Conditions: Non-small Cell Lung Cancer
Keywords: Non-small Cell Lung Cancer Bintrafusp alfa (proposed INN) M7824 Durvalumab Stage III INTR@PID LUNG 005
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 153
Healthy volunteers: no

Brief summary:
The main purpose of this study was to evaluate safety and efficacy in participants treated with concomitant chemoradiation therapy (cCRT) plus M7824 followed by M7824 compared to cCRT plus placebo followed by durvalumab.

Detailed description:

Arms:
arm 1: Participants received cCRT: Cisplatin/Etoposide or Carboplatin/Paclitaxel or Cisplatin/Pemetrexed concomitant with Intensity Modulated Radiation Therapy (IMRT) along with M7824 followed by M7824. arm 2: Participants received cCRT: Cisplatin/Etoposide or Carboplatin/Paclitaxel or Cisplatin/Pemetrexed concomitant with Intensity Modulated Radiation Therapy (IMRT) along with placebo matched to M7824 followed by durvalumab.

Interventions: intervention 1: M7824 intervention 2: Placebo intervention 3: Durvalumab intervention 4: Etoposide intervention 5: Pemetrexed intervention 6: Carboplatin intervention 7: Paclitaxel intervention 8: Cisplatin intervention 9: Intensity Modulated Radiation Therapy (IMRT)
Intervention descriptions: intervention 1: Participants received intravenous infusion of 1200 milligram (mg) M7824 over 1 hour every 2 weeks (q2w) during cCRT and up to 1 year after cCRT until unacceptable toxicity, confirmed disease progression assessed by investigator. intervention 2: Participants received intravenous infusion of placebo matched to M7824 over 1 hour q2w during cCRT until unacceptable toxicity, confirmed disease progression assessed by investigator. intervention 3: Participants received intravenous infusion of durvalumab 10 milligram per kilogram (mg/Kg) over 1 hour q2w up to 1 year after cCRT until unacceptable toxicity, confirmed disease progression assessed by investigator. intervention 4: Participants received etoposide 50 mg/m\^2 intravenously over a minimum of 30 minutes up to 60 minutes daily on Day 1 to 5 and Day 29 to 33 during cCRT. intervention 5: Participants received pemetrexed at a dose of 500 mg/m\^2 intravenously over 10 minutes or according to local standards on Days 1, 22, and 43 during cCRT. intervention 6: Participants received carboplatin intravenously based on area under curve (AUC) 2 over 30 minutes on Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 during cCRT. intervention 7: Participants received paclitaxel intravenously at a dose of 45 mg/m\^2 over 60 minutes on Day 1, Day 8, Day 15, Day 22, Day 29, Day 36, and Day 43 during cCRT. intervention 8: In combination with etoposide, participants received cisplatin 50 mg/m\^2 intravenously over 60 minutes on Days 1, 8, 29, and 36 during cCRT. In combination with pemetrexed, participants received cisplatin 75 mg/m2 intravenously over 60 minutes on Days 1, 22, and 43 during cCRT. intervention 9: Participants received IMRT 5 fractions per week for about 6 weeks (Total 60 gray \[Gy\]).

Protocol document:
Prot_000.pdf: 
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

SAP_001.pdf: 
Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
 
 
I nte gr ate d A n al ysis Pl a n  
Cli nic al St u d y  Pr ot oc ol 
I de ntific ati o n N o. 
M S 2 0 0 6 4 7 _ 0 0 0 5  
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 w e d  b y  M 7 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  
St u d y P h ase  
P hase II  
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)  
M 7 8 2 4  ( Bi ntraf us p alfa) 
Cli nic al St u d y  Pr ot oc ol 
Versi o n  
2 2 J u n 2 0 2 1 / Versi o n 4 . 0 
I nte gr ate d A n al ysis Pl a n 
A ut h or  
C o or di n ati n g A ut h or  
 
St u d y Bi o st ati sti ci a n , E M D S er o n o   
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
, 
 
 
, 
 
 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n  
2 2  Fe br uar y  2 0 2 2 / Versi o n 2  
I nte gr ate d A n al ysis Pl a n 
Re vie wers  
F u n cti o n  
N a m e  
S e ni or Bi o st ati sti c s R e vi e w er, 
 
S e ni or Bi o st ati sti c s R e vi e w er , 
 
L e a d Pr o gr a m m er, 
 
Gl o b al T h er a p e uti c M e di c al A d vi s or , 
 
  
Bi o st ati sti c s C o m p o u n d L e a d, 
 
St ati sti c al Pr o gr a m mi n g , M er c k 
H e alt h c ar e  
St ati sti c al Pr o gr a m m i n g, M er c k 
H e alt h c ar e  
Bi o st ati sti c s Pr o gr a m L e a d, M er c k 
H e alt h c ar e  
Gl o b al P ati e nt S af et y, I m m u n o-
O n c ol o g y, M er c k K G a A  
M e di c al L e a d, E M D S er o n o  
Cli ni c al P K / P D S ci e nti st, M er c k 
H e alt h c ar e  
D M P K S ci e nti st , E M D S er o n o 
Gl o bal Versi o n I D: 
1/ 8 8
Gl o bal Versi o n I D: 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI
P P D


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Cli ni c al P h ar m a c ol o gi st, E M D 
S er o n o  
 
Cli ni c al Bi o m ar k er L e a d, E M D 
S er o n o  
 
 
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies. 
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p yri g ht © 2 0 2 2  b y M erc k K G a A, D ar mst a dt, Ge r m a n y or its affili ate. All ri g hts reser ve d.  
Gl o bal Versi o n I D: 
2/ 8 8
Gl o bal Versi o n I D: 
P P D
P P D
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
A p pr o v al  P a ge   
 
I nte gr ate d A n al ysis Pl a n: M 2 0 0 6 4 7 _ 0 0 0 5  
A M ultice ntre, 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 M 7 8 2 4 vers us C o nc urre nt C he m ora di ati 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 n cer  
A p pr o val  of  t h e  I A P  b y  all  Merc k  Data  A nal ysis  Res p o nsi ble has  t o  b e d oc u me nte d  wit hi n  
B R E E Z E via e Si g nat ur e . Wit h t he a p pr o val wit hi n B R E E Z E , t he M erc k res p o nsi ble f or eac h of 
t he a nal ysis als o ta kes res p o nsi bilit y t hat all re vi e wers’ c o m me nts are a d dresse d a de q u atel y. 
 
Merc k D at a A n al ysis Res p o nsi ble  
D ate  
Si g n at ure  
, St u d y Bi ostatistic ia n, E M D 
Ser o n o  
 Via B R E E Z E 
a p pr o val pr o cess  
Via B R E E Z E  a p pr o val pr ocess  
 
 
 
Gl o bal Versi o n I D: 
3/ 8 8
Gl o bal Versi o n I D: 
P P D
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
1  
T a ble of C o nte nts   
I nte grate d A nal ysis Pla n ......................................................................................................1  
A p pr o val Pa ge  
3  
1  
Ta ble of C o nte nts  ..................................................................................4  
2  
List of A b bre viati o ns a n d Defi niti o n of Ter ms  ....................................8  
3  
M o dificati o n Hist or y  ..........................................................................1 2  
4  
P ur p ose of t he I nte grate d A nal ysis Pla n  .............................................1 5  
5  
O bjecti ves a n d E n d p oi nts  ...................................................................1 7  
6  
O ver vie w of Pla n ne d A n al yses  ...........................................................1 9  
6. 1  
I D M C ..................................................................................................1 9  
6. 2  
Pri mar y A nal ysis  ................................................................................1 9  
6. 3  
O ver vie w  of Pla n ne d A n al yses after Trial Disc o nti n uati o n  ...............2 1  
7  
C ha n ges t o t he Pla n n e d A nal ys es i n t he Cli nical St u d y Pr ot o c ol  ......2 2  
7. 1  
C O VI D -1 9 I m pact  ..............................................................................2 2  
8  
Pr ot oc ol De viati o ns a n d A nal ysis Sets  ...............................................2 3  
8. 1  
Defi niti o n of Pr ot oc ol De viati o ns a n d A nal ysis Sets  .........................2 3  
8. 2  
Defi niti o n of A nal ysis P o p ulati o ns a n d S u b gr o u ps  ............................2 4  
9  
Ge neral S pecificati o ns f or Data A n al ys es  ..........................................2 6  
1 0  
St u d y Partici pa nts  ...............................................................................3 3  
1 0. 1  
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns  ...............................3 3  
1 0. 2  
Pr ot oc ol De viati o ns  ............................................................................3 5  
1 0. 2. 1  
Im p ort a nt Pr ot oc ol De viati o ns  ............................................................3 5  
1 0. 2. 2  
Reas o ns Lea di n g t o t he E x cl usi o n fr o m a n A nal ysis P o p ulati o n  .......3 6  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................3 6  
1 1. 1  
De m o gra p hics  .....................................................................................3 6  
1 1. 2  
Me dical Hist or y  ..................................................................................3 8  
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................3 8  
1 1. 3. 1  
Vital Si g ns at Baseli ne  ........................................................................3 8  
1 1. 3. 2  
Disease Hist or y  ...................................................................................3 8  
1 1. 3. 3  
S ki n Stat us Hist or y  .............................................................................4 0  
1 1. 3. 4  
Nic oti ne C o ns u m pti o n  ........................................................................4 0  
1 1. 3. 5  
T u m or Bi o ps y  .....................................................................................4 0  
Gl o bal Versi o n I D: 
4/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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. 6  
P D -L 1 Stat us at Scree ni n g  ..................................................................4 1  
1 2  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures  .............................4 1  
1 2. 1  
Pre vi o us A nti -Ca ncer Treat me nts f or N o n -s mall Cell L u n g Ca ncer ..4 1  
1 2. 2  
Pre vi o us a n d C o nc o mita nt Me dicati o ns  .............................................4 2  
1 2. 3  
C o nc o mita nt Pr oce d u res .....................................................................4 2  
1 2. 4  
S u bse q ue nt A nti -Ca ncer Treat me nt  ....................................................4 3  
1 2. 5  
Pre me dicati o n  .....................................................................................4 3  
1 3  
St u d y i nter ve nti o n C o m plia nce a n d E x p os ure  ...................................4 4  
1 3. 1  
Ra di ot hera p y Pla n C o m plia nce  ..........................................................4 9  
1 4  
Efficac y A nal yses  ...............................................................................5 0  
1 4. 1  
Pr o gressi o n -Free S ur vi val  ..................................................................5 0  
1 4. 1. 1  
Pri mar y O bj ecti ve: P F S Acc or di n g t o R E CI S T 1. 1 Assesse d b y 
i n vesti gat or .........................................................................................5 0  
1 4. 1. 2  
Se nsiti vit y A nal ys es f or P F S  ..............................................................5 3  
1 4. 1. 3  
S u b gr o u p A nal ysis f or P F S  ................................................................5 4  
1 4. 2  
O verall S ur vi val  ..................................................................................5 4  
1 4. 2. 1  
Se nsiti vit y A nal ys es f or O S  ................................................................5 6  
1 4. 2. 2  
S u b gr o u p A nal ysis f or O S  ..................................................................5 6  
1 4 . 3 
F oll o w -U p Ti me  .................................................................................5 6  
1 4. 3. 1  
F oll o w -U p Ti me ( P F S)  .......................................................................5 6  
1 4. 3. 2  
F oll o w -U p Ti me ( O S)  .........................................................................5 6  
1 4. 4  
O bjecti ve Res p o nse Rate Acc or di n g t o R E CI S T 1. 1 as Assesse d 
b y I n v esti gat or  ....................................................................................5 6  
1 4. 4. 1  
S u b gr o u p A nal ysis f or O R R  ...............................................................5 9  
1 4. 5  
D urati o n of Res p o nse  .........................................................................5 9  
..6 0  
..6 0  
..6 1  
..6 1  
1 4. 1 0  
Dela ye d Res p o ns e after I nitial Pr o gressi o n  ........................................6 2  
.................................................6 2  
Gl o bal Versi o n I D: 
5/ 8 8
Gl o bal Versi o n I D: 
C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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. 1  
La n d m ar k A n al ysis of P F S  .................................................................6 2  
1 4. 1 1. 2  
La n d m ar k A n al ysis of O S  ..................................................................6 3  
1 4. 1 1. 3  
C o x Re gressi o n M o dels  ......................................................................6 3  
1 5  
Safet y A nal yses  ..................................................................................6 3  
1 5. 1  
A d verse E v e nts  ...................................................................................6 4  
1 5. 1. 1  
All A d verse E v e nts  .............................................................................6 7  
1 5. 1. 2  
A d verse E v e nts Lea di n g t o St u d y I nter ve nti o n Dis c o nti n uati o n  .......6 9  
1 5. 2  
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E v e nts  ...................................................................................7 0  
1 5. 2. 1  
Deat hs  .................................................................................................7 0  
1 5. 2. 2  
Seri o us A d verse E v e nts  ......................................................................7 1  
1 5. 2. 3  
A d verse E v e nts of S peci al I nt erest  .....................................................7 1  
1 5. 2. 3. 1  
I nf usi o n-relat e d Reacti o ns I n cl u di n g I m me di ate H yp erse nsiti vit y  ....7 2  
1 5. 2. 3. 2  
I m m u ne-relat e d A d verse E ve nts .........................................................7 2  
......................................7 3  
1 5. 2. 3. 4  
A ne mia A d verse E ve n ts .....................................................................7 4  
1 5. 2. 3. 5  
Ra diati o n/i m m u ne -me diate d P ne u m o nitis A d verse E ve nts  ...............7 5  
1 5. 2. 3. 6  
Blee di n g A d verse E v e nts  ....................................................................7 5  
1 5. 3  
Cli nical La b orat or y E val uati o n  ...........................................................7 5  
1 5. 4  
Vital Si g ns  ..........................................................................................7 8  
1 5. 5  
P ul m o nar y F u ncti o n Tests  ..................................................................7 9  
1 5. 6  
Ot her Safet y or T olera bilit y E val uati o ns  ............................................8 0  
1 6  
A nal ys es of Ot her E n d p oi nts  ..............................................................8 0  
1 6. 1  
P har mac o ki netics  ................................................................................8 0  
1 6. 1. 1  
Missi n g/ n o n -q ua ntifia ble P har mac o ki netic Data Ha n dli n g  ................8 0  
1 6. 1. 2  
Descri pti ve P har mac o ki n etic A nal ysis  ...............................................8 1  
...................................................8 2  
...................................................8 2  
1 6. 4  
I m m u n o ge nicit y ..................................................................................8 2  
...................................8 3  
...................................8 3  
1 7  
Refere n ces  ...........................................................................................8 5  
Gl o bal Versi o n I D: 
6/ 8 8
Gl o bal Versi o n I D: 
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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  
A p pe n dices  .........................................................................................8 6  
1 8. 1  
A p pe n di x 1 –  I D M C S A P ...................................................................8 6  
1 8. 2  
See se parate A p p e n di x of t his I A P. A p p e n di x 2 –  Defi niti o n of 
N CI -C T C A E gra di n g  ..........................................................................8 6  
1 8. 3  
See se parate A p p e n di x of t his I A P. A p p e n di x 3 –  List of I m p orta nt 
Pr ot oc ol De viati o ns  ............................................................................8 6  
1 8. 4  
A p pe n di x 4 –  I de ntificati o n of Pre vi o us or C o nc o mita nt 
Me dicati o ns/ Pr oce d ures  ......................................................................8 6  
1 8. 5  
A p pe n di x 5 - I A P _ M S 2 0 0 6 4 7-0 0 0 5 List of o ut p uts  ..........................8 7  
 
Ta ble 1 O ver vie w of Pla n ne d A nal yses  .............................................................................1 9  
Ta ble 2 O ver vie w of t he A nal ysis Set Use d i n t he Differe nt A nal yses  .............................2 5  
Ta ble 3 S u b gr o u p Defi niti o n ( wit h Refere n ce Le v el)  .......................................................2 6  
Ta ble 4  C ycle Le n gt h S pecificati o ns  ................................................................................4 7  
Ta ble 5 Defi niti o n of date of P F S e ve nt/ce ns ori n g  ............................................................5 1  
Ta ble 6 S ur vi val E ve nt/ Ce ns ori n g r ules f or O S  ................................................................5 5  
Ta ble 7 C o nfir mati o n R ules f or Best O verall Res p o nse  ....................................................5 7  
Ta ble 8 Al g orit h m f or t h e Deri vati o n of A D A Res ults  .....................................................8 2  
Ta ble 9 Partici pa nts C haracterize d Base d o n A D A Res ults  ..............................................8 3  
Ta ble 1 0 St o p pi n g r ules f or me dicati o n/ pr oce d ure e n d dates  ............................................8 6  
Ta ble 1 1 R ules t o defi ne pre vi o us a n d/ or c o n c o mi ta nt me dicati o ns .................................8 7  
 
Gl o bal Versi o n I D: 
7/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
2  
L ist of A b bre vi ati o ns a n d Defi niti o n of Ter ms  
 
A D A  
A nti -d r u g A nti b o d y  
A E  
A d verse eve nt  
A E SI  
A d verse eve nts of special interest  
A L K  
A na plastic ly m p h o ma k i nase 
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsf eras e  
A N C  
A bs ol ute ne utr o p hil c o u nt  
A S T  
As partate a mi n otra nsferase  
 
  
B MI  
B o d y mass i n de x  
B S A  
B o d y s urface area  
c C R T 
C o nc o mita nt C he m ora di ot hera p y  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C e oi 
C o nce ntrati o n o bser ve d i m me diatel y at t he e n d of i nf usi o n  
C R  
C o m plete res p o nse 
Cr C L  
Creati ni ne cleara n ce  
C S R  
Cli nical st u d y re p ort  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
ct D N A  
Circ ula ti n g T u m or  D N A  
C tr o u g h 
C o nce ntrati o n o bser ve d i m me diatel y b ef ore ne xt d osi n g (c orres p o n di n g t o pre -d ose or 
tr o u g h c o nce ntr ati o n f or m ulti ple d osi n g) 
 
 
 
 
Gl o bal Versi o n I D: 
8/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
D O R  
D urati o n of res p o ns e  
E C G  
Electr ocar di o gra m  
E C O G P S  
Easter n C o o perati ve O nc ol o g y G r o u p P erf or ma n ce S tat 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 f act or rece pt or  
 
 
 
 
F A S  
F ull (a nal ysis set)  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
 
 
 
 
F W E R  
Fa mil y w ise err or rate  
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 L T  
Hi g h le vel ter m  
H R  
Hazar d rati o 
 
 
IA P  
I nte grate d anal ysis p la n 
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 d e pe n de nt d ata m o nit ori n g c o m mittee 
 
 
Gl o bal Versi o n I D: 
9/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
i m A E 
I m m u ne-me diate d a d vers e e ve nt  
I M M 
I m m u n o ge nicit y (a nal ysis set) 
I M R T 
I nte nsit y-m o d ulate d ra di o thera p y  
I N R 
I nter nati o nal n or malize d rati o 
I P D 
I m p ort a nt pr ot oc ol de viati o n 
ir A E 
I m m u ne-relat e d a d verse e ve nt 
I R C 
I n d e pe n de nt re vie w c o m mittee 
I R R 
I nf usi o n-relat e d reacti o ns 
ir R E CI S T 
I m m u ne-relat e d Res p o ns e E val uati o n Criteria i n S oli d T u m ors  
I T T 
I nte nti o n-t o-treat 
I V R S/I W R S 
I nteracti ve v oice/ we b res p o nse s yste m  
K A  
Kerat oaca nt h o mas  
L L N  
L o wer li mit of n or mal  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
N CI -C T C A E  
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 v erse E v e nt,  
N S C L C  
N o n -s mall cell l u n g ca n cer 
 
 
O R R  
O bjecti ve res p o ns e rat e 
O S  
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 fu n cti o n tests  
P K  
P har mac o ki netics  
Gl o bal Versi o n I D: 
1 0/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
P K A S  
P har mac o ki netic (a nal ysis set)  
P R  
Partial res p o nse  
 
 
P T  
Pr ot hr o m bi n ti me 
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 or s Versi o n 1. 1 
R T  
Ra diati o n t hera p y  
S A E  
Seri o us a d verse e ve nt  
S A F  
Safet y (a n al ysis set) 
S C C  
S q ua m o us cell carci n o ma  
S C R  
Scree ni n g (a nal ysis set) 
S D  
Sta ble disease  
T BI LI  
T otal bilir u bi n  
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nt  
 
  
 
 
T S H  
T h yr oi d -Sti m ulati n g H or m o ne  
U L N  
U p per li mit of n or mal  
V A S  
Vis ual a nal o g ue scale 
 
 
 
 
 
Gl o bal Versi o n I D: 
1 1/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
3  
M o dific ati o n Hist or y   
U ni q ue  
I de ntifier f or 
Ve rsi o n  
D ate of  
I AP  Ve rsi o n  
A ut h or  
C h a n ges fr o m t he Pre vi o us Versi o n  
1. 0  
0 9  Oct o ber  2 0 1 9  
 
First Release  
2. 0  
 2 2  Fe br uar y  2 0 2 2  
 
U p date d wit h ne w  
 Statistical Te a m Lea d na me a n d ne w 
Merc k Bi ostatisticia n na me  
U p date d t he list of re vie wers wit h ne w Me dical a n d Safet y Le a ds at 
Merc k  
A d de d “ C O VI D -1 9” i n t h e list of a b bre viati o ns.  
 
Fi xe d t y p os acr oss t h e d oc u me nt.  
Secti o n 6. 3: A d d e d P D-L 1 stat us at scree ni n g.  
Secti o n 6. 5: Re place d te xt wit h a refere nce t o secti o n 1 5. 5.  
Secti o n 7 : A d de d secti o n 7. 1 C O VI D-1 9 I m pact  
Secti o n 9:  
1) U p date d defi niti o n of baseli ne t o s pecif y t h at it will be base d o n 
t h e pre-ra n d o mizati o n val u es (te xt a d de d b y M uriel).  
2) Err or: re place d "ti me of first st u d y i nter ve nti o n" wit h "ti me of 
ra n d o mizati o n" i n t he " Ti me si nc e d oc u me nte d, l ocall y a d va nce d or 
i n o pera ble disease dia g n osis ( m o nt hs)" defi niti o n. 
3) A d de d t he µ m ol/ L → m g/ d L c o n versi o n fact or.   
4) A d de d defi niti o n of pre, d uri n g, p ost pa n de mic p eri o d f or C O VI D -
1 9 i m pact assess me nt.  
 
Secti o n 1 0. 1:  
1) A d de d t he f oll o wi n g b ullet p oi nts  as p er t he dis p ositi o n ta ble 
fi n all y a gr ee d wit h S p o ns or: 
- N u m ber of ra n d o mize d partici pa nts w h o c o m plete d all st u d y 
inter ve nti o ns b y treat me nt ar m.  
- N u m ber of ra n d o mize d partici pa nts wit h a n y st u d y i nter ve nti o n 
o n g oi n g b y treat me nt ar m.  
- N u m ber of ra n d o mize d partici pa nts all o cate d t o eac h c he m ot h era p y 
re gi me n o verall a n d b y treat me nt ar m. 
- N u m ber of ra n d o mize d partici pa nts w h o disc o nti n ue d t h e st u d y, 
gr o u pe d b y treat me nt ar m a n d mai n reas o n (as re p orte d o n “ St u d y 
ter mi n ati o n” pa ge of t h e e C R F). 
2) U p date d i ncl u di n g C O VI D -1 9 a nal yses d etails  
Secti o n 1 0. 2 : U p date d i ncl u di n g C O VI D-1 9 a nal yses d etails  
 
Secti o n 1 1. 1:  A d de d P D -L 1 stat us at scree ni n g a n d Ka pla n -Meier 
pl ot of ti me t o treat me nt disc o nti n uati o n.  
Secti o n 1 1. 3. 2 : A d de d sta ge at st u d y e ntr y a n d k n o w n hist or y of o ne 
or m ore re nal/car diac i ns ufficie nc y, se ver e na usea or heari n g 
i m pair me nt. 
Secti o n 1 1. 3. 5:  A d de d details f or t h e o ver vie w ta ble f or P D -L 1 stat us 
at scree ni n g.  
Secti o n 1 3:  
1) A d de d details o n t h e t otal d urati o n of c he m ot h era p y re gi me n 
calc ulati o n.  
2) A d de d details o n t h e car b o plati n m g c o n versi o n.  
Gl o bal Versi o n I D: 
1 2/ 8 8
Gl o bal Versi o n I D: C CI
P P D
P P D
P P D


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
U ni q ue  
I de ntifier f or 
Ve rsi o n  
D ate of  
I AP  Ve rsi o n  
A ut h or  
C h a n ges fr o m t he Pre vi o us Versi o n  
3) A d de d s plit b y  i m m u n ot h era p y dr u g f or  c u m ulati ve d ose, DI a n d 
R DI re p orti n g i n u n bli n de d deli veries.  
Secti o n 1 4. 1. 1:  
U p date d P F S r ules t o c o nsi der 2 sc he d ule d t u m or assess me nts  a n d 
a d de d details i n P F S defi niti o n  
Secti o n 1 4. 4:  
1) Ta ble 7 : a d de d t he c orres p o n de nt " *" descri pti o n i n f o ot n ote. 
2) U p date d acr oss t h e w h ole d oc u me nt (as p er pr ot o c ol):  
•  
N o p ost -Baseli ne assess me nts d ue t o deat h wit hi n 8  6  
we e ks aft er ra n d o mizati o n  
•  
P D t o o late (i.e. t u m or assess me nt of P D was > 1 6  1 2  wee ks 
after ra n d o miz ati o n a n d t here was n o e val u a ble t u m or 
assess me nt i n bet wee n)  
Secti o n 1 4. 4. 1 : A d de d waterfall pl ots f or best p erce nt c ha n ge a n d 
c ha n ge at first sca n a n d u nc o nfir me d B O R b y i n vesti gat or s pi d er 
pl ot.  
Secti o n 1 4. 9. 1: U p date d defi niti o n of B O R acc or di n g t o ir R E CI S T  
Secti o n 1 5. 2. 3. 3 : A d de d Li p S q ua m o us Cell Carci n o ma a n d 
B o we n´s Diseas e t o Br oa d defi niti o n o f s ki n A Es p ossi bl y relate d t o 
T G F β i n hi biti o n.  
Secti o n 1 5. 2. 3. 4 : A d de d t h e O ver vie w A ne mia T E A Es ta ble.  
Secti o n 1 5. 3 : A d de d c orrecte d calci u m f or m ula 
Secti o n 1 7 : a d de d G F R a n d car b o plati n c o n versi o n refere nces.  
 
D R A F T 2 U p dates:  
A p pr o val pa ge: E L D O R A D O/ C A R A s yste m has b ee n re place d b y 
B R E E Z E  
Secti o n 4: P ur p ose of t h e i nte grate d a nal ysis pla n: re m o ve d i nteri m 
a nal yses as pr ot o c ol a me n d me nt ( v. 4. 0)  
Secti o n 5: O bjecti ve a n d e n d p oi n ts u p date d as pr ot o c ol a me n d me nt 
( v. 4. 0):  
•  
u p date d all o bjecti ves b ase d o n re sp o nse acc or di n g t o 
R E CI S T 1. 1: t h e y will be assesse d b y i n vesti gat or rat h er 
t h a n I R C 
•  
Re m o ve d o bjecti ve base d o n ir R E CI S T criteria  
Secti o n 6: o ver vie w of pla n ne d a nal ys es u p date d as pr ot oc ol 
a me n d me nt ( v. 4. 0):  
•  
Re m o ve d i nteri m a nal ys es , O S fi nal a nal ysis a n d 
se q ue ntial testi n g pr oce d ure fr o m t h e o ver vie w of pla n ne d 
a nal yses.  
•  
U p date d eff ic ac y a nal yses at P A as p er ne w st u d y 
o bjecti ves  
Secti o n 6: A d de d “ O ver vie w of Pla n ne d A nal yses after Trial 
Disc o nti n uati o n”  
Secti o n 8. 2  a n d acr oss t h e d oc u me nt : I T T a nal ysis set has b ee n 
re na me d as F A S as p er as pr ot o c ol a me n d me nt ( v. 4. 0) 
Secti o n 9: Si g ni fica nce le vel secti o n re m o ve d as n ot a n y m ore 
a p plica ble per pr ot o c ol a me n d me nt ( v. 4. 0)  
Secti o n 9: A d de d i m p utati o n r ules f or nic oti ne c o ns u m pti o n dates  
Gl o bal Versi o n I D: 
1 3/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
U ni q ue  
I de ntifier f or 
Ve rsi o n  
D ate of  
I AP  Ve rsi o n  
A ut h or  
C h a n ges fr o m t he Pre vi o us Versi o n  
Secti o n 9: A d de d c o m p utati o n of d urati o n of nic oti ne c o ns u m pti o n 
a n d years si n ce q uitti n g 
Secti o n 1 0. 1: A d de d cate g ories i n patie nt dis p ositi o n ta ble  
Secti o n 1 1. 1: A d de d p o ole d re gi o n a n d E E A i n de m o gra p hics as p er 
B O A 1 0  
Secti o n 1 1. 1: pl ot of ti me t o i m m u n ot h era p y disc o nti n uati o n has 
bee n m o ve d i n  Secti o n 1 0. 1  
Secti o n 1 1. 3. 4: A d de d nic oti n e c o ns u m pti o n sec ti o n 
S ecti o n 1 2. 3: A d de d descri pti o n of o ver vie w ta ble of c o nc o mita nt 
pr oce d ures  
Secti o n 1 3: A d de d f urt h er details f or listi n g of c he m ot h era p y s witc h  
Secti o n 1 4: Effic ac y a nal yses u p date d as p er pr ot o c ol a me n d me nt 
( v. 4. 0): 
•  
Re m o ve d se q ue ntial testi n g pr oce d ure a n d i nteri m a nal yses 
as n ot a n y m ore a p plica ble p er pr ot o c ol a me n d me nt ( v. 4. 0)  
•  
Re m o ve d h y p ot h esis test f or O S  
•  
U p date d t he e ve nt tri g geri n g t h e P A as d ate w he n 7 0 P F S 
e ve nts + 1 5 m o nt hs f -u p will be reac he d  
•  
u p date d all a nal yses b ase d o n res p o nse acc or di n g t o 
R E CI S T 1. 1 as per I R C: t he y will be assesse d b y 
i n vesti gat or rat h er t h a n I R C 
•  
P F S acc or di n g t o R E CI S T 1. 1 as assess e d b y i n vesti gat or 
will n ot a n y m ore  b e  a se nsiti vit y a nal ysis b ut rat h er t h e 
pri mar y a nal ysis  
•  
Re m o ve d a nal yses b ase d o n ir R E CI S T criteri a  
Secti o n 1 4: u p date d reas o n f or n o n -e val u a ble B O R. S D of 
i ns ufficie nt d urati o n has bee n set at 6 wee ks rat her t h a n 8 wee ks as 
gree d wit h Merc k Bi os.  S D ( or better) s pecifie d f or c o nfir me d 
res p o nse. 
 
Secti o n 1 5: Safet y a nal ys es u p date d as p er pr ot o c ol a me n d me nt 
( v. 4. 0): 
•  
A d diti o n of blee di n g e ve nts as a n A E SI  
•  
S ki n A d verse E v e nts re na me d as “ T G F -Beta i n hi biti o n 
me diate d s ki n reacti o ns”  
•  
Re m o ve d Ra diati o n/i m m u ne me diate d p ne u m o nitis as 
A E SI  
•  
Re m o ve d T hree tier a p pr oac h a nal ysis  
Secti o n 1 5: A d de d descri pti o n of list of Me d D R A Preferre d Ter ms 
c o nsi dere d as A E SI  
Secti o n 1 5: Re m o ve d E val u ati o n of P ote ntial Effect of A D A o n 
M 7 8 2 4 Safet y  
Secti o n 1 5. 1: A d de d o ver vie w ta ble of treat me nt -e mer ge nt A Es 
ass ociate d t o C O VI D -1 9  
Secti o n 1 5. 3: A d de d f urt h er details o n listi n gs of He m ostas e ol o g y, 
Uri nal ysis/ Uri nal ysis Micr osc o pic E val u ati o n, H or m o nal Tests, 
Ser ol o g y, Pre g na nc y Test  
Secti o n 1 5. 4 A d de d f urt h er details o n listi n g of ma xi m u m c ha n ge 
fr o m baseli ne i n vital si g ns 
Secti o n 1 5. 5 A d de d details o n a nal yses o n p ul m o nar y f u ncti o ns tests.  
Gl o bal Versi o n I D: 
1 4/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
U ni q ue  
I de ntifier f or 
Ve rsi o n  
D ate of  
I AP  Ve rsi o n  
A ut h or  
C h a n ges fr o m t he Pre vi o us Versi o n  
Secti o n 1 6. 4: I m m u n o ge nicit y a n al yses u p date d as p er last Merc k 
re q uire me nts: 
•  
A d de d A D A c ate g ories “ Treat me nt e mer ge nt ( A L L)” a n d 
“ A D A n o n -treat me nt e mer ge nt” 
•  
Missi n g val u es c o nsi dere d i n t h e c o m p utati o n of n u merat or 
a n d de n o mi n at or of treat me nt e mer ge nt cate g or y a n d 
cate g or y re na me d as “ Tr eat me nt e mer ge nt ( baseli ne 
i n d uce d)” 
•  
A d de d listi n g of A D A res ults  
Secti o n 1 8: A d de d a p pe n di x f or list of o ut p uts, w or di n g u p dates.  
 
