p h o nes).
Vital si g ns will be meas ure d i n a se mi-s u pi ne p ositi o n after 5 mi n utes rest a n d will i ncl u de 
te m perat ure, s yst olic a n d diast olic bl o o d press ure, a n d p ulse, a n d m ust be re p orte d i n t he e C R F.
8. 2. 3
Electr oc ar di o gr a ms
A si n gle 1 2 -lea d E C G will be o btai ne d as o utli ne d i n t he S o A.
8. 2. 4
Cli nic al S afet y L a b or at or y Assess me nts
Bl o o d a n d uri ne sa m ples will be c ollecte d f or t he cli nical la b orat or y  tests liste d i n A p pe n di x 5 , at 
t he ti me p oi nts liste d i n t he S o A (see Secti o n 1. 3). All sa m ples s h o ul d be clearl y i de ntifie d. 
A d diti o nal tests ma y  be perf or me d at a n y ti me d uri n g t he st u d y, as deter mi ne d necessar y  by t he 
I n vesti gat or or re q uire d b y  l ocal re g ulati o ns.
T he tests will be perf or me d b y  l ocal la b orat or y.
T he S p o ns or will recei ve a list of t he l ocal la b orat or y nor mal ra n ges bef ore s hi p me nt of st u d y 
i nter ve nti o n(s). A n y c ha n ges t o t he ra n ges d uri n g t he st u d y must be f or war de d t o desi g nate d 
or ga nizati o n.
T he I n vesti gat or will
re vie w eac h la b orat or y re port, d oc u me nt t heir re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n of t he eC R F.
T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d oc u me nts.
La b orat or y /a nalyt e res ults t hat c o ul d u n bli n d t he st u d y will n o t be re p orte d t o i n vesti gati ve sites 
or ot her bli n de d pers o n nel u ntil t he st u d y  has bee n u n bli n de d.
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts
T he defi niti o ns of a n A d verse E ve nt ( A E) a n d a Seri o us A d v erse E ve nt ( S A E) are i n A p pe n di x 4.
8. 3. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt a n d 
Seri o us A d verse E ve nt I nf or m ati o n
T he A E re p orti n g peri o d f or safet y s ur veilla nce be gi ns w he n t he partici pa nt is i nitiall y  incl u de d i n 
t he st u d y (da te of first si g nat ure of i nf or me d c o nse nt/ date of first si g nat ure of first i nf or me d 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 1 / 1 5 5
c o nse nt) a n d c o nti n ues u ntil st u d y’s 2 8-da y  Safet y F oll o w-u p Visit, defi ne d as 2 8 da y s ( ± 5 da y s) 
after t he last st u d y inter ve nti o n a d mi nistrati o n. After t he E n d - of-Treat me nt Visit, relate d A Es 
s h o ul d be d oc u me nte d u ntil t he last Safet y F oll o w -u p Visit, defi ne d as 1 2 wee ks ( ± 2 wee ks) after 
t he last st u d y inter ve nti o n. O n g oi n g e ve nts at t he 1 2 -wee k Safet y F oll o w -u p Visit s h o ul d c o nti n ue 
t o be m o nit ore d a n d d oc u me nte d u ntil res ol uti o n or res ol uti o n wit h se q uelae.
A n y S A E assesse d as relate d t o st u d y  i nter ve nti o n m ust be rec or de d a n d re p orte d, as i n dicate d i n 
A p pe n di x 4 , w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d si nce t he last ad mi nistrati o n of 
st u d y i nter ve nti o n.
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A Es (i ncl u di n g S A Es) a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are i n  A p pe n di x 4 .
8. 3. 2
Met h o d 
of Det ecti n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts
At eac h st u d y visit, t he partici pa nt will be q uerie d o n c ha n ges i n his or her c o n diti o n. D uri n g t he 
re p orti n g peri o d, a n y u nfa v ora ble c ha n ges i n t he partici pa nt’s c o n diti o n will be rec or de d as A Es, 
re gar dless if re p orte d by t he partici pa nt or o bser ve d b y t he I nvesti gat or.
C o m plete, acc urate a n d c o nsiste nt data o n all A Es e x perie nce d f or t he d urati o n of t he re p orti n g 
peri o d ( defi ne d bel o w) will be re p orte d o n a n o n g oi n g basis i n t he a p pr o priate secti o n of t he C R F. 
All S A Es m ust be a d diti o nall y doc u me nte d a n d re p orte d usi n g t he a p pr o pri ate Re p ort F or m as 
s pecifie d i n A p pe n di x 4 .
8. 3. 3
F oll o w -u p of A d verse E ve nts a n d Seri o us A d verse E ve nts
A Es are rec or de d a n d assesse d c o nti n u o usl y t hr o u g h o ut t he st u d y, as s pecifie d i n Secti o n 8. 3. 1
a n d are assesse d f or t heir o utc o me d uri n g t he L o n g -ter m F oll o w - u p. All S A Es o n g oi n g at t he 
E n d - of-Treat me nt Visit m ust be m o nit ore d a n d f oll o we d u p b y  t he I n vesti gat or u ntil sta bilizati o n 
or u ntil t he o utc o me is k n o w n, u nless t he partici pa nt is d oc u me nte d as “l ost t o f oll o w-u p”. 
Reas o na ble atte m pts t o o btai n t his i nf or mati o n m ust be ma de a n d d oc u me nte d. It is als o t he 
res p o nsi bilit y of t he I n vesti gat or t o e ns ure t hat a n y necessar y a d diti o nal t hera pe utic meas ures a n d 
f oll o w- u p pr oce d ures are perf or me d. F urt her i nf or mati o n o n f oll o w- u p pr oce d ures is gi ve n i n 
A p pe n di x 4 .
8. 3. 4
Re g ul at or y 
Re p orti n g 
Re q uire me nts 
f or Seri o us A d verse 
E ve nts
T he S p o ns or will se n d a p pr o priate safety n otificati o ns t o Healt h A ut h orities i n acc or da nce wit h 
a p plica ble la ws a n d re g ulati o ns.
T he I n vesti gat or m ust c o m pl y wit h a n y a p plica ble site-s pecific re q uire me nts relate d t o t he 
re p orti n g of S A Es ( partic ularl y deat hs) i n v ol vi n g st u d y partici pa nts t o t he I E C/IR B t hat a p pr o ve d 
t he st u d y.
I n acc or da nce wit h I C H G C P, t he S p o ns or/ desi g nee will i nf or m t he I n vesti gat or of fi n di n gs t hat 
c o ul d a d versel y affect t he safety of partici pa nts, i m pact t he c o n d uct of t he st u d y or alter t he 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 2 / 1 5 5
I E C’s/I R B’s a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he st u dy. I n li ne wit h res pecti ve re g ulati o ns, 
t he S p o ns or/ desi g nee will i nf or m t he I n vesti gat or of A Es t hat are b ot h seri o us a n d u ne x pecte d a n d 
c o nsi dere d t o be relate d t o t he a d mi nistere d pr o d uct (“s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns” or S U S A Rs). T he I n vesti gat or s h o ul d place c o pies of Safet y R e p orts i n t he I nvesti gat or
Site File. Nati o nal re g ulati o ns re gar di n g Saf et y Re p ort n otificati o ns t o I n vesti gat ors will be 
c o nsi dere d.
T he I n vesti gat or m ust re p ort S A Es ( partic ularly deat hs) i n acc or da nce wit h a p plica ble site-s pecific 
re q uire me nts t o t he I R B t hat a p pr o ve d t he st u dy.
I n acc or da nce wit h 
I C H G C P 
a n d t he Ja pa nese mi nisterial 
or di na nce o n G C P, 
t he 
S p o ns or/ desi g nee will i m me diatel y inf or m all t he st u d y I n vesti gat ors a n d t he Hea ds of t he st u d y 
sites of fi n di n gs t hat c o ul d a d versel y affect t he safet y of partici pa nts, i m pact the c o n d uct of t he 
st u d y or alter t he I RB’s a p pr o val/fa v ora ble o pi ni o n t o c o nti n ue t he st u d y. I n li ne wit h res pecti ve 
a p plica ble re g ulati o ns, t he S p o ns or/ desi g nee will i m me diatel y inf or m all t he st u d y I n vesti gat ors 
a n d t he Hea ds of t he st u d y sites of A Es t h at are b ot h seri o us a n d u ne x pecte d a n d c o nsi dere d t o be 
relate d t o t he a d mi nistere d pr o d uct (“s us pecte d u ne x pecte d seri o us a d verse reacti o ns” or 
S U S A Rs). I n ad diti o n, per a p plica ble re g ulati o ns, t he S p o ns or/ desi g nee will i nf or m t he st u d y 
I n vesti gat ors a n d t he Hea ds of t he st u d y sites of all S A Es w hic h were re p orte d t o t he healt h 
a ut h orities. I n acc or da nce wit h t he Ja pa nese re g ulat or y re q uire me nts c o ncer ni n g safety re p orti ng 
t he I nvesti gat or s h o ul d place c o pies of t he Safet y Re p orts i n t he I nvesti gat or Site File. T he Hea d 
of t he st u d y  site s h o ul d als o mai ntai n c o pies of safet y re p orts a p pr o priately.
W he n 
s pecificall y re q uire d b y  re g ulati o ns a n d g ui deli nes, t he S p o ns or/ desi g nee will pr o vi de 
a p pr o priate Safet y Re p orts directl y  to t he c o ncer ne d lea d I E C/IR B a n d will mai ntai n rec or ds of 
t hese n otificati o ns. W he n 
direct re p orti n g is n ot clearl y defi ne d b y  nati o nal or site-s pecific 
re g ulati o ns, t he I n vesti gat or will be res p o nsi ble f or pr o m ptl y  n otif yi n g t he c o ncer ne d I E C/IR B of 
a n y Safet y Re p orts pr o vi de d b y  the S p o ns or/ desi g nee a n d of fili n g c o pies of all relate d 
c orres p o n de nce i n t he I nvesti gat or Site File.
F or st u dies c o vere d b y  the E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, t he S p o ns or’s res p o nsi bilities 
re gar di n g t he re p orti n g of S A Es/ S U S A Rs/ Safet y  Iss ues will be carrie d o u t i n acc or da nce wit h t hat 
Directi ve a n d wit h t he relate d Detaile d G ui da nce d oc u me nts.
8. 3. 5
Pre g n a nc y
O nl y  pre g na ncies t he I n vesti gat or c o nsi ders t o be relate d t o t he st u d y i nter ve nti o n (e. g., res ulti n g 
fr o m a dr u g i nteracti o n wit h a c o ntrace pti ve met h o d) are A E s. H o we ver, all pre g na ncies wit h a n 
esti mate d c o nce pti o n da te d uri n g t he peri o d defi ne d i n Secti o n  8. 3. 1 m ust be rec or de d i n t he A E 
pa ge/secti o n of t he C R F f or b ot h pre g na ncies i n fe male partici pa nts a n d pre g na ncies i n fe male 
part ners of male partici pa nts. T he I nvesti gat or m ust n otif y  the S p o ns or/ desi g nee i n a n e x pe dite d 
ma n ner of a n y pre g na nc y  usi n g t he Pre g na nc y  Re p ort F or m, w hic h m ust be tra ns mitted b y  the 
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 4 .
I n vesti gat ors m ust 
acti vel y foll o w - u p, d oc u me nt a n d re p ort o n t he o utc o me of all t hese 
pre g na ncies, e ve n if t he partici pa nts are wit h dra w n fr o m t he st u d y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 3 / 1 5 5
T he I n vesti gat or m ust n otif y  t he S p o ns or/ desi g nee of t hese o utc o mes usi n g t he Pre g na nc y Re p ort 
F or m. If a n a b n or mal o utc o me occ urs, t he S A E Re p ort F or m will be use d if t he partici pa nt s ustai ns 
a n e ve nt a n d t he Pare nt -C hil d/ Fet us A d verse E ve nt Re p ort F or m if t he c hil d/fet us s ustai ns a n 
e ve nt. A n y a b n or mal o utc o me (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g na nc y ) m ust be re p orte d i n a n e x pe dite d ma n ner, as s pecifie d i n Secti o n 
8. 3. 1 , w hile n or mal o utc o mes m ust be re p orte d wit hi n 4 5 da ys after deli ver y.
I n t he e ve nt of a pre g na nc y  in a partici pa nt occ urri n g d uri n g t he st u d y, t he partici pa nt m ust be 
disc o nti n ue d fr o m st u d y inter ve nti o n. T he S p o ns or/ desi g nee m ust be n otifie d wit h o ut dela y  an d 
t he partici pa nt m ust be f oll o we d as i n dicate d a b o ve.
8. 4
Tre at me nt of O ver d ose
F or t his st u d y, a n y d ose of i m m u n ot hera py greater t ha n 2 ti mes m ore t ha n t he pla n ne d d o se 
a d mi nistere d wit hi n a 2 4 -h o ur ti me peri o d will be c o nsi dere d a n o ver d ose. 
F or c he m ot hera pe utic a ge nts use d i n t his st u d y , a n y si n gle d ose e xcee di n g 2 0 % of rec o m me n de d 
c he m ot hera p y d ose re gi me n will be c o nsi dere d o ver d ose. F or ra diati o n, refer t o t he Ra di ot hera p y 
G ui deli nes t hat will be pr o vi de d t o t he site. Pri or t o i nitiati n g R T, t he ra diati o n treat me nt pla n m ust 
be s u b mitte d b y  the I n vesti gat or t o t he ra diati o n o nc ol o g y  ve n d or f or re vie w. C o ns ult will M e dical 
M o nit or as dee me d necessar y .
I n case of o v er d ose wit h cli nical c orrelati o n, s ym pt o matic treat me nt m ust be use d; t here are n o 
k n o w n a nti d otes. N o s pecific i nf or mati o n is a vaila ble f or t he treat me nt of o ver d ose f or 
d ur val u ma b.
I n eve nt of o ver d ose, i nf usi o n s h o ul d be disc o nti n ue d, a n d partici pa nts sh o ul d be o bser ve d cl osel y 
f or a ny 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 dicate 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 rep orti n g criteria as i n dicate d i n 
A p pe n di x 4 .
T he S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose .
E ve n if it n ot ass ociate d wit h a n A E or a S A E, a n y over d ose is rec or de d i n t he C R F a n d re p orte d 
t o dr u g safet y i n a n e x pe dite d ma n ner. O ver d oses are re p orte d o n a S A E Re p ort F or m, f oll o wi n g 
t he pr oce d ure i n A p pe n di x 4 .
8. 5
P h ar m ac o k i netics
P K sa m ples will be c ollecte d acc or di n g t o S o A (Ta ble 1 a n d Ta ble 3) . 
T he f oll o wi n g P K para meters will be esti mate d a n d re p orte d i n t he P K A nal ysis Set:

C e oi

C tr o u g h
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 4 / 1 5 5
T he P K para meters will be s u m marize d usi n g descri pti ve statistics. I ndi vi d ual as well as mea n 
c o nce ntrati o n-ti me pl ots will be de picte d. U nres ol ve d missi n g data ma y be i m p ute d w he n t he 
a nal ys is i nte grity is affecte d. T he c o nser vati ve pri nci ple wi ll be use d f or data i m p utati o n.
T he f oll o wi n g P K para meters will be calc ulate d , w he n a p pr o priate:
S y m b ol
D efi niti o n
C e oi
T h e c o n c e ntr ati o n o b s er v e d i m m e di at el y at t h e e n d of i nf u si o n
C tr o u g h
T h e c o n c e ntr ati o n o b s er v e d i m m e di at el y b ef or e n e xt d o si n g ( c orr e s p o n di n g t o pr e-
d o s e or tr o u g h c o n c e ntr ati o n f or m ulti pl e d o si n g)
W h ole 
bl o o d sa m ples of a p pr o xi matel y 3. 5 m L will be c ollecte d f or meas ure me nt of ser u m 
c o nce ntrati o ns of i n vesti gati o nal me dici nal pr o d uct , as s pecifie d i n Ta ble 1 a n d Ta ble 3 . 
I nstr ucti o ns f or t he c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will be pr o vi de d b y  the S p o ns or. 
T he act ual date a n d ti me ( 2 4 -h o ur cl oc k ti me) of eac h sa m ple will be rec or de d t o calc ulate act ual 
ti me ela pse d si nce t he pri or d ose a d mi nistrati o n.
T he q ua ntificati o n of M 7 8 2 4
i n ser u m will be perf or me d usi n g a vali date d m et h o d. C o nce ntrati o ns 
will be use d t o e val uate t he P K of M 7 8 2 4 .
Re mai ni n g sa m ples c ollecte d f or a nal ys es of M 7 8 2 4
c o nce ntrati o n m a y  als o be use d t o e val uate 
i m m u n o ge nicity a n d safet y or efficac y as pects relate d t o c o ncer ns arisi n g d uri n g or after t he st u d y.
P K a n d A D A sa m ples c ollecte d at t he sa me ti me p oi nts m a y  be use d i nterc ha n gea bly if t he 
de dicate d sa m ple has i ns ufficie nt q ua ntit y  as t he partici pa nts will ha ve c o nse nte d t o all c ollecti o ns 
a n d tests.
Details o n pr ocesses f or c ollecti o n a n d s hi p me nt of these sa m ples are i n t he La b orat or y  Ma n ual. 
Rete nti o n ti me a n d p ossi ble a nal ys es of sa m ples after t he E n d of S t u d y are s pecifie d i n t he 
res pecti ve I CF.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 5 / 1 5 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 6 / 1 5 5
8. 8
I m m u n o ge nicit y Assess me nts
W h ole bl o o d sa m ples of a p pr o xi matel y  5 m L will be c ollecte d f or detecti o n of a nti b o dies a gai nst 
M 7 8 2 4 i n ser u m, as s pecifie d i n Ta ble 1 a n d Ta ble 3.  Sa m ples will be c ollecte d pri or t o M 7 8 2 4, 
place b o or d ur val u ma b a d mi nistrati o n o n t he sa me St u d y Da y.
T he detecti o n of a nti b o dies t o M 7 8 2 4 will be perf or me d usi n g a vali date d met h o d wit h tiere d 
testi n g of scree ni n g, c o nfir mat or y an d titrati o n. C o nfir me d p ositi ve a nti b o dies will be teste d f or 
t he prese nce of ne utralizi n g a nti b o dies w he n t he met h o ds are vali date d a n d ma y  be f urt her 
c haracterize d.
Re mai ni n g sa m ples c ollecte d f or a nal ys is of a nti-M 7 8 2 4 a nti b o dies ma y  als o be use d t o e val uate 
dr u g c o nce ntrati o n or e x pl orat or y  bi o mar kers d uri n g or after t he st u d y.
Details o n pr ocesses f or c ollecti o n a n d s hi p me nt of t hese sa m ples will be i n La b orat or y  Ma n ual. 
Rete nti o n ti me a n d p ossi ble a nal ys es of sa m ples after t he E n d of S t u d y are s pecifie d i n t he 
res pecti ve I CF.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 7 / 1 5 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 8 / 1 5 5
9. 3
P o p ul ati o ns f or A n al yses
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e xcl u de partici pa nts fr o m a ny 
a nal ys is p o p ulati o n will be ma de d uri n g a bli n de d data re vie w meeti n g pri or t o data base l oc k data.
F or p ur p oses of a nal y sis, t he a nal ys is p o p ulati o ns are defi ne d i n Ta ble 2 3.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 9 / 1 5 5
T a ble 2 3 
A n al ysis P o p ul ati o ns
A n al y s i s P o p ul ati o n
D e s cri pti o n
S cr e e ni n g ( S C R) 
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
r a n d o mi z ati o n a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y.
F ull a n al y si s s et ( F A S) 
All p arti ci p a nt s, w h o w er e r a n d o mi z e d. 
S af et y ( S A F -n J 
[ n o n-J a p a n e s e])
Fir st 3 0 n o n -J a p a n e s e p arti ci p a nt s w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y 
i nt er v e nti o n. 
S af et y ( S A F -J 
[ J a p a n e s e])
Fir st 1 2 J a p a n e s e p arti ci p a nt s w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y 
i nt er v e nti o n.
S af et y ( S A F)
All p arti ci p a nt s, w h o w er e a d mi ni st er e d a n y d o s e of a n y st u d y i nt er v e nti o n. 
P K
All p arti ci p a nt s w h o c o m pl et e at l e a st 1 i nf u si o n of M 7 8 2 4, a n d w h o pr o vi d e at l e a st 
1 s a m pl e wit h a m e a s ur a bl e c o n c e ntr ati o n of M 7 8 2 4.
A D A
All p arti ci p a nt s w h o c o m pl et e at l e a st 1 i nf u si o n of M 7 8 2 4 a n d h a v e at l e a st o n e 
v ali d A D A r e s ult.  All A D A a n al y s e s will b e b a s e d o n t hi s a n al y si s s et.
9. 4
St atistic al A n al yses
F ull details of all pla n ne d a nal yses will be descri be d i n t he st u d y Inte grate d A nal ys is Pla n (I A P). 
Maj or m o dificat i o ns of pla n ne d a nal yses will be reflecte d i n a pr ot oc ol a me n d me nt or i n t he 
cli nical st u d y re p ort. 
I n or der t o pr o vi de o verall esti mates of treat me nt effects, data will be p o ole d acr oss st u d y ce nters. 
T he fact or ‘ce nter’ will n ot be c o nsi dere d i n statist ical m o dels or f or s u b gr o u p a nalys es d ue t o t he 
hi g h n u m ber of partici pati n g ce nters i n c o ntrast t o t he a ntici pate d s mall n u m ber of partici pa nts 
ra n d o mize d at eac h ce nter.
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 nc y 
c o u nts a n d perce nta 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 nal ys is set of i nterest, u nless ot her wise s pecifie d i n t he I A P. If n ot e x plicitl y state d, n o i m p utati o n 
is use d i n t he a nal ys es. All safety a n d efficac y en d p oi nts will be s u m marize d b y  treat me nt ar m. 
T he Ja pa nese safet y c o h ort will be s u m marize d se paratel y.
9. 4. 1
Effic ac y A n al yses
All a nal yses o n efficac y en d p oi nts are pri maril y  do ne o n t he f ull a nal ysis set ( F A S). T he 
fra me w or k i n Ta ble 2 4 bel o w descri bes t he a nal ys is of Pri mar y a n d Sec o n dar y e n d p oi nts.
Stratifie d a nal yses will use t he che m ot hera p y r e gi me n a n d P D-L 1  e xpressi o n i n t u m or cells ( < 1 % 
vers us ≥ 1 % , retr os pecti ve test res ults f or partici pa nts fr o m t he safet y ru n- i n part a n d pr os pecti ve 
test res ults f or partici pa nts i n t he e x pa nsi o n part) as stratificati o n fact or s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 1 / 1 5 5
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
A nal y sis of 
 en d p oi nts will be c o nti n ge nt o n t he o utc o mes of pri mar y  an d 
sec o n dar y e n d p oi nts.
9. 4. 1. 1 
T u m or Assess me nt b y I R C
T he pri mar y  en d p oi nt i n t his st u d y  is P F S acc or di n g t o R E CIS T 1. 1 assesse d b y  t he I n vesti gat or. 
If a cli nicall y rele va nt P F S be nefit is o bser ve d at t he pri mar y  anal y sis, a n a d diti o nal a nal ys is of 
P F S per I RC assess me nt ma y  be c o n d ucte d. Details will b e defi ne d i n a se parate statistical a nal ys is 
pla n.
9. 4. 2
S afet y A n al yses
All safet y a nal ys es will be perf or me d o n t he Safet y  A nal ysis p o p ulati o n. 
Safet y  en d p oi nts i ncl u de A Es, cli nical la b orat or y assess me nts, vital si g ns, p h y sical e xa mi nati o n, 
E C G para meters, a n d E C O G P S as descri be d i n Secti o n 8. 2.
T a ble 2 5 
S afet y E n d p oi nts a n d St atistic al A n al ysis Met h o ds
E n d p oi nt
St ati sti c al A n al y si s M et h o d s
O c c urr e n c e of T E A E s 
a n d tr e at m e nt -r el at e d 
A E s 
S af et y will b e a n al y z e d o n t h e S A F p o p ul ati o n a n d will b e b a s e d o n all s af et y a n al y si s 
r e p orti n g o ut c o m e s li k e a d v er s e e v e nt s, A E SI s a n d l a b or at or y t e st s o ut c o m e s.
T h e s af et y e n d p oi nt s will b e t a b ul at e d u si n g d e s cri pti v e st ati sti c s. S af et y will al s o b e 
t a b ul at e d b y s u b gr ou p s ( e. g., et h ni cit y J a p a n e s e a n d n o n -J a p a n e s e).
T h e i n ci d e n c e of T E A E s
w hi c h i n cl u d e s A E SI s , r e g ar dl e s s of attri b uti o n, will b e 
s u m m ari z e d b y Pr ef err e d T er m a n d S y st e m Or g a n Cl a s s f or e a c h tr e at m e nt ar m, a n d 
d e s cri b e d i n t er m s of i nt e n sit y a n d r el ati o n s hi p t o tr e at m e nt.
T h e I D M C c orr e s p o n di n gl y e v al u at e s t h e s af et y o n t h e S A F -J a n d S A F -n J a n al y si s 
p o p ul ati o n i n t h e s af et y r u n -i n, w h er e a s d et ail s ar e s p e cifi e d i n t h e I D M C c h art er.
F urt h er d et ail s of s af et y a n al y s e s will b e pr o vi d e d i n t h e I A P
9. 4. 3
Ot her A n al yses
P K a nal ysis a n d 
 anal y ses will be s pecifie d i n t he I nte grate d A nal ys is Pla n 
fi nalize d bef ore data base l oc k. T he p o p ulati o n P K a nal ysis a n d e x p os ure-res p o nse m a y  be 
perf or me d usi n g c o m bi ne d data fr o m se veral M 7 8 2 4 cli nical st u dies a n d will be s pecifie d i n a 
se parate I A P. P o p P K, e x p os ure-res p o nse a n d  
 a nal ys es will be prese nte d se parately fr o m 
t he mai n cli nical st u d y re p ort ( C S R).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 2 / 1 5 5
9. 4. 4
Se q ue nce of A n al yses

R e g ular safet y a nalys es c o n d ucte d b y t he I D M C

P ri mar y anal ys is (c o n d ucte d o nce 7 0 P F S e ve nts per I n vesti gat or assess me nt ha ve bee n reac he d
a n d after a mi ni m u m f oll o w -u p of 1 5 m o nt hs after ra n d o mizati o n of t he last partici pa nt).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 3 / 1 5 5
1 0
Refere nces 
A h n MJ., Ya n g J, Y u H, et al. 1 3 6 O: Osi merti ni b c o m bi ne d wit h d ur val u ma b i n E G F R -m uta nt 
n o n- s mall cell l u n g ca ncer: res ults fr o m t he T A T T O N p hase I b trial . J. T h orac. O nc ol. 2 0 1 6; 1 1 ( 4 
S u p pl), S 1 1 5. 
 
 
 
 
 
A u péri n A, Le Péc h o u x C, R olla n d E, et al. Meta -a nal ysis of c o nc o mita nt vers us se q ue ntial 
ra di oc he m ot hera py i n l ocall y ad va nce d n o n- s mall-cell l u n g ca ncer. J Cli n O nc ol 2 0 1 0; 2 8: 
2 1 8 1- 9 0.
Bajaj G, Wa n g 
X, A gra wal S, et al. M o del -Base d P o p ulati o n P har mac o ki netic A nal ys is of 
Ni v ol u ma b i n Patie nts Wit h S oli d T u m ors. C P T P har mac o metr S y st P har mac ol 2 0 1 7; 6( 1): 5 8 -
6 6. Bae ver et al, 2 0 1 8 .
B o h nsac k O et al; E S M O 2 0 1 4, A bstract N o: 4 9 5 8
Bra dle y  JD, Pa ul us R, K o ma ki R, et al, Sta n dar d -d ose vers us hi g h -d ose c o nf or mal ra di ot hera py 
wi t h c o nc urre nt a n d c o ns oli dati o n car b o plati n pl us paclita xel wit h or wit h o ut cet u xi ma b f or 
patie nts wit h sta ge III A or III B n o n- s mall-cell l u n g ca ncer ( R T O G 0 6 1 7): a ra n d o mise d, t w o -b y -
t w o fact orial p hase 3 st u d y. La ncet O nc ol 2 0 1 5; 1 6: 1 8 7– 9 9.
Bra de A, Bez ja k A, Mac Rae R, et al. P hase I trial of ra diati o n wit h c o nc urre nt a n d c o ns oli dati o n 
pe metre xe d a n d cis plati n i n patie nts wit h u nresecta ble sta ge III A/ B n o n- s mall-cell l u n g ca ncer. I nt 
J Ra diat O nc ol Bi ol P h ys. 2 0 1 1 A pr 1; 7 9( 5): 1 3 9 5- 4 0 1. 
Bra h mer J, La cc hetti C, Sc h nei der B, et al. Ma na ge me nt of I m m u ne-Relate d A d verse E ve nts i n 
Patie nts Treate d Wit h 
I m m u ne C hec k p oi nt I nhi bit or T hera p y:  America n S ociet y  of Cli nical 
O nc ol o g y  Cli nical Practice G ui deli ne. J Cli n O nc ol. 2 0 1 8 Fe b 1 4:J C O 2 0 1 7 7 7 6 3 8 5.
Bretz F, Ma urer
W, Bra n nat h W, P osc h M. A gra p hical a p pr oac h t o se q ue ntiall y rejecti ve m ulti ple 
test pr oce d ures. Statistics i n Me dici ne 2 0 0 9; 2 8: 5 8 6- 6 0 4.
C ha m piat S, La m b otte O, Barrea u E, et al. Ma na ge me nt 
of i m m u ne c hec k p oi nt bl oc ka d e 
d y si m m u ne t o xicities: a c olla b orati ve p ositi o n pa per. A n n O nc ol. 2 0 1 6; 2 7( 4): 5 5 9- 7 4.
C h o y  H, Ger ber D E, Bra dle y  JD, et al. C o nc urre nt pe metre xe d a n d ra diati o n t hera p y in t he 
treat me nt of patie nts wit h i n o pera ble sta ge III n o n -s mall cell l u n g ca ncer: a s yste matic re vie w of 
c o m plete d a n d o n goi n g st u dies. L u n g Ca ncer. 2 0 1 5; Mar; 8 7( 3): 2 3 2 - 4 0. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 4 / 1 5 5
C h u n S G, H u C, C h o y  H. et al, I mpact of I nte nsit y-M o d ulate d Ra diati o n T hera p y Tec h ni q ue f or 
L ocall y  Ad va nce d N o n -S mall -Cell L u n g Ca ncer: A Sec o n dar y  Anal ys is of t he N R G O nc ol o g y 
R T O G 0 6 1 7 Ra n d o mize d Cli ni cal Trial. J Cli n O nc ol. 2 0 1 7 Ja n; 3 5( 1): 5 6 - 6 2.
 
 
 
 
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
Re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer 2 0 0 9; 4 5: 2 2 8 -4 7.
F D A. Dr u g I nteracti o n St u dies - St u d y  Desi g n, Data A nal y sis, I m plicati o ns f or D osi n g, a n d 
La beli n g Rec o m me n dati o ns, 2 0 1 2. A vaila ble Fr o m: htt ps:// w w w.f da. g o v
Fres h water T, K o n dic A, A ha ma di M, et al. E val uati o n of d osi n g strate g y  f or pe m br oliz u ma b f or 
o nc ol o g y  i n dicati o ns. J I m m u n o T her Ca ncer 2 0 1 7; 5: 4 3.
G ol de n E B, C h ha bra A, C hac h o ua A, et al. L o cal ra di ot hera py a n d gra n ul oc y t e-macr o p ha ge 
c ol o n y-sti m ulati n g fact or t o ge nerate a bsc o pal res p o nses i n patie nts wit h metastatic s oli d t u m o urs: 
a pr o of-of -pri nci ple trial. L a ncet O nc ol. 2 0 1 5; 1 6 ( 7), 7 9 5 – 8 0 3. 
 
 
G o u die D R, D' Alessa n dr o M, Merri ma n B, et al. A bstract L B -2 4 5: L o ss of f u ncti o n of t he T G F β RI
rece pt or lea ds t o t he s p o nta ne o usl y re gressi n g s q ua m o us carci n o ma c o n diti o n, m ulti ple self-
heali n g s q ua m o us e pit heli o ma ( Fer g us o n -S mit h disease). Ca ncer Res 2 0 1 1; 7 1 .
G o vi n da n R, B o gart J, V o kes E E J. L ocall y  ad va nce d n o n- s mall cell l u n g ca ncer: t he past, prese nt, 
a n d f ut ure T h orac O nc ol. 2 0 0 8 A u g; 3( 8): 9 1 7- 2 8. 
 
G uleria I, K h osr os ha hi A, A nsari MJ, et al. A C ritical R ole f or t he Pr o gra m me d D eat h L i ga n d 1 
i n Fet o mater nal T olera nce. J E x p Me d. 2 0 0 5; 2 0 2( 2): 2 3 1- 7.
Hil bis h K G, Marti n 
J A, Sta u ber AJ, et al. T G F -β 1 M o n ocl o nal A nti b o d y : Assess me nt of 
E m br y o- fetal T o xicit y  in R ats a n d R a b bits. Birt h Defects 
Res B De v 
Re pr o d T o xic ol. 
2 0 1 6; 1 0 7( 4 -5): 1 7 4 - 8 4.
 
 
 
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 5 / 1 5 5
 
 
 
Le ber A, Teles A, Ze ncl usse n A C. Re g ulat or y T C ells a n d T heir R ole i n P re g na nc y. A m J Re pr o d 
I m m u n ol. 2 0 1 0; 6 3( 6): 4 4 5 - 5 9.
 
Li n E. P Y, Ya n g C Y, Li n C W, et al. Pri mi n g P D -L 1  ex pressi o n b y  che m ot hera pe utic a ge nts i n 
n o n- s mall cell l u n g ca ncers. J o ur nal of Cli nical O nc ol o g y 2 0 1 7; 3 5: n o 1 5.
 
 
 
 
M or ga n G W, Breit S N. Ra diati o n a n d t he l u n g: a ree val uati o n of t he mec ha nis ms me diati n g 
p ul m o nar y  i nj ur y. I nt J Ra diat O nc ol Bi ol P h ys. 1 9 9 5 Ja n 1 5; 3 1( 2): 3 6 1-9.
M orris J C, Ta n A R, Ole nc ki T E, et al.  P hase I st u d y of G C 1 0 0 8 (fres oli m u ma b): a h u ma n a nti-
tra nsf or mi n g gr o wt h fact or-beta ( T G F β) m o n ocl o nal a nti b o d y in patie nts wit h a d va nce d mali g na nt 
mela n o ma or re nal cell carci n o ma. P L o S O ne 2 0 1 4; 9( 3):e 9 0 3 5 3 .
M o vsas B, H u C, Sl oa n , et al. Q ualit y  of Life A nal y sis of a Ra diati o n D ose -Escalati o n St u d y  of 
Patie n ts Wit h 
N o n -S mall -Cell L u n g Ca ncer: A Sec o n dar y  An al y sis of t he Ra diati o n T hera p y 
O nc ol o g y  Gr o u p 0 6 1 7 Ra n d o mize d Cli nical Trial. J A M A O nc ol. 2 0 1 6 Mar; 2( 3): 3 5 9- 6 7.
N C C N G ui deli nes f or Patie nts ® - A ntie mesis Versi o n 1/ 2 0 1 9 – Fe br uar y  28, 2 0 1 9. A vaila ble at 
w w w. ncc n. or g/ patie nts. Accesse d 2 7 Ma y , 2 0 1 9.
Niezi n k A G H, de J o n g R A, M uijs C T, et al. P ul m o nar y F u ncti o n C ha n ges After Ra di ot hera p y f or 
L u n g or Es o p ha geal Ca ncer: A S y ste matic Re vie w F oc usi n g o n D ose -V ol u me Para meters. 
O nc ol o gist. 2 0 1 7 Oct; 2 2( 1 0): 1 2 5 7 - 1 2 6 4.
 
