Conditions: Squamous Non-Small Cell Lung Cancer
Keywords: Avelumab Cetuximab Cisplatin Gemcitabine Non-Small Cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 43
Healthy volunteers: no

Brief summary:
The main purpose of the study was to investigate the clinical activity and safety of avelumab in combination with cetuximab plus gemcitabine and cisplatin in participants with treatment-naïve advanced squamous non-small-cell lung cancer (NSCLC).

Detailed description:

Arms:
arm 1: Participants received 800 milligrams Avelumab, 1250 milligrams per square meter (mg/m\^2) gemcitabine on Day 1 and Day 8, cisplatin at a dose of 75 mg/m\^2 on Day 1 along with 250 mg/m2 body surface area Cetuximab on Day 1 and 500 mg/m2 body surface area on Day 8 of each cycle as intravenous (IV) infusions up to maximum of 4 cycles (each cycle is of 3 weeks) until disease progression or unacceptable toxicities. In case of cisplatin toxicities, participants were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles. Subsequently participants were administered with avelumab and cetuximab as IV infusion at the dose of 800 mg and 500 mg/m\^2 respectively, every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities.

Interventions: intervention 1: Avelumab intervention 2: Cetuximab intervention 3: Gemcitabine intervention 4: Cisplatin intervention 5: Carboplatin
Intervention descriptions: intervention 1: Participants received avelumab intravenous infusions at a dose of 800 milligram (mg) on Day 1 and Day 8 of each 3-week cycle for the first 4 cycles. Thereafter, administered every 2 weeks in the Maintenance phase until disease progression or unacceptable toxicities. intervention 2: Participants received cetuximab intravenous infusions at a dose of 250 milligram per meter square (mg/m\^2) body surface area on Day 1 and 500 mg/m\^2 body surface area on Day 8 of first 4 cycles of concurrent chemotherapy. Thereafter, administered given at a dose of 500 mg/m\^2 intravenous every 2 weeks in the Maintenance phase, until disease progression or unacceptable toxicities. intervention 3: Participants received gemcitabine intravenous infusions at a dose of 1250 mg/m\^2 body surface area on Day 1 and Day 8 in 3-week cycles up to a maximum of 4 cycles, until disease progression or unacceptable toxicities. intervention 4: Participants received cisplatin intravenous infusions at a dose of 75 mg/m\^2 body surface area on Day 1 of 3-week cycles up to a maximum of 4 cycles, until disease progression or unacceptable toxicities. intervention 5: In case of cisplatin toxicities, participants were switched to carboplatin at a dose of target area under the serum concentration-time curve of 5 (AUC 5) on Day 1 for the remainder of cycles.

Protocol document:
Prot_000.pdf: 
2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1/ 1 2 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 
P hase IIa, si n gle-ar m, m ultice nter 
st u d y to 
i n vesti gate t he cli nical acti vit y an d safet y of 
a vel u ma b i n c o m bi nati o n wit h cet u xi ma b 
pl us 
ge mcita bi ne a n d cis plati n i n partici pa nts wit h 
a d va nce d s q ua m o us n o n -s mall-cell l u n g ca ncer
St u d y N u m ber:
M S 2 0 1 9 4 4 - 0 1 7 0
A m e n d me nt N u m ber :
1. 0
Merc k C o m p o u n d N u m ber s:
A vel u ma b: M S B 0 0 1 0 7 1 8 C
Cet u xi ma b: E M D 2 7 1 7 8 6
St u d y P h ase:
P hase IIa
S h ort Title:
P hase IIa St u d y  of A vel u ma b a n d Cet u xi ma b pl us 
Ge mcita bi ne a n d Cis plati n i n Partici pa nts wit h 
s q ua m o us N S C LC
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:
Merc k K Ga A
Fra n kf urter Strasse 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
Me dical Res p o nsi ble:
Na me:
A d dress: Merc k K Ga A
Fra n kf urter Strasse 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
P h o ne: 
M o bile :
E- mail:
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 n u m ber: 2 0 1 8 - 0 0 1 5 2 9- 2 4
Cli nical Trials. g o v: N C T 0 3 7 1 7 1 5 5
Pr ot oc ol Versi o n:
2 0 A u g ust 2 0 1 9/ Versi o n 2. 0
Re pl aces Versi o n:
2 1 J u ne 2 0 1 8/ Versi o n 1. 0
A p pr o v al D ate:
2 0 A u g ust 2 0 1 9
D oc u me nt N o. 
O bject N o. 
P P D
C CI
C CI
P P D
P P D
P P D
P P D
P P D




2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3/ 1 2 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
2 1 J u n e 2 0 1 8
2. 0
Gl o b al a m e n d m e nt 1. 0
2 0 A u g u st 2 0 1 9
Pr ot oc ol Versi o n 2. 0 ( 2 0 A u g ust 2 0 1 9)
T his a me n d me nt is s u bsta ntial base d o n t he 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.
O ver all R ati o n ale f or t he A me n d me nt
T he pr ot oc ol is bei n g a me n de d base d o n t he u p date of i ncl usi o n criteri o n n u m ber 1 re gar di n g t he 
u p per a ge li mit. I n ad diti o n, s witc h t o o n- st u d y a ntica ncer t hera py w it h car b o plati n will be all o we d 
f or partici pa nts w h o ca n n ot t olerate treat me nt wit h cis plati n. T he ot her ite ms are c orrecti o ns t o 
i nc o nsiste ncies a n d clarificati o ns.
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
A m e n d m e nt n u m b er a d d e d
A d mi ni str ati v e u p d at e
Titl e p a g e
St u d y P h a s e c orr e ct e d
A d mi ni str ati v e u p d at e
Titl e p a g e
I nf or m ati o n a b o ut t h e R e g ul at or y A g e n c y 
I d e ntif yi n g N u m b er s a d d e d
A d mi ni str ati v e u p d at e
Titl e p a g e
Pr ot o c ol V er si o n c h a n g e d
A d mi ni str ati v e u p d at e
Titl e p a g e
R e pl a c e s V er si o n a d d e d
A d mi ni str ati v e u p d at e
Titl e p a g e
A p pr o v al d at e a d d e d
A d mi ni str ati v e u p d at e
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4/ 1 2 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
Titl e p a g e
D et ail s f or t h e M e di c al R e s p o n si bl e a n d 
M e di c al M o nit or u p d at e d
A d mi ni str ati v e u p d at e
1. 1 S y n o p si s
St u d y I nt er v e nti o n 
G r o u p s a n d D ur ati o n
A d diti o n of t h e f oll o wi n g t e xt:
T h er e aft er, a v el u m a b a n d c et u xi m a b …. 
di s e a s e pr o gr e s si o n or u n a c c e pt a bl e 
t o xi cit y.
If ci s pl ati n t o xi cit y o c c ur s, s u bj e ct s m a y b e 
s wit c h e d t o c ar b o pl ati n tr e at m e nt at t h e 
di s cr eti o n of In v e sti g at or.
T hi s c h a n g e i n crit eri a w a s t o all o w 
p a rti ci p a nt s wit h ci s pl ati n t o xi cit y t o 
r e m ai n i n st u d y b y s wit c hi n g t o 
c ar b o pl ati n .
T a bl e 1 S c h e d ul e of 
A cti viti e s
R e pl a c e t h e f oll o wi n g w or di n g s:
Fr o m: Pri or t o t h e fir st 2 i nf u si o n s … at l e a st 1 
h o ur ….
of c et u xi m a b.
T o: Pri or t o t h e fir st 2 i nf u si o n s … 
a p pr o xi m at el y 1 h o ur ….
of c et u xi m a b.
A d diti o n of t h e f oll o wi n g t e xt:
If ci s pl ati n t o xi cit y o c c ur s, s u bj e ct s m a y b e 
s wit c h e d t o c ar b o pl ati n at t h e di s cr eti o n of t h e 
In v e sti g at or
T o c h a n g e t h e s p e cifi c ati o n of 
ti mi n g s f or pr e m e di c ati o n f or 
c et u xi m a b .
Ali g n m e nt wit h S e cti o n 4. 1 a n d 
crit eri a t o all o w p arti ci p a nt s wit h 
ci s pl ati n t o xi cit y t o r e m ai n i n t h e 
st u d y .
T a bl e 1 a n d T a bl e 2 
S c h e d ul e of A cti viti e s
C orr e cti o n of t u m or a s s e s s m e nt i nt er v al f or 
c o nfir mi n g C R or P R
Fr o m: … n o s o o n er t h a n 4 w e e k s a n d n o l at er 
t h a n 6 w e e k s aft er t h e i niti al d o c u m e nt ati o n of 
C R or P R.
T o: … 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 of C R or P R.
R e pl a c e t h e f oll o wi n g w or di n g:
Fr o m: Pri or t o …...
at l e a st 1 h o ur pri or t o 
a d mi ni str ati o n of c et u xi m a b.
T o: Pri or t o …...
a p pr o xi m at el y 1 h o ur pri or t o 
a d mi ni str ati o n of c et u xi m a b.
Ali g n m e nt wit h S e cti o n 9. 4. 1. 1 a n d 
p er r e c o m m e n d ati o n i n R E CI S T 
v 1. 1.
T a bl e 3 a n d T a bl e 4 
S c h e d ul e of A cti viti e s 
I n cl u si o n of t h e f oll o wi n g i nf or m ati o n:
Fr o m: wit hi n 2 h o ur s pri or t o t h e st u d y 
tr e at m e nt i nf u si o n.
T o: wit hi n 2 h o ur s pri or t o t h e fir st st u d y 
i nt er v e nti o n i nf u si o n.
T a bl e 3 u p d at e d t o cl arif y t h at 
c ert ai n s a m pl e s h a v e t o b e t a k e n 
b ef or e a n y st u d y i nt er v e nti o n, i. e. 
g e m c it a bi n e / ci s pl ati n ar e 
a d mi ni st er e d a n d ali g n m e nt wit h 
T a bl e 4.
T a bl e 3 a n d T a bl e 4 
S c h e d ul e of A cti viti e s
R e pl a c e of t h e f oll o wi n g i nf or m ati o n:
Fr o m: 2 h o ur s pri or t o t h e fir st st u d y tr e at m e nt
i nf u si o n
T o: 2 h o ur s pri or t o t h e fir st st u d y i nt er v e nti o n
inf u si o n
E dit ori al c h a n g e t o ali g n wit h 
pr ot o c ol w or di n g.
D oc u me nt N o
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5/ 1 2 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 a bl e 4 S c h e d ul e of 
A cti viti e s 
R e pl a c e t h e f oll o wi n g w or di n g:
O n vi sit s 9 a n d 1 2, a f urt h er s a m pl e f or 
c et u xi m a b d et er mi n ati o n will b e c oll e ct e d 
3 h o ur s aft er t h e e n d of a v el u m a b i nf u si o n.
Wi t h: “ O n vi sit s 9 a n d 1 2, a f urt h er s a m pl e f or 
a v el u m a b d et er mi n ati o n will b e c oll e ct e d 
3 h o ur s aft er t h e e n d of a v el u m a b i nf u si o n ”.
C orr e cti o n t o r efl e ct t h at P K s a m pl e s 
f or a v el u m a b d et er mi n ati o n ar e 
t a k e n a n d n ot f or c et u xi m a b.
2. 2 B a c k gr o u n d
A d diti o n of a p pr o v al st at u s f or p e m br oli z u m a b 
i n E ur o p e a n U ni o n a d d e d.
P er c o m m e nt of t h e I stit ut o 
S u p eri or e di S a nit á , It al y, t h e 
p ar a gr a p h w a s u p d at e d t o r efl e ct t h e 
c urr e nt a p pr o v al st at u s. 
2. 2 B a c k gr o u n d
R e pl a c e t h e f oll o wi n g w or di n g:
“ A E ur o p e a n M e di ci n e s A g e n c y m ar k eti n g 
a ut h ori z ati o n a p pli c ati o n f or t hi s tr e at m e nt 
r e gi m e n w a s wit h dr a w n b y t h e m a n uf a ct ur er i n 
N o v e m b er 2 0 1 7.”
Wi t h: “ T h e E ur o p e a n M e di ci n e s A g e n c y h a s 
gr a nt e d a m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
f or t hi s tr e at m e nt r e gi m e n i n S e pt e m b er 
2 0 1 8. ”
A d mi ni str ati v e u p d at e.
2. 2 B a c k gr o u n d
I nf or m ati o n u p d at e
A d diti o n of t h e f oll o wi n g t e xt:
B a s e d o n t h e s e r e s ult s, t hi s r e gi m e n r e c ei v e d 
a p pr o v al a n d m ar k eti n g a ut h ori z ati o n i n 
O ct o b er 2 0 1 8 b y U S F D A a n d i n M ar c h 2 0 1 9 
b y t h e E ur o p e a n C o m mi s si o n.
D u e t o c o m m e nt s r e c ei v e d fr o m 
I stit ut o S u p eri or e di S a nitá , It al y, t hi s 
p ar a gr a p h w a s al s o u p d at e d t o 
r efl e ct t h e c urr e nt a p pr o v al st at u s a s 
it h a s c h a n g e d si n c e t h e pr ot o c ol 
w a s fi n ali z e d.
D oc u me nt N o
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
6/ 1 2 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
2. 3 B e n efit/ Ri s k 
A s s e s s m e nt
R e pl a c e t h e f oll o wi n g w or di n g:
“ M ai n ri s k s a s s o ci at e d wit h c et u xi m a b ar e:”.
Wi t h: “Pri m ar y  ri s k s a s s o ci at e d wit h 
c et u xi m a b ar e:”.
E dit ori al c h a n g e.
2. 3 B e n efit/ Ri s k 
A s s e s s m e nt
R e pl a c e t h e f oll o wi n g w or di n g:
Fr o m: T h e effi c a c y a n d s af et y of g e m cit a bi n e 
a n d ci s pl ati n …. ; thi s c h e m ot h er a p y  
c o m bi n ati o n ….
i s al s o r efl e ct e d….
hi st ol o gi c al s u bt y p e .
T o: T h e effi c a c y a n d s af et y of g e m cit a bi n e a n d 
ci s pl ati n pl ati n u m -b a s e d d o u bl et 
c h e m ot h er a p y …... ; i s t h e c o m bi n ati o n of 
g e m cit a bi n e a n d ci s pl ati n i s al s o r efl e ct e d….
hi st ol o gi c al s u bt y p e .
H o w e v er, t o xi citi e s s u c h a s r e n al i m p air m e nt 
or ot ot o xi cit y pr e v e nt a n u m b er of p ati e nt s 
fr o m c o m pl eti o n of t h e r e c o m m e n d c y cl e s of 
t h er a p y wit h ci s pl ati n.
A d diti o n of t h e f oll o wi n g t e xt:
F or t h o s e p ati e nt s u n a bl e t o t ol er at e all 
r e q uir e d 4 c y cl e s of ci s pl ati n d u e t o li miti n g 
t o xi citi e s, f urt h er c o nti n u ati o n of a d o u bl et 
r e gi m e n wit h a s wit c h t o c ar b o pl ati n i n st e a d 
r e pr e s e nt s a vi a bl e o pti o n.
A d diti o n of f oll o wi n g w or di n g:
Fr o m: F or ci s pl ati n, g e m cit a bi n e , t h e S u m m ar y 
of Pr o d u ct C h ar a ct eri sti c … … wit h t h e 2
c o m p o u n d s .
T o: F or ci s pl ati n, a n d g e m cit a bi n e, a n d 
c ar b o pl ati n t h e S u m m ar y of Pr o d u ct 
C h ar a ct eri sti c s . …. 2 3 c o m p o u n d s
A d diti o n of b e n efit/ri s k f or 
c ar b o pl ati n w a s a d d e d.
4. 1 O v er all D e si g n
A d diti o n of t h e f oll o wi n g t e xt:
At t h e di s cr eti o n of t h e I n v e sti g at or, a s wit c h t o 
c ar b o pl ati n f or t h e r e m ai n d er of t h e pl ati n u m-
d o u bl et c y cl e s ( u p t o 4 c y cl e s i n t ot al) will b e 
all o w e d i n s u bj e ct s d e v el o pi n g u n a c c e pt a bl e 
t o xi citi e s t o ci s pl ati n. I n t h e s e s u bj e ct s, 
c ar b o pl ati n at will b e a d mi ni st er e d o n D a y 1 of 
e a c h 3 -w e e k c y cl e at a d o s e of t ar g et ar e a 
u n d er t h e s er u m c o n c e ntr ati o n -ti m e c ur v e of 5 
( A U C 5) u si n g t h e C al v ert f or m ul a.
T hi s c h a n g e i n crit eri a w a s t o all o w 
p a rti ci p a nt s wit h ci s pl ati n t o xi cit y t o 
r e m ai n i n t h e st u d y b y s wit c hi n g t o 
c ar b o pl ati n.
5. 1 I n cl u si o n Crit eri a
R e m o v e d u p p er a g e li mit of ≤6 9 y e ar s of a g e
T o b ett er r efl e ct t h e a g e of t h e 
t ar g et e d p ati e nt p o p ul ati 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
A d diti o n of t h e f oll o wi n g c ol u m n i n T a bl e 5:
C ar b o pl ati n (i n c a s e of ci s pl ati n t o xi citi e s) .
I n a d diti o n t o t h at, i nf or m ati o n of S u p pli er/ 
M a n uf a ct ur er 
d et ail s 
f or 
ci s pl ati n 
a n d 
g e m cit a bi n e c ol u m n h a s al s o b e e n u p d at e d.
R e pl a c e 
t h e 
f oll o wi n g 
t e xt
i n 
S u p pli er/ M a n uf a ct ur er d et ail f or ci s pl ati n a n d
g e m cit a bi n e :
Fr o m: Ci s pl ati n will b e s o ur c e d fr o m t h e l o c al 
h o s pit al p h ar m a c y.
S u p pli er a n d m a n uf a ct ur e d et ail f or 
c i s pl ati n a n d c ar b o pl ati n a d diti o n .
D oc u me nt N o
O bject N o. 
C CI
C CI


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P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7/ 1 2 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
G e m cit a bi n e 
will b e s o ur c e d fr o m t h e l o c al 
h o s pit al p h ar m a c y.
T o: C a n b e s u p pli e d l o c all y b y i n v e sti g ati o n al 
sit e 
or 
c e ntr all y 
d e p e n di n g 
o n 
l o c al 
r e q uir e m e nt s a n d r e g ul ati o n s.
A d diti o n 
of s a m e t e xt f or C ar b o pl ati n 
f or 
S u p pli er a n d m a n uf a ct ur e.
A d diti o n of a b br e vi ati o n A U C t o t h e f o ot n ot e
6. 2. 3 C h e m ot h er a p y
A d diti o n of t h e f oll o wi n g t e xt:
Fr o m: F or pr e p ar ati o n a n d st or a g e of 
g e m cit a bi n e a n d ci s pl ati n … ….
t h e r e s p e cti v e 
s u m m ar y of pr o d u ct c h ar a ct eri sti c s ( S m P C s).
T o: F or pr e p ar ati o n a n d st or a g e of 
g e m cit a bi n e a n d ci s pl ati n or c ar b o pl ati n , 
… … … … … …... t h e r e s p e cti v e s u m m ar y of 
pr o d u ct c h ar a ct eri sti c s ( S m P C s).
A d diti o n of c ar b o pl ati n
6. 5. 2 P er mitt e d 
M e di c ati o n
A d diti o n of f oll o wi n g t e xt:
F or p arti ci p a nt s w h o d e v el o p u n a c c e pt a bl e 
t o xi citi e s t o ci s pl ati n, c h e m ot h er a p y tr e at m e nt 
wit h c ar b o pl ati n i s all o w e d at t h e di s cr eti o n of 
t h e I n v e sti g at or.
T hi s c h a n g e i n crit eri a w a s t o all o w 
p arti ci p a nt s wit h ci s pl ati n t o xi ci t y t o 
r e m ai n i n t h e st u d y b y s wit c hi n g t o 
c ar b o pl ati n.
6. 6. 1 S e q u e n ci n g a n d 
C o nti n u ati o n of St u d y 
I nt er v e nti o n 
A d mi ni str ati o n
A d di n g a ti m e wi n d o w:
Fr o m … Tr e at m e nt wit h t h e r e m ai n d er of st u d y 
i nt er v e nti o n s will n ot b e d el a y e d f or a t o xi cit y 
attri b ut e d t o o n e of t h e c o m p o u n d s u nl e s s 
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. 
T h er ef or e, if t h er e i s a d el a y or a 
di s c o nti n u ati o n f or o n e of t h e dr u g s ….
T o: … Tr e at m e nt wit h t h e r e m ai n d er of st u d y 
i nt er v e nti o n s will n ot b e d el a y e d f or m or e 
t h a n 7 d a ys f or a t o xi cit y attri b ut e d t o o n e of 
t h e c o m p o u n d s u nl e s s 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. T h er ef or e, if t h er e i s a d el a y 
of m or e t h a n 7 d a y s or a di s c o nti n u ati o n f or 
o n e of t h e dr u g s …
D el a y of st u d y i nt er v e nti o n s d u e t o 
t o xi citi e s r el at e d t o c h e m ot h er a p y 
n e e d e d a s t hi s i s cli ni c al pr a cti c e f or 
c h e m ot h er a p y.
6. 6. 2 A v el u m a b
A d diti o n of t h e f oll o wi n g t e xt:
T hi s r e gi m e n m a y b e m o difi e d b a s e d o n l o c al 
tr e at m e nt st a n d ar d s a n d g ui d eli n e s i n cl u di n g 
pr etr e at m e nt m o d aliti e s f or c h e m ot h er a p y a s 
a p pr o pri at e.
Ali g n m e nt wit h w or di n g u s e d i n 
s c h e d ul e of a s s e s s m e nt s.
6. 6. 3 C et u xi m a b
R e pl a c e t h e f oll o wi n g w or di n g:
Fr o m: Pr etr e at m e nt wit h...i s m a n d at or y at 
l e a st 1 h o ur b ef or e t h e fir st 2 c et u xi m a b 
i nf u si o n s.
T o: Pr etr e at m e nt wit h...i s m a n d at or y 
a p pr o xi m at el y 1 h o ur b ef or e t h e f ir st 2 
c et u xi m a b i nf u si o n s.
Ali g n m e nt wit h w or di n g u s e d i n 
s c h e d ul e of a s s e s s m e nt s.
6. 6. 4. 1 G e m cit a bi n e 
a n d Ci s pl ati n
I n cl u si o n of f oll o wi n g i nf or m ati o n:
E dit ori al c h a n g e t o ali g n wit h 
pr ot o c ol w or di n g.
D oc u me nt N o. 
O bject N o
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8/ 1 2 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
Fr o m: Aft er t h e st arti n g d o s e, d o s e 
m o difi c ati o n s ( d o s e d el a y s a n d d o s e c h a n g e s) 
f or t o xi city …
T o: Af t er t h e st arti n g d o s e, d o s e m o difi c ati o n s
( d o s e d el a y s a n d d o s e c h a n g e s) f or 
c h e m ot h er a p y -r el at e d t o xi cit y….
T a bl e 7 
A d diti o n of T a bl e 7 Pr e d o si n g C o n si d er ati o n 
f or C ar b o pl ati n
A d diti o n of t a bl e f or r e c o m m e n d e d 
st e p s f or a d v er s e r e a cti o n o b s er v e d 
i n p arti ci p a nt s wit h c ar b o pl ati n 
t o xi cit y.
6. 6. 4. 2 C ar b o pl ati n
A d diti o n of t h e f oll o wi n g t e xt:
F or p arti ci p a nt s w h o m u st di s c o nti n u e 
tr e at m e nt wit h ci s pl ati n d u e t o u n a c c e pt a bl e 
t o xi citi e s, c o nti n u ati o n of pl ati n u m-b a s e d 
tr e at m e nt ( u p t o 4 c y cl e s i n t ot al) wit h 
c ar b o pl ati n i s all o w e d at t h e di s cr eti o n of t h e 
I n v e sti g at or. F or t h e s e s u bj e ct s, c ar b o plati n i s 
a d mi ni st er e d i ntr a v e n o u sl y at A U C 5 u si n g t h e 
C al v ert f or m ul a, o v er 3 0 t o 6 0 mi n ut e s o n D a y 
1 of e a c h 3 -w e e k c y cl e. P arti ci p a nt s r e c ei vi n g 
c ar b o pl ati n s h o ul d b e m o nit or e d f or 
m y el o s u p pr e s si o n wit h t hr o m b o p e ni a, 
l e u c o p e ni a, n e utr o p e ni a a n d a n e mi a; 
inf e cti o n s; h e p ati c t o xi cit y; r e n al t o xi cit y;
n a u s e a a n d v o miti n g; ot ot o xi cit y; a n d 
p eri p h er al n e ur o p at hi e s.
A d diti o n of t e xt f or p arti ci p a nt s w h o 
s wit c h t o c ar b o pl ati n d u e t o ci s pl ati n 
t o xi cit y.
T a bl e 8
A d diti o n of T a bl e f or pr e d o si n g c o n si d er ati o n 
f or c ar b o pl ati n
A d diti o n of pr e d o si n g c o n si d er ati o n 
f or p arti ci p a nt s w h o s wit c h t o 
c ar b o pl ati n.
T a bl e 9 D o s e 
M o difi c ati o n f or 
C h e m ot h er a p y
A d diti o n of d o s e m o difi c ati o n f or 
c h e m ot h er a p y
A d diti o n of d o s e m o difi c ati o n c ol u m n 
f or c ar b o pl ati n
6. 8. 1 A v el u m a b
U p d at e of t h e f oll o wi n g i nf or m ati o n:
Fr o m 1 h o ur: A s a r o uti n e pr e c a uti o n, 
p arti ci p a nt s e nr oll e d i n t hi s st u d y m u st b e 
o b s er v e d f or 1 -h o ur p o st a v el u m a b i nf u si o n f or 
t h e fir st 4 a v el u m a b i nf u si o n s,
T o: 2 h o ur s: … A s a r o uti n e pr e c a uti o n, 
p arti ci p a nt s e nr oll e d i n t hi s st u d y m u st b e 
o b s er v e d f or 2 h o ur s p o st a v el u m a b i nf u si o n 
f or t h e fir st 4 a v el u m a b i nf u si o n s …
Ali g n t h e o b s er v ati o n p eri o d s i n t h e 
diff er e nt pr ot o c ol s e cti o n s t o r efl e ct 
t h e 2 h o ur s o b s er v ati o n p eri o d aft er 
a v el u m a b i nf u si o n .
6. 8. 3 G e m cit a bi n e, 
Ci s pl ati n a n d 
C ar b o pl ati n
A d diti o n of t h e f oll o wi n g t e xt:
C ar b o pl ati n
P arti ci p a nt s w h o s wit c h t o tr e at m e nt wit h 
c ar b o pl ati n aft er e x p eri e n ci n g ci s pl ati n -r el at e d 
t o xi citi e s s h o ul d b e m o nit or e d f or s y m pt o m s of 
m y el o s u p pr e s si o n wit h t hr o m b o p e ni a, 
l e u c o p e ni a, n e utro p e ni a a n d a n e mi a; 
i nf e cti o n s; n a u s e a a n d v o miti n g; h e p ati c 
t o xi cit y, r e n al t o xi cit y, ot ot o xi cit y; a n d 
p eri p h er al n e ur o p at hi e s a s p er S m P C 
r e c o m m e n d ati o n s. Pr e m e di c ati o n wit h a nti -
e m eti c s a n d h y dr ati o n ar e p erf or m e d 
a c c or di n g t o l o c al st a n d ar d s.
S p e ci al pr e c a uti o n f or p arti ci p a nt s 
o n c ar b o pl ati n
8. 4 Tr e at m e nt of 
O v er d o s e
I n cl u si o n of f oll o wi n g i nf or m ati o n:
Fr o m: G e m cit a bi n e a n d Ci s pl ati n
A d diti o n of tr e at m e nt of o v er d o s e f or 
c ar b o pl ati n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9/ 1 2 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 o: G e m cit a bi n e a n d Ci s pl ati n or C ar b o pl ati n :
8. 1 0 I m m u n o g e ni cit y 
A s s e s s m e nt
C orr e cti o n of t h e f oll o wi n g i nf or m ati o n:
Fr o m: S a m pl e s will b e c oll e ct e d pri or t o a n y 
c et u xi m a b a d mi ni str ati o n o n t h e s a m e St u d y 
D a y.
T o: S a m pl e s will b e c oll e ct e d pri or t o a n y 
st u d y  i nt er v e nti o n a d mi ni str ati o n o n t h e 
s a m e St u d y D a y.
Ali g n m e nt wit h s c h e d ul e of 
a s s e s s m e nt s .
8. 1 0 I m m u n o g e ni cit y 
A s s e s s m e nt
C orr e cti o n of t h e f oll o wi n g i nf or m ati o n:
Fr o m: S a m pl e s will b e c oll e ct e d pri or t o a n y 
a v el u m a b a d mi ni str ati o n o n t h e s a m e St u d y 
D a y.
T o: S a m pl e s will b e c oll e ct e d pri or t o a n y 
st u d y  i nt er v e nti o n a d mi ni str ati o n o n t h e 
s a m e St u d y D a y.
Ali g n m e nt wit h s c h e d ul e of 
a s s e s s m e nt s .
9. 4. 2 S af et y A n al y s e s
C orr e cti o n of t h e f oll o wi n g i nf or m ati o n:
Fr o m: … a n d 1 2 -l e a d E C G, r e c or d e d at 
b a s eli n e a n d aft er a d mi ni str ati o n of st u d y 
tr e at m e nt will b e pr e s e nt e d.
T o: … a n d 1 2 -l e a d E C G, r e c or d e d at b a s eli n e 
a n d aft er e n d of st u d y tr e at m e nt will b e 
pr e s e nt e d.
Ali g n m e nt wit h s c h e d ul e of 
a s s e s s m e nt s .
9. 4. 3 Ot h er A n al y s e s
M o v e d t h e f oll o wi n g s e nt e n c e t o P K 
s u b s e cti o n i n t h e s a m e s e cti o n:
I nt e gr at e d a n al y s e s a cr o s s st u di e s, s u c h a s 
t h e p o p ul ati o n P K a n al y si s will b e pr e s e nt e d 
s e p ar at el y fr o m t h e m ai n cli ni c al st u d y r e p ort 
( C S R).
P K s u b s e cti o n i s m or e a p pr o pri at e .
1 0 R ef er e n c e s
R e m o v e d: P a z -Ar e s L G, L uft A, T afr e s hi A, et 
al. P h a s e 3 st u d y of c ar b o pl ati n-
p a clit a x el/ n a b - p a clit a x el wit h or wit h o ut 
p e m br oli z u m a b f or p ati e nt s wit h m et a st ati c 
s q u a m o u s n o n - s m all c ell l u n g c a n c er. J Cli n 
O n c ol 3 6, 2 0 1 8 ( s u p pl; a b str 1 0 5).
A d d e d: P a z -Ar e s L, L uft A, Vi c e nt e D, et al. 
P e m br oli z u m a b pl u s c h e m ot h er a p y f or 
s q u a m o u s n o n -s m all - c ell l un g c a n c er. N E n gl 
J M e d 2 0 1 8; 3 7 9: 2 0 4 0 -5 1.
U p d at e d u e t o u p d at e d i n 
i nf or m ati o n i n S e cti o n 2. 2.
A p p e n di x 1 
A b br e vi ati o n s
A d d e d “ C S R” = Cli ni c al St u d y R e p ort
A d d e d “ A U C” = Ar e a u n d er c o n c e ntr ati o n -ti m e 
c ur v e
E dit ori al c h a n g e.
A p p e n di x 4 A d v er s e 
E v e nt s: D e fi 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
R e pl a c e t h e f oll o wi n g w or di n g:
M ai n a d v er s e r e a cti o n s of c et u xi m a b ar e s ki n 
r e a cti o n s w hi c h m a y b e c o m e s e v er e, 
e s p e ci all y i n c o m bi n ati o n wit h c h e m ot h er a p y. 
T h e ri s k f or s e c o n d ar y i nf e cti o n s ( m ai nl y 
b a ct eri al) i s i n cr e a s e d a n d c a s e s of 
st a p h yl o c o c c al s c al d e d s ki n s y n dr o m e, 
n e cr oti s i n g f a s ciiti s a n d s e p si s, i n s o m e c a s e s 
wit h f at al o ut c o m e, h a v e b e e n r e p ort e d.
Cl arit y t o r efl e ct t h a t n o a d v er s e 
e v e nt s of s p e ci al i nt er e st ar e 
d efi n e d, a n d t h e k n o w n a d v er s e 
dr u g r e a cti o n s ar e li st e d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 / 1 2 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
Wi t h: “ T h er e ar e n o s p e cifi e d A E SI f or 
c et u xi m a b.”
A p p e n di x 1 1 S p o n s or
Si g n at ur e P a g e
I nf or m ati o n a d d e d t o t h e R e g ul at or y A g e n c y 
I d e ntif yi n g N u m b er s
Cli ni c al St u d y Pr ot o c ol V er si o n c h a n g e d
D et ail s f or t h e M e di c al R e s p o n si bl e u p d at e d
A d mi ni str ati v e u p d at e.
A p p e n di x 1 2
C o or di n ati n g 
I n v e sti g at or Si g n at ur e 
P a g e
I nf or m ati o n a d d e d t o t h e R e g ul at or y A g e n c y 
I d e ntif yi n g N u m b er s
Cli ni c al St u d y Pr ot o c ol V er si o n c h a n g e d
A d mi ni str ati v e u p d at e.
A p p e n di x 1 3 Pri n ci p al 
I n v e sti g at or Si g n at ur e 
P a g e
I nf or m ati o n a d d e d t o t h e R e g ul at or y A g e n c y 
I d e ntif yi n g N u m b er s
Cli ni c al St u d y Pr ot o c ol V er si o n c h a n g e d
A d mi ni str ati v e u p d at e.
-
 –
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 1 9 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
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 / 1 2 5
T a ble of C o nte nts
Title Pa ge
.............................................................................................................. 1
Pr ot oc ol A me n d me nt S u m mar y  of C ha n ges........................................................................ 3
Ta ble of C o nte nts
............................................................................................................ 1 1
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 vities ......................................................................... 1 8
2
I ntr o d ucti o n......................................................................................... 3 2
2. 2
Bac k gr o u n d ......................................................................................... 3 2
2. 3
Be nefit/ Ris k Assess me nt .................................................................... 3 4
3
O bjecti ves a n d E n d p oi nts ................................................................... 3 6
4
St u d y  Desi g n....................................................................................... 3 7
4. 1
O verall Desi g n .................................................................................... 3 7
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................ 3 8
4. 3
J ustificati o n f or D ose .......................................................................... 4 0
4. 4
E n d of St u d y  Defi niti o n...................................................................... 4 1
5
St u d y  P o p ulati o n................................................................................. 4 1
5. 1
I ncl usi o n Criteria ................................................................................ 4 1
5. 2
E xcl us i o n Criteria............................................................................... 4 3
5. 3
Lifest y le C o nsi derati o ns..................................................................... 4 5
5. 3. 1
Meals a n d Dietar y  Restricti o ns........................................................... 4 6
5. 3. 2
Caffei ne, Alc o h ol, a n d T o bacc o ......................................................... 4 6
5. 3. 3
Acti vit y ...............................................................................................4 6
5. 4
Scree n Fail ures ....................................................................................4 6
6
St u d y  Inter v e nti o n(s) ..........................................................................4 6
6. 1
St u d y  Inter ve nti o n(s) A d mi nistrati o n ................................................. 4 6
6. 1. 1
Pac ka gi n g a n d La beli n g of St u d y  Inter ve nti o n .................................. 4 8
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 ..................................................................................... 4 8
6. 2. 1
A vel u ma b ............................................................................................ 4 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 2 / 1 2 5
6. 2. 2
Cet u xi ma b ...........................................................................................4 9
6. 2. 3
C he m ot hera p y..................................................................................... 5 0
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 ..............................................................................................5 0
6. 3. 1
St u d y  Inter ve nti o n Assi g n me nt .......................................................... 5 0
6. 3. 2
Bli n di n g ..............................................................................................5 0
6. 4
St u d y  Inter ve nti o n C o m plia nce .......................................................... 5 0
6. 5
C o nc o mita nt T hera p y ......................................................................... 5 1
6. 5. 1
Resc ue Me dici ne ................................................................................. 5 1
6. 5. 2
Per mit te d Me dici nes........................................................................... 5 1
6. 5. 3
Pr o hi bite d Me dici nes .......................................................................... 5 2
6. 5. 4
Ot her I nter ve nti o ns ............................................................................. 5 2
6. 6
D ose Selecti o n a n d M o dificati o n ........................................................ 5 3
6. 6. 1
Se q ue nci n g a n d C o nti n uati o n of St u d y  Inter ve nti o n 
A d mi nistrati o n .................................................................................... 5 3
6. 6. 2
A vel u ma b ............................................................................................ 5 3
6. 6. 3
Cet u xi ma b ........................................................................................... 5 4
6. 6. 4
C he m ot hera p y ..................................................................................... 5 5
6. 6. 5
Treat me nt Be y o n d Disease Pr o gressi o n a n d C o m plete Res p o nse ..... 5 7
6. 7
St u d y  Inter ve nti o n after t he E n d of t he St u d y .................................... 5 9
6. 8
S pecial Preca uti o ns ............................................................................. 5 9
6. 8. 1
A vel u ma b ............................................................................................ 5 9
6. 8. 2
Cet u xi ma b ........................................................................................... 6 0
6. 8. 3
Ge mcita bi ne, Cis plati n, a n d Car b o plati n ............................................ 6 0
6. 9
Ma na ge me nt of A d verse E ve nts of I nterest ........................................ 6 1
6. 9. 1
A vel u ma b ............................................................................................6 1
6. 9. 2
Cet u xi ma b ...........................................................................................6 7
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 ...............................................................7 1
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................7 1
7. 1. 1
Rec halle n ge .........................................................................................7 2
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 ................... 7 2
7. 3
L ost t o F oll o w -u p ................................ ...............................................7 2
D oc u me nt N o
O bject N o
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 3 / 1 2 5
8
St u d y  Assess me nts a n d Pr oce d ures ....................................................7 3
8. 1
Efficac y  Assess me nts a n d Pr oce d ures................................................ 7 3
8. 1. 1
I m m u ne-relate d Res p o nse Criteria ..................................................... 7 4
8. 2
Safet y  Assess me nts a n d Pr oce d ures................................................... 7 8
8. 2. 1
P h y sical E xa mi nati o ns ........................................................................ 7 8
8. 2. 2
Vital Si g ns .......................................................................................... 7 8
8. 2. 3
Electr ocar di o gra ms ............................................................................. 7 9
8. 2. 4
Cl i nical Safet y La b orat or y Assess me nts............................................ 7 9
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts ..................................... 8 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 .................................................... 8 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 ... 8 0
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 ............... 8 0
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 ..... 8 1
8. 3. 5
Pre g na nc y ........................................................................................... 8 2
8. 4
Treat me nt of O ver d ose ....................................................................... 8 2
8. 5
P har mac o ki netics ................................................................................ 8 3
8. 1 0
I m m u n o ge nicity Assess me nts ............................................................ 8 8
9. 1
Statistical H y p ot heses ......................................................................... 8 8
9. 3
P o p ulati o ns f or A nal y ses .................................................................... 8 9
9. 4
Statistical A nal y ses .............................................................................8 9
9. 4. 1
Efficac y  A nalys es ............................................................................... 8 9
9. 4. 2
Safe t y A nalys es ..................................................................................9 1
9. 4. 3
Ot her A nal ys es ....................................................................................9 2
9. 4. 4
Se q ue nce of A nal ys es .........................................................................9 3
1 0
Refere nces ...........................................................................................9 3
1 1
A p pe n dices .........................................................................................9 7
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 4 / 1 2 5
A p pe n di x 1
A b bre viat i o ns......................................................................................9 8
A p pe n di x 2
St u d y  G o ver na nce............................................................................. 1 0 1
A p pe n di x 3
C o ntrace pti o n .................................................................................... 1 0 7
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 0 9
A p pe n di x 5
Li ver Safet y:  S u g geste d Acti o ns a n d F oll o w-u p Assess me nts ......... 1 1 3
A p pe n di x 6
Cli nical L a b orat or y Tests ................................................................. 1 1 4
A p pe n di x 7
Me dical De vice I nci de nts: Defi niti o n 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 1 5
A p pe n di x 1 0
Pr ot oc ol A me n d me nt Hist or y ........................................................... 1 2 2
A p pe n di x 1 1
S p o ns or Si g nat ure Pa ge .................................................................... 1 2 3
A p pe n di x 1 2
C o or di nati n g I n vesti gat or Si g nat ure Pa ge ........................................ 1 2 4
A p pe n di x 1 3
Pri nci pal I n vesti gat or Si g nat ure Pa ge ............................................... 1 2 5
List of T a bles
Ta ble 1
Sc he d ule of Acti vities ( A vel u ma b/ Cet u xi ma b pl us C he m ot hera p y) ..1 9
Ta ble 2
Sc he d ule of Acti vities ( A vel u ma b/ Cet u xi ma b Mai nte na nce a n d 
F oll o w - u p) .......................................................................................... 2 4
Ta ble 3
Sc he d ule of Ac ti vities – P har mac o ki netic, A nti dr u g A nti b o d y, a n d 
 Sa m pli n g ( A vel u ma b/ Cet u xi ma b pl us C he m ot hera p y).... 2 8
Ta ble 4
Sc he d ule of Acti vities – P har mac o ki netic, A nti dr u g A nti b o d y, a n d 
Sa m pli n g ( A vel u ma b/ Cet u xi ma b Mai nte na nce a n d 
F oll o w - u p) .......................................................................................... 3 0
Ta ble 5
St u d y  i nter ve nti o n(s) details...............................................................4 6
Ta ble 6
D ose a n d A d mi nistrati o n Pr oce d ure f or Cet u xi ma b ...........................5 4
Ta ble 7
Pre d osi n g C o nsi derati o ns f or Cis plati n.............................................. 5 5
Ta ble 8
Pre d osi n g C o nsi derati o n f or Car b o plati n ........................................... 5 6
Ta ble 9
D ose M o dificati o n f or C he m ot hera p y ................................................5 7
Ta ble 1 0
Treat me nt M o dificati o n f or S y m pt o ms of I nf usi o n- relate d 
Reacti o ns Ass ociate d wit h A vel u ma b ................................................ 6 1
Ta ble 1 1
Ma na ge me nt of I mm u ne -Relate d A d verse E ve nts .............................6 2
Ta ble 1 2
Rec o m me n de d Pr o p h yl a xis f or S ki n T o xicities .................................6 7
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 5 / 1 2 5
Ta ble 1 3
Treat me nt A dj ust me nt f or S y m pt o ms of Cet u xi ma b I nf usi o n -
relate d Reacti o ns................................................................................. 7 0
Ta ble 1 4
ir R E CIS T O verall T u m or Assess me nt ............................................... 7 6
Ta ble 1 5
A nal y ses P o p ulati o n ........................................................................... 8 9
Ta ble 1 6
Efficac y  E n d p oi nts a n d Statistical A nal ysis Met h o ds ........................ 8 9
Ta ble 1 7
Safet y  E n d p oi nts a n d Statistical A nal ysis Met h o ds ........................... 9 1
Ta ble 1 8
Pr ot oc ol -Re q uire d Cli nical La b orat or y  Assess me nts....................... 1 1 4
List of Fi g ures
Fi g ure 1
O verall St u d y  Desi g n Sc he ma............................................................ 1 8
Fi g ure 2
Treat me nt A dj ust me nt i n t he E ve nt of Gra de 3 S ki n Reacti o ns 
C o nsi dere d t o be Relate d t o Cet u xi ma b ( 2 5 0 m g/ m 2 D ose a n d 5 0 0 
m g/ m 2 D ose) ....................................................................................... 6 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI






