A Phase 1b/2 Dose Escalation and Expansion Study of Tucatinib in Combination With Trastuzumab and Oxaliplatin-based Chemotherapy or Pembrolizumab-containing Combinations for HER2+ Gastrointestinal Cancers
Phase: PHASE2
Conditions: Colorectal Carcinoma, Gastric Adenocarcinoma, GEJ Adenocarcinoma, Esophageal Adenocarcinoma, Cholangiocarcinoma, Gallbladder Carcinoma
Sponsor: Seagen, a wholly owned subsidiary of Pfizer

T his d oc u me nt a n d acc o mp a n y i n g ma terials c o ntai n c o nfi de ntial i nf or mati o n bel o n gi n g t o Pfizer. E xce pt as 
ot her wise a gree d t o i n writi n g, b y acce pti n g or re vie wi n g t hese d oc u me nts, y o u a gree t o h ol d t his i nf or mati o n i n 
c o nfi de nce a n d n ot c o p y or disc l ose it t o ot hers (e xce pt w here re q uire d b y  ap plica ble la w) or use it f or 
u na ut h orize d p ur p oses. I n t he e ve nt of a n y act ual or s us pecte d breac h of t he o bli gati o n, Pfizer m ust be pr o m ptl y 
n otifie d.
TI T L E P A G E
Pr ot oc ol N u m ber:
C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Versi o n:
A me n d me nt 0 6, 0 6 -N o v -2 0 2 4
Pr ot oc ol Title:
A p hase 1 b / 2 d ose escalati o n a n d e x pa nsi o n st u d y of t ucati ni b 
i n c o m bi nati o n wit h trast uz u ma b a n d o xali plati n-base d 
c he m ot hera p y o r pe m br oliz u ma b-c o ntai ni n g c o m bi nati o ns f or 
H E R 2 + gastr oi ntesti nal ca ncers
I n vesti g ati o n al 
Pr o d uct:
T ucati ni b
Brief Title:
T ucati ni b pl us trast uz u ma b a n d o xali plati n -base d 
c he m ot hera p y o r pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns f or 
H E R 2 + gastr oi ntesti nal ca ncers
P h ase:
1 b/ 2
I N D N u m ber:
1 3 4 8 4 0
S p o ns or:
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer
2 1 8 2 3 3 0t h Dri ve S E
B ot hel l, W A 9 8 0 2 1, U S A
S A E E m ail or F a x:
See e mail or fa x n u m ber s pecifie d o n t he S A E re p ort f or m.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 of 2 2 0
D O C U M E N T HI S T O R Y
Versi o n
Date
Ori gi nal
1 3 -A pr -2 0 2 0
A me n d me nt 1
0 5 -A u g -2 0 2 0
A me n d me nt 2
0 2 -Dec -2 0 2 0
A me n d me nt 2. 1
0 1 -Mar -2 0 2 1
A me n d me nt 3. 0
1 6 - Se p-2 0 2 1
A me n d me nt 3. 1
2 7 - Se p-2 0 2 1
A me n d me nt 4. 0
2 1 -Dec -2 0 2 1
A me n d me nt 5. 0
2 9 -Mar -2 0 2 4
A me n d me nt 6. 0
0 6- N o v -2 0 2 4
1. P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S ( S O C) T A B L E
A m e n d me nt 0 6 ( 0 6- N O V- 2 0 2 4)
O ver all R ati o n ale f or t he A me n d me nt: T he pri mar y  p ur p ose of t his a me n d me nt is t o ali g n 
wit h Pfizer re q uire d safet y  re p orti n g re q uire me nts a n d t o i nc or p orate ot her Pfizer s pecific 
te xt, re q uire me nts, a n d f or matti n g acr oss t he d oc u me nt.
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # a n d N a m e
S u bst a nti al M o dific ati o ns
N e w  secti o n pr o vi di n g details 
a b o ut re p orti n g lac k of efficac y.
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
Secti o n 9. 5. 1. 5 Lac k of Efficac y
N o n -S u bst a nti al M o dific ati o ns
A dj uste d te xt t o ali g n wit h Pfizer 
ma na ge me nt of o ver d ose 
g ui deli nes. A d de d te xt: O ver d ose 
is re p orta ble t o Pfizer Safet y o nl y 
w he n ass ociate d wit h a n S A E.
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
Secti o n 7. 1 2. 1 T ucati ni b 
( S u bsecti o n of Ma na ge me nt of 
O ver d ose);
Secti o n 7. 1 2. 2 Pe m br oliz u ma b 
( S u bsecti o n of Ma na ge me nt of 
O ver d ose)
A d de d refere nce t o A p pe n di x G 
f or m ore details o n rec or di n g a n d 
re p orti n g A Es a n d S A Es
A d de d te xt o n c o nsi derati o ns i n
deter mi ni n g t o rec or d a test 
res ult, me dical c o n diti o n, or ot her 
i nci de nt on A E eC R F. A d de d
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms
Secti o n 9. 5. 1 A d verse E ve nts
Secti o n 9. 5. 1. 1 Defi niti o ns, i n t he 
A d verse E ve nt s u bsecti o n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 of 2 2 0
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # a n d N a m e
ne w b ullets of te xt a b o ut e ve nts 
N O T meeti n g t he A E defi niti o n.
T o t he S A E defi niti o ns ta ble, 
a d de d te xt wit h a d diti o nal details 
f or t he ter ms “ H os pitalizati o n” 
a nd “ Disa bli n g/i nca pacitati n g
A d de d te xt wit h details if t he
i n vesti gat or d oes n ot k n o w if t he 
st u d y i nter ve nti o n ca use d t he 
e ve nt or n ot
A d de d te xt refere nci n g secti o ns 
wit h i nf or mati o n o n pr oce d ures 
f or A E SIs bei n g re p orte d as A Es 
or S A Es a n d t o i n dicate t he S A E 
s h o ul d be re p orte d t o Pfizer 
Safet y usi n g Pfizer S A E 
S u b missi o n Assista nt ( P S S A).
Re m o ve d o ver d ose of t ucati ni b or 
pe m br oliz u ma b fr o m A E SIs.
Secti o n 9. 5. 1. 1 Defi niti o ns, u n der 
ta ble i n t he “ Seri o us A d verse 
E ve nts” s u bsecti o n
Secti o n 9. 5. 1. 2 A d verse E ve nts of 
S pecial I nterest
Refere nce d a d diti o nal details o n 
rec or di n g A Es. 
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
Secti o n 9. 5. 1. 3 Pr oce d ures f or 
Eliciti n g a n d Rec or di n g A d verse 
E ve nts, u n der s u bsecti o n 
“ Rec or di n g Seri o us A d verse 
E ve nts”
A d de d c o nte nt pr o vi di n g
defi niti o ns a n d g ui da nce o n 
e n vir o n me ntal e x p os ure, 
e x p os ure d uri n g pre g na nc y, 
e x p os ure d uri n g breastfee di n g, 
a n d occ u pati o nal e x p os ure. 
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
Secti o n 9. 5. 1. 4 E n vir o n me ntal
E x p os ure , E x p os ure D uri n g 
Pre g na nc y or Breastfee di n g, a n d 
Occ u pati o nal E x p os ure (i ncl u di n g 
Secti o n 9. 5. 1. 4. 1 E n vir o n me ntal 
E x p os ure, Secti o n 9. 5. 1. 4. 2 
E x p os ure D uri n g Pre g na nc y , 
Secti o n 9. 5. 1. 4. 3 E x p os ure D uri n g
Breastfee di n g, a n d Secti o n 
9. 5. 1. 4. 4 Occ u pa ti o nal E x p os ure)
U p date d secti o n t o a d d re q uire d 
Pfizer pr ot oc ol te m plate la n g ua ge 
a b o ut safet y re p orti n g after t he 
partici pa nt has c o m plete d st u d y 
partici pati o n or if a partici pa nt 
has starte d a ne w  a ntica ncer 
t hera p y. 
T o s u p p ort St u d y tra nsiti o n t o 
Pf izer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
Secti o n 9. 5. 1. 7 Re p orti n g Peri o ds 
f or A d verse E ve nts a n d Seri o us 
A d verse E ve nts
U p date d secti o n t o a d d re q uire d 
Pfizer pr ot oc ol te m plate la n g ua ge 
a n d re m o ve re d u n da nt te xt d ue t o 
t his u p date.
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
Secti o n 9. 5. 1. 8 Seri o us A d verse 
E ve nts Re q uire I m me diate 
Re p orti n g
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 of 2 2 0
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # a n d N a m e
U p date secti o n wit h a d diti o nal 
re q uire d Pfizer pr ot oc ol te m plate 
la n g ua ge a b o ut S U S A Rs or ot her 
s pecific safet y i nf or mati o n.
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
Secti o n 9. 5. 1. 9 S p o ns or Safet y 
Re p orti n g t o Re g ulat or y A ut h orities
U p date d secti o n w it h a d diti o nal 
Pfizer pr ot oc ol te m plate la n g ua ge 
a b o ut pre g na nc y testi n g.
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
Secti o n 9. 5. 5 Pre g na nc y Testi n g
Re m o ve d re d u n da nt te xt a b o ut 
A E SIs bei n g re p orte d si nce
seri o us A E SIs will be re p orte d as 
S A Es. O nl y S A Es a n d 
pre g na ncies will be re p orte d 
usi n g t he P S S A d uri n g t he L T E P 
p orti o n of t he st u d y. .
C o nsiste nc y wit h u p date s ma de 
i n ot her secti o ns f or safet y 
re p orti n g nee de d as st u d y
tra nsiti o ns t o Pfizer 
P har m ac o vi gila nce pr ocesses a n d 
s yste ms
Secti o n 5. 1. 8 L o n g -Ter m  E xte nsi o n 
P hase;
Secti o n 8. 1 Sc he d ule of E ve nts;
Secti o n 1 0. 2 Data Ma na ge me nt 
Pr oce d ures;
A d de d te xt t o ali g n wit h Pfizer 
pr ot oc ol te m plate a b o ut sa m ple 
destr ucti o n i n t he e ve nt of 
partici pa nt wit h dra wal a n d t o 
i n dicate if t he partici pa nt 
wit h dra ws fr o m t he st u d y a n d 
als o wit h dra ws c o nse nt f or 
c ollecti o n of f ut ure i nf or mati o n, 
n o f urt her e val uati o ns will be 
perf or me d, a n d n o a d diti o nal data 
will be c ollecte d e xce pt f or 
p u blicl y a vaila ble i nf or mati o n i n 
acc or da nce wit h l ocal la w. T he 
s p o ns or ma y retai n a n d c o nti n ue 
t o use a n y data c ollecte d bef ore 
s uc h wit h dra wal of c o nse nt.
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 6. 4. 2 Partici pa nt 
Wit h dra w al fr o m St u d y
A d de d t his secti o n t o pr o vi de 
details a b o ut wit h dra w al of 
c o nse nt.
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 6. 4. 3 Wit h dra w al of 
C o ns e nt
A d de d Pfizer re q uire d te xt 
i ncl u di n g la n g ua ge a b o ut 
pre parati o n, ha n dli n g, st ora ge, 
a n d acc o u nta bilit y a p plica ble t o 
all st u d y i nter ve nti o ns, 
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 7. 1 Pre parati o n, Ha n dli n g, 
St ora ge, a n d Acc o u nta bilit y
A d de d Secti o n f or Si n gle 
Refere nce Safet y D oc u me nts 
( S R S D) i nf or mati o n
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 7. 2 Si n gle Refere nce Safet y 
D oc u me nt
A d de d t h ese secti o ns t o pr o vi de 
i nf or mati o n t o cli nical trial staff 
me m bers a b o ut pre parati o n a n d 
dis pe nsi n g t ucati ni b, F O L F O X or 
C A P O X c he m ot hera p y a ge nts , or 
pe m br oliz u ma b .
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 7. 4. 6 Pre parati o n a n d 
Dis pe nsi n g (f or t ucati ni b)
Secti o n 7. 5. 5 Pre parati o n a n d 
Dis pe nsi n g (f or F O L F O X)
Secti o n 7. 6. 5 Pre parati o n a n d 
Dis pe nsi n g (f or C A P O X)
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 of 2 2 0
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # a n d N a m e
Secti o n 7. 8. 6 Pre parati o n a n d 
Dis pe nsi n g (f or pe m br oliz u ma b)
Place d te xt a b o ut pre parati o n 
u n der ne w hea di n g Secti o n 7. 7. 6 
(see bel o w).
T o c o ns oli date pre parati o n te xt 
i nt o pre parati o n a n d dis pe nsi n g
secti o n of d oc u me nt
Secti o n 7. 7. 3 D ose a n d 
A d mi nistrati o n (f or trast uz u ma b)
Rel ocate d place me nt of st ora ge 
relate d te xt.
T o c o ns oli date st ora ge te xt i nt o 
st ora ge secti o n of d oc u me nt
Secti o n 7. 7. 4 St ora ge a n d Ha n dli n g 
(f or trast uz u ma b)
A d de d a hea der a n d ma de mi n or 
te xt a dj ust me nts.
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 7. 7. 6 Pre parati o n a n d 
Dis pe nsi n g (f or trast uz u ma b)
Rel ocate d te xt a b o ut pre parati o n 
of pe m br oliz u ma b i nf usi o n a n d 
a d mi nistrati o n of i nf usi o n 
s ol uti o n t o Secti o n 7. 8. 6.
T o c o ns oli date te xt a b o ut 
pre parati o n i nt o o ne secti o n t o 
ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate .
Secti o n 7. 8. 3 D ose a n d 
A d mi nistrati o n (f or 
pe m br oliz u ma b)
A d de d te xt a b o ut treat me nt of 
i m m u ne-relate d A Es base d o n 
se verit y.
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 7. 9. 5. 1 I m m u ne -Relate d 
E ve nts a n d D ose M o dificati o ns 
( Wit h h ol d, Treat, Disc o nti n ue) 
s u bsecti o n “ Treat me nt of I m m u ne-
relate d A d verse E ve nts” 
A d de d te xt a b o ut s u p p orti ve care 
f or h y perse nsiti vit y reacti o ns a n d 
t o i n dicate partici pa nts s h o ul d be 
cl osel y o bser ve d w hile recei vi n g 
st u d y i nter ve nti o n i nf usi o ns a n d 
m o nit ore d f or cli nical si g ns of a 
s yste mic reacti o n.
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 7. 9. 7 
Aller gic/ H y perse nsiti vit y Reacti o ns
A d de d le vel 3 hea di n g t o t his 
secti o n
A d m i nistrati ve
Secti o n 7. 9. 8 A na p h yla xis
Re m o ve d “a n d A E SIs” fr o m first 
b ullet
O nl y pre g na ncies a n d S A Es will 
be re p orte d d uri n g t he L T E P
Secti o n 8. 6 L o n g -ter m E xte nsi o n 
P hase – Be gi n ni n g of eac h C ycle 
a n d E n d of Treat me nt
A dj uste d l ocati o n of t his secti o n 
hea di n g s o t hat it e nc o m passe d 
pre g na nc y test b ullet p oi nts 
pre vi o usl y i n f oll o w - u p secti o n.
M o ve secti o n hea der t o m ore 
a p pr o priate l ocati o n .
Secti o n 8. 9 E n d of St u d y
U p date secti o n wit h a d diti o nal 
re q uire d Pfizer pr ot ocol te m plate 
la n g ua ge a b o ut m o dificati o ns 
all o we d f or t he S A P a n d t hat 
maj or m o dificati o ns m ust be 
reflecte d i n a pr ot oc ol 
a me n d me nt. 
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Secti o n 1 1. 3 Statistical a n d 
A nal ytical Pla ns
C o nte nt u p date t o use Pfizer 
t e mpl ate te xt – ori gi nal te xt t hat 
is re d u n da nt (i m pacts se veral 
s u bsecti o ns) was re m o ve d. 
Secti o n title was u p date d fr o m 
“I nf or me d C o nse nt, Et hical 
Re vie w,  a n d Re g ulat or y 
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer pr ocesses a n d t o ali g n wit h 
re q uire d Pfizer pr ot oc ol te m plate 
la n g ua ge.
Secti o n 1 2 Re g ulat or y, Et hical, a n d 
St u d y O versi g ht C o nsi derati o ns 
i ncl u des s u bsecti o n 1 2. 2 t hr o u g h 
1 2. 1 1
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 of 2 2 0
Descri pti o n of C h a n ge
Brief R ati o n ale
Secti o n # a n d N a m e
C o nsi derati o ns” t o “ Re g ulat or y, 
Et hical, a n d St u d y O versi g ht 
C o nsi derati o ns.”
Re m o val of I n vesti gat or’s 
a gree me nt a n d t he i n vesti gat or’s 
si g nat ure.
T he i n vesti gat or’s a gree me nt a n d 
si g nat ure are pers o nal i de ntifia ble 
i nf or mati o n.
F or m er A p pe n di x G 
C ha n ge Title of A p pe n di x t o 
Pr oce d ures f or Rec or di n g a n d 
Re p orti n g A Es a n d S A Es a n d 
a d de d preferre d Pfizer te xt n ot 
ca pt ure d i n b o d y of d oc u me nt t o 
i ncl u de a d diti o nal details rele va nt 
f or safet y re p orti n g.
T o s u p p ort St u d y tra nsiti o n t o 
Pfizer P har mac o vi gila nce 
pr ocesses a n d s yste ms.
U p date d A p pe n di x G
A d de d a n A p pe n di x “ hea di n g” t o 
h o use t he s u m mar y of c ha n ges 
ta bles f or all pri or a me n d me nts
A d mi nistrati ve u p date
A p pe n di x H S u m mar y of C ha n ges 
f or Pri or A me n d me nts 
A d de d Pfizer st u d y i de ntifier; 
A d de d state me nt i n dicati n g 
Sea ge n I nc. is a w h oll y o w ne d 
s u bsi diar y of Pfizer i n 
a p pr o priate l ocati o ns
T o ali g n wit h t he Pfizer pr ot oc ol 
t e mplate a n d t o pr o vi de Pfizer 
st u d y i de ntifier.
Title Pa ge;
S y n o psis;
F o oters t hr o u g h o ut 
Re m o ve d Me dical M o nit or a n d 
St u d y Direct or’s na me a n d 
c o ntact i nf or mati o n
T he me dical m o nit or’s na me a n d 
c o ntact i nf or mati o n is pers o nal 
i de ntifia ble i nf ormati o n
Title pa ge
U p date c o nfi de ntialit y state me nt
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
Title pa ge
M o ve d D oc u me nt Hist or y fr o m 
e n d of d oc u me nt t o pa ge 
i m me diatel y f oll o wi n g t he Title 
Pa ge
T o ali g n wit h Pfizer’s Pr ot oc ol 
T e m plate
D oc u me nt Hist or y Pa ge (t his was 
f or merl y A p pe n di x H at e n d of t he 
d oc u me nt; b ut was m o ve d t o pa ge 
i m me diatel y f oll o wi n g Title pa ge)
Re place d “ pac ka ge i nsert” wit h 
“ pr o d uct la bel” or “l o cal pr o d uct 
la beli n g.”
Pr o vi de m ore i nf or mati o nal 
ter mi n ol o g y of pr o d uct la beli n g 
or pr o d uc t la bel.
T hr o u g h o ut d oc u me nt  
A d mi nistrati ve u p dates i ncl u di n g, 
b ut n ot li mite d t o: u p dati n g 
“s u bject” t o “ partici pa nt,” 
u p dati n g “st u d y dr u g” t o “st u d y 
i nter ve nti o n,” a n d ot her mi n or 
e dit orial m o dificati o ns. U p dates 
t o secti o n n u m beri n g or a p pe n di x 
la bels were ma de t o meet Pfizer 
re q uire me nts.
A d mi nistrati ve u p dates t o ali g n 
wit h Pfizer d oc u me nt f or mat a n d 
re q uire me nts a n d/ or mi n or 
clarificati o ns.
T hr o u g h o ut d oc u me nt
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 of 2 2 0
2. P R O T O C O L S Y N O P SI S
Pr ot oc ol N u m ber
C 4 2 5 1 0 0 5; S G N T U C- 0 2 4
Versi o n
A me n d me nt 0 6
P h ase
1 b/ 2
Pr o d uct N a m e
T ucati ni b
S p o ns or
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer
2 1 8 2 3 3 0t h Dri ve S E
B ot hell, W A 9 8 0 2 1, U S A
Pr ot oc ol Title
A p hase 1 b / 2 d ose escalati o n a n d e x pa nsi o n st u d y of t ucati ni b i n c o m bi nati o n wit h 
trast uz u ma b a n d o xali plati n-base d c he m ot hera p y or pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns 
f or H E R 2 + gastr oi ntesti nal ca ncers.
St u d y O bjecti ves
P h ase 1 b T uc ati ni b D ose Esc al ati o n wit h Tr a st uz u m a b a n d F O L F O X ( C o h ort 1 A a n d 
C o h ort 1 B)
Pri mar y O bjecti ve
C orres p o n di n g Pri mar y E n d p oi nt

T o deter mi ne t he rec o m me n de d d ose of t ucati ni b 
w he n c o m bi ne d wit h trast uz u ma b a n d o xali plati n -
base d c he m ot hera p y  i n partici pa nts wit h h u ma n 
e pi der mal gr o wt h fact or rece pt or 2 p ositi ve 
( H E R 2 +) gastr oi ntesti nal ( GI) ca ncers

I nci de nce of re nal d ose-li miti n g t o xicities 
( D L Ts)
Sec o n dar y O bjecti ves
C orres p o n di n g Sec o n dar y E n d p oi nts

T o e val uate t he safet y  a n d t olera bilit y of t ucati ni b 
i n c o m bi nati o n wit h trast uz u ma b a n d o xali plati n-
base d c he m ot hera p y  

T y pe, i nci de nce, se verit y, seri o us ness, 
a n d relate d ness of a d verse e ve nts ( A Es) 
a n d la b orat or y a b n or malities

Vital si g ns a n d ot her rele va nt safet y  
varia bles

T o e val uate t he c o m bi nati o n of t ucati ni b, 
trast uz u ma b, a n d o xali plati n-base d c he m ot hera p y  
f or p ote ntial ne p hr ot o xicit y 

C ha n ge i n gl o mer ular filtrati o n rate 
( G FR), as esti mate d usi n g ser u m 
c ystati n C, fr o m baseli ne t hr o u g h 2 c ycles 
of c o m bi nati o n t hera p y

T o e val uate t he p har mac o ki netics ( P K) of 
t ucati ni b

P K para meters of t ucati ni b (i ncl u di n g b ut 
n ot li mite d t o A U C last, Cma x , Ctr o u g h, a n d 
T ma x )

T o e val uate t he P K of o xali plati n i n t he prese nce 
a n d a bse nce of t ucati ni b

P K para meters of o xali plati n (i ncl u di n g 
b ut n ot li mite d t o A U C last, Cma x, Tma x )
E x pl orat or y O bjecti ves
C orres p o n di n g E x pl orat or y E n d p oi nts

T o e val uate t he a ntit u m or acti vit y  of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b, a n d o xali plati n -
base d c he m ot hera p y

O bjecti ve res p o nse rate ( O R R) acc or di n g 
t o Res p o nse E val uati o n Criteria i n S oli d 
T u m ors ( R E CI S T) v 1. 1 per i n vesti gat or 
assess me nt (I N V)

T o e x pl ore c orrelati o ns bet wee n tiss ue a n d 
bl o o d -base d bi o mar kers a n d cli nical o utc o mes

P ote ntial bi o mar kers of res p o nse, 
resista nce, or t o xicit y ma y be e val uate d i n 
tiss ue a n d bl o o d
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 of 2 2 0
P h ase 1 b S afety Ev al u ati o n of T uc ati ni b i n C o m bi n ati o n wit h Tr ast uz u m a b + C A P O X 
( C o h ort 1 C), or i n C o m bi n ati o n wit h Tr ast uz u m a b a n d Pe m br oliz u m a b-C o nt ai ni n g 
C o m bi n ati o ns ( C o h orts 1 E, 1 F, a n d 1 G)
Pri mar y O bjecti ves
C orres p o n di n g Pri mar y E n d p oi nts

T o e val uate t he safet y  a n d t olera bilit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI  ca ncers

T y pe, i nci de nce, se verit y, seri o us ness, a n d 
relate d ness of A Es, i ncl u di n g D L Ts, a n d 
la b orat or y a b n or malities

Vital si g ns a n d ot her rele va nt safet y  
varia bles
Sec o n dar y O bjecti ves
C orres p o n di n g Sec o n dar y E n d p oi nts

T o e val uate t he a ntit u m or acti vit y  of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI  ca ncers as meas ure d b y o bjecti ve res p o nse rate 
( O R R) acc or di n g t o RE CI S T v 1. 1 per I N V

O R R acc or di n g t o R E CI S T v 1. 1 per I N V

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI  ca ncers as meas ure d b y d urati o n of res p o nse 
( D O R) acc or di n g t o R E CI S T v 1. 1 per I N V

D O R (c o nfir me d C R or P R) acc or di n g t o 
R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI  ca ncers as meas ure d b y pr o gressi o n-free s ur vi val 
( P FS) acc or di n g t o R E CI S T v 1. 1 per I N V

P F S acc or di n g t o R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucatini b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI  ca ncers as meas ure d b y o verall s ur vi val ( O S)

O S 

T o e val uate t he P K of t ucati ni b

P K para meters of t ucati ni b (i ncl u di n g b ut 
n ot li mite d t o C tr o u g h)
E x pl orat or y O bjecti ve
C orres p o n di n g E x pl orat or y E n d p oi nt

T o e x pl ore c orrelati o ns bet wee n tiss ue a n d 
bl o o d -base d bi o mar kers a n d cli nical o utc o mes

P ote ntial bi o mar kers of res p o nse, 
resista nce, or t o xicit y ma y be e val uate d i n 
tiss ue a n d bl o o d
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 of 2 2 0
P h ase 1 b J a p a n S afety Ev al u ati o n of T uc ati ni b i n C o m bi n ati o n wit h Tr ast uz u m a b a n d 
F O L F O X ( C o h ort 1 D)
Pri mar y O bjecti ve
C orres p o n di n g E n d p oi nts

T o assess t he safet y  a n d 
t olera bilit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d 
F O L F O X i n Ja pa nese partici pa nts

T y pe, i nci de nce, se verit y, seri o us ness, a n d 
relate d ness of A Es, i ncl u di n g D L Ts, a n d 
la b orat or y a b n or malities

Vital si g ns a n d ot her rele va nt safet y  
varia bles

Fre q ue nc y  of d ose h ol ds, d ose re d ucti o ns, 
a n d disc o nti n uati o ns of t ucati ni b, 
trast uz u ma b, a n d c o m p o ne nts of FO L F O X 
E x pl orat or y O bjecti ve
C orres p o n di n g E n d p oi nts

T o assess t he P K of t ucati ni b 
w he n a d mi nistere d i n c o m bi nati o n 
wit h trast uz u ma b a n d F O L F O X i n 
Ja pa nese partici pa nts

P K para meters of t ucati ni b (i ncl u di n g b ut 
n ot li mite d t o A U C last, Cma x , Ctr o u g h, a n d 
T ma x )
P h ase 2 T u m or S pecific Ex p a nsi o n
Pri mar y O bjecti ves
C orres p o n di n g E n d p oi nts

C o h ort 2 A: T o e val uate t he safet y  a n d t olera bilit y of 
t ucati ni b c o m bi ne d wit h pe m br oliz u ma b, 
trast uz u ma b, a n d o xali plati n-base d c he m ot hera p y  
( F O L F O X or C A P O X) as first-li ne ( 1 L) t hera p y i n 
partici pa nts wit h u nresecta ble or metastatic H E R 2 + 
gastric, es o p ha geal, or gastr oes o p ha geal j u ncti o n 
( G EJ) a de n ocarci n o ma

C o h ort 2 B: T o e val uate t he safet y  a n d t olera bilit y of 
t ucati ni b c o m bi ne d wit h trast uz u ma b a n d FO L F O X 
i n partici pa nts wit h u nresecta ble or metastatic 
H E R 2 + c ol orectal a de n ocarci n o ma ( C R C) 

T y pe, i nci de nce, se verit y, seri o us ness, 
a n d relate d ness of A Es, i ncl u di n g D L Ts, 
a n d la b orat or y a b n or malities

Vital si g ns a n d ot her rele va nt safet y  
varia bles
Sec o n dar y O bjecti ves
C orres p o n di n g E n d p oi nts

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b 
c o m bi ne d wit h pe m br oliz u ma b, trast uz u ma b, a n d 
o xali pl ati n -base d c he m ot hera p y ( F O L F O X or 
C A P O X) as 1 L t hera p y f or H E R 2 + gastric, 
es o p ha geal, or G EJ a de n ocarci n o ma as meas ure d b y  
c o nfir me d o bjecti ve res p o nse rate (c O R R), acc or di n g 
t o R E CI S T v 1. 1 per I N V

c O R R (c o nfir me d c o m plete res p o nse 
[ C R] or partial res p o nse [ P R]) acc or di n g 
t o R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b 
c o m bi ne d wit h pe m br oliz u ma b, trast uz u ma b, a n d 
o xali plati n -base d c he m ot hera p y as 1 L t hera p y  f or 
H E R 2 + gastric, es o p ha geal, or G EJ a de n ocarci n o ma 
as meas ure d b y D O R acc or di n g t o R E CI S T v 1. 1 per 
I N V

D O R (c o nfir me d C R or P R) acc or di n g t o 
R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b 
c o m bi ne d wit h pe m br oliz u ma b, trast uz u ma b, a n d 

P F S acc or di n g t o R E CI S T v 1. 1 per I N V 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 of 2 2 0
o xali plati n -base d c he m ot hera p y a s 1 L t hera p y f or 
H E R 2 + gastric, es o p ha geal, or G EJ a de n ocarci n o ma 
as meas ure d b y P F S acc or di n g t o R E CI S T v 1. 1 per 
I N V

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b 
c o m bi ne d wit h pe m br oliz u ma b, trast uz u ma b, a n d 
o xa li plati n-base d c he m ot hera p y as 1 L t hera p y  f or 
H E R 2 + gastric, es o p ha geal, or G EJ a de n ocarci n o ma 
as meas ure d b y O S

O S 
E x pl orat or y O bjecti ves
C orres p o n di n g E n d p oi nts

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b 
c o m bi ne d wit h trast uz u ma b a n d o xali plati n -base d 
c he m ot hera p y ( F O L F O X) as 1 L + t hera p y f or H E R 2 + 
C R C as meas ure d b y  c O R R, acc or di n g t o R E CI S T 
v 1. 1 per I N V

c O R R ( C R or P R) acc or di n g t o R E CI S T 
v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b 
c o m bi ne d wit h trast uz u ma b a n d o xali plati n -base d 
c he m ot hera p y as 1 L + t hera p y f or H E R 2 + C R C as 
meas ure d b y  D O R acc or di n g t o R E CI S T v 1. 1 per 
I N V

D O R (c o nfir me d C R or P R) acc or di n g 
t o R E CI S T v 1. 1 per I N V 

T o e v al uate t he a nti-t u m or acti vit y of t ucati ni b 
c o m bi ne d wit h trast uz u ma b a n d o xali plati n -base d 
c he m ot hera p y as 1 L + t hera p y f or H E R 2 + C R C as 
meas ure d b y  P F S acc or di n g t o R E CI S T v 1. 1 per I N V

P F S acc or di n g t o R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b 
c o m bi ne d wit h trast uz u ma b a n d o xali plati n -base d 
c he m ot hera p y as 1 L + t hera p y f or H E R 2 + C R C as 
meas ure d b y  O S

O S 

T o e val uate t he P K of t ucati ni b gi ve n wit h 
pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n -base d 
che m ot hera p y  as 1 L t hera p y f or u nresecta ble or 
metastatic H E R 2 + gastric, es o p ha geal, or G EJ 
a de n ocarci n o ma ( C o h ort 2 A) a n d t o e val uate t he P K 
of t ucati ni b gi ve n wit h trast uz u ma b a n d o xali plati n -
base d c he m ot hera p y  as 1 L + t hera p y f or metastatic 
H E R 2 + C R C ( C o h ort 2 B)

P K para meter of t ucati ni b ( C tr o u g h) 

T o e x pl ore c orrelati o ns bet wee n tiss ue a n d bl o o d -
base d bi o mar kers a n d cli nical o utc o mes

P ote ntial bi o mar kers of res p o nse, 
resista nce, or t o xicit y ma y be e val uate d 
i n tiss ue a n d bl o o d
St u d y P o p ul ati o n
T his st u d y will e nr oll partici pa nts wit h u nresecta ble or metastatic h u ma n e pi der mal gr o wt h 
fact or rece pt or 2 ( H E R 2 +) es o p ha geal a de n ocarci n o ma, G EJ a de n ocarci n o ma, gastric 
a de n ocarci n o ma, C R C, c h ola n gi ocarci n o ma, or gall bla d der carci n o ma. A ta ble s u m marizi n g 
t he st u d y p o p ulati o n t o be e nr olle d i n eac h c o h ort is i ncl u de d u n der St u d y Desi g n.
I ncl usi o n Criteri a
1.
Partici pa nts m ust ha ve a n u nresecta ble or metastatic s oli d mali g na nc y  t hat is 
hist ol o gicall y  or c yt ol o gicall y c o nfir me d t o be o ne of t he t u m or t ypes liste d bel o w:
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 of 2 2 0
C o h orts 1 A, 1 B, 1 C, a n d 1 D

C ol orectal a de n ocarci n o ma ( C R C)

Gastric a de n ocarci n o ma

G EJ a de n ocarci n o ma

Es o p ha geal a de n ocarci n o ma

C h ola n gi ocarci n o ma

Gall bla d der carci n o ma
C o h orts 1 E, 1 F, 1 G, a n d 2 A

Gastric a de n ocarci n o ma

G EJ a de n ocarci n o ma

Es o p ha geal a de n ocarci n o ma
C o h ort 2 B

C R C
2.
Partici pa nts m ust be ca n di dates t o recei ve a n o xali plati n- base d re gi me n as part of t heir 
sta n dar d- of-care treat me nt f or all c o h orts, wit h t he e xce pti o n of C o h ort 1 G. Partici pa nts 
i n C o h orts 1 A, 1 B, 1 C, or 2 B ca n be recei vi n g a n o xali plati n -base d re gi me n d uri n g t he 
scree ni n g peri o d:

F or C o h orts 1 A a n d 1 B: u p t o 2 c o nsec uti ve c y cles of le uc o v ori n, fl u or o uracil, 
o xali plati n ( F O L F O X) ( ≤8 5 m g/ m 2 o xali plati n per 2 -wee k c y cle) ma y ha ve bee n 
recei ve d d uri n g t he scree ni n g peri o d pri or t o C ycle 1 Da y 1 of st u d y treat me nt. 

F or C o h orts 1 C: u p t o 2 c o nsec uti ve c y cles of F O L F O X ( ≤8 5 m g / m2 o xali plati n 
per 2 -wee k c y cle) or o ne c ycle of C A P O X (≤1 3 0 m g/ m 2 o x ali plati n per 3-wee k 
c ycle) ma y ha ve bee n recei ve d d uri n g t he scree ni n g peri o d pri or t o C ycle 1 Da y 1 
of st u d y  treat me nt. 

F or C o h orts 1 A, 1 B, 1 C: if partici pa nt has recei ve d o xali plati n i n pri or c y cles at 
hi g her d oses t ha n t h ose liste d a b o ve, t here m ust b e a mi ni m u m of 2 8 da ys off 
treat me nt pri or t o Cycle 1 Da y 1 of treat me nt i n t his st u d y. 