Secti o n 1 6. 3: Re m o ve d P R O a nal yses d escri pti o n as n o a nal yses will 
be pr o v i de d f or t he a b bre viate d C S R 
 
Secti o n 1 6. 4: Re m o ve d i m m u n o ge nicit y a nal ys es d escri pti o n as n o 
a nal yses will be pr o vi d e d f or t h e a b bre viate d C S R  
 
Secti o n 1 6. 1: Re m o ve d P K a nal yses d escri pti o n as n o a nal yses will 
be pr o vi de d f or t he a b bre viate d C S R  
 
A p pe n di x: Re m o ve d P R O Sc ori n g G ui d eli nes a p pe n di x as n o 
a nal yses o n P R O will be pr o vi d e d f or t h e a b bre viate d C S R  
 
Mi n or a dj ust me nts acr oss t h e d oc u me nt i n or der t o ali g n it wit h 
s hells  
 
B O R was p artiall y c ha n ge d t o O R R acr oss t h e d oc u me nt t o be 
c o nsiste nt  wit h Merc k g ui d a nce v. 3. 0 “ Defi niti o n a n d A nal ysis of 
O bjecti ve Res p o nse i n O nc ol o g y St u dies fr o m G B S P ers pecti ve”  
 
 
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n  
T he  p ur p ose  of  t his  I nt e grate d  A nal ysis  Pla n  (I A P)  is  t o  d oc u me nt  t ec h nical  a n d  detaile d 
s pecificati o ns f or t h e pri mar y a nal ysis of dat a c ollecte d f or pr ot oc ol M S 2 0 0 6 4 7 _ 0 0 0 5.  
Res ults of t he a nal ys es descri be d i n t his I A P will be i ncl u de d i n t he Cli nical St u d y R e p ort ( C S R). 
A d diti o nall y, t he pla n ne d pri mar y a n al ys is i de ntifie d i n t his I A P will be i ncl u de d i n re g ulat or y 
s u b missi o ns  or  f ut ure  ma n uscri pts.  A n y  p ost-h oc,  or  u n pla n ne d  a nal yses  perf or me d  t o  pr o vi de 
res ults f or i ncl usi o n i n t he C S R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y i de ntifie d 
i n t he C S R.  
T he I A P is bas e d u p o n S ecti o n 9 ( Ge neral S pecifi cati o ns f or Data A n al yses ) of t he st u d y pr ot oc ol 
a n d is pre pare d i n c o m plia nce wit h I nter n ati o nal C o u ncil f or Har m o nizati o n (I C H) G ui deli ne E 9. 
Details  of  t he In de pe n de nt  Data  M o nit ori n g  C o m mittee  ( I D M C) a nal yses  are  pr o vi de d  i n 
a p pe n dices.  
Gl o bal Versi o n I D: 
1 5/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
 
 
Gl o bal Versi o n I D: 
1 6/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
5  
O bjecti ves a n d E n d p oi nts   
 
O bje cti ve  
E n d p oi nt  
S A P Secti o n  
Pri m ar y O bjecti v e  
T o e val u ate P F S i n partici p a nts treate d wit h c C R T pl us 
M 7 8 2 4 f oll o we d b y M 7 8 2 4 or c C R T pl us place b o f oll o we d 
b y d ur val u ma b  
•  
P F S acc or di n g t o R E CI S T 1. 1 
assess e d b y I n vesti g at or  
Efficac y A nal ysis: 
Secti o n 1 4. 1. 1  
S ec o n d ar y O bj ecti v es  
T o e val u ate t he safet y i n partici p a nts treate d wit h M 7 8 2 4 
pl us c C R T f oll o we d b y M 7 8 2 4 or c C R T pl us place b o 
f oll o we d b y d ur val u ma b 
•  
Occ urre nce of T E A Es a n d 
treat me nt-relate d A Es 
Safet y A nal ysis: 
Secti o n 1 5  
T o e val u ate O S i n partici pa nts treate d wit h M 7 8 2 4 pl us 
c C R T f oll o we d b y M 7 8 2 4 or c C R T pl us place b o f oll o we d 
b y d ur val u ma b  
•  
O S  
Efficac y A nal ysis  
Secti o n 1 4. 2  
T o e val u ate o bject i ve t u m or res p o nse i n partici pa nts treate d 
wit h c C R T pl us M 7 8 2 4 f oll o we d b y M 7 8 2 4 or c C R T pl us 
place b o f oll o we d b y d ur val u ma b  
O bjecti ve res p o nse acc or di n g t o 
R E CI S T 1. 1 assesse d b y I n vesti g at or  
•  
 
Efficac y A nal ysis  
Secti o n 1 4. 4  
T o e val u ate d urati o n of res p o nse i n partici pa nts treate d 
wit h M 7 8 2 4 pl us c C R T f oll o we d b y M 7 8 2 4 or c C R T pl us 
place b o f oll o we d b y d ur val u ma b  
•  
D urati o n of res p o nse assesse d fr o m 
C R or P R u ntil P D, deat h or last 
t u m or assess me nt 
Efficac y A nal ysis  
Secti o n 1 4. 5  
T o c haracterize P K pr ofile of M 7 8 2 4 pl us c C R T a n d after 
c C R T 
•  
P K pr ofile of M 7 8 2 4 i n ter ms of 
C e oi a n d C tr o u g h d uri n g treat me nt 
a n d Safet y F oll o w-u p visit  
A nal ysis of Ot her 
E n d p oi nts  
Secti o n 1 6. 1  
T o c haracterize t h e i m m u n o ge nicit y of M 7 8 2 4 pl us c C R T 
a n d after c C R T  
•  
I m m u n o ge nicit y of M 7 8 2 4 as 
m eas ure d b y A D A assa ys fr o m 
Scree ni n g t hr o u g h last Safet y 
F oll o w -u p visit  
A nal ysis of Ot her 
E n d p oi nts  
Secti o n 1 6. 4  
Gl o bal Versi o n I D: 
1 7/ 8 8
Gl o bal Versi o n I D: C CI
C
C
I
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
O bje cti ve  
E n d p oi nt  
S A P Secti o n  
, A D A =a nti-dr u g a nti b o d y, c C R T =c o nc o mita nt c he m ora diati o n t hera p y; C e oi=c o nce ntrati o n 
i m me diatel y at t h e e n d of i nf usi o n, C R =c o m plete res p o nse, 
, Ctr o u g h=c o nce ntrati o n 
i m me diatel y bef ore ne xt d osi n g; 
, E o T = E n d of Treat me nt, 
 
, I H C =i m m u n o hist o c he mistr y, 
 
, O S = o verall s ur vi val, P D = pr o gressi ve diseas e, P FS = pr o gressi o n -free s ur vi val, 
 
 P K = p har mac o ki n etics, P R = partial res p o nse, 
, T E A E =treat me nt-
e mer ge nt a d verse e ve nt, 
. 
N ote: a nal ysis of 
 e n d p oi nts will be c o nti n ge nt o n t he o utc o mes of pri mar y a n d sec o n dar y e n d p oi nts. 
 
 
 
Gl o bal Versi o n I D: 
1 8/ 8 8
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


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
6  
O ver vie w of Pl a n ne d A n al yses   
T his I A P will be f oc use d o n pri mar y a nal ys is. Ta bl e 1  bel o w dis pla ys a n o ver vie w of t he a nal ys es 
t o be pr o vi de d a n d t h e ti mi n g of t he pri mar y a n al ys is t hat will be tri g gere d b y t he data c ut-off  
p oi nts s pecifie d.   
T a ble 1  O ver vie w of Pl a n ne d A n al yses   
A n al y si s  
D at a c ut -off p oi n t 
Pri m ar y A n al y si s  
T o b e c o n d u ct e d w h e n 7 0 P F S e v e nt s p er i n v e sti g at or a s s e s s m e nt ar e r e a c h e d  a n d aft er a 
mi ni m u m f oll o w -u p of 1 5 m o nt h s aft er r a n d o mi z ati o n of t h e l a st p arti ci p a nt.  
 
R e g ul ar I D M C 
s af et y m e eti n g s  
T o b e c o n d u ct e d at t h e f oll o wi n g ti m e p oi nt s:  
D uri n g t h e s af et y r u n -i n p art 
•  
Aft er t h e fir st 1 8 N o n -J a p a n e s e p arti ci p a nt s h a v e c o m pl et e d c C R T p h a s e.  
•  
Aft er t h e fir st 3 0 N o n -J a p a n e s e p arti ci p a nt s h a v e c o m pl et e d c C R T p h a s e.  
•  
Aft er t h e 1 2 J a p a n e s e s u bj e ct s h a v e c o m pl et e d c C R T p h a s e.  
D uri n g t h e e x p a n si o n p art  
•  
3 m o nt h s aft er t h e st art of t h e e x p a n si o n p h a s e a n d 6 m o nt h s t h er e aft er  
S e e m or e d et ail s i n t h e I D M C C h art er.  
c C R T = C o n c o mit a nt c h e m or a di ati o n, I D M C =I n d e p e n d e nt d at a m o nit ori n g c o m mitt e e, P F S = Pr o gr e s si o n -fr e e s ur vi v al,  
A se parate Statistical A nal ysis Pla n will be pr o vi de d f or t he I D M C re g ular safet y m eeti n gs (see 
A p pe n di x 1 ). 
6. 1  
I D M C  
A n  I D M C  will  be  f or me d  a n d  will  be  res p o nsi ble  f or  p eri o dic  s afet y  e val uati o ns  of  t he  st u d y. 
Details f or t he I D M C re vie ws are stat e d i n t he I D M C S A P (see A p pe n di x 1 ). 
After t he pr os pecti vel y d eter mi ne d data c ut-off  d ate is reac h e d f or t he peri o dic safet y e v al uati o ns, 
t he data ce nter statisticia n will pre pare t he o ut p uts ( usi n g pr o gra ms pre pare d b y t he bli n de d tea m 
base d o n d u m m y treat me nt ar ms) i n a gree m e nt wit h t he  I D M C c harter a n d tra ns mit t he a nal ys es, 
ta b ulati o ns, a n d listi n gs t o t he I D M C f or t he m eeti n g. T he d ata ce nter statisticia n will be a vaila bl e 
at  t he  I D M C  meeti n g  s h o ul d  a n y  q uesti o ns  fr o m  t he  I D M C  me m bers  arise  re gar di n g  t he  d ata 
a n d/ or a nal yses.  
6. 2  
Pri m ar y A n al ysis   
T he  Pri mar y  A nal ysis  will  be  tri g gere d  b y  t he  d ata c ut-off  d ate  dis pla ye d  i n  Ta ble 1  an d  will 
i ncl u de t he f oll o wi n g: 
•  S u bject dis p ositi o n , ti me t o f oll o w-u p si nce ra n d o mizati o n , a n d i m p orta nt pr ot oc ol de viati o ns  
•  De m o gra p hics, me di cal hist or y a n d ot her Baseli n e  c haracteristics  
•  P D -L 1 Stat us at scree ni n g  
Gl o bal Versi o n I D: 
1 9/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  Pre vi o us a n d c o nc o mita nt me dicati o ns a n d pr oce d ures  
•  Pre vi o us a nti -ca ncer treat me nts f or N S C L C a n d s u bse q ue nt a nti -ca ncer treat me nts  
•  P re me dicati o ns f or i m m u n ot hera p y a n d c he m ot hera p y  
•  S u bse q ue nt a nti -ca n cer treat me nts  
•   Treat me nt e x p os ure a n d c o m plia nce (e. g. d urati o n of tr eat me nt, n u m ber of i nf usi o ns a n d d ose 
i nte nsit y) 
•  Efficac y a nal ys es:  
o  P F S acc or di n g t o R E CI S T 1. 1 criteria as assesse d b y I n v esti gat or  
o  O bjecti ve Res p o nse Rate  (O R R ) per R E CI S T 1. 1 criteria as assesse d b y I n vesti gat or  
o  Ti me t o res p o nse  
o  D urati o n of res p o ns e  ( D O R) 
o  O S  
o  P ul m o nar y f u ncti o n tests o ver vie w  
•  Safet y a nal yses ( o ver vie w  of A E s, S A Es, T E A Es, treat me nt-relate d A Es, A E SI a n d blee di n g 
e ve nts ), Easter n  C o o perati ve  O nc ol o g y  Gr o u p  P erf or ma n ce  Stat us  [ E C O G  P S ],  vital  si g ns, 
cli nical la b orat or y e val uati o ns, electr ocar di o gra ms [ E C G])  
•  I m m u n o ge nicit y a n d p h ar mac o ki netic ( P K) pr ofil e 
•  T u m or v ol u me s hri n ka ge  
Ra di o mics a nal ysis of i ma ges f or di gital feat ur es p ote ntiall y pre dicti ve of pr o g n osis a n d/ or f ut ure 
treatme nt be nefit a nal ysis will o nl y b e perf or me d retr os pecti vel y if d ee me d as a p pr o priat e.  
Gl o bal Versi o n I D: 
2 0/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T he  S p o ns or  st u d y  tea m will  be u n bli n de d  at  t h e  ti me  of  t he  P A  w hile  t he  I n vesti gat or s a n d 
partici pa nts re mai n bli n d e d u ntil E n d of St u d y  as s pecifie d i n t he I D M C C harte r. 
6. 3  
O ver vie w of Pl a n ne d A n al yses after Tri al Disc o nti n u ati o n   
F oll o wi n g re vie w a n d a n al ysis of dat a a vaila bl e fr o m M S 2 0 0 6 4 7 _ 0 0 0 5 i n Se pte m ber 2 0 2 1, a n d i n 
acc or da nce wit h t he I D M C rec o m me n dati o n, t h e S p o ns or ma de t h e decisi o n t o disc o nti n ue t he 
cli nical  st u d y  d u e  t o  a  l o w  li keli h o o d  t hat  t he  st u d y  will  ac hi e ve  s u p eri orit y  i n  t he  efficac y 
e n d p oi nts vs. t he sta n dar d of care.  
 
T heref ore, t he a n al ys es d escri be d i n Secti o n 6. 2  will n ot be perf or me d as pla n ne d, b ut o ne pri mar y 
a nal ysis  will  be  perf or m e d  f or  re p orti n g  p ur p os e  (a b bre viat e d  C S R).  T he  a nal ys es  c o nsi dere d 
rele va nt f or t his p ur p ose are  liste d bel o w:  
•  Partici pa nt dis p ositi o n  
•  I m p ort a nt pr ot oc ol de viati o ns 
•  E nr oll me nt  details  ( differe nce  bet wee n  pla n ne d  a n d  act ual  tr eat me nt  ar m  a n d  re -s cree ne d 
s u bjects) 
•  De m o gra p hics, me dical  hist or y  a n d ot her bas eli ne c h aracteristics  ( hei g ht, wei g ht ,  B S A  a n d 
B MI at bas eli ne, disease hist or y, s ki n stat us hist or y, nic oti ne c o ns u m pti o n , P D-L 1 e x pressi o n 
at scree ni n g )  
•  Pre vi o us a n d c o nc o mita nt pr oce d ures, f oll o w -u p tr eat me nts  
•  Treat me nt  e x p os ure  a n d  c o m plia nce  (e. g.  d urati o n  of  treat me nt s,  n u m ber  of 
i nf usi o ns/fracti o ns, c u m ulati ve d ose, d os e i nte nsit y  a n d relati ve d ose i nte nsit y, c h e m ot hera p y 
d ose re d ucti o ns ) 
•  Efficac y a nal ys es:  
o  P F S per R E CI S T 1. 1 as assesse d b y I n vesti gat or  
▪ P F S per R E CI S T 1. 1 as assesse d b y I n vesti gat or b y s u b gr o u ps  
o  O verall s ur vi val ( O S) 
▪ O S b y s u b gr o u ps   
o  F oll o w -u p ti me ( P F S a n d O S)  
o  O R R  per R E CI S T 1. 1 as assesse d b y I n v esti gat or  
▪ O R R per R E CI S T 1. 1 as assesse d b y I n v esti gat or b y s u b gr o u ps  
Gl o bal Versi o n I D: 
2 1/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
o  O verall Res p o nse per R E CI S T 1. 1 as ass esse d b y I n vesti gat or at t he e n d of c C R T  
o  Perce nta ge c h a n ge fr o m baseli ne i n s u m of l o n gest dia meters ( o verall a n d b y P D-L 1 
a n d hist ol o g y s u b gr o u ps)   
o  D urati o n of res p o ns e  
•  Safet y  a nal yses  ( o ver vi e w  of  treat me nt -e mer ge nt  a d verse  e ve nts  ( T E A Es),  seri o us  T E A Es 
( S A E),  
treat me nt-relate d  
T E A Es, 
T E A Es  
lea di n g  
t o  
treat me nt 
disc o nti n uati o n/i nterr u pti o n/ m o dificati o n, T E A Es Lea di n g t o deat h, a d v ers e e ve nts of s pecial 
i nterest ( A E SI), vital si g ns, E C O G,  cli nical la b orat or y e val uati o ns , p ul m o nar y f u ncti o n tests: 
D L C O, Sl o w s pir o metr y, F E V 1, F V C a n d 6-mi n utes wal ki n g test ) 
Data fr o m t he c ut off of 2 1 J ul y 2 0 2 1 were t he b asis f or t he decisi o n t o disc o nti n ue t he trial a n d 
will be use d f or t he pri m ar y a nal ysis.   
I n cas e a ne w safet y si g nal is o bser ve d, a n a d diti o nal a nal ysis will be d o ne at e n d of st u d y a n d 
i ncl u de d i n C S R a d den d u m. I n t he ot her cases, n o f urt her a n al yses will be pla n ne d.  
7  
C h a n ges  t o  t he  Pl a n ne d  A n al yses  i n  t he  Cli nic al 
St u d y  
Pr ot oc ol   
T he statistical met h o ds as descri be d i n t he st u d y pr ot oc ol will be a d o pte d. T here are n o c h a n ges t o 
t he pla n ne d a nal ys es, e x ce pt a d diti o nal o ut p uts t hat will be ge nerate d t o assess t he p ote ntial i m pact 
of C O VI D -1 9 p a n de mic a n d descri b e d i n t he Secti o n 7. 1  bel o w.  
7. 1  
C O VI D -1 9 I m p act   
N o c ha n ges t o t he pla n ne d a nal ysis of t he effi cac y e n d p oi nts will be perf or me d d ue t o t he i m pact 
of C O VI D -1 9 o ut brea k. I nstea d, a d diti o nal o ut p uts (s u m mar y ta bles a n d listi n gs) will be ge nerate d 
t o assess p ote ntial i m pacts of C O VI D-1 9 t o t his st u d y.  
•  A n o ver vie w t a ble of t he i m pact b y C O VI D -1 9  
•  A n o ver vie w ta bl e of partici pa nts w h o starte d t h e treat me nt pre/ d uri n g C O VI D -1 9 st u d y 
peri o d  
•  A ta ble of treat me nt -e mer ge nt a d verse e v e nts ass o ciate d t o C O VI D -1 9  
•  A listi n g of  C O VI D -1 9 i m pact  
•  A listi n g of C O VI D -1 9 relate d pr ot oc ol de vi ati o ns  
Details  of  t he  cate g orizati o n  of  partici pa nts  f or  C O VI D -1 9  i m pact  assess me nt  is  pr o vi de d  i n 
Secti o n  9  a n d details of t he a nal yses are pr o vi de d i n Sect i o ns 1 0. 1 , 1 0. 2 . 1 5. 1. 1 .  
Gl o bal Versi o n I D: 
2 2/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
8  
Pr ot oc ol De vi ati o ns  a n d A n al ysis Sets   
8. 1  
Defi niti o n of Pr ot oc ol De vi ati o ns a n d A n al ysis Sets   
I m p ort a nt p r ot oc ol d e viati o ns  are pr ot oc ol de vi ati o ns t hat mi g ht si g nifica ntl y affect t he 
c o m plete ness, acc urac y, a n d/ or relia bilit y of t he st u d y dat a or t hat mi g ht si g nifica ntl y affect a 
partici pa nt’s  ri g hts, safet y, or well-bei n g.  
I m p ort a nt pr ot oc ol de viati o ns i ncl u de: 
•  Partici pa nts w h o are d os e d o n t he st u d y d es pite n ot satisf yi n g t he i ncl usi o n criteria  
•  Partici pa nts w h o de vel o p wit h dra wal criteria w hilst o n t he st u d y b ut are n ot wit h dra w n  
•  Partici pa nts w h o recei ve a n i nc orrect d ose  
•  Partici pa nts w h o recei ve a n e x cl u de d c o nc o mita nt me dicati o n  
•  De viati o n s fr o m G o o d Cli nical Practices ( G C P). 
T he f oll o wi n g i m p orta nt pr ot oc ol de viati o ns will be i de ntifie d a n d c o nfir m e d pri or t o or at e ac h 
Cr oss -F u ncti o nal Pr ot oc ol De viati o n Re vie w  Meeti n gs a n d will i ncl u de:  
•  De viati o ns fr o m t he i ncl usi o n a n d e x cl usi o n criteria  
•  De viati o ns p ost i ncl usi o n . 
All  i m p orta nt  pr ot oc ol  de viati o ns  will  be  d oc u me nte d  i n  S D T M  datasets  w het her  i de ntifie d 
t hr o u g h site m o nit ori n g, me dical re vie w , or pr o gra m mi n g.  
I m p ort a nt  pr ot oc ol  d e vi ati o ns  will  be defi ne d i n  a  s pecific  d oc u me nt  (see A p p e n di x 4 ), a n d 
de viati o ns t o be c hec k e d pr o gra m maticall y will be i de ntifie d i n t his list.  
F urt her C o nsi der ati o ns f or P K  
E x a m ples of i m p orta nt pr ot oc ol de viati o ns or i m p orta nt e ve nts f or P K f or t his st u d y i ncl u de, b ut 
are n ot li mite d t o, t he f oll o wi n g:  
•  D ose dela ye d o utsi de t he all o we d wi n d o w (a n d act ual d osi n g ti me n ot rec or de d)  
•  Pre -d ose sa m ple c ollecte d  after t he act ual start of i nf usi o n  
•  E n d -of -i nf usi o n sa m ple c ollecte d bef ore t he act ual e n d of i nf usi o n 
•  Sa m ple pr ocessi n g err ors t hat ma y le a d t o i nacc urate bi oa nal ytical r es ults . 
F or t he a b o ve i m p orta nt pr ot oc ol de viati o ns or i m p orta nt e ve nts f or P K, t he r ele v a nt P K data will 
be e x cl u de d fr o m s u m maries a n d t he P K A nal ysis S et ( P K A S).  
Gl o bal Versi o n I D: 
2 3/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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  
Defi niti o n of A n al ysis P o p ul ati o ns a n d S u b gr o u ps   
Scree ni n g ( S C R) A n al ysis Set  
T he S C R a nal ysis set will i ncl u de all partici pa nts w h o pr o vi de d i nf or me d c o nse nt re gar dless of 
t he partici pa nt’s ra n d o mizati o n a n d st u d y i nter ve nti o n stat us i n t he st u d y.  
F ull  A n al ysis Set   (F A S )  
T he F A S  will  i ncl u de  all partici pa nts  w h o  were  ra n d o mize d  t o st u d y treat me nt.  A nal ys es 
perf or me d  o n  t he F A S  will  ta ke  i nt o  acc o u nt p artici pa nts ’  all ocati o n  t o  treat me nt  gr o u ps  as 
ra n d o mize d. 
N o n -J a p a nese S afet y  ( S A F-n J)  A n al ysis Set  
T he S A F -nJ a nal ysis set will i ncl u de t he first 3 0 n o n-J a pa nese partici pa nts w h o were a d mi nistere d 
a n y d os e of a n y st u d y i nt er ve nti o n. A nal yses will c o nsi der partici p a nts as treate d.  
J a p a nese S afet y  ( S A F-J)  A n al ysis Set  
T he S A F -J anal ysis set will i ncl u de t he first 1 2 Ja pa nese p artici pa nts w h o were a d mi nistere d a n y 
d ose of a n y st u d y i nter ve nti o n. A nal y ses will c o nsi der partici pa nts as tr eate d. 
S afet y ( S A F) A n al ysis Set  
T he S A F a n al ysis set will i ncl u de all partici pa nts w h o were a d mi nistere d a n y d ose of a n y st u d y 
i nter ve nti o n. A nal yses will c o nsi der partici pa nts as treate d. 
P h ar m a c o ki netic A n al ysis Set ( P K A S) 
T he  P K A S  will  i ncl u de all  partici pa nts  w h o  c o m plete d  at  least  1  i nf usi o n  of  M 7 8 2 4,  a n d  w h o 
pr o vi de d  at least 1 sa m ple wit h a meas ura bl e c o nce ntrati o n of M 7 8 2 4 , wit h o ut i m p orta nt pr ot oc ol 
de viati o ns or e ve nts de e me d t o affect P K e val uati o n.  
I m m u n o ge nicit y (I M M) A n al ysis Set   
T he I M M anal ysis set I M M will  i ncl u de  all  partici pa nts  w h o  c o m plete d  at  least  1  i nf usi o n  of 
M 7 8 2 4 a n d ha ve at least 1  vali d I M M res ult. All I M M a nal ys es will be bas e d o n t his a nal ysis set.  
 
Gl o bal Versi o n I D: 
2 4/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Err or!  Refere nce  s o urce  n ot  f o u n d. 2  dis pla ys  t he  use  of  t he  a nal ysis  sets  i n  t he  differe nt  a
nal yses.  
T a ble 2  O ver vie w of t he A n al ysis S et U se d i n t he D iffere nt A n al yses   
A n al y s e s  
S C R  
F A S  
S A F -n J/ S A F -
J/ S A F  
P K A S  
I M M 
 
 
S u bj e ct di s p o siti o n st at u s  
✓ 
✓ 
 
 
 
 
 
R a n d o mi z ati o n d et ail s  
 
✓ 
 
 
 
 
 
S u m m ar y of ti m eli n e s s/ cl e a nli n e s s of 
d at a  
 
 
✓ 
 
 
 
 
Pr ot o c ol d e vi ati o n s  
 
✓ 
 
 
 
 
 
D e m o gr a p hi c a n d B a s eli n e 
c h ar a ct eri sti c s  
 
✓ 
✓ 
 
 
 
 
Tr e at m e nt d ur ati o n  
 
 
✓ 
 
 
 
 
Effi c a c y  
 
✓ 
 
 
 
 
 
S af et y a n d T ol er a bilit y  
 
 
✓ 
 
 
 
 
P h ar m a c o ki n eti c s  
 
 
 
✓ 
 
 
 
I m m u n o g e ni cit y 
 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 I M M =I m m u n o g e ni cit y a n al y si s s et, F A S  = F ull a n al y si s s et, P K A S = P h ar m a c o ki n eti c s a n al y si s s et, 
, S A F = S af et y a n al y si s s et, S A F-J = J a p a n e s e S af et y a n al y si s s et, S A F -n J = N o n -
J a p a n e s e S af et y a n al y si s s et, S C R = S cr e e ni n g a n al y si s s et  
Tre at me nt All oc ati o n  
Partici pa nts  will  be  all o cate d  t o  t he  act ual  treat me nt  ar m  w here  first  pla n ne d  me dicati o n  a n d 
pre pare d me dicati o n, as re p orte d i n t he ra n d o mizati o n list, matc h.  
A d diti o n al S u b gr o u p A n al ysis P o p ul ati o n  
A nal ysis of effi cac y varia bles will als o be perf or m e d o n s u b gr o u ps of i nterest s pecifie d bel o w (see 
Ta ble 3 3 ). 
In or der t o i ncl u de  B aseli ne varia bles i nt o C o x's pr o p orti o nal hazar ds m o del a n d l o gistic m o dels , 
t he  f oll o wi n g  para meteri zati o n will be  use d.  F or  varia bles  wit h  m ore  t ha n  t w o  cate g ories,  a n 
i n dicat or varia bl e will be defi ne d f or eac h cate g or y e x ce pt f or t he first cate g or y, w hic h al wa ys 
defi nes t he refere nce. I n case of l o w partici p a nt n u m ber s wit hi n a cate g or y (i.e. 2 0 p artici pa nts ), 
cate g ories m a y be p o ole d.  
All t he s u b gr o u p a nal ys es will be  
 n o a dj ust me nt f or m ulti plicit y will be perf or m e d.  
T he s u b gr o u ps use d are d efi ne d i n Ta ble 3 3 . 
Gl o bal Versi o n I D: 
2 5/ 8 8
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


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T a ble 3  S u b gr o u p D efi niti o n ( wit h R efere nce L e vel)  
V ari a bl e  
L e v el s  
S e x  
M al e (r ef er e n c e l e v el)  
F e m al e  
A g e  
< 6 5 y e ar s (r ef er e n c e l e v el)  
≥6 5 y e ar s  
< 7 5 y e ar s (r ef er e n c e l e v el)  
≥7 5 y e ar s  
S m o ki n g hi st or y  
N e v er s m o k er (r ef er e n c e l e v el)  
E v er s m o k er  
Hi st ol o g y  
S q u a m o u s c ell c ar ci n o m a (r ef er e n c e l e v el)  
N o n -s q u a m o u s c ell c ar ci n o m a  
E G F R m ut ati o n  
M ut at e d  
Wil d ty p e  (r ef er e n c e l e v el) 
 
O v er all R e s p o n s e  at c C R T e n d  
C R + P R  
S D  
P D (r ef er e n c e l e v el)  
R a di ot h er a p y d o s e  
< 6 0 G y (r ef er e n c e l e v el)  
≥6 0 G y  
T y p e of c h e m ot h er a p y  
Ci s pl ati n/ e t o p o si d e (r ef er e n c e l e v el) 
P a clit a x el/ c ar b o pl ati n  
P e m etr e x e d/ c i s pl ati n 
R a c e  
C a u c a si a n/ W hit e (r ef er e n c e l e v el)  
Bl a c k or Afri c a n A m eri c a n  
A si a n  
Ot h er  
Et h ni cit y  
J a p a n e s e  
N ot J a p a n e s e (r ef er e n c e l e v el)  
Hi s p a ni c or L ati n o  
N ot  Hi s p a ni c or L ati n o (r ef er e n c e l e v el)  
E C O G  P S  
E C O G P S 0 (r ef er e n c e l e v el)  
E C O G P S 1  
N S C L C st a g e  
III A (r ef er e n c e l e v el) 
III B 
III C 
P D -L 1 ( S P 2 6 3)  
< 1 % (r ef er e n c e l e v el)  
≥1 %  
U n k n o w n  
P o ol e d R e gi o n  
N ort h A m eri c a (r ef er e n c e l e v el)  
L ati n A m eri c a  
E ur o p e  
A si a  
A u str ali a a n d O c e a ni a  
 
 
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 ot h er a p y,  C R = C o m pl et e  r e s p o n s e,  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 G F R = E pi d er m al  gr o wt h  f a ct or  r e c e pt or,  N S C L C = N o n -s m all  c ell  l u n g  c a n c er, 
, 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 
O verall res p o nse at c C R T e n d will be e x cl u de d fr o m t he C o x m o del a n d o nl y b e dis pla ye d f or 
descri pti ve p ur p oses.  
9  
Ge ner al S pecific ati o ns f or D at a A n al yses   
U nless ot her wis e i n dicat e d all a nal yses will be prese nte d se paratel y f or t he t w o tr eat me nt ar ms 
( Ar m 1 - c C R T pl us bi ntraf us p al fa f oll o we d b y bi ntraf us p al fa or Ar m 2 - c C R T pl us p lace b o 
Gl o bal Versi o n I D: 
2 6/ 8 8
Gl o bal Versi o n I D: C CI
C
CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
f oll o we d b y d ur val u ma b). T he s pecificati o ns f or P K data a nal ysis are prese nte d i n Secti o n  1 6. 1, 
a n d, i n case of discre p a n cies, Secti o n  1 6. 1 s hall s u perse de t his secti o n f or t he p ur p ose of P K data 
ha n dli n g, a n al ysis, a n d prese ntati o n.  
D at a H a n dli n g A fter C ut -off  D ate  
Data after t he c ut-off  will n ot u n der g o data cle a ni n g, a n d will be c ut at S D T M le vel, i.e. bef ore t he 
pr ocess of A D A M creati o n. T he se data will n ot be dis pla ye d i n a n y listi n gs or use d f or s u m mar y 
statistics, e. g. la b orat or y val ues of sa m ples ta ke n after data c ut-off , A Es wit h o nset date after data 
c ut-off , et c. will n ot be i ncl u de d i n a n y a n al ysis or listi n g.  
P o oli n g of C e nters  
B eca use  of  t he  hi g h  n u m ber  of  partici pati n g  ce nters  a n d  t he  a ntici p ate d  s mall  n u m ber  of 
partici pa nts  ra n d o mize d i n eac h ce nter, data will be p o ole d acr oss ce nters, a n d t he fact or ce nter 
will n ot be c o nsi dere d i n statistical m o dels or f or s u b gr o u p a nal yses.  
U nsc he d ule d A ssess me nts 
As per data base defi niti o n, u nsc he d ule d safet y ass ess me nts are al wa ys li n ke d t o a sc he d ule d ti me 
p oi nt (eac h u nsc he d ule d assess me nt is li n ke d t o t he pre vi o us sc he d ule d ti me p oi nt). Safet y d ata 
retrie ve d fr o m a n u nsc he d ule d ti me p oi nt ( vital si g ns, E C O G  P S , E C G  a n d la b orat or y dat a) will 
be a nal yz e d as f oll o ws : 
•  F or s hift  ta bles, dat a  will be ta ke n i nt o acc o u nt  i n  t he defi niti o n of t he w orst assess me nt 
d uri n g t he st u d y  
•  F or descri pti o n at eac h p ost -Baseli ne  ti me p oi nt, t he first a vaila ble res ult (i n c hr o n ol o gical 
or der) will be ta ke n i nt o acc o u nt i n t he a n al ysis i n case of m ulti ple val ues.  
F or I M M a n al ysis, u nsc h e d ule d visits will als o be ta ke n i nt o acc o u nt i n t he a nal ysis.  
F or P K A S , u nsc h e d ule d sa m ples will n ot be li n ke d t o a sc he d ul e d ti me p oi nt a n d will be e x cl u de d 
fr o m s u m maries. 
F or descri pti o n at B aseli n e, t he last a vaila ble/ n o n-missi n g res ult bef ore first st u d y i nter ve nti o n will 
be ta ke n i nt o acc o u nt i n t he a nal ysis i n case of m ulti ple val ues . 
Prese nt ati o n of C o nti n u o us a n d Q u alit ati ve V ari a bles  
C o nti n u o us varia bles , ot her t ha n P K, will be s u m mariz e d usi n g descri pti ve statistics, i.e.:  
•  N u m ber of s u bjects ( N), n u m ber of s u bjects wit h missi n g val ues  
•  Mea n, sta n dar d de viati o n  ( St D) 
•  Me dia n, 2 5t h p erce ntile - 7 5t h p erce ntile ( Q 1-Q 3)  
•  Mi ni m u m a n d ma xi m u m.  
If t here are n o missi n g val ues, t his will be i n dicate d b y a 0.  
Gl o bal Versi o n I D: 
2 7/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
P har mac o ki netic v aria bl es (c o n ce ntrati o ns  a n d p ara meters) will be s u m marize d as des cri be d i n 
Secti o n  1 6.1 . 
Q ualitati ve varia ble s will be s u m mariz e d b y c o u nts a n d perce nta ges. 
U nless ot her wis e state d , t he cal c ulati o n of pr o p orti o ns will be b ase d o n t he n u m ber of s u bjects of 
t he  a nal ysis  set  of  i nterest.  T heref ore,  c o u nts  of  missi n g  o bser vati o ns  will  be  i ncl u de d  i n  t he 
de n o mi nat or a n d prese nt e d as a se p arat e cat e g or y.  
W here a n a n al ysis refers o nl y t o certai n visits, perce nta ges will be b ase d o n t he n u m ber of s u bjects 
still prese nt i n t he st u d y at t hat visit, u nless ot her wise s pecifie d. 
Re p orti n g C o n ve nti o ns  
Mea n,  me dia n,  Q 1,  Q 3,  mi ni m u m  a n d  ma xi m u m  will  ha ve  t he  sa me  precisi o n  as  S D T M  data 
( n u m ber of di gits) f or n o n-deri ve d d ata, a n d sta n d ar d de viati o n will be dis pla ye d t o o ne di git m ore 
t ha n t he mea n. Statistics o n deri ve d data will be r o u n de d t o reas o na ble di gits, w hereas ma xi mal 
di gits s h o ul d be a vaila ble i n C DI S C A Da M data sets.  Perce nta ges will be re p orte d t o o ne deci mal 
place.    T he  r o u n di n g  will  be  perf or me d  t o  t he  cl osest  i nte ger/first  d eci m al  usi n g  t he  c o m m o n 
mi d -p oi nt  bet wee n  t he  t w o  c o nsec uti ve  val ues.    F or  e x a m ple,  5. 1  t o  5 . 4 will  be  r o u n de d  t o  a n 
i nte ger of 5, a n d 5. 5 t o 5. 9 will be r o u n de d t o a n i nte ger of 6.  
Defi niti o n of S t u d y Inter ve nti o n  
I n  t his  st u d y,  i m m u n ot hera p y,  c he m ot hera p y  a n d  ra di ot hera p y  are all c o nsi dere d  st u d y 
i nter ve nti o ns.  T he  d ate  of  first  st u d y i nter ve nti o n  will  be  defi ne d  as  t he  earliest  date  of  a n y 
treat me nts (i m m u n ot hera p y, c he m ot hera p y or ra di ot hera p y). T he date of last st u d y i nter ve nti o n 
will  be  defi ne d  as  t he  latest  date  of  a n y  treat me nts  (i m m u n ot hera p y,  c he m ot hera p y  or 
ra di ot hera p y). 
Defi n iti o n of B aseli ne  
T he  last  a vaila ble  assess me nt  pri or  t o  ra n d o mizati o n will  be  defi ne d  as  “ Bas eli ne ”  v al ue  or 
“Bas eli ne ” assess me nt f or efficac y a nal yses. If a n assess me nt is pla n ne d t o be perf or me d pri or t o 
ra n d o mizati o n  a n d  t he  assess me nt  is  perf or me d  o n t he  sa me  da y  as  ra n d o mizati o n,  it  will  be 
ass u me d t hat it was perf or me d pri or t o ra n d o mizati o n, if t he assess me nt ti me p oi nt is n ot c ollecte d 
or  is  missi n g.  If  n o  s uc h  a  val ue  is  a vaila ble,  t he  last  meas ur e me nt  pri or  t o  t he  first st u d y 
i nter ve nti o n will be use d as t he b aseli ne me as ure me nt e x ce pt f or pre -ra n d o mizati o n assess me nts 
use d f or t he deri vati o n of efficac y e n d p oi nts (e. g. t u m or assess me nt at Baseli ne , w hic h will be set 
t o missi n g, if n ot d o ne pri or t o ra n d o mizati o n). 
 
