Clinical trial NCT04515394
Conditions: Colorectal Neoplasms
Keywords: Colorectal cancer RAS wild-type Tepotinib Cetuximab Erbitux Epidermal growth factor receptor resistance Hepatocyte growth factor Panitumumab Mesenchymal epithelial transition
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2021-01-28; Completion date: 2022-03-31
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study was to assess the preliminary antitumor activity, safety and tolerability of tepotinib in combination with cetuximab in participants with RAS/BRAF wild-type left-sided Metastatic Colorectal Cancer (mCRC) having acquired resistance to anti-epidermal growth factor receptor (EGFR) antibody targeted therapy due to mesenchymal epithelial transition (MET) amplification.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Tepotinib intervention 2: Cetuximab
Intervention descriptions: intervention 1: Participants received Tepotinib film-coated tablets at a dose of 500 milligrams (mg) orally, once daily (QD) until disease progression (according to Response Evaluation Criteria in Solid Tumors Version 1.1 \[RECIST v1.1\]), death, Adverse event (AE) leading to discontinuation, study withdrawal, or withdrawal of consent, whichever occurs first. intervention 2: Participants received weekly intravenous infusions of Cetuximab at a dose of 250 milligrams per square meter (mg/m\^2) until disease progression (according to Response Evaluation Criteria in Solid Tumors Version 1.1 \[RECIST v1.1\]), death, Adverse event (AE) leading to discontinuation, study withdrawal, or withdrawal of consent, whichever occurs first.

Protocol documents:
Prot_000.pdf: 
M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 1 1 5
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 II si n gle-ar m st u d y to i n vesti gate te p oti ni b 
c o m bi ne d wit h cet u xi ma b i n R A S /B R A F
wil d -t yp e 
left-si de d metastatic 
c ol orectal 
ca ncer 
( m C R C) 
patie nts ha vi n g ac q uire d resista nce t o a nti-E G F R 
a nti b o d y tar geti n g t hera p y due t o M E T
a m plificati o n
( P E R S P E C TI V E) 
St u d y N u m ber:
M S 2 0 2 2 0 2 - 0 0 0 2
Merc k
C o m p o u n d :
M S B 0 0 1 0 4 4 2 D (cet u xi ma b)
M S C 2 1 5 6 1 1 9J (te p oti ni b)
Merc k Re gistere d C o m p o u n d N a me 
i n J a p a n:
N ot A p plica ble
St u d y P h ase:
II
S h ort Title:
P hase II si n gle-ar m st u d y of te p oti ni b c o m bi ne d wit h 
cet u xi ma b ( P E R S P E C TI V E)
Acr o n y m :
P E R S P E C TI V E
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 :
S p o ns or:
Affiliates of Merc k K Ga A, Dar msta dt, Ger ma n y
F or all c o u ntries, e xce pt t he U S a n d Ca na da:
Merc k Healt hcare K Ga A, Dar msta dt, Ger ma n y 
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y
Fra n kf urter Str. 2 5 0
Dar msta dt, Ger ma n y
I n t he U S a n d Ca na da:
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc.
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y
4 5 A Mi d dlese x T ur n pi ke
Billerica, M A, 0 1 8 2 1, U S A
D oc u me nt N o. 
O bject N o. 
P P D
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 1 1 5
Re g ul at or y 
A ge nc y 
I de ntif yi n g 
N u m bers:
I ND:
E u dra C T: 2 0 2 0- 0 0 1 7 7 6- 1 5
A p pr o v al D ate:
0 8 Mar 2 0 2 1
Me dic al
M o nit or N a me a n d C o nt act 
I nf or m ati o n:
P h o ne: 
e mail: 
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 7 A pr 2 0 2 0
1. 1 U S A
L o c al a m e n d m e nt f or U S A o nl y
3 0 J ul 2 0 2 0
1. 2 F R A
L o c al a m e n d m e nt f or Fr a n c e o nl y
0 6 O ct 2 0 2 0
2. 0
Gl o b al A m e n d m e nt
0 8 M ar 2 0 2 1
Pr ot oc ol Versi o n 2. 0 ( 0 8 M ar 2 0 2 1 )
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 p ur p ose of t his a me n d me nt is t o pr o vi de a gl o bal pr ot oc ol i nc or p orati n g c o u ntr y-s pecific 
Healt h A ut h orit y  re q uests fr o m t he U S A a n d Fra nce i n a d diti o n t o a d mi nistrati ve u p dates.  
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 , 1. 1 S y n o p si s, 
A p p e n di c e s 1 0, 1 1 , 1 2, 
p a g e h e a d er s
A d d e d t h e st u d y a cr o n y m 
“ P E R S P E C TI V E” t o st u d y titl e a n d 
s h ort titl e. A d d e d r o w o n titl e p a g e
i n di c ati n g t h e st u d y a cr o n y m 
“ P E R S P E C TI V E”.
A d mi ni str ati v e c h a n g e
1. 1 S y n o p si s
R e m o v e d “if a p pli c a bl e” aft er 
C o h ort B.
U p d at e d b e c a u s e C o h ort B will b e i niti at e d.
Sit e s i n N ort h A m eri c a will b e i n cl u d e d i n 
t hi s st u d y. T h e l a n g u a g e i n t h e st u d y 
a d mi ni str ati v e s e cti o n h a s b e e n c h a n g e d t o 
r efl e ct t hi s.
1. 2 S c h e m a 
R e m o v e d “ a n d mi g ht b e i niti at e d at 
a l at er ti m e p oi nt” aft er C o h ort B will 
i n cl u d e U S p arti ci p a nt s o nl y.
U p d at e d a s C o h ort B will b e i niti at e d i n 
p ar all el t o C o h ort A. Sit e s i n N ort h A m eri c a 
will b e i n cl u d e d i n t hi s st u d y. T h e l a n g u a g e 
i n t h e st u d y a d mi ni str ati v e s e cti o n h a s b e e n 
c h a n g e d t o r efl e ct t hi s .
1. 3 S c h e d ul e s of A cti viti e s
E n d of tr e at m e nt w a s c h a n g e d fr o m 
t h e l a st d o s e t a k e n t o t h e d e ci si o n 
t o wit h dr a w I M P. 
S af et y m e a s ur e t o all o w f or d e ci si o n s t o 
wit h dr a w fr o m st u d y if d o si n g of 
p arti ci p a nt’ s st u d y dr u g h a d b e e n 
i nt err u pt e d.
D oc u me nt N o. 
O bject N o. 
P P D
P P D
P P D
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
3/ 1 1 5
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
N ot e a d d e d t h at s cr e e ni n g 
l a b or at or y a s s e s s m e nt s s h o ul d b e 
p e rf or m e d wit hi n 7 d a y s pri or t o 
C y cl e 1 D a y 1. 
A d d e d s cr e e ni n g wi n d o w t o f a cilit at e 
pr ot o c ol a d h er e n c e . 
F or E C G a s s e s s m e nt s, a ll o w e d a 
6 0 -mi n ut e wi n d o w (fr o m t h e 
pr e vi o u s 2 0 -mi n ut e
wi n d o w) . 
U p d at e d t o f a cilit at e pr ot o c ol a d h er e n c e 
a n d r e d u c e b ur d e n at sit e s d u e t o l o gi sti c al 
c o n str ai nt s i n a gr e e m e nt wit h s af et y.
F or t h e A E a n d S A E a s s e s s m e nt s, 
r e m o v e d “ S cr e e ni n g” fr o m t h e 
d e s c ri pti o n of t h e I C F i n t h e N ot e s.
A d mi ni str ati v e c h a n g e
2 I ntr o d u cti o n
A d d e d “ T h e pr o p o s e d a d mi ni st er e d 
d o s e of 5 0 0 m g t e p oti ni b 
c orr e s p o n d s t o 5 0 0 m g t e p oti ni b 
h y dr o c hl ori d e h y dr at e a n d i s 
e q ui v al e nt t o 4 5 0 m g t e p oti ni b (fr e e 
b a s e f or m ). T h e 2 5 0 m g t e p oti ni b 
c orr e s p o n d s t o 2 5 0 m g t e p oti ni b 
h y dr o c hl ori d e h y dr at e a n d i s 
e q ui v al e nt t o 2 2 5 m g t e p oti ni b (fr e e 
b a s e f or m)” .
R e vi s e d t h e pr ot o c ol t o cl arif y t h e a m o u nt of 
t e p oti ni b fr e e b a s e a d mi ni st er e d.
2. 1 St u d y R ati o n al e
R e m o v e d “if C o h ort B i s i niti at e d”
a n d r e vi s e d t h e d e s cri pti o n of 
c o u ntri e s t o b e i n cl u d e d i n C o h ort s 
A a n d B.
U p d at e d a s C o h ort B will b e i niti at e d. Sit e s 
i n N ort h A m eri c a will b e i n cl u d e d i n t hi s 
st u d y. T h e l a n g u a g e i n t h e st u d y 
a d mi ni str ati v e s e cti o n h a s b e e n c h a n g e d t o 
r efl e ct t hi s.
2. 3 B e n efit/ Ri s k 
A s s e s s m e nt
U p d at e d t h e r e p orti n g p eri o d f or t h e 
m o st c urr e nt C et u xi m a b I B. 
A d mi ni str ati v e c h a n g e
U n d er T e p oti ni b – Ri s k s, cl arifi e d 
e d e m a a n d u p d at e d t o n a u s e a a n d 
v o miti n g a s ri s k s.  
U p d at e d t o pr o vi d e c urr e nt g ui d a n c e o n 
t et o pi ni b. 
U n d er B e n efit/ Ri s k A s s e s s m e nt: 
C o m bi n ati o n of t e p oti ni b wit h 
c et u xi m a b, r e vi s e d t o i n cl u d e t h at 
p arti ci p a nt s wit h a hi st or y of or 
d e v el o pi n g I L D w o ul d b e e x cl u d e d 
fr o m t h e st u d y. Mi n or r e str u ct uri n g 
c h a n g e t o pl a c e i n cl u si o n 
i nf or m ati o n f or p arti ci p a nt s wit h 
a d e q u at e h e p ati c f u n cti o n wit h 
i nf or m ati o n m or e dir e ctl y r el at e d. 
R e vi s e d t o r efl e ct c urr e nt e x cl u si o n crit eri a. 
R e vi si o n f or cl arifi c ati o n. 
4. 1 O v er all D e si g n
R e m o v e d “if C o h ort B i s i niti at e d” .
U p d at e d a s C o h ort B will b e i niti at e d. Sit e s 
i n N ort h A m eri c a will b e i n cl u d e d i n t hi s 
st u d y. 
R e vi s e d s e nt e n c e b e gi n ni n g “ Aft er 
t h e s af et y r u n-i n p eri o d …” i n C o h ort 
e x p a n si o n at R P 2 D s u b s e cti o n wit h 
“S af et y r u n -i n p eri o d c a n i n cl u d e 
p arti ci p a nt s fr o m C o h ort s A a n d/ or 
B”.
4. 2 S ci e ntifi c R ati o n al e f or 
St u d y D e si g n
C orr e ct e d h a z ar d r ati o s f or O S i n 
t h e fir st-li n e F O L FI RI pl u s 
c et u xi m a b t h er a p y. 
A d mi ni str ati v e c h a n g e
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
4/ 1 1 5
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
5. 1 I n cl u si o n Crit eri a
T o crit eri o n # 2, cl arifi e d l eft-si d e d 
C R C t u m or s, “fr o m s pl e ni c fl e x ur e t o 
r e ct u m.” I n cl u d e d r ef er e n c e t o 
c urr e nt N ati o n al C o m pr e h e n si v e 
C a n c er N et w or k ( N C C N) C R C 
v 1 . 2 0 21 g ui d eli n e s . 
A d d e d a d diti o n al d e s cri pti o n f or l eft-si d e d 
t u m or s.
T o crit eri o n # 2, cl arifi e d t h at 
a d v a n c e d t u m or s ar e al s o 
u nr e s e ct a bl e .
U p d at e d t o cl arif y t u m or s ar e u nr e s e ct a bl e 
t o b ett er r efl e ct t h e r e q uir e m e nt s of t h e 
p ati e nt p o p ul ati o n.
T o crit eri o n # 7 b, a d d e d “ Fir st -li n e 
tr e at m e nt m u st i n cl u d e a 
fl u or o p yri mi di n e a n d o x ali pl ati n or 
iri n ot e c a n a n d s e c o n d-li n e tr e at m e nt 
m u st i n cl u d e a fl u or o p yri mi di n e, 
o x ali pl ati n, or iri n ot e c a n” .
A d d e d at t h e r e q u e st of a H e alt h A ut h orit y
t o cl arif y t h at fir st -li n e tr e at m e nt m u st 
i n cl u d e a fl u or o p yri mi di n e a n d o x ali pl ati n or 
iri n ot e c a n a n d s e c o n d-li n e tr e at m e nt m u st 
i n cl u d e a fl u or o p yri mi di n e, o x ali pl ati n, or 
iri n ot e c a n.
T o crit eri o n # 1 1, c orr e ct e d t o a d d 
t h e s u p er s cri pt e d n u m b er s t o t h e 
e sti m at e d gl o m er ul ar filtr ati o n r at e 
f or m ul a.
A d mi ni str ati v e c h a n g e
5. 2 E x cl u si o n Crit eri a
A d d e d t o crit eri o n # 8 a s p oi nt “ g. 
C orr e ct e d Q T i nt er v al b y Fri d eri ci a 
( Q T c F > 4 8 0 m s)” .
S af et y m e a s ur e cl arifi c ati o n t o
e x cl u d e 
p ati e nt s wit h Q T c i nt er v al s > 4 8 0 m s e c. 
A d d e d n e w crit eri o n, # 1 6,” Hi st or y of 
I L D or i nt er stiti al p n e u m o niti s 
i n cl u di n g r a di ati o n p n e u m o niti s t h at 
r e q uir e d st er oi d tr e at m e nt”.
A d d e d i n or d er t o e x clu d e p ati e nt s wit h a 
hi st or y of i nt er stiti al l u n g di s e a s e or 
i nt er stiti al p n e u m o niti s t o b ett er r efl e ct t h e 
r e q uir e m e nt s of t h e 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 , t a bl e
A d d e d “ a n d if l o c al c et u xi m a b l a b el 
r e q uir e s” t o t h e i nf or m ati o n t h at a 
c orti c o st er oi d i s gi v e n pri or t o t h e 
fir st i nf u si o n of c et u xi m a b.
A d d e d t o i n di c at e t h e u s e of c orti c o st er oi d s,
a s a pr e m e di c ati o n, will b e b a s e d o n l o c al 
r e q uir e m e nt s.
6. 3. 1 St u d y I nt er v e nti o n 
A s si g n m e nt 
C orr e ct e d t h e n a m e of t h e s y st e m 
u s e d t o a s si g n st u d y n u m b er s t o 
p arti ci p a nt s. 
A d mi ni str ati v e c h a n g e
6. 5. 1 P er mitt e d M e di ci n e s 
A d d e d “ a n d if l o c al c et u xi m a b l a b el 
r e q uir e s” t o t h e i nf or m ati o n t h at a 
c orti c o st er oi d i s gi v e n pri or t o t h e 
fir st i nf u si o n of c et u xi m a b.
A d d e d t o cl arif y t h at if a c orti c o st er oi d w o ul d 
b e gi v e n pri or t o c et u xi m a b, will d e p e n d o n 
t h e l o c al c et u xi m a b l a b el.
6. 5. 4 S p e ci al Pr e c a uti o n s
6. 5. 4. 1 C et u xi m a b
W o r di n g u p d at e d u n d er E y e 
D i s or d er s.
U p d at e d f or t h e si g n s a n d s y m pt o m s 
s u g g e sti v e of k er atiti s .
6. 5. 4 S p e ci al Pr e c a uti o n s
6. 5. 4. 2 T e p oti ni b 
A d d e d i n str u cti o n t o r ef er t o t h e 
n e wl y i n p utt e d t a bl e o n t h e 
r e c o m m e n d e d t e p oti ni b d o s e 
m o difi c ati o n s
f or e d e m a.
A d mi ni str ati v e c h a n g e
6. 6 D o s e S el e cti o n a n d 
M o difi c ati o n
6. 6. 2 T e p oti ni b
U n d er T e p oti ni b: R e c o m m e n d e d 
D o s e ( s e c o n d p ar a gr a p h), a d d e d 
i n di c ati o n t h at t e p oti ni b i s al s o 
a p pr o v e d i n U S a s w ell a s J a p a n. 
U p d at e d wit h t h e a p pr o v al of t e p oti ni b i n t h e 
U S. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
5/ 1 1 5
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
A d d e d f urt h er cl arifi c ati o n (t a bl e)
u n d er t h e t e p oti ni b tr e at m e nt 
i nt err u pti o n s e cti o n t o i n cl u d e 
r e c o m m e n d e d d o s e m o difi c ati o n s i n 
c a s e of a d v er s e r e a cti o n s of cli ni c al 
i nt er e st. Al s o i n cl u d e d a f o ot n ot e 
t h at if A E s w er e t o o c c ur d uri n g t h e 
D L T p eri o d or t h e s af et y r u n -i n t h at 
D L T r ul e s f o r d o s e m o difi c ati o n 
s h o ul d a p pl y. 
S af et y m e a s ur e t o p r o vi d e d et ail e d 
g ui d eli n e s a c c or di n g t o t h e s e v erit y gr a d e of 
t h e t o xi cit y o b s er v e d, a n d t h e 
r e c o m m e n d e d t e p oti ni b d o s e m o difi c ati o n s.  
R e mi n d er a d d e d f or d o s e m o difi c ati o n 
g ui d a n c e f or e v e nt s o c c urri n g d uri n g t h e 
D L T p eri o d a n d t h e s af et y r u n -i n. 
6. 6. 3 D o s e Li miti n g 
T o xi cit y
A d d e d “ Gr a d e 4 v o miti n g or 
di arr h e a” a s D L T crit eri a.
H e alt h a ut h orit y r e q u e st t o i n cl u d e Gr a d e 4 
(lif e t hr e at e ni n g) v o miti n g or di arr h e a a s 
D L T crit eri a.
6. 7 St u d y I nt er v e nti o n 
aft er t h e E n d of t h e St u d y
A d d e d d et ail s o n pr o vi si o n of 
pr o vi di n g st u d y i nt er v e nti o n aft er t h e 
E n d of t h e St u d y. U p d at e d s e cti o n 
t o r efl e ct c urr e nt S p o n s or p oli c y.
U p d at e d t o s p e c if y t h e t er m s f or t h e 
pr o vi si o n i n g of st u d y dr u g( s) t o p a rtici p a nt s 
w h o b e n efit at t h e E n d of St u d y.
7. 1 Di s c o nti n u ati o n of 
St u d y I nt er v e nti o n
Gr a d e > 3 Q T c i nt er v al pr ol o n g ati o n 
w a s a d d e d a s r e a s o n f or 
di s c o nti n u ati o n of st u d y i nt er v e nti o n. 
A d diti o n all y, t h e i niti ati o n of cl o s e 
a n d a p pr o pri at e E C G m o nit ori n g i n 
h o s pit al a c c or di n g t o l o c al st a n d ar d s 
i s r ef err e d t o.
U p d at e d t o pr o vi d e cl arifi c ati o n i n e v e nt of 
Q T c F fi n di n g s.
7. 2 P arti ci p a nt 
Di s c o nti n u ati o n 
/ Wit h dr a w al fr o m t h e 
St u d y
B a s e d o n r e c e nt pr ot o c ol t e m pl at e 
r e vi si o n s, r e pl a c e d fir st f o ur b ull et s 
wit h u p d at e d l a n g u a g e.
A d mi ni str ati v e c h a n g e
8 St u d y A s s e s s m e nt s a n d 
Pr o c e d ur e s
A d d e d wit h t h e s cr e e ni n g 
e v al u ati o n s b ull et p oi nt, t h at 
s cr e e ni n g l a b or at or y t e st s s h o ul d b e 
p erf or m e d wit hi n 7 d a y s pri or t o
C y cl e 1 D a y 1. 
A d d e d s cr e e ni n g wi n d o w t o f a cilit at e 
pr ot o c ol a d h er e n c e .
8. 1. 1 T u m or A s s e s s m e nt s
D el et e d s e nt e n c e “ R e a d er s s h o ul d 
u s e c yt ol o g y r e s ult s a n d, if n ot 
a v ail a bl e, n o pr o gr e s si o n s ol el y o n 
eff u si o n s or a s cit e s s h o u l d b e 
d et er mi n e d” .
R e m o v e d i n or d er t o ali g n wit h c urr e nt 
a m e n d e d I R C c h art er g ui d a n c e f or 
i n v e sti g at or s.
9. 2 S a m pl e Si z e 
D et er mi n ati o n
R e m o v e d “if a p pli c a bl e” aft er 
C o h ort B, r e m o v e d “if i niti at e d” aft er 
C o h ort B , r e m o v e d “( or 2 2 if C o h ort 
A o nl y) ”. 
R e m o v e d a s t he e nr oll m e nt of C o h ort B i s 
n o w i n p ar all el wit h C o h ort A, a n d n ot l at er 
a s i niti all y i m pli e d. C o h ort A l a n g u a g e 
u n n e c e s s ar y.
9. 3 P o p ul ati o n s f or 
A n al y s e s, t a bl e
D e s cri pti o n of P K a n al y si s s et, 
c h a n g e d fr o m “ …cli ni c all y i m p ort a nt 
pr ot o c ol d e vi ati o n s ” t o “..r el e v a nt 
pr ot o c ol d e vi ati o n s” .
All P K r el e v a nt pr ot o c ol d e vi ati o n s will b e 
c o n si d er e d n o w r e g ar dl e s s if t h e s e ar e 
cli ni c all y i m p ort a nt . 
9. 4. 1 Effi c a c y A n al y s e s, 
t a bl e
A d d e d “ D ur ati o n of r e s p o n s e d at a 
will b e c e n s or e d …
f or p arti ci p a nt s 
wit h a n e v e nt aft er t h e p eri o d of 2 
s c h e d ul e d t u m or a s s e s s m e nt s ( 8 4 
or 1 6 8 d a y s) of t h e l a st t u m or 
a s s e s s m e nt ”.
A d d e d f urt h er d e s cri pti o n of t h e d eri v ati o n 
of d ur ati o n of r e s p o n s e .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
6/ 1 1 5
S e cti o n # a n d N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
A d d e d t o t h e d e s cri pti o n of t h e 
st ati sti c al a n al y si s m et h o d s f or t h e  
P F S e n d p oi nt : “Pr o gr e s si o n fr e e 
s ur vi v al i s d efi n e d a s …
or d e at h 
d u e t o a n y c a u s e wit hi n t h e p eri o d 
of 2 s c h e d ul e d t u m or a s s e s s m e nt s 
( 8 4 or 1 6 8 d a y s)  aft er t h e l a st t u m or 
a s s e s s m e nt, w hi c h e v er o c c ur s fir st. 
P F S d at a will b e c e n s or e d … f or 
p arti ci p a nt s wit h a n e v e nt aft er t h e 
p eri o d of 2 s c h e d ul e d t u m or 
a s s e s s m e nt s ( m or e t h a n 8 4 or 1 6 8 
d a y s) aft er t h e l a st t u m or 
a s s e s s m e nt ”.
A d d e d f urt h er d e s cri pti o n of t h e d eri v ati o n
of P F S .
9. 4. 2. 1 S af et y R u n -I n
P eri o d, D L T s, St o p pi n g 
R ul e s, D o s e R e d u cti o n 
a n d E s c al ati o n
A d d e d r ef er e n c e t o n e wl y a d d e d 
A p p e n di x 8 B OI N D e si g n.
A d mi ni str ati v e c h a n g e
9. 4. 4 S e q u e n c e of 
A n al y s e s
R el a b el e d m ai n a n al y si s t o pri m ar y 
a n al y si s. 
A d mi ni str ati v e c h a n g e
A p p e n di x 2 St u d y 
G o v er n a n c e
U n d er st u d y a d mi ni str ati v e s e cti o n, 
d el et e d “( sit e s i n N ort h A m eri c a will 
o nl y b e i n cl u d e d if C o h ort B i s 
i niti at e d)”.
Sit e s i n N ort h A m eri c a will b e i n cl u d e d i n 
t hi s st u d y. T h e l a n g u a g e i n t h e st u d y 
a d mi ni str ati v e s e cti o n h a s b e e n c h a n g e d t o 
r efl e ct t hi s.
A p p e n di x 4 Or d er of K e y 
A cti viti e s o n D a y 1 of 
C y cl e s 1 a n d 2
C h a n g e d t h e s cr e e ni n g E C G 
wi n d o w fr o m 2 0 t o 6 0 mi n ut e s. 
U p d at e d t o f a cilit at e pr ot o c ol a d h er e n c e 
a n d r e d u c e b ur d e n at sit e s d u e t o l o gi sti c al 
c o n str ai nt s i n a gr e e m e nt wit h s af et y.
A p p e n di x 6 Cli ni c al 
L a b or at or y T e st s
A d d e d p h o s p h or u s t o bi o c h e mi str y 
p ar a m et er s f or a s s e s s m e nt.
H e alt h a ut h orit y r e q u e st i n t h e st u d y 
m o nit ori n g pl a n t o i n cl u d e a s s e s s m e nt of 
p h o s p h or u s i n t h e bi o c h e mi str y p a n el.
D el et e d t h e s er u m or uri n e al c o h ol 
a n d dr u g s cr e e n. 
R e m o v e d a s t hi s a d diti o n al s af et y 
p ar a m et er w a s d e e m e d n ot n e c e s s ar y f or 
s af et y e v al u ati o n . 
A p p e n di x 8 B OI N D e si g n
A d d e d a p p e n di x w hi c h i n cl u d e s 
fl o w c h art a n d b o u n d ari e s of t h e 
B OI N d e si g n.  
A d d e d m or e d et ail e d 
i nf or m ati o n/ s p e cifi c ati o n s t o b e u s e d f or t h e 
B OI N d e si g n.
T hr o u g h o ut
Mi n or e dit ori al a n d d o c u m e nt 
f or m atti n g r e vi si o n s.
Mi n or; t h er ef or e, h a v e n ot b e e n 
s u m m ari z e d .
- C o nfi de ntial –
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its s u bsi diaries. It is i nte n de d f or restricte d us e o nl y 
a n d ma y n ot – i n f ull or part – be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut e x press per missi o n of Merc k K Ga A, Dar msta dt, 
Ger ma n y, or its s u bsi diar y. C o p yri g ht © 2 0 2 1 b y Merc k K Ga A, Dar msta dt, Ger ma n y, or its s u bsi diar y. All ri g hts reser ve d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
7/ 1 1 5
T a ble of C o nte nts
Title Pa ge
.............................................................................................................. 1
Ta ble of C o nte nts
.............................................................................................................. 7
1
Pr ot oc ol S u m mar y .............................................................................. 1 1
1. 1
S y n o psis ..............................................................................................1 1
1. 2
Sc he ma ................................................................................................1 2
1. 3
Sc he d ule of Acti vities ......................................................................... 1 4
2
I ntr o d ucti o n......................................................................................... 2 2
2. 1
St u d y  Rati o nale................................................................................... 2 2
2. 2
Bac k gr o u n d ......................................................................................... 2 3
2. 3
Be nefit/ Ris k Assess me nt .................................................................... 2 5
3
O bjecti ves a n d E n d p oi nts ................................................................... 2 8
4
St u d y  Desi g n....................................................................................... 2 9
4. 1
O verall Desi g n .................................................................................... 2 9
4. 2
Scie ntific Rati o nale f or St u d y  Desi g n ................................................ 3 1
4. 3
J ustificati o n f or D ose .......................................................................... 3 3
4. 4
E n d of St u d y  Defi niti o n...................................................................... 3 3
5
St u d y  P o p ulati o n................................................................................. 3 4
5. 1
I ncl usi o n Criteria................................................................................ 3 4
5. 2
E xcl usi o n Criteria ............................................................................... 3 7
5. 3
Lifest y le C o nsi derati o ns..................................................................... 3 8
5. 4
Scree n Fail ures .................................................................................... 3 9
6
St u d y  Inter v e nti o n(s) .......................................................................... 3 9
6. 1
St u d y  Inter ve nti o n(s) A d mi nistrati o n ................................................. 3 9
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 1
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.............................................................................................. 4 2
6. 3. 1
St u d y  Inter ve nti o n Assi g n me nt ..........................................................4 2
6. 3. 2
Bli n di n g................................ ..............................................................4 2
6. 4
St u d y  Inter ve nti o n C o m plia nce ..........................................................4 2
6. 5
C o nc o mita nt T hera p y................................ .........................................4 3
6. 5. 1
Per mitte d Me dici nes ...........................................................................4 3
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
8/ 1 1 5
6. 5. 2
Pr o hi bite d Me dici nes ..........................................................................4 4
6. 5. 3
Ot her I nter ve nti o ns ............................................................................. 4 5
6. 5. 4
S pecial Preca uti o ns ............................................................................. 4 5
6. 5. 4. 1
Cet u xi ma b ........................................................................................... 4 5
6. 5. 4. 2
Te p oti ni b ............................................................................................. 4 8
6. 6
D ose Selecti o n a n d M o dificati o n ........................................................ 4 9
6. 6. 1
Cet u xi ma b ........................................................................................... 5 0
6. 6. 2
Te p oti ni b ............................................................................................. 5 1
6. 6. 3
D ose L i miti n g T o xicit y....................................................................... 5 2
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 3
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 ...............................................................5 4
7. 1
Disc o nti n uati o n of St u d y I nter ve nti o n ................................................ 5 4
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 ................... 5 5
7. 3
L ost t o F oll o w -U p ............................................................................... 5 5
8
St u d y  Assess me nts a n d Pr oce d ures .................................................... 5 6
8. 1
Efficac y  Assess me nts a n d Pr oce d ures................................................ 5 6
8. 1. 1
T u m or assess me nts ............................................................................. 5 7
8. 1. 2
C ollecti o n a n d st ora ge of i ma ges ........................................................ 5 8
8. 2
Safet y  Assess me nts a n d Pr oce d ures................................................... 5 8
8. 2. 1
P h y sical E xa mi nati o ns ........................................................................ 5 9
8. 2. 2
Vital Si g ns .......................................................................................... 5 9
8. 2. 3
Electr ocar di o gra ms ............................................................................. 6 0
8. 2. 4
Cli nical Safet y  La b orat or y Assess me nts............................................ 6 0
8. 3
A d verse E ve nts a n d Seri o us A d verse E ve nts .....................................6 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.................................................... 6 1
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 ...6 1
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 ............... 6 1
8. 3. 4
Re g ulat or y  Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ..... 6 2
8. 3. 5
Pre g na nc y ...........................................................................................6 2
8. 3. 6
Disease -Relate d E ve nts a n d/ or Disease -Relate d O utc o mes N ot 
Q ualif yi n g as A Es or S A Es ................................................................6 4
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 1 1 5
8. 3. 7
A d verse E ve nts of S pecial I nterest ..................................................... 6 4
8. 4
Treat me nt of O ver d ose ....................................................................... 6 4
8. 5
P har mac o ki netics ................................................................................ 6 5
8. 5. 1
Te p oti ni b ............................................................................................. 6 5
8. 5. 2
Cet u xi ma b ........................................................................................... 6 5
8. 6
P har mac o d y na mics ............................................................................. 6 6
8. 7
P har mac o ge netics ............................................................................... 6 6
8. 8
Bi o mar kers .......................................................................................... 6 6
8. 9
I m m u n o ge nicity Assess me nts ............................................................ 6 7
8. 1 0
Me dical Res o urce Utilizati o n a n d Healt h Ec o n o mics ........................ 6 8
9
Statistical C o nsi derati o ns .................................................................... 6 8
9. 1
Statistical H y p ot heses ......................................................................... 6 8
9. 2
Sa m ple Size Deter mi nati o n ................................................................ 6 8
9. 3
P o p ulati o ns f or A nal y ses .................................................................... 6 9
9. 4
Statistical A nal y ses ............................................................................. 7 0
9. 4. 1
Ef ficac y A nalys es ............................................................................... 7 0
9. 4. 2
Safet y  A nalys es .................................................................................. 7 1
9. 4. 2. 1
Safet y  R u n-I n Peri o d, D L Ts, St o p pi n g R ules, D ose Re d ucti o n a n d 
Escalati o n ............................................................................................ 7 2
9. 4. 3
Ot her A nal ys es .................................................................................... 7 3
9. 4. 4
Se q ue nce of A nal ys es ......................................................................... 7 4
1 0
Refere nces ........................................................................................... 7 5
1 1
A p pe n dices ......................................................................................... 7 8
A p pe n di x 1
A b bre viati o ns ...................................................................................... 7 8
A p pe n di x 2
St u d y  G o ver na nce...............................................................................8 1
A p pe n d i x 3
C o ntrace pti o n ......................................................................................8 7
A p pe n di x 4
Or der of Ke y  Acti vities o n Da y 1 of C ycles 1 a n d 2 .......................... 8 9
A p pe n di x 5
Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) 
Versi o n 1. 1 .......................................................................................... 9 0
A p pe n di x 6
Cli nical L a b orat or y Tests .................................................................1 0 0
A p pe n di x 7
A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec o r di n g, 
E val uati n g, F oll o w -u p, a n d Re p orti n g .............................................. 1 0 1
A p pe n di x 8
B OI N Desi g n .................................................................................... 1 0 8
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 / 1 1 5
A p pe n di x 9
Pr ot oc ol A me n d me nt Hist or y ........................................................... 1 0 9
A p pe n di x 1 0
S p o ns or Si g nat ure Pa ge .................................................................... 1 1 3
A p pe n di x 1 1
C o or di nati n g I n vesti gat or Si g nat ure Pa ge ........................................ 1 1 4
A p pe n di x 1 2
Pri nci pal I n vesti gat or Si g nat ure Pa ge ............................................... 1 1 5
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 / 1 1 5
1
Pr ot oc ol S u m m ar y
1. 1
S y n o psis
Pr ot oc ol Title: A P hase II si n gle-ar m st u d y t o i n vesti gate te p oti ni b c o m bi ne d wit h cet u xi ma b i n 
R A S /B R A F wil d -t ype left-si de d metastatic c ol orectal ca ncer ( m C R C) patie nts ha vi n g ac q uire d 
resista nce t o a nti-E G F R a nti b o d y  tar geti n g t hera p y d ue t o M E T a m plificati o n ( P E R S P E C TIV E) .
S h ort Title: P hase II si n gle -ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi ma b ( P E R S P E C TIV E) .
R ati o n ale: T he p ur p ose of t his st u d y is t o assess t he preli mi nar y  antit u m or acti vit y, safety, a n d 
t olera bilit y, a n d t o e x pl ore t he p har mac o ki netics ( P K) of te p oti ni b i n c o m bi nati o n wit h cet u xi ma b 
i n partici pa nts wit h R A S /B R A F wil d -t ype left-si de d m C R C ha vi n g ac q uire d resista nce t o a nti-
e pi der mal gr o wt h fact or rece pt or (E G F R ) a nti b o d y tar gete d t hera p y due t o mese nc h y m al e pit helial 
tra nsiti o n fact or (M E T ) a m plificati o n. T he d ual t hera pe utic a p pr oac h of gi vi n g te p oti ni b a n d 
cet u xi ma b i n c o m bi nati o n is t o c o ntr ol t he disease via mai ntai ni n g t he i n hi biti o n of t he E G F R 
pat h wa y  wit h cet u xi ma b a n d tar geti n g t he e mer gi n g M E T acti vate d pat h wa y wit h te poti ni b.
O bjecti ves a n d E n d p oi nts: 
Safet y R u n -i n
O bj e cti v e s
E n d p oi nt s 
Pri m ar y
T o c o nfir m t h e r e c o m m e n d e d P h a s e II d o s e ( R P 2 D) of 
t e p oti ni b w h e n u s e d i n c o m bi n ati o n wit h c et u xi m a b
O c c urr e n c e of d o s e li miti n g t o xi citi e s ( D L T s)
O verall St u d y
O bj e cti v e s
E n d p oi nt s 
Pri m ar y
T o e v al u at e t h e pr eli mi n ar y effi c a c y of t e p oti ni b ( R P 2 D) 
i n c o m bi n ati o n wit h c et u xi m a b i n t er m s of t u m or 
r e s p o n s e
O bj e cti v e r e s p o n s e ( O R, c o nfir m e d c o m pl et e r e s p o n s e 
[ C R] or p arti al r e s p o n s e [ P R]) d et er mi n e d a c c or di n g t o 
R E CI S T V er si o n 1. 1 a s s e s s e d b y t h e I n v e sti g at or s
S e c o n d ar y
T o f urt h er e v al u at e t h e effi c a c y of t h e c o m bi n ati o n of 
t e p oti ni b ( R P 2 D) a n d c et u xi m a b i n t er m s of
d ur ati o n of r e s p o n s e ( D o R)
D o R ( m o nt h s) a c c or di n g t o R E CI S T V er si o n 1. 1 
a s s e s s e d b y t h e I n v e sti g at or s.
pr o gr e s si o n -fr e e s ur vi v al ( P F S)
P F S ( m o nt h s) a c c or di n g t o R E CI S T V er si o n 1. 1 
a s s e s s e d b y t h e I n v e sti g at or s.
o v er all s ur vi v al ( O S)
O S ( m o nt h s) a s s e s s e d b y t h e I n v e sti g at or s.
T o e v al u at e t h e s af et y a n d t ol er a bilit y of t e p oti ni b i n 
c o m bi n ati o n wit h c et u xi m a b

O c c urr e n c e of A d v er s e E v e nt s ( A E) a n d tr e at m e nt -
r el at e d A E s

O c c urr e n c e of cli ni c all y si g nifi c a nt c h a n g e s i n vit al 
si g n s, l a b or at or y p ar a m et er s a n d 1 2 -l e a d 
e l e ctr o c ar di o gr a m ( E C G) fi n di n g s
T o c h ar a ct eri z e t h e i m m u n o g e ni cit y of c et u xi m a b
I m m u n o g e ni cit y of c et u xi m a b a s m e a s ur e d b y a nti dr u g 
a nti b o d y ( A D A) a s s a y s o n D a y 1 C y cl e 1 a n d E n d of 
Tr e at m e nt Vi sit
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b ( P E R S P E C TI V E)
C O N F I D E N T I A L
I N F O R M A T I O N
1 2 / 1 1 5
O ver all Desi g n: T his is a P hase II, m ultice nter, si n gle -ar m, o pe n -la bel st u d y. A n i nitial s u bset of 
at least 6 partici pa nts will, irres pecti ve of t hera p y li ne, be e nr olle d i n a safety r u n-i n peri o d t o 
c o nfir m t hat t he d ose of 5 0 0 m g o nce dail y  (Q D ) of te p oti ni b (c urre ntly use d i n P hase II st u dies) 
ca n be a d mi nistere d t o get her wit h cet u xi ma b at 2 5 0 m g/ m 2 as a wee kl y  intra ve n o us a d mi nistrati o n. 
After t he safet y ru n- i n peri o d, the Safet y  Mo nit ori n g C o m mittee (S M C ) will deci de a n d c o nfir m 
t he rec o m me n de d P hase II d ose ( R P 2 D) of te p oti ni b t o be use d i n c o m bi nati o n wit h cet u xi ma b i n 
t he w h ole st u d y. P artici pa nts will recei ve a c o m bi nati o n of t he te p oti ni b d ose c o nfir me d b y  the 
S M C a n d cet u xi ma b i n c ycles of 2 1 d a y s d urati o n u ntil disease pr o gressi o n (acc or di n g t o R E CI S T 
Versi o n 1. 1), deat h, A E lea di n g t o disc o nti n uati o n, st u d y wit h dra wal, or wit h dra wal of c o nse nt, 
w hic he ver occ urs first.
Discl os ure St ate me nt: T his is a si n gle gr o u p treat me nt st u d y wit h 1 a r m t hat is o pe n-la bel.
N u m ber of Ar ms: 1
Bli n di n g: N o bli n di n g .
N u m ber of P artici p a nts: I n total, a ma xi m u m of 4 8 partici pa nts are pla n ne d t o be assi g ne d t o 
st u d y inter ve nti o n s uc h t hat a p pr o xi matel y 2 2 ( C o h ort A) a n d 2 0 ( C o h ort B) partici pa nts will be 
treate d at t he R P 2 D.
St u d y I nter ve nti o n Gr o u ps a n d D ur ati o n: F or eac h partici pa nt, t he st u d y will i ncl u de a 
Scree ni n g Peri o d of u p t o 5 6 d a y s, a St u d y  I nter ve nti o n Peri o d c o nsisti n g of 3- wee k c ycles ( Cycles 
are 2 1 d a y s) of te p oti ni b c o m bi ne d wit h cet u xi ma b u ntil disease pr o gressi o n, a n E n d - of-St u d y 
I nter ve nti o n Visit, a Safet y  Foll o w - u p Peri o d of 3 0 d a y s, a n d a 1- ye ar p ost st u d y foll o w -u p. 
T heref ore, ass u mi n g t here are 5 c ycles, t he a ntici pate d d urati o n of treat ment f or eac h partici pa nt 
is 1 9 1 da ys or ~ 6. 5 m o nt hs wit h a 1-ye ar f oll o w -u p peri o d t hereafter.
I n v ol ve me nt of S peci al C o m mittee(s): Yes
1. 2
Sc he m a
A hi g h -le vel sc he d ule of visits / assess me nts is s h o w n i n Secti o n 1. 3 . N u m ber of partici pa nts t o be 
scree ne d is descri be d i n Secti o n 9. 2.  
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 / 1 1 5
A b br e vi ati o n s: 2 L = 2 n d Li n e; 3 L + = 3 r d Li n e +; D L T = D o s e Li miti n g T o xi cit y; Q D = o n c e d ail y; R P 2 D = R e c o m m e n d e d P h a s e II D o s e; S M C = S af et y M o nit ori n g 
C o m mitt e e; U S = U nit e d St at e s.
a
R e q uir e d l o a di n g d o s e at a n i niti al d o s e of 4 0 0 m g/ m2 b o d y s urf a c e ar e a if p arti ci p a nt r e c ei v e d t h e f oll o wi n g:
-
P a nit u m u m a b a s pri or li n e
-
C et u xi m a b a s pri or li n e a n d l a st d o s e w a s m or e t h a n 3 w e e k s a g o.
N o l o a di n g d o s e r e q uir e d if p arti ci p a nt r e c ei v e d c et u xi m a b a s pri or li n e a n d l a st d o s e w a s gi v e n u p t o 3 w e e k s a g o.
b 
T h e 2 5 0 m g o n c e d ail y d o s e i s t h e st a n d ar d d o s e r e d u cti o n. If a p arti ci p a nt still d o e s n ot t ol er at e t h e 2 5 0 m g o n c e d ail y d o s e, or t h e A E d o e s n ot r e s ol v e f oll o wi n g tr e at m e nt 
i nt err u pti o n, p er m an e nt tr e at m e nt di s c o nti n u ati o n or ot h er d o si n g s c h e m a s s h o ul d b e di s c u s s e d wit h t h e S p o n s or.
c
C o h ort A will i n cl u d e p arti ci p a nt s fr o m o ut si d e t h e U S. A f utilit y a n al y si s i s c o n si d er e d w hi c h will b e p erf or m e d aft er 1 2 p arti ci p a nt s ar e e nr oll e d a n d m o nit or e d wit h o ut st o p pi n g 
r e cr uit m e nt of f urt h er p arti ci p a nt s i nt o t hi s st u d y.
d
Aft er t h e s af et y r u n -i n p eri o d, at l e a st 1 6 a d diti o n al p arti ci p a nt s will b e e nr oll e d at t h e R P 2 D e x p a n si o n i n C o h ort A, i n a d diti o n t o t h e 6 p artici p a nt s c o m pl eti n g t h e s af et y r u n -i n
at R P 2 D.
e
C o h ort B will i n cl u d e U S p arti ci p a nt s o nl y .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 / 1 1 5
1. 3
Sc he d ule of Acti vities
A cti vit y / 
A s s e s s m e nt
S cr e e ni n g / 
B a s eli n e
I nt er v e nti o n P eri o d (i n c ycl e s of 3 w e e k s)
E o T 
S af et y  
F oll o w u p /
Di s c o nti -
n u ati o n
S ur vi v al 
F oll o w -U p
/ E o S / 
1- Y e ar 
F oll o w -U p 
N ot e s
D a y -5 6 t o 
D a y - 1
C y cl e 1
(2 1 d a y s)
C y cl e 2
(2 1 d a y s)
C y cl e 3 a n d 
s u b s e q u e nt c y cl e s 
(2 1 d a y s)
Wit hi n 
1 4 d a y s 
aft er 
d e -
ci si o n 
t o wit h-
dr a w 
I M P
3 0 d a y s 
aft er t h e 
l a st d o s e
Aft er S af et y 
F oll o w -U p, 
e v er y  
3 m o nt h s, 
u p t o 
1- y e ar Sit e 
Vi sit or b y  
T el e p h o n e
C y cl e D a y
1
8
1 5
1
8
1 5
1
8
1 5
Vi sit Wi n d o w
± 3 d a y s
± 3 d a y s
± 3 d a y s
- 3 t o + 
7 d a y s
± 1 m o nt h
St u d y Sit e Vi sit s
X
X
X
X
X
X
X
X
X
X
X
X
X
At t h e I n v e sti g at or’ s di s cr eti o n, 
a d diti o n al a s s e s s m e nt s m a y 
b e p erf or m e d at u n s c h e d ul e d 
ti m e p oi nt s if cli ni c all y 
i n di c at e d.
Wr itt e n i nf or m e d 
c o n s e nt
X
I n cl u si o n a n d 
E x cl u si o n Crit eri a
X
R e c h e c k cli ni c al st at u s b ef or e 
1 st d o s e of st u d y i nt er v e nti o n.
S cr e e ni n g l a b s f or eli gi bilit y 
s h o ul d b e p erf or m e d wit hi n 7 
d a y s pri or t o C 1 D 1.
D e m o gr a p h y
X
M e di c al hi st or y
X
HI V S cr e e ni n g
X
HI V t e sti n g i s o pti o n al u nl e s s 
r e q uir e d l o c all y.
H e p atiti s B a n d C 
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 / 1 1 5
A cti vit y / 
A s s e s s m e nt
S cr e e ni n g / 
B a s eli n e
I nt er v e nti o n P eri o d (i n c ycl e s of 3 w e e k s)
E o T 
S af et y  
F oll o w u p /
Di s c o nti -
n u ati o n
S ur vi v al 
F oll o w -U p
/ E o S / 
1- Y e ar 
F oll o w -U p 
N ot e s
D a y -5 6 t o 
D a y - 1
C y cl e 1
(2 1 d a y s)
C y cl e 2
(2 1 d a y s)
C y cl e 3 a n d 
s u b s e q u e nt c y cl e s 
(2 1 d a y s)
Wit hi n 
1 4 d a y s 
aft er 
d e -
ci si o n 
t o wit h-
dr a w 
I M P
3 0 d a y s 
aft er t h e 
l a st d o s e
Aft er S af et y 
F oll o w -U p, 
e v er y  
3 m o nt h s, 
u p t o 
1- y e ar Sit e 
Vi sit or b y  
T el e p h o n e
C y cl e D a y
1
8
1 5
1
8
1 5
1
8
1 5
Vi sit Wi n d o w
± 3 d a y s
± 3 d a y s
± 3 d a y s
- 3 t o + 
7 d a y s
± 1 m o nt h
Pr e g n a n c y T e st 
(w o m e n of c hil d 
b e ari n g p ot e nti al
o nl y)
X
X
X
X
X 
X
S er u m t e st at S cr e e ni n g, uri n e 
t e st t h er e aft er. 
S e e S e cti o n  7. 1 f or E o T 
a s s e s s m e nt d u e t o o c c urr e n c e 
of pr e g n a n c y
P h y si c al 
e x a mi n ati o n 
X
X
X
X
X
X 
X
X
X
X
S y m pt o m dir e ct e d - p h y si c al 
e x a mi n ati o n s will b e 
p erf or m e d a s cli ni c all y 
i n di c at e d p er I n v e sti g at or’ s 
j u d g m e nt. 
Vit al si g n s
X
X
X
X
X
X 
X
X
X
I n cl u d e s h ei g ht ( c oll e ct at 
S cr e e ni n g o nl y) a n d w ei g ht.
St a n d ar d 1 2 -l e a d 
E C G i n cl u di n g 
Q T c
X
X
X
X
A s tri pli c at e s.
E C G a s s e s s m e nt s h o ul d b e 
p erf or m e d wit hi n 6 0 mi n ut e s 
pri or t o pr e d o s e P K bl o o d 
s a m pl e c oll e cti o n ( S e e 
A p p e n di x 4 ).
E C O G P S
X
X
X
X
X
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 / 1 1 5
A cti vit y / 
A s s e s s m e nt
S cr e e ni n g / 
B a s eli n e
I nt er v e nti o n P eri o d (i n c ycl e s of 3 w e e k s)
E o T 
S af et y  
F oll o w u p /
Di s c o nti -
n u ati o n
S ur vi v al 
F oll o w -U p
/ E o S / 
1- Y e ar 
F oll o w -U p 
N ot e s
D a y -5 6 t o 
D a y - 1
C y cl e 1
(2 1 d a y s)
C y cl e 2
(2 1 d a y s)
C y cl e 3 a n d 
s u b s e q u e nt c y cl e s 
(2 1 d a y s)
Wit hi n 
1 4 d a y s 
aft er 
d e -
ci si o n 
t o wit h-
dr a w 
I M P
3 0 d a y s 
aft er t h e 
l a st d o s e
Aft er S af et y 
F oll o w -U p, 
e v er y  
3 m o nt h s, 
u p t o 
1- y e ar Sit e 
Vi sit or b y  
T el e p h o n e
C y cl e D a y
1
8
1 5
1
8
1 5
1
8
1 5
Vi sit Wi n d o w
± 3 d a y s
± 3 d a y s
± 3 d a y s
- 3 t o + 
7 d a y s
± 1 m o nt h
A E a n d S A E 
a s s e s s m e nt
X
C o nti n u o u s
Fr o m t h e ti m e of si g ni n g t h e 
I C F t hr o u g h S af et y F oll o w-u p 
Vi sit.
C o n c o mit a nt 
m e di c ati o n a n d 
pr o c e d ur e s 
r e vi e w
X
C o nti n u o u s
Pr o c e d ur e s r e vi e w i n cl u d e s 
t h e c a pt ur e of c yt ol o g y r e s ult s.
Bl o o d 
h e m at ol o g y, 
bi o c h e mi str y
X
X
X 
X
X
X 
X
X 
X 
X
I n cl u di n g t hr o m b o c yt e s, aft er 
C y cl e ≥2 o nl y D 1.
S er u m c y st ati n C ( o nl y f or 
sit e s w h er e t h e t e st i s 
a v ail a bl e).
Uri n al y si s 
X
X
X
X
X
X 
X
C o a g ul ati o n ( P T, 
a P T T, I N R)
X 
X
X
X
X
X 
X
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 / 1 1 5
A cti vit y / 
A s s e s s m e nt
S cr e e ni n g / 
B a s eli n e
I nt er v e nti o n P eri o d (i n c ycl e s of 3 w e e k s)
E o T 
S af et y  
F oll o w u p /
Di s c o nti -
n u ati o n
S ur vi v al 
F oll o w -U p
/ E o S / 
1- Y e ar 
F oll o w -U p 
N ot e s
D a y -5 6 t o 
D a y - 1
C y cl e 1
(2 1 d a y s)
C y cl e 2
(2 1 d a y s)
C y cl e 3 a n d 
s u b s e q u e nt c y cl e s 
(2 1 d a y s)
Wit hi n 
1 4 d a y s 
aft er 
d e -
ci si o n 
t o wit h-
dr a w 
I M P
3 0 d a y s 
aft er t h e 
l a st d o s e
Aft er S af et y 
F oll o w -U p, 
e v er y  
3 m o nt h s, 
u p t o 
1- y e ar Sit e 
Vi sit or b y  
T el e p h o n e
C y cl e D a y
1
8
1 5
1
8
1 5
1
8
1 5
Vi sit Wi n d o w
± 3 d a y s
± 3 d a y s
± 3 d a y s
- 3 t o + 
7 d a y s
± 1 m o nt h
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 / 1 1 5
A cti vit y / 
A s s e s s m e nt
S cr e e ni n g / 
B a s eli n e
I nt er v e nti o n P eri o d (i n c ycl e s of 3 w e e k s)
E o T 
S af et y  
F oll o w u p /
Di s c o nti -
n u ati o n
S ur vi v al 
F oll o w -U p
/ E o S / 
1- Y e ar 
F oll o w -U p 
N ot e s
D a y -5 6 t o 
D a y - 1
C y cl e 1
(2 1 d a y s)
C y cl e 2
(2 1 d a y s)
C y cl e 3 a n d 
s u b s e q u e nt c y cl e s 
(2 1 d a y s)
Wit hi n 
1 4 d a y s 
aft er 
d e -
ci si o n 
t o wit h-
dr a w 
I M P
3 0 d a y s 
aft er t h e 
l a st d o s e
Aft er S af et y 
F oll o w -U p, 
e v er y  
3 m o nt h s, 
u p t o 
1- y e ar Sit e 
Vi sit or b y  
T el e p h o n e
C y cl e D a y
1
8
1 5
1
8
1 5
1
8
1 5
Vi sit Wi n d o w
± 3 d a y s
± 3 d a y s
± 3 d a y s
- 3 t o + 
7 d a y s
± 1 m o nt h
A D A c et u xi m a b
X
X
S er u m A D A s a m pl e s will b e 
c oll e ct e d pr e d o s e ( wit hi n 6 0 
mi n b ef or e t e p oti ni b d o s e) o nl y 
o n C y cl e 1 D a y 1 a n d at E o T 
( S e e A p p e n di x 4 ) a n d 
S e cti o n 8. 9 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 / 1 1 5
A cti vit y / 
A s s e s s m e nt
S cr e e ni n g / 
B a s eli n e
I nt er v e nti o n P eri o d (i n c ycl e s of 3 w e e k s)
E o T 
S af et y  
F oll o w u p /
Di s c o nti -
n u ati o n
S ur vi v al 
F oll o w -U p
/ E o S / 
1- Y e ar 
F oll o w -U p 
N ot e s
D a y -5 6 t o 
D a y - 1
C y cl e 1
(2 1 d a y s)
C y cl e 2
(2 1 d a y s)
C y cl e 3 a n d 
s u b s e q u e nt c y cl e s 
(2 1 d a y s)
Wit hi n 
1 4 d a y s 
aft er 
d e -
ci si o n 
t o wit h-
dr a w 
I M P
3 0 d a y s 
aft er t h e 
l a st d o s e
Aft er S af et y 
F oll o w -U p, 
e v er y  
3 m o nt h s, 
u p t o 
1- y e ar Sit e 
Vi sit or b y  
T el e p h o n e
C y cl e D a y
1
8
1 5
1
8
1 5
1
8
1 5
Vi sit Wi n d o w
± 3 d a y s
± 3 d a y s
± 3 d a y s
- 3 t o + 
7 d a y s
± 1 m o nt h
ct D N A s a m pl e
X
C y cl e 
3, 5, 9 
a n d 1 3 
o nl y
X
C oll e cti o n pr e d o s e ( wit hi n 
6 0 mi n pri or t o t e p oti ni b d o s e), 
b ef or e pr e m e di c ati o n, if 
a p pli c a bl e ( S e e  A p p e n di x 4 )
D o c u m e nt ati o n of 
R A S /B R A F wil d -
t y p e st at u s, a n d 
hi g h M E T
a m p 
l e v el s 
X
C o nfir m e d pri or t o e nr oll m e nt 
a n d aft er di s e a s e pr o gr e s si o n 
o n t h e pr e vi o u s a nti -E G F R 
t h er a p y b y a n e st a bli s h e d t e st.
T e p oti ni b u ntil P D 
or i nt ol er a bilit y
Q D
D e ci d e d b y t h e S p o n s or a n d 
S M C: D o si n g m a y b e st o p p e d 
at a n y ti m e t o r e vi e w s af et y
a n d P K d at a a n d all o w f or 
a dj u st m e nt s b ef or e d o si n g i s 
r e s u m e d.
A d diti o n al s c h e d ul e s m a y al s o 
b e e v al u at e d.
C et u xi m a b u ntil 
P D or 
i nt ol er a bilit y
W e e kl y
(D a y 1 )
S e e S e cti o n 6. 1 f or d et ail s of 
pr e m e di c ati o n r e q uir e d pri or t o 
fir st i nf u si o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 / 1 1 5
A cti vit y / 
A s s e s s m e nt
S cr e e ni n g / 
B a s eli n e
I nt er v e nti o n P eri o d (i n c ycl e s of 3 w e e k s)
E o T 
S af et y  
F oll o w u p /
Di s c o nti -
n u ati o n
S ur vi v al 
F oll o w -U p
/ E o S / 
1- Y e ar 
F oll o w -U p 
N ot e s
D a y -5 6 t o 
D a y - 1
C y cl e 1
(2 1 d a y s)
C y cl e 2
(2 1 d a y s)
C y cl e 3 a n d 
s u b s e q u e nt c y cl e s 
(2 1 d a y s)
Wit hi n 
1 4 d a y s 
aft er 
d e -
ci si o n 
t o wit h-
dr a w 
I M P
3 0 d a y s 
aft er t h e 
l a st d o s e
Aft er S af et y 
F oll o w -U p, 
e v er y  
3 m o nt h s, 
u p t o 
1- y e ar Sit e 
Vi sit or b y  
T el e p h o n e
C y cl e D a y
1
8
1 5
1
8
1 5
1
8
1 5
Vi sit Wi n d o w
± 3 d a y s
± 3 d a y s
± 3 d a y s
- 3 t o + 
7 d a y s
± 1 m o nt h
T u m or 
A s s e s s m e nt 
( R E CI S T V er si o n 
1. 1) b a s e d o n 
M RI a n d/ or C T 
s c a n s a n d ot h er 
pr ot o c ol - d efi n e d 
i m a gi n g 
m o d aliti e s.
X
X #)
X # #)
S e e S e cti o n  8. 1
S cr e e ni n g t u m or a s s e s s m e nt 
n e e d s t o h a p p e n wit hi n 
2 8 d a y s pri or t o d o si n g. All 
e v al u ati o n s s h o ul d b e 
d o c u m e nt e d b y t h e 
I n v e stig at or a n d i m a g e s 
u pl o a d e d t o t h e i m a gi n g 
r e p o sit or y, f or a p o s si bl e 
i n d e p e n d e nt r e a d at a l at er 
d at e.
#): C 3, C 5, C 7, C 9, C 1 1, C 1 3, 
C 1 5 a n d s u b s e q u e ntl y e v er y 4 
c y cl e s u ntil st u d y cl o s ur e, or 
di s e a s e pr o gr e s si o n 
r e g ar dl e s s of st u d y 
i nt er v e nti o n 
m o difi c ati o n s/ di s c o nti n u ati o n. 
If di s e a s e pr o gr e s si o n i s n ot 
c ert ai n, c o n si d er c o nti n ui n g t o 
i m a g e. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h 
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 / 1 1 5
A cti vit y / 
A s s e s s m e nt
S cr e e ni n g / 
B a s eli n e
I nt er v e nti o n P eri o d (i n c ycl e s of 3 w e e k s)
E o T 
S af et y  
F oll o w u p /
Di s c o nti -
n u ati o n
S ur vi v al 
F oll o w -U p
/ E o S / 
1- Y e ar 
F oll o w -U p 
N ot e s
D a y -5 6 t o 
D a y - 1
C y cl e 1
(2 1 d a y s)
C y cl e 2
(2 1 d a y s)
C y cl e 3 a n d 
s u b s e q u e nt c y cl e s 
(2 1 d a y s)
Wit hi n 
1 4 d a y s 
aft er 
d e -
ci si o n 
t o wit h-
dr a w 
I M P
3 0 d a y s 
aft er t h e 
l a st d o s e
Aft er S af et y 
F oll o w -U p, 
e v er y  
3 m o nt h s, 
u p t o 
1- y e ar Sit e 
Vi sit or b y  
T el e p h o n e
C y cl e D a y
1
8
1 5
1
8
1 5
1
8
1 5
Vi sit Wi n d o w
± 3 d a y s
± 3 d a y s
± 3 d a y s
- 3 t o + 
7 d a y s
± 1 m o nt h
N ot e: Vi sit wi n d o w i s + 7 d a y s 
f or C 3 o nl y. All ot h er c y cl e s, 
t h e vi sit wi n d o w i s ± 7 d a y s.
# #) b ef or e st arti n g a n y n e w 
tr e at m e nt
C h e st X -R a y
X
N ot n e c e s s ar y if t h or a ci c C T i s 
p erf or m e d a s p art of t h e t u m or 
a s s e s s m e nt
( R E CI S T V er si o n 1. 1) at 
s cr e e ni n g. T h e s e e v al u ati o n s 
s h o ul d b e d o c u m e nt e d b y t h e 
I n v e sti g at or a n d u pl o a d e d t o 
t h e i m a gi n g r e p o sit or y, f or a 
p o s si bl e i n d e p e n d e nt r e a d at a 
l at er d at e. 
A E = a d v er s e e v e nt; A D A = A nti - dr u g a nti b o d y; a P T T = a cti v at e d p arti al t hr o m b o pl a sti n ti m e; C = C y cl e; C T = C o m p ut e d t o m o gr a p h y; ct D N A = cir c ul ati n g t u m or 
D N A; E C G = el e ctr o c ar di o gr a m; E C O G P S = E a st er n C o o p er ati v e O n c ol o g y Gr o u p P erf or m a n c e St at u s; E G F R = e pi d er m al gr o wt h f a ct or r e c e pt or; E o T = E n d of 
T r e at m e nt; HI V = H u m a n i m m u n o d efi ci e n c y vir u s; I C F = I nf or m e d C o n s e nt F or m; I M P = in v e sti g ati o n al m e di ci n al p r o du ct ; I N R = I nt er n ati o n al n or m ali z e d r ati o; 
M RI
= M a g n eti c r e s o n a n c e i m a gi n g; P D = pr o gr e s si v e di s e a s e; P K = p h ar m a c o ki n eti c; P T = pr ot hr o m bi n ti m e; R E CI S T = R e s p o n s e E v al u ati o n Crit eri a i n S oli d 
T u m or s; S A E = S eri o u s a d v er s e e v e nt; S M C = S af et y M o nit ori n g C o m mitt e e.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 / 1 1 5
2
I ntr o d ucti o n
Te p oti ni b is a s mall m olec ule, re versi ble a de n osi ne tri p h os p hate c o m petiti ve i n hi bit or of t he 
mese nc h y m al e pit helial tra nsiti o n fact or ( M E T). It is bei n g de vel o pe d as a n a ntit u m or a ge nt i n 
patie nts wit h a wi de variet y  of h u ma n mali g na ncies i ncl u di n g carci no mas of t he l u n g, li ver, 
st o mac h, breast, o var y, ki d ne y, a n d t h yr oi d e x hi biti n g a berra nt M E T acti vati o n s uc h as hi g h -le vel 
M E T
ge ne a m plificati o n or acti vati n g m utati o ns. T he pr o p ose d a d mi nistere d d ose of 5 0 0 m g 
te p oti ni b c orres p o n ds t o 5 0 0 m g te p oti ni b h y dr oc hl ori de h y drate a n d is e q ui vale nt t o 4 5 0 m g 
te p oti ni b (free base f or m). T he 2 5 0 m g te p oti ni b c orres p o n ds t o 2 5 0 m g te p oti ni b h y dr oc hl ori de 
h y drate a n d is e q ui vale nt t o 2 2 5 m g te p oti ni b (free base f or m) .
Cet u xi ma b c o m mercial na me Er bit u x ® is a c hi meric h u ma n/ m o use m o n ocl o nal a nti b o d y of t he 
i m m u n o gl o b uli n G s u bclass t hat tar gets t he h u ma n t yr osi ne ki nase e pi der mal gr o wt h fact or 
rece pt or ( E G F R). Cet u xi ma b is i n dicate d f or t he treat me nt of patie nts wit h E G F R first-e x pressi n g, 
R A S wil d -t ype metastatic c ol or ectal ca ncer ( m C R C) a n d s q ua m o us cell carci n o ma of t he hea d a n d 
nec k.
Detaile d i nf or mati o n o n t he c he mistr y , p har mac ol o g y, efficac y, a n d safet y of cet u xi ma b is f o u n d 
i n t he I nvesti gat or’s Br oc h ure (I B)/ U S Pac ka ge I nserts ( PI)/ S u m mar y of Pr o d uct C haracteris tics 
( S m P Cs), a n d f or te p oti ni b i n t he In vesti gat or’s Br oc h ure (I B).
2. 1
St u d y R ati o n ale
T he p ur p ose of t his st u d y is t o assess t he preli mi nar y  antit u m or acti vit y, safety, a n d t olera bilit y, 
a n d t o e x pl ore t he p har mac o ki netics ( P K) of te p oti ni b i n c o m bi nati o n w it h cet u xi ma b i n 
partici pa nts wit h R A S/ B R A F wil d -t ype left-si de d m C R C ha vi n g ac q uire d resista nce t o a nti -E G F R 
a nti b o d y tar gete d t hera p y d ue t o M E T a m plificati o n. 
Pri or t o t he treat me nt p hase, t he safety r u n-i n peri o d will be c o n d ucte d a d mi nisteri n g te p otini b 
5 0 0 m g o nce dail y ( Q D ) i n c o m bi nati o n wit h 2 5 0 m g/ m 2 of cet u xi ma b o nce wee kl y . D ose Li miti n g 
T o xicities ( D LT) will be assesse d t o c o nfir m t he dail y  rec o m me n de d P hase II d ose ( R P 2 D) as 
c o m bin ati o n wit h cet u xi ma b. As per t he I n vesti gat or’s Br oc h ure/ U S PI / S m P C f or cet u xi ma b, a n 
i nitial l oa di n g d ose of 4 0 0 m g/ m 2 of cet u xi ma b will be gi ve n t o partici pa nts w h o recei ve d 
pa nit u m u ma b as pri or li ne or cet u xi ma b as pri or li ne if t he last d ose of cet u xi ma b was gi ve n m ore 
t ha n 3 wee ks pri or t o first d osi n g. N o l oadi n g d ose of cet u xi ma b will be re q uire d if t he partici pa nt 
recei ve d cet u xi ma b as pri or li ne a n d last d ose was gi ve n u p t o 3 wee ks pri or t o first d osi n g.
T he d ual t hera pe utic a p pr oac h of gi vi n g te p oti ni b a n d cet u xi ma b i n c o m bi nati o n is t o c o ntr ol t he 
diseas e via mai ntai ni n g t he i n hi biti o n of t he E G F R pat h wa y  wit h cet u xi ma b a n d tar geti n g t he 
e mer gi n g M E T acti vate d pat h wa y  wit h te p oti ni b. 
T he pri mar y efficac y a nal ysis will be base d o n all patie nts wit h M E T a m plificati o n i de ntifie d b y a 
p ositi ve li q ui d a n d/ or tiss ue-base d M E T
a m plificati o n test, b ot h wit h a n a p pr o priate re g ulat or y 
stat us w h o were a d mi nistere d at least 1 d ose at R P 2 D of te p oti ni b a n d/ or cet u xi ma b (f ull a nal ys is 
set).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