2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4 -0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 8 /1 2 5
s us pe nsi o n of e nr oll me nt after a n i nitial safet y r u n-i n of cet u xi ma b i n c o m bi nati o n wit h a vel u ma b 
pl us ge mcita bi ne a n d cis plati n a n d will re vie w all a vaila ble safet y data. T he s pecific w or ki n g 
pr oce d ures will be descri be d i n a n S M C c harter, w hic h will be esta blis he d pri or t o t he start of 
recr uit me nt.
1. 2
Sc h e m a
Fi g ure 1
O ver all St u d y Desi g n Sc he m a
1 L m et a st ati c s q u a m o u s N S C L C
1 L = fir st -li n e; E G F R = e pi d er m al gr o wt h f a ct or r e c e pt or ; Q 2 W  = e v er y 2 w e e k s ; s q N S C L C = s q u a m o u s n o n -s m all -c ell 
l u n g c a n c er.
1. 3
Sc he d ule of Acti vities
T hr o u g h o ut t he trial, t he S cree ni n g wi n d o w will be 2 8 da y s, f oll o we d b y a treat me nt peri o d a n d a 
safety f oll o w-u p peri o d. A ti me wi n d o w of u p t o 3 d a y s bef ore or 1 d a y  after t he sc he d ule d visit 
da y  (-3/ + 1 d a y s) will be per mitte d f or all treat me nt pr oce d ures. T he bi wee kl y  1 4-d a y  sc he d ule i n 
t he mai nte na nce p hase after c he m ot hera p y s h o ul d be strictl y ad here d t o, ret ur ni n g t o t he tar get 
date e ve n if t he pre vi o us visit was off sc he d ule a n d o utsi de of t he descri be d visit wi n d o ws .
T he 3 0 -d a y  Safety F oll o w -u p Visit ( ± 5 da y s) a n d 9 0-da y  Safety F oll o w -u p P h o ne Call ( ± 5 da y s) 
s h o ul d be c o n d ucte d, if p ossi ble, pri or t o t he start of a n y ne w a nti ne o plastic t hera p y. Partici pa nts 
wit h o ut P D at E n d of Treat me nt (E o T ) Visit will be f oll o we d u p f or t u m or assess me nt u ntil disease 
pr o gressi o n or start of s u bse q ue nt a nti -ca ncer t hera p y ( w hic he ver c o mes first).
I n a d diti o n, partici pa nts i n t he f oll o w-u p peri o d will be f oll o we d f or s ur vi val (i ncl u di n g assess me nt 
of a n y f urt her t u m or t hera p y).
Partici pa nt f oll o w-u p f or pr o gressi o n a n d s ur vi val will c o nti n ue u n til 1 2 m o nt hs after t he last 
partici pa nt recei ve d t he last d ose.
Re -i nitiati o n of a vel u ma b is p ossi ble f or partici pa nts w h o e x perie nce a C R, disc o nti n ue treat me nt, 
pr o gress a n d later r e-i nitiate treat me nt. T he r e-i nitiati o n s h o ul d be perf or me d as per t he i nstr ucti o ns 
i n Secti o n 6. 6 .
N = 4 0
4 c y cl e s of ci s pl ati n a n d g e m cit a bi n e
Ci s pl ati n D a y  1 of e a c h c ycl e 
G e m cit a bi n e D a y s 1 a n d 8 of e a c h c y cl e 
A v el u m a b D a y s 1 a n d 8 of e a c h c y cl e
C et u xi m a b D a y s 1 a n d 8 of e a c h c y cl e 
1 L s q N S C L C 
E G F R W T
M ai nt e n a n c e 
tr e at m e nt aft er 
c o m pl eti o n of 
c h e m ot h er a p y 
A v el u m a b Q 2 W
C et u xi m a b Q 2 W
D oc u me nt N o. 
O bject N o. 
C CI
C CI




























2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 2 / 1 2 5
2
I ntr o d ucti o n
A vel u ma b 
is a 
n o vel, 
i ntra ve n o usly- a d mi nistere d 
pr o gra m me d 
cell 
deat h 
li ga n d- 1
( P D-L 1 ) - bl oc ki n g h u ma n a nti b o d y. Cet u xi ma b is a n a nti-e pi der mal gr o wt h fact or rece pt or 
( E G F R) c hi meric m o n ocl o nal a nti b o d y that bl oc ks t he li ga n d bi n di n g site of t he E G F R. T he 
c o m bi nati o n of a vel u ma b a n d cet u xi ma b, pl us c he m ot hera p y, is bei n g de v el o pe d f or t he treat me nt 
of patie nts wit h a d va nce d s q ua m o us n o n-s mall cell l u n g ca ncer (N S C L C ).
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 an d safet y of a vel u ma b a n d 
cet u xi ma b is i n t he res pecti ve I n vesti gat or’s Br oc h ures a n d pac ka ge i nserts of t he res pecti ve 
c o m p o u n ds.
2. 2
B ac k gr o u n d
Metastatic N S C L C re mai ns a c halle n gi n g dia g n osis wit h a nee d f or ne w t hera pe utic a p pr oac hes 
des pite si g nifica nt a d va nces. F ort y p erce nt of patie nts wit h ne wl y dia g n ose d N S C LC prese nt wit h 
Sta ge I V disease. Treat me nt g oals i nte n d t o pr ol o n g s ur vi val a n d c o ntr ol disease -relate d s ym pt o ms 
w it h c urre nt treat me nt o pti o ns i ncl u di n g c yt ot o xic c he m ot hera p y a n d i m m u ne c hec k p oi nt 
i n hi bit ors or tar gete d a ge nts s uc h as t yr osi ne ki nase i n hi bit ors i n disti nct s u bsets of patie nts.
U ntil rece ntly, s yste mic t hera pe utic re gi me ns i n t he first-li ne f or patie nts wit h a d va nce d N S C L C 
w h ose t u m ors d o n ot har b or ana plastic l ym p h o ma ki nase (A L K ) rearra n ge me nts or E G F R 
m utati o ns were mai nl y c he m ot hera p y wit h cis plati n or car b o plati n -base d d o u blets i n patie nts w h o 
are eli gi ble a n d ca n t olerate t his treat me nt.
Besi des plati n u m -base d d o u blet re gi me ns, t he E G F R i n hi bit or necit u m u ma b is a p pr o ve d as part 
of a c o m bi nati o n re gi me n wit h ge mcita bi ne a n d cis plati n f or N S C L C wit h s q ua m o us hist ol o g y . 
T he res ults of t he P hase III trial S Q UI R E pr o ve d a s ur vi val be nefit f or patie nts treate d wit h 
necit u m u ma b pl us cis plati n a n d ge mcita bi ne c o m pare d t o c he m ot hera p y al o ne. Me dia n o verall 
s ur vi val f or t he tri plet c o m bi nati o n was 1 1. 5
m o nt hs 
vs 9. 9
m o nt hs 
( hazar d rati o 0. 8 4; 
9 5 % c o nfi de nce i nter val [ CI ] 0. 7 4 –0. 9 6; p = 0. 0 1;  T hatc her 2 0 1 5 ).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 3 / 1 2 5
I n Oct o ber 2 0 1 6, t he U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) a n d i n Ja n uar y 20 1 7 , t he E ur o pea n 
C o m missi o n, a p pr o ve d pe m br oliz u ma b (f ull a p pr o val) f or t he first -li ne treat me nt of patie nts wit h 
metastatic N S C L C w h ose t u m ors were hi g h i n P D -L 1  e xpressi o n (t u m or pr o p o rti o n sc ore > 5 0 %), 
wit h n o e pi der mal gr o wt h fact or E G F R or A L K ge n o mic t u m or a berrati o ns. T he re p orte d o verall 
res p o nse rate reac he d 4 5 % wit h a me dia n p r o gressi o n-free s ur vi val (P F S ) of 1 0. 3 m o nt hs. T his 
treat me nt e ntere d U S Nati o nal C o m pre he nsi ve Ca ncer Net w or k (N C C N ) treat me nt g ui deli nes a n d
t he 2 0 1 8 E ur o pea n S ociet y  f or Me dical O nc ol o g y (E S M O ) g ui deli nes.
M ore o ver, c o m bi nati o n t hera pies of i m m u n ot hera pe utic a ge nts a n d esta blis he d c he m ot hera p y 
re gi me n are bei n g in vesti gate d t o f urt her i m pr o ve res p o nse rates a n d s ur vi val i n patie nts wit h 
a d va nce d l u n g ca ncer si nce o nl y  a su bset of patie nts res p o n d t o m o n ot hera p y wit h a p pr o ve d 
c hec k p oi nt i n hi bit ors.
Accelerate d a p pr o val was gra nte d b y  the F D A i n Ma y  20 1 7 f or pe m br ol iz u ma b i n c o m bi nati o n 
wit h pe metre xe d a n d car b o plati n f or t he treat me nt of patie nts wit h pre vi o usl y u ntreate d metastatic 
n o n-s q ua m o us N S C L C base d o n a n e x pl orat or y st u d y. T he st u d y de m o nstrate d a n i m pr o ve me nt 
i n o verall res p o nse rate a n d i n pr o gressi o n -free s ur vi val f or patie nts ra n d o mize d t o a c o h ort wit h 
pe m br oliz u ma b pl us car b o plati n a n d pe metre xe d. T he o bjecti ve res p o nse rate (O R R ) was 5 5 % 
( 9 5 % CI : 4 2- 6 8 %, n = 6 0) f or t he pe m br oliz u ma b pl us c he m ot hera p y ar m a n d 2 9 % ( 9 5 % CI : 
1 8- 4 1 %, n = 6 3) f or c he m ot her a p y al o ne (La n ger 2 0 1 6 ); me dia n P F S reac he d 1 3. 0 m o nt hs v ers us
8. 9 m o nt hs. T he E ur o pea n Me dici nes A ge nc y has gra nte d a mar keti n g a ut h orizati o n a p plicati o n 
f or t his treat me nt re gi me n i n Se pte m ber 2 0 1 8.
I n a d diti o n, res ults of a P hase III st u d y eval uati n g t he efficac y of car b o plati n -paclita xel/ na b -
paclita xel wit h or wit h o ut pe m br oliz u ma b i n u ntreate d patie nts wit h metastatic s q ua m o us N S C L C 
were rece ntl y pu blis he d (Paz- Ares 2 0 1 8 ), re p orti n g a n o ve rall res p o nse rate of 5 7. 9 % i n t he 
pe m br oliz u ma b +c he m ot hera p y ar m ( N = 2 7 8 ) as c o m pare d t o 3 8. 4 % i n t he c he m ot hera p y ar m 
( N = 2 8 1 ). A t olera ble safety pr ofile wit h o ut a n y ne w safet y co ncer ns was o bser ve d f or t he 
pe m br oliz u ma b c o m bi nati o n treat me nt. Base d o n t hese res ults, t his re gi me n recei ve d a p pr o val a n d 
mar keti n g a ut h orizati o n i n Oct o ber 2 0 1 8 b y  t he U S F D A a n d i n Marc h 2 0 1 9 b y  the E ur o pea n 
C o m missi o n.
Des pite t hese pr o misi n g a d va nces, a hi g h u n met me dical nee d re mai ns i n t he fiel d of s q ua m o us 
a d va nce d N S C L C gi ve n t hat o nl y  a part of patie nts be nefit s fr o m t he sta n dar d of care or ne wl y 
a p pr o ve d treat me nt m o dalities wit h d ura ble res p o nses.
A vel u m a b
T he i m m u ne c hec k p oi nt m olec ule P D -L 1 a n d its rece pt or, pr o gra m me d cell deat h pr otei n - 1 
( P D-1), c o m prise a n i m porta nt i m m u n os u p pressi ve pat h wa y  im plicate d i n t u m or i m m u ne e vasi o n. 
T he P D -L 1 is ofte n u pre g ulate d i n ca ncer a n d c orrelates wit h p o or pr o g n osis i n s o me ca ncers 
(C he n 2 0 1 6,  Wa n g 2 0 1 6 ). A vel u ma b ( Ba ve nci o ®) is a h u ma n a nti-P D -L 1 i m m u n o gl o b uli n G 1 
m o n ocl o nal a nti b o d y de vel o pe d b y  the S p o ns or. A vel u ma b bi n ds t o P D -L 1 a n d c o m petiti vel y 
bl oc ks its i nteracti o n wit h P D - 1. Bl oc ka de of t he P D -L 1/ P D - 1 pat h wa y  re verses T cell s u p pressi o n 
wit hi n t u m ors, ther e b y pr o m oti n g effecti ve a ntit u m or i m m u ne res p o nses. A vel u ma b is als o k n o w n 
t o pr o m ote a T h 1 res p o nse a n d sti m ulate I F Nγ pr o d ucti o n . Fi nall y , A vel u ma b has als o bee n s h o w n 
t o i n d uce a nti b o d y-de pe n de nt cell -me diate d c y t ot o xicit y i n vitr o (B o ye ri nas 2 0 1 5).
D oc u me nt N o. 
O bject N o
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 4 / 1 2 5
D ue t o str o n g e vi de nce s u p p orti n g a maj or r ole f or t he P D L 1/ P D - 1 pat h wa y  in t u m or i m m u ne 
e vasi o n, t his pat h wa y  has bec o me rec o g nize d as a hi g hl y pr o misi n g tar get f or t hera pe utic 
i nter ve nti o n (Bla n k 2 0 0 6 ).
T he c o m bi nati o n of i m m u n ot hera pies s uc h as a vel u ma b wit h ot her ca ncer t hera pies s uc h as 
c he m ot hera p y a n d tar gete d t hera pies m a y  en ha nce t he a bilit y of t he i m m u ne s yste m, a n d pre ve nt 
i m m u ne esca pe. Tar geti n g m ulti ple mec ha nis ms b y  whic h t u m or cells a v oi d eli mi nati o n b y  th e 
i m m u ne s yste m m a y  all o w f or s yner gistic effects a n d offer i m pr o ve d efficac y in br oa der patie nt 
p o p ulati o ns.
Cet u xi m a b
Cet u xi ma b ( Er bit u x ®) is a n a nti-E G F R m o n ocl o nal a nti b o d y that bl oc ks t he li ga n d bi n di n g site 
of t he E G F R. T he E G F R is a c o m m o nl y e x presse d tra ns me m bra ne gl yc o pr otei n of t he t yr osi ne 
ki nase gr o wt h fact or rece pt or fa mil y. T he E G F R ge ne, w hic h is e x presse d i n ma n y  n or mal h u ma n 
tiss ues, has bee n f o u n d t o be a pr ot o - o nc o ge ne; its acti vati o n res ults i n t he hi g h e x pressi o n of 
E G F R i n ma n y  hu ma n t u m or t ypes. E G F R is ric hl y ex presse d b y  a wi de variet y of s oli d t u m ors 
i ncl u di n g N S C L C. E G F R is als o k n o w n t o me diate t he resista nce of ca ncer cells t o ra diati o n i n a 
ma n ner pr o p orti o nal t o t he de gree of rece pt or e x pressi o n. T he pr o g n ostic si g nifica nce of hi g h 
le vels of e x pressi o n has e m p hasize d t he i m p orta nce of E G F R as a n a nti -ca ncer dr u g tar get (Li a n g 
2 0 0 3, H ua n g 1 9 9 9 , Ma urizi 1 9 9 6 ).
Cet u xi ma b bl oc ks t he bi n di n g of e pi der mal gr o wt h fact or a n d ot her li ga n ds t o E G F R a n d pre ve nts 
E G F R di merizati o n ( Merc k 2 0 0 3), t here by i n hi biti n g li ga n d i n d uce d acti vati o n of t his rece pt or 
t yr osi ne ki nase. T his res ults i n t he i n hi biti o n of cell gr o wt h, i n ducti o n of a p o pt osis, a n d decrease d 
pr o d ucti o n of matri x metall o pr otei nase a n d vasc ular e n d ot helial gr o wt h fact or (Me n dels o h n 1 9 9 0 ). 
Cet u xi ma b 
als o sti m ulates E G F R 
i nter nalizati o n (Li  20 0 5 ) a n d eve nt ual de gra dati o n 
(Wa ksal
1 9 9 9 ). I n ad diti o n, cet u xi ma b ca n me diate a nti b o d y-de pe n de nt cell-me diate d c yt ot o xicit y 
(Ha dari 2 0 0 4 ), a pr ocess de pe n de nt o n b ot h t he affi nit y of cet u xi ma b f or t he extracell ular d o mai n 
of E G F R a n d t he le vel of cell ular E G F R e x pressi o n (Z h a n g 2 0 0 6 ).
2. 3
Be nefit/ Ris k  Assess me nt
T he be nefit /ris k relati o ns hi p has bee n caref ully c o nsi dere d i n t he pla n ni n g of t he st u d y. Base d o n 
t he a vaila ble n o ncli nical a n d cli nical i nf or mati o n t o date, a vel u ma b pr o vi des a p ositi ve be nefit /ris k 
stat us f or a d va nce d N S CL C, a n d t he c o n d uct of t he trial is c o nsi dere d j ustifia ble usi n g t he d ose a n d 
d ose re gi me n of a vel u ma b a n d cet u xi ma b as s pecifie d i n t his cli nical st u d y pr ot oc ol (see 
Secti o n 4. 3) . Cli nical acti vit y an d safety of cet u xi ma b i n c o m bi nati o n wit h plati n u m -base d d o u blet 
c he m ot hera p y was de m o nstrate d b y t he F L E X trial (Pir ker 2 0 0 9 ). M ore o ver, efficac y an d safety 
of c o m bi nati o n t hera pies of a n a nti -P D -1 a nti b o d y  wit h c he m ot hera py ha ve bee n de m o nstrate d i n 
t he fr o ntli ne setti n g of N S C LC (La n ger 2 0 1 6 ).
Rece nt res ults of t he S W O G 0 8 1 9 trial e val uati n g cet u xi ma b pl us car b o plati n a n d paclita xel wit h 
or wit h o ut be vaciz u ma b vers us car b o plati n a n d paclita xel wit h or wit h o ut be vaciz u ma b i n 
a d va nce d N S C L C pr o vi de d f urt her e vi de nce s u p p orti n g t he r ole of cet u xi ma b i n s q ua m o us cell 
N S C L C w here patie nts wit h s q ua m o us cell hist ol o g y  wh o were E G F R FI S H -p ositi ve ha d l o n ger 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 5 / 1 2 5
o verall s ur vi val wit h cet u xi ma b treat me nt t ha n t h ose patie nts w h o di d n ot recei ve cet u xi ma b 
(Her bst 2 0 1 8 ).
F urt her m ore, s u b gr o u p a nal yses of t he S Q UI R E trial w hic h was c o n d ucte d i n a s q ua m o us cell 
N S C L C p o p ulati o n treate d wit h cis plati n a n d ge mcita bi ne wit h or wit h o ut necit u m u ma b, s h o we d 
a n o verall s ur vi val gai n f or patie nts w h ose t u m ors s h o we d hi g h E G F R e x pressi o n i n t he 
necit u m u ma b ar m de m o nstrati n g
efficac y an d safety of a n a nti-E G F R a nti b o d y 
wit h a 
cis plati n/ ge mcita bi ne c o m bi nati o n (T hatc her 2 0 1 5 ). T he be nefit/ris k pr ofile of t he c o m bi nati o n of 
a n a nti -P D -1 a nti b o d y a n d a n E G F R a nti b o d y was als o s h o w n t o be safe i n a n N S C L C p o p ulati o n 
base d o n t he res ults p u blis he d fr o m a n e x pl orat or y c o m bi nati o n st u d y of pe m br oliz u ma b a nd
necit u m u ma b (Besse 2 0 1 7 ) w here n o ne w safet y co ncer ns were re p orte d f or t he d o u blet 
c o m bi nati o n.
T he efficac y an d safet y of ge mcita bi ne a n d plati n u m -base d d o u blet c he m ot hera p y i n s q ua m o us 
N S C L C ha ve alrea d y bee n wi del y  de m o nstrate d; t he c o m bi nati o n of ge mcita bi ne a n d cis plati n is 
als o reflecte d i n t he c urre nt E S M O g ui deli nes as a rec o m me n de d c o m bi nati o n f or l u n g t u m ors 
wit h s q ua m o us hist ol o gical s u bt ype. H o w e ver, t o xicities s uc h as re nal i m pair me nt or ot ot o xicit y  
pre ve nt a n u m ber of patie nts fr o m c o m pleti o n of t he rec o m me n d c y cles of t hera p y wit h cis plati n.
F or t h ose patie nts u na ble t o t olerate all re q uire d 4 c ycles of cis plati n d ue t o li miti n g t o xicities, 
f urt her c o nti n uati o n of a d o u blet re gi me n wit h a s witc h t o car b o plati n i nstea d re prese nts a via ble 
o pti o n.
S pecific ris ks ass ociate d wit h t he use of a vel u ma b a n d cet u xi ma b as m o n ocl o nal a nti b o dies ha ve 
bee n o bser ve d.
P ote ntiall y  o verla p pi n g ris ks o bser ve d wit h a vel u ma b a n d cet u xi ma b treat me nt are t he f oll o wi n g:

I nf usi o n-relate d reacti o ns, i ncl u di n g a na p h ylactic reacti o ns

C uta ne o us reacti o ns .
T he pri mar y  ris ks of e x p os ure t o a vel u ma b i ncl u des:

I nf usi o n-relate d reacti o ns

Im m u ne -relate d a d verse e ve nts (ir A Es) ( ot her t ha n i nf usi o n-relate d reacti o ns)
Pri mar y ris ks ass ociate d wit h cet u xi ma b are:

I nf usi o n-relate d reacti o ns

C uta ne o us reacti o ns .
Partici pa nts will be m o nit ore d cl osel y for a d verse e ve nts ( A Es) o bser ve d t hr o u g h o ut t he st u d y. 
P re me dicati o n re gi me n t o mi ni mize
i nf usi o n-relate d reacti o ns t o a vel u ma b a n d cet u xi ma b has 
bee n de ter mi ne d pre vi o usl y . Pre me dicati o n f or cis plati n a n d ge mcita bi ne will be a d mi nistere d 
acc or di n g t o l ocal sta n dar ds. Detaile d treat me nt m o dificati o n al g orit h ms ha ve bee n set u p f or t he 
st u d y i nter ve nti o ns t o pr o vi de g ui da nce t o In vesti gat ors f or t he ha n dli ng of A Es .
D oc u me nt N o. 
O bject N o
C CI
C CI






2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 8 / 1 2 5
St u d y  treat me nt will be a d mi nistere d as f oll o ws:
Ge mcita bi ne a n d cis plati n will be a d mi nistere d i n 3 -wee k c ycles u p t o a ma xi m u m of 4 c ycles of 
i ntra ve n o us (i v) i nf usi o ns u ntil disease pr o gress i o n or u nacce pta ble t o xicities. Ge mcita bi ne 
( 1 2 5 0 m g/ m 2) is a d mi nistere d o n D a y 1 a n d Da y 8 a n d cis plati n ( 7 5 m g/ m 2) is a d mi nistere d o n 
D a y 1 of eac h 3- wee k c ycle. At t he discreti o n of t he I n vesti gat or, a s witc h t o car b o plati n f or t he 
re mai n der of t he plati n u m - d o u blet c ycles ( u p t o 4 c ycles i n t otal) will be all o we d i n s u bjects 
de vel o pi n g u nacce pta ble t o xicities t o cis plati n. I n t hese s u bjects, car b o plati n will be a d mi nistere d 
o n D a y  1 of e a c h 3-w e e k c y cle at a d ose of tar get area u n der t he ser u m c o nce ntrati o n -ti me c ur ve 
of 5 ( A U C 5) usi n g t he Cal vert f or m ula .

A vel u ma b ( 8 0 0 m g  i v) will be a d mi nistere d o n Da y 1 a n d D a y 8 of eac h 3 -wee k c ycle f or t he 
first 4 c ycles al o n g wit h c o nc urre nt c he m ot hera p y as per sc he d ule. T hereafter, a vel u ma b will 
be gi ve n e ver y 2 wee ks i n t he M ai nte na nce p hase u ntil disease pr o gressi o n or u nacce pta ble 
t o xicities.