F or s afet y a nal yses, t he l ast meas ure me nt pri or t o t he first st u d y i nter ve nti o n will be us e d as t he 
Baseli ne  meas ure me nt. If a n assess me nt is pla n ne d t o be p erf or me d pri or t o t he first d ose of  a n y 
st u d y i nter ve nti o n as per  pr ot oc ol a n d t he assess me nt is perf or me d o n t he sa me da y as t he  first 
d ose of a n y st u d y i nter ve nti o n , it will be ass u me d t hat it was p erf or m e d pri or t o st u d y i nt er ve nti o n, 
if t he assess me nt ti me p oi nt is n ot c ollecte d or is missi n g.  
Gl o bal Versi o n I D: 
2 8/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T he sa me baseli ne val ues s h o ul d be us e d f or  t he d escri pti o n of bas eli ne c h aracteristics f or t he F A S  
a n d  safet y  p o p ulati o n.  T his  s h o ul d  be  i n  ge neral  t he  pre-ra n d o mizati o n val ues.  T h os e  val u es 
s h o ul d be als o use d f or s u b gr o u p classificati o n. 
Defi niti o n of O n -tre at me nt P eri o d  
O n -treat me nt  p eri o d  is  defi ne d  as  t he  ti me  fr o m  t he  first  st u d y  i nter ve nti o n  t o  t he  last  st u d y 
i nter ve nti o n date + 3 0 d a ys O R t he earliest date of s u bse q ue nt a ntica n cer t hera p y mi n us 1 da y, 
w hic he ver o cc urs first, u nless ot her wise state d. F or partici pa nts wit h treat me nt o n g oi n g at c ut -off 
date, all data fr o m t he first st u d y i nter ve nti o n u p t o t he c ut -off d ate will be c o nsi dere d u n d er t he 
o n -treat me nt peri o d. A n y s yste mic a ntica ncer t hera p y, a n y a ntica ncer s ur ger y a n d a n y a ntica ncer 
ra di ot hera p y, will be c o nsi dere d as s u bse q u e nt a ntica ncer t hera p y.    
Defi niti o n of D ur ati o n  
D urati o n will be calc ul ate d as t h e differe n ce of st art a n d st o p date + 1 (e. g. s ur vi val ti me ( da ys) = 
date of deat h –  date of ra n d o mizati o n + 1) , if n ot ot her wise s pecifie d. 
T he ti me si nc e a n e v e nt (e. g. ti me si nc e first dia g n osis) will be calc ulat e d as t he refere nce d ate 
mi n us date of e ve nt.   
C o n versi o n F act ors  
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o m o nt hs or years:  
•  1 m o nt h = 3 0. 4 3 7 5 da ys  
•  1 year = 3 6 5. 2 5 da ys  
I n or der t o all o w t he esti mate d Gl o mer ul ar Filtrati o n Rate ( G F R) f or t he car b o plati n c o n v ersi o n  
fr o m A U C t o m g, creati ni ne u nits c ollecte d i n e C R F as µ m ol/ L n ee d t o b e c o n vert e d i nt o m g-d L 
as  per  t h e  C oc kr oft -Ga ult  e q uati o n  ( Nati o nal  C o m p re he nsi ve  Ca ncer  Net w or k, T e m plates 
A p pe n di x  
B :  
Car b o plati n  
c o n versi o n.  
Retrie ve d  
fr o m: 
htt ps:// w w w. ncc n. or g/ pr ofessi o nals/ Or der Te m plates/ P D F/a p pe n di x _ B. p df  - last  accessed  0 4t h 
Fe br uar y 2 0 2 1).  
Ne p hr ol Dial Tra ns pla nt ( 2 0 0 4) 1 9 [ S u p pl 2]: ii 4 2 – ii 4 3. “ A p pe n di x C: Ta bles, c o n versi o ns a n d 
a b bre viati o ns”  
 
).  
T he c o n v ersi o n fact or us e d will be t he f oll o wi n g ( Ne p hr ol Dial Tra ns pla nt ( 2 0 0 4)  1 9 [ S u p pl 2]: 
ii 4 2– ii 4 3. “ A p pe n di x C: Ta bles, c o n versi o ns a n d a b bre viati o ns” 
): 
•  T o c o n vert µ m ol/l t o m g/ dl, m ulti pl y b y 0. 0 1 1 3  
Gl o bal Versi o n I D: 
2 9/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
H a n dli n g of M issi n g D at a  
U nless ot her wise s pecifie d i n t his I A P, missi n g dat a will n ot be i m p ute d.  
Missi n g  statistics,  e. g.  w he n  t he y  ca n n ot  be  calc ulate d,  s h o ul d  be  prese nte d  as  “ n d”  f or  n ot 
deter mi ne d. F or e x a m ple, if n = 1, t he meas ur e of v aria bilit y ( St D) ca n n ot b e c o m p ute d a n d s h o ul d 
be prese nt e d as “ n d ”.  
U nless  ot her wise  s pecifi e d, 
  will  be  score d  usi n g  t heir  p u blis he d 
a d mi nistrati o n  a n d  sc ori n g  ma n ual.  F or  ite ms  wit h  missi n g  res p o nses,  t he  res p o nse  will  be 
ma na ge d as p er t he sc ori n g ma n ual. See A p pe n di x 3  f or details. 
H a n dli n g of Inc o m plete D ates  
I n c o m plete dates ( date of i nf or me d c o nse nt, date of birt h) f or t he calc ulati o n of a ge will be i m p ute d 
as f oll o ws:  
•  I n case of missi n g da y f or at least o ne d ate, b ut m o nt h a n d year a vaila ble f or b ot h dates: 
t he da y of i nf or me d c o ns e nt a n d t he da y of birt h will be set t o 1.  
•  I n case of missi n g m o nt h f or at le ast o ne date, b ut year a v aila ble f or b ot h dates, t h e d a y 
a n d t he m o nt h of i nf or me d c o nse nt a n d t he da y a n d m o nt h of birt h will be set t o 1.  
•  I n all ot her cases, t he i nc o m plete dates will n ot be i m p ute d. 
I nc o m plete dates f or dise ase hist or y ( date of i nitial ca ncer dia g n osis, date of d oc u me nte d, l ocall y 
a d va nce d  or  i n o pera ble disease dia g n osis) a n d d ates of nic oti ne c o ns u m pti o n : 
•  If t he da y is missi n g, it will be i m p ute d t o t he 1st da y of t he m o nt h.  
•  If b ot h da y a n d m o nt h are missi n g, t he m o nt h a n d da y will be i m p ute d as Ja n uar y 1 st.  
•  If t he date is c o m plet el y missi n g, n o i m p utati o n will be perf or me d.  
I n c o m plete pri or/c o n c o mita nt me dicati o n dates will be i m p ute d as f oll o ws: 
F or start d ate of me dicati o n  
•  If t he da y is missi n g, it will be i m p ute d t o t he 1st da y of t he m o nt h.  
•  If b ot h da y a n d m o nt h are missi n g, t he m o nt h a n d da y will be i m p ute d as Ja n uar y 1 st.  
•  If t he date is c o m plet el y missi n g, n o i m p utati o n will be perf or me d.  
F or e n d d ate me dicati o n:  
•  If t he da y is missi n g, it will be i m p ute d t o t he last da y of t he m o nt h. 
•  If b ot h da y a n d m o nt h are missi n g, t he m o nt h a n d da y will be i m p ute d as Dece m b er 3 1 st. 
•  If t he date is c o m plet el y missi n g, n o i m p utati o n will be perf or me d.  
Gl o bal Versi o n I D: 
3 0/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
N ote: I n case t he i m p utati o n res ults i n a d ate l ater t ha n t he dat e of patie nt's deat h, t he n t h e dat e of 
deat h will be use d t o i m p ute t he i nc o m plete st o p date . 
I n c o m plete dates f or start date of s u bse q ue nt a nti -ca ncer t h era p y ( dr u g t hera p y, ra diati o n, s ur ger y) 
will be i m p ute d as f oll o ws a n d wil l be use d f or d eter mi ni n g ce ns ori n g d ates f or effic ac y a n al yses 
a n d i n t he deri vati o n of t he e n d of o n -treat me nt p eri o d:  
•  If o nl y da y is missi n g, it will be i m p ute d as t he last da y of t he m o nt h u nless t he e n d date 
of  s u bse q ue nt a nti-ca n cer t hera p y  is  bef ore  t hat  date.  I n  t hat  case,  t he  i nc o m plete 
a nti-ca ncer t hera p y start date will be i m p ute d as t he e n d date of t he a nti-ca ncer t hera p y. 
•  If b ot h da y a n d m o nt h are missi n g, n o i m p utati o n will be perf or me d.  
•  I n c o m plete s u bse q ue nt a nti -ca ncer t hera p y st o p dates will n ot be i m p ute d.  
I n c o m plete A E-relate d d ates will be i m p ute d as f oll o ws:  
•  I n case t h e o nset date is missi n g c o m pletel y or missi n g partiall y b ut t he o nset m o nt h a n d 
year, or t he o nset year are e q u al t o t he start of st u d y i nter ve nti o n, t he o ns et date will be 
re place d  b y  t he  mi ni m u m  of  start  of  st u d y  i nter ve nti o n  a n d  A E  res ol uti o n  date  (if  n ot 
missi n g).  
•  I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1. 
•  I n c o m plete st o p dates will be re place d b y t he last d a y of t he m o nt h (if da y is missi n g o nl y), 
if n ot res ulti n g i n a date l ater t ha n t he d ate of partici pa nt’s deat h. I n t h e latter cas e, t he dat e 
of deat h, will be use d t o i m p ute t he i nc o m plete st o p date.  
•  I n all ot her cases t he i nc o m plete st op date will n ot be i m p ute d.  
F or t he p ur p os e of s ur vi v al a nal yses  ( P F S a n d O S), partiall y missi n g deat h dates will be i m p ute d 
as f oll o ws:  
•  If o nl y t he d a y is missi n g, t he deat h date will be i m p ute d t o t he ma xi m u m of t he ( n o n-
i m p ute d) da y after t he date of last k n o w n ali ve dat e a n d t he 1 5 t h da y of t he m o nt h.  
•  Ot her wise it will n ot be i m p ute d.  
I n c o m plete date f or t u m or assess me nts will be i m p ute d as f oll o ws : 
•  If t h ere are m ulti ple sca n dates ass ociate d wit h a n e val uati o n, t he earliest of t he sca n dates 
ass ociate d wit h t he e v al u ati o n will be use d as t he date of assess m e nt.  
Partial dates, w hic h are n ot t o be i m p ute d acc or di n g t o t he I A P, will be prese nte d i n t he f or mat 
“ _ _ _ _ _ Y Y Y Y”. If val ues are i m p ute d acc or di n g t o t he I A P, i m p ute d val ues will be prese nte d i n 
parti ci pa nt data listi n gs a n d i m p ute d i nf or mati o n will be fla g ge d.  
S pecific ati o ns f or C o m p ut ati o n  
•  A ge (years ): ( d ate of gi v e n i nf or me d c o ns e nt - dat e of birt h + 1) / 3 6 5. 2 5  
Gl o bal Versi o n I D: 
3 1/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  B o d y Mass I n d e x ( B MI) ( k g/ m 2): wei g ht( k g)/[ hei g ht( m)]2 
•  B o d y S urface Area ( B S A) ( m 2): ([ hei g ht (c m) x wei g ht ( k g)] / 3 6 0 0) ^  ½  
•  Ti me si nce i nitial ca ncer dia g n osis ( m o nt hs) = ( date of ra n d o mizati o n –  date of i nitial ca n cer 
dia g n osis)/ 3 0. 4 3 7 5  
•  Ti me si nce d oc u me nte d, l ocall y a d va n ce d  or  i n o pera ble diseas e dia g n osis  ( m o nt hs) = ( date of 
ra n d o mizati o n –  date  of  d oc u me nt e d,  l o call y  a d va n ce d  or  i n o pera ble  disease 
dia g n osis )/ 3 0. 4 3 7 5. 
•  T he d urati o n of nic oti ne c o ns u m pti o n is c o m p ute d as f oll o ws:  
•  If a s u bject is a f or mer s m o ker, t he differe n ce i n years bet w ee n e n d date a n d start date of 
nic oti ne c o ns u m pti o n is c o m p ute d (e n d dat e of ni c oti ne c o ns u m pti o n –  start date of 
nic oti ne c o ns u m pti o n + 1) / 3 6 5. 2 5  
•  If a s u bject is a c urre nt s m o ker, t he differe n ce i n years bet w ee n nic oti ne c o ns u m pti o n 
c ollecti o n date a n d start date of nic oti ne c o ns u m pti o n is c o m p ute d. ( nic oti ne c o ns u m pti o n 
c ollecti o n date –  start dat e of nic oti ne c o ns u m pti o n + 1) / 3 6 5. 2 5 
•  Years  si nce  q uitti n g  of  nic oti ne  c o ns u m pti o n  is  c o m p ute d  f or  f or mer  s m o kers  o nl y  as 
(c ollecti o n of nic oti ne c o ns u m pti o n date - e n d dat e of s m o ki n g + 1)/ 3 6 5. 2 5.  
Prefe rre d T er m f or A n al ysis of W orl d He alt h Or g a niz ati o n’s Dr u g  Dicti o n ar y ( W H O -D D) 
C o de d D at a  
F or  data  c o de d  acc or di n g  t o  W H O -D D  (e. g.  c o nc o mita nt  me dicati o ns),  s u m maries  will  be 
prese nte d at t he preferre d ter m ( P T) le vel w here t h e preferre d ter m c orres p o n ds t o c o des e n di n g i n 
0 1 0 0 1. Wit h t his a p pr oac h, variati o ns of salt f or ms of acti ve i n gre die nts will be a n al yze d u n der 
t he sa me t er m, e. g. di p he n h y dra mi ne a n d di p he n h y dra mi ne h y dr oc hl ori de will be a n al yze d as t h e 
sa me preferre d ter m , di p he n h y dra mi ne.  
Re -scree ne d P artici p a nts  
Re -scree ne d partici pa nts will o nl y be c o u nt e d o nce i n t he S C R  a nal ysis set , c o nsi deri n g t he latest 
scree ni n g (scree ni n g wit h latest i nf or me d c o nse nt). If a partici pa nt is re -scree n e d se veral ti mes, 
t he y will be c o u nte d o nl y o nce i n t he d is p ositi o n ta ble i n t he n u m ber of re-scree n e d partici p a nts. 
Defi niti o n of Pre -, D uri n g-, P ost-p a n de mic Ti me Peri o ds  
Partici pa nts will be cate g orize d base d o n t he C O VI D -1 9 st u d y peri o d defi n e d as:  
•  Pre -pa n de mic  ti me  peri o d:  s u bjects  w h o  starte d  t he  treat me nt  (earliest  d ose  of  a n y  st u d y 
i nter ve nti o n) bef ore t he start of C O VI D-1 9 pa n de mic.  
•  D uri n g -pa n de mic ti me peri o d: s u bjects w h o starte d t he treat me nt (earliest d ose of a n y st u d y 
i nter ve nti o n) o n t he sa me date or after t he start of C O VI D-1 9 pa n d e mic . 
•  P ost -pa n d e mic ti me peri o d: t he e n d of pa n de mic is c o nsi dere d n ot yet reac he d a n y w here at 
t he ti me of t his I A P versi o n re d acti o n, c o ns e q ue ntl y n o partici pa nt will be gr o u pe d i nt o t he 
p ost C O VI D -1 9 st u d y p eri o d f or t his st u d y a n d n o p ost -pa n de mic date will be defi ne d . 
Gl o bal Versi o n I D: 
3 2/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T he start of C O VI D -1 9 pa n de mic is defi ne d b y c o u ntr y as t he earliest date of eit her t he date of 
t he first deat h fr o m C O VI D-1 9 o cc urre d i n eac h c o u ntr y acc or di n g t o t he p u blis he d data b y 
E ur o pea n  C e ntre  f or  Disease  Pre ve nti o n  a n d  C o ntr ol  o n  2 6t h  J u ne  2 0 2 0  
( htt ps:// w w w.ec dc.e ur o pa.e u/e n/ p u blicati o ns-data/ d o w nl oa d -t o da ys-data -ge o gra p hic -
distri b uti o n -c o vi d -1 9 -cas es -w orl d wi de)  or  1 1t h  Marc h  2 0 2 0  ( w he n  t he  W H O  declare d 
C O VI D -1 9 pa n d e mic).  
S oft w are  
All a nal ys es will be perf or me d usi n g S A S 9. 4 or hi g her i n t he S A S Gri d e n vir o n me nt.  
1 0  
St u d y P artici p a nt s  
T he  s u bsecti o ns  i n  t his  secti o n  i ncl u de  s pecifi cati o ns  f or  re p orti n g  s u bject  dis p ositi o n  a n d 
treat me nt/st u d y disc o nti n uati o ns.  A d diti o nally, pr oce d ures f or re p orti n g pr ot oc ol de viati o ns are 
pr o vi de d i n Secti o n  1 0. 2. 
1 0. 1  
Dis p ositi o n of P artici p a nt s a n d Disc o nti n u ati o ns  
Descri pti ve  statistics will be use d t o s u m marize s u bject dis p ositi o n a n d reas o n f or disc o nti n uati o n, 
base d o n t h e el ectr o nic case re p ort f or m (e C R F) d ata.  All p artici pa nts wit hi n t he S C R anal ysis set 
will be c o nsi dere d . 
T he f oll o wi n g i nf or mati o n will be re p orte d:  
•  T ot al n u m ber of scree n e d partici pa nts . 
•  T otal n u m ber of re -scree ne d partici pa nts . 
•  N u m ber of partici pa nts w h o disc o nti n ue d fr o m t he st u d y pri or t o ra n d o mizati o n o verall a n d 
gr o u pe d b y t he mai n r eas o n (as re p orte d i n o n “ St u d y E ntr y” pa ge of t he e C R F).  
•  N u m ber of  partici pa nts w h o c o m plete d t he scree ni n g ( mai n I C F si g ne d), b ut ha ve n ot bee n 
ra n d o mize d yet  
•  N u m ber of ra n d o mize d partici pa nts o verall a n d b y treat me nt ar m.  
•  N u m ber of ra n d o mize d partici pa nts w h o di d n ot recei ve a n y stu d y i nter ve nti o n  b y tr eat me nt 
ar m.  
•  N u m ber of ra n d o mize d partici pa nts w h o c o m plete d or disc o nti n ue d all st u d y i nter ve nti o ns 
b y treat me nt ar m.  
•  N u m ber of r a n d o mize d  partici pa nts  b ut n ot treate d a n d still i n st u d y  
•  N u m ber of ra n d o mize d partici pa nts wit h a n y st u d y i nter ve nti o n o n g oi n g b y treat me nt  ar m.  
•  N u m ber of ra n d o mize d p artici pa nts all ocate d t o eac h c he m ot hera p y re gi me n o verall a n d b y 
treat me nt ar m. 
•  N u m ber of ra n d o mize d partici pa nts w h o c o m plete d / disc o nti n ue d i m m u n ot hera p y gr o u pe d 
b y mai n reas o n , deat h or pr o gressi ve dise ase  b y tr eat me nt ar m .  
Gl o bal Versi o n I D: 
3 3/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  N u m ber of ra n d o mize d partici pa nts w h o c o m plete d c he m ot hera p y b y  mai n reas o n , deat h or 
pr o gressi ve dise ase  b y tr eat me nt ar m.  
•  N u m ber of ra n d o mize d partici pa nts w h o c o m plete d ra di ot hera p y  b y tr eat m e nt ar m.  
•  N u m ber of ra n d o mize d partici pa nts  wit h i m m u n ot hera p y o n g oi n g i n eac h tr eat me nt ar m . 
•  N u m ber of ra n d o mize d partici pa nts wit h c he m ot h era p y o n g oi n g i n eac h treat me nt ar m.  
•  N u m ber of ra n d o mize d partici pa nts wit h ra di ot hera p y o n g oi n g i n e ac h tr eat me nt ar m.  
•  N u m ber  of  ra n d o mize d  partici pa nts  w h o  c o m plete d  c C R T  p hase a n d  i m m u n ot hera p y 
treat me nt as per pr ot oc ol a n d are still i n t he st u d y f or f oll o w-u p, gr o u pe d b y treat me nt ar m.  
•  N u m ber  of  ra n d o mize d  partici pa nts  w h o ha v e  fi nalize d  c C R T  p hase  as  per  pr ot oc ol  a n d 
disc o nti n ue d im m u n ot hera p y b ut are still i n t he st u d y f or f oll o w-u p, gr o u pe d  b y tr eat me nt 
ar m. 
•  N u m ber  of  ra n d o mize d  partici pa nts  w h o  disc o nti n ue d  c C R T  p hase  b ut  c o m plete d 
i m m u n ot hera p y tr eat me nt as per pr ot oc ol a n d are still i n t he st u d y f or f oll o w-u p, gr o u pe d b y 
treat me nt ar m. 
•  N u m ber of ra n d o mize d partici pa nts w h o  disc o nti n ue d b ot h c C R T p hase a n d i m m u n ot hera p y 
a n d are still i n t he st u d y f or f oll o w -u p, gr o u pe d b y treat me nt ar m.  
•  N u m ber of s u bjects off -tr eat me nt a n d i n f oll o w-u p wit h last k n o w n t o be ali ve date wit hi n 1 
m o nt h, bet wee n 1 a n d 2 m o nt hs, bet wee n 2 a n d 3 m o nt hs a n d m ore t ha n 3 m o nt hs bef ore 
c ut-off dat e  
•  N u m ber  of  ra n d o mize d partici pa nts  w h o  disc o nti n ue d /c o m plete d t he  st u d y,  gr o u pe d  b y 
treat me nt ar m a n d mai n reas o n (as re p orte d o n “ St u d y ter mi nati o n” p a ge of t he e C R F). 
T he n u m ber of partici pa nts i n eac h a nal ysis set defi ne d i n Secti o n  8. 2 will als o be s u m marize d  b y 
treat me nt ar m a n d b y re gi o n a n d c o u ntr y. T he dis cre pa n cies bet wee n pla n ne d a n d treate d gr o u ps 
will be cr oss -ta b ulate d a n d pr o vi de d i n a listi n g. T he n u m ber of ra n d o mize d s u bjects (I W R S) b y 
re gi o n a n d c o u ntr y will be pr o vi de d, as w ell as t he n u m ber of s u bjects b y ra n d o mizati o n strata 
(I W R S).  
T he listi n g of i n di vi d ual dis p ositi o n will i ncl u de all partici pa nts (i.e. i ncl u di n g scree ni n g fail ures.). 
T he listi n g will i ncl u de t he f oll o wi n g i nf or mati o n (if a p plica ble): pla n ne d ar m (s u bjects ha vi n g 
act ual  ar m  differe nt  fr o m  pla n ne d  ar m  will  be  fla g ge d  a n d  dis pla ye d  i n  a  se parate  listi n g), 
partici pa nt i de ntifier, dat e of i nf or med c o nse nt, i ncl u de d i n t he trial a n d reas o n f or e x cl usi o n (if 
a p plica ble), ra n d o mizati o n date, first/last treat me nt date (f or im m u n ot hera p y, che m ot hera p y a n d 
ra di ot hera p y),  reas o n  off -treat me nt,  d ate (relati ve  da y) a n d  reas o n  off -st u d y,  p o p ulati o n  fla gs. 
W he n t he reas o ns, s uc h as t he reas o n off -treat me nt is cate g orize d as “ Ot h er, s pecif y” or “ Wit h dre w 
c o nse nt fr o m treat me nt, s pecif y”, t he ver bati m te xt as e ntere d i n t he e C R F will be prese nte d i n t he 
listi n g. 
If a n y re-scree n e d p artici pa nts ar e o bser ve d, t he listi n g of re -scree n e d p artici pa nts will be pr o vi de d 
a n d  will  i ncl u de  t he  f oll o wi n g  i nf or m ati o n:  pla n ne d  ar m,  s u bj ect  i de ntifier,  dat e  of  i nf or me d 
c o nse nt, date of ra n d o mi zati o n, s u bject  i de ntifier at  scree n fail ure, d ate of i nf or me d c o nse n t at 
scree n fail ure, d ate of s cree ni n g fail ure, reas o n of scree ni n g fail ure.  
Gl o bal Versi o n I D: 
3 4/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
A d diti o nall y, a Ka pla n -Meier pl ot of ti me t o per ma ne nt i m m u n ot hera p y disc o nti n uati o n will be 
prese nte d. Ti me t o i m m u n ot hera p y disc o nti n uati o n is calc ulate d as t he ti me fr o m ra n d o m izati o n 
u ntil  t he  i m m u n ot hera p y  is  disc o nti n ue d  or  c o m plete d.  S u bjects  w h o  ha ve  i m m u n ot hera p y 
o n g oi n g are ce ns ore d at l ast k n o w n t o be ali ve dat e.  T his pl ot will be pres e nte d w he n at least 1 0 
i m m u n ot hera p y disc o nti n uati o n e ve nts are o bs er ve d, a n d it will e x cl u de partici pa nts n ot treate d 
b y i m m u n ot hera p y.  
I n  a d diti o n,  f or  t he  assess me nt  of  C O VI D-1 9  i m pact  o n  t his  st u d y,  a n  o ver vie w  ta ble  will  be 
prese nte d b y tr eat me nt ar m wit h t he f oll o wi n g i nf or mati o n:  
•  S u bjects p ote ntiall y affecte d b y C O VI D -1 9 (i.e. s u bjec ts w h o st arte d treat me nt after start 
of  t he  C O VI D -1 9  p a n de mic,  or  w h o  starte d  treat me nt  pri or  t o  start  of  t he  C O VI D -1 9 
pa n de mic a n d are still o n g oi n g aft er t he start of t he pa n de mic)  
•  S u bjects wit h at least o ne C O VI D -1 9 i m pact    
•  S u bjects wit h at least o ne  C O VI D -1 9 i m pact i n t he f oll o wi n g cate g ories: a d verse e v e nts, 
deat h,  pr ot oc ol  de viati o ns,  misse d  dr u g  a d mi nistrati o n,  treat me nt  a d mi nistrati o n 
m o dificati o ns, misse d or dela ye d t u m or assess me nts, misse d visits, tele -visits re placi n g o n -
site visits, treat me nt disc o nti n uati o n, st u d y disc o nti n uati o n. 
•  N u m ber of s u bjects wit h misse d or d ela ye d t u m or assess me nts, misse d visits, tele -visits 
re placi n g o n-site visits ( 1 / 2 / 3 / > 3) 
T he fre q u e nc y distri b uti o n of partici pa nts w h o starte d t he treat me nt bef ore or d uri n g t h e pa n de mi c 
per c o u ntr y -s pecific start of C O VI D-1 9 st u d y peri o d (see Secti o n 9  f or details o n t he C O VI D-1 9 
cate g orizati o n b y st u d y p eri o d) will be als o dis pla ye d.  
A listi n g of C O VI D -1 9 i m pact will be pr o vi de d wit h t he f oll o wi n g i nf or mati o n: treat me nt ar m, 
partici pa nt  i de ntifier,  first  a n d  last  date  of  treat me nt  a d mi nistrati o n s,  date  of  t he  e ve nt,  visit, 
cate g or y, e ve nt, e ve nt descri pti o n/reas o n.  
1 0. 2  
Pr ot oc ol De vi ati o ns   
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns  
I m p ort a nt  pr ot oc ol  de viati o ns  will  be  deter mi ne d  f or  all  partici pa nts b y  eit her  me dical  re vie w 
pr ocesses,  site  m o nit ori n g  or  pr o gra m mi n g  b as e d  o n  t he  i ncl usi o n/e x cl usi o n  criteria  or  ot her 
criteria prese nte d i n t he pr ot oc ol a n d d oc u me nte d i n S D T M.  
T he  f oll o wi n g  s u m mar y  ta bles  a n d  listi n gs  of  i m p orta nt  pr ot oc ol  de vi ati o ns  wi ll  be  pr o vi de d 
(se paratel y f or pre-/ p ost i ncl usi o n de viati o ns): 
•  Fre q u e nc y ta ble p er reas o n of i m p orta nt pr ot oc ol de viati o ns.  
•  Listi n g of i m p orta nt pr ot oc ol de viati o ns.  
S u m maries will be perf or me d o n t he F A S  
Gl o bal Versi o n I D: 
3 5/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
F urt her c o nsi der ati o ns f or P K  
 