F or C o h ort 2 B pri or t o e nr oll me nt ( C y cle 1 Da y 1):
o
Partici pa nts ma y  ha ve recei ve d u p t o 1 c ycle of F O L F O X (≤8 5 m g/ m 2
o xali plati n per 2 -wee k c ycle) d uri n g t he scree ni n g peri o d pri or t o C y cle 1 
D a y  1 b ut ma y n ot ha ve recei ve d pri or o xali plati n f or metastatic disease
o
O xali plati n recei ve d i n a n a dj u va nt setti n g is per mitte d if > 6 m o nt hs pri or t o 
C y cle 1 Da y 1
o
At least 2 1 da y s m ust ha ve ela pse d fr o m pri or sys te mic a ntica ncer t hera p y 
(i ncl u di n g h or m o nal a n d bi ol o gic t hera py b ut e xcl u di n g 1 c ycle of 
F O L F O X), n o n -ce ntral ner v o us s ys te m ra diati o n, a n d treat me nt wit h ot her 
e x peri me ntal a ge nts 
3.
H E R 2 + disease, as deter mi ne d b y  hist oric or l ocal la b orat or y testi n g base d o n o ne of t he
f oll o wi n g:

F or C R C, c h ola n gi ocarci n o ma, a n d gall bla d der carci n o ma: 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 of 2 2 0
o
H E R 2 a m plificati o n or o vere x pressi o n fr o m fres h or arc hi val t u m or tiss ue 
utilizi n g o ne of t he f oll o wi n g tests pr ocesse d i n a Cli nical L a b orat or y 
I m pr o ve me nt A me n d me nts ( C LI A)- or I nter nati o nal Or ga nizati o n f or 
Sta n dar dizati o n (I S O) -accre dite d la b orat or y:
H E R 2 o vere x pressi o n ( 3 + i m m u n o hist oc he mistr y [I H C])
H E R 2 ( E R B B 2) a m plificati o n b y  i n sit u h ybri dizati o n assa y  (fl u oresce nce 
i n sit u h ybri dizati o n [ FI S H] or c hr o m o ge nic i n sit u h y bri dizati o n ( CI S H) 
si g nal rati o ≥2. 0 or ge ne c o p y  n u m ber > 6)
H E R 2 ( E R B B 2) a m plificati o n b y  ne xt ge nerati o n se q ue nci n g ( N G S) assa y
o
H E R 2 a m plificati o n i n a C LI A certifie d or I S O accre dite d bl o o d -base d N G S 
assa y 

F or Gastric, G EJ, a n d es o p ha geal a de n ocarci n o ma: H E R 2 
o v ere x pressi o n/a m plificati o n b y IH C a n d I SH (I H C 3 + or I H C 2 +/I S H +) fr o m a 
t u m or tiss ue sa m ple, pr ocesse d i n a C LI A- or I S O -accre dite d la b orat or y a n d 
e val uate d f oll o wi n g A S C O/ C A P g ui deli nes f or H E R 2 testi n g i n gastr oes o p ha geal 
a de n ocarci n o ma.
4.
P hase 1 b c o h orts: meas ura ble or n o n -meas ura ble disease acc or di n g t o Res p o nse 
E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) v 1. 1 as deter mi ne d b y t he i n vesti gat or
P hase 2 c o h orts: meas ura ble disease acc or di n g t o R E CI S T v 1. 1 as deter mi ne d b y  t he 
i n vesti gat or
5.
A ge 1 8 years or o l der at ti me of c o nse nt or ≥ t he a ge of maj orit y per re gi o nal 
re q uire me nts
6.
A n Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us sc ore of 0 or 1 
7.
Life e x pecta nc y  ≥3 m o nt hs, i n t he o pi ni o n of t he i n vesti gat or
8.
A de q uate he patic f u ncti o n, as defi ne d b y :

T otal bilir u bi n ≤1. 5 × u p per li mit of n or mal ( U L N), e xce pt f or partici pa nts wit h 
k n o w n Gil bert’s disease, w h o ma y  e nr oll if t he c o nj u gate d bilir u bi n is ≤1. 5 × U L N

Tra nsa mi nases (as partate a mi n otra nsferase [ A S T] a n d ala ni ne a mi n otra nsferase 
[ A LT]) ≤2. 5 × U L N ( ≤5 × U L N if li ver metastases are prese nt)
9.
A de q uate baseli ne he mat ol o gic para meters as defi ne d b y:

A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 5 × 1 0 ³/ µ L

Platelet c o u nt ≥1 0 0 × 1 0 ³/ µ L; partici pa nts wit h sta ble platelet c o u nt fr o m 7 5–
1 0 0 × 1 0³/ µ L  ma y be i ncl u de d wit h a p pr o val fr o m t he me dical m o nit or

He m o gl o bi n ≥8 g/ d L. Partici pa nts o n a sta ble d ose of er y t hr o p oieti n ( ≥ 
a p pr o xi matel y 3 m o nt hs) are eli gi ble.

I n partici pa nts tra nsf use d bef ore st u dy e ntr y, tra nsf usi o n m ust be ≥1 4 da y s pri or 
t o start of t hera py t o esta blis h a de q uate he mat ol o gic para meters i n de pe n de nt fr o m 
tra nsf usi o n s u p p ort
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 of 2 2 0
1 0. Esti mate d gl o mer ular filtrati o n rate ( G F R): 

C o h orts 1 A, 1 B: ≥9 0 m L/ mi n/ 1. 7 3 m ² usi n g t he M o dificati o n of Diet i n Re nal 
Disease ( M D R D) e q uati o n. 
o
Partici pa nts wit h esti mate d G F R ≥6 0 t o < 9 0 m L / mi n/ 1. 7 3 m² ma y be e nr olle d 
i n C o h ort 1 B wit h me dical m o nit or a p pr o val. 

C o h orts 1 C, 1 D, 1 E, 1 F, 2 A, a n d 2 B: ≥6 0 m L/ mi n/ 1. 7 3 m ² usi n g t he M D R D 
e q uati o n. 
1 1. I nter nati o nal n or malize d rati o (I N R) a n d partial t hr o m b o plasti n ti me ( P T T)/acti vate d 
partial t hr o m b o plasti n ti me (a P T T) ≤1. 5 × U L N, u nless o n me dicati o n k n o w n t o alter I N R 
a n d P T T/a P T T ( N ote: warfari n a n d ot her c o u mari n deri vati ves are pr o hi bite d f or 
partici pa nts recei vi n g C A P O X.)
1 2. Left ve ntric ular ejecti o n fracti o n ( L V E F) ≥5 0 % as assesse d b y ec h ocar di o g ra m ( E C H O) 
or m ulti gate d ac q uisiti o n ( M U G A) sca n d oc u me nte d wit hi n 4 wee ks pri or t o e nr oll me nt
1 3. Partici pa nts of c hil d beari n g p ote ntial u n der t he f oll o wi n g c o n diti o ns:
a
M ust ha ve a ne gati ve ser u m/ plas ma or uri ne pre g na nc y  test ( mi ni m u m se nsiti vit y 
2 5 mI U/ m L or e q ui vale nt u nits of beta h u ma n c h ori o nic g o na d otr o pi n [ β -h C G]) 
res ult 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. Partici pa nts wit h 
false p ositi ve res ults a n d d oc u me nte d verificati o n t hat t he partici pa nt is n ot 
pre g na nt are eli gi ble f or partici pati o n
b
M ust a gree n ot t o tr y  t o bec o me pre g na nt d uri n g t he st u d y a n d f or at least 
7 m o nt hs after t he fi nal d ose of st u d y treat me nt
c
M ust a gree n ot t o breastfee d or d o nate o va, starti n g at ti me of i nf or me d c o nse nt 
a n d c o nti n ui n g t hr o u g h 7 m o nt hs after t he fi nal d ose of st u d y treat me nt
d
If se x uall y acti ve i n a wa y t hat c o ul d lea d t o pre g na nc y, m ust c o nsiste ntl y use 
2 hi g hl y effecti ve met h o ds of birt h c o ntr ol starti n g at t he ti me of i nf or me d 
c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he st u d y a n d f or at least 7 m o nt hs after t he 
fi nal d ose of st u dy treat me nt 
1 4. Partici pa nts w h o ca n fat her c hil dre n, u n der t he f oll o wi n g c o n diti o ns:
a
M ust a gree n ot t o d o nate s per m starti n g at ti me of i nf or me d c o nse nt a n d 
c o nti n ui n g t hr o u g h o ut t he st u d y peri o d a n d f or at least 7 m o nt hs after t he fi nal 
d ose of st u d y  treat ment
b
If se x uall y acti ve wit h a pers o n of c hil d beari n g p ote ntial i n a wa y t hat c o ul d lea d 
t o pre g na nc y, m ust c o nsiste ntl y use 2 hi g hly effecti ve met h o ds of birt h c o ntr ol 
starti n g at ti me of i nf or me d c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he st u dy a n d f or 
at least 7 m o nt hs after t he fi nal d ose of st u d y treat me nt
c
If se x uall y acti ve wit h a pers o n w h o is pre g na nt or breastfee di n g, m ust 
c o nsiste ntl y use o ne of 2 c o ntrace pti o n o pti o ns starti n g at ti me of i nf or me d 
c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he st u d y a n d f or at least 7 m o nt hs after t he 
fi nal d ose of st u dy treat me nt 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 of 2 2 0
1 5. Partici pa nt m ust pr o vi de si g ne d i nf or me d c o nse nt t hat has bee n a p pr o ve d b y a n 
i nstit uti o nal re vie w b oar d/i n de pe n de nt et hics c o m mittee (IR B/I E C) pri or t o i nitiati o n of 
a n y st u d y relate d tests or pr oce d ures t hat are n ot part of sta n dar d - of-care f or t he 
partici pa nt’s disease
1 6. Partici pa nt m ust be willi n g a n d a ble t o c o m pl y wit h st u d y  pr oce d ures, la b orat or y tests, 
a n d ot her re q uire me nts of t he st u d y . Partici pa nts wit h a k n o w n ps yc hiatric or s u bsta nce 
a b use dis or der t hat w o ul d i nterfere wit h t he partici pa nt’s a bilit y  t o c o o perate wit h t he 
re q uire me nts of t he st u d y are n ot eli gi ble.
1 7. F or partici pa nts wit h pri or ce ntral ner v o us s ys te m ( C N S)-directe d ra diati o n t hera p y, at 
least 7 da ys m ust ha ve ela pse d fr o m pri or stere otactic ra di os ur ger y ( S R S) a n d at least 2 1 
da y s m ust ha ve ela pse d fr o m pri or w h ole brai n ra diati o n t hera p y ( W B R T). Partici pa nts 
m ust ha ve rec o vere d fr o m all ra diati o n-relate d t o xicities a n d n ot re q uire c ortic oster oi ds. 
F or n o n -C N S -directe d ra diati o n t hera py, partici pa nts m ust ha ve rec o vere d fr o m all 
ra diati o n-relate d t o xicities, n ot re q uire c ortic oster oi ds, a n d n ot ha ve ha d ra diati o n 
p ne u m o nitis. A 1 - wee k was h o ut is per mitte d f or palliati ve ra diati o n (≤2 wee ks of 
ra di ot hera py)  t o n o n-C N S disease.
1 8. Part ici pa nts i n t he p hase 2 1 L+ C R C e x pa nsi o n ( C o h ort 2 B) m ust ha ve a rat sarc o ma 
vir us ( R A S) wil d- t ype ge n ot y pe i n pri mar y  or metastatic t u m or tiss ue, base d o n e x pa n de d 
R A S hist oric or l ocal testi n g i ncl u di n g K R A S e x o n 2 (c o d o ns 1 2 a n d 1 3), e x o n 3 (c o d o ns 
5 9 a n d 6 1), a n d e x o n 4 (c o d o ns 1 1 7 a n d 1 4 6), a n d N R A S e x o n 2 (c o d o ns 1 2 a n d 1 3), 
e x o n 3 (c o d o ns 5 9 a n d 6 1), a n d e x o n 4 (c o d o ns 1 1 7 a n d 1 4 6) 
1 9. Partici pa nts m ust be willi n g a n d a ble t o a d here t o a nti diarr heal pr o p h yl a xis, if re q uire d. 
E xcl usi o n Criteri a
1.
Hist or y of k n o w n h y perse nsiti vit y  t o pla n ne d st u d y treat me nt:
a
All c o h orts: trast uz u ma b or c o m p o u n ds c he micall y  or bi ol o gically si milar t o 
t ucati ni b 
b
All c o h orts e xce pt f or C o h ort 1 G: o xali plati n, fl u or o p y ri mi di nes, or le uc o v ori n 
c
F or C o h orts 1 E, 1 F, 1 G or 2 A: se v ere h y perse nsiti vit y  (≥ Gra de 3) t o 
pe m br oliz u ma b 
Partici pa nts w h o ha ve ha d Gra de 1 or 2 i nf usi o n -relate d reacti o ns t o o xali plati n, 
pe m br oliz u ma b, a n d/ or trast uz u ma b t hat were s uccessf ull y ma na ge d ma y  e nr oll. 
Partici pa nts wit h k n o w n aller g y  t o a ny of t he e xci pie nts i n t he st u d y treat me nt(s) ma y 
e nr oll u nless se vere h y perse nsiti vit y  (≥ Gra de 3) t o e xci pie nts has occ urre d. 
Partici pa nts wit h k n o w n h y perse nsiti vit y  or aller g y t o re q uire d c o nc o mita nt 
me dicati o ns are e xcl u de d.
2.
Partici pa nts i n C o h orts 1 A, 1 B, 1 C, a n d 2 B: Treat me nt wit h o xali plati n i n e xcess of t he 
li mitati o ns s pecifie d i n i ncl usi o n criteri o n 2
3.
Maj or s ur ger y  < 2 8 da ys pri or t o C ycle 1, Da y 1
4.
Partici pa nts i n t he P hase 1 b c o h orts wit h k n o w n acti ve C N S metastasis (irra diate d or 
resecte d lesi o ns are permitte d, pr o vi de d t he lesi o ns are f ull y treate d a n d i nacti ve, 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 of 2 2 0
partici pa nt is as y m pt o matic, a n d n o ster oi ds ha ve bee n a d mi nistere d f or at least 3 0 da y s). 
Partici pa nts i n C o h orts 2 A a n d 2 B wit h k n o w n acti ve C N S lesi o ns ma y  be i ncl u de d b ut 
m ust n ot ha ve a n y  of t he f oll o wi n g:
a
A n y  u ntreate d brai n lesi o ns > 2. 0 c m i n size, u nless a p pr o ve d b y t he me dical 
m o nit or
b
A n y  brai n lesi o n t h o u g ht t o re q uire i m me diate l ocal t hera p y, i ncl u di n g ( b ut n ot 
li mite d t o) a lesi o n i n a n a nat o mic site w here i ncrease i n size or p ossi ble 
treat me nt-relate d e de ma ma y p ose ris k t o partici pa nt (e g, brai n ste m lesi o ns). 
Partici pa nts w h o u n der g o l ocal treat me nt f or s uc h lesi o ns i de ntifie d b y  scree ni n g 
brai n ma g netic res o na nce i ma gi n g ( M RI) ma y  still be eli gi ble f or t he st u d y 
c
K n o w n or s us pecte d le pt o me ni n geal disease as d oc u me nte d b y t he i n vesti gat or 
d
Ha ve p o orl y c o ntr olle d ( > 1/ wee k) ge neralize d or c o m ple x partial seiz ures, or 
ma nifest ne ur ol o gic pr o gressi o n d ue t o brai n lesi o ns n ot wit hsta n di n g C N S -
directe d t hera p y 
5.
A n y  t o xicit y relate d t o pri or ca ncer t hera pies t hat has n ot res ol ve d t o ≤Gra de 1, wit h t he 
f oll o wi n g e xce pti o ns:

Al o pecia

Cli nicall y  i nsi g nifica nt electr olyt e a b n or malities

He m o gl o bi n < 8 g/ d L
6.
Cli nicall y  si g nifica nt car di o p ul m o nar y disease s uc h as:

Ve ntric ular arr h yt h mia re q uiri n g t her a p y

S y m pt o matic h y perte nsi o n or u nc o ntr olle d as y m pt o matic h y perte nsi o n 
≥1 5 0/ ≥9 0 m m H g des pite sta n dar d me dical ma na ge me nt, as deter mi ne d b y t he 
i n vesti gat or

A n y  hist or y of sy m pt o matic c o n gesti ve heart fail ure ( C H F), left ve ntric ular 
s yst olic d ysf u ncti o n, or decrease i n ejecti o n fracti o n

Se vere d ys p nea at rest ( Nati o nal Ca ncer I nstit ute [ N CI ] C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts [ C T C A E] v 5. 0 Gra de 3 or a b o ve) d ue t o 
c o m plicati o ns of a d va nce d mali g na nc y  or h y p o xia re q uiri n g s u p ple me ntar y 
o x y ge n t hera p y , e xce pt w he n t hera py is nee de d f or o bstr ucti ve slee p a p nea
7.
K n o w n m y ocar dial i nfarcti o n or u nsta ble a n gi na wit hi n 6 m o nt hs pri or t o e nr oll me nt
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 of 2 2 0
8.
K n o w n t o be p ositi ve f or he patitis C i nfecti o n ( p ositi ve b y  p ol ymerase c hai n reacti o n 
[ P C R]). Partici pa nts w h o ha ve bee n treate d f or he patitis C i nfecti o n are per mitte d if t he y  
ha ve d oc u me nte d s ustai ne d vir ol o gic res p o nse of at least 1 2 wee ks. 
K n o w n t o be p ositi ve f or he patitis B ( H B V) b y s urface a nti ge n ( H Bs A g) e x pressi o n. 
Partici pa nts w h o are p ositi ve f or eit her he patitis B s urface a nti b o d y  ( H Bs A B) or 
a nti b o dies t o t he he patitis B c ore a nti ge n ( H Bc A B) s h o ul d be scree ne d usi n g P C R 
meas ure me nt of he patitis B D N A le vels. Partici pa nts wit h he patitis B D N A le vels b y  
P C R t hat re q uire n ucle osi de a nal o g ue t hera p y are n ot eli gi ble f or t he trial. T he latest l ocal 
g ui deli nes s h o ul d be f oll o we d re gar di n g t he m o nit ori n g of he patitis B D N A le vels b y  
P C R f or partici pa nts o n st u d y treat me nt.
9.
Prese nce of k n o w n c hr o nic li ver disease
1 0. K n o w n di h y dr o p y ri mi di ne de hy dr o ge nase deficie nc y (f or all c o h orts e xce pt f or C o h ort 
1 G)
1 1. Partici pa nts k n o w n t o be p ositi ve f or h u ma n i m m u n o deficie nc y  vir us ( HI V) are e xcl u de d 
if t he y meet a n y of t he f oll o wi n g criteria:

C D 4 + T -cell c o u nt of < 3 5 0 cells/ µ L

Detecta ble HI V viral l oa d

Hist or y  of a n o p p ort u nistic i nfecti o n wit hi n t he past 1 2 m o nt hs

O n sta ble a ntiretr o viral t hera p y f or < 4 wee ks
N ote: N o testi n g f or HI V is re q uire d u nless ma n date d b y a l ocal healt h a ut h orit y.
1 2. Partici pa nts w h o are pre g na nt, breastfee di n g, or pla n ni n g t o bec o me pre g na nt fr o m ti me 
of i nf or me d c o nse nt u ntil 7 m o nt hs f oll o wi n g t he last d ose of st u d y treat me nt
1 3. U na ble t o s wall o w pills or re q uires e nteral fee di n g or pare nteral n utriti o n
1 4. Ha ve use d a str o n g C y t oc hr o me ( C Y P) P 4 5 0 2 C 8 i n hi bit or wit hi n 5 half-li ves of t he 
i n hi bit or or ha ve use d a str o n g C Y P 2 C 8 or C Y P 3 A 4 i n d ucer wit hi n 5 da y s pri or t o 
e nr oll me nt
1 5. Ot her me dical, s ocial, or ps y c h os ocial fact ors t hat, i n t he o pi ni o n of t he i n vesti gat or, 
c o ul d i m pact safet y or c o m plia nce wit h st u d y  pr oce d ures
1 6. Has a n acti ve i nfecti o n re q uiri n g s ys te mic t hera p y.
1 7. Re q uire t hera p y wit h warfari n or ot her c o u mari n deri vati ves if recei vi n g C A P O X 
( C o h orts 1 C, 1 F, 2 A) as part of t his st u d y ( n o n-c o u mari n a ntic oa g ula nts are all o we d)
1 8. C urre ntl y  partici pati n g i n a n ot her i nter ve nti o nal trial
1 9. Partici pa nts e nr olle d i n C o h orts 1 E, 1 F, 1 G, a n d 2 A w h o ha ve u nresecta ble or metastatic, 
gastric, es o p ha geal, a n d G EJ a de n ocarci n o ma ca n n ot ha ve ha d pre vi o us c he m ot hera p y 
f or metastatic/ u nresecta ble disease; a dj u va nt or ne oa dj u va nt c he m ot hera py,  or bi ol o gic 
t hera py is per mitte d if m ore t ha n 6 m o nt hs ha ve ela pse d bet wee n t he e n d of t hera p y a n d 
first rec urre nce
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 7 of 2 2 0
2 0. Partici pa nts e nr olle d i n C o h ort 2 A a n d C o h ort 2 B ca n n ot ha ve recei ve d pri or a nti - H E R 2 
t hera pies
2 1. Ha ve recei ve d a li ve vacci ne < 3 0 da y s of e nr oll me nt 
2 2. Has o n g oi n g ≥ Gra de 2 diarr h ea of a n y eti ol o g y at scree ni n g
2 3. Partici pa nts i n C o h orts 1 E, 1 F, 1 G: Has k n o w n acti ve C N S metastases a n d/ or 
carci n o mat o us me ni n gitis. Partici pa nts wit h pre vi o usl y  treate d brai n metastases ma y 
partici pate pr o vi de d t he y are ra di ol o gicall y  sta ble, (ie, wit h o ut e vi de nce of pr o gressi o n) 
f or at least 4 wee ks by re peat i ma gi n g ( N ote: T he re peat i ma gi n g s h o ul d be perf or me d 
d uri n g st u d y scree ni n g.), cli nicall y sta ble a n d wit h o ut re q uire me nt of ster oi d treat me nt 
f or at least 3 0 da ys bef ore t he first d ose of st u d y i nter ve nti o n. 
2 4. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has recei ve d pri or t hera p y  wit h a n a nti-
pr o gra m me d cell deat h 1 ( P D -1), a nti -pr o gra m me d cell deat h li ga n d 1 ( P D -L 1), or a nti -
pr o gra m me d cell deat h li ga n d 2 ( P D -L 2) a ge nt or wit h a n a ge nt directe d t o a n ot her 
sti m ulat or y or c o-i n hi bit or y T-cell rece pt or (e g, c yt ot o xic T-l ym p h oc y te-ass ociate d 
pr otei n 4 [ C T L A -4], O X 4 0, C D 1 3 7), a n d was disc o nti n ue d fr o m t hat treat me nt d ue t o a 
Gra de 3 or hi g her i m m u ne -relate d a d verse e ve nt (ir A E).
2 5. Partici pa nts i n C o h or ts 1 E, 1 F, 1 G, 2 A: Has ha d a n all o ge neic tiss ue/s oli d or ga n 
tra ns pla nt.
2 6. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has a dia g n osis of i m m u n o deficie nc y  (e xcl u di n g 
HI V) or is recei vi n g c hr o nic s y ste mic ster oi d t hera p y (i n d osi n g e xcee di n g 1 0 m g daily of 
pre d nis o ne e q ui vale nt) or a n y  ot her f or m of i m m u n os u p pressi ve t hera p y wit hi n 7 da ys 
pri or t o t he first d ose of st u d y treat me nt.
2 7. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has a k n o w n a d diti o nal mali g na nc y  t hat is 
pr o gressi n g or has re q uire d acti ve treat me nt wit hi n t he past 3 y ears. 
N ote: Partici pa nts wit h basal cell carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of t he 
s ki n, or carci n o ma i n sit u (e g, breast carci n o ma, cer vical ca ncer i n sit u) t hat ha ve 
u n der g o ne p ote ntiall y c urati ve t hera p y are n ot e xcl u de d.
2 8. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has a n acti ve a ut oi m m u ne disease t hat has 
re q uire d sys te mic treat me nt i n past 2 years (ie, wit h use of disease m o dif yi n g a ge nts, 
c ortic oster oi ds or i m m u n os u p pressi ve dr u gs). Re place me nt t hera p y (e g, t h yr o xi ne, 
i ns uli n, or ph y si ol o gic c ortic oster oi d re place me nt t hera p y f or a dre nal or pit uitar y 
i ns ufficie nc y) is n ot c o nsi dere d a f or m of sys te mic treat me nt a n d is all o we d.
2 9. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has a hist or y  of ( n o n-i nfecti o us) 
p ne u m o nitis/i nterstitial l u n g dis ease t hat re q uire d ster oi ds or has c urre nt p ne u m o nitis / 
i nterstitial l u n g disease.
3 0. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has recei ve d ra diati o n t hera p y  t o t he l u n g t hat is 
> 3 0 G y  wit hi n 6 m o nt hs of t he first d ose of trial treat me nt.
N u m ber of Pl a n ne d P a rtici p a nts
A p pr o xi matel y  4 0 partici pa nts will be e nr olle d a n d treate d i n t he st u d y.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 of 2 2 0
St u d y Desi g n
T his is a p hase 1 b/ 2, d ose escalati o n a n d e x pa nsi o n st u d y  of t ucati ni b i n c o m bi nati o n wit h 
trast uz u ma b a n d o xali plati n-base d c he m ot hera p y ( F O L F O X or C A P O X), or pe m br oliz u ma b -
c o ntai ni n g c o m bi nati o ns f or partici pa nts wit h u nresecta ble or metastatic H E R 2 + GI ca ncers. 
Partici pa nts wit h gastric, es o p ha geal, or G EJ a de n ocarci n o ma, c h ola n gi ocarci n o ma, 
gall bla d der carci n o ma, or C R C will be i ncl u de d i n p hase 1 b. D uri n g t he p hase 2 p orti o n of 
t he st u d y, e x pa nsi o n c o h orts i n partici pa nts wit h u nresecta ble or metastatic H E R 2 + 
es o p ha geal, G EJ, a n d gastric a de n ocarci n o ma a n d u nresecta ble or metastatic H E R 2 + C R C 
ma y  be e nr olle d t o f urt her c haracterize safety a n d o btai n preli mi n ar y e vi de nce of a ntit u m or 
acti vit y. 
S u m m ary of c o h orts, tre at me nts, p o p ul ati o ns, a n d n u m ber of p artici p a nts
St u d y P h ase
C o h ort
T uc ati ni b 
D ose
P O BI D
Tre at m e nt
P o p ul ati o n(s)
A p pr o xi m ate 
P artici p a nts 
per C o h ort b
P hase 1 b 
T ucati ni b 
D ose 
Escalati o n 
wit h 
Trast uz u ma b 
a n d F O L F O X
1 A
1 5 0 m g
T ucati ni b, 
Trast uz u ma b,
m F O L F O X 6 
or 
m F O L F O X 7
1 L +

C h ola n gi ocarci n o ma

Gall bla d der ca ncer

Gastric 
a de n ocarci n o ma

Es o p ha geal 
a de n ocarci n o ma

G EJ 
a de n ocarci n o ma

C R C
≥3
1 B
3 0 0 m g
≥6
P hase 1 b
Safet y 
E val uati o n of 
T ucati ni b wit h 
Trast uz u ma b 
a n d C A P O X 
( C o h ort 1 C) or 
wit h 
Trast uz u ma b 
a n d 
Pe m br oliz u ma
b- C o ntai ni n g 
C o m bi nati o ns 
( C o h orts 1 E, 
1 F, 1 G)
1 C
3 0 0 m g
T ucati ni b, 
Trast uz u ma b, 
C A P O X
1 L +
≥6 a
1 E
3 0 0 m g
T ucati ni b, 
Trast uz u ma b, 
Pe m br oliz u ma
b,
m F O L F O X 6
1 L

Gastric 
a de n ocarci n o ma

Es o p ha geal 
a de n ocarci n o ma

G EJ 
a de n ocarci n o ma
≥6 a
1 F
T ucati ni b, 
Trast uz u ma b, 
Pe m br oliz u ma
b, C A P O X
≥6 a
1 G
T ucati ni b, 
Trast uz u ma b, 
Pe m br oliz u ma
b
≥6 a
P hase 1 b 
T ucati ni b 
Ja pa n Safet y 
E val uati o n i n 
C o m bi nati o n 
wit h 
Trast uz u ma b 
a n d F O L F O X
1 D
3 0 0 m g
T ucati ni b, 
Trast uz u ma b,
m F O L F O X 6
1 L +

C h ola n gi ocarci n o ma

Gall bla d der ca ncer

Gastric 
a de n ocarci n o ma

Es o p ha geal 
a de n ocarci n o ma

G EJ 
a de n ocarci n o ma

C R C
≥3
P hase 2
T u m or 
S pecific 
E x pa nsi o n
2 A
3 0 0 m g
T ucati ni b, 
Pe m br oliz u ma
b,
Trast uz u ma b,
1 L

Gastric 
a de n ocarci n o ma

Es o p ha geal 
a de n ocarci n o ma
u p t o 4 0
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 of 2 2 0
St u d y P h ase
C o h ort
T uc ati ni b 
D ose
P O BI D
Tre at m e nt
P o p ul ati o n(s)
A p pr o xi m ate 
P artici p a nts 
per C o h ort b
m F O L F O X 6 
or C A P O X

G EJ 
a de n ocarci n o ma
2 B
T ucati ni b, 
Trast uz u ma b,
m F O L F O X 6
1 L +

C R C
u p t o 2 0
BI D =t w ice dail y; C R C =c ol orectal a de n ocarci n o ma; G EJ = gastr oes o p ha geal j u ncti o n; P O = oral; 1 L =first-li ne
a E nr oll me nt ma y re mai n o pe n u ntil at least 3 partici pa nts are e nr olle d i n Ja pa n
b N o a d diti o nal e nr oll me nt will occ ur f or a n y c o h ort as of A me n d me nt 5.
I n t he c urre nt st u d y ( C 4 2 5 1 0 0 5), as of 1 7 N o ve m ber 2 0 2 1, 1 1 partici pa nts ha ve bee n e nr olle d 
i n t he t ucati ni b 3 0 0 m g P O BI D d ose c o h ort ( C o h ort 1 B) a n d 8 partici pa nts ha ve c o m plete d 
t he D L T peri o d a n d are e val ua ble f or D L Ts. N o D L Ts were o bser ve d i n t hese partici pa nts, 
a n d t he plas ma a n d ultrafiltrate p har mac o ki netics pr ofile a n d t he mea n uri nar y  plati n u m 
o ut p ut pr ofile of o xali plati n were si milar w he n partici pa nts recei ve d o xali plati n al o ne 
c o m pare d t o w he n o xali plati n was recei ve d i n c o m bi nati o n wit h t ucati ni b ( 1 5 0 or 3 0 0 m g P O 
BI D), s u g gesti n g t hat t ucati ni b di d n ot i m pact t he re nal dis p ositi o n of o xali plati n. 
Preli mi nar y data i n dicate all D L T e val ua ble partici pa nts w h o ha ve recei ve d t ucati ni b ( 3 0 0 
m g), trast uz u ma b, a n d F O L F O X e x perie nce d diarr hea, i ncl u di n g 3 partici pa nts wit h 
gastr oes o p ha geal a de n ocarci n o ma w h o e x perie nce d Gra de 3 diarr hea e ve nts. T he re mai ni n g 
5 partici pa nts e x perie nce d eit her Gra de 1 diarr hea ( n = 3) or Gra de 2 diarr hea ( n = 2). N o Gra de 
4 or fatal diarr hea e ve n ts were o bser ve d. T he me dia n ti me t o t he first e ve nt of diarr hea (a n y 
gra de) was 8 da y s after t he first d ose of t ucati ni b. I n t he t hree partici pa nts wit h Gra de 3 
e ve nts, diarr hea was n ote d after n o n ‑a d here nce t o t he rec o m me n de d a nti diarr heal 
ma na ge me nt str ate g y; h o we ver, all e ve nts res ol ve d t o ≤ Gra de 1 diarr hea wit h a ma na ge me nt 
strate g y of d ose m o dificati o n  a n d a nti diarr heal treat me nt wit h l o pera mi de. N o A E SIs 
( ne p hr ot o xicit y or he pat ot o xicit y) ha ve bee n re p orte d.
Base d o n t he Gra de 3 diarr hea e ve nts o bser ve d i n C o h ort 1 B, a nti diarr heal pr o p h y la xis will 
be re q uire d f or all partici pa nts e nr olle d i n C o h orts 1 D, 1 E, a n d f or all partici pa nts i n C o h ort 
2 A w h o are treate d wit h t ucati ni b + trast uz u ma b + pe m br oliz u ma b + m F O L F O X 6. As of 1 2 -
Dec -2 0 2 3, a nti diarr heal pr o p h y la xis is als o re q uire d i n C o h ort 2 B. Be gi n ni n g o n Cycle 1 Da y 
1, l o pera mi de will be a d mi nistere d at a d ose of 4 m g t hree ti mes dail y  f or 1 4 da ys ( Da ys 1-
1 4), f oll o we d b y 4 m g t wice dail y o n Da ys 1 5 -4 2 f or all p artici pa nts e nr olle d i n C o h orts 1 D, 
1 E, a n d 2 B. T he first d ose of l o pera mi de m ust be a d mi nistere d c o nc o mita ntl y  wit h t he first 
d ose of t ucati ni b. T he d osi n g of l o pera mi de s h o ul d be titrate d f or a g oal of 1 -2 st o ols per da y  
t hr o u g h o ut Da ys 1-4 2 a n d after war ds, as necessar y . T he d ose of l o pera mi de ca n be m o difie d, 
or l o pera mi de ca n be hel d at a n y  p oi nt d uri n g t he st u d y as per i n vesti gat or discreti o n if 
partici pa nt has c o nsti pati o n or < 1 st o ol per da y . F oll o wi n g t his i nitial 4 2-da y  peri o d, 
partici pa nts ma y  c o nti n ue o n a nti diarr heal pr o p h yla xis at a d ose of 2 t o 4 m g as nee de d, n ot 
t o e xcee d 1 6 m g per da y. 
A nti diarr heal pr o p h yl a xis, as descri be d a b o ve, will n ot be re q uire d f or partici pa nts e nr olle d 
i n C o h orts 1 C, 1 F, a n d 1 G or f or partici pa nts i n C o h ort 2 A w h o are treate d wit h t ucati ni b + 
trast uz u ma b + pe m br oliz u ma b + C A P O X, u nless rec o m me n de d by t he S M C a n d re q uire d b y 
t he S p o ns or base d o n a re vie w of t he data fr o m t hese c o h orts d uri n g t he c o urse of t he st u dy. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 of 2 2 0
Partici pa nts m ust be i nstr ucte d o n t he o pti mal use of a nti diarr heals f or s y m pt o matic c o ntr ol 
of treat me nt -ass ociate d diarr hea. 
T he S M C will re vie w safet y  data after 3 partici pa nts i n eac h c o h ort are treate d wit h o ut 
a nti diarr heal pr o p h yl a xis. 

If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use of 
a nti diarr heals are o bser ve d i n ≤1 partici pa nt, treat me nt wit h o ut a nti diarr heal 
pr o p h y la xis is c o nti n ue d a n d e val uate d i n 3 m ore partici pa nts i n t he c o h ort. 
o
If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use 
of a nti di arr heals are o bser ve d i n ≤1 of 6 partici pa nts, a nti diarr heal 
pr o p h y la xis will n ot be re q uire d i n t he c o h ort. 
o
If Gra de 3 or hi g her diarr hea e ve nts are o bser ve d i n ≥2 of 6 partici pa nts, 
a nti diarr heal pr o p h yl a xis will be re q uire d i n t he c o h ort. 