MSC2156119J, MSB0010442D
Phase II single arm study of tepotinib combined with
MS202202-0002
cetuximab
C O N F I D E N T I A L
I N F O R M A T I O N
23/115
Participants with mCRC with only one prior treatment line will be enrolled into the study for 2nd
line treatment (2L) into Cohort A (countries outside of US). Participants with two or more prior 
treatment lines will be enrolled for 3rd line + (3L+) treatment into Cohort B (US only).
For further discussion of the scientific rationale for study design, see Section 4.2, and for 
justification for dose, see Section 4.3.
2.2
Background
Cetuximab
Cetuximab blocks the binding of EGF and other ligands to the EGFR and prevents EGFR 
dimerization, thereby inhibiting ligand induced activation of this receptor tyrosine kinase. This 
results in the inhibition of cell growth, induction of apoptosis, and decreased production of matrix 
metalloproteinases and vascular endothelial growth factor (reviewed by Moosmann 2007 and 
Vincenzi 2008).
Cetuximab also stimulates EGFR internalization and eventual degradation, by removing the 
receptor from the cell surface and thereby preventing interaction with its ligand (Feng 2007, Perez-
Torres 2006). In addition, cetuximab can mediate antibody-dependent cell-mediated cytotoxicity, 
a process dependent on both the affinity of cetuximab for the extracellular domain of EGFR and 
the level of cellular EGFR expression (Patel 2010).
Inhibition of tumor growth as a single agent, synergy with radiation, and utility in chemo resistant 
tumor cell lines made development of this antibody for anticancer therapy attractive (reviewed by 
Moosmann 2007 and Vincenzi 2008). Additionally, targeted biologic response agents might be 
less likely to damage normal cells than cytotoxic agents. They frequently have nonoverlapping 
toxicities with conventional cytotoxic agents, making them optimal candidates for combination 
therapies. Potential clinical benefits are objective clinical responses or stabilization of disease in 
patients with tumors that are EGFR-positive as the most likely clinical targets. Cetuximab is 
indicated for the treatment of patients with EGFR-expressing, RAS wild-type mCRC in first-line 
treatment and above (Van Cutsem 2015, Bokemeyer 2015, Karapetis 2008). 
MET amplification as a mechanism of acquired resistance to anti-EGFR therapy has been 
demonstrated for cetuximab therapy. Amplification of the MET protooncogene is associated with 
acquired resistance in patients who do not develop KRAS mutations during anti-EGFR therapy. 
Incidence of MET amplification in EGFR-resistant colorectal cancer (CRC) has been observed and 
ranges between 4.1% to 22.6% (Bardelli 2013, LC-SCRUM, ASCO 2019 [Nakamura 2019], 
Raghav 2016, Siravegna 2015, Mohan 2014, Morelli 2014). 
Tepotinib
The in vitro and in vivo primary pharmacology studies demonstrated that tepotinib is a potent and 
highly selective Type I, adenosine triphosphate-competitive inhibitor of the receptor tyrosine 
kinase MET. Tepotinib inhibited hepatocyte growth factor (HGF)-dependent and constitutive 
MET activation in biochemical and cellular assays with IC50 values being consistently in the 
single-digit nanomolar range. With the same potency, tepotinib inhibited MET-mediated signal 
Document No. 0900babe8156c2f9v4.0
Object No. 0900babe815d3301


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 4 / 1 1 5
tra ns d ucti o n, t u m or cell pr oliferati o n a n d a nc h ora ge -i n de pe n de nt gr o wt h i n M E T- de pe n de nt 
t u m or cells.
Gi ve n t he i m p orta nt r ole of a berra nt M E T/ H G F si g nali n g i n ca ncer, se veral differe nt t hera pe utic 
strate gies, ai me d at i n hi biti n g M E T/ H G F si g nali n g, ha ve bee n de vel o pe d a n d are bei n g e val uate d 
i n cli nical st u dies. T hese i ncl u de a ge nts t hat directl y  in hi bit H G F a n d/ or its bi n di n g t o M E T, 
a nti b o dies tar gete d at M E T, 
a n d s mall m olec ule 
M E T 
t yr osi ne ki nase i n hi bit ors (T KI s)
(A wa d 2 0 1 6 , C o m o gli o 2 0 1 8 ).
T he resista nce of a d va nce d e pit helial t u m ors t o c o n ve nti o nal sta n dar d c he m ot hera pies has bee n 
li n ke d t o t heir ge netic c o m ple xit y; h o we ver rece nt fi n di n gs i n dicate t hat ma n y  soli d t u m ors are 
“a d dicted” t o partic ular acti vate d ki nases. Tar geti n g s uc h ki nases wit h selecti ve i n hi bit ors 
re prese nts a pr o misi n g a ntica ncer a p pr oac h. T he r ole of M E T i n t u m or pr o gressi o n a n d metastatic 
disse mi nati o n ma kes it a pri vile ge d ca n di date f or t hera pe utic i nter ve nti o n. F u ncti o nal st u dies 
de m o nstrate t hat M E T acti vati o n c o nfers resista nce t o a nti-E G F R t hera py b ot h i n vitr o a n d i n vi v o. 
N ota bl y , i n patie nt -deri ve d C R C xe n o grafts, M E T
a m plificati o n c orrelate d wit h resista nce t o 
E G F R bl oc ka de w hic h c o ul d be o verc o me b y M E T ki nase i n hi bit ors.
Te p oti ni b a n d Cet u xi m a b C o m bi n ati o n
I n n o n-s mall cell l u n g ca ncer (N S C L C ) t u m ors wit h acti vati n g E G F R ki nase d o mai n m utati o ns, 
t he c o m bi nati o n of te p oti ni b a n d E G F R -T KIs (e. g., gefiti ni b) was s h o w n t o o verc o me resista nce 
t o E G F R-T KI  tr eat me nt me diate d b y  M E T
a m plificati o n ( St u d y EM R 2 0 0 0 9 5 -0 0 6, te p oti ni b wit h 
gefiti ni b [a first ge nerati o n E G F R -T KI ]). T he c o m bi nati o n treat me nt le d t o t u m or re gressi o ns of 
esta blis he d N S C LC -deri ve d h u ma n t u m or xe n o grafts a n d t he a ntit u m or acti vit y  was str o n ger wit h 
t he c o m bi nati o n treat me nt t ha n wit h te p oti ni b al o ne. T he data pr o vi des a rati o nale f or t he treat me nt 
of patie nts w h o de vel o pe d resista nce t o a nti-E G F R t hera py d ue t o M E T
a m plificati o n wit h t he 
c o m bi nati o n of te p oti ni b i n a n a nti-E G F R resista nt setti n g. I nitial si g nals of efficac y of te p oti ni b 
i n P hase I st u dies i n dicate d t he nee d t o stratif y patie nt p o p ulati o ns base d o n pre dicti ve M E T
alterati o ns f or t his hi g hl y  selecti ve dr u g. T hese res ults warra nt f urt her i n vesti gati o n of te p oti ni b 
n ot o nl y  i n N S C LC b ut als o ot her t u m or t y pes s uc h as m C R C i n c o m bi nati o n t hera p y.
T he ge neral c o m bi nati o n of a nti-E G F R t hera py wit h a M E T i n hi bit or t o treat m C R C has bee n 
i n vesti gate d i n se veral st u dies, i n dicati n g t he me dical nee d b ut als o p ote ntial mec ha nis m of acti o n. 
I n pretreate d K R A S wil d -t ype m C R C patie nts wit h n o pri or a nti-E G F R i n hi bit or t hera p y, t he 
c o m bi nati o n of pa nit u m u ma b (a n a nti-E G F R a nti b o d y) wit h ril ot u m u ma b ( h u ma n m o n ocl o nal 
a nti b o d y a gai nst H G F) s h o we d i m pr o ve d res p o nse c o m pare d wit h pa nit u m u ma b al o ne. W hile 
patie nts were n ot selecte d f or M E T a m plificati o n, t he t hera py s h o we d i ncrease d o bjecti ve res p o nse 
rate (O R R ) ( 2 1 % v ersus 3 1 %), me dia n pr o gressi o n -free s ur vi val (P F S ) ( 3. 7 v ersus 5. 2 m o nt hs), 
a n d me dia n o verall s ur vi val (O S ) ( 1 1. 6 v ers us 1 3. 8 m o nt hs) (Va n C utse m 2 0 1 4 ). F urt her m ore, 
ti va nti ni b ( q uesti o na ble M E T i n hi bit or re gar di n g m o de of acti o n [Calles 2 0 1 5 ]) was st u die d i n 
c o m bi nati o n wit h cet u xi ma b pl us iri n oteca n. T he st u d y enr olle d p atie nts wit h wil d -t ype K R A S
m C R C treate d wit h o ne pri or li ne of t hera p y, i ncl u di n g a n iri n oteca n-base d re gi me n b ut n ot a n 
E G F R i n hi bit or. W hile patie nts were n ot selecte d f or M E T a m plificati o n, patie nts i n t he ti va nti ni b 
gr o u p s h o we d i m pr o ve d O R R ( 4 5 % v ersus 3 3 %), me dia n P F S ( 8. 3 v ersus 7. 3 m o nt hs), a n d me dia n 
O S ( 1 9. 8 v ers us 1 6. 9 m o nt hs) c o m pare d wit h t he place b o gr o u p, h o we ver t his st u d y di d n ot reac h 
statistical si g nifica nce t o c o ncl u de t hat a d di n g ti va nti ni b t o cet u xi ma b pl us iri n oteca n lea ds t o 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 / 1 1 5
i m pr o ve d P F S or O S (E n g 2 0 1 6 ). T he c o m bi nati o n of ti va nti ni b a n d cet u xi ma b was i n vesti gate d 
i n patie nts wit h wil d -t ype K R A S , E G F R -resista nt M E T- hi g h (stai ni n g) m C R C, w h o ha d pre vi o usl y  
recei ve d m ore t ha n 1 s yste mic t hera py (last o ne c o ntai n a nti-E G F R) a n d s h o we d t u m or pr o gressi o n 
o n a nti-E G F R t hera p y wit hi n 3 m o nt hs pri or t o e nr oll me nt. T he st u d y di d n ot meet its pri mar y  
e n d p oi nt, wit h a n O R R of 9. 8 %. Me dia n P F S a n d O S were 2. 6 a n d 9. 2 m o nt hs, res pecti vely. Here, 
the maj orit y  of patie nts ha d m ore t ha n 1 li ne of pri or s yste mic t hera pies (Ri massa 2 0 1 9) . 
Sa v oliti ni b (a M E T i n hi bit or) is c urre ntl y bei n g st u die d i n a P hase II trial ( N C T 0 3 5 9 2 6 4 1) i n 
patie nts 
wit h 
M E T -a m plifie d metastatic 
a n d/ or u nresecta ble 
C R C, 
wit h 
wil d -t ype 
i n 
K R A S /N R A S /B R A F . Patie nts are selecte d b y li qui d bi o ps y , h o we ver, d o n ot u n der g o c o m bi nati o n 
t hera py wit h a n a nti-E G F R treat me nt. T his st u d y is o n g oi n g a n d n o data o n t his c o m bi nati o n are 
a vaila ble.
I n s u m mar y, des pite si g nifica nt pr o gress i n t he earl y detecti o n, dia g n osis, a n d treat me nt of t u m ors, 
the efficac y of m ost ca ncer treat me nts re mai ns u nsatisfact or y , a n d re mai ns a n u n met me dical nee d. 
I n a d diti o n, t he hi g h selecti vit y of te p oti ni b (Bla dt 2 0 1 3 ) s u g gests t hat b y  co m bi ni n g te p oti ni b wit h 
ot her ca ncer t hera pies , t he a ntit u m or acti vit y mi g ht be ma xi mize d wit h n o or o nl y  li mite d i ncrease 
i n t o xicit y.
2. 3
Be nefit / Ris k Assess me nt
Cet u xi m a b - Be nefi t
I n patie nts wit h R A S wil d -t ype t u m ors, a si g nifica nt be nefit acr oss all e n d p oi nts was ass ociate d 
wit h t he a d diti o n of cet u xi ma b t o F O L FI RI (Va n C utse m 2 0 1 5 ). T he differe nce i n me dia n O S was 
2 8. 4 m o nt hs i n t he cet u xi ma b pl us F O L FI RI ar m vers us 2 0. 2 m o nt hs i n t he F O L FI RI  al o ne ar m 
( hazar d rati o = 0. 6 9, 9 5 % c o nfi de nce i nter val: 0. 5 4, 0. 8 8; p = 0. 0 0 2). C o m pare d t o t he R A S
e val ua ble p o p ulati o n, all ke y  efficac y en d p oi nts were n u mericall y better i n t he R A S wil d -t ype 
p o p ulati o n. I n patie nts wit h ot her t ha n K R A S e x o n 2 R A S -m uta nt t u m ors, n o clear differe nce i n 
efficac y o utc o mes bet wee n t he treat me nt gr o u ps was see n.
T he precli nical, cli nical -p har mac ol o gical, a n d c urre nt cli nical data o n cet u xi ma b s u g gest a 
fa v ora ble be nefit/ris k of cet u xi ma b i n c o m binati o n wit h F O L F O X 4 vers us F O L F O X 4 al o ne i n t he 
first-li ne treat me nt of m C R C partici pa nts wit h R A S wil d -t ype stat us ( St u d y EM R 6 2 2 0 2 -0 5 7 
( T AI L O R)). 
I n t he re p orti n g peri o d fr o m t he m ost c urre nt versi o n of t he Cet u xi ma b I B (0 1 Oct o ber 2 0 1 9 t o 3 0 
Se pte m ber 2 0 2 0 ) a n esti mate d 8 5, 5 9 9 patie nts ( C R C: 5 1, 1 4 3; s q ua m o us cell carci n o ma of t he hea d 
a n d nec k : 3 4, 4 5 5) were treate d wit h c o m merciall y availa ble cet u xi ma b. T he o verall be nefit/ris k 
pr ofile of cet u xi ma b re mai ns fa v ora ble f or t he a p pr o ve d i n dicati o ns.
Cet u xi m a b – Ris ks
Ver y  co m m o nl y  occ urri n g ris ks i ncl u de mil d t o m o derate i nf usi o n-relate d reacti o ns (I R Rs), s ki n 
reacti o ns, h y p o ma g nese mia, a n d i ncrease i n li ver e nz ymes. M ore detaile d safety i nf or mati o n is 
pr o vi de d i n t he I B / U S PI/ S m P C .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 / 1 1 5
Te p oti ni b - Be nefi t
T he 5 0 0 m g o nce dail y d ose is c o nsi dere d t o be well t olerate d a n d i n t he bi ol o gicall y a cti ve ra n ge, 
it was c h ose n as t he d ose f or t his st u d y. O verall, i n t he o n g oi n g a n d c o m plete d st u dies, te p oti ni b 
was well t olerate d (refer t o t he c urre nt I B). T o f urt he r i m pr o ve t he be nefit/ris k rati o of t he st u d y, 
o nl y  partici pa nts wit h M E T
a m plificati o n p ositi ve t u m ors will be e nr olle d, t h us e na bli n g 
i n vesti gati o n of t he efficac y an d safet y of t he c o m p o u n d i n t he m ost rele va nt p o p ulati o n a n d 
li miti n g f urt her e x p os ure t o t he n o n -tar gete d p o p ulati o n. Te p oti ni b efficac y c o m pares fa v ora bly 
t o a vaila ble t hera pies i n a d va nce d N S C L C. I n a d diti o n, te p oti ni b e x hi bits a n acce pta ble, 
ma na gea ble, a n d t olera ble safet y pr ofile c o m pare d t o c he m ot hera p y  co ntai ni n g re gi me ns, as well 
as t he facilitati o n of treat me nt b y o nce daily oral d osi n g is t o be ta ke n i nt o c o nsi derati o n.
T he pri mar y  en d p oi nt of t he pi v otal VI SI O N st u d y (M S 2 0 0 0 9 5 - 0 0 2 2, a si n gle-ar m [te p oti ni b], 
o pe n -la bel P hase II trial i n partici pa nts wit h N S C L C har b ori n g M E T e x 1 4 alterati o ns or M E T
a m plificati o n), is defi ne d as o bjecti ve res p o nse assesse d b y  in de pe n de nt rea d. T here b y, f or 
M E T e x 1 4 patie nts a rele va nt O R R of 4 6. 5 % ( 9 5 % CI : 3 6. 4, 5 6. 8.) ass ociate d wit h a me dia n
d urati o n of res p o nse ( D o R) of 1 1. 1 m o nt hs (9 5 % CI : 7. 2, n ot esti ma ble) as assesse d b y  
i n de pe n de nt rea d after te p oti ni b m o n ot hera p y is o bser ve d i n t he o verall p o p ulati o n as of t he data 
c ut off date 0 1 Ja n uar y 2 0 2 0 ( patie nts i n t he I T T gr o u p d ose d bef ore 0 2 A pril 2 0 1 9 wit h 9 m o nt hs 
of f oll o w-u p). M ore o ver, a c o nsiste nt pr o p orti o n of res p o n ders is see n acr oss li nes of t hera py, wit h 
O R Rs ra n gi n g bet wee n 4 4 % t o 4 8. 5 %,
w hic h a gai n s u p p orts t he n oti o n of M E T e x 1 4 s ki p pi n g 
alterati o ns bei n g a n o nc o ge nic dri ver f or N S C L C.
Cli nical efficac y  a n d safet y i nf or mati o n of c o m bi nati o ns of M E T i n hi bit ors wit h E G F R i n hi bit ors 
is alrea d y a vaila ble fr o m se veral st u dies. T his i ncl u des i nf or mati o n of te p oti ni b wit h t he 1 st
ge nerati o n E G F R T KI gefiti ni b i n patie nts wit h a d va nce d N S C LC after fail ure t o pre vi o us E G F R 
T KI treat me nt ( N C T 0 1 9 82 9 5 5,  C he n g 2 0 1 8 ). I n partic ular, t he s u b gr o u p of partici pa nts wit h M E T -
a m plifie d, T 7 9 0 M ne gati ve t u m ors, de m o nstrate d p ositi ve efficac y si gnals i ncl u di n g a n O R R of 
6 7 % a n d a me dia n P F S of 1 6. 6 m o nt hs were see n. F urt her m or e, 6 0 partici pa nts were e x p ose d t o 
te p oti ni b wit h t he E G F R i n hi bit or. W hile all partici pa nts recei vi n g t his treat me nt e x perie nce d 
treat me nt‑e mer ge nt a d verse e ve nts ( T E A Es), t he maj orit y  of t hese T E A Es were mil d or m o derate. 
A c o m paris o n of te p oti ni b pl us g efiti ni b vers us c he m ot hera p y s h o we d 9. 7 % vers us 4. 3 % ha vi n g 
T E A Es lea di n g t o per ma ne nt disc o nti n uati o n, 3. 2 % vers us 0 % of T E A Es lea di n g t o deat h ( n o ne 
of t he T E A Es was relate d), 1 6. 1 % vers us 3 0. 4 % ha d seri o us relate d T E A Es, 5 1. 6 % vers us 5 2. 2 % 
ha d Gra de ≥3 relate d T E A Es, a n d 1 2. 9 % vers us 8. 7 % ha d li pase/a myl ase i ncrease Gra de ≥3 n ot 
acc o m pa nie d b y  pa ncreatitis or res pecti ve s ym pt o ms. O verall, te p oti ni b i n c o m bi nati o n wit h 
gefiti ni b was c o nsi dere d safe a n d well t olerate d ( Che n g 2 0 1 8 ).
Bar delli et al. de m o nstrate d t hat M E T acti vati o n i n C R C t u m or cells c o nferre d resista nce t o a nti-
E G F R t hera py i n vitr o a n d i n vi v o . I n patie nt-deri ve d C R C xe n o grafts, M E T
a m plificati o n 
c orrelate d wit h resista nce t o E G F R bl oc ka de w hic h c o ul d be o verc o me b y M E T ki nase i n hi bit ors 
(Bar delli 2 0 1 4 ).
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 / 1 1 5
Te p oti ni b - Ris ks
I nterstitial l u n g disease (I L D) is c o nsi dere d a ris k i n patie nts wit h a d va nce d N S C L C, as well as 
e de ma ( mai nl y peri p heral e de ma), creati ni ne i ncrease d, h y p oal b u mi ne mia, a m yl ase a n d li pase 
i ncrease 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) i ncrease d,  
diarr hea , a n d na usea a n d v o miti n g. All t hese ris ks ha ve bee n a d verse reacti o ns t o te p oti ni b. M ore 
detaile d safet y  i nf or mati o n o n classificati o n of ris ks is pr o vi de d i n t he I B. 
As l o n g as safety meas ures descri be d i n t he pr ot oc ol are strictly f oll o we d, it is reas o na ble t o belie ve 
t hat t he p ote ntial be nefit of te p oti ni b o ut wei g hs its ris k i n partici pa nts wit h m C R C w h o ha ve 
pr o gresse d o n a nti-E G F R a nti b o d y tar geti n g t hera p y due t o M E T
a m plificati o n. F urt her m ore, a 
S M C will re g ularl y m o nit or safet y t hr o u g h o ut t he st u d y .
Be nefit/ Ris k Assess me nt: C o m bi n ati o n of te p oti ni b wit h cet u xi m a b
I n t his st u d y, p ossi ble o verla p pi n g t o xicities f or t he c o m bi nati o n of te p oti ni b pl us cet u xi ma b are 
diarr hea, i ncrease i n li ver e nz y mes: A S T a n d A L T, a n d I L D.
Diarr hea, A L T a n d A S T i ncrease are ge nerall y  mil d t o m o derate i n se verit y. F or b ot h dr u gs t hese 
are ris ks t hat are well ma na gea ble. As per cet u xi ma b la bel, i ncrease i n li ver e nz ymes le vels are 
ver y  co m m o n, h o we ver i n a m o n ot hera p y  st u d y the y  were n ot a m o n g t he m ost c o m m o n a d verse 
e ve nts (A Es ) re p orte d ( ≥1 5 %). I ncl usi o n will be o nl y  all o we d f or partici pa nts wit h a de q uate 
he patic f u ncti o n. 
T h o u g h I L D is a ris k f or b ot h pr o d ucts, it was see n o nl y i n patie nts wit h N S C L C ( 1. 9 %) w he n 
treate d wit h te p oti ni b. F or cet u xi ma b it is a n u nc o m m o n ( < 1 %) e ve nt. T h us, t he li keli h o o d of a 
part ici pa nt t o e x perie nce a n I L D i n t his st u d y is c o nsi dere d l o w. O verall , t he ris k fr o m o verla p pi n g 
t o xicities is c o nsi dere d as ma na gea ble a n d a de q uate meas ure me nts s uc h as eli gi bilit y criteria a n d 
d ose m o dificati o ns are i n place. P artici pa nt s wit h a hist or y  of I L D or w h o de vel o p I L D will be 
e xcl u de d fr o m t he st u d y.
M ore 
detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks f or t he use 
c o m bi nati o n of te p oti ni b wit h cet u xi ma b, see Secti o n 4. 2 a n d m ore detail o n t he reas o na bly 
e x pecte d a d verse e ve nts of te p oti ni b a n d cet u xi ma b ma y  be f o u n d i n t he res pecti ve I Bs a n d 
S m P C/ U S PI  f or cet u xi ma b.
Base d o n t he a vaila ble te p oti ni b a n d cet u xi ma b n o ncli nical a n d cli nical data t o date, t he c o n d uct 
of t h e st u d y, as s pecifie d i n t his pr ot oc ol, is c o nsi dere d j ustifia ble.
M ore o ver, a Safet y R u n -i n Peri o d has bee n pla n ne d t o all o w f or a detaile d e val uati o n of t he 
c o m bi nati o n re gi me n b y  a Safet y M o nit ori n g C o m mittee ( S M C) after t he first 3 patie nts bef ore 
m ore partici pa nts are e nr olle d i nt o t he st u d y .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 / 1 1 5
3
O bjecti ves a n d E n d p oi nts
Safet y R u n -i n
O bj e cti v e s
E n d p oi nt s 
Pri m ar y
T o c o nfir m t h e r e c o m m e n d e d P h a s e II d o s e ( R P 2 D) of 
t e p oti ni b w h e n u s e d i n c o m bi n ati o n wit h c et u xi m a b
O c c urr e n c e of d o s e li miti n g t o xi citi e s ( D L T s)
O verall St u d y
O bj e cti v e s
E n d p oi nt s 
Pri m ar y
T o e v al u at e t h e pr eli mi n ar y effi c a c y of t e p oti ni b ( R P 2 D) 
i n c o m bi n ati o n wit h c et u xi m a b i n t er m s of t u m or 
r e s p o n s e
O bj e cti v e r e s p o n s e ( O R, c o nfir m e d c o m pl et e r e s p o n s e 
[ C R] or p arti al r e s p o n s e [ P R]) d et er mi n e d a c c or di n g t o 
R E CI S T V er si o n 1. 1 a s s e s s e d b y t h e I n v e sti g at or s
S e c o n d ar y
T o f urt h er e v al u at e t h e effi c a c y of t h e c o m bi n ati o n of 
t e p oti ni b ( R P 2 D) a n d c et u xi m a b i n t er m s of
d ur ati o n of r e s p o n s e ( D o R)
D o R ( m o nt h s) a c c or di n g t o R E CI S T V er si o n 1. 1 
a s s e s s e d b y t h e I n v e sti g at or s
pr o gr e s si o n -fr e e s ur vi v al ( P F S)
P F S ( m o nt h s) a c c or di n g t o R E CI S T V er si o n 1. 1 
a s s e s s e d b y t h e I n v e sti g at or s
o v er all s ur vi v al ( O S)
O S ( m o nt h s) a s s e s s e d b y t h e I n v e sti g at or s
T o e v al u at e t h e s af et y a n d t ol er a bilit y of t e p oti ni b i n 
c o m bi n ati o n wit h c et u xi m a b

O c c urr e n c e of A d v er s e E v e nt s ( A E) a n d tr e at m e nt -
r el at e d A E s

O c c urr e n c e of cli ni c all y si g nifi c a nt c h a n g e s i n vit al 
si g n s, l a b or at or y p ar a m et er s a n d 1 2 -l e a d 
e l e ctr o c ar di o gr a m ( E C G) fi n din g s
T o c h ar a ct eri z e t h e i m m u n o g e ni cit y of c et u xi m a b
I m m u n o g e ni cit y of c et u xi m a b a s m e a s ur e d b y a nti dr u g 
a nti b o d y ( A D A) a s s a y s o n C y cl e 1 D a y 1 a n d E n d of 
Tr e at m e nt Vi sit
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 / 1 1 5
4
St u d y Desi g n
4. 1
O ver all Desi g n
Please als o see cr oss-refere nces t o Secti o n 1. 2,  Secti o n 1. 3, a n d Secti o n 6. 7.
T his is a P hase II, m ultice nter, si n gle-ar m, o pe n -la bel st u d y. A t olera ble d ose of te p oti ni b a n d 
cet u xi ma b will be defi ne d i n t he safety ru n- i n peri o d. It will assess t he preli mi nar y  antit u m or 
acti vit y, safety, t olera bilit y, a n d e x pl ore t he P K of t he M E T i n hi bit or te p oti ni b c o m bi ne d wit h 
cet u xi ma b (a c hi meric m o n ocl o nal i m m u n o gl o b uli n G
a nti-E G F R m o n ocl o nal a nti b o d y) i n 
R A S /B R A F
wil d -t ype m C R C partici pa nts ha vi n g ac q uire d resista nce t o a nti-E G F R a nti b o d y 
tar gete d t hera p y due t o M E T
a m plificat i o n. Visits a n d d urati o n of treat me nt are descri be d as 
f oll o ws:
Scree ni n g
After ha vi n g gi ve n writte n i nf or me d c o nse nt f or scree ni n g pr oce d ures, M E T
a m plificati o n stat us 
will be assesse d b y a li q ui d a n d/ or tiss ue -base d M E T a m plificati o n test i n partici pa nts wit h m C R C 
wit h d oc u me nte d rela pse o n pre vi o us E G F R - m o n ocl o nal a nti b o dy treat me nt. Tiss ue a n d/ or li q ui d 
bi o ps y  sa m ples pr o vi de d f or t he i ncl usi o n testi n g will ha ve t o be c ollecte d after disease pr o gressi o n 
of t he pre vi o us a nti-E G F R t hera py.  Please see Sect i o n 8. 8 f or m ore detail o n re q uire me nts a n d 
tests f or M E T a m plificati o n stat us a n d R A S /B R A F wil d -t ype stat us.
R A S /B R A F wil d -t ype stat us will be c o nfir me d f or eli gi bilit y bef ore e nr olli n g t he partici pa nt, a n d 
after disease pr o gressi o n o n t he pre vi o us a nti- E G F R t hera p y  b y a n esta blis he d test.
After ha vi n g gi ve n writte n i nf or me d c o nse nt, eli gi bilit y  criteria will be assesse d pri or t o te p oti ni b 
a n d cet u xi ma b c oa d mi nistratio n o n Da y 1. If, at scree ni n g, t he partici pa nt meets 
all t he 
pr ot oc ol -defi ne d i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria, t he partici pa nt will be 
e nr olle d i nt o eit her C o h ort A ( 2 L treat me nt, o utsi de U S) or C o h ort B ( 3L + i n t he U S o nl y) i n t he 
st u d y; U S partici pa nts are o nl y all o we d t o be e nr olle d i nt o C o h ort B.
T he scree ni n g peri o d will i ncl u de a B aseli ne t u m or R E CI S T Versi o n 1. 1 assess me nt base d o n 
c o m p ute d t o m o gra p hy (C T ) or m a g netic res o na nce i ma gi n g (M RI ) a n d t he c o nfir mati o n of 
meas ura ble t u m or disease b y  the In vesti gat or wit hi n 2 8 da y s bef ore d osi n g . All ra di ol o gical 
i ma ges will be c ollecte d, q ualit y  chec ke d a n d st ore d f or a p ote ntial p ost -st u d y ce ntralize d rea d. 
Partici pa nts w h o fail t o meet t he pr ot oc ol -s pecifie d criteria or w h o disc o nti n ue t he st u d y bef ore 
start of st u d y i nter ve nti o n will be c o nsi dere d scree ni n g fail ures. 
Tre at me nt Peri o d
Eli gi ble partici pa nts will recei ve a c o m bi nati o n of t he te p oti ni b d ose c o nfir me d b y  the S M C a n d 
cet u xi ma b i n c ycles of 2 1 da y s d urati o n u ntil disease pr o gressi o n (acc or di n g t o R E CIS T Versi o n 
1. 1), deat h, A E lea di n g t o disc o nti n uati o n of b ot h st u d y inter ve nti o ns , st u d y wit h dra wal, or 
wit h dra wal of c o nse nt, w hic he ver occ urs first.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 0 / 1 1 5
S afet y R u n -i n
A n i nitial s u bset of at least 6 partici pa nts will, irres pecti ve of t hera py li ne, be e nr olle d i n a safet y 
r u n-i n peri o d t o c o nfir m t hat t he d ose of 5 0 0 m g Q D of te p oti ni b (c urre ntl y use d i n P hase II st u dies) 
ca n be a d mi nistere d t o get her wit h cet u xi ma b at 2 5 0 m g/ m 2 as a wee kl y  intra ve n o us ad mi nistrati o n. 
C o h orts of 3 partici pa nts will be e nr olle d bef ore S M C e val uat i o n. U n der certai n c o n diti o ns, 
de pe n di n g o n pri or t hera p y , a n i nitial l oa di n g d ose of 4 0 0 m g/ m2 of cet u xi ma b is re q uire d bef ore 
t he wee kl y  25 0 m g / m2 d ose is gi ve n. See Secti o n 6. 1 w hic h pr o vi des t he g ui da nce t o w he n t he 
i nitial l oa di n g d ose is gi ve n a n d w he n n ot t o gi ve. If t he d ose of te p oti ni b is n ot t olerate d, t he d ose 
will be c ha n ge d ba se d o n o bser ve d D L Ts f or t he sec o n d r u n-i n c o h ort. T his decisi o n will be ta ke n 
b y  a SM C c o nsisti n g of S p o ns or re prese ntati ves i ncl u di n g, b ut n ot li mite d t o t he Patie nt Safet y 
Strate g y  Lea d (c hair), t he Me dical Res p o nsi ble, a n d t he Bi ostatisticia n, a n d t he c o or di nati n g 
I n vesti gat ors or t heir de p uties, base d o n safety data, a n d if a vaila ble, P K data. If n ot t olerate d, t he 
d ose of te p oti ni b will be a dj uste d t o a d ose t hat will be gi ve n t o at least 6 a d diti o nal partici pa nts 
d uri n g t he safet y r u n -i n peri o d. F urt her details o n t he Bayesia n o pti mal i nter val ( B OI N ) m o del are 
s h o w n i n Secti o n 9. 4. 2. 1.
T he first partici pa nt of t he safet y r u n -i n peri o d will be closel y  m o nit ore d f or at least 3 d a y s b y  t he 
e nr olli n g I n vesti gat or, wit h safety p h o ne calls eac h d a y , bef ore t he sec o n d partici pa nt ca n b e 
treate d. I nterr u pti o n of e nr oll me nt a n d a relate d S M C meeti n g m a y  be re q ueste d at a n y ti me b y  
a n y SM C me m ber(s) if a safet y o r t olera bilit y si gnal re q uires e x pe dite d disc ussi o ns. T he S M C ca n 
pr o vi de f urt her treat me nt re gi me n s u g gesti o ns as i.e. h oli da y sc he d ules or te p oti ni b e ver y sec o n d 
da y .
C o h ort e x p a nsi o n at R P 2 D
T he S M C will deci de a n d c o nfir m t he rec o m me n de d P hase II d ose ( R P 2 D) of te p oti ni b t o be use d 
i n c o m bi nati o n wit h cet u xi ma b i n t he w h ole st u d y. T he S M C ma y  als o deci de t o re d uce t he 
te p oti ni b d ose t o 2 5 0 m g Q D base d o n t he data c ollecte d d uri n g t he safety r u n -i n a n d f or t he w h ole 
st u d y. If t he d ose of 2 5 0 m g QD is i n ge neral n ot t olerate d, d osi n g i n t his st u d y mi g ht be st o p pe d. 
D osi n g ca n als o be st o p pe d at a n y ti me t o re vie w safety a n d, if a vaila ble, P K data , t o all o w f or 
a dj ust me nts bef ore d osi n g is res u me d w hic h will be deci de d b y  t he S p o ns or a n d t he S M C. Sa fety 
r u n-i n peri o d ca n i ncl u de partici pa nts fr o m C o h orts A a n d/ or B. T he S M C’s r ules f or assessi n g 
d ose escalati o n a n d st o p pi n g r ules are descri be d u n der Secti o n  9. 4. 2. 1.
F oll o w -u p Peri o d
All partici pa nts are t o be f oll o we d u p after st o p of treat me nt wit h te p oti ni b a n d cet u xi ma b, 
i ncl u di n g a n E n d of Treat me nt ( E o T) V isit wit hi n 1 4 d a y s of t he last d ose of te p oti ni b a n d/ or 
cet u xi ma b. A Safet y F oll o w -u p Visit will occ ur 3 0 (- 3 t o + 7) da y s after t he last d ose of te p oti ni b 
a n d/ or cet u xi ma b f or all partici pa nts w h o disc o nti n ue d t he st u d y inter ve nti o n per ma ne ntl y. After 
t he Safety F oll o w - u p V isit, t he S ur vi val F oll o w -u p is t o be perf or me d e ver y 3 m o nt hs ( ± 1 m o nt h) 
at cli nic visits or b y  tele p h o ne c o ntact f or u p t o 1 ye ar. Partici pa nts’ s ur vi val i nf or mati o n will be 
c ollecte d. A n y s u bse q ue nt a ntica ncer t hera p y gi ve n t o t he partici pa nt u ntil deat h s h o ul d be 
rec or de d. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 1 / 1 1 5
Partici pa nts w h o disc o nti n ue treat me nt f or reas o ns ot her t han pr o gressi ve disease ( P D) or deat h 
will ha ve a d diti o nal visits f or t u m or assess me nts e ver y 6 wee ks u ntil 9 m o nt hs a n d e ver y 12 wee ks 
t hereafter u ntil disease pr o gressi o n, deat h, or wit h dra wal of c o nse nt. A ± 7- d a y  ti me wi n d o w is 
per mitte d f or t hese a d diti o nal f oll o w- u p visits u ntil 9 m o nt hs, a n d ± 1 4 da ys t hereafter.
D ur ati o n of st u d y f or e ac h p artici p a nt, a n d d ur ati o n of t he st u d y i nter ve nti o n peri o d
F or eac h partici pa nt, t he st u d y  will i ncl u de a Scree ni n g Peri o d of u p t o 5 6 da ys, a St u d y
I nter ve nti o n Per i o d c o nsisti n g of 3- wee k c ycles ( C ycles are 2 1 d a y s) of te p oti ni b c o m bi ne d wit h 
cet u xi ma b u ntil disease pr o gressi o n, a n E n d - of-St u d y  Inter ve nti o n Visit, a Safet y  Foll o w - u p 
Peri o d of 3 0 d a y s, a n d a 1- ye ar p ost st u d y foll o w -u p. T heref ore, ass u mi n g t here are 5 c y cles, t he 
a ntici pate d d urati o n of treat me nt f or eac h partici pa nt is 1 9 1 da y s or ~ 6. 5 m o nt hs wit h a 1- year 
f oll o w-u p peri o d t hereafter.
Partici pa nts w h o disc o nti n ue t he st u d y for a n y reas o n, e xce pt f or partici pa nt wit h dra wal, will 
c o m plete t he E n d -of -St u d y  Inter ve nti o n ( E n d of Treat me nt), a n d Safet y F oll o w - u p Visit. See 
Secti o n  1. 3 .
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
D y sre g ulati o n of M E T si g nali n g is a n o nc o ge ni c dri ver i n a n u m ber of t u m ors a n d i nterferi n g wit h 
t he acti vit y of M E T is a n effecti ve w a y  to i n d uce t u m or re gressi o n a n d sta bilizati o n. T he hi g h 
fre q ue nc y of o ver 5 0 % of 1 2 m o nt hs a n d l o n ger lasti n g t u m or res p o nses re p orte d i n N S C L C 
patie nts wit h t u m ors carr yi n g a M E T e x 1 4 s ki p pi n g m utati o n de m o nstrate d t his (Pai k 2 0 1 9 ). 
F urt her m ore, te p oti ni b cli nical acti vit y was re p orte d i n t u m ors o vere x pressi n g M E T , s uc h as 
E G F R -m utate d N S C L C pr o gressi n g o n E G F R i n hi bit ors a n d he pat ocell ular carci n o mas (Decae ns 
2 0 1 8, R y o o 2 0 1 8 , Ya n g 2 0 1 9 ). Es peciall y  i n t u m ors s uc h as gastric t u m ors, mela n o ma, p a pillar y 
re nal cell carci n o ma, hea d a n d n ec k t u m ors, o varia n ca ncer, gli o ma a n d bla d der ca ncer, M E T
a m plificati o n was o bser ve d a n d mi g ht be a tar get f or s pecific t hera p y  resista nce 
 
It has bee n o bser ve d t hat de n o v o M E T a m plificati o n occ urs rarely i n m C R C ( 1 % t o 2 %), 
(Ra g ha v 2 0 1 6 ). H o we ver, ac q uire d M E T a m plificati o n ca n be i de ntifie d b y  circ ulati n g t u m or D N A 
(ct D N A) i n a si g nifica nt s u bset of m C R C patie nts t hat are refract or y to a nti-E G F R a nti b o dies  
(Bar delli 2 0 1 3,  L C -S C R U M, A S C O 2 0 1 9 [Na ka m ura 2 0 1 9 ], Ra g ha v 2 0 1 6 , Sira ve g na 2 0 1 5 , 
M o ha n 2 0 1 4 , M orelli 2 0 1 4 ). T heref ore, M E T a m plificati o ns m ost li kel y pla y a n i m p orta nt r ole i n 
ac q uire d a nti-E G F R resista nce. T hese fi n di n gs ha ve clear im plicati o ns f or i de ntif yi n g patie nt 
p o p ulati o ns a n d f or desi g ni n g a p pr o priate cli nical trials usi n g M E T i n hi bit ors i n m C R C a n d 
p ote ntiall y  ser ve as a usef ul pre dicti ve bi o mar ker of M E T i n hi bit or res p o nse i n m C R C cli nical 
trials (Ra g ha v 2 0 1 6) . E G F R tar gete d m o n ocl o nal a nti b o dies are effecti ve i n a s u bset of m C R C. 
I ne vita bl y, all patie nts de vel o p resista nce, w hic h occ urs t hr o u g h e mer ge nce of R A S m utati o ns i n 
a p pr o xi matel y 50 % of t he cases. Partici pa nts wit h these R A S m utat i o ns will be e x cl u de d i n t his 
st u d y po p ulati o n. A m plificati o n of t he M E T pr ot o o nc o ge ne is a n a d diti o nal mec ha nis m ass ociate d 
wit h ac q uire d resista nce i n patie nts w h o d o n ot de vel o p R A S m utati o ns d uri n g a nti-E G F R t hera py. 
Ac q uire d M E T
a m plificati o n was see n i n 3 o ut of 7 patie nts wit h p ost a nti-E G F R treat me nt 
sa m ples. M E T a m plificati o n was detecte d i n ct D N A bef ore rela pse beca me cli nicall y evi de nt 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 2 / 1 1 5
(Bar delli 2 0 1 3 ). I n vitr o a n d i n vi v o st u dies de m o nstrate d t hat M E T acti vati o n c o nferre d resista nce 
t o a nti-E G F R t hera p y. I n patie nt -deri ve d C R C xe n o grafts, M E T a m plificati o n c orrelate d wit h 
resista nce t o E G F R bl oc ka de w hic h c o ul d be o verc o me b y  ME T ki nase i n hi bit ors s uc h as te p oti ni b 
a n d ot hers (Bar delli 2 0 1 3 ). T he e mer ge nce of M E T
a m plificati o n i n ct D N A of m C R C patie nts 
after treat me nt wit h cet u xi ma b or pa nit u m u ma b was c o nfir me d i n f urt her i n de pe n de nt st u dies: it 
was f o u n d i n 2 o ut of 1 0 ( 2 0 %) patie nts (M o ha n
2 0 1 4 ), 3 o ut of 1 6 ( 1 9 %) patie nts (Sira ve g na 
2 0 1 5 ), 1 2 o ut of 5 3 ( 2 3 %) patie nts (Ra g ha v 2 0 1 6 ), a n d 1 0 o ut of 7 1 ( 1 4 %) patie nts (Na ka m ura 
2 0 1 9 ). M E T
a m plificati o n was s pecifically detecte d after a nti-E G F R t hera p y, b ut n ot after a nti-
V E G F treat me nt, c he m ot hera p y o r re g orafe ni b (Ra g ha v 2 0 1 6 ). R A S -m uta nt t u m or stat us is k n o w n 
t o be a ver y  str o ng ne gati ve pre dict or f or E G F R a nti b o d y thera p y w hilst, R A S w il d-ty pe t u m or
stat us is a relati vel y str o n g pre dicti ve mar ker f or t he efficac y of E G F R a nti b o d y thera p y. B R A F
t u m or m utati o ns are str o n g ne gati ve pr o g n ostic mar kers b ut als o pre dicti ve mar kers f or alter nati ve 
t hera py o pti o ns . R A S /B R A F wil d -t ype was p ote ntiall y  c h ose n as all g ui deli nes disc o ura ge t he use 
of a nti-E G F R m o n ocl o nal a nti b o dies i n patie nts wit h B R A F - muta n t disease des pite of a still 
i nc o ncl usi ve e vi de nce sit uati o n. 
T he d ual t hera pe utic a p pr oac h t o c o ntr ol t he disease via mai ntai ni n g t he i n hi biti o n of t he E G F R 
pat h wa y  wit h cet u xi ma b a n d at t he sa me ti me tar geti n g t he e mer gi n g M E T acti vate d pat h wa y  wit h 
te p oti ni b offers a p ote ntial treat me nt o pti o n f or t h ose patie nts. T here is c urre ntl y no pers o nalize d 
treat me nt o pti o n a vaila ble f or t hese selecte d m C R C patie nts a n d t heref ore c o nstit utes a cli nical 
c o n diti o n wit h hi g h u n met me dical nee d. Si nce it is descri be d t hat a nti-E G F R resista nt cl o nes 
deca y  ex p o ne ntiall y  after st o p pi n g t he a nti-E G F R t hera p y p ost -pr o gressi o n (Parse g hia n 2 0 1 9 ), a 
ti mel y i nitiati o n of t he d ual t hera py is re q uire d. 
D ue t o t he differe nt nat ure of t he t w o dr u gs (s mall m olec ule a n d pr otei n) a n d t he c o nse q ue nt 
differe nt meta b olic pat h wa ys , t he p ote ntial f or P K i nteracti o ns bet wee n b ot h dr u gs is c o nsi dere d 
l o w. Als o, t he ris k f or o verla p pi n g t o xicit y is c o nsi dere d l o w, h o we ver, t his will be cl osel y 
m o nit ore d.
T he pr o p ose d st u d y in vesti gates te p oti ni b c o m bi ne d wit h cet u xi ma b i n R A S /B R A F wi l d-t ype 
m C R C patie nts w h o ha ve ac q uire d resista nce t o a nti-E G F R a nti b o d y thera p y d ue t o M E T 
a m plificati o n.
T he pr o g n ostic i m pact of t he pri mar y  tu m or l ocati o n i n metastatic C R C has bee n disc usse d 
e xte nsi vel y, i ncl u di n g a meta -a nal ys is w hic h has bee n i nitiate d b y  ES M O a n d pr o vi de d e vi de nce 
i n t he first-li ne treat me nt setti n g t o rei nf orce t he use of E G F R a nti b o d y thera p y i n patie nts wit h 
m C R C 
a n d left-si de d R A S
w il d-ty pe
t u m ors (Ar n ol d 
2 0 1 7
a n d E S M O Asia 
g ui deli nes 
[Y os hi n o 2 0 1 8] ). Patie nts wit h left -si de d t u m ors ha d a mar ke dl y  better pr o g n osis t ha n t h ose wit h 
ri g ht-si de d t u m ors i n t he R A S
w il d-ty pe p o p ulati o ns of C R Y S T A L  (P hase III Cet u xi ma b 
C o m bi ne d Wit h 
Iri n oteca n i n First -li ne T hera p y f or m C R C [ C R Y S T A L]) st u d y an d FI R E -3 
( Phase III, T he F O L FI RI  Pl us Cet u xi ma b Vers us F O L FI RI  Pl us be vaciz u ma b as First -Li n e 
Treat me nt F or Patie nts Wit h 
m C R C [FI R E - 3]). First -li ne F O L FI RI pl us cet u xi ma b clearl y 
be nefitte d patie nts wit h left-si de d t u m ors ( versus F O L FI RI or F O L FI RI  pl us be vaciz u ma b), 
si g nifica ntly i m pr o vi n g O S ( C R Y S T A L: hazar d rati o [ H R] = 0. 6 5 ; 9 5 % CI : 0. 5 0 , 0.8 6 a n d 
FI R E -3: H R = 0. 6 3 ; 9 5 % CI : 0. 4 8, 0. 8 5) wit hi n t he R A S w il d-ty pe p o p ulati o ns of b ot h st u dies i n 
m ulti varia ble m o dels t hat als o i ncl u de d se x, pri or a dj u va nt t hera py, a n d B R A F m utati o nal stat us
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 3 / 1 1 5
(Tej par 2 0 1 7) . Patie nts wit h ri g ht-si de d t u m ors deri ve d li mite d be nefit fr o m sta n dar d treat me nts 
(i.e. F O L FI RI, F O L FI RI  pl us be vaciz u ma b, a n d F O L FI RI pl us cet u xi ma b (Tej par 2 0 1 7 ). T hese 
differe nces are base d o n t he differe nt ge netic p he n ot y pe of b ot h pri mar y t u m or l ocati o ns. 
T heref ore, partici pa nts wit h a d va nce d (l ocally a d v a nce d or metastatic) left-si de d c ol orectal ca ncer 
are i ncl u de d i n t his st u d y.
W hile cet u xi ma b a n d pa nit u m u ma b are a p pr o ve d as treat me nt o pti o ns f or patie nts i n a first-li ne 
a n d later li ne setti n g, differe nt sta n dar d of cares are e sta blis he d bet wee n U S a n d E ur o pe a n d ot her 
re gi o ns. I n E ur o pe, cet u xi ma b is m ore c o m m o nly use d i n first -li ne, w hereas i n U S it is m ore ofte n 
use d after be vaciz u ma b + c he m ot hera p y. T heref ore, t he st u d y will i ncl u de partici pa nts wit h a pri or 
first-li ne of a nti-E G F R c o ntai ni n g t hera p y  o utsi de of U S ( C o h ort A) , a n d i n U S partici pa nts wit h 
m ore t ha n o ne pri or li ne of t hera pies ( wit h t he m ost rece nt li ne bei n g a n a nti-E G F R c o ntai ni n g 
t hera py , C o h ort B). A se parate a nal ysis e val uati n g t he safety a n d res p o nses will be perf or me d f or 
all c o h orts.
4. 3
J ustific ati o n f or D ose
Cet u xi ma b will be use d acc or di n g t o t he a p pr o ve d la bel, wit h a n i nitial d ose of 4 0 0 m g/ m 2 (if 
nee de d, f oll o we d b y  re petiti ve wee kl y d oses of 2 5 0 m g/ m 2, see Secti o n  6. 1 f or g ui da nce). Detaile d 
i nf or mati o n o n t he P K of cet u xi ma b i n h u ma ns ca n be f o u n d i n t he I B/ U S PIs/ S m P Cs.
Te p oti ni b will be use d at a starti n g d ose of 5 0 0 m g Q D i n a 2 1- da y c ycle, w hic h is t he
rec o m me n de d d ose a n d has bee n i n vesti gate d i n ot her st u dies. F or p ote ntial d ose de -escalati o n, 
t he a vaila ble 2 5 0 m g d ose stre n gt h will be use d i n case 5 0 0 m g Q D i n c o m bi nati o n wit h wee kl y 
cet u xi ma b is n ot t olerate d. N o dr u g -dr u g i nteracti o ns are e x pecte d ( See Secti o n 4. 2 ). T he 
a ntici pate d i nitial d ose le vels f or c o m bi nati o n t hera py ta ke i nt o c o nsi derati o n a p ote ntiall y 
o verla p pi n g t o xicit y  of i nterstitial l u n g disease. Diarr hea, A L T, a n d A S T i ncrease are mai nl y m il d 
t o m o derate i n se verit y, ris ks f or b ot h dr u gs a n d well ma na gea ble wit h sta n dar d t hera p y.
T he pr o p ose d cli nical d ose of 5 0 0 m g  te p oti ni b o nce dail y was defi ne d b y  a tra nslati o nal 
m o del -base d a p pr oac h t hat util ize d n o ncli nical P K a n d p har mac o d y na mic s (P d ) data (i n hi biti o n 
of t he M E T pat h wa y), n o ncli nical efficac y  data (i n hi biti o n of t u m or gr o wt h), a n d cli nical P K a n d 
P d data, a n d was c o nfir me d b y  cli nical safety a n d efficac y data.
Acc or di n g t o t he tra nslati o nal P K/ P d m o del, dail y a d mi nistrati o n of 5 0 0 m g te p oti ni b is pre dicte d 
t o ac hie ve a stea dy state ≥ 9 5 % M E T i n hi biti o n i n greater t ha n 9 0 % of t he p o p ulati o n. T he d ose 
re d ucti o n-le vel of 2 5 0 m g is pre dicte d t o mai ntai n t he tar get P d res p o nse i n greater t ha n 8 0 % of 
t he p o p ulati o n.
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 S afet y 
F oll o w - u p Visit after e n d of treat me nt a n d t he S ur vi val F oll o w -u p, f or u p t o 1 -ye ar.
T he e n d of t he st u d y is defi ne d as t he date w he n t he last partici pa nt has c o m plete d t he last visit i n 
t he S ur vi val F oll o w- u p.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 4 / 1 1 5
Partici pa nts will n ot be f oll o we d f or t he 1- ye ar S ur vi val F oll o w -u p if t he S p o ns or ter mi nates t he 
st u d y early f or a n y reas o n.
See als o Secti o n  7. 2.
5
St u d y P o p ul ati o n
T he criteria i n Secti o ns  5. 1 a n d 5. 2 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 by,  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 are c o nsi dere d w he n deci di n g w het her a partici pa nt is s uita ble f or t his 
st u d y.
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o i ncl usi o n a n d e xcl usi o n criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.
Bef 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 ( w here 
all o we d b y  local la ws a n d re g ulati o ns) has pr o vi de d writte n i nf or me d c o nse nt, as i n dicate d i n 
A p pe n di x 2 .
5. 1
I ncl usi o n Criteri a
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all t he f oll o wi n g criteria a p pl y:
A ge
1.
A re ≥ 1 8 ye ars of a ge ( or ha vi n g reac he d t he a ge of maj orit y  acc or di n g t o l ocal la ws a n d 
re g ulati o ns, if t he a ge of maj orit y  is > 1 8 ye ars of a ge) at t he ti me of si g ni n g t he i nf or me d 
c o nse nt.
T y pe of P artici p a nt a n d Dise ase C h ar acteristics
2.
A d va nce d (l ocall y a d va nce d or metastatic , u nresecta ble ) left-si de d (fr o m s ple nic fle x ure t o 
rect u m –
N ati o nal C o m pre he nsi ve C a ncer N et w or k C R C Versi o n 1. 2 0 2 1 g ui deli nes ) C R C
wit h R A S /B R A F wil d -t ype at st u d y entr y  co nfir me d pri or t o e nr oll me nt, wit h pre vi o us a nti-
E G F R t herap y a n d ac q uire d resista nce o n t he m ost rece nt a nti-E G F R m o n ocl o nal a nti b o d y 
t hera py ( pa nit u m u ma b or cet u xi ma b) b y  ra di ol o gical d oc u me ntati o n of disease pr o gressi o n 
acc or di n g t o R E CIS T Versi o n 1. 1.
3.
M E T
a m plificati o n detecte d b y  a positi ve li q ui d bi o ps y  an d/ or tiss ue wit h a p pr o priate 
re g ulat or y stat us (c ollecte d after disease pr o gressi o n of t he pre vi o us a nti-E G F R t hera p y) .
4.
Meas ura ble disease b y I nvesti gat or i n acc or da nce wit h R E CI S T Versi o n 1. 1.
5.
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) of 0 or 1.
6.
Life e x pecta nc y  > 3 m o nt hs.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 5 / 1 1 5
7. Partici pa nts ha vi n g at least o ne s yste mic treat me nt f or m C R C 
i ncl u di n g 1 a nti-E G F R 
m o n ocl o nal a nti b o d y  t hera p y as t he m ost rece nt li ne of t hera p y f or m C R C bef ore st u d y treat me nt 
a n d m ust ha ve s h o w n a ra di ol o gicall y c o nfir me d b y  RE CI S T Versi o n 1. 1 c o m plete res p o nse ( C R)
or partial res p o nse ( P R), b ot h f or at least 4 m o nt hs or sta ble disease ( S D) f or at least 6 m o nt hs t o 
t hat t hera py pri or t o disease pr o gressi o n.
a. F or C o h ort A i n sites o utsi de of U S, partici pa nts m us t o nl y  ha ve ha d o ne pri or s yste mic treat me nt 
f or m C R C.
b. F or C o h ort B i n sites i n t he U S o nl y , partici pa nts m ust ha ve ha d at least t w o pri or s yste mic 
treat me nts f or m C R C.
First- li ne treat me nt m ust i ncl u de a fl u or o pyri mi di ne a n d o xali plati n or 
iri n oteca n a n d sec o n d -li ne treat me nt m ust i ncl u de a fl u or o p yri mi di ne, o xali plati n, or iri n oteca n.
8. Less t ha n 2 m o nt hs bet wee n t he last a d mi nistrati o n of t he m ost rece nt E G F R c o ntai ni n g re gi me n 
a n d first d osi n g i n t his st u d y.
9. A de q uate he mat ol o gical f u ncti o n i n t h e a bse nce of tra nsf usi o ns i n 7 da ys bef ore testi n g defi ne d
b y  w hite bl o o d cell c o u nt ≥ 3 × 1 0 9/ L wit h a bs ol ute ne utr o p hil c o u nt, ≥ 1. 5 × 1 0 9/ L, platelet c o u nt 
≥ 1 0 0 × 1 0 9/ L, a n d he m o gl o bi n ≥ 8. 5 g/ d L.
1 0. 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 × u p per li mit of n or mal 
( U L N), A S T ≤ 3 × U L N, a n d A L T ≤ 3 × U L N. F or partici pa nts wit h li ver metastases: t otal bilir u bi n 
≤ 1. 5 × U L N, A S T/ A L T ≤5 × U L N.
1 1. A de q uate re nal f u ncti o n defi ne d b y  an esti mate d gl o mer ular filtrati o n rate > 3 0 m L / mi n 
acc or di n g t o t he 4- c o m p o ne nt M o dificati o n of Diet i n Re nal Disease ( M D R D) e q uati o n ( G F R 
[ m L/ mi n/ 1. 7 3 m2] = 1 7 5 × ser u m creati ni ne ( Scr) -1. 1 5 4 × a ge -0. 2 0 3 × 1. 2 1 2 [if Africa n A merica n] ×
0. 7 4 2 [if fe male]).
Se x
1 2. Are male or fe male
C o ntrace pti ve use b y  
males or fe males will 
be c o nsiste nt wit h 
l ocal re g ulati o ns o n 
c o ntrace pti o n met h o ds f or t h ose partici pati n g i n cli nical st u dies.
a.
Male Partici pa nts:
A gree t o t he f oll o wi n g 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 4 m o nt h s after 
t he last d ose of st u d y i nter ve nti o n:

Refrai n fr o m d o nati n g s per m
P L U S, eit her:

A bstai n fr o m i nterc o urse wit h a w o m an of c hil d beari n g p ote ntial
O R
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 6 / 1 1 5

Use a male c o n d o m:

W he n ha vi n g se x ual i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial , w h o is n ot
c urre ntl y pre g na nt, a n d a d vise her t o use a hi g hl y  effecti ve c o ntrace pti ve met h o d 
wit h a fail ure rate of < 1 % per year, as descri be d i n  A p pe n di x 3 , si nce a c o n d o m ma y 
brea k or lea k.
b.
Fe male Partici pa nts:

Are n ot pre g na nt or brea stfee di n g, a n d at least o ne of t he f oll o wi n g c o n diti o ns a p plies:

N ot a w o ma n of c hil d beari n g p ote ntial
O R

If a w o ma n of c hil d beari n g p ote ntial , use a hi g hly effecti ve c o ntrace pti ve met h o d (i.e., 
wit h a fail ure rate of < 1 % per y ear), prefera bl y wit h l o w u ser de pe n de nc y, as descri be d 
i n A p pe n di x 3 f or t he f oll o wi n g ti me peri o ds:

Bef ore t he first d ose of t he st u d y  i nter ve nti o n(s), if usi n g h or m o nal c o ntrace pti o n:
o
Has c o m plete d at least o ne 4- wee k c ycle of a n oral c o ntrace pti o n pill a n d 
eit her ha d or has be g u n her me nses
O R
o
Has use d a de p ot c o ntrace pti ve or e xte n de d-c ycle oral c o ntrace pti ve f or least 
2 8 d a y s a n d has a d oc u me nte d ne gati ve pre g na nc y  test usi n g a hi g hl y 
se nsiti ve assa y.
A N D
A barrier met h o d, as descri be d i n  A p pe n di x 3.

D uri n g t he i nter ve nti o n peri o d

After t he st u d y inter ve nti o n peri o d (i.e., after t he last d ose of st u d y inter ve nti o n is 
a d mi nistere d) f or at least 2 m o nt h s after t he last d ose of st u d y i nter ve nti o n a n d a gree 
n ot t o d o n ate e g gs ( o va, o oc ytes) f or re pr o d ucti o n d uri n g t his peri o d.

T he i n vesti gat or e val uates t he effecti ve ness of t he c o ntrace pti ve met h o d 
i n 
relati o ns hi p t o t he first d ose of st u d y i nter ve nti o n.

Ha ve a ne gati ve ser u m or hi g hl y se nsiti ve uri ne pre g na nc y  test, as re q uire d b y l ocal 
re g ulati o ns, wit hi n 2 4 h o urs bef ore t he first d ose of st u d y i nter ve nti o n. If a uri ne test 
ca n n ot be c o nfir me d as ne gati ve (e. g., a n a m bi g u o us res ult), a ser u m pre g na nc y  test 
is re q uire d.

A d diti o nal re q uire me nts f or pre g na nc y testi n g d uri n g a n d after st u dy i nter ve nti o n are i n 
Secti o n  8. 2. 4.

T he i n vesti gat or re vie ws t he me dical hist or y , me nstr ual hist or y , a n d rece nt se x ual 
acti vit y to decrease t he ris k f or i ncl usi o n of a fe male wit h a n earl y u n detecte d pre g na nc y .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 7 / 1 1 5
I nf or me d C o nse nt
1 3. Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt, as i n dicate d i n A p pe n di x 2 w hic h i ncl u des 
c o m plia nce wit h t he re q uire me nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt f or m (I C F) 
a n d t his pr ot oc ol.
5. 2
E xcl usi o n Criteri a
Partici pa nts are e xcl u de d fr o m t he st u d y  if a n y of t he f oll o wi n g criteria a p pl y:
Me dic al C o n diti o ns
1.
Partici pa nts 
wit h 
s ym pt o matic 
ce ntral ner v o us s yste m ( C N S) meta stases w h o 
are 
ne ur ol o gicall y u nsta ble or ha ve re q uire d i ncreasi n g d oses of ster oi ds wit hi n t he 2 wee ks pri or 
t o st u d y entr y  t o ma na ge C N S metastases. Als o e xcl u de d are partici pa nts wit h carci n o mat o us 
me ni n gitis.
2.
Partici pa nts w h o ha ve brai n metastasis as t he o nl y meas ura ble lesi o n.
Pri or/ C o nc o mit a nt T her a p y
3.
Pri or c he m ot hera p y, bi ol o gical t hera py, ra diati o n t hera p y, h or m o nal t hera p y for a nti-ca ncer 
p ur p oses, tar gete d t hera p y, or ot her i n vesti gati o nal a ntica ncer t hera p y (n ot i ncl u di n g palliati ve 
ra di ot hera py at f ocal sites) wit hi n 2 1 da y s pri or t o t he first d ose of st u d y i nter ve nti o n, e xce pt 
f or t he a nti-E G F R c o ntai ni n g re gi me n i ncl u di n g ass ociate d c he m ot hera p y i f a p plica ble, w hic h 
ma y  be c o nti n ue d u ntil e nr oll me nt of t he partici pa nt i n t he st u d y.
4.
A n y  u nres ol ve d t o xicit y Gra de 2 or m ore acc or di n g t o t he Nati 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) V ersi o n 5. 0, fr o m pre vi o us 
a ntica ncer t hera p y e xcl u di n g ne ur o pat h y, al o pecia a n d ras h.
Ot her E xcl usi o ns
5.
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 ( Gra de ≥ 3 N CI -C T C A E v 
5. 0), a n y hist or y of a na p h yla xis, or u nc o ntr olle d ast h ma (i.e., 3 or m ore occ urre nces of partiall y  
c o ntr olle d ast h ma).
6.
Disc o nti n uati o n of t he m ost rece nt cet u xi ma b or pa nit u m u ma b c o ntai ni n g t hera py d ue t o a n 
a d verse e ve nt.
7.
Pri or treat me nt wit h ot her a ge nts tar geti n g t he H G F/ M E T pat h wa y .
8.
I m paire d car diac f u ncti o n: 
a.
Left ve ntric ular ejecti o n fracti o n < 4 5 % defi ne d b y  ec h ocar di o gra p h y (a scree ni n g 
assess me nt n ot re q uire d f or partici pa nts wit h o ut a hist or y  of c o n gesti ve heart fail ure 
u nless cli nicall y  i n dicate d)
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 8 / 1 1 5
b.
Seri o us arr h yt h mia
c.
U nsta ble a n gi na pect oris
d.
Ne w Y or k Heart Ass ociati o n heart fail ure C lass III a n d I V
e.
M y ocar dial i nfarcti o n wit hi n t he last 1 2 m o nt hs pri or t o st u d y e ntr y 
f.
S y m pt o matic pericar dial eff usi o n
g.
C orrecte d Q T i nter val b y Fri dericia ( Q Tc F) > 4 8 0 ms
9.
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).
1 0. Past or c urre nt hist or y  of ne o plas m ot her t ha n m C R C, e x ce pt f or c urati vel y treate d n o n-
mela n o ma s ki n ca ncer, i n sit u carci n o ma of t he cer vi x, or ot her ca ncer c urati vel y treate d a n d 
wit h n o e vi de nce of disease f or at least 5 y ears.
1 1. Me dical hist or y  of diffic ult y  swall o wi n g, mala bs or pti o n, or ot her c hr o nic gastr oi ntesti nal 
disease, or c o n diti o ns t hat ma y  ha m per c o m plia nce a n d/ or a bs or pti o n of t he test pr o d ucts. 
1 2. Maj or s ur ger y  wit hi n 2 8 da ys pri or t o Da y 1 of st u d y i nter ve nti o n.
1 3. K n o w n i nfecti o n wit h h u ma n i m m u n o deficie nc y  vir us, or a n acti ve i nfecti o n wit h he patitis B 
or he patitis C vir us.
1 4. S u bsta nce a buse, acti ve i nfecti o n, or ot her ac ute or c hr o nic me dical or ps yc hiatric c o n diti o n or 
la b orat or y a b n or malities t hat mi g ht i ncrease t he ris k ass ociate d wit h st u d y partici pati o n at t he 
discreti o n of I n vesti gat ors.
1 5. I M P use i n a n ot her st u dy wit hi n 3 wee ks of t h e first d ose of st u d y i nter ve nti o n.
1 6. Hist or y  of I L D or i nterstitial p ne u m o nitis i ncl u di n g ra diati o n p ne u m o nitis t hat re q uire d ster oi d 
treat me nt.
5. 3
Lifest yle C o nsi der ati o ns
Partici pa nts will a bstai n fr o m stre n u o us e xercise f or 4 8 h o urs bef ore eac h bl o o d c ollecti o n f or 
cli nical la b orat or y tests. Partici pa nts ma y partici pate i n li g ht recreati o nal acti vities (e. g., watc hi n g 
tele visi o n or rea di n g).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
3 9 / 1 1 5
5. 4
Scree n F ail ures
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) m a y  be
rescree ne d o nce. Rescree ne d partici pa nts will be assi g ne d a ne w partici pa nt n u m ber a n d will 
u n der g o all Scree ni n g pr oce d ures as pla n ne d b y  the pr ot oc ol , e xce pt li q ui d b i o ps y/ tiss ue bi o ps y
testi n g. Rescree ni n g is per mitte d o nl y  for partici pa nts wit h c o nfir me d M E T
a m plificati o n if t he y 
d o n ot meet 1 of t he ot her i ncl usi o n or e xcl usi o n criteria a n d after disc ussi o n wit h t he S p o ns or.
F or Rescree ni n g n o re petiti o n f or M E T a m plificati o n stat us is nee de d.
6
St u d y I nter ve nti o n(s)
St u d y  inter ve nti o n is a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s), place b o, or me dical 
de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  partici pa nt per t he st u dy pr ot oc ol.
6. 1
St u d y I nter ve nti o n(s) A d mi nistr ati o n
D urati o n of st u d y f or eac h partici pa nt, a n d fle xi bilit y o n d osi n g sc he d ule is c o vere d u n der Secti o n 
4. 1 . 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 0 / 1 1 5
A R M N a m e
N ot a p pli c a bl e 
I nt er v e nti o n N a m e
T e p oti ni b
C et u xi m a b
T y p e 
C o m bi n ati o n
D o s e F or m ul ati o n
Fil m -c o at e d t a bl et s
S ol uti o n f or i ntr a v e n o u s i nf u si o n
U nit D o s e Str e n gt h( s)
2 5 0 m g
Vi al of 2 0 m L c o nt ai ni n g 1 0 0 m g c et u xi m a b 
( 5 m g/ m L) o ut si d e of U S . Vi al of 5 0 m L or 
1 0 0 m L c o nt ai ni n g 1 0 0 m g or 2 0 0 m g 
c et u xi m a b ( 2 m g/ m L) r e s p e cti v el y f or U S 
p arti ci p a nt s o nl y.
D o s e A m o u nt a n d Fr e q u e n c y
Aft er f o o d i nt a k e, e. g. a n or m al 
br e a kf a st, o n c e a d a y.
T e p oti ni b will b e u s e d i niti all y 
at 5 0 0 m g Q D ( 2 t a bl et s of 
2 5 0 m g Q D). F or p ot e nti al 
d o s e d e -e s c al ati o n, t h e 
a v ail a bl e 2 5 0 m g d o s e 
str e n gt h will b e u s e d ( 1 t a bl et 
o n c e d ail y). 
P l e a s e s e e al s o S e cti o n 6. 6
T e p oti ni b will b e gi v e n 
a p pr o xi m at el y 3 0 mi n s b ef or e 
t h e st art of e a c h c et u xi m a b 
i nf u si o n.
A d mi ni st er e d o n c e a w e e k.
Pri or t o t h e fir st i nf u si o n, p arti ci p a nt s m u st 
r e c ei v e pr e m e di c ati o n wit h a n a nti hi st a mi n e 
a n d if l o c al c et u xi m a b l a b el r e q uir e s, a 
c orti c o st er oi d 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 hi s 
pr e m e di c ati o n i s r e c o m m e n d e d pri or t o all 
s u b s e q u e nt i nf u si o n s .
W h e n t o st art wit h a l o a di n g d o s e:
R e q uir e d l o a di n g d o s e at a n i niti al d o s e of 
4 0 0 m g/ m 2 b o d y s urf a c e ar e a if p arti ci p a nt 
r e c ei v e d t h e f oll o wi n g:
P a nit u m u m a b a s pri or li n e
C et u xi m a b a s pri or li n e a n d l a st d o s e w a s 
m or e t h a n 3 w e e k s a g o.
N o l o a di n g d o s e r e q uir e d if p arti ci p a nt:
r e c ei v e d c et u xi m a b a s pri or li n e a n d l a st 
d o s e w a s gi v e n u p t o 3 w e e k s a g o.
L o a di n g d o s e ( w h er e r e q uir e d): C et u xi m a b, 
i s a d mi ni st er e d at a n i niti al d o s e of 
4 0 0 m g/ m
2 b o d y s urf a c e ar e a, o v er a 
r e c o m m e n d e d i nf u si o n p eri o d of 
1 2 0 mi n ut e s a n d a m a xi m u m i nf u si o n r at e of 
5
m g/ mi n, f oll o w e d b y or st arti n g wit h 
w e e kl y i nf u si o n s at a d o s e of 2 5 0 m g/ m 2
o v er a r e c o m m e n d e d i nf u si o n p eri o d of 
6 0 mi n ut e s a n d a m a xi m u m i nf u si o n r at e of 
1 0 m g/ mi n
R o ut e of A d mi ni str ati o n
Or al
I ntr a v e n o u s
U s e
E x p eri m e nt al
E x p eri m e nt al
I M P a n d N o n- I n v e sti g ati o n al 
M e di ci n al Pr o d u ct
I M P
I M P
S o ur ci n g
Pr o vi d e d c e ntr all y b y t h e 
S p o n s or
Pr o vi d e d c e ntr all y b y t h e S p o n s or
P a c k a gi n g a n d L a b eli n g
T e p oti ni b will b e pr o vi d e d i n 
 t a bl et s. E a c h w all et 
c o nt ai ni n g t h e  
t a bl et s
will b e l a b el e d p er c o u ntr y 
r e q uir e m e nt
C et u xi m a b will b e pr o vi d e d i n vi al s . E a c h 
vi al will b e l a b el e d p er c o u ntr y r e q uir e m e nt
C urr e nt/ F or m er N a m e( s) or 
Ali a s( e s)
N ot a p pli c a bl e
Er bit u x
A b br e vi ati o n s: I M P = i n v e sti g ati o n al m e di ci n al pr o d u ct; Q D = d ail y; U S = U nit e d St at e s.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 1 / 1 1 5
6. 2
St u d y I nter ve nti o n(s) Pre p ar ati o n, H a n dli n g, St or a ge, a n d 
Acc o u nt a bilit y
T he I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is res p o nsi ble 
f or st u d y inter ve nti o n acc o u nta bilit y, rec o ncili ati o n, a n d rec or d mai nte na nce 
(i.e., recei pt, 
rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).

U p o n recei pt of t he st u d y inter ve nti o n(s), t he I n vesti gat or or desi g nee will c o nfir m 
a p pr o priate te m perat ure c o n diti o ns ha ve bee n mai ntai ne d 
d uri n g tra nsit a n d a n y 
discre pa ncies are re p orte d a n d res ol ve d bef ore use. Als o, t he res p o nsi ble pers o n will 
c hec k f or acc urate deli ver y . F urt her g ui da nce a n d i nf or mati o n f or st u d y inter ve nti o n 
acc o u nta bilit y are pr o vi de d i n t he P har mac y Ma n ual.

O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y inter ve nti o n(s) a n d o nl y 
a ut h orize d site staff ma y s u p pl y it. All st u d y inter ve nti o n(s) will be st ore d i n a sec ure, 
e n vir o n me ntall y co ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area, per t he la bele d 
st ora ge c o n diti o ns, a n d wit h access li mite d t o t he I n vesti gat or a n d a ut h orize d site staff.

Dis pe nsi n g will be rec or de d o n t he a p pr o priate acc o u nta bilit y for ms s o t hat acc urate 
rec or ds will be a vaila ble f or verificati o n at eac h m o nit ori n g visit.

St u d y  i nter ve nti o n(s) acc o u nta bilit y rec or ds at t he st u d y site will i ncl u de t he f oll o wi n g:

C o nfir mati o n of recei pt, i n g o o d c o n diti o n a n d i n t he defi ne d te m perat ure ra n ge.

T he i n ve nt or y  pr o vi de d f or t he cli nical st u d y a n d pre pare d at t he site.

T he d ose(s) eac h partici pa nt use d d uri n g t he st u d y.

T he dis p ositi o n (i ncl u di n g ret ur n, if a p plica ble) of a n y  u n use d st u d y i nter ve nti o n(s).

Dates , q ua ntities, batc h n u m bers, c o ntai ner n u m bers, e x pir y dates, 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 ull y rec o ncile d.

U n use d st u d y inter ve nti o n(s) will 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 inter 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  collect t he st u d y i nter ve nti o n(s) acc o u nta bilit y for ms.

F urt her 
g ui da nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y 
i nter ve nti o n(s) are pr o vi de d i n t he P har mac y Ma n ual.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 2 / 1 1 5
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
D ue t o t he nat ure of t he si n gle -ar m st u d y desi g n, t his st u d y is perf or me d o pe n-la bel. 
A n I nteracti ve We b Res p o nse S y ste m (IW R S) will be e m pl o ye d t o assi g n a st u d y n u m ber t o
partici pa nts a n d facilitate s u p pl y a n d res u p ply of st u d y i nter ve nti o n at st u d y sites.
Partici pa nt n u m bers will be assi g ne d i n t he a p pr o priate f or mat a n d will reflect st u d y  n u m ber, site 
n u m ber a n d partici pa nt i de ntificati o n. Partici pa nt n u m bers will n ot be reassi g ne d t o ot her 
partici pa nts or re use d i n t his st u d y . If a partici pa nt is all o we d t o be rescree ne d f or t he st u dy, a ne w 
partici pa nt n u m ber will ha ve t o be assi g ne d.
St u d y usi n g I WR S
After c o nfir mati o n of partici pa nt’s eli gi bilit y, partici pa nts will be
ce ntrall y assi g n e d t o u ni q ue partici pa nt n u m bers.
Bef ore t he st u d y is i nitiate d, t he directi o ns f or t he IW R S will be 
pr o vi de d t o eac h site. T he site will c o ntact t he IW R S pri or t o starti n g 
st u d y i nter ve nti o n a d mi nistrati o n f or eac h partici pa nt.
6. 3. 2
Bli n di n g
T his is a n o pe n -la bel si n gle ar m st u d y. P ote ntiall y , a re-assess me nt of t u m or meas ure me nts will 
be perf or me d b y a n i n de pe n de nt re vie w c o m mittee t o re d uce bias.
6. 4
St u d y I nter ve nti o n C o m pli a nce
Acce pta ble c o m plia nce f or t his st u d y  will be defi ne d i n t he M o nit ori n g Pla n.
W he n partici pa nts are d ose d at t he site, t he y will recei ve st u d y inter ve nti o n directl y  fr o m t he 
I n vesti gat or or desi g nee, u n der me dical s u per visi o n. T he date a n d ti me of eac h d ose a d mi nistere d 
i n t he cli nic will be rec or de d i n t he s o urce d oc u me nts a n d rec or de d i n t he electr o nic C R F (e C R F).
T he d ose of st u d y i nter ve nti o n a n d st u d y  partici pa nt i de ntificati o n will be c o nfir me d at t he ti me of 
d osi n g b y  a me m ber of t he st u d y site staff ot her t ha n t he pers o n a d mi nisteri n g t he st u d y 
i nter ve nti o n. 
W he n 
partici pa nts self-a d mi nister st u d y inter ve nti o n(s) at h o me, c o m plia nce wit h 
st u d y 
i nter ve nti o n will be assesse d at eac h visit. C o m plia nce will be assesse d b y  co u nti n g ret ur ne d 
te p oti ni b ta blets d uri n g t he site visits a n d d oc u me nte d i n t he s o urce d oc u me nts a n d e C R F. A n y 
de viati o n(s) fr o m t he prescri be d d osa ge re gi me n are rec or de d i n t he e C R F.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 3 / 1 1 5
A rec or d of t he n u m ber of te p oti ni b ta blets dis pe nse d t o a n d ta ke n b y  eac h partici pa nt will be 
mai ntai ne d a n d rec o ncile d wit h st u d y  i nter ve nti o n a n d c o m plia nce rec or ds. I nter ve nti o n start a n d 
st o p dates, i ncl u di n g dates f or i nter ve nti o n dela ys a n d/ or d ose re d ucti o ns will als o be rec or de d i n 
t he eC R F .
Partici pa nts ma y  be wit h dra w n fr o m t he st u d y i nter ve nti o ns i n t he e ve nt of n o nc o m plia nce t hat is 
dee me d b y  the I n vesti gat or or S p o ns or t o c o m pr o mise partici pa nt safety or st u d y inte grit y (see
Secti o n  7. 1 a n d Secti o n 8. 4 ).
6. 5
C o nc o mit a nt T her a p y
Rec or d i n t he eC R F all c o nc o mita nt t hera pies (e. g., me dici nes or n o n dr u g i nter ve nti o ns) use d fr o m 
t he ti me t he partici pa nt si g ns t he i nf or me d c o nse nt u ntil c o m pleti o n of t he st u d y, i ncl u di n g a n y 
c ha n ges. F or prescri pti o n a n d o ver-t he-c o u nter me dici nes, 
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 mati o n.
C o ntact t he Me dical M o nit or f or a n y q uesti o ns o n c o nc o mita nt or pri or t hera p y.
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 welf are i n e mer ge ncies 
ma y  be gi ve n at t he I n vesti gat or’s discreti o n.
Sta n dar d s u p p orti ve t hera p y sh o ul d f oll o w ge neral pri nci ples i n o nc ol o g y  (refer t o A merica n 
S ociet y  of Cli nical O nc ol o g y g ui deli nes f or s u p p orti ve care). Use of he mat o p oietic gr o wt h fact ors 
is per mitte d w here i n dicate d i n acc or da nce wit h t he A merica n S ociet y of Cli nical O nc ol o g y 
g ui deli ne.
6. 5. 1
Per mitte d Me dici nes
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.
T he I nvesti gat or will rec or d all c o nc o mita nt me dicati o ns/ pr oce d ures ta ke n b y  the partici pa nt 
d uri n g t he st u d y, fr o m t he date of si g nat ure of mai n i nf or me d c o nse nt, i n t he a p pr o priate secti o n 
of t he e C R F. 
Cet u xi m a b
Pri or t o t he first i nf usi o n, partici pa nts m ust recei ve pre me dicati o n wit h a n a nti hista mi ne a n d if 
l ocal cet u xi ma b la bel re q uires, a c ortic oster oi d at least 1 h o ur pri or t o a d mi nistrati o n of cet u xi ma b. 
T his pre me dicati o n is rec o m me n de d pri or t o all s u bse q ue nt i nf usi o ns.
S ee A p pe n di x 3 f or c o ntrace pti ve met h o ds.
F or a n y s ki n A E of Gra de 1 t o 3, t o pical a n d/ or oral a nti bi otics are per mitte d. Partici pa nts wit h 
Gra de 3 or hi g her reacti o ns s h o ul d be referre d t o a der mat ol o gist f or a d vice a n d ma na ge me nt if 
nee de d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 4 / 1 1 5
Te p oti ni b
T he f oll o wi n g are per mitte d:

C o nc o mita nt me dicati o ns t hat ha ve a narr o w t hera pe utic wi n d o w a n d are k n o w n t o be 
tra ns p orte d b y P -g p (e. g., ri var o xa ba n, a pi xa ba n, ra n olazi ne, tali nol ol, di g o xi n), B C R P 
(e. g., r os u vastati n), O C T 2, M A T E 1, 
a n d M A T E 2 
(e. g., d ofetili de, metf or mi n) a n d 
O C T 1 are per mitte d, b ut s h o ul d be use d wit h ca uti o n. Te p oti ni b is a s u bstrate f or P - g p. 
Str o n g P- g p i n d ucers ma y  ha ve t he p ote ntial t o decrease te p oti ni b e x p os ure. 
C o nc o mita nt use of str o n g P- g p i n d ucers (e. g., car ba maze pi ne, p he n yt oi n, rifa m pici n, 
a n d St. J o h n's w ort) s h o ul d be a v oi de d. M o nit ori n g t he 
cli nical effects of P- g p -
de pe n de nt s u bsta nces wit h a narr o w t hera pe utic i n de x (e. g., di g o xi n) is rec o m me n de d
d uri n g c oa d mi nistrati o n wit h te p oti ni b. Te p oti ni b ca n i n hi bit t he tra ns p ort of se nsiti ve 
s u bstrates of B C R P. M o nit ori n g t he cli nical effects of se nsiti ve B C R P s u bstrates (e. g., 
r os u vastati n) is rec o m me n de d d uri n g c o-a d mi nistrati o n wit h te p oti ni b. Base d o n i n vitr o 
data, te p oti ni b a n d its meta b olite m a y  ha ve t he p ote ntial t o i ncrease t he A U C of c o 
a d mi nistere d metf or mi n i n h u ma ns, t hr o u g h i n hi biti o n of its re nal e xcreti o n me diate d 
via O C T 1 a n d O C T 2, a n d M A T E 1 a n d M A T E 2. M o nit ori n g of t he effect of metf or mi n
is rec o m me n de d d uri n g c o-a d mi nistrati o n wit h te p oti ni b.

T he I n vesti gat or m a y  deci de n ot t o i ncl u de a partici pa nt i n t he st u d y, if t he partici pa nt 
ca n n ot wit h dra w t he dr u gs t hat ha ve a narr o w t hera pe utic ra n ge a n d t hat are k n o w n t o 
be tra ns p orte d via P -g p.

If t he I n vesti gat or deci des t o e nr oll a partici pa nt w h o is treate d wit h a dr u g t hat is 
tra ns p orte d via P- g p a n d has a narr o w t hera pe utic ra n ge, cl ose safety m o nit ori n g is 
a d vise d.

Refer t o A p pe n di x 3 C o ntrace pt i o n f or c o ntrace pti ve met h o ds.

S u p p orti ve treat me nt, e. g., bis p h os p h o nates, a ge nts f or i m pr o vi n g a p petite, if i nitiate d 
pri or t o st u d y e ntr y, is all o we d t o c o nti n ue. C ha n ge i n d ose/sc he d ule o n st u d y is 
disc o ura ge d. I nitiati o n of bis p h os p h o nates wit h pr o p h y lactic p ur p ose d uri n g st u d y 
i nter ve nti o n s h o ul d be a v oi de d.

S y m pt o matic treat me nt of brai n metastasis wit h a ntic o n v ulsa nts k n o w n t o ha ve a 
re d uce d ris k f or dr u g i nteracti o ns s uc h as la m otri gi ne, le vetiraceta m, pre ga bali n or 
val pr oic aci d is all o we d.
6. 5. 2
Pr o hi b ite d Me dici nes
If t he a d mi nistrati o n of a n o n per mitte d c o nc o mita nt dr u g bec o mes necessar y d uri n g t he st u d y, e. g., 
f or A Es or i n a n ur ge nt me dical sit uati o n, it is at t he I n vesti gat or’s discreti o n. I n s uc h a case, t his 
partici pa nt has t o be wit h dra w n fr o m st u d y i nter ve nti o n a n d detaile d i nf or mati o n nee ds t o be 
rec or de d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 5 / 1 1 5
Cet u xi m a b
Cet u xi ma b is c o ntrai n dicate d i n partici pa nts wit h k n o w n se vere ( Gra de 3 or 4) h y perse nsiti vit y 
reacti o ns t o cet u xi ma b. 
Te p oti ni b
T he f oll o wi n g are n ot per mitte d d uri n g t he st u d y:

A n y  ot her ca ncer t hera p y, i ncl u di n g c he m ot hera p y, bi ol o gical t hera p y, tra diti o nal 
C hi nese
me dici ne, h or m o nal t hera p y for a ntica ncer p ur p oses, tar gete d t hera p y, or a n y i n vesti gati o nal
pr o d uct ot her t ha n te p oti ni b a n d cet u xi ma b as defi ne d i n t his pr ot oc ol .

D r u g(s), f or w hic h t he pac ka ge i nsert/s u m mar y of pr o d uct c haracteristics i ncl u des a 
c o ntrai n dicati o n f or P- g p (e. g., da bi gatra n, alis kire n), B C R P, O C T 1, O C T 2, M A T E 1, 
a n d M A T E 2 i n hi biti n g dr u gs.

Dr u g(s) t hat are k n o w n t o i n d uce P- g p a n d t here b y ma y decrease efficac y of te p oti ni b 
(e. g., a vasi mi be, car ba maze pi ne, p he n yt oi n, rifa m pi n a n d St. J o h n's w ort).
6. 5. 3
Ot her I nter ve nti o ns
Te p oti ni b
L ocalize d ra diati o n t hera p y t o alle viate s ym pt o ms s uc h as b o ne pai n is all o we d pr o vi de d t hat t he 
t otal d ose deli vere d is i n a palliati ve ra n ge acc or di n g t o i nstit uti o nal sta n dar ds a n d d oes n ot i n v ol ve 
a n y tar get lesi o n(s) utilize d f or res p o nse deter mi nati o n.
Cet u xi m a b
Cet u xi ma b m ust be a d mi nistere d u n der t he s u per visi o n of a p h y sicia n e x perie nce d i n t he use of 
a nti ne o plastic me di ci nal pr o d ucts. Cl ose m o nit ori n g is re q uire d d uri n g t he i nf usi o n a n d f or at least 
1 h o ur after t he e n d of t he i nf usi o n. A vaila bilit y  of res uscitati o n e q ui p me nt m ust be e ns ure d.
6. 5. 4
S peci al Prec a uti o ns
6. 5. 4. 1
Cet u xi m a b 
I nf usi o n-relate d reacti o ns
Se vere I R Rs, i ncl u di ng a na p h yl actic reacti o ns, ma y  co m m o nl y occ ur, i n s o me cases wit h fatal 
o utc o me. Occ urre nce of a se vere I R R re q uires i m me diate a n d per ma ne nt disc o nti n uati o n of 
cet u xi ma b t hera py a n d ma y  necessitate e mer ge nc y treat me nt. S o me of t hese reacti o ns m a y  be 
a na p h yl actic or a na p h yl act oi d i n nat ure or re prese nt a c yt o ki ne release s yn dr o me ( C R S). 
S y m pt o ms m a y  occ ur d uri n g t he first i nf usi o n a n d f or u p t o se veral h o urs after war ds or wit h 
s u bse q ue nt i nf usi o ns. It is rec o m me n de d t o war n patie nts of t he p ossi bilit y  of s uc h a late o nset a n d 
i nstr uct t he m t o c o ntact t heir p h y sicia n if s ym pt o ms or si g ns of a n I R R occ ur. S y m pt o ms ma y 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 6 / 1 1 5
i ncl u de br o nc h os pas m, urticaria, i ncrease or decrease i n bl o o d press ure, l oss of c o nsci o us ness or 
s h oc k. I n rare cases, a n gi na pect oris, my ocar dia l 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 early as wit hi n a fe w mi n utes of t he first i nf usi o n e. g. d ue t o 
pref or me d I mm u n o gl o b uli n E ( I g 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 .
T he ris k f or a na p h yl actic reacti o ns is m uc h i ncrease d i n patie nts wit h a hist or y of aller g y to re d 
meat or tic k bites or p ositi ve res ults of tests f or I g E a nti b o dies a gai nst cet u xi ma b ( α- 1- 3-galact ose). 
I n t hese patie nts cet u xi ma b s h o ul d be a d mi nistere d o nl y after a caref ul assess me nt of be nefit/ris k, 
i ncl u di n g alter nati ve treat me nts, a n d o nl y  un der cl ose s u per visi o n of well -trai ne d pers o n nel wit h 
res uscitati o n e q ui pme nt rea d y.
T he first d ose s h o ul d be a d mi nistere d sl o wl y, a n d t he s pee d m ust n ot e xcee d 5 m g/ mi n w hilst all 
vital si g ns are cl osely m o nit ore d f or at least t w o h o urs. If d uri n g t he first i nf usi o n, a n I RR reacti o n 
occ urs wit hi n t he first 1 5 mi n utes, t he i nf usi o n s h o ul d be st o p pe d. A caref ul be nefit/ris k assess me nt 
s h o ul d be u n derta ke n i ncl u di n g c o nsi derati o n w het her t he patie nt ma y  ha ve pref or me d I g E 
a nti b o dies bef ore a s u bse q ue nt i nf usi o n is gi ve n. If a n I RR de vel o ps later d uri n g t he i nf usi o n or at 
a s u bse q ue nt i nf usi o n f urt her ma na ge me nt will de pe n d o n its se verit y:
a) Gra de 1: c o nti n ue sl o w i nf usi o n u n der cl ose s u per visi o n 
b) Gra de 2: c o nti n ue sl o w i nf usi o n a n d i m me diatel y  a d mi nister treat me nt f or sy m pt o ms 
c) Gra de 3 a n d 4: st o p i nf usi o n i m me diatel y, treat s ym pt o ms vi g or o usl y a n d c o ntrai n dicate f urt her 
use of cet u xi ma b. See Cet u xi ma b: D ose M o dificati o ns u n der Secti o n  6. 6. 1.
A C R S t ypicall y occ urs wit hi n o ne 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. C R S is n or mall y  m ost se vere i n relati o n t o t he first i nf usi o n.
Mil d or m o derate I R Rs are ver y c o m m o n c o m prisi n g s y m pt o ms s uc h as fe ver, c hills, dizzi ness, or 
d y s p nea t hat occ ur i n a cl ose te m p oral relati o ns hi p mai nl y  to t he first cet u xi ma b i nf usi o n. If t he 
patie nt e x perie nces a mil d or m o derate i nf usi o n-relate d reacti o n, t he i nf usi o n rate m a y  be 
decrease d. It is rec o m me n de d t o ma i ntai n t his l o wer i nf usi o n rate i n all s u bse q ue nt i nf usi o ns.
A cl ose m o nit ori n g of patie nts, partic ularl y d uri n g t he first a d mi nistrati o n, is re q uire d. S pecial 
atte nti o n is rec o m me n de d f or patie nts wit h re d uce d perf or ma nce stat us a n d pre -e xisti n g car di o-
p u l m o nar y disease.
Res pirat or y  Dis or ders a n d I L D
Cases of I L D, w hic h ca n be fatal, ha ve bee n re p orte d wit h t he maj orit y of patie nts fr o m t he 
Ja pa nese p o p ulati o n. C o nf o u n di n g or c o ntri b uti n g fact ors, s uc h as c o nc o mita nt c he m ot hera p y 
k n o w n t o be ass ociate d wit h I L D, a n d pre -e xisti n g p ul m o nar y  diseases were fre q ue nt i n fatal cases. 
S uc h patie nts s h o ul d be cl osel y mo nit ore d. I n t he e ve nt of s ym pt o ms (s uc h as d y s p nea, c o u g h, 
fe ver) or ra di o gra p hic fi n di n gs s u g gesti ve of I L D, pr o m pt dia g n ostic i n vesti gati o n s h o ul d occ ur. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 7 / 1 1 5
Patie nts wit h ac ute o nset or w orse ni n g of p ul m o nar y  sy m pt o ms s h o ul d be cl osel y mo nit ore d. If 
i nterstitial l u n g disease is dia g n ose d, cet u xi ma b m ust be disc o nti n ue d a n d t he patie nt be treate d 
a p pr o priatel y.
S ki n Reacti o ns
If a patie nt e x perie nces a se vere s ki n reacti o n (≥Gra de 3; C T C A E), cet u xi ma b t hera p y must be 
i nterr u pte d. Treat me nt ma y o nly be res u me d if t he reacti o n has res ol ve d t o Gra de ≤ 2. 
If t he se vere s ki n reacti o n occ urre d f or t he first ti me, treat me nt ma y  be res u me d wit h o ut a n y 
c ha n ge i n d ose le vel. Wit h t he sec o n d a n d t hir d occ urre nces of se vere s ki n reacti o ns, cet u xi ma b 
t hera py m ust a gai n be i nterr u pte d. Treat me nt ma y  onl y be res u me d at a l o wer d ose le vel 
( 2 0 0 m g/ m 2 B S A after t he sec o n d occ urre nce a n d 1 5 0 m g/ m 2 after t he t hir d occ urre nce ), if t he 
reacti o n has res ol ve d t o Gra de ≤ 2. 
If se vere s ki n reacti o ns occ ur a f o urt h ti me or d o n ot res ol ve t o Gra de ≤ 2 d uri n g i nterr u pti o n of 
treat me nt, per ma ne nt disc o nti n uati o n of cet u xi ma b treat me nt is re q uire d.
Electr ol yt e A b n or malities
Pr o gressi ve l y decreasi n g ser u m ma g nesi u m 
le vels ha ve bee n o bser ve d. Ot her 
electr ol yt e 
dist ur ba nces ha ve als o bee n o bser ve d a n d ma y lea d t o se vere h y p o ma g nese mia. I n a d diti o n, 
h y p o kale mia m a y  de vel o p. H y p ocalce mia m a y  als o occ ur; i n partic ular i n c o m bi nati o n wit h 
plat i n u m-base d c he m ot hera p y t he fre q ue nc y of se vere h y p ocalce mia
m a y  be i ncrease d. 
Deter mi nati o n of ser u m electr ol yt e le vels is rec o m me n de d pri or t o a n d peri o dicall y d uri n g 
cet u xi ma b treat me nt. Electr ol yte re pleti o n is rec o m me n de d, as a p pr o priate.
E y e D is or ders
Cases of keratitis a n d ulcerati ve keratitis ha ve bee n re p orte d wit h t he use of cet u xi ma b. Patie nts 
prese nti n g wit h si g ns a n d s ym pt o ms s u g gesti ve of keratitis s uc h as ac ute or w orse ni n g: e ye 
i nfla m mati o n, lacri mati o n, li g ht se nsiti vit y, bl urre d visi o n, e ye pai n a n d/ or re d e ye s h o ul d be 
referre d pr o m ptl y t o a n o p ht hal m ol o g y s pecialist.
If a dia g n osis of ulcerati ve keratitis is c o nfir me d, treat me nt wit h cet u xi ma b s h o ul d be i nterr u pte d 
or disc o nti n ue d. If keratitis is dia g n ose d, t he be nefits a n d ris ks of c o nti n ui n g treat me nt s h o ul d be 
caref ull y c o nsi dere d.
Cet u xi ma b s h o ul d be use d wit h ca uti o n i n patie nts wit h a hist or y  of keratitis, ulcerati ve keratitis 
or se vere dr y  e ye. C o ntact le ns use is als o a ris k fact or f or keratitis a n d ulcerati o n.
Patie nts wit h R A S -m uta nt Metastatic C ol orectal Ca ncer
T he a d diti o nal a nal ys es of pi v otal st u dies c o ncl u de t hat patie nts wit h ot her t ha n K R A S e x o n 2 R A S -
m uta nt t u m ors ma y  be less li kel y to be nefit fr o m cet u xi ma b. Gi ve n t he a vaila ble R A S data, t he 
t otalit y of t he e vi de nce is s ufficie nt t o rec o m me n d a d mi nistrati o n of cet u xi ma b o nl y  in patie nts 
wit h R A S -wil d -t ype m C R C.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 8 / 1 1 5
C ol orectal Ca ncer Patie nts wit h R A S -m uta nt T u m ors
Cet u xi ma b s h o ul d n ot be use d i n t he treat me nt of c ol orectal ca ncer patie nts w h ose t u m ors ha ve 
R A S m utati o ns o r f or w h o m R A S t u m or stat us is u n k n o w n. Res ults fr o m cli nical st u dies s h o w a 
ne gati ve be nefit -ris k bala nce i n t u m ors wit h R A S m utati o ns, i n partic ular, i n c o m bi nati o n wit h 
c o nti n u o us i nf usi o nal 5- fl u or o uracil/f oli nic aci d pl us o xali plati n.
S pecial P o p ulati o ns
T he effecti ve ness of cet u xi ma b i n pe diatric patie nts has n ot bee n esta blis he d. N o ne w safety 
si g nals were i de ntifie d i n pe diatric patie nts as re p orte d fr o m a P hase I st u dy.
T here is li mite d e x perie nce i n t he use of cet u xi ma b i n c o m bi nati o n wit h ra diati o n t hera p y i n C R C.
Pre g na nc y  a n d Lactati o n
A ni mal data d o n ot s u g gest a terat o ge nic effect. H o we ver, a n i ncrease d i nci de nce of a b orti o n was 
o bser ve d i n m o n ke ys a d mi nistere d d oses greater t ha n h u ma n e x p os ure. T here are n o a de q uate a n d 
well -c o ntr olle d st u dies i n pre g na nt or lactati n g w o me n.
6. 5. 4. 2
Te p oti ni b
I nterstitial Lu n g Disease
I nterstitial l u n g disease or I L D-li ke a d verse reacti o ns ha ve bee n re p orte d i n t he cli nical st u d y 
pr o gra m wit h te p oti ni b i n patie nts wit h N S C L C.
Partici pa nts s h o ul d be m o nit ore d f or p ul m o nar y  sy m pt o ms i n dicati ve f or I L D or I L D-li ke 
reacti o ns. Te p oti ni b s h o ul d be wit h hel d a n d partici pa nts s h o ul d be pr o m ptl y  in vesti gate d f or 
alter nati ve dia g n osis or s pecific eti ol o g y of I L D. Te p oti ni b m ust be per ma ne ntl y  disc o nti n ue d if 
I L D is c o nfir me d a n d t he partici pa nt be treate d a p pr o priately.
E de ma
E de ma has bee n re p orte d fre q ue ntl y i n t he st u d y pr o gra m. It is a n i de ntifie d ris k f or treat me nt wit h 
te p oti ni b. T o gai n f urt her i nf or mati o n, t o t he occ urre nce a n d res ol uti o n of e de ma, a n y A Es of 
e de ma, t he c urre nt e de ma stat us or A E res ol uti o n is t o be s pecifically d oc u me nte d at eac h visit.
I n the case of e de ma, please f oll o w t he a d vice i n t he Rec o m me n de d D ose M o dificati o ns f or 
Te p oti ni b t a ble i n Secti o n 6. 6. 2 .
As y m pt o matic Pa ncreatic E nz y me Ele vati o n
If a n as y m pt o matic li pase/a m ylase ele vati o n of Gra de ≥ 3 occ urs, t he partici pa nt will u n der g o 
cli nical e val uati o n f or t he prese nce of si g ns a n d s ym pt o ms t ypical of ac ute pa ncreatitis a n d f or 
ot her ris k fact ors f or pa ncreatitis. I n a d diti o n, a C T sca n a n d/ or M RI  of t he a b d o me n will be 
perf or me d t o assess t he pa ncreas. T he S p o ns or ( or dele gate) will be n otifie d of t he o utc o me of t he 
C T/ M RI . D osi n g wit h st u d y i nter ve nti o n ca n c o nti n ue d uri n g t he e val uati o n peri o d u nless t he 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
4 9 / 1 1 5
cli nical e val uati o n i n dicates pa ncreatitis. H o we ver, t he c o nti n uati o n of st u d y i nter ve nti o n f or t he 
partici pa nt will be i n di vi d uall y disc usse d wit h t he I n vesti gat or o n a partici pa nt b y  partici pa nt basis.
Li pase a n d a m ylase ele vati o ns are c o nsi dere d a d verse reacti o ns a n d ma y  o cc ur d uri n g or be y o n d 
C y cle 1, a n d 3 differe nt sce nari os are f orecaste d:

Persiste nt as y m pt o matic li pase/a m y lase ele vati o n at t he sa me gra de of Gra de ≥ 3

Rec urre nt as y m pt o matic li pase/a m y lase ele vati o n of Gra de ≥ 3, after a n i nitial Gra de ≥ 
3 ele vati o n wit h s u bse q ue nt res ol uti o n; a n d

As y m pt o matic li pase/a m ylase ele vati o n of Gra de ≥ 3 wit h persiste nt ele vati o n at t he 
sa me gra de, f oll o we d by s u bse q ue nt f urt her i ncrease in gra de.
I n all cases, t he partici pa nt will u n der g o cli nical e val uati o n f or t he prese nce of si g ns a n d s ym pt o ms 
t ypical of ac ute pa ncreatitis a n d f or ot her ris k fact ors f or pa ncreatitis. A gastr oi ntesti nal c o ns ult 
s h o ul d be re q ueste d a n d a d diti o nal i n vesti gati o ns (e. g., re peate d a b d o mi nal C T sca n) s h o ul d be 
c o nsi dere d, as a p pr o priate. T he case will be disc usse d wit h t he S p o ns or ( or dele gate). Treat me nt 
wit h te p oti ni b ma y  be c o nti n ue d d uri n g t he e val uati o n peri o d, at t he discreti o n of t he treati n g 
p h y sicia n an d de pe n di n g o n t he circ u msta nces of t he i n di vi d ual case.
If t here is n o cli nical or ra di ol o gical e vi de nce of pa ncreatitis, treat me nt wit h te p oti ni b s h o ul d be 
c o nti n ue d, partic ularl y  if t here is a p ote ntiall y p ositi ve be nefit f or t he i n di vi d ual partici pa nt . 
E val uati o n of p ote ntial cli nical be nefit will be base d o n e vi de nce fr o m t he literat ure, n o ncli nical 
m o dels, a n d/ or c urre nt e x perie nce wit h te p oti ni b i n t he partici pa nt or ot her partici pa nts wit h t his 
t u m or t ype. Ot her wise, treat me nt wit h te p oti ni b s h o ul d be disc o nti n ue d.
I n case of d ose re d ucti o n Secti o n 6. 6 , t he I n vesti gat or s h o ul d n otif y t he S p o ns or i m me diatel y a n d 
eac h case s h o ul d be disc usse d o n a case -b y -case basis, pr o vi di n g t he reas o n f or d ose re d ucti o n.
E m br y o- fetal T o xicit y
Te p oti ni b ca n ca use fetal har m w he n a d mi nistere d t o pre g na nt w o me n.
W o me n 
of c hil d beari n g p ote ntial or male partici pa nts wit h fe male part ners of c hil d beari n g 
p ote ntial s h o ul d be a d vise d of t he p ote ntial ris k t o a fet us.
6. 6
D ose Selecti o n a n d M o dific ati o n
See als o Secti o n  4. 3 f or j ustificati o n of t he te p oti ni b a n d cet u xi ma b d oses. T he rec o m me n dati o n 
t o pr ocee d t o a n i nter me diate d ose le vel, t o decrease t he d ose will be ma de b y t he S M C base d o n 
safety, t olera bilit y, a n d a vaila ble P K data.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 0 / 1 1 5
6. 6. 1
Cet u xi m a b
Cet u xi m a b: Rec o m me n de d D ose
I n all i n dicati o ns, cet u xi ma b is a d mi nistere d o nce a wee k. T he ver y  first d ose is 4 0 0 m g cet u xi ma b 
per m 2 b o d y  surface area (if nee de d, see Secti o n  6. 1 f or g ui da nce ). All s u bse q ue nt wee kl y d oses 
are 2 5 0 m g/ m 2 eac h.
Cet u xi m a b: D ose M o dific ati o n
I n case a d ose re d ucti o n is necessar y , t he st u d y inter ve nti o n will be a d mi nistere d as f oll o ws a n d 
descri be d i n t he ‘I n vesti gat or’s Br oc h ure A p pe n di x’ ( part of t he cet u xi ma b I B, that refers t o t he 
Merc k c ore c o m pa n y data s heet ).
I nf usi o n-rel ate d R e acti o ns
If d uri n g t he first i nf usi o n, a n I RR occ urs wit hi n t he first 1 5 mi n utes, t he i nf usi o n s h o ul d be 
st o p pe d. A caref ul be nefit/ris k assess me nt s h o ul d be u n derta ke n i ncl u di n g c o nsi derati o n w het her 
t he partici pa nt ma y  ha ve perf or me d I g E a nti b o dies bef ore a s u bse q ue nt i nf usi o n is gi ve n. If a n 
I R R d e vel o ps later d uri n g t he i nf usi o n or at a s u bse q ue nt i nf usi o n f urt her ma na ge me nt will de pe n d 
o n its se verit y :
a) Gra de 1: c o nti n ue sl o w i nf usi o n u n der cl ose s u per visi o n
b) Gra de 2: c o nti n ue sl o w i nf usi o n a n d i m me diatel y  a d mi nister treat me nt f or sy m pt o ms
c) Gra de 3 a n d 4: st o p i nf usi o n i m me diatel y, treat s ym pt o ms vi g or o usl y a n d c o ntrai n dicate 
f urt her use of cet u xi ma b.
S ki n R e acti o ns

If a partici pa nt e x perie nces a se vere s ki n reacti o n (≥Gra de 3; C T C A E), cet u xi ma b 
t hera py m ust be i nterr u pte d. Treat me nt ma y  onl y b e res u me d if t he reacti o n has res ol ve d 
t o Gra de ≤2.