E x a m ples of I P Ds or i m p orta nt e ve nts f or P K i n ter ms of t his st u d y ma y i ncl u de, b ut are n ot li mite d  
t o, t he f oll o wi n g: 
•  D ose dela ye d o utsi de t he all o we d wi n d o w (a n d act ual d osi n g ti me n ot rec or de d)  
•  D ose c ha n ge or misse d d ose  
•  Pre -d ose sa m ple c ollecte d after t he act ual start of i nf usi o n  
•  E n d -of -i nf usi o n sa m ple c ollecte d bef ore t he act ual e n d of i nf usi o n 
•  Sa m ple pr ocessi n g err ors t hat ma y le a d t o i nacc urate bi oa nal ytical r es ults  
F or  t he  a b o ve  I P Ds  or  i m p orta nt  e ve nts  f or  P K,  t he  rel e va nt  P K  dat a  will  be  e x cl u de d  fr o m 
s u m maries base d o n t he P K a nal ysis set.  
Refer t o Secti o n  1 6. 1 f or m ore details of pr ot oc ol de viati o ns a n d ha n dli n g rele va nt t o P K. 
I m p act of C O VI D-1 9 p a n de mic  
P ote ntial i m pact of C O VI D -1 9 pa n d e mic i n M S 2 0 0 6 4 7 -0 0 0 5 will be e val uate d b y a n a nal ysis of 
pr ot oc ol de viati o ns:  
T he listi n g of i m p orta nt pr ot oc ol de viati o ns will be e nric h e d b y t he vari a ble “ C O VI D -1 9 Relate d 
Pr ot oc ol De viati o ns” fla g gi n g all pr ot oc ol de vi ati o ns d ue t o C O VI D -1 9.  
1 0. 2. 2  
Re as o ns  Le a di n g  t o  t he  E xcl usi o n  fr o m  a n 
A n al ys is P o p ul ati o n   
Cli nicall y i m p ort a nt pr ot oc ol de viati o ns w hic h t h at will lea d t o t he e x cl usi o n of a partici p a nt of 
t he P K a nal ysis set will be descri b e d cas e b y cas e at t he ti me of t he P K a nal ysis. 
1 1  
De m o gr a p hics a n d Ot her B aseli ne  C h ar acteristics   
If n ot stat e d ot her wise, s u m maries will be pres e nt e d f or t he F A S b y treat me nt ar m a n d o v erall.  I n 
case of I D M C, de m o gra p hics will be prese nte d usi n g S A F a nal ysis set.  
1 1. 1  
De m o gr a p hics   
De m o gra p hic  c haracteristics  will  be  s u m marize d  usi n g  t he  f oll o wi n g  i nf or mati o n  fr o m  t he 
“ De m o gra p hi cs” eC R F p a ge.  
•  De m o gra p hic c haracteristics  
•  Se x : male, fe male 
•  Race : W hite, Blac k or Africa n A merica n, Asia n, A merica n I n dia n or Alas ka Nati ve, Nati ve 
Ha waiia n or Ot her Pacific Isla n der, N ot c ollecte d at t his site a n d Ot her  
Gl o bal Versi o n I D: 
3 6/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
o  F or  partici pa nts  re p orti n g  se veral  races,  all  c o m bi nati o ns  will  be  re p orte d  u n der 
‘ M ore t ha n o ne race” cat e g or y.  
•  Et h nicit y: His pa nic or Lati n o/ N ot His pa nic or Lati n o ; J a pa nese/ N ot J a pa nese 
•   A ge ( years) : s u m mar y st atistics 
•   A ge cat e g ories:  
•  < 6 5 years, ≥ 6 5  years  
•  6 5 -< 7 5 , 7 5-< 8 5 , ≥8 5  years  
•  P o ole d Re gi o n:  
•  N ort h A merica  
•  E ur o pe  
•  Asia  
•  Rest of t he W orl d  
•  Ge o gra p hic R e gi o n:  
•  N ort h A merica  
•  E ur o pe  
•  Asia  
•  Lati n A merica  
•  A ustralia a n d Ocea ni a  
•  E E A ( E ur o pea n Ec o n o mi c Area)  
•  Yes  
•  N o  
•  P D -L 1 stat us at s cree ni n g  
•  < 1 %  
•  ≥1 %  
S pecificati o ns f or c o m p utati o n  are detaile d i n Secti o n  9 a n d i n Secti o n 1 1. 3. 6  f or P D-L 1 stat us at 
scree ni n g.  
A listi n g of i n di vi d ual de m o gra p hi cs will be als o pr o vi de d  wit h t he f oll o wi n g i nf or mati o n: pla n ne d 
ar m,  s u bject  i de ntifier,  se x,  race  (i ncl u di n g  all  re p orte d  races  i n  case  of  “ m ulti ple”  races,  a n d 
details i n case of “ ot her” race), et h nicit y, ge o gra p hic re gi o n, a ge, a n d a ge cate g or y, b o d y mass 
i n de x, b o d y s urface area, wei g ht a n d hei g ht at Bas eli ne  a n d P D-L 1 stat us at scree ni n g . 
Gl o bal Versi o n I D: 
3 7/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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  
Me dic al Hist or y   
Rele va nt past a n d o n g oi n g me dical c o n diti o ns at Baseli ne  will be s u m mari ze d fr o m t he “ Me dical 
Hist or y  Details”  e C R F  pa ge,  usi n g  t he  latest  a vaila ble  versi o n  of  Me dical  Di cti o nar y  f or 
Re g ulat or y Acti vities ( Me d D R A), P T  as e ve nt cat e g or y a n d Me d D R A s yste m or ga n class ( S O C) 
b o d y ter m as B o d y S yste m cate g or y.  
Me dical  hist or y  will  be  dis pla ye d  i n  ter ms  of  fre q ue nc y  t a bles  b y  tr eat me nt  ar m  a n d  o verall: 
or dere d b y S O C a n d P T i n al p ha betical or der. E ac h partici pa nt will be c o u nte d o nl y o nce wit hi n 
eac h P T or S O C.  
T he relate d listi n g will pr o vi de t he f oll o wi n g i nf or mati o n: pla n ne d ar m, et h nicit y (J a pa nese, N o n -
J a pa nese), partici pa nt i de ntifier, a ge, se x, race, P T , re p ort e d me dical hist or y t er m, start date, e n d 
date, relate d t o st u d y c o n diti o n, o n g oi n g, a n d gra d e. T h is listi n g will be s orte d b y treat me nt ar m, 
s u bject i de ntifier, start date, e n d date, a n d P T.  
1 1. 3  
Ot her B aseli ne  C h ar acteristics   
Ot her Baseli ne  c haracteristics i ncl u de disease hist o r y, E C O G P S (see Secti o n  1 5. 6), vital si g ns, 
a n d s ki n stat us hist or y. E C G a n d l a b orat or y res ults at Baseli ne  will be pres e nte d t o get her wit h t he 
res ults  of  all  ot her assess me nts  perf or m e d  d uri n g  t h e  st u d y  i n Secti o n   1 5. 6 a n d Secti o n   1 5. 3 
res pecti vel y.  
1 1. 3. 1  
Vit al Si g ns at B aseli ne   
T he f oll o wi n g vital si g ns a t Baseli ne  will be c ollecte d fr o m t he “ Vital si g ns” e C R F pa ge a n d will 
be s u m marize d:  
•  Hei g ht ( c m)  
•  Wei g ht at Baseli ne  ( k g) 
•  B MI ( k g/ m
2) 
•  B S A ( m2) 
S pecificati o ns f or c o m p utati o n of B MI a n d B S A are s pecifi e d i n Secti o n  9. 
1 1. 3. 2  
Dise ase Hist or y   
I nf or mati o n  o n  dise ase  c haracteristics  c ollecte d  o n  t he  “ Dis ease  Hist or y”  e C R F  p a ge  will  be 
s u m marize d as f oll o ws b y treat me nt ar m a n d o verall: 
•  T u m or  h ist ol o g y:  a d e n ocarci n o ma,  s q ua m o us  cell  carci n o ma,  lar ge  cell  carci n o ma, 
a de n os q ua m o us  carci n o ma,  sarc o mat oi d  carci n o ma,  ne ur oe n d ocri ne  carci n o ma,  diff use 
i di o patic carci n o ma, ot h er 
•  Ti me si nce i nitial ca ncer dia g n osis ( m o nt hs) c o m p ute d as f oll o ws:  
( date of ra n d o mizati o n –  date of i nitial ca ncer dia g n osis)/ 3 0. 4 3 7 5  
Gl o bal Versi o n I D: 
3 8/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  Ti me si nce d o c u me nte d, l ocall y a d va n ce d  or  i n o p era ble disease dia g n osis ( m o nt hs) c o m p ute d 
as f oll o ws:  
( date  of  ra n d o mizati o n –  date  of  d oc u me nte d,  l ocall y  a d va nce d  or  i n o p era ble  dise ase 
dia g n osis )/ 3 0. 4 3 7 5 
•  T u m or, N o de a n d Metast asis ( T N M ) classificati o n at st u d y e ntr y: eac h T, N, M cate g or y will 
be descri b e d ( T X, T 0, N 1, etc.)  
•  M olec ular a b n or malities:  
o  E pi der mal g r o wt h fact or rece pt or ( E G F R) (n ot d o ne, m utate d, wil d t y p e)  
o  A na plastic  l y m p h o ma  ki nase  (A L K)  tr a nsl oc ati o n  ( n ot  d o ne, yes,  n o,  n ot 
a p plica ble)  
o  R O S 1 rearra n ge me nt ( n ot d o ne, yes, n o, n ot a p plica ble)  
o  B R A F V 6 0 0 E m utati o n ( n ot d o ne, yes, n o, n ot a p plica ble)  
o  Ot her m olec ular a b n or m alities ( n or mal, a b n or mal)  
•  Sta ge at st u d y e ntr y (acc or di n g t o I A S L C sta gi n g ma n ual v 8) 
o  IIIa 
o  III b 
o  IIIc 
•  Has t he s u bject a k n o w n hist or y of o n e or m ore of t he f oll o wi n g ( wit h or wit h o ut t he use of 
cis plati n)?  
o  Re nal i ns ufficie nc y  
o  Car diac i ns uffici e nc y  
o  Se vere na us ea a n d/ or v o miti n g  
o  Heari n g i m pair me nt  
o  N o  
A d e dicate d listi n g will als o be pr o vi de d wit h t he f oll o wi n g i nf or mati o n:  
•  T u m or  hist ol o g y,  d ate  of  i nitial  ca n cer  dia g n osis  a n d  ti me  si nc e  i nitial  ca ncer  dia g n osis 
( m o nt hs),  date  of  d oc u me nte d,  l ocall y  a d v a nce d or  i n o pera ble  dise ase  a n d  ti me  si nce 
d oc u me nte d , l ocall y a d v a nce d or  i n o pera ble dise ase ( m o nt hs), T N M classificati o n at st u d y 
e ntr y, sta ge at st u d y e ntr y a n d k n o w n hist or y of re nal or car diac i ns ufficie nc y, se v ere na us ea, 
heari n g i m pair me nt . 
•  M olec ular  a b n or malit y  (res ult  f or  E G F R  ( n ot  d o ne/ m utate d/ wil d  t y pe),  prese nce  of  A L K 
tra nsl ocati o n  (n ot  d o ne/ yes/ n o / n ot  a p plica bl e),  prese n ce  of  R O S 1  rearra n ge me nt  (n ot 
d o ne/ yes/ n o / n ot  a p plica ble),  prese n ce  of  B R A F  6 0 0 E  m utati o n  rearra n ge me nt  (n ot 
d o ne/ yes/ n o / n ot a p plica ble), ot her m olec ul ar a b n or malities ( n or mal/a b n or mal) . 
Gl o bal Versi o n I D: 
3 9/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T h is listi n g will be s orte d b y pla n ne d treat me nt ar m a n d partici pa nt i de ntifi er, a n d will als o dis pla y 
a ge, se x , a n d race.  
1 1. 3. 3  
S ki n St at us Hist or y   
S ki n stat us hist or y c ollecte d o n t he “ S ki n Stat us Hist or y” e C R F pa ge  will be s u m marize d  b y t he 
fre q ue n c y a n d p erce nta ge of partici p a nts ha vi n g t he f oll o wi n g s ki n stat us hist or y: 
•  Pers o nal hist or y of fre q u e nt s u n b ur n ( yes, n o, u n k n o w n) 
•  Pers o nal hist or y of eas y s u n b ur n ( yes, n o, u n k n o w n)  
•  Pers o nal hist or y of s ki n ca ncer ( yes, n o, u n k n o w n)  
•  Pers o nal hist or y of si g nifica nt e x p os ure t o ultra vi olet li g ht  ( yes, n o, u n k n o w n)  
•  Pers o nal hist or y of p h ot ose nsiti vit y d u e t o s ki n dis or der ( yes, n o, u n k n o w n)  
•  Pers o nal hist or y of p h ot ose nsiti v it y d u e t o me dicati o n ( yes, n o, u n k n o w n)  
•  Fa mil y hist or y of s ki n  ca ncer i n  first  de gree relati ve (i.e. pare nts,  si bli n gs a n d/ or c hil dre n) 
( yes, n o, u n k n o w n)  
•  Partici pa nts ha vi n g hist or y of s ki n c o n diti o ns ( 0, 1, 2, > = 3 c o n diti o ns liste d)  
T his ta ble will us e F A S a n d prese nte d b y tr eat me nt ar m.  
1 1. 3. 4  
Nic oti ne C o ns u m pti o n   
T he nic oti ne c o ns u m pti o n i nf or mati o n will be c ollecte d fr o m t he “ Nic oti ne c o ns u m pti o n” e -C R F 
pa ge a n d it will be descr i be d as f oll o ws: 
•  Nic oti ne use: Ne ver s m o ker, E ver s m o ker (i ncl u di n g f urt her brea k d o w n: f or mer / c urre nt) as 
c ollecte d i n e-C R F  
•  S m o ki n g e x p os ure ( pac k -years): 0, < 2 0, 2 0 -< 4 0, ≥4 0 a n d s u m mar y st atistics  
•  Years si nce q uitti n g: < 5, 5 -< 1 0, ≥1 0 a n d s u m mar y statistics 
•  A listi n g of nic oti ne c o ns u m pti o n, i ncl u di n g treat me nt ar m, p artici pa nt i d e ntifier, a ge, se x, race, 
will  als o  be  pr o d uce d  wit h  t he  f oll o wi n g  data:  nic oti ne  c o ns u m pti o n  c ollecti o n  date  ( da ys),  
nic oti ne use stat us, start/e n d date of nic oti ne c o ns u m pti o n, a n d d urati o n of c o ns u m pti o n ( years).  
1 1. 3. 5  
T u m or Bi o ps y   
I nf or mati o n re gar di n g t u m or bi o ps y c ollecte d o n t he “ T u m or Bi o ps y ( Bl o c k or Sli des)” e C R F p a ge 
will  be  dis pla ye d  o n  a  li sti n g,  i ncl u di n g  t he  f oll o wi n g  i nf or mati o n: pla n ne d treat me nt  ar m, 
partici pa nt i de ntifier,  a ge,  se x,  race,  s peci me n  i de ntifier, visit, bl oc k  or  sli de  a vaila ble, t u m or 
bi o ps y ( bl oc k/sli de) d ate, bl oc k sa m ple t y pe (arc hi val/fres h), bl o c k met h o d t y p e,  a n d n u m ber of 
Gl o bal Versi o n I D: 
4 0/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
sli des c ollecte d. T his listi n g will be s orte d b y pl a n ne d treat me nt ar m, partici pa nt i de ntifier, a n d 
sa m ple c ollecti o n date. 
1 2  
P re vi o us  or C o nc o mit a nt Me dic ati o ns/ Pr oce d ures   
S u m maries will be perf or me d o n t he F A S .  
1 2. 1  
Pre vi o us  A nti -C a ncer  Tre at me nts  f or  N o n -s m all  Cell  L u n g 
C a ncer   
Pre vi o us  a nti -ca n cer  treat me nts  f or  N S C L C  are  c ollecte d  u n d er  t he  “ Pri or  A nti -ca n cer  Dr u g 
T hera pies  f or  N S C L C  Details”,  “ Pri or  A nti -ca ncer  Ra di ot hera p y  f or  N S C L C  Details”,  a n d  t he 
“ Pri or A nti -ca n cer S ur geries f or N S C L C Details” e C R F pa ges.  
Pre vi o us a nti -ca ncer dr u g t hera p y, pre vi o us ra di ot hera p y, a n d pre vi o us a nti -ca ncer s ur ger y will be 
prese nte d i n a listi n g as f oll o ws: 
•  T he pre vi o us a nti-ca ncer  dr u g listi n g will c o ntai n pla n ne d  treat me nt ar m, partici pa nt i de ntifier, 
a ge, se x, race, P T , me dicati o n na me, start date, e n d date, r o ute, i nte nt of t hera p y a n d li ne n u m ber 
i n case of metastatic/l ocall y a d va n ce d, best res p o nse a n d d oc u me nte d pr o gressi o n disease date. 
T his listi n g will be s orte d b y tr eat me nt ar m, s u bj ect i de ntifier, a nti-ca n cer dr u g start date, e n d 
date , a n d P T .  
Gl o bal Versi o n I D: 
4 1/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  T he pre vi o us ra di ot hera p y listi n g will c o ntai n pla n ne d treat me nt ar m, s u bj ect i de ntifier, a ge, 
se x, race, start date, e n d d ate, l ocati o n of ra di ot hera p y, t otal d ose, a n d n u m ber of fracti o ns . T his 
listi n g will be s orte d b y treat me nt ar m, s u bject i de ntifier, ra di ot hera p y start date, ra di ot hera p y 
e n d date, a n d l o cati o n.  
•  T he pre vi o us a nti-ca ncer  s ur ger y listi n g will c o ntai n pla n ne d tr eat me nt ar m, s u bject i de ntifier, 
a ge, se x, race, d ate of s ur ger y, na me a n d l ocati o n of s ur ger y, c urati ve i nte nt of s ur ger y ( yes, 
n o) , a n d o utc o me of s ur ger y. T his listi n g will be s orte d b y treat me nt ar m, su bject  i de ntifier, 
s ur ger y date, na me of s ur ger y, a n d l oc ati o n . 
1 2. 2  
Pre vi o us a n d C o nc o mit a nt M e dic ati o ns   
Pre vi o us me dicati o ns are me dicati o ns, ot her t ha n st u d y i nter ve nti o n a n d pre -m e dicati o ns f or st u d y 
i nter ve nti o n, w hic h starte d pri or t o t he date of t he first d ose of t he first st u d y i nter ve nti o n. In cas e 
t he date val u es will n ot all o w t o u ne q ui v ocall y all ocate a me dicati o n t o pre vi o us me dicati o n, t he 
me dicati o n will be c o nsi dere d as  pre vi o us me dicati o n.  
C o nc o mita nt me dicati o ns are me dicati o ns, ot her t ha n st u d y i nter ve nti o ns a n d pre -me dicati o ns f or 
st u d y i nter ve nti o n, w hic h are ta ke n b y partici pa nts at a n y ti me d uri n g t he  o n -treat me nt peri o d (see 
defi niti o n of o n -tr eat me nt i n Secti o n  9). Me di cati o ns ta ke n o n t h e first d a y of st u d y i nter ve nti o n 
will be c o nsi dere d o n -tr eat me nt. I n case t he date v al ues cle arl y i n dicate t hat t he me dicati o n ca n n ot 
be all ocate d t o pre vi o us me dicati o n a n d d o n ot all o w t o u ne q ui v ocall y all ocate it t o c o nc o mita nt 
m e dicati o n, t he me dicati o n will be c o nsi dere d as c o nc o mita nt me dicati o n.  
S pecific  r ules  will  be  use d  t o  defi ne  if  a  m e dicati o n/ pr oce d ure  is  c o nsi dere d  as  a  pre vi o us, 
c o nc o mita nt or b ot h pre vi o us a n d c o nc o mita nt me dicati o n/ pr oce d ure as det aile d i n A p pe n di x 5 .  
C o nc o mita nt me dicati o ns will be s u m marize d fr o m t he “ C o nc o mita nt Me dicati o n Details” e C R F. 
A nat o mical  T hera pe utic  C he mical  ( A T C) -2 n d le vel  a n d P T  will  be  ta b ulate d acc or di n g  t o  t he 
c urre nt versi o n of t he W H O -D D dicti o na r y. I n cas e m ulti ple A T Cs are assi g ne d t o a dr u g, all A T C-
2 n d le vel will be use d f or re p orti n g.  
A partici pa nt will be c o u nte d o nl y o nce wit hi n a gi ve n dr u g class a n d a gi v e n dr u g na me, e ve n if 
he/s he recei ve d t h e sa me me dicati o n at differe nt ti mes. T he s u m mar y will be s orte d b y Dr u g Class 
a n d preferre d ter m  i n al p ha betical or d er.  
Pre vi o us a n d c o nc o mita nt me dicati o ns will be prese nte d i n listi n g s i n cl u di n g pla n n e d tr eat me nt 
ar m, partici pa nt i de ntifier,  a ge,  se x,  race, preferre d  ter m , me dicati o n  na me  as  pr o vi de d  b y  t he 
I n v esti gat or, start/e n d dat e, d ose, d ose u nits, fre q ue nc y, r o ut e, a n d reas o n f or t he me dicati o n. T hese 
listi n gs will be s orte d b y treat me nt ar m, s u bject i de ntifier, start date, e n d date ( n ote t hat e ntries 
wit h a missi n g e n d dat e will be c o nsi dere d as o n g oi n g a n d will be dis pla ye d after n o n -missi n g d ate 
i n case of sa m e start date), a n d preferre d ter m . 
1 2. 3  
C o nc o mit a nt Pr oce d ures   
All  c o nc o mita nt  pr oce d ures,  w hic h  were u n d erta ke n  a n y  ti me  d uri n g  o n -treat me nt  peri o d  (see 
defi niti o n  of o n -treat me nt i n Secti o n   9),  will  be  s u m marize d  acc or di n g  t o  t he  C R F  pa ge 
“ C o nc o mita nt Pr oce d ures Details” . 
Gl o bal Versi o n I D: 
4 2/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
A n o ver vie w t a ble of c o n c o mita nt pr o ce d ures will be prese nt e d wit h t he f oll o wi n g i nf or m ati o n:  
•  S u bjects wit h at least o ne C o nc o mita nt  Pr oce d ure a n d t y p e of pr o ce d ure  
•  S u bjects wit h c o nc o mita nt pr oce d ures, starti n g pri or t o first d ose of a n y st u d y i nter ve nti o n 
a n d t y p e of pr o ce d ure  
•  S u bjects wit h c o nc o mita nt pr oce d ures, starti n g d uri n g t he o n -treat me nt peri o d a n d t y p e of 
pr oce d ure  
C o nc o mita nt pr oce d ures will be prese nte d i n a listi n g i ncl u di n g pla n ne d tr eat me nt ar m, s u bject 
i de ntifier, a ge, se x, race, na me of pr oce d ure (as pr o vi de d b y t he i n vestigat or  i n case of “ Ot her, 
please  s pecif y” ),  start  date,  e n d  date, o n g oi n g  ( yes,  n o ), i n dicati o n  (as  pr o vi de d  b y  t he 
i n vesti gat or), a n d reas o n f or pr oce d ure. T he listi n g will be s orte d b y treat me nt ar m, partici pa nt 
i de ntifier,  start  date,  e n d  date  ( n ote  t hat e ntries  wit h  a missi n g  e n d  date will  be c o nsi dere d  as 
o n g oi n g a n d will be dis pla ye d after n o n -missi n g date i n case of s a me start date) , a n d pr oce d ure 
na me.  
1 2. 4  
S u bse q ue nt A nti -C a ncer Tre at me nt   
S u bse q ue nt  a nti -ca ncer  treat me nt  is  c ollecte d  u n der  t he  “ A nti -Ca ncer  Treat me nt  After 
Disc o nti n uati o n  Details”,  “ Ra di ot hera p y  After  Disc o nti n uati o n  Details”  a n d  “ S ur ger y  After 
Disc o nti n uati o n Details” e C R F pa ges.  
T he n u m ber of partici pa nts wit h  at least o ne s u bse q ue nt a nti -ca n cer tr eat me nt  or pr oce d ure  ( dr u g 
t hera p y, ra di ot hera p y or s ur ger y), at le ast o ne s u bse q ue nt a nti-ca ncer dr u g t hera p y, at le ast o ne 
s u bse q ue nt  ra di ot hera p y, a n d at  least  o ne  s u bs e q ue nt  s ur ger y  will  be  ta b ulate d. Best  res p o ns e 
acr oss all s u bse q ue nt a nti -ca ncer treat me nts will be i ncl u de d.   
S u bse q ue nt a nti -ca n cer treat me nt ( m e dicati o n, ra di ot hera p y a n d s ur ger y) will be pres e nte d i n  a 
listi n g  i ncl u di n g pla n ne d treat me nt  ar m, partici pa nt i de ntifier,  a ge,  se x,  race,  treat me nt  t y pe, 
preferre d ter m / me dicati o n na me, re gi me n na me (if me dicati o n), best res p o nse (if me dicati o n), start 
date,  e n d  d ate  (if  me dicati o n  or  ra di ot hera p y),  ra di ot hera p y  site/ na me  of  s ur ger y/l ocati o n  (if 
ra di ot hera p y or s ur ger y). T his listi n g will be s orte d b y treat me nt ar m, s u bject i de ntifier, start date, 
e n d date, me dicati o n t y p e, preferre d ter m , a n d m e dicati o n na me.  
1 2. 5  
Pre me dic ati o n   
Pre me dicati o n  are d efi ne d as me dicati o ns a d mi nistere d p er pr ot oc ol o n t he sa me da y as, b ut pri or 
t o, st u d y i nter ve nti o n.  
Pre me dicati o n f or im m u n ot hera p y will be base d o n t he “ Pre me dicati o n I m m u n ot hera p y” e C R F 
pa ge  ( partici pa nts  f or  w h o m  t he  q uesti o n  “ Has  t he  s u bject  r ecei ve d pre me dicati o n  bef ore 
i m m u n ot hera p y  i nf usi o n ? ”  is  a ns were d  “ Y es”  at  t he  c orres p o n di n g  visit).  Pre me dicati o n  f or 
c he m ot hera p y will be base d o n t he “ Pre me di cati o n C he m ot hera p y” e C R F pa ge ( partici pa nts f or 
w h o m t he q uesti o n “ Has t he s u bject recei ve d pr e me dicati o n  bef ore c h e m ot hera p y i nf usi o n? ” is 
a ns were d “ Yes” at t he c orres p o n di n g visit).  
Gl o bal Versi o n I D: 
4 3/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T he  n u m ber  of  partici pa nts  recei vi n g  pre me di cati o n  f or  i m m u n ot hera p y  a n d  t he  n u m ber  of 
partici pa nts  recei vi n g  pre me dicati o n  f or  c he m ot hera p y  will  be  s u m marize d  f or  eac h  treat me nt 
visit. Perce nta ges will be calc ulate d o n t he n u m ber of partici pa nts w h o act ua ll y recei ve d a d ose of 
i m m u n ot hera p y d os e (or a c he m ot hera p y d ose , res pecti vel y) at t he ass ociat e d visit. 
L isti n gs of  pre m e dicati o n  f or  i m m u n ot hera p y  a n d  of  pre me di cati o n  f or  c he m ot hera p y  will  be 
pr o vi de d. T hese listi n gs will i ncl u de pla n ne d treat me nt ar m, partici pa nt i d e ntifier, a ge, s e x, race, 
na me  of  me dicati o n,  visit,  date  of  a d mi nistrati o n  (f or  i m m u n ot hera p y),  start  a n d  e n d  date  (f or 
c he m ot hera p y)  ,  d os e,  u nit, a n d r o ute.  T h ese  listi n gs  will  be  s orte d  b y  tr eat me nt  ar m,  s u bj ect 
i de ntifier, start date/ti me of pre m e dicati o n, e n d dat e/ti me of pre me dicati o n , a n d me dicati o n na me.  
 
1 3  
St u d y i nter ve nti o n C o m pli a nce a n d E x p os ure   
S u m maries will be perf or me d o n t he S A F a n al ysis set b y tr eat me nt ar m.  
Partici pa nts will be treat e d wit h i m m u n ot hera p y ( M 7 8 2 4  f or Ar m 1 a n d Place b o f or Ar m 2) i n 
c o m bi nati o n wit h c o nc o mita nt c he m o -ra di ot hera p y (c C R T), f oll o w e d b y i m m u n ot hera p y ( M 7 8 2 4 
f or Ar m 1 a n d d ur val u ma b f or Ar m 2).  A d mi nistrati o n detai ls of all st u d y i nter ve nti o ns are gi ve n 
i n Secti o n 6 of t he st u d y pr ot oc ol. I n cas e of c h e m ot hera p y s witc h ers, i nf or m ati o n after t heir s witc h 
will n ot be pr o vi de d.  
D urati o n of treat me nt a n d n u m ber of i nf usi o ns  ( or fracti o ns i n case of ra di ot hera p y) s u m maries 
will  be  base d  o n  “I m m u n ot hera p y  A d mi nistrati o n  Details”  a n d “ Ra di ot hera p y  A d mi nistrati o n 
Details” eC R Fs p a ges. F or c he m ot hera p y, eac h c o m p o ne nt has a u ni q ue a d mi nistrati o n e C R F pa ge 
s o  d osi n g  details  will  be  c ollecte d  fr o m:  “ Paclita x el  A d mi nistrati o n  De tails”,  “ Car b o plati n 
A d mi nistrati o n Details”, “ Cis plati n A d mi nistrati o n Details”, “ Et o p osi de A d mi nistrati o n Details” , 
a n d “ Pe metre x e d A d mi nistrati o n Details” e C R F pa ges. D osi n g calc ulati o ns f or c he m ot hera p y a n d 
ra di ot hera p y will als o be base d o n t he c orres p o n d i n g e C R F pa ges me nti o ne d pre vi o usl y w het her 
f or i m m u n ot hera p y, t h e pla n ne d d ose ( pre p are d b y t he u n bli n de d p har macist) will be ca pt ure d i n 
t he dr u g pre p arati o n f or m. 
 
D ur ati o n of  T her a p y  ( Wee ks)  a n d  N u m ber  of  I nf usi o ns/ Fr acti o ns  f or  I m m u n ot her a p y, 
C he m ot her a p y a n d R a di ot her a p y  
A n i nf usi o n is re gar de d as bei n g a d mi nistere d if t h e act ual d ose recei ve d is > 0.  
D urati o n of treat me nt will be calc ulate d, as f oll o ws:  
•  I m m u n ot hera p y: 
D urati o n  of  i m m u n ot hera p y  ( wee ks)  =  ( date  of  last  i m m u n ot hera p y d ose –  dat e  of  first 
i m m u n ot hera p y d os e  + 1 4 )/ 7 
•  Cis plati n ( 5 0 m g/ m 2)/et o p osi de ( 5 0 m g/ m2) re gi m e n: 
Gl o bal Versi o n I D: 
4 4/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
D urati o n of cis plati n ( wee ks) =  (d ate of last cis plati n d ose  –  date of first cis plati n d ose  +  2 1) / 7 
D urati o n of et o p osi de ( wee ks) = ( date of last  et o p osi de  d ose  –  date of first et o p osi de d ose + 2 4)/ 7  
•  Car b o plati n ( A U C 2)/ paclita xel ( 4 5 m g/ m 2) re gi m e n: 
D urati o n of car b o plati n ( wee ks) = ( date of last car b o plati n d ose  –  date of first car b o plati n d ose + 
7)/ 7  
D urati o n of paclita xel ( wee ks) = ( date of last paclita x el d ose  –  date of first  paclita x el  d ose + 7)/ 7  
•  Cis plati n ( 7 5 m g/ m 2) / pe metre x e d ( 5 0 0 m g/ m2) re gi me n: 
D urati o n of cis plati n ( wee ks) = ( date of last cis plati n d ose  –  date of first  cis plati n  d ose + 2 1)/ 7  
D urati o n of pe metre x e d ( wee ks) = ( date of last pe metre x e d  d ose  –  date of first  pe metre x e d  d ose + 
2 1)/ 7  
•  Ra di ot hera p y:  
D urati o n of ra di ot hera p y ( wee ks) = ( date of last  d ose –  date of first ra di ot hera p y d ose + 1) / 7  
I n  cas e  of  c he m ot hera p y t otal re gi me n  calc ulati o ns, t he  date  of  t h e  fir st c o m p o ne nt  t o  be 
a d mi nistere d  a n d  t he date  of  t he  last  d ose  of  t he  last  c o m p one nt  t o  be  a d mi nistere d  will  be 
c o nsi dere d as first a n d last d ose res pecti vel y.  F or t otal d urati o n of t he re gi me n:  
T otal d urati o n of c h e m ot hera p y re gi me n  ( wee ks): ( date of last d ose –  date  of first d ose + c ycle 
le n gt h) / 7 
C o nsi deri n g  as  t he  re gi me n  c ycle  le n gt h  2 8  d a ys  f or  cis plati n/et o p osi de  re gi me n,  7  da ys 
car b o plati n/ paclita xel re gi me n a n d 2 1 da ys f or cis plati n/ pe metre x e d re gi me n.  
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d:  
•  D urati o n of t hera p y ( wee ks) f or eac h tr eat me nt (i m m u n ot hera p y, c he m ot h era p y –  b y re gi me n 
a n d b y c o m p o ne nt  –  a n d ra di ot hera p y)  
•  N u m ber of i nf usi o ns /fracti o ns recei ve d f or eac h tr eat me nt (i m m u n ot hera p y, c he m ot hera p y –  
cis plati n, et o p osi de, pe metre x e d, paclita x el or ca r b o plati n –  a n d ra di ot hera p y)  
C u m ul ati ve D os e, D ose I nte nsit y a n d Rel ati ve D ose I nte nsit y  
I m m u n ot hera p y a n d c he m ot hera p y cal c ulati o ns  a n d  s u m maries  will  be  base d  o n  t he 
“ A d mi nistrati o n Details” e C R F pa ge f or eac h t hera p y. I n cas e of c he m ot h era p y, eac h i n di vi d ual 
c o m p o ne nt a d mi nistrati o n e C R F pa ge will be use d.  
D ue  t o  t he  d o u ble -bli n d  desi g n  of  t he  st u d y,  i n  or der  t o  d eter mi ne  t he  act ual  d ose  of 
i m m u n ot hera p y i nf us e d t o t he partici pa nt , t he f oll o wi n g calc ulati o n will be perf or me d:  
 
Gl o bal Versi o n I D: 
4 5/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Act u al  𝑖𝑚𝑚𝑢𝑛𝑜𝑡ℎ𝑒𝑟𝑎𝑝𝑦 d os e  i nf us e d (m g ) = D os e  pr e p ar e d × V ol u m e  i nf us e d
V ol u m e  pr e p ar e d
 
 
A d diti o nall y, f or car b o pl ati n a d mi nistrati o n, t he pla n ne d d ose is re p orte d as A U C a n d t he act u al 
d ose is re p orte d i n m g, h e nce t he Cal v ert e q uati o n will be use d t o c o n vert t he pla n n e d d ose t o 
m g, i n or der t o calc ul ate R DI:  
 
𝑀𝑎𝑥𝑖𝑚𝑢𝑚 𝐶𝑎𝑟𝑏𝑜𝑝𝑙𝑎𝑡𝑖𝑛 𝐷𝑜𝑠𝑒 (𝑚𝑔) = 𝑇𝑎𝑟𝑔𝑒𝑡 𝐴𝑈𝐶 (m g ∙mi n / m L ) × (Gl o m er ul ar  Filtr ati o n  R at e / mi n +  2 5 ) 
T he Gl o mer ular Filtrati o n Rate ( G F R ) val ue will be ca p p e d at 1 2 5 ml/ mi n f or use i n t he 
car b o plati n pla n ne d d os e f or m ula, f oll o wi n g t h e C oc kr oft -G a ult  e q uati o n:  
 
𝐸𝑠𝑡𝑖𝑚𝑎𝑡𝑒𝑑 𝐺𝐹𝑅 = (1 4 0  − 𝑎𝑔𝑒 (𝑦𝑒𝑎𝑟𝑠)) ∗ 𝑤𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔) ∗ (0 .8 5  𝑓𝑜𝑟 𝑓𝑒𝑚𝑎𝑙𝑒𝑠 𝑜𝑛𝑙𝑦) 
(7 2  ∗ 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒(𝑚𝑔/ 𝑑𝐿))
  
 
I n case of missi n g a ge, wei g ht or creati ni ne val ues at a gi ve n visit, t he val ue fr o m t he pre vi o us 
visit will be use d.  
Act ual d ose of c he m ot hera p y will be cal c ulate d c o nsi deri n g B S A  at e ac h visit : 
 
𝐴𝑐𝑡𝑢𝑎𝑙 𝑐ℎ𝑒𝑚𝑜𝑡ℎ𝑒𝑟𝑎𝑝𝑦 𝑑𝑜𝑠𝑒 𝑖𝑛𝑓𝑢𝑠𝑒𝑑 (𝑚𝑔/ 𝑚2 ) = 𝐴𝑐𝑡𝑢𝑎𝑙 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝐵𝑆𝐴 (𝑚2 )
 
 
•  C u m ulati ve d ose:  
T he c u m ulati ve d ose of i m m u n ot hera p y  a n d c h e m ot hera p y per partici pa nt i n a ti me peri o d will 
be t he s u m of t he act ual d ose le vels t hat t he partici pa nt recei v e d wit hi n t hat peri o d (i.e. t otal d ose 
a d mi nistere d [m g  –  f or i m m u n ot hera p y; m g/ m 2 - for c he m ot hera p y ]).  
Se parate c u m ulati ve d oses b y i m m u n ot hera p y dr u g will be dis pla ye d i n u n bli n de d deli veries 
( place b o, d ur val u ma b, bi ntrafus p alf a).  
F or ra di ot hera p y, t otal d ose ( G y) as c ollecte d i n t h e e C R F will be dis pla ye d.   
•  D ose I nte nsit y:  
D ose i nte nsit y ( DI) of i m m u n ot hera p y  ( m g/c ycl e) a n d c he m ot hera p y ( m g/m 2/c ycle) p er p artici pa nt 
i n a ti me peri o d will be defi ne d as: 
 
Gl o bal Versi o n I D: 
4 6/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
D os e  I nt e nsit y (𝑖𝑚𝑚𝑢𝑛) =
C u m ul ati v e  D os e  (𝑜𝑡𝑒𝑟)
𝑎𝑝𝑦𝑀𝑎𝑥𝑖𝑚 𝑢𝑚 𝐶𝑎𝑟𝑏𝑜𝑝𝑙𝑎𝑡 (𝑖𝑛𝐷𝑜𝑠)
𝑒𝑚𝑔𝑇𝑎 𝑟𝑔𝑒𝑡𝐴ℎ (𝑈𝐶𝐸𝑠𝑡)
 
 
Se parate DI b y i m m u n ot hera p y dr u g will be dis pla ye d i n u n bli n de d deli veries ( place b o, 
d ur val u ma b, bi ntraf us p alfa).  
DI f or eac h i n di vi d ual c he m ot hera p y c o m p o ne nt (cis plati n, et o p osi de, car b o plati n, pe metre x e d , 
a n d paclita x el) will be calc ulate d acc or di n g t o t heir c he m ot hera p y re gi me n a d mi nistrati o n sc he me . 
DI will n ot be calc ulat e d f or ra di ot hera p y.  
As c ycl e le n gt h differs bet wee n st u d y i nter ve nti o ns (i m m u n ot hera p y a n d c he m ot hera p y), Err o r! R
efere nce s o urce n ot f o u n d.  s pecifies w hic h val ue s h o ul d be use d i n eac h case. 
T a ble 4   C ycle  Le n gt h  S pecific ati o ns   
St u d y 
i nt er v e nti o n 
R e gi m e n ( c h e m ot h er a p y c o m p o n e nt s)  
C y cl e l e n gt h  
N u m b er of pl a n n e d 
d o s e s p er c y cl e  
I m m u n ot h er a p y 
N ot A p pl i c a bl e 
2 w e e k s  
1 d o s e  
C h e m ot h er a p y  
Ci s pl ati n ( 5 0 m g/ m 2 ) / et o p o si d e ( 5 0 m g/ m2 ) 
4 w e e k s  
Ci s pl ati n: 2  d o s e s  
Et o p o si d e: 5  d o s e s  
C ar b o pl ati n ( A U C 2) / p a clit a x el ( 4 5 m g/ m 2 ) 
1 w e e k  
1 d o s e  
Ci s pl ati n ( 7 5 m g/ m 2 ) / p e m etr e x e d ( 5 0 0 m g/ m2 ) 
3 w e e k s  
1 d o s e  
A U C = Ar e a U n d er t h e C ur v e  
 
•  Relati ve D ose I nte nsit y:  
T he Relati ve D ose I nt e nsit y ( R DI) f or i m m u n ot hera p y  a n d c he m ot hera p y will be defi ne d as t he 
act ual DI  di vi de d b y t he pla n ne d d ose per wee k a n d e x presse d as a perce nta ge:  
R el ati v e  D os e  I nt e nsit y (% ) = D os e  I nt e nsit y 𝑖𝑚𝑎 𝑡𝑒𝑑𝐺𝐹
Pl a n n e d  d os e  p er  𝑅𝑎𝑔𝑒𝑦× 1 0 0  
Pla n ne d d ose p er c ycle  ( m g –  f or i m m u n ot hera p y; m g/ m2 - f or c h e m ot hera p y), will be d eter mi ne d 
as f oll o ws:  
Pl a n n e d  d os e  p er  𝑒𝑎𝑟𝑠𝑤 (𝑒𝑖𝑔𝑡𝑘) = 𝑔𝑓𝑜 𝑟𝑓 𝑒𝑚𝑎𝑙𝑒𝑠𝑜 𝑛𝑙𝑦𝑐𝑟 𝑒𝑎 1  𝑡𝑖𝑛𝑖𝑛 
 
F or car b o plati n a n d d ur v al u ma b, t he d ose a d mi nistere d at w ee k 1 da y 1 will be use d as pla n ne d 
d ose.  
Se parate R DI b y i m m u n ot hera p y dr u g will be dis pla ye d i n u n bli n de d deli veries ( place b o, 
d ur val u ma b, bi ntraf us p alfa).  
Gl o bal Versi o n I D: 
4 7/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
R DI f or eac h i n di vi d ual c he m o t hera p y c o m p o ne nt (cis plati n, et o p osi de, car b o plati n, pe metre x e d, 
a n d paclita x el) will be calc ulate d acc or di n g t o t heir c he m ot hera p y re gi me n a d mi nistrati o n sc he me.  
R DI will n ot be calc ulate d f or ra di ot hera p y.  
A s u m mar y t a ble will b e pr o vi de d f or i m m u n ot her a p y a n d c h e m ot hera p y (cis plati n, car b o pl ati n, 
pe metre x e d, et o p osi de , a n d paclita xel) dis pla yi n g: C u m ulati ve d ose, D I, a n d R DI . Ra di ot hera p y 
t otal d ose will be als o s u m marize d. 
A listi n g of treat me nt c o m plia nce  a n d e x p os ure will i ncl u de treat me nt ar m, partici pa nt i de ntifier, 
a ge, se x, race , ra di ot hera p y start  a n d st o p  date, ra di ot hera p y d ose, visit,  i nf usi o n start  date a n d 
ti me, i nf usi o n e n d date a n d ti me, t y pe of st u d y i nter ve nti o n, if a d mi nistrati o n was c o m plete d ( yes, 
n o) ,  if  a d mi nistrati o n  was  m o difie d  ( yes,  n o),  m o dificati o n  descri pti o n  a n d  reas o n  f or 
m o dificati o n,  act ual  d os e  i nf use d. T his  listi n g  will  be  s orte d  b y  treat me nt  ar m, partici pa nt 
i de ntifier, i nf usi o n start d ate, a n d i nf usi o n e n d d ate.  
A n a d diti o nal listi n g of tr eat me nt e x p os ure will i n c l u de treat me nt ar m, partici pa nt i de ntifier, a ge, 
se x, race, d urati o n of t hera p y ( wee ks), t otal n u m ber of i nf usi o ns /fracti o ns recei ve d, c u m ulati v e 
d ose of t hera p y, DI , a n d R DI  ( %).  T his listi n g will be s orte d b y tr eat m e nt ar m a n d partici pa nt 
i de ntifier.  
 