If Gra de 3 or hi g her diarr hea e ve nts wit h o ut o pti mal use of a nti diarr heals are 
o bser ve d i n 2 or m ore partici pa nts, a nti diarr heal pr o p h y la xis will be re q uire d i n 
t he c o h ort. 
P h ase 1 b T uc ati ni b D ose Esc al ati o n wit h Tr ast uz u m a b a n d F O L F O X ( C o h orts 1 A a n d 
1 B)
T he d ose es calati o n p orti o n of t he st u d y will deter mi ne t he rec o m me n de d d ose of t ucati ni b t o 
be a d mi nistere d wit h o xali plati n -base d c he m ot hera p y. 
D ose Escalati o n Pr ocess
D ose escalati o n will use a 3 + 3 desi g n. A p pr o xi matel y  5 partici pa nts ma y be e nr olle d a n d 
treate d at t he 1 5 0 m g  t wice daily ( BI D) d ose le vel t o e ns ure t here are at least 3 d ose -li miti n g 
t o xicit y ( D L T)-e val ua ble partici pa nts f or safety m o nit ori n g c o m mittee ( S M C) re vie w 
( C o h ort 1 A). If n o re nal D LTs are o bser ve d at t he 1 5 0 m g BI D d ose le vel ( C o h ort 1 A), t he 
S M C ma y  rec o m me n d escalati n g t o t he 3 0 0 m g BI D d ose le vel f or C o h ort 1 B. 
A p pr o xi matel y  8 partici pa nts will be e nr olle d i n C o h ort 1 B t o e ns ure at least 6 D L T a n d 
p har mac o ki netic ( P K) e val ua ble partici pa nts. 
A re nal D L T is defi ne d as a s ustai ne d i ncreas e i n ser u m c ystati n C > 1. 5 × baseli ne t hat is n ot 
relate d t o pre-re nal or p ost-re nal eti ol o gies (i ncl u di n g disease pr o gressi o n, de h ydrati o n a n d 
i nterc urre nt ill ness), a n d occ urs d uri n g t he peri o d of treat me nt wit h t ucati ni b i n c o m bi nati o n 
wit h trast uz u ma b a n d F O L F O X, bet wee n t he first d ose of t ucati ni b a n d t he e n d of C y cle 3. If 
1 re nal D L T is o bser ve d at t he i nitial 1 5 0 m g BI D d ose le vel ( C o h ort 1 A), a n a d diti o nal 
3 partici pa nts (f or a t otal of 6 e val ua ble partici pa nts) will be treate d at t his d ose le vel, a n d t he 
S M C will e val uate d ose escalati o n t o 2 0 0 or 2 5 0 m g BI D if n o f urt her re nal D L Ts are 
o bser ve d. 
If 1 re nal D L T is o bser ve d i n t he first 3 partici pa nts at t he i nter me diate d ose, a n a d diti o nal 3 
partici pa nts (f or a t otal of 6 e val ua ble partici pa nts) wi ll be treate d at t his d ose le vel, a n d t he 
S M C will e val uate d ose escalati o n if n o f urt her D L Ts are o bser ve d. If ≥2 re nal D L Ts are 
o bser ve d i n t he first 3 ( or 6) partici pa nts treate d at t he i nitial 1 5 0 m g BI D t ucati ni b d ose le vel 
( C o h ort 1 A), alter nati ve d ose le vels a n d/ or re gi me ns < 1 5 0 m g BI D ma y be c o nsi dere d b y t he 
S M C. I f ≥2 re nal D L Ts are o bser ve d i n t he 6 partici pa nts of t he escalate d t ucati ni b d osi n g 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 of 2 2 0
c o h ort ( C o h ort 1 B) ( or ≥3 3 % of partici pa nts if m ore t ha n 6 D L T- e val ua ble partici pa nts are 
e nr olle d i n a c o h ort), t he S M C will c o nsi der a p pr o priate d ose m o dificati o n.
If ≤1 re nal D L Ts are o bser ve d i n eac h of t he 6 D L T -e val ua ble partici pa nts treate d at t he 3 0 0 
m g BI D d ose le vel ( C o h ort 1 B), t his will be declare d t he rec o m me n de d p hase 2 d ose of 
t ucati ni b wit h o xali plati n.
I n a d diti o n t o e val uati n g re nal D L Ts, t he S M C will re vie w t he t otalit y of t he safety data a n d 
ma y  rec o m me n d e x pa n di n g e nr oll me nt t o eit her c o h ort wit h c o nti n ue d m o nit ori n g f or safety 
b y  t he S M C or ma y rec o m me n d e val uati o n of alter nati ve d osi ng. 
After t he rec o m me n de d p hase 2 d ose of t ucati ni b has bee n i de ntifie d, a n a d diti o nal 1 0 
partici pa nts ma y  be e nr olle d i n eit her c o h ort t o f urt her c haracterize t he safet y pr ofile of t he 
c o m bi nati o n a n d t o e val uate ma na ge me nt of p ote ntial a d verse e ve nts ( A E s). 
Trast uz u ma b a n d F O L F O X – C o h ort 1 A
Partici pa nts s h o ul d be ca n di dates t o recei ve a n o xali plati n- base d re gi me n as part of t heir 
sta n dar d- of-care treat me nt pri or t o e nr oll me nt a n d ma y  ha ve recei ve d u p t o 2 c o nsec uti ve 
c ycles of F O L F O X ( ≤8 5 m g/ m 2 o xali pla ti n per 2-wee k c y cle) d uri n g t he scree ni n g peri o d 
pri or t o C y cle 1 Da y 1 of st u d y treat me nt. If partici pa nts ha ve recei ve d o xali plati n i n pri or 
c ycles at d oses hi g her t ha n 8 5 m g/ m 2, t here m ust be a mi ni m u m of 2 8 da ys fr o m t he last d ose 
of t he pre vi o us re gi me n pri or t o C y cle 1 Da y 1 of treat me nt i n t his st u d y. C o nc urre nt 
treat me nt wit h a nti-vasc ular e n d ot helial gr o wt h fact or (a nti -V E G F) a nti b o dies is pr o hi bite d 
w hile o n trial. T here is n o u p per li mit f or t he n u m ber of pri or li nes of t hera p y  recei ve d, a n d 
pri or e x p os ure t o o xali plati n is all o we d, pr o vi de d t he partici pa nt ha d n ot e x perie nce d Gra de 
≥3 h y perse nsiti vit y  d ue t o o xali plati n.
E nr olle d partici pa nts will be treate d wit h F O L F O X , trast uz u ma b, a n d t ucati ni b gi ve n i n 1 4-
da y  c ycles. After e nr olli n g o n st u d y, partici pa nts i n C o h ort 1 A will recei ve 7 da ys of 
F O L F O X a n d trast uz u ma b wit h o ut t ucati ni b. T he starti n g d ose of t ucati ni b f or C o h ort 1 A is 
1 5 0 m g orall y  ( P O) t wice dail y ( BI D), a n d t he first d ose will be a d mi nistere d o n C y cle 1 Da y 
8 a n d c o nti n u o usl y  t hereafter u ntil t he partici pa nt c o mes off st u d y. Partici pa nts will c o nti n ue 
o n t hera p y u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, deat h, or 
st u d y cl os ure.
Trast uz u ma b a n d F O L F O X - C o h ort 1 B
Partici pa nts s h o ul d be ca n di dates t o recei ve a n o xali plati n- base d re gi me n as part of t heir 
sta n dar d- of-care treat me nt pri or t o e nr oll me nt a n d ma y  ha ve recei ve d u p t o 2 c o nsec uti ve 
c ycles of F O L F O X ( ≤8 5 m g/ m 2 o xali plat i n per 2-wee k c y cle) d uri n g t he scree ni n g peri o d 
pri or t o C y cle 1 Da y 1 of st u d y treat me nt. If partici pa nts ha ve recei ve d o xali plati n i n pri or 
c ycles at d oses hi g her t ha n 8 5 m g/ m 2, t here m ust be a mi ni m u m of 2 8 da ys fr o m t he last d ose 
of t he pre vi o us re gi m e n pri or t o C ycle 1 Da y 1 of treat me nt i n t his st u d y. C o nc urre nt 
treat me nt wit h a nti- V E G F a nti b o dies is pr o hi bite d w hile o n trial. T here is n o u p per li mit f or 
t he n u m ber of pri or li nes of t hera py recei ve d, a n d pri or e x p os ure t o o xali plati n is all o we d, 
pr o v i de d t he partici pa nt ha d n ot e x perie nce d Gra de ≥3 h y perse nsiti vit y  d ue t o o xali plati n.
E nr olle d partici pa nts will be treate d wit h F O L F O X, trast uz u ma b, a n d t ucati ni b gi ve n i n 1 4 -
da y  c ycles. After e nr olli n g o n st u d y, partici pa nts i n C o h ort 1 B will recei ve 7 da y s of 
F O L F O X a n d trast uz u ma b wit h o ut t ucati ni b. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 2 of 2 2 0
a n i nter me diate d ose as rec o m me n de d b y t he safet y m o nit ori n g c o m mittee [ S M C]) will be 
a d mi nistere d o n C ycle 1 Da y 8 a n d c o nti n u o usly t hereafter u ntil t he partic i pa nt c o mes off 
st u d y. Partici pa nts will c o nti n ue o n t hera p y u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, 
wit h dra wal of c o nse nt, deat h, or st u d y cl os ure.
P h ase 1 b S afet y E v al u ati o n of T uc ati ni b wit h Tr ast uz u m a b a n d C A P O X ( C o h ort 1 C) 
or wit h Tr ast uz u m a b a n d Pe m br oliz u m a b -C o nt ai ni n g C o m bi n ati o ns ( C o h orts 1 E, 1 F, 
1 G)
After t he rec o m me n de d p hase 2 d ose of t ucati ni b wit h o xali plati n -base d c he m ot hera p y has 
bee n i de ntifie d, a d diti o nal c o h orts ma y  be o pe ne d t o f urt her e val uate t he safet y a n d 
t olera bilit y of t ucati ni b c o m bi ne d wit h t he f oll o wi n g re gi me ns:

Trast uz u ma b + C A P O X ( C o h ort 1 C)

Pe m br oliz u ma b + Trast uz u ma b + m F O L F O X 6 ( C o h ort 1 E)

Pe m br oliz u ma b + Trast uz u ma b + C A P O X ( C o h ort 1 F)

Pe m br oliz u ma b + Trast uz u ma b ( C o h ort 1 G)
Partici pa nts will be cl osel y  f oll o we d for u nacce pta ble t o xicities f or eit her 2 1- d a y s (f or 
partici pa nts e nr olle d i n C o h orts 1 C, 1 F, or 1 G) or 2 8 da y s (f or partici pa nts e nr olle d i n C o h ort 
1 E) after t he first d ose of st u d y  i nter ve nti o n (ie, t he D L T e val uati o n peri o d) f or t he 
occ urre nce of s pecific A Es t hat are dee me d t o be d ose -li miti n g. If 3 or m ore D L Ts are 
o bser ve d i n a c o h ort, e nr oll me nt t o t hat c o h ort ma y be dela y e d t o f urt her e xa mi ne safet y data 
a n d c o nsi der st u d y desi g n c ha n ges as rec o m me n de d b y t he S M C.
Trast uz u ma b a n d C A P O X – C o h ort 1 C
Partici pa nts i n C o h ort 1 C s h o ul d be ca n di dates t o recei ve a n o xali plati n- base d re gi me n as 
part of t heir sta n dar d - of-care treat me nt pri or t o e nr oll me nt. Eli gi ble partici pa nts ma y  ha ve 
recei ve d o xali plati n-base d c he m ot hera p y ( 1 c ycle of C A P O X at a d ose of ≤1 3 0 m g/ m 2 per 3 -
wee k c y cle or 2 c o nsec uti ve c ycles of F O L F O X at a d ose of ≤8 5 m g / m2 per 2 -wee k c y cle) 
d uri n g t he scree ni n g peri o d pri or t o C y cle 1 Da y 1. C o nc urre nt treat me nt wit h a nti-V E G F 
a nti b o dies is pr o hi bite d w hile o n trial. T here is n o u p per li mit f or t he n u m ber of pri or li nes of 
t hera py recei ve d, a n d pri or e x p os ure t o o xali plati n is all o we d, pr o vi de d t he partici pa nt ha d 
n ot e x perie nce d Gra de ≥3 h y perse nsiti vit y  d ue t o o xali plati n.
E nr olle d partici pa nts will be treate d wit h C A P O X, trast uz u ma b, a n d t ucati ni b gi ve n i n 2 1 -
da y  c ycles. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or a n i nter me diate d ose as 
rec o m me n de d by t he S M C) ma y  be a d mi nistere d o n C ycle 1 Da y 1. Partici pa nts will 
c o nti n ue o n t hera p y u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, 
deat h, or st u d y cl os ure. 
A nti diarr heal pr o p h yl a xis will n ot be re q uire d f or partici pa nts e nr olle d i n C o h ort 1 C, u nless 
rec o m me n de d by t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he data fr o m 
t his c o h ort d uri n g t he c o urse of t he st u d y. Partici pa nts s h o ul d be i nstr ucte d o n t he o pti mal 
use of a nti diarr heals f or s y m pt o matic diarr hea. 
A p pr o xi matel y 8 partici pa nts ma y  be e nr olle d t o C o h ort 1 C t o e ns ure t hat 6 partici pa nts 
c o m plete 1 c ycle of t ucati ni b +trast uz u ma b + C A P O X. If 8 partici pa nts are e nr olle d, 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 3 of 2 2 0
e nr oll me nt ma y re mai n o pe n t o e ns ure at least 3 t o 6 partici pa nts fr o m Ja pa n are e nr olle d i n 
t his c o h ort.
O nce at least 3 partici pa nts ha ve c o m plete d 1 c y cle of t ucati ni b +trast uz u ma b + C A P O X, a 
c o m pre he nsi ve re vie w of t he safet y pr ofile b y  t he S M C will occ ur. Base d o n t he t otalit y of 
t he safety data, t he S M C ma y declare t he c o m bi nati o n safe a n d t olera ble, or ma y rec o m me n d 
e x pa n di n g e nr oll me nt t o t he c o h ort wit h c o nti n ue d m o nit ori n g f or safet y b y t he S M C or ma y 
rec o m me n d e val uati o n of alter nati ve d osi n g. 
Pe m br oliz u ma b, Trast uz u ma b, m F O L F O X 6 ( C o h ort 1 E)
C o h ort 1 E will e val uate t he safet y a n d t olera bilit y of t ucati ni b c o m bi ne d wit h 
pe m br oliz u ma b, trast uz u ma b a n d m F O L F O X 6 i n partici pa nts wit h u nresecta ble or metastatic 
H E R 2 + gastric, es o p ha geal, or G EJ a de n ocarci n o ma w h o ha ve n ot pre vi o usl y  recei ve d 
treat me nt i n t he first-li ne ( 1 L) setti n g. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or a n 
i nter me diate d ose as rec o m me n de d b y t he S M C) will be a d mi nistere d o n C ycle 1 Da y  1.
E nr olle d partici pa nts will be treate d wit h m F O L F O X 6 a n d t ucati ni b gi ve n i n 1 4 -da y  c ycles. 
Trast uz u ma b will be gi ve n i n 2 1- d a y c y cles. Pe m br oliz u ma b will be gi ve n i n 4 2 -d a y c y cles. 
A nti diarr heal pr o p h yl a xis will als o be a d mi nistere d f or t he first 4 2 da y s of st u d y treat me nt
a n d as nee de d t hereafter. Partici pa nts will c o nti n ue o n t hera p y u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, deat h, or st u d y cl os ure. A p pr o xi matel y 8 
partici pa nts ma y  be e nr olle d t o e ns ure t hat 6 partici pa nts c o m plete 2 8 da ys of st u d y 
treat me nt. If 8 partici pa nts are e nr olle d, e nr oll me nt ma y re mai n o pe n t o e ns ure at least 3 t o 6 
partici pa nts fr o m Ja pa n are e nr olle d i n t his c o h ort. 
O nce at least 6 partici pa nts ha ve c o m plete d 2 8 da ys of st u d y  treat me nt, a c o m pre he nsi ve 
re vie w of t he safet y pr ofile b y t he S M C will occ ur. Base d o n t he t otalit y of t he safety data, 
t he S M C ma y declare t he c o m bi nati o n safe a n d t olera ble, or ma y rec o m me n d e x pa n di n g 
e nr oll me nt t o t he c o h ort wit h c o nti n ue d m o nit ori n g f or safet y  b y t he S M C or ma y 
rec o m me n d e val uati o n of alter nati ve d osi n g.
Pe m br oliz u ma b, Trast uz u ma b, C A P O X ( C o h ort 1 F)
C o h ort 1 F will e val uate t he safet y a n d t olera bilit y of t ucati ni b c o m bi ne d wit h 
pe m br oliz u ma b, trast uz u ma b, a n d C A P O X i n partici pa nts wit h u nresecta ble or metastatic 
H E R 2 + gast ric, es o p ha geal, or G EJ a de n ocarci n o ma w h o ha ve n ot pre vi o usl y recei ve d 
treat me nt i n t he 1 L setti n g. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or a n i nter me diate 
d ose as rec o m me n de d b y t he S M C) will be a d mi nistere d o n C ycle 1 Da y 1.
E nr olle d partici pa nts will be treate d wit h C A P O X, trast uz u ma b, a n d t ucati ni b gi ve n i n 2 1 -
da y  c ycles. Pe m br oliz u ma b will be gi ve n i n 4 2 -da y  c ycles. Partici pa nts will c o nti n ue o n 
t hera py u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, deat h, or 
st u d y cl osure.
A nti diarr heal pr o p h yl a xis will n ot be re q uire d f or partici pa nts e nr olle d i n C o h ort 1 F, u nless 
rec o m me n de d by t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he data fr o m 
t his c o h ort d uri n g t he c o urse of t he st u dy. Partici pa nts s h o ul d be i nst r ucte d o n t he o pti mal 
use of a nti diarr heals f or s y m pt o matic diarr hea.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 4 of 2 2 0
A p pr o xi matel y  8 partici pa nts will be e nr olle d t o e ns ure t hat 6 partici pa nts c o m plete 2 1 da ys 
of st u d y  treat me nt. If 8 partici pa nts are e nr olle d, e nr oll me nt ma y  re mai n o pe n t o e ns ure at 
least 3 t o 6 partici pa nts fr o m Ja pa n are e nr olle d i n t his c o h ort. 
O nce at least 6 partici pa nts ha ve c o m plete d 2 1 da ys of st u d y  treat me nt, a c o m pre he nsi ve 
re vie w of t he safet y pr ofile b y t he S M C will occ ur. Base d o n t he t otalit y of t he safety data, 
t he S M C ma y  declare t he c o m bi nati o n safe a n d t olera ble, or ma y rec o m me n d e x pa n di n g 
e nr oll me nt t o t he c o h ort wit h c o nti n ue d m o nit ori n g f or safet y  b y t he S M C or ma y 
rec o m me n d e val uati o n of alter nati ve d osi n g.
Trast uz u ma b, Pe m br oliz u ma b ( C o h ort 1 G)
C o h ort 1 G will e va l uate t he safety a n d t olera bilit y of t ucati ni b c o m bi ne d wit h 
pe m br oliz u ma b a n d trast uz u ma b i n partici pa nts wit h u nresecta ble or metastatic H E R 2 + 
gastric, es o p ha geal, or G EJ a de n ocarci n o ma w h o ha ve n ot pre vi o usl y recei ve d treat me nt i n 
t he 1 L setti n g. T his co h ort ma y  be o pe ne d base d o n S M C re vie w of t he safet y fr o m C o h orts 
1 A, 1 B, 1 C, 1 E, a n d/ or 1 F. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or a n i nter me diate 
d ose as rec o m me n de d b y t he S M C) will be a d mi nistere d o n C ycle 1 Da y  1.
E nr olle d partici pa nts will be treate d wit h trast uz u ma b a n d t ucati ni b gi ve n i n 2 1 -d a y c y cles. 
Pe m br oliz u ma b will be gi ve n i n 4 2- d a y c y cles. Partici pa nts will c o nti n ue o n t hera p y u ntil 
disease pr o gressi o n, u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, deat h, or st u d y  cl os ure.
A nti diarr heal pr o p h yl a xis will n ot be re q uire d f or partici pa nts e nr olle d i n C o h ort 1 G, u nless 
rec o m me n de d by t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he data fr o m 
t his c o h ort d uri n g t he c o urse of t he st u dy. Partici pa nts s h o ul d be i nstr ucte d o n t he o pti mal 
use of a nti diarr heals f or s y m pt o matic diarr hea.
A p pr o xi matel y  8 partici pa nts will be e nr olle d t o e ns ure t hat 6 partici pa nts c o m plete 2 1 da ys 
of st u d y  treat me nt. If 8 partici pa nts are e nr olle d, e nr oll me nt ma y  re mai n o pe n t o e ns ure at 
least 3 t o 6 partici pa nts fr o m Ja pa n are e nr olle d i n t his c o h ort. 
O nce at least 6 partici pa nts ha ve c o m plete d 2 1 da ys of st u d y treat me nt a n d are e val ua ble f or 
safety, a c o m pre he nsi ve re vie w of t he safet y pr ofile b y t he S M C will occ ur. Base d o n t he 
t otalit y of t he safety data, t he S M C ma y declare t he c o m bi nati o n safe a n d t olera ble, or ma y  
rec o m me n d e x pa n di n g e nr oll me nt t o t he c o h ort wit h c o nti n ue d m o nit ori n g f or safet y b y t he 
S M C or ma y  rec o m me n d e val uati o n of alter nati ve d osi n g.
P h ase 1 b J a p a n S afet y E v al u ati o n of T uc ati ni b i n C o m bi n ati o n wit h Tr ast uz u m a b a n d 
F O L F O X ( C o h ort 1 D)
After t he rec o m me n de d d ose of t ucati ni b wit h o xali plati n- base d c he m ot hera p y has bee n 
i de ntifie d, C o h ort 1 D ma y be o pe ne d t o e val uate t he safety a n d t olera bilit y of t ucati ni b 
c o m bi ne d wit h trast uz u ma b, a n d m F O L F O X 6 i n partici pa nts wit h H E R 2 + GI mali g na ncies 
e nr olle d fr o m Ja pa n. Partici pa nts s h o ul d be ca n di dates t o recei ve a n o xali plati n -base d 
re gi me n as part of t heir sta n dar d- of-care treat me nt pri or t o e nr oll me nt. C o nc urrent treat me nt 
wit h a nti- V E G F a nti b o dies is pr o hi bite d w hile o n trial. T here is n o u p per li mit f or t he 
n u m ber of pri or li nes of t hera p y recei ve d, a n d pri or e x p os ure t o o xali plati n is all o we d, 
pr o vi de d t he partici pa nt ha d n ot e x perie nce d Gra de ≥3 h y perse nsiti vit y  d ue t o o xali plati n.
E nr olle d partici pa nts will be treate d wit h m F O L F O X 6 a n d t ucati ni b gi ve n i n 1 4 -da y  c ycles; 
trast uz u ma b will be gi ve n e ver y 2 1 da ys. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D) or a n 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 5 of 2 2 0
i nter me diate d ose as rec o m me n de d b y t he S M C) will be a d mi nistere d o n C y cle 1 Da y 1 a n d 
c o nti n u o usl y t hereafter u ntil t he partici pa nt c o mes off st u d y. A nti diarr heal pr o p h yla xis will 
als o be a d mi nistere d f or t he first 4 2 da y s of st u d y treat me nt a n d as nee de d t hereafter. 
Partici pa nts will c o nti n ue o n t hera p y u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , 
wit h dra wal of c o nse nt, deat h, or st u d y cl os ure.
Partici pa nts i n C o h ort 1 D will be caref ull y m o nit ore d t hr o u g h t he 2 8 -d a y s of treat me nt a n d 
e val uate d f or A Es t hat are u ne x pecte d base d o n t he k n o w n safet y  profile of eac h i n di vi d ual 
a ge nt a n d of t he c o m bi nati o n of t ucati ni b, trast uz u ma b, a n d m F O L F O X 6. I n vesti gat ors m ust 
e ns ure t hat partici pa nts d o n ot ha ve ot her me dical, s ocial, or ps yc h os ocial fact ors t hat, i n t he 
o pi ni o n of t he i n vesti gat or, c o ul d i m pact saf et y or c o m plia nce wit h st u d y pr oce d ures 
re q uire d per t he pr ot oc ol (s uc h as c o m plia nce wit h a d diti o nal st u d y visits, la b orat or y 
assess me nts, oral me dicati o ns, a n d cl ose o ut patie nt m o nit ori n g). D uri n g t he first c y cle, t he 
partici pa nt ma y  be h os pitalize d f or a mi ni m u m of 1 5 da ys wit h disc har ge per mitte d if a 
partici pa nt has n o o n g oi n g ≥ Gra de 3 A Es a n d is ot her wise c o nsi dere d a p pr o priate f or 
disc har ge b y t he i n vesti gat or base d o n hist or y  ( w hic h i ncl u des assess me nt of a n y ne w or 
o n g oi n g A Es a n d c o nc o mita nt me di cati o n use), p h ysical e xa m (i ncl u di n g vital si g ns), a n d 
la b orat or y e val uati o ns (i ncl u di n g c o m plete bl o o d c o u nt, bl o o d c he mistr y, re nal f u ncti o n 
tests, a n d li ver e nz yme tests). F or partici pa nts u n der g oi n g o ut patie nt f oll o w -u p, t he 
i n vesti gat or m ust e ns ure that t he partici pa nt will be f oll o we d cl osel y i n t he o ut patie nt setti n g 
b y  met h o ds t he y deter mi ne t o be a p pr o priate t o ass ure t he partici pa nt’s safet y, a n d 
partici pa nts s h o ul d be i nstr ucte d t o c o ntact t he i n vesti gat or i m me diatel y i n t he e ve nt t he y  
e x perie nce a n A E. I n case of e mer ge nc y , a de q uate mea ns of c o m m u nicati o n bet wee n t he site 
a n d t he partici pa nt s h o ul d be e ns ure d b y t he i n vesti gat or re gar dless of ti me of da y  or i n t he 
e ve nt of a h oli da y. 
A mi ni m u m of 3 partici pa nts will be e nr olle d a n d recei ve t uca ti ni b, trast uz u ma b, a n d 
m F O L F O X 6. T he gl o bal me dical m o nit or, Ja pa nese i n vesti gat ors, st u d y  statisticia n, a n d 
ot her st u d y  tea m me m bers will c o n d uct a n e val uati o n of o verall safety after 3 partici pa nts 
ha ve e nr olle d a n d c o m plete d 2 8 da y s of st u d y treat me nt. If t he o verall safet y i n t he first 3 
partici pa nts e nr olle d is dee me d acce pta ble, n o f urt her e nr oll me nt will ta ke place. If o ne D L T 
is o bser ve d, a n a d diti o nal 3 partici pa nts will be e nr olle d. If a D L T is re p orte d f or 1/ 6 
partici pa nts, treat me nt is c o nsi der e d t o be t olerate d; if 2/ 6 D LTs are o bser ve d, t he 
i n vesti gat ors a n d s p o ns or will e val uate t he t otalit y of t he safety data a n d deter mi ne if t he 
re gi me n is safe a n d t olera ble. If 3 or m ore D L Ts are o bser ve d, e nr oll me nt t o t he c o h ort ma y 
be dela y e d t o f urt her e xa mi ne safet y data a n d c o nsi der st u d y desi g n c ha n ges. A d h oc 
meeti n gs wit h t he gl o bal me dical m o nit or, Ja pa nese i n vesti gat ors, st u d y  statisticia n, a n d 
ot her st u d y  tea m me m bers ma y be calle d t o re vie w safety data as nee de d.
P h ase 2 T u m or -S pecific E x p a nsi o n C o h orts ( C o h orts 2 A a n d 2 B)
T u m or s pecific e x pa nsi o n c o h orts ma y  be e nr olle d f oll o wi n g t he c o m pleti o n of t he p hase 1 b 
p orti o n of t he st u d y  t o deter mi ne t he safet y a n d t olera bilit y of t he treat me nt re gi me ns t o be 
e val uate d i n P hase 2. 
A 1 L  H E R 2 + gastric, es o p ha geal or G EJ a de n ocarci n o ma e x pa nsi o n c o h ort f or t ucati ni b i n 
c o m bi nati o n wit h pe m br oliz u ma b, trast uz u ma b, a n d m F O L F O X 6 or C A P O X ( C o h ort 2 A) 
ma y  be o pe ne d a n d e nr oll a p pr o xi matel y 4 0 partici pa nts. E nr oll me nt will be gate d o n S M C 
re vie w of data fr o m C o h orts 1 E a n d 1 F. A nti diarr heal pr o p hyl a xis will als o be a d mi nistere d 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 6 of 2 2 0
f or t he first 4 2 da ys of st u d y treat me nt f or partici pa nts w h o are treate d wit h m F O L F O X 6 a n d 
as nee de d t hereafter. Partici pa nts i n C o h ort 2 A treate d wit h C A P O X will n ot re q uire 
a nti diarr h eal pr o p h yla xis, u nless rec o m me n de d b y t he S M C a n d re q uire d b y t he S p o ns or 
base d o n a re vie w of t he data fr o m C o h ort 1 C a n d/ or C o h ort 1 F. Partici pa nts i n C o h ort 2 A 
s h o ul d be i nstr ucte d o n t he o pti mal use of a nti diarr heals f or sy m pt o matic diarr hea. 
A 1 L + H E R 2 + C R C e x pa nsi o n c o h ort f or t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
m F O L F O X 6 ( C o h ort 2 B) ma y  als o be e nr olle d wit h a p pr o xi matel y 2 0 partici pa nts. 
E nr oll me nt will be gate d o n S M C re vie w of data fr o m C o h ort 1 B (i ncl u di n g D L T fre q ue nc y  
a n d P K data). A s of 1 2-Dec -2 0 2 3, 5 partici pa nts were e nr olle d a n d treate d i n C o h ort 2 B. 
T ucati ni b -relate d Gra de 3 diarr hea was re p orte d i n 2 of 5 partici pa nts d uri n g t he first 4 2-d a y s 
of st u d y  treat me nt. Base d o n t his fi n di n g, l o pera mi de pr o p h yla xis is n o w re q uire d f or C o h ort 
2 B. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 7 of 2 2 0
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 8 of 2 2 0
I n vesti g ati o n al Pr o d uct, D ose, a n d M o de of A d mi nistr ati o n ( All C o h orts)
F or t he p hase 1 b t ucati ni b d ose escalati o n wit h o xali plati n ( C o h orts 1 A a n d 1 B), t ucati ni b 
will be a d mi nistere d 1 5 0 m g or 3 0 0 m g P O BI D fr o m C y cle 1 Da y 8 o n war ds. Inter me diate 
d ose le vels of t ucati ni b ( 2 0 0 or 2 5 0 m g P O BI D) ma y  be e val uate d per S M C 
rec o m me n dati o n base d o n t he i nci de nce of re nal D LTs o bser ve d i n C o h ort 1 A or 1 B. F or 
P hase 1 b C o h orts 1 D, 1 E, a n d 1 G a n d t he P hase 2 c o h orts, t ucati ni b will be a d mi nistere d 
fro m C y cle 1 Da y 1 o n war ds. F or C o h orts 1 C a n d 1 F, t he first d ose of t ucati ni b will be 
a d mi nistere d o n C ycle 1 Da y 1.
F or t he p hase 2 e x pa nsi o n c o h orts ( C o h orts 2 A a n d 2 B), t ucati ni b 3 0 0 m g P O BI D ( or 
rec o m me n de d p hase 2 d ose) will be a d mi nistere d starti n g on C ycle 1 Da y 1. 
Trast uz u ma b d osi n g sc he d ule: 

F or C o h orts 1 A a n d 1 B, a 6 m g/ k g l oa di n g d ose will be a d mi nistere d 
i ntra ve n o usl y (IV) o n C ycle 1 Da y  1, f oll o we d b y a d ose of 4 m g / k g I V e ver y 2 
wee ks starti n g o n C ycle 2 Da y 1.

F or all ot her c o h orts ( C o h orts 1 C, 1 D, 1 E, 1 F, 1 G, 2 A, 2 B), a n 8 m g/ k g l oa di n g 
d ose will be a d mi nistere d I V o n C y cle 1 Da y 1, f oll o we d b y a d ose of 6 m g / k g I V 
e ver y 3 wee ks t hereafter.
F O L F O X d osi n g sc he d ules ( C o h orts 1 A, 1 B, 1 D, 1 E, 2 A, 2 B):
Partici pa nts e nr olle d i n C o h orts 1 A or 1 B recei vi n g F O L F O X o n st u dy ma y be d ose d usi n g 
eit her t he m F O L F O X 6 or m F O L F O X 7 re gi me n per i n vesti gat or prefere nce b ut s h o ul d 
re mai n o n t he sa me F O L F O X re gi me n t hr o u g h o ut st u d y partici pati o n. Partici pa nts e nr olle d 
i n C o h orts 1 D, 1 E, 2 A, a n d 2 B will recei ve m F O L F O X 6.

m F O L F O X 6: o xali plati n 8 5 m g/ m 2, le uc o v ori n 4 0 0 m g/ m 2, fl u or o uracil 
4 0 0 m g/ m 2 (I V B ol us after le uc o v ori n), a n d fl u or o uracil 2 4 0 0 m g/ m 2 (c o nti n u o us 
i nf usi o n o ver 4 6 h o urs) will be a d mi nistere d I V e ver y 2 wee ks starti n g fr o m 
C y cle 1 Da y 1 o n war ds.
O R