If t he se vere s ki n reacti o n occ urre d f or t he first ti me, treat me nt m a y  be res u me d wit h o ut 
a n y cha n ge i n d ose le vel. Wit h t he sec o n d a n d t hir d occ urre nces of se vere s ki n reacti o ns, 
cet u xi ma b t hera p y must a gai n be i nterr u pte d. Treat me nt ma y  onl y b e res u me d at a l o wer 
d ose le vel ( 2 0 0 m g/ m 2 after t he sec o n d occ urre nce a n d 1 5 0 m g/ m 2 after t he t hir d 
occ urre nce), if t he reacti o n has res ol ve d t o Gra de ≤2.

If se vere s ki n reacti o ns occ ur a f o urt h ti me or d o n o t res ol ve t o Gra de ≤2 d uri n g 
i nterr u pti o n of treat me nt, per ma ne nt disc o nti n uati o n of cet u xi ma b treat me nt is re q uire d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 1 / 1 1 5
6. 6. 2
Te p oti ni b
Te p oti ni b: Rec o m me n de d D ose
T he pr o p ose d cli nical d ose of 5 0 0 m g te p oti ni b o nce dail y was defi ne d b y  a tra nslati o nal m o del-
base d a p pr oac h t hat utilize d n o ncli nical P K a n d P d data (i n hi biti o n of t he M E T 
pat h wa y ), 
n o ncli nical efficac y data (i n hi biti o n of t u m or gr o wt h), a n d cli nical P K a n d P d data, a n d was 
c o nfir me d b y cli nical safet y a n d efficac y  data.
I n t he o n g oi n g P hase II si n gle-ar m pi v otal st u d y (VI SI O N) t hat ai ms t o i n vesti gate te p oti ni b i n 
a d va nce d ( Sta ge III B/I V) N S C L C wit h M E T e x 1 4 s ki p pi n g alterati o ns or M E T a m plificati o n, dail y  
d oses of 5 0 0 m g te p oti ni b were a d mi nistere d after brea kfast a n d s h o w n t o be efficaci o us wit h a n 
acce pta ble safet y pr ofile, c o nfir mi n g t he selecte d cli nical d ose a n d re gi me n , a n d t his is t he la bele d 
d ose i n U S a n d Ja pa n f or patie nts wit h N S C LC wit h M E T e x 1 4 s ki p pi n g alterati o ns .
T he e x p os ure -efficac y anal y sis f or t he pri mar y  cli nical e n d p oi nt i n VI SI O N, o bjecti ve res p o nse 
( O R), s h o ws si milar O R rates acr oss t he e x p os ure ra n ge ac hie ve d wit h a d mi nistrati o n of t he 
cli nical d ose of 5 0 0 m g . T his c o nfir ms t he si m ulati o ns fr o m t he tra nslati o nal P K/ P d m o del t hat 
pre dicte d bi ol o gicall y  m ea ni n gf ul tar get i n hi biti o n i n a lar ge pr o p orti o n of t he patie nt p o p ulati o n 
at t he cli nical d ose of 5 0 0 m g.
Te p oti ni b: D ose M o dific a ti o n
De pe n de nt o n circ u msta nces, t he I n vesti gat or c o ul d eit her te m p oraril y interr u pt te p oti ni b 
treat me nt, or c o nti n ue te p oti ni b treat me nt at a l o wer d ose le vel u ntil t he A E relate d t o te p oti ni b 
rec o vers t o ≤ Gra de 2 or t o B aseli ne val ues.
D ose R e d ucti o n
I n case a d ose re d ucti o n is necessar y, t he st u d y i nter ve nti o n will be a d mi nistere d as f oll o ws:
T he 2 5 0 m g o nce dail y  dose is t he sta n dar d d ose re d ucti o n. If a partici pa nt d oes n ot t olerate t he 
2 5 0 m g o nce dail y d ose, or t he A E d oes n ot res ol ve f oll o wi n g treat me nt i nterr u pti o n, per ma ne nt 
treat me nt disc o nti n uati o n or ot her d osi n g sc he mas (i.e. h oli da y  sc he d ules or te p oti ni b e ver y 2n d
da y ) s h o ul d be disc usse d wit h t he S p o ns or.
Treat me nt I nterr u pti o n
T he ma xi m u m per mitte d peri o d of c o nti n u o us treat me nt i nterr u pti o n is 2 1 da y s. F oll o wi n g a 
treat me nt i nterr u pti o n, partici pa nts ca n be re-c halle n ge d at t he i nitial d ose le vel. Re -e x p os ure at 
differe nt d ose le vel after a treat me nt i nterr u pti o n is s u bject t o case b y case decisi o ns; t he S p o ns or 
s h o ul d be i nf or me d of a n y s uc h decisi o ns. 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 2 / 1 1 5
Rec o m me n de d D ose M o dific ati o ns f or Te p oti ni b 
T ar g et or g a n 
A d v er s e e v e nt a
D o s e m o difi c ati o n 
P ul m o n ar y 
C o nfir m e d I L D/ p n e u m o niti s
P er m a n e ntl y di s c o nti n u e t e p oti ni b. 
C ar di a c 
Q T c i nt er v al pr ol o n g ati o n of Gr a d e ≥3
Di s c o nti n u e t e p oti ni b
B o d y
E d e m a Gr a d e 1 or 2
D o s e l e v el of t e p oti ni b c a n b e m ai nt ai n e d
E d e m a Gr a d e 3 
T h e d o s e of t e p oti ni b m u st b e i nt err u pt e d u ntil e d e m a 
r e c o v er s t o ≤ Gr a d e 2 or b a s eli n e b ut f or n o m or e t h a n 
2 1 d a y s.
Aft er r e c o v er y t h e p ati e nt c a n r e st art at t h e s a m e d o s e 
or at 2 5 0 m g d ail y. 
If e d e m a Gr a d e 3 r e o c c ur s t h e t e p oti ni b d o s e m u st b e 
i nt err u pt e d a g ai n u ntil e d e m a r e c o v er s t o ≤ Gr a d e 2 or 
b a s eli n e b ut f or n o m or e t h a n 2 1 d a y s. Aft er r e c o v er y, 
t e p oti ni b m u st t h e n b e d o s e r e d u c e d t o 2 5 0 m g d ail y (if 
t h e pr e vi o u s d o s e w a s 5 0 0 m g d ail y).
If e d e m a Gr a d e 3 r e o c c ur s at 2 5 0 m g d o s e, t e p oti ni b 
m u st b e p er m a n e ntl y di s c o nti n u e d. 
G e n er ali s e d e d e m a Gr a d e 4
P er m a n e ntl y di s c o nti n u e t e p oti ni b.
P a n cr e a s
P a n cr e ati c e n z y m e el e v ati o n Gr a d e ≥3
S e e d et ail e d i n str u cti o n i n S e cti o n  6. 5. 4. 2 .
Ot h er
A n y ot h er r el at e d a d v er s e e v e nt of Gr a d e 3
T h e d o s e of t e p oti ni b m u st b e i nt err u pt e d u ntil e v e nt 
r e s ol v e s t o ≤ Gr a d e 2 or b a s eli n e b ut f or n o m or e t h a n 
2 1 d a y s. Aft er r e c o v er y, t e p oti ni b m a y b e r e st art e d at 1 
d o s e l e v el b el o w; 2 5 0 m g d ail y.
If a n y ot h er r el at e d A E of Gr a d e 3 r e o c c ur s at 2 5 0 m g 
d o s e, t e p oti ni b m u st b e p er m a n e nt l y di s c o nti n u e d 
Gr a d e 4
P er m a n e ntl y di s c o nti n u e t e p oti ni b
A b br e vi ati o n: A E = a d v er s e e v e nt; .
Al s o c o n si d er D L T r ul e s d uri n g D L T p eri o d a n d S af et y R u n -i n. 
a
A d v er s e e v e nt s gr a d e d b y N CI- C T C A E v 5. 0.
F oll o wi n g d ose m o dificati o ns, t he d ose of te p oti ni b ma y  be i ncrease d a gai n t o t he i nitial d ose le vel 
at t he discreti o n of t he I nvesti gat or.
Cli nical circ u msta nces w hic h are n ot c o vere d b y  ab o ve criteria m a y  be gr o u n ds f or d ose re d ucti o ns 
or treat me nt i nterr u pti o ns a n d s h o ul d be disc usse d wit h t he S p o ns or o n a case-b y -case basis.
6. 6. 3
D ose Li miti n g T o xicit y
D ose -li miti n g t o xicities will be e val uate d usi n g t he N CI -C T C A E v 5. 0. Li mits f or d ose escalati o ns 
will be c o nsi dere d i n acc or da nce t o Ba yesia n O pti mal I nter val desi g n ( B OI N) base d o n a 
ma xi m u m tar get t o xicit y  rate of 3 0 % a n d a ma xi m u m n u m ber of 1 2 partici pa nts (Y ua n 2 0 1 6 ). 
I n the safety r u n-i n part of t he st u d y, D L Ts are defi ne d as a n y of t he f oll o wi n g t o xicities a n d j u d ge d 
b y  the I n vesti gat or a n d/ or t he S p o ns or t o be n ot attri b uta ble t o t he disease or disease -relate d 
pr ocesses u n der i n vesti gati o n: 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 3 / 1 1 5
1.
Gra de 4 ne utr o pe nia f or m ore t ha n 7 da y s 
2.
Gra de ≥ 3 fe brile ne utr o pe nia wit h a bs ol ute ne utr o p hil c o u nt < 1 0 0 0/ m m 3 a n d a si n gle 
te m perat ure of > 3 8. 3° C ( 1 0 1° F) or a s ustai ne d te m perat ur e of ≥ 3 8° C ( 1 0 0. 4° F) f or m ore 
t ha n 1 ho ur
3.
Gra de 4 t hr o m b oc y t o pe nia or Gra de 3 t hr o m b oc yt o pe nia wit h n o n-tra u matic blee di n g 
4.
Gra de 3 u nc o ntr olle d na usea/ v o miti n g a n d/ or diarr hea t hat has n ot i m pr o ve d wit hi n 
7 2 h o urs des pite a de q uate a n d o pti mal treat me nt 
5.
Gra de 4 v o miti n g a n d/ or diarr hea
6.
Gra de ≥ 3 s ki n t o xicit y that has n ot res ol ve d t o G ra de 2 after 1 4 d a y s of a de q uate treat me nt
7.
A n y  ot her Gra de ≥ 3 n o n -he mat ol o gical A E will be defi ne d as D L T. E xce pti o ns are 
al o pecia or a n is olate d li pase a n d/ or a m yl ase ele vati o n of Gra de ≥ 3 wit h o ut cli nical or 
ra di ol o gical e vi de nce of pa ncreatitis 
8.
Occ urre nce of H y's la w cases ( defi ne d as a mi n otr a nsferases > 3 × U L N, t otal bilir u bi n ≥ 2 
× U L N, a n d al kali ne p h os p hatase ( AL P ) < 2 × U L N, wit h n o ot her reas o n t o acc o u nt f or 
t hese a b n or malities)
9. I nterstitial l u n g disease (I L D)/ p ne u m o nitis. 
All partici pa nts e nr olle d i n t he safet y ru n- i n peri o d w h o miss
> 2 5 % of t he pla n ne d d oses of 
te p oti ni b a n d/ or cet u xi ma b wit hi n C ycle 1 will be re place d if t he d ose re d ucti o n/i nterr u pti o n was 
n ot ca use d b y  a n y s af et y reas o ns/ D L Ts. Partici pa nts w h o e x perie nce at least o ne D L T d uri n g t he 
D L T assess me nt peri o d are i ncl u d e d re gar dless of t he c u m ulati ve d ose a d mi nistere d.
All partici pa nts e nr olle d i n t he st u d y are selecte d base d o n t he sa me i ncl usi o n a n d e xcl usi o n criteria 
as s pecifie d i n t he eli gi bilit y criteria.
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
If t he st u d y is pre mat urel y  ter mi nate d or s us pe n de d, partici pa nts w h o c o nti n ue t o de m o nstrate 
cli nical be nefit will be eli gi ble t o recei ve st u d y inter ve nti o n. St u d y  inter ve nti o n will be pr o vi de d 
via a n e xte nsi o n of t he st u d y, a r oll o ver st u d y re q uiri n g a p pr o val b y  the res p o nsi ble healt h 
a ut h orit y an d i n de pe n de nt et hics c o m mittee, or mec ha nis ms i.e., si n gle patie nt p ost st u d y  access, 
or patie nt s u p p ort, or ot her access pr o gra ms as per l ocal re g ulati o ns, at t he discreti o n of t he 
S p o ns or. T he S p o ns or reser ves t he ri g ht t o ter mi nate access t o st u d y inter ve nti o n if a n y of t he 
f oll o wi n g occ ur: a) t he st u d y is ter mi nate d d ue t o safety c o ncer ns, or b) a mar keti n g a ut h orizati o n 
is gra nte d i n t he l ocal mar ket a n d t he c orres p o n di n g me dicati o n is rei m b urse d b y t he p u blic s ocial 
sec urit y sys te m ma ki n g it accessi ble t o t he partici pa nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 4 / 1 1 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
I n rare i nsta nces, it ma y be necessar y  for a partici pa nt t o per ma ne ntl y  disc o nti n ue (defi niti ve 
disc o nti n uati o n) st u d y inter ve nti o n. If st u d y inter ve nti o n is defi niti vel y disc o nti n ue d, t he 
partici pa nt will re mai n i n t he st u d y to be e val uate d f or w hat is s pecifie d i n t he Sc he d ule of 
Acti vities (S o A ) ( Secti o n 1. 3 ).T he S o A i n dicates data t o be c ollecte d at t he ti me of disc o nti n uati o n 
of st u d y  i nter ve nti o n a n d f oll o w-u p a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d.

T he partici pa nt m ust be wit h dra w n fr o m st u d y inter ve nti o n i n t he e ve nt of a n y of t he 
f oll o wi n g:

Wit h dra wal of c o nse nt.

De vel o p me nt of u nacce pta ble t o xicit y .

Occ urre nce of pr o gressi ve disease acc or di n g t o R E CI S T Versi o n 1. 1 or i nitiati o n of 
a n y ot her a ntica ncer t hera p y.

Occ urre nce of a n i ncl usi o n or e xcl usi o n criteri o n t hat is cli nicall y rele va nt a n d affects 
t he partici pa nt's safety, if disc o nti n uati o n is c o nsi dere d necessar y  by t he I n vesti gat or 
a n d / or S p o ns or pri or t o st u d y i nter ve nti o n c o m pleti o n.

Occ urre nce of pre g na nc y , w hic h at t he E o T visit is d o ne as a ser u m test o nl y  for 
c o nfir mati o n as uri ne test will be p ositi ve, bef ore bei n g disc har ge d fr o m t he st u d y .

Use of a n o n per mitte d c o nc o mita nt dr u g (i ncl u di n g a n y ot her dr u g wit h k n o w n 
a ntica ncer acti vit y unless s pecifie d ot her wise) , if disc o nti n uati o n is c o nsi dere d 
necessar y  b y t he I n vesti gat or a n d/ or t he S p o ns or.

N o nc o m plia nce t hat is dee me d b y  the I n vesti gat or or t he S p o ns or t o c o m pr o mise 
partici pa nt safet y  or st u d y i nte grity.
T he I n vesti gat or will c o nsi der disc o nti n uati o n of st u dy i nter ve nti o n f or a b n or mal li ver f u ncti o n 
w he n a partici pa nt meets o ne of t he c o n diti o ns o utli ne d a n d n ot meeti n g i ncl usi o n criteri o n 1 0
u n der Secti o n  5. 1 or if t he I n vesti gat or belie ves t hat it is i n best i nterest of t he partici pa nt.
T he I n vesti gat or m ust c o nsi der disc o nti n uati o n of st u d y inter ve nti o n f or a n I L D-li ke e ve nt w he n 
a partici pa nt meets o ne of t he c o n diti o ns o utli ne d i n Secti o n 6. 5. 4. 1 a n d Secti o n 6. 5. 4. 2 u n der 
Res pirat or y  Dis or ders a n d I L D, or if t he I n vesti gat or belie ves t hat it is i n best i nterest of t he 
partici pa nt.  
If a cli nicall y si gnifica nt fi n di n g is i de ntifie d (i ncl u di n g c ha n ges fr o m B aseli ne i n Q T i nter val 
c orrecte d usi n g Fri dericia’s f or m ula [ Q Tc F]) after e nr oll me nt, t he I n vesti gat or or q ualifie d 
desi g nee will deter mi n e if t he partici pa nt ca n c o nti n ue i n t he st u d y an d if a n y c ha n ge i n partici pa nt 
ma na ge me nt is nee de d. If t he partici pa nt has a Gra de ≥3 Q Tc i nter val pr ol o n gati o n st u d y 
i nter ve nti o n m ust be disc o nti n ue d. A d diti o nall y , cl ose a n d a p pr o priate E C G m o nit ori n g i n h os pital 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 5 / 1 1 5
acc or di n g t o l ocal sta n dar d s h o ul d be i nitiate d. T his re vie w of t he E C G pri nte d at t he ti me of 
c ollecti o n will be d oc u me nt e d. A n y ne w cli nicall y rele va nt fi n di n g is re p orte d as a n A E.
T he S o A ( Secti o n 1. 3) s pecifies t he data t o c ollect at st u d y inter ve nti o n disc o nti n uati o n a n d f oll o w-
u p , a n d a ny a d diti o nal e val uati o ns t hat nee d t o be c o m plete d. Wit h dra wals will be d oc u me nte d i n 
t he e C R F as per t he S o A ( Secti o n 1. 3) .
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 m a y  disc o nti n ue fr o m t he st u d y at a n y ti me, at his/ her o w n re q uest or at 
t he discreti o n of t he I n vesti gat or f or safet y, be ha vi oral, c o m plia nce, or a d mi nistrati ve 
reas o ns. 

At t he ti me of st u d y disc o nti n uati o n, if p ossi bl e, a disc o nti n uati o n visit will be 
c o n d ucte d, as liste d i n t he S o A. T he S o A 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. 

If t he partici pa nt re v o kes c o nse nt f or t he st u d y , a n y data c ollecte d u p t o t hat p oi nt ma y 
still be use d, b ut n o f ut ure data ca n be ge nerate d, a n d a n y bi ol o gical sa m ples c ollecte d 
will be destr o y e d. 

A partici pa nt has t he ri g ht at a n y ti me t o re q uest destr u cti o n of a n y bi ol o gical sa m ples 
ta ke n. T he i n vesti gat or will d oc u me nt t his i n t he site st u d y rec or ds a n d t he C R F a n d 
i nf or m t he S p o ns or. T he sa m ples will be destr oye d.

A d diti o nal partici pa nts m ust be e nr olle d f or eac h partici pa nt w h o wit h dra ws fr o m t he 
st ud y  after si g ni n g c o nse nt a n d s uccessf ull y meeti n g e ntr y criteria b ut di d n ot recei ve 
te p oti ni b a n d/ or cet u xi ma b. A d diti o nall y , partici pa nts e xcl u de d fr o m t he D L T a nal ys is 
set ma y be re place d; t he decisi o n will be ma de b y t he S M C.

T he I n vesti gat or will sec u re t he safety of t he st u d y  partici pa nts a n d ma ke e ver y atte m pt 
t o c ollect data.
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 will be ta ke n if a partici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d st u d y 
visit:

T he site will 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 n vesti gat or or desi g nee will 
ma ke e ver y eff ort t o re gai n c o ntact wit h t he parti ci 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 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 / 1 1 5
a p pr o priate c o nse nt, c o ntact t he partici pa nt’ s ge neral practiti o ner f or i nf or mati o n. T hese 
c o ntact atte m pts will be d oc u me nte d i n t he partici pa nt’s me dical rec or d.

If t he partici pa nt c o nti n ues t o be u nreac ha ble, he/s he will be dee me d as “l ost t o f oll o w-
u p”.
8
St u d y Assess me nts a n d Pr oce d ures

St u d y  assess me nts a n d pr oce d ures a n d t heir ti mi n g are s u m marize d i n t he S o A ( Secti o n 
1. 3 ). A s u m mar y of k e y  st u d y acti vities o n Da y 1 of C y cles 1 a n d 2 is pr o vi de d i n 
A p pe n di x 4 . 

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 are disc usse d wit h t he S p o ns or i m me diatel y up o n occ urre nce 
or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y 
i nter ve nti o n.

A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A
( Secti o n 1. 3 ), is esse ntial a n d re q uire d f or st u d y c o n d uct.

All scree ni n g e val uati o ns will 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. La b orat or y  tests f or eli gi bilit y s h o ul d be 
perf or me d wit hi n 7 d a y s pri or t o C 1 D 1. T he I nvesti 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 t hat 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 . 

Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne me dical care (e. g., bl o o d c o u nt) 
a n d o btai ne d bef ore si g ni n g of t he I C F ma y be use d f or S cree ni n g or B aseli 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.

A ma xi m u m of a p pr o xi matel y 25 0 m L  of bl o o d will be c ollecte d i n a n y o ne- m o nt h 
peri o d fr o m eac h partici pa nt i n t he st u d y, i ncl u di n g a n y e xtra assess me nts t hat ma y  be 
re q uire d.

Date of birt h, se x ( ge n der), race, a n d et h nicit y will be c ollecte d o nl y where all o we d b y 
l ocal la w/re g ulati o ns.
8. 1
Effic ac y Assess me nts a n d Pr oce d ures
F or assess me nt ti me p oi nts a n d pr oce d ures f or pri mar y , sec o n dar y, a n d 
 
efficac y e n d p oi nts, see Secti o n 1. 3.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 / 1 1 5
8. 1. 1
T u m or assess me nts
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 sca ns will be perf or me d a nd 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 Versi o n 1. 1 or start of 
ne w a nti-ca ncer t hera py.  Ra di o gra p hic i ma ges a n d p h y sical fi n di n gs ( p hys ical assess me nts) will 
be use d b y  the I n vesti gat ors f or t he l ocal det er mi nati o n of disease pr o gressi o n a n d patie nt's 
treat me nt decisi o ns. A B aseli ne b o ne sca n s h o ul d be perf or me d i n partici pa nts k n o w n or s us pecte d 
t o ha ve b o ne metastases at B aseli ne. At B aseli 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 Versi o n 1. 1. Res ults f or t hese e val uati o ns will be 
rec or de d wit h as m uc h s pecificity 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.
C T or M RI of t he c hest, ab d o me n, a n d pel vis s h o ul d be c o n d ucte d t o e val uate disease i n t hese 
l ocati o ns. I ma gi n g ( prefera bly M RI 
a n d i ncl u di n g T 2/ F L AI R) of t he hea d at B aseli ne f or 
partici pa nts w h o ha ve or are s us pecte d t o ha ve ce ntral ner v o us s yste m metastases s h o ul d be 
c o n d ucte d. All lesi o ns i n t he brai n s h o ul d be c o nsi dere d n o n- tar get lesi o ns. A d diti o nal a nat o mic 
areas s h o ul d be i n vesti gate d i n case of s us pici o n of prese nce of metastases base d o n si g ns a n d 
s ym pt o ms of i n di vi d ual partici pa nts. All assess me nts s h o ul d be pr o vi de d b y t he sa me p h y sicia n or 
ra di ol o gist if p ossi ble, d uri n g t he st u d y.
F or patie nts w h o are e nr olle d i n t he st u d y a n d prese nt wit h brai n metastasis M RI  assess me nts of 
brai n lesi o ns s h o ul d be perf or me d if p ossi ble. W he n p ossi ble, t he M RI assess me nt s hall i ncl u de
C or o nal 3 D G d -T 1 WI, A xial T S E/ T 2 WI , A xial F L AIR, A xial T 1 WI , a n d A xial G d -T 1 WI . 
S keletal lesi o ns i de ntifie d at B aseli ne s h o ul d c o nti n ue t o be i ma ge d at s u bse q ue nt i ma gi n g 
sc he d ule d visits usi n g l ocalize d C T, M RI , or X- ra y (usi n g t he sa me met h o d use d at B aseli ne f or 
all visits f or a n y gi ve n lesi o n). After B aseli ne, w h ole b o d y  bo ne sca ns nee d n ot be re peate d, u nless 
p ositi ve at B aseli ne or cli nicall y i n dicate d.
All pr ot oc ol -re q uire d i ma ges s h o ul d be u pl oa de d t o t he i ma gi n g re p osit or y, mai ntai ne d b y  or o n 
be half of a n I ma gi n g Researc h Or ga nizati o n f or a p ote ntial i n de pe n de nt rea d w hic h ma y  be d o ne 
at a n y a p pr o priate ti me, i ncl u di n g at t he e n d of st u d y or later.
C y t ol o g y res ults will be c ollecte d w he n a vaila ble. E nlar gi n g ple ural/ pericar dial eff usi o n a n d/ or 
ascites (fl ui d c ollecti o ns) ma y or ma y n ot de n ote pr o gressi o n. T he ra di ol o gist ca n utilize c yt ol o g y 
fi n di n gs (if a vaila ble) t o deci de if si g nifica nt ne w fl ui d or u ne q ui v ocal a n d si g nifica nt e nlar gi n g 
fl ui d is a n i n dicati o n of pr o gressi o n.
T he I n 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 st u d y sca n f or me dical reas o ns or 
if t he I n vesti gat or s us pects P D. Partici pa nts w h o wit h dra w fr o m t he st u d y f or cli nical or 
s ym 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 Versi o n 1. 1.
Partici pa nts will be assesse d e ver y  6 wee ks starti n g fr o m C ycle 3 D a y  1 visit u ntil 9 m o nt hs, a n d 
e ver y 12 w ee ks t hereafter acc or di n g t o R E CI S T Versi o n 1. 1, u ntil disease pr o gressi o n, deat h, 
wit h dra wal of c o nse nt, or st u d y cl os ure. Details o n h o w t o perf or m R E CI S T Versi o n 1. 1 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 8 / 1 1 5
assess me nts are pr o vi de d i n  A p pe n di x 5.  I n vestigat or assess me nts will be c o n d ucte d. A n y C R 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 6- wee k i nter val or at t he ne xt sc he d ule d 
i ma gi n g visit, 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. In t he case 
of s ym pt o ms s u g gesti n g pr o gressi o n, partici pa nts s h o ul d be e val uate d b y  ima gi n g t hereafter f or 
d oc u me ntati o n a n d c o nfir mati o n of t he t u m or res p o nses. 
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at B aseli ne a n d d uri n g t he st u d y. If a c hest X -ra y in dicates metastatic 
disease w hile t he partici pa nt is e nr olle d i n t his st u d y, a C T of t he c hest is re q uire d f or c o nfir mati o n. 
All assess me nts s h o ul d be pr o vi de d b y  the sa me p h y sicia n or ra di ol o gist if p ossi b le d uri n g t he 
st u d y. 
Partici pa nts w h o wit h dra w fr o m t he treat me nt f or reas o ns ot her t ha n pr o gressi ve disease will ha ve 
a d diti o nal visits f or t u m or assess me nts e ver y 6 wee ks u ntil 9 m o nt hs, a n d e ver y 12 wee ks 
t hereafter u ntil disease pr o gressi o n. A ± 7- da y ti me wi n d o w is per mitte d f or t hese a d diti o nal 
f oll o w-u p visits u ntil 9 m o nt hs, a n d ± 1 4 da ys t hereafter. Reas o ns f or st u d y ter mi nati o n s h o ul d be 
rec or de d if t his visit is t he last visit f or t he partici pa nt. Rec or di n g of a n y ne w a ntica ncer t hera p y 
will be ma de (a t u m or assess me nt is ma n dat or y bef ore i nitiati n g t he ne w t hera p y).
S ur vi val F oll o w -u p is t o be perf or me d e ver y  3 m o nt hs ± 1 m o nt h at a cli nic visit or b y tele p h o ne 
c o ntact f or u p t o 1- ye ar. Partici pa nts’ s ur vi val i nf or mati o n will be c ollecte d. A n y su bse q ue nt 
a ntica ncer t hera p y gi ve n t o t he partici pa nt u ntil deat h s h o ul d be rec or de d.
T he i ma gi n g e n d p oi nts t o be assesse d f or efficac y eval uati o n acc or di n g t o R E CI S T Versi o n 1. 1 
i ncl u de:

Ra di o gra p hic res p o nse: best o verall res p o nse ( B O R), D o R , a n d pr o gressi o n -free 
s ur vi val ( P F S) per I n vesti gat or acc or di n g t o R E CI S T Versi o n 1. 1. 

T u m or assess me nt d uri n g f oll o w-u p: See S o A ( Secti o n 1. 3 ). Partici pa nts wit h o ut 
pr o gressi ve disease acc or di n g t o R E CI S T Versi o n 1. 1 at t he E n d of Treat me nt Visit will 
be f oll o we d f or disease pr o gressi o n acc or di n g t o t he S o A ( Secti o n 1. 3) u ntil P D was 
c o nfir me d or t he ma xi m u m d urati o n of st u d y i nter ve nti o n has bee n reac he d or t he st u d y 
e n de d, w hate ver is reac he d first.
8. 1. 2
C ollecti o n a n d st or a ge of i m a ges
All st u d y-relate d i ma ges will be c ollecte d b y  an I ma gi n g Researc h Or ga nizati o n, t he n q ualit y -
c hec ke d a n d st ore d f or a p ossi ble later i n de pe n de nt re vie w of i ma gi n g.
8. 2
S afet y Assess me nts a n d Pr oce d ures
T he safet y profile of t he st u d y inter ve nti o n will be assesse d t hr o u g h t he rec or di n g, re p orti n g a n d 
a nal ys is of B aseli ne me dical 
c o n diti o ns, A Es, p h y sical e xa mi nati o n fi n di n gs, vital si g ns, 
electr ocar di o gra ms, a n d la b orat or y  tests.
C o m pre he nsi ve assess me nt of a n y pote ntial t o xicit y ex perie nce d b y  eac h partici pa nt will be 
c o n d ucte d starti n g w he n t he partici pa nts gi ve i nf or me d c o nse nt a n d t hr o u g h o ut t he st u d y. T he 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
5 9 / 1 1 5
I n vesti gat or will re p ort a n y A Es, w het her o bser ve d b y  the I n vesti gat or or re p orte d b y  th e 
partici pa nt; t he re p orti n g peri o d is s pecifie d i n Secti o n  8. 3. 1.
A part fr o m t he I n vesti gat or, safety d ata will als o be assesse d c o nti n u o usl y b y t he S p o ns or me dical 
m o nit ori n g acti vities, as well as b y t he f oll o wi n g c o m mittees:

S M C d uri n g t he safet y r u n -i n (refer t o Secti o n 4. 1 ).
8. 2. 1
P h ysic al E x a mi n ati o ns

A c o m plete p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he 
Car di o vasc ular, Res pirat or y , Gastr oi ntesti nal a n d Ne ur ol o gical s yste ms. I n ad diti o n, 
s ki n e xa mi nati o n is t o be perf or me d.

A brief p h y sical e xa mi nati o n will i ncl u de, at a mi ni m u m, assess me nts of t he s ki n, l u n gs, 
car di o vasc ular s ys te m a n d a b d o me n (li ver).

I n vesti gat ors will p a y  special atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us 
ill nesses, i ncl u di n g I L D, pa ncreatitis , a n d car di o vasc ular diseases.
8. 2. 2
Vit al Si g ns

Hei g ht ( meas ure d at Scree n i n g o nly) a n d wei g ht will be meas ure d a n d rec or de d.

T e m perat ure, p ulse rate, res pirat or y rate, a n d bl o o d press ure will be assesse d. T he 
met h o d use d f or te m perat ure assess me nt will be rec or de d.

Bl o o d press ure a n d p ulse meas ure me nts will be assesse d wit h a c o m pletel y a ut o mate d 
de vice. Ma n ual tec h ni q ues will be use d o nl y if a n a ut o mate d de vice is n ot a vaila ble.

Bl o o d press ure a n d p ulse meas ure me nts will be prece de d b y  at least 5 mi n utes of rest 
f or t he partici pa nt i n a q uiet setti n g wit h o ut distracti o ns (e. g., tele visi o n, cell p h o nes).

Vital si g ns will be meas ure d prefera bl y  i n a sitti n g p ositi o n after 5 mi n utes rest a n d will 
i ncl u de te m perat ure, s yst olic a n d diast olic bl o o d press ure, p ulse , a n d res pirat or y rate.
T he partici pa nt p ositi o n will be rec or de d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 0 / 1 1 5
8. 2. 3
Electr oc ar di o gr a ms

Tri plicate 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 ( Secti o n 1. 3 ) 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, Q T, 
a n d Q Tc F i nter vals. Partici pa nts will rest f or 5 mi n utes i n a se mi-s u pi ne or s u pi ne 
p ositi o n bef ore t he rea di n g is ta ke n. F or st u d y disc o nti n uati o n criteria i n v ol vi n g 
cli nicall y si g nifica nt Q Tc F fi n di n gs, refer t o Secti o n 7. 1.
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 ( Secti o n 1. 3) . All sa m ples will be clearl y 
i de ntifie d. 

A d diti o nal tests ma y  be perf or me d at a n y t i me d uri n g t he st u d y, as deter mi ne d necessar y  
b y  t he I n vesti gat or or re q uire d b y  l ocal re g ulati o ns.
T he tests will be perf or me d b y  local la b orat ories. It is re q uire d t hat t hese l ocal la b orat ories are 
certifie d, perf or m a n d d oc u me nt i nterla b orat or y  testi n g at re g ular ti me i nter vals a n d pr o vi de a list 
of n or mal ra n ge la b orat or y  val ues i ncl u di n g u nits as defi ne d by i nter nati o nal s yste m of u nits ( SI). 
T he S p o ns or will recei ve a list of t he l ocal la b orat or y nor mal ra n ges bef ore s hi p me nt of st u d y 
i nter ve nti o n(s). A ny c ha n ges t o t he ra n ges d uri n g t he st u d y will be f or war de d t o t he S p o ns or.

T he I n vesti gat or will re vie w eac h la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d 
a n y cli nically rele va nt c ha n ges occ urri n g d uri n g t he st u d y in t he A E secti o n of t he eC R F . 
T he la b orat or y  re p orts will be file d wit h t he s o urce d oc u me nts.

Met h o ds f or sa mple i de ntificati o n d uri n g s hi p pi n g a n d ha n dli n g, as well as sa m pli n g 
met h o ds, pr ocessi n g a n d st ora ge of sa m ples are detaile d i n t he l ocal La b orat or y 
Ma n uals.

Pre g na nc y  testi n g (ser u m or hi g hl y  se nsiti ve uri ne, as re q uire d b y  local re g ulati o ns) will 
be c o n d ucte d as s h o w n i n t he S o A ( Secti o n 1. 3) .

Pre g na nc y  testi n g (ser u m or hi g hl y  se nsiti ve uri ne, as re q uire d b y  local re g ulati o ns) will 
be c o n d ucte d at t he e n d of rele vant s yste mic e x p os ure of t he st u d y inter ve nti o n a n d 
c orres p o n d wit h t he ti me fra me f or fe male partici pa nt c o ntrace pti o n i n Secti o n  5. 1.
8. 3
A d verse E ve nts a n d Seri o us A d ver se 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 7.

T he I nvesti gat or a n d a n y qualifie d desi g nees (e. g., S u b -I n vesti gat ors) are res p o nsi ble 
f or detecti n g, d oc u me nti n g, a n d rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or 
S A E. T he I n vesti gat or re mai ns res p o nsi ble f or f oll o wi n g u p A Es t hat are seri o us or t hat 
ca use d t he partici pa nt t o disc o nti n ue t he st u d y inter ve nti o n or st u d y, as s pecifie d i n 
Secti o n  8. 3. 3.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 1 / 1 1 5

Re q uests f or f oll o w-u p will us uall y  be ma de via t he St u d y  
Mo nit or, alt h o u g h i n 
e xce pti o nal circ u msta nces t he gl o bal patie nt safety de part me nt m a y  co ntact t he 
I n vesti gat or directl y t o o btai n f urt her i nf or mati o n or t o disc uss t he e ve nt.
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

All S A Es will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil t he Safet y  Foll o w - u p Visit 
at t he ti me p oi nts s pecifie d i n t he S o A ( Secti o n 1. 3 ). Be y o n d t his re p orti n g peri o d, a n y 
ne w u ns olicite d S A Es t hat t he I n vesti gat or s p o nta ne o usl y  re p orts t o t he S p o ns or will be 
c ollecte d a n d pr ocesse d.

All A Es will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil t he Safet y F oll o w - u p Visit at 
t he ti me p oi nts s pecifie d i n t he S o A ( Secti o n 1. 3) .

All S A Es will be rec or de d a n d re p orte d t o t he S p o ns or or desi g nee i m me diately a n d 
u n der n o circ u msta nce will t his e xcee d 2 4 h o urs, as i n dicate d i n A p pe n di x 7. T he 
I n vesti gat or will s u b mit a n y u p date d S A E data t o t he S p o ns or wit hi n 2 4 h o urs of it bei n g 
a vaila ble usi n g t he sa me pr oce d ure t hat was use d f or t he i nitial re p ort.

I n vesti gat ors are n ot o bli gate d t o acti vel y s olicit A Es or S A Es after t he e n d of st u d y 
partici pati o n. H o we ver, if t he i n vesti gat or lear ns of a n y SA E , i ncl u di n g a deat h, at a n y 
ti me after a partici pa nt has bee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he 
e ve nt t o be reas o na bl y relate d t o t he st u d y inter ve nti o n or st u d y partici pati o n, t he 
I n vesti gat or will pr o m ptl y n otif y t he S p o ns or.
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. 
Care will be ta ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es. O pe n -e n de d a n d n o n -
lea di n g ver bal q uesti o ni n g of t he partici pa nt is t he preferre d met h o d t o i n q uire a b o ut A E 
occ urre nces.
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 a n d 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 7 . All S A Es a n d all n o nseri o us A Es 
of s pecial i nterest ( A E SI) (see Secti o n 8. 3. 7 ) m ust be a d diti o nall y d oc 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 7 .
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
After t he i nitial A E/ S A E re p ort, t he I n vesti gat or is re q uire d t o pr oacti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts. All S A Es a n d A E SI s (as defi ne d i n Secti o n  8. 3. 7) will be f oll o we d 
u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w -
u p (as defi ne d i n Secti o n  7. 3 ). N o ne w i nf or mati o n is e x pecte d. Reas o na ble atte m pts t o o btai n t his 
i nf or mati o n will be ma de a n d d oc u me nte d. It is als o t he I n vesti gat or’s res p o nsi bilit y to e ns ure t hat 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 2 / 1 1 5
a n y necessar y ad 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 i n  A p pe n di x 7 .
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
Pr o m pt n otificati o n b y  the I n vesti gat or t o t he S p o ns or of a n S A E ( partic ularl y life-t hreate ni n g a n d 
deat hs) is esse nti al s o t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safety of 
partici pa nts a n d t he safet y  of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n are met.
T he S p o ns or has a le gal res p o nsi bilit y to n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y age ncies a b o ut t he safety of a st u d y i nter ve nti o n u n der cli nical i n vesti gati o n. T he 
S p o ns or will c o m pl y  wit h c o u ntr y-s pecific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g t o 
t he re g ulat or y aut h orit y, I nstit uti o nal Re vie w B oar ds (IR B)/I n de pe n de nt Et hics C o m mittees 
(I E C), a n d I n vesti gat ors.
I n di vi d ual Case Safet y  Re p orts will be pre pare d f or s us pecte d u ne x pecte d seri o us a d verse 
reacti o ns ( S U S A R) acc or di n g t o l ocal re g ulat or y re q uire me nts a n d S p o ns or p olic y a n d f or war de d 
t o In vesti g at ors, as necessar y.
A n I nvesti gat or w h o recei ves a n I ndi vi d ual Case Safet y  Re p ort descri bi n g a S U S A R or ot her 
s pecific safety i nf or mati o n (e. g., E mer gi n g Safet y Iss ue Re p ort, s u m mar y or listi n g of 
S A Es/ S U S A Rs) fr o m t he S p o ns or will re vie w a n d t he n file it al o n g wit h t he I n vesti gat or Br oc h ure 
i n t he I nvesti gat or’s Site File a n d will n otif y  the I RB/I E C, if a p pr o priate acc or di n g t o l ocal 
re q uire me nts.
I n t his gl o bal cli nical m ultice nter st u d y, t he S p o ns or is i n t he best p ositi o n t o deter mi ne a n 
u na ntici pate d pr o ble m (as defi ne d i n U S Re g ulati o ns 2 1 C F R 3 1 2. 6 6). T he S p o ns or will 
i m me diatel y notif y  all I n vesti gat ors of fi n di n gs t hat c o ul d a d versel y affect t he safet y of 
partici pa nts, i m pact t he c o n d uct of t he st u d y or alter t he I RB’s a p pr o val/fa v ora ble o pi ni o n t o
c o nti n ue t he st u d y. A n u na ntici pate d pr o ble m is a seri o us a d verse e ve nt t hat b y  its nat ure, 
i nci de nce, se verity, or o utc o me has n ot bee n i de ntifie d i n t he c urre nt versi o n of t he ris k a nal ys is 
re p ort, s pecifie d i n Secti o n 2. 3.
A E SI s s pecifie d i n Secti o n 8. 3. 7 will be re p orte d t o t he S p o ns or ( or de le gate) i n a n e x pe dite d 
ma n ner as descri be d i n  A p pe n di x 7 .
8. 3. 5
Pre g n a nc y

Details of all pre g na ncies i n fe male partici pa nts a n d, fe male part ners of male partici pa nts 
will be c ollecte d after t he start of st u d y inter ve nti o n a n d u ntil t he Safet y  Foll o w - u p Visit .

If a pre g na nc y  is re p orte d, t he I nvesti gat or will i nf or m t he S p o ns or wit hi n 2 4 h o urs of 
lear ni n g of t he pre g na nc y an d will f oll o w t he pr oce d ures s pecifie d bel o w f or c ollecti o n 
of pre g na nc y  i nf or mati o n.

A b n or mal pre g na nc y  outc o mes (e. g., s p o nta ne o us a b orti o n, fetal deat h, still birt h, 
c o n ge nital a n o malies, ect o pic pre g na nc y ) are c o nsi dere d S A Es.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 3 / 1 1 5
C ollecti o n of Pre g n a nc y I nf or m ati o n
Male partici pa nts wit h part ners w h o bec o me pre g na nt

T he I n vesti gat or will atte m pt t o c ollect pre g na nc y  inf or mati o n o n a n y m ale partici pa nt’s 
fe male part ner, w h o bec o mes pre g na nt w hile t he partici pa nt is i n t his st u d y. T his a p plies 
o nl y  t o partici pa nts w h o recei ve st u d y i nter ve nti o n.

After 
o b tai ni n g si g ne d c o nse nt fr o m t he pre g na nt fe male part ner directl y , t he 
I n vesti gat or will rec or d t he pre g na nc y  inf or mati o n o n t he a p pr o priate f or m a n d s u b mit 
it t o t he S p o ns or wit hi n 2 4 h o urs of lear ni n g of t he pre g na nc y . T he fe male part ner will 
als o be f ollo we d t o deter mi ne t he o utc o me of t he pre g na nc y . I nf or mati o n o n t he stat us 
of t he m ot her a n d c hil d will be f or war de d t o t he S p o ns or. Ge nerall y, t he f oll o w- u p will 
be n o l o n ger t ha n 6 t o 8 wee ks f oll o wi n g t he esti mate d deli ver y  date. A n y ter mi nati o n 
of t he p re g na nc y will be re p orte d re gar dless of fetal stat us ( prese nce or a bse nce of 
a n o malies) or i n dicati o n f or t he pr oce d ure.
Fe male Partici pa nts w h o bec o me pre g na nt

T he I nvesti gat or will c ollect pre g na nc y  inf or mati o n o n a n y fe male partici pa nt w h o 
bec o mes pre g n a nt w hile s he is i n t he st u d y. T he i nitial i nf or mati o n will be rec or de d o n 
t he a p pr o priate
f or m a n d s u b mitte d t o t he S p o ns or wit hi n 2 4 h o urs of lear ni n g of t he pre g na nc y. 

T he partici pa nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y . T he 
I n vesti gat or will c ollect f oll o w-u p i nf or mati o n o n t he partici pa nt a n d t he ne o nate, a n d 
t he i nf or mati o n will be f or war de d t o t he S p o ns or. Ge nerall y, f oll o w-u p will n ot be 
re q uire d f or l o n ger t ha n 6 t o 8 wee ks be y o n d t he esti mate d deli ver y  date. A n y  
ter mi nati o n of pre g na nc y  will be re p orte d, re gar dless of fetal stat us ( prese nce or a bse nce 
of a n o malies) or i n dicati o n f or t he pr oce d ure.

W hile 
pre g na nc y  itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na nc y 
c o m plicati o n or electi ve ter mi nati o n of a pre g na nc y f or me dical reas o ns will be re p orte d 
as a n A E or S A E.

A s p o nta ne o us a b orti o n ( occ urri n g at < 2 2 wee ks gestati o nal a ge) or still birt h ( occ urri n g 
at > 2 2 wee ks gestati o nal a ge) is al wa ys c o nsi dere d t o be a n S A E a n d will be re p orte d as 
s uc h.

A n y  post -st u d y pre gna nc y  relate d S A E c o nsi dere d reas o na bl y relate d t o t he st u d y 
i nter ve nti o n b y  the I n vesti gat or will be re p orte d t o t he S p o ns or as s pecifie d i n Secti o n 
8. 3. 4 . W hile t he I nvesti gat or is n ot o bli gate d t o acti vel y  see k t his i nf or mati o n i n f or mer 
st u d y partici pa nts, he or s he ma y lear n of a n S A E t hr o u g h s p o nta ne o us re p orti n g.

A n y  fe male partici pa nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will 
disc o nti n ue st u d y  i nter ve nti o n or be wit h dra w n fr o m t he st u d y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 4 / 1 1 5
8. 3. 6
Dise ase -Rel ate d E ve nts a n d/ or Dise ase -Rel ate d O utc o mes N ot 
Q u alif yi n g as A Es or S A Es
T he f oll o wi n g disease -relate d e ve nts are c o m m o n i n partici pa nts wit h metastatic c ol orectal ca ncer 
a n d ca n be seri o us/life t hreate ni n g:

Pr o gressi ve disease
Beca use t hese e ve nts are t ypicall y  ass ociate d wit h t he disease u n der st u d y (e. g., pr o gressi ve 
disease), t he y will n ot be re p orte d acc or di n g t o t he sta n dar d pr ocess f or e x pe dite d re p orti n g of 
S A Es e ve n t h o u g h t he e ve nt ma y  meet t he defi niti o n of a S A E. T hese e ve nts will be rec or de d o n 
t he a p plica ble eC R F pa ge wit hi n t he a p pr o priate ti me fra me. 
H o we ver, if eit her of t he f oll o wi n g c o n diti o ns a p plies, t he n t he e ve nt will be rec or de d a n d re p orte d 
as a n S A E (i nstea d of a disease -relate d e ve nts):

T he e ve nt is, i n t he I nvesti gat or’s o pi ni o n, of greater i nte nsit y, fre q ue nc y, or d urati o n 
t ha n e x pecte d f or t he i n di vi d ual partici pa nt.
O R

T he I n vesti gat or c o nsi ders t hat t here is a reas o na ble p ossi bilit y  that t he e ve nt was relate d 
t o st u dy i nter ve nti o n.
8. 3. 7
A d verse E ve nts of S peci al I nterest
F or t his st u d y , A E SIs i ncl u de o nl y t he f oll o wi n g:

A Es s u g gesti ve of dr u g-i n d uce d li ver i nj ur y i ncl u di n g he patic/li ver fail ure a n d he patitis
( n o n-i nfecti o us) are c o nsi dere d A E SIs.
A E SI s will be re p orte d t o t he S p o ns or ( or de le gate) i n a n e x pe dite d ma n ner as descri be d i n 
A p pe n di x 7 .
8. 4
Tre at me nt of O ver d ose
F or t his st u d y, a n y d ose of te p oti ni b or cet u xi ma b greater t ha n t he d ose t hat is defi ne d i n t his 
cli nical st u d y pr ot oc ol will be c o nsi dere d a n o ver d ose.
T he S p o ns or d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose.
E ve n if 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 eC R F a n d re p orte d 
t o gl o bal patie nt safet y in a n e x pe dite d ma n ner. O ver d oses are re p orted o n a S A E a n d O ver d ose 
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 7 .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 / 1 1 5
8. 5
P h ar m ac o k i netics
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 6 / 1 1 5

L i q ui d bi o ps y ( w h ole bl o o d) a n d/ or tiss ue bi o ps y sa m ples will be c ollecte d t o test M E T
a m plificati o n t hat s h o ul d be detecte d b y  a positi ve test wit h a p pr o priate re g ulat or y stat us 
(c ollecte d after disease pr o gressi o n of t he pre vi o us a nti-E G F R t hera p y). L o cal M E T
a m plificati o n testi n g of tiss ue a n d/ or S p o ns or o versee n ce ntral li q ui d bi o ps y  sa m ple 
testi n g will be all o we d f or e nr ol me nt o nl y  wit h a n assay wit h a p pr o priate vali dati o n a n d 
re g ulat or y stat us. If l ocal M E T a m plificati o n tests d o n ot ha ve t he a p pr o priate re g ulat or y 
stat us or if t he sa m ples are n ot a nal yz e d l ocall y, ce ntral c o nfir mati o n of M E T
a m plificati o n is offere d a n d nee de d bef ore e nr olli n g. Partici pa nts s h o ul d ha ve s h o w n 
be nefit fr o m t he pre vi o us a nti -E G F R t hera p y b y C R or P R , b ot h at least f or 4 m o nt hs or 
S D f or at least 6 m o nt hs pri or t o disease pr o gressi o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 / 1 1 5
8. 9
I m m u n o ge nicit y Assess me nts
W h ole bl o o d sa m ples of a p pr o xi matel y 3. 5 m L  will be c ollecte d f or detecti o n of a nti b o dies a gai nst 
cet u xi ma b i n ser u m. C ollecti o n ti mes are s pecifie d i n t he S o A ( Secti o n 1. 3) . 
T he detecti o n of a nti b o dies t o cet u xi ma b will be perf or me d usi n g a vali date d i m m u n oassa y met h o d 
wit h tiere d testi n g of scree ni n g, c o nfir mat or y  a n d titrati o n. C o nfir me d p ositi ve a nti b o dies ma y be 
f urt her c haracterize d.
 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 8 / 1 1 5
Details o n pr ocesses f or c ollecti o n a n d ha n dli n g of t hese sa m ples are i n a La b orat or y Ma n ual. 
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 CF.
8. 1 0
Me dic al Res o urce Utiliz ati o n a n d He alt h Ec o n o mics
N ot a p plica ble. T here is n o healt h ec o n o mic o bjecti ve, n or a n y res o urce utilizati o n o utc o mes 
meas ures f or t his st u d y .
9
St atistic al C o nsi der ati o ns
A nal y sis of all data will be perf or me d b y t he S p o ns or or its desi g nee. T he res ults of all st u d y parts 
will be re p orte d i n t he cli nical st u d y re p ort. A nal ys es will be perf or me d se parately f or eac h c o h ort. 
Details of t he a nal ys is of safety, efficac y, P K, a n d bi o mar ker data will be prese nte d i n t he 
I nte grate d A nalys is Pla n (I A P) , w hic h will be fi nalize d bef ore t he data base is l oc ke d f or a nal y sis.
9. 1
St atistic al H y p ot heses
N o f or mal statistical h y p ot hesis will be teste d, as t he st u d y  is desi g ne d t o be e x pl orat or y.
9. 2
S a m ple Size Deter mi n ati o n
T he n u m ber of partici pa nts t o be s cree ne d is e x pecte d t o be ar o u n d 3 4 2 partici pa nts t o acc o u nt f or 
t he descri be d heter o ge nicit y  for M E T
a m plificati o n i n t he pla n ne d setti n g (Pietra nt o ni o 2 0 1 7 ; 
Pietra n t o ni o 2 0 1 5 ; Ra g ha v 2 0 1 6 ; Li u 2 0 1 9 ; M o ha n 2 0 1 4 ; Sira ve g na 2 0 1 5 ; M or elli 2 0 1 4 ; M o nta g ut 
2 0 1 8 ; L C -S C R U M, A S C O 2 0 1 9 [Na ka m ura 2 0 1 9 ]).
I n t otal, a ma xi m u m of 4 8 partici pa nts are pla n ne d t o be assi g ne d t o st u d y i nter ve nti o n s uc h t hat 
a p pr o xi matel y 2 2 ( C o h ort A) a n d 2 0 ( C o h ort B) partici pa nts will be treate d at R P 2 D . T he 4 2 
partici pa nts will be u n der t he sa me d ose le vel. T he sa m ple size calc ulati o n of 4 2 partici pa nts is 
base d o n t he f ull a na l ysis set ( F A S).
T he ai m is t o ha ve 2 2 partici pa nts treate d wit h t he R P 2 D of te p oti ni b f or 2 L li ne treat me nt ( C o h ort 
A) a n d 2 0 partici pa nts treate d wit h t he R P 2 D f or t he 3 L + treat me nt ( C o h ort B) wit h at least 6 
partici pa nts i n t he safet y  r u n-i n peri o d, irres pecti ve of c o h ort.
It is a ntici pate d t hat 6 eli gi ble partici pa nts irres pecti ve of t hera py li ne, will be e nr olle d i nt o t he 
first part of t he st u dy f or t he deter mi nati o n of R P 2 D of te p oti ni b de pe n di n g o n D LTs o bser ve d. If 
2 5 0 m g te p oti ni b is t o be use d t he n u m ber of partici pa nts e nr olle d f or t he deter mi nati o n of R P 2 D 
will i ncrease u p t o 1 2 ( See Secti o n  9. 4. 2. 1 ).
2 n d Li ne tre at me nt ( C o h ort A):
A sa m ple size of 2 2 partici pa nts treate d wit h t he R P 2 D of te p oti ni b (i ncl u di n g t h ose R P 2 D -d ose d 
partici pa nts fr o m t he safet y  r u n-i n), is c h ose n f or t he f oll o wi n g reas o ns: 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
6 9 / 1 1 5
T he pr o ba bilit y  to o bser ve 5 or m ore res p o n ders (c o nfir me d C R or P R) o ut of 2 2 treate d 
partici pa nts ( 5/ 2 2 = 2 2. 7 % res p o nse rate) is 8 0. 8 % u n der t he ass u m pti o n of a tr ue res p o nse rate of 
3 0 % (rele va nt cli nical effect); w hereas, if t he tr ue res p o n der rate is 1 0 % ( n o n-rele va nt cli nical 
effect re gar di n g f urt her de vel o p me nt of t his c o m bi nati o n t hera py i n t his i n dicati o n), t he pr o ba bilit y 
t o o bser ve 5 or m ore res p o n ders is 5. 7 %. I n t hese calc ulati o ns, a f utilit y anal ys is is c o nsi dere d 
w hic h will be perf or me d after 1 2 partici pa nts are e nr olle d a n d m o nit ore d wit h o ut st o p pi n g 
recr uit me nt of f urt her partici pa nts i nt o t his st u d y: If t here are less t ha n 2 res p o n ders wit hi n t he first 
1 2 treate d partici pa nts, t he e nr oll me nt of 2 L partici pa nts f or t he st u d y  will be st o p pe d f or f utilit y. 
U n der t he ass u m pti o n of a tr ue rate of 3 0 %, t he pr o ba bilit y of a false st o p will be 8. 5 %; w hereas 
i n case of a tr ue rate of 1 0 %, t he pr o ba bilit y of a c orrect st o p will be 6 5. 9 %.
T he o verall t hres h ol d of > 2 0 % res p o n ders at t he e n d of t he st u d y was set base d o n t he de vel o p me nt 
c o nsi derati o n f or 2 L w here be vaciz u ma b + c he m ot hera py s h o we d a res p o nse rate of 2 2. 7 % 
( Gia nt o ni o 2 0 0 7).
3 r d Li ne + tre at me nt ( C o h ort B):
A sa m ple size of 2 0 partici pa nts treate d wit h t he R P 2 D of te p oti ni b (i ncl u di n g t h ose R P 2 D -d ose d 
partici pa nts fr o m t he safet y r u n-i n), is re q uire d, s o t hat t he pr o ba bilit y  to o bser ve 2 or m ore 
res p o n ders (c o nfir me d C R or P R) o ut of 2 0 treate d partici pa nts ( 2/ 2 0 = 1 0. 0 % res p o nse rate) is 
8 2. 4 % u n der t he ass u m pti o n of a tr ue res p o nse rate of 1 5 % (rele va nt cli nical effect); w hereas , if 
t he tr ue res p o nse rate is 2. 5 % ( n o n-rele va nt cli nical effect re gar di n g f urt her de vel o p me nt of t his 
c o m bi nati o n t hera py i n t his i n dicati o n), t he pr o ba bilit y  to o bser ve 2 or m or e res p o n ders is 8. 8 %. 
N o f utilit y  a nalys is is pla n ne d here d ue t o t he l o w rate of e x pecte d res p o n ders i n t he 3 L + setti n g. 
T he t hres h ol d of ≥1 0 % f or 3 L + was set base d o n data f or re g orafe ni b or trifl uri di ne/ti piracil, w hic h 
s h o we d a res p o nse rate of ma xi m u m 4 % (Li  2 0 1 5, Ma y e r 2 0 1 5).
9. 3
P o p ul ati o ns f or A n al yses
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e xcl u de partici pa nts fr o m a ny 
a nal ys is p o p ulati o n will be ma de d uri n g a data re vie w meeti n g pri or t o data base l oc k.
A n al y s i s S et
D e s cri pti o n
S cr e e ni n g ( S C R) 
All p arti ci p a nt s, w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
st u d y i nt er v e nti o n st at u s i n t h e st u d y.
F ull ( F A S)/ S af et y ( S A F)
All p arti ci p a nt s, w h o w er e a d mi ni st er e d at l e a st o n e d o s e of a n y st u d y 
i nt er v e nti o n.
D L T
All p arti ci p a nt s tr e at e d i n t h e s af et y r u n -i n p eri o d w h o r e c ei v e d at l e a st 7 5 % of t h e 
t e p oti ni b a n d c et u xi m a b pl a n n e d d o s e a n d c o m pl et e t h e D L T p eri o d ( 3 w e e k s 
aft er st art of tr e at m e nt wit h st u d y i nt er v e nti o n), or w h o e x p eri e n c e a D L T d uri n g 
t h e D L T p eri o d r e g ar dl e s s of t h e r e c ei v e d a m o u nt of e a c h st u d y i nt er v e nti o n.
P K
All p arti ci p a nt s, w h o r e c ei v e at l e a st o n e d o s e of st u d y i nt er v e nti o n, h a v e n o 
r el e v a nt pr ot o c ol d e vi ati o n s or i m p ort a nt e v e nt s aff e cti n g P K, a n d pr o vi d e at l e a st 
o n e m e a s ur a bl e p o st - d o s e c o n c e ntr ati o n. P arti ci p a nt s will b e a n al y z e d p er t h e 
a ct u al st u d y i nt er v e nti o n t h e y r e c ei v e d.
I m m u n o g e ni cit y
All p arti ci p a nt s w h o r e c ei v e at l e a st o n e d o s e of st u d y i nt er v e nti o n a n d h a v e at 
l e a st o n e v ali d A D A r e s ult. All A D A a n al y s e s will b e b a s e d o n t hi s a n al y si s s et.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 0 / 1 1 5
9. 4
St atistic al A n al yses
9. 4. 1
Effic ac y A n al yses
All efficac y  anal ys es will be perf or me d o n t he F A S p o p ulati o n u nless ot her wise s pecifie d. T hese 
a nal yses will be d o ne b y  co h ort a n d assi g ne d d ose le vel of te p oti ni b. 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 nalys es are c o nsi dere d descri pti ve.
E n d p oi nt
St ati sti c al A n al y si s M et h o d s 
Pri m ar y
O bj e cti v e r e s p o n s e 
d et er mi n e d a c c or di n g t o 
R E CI S T V er si o n 1. 1 b y 
I n v e sti g at or A s s e s s m e nt 
B e st O v er all R e s p o n s e ( B O R) b a s e d o n c o nfir m e d r e s p o n s e s will b e d eri v e d a s 
f oll o w s:

C o m pl et e R e s p o n s e ( C R) d efi n e d a s at l e a st t w o d et er mi n ati o n s of C R at l e a st 
4 w e e k s a p art ( wit h n o P D i n b et w e e n) 

P arti al R e s p o n s e ( P R) d efi n e d a s at l e a st t w o d et er mi n ati o n s of P R or b ett er ( P R 
f oll o w e d b y P R or P R f oll o w e d b y C R) at l e a st 4 w e e k s a p art ( a n d n ot q u alif yi n g 
f or a C R), wit h n o P D i n b et w e e n 

St a bl e Di s e a s e ( S D) d efi n e d a s at l e a st o n e S D a s s e s s m e nt ( or b ett er) 
[ ≥6 w e e k s] aft er st art d at e ( a n d n ot q u alif yi n g f or c o nfir m e d C R or P R.