Cet u xi ma b will be a d mi nistere d d uri n g t he first 4 c ycles of c o nc urre nt c he m ot hera p y, wit h a n 
i v d ose of 2 5 0 m g / m2 b o d y  surface area o n Da y 1 of eac h c ycle a n d at a d ose of 5 0 0 m g / m2
b o d y  surface area o n Da y 8 of eac h c ycle. T hereafter, cet u xi ma b will be gi ve n e ver y 2 wee ks 
i n t he M ai nte na nce p hase, at t he d ose of 5 0 0 m g / m2 i v u ntil disease pr o gressi o n or u nacce pta ble 
t o xicities.
T u m or meas ure me nts t o deter mi ne res p o nse will be perf or me d e ver y 9 wee ks f or t he first 
6 m o nt hs, a n d e ver y 12 wee ks t hereafter. Res p o nse t o treat me nt will be e val uate d b y  RE CI S T v 1. 1 
( pri mar y a n d sec o n dar y efficac y e n d p oi nts) a n d b y  ir R E CIS T ( ot her efficac y  e n d p oi nts).
A d verse e ve nts will be assesse d t hr o u g h o ut t he st u d y peri o d a n d e val uate d usi n g t he N CI -
C T C A E v 5. 0.
Partici pa nt foll o w -u p f or pr o gressi o n a n d s ur vi val will c o nti n ue u n til 1 2 m o nt hs after t he last 
partici pa nt recei ve d t he last d ose .
See Secti o ns 1. 2 ( Sc he ma), 1. 3 ( Sc he d ule of Acti vities) , 4. 4 (E n d of St u d y  Defi niti o n), a n d 6. 7
( St u d y Inter ve nti o n a fter t he E n d of t he St u d y ) f or a d diti o nal details.
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
Be y o n d t he d oc u me nte d cli nical acti vit y of b ot h a vel u ma b a n d cet u xi ma b i n a d va nce d N S C L C, 
m ore rece nt data pr o vi de c o m pelli n g scie ntific rati o nale t o c o m bi ne t hese 2 treat me nt m o dalities 
wit h c he m ot hera p y p artic ularl y in N S C L C wit h s q ua m o us cell hist ol o g y . T he i ncrease d e x pressi o n 
of E G F R ( E G F R H- sc ore ≥2 0 0) i n s q ua m o us cell N S C L C t u m ors i n a s u bset of patie nts w h o 
recei ve d cet u xi ma b i n c o m bi nati o n wit h cis plati n a n d vi n orel bi ne i n t he F L E X st u d y (H R 0. 6 2; 
9 5 % CI  0. 4 3– 0. 8 8) was ass ociate d wit h i m pr o ve d s ur vi val o utc o mes i n a p ost -h oc a nal ys is 
(Pir ker 2 0 1 2 ). F urt her m ore, s u b gr o u p a nal ys es of t he S Q UI R E trial w hic h was c o n d ucte d i n a 
s q ua m o us cell N S C L C p o p ulat i o n treate d wit h cis plati n a n d ge mcita bi ne wit h or wit h o ut 
necit u m u ma b, s h o we d a n o verall s ur vi val gai n f or patie nts w h ose t u m ors s h o we d hi g h E G F R 
e x pressi o n i n t he necit u m u ma b ar m ( hazar d rati o 0. 7 5; 9 5 % CI  0. 6 0 – 0. 9 4) (T hatc her 2 0 1 5 ).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 9 / 1 2 5
Rece nt res ults of t he S W O G 0 8 1 9 trial e val uati n g cet u xi ma b pl us car b o plati n a n d paclita xel wit h 
or wit h o ut be vaciz u ma b vers us car b o plati n a n d paclita xel wit h or wit h o ut be vaciz u ma b i n 
a d va nce d N S C L C pr o vi de d f urt her e vi de nce s u p p orti n g t he r ole of cet u xi ma b i n t he treat me nt of 
s q ua m o us cell N S C LC. Alt h o u g h s u b gr o u p a nal yses s h o we d t hat E G F R FI S H -p ositi vit y  was n ot 
pre dicti ve i n t he o verall N S C L C patie nt p o p ulati o n i n t he trial, patie nts wit h s q ua m o us cell 
hist ol o g y  wh o were E G F R FI S H -p ositi ve ha d l o n ger o verall s ur vi val wit h cet u xi ma b treat me nt 
t ha n t h ose patie nts w h o di d n ot recei ve cet u xi ma b (Her bst 2 0 1 8 ). After t he e nr oll me nt of 
4 0 partici pa nts , s u b gr o u p a nal yses will be c o n d ucte d i n t his trial as well f or efficac y in t u m ors 
wit h , f or e xa m ple, P D -L 1 e x pressi o n, hi g h E G F R e x pressi o n a n d E G F R ge ne a m plificati o n. I n 
case of pr o misi n g efficac y res ults fr o m a n i n di vi d ual s u bset of patie nts, t he st u d y ca n be a me n de d 
t o i ncl u de a d diti o nal partici pa nts t o s u bsta ntiate t he i nitial res ults.
T he pri mar y  en d p oi nt of c o nfir me d B O R acc or di n g t o R E CI S T v 1. 1 as per In vesti gat or assess me nt 
is bei n g use d as a direct earl y meas ure of a ntit u m or acti vit y i n partici pa nts treate d wit h t he 
q ua dr u plet c o m bi nati o n. C o nfir me d B O R (c o nfir me d C R or P R) is s uita ble f or a si n gle-ar m 
earl y- p hase st u d y . T he D O R, P F S, a n d O S ti mes will als o be deter mi ne d a n d will ser ve t o assess 
w het her o bjecti ve t u m or res p o nse is ass ociate d wit h lasti n g cli nical be nefit or pr ol o n gs s ur vi val. 
T he
sec o n dar y e n dp oi nt of occ urre nce of T E A Es, treat me nt-relate d A Es, treat me nt-relate d 
Gra de ≥3 A Es, a n d i m m u ne-relate d A Es acc or di n g t o t he N CI -C T C A E v 5. 0 d uri n g t he defi ne d 
o bser vati o n peri o d are bei n g use d as o bjecti ve meas ure s of safet y.
A safety r u n-i n of t he first 6 e nr olle d partici pa nts wit h se q ue ntial treat me nt of i n di vi d ual 
partici pa nts is c o nsi dere d t o be a de q uate t o esta blis h i nitial safet y an d t olera bilit y gi ve n t hat t he 
i n di vi d ual c o m p o ne nts as well 
as t he c o m bi nati o n of cet u xi ma b wit h 
plati n u m- base d 
c he m ot hera p y ha ve bee n teste d i n t his p o p ulati o n i n differe nt P hase II a n d III st u dies bef ore, a n d 
gi ve n t hat t he c o m para ble c o m bi nati o n of t he E G F R a nti b o d y necit u m u ma b a n d P D - 1 a nti b o d y 
pe m br oliz u ma b ha d a n acce pta ble safety pr ofile i n a P hase I b st u d y in N S C L C patie nts 
(Besse 2 0 1 7 ).
Cli nical efficac y of a vel u ma b m o n ot hera p y  was i nitiall y eval uate d i n a c o h ort of 1 5 6 s u bjects wit h 
treat me nt-naï ve N S C L C w h o were treate d wit h a vel u ma b. At t he ti me of t he a nal ys es, 2 6 s ubjects 
( 1 6. 7 %) were still o n st u d y treat me nt, 1 3 0 s u bjects ( 8 3. 3 %) were off -treat me nt, 2 6 s u bjects 
( 1 6. 7 %) were i n f oll o w-u p, a n d 1 0 4 s u bjects ( 6 6. 7 %) ha d disc o nti n ue d fr o m t he st u d y .
C o nfir me d o bjecti ve res p o nse acc or di n g t o R E CI S T 1. 1 was o bser ve d f or 3 1 s u bjects ( 1 9. 9 % [ 9 5 % 
CI : 1 3. 9, 2 7. 0]). T hree of 1 5 6 s u bjects ( 1. 9 %) ha d a C R a n d 2 8 s u bjects ( 1 7. 9 %) ha d a P R. T he 
me dia n D O R was 1 2. 0 2 m o nt hs ( 9 5 % CI : 6. 9 3, N E); t he Ka pla n -Meier
esti mate of 6- m o nt h 
d ura bilit y  of res p o nse was 7 0. 7 % ( 9 5 % CI : 5 1. 2, 8 3. 6). M ost res p o nses occ urre d wit hi n t he first 
1 2 wee ks of treat me nt ( 2 3 of 3 1 res p o nses), wit h t he o nset of t he first d oc u me nte d res p o nse 
c orres p o n di n g t o t he first or sec o n d t u m or assess me nt. T he Ka pla n -Meier esti mate d me dia n O S 
ti me was 1 4. 2 3 m o nt hs ( 9 5 % CI : 1 1. 8 9, 1 7. 1 8). Refer t o t he c urre nt versi o n of t he I nvesti gat or’s 
Br oc h ure f or f urt her details.
T he m ost rece ntl y e val uate d res ults of t he P hase III st u d y EM R 1 0 0 0 7 0 - 0 0 4 i n 2 L  NS C L C 
c o m pari n g a vel u ma b m o n ot hera p y  to c he m ot hera p y di d n ot ac hie ve its pri mar y  o bjecti ve . 
H o we ver, t he rate of patie nts i n t he c he m ot hera p y c o ntr ol ar m cr ossi n g o ver t o i m m u ne c hec k p oi nt 
i n hi bit or t hera py u p o n disease pr o gressi o n was 2 6. 4 %, w hic h m a y  ha ve c o nf o u n de d t he res ults.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 0 / 1 2 5
Alt h o u g h n ot ac hie vi n g its pri mar y  objecti ve i n i m pr o vin g o verall s ur vi val i n P D -L 1  positi ve 
( > 1 %) patie nts ( H R: 0. 9 0 [ 9 6 % CI : 0. 7 2 – 1. 1 2], t he res ults i n dicate d n o mi nal statistical si g nifica nt
i m pr o ve me nts i n o verall s ur vi val vers us t he c o ntr ol ar m i n s u b gr o u ps wit h m o derate -t o-hi g h 
P D -L 1  ex pressi o n ( 5 0 % or greater, w hic h re prese nte d a p pr o xi matel y 40 % of t he st u d y po p ulati o n) 
a n d hi g h P D -L 1 e x pressi o n p o p ulati o n ( P D-L 1 e x pressi o n 8 0 % or greater, w hic h re prese nte d 
a p pr o xi matel y 30 % of t he st u d y po p ulati o n) ( H R: 0. 6 7 [ 9 5 % CI : 0. 5 1 – 0. 8 9], a n d H R 0. 5 9 [ 9 5 % 
CI : 0.4 2 – 0. 8 3], res pecti vel y  ( Merc k data o n file).
A ra n d o mize d c o ntr olle d P hase III st u d y of a vel u ma b i n first-li ne a d va nce d N S C L C is c urre ntl y 
o n g oi n g.
4. 3
J ustific ati o n f or D ose
A vel u m a b
A flat d ose 8 0 0 m g  of a vel u ma b, i v, e ver y 2 wee ks was selecte d base d o n P K, tar get occ u pa nc y
( T O), safety d ata, a n d p o p ulati o n P K a nal ysis a n d si m ulati o n. A vel u ma b has bee n st u die d at d oses 
u p t o 2 0 m g/ k g e ver y 2 wee ks , at w hic h it was well t olerate d, a n d ma xi m u m t olerate d d ose was 
n ot reac he d. T o date, a vel u ma b has bee n a d mi nistere d at t he cli nicall y acti ve, safe, a n d t olera ble 
d ose of 1 0 m g / k g e ver y 2 wee ks
t o m ore t ha n 1 7 0 0 patie nts acr oss m ulti ple i n dicati o ns.
A d diti o nall y , t his d osi n g of a vel u ma b has bee n a p pr o ve d f or t he treat me nt of Mer kel 
cell 
carci n o ma a n d ur ot helial carci n o ma ( U C), as well as use d i n o n g oi n g st u dies f or t he treat me nt of 
N S C L C. M ore o ver, a wee kl y  dosi n g re gi me n wit h 1 0 m g/ k g of a vel u ma b di d n ot s h o w a n y ne w 
safety c o ncer ns base d o n t he a nal ys is of o verall 5 0 N S C LC patie nts treate d f or a peri o d of at least 
4 wee ks. A vel u ma b was ori gi nall y  dose d o n a m g/ k g basis i n or der t o re d uce i nter-s u bject 
varia bilit y  in dr u g e x p os ure. H o we ver, e mer gi n g data f or m A bs, i ncl u di n g t he mar kete d P D -1 a n d 
P D -L 1  im m u ne c hec k p oi nt i n hi bit ors ni v ol u ma b, pe m br oliz u ma b , a n d atez oliz u ma b, re veal t hat 
b o d y -wei g ht base d d osi n g re gi me ns d o n ot res ult i n less varia bilit y i n meas ures of e x p os ure o ver 
fi xe d (ie, b o d y-wei g ht i n de pe n de nt) d osi n g re gi me ns (Wa n g 2 0 0 9 , Fres h water 2 0 1 7, Z ha o 2 0 1 7 ). 
T he sa me has bee n c o nfir me d f or a vel u ma b t hro u g h m o deli n g a n d si m ulati o n. A d diti o nall y , flat 
d ose re gi me n offers t he a d va nta ges of less p ote ntial f or dis pe nsi n g err ors, s h orter d ose pre parati o n 
ti mes i n a cli nical setti n g, a n d greater ease of a d mi nistrati o n.
P har mac o ki netic si m ulati o ns s u g gest t hat e x p os ures t o a vel u ma b acr oss t he a vaila ble ra n ge of 
b o d y  wei g hts are less varia ble wit h 8 0 0 m g e ver y 2 wee ks c o m pare d wit h 1 0 m g/ k g e ver y 2 wee ks ; 
e x p os ures were si milar near t he p o p ulat i o n me dia n wei g ht. L o w -wei g ht s u bjects te n de d t o war ds 
mar gi nall y  lo wer e x p os ures relati ve t o t he rest of t he p o p ulati o n w he n wei g ht -base d d osi n g was 
use d, a n d mar gi nall y hi g her e x p os ure s w he n flat d osi n g was a p plie d. H o we ver, t he i m plicati o ns 
of t hese e x p os ure differe nces are n ot e x pecte d t o be cli nicall y mea ni n gf ul at a n y wei g ht acr oss t he 
w h ole p o p ulati o n. F urt her m ore, t he 8 0 0 m g e ver y 2 wee ks d osi n g re gi me n is e x pecte d t o res ult i n 
C tr o u g h > 1 m g/ m L  re q uire d t o mai ntai n a vel u ma b ser u m c o nce ntrati o ns at > 9 5 % T O t hr o u g h o ut 
t he e ntire e ver y 2 wee ks d osi n g i nter val i n all wei g ht cate g ories.
D uri n g t he 4 c he m ot hera p y cycl es, a d mi nistrati o n of a vel u ma b will be s ync hr o nize d wit h t he 
c he m ot hera p y c ycles, ie, d osi n g will be o n D a y 1 a n d D a y 8 of eac h c y cle. E x p os ures ( C ma x,ss a n d
A U C ss) u n der t his d ose re gi me n of a vel u ma b d uri n g t he c he m ot hera p y c ycles are n ot e x pecte d t o 
e xcee d t h ose f or pre vi o usl y a d mi nistere d re gi me ns i ncl u di n g 2 0 m g/ k g e ver y 2 wee ks. A flat d ose 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 1 / 1 2 5
of 8 0 0 m g e ver y 2 wee ks wi ll be a d mi nistere d as a 1 -h o ur i v i nf usi o n d uri n g t he mai nte na nce 
p hase of t his st u d y .
Cet u xi m a b
A n i nitial l oa di n g d ose of 4 0 0 m g/ m 2 f oll o we d b y s u bse q ue nt wee kl y d oses of 2 5 0 m g/ m 2 is t he 
d osi n g re gi me n i ncl u de d i n t he a p pr o ve d la bel.
Alt h o u g h c urre ntl y  a p pr o ve d o nl y f or wee kly a d mi nistrati o n, se veral st u dies ha ve e val uate d o nce 
e ver y 2 wee ks a d mi nistrati o ns of cet u xi ma b f or treat me nt of m C R C, s h o wi n g c o m para ble safety 
a n d efficac y (H u b bar d 2 0 1 3 ). A p o p ulati o n P K a nal ysis s h o we d n o si g nifica nt differe nces i n t u m or 
s hri n ka ge or O S bet wee n t he wee kl y a n d e ver y 2 wee ks re gi me ns (Girar d 2 0 1 3 ). A n e ver y 2- wee k 
d ose re gi me n all o ws a treat me nt s ync hr o nizati o n wit h a vel u ma b a n d wit h c he m ot hera pies, 
re d uci n g t he b ur de n t o partici pa nts. T heref ore, i n t his st u d y, cet u xi ma b a d mi nistrati o n will be 
s ync hr o nize d wit h t he c he m ot hera p y c ycl es, ie, cet u xi ma b will be a d mi nistere d wit h a n i v d ose of 
2 5 0 m g / m2 b o d y  surface area o n D a y  1 of eac h c yc le a n d at a d ose of 5 0 0 m g / m2 b o d y  surface area 
o n D a y 8 of eac h c ycle. T hereafter, d uri n g t he m ai nte na nce p hase, cet u xi ma b will be s ync hr o nize d 
wit h a vel u ma b a n d a d mi nistere d o nce e ver y  2 wee ks at t he mai nte na nce d ose of 5 0 0 m g/ m² i v.
4. 4
E n d of St u d y Defi niti o n
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 safet y 
a n d s ur vi val foll o w - up as s h o w n i n Sectio n  1. 3 ( Sc he d ule of Acti vities).
T he e n d of st u d y is defi ne d as 1 year after t he last partici pa nt recei ves t he last d ose of pr ot oc ol 
treat me nt. O nce t he pri mar y  a n d sec o n dar y o bjecti ves of t his st u dy ha ve bee n a nal yze d , t his st u dy 
ma y  be cl ose d bef ore t he e n d of st u d y defi niti o n has bee n met. Partici pa nts w h o are still o n pr ot oc ol 
treat me nt will be offere d t o recei ve f urt her treat me nt o n a r oll-o ver pr ot oc ol i n case t he st u d y 
treat me nt or a de q uate alter nati ve treat me nts, as j u d ge d by t he In vesti gat or, are n ot a vaila ble t o t he 
partici pa nt.
5
St u d y P o p ul ati o n
T he criteria i n Secti o n s 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 ens uri n g t he st u d y fulfills its 
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 ppr 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 ore 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 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 ( St u d y G o ver na nce).
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:
D oc u me nt N o. 
O bject N o
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 2 / 1 2 5
A ge
1.
Are 1 8 ye ars or ol der, at t he ti me of si g ni n g t he i nf or me d c o nse nt
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2.
H ist ol o gically- c o nfir me d Sta ge I V metastatic or rec urre nt ( Sta ge I V) N S C L C of s q ua m o us 
hist ol o g y  as per t he 7 t h I nter nati o nal Ass ociati o n f or t he St u d y  of L u n g Ca ncer a n d t he 
A merica n J oi nt C o m mittee o n Ca ncer classificati o ns.
3.
A vaila bilit y  of f or mali n-fi xe d paraffi n -e m be d de d ( F F P E) bl oc k c o ntai ni n g t u m or tiss ue or a 
mi ni m u m of 1 5 ( prefera bl y  2 5) u nstai ne d t u m or sli des (c ut wit hi n 1 wee k) s uita ble f or P D-L 1  
e x pressi o n a n d E G F R e x pressi o n /a m plificati o n assess me nt s, fr o m a rece ntl y o btai ne d ( wit hi n 
6 m o nt hs) bi o ps y  or a fres h baseli ne t u m or bi o ps y c ollecte d fr o m a n o n-irra diate d area.
4.
At least 1 meas ura ble lesi o n per R E CI S T v 1. 1 criteria. A lesi o n t hat has bee n irra diate d ca n be 
use d as a meas ura ble lesi o n pr o vi di n g t hat disease has pr o gresse d at t hat site
5.
Easte r 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 ) of 0 t o 1 at st u d y e ntr y.
6.
A de q uate he mat ol o gical f u ncti o n defi ne d b y w hit e bl o o d cell ( W B C) c o u nt ≥2. 5 × 1 0 9/ L wit h 
a bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 5 × 1 0 9/ L, l ym p h oc y te c o u nt ≥0. 5 × 1 0 9/ L, platelet c o u nt 
≥1 0 0 × 1 0 9/ L, a n d he m ogl o bi n ≥9 g/ d L ( ma y  ha ve bee n tra nsf use d).
7.
A de q uate he patic f u ncti o n defi ne d b y  a total bilir u bi n le vel ≤1. 5 × t he u p per li mit of n or mal 
( U L N) ra n ge a n d as partate a mi n otra nsferase ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) le vels 
≤2. 5 × U L N e xce pt f or partici pa nts wit h d oc u me nte d metastatic disease t o t he li ver f or w h o m 
A S T a n d A L T le vels ≤5 × U L N are acce pta ble . Patie nts wit h d oc u me nte d Gil bert disease are 
all o we d if t otal bilir u bi n is less t ha n 3 × U L N .
8.
A de q uate re nal f u ncti o n defi ne d b y  an e sti mate d creati ni ne cleara nce > 6 0 m L / mi nute
acc or di n g t o t he C oc kcr oft -Ga ult f or m ula or b y  2 4- h o ur uri ne c ollecti o n f or creati ni ne 
cleara nce or acc or di n g t o l ocal i nstit uti o nal sta n dar d met h o d.
9.
Esti mate d life e x pecta nc y  of at least 3 m o nt hs.
Se x
1 0. Are male or fe male.

A male partici pa nt m ust a gree t o use a n d t o ha ve t heir fe male part ners use a hi g hl y  effecti ve 
c o ntrace pti o n (ie, met h o ds wit h a fail ure rate of less t ha n 1 % per ye ar) as detaile d i n A p pe n di x 3
of t his pr ot oc ol 3 0 da y s bef ore t he first d ose of st u d y inter ve nti o n (as a p pr o priate), d uri n g t he 
st u d y inter ve nti o n peri o d a n d f or at least 6 0 da y s after t he last d ose of st u d y inter ve nti o n a n d 
refrai n fr o m d o nati n g s per m d uri n g t his peri o d.

A fe male is eli gi ble if s he is n ot pre g na nt (i e, after a c o nfir me d me nstr ual peri o d a n d a ne gati ve
ser u m pre g na nc y  test), n ot 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:
a. Is n ot a w o ma n of c hil d beari n g p ote ntial ( W O C B P), as defi ne d i n  A p pe n di x 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 3 / 1 2 5
O R
b. Is a W O C B P w h o a grees t o use a hi g hl y  effective c o ntrace pti ve met h o d (ie, has a 
fail ure rate of less t ha n 1 % per year), as liste d i n  A p pe n di x 3 , 3 0 da y s bef ore t he start 
of t he first d ose of st u dy i nter ve nti o n (as a p pr o priate), d uri n g t he st u d y inter ve nti o n 
peri o d a n d f or at least 6 0 da y s after t he last d ose of st u d y  i nter ve nti o n.
I nf or me d C o nse nt
1 1. 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 ( St u d y Go ver na nce), 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 
(IC 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.
Partici pa nts 
w h ose 
t u m or disease har b ors a n acti vati n g E G F R 
m utati o n 
or A L K 
rearra n ge me nt. Partici pa nts wit h t u m ors of u n k n o w n E G F R or A L K stat us will re q uire testi n g 
o nl y  i n ne ver sm o kers.
2.
All partici pa nts wit h brai n metastases, e xce pt t h ose meeti n g t he f oll o wi n g criteria:
a.
Brai n metastases t hat ha ve bee n treate d l ocall y a n d are cli nicall y s ta ble f or at least 4 wee ks 
pri or t o treat me nt start.
b.
N o o n g oi n g ne ur ol o gical s y m 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).
c.
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 dail y 
pre d nis o ne ( or e q ui vale nt ).
3.
Pre vi o us mali g na nt disease ( ot her t ha n N S C L C) wit hi n t he last 5 years (e xce pt a de q uatel y 
treate d n o n- mela n o ma s ki n ca ncers, carci n o ma i n sit u of s ki n, bla d der, cer vi x, c ol o n/rect u m, 
breast, or pr ostate) u nless a c o m plete re missi o n wit h o ut f urt her rec urre nce was ac hie ve d at 
least 2 years pri or t o st u d y entr y  an d t he partici pa nt was dee me d t o ha ve bee n c ure d wit h n o 
a d diti o nal t hera p y re q uire d or a ntici pate d t o be re q uire d.
4.
Acti ve i nfecti o n re q uiri n g s ys te mic t hera p y.
5.
K n o w n hist or y  of h u ma n i m m u n o deficie nc y vir us or k n o w n ac q uire d i m m u n o deficie nc y 
s yn dr o me.
6.
He patitis B vir us ( H B V) or he patitis C vir us ( H C V) i nfecti o n at S cree ni n g ( p ositi ve H B V 
s urface a nti ge n or H C V ri b o n ucleic aci d (R N A ) if a nti-H C V a nti b o d y scree ni n g test p ositi ve).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 4 / 1 2 5
7.
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 
a ge nt:
a.
Partici pa nts wit h dia betes t ype I, vitili g o, ps oriasis, h y p o- or h y pert h y r 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.
b.
A d mi nistrati o n of ster oi ds t h r o u g h a r o ute k n o w n t o res ult i n a mi ni mal sys te mic e x p os ure 
(t o pical, i ntra nasal, i ntr o-oc ular, or i n halati o n) are acce pta ble.
8.
I nterstitial pare nc hy m al l u n g disease.
9.
Pre g na nc y  or lactati o n.
1 0. K n o w n alc o h ol or dr u g a b use as deter mi ne d b y t he In vesti gat or.
1 1. Hi st or y of 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:
a.
H y perte nsi o n u nc o ntr olle d b y  sta n dar d t hera pies ( n ot sta bilize d t o 1 5 0/ 9 0 m m H g or l o wer)
b.
U nc o ntr olle d acti ve i nfecti o n.
c.
U nc o ntr olle d dia betes ( f or e xa m ple, he m o gl o bi n A 1c ≥8 %).
1 2. Cli ni call y si gnifica nt (ie, acti ve) car di o vasc ular disease: cere bral vasc ular acci de nt/str o ke 
( < 6 m o nt hs pri or t o e nr ollme nt), m y ocar dial i nfarcti o n ( < 6 m o nt hs pri or t o e nr oll me nt), 
u nsta ble a n gi na, c o n gesti ve heart fail ure ( ≥Ne w Y or k Heart Ass ociati o n Classificati o n Class II), 
or seri o us car diac arr h yt h mia re q uiri n g me dicati o n.
1 3. K n o w n hist or y  of i nfla m mat or y c olitis, i nfla m mat or y b o wel disease, p ne u m o nitis, p ul m o nar y 
fi br osis.
1 4. A n y  ps yc hiatric c o n diti o n t hat w o ul d pr o hi bit t he u n dersta n di n g or re n deri n g of i nf or me d 
c o nse nt or t hat w o ul d li mit c o m plia nce wit h st u d y  re q uire me nts.
Pri or/ C o nc o mit a nt T her a p y
1 5. Pri or s y ste mic t hera p y f or metastatic N S C LC.
1 6. Pri or t hera py wit h 
a n y a nti b o d y/ 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 -pr o gra m me d deat h 1 ( P D -1), a nti -P D L 1, a nti -P D -L 2 , a nti-c yt ot o xic 
T l y m p h oc y te a nti ge n-4 ( C T L A- 4), a nti -TI M 3, a nti -L A G 3, a nti -TI GI T or ot her a nti b o dies.
1 7. C o nc urre nt a nti -ca ncer treat me nt (f or e xa m ple, c yt o -re d ucti ve t hera py, ra di ot hera p y [ wit h t he 
e xce pti o n of palliati ve ra di ot hera py] , i m m u ne t hera py, or c yt o ki ne t hera p y, e xce pt f or 
er yt hr o p oieti n) wit hi n t he pre vi o us 2 8 da y s fr o m start of treat me nt.
1 8. Pri or c hest irra diati o n wit hi n 2 wee ks bef ore st u d y  e ntr y.
D oc u me nt N o. 
O bject N o
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 5 / 1 2 5
1 9. Maj or s ur ger y  f or a ny re as o n, e xce pt dia g n ostic bi o ps y, wit hi n 4 wee ks of t he st u d y treat me nt 
a n d/ or if t he partici pa nt has n ot f ull y rec o vere d fr o m t he s ur ger y wit hi n 4 wee ks of t he st u d y 
treat me nt.
2 0. C urre nt use of t he f oll o wi n g me dicati o ns at t he ti me of e nr oll me nt:
a.
I m m u n ot hera py or i m m u n os u p pressi ve dr u gs (f or e xa m ple, c he m ot hera p y or 
s yste mic c ortic oster oi ds) E X C E P T f or t he f oll o wi n g: a. i ntra nasal, i n hale d, t o pical 
ster oi ds, or l ocal ster oi d i njecti o n (f or e xa m ple, i ntra-artic ular i njecti o n); 
b. s yste mic c ortic oster oi ds at p h y si ol o gic d oses ≤1 0 m g/ da y  of pre d nis o ne or 
e q ui vale nt; c. ster oi ds as pre me dicati o n f or h y perse nsiti vit y  reacti o ns (f or e xa m ple,
c o m p ute d t o m o gra p h y [C T ] sca n pre me dicati o n).
b.
Gr o wt h fact ors E X C E P T f or gra n ul oc y te-c ol o n y sti m ulati n g fact or ( G-C S F), 
er yt hr o p oieti n a n d dar be p oieti n al p ha.
c.
Her bal re me dies wit h i m m u n osti 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  interfere wit h maj or or ga n f u ncti o n (f or e xa m ple,
h y perici n).
2 1. Pri or or ga n tra ns pla ntati o n, i ncl u di n g all o ge nei c ste m cell tra ns pla ntati o n.
2 2. K n o w n pri or se vere h y perse nsiti vit y  to t he st u d y inter ve nti o ns or a n y c o m p o ne nt i n its 
f or m ulati o ns, i ncl u di n g k n o w n se vere h y perse nsiti vit y  reacti o ns t o m o n ocl o nal a nti b o dies 
( N CI-C T C A E v 5. 0 Gra de ≥3) a n d ot her ac ute a n d c hr onic me dical c o n diti o ns i ncl u di n g a n y 
hist or y  of a na p hyl a xis, or u nc o ntr olle d ast h ma.
2 3. Persisti n g t o xicit y  relate d t o pri or t hera p y of Gra de > 1 N CI -C T C A E v 5. 0 (e xce pt ne ur o pat h y 
a n d al o pecia) h o we ver, al o pecia, se ns or y ne ur o pat h y Gra de ≤2, or ot her Gra de ≤2 A Es n ot 
c o nst it uti n g a safet y ris k base d o n In vesti gat or’s j u d g me nt are acce pta ble.
2 4. A d mi nistrati o n of a li ve vacci ne 3 0 d a y s bef ore t he start of st u d y  treat me nt.
Pri or/ C o nc urre nt Cli nic al St u d y E x perie nce
2 5. Use of a n y i n vesti gati o nal dr u g wit hi n 2 8 da ys bef ore t he start of st u d y  treat me nt.
Di a g n ostic Assess me nts
N ot a p plica ble.
Ot her E xcl usi o ns
2 6. Le gal i nca pacit y or li mite d le gal ca pacit y.
5. 3
Lifest yle C o nsi der ati o ns
N o s pecific lifest yl e or dietar y restricti o ns are re q uire d 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. 
C CI
C CI








2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 9 / 1 2 5

T he dis p ositi o n (i ncl u di n g ret ur n, if a p pli ca 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, vial 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 uatel y 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 pe nse d t o a partici pa nt ma y be re-dis 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 u d 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 inter ve nti o n(s) are 
pr o vi de d i n t he St u d y  Refere nce Ma n ual.
6. 2. 1
A vel u m a b
6. 2. 2
Cet u xi m a b
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 0 / 1 2 5
6. 2. 3
C he m ot her a p y
F or pre parati o n a n d st ora ge of ge mcita bi ne a n d cis plati n or car b o plati n , please c o ns ult t he l ocal 
prescri bi n g i nf or mati o n or t he res pecti ve s u m mar y of pr o d uct c haracteristics (S m P Cs ).
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
A n I nteracti ve V oice Res p o nse S y ste m will be e m pl o ye d t o assi g n st u d y inter ve nti o n t o 
partici pa nts a n d facilitate res u p pl y  of st u d y i nter ve nti o n at st u d y sites.
6. 3. 2
Bli n di n g
N ot a p plica ble.
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 nts 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 dr u g a d mi nistrati o n. T he i nf or mati o n of eac h 
st u d y dr u g a d mi nistrati o n i ncl u di n g t he date, ti me, a n d d ose of st u d y dr u g will be rec or de d o n t he 
electr o nic case re p ort f or m (e C R F). T he In 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 ad mi nistrat i o n is acc urate f or eac h partici pa nt . 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 nc o m plia nce is defi ne d as a pa rtici pa nt missi n g > 1 c ycle of trial treat me nt f or n o n me dical 
reas o ns a n d barri n g a n y e xte n uati n g circ u msta nces i n the o pi ni o n of t he In vesti gat or. If 1 c ycle 
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 1 / 1 2 5
was misse d a n d t he i nter val bet wee n t he s u bse q ue nt treat me nt c ycle a n d t he last a d mi nistere d 
treat me nt c ycle is l o n ger t ha n 4 wee ks f or n o n me dical reas o ns, t he criteria of i ns ufficie nt 
c o m plia nce are met as well.
C o nti n uati o n of treat me nt s h o ul d be disc usse d wit h t he Me dical 
M o nit or 
u n der c o nsi derati o n of p ote ntial be nefits a n d ris ks of st u d y inte r ve nti o ns a n d a n y 
alter nati ve o pti o ns.
6. 5
C o nc o mit a nt T her a p y
6. 5. 1
Resc ue Me dici ne
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 ap pr o priate me dical 
t hera py (i ncl u di n g e pi ne p hri ne, c ortic oster oi ds, i v a nti hista mi nes, br o nc h o dilat ors, a n d o x y ge n) 
m ust be a vaila ble f or use i n t he treat me nt of i nf usi o n -relate d reacti o ns.
If h y perse nsiti vit y  reacti o n occ urs, t he partici pa nt m ust be treate d acc or di n g t o t he be st a vaila ble 
me dical 
practice. Partici pa nts
s h o ul d be i nstr ucte d t o re p ort a n y dela y e d reacti o ns t o t he 
In vesti gat or i m me diatel y. I n ad diti o n, all h y perse nsiti vit y  reacti o ns are t o be re p orte d i n a ti mel y 
ma n ner.
6. 5. 2
Per mitte d Me dici nes

A n y  me dicati o ns, t hera pies, or pr oce d ures ( ot her t ha n t h ose e xcl u de d b y t he cli nical st u d y 
pr ot oc ol) t hat ar e c o nsi dere d necessar y f or t he partici pa nts’ welfare a n d will n ot i nterfere wit h 
t he st u d y me dicati o n 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 per mitte d.

Pr o p h y lactic or resc ue me dicati o ns ma y  be a d mi nistere d d ue t o a ntici pate d or o bser ve d a d verse 
reacti o ns or e mer ge nc y sit uati o ns.

F or partici pa nts w h o de vel o p u nacce pta ble t o xicities t o cis plati n, a s witc h t o c he m ot hera p y 
treat me nt wit h car b o plati n is all o we d at t he discreti o n of t he I n vesti gat or .
T he o nl y  per mitte d c ortic oster oi ds a n d gr o wt h fact ors are t he f oll o wi n g:

Intra nasal, i n hale d, t o pical ster oi ds, or l ocal ster oi d i njecti o n (f or e xa m ple, i ntra-artic ular 
i njecti o n).

S ys te 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.

S ter oi ds as pre me dicati o n f or h y perse nsiti vit y  reacti o ns (f or e xa m ple, pre me dicati o n pri or t o 
cet u xi ma b a d mi nistrati o n or C T sca n s).

E r yt hr o p oieti n, dar be p oieti n al p ha, a n d G-C S F .
A n y  me 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 
ma y  be gi ve n at t he I n vesti gat or’s discreti o n, re gar dless if it res ults i n a pr ot oc ol de viati o n.
D oc u me nt N o
O bject N o
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 2 / 1 2 5
6. 5. 3
Pr o hi bite d Me dici nes

P ri or s yste mic t hera p y f or metastatic N S C L C.

Pri or t hera p y 
wit h a n y anti b o d y / 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 -pr o gra m me d deat h 1 ( P D-1), a nti-P D L 1, a nti-P D -L 2, a nti-c yt ot o xic 
T l y m p h oc y te a nti ge n-4 ( C T L A- 4), a nti -TI M 3, a nti -L A G 3, a nti -TI G I T or ot her a nti b o dies.

Pri or c hest irra diati o n wit hi n 2 wee ks bef ore st u d y  e ntr y.

I m m u n ot hera py, i m m u n os u p pressi ve dr u gs (ie, c he m ot hera p y n ot s pecifie d i n t he pr ot oc ol or 
s yste mic c ortic oster oi ds e xce pt f or t h ose s pecifie d i n Secti o n 6. 5. 2) .

Gr o wt h fact ors , f or e xce pti o ns see Secti o n  6. 5. 2.

A d mi nistrati o n of a li ve vacci ne wit hi n 3 0 da y s of st u d y treat me nt.

Her bal re me dies wit h i m m u n osti 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).

C o nc urre nt 
a nti-ca ncer treat me nt (f or e xa m ple, c yt o-re d ucti ve t hera p y, n o n-palliati ve 
ra di ot hera py,  im m u ne t hera p y, or c yt o ki ne t hera p y e xce pt f or t he st u d y inter ve nti o ns ) wit hi n 
t he pre vi o us 2 8 da ys fr o m start of treat me nt or d uri n g st u d y treat me nt .
Use of a pr o hi bite d c o nc o mita nt dr u g will res ult i n wit h dra wal fr o m st u d y treat me nt, w here t he 
pre defi ne d c o nse q ue nce is treat me nt wit h dra wal if c o nsi dere d necessar y by t he I n vesti gat or or t he 
S p o ns or.
6. 5. 4
Ot her I nter ve nti o ns
Per mitte d

Palliati ve s h ort c o urse, li mite d fiel d (ie, ≤1 0 fracti o ns a n d ≤3 0 % b o ne marr o w i n v ol ve me nt or 
per i nstit uti o nal sta n dar d) b o ne- directe d ra di ot hera p y ma y be a d mi nistere d d uri n g t he st u d y. 
T he assess me nt of P D will be ma de acc or di n g t o R E CI S T v 1. 1 (Eise n ha uer 2 0 0 9 ) a n d n ot base d 
o n t he necessit y f or ra di ot hera p y.
Pr o hi bite d
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 (a n d wit hi n 2 8 d a y s 
bef ore t he start of st u d y t reat ment):

S ur ger y  to a n y t u m or lesi o n f or s ym pt o m ma na ge me nt or t u m or c o ntr ol is n ot per mitte d d uri n g 
t he st u d y treat me nt e xce pt as descri be d i n S ecti o n 6. 6. 5. F or a n y ot her s ur gical i nter ve nti o ns 
pla n ne d d uri n g t he st u d y, st u d y treat me nt s h o ul d be dela y e d t o all o w partici pa nt’s rec o ver y, 
f or u p t o a ma xi m u m of 4 wee ks.

Ra di ot hera p y wit h t he e xce pti o n of palliati ve ra di ot hera py if c o nsi dere d me dicall y  necessar y 
b y  t he In vesti gat or f or partici pa nts wit h c o nfir me d P D.
Rec or d i n t he case re p ort f or m (C R F ) all c o nc o mita nt t hera pies (f or e xa m ple, me dici nes or 
n o n dr u g i nteracti 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 
D oc u me nt N o. 
O bject N o
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 3 / 1 2 5
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, 
vacci 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 m ati o n.
Use of a pr o hi bite d i nter ve nti o n will res ult i n wit h dra wal fr o m st u d y treat me nt, w here t he 
pre defi ne d c o nse q ue nce is treat me nt wit h dra wal if c o nsi dere d necessar y b y t he I n vesti gat or or t he 
S p o ns or ( See Secti o n 7 ).
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. 6
D ose Selecti o n a n d M o dific ati o n
6. 6. 1
Se q ue nci n g 
a n d 
C o nti n u ati o n 
of 
St u d y 
I nter ve nti o n 
A d mi nistr ati o n
O n a d mi nistrati o n visits, c he m ot hera p y a d mi nistrati o n will be i nitiate d first, f oll o we d b y i nf usi o n 
of t he a nti b o dies cet u xi ma b a n d fi nall y  avel u ma b . C o-a d mi nistrati o n of a vel u ma b a n d cet u xi ma b 
or c he m ot hera p y at t he sa me ti me is n ot all o we d .
A vel u ma b i nf usi o ns s h o ul d n ot start earlier t ha n 1 h o ur after t he c o m pleti o n of cet u xi ma b 
i nf usi o ns.
O n d a y s w here b ot h a vel u ma b a n d cet u xi ma b are sc he d ule d, a d mi nistrati o n of pre me dicati o n 
s olel y pri or t o t he cet u xi ma b i nf usi o n, is acce pta ble. H o we ver, if t he a vel u ma b i nf usi o n is gi ve n 
m ore t ha n 4 h o urs after t he i nitial pre me dicati o n, a ne w se q ue nce of pre me dicati o n has t o be 
a d mi nistere d bef ore t he a vel u ma b i nf usi o n.
T reat me nt wit h t he re mai n der of st u d y i nter ve nti o ns will n ot be dela y e d f or m ore t ha n 7 da ys f or 
a t o xicit y attri b ute d t o o ne of t he c o m p o u n ds u nless dee me d necessar y  by t he In vesti g at or. 
T heref ore, if t here is a dela y of m ore t ha n 7 da ys or a disc o nti n uati o n f or o ne of t he dr u gs , t he 
partici pa nt will c o nti n ue t o recei ve sc hed ule d i nf usi o ns of t he ot her dr u gs a n d t he ot her I M Ps m a y  
be c o nti n ue d u p t o u ntil eit her P D, as assesse d b y  t he I n vesti gat or, u nacce pta ble t o xicit y, or ot her 
wit h dra wal criteria a p pl y. Partici pa nts will c o nti n ue t o recei ve sc he d ule d e val uati o n visits u nti l 
P D, as assesse d b y t he I n vesti gat or.
6. 6. 2
A vel u m a b
Partici pa nts will recei ve a vel u ma b as a n i v i nf usi o n at a fi xe d d ose of 8 0 0 m g o ver a d urati o n of 
1 h o ur ( - 1 0 mi n utes , ie, o ver 5 0 t o 6 0 mi n utes) o n Da y 1 a n d Da y 8 of eac h 3 -wee k c he m ot hera p y 
c ycle. After co m pleti o n of c he m ot hera p y, a vel u ma b will be a d mi nistere d o nce e ver y 2 wee ks. 
A part fr o m a c ha n ge fr o m a b o d y -wei g ht base d d ose t o a fi xe d d ose, relati ve t o earlier st u dies, t his 
st u d y will f oll o w sta n dar d pr oce d ures f or t he a d mi nistrati o n of a vel u ma b. I n or der t o miti gate 
i nf usi o n-relate d reacti o ns, ma n dat or y  pre me dicati o n wit h 
a nti hista mi ne a n d paraceta m ol 
(aceta mi n o p he n) f or t he first 4 d oses is re q uire d. 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 i ncl u di n g pretreat me nt m o dalities 
f or c he m ot hera p y as 
a p pr o priate. Pre me dicati o n s h o ul d be a d mi nistere d f or s u bse q ue nt a vel u ma b d oses 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 nf usi o n reacti o ns. M o dificati o ns of t he i nf usi o n 
D oc u me nt N o. 
O bject N o. 
C CI
C CI










2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 8 / 1 2 5
6. 6. 5. 1. 2
Tre at me nt be y o n d c o nfir me d pr o gressi o n
After c o nfir me d P D, if t he In vesti gat or feels t hat t he partici pa nt c o nti n ues t o ac hie ve cli nical 
be nefit b y  c o nti n ui n g treat me nt, 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 nti n ue t o recei ve 
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 treat me nt b e y o n d 
c o nfi r 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. Treat me nt s h o ul d be disc o nti n ue d per ma ne ntl y u p 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 In vesti gat or a n d t he M e dical 
M o nit or. I n case of c o nti n uati o n of treat me nt be y o n d P D, treat me nt will be disc o nti n ue d o nce a n y 
ot her criteria f or wit h dr a wal are met ( See Secti o n  7. 1) .
6. 6. 5. 2
C o nti n u ati o n of st u d y i nter ve nti o n after l oc al tre at me nt of 
dise ase pr o gressi o n:
If disease pr o gressi o n is d ue t o brai n 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 lesi o ns 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:

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 CIS T v 1. 1 pri or t o t he pr oce d ure.

Brai 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 re-i nitiati 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 y m 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 dai l y 
pre d nis o ne ( or e q ui vale nt).

Be nefit /ris k assess me nt t o c o nti n ue st u d y inter 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 n vesti gat or.
I n a d diti o n, if disease pr o gressi o n is mai nl y d ue t o a metastatic lesi o n w hic h i n t he o pi ni o n of t he 
In vesti gat or m a y  be s ur gicall y re m o ve d, 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 s uc h a lesi o n pr o vi de d t hat:

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 CIS T v 1. 1 pri or t o t he pr oce d ure.

It has bee n at least 2 wee ks a n d t he partici pa nt has f ull y rec o vere d fr o m t he s ur ger y.