Peters S, R u y ssc her D, Daf ni U, et al. Safet y e val uati o n of ni v ol u ma b a d de d c o nc urre ntl y to 
ra di ot hera py i n a sta n dar d first l i ne c he m o-R T re gi me n i n u nresecta ble l ocall y a d va nce d N S C L C: 
T he E T O P NI C O L A S p hase II trial., a bstract # 8 5 1 0, A S C O 2 0 1 8 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 6 / 1 5 5
 
 
 
 
 
Sa ma nta D, Par k Y, Ni X, et al. C he m ot hera p y i n d uces e nric h me nt of C D 4 7 +/ C D 7 3 +/ P D L 1 + 
i m m u ne e vasi ve tri ple-ne gati ve 
breast 
ca ncer cells. Pr oc 
Natl 
Aca d 
Sci 
U 
S 
A. 
2 0 1 8; 1 1 5( 6): E 1 2 3 9 -E 1 2 4 8.
Ste uer C E, Be hera M, Er na ni V, et al. C o m paris o n of C o nc urre nt Use of T h oracic Ra diati o n Wit h 
Eit her Car b o plati n -Paclita xel or Cis plati n -Et o p osi de f or Patie nts Wit h Sta ge III N o n -S mall -Cell 
L u n g Ca ncer: A S ys te matic Re vie w. J A M A O nc ol. 2 0 1 7 A u g 1; 3( 8): 1 1 2 0- 1 1 2 9.
Se na n S, Bra de 
A, 
Wa n g 
L H, 
et al. P R O C L AI M: 
Ra n d o mize d 
P hase 
III Trial 
of 
Pe metre xe d- Cis plati n or Et o p osi de -Cis plati n Pl us T h oracic Ra diati o n T hera p y F oll o we d b y  
C o ns oli dati o n C he m ot hera p y  i n L o call y A d va nce d N o ns q ua m o us N o n – S mall -Cell L u n g Ca ncer. 
J o ur nal of Cli nical O nc ol o g y 2 0 1 6; 3 4( 9): 9 5 3- 6 2.
S ul oc ha na S P, S y e d M, C ha n drase kar D V, et al. Cli nical Dr u g -Dr u g P har mac o ki net ic I nteracti o n 
P ote ntial of S ucralfate wit h 
Ot her 
Dr u gs: 
Re vie w a n d Pers pecti ves. E ur J Dr u g 
Meta b 
P har mac o ki net. 2 0 1 6; 4 1( 5): 4 6 9- 5 0 3.
 
 
Va nstee n kiste J. Ni v ol u ma b f or N S C L C i n Ja pa nese patie nts: si milar be nefits, b ut be ware of 
p ne u m o nitis. E S M O O pe n 2 0 1 6 2 0 1 7; 1:e 0 0 0 1 1 9.
 
Ver ma 
V, 
Si m o ne C B, 
Wer ner -Wasi k 
M. 
Ac ute 
a n d Late 
T o xicities 
of C o nc urre nt 
C h e m ora di ot hera p y f or L ocall y-A d va nce d N o n -S mall Cell L u n g Ca ncer. Ca ncers ( Basel). 2 0 1 7 .
V ujas k o vic Z, Gr oe n HJ. T G F -beta, ra diati o n-i n d uce d p ul m o nar y  inj ur y  an d l u n g ca ncer. I nt J 
Ra diat Bi ol. 2 0 0 0 A pr; 7 6( 4): 5 1 1- 6.
Y o o n S M, S hai k h T, Hall ma n M. T hera pe utic ma na ge me nt o pti o ns f or sta ge III n o n- s mall cell 
l u n g ca ncer. W orl d J Cli n O nc ol 2 0 1 7; 8: 1- 2 0. 
Waf ula 
P O, Teles A, Sc h u mac her A, et al. P D - 1 b ut n ot C T L A- 4 Bl oc ka ge A br o gates t he 
P r otecti ve E ffect of R e g ulat or y T Cells i n a P re g na nc y Muri ne M o del. A m J R e pr o d I mm u n ol. 
2 0 0 9; 6 2( 5): 2 8 3 - 9 2.
Wa n g 
D, Z h a n g S, Z ha o H. Fi xe d D osi n g Vers us B o d y  Size– Base d D osi n g of M o n ocl o nal 
A nti b o dies i n A d ult Cli nical Trials. J Cli n P har mac ol, 2 0 0 9; 4 9: 1 0 1 2 -1 0 2 4.
Wa n g 
L, W u S, O u G, et al. Ra n d o mize d p hase II st u d y of c o nc urre nt cis plati n/et o p osi de or 
paclita xel/car b o plati n a n d t h oracic ra di ot hera py i n patie nts wit h sta ge III n o n- s mall cell l u n g 
ca ncer. L u n g Ca ncer 2 0 1 2; 7 7: 8 9 -9 6 .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 7 / 1 5 5
Weic hsel ba u m R R, Li a n g H, De n g L, et al. Ra di ot hera p y a n d i m m u n ot hera p y: a be neficial liais o n? 
Nat. R e v. Cli n. O nc ol. 2 0 1 7; 1 4 ( 6), 3 6 5 - 3 7 9.
 
 
 
W u 
V W, K w o n g D L, S ha m J S, et al. Tar get d ose c o nf or mit y in 3- di me nsi o nal c o nf or mal 
ra di ot hera py a n d i nte nsit y m o d ulate d ra di ot hera p y. Ra di ot her O nc ol. 2 0 0 4 Ma y; 7 1( 2): 2 0 1 - 6.
 
 
Ze ncl usse n A C. A da pti ve I mm u ne R es p o nses D uri n g P re g na nc y. A m J Re pr o d I mm u n ol. 
2 0 1 3; 6 9 : 2 9 1- 3 0 3.
 
 
 
Z ha o X, S ur y a wa ns hi S, Hr us ka M, et al. Assess me nt of ni v ol u ma b be nefit –ris k pr ofile of a 
2 4 0- m g flat d ose relati ve t o a 3 -m g/ k g d osi n g re gi me n i n patie nts wit h a d va nce d t u m ors. A n n 
O nc ol 2 0 1 7; 2 8: 2 0 0 2- 8.
 
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 8 / 1 5 5
1 1
A p pe n dices
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 9 / 1 5 5
A p pe n di x 1 
A b bre vi ati o ns 
A D A
A nti- dr u g a nti b o d y
A D R
A d verse dr u g reacti o n
A E
A d verse e ve nt
A E SI
A d verse e ve nts of s pecial i nterest
A L K
A na plastic l y m p h o ma ki nase
A L T
Ala ni ne a mi n otra nsferase
A N C
A bs ol ute ne utr o p hil c o u nt
a P T T 
Acti vate d partial t hr o m b o plasti n ti me
A S C O 
A merica n S ociet y of Cli nical O nc ol o g y
A S T
As partate a mi n otra nsferase
B O R
Best o verall res p o nse 
β- h C G 
Beta h u ma n c h ori o nic g o na d otr o pi n 
C R
C o m plete res p o nse
Cr C L 
Creati ni ne cleara nce
cC R T 
C o nc o mita nt C he m ora di ot hera p y
C N S
Ce ntral ner v o us s ys te m
C R O
C o ntract Researc h Or ga nizati o n 
c S C C 
C uta ne o us s q ua m o us cell carci n o mas
C T
C o m p ute d t o m o gra p h y
C T C A E 
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts 
ct D N A 
circ ular Tu m or D N A
C T L A- 4 
C y t ot o xic T-l ym p h oc y te-ass ociate d a nti ge n - 4
E C G
E lectr ocar di o gra m
E C O G P S 
Easter n C o o perati ve O nc ol o g y  Gr o u p Perf or ma nce Stat us
e C R F 
Electr o nic case re p ort f or m
E G F R 
E pi der mal gr o wt h fact or rece pt or
 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 0 / 1 5 5
F N
Fe brile N e utr o pe nia
it y
F D A
F o o d a n d Dr u g A d mi nistrati o n
1 L
First -li ne
G C P
G o o d Cli nical Practice
G F R
Gl o mer ular filtrati o n rate
H B V
He patitis B vir us
H C V
He patitis C vir us
HI V
H u ma n i m m u n o deficie nc y vir us
H R
Hazar d rati o
I A P
I nte grate d A nalys is Pla n
I CF
I nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee
I E C
I n de pe n de nt Et hics C o m mittee
I g
I m m u n o gl o b uli n 
I L
Ite m li brar y
I L D
I nterstitial l u n g disease 
I M R T 
I nte nsity- m o d ulate d R T
I N R
I nter nati o nal n or malize d rati o
ir A E 
I m m u ne-relate d A E
ir R E CIS T 
I m m u ne-relate d Res p o nse E val uati o n Criteria i n S oli d T u m ors
I RB
I nstit uti o nal Re vie w B oar d
I R C
I n de pe n de nt Re vie w C o m mittee
I R R
I nf usi o n-relate d reacti o ns 
I T T
I nte nti o n-t o-Treat
I UO
I n vesti gati o nal use o nl y
I V
I ntra ve n o us 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 1 / 1 5 5
I W R S 
I nteracti ve V oice/ We b Res p o nse S yste m
L D H  
Lactate D e h y dr o ge nase
L L N
l o wer li mit of n or mal
K A
Kerat oaca nt h o mas
m A b
M o n ocl o nal a nti b o dies 
Me d D R A 
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M RI
Ma g netic res o na nce i ma gi n g
N C C N 
Nati o nal C o m pre he nsi ve Ca ncer Net w or k
N CI
Nati o nal Ca ncer I nstit ute 
N S AI D 
N o nster oi dal a nti -i nfla m mat or y dr u g 
N S C L C 
N o n -s mall cell l u n g ca ncer 
N S C L C- S A Q 
N o n -s mall cell l u n g ca ncer sy m pt o m assess me nt q uesti o n naire
O R R
O bjecti ve res p o nse rate 
m O S
Me dia n O verall s ur vi val 
P D
Pr o gressi ve disease
 
P F S
Pr o gressi o n -free s ur vi val
P F Ts 
P ul m o nar y  F u ncti o n Tests
m P F S 
Me dia n Pr o gressi o n -free s ur vi val 
P K
P har mac o ki netics
p o p P K 
P o p ulati o n p har mac o ki netic
P R
Partial res p o nse
P T
Pr ot hr o m bi n ti me
q 2 w
E ver y  2 wee ks
q 3 w
E ver y  3 wee ks
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
R M P
Ris k Ma na ge me nt Pla n
R P 2 D 
Rec o m me n de d P hase II D ose
R T
Ra diati o n t hera p y
S A E
Seri o us a d verse e ve nt
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 2 / 1 5 5
S A F
Safet y  (a nal ysis p o p ulati o n)
S C R
Scree ni n g (a nal ys is p o p ulati o n)
S U S A R 
S us pecte d u ne x pecte d seri o us a d verse reacti o ns
T G F β RII 
Tra nsf or mi n g gr o wt h fact or β rece pt or II
T E A E 
Treat me nt -e mer ge nt A d verse E ve nt
U L N
U p per li mit of n or mal
V A S
Vis ual a nal o g scale
W O C B P   
W o ma n of c hil d beari n g p ote ntial
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 3 / 1 5 5
A p pe n di x 2 
St u d y G o ver n a nce
Fi n a nci al Discl os ure
I n vesti gat ors a n d S u b -I nvesti gat or s will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mati o n, as re q ueste d, f or t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial certificati o n 
or discl os ure state me nts t o t he a p pr o priate re g ulat or y aut h orities. T his i nf or mati o n is re q uire d 
d uri n g t he st u d y a n d f or 1 year after c o m pleti o n o f t he st u d y.
I nf or me d C o nse nt Pr ocess

T he I n vesti gat or or his/ her re prese ntati ve will e x plai n t he nat ure of t he st u d y  t o t he partici pa nt 
or his/ her le gall y aut h orize d re prese ntati ve (w here all o we d b y  local la ws a n d re g ulati o ns) a n d 
a ns wer all q uesti o ns o n t he st u d y.

Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y .

Partici pa nts or t heir le gall y-a ut h orize d re prese ntati ve (w here all o we d b y  local la ws a n d 
re g ulati o ns) will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he req uire me nts 
of 2 1 C F R 5 0; t he Ja pa nese mi nisterial or di na nce o n G C P; l ocal re g ulati o ns; I CH g ui deli nes; 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y  Act ( HI P A A) re q uire me nts, w here a p plica ble; 
a n d t he I R B/I E C or st u d y ce nter.

T he me dical rec or d m ust i nclu de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt was e nr olle d i n t he st u d y an d t he date t he writte n c o nse nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.

If t he I C F is u p date d d u ri n g t heir partici pati o n i n t he st u d y, partici pa nts m ust be re-c o nse nte d 
t o t he m ost c urre nt, a p pr o ve d versi o n.

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 prese ntati ve.

T he ori gi nal si g ne d a n d date d c o nse nt will re mai n at t he I nvesti gat or ’s site a n d m ust be safel y 
arc hi ve d s o t hat it ca n be retrie ve d at a n y ti me f or m o nit ori n g, a u diti n g a n d i ns pecti o n p ur p oses.

Partici pa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F.
D at a Pr otecti o n

T he S p o ns or will assi g n a u ni q ue i de ntifier t o partici pa nts after o btai ni n g t heir i nf or me d 
c o nse nt. All partici pa nt rec or ds or datasets 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 na mes or a n y i de ntifia ble i nf or mati o n will n ot be tra nsferre d.

T he S p o ns or m ust i nf or m partici pa nts t hat t heir pers o nal st u d y-relate d data will be use d per 
l ocal data pr otecti o n a n d pri vac y  la ws. T he le vel of discl os ure m ust als o be e x plai ne d t o t he 
partici pa nt.

T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y  be e xa mi ne d b y  Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, b y  ap pr o priate 
I RB/I E C me m bers, a n d b y  re g ulat or y aut h orit y i ns pect ors. All s uc h pers o ns will strictl y 
mai ntai n partici pa nts’ c o nfi de ntialit y .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 4 / 1 5 5

T he I n vesti gat or will c o m plete t he partici pa nt re gistrati o n f or m a n d fa x it t o t he re gistrati o n 
ce nter. If t he partici pa nt meets all i ncl usi o n criteria a n d d oes n ot meet a n y of t he e xcl usi o n 
criteria, t he partici pa nt re gistrati o n ce nter will recei ve c o nfir mati o n, re gister t he partici pa nt a n d 
i nf or m t he I nvesti gat or a n d t he S p o ns or of t he re gistrati o n n u m ber b y  fa x. If t he partici pa nt is 
i neli gi ble f or t he st u d y, a partici pa nt n u m ber will be all ocate d a n d d oc u me nte d.
St u d y A d mi nistr ati ve
T he S p o ns or of t his cli nical st u d y  is E M D Ser o n o Researc h & De vel o p me nt Instit ute, I nc. ( E M D 
Ser o n o R & D), Billerica, M A, i n t he U nite d States ( U S A); Merc k Ser o n o C o., Lt d., Me g ur o -k u, 
T o k y o, Ja pa n, i n Ja pa n; a n d Merc k K Ga A, Dar msta dt, Ger ma n y, f or sites o utsi de t he U S A a n d 
Ja pa n.
T he st u d y will be c o n d ucte d at a p pr o xi matel y 10 0 ce nters i n N ort h a n d S o ut h A merica, E U, a n d 
Asia -Pacific. A p pr o xi matel y  2 0 t o 3 0 sites will be i n t he U S A.
T he C o or di nati n g I n vesti gat or liste d o n t he title pa ge re prese nts all I n vesti gat ors f or decisi o ns a n d 
disc ussi o ns o n t his st u d y, per I C H G C P. T he C o or di nati n g I n vesti gat or will pr o vi de e x pert me dical 
i n p ut a n d a d vice o n t he st u d y desi g n a n d e xec uti o n a n d is res p o nsi ble f or t he re vie w a n d si g n off 
of t he cli nical st u d y re p ort.
T he st u d y will a p pear i n t he f oll o wi n g cli nical st u dies re gistries: cli nicaltrials. g o v a n d E u dra C T. 
Details of str uct ures a n d ass ociate d pr oce d ures will be defi ne d i n a se parate I nte grate d Pr oject 
Ma na ge me nt Pla n, w hic h will be pre pare d u n der t he s u per visi o n of t he Cli nical St u d y Lea der.
Refer t o t he St u d y  Or ga nizati o n a n d t he St u d y Sites i n Ja pa n i n s u p p orti n g d oc u me nt.
A n I D M C will be f o r me d i n t his st u d y.
Re g ul at or y a n d Et hic al C o nsi der ati o ns

T his st u d y  will be c o n d ucte d i n acc or da nce wit h t he pr ot oc ol a n d t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he Declarati o n 
of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S) 
I nter nati o nal Et hical G ui deli nes

A p plica ble I C H G o o d Cli nical Practice ( G C P) G ui deli nes

T he Ja pa nese mi nisterial or di na nce o n G C P 

A p plica ble la ws a n d re g ulati o ns

T he I n vesti gat or m ust 
s u b mit t he pr ot oc ol, pr ot oc ol a me n d me nts (if a p plica ble), I CF, 
I n vesti gat or Br oc h ure, a n d ot her rele va nt d oc u me nts (e.g, a d vertise me nts) t o a n I RB/I E C a n d 
t he IR B/I E C m ust re vie w a n d a p pr o ve t he m bef ore t he st u d y is i nitiate d.

T he S p o ns or i nitiates t he st u d y at a site after o btai ni n g writte n a p pr o val fr o m t he Hea d of t he 
st u d y site, base d o n fa v ora ble o pi ni o n/a p pr o val fr o m the c o ncer ne d I R B.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 5 / 1 5 5

A n y  pr ot oc ol a me n d me nts (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g a n d 
re q uire I RB/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges, e xce pt f or c ha n ges necessar y  to 
eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. W he n
a p plica ble, a me n d me nts will be 
s u b mitte d t o t he a p pr o priate Healt h A ut h orities.