T her a p y D el a ys  
Dela ys of t hera p y will be defi ne d b y i nf usi o n as f oll o ws:  
•  F or i m m u n ot hera p y a d mi nistrati o ns as t he n u m ber  of da ys si nce last i nf usi o n –  1 4  
•  F or c h e m ot hera p y a d mi nistrati o ns:  
•  If t he partici p a n t is recei vi n g cis plati n ( 5 0 m g/ m2) / et o p osi de ( 5 0 m g/ m 2) re gi me n: 
o  Dela ys of t hera p y f or cis plati n will be deri ve d b y i nf usi o n as t he n u m ber of d a ys 
si nce t he start of last i nf usi o n – 7 if t he last i nf usi o n was t he first i nf usi o n wit hi n 
a c ycle, ot h er wise as t he n u m ber of da ys si nce t he start of last i nf us i o n –  2 1 . 
o  Dela ys of t hera p y f or et o p osi de will be deri ve d b y i nf usi o n f or c ycl e da y 1 as 
t he n u m ber of d a ys si n ce start of last i nf usi o n -2 4, f or da y 2,  3,  4 a n d 5 wit hi n 
a c ycle as t he n u m ber of da ys si nce last i nf usi o n -1.  
•  If t he partici p a nt is recei vi n g c ar b o plati n ( A U C 2) / p aclita x el ( 4 5 m g/ m 2) re gi me n: 
o  Dela y i n car b o plati n as t he n u m ber of da ys si nce last i nf usi o n –  7.  
o  Dela y i n paclita xel as t he n u m ber  of da ys si nce last i nf usi o n –  7.  
•  If t he p artici pa nt is recei vi n g cis plati n ( 7 5 m g/ m2) / p e metre x e d ( 5 0 0 m g/ m 2) re gi me n: 
o  Dela y i n cis plati n as t he n u m ber  of da ys si nce last i nf usi o n –  2 1.  
o  Dela y i n pe metr e x e d as t he n u m ber  of da ys si nce last i nf usi o n –  2 1.  
Dela y o n ra di ot hera p y a d mi nistrati o n will n ot be pr o vi de d.  
Gl o bal Versi o n I D: 
4 8/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
If t he val ue a b o ve is > 0 da ys, t his will be classe d as a del a y. A partici p a nt ma y ha v e m or e t ha n 
o ne treat me nt del a y t hr o u g h o ut t he c o urse of treat me nt.  
T he f oll o wi n g will be s u m marize d i n a ta ble:  
•  N u m ber of s u bjects wit h at least o ne dela ye d i nf usi o n  
•  N u m ber of s u bjects wit h dela ys ( 1 -2 da ys, 3 -8  da ys, 9 -1 5 da ys, ≥ 1 6 da ys)  
•  N u m ber of del a ys per s u bject ( 1 dela y, 2 d ela ys, 3 dela ys, ≥ 4 d ela ys).  
A s u m mar y ta ble will be pr o vi de d dis pla yi n g  f or i m m u n ot hera p y a n d c h e m ot hera p y (cis plati n, 
car b o plati n, pe metre x e d, paclita xel, et o p osi de) . 
D ose Re d ucti o ns  
C he m ot hera p y d ose re d u cti o ns as rec or de d o n t h e “ Cis plati n A d mi nistrati o n Details”, Et o p osi de 
A d mi nistrati o n  Details”,  “ Car b o plati n  A d mi nistrati o n  Details”,  “ Paclita x el  A d mi nistrati o n 
Details” a n d “ Pe metre x e d A d mi nistrati o n Details” pa ges of t he e C R F (i.e . a ns wer t o t he q uesti o n 
“Is  t here  a  c ha n ge  i n  d ose? ”  =  “ D ose  a dj uste d”)  will  be  use d  f or  a nal ysis. T he  n u m ber  of 
partici pa nts wit h at least o ne d ose re d ucti o n, reas o ns f or d ose re d u cti o n, as well as a cat e g orizati o n 
of t he n u m ber of i nf usi o n s wit h d ose re d uce d ( 1 / 2 / ≥ 3) will be s u m marize d.  
S u m mar y  ta bles  will  be  pr o vi de d  f or  eac h  c h e m ot hera p y  (cis plati n,  et o p osi de,  car b o plati n, 
paclita xel , a n d pe metre x e d). N o d ose re d ucti o n is all o we d f or i m m u n ot hera p y or ra di ot hera p y . 
Tre at me nt T e m p or ar y I nterr u pti o n  
Te m p orar y  i nterr u pti o ns  t o  i m m u n ot hera p y a n d  c he m ot hera p y i nf usi o n  as  rec or de d  o n  t h e 
“ Treat me nt A d mi nistrati o n D etails” pa ge s of t he e C R F will be use d f or a n al ysis. T he n u m ber of 
s u bjects wit h at least o ne i nf usi o n i nterr u pti o n, reas o n f or te m p orar y i nf usi o n i nterr u pti o ns, as well 
as  a  cat e g orizati o n  of  t he  n u m ber  of st u d y  i nter ve nti o n i nterr u pti o ns  ( 1  /  2  /  ≥ 3)  will  be 
s u m marize d. 
C he m ot her a p y S witc h  
A  listi n g  of partici pa nts  w h o  ha d  a c he m ot hera p y  s witc h  will  be  pr o vi de d  base d  o n t h e 
“ C he m ot hera p y S witc h” e C R F pa ge  a n d it will i n cl u de: treat me nt ar m, partici pa nt i de ntifier, a ge, 
se x, race, i nitial c he m ot hera p y re gi me n, ne w c he m ot hera p y re gi me n, reas o n f or s witc h.  
1 3. 1  
R a di ot her a p y Pl a n C o m pli a nce   
C o m plia nce or n o n -c o m plia nce wit h t he ra di ot hera p y pla n will be cate g oriz e d as f oll o ws:  
•  P artici p a nts  wit h  c o m pli a nt  pl a ns :  are t h ose ra di ot hera p y  pla ns wit h  a  fi nal  sc ore  of 
‘ Pass”. T his will i ncl u de pla ns t hat ha ve n o variati o ns fr o m t he R T g ui deli nes (ie, w hic h 
pass  t he  i nitial  Certifie d  Me dical  D osi metrist  ( C M D)  case  re vie w) a n d  t h ose  t hat  ha ve 
acce pta ble variati o ns fr o m g ui deli nes bas e d o n t he deter mi nati o n of t he Me dical D oct or 
( M D) re vi e wer. 
Gl o bal Versi o n I D: 
4 9/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  P artici p a nts wit h n o n -c o m pli a nt  pl a ns : are t h ose ra di ot hera p y pla ns wit h a fi nal sc ore of 
“ Fail”.  All of t hese pla ns will ha ve bee n escalate d f or M D re vie w a n d sc ore d as a ‘ Fail” 
d ue t o u nacce pta ble variati o ns fr o m g ui deli nes.  
A  s u m mar y  ta ble  dis pla yi n g  t he  pr o p orti o n  of  partici pa nts  wit h  c o m plia nt  a n d  n o n-c o m plia nt 
ra di ot hera p y pl a ns per treat me nt ar m will be pr o vi de d.  
 