m F O L F O X 7: o xali plati n 8 5 m g/ m 2, le uc o v ori n 2 0 0 m g/ m 2, a n d fl u or o uracil 
2 4 0 0 m g/ m 2 (c o nti n u o us i nf usi o n o ver 4 6 h o urs) will be a d mi nistere d I V e ver y 
2 wee ks starti n g fr o m C ycle 1 Da y  1 o n war ds. 
C A P O X d osi n g sc he d ule ( C o h orts 1 C, 1 F, a n d 2 A): o xali plati n 1 3 0 m g/ m 2 will be 
a d mi nistere d I V e ver y 3 wee ks starti n g fr o m C ycle 1 Da y 1 o n war ds, a n d ca pecita bi ne 
1 0 0 0 m g/ m g 2 is ta ke n P O BI D ( Da ys 1-1 4 of eac h 2 1 -d a y c y cle).
Pe m br oliz u ma b d osi n g sc he d ules ( C o h orts 1 E, 1 F, 1 G, a n d 2 A): 4 0 0  m g a d mi nistere d I V 
e ver y 4 2 d a y s. 
D ur ati o n of Tre at me nt
St u d y  treat me nt will c o nti n ue u ntil u nacce pta ble t o xicit y, disease pr o gressi o n, wit h dra wal of 
c o nse nt, deat h, or st u d y cl os ure. Pe m br oliz u ma b will be gi ve n f or a ma xi m u m of 1 8 d oses 
( C o h orts 1 E, 1 F, 1 G, 2 A); st u d y treat me nt will c o nti n ue i n t hese c o h orts u ntil u nacce pta ble 
t o xicit y, disease pr o gressi o n, wit h dra wal of c o nse nt, deat h, or st u d y cl os ure.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 9 of 2 2 0
Partici pa nts still recei vi n g cli nical be nefit a n d re mai ni n g o n st u d y treat me nt as of 
A me n d me nt 5 ma y  c o nti n ue recei vi n g st u d y inter ve nti o n d uri n g t he L T E P. Partici pa nts ma y  
re mai n i n L T E P u ntil u nacce pta ble t o xicit y, disease pr o gressi o n, wit h dra wal of c o nse nt, 
deat h, or st u d y cl os ure.
Effic ac y Assess me nts
Disease res p o nse will be assesse d b y t he i n vesti gat or acc or di n g t o R E CI S T v 1 . 1. Treat me nt 
decisi o ns will be ma de base d u p o n l ocal assess me nt of ra di ol o gic sca ns. Ra di o gra p hic 
disease assess me nts will e val uate all k n o w n sites of disease, prefera bl y usi n g hi g h q ualit y 
s piral c o ntrast c o m p ute d t o m o gra p hy ( C T), a n d c o veri n g, at a mi ni m u m, t he c hest, a b d o me n, 
a n d pel vis. P ositr o n e missi o n t o m o gra p h y- C T sca ns (if hi g h q ualit y  C T sca n is i ncl u de d) 
a n d/ or M RI sca ns ma y als o be use d as a p pr o priate, as well as a d diti o nal i ma gi n g of a ny ot her 
k n o w n sites of disease (e g, n uclear b o ne sca n i ma g i n g f or b o ne lesi o ns). F or eac h partici pa nt, 
t he sa me i ma gi n g m o dalit y as use d at scree ni n g/ baseli ne s h o ul d be use d t hr o u g h o ut t he 
st u d y. I ma ges ma y be c ollecte d by a n i n de pe n de nt ce ntral re vie w (I C R) facilit y  f or p ossi ble 
f ut ure a nal ysis. Disease assess ments will be d o ne at scree ni n g/ baseli ne a n d e ver y  8 wee ks f or 
t he first 2 4 wee ks i n C o h orts 1 A a n d 1 B a n d t he n e ver y 1 2 wee ks t hereafter a n d e ver y 6 
wee ks f or t he first 2 4 wee ks i n C o h orts 1 C, 1 D, 1 E, 1 F, 1 G, 2 A, a n d 2 B a n d t he n e ver y  9 
wee ks t hereafter, ir res pecti ve of d ose i nterr u pti o ns.
D uri n g t he L T E P, efficac y assess me nts will be perf or me d per i nstit uti o nal g ui deli nes a n d 
i n vesti gat or-deter mi ne d us ual a n d c ust o mar y  cli nical care. 
P h ar m ac o ki netic Assess me nts
Bl o o d ( o xali plati n a n d t ucati ni b) a n d uri ne ( o xali plati n) sa m ples f or P K assess me nts will be 
c ollecte d at pr ot oc ol - defi ne d ti me p oi nts. Plas ma c o nce ntrati o ns of t ucati ni b will be a nalyz e d 
usi n g vali date d mass s pectr o metr y  met h o ds. C o nce ntrati o ns of t otal plati n u m i n plas ma, free 
plati n u m i n plas ma ul trafiltrates, a n d plati n u m i n uri ne will be deter mi ne d usi n g vali date d 
met h o ds. Re mai ni n g P K sa m ples will be arc hi ve d a n d ma y  be use d f or t he a nalys is of 
a d mi nistere d c o m p o u n ds or relate d s pecies wit h e x pl orat or y , n o n-vali date d assa y s. 
P K para meters will be calc ulate d usi n g sta n dar d n o n-c o m part me ntal met h o ds. P K para meters 
t o be esti mate d i ncl u de, b ut are n ot li mite d t o, area u n der t he plas ma c o nce ntrati o n-ti me 
c ur ve t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U C last), ma xi m u m o bser ve d 
c o nce ntratio n ( C ma x ), o bser ve d tr o u g h c o nce ntrati o n i n plas ma ( Ctr o u g h; t ucati ni b o nl y), a n d 
ti me of Cma x ( Tma x ).
F oll o wi n g i m ple me ntati o n of A me n d me nt 5, n o P K sa m ples will be c ollecte d at E O T.
Bi o m ar ker Assess me nts
Bi o mar ker assess me nts will be perf or me d i n peri p he ral bl o o d a n d t u m or tiss ue as o utli ne d i n 
t his secti o n. H E R 2 stat us f or eli gi bilit y will be deter mi ne d b y hist oric/l ocal N G S, I H C, FI S H, 
or cell -free D N A-base d N G S. E x pl orat or y , pre dicti ve, a n d pr o g n ostic bi o mar kers ass ociate d 
wit h res p o nse, resista nce, or safety o bser vati o ns ma y be m o nit ore d bef ore a n d d uri n g 
treat me nt wit h t ucati ni b. P har mac o dy na mic assess me nts will i ncl u de disease b ur de n 
m o nit ori n g a n d c ha n ges t o tar get e x pressi o n. C orrelati ve st u dies will be c o n d ucte d t o gai n a 
better u n dersta n di n g of t ar get -res p o nse relati o ns hi p, pre dicti ve/ pr o g n ostic bi o mar kers, 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 0 of 2 2 0
mec ha nis m of acti o n, resista nce mec ha nis ms, a n d p har mac o d y n a mics. Assa ys ma y i ncl u de 
I H C, i n sit u hy bri dizati o n, a n d tiss ue or bl o o d -base d N G S of R N A or D N A.
F oll o wi n g i m ple me ntati o n of A me n d me nt 5, n o bl o o d sa m ples f or bi o mar ker assess me nts 
will be dra w n at E O T.
S afet y Assess me nts
Safet y  assess me nts will i ncl u de t he s ur veilla nce a n d rec or di n g of A Es, i ncl u di n g seri o us 
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, c o nc o mit a nt 
me dicati o ns, pre g na nc y  testi n g, a n d la b orat or y tests. Assess me nt of car diac ejecti o n fracti o n 
will be perf or me d usi n g M U G A sca n or E C H O. D uri n g t he L T E P, all safet y  assess me nts 
ot her t ha n pre g na nc y  testi n g will be perf or me d per i nstit uti o nal g ui deli nes a n d i n vesti gat or -
deter mi ne d us ual a n d c ust o mar y  cli nical care. Pre g na nc y testi n g will c o nti n ue t o be 
perf or me d as o utli ne d i n t he sc he d ule of e ve nts f or partici pa nts of c hil d beari n g p ote ntial. 
D uri n g t he L T E P, o nl y  i nf or mati o n relate d t o pre g na ncies, S A Es, a n d A E SIs will be re p orte d 
t o t he S p o ns or. 
St atistic al Met h o ds
Safet y  a n d efficac y will be assesse d usi n g descri pti ve statistics, i ncl u di n g t he n u m ber of 
o bser vati o ns, mea n, me dia n, sta n dar d de viati o n, mi ni m u m a n d ma xi m u m f or c o nti n u o us 
varia bles, a n d t he n u m ber a n d perce nta ges ( of n o n- missi n g) per cate g or y  f or cate g orical 
varia bles. C o nfir me d o bjecti ve res p o nse rate (c O R R) per i n vesti gat or is defi ne d as t he 
pr o p orti o n of partici pa nts wit h c o nfir me d c o m plete res p o nse ( C R) or partial res p o nse ( P R), 
acc or di n g t o R E CIS T v 1. 1. T he 2 -si de d 9 0 % e xact c o nfi de nce i nter val ( CI) usi n g Cl o p per-
Pears o n met h o d will be calc ulate d f or t he res p o nse rates.
P hase 1 b T ucati ni b D ose Escalati o n wit h F O L F O X ( C o h orts 1 A a n d 1 B)
T he t ucati ni b d ose escalati o n will f oll o w a 3 + 3 sc he me. A p pr o xi matel y  6 D LT- e val ua ble 
partici pa nts ma y  be treate d i n eac h p hase 1 b d ose escalati o n c o h ort i n or der t o i de ntif y t he 
rec o m me n de d p hase 2 d ose of t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d o xali plati n-
base d re gi me ns. 
T he D L T -E val ua ble A nal y sis Set i ncl u des all partici pa nts i n C o h ort 1 A or 1 B w h o meet o ne 
of t he f oll o wi n g criteria: ( 1) ha d a re nal D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d 
o xali plati n a n d t ucati ni b d oses per c y cle a n d ha ve bee n f oll o we d f or at least 2 c ycles of st u d y 
treat me nt (t hr o u g h t he e n d of C ycle 3 f or F O L F O X re gi me ns), i ncl usi ve of d ose dela y s.
C o h ort 1 A ma y  e nr oll a p pr o xi matel y 5 partici pa nts i n or der t o ha ve at least 3 D LT- e val ua ble 
partici pa nts, a n d a p pr o xi matel y  8 partici pa nts i n C o h ort 1 B i n or der t o ha ve at least 6 D L T -
e val ua ble partici pa nts i n t he case t hat a re nal D L T is o bser ve d i n t he first 3 D L T- e val ua ble 
partici pa nts. 
P hase 1 b Safet y E val uati o n of T ucati ni b wit h Trast uz u ma b a n d C A P O X ( C o h ort 1 C) or wit h 
Tras t uz u ma b a n d Pe m br oliz u ma b-C o ntai ni n g Re gi me ns ( C o h orts 1 E, 1 F, 1 G)
C o h orts 1 C, 1 E, 1 F, a n d 1 G ma y  e nr oll a p pr o xi matel y 8 partici pa nts i n eac h c o h ort t o e ns ure 
at least 6 partici pa nts i n eac h c o h ort c o m plete t he a p pr o priate D L T peri o d ( 2 1 -d a y s f or 
C o h orts 1 C, 1 F a n d 1 G; 2 8 -d a y s f or C o h ort 1 E). E nr oll me nt ma y re mai n o pe n t o e ns ure at 
least 3 partici pa nts fr o m Ja pa n are e nr olle d i nt o eac h c o h ort.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 1 of 2 2 0
T he D L T -E val ua ble A nal y sis Set f or C o h ort 1 C i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d ca pecita bi ne, 
o xali plati n, trast uz u ma b, a n d t ucati ni b f or t he first 2 1 da y s of st u d y treat me nt a n d ha ve bee n 
f oll o we d f or at 2 1 da ys of st u d y treat me nt.
T he D L T -E val ua ble A nal y sis Set f or C o h ort 1 E i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d fl u or o uracil, 
o xali plati n, pe m br oliz u ma b, trast uz u ma b, a n d t ucati ni b f or t he first 2 8 da y s of st u d y 
treat me nt a n d ha ve bee n f oll o we d f or at 2 8 d a y s of st u d y treat me nt.
T he D L T -E val ua ble A nal y sis Set f or C o h ort 1 F i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d ca pecita bi ne, 
o xali plati n, pe m br oliz u ma b, trast uz u ma b, a n d t ucat i ni b f or t he first 2 1 da ys of st u d y 
treat me nt a n d ha ve bee n f oll o we d f or at 2 1 da ys of st u d y treat me nt.
T he D L T -E val ua ble A nal y sis Set f or C o h ort 1 G i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 75 % of pla n ne d pe m br oliz u ma b, 
trast uz u ma b, a n d t ucati ni b f or t he first 2 1 da ys of st u d y treat me nt a n d ha ve bee n f oll o we d f or 
at 2 1 da ys of st u d y treat me nt.
P hase 1 b T ucati ni b Ja pa n Safet y E val uati o n i n C o m bi nati o n wit h Trast uz u ma b a n d F O L F O X 
( C o h ort 1 D)
C o h ort 1 D (Ja pa n -s pecific c o h ort) will e nr oll a mi ni m u m of 3 partici pa nts t o recei ve 
t ucati ni b, trast uz u ma b, a n d m F O L F O X 6. T he D L T-e val ua ble a nal ys is set i n C o h ort 1 D 
i ncl u des all partici pa nts w h o meet o ne of t he f oll o wi n g criteria: ( 1) ha d a D LT or ( 2) ha d 
ta ke n at least 7 5 % of pla n ne d fl u or o uracil, o xali plati n, trast uz u ma b, a n d t ucati ni b d oses a n d 
ha ve bee n f oll o we d f or at least 2 8 da y s.
P hase 2 T u m or S pecific E x pa nsi o n
T u m or s pecific e x pa nsi o n c o h orts ma y  be e nr olle d. F or e xa m ple, a 1 L gastric, es o p ha geal, 
a n d G EJ a de n ocarci n o ma e x pa nsi o n c o h ort ( C o h ort 2 A) ma y  e nr oll u p t o 4 0 partici pa nts, a n d 
a 1 L + C R C e x pa nsi o n c o h ort ( C o h ort 2 B) ma y  e nr oll u p t o 2 0 partici pa nts.
F or a sa m ple size of 4 0 partici pa nts i n C o h ort 2 A, ass u mi n g c O R R is bet wee n 6 0 % a n d 8 0 %, 
t he 2-si de d 9 0 % e xact CIs are s u m marize d bel o w:
C o nfir me d O R R
9 0 % E xact CI s ( N = 4 0)
6 0 %
( 4 6 %, 7 3 %)
7 0 %
( 5 6 %, 8 2 %)
8 0 %
( 6 7 %, 9 0 %)
F or a sa m ple size of 2 0 partici pa nts i n C o h ort 2 B, ass u mi n g c o nfir me d O R R is bet wee n 5 5 % 
a n d 6 5 %, t he 2 -side d 9 0 % e xact CI are s u m marize d bel o w:
C o nfir me d O R R
9 0 % E xact CI s ( N = 2 0)
5 5 %
( 3 5 %, 7 4 %)
6 0 %
( 3 9 %, 7 8 %)
6 5 %
( 4 4 %, 8 2 %)
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 2 of 2 2 0
T A B L E O F C O N T E N T S
TI T L E P A G E .............................................................................................................................1
D O C U M E N T HI S T O R Y ........................................................................................................... 2
1. P R O T O C O L  A M E N D M E NT S U M M A R Y O F C H A N G E S ( S O C) T A B L E ......................2
2. P R O T O C O L  S Y N O P SIS ................................ ......................................................................7
LI S T O F A P P E N DI C E S ..........................................................................................................4 0
LI S T O F T A B L E S ...................................................................................................................4 1
LI S T O F FI G U R E S .................................................................................................................4 2
LI S T O F A B B R E VI A T I O N S A N D D E FI NITI O N S O F T E R M S ..........................................4 3
3. I N T R O D U C TI O N ...............................................................................................................4 8
3. 1. H E R 2 i n Ca ncer ......................................................................................................4 8
3. 2. T ucati ni b ..................................................................................................................4 8
3. 3. Pe m br oliz u ma b ........................................................................................................4 8
3. 4. St u d y  Rati o nale.......................................................................................................4 9
4. O BJ E C TI V E S ......................................................................................................................5 2
4. 1. P hase 1 b T ucati ni b D ose Escalati o n wit h Trast uz u ma b a n d F O L F O X 
( C o h ort 1 A a n d C o h ort 1 B) .......................................................................................5 2
4. 2. P hase 1 b Safet y E val uati o n of T ucati ni b i n C o m bi nati o n wit h Trast uz u ma b + 
C A P O X ( C o h ort 1 C), or i n C o m bi nati o n wit h Trast uz u ma b a n d 
Pe m br oliz u ma b -C o ntai ni n g C o m bi nati o ns ( C o h orts 1 E, 1 F, a n d 1 G) ......................5 3
4. 3. P hase 1 b Ja pa n Safet y  E val uati o n of Tucati ni b i n C o m bi nati o n wit h 
Trast uz u ma b a n d m F O L F O X 6 ( C o h ort 1 D) .............................................................5 4
4. 4. P hase 2 T u m or -S pecific E x pa nsi o n ........................................................................5 4
5. I N V E S TI G A T I O N A L PL A N ..............................................................................................5 6
5. 1. S u m mar y  of St u d y Desi g n ......................................................................................5 6
5. 1. 1. P hase 1 b T ucati ni b D ose Escalati o n Wit h Trast uz u ma b a n d 
F O L F O X ( C o h ort 1 A a n d 1 B) .........................................................................5 8
5. 1. 1. 1. Trast uz u ma b a n d F O L F O X – C o h o rt 1 A..................................5 8
5. 1. 1. 2. Trast uz u ma b a n d F O L F O X - C o h ort 1 B ...................................5 9
5. 1. 1. 3. D ose -escalati o n Pr ocess ............................................................5 9
5. 1. 2. P hase 1 b Safet y E val uati o n wit h Trast uz u ma b a n d C A P O X ( C o h ort 
1 C) or wit h Trast uz u ma b a n d Pe m br oliz u ma b- C o ntai ni n g C o m bi nati o ns 
( C o h orts 1 E, 1 F, 1 G)........................................................................................6 0
5. 1. 2. 1. Trast uz u ma b a n d C A P O X ( C o h ort 1 C)................................ ....6 1
5. 1. 2. 2. Pe m br oliz u ma b, Trast uz u ma b, F O L F O X ( C o h ort 1 E)............. 6 2
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 3 of 2 2 0
5. 1. 2. 3. Pe m br oliz u ma b, Trast uz u ma b, C A P O X ( C o h ort 1 F) ...............6 2
5. 1. 2. 4. Trast uz u ma b, Pe m br oliz u ma b ( C o h ort 1 G) ..............................6 3
5. 1. 3. P hase 1 b T ucati ni b Ja pa n Safet y  E val uati o n i n C o m bi nati o n wit h 
Trast uz u ma b a n d F O L F O X ( C o h ort 1 D) .........................................................6 4
5. 1. 4. P hase 2 T u m or S pecific E x pa nsi o n C o h orts .............................................. 6 5
5. 1. 4. 1. P hase 2 T u m or S pecific E x pa nsi o n C o h ort 2 A .........................6 5
5. 1. 4. 2. P hase 2 T u m or S pecific E x pa nsi o n C o h ort 2 B......................... 6 6
5. 1. 5. Re nal D ose -li miti n g T o xicit y f or P hase 1 b D ose Escalati o n ( C o h ort 
1 A, 1 B) .............................................................................................................6 7
5. 1. 6. D ose -li miti n g T o xicities f or P hase 1 b Safet y E val uati o n of T ucati ni b 
wit h Trast uz u ma b + C A P O X ( C o h ort 1 C), T ucati ni b wit h Trast uz u ma b 
+ Pe m br oliz u ma b - C o ntai ni n g C o m bi nati o ns ( C o h orts 1 E, 1 F, 1 G), a n d 
Ja pa n Safet y E val uati o n wit h T ucati ni b wit h Trast uz u ma + F O L F O X 
( C o h ort 1 D)......................................................................................................6 8
5. 1. 7. Safet y M o nit ori n g C o m mittee ....................................................................6 9
5. 1. 7. 1. P hase 1 b T ucati ni b D ose Escalati o n wit h Trast uz u ma b 
a n d F O L F O X ( C o h orts 1 A, 1 B) ........................................................6 9
5. 1. 7. 2. P hase 1 b Safet y E val uati o n of T ucati ni b wit h 
Trast uz u ma b a n d C A P O X or wit h Trast uz u ma b a n d 
Pe m br oliz u ma b -C o ntai ni n g C o m bi nati o ns ( C o h orts 1 C, 1 E, 
1 F, 1 G) ...............................................................................................7 0
5. 1. 7. 3. P hase 2 T u m or -S pecific E x pa nsi o n ( C o h orts 2 A, 2 B) ..............7 0
5. 1. 8. L o n g -ter m E xte nsi o n P hase........................................................................7 0
5. 1. 9. E n d of St u d y ...............................................................................................7 1
5. 2. Disc ussi o n a n d Rati o nale f or St u d y Desi g n ............................................................7 1
5. 2. 1. Met h o d of Assi g ni n g Partici pa nts t o Treat me nt Gr o u ps............................ 7 1
5. 2. 2. Rati o nale f or Selecti o n of D oses ................................................................7 1
5. 2. 3. Bli n di n g a n d U n bli n di n g............................................................................ 7 4
6. S T U D Y P O P U L A T I ON................................ ......................................................................7 4
6. 1. I ncl usi o n Criteria .....................................................................................................7 4
6. 2. E xcl usi o n Criteria ....................................................................................................7 8
6. 3. C hil d beari n g P ote ntial................................ .............................................................8 1
6. 4. Re m o val of Partici pa nts fr o m T hera p y or Assess me nt ...........................................8 2
6. 4. 1. Disc o nti n uati o n of St u d y  Treat me nt ...........................................................8 2
6. 4. 2. Partici pa nt Wit h dra wal fr o m St u d y ............................................................8 2
6. 4. 3. Wit h dra wal of C o nse nt ...............................................................................8 3
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 4 of 2 2 0
7. T R E A T M E N T S ...................................................................................................................8 3
7. 1. Pre parati o n, Ha n dli n g, St ora ge, a n d Acc o u nta bilit y ...............................................8 3
7. 2. Si n gle Refere nce Safet y  D oc u me nts.......................................................................8 4
7. 3. Treat me nts A d mi nistere d ........................................................................................8 4
7. 3. 1. T ucati ni b, Trast uz u ma b, a n d F O L F O X ( C o h orts 1 A, 1 B, 1 D, 2 B) ...........8 4
7. 3. 2. T ucati ni b, Trast uz u ma b, a n d C A P O X ( C o h ort 1 C) ...................................8 6
7. 3. 3. T ucati ni b, Trast uz u ma b, F O L F O X, a n d Pe m br oliz u ma b ( C o h orts 
1 E, 2 A) .............................................................................................................8 6
7. 3. 4. T ucati ni b, Trast uz u ma b, C A P O X, a n d Pe m br oliz u ma b ( C o h orts 1 F, 
2 A) ...................................................................................................................8 7
7. 3. 5. T ucati ni b, Trast uz u ma b, a n d Pe m br oliz u ma b ( C o h ort 1 G) .......................8 8
7. 4. I n vesti gati o nal Pr o d uct ( T ucati ni b) .........................................................................8 8
7. 4. 1. Descri pti o n ..................................................................................................8 9
7. 4. 2. Met h o d of Pr oc ure me nt ..............................................................................8 9
7. 4. 3. D ose a n d A d mi nistrati o n ............................................................................8 9
7. 4. 4. St ora ge a n d Ha n dli n g ................................................................................. 8 9
7. 4. 5. Pac ka gi n g a n d La beli n g ..............................................................................9 0
7. 4. 6. Pre parati o n a n d Dis pe nsi n g ........................................................................9 0
7. 4. 7. St u d y  Inter ve nti o n Acc o u nta bilit y ..............................................................9 0
7. 5. F O L F O X Re gi me n ( C o h orts 1 A, 1 B, 1 D, 1 E, 2 A, a n d 2 B) ...................................9 0
7. 5. 1. Descri pti o n ..................................................................................................9 0
7. 5. 2. Met h o d of Pr oc ure me nt ..............................................................................9 0
7. 5. 3. D ose a n d A d mi nistrati o n ............................................................................9 0
7. 5. 4. St ora ge a n d Ha n dli n g ................................................................................. 9 1
7. 5. 5. Pre parati o n a n d Dis pe nsi n g ........................................................................9 1
7. 6. C A P O X Re gi me n ( C o h orts 1 C, 1 F, a n d 2 A) ..........................................................9 1
7. 6. 1. Descri pti o n ..................................................................................................9 1
7. 6. 2. Met h o d of Pr oc ure me nt ..............................................................................9 1
7. 6. 3. D ose a n d A d mi nistrati o n ............................................................................9 1
7. 6. 4. St ora ge a n d Ha n dli n g ................................................................................. 9 2
7. 6. 5. Pre parati o n a n d Dis pe nsi n g ........................................................................9 2
7. 7. Trast uz u ma b................................ ............................................................................9 2
7. 7. 1. Descri pti o n ..................................................................................................9 2
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 5 of 2 2 0
7. 7. 2. Met h o d of Pr oc ure me nt ..............................................................................9 2
7. 7. 3. D ose a n d A d mi nistrati o n ............................................................................9 2
7. 7. 4. St ora ge a n d Ha n dli n g ................................................................................. 9 2
7. 7. 5. Pac ka gi n g a n d La beli n g ..............................................................................9 3
7. 7. 6. Pre parati o n a n d Dis pe nsi n g ........................................................................9 3
7. 7. 7. St u d y  Treat me nt Acc o u nta bilit y.................................................................9 3
7. 8. Pe m br oliz u ma b ( C o h orts 1 E, 1 F, 1 G, a n d 2 A)................................ .......................9 3
7. 8. 1. Descri pti o n ..................................................................................................9 3
7. 8. 2. Met h o d of Pr oc ure me nt ..............................................................................9 3
7. 8. 3. D ose a n d A d mi nistrati o n ............................................................................9 3
7. 8. 4. St ora ge a n d Ha n dli n g ................................................................................. 9 4
7. 8. 5. Pac ka gi n g a n d La beli n g ..............................................................................9 4
7. 8. 6. Pre parati o n a n d Dis pe nsi n g ........................................................................9 4
7. 8. 7. St u d y  Treat me nt Acc o u nta bilit y.................................................................9 4
7. 9. D ose M o dificati o ns .................................................................................................9 4
7. 9. 1. T ucati ni b D ose M o dificati o ns.................................................................... 9 4
7. 9. 2. F O L F O X D ose M o dificati o ns ....................................................................9 6
7. 9. 3. C A P O X D ose M o dificati o ns ......................................................................9 9
7. 9. 4. Trast uz u ma b D ose M o dificati o ns .............................................................1 0 3
7. 9. 4. 1. D ose M o dificati o ns f or Left Ve ntric ular D y sf u ncti o n ............1 0 4
7. 9. 5. Pe m br oliz u ma b D ose M o dificati o ns ........................................................1 0 4
7. 9. 5. 1. I m m u ne -Relate d E ve nts a n d D ose M o dificati o n 
( Wit h h ol d, Treat, Disc o nti n ue)........................................................1 0 4
7. 9. 5. 2. D ose M o dificati o n a n d T o xicit y  Ma na ge me nt of I nf usi o n 
Reacti o ns Relate d t o Pe m br oliz u ma b ..............................................1 1 0
7. 9. 5. 3. Ot her All o we d D ose I nterr u pti o n f or Pe m br oliz u ma b............ 1 1 1
7. 9. 6. I nf usi o n -relate d Reacti o ns ........................................................................1 1 1
7. 9. 7. Aller gic/ H y perse nsiti vit y  Reacti o ns.........................................................1 1 2
7. 9. 8. A na p h yl a xis ..............................................................................................1 1 2
7. 9. 9. Ma na ge me nt of Diarr hea ..........................................................................1 1 2
7. 9. 1 0. D ose M o dificati o ns f or Diarr hea ............................................................1 1 3
7. 1 0. Re q uire d Pre me dicati o n a n d P ost me dicati o n................................ ......................1 1 3
7. 1 1. C o nc o mita nt T hera p y ..........................................................................................1 1 4
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 6 of 2 2 0
7. 1 1. 1. P ote ntial C o nc o mita nt Dr u g I nteracti o ns ...............................................1 1 4
7. 1 1. 1. 1. T ucati ni b ................................................................................1 1 4
7. 1 1. 1. 2. Trast uz u ma b................................ ..........................................1 1 4
7. 1 1. 1 . 3. F O L F O X ...............................................................................1 1 4
7. 1 1. 1. 4. C A P O X .................................................................................1 1 4
7. 1 1. 1. 5. Pe m br oliz u ma b ......................................................................1 1 4
7. 1 1. 2. Re q uire d C o nc o mita nt T hera p y.............................................................. 1 1 5
7. 1 1. 3. All o we d C o nc o mita nt T hera p y ...............................................................1 1 6
7. 1 1. 4. C o nc o mita nt T hera pies t o be Use d wit h Ca uti o n................................... 1 1 7
7. 1 1. 5. Pr o hi bite d C o nc o mita nt T hera p y............................................................ 1 1 7
7. 1 2. Ma na ge me nt of O ver d ose ................................ ...................................................1 1 8
7. 1 2. 1. T ucati ni b .................................................................................................1 1 8
7. 1 2. 2. Pe m br oliz u ma b .......................................................................................1 1 8
7. 1 2. 3. Trast uz u ma b, O xali plati n, Ca pecita bi ne, Le uc o v ori n, a n d 
Fl u or o uracil ....................................................................................................1 1 8
7. 1 3. Treat me nt C o m plia nce ........................................................................................1 1 8
8. S T U D Y A C TI VI TI E S .......................................................................................................1 1 9
8. 1. Sc he d ule of E ve nts ................................................................................................1 1 9
8. 2. Scree ni n g Visit ( Da ys – 2 8 t o – 1)................................ ..........................................1 1 9
8. 2. 1. Baseli ne Visit ( Da y  –7 t o Da y  – 1) * ..........................................................1 2 0
8. 3. F O L F O X Treat me nt Peri o d ( 1 4 -d a y  c ycles) P hase 1 b T ucati ni b D ose 
Escalati o n ( C o h orts 1 A a n d 1 B), Ja pa n -s pecific C o h ort 1 D, Pe m br oliz u ma b 
C o h ort 1 E, a n d P hase 2 T u m or S pecif ic E x pa nsi o n C o h orts ( C o h orts 2 A a n d 
2 B) ...........................................................................................................................1 2 0
8. 3. 1. C y cle 1 Da y 1 – F O L F O X ........................................................................1 2 0
8. 3. 2. C y cle 1 Da y 3 ( ± 1 d) – F O L F O X ( C o h orts 1 A a n d 1 B o nl y) ..................1 2 2
8. 3. 3. C y cle 1 Da y 8 ( ± 1 d) – F O L F O X ( C o h orts 1 A, 1 B, 1 D, 1 E, 2 A a n d 
2 B) ..................................................................................................................1 2 2
8. 3. 4. C y cle 2 a n d C y cle 3 Da y 1 ( ± 1 d) – F O L F O X ( C o h orts 1 A, 1 B, 1 D, 
1 E, 2 A, a n d 2 B) .............................................................................................1 2 2
8. 3. 5. C y cle 2 a n d C ycle 3 Da y 3 ( ± 1 d) – F O L F O X ( C o h orts 1 A a n d 1 B 
o nl y )...............................................................................................................1 2 3
8. 3. 6. C y cle 2 a n d C ycle 3 Da y 8 ( ± 1 d) – F O L F O X ( C o h orts 1 A, 1 B, 1 D, 
1 E, 2 A a n d 2 B) ..............................................................................................1 2 3
8. 3. 7. C y cle 4 (a n d All S u bse q ue nt C y cles) Da y 1 ( ± 1 d) – F O L F O X ..............1 2 4
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 7 of 2 2 0
8. 3. 8. E ver y  6 Wee ks * or 8 Wee ks† ( ± 7 d) – F O L F O X .....................................1 2 4
8. 3. 9. E ver y  1 2 Wee ks ( ± 7 d) – F O L F O X .........................................................1 2 5
8. 4. C A P O X Treat me nt Peri o ds ( 2 1- d a y c y cles) – P hase 1 b C A P O X C o h ort 
( C o h ort 1 C), P hase 1 b Pe m br oliz u ma b ( C o h ort 1 F), a n d P hase 2 T u m or -
S pecific E x pa nsi o n C o h ort ( C o h ort 2 A) ................................ .................................1 2 5
8. 4. 1. C y cle 1 Da y 1 – C A P O X ..........................................................................1 2 5
8. 4. 2. C y cle 1 Da y 8 ( ± 1 d) – C A P O X ...............................................................1 2 6
8. 4. 3. C y cle 2 Da y 1 ( ± 1 d) – C A P O X ...............................................................1 2 6
8. 4. 4. C y cle 2 Da y 8 ( ± 1 d) – C A P O X ...............................................................1 2 7
8. 4. 5. C y cle 3 (a n d All S u bse q ue nt C y cles) Da y 1 ( ± 1 d) – C A P O X ................1 2 7
8. 4. 6. E ver y  6 Wee ks ( ± 7 d) C A P O X u p t o 2 4 Wee ks a n d E ver y 9 Wee ks 
T hereafter .......................................................................................................1 2 8
8. 4. 7. E ver y  1 2 Wee ks ( ± 7 d) - C A P O X ............................................................1 2 8
8. 5. Pe m br oliz u ma b ( C he m ot hera p y- free) Treat me nt Peri o ds ( 2 1 -d a y  c ycles) –
Pe m br oliz u ma b C o h ort 1 G................................ ......................................................1 2 8
8. 5. 1. C y cle 1 Da y 1 ...........................................................................................1 2 8
8. 5. 2. C y cle 1 Da y 8 ( ± 1 d) ................................................................................1 2 9
8. 5. 3. C y cle 2 Da y 1 ( ± 1 d) ................................................................................1 2 9
8. 5. 4. C y cle 2 Da y 8 ( ± 1 d) ................................................................................1 3 0
8. 5. 5. C y cle 3 (a n d All S u bse q ue nt C y cles) Da y 1 ( ± 1 d)..................................1 3 0
8. 5. 6. E ver y  6 Wee ks ( ± 7 d) u p t o 2 4 Wee ks a n d E ver y 9 Wee ks T hereafter...1 3 1
8. 5. 7. E ver y  1 2 Wee ks ( ± 7 d).............................................................................1 3 1
8. 6. L o n g -ter m E xte nsi o n P hase – Be gi n ni n g of eac h C y cle a n d E n d of 
Treat me nt .................................................................................................................1 3 1
8. 7. E n d of Treat me nt Visit ( 3 0 t o 3 7 Da y s After Last D ose of St u d y Treat me nt) .....1 3 1
8. 8. F oll o w -u p ( E ver y  9 or 1 2 Wee ks ± 1 4 Da ys) ........................................................1 3 2
8. 9. E n d of St u d y ..........................................................................................................1 3 2
9. S T U D Y A S S E S S M E N T S .................................................................................................1 3 3
9. 1. Scree ni n g/ Baseli ne Assess me nts................................ ...........................................1 3 3
9. 2. Res p o nse/ Efficac y  Assess me nts ...........................................................................1 3 3
9. 3. P har mac o ki netic Assess me nts................................ ...............................................1 3 3
9. 4. Bi o mar ker Assess me nts ................................ ........................................................1 3 6
9. 5. Safet y Assess me nts ...............................................................................................1 3 6
9. 5. 1. A d verse E ve nts .........................................................................................1 3 6
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 8 of 2 2 0
9. 5. 1. 1. Defi niti o ns................................ ...............................................1 3 6
9. 5. 1. 2. A d verse E ve nts of S pecial I nterest ..........................................1 3 9
9. 5. 1. 3. Pr oce d ures f or Eliciti n g a n d Rec or di n g A d verse E ve nts ........1 4 0
9. 5. 1. 4. E n vir o n me ntal E x p os ure, E x p os ure D uri n g Pre g na nc y  or 
Breastfee di n g, a n d Occ u pati o nal E x p os ure .....................................1 4 1
9. 5. 1. 5. Lac k of Efficac y ......................................................................1 4 3
9. 5. 1. 6. P ote ntial Dr u g- i n d uce d Li ver I nj ur y .......................................1 4 3
9. 5. 1. 7. Re p orti n g Peri o ds f or A d verse E ve nts a n d Seri o us 
A d verse E ve nts ................................................................................1 4 4
9. 5. 1. 8. Seri o us A d verse E ve nts Re q uire I m me diate Re p orti n g ..........1 4 5
9. 5. 1. 9. S p o ns or Safet y  Re p orti n g t o Re g ulat or y A ut h orities..............1 4 5
9. 5. 2. Vital Si g ns ................................................................................................1 4 6
9. 5. 3. C li nical La b orat or y Tests .........................................................................1 4 6
9. 5. 3. 1. M o nit ori n g f or Re nal T o xicit y ................................................1 4 6
9. 5. 4. P h y sical E xa mi nati o n ...............................................................................1 4 7
9. 5. 5. Pre g na nc y  Testi n g ....................................................................................1 4 7
9. 5. 6. Car diac F u ncti o n .......................................................................................1 4 8
9. 5. 6. 1. M U G A or E C H O ................................ ....................................1 4 8
9. 5. 6. 2. Electr ocar di o gra m ...................................................................1 4 8
9. 6. A p pr o priate ness of Meas ure me nts ........................................................................1 4 8
1 0. D A T A Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E ................................... 1 4 8
1 0. 1. Site Trai ni n g a n d M o nit ori n g Pr oce d ures ...........................................................1 4 8
1 0. 2. Data Ma na ge me nt Pr oce d ures .............................................................................1 4 9
1 0. 3. Access t o S o urce Data................................ .........................................................1 4 9
1 0. 4. Acc urac y  a n d Relia bilit y of Data........................................................................1 5 0
1 0. 5. Q ualit y  Ass ura nce Pr oce d ures ............................................................................1 5 0
1 0. 6. Data Ha n dli n g a n d Rec or d Kee pi n g................................ ....................................1 5 0
1 0. 6. 1. Data Ha n dli n g......................................................................................... 1 5 0
1 0. 6. 2. I n vesti gat or Rec or d Rete nti o n ................................................................1 5 0