T he I n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:

Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y to t he I RB/I E C a n n uall y or m ore 
fre q ue ntly per t he I R B’s/I E C’s r e q uire me nts, p olicies, a n d pr oce d ures.

N otif y i n g t he I RB/I E C of S A Es or ot her si g nifica nt safety fi n di n gs, as re q uire d b y  IR B/ I E C 
pr oce d ures

Pr o vi di n g o versi g ht of t he st u d y co n d uct at t he site a n d a d here nce t o re q uire me nts of 2 1 C F R, 
I C H g ui deli nes, t he IR B/I E C, E ur o pea n re g ulati o n 5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), 
a n d all ot her a p plica ble l ocal re g ulati o ns

T he pr ot oc ol a n d a n y a p plica ble d oc u me ntati o n will be s u b mitte d or n otifie d t o t he Healt h 
A ut h orities i n acc or da nce wit h all l ocal a n d nat i o nal re g ulati o ns f or eac h site.
E mer ge nc y Me dic al S u p p ort

T he S p o ns or or desi g nee will pr o vi de E mer ge nc y Me dical S u p p ort car ds t o partici pa nts f or use 
d uri n g t he st u d y. T hese pr o vi de t he mea ns 
f or partici pa nts t o i de ntif y the msel ves as 
partici pati n g i n a cli nical st u d y. Als o, t hese gi ve healt h care pr o vi ders access t o a n y inf or mati o n 
a b o ut t his partici pati o n t hat m a y  be nee de d t o deter mi ne t he c o urse of me dical treat me nt f or t he 
partici pa nt. T he i nf or mati o n o n t he E mer ge nc y Me dical S u p p ort car d ma y incl u de t he pr ocess 
f or e mer ge nc y u n bli n di n g (if a p plica ble).

T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical st u d y I n vesti gat or cari n g f or 
t he partici pa nt. C o nse q ue ntl y , t he I n vesti gat or a grees t o pr o vi de his or her e mer ge nc y co ntact 
i nf or mati o n o n t he car d. If t he I n vesti gat or is a vaila ble w he n a n e ve nt occ urs, t he y will a ns wer 
a n y questi o ns. A n y s u bse q ue nt acti o n (e.g, u n bli n di n g) will f oll o w t he sta n dar d pr ocess 
esta blis he d f or I n vesti gat ors.

W he n t he I n vesti gat or is n ot a vaila ble, t he S p o ns or pr o vi des t he a p pr o priate mea ns t o c o ntact a 
S p o ns or p h y sicia n. T his i ncl u des pr o visi o n of a 2 4- h o ur c o ntact n u m ber at a call ce nter, 
w here b y t he healt h care pr o vi ders will be gi ve n access t o t he a p pr o priate S p o ns or p h ysicia n t o 
assist wit h t he me dical e mer ge nc y an d t o pr o vi de s u p p ort f or t he p ote ntial u n bli n di n g of t he 
partici pa nt c o ncer ne d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 6 / 1 5 5
Cli nic al St u d y I ns ur a nce a n d C o m pe ns ati o n t o P artici p a nts
T he S p o ns or is e ntirel y res p o nsi ble f or A Es t hat are ass ociate d wit h t his st u d y  a n d ca use da ma ge 
t he healt h of t he partici pa nts, e xce pt f or A Es ca use d b y a n i nte nti o nal a n d/ or si g nifica nt de viati o n 
o n t he part of t he I n vesti gat or, t he st u d y site, a n d/ or t he partici pa nt. T he S p o ns or will pr o vi de 
i ns ura nce t o f ulfill t his res p o nsi bilit y.
I ns ura nce c o vera ge will
be pr o vi de d f or eac h c o u ntr y partici pati n g i n t he st u d y. I ns ura nce 
c o n diti o ns s hall meet g o o d l ocal sta n dar ds, as a p plica ble.
Cli nic al St u d y Re p ort
After st u d y co m pleti o n, t he S p o ns or will write a cli nical st u d y re p ort i n c o ns ultati o n wit h t he 
C o or di nati n g I n vesti gat or.
P u blic ati o n

T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie ntific meeti n gs. If t his is f oresee n, 
t he I n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or bef ore s u b missi o n. 
T his all o ws Merc k t o pr otect p r o prietar y i nf or mati o n a n d t o pr o vi de c o m me nts. 

T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. Per sta n dar d 
e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p ort p u blicati o n of m ultice nter 
st u dies o nl y  in t heir e ntiret y an d n ot as i n di vi d ual site data. I n this case, a C o or di nati n g 
I n vesti gat or will be desi g nate d b y  a gree me nt.

A ut h ors hi p will be deter mi ne d b y  agree me nt a n d i n li ne wit h I nter nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.
D isse mi n ati o n of Cli nic al St u d y D at a
P osti n g of data o n Cli ntrials. g o v, E u dra C T, a n d all ot her re q uire d re gistries is pla n ne d a n d will 
occ ur 1 2 m o nt hs after t he last cli nic visit of t he fi nal st u d y  partici pa nt or a n ot her a p pr o priate date 
t o meet a p plica ble re q uire me nts.
D at a Q u alit y Ass ur a nce

All partici pa nt st u d y data will be rec or de d o n pri nte d or electr o nic e C R Fs or tra ns mitte d t o t he 
S p o ns or or desi g nee electr o nicall y (e.g, la b orat or y data). T he I n vesti gat or is res p o nsi ble f or 
verif y i n g t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mel y b y  ph y sically or 
electr o nicall y si g ni n g t he e C R F. Details f or ma na gi n g e C R Fs are i n t he Ma n ual of O perati o ns.

F or P R O data (e .g, Q o L a n d pai n assess me nts), e P R O wil l be use d.

T he I n vesti gat or m ust 
mai ntai n 
acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mati o n i n t he e C R F.

T he I n vesti gat or m ust per mit st u d y-relate d m o nit ori n g, q ualit y ass ura nce a u dits, I RB/I E C 
re vie w, a n d re g ulat or y age nc y  ins pecti o ns a n d pr o vi de direct access t o t he st u d y file a n d s o urce 
data.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 7 / 1 5 5

T he S p o ns or or desi g nee is res p o nsi ble f or data ma na ge me nt of t his st u d y, i ncl u di n g q ualit y  
c hec ki n g of t he data a n d mai ntai ni n g a vali date d data base. Data base l oc k will occ ur o nce q ualit y 
c o ntr ol an d q ualit y  ass ura nce pr oce d ures ha ve bee n c o m plete d. P D F files of t he e C R Fs will be 
pr o vi de d t o t he I n vesti gat or s at st u d y c o m pleti o n.

St u d y  m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data i n t he e C R F 
are acc urate, c o m plete, a n d verifia ble; t hat t he safety a n d ri g hts of partici pa nts are bei n g 
pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d per t he c urre ntl y ap pr o ve d pr ot oc ol a n d a n y 
ot her st u d y agree me nts, I CH G C P, t he Ja pa nese mi nisterial or di na nce o n G C P, a n d all 
a p plica ble re g ulat or y  re q uire me nts.

Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o t he c o n d uct of t his st u d y m ust be 
retai ne d b y  the I n vesti gat or f or 1 5 ye ars after st u d y co m pleti o n, u nless l ocal re g ulati o ns, 
i nstit uti o nal p olicies, or t he S p o ns or re q uires a l o n ger rete nti o n. N o rec or ds ma y  be destr o ye d 
d uri n g t he rete nti o n peri o d wit h o ut t he S p o ns or’s writte n a p pr o val. N o rec or ds m a y  be 
tra nsferred t o a n ot her l ocati o n or part y wit h o ut t he S p o ns or’s writte n n otificati o n.
S o urce D oc u me nts

S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d.

T he I n vesti gat or m ust kee p a pa per or electr o nic file ( me dical file a n d ori gi nal me dical rec or ds) 
at t he site f or eac h st u d y partici pa nt. T he file m ust i de ntif y eac h partici pa nt, c o ntai n t he 
f oll o wi n g de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt, a n d s h o ul d be as c o m plete 
as p ossi ble:

Partici pa nt’s f ull na me, date of birt h, se x, hei g ht, a n d wei g ht

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he st u d y )

St u d y  i de ntifier (i.e., t he S p o ns or’s st u d y n u m ber) a n d partici pa nt’s st u d y n u m ber.

Dates of e ntr y  i nt o t he st u d y (i.e., si g nat ure date o n t he i nf or me d c o nse nt) a n d eac h visit t o t he 
site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t he pr ot oc ol

All A Es

Date t hat t he partici pa nt left t he st u d y, i ncl u di n g a n y reas o n f or earl y wit h dra wal fr o m t he st u d y 
or st u d y  i nter ve nti o n, if a p plica ble.

All s o urce data m ust be file d (e.g, C T or M RI  sca n i ma ges, E C G rec or di n gs, a n d la b orat or y 
res ults). Eac h d oc u me nt m ust ha ve t he partici pa nt n u m ber a n d t he pr oce d ure date; i deall y, 
pri nt e d b y  the i nstr u me nt use d f or t he pr oce d ure. As necessar y , me dical e val uati o n of t hese 
rec or ds s h o ul d be perf or me d, d oc u me nte d, si g ne d a n d date d by t he I n vesti gat or. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 8 / 1 5 5

Data rec or de d o n pri nte d or electr o nic C R Fs t hat are tra nscri be d fr o m s o urce d oc u me nts m ust 
be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust 
be e x plai ne d. T he 
I n vesti gat or m a y  nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, de pe n di n g o n t he 
st u d y. Als o, c urre nt me dical rec or ds m ust be a vaila ble.

T he st u d y mo nit or s will use pri nt o uts of electr o nic files f or s o urce data verificati o n. T hese 
pri nt o uts m ust be si g ne d a n d date d b y t he I n vesti gat or a n d ke pt i n t he st u d y file.

S o urce d oc u me nts are st ore d at t he site f or t he l o n gest p ossi ble ti me per mitte d b y  the a p plica bl e 
re g ulati o ns, a n d/ or as per IC H G C P g ui deli nes, w hic he ver is l o n ger. T he Hea d of t he st u d y  site
e ns ures t hat n o destr ucti o n of me dical rec or ds is perf or me d wit h o ut t he S p o ns or’s writte n 
a p pr o val.

Defi niti o n of w hat c o nstit utes s o urce data is f o u n d i n t he e C R F g ui deli nes.
St u d y a n d Site St art a n d Cl os ure
First Act of Recr uit me nt

T he st u d y  start date is t he date w he n t he cli nical st u d y will be o pe n f or recr uit me nt.

T he first act of recr uit me nt is w he n t he first site is o pe ne d a n d will be t he st u d y  start date.
St u d y  Cl os ure a n d Site Ter mi nati o n

T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y ti me a n d f or 
a n y reas o n. St u d y sites will be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is c o nsi dere d cl ose d 
w he n all re q uire d d oc u me nts a n d st u d y s u p plies ha ve bee n c ollecte d a n d a site cl os ure visit has 
bee n c o m plete d.

T he I n vesti gat or m a y  initiate site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use a n d 
s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n.

Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I nvesti gat or ma y  i ncl u de:

Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he I RB/I E C or 
l ocal Healt h A ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes

I na de q uate recr uit me nt of partici pa nts b y t he I n vesti gat or

Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 9 / 1 5 5
A p pe n di x 3 
C o ntr ace pti o n
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)
A w o ma n is of c hil d beari n g p ote ntial ( i.e., fertile), f oll o wi n g me narc he a n d u ntil eit her:
1)
Bec o mi n g p ost me n o pa usal; or,
2)
is per ma ne ntl y sterile b y  
mea ns of a h y sterect o m y, bilateral sal pi n gect o m y, t u bal 
occl usi o n, or bilateral o o p h orect o m y.
P ost me n o pa usal is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me d ical ca use. A 
hi g h f ollicle-sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge m a y  be use d t o 
c o nfir m a p ost me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal 
re place me nt t hera p y. H o we ver, i n t he a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H 
meas ure me nt is i ns ufficie nt.
Hi g hl y Effecti ve C o ntr ace pti ve Met h o ds ( as s pecifie d i n t he C T F G rec o m me n d ati o ns)
Hi g hl y effecti ve met h o ds are t h ose wit h a fail ure rate of less t ha n 1 % per ye ar w he n use d 
c o nsiste ntl y a n d c orrectl y.
T hese met h o ds are f urt her classifie d i nt o user -i n de pe n de nt a n d user - de pe n de nt met h o ds. 
Beca use user -i n de pe n de nt met h o ds d o n ot de pe n d o n t he partici pa nt’s a bilit y to use t he m 
c o nsiste ntl y an d c orrectl y, t he y are preferre d w he n c o ntrace pti o n is i ntr o d uce d as a c o n diti o n 
f or st u d y partici pati o n.
Ca uti o n s h o ul d be ta ke n f or h or m o nal c o ntrace pti o n, as it m a y  be s usce pti ble t o i nteracti o n wit h 
t he st u d y inter ve nti o n(s), w hic h ma y  re d uce t he efficac y of t he c o ntrace pti o n met h o d. I n this 
case, a sec o n d hi g hl y effecti ve met h o d of c o ntrace pti o n s h o ul d be use d d uri n g t he treat me nt 
peri o d a n d f or at least 4 m o nt hs after t he last d ose of st u d y  treat me nt.
User -De pe n de nt

C o m bi ne d (estr o ge n- a n d pr o gest o ge n -c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h 
i n hi biti o n of o v ulati o n

Oral

I ntra va gi nal *

Tra ns der mal *

Pr o gest o ge n - o nly h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n

Oral

I njecta ble *
User -I n de pe n de nt

I m pla nta ble pr o gest o ge n -o nl y  hor m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n *

I ntra uteri ne de vice (I U D)

I ntra uteri ne h or m o ne-releasi n g sys te m (I U S)
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 0 / 1 5 5

Bilateral t u bal occl usi o n

Vasect o mize d part ner: T his is a hi g hl y effecti ve c o ntrace pti o n met h o d o nl y  if t he part ner 
is t he s ole se x ual part ner of t he W O C B P a n d he has recei ve d me dical assess me nt of t he 
sur gical s uccess.

Se x ual a bsti ne nce: T his is a hi g hl y effecti ve met h o d o nl y  if t he W O C B P refrai ns fr o m 
heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y 
i nter ve nti o n. T he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uat e d i n relati o n t o t he 
d urati o n of t he st u d y  a n d t he preferre d a n d us ual lifest yle of t he partici pa nt.
 
* N ot a p pr o ve d i n Ja pa n .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 1 / 1 5 5
A p pe n di x 4 
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, a n d Re p orti n g
Defi niti o ns
A d verse E ve nt
A n A E is a n y u nt o war d me dical occ urre nce i n a partici pa nt a d mi nistere d a p har mace utical 
pr o d uct, re gar dless of ca usal relati o ns hi p wit h t his treat me nt. T heref ore, a n A E ca n be a n y 
u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s ym pt o m, or 
disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, re gar dless if it is c o nsi dere d 
relate d t o t he me dici nal pr o d uct.
F or s ur gical or dia g n ostic pr oce d ures, t he c o n diti o n/ill ness lea di n g t o s uc h a pr oce d ure is 
c o nsi dere d as t he A E rat her t ha n t he pr oce d ure itself.
C o m pare d t o baseli ne ( Scree ni n g or t he Wee k 1, Da y  1 visit), me dical c o n diti o ns t hat d o n ot 
w orse n i n se verity o r fre q ue nc y duri n g t he st u d y are defi ne d as baseli ne me dical c o n diti o ns a n d
are N O T t o be c o nsi dere d as A Es. 
All ne wl y dia g n ose d or w orse ni n g pre -e xisti n g c o n diti o ns (cli nicall y si gnifica nt c ha n ges i n 
fre q ue nc y, a n d/ or i nte nsit y), si g ns, a n d s ym pt o ms o bser ve d fr o m Baseli ne ( Scree ni n g or t he 
Wee k 1, Da y  1 visit), w het her relate d t o st u d y i nter ve nti o n or n ot, are t o be re p orte d as A Es.
Pr o gressi o n of t he ca ncer u n der st u d y is n ot c o nsi dere d a n A E.
T he I n vesti gat or is re q uire d t o gra de t he se verity or t o xicit y  of eac h A E.
I n vesti gat ors will refere nce t he 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 Es ( C T C A E), versi o n 5. 0 ( p u blicati o n date: 2 7 N o v 2 0 1 7), a descri pti ve ter mi n ol o g y t hat ca n 
be use d f or A E t o xicit y  gra de re p orti n g.
A ge neral gra di n g (se verit y/i nte nsity;  hereafter referre d t o as se verity) scale is pr o vi de d at t he 
be gi n ni n g of t he a b o ve refere nce d d oc u me nt, a n d s pecific e ve nt gra des are als o pr o vi de d.
If t he se verity f or a n A E is n ot s pecificall y gra de d b y  NCI -C T C A E, t he I n vesti gat or is t o use 
t he ge neral N CI-C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5, usi n g his or her best me dical 
j u d g me nt.
T he 5 ge neral gra des are:
Gra de 1 or Mil d
Gra de 2 or M o derate
Gra de 3 or Se vere 
Gra de 4 or L ife-t hreate ni n g 
Gra de 5 or Deat h 
A n y  cli nical A E wit h se verit y of Gra de 4 or 5 m ust als o be re p orte d as a n S A E. H o we ver, a 
la b orat or y a b n or mality o f Gra de 4, s uc h as a ne mia or ne utr o pe nia, is c o nsi dere d seri o us o nl y i f 
t he c o n diti o n meets o ne of t he seri o us criteria s pecifie d bel o w.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 2 / 1 5 5
If deat h occ urs, t he pri mar y  ca use of deat h or e ve nt lea di n g t o deat h s h o ul d be rec or de d a n d 
re p orte d as a n S A E. “ Fatal” wi ll be rec or de d as t he o utc o me of t his s pecific e ve nt a n d deat h 
will n ot be rec or de d as se parate e ve nt. O nl y,  if n o ca use of deat h ca n be re p orte d (e.g, s u d de n 
deat h, u ne x plai ne d deat h), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
I n vesti gat ors m ust 
als o s yste matically assess t he ca usal relati o ns hi p of A Es 
t o st u d y 
i nter ve nti o n (i ncl u di n g a n y ot her n o nst u d y  inter ve nti o ns, ra diati o n t hera p y, etc.) usi n g t he 
f oll o wi n g defi niti o ns. Decisi ve fact ors f or t he assess me nt of ca usal relati o ns hi p of a n A E t o t he 
st u d y inter ve nti o n i ncl u de, b ut ma y  not be li mite d t o, te m p oral relati o ns hi p bet wee n t he A E a n d 
t he st u d y inter ve nti o n, k n o w n si de effects of st u d y inter ve nti o n, me dical hist or y , c o nc o mita nt 
me dicati o n, c o urse of t he u n derl y i n g disease, a n d st u d y pr oce d ures.
U nrel ate d: 
N ot reas o na bly relate d t o t he st u d y inter ve nti o n. A E c o ul d n ot me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der st u d y 
i n t his cli nical st u d y pr ot oc ol. A reas o na ble alter nati ve e x pla nati o n m ust be 
a vailable.
Rel ate d: 
Reas o na bl y 
relate d t o t he st u d y inter ve nti o n. 
A E 
c o ul d 
me dicall y 
( p har mac ol o gically/ cli nicall y) be attri b ute d t o t he st u d y inter ve nti o n u n der st u d y 
i n t his cli nical st u d y pr ot oc ol. 
A b n or m al L a b or at or y Fi n di n gs a n d Ot her A b n or m al I n vesti g ati o n al Fi n di n gs
A b n or mal la b orat or y fi n di n gs a n d ot her a b n or mal i n vesti gati o nal fi n di n gs (e.g, o n a n E C G 
trace) s h o ul d n ot be re p orte d as A Es u nless t he y are ass ociate d wit h cli nical si g ns a n d 
s ym pt o ms, lea d t o st u d y i nter ve nti o n disc o nti n uati o n o r are c o nsi dere d ot her wise me dicall y 
i m p orta nt b y  the I n vesti gat or. If a la b orat or y ab n or malit y  fulfills t hese criteria, t he i de ntifie d 
me dical c o n diti o n (e.g, a ne mia or i ncrease d A L T) m ust be re p orte d as t he A E rat her t ha n t he 
a b n or mal val ue itself.
Seri o us A d verse E ve nts
A n S A E is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life-t hreate ni n g. Life -t hreate ni n g refers t o a n e ve nt i n w hic h t he partici pa nt is at ris k of 
deat h at t he ti me of t he e ve nt, n ot a n e ve nt t hat h y p ot heticall y  mi g ht ha ve ca use d deat h if it 
was m ore se vere.