1 4  
Effic ac y A n al yses   
T he pri mar y e n d p oi nt of t his st u d y is base d o n P F S acc or di n g t o R E CI S T 1. 1 crit eria assesse d b y 
i n vesti gat or. E vi de nce of efficac y (st u d y s uccess) is e ntitle d w he n t he stratifie d l o g ra n k test is 
si g nifica nt at t he pri mar y a nal ysis (w he n 7 0 P F S e ve nts  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  are reac he d ).  
T he  h y p ot h es is re gar di n g t he pri mar y P F S e n d p oi nt is: 
𝑖0
𝑚𝑚𝑢:𝑛𝑜
𝑡𝑒𝑟(𝑎) = 𝑝𝑦𝑀
𝑎𝑥𝑖(𝑚),𝑢≥1  vers us  𝑚1
𝐶𝑎𝑟: 𝑏𝑜
𝑝𝑙𝑎(𝑡) = 𝑖𝑛𝐷
𝑜𝑠𝑒(𝑚),𝑔< 1 ;  αP F S  =  2. 5 % 
o ne -si de d;  where 𝑇𝑎𝑟𝑔(𝑒) re prese nts  t he  hazar d  at  ti me  (t)  a n d  θ  t he  u n k n o w n  c o nsta nt  of 
pr o p orti o nalit y of hazar ds i n t he treat me nt gr o u ps M ( Ar m 1) a n d D ( Ar m 2).  
Efficac y a nal ysis will be perf or me d usi n g t he F A S . 
1 4. 1  
Pr o gressi o n -F ree S ur vi v al   
1 4. 1. 1  
Pri m ar y  O bjecti ve:  P F S 
A cc or di n g  t o 
R E CI S T 1. 1 A ssesse d b y i n vesti g at or  
T he P F S  ti me is defi ne d as t he ti me fr o m ra n d o mizati o n t o t he date of t he first d oc u me ntati o n of 
o bjecti ve  Pr o gressi ve  Disease  ( P D)  as  assess e d  b y  t he i n vesti gat or acc or di n g  t o  R E CI S T  1. 1 
criteria or d eat h  d ue t o  a n y  ca use, w hi c he ver occ urs first.  Deat h  will be  c o nsi d ere d as  e ve nt  if 
re p orte d wit hi n: 
•  1 6 wee ks ( 1 1 2 da ys) after t he l ast t u m or assess me nt wit h o ut pr o gressi o n or t he ra n d o mizati o n 
( w hic he ver occ urs later) –  d uri n g t he first 2 4 m o nt hs of f oll o w -u p  
•   2 4 wee ks ( 1 6 8 da ys) after t he last t u m or assess me nt wit h o ut pr o gressi o n or t he ra n d o mizati o n 
( w hic he ver occ urs later) - after 2 4 m o nt hs of f oll o w -u p.  
P F S ti me i n m o nt hs will be c o m p ute d as f oll o ws:  
P F S  =  ( date  of  P D  or  d eat h/ce ns ori n g –  d ate  of  ra n d o mizati o n  +  1)  /  3 0. 4 3 7 5  ( m o nt hs) T h e 
f oll o wi n g ce ns ori n g r ules, s um marize d i n Ta ble 5 , will be a p plie d f or t he P F S c o m p utati o n: 
•  Partici pa nts  wit h neit her assess me nt of t u m or pr o gressi o n, n or deat h dat e wit hi n  t w o sc he d ule d 
t u m or  assess me nts  i nter vals  after  last  t u m or  assess me nt or  date  of ra n d o mizati o n will  be 
Gl o bal Versi o n I D: 
5 0/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
ce ns ore d o n t he date of t he last t u m or assess me nt or at t he ra n d o mizati o n date , w h ic he v er is 
later. F or t w o sc he d ule d t u m or assess me nts i nter vals it is mea nt:  
•  d uri n g t he first 2 4 m o nt hs fr o m ra n d o mizati o n, 1 6 wee ks   
•  after t he first 2 4 m o nt hs fr o m ra n d o mizati o n, 2 4 wee ks   
•  Partici pa nts  wit h  a n  e v e nt  after  t w o  sc he d ule d  t u m or  assess me nt  i nter vals  after  t he  last 
e val ua ble  res p o nse  assess me nt will  be  ce ns or e d  at  t he  dat e  of  t he  last  e val ua ble  res p o nse 
assess me nt or at t he ra n d o mizati o n date, w hic he v er c o m es later.  F or e v e nt after t w o sc he d ul e d 
t u m or assess me nt i nter vals it is mea nt: 
•  d uri n g t he first 2 4 m o nt hs  fr o m ra n d o mizati o n, e ve nt after 1 6 wee ks wit h o ut assess me nts 
•  after t he first 2 4 m o nt hs fr o m ra n d o mizati o n, e ve nt after 24 w ee ks wit h o ut assess me nts  
•  Partici pa nts w h o start ne w a nti -ca ncer treat me nt pri or t o a n e ve nt will be ce ns ore d o n t he date 
of t he last e val ua ble assess me nt bef ore a nti -ca ncer t hera p y is gi ve n or at t he ra n d o mizati o n date , 
w hic he ver  c o mes later.  
N ote t hat  i n t his st u d y, palliati ve b o ne ra di ot hera p y ca n be gi ve n w hile t he patie nt is still 
recei vi n g t he st u d y dr u g (as per pr ot oc ol, see s ecti o n treat me nt be y o n d pr o gressi o n) b ut 
disease pr o gressi o n m ust ha ve bee n d oc u me nte d a n d t he partici pa nt will n ot be ce ns ore d.  
•  Partici pa nts wit h  n o n -e v al ua ble Baseli ne  assess me nt  or  wit h  all  p ost -Baseli ne  ass ess me nts 
state d as n o n-e v al ua ble will be ce ns ore d at t h e ra n d o mizati o n date  u nless deat h oc c urre d o n or 
bef ore t he ti me of t h e sec o n d pla n ne d t u m or ass ess me nt  (i.e.1 6 we e ks), i n w hic h case t he deat h 
will be c o nsi dere d a n e ve nt . 
T a ble 5  Defi niti o n of d ate of P F S e v e nt/ce ns ori n g   
St at u s  
C e n s ori n g  
D at e of e v e nt / c e n s ori n g  
Pr o gr e s s e d 
or di e d  
Wit hi n t w o s u b s e q u e nt s c h e d ul e d t u m or 
a s s e s s m e nt s aft er l a st e v al u a bl e 
r e s p o n s e a s s e s s m e nt of C R, P R, S D , or 
r a n d o mi z ati o n 
E v e nt  
Mi ni m u m ( d at e of P D, d at e of d e at h)  
Ot h er wi s e  
C e n s or e d  
D at e of l a st e v al u a bl e a s s e s s m e nt wit h 
o ut c o m e C R, P R , S D , or d at e of 
r a n d o mi z ati o n, w hi c he v er i s l at er  
N eit h er pr o gr e s s e d n or di e d  
C e n s or e d  
D at e of l a st e v al u a bl e a s s e s s m e nt 
b ef or e t h e st art of a n e w a nti -c a n c er -
tr e at m e nt or d at e of r a n d o mi z ati o n, 
w h i c he v er i s l at er  
B a s eli n e  or all p o st -B a s eli n e  a s s e s s m e nt s n o n -
e v al u a bl e  
C e n s or e d  
R a n d o mi z ati o n d at e  
C R = C o m pl et e r e s p o n s e, 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, P D = Pr o gr e s si v e di s e a s e  
T he last t u m or assess me nt date is defi ne d as t he last a vaila ble a n d e v al ua ble t u m or assess me nt 
perf or me d pri or t o t he c ut-off  date or pri or t o s u bse q ue nt a nti -ca ncer t hera p y. If n o e val ua bl e t u m or 
assess me nt date is a vaila ble, t his date will be re pl ace d b y t he ra n d o mizati o n date.  
Pri m ar y A n al ysis  
Gl o bal Versi o n I D: 
5 1/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T he pri mar y a nal ysis ( P A), will be c o n d ucte d w he n at least 7 0  P F S e ve nts 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 ha ve b ee n reac he d.  It will f oc us o n 
e val uati n g t he differe nces bet wee n Ar m 1 (c C R T + M 7 8 2 4 f oll o we d b y M 7 8 2 4) a n d Ar m 2 (c C R T 
+ p lace b o f oll o we d b y d ur val u ma b) i n ter ms of P F S.  
K a pl a n -Meier A n al ysis  
Ka pla n -Mei er esti mates ( pr o d uct -li mit esti mates) will be prese nte d b y treat me nt ar m t o get h er wit h 
a s u m mar y of ass ociate d statistics ( P F S rates at 6, 9, 1 2, 1 8, 2 4 , 3 6 , 4 8, a n d 6 0  m o nt hs) i ncl u di n g 
t he c orres p o n di n g t w o-si de d 9 5 % CIs .  
T he CIs  f or t he me dia n will be calc ulat e d acc or di n g t o Br o o k me yer a n d Cr o wle y ( 1 9 8 2 ) a n d CIs  
f or t he s ur vi val f u ncti o n esti mates at t he ti me p oi nts defi ne d a b o ve will be deri ve d usi n g t he l o g -
l o g  tr a nsf or mati o n  acc or di n g  t o Kal bfleisc h  a n d  Pre ntice  ( 1 9 8 0)  ( C O N F T Y P E =l o gl o g  d efa ult 
o pti o n  i n  S A S  Pr oc  LI F E T E S T).  T he  esti mate  of  t he  sta n dar d  err or  will  be  c o m p ute d  usi n g 
Gree n w o o d's f or m ula.  A Ka pla n -Mei er pl ot will als o be dis pla ye d . 
Fre q u e nc y  ( n u m ber  a n d  perce nta ge)  of  partici p a nts  wit h  eac h  e ve nt  t y pe  ( P D  or  d eat h)  a n d 
ce ns ori n g reas o ns will be prese nte d b y tr eat me nt ar m. Ce ns ori n g reas o ns are as f oll o ws:  
•  O n g oi n g i n t he st u d y wit h o ut a n e ve nt  
•  N o Bas eli ne  assess me nt  
•  N o e val ua ble p ost -Bas eli ne  assess me nt  
•  Start of ne w a nti-ca ncer  t hera p y bef ore a n d e v e nt  
•  E ve nt  a fter t w o sc he d ule d  t u m or  assess me nt  i nter vals  after  t he  last  e val ua ble  res p o ns e 
assess me nt  
•  Wit h dra wal of c o nse nt  
•  L ost t o f oll o w -u p :  
L ost t o f oll o w -u p will i ncl u de t he f oll o wi n g parti ci pa nts:  
•  L ost t o f oll o w -u p stat us will be c ollect e d o n t he e C R F treat me nt ter mi nati o n pa ge or e C R F 
st u d y ter mi nati o n pa ge or e n d of ass ess me nt visit pa ge pri or t o t he a nal ysis c ut-off .  
•  Partici pa nts wit h t he last date k n o w n t o be ali ve > 1 4  wee ks pri or t o t he a nal ysis c ut-off  
date ( s ur vi val f oll o w-u p will ta ke place e v er y 1 2 wee ks ± 2 wee ks)  
A  listi n g  of  P F S  acc or di n g  t o  R E CI S T  1. 1  assesse d  b y i n v esti gat or will  be  pr o vi de d  wit h  t he 
f oll o wi n g  i nf or mati o n:  pla n ne d  treat me nt  ar m,  s u bject  i de ntifier,  a ge,  se x,  race,  date  of 
ra n d o mizati o n,  date  of  last  t u m or  assess me nt,  ce ns ore d  ( yes/ n o),  dat e  of  e ve nt/ce ns ori n g, 
e ve nt/ce ns ori n g reas o n, a n d ti me t o e ve nt. T h is listi n g will be s orte d b y pla n ne d treat me nt ar m a n d 
s u bject I D. 
C o x’s R e gressi o n M o del  
T he C o x’s re gressi o n m o del will be a p plie d i n a d diti o n t o t he Ka pla n -M eier met h o d i n or der t o 
c o m pare t he P F S ti me bet wee n t he ra n d o mizati o n gr o u ps ( Ar m 1 vs Ar m 2).  
Gl o bal Versi o n I D: 
5 2/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Stratifie d a nal yses will us e t he str atificati o n fact or s: 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 % vs ≥ 1 %). P D -L 1 e x pressi o n will be d eter mi ne d retr os pecti vel y d uri n g t h e 
safet y  r u n-i n  a n d pr os pecti vel y  d uri n g t he e x pa nsi o n  p hase  b y  t he  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) ass a y i n ce ntr al la b orat ories. 
T he  treat me nt  effect  will  be  esti mate d  usi n g  a  C o x’s  Pr o p orti o nal  Hazar d  m o del  str atifie d  b y 
P D -L 1  e x pressi o n  stat us  a n d  c he m ot hera p y  re gi me n  t o  calc ulate  t he  hazar d  rati o  ( H R). Eac h 
strat u m will defi ne a se parate Baseli ne  hazar d f u ncti o n ( usi n g t he ' S T R A T A' state me nt i n S A S 
P R O C  P H R E G),  i.e.  f or  t he  i -t h  strat u m, t he  h azar d  f u ncti o n  is  e x press e d  as:  h(i;t)  =  h(i, 0;t) 
e x p( β X), w here h(i, 0;t) defi nes t he Bas eli ne  hazar d f u ncti o n f or t he i -t h strat u m a n d x defi nes t he 
treat ment gr o u p ( 0 = Ar m  2, 1 = Ar m 1) a n d b eta is t he u n k n o w n re gressi o n p ara meter.  
Ties will be ha n dle d b y re placi n g t he pr o p orti o nal hazar ds m o del b y t he discrete l o gistic m o del. 
Wit h t his ties o pti o n , t he Sc ore test i n t he C o x’s pr o p orti o nal hazar ds m o del is i de ntical t o t h e 
l o g-ra n k test.  
F or t he P A, a ta bl e  i ncl u di n g  t he  Ka pla n-Meier  esti mates  a n d  t he  C o x’s  pr o p orti o nal  hazar ds 
m o del res ults will be pr o vi de d, t o get h er wit h a K a pla n -Meier pl ot.  
1 4. 1. 2  
Se nsiti vit y A n al yses f or P F S  
T o assess t he r o b ust ness of t he P A , t he f oll o wi n g se nsiti vit y a nal yses will be c o n d ucte d: 
•  P F S  acc or di n g  t o  R E CI S T  1. 1  as assesse d b y i n vesti gat or c o nsi deri n g  all  deat hs  as  e ve nts 
wit h o ut a p pl yi n g t he ce ns ori n g r ul e f or d eat h. 
•  P F S  acc or di n g  t o  R E CI S T  1. 1  as assesse d b y i n vesti gat or c o nsi deri n g  all  P D  a n d  deat hs  as 
e ve nts wit h o ut a p pl yi n g t he ce ns ori n g r ules f or P D or deat h.  
•  P F S  acc or di n g  t o R E CI S T  1. 1  as assesse d b y i n vesti gat or c o nsi d eri n g  t he  i nitiati o n  of  a n y 
s u bse q ue nt a nti-ca n cer  t hera pies as P D i nstea d of ce ns ori n g. 
•  U nstratifie d P F S acc or di n g t o  R E CI S T 1. 1  as assesse d b y i n v esti gat or , c o nsi deri n g deat h a n d 
P D as P F S e ve nt re gar dl ess of t he start of a ne w a nti -ca ncer t hera p y a n d i g n ori n g t he n u m ber 
of missi n g e val ua bl e t u m or assess me nts bef ore pr o gressi o n or deat h.  
•  I n case 1 0 % or m ore p artici pa nts s witc h c he m ot hera p y, t he a nal ysis f or P F S  will be re peate d 
usi n g P D -L 1 e x pressi o n a n d t he c he m ot hera p y re gi me n t hat was gi ve n m ostl y f or stratificati o n. 
M ulti v ari a ble C o x R e gressi o n  
M ulti varia ble C o x re gressi o n a nal ysis will be carrie d o ut t o assess a n d a dj ust t he treat me nt effect 
f or  rele va nt Baseli ne  fact ors  of  p ote ntial  pr o g n ostic  i m pact.  T he  s u b gr o u p  varia bles  defi ne d  i n 
Secti o n  8. 2 “Defi niti o n of A nal ysis Sets a n d S u b gr o u ps ” will be i ncl u de d i n t he m o del.  A ste p wise 
selecti o n  pr oce d ure  will  ser ve  t o  i de ntif y  e x pla nat or y  varia bles  of  p ote ntial  pr o g n ostic  val ues 
a d diti o nal t o t he ra n d o mizati o n strata , w hic h will be i ncl u de d i n all m o dels d uri n g t he sel ecti o n 
pr oce d ur e.  The  ste p wise  selecti o n  met h o d  i n  S A S  ( P R O C  P H R E G)  will  be  use d.  T he  le vel  of 
si g nifica n ce f or a n e x pla nat or y varia ble t o e nter t he m o del is set t o 0. 1 5 ( b o u n dar y f or p -v al ue of 
Sc ore test f or i n cl usi o n ) a n d t he si g nifi ca nce le vel f or re m o vi n g it is set t o 0. 4 0 (b o u n dar y f or p -
val ue of Wal d test f or e x cl usi o n ). O nce t he s electi o n pr oce d ure is fi nalize d, t he treat me nt gr o u p 
Gl o bal Versi o n I D: 
5 3/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
will  be  a d de d  t o  t he  effect  of  tr eat me nt  o n  P F S w he n  a dj uste d  f or  t h e  selecte d  e x pla nat or y 
varia bles.  
T he C o x's Pr o p orti o nal Hazar d m o del is defi ne d as: h(t) = h( 0;t) e x p( X b), w here h( 0;t) defi nes t h e 
Baseli ne  hazar d f u n cti o n , X defi nes t he vect or of e x pla nat or y v aria bles a n d b t he u n k n o w n vect or 
of re g ressi o n para meters. T he H R of all selecte d e x pla nat or y varia bl es a n d of treat me nt effects 
will  be  re p orte d  i ncl u di n g  2 -si de d  9 5 %  CIs.  N o  i nteracti o ns  will  be  c o nsi dere d.  P ost-Baseli n e  
fact ors will n ot be c o nsi d ere d f or t he m o del. 
Met h o ds f or E v al u ati n g t he  V ali dit y of M o del A ss u m pti o ns 
T he  pr o p orti o nal  hazar ds  ass u m pti o n  will  be  c hec ke d  vis uall y  f or  t h e P A  b y  pl otti n g  l o g( -
l o g( P F S)) vers us l o g(ti m e) wit hi n eac h ra n d o mizati o n strat u m. Sc h oe nfel d resi d uals i ncl u di n g a 
L O E S S  c ur ve  will  be  pl otte d  t o  i n vesti gat e  gra p hicall y  vi olati o ns  of  t he  pr o p orti o nal  hazar d’s 
ass u m pti o n. Sc h oe nfel d resi d uals will be c o m p ute d i n S A S usi n g t he P H R E G pr oce d ure a n d usi n g 
t he O U T P U T state me nt a n d t he ke y w or d R E S S C H. Wit h pr o p orti o nal hazar ds t he L O E S S c ur ve 
s h o ul d be parallel t o t he x-a xis.  
1 4. 1. 3  
S u b gr o u p A n al ysis f or P F S   
T he s u b gr o u p varia bl es defi ne d i n Secti o n  8. 2 “ Defi niti o n of A n al ysis Sets a n d S u b gr o u ps ” will 
be c o nsi dere d f or t he f oll o wi n g a n al yses : 
•  T he P F S ti me bet wee n Ar m 1 a n d Ar m 2 will b e c o m pare d usi n g a t w o -si de d u nstratifie d l o g 
ra n k test per s u b gr o u p l e vel; a n d t he u nstratifie d H R a n d its c orres p o n di n g 9 5 % CI will be 
c o m p ute d per s u b gr o u p l e vel.  T he H R a n d its c orres p o n di n g 9 5 % CI of all s u b gr o u ps will als o 
be prese nt e d i n a f orest pl ot.  
T o assess t he heter o ge neit y of treat me nt effects acr oss t he s u b gr o u p le vels, t w o C o x re gressi o n 
m o dels will be fitte d wit h t he P F S ti me as t he de pe n de nt vari a ble ; s u b gr o u p, treat me nt ar m, 
a n d wit h a n d wit h o ut t he treat me nt ar m -b y -s u b gr o u p i nteracti o n as e x pla nat or y varia bles: 
M o del 1 :  treat me nt ar m + s u b gr o u p 
M o del 2 :  treat me nt ar m + s u b gr o u p + tr eat me nt ar m *s u b gr o u p-vari a ble  
A p -val ue f or t he i nteracti o n test w ill  be pr o vi de d t o get her wit h  t he H R a n d c orres p o n di n g 
9 5 % CI of t he i nteracti o n m o del para meter.  
1 4. 2  
O ver all S ur vi v al   
O verall sur vi val ( O S) will be teste d as a sec o n dar y e n d p oi nt of  t his st u d y. T he sa me met h o d ol o g y 
as use d f or t he P F S a nal ysis will a p pl y  t o O S (s ee Secti o n  1 4). 
T he O S ti me is defi ne d as t he ti me fr o m t he date  of  ra n d o mizati o n t o t he date of deat h d ue t o a n y 
ca use:  
O S = ( date of e ve nt/ce ns ori n g –  d ate of first st u d y i nter ve nti o n + 1)/ 3 0. 4 3 7 5 ( m o nt hs).  
Gl o bal Versi o n I D: 
5 4/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
F or partici pa nts ali ve at t he ti me of t he data c ut-off  date or w h o are l ost t o f oll o w u p, O S will be 
ce ns ore d at t he last date k n o w n t o be ali ve.  
T he date of e ve nt /cens ori n g is defi n e d i n  t he f oll o wi n g ta ble: 
T a ble 6  S ur vi v al E ve nt /Ce ns ori n g  r ules f or O S   
S ur vi v al st at u s  
D at e of e v e nt / c e n s ori n g  
C e n s ori n g  
P arti ci p a nt s ali v e or l o st t o f oll o w -u p b ef or e or at c ut -off  d at e  
L a st d at e k n o w n t o b e ali v e  
C e n s or e d  
P arti ci p a nt s w h o di e d b ef or e or at c ut -off  d at e  
D at e of d e at h  
N o  c e n s ori n g  
T he f oll o wi n g  c o m plet e dates will be use d t o deter mi ne t he last date k n o w n t o be ali ve. O nl y t h ose  
t hat are bef ore or at t he d ata c ut-off  s h all be use d i n t he deri vati o n. Dates after t he data c ut-off  will 
be i g n ore d b y t he deri vati o n:  
•  All partici pa nt assess me nt dates ( bl o o d dra ws [la b orat or y, P K ], vital si g ns, p erf or ma n ce stat us, 
E C G, t u m or assess me nts, P R O assess me nts).  
•  Start  a n d  e n d  dates  of 
a nti-ca n cer t h era pies  a d mi nistere d  after  st u d y  i nter ve nti o n 
disc o nti n uati o n   
•  A E start a n d e n d d ates  
•  Last k n o w n ali ve dat e c ollecte d o n t he ‘S u bject St at us / S ur vi val F oll o w -U p” e C R F pa ge  ( d o 
n ot use t he f oll o w u p dat e) .  
•  St u d y i nter ve nti o ns start a n d e n d dates  
•  Ra n d o mizati o n date  
•  Date of disc o nti n uati o n fr o m t he “ St u d y Ter mi nati o n” e C R F pa ge ( d o n ot use if reas o n f or 
disc o nti n uati o n is l ost t o f oll o w-u p or deat h ) 
O nl y dates ass oci ate d wit h  act ual e x a mi nati o ns of t he partici pa nt re p orte d i n  t he e C R F will be 
use d i n t he deri vati o n.   Dates ass ociate d wit h a tec h nical o perati o n u nrelate d t o partici pa nt stat us 
s uc h as t he date a bl o o d sa m ple was pr o cesse d will n ot be use d.  
T he a nal ysis of O S ti me will be perf or me d usi n g t he Ka pla n -M eier met h o d a n d t he sa me a p pr oac h 
descri be d  f or  P F S  i n S ecti o n  1 4. 1 .  Ka pla n-Mei er  esti mates  ( pr o d uct -li mit  esti mates)  will  be 
prese nte d t o get her wit h a s u m mar y of ass ociate d st atistics i ncl u di n g c orres p o n di n g t w o -si de d 9 5 % 
CIs. T he y will be esti mate d at 1 2 , 1 8 , 2 4 , 3 6, 4 8, a n d 6 0 m o nt hs.  
A C o x m o del will be use d wit h t he sa me a p pr oac h as f or P F S descri be d i n Secti o n  1 4. 1.   
A s u bject listi n g will pr o vi de t he f oll o wi n g i nf or mati o n: treat me nt ar m, partici pa nt i de ntifier, a ge, 
se x,  race,  d ate  of  ra n d o mizati o n,  date  of  e v e nt/ce ns ori n g,  e ve nt/ce ns ori n g  reas o n,  a n d  ti me  t o 
e ve nt.  
Gl o bal Versi o n I D: 
5 5/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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  
Se nsiti vit y A n al yses f or O S   
T o assess t he r o b ust ness of t he O S  a nal ysis, t he f oll o wi n g se nsiti vit y a n al ys es will be c o n d ucte d:  
•  U nstratifie d O S  a nal ysis  
•  I n  case  1 0 %  or  m ore  partici pa nts  s witc he d  c h e m ot hera p y,  t he  a n al ysis  f or  O S  will  be 
re peat e d usi n g P D-L 1 e x pressi o n a n d t h e c h e m ot hera p y re gi me n t hat was gi ve n m ostl y f or 
stratificati o n. 
1 4. 2. 2  
S u b gr o u p A n al ysis f or O S   
T he O S a nal ysis as descri be d i n Secti o n  1 4.1. 3  will be c o n d u cte d i n t he s u bsets of partici pa nts 
defi ne d i n Secti o n  8. 2. 
1 4. 3  
F oll o w -U p Ti me   
1 4. 3. 1  
F oll o w -U p Ti me ( P F S)   
A Ka pla n -Meier a n al ysis f or P F S assess e d b y i n v esti gat or f oll o w-u p will be ge n erat e d t o assess 
t he f oll o w-u p ti me i n t he treat me nt ar ms r e versi n g t he P F S ce ns ori n g a n d e v e nt.  
Ka pla n -Mei er esti mates will be prese nte d b y treat me nt gr o u p t o get her wit h t he me dia n ti me of 
f oll o w-u p f or P F S. I n partic ular, t he f oll o w-u p rat e at 6, 9, 1 2, 1 8, 2 4, 3 6, 4 8, a n d 6 0 m o nt hs will 
be esti mate d wit h c orres p o n di n g t w o -si de d 9 5 % CIs. A Ka pla n -Mei er pl ot will als o be dis pla ye d . 
1 4. 3. 2  
F oll o w -U p Ti me ( O S)   
T he a nal yses perf or me d i n  S ecti o n1 4. 3. 1  will be c o n d ucte d o n O S data. A Ka pla n -Mei er pl ot will 
als o be dis pla ye d.  
1 4. 4  
 O bj ecti ve  Res p o nse  R ate  Acc or di n g  t o  R E CI S T  1. 1  as 
A ssesse d b y I n vesti g at or   
T he c o nfir me d O bjecti ve Res p o nse Rate ( O R R) is defi ne d as t he n u m ber of partici pa nt s ha vi n g a 
c o nfir me d best o verall res p o nse assess me nt of C R or P R, o ut of t he t otal n u m ber of partici pa nts 
bel o n gi n g t o t he a n al ysis set of i nterest. U nc o nfir me d O R R will als o be prese nte d.  
Best o verall res p o nse will be assesse d base d o n t he t u m or res p o nse at differe nt e v al uati o n ti me 
p oi nts fr o m ra n d o mizati o n u ntil t he first d o c u me nte d P D  acc or di n g t o R E CI S T 1. 1 . O nl y t u m or 
assess me nts perf or me d b ef ore t he start of a n y f urt her a nti -ca n cer tr eat me nt will be c o nsi dere d i n 
t he  assess me nt  of best  o verall  res p o nse .  Cli nical  deteri orati o n  will  n ot  be  c o nsi dere d  as 
d oc u me nte d P D . 
T he best o verall res p o nse acc or di n g t o R E CI S T 1. 1 as assesse d b y i n vesti gat or ca n be C R, P R, 
n o n -C R/ n o n -P D, S D, P D, or N E.  
T he f oll o wi n g re q uir e me nt s are ta ke n i nt o acc o u nt f or u nc o nfir m e d best o v erall res p o ns e : 
Gl o bal Versi o n I D: 
5 6/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  C R = at least o ne deter mi nati o n of C R bef ore dise ase pr o gressi o n  
•  P R = at least o ne deter mi nati o n of P R bef ore disease pr o gressi o n (a n d n ot q ualif yi n g f or a 
C R)  
•  S D  = at  least  o ne  S D  assess me nt  ≥  6  wee ks  after  t he  first  st u d y  i nter ve nti o n  a n d  bef ore 
disease pr o gressi o n (a n d n ot q ualif yi n g f or C R or P R)  
•  N o n -C R/ N o n -P D = at least o ne n o n -C R/ n o n -P D assess me nt ≥ 6 wee ks after start date a n d 
bef ore pr o gressi o n wit h n o meas ura bl e diseas e at b aseli ne (a n d n ot q ualif yi n g f or C R or P R)  
•  P D = at least o ne P D ass ess me nt (a n d n ot q ualif yi n g f or C R, P R , S D  or n o n -C R/ n o n -P D ) 
•  If a s u bject has a missi n g Baseli ne  t u m or assess m e nt a n d/ or n o ( or N E) t u m or assess me nts 
o n -treat me nt, best o vera ll res p o nse will be “ N ot E val ua ble” ( N E).  
•  I n t h e cas e t he si n gle res p o nse is S D, S D m ust ha ve bee n assesse d n o less t ha n 6  wee ks (at 
least 4 2  da ys) after ra n d o mizati o n, ot her wise, t he best res p o nse will be N E.  
Ta ble 7 7  s u m marizes t he deri vati o n r ules descri be d b y Eise n h a uer, et al . ( 2 0 0 9) f or t he best o verall 
res p o nse w he n c o nfir m ati o n fr o m s u bse q ue nt assess me nt is nee d e d. F or s u bjects w h o ha ve n o n -
tar get  lesi o ns  o nl y  at Baseli ne ,  t he  ti me p oi nt  t u m or  assess me nt  of  “ N o n-C R/ n o n -P D”  will  be 
e val uate d wit h t he s a me criteria as S D ( mi ni m u m criteria f or S D d urati o n) i n deri vi n g t he o v erall 
best o verall res p o ns e . 
T a ble 7  C o nfir m ati o n R ules f or Best O ver all Res p o nse   
O v er all 
r e s p o n s e at 1 st 
ti m e p oi nt 
O v er all r e s p o n s e 
at s u b s e q u e nt 
ti m e p oi nt  
B e st O v er all R e s p o n s e  
C R  
C R*  
C R  
C R  
P R  
S D, P D , or P R a  
C R  
S D  
S D pr o vi d e d mi ni m u m crit eri a f or S D d ur ati o n m et; ot h er wi s e, P D  
C R  
P D  
S D pr o vi d e d mi ni m u m crit eri a f or S D d ur ati o n m et; ot h er wi s e, P D  
C R  
N E  
S D pr o vi d e d mi ni m u m crit eri a f or S D d ur ati o n m et, ot h er wi s e N E  
P R  
C R*  
P R  
P R  
P R*  
P R  
P R  
S D  
S D  
P R  
P D  
S D pr o vi d e d mi ni m u m crit eri a f or S D d ur ati o n m et, ot h er wi s e, P D  
P R  
N E  
S D pr o vi d e d mi ni m u m crit eri a f or S D d ur ati o n m et, ot h er wi s e N E  
N E  
N E  
N E  
C R = c o m pl et e r e s p o n s e, 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, P D = pr o gr e s si v e di s e a s e, N E = n o n -
e v al u a bl e  
a  If a C R i s tr ul y m et at fir st ti m e p oi nt, t h e n a n y di s e a s e s e e n at a s u b s e q u e nt ti m e p oi nt, e v e n di s e a s e 
m e eti n g P R crit eri a r el ati v e t o B a s eli n e , m a k e s t h e di s e a s e P D at t h at p oi nt ( si n c e di s e a s e m u st h a v e 
r e a p p e ar e d aft er C R). B e st o v er all r e s p o n s e  w o ul d d e p e n d o n w h et h er mi ni m u m d ur ati o n f or S D w a s m et. 
H o w e v er, s o m eti m e s ‘ C R’ m a y b e cl ai m e d w h e n s u b s e q u e nt s c a n s s u g g e st s m all l e si o n s w er e li k el y still 
pr e s e nt a n d i n f a ct t h e p ati e nt h a d P R, n ot C R at t h e fir st ti m e p oi nt. U n d er t h e s e cir c u m st a n c e s, t h e ori gi n al 
C R s h o ul d b e c h a n g e d t o P R a n d t h e b e st o v er all r e s p o n s e i s P R.   
* T h e s e c o n d a s s e s s m e nt s h o ul d b e at l e a st 4 w e e k s aft er t h e fir st o n e t o c o nfir m r e s p o n s e.  
Gl o bal Versi o n I D: 
5 7/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T he f oll o wi n g re q uir e me nts are ta ke n i nt o acc o u nt f or c o nfir m e d best  o verall res p o nse : 
•  C R = at least t w o deter mi nati o ns of C R at least 4 wee ks a p art ( wit h n o P D i n bet wee n)  
•  P R = at l east t w o deter mi nati o ns of P R or better ( P R f oll o we d b y P R or P R f oll o we d b y C R) 
at least 4 wee ks a part (a n d n ot q ualif yi n g f or a C R), wit h n o P D i n bet wee n  
•  S D = at least o ne S D assess me nt ( or better) ≥ 6 w ee ks after ra n d o mizati o n date a n d bef ore 
pr o gressi o n (a n d n ot q u alif yi n g f or C R or P R)  
•  N o n -C R/ N o n -P D = at least o ne n o n -C R/ n o n -P D assess me nt ( or b etter) ≥ 6 wee ks after start 
date a n d bef ore  pr o gressi o n wit h n o meas ura ble disease at baseli ne (a n d n ot q ualif yi n g f or 
C R or P R)  
•  P D = pr o gressi o n ≤ 1 6 wee ks after ra n d o mizati o n date (a n d n ot q u alif yi n g f or C R, P R, S D 
or n o n -C R/ n o n -P D).  
•   N ot E val ua ble ( N E):   all ot her cas es.  
T he Diseas e C o ntr ol Rat e (D C R) is defi n e d as t h e pr o p orti o n of p artici pa nts wit h c o nfir me d best 
o verall res p o nse acc or di n g t o t he e val u ati o n criteria of C R, P R, or S D o ut of t he t otal n u m ber of 
partici pa nts bel o n gi n g t o t he a nal ysis set of i nterest.  D C R f or u nc o nfir me d best o verall res p o ns e 
will als o be prese nte d.  
T he n u m ber a n d p erce nta ge of p artici pa nts wit h c o nfir me d  a n d u nc o nfir m e d best o verall res p o ns e 
of C R, P R, S D, P D, a n d N E will be ta b ulate d f or b ot h treat me nt ar m s. Ta bles will i ncl u de D C R.  
A listi n g will be pr o vi de d wit h t he f oll o wi n g i nf or mati o n: treat me nt ar m, s u bject i de ntifier, a ge, 
se x,  race, eac h  st u d y  i nt er ve nti o n first/last  d ose,  c o nfir me d/ u nc o nfir m e d best  o verall  res p o nse , 
date  of  s u bse q ue nt a nti -ca ncer t hera p y,  date  of  deat h,  visit,  date(s)  of  i ma gi n g ( da ys  si nc e 
ra n d o mizati o n),  lesi o n  t y p e  (tar get  lesi o n,  n o n-tar get  lesi o n,  ne w  lesi o n),  descri pti o n  of  tar get 
lesi o ns (size, site, met h o d, res p o nse), n o n-tar get lesi o ns (stat us, site, met h o d, res p o nse) a n d ne w 
lesi o ns (site, met h o d), s u m of lesi o n dia meters, p erce nt c h a n ge i n t ar get lesi o ns fr o m Baseli ne , a n d 
o verall res p o nse. T his listi n g will be s orte d b y treat me nt ar m,  partici pa nt i de ntifier, visit, date of 
i ma gi n g a n d lesi o n I D.  
T he  c o nfir me d  a n d  u nc o nfir me d  best  o v erall  res p o nse  (i ncl u di n g O R R  a n d  D C R ) will  b e 
calc ulate d per treat me nt ar m wit h a t w o-si de d 9 5 % CI usi n g t he Cl o p per-Pears o n met h o d (e x act 
CI f or a bi n o mial pr o p orti o n as c o m p ute d b y d efa ult b y t he F R E Q pr oce d ure usi n g t h e E X A C T 
o pti o n). O verall Res p o nse at t he e n d of c C R T p hase assesse d b y in vesti gat or will als o be ta b ulate d.  
F or t he c o m p utati o n o verall res p o nse at t he e n d of cc R T p hase, assess me nts at “ E val uati o n visit 
1”/ “ U nsc h e d ule d e val uati o n visit 1” occ urri n g wit hi n 4 7 a n d 6 7 da ys fr o m ra n d o mizati o n a n d 
bef ore t he start of a n y s u bse q ue nt a ntica ncer treat me nt will be c o nsi dere d. S u bjects wit h missi n g 
assess me nt/ missi n g date of assess me nt/ass ess me nt o ut of ra n ge/ assess me nt perf or m e d after t he 
start of t he s u bse q ue nt a ntica ncer treat me nt will be classifie d i n t he “ Missi n g” cate g or y.  
A s u m mar y ta bl e of t he f oll o wi n g reas o ns f or n o n-e val ua ble c o nfir me d b est o verall res p o ns e as 
a dj u dicate d b y t he i n vesti gat or b y tr eat me nt ar m will be pr o vi de d:  
•  N o Bas eli ne  assess me nt  
Gl o bal Versi o n I D: 
5 8/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  N o p ost -Bas eli ne  assess me nts d ue t o deat h wit hi n 8  wee ks after ra n d o mizati o n  
•  N o p ost -Bas eli ne  assess me nts d ue t o ot her reas o ns  
•  All p ost -Baseli ne  assess me nts ha ve o verall res p o nse ‘N o n -e val ua ble ’ 
•  Ne w a nti-ca ncer  t hera p y starte d bef ore first e v al ua ble p ost-Bas eli ne  assess me nt  
•  S D ( or  better) of  i ns uffi cie nt  d urati o n  ( <  6  wee ks  after ra n d o mizati o n wit h o ut  f urt her 
e val ua ble t u m or assess m e nt)  - N ot e: S pecial a n d rare cases w here best o v erall res p o nse is 
N E d ue t o b ot h earl y S D a n d late P D will be classifie d i nt o t his cate g or y 
•  P D t o o late (i.e. t u m or assess me nt of P D was > 1 6  wee ks after ra n d o mizati o n a n d t here was 
n o e val ua ble t u m or ass ess me nt i n bet wee n)  
•  N o n -C R/ n o n -P D of i ns ufficie nt d urati o n ( <  6 w ee ks after ra n d o mizati o n wit h o ut f urt her 
e val ua ble t u m or ass ess me nt)  
A w aterfall pl ot f or best  p erce nt c ha n ge fr o m Baseli ne i n s u m of dia meters of all tar get lesi o ns a n d 
f or  t he  perce nta ge  c h a n ge  of  s u m  of  l o n gest  dia meter  at  first  sca n  of  all  tar get  lesi o ns  will  be 
pr o vi de d. P artici pa nts wit h missi n g/ n o n -e val u a ble baseli ne a n d/ or p ost -bas eli ne t u m or assess me nt 
will be e x cl u de d fr o m t he pl ot.  
A d diti o nall y,  a  s pi der  pl ot  will  be  dis pla ye d  b y  treat me nt  ar m. T he  u nc o nfir me d  best  o verall 
res p o nse  ass esse d  b y  I n vesti gat or  will  be  s h o w e d  i n  t he  pl ot  a n d col or  c o de  will  be  us e d  t o 
differe ntiat e  res p o nses: “ C R”, “ P R”  vs  “ S D,  P D  or  N E”.  S u bjects  wit h  missi n g/ n o n -e val ua ble 
baseli ne a n d/ or p ost -b aseli ne t u m or assess me nt will n ot be i ncl u de d i n t his a nal ysis. Ti me p oi nts 
f or t he first occ urre nce of a ne w lesi o n a n d of treat me nt disc o nti n uati o n (all st u d y i nter ve nti o ns –  
i m m u n ot hera p y, c he m ot hera p y a n d ra di ot hera p y –  ha ve t heir tr eat me nt ter mi nati o n pa ges fille d) 
will be s h o w n i n t he pl ot.  
1 4. 4. 1  
S u b gr o u p A n al ysis  f or O R R   
L o gistic m o dels will b e fitte d t o assess t he heter o ge neit y of treat me nt effect acr oss s u b gr o u p le vels 
f or t he c o nfir me d O R R (usi n g s u b gr o u ps defi ne d i n Secti o n  8. 2). A l o gisti c re gressi o n m o del will 
be fitte d wit h best o verall res p o nse  as de pe n de nt v aria ble ( 1 f or s u bjects wit h best o verall res p o nse  
of P R or C R, 0 ot her wis e) s u b gr o u p, tr eat me nt, a n d wit h a n d wit h o ut t he treat me nt b y s u b gr o u p 
i nteracti o n as e x pla nat or y varia bles. A p-val ue f or t he i nteracti o n ter m will be pr o vi de d t o get her 
wit h t he o d ds rati o a n d c orres p o n di n g 9 5 % CI of t he i nteracti o n m o del para meter. A f orest pl ot of 
o d ds  rati os a n d t heir c orres p o n di n g 9 5 % Cis will be dis pla ye d.  
1 4. 5  
D ur ati o n of Res p o nse   
D O R is defi ne d as t he ti me fr o m first  d oc u me ntati o n of o bjecti ve res p o nse ( C R or P R) t o t he date 
of  first  d oc u me ntati o n  of  o bjecti ve  P D  or  deat h  d ue  t o  a n y  ca use , w hic h e ver  occ urs  first. T he 
a nal ysis of D O R will be perf or me d o n c o nfir m e d  a n d u nc o nfir me d  o bjecti ve res p o nse of C R or 
P R acc or di n g t o R E CI S T 1. 1 as a dj u dicate d  b y  i n vesti gat or. T he  ce ns ori n g r ules f or D O R are as 
descri be d f or P F S  (see Secti o n  1 4. 1). 
Gl o bal Versi o n I D: 
5 9/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
D O R = ( date of P D or deat h/ce ns or i n g –  date of o bjecti ve res p o nse + 1)/ 3 0. 4 3 7 5 ( m o nt hs).  
T he a nal ysis of D O R will be perf or me d wit h a Ka pla n -Meier met h o d ( pr o d u ct -li mit esti mates) a n d 
a s u m mar y of ass ociate d statistics will be prese nte d i ncl u di n g c orres p o n di n g t w o -si de d 9 5 % CIs. 
T he CIs f or t he me dia n will be calc ulat e d acc or di n g t o Br o o k me yer a n d Cr o wle y ( 1 9 8 2)  a n d CIs 
f or t he s ur vi val f u n cti o n esti mates at 6, 9, 1 2, 1 8, 2 4, 3 6, 4 8 , a n d 6 0 m o nt hs will be deri ve d usi n g 
t he  l o g-l o g  tra nsf or mati o n  acc or di n g  t o Kal bfleisc h  a n d  Pre ntice  ( 1 9 8 0)  ( C O N F T Y P E =l o gl o g 
defa ult o pti o n i n S A S P R O C LI F E T E S T).  T he esti mate of sta n dar d err or will be c o m p ute d usi n g 
Gree n w o o d’s f or m ula.  
A partici pa nt listi n g will pr o vi d e t he f oll o wi n g i nf or mati o n: treat me nt ar m, partici pa nt  i de ntifier, 
a ge, se x, race, date of ra n d o mizati o n, date of first res p o nse, ti me t o res p o nse, date of last t u m or 
assess me nt, ce ns ore d ( yes, n o), date of e ve nt/ce ns ori n g, e v e nt/ce ns ori n g reas o n, a n d D O R .  
T he  Ti me  t o  Res p o nse  will  be  calc ulate d  f or  eac h  partici p a nt  wit h  a n  u nc o nfir me d  res p o nse 
acc or di n g t o R E CI S T 1. 1 as t he ti me fr o m ra n d o mizati o n u ntil first o bser vati o n of res p o nse as 
deter mi ne d b y t he  i n vesti gat or .  
Ti me t o res p o nse = ( date of C R or P R –  date of ra n d o mizati o n + 1)/ 3 0. 4 3 7 5 ( m o nt hs).  
Descri pti ve statistics of ti me t o res p o nse will be pr o vi de d.  
Gl o bal Versi o n I D: 
6 0/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Gl o bal Versi o n I D: 
6 1/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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 0  
Del a ye d Res p o nse after I niti al Pr o gressi o n   
A dela ye d res p o nse will be defi n e d as a d o c u me nt e d o bjecti ve res p o ns e (C R or P R ) t hat occ urre d 
after t h e i nitial  pr o gressi o n of disease. F or t h ose  partici pa nts, t he d urati o n of dela ye d res p o nse 
( D o D R) will be defi n e d as:  
D o D R = ( date of e n d of res p o nse –  date of o bjecti ve res p o nse + 1)/ 3 0. 4 3 7 5 ( m o nt hs ),), 
wit h e n d of res p o nse bei n g t he earliest date bet w ee n P D occ urri n g after res p o nse, deat h, start of 
ne w a ntica n cer treat me nt or c ut -off d ate.  
A  listi n g  of  d urati o n  of  res p o nse  f or  partici pa nts  ha vi n g  a  d ela ye d  res p o nse  will  be  pr o vi de d 
i ncl u di n g: pla n ne d  tr eat me nt  ar m ,  partici pa nt  i de ntifier,  a ge,  se x,  race,  date  of  first  st u d y 
i nter ve nti o n, date/st u d y da y of  first P D, date/st u d y d a y of  first res p o nse ( C R or P R), o n g oi n g 
res p o nse  at c ut-off  date ( yes,  n o),  d ate/st u d y  d a y  of  e n d  of  res p o nse  ( wit h  reas o n  f or e n d  of 
res p o nse bei n g P D, deat h, ne w a ntica n cer treat me nt, c ut-off), d urati o n of d ela ye d res p o nse.  
Gl o bal Versi o n I D: 
6 2/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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. 3  
C o x Re gressi o n M o dels   
C o x m o dels will be use d wit hi n t he La n d mar k a n al ysis setti n g t o e val uate t he treat me nt effect o n 
s u b gr o u ps as defi ne d i n Secti o n  8. 2  c o m ple me nte d b y f urt her s u b gr o u ps as c C R T c o m pleti o n a n d 
ra di ol o gic c o m plia nce. U ni variate or m ulti variate C o x m o dels ma y be us e d u p o n discreti o n of t he 
S p o ns or  t o  f urt her  e v al uate  t he  effects  of  baseli ne  c o variates  a n d  c C R T  relate d  c o variat es  i n 
a d diti o n t o t he treat me nt effect i n t he sc o pe of t he La n d m ar k a n al ysis.  
1 5  
S afet y A n al yses   
T he f oll o wi n g s u bsecti o ns  i ncl u de  specificati o ns  f or  s u m marizi n g  safet y  e n d p oi nts  t hat  are 
c o m m o n  acr oss  cli nical st u dies s uc h  as  a d v erse  e ve nts ( A Es),  la b orat or y  tests  a n d  vital  si g ns. 
Baseli ne  v al ues f or safet y a n al ysis are d efi ne d i n Secti o n  9 . 
Gl o bal Versi o n I D: 
6 3/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
If n ot state d ot her wise, s u m maries will be prese nte d f or t he S A F a nal ysis set b y tr eat me nt ar m a n d 
o verall.  F or  I D M C  p ur p oses  d uri n g  t he  Safet y  r u n -i n  p hase  of  t he  st u d y,  S A F-nJ  a n d  S A F -J 
a nal ysis s ets will be pres e nte d se paratel y.  
1 5. 1  
A d verse E ve nts   
Treat me nt e mer ge nt a d v erse e v e nts ( T E A Es) are t h ose e ve nts wit h o nset dates occ urri n g d uri n g 
t he o n-treat me nt peri o d ( o n-treat me nt peri o d defi n e d i n Secti o n  9) or if t he w orse ni n g of a n e ve nt 
is d uri n g t he o n-tr eat me nt peri o d. 
C ha n ges i n t o xicit y gra d e, seri o us ness or o utc o m e of A Es are rec or de d as se parate e ntri es i n t he 
e C R F wit h ass ociate d e n d a n d start dates (start date e q uals e n d date  of pre vi o us e ntr y). S uc h e ntri es 
re p orti n g t he sa me e ve nt i n s uc h i m me diatel y c o ns ec uti ve peri o ds will be c o nsi dere d as o ne e ve nt 
i n t he a nal ysis. T hese e v e nts will be ke pt as se parate rec or ds i n t he data bas e i n or der t o mai ntai n 
t he f ull detaile d hist or y of t he e ve nts. T h e start dat e of t he i nitial rec or d i n t he se q ue n ce is ta ke n as 
start date of t he e ntire e v e nt, si milarl y t he e n d d at e of t he last e v e nt i n t he se q ue nce is ta ke n as e n d 
date of t he e ntire e ve nt. T he o verall o utc o me of t he a d verse e v e nt is t he o utc o me of t he last e ve nt 
i n t he se q ue nce. D urati o n of t he A E a n d t he T E A E fla g will be a dj uste d acc or di n gl y i n t he a nal ysis.  
All a nal ys es descri be d i n t his secti o n will be base d o n T E A Es d uri n g t he o n -treat me nt peri o d if 
n ot ot her wise s pecifie d a n d w ill be descri be d b y treat me nt ar m a n d o v erall. T he A E listi n gs will 
i ncl u de all A Es ( w het her treat me nt-e mer ge nt or n ot). A Es o utsi de t he o n -tr eat me nt peri o d will be 
fla g ge d i n t he listi n gs. 
I n c o m plete A E-relate d d ates will be ha n dle d as st ate d i n Secti o n  9. 
Tre at me nt -rel ate d A d verse E ve nts  
I m m u n ot hera p y rel ate d A Es  are t h ose A Es wit h relati o ns hi p t o i m m u n ot hera p y re p orte d b y t h e 
I n v esti gat or as relate d (i.e. a ns wer t o t he q uesti o n “ Relati o ns hi p wit h i m m u n ot hera p y” = “ Relat e d” 
o n “ A d verse E ve nts Det ails” e C R F pa ge).  
C he m ot hera p y  relat e d  A Es  are  t h ose  A Es  wit h  relati o ns hi p  t o c he m ot hera p y re p orte d  b y  t he 
I n v esti gat or as relate d (i.e. a ns wer t o t he q uesti o n “ Relati o ns hi p wit h Car b o plati n” = “ Relat e d”, or  
“ Relati o ns hi p  wit h  Paclita xel”  =  “ Relate d”, or  “ Relati o ns hi p  wit h  Cis plati n”  =  “ Relate d ”, or  
“ Relati o ns hi p wit h Pe met re x e d” = “ Relate d”, or  “ Relati o ns hi p wit h Et o p osi de” = “ Relate d ”  o n 
“ A d verse E ve nts Det ails” e C R F pa ge).  
If  a n y  of  t he  c h e m ot hera p y  c o m p o u n ds  ( Car b o plati n,  Paclita x el,  Cis plati n,  Pe metre x e d, or 
Et o p osi de) are m ar ke d as “ Relate d” , t he A E will be c o nsi dered as “ C he m ot hera p y -relate d ”.  
Ra di ot hera p y  rel ate d  A Es  are  t h ose  A Es  wit h  relati o ns hi p  t o  ra di ot hera p y  re p orte d  b y  t h e 
I n v esti gat or as relate d (i. e. a ns w er t o t he q u esti o n “ Relati o ns hi p wit h ra di ot hera p y” = “ R elate d” 
o n “ A d verse E ve nts Det ails” e C R F pa ge).  
If  relati o ns hi p  t o  a n y  st u d y  i nter ve nti o n  is  u n k n o w n  or  missi n g  t he  A E  will  be  c o nsi dere d  as 
“ Relate d”.  
Gl o bal Versi o n I D: 
6 4/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Seri o us A d verse E ve nts  
Seri o us ad verse eve nts ( S A Es) are t h ose e ve nts re p orte d o n t he “ A d verse E ve nts Details” e C R F 
pa ge wit h t he “ Seri o us A d verse E ve nt ” fiel d tic ke d “ Yes”.  
A d verse E ve nts Le a di n g t o Te m p or ar y Tre at me nt Disc o nti n u ati o n  
A d verse  E ve nts  Lea di n g  t o  T e m p orar y  Disc o nti n uati o n  of Im m u n ot hera p y:  A Es  le a di n g  t o 
per ma ne nt disc o nti n uati o n of st u d y i nter ve nti o n (i.e. a ns wer t o t he q uesti o n “ Acti o n(s)  ta ke n wit h 
I m m u n ot hera p y” = “Dr u g i nterr u pte d ” o n “ A d verse E ve nts Details” e C R F pa ge).  
A d verse  E ve nts  Lea di n g  t o  T e m p orar y  Disc o nti n uati o n  of C he m ot hera p y :  A Es  le a di n g  t o 
per ma ne nt disc o nti n uati o n of st u d y i nter ve nti o n (i.e. a ns wer t o t he q uesti o n “ Acti o n(s) ta ke n wit h 
Car b o plati n” = “ Dr u g i nt err u pte d”, or  “ Paclita x el” = “ Dr u g i nterr u pte d”, or  “ Cis plati n” = “ Dr u g 
i nterr u pte d”, or  “ Pe metre x e d”  =  “ Dr u g  i nterr u pt e d”, or  “ Et o p osi de”  =  “ Dr u g  i nterr u pte d” o n 
“ A d verse E ve nts Det ails” e C R F pa ge).  
A d verse  E ve nts  Lea di n g  t o  T e m p orar y  Disc o nti n uati o n  of  Ra di ot hera p y:  A Es  le a di n g  t o 
per ma ne nt disc o nti n uati o n of st u d y i nter ve nti o n (i.e. a ns wer t o t he q uesti o n “ Acti o n(s) ta ke n wit h 
Ra di ot hera p y” = “ Ra di ot hera p y i nterr u pte d” o n “ A d verse E v e nts Details” e C R F pa ge).  
A d verse  E ve nts  Lea di n g  t o  Te m p orar y  Disc o nti n uati o n  of  at L east O ne  C he m ot hera p y:  A Es 
lea di n g  t o  te m p orar y  disc o nti n uati o n  of  Car b o plati n, Paclita x el , Cis plati n , Pe metre x e d , or 
Et o p osi de , as defi ne d  a b o ve. 
A d verse E ve nts Lea di n g t o Te m p orar y Disc o nti n u ati o n of at Least O ne Tri al Dr u g : A Es le a di n g 
t o te m p orar y disc o nti n uati o n of i m m u n ot hera p y ( defi niti o n a b o ve) or A Es lea di n g t o te m p orar y 
disc o nti n uati o n of at least  o ne c he m ot hera p y ( defi niti o n a b o ve) or te m p orar y disc o nti n uati o n of at 
least o ne ra di ot hera p y ( defi niti o n a b o ve). 
A d verse E ve nts Le a di n g t o Per m a ne nt T re at me nt Disc o nti n u ati o n  
A d verse  E v e nts  Lea di n g  t o  Per ma n e nt  Disc o nti n uati o n  of Im m u n ot hera p y:  A Es  lea di n g  t o 
per ma ne nt disc o nti n uati o n of st u d y i nter ve nti o n (i.e. a ns wer t o t he q uesti o n “ Acti o n(s) ta ke n wit h 
I m m u n ot hera p y” = “ Dr u g wit h dra w n” o n “ A d verse E ve nts Details” e C R F pa ge). 
A d verse  E v e nts  Lea di n g  t o  Per ma n e nt  Disc o nti n uati o n  of 
C he m ot hera p y :  A Es  le a di n g  t o 
per ma ne nt disc o nti n uati o n of st u d y i nter ve nti o n (i.e. a ns wer t o t he q uesti o n “ Acti o n(s) ta ke n wit h 
Car b o plati n” = “ Dr u g wit h dra w n” , or  “ Paclita x el” = “ Dr u g wit h dra w n ”, or  “ Cis plati n” = “ Dr u g 
wit h dra w n”, or  “ Pe metre x e d”  =  “ Dr u g  wit h dra w n”, or  “ Et o p osi de”  =  “ Dr u g  wit h dra w n”  o n 
“ A d verse E ve nts Det ails” e C R F pa ge).  
A d verse E v e nts Lea di n g t o Per ma ne nt Disc o nti n uati o n of Ra di ot hera p y: A Es lea di n g t o per m a ne nt 
disc o nti n uati o n  of  st u d y  i nter ve nti o n  (i.e.  a ns wer  t o  t he  q uesti o n  “ Acti o n(s)  ta k e n  wit h 
R a di ot hera p y” = “ Ra di ot hera p y wit h dr a w n” o n “ A d verse E v e nts Details” e C R F pa ge).  
Gl o bal Versi o n I D: 
6 5/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
A d verse  E v e nts  Lea di n g  t o  Per ma ne nt  Disc o nti n uati o n  of  at L east O ne  C he m ot hera p y:  A Es 
lea di n g  t o  per ma n e nt  disc o nti n uati o n  of  Car b o plati n, Paclita x el , Cis plati n , Pe metre x e d , or  
Et o p osi de , as defi ne d  a b o ve. 
A d verse E v e nts Lea di n g t o Per ma ne nt Disc o nti n uati o n  of at Least O n e Tri al Dr u g : A Es lea di n g 
t o per ma n e nt disc o nti n uati o n of i m m u n ot hera p y ( defi niti o n a b o ve) or A Es lea di n g t o per ma n e nt 
disc o nti n uati o n of at least o ne c he m ot her a p y ( defi niti o n a b o ve) or p er ma n e nt disc o nti n uati o n of 
at least o ne ra di ot hera p y ( defi niti o n a b o ve).  
A d verse E ve nt s Le a di n g t o De at h  
A Es lea di n g t o deat h (as rec or de d o n t he “ A d verse E ve nts Details” e C R F pa ge, “ C ha n ge i n gra d e” 
= “ N o” a n d o utc o me = “ Fatal” , or “ Gra de” = “ Gra de 5 or deat h relate d t o A E” or “seri o us a d verse 
e ve nt” = “ Yes ” a n d seri o us ness criteria i ncl u d e “ Res ults i n deat h”).  
A d verse E ve nts of S peci al I nterest ( A E SI)  
A d verse E v e nts of S peci al I nt erest ( A E SI) will be i de ntifie d acc or di n g t o a pre -s p ecifie d s earc h 
list usi n g t he last a vaila bl e versi o n of Me d D R A Preferre d T er ms.    
Cate g ories of A E SI c o nsi dere d i ncl u de:  
•  I nf usi o n-relat e d reacti o ns (I R Rs) i ncl u di n g i m me di ate h y p erse nsiti vit y: a n y i nf usi o n-relate d 
reacti o n, or h y p erse nsiti vit y (re ga r dless of gra d e). 
•  ir A Es i ncl u di n g a ut oi m m u ne dis or ders 
 