1 1. D A T A A N A L Y SI S M E T H O D S .....................................................................................1 5 1
1 1. 1. Deter mi nati o n of Sa m ple Size .............................................................................1 5 1
1 1. 2. St u d y  E n d p oi nt Defi niti o ns.................................................................................1 5 1
1 1. 2. 1. O bjecti ve Res p o nse Rate........................................................................ 1 5 1
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 3 9 of 2 2 0
1 1. 2. 2. D urati o n of Res p o nse .............................................................................1 5 2
1 1. 2. 3. Pr o gressi o n -free S ur vi val .......................................................................1 5 2
1 1. 2. 4. O verall S ur vi val ......................................................................................1 5 2
1 1. 3. Statistical a n d A nal ytical Pla ns ...........................................................................1 5 2
1 1. 3. 1. Ge neral C o nsi derati o ns ...........................................................................1 5 2
1 1. 3. 1. 1. Ra n d o mizati o n a n d Bli n di n g .................................................1 5 2
1 1. 3. 1. 2. A dj ust me nts f or C o variates ...................................................1 5 2
1 1. 3. 1. 3. Ha n dli n g of Dr o p o uts a n d Missi n g Data ...............................1 5 2
1 1. 3. 1. 4 . M ultice nter St u dies ...............................................................1 5 3
1 1. 3. 1. 5. M ulti ple C o m paris o ns a n d M ulti plicit y ................................1 5 3
1 1. 3. 1. 6. Data Tra nsf or mati o ns a n d Deri vati o ns .................................1 5 3
1 1. 3. 1. 7. A nal y sis Sets .........................................................................1 5 3
1 1. 3. 1. 8. E xa mi nati o n of S u b gr o u ps ....................................................1 5 4
1 1. 3. 1. 9. Ti mi n g of A nal yses ...............................................................1 5 4
1 1. 3. 2. Partici pa nt Dis p ositi o n ............................................................................ 1 5 5
1 1. 3. 3. Partici pa nt C haracteristics ......................................................................1 5 5
1 1. 3. 4. Treat me nt C o m plia nce ............................................................................1 5 5
1 1. 3. 5. Efficac y  A nalys es ...................................................................................1 5 5
1 1. 3. 6. P har mac o ki netic A nal y ses ......................................................................1 5 5
1 1. 3. 7. Bi o mar ker A nal yses ................................................................................1 5 5
1 1. 3. 8. Safet y A nal ys es ......................................................................................1 5 5
1 1. 3. 8. 1. E xte nt of E x p os ure ................................................................1 5 5
1 1. 3. 8. 2. A d verse E ve nts ......................................................................1 5 5
1 1. 3. 8. 3. D ose -li miti n g T o xicit y..........................................................1 5 6
1 1. 3. 8. 4. Deat hs a n d Seri o us A d verse E ve nts ......................................1 5 6
1 1. 3. 8. 5. Cli nical L a b orat or y Res ults...................................................1 5 6
1 1. 3. 8. 6. Gl o mer ular Filtrati o n Rate................................ ....................1 5 6
1 1. 3. 8. 7. Ot her Safet y A nal yses ...........................................................1 5 6
1 1. 3. 9. I nteri m A nal ys es .....................................................................................1 5 6
1 2. R E G U L A T O R Y, E T HI C A L , A N D S T U D Y O V E R SI GH T C O N SI D E R A TI O N S .......1 5 6
1 2. 1. Pr ot oc ol A me n d me nts a n d St u d y  Ter mi nati o n...................................................1 5 6
1 2. 2. Re g ulat or y  a n d Et hical C o nsi derati o ns...............................................................1 5 7
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 0 of 2 2 0
1 2. 2. 1. Re p orti n g of Safet y  Iss ues a n d Seri o us Breac hes of t he Pr ot oc ol or 
I C H G C P........................................................................................................1 5 7
1 2. 3. I nf or me d C o nse nt Pr ocess ...................................................................................1 5 8
1 2. 4. Data Pr otecti o n ....................................................................................................1 5 8
1 2. 5. Disse mi nati o n of Cli nical St u d y  Data.................................................................1 5 9
1 2. 6. Data Q ualit y Ass ura nce .......................................................................................1 6 0
1 2. 7. S o urce D oc u me nts ...............................................................................................1 6 1
1 2. 8. Use of Me dical Rec or ds ......................................................................................1 6 1
1 2. 9. St u d y  a n d Site Start a n d Cl os ure.........................................................................1 6 2
1 2. 1 0. P u blicati o n P olic y .............................................................................................1 6 3
1 2. 1 1. S p o ns or’s Me dicall y  Q ualifie d I n di vi d ual ........................................................1 6 4
1 2. 1 2. Cli nical Trial A gree me nt ...................................................................................1 6 4
1 3. LI S T O F R E F E R E N C E S .................................................................................................1 6 5
LI S T O F A P P E N DI C E S
A p pe n di x A. Sc he d ule of E ve nts: P hase 1 b a n d P hase 2 C o h orts Utilizi n g F O L F O X .........1 6 9
Sc he d ule of E ve nts: P hase 1 b a n d P hase 2 C o h orts Utilizi n g C A P O X a n d 
Pe m br oliz u ma b C o h ort 1 G..................................................................... 1 7 3
A p pe n di x B. Perf or ma nce Stat us Scales C o n versi o n ............................................................1 7 8
A p pe n di x C. G ui da nce O n C o ntrace pti o n .............................................................................1 7 9
A p pe n di x D. C Y P 3 A I n d ucers a n d T heir Eli mi nati o n Half -li ves.........................................1 8 0
A p pe n d i x E. C Y P 2 C 8 i n hi bit ors/i n d ucers a n d T heir eli mi nati o n Half- li ves ........................1 8 1
A p pe n di x F. E xa m ples of Cli nical S u bstrates f or C Y P 3 A- me diat e d Meta b olis m ................1 8 2
A p pe n di x G. Pr oce d ures f or Rec or di n g a n d Re p orti n g A E s a n d S A Es ................................1 8 3
A p pe n di x H. S u m mar y  of C ha n ges f or Pri or Gl o bal A me n d me nts ...................................... 1 8 5
S u m mar y  of C ha n ges i n A me n d me nt 2.................................................................................1 8 8
S u m mar y  of C ha n ges i n A me n d me nt 2. 1..............................................................................1 9 6
S u m mar y  of C ha n ges i n A me n d me nt 3. 0..............................................................................1 9 8
S u m mar y  of C ha n ges i n A me n d me nt 3. 1..............................................................................2 1 0
S u m mar y  of C ha n ges i n A me n d me nt 4.................................................................................2 1 1
S u m mar y  of C ha n ges i n A me n d me nt 5.................................................................................2 1 5
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 1 of 2 2 0
LI S T O F T A B L E S
Ta ble 1.
O bjecti ves a n d C orres p o n di n g E n d p oi nts ................................................ 5 2
Ta ble 2.
O bjecti ves a n d C orres p o n di n g E n d p oi nts ................................................5 3
Ta ble 3.
O bjecti ves a n d C orres p o n di n g E n d p oi nts ................................................ 5 4
Ta ble 4.
O bjecti ves a n d C orres p o n di n g E n d p oi nts ................................................ 5 4
Ta ble 5.
S u m mar y  of C o h orts, Treat me nts, P o p ulati o ns, a n d N u m ber of 
Partici pa nts ...............................................................................................5 6
Ta ble 6.
Si n gle Refere nce Safet y  D oc u me nts f or St u d y  Inter ve nti o ns ..................8 4
Ta ble 7.
T ucati ni b a n d m F O L F O X 6 A d mi nistere d i n 1 4 -d a y  Cycl es Wit h 
Trast uz u ma b ( C o h orts 1 A, 1 B, 1 D, 2 B) ...................................................8 5
Ta ble 8.
T ucati ni b, m F O L F O X 7, a n d Trast uz u ma b A d mi nistere d i n 1 4 -d a y  
C y cles ( C o h orts 1 A a n d 1 B O nl y) ............................................................8 5
Ta ble 9.
T ucati ni b, C A P O X, a n d Trast uz u ma b A d mi nistere d i n 2 1- d a y  
C y cles ( C o h ort 1 C) ...................................................................................8 6
Ta ble 1 0.
T ucati ni b a n d m F O L F O X 6 A d mi nistere d i n 1 4 -d a y  Cycl es Wit h 
Trast uz u ma b ( Q 3 W) a n d Pe m br oliz u ma b ( Q 6 W) ( C o h orts 1 E, 2 A)....... 8 7
Ta ble 1 1.
T ucati ni b, C A P O X, a n d trast uz u ma b, a n d a d mi nistere d i n 2 1 -d a y  
c ycles wit h Pe m br oliz u ma b ( Q 6 W) ( C o h orts 1 F, 2 A) .............................8 8
Ta ble 1 2.
T ucati ni b, trast uz u ma b a d mi nistere d i n 2 1- d a y  c ycles a n d 
pe m br oliz u ma b ( C o h ort 1 G)..................................................................... 8 8
Ta ble 1 3.
T ucati ni b D ose M o dificati o ns f or A Es a....................................................9 5
Ta ble 1 4.
O xali plati n ( N o n -ne ur ol o gical T o xicit y ) a n d Fl u or o uracil D ose 
Re d ucti o n Le vels f or F O L F O X ................................................................9 7
Ta ble 1 5.
D ose M o dificati o ns f or A Es Attri b ute d t o F O L F O X............................... 9 7
Ta ble 1 6.
D ose M o dificati o n f or O xali plati n -ass ociate d Ne ur ot o xicit y 
Attri b ute d t o F O L F O X .............................................................................9 8
Ta ble 1 7.
O xali plati n ( N o n -ne ur ol o gical T o xicit y ) a n d Ca pecita bi ne D ose 
Re d ucti o n Le vels f or C A P O X................................................................ 1 0 0
Ta ble 1 8.
D ose M o dificati o ns f or A Es attri b ute d t o C A P O X................................ 1 0 0
Ta ble 1 9.
D ose M o dificati o n f or O xali plati n -ass ociate d Ne ur ot o xicit y 
Attri b ute d t o C A P O X a ............................................................................1 0 2
Ta ble 2 0.
Trast uz u ma b D ose M o dificati o n G ui deli nes f or Left Ve ntric ular 
D y sf u ncti o n.............................................................................................1 0 4
Ta ble 2 1.
D ose M o dificati o n a n d T o xicit y  Ma na ge me nt G ui deli nes f or 
Im m u ne -relate d A Es Ass ociate d wit h Pe m br oliz u ma b ..........................1 0 6
Ta ble 2 2.
Pe m br oliz u ma b I nf usi o n Reacti o n D ose M o dificati o n a n d 
Treat me nt G ui deli nes ..............................................................................1 1 0
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 2 of 2 2 0
Ta ble 2 3.
Plas ma P har mac o ki netic Sa m ple C ollecti o n i n F O L F O X P hase 1 b 
C o h orts ( C o h orts 1 A, 1 B) .......................................................................1 3 4
Ta ble 2 4.
Uri ne P har mac o ki netic Sa m ple C ollecti o n i n F O L F O X P hase 1 b 
C o h orts ( C o h orts 1 A, 1 B) a......................................................................1 3 5
Ta ble 2 5.
Plas ma P har mac o ki netic Sa m ple C ollecti o n Ti me p oi nts: Ja pa n -
s pecific C o h ort ( 1 D) ...............................................................................1 3 5
Ta ble 2 6.
Plas ma P har mac o ki netic Sa m ple C ollecti o n f or C o h orts 1 C, 1 E, 1 F, 
1 G, 2 A, 2 B ..............................................................................................1 3 5
Ta ble 2 7.
Re p orti n g S A Es via P S S A...................................................................... 1 8 3
LI S T O F FI G U R E S
Fi g ure 1:
St u d y  desi g n..............................................................................................6 7
Fi g ure 2:
T ucati ni b D ose Re d ucti o n Sc he d ule f or A Es Base d o n Starti n g 
D ose ..........................................................................................................9 5
Fi g ure 3:
Decisi o n Tree f or C ha n ges i n Re nal F u ncti o n ........................................1 4 7
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 3 of 2 2 0
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S
Ter m
Defi niti o n
1 L
first li ne
5- F U
5- fl u or o uracil
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 a mi n otra nsferase
A N C
a bs ol ute ne utr o p hil c o u nt
a P T T
acti vate d partial t hr o m b o plasti n ti me
A S T
as partate a mi n otra nsferase
A U C
area u n der t he c o nce ntrati o n -ti me c ur ve
A U C last
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve t o t he ti me of t he last q ua ntifia ble 
c o nce ntrati o n
β- h C G
beta h u ma n c h ori o nic g o na d otr o pi n 
B A P
bi o mar ker a nal ysis pla n
BI C R
bli n de d i n de pe n de nt ce ntral re vie w
BI D
t wice dail y
B U N
bl o o d urea nitr o ge n
C ma x
ma xi m u m o bser ve d c o nce ntrati o n
C tr o u g h
o bser ve d tr o u g h c o nce ntrati o n i n plas ma
C A P O X
ca pecita bi ne a n d o xali plati n
C B C
c o m plete bl o o d c o u nt
C F R
C o de of Fe deral Re g ulati o ns
C H F
c o n gesti ve heart fail ure
CI
c o nfi de nce i nter val
CI S H
c hr o m o ge nic i n sit u h y bri dizati o n
C LI A
Cli nical La b orat or y I m pr o ve me nt A me n d me nts
C N S
ce ntral ner v o us s yste m
c O R R
c o nfir me d o bjecti ve res p o nse rate
C R
c o m plete res p o nse
C R C
c ol orectal a de n ocarci n o ma 
C S R
cli nical st u d y re p ort
C T
c o m p ute d t o m o gra p h y
C T L A - 4
c yt ot o xic T- l y m p h oc yte-ass ociate d pr otei n 4
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C Y P
c yt oc hr o me 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 4 of 2 2 0
Ter m
Defi niti o n
D C T
data c ollecti o n t o ol
D DI
dr u g -dr u g i nteracti o n
DI LI
dr u g -i n d uce d li ver i nj ur y
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
D R E S S
Dr u g Ras h wit h E osi n o p hilia a n d S yste mic S y m pt o ms
E C
e xcl usi o n criteri o n
E C G
electr ocar di o gra m
E C H O
ec h ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
e C R F
electr o nic case re p ort f or m
E D B
e x p os ure d uri n g breastfee di n g
E D P
e x p os ure d uri n g pre g na nc y
E G F R
e pi der mal gr o wt h fact or rece pt or
E nr oll me nt
C y cle 1 Da y 1
E OI
e n d of i nf usi o n
E O T
e n d of treat me nt
E U
E ur o pea n U ni o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F F P E
f or mali n-fi xe d, paraffi n e m be d de d
FI S H
fl u oresce nce i n sit u h y bri dizati o n
F O L F O X
le uc o v ori n, fl u or o uracil, o xali plati n
F T 3
free trii o d ot h yr o ni ne
F T 4
free t h yr o xi ne
G E C
gastr oes o p ha geal ca ncer
G EJ
gastr oes o p ha geal j u ncti o n
G F R
gl o mer ular filtrati o n rate
GI
gastr oi ntesti nal
G y
gra y
H bc A B
he patitis B c ore a nti ge n
H bs A B
he patitis B s urface a nti b o d y
H bs A g
he patitis B s urface a nti ge n e x pressi o n 
H B V
he patitis B
H E R 2
h u ma n e pi der mal gr o wt h fact or rece pt or 2
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 5 of 2 2 0
Ter m
Defi niti o n
HI V
h u ma n i m m u n o deficie nc y vir us
I C
i ncl usi o n criteri o n
I C D
i nf or me d c o nse nt d oc u me nt
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har m ace uticals f or H u ma n Use
I C R
i n de pe n de nt ce ntral re vie w
I E C
i n de pe n de nt et hics c o m mittee
I F N-γ
i nterfer o n- γ
I g
i m m u n o gl o b uli n
I H C
i m m u n o hist oc he mistr y
I N D
i n vesti gati o nal ne w dr u g
I N R
i nter nati o nal n or m alize d rati o
I N V
i n vesti gat or assess me nt
I O
I m m u n o-o nc ol o g y
ir A E
I m m u ne-relate d a d verse e ve nt
I R B
i nstit uti o nal re vie w b oar d
I R R
i nf usi o n-relate d reacti o n
I S O
i nter nati o nal or ga nizati o n f or sta n dar dizati o n
I V
i ntra ve n o us(l y)
L T E P
l o n g-ter m e xte nsi o n p hase
L V E F
left ve ntric ular ejecti o n fracti o n
M A T E 1
m ulti dr u g a n d t o xi n e xtr usi o n pr otei n 1
M A T E 2 - K
m ulti dr u g a n d t o xi n e xtr usi o n pr otei n 2 K
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M D R D
M o dificati o n of Diet i n Re nal Disease [st u d y]
m F O L F O X
m o difie d F O L F O X
M RI
ma g netic res o na nce i ma gi n g
M SI
micr osatellite i nsta bilit y -hi g h/ deficie nt mis matc h re pair  
M QI
me dicall y q ualifie d i n di vi d ual
M U G A
m ulti gate d ac q uisiti o n
N CI
Nati o nal Ca ncer I nstit ute
N E
n ot esti ma ble
N G S
ne xt ge nerati o n se q ue nci n g
N S AI Ds
N o nster oi dal a nti -i nfla m mat or y dr u gs
N S C L C
n o n- s mall cell l u n g ca ncer (
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 6 of 2 2 0
Ter m
Defi niti o n
O C T 2
or ga nic cati o n tra ns p orter 2
O R R
o bjecti ve res p o nse rate
O S
o verall s ur vi val
P C R
p ol y merase c hai n reacti o n
P D
pr o gressi ve disease
P D - 1
pr o gra m me d cell deat h 1
P D -L 1/ 2
pr o gra m me d cell deat h li ga n d 1/ 2
P E T
p ositr o n e missi o n t o m o gra p h y
P F S
pr o gressi o n -free s ur vi val
P- g p
p- gl yc o pr otei n
P K
p har mac o ki netic(s)
P K C θ
pr otei n ki nase C -t heta
P L T
platelet
P O
orall y
P R
partial res p o nse
P S S A
Pfizer S A E s u b missi o n assista nt
P T T
partial t hr o m b o plasti n ti me
Q 2 W
e ver y 2 wee ks
Q 3 W
e ver y 3 wee ks
Q 6 W
e ver y 6 wee ks
R A S
rat sarc o ma vir us
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
SJ S
Ste ve ns -J o h ns o n S y n dr o me
S M C
Safet y M o nit ori n g C o m mittee
S O E
sc he d ule of e ve nts
S R S
stere otactic ra di os ur ger y
S R S D
si n gle refere nce safet y d oc u me nt
T 3
trii o d ot h yr o ni ne
T E N
t o xic e pi der mal necr ol ysis
T 1 D M
T y pe 1 dia betes mellit us
T ma x
ti me at w hic h t he ma xi m u m plas ma c o nce ntrati o n ( C ma x ) occ urs
U L N
u p per li mit of n or mal
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 7 of 2 2 0
Ter m
Defi niti o n
U P C
Uri ne Pr otei n/ Creati ni ne
U S
U nite d States
V E G F
vasc ular e n d ot helial gr o wt h fact or
W B C
w hite bl o o d cell
W B R T
w h ole brai n ra diati o n t hera p y
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 8 of 2 2 0
3. I N T R O D U C TI O N
3. 1. H E R 2 i n C a ncer
E nc o de d b y t he E R B B 2 ge ne, h u ma n e pi der mal gr o wt h fact or rece pt or 2 ( H E R 2) is part of a 
fa mil y of 4 relate d rece pt or t yr osi ne ki nases, w hic h i ncl u de H E R 1 (als o k n o w n as e pi der mal 
gr o wt h fact or rece pt or [ E G F R]), H E R 2, H E R 3, a n d H E R 4. H E R 1 -4 are s i n gle-pass 
tra ns me m bra ne glyc o pr otei n rece pt ors c o ntai ni n g a n e xtracell ular li ga n d bi n di n g re gi o n a n d 
a n i ntracell ular si g nali n g d o mai n. H E R 2 has n o k n o w n li ga n d, b ut it is t he preferre d 
di merizati o n part ner f or t he ot her H E R fa mil y rece pt ors. W he n o vere x presse d i n t u m ors, 
H E R 2 f or ms li ga n d -i n de pe n de nt h o m o di meric c o m ple xes t hat a ut o p h os p h or ylate. H E R 2 
h o m o - or heter o di merizati o n res ults i n t he acti vati o n of m ulti ple si g nali n g casca des, 
i ncl u di n g t he Ras/ Raf/ M E K/ M A P K, PI3 K/ A K T, Src, a n d S T A T pat h wa y s. T hese si g nali n g 
pat h wa y s lea d t o cell pr oliferati o n, i n hi biti o n of a p o pt osis, a n d metastasis (Riese 1 9 9 8 ; 
Ola y i o ye 2 0 0 0; Yar de n 2 0 0 1 ; Sc hlessi n ger 2 0 0 2 ; H ol br o 2 0 0 4 ; H y nes 2 0 0 5 ).
H E R 2 is a vali date d tar get i n m ulti ple s oli d t u m ors, wit h a nti- H E R 2 bi ol o gics a n d s mall 
m olec ule dr u gs a p pr o ve d f or patie nts wit h H E R 2 + breast a n d gastric ca ncer s. A m plificati o n 
of t he H E R 2 -ge ne or o vere x pressi o n of its pr otei n occ urs i n a p pr o xi matel y 1 5 % t o 2 0 % of 
breast ca ncers (Ha q ue 2 0 1 2 ; A merica n Ca ncer S ociet y  ( A C S) 2 0 1 8) a n d 6 % t o 3 0 % of 
gastric a n d es o p ha geal ca ncers (Kell y  2 0 1 6). Rece ntl y, i nterest has gr o w n i n H E R 2-tar geti n g 
strate gies f or patie nts wit h refract or y  metastatic c ol orectal carci n o ma, w here o vere x pressi o n 
of H E R 2 has bee n f o u n d t o occ ur i n a p pr o xi matel y 3 % t o 5 % of patie nts (Valt orta 2 0 1 5 ; 
Ta ke ga wa 2 0 1 7 ). H E R 2 ca n als o be o vere x presse d i n ot her gastr oi ntesti nal ( GI) ca ncers, 
s uc h as c h ola n gi ocarci n o ma a n d gall bla d der carci n o ma, w here st u dies s u g gest E R B B 2 
a m plificati o n ra n ges fr o m 1 % t o 6 % ( Wei n ber g 2 0 1 9 ; Al brec ht 2 0 2 0 ). 
3. 2. T uc ati ni b
T ucati ni b ( pre vi o usl y k n o w n as O N T -3 8 0 a n d A R R A Y - 3 8 0 a n d mar kete d as T U K Y S A® ) is 
a n oral, p ote nt, H E R 2-s pecific tyr osi ne ki nase i n hi bit or t hat is bei n g de vel o pe d b y  Sea ge n, a 
w h oll y  o w ne d s u bsi diar y of Pfizer ( B ot hell, W A). U nli ke ot her s mall m olec ule i n hi bit ors of 
H E R 2, i ncl u di n g la pati ni b, nerati ni b, a n d afati ni b, all of w hic h are d ual -i n hi bit ors of b ot h 
E G F R a n d H E R 2, t ucati ni b selecti vel y  i n hi bits H E R 2. T his e na bles t ucati ni b t o pr o vi de 
p ote nt i n hi biti o n of H E R 2 w hile mi ni mizi n g ma n y of t he E G F R -relate d si de effects i ncl u di n g 
se vere s ki n ras h a n d GI t o xicit y.
A c o m plete s u m mar y  of t he cli nical a n d n o ncli nical data rele va nt t o t ucati ni b a n d its st u d y i n 
h u ma n partici pa nts is pr o vi de d i n t he I n vesti gat or’s Br oc h ure.
3. 3. Pe m br oliz u m a b
Pe m br oliz u ma b is a p ote nt h u ma nize d i m m u n o gl o b uli n G 4 (I g G 4) m o n ocl o nal a nti b o d y  
( m A b) wit h hi g h s pecificit y of bi n di n g t o t he pr o gra m me d cell deat h 1 ( P D 1) rece pt or, t h us 
i n hi biti n g its i nteracti o n wit h pr o gra m me d cell deat h li ga n d 1 ( P D-L 1) a n d pr o gra m me d cell 
deat h li ga n d 2 ( P D -L 2). Base d o n precli nical i n vitr o data, pe m br oliz u ma b has hi g h affi nit y 
a n d p ote nt rece pt or bl oc ki n g acti vit y  f or P D 1. Pe m br oliz u ma b has a n acce pta ble precli nical 
safety pr ofile a n d is i n cli nical de vel o p me nt as a n i ntra ve n o us (I V) i m m u n ot hera p y f or 
a d va nce d mali g na ncies. Ke ytr u da® ( pe m br oliz u ma b) is i n dicate d f or t he treat me nt of patie nts 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 4 9 of 2 2 0
acr oss a n u m ber of i n dicati o ns. F or m ore details o n s pecific i n dicati o ns refer t o t he 
I n vesti gat or’s Br oc h ure.
Refer t o t he I n vesti gat or’s Br oc h ure (I B)/ prescri bi n g i nf or mati o n f or detaile d 
p har mace utical/t hera pe utic bac k gr o u n d of pe m br oliz u ma b.
3. 4. St u d y R ati o n ale
5 -fl u or o uracil, a n i n hi bit or of n ucleic aci d sy nt hesis, has bee n use d f or ye ars f or treat me nt of 
GI  ca ncers, b ot h as a si n gle a ge nt a n d i n c o m bi nati o n wit h ot her c he m ot hera pe utic a ge nts, 
i ncl u di n g o xali plati n (a plati n u m a nal o g t hat bl oc ks D N A re plicati o n) a n d le uc o v ori n (a 
f olate a nal o g). T he c o m bi nati o n of o xali plati n, fl u or o uracil, a n d le uc o v ori n ( F O L F O X) has 
bee n f o u n d t o be a safe a n d effecti ve a n d is use d as t he sta n dar d -of -care treat me nt f or 
gastr oes o p ha geal, c ol orectal, biliar y  tract, a n d gall bla d der ca ncers. A d diti o nall y, t he 
c o m bi nati o n of ca pecita bi ne, a pr o dr u g of fl u or o uracil, a n d o xali plati n ( C A P O X) has bee n 
f o u n d t o be safe a n d effecti ve f or t he treat me nt of gastric, es o p ha geal, a n d gastr oes o p ha geal 
j u ncti o n ( G EJ) a de n ocarci n o ma, metastatic c ol orectal a de n ocarci n o ma ( C R C), a n d biliar y 
tract ca ncer. F O LF O X a n d C A P O X re gi me ns are vie we d as cli nicall y  i nterc ha n gea ble i n 
treat me nt g ui deli nes a n d are use d wit h differe nt fre q ue ncies base d pri maril y o n ge o gra p hic 
l ocati o n a n d l ocal treat me nt prefere nce (L o ree 2 0 1 4; Ja nji gia n 2 0 2 0).
Trast uz u ma b is a h u ma nize d a nti -H E R 2 a nti b o d y  t hat bi n ds t o s u b d o mai n I V of t he H E R 2 
e xtracell ular d o mai n a n d e xerts its a ntit u m or effects b y  bl oc ki n g H E R 2-clea va ge, sti m ulati n g 
a nti b o d y-de pe n de nt, cell -me di ate d c yt ot o xicit y a n d i n hi biti n g li ga n d i n de pe n de nt, 
H E R 2 - me diate d mit o ge nic si g nali n g (Artea ga 2 0 1 1 ). Trast uz u ma b is a p pr o ve d f or treat me nt 
of patie nts wit h metastatic H E R 2 + gastric or G EJ a de n ocarci n o mas. W hile t he pr o g n ostic 
val ue of H E R 2 stat us i n gastr oes o p ha geal ca ncer ( G E C) is n ot clear, patie nts wit h 
H E R 2 p ositi ve ( H E R 2 +) a d va nce d sta ge disease ma y  be nefit fr o m t he a d diti o n of 
trast uz u ma b (a H E R 2-directe d m o n ocl o nal a nti b o d y ) t o c he m ot hera p y as first-li ne ( 1 L) 
t hera py (Ba n g 2 0 1 0 ). Trast uz u ma b i n c o m bi nati o n wit h a sec o n d H E R 2 i n hi bit or (eit her 
pert uz u ma b or la pati ni b) is a rec o m me n de d treat me nt o pti o n i n t he U nite d States f or 
a d va nce d or metastatic c ol o n ca ncer t hat is H E R 2-a m plifie d a n d rat sarc o ma vir us ( R A S ) a n d 
B R A F wil d -t ype (Be ns o n 2 0 2 1 ). 
T he a d diti o n of t ucati ni b a n d trast uz u ma b t o o xali plati n- base d c he m ot hera p y  ( F O L F O X or 
C A P O X) is bei n g e val uate d i n t his st u d y  base d o n precli nical a n d cli nical data de m o nstrati n g 
s u peri or acti vity of d ual tar get e d i n hi biti o n of H E R 2 wit h t ucati ni b a n d trast uz u ma b 
c o m pare d wit h eit her si n gle a ge nt al o ne.
A ra n d o mize d, d o u ble- bli n d, place b o -c o ntr olle d, acti ve-c o m parat or gl o bal cli nical trial 
( O N T- 3 8 0-2 0 6; H E R 2 C LI M B) has bee n c o n d ucte d t o e val uate t ucati ni b ( 3 0 0 m g t wice dail y 
[ BI D]) i n c o m bi nati o n wit h trast uz u ma b a n d ca pecita bi ne c o m pare d t o trast uz u ma b a n d 
ca pecita bi ne al o ne i n 6 1 2 partici pa nts wit h l ocall y  a d va nce d u nresecta ble or metastatic 
H E R 2 + breast ca ncer w h o ha ve ha d pri or treat me nt wit h trast uz u ma b, pert u z u ma b, a n d 
T- D M 1 (M urt h y  2 0 2 0). T he a d diti o n of t ucati ni b t o the c o m bi nati o n res ulte d i n a c o m para ble 
safety pr ofile t o trast uz u ma b a n d ca pecita bi ne al o ne. T he pri mar y e n d p oi nt f or St u d y 
O N T - 3 8 0-2 0 6, pr o gressi o n -free s ur vi val ( P F S) per Res p o nse E val uati o n Criteria i n S oli d 
T u m ors ( R E CI S T) v 1. 1 base d o n bli n de d i n de pe n de nt ce ntral re vie w ( BI C R), was met. Wit h 
a me dia n P F S f oll o w-u p of 1 0. 4 m o nt hs, t he pri mar y  a nalys is of P F S per BI C R de m o nstrate d 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 0 of 2 2 0
treat me nt o n t he t ucati ni b ar m was s u peri or t o t he c o ntr ol ar m a n d res ulte d i n a 
4 6 % re d ucti o n i n t he ris k of disease pr o gre ssi o n or deat h (stratifie d hazar d rati o = 0. 5 4 [ 9 5 % 
c o nfi de nce i nter val { CI }: 0. 4 2, 0. 7 1], P < 0. 0 0 0 0 1). T he me dia n P F S was 7. 8 m o nt hs ( 9 5 % 
CI : 7. 5, 9. 6) a n d 5. 6 m o nt hs ( 9 5 % CI: 4. 2, 7. 1) f or t he t ucati ni b a n d c o ntr ol ar ms, 
res pecti vely. O verall s ur vi val ( O S) was si g nifica ntl y  pr ol o n ge d o n t he t ucati ni b ar m vers us 
t he c o ntr ol ar m, wit h a 3 4 % re d ucti o n i n t he ris k of deat h ( hazar d rati o = 0. 6 6 [ 9 5 % CI: 0. 5 0, 
0. 8 8]; P = 0. 0 0 4 8). T he me dia n O S was 2 1. 9 m o nt hs ( 9 5 % CI : 1 8. 3, 3 1. 0) a n d 1 7. 4 m o nt hs 
( 9 5 % CI: 1 3. 6, 1 9. 9) for t he t ucati ni b a n d c o ntr ol ar ms, res pecti vel y.
I n a d diti o n t o res ults see n i n t he H E R 2 C LI M B trial, t he c o m bi nati o n of t ucati ni b ( 3 0 0 m g 
BI D) a n d trast uz u ma b has s h o w n pr o misi n g acti vit y  i n H E R 2 + metastatic C R C, base d o n 
i nitial res ults re p orte d fr o m t he si n gle-ar m, p hase 2 trial, C 4 2 5 1 0 0 2 ( S G N T U C - 0 1 7, 
M O U N T AI N E E R) (Stric kler 2 0 1 9 ). I n t his st u d y, partici pa nts wit h H E R 2 +, R A S-wil dt y pe 
metastatic C R C w h o ha d bee n pre vi o usl y treate d wit h fl u or o uracil, o xali plati n, iri n oteca n 
a n d a n a nti -vasc ular e n d ot helial gr o wt h fact or ( V E G F) a nti b o d y  recei ve d t ucati ni b ( 3 0 0 m g 
BI D) i n c o m bi nati o n wit h trast uz u ma b ( 8 m g/ k g I V f oll o we d b y 6 m g / k g e ver y 3 wee ks 
[ Q 3 W]). T he pri mar y e n d p oi nt was o bjecti ve res p o nse rate ( O R R). I nteri m data fr o m t he 
i nitial 2 6 partici pa nts was prese nte d at t he E ur o pea n S ociet y f or Me dical O nc ol o g y 2 0 1 9 
C o n gress. T he i n vesti gat ors re p orte d a n O R R of 5 2. 2 % ( 1 2 of 2 3 partici pa nts; 9 5 % CI : 3 0. 6, 
7 3. 2) t hat c o nsiste d of 1 2 partial res p o nses ( P Rs) i n 2 3 e val ua ble partici pa nts, 1 1 of w hic h 
were c o nfir me d at a sec o n d assess me nt ti me p oi nt (Stric kler 2 0 1 9 ). A d diti o nall y, t he me dia n 
d urati o n of res p o nse ( D O R) was 1 0. 4 m o nt hs ( 6. 0 – n ot esti ma ble [ N E]), wit h a me dia n P F S 
of 8. 1 m o nt hs ( 3. 8 – N E) a n d a me dia n O S of 1 8. 7 m o nt hs ( 1 2. 3 – N E).
T he pri mar y  o bjecti ve of t he p hase 1 b t ucati ni b d ose escalati o n wit h o xali plati n p orti o n of 
t his st u d y is t o deter mi ne t he rec o m me n de d d ose of t ucati ni b w he n c o m bi ne d wit h 
trast uz u ma b a n d o xali plati n-base d c he m ot hera p y i n partici pa nts wit h H E R 2 + GI ca ncers. I n 
a d diti o n, t he p ote ntial f or ne p hr ot o xicit y of o xali plati n w he n use d i n c o m bi nati o n wit h
t ucati ni b will be e val uate d. T ucati ni b i n hi bits t he m ulti dr u g a n d t o xi n e xtr usi o n pr otei ns 1 
a n d 2-K ( M A T E 1/ M A T E 2 - K) a n d or ga nic cati o n tra ns p orter 2 ( O C T 2). T hese tra ns p orters 
acti vel y secrete creati ni ne fr o m t he bl o o d t o t he uri ne t hr o u g h re nal t u b ular cells. I n hi biti o n 
of t hese tra ns p orters res ults i n a n i ncrease i n ser u m creati ni ne, w hic h d oes n ot reflect a 
c ha n ge i n gl o mer ular f u ncti o n. I n t he H E R 2 C LI M B trial, 1 3. 9 % of partici pa nts ra n d o mize d 
t o t he t ucati ni b ar m ha d ele vati o ns i n ser u m creati ni ne after t he first c ycle of treat me nt wit h 
t ucati ni b. T he mea n i ncrease i n creati ni ne was a p pr o xi matel y 3 0 %, re mai ne d sta ble w hile o n 
t hera py, a n d ret ur ne d t o baseli ne u p o n treat me nt disc o nti n uati o n. A de dicate d p har mac ol o g y 
st u d y ( S G N T U C-0 2 0) was c o n d ucte d a n d de m o nstrate d t hat t ucati ni b ha d n o effects o n re nal 
f u ncti o n as assesse d by i o he x ol, a n d ele vati o ns of ser u m creati ni ne are a res ult of t ucati ni b 
i n hi biti o n of ki d ne y tra ns p orters res p o nsi ble f or t he re nal secreti o n of creati ni ne 
( O C T 2/ M A T E 1).
O xali plati n is als o a s u bstrate f or M A T E 1/ 2-K a n d O C T 2 tra ns p orters a n d is acti vel y  
tra ns p orte d t hr o u g h t he pr o xi mal re nal t u b ular e pit helial cell. T he relati ve i m p orta nce of t his 
acti ve tra ns p ort i n t he meta b olis m of o xali plati n is u n k n o w n. D ue t o t his u ncertai nt y, a n d t he 
t he oretical ris k of o xali plati n acc u m ulati o n i n t he ki d ne y a n d res ulta nt ne p hr ot o xicit y, a 
l o wer starti n g d ose of t ucati ni b ( 1 5 0 m g BI D) has bee n c h ose n f or t he p hase 1 b C o h ort 1 A 
f or t his trial. In a d diti o n t o sta n dar d met h o ds f or e val uati n g re nal t o xicit y, n o n-creati ni ne 
meas ures of gl o mer ular f u ncti o n (c y stati n C) will be cl osely m o nit ore d i n or der t o detect 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 1 of 2 2 0
re d uce d gl o mer ular f u ncti o n t hat ma y be ass ociate d wit h o xali plati n-i n d uce d ne p hr ot o xicit y. 
T he p har mac o ki netics ( P K) of o xali plati n i n t he b l o o d a n d uri ne will be e xa mi ne d as well i n 
or der t o acc uratel y c haracterize t he dis p ositi o n of o xali plati n i n t he prese nce of t ucati ni b.
Precli nical a n d cli nical e vi de nce s u p p ort c o m bi ni n g pe m br oliz u ma b wit h trast uz u ma b a n d 
c yt ot o xic c he m ot hera p y t o treat H E R 2 + ca ncers. T he c o m bi nati o n ca n i n d uce d ura ble 
cli nical res p o nses i n a s u bset of patie nts wit h trast uz u ma b- refract or y H E R 2 + metastatic 
breast ca ncer (L oi 2 0 1 9 ). Alt h o u g h t he mec ha nistic basis f or sy ner g y  bet wee n a nti- H E R 2 
a n d a nti P D - 1-base d t hera pies has n ot bee n defi niti vel y  esta blis he d, p ossi ble c o ntri b ut ors 
ha ve bee n i de ntifie d. A nal y sis of t u m or sa m ples fr o m patie nts treate d wit h trast uz u ma b 
s h o ws u pre g ulati o n of P D- 1 a n d e n ha nce d ge ne e x pressi o n si g nat ures of i m m u ne i nfiltrati o n 
(Vara da n 2 0 1 6 ), w hic h c o ul d i ncrease t he efficac y of pe m br oliz u ma b. Si milarl y, trast uz u ma b 
i ncreases P D-L 1 e x pressi o n i n a m o use m o del of breast ca ncer (C ha ga nt y 2 0 1 8 ). I n a d diti o n, 
a d mi nistrati o n of trast uz u ma b wit h pe m br oliz u ma b ca n a u g me nt H E R 2 -s pecific T-cell 
res p o nses, pr o m ote T cell a n d de n dritic cell traffic ki n g, a n d i n d uce e x pa nsi o n of peri p heral 
me m or y  T cells (Ta yl or 2 0 0 7 ; Par k 2 0 1 0 ; M orte ns o n 2 0 1 3 ). 
T he res ults of a n i nteri m a nal ys is of pe m br oliz u ma b or place b o pl us trast uz u ma b a n d 
c he m ot hera p y i n partici pa nts wit h H E R 2 + metastatic gastric or G EJ ca ncer s h o we d a 
si g nifica nt i m pr o ve me nt i n O R R f or partici pa nts i n t he e x peri me ntal ar m, w hile t he 
i nci de nce of A Es was si milar bet wee n ar ms wit h n o safety c o ncer ns o bser ve d (Ja nji gia n 
2 0 2 1 ). T he c o nfir me d O R R ( 9 5 % CI) was 7 4. 4 % ( 6 6. 2-8 1. 6) f or pe m br oliz u ma b + S O C vs 
5 1. 9 % ( 4 3. 0 -6 0. 7) f or place b o + S O C ( differe nce, 2 2. 7 perce nta ge p oi nts [ 9 5 % CI , 1 1. 2-
3 3. 7], P = 0. 0 0 0 0 6). 
T he effects of t ucati ni b o n t u m or gr o wt h ki netics, as well as t ucati ni b a nti-t u m or efficac y i n 
c o m bi nati o n wit h trast uz u ma b a n d P D -1 c hec k p oi nt bl oc ka de, were e val uate d usi n g H E R 2 + 
m uri ne ca ncer m o dels (trast uz u ma b- se nsiti ve H 2 N 1 1 3 a n d trast uz u ma b-resista nt f o 5) (Li  
2 0 2 1 ). A n a nti-t u m or i m m u ne res p o nse ma y be a n i m p orta nt c o m p o ne nt of t he efficac y of 
t ucati ni b. T his is s u p p orte d b y i n vitr o data de m o nstrati n g t ucati ni b sti m ulate d h u ma n 
peri p heral T cells a n d i n vi v o data s h o wi n g fa v ora ble effects o n t he t u m or i m m u ne 
micr oe n vir o n me nt me diate d b y  t ucati ni b treat me nt. T hese c ha n ges were ass ociate d wit h 
i m pr o ve d efficac y w he n t ucati ni b was c o m bi ne d wit h P D- 1 i n hi biti o n or trast uz u ma b i n t he 
setti n g of trast uz u ma b resista nce. T hese fi n di n gs s u g gest t hat t he c o m bi nati o n of t ucati ni b 
a n d P D- 1 i n hi biti o n is a rati o nal c o m bi nati o n t hat warra nts i n vesti gati o n i n t he cli nical 
setti n g. T o deter mi ne w het her pe m br oliz u ma b ca n be safely c o m bi ne d wit h trast uz u ma b a n d 
t ucati ni b, c o m bi nati o n treatme nt re gi me ns wit h a n d wit h o ut c he m ot hera p y will be e val uate d 
i n P hase 1 b.
T he p hase 2 p orti o n of t his st u d y  m a y i ncl u de t u m or-s pecific e x pa nsi o n c o h orts as 1 L 
t hera py f or partici pa nts wit h gastric, es o p ha geal, a n d G EJ a de n ocarci n o ma ( C o h ort 2 A) a n d 
as 1 L + t hera p y f or partici pa nts wit h C R C ( C o h ort 2 B). T he pri mar y o bjecti ve of t he p hase 2 
p orti o n of t he st u d y  will be t o e val uate t he safety a n d t olera bilit y of t ucati ni b c o m bi ne d wit h 
pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n -base d c he m ot hera p y as 1 L t hera p y f or 
partici pa nts wit h gastric, es o p ha geal a n d G EJ a de n ocarci n o ma ( C o h ort 2 A) a n d t ucati ni b 
c o m bi ne d wit h trast uz u ma b a n d o xali plati n -base d c he m ot hera p y as 1 L + t hera p y f or 
partici pa nts wit h C R C ( C o h ort 2 B). Sec o n dar y  o bjecti ves will i ncl u de e val uati o n of t he a nti-
t u m or acti vit y of t ucati ni b c o m bi ne d wit h pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n-
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 2 of 2 2 0
base d c he m ot hera p y as 1 L t hera p y i n partici pa nts wit h H E R 2 + 1 L  gastric, es o p ha geal, a n d 
G EJ a de n ocarci n o ma ( C o h ort 2 A). E x pl orat or y  o bjecti ves i ncl u de e val uati o n of t he a nti -
t u m or acti vit y of t ucati ni b c o m bi ne d wit h trast uz u ma b a n d o xali plati n-base d c he m ot hera p y 
i n H E R 2 + 1 L + C R C ( C o h ort 2 B) a n d t o e val uate t he P K of t ucati ni b gi ve n wit h trast uz u ma b 
a n d o xali plati n-base d c he m ot hera p y ( wit h or wit h o ut pe m br oliz u ma b) ( C o h orts 2 A, 2 B). 
4. O B J E C TI V E S
T his st u d y  will e val uate t he safety a n d t olera bilit y, efficac y, a n d P K of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d o xali plati n-base d c he m ot hera p y ( F O L F O X or C A P O X) 
or wit h pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n partici pa nts wit h u nresecta ble or 
metastatic H E R 2 + GI ca ncers . S pecific o bjecti ves a n d c orres p o n di n g e n d p oi nts f or t he st u d y 
are s u m marize d bel o w ( Ta ble 1 , Ta ble 2 , Ta ble 3 , Ta ble 4 ).
4. 1. P h ase 1 b T uc ati ni b D ose Esc al ati o n wit h Tr ast uz u m a b a n d F O L F O X ( C o h ort 1 A 
a n d C o h ort 1 B)
T a ble 1 .
O bjecti ves a n d C orres p o n di n g E n d p oi nts
Pri mar y O bjecti ve
C orres p o n di n g Pri mar y E n d p oi nt