Re q uires i n patie nt h os pitalizati o n or pr ol o n gs a n e xisti n g h os pitalizati o n

Res ults i n persiste nt or si g nifica nt disa bilit y  or i nca pacity

Is a c o n ge nital a n o maly or birt h defect

Is ot her wise c o nsi dere d t o be a me dicall y i m p orta nt e ve nt as i n pri mar y  ca ncer. I mp orta nt 
me dical e ve nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire h os pitalizati o n 
ma y  be c o nsi dere d as S A Es w he n, base d u p o n a p pr o priate me dical j u d g me nt, t h e y ma y 
je o par dize t he partici p a nt or ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of 
t he o utc o mes liste d a b o ve. E xa m ples of s uc h e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g 
i nte nsi ve treat me nt i n a n e mer ge nc y ro o m or at h o me, bl o o d d y scrasias or c o n v ulsi o ns t hat 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 3 / 1 5 5
d o n o t res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de nc y  or dr u g 
a b use.
F or t he p ur p oses of re p orti n g, a n y s us pecte d tra ns missi o n of a n i nfecti o us a ge nt via a st u d y 
i nter ve nti o n is als o c o nsi dere d a n S A E, as s pecifie d bel o w f or re p orti n g S A Es a n d D L Ts.
F or Ja pa nese sites w here h os pitalizati o n is c o nsi dere d i n t he safety r u n-i n f or o bser vati o nal 
meas ures, a n y A E occ urri n g d uri n g t his h os pitalizati o n s h o ul d n ot be re p orte d as seri o us, u nless 
seri o us ness criteria is met f or A E re p orta bilit y p ur p ose.
E ve nts t h at D o N ot Meet t he Defi niti o n of a n S A E
Electi ve h os pitalizati o ns t o a d mi nister, or t o si m plif y  st u d y i nter ve nti o n or pr oce d ures (e.g, a n 
o ver ni g ht sta y to facilitate c he m ot hera p y a n d relate d h y drati o n t hera p y ap plicati o n) are n o t 
c o nsi dere d S A Es. H o we ver, all e ve nts lea di n g t o u n pla n ne d h os pitalizati o ns or u n pla n ne d 
pr ol o n gati o n of a n electi ve h os pitalizati o n (i.e., u n desira ble effects of a n y a d mi nistere d 
treat me nt) m ust be d oc u me nte d a n d re p orte d as S A Es.
E ve nts N ot t o Be C o nsi d ere d as A Es/ S A Es
Me dical c o n diti o ns prese nt at t he i nitial st u d y  visit t hat d o n ot w orse n i n se verit y or fre q ue ncy 
d uri n g t he st u d y are defi ne d as baseli ne me dical c o n diti o ns, a n d are n ot t o be c o nsi dere d A Es.
A E/ S A Es O bser ve d i n Ass oci ati o n wit h Dise ase P r o gressi o n
Pr o gressi o n of t he disease/ dis or der bei n g st u die d assesse d b y  meas ure me nt of lesi o ns o n 
ra di o gra p hs or ot her met h o ds as well as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) s h o ul d n ot be re p orte d as a n ( S) A E, u nless t he patie nt’s ge neral 
c o n diti o n is m ore se vere t ha n e x pecte d f or t he partici pa nt’s c o n diti o n a n d/ or u nless t he o utc o me 
is fatal wit hi n t he a d verse e ve nt re p orti n g peri o d, as defi ne d i n Secti o n 8. 3. 2 ( Met h o d of 
Detecti n g A d verse E ve nts a n d Seri o us A d verse E ve nts)
A d verse E ve nts of S peci al I nterest
A d verse e ve nts of s pecial i nterest ca n be seri o us or n o nseri o us e ve nts.
Cate g ories of A E SIs relate d t o M 7 8 2 4 i ncl u de:

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

I m m u ne-relate d a d verse e ve nts

T G F - β i n hi biti o n me diate d s ki n reacti o ns

Blee di n g a d verse e ve nts

A ne mia
F or t his st u d y , p ne u m o nitis (ra diati o n or i m m u ne me diate d) is c o nsi dere d a n A E SI .
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E
It is i m p orta nt t hat eac h A E re p ort i ncl u de a descri pti o n of t he e ve nt, its d urati o n ( o nset a n d 
res ol uti o n dates a n d als o o nset a n d res ol uti o n ti mes, w he n it is i m p orta nt t o assess t he ti me of 
A E o nset relati ve t o t he rec or de d st u d y i nter ve nti o n a d mi nistrati o n ti me), its se verit y, its ca usal 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 4 / 1 5 5
relati o ns hi p wit h t he st u d y i nter ve nti o n, a ny ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n 
or ot her acti o n ta ke n, i ncl u di n g d ose m o dificati o n or disc o nti n uati o n of t he st u d y i nter ve nti o n, 
a n d its o utc o me. In a d diti o n, seri o us cases s h o ul d be i de ntifie d a n d t he a p pr o priate seri o us ness 
criteria d oc u me nte d.
S pecific g ui da nce is i n t he C R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns pr o vi de d b y  the 
S p o ns or.
Re p orti n g Seri o us A d verse E ve nts 
Seri o us A d verse E ve nts
I n t he e ve nt of a n y ne w S A E occ urri n g d uri n g t he re p orti n g peri o d, t he I nvesti gat or m ust 
i m me diatel y ( wit hi n a ma xi m u m of 2 4 H O U R S after bec o mi n g a ware of t he e ve nt) i nf or m t he 
S p o ns or or its desi g nee usi n g t he S A E re p ort f or m i n t he e C R F f oll o wi n g s pecific c o m pleti o n 
i nstr ucti o ns.
Re p orti n g of S A Es via pa per re p ort f or m is re q uire d as a bac k - u p met h o d o nl y  in t he case of 
E D C fail ure. Na mes, a d dresses, a n d tele p h o ne a n d fa x n u m bers will be i ncl u de d o n t he pa per 
re p ort f or m. All i nf or mati o n re p orte d via pa per f or m m ust be tra nscri be d i nt o t he e C R F as s o o n 
as t he s yste m bec o mes a vaila ble.
I n exce pti o nal circ u msta nces, a n S A E ( or f oll o w-u p i nf or mati o n) m a y  be re p orte d b y  tele p h o ne; 
i n t hese cases, a n S A E re p ort f or m m ust be c o m plete d i m me diatel y t hereafter i n t he e C R F. 
Rele va nt pa ges fr o m t he e C R F ma y  be pr o vi de d i n parallel (e.g, me dical h ist or y, c o nc o mita nt 
dr u gs). A d diti o nal d oc u me nts ma y  be pr o vi de d b y t he I n vesti gat or, if a vaila ble (e.g, la b orat or y 
res ults, h os pital re p ort, a ut o ps y re p ort). 
T he I nvesti gat or m ust res p o n d t o a n y re q uest f or f oll o w-u p i nf or mati o n (e.g, a d diti o nal 
i nf or mati o n, o utc o me, fi nal e val uati o n, ot her rec or ds w here nee de d) or t o a n y questi o n t he 
S p o ns or/ desi g nee m a y  ha ve o n t he A E wit hi n t he sa me ti meli nes as t h ose n ote d a b o ve f or i nitial 
re p orts. T his is necessar y t o e ns ure pr o m pt assess me nt of t he e ve nt b y t he S p ons or or desi g nee 
a n d (as a p plica ble) t o all o w t he S p o ns or t o meet strict re g ulat or y ti meli nes ass ociate d wit h 
e x pe dite d safet y re p orti n g o bli gati o ns.
Re q uests f or f oll o w-u p will us uall y  be ma de via t he res p o nsi ble M o nit or, 
alt h o u g h i n 
e xce pti o nal circ u mstances t he dr u g safety de part me nt ma y  co ntact t he I nvesti gat or directl y t o 
o btai n f urt her i nf or mati o n or t o disc uss t he e ve nt.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 5 / 1 5 5
A p pe n di x 5 
Cli nic al L a b or at or y Tests
T a ble 2 6 
Pr ot oc ol -Re q uire d Cli nic al L a b or at or y Assess me nts
L a b or at or y  
A s s e s s m e nt s 
P ar a m et er s
H e m at ol o g y 
Pl at el et C o u nt
R B C C o u nt
H e m o gl o bi n
H e m at o crit
R B C I n di c e s :
 
M C V
 
M C H
 
M C H C
 
R D W
 
%r eti c ul o c yt e s 
W B C C o u nt wit h Diff er e nti al:
 
n e utr o p hil s ( A N C)
 
l y m p h o c yt e s ( a b s ol ut e 
c o u nt)
 
m o n o c yt e s
 
e o si n o p hil s
 
b a s o p hil s
H e m o st a s e ol o g y 
Pr ot hr o m bi n ti m e 
I N R
a P T T
F ull Cli ni c al 
C h e mi str y 
P a n el A a
Li v er P a n el : al k ali n e 
p h o s p h at a s e, A L T, A S T, 
G G T, t ot al a n d 
i n dir e ct/ dir e ct bilir u bi n, 
al b u mi n, t ot al pr ot ei n, 
a n d cr e ati n e ki n a s e
S er u m El e ctr ol yt e s:
s o di u m p ot a s si u m, 
c al ci u m, m a g n e si u m, 
c hl ori d e, p h o s p h or u s/ 
p h o s p h at e s
R e n al P a n el : B U N/t ot al 
ur e a, cr e ati ni n e, 
e sti m at e d G F R, uri c a ci d
P a n cr e ati c 
P a n el :
a m yl a s e, li p a s e
Gl u c o s e
L a ct o s e 
d e h y dr o g e n a s e
F ull Cli ni c al 
C h e mi str y 
P a n el B b
T- S P O T T B t e st or 
T S T or Q u a nti F E R O N 
T B G ol d T e st 
( Q F T-G) (if p o siti v e 
hi st or y of t u b er c ul o si s 
e x p o s ur e)
Vir ol o g y : H B V a n d H C V 
s er ol o g y (r e p e at a s p er 
S c h e d ul e s of 
A s s e s s m e nt s if 
p arti ci p a nt wit h i nf e cti o n 
hi st or y)
C or e C h e mi str y
a
Li v er P a n el : al k ali n e 
p h o s p h at a s e, A L T, A S T, 
t ot al a n d i n dir e ct/ dir e ct 
bilir u bi n, 
S er u m El e ctr ol yt e s : 
s o di u m, p ot a s si u m, 
R e n al P a n el : B U N/t ot al 
ur e a, cr e ati ni n e, 
Gl u c o s e, 
a m yl a s e, li p a s e
T h yr oi d P a n el
 
T 4 , T S H
R o uti n e 
Uri n al y si s b
 
S p e cifi c gr a vit y, p h y si c al a p p e ar a n c e, c ol or
 
p H, gl u c o s e, pr ot ei n, bl o o d, k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, l e u k o c yt e e st er a s e b y 
di p sti c k
 
Mi cr o s c o pi c e x a mi n ati o n
Ot h er S cr e e ni n g 
T e st s
 
F olli cl e -sti m ul ati n g h or m o n e a n d e str a di ol ( a s n e e d e d i n w o m e n of n o n c hil d b e ari n g p ot e nt i al 
o nl y )
 
S er u m or hi g hl y s e n siti v e uri n e h u m a n c h ori o ni c g o n a d otr o pi n ( β - h C G) pr e g n a n c y t e st ( a s 
n e e d e d f or w o m e n of c hil d b e ari n g p ot e nti al). 
 
S er u m K L -6, S P -A a n d S P - D
A L T = al a ni n e a mi n otr a n sf er a s e; A N C = a b s ol ut e n e utr o p hil c o u nt; a P T T = a cti v at e d p ar ti al t hr o m b o pl a sti n ti m e; 
A S T = a s p art at e a mi n otr a n sf er a s e; β -h C G = h u m a n c h ori o ni c g o n a d otr o pi n; B U N = bl o o d ur e a nitr o g e n; 
G F R = gl o m er ul ar filtr ati o n r at e; G G T = g a m m a -gl ut a m yltr a n sf er a s e; H B V = H e p atiti s B vir u s; H C V = H e p atiti s C 
vir u s; I N R = i nt er n ati o n al n or m ali z e d r ati o; M C H =
m e a n c or p u s c ul ar h e m o gl o bi n; M C H C = m e a n c or p u s c ul ar 
h e m o gl o bi n c o n c e ntr ati o n; M C V = m e a n c or p u s c ul ar v ol u m e; R B C
= r e d bl o o d c ell; R DW = r e d c ell di stri b uti o n 
wi dt h; T 4 = fr e e t h yr o xi n e; T S H = t h yr oi d-sti m ul ati n g h or m o n e; W B C = w hit e bl o o d c ell; T S T = t u b er c uli n s ki n t e st.
a              P erf or m e d a s i n di c at e d i n t h e S c h e d ul e s of A s s e s s m e nt s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 6 / 1 5 5
L a b or at or y  
A s s e s s m e nt s 
P ar a m et er s
b              P erf or m e d at S cr e e ni n g o nl y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 7 / 1 5 5
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 8 / 1 5 5
A p pe n di x 7 
Pr o hi bite d Tr a diti o n al C hi nese Me dici ne
N a m e of A p pr ov e d T C M wit h a ntic a nc er i n dic ati o n
E n glis h
1
Ai Di i njecti o n ®
2
De L i S he n, Delis he n g, i njecti o n
3
Ka n glaite i njecti o n, or K L T 
4
Ga nf ule, Ga n F u Le, Ga n F u Le ta blet/ca ps ules
5
H uaier, H uaier Keli, gra n ules
6
Ji nl o n g ca ps ules
7
Ci n o b ufaci ni i njecti o n 
8
Jie d u Gra n ules
9
Ele me ne i njecti o n, Ele me n u m 
e m ulsi o n, I njecti o E m ulsi o ni Ele me ni
1 0
Xia oai pi n g ta blets
1 1
C hl or o x o q ui n oli ne ca ps ules
1 2
Ka n gli xi n ca ps ules
1 3
Ka n gli xi n ta blets
1 4
S o di u m Ca nt hari di nate F or I njecti o n
1 5
c o m p o u n d ca ps ules ca nt hari di n
1 6
Ja va br ucea fr uit oil e m ulsi o n
1 7
Ja va br ucea fr uit oil ca ps ules
1 8
Ja va br ucea fr uit oil i njecti o n
1 9
Wei mai ni n g ca ps ules
2 0
S he n y i Ca ps ule
2 1
S helia n ca ps ule
2 2
Ka n gai i njecti o n
2 3
U be ni me x
2 4
Xia nc ha n ta blet
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 9 / 1 5 5
Na me of c hr o nic s ys te mic i m m u ne treat me nt
1
I nterle u ki n- 2
2
i nterfer o n
3
T h y m osi n/t h y m o pe nti n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 0 / 1 5 5
A p pe n di x 8   
Res p o nse E v al u ati o n
Criteri a i n S oli d T u m ors Versi o n 1. 1 
( R E CI S T 1. 1)
T he te xt bel o w was o btai ne d fr o m t he f oll o wi n g refere nce: Eise n ha uer E A, T herasse P, B o gaerts 
J, Sc h wartz L H, Sar ge nt D, F or d R, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m ors: re vise d 
R E CI S T g ui deli ne ( Versi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5: 2 2 8- 2 4 7.
Defi niti o ns
Res p o nse a n d pr o gressi o n will be e val uate d i n t his st u d y  usi n g t he i nter nati o nal criteria pr o p ose d 
b y  the R E CI S T C o m mittee ( Versi o n 1. 1). C ha n ges i n o nl y  the lar gest dia meter ( u ni di me nsi o nal 
meas ure me nt) of t he t u m or lesi o ns are use d i n t he R E CI S T criteria. N ote: Lesi o ns are eit her 
meas ura ble or n o n- meas ura ble usi n g t he criteria pr o vi de d bel o w. T he ter m “e val ua ble” i n 
refere nce t o meas ura bilit y  will n ot be use d beca use it d oes n ot pr o vi de a d diti o nal mea ni n g or 
acc urac y.
Meas ura ble Disease
T u m or lesi o ns: M ust be acc uratel y meas ure d i n at least 1 di me nsi o n (l o n gest dia meter i n t he pla ne 
of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of: 