N o n -C R/ n o n -P D ( a p pli c a bl e o nl y t o p arti ci p a nt s wit h n o n -m e a s ur a bl e di s e a s e at 
B a s eli n e) = at l e a st o n e n o n -C R/ n o n -P D a s s e s s m e nt ( or b ett e r) [≥6 w e e k s] aft er 
st art d at e ( a n d n ot q u alif yi n g f or C R or P R).

P D = P D ≤ 1 2 w e e k s aft er st art d at e ( a n d n ot q u alif yi n g f or C R, P R, n o n- C R/ n o n -
P D or S D).

N ot E v al u a bl e ( N E): all ot h er c a s e s.
S D c a n f oll o w P R o nl y i n t h e r ar e c a s e t h at t u m or i n cr e a s e s b y l e s s t h a n 2 0 % fr o m 
t h e n a dir, b ut e n o u g h t h at a pr e vi o u sl y d o c u m e nt e d 3 0 % d e cr e a s e fr o m B a s eli n e n o 
l o n g er h ol d s. If t hi s o c c ur s t h e s e q u e n c e P R-S D - P R i s c o n si d er e d a c o nfir m e d P R.  A 
s e q u e n c e of P R – S D – S D – P D w o ul d b e a b e st r e s p o n s e of S D if t h e mi ni m u m 
d ur ati o n f or S D d efi niti o n h a s b e e n m et.
O bj e cti v e R e s p o n s e ( O R) i s d efi n e d a s a B O R of c o m pl et e r e s p o n s e ( C R) or p arti al 
r e s p o n s e ( P R) a c c or di n g t o R E CI S T V er si o n 1. 1.
O bj e cti v e r e s p o n s e r at e ( c o nfir m e d C R or P R) a n d t h e c orr e s p o n di n g 2-si d e d e x a ct 
Cl o p p er -P e ar s o n 9 5 % CI will b e pr e s e nt e d. 
S e c o n d ar y
D o R ( m o nt h s) a c c or di n g 
t o R E CI S T V er si o n 1. 1 
a s s e s s e d b y t h e 
I n v e sti g at or s.
F or p arti ci p a nt s wit h o bj e cti v e r e s p o n s e, d ur ati o n of r e s p o n s e i s t h e ti m e fr o m w h e n 
t h e C R/ P R ( w hi c h e v er i s fir st) crit eri a ar e fir st m et u ntil P D or d e at h d u e t o a n y c a u s e 
wit hi n t h e p eri o d of 2 s c h e d ul e d t u m or a s s e s s m e nt s ( 8 4 or 1 6 8 d a y s) aft er t h e l a st 
t u m or a s s e s s m e nt, w hi c h e v er o c c ur s fir st.
D ur ati o n of r e s p o n s e d at a will b e c e n s or e d o n t h e d at e of t h e l a st a d e q u at e t u m or 
a s s e s s m e nt f or p arti ci p a nt s w h o d o n ot h a v e a n e v e nt ( P D or d e at h) or f or 
p arti ci p a nt s wit h a n e v e nt aft er t h e p eri o d of 2 s c h e d ul e d t u m or a s s e s s m e nt s (8 4 or 
1 6 8 d a y s ) of t h e l a st t u m or a s s e s s m e nt. P arti ci p a nt s w h o d o n ot h a v e a t u m or 
a s s e s s m e nt aft er o bj e cti v e r e s p o n s e will b e c e n s or e d at t h e d at e C R/ P R crit eri a ar e 
fir st m et.
D ur ati o n of r e s p o n s e will b e s u m m ari z e d d e s cri pti v el y. K a pl a n- M ei er pl ot s a s w ell a s 
t h e c orre s p o n di n g n u m b er of e v e nt s, 1 st a n d 3 r d q u artil e ( Q 1 a n d Q 3), m e di a n, 
mi ni m u m a n d m a xi m u m fr o m t h e K a pl a n -M ei er pr o d u ct -li mit e sti m at e s of t h e s ur vi v al 
f u n cti o n a n d s ur vi v al r at e s at 3, 6, 9, 1 2, 1 5, a n d 1 8 m o nt h s t o g et h er wit h 
c orr e s p o n di n g 9 5 % CI will b e pr e s e nt e d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 1 / 1 1 5
E n d p oi nt
St ati sti c al A n al y si s M et h o d s 
P F S ( m o nt h s) a c c or di n g 
t o R E CI S T V er si o n 1. 1 
a s s e s s e d b y t h e 
I n v e sti g at or s.
Pr o gr e s si o n fr e e s ur vi v al i s d efi n e d a s t h e ti m e (i n m o nt h s) fr o m fir st a d mi ni str ati o n of 
st u d y i nt er v e nti o n t o t h e d at e of t h e fir st d o c u m e nt ati o n of P D or d e at h d u e t o a n y 
c a u s e wit hi n t h e p eri o d of 2 s c h e d ul e d t u m or a s s e s s m e nt s (8 4 or 1 6 8 d a y s ) aft er t h e 
l a st t u m or a s s e s s m e nt, w hi c h e v er o c c ur s fir st. 
P F S d at a will b e c e n s or e d o n t h e d at e of t h e l a st e v al u a bl e t u m or a s s e s s m e nt f or 
p arti ci p a nt s w h o d o n ot h a v e a n e v e nt ( P D or d e at h) or f or p arti ci p a nt s wit h a n e v e nt 
aft er t h e p eri o d of 2 s c h e d ul e d t u m or a s s e s s m e nt s ( m or e t h a n 8 4 or 1 6 8 d a y s ) aft er 
t h e l a st t u m or a s s e s s m e nt. P arti ci p a nt s w h o d o n ot h a v e a B a s eli n e t u m or 
a s s e s s m e nt or w h o d o n ot h a v e a n y p o st B a s eli n e t u m or a s s e s s m e nt s will b e 
c e n s or e d at t h e d at e of t h e st art of st u d y i nt er v e nti o n.
P F S will b e s u m m ari z e d d e s cri pti v el y. K a pl a n - M ei er pl ot s a s w ell a s t h e 
c orr e s p o n di n g n u m b er of e v e nt s, fir st a n d t hir d q u artil e ( Q 1 a n d Q 3), m e di a n, 
mi ni m u m a n d m a xi m u m fr o m t h e K a pl a n-M ei er pr o d u ct -li mit e sti m at e s of t h e s ur vi v al 
f u n cti o n a n d s ur vi v al r at e s at 3, 6, 9, 1 2, 1 5, a n d 1 8 m o nt h s t o g et h er wit h 
c orr e s p o n di n g 9 5 % CI will b e pr e s e nt e d.
O S ( m o nt h s) a s s e s s e d 
b y t h e I n v e sti g at or s
O v er all s ur vi v al i s d efi n e d a s t h e ti m e (i n m o nt h s) fr o m fir st a d mi ni str ati o n of st u d y 
i nt er v e nti o n t o t h e d at e of d e at h. F or p arti ci p a nt s n ot k n o w n t o b e d e c e a s e d at ti m e of 
a n al y si s, O S ti m e will b e c e n s or e d at t h e l a st d at e t h e p arti ci p a nt w a s k n o w n t o b e 
ali v e. If t hi s d at e i s aft er t h e d at a c ut off, p arti ci p a nt s will b e c e n s or e d at t h e d at e of 
d at a c ut off.
O v er all s ur vi v al will b e s u m m ari z e d d e s cri pti v el y. K a pl a n - M ei er pl ot s a s w ell a s t h e 
c orr e s p o n di n g n u m b er of e v e nt s, fir st a n d t hir d q u artil e ( Q 1 a n d Q 3), m e di a n, 
mi ni m u m a n d m a xi m u m fr o m t h e K a pl a n -M ei er pr o d u ct -li mit e sti m at e s of t h e s ur vi v al 
f u n cti o n a n d s ur vi v al r at e s at 3, 6, 9, 1 2, 1 5, a n d 1 8 m o nt h s t o g et h er wit h 
c orr e s p o n di n g 9 5 % CI will b e pr e s e nt e d.
9. 4. 2
S afet y A n al yses
All safety a nal yses will be perf or me d o n t he Safet y A nal ys is p o p ulati o n u nless ot her wise s pecifie d. 
All a nal yses will be prese nte d b y  c o h ort a n d d ose le vel, if a p plica ble. T he safet y a nalys es will als o 
be d o ne p urel y descri pti vel y . F urt her details will be pr o vi de d i n t he I A P.
E n d p oi nt
St ati sti c al A n al y si s M et h o d s 
Pri m ar y
O c c urr e n c e of D L T s
T h e n u m b er a n d p er c e nt a g e of p arti ci p a nt s i n t h e D L T a n al y si s s et d uri n g t h e D L T 
o b s er v ati o n p eri o d will b e t a b ul at e d.
S e c o n d ar y
O c c urr e n c e of A d v er s e 
E v e nt s ( A E s) a n d 
tr e at m e nt-r el at e d A E s 
A d v er s e e v e nt s will b e c o d e d a c c or di n g t o t h e l at e st a v ail a bl e v er si o n of t h e M e di c al 
Di cti o n ar y f or R e g ul at or y A cti viti e s v er si o n 2 1. 0 or hi g h er. S e v erit y of A E s will b e 
gr a d e d u si n g t h e N CI - C T C A E ( v 5. 0) t o xi cit y gr a d e s. A d v er s e e v e nt s r el at e d t o st u d y 
i nt er v e nti o n will b e d efi n e d a s a n y A E c o n si d er e d a s r el at e d t o t e p oti ni b a n d/ or 
c et u xi m a b. Mi s si n g cl a s sifi c ati o n s c o n c er ni n g st u d y i nt er v e nti o n r el ati o n s hi p s will b e 
c o n si d er e d r el at e d t o t h e st u d y i nt er v e nti o n.
A n y T E A E s will b e s u m m ari z e d, i. e., t h o s e e v e nt s t h at ar e e m er g e nt d uri n g tr e at m e nt 
h a vi n g b e e n a b s e nt pri or t o tr e at m e nt or w or s e n e d r el ati v e t o t h e pr etr e at m e nt st at e 
a n d wit h o n s et d at e s o c c urri n g wit hi n t h e fir st d o si n g d a y of st u d y i nt er v e nti o n u ntil 
3 0 d a y s aft er t h e l a st d o s e of st u d y i nt er v e nti o n.
F oll o wi n g s u bt y p e s of T E A E s will b e pr e s e nt e d i n s u m m ari e s a n d t a bl e s a c c or di n g t o 
S y st e m Or g a n Cl a s s e s a n d Pr ef err e d T er m s:

T E A E s 

S A E s 
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 2 / 1 1 5
E n d p oi nt
St ati sti c al A n al y si s M et h o d s 

T E A E s r el at e d t o t e p oti ni b a n d/ or c et u xi m a b

S A E s r el at e d t o t e p oti ni b a n d/ or c et u xi m a b

N CI -C T C A E Gr a d e 3 or hi g h er T E A E s

N CI -C T C A E Gr a d e 3 o r hi g h er T E A E s r el at e d t o t e p oti ni b a n d/ or c et u xi m a b

T E A E s l e a di n g t o t e p oti ni b a n d/ or c et u xi m a b i nt err u pti o n s

T E A E s l e a di n g t o p er m a n e nt t e p oti ni b a n d/ or c et u xi m a b di s c o nti n u ati o n

T E A E s l e a di n g t o d e at h s

A E s l e a di n g t o wit h dr a w al, d o s e m o difi c ati o n s, or p er m a n e nt st u d y i nt er v e nti o n 
di s c o nti n u ati o n

A E SI s
D e at h s ( pri m ar y c a u s e) d uri n g t h e st u d y will al s o b e pr e s e nt e d i n s u m m ari e s a n d 
t a bl e s. D e at h s wit hi n 3 0 d a y s fr o m l a st d o s e a d mi ni str ati o n a n d d e at h s b e y o n d t hi s 
p eri o d u p t o 9 0 d a y s f oll o w -u p a n d r e a s o n s f or t h e m will al s o b e t a b ul at e d.
A E SI s ar e d efi n e d a s e v e nt s s u g g e sti v e of dr u g- i n d u c e d li v er i nj ur y i n cl u di n g
h e p ati c/li v er f ail ur e a n d h e p atiti s ( n o n -i nf e cti o u s).
L a b or at or y v ari a bl e s
D e s cri pti v e s u m m ari e s o v er ti m e of a ct u al ( a b s ol ut e) l a b or at or y v al u e s a n d c h a n g e s 
fr o m B a s eli n e will b e pr e s e nt e d. Gr a d a bl e l a b or at or y r e s ult s will b e cl a s sifi e d b y 
gr a d e a c c or di n g t o N CI -C T C A E ( v 5. 0); n o n -gr a d a bl e p ar a m et er s will b e cl a s sifi e d a s 
n or m al, hi g h or l o w. S hift t a bl e s will b e pr e s e nt e d w h er e a p pli c a bl e.
P h y si c al e x a mi n ati o n,
Cli ni c all y si g nifi c a nt, a b n or m al fi n di n g s fr o m t h e p h y si c al e x a mi n ati o n ar e t o b e 
r e p ort e d a s A E s. S e p ar at e s u m m ari e s of t h e p h y si c al e x a mi n ati o n d uri n g a n d aft er 
tr e at m e nt will n ot b e pr o vi d e d.
Vit al si g n s, b o d y w ei g ht, 
E C O G
I n cr e a s e/ d e cr e a s e i n vit al sig n s ( b o d y t e m p er at ur e, h e art r at e, bl o o d pr e s s ur e a n d 
r e s pir at or y r at e), E C O G p erf or m a n c e st at u s a n d b o d y w ei g ht will b e c at e g ori z e d a n d 
s u m m ari z e d d e s cri pti v el y i n s hift t a bl e s fr o m B a s eli n e t o mi ni m u m a n d m a xi m u m o n -
tr e at m e nt v al u e s.
E C G
Cli ni c all y si g n ifi c a nt, a b n or m al fi n di n g s fr o m 1 2-l e a d E C G d uri n g t h e tr e at m e nt p h a s e 
will b e pr e s e nt e d d e s cri pti v el y. C h a n g e fr o m B a s eli n e t o w or st o n -tr e at m e nt v al u e will 
b e s u m m ari z e d d e s cri pti v el y f or t h e Q T c F i nt er v al i n a c c or d a n c e t o I C H E 1 4 crit eri a.
9. 4. 2. 1
S afet y R u n -In Peri o d, D L Ts, St o p pi n g R ules, D ose Re d ucti o n 
a n d Esc al ati o n
I n t he safety r u n -i n peri o d, a B OI N (B a yesia n O pti mal I Nter val) desi g n (Y ua n 2 0 1 6 ) will s u p p ort 
d ose decisi o ns starti n g wit h a te p oti ni b d ose of 5 0 0 m g wit h t he o pti o n t o decrease t o 2 5 0 m g, wit h 
a tar get D L T rate of 3 0 % a n d a ma xi m u m n u m ber of 1 2 partici pa nts (see A p pe n di x 8 f or a d diti o nal 
i nf or mati o n).
A cti o n
N u m b er of D L T e v al u a bl e p arti ci p a nt s 
tr e at e d at t h e c urr e nt d o s e
1 
2 
3 
4 
5 
6
* D e e s c al at e fr o m 5 0 0 m g t o 2 5 0 m g i n c a s e t h e n u m b er of D L T s i s 
≥
1 
1 
2 
2 
2 
3
All o w s t o e s c al at e b a c k fr o m 2 5 0 m g t o 5 0 0 m g i n c a s e t h e n u m b er 
of D L T s i s ≤
0 
0 
0 
0 
1 
1
* T h e s c h e m e will al s o b e u s e d f or 2 5 0 m g a s st o p pi n g r ul e.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 3 / 1 1 5
At least 6 treate d partici pa nts o n a d ose le vel are re gar de d as necessar y  to select a d ose f or t he 
R P 2 D part of t he st u d y. C o h orts of 3 partici pa nts will be e nr olle d. S M C meeti n gs will ta ke place 
at a ti me of 3 treate d partici pa nts wit hi n a c o h ort; o n re q u est a d diti o nal S M C meeti n gs mi g ht ta ke 
place. Partici pa nts w h o are n ot D L T e val ua ble will be re place d .
9. 4. 3
Ot her A n al yses
, 
 a n d 
 a nal ys es will be s pecifie d i n t he I nte grate d 
A nal y sis Pla n fi nalize d bef ore data base l oc k. I nte grate d a nal ys es acr oss st u dies, s uc h as t he 
p o p ulati o n P K a nal y sis will be prese nte d se paratel y fr o m t he mai n C S R.
Ge ner al C o nsi der ati o ns
T he f oll o wi n g statistics will be use d t o s u m marize t he st u d y data (f or e xa m ple, Baseli ne 
C haracteristics) u nless o t 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
D oc u me nt N o. 
O bject N o. 
C C
I
C CI
C CI
C CI
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 4 / 1 1 5
9. 4. 4
Se q ue nce of A n al yses
Pri mar y  a nal ysis is pla n ne d ar o u n d 5 m o nt hs after last patie nt first visit. A f utilit y a nalys is f or t he 
2 L is pla n ne d (see Secti o n  9. 2 ). U n pla n ne d a nal yses m a y  be perf or me d i n t his si n gle ar m st u d y. 
T he fi nal a nal y sis will be perf or me d after e n d of st u d y. 
A 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 Cli nical Researc h Or ga nizati o n , 
t he C o or di na ti n g I n vesti gat or, a n d ot her o pti o nal me m bers wit h e x pertise i n t he ma na ge me nt of 
ca ncer partici pa nts, 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 st u d y. T he S M C 
will deci de b y  co nse ns us a n d pr o vi de t heir rec o m me n dati o n 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 te p oti ni b a n d will re vie w 
all a vaila ble safety 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.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 5 / 1 1 5
1 0
Refere nces 
Ar n ol d D, L ueza B, D o uillar d J Y, et al. Pr o g n ostic a n d pre dicti ve val ue of pri mar y  t u m o ur si de i n 
patie nts wit h R A S wil d -t ype metastatic c ol orectal ca ncer treate d wit h c he m ot hera p y a n d E G F R 
directe d a nti b o dies i n si x ra n d o mize d trials. A n n O nc ol. 2 0 1 7; 2 8: 1 7 1 3- 2 9.
A wa d M M, O x nar d G R, Jac k ma n D M, et al. M E T ex o n 1 4 m utati o ns i n n o n-s mall -cell l u n g ca ncer 
are ass ociate d w it h ad va nce d age a n d sta ge- de pe n de nt M E T
g e n o mic am plificati o n a n d c-Met 
o vere x pressi o n. J Cli n O nc ol. 2 0 1 6; 3 4: 7 2 1 -3 0.
Bar delli A, C ors o S, Bert otti A, et al. A m plificati o n of t he M E T rece pt or dri ves resista nce t o a nti-
E G F R t hera pies i n c ol orectal ca ncer. Ca ncer Disc o v. 2 0 1 3; 3: 6 5 8 - 7 3.
Bla dt F, Fa de n B, Friese- Ha mi m M, et al. E M D 1 2 1 4 0 6 3 a n d E M D 1 2 0 4 8 3 1 c o nstit ute a ne w 
class of p ote nt a n d hi g hl y selecti ve c-Met i n hi bit ors. Cli n Ca ncer Res. 2 0 1 3; 1 9: 2 9 4 1 - 5 1.
B o ke me y er C, K ö h ne C H, Ciar diell o F, et al. F O L F O X 4 pl us cet u xi ma b treat me nt a n d R A S
m utati o ns i n c ol orectal ca ncer. E ur J Ca ncer. 2 0 1 5; 5 1: 1 2 4 3 - 5 2.
Calles A, K wiat k o ws ki N, Ca m marata B K, et al. Ti va nti ni b ( A R Q 1 9 7) efficac y is i n de pe n de nt of 
M E T i n hi biti o n i n n o n -s mall-cell l u n g ca ncer cell li nes. M ol O nc ol. 2 0 1 5; 9: 2 6 0- 9.
C he n g Y, Z h o u J, L u S, et al. P hase II st u d y of te p oti ni b + gefiti ni b ( T E P + G E F) i n M E T p ositi ve 
( M E T +)/e pi der mal gr o wt h fact or rece pt or( E G F R)-m uta nt ( M T) n o n- s mall cell l u n g ca ncer. A n n 
O nc ol. 2 0 1 8; 2 9( S u p pl _ 8): viii 4 9 3 -5 4 7.
C o m o gli o P M, Tr us oli n o L, B occacci o C. K n o w n a n d n o vel r oles of t he M E T o nc o ge ne i n ca ncer: 
a c o here nt a p pr oac h t o tar gete d t hera p y . Nat Re v Ca ncer. 2 0 1 8; 1 8: 3 4 1- 5 8.
Decae ns T, Bar o ne C, Asse nat E, et al. Efficac y  an d safety o f t he Met i n hi bit or te p oti ni b i n patie nts 
( pts) wit h a d va nce d Met+ he pat ocell ular carci n o ma ( H C C) pre vi o usl y  treate d wit h s orafe ni b. A n n 
O nc ol. 2 0 1 8; 2 9( S u p pl _ 9):i x 4 8.
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m ors: 
re vise d R E 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.
E n g C, Bess u d o A, Hart L L, et al. A ra n d o mize d, place b o -c o ntr olle d, p hase 1/ 2 st u d y of ti va nti ni b 
( A R Q 1 9 7) i n c o m bi nati o n wit h iri n oteca n a n d cet u xi ma b i n patie nts wit h metastatic c ol orectal 
ca ncer wit h wil d -t ype K R A S
w h o ha ve recei ve d first-li ne s yste mic t hera py. I nt J Ca ncer. 
2 0 1 6; 1 3 9: 1 7 7 - 8 6.
Fe n g F Y, L o pez C A, N or m oll e D P, et al. Effect of e pi der mal gr o wt h fact or rece pt or i n hi bit or class 
i n t he treat me nt of hea d a n d nec k ca ncer wit h c o nc urre nt ra di oc he m ot hera p y i n viv o. Cli n Ca ncer 
Res 2 0 0 7; 1 3: 2 5 1 2 - 8.
Gia nt o ni o BJ, Catala n o PJ, Mer o p ol NJ , et al. Be vaciz u ma b i n c o m bi nati o n wit h o xali plati n, 
fl u or o uracil, a n d le uc o v ori n ( F O L F O X 4) f or pre vi o usl y  treate d metastatic c ol orectal ca ncer: 
res ults fr o m t he Easter n C o o perati ve O nc ol o g y Gr o u p St u d y E 3 2 0 0. J Cli n O nc ol. 2 0 0 7; 2 5: 1 5 3 9-
4 4.
Kara petis C S, K ha m bata- F or d S, J o n ker DJ, et al. K- r as m utati o ns a n d be nefit fr o m cet u xi ma b i n 
a d va nce d c ol orectal ca ncer. N E n gl J Me d. 2 0 0 8; 3 5 9: 1 7 5 7 - 6 5.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 6 / 1 1 5
Li J, Qi n S, X u R, et al. Re g orafe ni b pl us best s u p p orti ve care vers us place b o pl us best s u p p orti ve 
care i n Asia n patie nts wit h pre vi o usl y  treate d metastatic c ol orectal ca ncer ( C O N C U R): a 
ra n d o mise d, d o u ble-bli n d, place b o -c o ntr olle d, p hase 3 trial. La ncet O nc ol. 2 0 1 5; 1 6: 6 1 9 - 2 9.
Li u R, C he n Z Y, G u o W. O nc o ge nic alterati o ns detecte d b y  dr o plet di gital P C R i n patie nts wit h 
metastatic c ol orectal ca ncer resista nt t o cet u xi ma b. J Cli n O nc ol. 2 0 1 9; 3 7( 4) S u p pl ( Fe br uar y 01, 
2 0 1 9): 5 7 5 .
Ma y er RJ, Va n C utse m E, Falc o ne A, et al. Ra n d o mize d trial of T A S - 1 0 2 f or refract or y metastatic 
c ol orectal ca ncer. N E n gl J Me d. 2 0 1 5; 3 7 2: 1 9 0 9 -1 9.
M o ha n S, Heitzer E, Ulz P, et al. C ha n ges i n c ol orectal carci n o ma ge n o mes u n der a nti-E G F R 
t hera p y i de ntifie d b y w h ole-ge n o me plas ma D N A se q ue nci n g. P L o S Ge net. 2 0 1 4; 1 0:e 1 0 0 4 2 7 1.
M o nta g ut 
C, Ar gilés G, Ciar diell o F, et al. Efficac y  of s ym 0 0 4
i n patie nts wit h metastatic 
c ol orectal ca ncer wit h ac q uire d resista nce t o a nti-E G F R t hera py a n d m olec ularl y selecte d b y 
circ ulati n g t u m or D N A 
a nal ys es: a p hase 2 ra n d o mize d cli nical trial. J A M A O nc ol. 
2 0 1 8; 4:e 1 7 5 2 4 5.
M o os ma n n N, Hei ne ma n n V. Cet u xi ma b i n t he treat me nt of metastatic c ol orectal ca ncer. E x pert 
O pi n Bi ol T her. 2 0 0 7; 7: 2 4 3 - 5 6.
M orelli M P, O ver ma n MJ, Sa nc hez E V, et al. Fre q ue nc y  of c o nc urre nt ge ne m utati o ns a n d c o p y 
n u m ber alterati o ns i n circ ulati n g cell-free D N A (cf D N A) fr o m refract or y metastatic C R C patie nts . 
J Cli n O nc ol. 2 0 1 4; 3 2( 1 5) S u p pl ( Ma y  2 0, 2 0 1 4): 1 1 1 1 7.
Na ka m ura Y, Ya mas hita R, O ka m ot o W, 
et al. Ge n o mic alterati o ns after E G F R bl oc ka de i n 
patie nts wit h R A S
wil d -t ype metastatic c ol orectal ca ncer: C o m bi ne d tiss ue a n d bl o o d -base d 
a nal ys is fr o m S C R U M -Ja pa n GI -S C R E E N a n d G O ZI L A. J Cli n O nc ol . 2 0 1 9; 3 7( 1 5) S u p pl ( Ma y 
2 0, 2 0 1 9): 3 5 2 8.
Pai k P K, Veill o n R, C ort ot A B, et al. P hase II st u d y of te p oti ni b i n N S C L C patie nts wit h M E T e x 1 4 
m utati o ns. J Cli n O nc ol. 2 0 1 9; 3 7( 1 5) S u p pl ( Ma y  2 0, 2 0 1 9): 9 0 0 5.
Parse g hia n C M, L o ree J M, M orris V K, et al. A nti- E G F R -resista nt cl o nes deca y  ex p o ne ntiall y  after 
pr o gressi o n: i m plicati o ns f or a nti -E G F R re -c halle n ge. A n n O nc ol. 2 0 1 9; 3 0: 2 4 3 - 9.
Patel D, G u o X, N g S, et al. I g G is ot ype, gl yc o s ylati o n, a n d E G F R e x pressi o n det er mi ne t he 
i n d ucti o n of a nti b o d y- de pe n de nt cell ular c yt ot o xicit y i n vitr o b y  cet u xi ma b. H u m A nti b o dies. 
2 0 1 0; 1 9: 8 9 - 9 9.
Perez - T orres M, G ui x M, G o nzalez A, et al. E pi der mal gr o wt h fact or rece pt or ( E G F R) a nti b o d y 
d o w n -re g ulates m uta nt rece pt ors a n d i n hi bits t u m ors e x pressi n g E G F R m utati o ns. J Bi ol C he m .
2 0 0 6; 2 8 1: 4 0 1 8 3 - 9 2.
Pietra nt o ni o F, Bere nat o R, Perr o ne F, et al. C o m pre he nsi ve m olec ular c haracterizati o n of 
ac q uire d resista nce t o a nti-E G F R m o n ocl o nal a nti b o dies ( M o A bs) i n patie nts wit h metastatic 
c ol orectal ca ncer ( m C R C). M ol Ca ncer T her. 2 0 1 5; 1 4( 1 2 S u p pl 2): A bstract nr B 5 7.
Pietra nt o ni o F, Ver nieri C, Sira ve g na G, et al. Heter o ge neit y of ac q uire d resista nce t o anti -E G F R 
m o n ocl o nal anti b o dies i n p atie nts wit h 
m etastatic col orectal ca ncer. Cli n 
Ca ncer 
Res. 
2 0 1 7; 2 3: 2 4 1 4 - 2 2.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 7 / 1 1 5
Ra g ha v K, M orris V, Ta n g C, et al. M E T a m plificati o n i n metastatic c ol orectal ca ncer: a n ac q uire d 
res p o nse t o E G F R i n hi biti o n, n ot a de n ov o p he n o me n o n. O nc otar get. 2 0 1 6; 7: 5 4 6 2 7 - 3 1.
Ri massa L,  Bozzarelli S, Pietra nt o ni o F, et al. P hase II st u d y of ti va nti ni b a n d cet u xi ma b i n p atie nts 
w it h K R A S w il d-t ype m etastatic col orectal ca ncer w it h ac q uire d resista nce t o E G F R in hi bit ors a n d 
emer ge nce of M E T 
o vere x pressi o n: less o n lear ne d f or fut ure trials w it h E G F R/ M E T d ual 
i n hi biti o n. Cli n C ol orectal Ca ncer. 2 0 1 9; 1 8: 1 2 5 -3 2.
R y o o B Y, Re n Z, Ki m T Y, P hase II trial of te p oti ni b vs s orafe ni b i n Asia n patie nts ( pts) wit h 
a d va nce d he pat ocell ular carci n o ma ( H C C). A n n O nc ol. 2 0 1 8; 2 9( S u p pl _ 8): viii 2 0 7.
Sira ve g na G, M uss oli n B, B uscari n o M, et al. Cl o nal e v ol uti o n a n d resista nce t o E G F R bl oc ka de 
i n t he bl o o d of c ol orectal ca ncer patie nts. Nat Me d. 2 0 1 5; 2 1:7 9 5- 8 0 1.
Tej par S, Sti ntzi n g S, Ciar diell o F, et al. Pr o g n ostic a n d p re dicti ve rele va nce of p ri mar y tu m or 
locati o n i n patie nts w it h R A S w il d-ty pe m etastatic col orectal ca ncer: retr os pecti ve anal ys es of t he 
C R Y S T A L  a n d FI R E- 3 trials. J A M A O nc ol. 2 0 1 7; 3: 1 9 4- 2 0 1.
Va n C utse m E, E n g C, N o wara E, et al. Ra n d o mize d p hase I b/II trial of ril ot u m u ma b or ga nit u ma b 
wit h pa nit u m u ma b vers us pa nit u m u ma b al o ne i n patie nts wit h wil d -t ype K R A S
metastatic 
c ol orectal ca ncer. Cli n Ca ncer Res. 2 0 1 4; 2 0: 4 2 4 0- 5 0.
Va n C utse m E, Le nz HJ, K ö h ne C H, et al. Fl u or o uracil, le uc o v ori n, a n d iri n oteca n pl us cet u xi ma b 
treat me nt a n d R A S m utati o ns i n c ol orectal ca ncer. J Cli n O nc ol. 2 0 1 5; 3 3: 6 9 2 - 7 0 0.
Vi nce nzi B, Sc hia v o n G, Silletta M, et al. T he bi ol o gical pr o perties of cet u xi ma b. Crit Re v O nc ol 
He mat ol. 2 0 0 8; 6 8: 9 3- 1 0 6.
Ya n g J C H, Z h o u J, Ki m D W, et al. Te p oti ni b + gefiti ni b vs c he m ot hera p y in M E T -a m plifie d 
E G F R -m uta nt n o n- s mall cell lu n g ca ncer ( N S C L C): p re defi ne d s u b gr o u p a nal ysis of a P hase I b/II 
st u d y. Ca ncer Res 2 0 1 9; 7 9( 1 3 S u p pl): A bstract nr C T 1 9 3 .
Y os hi n o T, Ar n ol d D, Ta ni g uc hi H, et al. Pa n- Asia n a da pte d E S M O c o nse ns us g ui deli nes f or t he 
ma na ge me nt of patie nts wit h metastatic c olorectal ca ncer: a J S M O-E S M O i nitiati ve e n d orse d b y  
C S C O, K A C O, M O S, S S O a n d T O S. A n n O nc ol. 2 0 1 8; 2 9: 4 4 -7 0.
Y ua n Y, Hess K R, Hilse n bec k S G, et al. B a y esia n o pti mal inter val d esi g n: a si m ple a n d w ell-
p erf or mi n g d esi g n f or p hase I o nc ol o g y  trials. Cli n Ca ncer Res. 2 0 1 6; 2 2: 4 2 9 1 - 3 0 1.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 8 / 1 1 5
1 1
A p pe n dices
A p pe n di x 1
A b bre vi ati o ns
2 L
Sec o n d li ne
3 L +
T hir d li ne +
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 nts of S pecial I nterest 
A L T
Ala ni ne tra nsa mi nase
A S T
As partate tra nsa mi nase
A U C
Area u n der t he c ur ve
B OI N
Ba yesia n o pti mal i nter val
B O R
Best o verall res p o nse
B U N
Bl o o d urea nitr o ge n
CI O M S
C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical Scie nces
C N S
Ce ntral ner v o us s ys te m
C R
C o m plete res p o nse
C R C
C ol orectal ca ncer
C R S
C y t o ki ne release sy n dr o me
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
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
ct D N A
Circ ulati n g t u m or D N A
D L T
D ose li miti n g t o xicit y
D o R
D urati o n of res p o nse
e C R F
Electr o nic Case Re p ort F or m
E C G
Electr ocar di o gra 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
F A S
F ull a nal ys is set
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


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
7 9 / 1 1 5
H G F
He pat oc y te gr o wt h fact or
I A P
I nte grate d A nalys is Pla n
I B
I n vesti gat or’s Br oc h ure
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 nizati o n
I E C
I n de pe n de nt Et hics C o m mittee
I g E
I m m u n o gl o b uli n E
I L D
I nterstitial l u n g disease
I M P
I n vesti gati o nal Me dici nal Pr o d uct
I RB 
I nstit uti o nal Re vie w B oar d
I R R
I nf usi o n-relate d reacti o n
I WR S
I nteracti ve We b
Res p o nse S y ste m
I T T
I nte nti o n-t o-Treat
m C R C
Metastatic c ol orectal ca ncer
M E T
Mese nc h y m al e pit helial tra nsiti o n
M RI
Ma g netic res o na nce i ma gi n g
N CI
Nati o nal Ca ncer I nstit ute
N E
N ot e val ua ble
N S C L C
N o n -s mall cell l u n g ca ncer
O R
O bjecti ve res p o nse
O R R
O bjecti ve res p o nse rate
O S
O verall s ur vi val
P d
P har mac o d y na mics
P D
Pr o gressi ve disease
P F S
Pr o gressi o n -free s ur vi val
P K
P har mac o ki netics
P P D
Pr otecte d pers o nal data
P R
Partial res p o nse
Q D
O nce dail y
Q Tc F
Q T i nter val c orrecte d usi n g Fri dericia’s f or m ula
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 0 / 1 1 5
R P 2 D
Rec o m me n de d P hase II d ose
S A E
Seri o us A d verse E ve nt
S D
Sta ble Disease
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
S o A
Sc he d ule of A cti vities
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o ns
T E A E
Treat me nt e mer ge nt a d verse e ve nts
T KI
T y r osi ne ki nase i n hi bit or
U L N
U p per li mit of n or mal
U S PI
U nite d States prescri bi n g i nf or mati o n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 1 / 1 1 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 e n o u g h, 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 oriti es. 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 nvesti 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 to t he 
partici pa nt or his/ her le gall y aut h orize d re prese ntati ve ( w here all o we d b y  local la ws a n d 
re g ulati o ns) a n d a ns wer all q uesti o ns o n t he st u d y.

Partici pa nts will be i nf or me d t hat t heir partici pati o n is v ol u ntar y .

Partici pa nts or t heir le gall y -a ut h orize d re prese ntati ve ( w here all o we d by l ocal la ws a n d 
re g ulati o ns) will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets t he 
re q uire me nts of 2 1 C F R 5 0; l ocal re g ulati o ns; I CH g ui deli nes; Healt h I ns ura nce 
P orta bilit y  an 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 RB/I E C or st u d y  ce nter.

T he me dical rec or d will i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici pa nt was e nr olle d i n t he st u d y an d t he date t he writte n c o nse nt was 
o btai ne d. T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt will als o si g n t he I C F.

If t he I CF is u p date d d uri n g t heir partici pati o n i n t he st u d y, partici pa nts will 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.

Partici pa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F.
D at a Pr otecti o n

T he S p o ns or will assig 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. A n y partici pa nt rec or ds or datasets t hat are tra nsferre d t o t he S p o ns or will 
c o ntai n t he i de ntifier o nl y; partici pa nt 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 will i nf or m partici pa nts t hat t heir pers o nal st u d y -relate d data will be use d 
per l ocal data pr otecti o n a n d pri vac y  la ws. T he le vel of discl os ure will als o be e x plai ne d 
t o t he partici pa nt a n d pre g na nt part ners (if a p plica ble), w h o will be req uire d t o gi ve 
c o nse nt f or t heir data t o be use d, as s pecifie d i n t he i nf or me d c o nse nt.

T he partici pa nt will be i nf or me d t hat his/ her me dical rec or ds m a y  be e xa mi ne d b y  
Cli nical Q ualit y  Ass ura nce a u dit ors or ot her S p o ns or -a p p oi nte d, a ut h orize d pers o n nel, 
b y a p pr o priate I R B/I E C me m bers, a n d b y  re g ulat or y aut h orit y  ins 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


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 2 / 1 1 5
St u d y A d mi nistr ati ve
S t u d y sites i n E ur o pe , N ort her n Asia a n d N ort h A merica are pla n ne d t o partici pate i n t his st ud y .
A d diti o nal re gi o ns/c o u ntries mi g ht be a d de d acc or di n g t o recr uit me nt nee ds. 
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 CH G o o d Cli nical Practice (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 dy 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 nical Tr ials. g o v: n u m ber is n ot a vaila ble at t he ti me of pr ot oc ol fi nalizati o n

E u dra C T: 2 0 2 0 - 0 0 1 7 7 6- 1 5
A pr oce d ure f or i n de pe n de nt re vie w of ra di ol o gical i ma ges mi g ht
be esta blis he d at a later 
ti me p oi nt.
T he Cli nical Researc h Or ga nizati o n, C o va nce, will be res p o nsi ble f or t he acti vities dele gate d o n 
t he Tra nsfer of Res p o nsi bilities & O bli gati o ns ( T O R O) a n d o utli ne d i n se parate o perati o nal 
ma n uals (i,e., Pr oject Ma na ge me nt Pla n , La b orat or y Ma n ual, M o nit ori n g Pla n , etc.). 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 Pr oject Ma na ge me nt Pla n.
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 udi 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 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 will s u b mit t he pr ot oc ol, pr ot oc ol a me nd me nts (if a p plica ble), I CF, 
I n vesti gat or Br oc h ure, a n d ot her rele va nt d oc u me nts (e. g., a d vertise me nts) t o a n 
I RB/I E C a n d t he I R B/I E C will 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 (i.e., c ha n ges t o t he pr ot oc ol) will be d oc u me nte d i n writi n g 
a n d re q uire I R B/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 ntl y 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 RB/I E C of S A Es or ot her sig nifica nt safety fi n di n gs, as re q uire d b y  
I RB/I E C pr oce d ures
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 3 / 1 1 5

Pr o vi di n g o versi g ht of t he st u d y c o 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 ulati o ns

T he pr ot oc ol a n d a n y ap 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 dical S u p p ort car ds t o partici pa nts 
f or use d uri n g t he st u d y. T hese pr o vi de t he mea ns f or partici pa nts t o i de ntif y t he msel ves 
as partici pati n g i n a cli nical st u d y. Als o, t hese gi ve healt h care pr o vi ders access t o a n y 
i nf ormati 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  i ncl u de t he pr ocess f or e mer ge nc y u n bli n di n g (if a p plica ble).

T he first p oi nt of c o ntact f or all e mer ge ncies will be t he cli nical st u d y I nvesti 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 
c o 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 q uesti o ns. A n y  su bse q ue nt acti o n (e. g., u n bli n di n g) will f oll o w t he 
sta n dar d pr ocess esta blis he d f or I n vesti gat ors.
W he n t he I nvesti 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 ( or desi g nee) p h y sicia n. T his i ncl u des pr o visi o n of a 2 4- h o ur c o ntact n u m ber at a call 
ce nter, w here b y t he healt h care pr o vi ders will be gi ve n access t o t he a p pr o priate S p o ns or ( or 
desi g nee) p h ys icia n t o assist wit h t he me dical e mer ge nc y.
Cli nic al St u d y I ns ur a nce a n d C o m p e 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 will meet g o o d l ocal sta n dar ds, as a p plica ble.
Cli nic al St u d y Re p ort
After st u d y co m pleti o n, t he S p o ns or will write a cli nical st u d y re p ort i n c o ns ultati o n wit h t he 
C o or di nati n g I n vesti gat or.
P u blic ati o n

T he res ults of t his st u d y ma y be p u blis he d or prese nte d at scie ntific meeti n gs. If t his is 
f oresee n, t he I n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or 
bef ore s u b missi o n. T his all o ws Merc k t o pr otect 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 or t 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 t his case, a 
c o or di nati n g I n vesti gat or will be desi g nate d by a gree me nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 4 / 1 1 5

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 M e 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
A n y  pu blicati o ns a n d prese ntati o ns of t he res ults eit her i n w h ole or i n part, b y  In vesti gat ors or 
t heir re prese ntati ves will re q uire re vie w b y  the S p o ns or bef ore s u b missi on. T he S p o ns or will n ot 
s u p press p u blicati o n b ut mai ntai ns t he ri g ht t o dela y  pu blicati o n t o pr otect i ntellect ual pr o pert y 
ri g hts.
P osti n g of data o n Cli nical Trials. g o v a n d E u dra C T will occ ur at a n a p pr o priate date t o meet 
a p plica ble re q uire me nts.
D at a Q u a lit y Ass ur a nce

All partici pa nt st u d y data will be rec or de d o n electr o nic e C R Fs or tra ns mitte d t o t he 
S p o ns or or desi g nee electr o nicall y (e. g., la b orat or y data). T he I n vesti gat or is res p o nsi ble 
f or verif y i n g t hat data e ntries are c o m plete, acc urate, le gi ble, a n d ti mel y by p h y sicall y 
or electr o nicall y si g ni n g t he e C R F. Details f or ma na gi n g e C R Fs are i n t he Pr oject 
Ma na ge me nt Pla n .

T he I nvesti gat or will 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 eC R F .

T he I n vesti gat or wi ll 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.

M o nit ori n g details descri bi n g strate g y (e. g., ris k-base d i nitiati ves i n o perati o ns a n d 
q ualit y  s uc h as Ris k Ma na ge me nt a n d Miti gati o n Strate gies a n d A nalyt ical Ris k-Base d 
M o nit ori n g), 
met h o ds, 
res p o nsi bilities a n d re q uire me nts, i ncl u di n g ha n dli n g of 
n o nc o m plia nce iss ues a n d m o nit ori n g 
tec h ni q ues (ce ntral, re m ote, or o n- site 
m o nit ori n g) a re i n t he M o nit ori n g Pla n.

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  chec 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 ure s ha ve bee n c o m plete d. 
Details will be o utli ne d i n Data Ma na ge me nt d oc u me nts a n d pr oce d ures.

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 
eC R F are acc urate, c o m plete, a n d verifia ble; t hat t he safety a n d ri g hts of partici pa nts are 
bei n g pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d per t he c urre ntl y ap pr o ve d 
pr ot oc ol a n d a n y ot her st u d y agree me nts, I C H G C P, a n d all a p plica ble re g ulat or y 
re q uire me nts.

T he I n vesti gat or will retai n rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Fs, pertai ni n g t o 
t he c o n d uct of t his st u d y for 1 5 years 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 y e d d uri n g t he rete nti o n peri o d wit h o ut t he S p o n s or’s writte n a p pr o val. N o rec or ds 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 5 / 1 1 5
ma 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 grity of t he dat a c ollecte d.

T he I n vesti gat or will 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 will i de ntif y eac h partici pa nt, 
c o ntai n t he f oll o wi n g de m o gra p hic a n d me dical i nf or mati o n f or t he partici pa nt, a n d will 
be as c o m plete as p ossi ble:

Partici pa nt’s f ull na me, date of birt h, se x, hei g ht, a n d wei g ht

Me dical hist or y  a n d c o nc o mita nt diseases

Pri or a n d c o nc o mita nt t hera pies (i ncl u di n g c ha n ges d uri n g t he st u d y )

St u d y  i de ntifier (i.e., t he S p o ns or’s st u d y  n u m ber) a n d partici pa nt’s st u d y n u m ber.

Dates of e ntr y int o t he st u d y (i.e., si g nat ure date o n t he i nf or me d c o nse nt) a n d eac h 
visit t o t he site

A n y  me dical e xa mi nati o ns a n d cli nical fi n di n gs pre defi ne d i n t he pr ot oc ol

All A Es

Date t hat t he partici pa nt left t he st u d y, i ncl u di n g a n y reas o n f or earl y wit h dra wal 
fr o m t he st u d y or st u d y i nter ve nti o n, if a p plica ble.

Data rec or de d o n pri nte d or electr o nic e C R Fs t hat are tra nscri be d fr o m s o urce 
d oc u me nts will be c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies will be 
e x plai ne d. T he I n vesti gat or m a y  nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer 
rec or ds, de pe n di n g o n t he st u d y. Als o, c urre nt me dical rec or ds will be a vaila ble.

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 oss i 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 C H 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 wit h o ut t he 
S p o ns or’s writte n a p pr o val.

Defi niti o n of w hat c o nstit utes s o urce data is f o u n d i n t he M o nit ori n g Pla n.
St u d y a n d Site St art a n d Cl os ure
First Act of Recr uit me nt

T he st u d y  start date is t he date w he n t he cli nical st u d y will be o pe n f or recr uit me nt.

T he first act of recr uit me nt is w he n t he first site is o pe ne d (first site i nitiati o n visit) a n d 
will be t he st u d y  start date.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 6 / 1 1 5
St u d y  Cl os ure a n d Site Ter mi nati o n

T he S p o ns or reser ves t he ri g ht t o cl ose t he st u d y  site or ter mi nate t he st u d y at a n y ti me 
a n d f or a n y reas o n. St u d y  sites will be cl ose d u p o n st u d y co 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 ma 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 e n o u g h 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 re q uire me nts of t he 
I RB/I E C or l ocal healt h a ut h orities, t he S p o ns or's pr oce d ures, or G C P g ui deli nes .

I na de q uate recr uit me nt of partici pa nts b y  t he I n vesti gat or.

Disc o nti n uati o n of f urt her de vel o p me nt of t he S p o ns or’s c o m p o u n d .

If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d, t he S p o ns or will pr o m ptl y  inf or m 
t he I nvesti gat ors, t he I ECs/I R Bs, t he re g ulat or y aut h orities, a n d a n y c o ntract researc h 
or ga nizati o n(s) use d i n t he st u d y of t he reas o n f or ter mi nati o n or s us pe nsi o n, as s pecifie d 
b y  the a p plica ble re g ulat or y re q uire me nts. T he I n vesti gat or will pr o m ptl y  inf o r m t he 
partici pa nts a n d ass ure a p pr o priate partici pa nt t hera p y a n d/ or f oll o w - u p.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 7 / 1 1 5
A p pe n di x 3
C o ntr ace pti o n
Defi niti o ns:
W o m a n of C hil d be ari n g P ote nti al 
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile, as s pecifie d bel o w.
If fertilit y is u nclear (e. g., a me n orr hea i n a d olesce nts or at hletes) a n d a me nstr ual c ycle ca n n ot be 
c o nfir me d bef ore t he first d ose of st u d y  i nter ve nti o n, c o nsi der a d diti o nal e val uati o n.
A w o ma n of c hil d beari n g p ote ntial is n ot :
1.
Pre me narc hal
2.
A pre me n o pa usal fe male wit h 1 of t he f oll o wi n g:
D oc u me nte d h ys terect o m y
D oc u me nte d bilateral sal pi n gect o m y
D oc u me nte d bilateral o o p h orect o m y
D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he fe male’s me dical rec or ds, 
me dical e xa mi nati o n, or me dical hist or y  i nter vie w.
F or a fe male wit h per ma ne nt i nfertilit y due t o a n alter nate me dical ca use ot her t ha n t he 
a b o ve, (e. g., m ulleria n a ge nesis, a n dr o ge n i nse nsiti vit y ), In vesti gat or discreti o n a p plies t o 
deter mi ne st u d y e ntr y.
3
A p os t me n o pa usal fe male
A p ost me n o pa usal state 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 ma y be use d 
t o c o nfir m a p ost me n o pa usal state i n a fe male 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 R T). H o we ver, i n t he a bse nce of 1 2 m o nt hs 
of 
a me n orr hea, m ore t ha n 1 F S H meas ure me nt is re q uire d i n t he p ost me n o pa usal ra n ge.
A fe male o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use o ne of 
t he n o n- estr o ge n h or m o nal hi g hl y  effecti ve c o ntrace pti o n met h o ds if s he wis hes t o 
c o nti n ue her H R T d uri n g t he st u d y. Ot her wise, s he m ust disc o nti n ue H R T t o all o w 
c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y  e nr oll me nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
8 8 / 1 1 5
C o ntr ace pti o n G ui d a nce:
C O N T R A C E P TI V E S A L L O W E D D U RI N G T H E S T U D Y I N C L U D E:
Hi g hl y  Eff e cti v e M et h o d s T h at H a v e L o w U s er D e p e n d e n c y

I m pl a nt a bl e pr o g e st o g e n-o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n

I ntr a ut eri n e d e vi c e (I U D)

I ntr a ut eri n e h or m o n e -r el e a si n g s y st e m (I U S)

Bil at er al t u b al o c cl u si o n

V a s e ct o mi z e d p art n er: a hi g hl y eff e cti v e c o ntr a c e pti v e m et h o d pr o vi d e d t h at t h e p art n er i s t h e s ol e s e x u al 
p art n er of a w o m a n of c hil d b e ari n g p ot e nti al a n d t h e a b s e n c e of s p er m h a s b e e n c o nfir m e d. O t h er wi s e, u s e 
a n a d diti o n al hi g hl y eff e cti v e m et h o d of c o ntr a c e pti o n. T h e s p er m at o g e n e si s c y cl e i s a p pr o xi m at el y 9 0 d a y s.
Hi g hl y Eff e cti v e M et h o d s T h at Ar e U s er D e p e n d e nt

C o m bi n e d ( e str o g e n - a n d pr o g e st o g e n - c o nt ai ni n g) h or m o n al c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of 
o v ul ati o n

Or al

I ntr a v a gi n al

Tr a n s d er m al

I nj e ct a bl e

Pr o g e st o g e n -o nl y h or m o n e c o ntr a c e pti o n a s s o ci at e d wit h i n hi biti o n of o v ul ati o n

Or al

I nj e ct a bl e

S e x u al a b sti n e n c e: a hi g hl y eff e cti v e m et h o d o nl y if d efi n e d a s r efr ai ni n g fr o m i nt er c o ur s e d uri n g t h e e ntir e 
p eri o d of ri s k a s s o ci at e d wit h t h e st u d y i nt er v e nti o n. T h e r eli a bilit y of s e x u al a b sti n e n c e n e e d s t o b e e v al u at e d 
i n r el ati o n t o t h e d ur ati o n of t h e st u d y.
N ot e s:
C o ntr a c e pti v e u s e b y m e n or w o m e n i s c o n si st e nt wit h l o c al r e g ul ati o n s o n t h e u s e of c o ntr a c e pti v e m et h o d s f or 
cli ni c al st u d y p arti ci p a nt s.
Hi g hl y eff e cti v e m et h o d s ar e t h o s e wit h a f ail ur e r at e of < 1 % p er y e ar w h e n u s e d c o n si st e ntl y a n d c orr e ctl y. 
T y pi c al u s e f ail ur e r at e s diff er fr o m t h o s e w h e n u s e d c o n si st e ntl y a n d c orr e ctl y.
If l o c all y r e q uir e d, i n a c c or d a n c e wit h Cli ni c al Tri al F a cilit ati o n Gr o u p ( C T F G) g ui d eli n e s, a c c e pt a bl e c o ntr a c e pti v e 
m et h o d s ar e li mit e d t o t h o s e w hi c h i n hi bit o v ul ati o n a s t h e pri m ar y m o d e of a cti o n.
P eri o di c a b sti n e n c e ( c al e n d ar, s y m pt ot h er m al, p o st -o v ul ati o n m et h o d s), wit h dr a w al ( c oit u s i nt err u pt u s), 
s p er mi ci d e s o nl y, a n d l a ct ati o n al a m e n orr h e a m et h o d ( L A M) ar e n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n f or t hi s 
st u d y. M al e c o n d o m a n d f e m al e c o n d o m c a n n ot b e u s e d t o g et h er ( d u e t o ri s k of f ail ur e wit h fri c ti o n).
D oc u me nt N o. 
O bject N o. 
C CI
C CI


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


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 1 / 1 1 5

L yt ic b o ne lesio ns or mi xe d 
l ytic- blastic lesi o ns, wit h i de ntifia ble 
s oft tiss ue 
c o m p o ne nts, t hat ca n be e val uate d b y cr oss -secti o nal i ma gi n g tec h ni q ues s uc h as C T or 
M RI  ca n be c o nsi dere d as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets t he 
defi niti o n of meas ura bilit y  descri be d a b o ve. 

Blastic b o ne lesi o ns are n o n- meas ura ble.
Cystic lesi o ns:

Lesi o ns t hat meet t he criteria f or ra di o gra p hically defi ne d si m ple c ysts s h o ul d n ot be 
c o nsi dere d as mali g na nt lesi o ns ( neit her meas ura ble n or n o n- meas ura ble) si nce t he y are,
b y  defi niti o n, si m ple c ysts. 