Be nefit /ris k assess me nt t o c o nti n ue st u d y inter 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 n vesti gat or.
D oc u me nt N o
O bject N o
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 9 / 1 2 5
6. 6. 5. 3
Tre at me nt Be y o n d C o m plete Res p o nse
A d diti o nall y , partici pa nts recei vi n g a vel u ma b w h o ha ve e x perie nce d a C R s h o ul d be treate d f or a 
mi ni m u m of 1 2 m o nt hs base d o n cli nical j u d gme nt of be nefit a n d/ or u ntil disease pr o gressi o n or 
u nacce pta ble t o xicit y, after c o nfir mati o n of res p o nse at t he discreti o n of t he I n vesti gat or. I n case 
s uc h partici pa nt’s disease rela pses after st o p pi n g treat me nt, b ut pri or t o t he e n d of t he st u d y, 1 
re-i nitiati o n of treat me nt is all o we d at t he discreti o n of t he In vesti gat or a n d a gree me nt wit h t he 
M e dical M o nit or. T o be eli gi ble f or re-treat me nt, t he partici pa nt m ust n ot ha ve e x perie nce d a n y 
t o xicit y t hat lea ds t o treat me nt disc o nti n uati o n of t he i nitial a vel u ma b. Partici pa nts w h o re -i nitiate 
treat me nt will sta y on st u d y an d will be treate d a n d m o nit ore d acc or di n g t o t he pr ot oc ol a n d t he 
“ u ntil pr o gressi o n” sc he d ule i n t he Sc he d ule of Acti vities.
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
After a partici pa nt has c o m plete d t he st u d y or has wit h dra w n earl y, us ual treat me nt will be 
a d mi nistere d, if re q uire d, i n acc or da nce wit h t he st u d y site’s sta n dar d of care a n d ge nerall y 
acce pte d me dical practice a n d de pe n di n g o n t he partici pa nt’s i n di vi dual me dical nee ds. T he 
S p o ns or will n ot pr o vi de a n y ad diti o nal care t o partici pa nts after t he y lea ve t he st u d y beca use s uc h 
care s h 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 N S C LC.
Partici pa nts will be f oll o we d f or s ur vi val, s u bse q ue nt use of a nti-ca ncer t hera py a n d A Es as 
s pecifie d i n t he Sc he d ule of Acti vities. F oll o w -u p ma y  be perf or me d b y p h o ne.
S ur vi val f oll o w- u p will c o nti n ue u ntil u p t o 1 2 m o nt hs after t he last partici pa nt recei ves t he last 
d ose of a vel u ma b/cet u xi ma b. S p o ns or ma y ter mi nate t he st u d y at a n y ti me a n d t here ma y  be 
all o wa nce f or partici pa nt s t o e nter a r oll o ver st u d y, e x pa n de d access, or ot her mec ha nis m f or 
a vel u ma b a n d cet u xi ma b access as a p pr o priate.
6. 8
S peci al Prec a uti o ns
6. 8. 1
A vel u m a b
As a r o uti ne preca uti o n, partici pa nts e nr olle d i n t his st u d y must be o bser ve d f or 2 h o urs p ost 
a vel u ma b i nf usi o n f or t he first 4 a vel u ma b i nf usi o ns, a n d t he n acc or di n g t o cli nical si g ns a n d 
s ym pt o ms, i n a n area wit h res uscitati o n e q ui p me nt a n d e mer ge nc y ag e nts. At all ti mes d uri n g 
a vel u ma b treat me nt, i m me diate e mer ge nc y treat me nt of a n i nf usi o n-relate d reacti o n or a se vere 
h y perse nsiti vit y  reacti o n acc or di n g t o i nstit uti o nal sta n dar ds m ust be ass ure d. I n or der t o treat 
p ossi ble h y perse nsiti vit y reacti o ns, for i nsta nce, de xa met has o ne 1 0 m g a n d e pi ne p hri ne i n a 
1: 1 0 0 0 dil uti o n or e q ui vale nts s h o ul d al wa ys be a vaila ble al o n g wit h e q ui p me nt f or assiste d 
ve ntilati o n.
T he treat me nt rec o m me n dati o ns f or i nf usi o n -relate d reacti o ns are o utli ne d i n  Ta ble 1 0.
I n vesti gat ors s h o ul d als o m o nit or partici pa nts cl osel y for p ote ntial ir A Es, w hic h ma y  bec o me 
ma nifest at a n y ti me d uri n g treat me nt. S uc h e ve nts i ncl u de b ut are n ot li mite d t o p ne u m o nitis, 
he patitis, c olitis, e n d ocri n o pat hies ( h yp ot h y r oi dis m, h y pert h y r oi dis m, a dre nal i ns ufficie nc y, t yp e 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
6 0 / 1 2 5
1 dia betes mellit us), m y ocar ditis, m y ositis, a n d ras h. See Secti o n 6. 9. 1 f or details o n t he 
ma na ge me nt of ir A Es.
I m me diate access t o a n I nte nsi ve C are U nit or e q ui vale nt e n vir o n me nt a n d a p pr o priate me dical 
t hera py (i ncl u di n g e pi ne p hri ne, c ortic oster oi ds, i v a nti hista mi nes, br o nc h o dilat ors, a n d o x y ge n) 
m ust be a vaila ble f or use i n t he treat me nt of i nf usi o n -relate d reacti o ns. Inf usi o n of a vel u ma b wil l 
be st o p pe d i n case of Gra de ≥2 i nf usi o n -relate d, aller gic, or a na p h ylact oi d reacti o ns.
If h y perse nsiti vit y  reacti o n occ urs, t he partici pa nt m ust be treate d acc or di n g t o t he best a vaila ble 
me dical 
practice. Partici pa nts s h o ul d be i nstr ucte d t o re p ort a n y dela y e d reacti o ns t o t he 
I n vesti gat or i m me diately.
O n d a y s w here se veral st u d y inter ve nti o ns are sc he d ule d, a d mi nistrati o n of pre me dicati o n 
i ncl u di n g a c ortic oster oi d, a n a nti hista mi ne , a n d paraceta m ol pri or t o t he cet u xi ma b i nf usi o n, 
w hic h is al wa ys a d mi nistere d bef ore a vel u ma b, is acce pta ble. H o we ver, if t he a vel u ma b i nf usi o n 
is gi ve n m ore t ha n 4 h o urs after t he i nitial pre me dicati o n, a ne w se q ue nce of pre me dicati o n has t o 
be a d mi nistere d bef ore t he a vel u ma b i nf usi o n.
6. 8. 2
Cet u xi m a b
Partici pa nts s h o ul d be m o nit ore d f or at least 1 h o ur f oll o wi n g cet u xi ma b i nf usi o ns i n a setti n g wit h 
res uscitati o n e q ui p me nt a n d ot her a gents necessar y t o treat a na p h yl a xis (f or e xa m ple, e pi ne p hri ne, 
c ortic oster oi ds, i v a nti hista mi nes, br o nc h o dilat ors, a n d o x y ge n). M o nit or i n g s h o ul d be l o n ger t o 
c o nfir m res ol uti o n of t he e ve nt i n patie nts re q uiri n g treat me nt f or i nf usi o n reacti o ns.
6. 8. 3
Ge mcit a bi ne , Cis pl ati n , a n d C ar b o pl ati n
Ge mcit a bi ne
Ge mcita bi ne d osa ge a dj ust me nt f or he mat ol o gic t o xicities is base d u p o n t he gra n ul oc y te a n d 
platelet c o u nts o n t he da y  of treat me nt. Partici pa nt s recei vi n g ge mcita bi ne s h o ul d be m o nit ore d 
pri or t o eac h d os e usi n g c o m plete bl o o d c o u nts.
Cis pl ati n
Partici pa nt s w h o recei ve cis plati n m ust 
be m o nit ore d 
f or ne p hr ot o xicit y , ot ot o xicit y , a n d 
ne ur o pat h y i n a d diti o n t o m y el os u p pressi o n. Cis plati n s h o ul d n ot be e m pl o ye d i n partici pa nt s wit h 
heari n g i m pair me nt. Ca uti o n 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 d rati o n. 
Pre me dicati o n wit h a nti -e metics a n d h y drati o n are perf or me d acc or di n g t o l ocal sta n dar ds a n d t he 
S m P C.
C ar b o pl ati n
Partici pa nts w h o s witc h t o treat me nt wit h car b o plati n after e x perie nci n g cis plati n -relate d t o xicities 
s h o ul d be m o nit ore d 
f or s ym pt o ms 
of m y el o s u ppressi o n wit h 
t hr o m b o pe nia, le uc o pe nia, 
ne utr o pe nia a n d a ne mia; i nfecti ons ; na usea a n d v o miti n g; he patic t o xicit y, re nal t o xicit y, 
ot ot o xicit y ; a nd peri p heral ne ur o pat hies as per S m P C rec o m me n dati o ns. Pre me dicati o n wit h a nti -
e metics s h o ul d be perf or me d acc or di n g t o l ocal treat me nt sta n dar ds.
D oc u me nt N o
O bject N o. 
C CI
C CI


















2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
6 9 / 1 2 5
Fi g ure 2
Tre at me nt 
A dj ust me nt 
i n t he E ve nt 
of Gr a de 
3 S ki n Re acti o ns
C o nsi dere d t o be Rel ate d t o Cet u xi m a b ( 2 5 0 m g/ m2 D ose a n d 5 0 0 m g / m2
D ose )
Gr a d e 3 
t oxicit y
R es olv e d t o 
≤Gr a d e 2 ?
W hic h Gr a d e 3 
occ urr e nc e ?
Y E S
N O
1 st w e e k
D el a y i nf usi o n
D el a y i nf usi o n
2 n d w e ek
Disc o nti n u e c et uxi m a b
First
C o nti n u e at 2 5 0 m g/ m 2/ 5 0 0 m g/ m2
R e d uc e t o 2 0 0 m g/ m 2/ 4 0 0 m g/ m2
S ec o n d
T hir d
R e d uc e t o 1 5 0 m g/ m 2/ 3 0 0 m g/ m2
F o urt h
Disc o nti n u e c et uxi m a b
I nf usi o n-rel ate d Re acti o ns
Mil d or m o derate i nf usi o n-relate d reacti o ns are ver y  co m m o n. S y m pt o ms i ncl u de fe ver, c hills, 
dizzi ness or d y s p nea occ urri n g i n a cl ose te m p oral relati o ns hi p mai nl y t o t he first cet u xi ma b 
i nf usi o n.
Se vere i nf usi o n-relate d reacti o ns m a y  occ ur, i n s o me cases wit h a fatal o utc o me. S o me of t hese 
reacti o ns m a y  be a na p h ylact oi d/a na p h ylactic i n nat ure or re prese nt a c yt o ki ne release s yn dr o me. 
T his s y n dr o me t y picall y occ urs wit hi n 1 h o ur after i nf usi o n a n d is less c o m m o nl y ass ociate d wit h 
br o nc h os pas m a n d urticaria b ut m a y  als o occ ur f or u p t o se veral h o urs after i nf usi o n or wit h 
s u bse q ue nt i nf usi o ns. C y t o ki ne release s yn dr o me is n or mall y  most se vere i n relati o n t o t he first 
i nf usi o n.
S y m pt o ms of se vere i nf usi o n -relate d reacti o n ma y i ncl u de br o nc h os pas m, urticaria, h yperte ns i o n 
or h y p ote nsi o n, l oss of c o nsci o us ness, or s h oc k. I n rare cases a n gi na pect oris, m y ocar dial 
i nfarcti o n, or car diac arrest ha ve bee n o bser ve d.
A na p h yl actic reacti o ns ma y  occ ur as earl y as wit hi n a fe w mi n utes of t he first i nf usi o n, f or 
e xa m ple, d ue t o pr ef or me d i m m u n o gl o b uli n E a nti b o dies cr oss -reacti n g wit h cet u xi ma b. T hese 
reacti o ns are c o m m o nl y ass ociate d wit h br o nc h os pas m a n d urticaria. T he y ca n occ ur des pite t he 
use of pre me dicati o n.
D oc u me nt N o. 
O bject N o
C CI
C CI




2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7 1 / 1 2 5
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
Partici pa nts m ust be wit h dra w n fr o m st u d y  treat me nt if a ny of t he f oll o wi n g occ urs:

Partici pa nts meeti n g t he defi niti o n of c o nfir me d P D w hile o n treat me nt base d o n R E CI S T v 1. 1. 
Partici pa nts w h o e x perie nce disease pr o gressi o n ma y  co nti n ue treat me nt u n der c on diti o ns 
descri be d i n S ecti o n 6. 6. 5
o
I n case of pre mat ure wit h dra wal fr o m t he st u d y treat me nt f or reas o ns ot her t ha n 
P D, t he partici pa nt s will be aske 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 u ntil c o nfir me d P D a n d e n d of st u d y  
or deat h.

Si g nifica nt cli nical deteri orati o n (cli nical pr o gressi o n), defi ne d as ne w s ym pt o ms t hat are 
dee me d b y  the In 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 .

Wit h dra wal 
of c o nse nt fr o m f urt her treat me nt: I n case of selecti ve wit h dra wal fr o m st u d y 
treat me nt ot her st u dy- relate d pr oce d ures a n d assess me nts s h o ul d be co nti n ue d as pla n ne d.

Wit h dra wal of c o nse n t fr o m f urt her st u dy p artici pati o n : Partici pa nt s s h o ul d be e x plicitl y as ke d 
at t he ti me of wit h dra wal of c o nse nt if t he y wo ul d all o w c ollecte d sa m ples t o be use d a n d 
s ur vi val i nf or mati o n t o be c ollecte d, i ncl u di n g verificati o n of me dical/ p u blic rec or ds as 
per mitte d b y l ocal re g ulati o ns. T hese res p o nse s s h o ul d acc or di n gly be ca pt ure d i n t he e C R F.

Occ urre nce of a n e xcl usi o n criteri o n, w hic h is cli nicall y rele va nt a n d affects t he partici pa nt’s 
safety, if st u d y treat me nt disc o nti n uati o n is c o nsi dere d necessar y  by t he In vesti gat or a n d/ or 
S p o ns or.

T hera pe utic fail ure re q uiri n g ur ge nt a d diti o nal or alter nati ve a nti -ca 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 trial treat me nt bei n g 
de sire d or c o nsi dere d necessar y b y t he In vesti gat or a n d/ or t he partici pa nt.

Occ urre nce of pre g na nc y i n a fe male st u dy partici pa nt .

Use of a pr o hi bite d c o nc o mita nt me dicati o n , as defi ne d i n Secti o n 6. 5 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 treat me nt if c o nsi dere d necessar y  by t he In vesti gat or 
or t he S p o ns or.

N o nc o m plia nce
if t he be nefit /ris k f or c o nti n uati o n of treat me nt is ne gati ve acc or di n g t o 
In vesti gat or ’s assess me nt.
T he S o A s pecifies t he data t o c ollect at st u d y  i nter ve nti o n 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 ( Secti o n 1. 3) .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7 2 / 1 2 5
7. 1. 1
Rec h alle n ge
Rec halle n ge wit h st u d y inter ve nti o n after disc o nti n uati o n d ue t o a d verse e ve nts is all o we d as 
defi ne d i n S ecti o n 6. 9 ( Ma na ge me nt of A d verse Eve nts of I nterest ).
If patie nts disc o nti n ue t he st u d y i nter ve nti o n f or a c o nfir me d c o m plete res p o nse, 1 re-i nitiati o n of 
st u d y i nter ve nti o n is per mitte d.
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 (ie, 
wit h dra wal of c o nse nt), a n d wit h o ut gi vi n g a reas o n.

T he partici pa nt m a y  be wit h dra w n b y  the I n vesti gat or d ue t o partici pati o n i n a n ot her cli nical 
st u d y. H o we ver, partici pa nts will c o nti n ue t o be f oll o we d f or d oc u me ntati o n of f urt her 
a nti-ca ncer t hera p y a n d f or s ur vi val.

T he partici pa nt m a y  be wit h dra w n at a n y t i me at t he discreti o n of t he I n vesti gat or f or safety,
be ha vi oral, c o m plia nce, or a d mi nistrati ve reas o ns.

T he Sc he d ule of Acti vities (S o A ) ( Secti o n 1. 3 ) s pecifies t he data t o c ollect at st u 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.
T he a p pr o priate E n d of Safet y Foll o w - u p electr o nic case re p ort f or m (e C R F) pa ge m ust be 
c o m plete d.
Wit h dra wal of c o nse nt will be c o nsi dere d wit h dra wal fr o m t he st u d y  u nless t he partici pa nt a grees 
t o partici pate i n f urt her st u d y-relate d assess me nts a n d/ or a grees t o be f oll o we d f or s ur vi val. 
Partici pa nts s h o ul d be e x plicitl y as ke d at t he ti me of wit h dra wal of c o nse nt if t he y wo ul d all o w 
usa ge of t heir sa mples a n d f urt her st u d y-relate d assess me nts, es peciall y tu m or assess me nt, 
safety-relate d assess me nts, d oc u me ntati o n of f urt her a nti-ca ncer t hera p y, or s ur vi val i nf or matio n 
t o be c ollecte d i ncl u di n g verificati o n of me dical/ p u blic rec or ds or c o ntacti n g of t he partici pa nt’s 
pri mar y  ph y sicia n or fa mil y as per mitte d b y  local re g ulati o ns. T hese res p o nses s h o ul d acc or di n gl y 
be ca pt ure d i n t he C R F.
If a partici pa nt fails t o atte nd sche d ule d st u d y assess me nts, t he In vesti gat or m ust deter mi ne t he 
reas o ns a n d t he circ u msta nces as c o m pletely a n d acc uratel y as p ossi ble.
If a partici pa nt is wit h dra w n pri or t o disease pr o gressi o n f or a ny re as o n, t he partici pa nt will n ot be 
re place 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:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7 3 / 1 2 5

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 .

Bef ore a partici pa nt is dee me d “l ost t o f oll o w-u p”, t he I nvesti 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 a n d all o we d acc or di n g 
t o l ocal re g ulati o ns, c o ntact t he partici pa nt’s ge neral practiti o ner or fa mil y 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.

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 c o nsi dere d t o ha ve wit h dra w n 
fr o m t he st u d y.
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 t he S o A.

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 ntin 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 t he S o A, 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 gat or 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 that are n ot part of t he partici pa nt’s r o uti ne 
me dical 
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 ( St u d y G over na nce).

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 (f or e xa m ple, 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 C F 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 t he S o A.

Sa m ple c ollecti o n, details of bl o o d v ol u me b y  visit a n d assess me nt, la beli n g, st ora ge, a n d 
s hi p me nt re q uire me nts will be s u m marize d i n a se parate La b orat or y  Ma n ual or Ma n ual of 
O perati o ns.
8. 1
Effic ac y Assess me nts a n d Pr oce d ures
C o m p ute d t o m o gra p hy/ ma g netic res o na nce i ma gi n g (M RI ) sca ns will be perf or me d a n d c ollecte d 
u ntil disease pr o gressi o n is assesse d b y  the I n vesti gat ors acc or di n g t o R E CI S T v 1. 1 or start of ne w 
a nti-ca ncer t hera p y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7 4 / 1 2 5
Ra di o gra p hic 
i ma ges a n d p h y sical fi n di n gs ( p h ysical assess me nts) will 
be
use d b y  the 
I n vesti gat ors f or t he local deter mi nati o n of disease pr o gressi o n a n d patie nt’s treat me nt decisi o ns.
F or eac h partici pa nt , t u m or res p o nse assess me nt will be perf or me d by C T sca n or M RI (if M RI is 
use d, c hest C T is ma n dat or y ) i ma gi n g of t he c hest/a b d o me n/ pel vis ( pl us ot her re gi o ns as 
s pecifically re q uire d) a n d ot her esta blis he d assess me nts of t u m or b ur de n if C T/ M RI  ima gi n g is
i ns ufficie nt f or t he i n di vi d ual partici pa nt . All t he sca ns perf or me d at baseli ne a n d ot her i ma gi n g 
perf or me d as cli nicall y re q uire d ( ot her s u p p orti ve i ma gi n g) nee d t o be re peate d at s u bse q ue nt 
visits. I n ge neral, lesi o ns detecte d at b aseli 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 a n d prefera bl y  t he 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.
F or eac h partici pa nt , t he In vesti gat or will desi g nate 1 or m ore of t he f oll o wi n g meas ures of t u m or 
stat us t o f oll o w f or deter mi ni n g res p o nse: C T or M RI  i ma ges of pri mar y a n d/ or metastatic t u m or 
masses, p h y sical e xa mi nati o n fi n di n gs, a n d t he res ults of ot her assess me nts. All a vaila ble i ma ges 
c ollecte d d uri n g t he trial peri o d will be c o nsi dere d. T he m ost a p pr o priate meas ures t o e val uate t he 
t u m or stat us of a partici pa nt s h o ul d be use d. T he meas ure(s) t o be c h ose n f or se q ue ntial e val uati o n 
d uri n g t he trial m ust c orres p o n d t o t he meas ures use d t o d oc u me nt t he pr o gressi ve t u m or stat us 
t hat q ualifies t he partici pa nt f or e nr oll me nt. T he t u m or res p o nse assess me nt will be perf or me d a n d 
liste d acc or di n g t o t he Sc he d ules of Assess me nts.
Treat me nt decisi o ns will be ma de b y  the In vesti gat or base d o n t he In vesti gat or’s assess me nt of 
disease stat us. I n vesti gat or’s assess me nt of o bjecti ve t u m or res p o nse t o treat me nt will be 
perf or me d acc or di n g t o R E CI S T v 1. 1 (all meas ure me nts s h o ul d be rec or de d i n metric n otati o n, as 
descri be d i n R E CI S T v 1. 1. )
At baseli ne, t u m or lesi o ns will be cate g orize d i n tar get a n d n o n- tar get lesi o ns as descri be d i n 
R E CI S T v 1. 1.
Res u lts f or t hese e val uati o ns will be rec or de d wit h as m uc h s pecificit y as p ossi ble s o t hat pre- a n d 
p ost -treat me nt res ults will pr o vi de t he best o p p ort u nit y f or e val uati n g t u m or res p o nse.
A n y  CR or P R s h o ul d be c o nfir me d, prefera bl y at t he sc he d ule d 9- wee k i nter val, 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 of C R or P R.
T he In vesti gat or ma y  perf or m sca ns i n a d diti o n t o a sc he d ule d trial sca n f or me dical reas o ns or if 
t he In vesti gat or s us pects P D. Partici pa nt s w h o wit h dra w fr o m t he trial f or cl i nical or sy m pt o matic 
deteri orati o n bef ore o bjecti ve d oc u me ntati o n of P D will be re q ueste d t o u n der g o a p pr o priate 
i ma gi n g t o c o nfir m P D. E ver y  eff ort s h o ul d be ma de t o c o nfir m a cli nical dia g n osis of P D b y  
i ma gi n g acc or di n g t o R E CIS T v 1. 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7 5 / 1 2 5
8. 1. 1. 1
O ver all T u m or Assess me nt (ir R E CI S T)
O verall t u m or assess me nt per ti me p oi nt will be deri ve d fr o m t u m or res p o nse assess me nts o btai ne d 
f or meas ure d lesi o ns, n o n-tar get lesi o ns, an d ne w lesi o ns, as defi ne d i n Ta ble 1 4.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI






2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7 8 / 1 2 5
T u m or meas ure me nts 
t o deter mi ne res p o nse will 
be perf or me d
e ver y 9 wee ks 
(starti n g 
D a y 6 4/ Wee k 1 0) f or t he first 6 m o nt hs ( u ntil W ee k 2 8), a n d e ver y 1 2 wee ks t hereafter . Res p o nse 
t o treat me nt will be e val uate d b y  RE CI S T v 1. 1 ( pri mar y an d sec o n dar y efficac y en d p oi nts) a n d 
b y  ir R E CIS T ( ot her efficac y en d p oi nts). See Secti o n 1. 3 ( Sc he d ule of Acti vities) f or f urt her 
details.
T he t u m or res p o nse assess me nt will be perf or me d as liste d acc or di n g t o t he Sc he d ule of Acti vities
b y  CT or M RI . I n ge neral, lesi o ns detecte d d u ri n g Scree ni n g nee d t o be f oll o we d usi n g t he sa me 
met h o d ol o g y  a n d prefera bl y t he sa me e q ui p me nt at s u bse q ue nt t u m or assess me nt visits.
A d diti o nal efficac y anal y ses o n B O R, D O R a n d P F S acc or di n g t o ir R E CIS T e val uate d b y  an 
in de pe n de nt re vie w co m mittee mi g ht be c o n d ucte d retr os pecti vel y.
8. 2
S afet y Assess me nts a n d Pr oce d ures
T he safet y pr ofile of t he st u d y treat me nts 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 yz i n g of Baseli ne M e dical C o n diti o ns, A Es, p h y sical e xa mi nati o n fi n di n gs, i ncl u di n g vital
si g ns, 1 2- lea d E C G a n d la b orat or y tests.
C o m pre he nsi ve assess me nt of a n y ap pare nt t o xicit y ex perie nce d b y  the partici pa nt will be 
perf or me d t hr o u g h o ut t he c o urse of t he st u d y, fr o m t he ti me of t he partici pa nt’s si g nat ure of 
i nf or me d c o nse nt. St u d y  site pers o n nel will re p ort a n y AE, w het her o bser v e d b y  the In vesti gat or 
or re p orte d b y t he partici pa nt.
See  A p pe n di x 4 f or i nf or mati o n relati n g t o A Es a n d A E SIs ( A d verse e ve nts of s pecial i nterest).
8. 2. 1
P h ysic al E x a mi n ati o ns
A p h ysical e xa mi nati o n will be c o n d ucte d at Scree ni n g a n d at s u bse q ue nt visits as i n dicate d i n t he 
Sc he d ule of Acti vities ( Secti o n 1. 3 ) a n d d oc u me nte d i n t he e C R F. A b n or mal fi n di n gs are t o be 
reassesse d at s u bse q ue nt visits.
A c o m plete p h y sical e xa mi nati o n (i ncl u di n g, ge neral a p peara nce, der mat ol o gical, p ul m o nar y , 
car di o vasc ular, gastr oi ntesti nal, ge nit o uri nar y , l ym p hatic, 
ne ur ol o gic a n d m usc ul os keletal 
s yste ms, hea d/ nec k, e xtre mities, e yes, ears, n ose, t hr oat, a n d c o g niti ve stat us) will be perf or me d 
a n d t he res ults d oc u me nte d. All ne wl y  dia g n ose d or w orse ni n g c o n diti o ns, si g ns, a n d s ym pt o ms 
o bser ve d fr o m scree ni n g, w het her relate d t o st u d y treat me nt or n ot, are t o be re p orte d as A Es.
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.
8. 2. 2
Vit al Si g ns
As n ote d i n Secti o n  6. 8. 1, partici pa nts m ust ha ve t heir vital si g ns cl osel y m o nit ore d bef ore, d uri n g, 
a n d u p t o 2 h o urs after eac h a vel u ma b i nf usi o n f or t he first 4 i nf usi o ns i n a n area wit h res uscitati o n
e q ui p me nt a n d e mer ge nc y age nts , a n d t he n acc or di n g t o cli nical si g ns a n d s ym pt o ms , t o detect 
a n y A Es (s pecifically, aller gic/ h y perse nsiti vit y  reacti o ns).
As n ote d i n Secti o n  6. 8. 2, partici pa nts m ust ha v e t heir vital si g ns cl osel y m o nit ore d bef ore, d uri n g, 
a n d u p t o 2
h o urs
after eac h cet u xi ma b i nf usi o n, t o detect a n y 
AEs 
(s pecificall y, 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7 9 / 1 2 5
aller gic/ h y perse nsiti vit y  reacti o ns). A p h y sicia n s h o ul d be a vaila ble d uri n g eac h cet u xi ma b 
a d mi nistrati o n, ie, u ntil t he c o m plete i nf usi o n has bee n gi ve n a n d f or 1 h o ur after t he e n d of t he 
i nf usi o n.
I n ad diti o n, t he bel o w a p plies t o all partici pa nts:

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 (f or e xa m ple, tele visi o n, cell p h o nes).
8. 2. 3
Electr oc ar di o gr a ms
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 usi n g a n E C G mac hi ne t hat 
a ut o maticall y calc ulates t he heart rate a n d meas ures P R, Q R S, a n d Q T i nter vals, after t he 
partici pa nt has bee n i n a s u pi ne p ositi o n br eat hi n g q uietl y  for 5 mi n utes. T he E C G will be re peate d 
at a n y ot her sc he d ule d or u nsc he d ule d visit o nl y if it is cli nicall y warra nte d i n t he o pi ni o n of t he 
In vesti gat or .
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 6 , at 
t he ti me p oi nts liste d i n t he S o A. All sa m ples s h o ul d be clearly 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 t hat will be perf or me d b y  t he l ocal la b orat or y are scree ni n g pre g na nc y  testi n g, he patitis 
B vir us, he patitis C vir us testi n g, u ri nalys is, a n d uri ne pre g na nc y testi n g.
Sa m ples f or c o m plete bl o o d c o u nt a n d c ore c he mistr y must be a vaila ble a n d re vie we d pri or t o 
d ose a d mi nistrati o n. Res ults of all l ocal la b orat or y testi n g will be tra nsferre d t o t he cli nical 
data base .
L ocal la b orat or y  sa m ples will be dra w n a n d are re q uire d t o be rec or de d i n t he e C R Fs. A d diti o nal
local la b orat ories m a y  b e us e d at t he discreti o n of t he I nvesti gat or as cli nicall y nee de d f or safet y 
ma na ge me nt of t he partici pa nt . Rele va nt l ocal la b orat or y res ults will be rec or de d acc or di n g t o t he 
e C R F c o m pleti o n g ui deli nes w he n use d t o ma ke a n y  c ha n ges i n treat me nt.
F or fe male partici pa nts of c hil d beari n g p ote ntial, a ser u m β h u ma n c h ori o nic g o na d otr o pi n
pre g na nc y  test will be carrie d o ut d uri n g t he Scree ni n g p hase (fr o m ser u m) a n d at t he visits 
i n dicate d i n t he Sc he d ule of Acti vities (fr o m uri ne) ( Secti o n 1. 3 ). F ollicle sti m ulati n g h or m o ne
mi g ht be e val uate d at Scree ni n g f or c o nfir mati o n of me n o pa usal stat us.
I n case of li ver f u ncti o n test ele vati o ns ( A S T, A L T, a n d/ or t otal bilir u bi n) re q uiri n g a d diti o nal 
la b orat or y dra ws, a n u nsc he d ule d la b orat or y dra w s h o ul d be se nt t o t he la b orat or y f or a nal ys is.
Bl o o d sa m ples will be dra w n, pr ocesse d, a n d st ore d i n acc or da nce wit h directi o ns pr o vi de d i n t he 
St u d y  Ma n ual a n d as per ti mi n g s h o w n i n t he Sc he d ule of Acti vities .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8 0 / 1 2 5
T he re p ort of t he res ults m ust be retai ne d as a part of t he partici pa nt ’s me dical rec or d or s o urce 
d oc u me nts. Bl o o d sa m ples f or f ull safet y tests will be ta ke n fr o m n o nfaste d partici pa nt s as detaile d 
i n t he Sc he d ule of Acti vities . Free t h yr o xi ne, t h yr oi d sti m ulati n g h or m o ne, a n d uri nal ys is will o nl y 
be assesse d at t he pres pecifie d ti me p oi nts. If c o nfir mati o n of a partici pa nt’s p ost me n o pa usal stat us 
is necessar y, a n F S H le vel testi n g will als o be perf or me d at Scree ni n g .
T he I n vesti gat or m ust re vie w eac h la b orat or y re p ort, 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 C R F. T he la b orat or y 
re p orts m ust be file d wit h t he s o urce d oc u me nts.
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 verse 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 s u bject is i nitiall y incl u de d i n t he 
trial ( date of first si g nat ure of i nf or me d c o nse nt) a n d c o nti n ues t hr o u g h t he 3 0- d a y s (± 5 d a y s) 
S afet y Foll o w - u p visit. After t he Safet y F oll o w -u p visit all S A Es a n d treat me nt-relate d n o n- seri o us 
A Es nee d t o b e d oc u me nte d u p u ntil t he Safet y  F oll o w- u p P h o ne Call, w hic h is defi ne d as 9 0 d a y s 
( ± 5 da ys) after last a d mi nistrati o n of st u d y i nter ve nti o n.
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 a d 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 Detecti 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 partici pa nt or o bser ve d b y  t he I n vesti 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 a b o ve) 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 priate 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 thr o u g h o ut t he st u d y, as s pecifie d i n Secti o n 8. 3. 1
( Ti me Peri o d a n d Fre q ue nc y  for C ollecti n g A d v erse E ve nt a n d Seri o us A d verse 
E ve nt 
I nf or mati o n) a n d are assesse d f or t heir o utc o me at t he 3 0- da y  Safet y F oll o w -u p visit . After t his 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8 1 / 1 2 5
visit, S A Es a n d treat me nt-relate d n o n- seri o us A Es are rec or de d a n d assesse d c o nti n u o usl y until 
t he 9 0-d a y  Safet y F oll o w - u p P h o ne Call .
At 9 0 da y s ( ± 5 da y s) after t he last d ose of st u d y inter ve nti o n , the In vesti gat or will c o ntact 
partici pa nt s b y  tele p h o ne t o c ollect i nf or mati o n o n ne w or o n g oi n g S eri o us A d verse E ve nts (S A Es )
a n d treat me nt-relate d n o n -seri o us A Es. A n y S A E assesse d b y  t he In vesti gat or as relate d t o st u d y 
treat me nt m ust be re p orte d w he ne ver it occ urs, irres pecti ve of t he ti me ela pse d si nce t he last 
a d mi nistrati o n of st u d y treat me nt. I n ad diti o n , s uc h partici pa nts m a y  be i n vite d t o t he site f or 
f urt her e val uati o n at t he In vesti gat or’s discreti o n. Partici pa nt s will als o be as ke d a b o ut a n y ne w 
a ntit u m or t hera p y.
All S A Es o n g oi n g at t he 9 0 -d a y  Safet y F oll o w -u p P h o ne Call m ust be m o nit ore d a n d f oll o we d u p 
b y  the 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 nvesti 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 ( 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 orts).
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 ularly deat hs) i n v ol vi n g st u d y partici pa nts t o t he I n de pe n de nt Et hics 
C o m mittees (I E Cs)/I nstit uti o nal Re vie w B oar ds (I R Bs) t hat a p pr o ve d t he st u d y.
I n acc or da nce wit h I nter nati o nal C o u ncil f or Har m o nisati o n (I CH) G o o d Cli nical Practice (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 I E C’s/IR 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 d y. 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 Re 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 Safet y Re p ort n otificati o ns t o In vesti gat or s will be c o nsi dere d.
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.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8 2 / 1 2 5
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 ut 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 n ce 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 inter ve nti o n (f or e xa m ple,
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 Es. H o we ver, all pre g na ncies 
wit h a n esti mate d c o nce pti o n date d uri n g t he peri o d defi ne d i n Secti o n  8. 3. 1 (fr o m first d ose t o t he 
E o T Visit ) 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 n vesti gat or m ust n otif y 
t he 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 mitte d 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,  secti o n 
o n Re p orti n g Seri o us A d verse E ve nts a n d A d verse E ve nts of S pecial I nterest.
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 pa rtici pa nts are wit h dra w n fr o m t he st u d y.
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 n t-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  ab n or mal o utc o me (f or e xa m ple, 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 i n a fe male 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 om 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
A vel u ma b:
A n o ver d ose of a vel u ma b is defi ne d as a n y d ose ≥1 0 % t ha n t he d ose f or t hat partic ular 
a d mi nistrati o n.
T here are n o k n o w n s ym pt o ms of a vel u ma b o ver d ose t o date. T he In vesti gat or s h o ul d use his or 
her cli nical j u d g me nt w he n treati n g a n o ver d ose of t he st u d y i nter ve nti o n
Cet u xi ma b:
A n o ver d ose of cet u xi ma b is defi ne d as a ny d ose greater t ha n t he hi g hest dail y  d ose i ncl u de d i n a 
cli nical st u d y pr ot oc ol or pla n ne d f or a n i n di vi d ual partici pa nt e nr olle d i n t he st u d y.
T o date, t here is li mite d e x perie nce wit h si n gle cet u xi ma b d oses hi g her t ha n 4 0 0 m g/ m 2 B S A or
wee kl y a d mi nistrati o ns of cet uxi ma b d oses hi g her t ha n 2 5 0 m g/ m 2 B S A. I n cli nical st u dies wit h
cet u xi ma b d oses u p t o 7 0 0 m g/ m 2 gi ve n e ver y 2 wee ks, t he safet y pr ofile was c o nsiste nt wit h t he 
safety pr ofile descri be d i n t he cet u xi ma b I B .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8 3 / 1 2 5
G e mcita bi ne a n d Cis plati n or Car b o plati n :
I n t he case of o ver d ose of c he m ot hera p y, t he I nvesti gat or s h o ul d pr o vi de a n y p ossi ble me dical
care a n d treat me nt i n acc or da nce wit h l ocal me dical practice.
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,  secti o n o n Re p orti n g Seri o us A d verse E ve nts a n d A d verse E ve nts 
of S pecial I nterest.
8. 5
P h ar m ac o k i netics

W h ole 
bl o o d sa m ples of a p pr o xi matel y 2 m L  will be c ollecte d f or meas ure me nt of ser u m 
c once ntrati o ns of cet u xi ma b, as s pecifie d i n t he S o A ( Secti o n 1. 3 ). 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 he q ua nti ficati o n of cet u xi ma b i n ser u m will be perf or me d usi n g a vali date d i m m u n oassa y 
met h o d . C o nce ntrati o ns will be use d t o e val uate t he P K of cet u xi ma b.

W h ole 
bl o o d sa m ples of a p pr o xi matel y 2 m L  will be c ollecte d f or meas ure me nt of ser u m 
c o nce ntrati o ns of a vel u ma b, as s pecifie d i n t he S o A ( Secti o n 1. 3 ). 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 he q ua ntifica ti o n of a vel u ma b i n ser u m will be perf or me d usi n g a vali date d i m m u n oassa y 
met h o d . C o nce ntrati o ns will be use d t o e val uate t he P K of a vel u ma b.
B l o o d sa m ples f or P K deter mi nati o ns s h o ul d be c ollecte d acc or di n g t o t he a p pr o priate Sc he d ules 
of Assess me nts. E ver y  eff ort s h o ul d be ma de t o c ollect sa m ples per t he sc he d ule d ti me p oi nt a n d 
wit hi n t he s pecifie d wi n d o ws. T he o bjecti ve is f or sa m ples t o be c ollecte d wit hi n t he wi n d o ws 
s pecifie d, b ut a ny e x c ursi o ns o utsi de t hese wi n d o ws will o nl y be c o u nte d as pr ot oc o l de viati o ns if 
t he ti me of t he sa m ple c ollecti o n is n ot rec or de d or if t he sa m ples are n ot c ollecte d.
Re mai ni n g sa m ples c ollecte d f or a nal ys is of cet u xi ma b or a vel u ma b ser u m 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 . 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 are i n
t he La b orat or y  Ma n ual . T he S p o ns or will st ore t he sa m ples i n a sec ure st ora ge s pace wit h a de q uate 
meas ures t o pr otect c o nfi de ntialit y . Rete nti o n ti me a n d p ossi ble a nal yses of sa m ples after t he e n d 
of st u d y  are s pecifie d i n t he res pecti ve I C F.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8 4 / 1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8 5 / 1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8 6 / 1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8 7 / 1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI






2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9 0 / 1 2 5
F or ti m e -t o- e v e nt a n al y s e s, t h e K a pl a n- M ei er e sti m at e s will b e pr o vi d e d. T h e 
c o nfi d e n c e i nt er v al f or t h e m e di a n will b e c al c ul at e d a c c or di n g t o  Br o o k m e y er 1 9 8 2 .
All a n al y s e s f or s e c o n d ar y e n d p oi nt s will b e p erf or m e d o n t h e F A S u nl e s s ot h er wi s e 
s p e cifi e d .
T here is n o f or mal si g nifica nce le vel f or t his st u d y a n d all a nal ys es are c o nsi dere d descri pti ve.
S u b gr o u p a nal ys es re gar di n g E G F R H-s c ore ( < 2 0 0, ≥2 0 0), bet wee n P D -L 1  lo w a n d hi g h 
e x pressi o n le vels ( < 5 0 %, ≥5 0 % < 8 0 %, ≥8 0 % T P S base d o n 7 3 -1 0 assa y), a n d f urt her varia bles, 
will be perf or me d.
9. 4. 1. 1
B O R Acc or di n g t o R E CI S T v 1. 1
Best o verall res p o nse ( B O R) will be assesse d base d o n re p orte d o v erall ti me p oi nt res p o nses at 
differe nt e val uati o n ti me p oi nts fr o m t he start date u ntil d oc u me nte d disease pr o gressi o n, 
acc or di n g t o t he f oll o wi n g r ules. O nl y t u m or assess me nts perf or me d bef ore t he start of a n y f urt her 
a nti-ca ncer t hera pies will be c o nsi d ere d i n t he assess me nt of B O R. Cli nical deteri orati o n will n ot 
be c o nsi dere d as d oc u me nte d disease pr o gressi o n.
B O R B ase d o n C o nfir me d Res p o nses:

C R = at least 2 deter mi nati o ns of C R at least 4 wee ks a part a n d bef o re pr o gressi o n.

P R = at least 2 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 bef ore pr o gressi o n (a n d n ot q ualif y i n g f or a C R).

S D (a p plica ble o nl y t o patie nt wit h meas ura ble disease at baseli ne) = at least 1 S D 
assess me nt ( or better) ≥6 wee ks after start date a n d bef ore pr o gressi o n (a n d n ot q ualif y i n g 
f or C R or P R).