1 0 m m b y  CT sca n (irres pecti ve of sca n ner t ype) a n d M RI ( n o less t ha n d o u ble t he slice 
t hic k ness a nd a mi ni m u m of 1 0 m m)

1 0 m m cali per meas ure me nt b y  cli nical e xa m ( w he n s u perficial)

2 0 m m b y  c hest X-ra y (if clearly defi ne d a n d s urr o u n de d b y aerate d l u n g).
M ali g n a nt ly m p h n o des : T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d meas ura ble, a ly m p h n o de 
m ust be ≥1 5 m m i n s h ort a xis w he n assesse d b y  C T sca n ( C T sca n slice t hic k ness rec o m me n de d 
t o be n o greater t ha n 5 m m). At baseli ne a n d i n F oll o w - u p, o nly t he s h ort a xis will be meas ure d 
a n d f oll o we d.
N o n - meas ura ble Disease
All ot her lesi o ns ( or sites of disea se), i ncl u di n g s mall lesi o ns (l o n gest dia meter ≥1 0 t o < 1 5 m m 
wit h c o n ve nti o nal tec h ni q ues or < 1 0 m m usi n g s piral C T sca n), are c o nsi dere d n o n- meas ura ble 
disease. Le pt o me ni n geal disease, ascites, ple ural or pericar dial eff usi o n, i nfla m mat or y breast 
disea se, l ym p ha n gitic i n v ol ve me nt of s ki n or l u n g, a b d o mi nal masses/a b d o mi nal or ga n o me gal y 
i de ntifie d b y p h ysical e xa mi nati o n t hat is n ot meas ura ble b y re pr o d uci ble i ma gi n g tec h ni q ues are 
all n o n-meas ura ble.
B o ne lesi o ns:

B o ne sca n, p ositr o n e missi o n t o m o gra p h y ( P E T) sca n, or plai n fil ms are n ot c o nsi dere d 
a de q uate i ma gi n g tec h ni q ues t o meas ure b o ne lesi o ns. H o we ver, t hese tec h ni q ues ca n be use d 
t o c o nfir m t he prese nce or disa p peara nce of b o ne lesi o ns.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 1 / 1 5 5

L yt ic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns, wit h i de n tifia ble s oft tiss ue c o m p o ne nts, t hat 
ca n be e val uate d b y  cr oss-secti o nal i ma gi n g tec h ni q ues s uc h as C T or M RI  ca n be c o nsi dere d 
as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets t he defi niti o n of meas ura bilit y  
descri be d a b o ve.

Blastic b o ne lesi o ns are n o n -meas ura ble.
Cystic lesi o ns:

Lesi o ns t hat meet t he criteria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot be c o nsi dere d 
as mali g na nt lesi o ns ( neit her meas ura ble n or n o n -meas ura ble) si nce t he y are, b y  defi niti o n, 
si m ple c ysts.

C y stic lesi o ns th o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as meas ura ble lesi o ns, 
if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve. H o we ver, if n o n-c ystic lesi o ns are 
prese nt i n t he sa me partici pa nt, t hese are preferre d f or selecti o n as tar get les i o ns.
Lesi o ns wit h pri or l oc al tre at me nt:

T u m or lesi o ns sit uate d i n a pre vi o usl y irra diate d area, or i n a n area s u bjecte d t o ot her l ocal 
re gi o nal t hera py, are us uall y  not c o nsi dere d meas ura ble u nless t here has bee n de m o nstrate d 
pr o gressi o n i n t he lesi o n. S t u d y pr ot oc ols s h o ul d detail t he c o n diti o ns u n der w hic h s uc h lesi o ns 
w o ul d be c o nsi dere d meas ura ble.
Tar get Lesi o ns
All meas ura ble lesi o ns u p t o a ma xi m u m of 2 lesi o ns per or ga n a n d 5 lesi o ns i n t otal, s h o ul d be 
i de ntifie d as t ar get lesi o ns a n d rec or de d a nd meas ure d at baseli ne . Tar get lesi o ns s h o ul d be 
selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter), be re prese ntati ve of all 
i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble re peate d 
meas ure me nts.
L y m p h n o des merit s pecial me nti o n si nce t he y are n or mal a nat o mical str uct ures w hic h m a y  be 
visi ble b y  ima gi n g e ve n if n ot i n v ol ve d b y  tu m or. Pat h ol o gical n o des w hic h are defi ne d as 
meas ura ble a n d m a y  be i de ntifie d as tar get lesi o ns m ust meet t he criteri o n of a s h ort a xis of 
≥1 5 m m b y  CT sca n. O nl y  the s h ort a xis of t hese n o des will c o ntri b ute t o t he baseli ne s u m. T he 
s h ort a xis of t he n o de is t he dia meter n or mally use d b y  ra di ol o gists t o j u d ge if a n o de is i n v ol ve d 
b y  soli d t u m or. N o dal size is n or mall y re p orte d as 2 di me nsi o ns i n t he pla ne i n w hic h t he i ma ge is 
o btai ne d (f or C T sca n t his is al m ost al wa y s t he a xial pla ne; f or M RI t he pla ne of ac q uisiti o n ma y 
be a xial, sa gittal, or c or o nal). T he s maller of t hese meas ures is t he s h ort a xis. F or e xa m ple, a n 
a bd o mi nal n o de w hic h is re p orte d as bei n g 2 0 m m x 3 0 m m has a s h ort a xis of 2 0 m m a n d q ualifies 
as a mali g na nt, meas ura ble n o de. I n t his e xa m ple, 2 0 m m s h o ul d be rec or de d as t he n o de 
meas ure me nt. All ot her pat h ol o gical n o des (t h ose wit h s h ort a xis ≥1 0 m m b u t < 1 5 m m) s h o ul d 
be c o nsi dere d n o n -tar get lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n-
pat h ol o gical a n d s h o ul d n ot be rec or de d or f oll o we d.
A s u m of t he dia meters (l o n gest f or n o n- n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get 
lesi o ns will be calc ulate d a n d re p orte d as t he baseli ne s u m dia meters. If l ym p h n o des are t o be 
i ncl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o t he s u m. T he baseli ne 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 2 / 1 5 5
s u m dia meters will be use d as refere nce t o f urt her c haracterize a n y objecti ve t u m or re gressi o n i n 
t he meas ura ble di me nsi o n of t he disease. 
N o n -tar get Lesi o ns
All ot her lesi o ns ( or sites of disease) i ncl u di n g pat h ol o gical l ym p h n o des s h o ul d be i de ntifie d as 
n o n- tar get lesi o ns a n d s h o ul d als o be rec or de d at basel i ne. Meas ure me nts are n ot re q uire d, a n d 
t hese lesi o ns s h o ul d be f oll o we d as ‘ prese nt’, ‘a bse nt’, or i n rare cases ‘ u ne q ui v ocal pr o gressi o n’ 
( m ore details t o f oll o w). I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n -tar get lesi o ns i n v ol vi n g 
t he sa me or ga n as a si n gle ite m o n t he case rec or d f or m (e g, ‘ m ulti ple e nlar ge d pel vic l ym p h n o des’ 
or ‘ m ulti ple li ver metastases’). 
G UI D E LI N E S F O R E V A L U A TI O N O F M E A S U R A B L E DI S E A S E
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g cali pers if cli nicall y  assesse d. All 
baseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d ne ver m ore 
t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt.
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w-u p. I ma gi n g-base d e val uati o n s h o ul d 
al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) b ei n g f oll o we d ca n n ot be 
i ma ge d b ut are assessa ble b y cli nical e xa mi nati o n.
N o p h ot o gra p hs, n o s ki n lesi o n meas ure me nt b y  cali pers a n d n o meas ure me nts o n c hest X -ra y will 
be d o ne i n t his st u d y .
C T, M RI: C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble me t h o d t o meas ure lesi o ns selecte d 
f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T sca n base d o n 
t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. As is descri be d i n A p pe n di x II of t he 
ori gi nal s o urce article cite d a bo ve, w he n C T sca ns ha ve slice t hic k ness greater t ha n 5 m m, t he 
mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. M RI  is als o acce pta ble 
i n certai n sit uati o ns (e g, f or b o d y sca ns). 
Ultr as o u n d: Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as a 
met h o d of meas ure me nt. Ultras o u n d e xa mi nati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y f or 
i n de pe n de nt re vie w at a later date a n d, beca use t he y are o perat or de pe n de nt, it ca n n ot be 
g uara ntee d t hat t he sa me tec h ni q ue a n d meas ure me nts will be ta ke n fr o m 1 assess me nt t o t he ne xt. 
If ne w lesi o ns are i de ntifie d b y ultras o u n d i n t he c o urse of t he st u d y, c o nfir mati o n b y C T or M RI 
is a d vise d. If t here is c o ncer n a b o ut ra diati o n e x p os ure at C T, M RI m a y be use d i nstea d of C T i n 
selecte d i nsta nces.
E n d osc o p y, l a p ar osc o p y: T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or e val uati o n is n ot 
a d vise d. H o we ver, t he y ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n bi o psies 
are o btai ne d or t o deter mi ne rela pse i n stu dies w here rec urre nce f oll o wi n g c o m plete res p o nse or 
s ur gical resecti o n is a n e n d p oi nt.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 3 / 1 5 5
T u m or m a r kers: T u m or mar kers al o ne ca n n ot be use d t o assess o bjecti ve t u m or res p o nse. If 
mar kers are i nitiall y a b o ve t he u p per n or mal li mit; h o we ver, t he y m ust n or mali ze f or a partici pa nt 
t o be c o nsi dere d i n c o m plete res p o nse. Beca use t u m or mar kers are disease s pecific, i nstr ucti o ns 
f or t heir meas ure me nt s h o ul d be i nc or p orate d i nt o pr ot oc ols o n a disease s pecific basis. S pecific 
g ui deli nes f or b ot h C A - 1 2 5 res p o nse (i n rec urre nt o varia n ca ncer) a n d pr ostate -s pecific a nti ge n 
res p o nse (i n rec urre nt pr ostate ca ncer), ha ve bee n p u blis he d. In a d diti o n, t he G y nec ol o gic Ca ncer 
I nter gr o u p has de vel o pe d C A - 1 2 5 pr o gressi o n criteria w hic h are t o be i nte grate d wit h o bjecti ve 
t u m or assess me nt f or use i n first-li ne st u dies i n o varia n ca ncer.
C yt ol o g y, hist ol o g y: T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n rare 
cases if re q uire d b y  pr ot oc ol (e g, resi d ual lesi o ns i n t u m or t ypes s uc h as ger m cell t u m ors, w here 
k n o w n resi d ual be ni g n t u m ors ca n re mai n). W he n eff usi o ns are k n o w n t o be a p ote ntial A E of 
treat me nt (e g, wit h certai n ta xa ne c o m p o u n ds or a n gi o ge nesis i n hi bit ors), t he c yt ol o gical 
c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or w orse ns d ur i n g treat me nt ca n 
be c o nsi dere d if t he meas ura ble t u m or has met criteria f or res p o nse or S D i n or der t o differe ntiate 
bet wee n res p o nse ( or S D) a n d P D.
R E S P O N S E C RI T E RI A
E val uati o n of Tar get Lesi o ns
C R: Disa p peara nce of all tar get lesi o ns. A n y pat h ol o gical l ym p h n o des ( w het her tar get or n o n-
tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m.
P R : At least a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as refere nce t he 
baseli ne s u m dia meters. 
P D: At least a 2 0 % i ncrease i n t he s u m of dia me ters of tar get lesi o ns, ta ki n g as refere nce t he 
s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m if t hat is t he s mallest o n st u d y). In a d diti o n 
t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 
5 m m. ( N ote : t he a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n). 
S D: Neit her s ufficie nt s hri n ka ge t o q ualif y  for partial res p o nse n or s ufficie nt i ncrease t o q ualif y 
f or P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile o n st u dy. 
Ly m p h n o des. L y m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne e xa mi nati o n), e ve n 
if t he n o des re gress t o bel o w 1 0 m m o n st u d y. T his mea ns t hat w he n l ym p h n o des are i ncl u de d as 
tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y  not be zer o e ve n if c o m plete res p o nse criteria are met, 
si nce a n or mal l ym p h n o de is defi ne d as ha vi n g a s h ort a xis of < 1 0 m m. Case re p ort f or ms or 
ot her data c ollecti o n met h o ds ma y  theref ore b e desi g ne d t o ha ve tar get n o dal lesi o ns rec or de d i n 
a se parate secti o n w here, i n or der t o q ualif y  f or C R, eac h n o de m ust ac hie ve a s h ort a xis < 1 0 m m. 
F or partial res p o nse, S D, a n d P D, t he act ual s h ort a xis meas ure me nt of t he n o des is t o be i ncl u de d 
i n t he s u m of tar get lesi o ns.
T ar get lesi o ns t h at bec o me ‘t o o s m all t o me as ure’.
W hile 
o n st u d y, all lesi o ns ( n o dal a n d 
n o n- n o dal) rec or de d at baseli ne s h o ul d ha ve t heir act ual meas ure me nts 
rec or de d at eac h 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 4 / 1 5 5
s u bse q ue nt e val uati o n, e ve n w he n ver y s mall (e. g., 2 m m). H o we ver, s o meti mes lesi o ns or l y m p h 
n o des w hic h are rec or de d as tar get lesi o ns at baseli ne bec o me s o fai nt o n C T sca n t hat t he 
ra di ol o gist m a y  not feel c o mf orta ble assi g ni n g a n e xact meas ure a n d ma y re p ort t he m as bei n g 
‘t o o s mall t o meas ure’. W hen t his occ urs, it is i m p orta nt t hat a val ue be rec or de d o n t he e C R F. If 
it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, t he meas ure me nt s h o ul d 
be rec or de d as 0 m m. If t he lesi o n is belie ve d t o be prese nt a n d is fai ntly see n b ut t o o s mall t o 
meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d. ( N ote: It is less li kel y that t his r ule will be 
use d f or l ym p h n o des si nce t he y us ually ha ve a defi na ble size w he n n or mal a n d are fre q ue ntly 
s urr o u n de d b y  fat, s uc h as i n t he retr o perit o ne um; h o we ver, if a l ym p h n o de is belie ve d t o be 
prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d i n 
t his circ u msta nce as well). T his defa ult val ue is deri ve d fr o m t he 5 m m C T slice t hic k ness ( b ut 
s h o ul d n ot be c ha n ge d wit h var y i n g C T slice t hic k ness). T he meas ure me nt of t hese lesi o ns is 
p ote ntiall y  no n- re pr o d uci ble; t heref ore, pr o vi di n g t his defa ult val ue will pre ve nt false res p o nses 
or pr o gressi o ns base d u p o n meas ure me nt err or. T o reiterate, h o we ver, if t he ra d i ol o gist is a ble t o 
pr o vi de a n act ual meas ure, t hat s h o ul d be rec or de d, e ve n if it is bel o w 5 m m.
Lesi o ns t h at s plit or c o alesce o n tre at me nt. W he n 
n o n- n o dal lesi o ns ‘fra g me nt’, t he l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o c alc ulate t he tar get lesi o n s u m. 
Si milarl y , as lesi o ns c oalesce, a pla ne bet wee n t he m ma y  be mai ntai ne d t hat w o ul d ai d i n o btai ni n g 
ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o n. If t he lesi o ns ha ve tr uly c oalesce d s uc h 
t hat t he y are n o l o n ger se para ble, t he vect or of t he l o n gest dia meter i n t his i nsta nce s h o ul d be t he 
ma xi mal l o n gest dia meter f or t he ‘c oalesce d lesi o n’.
E val uati o n of N o n -tar get Lesi o ns
W hile s o me n o n- tar get lesi o ns ma y  act uall y be meas ura ble, t he y nee d n ot be meas ure d a n d i nstea d 
s h o ul d be assesse d o nly q ualitati vel y  at t he ti me p oi nts s pecifie d i n t he pr ot oc ol. 
C R: Disa p peara nce of all n o n- tar get lesi o ns a n d n or malizati o n of t u m or mar ker le vel. All l ym p h 
n o des m ust be n o n -pat h ol o gical i n size ( < 1 0 m m s h ort a xis). 
N o n -C R/ N o n -P D: Persiste nce of 1 or m ore n o n- tar get lesi o n(s) a n d/ or mai nte na nce of t u m or 
mar ker le vel a b o ve t he n or mal li mits.
P D: U ne q ui v ocal pr o gressi o n (see c o m me nts bel o w) of e xisti n g n o n- tar get lesi o ns. ( N ote: t he 
a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi de re d pr o gressi o n). 
W h e n t he p artici p a nt als o h as me as ur a ble dise ase. I n t his setti n g, t o ac hie ve ‘ u ne q ui v ocal 
pr o gressi o n’ o n t he basis of t he n o n- tar get disease, t here m ust be a n o verall le vel of s u bsta ntial 
w orse ni n g i n n o n -tar get disease s uc h t hat, e ve n i n t he prese nce of S D or partial res p o nse i n tar get 
disease, t he o verall t u m or b ur de n has i ncrease d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y. A 
m o dest ‘i ncrease’ i n t he size of 1 or m ore n o n -tar get lesi o ns is us uall y n ot s ufficie nt t o q ualit y f or 
u ne q ui v ocal pr o gressi o n stat us. T he desi g nati o n of o verall pr o gressi o n s olel y on t he basis of 
c ha n ge i n n o n- tar get disease i n t he face of S D or partial res p o nse of tar get disease will t heref ore 
be e xtre mel y  rare.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 5 / 1 5 5
W h e n t he p artici p a nt h as o nly n o n -me as ur a bl e dise ase. T his circ u msta nce arises i n s o me P hase 
III st u dies w he n it is n ot a criteri o n of st u d y entr y t o ha ve meas ura ble disease. T he sa me ge neral 
c o nce pt a p plies here as n ote d a b o ve; h o we ver, i n t his i nsta nce t here is n o meas ura ble disease 
assess me nt t o fact or i nt o t he i nter pretati o n of a n i ncrease i n n o n- meas ura ble disease b ur de n. 
Beca use w orse ni n g i n n o n -tar get disease ca n n ot be easil y qua ntifie d ( by defi niti o n: if all lesi o ns 
are tr ul y no n- meas ura ble), a usef ul test t hat ca n be a p plie d w he n assessi n g partici pa nts f or 
u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease i n o verall disease b ur de n base d o n t he c ha n ge 
i n n o n- meas ura ble disease is c o m para ble i n ma g nit u de t o t he i ncrease t hat w o ul d be re q uire d t o 
declare P D f or meas ura ble disease: i.e., a n i ncrease i n t u m or b ur de n re prese nti n g a n a d diti o nal 
7 3 % i ncrease i n ‘ v ol u me’ ( w hic h is e q ui vale nt t o a 2 0 % i ncrease dia meter i n a meas ura ble lesi o n). 
E xa m ples i ncl u de a n i ncrease i n a ple ural eff usi o n fr o m ‘trace’ t o ‘lar ge’, a n i ncrease i n 
l ym p ha n gitic d isease fr o m l ocalize d t o wi des prea d, or ma y be descri be d i n pr ot oc ols as ‘s ufficie nt 
t o re q uire a c ha n ge i n t hera py’.  If ‘ u ne q ui v ocal pr o gressi o n’ is see n, t he partici pa nt s h o ul d be 
c o nsi dere d t o ha ve ha d o verall P D at t hat p oi nt. W hile it w o ul d be i deal t o ha ve o bjecti ve criteria 
t o a p pl y to n o n- meas ura ble disease, t he ver y  nat ure of t hat disease ma kes it i m p ossi ble t o d o s o; 
t heref ore, t he i ncrease m ust be s u bsta ntial.
Ne w Lesi o ns
T he a p peara nce of ne w mali g na nt lesi o ns de n otes P D ; t heref ore, s o me c o m me nts o n detecti o n of 
ne w lesi o ns are i m p orta nt. T here are n o s pecific criteria f or t he i de ntificati o n of ne w ra di o gra p hic 
lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be u ne q ui v ocal: i.e., n ot attri b uta ble t o 
differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g m o dalit y , or fi n di n gs t h o u g ht t o re prese nt 
s o met hi n g ot her t ha n t u m or (e.g. , s o me ‘ ne w’ b o ne lesi o ns ma y be si m pl y heali n g or flare of pre-
e xisti n g lesi o ns). T his is partic ularl y i m p orta nt w he n t he partici pa nt’s baseli ne lesi o ns s h o w partial 
or c o m plete res p o nse. F or e xa m ple, necr osis of a li ver lesi o n ma y be re p orte d o n a C T sca n re p ort 
as a ‘ ne w’ c ystic lesi o n, w hic h it is n ot. 
A lesi o n i de ntifie d o n a f oll o w -u p st u d y  in a n a nat o mical l ocati o n t hat was n ot sca n ne d at baseli ne
is c o nsi dere d a n e w lesi o n a n d will i n dicate P D. A n e xa m ple of t his is t he partici pa nt w h o has 
visceral disease at baseli ne a n d w hile o n st u d y has a brai n C T or M RI  or dere d w hic h re veals 
metastases. T he partici pa nt’s brai n metastases are c o nsi dere d t o be e vi de nce of P D e ve n if he/s he 
di d n ot ha ve brai n i ma gi n g at baseli ne .
If a ne w lesi o n is e q ui v ocal, e g, beca use of its s mall size, c o nti n ue d t hera py a n d f oll o w-u p 
e val uati o n will clarif y if it re prese nts tr ul y ne w disease. If re peat sca ns c o nfir m t here is defi nitel y 
a ne w l esi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n.
W hile 
fl u de o xy gl uc ose p ositr o n e missi o n t o m o gra p hy ( F D G-P E T) res p o nse assess me nts nee d 
a d diti o nal st u dies, it is s o meti mes reas o na ble t o i nc or p orate t he use of F D G -P E T sca n ni n g t o 
c o m ple me nt C T sca n ni n g i n assess me nt of pr o gressi o n ( partic ularl y p ossi ble ‘ ne w’ disease). Ne w 
lesi o ns o n t he basis of F D G- P E T i ma gi n g ca n be i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m:
a.
Ne gati ve F D G -P E T at baseli ne , wit h a p ositi ve F D G -P E T at f oll o w- u p is a si g n of P D base d 
o n a ne w lesi o n.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 6 / 1 5 5
b.
N o F D G -P E T at baseli ne a n d a p ositi ve F D G -P E T at f oll o w-u p: If t he p ositi ve F D G -P E T at 
f oll o w- u p c orres p o n ds t o a ne w site of disease c o nfir me d b y  CT, t his is P D. If t he p ositi ve 
F D G -P E T at f oll o w- u p is n ot c o nfir me d as a ne w site of disease o n C T, a d diti o nal f oll o w-u p 
C T sca ns are nee de d t o deter mi ne if t here is tr ul y pr o gressi o n occ urri n g at t hat site (if s o, t he 
date of P D will be t he date of t he i nitial a b n or mal F D G -P E T sca n). If t he p ositi ve F D G -P E T 
at f oll o w-u p c orres p o n ds t o a pre -e xisti n g site of disease o n C T t hat is n ot pr o gressi n g o n t he 
basis of t he a nat o mic i ma ges, t his is n ot P D.
E val uati o n of Best O verall Res p o nse
T he best o verall res p o nse ( B O R) is t he best res p o nse rec or de d fr o m t he start of t he st u d y 
i nter ve nti o n u ntil t he e n d of treat me nt ta ki n g i nt o acc o u nt a n y re q uire me nt f or c o nfir mati o n. O n 
occasi o n, a res p o nse ma y n ot be d oc u me nte d u ntil after t he e n d of t hera p y, s o pr ot oc ols s h o ul d be 
clear if p ost treat me nt assess me nts are t o be c o ns i dere d i n deter mi nati o n of B O R. Pr ot oc ols m ust 
s pecif y h o w a ny ne w t hera p y i ntr o d uce d bef ore pr o gressi o n will affect best res p o nse desi g nati o n. 
T he partici pa nt’s B O R assi g n me nt will de pe n d o n t he fi n di n gs of b ot h tar get a n d n o n- tar get disease 
a n d will als o ta ke i nt o c o nsi derati o n t he a p peara nce of ne w lesi o ns. F urt her m ore, de pe n di n g o n 
t he nat ure of t he st u d y an d t he pr ot oc ol re q uire me nts, it ma y  als o re q uire c o nfir mat or y 
meas ure me nt. S pecificall y , i n n o n -ra n d o mize d st u dies w here res p o nse is t he pri mar y  en d p oi nt, 
c o nfir mati o n of partial res p o nse or C R is nee de d t o dee m eit her 1 t he ‘ B O R’. 
T he B O R is deter mi ne d o nce all t he data f or t he partici pa nt is k n o w n. Best res p o nse deter mi nati o n 
i n st u dies w here c o nfir mati o n of c o m plete or partial res p o nse I S NO T re q uire d: Best res p o nse i n 
t hese st u dies is defi ne d as t he best res p o nse acr oss all ti me p oi nts (f or e xa m ple, a partici pa nt w h o 
has S D at first assess me nt, partial res p o nse at sec o n d assess me nt, a n d P D o n last assess me nt has a 
B O R of partial res p o nse). W he n 
S D is belie ve d t o be best res p o nse, it m ust als o meet t he 
pr ot oc ol -s pecifie d mi ni m u m ti me fr o m baseli ne. If t he mi ni m u m ti me is n ot met w he n S D is 
ot her wise t he best ti me p oi nt res p o nse, t he partici pa nt’s best res p o nse de pe n ds o n t he s u bse q ue nt 
assess me nts. F or e xa m ple, a partici pa nt w h o has S D at first assess me nt, P D at sec o n d a n d d oes n ot 
meet mi ni m u m d urati o n f or S D, will ha ve a best res p o nse of P D. T he sa me partici pa nt l ost t o 
f oll o w-u p after t he first S D assess me nt w o ul d be c o nsi dere d i ne val ua ble.
T ar g e t L e si o n s
N o n -t ar g et L e si o n s 
N e w  L e si o n s 
O v er all R e s p o n s e
C R*
C R
N o
C R
C R
C R
N o n -C R/ n o n -P D
N ot E v al u at e d
N o
N o
P arti al r e s p o n s e
P arti al r e s p o n s e
P arti al r e s p o n s e 
N o n - P D or n ot all e v al u at e d 
N o
P arti al r e s p o n s e
S D
N ot all e v al u at e d
N o n -P D or n ot all e v al u at e d
N o n -P D
N o
N o
S D
N E
P D
A n y
Y e s or N o
P D
A n y
P D
Y e s or N o
P D
A n y
A n y
Y e s
P D
* C R = c o m pl et e r e s p o n s e; S D = st a bl e di s e a s e; P D = pr o gr e s si o n of di s e a s e.
S e e t e xt f or m or e d et ail s.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 7 / 1 5 5
N ote:
W he n n o dal disease is i ncl u de d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o ‘ n or mal’ 
size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt re p orte d o n sca ns. T his meas ure me nt s h o ul d 
be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o versta te pr o gressi o n s h o ul d it be 
base d o n i ncrease i n size of t he n o des. As n ote d earlier, t his mea ns t hat partici pa nts wit h C R ma y  
n ot ha ve a t otal s u m of ‘zer o’ o n t he e C R F. 
I n st u dies w here c o nfir mati o n of res p o nse is re q uire d, re peate d ‘ N E’ ti me p oi nt assess me nts ma y 
c o m plicate best res p o nse deter mi nati o n. T he a nal ysis pla n f or t he st u d y must a d dress h o w missi n g 
data/assess me nts will be a d dresse d i n deter mi nati o n of res p o nse a n d pr o gressi o n. F or e xa m ple, i n 
m ost st u dies, it is reas o na ble t o c o nsi der a p artici pa nt wit h ti me p oi nt res p o nses of partial 
res p o nse-N E -partial res p o nse as a c o nfir me d res p o nse.
Partici pa nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of P D at t hat ti me s h o ul d be re p orte d as ‘s ym pt o matic deteri orati o n’. 
E ver y  eff ort s h o ul d be ma de t o d oc u me nt o bjecti ve pr o gressi o n e ve n after disc o nti n uati o n of 
treat me nt. Sy m pt o matic deteri orati o n is n ot a descri pt or of a n o bjecti ve res p o nse; it is a reas o n f or 
st o p pi n g st u d y t hera p y. 
C o n diti o ns t hat defi ne ‘earl y pr o gressi o n, earl y deat h, a n d i ne val ua bilit y’ are st u d y-s pecific a n d 
s h o ul d be clearl y descri be d i n eac h pr ot oc ol ( de pe n di n g o n treat me nt d urati o n, a n d treat me nt 
peri o dicit y ).
I n s o me circ u msta nces it ma y  be diffic ult t o di sti n g uis h resi d ual disease fr o m n or mal tiss ue. W he n 
t he e val uati o n of C R de pe n ds u p o n t his deter mi nati o n, it is rec o m me n de d t hat t he resi d ual lesi o n 
be i n vesti gate d (fi ne nee dle as pirate/ bi o ps y) bef ore assi g ni n g a stat us of C R. T he use of F D G -P E T 
ma y  be us e d t o u p gra de a res p o nse t o a C R i n a ma n ner si milar t o a bi o ps y  in cases w here a resi d ual 
ra di o gra p hic a b n or malit y is t h o u g ht t o re prese nt fi br osis or scarri n g. T he use of F D G-P E T i n t his 
circ u msta nce s h o ul d be pr os pecti vely descri be d i n t he pr ot oc ol a n d s u p p orte d b y  disease s pecific 
me dical literat ure f or t he i n dicati o n. H o we ver, it m ust be ac k n o wle d ge d t hat b ot h a p pr oac hes ma y 
lea d t o false p ositi ve C R d ue t o li mitati o ns of F D G-P E T a n d bi o ps y  res ol uti o n/se nsiti vit y.
F or e q ui v ocal fi n di n gs of pr o gressi o n (e g, ver y s mall a n d u ncertai n ne w lesi o ns; c ystic c ha n ges or 
necr osis i n e xisti n g lesi o ns), treat me nt ma y c o nti n ue u ntil t he ne xt sc he d ule d assess me nt. If at t he 
ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he date of pr o gressi o n s h o ul d be t he ear lier 
date w he n pr o gressi o n was s us pecte d.
C O N FI R M A T O R Y M E A S U R E M E N T/ D U R A TI O N O F R E S P O N S E
C o nfir mati o n
I n no n -ra n d o mize d st u dies w here res p o nse is t he pri mar y  en d p oi nt, c o nfir mati o n of partial 
res p o nse a n d C R is re q uire d t o e ns ure t he res p o nses i de ntifie d are n ot t he res ult of meas ure me nt 
err or. T his will als o per mit a p pr o priate i nter pretati o n of res ults i n t he c o nte xt of hist orical data 
w here res p o nse has tra diti o nall y re q uire d c o nfir mati o n i n s uc h st u dies. H o we ver, i n all ot her 
circ u msta nces, i .e., i n ra n d omize d st u dies ( P hase II or III) or st u dies w here S D or pr o gressi o n are 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 8 / 1 5 5
t he pri mar y  en d p oi nts, c o nfir mati o n of res p o nse is n ot re q uire d si nce it will n ot a d d val ue t o t he 
i nter pretati o n of t he st u d y res ults. H o we ver, eli mi nati o n of t he re q uire me nt f or res p onse 
c o nfir mati o n ma y i ncrease t he i m p orta nce of ce ntral re vie w t o pr otect a gai nst bias, i n partic ular i n 
st u dies w hic h are n ot bli n de d.
I n t he case of S D, meas ure me nts m ust ha ve met t he S D criteria at least o nce after st u d y e ntr y at a 
mi ni m u m i nter val (i n ge neral n ot less t ha n 6 t o 8 wee ks) t hat is defi ne d i n t he st u d y  pr ot oc ol.
D urati o n of O verall Res p o nse
T he d urati o n of o verall res p o nse is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or 
C R/ partial res p o nse ( w hic he ver is first rec or de d) u nti l t he first date t hat rec urre nt or P D is 
o bjecti vel y  doc u me nte d (ta ki n g as refere nce f or P D t he s mallest meas ure me nts rec or de d o n st u d y).
T he d urati o n of o verall C R is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or C R 
u ntil t he first date t h at rec urre nt disease is o bjecti vel y  d oc u me nte d. 
D urati o n of Sta ble Disease
Sta ble disease is meas ure d fr o m t he start of t he treat me nt (i n ra n d o mize d st u dies, fr o m date of 
ra n d o mizati o n) u ntil t he criteria f or pr o gressi o n are met, ta ki n g as refere nce t he smallest s u m o n 
st u d y (if t he baseli ne s u m is t he s mallest, t his is t he refere nce f or calc ulati o n of P D).
T he cli nical rele va nce of t he d urati o n of S D varies i n differe nt st u dies a n d diseases. If t he 
pr o p orti o n of partici pa nts ac hie vi n g S D f or a mi ni m u m per i o d of ti me is a n e n d p oi nt of i m p orta nce 
i n a partic ular st u d y, t he pr ot oc ol s h o ul d s pecif y the mi ni mal ti me i nter val re q uire d bet wee n 
2 meas ure me nts f or deter mi nati o n of S D.
N ote: T he d urati o n of res p o nse a n d S D as well as t he pr o gressi o n-free s ur vi val are i nfl ue nce d b y 
t he fre q ue nc y of f oll o w-u p after baseli ne e val uati o n. It is n ot i n t he sc o pe of t his g ui deli ne t o defi ne 
a sta n dar d f oll o w- u p fre q ue nc y. T he fre q ue nc y s h o ul d ta ke i nt o acc o u nt ma n y  para meters 
i ncl u di n g disease t ypes a n d sta ges, treat me nt pe ri o dicit y, a n d sta n dar d practice. H o we ver, t hese 
li mitati o ns of t he precisi o n of t he meas ure d e n d p oi nt s h o ul d be ta ke n i nt o acc o u nt if c o m paris o ns 
bet wee n st u dies are t o be ma de.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 9 / 1 5 5
A p pe n di x 9 
Pr ot oc ol A me n d me nt Hist or y
T he i nf or mati o n f or t he c urre nt a me n d me nt is o n t he title pa ge.
Pr ot oc ol Versi o n [ 3. 1] ( 0 5- N o v - 2 0 1 9)
O ver all R ati o n ale f or t he A me n d me nt
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
1. 3 S c h e d ul e of A cti viti e s 
a n d t hr o u g h o ut t h e 
pr ot o c ol
R ef er e n c e t o S e cti o n 6. 9. 1. 5 i s 
c h a n g e d t o S e cti o n 6. 9. 1. 6
C orr e ct e d a n err or
S e cti o n 6. 1 St u d y 
I nt er v e nti o n( s) 
A d mi ni str ati o n, T a bl e 7
Cl arifi e d a n d a d d e d d ur v al u m a b 
s u p pli er a n d m a n uf a ct ur er f or K or e a
Cl arifi c ati o n a n d c orr e cti o n
A p p e n di x 5 
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
A d d e d st at e m e nt t o T a bl e 3 3, 8. 5 
L y m p h o p e ni a, t o st at e t h at If t h e 
e v e nt i s c o n si d er e d i m m u n e r el at e d 
b ut r e s ol v e s t o ≤ G 1 wit hi n 1 4 d a y s 
r e st arti n g tr e at m e nt m a y b e 
c o n si d er e d.
T o cl arif y t h e crit eri a f or t h e r e -tr e at m e nt o n
i m m u n e r el at e d l y m p h o p e ni a
Pr ot oc ol Versi o n [ 3. 0] ( 0 5-J ul - 2 0 1 9)
O ver all R ati o n ale f or t he A me n d me nt
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
Titl e p a g e
U p d at e d S p o n s or N a m e a n d L e g al 
R e gi st er e d A d dr e s s f or J a p a n
A d mi ni str ati v e u p d at e
U p d at e d t h e d et ail s f or M e di c al 
M o nit or a n d C o nt a ct I nf or m ati o n
A d mi ni str ati v e u p d at e
1. 1 S y n o p si s
A d d e d/ u p d at e d t h e i nf or m ati o n 
r e g ar di n g t h e I D M C s af et y r e vi e w s 
t o t h e O v er all D e si g n a n d 
I n v ol v e m e nt of S p e ci al C o m mitt e e 
s e cti o n s
T o pr o vi d e d et ail e d i nf or m ati o n r e g ar di n g 
t h e I D M C s af et y r e vi e w s 
1. 3 S c h e d ul e of A cti viti e s 
a n d
t hr o u g h o ut t h e
d o c u m e nt a s
a p pli c a bl e
R e pl a c e d i nf or m ati o n r e g ar di n g t h e 
c oll e cti o n of t h e s a m pl e s (fr o m “ 4 8 
h o ur s” t o “ 3 d a y s”) f or t h e 
L a b or at or y A s s e s s m e nt s
T o u p d at e t h e wi n d o w of l a b t e st s c oll e cti o n 
a n d r e vi e w pri or d o si n g
I n cl u d e d s m o ki n g i nf or m ati o n a s 
p art of m e di c al hi st or y
T o cl arif y t h at s m o ki n g/ ni c oti n e hi st or y i s 
c oll e ct e d o n t h e e C R F
A d d e d i nf or m ati o n r e g ar di n g t h e 
J a p a n e s e p arti ci p a nt s f or s er u m 
K L -6, S P -A, a n d S P -D 
m e a s ur e m e nt s
T o cl arif y t h e c o u ntr y w h er e t h e t e st s ar e 
m a n d at or y
 