C y stic lesi o ns t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as meas ura ble 
lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y  descri be d a b o ve. H o we ver, if n o n-
c ystic lesi o ns are prese nt i n t he sa me partici pa nt, t hese are preferre d f or selecti o n as 
tar get lesi o ns.
Lesi o ns wit h pri or l oc al tre at me nt:

T u m or lesi o ns sit uate d i n a pre vi o usl y irra diate d area, or i n a n area s u bjecte d t o ot her 
l ocal re gi o nal t hera p y, are us uall y n ot c o nsi dere d meas ura ble u nless t here has bee n 
de m o nstrate d pr o gressi o n i n t he lesi o n. St u d y  pr ot oc ols s h o ul d detail t he c o n diti o ns 
u n der w hic h s uc h lesi o ns w o ul d be c o nsi dere d meas ura ble.
Tar get Lesi o ns 
All meas ura ble lesi o ns u p t o a ma xi m u m of 2 lesi o ns per or ga n a n d 5 lesi o ns i n t otal, s h o ul d be 
i de ntifie d as t ar get lesi o ns a n d rec or de d a n d meas ure d at B aseli ne. Tar get lesi o ns s h o ul d be 
selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter), be re prese ntati ve of all 
i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o re pr o d uci ble re peate d 
meas ure me nts.
L y m p h n o des merit s pecial me nti o n si nce t he y are n or mal a nat o mical str uct ures w hic h m a y  be 
visi ble b y  ima gi n g e ve n if n ot i n v ol ve d b y  tu m or. Pat h ol o gical n o des w hic h are defi ne d as 
meas ura ble a n d m a y  be i de ntifie d as tar get lesi o ns m ust meet t he criteri o n of a s h ort a xis of 
≥1 5 m m b y  C T sca n. O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o t he B aseli ne s u m. T he 
s h ort a xis of t he n o de is t he dia meter n or mally use d b y  ra di ol o gists t o j u d ge if a n o de is i nv ol ve d 
b y  soli d t u m or. N o dal size is n or mall y re p orte d as 2 di me nsi o ns i n t he pla ne i n w hic h t he i ma ge is 
o btai ne d (f or C T sca n t his is al m ost al wa y s t he a xial pla ne; f or M RI t he pla ne of ac q uisiti o n ma y 
be a xial, sa gittal, or c or o nal). T he s maller of t hese meas ures is t he s h ort a xis. F or e xa m ple, a n 
a b d o mi nal n o de w hic h is re p orte d as bei n g 2 0 m m x 3 0 m m has a s h ort a xis of 2 0 m m a n d q ualifies 
as a mali g na nt, meas ura ble n o de. I n t his e xa m ple, 2 0 m m s h o ul d be rec or de d as t he n o de 
meas ure me nt. All ot her pat h ol o gical n o des (t h ose wit h s h ort a xis ≥ 1 0 m m b ut < 1 5 m m) s h o ul d 
be c o nsi dere d n o n- tar get lesi o ns. N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n-
pat h ol o gical a n d s h o ul d n ot be rec or de d or f oll o we d.
A s u m of t he dia meters (l o n gest f or n o n- n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get 
lesi o ns will be calc ulate d a n d re p orte d as t he B aseli ne s u m dia meters. If l ym p h n o des are t o be 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 2 / 1 1 5
i ncl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o t he s u m. T he B aseli ne 
s u m dia me ters will be use d as refere nce t o f urt her c haracterize a n y objecti ve t u m or re gressi o n i n 
t he meas ura ble di me nsi o n of t he disease.
N o n -tar get Lesi o ns 
All ot her lesi o ns ( or sites of disease) i ncl u di n g pat h ol o gical l ym p h n o des s h o ul d be i de ntifie d as 
n o n- tar get lesi o ns a n d s h o ul d als o be rec or de d at B aseli ne. Meas ure me nts are n ot re q uire d, a n d 
t hese lesi o ns s h o ul d be f oll o we d as ‘ prese nt’, ‘a bse nt’, or i n rare cases ‘ u ne q ui v ocal pr o gressi o n’ 
( m ore details t o f oll o w). I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n -tar get lesi o ns i n v ol vi n g 
t he sa me or ga n as a si n gle ite m o n t he case rec or d f or m (e.g., ‘ m ulti ple e nlar ge d pel vic l ym p h 
n o des’ or ‘ m ulti ple l i ver metastases’).
G UI D E LI N E S F O R E V A L U A TI O N O F M E A S U R A B L E DI S E A S E 
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n, usi n g cali pers if cli nicall y  assesse d. All 
B aseli ne e val uati o ns s h o ul d be perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d ne ver m ore 
t ha n 4 wee ks bef ore t he be gi n ni n g of t he treat me nt. 
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at B aseli ne a n d d uri n g f oll o w-u p. I ma gi n g base d e val uati o n s h o ul d 
al wa ys be d o ne rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d ca n n ot be 
i ma ge d b ut are assessa ble b y cli nical e xa mi nati o n. 
N o p h ot o gra p hs, n o s ki n lesi o n meas ure me nt b y  ca li pers a n d n o meas ure me nts o n c hest X -ra y will 
be d o ne i n t his st u d y .
C o m p ute d t o m o gr a p h y, M RI:
C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o 
meas ure lesi o ns selecte d f or res p o nse assess me nt. T his g ui deli ne has defi ne d meas ura bilit y  of 
lesio ns o n C T sca n base d o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less. As is descri be d 
i n A p pe n di x II of t he ori gi nal s o urce article cite d a b o ve, w he n C T sca ns ha ve slice t hic k ness 
greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. 
M RI  is als o acce pta ble i n certai n sit uati o ns (e. g., f or b o d y sca ns).  
Ultr as o u n d: Ultras o u n d is n ot usef ul i n assess me nt of lesi o n size a n d s h o ul d n ot be use d as a 
met h o d of meas ure me nt. Ultras o u n d e xa mi nati o ns ca n n ot be re pr o d uce d i n t heir e ntiret y f or 
i n de pe n de nt re vie w at a later date a n d, beca use t he y are o perat or de pe n de nt, it ca n n ot be 
g uara ntee d t hat t he sa me tec h ni q ue a n d meas ure me nts will be ta ke n fr o m 1 assess me nt t o t he ne xt. 
If ne w lesi o ns are i de ntifie d b y ultraso u n d i n t he c o urse of t he st u d y , c o nfir mati o n b y C T or M RI 
is a d vise d. If t here is c o ncer n a b o ut ra diati o n e x p os ure at C T, M RI m a y be use d i nstea d of C T i n 
selecte d i nsta nces.
E n d osc o p y, l a p ar osc o p y: T he utilizati o n of t hese tec h ni q ues f or o bjecti ve t u m or e val uati o n is n ot 
a d vise d. H o we ver, t he y ca n be usef ul t o c o nfir m c o m plete pat h ol o gical res p o nse w he n bi o psies 
are o btai ne d or t o deter mi ne rela pse i n st u dies w here rec urre nce f oll o wi n g C R or s ur gical resecti o n 
is a n e n d p oi nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 3 / 1 1 5
T u m or m a r kers: T u m or mar kers al o ne ca n n ot be use d t o assess o bjecti ve t u m or res p o nse. If 
mar kers are i nitiall y a b o ve t he u p per n or mal li mit; h o we ver, t he y m ust n or malize f or a partici pa nt 
t o be c o nsi dere d i n C R . Beca use t u m or mar kers are disease s pecific, i nstr ucti o ns f or t heir 
meas ur e me nt s h o ul d be i nc or p orate d i nt o pr ot oc ols o n a disease s pecific basis. S pecific g ui deli nes 
f or b ot h C A-1 2 5 res p o nse (i n rec urre nt o varia n ca ncer) a n d pr ostate -s pecific a nti ge n res p o nse (i n 
rec urre nt pr ostate ca ncer), ha ve bee n p u blis he d. I n a d diti o n, t he G y nec ol o gic Ca ncer I nter gr o u p 
has de vel o pe d C A - 1 2 5 pr o gressi o n criteria w hic h are t o be i nte grate d wit h o bjecti ve t u m or 
assess me nt f or use i n 1 st-li ne st u dies i n o varia n ca ncer.
C yt ol o g y, hist ol o g y: T hese tec h ni q ues ca n be use d t o differe ntiate bet wee n P R a n d C R i n rare 
cases if re q uire d b y pr ot oc ol (e . g., resi d ual lesi o ns i n t u m or t y pes s uc h as ger m cell t u m ors, w here 
k n o w n resi d ual be ni g n t u m ors ca n re mai n). W he n eff usi o ns are k n o w n t o be a p ote ntial A E of 
treat me nt (e. g., wit h certai n ta xa ne c o m p o u n ds o r a n gi o ge nesis i n hi bit ors), t he c yt ol o gical 
c o nfir mati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat a p pears or w orse ns d uri n g treat me nt ca n 
be c o nsi dere d if t he meas ura ble t u m or has met criteria f or res p o nse or ( S D i n or der t o differe ntiate 
bet wee n res p o nse ( or S D) a n d P D.
R E S P O N S E C RI T E RI A
E val uati o n of Tar get Lesi o ns 
C o m plete res p o nse: Disa p peara nce of all tar get lesi o ns. A n y  pat h ol o gical l ym p h n o des ( w het her 
tar get or n o n-tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m. 
Partial res p o nse: At least a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as 
refere nce t he Baseli ne s u m dia meters.
Pr o gressi ve disease: At least a 2 0 % i ncrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as 
refere nce t he s mallest s u m o n st u d y (t his i ncl u des t he B aseli ne s u m if t hat is t he s mallest o n st u d y). 
I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute i ncrease of 
at least 5 m m. ( N ote: t he a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).  
Sta ble disease: Neit her s ufficie nt s hri n ka ge t o q ualif y  f or P R n or s ufficie nt i ncrease t o q ualif y  f or 
P D, ta ki n g as refere nce t he s mallest s u m dia meters w hile o n st u d y .
Ly m p h n o des. L y m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha ve t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he B aseli ne e xa mi nati o n), e ve n 
if t he n o des re gress t o bel o w 1 0 m m o n st u d y. T his mea ns t hat w he n l ym p h n o des are i ncl u de d as 
tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y  not be zer o e ve n if C R criteria are met, si nce a n or mal 
l ym p h n o de is defi ne d as ha vi n g a s h ort a xis of < 1 0 m m. Electr o nic c ase re p ort f or ms e C R Fs or 
ot her data c ollecti o n met h o ds ma y  theref ore be desi g ne d t o ha ve tar get n o dal lesi o ns rec or de d i n 
a se parate secti o n w here, i n or der t o q ualif y f or C R, eac h n o de m ust ac hie ve a s h ort a xis < 1 0 m m. 
F or P R , S D, a n d P D, t he act ual s h ort a xis meas ure me nt of t he n o des is t o be i ncl u de d i n t he s u m 
of tar get l esi o ns.
T ar get lesi o ns t h at bec o me ‘t o o s m all t o me as ure’ . W hile o n st u d y, all lesi o ns ( n o dal a n d n o n-
n o dal) rec or de d at B aseli ne s h o ul d ha ve t heir act ual meas ure me nts rec or de d at eac h s u bse q ue nt 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 4 / 1 1 5
e val uati o n, e ve n w he n ver y  small ( e. g., 2 m m). H o we ver, s o meti mes lesi o ns or l ym p h n o des w hic h 
are rec or de d as tar get lesi o ns at B aseli ne bec o me s o fai nt o n C T sca n t hat t he ra di ol o gist ma y n ot 
feel c o mf orta ble assi g ni n g a n e xact meas ure a n d ma y re p ort t he m as bei n g ‘t o o s mall t o meas ure’. 
W he n t his occ urs it is i mp orta nt t hat a val ue be rec or de d o n t he e C R F. If it is t he o pi ni o n of t he 
ra di ol o gist t hat t he lesi o n has li kely dis a p peare d, t he meas ure me nt s h o ul d be rec or de d as 0 m m. If 
t he lesi o n is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 
5 m m s h o ul d be assi g ne d. ( N ote: It is less li kel y t hat t his r ule will be use d f or l ym p h n o des si nce 
t he y us ually ha ve a defi na ble size w he n n or mal a n d are fre q ue ntly s urr o u n de d b y  fat, s uc h as i n 
t he retr o perit o ne u m; h o we ver, if a ly m p h n o de is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o 
s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d i n t his circ u msta nce as well). T his 
defa ult val ue is deri ve d fr o m t he 5 m m C T slice t hic k ness ( b ut s h o ul d n ot be c ha n ge d wit h var y i n g 
C T slice t hic k ness). T he meas ure me nt of t hese lesi o ns is p ote ntiall y  no n- re pr o d uci ble; t heref ore, 
pr o vi di n g t his defa ult val ue will pre ve nt false res p o nses or pr o gressi o ns base d u p o n meas ure me nt 
err or. T o reiterate, h o we ver, if t he ra di ol o gist is a ble t o pr o vi de a n act ual meas ure, t hat s h o ul d be 
rec or de d, e ve n if it is bel o w 5 m m.
Lesi o ns t h at s plit or c o alesce o n tre at me nt. W he n 
n o n- n o dal lesi o ns ‘fra g me nt’, t he l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n s u m. 
Si milarl y , as lesi o ns c oalesce, a pla ne bet wee n t he m ma y  be mai ntai ne d t hat w o ul d ai d i n o btai ni n g 
ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o n. If t he lesi o ns ha ve tr uly c oalesce d s uc h 
t hat t he y are n o l o n ger se para ble, t he vect or of the l o n gest dia meter i n t his i nsta nce s h o ul d be t he 
ma xi mal l o n gest dia meter f or t he ‘c oalesce d lesi o n’.
E val uati o n of N o n -tar get Lesi o ns
W hile s o me n o n- tar get lesi o ns ma y  act uall y be meas ura ble, t he y nee d n ot be meas ure d a n d i nstea d 
s h o ul d be assesse d o nly q ualitati vel y  at t he ti me p oi nts s pecifie d i n t he pr ot oc ol.  
C o m plete res p o nse: Disa p peara nce of all n o n- tar get lesi o ns a n d n or malizati o n of t u m or mar ker 
le vel. All l ym p h n o des m ust be n o n -pat h ol o gical i n size ( < 1 0 m m s h ort a xis).  
N o n -C o m plete res p o nse/ N o n-Pr o gressi ve disease : Persiste nce of 1 or m ore n o n- tar get lesi o n(s) 
a n d/ or mai nte na nce of t u m or mar ker le vel a b o ve t he n or mal li mits. 
Pr o gressi ve disease: U ne q ui v ocal pr o gressi o n (see c o m me nts bel o w) of e xisti n g n o n- tar get 
lesi o ns. ( N ote: t he a p pearance of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).
W h e n t he p artici p a nt als o h as me as ur a ble dise ase . I n t his setti n g, t o ac hie ve ‘ u ne q ui v ocal 
pr o gressi o n’ o n t he basis of t he n o n- tar get disease, t here m ust be a n o verall le vel of s u bsta ntial 
w ors e ni n g i n n o n-tar get disease s uc h t hat, e ve n i n t he prese nce of S D or P R i n tar get disease, t he 
o verall t u m or b ur de n has i ncrease d s ufficie ntly t o merit disc o nti n uati o n of t hera py. A m o dest 
‘i ncrease’ i n t he size of 1 or m ore n o n- tar get lesi o ns is us uall y  not s ufficie nt t o q ualit y f or 
u ne q ui v ocal pr o gressi o n stat us. T he desi g nati o n of o verall pr o gressi o n s olel y on t he basis of 
c ha n ge i n n o n-tar get disease i n t he face of S D or P R of tar get disease will t heref ore be e xtre mel y 
rare.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 5 / 1 1 5
W h e n t he p artici p a nt h as o nl y n o n -me as ur a ble dise ase . T his circ u msta nce arises i n s o me P hase 
III st u dies w he n it is n ot a criteri o n of st u d y entr y t o ha ve meas ura ble disease. T he sa me ge neral 
c o nce pt a p plies here as n ote d a b o ve; h o we ver, i n t his i nsta nce t here is n o meas ura ble diseas e 
assess me nt t o fact or i nt o t he i nter pretati o n of a n i ncrease i n n o n- meas ura ble disease b ur de n. 
Beca use w orse ni n g i n n o n -tar get disease ca n n ot be easil y qua ntifie d ( by defi niti o n: if all lesi o ns 
are tr ul y no n- meas ura ble), a usef ul test t hat ca n be a p plie d w he n assessi n g partici pa nts f or 
u ne q ui v ocal pr o gressi o n is t o c o nsi der if t he i ncrease i n o verall disease b ur de n base d o n t he c ha n ge 
i n n o n- meas ura ble disease is c o m para ble i n ma g nit u de t o t he i ncrease t hat w o ul d be re q uire d t o 
declare P D f or meas ura ble di sease: i.e., a n i ncrease i n t u m or b ur de n re prese nti n g a n a d diti o nal 
7 3 % i ncrease i n ‘ v ol u me’ ( w hic h is e q ui vale nt t o a 2 0 % i ncrease dia meter i n a meas ura ble lesi o n). 
E xa m ples i ncl u de a n i ncrease i n a ple ural eff usi o n fr o m ‘trace’ t o ‘lar ge’, a n i ncrease i n
l ym p ha n gitic disease fr o m l ocalize d t o wi des prea d, or ma y  be descri be d i n pr ot oc ols as ‘s ufficie nt 
t o re q uire a c ha n ge i n t hera py’.  If ‘ u ne q ui v ocal pr o gressi o n’ is see n, t he partici pa nt s h o ul d be 
c o nsi dere d t o ha ve ha d o verall P D at t hat p oi nt. W hile it w o ul d be i deal t o ha ve o bjecti ve criteria 
t o a p pl y to n o n- meas ura ble disease, t he ver y  nat ure of t hat disease ma kes it i m p ossi ble t o d o s o; 
t heref ore, t he i ncrease m ust be s u bsta ntial.
Ne w Lesi o ns 
T he a p peara nce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me c o m me nts 
o n detecti o n of ne w lesi o ns are i m p orta nt. T here are n o s pecific criteria f or t he i de ntificati o n of 
ne w ra di o gra p hic lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be u ne q ui v ocal: i.e., n ot 
attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g m o dalit y, or fi n di n gs t h o u g ht 
t o re prese nt s o met hi n g ot her t ha n t u m or (e.g. , s o me ‘ ne w’ b o ne lesi o ns ma y be si m pl y heali n g or 
flare of pre -e xisti n g lesi o ns). T his is partic ularl y i m p orta nt w he n t he parti ci pa nt’s B aseli ne lesi o ns 
s h o w P R or C R . F or e xa m ple, necr osis of a li ver lesi o n ma y be re p orte d o n a C T sca n re p ort as a 
‘ ne w’ c ystic lesi o n, w hic h it is n ot.
A lesi o n i de ntifie d o n a f oll o w- u p st u d y in a n a nat o mical l ocati o n t hat was n ot sca n ne d at B aseli ne 
is c o nsi dere d a ne w lesi o n a n d will i n dicate P D. A n e xa m ple of t his is t he partici pa nt w h o has 
visceral disease at B aseli ne a n d w hile o n st u d y has a brai n C T or M RI  or dere d w hic h re veals 
metastases. T he partici pa nt’s brai n metastases are c o nsi dere d t o be e vi de nce of P D e ve n if he/s he 
di d n ot ha ve brai n i ma gi n g at B aseli ne. 
If a ne w lesi o n is e q ui v ocal, e. g., beca use of its s mall size, c o nti n ue d t hera py a n d f oll o w-u p 
e val uati o n will clarif y if it re prese nts tr ul y ne w disease. If re peat sca ns c o nfir m t here is defi nitel y 
a ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n. 
W hil e fl u de o xy gl uc ose p ositr o n e missi o n t o m o gra p hy ( F D G-P E T) res p o nse assess me nts nee d 
a d diti o nal st u dies, it is s o meti mes reas o na ble t o i nc or p orate t he use of F D G -P E T sca n ni n g t o 
c o m ple me nt C T sca n ni n g i n assess me nt of pr o gressi o n ( partic ularl y p ossi ble ‘ ne w’ disease). Ne w 
lesi o ns o n t he basis of F D G- P E T i ma gi n g ca n be i de ntifie d acc or di n g t o t he f oll o wi n g al g orit h m:
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 6 / 1 1 5
1. Ne gati ve F D G -P E T at B aseli ne, wit h a p ositi ve F D G -P E T at f oll o w- u p is a si g n of P D base d 
o n a ne w lesi o n. 
2. N o F D G -P E T at B aseli ne a n d a p ositi ve F D G -P E T at f oll o w-u p: If t he p ositi ve F D G -P E T at 
f oll o w- u p c orres p o n ds t o a ne w site of disease c o nfir me d b y  CT, t his is P D. If t he p ositi ve 
F D G -P E T at f oll o w- u p is n ot c o nfir me d as a ne w site of disease o n C T, a d diti o nal f oll o w- u p 
C T sca ns are nee de d t o deter mi ne if t here is tr ul y pr o gressi o n occ urri n g at t hat site (if s o, t he 
date of P D will be t he date of t he i nitial a b n or mal F D G -P E T sca n). If t he p ositi ve F D G -P E T at 
f oll o w- u p c orres p o n ds t o a pre -e xisti n g site of disease o n C T t hat is n ot pr o gressi n g o n t he basis 
of t he a nat o mic i ma ges, t his is n ot P D.
E val uati o n of Best O verall Res p o nse 
T he best o verall res p o nse ( B O R) is t he best res p o nse rec or de d fr o m t he start of t he st u d y 
i nter ve nti o n u ntil t he e n d of treat me nt ta ki n g i nt o acc o u nt a ny re q uire me nt for c o nfir mati o n.
O n occasi o n, a res p o nse ma y  n ot be d oc u me nte d u ntil after t he e n d of t hera p y, s o pr ot oc ols s h o ul d 
be clear if p ost treat me nt assess me nts are t o be c o nsi dere d i n deter mi nati o n of B O R. Pr ot oc ols 
m ust s pecif y ho w a n y ne w t hera p y intr o d uce d bef ore pr o gressi o n will affect best res p o nse 
desi g nati o n. T he partici pa nt’s B O R assi g n me nt will de pe n d o n t he fi n di n gs of b ot h tar get a n d n o n-
tar get disease a n d will als o ta ke i nt o c o nsi derati o n t he a p peara nce of ne w lesi o ns. F urt her m ore, 
de pe n di n g o n t he na t ure of t he st u d y an d t he pr ot oc ol re q uire me nts, it ma y  als o re q uire 
c o nfir mat or y meas ure me nt. S pecificall y , i n n o n- ra n d o mize d st u dies w here res p o nse is t he pri mar y 
e n d p oi nt, c o nfir mati o n of P R or C R is nee de d t o dee m eit her 1 t he ‘ B O R’.  
T he B O R is deter mi ne d o nce all t he data f or t he partici pa nt is k n o w n. Best res p o nse deter mi nati o n 
i n st u dies w here c o nfir mati o n of C R or P R I S N O T re q uire d: Best res p o nse i n t hese st u dies is 
defi ne d as t he best res p o nse acr oss all ti me p oi nts (f or e xa m ple, a partici pa nt w h o has S D at first 
assess me nt, P R at sec o n d assess me nt, a n d P D o n last assess me nt has a B O R of P R ). W he n S D is 
belie ve d t o be best res p o nse, it m ust als o meet t he pr ot oc ol -s pecifie d mi ni m u m ti me fr o m B aseli ne. 
If t he mi ni m u m ti me is n ot met w he n S D is ot he r wise t he best ti me p oi nt res p o nse, t he partici pa nt’s 
best res p o nse de pe n ds o n t he s u bse q ue nt assess me nts. F or e xa m ple, a partici pa nt w h o has S D at 
first assess me nt, P D at sec o n d a n d d oes n ot meet mi ni m u m d urati o n f or S D, will ha ve a best 
res p o nse of P D. T he sa me partici pa nt l ost t o f oll o w- u p after t he first S D assess me nt w o ul d be 
c o nsi dere d i ne val ua ble.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 7 / 1 1 5
T ar g et L e si o n s
N o n -t ar g et L e si o n s
N e w  L e si o n s
O v er all R e s p o n s e
C R a
C R
N o
C R
C R
N o n -C R/ n o n -P D
N o
P R
C R
N ot E v al u at e d
N o
P R
P R
N o n -P D or n ot all 
e v al u at e d
N o
P R
S D
N o n -P D or n ot all 
e v al u at e d
N o
S D
N ot all e v al u at e d
N o n -P D
N o
N E
P D
A n y
Y e s or N o
P D
A n y
P D
Y e s or N o
P D
A n y
A n y
Y e s
P D
a C R: c o m pl et e r e s p o n s e; N E: N ot e v al u a bl e; P D: pr o gr e s si v e di s e a s e ; P R: p arti al r e s p o n s e; S D: st a bl e di s e a s e;. 
S e e t e xt f or m or e d et ail s.
N ote: 
W he n n o dal disease is i ncl u de d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o ‘ n or mal’ 
size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt re p orte d o n sca ns. T his meas ure me nt s h o ul d 
be rec or de d e ve n t h o u g h t he n o d es are n or mal i n or der n ot t o o verstate pr o gressi o n s h o ul d it be 
base d o n i ncrease i n size of t he n o des. As n ote d earlier, t his mea ns t hat partici pa nts wit h C R ma y  
n ot ha ve a t otal s u m of ‘zer o’ o n t he e C R F.  
I n st u dies w here c o nfir mati o n of res p o nse is re q uire d, re peate d ‘ N E’ ti me p oi nt assess me nts ma y 
c o m plicate best res p o nse deter mi nati o n. T he a nal ysis pla n f or t he st u d y must a d dress h o w missi n g 
data/assess me nts will be a d dresse d i n deter mi nati o n of res p o nse a n d pr o gressi o n. F or e xa m ple, i n 
m ost st u dies , it is reas o na ble t o c o nsi der a partici pa nt wit h ti me p oi nt res p o nses of P R -N E -P R as 
a c o nfir me d res p o nse. 
Partici pa nts wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of P D at t hat ti me s h o ul d be re p orte d as ‘s ym pt o matic deteri orati o n’. 
E ver y  eff ort s h o ul d be ma de t o d oc u me nt o bjecti ve pr o gressi o n e ve n after disc o nti n uati o n of 
treat me nt. Sy m pt o matic deteri orati o n is n ot a descri pt or of a n o bjecti ve res p o nse; it is a reas o n f or 
st o p pi n g st u d y t hera p y.  
C o n diti o ns t hat defi ne ‘earl y pr o gressi o n, earl y deat h, a n d i ne val ua bilit y’ are st u d y-s pecific a n d
s h o ul d be clearl y descri be d i n eac h pr ot oc ol ( de pe n di n g o n treat me nt d urati o n, a n d treat me nt 
peri o dicit y ). 
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 8 / 1 1 5
I n s o me circ u msta nces it ma y  be diffic ult t o disti n g uis h resi d ual disease fr o m n or mal tiss ue. W he n 
t he e val uati o n of C R de pe n ds u p o n t his deter mi na ti o n, it is rec o m me n de d t hat t he resi d ual lesi o n 
be i n vesti gate d (fi ne nee dle as pirate/ bi o ps y) bef ore assi g ni n g a stat us of C R. T he use of F D G -P E T 
ma y  be use d t o u p gra de a res p o nse t o a C R i n a ma n ner si milar t o a bi o ps y  in cases w here a resi d ual 
ra di o gra phic a b n or malit y is t h o u g ht t o re prese nt fi br osis or scarri n g. T he use of F D G -P E T i n t his 
circ u msta nce s h o ul d be pr os pecti vely descri be d i n t he pr ot oc ol a n d s u p p orte d b y  disease s pecific 
me dical literat ure f or t he i n dicati o n. H o we ver, it m ust be ac k n o wle d ge d t hat b ot h a p pr oac hes ma y 
lea d t o false p ositi ve C R d ue t o li mitati o ns of F D G-P E T a n d bi o ps y  res ol uti o n/se nsiti vit y. 
F or e q ui v ocal fi n di n gs of pr o gressi o n (e . g., v er y s mall a n d u ncertai n ne w lesi o ns; c ystic c ha n ges 
or necr osis i n e xisti n g lesi o ns), treat me nt ma y  co nti n ue u ntil t he ne xt sc he d ule d assess me nt. If at 
t he ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he date of pr o gressi o n s h o ul d be t he 
earlier date w he n pr o gressi o n was s us pecte d.
C O N FI R M A T O R Y M E A S U R E M E N T/ D U R A TI O N O F R E S P O N S E
C o nfir mat i o n 
I n n o n-ra n d o mize d st u dies w here res p o nse is t he pri mar y e n d p oi nt, c o nfir mati o n of P R a n d C R is 
re q uire d t o e ns ure t he res p o nses i de ntifie d are n ot t he res ult of meas ure me nt err or. T his will als o 
per mit a p pr o priate i nter pretati o n of res ults i n t he c o nte xt of hist orical data w here res p o nse has 
tra diti o nall y re q uire d c o nfir mati o n i n s uc h st u dies. H o we ver, i n all ot her circ u msta nces, i. e., i n 
ra n d o mize d st u dies ( P hase II or III) or st u dies w here S D or pr o gressi o n are t he pri mary e n d p oi nts, 
c o nfir mati o n of res p o nse is n ot re q uire d si nce it will n ot a d d val ue t o t he i nter pretati o n of t he st u d y 
res ults. H o we ver, eli mi nati o n of t he re q uire me nt f or res p o nse c o nfir mati o n ma y  increase t he 
i m p orta nce of ce ntral re vie w t o pr otect a gai nst bias, i n partic ular i n st u dies w hic h are n ot bli n de d. 
I n t he case of S D, meas ure me nts m ust ha ve met t he S D criteria at least o nce after st u d y e ntr y at a 
mi ni m u m i nter val (i n ge neral n ot less t ha n 6 t o 8 wee ks) t hat is defi ne d i n t he st u d y  pr ot oc ol.
D urati o n of O verall Res p o nse
T he d urati o n of o verall res p o nse is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or 
C R/ P R ( w hic he ver is first rec or de d) u ntil t he first date t hat rec urre nt or P D is o bjecti vel y 
d oc u me nte d (ta ki n g as refere nce f or P D t he s mallest meas ure me nts rec or de d o n st u d y ). 
T he d urati o n of o verall C R is meas ure d fr o m t he ti me meas ure me nt criteria are first met f or C R 
u ntil t he first date t hat rec urre nt disease is o bjecti vel y d oc u me nte d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
9 9 / 1 1 5
D urati o n of Sta ble Disease 
Sta ble disease is meas ure d fr o m t he start of the treat me nt (i n ra n d o mize d st u dies, fr o m date of 
ra n d o mizati o n) u ntil t he criteria f or pr o gressi o n are met, ta ki n g as refere nce t he s mallest s u m o n 
st u d y (if t he B aseli ne s u m is t he s mallest, t his is t he refere nce f or calc ulati o n of P D). 
T he cli nical rele va nce of t he d urati o n of S D varies i n differe nt st u dies a n d diseases. If t he 
pr o p orti o n of partici pa nts ac hie vi n g S D f or a mi ni m u m peri o d of ti me is a n e n d p oi nt of i m p orta nce 
i n a partic ular st u d y, t he pr ot oc ol s h o ul d s pecif y t he mi ni mal ti me i nter val re quire d bet wee n 2 
meas ure me nts f or deter mi nati o n of S D. 
N ote: T he d urati o n of res p o nse a n d S D as well as t he pr o gressi o n-free s ur vi val are i nfl ue nce d b y 
t he fre q ue nc y of f oll o w- u p after B aseli ne e val uati o n. It is n ot i n t he sc o pe of t his g ui deli ne t o 
defi ne a sta n dar d f oll o w- u p fre q ue nc y. T he fre q ue nc y sh o ul d ta ke i nt o acc o u nt ma n y  p ara meters 
i ncl u di n g disease t ypes a n d sta ges, treat me nt peri o dicit y , a n d sta n dar d practice. H o we ver, t hese 
li mitati o ns of t he precisi o n of t he meas ure d e n d p oi nt s h o ul d be ta ke n int o acc o u nt if c o m paris o ns 
bet wee n st u dies are t o be ma de.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 0 / 1 1 5
A p pe n di x 6
Cli nic al L a b or at or y Tests
L a b or at or y  
A s s e s s m e nt s
P ar a m et er s
H e m at ol o g y
Pl at el et c o u nt
M e a n c or p u s c ul ar 
v ol u m e ( M C V)
W h it e Bl o o d C ell 
C o u nt wit h 
Diff er e nti al:

N e utr o p hil s

L y m p h o c yt e s

M o n o c yt e s

E o si n o p hil s

B a s o p hil s
H e m o gl o bi n
M e a n c or p u s c ul ar 
h e m o gl o bi n ( M C H)
H e m at o crit
C o a g ul ati o n
Pr ot hr o m bi n ti m e
A cti v at e d p arti al 
t hr o m b o pl a sti n ti m e
I nt er n ati o n al 
n or m ali z e d r ati o
Bi o c h e mi str y
Bl o o d Ur e a Nitr o g e n 
P ot a s si u m
A s p art at e 
a mi n otr a n sf er a s e
T ot al bilir u bi n
Ur e a a
Cr e ati ni n e
S o di u m
Al a ni n e 
a mi n otr a n sf er a s e
Gl u c o s e 
C al ci u m 
Al k ali n e p h o s p h at a s e 
Pr ot ei n 
T ot al a m yl a s e
Li p a s e
G a m m a -gl ut a m yl 
tr a n s p e pti d a s e
Al b u mi n
M a g n e si u m 
S er u m c y st ati n C (f or 
sit e s w h er e t h e t e st i s
a v ail a bl e)
P h o s p h or u s
D et ail s of li v er c h e mi str y st o p pi n g crit eri a a n d r e q uir e d a cti o n s a n d f oll o w -u p a s s e s s m e nt s aft er li v er st o p pi n g or 
m o nit ori n g e v e nt ar e gi v e n i n S e cti o n  7. 1 .
R o uti n e 
Uri n al y si s

S p e cifi c gr a vit y, p h y si c al a p p e ar a n c e, c ol or

p H, gl u c o s e, pr ot ei n, bl o o d, k et o n e s, bilir u bi n, ur o bili n o g e n, nitrit e, l e u k o c yt e e st er a s e b y 
di p sti c k

Mi cr o s c o pi c e x a mi n ati o n (if bl o o d or pr ot ei n i s a b n or m al)
Ot h er 
S cr e e ni n g 
T e st s

F olli cl e -sti m ul ati n g h or m o n e ( F S H) a n d e str a di ol ( a s n e e d e d i f n ot a w o m a n of c hil d b e ari n g 
p ot e nti al o nl y)

S er u m or hi g hl y s e n siti v e uri n e h u m a n c h ori o ni c g o n a d otr o pi n ( h C G ) pr e g n a n c y t e st ( a s 
n e e d e d f or a w o m a n of c hil d b e ari n g p ot e nti al ). 

S er ol o g y ( HI V a nti b o d y, h e p atiti s B s urf a c e a nti g e n [ H B s A g], a n d h e p atiti s C vir u s a nti b o d y)

All of t h e s af et y l a b s will b e p erf or m e d l o c all y 
a Ur e a c a n b e c al c ul at e d u si n g bl o o d ur e a nitr o g e n ( B U N ), a s f oll o w s:
If B U N i s e x pr e s s e d i n m m ol/ L t h e n ur ea = B U N (f a ct or = 1 f or c o n v er si o n s i n m m ol ( 1 m ol e N 2 = 2 m ol e s N p er m ol e 
of ur e a) t h e n ur e a [ m m ol/ L] = B U N [ m m ol/ L])
If B U N i s e x pr e s s e d i n m g/ d L it n e e d s t o b e c o n v ert e d a c c or di n g t o t h e f oll o wi n g f or m ul a: ur e a [ m g/ d L] = B U N 
[ m g/ d L] × 2. 1 4 2 8. ( c o n v er si o n f a ct or d eri v e d b y: MW of ur e a = 6 0, M W of ur e a nitr o g e n = 1 4 × 2 = > 6 0/ 2 8 = 2. 1 4 2 8)
If B U N i s e x pr e s s e d i n m m ol/ L a n d n e e d s t o b e c o n v ert e d t o ur e a m g/ d L, t h e f oll o wi n g f or m ul a m u st b e u s e d: ur e a 
( m g/ d L) = B U N ( m m ol/ L) × 0. 3 5 7.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 1 / 1 1 5
A p pe n di x 7
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
A E Defi niti o n
A E Defi niti o n

A n A E is a n y unt o war d me dical occ urre nce i n a patie nt or cli nical st u d y partici pa nt, 
te m p orall y ass ociate d wit h t he use of st u d y i nter ve nti o n, w het her c o nsi dere d relate d t o t he 
st u d y i nter ve nti o n or n ot.

A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s ym pt o m, or disease ( ne w or e xacer bate d) te m p orally a ss ociate d wit h t he 
use of st u d y inter ve nti o n . 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.
E ve nts Meeti n g
t he A E Defi niti o n

A n y  ab n or mal la b orat or y test res ults ( he mat ol o g y , cli nical c he mistr y, or uri nal ysis) or ot her 
safety a ssess me nts (e. g., E C G, ra di ol o gical sca ns, vital si g ns meas ure me nts), i ncl u di n g t h ose 
t hat w orse n fr o m B aseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he me dical a n d scie ntific 
j u d g me nt of t he I n vesti gat or (i.e., n ot relate d t o pr o gressi o n of u n derlyi n g disease).

E xacer bati o n of a c hr o nic or i nter mitte nt pre-e xisti n g c o n diti o n i ncl u di n g eit her a n i ncrease 
i n fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n.

Ne w c o n diti o ns detecte d or dia g n ose d after st u d y i nter ve nti o n a d mi nistrati o n e ve n t h o u g h it 
ma y  ha ve bee n prese nt bef ore t he start of t he st u d y.

Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.

Si g ns, s ym pt o ms, or t he cli nical seq uelae of a s us pecte d o ver d ose of eit her st u d y inter ve nti o n 
or a c o nc o mita nt me dicati o n.

Lac k of efficac y” or “fail ure of e x pecte d p har mac ol o gical acti o n” per se will n ot be re p orte d 
as a n A E or a S A E. H o we ver, t he si g ns, s ym pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m 
lac k of efficac y will be re p orte d as a n A E or a S A E if t he y fulfil t he defi niti o n of a n A E or 
S A E.
E ve nts N O T Meeti n g t he A E Defi niti o n

U nless j u d ge d b y  the I nvesti gat or t o be m ore se vere t ha n e x pecte d f or t he partici pa nt’s 
c o n diti o n, a n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs, ot her a b n or mal safety 
assess me nts t hat are ass ociate d wit h t he u n derl y i n g disease, t he disease/ dis or der bei n g 
st u die d, or e x pecte d pr o gressi o n, si g ns, or sy m pt o ms of t he disease/ dis or der bei n g st u die d.

Me dical or s ur gical pr oce d ure (e. g., e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat lea ds t o 
t he pr oce d ure is t he A E.

Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or c o n ve nie nce 
a d missi o n t o a h os pital).

A ntici pate d d a y -t o-d a y fl uct uati o ns of pre -e xisti n g disease(s) or c o n diti o n(s) prese nt or 
detecte d at t he start of t he st u d y  t hat d o n ot w orse n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 2 / 1 1 5
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 her met h o ds as well as ass ociate d cli nical si g ns or s ym pt o ms (i ncl u di n g 
la b orat or y ab n or malities) will n ot be re p orte d as A Es/ S A Es, u nless t he partici pa 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 his/ her c o n diti o n a n d/ or if t he i n vesti gat or c o nsi ders 
t hat t here is a reas o na ble p ossi bilit y t hat t he e ve nt was relate d t o st u d y i nter ve nti o n.
Ot her A d verse E ve nts t o be Re p orte d Usi n g a S peci alize d Pr oce d ure or F or m

O ver d oses (see Secti o n  8. 4) as descri be d u n der “ Re p orti n g of S A Es” bel o w.

Pre g na ncies (see Secti o n  8. 3. 5) as descri be d u n der “ Re p orti n g of Pre g na ncies” bel o w.

D L Ts (see Secti o n  6. 6. 3 ) as descri be d u n der “ Re p orti n g of D L Ts” bel o w.

A E SI s (see Secti o n 8. 3. 7 ) as descri be d u n der “ Re p orti n g of “ A E SIs” bel o w.
S A E Defi niti o n
If a n e ve nt is n ot a n A E per t he defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us c o n diti o ns 
are met (e. g., h os pitalizati o n f or sig ns/s y m pt o ms of t he disease u n der st u d y, deat h d ue t o 
pr o gressi o n of disease).
A S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
a .
Res ults i n de at h
b.
Is life-t hre ate ni n g
T he ter m 'life-t hreate ni n g' i n t he defi niti o n of 'seri o us' refers t o a n e ve nt i n w hic h t he partici pa nt 
was at ris k of deat h at t he ti me of t he e ve nt. It d oes n ot refer t o a n e ve nt, w hic h h y p ot heticall y 
mi g ht ha ve ca use d deat h, if it were m ore se vere.
c.
Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n

I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n detai ne d ( us uall y 
i n v ol vi n g at least a n o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n 
a n d/ or treat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ys icia n’s office or 
o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es. If a 
c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he e ve nt is 
seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was necessar y , t he 
A E will be c o nsi dere d seri o us.

H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n 
fr o m B aseli ne is n ot c o nsi dere d a n A E.

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.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 3 / 1 1 5
A S A E is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:
d.
Res ults i n persiste nt dis a bilit y/i nc a p acit y
T he ter m disa bilit y  mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y to c o n d uct n or mal life 
f u ncti o ns.
T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical si g nifica nce 
s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d acci de ntal tra u ma 
(e. g., s prai ne d a n kle) w h ic h ma y  interfere wit h or pre ve nt e ver yd a y  life f u ncti o ns b ut d o n ot 
c o nstit ute a s u bsta ntial disr u pti o n.
e.
Is a c o n ge nit al a n o m al y/ birt h defect
f.
Ot her sit u ati o ns:

Me dical or scie ntific j u d g me nt will be e xercise d i n deci di n g w het her S A E re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat m a y  not be i m me diatel y 
life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut m a 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 ot her o utc o mes liste d i n t he 
a b o ve defi niti o n. T hese e ve nts are us uall y c o nsi dere d as seri o us.

E xa m ples of s uc h e ve nts i ncl u de i n vasi ve or mali g na nt ca ncers, i nte nsi ve treat me nt 
i n a n e mer ge nc y ro o m or at h o me f or aller gic br o nc h os pas m, 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 h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y 
or dr u g a b use.
Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E
A E a n d S A E Rec or di n g

W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he I n vesti gat or t o re vie w all 
d oc u me ntat i o n (e. g., h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics 
re p orts) relate d t o t he e ve nt.

T he I n vesti gat or will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he eC R F .

As nee de d, t he S p o ns or or its desi g nee ma y  as k f or c o pies of certai n me dical rec or ds 
(e. g., a ut o ps y 
re p orts, s u p ple me ntal 
la b re p orts, d oc u me nts 
o n 
me dical 
hist or y /c o nc o mita nt me dicati o ns, 
disc har ge 
letters), as 
s u p p orti n g 
s o urce 
d oc u me ntati o n. All partici pa nt i de ntifiers, e xce pt t he partici pa nt n u m ber, will be 
re dacte d o n t hese c o pies bef ore s u b missi o n t o t he S p o ns or or its desi g nee.

T he I n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, 
s ym pt o ms, a n d/ or ot her cli nical i nf or mati o n. W he ne ver p ossi ble, t he dia g n osis ( n ot 
t he i n di vi d ual si g ns/s ym pt o ms) will be d oc u me nte d as t he A E/ S A E.

If a n A E c o nstit utes a D L T t his is d oc u me nte d acc or di n gly.

S pecific g ui da nce is i n t he eC R F C o m pleti o n a n d M o nit ori n g C o n ve nti o ns.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 4 / 1 1 5
Assess me nt of I nte nsit y
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), V ersi o n 5. 0 ( p u blicati o n date: 2 7 N o v 2 0 1 7), a descri pti ve ter mi n ol o g y t hat ca n 
be use d f or A E re p orti n g.
A ge neral gra di n g (se verit y/i nte nsity;  hereafter referre d t o as se verit y) 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 ge neral N CI -C T C A E defi niti o ns of Gra de 1 t hr o u g h Gra de 5, usi n g his or her best me dical 
j u d g me nt.
T he 5 ge neral gra des are:

Gra de 1 or Mil d

Gra de 2 or M o derate

Gra de 3 or Se vere 

Gra de 4 or L ife-t hreate ni n g 

Gra de 5 or Deat h 
A n y  cli nical A E wit h se verit y of Gra de 4 or 5 m ust als o be re p orte d as a n S A E. H o we ver, a 
la b orat or y a b n or malit y of 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 nly 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 deat h or e ve nt lea di n g t o deat h will 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 
n ot be rec or de d as se parate e ve nt. O nl y, if n o  ca use of deat h ca n be re p orte d (e. g., s u d de n deat h, 
u ne x plai ne d deat h ), t he deat h per se mi g ht t he n be re p orte d as a n S A E.
Assess me nt of C a us alit y

T he I n vesti gat or will assess t he relati o ns hi p bet wee n st u d y inter ve nti o n a n d eac h 
A E/ S A E occ urre nce:

U nrelate d: N ot 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 n ot 
me dicall y  ( p har mac ol o gicall y/cli nicall y) be attri b ute d t o t he st u d y i nter ve nti o n. A 
reas o na ble alter nati ve e x pla nati o n will be a vaila ble.

Relate 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 i nter ve nti o n.

A “reas o na ble p ossi bilit y ” of a relati o ns hi p c o n ve ys t hat t here are facts, e vi de nce, 
a n d/ or ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n a relati o ns hi p ca n n ot be 
r ule d o ut.

T he I n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 5 / 1 1 5
Assess me nt of C a us alit y

Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y inter ve nti o n 
a d mi nistrati o n will be c o nsi dere d a n d i n vesti gate d.

T he In vesti gat or will als o c o ns ult t he I nvesti gat or Br oc h ure (I B) a n d/ or Pr o d uct 
I nf or mati o n, f or mar kete d pr o d ucts, i n his/ her assess me nt.

F or eac h A E/ S A E, t he I n vesti gat or will d oc u me nt i n t he me dical n otes t hat he/s he has 
re vie we d t he A E/ S A E a n d assesse d ca usalit y.

T here ma y be sit uati o ns w he n a n S A E has occ urre d, a n d t he I n vesti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he S p o ns or or its desi g nee. T o meet t he 
re p orti n g ti meli ne, t he ca usalit y assess me nt is n ot re q uire d f or t he i nitial re p ort.

T he I n vesti gat or m a y  c ha n ge his/ her ca usalit y assess me nt after c o nsi deri n g f oll o w- u p 
i nf or mati o n a n d se n d a S A E f oll o w-u p re p ort wit h t he u p date d ca usalit y  assess me nt.

T he ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat ory 
re p orti n g re q uire me nts.
F oll o w - u p of A Es a n d S A Es

T he 
I nvesti gat or will 
perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns, as me dicall y  in dicate d or as re q ueste d b y  the 
S p o ns or or its desi g nee t o el uci date t he nat ure a n d/ or ca usalit y of t he A E or S A E, as 
f ull y as p ossi ble. T his ma y  incl u de a d diti o nal la b orat or y tests or i n vesti gati o ns, 
hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care pr ofessi o nals.

If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w- u p 
peri o d, t he I n vesti gat or will pr o vi de t he S p o ns or or its desi g nee wit h a c o p y of a n y 
p ost -m orte m fi n di n gs i ncl u di n g hist o pat h ol o g y . 

Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y  c o m plete d e C R F .

T he In vesti gat or will s u b mit a n y up date d S A E data t o t he S p o ns or or its desi g nee 
wit hi n 2 4 h o urs of recei pt of t he i nf or mati o n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 6 / 1 1 5
Re p orti n g of S A Es
S A E Re p orti n g b y a n Electr o nic D at a C ollecti o n T o ol
1.
T he pri mar y  mec ha nis m f or re p orti n g a n S A E t o t he S p o ns or or its desi g nee will be t he 
electr o nic data c ollecti o n t o ol.
2.
If t he electr o nic s yste m is u na vaila ble, t he n t he site will use t he pa per S A E data 
c ollecti o n t o ol, s pecifie d bel o w, t o re p ort t he e ve nt wit hi n 2 4 h o urs.
3.
T he site will e nter t he S A E data i nt o t he electr o nic s yste m as s o o n as it bec o mes 
a vaila ble.
4.
After t he st u d y is c o m plete d at a site, t he electr o nic data c ollecti o n t o ol will be ta ke n off -
li ne t o pre ve nt t he e ntr y of ne w data or c ha n ges t o e xisti n g data.
5.
If a site recei ves a re p ort of a ne w S A E fr o m a st u d y partici pa nt or recei ves u p date d data 
o n a pre vi o usl y  re p orte d S A E after t he electr o nic data c ollecti o n t o ol has bee n ta ke n off -
li ne, t he n t he site ca n re p ort t his i nf or mati o n o n a pa per S A E f or m or t o t he S p o ns or’s 
safety de part me nt.
6.
B y  exce pti o n, a n S A E ( or f oll o w- u p i nf or mati o n) ma y  be re p orte d b y  tele p h o ne. T he site 
will c o m plete t he electr o nic S A E data e ntr y  i m me diatel y t hereafter.
S A E Re p orti n g b y a P a per F or m
1.
S A E re p orti n g o n a pa per re p ort f or m is use d as a bac k -u p met h o d f or a n electr o nic data 
ca pt ure s yste m fail ure. T he f or m i ncl u des c o m pleti o n i nstr ucti o ns f or t he I n vesti gat or, 
na mes, a d dresses, a n d tele p h o ne a n d fa x n u m bers. All i nf or mati o n fr o m t he pa per f or m 
will be tra nscri be d i nt o t he electr o nic f or m as s o o n as t he s y ste m bec o mes a vaila ble.
2.
Facsi mile tra ns missi o n (fa x t o mail) of t he pa per f or m or a n y f oll o w- u p i nf or mati o n is 
t he preferre d met h o d f or tra ns missi o n a n d will be d o ne wit hi n 2 4 h o urs t o t he S p o ns or 
or its desi g nee.
3.
I n rare circ u msta nces a n d i n t he a bse nce of facsi mile e q uip me nt, n otificati o n b y 
tele p h o ne is acce pta ble wit h a c o p y o f t he f or m se nt b y  over ni g ht mail or c o urier ser vice.
4.
I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he I n vesti gat or t o 
c o m plete a n d si g n t he f or m wit hi n 2 4 h o urs after bec o mi n g a ware of t he e ve nt.
5.
A d diti o nal d oc u me nts (e. g. la b orat or y  re p orts, a ut o ps y re p ort, h os pital disc har ge letter) 
a n d rele va nt pa ges fr o m t he eC R F m a y  be re q uire d i n a d diti o n (e. g. me dical hist or y , 
c o nc o mita nt me dicati o n). T he data pr o vi de d will be c o nsiste nt wit h t he i nf or mati o n i n 
t he e C R F.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 7 / 1 1 5
Rec or di n g a n d Re p orti n g of D L Ts
1.
Eac h e ve nt t hat meets t he D L T criteria, as s pecifie d i n Secti o n  6. 6. 3 , will be rec or de d i n 
t he eC R F wit hi n 2 4 h o urs after a ware ness of t he e ve nt.
2.
Seri o us D L Ts will be re p orte d i n a n e x pe dite d ma n ner, usi n g t he S A E re p orti n g pr ocess, 
as s pecifie d a b o ve.
3.
N otificati o n of eac h D L T relate d e ve nt ( n o n -seri o us a n d seri o us) will be re p orte d t o t he 
S p o ns or or its desi g nee wit hi n 2 4 h o urs fr o m t he date of a ware ness.
Re p orti n g of A E SIs
1.
F or a n o n -seri o us A E SI, t he site will c o m plete t he s pecific A E SI re p ort f or m a n d n otif y 
t he S p o ns or i m me diatel y ( wit hi n 2 4 h o urs), usi n g t he sa me pr ocess f or re p orti n g S A Es, 
as s pecifie d a b o ve.
2.
F or a seri o us A E SI, t he site will c o m plete a n S A E re p ort f or m, usi n g t he S A E re p orti n g 
pr ocess, s pecifie d a b o ve.
Re p orti n g of P re g n a ncies
1.
Pre g na nc y  will be re p orte d w het her relate d t o t he st u d y inter ve nti o n usi n g t he a p plica ble 
pa per f or m.
2.
T he a p plica ble f or m will be use d t o re p ort if a n a b n or mal o utc o me of t he pre g na nc y 
occ urs a n d t he c hil d/fet us s ustai ns a n e ve nt.
3.
Facsi mile tra ns missi o n (fa x t o mail) of t he pa per f or m or a n y f oll o w- u p i nf or mati o n is 
t he preferre d met h o d f or tra ns missi o n a n d will be d o ne wit hi n 2 4 h o urs t o t he S p o ns or 
or its desi g nee.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 8 / 1 1 5
A p pe n di x 8
B OI N Desi g n
I n Secti o n 9. 4. 2. 1 t he B OI N desi g n b y Y ua n 2 0 1 6 is i ntr o d uce d. T he tar get t o xicit y f or t his st u d y 
is 3 0 %; t he ma xi m u m t otal n u m ber of partici pa nts f or t he Safety R u n -i n is 1 2 ( ma xi m u m n u m ber 
of partici pa nts f or a certai n d ose le vel is 6). T he res pecti ve b o u n daries are pr o vi de d i n  Y ua n 2 0 1 6
( Ta ble 1 i n t hat article a n d t he fi g ure bel o w) as well as t he r ules f or escalati o n a n d de- escalati o n 
(see Ta ble 2 i n t hat article a n d t he res pecti ve ta ble i n Secti o n  9. 4. 2. 1 i n t his pr ot oc ol) will be use d. 
Y ua n 2 0 1 6 als o perf or me d si m ulati o ns t o i n vesti gate t he o perati o n c haracteristic of t he B O I N 
desi g n i n c o m paris o n t o ot her desi g ns f or certai n sit uati o ns (see Fi g ure 3 i n t hat article). 
Fl o wc h art of t he B OI N desi g n
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 9 / 1 1 5
A p pe n di x 9
Pr ot oc ol A me n d me nt Hist or y
T he i nf or mati o n f or t he c urre nt a me n d me nt is o n t he title pa ge.
Pr ot oc ol 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 7 -A pr -2 0 2 0
1. 1 -U S A
C o u ntr y -s p e cifi c A m e n d m e nt
3 0 -J ul -2 0 2 0
1. 2 -F R A
C o u ntr y -s p e cifi c A m e n d m e nt 
0 6 -O ct -2 0 2 0
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 0 / 1 1 5
C o u ntr y -s pecific A me n d me nt Versi o n 1. 2 -F R A t o P r ot oc ol Versi o n 1:
Pr ot oc ol Versi o n [ 1. 2 F R A] ( 0 6 Oct o ber 2 0 2 0)
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 ou 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
C ha n ges ma de t o i m pr o ve t he clarit y of t he st u d y in li ne wit h c o m me nts raise d b y  IE C/I R Bs a n d 
nati o nal re g ulat or y  a ut h orities.
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
5. 1 I n cl u si o n 
Crit eri a
T o crit eri o n # 2, a n d cl arifi e d t h at a d v a n c e d 
t u m or s ar e al s o u nr e s e ct a bl e.
U p d at e d t o cl arif y t u m or s ar e u nr e s e ct a bl e 
t o b ett er r efl e ct t h e r e q uir e m e nt s of t h e 
p ati e nt p o p ul ati o n.
5. 2 E x cl u si o n
Crit eri a
A d d e d n e w crit eri o n, # 1 6,” Hi st or y of I L D or 
i nt er stiti al p n e u m o niti s i n cl u di n g r a di ati o n 
p n e u m o niti s t h at r e q uir e d st er oi d tr e at m e nt.”
E x cl u si o n of p ati e nt s wit h a hi st or y of 
i nt er stiti al l u n g di s e a s e (I L D) or i nt er stiti al 
p n e u m o niti s t o b ett er r efl e ct t h e 
r e q uir e m e nt s of t h e p ati e nt p o p ul ati o n
6. 5. 4 S p e ci al 
Pr e c a uti o n s
6. 5. 4. 1 C et u xi m a b
W o r di n g u p d at e d u n d er E y e di s or d er s.
U p d at e d t o ali g n wit h t h e w or di n g fr o m t h e 
E U 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) f or c et u xi m a b.
6. 5. 4 S p e ci al 
Pr e c a uti o n s
6. 5. 4. 2 T e p oti ni b 
A d d e d s p e cifi c d et ail s f or e d e m a.
Pr o vi d e d d et ail e d g ui d eli n e s a c c or di n g t o 
t h e s e v erit y gr a d e of t h e t o xi cit y o b s er v e d, 
a n d t h e r e c o m m e n d e d f or t e p oti ni b d o s e 
m o difi c ati o n s.
6. 6 D o s e S el e cti o n 
a n d M o difi c ati o n
6. 6. 2 T e p oti ni b
A d d e d f urt h er cl arifi c ati o n u n d er t h e t e p oti ni b 
tr e at m e nt i nt err u pti o n s e cti o n t o i n cl u d e 
r e c o m m e n d e d d o s e m o difi c ati o n s i n c a s e of 
a d v er s e r e a cti o n s of cli ni c al i nt er e st. 
Pr o vi d e d d et ail e d g ui d eli n e s a c c or di n g t o 
t h e s e v erit y gr a d e of t h e t o xi cit y o b s er ve d, 
a n d t h e r e c o m m e n d e d f or t e p oti ni b d o s e 
m o difi c ati o n s.
6. 7 St u d y 
I nt er v e nti o n aft er 
t h e E n d of t h e 
St u d y
A d d e d d et ail s o n pr o vi si o n of pr o vi di n g st u d y 
i nt er v e nti o n aft er t h e E n d of t h e St u d y.
U p d at e d t o s p e cif y t h e t er m s f or t h e fr e e of 
c h ar g e pr o vi si o n of st u d y i nt er v e nti o n f or 
p arti ci p a nt s w h o b e n efit at t h e E n d of t h e 
St u d y.
7. 1 Di s c o nti n u ati o n 
of St u d y 
I nt er v e nti o n
U p d at e d t hi s s e cti o n t o cl arif y f urt h er i n e v e nt 
of Q T c F fi n di n g s.
Q T c i nt er v al pr ol o n g ati o n w er e a d d e d a s 
r e a s o n s f or di s c o nti n u ati o n of st u d y 
i nt er v e nti o n. A d diti o n all y, t h e i niti ati o n of 
cl o s e a n d a p pr o pri at e E C G m o nit ori n g i n 
h o s pit al a c c or di n g t o l o c al st a n d ar d s i s 
r ef err e d t o.
A p p e n di x 8
C o u ntr y -s p e cifi c 
R e q uir e m e nt s 
R ef er e n c e t o c h a n g e s d e s cri b e d i n t hi s t a bl e. 
A d mi ni str ati v e u p d at e.
A p p e n di x 9
Pr ot o c ol 
A m e n d m e nt Hi st or y
R ef er s t o c h a n g e s m a d e t o pr e vi o u s l o c al 
c o u ntr y s p e cifi c a m e n d m e nt s.
A d mi ni str ati v e u p d at e.
A p p e n di x 1 0 
S p o n s or Si g n at ur e 
P a g e
Cli ni c al st u d y pr ot o c ol v er si o n u p d at 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