 
 
 
 
 
. 
•  A ne mia A Es  
•  P ne u m o nitis (ra diati o n -i n d uce d a n d i m m u ne-me diate d) , i ncl u di n g: 
o  Ac ute i nterstitial p ne u m o nitis  
o  I nterstitial l u n g diseas e 
o  P ne u m o nitis  
o  A ut oi m m u ne l u n g diseas e  
o  Ra diati o n -i n d uce d p ne u m o nitis  
N ote  t hat  i m m u ne -m e diate d  p ne u m o nitis  will  b e  re p orte d  t wice:  o n ce  u n der  “ir A E”  a n d 
sec o n dl y u n der “ P ne u m o nitis (ra diati o n-i n d uce d a n d i m m u ne-me diate d)” . 
•  Blee di n g E v e nts  
Blee di n g e ve nts are d efi ne d as t h ose A Es wit h a preferre d ter m acc or di n g t o t he Me d D R A 
f or He m orr ha ge  t er ms (e x cl u di n g la b orat or y ter ms). See Secti o n  1 5. 2.3. 6  f or m ore details. 
Gl o bal Versi o n I D: 
6 6/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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  
All A d verse E ve nts   
A d verse e ve nts will be s u m marize d b y w orst se v erit y acc or di n g t o  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 o r A d v erse  E v e nts  ( N CI -C T C A E ) versi o n  5. 0  per partici pa nt , 
usi n g t he last a vaila ble v ersi o n of Me d D R A preferre d t er m  as e v e nt cate g or y a n d pri mar y S O C 
b o d y ter m as B o d y S yste m cate g or y.  
U nless ot her wise state d , A Es will be dis pla ye d i n ter ms of fre q u e nc y t a bles: preferre d ter m a n d 
pri mar y S O C , i n al p ha betical or der.  
If a n A E is re p orte d f or a gi ve n p artici pa nt m or e t ha n o nce d uri n g t he o n-treat me nt p eri o d , t he 
w orst se verit y a n d t he w orst relati o ns hi p t o st u d y tr eat me nt will be ta b ulate d.  I n case a partici pa nt 
ha s e ve nts wit h missi n g a n d n o n -missi n g gra des, t he ma xi m u m of t he n o n -missi n g gra des will be 
dis pla ye d.  
A ta ble prese nti n g t he o verall s u m mar y of T E A Es , as defi ne d i n Secti o n  1 5. 1, will be prese nte d 
b y treat me nt ar m wit h t h e f oll o wi n g i nf or mati o n:  
•  T E A Es  
•  I m m u n ot hera p y rel ate d T E A Es  
•  C he m ot hera p y  rel ate d T E A Es (b y re gi me n ) 
•  Ra di ot hera p y  rel ate d T E A Es  
•  Seri o us T E A Es  
•  I m m u n ot hera p y rel ate d s eri o us T E A Es 
•  C he m ot hera p y  rel ate d seri o us T E A Es ( b y re gi me n) 
•  Ra di ot hera p y  rel ate d seri o us T E A Es 
•  T E A Es b y N CI -C T C A E se verit y gra d e (  3,  4)  
•  I m m u n ot hera p y rel ate d T E A Es N CI-C T C A E se verit y gra de (  3,  4)  
•  C he m ot hera p y  rel ate d T E A Es N CI-C T C A E se verit y gra de (  3,  4)  (b y re gi me n ) 
•  Ra di ot hera p y  rel ate d T E A Es N CI-C T C A E se verit y gra de (  3,  4)  
•  T E A Es lea di n g t o deat h  
•  I m m u n ot hera p y rel ate d T E A Es lea di n g t o deat h 
•  C he m ot hera p y  rel ate d T E A Es lea di n g t o deat h ( b y re gi me n) 
•  Ra di ot hera p y  rel ate d T E A Es lea di n g t o deat h 
•  A d verse E v e nts of S peci al Int erest (relate d or n o n -relate d as assesse d b y i n vesti gat or) :  
o  I R R 
o  ir A Es 
Gl o bal Versi o n I D: 
6 7/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
o  T G F β i n hi biti o n  me diate d s ki n reacti o ns  
o  A ne mia A Es  
o  Ra diati o n/i m m u ne  -me diate d p ne u m o nitis A Es  
o  Blee di n g A Es  
•  I m m u n ot hera p y-relate d Ad verse E ve nt  of s pecial i nterest  (relati o ns hi p wit h i m m u n ot hera p y 
as assesse d b y i n vesti gat or  i n t he “ A d verse E ve nts Details” e C R F pa ge ): 
o  I R R 
o  ir A Es 
o  T G F β i n hi biti o n me diate d s ki n reacti o ns  A ne mia A Es  
o  Ra diati o n/i m m u ne me diate d p ne u m o nitis A Es  
o  Blee di n g A Es  
Ta bles f or T E A Es fre q u e nc y c orres p o n di n g t o eac h cate g or y bel o w will be pr o vi de d b y Me d D R A 
pri mar y  S O C  ( or d ere d  al p ha beticall y)  a n d preferre d  ter m ( or dere d  al p ha beticall y).  Eac h 
partici pa nt will be c o u nte d o nl y o nce wit hi n eac h preferre d t er m or S O C.  
•  T E A Es   
•  I m m u n ot hera p y rel ate d T E A Es 
•  C he m ot hera p y  rel ate d T E A Es ( b y c o m p o u n d ) 
•  Ra di ot hera p y  rel ate d T E A Es 
•  T E A Es lea di n g t o deat h  
•  I m m u n ot hera p y rel ate d T E A Es lea di n g t o deat h 
•  C he m ot hera p y  rel ate d T E A Es lea di n g t o deat h ( b y c o m p o u n d ) 
•  Ra di ot hera p y  rel ate d T E A Es lea di n g t o deat h 
T he f oll o wi n g fre q u e nc y ta bles will be pr o vi de d b y w orst gra de, S O C, a n d preferre d t er m : 
•  T E A Es  
•  I m m u n ot hera p y rel ate d T E A Es  
•  C he m ot hera p y  rel ate d T E A Es ( b y c o m p o u n d ) 
•  Ra di ot hera p y  rel ate d T E A Es  
•  Blee di n g E v e nts  
•  I m m u n ot hera p y rel ate d Blee di ng e v e nts  
E v al u ati o n of C O VI D -1 9 effects o n A Es  
T he direct effect  of C O VI D -1 9 f or A Es will be assesse d b y mea ns of:  
Gl o bal Versi o n I D: 
6 8/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  A n o ver vie w ta bl e of treat me nt -e mer ge nt A Es ass ociate d t o C O VI D -1 9 b y Me d D R A pri mar y 
S O C, hi g h le vel ter ms ( H L T) a n d P Ts ( or dere d al p ha beticall y).  
C O VI D -1 9 A Es will  be i de ntifie d usi n g t he  M e d D R A  S M Q ‘ C O VI D-1 9 ’. 
Cli nic altri als. g o v a n d E u dr a C T -R e q uire me nts  
S u m mar y ta bles f or n o n -seri o us T E A Es e x cl u di n g S A Es a p pl yi n g fre q ue n c y t hres h ol d of 5 % will 
be pr o vi de d.  
A listi n g of A Es will c o ntai n t he f oll o wi n g i nf or mati o n: treat me nt ar m, partici pa nt i de ntifier, a ge, 
se x,  race, preferre d  t er m ,  re p ort e d  ter m  f or  t he A E  (In v esti gat or  ter m),  start  a n d  e n d  d ate  f or 
i m m u n ot hera p y,  c he m ot hera p y, a n d  ra di ot hera p y  a n d  t heir  c u m ulati ve  d ose  a n d  n u m ber  of 
i nf usi o ns/fracti o ns, d urati o n of A E (i n da ys), e ve nt start or c ha n ge date a n d e n d date, da y si nce 
m ost  rece nt  a d mi nistrati o n  pri or  t o  A E  o nset/c ha n ge,  relati o ns hi p  t o  st u d y  treat me nt 
(i m m u n ot hera p y,  c h e m ot hera p y, a n d  ra di ot hera p y),  t o xicit y  gra de, acti o n(s)  ta ke n  o n 
i m m u n ot hera p y, c he m ot hera p y a n d ra di ot hera p y, o utc o me, seri o us ness ( yes, n o), a n d A E SI ( yes, 
n o) . A Es  w hic h  lea d  t o  c he m ot hera p y  s witc h  will  be  fla g ge d. T his  listi n g  will  be  s orte d  b y 
treat me nt ar m, partici pa nt i de ntif ier, start date of A E a n d A E preferre d t er m . 
Listi n gs will als o be pr o vi de d wit h t he rele va nt i nf or mati o n:  
•  T E A Es  
•  A Es wit h o nset or w orse ni n g date after t he o n -tr eat me nt peri o d. 
T he f oll o wi n g fi g ures will be dis pla ye d:  
•  T E A Es wit h ris k differe n ce ≥ 5 % bet w ee n tr eat me nt ar ms  
•  Seri o us T E A Es wit h ris k differe n ce ≥ 5 % b et wee n treat me nt ar ms  
E v al u ati o n of P ote nti al Effect of A D A o n M 7 8 2 4 S af et y  
T he o verall s u m mar y of t he A Es ta ble as descri b e d a b o ve will als o be pr o vi de d b y A D A stat us 
(e ver p ositi ve, ne v er p ositi ve). 
A listi n g of all A Es (i ncl u di n g I R R) f or e v er -p ositi ve A D A partici p a nts ( pre -e xisti n g, tra nsie nt 
treat me nt-e mer ge nt,  persiste nt -treat me nt  e mer ge nt)  will  be  pre pare d  i ncl u di n g  partici pa nt 
i de ntifier a n d s h o wi n g t h e date(s) of t he p ositi ve A D A res ult t o get h er wit h t he A Es or I R Rs. F or 
t he A Es a n d I R Rs, start a n d st o p date will be s h o w n al o n g wit h gra de. A d verse e ve nts rec or de d 
d uri n g t he peri o d of 2 -wee ks pri or t o t he p os iti ve A D A val ue till t w o wee ks after t he p ositi ve A D A 
val ue will be fla g ge d.  
1 5. 1. 2  
A d verse  
E ve nts  
Le a di n g  
t o 
St u d y 
I nter ve nti o n Disc o nti n u ati o n   
T he f oll o wi n g fre q ue nc y ta ble s, as defi n e d i n Secti o n  1 5. 1,  will be pre p are d f or t he T E A Es acti o ns 
o verall a n d b y pri mar y S O C a n d preferre d ter m i n al p ha betical or d er: 
Gl o bal Versi o n I D: 
6 9/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  T E A Es lea di n g t o te m p orar y disc o nti n uati o n of at least o ne st u d y dr u g  
•  T E A Es lea di n g t o te m p orar y i m m u n ot hera p y disc o nti n uati o n  
•  T E A Es lea di n g t o te m p orar y c h e m ot hera p y dis c o nti n uati o n  
•  T E A Es lea di n g t o te m p orar y ra di ot hera p y disc o nti n uati o n  
•  I m m u n ot hera p y rel ate d T E A Es lea di n g t o te m p orar y i m m u n ot hera p y disc o nti n uati o n  
•  C he m ot hera p y  related  T E A Es  lea di n g  t o  te m p orar y  c h e m ot hera p y  disc o nti n uati o n  ( b y 
re gi me n) 
•  Ra di ot hera p y  rel ate d T E A Es lea di n g t o te m p orar y ra di ot hera p y disc o nti n u ati o n  
•  T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of at least o ne st u d y i nter ve nti o n 
•  T E A Es lea di n g t o per ma ne nt i mm u n ot hera p y dis c o nti n uati o n  
•  T E A Es lea di n g t o per ma ne nt c he m ot hera p y disc o nti n uati o n  
•  T E A Es lea di n g t o per ma ne nt ra di ot hera p y disc o nti n uati o n  
•  I m m u n ot hera p y rel ate d T E A Es lea di n g t o per ma n e nt i m m u n ot hera p y dis c o nti n uati o n  
•  C he m ot hera p y  relate d  T E A Es  lea di n g  to  per ma ne nt  c he m ot hera p y  disc o nti n uati o n ( b y 
re gi me n) 
•  Ra di ot hera p y  rel ate d T E A Es lea di n g t o per ma n e nt ra di ot hera p y disc o nti n u ati o n.  
•  T E A Es lea di n g t o d ose re d ucti o n of c he m ot hera p y  
•  C he m ot hera p y rel ate d T E A Es lea di n g t o d ose re d ucti o n of c he m ot hera p y  
T he listi n g  of  A Es  lea di n g  t o  per ma ne nt  treat me nt  disc o nti n uati o n  will  pr o vi de  rele va nt 
i nf or mati o n (as des cri be d i n Secti o n  1 5. 1. 1), s ort e d b y partici pa nt i d e ntifier, start d ate of A E a n d 
A E p referre d ter m.  
1 5. 2  
De at hs, Ot her  Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts   
1 5. 2. 1  
De at hs   
All deat hs, deat hs wit hi n 3 0 da ys after last d ose of st u d y i nter ve nti o n, deat h wit hi n 6 0 da ys after 
first d ose as well as reas o n f or deat h, will be ta b ulate d base d o n i nf or mati o n fr o m t he “ Deat h” 
pa ge.  
•  N u m ber of d eat hs  
•  N u m ber of d eat hs wit hi n 3 0 da ys after l ast d ose of st u d y i nter ve nti o n  
•  N u m ber of d eat hs wit hi n 6 0 da ys after first d ose of st u d y i nter ve nti o n 
•  Pri mar y reas o n f or deat h:  
o  Pr o gressi ve disease a n d/ or disease relate d c o n diti o n  
Gl o bal Versi o n I D: 
7 0/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
o  E ve nt u nrelate d t o st u d y i nter ve nti o n. 
o  E ve nt r elate d t o st u d y i nter ve nti o n, i ncl u di n g: 
o  E ve nt relate d t o im m u n ot hera p y  
o  E ve nt relate d t o che m ot hera p y  
o  E ve nt relate d t o ra di ot hera p y 
o  U n k n o w n . 
I n a d diti o n, date a n d ca use of d eat h will be pr o vi de d i n a n i n di vi d ual s u bject data listi n g t o get h er 
wit h  treat me nt ar m, p artici pa nt  i de ntifier,  s e x,  race,  a ge, sel ecte d  d osi n g  i nf or mati o n  (st u d y 
i nter ve nti o n recei ve d, dat e of first/last a d mi nistrati o n, a n d d ose a n d n u m ber of i nf usi o ns /fracti o ns) 
a n d will i ncl u de c ol u m ns f or:  
•  A Es wit h fatal o utc o me ( list of preferre d t er ms f or A Es wit h o utc o me =fatal, Gra de 5 or Seri o us 
res ulti n g i n deat h). 
•  A ut o ps y perf or me d ( yes, n o, u n k n o w n)  
•  Fla g f or d eat h wit hi n 3 0 da ys of last st u d y i nter ve nti o n. 
•  Fla g f or d eat h wit hi n 6 0 da ys of first st u d y i nter ve nti o n. 
1 5. 2. 2  
Seri o us A d verse E ve nts   
T he n u m ber of s u bjects wit h S A Es will be descri be d b y S O C a n d preferre d ter m :  
•  S A Es  
•  S A Es r elate d t o im m u n ot hera p y, ch e m ot hera p y or ra di ot hera p y  
T he listi n g of S A Es will als o pr o vi de  t he rel e va nt i nf or mati o n (as descri be d  i n Secti o n  1 5. 1. 1). 
1 5. 2. 3  
A d verse E ve nts of S peci al I nterest   
A listi n g s u m marizi n g A E SI  will be dis pla ye d  c o ntai ni n g t he f oll o wi n g i nf or mati o n: treat me nt 
ar m, partici pa nt i de ntifier, a ge, se x, race, preferre d ter m , re p orte d ter m f or t he A E  (In vesti gat or 
ter m), start a n d e n d date f or i m m u n ot hera p y, c he m ot hera p y, a n d ra di ot hera p y a n d t heir c u m ulati ve 
d ose a n d n u m ber of i nf usi o ns/fracti o ns, d urati o n of A E (i n da ys), e ve nt start or c ha n ge d ate a n d 
e n d date, d a y si nce first a d mi nistrati o n of st u d y dr u g ( da ys), d a y si nce m ost rece nt a d mi nistrati o n 
pri or t o A E o nset/c ha n ge ( da ys), t o xicit y gra de, o utc o me, seri o us ness (yes, n o ), A E SI : I R R (yes, 
n o ), I R R: reacti o n (yes, n o ), I R R: si g n a n d s y m pt o m ( yes, n o), i m m u ne-relate d reacti o n ( yes, n o), 
s ki n  A E SI ( yes,  n o),   ane mia ( yes,  n o), p ne u m o nitis  (ra diati o n/i m m u ne  me diate d)  ( yes,  n o ), 
blee di n g ( yes, n o) . T his listi n g will be s orte d b y tr eat me nt ar m, partici pa nt i de ntifier,  start date of 
A E , a n d A E preferre d t er m . 
A Pre -s pecifie d Searc h List of Me d D R A Preferre d Ter ms c o nsi dere d as A E SI will be pr o vi de d.  
Gl o bal Versi o n I D: 
7 1/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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. 3. 1  
I nf usi o n-rel ate d 
R e acti o ns 
Incl u di n g 
Im me di ate 
H y per se nsiti vit y  
I R Rs are defi ne d as A Es  wit h preferre d ter ms o n a pre -s p ecifie d list of M e d D R A preferre d t er ms 
a n d di vi de d i nt o Reacti o ns vs Si g ns a n d S y m pt o ms . 
Re acti o ns  of  I R R:  s h oul d  be  c o nsi dere d  w he n  o nset  is  o n  t he  da y  of  i m m u n ot hera p y a n d/ or 
c he m ot hera p y i nf usi o n ( d uri n g or after t he i nf usi o n) or t he da y after t he i nf usi o n (irres p ecti ve of 
res ol uti o n  date)  f or  a n y  i nf usi o n-relate d  reacti o n,  dr u g  h y p erse nsiti vit y,  a na p h yl actic  reacti o n, 
h y perse nsiti vit y a n d/ or T y p e  1 h y p erse nsiti vit y.  
Si g ns  a n d  s y m pt o ms  of  I R Rs  a n d  h y perse nsiti vit y/ aller gic  re acti o ns:  s h o ul d  be  c o nsi dere d 
w he n o nset  is  o n t he da y  of  i m m u n ot hera p y a n d/ or c he m ot hera p y i nf usi o n  ( d uri n g  or after t h e 
i nf usi o n) a n d resol ve d c o m pletel y wit h t he e n d d ate wit hi n 2 da ys after o ns et.  
I R R will be s u m marize d b y t he f oll o wi n g varia bles per s u b gr o u p of I R R a n d o verall: 
•  N u m ber  of  partici pa nts  wit h  at  least  o ne  I R R  b y  t he  w orst  N CI -C T C A E  t o xicit y  gra de 
( Gra d e 1/ Gra d e 2/ Gra d e 3/  Gra de 4/ Gra de 5/ missi n g gra d e)  
•  N u m ber of partici pa nts wit h I R R lea di n g t o per m a ne nt i m m u n ot hera p y dis c o nti n uati o n  
•  Ti me relate d t o first o nset (I nf usi o n 1/ I nf usi o n 2/ I nf usi o n 3/ I nf usi o n 4 or later).   
T he e v e nts s h o ul d be assi g ne d t o t he act ual dr u g i nf usi o ns t hat t he partici pa nt recei ve d, n ot t o t he 
pla n ne d dates.  A n I R R is assi g ne d t o a dr u g i nf usi o n if its o nset is at t he sa me date ( b ut n ot bef ore 
d osi n g) or t h e f oll o wi n g da y of dr u g i nf usi o n.   
A  fre q u e nc y ta ble of I R R A Es b y w orst gra d e, S O C, a n d preferre d t er m will be pr o vi de d.  
A listi n g of I R Rs f or b ot h reacti o ns a n d si g ns a n d s y m pt o ms will als o be pr o vi de d wit h t he rele va nt 
i nf or mati o n (as descri be d  i n Secti o n  1 5. 1. 1). 
1 5. 2. 3. 2  
I m m u ne-rel ate d Ad verse E ve nts   
ir A Es will be i de ntifie d pr o gra m maticall y. A Es w hic h satisf y all of t he f oll o wi n g criteria will be 
fla g ge d as i m m u ne-relate d: 
1 - T he A E P T  matc hes a P T  o n t he list of pre -sele cte d Me d D R A ter ms  
2 - T he A E o nset  or w ors e ni n g  occ urs after t he first i m m u n ot hera p y a d mi nistrati o n a n d n o 
m ore t ha n 9 0 da ys after  i m m u n ot hera p y l ast d ose 
3 - O n  t he  “ A d verse  E v e nts  Details”  e C R F  pa ge,  t he  q uesti o n  “ Were  C ortic oster oi ds, 
I m m u n os u p pressa nts, or H or m o nal T hera p y ( E g. T h yr oi d) A p plie d? ” has t he a ns wer “ Yes” 
selecte d 
4 - O n t he “ i m A E S pecific Q uesti o ns” e C R F pa ge, eit her:  
Gl o bal Versi o n I D: 
7 2/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
a)  T he q uesti o n “ D oes a n y of t he f oll o wi n g pr o vi d e a clear eti ol o g y f or t he e ve nt? ” 
has  t he  a ns wer  “ N o”  selecte d,  i n dicati n g  t hat  t he  A E  is  n ot  attri b uta ble  t o 
u n derl yi n g  ca ncer  diseas e/ P D,  pri or  or  c o nc o mita nt  me dicati o ns/ pr oce d ures,  n or 
a n ot her me dical c o n d iti o n s uc h as a n i nf ecti o n or pre-e xisti n g disease  
O R  
b)  T he “i m A E S pecific Q uesti o ns” e C R F pa ge i n dicates t hat a bi o ps y was perf or me d 
a n d  t he  q u esti o n  “Is  t he  hist o pat h ol o g y/ bi o ps y  c o nsiste nt  wit h  a n  i m m u ne -
me diate d e ve nt? ” has t he a ns wer “ Yes ” select e d.  
In  t h e  cas e  t hat  criteria  ( 1)  t hr o u g h  ( 3)  are  met,  a n d  e ntries  f or  c o n diti o n  ( 4)  are  missi n g,  t he 
f oll o wi n g r ules will be a p plie d:  
•  If t he a ns wer t o “ D oes a n y of t he f oll o wi n g pr o vi d e a clear eti ol o g y f or t he e ve nt? ” ( 4a) is 
missi n g, t he e ve nt will b e c o nsi dere d as ir A E (irres pecti ve of bi o ps y res ults).  
•  If t h e a ns wer t o “Is t he hist o pat h ol o g y/ bi o ps y c o nsiste nt wit h a n i m m u ne-me diate d e ve nt? ” 
( 4 b) is missi n g, or if n o bi o ps y was perf or me d, a n d c o n diti o n ( 4a) is n ot satisfie d (i.e. “ Yes” 
is selecte d as t he a ns wer t o t he q uesti o n “ D o es a n y of t he f oll o wi n g pr o vi d e a cle ar eti ol o g y 
f or t he e v e nt? ”), t he e ve nt will be c o nsi dere d as a n o n-ir A E. 
P Ts will be c o m pile d i nt o cate g ori es: I m m u n e -me diate d ras h, I m m u ne -me diate d c olitis, I m m u ne -
me diate d  p ne u m o nitis,  I m m u ne -me diate d  h e p atitis,  I m m u ne -me di ate d  ne p hritis  a n d  re n al 
d ysf u ncti o n,  I m m u ne -me diate d  e n d ocri n o p at hies  ( A dre n al  i ns ufficie nc y,  H y p o g o na dis m, 
Pit uitar y  d ysf u ncti o n,  T y p e  1  Dia b etes  Mellit us,  T h yr oi d  dis or ders),  Ot her  i m m u ne -me diate d 
m y ositis, Ot her i m m u ne -me diate d a d verse e v e nts.  
A n o ver vie w t a ble of ir A Es c o ntai ni n g fre q u e nc y of partici pa nts  wit h:  
•  At least o ne ir A E b y w orst gra d e  
•  At least o ne st u d y i nter ve nti o n relate d ir A E b y w orst gra de  
•  I m m u ne-relat e d A E SI lea di n g t o per ma ne nt treat me nt disc o nti n uati o n 
•  Ser i o us ir A Es. 
F re q u e nc y ta ble of ir A Es b y w orst gra de, cate g or y, a n d P T will als o be pr o vi de d.  
A  listi n g of ir A Es will als o  be pr o vi de d wit h  t he rele va nt  i nf or mati o n  (as  descri be d  i n Secti o n  
1 5. 1. 1 ). 
1 5. 2. 3. 3  
T G F -β i n hi biti o n me di ate d S ki n Re acti o ns   
T G F β  i n hi biti o n me diate d  s ki n  reacti o ns will  b e  sele cte d  bas e d  o n  M e d D R A preferre d  ter ms  
acc or di n g t o a pre -s p ecifi e d Me d D R A searc h list:  
N arr o w D efi niti o n  
•  K A  
Gl o bal Versi o n I D: 
7 3/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
•  S C C of s ki n  
Br o a d D efi niti o n   
Br oa d d efi niti o n h as a d diti o nal P Ts:  
•  H y p er kerat osis  
•  Acti nic kerat osis  
•  Basal cell carci n o ma  
•  Li p S q ua m o us Cell Carci n o ma  
•  B o we n´s Diseas e  
A ta ble f or fre q u e nc y of s ki n T E A Es  will be pr o vi de d b y Me d D R A P Ts (i ncl u di n g b ot h narr o w 
a n d br oa d defi niti o n P Ts).  
A listi n g of s ki n A Es will als o be pr o vi de d wit h t he rele v a nt i nf or mati o n ( as descri b e d i n Secti o n  
1 5. 1. 1 ). 
1 5. 2. 3. 4  
A ne mi a A d verse E ve nts   
T he f oll o wi n g H L Ts a n d P Ts ( usi n g t he latest versi o n of Me d D R A a vaila bl e) will be use d t o select 
t he a nae mia A Es:  
•  A nae mias N E C ( H L T)  
•  A nae mias hae m ol ytic i m m u ne ( H L T)  
•  A nae mias ha e m ol ytic N E C ( H L T)  
•  Hae m o gl o bi n decreas e d ( P T)  
A n  o ver vie w  ta ble  f or o n -treat me nt a n ae mia A Es  will  be  pr o vi de d,  dis pla yi n g  t he  n u m b er  of 
partici pa nts  wit h :  
•  A t least o ne a nae mia b y w orst gra de  
•  At least o ne i m m u n ot hera p y relate d a nae mia b y w orst gra de  
•  A nae mi a lea di n g t o p er m a ne nt i m m u n ot hera p y dis c o nti n uati o n  
•  Seri o us a nae mia  
T he listi n g of a ne mia A Es  will be pr o vi de d wit h t he rele v a nt i nf or mati o n ( as descri be d  i n Secti o n  
1 5. 1. 1 ). 
Gl o bal Versi o n I D: 
7 4/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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. 3. 5  
R a di ati o n/i m m u ne -me di ate d P ne u m o nitis A d verse E ve nts   
Ra diati o n/i m m u ne  me diate d  p ne u m o nitis A Es  are  defi ne d  o n  a  pre -s p ecifie d  list  of  Me dical 
Dicti o nar y f or Re g ulat or y Acti vities ter ms ( Me d D R A latest v ersi o n) a n d i n t he “i m m u ne-relate d 
p ne u m o nitis” cate g or y i n t he ge neral ir A E list. It i ncl u des t he f oll o wi n g ter ms:  ac ute i nterstitial 
p ne u m o nitis ,  interstitial  l u n g  disease ,  pne u m o nitis , aut oi m m u ne  l u n g  disease  a n d  ra diati o n -
i n d uce d p ne u m o nitis. 
T he listi n g of Ra diati o n /i m m u ne me diate d p ne u m o nitis A Es  will be pr o vi de d wit h t he rele va nt 
i nf or mati o n (as descri be d  i n Secti o n  1 5. 1. 1). 
1 5. 2. 3. 6  
Blee di n g A d verse E ve nts   
B lee di n g e v e nts are d efi ne d as A Es  wit h P Ts acc or di n g t o t he Me d D R A f or He m orr h a ge  ter ms 
(ex cl u di n g  la b orat or y  ter ms).  Blee di n g  e ve nts  a n d st u d y dr u g  relate d  blee di n g  e ve nts  will  be 
s u m marize d i n a fre q ue n c y ta ble prese nti n g S O C a n d P T s orte d b y al p ha b etica l or der. T h e w orst 
gra de per partici p a nt, per S O C , a n d per P T will be re p orte d:  
 