N o n -C R/ n o n -P D (a p plica ble o nl y  to patie nts wit h n o n- meas ura ble disease at baseli ne) = at 
least 1 n o n- C R/ n o n -P D assess me nt ( or better) ≥6 wee ks after date of first st u d y treat me nt
a n d bef ore pr o gressi o n (a n d n ot q ualif y i n g f or C R or P R).

P D = pr o gressi o n ≤1 2 wee ks after start date (a n d n ot q ualif y i n g f or C R, P R or S D).

N ot E val ua ble ( N E): all ot her cases .
M ore details will be pr o vi de d i n t he I A P.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI




2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9 2 / 1 2 5

T E A Es relate d t o st u d y treat me nt wit h N CI - C T C A E Gra des ≥3

A Es 
lea din g t o wit h dra wal, 
d ose
m o dificati o ns, 
or per ma ne nt
st u d y
treat me nt 
disc o nti n uati o n

Deat hs.
Partici pa nts w h o ter mi nate treat me nt w ill be dis pla ye d i n a b y-partici pa nt listi n g a n d s u m marize d 
b y  pri mar y wit h dra wal reas o n.
All re p orte d deat hs after first d ose of st u d y treat me nt as well as reas o ns f or deat h wil l be ta b ulate d 
(f or all partici pa nts e nr olle d). Deat hs wit hi n 3 0 da y s fr o m last d ose a d mi nistrati o n a n d deat hs 
be y o n d t his peri o d u p t o 9 0 d a ys f oll o w-u p a n d reas o ns f or t he m will als o be ta b ulate d.
L a b or at or y V ari a bles
La b orat or y  res ults will be classifie d by gr a de acc or di n g t o N CI-C T C A E v 5. 0 . T he w orst o n-st u d y 
gra des after t he first st u d y treat me nt will be s u m marize d.
S hifts i n t o xicit y gra des fr o m first treat me nt t o hi g hest gra de will be dis pla y e d. Res ults f or 
varia bles t hat are n ot part of N CI -C T C A E will be prese nte d as bel o w, wit hi n, or a b o ve n or mal 
li mits. O nl y partici pa nt s wit h p ost-baseli ne la b orat or y  val ues will be i ncl u de d i n t hese a nalys es.
P h ysic al E x a mi n ati o n
P h y sical e xa mi nati o n, i ncl u din g vital si g ns ( b o d y te m perat ure, res pirat or y rate, heart rate, a n d 
bl o o d press ure), a n d 1 2- lea d E C G, rec or de d at baseli ne a n d after e n d of st u d y treat me nt will be 
prese nte d. F urt her details will be pr o vi de d i n t he I A P.
9. 4. 3
Ot her A n al yses
Ge ner al C o nsi der ati o n s
T he f oll o wi n g statistics will be use d t o s u m marize t he trial data (f or e xa m ple, Baseli ne 
C haracteristics) u nless ot her wise s pecifie d:

C o nti n u o us varia bles: n u m ber of n o n -missi n g o bser vati o ns, mea n, sta n dar d de viati o n, me dia n, 
mi ni m u m, a n d ma xi m u m, 9 5 % c o nfi de nce i nter vals f or t he mea n, as a p pr o priate.

Cate g orical varia bles: fre q ue ncies a n d perce nta ges .
Esti m ati o n of I n di vi d u al P K P ar a meters

P har mac o ki netic para meters will be calc ulate d b y  the P K/ P D Data Pr ocessi n g Gr o u p of Q P D, 
Merc k, 
Dar msta dt, 
Ger ma n y , or b y  a CR O selecte d b y  the S p o ns or, usi n g sta n dar d 
n o n- c o m part me ntal met h o ds a n d t he act ual a d mi nistere d d ose. P K para meters will be calc ulate d 
usi n g t he actual ela pse d ti me si nce d osi n g. W he n 
t he act ual sa m pli n g ti me is missi n g, 
calc ulati o ns wil l be perf or me d usi n g t he sc he d ule d ti me. Ot her wise, t here will be n o f urt her 
i m p utati o n of missi n g data. T he act ual c ollecti o n i nter vals will be use d i n t he calc ulati o n of 
uri ne a n d fecal para meters.
D oc u me nt N o. 
O bject N o. 
C CI
C CI






2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9 5 / 1 2 5
La n ger CJ, Ga d geel S M, B or g haei H, et al. Car b o plati n a n d pe metre xe d wit h or wit h o ut 
pe m br oliz u ma b f or a d va nce d, n o n-s q ua m o us n o n- s mall-cell l u n g ca ncer: a ra n d o mize d, p hase 2 
c o h ort of t he o pe n -la bel K E Y N O T E-0 2 1 st u d y . La ncet O nc ol 2 0 1 6; 1 7( 1 1) 1 4 9 7 – 1 5 0 8.
Li S, Sc h mitz K R, Jeffre y  P D, et al. Str uct ural basis f or i n hi biti o n of t he e pi der mal gr o wt h fact or 
rece pt or by cet u xi ma b. Ca ncer Cell 2 0 0 5; 7: 3 0 1 - 1 1.
Lia n g S C, Latc h ma n Y E, B u hl ma n n J E, et al. Re g ulati o n of P D -1, P D -L 1, a n d P D -L 2 e x pressi o n 
d uri n g n or mal a n d a ut oi m m u ne res p o nses. E ur J I m m u n ol 2 0 0 3; 3 3( 1 0): 2 7 0 6 - 1 6.
Ma urizi M, Al ma d ori G, Ferra n di na G et al. Pr o g n ostic si g nifica nce of e pi der mal gr o wt h fact or 
rece pt or i n lar yn geal s q ua m o us cell carci n o ma. Br J Ca ncer 1 9 9 6; 7 4( 8): 1 2 5 3 - 7.
Me n dels o h n J, Ka wa m ot o T, Sat o G, et al. H y bri d cell li nes t hat pr o d uce m o n ocl o nal a nti b o dies 
t o e pi der mal gr o wt h rece pt or. Pate nt U S 4, 9 4 3, 5 3 3. 1 9 9 0.
Paz- Ares L, L uft A, Vice nte D, et al. Pe m br oliz u ma b pl us c he m ot hera p y for s q ua m o us n o n-
s mall-cell l u n g ca ncer. N E n gl J Me d 2 0 1 8; 3 7 9: 2 0 4 0- 5 1.
Pir ker R, Pereira J R, Szczes na A, et al. Cet u xi ma b pl us c he m ot hera p y i n patie nts wit h a d va nce d 
n o n- s mall-cell l u n g ca ncer ( F L E X): a n o pe n -la bel ra n d o mise d p hase III trial. T he La ncet, 2 0 0 9; 
3 7 3 ( 9 6 7 4): 1 5 2 5- 3 1.
Pir ker R, Pereira J R, v o n Pa wel J, et al. E G F R e x pressi o n as a pre dict or of s ur vi val f or first-li ne 
c he m ot hera p y pl us cet u xi ma b i n patie nts wit h a d va nce d n o n- s mall-cell l u n g ca ncer: a nal ys is of 
data fr o m t he p hase 3 F L E X st u d y . La ncet O nc ol 2 0 1 2; 1 3( 1): 3 3 - 4 2.
P ozzi C, C u o m o A, S pa d o ni I, et al. T he E G F R -s pecific a nti b o d y cet u xi ma b c o m bi ne d wit h 
c he m ot hera p y t ri g gers i m m u n o ge nic cell deat h. Nat Me d. 2 0 1 6; 2 2 ( 6): 62 4- 3 1.
T hatc her N, Hirsc h F R, L u ft A V , et al. Necit u m u ma b pl us ge mcita bi ne a n d cis plati n vers us 
ge mcita bi ne a n d cis plati n al o ne as first-li ne t hera p y in patie nts wit h sta ge I V sq ua m o us n o n-
s mall-cell l u n g ca ncer ( S Q UIR E): a n o pe n -la bel, ra n d o mize d, c o ntr ol le d p hase 3 trial. La ncet 
O nc ol 2 0 1 5; 1 6 ( 7): 7 6 3– 7 4.
Ti nc hell o D G, O we n R K, Slac k M C, et al. Vali dati o n of t he Patie nt Gl o bal I m pressi o n scales f or 
use i n detr us or o veracti vit y: sec o n dar y a nal ys is of t he R E L A X st u d y. BJ O G 2 0 1 3; 1 2 0 ( 2): 2 1 2 1 6.
Wa ksal 
H W. R ole of a n a nti-e pi der mal gr o wt h fact or rece pt or i n treati n g ca ncer. Ca nc er 
Metastasis Re v 1 9 9 9; 1 8: 4 2 7 - 3 6.
Wa n g D D , Z h a n g S, Z h a o H, et al. 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 ( 9): 1 0 1 2- 2 4.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9 6 / 1 2 5
Wa n g X, Te n g F, K o n g L, et al. P D -L 1 e x pressi o n i n h u ma n ca ncers a n d its ass ociati o n wit h 
cli nical o utc o mes. O nc o Tar gets T her 2 0 1 6; 9: 5 0 2 3 - 3 9.
Yalci n I, Bu m p R C. Vali dati o n of t w o gl o bal i m pressi o n q uesti o n naires f or i nc o nti ne nce. A m J 
O bst G y nec o 2 0 0 3; 1 8 9 ( 1): 9 8 - 1 0 1.
Z ha n g W, G or d o n M, Press O A, et al. C y cli n D 1 a n d e pi der mal gr o wt h fact or p ol y m or p his ms 
ass ociate d wit h s ur vi val i n patie nts wit h a d va nce d c ol orectal ca ncer treate d wit h cet u xi ma b. 
P har mac o ge net Ge n o mics 2 0 0 6; 1 6 ( 7): 4 7 5- 8 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 ( 8): 2 0 0 2-8.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9 7 / 1 2 5
1 1
A p pe n dices
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9 8 / 1 2 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 E
A d verse eve nt
A E SI
A d verse e ve nt of s pecial i nterest
A L T  
Ala ni ne a mi n otra nsferase
A S T
A s partate a mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n-ti me c ur ve
B O R
B est o verall res p o nse
B S A
B o d y s urface area
CI
C o nfi de nce i nter val
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n 
C R
C o m plete res p o nse
C R F
Case Re p ort F or m
C R O
C o ntract Researc h Or ga nizati o n
C S R
Cli nical St u d y  Re p ort
C T
C o m p ute d t o m o gra p h y
C T C A E v 5. 0
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts Versi o n 5. 0
C tr o u g h
T he c o nce ntrati o n o bser ve d i m me diatel y bef 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 ntrati o n f or m ulti ple d osi n g)
D N A
De o x yri b o n ucleic aci d
D O R
D urati o n of res p o nse
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
E o T
E n d of Treat me nt
E S M O
E ur o pea n S ociet y f or Me dical O nc ol o g y
F D A
F o o d a n d Dr u g A d mi nistrati o n
F F P E
F or mali n-fi xe d paraffi n- e m be d de d
G C P
G o o d Cli nical Practice
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9 9 / 1 2 5
H B V
He patitis B vir us
H C V
He patitis C vir us
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 ni sati o n
I E C
I n de pe n de nt Et hics C o m mittee
I H C
I m m u n o hist oc he mistr y
I RB 
I nstit uti o nal Re vie w B oar d
i v
I ntra ve n o us
ir A E
I m m u ne-relate d a d verse e ve nt
M RI
M a g netic res o na nce i ma gi n g
m R N A
M esse n ger ri b o n ucleic aci d
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 C L C  
N o n- s mall cell l u n g ca ncer
O R R
O bjecti ve res p o nse rate
O S
O verall s ur vi val
P D
P r o gressi o n of disease
P D - 1
Pr o gra m me d cell deat h pr otei n - 1
P D -L 1
Pr o gra m me d deat h li ga n d 1
P F S
P r o gressi o n-free s ur vi val
P K
P har mac o ki netics
P R
Partial res p o nse
R E CI S T 
v 1. 1
Res p o nse e val uati o n criteria i n soli d tu m ors versi o n 1. 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 0 / 1 2 5
R N A
Ri b o n ucleic aci d
S A E
Seri o us a d verse e ve nt
S M C
Safet y  M o nit ori n g C o m mittee
S m P C
S u m mar y of pr o d uct c haracteristics
T E A E
T reat me nt-e mer ge nt a d verse e ve nt
T M T B 
T otal meas ure d t u m or b ur de n
U L N
U p per li mit of n or mal
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. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 1 / 1 2 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 ors 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 o rities. 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 of 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 a ut h orize d re prese ntati ve 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 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 re q uireme nts of 2 1 C F R 5 0 ; l ocal re g ulati o ns; IC H 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 ncl u de a state me nt t hat writte n i nf or me d c o nse nt wa s 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 uri n g t heir partici pati o n i n t he st u d y, partici pants 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 nd 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.
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 ot ecti 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 ne l, b y  ap pr o priate 
I RB/I E C me m bers, a n d b y  reg 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. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 2 / 1 2 5
Partici pa nt’s ri g hts u n der data pr otecti o n la ws:

Partici pa nt ma y  use his/ her ri g hts u n der his/ her a p plica ble d ata pr otecti o n la ws t o access a n d 
c orrect his/ her pers o nal i nf or mati o n, as k f or it t o be delete d, t o ha ve it tra nsferre d i n a c o m m o n 
electr o nic f or mat t o a n ot her st u d y ce nter or t o o bject t o s hari n g de -i de ntifie d data f or ot her 
researc h p ur p oses

H o we ver, i f a n d t o t he e xte nt his/ her re q uest ma y i n hi bit t he f urt her c o n d ucti n g of t he st u d y or 
t he s hari n g of data f or researc h p ur p oses t he re q uest ma y  be rejecte d acc or di n g t o a p plica ble 
la ws

Partici pa nt ca n als o re q uest a c o p y of data tra nsfer cla uses if his/ he r pers o nal data is s hare d 
o utsi de t he E U. Partici pa nt s h o ul d c o ntact t he st u d y ce nter ( w here a p plica ble: or its data 
pr otecti o n officer) i n case he/s he wa nt t o ma ke use of his/ her ri g hts u n der data pr otecti o n la ws. 
Partici pa nt ma y  als o c o ntact his/ her data pr otecti o n a ut h orit y  if s he/ he has a n y co ncer ns a b o ut 
ha n dli n g of his/ her pers o nal data.
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 Merc k K Ga A, Dar msta dt, Ger ma n y.
T he st u d y  will be c o n d ucte d i n a p pr o xi matel y 2 5 cli nical ce nters i n E ur o pe.
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 n icaltrials. g o v, E u dra C T. As 
per c o m pa n y p olic y  st u d y will be p u blis he d a p pr o xi matel y 2 wee ks pri or t o first pati e nt-i n. 
T heref ore N C T n u m ber fr o m Cli n icaltrials. g o v ca n n ot bee n pr o vi de d bef ore t hat p oi nt i n ti me.
A Safet y M o nit ori n g C o m mittee ( S M C), c o nsisti n g of per ma ne nt me m bers fr o m t he S p o ns or a n d 
C R O, t he C o or di nati n g 
I nvesti gat or, a n d ot her o pti o nal me m bers 
wi t h e x pertise i n t he 
ma na ge me nt of ca ncer s u bjects, will re vie w t he safet y data o n a re g ular basis t hr o u g h o ut t he trial. 
T he S M C will deci de b y c o nse ns us o n t he c o nti n uati o n or s us pe nsi o n of e nr oll me nt after a n i nitial 
safety r u n-i n of cet u xi ma b i n c o m bi nati o n wit h a vel u ma b pl us ge mcita bi ne a n d cis plati n a n d will 
re vie w all a vaila ble safet y data. T he s pecific w or ki n g pr oce d ures will be descri be d i n a n S M C 
c harter, w hic h will be esta blis he d pri or t o t he start of recr uit me nt.
A c o ntract researc h or ga nizati o n, 
, will u n derta ke t he o perati o nal 
as pects of t his st u d y. Details of s uc h 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 Pl a n (I P M P) mai ntai ne d b y  
. T he I P M P will be 
pre pare d b y t he 
 Cli nical Pr oject Ma na ger i n c o o perati o n wit h ot her 
 O perati o nal 
Tea m Lea ds.
T he Cli nical St u d y  Su p plies de part me nt of t he S p o ns or will s u p pl y the st u d y me dicati o n of 
a vel u ma b a n d as a p plica ble place b o a n d/ or c o m parat or treat me nt(s). Cli nic al s u p pl y is perf or me d 
b y  t he Cli nical Trial S u p pl y f u ncti o n of t he S p o ns or.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
P P D
P P D
P P D
P P D


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 3 / 1 2 5
T he Gl o bal Patie nt Safet y  De part me nt, Merc k K Ga A, Dar msta dt, Ger ma n y , or t heir desi g nate d 
re prese ntati ves will s u per vise dr u g safety a n d t he ti mel y re p orti n g of a d verse e ve nts ( A Es) a n d 
S eri o us A d verse E ve nts ( S A Es).
Q ualit y  ass ura nce of t he st u d y c o n d uct will be perf or me d b y t he De vel o p me nt Q uality Ass ura nce 
De part me nt, Merc k K Ga A, Dar msta dt, Ger ma n y.
T he de part me nt of Gl o bal Bi ostatistics will s u per vise t he statistical a nal yses ( wit h t he e xce pti o n 
of t he P K data a nal y ses), w hic h will be o uts o urce d t o a C R O.
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 St u d y  Refere nce 
Ma n ual , 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.
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

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 (f or e xa m ple, a d vertise me nts) t o a n 
I RB/I E C a n d t he I R 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.

A n y  pr ot oc ol a me n d me nts (ie, 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 re q uire me nts, p olicies, a n d pr oce d ures.

N otif y i n g t he I R B/I E C of S A Es or ot her si g nifica nt safety fi n di n gs, as req uire d b y  
I RB/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 I R 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 ul ati 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 nati 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 di cal 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 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 4 / 1 2 5
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 In 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  su bse q ue nt acti o n (f or e xa m ple, 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 u r 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.
Cli nic al S t 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
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 a n d a n y Steeri n g C o m mittee or ot her rele va nt st u d y-a p p oi nte d 
c o m mittees or gr o u ps.
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 pr 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 gnate 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.
Disse 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 n icaltrials. g o v, E u dra C T, a n d all ot her r e 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 .

A C S R will be writte n wit hi n 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. T he C S R will be distri b ute d i n 
acc or da nce t o E U 5 3 6/ 2 0 1 4 a n d all ot her a p plica ble re g ulati o ns. Cli nical sites, I RBs a n d l ocal
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 5 / 1 2 5
a ut h orities will recei ve t he C S R s yn o psis, e xce pt t he f ull C S R is req ueste d b y  nati o nal 
re g ulati o ns. T his i ncl u des access t o C S Rs fr o m st u dies wit h ne gati ve o utc o mes a n d fr o m 
ter mi nate d de vel o p me nt pr o gra ms.

Peri o dic S afet y R e p orts, a n d cli nical st u d y su m mar y  re p orts will be s u b mitte d acc or di n g t o 
nati o nal re g ulati o ns t hat nee d t o be f oll o we d.
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 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 (f or e xa m ple, 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 mely b y  
p h y sically or electr o nicall y si gni n g t he C R F. Details f or ma na gi n g C R Fs are i n t he St u d y 
Refere nce Ma n ual .

T he I n vesti gat or m u st 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 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.

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 a n 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 C R Fs will be 
pr o vi de d t o t he I n vesti gat ors at st u d y  c o m pleti o n.

St u d y  mo 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 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  a gree me nts, I C H 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 n i 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 nsferre d 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 grit y 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 inf 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 )
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 6 / 1 2 5

St u d y  i de ntifier (ie, 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 (ie, 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 (f or e xa m ple, 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 nte 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.

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 h e 
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 ors 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, c o u ntersi g ne d b y  t he M o nit or a n d ke pt 
i n t he stu 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 ble 
re g ulati o ns, a n d/ or as per I CH G C P g ui deli nes, w hic he ver is l o n ger. T he I n vesti gat or e ns ures
t hat n o destr ucti o n of me dical rec or ds is perf or me d with 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 fo u n d i n S o urce Data I de ntificati o n Lo g .
St u d y a n d Site Cl os ure

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 n vesti 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 req uire me nts of t he I R B/I E C 
or l ocal H ealt 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. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 7 / 1 2 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 (ie, 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 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 dical 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
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 a n 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 6 0 da y s 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. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 8 / 1 2 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 s ur 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 uate 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.
Acce pt a ble C o ntr ace pti ve Met h o d
All o we d o nl y u n der certai n sit uati o ns, as s pecifie d i n t he C T F G rec o m me n dati o ns, beca use 
t he y ha ve a fail ure rate of m ore t h a n 1 % per year a n d t heref ore are n ot c o nsi dere d t o be hi g hl y 
effecti ve met h o ds.

Pr o gest o ge n - o nly oral h or m o nal c o ntrace pti o n, w here i n hi biti o n of o v ulati o n is n ot t he 
pri mar y  m o de of acti o n

Male or fe male c o n d o m wit h or wit h o ut s per mici de

Ca p, dia p hra g m or s p o n ge wit h s per mici de

C o m bi nati o n of a male c o n d o m wit h ca p, dia p hra g m or s p o n ge wit h s per mici de (ie, d o u ble 
barrier met h o d) .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 0 9 / 1 2 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 ny 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 orally 
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.
T he I n vesti gat or is re q uire d t o gra de t he se verit y 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 that ca n be use d 
f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsit y; 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 verit y for 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 
g e 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 G ra 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 ab n or malit y 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  if t he 
c o n diti o n meets o ne of t he seri o us criteria s pecifie d bel o w.
If deat h occ urs, t he pri mar y  ca use of d eat 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” will 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 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 0 / 1 2 5
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 ( f or e xa m ple, 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 maticall y assess t he ca usal relati o ns hi p of A Es t o st u d y inter ve nti o n 
(i ncl u di n g a n y ot her n o n -st u d y inter ve nti o ns, ra diati o n t hera py, 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 
i nter ve nti o ns 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 ns , k n o w n si de effects of t he st u d y inter ve nti o ns , 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 i nter 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 vaila ble.
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 (f or e xa m ple, 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 inter ve nti o n disc o nti n uati o n or 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  fulfill s t hese criteria, t he i de ntifie d 
me dical c o n diti o n ( f or e xa m ple, 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 me dicall y  im p orta nt. I mp orta nt me dical e ve nts t hat ma y  not 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 he y ma y je o par dize t he partici pa 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 r o 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 o n ot 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.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 1 / 1 2 5
F or t he p ur p oses of re p orti n g, an y  sus 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 A E SIs .
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 inter ve nti o n or pr oce d ures (f or 
e xa m ple, 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 py a p plicati o n) 
are n ot 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 dere 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 verity or fre q ue nc y 
d ur i n g t he st u dy 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 Pr 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 he r 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 m e 
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 E SI)
I nf usi o n-relate d reacti o ns i ncl u di n g dr u g h y perse nsiti vit y  reacti o ns a n d i m m u ne-me diate d a d verse 
reacti o ns (i m m u ne-relate d p ne u m o nitis, i m m u ne-relate d c olitis, i m m u ne-relate d he patitis, 
i m 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, ne w o nset t ype I 
dia betes mellit us, pit uitar y  dis or ders), i m m u ne-relate d ne p hritis a n d re nal d y sf u ncti o n a n d ot her 
i m m u ne-relate d A Es 
( m yositis, m y ocar ditis, G uillai n -Barré s yn dr o me, u veitis) ha ve bee n 
i de ntifie d as a d verse e ve nts of s pecial i nterest f or a vel uma b . A n y A E t hat is s us pecte d t o be a 
p ote ntial i m m u ne-me diate d a d verse reacti o n or i nf usi o n-relate d reacti o n will be c o nsi dere d a n 
a d verse e ve nt of s pecial i nterest ( A E SI).
T hese A E SI d o n ot re q uire e x pe dite d re p orti n g u nless t he y are seri o us. S h o ul d t he A E SI be seri o us, 
a S A E f or m s h o ul d be fille d i nstea d a n d t he re p orti n g pr ocess f or S A Es s h o ul d be f oll o we d. 
A d diti o nal i nf or mati o n o n A E SI s are i n t he a vel u ma b a n d cet u xi ma b I Bs.
T here are n o s pecifi e d A E SI  f or cet u xi ma b.
Rec or di n g a n d F oll o w - up 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 inter ve nti o n a d mi nistrati o n ti me), its se verit y, its ca usal 
relati o ns hi p wit h t he st u d y i nter ve nti o n, a n y ot her p ote ntial ca usal fact ors, a n y treat me nt gi ve n or 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 2 / 1 2 5
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 inter ve nti o n, a n d 
its o utc o me. I n 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 a n d A d verse E ve nts of S peci al I nterest
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 n vesti 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 i n writi n g. All writte n re p orts s h o ul d be tra ns mitte d usi n g t he S A E Re p ort 
F or m, w hic h m ust be c o m plete d b y  t he I n vesti gat or f oll o wi n g s pecific c o m pleti o n i nstr ucti o ns.
I n e xce 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 writte n re p ort m ust be se nt i m me diatel y thereafter b y  fa x or e-mail. Na mes, 
a d dresses, a n d tele p h o ne a n d fa x n u m bers f or S A E re p orti n g will be i ncl u de d i n t he st u d y s pecific 
S A E Re p ort F or m.
Rele va nt pa ges fr o m t he C R F m a y  be pr o vi de d i n parallel (f or e xa m ple, me dical hist 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  the I n vesti gat or, if a vaila ble (f or 
e xa m ple, la b orat or y res ults, h os pital re p ort, a ut o ps y re p ort). I n all cases, t he i nf or mati o n pr o vi de d 
o n t he S A E Re p ort F or m m ust be c o nsiste nt wit h t he data a b o ut t he e ve nt rec or de d i n t he C R F.
T he I n vesti 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 (f or e xa m ple, 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  h ave 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  to e ns ure pr o m pt assess me nt of t he e ve nt b y  the S p o ns 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 
safety 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 msta nces t he dr u g safety de part me nt m a y  co ntact t he I n vesti gat or directl y  to o btai n f urt her 
i nf or mati o n or t o disc uss t he e ve nt.
A d verse E ve nts of S peci al I nterest
I n t he e ve nt of a n o n- seri o us A E SI , t he I n vesti gat or will c o m plete t he A E SI Re p ort F or m a n d se n d 
it t o t he S p o ns or/ desi g nee 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 eve nt . 
Na mes, a d dresses, a n d tele p h o ne a n d fa x n u m bers f or A E SI re p orti n g will be i ncl u de d o n t he 
Re p ort F or m. Seri o us A E SI s m ust be re p orte d i n a n e x pe dite d ma n ner as S A Es as o utli ne d a b o ve.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 3 / 1 2 5
A p pe n di x 5
Li ver S afet y: S u g geste d Act i o ns a n d F oll o w-u p Assess me nts
See Secti o n  6. 9. 1 f or details o n ma na ge me nt of li ver ir A Es.
D oc u me nt N o. 
O bject N o. 
C CI
C CI




2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 5 / 1 2 5
A p pe n di x 7
Me dic al 
De vice 
I nci de nts: Defi niti o n 
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
N ot a p plica ble.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 6 / 1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 7 / 1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 8 / 1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 1 9 / 1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4 -0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 2 0 /1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4 -0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 2 1 /1 2 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 2 2 / 1 2 5
A p pe n di x 1 0
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.
D oc u me nt N o. 
O bject N o. 
C CI
C CI






2 0 1 9 4 4
P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge mcit a bi ne a n d 
M S 2 0 1 9 4 4- 0 1 7 0
Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 2 5 / 1 2 5
A p pe n di x 1 3
Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A P hase IIa, si n gle-ar m, m ultice nter st u d y to i n vesti gate 
t he cli nical acti vit y an d safet y of a vel u ma b i n c o m bi nati o n 
wit h cet u xi ma b 
pl us ge mcita bi ne a n d cis plati n i n 
partici pa nts wit h a d va nce d s q ua m o us n o n -s mall-cell l u 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 n u m ber: 2 0 1 8 - 0 0 1 5 2 9- 2 4
Cli nical Trials. g o v: N C T 0 3 7 1 7 1 5 5
Cli nic al St u d y Pr ot oc ol Versi o n:
2 0 A u g ust 2 0 1 9/ Versi o n 2. 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 ni zati o n
G o o d 
Cli nical 
Practice ( T o pic E 6) a n d all a p plica ble He alt h 
A ut h orit y 
re q uire me nts a n d nati o nal la ws.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
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. 
C CI
C CI

SAP_001.pdf: 
M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1/ 6 2
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 1 9 4 4 - 0 1 7 0
Title
A P hase IIa, si n gle-ar m, m ultice nter st u d y to i n vesti gate t he 
cli nical acti vit y an d safet y of a vel u ma b i n c o m bi nati o n wit h 
cet u xi ma b pl us ge mcita bi ne a n d cis plati n i n partici pa nts wit h 
a d va nce d s q ua m o us n o n -s mall-cell l u n g ca ncer ( N S C LC)
St u d y P h ase
IIa
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)
A vel u ma b: M S B 0 0 1 0 7 1 8 C
Cet u xi ma b: E M D 2 7 1 7 8 6
Cli nic al St u d y Pr ot oc ol 
Versi o n
2 0 A u g ust 2 0 1 9 / Versi o n 2. 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
, M er c k H e alt h c ar e K G a A
F u n cti o n
A ut h or( s) / D at a A n al y s t( s)
I nte gr ate d A n al ysis Pl a n
D ate a n d Versi o n
1 0 A u g ust 2 0 2 0 / Versi o n 2. 0
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
, 
Gl o b al Bi o st ati sti c s L e a d , M er c k H e alt h c ar e K G a A
Gl o b al Bi o st ati sti c s L e a d, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e K G a A
Pri n ci p al Cli ni c al Tri al L e a d, E M D S er o n o
, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e K G a A
, E M D S er o n o
, E M D S er o n o
St at Pr o gr a m mi n g L e a d, M er c k H e alt h c ar e K G a A
, M er c k H e alt h c ar e 
K G a A
, M er c k H e alt h c ar e K G a A
D oc u me nt N o. 
O bject N o. 
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
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
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
P P D
C CI
C CI
P P D


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2/ 6 2
T his d oc u me nt is t he pr o pert y of Merc k Healt hcare 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 Healt hcare K Ga A, Dar msta dt, Ger ma n y or its affili ate. 
C o p yri g ht © 2 0 2 0 b y Merc k He alt hc are K G a A, D ar mst a dt, Ger m a n y or its affili ate. All ri g hts reser ve d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3/ 6 2
A p pr o v al P a ge
I nte gr ate d A n al ysis Pl a n: M S 2 0 1 9 4 4 - 0 1 7 0
A P hase IIa, si n gle -ar m, m ultice nter st u d y t o i n vesti gate t he cli nical acti vit y a n d safety of
a vel u ma b i n c o m bi nati o n wit h cet u xi ma b pl us ge mcita bi ne a n d cis plati n i n partici pa nts wit h 
a d va nce d s q ua m o us n o n -s mall-cell l u n g ca ncer ( N S C LC)
A p pr o val of t he I A P b y  all Merc k Data A nalys is Res p o nsi ble is d oc u me nte d wit hi n E L D O R A D O
via e Si g nat ure. Wit h t he a p pr o val wit hi n El d ora d o, t he Merc k res p o nsi ble f or eac h of t he a nalys is 
als o ta kes res p o nsi bilit y t hat all re vie wers’ c o m me nts are a d dresse d a de q uatel y.
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4/ 6 2
1
T a ble of C o nte nts
I nte grate d A nal ys is 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 br e viati o ns a n d Defi niti o n of Ter ms .................................... 7
3
M o dificati o n Hist or y
.......................................................................... 1 0
4
P ur p ose of t he I nte grate d A nal y sis Pla n ............................................. 1 1
5
O bjecti ves a n d E n d p oi nts ................................................................... 1 1
6
O ver vie w of Pla n ne d A nal y ses........................................................... 1 2
6. 1
Mai n A nal ys is..................................................................................... 1 2
6. 2
Fi nal A nal ys is..................................................................................... 1 2
7
C ha n ges t o t he Pla n ne d A nal y ses i n t he Cli nical St u d y ..................... 1 2
8
Pr ot oc ol De viati o ns a n d A nal y sis P o p ulati o ns ................................... 1 3
8. 1
Defi niti o n of Pr ot oc ol De viati o ns a n d A nal ys is P o p ulati o ns............. 1 3
8. 2
Defi niti o n of A nal ys is P o p ulati o ns a n d S u b gr o u ps............................ 1 4
9
Ge neral S pecificati o ns f or Data A nal y ses .......................................... 1 5
1 0
St u d y  Partici pa nts............................................................................... 2 0
1 0. 1
Dis p ositi o n of Partici pa nts a n d Disc o nti n uati o ns ............................... 2 0
1 0. 2
Pr ot oc ol De viati o ns ............................................................................ 2 1
1 0. 2. 1
I m p orta nt Pr ot oc ol De viati o ns............................................................ 2 1
1 0. 2. 2
Reas o ns Lea di n g t o t he E xcl usi o n fr o m a n A nal y sis P o p ulati o n ....... 2 1
1 1
De m o gra p hics a n d Ot her Baseli ne C haracteristics ............................. 2 2
1 1. 1
De m o gra p hics ..................................................................................... 2 2
1 1. 2
Me dical Hist or y .................................................................................. 2 3
1 1. 3
Ot her Baseli ne C haracteristics ............................................................ 2 3
1 1. 4
Pri or A nti -ca ncer Treat me nts a n d Pr oce d ures ....................................2 4
1 2
C o nc o mita nt Me dicati o ns/ Pr oce d ures ................................................ 2 5
1 2. 1
Pre vi o us Me dicati o ns ..........................................................................2 5
1 2. 2
C o nc o mita nt Me dicati o ns................................ ...................................2 5
1 2. 3
C o nc urre nt Pr oce d ures ........................................................................2 6
1 2. 4
A nti- Ca ncer P ost -I nter ve nti o n............................................................2 6
1 3
St u d y  Inter ve nti o n C o m plia nce a n d E x p os ure ................................... 2 7
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5/ 6 2
1 4
Efficac y  A nalys es ...............................................................................3 2
1 4. 1
Pri mar y  E n d p oi nt A nalys is................................................................. 3 2
1 4. 1. 1
Pri mar y  O bjecti ve: A nal ysis of t he C o nfir me d Best O verall 
Res p o nse ( B O R) ................................................................................. 3 2
1 4. 1. 2
Se nsiti vit y  A nalys es of C o nfir me d B O R ............................................ 3 4
1 4. 1. 3
S u b gr o u p A nal y ses of C o nfir me d B O R ............................................. 3 5
1 4. 2
Sec o n dar y  E n d p oi nt A nal ysis ............................................................. 3 6
1 4. 2. 1
Sec o n dar y  E n d p oi nts.......................................................................... 3 6
1 4. 2. 2
Se nsiti vit y  A nalys es of Sec o n dar y E n d p oi nts.................................... 3 9
1 4. 2. 3
S u b gr o u p A nal y ses of Sec o n dar y E n d p oi nts...................................... 3 9
1 5
Safet y  A nalys es .................................................................................. 4 1
1 5. 1
A d verse E ve nts ................................................................................... 4 1
1 5. 1. 1
All A d verse E ve nts ............................................................................. 4 2
1 5. 1. 2
A d verse E ve nts Lea di n g t o Treat me nt Disc o nti n uati o n ..................... 4 3
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 ve nts ................................................................................... 4 4
1 5. 2. 1
Deat hs ................................................................................................. 4 4
1 5. 2. 2
Seri o us A d verse E ve nts ...................................................................... 4 5
1 5. 2. 3
Ot her Si g nifica nt A d verse E ve nts ...................................................... 4 5
1 5. 3
Cli nical L a b orat or y E val uati o n........................................................... 4 7
1 5. 3. 1
He mat ol o g y  a n d C he mistr y Para meters ............................................. 4 7
1 5. 3. 2
Ot her La b orat or y  Para meters..............................................................4 9
1 5. 4
Vital Si g ns .......................................................................................... 4 9
1 5. 5
Ot her Safet y or T olera bilit y  E val uati o ns............................................ 5 0
1 5. 5. 1
E C G .................................................................................................... 5 0
1 5. 5. 2
E C O G Perf or ma nc e Stat us ................................................................. 5 1
1 6
A nal y ses of Ot her E n d p oi nts ..............................................................5 1
1 6. 1
P har mac o ki netics ................................................................................5 1
1 6. 1. 1
Missi n g/ n o n -q ua ntifia ble P K Data Ha n dli n g .....................................5 1
1 6. 1. 2
Descri pti ve P K A nal ys is.....................................................................5 2
1 6. 1. 3
P har mac o ki netic Para meter A nal ys is ................................................. 5 3
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
6/ 6 2
1 6. 4
C O VI D -1 9 I m pact ..............................................................................5 7
1 7
Refere nces ........................................................................................... 5 8
1 8
A p pe n dices ......................................................................................... 5 9
1 8. 1
A p pe n di x I  – Descri pti o n of t he Case Defi niti o n f or Assess me nt 
of ir A Es a n d I R Rs ............................................................................... 5 9
1 8. 2
A p pe n di x II – N CI -C T C Gra da ble a n d N o n -Gra da ble Safet y 
La b orat or y  Test Para meters a n d Directi o n(s) of A b n or malit y........... 6 1
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
7/ 6 2
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 dr u g A nti b o d y
A E
A d verse E ve nt
A E SI
A d verse E ve nt of S pecial I nterest
A L T
Ala ni ne A mi n otra nsferase 
A S T
As partate A mi n otra nsferase
A T C
A nat o mical T hera pe utic C he mical
B O R
Best O verall Res p o nse
B S A
B o d y S urface Area
C e oi
I m me diate E n d of I nf usi o n O bser ve d C once ntrati o n
CI
C o nfi de nce I nter val
C ma x
Ma xi m u m O bser ve d C o nce ntrati o n
C O VI D - 1 9
2 0 1 9 N o vel C or o na vir us Disease
C R
C o m plete Res p o nse
C R O
C o ntract Researc h Or ga nizati o n
C S R
Cli nical St u d y  Re p ort
C T C A E v 5. 0
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts Versi o n 5. 0
C tr o u g h
T he c o nce ntrati o n o bser ve d i m me diatel y bef 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 ntrati o n f or m ulti ple d osi n g)
D O R
D urati o n of Res p o nse
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  Gr o u p Perf or ma nce Stat us
e C R F
E lectr 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
E N R
E nr olle d A nal ys is Set/ P o p ulati o n
E o T
E n d of Treat me nt
F A S
F ull A nal ys is Set/ P o p ulati o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
G B S
Gl o bal Bi ostatistics
H R
Hazar d Rati o
I A P
I nte grate d A nalys is Pla n
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I H C
I m m u n o hist oc he mistr y
ir A E
I m m u ne-relate d A d verse E ve nt
I R C
I n de pe n de nt Re vie w C o m mittee
i v
I ntra ve n o us
K M
Ka pla n -Meier
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
8/ 6 2
L L N
L o wer Li mit of N or mal
L O C F
Last O bser vati o n Carrie d F or war d
Ma x
Ma xi m u m
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
Mi n
Mi n u m u m
N
N u m ber of s u bjects
n
N u m ber of s u bjects wit h n o n -missi n g val ues
N A
N ot A p plica ble
N CI
Nati o nal Ca ncer I nstit ute
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 verse E ve nts
N E
N ot E val ua ble
N o n -C R/ N o n -P R
N o n -C o m plete Res p o nse/ N o n -Pr o gressi ve Disease
N S C L C
N o n -s mall Cell L u n g Ca ncer
O R R
O bjecti ve Res p o nse Rate
O S
O verall S ur vi val
P C S A
P ote ntiall y  Cli nically S i g nifica nt A b n or malities
P D
Pr o gressi ve Disease
P D - 1
Pr o gra m me d Cell Deat h Pr otei n- 1
P D -L 1
Pr o gra m me d Deat h L i ga n d 1
P F S
Pr o gressi o n Free S ur vi val
P K
P har mac o ki netics
P K A S
P har mac o ki netics A nal y sis Set
P R
Partial Res p o nse
P T
Preferre d Ter m
R E CI S T v 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
S A E
Seri o us A d verse E ve nt
S A F
Safet y  A nalys is Set/ P o p ulati o n
S C R
Scree ni n g a nal y sis p o p ulati o n
S D
Sta ble Disease
S M C
Safet y  M o nit ori n g C o m mittee
S O C
S y ste m Or ga n Class
St d De v
Sta n dar d De viati o n
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
9/ 6 2
T E A E
Treat me nt -E mer ge nt A d verse E ve nt
T L F
Ta bles, L isti n gs, a n d Fi g ures
T N M
T u m or N o de Metastasis
T P S
T u m or Pr o p orti o n Sc ore
U L N
U p per Li mit of N or mal
W H O -D D
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI








M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 3 /6 2
A d diti o nall y , i n t he deri vati o n of B O R, t he re q uire d ti mefra me f or deter mi nati o n of P D was 
c ha n ge d t o ≤ 1 8 wee ks (as o p p ose d t o ≤ 1 2 wee ks, as s pecifie d i n t he P r ot oc ol). T his u p date was 
ma de d ue t o t he pla n ne d i nter val of t u m or assess me nts, w hic h are sc he d ule d t o occ ur e ver y 9 
wee ks f or t he first 6 m o nt hs of treat me nt.
O ne f urt her efficac y  e n d p oi nt, ti me t o res p o nse ( T T R) was deter mi ne d t o be of i nterest des pite n ot 
bei n g pre -s pecifie d i n t he Pr ot oc ol. T he a nal ysis of T T R c o nsists of si m ple s u m mar y statistics 
( mea n, S D, me dia n, mi n, ma x, Q 1, Q 3) base d o n partici pa nts i n t he F A S wit h c o nfir me d o bjecti ve 
res p o nse. T he val ue is calc ulate d as:
T T R ( wee ks) = ( Date of first C R or P R – Date of first d ose + 1)/ 7
Fi nall y , the C O VI D - 1 9 pa n de mic was u nf oresee n at t he ti me t his Pr ot oc ol was fi nalize d; t heref ore, 
t he res pecti ve se nsiti vit y a nalys es were a d de d later.
8
Pr ot oc ol De vi ati o ns a n d A n al ysis P o p ul ati o ns
8. 1
Defi niti o n of Pr ot oc ol De vi ati o ns a n d A n al ysis P o p ul ati o ns
I m p orta nt pr ot oc ol de viati o ns are pr ot oc ol de viati 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 data or t hat mi g ht si g nifica ntl y affect a 
s u bject's ri g hts, safety, or well -bei n g. 
I m p orta nt pr ot oc ol de viati o ns i ncl u de :

Partici pa nts t hat are d ose d o n t he st u d y  des pite n ot satisf yi n g t he i ncl usi o n criteria

Partici pa nts t hat 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 t hat recei ve t he wr o n g st u d y  i nter ve nti o n or a n i nc orrect d ose

Partici pa nts t hat recei ve a n e xcl u de d c o nc o mita nt me dicati o n

De viati o n fr o m G o o d Cli nical Practice
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 4 /6 2
All i m p orta nt pr ot oc ol de viati o ns will be d oc u me nte d i n t he Cli nical Trial Ma na ge me nt S y ste m 
( C T M S) a n d i n t he St u d y  Data Ta b ulati o n M o del (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 data ma na ge me nt pr o gra m mi n g.
Se parate s u m maries will be pr o vi de d f or all pr ot oc ol de viati o ns a n d t he s u bset of pr ot oc ol 
de viati o ns t hat were attri b ute d t o t he i m pact of t he C O VI D -1 9 pa n de mic.
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
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 data re vie w meeti n g pri or t o data base l oc k.
E nr olle d A n al ysis Set ( E N R)
T he e nr olle d a nal ys is set i ncl u des all partici pa nts w h o si g ne d t he i nf or me d c o nse nt f or m.
F ull A n al ysis Set ( F A S) / S afet y A n al ysis Set ( S A F)
T he f ull or safet y anal ys is set will i ncl u de all partici pa nts w h o recei ve at least o ne n o n- zer o d ose 
of a n y st u d y treat me nt.
P h ar m ac o ki netic A n al ysis Set ( P K A S)
T he p har mac o ki netic ( P K) a nal ys is set will c o nsist of all partici pa nts w h o recei ve at least o ne d ose 
of a vel u ma b a n d/ or cet u xi ma b, ha ve n o i m p orta nt e ve nts affecti n g P K, a n d pr o vi de at least o ne
meas ura ble p ost -d ose c o nce ntrati o n. 
S u b gr o u p defi niti o n a n d p ar a meteriz ati o n:
S u b gr o u p a nal ys es will be perf or me d o n pri mar y  an d sec o n dar y efficac y en d p oi nts base d o n t he 
s u b gr o u ps of t he S A F A nal y sis Set, as defi ne d bel o w.
 T he 
p ur p ose of s u b gr o u ps se x, a ge, a n d c o u ntr y are t o c hec k i nter nal c o nsiste nc y wit hi n t he tar gete d 
p o p ulati o n. S u b gr o u ps hist ol o g y , 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 ) a n d s m o ki n g ha bits are k n o w n pr o g n ostic f or l u n g ca ncer patie nts. I n t he case of a 
l o w n u m ber of partici pa nts wit hi n a cate g or y ( <1 0 % of t he p o p ulati o n ), t he cate g ories will be 
p o ole d w he n mea ni n gf ul .
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 5 /6 2
Dia g n ostic stat us 8 0: ≥8 0 % of t u m or cells wit h i nte nsit y 2+ or 3 + ( Dia g n ostic stat us 8 0 p ositi ve)
Dia g n ostic stat us 8 0: < 8 0 % of t u m or cells wit h i nte nsit y 2+ or 3 + ( Dia g n ostic stat us 8 0 
ne gati ve)
Dia g n ostic stat us 9 0: ≥9 0 % of t u m or cells wit h i nte nsit y 2+ or 3 + ( Dia g n ostic stat us 9 0 p ositi ve)
Dia g n ostic stat us 9 0: < 9 0 % of t u m or cells wit h i nte nsit y 2+ or 3 + ( Dia g n ostic stat us 9 0 
ne gati ve)

Se x ( male vers us fe male)

A ge ( < 6 5 vers us ≥ 6 5 y ears)

C o u ntr y  ( S pai n vers us H u n gar y vers us Ser bia)

E C O G perf or ma nce stat us at baseli ne ( 0 vers us 1)

S m o ki n g hist or y  (e ver s m o ker vers us ne ver-s m o ker)

Li ver metastases at baseli ne ( y es vers us n o)

Brai n metastases at baseli ne ( y es vers us n o)

Pre vi o usl y  treate d f or n o n-metastatic disease ( y es vers us n o)
9
Ge ner al S pecific ati o ns f or D at a A n al yses
U nless ot her wise i n dicate d, s u m mar y ta bles will be prese nte d base d o n t he a nal ysis set of i nterest; 
listi n gs will be prese nte d usi n g t he sa me a nalys is sets as c orres p o n di n g ta bles.
T here is n o f or mal si g nifica nce le vel f or t his st u d y a n d all a nal ys es are c o nsi dere d descri pti ve.
P o oli n g of ce nters:
Data will be p o ole d acr oss ce nters.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 6 /6 2
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 will be s u m marize 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 n o n -missi n g val ues ( n)
arit h metic mea n ( Mea n), sta n dar d de viati o n ( St d De v)
me dia n, 2 5t h Perce ntile - 7 5t h Perce ntile ( Q 1 -Q 3)
mi ni m u m ( Mi n) , ma xi m u m ( Ma x)
9 5 % c o nfi de nce i nter vals ( CI s) f or t he mea n, as a p pr o priate
Q ualitati ve varia bles will be s u m marize d b y  c o u nts a n d perce nta ges.
U nless ot her wise state d t he calc ulati o n of pr o p orti o ns will be base 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 nclu de d i n t he 
de n o mi nat or a n d prese nte d as a se parate cate g or y .
I n case t he a nal ys is refers o nl y  to certai n visits, perce nta ges will be base d o n t he n u m ber of 
partici pa nts still prese nt i n t he trial at t hat visit, u nless ot her wise s pecifie d.
Defi niti o n of b a seli ne:
T he last n o n- missi n g meas ure me nt pri or t o t he first a d mi nistrati o n of a n y st u d y treat me nt will 
ser ve as t he baseli ne meas ure me nt. 
Defi niti o n of d ur ati o n:
D urati o n will be calc ulate d b y t he (differe nce of start a n d st o p date ) + 1 (e. g. , s ur vi val ti me ( da ys) 
= date of deat h – date of treat me nt start + 1) (if n ot ot her wise s pecifie d).
T he ti me si nce a n e ve nt (e. g. , ti me si nce first dia g n osis) will be calc ulate d as date of e ve nt mi n us 
refere nce date (e. g., ti me si nce last d ose date will be calc ulate d as t he e ve nt date – t he date of last 
d ose).
U nsc he d ule d visits:
Assess me nts fr o m u nsc he d ule d visits will be use d f or t he deri vati o n of baseli ne val ues a n d w orst 
o n- treat me nt val ues. H o we ver, descri pti ve statistics b y  no mi nal visit or ti me p oi nt f or safet y 
e n d p oi nts s uc h as la b orat or y meas ure me nts, E C Gs a n d vital si g ns will i ncl u de o nl y  data fr o m 
sc he d ule d visits per pr ot oc ol. 
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 d a y s i nt o m o nt hs or ye ars: 1 m o nt h = 
3 0. 4 3 7 5 da y s, 1 year = 3 6 5. 2 5 da ys.
H a n dli n g of missi n g d at a:
U nless ot her wise s pecifie d, missi n g data will n ot be re place d. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 7 /6 2
I n all s u bject data listi n gs, i m p ute d val ues will be prese nte d a n d fla g ge d as s uc h. 
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” ( n ot d o ne).  
F or e xa m ple, if n = 1, t he meas ure of varia bilit y  (St d De v) ca n n ot be c o m p ute d a n d will be prese nte d 
as “ n d”.
Tre at me nt d a y
Treat me nt d a y  is defi ne d relati ve t o t he start date of st u d y treat me nt. Treat me nt Da y  1 is t he da y 
of t he first a d mi nistrati o n of a n y st u d y treat me nt. T he d a y  bef ore Treat me nt Da y  1 is defi ne d as 
Treat me nt Da y  -1. ( N o Treat me nt Da y  0 is defi ne d.)
D ate of l ast c o nt act
T he date of last c o ntact will be deri ve d f or part ici pa nts n ot k n o w n t o ha ve die d at t he a nal ysis c ut -
off usi n g t he latest c o m plete date a m o n g t he f oll o wi n g:

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, perf or ma nce 
stat us, E C G, t u m or assess me nts, q ualit y of life assess me nts)

Start a n d e n d dates of a nti-ca ncer
t hera pies a d mi nistere d after st u d y treat me nt
disc o nti n uati o n.

A E start a n d e n d dates

Last k n o w n t o be ali ve date c ollecte d o n t he ‘ S u bject Stat us / S ur vi val F oll o w- u p’ e C R F 

St u d y  dr u g start a n d e n d dates

Date of disc o n ti n uati o n o n dis p ositi o n e C R F pa ges ( 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).
O nl y  dates ass ociate d wit h act ual e xa 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 p erati 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 ocesse d will n ot be use d. A ssess me nt dates after t he c ut-off
date will n ot be a p plie d t o deri ve t he last c o ntact date.
H a n dli n g of i nc o m plete d ates :
Dise ase h ist or y
I nc o m plete dates f or disease hist or y  (i nitial dia g n osis date, date of c o nfir me d sta ge I V ( metastatic 
or rec urre nt) dia g n osis) will be i m p ute d as f oll o ws:

If t he da y is missi n g, it will be i m p ute d t o t he 1 5t h da y  of t he m o nt h. 

If b ot h da y an d m o nt h are missi n g a n d t h e ye ar is pri or t o t he ye ar of t he first st u d y treat me nt, 
t he m o nt h a n d da y will be i m p ute d as J ul y 1st.

If b ot h da y a n d m o nt h are missi n g a n d t he year is sa me as t he year of t he first st u d y treat me nt, 
t he m o nt h a n d da y will be i m p ute d as Ja n uar y 1st. 

If t he date is c o m pletel y missi n g, n o i m p utati o n will be perf or me d.
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 8 /6 2
A d verse e ve nts
I nc o m plete A E -relate d dates will be i m p ute d as f oll o ws:

If t he A E o nset date is missi n g c o m pletel y, t he n t he o nset date will be re place d b y  the start of 
st u d y treat me nt.

If o nl y t he d a y  part of t he A E o nset date is missi n g, b ut t he m o nt h a n d year are e q ual t o t he start 
of st u d y treat me nt, t he n t he A E o nset date will be re place d b y  t he start of st u d y treat me nt. F or 
e xa m ple, if t he A E o nset date is --/J A N/ 2 0 19, a n d st u d y treat me nt start date is 1 5/J A N/ 2 0 1 9, 
t he n t he i m p ute d A E o nset date will be 1 5/J A N 2 0 19.

If b ot h t he d a y  an d m o nt h of t he A E o nset date are missi n g b ut t he o nset ye ar is e q ual t o t he 
start of st u d y treat me nt, t he n t he o nset date will be re place d by t he start of st u d y treat me nt. F or 
e xa m ple, if A E o nset date is --/---/ 2 0 19, a n d st u d y treat me nt start date is 1 9/ N O V/ 2 0 1 9, t he n 
t he i m p ute d A E o nset date will be 1 9/ N O V/ 2 0 19.

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 nc o m plete st o p da te will be re place d b y  the last da y  of t he m o nt h (if da y  is missi n g o nl y ), if 
n ot res ulti n g i n a date later t ha n t he date of partici pa nt 's deat h. I n t he latter case t he date of deat h 
will be use d t o i m p ute t he i nc o m plete st o p date. 

I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d.  If st o p date of A E is after date 
of c ut -off o utc o me of A E is o n g oi n g at c ut -off. 
F urt her i nf or mati o n after c ut -off (li ke fatal o utc o me) mi g ht be ta ke n fr o m t he Safet y data base a n d 
i ncl u de d se parately i n t o t he C S R.
Pri or/c o nc o mit a nt me dic ati o n
I nc o m plete pri or/c o nc o mita nt me dicati o n dates will be i m p ute d as f oll o ws:

If t he me dicati o n start date is missi n g c o m pletel y , t he n t he me dicati o n date will be re place d b y 
t he start of st u d y treat me nt.

If t he d a y  of me dicati o n start date is missi n g, b ut t he m o nt h a n d year are e q ual t o t he start of 
st u d y treat me nt, t he n t he me dicati o n start date will be re place d b y  t he start of st u d y treat me nt. 
F or e xa m ple, if t he me dicati o n start date is --/J A N/ 2 0 19, a n d st u d y treat me nt start date is 
1 5/J A N/ 2 0 1 9 , t he n t he i m p ute d me dicati o n start date will be 1 5/J A N 2 0 19. 

If b ot h t he d a y  an d m o nt h of me dicati o n start date are missi n g b ut t he start ye ar is e q ual t o t he 
start of st u d y treat me nt, t he n t he me dicati o n date will be re place d b y  the start of st u d y treat me nt. 
F or e xa m ple, if t he me dicati o n start date is --/---/ 2 0 19 , a n d st u d y treat me nt start date is 
1 9/ N O V/ 2 0 1 9 , t he n t he i m p ute d me dicati o n start date will be 1 9/ N O V/ 2 0 19.

I n all ot her cases t he missi n g me dicati o n
d a y  or m issi n g me dicati o n
m o nt h will be re place d 
b y 1.

I nc o m plete st o p date will be re place d b y  the last da y  of t he m o nt h (if da y  is missi n g o nl y ), if 
n ot res ulti n g i n a date later t ha n t he date of partici pa nt 's deat h. I n t he latter case t he date of deat h 
will be use d t o i m p ute t he i nc o m plete st o p date. 
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
1 9 /6 2

I n all ot her cases t he i nc o m plete me dicati o n st o p date will n ot be i m p ute d. 
S u bse q ue nt a nti -c a ncer t her a p y
I nc o m plete dates f or start date of s u bse q ue nt a nti -ca ncer t hera p y (dr u g t hera p y, ra diati o n, 
a n d s ur ger y) will be i m p ute d as f oll o ws, a n d will be use d f or deter mi ni n g ce ns ori n g dates f or 
efficac y a nalys es a n d i n t he deri vati o n of t he e n d of o n -treat me nt peri o d. 

If o nl y  da y is missi n g, it will be i m p ute d as t he last d a 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 ncer t hera p y is bef ore t hat date. I n that case, t he i nc o m plete a nti-ca ncer 
t hera py 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 nc 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.
Missi n g or partial deat h dates will be i m p ute d base d o n t he last c o ntact date:

If t he date is missi n g it will be i m p ute d as t he da y after t he date of last c o ntact 

If t he d a y  or b ot h, d a y  a nd m o nt h, is missi n g, deat h will be i m p ute d t o t he ma xi m u m of t he 
f ull ( n o n-i m p ute d) da y after t he date of last c o ntact  a n d t he f oll o wi n g:
-
Missi n g da y :
1 st da y  of t he m o nt h a n d year of deat h
-
Missi n g da y  a n d m o nt h: Ja n uar y 1st of t he ye ar of deat h
O n -tre at me nt peri o d
T he o n- treat me nt peri o d is defi ne d as t he date of t he first d ose of i nitial st u d y treat me nt u ntil t he 
mi ni m u m (last d ose date + 3 0 d a y s, earliest date of s u bse q ue nt a nti-ca ncer dr u g t hera p y – 1 da y ).
Defi nit o n of Missi n g c ate g or y
If n ot ot her wise s pecifie d t he f oll o wi n g cate g ories will be s u m marize d u n der t he missi n g cate g or y:

missi n g

u n k n o w n
S A S versi o n:
All a nal y ses will be perf or me d usi n g
versi o n 9. 4 or hi g her.
Prese nt ati o n of P K C o nce ntr ati o n a n d P K P ar a meter D at a
T he prese ntati o n of P K c o nce ntrati o n a n d P K para meter data is descri be d i n detail i n  S ecti o n 16. 1
P har mac o ki netics. 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. 
D oc u me nt N o
O bject N o
P P D
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 0 /6 2
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 pecificati o ns f or re p orti n g s u bject dis p ositi o n a n d st u d y 
i nter ve nti o n/st u d y disc o nti n uati o ns. A d diti o nall y , 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.
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
A n alysis set: E N R
T he dis p ositi o n ta ble will i ncl u de t he f oll o wi n g i nf or mati o n:

N u m ber of partici pa nts scree ne d

N u m ber a n d perce nta ge of partici pa nt s w h o disc o nti n ue d fro m t he st u d y pri or t o treat me nt,
o verall a n d b y  reas o n f or disc o nti n uati o n

N u m ber of partici pa nts i n t he F A S/ S A F a nal ysis set

N u m ber a n d perce nta ge of partici pa nts w h o t o o k at least o ne d ose of ge mcita bi ne 

N u m ber a n d perce nta ge of partici pa nts w h o t o o k at least o ne d ose of cis plati n 

N u m ber a n d perce nta ge of partici pa nts w h o t o o k at least o ne d ose of car b o plati n 

N u m ber a n d perce nta ge of partici pa nts w h o t o o k at least o ne d ose of a vel u ma b

N u m ber a n d perce nta ge of partici pa nts w h o t o o k at least o ne d ose of cet u xi ma b

N u m ber a n d perce nta ge of partici pa nts still o n treat me nt

N u m ber a n d perce nta ge of partici pa nts off -treat me nt

N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d t he treat me nt b ut are still i n 
f oll o w- u p

N u m ber a n d perce nta ge of partici pa nts w h o c o m plete d t he c he m ot hera p y peri o d

N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d g e mcita bi ne, o verall a n d b y 
reas o n f or disc o nti n uati o n 

N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d c is plati n, o verall a nd b y  reas o n 
f or disc o nti n uati o n

N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d car b o plati n , o verall a nd b y  
reas o n f or disc o nti n uati o n

N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d avel u ma b , o verall a nd b y reas o n 
f or disc o nti n uati o n

N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d c et u xi ma b , o verall a nd b y  reas o n 
f or disc o nti n uati o n

N u m ber a n d perce nta ge of partici pa nts w h o re -i nitiate d a vel u ma b treat me nt
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 1 /6 2

N u m ber a n d perce nta ge partici pa nts w h o re-i nitiate d a vel u ma b treat me nt a n d disc o nti n ue d 
t he treat me nt after re-i nitiati o n, o verall a n d by reas o n of disc o nti n uati o n 

N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d assess me nt , o verall a nd b y  reas o n 
f or disc o nti n uati o n

N u m ber a n d perce nta ge of partici pa nts w h o disc o nti n ue d t he st u d y, o verall a n d b y  
disc o nti n uati o n reas o n
A s u m mar y  of partici pa nts w h o disc o nti n ue d o ne or m ore treat me nts a n d/ or t he st u d y f or reas o ns 
attri b ute d t o t he C O VI D- 1 9 pa n de mic will be pr o vi de d.
Se parate s u m mar y tables of a nal ys is p o p ulati o ns as well as e nr oll me nt f or eac h c o u ntr y an d site 
will be pr o vi de d. 
All rele va nt dis p ositi o n data will be prese nte d i n data listi n gs i ncl u di n g reas o ns f or e xcl usi o n fr o m 
a nal ys is sets.
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 viati o ns
A n alysis set: S A F
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 viati o ns will be pr o vi de d 
(se parately f or pre -/ p ost i ncl usi o n de viati o ns):

Fre q ue nc y  ta ble per 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
T he a b o ve ta ble a n d listi n g will be re peate d, i ncl u di n g o nl y t he s u bset of i m p orta nt de viati o ns t hat 
are attri b ute d t o t he i m pact of C O VI D -1 9, as re p orte d i n C T M S.
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 ysis 
P o p ul ati o n
F or partici pa nts e xcl u de d fr o m t he P K, t he reaso ns f or e xcl usi o n will be liste d a n d s u m marize d
usi n g fre q ue nc y  c o u nts:

Di d n ot recei ve a vel u ma b or cet u xi ma b

I m p orta nt e ve nts affecti n g P K

N o meas urea ble p ost -d ose c o nce ntrati o n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 2 /6 2
1 1
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristi cs
A n alysis set: F A S
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 
Scree ni n g/ Baseli ne Visit C R F pa ges.
T he f oll o wi n g d e m o gra p hic c haracteristics will be i ncl u de d:

Se x: male, fe male 

Race: W hite, B lac 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, ot her 

A ge ( y ears): s u m mar y statistics 

A ge cate g ories:

< 6 5 ye ars, ≥ 6 5 ye ars

C o u ntr y :

H u n gar y

Ser bia

S pai n

Hei g ht (c m) at Baseli ne: s u m mar y statistics

Wei g ht ( k g) at Baseli ne: s u m mar y  statistics

B o d y S urface Area ( B S A ) at Baseli ne: s u m mar y statistics

B o d y Mass I n de x ( B MI) at Baseli ne: s u m mar y  statistics

Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us: 0 or 1
S pecificati o ns f or c o m p utati o n:

A ge (ye ars): 
( date of gi ve n i nf or me d c o nse nt - date of birt h + 1) / 3 6 5. 2 5
I n case of missi n g da y f or at least o ne date, b ut m o nt h a n d year a vaila ble f or b ot h dates: 
F or t he deri vati o n of a ge, t he da y of i nf or me d c o nse nt a n d t he da y of birt h will be set t o 1 
a n d t he f or m ula a b o ve will be use d
I n case of missi n g m o nt h f or at least o ne date, b ut year a vaila ble f or b ot h dates: 
F or t he deri vati o n of a ge, t he d a y  an d t he m o nt h of i nf or me d c o nse nt a n d t he d a y  an d m o nt h 
of birt h will be set t o 1 a n d t he f or m ula a b o ve will be use d

B MI ( k g/ m²) = wei g ht ( k g) / [ hei g ht (c m) x hei g ht (c m)] x 1 0 0 0 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 3 /6 2
All rele va nt de m o gra p hic data will be prese nte d i n data listi n gs.
Baseli ne 
c haracteristics 
wit h 
res pect 
t o 
vital 
si g ns, 
p h y sical 
e xa mi nati o ns, 
a n d 
he mat ol o g y / bi oc he mistr y will be part of Secti o n 1 5 ( Safet y E val uati o n).
1 1. 2
Me dic al Hist or y
A n alysis set: F A S
T he me dical hist or y  will be s u m marize d fr o m t he “ Me dical Hist or y ” e C R F pa ge, usi n g t he latest 
versi o n of Me dical Dicti o nar y  f or Re g ulat or y Acti vities ( Me d D R A), preferre d ter m ( P T) as e ve nt 
cate 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 dy S ys te m cate g or y. 
Me dical hist or y  will be dis pla y e d i n ter ms of fre q ue nc y ta bles: or dere d b y  pri mar y SO C a n d P T 
i n al p ha betical or der.
A s u p p orti ve listi n g of me dical hist or y  data b y  su bject will i ncl u de all t he rele va nt data fiel ds as 
c ollecte d o n t he “ Me dica l Hist or y” e C R F pa ge.
1 1. 3
Ot her B aseli ne C h ar acteristics
A n alysis set: F A S
T he disease hist or y  ta ble will i ncl u de descri pti ve statistics f or t he f oll o wi n g varia bles:

Site of pri mar y  t u m or

Disease sta ge at i nitial dia g n osis i ncl u di n g T u m or N o de Metastasis Class ificati o n of Mali g na nt 
T u m ors (T N M ) stat us

T i me si nce i nitial dia g n osis ( m o nt hs) defi ne d as (start date of first st u d y dr u g – date of i nitial 
ca ncer dia g n osis)/ 3 0. 4 3 7 5

Hist o pat h ol o gical classificati o n: S q ua m o us hist ol o g y , Ot her

Disease sta ge at st u d y e ntr y i ncl u di n g T N M stat us

Li ver metastases at baseli ne

Brai n metastases at baseli ne
Ge ne m utati o ns will be e xtracte d fr o m t he “ Disease Hist or y ” e C R F pa ge a n d s u m marize d as 
f oll o ws:

Kirste n rat sarc o ma viral o nc o ge ne h o m ol o g ( K R A S ) ( m utate d / n ot m utate d / u n k n o w n)

P r ot o-o nc o ge ne B- Raf a n d v- Raf m uri ne 
sarc o ma viral o nc o ge ne h o m ol o g B
( B R A F) 
( m utate d / n ot m utate d / u n k n o w n)

( R O S 1) ( m utate d / n ot m utate d / u n k n o w n)

A na plastic L y m p h o ma K i nase ( A L K) ( m utate d / n ot m utate d / u n k n o w n)
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 4 /6 2
A listi n g of disease hist or y  as c ollecte d o n t he “ Disease Hist or y” e C R F pa ge will be pr o vi de d wit h 
all rele va nt data (pri mar y  tu m or site, i nitial dia g n osis date, date of c o nfir me d sta ge I V, 
hist o pat h ol o gical classificati o n, sta ge (at i nitial dia g n osis a n d st u d y e ntr y ), T N M classificati o n at 
i nitial dia g n osis a n d st u d y entr y , a n d ge ne m utati o ns ) a n d deri ve d varia bles use d i n t he a b o ve ta ble.
Nic oti ne c o ns u m pti o n will be s u m marize d as f oll o ws:

Nic oti ne use stat us ( ne ver use d / re g ular user / occasi o nal user / f o r mer user)

E x p os ure t ype (ci garettes / ci gars / pi pes / c he wi n g t o bacc o / nic oti ne g u m / e-ci garettes a n d 
va p or) 

E x p os ure s u m mar y  statistics per wee k f or eac h e x p os ure t yp e
A l isti n g of nic oti ne c o ns u m pti o n as c ollecte d o n t he “ Nic oti ne C o ns u m pti o n” e C R F pa ge will be 
pr o vi de d wit h all rele va nt data .
1 1. 4
Pri or A nti -c a ncer Tre at me nts a n d Pr oce d ures
A n alysis set: S A F
T he pri or a nti-ca ncer t hera pies are c ollecte d u n der t he “ Pri or A nti- Ca ncer Dr u g T hera pies 
Details”, “ Pri or A nti- Ca ncer Ra di ot hera p y Details” a n d “ Pri or A nti- Ca ncer S ur geries Details” 
e C R F pa ges.
T he n u m ber a n d perce nta ge of partici pa nts i n eac h of t he f oll o wi n g a nti -ca ncer t hera p y cate g ories 
will be ta b ulate d:

Partici pa nts wit h at least o ne t y pe of pri or a nti -ca ncer treat me nt

Partici pa nts wit h at least o ne pri or a nti-ca ncer dr u g t hera p y

Partici pa nts wit h at least o ne pri or a nti -ca ncer ra di ot hera p y

Partici pa nts wit h at least o ne pri or a nti -ca ncer s ur ger y
Pri or a nti -ca ncer dr u g t hera p y will be s u m marize d as f oll o ws base d o n t he n u m ber a n d perce nta ge 
of partici pa nts wit h t he f oll o wi n g:

At least o ne pri or a nti -ca ncer dr u g t hera p y

A n y  pri or a nti-ca ncer t hera p y re gi me ns: missi n g / 1 / 2 / 3 / ≥4

T y pe of t hera p y: c yt ot o xic t hera py, m o n ocl o nal a nti b o dies t hera p y, tar gete d t hera py, or 
ot her

I nte nt of pri or anti -ca ncer dr u g t hera p y:  ne oa dj u va nt, a dj u va nt, l ocally a d va nce d, or ot her

Best res p o nse t o re gi me n fr o m pri or a nti-ca ncer dr u g t hera p y: c o m plete res p o nse ( C R), 
partial res p o nse ( P R), sta ble disease ( S D), pr o gressi ve disease ( P D), n o n- c o m plete 
res p o nse/ n o n-pr o gressi ve disease ( N o n -C R/ N o n - P D), n ot e val ua ble ( N E), or u n k n o w n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 5 /6 2

Ti me ela pse d si nce m ost rece nt a nti-ca ncer dr u g t hera p y  t o first st u d y treat me nt ( m o nt hs) 
defi ne d as (start date of first st u d y dr u g – e n d date of latest pri or a nti-ca ncer dr u g t hera p y 
+ 1 d a y )/ 3 0. 4 3 7 5: s u m mar y statistics

D urati o n of m ost rece nt a nti-ca ncer dr u g t hera p y (m o nt hs) defi ne d as (e n d date of latest 
pri or a nti -ca ncer dr u g t hera p y – start date of latest pri or a nti-ca ncer dr u g t hera p y + 1  day)/
3 0. 4 3 7 5: s u m mar y  statistics
S u m mar y  of pri or ra di ot hera py will be s u m marize d acc or di n g t o t he e C R F pa ge “ Pri or A nti-
Ca ncer Ra di ot hera p y Details”.

N u m ber of partici pa nts wit h at least o ne pri or ra di ot hera p y

Best res p o nse t o re gi me n fr o m pri or a nti-ca ncer ra di ot hera py:  co m plete res p o nse ( C R), 
partial res p o nse ( P R), sta ble disease ( S D), pr o gressi ve disease ( P D), n o n- c o m plete 
res p o nse/ n o n-pr o gressi ve disease ( N o n -C R/ N o n - P D), n ot e val ua ble ( N E), or u n k n o w n
T he f oll o wi n g listi n gs of pri or a nti- ca ncer t hera pies will als o be pr o vi de d:

Listi n gs of pri or a nti -ca ncer dr u g t hera pies

Listi n g of pri or ra di ot hera pies

Listi n g of pri or a nti-ca ncer s ur geries as c ollecte d o n t he “ Pri or A nti- Ca ncer S ur geries 
Details” e C R F pa ge.
T hese will i ncl u de s u bject i de ntifier a n d all t he rele va nt data c ollecte d o n t he c orre s p o n di n g e C R F 
pa ges.  Dr u gs gi ve n as part of t he pri or a nti-ca ncer dr u g t hera pies will be i ncl u de d i n t he res pecti ve 
listi n g.  Anat o mical T hera pe utic C he mical ( AT C )- 2 n d le vel a n d preferre d ter m will be ta b ulate d 
as gi ve n fr o m t he latest versi o n of W orl d H e alt h Or ga nizati o n- Dr u g Dicti o nar y  (W H O -D D ). I n 
case m ulti ple A T Cs are assi g ne d t o a dr u g, all A T C - 2n d le vel will be use d f or re p orti n g.
1 2
C o nc o mit a nt Me dic ati o ns/ Pr oce d ures
A n alysis set: S A F
1 2. 1
Pre vi o us Me dic ati o ns
Pre vi o us me dic ati o ns
are me dicati o ns, ot her t ha n st u d y me dicati o ns a n d pre -me dicati o ns f or 
st u d y treat me nt, w hic h starte d bef ore first a d mi nistrati o n of st u d y  i nter ve nti o n. 
T he o nl y pre vi o us me dicati o ns c ollecte d per e C R F are t h ose ca pt ure d as part of t he “ Pri or A nti-
Ca ncer D r u g T hera pies” a n d will be liste d as n ote d i n Secti o n 1 1. 4.
1 2. 2
C o nc o mit a nt Me dic ati o ns
C o nc o mit a nt me dic ati o ns
are me dicati o ns, ot her t ha n st u d y me dicati o ns, w hic h are ta ke n b y  
partici pa nts d uri n g t he o n -treat me nt peri o d ( o n or after t he first da y of st u d y i nter ve nti o n f or eac h 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 6 /6 2
partici pa nt or mi n( wit hi n 3 0 da y s after last d ose of st u d y treat me nt, earliest date of s u bse q ue nt 
a nti-ca ncer dr u g t hera p y – 1 da y )). 
C o nc o mita nt treat me nt will be s u m marize d fr o m t he “ C o nc o mita nt Me dicati o ns
Details ” e C R F 
pa ge. A T C - 2 n d le vel a n d preferre d ter m will be ta b ulate d as gi ve n fr o m t he W H O -D D c urre nt 
versi o n. I n case m ulti ple A T Cs are assi g ne d t o a dr u g, all A T C - 2n d le vel will be use d f or re p orti n g. 
I n case t he date val ues wi ll n ot all o w u ne q ui v ocal all ocati o n of a me dicati o n as a c o nc o mita nt 
me dicati o n , t he me dicati o n will be c o nsi dere d a c o nc o mita nt me dicati o n.
All rele va nt c o nc o mita nt me dicati o n data will be liste d.
1 2. 3
C o nc urre nt Pr oce d ures
All c o nc urre nt pr oce d ures , w hic h are ta ke n b y  partici pa nts d uri n g t he o n -treat me nt peri o d ( o n 
or after t he first d a y  of st u d y inter ve nti o n f or eac h partici pa nt or mi n (wit hi n 3 0 d a y s after last d ose 
of st u d y treat me nt, earliest date of s u bse q ue nt a nti-ca ncer dr u g t hera p y – 1 d a y )), will be 
s u m marize d acc or di n g t o t he e C R F pa ge “C o nc o mita nt Pr oce d ures Details” . 
C o nc urre nt pr oce d ures will be deri ve d i n t he sa me wa y  as c o nc o mita nt me dicati o ns. I n case t he 
date val ues will n ot all o w u ne q ui v ocal all ocati o n of a pr oce d ure as a c o nc urre nt pr oce d ure, t he 
pr oce d ure will be c o nsi dere d a c o nc urre nt pr oce d ure.
All c o nc urre nt pr oce d ure data will be liste d, i ncl u di n g fla gs f or pr oce d ures t hat t o o k place pri or 
t o, o n or after t he date of first st u d y inter ve nti o n , or wit hi n 3 0 da y s after t he last d o se of a st u d y 
treat me nt.
1 2. 4
A nti -C a ncer P ost -I nter ve nti o n
A nti- ca ncer t hera p y after e n d of st u d y i nter ve nti o n t hat will be s u m marize d acc or di n g t o t he C R F 
pa ge " A nti-Ca ncer Treat me nt After Disc o nti n uati o n Details”. I n a d diti o n, co nc o mita nt me dicati o n 
will be c hec ke d f or p ost -i nter ve nti o ns b y  me dical re vie w. Treat me nts will be cate g orize d b y  mea ns 
of c o di n g a n d me dical re vie w.

N u m ber of partici pa nts wit h at least o ne a nti -ca ncer treat me nt after disc o nti n uati o n

T y pe of t hera p y : c yt ot o xic t hera py, m o n ocl o nal a nti b o dies t hera p y, tar gete d t hera p y, or ot her

I nte nt of t hera py:  ne oa dj u va nt, a dj u va nt, l ocally a d va nce d, or ot her

Best res p o nse acr oss all re gi me ns fr o m a nti-ca ncer treat me nt after disc o nti n uati o n: c o m plete 
res p o nse ( C R), partial res p o nse ( P R), sta ble diseas e ( S D), pr o gressi ve disease ( P D), n o n-
c o m plete res p o nse/ n o n-pr o gressi ve disease ( N o n-C R/ N o n - PD) , n ot e val ua ble ( N E), or 
u n k n o w n
All rele va nt a nti-ca ncer treat me nt after disc o nti n uati o n data will be liste d wit h data retrie ve d fr o m 
“ A nti-Ca ncer Treat me nt Aft er 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.
D oc u me nt N o
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 7 /6 2
1 3
St u d y Inter ve nti o n C o m pli a nce a n d E x p os ure
A n alysis set: S A F
D osi n g i nf or mati o n is c ollecte d fr o m t he “ A vel u ma b A d mi nistrati o n Details”, “ Cet u xi ma b 
A d mi nistrati o n 
Details”, 
“ Cis plati n A d mi nistrati o n 
Details”, 
“ Car b o plati n A d mi nistrati o n 
Details” , “ Ge mcita bi ne A d mi nistrati o n Details”, a n d “ Pre me dicati o n Details” e C R F pa ges.