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 1 / 1 1 5
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
A p p e n di x 1 1 
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
Cli ni c al St u d y pr ot o c ol v er si o n 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 
Pri n ci p al 
I n v e sti g at or 
Si g n at ur e P a g e
Cli ni c al st u d y pr ot o c ol v er si o n u p d at e d.
A d mi ni str ati v e u p d at e.
C o u ntr y -s pecific A me n d me nt Versi o n 1. 1- U S A t o P r ot oc ol Versi o n 1:
Pr ot oc ol Versi o n [ 1. 1 U S A] ( 3 0 J ul y 2 0 2 0)
O ver all R ati o n ale f or t he A me n d me nt
T he p ur p ose of t his a me n d me nt is t o i nc or p orate F D A re q uest recei ve d o n 0 6 J ul y 20 2 0 , a n d o n 
2 4 J ul y  2 0 2 0.
S e cti o n # a n d 
N a m e
D e s cri pti o n of C h a n g e
Bri ef R ati o n al e
1. 1 S y n o p si s
R e m o v e d “if a p pli c a bl e” aft er C o h ort B 
U p d at e f or cl arifi c ati o n o n H e alt h a ut h orit y 
f e e d b a c k.
1. 2 S c h e m a 
R e m o v e d “ a n d mi g ht b e i niti at e d at a l at er 
ti m e p oi nt” aft er C o h ort B will i n cl u d e U S 
p arti ci p a nt s o nl y 
2 I ntr o d u cti o n
A d d e d t e xt “ T h e pr o p o s e d a d mi ni st er e d 
d o s e of 5 0 0 m g t e p oti ni b c orr e s p o n d s t o 
5 0 0 m g t e p oti ni b h y dr o c hl ori d e h y dr at e a n d 
i s e q ui v al e nt t o 4 5 0 m g t e p oti ni b (fr e e b a s e 
f or m) t hr o u g h o ut t h e d o c u m e nt. T h e 2 5 0 
m g t e p oti ni b c orr e s p o n d s t o 2 5 0 m g 
t e poti ni b h y dr o c hl ori d e h y dr at e a n d i s 
e q ui v al e nt t o 2 2 5 m g t e p oti ni b (t h e fr e e 
b a s e f or m).”
H e alt h a ut h orit y f e e d b a c k t o re vi s e t h e 
pr ot o c ol t o cl arif y t h e a m o u nt of t e p oti ni b fr e e 
b a s e a d mi ni st er e d.
2. 1 St u d y 
R ati o n al e
R e m o v e d “if C o h ort B i s i niti at e d”
U p d at e f or cl arifi c ati o n o n H e alt h a ut h orit y 
f e e d b a c k.
4. 1 O v er all 
D e si g n
R e m o v e d “if C o h ort B i s i niti at e d”
U p d at e f or cl arifi c ati o n o n H e alt h a ut h orit y 
f e e d b a c k.
5. 1 I n cl u si o n 
Crit eri a
T o crit eri o n # 2, a d d e d t h at l eft -si d e d C R C 
t u m or s, “fr o m s pl e ni c fl e x ur e t o r e ct u m.” 
M a d e r ef er e n c e t o c urr e nt N ati o n al 
C o m pr e h e n si v e C a n c er N et w or k ( N C C N) 
C R C v 4. 2 0 2 0 g ui d eli n e s
H e alt h a ut h orit y f e e d b a c k t o d efi n e l eft si d e d 
t u m or s.
T o crit eri o n # 7 b, a d d e d “ Fir st -li n e tr e at m e nt 
m u st i n cl u d e a fl u or o p yri mi di n e a n d 
o x ali pl ati n or iri n ot e c a n a n d s e c o n d -li n e 
tr e at m e nt m u st i n cl u d e a fl u or o p yri mi di n e, 
o x ali pl ati n, or iri n ot e c a n.”
H e alt h a ut h orit y f e e d b a c k t o cl arif y t h at fir st-
li n e tr e at m e nt m u st i n cl u d e a fl u or o p yri mi di n e 
a n d o x ali pl ati n or iri n ot e c a n a n d s e c o n d- li n e 
tr e at m e nt m u st i n cl u d e a fl u or o p yri mi di n e, 
o x ali pl ati n, or iri n ot e c a n.
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 2 / 1 1 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
5. 2 E x cl u si o n 
Crit eri a
A d d d e d t o crit eri o n # 8 a s p oi nt “ g.
C orr e ct e d Q T i nt er v al b y Fri d eri ci a ( Q T c F 
> 4 8 0 m s) ”
H e alt h a ut h orit y f e e d b a c k t o cl arif y t h at w e 
e x cl u d e p ati e nt s wit h Q T c i nt er v al s 
> 4 8 0 m s e c. 
A d d e d n e w crit eri o n , # 1 6, ”Hi st or y of I L D or 
i nt er stiti al p n e u m o niti s i n cl u di n g r a di ati o n 
p n e u m o niti s t h at r e q uir e d st er oi d 
tr e at m e nt.”
H e alt h a ut h orit y f e e d b a c k f or e x cl u si o n of 
p ati e nt s wit h a hi st or y of I L D or i nt er stiti al 
p n e u m o niti s.
6. 1 St u d y 
I nt er v e nti o n( s) 
A d mi ni str ati o n
A d d e d, “ a n d if l o c al c et u xi m a b l a b el 
r e q uir e s”, a c orti c o st er oi d i s gi v e n pri or t o 
t h e fir st i nf u si o n of c et u xi m a b
H e alt h a ut h orit y f e e d b a c k t o a c k n o wl e d g e t h e 
diff er e n c e b et w e e n U S A a n d o ut si d e t h e U S A
r e q uir e m e nt s r el at e d t o pr e m e di c ati o n. T o 
s p e cif y t h e u s e of c orti c o st er oi d s will b e b a s e d 
o n l o c al r e q uir e m e nt s.
6. 5. 1 P er mitt e d 
M e di ci n e s
A d d e d, “ a n d if l o c al c et u xi m a b l a b el 
r e q uir e s”, a c orti c o st er oi d i s gi v e n pri or t o 
t h e fir st i nf u si o n of c et u xi m a b
6. 6. 3 D o s e 
Li miti n g 
T o xi cit y
A d d e d “Gr a d e 4 v o miti n g or di arr h e a” a s 
D L T crit eri a .
H e alt h a ut h orit y f e e d b a c k t o i m pl e m e nt t h at 
t h at D L T crit eri a will b e r e vi s e d s o Gr a d e 4 (lif e 
t hr e at e ni n g) v o miti n g or di arr h e a ar e 
c o n si d er e d a s D L T crit eri a. 
9. 2 S a m pl e 
Si z e 
D et er mi n ati o n
R e m o v e d “if a p pli c a bl e” aft er C o h ort B, a n d 
r e m o v e d “if i niti at e d” aft er C o h ort B
H e alt h a ut h orit y f e e d b a c k a d dr e s s e d t o cl arif y 
t h at e nr oll m e nt of C o h ort B i s n o w t ar g et e d t o 
i niti at e i m m e di at el y i n t h e U S A, a n d n ot 
p o s si bl y l at e r a s i niti all y i m pli e d.
A p p e n di x 2 
St u d y 
G o v er n a n c e
U n d er st u d y a d mi ni s tr ati v e s e cti o n, d el et e d 
“( sit e s i n N ort h A m eri c a will o nl y b e 
i n cl u d e d if C o h ort B i s i niti at e d)”
A p p e n di x 6 
Cli ni c al 
L a b or at or y 
T e st s
A d d e d p h o s p h or u s t o bi o c h e mi str y 
p ar a m et er s f or a s s e s s m e nt.
H e alt h a ut h orit y f e e d b a c k i n t h e st u d y 
m o nit ori n g pl a n t o i n cl u d e a s s e s s m e nt of 
p h o s p h or u s i n t h e bi o c h e mi str y p a n el .
D oc u me nt N o. 
O bject N o. 
C CI
C CI


M S C 2 1 5 6l 1 9 J, M S B 0 0I 0 4 4 2 D 
M S 2 0 2 2 0 2- 0 0 0 2 
P h as e n si n gl e a r m st u d y oft e p oti ni b c o m bi n e d wit h 
c et u xi m a b 
A p p e n di x 1 0 
St u d y Title: 
S p o ns o r Si g n at u r e P a g e 
A 
P hase II si n gl e- ar m st u d y t o i n v esti g at e t e p oti ni b 
c o m bi n e d wit h 
c et u xi m a b i n R A SI B R A F 
wil d-t y p e 
l eft-si de d m et ast ati c c ol or e ct al c a n c er ( m C R C) p ati e nts 
h a vi n g 
a c q uir e d 
r esist a n c e t o a nti- E G F R a nti b o d y 
t ar g eti n g 
t h er a p y 
d u e 
t o 
M E T 
a m plifi c ati o n 
(P E R S P E C TI V E) 
R e g ul at o r y 
A g e n c y 
I d e ntif yi n g E u dr a C T: 2 0 2 0- 0 0 1 7 7 6- 1 5 
N u m b e rs: 
I N D: 
 
Cli ni c al St u d y P r ot o c ol Versi o n: 
0 8 M ar 2 0 2 1 N ersi o n 2. 0 
Si g n at ur e 
N a m e, a c a d e mi c de gree: 
F u n cti o n/fitl e: 
I nstit uti o n: 
A d d r ess: 
T el e p h o n e n u m ber: 
F a x n u m ber: 
E- m ail a d d r ess: 
D or u m c nl N o . 
 
O bj e ct N o . 
 
D at e of Si g n at ur e 
 
Me dical Dir e ct or 
M er c k H e alt h c ar e K G a A 
Fr a n kf urt er Str. 2 5 0 
D ar mst a dt, G er m a n y 
 
N ot A p pli c a bl e 
 
C O N fl D E N TI Al 
I NI O R M A TI O N 
1 1 3/ 1 1 5 
C CI
P P D
P P D
P P D
P P D
P P D
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D 
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 4/ 1 1 5
A p pe n di x 1 1  
C o or di n ati n g I n vesti g at or Si g n at ure P a ge
St u d y Title:
A P hase II si n gle-ar m st u d y t o i n vesti gate te p oti ni b 
c o m bi ne d 
wit h cet u xi ma b i n R A S /B R A F
wil d-t y pe 
left-si de d metastatic c ol orectal ca ncer ( m C R C) patie nts 
ha vi n g ac q uire d resista nce t o a nti- E G F R a nti b o d y 
tar geti n g 
t hera p y 
d ue 
t o 
M E T
a m plificati o n
( P E R S P E C TI V E)
Re g ul at or y A ge nc y I de ntif yi n g 
N u m bers:
E u dra C T: 2 0 2 0- 0 0 1 7 7 6- 1 5
I N D: 
Cli nic al St u d y Pr ot oc ol Versi o n:
0 8 Mar 2 0 2 1/ Versi o n 2. 0
Site N u m ber:
I a p pr o ve t he desi g n of t he cli nical st u d y, 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 a p pr o ve d pr ot oc ol 
a me n d me nts, I nter nati o nal C o u ncil o n Har m o nisati o n G o o d Cli nical Practice ( T o pic E 6) a n d all 
a p plica ble Healt 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. 
0 9- M A R- 2 0 2 1
C CI
P P D
P P D
C CI
C CI


M S C 2 1 5 6 1 1 9 J,
M S B 0 0 1 0 4 4 2 D
P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h
M S 2 0 2 2 0 2- 0 0 0 2
cet u xi m a b
C O N F I D E N T I A L
I N F O R M A T I O N
1 1 5 / 1 1 5
A p pe n di x 1 2
Pri nci p al I n vesti g at or Si g n at ure P a ge
St u d y Title:
A P hase II si n gle-ar m st u d y to i n vesti gate te p oti ni b 
c o m bi ne d wit h cet u xi ma b 
i n R A S /B R A F
wil d -t ype 
left-si de d metastatic c ol orectal ca ncer ( m C R C) patie nts 
ha vi n g 
ac q uire d resista nce t o a nti-E G F R 
a nti b o d y 
tar geti n g 
t hera p y 
due 
t o 
M E T
a m plificati o n
( P E R S P E C TI VE)
Re g ul at or y 
A ge nc y 
I de ntif yi n g 
N u m bers:
E u dra C T: 2 0 2 0 - 0 0 1 7 7 6- 1 5
I ND: 
Cli nic al St u d y Pr ot oc ol Versi o n:
0 8 Mar 2 0 2 1 / 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 a p pr o ve d pr ot oc ol a me n d me nts, I nter nati o nal C o u ncil 
o n 
Har m o nisati o n 
G o o d 
Cli nical 
Practice ( T o pic E 6) a n d all a p plica ble Healt h 
A ut h orit y 
re q uire me nts a n d nati o nal la ws.
I als o u n dersta n d t hat Healt h A ut h orities ma y  re q uire the S p o ns ors of cli nical st u dies t o o btai n a n d 
s u p pl y details a b o ut o w ners hi p i nterests i n t he S p o ns or or I n vesti gati o nal Me dici nal Pr o d uct a n d 
a n y ot her fi na ncial ties wit h t he S p o ns or. T he S p o ns or will use a n y s uc h i nf or mati o n s olel y for 
c o m pl yi n g wit h t he re g ulat or y re q uire me nts. T heref ore, I a gree t o s u p pl y the S p o ns or wit h a n y 
necessar y  inf or mati o n re gar di n g o w ners hi p i nterest a n d fi na ncial ties i ncl u di n g t h ose of m y  sp o use 
a n d de pe n de nt c hil dre n, a n d t o pr o vi de u p dates as necessar y  to meet 
Healt h 
A ut h o rity 
re q uire me nts.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Si g nat ure
Date of Si g nat ure
N a me, ac a de mic de gree:
F u ncti o n/ Title:
I nstit uti o n:
A d dress:
Tele p h o ne n u m ber:
F a x n u m ber:
E- m ail a d dress:
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI

SAP_001.pdf: 
M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D       P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi m a b
M S 2 0 2 2 0 2 _ 0 0 0 2
v 1. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 6 1
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 2 2 0 2 _ 0 0 0 2
Title
A P hase II si n gle-ar m st u d y to i n vesti gate te p oti ni b c o m bi ne d wit h 
cet u xi ma b i n R A S/ B R A F
wil d -t ype left-si de d metastatic c ol orectal 
ca ncer ( m C R C) patie nts ha vi n g ac q uire d resista nce t o a nti-E G F R 
a nti b o d y tar geti n g t hera p y d ue t o M E T a m plificati o n
St u d y P h ase
II 
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)
Te p oti ni b i n c o m bi nati o n wit h cet u xi ma b
Cli nic al St u d y Pr ot oc ol 
Versi o n
2 7 A pril 2 0 2 0/ Versi o n 1. 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
, Merc k K Ga A
F u ncti o n
A ut h or(s) / D at a A n al yst(s)
, Merc k
K Ga A
I nte gr ate d A n al ysis Pl a n
D ate a n d Versi o n
1 0 Mar 2 0 2 1 / Versi o n 1. 0
I nte gr ate d A n al ysis Pl a n 
Re vie wers
F u ncti o n
N a me
, Merc k
K Ga A
, Merc k
K Ga A
Me dical Lea d , Merc k K Ga A
, Merc k K Ga A
 
, Merc k K Ga A
, Merc k K Ga A
, Merc k
, Merc k K Ga A
, Merc k K Ga A
, Merc k
, Merc k K Ga A
, Merc k K Ga A
m 
 Merc k K Ga A
Cli nical Trial Lea d , E M D Ser o n o
C o nfi de nti al
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut e x press 
per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate. 
C o p yri g ht © 2 0 2 0 b y Merc k 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. 
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 C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D       P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi m a b
M S 2 0 2 2 0 2 _ 0 0 0 2
v 1. 0
C O N F I D E N T I A L
I N F O R M A T I O N
2/ 6 1
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 2 2 0 2 _ 0 0 0 2
A P hase II si n gle -ar m st u d y t o i n vesti gate te p oti ni b c o m bi ne d wit h cet u xi ma b i n R A S/ B R A F wil d -
t ype left-si de d metastatic c ol orectal ca ncer ( m C R C) patie nts ha vi n g ac q uire d resista nce t o a nti -E G F R 
a nti b o d y tar geti n g t hera p y d ue t o M E T a m plificati o n.
A p pr o val of t he I A P b y  all Merc k 
Data A nal y sis Res p o nsi ble has t o be 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, t he Merc k res p o nsi ble f or eac h of t he a nal ys es 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 uately.
B y  usi n g e Si g nat ure, t he si g nat ure will a p pear at t he e n d of t he d oc u me nt.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
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1
Table of Contents
Approval Page
..............................................................................................................2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................6
3
Modification History ............................................................................9
4
Purpose of the Integrated Analysis Plan...............................................9
5
Objectives and Endpoints ...................................................................10
6
Overview of Planned Analyses...........................................................11
6.1
Analyses for SMC meetings ...............................................................11
6.2
Interim analysis for futility.................................................................12
6.3
Primary analysis..................................................................................12
6.4
Final analysis ......................................................................................12
7
Changes to the Planned Analyses in the Clinical Study Protocol ......12
7.1
COVID-19 Impact ..............................................................................12
8
Analysis Populations and Subgroups..................................................13
8.1
Definition of Analysis Populations.....................................................13
8.2
Subgroup Definition and Parameterization ........................................15
9
General Specifications for Data Analyses ..........................................17
9.1
Data Handling After Cut-off Date ......................................................19
9.2
Definition of Baseline and Change from Baseline .............................19
9.3
Study Day / Study Treatment Day......................................................19
9.4
Definition of Duration and ‘time since’ Variables .............................20
9.5
Conversion Factors.............................................................................20
9.6
Date of last Contact ............................................................................20
9.7
Definition of On-treatment Period......................................................21
9.8
Imputation of Missing Data................................................................21
9.9
Tumor Evaluation and Adjudication ..................................................25
10
Study Participants ...............................................................................25
10.1
Disposition of Participants and Discontinuations...............................25
10.2
Protocol Deviations / Exclusion from Analysis Populations..............26
10.2.1
Important Protocol Deviations............................................................26
10.2.2
Reasons Leading to the Exclusion from an Analysis Population.......27
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11
Demographics and Other Baseline Characteristics.............................27
11.1
Demographics.....................................................................................28
11.2
Medical History ..................................................................................29
11.3
Disease History...................................................................................29
11.4
Baseline Tumor Assessment...............................................................29
11.5
Prior Anti-Cancer Therapy .................................................................30
11.6
Other Baseline Characteristics............................................................31
12
Previous or Concomitant Medications/Procedures.............................32
13
Study Treatment: Compliance and Exposure .....................................33
14
Efficacy Analyses ...............................................................................36
14.1
Primary Endpoint (Overall Study): Objective Response....................37
14.1.1
Derivation and analysis.......................................................................37
14.1.2
Sensitivity Analyses............................................................................39
14.1.3
Futility Analysis..................................................................................39
14.1.4
Subgroup Analyses .............................................................................39
14.2
Secondary Endpoints ..........................................................................39
14.2.1
Duration of Response .........................................................................39
14.2.2
Progression Free Survival...................................................................41
14.2.3
Overall Survival..................................................................................43
14.2.4
Immunogenicity..................................................................................44
14.2.5
Subgroup Analyses .............................................................................44
14.3
Tertiary/Exploratory Endpoint............................................................45
15
Safety Analyses ..................................................................................45
15.1
Primary Endpoint (Safety Run-in): Occurrence of DLTs...................45
15.2
Secondary Endpoints ..........................................................................46
15.2.1
Adverse Events ...................................................................................46
15.2.2
All Adverse Events.............................................................................47
15.2.3
Adverse Events Leading to Discontinuation / Dose Reduction of Study 
Treatment............................................................................................48
15.3
Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events .................................................................................................49
15.3.1
Deaths .................................................................................................49
15.3.2
Serious Adverse Events......................................................................50
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15.3.3
Other Significant Adverse Events ......................................................50
15.4
Clinical Laboratory Evaluation...........................................................50
15.5
Vital Signs ..........................................................................................54
15.6
Other Safety or Tolerability Evaluations............................................55
15.6.1
ECOG Performance Status .................................................................55
15.6.2
Electrocardiogram (ECG)...................................................................55
16
Analyses of Other Endpoints..............................................................56
16.1
Pharmacokinetics................................................................................56
16.2
Pharmacodynamics.............................................................................57
16.3
Patient Reported Outcome..................................................................57
17
References...........................................................................................58
18
Appendices .........................................................................................59
18.1
Appendix 1 – NCI-CTC Gradable and Non-Gradable Safety 
Laboratory Test Parameters and Direction(s) of Abnormality...........59
18.2
Appendix 2 – Correspondence between TNM classification, clinical 
stage and subgroup level.....................................................................61
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2
List of Abbreviations and Definition of Terms
2L
2nd Line
3L+
3rd Line +
ACCRU
Academic and Community Cancer Research United
ADA
Anti-Drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline phosphatase
ALT
Alanine transaminase
AST
Aspartate transaminase
ATC
Anatomical Therapeutic Chemical classification 
BMI
Body Mass Index
BOR
Best Overall Response
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CDISC
Clinical Data Interchange Standards Consortium
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence Interval
COVID-19
Coronavirus disease 2019
CR
Complete Response
(e)CRF
(electronic) Case Report Form
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
CV
Coefficient of variation
DLT
Dose Limiting Toxicity
DoR
Duration of Response
ECG
Electrocardiogram
ECOG
Eastern Co-operative Oncology Group
EGFR
Epidermal growth factor receptor
FAS
Full Analysis Set
FLC
Free Light Chain
FU
Follow-up
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GFR
glomerular filtration rate
ICH
International Conference on Harmonization
IAP
Integrated Analysis Plan
ICH
International Conference on Harmonization
IPD
Important Protocol Deviation
IRC
Independent Review Committee
LLN
Lower Limit of Normal
LLOQ
Lower limit of quantification
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MRI
Magnetic Resonance Imaging
NA
Not Applicable
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse
Events
OR
Objective Response
ORR
Objective Response Rate
PD
Progressive Disease 
Pd 
Pharmacodynamics
PFS
Progression Free Survival
PR
Partial Response
PT
Preferred Term
PK
Pharmacokinetics
PP
Per Protocol
QD
Once Daily
PR
Partial Response
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommend Phase II Dose
SAE
Serious Adverse Event
SAF
Safety
SCR
Screening analysis population
SD
Stable Disease
StDev
Standard Deviation
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SDTM
Study Data Tabulation Model
SI
International System of Units 
SMC
Safety Monitoring Committee
SOC
System Organ Class
TEAE
Treatment-Emergent Adverse Event
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary 
Document No. 
Object No. 


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D       P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi m a b
M S 2 0 2 2 0 2 _ 0 0 0 2
v 1. 0
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 6 1
3
M o dific ati o n Hist or y
U ni q ue
I de ntifier f or
Versi o n
D ate of
I A P Versi o n
A ut h or
C h a n ges fr o m t he Pre vi o us Versi o n
1. 0
1 0 Mar 2 0 2 1
First versi o n
4
P ur p ose of t he I nte gr ate d A n al ysis Pl a n
T he p ur p ose of t his I nte grate d A nal ys is Pla n (IA P) is t o d oc u me nt tec h nical a n d detaile d s pecificati o ns 
f or all t he a nal yses of data c ollecte d f or pr ot oc ol M S 2 0 2 2 0 2 _ 0 0 0 2. 
Res ults of t he a nal y ses descri be d i n t his I A P will be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R) or i n 
se parate re p orts. A d diti o nall y , t he pla n ne d a nal ys es i de ntifie d i n t his I A P ma y  be i ncl u de d i n re g ulat or y 
s u b missi o ns or f ut ure ma n uscri pts. A n y p ost-h oc, or u n pla n ne d a nal ys es perf or me d t o pr o vi de res ults 
f or i ncl usi o n i n t he C S R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y i de ntifie d i n t he C S R.
T he I A P is base d u p o n S ecti o n 9 ( Statistic al c o nsi derati o ns) of t he P r ot oc ol versi o n 1. 0 date d 2 7 A pril 
2 0 2 0 a n d is pre pare d i n c o m plia nce wit h IC H E 9. It descri bes a nal ys es pla n ne d i n t he pr ot oc ol .
Details o n o ut p uts use d t o s u p p ort re vie w of t he st u d y by a  Safet y M o nit ori n g C o m mittee ( S M C) d uri n g 
t he safety r u n -i n peri o d are a vaila ble i n t he S M C C harter.
D oc u me nt N o. 
O bject N o. 
P P D


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D       P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi m a b
M S 2 0 2 2 0 2 _ 0 0 0 2
v 1. 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 /6 1
5
O bjecti ves a n d E n d p oi nts
S afet y R u n -i n
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
I A P secti o n
Pri m ar y
T o c o nfir m t he rec o m me n de d P hase II d ose ( R P 2 D) 
of te p oti ni b w he n use d i n c o m bi nati o n wit h 
cet u xi ma b
Occ urre nce of d ose li miti n g t o xicities 
( D L Ts)
Secti o n  1 5. 1
O ver all St u d y
O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
I A P secti o n
Pri m ar y
T o e val uate t he preli mi nar y efficac y of te p oti ni b 
( R P 2 D) i n c o m bi nati o n wit h cet u xi ma b i n ter ms of 
t u m or res p o nse
O bjecti ve res p o nse ( O R, c o nfir me d 
c o m plete res p o nse [ C R] or partial res p o nse 
[ P R]) deter mi ne d acc or di n g t o R E CI S T 
Versi o n 1. 1 assesse d b y t he I n vesti gat ors
Secti o n  1 4. 1
Sec o n d ar y
T o f urt her e val uate t he efficac y of t he c o m bi nati o n of 
te p oti ni b ( R P 2 D) a n d cet u xi ma b i n ter ms of
d urati o n of res p o nse ( D o R)
D o R ( m o nt hs) acc or di n g t o R E CI S T 
Versi o n 1. 1 assesse d b y t he I n vesti gat ors.
Secti o n  1 4. 2. 1
pr o gressi o n -free s ur vi val ( P F S)
P F S ( m o nt hs) acc or di n g t o R E CI S T 
Versi o n 1. 1 assesse d b y t he I n vesti gat ors.
Secti o n  1 4. 2. 2
o verall s ur vi val ( O S)
O S ( m o nt hs) assesse d b y t he I n vesti gat ors.
Secti o n  1 4. 2. 3
T o e val uate t he safet y a n d t olera bilit y of te p oti ni b i n 
c o m bi nati o n wit h cet u xi ma b

Occ urre nce of A d verse E ve nts ( A E) 
a n d treat me nt-relate d A Es

Occ urre nce of cli nicall y si g nifica nt 
c ha n ges i n vital si g ns, la b orat or y 
para meters a n d 1 2 -lea d 
electr ocar di o gra m ( E C G) fi n di n gs
Secti o n  1 5
T o c haracterize t he i m m u n o ge nicit y of cet u xi ma b
I m m u n o ge nicit y of cet u xima b as meas ure d 
b y a nti dr u g a nti b o d y ( A D A) assa ys o n Da y 
1 C ycle 1 a n d E n d of Treat me nt Visit
Secti o n  1 4. 2. 4
D oc u me nt N o. 
O bject N o. 
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D       P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi m a b
M S 2 0 2 2 0 2 _ 0 0 0 2
v 1. 0
C O N F I D E N T I A L
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O bjecti ves
E n d p oi nts ( O utc o me Me as ures)
I A P secti o n
6
O ver vie w of Pl a n ne d A n al yses
T his I AP c o vers t he a nal yses f or efficac y, safety, 
a n d 
 data t o be perf or me d f or t he 
pri mar y  an d fi nal a nal ys es. M ore details a b o ut eac h
ecific a nal ys is are pr o vi de d i n t he s u bsecti o ns 
bel o w. 
Statistical a nal yses will be perf or me d o n t he basis of C DI S C S D T M data. T hese S D T M data c o ntai n 
as clea n as p ossi ble e C R F data as well as e xter nal data i ncl u di n g la b orat or y data, bi o mar ker data, a n d
t u m or assess me nt res ults b y  I n vesti gat or.
A data re vie w meeti n g will be hel d pri or t o a n y data base l oc k. I n a d diti o n, n o data base ca n be l oc ke d 
u ntil t his I A P has bee n a p pr o ve d.
6. 1
A n al yses f or S M C meeti n gs
T he pri mar y  safety e n d p oi nt (i.e. t he occ urre nce of D L Ts d uri n g t he first treat me nt c y cle of t he safet y 
ru n- i n peri o d) will be e val uate d d uri n g S M C meeti n gs a n d base d o n partici pa nt pr ofiles. M ore details 
are pr o vi de d i n t he S M C C harter.
T he Safet y  Mo nit ori n g C o m mittee ( S M C) will deci de o n d ose escalati o n, d ose de -escalati o n, e x pa nsi o n 
of t he c urre nt d ose le v el, or s us pe nsi o n of e nr oll me nt base d o n safet y a n d , if a vaila ble, P K data. I n t he 
safety r u n-i n peri o d, at least 6 treate d partici pa nts o n a d ose le vel are re gar de d as necessar y t o c o nfir m 
t he R P 2 D of te p oti ni b . C o h orts of 3 partici pa nts will be e nr olle d. S M C meeti n gs will ta ke place after 3 
treate d partici pa nts wit hi n a d ose -s pecific c o h ort c o m plete d t he first c ycle. On re q uest a d diti o nal S M C 
meeti n gs mi g ht ta ke place. Partici pa nts w h o are n ot D L T e val ua ble will be re place d. O nce all 
partici pa nts of t he res pecti ve d ose -s pecific c o h ort ha ve c o m plete d t he D L T peri o d or disc o nti n ue d fr o m 
trial pre mat urely, a data s na ps h ot will be ta ke n f or pr o visi o n of S M C partici pa nt pr ofiles . T here will be 
n o data c ut - off a p plie d. 
T he S M C will deci de a n d c o nfir m t he rec o m me n de d P hase II d ose ( R P 2 D) of te p oti ni b t o be use d i n 
c o m bi nati o n wit h cet u xi ma b. T he S M C m a y  als o deci de t o re d uce t he te p oti ni b d ose t o 2 5 0 m g  QD 
base d o n t he data c ollecte d d uri n g t he safet y  r u n-i n a n d f or t he w h ole st u d y.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
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6.2
Interim analysis for futility
A futility analysis will be performed after the first 12 participants are enrolled for second line (2L) 
treatment (Cohort A). The date 13 weeks after the first dose date (the scheduled time point of the second 
scan, C5D1, including a time window of 7 days) of the 12th patient enrolled will be used here as cut-
off date. Recruitment of further participants into this study, both cohorts, will continue. If there are less 
than 2 responders (confirmed CR or PR) within the first 12 participants treated with RP2D, the 
enrolment of 2L participants for this study might be stopped for futility.
6.3
Primary analysis
The primary analysis will be the main analysis that is planned around 5 months after last participant
first dose.
6.4
Final analysis
The final analysis will be performed after end of study. An extract of the primary analysis as specified 
in the table of contents for TFLs will be created for the follow-up analysis after database lock. 
7
Changes to the Planned Analyses in the Clinical Study Protocol
7.1
COVID-19 Impact
No changes to the planned analysis of the efficacy or safety endpoints are planned due to the impact of 
Coronavirus disease 2019 (COVID-19) outbreak. Sensitivity analyses may be considered depending 
on the observed COVID-19 findings.
Additional outputs (summary table and listing) will be generated for a description of the impact by 
COVID-19 on the study. The number and percentage of participants will be presented for the following 
findings due to COVID-19:

Potentially affected by COVID-19

Adverse Events 

Protocol deviations (important and non-important)

Missed Visits (including number of missed visits)

Missed efficacy evaluations (including number of missed efficacy evaluations)

Tele-visits performed (including number of tele-visits) 

Drug administration - missed doses
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
Drug administration - dose adjustments

Laboratory testing performed by external laboratory unit (only if at least 10 participants are 
affected)

Treatment discontinuation (of cetuximab and/or tepotinib)

Study discontinuation

Death
Potentially affected participants (either due to infection or due to circumstances of social distancing 
affecting the capabilities of sites/hospitals etc.) are defined as:
a) Participants who started treatment after start of the COVID-19 pandemic, or
b) Participants who started treatment prior to start of the COVID-19 pandemic and had tumor 
assessments planned after the start of the pandemic (i.e., did neither have progressive disease, 
died or withdrew from tumor assessments prior to start of the pandemic).
A frequency table will be produced for the Safety Analysis Set to present the number of participants 
with important protocol deviations related to COVID-19 (categorized by frequency of participants with 
an important protocol deviation overall as well as by category of protocol deviation and type of protocol 
deviation). A separate table for the non-important protocol deviations related to COVID-19 
(categorized by frequency of subjects with a non-important protocol deviation overall as well as by 
category of protocol deviation) will also be produced.
In addition, separate listings of COVID-19 related adverse events and protocol deviations will also be 
produced.
Outputs related to disposition and exposure will be amended to present reason of treatment/study 
discontinuations due to COVID-19 and treatment delays due to COVID-19 (if possible). 
Laboratory results performed by external laboratory units will be included in the summary statistics 
and shift analyses, provided that normal ranges are not missing; if they are missing, results will be listed 
and included in summary statistics outputs only. 
8
Analysis Populations and Subgroups
8.1
Definition of Analysis Populations
The analysis populations are specified below. The final decision to exclude participants from any 
analysis population will be made during a data review meeting prior to database lock.
Screening Analysis Set (SCR)
The Screening analysis set includes all participants, who provided informed consent, regardless of the 
participant’s study intervention status in the study.
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Full Analysis Set (FAS)/ Safety Analysis Set (SAF)
These analysis sets will include all participants, who were administered at least one dose of any study 
intervention.
Dose Limiting Toxicity Analysis Set (DLT)
The Dose Limiting Toxicity analysis set (DLT) will include all participants who received at least one 
dose of study treatment in the safety run-in period and meet at least one of the following criteria:

Received at least 75% of the tepotinib and cetuximab planned dose and complete the DLT period 
(3 weeks after start of treatment with study intervention). 

Experienced a DLT during the DLT period, regardless of the received amount of each study 
intervention.
Pharmacokinetics Analysis Set (PKAS)
The pharmacokinetics analysis set will include all participants, who received at least one dose of study 
intervention, have no relevant protocol deviations or important events affecting PK, and provide at least 
one measurable post-dose concentration. Participants will be analyzed per the actual study intervention 
they received.
Immunogenicity Analysis Set (IMAS)
All participants who receive at least one dose of study intervention and have at least one valid ADA 
result. Participants will be analyzed per the actual study intervention they received.
Analyses per Analysis Set 
The following table summarizes the use of the analysis sets in the different analyses. 
Analysis Set
Analyses
DLT
FAS
SAF
PK
IMAS
DLT

Baseline Characteristics

Previous and Concomitant 
Therapies

Compliance and Exposure

Efficacy: Primary 

Efficacy: Secondary 

Safety and Tolerability

PK

Immunogenicity

DLT = Dose Limiting Toxicity; FAS = Full Analysis Set; SAF = Safety Analysis Set; PK = Pharmacokinetics; IMAS = 
Immunogenicity Analysis Set.
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All safety analyses will be presented by cohort and dose level, if applicable. Efficacy analyses will be 
done by cohort and assigned dose level of tepotinib.
For more details see Section 0 General Specifications for Data Analyses.
8.2
Subgroup Definition and Parameterization
Subgroup analyses will be performed on the primary efficacy endpoint OR and the secondary efficacy 
endpoints DoR/PFS/OS as defined in Table 1. All subgroup analyses will be exploratory, no adjustment 
for multiplicity will be performed. Endpoints for which subgroup analyses will be performed can be 
found in Section 14. In case of low number of participants within a subgroup level (< 5 participants), 
levels will be pooled when meaningful.
For the definition of subgroup levels, data as documented in the electronic case report form (eCRF) or 
provided in the SDTM datasets will be taken. The category “missing” will not be included in any 
subgroup analysis. 
Table 1.   Subgroups 
Subgroup
Subgroup level
Definition/ Derivation
Treatment line

2nd line (Cohort A)

3rd line

4th line

5th + line
CRF: 
PRIOR 
ANTI-
CANCER 
DRUG 
THERAPIES DETAILS: 
Regimen number
Site location
(Cohort B)

ACCRU sites

Other US sites
Mutations in the extracellular domain 
of EGFR

Yes

No
The following mutations 
are of relevance and 
should be taken into 
account:  F404, T414, 
V441, S442, I462, S464, 
G465, K467, K489, I491, 
S492
MET amplification
(if available)

Focal

Non-focal
MET amplification

Liquid

Tissue
CRF: TISSUE BIOPSY 
FOR MET 
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AMPLIFICATION: MET 
amplification result
Prior EGFR therapy

Panitumumab

Cetuximab
Time since last EGFR therapy in 
months

1

2

> 2
HGF protein expression level
(if available)

< median

≥ median
Age group

< 65 years

≥ 65 years
Race

White

Black 
or 
African 
American

Asian

Not collected at this site

Other
White
Black or African 
American
Asian
Other (including 
American Indian or 
Alaska Native and 
Native Hawaiian or 
Other Pacific 
Islander)
“Not collected at this 
site” will be handled as 
missing
Sex

Male

Female
Brain metastases at baseline

Present

Absent
ECOG at baseline

0

1
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9
General Specifications for Data Analyses
This section describes any general specifications not included in subsequent sections. 
Study treatment and study treatment component:
Participants will receive tepotinib (RP2D mg daily) in combination with cetuximab (loading dose 
(where required) 400 mg/m2, followed by or starting with weekly infusions at a dose of 250 mg/m2).
In this IAP, “study treatment” will be used to indicate the combination of tepotinib and cetuximab; 
“study treatment component” will be used to refer to tepotinib or cetuximab.
Study treatment start date:
For each participant, the “start date” of this study is the date of first administration of the study 
treatment. If, for any reason, the first administration of tepotinib and cetuximab does not happen on the 
same day, the date of administration of the first study treatment component taken should be considered 
as the “start date”. 
Study treatment end date:
The last tepotinib and cetuximab administration dates are collected on the “Tepotinib Termination” and 
“Cetuximab Termination” eCRF pages. These should be considered the dates of permanent 
discontinuation of tepotinib and cetuximab respectively.
The end of study treatment will be the last study tepotinib administration date or the last study 
cetuximab administration date, whichever comes later.
Dose Level:
As stated in Section 6.1, the SMC will decide whether the tepotinib 500 mg dose level is considered 
safe or if the 250 mg dose level should be used instead. Cetuximab will be administered as intravenous 
infusion as detailed in protocol Section 6.1.
Cohort:
Cohort A – includes participants outside of US for 2L treatment.
Cohort B – includes US participants for 3L+ treatment.
Presentation of analysis results:
Unless stated otherwise, for disposition, baseline characteristics (e.g. demographics, medical history, 
disease history, etc.), previous and concomitant medications and procedures, results will be presented 
by cohort, by assigned dose level of tepotinib and overall.
For efficacy analyses, results will be presented by cohort and assigned dose level of tepotinib.
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Exposure and safety will be presented by cohort and dose level, if applicable, and overall.
Presentation of continuous and qualitative variables:
Continuous variables other than PK will be summarized using descriptive statistics, i.e. 

number of participants with non-missing values (n) 

mean, standard deviation (StDev)

median, 25th percentile - 75th percentile (Q1-Q3)

minimum, maximum
Mean, median, Q1, Q3, Min, and Max will have the same precision as collected in SDTM datasets for 
non-derived data. Standard deviation will be presented with one digit more than the mean. Percentage 
and percent change from baseline will be reported using one decimal digit, if not specified otherwise. 
Derived data such as duration and “time since” variables (see Section 9.4) will be displayed with one 
decimal digit, unless stated otherwise.
If there are no missing values, the number of participants with missing values should be indicated by a 
0.
Qualitative variables will be summarized by frequency counts and percentages. Unless otherwise stated 
the calculation of proportions will be based on the number of participants in the analysis set of interest. 
Therefore, counts of missing observations will be included in the denominator and presented as a 
separate category.
For variables where a participant may have more than one category due to multiple responses per 
participant, the number of participants included in each category will be summarized as a percentage 
from all participants. Therefore, the total frequency across categories may not equal the total number 
of all participants in that analysis group.
Scheduled and unscheduled visits
Data collected at both scheduled and unscheduled visits will be included in the derivation of safety and 
efficacy endpoints.
Unscheduled visits will be included in the derivation of baseline or worst on-treatment values. 
Descriptive statistics by nominal visit or time point, e.g. for laboratory measurements, will include only 
data from scheduled visits
Significance level:
There is no formal significance level for this study, and all analyses are considered descriptive.
There will be no statistical tests performed. If confidence or credibility intervals are mentioned, the 
level will be 95% unless otherwise specified.
Statistical software:
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All analyses will be performed using SAS® Software version 9.4 or higher.
9.1
Data Handling After Cut-off Date
By its nature, data after cut-off may be incomplete and subject to further change and will not be used 
for summary statistics, statistical analyses, listings or imputations. 
Stop dates are not affected by this rule, e.g. a stop date of AEs, which starts prior to the cut-off, but 
stops after date of cut-off, will not be changed.
These rules will be applied to all analyses performed for the interim analysis for futility and main 
analysis. For the final analysis no cut-off date will be applied: the analysis will be performed only after 
all the data have been collected, fully cleaned and the database has been locked.
9.2
Definition of Baseline and Change from Baseline
In general, the last non-missing measurement prior to the first study drug administration will be used 
as the baseline measurement.
If the assessment time of any pre-dose baseline assessments (as planned per protocol) and/or the time 
of initial dosing are unknown, but they are known to have been performed on the same day, it will be 
assumed that it was performed prior to dosing. Unscheduled assessments may be used in the 
determination of baseline; however, if the time of either the assessment or initial dose is missing, the 
unscheduled assessment will be considered to have been obtained after study treatment administration.
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding measurement 
will be analyzed similar to an unscheduled post-dose measurement.
Absolute and percent changes from baseline are defined as 
absolute change = post baseline value – baseline value
percent change = 100 * (post baseline value – baseline value) / baseline value
9.3
Study Day / Study Treatment Day
Day 1 is the day of start of study treatment, the day before is Day -1 (no Day 0 is defined). Study day / 
Study treatment day is defined relative to Day 1.
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9.4
Definition of Duration and ‘time since’ Variables
If not otherwise specified, duration will be calculated by the difference of start and stop date + 1 (e.g. 
survival time (days) = date of death – date of first study drug administration + 1). 
The time since an event (e.g. time since first diagnosis) will be calculated as reference date minus date 
of event.  
9.5
Conversion Factors
The following conversion factors will be used to convert days into weeks, months or years: 
1 week = 7 days, 1 month = 30.4375 days, 1 year = 365.25 days.
If height is recorded in inches, height (cm) = height (in) × 2.54.
If weight is recorded in pounds, weight (kg) = weight (lb) ÷ 2.2046.
9.6
Date of last Contact
The date of last contact will be derived for participants not known to have died at the analysis cut-off 
using the latest complete date prior to or at the data cut-off date among the following:

All participant assessment dates (blood draws (laboratory, PK), vital signs, performance 
status, ECG, tumor assessments, quality of life assessments)

Start and end dates of anti-cancer therapies administered after study treatment 
discontinuation.

AE start and end dates

Concomitant medication/procedures start and end dates

Last known to be alive date collected on the ‘Survival Follow-up’ eCRF 

Tepotinib and cetuximab administration start and end dates

Date of discontinuation on disposition eCRF pages (do not use if reason for discontinuation 
is lost to follow-up)
Only dates associated with actual examinations of the participant reported in the eCRF will be used in 
the derivation. Dates associated with a technical operation unrelated to participant status such as the 
date a blood sample was processed will not be used. Assessment dates after the cut-off date will not be 
applied to derive the last contact date. This rule is to be applied to AE stop dates, too: if an AE started 
before the cut-off date and ended after the cut-off date, only the complete start date will be used in the 
derivation of the last date of contact.  
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9.7
Definition of On-treatment Period
The on-treatment period is defined as the time from the first dose of study treatment day to the last 
administration day of study treatment + 30 days, or the cut-off date or death or the start day of 
subsequent anti-cancer drug therapy - 1 day, whichever occurs first.
9.8
Imputation of Missing Data
Unless otherwise specified all data will be evaluated as observed, and no imputation method for missing 
values will be used.
Imputed dates will be used for the calculation of durations.
In all participant data listings, imputed or censored values will be presented, and imputed or censored 
information will be flagged.
Missing statistics, e.g. when they cannot be calculated, should be presented as “nd”. For example, if 
n=1, the measure of variability (StDev) cannot be computed and should be presented as “nd”.
Where tables are presented over different time points, the total of missing and non-missing observations 
at each time-point should reflect the population still in the trial at that time. This does not apply when 
imputations are made beyond trial withdrawal. For example, if a participant is still in the trial at the 
time-point but with missing data, they should be counted in the number of missing observations.
The following rules for imputation will be considered:
Disease history
Incomplete dates for disease history (e.g. initial diagnosis date, date of documented, locally advanced, 
inoperable or metastatic disease diagnosis) will be imputed as follows:

If the day is missing, it will be imputed to the 15th day of the month. 

If both day and month are missing and the year is prior to the year of the first study treatment, 
the month and day will be imputed as July 1st.

If both day and month are missing and the year is same as the year of the first study 
treatment, the month and day will be imputed as January 1st. 

If the date is completely missing, no imputation will be performed.
Adverse events
Incomplete AE-related dates will be imputed as follows:

If the AE onset date is missing completely, then the onset date will be replaced by the start 
of study treatment.
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
If only the day part of the AE onset date is missing, but the month and year are equal to the 
start of study treatment, then the AE onset date will be replaced by the start of study 
treatment. For example, if the AE onset date is --/JAN/2015, and study treatment start date 
is 15/JAN/2015, then the imputed AE onset date will be 15/JAN/2015. If the end date or 
resolution date indicates that the AE has stopped before start of treatment, this date will be 
used for imputation instead of start of treatment date.

If both the day and month of the AE onset date are missing but the onset year is equal to the 
start of study treatment, then the onset date will be replaced by the start of study treatment. 
For example, if AE onset date is --/---/2014, and study treatment start date is 19/NOV/2014, 
then the imputed AE onset date will be 19/NOV/2014.

In all other cases the missing onset day or missing onset month will be replaced by 1.

Incomplete stop date will be replaced by the last day of the month (if day is missing only), 
if not resulting in a date later than the date of participant's death. In the latter case the date 
of death will be used to impute the incomplete stop date.  

In all other cases the incomplete stop date will not be imputed. If stop date of AE is after 
date of cut-off this date will be kept.
Previous and concomitant medication/procedure
For identification of previous or concomitant medications/procedures, no formal imputation will be 
performed on missing or incomplete dates. Rules presented in Table 2 and Table 3 will be used to 
define if a medication/procedure is considered as a previous, concomitant or both previous and 
concomitant medication/procedure.
Table 2
Stopping rules for medication/procedure end dates
End date of medication/procedure
Stopping rule
Day
Month
Year
UNK
UNK
UNK
After treatment start (ongoing)
UNK
UNK
< Treatment start (year)
Before treatment start
UNK
UNK
>= Treatment start (year)
After treatment start
UNK
< Treatment start (month and year)
Before treatment start
UNK
>= Treatment start (month and year)
After treatment start
< Treatment start (complete date)
Before treatment start
>= Treatment start (complete date)
After treatment start
UNK = Unknown
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Table 3
Rules to define previous and/or concomitant medication
Start date of medication/procedure
Stopping rule
(see Table 2)
Medication/procedure
Day
Month
Year
UNK
UNK
UNK
Before treatment 
start
Previous
UNK
UNK
UNK
After treatment 
start
Previous and concomitant
UNK
UNK
<= Treatment start (year)
Before treatment 
start
Previous
UNK
UNK
<= Treatment start (year)
After treatment 
start
Previous and concomitant
UNK
UNK
> Treatment start (year) 
and <= Treatment end + 
30 days (year)
After treatment 
start
Concomitant
UNK
<= Treatment start (month and year)
Before treatment 
start
Previous
UNK
<= Treatment start (month and year)
After treatment 
start
Previous and concomitant
UNK
> Treatment start (month and year) 
and <= Treatment end + 30 days 
(month and year)
After treatment 
start
Concomitant
<= Treatment start (date)
Before treatment 
start
Previous
<= Treatment start (date)
After treatment 
start
Previous and concomitant
> Treatment start (date) and <= Treatment end + 
30 days (date)
After treatment 
start
Concomitant
UNK = Unknown
Dates of study treatment
Start date of study treatments:

No imputation will be done.
End date of study treatments:

In case the last date of study drug is missing or incomplete the date of last administration of 
study drug will be taken from the treatment termination eCRF pages.

If the last date of study drug is completely missing and there is no End of Treatment eCRF 
page and no death date the participant should be considered to be ongoing and use the cut-
off date for the analysis as the last dosing date

If the last date of study drug is completely or partially missing and there is EITHER an End 
of Treatment eCRF page OR a death date available (within the cut-off date) then imputed 
last dose date is:
o
31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date)
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o
Last day of the month, if both Year and Month are available and Year = Year of min (EOT 
date, death date) and Month < the month of min (EOT date, death date)
o
min (EOT date, death date), for all other case
Death date
In general, missing or partial death dates will not be imputed. However, for the purpose of survival 
analyses, partially missing death dates will be imputed as follows: if only the day is missing, the death 
date will be imputed to the maximum of the (non-imputed) day after the date of last contact (see Section 
9.6) and the 15th day of the month.
Tumor assessments
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If there are multiple scan dates associated with an evaluation, i.e., radiological assessments occur over 
a series of days rather than the same day, the choice of date of assessment could impact the date of 
progression and/or date of response. If there are multiple scan dates associated with an evaluation, the 
earliest of the scan dates associated with the evaluation will be used as the date of assessment.
If one or more investigation dates for an evaluation are incomplete but other investigation dates are 
available, the incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the earliest of all investigation dates (e.g. X-ray, CT-scan).  
If all measurement dates for an evaluation have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations for an evaluation, the respective assessment 
will be considered to be at the date which is exactly between the previous and the following assessment. 
If both a previous and following assessments are not available, this assessment will not be used for any 
calculations.
Dates of subsequent anti-cancer therapy
Incomplete dates for start date of subsequent anti-cancer therapy (drug therapy, radiation, surgery) will 
be imputed as follows and will be used for determining censoring dates for efficacy related sensitivity 
analyses: 

If only day is missing, it will be imputed as the first day of the month unless it results in a 
date before the end date of study treatment. In that case, the incomplete anti-cancer therapy 
start date will be imputed as the end date of study treatment

If both day and month are missing, the incomplete anti-cancer therapy start date will be 
imputed as the end date of study treatment if the subsequent therapy started on the same 
year as the end of study treatment; otherwise day and month will be imputed as the 1st of 
January.
Incomplete subsequent anti-cancer therapy stop dates will not be imputed.
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9.9
Tumor Evaluation and Adjudication
Missing data from scheduled Tumor assessments not performed will not be imputed. Evaluable Tumor 
assessments are defined as those with overall response CR, PR, SD or PD. Data from non-evaluable 
(NE) Tumor assessments will be used in the derivation of endpoints in accordance with Eisenhauer et 
al., (2009). 
In case IRC assessments are performed only the response assessments which are flagged as accepted 
after adjudication will be taken over to ADaM datasets and will be analyzed. In case of a missing 
adjudication flag for a response assessment and earliest image dates are equal, the assessment of reader 
1 (the reader who completed baseline first) will be taken for analysis. Otherwise the assessment for the 
reviewer who reviewed the record with the earliest image date will be analyzed. Analyses of tumor 
sizes will be based only on assessments of the reader whose assessment was accepted at baseline.
10
Study Participants
The subsections in this section include specifications for reporting participant disposition and study 
treatment/study discontinuations. Additionally, procedures for reporting protocol deviations are 
provided.
10.1
Disposition of Participants and Discontinuations
The number and percentage of participants in each of the below disposition categories will be presented 
by cohort, by assigned dose level of tepotinib and overall. Percentages will be presented with respect 
to the number of participants in FAS/SAF analysis set. 
Participant disposition will be summarized as follows:

Number of participants in each analysis set (SCR, SAF, DLT, PKAS, IMAS)

Number of participants who discontinued from the study prior to treatment overall and 
grouped by the main reason (e.g. the failed specific inclusion or exclusion criteria, 
withdrawal of consent)
The end of treatment status will be summarized by:

Number of participants who received at least one dose of study treatment 

Number and percentage of participants who have permanently discontinued study treatment 

Number and percentage of participants with study treatment ongoing

Number and percentage of participants who did not receive tepotinib

Number and percentage of participants with tepotinib treatment ongoing
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
Number and percentage of participants who permanently discontinued tepotinib treatment 
(overall and by primary reason)

Number and percentage of participants who did not receive cetuximab

Number and percentage of participants with cetuximab treatment ongoing

Number and percentage of participants who permanently discontinued cetuximab treatment 
(overall and by primary reason)
The end of study status will be summarized by:

Number and percentage of participants with any study treatment ongoing

Number and percentage of participants off-treatment and in safety or survival follow-up

Number and percentage of participants who discontinued the study (overall and by primary 
reason)
For each participant in the FAS/SAF analysis set, the first and last dosing date for each study component 
(including reason for treatment discontinuation) and study discontinuation date (including reason for 
study discontinuation) will be listed. 
Additionally, the number of participants enrolled in each analysis population will be provided overall, 
by region, by country within region and by site. Results will be presented by cohort and by assigned 
dose level of tepotinib. This information will also be provided for each participant in the FAS/SAF 
analysis set in a listing.
Disposition of participants will be presented in a CONSORT Flow Diagram.
10.2
Protocol Deviations / Exclusion from Analysis Populations
10.2.1
Important Protocol Deviations
Important protocol deviations (IPDs) are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being.
Important protocol deviations include, but are not limited to:

Participants enrolled and dosed on the study who did not satisfy enrolment criteria

Participants who are not compliant with treatment: overdose, dose modifications not as per 
protocol, incorrect dose, etc.

Participants who receive a prohibited concomitant medication

Failure to collect data necessary to interpret primary endpoints

Failure to collect necessary key safety data

Deviation from Good Clinical Practice (GCP)
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
Any other protocol deviation that might significantly affect the completeness, accuracy, 
and/or reliability of the study data or that might significantly affect a participant's rights, 
safety, or well-being.
All important protocol deviations are documented in SDTM datasets whether identified for all 
participants by either medical review processes or programming and confirmed prior to or at the Data 
Review Meeting at the latest. 
The protocol deviations recorded in the Clinical Trial Management System (CTMS) may utilize 
different terminology. The table below displays how the terminology used in CTMS translates to the 
terminology used in the IAP, the SDTM and ADaM datasets, and ultimately the CSR:
CTMS
IAP
SDTM
ADaM
Non-important
Non-important (only for 
protocol deviations 
related to COVID-19)
Only protocol 
deviations related to 
COVID-19 are 
included
Only protocol 
deviations related to 
COVID-19 are 
included
Important
Important
Flagged with 
PDEVXXX code
Flagged with 
PDEVXXX code
Relevant
Relevant for PK 
Mapped to 
Important
Mapped to Important
A full list of potential protocol deviations including definition and categorization is maintained by 
Covance in the “Study Specific Protocol Deviation List” attached to the Protocol Deviation 
Management Plan.
A frequency table (split by deviations from the inclusion and exclusion criteria as well as all other 
deviations) and a listing of important protocol deviations will be provided based on the SAF analysis 
set. 
10.2.2
Reasons Leading to the Exclusion from an Analysis Population
Participants who have relevant protocol deviations or important events affecting PK will be excluded 
from PKAS. 
11
Demographics and Other Baseline Characteristics
Demographic data and other baseline characteristics will be presented for the FAS/SAF analysis set 
using summary statistics for continuous variables and frequency statistics (i.e. counts and percentages) 
for categorical variables. Results will be presented as indicated in Section 10.  
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Listings showing demographic data and other baseline characteristics will be presented for the FAS.
11.1
Demographics
Demographic characteristics will be summarized descriptively using the following information from 
the Screening/Baseline Visit eCRF pages.

Sex: male, female, undifferentiated

Race: white, black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or Other Pacific Islander, not collected at this site, more than one race, other, 
missing

Ethnicity:
o
Hispanic or Latino / Not Hispanic or Latino

Age (years)

Age categories:
o
< 65 years, 
o
≥ 65 years
o
65-74, 
o
75-84, 
o
≥85 years 

Pooled Regions: Europe, North America

Country (e.g.: Belgium, Czech Republic, France, Italy, Russia, Spain, United Kingdom, 
USA)
Specifications for computation:

Age [years]: 
o
Age = (01.JAN.YEAR informed consent date for screening – 01.JAN.YEAR of birthdate 
+ 1) / 365.25.
The integer part of the calculated age will be used for reporting purposes.

Site codes will be used for the determination of the participant’s pooled region and country.