•  A n y gra de (i ncl u di n g missi n g gra d e)  
•  Gra de 1  
•  Gra de 2  
•  Gra de 3  
•  Gra de 4  
•  Gra de 5  
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n   
O n -treat me nt  la b orat or y  val ues  (i ncl u di n g  c orres p o n di n g  n or mal  ra n ges)  c o n verte d t o sta n dar d 
u nits will be use d f or s u m mar y statistics a n d s hift ta bles ( o n -treat me nt peri o d define d i n Secti o n  
9 ).  
A  s u m mar y  t a ble  o ver  ti me  b y  tr eat me nt  ar m  will  be  dis pla ye d,  i n cl u di n g a bs ol ute  v al ues  a n d 
a bs ol ute c ha n ge  fr o m Baseli ne  val ues p er  visit.  O nl y  para met ers  a n d  visits  wit h  at  least  2 
o bser v ati o ns a vaila ble  will be dis pla ye d.  
La b orat or y res ults will be classifie d acc or di n g t o t he N CI -C T C A E Versi o n 5. 0 a n d as s pecifie d i n 
A p pe n di x  2 .  A d diti o nal  la b orat or y  res ults  t hat  are  n ot  part  of  N CI-C T C A E  will  be  prese nte d  
acc or di n g t o t he cate g ories: l o w, n or mal a n d hi g h (acc or di n g t o t he la b orat or y n or mal ra n ges).  
Q ua ntitati ve data will be e x a mi ne d f or tr e n ds usi n g descri pti ve statistics ( m ea n, St D, m e dia n, Q 1, 
Q 3, m i n, a n d m a x) of act ual Baseli ne  val u es, o n -treat me nt values , a n d c h a n ges fr o m Bas eli ne  t o 
eac h o n-treat me nt visit o ver ti me. T he c h a n ges c o m p ute d will be t he differe nces fr o m Baseli ne . 
Q ualitati ve data b ase d o n refere n ce ra n ges will be descri be d acc or di n g t o t h e cat e g ories (i. e. l o w, 
n or mal, a n d hi g h).  
Gl o bal Versi o n I D: 
7 5/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
L a b or at or y P ar a meters wit h N CI -C T C G r a des A v ail a ble  
La b orat or y  para meters  wit h  N CI -C T C  gra des  a vaila ble  will  be  a nal yz e d  wit h  t heir  res pecti ve 
N CI -C T C na me a n d dir ecti o n of a b n or malit y. F or para m eters w hic h are gra de d wit h b ot h l o w a n d 
hi g h val u es, t he t o x icities will be s u m marize d se paratel y. L o w directi o n t o xicit y gra des at Baseli ne  
a n d p ost -Baseli ne  will be set t o 0 w he n t he varia bles are deri ve d f or s u m marizi n g hi g h directi o n 
t o xicit y, a n d vice versa.  
F or gra da ble para met ers, t he f oll o wi n g s u m maries wi ll be dis pla ye d b y tr eat me nt ar m: 
•  N u m ber a n d p erce nta ge of partici pa nts b y w orst o n -treat me nt gra de (≥ 1, ≥ 3, ≥ 4)  
•  S hift i n t o xicit y gra di n g fr o m Baseli ne  t o hi g hest o n -treat me nt gra de.  
T he defi niti o ns of t he N CI -C T C A E t o xicit y gra d e V ersi o n 5. 0 f or eac h para meter are pr o vi d e d i n 
A p pe n di x 2 .  
F or c alci u m, C T C A E gra di n g is base d o n C orrect e d Calci u m a n d I o niz e d Calci u m ( C A L CI O), if 
a vaila ble. C orrecte d Calci u m is calc ulate d fr o m Al b u mi n a n d Calci u m as f oll o ws:  
o  C orrecte d  cal ci u m  ( m m ol/ L)  =  me as ure d  t otal  calci u m  ( m m ol/ L)  +  0. 0 2  ( 4 0 –  s er u m 
al b u mi n [ g/ L])  
C re ati ni ne Cle ar a nce ( Cr Cl)  will be d eri ve d t hr o u g h t h e C oc kcr oft -Ga ult f or m ula ( C oc kcr oft 
a n d Ga ult, 1 9 7 6) , fr o m t he ser u m creati ni ne meas ure me nts i n t he “ F U L L S E R U M CH E MI S T R Y 
P A N E L A” a n d “ C O R E C H E MI S T R Y” e -C R F  p a ges, t he wei g ht i n t he “ VI T A L SI G N S” e-C R F 
pa ge a n d t he a ge re -calc ulate d at t he sa m pli n g d ate as f oll o ws:  
•  𝑖𝑚𝑚𝑢= 𝑛𝑜𝑡𝑒𝑟𝑎∗(1 4 0 −𝑝𝑦𝑀) ∗
𝑎𝑥
𝑖𝑚𝑢𝑚𝐶∗0 .8 1 3 6  
o  w here  F A C T O R is  ge n d er -de p e n de nt  wit h  v al ue  1 ( male) or 0. 8 5 (fe male), A G E is  t he 
s u bject  a ge  i n  years,  W T  is  t he  s u bject  w ei g ht  i n  k g  a n d  S C R E A  is  t he  o bser ve d  s er u m 
creati ni ne i n u m ol/l.  
o  T o xicit y  gra di n g  f or  creati ni ne  cleara n ce  will  be  defi ne d  as  per  N CI -C T C A E  t o xicit y 
gra di n g versi o n 5. 0, t he f oll o wi n g n or mal ra n ges will be c o nsi dere d: 1 1 0 t o 1 5 0  m L/ mi n 
i n males a n d 1 0 0 t o 1 3 0 m L/ mi n i n fe males.  
L a b or at or y P ar a meters wit h N CI -C T C G r a des N ot A v ail a ble  
F or all n o n -gra da ble para meters, t he f oll o wi n g s u m maries will be dis pla ye d b y treat me nt ar m: 
•  S hift fr o m Baseli ne  t o l o west o n-treat me nt v al ue (classifie d as n or mal, hi g h, l o w) 
•  S hift fr o m Baseli ne  t o t h e hi g h est o n-treat me nt v al ue (classifie d as n or mal, hi g h, l o w) 
•  N u m ber a n d p erce nta ge of partici pa nts b y w or st o n-treat me nt v al ue (classifie d as n or mal, hi g h, 
l o w). 
Gl o bal Versi o n I D: 
7 6/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Li ver F u ncti o n T ests  
T he n u m ber a n d perce nt a ge of partici pa nts wit hi n eac h of t he f oll o wi n g li ver f u ncti o n cate g ories  
( base d o n ala ni ne a mi n otra nsferase [ A L T], as p art ate a mi n otra nsferase [ A S T], u p per li mit n or mal 
[ U L N] a n d t otal bilir u bi n v al ues) d uri n g t he o n -tr eat me nt peri o d will be des cri be d: 
•  A L T <  3  ×  U L N, A L T ≥ 3 × U L N, A L T ≥ 5 × U L N, A L T ≥ 1 0  ×  U L N, A L T ≥ 2 0  ×  U L N  
•  A S T <  3  ×  U L N, A S T ≥ 3 × U L N, A S T ≥ 5 x U L N, A S T ≥ 1 0  ×  U L N, A S T ≥ 2 0  ×  U L N  
•  ( A L T a n d A S T) < 3  ×  U L N, ( A L T or A S T)  ≥ 3  ×  U L N, ( A L T or A S T) ≥ 5  ×  U L N, ( A L T or 
A S T) ≥ 1 0  ×  U L N, ( A L T or A S T)  ≥ 2 0  ×  U L N  
•  T otal bilir u bi n < 2 × U L N, t otal bilir u bi n ≥ 2  ×  U L N  
•  C o nc urre nt A L T ≥ 3  ×  U L N a n d t otal bilir u bi n ≥ 2  ×  U L N  
•  C o nc urre nt A S T ≥ 3  ×  U L N a n d t otal bilir u bi n ≥ 2  ×  U L N  
•  C o nc urre nt ( A L T or A S T)  ≥ 3  ×  U L N a n d t otal bilir u bi n ≥ 2  ×  U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3  ×  U L N a n d t otal bilir u bi n ≥ 2  ×  U L N a n d A L P > 2  ×  U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3  ×  U L N a n d t otal bilir u bi n ≥ 2  ×  U L N a n d (A L P ≤ 2  ×  U L N or 
missi n g ) 
C o nc urre nt meas ure me nts are t h ose occ urri n g o n t he sa me date.  Cate g ori es will be c u m ulati ve, 
i.e., a partici pa nt wit h a n ele vati o n of A S T ≥ 1 0  ×  U L N will als o a p pear i n t he cate g ories ≥ 5  ×  
U L N a n d ≥ 3  ×  U L N.  
A pl ot of pea k A L T vers us pea k t otal bilir u bi n ( T BI LI), b ot h relati ve t o t he U L N will be pr o vi de d. 
T his  e DI S H  pl ot  (e val u ati o n  of  dr u g -i n d u ce d  s eri o us  he pat ot o xicit y)  will  be  di vi de d  i nt o  4 
q ua dra nts b y t he li nes t hr o u g h A L T ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N. T he left l o wer q ua dra nt is 
t he n  c o nsi dere d  n or mal  or  i nsi g nifica nt  ele v ati o ns i n  li ver c he mistries;  t he  u p per  q u a dra nts 
i n dicate patie nts wit h p ossi ble Gil bert’s c h olestasis; t he ri g ht u p per q ua dra nt are t he p ossi ble H y’s 
La w patie nts; t he ri g ht l o wer q ua dra nt is p ossi ble Te m ple’s C or ollar y ( pati e nts wit h A L T ≥ 3 x U L N 
b ut n ot satisf yi n g H y’s La w).  A pl ot of pea k A S T vers us pea k t otal bilir u bi n, b ot h relati ve t o t he 
U L N will be als o pr o vi de d . 
A pl ot of pea k A S T vers us pea k t otal bilir u bi n, b ot h relati ve t o t he U L N will be als o pr o vi de d.  
Se parate  listi n gs  of  he m at ol o g y  a n d  bi oc h e mistr y  will  be  create d.    Eac h  listi n g  will  i ncl u de 
treat me nt ar m, partici pa nt i de ntifier, a ge, se x, race, wei g ht,  eac h st u d y i nt er ve nti o n first a n d last 
d ose , c u m ulati ve d ose a n d n u m ber of i nf usi o ns/fracti o ns, la b orat or y p ara meter ( u nits), visit, date, 
val ue, c ha n ge fr o m Bas eli ne , l o wer li mit of n or mal ( L L N), U L N, i n dicat or of n or mal ra n ge (l o w, 
n or mal,  hi g h), t o xicit y  gra de acc or di n g t o  N CI -C T C A E , a n d hi g hest/l o west  o n treat me nt  val ue 
fla g.  T h ese listi n gs will be s ort e d b y treat me nt ar m, s u bject i de ntifier, la borat or y me as ure m e nt 
date , a n d para meter . T he Baseli ne  val ues a n d p ost -Baseli ne  v al ues after t he o n -treat me nt peri o d 
will be fla g ge d.  
I n a d diti o n, a listi n g of all T BI LI, A L T, A S T a n d al kali ne p h os p hatase ( A L P) val ues f or s u bjects 
wit h  a  p ost -Baseli ne  T BI L I  ≥  2 × U L N,  A L T  ≥  3 × U L N  or  A S T  ≥  3 × U L N  will  be  pr o vi de d, 
Gl o bal Versi o n I D: 
7 7/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
i ncl u di n g  val ues  e x presse d  as  m ulti ples  of  U L N.  T he  sa me  i nf or mati o n  as  he mat ol o g y  a n d 
bi oc he mistr y listi n gs will be pr o vi de d.  
He m ost ase ol o g y, U ri n al ysis/ U ri n al ysis M icr osc o pic E v al u ati o n, H or m o n al T ests, S er ol o g y  
All test res ults f or he m ostase ol o g y, uri nal ysis / uri nal ysis micr osc o pic e val uati o n, h or m o nal tests, 
ser ol o g y will be liste d. 
He m ostase ol o g y listi n g will i ncl u de treat me nt ar m, partici pa nt i de ntifier, a ge, se x, race, eac h st u d y 
i nter ve nti o n first  a n d last d ose, c ollecti o n date a n d ti me ( or n ot  d o ne), pr ot hr o m bi n ti me (sec), 
pr ot hr o m bi n  ti me/sta n dar d  ( %  or  rati o),  acti vate d  partial  t hr o m b o plasti n  ri me  (sec),  acti vate d 
P T T/sta n dar d ( % or rati o), pr ot hr o m bi n i nter nati o nal n or malize d rati o.  
Uri nal ysis/ Uri n al ysis  Mi cr osc o pic  E v al uati o n  listi n g  will  i ncl u de  treat m e nt  ar m,  partici p a nt 
i de ntifier, a ge, s e x, race, la b orat or y para meter ( u nits), visit, c ollecti o n date a n d ti me ( or n ot d o ne), 
val ue.  
H or m o nal Tests listi n g will i ncl u de treat me nt ar m, partic i pa nt i de ntifier, a ge, se x, race, eac h st u d y 
i nter ve nti o n  first  a n d  last  d ose,  c ollecti o n  date  a n d  ti me  ( or  n ot  d o ne),  T h yr otr o pi n  ( T h yr oi d-
Sti m ulati n g H or m o ne; T S H) ( u nit), T h yr o xi ne Free ( Free T 4) ( u nit).  
Ser ol o g y  listi n g  will  i ncl u de  treat me nt  ar m,  part ici pa nt  i de ntifier,  a ge,  se x,  race,  eac h  st u d y 
i nter ve nti o n first a n d last d ose, i nf or mati o n o n He patitis B Vir us / He patitis C Vir us Testi n g a n d 
(i.e. c ollecti o n date a n d ti me ( or n ot d o ne), met h o d a n d res ult) , i nf or mati o n o n He patitis B D N A 
/ He patitis C R N A (i.e. c ollecti o n date a n d ti me ( or n ot d o ne) a n d res ult).  
Pre g n a nc y T est  
All  pre g na n c y  t est res ults as  c ollecte d  o n  t he  “ Pre g na nc y  T est”  e C R F  pa ge  will  be  liste d. 
Pre g n a nc y  listi n g  will  i ncl u de treat me nt  ar m,  p artici pa nt  i de ntifier,  a ge,  se x,  race,  eac h  st u d y 
i nter ve nti o n  first  a n d  last  d ose,  la b orat or y  para m eter,  visit,  date  ( da ys),  s peci me n  t y pe,  val u e, 
reas o ns f or test n ot d o ne. 
1 5. 4  
Vit al Si g ns   
O n -treat me nt vital si g ns val ues will be use d f or s u m mar y statistics a n d s hift ta bles ( o n -treat me nt 
peri o d defi ne d i n Secti o n  9).  
T he  f oll o wi n g  s u m maries  will  be  pre pare d  f or  vital  si g n s para meters as  c ollecte d  i n  t he  " Vital 
Si g ns e C R F pa ge"  c o nsi deri n g o nl y p artici pa nts wit h p ost Baseli ne  val ues:  
•  S u m mar y st atistics o ver ti me b y treat me nt  ar m. T his  ta ble will i ncl u de a bs ol ute val ues a n d 
a bs ol ute  c ha n ge  fr o m Baseli ne  val u es  per  visit  ( o nl y  para meters  a n d  visits  wit h  at  least  2 
o bser vati o n s a vaila ble will be dis pla ye d) 
•  Listi n g of ma xi m u m c ha n ge fr o m Bas eli ne  per partici pa nt . T he listi n g will i ncl u de treat me nt 
ar m,  partici pa nt  i de ntifier,  para meter,  visit,  date,  val ue,  u nit,  b aseli ne  val ue  a n d  m a xi m u m 
c ha n ge fr o m baseli ne .  
Gl o bal Versi o n I D: 
7 8/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
 
T he  f oll o wi n g  p o te ntiall y  cli nicall y  si g nifica nt  a b n or malities  i n  vital  si g ns  will  be  als o 
s u m marize d: 
•  ≤ 9 5 m m H g a n d decrease fr o m Bas eli ne  ≥ 2 0 m m H g i n s yst olic bl o o d press ure  
•  ≥ 1 4 0 m m H g a n d i ncreas e fr o m Baseli ne  ≥ 2 0 m m H g i n s yst olic bl o o d press ure  
•  ≤ 4 5 m m H g a n d decrea se fr o m Bas eli ne  ≥ 2 0 m m H g i n diast olic bl o o d press ure  
•  ≥ 9 0 m m H g a n d i ncreas e fr o m Bas eli ne  ≥ 2 0 m m H g i n diast olic bl o o d press ure  
•  ≤ 5 0 b p m a n d decrease fr o m Baseli ne  ≥ 2 0 b p m i n p ulse  
•  ≥ 1 0 0 b p m a n d i ncreas e fr o m Baseli ne  ≥ 2 0 b p m i n p ulse  
•  ≥ 1 0 % wei g ht i ncr ease  
•  ≥ 1 0 % wei g ht decreas e  
•  Res pirati o n Rate: < 2 0 breat hs/ mi n a n d decrease fr o m baseli ne ≥ 5 breat hs/ mi n  
•  Res pirati o n Rate: ≥ 2 0 breat hs/ mi n a n d decrease fr o m baseli ne ≥ 5 breat hs/ mi n  
•  O x y ge n sat urati o n: < 9 0 % or a decrease fr o m bas eli ne ≥ 1 0 %  
All  vital  si g ns  will  als o  be  liste d, Baseli ne  v al ues  a n d P ost -Baseli ne  val u es  c ollecte d  aft er  t he 
o n -treat me nt p eri o d will be fla g ge d i n t he listi n g. T he listi n g will i ncl u de tr eat me nt ar m, p artici pa nt 
i de ntifier, a ge, s e x, race, vital si g n p ara m eter, u nit, visit, date, o n-treat me nt fla g, val ue  a n d c h a n ge 
fr o m Baseli ne . Listi n gs will be s orte d b y treat me nt ar m, partici pa nt i de ntifi er, vital si g n para meter, 
a n d vital si g n meas ure me nt date a n d ti me . 
1 5. 5  
P ul m o n ar y F u ncti o n Tests   
P ul m o nar y F u ncti o n T ests ( P F Ts), i ncl u di n g D L C O, Sl o w s pir o metr y, H R C T, F E V 1, F V C a n d 6-
mi n utes  wal ki n g  test  will  be  a nal yze d  usi n g  t he a bs ol ute c ha n ge  at  a  pres pecifie d  ti me  p oi nt 
re gar di n g t o Baseli ne  (as defi ne d i n Secti o n  9 “ D efi niti o n of Baseli ne ”) f or eac h p artici pa nt.  
A s u m mar y ta ble o ver ti me b y treat me nt ar m will be dis pla ye d, i ncl u di n g a bs ol ute P F Ts v al ues 
a n d a bs ol ute c ha n ge fr o m Bas eli ne v al ues per visit. A b o x pl ot of P F Ts v al ues o ver ti me will be 
dis pla ye d t o o.  
A s u m mar y listi n g of P F Ts will be pr o vi de d, t he f oll o wi n g i nf or m ati o n will be i ncl u de d: tr eat me nt 
ar m, partici pa nt i de ntifier, et h nicit y (Ja pa nes e/ N o n -J a pa nese), a ge, se x, race, visit, date, re petiti o n 
n u m ber, a bs ol ute a n d rel ati ve c ha n ge fr o m bas eli ne of
. 
I n  a d diti o n,  f or  
  para meters  (i.e. 
,  Al ve olar  v ol u me,  I ns pirat or y  vital 
ca pacit y,  Breat h  h ol d  ti me,  I ns pirati o n  ti me,  Ma xi mal  vital  ca pacit y)    a  s p ecific  listi n g  will  be 
dis pla ye d i ncl u di n g treat me nt ar m, p artici pa nt i de ntifier, a ge, se x, race, visit, date, para meter v al ue 
a n d its a bs ol ute a n d relati ve c ha n ge fr o m bas eli ne.  
S pecific listi n gs will be als o pr o vi de d f or Sl o w s pir o metr y, 
 
 
Gl o bal Versi o n I D: 
7 9/ 8 8
Gl o bal Versi o n I D: C CI
C CI
C CI
C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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. 6  
Ot her S afet y or T oler a bilit y E v al u ati o ns   
E C O G Perf or m a nce St at us  
T he E C O G Perf or ma nce Stat us will be deri ve d fr o m t he data c ollecte d o n t he “ E C O G Perf or ma n ce 
Stat us”  e C R F  pa ge  a n d  will  be  s u m marize d  i n  a  listi n g  i ncl u di n g treat me nt  ar m,  partici pa nt 
i de ntifier, a ge, s e x, race, E C O G  P S  val ues at scree ni n g a n d p er visit , date of visit ( da ys). 
E C G  
A listi n g of E C G val ues will pr o vi de t he f oll o wi n g i nf or mati o n: t reat me nt ar m, s u bject i de ntifier, 
a ge, se x, race, E C G para meter a n d u nit, visit, E C G date a n d val ue, a n d c ha n ge fr o m Baseli ne.  T he 
listi n g will be s orte d b y treat me nt ar m, s u bject i d e ntifier, E C G para m eter, a n d E C G date. It will 
i ncl u de E C G val ues c ollecte d at scree ni n g a n d at safet y f oll o w -u p visits.  
1 6  
A n al yses of Ot her E n d p oi nts   
1 6. 1  
P h ar m ac o ki netics   
T he a n al yses d escri b e d i n t his secti o n will be perf or me d b y t he Cli nical P K/ P D gr o u p ( C P K) of 
Tra nslati o nal Me di ci ne, Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y, or b y a C o ntract Researc h 
Or ga nizati o n  select e d  b y  t h e  S p o ns or.  P har mac o ki netic  listi n gs  a n d  i n di vi d u al  data  will  b e 
prese nte d f or t he Safet y A nal ysis Set. S u m maries a n d statistical a nal yses will be bas e d o n t he P K 
A nal ysis Set.  
P har mac o ki netic c o n ce ntrati o ns/ para meters refer t o M 7 8 2 4 c o nce ntr ati o ns/ P K para meters.  
1 6. 1. 1  
Missi n g/ n o n -q u a ntifi a ble  P h ar m ac o ki netic  
D at a H a n dli n g   
C o nce ntr ati o ns Bel o w t he L o wer Li mit of Ass a y Q u a ntific ati o n  
P har mac o ki netic  c o nce ntrati o ns  bel o w  t he  l o w er  li mit  of  q ua ntificati o n  will  be  set  t o  zer o  f or 
calc ulati n g para meters a n d descri pti ve statistics.  
U nsc he d ule d S a m ples  
F or  P K  a nal ysis,  u nsc he d ule d  sa m ples  will  n ot  be  li n ke d  t o  a  sc he d ule d  ti me p oi nt  a n d  will  be 
e x cl u de d fr o m s u m maries.  
De vi ati o ns , Missi n g C o nce ntr ati o ns a n d A n o m al o us V al ues 
T here will be n o i m p utati o n of missi n g data. C o nce ntrati o ns will be set t o missi n g i n s u m mar y 
ta bles if t he val ue is re p orte d as n o res ult. P har mac o ki netic c o nce ntr ati o ns w hic h are err o ne o us 
d ue t o a pr ot oc ol vi olati o n (as d efi ne d i n t he cli nical st u d y pr ot oc ol), d o c u me nte d ha n dli n g err or, 
or  a nal ytical  err or  (as  d oc u me nte d  i n  t he  bi oa nal ytical  re p ort)  ma y  be  e x cl u de d  fr o m  t he  P K 
a nal ysis  if  a gree d  u p o n  pri or  t o  perf or mi n g  a  st atistical  a nal ysis.  I n  t his  case  t he  rati o nale  f or 
Gl o bal Versi o n I D: 
8 0/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
e x cl usi o n will be pr o vi de d i n t he C S R. A n y ot her P K c o nce ntrati o ns t hat a p pear i m pla usi ble t o t he 
P har mac o ki neticist/ P K  Data  A nal yst  m ust  n ot  b e  e x cl u de d  fr o m  t he  a n al ysis.  A n y  i m pla usi ble 
data will be d oc u me nte d i n t he C S R.  
If a P K para meter ca n n ot be deri ve d fr o m a partici pa nt’s c o nce ntr ati o n data, t he para meter will be 
c o de d as N C ( n ot calc ul ate d). ( N ote t hat N C val ues will n ot be ge nerate d be y o n d t he da y t hat a 
partici pa nt disc o nti n ues t he treat me nt). F or statistical a n al ys es, P K p ara met ers c o d e d as N C will 
be set t o missi n g.  
If a n i n di vi d ual partici pa nt has a k n o w n biase d esti mate of a P K para met er ( d ue f or e x a m ple t o a 
de viati o n fr o m t he assi g n e d d ose le vel), t his partici pa nt/ val ue will be e x cl u d e d fr o m t he descri pti ve 
statistics, a n d i nstea d t he res ult will be liste d o nl y. 
Rele va nt decisi o ns  o n partici pa nt i ncl usi o n i n t he P K a nal ysis set will be ma de bef ore data bas e 
l oc k i n t he Data bas e Re vie w Meeti n g. 
1 6. 1. 2  
Descri pti ve P h ar m ac o ki netic  A n al ysis   
Prese nt ati o n of P h ar m a c o ki netic  C o nce ntr ati o n D at a  
A  b y -partici pa nt  listi n g  will  prese nt  P K  sa m pl e  ti mes,  ti me  de vi ati o ns,  a n d  c o nce ntr ati o ns.  
C o nce ntrati o n listi n gs will be base d o n t he S A F  a n al ysis set . C o nce ntrati o ns will be re p orte d wit h 
t he sa me precisi o n as t he s o urce data. Act ual ela pse d sa m ple c ollecti o n ti mes will be r o u n de d t o 
t w o deci mal places wit h u nits of h o urs f or re p orti n g p ur p os es i n listi n gs.  
Prese nt ati o n of P h ar m a c o ki netic  P a r a meter D at a  
T he  P K  para meters  liste d  bel o w  will  be  ta ke n  directl y  fr o m  t he  o bs er ve d  M 7 8 2 4 
c o nce ntr ati o n -ti me data.  
C tr o u g h 
T he c o nce ntrati o n o bser ve d i m me diatel y b ef ore ne xt d osi n g (c orres p o n di n g 
t o pre-d ose or tr o u g h c o n ce ntrati o n f or m ulti ple d osi n g)  
C e oi 
T he c o nce ntrati o n o bser ve d i m me diatel y at t he e n d of i nf usi o n.  
I n di vi d ual P K para m eters will be liste d b y n o mi n al st u d y d a y. I n di vi d ual P K para meters will be 
re p orte d wit h t he sa m e precisi o n as t he s o urce data. 
P har mac o ki netic para met er data will be prese nte d i n ta bles a n d descri pti vel y s u m marize d f or t he 
P K A S b y  n o mi nal  st u d y da y  usi n g:  n u m ber  of  n o n -missi n g  o bser vati o ns  ( n),  arit h metic  mea n 
( Mea n), sta n dar d  d e viati o n  (St D ),  c oefficie nt  of  variati o n  ( C V %),  mi ni m u m  ( Mi n),  me dia n 
( Me dia n), m a xi m u m ( Ma x), ge o m etric me a n ( Ge o Mea n), t he ge o metri c c oefficie nt of variati o n 
( Ge o C V %), an d t he 9 5 % CI f or t he Ge o M ea n. A d diti o nal ta ble(s) will s u m marize wit h f urt her 
stratificati o n b y A D A s u bsets e ver p ositi ve a n d n e ver p ositi ve.  
I n e x p ort datasets, as well as i n t he S D T M P P d o mai n, P K para met ers will be pr o vi de d wit h f ull 
precisi o n a n d will  n ot be r o u n de d. Descri pti ve statistics of P K para meter d ata will be calc ulate d 
usi n g f ull precisi o n val ues a n d r o u n de d f or re p orti n g p ur p os es o nl y.  
Gl o bal Versi o n I D: 
8 1/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
T he f oll o wi n g c o n v e nti o ns will be a p plie d w he n re p orti n g des cri pti ve statistics of P K para meter 
data:  
•  Mea n,  Mi n, Me dia n, Ma x, Ge o Mea n, 9 5 % CI:  
3 si g nifica nt di gits  
•  St D:  
 
 
 
 
 
 
4 si g nifica nt di gits  
•  C V %, Ge o C V %:  
 
 
 
 
1 deci mal place . 
I n di vi d ual P K Ctr o u g h a n d C e oi val ues will be pl otte d vers us act u al st u d y d a y o n a li near s cale, f or 
all partici pa nts.  I n di vi d u al data will be pres e nte d base d o n t he S A F  
Arit h metic mea n ( ±  St D) a n d me dia n C tr o u g h a n d C e oi will be pl otte d vers us n o mi nal st u d y d a y o n 
a li near scal e.  S u m maries will be base d o n t he P K A S.  A d diti o nal fi g ure(s) will be prese nte d wit h 
f urt her stratifi cati o n b y A D A s u bsets e ver p ositi ve a n d ne v er p ositi ve. 
1 6. 2  
P h ar m ac o d y n a mics   
N ot a p plica ble.  
1 6. 4  
I m m u n o ge nicit y  
T he I M M a n al ysis set will be us e d t o e val uate t he i m m u n o ge nicit y of M 7 8 2 4. As per pr ot oc ol, t he 
bi oa nal yst m a y ha v e access t o t he ra n d o mizati o n list, b ut neit her t he ra n d o miz ati o n details n or t he 
a nal ysis res ults descri be d bel o w  will be s hare d b ef ore u n bli n di n g.  
A D A  will  be  assesse d  pri or  t o  st u d y  i nter ve nti o n  i nf usi o ns.  Sa m ples  c ollecte d  after  t he  o n -
treat me nt peri o d (e. g. safet y f oll o w-u p) will be i ncl u de d i n t he a nal ysis as well. If t he sa m ple is 
p ositi ve f or A D A, it will be re -a n al yze d t o deter mi ne t he titer. T h e A D A res ults will be d eri ve d 
base d o n t he al g orit h m i n Err or!  Refere nce  s o urce n ot  f o u n d.8 . 
T a ble 8  Al g orit h m f or t he Deri v ati o n of A D A Res ults   
S a m pl e S cr e e n R e s ult  
C o nfir m at or y  
Tit er  
A D A R e s ult  
N e g ati v e  
N A  
N A  
N e g ati v e  
N R  
N A  
N A  
N R  
P o siti v e  
N e g ati v e  
N A  
N e g ati v e  
P o siti v e  
N R  
N A  
N R  
P o siti v e  
P o siti v e  
N u m b er  
N u m b er  
P o siti v e  
P o siti v e  
N R  
P o siti v e -T N R  
A D A = a nti -dr u g a nti b o d y , N A = n ot a p pli c a bl e,  N R = n o r e s ult,  T N R =tit er n o r e s ult.  
Gl o bal Versi o n I D: 
8 2/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Ne gati ve,  n u m ber,  or  p ositi ve -T N R  are  vali d  res ults  w hile  n u m ber  a n d  p ositi ve -T N R  are 
c o nsi dere d  as  p ositi ve.  Partici pa nts  will  be  c h aracteriz e d  i nt o  differe nt  cate g ori es  base d  o n  t he 
criteria i n Ta bl e 9 9 . 
T a ble 9  P artici p a nts C h ar acterize d B ase d o n A D A Res ults   
C at e g or y  
D efi niti o n  
P arti ci p a nt at Ri s k ( D e n o mi n at or f or 
I n ci d e n c e) 
N e v er 
p o siti v e  
N o p o siti v e r e s ult s at a n y ti m e p oi nt  
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
r e s ult at a n y ti m e p oi nt 
E v er p o siti v e  
At l e a st o n e p o siti v e r e s ult at a n y ti m e p oi nt, 
i n cl u di n g B a s eli n e  
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
r e s ult at a n y ti m e p oi nt 
Pr e -e xi sti n g  
A p o siti v e A D A r e s ult pri or t o tr e at m e nt wit h 
M 7 8 2 4  
N u m b er of p arti ci p a nt s wit h v ali d B a s eli n e  
r e s ult 
Tr e at m e nt 
b o o st e d  
A p o siti v e A D A r e s ult pri or t o tr e at m e nt wit h 
M 7 8 2 4 a n d t h e tit er ≥ 8* B a s eli n e  tit er at l e a st o n e 
p o st -B a s eli n e  v al u e  
N u m b er of p arti ci p a nt s wit h v ali d B a s eli n e  
r e s ult a n d at l e a st o n e v ali d p o st-B a s eli n e  
r e s ult 
Tr e at m e nt 
e m er g e nt  
N ot p o siti v e pri or t o tr e at m e nt wit h M 7 8 2 4 a n d 
wit h at l e a st o n e p o siti v e p o st -B a s eli n e  r e s ult 
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
p o st -B a s eli n e  r e s ult a n d wit h o ut p o siti v e 
B a s eli n e  r e s ult (i n cl u di n g N R) 
Tr a n si e nt 
p o siti v e  
If tr e at m e nt e m er g e nt p arti ci p a nt s h a v e  
- a si n gl e p o siti v e e v al u ati o n,  
or  
- d ur ati o n b et w e e n fir st a n d l a st p o siti v e r e s ult 
< 1 6  w e e k s a n d l a st a s s e s s m e nt n ot p o siti v e  
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
p o st -B a s eli n e  r e s ult a n d wit h o ut p o siti v e 
B a s eli n e  r e s ult (i n cl u di n g N R) 
P er si st e nt 
p o siti v e  
If tr e at m e nt e m er g e nt p arti ci p a nt s h a v e d ur ati o n 
b et w e e n  fir st a n d l a st p o siti v e r e s ult ≥1 6 w e e k s or 
a p o siti v e e v al u ati o n at t h e l a st a s s e s s m e nt  
N u m b er of p arti ci p a nt s wit h at l e a st o n e v ali d 
p o st -B a s eli n e  r e s ult a n d wit h o ut p o siti v e 
B a s eli n e  r e s ult (i n cl u di n g N R) 
A D A = a nti -dr u g a nti b o d y, N R = n o r e s ult  
Gl o bal Versi o n I D: 
8 3/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
Gl o bal Versi o n I D: 
8 4/ 8 8
Gl o bal Versi o n I D: C CI
C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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  
Refere nces   
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 reje cti 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.  
Br o o k me yer, R. a n d Cr o wle y, J. ( 1 9 8 2), A C o nfi de nce I nt er val f or t he Me dia n S ur vi val Ti me, 
Bi o metrics, 3 8, 2 9 – 4 1.  
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 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 -4 7.  
Kal bfleisc h, J. D. a n d Pre ntice, R. L. ( 1 9 8 0) T h e statistical a nal ysis of fail ure ti me data. J o h n Wile y 
a n d S o ns, Ne w Y or k.  
M or ga n, C harit y J. " La n d mar k a nal ysis: A pri mer." ( 2 0 1 9): 3 9 1 -3 9 3.  
Nati o nal  C o m p re he nsi ve  Ca ncer  Net w or k,  Te m plates  A p pe n di x  B:  Car b o plati n  c o n versi o n. 
Retrie ve d fr o m: htt ps:// w w w. ncc n. or g/ pr ofessi o nals/ Or der Te m plates/ P D F/a p pe n di x _ B. p df  - last 
accessed 0 4t h Fe br uar y 2 0 2 1).  
Ne p hr ol Dial Tra ns pla nt ( 2 0 0 4) 1 9 [ S u p pl 2]: ii 4 2 – ii 4 3. “ A p pe n di x C: Ta bles, c o n versi o ns a n d 
a b bre viati o ns”  
 
 
 
 
Gl o bal Versi o n I D: 
8 5/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
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  
A p pe n dices   
1 8. 1  
A p pe n di x 1  –  I D M C S A P  
See se parate A p p e n di x of t his I A P . 
1 8. 2  
A p pe n di x 2 –  Defi niti o n of N CI -C T C A E gr a di n g    
See se parate A p p e n di x of t his I A P .  
1 8. 3  
A p pe n di x 3  –  List  of  I m p ort a nt Pr ot oc ol De vi ati o ns    
See se parate A p p e n di x of t his I A P.  
1 8. 4  
A p pe n di x  4  –  I de ntific ati o n  of P re vi o us  or C o nc o mit a nt 
M e dic ati o ns/ P r oce d ures   
F or  i de ntificati o n  of  pre vi o us  or  c o nc o mita nt  me dicati o ns/ pr oce d ures,  r ules  prese nte d  i n  ta bl es 
bel o w will be use d t o defi ne if a me dicati o n/ pr oce d ure is c o nsi dere d as a pre vi o us, c o nc o mita nt or 
b ot h pre vi o us a n d c o nc o mita nt me dicati o n/ pr oce d ure.  
T a ble 1 0  St o p pi n g r ules f or me dic ati o n/ pr oce d ure e n d d ates   
E n d d at e of m e di c ati o n/ pr o c e d ur e  
St o p pi n g r ul e  
D a y  
M o nt h  
Y e ar  
  
U N K  
U N K  
U N K  
Aft er tr e at m e nt st art ( o n g oi n g) 
U N K  
U N K  
< Tr e at m e nt st art ( y e ar)  
B ef or e tr e at m e nt st art  
U N K  
U N K  
> = Tr e at m e nt st art ( y e ar)  
Aft er tr e at m e nt st art  
U N K  
< Tr e at m e nt st art ( m o nt h a n d y e ar)  
B ef or e tr e at m e nt st art  
U N K  
> = Tr e at m e nt st art ( m o nt h a n d y e ar)  
Aft er tr e at m e nt st art  
< Tr e at m e nt st art ( c o m pl et e d at e)  
B ef or e tr e at m e nt st art  
> = Tr e at m e nt st art ( c o m pl et e d at e)  
Aft er tr e at m e nt st art  
U N K : U n k n o w n  
Gl o bal Versi o n I D: 
8 6/ 8 8
Gl o bal Versi o n I D: C CI


Bi ntr af us p alf a ( 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  
 
Versi o n N o. 2  
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
 
 
 
T a ble 1 1  R ules t o defi ne pre vi o us a n d/ or c o nc o mit a nt me dic ati o ns   
U N K = U n k n o w n  
1 8. 5  
A p pe n di x 5  - I A P _ M S 2 0 0 6 4 7-0 0 0 5 List of o ut p uts   
See se parate A p p e n di x of t his I A P.  
St art d at e of m e di c ati o n/ pr o c e d ur e  
St o p pi n g r ul e   
( s e e Ta ble 1 0 0 ) 
M e di c ati o n/ pr o c e d ur e  
D a y  
M o nt h  
Y e ar  
  
  
U N K  
U N K  
U N K  
B ef or e tr e at m e nt st art  
Pr e vi o u s  
U N K  
U N K  
U N K  
Aft er tr e at m e nt st art  
Pr e vi o u s a n d c o n c o mit a nt  
U N K  
U N K  
< = Tr e at m e nt st art ( y e ar)  
B ef or e tr e at m e nt st art  
Pr e vi o u s  
U N K  
U N K  
< = Tr e at m e nt st art ( y e ar)  
Aft er tr e at m e nt st art  
Pr e vi o u s a n d c o n c o mit a nt  
U N K  
U N K  
>  Tr e at m e nt  st art  ( y e ar)  a n d  < = 
Tr e at m e nt e n d [ + 3 0] d a y s ( y e ar)  
Aft er tr e at m e nt st art  
C o n c o mit a nt  
U N K  
< = Tr e at m e nt st art ( m o nt h a n d y e ar)  
B ef or e tr e at m e nt st art  
Pr e vi o u s  
U N K  
< = Tr e at m e nt st art ( m o nt h a n d y e ar)  
Aft er tr e at m e nt st art  
Pr e vi o u s a n d c o n c o mit a nt  
U N K  
> Tr e at m e nt st art ( m o nt h a n d y e ar) a n d < = 
Tr e at m e nt e n d [ + 3 0] d a y s ( m o nt h a n d y e ar)  
Aft er tr e at m e nt st art  
C o n c o mit a nt  
< = Tr e at m e nt st art ( d at e)  
B ef or e tr e at m e nt st art  
Pr e vi o u s  
< = Tr e at m e nt st art ( d at e)  
Aft er tr e at m e nt st art  
Pr e vi o u s a n d c o n c o mit a nt  
> Tr e at m e nt st art ( d at e) a n d < = Tr e at m e nt e n d [ + 3 0] 
d a y s ( d at e)  
Aft er tr e at m e nt st art  
C o n c o mit a nt  
Gl o bal Versi o n I D: 
8 7/ 8 8
Gl o bal Versi o n I D: C CI


i na
re a e or V V
I
2 8 7 7 9 9 1 0
i na
re a e or 
r o al
2 4
e b 2 0 2 2 1 4: 5 1: 3 3 G
0 0 0 0
Gl o bal Versi o n I D: 
8 8/ 8 8
Gl o bal Versi o n I D: C CI
P P D
C CI