Ge mcita bi ne a n d cis plati n will be a d mi nistere d i n 3 -wee k c y cles u p t o a ma xi m u m of 4 c ycles 
of i ntra ve n o us (i v) i nf usi o ns u ntil disease pr o gressi o n or u nacce pta ble t o xicities. Ge mcita bi ne 
( 1 2 5 0 m g/ m 2) is a d mi nistere d o n D a y  1 a n d Da y 8 a n d cis plati n ( 7 5 m g/ m 2) is a d mi nistere d o n 
D a y  1 of eac h 3- wee k c ycle.
o
At t he discreti o n of t he I n vesti gat or, a s witc h t o car b o plati n f or t he re mai n der of t he
plati n u m - d o u blet c ycles ( u p t o 4 c ycles i n t otal) will be all o we d i n partici pa nts 
de vel o pi n g u nacce pta ble to xicities t o cis plati n. I n these partici pa nts , car b o plati n will 
be a d mi nistere d o n D a y  1 of eac h 3- wee k c ycle at a d ose of tar get area u n der t he ser u m 
c o nce ntrati o n-ti me c ur ve of 5 ( A U C 5) usi n g t he Cal vert f or m ula:
D ose ( m g) = ( 5 m g/ m L * mi n) x [ G F R ( m L / mi n) + 2 5 ( m L/ mi n)]

A vel u ma b ( 8 0 0 m g i v) will be a d mi nistere d o n Da y  1 a n d Da y 8 of eac h 3-wee k c y cle f or t he 
first 4 c y cles al o n g wit h c o nc urre nt c he m ot hera p y as per sc he d ule. T hereafter, a vel u ma b will 
be gi ve n e ver y 2 wee ks i n t he Mai nte na nce p hase u ntil di sease pr o gressi o n or u nacce pta ble 
t o xicities.

Cet u xi ma b will be a d mi nistere d d uri n g t he first 4 c y cles of c o nc urre nt c he m ot hera p y, wit h a n 
i v d ose of 2 5 0 m g/ m 2 b o d y s urface area o n Da y  1 of eac h c ycle a n d at a d ose of 5 0 0 m g/ m 2
b o d y  s urface area o n Da y 8 of eac h c ycle. T hereafter, cet u xi ma b will be gi ve n e ver y  2 wee ks 
i n t he Mai nte na nce p hase, at t he d ose of 5 0 0 m g/ m 2 i v u ntil disease pr o gressi o n or u nacce pta ble 
t o xicities.
T ot al n u m ber of i nf usi o ns
F or eac h of t he st u d y me dicati o ns, t he t otal n u m ber of i nfusi o ns is calc ulate d as t he s u m of t he 
act ual n u m ber of i nf usi o ns t hat a partici pa nt recei ve d f or t hat me dicati o n acr oss c ycles, re gar dless 
of i nf usi o n dela ys, i nterr u pti o ns, or a n y ot her de viati o ns fr o m t he pr ot oc ol re q uire d sc he d ules. A n 
i nf usi o n is re gar de d t o be a d mi nistere d if eit her t he act ual d ose recei ve d is > 0 m g or t he d urati o n 
of t he i nf usi o n is > 0 mi n utes.
D ur ati o n of t her a p y
D urati o n of t hera p y (i n wee ks) d uri n g t he st u d y will be calc ulate d differe ntl y  base d o n t he d osi n g 
da y s a n d fre q ue nc y as f oll o ws:
Ge mcita bi ne , A vel u ma b, a n d Cet u xi ma b: D uri n g eac h 2 1 -d a y  c ycle, ge mcita bi ne , a vel u ma b, a n d 
cet u xi ma b are a d mi nistere d b y i v i nf usi o n o n treat me nt D a ys 1 a n d 8. D urati o n of t hera p y  d uri n g 
t he c he m ot hera py treat me nt peri o d is calc ulate d as f oll o ws:
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 8 /6 2
D urati o n of G e mcita bi ne ( wee ks) = (
                              )
D urati o n of A vel u ma b ( wee ks) = (
                              )
D urati o n of Cet u xi m a b ( wee ks) = (
                              )
w here t he a d d o n is 1 4 w he n t he last d ose is gi ve n o n da y 8 of t he last c ycle a n d a d d o n is 7 w he n 
t he last d ose is gi ve n o n da y 1 of t he last c ycle.
Cis plati n or Car b o plati n : D uri n g eac h 2 1 d a y  cycle, cis plati n or car b o plati n is a d mi nistere d b y 
i ntra ve n o us i nf usi o n o n D a y 1 of t he c ycle (e xcl u di n g C y cle 1 f or Car b o plati n) . D urati o n is 
calc ulate d as f oll o ws:
D urati o n of C is plati n ( wee ks) = (
                           )
D urati o n of Car b o plati n ( wee ks) = (
                           )
D urati o n of Cis plati n pl us Car b o plati n ( wee ks) = D urati o n of Cis plati n ( wee ks) + D urati o n of 
Car b o plati n ( wee ks)
Partici pa nts will be c o nsi dere d as ha vi n g recei ve d a mai nte na nce t hera p y w he n t he c he m ot hera py 
( ge mcita bi ne a n d cis plati n or car b o plati n ) has bee n defi nitel y  st o p pe d (after f o ur c ycles) a n d at 
least o ne d ose of cet u xi ma b a nd/ or a vel u ma b has bee n recei ve d after t he date of last c he m ot hera p y 
d ose.
T he d urati o n of mai nte na nce t hera p y (i n wee ks) for partici pa nts wit h a vel u ma b a n d cet u xi ma b 
mai nte na nce is defi ne d as:
d ur ati o n =                          −                        + 1 4
7
w here t he date of first d ose of mai nte na nce t hera p y is t he date of first d ose of res pecti ve dr u g after 
t he date of last d ose i n t he fi nal c he m ot hera p y c yc le.
O verall d urati o n o f t hera p y for a vel u ma b a n d cet u xi ma b is t he s u m of t he d urati o n d uri n g t he 
c he m ot hera p y a n d mai nta ne nce treat me nt peri o ds.
C u m ul ati ve d ose
Ge mcita bi ne, cis plati n, a n d cet u xi ma b: T he c u m ulati ve d ose ( m g/ m²) per partici pa nt i n a ti me 
peri o d is t he s u m of t he t otal d ose le vels t hat t he partici pa nt recei ve d wit hi n t hat peri o d (i.e., t otal 
d ose a d mi nistere d ( m g) / B S A ( m2)). F or st u d y dr u gs a d mi nistere d base d o n t he partici pa nt’s B S A, 
t he calc ulati o n will be base d o n t he B S A meas ure d at eac h rela va nt visit .  I n case t he B S A is 
missi n g , t he latest B S A a vaila ble will be use d f or calc ulati o n f oll o wi n g t he last o bser vati o n carrie d 
f or war d ( L O C F) pri nci ple. T he i n di vi d ual d ose a d mi nistere d ( m g) is ta ke n fr o m t he “ Act ual D ose” 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
2 9 /6 2
fiel d fr o m t he res pecti ve “ A d mi nistrati o n Details” e C R F pa ges at eac h d osi n g d a y . Eac h i n di vi d ual 
act ual d ose is t he n di vi de d b y  t he rela va nt B S A a n d s u m me d acr oss t he ti me peri o d of i nterest.
A vel u ma b a n d car b o plati n : T he c u m ulati ve d ose ( m g) per partici pa nt i n a ti me peri o d is t he s u m 
of t he t ot al d ose le vels t hat t he partici pa nt recei ve d wit hi n t hat peri o d . T he i n di vi d ual act ual d ose 
( m g) is ta ke n fr o m t he “Act ual D ose ” fiel d fr o m t he res pecti ve “A d mi nistrati o n Details ” e C R F 
pa ge at eac h d osi n g da y.
D ose i nte nsit y

Ge mcita bi ne
D ose i nte nsit y  ( m g/ m2/ 3-wee k c ycle) = (
                     (  / ²)
(                (       ) / ) )

Cis plati n
D ose i nte nsit y  (m g / m2/ 3-wee k c y cle) = (
                  (   / ²)
(             (       ) / ) )

Car b o plati n
D ose i nte nsit y  ( m g/ 3-wee k c y cle) = (
                     (  )
(                (       ) / ))

Cet u xi ma b d uri n g t he c he m ot hera p y peri o d
D ose i nte nsit y  (m g / m2/ 3-wee k c y cle) = (
                        (               (       ) / ))

Cet u xi ma b d uri n g mai nte na nce peri o d
D ose i nte nsi t y ( m g/ m2/ 2-wee k c y cle) = (
                    (  / ²)
(               (       ) / ) )

A vel u ma b d uri n g t he c he m ot hera p y  peri o d
D ose i nte nsit y  ( m g/3- wee k c y cle ) = (
                        (  )
(               (       )/ )
)

A vel u ma b d uri n g mai nta ne nce peri o d
D ose i nte nsit y  ( m g/ 2-wee k c y cle) = (
                       (  )
(                (       ) / )
)
Rel ati ve d ose i nte nsit y
T he relati ve d ose i nte nsit y of a vel u ma b is defi ne d as t he act ual d ose i nte nsit y di vi de d b y  the 
pla n ne d d ose as s pecifie d i n t he pr ot oc ol per c y cle a n d e x presse d i n %:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 0 /6 2

Ge mcita bi ne
Relati ve i nte nsit y  ( %) = (
                      (  ⁄
/     )
      /  
Cis plati n
Relati ve i nte nsit y  ( %) = (
                   (  ⁄
/     )
    /  )

Car b o plati n
Relati ve i nte nsit y  ( %) = (
                      (   )
   )

Cet u xi ma b d uri n g t he c he m ot hera p y peri o d
Relati ve i nte nsit y  ( %) = (
                     (  ⁄
/     )
     /  )

Cet u xi ma b d uri n g t he mai nte na nce peri o d
Relati ve i nte nsit y  ( %) = (
                     (  ⁄
/     )
     /  )

A vel u ma b d uri n g t he c he m ot hera p y peri o d
Relati ve i nte nsit y  ( %) = (
                     (  /     )
     )

A vel u ma b d uri n g t he mai nte na nce peri o d
Relati ve i nte nsit y  ( %) = (
                     (  /     )
    )
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d:
F or t he c he m ot hera p y  treat me nt peri o d

N u m ber of c y cles

T otal n u m ber of i nf usi o ns recei ve d o verall a n d by c ycle f or eac h st u d y dr u g

D urati o n of t hera p y ( wee ks) f or eac h st u d y dr u g

C u m ulati ve d ose ( m g f or avel u ma b a n d car b o plati n; m g/ m 2 f or ge mcita bi ne, cis plati n, a n d 
cet u xi ma b)

D ose i nte nsit y (m g / 3- wee k c ycle f or a vel u ma b a n d car b o plati n; m g/ m 2/ 3-wee k c ycle f or 
ge mcita bi ne, cis plati n, a n d cet u xi ma b )

Relati ve d ose i nte nsit y  of t hera py ( %) f or eac h st u d y dr u g
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 1 /6 2

Relati ve d ose i nte nsity of thera p y cate g ories: < 8 0 %, 8 0 % - < 9 0 %, 9 0 % - < 1 1 0 %, > = 
1 1 0 %.
F or t he mai nte na nce treat me nt peri o d

N u m ber a n d perce nta ge of partici pa nts wit h mai nte na nce f or eac h st u dy dr u g

N u m ber of mai nte na nce c y cles f or partici pa nts wit h mai nte na nce f or eac h st u d y dr u g

D urati o n of t hera p y ( wee ks) f or eac h st u d y dr u g

O verall d urati o n of t hera p y  ( wee ks) f or eac h st u d y dr u g

C u m ulati ve d ose ( m g f or a vel u ma b a n d m g/ m2 f or cet u xi ma b)

D ose i nte nsit y  ( m g/2- wee k c y cle f or a vel u ma b a n d m g/ m 2/2 -wee k c y cle f or cet u xi ma b)

Relati ve d ose i nte nsit y  of t hera py ( %) f or eac h st u d y dr u g
D ose re d ucti o ns 
D ose re d ucti o ns are i de ntifie d b y  the I n vesti gat or o n t he “A d mi nistrati o n Details ” e C R F pa ges f or 
Ge mcita bi ne, Cet u xi ma b, Cis plati n, a n d Car b o plati n .  T he n u m ber a n d perce nta ge of partici pa nts 
wit h at least o ne d ose re d ucti o n as rec or de d i n t he e C R F,as well as a brea k d o w n of d ose re d ucti o ns 
( 1 / 2 / 3 / ≥4), will be s u m marize d f or eac h st u d y dr u g.
I nf usi o n r ate re d ucti o ns 
F or eac h st u d y dr u g, i nf usi o n rate re d ucti o ns are i de ntifie d o n t he “A d mi nistrati o n Details” e C R F 
pa ge b y t he In vesti gat or. T he n u m ber a n d perce nta ge of partici pa nts wit h at least o ne i nf usi o n rate 
re d ucti o n as rec or de d i n t he e C R F, as well as a brea k d o w n of i nf usi o n rate re d ucti o ns ( 1 / 2 / 3 / 
≥4 ), will be s u m ma rize d f or eac h st u d y dr u g.
T her a p y D el a ys 
T hera p y d ela ys will be deri ve d f or eac h st u d y dr u g b y  inf usi o n base d o n st u d y dr u g a d mi nistrati o n 
date. Dela y s will be gr o u pe d i nt o t he f oll o wi n g cate g ories base d o n t he de viati o n t o t he pla n ne d 
treat me nt a d mi nistrati o n da y (acc or di n g t o t he pr ot oc ol -s pecifie d sc he d ule):

N o dela y  (i ncl u di n g 1-2 da y  dela ys)

3- 8 da y  dela y

9- 1 5 da y  dela y

> = 1 6 da y  dela y
All rele va nt st u d y dr u g e x p os ure data will be prese nte d i n data listi n gs, i ncl u di n g d ose re d ucti o n 
or dela y  reas o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI




M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 3 /6 2
Ta ble 1 s u m marizes t he deri vati o n r ules descri be d b y Eise n ha uer, et al ( 2 0 0 9) f or t he B O R w he n 
c o nfir mati o n fr o m s u bse q ue nt assess me nt is nee de d.
B O R B ase d o n C o nfir me d Res p o nses:

C R = at least t w o deter mi nati o ns of C R at least 4 wee ks a part ( wit h n o P D i n bet wee n)

P R = at least t w o deter mi nati o ns of P R or better ( P R f oll o we d b y  PR 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 (a p plica ble o nl y t o partici pa nt wit h meas ura ble disease at baseli ne) = at least o ne S D 
assess me nt ( or better) ≥ 6 wee ks after start date (a n d n ot q ualif y i n g f or C R or P R).

N o n -C R/ n o n -P D (a p plica ble o nl y t o partici pa nts wit h n o n -meas ura ble disease at baseli ne) 
= at least o ne n o n- C R/ n o n -P D assess me nt ( or better) ≥6 wee ks after start date  (a n d n ot 
q ualif y i n g f or C R or P R).

P D = pr o gressi o n ≤ 1 8 wee ks after start date (a n d n ot q ualif y i n g f or C R, P R or S D).

N ot E val ua ble ( N E) = all ot her cases .
S D ca n f oll o w P R o nl y  i n t he rare case t hat t he t u m or i ncreases b y less t ha n 2 0 % fr o m t he na dir, 
b ut e n o u g h t hat a pre vi o usl y  doc u me nte d 3 0 % decrease fr o m baseli ne n o l o n ger h ol ds. If t his 
occ urs, t he se q ue nce P R -S D -P R is c o nsi dere d a c o nfir me d P R. A se q ue nce of P R -S D -S D -P D 
w o ul d be a best res p o nse of S D if t he mi ni m u m d urati o n f or S D defi niti o n has bee n met.
O bjecti ve Res p o nse ( O R) is defi ne d as a c o nfir me d B O R of c o m plete res p o nse ( C R) or partial 
res p o nse ( P R) acc or di n g t o R E CIS T v 1. 1.
T a ble 1
B O R w he n c o nfir m ati o n of C R/ P R is re q uire d
O v er all r e s p o n s e 
fir st ti m e p oi nt
O v er all r e s p o n s e 
s u b s e q u e nt ti m e p oi nt a
C o nfir m e d B O R
C R
C R
C R
C R
P R
S D, if mi ni m u m crit eri a f or S D d ur ati o n m et at fir st ti m e 
p oi nt. Ot h er wi s e P D
C R
S D
S D, if mi ni m u m crit eri a f or S D d ur ati o n m et at fir st ti m e 
p oi nt. Ot h er wi s e P D.
C R
P D
S D, if mi ni m u m crit eri a f or S D d ur ati o n m et at fir st ti m e 
p oi nt. Ot h er wi s e P D.
C R
N E
S D, if mi ni m u m crit eri a f or S D d ur ati o n m et at fir st ti m e 
p oi nt. 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, if mi ni m u m crit eri a f or S D d ur ati o n m et at s u b s e q u e nt 
ti m e p oi nt. Ot h er wi s e N E
P R
P D
S D, if mi ni m u m crit eri a f or S D d ur ati o n m et at fir st ti m e 
p oi nt. Ot h er wi s e P D.
P R
N E
S D, if mi ni m u m crit eri a f or S D d ur ati o n m et at fir st ti m e 
p oi nt. Ot h er wi s e N E.
N E
N E
N E
a S u b s e q u e nt ti m e p oi nt i s n ot n e c e s s aril y t h e dir e ct s u b s e q u e nt s c a n ( e. g. P R -S D -P R will h a v e P R a s c o nfir m e d B O R).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 4 /6 2
A s wi m mer pl ot dis pla y i n g k e y  ra di ol o gical milest o nes will be pr o d uce d. F or eac h partici pa nt , t he 
ti me fr o m treat me nt start u ntil e n d of f oll o w-u p will be re prese nte d (fr o m treat me nt start t o last 
date k n o w n t o be ali ve or date of deat h). I n a d diti o n, t he f oll o wi n g i nf or mati o n will be dis pla ye d: 
ti me t o c o nfir me d B O R ( C R or P R ), ti me t o pr o gressi o n , a n d stat us at t he e n d of t he f oll o w-u p 
(ali ve or dea d).
Partici pa nts wit h a B O R of N E will be s u m marize d b y  reas o n f or ha vi n g N E stat us a n d dis pla ye d 
i n a listin g wit h rele va nt data. T he f oll o wi n g reas o ns will be use d:

N o p ost - baseli ne assess me nts

All p ost -baseli ne assess me nts ha ve o verall res p o nse N E

Ne w a nti -ca ncer t hera p y starte d bef ore first p ost-baseli ne assess me nt

S D of i ns ufficie nt d urati o n ( < 6 wee ks after start date wit h o ut f urt her e val ua ble t u m or 
assess me nt)

P D t o o late ( > 1 8 wee ks after start date)
Ti me p oi nt t u m or res p o nse a n d B O R will be prese nte d i n a listi n g.
1 4. 1. 2
Se nsiti vit y A n al ys es of C o nfir me d B O R
T he a nal ys es n ote d i n Secti o n 1 4. 1. 1 will als o be perf or me d o n certai n s u bsets of partici pa nts fr o m 
t he F A S:

E xcl u di n g t h ose w h o disc o nti n ue d cis plati n treat me nt d ue t o t o xicit y wit h o ut s witc hi n g t o 
car b o plati n .

I ncl u di n g o nl y  t h ose w h o starte d treat me nt at least 1 8 wee ks pri or t o l ocal o nset of t he C O VI D -
1 9 pa n de mic. T he date of l ocal o nset f or eac h c o u ntr y is defi ne d as t he mi ni m u m of t he first 
deat h date per c o u ntr y as re p orte d b y  the E ur o pea n Ce ntre f or Disease Pre ve nti o n a n d C o ntr ol, 
or 1 1- Mar -2 0 2 0. T he 1 8 wee ks w o ul d ha ve all o we d eac h partici pa nt t o ha ve c o m plete d t w o 
t u m or sca ns pri or t o t he l ocal o nset of t he C O VI D-1 9 pa n de mic.

I ncl u di n g o nl y t h ose w h o ha d at least t w o p ost -baseli ne t u m or assess me nts, or e x perie nce d 
pr o gressi ve disease ( P D) or deat h b y t he ti me of t he sec o n d sc he d ule d p ost -baseli ne 
assess me nt.
Eac h se nsiti vit y anal y sis will be c o m plete d o nl y  if > 5 % of partici pa nts fr o m t he F A S w o ul d be 
e xcl u de d; ot her wise, a se nsiti vit y a nalys is is n ot e x pecte d t o lea d t o differe nt c o ncl usi o ns, a n d t he
i m pact c o ul d be e xa mi ne d o n t he s u bject le vel.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 5 /6 2
1 4. 1. 3
S u b gr o u p A n al yses of C o nfir me d B O R
S u b gr o u p a nal yses will be perf or me d o n t he pri mar y  en d p oi nt f or all s u b gr o u p le vels defi ne d i n 
Secti o n 8. 2 “ S u b gr o u p defi niti o n a n d para meterizati o n” .
I n a d diti o n, t here will be a s u b gr o u p a nal ys is of t he patie nts dr o p pi n g off of cis plati n, c o m pari n g 
t h ose w h o s witc he d t o car b o plati n a n d t h ose w h o di d n ot.
All t he s u b gr o u p a nal ys es will be e x pl orat or y; n o a dj ust me nt f or m ulti plicit y will be perf or me d.  
I n t he case of a l o w n u m ber of partici pa nts wit hi n a cate g or y (< 5 % of t he p o p ulati o n ), t he 
cate g ories will be p o ole d w he n mea ni n gf ul .
Fre q ue nc y of c o nfir me d B O R , perce nta ge, a n d 9 5 % CI of c o nfir me d B O R will be esti mate d f or 
all t he s ub gr o u p a nal ys es o n B O R a n d prese nte d i n a f orest pl ot . CI s will be base d o n e xact 
Cl o p per -Pears o n met h o d. 
S u b gr o u p i nf or mati o n a n d B O R will be prese nte d i n a data listi n g.
D oc u me nt N o. 
O bject N o. 
C CI
C CI




M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 7 /6 2
A n al yses of pr o gressi o n free s ur vi v al ti me a n d d ur ati o n of res p o nse : a d diti o n al i nf or m ati o n
T a ble 2
O utc o me a n d e ve nt d ates f or P F S a n d d ur ati o n of res p o nse a n al yses
S c e n ari o
D at e of e v e nt/ c e n s ori n g
O ut c o m e
N o b a s eli n e a s s e s s m e nt
D at e of fir st d o s e
C e n s or e d a
N o p o st -b a s eli n e a s s e s s m e nt
D at e of fir st d o s e
C e n s or e d a
Pr o gr e s si o n or d e at h ≤ 1 8 w e e k s aft er l a st 
t u m or a s s e s s m e nt or ≤ 1 8 w e e k s aft er d at e of 
fir st d o s e
D at e of pr o gr e s si o n or d e at h
E v e nt
Pr o gr e s si o n or d e at h > 1 8 w e e k s aft er t h e l a st 
t u m or a s s e s s m e nt 
D at e of l a st a d e q u at e 
a s s e s s m e nt d o c u m e nti n g n o 
P D b ef or e s u b s e q u e nt a nti -
c a n c er t h er a p y i s gi v e n or 
mi s s e d a s s e s s m e nt s
C e n s or e d
N o pr o gr e s si o n
D at e of l a st a d e q u at e 
a s s e s s m e nt d o c u m e nti n g n o 
P D b ef or e s u b s e q u e nt a nti -
c a n c er t h er a p y i s gi v e n or 
mi s s e d a s s e s s m e nt s
C e n s or e d
Tr e at m e nt di s c o nti n u ati o n d u e t o ‘ Di s e a s e 
pr o gr e s si o n’ wit h o ut d o c u m e nt e d pr o gr e s si o n
N ot a p pli c a bl e
I nf or m ati o n i s i g n or e d. 
O ut c o m e i s d eri v e d b a s e d o n 
d o c u m e nt e d pr o gr e s si o n 
o nl y.
N e w a nti -c a n c er m e di c ati o n gi v e n b ef or e P D
D at e of l a st a d e q u at e 
a s s e s s m e nt d o c u m e nti n g n o 
P D b ef or e s u b s e q u e nt a nti -
c a n c er t h er a p y i s gi v e n or 
mi s s e d a s s e s s m e nt s
C e n s or e d
a H o w e v er if t h e p ati e nt di e s ≤1 8 w e e k s aft er i niti al d o s e t h e d e at h i s a n e v e nt wit h d at e of d e at h
P F S ti me = (date of P D or deat h/ce ns ori n g - date of first d ose + 1 )/ 3 0. 4 3 7 5 ( m o nt hs).
F or i m p uti n g missi n g parts of dates of deat h, t he r ules defi ne d i n Secti o n 9 will be use d. I n all 
ot her cases missi n g or i nc o m plete dates will n ot be i m p ute d. Pr o gressi o n dates are e x pecte d t o be 
re p orte d as c o m plete dates.
Ka pla n -Meier pl ots
of P F S ti me a n d listi n g of P F S will be pr o vi de d as well.
Fre q ue nc y  ( n u m ber a n d perce nta ge) of patie nts wit h eac h e ve nt t ype ( P D or deat h) a n d ce ns ori n g 
reas o ns will be prese nte d. 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 ( P D or deat h)

N o baseli ne assess me nt

N o p ost -baseli ne assess me nt

N o d oc u me nte d P D a n d deat h m o re t ha n 1 8 wee ks after last e val ua ble t u m or assess me nt

Start of ne w a nti -ca ncer t hera p y
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
3 8 /6 2
T he P F S ti me or ce ns ori n g ti me a n d t he reas o ns f or ce ns ori n g will als o be prese nte d i n a listi n g.
D O R = (date of P D or deat h/ce ns ori n g – date of first d oc u me nte d o bject i ve res p o nse + 1)/ 3 0. 4 3 7 5 
( m o nt hs).
A listi n g wit h perti ne nt D O R i nf or mati o n will be pr o vi de d.
A n al yses of o ver all s ur vi v al ti me: a d diti o n al i nf or m ati o n
T a ble 3
D ate of e ve nt / ce ns ori n g defi niti o n f or O S a n al ysis
S ur vi v al St at u s
S o ur c e
C e n s ori n g
D at e of e v e nt/ c e n s ori n g
Di e d
B ef or e c ut -off
D e at h e C R F
E v e nt
D at e of d e at h
Aft er c ut -off
D e at h e C R F
C e n s or e d
D at e of c ut -off
Ali v e 
( n o d at e of d e at h)
Ali v e aft er c ut -off
F oll o w -u p e C R F
C e n s or e d
D at e of c ut -off
Ot h er wi s e
A n y d o c u m e nt e d 
a s s e s s m e nt or d at a 
c oll e ct e d fr o m a n a ct u al 
e x a mi n ati o n ( d et ail s b el o w)
C e n s or e d
L a st d at e k n o w n t o b e ali v e
T he date last k n o w n t o be ali ve will be deri ve d f or partici pa nt s n ot k n o w n t o ha ve die d at t he 
a nal ys is c ut- off usi n g t he latest c o m plete date a m o n g t he f oll o wi n g:

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, perf or ma nce stat us, 
E C G, t u m or assess me nts , q ualit y of life assess me nts)

Start 
a n d e n d dates of a nti-ca ncer t hera pies a d mi nistere d after st u d y inter ve nti o n 
disc o nti n uati o n

A E start a n d e n d dates

Last k n o w n ali ve date c ollecte d o n t he “S ur vi val i nf or mati o n ” e C R F pa ge

St u d y  i nter ve nti o n start a n d e n d dates w here d ose is > 0

Date of disc o nti n uati o n o n dis p ositi o n e C R F pa ges ( 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 ow - u p)
O nl y  dates ass ociate d wit h act ual e xa 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 ocesse d will n ot be use d. A ssess me nt dates after t he c ut-off
date will n ot be a p plie d t o deri ve t he last k n o w ali ve date.
T he Ka pla n -Meier ( K M) pl ots of O S ti me a n d listi n g of O S will be pr o vi de d as well.
Fre q ue nc y  (n u m ber a n d perce nta ge) of patie nts wit h a n e ve nt ( deat h) a n d ce ns ori n g reas o ns will 
be prese nte d. Ce ns ori n g reas o ns are as f oll o ws:

Ali ve

Wit h dra wal of c o nse nt

L ost t o f oll o w - u p
D oc u me nt N o. 
O bject N o. 
C CI
C CI




M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 0 /6 2
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 1 /6 2
1 5
S afet y A n al yses
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or s u m marizi n g safet y en 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 verse e ve nts, la b orat or y tests, a n d vital si g ns.
A n alysis set: S A F
1 5. 1
A d verse E ve nts
Defi niti o ns
Tre at me nt -e mer ge nt a d verse e ve nts ( T E A Es): t h ose e ve nts wit h o nset dates occ urri n g wit hi n 
t he o n- treat me nt peri o d as defi ne d i n  Secti o n 9 .
All a nal y ses descri be d i n Secti o n 15 . 1 will be base d o n T E A Es if n ot ot her wise s pecifie d.
T he listi n g f or all A Es ( w het her treat me nt-e mer ge nt or n ot) will i ncl u de all t he data fiel ds as 
c ollecte d o n t he “ A d verse E ve nts Details” e C R F pa ge. A se parate listi n g will als o be pr o vi de d f or 
A Es t hat starte d after t he o n- treat me nt peri o d , as well as a listi n g of A Es attri b ute d t o t he i m pact 
of C O VI D - 1 9.
Missi n g d at a h a n dli n g
I nc o m plete A E -relate d dates will be ha n dle d as f oll o ws:

I n case t he o nset date is missi n g c o m pletely or missi n g partiall y  b ut t he o nset m o nt h a n d ye ar, 
or t he o nset year are e q ual t o t he start of st u d y i nter ve nti o n t he n t he o nset date will be re place d 
b y  t he mi ni m u m of start of st u d y treat me nt a n d A E res ol uti o n date.

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 nc o m plete st o p dates will be re place d b y t he last da y  of t he m o nt h (if da y is missi n g o nl y), if 
n ot res ulti n g i n a date later t ha n t he date of partici pa nt’s dea t h. I n the later case, t he date of 
deat h will be use d t o i m p ute t he i nc o m plete st o p date.

I n all ot her cases , t he i nc o m plete st o p date will n ot be i m p ute d. If st o p date of A E is after date 
of c ut -off , o utc o me of A E is o n g oi n g at c ut-off.

F urt her i nf or mati o n after c ut -off (li ke fatal o utc o me) mi g ht be ta ke n fr o m Safety data base a n d 
i ncl u de d se parately i nt o t he C S R.
T he f oll o wi n g cate g ories of T E A Es are defi ne d f or re p orti n g:
Rel ate d A d verse E ve nts: a d verse e ve nts wit h relati o ns hi p t o st u d y treat me nt (as rec or de d o n 
t he A E e C R F pa ge : Relati o ns hi p wit h A vel u ma b, Cet u xi ma b, Cis plati n, Car b o plati n, or 
Ge mcita bi ne = Relate d) re p orte d b y  the In vesti gat or a n d t h ose of u n k n o w n relati o ns hi p (i.e.,
n o a ns wer t o t he q uesti o n “ Relati o ns hi p wit h st u d y treat me nt”). U nless s pecifie d per 
treat me nt, A Es relate d t o st u d y treat me nt will be defi ne d as a n y A E c o nsi dere d relate d t o 
a n y st u d y treat me nt.
Seri o us A d verse E ve nts ( S A Es): seri o us a d verse e ve nts (as rec or de d o n t he A E e C R F pa ge, 
Seri o us A d verse E ve nt = Yes).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 2 /6 2
A d ver se E ve nts Le a di n g t o Tre at me nt Disc o nti n u ati o n: 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 treat me nt (as rec or de d o n t he A E e C R F pa ge, Acti o n ta ke n wit h 
A vel u ma b, Cet u xi ma b, Cis plati n, Car b o plati n, or Ge mcita bi ne = Dr u g wit h dra w n).
A d vers e E ve nts Le a di n g t o De at h: a d verse e ve nt lea di n g t o deat h (as rec or de d o n t he A E 
e C R F pa ge, O utc o me = Fatal , as well as A Es of Gra de 5).
I m m u ne Rel ate d A d verse E ve nts (ir A Es): ir A Es are i de ntifie d base d o n a list of Me d D R A 
P Ts a n d ot her criteria as s pecifie d i n Ta ble 6 of  A p pe n di x I .
I nf usi o n R el ate d R e acti o n s (I R Rs): I RRs are i de ntifie d base d o n a list of Me d D R A P Ts. T he
detaile d criteria of t he ti mi n g relati o ns hi p t o i nf usi o n are s pecifie d i n Ta ble 6 of  A p pe n di x 
I.
U nless ot her wise s pecifie d, A Es will be dis pla y e d i n ter ms of fre q ue nc y ta bles i n al p ha betical 
or der b y pri mar y  S O C a n d P T. If a n A E is re p orte d f or a gi ve n partici pa nt m ore t ha n o nce d uri n g 
treat me nt, 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 treat me nt will be ta b ulate d.
Eac h partici pa nt will be c o u nte d o nl y o nce wit hi n eac h S O C or P T . If a partici pa nt e x perie nces 
m ore t ha n o ne A E wit hi n a n S O C or P T f or t he sa me s u m mar y peri o d, o nl y  the A E wit h t he 
str o n gest relati o ns hi p or t he w orst se verity, as a p pr o priate, will be i ncl u de d i n t he s u m maries of 
relati o ns hi p a n d se verit y.
1 5. 1. 1
All A d verse E ve nts
A E s will be s u m marize d b y w orst se verit y (acc or di n g t o t he N ati o nal Ca ncer Instit 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 ) per partici pa nt , usi n g 
Me d D R A P T as e ve nt cate g or y a n d Me d D R A pri mar y S O C as b o d y  sys te m cate g or y. 
I n case a partici pa nt has e ve nts wit h missi n g a n d n o n- mis si 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 y e d. N o i m p utati o n of missi n g gra des will be perf or me d.
T he f oll o wi n g o verall fre q ue nc y  ta bles will be pre pare d. 

A n y  T E A E 

A n y  st u d y treat me nt relate d T E A Es *

A n y  seri o us T E A Es 

A n y  st u d y treat me nt relate d seri o us T E A Es *

A n y  T E A E b y N C I-C T C A E se verit y G ra de 3

A n y  st u d y treat me nt relate d T EA E b y N C I-C T C A E se verit y G ra de 3 *

T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n

Relate d T E A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n *

A n y  T E A Es lea di n g t o deat h (T E A Es
wit h Gra de 5 or o utc o me “fatal” if G ra de 5 n ot 
a p plica ble) 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 3 /6 2

A n y  st u d y treat me nt relate d T E A Es lea di n g t o deat h (T E A Es wit h Gra de 5 or o utc o me 
“fatal” if G ra de 5 n ot a p plica ble) *

Treat me nt -e mer ge nt ir A Es

Relate d treat me nt -e mer ge nt ir A Es*

Treat me nt -e mer ge nt I RRs

Relate d treat me nt -e mer ge nt IR Rs *
I n a d diti o n t he ta bles will be pr o vi de d by P T a n d pri mar y  S O C i n al p ha betical or der:

T E A Es b y  S O C a n d P T a n d w orst gra de

Relate d T E A Es b y S O C a n d P T a n d w orst gra de

T E A Es lea di n g t o deat h b y S O C a n d P T

Relate d T E A Es lea di n g t o deat h b y S O C a n d P T

T E A Es b y S O C a n d P T: dis pla yi n g i n se parate c ol u m ns t he All T E A Es / Relate d T E A Es /
Gra de ≥3 T E A Es / Relate d Gra de ≥3 T E A Es
Cate g ories a n n otate d b y  * will be f urt her s u mmarize d f or eac h st u d y dr u g (i.e., avel u ma b, 
cet u xi ma b, cis plati n, car b o plati n , a n d g e mcita bi ne) as part of t he o ver vie w fre q ue nc y ta ble.
Cli nic al tri al. g o v a n d E u dr a C T -re q uire me nts
S u m mar y  ta bles f or n o n- seri o us a d verse e ve nts e xcl u di n g S A Es a p pl yi n g fre q ue nc y thres h ol d of 
5 % will be pr o vi de d. T he n o n -seri o us A Es are n ot restricte d t o n o n-seri o us T E A Es.
1 5. 1. 2
A d verse E ve nts Le a di n g t o Tre at me nt Disc o nti n u ati o n
T he f oll o wi n g o verall fre q ue nc y  ta bles will be pr o vi de d .
Dr u g I nterr u pte d

A n y  T E A Es lea di n g t o dr u g i nterr u pti o n *

A n y  st u d y treat me nt relate d T E A Es lea di n g t o dr u g i nterr u pti o n *
Per m a ne nt disc o nti n u ati o n

A n y  T E A Es lea di n g t o per ma ne nt disc o nti n uati o n*

A n y  st u d y treat me nt relate d T E A Es lea di n g t o per ma ne nt disc o nti n uati o n*

A vel u ma b relate d T E A Es lea di n g t o st u d y dr u g disc o nti n u ati o n

ir A Es lea di n g t o per ma ne nt A vel u ma b disc o nti n uati o n

I R Rs lea di n g t o per ma ne nt A vel u ma b disc o nti n uati o n

I R Rs lea di n g t o per ma ne nt Cet u xi ma b disc o nti n uati o n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 4 /6 2
T he f oll o wi n g s u m maries b y  S O C a n d P T will be pr o d uce d:

T E A Es lea di n g t o p er ma ne nt treat me nt d isc o nti n uati o n*

Treat me nt relate d A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n*
Cate g ories a n n otate d b y  * will be f urt her s u m marize d f or eac h st u d y dr u g (i.e., avel u ma b, 
cet u xi ma b, cis plati n, car b o plati n a n d g e mcita bi ne ).
T he listi n g of A Es lea di n g t o dr u g i nterr u pti o n or treat me nt disc o nti n uati o n will als o be pr o vi de d 
wit h t he rele va nt i nf or mati o n.
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
Deat h s u m marizati o n will be ta b ulate d base d o n i nf or mati o n fr o m t he “ E n d of Assess me nt Visit”, 
eac h st u d y dr u g “ Ter mi nati o n”, “S u bject Stat us / S ur vi val F oll o w -U p” , “ St u d y Ter mi nati o n”, a n d 
“ Deat h” eC R F pa ges . 