Participants with more than one race will be summarized in the “more than one race” 
category. 
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11.2
Medical History
The medical history will be summarized from the “Medical History” eCRF page, using the most recent 
MedDRA version at time of database lock, preferred term as event category and system organ class 
(SOC). Each participant will be counted only once within each PT or SOC.
Medical history will be displayed in terms of frequency tables ordered by primary SOC in alphabetic 
order and PT in alphabetical order. 
A listing will be provided with SOC term, PT term, toxicity grade and whether related to the study 
condition.
11.3
Disease History
Information on disease history is collected during the screening visit on the “Disease History” eCRF 
page. Data will be summarized and listed as follows:

Site of Primary Tumor by International Classification of Diseases for Oncology (ICD-O) 
codes will be translated into text for presentation in outputs

Time since initial cancer diagnosis (years) = (date of start of study treatment – date of initial 
cancer diagnosis + 1) / 365.25

Time since documented locally advanced, inoperable or metastatic disease diagnosis (years) 
= (date of start of study treatment – date of documented locally advanced, inoperable or 
metastatic disease diagnosis + 1) / 365.25

Tumor histopathologic / cytologic type: Adenocarcinoma / Mucinous adenocarcinoma/ Not 
differentiated cancer/ Neuroendocrine tumor/ Other

Disease stage at initial diagnosis

Disease stage at study entry

TNM classification at initial diagnosis

TNM classification at study entry
Incomplete dates for initial cancer diagnosis and documented locally advanced, inoperable or metastatic 
disease diagnosis will be handled as specified in Section 9.8.
11.4
Baseline Tumor Assessment
Information collected by the Investigator on the baseline tumor assessment collected at the screening 
visit on the “Tumor Assessment (according to RECIST 1.1)” eCRF pages and “Sum of Diameters 
(according to RECIST 1.1)” eCRF page will be presented. Summaries will be presented for the 
following:
Document No. 
Object No. 


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
Target lesions (by investigator)
o
Number of target lesions 
o
Sum of diameters (sum of longest diameters for non-nodal lesions, short axis for nodal 
lesions) 
o
Type: Primary / Recurrence, Node, Metastasis
o
Site

Non-target lesions (by investigator)
o
Number of participants with at least one non-target lesion
o
Number of non-target lesions 
o
Type: Primary / Recurrence, Node, Metastasis
o
Site
Tumor information based on Investigator that is collected during the study will be listed.
11.5
Prior Anti-Cancer Therapy
The prior anti-cancer therapies are collected under the “Prior Anti-Cancer Drug Therapies Details”, 
“Prior Anti-Cancer Radiotherapy Details”, “Prior Anti-Cancer Surgeries Details”, “Previous EGFR 
Therapy” and “Previous EGFR Therapy Drugs” eCRF pages.
The number and percentage of participants in each of the following anti-cancer therapy categories will 
be tabulated:

Prior anti-cancer drug therapy for locally advanced or metastatic disease (anti-EGFR as 
prior drug therapy)
o
Number of prior anti-cancer drug therapy lines: 1 / 2 / 3 / 4 / ≥ 5 
o
Prior anti-cancer drug therapies 
o
Prior anti-cancer drug combinations
o
Best response across all prior anti-cancer drug therapies: Complete Response (CR) / 
Partial Response (PR) / Stable Disease (SD) / Progressive Disease (PD) / Non-Complete 
Response/Non-Progressive Disease (Non-CR/Non-PD) / Not Evaluable / Unknown 

Prior anti-cancer radiotherapy
o
Any prior anti-cancer radiotherapy: Yes / No
o
Number of prior anti-cancer radiotherapy regimen: 1 / 2 / 3 / ≥ 4 
o
Best response across all prior anti-cancer radiotherapies: Complete Response (CR) / 
Partial Response (PR) / Stable Disease (SD) / Progressive Disease (PD) / Non-Complete 
Response/Non-Progressive Disease (Non-CR/Non-PD) / Not Evaluable / Unknown.
Document No. 
Object No. 


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
Prior anti-cancer surgery 
o
Any prior anti-cancer surgery: Yes / No
o
Number of prior anti-cancer surgeries: 1 / 2 / 3 / ≥ 4 
o
Prior anti-cancer surgeries outcome
o
Any prior surgery curative in intent: Yes / No
o
Best outcome across all prior anti-cancer surgeries: No residual tumor after resection (R0) 
/ Tumor/metastases not resected completely with microscopic residual lesions (R1) / 
Tumor/metastases not resected completely with macroscopic residual lesions (R2) / 
Metastases not resected (NR), Other
The listings of prior anti-cancer treatments and procedures will also be provided as follows. These will 
include the participant identification number, and all the relevant collected data fields on the 
corresponding eCRF pages.

Listing of prior anti-cancer drug therapies 

Listing of prior anti-cancer radiotherapy 

Listing of prior anti-cancer surgeries
11.6
Other Baseline Characteristics
Information on other characteristics collected at baseline will be summarized and listed. Summary
statistics will be presented for

ECOG PS

Height, weight, body surface area (BSA), and body mass index (BMI)
Specifications for computation: 

BSA [m²] = 	
[]×	
[
]


BMI [kg/m²] = 
 []
[] × 10000

In the formula above, values at baseline should be used for both weight and height.
ECOG PS, height, weight, BSA and BMI will be added to the listing presenting demographic data. 
Other baseline characteristics such as vital signs, clinical laboratory evaluations and ECGs will be part 
of Section 15 (Safety Analyses).
Document No. 
Object No. 


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12
Previous or Concomitant Medications/Procedures
The following analyses will be performed based on the SAF analysis set and presented as indicated in 
Section 9.  
Concomitant medications are medications, other than study treatment, which are taken by participants 
any time during the on-treatment period, see Section 9.7.
Previous medications are medications, other than study treatment and pre-medications for study 
treatments, which started before first administration of study treatments. 
A medication may be classified as both concomitant and previous. The respective flags will be derived 
based on start and end date. To derive these flags in case of missing or partial dates, see Section 9.8. 
Concomitant and previous medications each will be summarized by number and percentage of 
participants from the “Concomitant Medications Details” eCRF page. ATC-2nd level and preferred term
level will be tabulated as given from the WHO-DD dictionary most current version. If any previous or 
concomitant medication is classified into multiple ATC classes, the medication will be summarized 
separately under each of these ATC classes. The summary tables will be sorted by ATC-2nd level and 
preferred term in alphabetical order. In case any specific medication does not have an ATC-2nd level 
coded term, it will be summarized under “UNCODED” ATC classification category. Each participant 
will only be counted once, even if he/she received the same medication at different times.
Any medication recorded on the “Concomitant Medications Details” eCRF page will be listed with an 
indication of whether the medication was previous, concomitant or both. 
All concurrent procedures, which were undertaken during the on-treatment period, will be 
summarized according to the “Concomitant Procedures Details” eCRF page. Concurrent procedures 
will be classified using the most recent MedDRA version at the time of analysis. 
A procedure will be considered concurrent if it started before the first dose of study treatment and was 
still ongoing when study treatment started or if it started after the first dose but during the on-treatment 
period. Number and percentage of participants with concurrent procedures will be presented by SOC 
and PT in descending frequency of the total column.  
A listing with the relevant information about concurrent procedures will also be produced. A flag will 
be added to indicate whether the procedure is:

Prior: the procedure started before the first dose of study treatment

Concurrent: as defined above  

Post: the procedure started after the on-treatment period or during the on-treatment period 
but was still ongoing at the end of it. 
A procedure could therefore be prior and concurrent as well as concurrent and post-treatment.
Document No. 
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Subsequent anti-cancer therapy
The subsequent anti-cancer therapies are collected under the “Anti-Cancer Treatment After 
Discontinuation Details”, “Radiotherapy after Discontinuation Details” and “Anti-Cancer Treatment 
After Discontinuation Details – Maximum Drugs” eCRF pages.
The number and percentage of participants in each of the following anti-cancer treatment categories 
will be tabulated:

Number of participants with subsequent anti-cancer treatment

Subsequent anti-cancer drug therapy 
o
Any subsequent anti-cancer drug therapy: Yes / No
o
Number of subsequent anti-cancer drug therapy lines: 1 / 2 / 3 / ≥ 4  
o
Type of therapy 
o
Intent of therapy: Metastatic/Locally advanced / Neoadjuvant / Adjuvant
o
Subsequent anti-cancer drugs 
o
Best response across all subsequent anti-cancer drug therapies: Complete Response (CR) 
/ Partial Response (PR) / Stable Disease (SD) / Progressive Disease (PD) / Non-Complete 
Response/Non-Progressive Disease (Non-CR/Non-PD) / Not Evaluable / Unknown. For 
participants who received more than one anti-cancer drug therapy after treatment 
discontinuation, the best overall response among all anti-cancer drug therapies will be 
summarized.

Subsequent radiotherapy
o
Any subsequent anti-cancer radiotherapy: Yes / No
The listings of subsequent anti-cancer treatments will also be provided as follows. These will include 
the participant identification number, and all the relevant collected data-fields on the corresponding 
eCRF pages.

Listing of subsequent anti-cancer drug therapies 

Listing of subsequent anti-cancer radiotherapy 
13
Study Treatment: Compliance and Exposure
All summaries and listings related to study treatment compliance and exposure will be based on the 
SAF analysis set.
All dosing calculations and summaries will be based on “Tepotinib Administration” and “Cetuximab
Administration” CRF pages. The date of last drug administration will be taken from the “Tepotinib 
Termination” and “Cetuximab Termination” eCRF pages for those participants who have discontinued 
treatment by the cut-off date whereas for those participants who are still on-treatment, the last dosing 
date before or at the cut-off date will be used. 
Document No. 
Object No. 


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The date of last study drug administration will be defined as the last date in the “Tepotinib
Administration” and “Cetuximab Administration” CRF pages, with dose > 0.
A dose of tepotinib will be regarded as being taken on a particular day if the actual dose of tepotinib 
taken is > 0 mg. Therefore, interruptions, compliance, and dose changes are not taken into account for 
the calculation of duration of therapy. The same would apply to cetuximab. 
The following summary tables will be provided:

Duration of therapy (weeks)

Total number of 3-week cycles

Cumulative actual dose (mg)

Dose intensity (mg/3-week cycle)

Relative dose intensity (%)

Number of cetuximab infusions 
Duration of therapy 
Duration of therapy is defined as
Duration of therapy (in weeks) = !Date of last dosing day - Date of first dosing day + D
7
$
where D = 1 for tepotinib and D = 7 for cetuximab.
The total number of 3-week cycles is defined as the duration of therapy (in weeks)/3.
For categorical summary, use floor (duration of therapy) i.e. round the value to completed cycles. For 
summary statistics take the duration value as such.
Cumulative actual dose of tepotinib
The cumulative actual dose (mg) per participant in a time period is the sum of the total doses that the 
participant received within that period (i.e. total dose administered (mg)).
Dose intensity and relative dose intensity of tepotinib
The dose intensity and the relative dose intensity will be calculated for a 3-week cycle. The dose 
intensity (mg/3-week cycle) per participant) is defined as:
Actual dose intensity (mg/3-week cycle) = ! Cumulative actual dose (mg) 
Total number of 3-week cycles$
Document No. 
Object No. 


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Relative dose intensity per participant is defined as:
Relative dose intensity (%) = 100 x !
Actual dose intensity
Intended dose intensity by 3-week cycle$
where intended dose intensity (mg/3-week cycle) = RP2D mg * 21 days for tepotinib.
A dose of cetuximab is regarded to be administered, if the actual dose of cetuximab received is > 0, or 
the duration of the infusion is > 0.
For Cycle X, actual cycle start date for each participant is

the earliest start date of dosing in the Cycle X day 1 visit eCRF exposure page, if the 
participant received study treatment on that visit (i.e., any study drug with dose > 0 at that 
visit)

the first day of assessments in the Cycle X day 1 visit, if the participant did not receive study 
treatment on that visit (i.e., all study drugs had dose = 0 at that visit). Use start date in the 
exposure page if available; if start date is not available then use date of collection of vital 
signs (assuming vital signs are the first assessment of the cycle on Cycle X day 1 visit).
Actual cycle end date for each participant is, 

for all cycles X except the last cycle, actual cycle end date = actual cycle (X+1) start date –
1 day;

for the last cycle, actual cycle end date = actual cycle start date + intended cycle duration 
(21 days) – 1 day
Cumulative actual dose of cetuximab
The cumulative dose (mg/m²) from 1st infusion per participant in a time period is the sum of the total 
dose levels that the participant received within that period (i.e. total dose administered (mg) / 
recalculated BSA (m2)).
Dose intensity and relative dose intensity of cetuximab
Actual dose intensity (mg/m²/3-week cycle) per participant is defined as:
Actual dose intensity = !Cumulative dose from 1st infusion
Total number of 3-week cycles $
Relative dose intensity per participant is defined as:
Relative dose intensity (%) = 100 x !
Actual dose intensity
Intended dose intensity by 3-week cycle$
Document No. 
Object No. 


MSC2156119J, MSB0010442D      Phase II single arm study of tepotinib combined with cetuximab
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v1.0
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where intended dose intensity by 3-week cycle (mg/m2/3-week cycle) per participant is defined as

for the first cycle: 
o
400 mg/m2 + 2 x 250 mg/m2 per 3-week cycle, if loading dose is needed
o
3 x 250 mg/m2 per 3-week cycle, if loading dose is not needed

for the subsequent cycles: 3 x 250 mg/m2 per 3-week cycle
Dose reductions
If the 500 mg dose for tepotinib will be the selected RP2D, participants may have a dose reduction to 
250 mg, which is also the minimum possible dose in this study. If 250 mg is the RP2D for tepotinib, 
then no further reduction will be possible. 
For cetuximab the loading dose is 400 mg/m2 and subsequent weekly doses are 250 mg/m2 if the loading 
dose is required or the weekly dose is 250 mg/m2 if the loading dose is not required. The weekly dose 
can be reduced to 200 mg/m2 or 150 mg/m2 for safety reasons if necessary.
The number of participants with and without any dose reduction will be summarized. In case the 
selected RP2D is 250 mg, the tepotinib sections will contain “NA” (Not Applicable).
Number of participants with any dose adjustment due to Adverse Event/Other will be provided.
Dose interruptions and therapy delays
For tepotinib any days within the treatment period where the participants did not take any tepotinib will 
be counted as dose interruptions. Number of participants with any tepotinib interruptions will be 
presented.
Dose delays are applicable for cetuximab only. It will be derived by administration as the number of 
days between two successive administrations greater than 7 and will be presented as follows:

Number of participants with delayed infusions, and maximum length of delay (no delay, 3-
8 days, 9-15 days, ≥16 days) – worst case
Treatment administration of tepotinib and cetuximab by time point will be listed.
14
Efficacy Analyses
The following analyses will be performed based on the FAS and will be presented by cohort and 
assigned dose level of tepotinib, except when otherwise stated.
Document No. 
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14.1
Primary Endpoint (Overall Study): Objective Response 
14.1.1
Derivation and analysis 
Best Overall response (BOR) will be assessed based on reported overall responses at different 
evaluation time points from the study treatment start date until documented disease progression in 
accordance to RECIST v1.1 by investigator, taking requirements for confirmation into account as 
detailed below.
Only tumor assessments performed before the start of any subsequent anti-cancer therapies will be 
considered in the assessment of BOR. If a tumor assessment was performed on the same day as start of 
new anti-cancer therapy, it will be assumed that the tumor assessment was performed prior to the start 
of the new anti-cancer therapy, therefore the tumor assessment will be included in the assessment of 
BOR.
Clinical deterioration will not be considered as documented disease progression. The date of the overall 
response assessment is the earliest date for imaging of target, non-target and new lesions of images 
taken at that response assessment.
BOR Based on Confirmed Responses:

Complete Response (CR) = at least two determinations of CR at least 4 weeks apart (with 
no PD in between) 

Partial Response (PR) = at least two determinations of PR or better (PR followed by PR or 
PR followed by CR) at least 4 weeks apart (and not qualifying for a CR), with no PD in 
between 

Stable Disease (SD) = at least one SD assessment (or better) ≥ 6 weeks after start date (and 
not qualifying for CR or PR).

Non-CR/non-PD (applicable only to participants with non-measurable disease at baseline) 
= at least one non-CR/non-PD assessment (or better) ≥ 6 weeks after start date (and not 
qualifying for CR or PR).

Progressive Disease (PD) = PD ≤ 12 weeks after start date of study treatment (and not 
qualifying for CR, PR, non-CR/non-PD or SD).

Not Evaluable (NE):  all other cases.
SD can follow PR only in the rare case that tumor increases by less than 20% from the nadir, but enough 
that a previously documented 30% decrease from baseline no longer holds.  If this occurs the sequence 
PR-SD-PR is considered a confirmed PR.  A sequence of PR – SD – SD – PD would be a best response 
of SD if the minimum duration for SD definition has been met.
Participants are defined as having an Objective Response (OR) if they achieved either a BOR of 
confirmed CR or confirmed PR according to RECIST v1.1 as assessed by the investigator, from first 
administration of study treatment to first observation of PD. 
Participants who do not have an on-treatment radiographic tumor assessment due to early progression, 
who receive anti-tumor treatments other than the study treatments prior to reaching confirmed CR or 
Document No. 
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PR, or who die, progress, or drop out for any reason prior to reaching confirmed CR or PR will be 
counted as non-responders in the assessment of OR. Each participant will have an objective response 
status (0: ‘no OR’; 1: ‘OR’).  OR rate (ORR) is the proportion of participants with OR in the analysis 
set. No formal statistical hypotheses will be tested.
The number and percentage of participants with BOR of confirmed CR, confirmed PR, SD, PD, and 
NE will be tabulated. 
The confirmed ORR by cohort and assigned dose level of tepotinib will be presented along with the 
two-sided 95% CI using the Clopper-Pearson method (1934) (exact CI for a binomial proportion as 
computed by default by the SAS FREQ procedure using the EXACT option). 
A spider plot will show the participant profiles of the sum of target lesion diameters (sum of longest 
diameters for non-nodal lesions, short axis for nodal lesions) over time (presenting all participants on 
the same graph). In addition, a waterfall plot will show the change in sum of target lesion diameters 
between baseline and the best post-baseline assessment for each participant. 
Time to and duration of response by investigator assessment for every participant will be plotted using 
a swimmer plot. Color coded symbols will be used to show the time of the following events: CR, PR, 
PD, death, ongoing response and end of treatment.
Estimand Attributes
Endpoint:

OR according to RECIST 1.1 assessed by Investigator prior to further anti-cancer therapy and
progression
Population:

Participants with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC) 
having acquired resistance to anti-EGFR antibody targeting therapy due to MET
amplification
Treatment:

Tepotinib combined with cetuximab
Intercurrent Event Strategy:

Discontinuation of treatment (treatment-policy strategy, i.e. regardless of the intercurrent
event)

Start of subsequent anti-cancer therapy (while not treated with subsequent anti-cancer 
therapy strategy, i.e. assessments up to the intercurrent event)

Progression according to RECIST 1.1 (while not progressed strategy, i.e. assessments up to 
the intercurrent event)
Population Level Summary: 

Rate
Document No. 
Object No. 


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14.1.2
Sensitivity Analyses
A sensitivity analysis will be conducted in which the start of any other anti-cancer treatment or 
procedure prior to study discontinuation will be considered as PD, and any subsequent tumor 
assessments will not be considered in the objective response assessment. If only partial dates are known 
for the start of other anti-cancer treatment or procedures, the imputation rules described in Section 9.8
should be followed.
14.1.3
Futility Analysis
Best Overall Response (BOR) as described above will be reported for the first 12 participants, in Cohort 
A. If there are less than 2 responders (confirmed CR or PR) the enrollment of 2nd line participants for 
the study might be stopped for futility.
14.1.4
Subgroup Analyses
Subgroup analyses will be performed on the primary endpoint by cohort and assigned dose level of 
tepotinib for all the baseline subgroup levels defined in Section 8.2. All the subgroup analyses are 
exploratory and no adjustment for multiplicity will be performed. In case of low number of participants 
within a subgroup level (< 5 participants), levels will be pooled when meaningful.
For each subgroup, the BOR, the number of participants achieving objective response, and the ORR 
along with the two-sided exact Clopper-Pearson 95% CIs will be presented.
In addition to the presentation in summary tables, forest plots will be created to graphically present 
ORRs and corresponding 95% CIs.
14.2
Secondary Endpoints
14.2.1
Duration of Response
Duration of Response (DoR) as assessed by Investigator will only be evaluated in participants with 
objective response (as defined in Section 14.1.1). 
DoR is the time from when the CR/PR (whichever is first) criteria are first met until PD or death due 
to any cause within the period of 2 scheduled tumor assessments (84 or 168 days) after the last tumor 
assessment, whichever occurs first (see Eisenhauer EA, et al 2009) (i.e. date of PD/death - date of last 
evaluable tumor assessment ≤ 84 or 168). 
DoR data will be censored on the date of the last evaluable tumor assessment for participants who do 
not have an event (PD or death) or for participants with an event after the period of 2 scheduled tumor 
assessment (more than 84 or 168 days) after the last evaluable tumor assessment (i.e. date of PD/death 
Document No. 
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- date of last evaluable tumor assessment > 84 or 168). Participants who do not have a tumor assessment 
after objective response will be censored at the date CR/PR criteria are first met.
The last evaluable tumor assessment is defined as the last tumor assessment result that is not “NE”.
Kaplan-Meier estimates (product-limit estimates) will be presented together with a summary of 
associated statistics for duration of response: median and corresponding two-sided 95% confidence 
interval (CI), Q1 and Q3, minimum and maximum. DoR rate estimates at 3, 6, 9, 12, 15, 18 months 
and for every 3 months thereafter as applicable including the corresponding two-sided 95% CIs will 
also be reported. The CI for the median will be calculated according to Brookmeyer and Crowley (1982) 
and CIs for the survival function estimates at the above defined time points will be derived using the 
log-log transformation according to Kalbfleisch and Prentice (1980) (conftype=loglog default option 
in SAS Proc LIFETEST). The estimate of the standard error will be computed using Greenwood's 
formula. Kaplan-Meier plots will also be presented.
Time to and duration of response as assessed by Investigator for every participant will be plotted using 
a swimmer plot. Symbols color coded will be used to show the time of the following events: complete 
response, partial response, progressive disease, death, ongoing response and end of treatment.
Estimand Attributes
Endpoint:

DoR according to RECIST 1.1 as assessed by Investigator, measured by time from first 
documentation of objective response to PD or death, occurring within 2 scheduled tumor 
assessments (84 or 164 days, respectively) after last evaluable assessment or first dose 
Population:

Participants with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC) 
having acquired resistance to anti-EGFR antibody targeting therapy due to MET
amplification
Treatment:

Tepotinib combined with cetuximab
Intercurrent Event Strategy:

Discontinuation of treatment (treatment-policy strategy, i.e. regardless of the intercurrent
event)

Start of subsequent anti-cancer treatment (treatment-policy strategy, i.e. regardless of the 
intercurrent event)

Death within two scheduled tumor assessments after last evaluable assessment will be 
considered as event of interest (composite strategy)
Population Level Summary: 

Kaplan-Meier estimates
Follow-up for duration of response
In order to assess the follow-up for duration of response, Kaplan-Meier estimates will be calculated 
using the censoring rules with reverse censoring indicator.
Document No. 
Object No. 


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Kaplan-Meier estimates (product-limit estimates) will be presented in the same way as in the analysis 
described above for duration of response.  
The following information will also be presented:

Number of participants with Objective Response (confirmed CR/PR)

Number of responders (confirmed CR/PR) with duration of response: ≥ 6 months / ≥ 9 
months / ≥ 12 months

Number of responders (confirmed CR/PR): 
o
with ≥ 6 months follow-up from onset of response (CR, PR or SD) or event (PD or death)
or who discontinued treatment < 6 months after onset of response
o
Ongoing response with < 6 months duration, on treatment
14.2.2
Progression Free Survival 
Progression Free Survival (PFS) time as assessed by Investigator is defined as the time (in months) 
from first administration of study intervention to the date of the first documentation of PD or death due 
to any cause, whichever occurs first if only the event happened within the period of 2 scheduled 
assessments (84 or 168 days) after the last tumor assessment (i.e. time between date of PD/death - date 
of last evaluable tumor assessment ≤ 84 or 168 days). The tumor response will be determined according 
to RECIST 1.1. and assessed by the investigator.
PFS data will be censored on the date of the last evaluable tumor assessment for participants who do 
not have an event (PD or death) or for participants with an event after the period of 2 scheduled tumor 
assessments (84 or 168 days) after the last tumor assessment (i.e. date of PD/death - date of last 
evaluable tumor assessment > 84 or >168 days). 
The last evaluable tumor assessment is defined as the last tumor assessment result that is not “NE”.
Participants who do not have a baseline tumor assessment or who do not have any post baseline 
tumor assessments will be censored at the date of the start of study intervention.
Participants who do not have an evaluable post-baseline tumor assessment will be censored at the date 
of the start of study treatment unless death occurred within the period of 2 scheduled tumor assessments
(84 or 168 days, respectively) after the first dose of study treatment in which case the death will be 
considered an event.
The censoring and event date options to be considered for the PFS are presented in Table 5.
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Table 4.   Date of event / censoring definition for PFS analysis
Status
Censoring
Date of event / censoring
Progressed or died
Within the period of 2 scheduled tumor 
assessment (84 or 168 days, respectively)
after last response assessment of CR, PR 
or SD or start of treatment
Event
Minimum (Date of PD, Date of 
death) 
Otherwise
Censored
Date of last tumor assessment with 
outcome CR, PR or SD or date of 
start of treatment, whatever is later
Neither progressed nor died 
Censored
Date of last tumor assessment with 
outcome CR, PR or SD or date of 
start of treatment, whatever is later
CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease.
Kaplan-Meier product-limit estimates will be presented together with a summary of associated statistics 
for PFS: median and corresponding two-sided 95% confidence interval (CI), Q1 and Q3, minimum and 
maximum. Progression-free rate estimates at 3, 6, 9, 12, 15, 18 months and for every 3 months thereafter 
as applicable including the corresponding two-sided 95% CIs will also be reported. The CI for the 
median will be calculated according to Brookmeyer and Crowley (1982) and CIs for the survival 
function estimates at the above defined time points will be derived using the log-log transformation 
according to Kalbfleisch and Prentice (1980) (conftype=loglog default option in SAS Proc LIFETEST). 
The estimate of the standard error will be computed using Greenwood's formula. Kaplan-Meier plots 
will also be presented.
Estimand Attributes
Endpoint:

Progression-free survival time, defined as the time from first dose until PD according to 
RECIST 1.1 or death events occurring within two scheduled tumor assessments after last 
evaluable assessment or first dose
Population:

Participants with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC) 
having acquired resistance to anti-EGFR antibody targeting therapy due to MET
amplification
Treatment:

Tepotinib combined with cetuximab
Intercurrent Event Strategy:

Discontinuation of treatment (treatment-policy strategy, i.e. regardless of the intercurrent
event)

Start of subsequent anti-cancer treatment (treatment-policy strategy, i.e. regardless of the 
intercurrent event)
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
Death within two scheduled tumor assessments after last evaluable assessment will be 
considered as event of interest (composite strategy)
Population Level Summary: 

Kaplan-Meier estimates
Follow-Up Duration of PFS
In order to assess the follow-up duration of PFS, Kaplan-Meier estimates will be calculated using the 
censoring rules with the reverse censoring indicator.
Kaplan-Meier estimates (product-limit estimates) will be presented in the same way as in the analysis 
described above for PFS. 
14.2.3
Overall Survival 
Overall survival (OS) time is defined as the time (in months) from the first administration of study 
treatment to the date of death. 
For participants not known to be deceased at time of analysis or who died after the cut-off date, OS 
time will be censored at the date of last contact before data cut-off date as defined in Section 9.66. 
The Kaplan-Meier based analysis described in Section 14.2.2 for the derivation of progression-free 
related estimates will be repeated for the survival related estimates.
The censoring and event status with respect to OS will be summarized
Estimand Attributes
Endpoint:

OS as measured by time from first dose to death 
Population:

Participants with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC) 
having acquired resistance to anti-EGFR antibody targeting therapy due to MET
amplification
Treatment:

Tepotinib combined with cetuximab
Intercurrent Event Strategy:

Discontinuation of treatment (treatment-policy strategy, i.e. regardless of the intercurrent
event)

Start of subsequent anti-cancer treatment (treatment-policy strategy, i.e. regardless of the 
intercurrent event)
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Population Level Summary: 

Kaplan-Meier estimates
Follow-Up Duration of OS
In order to assess the follow-up duration of OS, Kaplan Meier estimates will be calculated reversing 
the OS censoring and event indicators.
Kaplan-Meier estimates (product-limit estimates) will be presented in the same way as in the analysis
described above for OS.
14.2.4
Immunogenicity
Immunogenicity of cetuximab will be measured by ADA assays at Baseline on Day 1 Cycle 1 and End 
of Treatment Visit.
Immunogenicity of cetuximab will be tabulated by cohort and dose level, if applicable, based on 
Immunogenicity Analysis Set. The immunogenicity status of each study participant will be evaluated 
according to the criteria described in Table 5.
Table 5
Immunogenicity classification
ADA result at Baseline
ADA result at EOT
Classification
Negative
Negative
Treatment-emergent negative
Negative
Positive
Treatment-emergent positive
Positive
Negative, or positive with titer lower or equal 
to baseline
Treatment-emergent negative
Positive
Positive with titer higher than baseline
Treatment-emergent positive
Missing
Negative or positive
Not evaluable
Negative or positive
Missing
Not evaluable
Missing
Missing
Not evaluable
Immunogenicity of cetuximab will be listed.
14.2.5
Subgroup Analyses
Subgroup analyses for secondary endpoints of DoR, PFS and OS will be performed by cohort and 
assigned dose level of tepotinib for all the baseline subgroup levels identified in Section 8.2.
The Kaplan-Meier based analysis described in Section 14.2.2 will be repeated for all the baseline 
subgroups. The same rules described in the first paragraph of Section 14.2.2 will apply. 
Document No. 
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M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D       P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi m a b
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1 5
S afet y A n al yses
T he a nal ysis of t he pri mar y  safet y e n d p oi nt will be perf or me d o n t he D L T a nal ys is set w hereas t he 
a nal ys es of t he sec o n dar y safety e n d p oi nt s will be perf or me d o n t he S A F a nalys is set.
I n case t he R P 2 D f or te p oti ni b is 2 5 0 m g a n d t here are partici pa nts w h o starte d o n t he 5 0 0 m g d ose, a 
selecti o n of t he safety ta bles m a y  be re peate d o n t hese partici pa nts, ot her wise t heir data will o nl y  be 
liste d.
T he safet y a nal ys es will be d o ne p urel y descri pti vel y . 
1 5. 1
Pri m ar y E n d p oi nt ( Safet y R u n -i n): Occ urre nce of D L Ts 
T he n u m ber a n d perce nta ge of partici pa nts i n t he D L T a nal ys is set wit h n o D LT, 1 D L T or 2 or m ore 
D L Ts o bser ve d d uri n g t he D L T o bser vati o n peri o d will be ta b ulate d t o get her wit h t he res pecti ve S O Cs 
a n d P Ts as well as t he n u m ber of partici pa nts wit h a n y  T E A E d uri n g c ycle 1. 
All D L T rele va nt data will als o be liste d. 
D L T e val uati o n b y  the I n vesti gat or as well as b y t he S M C will be a vaila ble f or t he a nal yses. I n t he 
“ A d verse E ve nt Details” e C R F pa ge, t he q uesti o n “Is t his ad verse e ve nt a d ose li miti n g t o xicit y ” will 
D oc u me nt N o. 
O bject N o. 
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be used to identify the DLTs within 21 days after start of study treatment (DLT observation period) by
Investigator assessment. SMC decisions will be implemented programmatically into SDTM dataset 
based on SMC feedback received.
15.2
Secondary Endpoints
15.2.1
Adverse Events
Adverse events will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA;
latest version at the time of database lock for each analysis will be used and be specified in outputs). 
Severity of AEs will be graded using the NCI-CTCAE (Version 5.0) toxicity grades. 
Relationship with the study treatment components are collected in the “Adverse Events Details” eCRF 
page. Adverse Events can be related to tepotinib, cetuximab or both. In case the relationship 
information is missing for a study treatment component, the AE will be considered as related to that 
component.
Incomplete AE-related dates will be handled as specified in Section 9.8.
Treatment emergent adverse events (TEAE) are those events that occurred during on-treatment 
period, having been absent prior to treatment or worsened relative to the pre-treatment state and with 
onset dates occurring within the first dosing day of study intervention until 30 days after the last dose 
of study intervention.
For the Adverse Event that started before the first administration of study treatment, the latest toxicity 
grade before first dose will be considered as the baseline grade and used to assess whether the AE 
worsens during the on-treatment period. 
Pre-existing conditions continuing on-treatment with grade equal or lower than the baseline grade will 
not be considered as TEAEs.
All analyses described in Section 15.2.2 and 15.2.3 will be based on TEAEs if not otherwise specified. 
The AE listings will include all AEs (whether treatment emergent or not). A flag will be added to 
indicate if the AE is treatment emergent (i.e. started or worsened between the date of first dose of the 
study treatment and the date of last dose + 30 days).   
Unless otherwise specified, TEAEs will be summarized by number and percentage of participants with 
the TEAE in the category of interest and sorted by primary System Organ Class (SOC) and Preferred 
Term (PT) in alphabetic order.  
Each participant will be counted only once within each SOC or PT. If a participant experiences more 
than one AE within a SOC or PT for the same summary period, only the AE with the strongest 
relationship or the worst severity, as appropriate, will be included in the summaries of relationship and 
severity. 
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15.2.2
All Adverse Events
Adverse Event information is collected on the “Adverse Events Details” eCRF page.
Adverse events will be summarized by worst severity (according to NCI-CTCAE version 5.0) per 
participant, using the latest version of MedDRA preferred term (PT) as event category and MedDRA 
primary system organ class (SOC). 
In case a participant has events with missing and non-missing grades, the maximum of the non-missing 
grades will be displayed. No imputation of missing grades will be performed.
Incomplete AE-related dates will be handled as specified in Section 9.8.
The overall summary of AEs table will include the frequency (number and percentage) of participants 
within the following categories:

TEAEs

Study treatment related TEAEs (any study treatment and by study treatment components)

Serious TEAEs

Study treatment related serious TEAEs (any study treatment and by study treatment 
components)

TEAEs with NCI-CTCAE Grade 3 and 4

Study treatment related TEAEs with NCI-CTCAE Grade 3 and 4 (any study treatment 
and by study treatment components)

TEAEs leading to death

Study treatment related TEAEs leading to death (any study treatment and by study treatment 
components)

Adverse Events of Special Interest (AESIs) 
Adverse events of special interest are defined as events suggestive of drug-induced liver injury 
including hepatic / liver failure and hepatitis (non-infectious). The question “Is this an adverse event of 
special interest” present on the “Adverse Event Details” eCRF page will be used to identify these AEs.
In addition, the following tables summarizing the frequency of participants with TEAEs by SOC and 
PT will be produced:

TEAEs

Study treatment related TEAEs (any study treatment and by study treatment components)

Serious TEAEs

Non-serious TEAEs applying a frequency threshold of 5%
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
Study treatment related serious TEAEs (any study treatment and by study treatment 
components)

TEAEs by worst NCI-CTCAE Grade (Any, 3, 4 and 5)

Study treatment related TEAEs by worst NCI-CTCAE Grade (Any, 3, 4) (any study 
treatment and by study treatment components)

TEAEs leading to death

Study treatment related TEAEs leading to death (any study treatment and by study treatment 
components)

Adverse Events of Special Interest (AESIs)  
Participant listings of AEs details collected on the “Adverse Events Details” eCRF page will also be 
provided for each of the following:

AEs

AESIs 

Serious TEAEs
TEAEs frequency and worst grade for TEAEs occurring in >= 10% participants will be plotted by 
cohort.
15.2.3
Adverse Events Leading to Discontinuation / Dose Reduction of 
Study Treatment
The frequency (number and percentage) of participants with each of the following will be presented in 
a summary table:

TEAEs leading to temporary discontinuation of study treatment (any study treatment and 
by study treatment components)

Study treatment related TEAEs leading to temporary discontinuation of study treatment 
(any study treatment and by study treatment components) 

TEAEs leading to permanent discontinuation of study treatment (any study treatment and 
by study treatment components)

Study treatment related TEAEs leading to permanent discontinuation of study treatment 
(any study treatment and by study treatment components) 

TEAEs leading to dose reduction of study treatment (any study treatment and by study 
treatment components)

Study treatment related TEAEs leading to dose reduction of study treatment, (any study 
treatment and by study treatment components) 
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In addition, tables summarizing the frequency of participants with AEs, presented by SOC and PT, in 
the above categories will be prepared. Tables summarizing TEAEs related to study treatment will be 
created to summarize TEAEs related to any study treatment and will be repeated to summarize TEAEs 
related to specific study treatment components (i.e. tepotinib and cetuximab).
Actions that can be taken by the Investigator to address an Adverse Event are collected by sections 
“Action(s) taken with Tepotinib” and “Action(s) taken with cetuximab” on the “Adverse Events 
Details” eCRF page. It is possible that a TEAE leads to more than one action: for example, a drug 
interruption followed by drug withdrawn. In this case the TEAE will be counted among the TEAEs 
leading to temporary discontinuation as well as among the TEAEs leading to permanent
discontinuation.  
Participant listings showing the relevant information will also be provided:

AEs leading to permanent discontinuation of study treatment

AEs leading to temporary discontinuation of study treatment
15.3
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.3.1
Deaths
All deaths, deaths within 30 days after last dose of study treatment and deaths beyond this period up 
to 90 days follow-up and reasons for them will be tabulated based on information from the “Death” 
eCRF page.

Number of deaths overall and by primary reason

Number of deaths within 30 days after last dose of study treatment overall and by primary 
reason

Number of deaths within 90 days after last dose of study treatment overall and by primary 
reason
Primary reasons for death can be:

Progressive disease and/or disease related condition

Event unrelated to tepotinib and cetuximab

Event related to tepotinib

Event related to cetuximab

Event related to tepotinib and cetuximab

Unknown

Missing
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In addition, date and cause of death will be provided in individual participant data listing together with 
selected dosing information (date of first / last administration, dose and number of doses separately for 
tepotinib and cetuximab). This listing will also include:

AEs with fatal outcome (list preferred terms of AEs with outcome = fatal)

Flag for death within 30 days of last study treatment

Flag for death within 90 days of last study treatment
Note: for the definition of “study treatment”, “first” and “end”/last date of study treatment, please see 
Section 9.  
15.3.2
Serious Adverse Events
The frequency tables as listed in Section 15.2.2 will be prepared for serious adverse events (SAEs).
The listings of SAEs will also be provided with the relevant information with a flag for SAEs with 
onset outside of the on-treatment period.
15.3.3
Other Significant Adverse Events
Please refer to Section 15.2.2 for the analysis of AEs of special interest.
15.4
Clinical Laboratory Evaluation
Laboratory assessments such as hematology and coagulation, biochemistry, urinalysis and other 
screening tests (e.g.: pregnancy tests) will be performed by local laboratories.
Laboratory results will be classified according to the NCI-CTCAE criteria version 5.0. Additional 
laboratory results that are not part of NCI-CTCAE will be presented according to the categories: below 
normal limit, within normal limits and above normal limit (according to the laboratory normal ranges).
The last measurement before study treatment first dose (including unscheduled measurements) will 
serve as the baseline measurement. For further details about baseline and change from baseline, please 
refer to Section 9.2.
Values below the detection limit will be imputed by half of the detection limit. 
In case just a text value with an “> x” is reported it will be analyzed as +1 significant digit, e.g. “> 7.2 
mmol” will be analyzed as 7.3.
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Quantitative data will be summarized using descriptive statistics (n, mean, StDev, median, Q1, Q3, 
minimum, and maximum) of actual values and absolute changes from baseline to each scheduled visit 
over time. Scheduled visits performed during the safety run-in are to be presented, too.
Qualitative data based on reference ranges will be described according to the categories Low, Normal, 
and High (Hematology, Biochemistry and Coagulation). For qualitative data of urinalysis 
measurements, the raw classifications Normal, Trace/+, ++, +++, ++++ will be used instead. Results 
from the urinalysis microscopic examination (Erythrocytes, Leukocytes, Epithelial cells, Bacteria, 
Crystals and Casts) will only be listed. 
Abnormalities classified according to NCI-CTCAE toxicity grading version 5.0 will be described using 
the worst on-treatment grade. Measurements from both scheduled and unscheduled visits should be 
considered for the worst on-treatment grade derivation; also measurements performed during the safety 
run-in are to be taken into account. For those parameters which are graded with two directions of 
toxicities such as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (e.g., hypokalemia) grades at baseline and post baseline will be set to 0 when 
the variables are derived for summarizing high direction toxicity (e.g., hyperkalemia), and vice versa.  
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, eosinophil, 
and basophil counts), the absolute value will be used when reported.  When only percentages are 
available (this is mainly important for neutrophils and lymphocytes, because the NCI-CTC grading is 
based on the absolute counts), the absolute value is derived as follows: 
Derived differential absolute count = (WBC count) * (Differential %value / 100)
If the range for the differential absolute count is not available (only range for value in % is available) 
then Grade 1 will be attributed to as follows: 

Lymphocyte count decreased:  
o
derived absolute count does not meet Grade 2-4 criteria, and
o
% value < % LLN value, and
o
derived absolute count ≥ 800/mm3

Neutrophil count decreased 
o
derived absolute count does not meet Grade 2-4 criteria, and
o
% value < % LLN value, and
o
derived absolute count ≥ 1500/mm3
For calcium, NCI-CTC grading is based on Corrected Calcium and Ionized Calcium (CALCIO), if 
available. Corrected Calcium is calculated from Albumin and Calcium as follows
Corrected calcium (mmol/L) = 
measured total Calcium (mmol/L) + 0.02 (40 - serum albumin 
[g/L])
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where the albumin values should be taken from the same sample, analyzed in the same laboratory as 
calcium.
Liver function tests: Alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP) and total bilirubin (TBILI) are used to assess possible drug induced liver toxicity. 
The ratios of test result over upper limit of normal (ULN) will be calculated and classified for these 
three parameters during the on-treatment period.   
Summary of liver function tests will include the following categories.  The number and percentage of 
participants with each of the following during the on-treatment period will be summarized:

ALT ≥ 3 × ULN, ALT ≥ 5 × ULN, ALT ≥ 10 × ULN, ALT ≥ 20 × ULN

AST ≥ 3 × ULN, AST ≥ 5 × ULN, AST ≥ 10 × ULN, AST ≥ 20 × ULN

(ALT or AST) ≥ 3 × ULN, (ALT or AST) ≥ 5 × ULN, (ALT or AST) ≥ 10 × ULN, (ALT 
or AST) ≥ 20 × ULN

TBILI ≥ 2 × ULN

Concurrent ALT ≥ 3 × ULN and TBILI ≥ 2 × ULN

Concurrent AST ≥ 3 × ULN and TBILI ≥ 2 × ULN

Concurrent (ALT or AST) ≥ 3 × ULN and TBILI ≥ 2 × ULN 

Concurrent (ALT or AST) ≥ 3 × ULN and TBILI ≥ 2 × ULN and ALP > 2 × ULN

Concurrent (ALT or AST) ≥ 3 × ULN and TBILI ≥ 2 × ULN and ALP ≤ 2 × ULN or missing
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, i.e., a participant with an elevation of AST ≥10 × ULN will also appear 
in the categories ≥5 × ULN and ≥3 × ULN. 
Liver function elevation and possible Hy’s Law cases will be summarized using frequency and 
percentage. An evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plot will also be created, 
with different symbols for different treatment groups, by graphically displaying

peak serum ALT(/ULN) vs peak total bilirubin (/ULN) including reference lines at ALT = 3
× ULN and total bilirubin = 2 × ULN. 

peak serum AST(/ULN) vs peak total bilirubin (/ULN) including reference lines at AST = 3
× ULN and total bilirubin = 2 × ULN. 
In addition, a listing of all TBILI, ALT, AST and ALP values for participants with a post-baseline 
TBILI ≥ 2 × ULN, ALT ≥ 3 × ULN or AST ≥ 3 × ULN will be provided.
Estimated glomerular filtration rate (GFR [mL/min/1.73 m2]) will be derived using 4-component 
Modification of Diet in Renal Disease (MDRD) formula:

GFR [mL/min/1.73 m2] = 175 × serum creatinine (mg/dL)-1.154 × age-0.203 × 1.212 [if African 
American] × 0.742 [if female]
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In case only Urea or only Blood Urea Nitrogen (BUN) is collected for a participant at a specific visit 
conversion factors will be programmatically applied. Urea results will only be presented in listings.
Urea will be calculated using BUN, as follows:

if BUN is expressed in mmol/L then 
o
urea [mmol/L] = BUN [mmol/L]
and needs to be converted to urea [mg/dL] using the following formula: 
o
urea [mg/dL] = BUN [mmol/L] × 0.357

if BUN is expressed in mg/dL then: 
o
urea [mg/dL] = BUN [mg/dL] × 2.1428
Parameters with NCI-CTC grades available:
Laboratory toxicities will be tabulated (count and percentage) for each gradable parameter by the worst 
on-treatment NCI-CTC grade. For selected parameters with the on-treatment grading depending on 
baseline grading (as indicated in Appendix 1), the worst on-treatment grade will be tabulated by the 
status at baseline (normal or abnormal). Shifts from baseline to worst NCI-CTC grade during the on-
treatment period will also be tabulated. The denominator to calculate percentages for each laboratory 
parameter is the number of participants in each analyzed group. Participants without baseline or on-
treatment post-baseline results for a given parameter will be presented in the “Missing” category and 
will contribute to the denominator.
Please see Appendix 1 for a list of the NCI-CTC -gradable parameters.
Parameters with NCI-CTC grades not available:
Laboratory abnormalities will be tabulated (count and percentage) for each non-gradable parameter by 
the worst on-treatment abnormality. Shift tables from baseline to each time point as well as to worst 
abnormality during the on-treatment period will also be tabulated. For each parameter, the shift to the 
maximum post-baseline as well as the minimum post-baseline value will be presented. The 
denominator to calculate percentages for each laboratory parameter is the number of participants in 
each analyzed group. Participants without baseline or post-baseline results for a given parameter will 
be presented in the “Missing” category and will contribute to the denominator.
Following figures will be provided for each above-mentioned test:

Boxplots of the laboratory values by time point.

Boxplots of the change from baseline by time point.
Boxplots for laboratory parameters where toxicity grades are defined based on the ratio of the parameter 
values and the upper limit of normal (ULN) will not be displayed using the unit of measurement but
instead using the ratio of the measured value over ULN. This comprises ALP, ALT, AST, bilirubin, 
creatinine. 
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The listings of laboratory results will be provided for all laboratory parameters. The listings will be 
sorted by parameters and assessment dates or visits for each participant. Laboratory values that are 
outside the normal range will be flagged in the data listings, along with corresponding normal ranges 
and CTCAE grades.
Results from pregnancy tests, both serum and urine, collected on the “Pregnancy Test” eCRF page will 
be listed.
15.5
Vital Signs
The maximum change (increase and decrease) in each vital sign measurement from baseline (where 
baseline is defined in Section 9.2) across on-treatment scheduled and unscheduled visits will be derived 
for each participant as shown below. Measurements performed during the safety run-in are to be taken 
into account, too. Refer to Section 9.7 for the definition of on-treatment.
Baseline category
Maximum change from baseline categories
Body temperature increase
< 37 °C, 37 - < 38 °C, 38 - < 39 °C, 39 - < 40 °C, >= 40 °C
< 1 C, 1 -< 2 C, 2 -< 3 C, 3 C
Pulse increase from baseline < 100 bpm; ≥ 100 bpm
20 bpm, > 20 – 40 bpm, > 40 bpm
Pulse decrease from baseline < 100 bpm; ≥ 100 bpm
20 bpm, > 20 – 40 bpm, > 40 bpm
SBP increase from baseline < 140 mmHg; ≥ 140 mmHg 
20 mmHg, > 20 – 40 mmHg, > 40 mmHg
SBP decrease from baseline < 140 mmHg; ≥ 140 mmHg
20 mmHg, > 20 – 40 mmHg, > 40 mmHg
DBP increase from baseline < 90 mmHg; ≥ 90 mmHg 
20 mmHg, > 20 – 40 mmHg, > 40 mmHg
DBP decrease from baseline < 90 mmHg; ≥ 90 mmHg
20 mmHg, > 20 – 40 mmHg, > 40 mmHg
Respiration rate increase from baseline < 20 bpm; ≥ 20 bpm
5 bpm, > 5 – 10 bpm, > 10 bpm
Respiration rate decrease from baseline < 20 bpm; ≥ 20 bpm
5 bpm, > 5 – 10 bpm, > 10 bpm
The number and percentage of participants in each category will be presented as a shift table showing 
baseline category versus the maximum change. The denominator to calculate percentages for each vital 
sign parameter is the number of participants in each analyzed group. Participants without baseline or 
post-baseline results for a given parameter will be presented in the “Missing” category and will 
contribute to the denominator. 
For body weight, the number and percentage of participants with a maximum on-treatment percentage 
change from baseline increase and decrease will be presented. Categories will be: < 10%, ≥ 10% and 
missing. Those subjects with no baseline and/or post-baseline measurement will be presented in the 
“Missing” category. 
A participant data listing will present the baseline value and maximum changes (increases and 
decreases) in each vital sign measurement. A listing presenting all vital sign measurements will also be 
produced.
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15.6
Other Safety or Tolerability Evaluations
15.6.1
ECOG Performance Status
ECOG Performance Status information is collected on the “ECOG Performance Status” eCRF page.
ECOG Performance Status will be summarized using shift tables showing baseline versus minimum 
and maximum on-treatment values. Participants without baseline or on-treatment post-baseline results 
will be presented in the “Missing” category and will contribute to the denominator. Refer to Section 
9.7 for the definition of on-treatment.
Listings of each participant’s ECOG Performance Status over time will be provided.
15.6.2
Electrocardiogram (ECG)
Triplicate 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT and QTcF intervals. Electrocardiogram (ECG) results will be read 
locally, and all the three results will be reported in EDC. 
For each of the ECG parameters (HR, and QT, QTcF, QRS, PR intervals), descriptive statistics for the 
average at baseline, at each post-baseline time point and changes from baseline at each post-baseline 
time point will be presented. Scheduled visits performed during the safety run-in are to be presented,
too.
The ECG assessment [Normal, Abnormal (not clinically significant), Abnormal (clinically significant)] 
will be presented as a shift table showing baseline versus the worst on-treatment result. For the 
derivation of the worst on-treatment value, measurements collected during the safety run-in should be 
considered too. Refer to Section 9.7 for the definition of on-treatment.
The change in QT interval corrected for the heart rate by the Fridericia’s formula (i.e. QTcF) between 
baseline and the worst (longest) on-treatment result will be summarized in shift tables as follows:
Categorical shift from baseline to worst on-treatment value for the QTcF:
Parameter
Baseline category
Worst on-treatment value 
QTc (Fridericia)
<= 450 ms
> 450 ms
> 480 ms
> 500 ms
<= 450 ms
> 450 ms
> 480 ms
> 500 ms
Document No. 
Object No. 


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D       P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi m a b
M S 2 0 2 2 0 2 _ 0 0 0 2
v 1. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 6 /6 1
Cate g orical s hift fr o m baseli ne t o w orst o n-treat me nt c ha n ge fr o m baseli ne f or t he Q Tc F: 
Para meter
Baseli ne cate g or y
W orst c ha n ge fr o m baseli ne 
Q Tc ( Fri dericia)
< = 4 5 0 ms
> 4 5 0 ms
> 4 8 0 ms
> 5 0 0 ms 
< = 3 0 ms
> 3 0 ms
> 6 0 ms 
T he Q Tc F will be c ollecte d i n t he e C R F pa ge; if t he E C G mac hi ne o nl y  pr o vi des t he Q T i nter val 
c orrecte d wit h t he Bazett f or m ula, t he e C R F will use it t o a ut o maticall y  calc ulate t he Q Tc F.
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 at eac h p ost -baseli ne ti me p oi nt. H o we ver, t h e y will be use d i n t he deri vati o n of w orst 
o n-treat me nt val ues.
Listi n gs of all partici pa nts E C G res ults will be prese nte d. A fla g will be use d t o i n dicate w hic h 
meas ure me nts bel o n g t o t he o n -treat me nt peri o d.
Ec h o car di o gra m res ults fr o m meas ure me nts perf or me d at scree ni n g a n d at t he e n d of treat me nt visit 
will als o be liste d.
D oc u me nt N o. 
O bject N o. 
C CI
C CI
C CI


M S C 2 1 5 6 1 1 9 J, M S B 0 0 1 0 4 4 2 D       P h ase II si n gle ar m st u d y of te p oti ni b c o m bi ne d wit h cet u xi m a b
M S 2 0 2 2 0 2 _ 0 0 0 2
v 1. 0
C O N F I D E N T I A L
I N F O R M A T I O N
5 7 /6 1
1 6. 2
P h ar m ac o d y n a mics
N o s pecific p har mac o d y na mic a nal ys is will be perf or me d.
1 6. 3
P atie nt Re p orte d O utc o me
N o patie nt re p orte d o utc o me data will be c ollecte d .
D oc u me nt N o. 
O bject N o. 
C CI


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17
References
Brookmeyer, R., and Crowley, J. (1982). “A Confidence Interval for the Median Survival Time.” 
Biometrics 38:29–41.
Clopper, C. J., and Pearson, E. S. (1934). “The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial.” Biometrika 26:404–413.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: revised 
RECIST guideline (Version 1.1). Eur J Cancer. 2009;45: 228-247.
James D. Brierley (Editor), Mary K. Gospodarowicz (Editor), Christian Wittekind (Editor). TNM 
Classification of Malignant Tumours, 8th Edition, ISBN: 978-1-119-26357-9, January 2017, Wiley-
Blackwell, 272 Pages
Kalbfleisch, J. D., and Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data. New York: 
John Wiley & Sons.
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18
Appendices
18.1
Appendix 1 – NCI-CTC Gradable and Non-Gradable Safety 
Laboratory Test Parameters and Direction(s) of Abnormality
NCI-CTC gradable parameters
Laboratory Assessment
Parameters 
Name in NCI-CTC
Direction(s) of 
abnormality
Hematology
Hemoglobin
Anemia/Hemoglobin increased
Low/High
Leukocytes (WBC)
White blood cell decreased / Leukocytosis 
Low/High
Neutrophils
Neutrophil count decreased 
Low
Lymphocytes
Lymphocyte count decreased / increased
Low/High
Eosinophils
Eosinophila [a]
High
Platelets
Platelet count decreased
Low
Biochemistry
Albumin
Hypoalbuminemia 
Low
Alanine Aminotransferase 
(ALT)
Alanine Aminotransferase increased [a]
High
Aspartate Aminotransferase 
(AST)
Aspartate Aminotransferase increased [a]
High
Alkaline Phosphatase
Alkaline Phosphatase increased [a]
High
Gamma Glutamyl Transferase 
(GGT)
GGT increased [a]
High
Total Bilirubin
Blood bilirubin increased [a]
High
Amylase
Serum amylase increased 
High
Lipase
Lipase increased 
High
Creatinine
Creatinine increased [a]
High
Sodium
Hyponatremia / Hypernatremia
Low / High
Potassium
Hypokalemia / Hyperkalemia
Low / High
Calcium
Hypocalcemia / Hypercalcemia
Low / High
Glucose
Hypoglycemia / Hyperglycemia
Low / High
Coagulation
Activated Partial 
Thromboplastin Time
Activated Partial Thromboplastin Time 
prolonged
High
Prothrombin Intl. Normalized 
Ration (INR)
INR increased
High
Note: parameters with both Low and High directions of abnormality are going to be split. For example, Calcium is going to be 
split in Calcium Low and Calcium High.
a on-treatment grading dependent on baseline status.
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NCI-CTC non-gradable parameters
Laboratory Assessment
Parameters 
Hematology
Hematocrit 
Mean corpuscular volume (MCV)
Mean corpuscular hemoglobin (MCH)
Reticulocytes
Reticulocytes/Erythrocytes
Neutrophils/Leukocytes (%) 
Lymphocytes/Leukocytes (%)
Basophils
Basophils/Leukocytes (%)
Eosinophils/Leukocytes (%)
Monocytes
Monocytes/Leukocytes (%)
Biochemistry
Total Protein
Urea Nitrogen (BUN)
Serum cystatin C
Coagulation
Prothrombin Time
Prothrombin Time/Standard
Urinalysis
Blood
Bacteria (Microscopic analysis)
Casts (Microscopic analysis)
Crystals (Microscopic analysis)
Epithelial Cells (Microscopic analysis)
Bilirubin
Glucose in Urine
Urobilinogen
Ketones
Nitrite
pH
Proteins in Urine
Erythrocytes in Urine (Microscopic analysis)
Leukocytes esterase
Leukocytes in Urine (Microscopic analysis)
Specific gravity
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18.2
Appendix 2 – Correspondence between TNM classification, 
clinical stage and subgroup level
TNM Classification Version 8
Subgroup Level 
Stage
T
N
M
Advanced
IIIB
T1/T2
N3
M0
T3/T4
N2
M0
IIIC
T3/T4
N3
M0
Metastatic
IV
Any T
Any N
M1
IVA
Any T
Any N
M1a
IVB
Any T
Any N
M1b
IVC
Any T
Any N
M1c
TNM Classification Version 7
Subgroup Level 
Stage
T
N
M
Advanced
IIIB
T1/T2/T3
N3
M0
T4 
N1/N2/N3
M0
Metastatic
IV
Any T
Any N
M1
T = tumour, N = nodus, M = metastases.
Note: the use of either TNM version 8 or version 7 does not affect the categorization of participants in 
“Advanced” or “Metastatic”.
Document No. 
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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 2 2 0 2- 0 0 0 2-i a p
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)
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val
2 1- A pr- 2 0 2 1 1 2: 1 1
Tas k C o m plete d ( A p pr o val
e Si g n): A p pr o ve d
B usi ness A p pr o val
2 2- A pr- 2 0 2 1 1 2: 3 3
D oc u me nt N o. 
O bject N o. 
P P D
P P D