T o deter mi ne t he rec o m me n de d d ose of t ucati ni b w he n 
c o m bi ne d wit h trast uz u ma b a n d o xali plati n -base d 
c he m ot hera p y i n partici pa nts wit h h u ma n e pi der mal 
gr o w t h fact or rece pt or 2 p ositi ve ( H E R 2 +) GI ca ncers

I nci de nce of re nal d ose-li miti n g 
t o xicities ( D L Ts)
Sec o n dar y O bjecti ves
C orres p o n di n g Sec o n dar y E n d p oi nts

T o e val uate t he safet y a n d t olera bilit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d o xali plati n -base d 
c he m ot hera p y 

T y pe, i nci de nce, se verit y, seri o us ness, 
a n d relate d ness of a d verse e ve nts ( A Es) 
a n d la b orat or y a b n or malities

Vital si g ns a n d ot her rele va nt safet y 
varia bles

T o e val uate t he c o m bi nati o n of t ucati ni b, trast uz u ma b, 
a n d o xali plati n-base d c he m ot hera p y f or p ote ntial 
ne p hr ot o xic it y 

C ha n ge i n gl o mer ular filtrati o n rate 
( G F R), as esti mate d usi n g ser u m 
c ystati n C, fr o m baseli ne t hr o u g h 2 
c ycles of c o m bi nati o n t hera p y

T o e val uate t he p har mac o ki netics ( P K) of t ucati ni b

P K para meters of t ucati ni b (i ncl u di n g 
b ut n ot li mite d t o A U C last, Cma x , Ctr o u g h, 
a n d T ma x )

T o e val uate t he P K of o xali plati n i n t he prese nce a n d 
a bse nce of t ucati ni b

P K para meters of o xali plati n (i ncl u di n g 
b ut n ot li mite d t o A U C last, Cma x , Tma x )
E x pl orat or y O bjecti ves
C orres p o n di n g E x pl orat or y E n d p oi nts

T o e val uate t he a ntit u m or acti vit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b, a n d o xali plati n -base d 
c he m ot hera p y

O bjecti ve res p o nse rate ( O R R) acc or di n g 
t o Res p o nse E val uati o n Criteria i n S oli d 
T u m ors ( R E CI S T) v 1. 1 per i n vesti gat or 
assess me nt (I N V)

T o e x pl ore c orrelati o ns bet wee n tiss ue a n d bl o o d -base d 
bi o mar kers a n d cli nical o utc o mes

P ote ntial bi o mar kers of res p o nse, 
resista nce, or t o xicit y ma y be e val uate d 
i n tiss ue a n d bl o o d
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 3 of 2 2 0
4. 2. P h ase 1 b S afet y E v al u ati o n of T uc ati ni b i n C o m bi n ati o n wit h Tr ast uz u m a b + 
C A P O X ( C o h ort 1 C), or i n C o m bi n ati o n wit h Tr ast uz u m a b a n d Pe m br oliz u m a b -
C o nt ai ni n g C o m bi n ati o ns ( C o h orts 1 E, 1 F, a n d 1 G)
T a ble 2 .
O bjecti ves a n d C orres p o n di n g E n d p oi nts
Pri mar y O bjecti ves
C orres p o n di n g Pri mar y E n d p oi nts

T o e val uate t he safet y a n d t olera bilit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI ca ncers

T y pe, i nci de nce, se verit y, seri o us ness, 
a n d relate d ness of a d verse e ve nts ( A Es), 
i ncl u di n g D L Ts, a n d la b orat or y 
a b n or malities

Vital si g ns a n d ot her rele va nt safet y 
varia bles
Sec o n dar y O bjecti ves
C orres p o n di n g Sec o n dar y E n d p oi nts

T o e val uate t he a ntit u m or acti vit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI ca ncers as meas ure d b y o bjecti ve res p o nse rate 
( O R R) acc or di n g t o RE CI S T v 1. 1 per I N V

O R R acc or di n g t o R E CI S T v 1. 1 per 
I N V

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI ca ncers a s meas ure d b y d urati o n of res p o nse 
( D O R) acc or di n g t o R E CI S T v 1. 1 per I N V

D O R (c o nfir me d C R or P R) acc or di n g 
t o R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI ca ncers as meas ure d b y pr o gressi o n -free s ur vi val 
( P F S) acc or di n g t o R E CI S T v 1. 1 per I N V

P F S acc or di n g t o R E CI S T v 1. 1 per I N V 


T o e val uate t he a nti -t u m or acti vit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or 
t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
pe m br oliz u ma b -c o ntai ni n g c o m bi nati o ns i n H E R 2 + 
GI ca ncers as meas ure d b y o verall s ur vi val ( O S)

O S 

T o e val uate t he P K of t ucati ni b

P K para meters of t ucati ni b (i ncl u di n g 
b ut n ot li mite d t o C tr o u g h)
E x pl orat or y O bjecti ve
C orres p o n di n g E x pl orat or y E n d p oi nt

T o e x pl ore c orrelati o ns bet w ee n tiss ue a n d 
bl o o d -base d bi o mar kers a n d cli nical o utc o mes

P ote ntial bi o mar kers of res p o nse, 
resista nce, or t o xicit y ma y be e val uate d 
i n tiss ue a n d bl o o d
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 4 of 2 2 0
4. 3. P h ase 1 b J a p a n S afet y E v al u ati o n of T uc ati ni b i n C o m bi n ati o n wit h Tr ast uz u m a b 
a n d m F O L F O X 6 ( C o h ort 1 D)
T a ble 3 .
O bjecti ves a n d C orres p o n di n g E n d p oi nts
Pri mar y O bjecti ve
C orres p o n di n g E n d p oi nt

T o assess t he safet y a n d 
t olera bilit y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d 
F O L F O X i n Ja pa nese partici pa nts

T y pe, i nci de nce, se verit y, 
seri o us ness, a n d relate d ness of A Es, 
i ncl u di n g D L Ts, a n d la b orat or y 
a b n or malities

Vital si g ns a n d ot her rele va nt safet y 
varia bles

Fre q ue nc y of d ose h ol ds, d ose 
re d ucti o ns, a n d disc o nti n uati o ns of 
t ucati ni b, trast uz u ma b, a n d 
c o m p o ne nts of F O L F O X 
E x pl orat or y O bjecti ve
C orres p o n di n g E n d p oi nt

T o assess t he P K of t ucati ni b w he n 
a d mi nistere d i n c o m bi nati o n wit h 
trast uz u ma b a n d F O L F O X i n 
Ja pa nese partici pa nts

P K para meters of t ucati ni b (i ncl u di n g 
b ut n ot li mite d t o A U C last, Cma x , 
C tr o u g h, a n d Tma x )
4. 4. P h ase 2 T u m or -S pecific E x p a nsi o n
T a ble 4 .
O bjecti ves a n d C orres p o n di n g E n d p oi nts
Pri mar y O bjecti ve
C orres p o n di n g E n d p oi nt

C o h ort 2 A: T o e val uate t he safet y a n d t olera bilit y of 
t ucati ni b c o m bi ne d wit h pe m br oliz u ma b, trast uz u ma b, 
a n d o xali plati n-base d c he m ot hera p y ( F O L F O X or 
C A P O X) as first -li ne (1 L) t hera p y i n partici pa nts wit h 
u nresecta ble or metastatic H E R 2 + gastric, es o p ha geal, or 
gastr oes o p ha geal j u ncti o n ( G EJ) a de n ocarci n o ma

C o h ort 2 B: T o e val uate t he safet y a n d t olera bilit y of 
t ucati ni b c o m bi ne d wit h trast uz u ma b a n d F O L F O X i n 
partici pa nts wi t h u nresecta ble or metastatic H E R 2 + 
c ol orectal a de n ocarci n o ma ( C R C) 

T y pe, i nci de nce, se verit y, seri o us ness, 
a n d relate d ness of A Es, i ncl u di n g 
D L Ts, a n d la b orat or y a b n or malities

Vital si g ns a n d ot her rele va nt safet y 
varia bles
Sec o n dar y O bjecti ves
C orres p o n di n g E n d p oi nts

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b c o m bi ne d 
wit h pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n -base d 
c he m ot hera p y ( F O L F O X or C A P O X) as 1 L t hera p y f or 
H E R 2 + gastric, es o p ha geal, or G EJ a de n ocarci n o ma as 
meas ure d b y c o nfir me d o bj ecti ve res p o nse rate (c O R R), 
acc or di n g t o R E CI S T v 1. 1 per I N V

c O R R (c o nfir me d c o m plete res p o nse 
[ C R] or partial res p o nse [ P R]) 
acc or di n g t o R E CI S T v 1. 1 per I N V 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 5 of 2 2 0
T a ble 4 .
O bjecti ves a n d C orres p o n di n g E n d p oi nts

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b c o m bi ne d 
wit h pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n -base d 
c he m ot hera p y as 1 L t hera p y f or H E R 2 + gastric, 
es o p ha geal, or G EJ a de n ocarci n o ma as meas ure d b y 
D O R acc or di n g t o R E CI S T v 1. 1 per I N V

D O R (c o nfir me d C R or P R) acc or di n g 
t o R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b c o m bi ne d 
wit h pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n -base d 
c he m ot hera p y as 1 L t hera p y f or H E R 2 + gastric, 
es o p ha geal, or G EJ a de n ocarci n o ma as meas ure d b y P F S 
acc or di n g t o R E CI S T v 1. 1 per I N V

P F S acc or di n g t o R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b c o m bi ne d 
wit h pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n -base d 
c he m ot hera p y as 1 L t hera p y f or H E R 2 + gastric, 
es o p ha geal, or G EJ a de n ocarci n o ma as meas ure d b y O S

O S
E x pl orat or y O bjecti ves
C orres p o n di n g E n d p oi nts

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b c o m bi ne d 
wit h trast uz u ma b a n d o xali plati n -base d c he m ot hera p y 
( F O L F O X) as 1 L + t hera p y f or H E R 2 + C R C as meas ure d 
b y c O R R, acc or di n g t o R E CI S T v 1. 1 per I N V

c O R R ( C R or P R) acc or di n g t o 
R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b c o m bi ne d 
wit h trast uz u ma b a n d o xali plati n -base d c he m ot hera p y as 
1 L + t hera p y f or H E R 2 + C R C as meas ure d b y D O R 
acc or di n g t o R E CI S T v 1. 1 per I N V

D O R (c o nfir me d C R or P R) acc or di n g 
t o R E CI S T v 1. 1 per I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b c o m bi ne d 
wit h trast uz u ma b a n d o xali plati n -base d c he m ot hera p y as 
1 L + t hera p y f or H E R 2 + C R C as meas ure d b y P F S 
acc or di n g t o R E CI S T v 1. 1 per I N V

P F S acc or di n g t o R E CI S T v 1. 1 per 
I N V 

T o e val uate t he a nti -t u m or acti vit y of t ucati ni b c o m bi ne d 
wit h trast uz u ma b a n d o xali plati n -base d c he m ot hera p y as 
1 L + t hera p y f or H E R 2 + C R C as meas ure d b y O S

O S 

T o e val uate t he P K of t ucati ni b gi ve n wit h 
pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n -base d 
c he m ot hera p y as 1 L t hera p y f or u nresecta ble or 
metastatic H E R 2 + gastric, es o p ha geal, or G EJ 
a de n ocarci n o ma ( C o h ort 2 A) a n d t o e val uate t he P K of 
t ucati ni b gi ve n wit h trast uz u ma b a n d o xali plati n-base d 
c he m ot hera p y as 1 L + t hera p y f or metastatic H E R 2 + C R C 
( C o h ort 2 B)

P K para meter of t ucati ni b ( C tr o u g h) 

T o e x pl ore c orrelati o ns bet w ee n tiss ue a n d bl o o d -base d 
bi o mar kers a n d cli nical o utc o mes

P ote ntial bi o mar kers of res p o nse, 
resista nce, or t o xicit y ma y be 
e val uate d i n tiss ue a n d bl o o d
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 6 of 2 2 0
5. I N V E S TI G A TI O N A L P L A N
5. 1. S u m m ar y of St u d y Desi g n
T his is a p hase 1 b/ 2 d ose escalati o n a n d e x pa nsi o n st u d y of t ucati ni b i n c o m bi nati o n wit h 
trast uz u ma b, a n d o xali plati n-base d c he m ot hera p y ( F O L F O X or C A P O X) or pe m br oliz u ma b -
c o ntai ni n g c o m bi nati o ns f or partici pa nts wit h u nresecta ble or metastatic H E R 2 + GI ca ncers. 
A p pr o xi matel y  4 0 partici pa nts will be e nr olle d acr oss a p pr o xi matel y 2 5 cli nical sites. 
Partici pa nts are eli gi ble if t he y  ha ve o ne of t he f oll o wi n g ca ncers: 

C R C

Gastric a de n ocarci n o ma

Es o p ha geal a de n ocarci n o ma 

G EJ a de n ocarci n o ma

C h ola n gi ocarci n o ma

Gall bla d der carci n o ma
T a ble 5 . 
S u m m ar y of C o h orts, Tre at me nts, P o p ul ati o ns, a n d N u m ber of 
P artici p a nts
St u d y P h a se
C o h ort
T uc ati ni b 
D ose
P O BI D
Tre at m e nt
P o p ul ati o n(s)
A p pr o xi m ate 
P artici p a nts 
per C o h ort b
P hase 1 b 
T ucati ni b D ose 
Escalati o n 
wit h 
Trast uz u ma b 
a n d F O L F O X
1 A
1 5 0 m g
T ucati ni b, 
Trast uz u ma b,
m F O L F O X 6 or 
m F O L F O X 7
1 L +

C h ola n gi ocarci
n o m a

Gall bla d der 
ca ncer

Gastric 
a de n ocarci n o ma

Es o p ha geal 
a de n ocarci n o ma

G EJ 
a de n ocarci n o ma

C R C
≥3
1 B
3 0 0 m g
≥6
P hase 1 b 
Safet y 
E val uati o n of 
T ucati ni b wit h 
Trast uz u ma b 
a n d C A P O X 
( C o h ort 1 C) or 
wit h 
Trast uz u ma b 
a n d 
Pe m br oliz u ma
b- C o ntai ni n g 
C o m bi nati o ns 
( C o h orts 1 E, 
1 F, 1 G)
1 C
3 0 0 m g
T ucati ni b, 
Trast uz u ma b, 
C A P O X
1 L +
≥6 a
1 E
3 0 0 m g
T ucati ni b, 
Trast uz u ma b, 
Pe m br oliz u ma b,
m F O L F O X 6
1 L

Gastric 
a de n ocarci n o ma

Es o p ha geal
a de n ocarci n o ma

G EJ 
a de n ocarci n o ma
≥6 a
1 F
T ucati ni b, 
Trast uz u ma b, 
Pe m br oliz u ma b, 
C A P O X
≥6 a
1 G
T ucati ni b, 
Trast uz u ma b, 
Pe m br oliz u ma b
≥6 a
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 7 of 2 2 0
T a ble 5 . 
S u m m ar y of C o h orts, Tre at me nts, P o p ul ati o ns, a n d N u m ber of 
P artici p a nts
St u d y P h a se
C o h ort
T uc ati ni b 
D ose
P O BI D
Tre at m e nt
P o p ul ati o n(s)
A p pr o xi m ate 
P artici p a nts 
per C o h ort b
P hase 1 b
T ucati ni b 
Ja pa n Safet y 
E val uati o n i n 
C o m bi nati o n 
wit h 
Trast uz u ma b 
a n d F O L F O X
1 D
3 0 0 m g
T ucati ni b, 
Trast uz u ma b,
m F O L F O X 6
1 L +

C h ola n gi ocarci
n o m a

Gall bla d der 
ca ncer

Gastric 
a de n ocarci n o ma

Es o p ha geal 
a de n ocarci n o ma

G EJ 
a de n ocarci n o ma

C R C
≥3
P hase 2
T u m or 
S pecific 
E x pa nsi o n
2 A
3 0 0 m g
T ucati ni b, 
Pe m br oliz u ma b,
Trast uz u ma b,
m F O L F O X 6 or 
C A P O X
1 L

Gastric 
a de n ocarci n o ma

Es o p ha geal 
a de n ocarci n o ma

G EJ 
a de n ocarci n o ma
u p t o 4 0
2 B
T ucati ni b, 
Trast uz u ma b,
m F O L F O X 6
1 L +

C R C
u p t o 2 0
BI D = t w ice dail y; C R C = c ol orectal a de n ocarci n o ma; G EJ = gastr oes o p ha geal j u ncti o n; P O = oral; 1 L = 
first-li ne
a
E nr oll me nt ma y re mai n o pe n u ntil at least 3 partici pa nts are e nr olle d i n Ja pa n
b
N o a d diti o nal e nr oll me nt will occ ur f or a n y c o h ort as of A me n d m e nt 5.
I n t he c urre nt st u d y ( C 4 2 5 1 0 0 5; S G N T U C- 0 2 4), as of 1 7 N o ve m ber 2 0 2 1, 1 1 partici pa nts 
ha ve bee n e nr olle d i n t he t ucati ni b 3 0 0 m g P O BI D d ose c o h ort ( C o h ort 1 B) a n d 8 
partici pa nts ha ve c o m plete d t he D L T peri o d a n d are e val ua ble f or D L Ts. N o D L Ts were 
o bser ve d i n t hese partici pa nts, a n d t he plas ma a n d ultrafiltrate p har mac o ki netics pr ofile a n d 
t he mea n uri nar y o ut p ut pr ofile of o xali plati n were si milar w he n partici pa nts recei ve d 
o xali plati n al o ne c o m pare d t o w he n o xali plati n was recei ve d i n c o m bi n ati o ns wit h t ucati ni b 
( 1 5 0 or 3 0 0 m g P O BI D), s u g gesti n g t hat t ucati ni b di d n ot i m pact t he re nal dis p ositi o n of 
o xali plati n. Preli mi nar y  data i n dicate all D L T e val ua ble partici pa nts w h o ha ve recei ve d 
t ucati ni b ( 3 0 0 m g), trast uz u ma b, a n d F O L F O X e x perie nce d diarr hea, i ncl u di n g 3 partici pa nts 
wit h gastr oes o p ha geal a de n ocarci n o ma w h o ha ve e x perie nce d Gra de 3 diarr hea e ve nts. T he 
re mai ni n g 5 partici pa nts e x perie nce d eit her Gra de 1 diarr hea ( n = 3) or Gra de 2 diarr hea 
( n = 2). N o Gra de 4 or fatal diarr hea e ve nts were o bser ve d. T he me dia n ti me t o t he first e ve nt 
of diarr hea (a n y gra de) was 8 da y s after i nitiati o n of t ucati ni b. I n t he t hree partici pa nts wit h 
Gra de 3 e ve nts, diarr hea was n ote d after n o n ‑a d here nce t o t he rec o m me n de d a nti diarr heal 
ma na ge me nt strate g y ; h o wever, all e ve nts res ol ve d t o ≤Gra de 1 diarr hea wit h a ma na ge me nt 
strate g y of d ose m o dificati o n (as per Secti o n 7. 9. 1 0 ) a n d a nti diarr heal treat me nt wit h 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 8 of 2 2 0
l o pera mi de. N o a d verse e ve nts of s pecial i nterest ( A E SIs; ne p hr ot o xicit y or he pat ot o xicit y) 
ha ve bee n re p orte d. 
Base d o n t he Gra de 3 diarr hea e ve nts o bser ve d i n C o h ort 1 B, a nti diarr heal pr o p h y la xis will 
be re q uire d f or all partici pa nts e nr olle d i n C o h orts 1 D, 1 E, a n d f or all partici pa nts i n C o h ort 
2 A w h o are treate d wit h t ucati ni b + trast uz u ma b + pe m br oliz u ma b + m F O L F O X 6. As of 1 2 -
Dec -2 0 2 3, 5 partici pa nts were e nr olle d a n d treate d i n C o h ort 2 B. T ucati ni b -relate d Gra de 3 
diarr hea was re p orte d i n 2 of 5 part ici pa nts d uri n g t he first 4 2-d a y s of st u d y treat me nt. Base d 
o n t his fi n di n g, l o pera mi de pr o p h yl a xis is n o w re q uire d f or C o h ort 2 B. Be gi n ni n g o n C y cle 1 
D a y 1, l o pera mi de will be a d mi nistere d at a d ose of 4 m g t hree ti mes dail y f or 1 4 da ys 
( Da ys 1-1 4), f oll o we d b y 4 m g t wice dail y o n Da ys 1 5 - 4 2 (see als o Secti o n 7. 1 1. 2 ). T he first 
d ose of l o pera mi de m ust be a d mi nistere d c o nc o mita ntl y  wit h t he first d ose of t ucati ni b. T he 
d osi n g of l o pera mi de s h o ul d be titrate d s uc h t hat partici pa nts ha ve 1 -2 st o ols per da y  
t hr o u g h o ut Da ys 1-4 2 a n d after war ds, as necessar y . T he d ose of l o pera mi de ca n m o difie d, or 
l o pera mi de ca n be hel d at a n y p oi nt d uri n g t he st u d y as per i n vesti gat or discreti o n if 
partici pa nt has c o nsti pati o n or < 1 st o ol per da y . F oll o wi n g t his i nitial 4 2-da y  peri o d, 
partici pa nts ma y  c o nti n ue o n a nti diarr heal pr o p h yla xis at a d ose of 2 t o 4 m g as nee de d, n ot 
t o e xcee d 1 6 m g per da y. 
A nti diarr heal pr o p h yl axis, as descri be d a b o ve, will n ot be re q uire d f or partici pa nts e nr olle d 
i n C o h orts 1 C, 1 F, a n d 1 G, or f or partici pa nts i n C o h ort 2 A w h o are treate d wit h t ucati ni b + 
trast uz u ma b + pe m br oliz u ma b + C A P O X, u nless rec o m me n de d by t he S M C a n d re q uire d b y 
t he S p o ns or base d o n a re vie w of t he data fr o m t hese c o h orts d uri n g t he c o urse of t he st u d y. 
S h o ul d a nti diarr heal pr o p h y la xis be re q uire d, t he d ose a n d sc he d ule of l o pera mi de as 
descri be d a b o ve will be f oll o we d (see als o Secti o n 7. 1 1. 2 ). Partici pa nts m ust be i nstr ucte d o n 
t he o pti mal use of a nti diarr heals f or sy m pt o matic c o ntr ol of treat me nt -ass ociate d diarr hea as 
descri be d i n Secti o n 7. 9. 9 . 
5. 1. 1. P h ase 1 b T uc ati ni b D ose Esc al ati o n Wit h Tr ast uz u m a b a n d F O L F O X ( C o h ort 
1 A a n d 1 B)
T he d ose escalati o n p orti o n of t he st u d y will deter mi ne t he rec o m me n de d d ose of t ucati ni b t o 
be a d mi nistere d wit h o xali plati n -base d c he m ot hera p y.
5. 1. 1. 1. Tr ast uz u m a b a n d F O L F O X – C o h ort 1 A
F or t he t ucati ni b d ose escalati o n utilizi n g F O L F O X ( C o h orts 1 A a n d 1 B) ( Fi g ure 1 ), 
partici pa nts s h o ul d be ca n di dates t o recei ve a n o xali plati n- base d re gi me n as part of t heir 
sta n dar d- of-care treat me nt pri or t o e nr oll me nt a n d ma y  ha ve recei ve d u p t o 2 c o nsec uti ve 
c ycles of F O L F O X ( ≤8 5 m g/ m 2 o xali plati n per 2 -wee k c y cle) d uri n g t he scree ni n g peri o d 
pri or t o C y cle 1 Da y 1 of st u d y  treat me nt. If partici pa nts ha ve recei ve d o xali plati n i n pri or 
c ycles at d oses hi g her t ha n 8 5 m g/ m 2, t here m ust be a mi ni m u m of 2 8 da ys fr o m t he last d ose 
of t he pre vi o us re gi me n pri o r t o C ycle 1 Da y 1 of treat me nt i n t his st u d y. C o nc urre nt 
treat me nt wit h a nti- V E G F a nti b o dies is pr o hi bite d w hile o n trial. T here is n o u p per li mit f or 
t he n u m ber of pri or li nes of t hera py recei ve d, a n d pri or e x p os ure t o o xali plati n is all o we d, 
pr o vi de d t h e partici pa nt ha d n ot e x perie nce d Gra de ≥3 h y perse nsiti vit y  d ue t o o xali plati n.
E nr olle d partici pa nts will be treate d wit h F O L F O X, trast uz u ma b, a n d t ucati ni b gi ve n i n 
1 4 -d a y c y cles. After e nr olli n g o n st u d y, partici pa nts i n C o h ort 1 A will recei ve 7 da ys of
F O L F O X a n d trast uz u ma b wit h o ut t ucati ni b. T he starti n g d ose of t ucati ni b f or C o h ort 1 A is 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 5 9 of 2 2 0
1 5 0 m g orall y  ( P O) BI D a n d t he first d ose will be a d mi nistere d o n C ycle 1 Da y 8 a n d 
c o nti n u o usl y t hereafter u ntil t he partici pa nt c o mes off st u d y. Partici pa nts s h o uld recei ve 
pr o p h y la xis f or c he m ot hera p y i n d uce d na usea a n d v o miti n g as per t he i n vesti gat or’s 
i nstit uti o nal sta n dar ds. Partici pa nts will c o nti n ue o n t hera py u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, deat h, or st u d y cl os ure. 
5. 1. 1. 2. T r ast uz u m a b a n d F O L F O X - C o h ort 1 B
Partici pa nts i n C o h ort 1 B s h o ul d be ca n di dates t o recei ve a n o xali plati n -base d re gi me n as 
part of t heir sta n dar d - of-care treat me nt pri or t o e nr oll me nt a n d ma y  ha ve recei ve d u p t o 2 
c o nsec uti ve c ycles of F O L F O X ( ≤8 5 m g / m2 o xali plati n per 2 -wee k c y cle) d uri n g t he 
scree ni n g peri o d pri or t o C ycle 1 Da y 1 of st u d y treat me nt. If partici pa nts ha ve recei ve d 
o xali plati n i n pri or c y cles at d oses hi g her t ha n 8 5 m g/ m 2, t here m ust be a mi ni m u m of 2 8 
da y s fr o m t he last d ose of t he pre vi ous re gi me n pri or t o C y cle 1 Da y 1 of treat me nt i n t his 
st u d y. C o nc urre nt treat me nt wit h a nti-V E G F a nti b o dies is pr o hi bite d w hile o n trial. T here is 
n o u p per li mit f or t he n u m ber of pri or li nes of t hera p y recei ve d, a n d pri or e x p os ure t o 
o xali plati n is all o w e d, pr o vi de d t he partici pa nt ha d n ot e x perie nce d Gra de ≥3 
h y perse nsiti vit y  d ue t o o xali plati n.
E nr olle d partici pa nts will be treate d wit h F O L F O X, trast uz u ma b, a n d t ucati ni b gi ve n i n 1 4 -
da y  c ycles. After e nr olli n g o n st u d y, partici pa nts i n C o h ort 1 B will re cei ve 7 da ys of 
F O L F O X a n d trast uz u ma b wit h o ut t ucati ni b. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or 
a n i nter me diate d ose as rec o m me n de d b y t he safet y m o nit ori n g c o m mittee [ S M C]) will be 
a d mi nistere d o n C ycle 1 Da y 8 a n d c o nti n u o usl y t hereafter u ntil t h e partici pa nt c o mes off 
st u d y. Partici pa nts s h o ul d recei ve pr o p h y la xis f or c he m ot hera py i n d uce d na usea a n d 
v o miti n g as per t he i n vesti gat or’s i nstit uti o nal sta n dar ds. Partici pa nts will c o nti n ue o n 
t hera py u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , wit h dra wal of c o nse nt, deat h, or 
st u d y cl os ure.
5. 1. 1. 3. D ose -esc al ati o n Pr ocess
D ose -escalati o n will use a 3 + 3 desi g n t o deter mi ne a safe d ose of t ucati ni b c o m bi ne d wit h 
o xali plati n b y  assessi n g re nal D L Ts ( See Secti o n 5. 1. 5 ). A re nal D L T is defi ne d as a 
s ustai ne d i ncrease i n ser u m c ystati n C > 1. 5 × baseli ne t hat is n ot relate d t o pre-re nal or p ost-
re nal eti ol o gies (i ncl u di n g disease pr o gressi on, de h y drati o n a n d i nterc urre nt ill ness) a n d 
occ urs d uri n g t he peri o d of treat me nt wit h t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d 
F O L F O X bet wee n t he first d ose of t ucati ni b a n d t he e n d of C ycle 3.
A p pr o xi matel y 5 partici pa nts ma y  be e nr olle d a n d treated wit h t ucati ni b at t he 1 5 0 m g BI D 
d ose le vel t o e ns ure t here are at least 3 D L T -e val ua ble partici pa nts f or t he S M C re vie w 
(Fi g ure 1 ; C o h ort 1 A). O nce t he 3 partici pa nts are e val ua ble f or re nal D L T ( Secti o n 5. 1. 5 ), 
e nr oll me nt will be pa use d, a n d t he S M C will u n derta ke a safet y  e val uati o n. 

If n o re nal D L Ts are o bser ve d at t he 1 5 0 m g  BI D d ose le vel, t he S M C ma y 
rec o m me n d escalati n g t o t he 3 0 0 m g BI D d ose le vel, wit h a p pr o xi matel y  8 
partici pa nts bei n g e nr olle d i n C o h ort 1 B treate d at t his d ose t o e ns ure at least 6 
D L T a n d P K -e val ua ble partici pa nts i n C o h ort 1 B.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 0 of 2 2 0

If ≤1 re nal D L Ts are o bser ve d i n 6 D L T-e val ua ble partici pa nts treate d at t he 
3 0 0 m g BI D d ose le vel i n C o h ort 1 B, t his will be declare d t he rec o m me n de d 
p hase 2 d ose of t ucati ni b wit h o xali plati n -base d c he m ot hera p y.

If 1 re nal D L T is o bser ved at t he 1 5 0 m g BI D d ose le vel i n C o h ort 1 A, a n 
a d diti o nal 3 partici pa nts (f or a t otal of 6 e val ua ble partici pa nts) will be treate d at 
t his d ose le vel. O nce 6 partici pa nts are e val ua ble f or re nal D L Ts, e nr oll me nt will 
be pa use d, a n d t he S M C will u n derta ke a safet y e val uati o n. 
o
If 1 re nal D L T is o bser ve d i n t he 6 partici pa nts treate d at 1 5 0 m g BI D i n 
C o h ort 1 A, t he S M C ma y rec o m me n d escalati o n t o t he 2 0 0 m g BI D or 
2 5 0 m g BI D d ose le vel. T he S M C ma y  als o rec o m me n d a n alter nati ve 
d ose le vel/sc he d ule as warra nt e d b y t he c u m ulati ve safet y data. 

If 1 re nal D L T is o bser ve d i n t he first 3 partici pa nts at a n i nter me diate d ose, 
a n a d diti o nal 3 partici pa nts (f or a t otal of 6 e val ua ble partici pa nts) will be treate d 
at t his d ose le vel a n d t he S M C will e val uate d ose escalati o n if n o f urt her D L Ts 
are o bser ve d.

If t he d ose escalati o n has pr ocee de d fr o m 1 5 0 m g t o 2 0 0 m g or 2 5 0 m g, a n d 
≥2 re nal D L Ts are o bser ve d i n u p t o 6 e val ua ble partici pa nts treate d at t his le vel, 
t he n t he S M C ma y rec o m me n d d ose de-escalati o n t o t he 1 5 0 m g or 2 0 0 m g  d ose 
le vel, res pecti vel y.

If ≥2 re nal D L Ts are o bser ve d i n t he first 3 or 6 partici pa nts treate d at t he 1 5 0 m g 
BI D d ose le vel i n C o h ort 1 A, alter nati ve d ose le vels a n d/ or re gi me ns < 1 5 0 m g 
BI D ma y  be c o nsi dere d b y t he S M C.