 
 
 
A d d e d i nf or m ati o n a b o ut t h e 
all o w e d wi n d o w f or t h e M 7 8 2 4 or 
pl a c e b o tr e at m e nt
T o cl arif y all o w e d wi n d o w of tr e at m e nt 
a d mi ni str ati o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 0 / 1 5 5
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
A d d e d i nf or m ati o n a b o ut t h e 
all o w e d wi n d o w f or t h e 
Ci s pl ati n/ Et o p o si d e, 
P a clit a x el/ C ar b o pl ati n, a n d 
P e m etr e x e d/ Ci s pl ati n tr e at m e nt s
T o cl arif y all o w e d wi n d o w of tr e at m e nt 
a d mi ni str ati o n
R e pl a c e d t e xt r e g ar di n g 
pr e m e di c ati o n f or all c h e m ot h er a p y 
r e gi m e n s
T o pr o vi d e cl arit y f or u s e of c orti c o st er oi d 
a s p art of c h e m ot h er a p y pr e m e di c ati o n a n d 
t o ali g n wit h l at e st N C C N r e c o m m e n d ati o n
A d d e d i nf or m ati o n a b o ut t h e 
all o w e d wi n d o w f or t h e M 7 8 2 4 or 
D ur v al u m a b tr e at m e nt s
T o cl arif y all o w e d wi n d o w of tr e at m e nt 
a d mi ni str ati o n
A d d e d wi n d o w of ± 7 d a y s f or t h e 
T h or a x A b d o m e n P el vi s C T 
( pr ef err e d) / M RI
F or cl arit y a n d c o n si st e n c y
2 I ntr o d u cti o n
U p d at e d i nf or m ati o n wit h t h e 
c urr e nt I B
Bi ntr af u s p alf a w a s i n cl u d e d a s t h e 
pr o p o s e d i nt er n ati o n al 
n o n pr o pri et ar y n a m e f or M 7 8 2 4
F or c o n si st e n c y a cr o s s t h e d e v el o p m e nt 
pr o gr a m
3 O bj e cti v e s a n d 
E n d p oi nt s
 
 
 
4. 1 O v er all D e si g n
U p d at e d t e xt r e g ar di n g t h e I D M C 
s af et y r e vi e w s a n d a b o ut t h e p eri o d 
if p arti ci p a nt s r e q uir e wit h h ol di n g of 
t h e st u d y i nt er v e nti o n d u e t o 
t o xi citi e s. 
T o cl arif y t h e r ol e s of t h e I D M C a n d w h e n 
t h e p eri o d of c C R T c a n b e e xt e n d e d
4. 1. 1 St u d y I nt er v e nti o n 
B e y o n d Pr o gr e s si o n
A d d e d i nf or m ati o n f or b o n e 
m et a st a si s/l e si o n
T o cl arif y t h at b o n e p alli ati v e r a di ot h er a p y 
i s all o w e d d uri n g t h e st u d y
5. 2 E x cl u si o n Crit eri a 
Cl arifi e d t h e e x cl u si o n crit eri a # 7
T o e x cl u d e p arti ci p a nt s wit h hi st or y of 
bl e e di n g di at h e s e s or r e c e nt m aj or bl e e di n g 
e v e nt s
6. 1 St u d y I nt er v e nti o n( s) 
A d mi ni str ati o n
A d d e d i nf or m ati o n r e g ar di n g t h e 
s e q u e n c e of tr e at m e nt 
a d mi ni str ati o n
T o s p e cif y t h e s e q u e n c e of tr e at m e nt 
a d mi ni str ati o n w h e n t h e r a di ot h er a p y i s 
d eli v er e d at a s e p ar at e l o c ati o n 
6. 5. 3 P er mitt e d/ Pr o hi bit e d 
Pr o c e d ur e s
A d d e d i nf or m ati o n r e g ar di n g t h e 
p alli ati v e r a di ot h er a p y
T o cl arif y t h at p alli ati v e r a di ot h er a p y i s 
all o w e d i n p arti ci p a nt s w h o e x p eri e n c e P D 
d uri n g t h e st u d y
6. 8. 1 A d diti o n al P ot e nti al 
Ri s k s
I n cl u d e d alt er ati o n s i n w o u n d 
h e ali n g or r e p air of ti s s u e d a m a g e, 
e m br y o -f et al t o xi citi e s, a n d mil d t o 
m o d er at e m u c o s al
bl e e di n g e v e nt s 
a s a d diti o n al p ot e nti al ri s k s
T o ali g n wit h n e wl y i d e ntifi e d p ot e nti al ri s k 
a s p er c urr e nt I B a n d pr ot o c ol t e m pl at e 
a cr o s s t h e pr o gr a m
6. 9. 1. 1 I nf u si o n-R el at e d 
R e a cti o n s
A d d e d i nf or m ati o n r e g ar di n g 
a d mi ni str ati o n of t h e st u d y 
i nt er v e nti on s 
T o cl arif y t h at t h e tr e at m e nt s h o ul d b e 
a d mi ni st er e d i n a n o ut p ati e nt b a si s u nl e s s 
h o s pit ali z ati o n i s r e q uir e d b y h e alt h 
a ut h oriti e s or i s p art of t h e st a n d ar d 
pr a cti c e 
6. 9. 1. 3 P ot e nti al 
T G F β -M e di at e d S ki n 
A d v er s e E v e nt s
R e pl a c e d i nf or m ati o n r e g ar di n g t h e 
m a n a g e m e nt of p ot e nti al T G F β 
u si n g s ki n t o xi citi e s g ui d eli n e s
T o pr o vi d e g ui d eli n e s f or t h e m a n a g e m e nt 
of p ot e nti al T G F β -r el at e d s ki n t o xi citi e s
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 1 / 1 5 5
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
6. 9. 1. 5 M a n a g e m e nt of 
Bl e e di n g E v e nt s
A d d e d t e xt t o d e s cri b e 
m a n a g e m e nt of bl e e di n g e v e nt s
T o pr o vi d e t h e g ui d eli n e s f or t h e 
m a n a g e m e nt of bl e e di n g e v e nt s a n d 
i n di c ati o n s f or w h e n p ati e nt s s h o ul d h a v e 
st u d y tr e at m e nt h el d or di s c o nti n u e d
6. 9. 1. 6 Ri s k M a n a g e m e nt 
f or C h e m or a di ati o n
A d d e d i nf or m ati o n r e g ar di n g t h e 
tr e at m e nt v s pl at el et a n d n e utr o p hil 
c o u nt s
T o cl arif y t h e c o n diti o n s t o r e s u m e t h e 
tr e at m e nt 
F o ot n ot e s a d d e d t o T a bl e s 1 0, 1 1, 
1 6, a n d 1 8 r e g ar di n g t h e p arti ci p a nt 
p er m a n e nt di s c o nti n u ati o n if t h e 
tr e at m e nt wit h h ol di n g ≥2 w e e k s
T o cl arif y tr e at m e nt di s c o nti n u ati o n i n c a s e 
of tr e at m e nt wit h h ol di n g ≥2 w e e k s
8. 3. 2 M et h o d of D et e cti n g 
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
(i n cl u di n g A p p e n di x 4)
M o difi e d
n o n s eri o u s A E SI r e p orti n g 
T o di s c o nti n u e e x p e dit e d r e p orti n g of 
n o n -s eri o u s A E SI
8. 5 P h ar m a c o ki n eti c s   
C orr e cti o n of pl a s m a t o s er u m f or 
t h e q u a ntifi c ati o n of M 7 8 2 4.
T o c orr e ct t e xt.
8. 6 P h ar m a c o g e n eti c s 
C orr e cti o n of “ pl a s m a s a m pl e” t o 
“ bl o o d s a m pl e” f or t h e 
p h ar m a c o g e n eti c r e s e ar c h
T o c orr e ct t e xt
A p p e n di x 5
R e vi s e d t h e r e c o m m e n d ati o n s f or 
i m m u n e r el at e d a d v er s e e v e nt s 
(ir A E) m a n a g e m e nt
T h e c o nt e nt s w er e r e vi s e d t o i n cl u d e N C C N 
ir A E m a n a g e m e nt g ui d eli n e s a n d F D A 
r e c o m m e n d ati o n s. Criti c al i n str u cti o n s 
i n cl u d e t h e r e q uir e m e nt t h at tr e at m e nt m u st 
b e p er m a n e ntl y di s c o nti n u e d f or c ert ai n 
Gr a d e 4 ir A E t o xi citi e s
A p p e n di x 9
U p d at e d i nf or m ati o n r e g ar di n g 
pr ot o c ol a m e n d m e nt hi st or y
F or cl arit y a n d c o n si st e n c y
T hr o u g h o ut
Mi n or e dit ori al a n d d o c u m e nt 
f or m atti n g r e vi si o n s
Mi n or t e xt r e vi si o n s ar e m a d e f or cl arit y, 
r e a d a bilit y, c o n si st e n c y of l a n g u a g e a cr o s s 
t h e d e v el o p m e nt pr o gr a m, a n d c o m pli a n c e 
wit h c urr e nt S p o n s or g ui d eli n e s
Pr ot oc ol Versi o n 2. 2 ( 2 1 M a y 2 0 1 9)
O ver all R ati o n ale f or t he A me n d me nt
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
4. 1 O v er all D e si g n
A d d e d P h a s e II st u d y i n d e s cri pti o n  
T o cl arif y st u d y d e si g n
4. 4 E n d of St u d y D efi niti o n 
A d d e d r ef er e n c e t o A p p e n di x 2 
T o r ef er t o f urt h er d et ail s f or st u d y a n d sit e 
cl o s ur e
6. 5. 2. 1 M e di ci n e s t o U s e 
wit h C a uti o n
A m e n d e d t e xt r e g ar di n g 
a nti c o a g ul a nt s
T o cl arif y u s e of a nti c o a g ul a nt s a n d pr o vi d e 
e x a m pl e
6. 9. 1. 5 Ri s k M a n a g e m e nt 
f or C h e m or a di ati o n; 
1 0 R ef er e n c e s
A d d e d r ef er e n c e
T o pr o vi d e r ef er e n c e t o d et ail e d i nf or m ati o n 
o n dr u g - dr u g i nt er a cti o n s wit h s u cr alf at e
7. 1. 1 P er m a n e nt 
Di s c o nti n u ati o n
A d d e d e x a m pl e s of r e a s o n s f or 
p arti ci p a nt wit h dr a w al
T o cl arif y r e a s o n s p arti ci p a nt c o ul d b e 
wit h dr a w n fr o m st u d y
7. 2 P arti ci p a nt 
Di s c o nti n u ati o n/ Wi t h dr a w al 
fr o m t h e St u d y
A d d e d e x a m pl e s of r e a s o n s f or 
p arti ci p a nt wit h dr a w al
T o cl arif y r e a s o n s p arti ci p a nt c o ul d b e 
wit h dr a w n fr o m st u d y
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI
C CI
C CI

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 2 / 1 5 5
Pr ot oc ol Versi o n 2. 1 ( 0 8 M a y 2 0 1 9)
O ver all R ati o n ale f or t he A me n d me nt
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
8. 5 
P h ar m a c o ki n eti c s
C orr e cti o n of pl a s m a t o s er u m f or t h e 
q u a ntifi c ati o n of M 7 8 2 4.
T o c orr e ct t e xt.
Pr ot oc ol Versi o n 2. 0 ( 0 5 M arc h 2 0 1 9)
O ver all R ati o n ale f or t he A me n d me nt
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
S y n o p si s, O v er all 
D e si g n; 4. 1 
O v er all D e si g n; 
4. 1. 1. 5 
Str atifi c ati o n; 6. 3. 1 
St u d y I nt er v e nti o n 
A s si g n m e nt; 9. 5. 1 
Effi c a c y A n al y s e s
A d d e d t e xt r e g ar di n g P D - L 1 e x pr e s si o n 
i n t u m or c ell s
T o i n cl u d e P D -L 1 e x pr e s si o n i n t u m or c ell s a s 
str atifi c ati o n f a ct or i n t h e e x p a n si o n p art of t h e 
st u d y
1. 3 S c h e d ul e of 
A cti viti e s
A d diti o n of f o ot n ot e s a n d c orr e cti o n s 
T o m a k e c orr e cti o n s i n t h e S c h e d ul e of A cti viti e s 
t a bl e s
4. 1 O v er all 
D e si g n; 7. 1. 1 
P er m a n e nt 
Di s c o nti n u ati o n
A d d t e xt r e g ar di n g a d v er s e e v e nt s 
r e s ulti n g i n p er m a n e nt di s c o nti n u ati o n 
of st u d y i nt er v e nti o n
T o i n cl u d e i n str u cti o n s f or r e s u mi n g tr e at m e nt
5. 1 I n cl u si o n 
Crit eri a
U p d at e d I n cl u si o n Crit eri o n # 3 a n d 
I n cl u si o n Crit eri o n # 1 0
T o i n cl u d e i nf or m ati o n r e g ar di n g P D - L 1 t u m or 
e x pr e s si o n a n d cl arif y i n cl u si o n crit eri a
6. 1 St u d y 
I nt er v e nti o n( s) 
A d mi ni str ati o n
A d d e d i n v e sti g ati o n al a n d m e di ci n al 
p a c k a gi n g a n d l a b eli n g i nf or m ati o n f or 
d ur v al u m a b
T o i n cl u d e c orr e ct i nf or m ati o n
9. 5. 1 Effi c a c y 
A n al y s e s
A d d e d T a bl e 2 4
T o a d d d et ail s o n pl a n n e d t e st s f or o v er all 
s ur vi v al a n al y s e s
A p p e n di x 5 
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
U p d at e d i m m u n e -r el at e d a d v er s e e v e nt 
m a n a g e m e nt i n str u cti o n s
U p d at e d f or c o n si st e n c y wit h t h e I M FI N ZI 
pr o d u ct l a b elli n g
D oc u me nt N o. 
O bject N o.
Gl o bal Versi o n I D:
C CI
C CI
C CI

Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
P P D
P P D
P P D
P P D
P P D

Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI
P P D
P P D
P P D

M 7 8 2 4
M 7 8 2 4 wit h c C R T i n U nresect a ble St a ge III N S C L C
M S 2 0 0 6 4 7 _ 0 0 0 5
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 5 / 1 5 5
A p pe n di x 1 2 
Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A M ultice nter, 
D o u ble Bli n d, Ra n d o mize d, C o ntr olle d 
St u d y  of M 7 8 2 4 
wit h 
C o nc urre nt 
C he m ora diati o n 
F oll o we d b y  M7 8 2 4 vers us C o nc urre nt C he m o ra diati o n 
Pl us Place b o F oll o we d b y  Dur val u ma b i n Partici pa nts 
wit h U nresecta ble Sta ge III N o n -s mall Cell Lu n g Ca ncer
Re g ul at or y 
A ge nc y I de ntif yi n g 
N u m bers:
E u dra C T 2 0 1 8 - 0 0 3 2 6 5-3 4
Cli nic al St u d y Pr ot oc ol Versi o n:
2 2 J u ne 2 0 2 1/ Versi o n 4. 0
Site N u m ber:
I a m res p o nsi ble f or t he c o n d uct of t he st u d y at t his site, a n d u n dersta n d a n d will c o n d uct it per t he 
cli nical st u d y pr ot oc ol, a n y ap pr o ve d pr ot oc ol a me n d me nts, I nter nati o nal C o u ncil 
f or 
Har m o nisati o n 
G o o d 
Cli nical 
Practice ( T o pic E 6) a n d all a pplica ble Healt h 
A ut h orit y 
re q uire me nts a n d nati o nal la ws.
I als o u n dersta n d t hat Healt h A ut h orities ma y  re q uire t he S p o ns ors of cli nical st u dies t o o btai n a n d 
s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal Pr o d uct a n d 
a n y ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n s olel y for 
c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y the S p o ns or wit h a n y 
necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties i ncl u di n g t h ose of m y  sp o use 
a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y  to meet 
Healt h 
A ut h orit y 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D:
C CI
C CI
C CI
C CI