N u m ber a n d perce nta ge of partici pa nts w h o die d 

Pri mar y  reas o n f or deat h 
o
Disease pr o gressi o n 
o
A d ver se e ve nt relate d t o st u d y treat me nt 
o
A d verse e ve nt n ot relate d t o st u d y  treat me nt 
o
C o vi d 1 9
o
Ot her 
o
U n k n o w n 

N u m ber a n d perce nta ge of partici pa nts w h o die d wit hi n 3 0 da y s of t he last st u d y treat me nt 
a d mi nistrati o n 

Pri mar y  reas o n f or deat h 
o
Disease pr o gressi o n 
o
A d verse e ve nt relate d t o st u d y  treat me nt 
o
A d verse e ve nt n ot relate d t o st u d y  treat me nt 
o
C o vi d 1 9
o
Ot her 
o
U n k n o w n 

N u m ber a n d perce nta ge of partici pa nts w h o die d wit hi n 6 0 da y s of t he first st u d y treat me nt 
a d mi nistrati o n 
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 5 /6 2

Pri mar y  reas o n f or deat h
o
Disease pr o gressi o n 
o
A d verse e ve nt relate d t o st u d y  treat me nt 
o
A d verse e ve nt n ot relate d t o st u d y  treat me nt 
o
C O VI D - 1 9
o
Ot her 
o
U n k n o w n 
I n a d diti o n, date a n d ca use of deat h will be pr o vi de d i n i n di vi d ual s u bject data listi n g t o get her wit h 
selecte d d osi n g i nf or mati o n a n d will i ncl u de t he f oll o wi n g i nf or mati o n:

A Es wit h fatal o utc o me (list preferre d ter ms of A Es wit h o utc o me = Fatal , as well as A Es of 
Gra de 5 ), 

F la g f or deat h wit hi n 3 0 da ys of last st u d y treat me nt 

Fla g f or deat h wit hi n 6 0 da y s of first st u d y treat me nt
1 5. 2. 2
Seri o us A d verse E ve nts
Please refer t o  Secti o n 1 5. 1. 1 f or seri o us a d verse e ve nt ( S A E) relate d o ut p uts. T he fre q ue nc y  
( n u m ber a n d perce nta ge) of s u bjects wit h eac h of t he f oll o wi n g will be prese nte d f or treat me nt-
e mer ge nt S A Es :

S A Es b y  S O C a n d P T

Relate d S A Es b y  S O C a n d P T
T he listi n gs of S A Es will als o be pr o vi de d wit h rele va nt i nf or mati o n s uc h as A E S O C/ P T, 
start/st o p date, t o xicit y gra de, relati o ns hi p t o eac h st u d y dr u g, acti o n ta ke n wit h eac h st u d y dr u g , 
a n d o utc o me.
1 5. 2. 3
Ot her Si g nific a nt A d verse E ve nt s
1 5. 2. 3. 1 I nf usi o n Rel ate d Re acti o n
T he fre q ue nc y (n u m ber a n d perce nta ge) of partici pa nts wit h eac h of t he f oll o wi n g will be 
prese nte d f or treat me nt e mer ge nt I R Rs:

I R Rs lea di n g t o deat h, b y P T

Relate d I R Rs lea di n g t o deat h, b y  P T

I R Rs, by P T

I R Rs, Gra de ≥ 3 , b y P T

Relate d I R Rs, b y  P T

R elate d I RRs, G ra de ≥ 3 , b y P T
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 6 /6 2

I R Rs lea di n g t o per ma ne nt treat me nt disc o nti n uati o n, b y P T 

Relate d I R R s lea di n g t o per ma ne nt treat me nt disc o nti n uati o n, b y P T 

Seri o us I RRs, b y  P T

Relate d seri o us I R Rs, b y  P T

Ti me relate d t o first o nset of a n I R R (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 listi n g of all I R Rs will als o be pr o vi de d wit h t he rele va nt i nf or mati o n. 
T he listi n g of all I RRs will als o be pr o vi de d wit h t he rele va nt i nf or mati o n wit h a fla g f or I R Rs 
wit h o nset o utsi de of t he o n -treat me nt peri o d.
1 5. 2. 3. 2 I m m u ne Rel ate d A d verse E ve nt
T he f oll o wi n g ta bles will be create d f or treat me nt-e mer ge nt ir A Es, as i de ntifie d b y  the I n vesti gat or 
o n t he A E e C R F pa ge .

T he fre q ue nc y (n u m ber a n d perce nta ge) of s u bjects wit h eac h of t he f oll o wi n g will be 
prese nte d f or treat me nt e mer ge nt ir A Es :
-
All ir A Es
-
Seri o us ir A E s
-
ir A Es, gra de ≥ 3
-
ir A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati o n*
-
ir A Es lea di n g t o deat h

ir A Es lea di n g t o deat h, b y S O C a n d P T

ir A Es b y S O C a n d P T

ir A Es, gra de ≥ 3, b y  S O C a n d P T

ir A Es lea di n g t o per ma ne nt disc o nti n uati o n of a n y  st u d y treat me nt b y  S O C a n d P T

ir A Es b y S O C , P T , a n d w orst gra de
Cate g ories a n n otate d b y  * will be f urt her s u mmarize d f or eac h st u d y dr u g (i.e., a vel u ma b, 
cet u xi ma b, cis plati n, car b o plati n, a n d ge mcita bi ne) as part of t he o ver vie w fre q ue nc y  ta ble.
T he listi n g of all ir A Es will als o be pr o vi de d wit h all rele va nt i nf or mati o n i ncl u di n g a fla g f or 
ir A Es wit h o nset o ut si de of t he o n- treat me nt peri o d . T he f oll o wi n g i nf or mati o n will be pr o vi de d 
f or eac h ir A E:

T he ti me fr o m first treat me nt of a vel u ma b t o start of irA E

T he ti me fr o m m ost rece nt treat me nt of a vel u ma b u ntil start of irA E

T he d urati o n of t he irA E
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 7 /6 2
1 5. 3
Cli nic al L a b o r at or y E v al u ati o n
A n alysis set : S A F
1 5. 3. 1
He m at ol o g y a n d C he mistr y P ar a meters
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 as pr o vi de d b y t he 
ce ntral or l ocal la b orat or y. Ad 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: bel o w n or mal li mits, wit hi n n or mal li mits a n d a b o ve n or mal 
li mits (acc or di n g t o t he la b orat or y nor mal ra n ges). Please see A p pe n di x II f or a list of t he C T C A E -
gra da ble para meters.
T he w orst o n- treat me nt gra de will be s u m marize d c o nsi deri n g o nl y partici pa nt s wit h p ost baseli ne 
la b orat or y sa m ples: La b orat or y tests b y N CI-C T C A E gra de ( 0, 1, 2, 3, 4, a n y ).
Q ua ntitati ve data will be e xa mi ne d f or tre n ds usi n g descri pti ve statistic s (mea n, S D, me dia n , Q 1, 
Q 3, mi ni m u m, a n d ma xi m u m) of act ual val ues a n d c ha n ges fr o m baseli ne t o eac h visit o ver ti me. 
T he c ha n ges c o m p ute d will be t he differe nces fr o m baseli ne. E n d of Treat me nt visit will be 
s u m marize d se parately. Q ualitati ve data base d o n refere nce ra n ges will be descri be d acc or di n g t o 
t he cate g ories (i.e. L o w, N or mal, a n d Hi g h ). T he n u m ber of partici pa nt s wit h cli nical la b orat or y 
val ues bel o w, wit hi n, or a b o ve n or mal ra n ges at baseli ne c o m pare d t o e n d p oi nt will be ta b ulate d 
f or eac h test. S hift ta bles of baseli ne vers us t he w orst val ue at a n y p ost -baseli ne visit will b e 
prese nte d. 
A b n or malities classifie d acc or di n g t o N CI -C T C A E t o xicit y  gra di n g versi o n 5. 0 will be descri be d 
usi n g t he w orst gra de. F or t h ose para meters w hic h are gra de d wit h t w o t o xicities s uc h as p otassi u m 
( hy p o kale mia/ h y per kale mia ), t he t o xicities will be s u m marize d se parately.  Lo w directi o n t o xicit y  
(e. g., h y p o kale mia) 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  (e. g., hy per kale mia), a n d vice versa.  
F or W B C 
differe nti al c o u nts (t otal ne utr o p hil [i ncl u di n g ba n ds], l ym p h oc y te, m o n oc y te, 
e osi n o p hil, a n d bas o p hil c o u nts), t he a bs ol ute val ue will be use d w he n re p orte d.  Whe n o nl y 
perce nta ges are a vaila ble (t his is mai nl y  im p orta nt f or ne utr o p hils a n d l ym p h oc y tes, beca use t he 
C T C A E gra di n g is base d o n t he a bs ol ute c o u nts) , t he a bs ol ute val ue is deri ve d as f oll o ws: 
Deri ve d differe ntial a bs ol ute c o u nt = ( W B C c o u nt) * ( Differe ntial % val ue / 1 0 0)
If t he ra n ge f or t he differe ntial a bs ol ute c o u nt is n ot a vaila ble ( o nly ra n ge f or val ue i n % is 
a vaila ble) t he n Gra de 1 will be attri b ute d t o as f oll o ws: 

L y m p h oc y te c o u nt decrease d:  
o
deri ve d a bs ol ute c o u nt d oes n ot me et Gra de 2 -4 criteria, a n d
o
% val ue < % L L N val ue, a n d
o
deri ve d a bs ol ute c o u nt  ≥ 8 0 0/ m m 3
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 8 /6 2

Ne utr o p hil c o u nt decrease d 
o
deri ve d a bs ol ute c o u nt d oes n ot meet Gra de 2 -4 criteria, a n d
o
% val ue < % L L N val ue, a n d
o
deri ve d a bs ol ute c o u nt  ≥ 1 5 0 0/ m m 3
F or c alci u m, C T C AE gra di n g is base d o n C orrecte d C alci u m a n d Io nize 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 C alci u m as f oll o ws
C orrecte d calci u m ( m m ol/ L) = meas ure d t otal Calci u m ( m m ol/ L) + 0. 0 2 ( 4 0 - ser u m 
al b u mi n [ g/ L])
N CI -C T C A E gra des a vaila ble:

N u m ber a n d perce nta ge of partici pa nt s wit h a n y, N C I-C T C gra de 0, 1, 2, 3, 4, 3 or 4 la b orat or y 
a b n or malities d uri n g t he o n -treat me nt peri o d – ( w orst case)

S hifts i n t o xicit y  gra di n g baseli ne t o w orst o n- treat me nt C T C A E gra de
N CI -C T C A E gra des n ot a vaila ble:

N u m ber of partici pa nt s wit h s hifts baseli ne n or mal t o at least o ne res ult a b o ve n or mal o n-
treat me nt

N u m ber of partici pa nt s wit h s hifts baseli ne n or mal t o at least o ne res ult bel o w n or mal o n-
treat me nt
La b orat or y  val ues t hat are o utsi de t he n or mal ra n ge will als o be fla g ge d i n t he data listi n gs, al o n g 
wit h c orres p o n di n g n or mal ra n ges. 
Baseli ne ( Wee k 0) is t he last meas ure me nt pri or t o t he first d ose of a n y st u d y i nter ve nti o n.
Partici pa nts wit h o ut p ost -baseli ne la b orat or y sa m ples will b e e xcl u de d fr o m a nal ys es wit h res pect 
t o val ues after baseli ne.
S u m mar y  of li ver f u ncti o n test will i ncl u de t he f oll o wi n g cate g ories. T he n u m ber a n d perce nta ge 
of partici pa nts wit h eac h of t he f oll o wi n g d uri n g t he o n -treat me nt peri o d will be s u m marize d:
A L T: ≥3 × U L N / ≥5 × U L N / ≥1 0 × U L N / ≥2 0 × U L N.
A S T: ≥3 × U L N / ≥5 × U L N / ≥1 0 × U L N / ≥2 0 × U L N.
( AL T or A S T) : ≥3 × U L N / ≥5 × U L N / ≥1 0 × U L N / ≥2 0 × U L N.
T otal bilir u bi n: ≥2 × U L N.
A L T ≥3 × U L N c o nc urre ntl y wit h t otal bilir u bi n ≥2 × U L N.
A S T ≥3 × U L N c o nc urre ntl y wit h t otal bilir u bi n ≥2 × U L N.
( A L T or A S T) ≥3 × U L N c o nc urre ntl y wit h t otal bilir u bi n ≥2 × U L N.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
4 9 /6 2
( A L T or A S T) ≥3 × U L N c o nc urre ntl y wit h t otal bilir u bi n ≥2 × U L N a n d A L P > 2 × U L N.
( A L T or A S T) ≥3 × U L N c o nc urre ntl y wit h 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 ories 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 n e val uati o n of Dr u g -I n d uce d Seri o us He pat ot o xicit y  (e D I SH) pl ot will als o be create d, b y 
gra p hicall y dis pla y i n g
pea k ser u m A L T(/ U L N) vs pea k t otal bilir u bi n (/ U LN) i ncl u di n g refere nce li nes at A L T 
> 3 × U L N a n d t otal bilir u bi n > 2 × U L N ;
pea k ser u m A S T(/ U L N) vs pea k t otal bilir u bi n (/ U LN)
i ncl u di n g refere nce li nes at A S T 
> 3 × U L N a n d t otal bilir u bi n > 2 × U L N . 
I n ad diti o n, a listi n g of all T BI LI, A L T, A S T a n d A L P val ues f or patie nts wit h a p ost -baseli ne 
T BI LI ≥ 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.
1 5. 3. 2
Ot her L a b or at or y P ar a meters
All ot her para meters c ollecte d o n t he e C R F will be liste d i n de dicate d listi n gs prese nti n g all 
c orres p o n di n g c ollecte d data- fiel ds o n t he e C R F. 

C oa g ulati o n: a P T T, pr ot hr o m bi n ti me I NR

Uri nal y sis: all uri nalys is para meters

Ot her para meters: s uc h as i m m u n ol o g y, s ol u ble fact or

Pre g na nc y  test

Ser ol o g y

H or m o nes: free t h yr o xi ne a n d t h yr oi d -sti m ulati n g h or m o ne
1 5. 4
Vit al Si g ns
A n alysis set : S A F
Vital si g n s u m maries will i ncl u de all vital si g n assess me nts fr o m t he o n- treat me nt peri o d. All vital 
si g n assess me nts will be liste d, a n d t h ose c ollecte d o utsi de t he o n-treat me nt peri o d will be fla g ge d 
i n t he listi n g. 
All vital si g n para meters will be s u m marize d usi n g descri pti ve statistics ( mea n, S D, me dia n, Q 1, 
Q 3, mi ni m u m, a n d ma xi m u m) of act ual val ues a n d c ha n ges fr o m baseli ne f or eac h visit o ver ti me. 
E n d of treat me nt visit will be s u m marize d se parately. T he c ha n ges c o m p ute d will be t he 
differe nces fr o m baseli ne.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 0 /6 2
T he ma xi m u m c ha n ges of vital si g n meas ure me nts fr o m scree ni n g/ baseli ne t o o n- treatme nt val ues
will be gr o u pe d as f oll o ws:
T a ble 4
Vit al Si g n M a xi m u m C h a n ge C ate g ories
B o d y t e m p er at ur e i n cr e a s e
< 1 C , 1 -< 2 C , 2 -< 3 C, 3 C
W ei g ht i n cr e a s e
< 1 0 %, 1 0 %
W ei g ht d e cr e a s e
< 1 0 %, 1 0 %
H e art r at e i n cr e a s e fr o m b a s eli n e 
< 1 0 0 b p m ; ≥ 1 0 0 b p m
2 0 b p m, > 2 0 – 4 0 b p m, > 4 0 b p m
H e art r at e d e cr e a s e fr o m b a s eli n e 
< 1 0 0 b p m ; ≥ 1 0 0 b p m
2 0 b p m, > 2 0 – 4 0 b p m, > 4 0 b p m
S B P i n cr e a s e fr o m b a s eli n e 
< 1 4 0 m m H g; ≥ 1 4 0 m m H g 
2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g
S B P d e cr e a s e fr o m b a s eli n e 
< 1 4 0 m m H g; ≥ 1 4 0 m m H g,
2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g
D B P i n cr e a s e fr o m b a s eli n e 
< 9 0 m m H g; ≥ 9 0 m m H g 
2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g
D B P d e cr e a s e fr o m b a s eli n e 
< 9 0 m m H g; ≥ 9 0 m m H g,
2 0 m m H g, > 2 0 – 4 0 m m H g, > 4 0 m m H g
R e s pir ati o n r at e i n cr e a s e fr o m b a s eli n e < 2 0 
b p m ; ≥ 2 0 b p m
5 b p m, > 5 – 1 0 b p m, > 1 0 b p m
R e s pir ati o n r at e d e cr e a s e fr o m b a s eli n e < 2 0 
b p m ; ≥ 2 0 b p m
5 b p m, > 5 – 1 0 b p m, > 1 0 b p m
b p m = b e at s p er mi n ut e f or h e art r at e a n d br e at h s p er mi n ut e f or r e s pir ati o n r at e; D B P = di a st oli c bl o o d 
pr e s s u r e; S B P = s y st oli c bl o o d pr e s s ur e.
T he f oll o wi n g s u m maries will be pre pare d f or vital si g n para meters as gr o u pe d a b o ve c o nsi deri n g 
o nl y  partici pa nt s wit h p ost baseli ne val ues:

Ma xi mal S hifts (c ha n ges i n cate g ories)
fr o m baseli ne

Listi n g of hi g hest c ha n ge per partici pa nt
A n a d diti o nal partici pa nt data listi n g will prese nt all c ha n ges fr o m baseli ne re p orte d i n t he hi g hest 
cate g ories.
1 5. 5
Ot her S afet y or T oler a bilit y E v al u ati o ns
1 5. 5. 1
E C G
T he 1 2 -lea d Electr ocar di o gra m ( E C G) assess me nt will be perf or me d d uri n g scree ni n g ( baseli ne) 
a n d at t he Disc o nti n uati o n / E n d - of-Treat me nt visit . F or eac h of t he E C G para meters, descri pti ve 
statistics at baseli ne a n d at t he Disc o nti n uati o n / E n d - of-Treat me nt visit a n d c ha n ges fr o m baseli ne 
will be prese nte d. 
T he i nci de nce a n d perce nta ge of partici pa nts wit h t he w orst p ote ntiall y  cli nicall y si gnifica nt 
a b n or malities ( P C S A) f or E C G para meters will be s u m marize d d uri n g t he o n- treat me nt peri o d. 
Eac h partici pa nt will be c o u nte d o nl y o nce wit hi n eac h cate g or y. As E C G assess me nts are o nl y  
perf or me d d uri n g scree ni n g a n d at t he Disc o nti n uati o n/ E n d - of-Treat me nt visit, t he de n o mi nat or 
D oc u me nt N o. 
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 1 /6 2
t o calc ulate perce nta ges f or eac h P C S A cate g or y is t he n u m ber of part ici pa nts wit h
a 
Disc o nti n uati o n/ E n d of Treat me nt visit. T he P C S A criteria are pr o vi de d i n  Ta ble 5 bel o w.
T a ble 5 
P ote nti all y Cli nic all y Si g nific a nt A b n or m alities criteri a f or E C G
Test
P ote nti all y Cli nic all y Si g nific a nt A b n or m alities ( P C S A) Criteri a
Heart Rate
≤ 5 0 b p m a n d decrease fr o m baseli ne ≥ 2 0 b p m
≥ 1 2 0 b p m a n d i ncrease fr o m baseli ne ≥ 2 0 b p m
P R  I nter val
≥ 2 2 0 ms a n d i ncrease fr o m baseli ne ≥ 2 0 ms
Q R S
≥ 1 2 0 ms
Q T I nter val
I nter val > 4 5 0 m s a n d i nter val ≤ 4 8 0 ms
I nter val > 4 8 0 m s a n d i nter val ≤ 5 0 0 ms
I nter val > 5 0 0 ms
Q T I nter val
I ncrease fr o m baseli ne > 3 0 ms a n d ≤ 6 0 ms
I ncrease fr o m baseli ne > 6 0 ms
A listi n g of a b n or mal 1 2- lea d E C Gs will be pr o vi de d wit h all rele va nt i nf or mati o n a n d deri ve d 
varia bles.
U nsc he d ule d E C G meas ure me nts will n ot be use d i n c o m p uti n g t he descri pti ve statistics f or 
c ha n ge fr o m baseli ne. H o we ver, t he y will be use d i n t he a nal ys is of n ota ble E C G c ha n ges.
1 5. 5. 2
E C O G Perf or m a nce St at us
T he E C O G shift fr o m baseli ne t o hi g hest sc ore d uri n g t he o n -treat me nt peri o d will be s u m marize d. 
E C O G perf or ma nce stat us wit h s hift fr o m E C O G = 0 or 1 t o E C O G = 2 or hi g her will als o be 
prese nte d i n a data listi n g wit h s u bject i de ntifier a n d ot her rele va nt i nf or mati o n.
1 6
A n al yses of Ot her E n d p oi nts
1 6. 1
P h ar m ac o k i netics
T he a nal ys es descri be d i n t his secti o n will be perf or me d b y  the Cli nical P K/ P D Gr o u p, 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 ( C R O ) selecte d 
b y  t he S p o ns or.
A nal y sis will be pr o vi de d f or t he S A F a n d P K A S, res pectivel y. 
1 6. 1. 1
Missi n g/ n o n -q u a ntifi a ble P K 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 wer li mit of q ua ntificati o n ( B L Q) are set t o zer o f or 
calc ulati n g para meters a n d descri pti ve statistics.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 2 /6 2
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 ntrati 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 defi ne d i n t he 
cli nical st u d y pr ot oc ol a n d/ or Secti o n 1 0 . 2), d oc 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 pr o t oc ol de viati o n l o g, bi oa nal y tical data, a n d/ or bi oa nal y tical re p ort) m a y  b e 
e xcl 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 statistical a nal ys is. I n t his case 
t he rati o nale f or e xcl usi o n m ust 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/ P D Data A nal ys t m ust n ot be e xcl u de d fr o m t he 
a nal ys is. 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 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 meter ( d ue f or e xam ple t o a 
de viati o n fr o m t he assi g ne d d ose le vel), t his partici pa nt/ val ue will be e xcl u de 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 ys is set will be ma de bef ore d ata base 
l oc k i n t he Data base Re vie w Meeti n g ( D R M).
1 6. 1. 2
Descri pti ve P K A n al ysis
Prese nt ati o n of P K C o nce ntr ati o n D at a
Listi n gs
I n di vi d ual P K sa m ple ti mes, ti me de viati o ns, a n d c o nce ntrati o n data will be liste d b y  partici pa nt, 
st u d y da y, a n d n o mi nal ti me. C o nce n trati o n listi n gs will be base d o n t he S A F. P har mac o ki netic 
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 pr o vi de d b y  the 
bi oa nal y tical la b orat or y. 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 oses i n listi n gs.
T a bles
P har mac o ki netic c o nce ntrati o n data will be prese nte d f or b ot h c o m p o u n ds ( A vel u ma b a n d 
Cet u xi ma b) i n ta bles a n d descri pti vely s u m marize d f or t he P K A S , b y  st u d y d a y  a n d n o mi nal ti me 
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 de viati o n 
(St d D e v), c oefficie nt of variati o n ( C V %), mi ni m u m (Mi n ), me dia n (Me dia n ), a n d ma xi m u m 
(Ma x ). 
S u m maries of pre -d ose a n d e n d - of-i nf usi o n c o nce ntrati o ns ot her t ha n first d osi n g i nter val will be 
c o vere d b y t he para meter s u m maries o nl y.
Descri pti ve statistics of P K c o nce ntrati o n data will be calc ulate d usi n g val ues wit h t he sa me 
precisi o n as t he s o urce data pr o vi de d b y  the bi oa nal y tical la b orat or y an d r o u n de d f or re p orti n g 
p ur p oses o nl y . T he f oll o wi n g c o n ve nti o ns will be a p plie d w he n re p orti n g descri pti ve statistics of 
P K c o nce ntrati o n data:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 3 /6 2
Mea n, Mi n, Me dia n, Ma x: 
3 si g nifica nt di gits
St d D e v:
4 si g nifica nt di gits
C V %:
1 deci mal place 
Fi g ures
I n di vi d ual P K c o nce ntrati o n-ti me pr ofiles s h o wi n g all partici pa nts will be create d usi n g t he act ual 
ti me p oi nts a n d t he n u meric c o nce ntrati o n data. Arit h metic mea n a n d me dia n c o nce ntrati o n-ti me 
pr ofiles will be pr o vi de d usi n g sc he d ule d ( n o mi nal) ti me p oi nts a n d t he n u me ric c o nce ntrati o n 
data. All c o nce ntrati o n-ti me pl ots f or P K data will be prese nte d b ot h o n a li near a n d o n a se mi-
l o garit h mic scale. Mea n P K pl ots will i ncl u de St d D e v err or bars w he n pl otte d o n a li near scale. 
I n di vi d ual data will be prese nte d base d o n t he S A F, a n d s u m maries will be base d o n t he P K A S. 
Fi g ures of Ce oi (c o nce ntrati o n at e n d -of- i nf usi o n) a n d Ctr o u g h (c o nce ntrati o ns i m me diatel y 
bef ore ne xt treat me nt ot her t ha n first d osi n g i nter val ) will be c o vere d b y t he para meter s u m maries 
o nl y .
1 6. 1. 3
P h ar m ac o k i netic P ar a meter A n al ysis
Prese nt ati o n of P K P ar a meter D at a
Listi n gs
I n di vi d ual P K para meter data ( Ce oi a n d Ctr o u g h) will be liste d f or b ot h c o m p o u n ds ( A vel u ma b 
a n d Cet u xi ma b) b y partici pa nt a n d st u d y da y. Para meter listi n gs will be base d o n t he S A F. 
P har mac o ki netic para meters will be re p orte d t o 3 si g nifica nt di gits i n listi n gs.
T a bles
P har mac o ki netic para meter data ( Ce oi a n d Ctr o u g h) 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 f or b ot h c o m p o u n ds ( A vel u ma b a n d Cet u xi ma b) b y  st u d y d a 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 de viati o n (St d D e v), 
c oefficie nt of variati o n ( C V %), mi ni m u m (Mi n ), me dia n (Me dia n ), ma xi m u m (Ma x), ge o metric 
mea n ( Ge o Mea n), t he ge o metric c oefficie nt of variati o n ( Ge o C V %), a n d t he 9 5 % c o nfi de nce 
i nter val f or t he Ge o Mea n ( LCI  9 5 % G M: l o wer 9 5 % CI f or Ge o Mea n, U CI  9 5 % G M: u p per 9 5 % 
CI  f or Ge o Mea n). 
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 meters 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 data 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 oses o nl y . 
T he f oll o wi n g c o n ve nti o ns will be a p plie d w he n re p orti n g descri 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
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 4 /6 2
St d D e v:
4 si g nifica nt di gits
C V %, Ge o C V %:
1 deci mal place 
T he P K para meters liste d bel o w will be calc ulate d f or A vel u ma b a n d Cet u xi ma b a n d be a nal yz e d 
wit h t he sa me precisi o n as t he s o urce data pr o vi de d b y  t he bi oa nalyt ical la b orat or y. 
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. 
T his will be ta ke n directl y  fr o m t he o bser ve d A vel u ma b or 
Cet u xi ma b c o nce ntratio 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 diately bef 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 ntrati o n f or m ulti ple 
d osi n g). T his will be ta ke n directl y fr o m t he o bser ve d A vel u ma b 
or Cet u xi ma b c o nce ntrati o n -ti me data.
Fi g ures
I n di vi d ual P K tr o u g h c o nce ntrati o n ( Ctr o u g h) a n d e n d of i nf usi o n c o nce ntrati o n ( Ce oi) val ues will be 
pl otte d a gai nst act ual st u d y da y on a li near scale, f or all partici pa nts b y  part a n d treat me nt. 
I n di vi d ual data will be prese nte d base d o n t he S A F.
Arit h me tic mea n ( ± Std D e v) 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 da y 
b y  part, a n d treat me nt o n a li near scale. S u m maries will be base d o n t he P K A S. 
D oc u me nt N o
O bject N o. 
C CI
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 5 /6 2
D oc u me nt N o. 
O bject N o
C CI
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 6 /6 2
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 7 /6 2
1 6. 4
C O VI D -1 9 I m p act
A n alysis set: S A F
I n ad diti o n t o t he se nsiti vit y anal y ses descri be d i n Secti o n 1 4, C O VI D -1 9 relate d i m pact o n t he 
pla n ne d trial pr oce d ures will be s u m marize d base d u p o n t he e C R F pa ges relate d t o dis p ositi o n 
(‘ T T E R M’, ‘ ST E R M’, a n d ‘ D E A T H’), as well as t he pr ot oc ol de viati o ns re p orte d i n C T M S wit h 
t he c o di n g prefi x ‘ C O VI D - 1 9’. T he s u m mar y will i ncl u de:

T otal n u m ber of occ urre nces, as well as n u m ber of u ni q ue partici pa nts, wit h a n y  C O VI D-
1 9 relate d pr ot oc ol de viati o n
o
Misse d visits o verall (t otal n u m ber a n d u ni q ue partici pa nts)
o
Misse d efficac y  e val uati o ns (t otal n u m ber a n d u ni q ue partici pa nts)
o
Misse d d osi n g visits (t otal n u m ber a n d u ni q ue partici pa nts)

N u m ber of partici pa nts w h o disc o nti n ue d a n y st u d y treat me nt f or a n y reas o n relate d t o 
C O VI D - 1 9

N u m ber of partici pa nts w h o disc o nti n ue d t he st u d y  f or a n y reas o n relate d t o C O VID- 1 9

N u m ber of partici pa nts wit h ca use of deat h relate d t o C O VI D- 1 9
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 8 /6 2
1 7
Refere nces
Br o o k me y er R, Cr o wle y J. A C o nfi de nce Inter val f or t he Me dia n S ur vi val Ti me. Bi o metrics 
1 9 8 2; 3 8, 2 9 – 4 1. D OI : 1 0. 2 3 0 7/ 2 5 3 0 2 8 6
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, Da nce y  J, Ar b uc k S, 
G w y t her S, M o o ne y M, R u bi nstei n L, S ha n kar L, D o d d L, Ka pla n R, Lac o m be D., Ver weij J. 
Ne w res p o nse e val uati o n crite ria i n s oli d t u m o urs: re vise d R E CIS 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, Pre ntice L P. T he Statistical A nal ysis of Fail ure Ti me Data. C ha pter 8: 
C o m peti n g Ris ks a n d M ultistate M o dels. Wile y  Series i n Pr o ba bilit y a n d Statistics, 2n d e diti o n, 
2 0 1 1. Pri nt I S B N: 9 7 8 0 4 7 1 3 6 3 5 7 6, O nli ne I S B N: 9 7 8 1 1 1 8 0 3 2 9 8 5 
(htt p:// o nli neli brar y . wile y.c o m/ b o o k/ 1 0. 1 0 0 2/ 9 7 8 1 1 1 8 0 3 2 9 8 5)
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
5 9 /6 2
1 8
A p pe n dices
1 8. 1
A p pe n di x 
I –
Descri pti o n 
of t he C ase 
Defi niti o n 
f or 
Assess me nt of ir A Es a n d I R Rs
ir A Es
I m m u ne-relate d a d 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 preferre d ter m matc hes a preferre d ter m o n t he list of pre -selecte d Me d D R A ter ms.
2) T he A E o nset occ urs after t he first st u d y dr u g a d mi nistrati o n a n d n o m ore t ha n 9 0 d a y s after 
last d ose.
3) O n t he A E 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 py (e. g. T h yr oi d) a p plie d?” has “Yes ” selecte d.
4a) O n t he A E e C R F pa ge, t he q uesti o n, “ D oes a n y of t he f oll o wi n g pr o vi de a clear eti ol o g y for 
t he e ve nt?” has “ N o” selecte d or is left bla n k
O R 
4 b) O n t he A E e C R F p a ge, t he q uesti o n, “Is t he hist o pat h ol o g y  or bi o ps y  co nsiste nt wit h a n 
i m m u ne-me diate d e ve nt?” has “ Yes” selecte d.
I R Rs
I nf usi o n relate d reacti o ns are i de ntifie d base d o n a list of Me d D R A P Ts a n d criteria o n t he ti mel y 
relati o ns hi p acc or di n g t o Ta ble 6.
D oc u me nt N o
O bject N o
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
6 0 /6 2
T a ble 6
Criteri a f or i nf usi o n rel ate d re acti o ns
I nf usi o n relate d reacti o ns
Re acti o ns - C o nsi dere d w he n o nset is o n t he d a y of st u d y dr u g 
i nf usi o n ( d uri n g or after t he i nf usi o n) or t he d a y after t he st u d y 
dr u g i nf usi o n (irres pecti ve of res ol uti o n d ate):

I nf usi o n relate d reacti o n

Dr u g h y perse nsiti vit y

A na p h ylactic reacti o n

H y perse nsiti vit y

T y pe 1 h y perse nsiti vit y 
Si g ns a n d S y m pt o ms - occ urri n g o n t he d a y of st u d y dr u g 
i nf usi o n ( d uri n g or after t he i nf usi o n) a n d res ol ve d wit h e n d d ate 
wit hi n 2 d a ys after o nset

P y re xia

C hills

Fl us hi n g 

H y p ote nsi o n

D y s p n oea

W heezi n g

Bac k pai n

A b d o mi nal pai n

Urticaria

Dizzi ness

L oss of c o nsci o us ness or s h oc k
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
6 1 /6 2
1 8. 2
A p pe n di x II – N CI -C T C Gr a d a ble a n d N o n- Gr a d a ble S afet y 
L a b or at or y Test P ar a meters a n d Directi o n(s) of A b n or m alit y
N CI -C T C gr a d a ble p ar a meters
C at e g or y
P ar a m et er 
N a m e i n N CI -C T C
Dir e cti o n( s) of 
a b n or m alit y
S er u m c h e mi str y
El e ctr ol yt e s
C orr e ct e d C al ci u m
H y p o c al c e mi a/ H y p er c al c e mi a
L o w/ Hi g h
El e ctr ol yt e s
M a g n e si u m
H y p o m a g n e s e mi a/ H y p er m a g n e s e mi a
L o w/ Hi g h
El e ctr ol yt e s
P ot a s si u m
H y p o k al e mi a/ H y p er k al e mi a
L o w/ Hi g h
El e ctr ol yt e s
S o di u m
H y p o n atr e mi a/ H y p er n atr e mi a
L o w/ Hi g h
E n z y m e s/ c ar di al
Cr e ati ni n e P h o s p h o ki n a s e
C P K i n cr e a s e d
Hi g h
E n z y m e s/ c ar di al 
L a ct at e d e h y dr o g e n a s e
Bl o o d l a ct at e d e h y dr o g e n a s e i n cr e a s e d
Hi g h
E n z y m e s/li v er
Al a ni n e A mi n otr a n sf er a s e
Al a ni n e A mi n otr a n sf er a s e i n cr e a s e d
Hi g h
E n z y m e s/li v er
Al k ali n e P h o s p h at a s e
Al k ali n e P h o s p h at a s e i n cr e a s e d
Hi g h
E n z y m e s/li v er
A s p art at e A mi n otr a n sf er a s e
A s p art at e A mi n otr a n sf er a s e i n cr e a s e d
Hi g h
E n z y m e s/li v er
G a m m a -gl ut a m yl tr a n sf er a s e
G G T i n cr e a s e d
Hi g h
E n z y m e s/li v er
T ot al bilir u bi n
Bl o o d bilir u bi n i n cr e a s e d
Hi g h
M et a b oli s m
Gl u c o s e
H y p o gl y c e mi a
L o w
M et a b oli s m
Uri c A ci d
H y p er uri c e mi a
Hi g h
Pl a s m a pr ot ei n s
Al b u mi n
H y p o al b u mi n e mi a
L o w
R e n al/ ki d n e y
Cr e ati ni n e
Cr e ati ni n e i n cr e a s e d
Hi g h
H e m at ol o g y
Pl at el et s
Pl at el et s C o u nt
Pl at el et c o u nt d e cr e a s e d
L o w
R e d bl o o d c ell s
H e m o gl o bi n
A n e mi a/ H e m o gl o bi n i n cr e a s e d
L o w/ Hi g h
W h it e bl o o d 
c ell s/ diff er e nti al
W h it e Bl o o d C ell C o u nt
W h it e bl o o d c ell 
d e cr e a s e d/ L e u k o c yt o si s
L o w/ Hi g h
W h it e bl o o d 
c ell s/ diff er e nti al
A b s ol ut e L y m p h o c yt e s C o u nt
L y m p h o c yt e c o u nt d e cr e a s e d/i n cr e a s e d
L o w/ Hi g h
W h it e bl oo d 
c ell s/ diff er e nti al
A b s ol ut e N e utr o p hil s C o u nt
N e utr o p hil c o u nt d e cr e a s e d
L o w
W h it e bl o o d 
c ell s/ diff er e nti al
E o si n o p hil s
E o si n o p hili a
Hi g h
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 0 1 9 4 4 -0 1 7 0
             P h ase II a St u d y of A vel u m a b a n d Cet u xi m a b pl us Ge m cit a bi ne a n d
Versi o n 2
                 Cis pl ati n i n P artici p a nts wit h s q u a m o us N S C L C
6 2 /6 2
N CI -C T C n o n -gr a d a ble p ar a meters
C at e g or y
P ar a m et er ( L B T E S T)
Dir e cti o n ( s) of a b n or m alit y
S er u m c h e mi str y
El e ctr ol yt e s
C al ci u m
Hi g h/ L o w
El e ctr ol yt e s
C hl ori d e
Hi g h/ L o w
El e ctr ol yt e s
P h o s p h at e
L o w
M et a b oli s m
Gl u c o s e 
Hi g h
Pl a s m a pr ot ei n s
T ot al pr ot ei n
L o w
Pl a s m a pr ot ei n s
C R e a cti v e pr ot ei n
Hi g h
R e n al/ ki d n e y
Ur e a
Hi g h
R e n al/ ki d n e y
Bl o o d Ur e a Nitr o g e n
Hi g h
H e m at ol o g y
R e d bl o o d c ell s
H e m at o crit 
Hi g h/ L o w
R e d bl o o d c ell s
R e d bl o o d c ell s ( Er yt hr o c yt e s)
Hi g h/ L o w
W h it e bl o o d c ell s/ diff er e nti al
B a s o p hil s
Hi g h
W h it e bl o o d c ell s/ diff er e nti al  
M o n o c yt e s
Hi g h/ L o w
D oc u me nt N o. 
O bject N o
C CI
C CI


E L E C T R O NI C SI G N A T U R E S
D oc u me nt: ct p- ms 2 0 1 9 4 4- 0 1 7 0-i a p- v 2
Si g ne d B y
E ve nt N a me
Me a ni n g of Si g n at ure
Ser ver D ate
( d d- M M M- y y y y
H H: m m ‘ G M T’ Z)
Tec h nical A p pr o val
B usi ness A p pr o val
D oc u me nt N o. 
O bject N o
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D