If ≥2 re nal D L Ts are o bser ve d i n t he 6 D L T -e val ua ble partici pa nts treate d at t he 
3 0 0 m g d ose le vel ( C o h ort 1 B) ( or ≥3 3 % of partici pa nts if m ore t ha n 6 
partici pa nts are e nr olle d i n a c o h ort), d ose le vels of 2 5 0 a n d/ or 2 0 0 m g  ma y be 
e x pl ore d, or a n alter nati ve d ose le vel/sc he d ul e as rec o m me n de d b y t he S M C. 
I n a d diti o n t o re nal D L Ts, t he S M C will ta ke i nt o c o nsi derati o n ot her a d verse e ve nts ( A Es) 
w he n ma ki n g t he deter mi nati o n t o escalate, de- escalate, or declare t he rec o m me n de d d ose 
le vel. T he criteria f or t hese a d diti o nal A Es t o be c o nsi dere d are pr o vi de d i n Secti o n 5. 1. 7. 1 . 
A d diti o nal safet y e x perie nces i n later c y cles will als o be c o nsi dere d w he n c o nfir mi n g t he 
rec o m me n de d dose. Base d o n t he t otalit y  of t he safet y data, t he S M C ma y rec o m me n d 
e x pa n di n g e nr oll me nt t o eit her c o h ort wit h c o nti n ue d m o nit ori n g f or safet y b y t he S M C, 
e val uati o n of alter nati ve d osi n g, or s u p p orti ve care meas ures f or t he ma na ge me nt of A Es.
D ose m o difi cati o ns are descri be d i n Secti o n 7. 9 .
5. 1. 2. P h ase 1 b S afet y E v al u ati o n wit h Tr ast uz u m a b a n d C A P O X ( C o h ort 1 C) or wit h 
Tr ast uz u m a b a n d Pe m br oliz u m a b -C o nt ai n i n g C o m bi n ati o ns ( C o h orts 1 E, 1 F, 1 G)
After t he rec o m me n de d d ose of t ucati ni b wit h o xali plati n- base d c he m ot hera p y has bee n 
i de ntifie d, a d diti o nal c o h orts ma y be o pe ne d t o f urt her e val uate t he safety a n d t olera bilit y of 
t ucati ni b c o m bi ne d wit h t he f oll o wi n g re gi me ns:

Trast uz u ma b + C A P O X ( C o h ort 1 C)

Pe m br oliz u ma b + Trast uz u ma b + F O L F O X ( C o h ort 1 E)
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 1 of 2 2 0

Pe m br oliz u ma b + Trast uz u ma b + C A P O X ( C o h ort 1 F)

Pe m br oliz u ma b + Trast uz u ma b ( C o h ort 1 G)
Partici pa nts will be cl osel y  f oll o we d f or u nacce pta ble t o xicities f or eit her 2 1 -d a y s (f or 
partici pa nts e nr olle d i n C o h orts 1 C, 1 F, or 1 G) or 2 8 da y s (f or partici pa nts e nr olle d i n C o h ort 
1 E) after t he first d ose of st u d y  i nter ve nti o n (ie, t he D L T e val uati o n peri o d) f or t he 
occ urre nce of s pecific A Es t hat are dee me d t o be d ose- li miti n g. If 3 or m ore D L Ts are 
o bser ve d i n a c o h ort, e nr oll me nt t o t hat c o h ort ma y be dela y e d t o f urt her e xa mi ne safet y data 
a n d c o nsi der st u d y desi g n c ha n ges as rec o m me n de d b y t he S M C.
5. 1. 2. 1. Tr ast uz u m a b a n d C A P O X ( C o h ort 1 C)
Partici pa nts i n C o h ort 1 C ( Fi g ure 1 ) s h o ul d be ca n di dates t o recei ve a n o xali plati n-base d 
re gi me n as part of t heir sta n dar d- of-care treat me nt pri or t o e nr oll me nt. Eli gi ble partici pa nts 
ma y  ha ve recei ve d o xali plati n-base d c he m ot hera p y  ( 1 c ycle of C A P O X at a d ose of 
≤1 3 0 m g/ m 2 per 3 -wee k c y cle or 2 c o nsec uti ve c ycles of F O L F O X at a d ose of ≤8 5 m g/ m 2
per 2 -wee k c y cle) d uri n g t he scree ni n g peri o d pri or t o C y cle 1 Da y 1. C o nc urre nt treat me nt 
wit h a nti- V E G F a nti b o dies is pr o hi bite d w hile o n trial. T here is n o u p per li mit f or t he 
n u m ber of pri or li nes of t hera p y recei ve d, a n d pri or e x p os ure t o o xali plati n is all o we d, 
pr o vi de d t he partici pa nt ha d n ot e x perie nce d Gra de ≥3 h y perse nsiti vit y  d ue t o o xali plati n.
E nr olle d partici pa nts will be treate d wit h C A P O X, trast uz u ma b, a n d t ucati ni b gi ve n i n 2 1 -
da y  c ycles. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or a n i n ter me diate d ose as 
rec o m me n de d by t he S M C) will be a d mi nistere d o n C y cle 1 Da y 1. Partici pa nts s h o ul d 
recei ve pr o p hyl a xis f or c he m ot hera p y i n d uce d na usea a n d v o miti n g as per t he i n vesti gat or’s 
i nstit uti o nal sta n dar ds. Partici pa nts m ust be i nstr ucte d o n t he o pti mal use of a nti diarr heals f or 
s ym pt o matic c o ntr ol of treat me nt- ass ociate d diarr hea as descri be d i n Secti o n 7. 9. 9 . 
A nti diarr heal pr o p h yl a xis will n ot be re q uire d f or partici pa nts e nr olle d i n C o h ort 1 C, u nless 
rec o m me n de d by t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he data fr o m 
t his c o h ort.
T he S M C will re vie w safet y data after 3 partici pa nts i n t his c o h ort are treate d wit h o ut 
a nti diarr heal pr o p h yl a xis. 

If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use of 
a nti diarr heals are o bser ve d i n ≤1 partici pa nt, treat me nt wit h o ut a nti diarr heal pr o p h y la xis 
is c o nti n ue d a n d e val uate d i n 3 m ore partici pa nts i n t his c o h ort. 
o
If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use 
of a nti diarr heals are o bser ve d i n ≤1 of 6 partici pa nts, a nti diarr heal 
pr o p h y la xis will n ot be re q uire d i n t his c o h ort. 
o
If Gra de 3 or hi g her diarr hea e ve nts are o bser ve d i n ≥2 of 6 partici pa nts, 
a nti diarr heal pr o p h yl a xis will be re q uire d i n t his c o h ort. 

If Gra de 3 or hi g her diarr hea e ve nts wit h o ut o pti mal use of a nti diarr heals are o bser ve d i n 
2 or m ore partici pa nts, a nti diarr heal pr o p h yl a xis will be re q uire d i n t his c o h ort. 
Part ici pa nts will c o nti n ue o n t hera py u ntil disease pr o gressi o n, u nacce pta ble t o xicit y , 
wit h dra wal of c o nse nt, deat h, or st u d y cl os ure. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 2 of 2 2 0
A p pr o xi matel y  8 partici pa nts will be e nr olle d t o e ns ure t hat 6 partici pa nts c o m plete 1 c ycle 
of t ucati ni b + trast uz u ma b + C A P O X. If 8 partici pa nts are e nr olle d, e nr oll me nt ma y  re mai n 
o pe n t o e ns ure at least 3 t o 6 partici pa nts fr o m Ja pa n are e nr olle d i n t his c o h ort.
O nce at least 6 partici pa nts ha ve c o m plete d 1 c y cle a n d are e val ua ble f or safet y, t he S M C 
will e val uate w het her t he c o m bi nati o n is safe a n d t olera ble. T he S M C will re vie w t he t otality 
of t he safet y data, wit h a f oc us o n D L Ts descri be d i n Secti o n 5. 1. 7. 2 . A d diti onal safet y 
e x perie nces i n later c ycles will als o be c o nsi dere d. T he S M C ma y  als o rec o m me n d 
e x pa n di n g e nr oll me nt t o t he c o h ort wit h c o nti n ue d m o nit ori n g f or safet y or e val uati o n of 
alter nati ve d osi n g. 
5. 1. 2. 2. Pe m br oliz u m a b, Tr ast uz u m a b, F O L F O X ( C o h ort 1 E)
C o h ort 1 E will e val uate t he safet y a n d t olera bilit y of t ucati ni b c o m bi ne d wit h 
pe m br oliz u ma b, trast uz u ma b, a n d m o difie d F O L F O X ( m F O L F O X 6) i n partici pa nts wit h 
u nresecta ble or metastatic H E R 2 + gastric, es o p ha geal, or G EJ a de n ocarci n o ma w h o ha ve n ot 
pre vi o usl y  receive d treat me nt f or metastatic/ u nresecta ble disease i n t he 1 L setti n g. 
Partici pa nts i n C o h ort 1 E s h o ul d be ca n di dates t o recei ve a n o xali plati n -base d re gi me n as 
part of t heir sta n dar d - of- care treat me nt pri or t o e nr oll me nt. T he first d ose of t ucati ni b ( 3 0 0 
m g P O BI D or a n i nter me diate d ose as rec o m me n de d b y  t he S M C) will be a d mi nistere d o n 
C y cle 1 Da y  1).
E nr olle d partici pa nts will be treate d wit h m F O L F O X 6 a n d t ucati ni b gi ve n i n 1 4 -da y  c ycles. 
Trast uz u ma b will be gi ve n i n 2 1- d a y c y cles. Pe m br oliz u ma b will be g i ve n i n 4 2-d a y c y cles. 
A nti diarr heal pr o p h yl a xis will als o be a d mi nistere d f or t he first 4 2 da y s of st u d y treat me nt 
a n d as nee de d t hereafter (see Secti o n 7. 1 1. 2 ).
A p pr o xi matel y 8 partici pa nts ma y  be e nr olle d t o e ns ure t hat 6 partici pa nts c o m plete 2 8 da ys 
of st u d y  treat me nt. If 8 partici pa nts are e nr olle d, e nr oll me nt ma y re mai n o pe n t o e ns ure at 
least 3 t o 6 partici pa nts fr o m Ja pa n are e nr olle d i n t his c o h ort.
O nce at least 6 partici pa nts ha ve c o m plete d 2 c y cles of t ucati ni b + pe m br oliz u ma b + 
trast uz u ma b + F O L F O X, t he S M C will e val uate w het her t he c o m bi nati o n is safe a n d 
t olera ble. T he S M C will re vie w t he t otality of t he safet y data, wit h a f oc us o n t he D L Ts 
descri be d i n Secti o n 5. 1. 6 . A d diti o nal safety e x perie nces i n later c ycles will als o be 
c o nsi dere d. T he S M C ma y als o rec o m me n d e x pa n di n g e nr oll me nt t o t he c o h ort wit h 
c o nti n ue d m o nit ori n g f or safet y or e val uati o n of alt er nati ve d osi n g.
5. 1. 2. 3. Pe m br oliz u m a b, Tr ast uz u m a b, C A P O X ( C o h ort 1 F)
C o h ort 1 F will e val uate t he safet y a n d t olera bilit y of t ucati ni b c o m bi ne d wit h 
pe m br oliz u ma b, trast uz u ma b, a n d C A P O X i n partici pa nts wit h u nresecta ble or metastatic 
H E R 2 + gastric, es o p ha geal, o r G EJ a de n ocarci n o ma w h o ha ve n ot pre vi o usl y recei ve d 
treat me nt f or metastatic/ u nresecta ble disease i n t he 1 L setti n g. Partici pa nts i n C o h ort 1 F 
s h o ul d be ca n di dates t o recei ve a n o xali plati n-base d re gi me n as part of t heir sta n dar d -of -care 
treat me nt pri or t o e nr oll me nt. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or a n i nter me diate 
d ose as rec o m me n de d b y t he S M C) will be a d mi nistere d o n C ycle 1 Da y 1. 
E nr olle d partici pa nts will be treate d wit h C A P O X, trast uz u ma b, a n d t ucati ni b gi ve n i n 2 1 -
da y  c ycles. Pe m br o liz u ma b will be gi ve n i n 4 2-da y  c ycles. Partici pa nts m ust be i nstr ucte d o n 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 3 of 2 2 0
t he o pti mal use of a nti diarr heals f or sy m pt o matic c o ntr ol of treat me nt -ass ociate d diarr hea as 
descri be d i n Secti o n 7. 9. 9 . 
A nti diarr heal pr o p h yl a xis will n ot be re q uire d f or partici pa nts e nr olle d i n C o h ort 1 F, u nless 
rec o m me n de d by t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he data fr o m 
t his c o h ort.
T he S M C will re vie w safet y  data after 3 partici pa nts i n t his c o h ort are treate d wit h o ut 
a nti diarr heal pr o p h yl a xis.

If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use of 
a nti diarr heals are o bser ve d i n ≤1 partici pa nt, treat me nt wit h o ut a nti diarr heal pr o p h y la xis 
is c o nti n ue d a n d e val uate d i n 3 m ore partici pa nts i n t his c o h ort. 
o
If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use 
of a nti diarr heals are o bser ve d i n ≤1 of 6 partici pa nts, a nti diarr heal 
pr o p h y la xis will n ot be re q uired i n t his c o h ort.
o
If Gra de 3 or hi g her diarr hea e ve nts are o bser ve d i n ≥2 of 6 partici pa nts, 
a nti diarr heal pr o p h yl a xis will be re q uire d i n t his c o h ort.

If Gra de 3 or hi g her diarr hea e ve nts wit h o ut o pti mal use of a nti diarr heals are o bser ve d i n 
2 or m ore par tici pa nts, a nti diarr heal pr o p h yla xis will be re q uire d i n t his c o h ort.
A p pr o xi matel y  8 partici pa nts will be e nr olle d t o e ns ure t hat 6 partici pa nts c o m plete 2 1 da y s 
of st u d y  treat me nt. If 8 partici pa nts are e nr olle d, e nr oll me nt ma y re mai n o pe n t o e ns ure at 
least 3 t o 6 partici pa nts fr o m Ja pa n are e nr olle d i n t his c o h ort. 
O nce at least 6 partici pa nts ha ve c o m plete d 2 1 da ys of st u d y  treat me nt, a c o m pre he nsi ve 
re vie w of t he safet y pr ofile b y t he S M C will occ ur. Base d o n t he t otalit y of t he safety data, 
t he S M C ma y  declare t he c o m bi nati o n safe a n d t olera ble, or ma y rec o m me n d e x pa n di n g 
e nr oll me nt t o t he c o h ort wit h c o nti n ue d m o nit ori n g f or safet y  b y t he S M C, or ma y 
rec o m me n d e val uati o n of alter nati ve d osi n g
5. 1. 2. 4. Tr ast uz u m a b, Pe m br oliz u m a b ( C o h ort 1 G)
C o h ort 1 G will e va l uate t he safety a n d t olera bilit y of t ucati ni b c o m bi ne d wit h 
pe m br oliz u ma b a n d trast uz u ma b i n partici pa nts wit h u nresecta ble or metastatic H E R 2 + 
gastric, es o p ha geal, or G EJ a de n ocarci n o ma w h o ha ve n ot pre vi o usl y recei ve d treat me nt f or 
metastatic/ u nresecta b le disease i n t he 1 L setti n g. T his c o h ort ma y be o pe ne d base d o n S M C 
re vie w of t he safet y res ults fr o m C o h orts 1 A, 1 B, 1 C, 1 E, a n d/ or 1 F. T he first d ose of 
t ucati ni b ( 3 0 0 m g P O BI D or a n i nter me diate d ose as rec o m me n de d by t he S M C) will be 
a d mi nistere d o n C y cle 1 Da y  1.
E nr olle d partici pa nts will be treate d wit h trast uz u ma b a n d t ucati ni b gi ve n i n 2 1 -d a y c y cles. 
Pe m br oliz u ma b will be gi ve n i n 4 2- d a y c y cles. Partici pa nts m ust be i nstr ucte d o n t he o pti mal 
use of a nti diarr heals f or s y m pt o matic c o ntr ol of treat m e nt-ass ociate d diarr hea as descri be d i n 
Secti o n 7. 9. 9 .
A nti diarr heal pr o p h yl a xis will n ot be re q uire d f or partici pa nts e nr olle d i n C o h ort 1 G, u nless 
rec o m me n de d b y t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he data fr o m 
t his c o h ort.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 4 of 2 2 0
T he S M C will re vie w safet y data after 3 partici pa nts i n t his c o h ort are treate d wit h o ut 
a nti diarr heal pr o p h yl a xis. 

If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use of 
a nti diarr heals are o bser ve d i n ≤1 partici pa nt, treat me nt wit h o ut a nti diarr heal pr o p h y la xis 
is c o nti n ue d a n d e val uate d i n 3 m ore partici pa nts i n t his c o h ort. 
o
If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use 
of a nti diarr heals are o bser ve d i n ≤1 of 6 partici pa nts, a nti diarr heal 
pr o p h y la xis will n ot be re q uire d i n t his c o h ort. 
o
If Gra de 3 or hi g her diarr hea e ve nts are o bser ve d i n ≥2 of 6 partici pa nts, 
a nti diarr heal pr o p h yl a xis will be re q uire d i n t h is c o h ort. 

If Gra de 3 or hi g her diarr hea e ve nts wit h o ut o pti mal use of a nti diarr heals are o bser ve d i n 
2 or m ore partici pa nts, a nti diarr heal pr o p h yl a xis will be re q uire d i n t his c o h ort.
A p pr o xi matel y  8 partici pa nts will be e nr olle d t o e ns ure t hat 6 participa nts c o m plete 2 1 da y s 
of st u d y  treat me nt. If 8 partici pa nts are e nr olle d, e nr oll me nt ma y re mai n o pe n t o e ns ure at 
least 3 t o 6 partici pa nts fr o m Ja pa n are e nr olle d i n t his c o h ort.
O nce at least 6 partici pa nts ha ve c o m plete d 2 1 da ys of st u d y treat me nt a n d are e val ua ble f or 
safety, a c o m pre he nsi ve re vie w of t he safet y pr ofile b y t he S M C will occ ur. Base d o n t he 
t otalit y of t he safety data, t he S M C ma y declare t he c o m bi nati o n safe a n d t olera ble, or ma y  
rec o m me n d e x pa n di n g e nr oll me nt t o t he c o h ort wit h c o nti n ue d m o nit ori n g f or safet y b y t he 
S M C or ma y  rec o m me n d e val uati o n of alter nati ve d osi n g.
5. 1. 3. P h ase 1 b T uc ati ni b J a p a n S afet y E v al u ati o n i n C o m bi n ati o n wit h Tr ast uz u m a b 
a n d F O L F O X ( C o h ort 1 D)
After t he rec o m me n de d d ose of t ucati ni b wit h o xali plati n- base d c he m ot hera p y has bee n 
i de ntifie d, C o h ort 1 D will e val uate t he safety a n d t olera bilit y of t ucati ni b c o m bi ne d wit h 
trast uz u ma b a n d m F O L F O X 6 i n Ja pa nese partici pa nts wit h H E R 2 + GI mali g na ncies. 
A mi ni m u m of 3 partici pa nts will be e nr olle d a n d recei ve t ucati ni b (at t he rec o m me n de d d ose 
deter mi ne d i n p hase 1 b d ose escalati o n) trast uz u ma b, a n d m F O L F O X 6. E nr olle d partici pa nts 
will be treate d wit h m F O L F O X 6 a n d t ucati ni b gi ve n i n 1 4 -d a y c y cles; trast uz uma b will be 
gi ve n e ver y  2 1 d a y s. T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or a n i nter me diate d ose as 
rec o m me n de d by t he S M C) will be a d mi nistere d o n C y cle 1 Da y 1 a n d c o nti n u o usl y 
t hereafter u ntil t he partici pa nt c o mes off st u dy. A nti diarr heal pr o p h yl a xis will als o be 
a d mi nistere d f or t he first 4 2 da ys of st u d y treat me nt a n d as nee de d t hereafter (see 
Secti o n 7. 1 1. 2 ). Partici pa nts will c o nti n ue o n t hera p y u ntil disease pr o gressi o n, u nacce pta ble 
t o xicit y, wit h dra wal of c o nse nt, deat h, or st u dy cl os ure. D ose m o dificati o ns d ue t o A Es will 
be per mitte d a n d g ui deli nes re gar di n g t he res u m pti o n or disc o nti n uati o n of st u d y  treat me nt 
will be f oll o we d per Secti o n 7. 9 . Data fr o m partici pa nts w h o are n ot D L T-e val ua ble will be 
i ncl u de d i n t he safety e val uati o n. 
Partici pa nts i n t he Ja pa n -s pecific c o h ort will be caref ully m o nit ore d t hr o u g h t he first c y cle of 
treat me nt a n d e val uate d f or A Es t hat are u ne x pecte d base d o n t he k n o w n safety pr ofile of 
eac h i n di vi d ual a ge nt a n d of t he c o m bi nati o n of t ucati ni b, trast uz u ma b, a n d o xali plati n -base d 
c he m ot hera p y. I n vesti gat ors m ust e ns ure t hat partici pa nts d o n ot ha ve ot her me dical, s ocial, 
or ps y c h os ocial fact ors t hat, i n t he o pi ni o n of t he i n vesti gat or, c o ul d i m pact safet y or 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 5 of 2 2 0
c o m plia nce wit h st u d y pr oce d ures re q uire d per t he pr ot oc ol (s uc h as c o m plia nce wit h 
a d diti o nal st u d y visits, la b orat or y assess me nts, oral me dicati o ns, a n d cl ose o ut patie nt 
m o nit ori n g). D uri n g t he first c y cle, t he partici pa nt ma y be h os pitalize d f or a mi ni m u m of 1 5 
da y s wit h disc har ge per mitte d if a partici pa nt has n o o n g oi n g ≥ Gra de 3 A Es a n d is ot her wise 
c o nsi dere d a p pr o priate f or disc har ge b y t he i n vesti gat or base d o n hist or y  ( w hic h i ncl u des 
assess me nt of a n y ne w or o n g oi n g A Es a n d c o nc o mita nt me dicati o n use), p h ysical e xa m 
(i ncl u di n g vital si g ns), a n d la b orat or y e val uati o ns (i ncl u di n g c o m plete bl o o d c o u nt [ C B C], 
bl o o d c he mistr y , re nal f u ncti o n tests, a n d li ver e nz y me tests). F or partici pa nts u n der g oi n g 
o ut patie nt f oll o w - u p, t he i n vesti gat or m ust e ns ure t hat t he partici pa nt will be f oll o we d 
cl osel y i n t he o ut patie nt setti n g b y met h o ds t he y deter mi ne t o be a p pr o priate t o ass ure t he 
partici pa nt’s safet y, a n d partici pa nts s h o ul d be i nstr ucte d t o c o ntact t he i n vesti gat or 
i m me diatel y i n t he e ve nt t he y e x perie nce a n A E. I n case of e mer ge nc y, a de q uate mea ns of 
c o m m u nicati o n bet wee n t he site a n d t he partici pa nt s h o ul d be e ns ure d b y t he i n vesti gat or 
re gar dless of ti me of da y or i n t he e ve nt of a h oli da y.
T he gl o bal me dical m o nit or, Ja pa nese i n vesti gat ors, st u d y  statisticia n, a n d ot her st u d y tea m 
me m bers will c o n d uct a n e val uati o n of o verall safet y  after 3 partici pa nts ha ve e nr olle d a n d 
c o m plete d 2 8 da ys of st u d y treat me nt. If t he o verall safet y i n t he first 3 partici pa nts e nr olle d 
is dee me d acce pta ble, n o f urt her e nr oll me nt will ta ke place. If o ne D L T is o bser ve d, a n 
a d diti o nal 3 partici pa nts will be e nr olle d. If a D L T is re p orte d f or 1/ 6 partici pa nts, treat me nt 
is c o nsi dere d t o be t olerate d; if 2/ 6 D LTs ar e o bser ve d, t he i n vesti gat ors a n d s p o ns or will 
e val uate t he t otalit y of t he safet y data a n d deter mi ne if t he re gi me n is safe a n d t olera ble. If 3 
or m ore D L Ts are o bser ve d, e nr oll me nt t o t he c o h ort ma y  be dela ye d t o f urt her e xa mi ne 
safety data a n d c o nsi der st u d y desi g n c ha n ges. A d h oc meeti n gs wit h t he gl o bal me dical 
m o nit or, Ja pa nese i n vesti gat ors, st u d y statisticia n, a n d ot her st u d y tea m me m bers ma y be 
calle d t o re vie w safet y data as nee de d.
5. 1. 4. P h ase 2 T u m or S pecific E x p a nsi o n C o h orts
T u m or s pecific e x pa nsi o n c o h orts (Fi g ure 1 ) ma y be e nr olle d f oll o wi n g t he c o m pleti o n of 
p hase 1 b, t o deter mi ne safet y  a n d t olera bilit y of t he s pecific re gi me ns t o be e val uate d in t he 
P hase 2 c o h orts. 
5. 1. 4. 1. P h ase 2 T u m or S pecific E x p a nsi o n C o h ort 2 A
A 1 L  H E R 2 + gastric, es o p ha geal or G EJ a de n ocarci n o ma e x pa nsi o n c o h ort f or t ucati ni b i n 
c o m bi nati o n wit h pe m br oliz u ma b, trast uz u ma b, a n d m F O L F O X 6 or C A P O X ( C o h ort 2 A) 
ma y  be e nr olle d wit h a ppr o xi matel y  4 0 partici pa nts. E nr oll me nt will be gate d o n S M C 
re vie w of data fr o m C o h orts 1 E a n d 1 F. A nti diarr heal pr o p hyl a xis will als o be a d mi nistere d 
f or t he first 4 2 da ys of st u d y treat me nt f or partici pa nts w h o are treate d wit h m F O L F O X 6. 
Partici pa nts i n C o h ort 2 A treate d wit h C A P O X will n ot re q uire a nti diarr heal pr o p h yl a xis 
u nless rec o m me n de d b y t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he data 
fr o m C o h ort 1 C a n d/ or C o h ort 1 F. A nti diarr heal pr o p h yla xis, if re q uire d, will be f oll o we d as 
de scri be d i n Secti o n 7. 1 1. 2 . 
T he pri mar y  o bjecti ve f or C o h ort 2 A will be e val uati o n of t he safety a n d t olera bilit y of 
t ucati ni b c o m bi ne d wit h pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n-base d c he m ot hera p y. 
Sec o n dar y  o bjecti ves will i ncl u de e val uati o n of t he a nti-t u m or acti vit y of t ucati ni b gi ve n i n 
c o m bi nati o n wit h pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n -base d c he m ot hera p y. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 6 of 2 2 0
E x pl orat or y  o bjecti ves will i ncl u de e val uati o n of t he P K of t ucati ni b gi ve n i n c o m bi nati o n 
wit h pe m br oliz u ma b, trast uz u ma b, a n d o xali plati n- base d c he m ot hera p y.
5. 1. 4. 2. P h ase 2 T u m or S pecific E x p a nsi o n C o h ort 2 B
A 1 L + H E R 2 + C R C t u m or s pecific e x pa nsi o n c o h ort f or t ucati ni b i n c o m bi nati o n wi t h 
trast uz u ma b a n d m F O L F O X 6 ( C o h ort 2 B) ma y als o be e nr olle d wit h a p pr o xi matel y 2 0 
partici pa nts. E nr oll me nt will be gate d o n S M C re vie w of data fr o m C o h ort 1 B (i ncl u di n g 
D L T fre q ue nc y  a n d P K data). T he pri mar y o bjecti ve f or C o h ort 2 B will be e val uati o n of t he 
safety a n d t olera bilit y of t ucati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b a n d o xali plati n -
base d c he m ot hera p y. E x pl orat or y  o bjecti ves will i ncl u de e val uati o n of a nti-t u m or acti vit y 
a n d t he P K of t ucati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b a n d o xali plati n -base d 
c he m ot hera p y.
Partici pa nts m ust be i nstr ucte d o n t he o pti mal use of a nti diarr heals f or s y m pt o matic c o ntr ol 
of treat me nt - ass ociate d diarr hea as descri be d i n Secti o n 7. 9. 9 .
T he S M C will re vie w safet y  data after 3 partici pa nts i n C o h ort 2 B are treate d wit h o ut 
a nti diarr heal pr o p h yl a xis. 

If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use of 
a nti diarr heals are o bser ve d i n ≤1 partici pa nt, treat me nt wit h o ut a nti diarr heal pr o p h y la xis 
is c o nti n ue d a n d e val uate d i n 3 m ore partici pa nts i n t his c o h ort. 
o
If Gra de 3 or hi g her treat me nt-relate d diarr hea e ve nts wit h o ut o pti mal use 
of a nti diarr heals are o bser ve d i n ≤1 of 6 partici pa nts , a nti diarr heal 
pr o p h y la xis will n ot be re q uire d i n t his c o h ort. 
o
If Gra de 3 or hi g her diarr hea e ve nts are o bser ve d i n ≥2 of 6 partici pa nts, 
a nti diarr heal pr o p h yl a xis will be re q uire d i n t his c o h ort. 

If Gra de 3 or hi g her diarr hea e ve nts wit h o ut o pti mal use of a nti diarr heals are o bser ve d i n 
2 or m ore partici pa nts, a nti diarr heal pr o p h yl a xis will be re q uire d i n t his c o h ort.
A s of 1 2-Dec -2 0 2 3, 5 partici pa nts were e nr olle d a n d treate d i n C o h ort 2 B. T ucati ni b -relate d 
Gra de 3 diarr hea was re p orte d i n 2 of 5 parti ci pa nts d uri n g t he first 4 2 -d a y s of st u d y 
treat me nt. Base d o n t his fi n di n g, l o pera mi de pr o p h yla xis is n o w re q uire d f or C o h ort 2 B. 
A nti diarr heal pr o p h yl a xis will be f oll o we d as descri be d i n Secti o n 7. 1 1. 2 .
A st u d y  sc he ma is pr o vi de d i n Fi g ure 1 . See A p pe n di x A f or a sc he d ule of e ve nts.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 7 of 2 2 0
Fi g ure 1:
St u d y desi g n
5. 1. 5. Re n al D ose -li miti n g T o xicit y f or P h ase 1 b D ose Esc al ati o n ( C o h ort 1 A, 1 B)
A re nal D L T is defi ne d as a n i ncrease i n ser u m c ystati n C > 1. 5 × baseli ne t hat is n ot relate d t o 
pre -re nal or p ost-re nal eti ol o gies (i ncl u di n g disease pr o gressi o n, de hy d rati o n a n d i nterc urre nt 
ill ness), a n d occ urs d uri n g t he peri o d of treat me nt wit h t ucati ni b i n c o m bi nati o n wit h 
trast uz u ma b a n d F O L F O X bet wee n t he first d ose of t ucati ni b a n d t he e n d of C y cle 3. 
I ncreases of ser u m c ystati n C f or w hic h t here is a n alter nati ve cli nical e x pla nati o n 
(e g, clearl y relate d t o a n i nterc urre nt ill ness or disease pr o gressi o n) will n ot be c o nsi dere d 
re nal D L Ts. T he relati o ns hi p of a n i ncrease i n ser u m c ystati n C t o st u d y treat me nt will be 
deter mi ne d b y t he i n vesti gat or. I n t he e ve nt t hat it is n ot clear if t he la b orat or y a b n or mality 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 8 of 2 2 0
meets t he criteria f or a re nal D L T, t he st u d y me dical m o nit or s h o ul d be c o ntacte d, a n d t he 
S M C c o ns ulte d as nee de d.
Partici pa nts i n C o h orts 1 A a n d 1 B will be c o nsi dere d D L T- e val ua ble if t he y ha ve met o ne of 
t he f oll o wi n g criteria: ( 1) ha d a re nal D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d 
o xali plati n, a n d t ucati ni b d oses per c y cle a n d bee n f oll o we d f or at least 2 c ycles of st u d y  
treat me nt (t hr o u g h t he e n d of C ycle 3 of F O L F O X), i ncl usi ve of d ose dela ys. Partici pa nts 
t hat are deter mi ne d n ot t o be D L T-e val ua ble will be re place d.
T he starti n g d ose le vel of t ucati ni b will be 1 5 0 m g P O BI D i n C o h ort 1 A. T his d ose will be 
i nitiate d o n C ycle 1 Da y 8, w hic h will all o w assess me nt of o xali plati n P K i n t he a bse nce of 
t ucati ni b a n d will be gi ve n c o nti n u o usl y wit h eac h s u bse q ue nt 1 4-d a y  c ycle of treat me nt u ntil 
u nacce pta ble t o xicit y , disease pr o gressi on, wit h dra wal of c o nse nt, deat h, or st u d y  cl os ure. 
Partici pa nts e nr olle d o n C o h ort 1 B will be treate d wit h t ucati ni b ( 3 0 0 m g P O BI D or 
i nter me diate d ose) starti n g o n C ycle 1 Da y 8. T he S M C will be res p o nsi ble f or m o nit ori n g 
t he safety of partici pa nts at re g ular i nter vals (see Secti o n 5. 1. 7 ). T ucati ni b d ose i n C o h orts 
1 B will be base d o n rec o m me n dati o ns fr o m t he S M C after e val uati o n of t he C o h ort 1 A data.
T he t ucati ni b d ose t o be use d i n all s u bse q ue nt o xali plati n- c o ntai ni n g c o h orts of t he st u d y  
( C o h orts 1 C-1 F a n d 2 A -2 B) will be deter mi ne d b y  t he S M C after re vie w of t he C o h ort 1 B 
data ( F O L F O X).
5. 1. 6. D ose -li miti n g T o xicities f or P h ase 1 b S afet y E v al u ati o n of T ucati ni b wit h 
Tr ast uz u m a b + C A P O X ( C o h ort 1 C), T uc ati ni b wit h Tr ast uz u m a b + Pe m br oliz u m a b -
C o nt ai ni n g C o m bi n ati o ns ( C o h orts 1 E, 1 F, 1 G), a n d J a p a n S afet y E v al u ati o n wit h 
T uc ati ni b wit h Tr ast uz u m a b + F O L F O X ( C o h ort 1 D)
F or partici pa nts e nr olle d i n C o h orts 1 C, 1 D, 1 E, 1 F, a n d 1 G, D L Ts will be A Es or la b orat or y  
a b n or malities t hat occ ur d uri n g t he defi ne d D L T peri o d f or eac h c o h ort ( 2 1 da y s f or C o h orts 
1 C, 1 F, a n d 1 G; 2 8 da y s f or C o h orts 1 D a n d 1 E). D LTs will be A Es or la b orat or y  
a b n or malities t hat are c o nsi dere d t o be relate d t o t ucati ni b or t ucati ni b i n c o m bi nati o n wit h 
c he m ot hera p y ( m F O L F O X 6/ C A P O X) a n d/ or trast uz u ma b a n d/ or pe m br oliz u ma b. D LT is 
defi ne d as a n y of t he f oll o wi n g: 
He patic

A n y  i nsta nce of as partate a mi n otra nsferase ( A S T)/ala ni ne a mi n otra nsferase 
( AL T) > 3 × u p per li mit of n or mal ( U L N) A N D t otal bilir u bi n > 2 × U L N t hat is 
N O T t h o u g ht t o be d ue t o disease pr o gressi o n or ot her me dical ill ness
N o n -he mat ol o gic

A n y  cli nicall y si g nifica nt, n o n- he mat ol o gic treat me nt-relate d A E ≥ Gra de 3, wit h 
t he f oll o wi n g e xce pti o ns:
o
Gra de 3 fati g ue ≤7 da y s
o
Gra de 3 diarr hea, na usea, or v o miti n g wit h o ut o pti mal use of a nti -e metics 
or a nti diarr heals
o
Gra de 3 ras h wit h o ut ma xi mal use of c ortic oster oi ds or a nti- i nfecti ves
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 6 9 of 2 2 0
He mat ol o gic:

≥ Gra de 3 fe brile ne utr o pe nia

A bs ol ute ne utr o p hil c o u nt ( A N C) decrease d Gra de 4 f or > 7 da y s

T hr o m b oc y t o pe nia Gra de 4, or Gra de 3 ass ociate d wit h si g nifica nt blee di n g

Gra de 4 a ne mia
A Es or la b orat or y  a b n or malities t hat are attri b ute d o nl y t o trast uz u ma b a n d/ or c he m ot hera p y 
( m F O L F O X 6/ C A P O X) a n d/ or pe m br oliz u ma b al o ne will n ot be c o nsi dere d D LTs. E ve nts 
f or w hic h t here is a n alter nati ve cli nical e x pla nati o n (e g, clearly relate d t o a n i nterc urre nt 
ill ness or disease pr o gressi o n), will n ot be c o nsi dere d D L Ts. 
Partici pa nts will be c o nsi dere d e val ua ble f or D L T if t he y  recei ve d at least 7 5 % of t he 
pla n ne d a d mi nistrati o ns of eac h st u d y i nter ve nti o n a n d were f oll o we d d uri n g t he D L T 
peri o d, or if t he y  e x perie nce d a D L T d uri n g t he D L T peri o d. 
Partici pa nts w h o e x perie nce a D L T ma y  c o nti n ue o n st u d y treat me nt if treat me nt 
disc o nti n uati o n is n ot re q uire d b y  pr ot oc ol d ose m o dificati o n criteria ( Secti o n 7. 9 ) a n d t he 
i n vesti gat or belie ves it t o be i n t he partici pa nt's i nterest. 
5. 1. 7. S afet y M o nit ori n g C o m mittee
5. 1. 7. 1. P h ase 1 b T uc ati ni b D ose Esc al ati o n wit h Tr ast uz u m a b a n d F O L F O X ( C o h orts 
1 A, 1 B)
T he S M C will be res p o nsi ble f or m o nit ori n g t he safet y  of partici pa nts at re g ular i nter vals a n d 
will meet after all parti ci pa nts i n C o h ort 1 A are D L T -e val ua ble a n d a gai n after all 
partici pa nts i n C o h ort 1 B are D L T -e val ua ble. I n partic ular, t he S M C will e val uate re nal 
D L Ts, o verall safet y data, a n d P K data (if a vaila ble) at eac h e val uati o n of a d ose le vel d uri n g 
t he p hase 1 b d ose escalati o n p orti o n of t he st u d y . T he S M C will l o o k at t he c u m ulati ve data 
i ncl u di n g deat hs, disc o nti n uati o ns, d ose re d ucti o ns, A Es, a n d seri o us a d verse e ve nts ( S A Es), 
a n d P K data o n a re g ular basis. 
I n a d diti o n t o re nal D L Ts ( Secti o n 5. 1. 5 ), t he S M C will ta ke i nt o c o nsi derati o n ot her A Es 
w he n ma ki n g t he deter mi nati o n t o escalate, de- escalate, or declare t he rec o m me n de d d ose 
le vel i n d ose escalati on. T he A Es m ust be deter mi ne d t o be relate d t o t ucati ni b, t ucati ni b i n 
c o m bi nati o n wit h F O L F O X a n d/ or trast uz u ma b a n d n ot attri b ute d t o F O L F O X a n d/ or 
trast uz u ma b al o ne. 
He patic

A n y  i nsta nce of as partate a mi n otra nsferase ( A S T)/ala ni ne a mi n otra nsferase 
( A L T) > 3 × u p per li mit of n or mal ( U L N) A N D t otal bilir u bi n > 2 × U L N t hat is 
N O T t h o u g ht t o be d ue t o disease pr o gressi o n or ot her me dical ill ness
N o n -he mat ol o gic

A n y  cli nicall y si g nifica nt, n o n- he mat ol o gic treat me nt-relate d A E ≥ Gra de 3, wit h 
t he f oll o wi n g e xce pti o ns:
o
Gra de 3 fati g ue ≤7 da y s
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 0 of 2 2 0
o
Gra de 3 diarr hea, na usea, or v o miti n g wit h o ut o pti mal use of a nti -e metics 
or a nti diarr heals
o
Gra de 3 ras h wit h o ut ma xi mal use of c ortic oster oi ds or a nti- i nfecti ves
He mat ol o gic:

≥ Gra de 3 fe brile ne utr o pe nia

A bs ol ute ne utr o p hil c o u nt ( A N C) decrease d Gra de 4 f or > 7 da y s

T hr o m b oc y t o pe nia Gra de 4, or Gra de 3 ass ociate d wit h si g nifica nt blee di n g

Gra de 4 a ne mia
T he S M C will ma ke rec o m me n dati o ns t o t he s p o ns or re gar di n g t he c o n d uct of t he st u d y , 
i ncl u di n g c ha n ges t o d ose le vels/a d mi nistrati o n sc he d ule, e x pa nsi o n of c o h orts t o e nr oll 
a d diti o nal partici pa nts, a n d ma ke rec o m me n dati o ns c o ncer ni n g st u d y  c o nti n uati o n as 
pla n ne d, pr ot oc ol a me n d me nt, or earl y disc o nti n uati o n of t he st u d y  f or e xcessi ve t o xicit y. 
T he s p o ns or will pr o vi de a c o p y  of eac h S M C rec o m me n dati o n t o t he i n vesti gat ors.
F urt her details are d oc u me nte d i n t he st u d y  S M C c harter.
5. 1. 7. 2. P h ase 1 b S afet y E v al u ati o n of T uc ati ni b wit h Tr ast uz u m a b a n d C A P O X or 
wit h Tr ast uz u m a b a n d Pe m br oliz u m a b -C o nt ai ni n g C o m bi n ati o ns ( C o h orts 1 C, 1 E, 1 F, 
1 G)
S h o ul d partici pa nts e nr oll t o C o h orts 1 C, 1 E, 1 F, or 1 G, t he S M C will be res p o nsi ble f or 
m o nit ori n g t he safet y  of partici pa nts i n t hese c o h orts at re g ular i nter vals. I n partic ular, t he 
S M C will e val uate D L Ts as descri be d i n Secti o n 5. 1. 7 a n d ot her safet y data; P K data ma y 
als o be e val uate d, if a vaila ble. 
T he S M C will ma ke rec o m me n dati o ns t o t he s p o ns or re gar di n g t he c o n d uct of t he st u d y , 
i ncl u di n g c ha n ges t o d ose le vels/a d mi nistrati o n sc he d ule, e x pa nsi o n of c o h orts t o e nr oll 
a d diti o nal partici pa nts, a n d ma ke rec o m me n dati o ns c o ncer ni n g st u d y  c o nti n uati o n as 
pla n ne d, pr ot oc ol a me n d me nt, or earl y disc o nti n uati o n of t he st u d y  f or e xcessi ve to xicit y . 
T he s p o ns or will pr o vi de a c o p y of eac h S M C rec o m me n dati o n t o t he i n vesti gat ors.
F urt her details are d oc u me nte d i n t he st u d y  S M C c harter.
5. 1. 7. 3. P h ase 2 T u m or -S pecific E x p a nsi o n ( C o h orts 2 A, 2 B)
T he S M C will be res p o nsi ble f or m o nit ori n g t he safet y  of partici pa nts at re g ular i nter vals, i n 
partic ular, t he S M C will e val uate A Es, S A Es, treat me nt m o dificati o ns, la b orat or y  
a b n or malities, a n d deat hs a n d ma y  ma ke rec o m me n dati o ns t o t he s p o ns or re gar di n g t he 
c o n d uct of t he st u d y.
5. 1. 8. L o n g -ter m E xte nsi o n P h ase
N o a d di ti o nal e nr oll me nt t o a n y c o h ort will occ ur as of A me n d me nt 5. 
Partici pa nts still o n st u d y  treat me nt w h o ha ve n ot met a pr ot oc ol defi ne d reas o n f or e n d of 
treat me nt ma y c o nti n ue i nt o t he LT E P. Partici pa nts w h o ha ve e x perie nce d pr o gressi ve 
disease, e n de d st u d y  treat me nt, or are i n l o n g ter m f oll o w-u p will n ot pr ocee d t o t he L T E P. 
D uri n g t he L T E P, o nl y  i nf or mati o n relate d t o pre g na ncies a n d S A Es will be re p orte d t o t he 
S p o ns or. All safet y  a n d efficac y assess me nts will be perf or me d per i nstit uti o nal g ui deli nes
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 1 of 2 2 0
a n d i n vesti gat or-deter mi ne d us ual a n d c ust o mar y  cli nical care, wit h t he e xce pti o n of 
pre g na nc y  testi n g w hic h will c o nti n ue as o utli ne d i n t he sc he d ule of e ve nts f or partici pa nts of 
c hil d beari n g p ote ntial. Partici pa nts e nr olle d i n t he L T E P ma y  re mai n o n stu d y  treat me nt u ntil 
u nacce pta ble t o xicit y , disease pr o gressi o n, wit h dra wal of c o nse nt, deat h, or st u d y cl os ure. 
5. 1. 9. E n d of St u d y
T he st u d y  will e n d w he n t he last LT E P partici pa nt has ha d t heir last visit/c o ntact. 
Partici pa nts i n l o n g -ter m f oll o w-u p will ha ve a last visit/c o ntact u p o n i m ple me ntati o n of 
A me n d me nt 5. Pe m br oliz u ma b will be gi ve n f or a ma xi m u m of 1 8 d oses ( C o h orts 1 E, 1 F, 
1 G, 2 A); st u d y  treat me nt will c o ntin ue i n t hese c o h orts u ntil u nacce pta ble t o xicit y , disease 
pr o gressi o n, wit h dra wal of c o nse nt, deat h, or st u d y cl os ure. I n a d diti o n, t he s p o ns or ma y  
ter mi nate t he st u dy at a n y ti me (see Secti o n 1 2. 1 ). 
5. 2. Disc ussi o n a n d R ati o n ale f or St u d y Desi g n
T his p hase 1 b/ 2 st u d y  is desi g ne d t o deter mi ne t he rec o m me n de d d ose of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d o xali plati n -base d c he m ot hera p y. S pecificall y, t he 
t he oretical p ote ntial f or o xali plati n i n d uce d ne p hr ot o xicit y as a res ult of m ulti dr u g a n d t o xi n 
e xtr usi o n ( M A T E) pr otei n i n hi biti o n will be assesse d. T he st u d y will be c o n d ucte d usi n g a 
sta n dar d 3 + 3 desi g n a n d i ncl u de 2 t ucati ni b d ose le vels. I nter me diate d ose le vels or alter nate 
d osi n g sc he d ules ma y  be e x pl ore d base d u p o n S M C rec o m me n dati o ns. O nce t he i nitial d ose 
of t ucati ni b ( 1 5 0 m g) is dee me d safe b y t he S M C, a n escalati o n c o h ort ( C o h ort 1 B) wit h u p 
t o 8 partici pa nts (t o e ns ure 6 D L T -e val ua ble a n d P K e val ua ble partici pa nts) will be e nr olle d 
wit h a t ucati ni b d ose of 3 0 0 m g ( or i nter me diate d ose) i n c o m bi nati o n wit h trast uz u ma b a n d 
F O L F O X. F O L F O X is esta blis he d as safe a n d effecti ve f or t he treat me nt of GI ca ncers. 
A d diti o nall y , t he st u d y ma y assess t he safet y, t olera bilit y , a n d efficac y of t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d C A P O X or pe m br oliz u ma b-c o ntai ni n g c o m bi nati o ns. 
I n a d diti o n t o t he pri mar y e n d p oi nt of safety a n d t olera bilit y, sec o n dar y e n d p oi nts will assess 
t he P K of t ucati ni b a n d oxali plati n w he n use d i n c o m bi nati o n. A preli mi nar y a nal ys is of 
efficac y i n t he p hase 1 b p orti o n of t he st u d y, base d o n O R R, ma y be perf or me d. Efficac y 
a nal ys es are pla n ne d d uri n g t he p hase 2 p orti o n of t he st u d y .
5. 2. 1.
Met h o d of Assi g ni n g P artici p a nts t o Tre at me nt Gr o u ps
T his is a n o pe n -la bel, d ose escalati o n a n d e x pa nsi o n st u d y. F oll o wi n g i nf or me d c o nse nt a n d 
scree ni n g assess me nts, eli gi ble partici pa nts wit h H E R 2 + GI mali g na ncies will be assi g ne d t o 
c urre ntl y e nr olli n g c o h orts. W he n disease s pecific c o h orts are o pe ne d, partici pa nts will be 
e nr olle d o n t he basis of t he partici pa nts’ disease t y pe. 
5. 2. 2. R ati o n ale f or Selecti o n of D oses
I n vitr o st u dies usi n g tra nsfecte d M D C KII cells s h o we d t hat t ucati ni b si milarl y i n hi bite d 
O C T 2 a n d M A T E 1 -me diate d tra ns p ort of creati ni n e a n d o xali plati n. T he i nitial d ose le vel of 
t ucati ni b was c h ose n base d o n P K m o deli n g t hat s h o we d t hat t he 1 5 0 m g d ose le vel res ulte d 
i n mi ni mal M A T E i n hi biti o n, as assesse d by ser u m creati ni ne. T heref ore, if a dr u g -dr u g 
i nteracti o n ( D DI) tr uly e xists, t h is d ose le vel s h o ul d ha ve mi ni mal i m pact o n t he dis p ositi o n 
of o xali plati n. 
Res ults fr o m a cli nical dr u g i nteracti o n st u d y  ( S G N T U C-0 2 0) i n healt h y v ol u nteers wit h 
metf or mi n (a s u bstrate of M A T E 1/ 2 -K) s h o we d t hat c o -a d mi nistrati o n of t ucati ni b ( m ulti ple 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 2 of 2 2 0
d oses, 3 0 0 m g BI D) wit h metf or mi n i ncrease d t he metf or mi n plas ma e x p os ure b y 4 8 % a n d 
ca use d a tra nsie nt i ncrease i n ser u m creati ni ne le vel wit h o ut a n y  effect o n ki d ne y f u ncti o n. 
Meas ures of re nal f u ncti o n i ncl u di n g act ual gl o mer ular filtrati o n rate ( G F R) as
assesse d b y 
i o he x ol a n d uri ne al b u mi n le vels were n ot affecte d b y t ucati ni b. T h us, o bser ve d ser u m 
creati ni ne i ncrease i n cli nical st u dies wit h t ucati ni b is d ue t o i n hi biti o n of t u b ular secreti o n of 
creati ni ne via O C T 2 a n d M A T E 1. 
A clear d ose -res p o nse relati o ns hi p was o bser ve d i n a n ot her healt h y  v ol u nteer st u d y 
( S G N T U C-0 1 5), w here c ha n ge i n ser u m creati ni ne fr o m baseli ne i ncrease d as t ucati ni b d ose 
i ncrease d ( 5 0, 1 5 0, a n d 3 0 0 m g BI D). Me dia n ser u m creati ni ne ma xi m u m c o nce ntrati o ns 
re mai ne d bel o w U L N ( N CI C T C A E v 5. 0 criteria) i n partici pa nts recei vi n g m ulti ple d oses of 
1 5 0 m g BI D t ucati ni b; t h us, t he c ha n ge i n ser u m creati ni ne i n t he prese nce of 1 5 0 m g BI D 
was c o nsi dere d safe as it was d ue t o tra ns p ort i n hi biti o n a n d di d n ot re prese nt ki d ne y  i nj ur y. 
Alt h o u g h t he e xte nt of o xali plati n cleara nce d ue t o t u b ular secreti o n via O C T 2 a n d/ or 
M A T E 1/ 2 -K tra ns p ort is n ot well c haracterize d, t he si milarit y of creati ni ne a n d o xali plati n 
O C T 2/ M A T E 1/ M A T E 2 -K i n vitr o i n hi biti o n b y  t ucati ni b a n d t he k n o w n d ose-res p o nse of 
ser u m creati ni ne c ha n ges i n t he prese nce of t ucati ni b i n healt h y v ol u nteers were use d t o i nfer 
t hat o xali plati n dis p ositi o n at t he pr o xi mal t u b ule le vel mi g ht si milarl y be t ucati ni b 
d ose - de pe n de nt. 
Des pite t his t he oretical ris k, se veral M A T E tra ns p orter i n h i bit ors ha ve bee n c o-a d mi nistere d 
wit h o xali plati n i n t he cli nic wit h o ut e x hi biti n g a p pare nt si g ns of ac ute ki d ne y  i nj ur y. In vitr o 
i n hi biti o n data f or b ot h o n da nsetr o n a n d i mati ni b dis pla ye d p ote ntial f or i n vi v o i nteracti o n 
wit h M A T E ( O C T 2 t o a m uc h lesser e xte nt) tra ns p orter s u bstrates base d o n criteria as 
descri be d i n t he 2 0 2 0 i n vitr o i nteracti o n st u dies g ui da nce (I n Vitr o Dr u g I nteracti o n St u dies-
C y t oc hr o me ( C Y P) P 4 5 0 E nz ym e - a n d Tra ns p orter - Me diate d Dr u g I nteracti o ns; G ui da nce 
f or I n d ustr y, 2 0 2 0). On da nsetr o n is a n a nti- e metic t hat is rec o m me n de d f or pre ve nti o n of 
c he m ot hera p y i n d uce d na usea a n d v o miti n g. As F O L F O X is c o nsi dere d a m o deratel y 
e met o ge nic re gi me n, o n da nsetr o n is fre q ue ntl y  gi ve n pr o p h ylacticall y a n d as a treat me nt f or 
na usea a n d v o miti n g ass ociate d wit h t his re gi me n. I t is als o i ncl u de d as part of t he A merica n 
S ociet y  f or Cli nical O nc ol o g y a n d Nati o nal C o m pre he nsi ve Ca ncer Net w or k g ui deli nes as a 
rec o m me n de d me dicati o n i n t his setti n g. Des pite t he p ote ntial f or i n vi v o i nteracti o n base d 
o n M A T E tra ns p orter i n hi biti o n, t here are n o rec o m me n de d d ose m o dificati o ns f or 
o n da nsetr o n w he n use d i n c o m bi nati o n wit h o xali plati n. 
I mati ni b, a sec o n d M A T E tra ns p orter i n hi bit or, has bee n a d mi nistere d i n c o m bi nati o n wit h 
F O L F O X f or patie nts wit h pa ncre atic ca ncer a n d metastatic C R C (Starli n g 2 0 1 2 ; H oe hler 
2 0 1 3 ; Mic hael 2 0 1 3 ). I n t hese st u dies, wit h a t otal of 8 6 partici pa nts, t here were n o re p orts of 
re nal t o xicities. T he m ost c o m m o n D LTs re p orte d were fe brile ne utr o pe nia a n d Gra de 3/ 4 
ne utr o pe nia. I mati ni b has als o bee n a d mi nistere d i n c o m bi nati o n wit h 1 3 0 m g/ m 2 o xali plati n 
(s uc h as is use d i n C A P O X) f or patie nts wit h metastatic C R C wit h n o re p orts of re nal 
t o xicities (H oe hler 2 0 1 3 ).
As t ucati ni b i n vitr o data e x hi bite d si milar M A T E/ O C T 2 i n hi biti o n pr o pe nsit y  as 
o n da nsetr o n a n d i mati ni b, t he cli nical e x perie nce wit h o n da nsetr o n a n d i mati ni b i n 
c o m bi nati o n wit h o xali plati n s u g gests a relati vel y l o w ris k f or d ose escalati n g directl y t o 
3 0 0 m g t ucati ni b BI D (t he t h era pe utic d ose le vel) if n o re nal D L Ts are o bser ve d wit h 
o xali plati n i n c o m bi nati o n wit h 1 5 0 m g BI D t ucati ni b.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 3 of 2 2 0
F O L F O X re gi me ns were c h ose n as t he y  are well-t olerate d a n d c o m m o nl y utilize d i n t he 
sta n dar d- of-care treat me nt f or GI mali g na ncies. A d diti o nall y , t hese re gi me ns use a l o wer 
o verall d ose of o xali plati n as c o m pare d t o ot her F O L F O X re gi me ns. T he m F O L F O X 6 
re gi me n ( 1 4-d a y  c ycle) c o nsists of o xali plati n 8 5 m g/ m 2, le uc o v ori n 4 0 0 m g/ m 2, fl u or o uracil 
4 0 0 m g/ m 2 (I V b ol us), t he n fl u or o uracil 2 4 0 0 m g/ m 2 (IV a d mi nistrati o n o ver 4 6 h o urs). T he 
m F O L F O X 7 ( 1 4 -d a y  c ycle) re gi me n c o nsists of o xali plati n 8 5 m g/ m 2, le uc o v ori n 
2 0 0 m g/ m 2, a n d fl u or o uracil 2 4 0 0 m g/ m 2 (I V a d mi nistrati o n o ver 4 6 h o urs). Partici pa nts 
recei vi n g F O L F O X i n C o h orts 1 A a n d 1 B ma y be d ose d usi n g eit her t he m F O L F O X 6 or 
m F O L F O X 7 re gi me n per i n vesti gat or prefere nce b ut m ust re mai n o n t he sa me F O L F O X 
re gi me n t hr o u g h o ut st u d y partici pati o n. Partici pa nts e nr olle d i n C o h orts 1 D, 1 E, 2 A, a n d 2 B 
will be treate d wit h m F O L F O X 6.
Trast uz u ma b is a p pr o ve d f or treat me nt of H E R 2- o vere x pressi n g metastatic gastric or G EJ 
a de n ocarci n o ma. I n C o h orts 1 A a n d 1 B utilizi n g F O L F O X, trast uz u ma b will be gi ve n at a 
l oa di n g d ose of 6 m g/ k g i n C y cle 1 f oll o we d b y 4 m g/ k g i n s u bse q ue nt c y cles. T he bi wee kl y  
trast uz u ma b sc he d ule has bee n e val uate d i n vari o us p hase 2 st u dies a n d bee n f o u n d t o be safe 
a n d t olera ble (Orla n d o 2 0 1 4 ; Qi u 2 0 1 4 ; M o n daca 2 0 1 9 ).
I n C o h orts 1 C, 1 D, 1 E, 1 F, 1 G, 2 A, a n d 2 B, trast uz u ma b will be gi ve n as a l oa di n g d ose of 
8 m g/ k g i n C y cle 1 f oll o we d b y 6 m g/ k g i n s u bse q ue nt c y cles ( 2 1 -d a y c y cles). T his is t he 
a p pr o ve d d osi n g sc he d ule of trast uz u ma b i n t he treat me nt of H E R 2 + breast ca ncer a n d 
metastatic gastric or gastr oes o p ha geal j u ncti o n a de n ocarci n o ma.
I n C o h ort 1 C, 1 F a n d 2 A, t he C A P O X re gi me n ( 2 1-d a y c y cle) was c h ose n as a c he m ot hera p y 
bac k b o ne beca use it is well -t olerate d a n d utilize d i n t he treat me nt of metastatic C R C, 
es o p ha geal, gastric, a n d G EJ a de n ocarci n o ma (H oe hler 2 0 1 3 ). T he C A P O X re gi me n c o nsists 
of 1 0 0 0 m g/ m 2 ca pecita bi ne ( P O BI D f or 1 4 d a y s) a n d o xali plati n 1 3 0 m g/ m 2 (IV, Da y  1) 
gi ve n o ver a 2 1 -d a y c y cle. T he a d diti o n of trast uz u ma b t o C A P O X has bee n s h o w n t o be safe 
a n d t olera ble (Ri vera 2 0 1 9 ).
Pe m br oliz u ma b is a p pr o ve d f or t he treat me nt of m ulti ple GI  mali g na ncies, i ncl u di n g 
micr osatellite i nsta bilit y - hi g h/ deficie nt mis matc h re pair ( M SI- H/ d M M R) C R C, es o p ha geal 
a de n ocarci n o ma, a n d H E R 2 + gastric or G EJ a de n ocarci n o ma. T he c urre nt a p pr o ve d d osi n g 
re gi me ns of pe m br oliz u ma b f or I V a d mi nistrati o n are 2 0 0 m g I V Q 3 W a n d 4 0 0 m g I V Q 6 W 
f or a d ults. T he pla n ne d d ose of pe m br oliz u ma b i n C o h orts 1 E, 1 F, 1 G a n d 2 A is 4 0 0 m g 
e ver y 6 wee ks. T he 4 0 0 m g Q 6 W d osi n g re gi me n of pe m br oliz u ma b is e x pecte d t o ha ve a 
si milar be nefit-ris k pr ofile as 2 0 0 m g Q 3 W, i n all treat me nt setti n gs i n w hic h 2 0 0 m g Q 3 W 
pe m br oliz u ma b is c urre ntl y a p pr o priate (Lala 2 0 1 8 ). S pecifically, t he d osi n g re gi me n of 
4 0 0 m g Q 6 W f or pe m br oliz u ma b is c o nsi dere d a de q uate base d o n m o deli n g a n d si m ulati o n 
a nal ys es, gi ve n t he f oll o wi n g rati o nale:
P har mac o ki netic si m ulati o ns de m o nstrati n g t hat i n ter ms of pe m br oliz u ma b e x p os ures:

C a v g ( or area u n der t he c o nce ntrati o n-ti me c ur ve [ A U C]) at 4 0 0 m g Q 6 W is 
si milar t o t he a p pr o ve d 2 0 0 m g Q 3 W d ose, t h us bri d gi n g efficac y bet wee n d osi n g 
re gi me ns.

Tr o u g h c o nce ntrati o ns ( C mi n ) at 4 0 0 m g Q6 W are ge nerall y wit hi n t he ra n ge of 
t h ose ac hie ve d wit h 2 m g/ k g or 2 0 0 m g Q 3 W i n t he maj orit y  ( > 9 9 %) of patie nts.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 4 of 2 2 0

Ma xi m u m o bser ve d c o nce ntrati o ns ( C
ma x ) at 4 0 0 m g Q 6 W are well bel o w t he 
C ma x f or t he hi g hest cli nicall y teste d d ose of 1 0 m g / k g Q 2 W, s u p p ortin g t hat t he 
safety pr ofile f or 4 0 0 m g Q 6 W s h o ul d be c o m para ble t o t he esta blis he d safet y  
pr ofile of pe m br oliz u ma b.

E x p os ure -res p o nse f or pe m br oliz u ma b has bee n s h o w n t o be flat acr oss 
i n dicati o ns, a n d O S pre dicti o ns i n mela n o ma a n d n o n-s mall cell l u n g ca ncer 
( N S C LC) s h o w t hat efficac y  at 4 0 0 m g Q 6 W is e x pecte d t o be si milar t o 2 0 0 m g 
or 2 m g/ k g Q 3 W, gi ve n t he si milar e x p os ures; t h us, 4 0 0 m g Q 6 W is e x pecte d t o 
be efficaci o us acr oss i n dicati o ns.
T he res ults of a n i nteri m a nal ys is of pe m br oliz u ma b or place b o pl us trast uz u ma b a n d 
c he m ot hera p y i n partici pa nts wit h H E R 2 + metastatic gastric or G EJ ca ncer s h o we d a 
si g nifica nt i m pr o ve me nt i n O R R f or partici pa nts i n t he e x peri me ntal ar m, w hile t he 
i nci de nce of A Es was si milar bet wee n ar ms wit h n o safety c o ncer ns o bser ve d (Ja nji gia n 
2 0 2 1 ). T he c O R R ( 9 5 % CI) was 7 4. 4 % ( 6 6. 2-8 1. 6) f or pe m br oliz u ma b + S O C vs 5 1. 9 % 
( 4 3. 0- 6 0. 7) f or place b o + S O C ( differe nce, 2 2. 7 perce nta ge p oi nts [ 9 5 % CI, 1 1. 2-3 3. 7], P = 
0. 0 0 0 0 6. Base d o n t he res ults of t his st u d y , accelerate d a p pr o val was gra nte d i n t he U S f or 
pe m br oliz u ma b pl us trast uz u ma b a n d c he m ot hera p y  i n t he treat me nt of 1 L H E R 2 + G E C. 
T hese res ults ser ve as t he basis f or e val uati n g t ucati ni b wit h pe m br oliz u ma b -c o ntai ni n g 
re gi me ns i n C o h orts 1 E, 1 F, 1 G, a n d 2 A.
5. 2. 3. Bli n di n g a n d U n bli n di n g
T his is a n o pe n -la bel st u d y.
6. S T U D Y P O P U L A TI O N
T his st u d y  will e nr oll partici pa nts wit h u nresecta ble or metastatic H E R 2 + gastric 
a de n ocarci n o ma, es o p ha geal a de n ocarci n o ma, G EJ a de n ocarci n o ma, C R C, 
c h ola n gi ocarci n o ma, a n d gall bla d der carci n o ma. 
Pa rtici pa nts m ust meet all of t he e nr oll me nt criteria t o be eli gi ble f or t his st u d y. Eli gi bilit y 
criteria ma y n ot be wai ve d b y t he i n vesti gat or a n d are partici pa nt t o re vie w i n t he e ve nt of a 
g o o d cli nical practice a u dit a n d/ or healt h re g ulat or y  a ut h orit y i ns pecti o n.
6. 1. I ncl usi o n Criteri a
1.
Partici pa nts m ust ha ve a n u nresecta ble or metastatic s oli d mali g na nc y t hat is 
hist ol o gicall y  or c yt ol o gicall y c o nfir me d t o be o ne of t he t u m or t ypes liste d bel o w:
C o h orts 1 A, 1 B, 1 C, a n d 1 D

C R C

Gastric a de n ocarci n o ma

G EJ a de n oc arci n o ma

Es o p ha geal a de n ocarci n o ma

C h ola n gi ocarci n o ma

Gall bla d der carci n o ma
C o h orts 1 E, 1 F, 1 G, a n d 2 A
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 5 of 2 2 0

Gastric a de n ocarci n o ma

G EJ a de n ocarci n o ma

Es o p ha geal a de n ocarci n o ma
C o h ort 2 B

C R C
2.
Partici pa nts m ust be ca n di dates t o recei ve a n o xali plati n- base d re gi me n as part of 
t heir sta n dar d-of -care treat me nt f or all c o h orts, wit h t he e xce pti o n of C o h ort 1 G. 
Partici pa nts i n C o h orts 1 A, 1 B, 1 C, or 2 B ca n be recei vi n g a n o xali plati n -base d 
re gi me n d uri n g t he scree ni n g peri o d:

F or C o h orts 1 A a n d 1 B: u p t o 2 c o nsec uti ve c y cles of F O L F O X ( ≤8 5 m g/ m 2
o xali plati n per 2 -wee k c ycle) ma y  ha ve bee n recei ve d d uri n g t he scree ni n g peri o d 
pri or t o C y cle 1 Da y 1 of st u d y treat me nt. 

F or C o h orts 1 C: u p t o 2 c o nsec uti ve c y cles of F O L F O X ( ≤8 5 m g / m2 o xali plati n 
per 2 -wee k c y cle) or o ne c ycle of C A P O X (≤1 3 0 m g/ m 2 o xali plati n per 3 -wee k 
c ycle) ma y ha ve bee n recei ve d d uri n g t he scree ni n g peri o d pri or t o C ycle 1 Da y 1 
of st u d y  treat me nt. 

F or C o h orts 1 A, 1 B, 1 C: if partici pa nt has recei ve d o xali plati n i n pri or c y cles at 
hi g her d oses t ha n t h ose liste d a b o ve, t here m ust be a mi ni m u m of 2 8 da y s off 
treat me nt pri or t o Cycle 1 Da y  1 of treat me nt i n t his st u d y. 

F or C o h ort 2 B pri or t o e nr oll me nt ( C y cle 1 Da y 1):
o
Partici pa nts ma y  have recei ve d u p t o 1 c y cle of F O L F O X (≤8 5 m g/ m 2
o xali plati n per 2 -wee k c ycle) d uri n g t he scree ni n g peri o d pri or t o C ycle 1 
D a y  1 b ut ma y n ot ha ve recei ve d pri or o xali plati n f or metastatic disease
o
O xali plati n recei ve d i n a n a dj u va nt setti n g is per mitte d if > 6 m o nt hs pri or t o 
C y cle 1 Da y  1
o
At least 2 1 da y s m ust ha ve ela pse d fr o m pri or sys te mic a ntica ncer t hera py 
(i ncl u di n g h or m o nal a n d bi ol o gic t hera py b ut e xcl u di n g 1 c ycle of 
F O L F O X), n o n -ce ntral ner v o us s ys te m ra diati o n, a n d treat me nt wit h ot her 
e x peri me ntal a ge nts 
3.
H E R 2 + disease, as deter mi ne d b y  hist oric or l ocal la b orat or y testi n g base d o n o ne of 
t he f oll o wi n g:

F or C R C, c h ola n gi ocarci n o ma, a n d gall bla d der carci n o ma: 
o
H E R 2 a m plificati o n or o vere x pressi o n fr o m fres h or arc hi val t u m or tiss ue 
utilizi n g o ne of t he f oll o wi n g tests pr ocesse d i n a Cli nical La b orat or y 
I m pr o ve me nt A me n d me nts ( C LI A)- or I nter nati o nal Or ga nizati o n f or 
Sta n dar dizati o n (I S O) -accre dite d la b orat or y:

H E R 2 o vere x pressi o n ( 3 + i m m u n o hist oc he mistr y [I H C])
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 6 of 2 2 0

H E R 2 ( E R B B 2) a m plificati o n b y  i n sit u hy b ri dizati o n assa y (fl u oresce nce 
i n sit u h ybri dizati o n [ FI S H] or c hr o m o ge nic i n sit u h y bri dizati o n si g nal 
rati o ≥2. 0 or ge ne c o p y n u m ber > 6)

H E R 2 ( E R B B 2) a m plificati o n b y  ne xt ge nerati o n se q ue nci n g ( N G S) assa y
o
H E R 2 a m plificati o n i n a C LI A certifie d or I S O accre dite d bl o o d -base d N G S 
assa y 

F or Gastric, G EJ, a n d es o p ha geal a de n ocarci n o mas : H E R 2 
o vere x pressi o n/a m plificati o n b y  IH C a n d I SH (I H C 3 + or I H C 2 +/I S H +) assa y of a 
t u m or tiss ue sa m ple, pr ocesse d i n a C LI A- or I S O -accre dite d la b orat or y a n d 
e val uate d f oll o wi n g A S C O/ C A P 2 0 1 6 g ui deli nes f or H E R 2 testi n g i n 
gastr oes o p ha geal a de n ocarci n o ma.
4.
P hase 1 b c o h orts : meas ura ble or n o n -meas ura ble disease acc or di n g t o R E CI S T v 1. 1 
as deter mi ne d b y t he i n vesti gat or
P hase 2 c o h orts: meas ura ble disease acc or di n g t o R E CI S T v 1. 1 as deter mi ne d b y  t he 
i n vesti gat or
5.
A ge 1 8 years or ol der at ti me of c o nse nt or ≥ t he a ge of maj orit y per re gi o nal 
re q uire me nts
6.
A n Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us sc ore of 0 or 1 
(A p pe n di x B )
7.
Life e x pecta nc y  ≥3 m o nt hs, i n t he o pi ni o n of t he i n vesti gat or
8.
A de q uate he patic f u ncti o n, as defi ne d b y:

T otal bilir u bi n ≤1. 5 × U L N , e xce pt f or partici pa nts wit h k n o w n Gil bert’s disease, 
w h o ma y  e nr oll if t he c o nj u gate d bilir u bi n is ≤1. 5 × U L N

Tra nsa mi nases ( A S T a n d A L T) ≤2. 5 × U L N ( ≤5 × U L N if li ver metastases are 
prese nt)
9.
A de q uate baseli ne he mat ol o gic para meters as defi ne d b y:

A N C ≥1. 5 × 1 0³/ µ L

Platelet c o u nt ≥1 0 0 × 1 0 ³/ µ L; partici pa nts wit h sta ble platelet c o u nt fr o m 7 5–
1 0 0 × 1 0³/ µ L  ma y be i ncl u de d wit h a p pr o val fr o m t he me dical m o nit or

He m o gl o bi n ≥8 g/ d L. Partici pa nts o n a sta ble d ose of er y t hr o p oieti n ( ≥ 
a p pr o xi matel y 3 m o nt hs) are eli gi bl e.

I n partici pa nts tra nsf use d bef ore st u dy e ntr y, tra nsf usi o n m ust be ≥1 4 da y s pri or 
t o start of t hera py t o esta blis h a de q uate he mat ol o gic para meters i n de pe n de nt fr o m 
tra nsf usi o n s u p p ort
1 0. Esti mate d G F R: 

C o h orts 1 A, 1 B: ≥9 0 m L/ mi n/ 1. 7 3 m ² usi n g t he M o dificati o n of Diet i n Re nal 
Disease ( M D R D) e q uati o n. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 7 of 2 2 0
o
Partici pa nts wit h esti mate d G F R ≥6 0 t o < 9 0 m L/ mi n/ 1. 7 3 m ² ma y be 
e nr olle d i n C o h ort 1 B wit h me dical m o nit or a p pr o val. 

C o h orts 1 C, 1 D, 1 E, 1 F, 2 A, a n d 2 B: ≥6 0 m L/ mi n/ 1. 7 3 m ² usi n g t he M D R D 
e q uati o n. 
1 1. I nter nati o nal n or malize d rati o (I N R) a n d partial t hr o m b o plasti n ti me ( P T T)/acti vate d 
partial t hr o m b o plasti n ti me (a P T T) ≤1. 5 × U L N, u nless o n me dicati o n k n o w n t o alter 
I N R a n d P T T/a P T T ( N ote: warfari n a n d ot her c o u mari n deri vati ves are pr o hi bite d f or 
partici pa nts r ecei vi n g C A P O X.)
1 2. Left ve ntric ular ejecti o n fracti o n ( L V E F) ≥5 0 % as assesse d b y ec h ocar di o gra m 
( E C H O) or m ulti gate d ac q uisiti o n ( M U G A) sca n d oc u me nte d wit hi n 4 wee ks pri or t o 
e nr oll me nt.
1 3. Partici pa nts of c hil d beari n g p ote ntial, as defi ne d i n Secti o n 6. 3 , u n der t he f oll o wi n g 
c o n diti o ns:
a
M ust ha ve a ne gati ve ser u m/ plas ma or uri ne pre g na nc y  test ( mi ni m u m se nsiti vit y 
2 5 mI U/ m L or e q ui vale nt u nits of beta h u ma n c h ori o nic g o na d otr o pi n [ β -h C G]) 
res ult 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. Partici pa nts wit h 
false p ositi ve res ults a n d d oc u me nte d verificati o n t hat t he partici pa nt is n ot 
pre g na nt are eli gi ble f or partici pati o n
b
M ust a gree n ot t o
tr y t o bec o me pre g na nt d uri n g t he st u d y a n d f or at least 
7 m o nt hs after t he fi nal d ose of st u d y treat me nt
c
M ust a gree n ot t o breastfee d or d o nate o va, starti n g at ti me of i nf or me d c o nse nt 
a n d c o nti n ui n g t hr o u g h 7 m o nt hs after t he fi nal d ose of st u d y  treat me nt
d
If se x uall y acti ve i n a wa y t hat c o ul d lea d t o pre g na nc y, m ust c o nsiste ntl y use 
2 hi g hl y effecti ve met h o ds of birt h c o ntr ol (as defi ne d i n A p pe n di x C ) starti n g at 
t he ti me of i nf or me d c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he st u dy a n d f or at least 
7 m o nt hs after t he fi nal d ose of st u d y  treat me nt. 
1 4. Partici pa nts w h o ca n fat her c hil dre n, u n der t he f oll o wi n g c o n diti o ns:
a
M ust a gree n ot t o d o nate s per m starti n g at ti me of i nf or me d c o nse nt a n d 
c o nti n ui n g t hr o u g h o ut t he st u d y peri o d a n d f or at least 7 m o nt hs after t he fi nal 
d ose of st u d y  treat me nt
b
If se x uall y acti ve wit h a pers o n of c hil d beari n g p ote ntial i n a wa y t hat c o ul d lea d 
t o pre g na nc y, m ust c o nsiste ntl y use 2 hi g hly effecti ve met h o ds of birt h c o ntr ol (as 
defi ne d i n A p pe n di x C ) starti n g at ti me of i nf or me d c o nse nt a n d c o nti n ui n g 
t hr o u g h o ut t he st u dy a n d f or at least 7 m o nt hs af ter t he fi nal d ose of st u d y 
treat me nt
c
If se x uall y acti ve wit h a pers o n w h o is pre g na nt or breastfee di n g, m ust 
c o nsiste ntl y use o ne of 2 c o ntrace pti o n o pti o ns (as defi ne d i n A p pe n di x C ) 
starti n g at ti me of i nf or me d c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he st u dy a n d f or 
at least 7 m o nt hs after t he fi nal d ose of st u d y treat me nt 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 8 of 2 2 0
1 5. Partici pa nt m ust pr o vi de si g ne d i nf or me d c o nse nt t hat has bee n a p pr o ve d b y a n 
i nstit uti o nal revie w b oar d/i n de pe n de nt et hics c o m mittee (I R B/I E C) pri or t o i nitiati o n 
of a n y st u d y relate d tests or pr oce d ures t hat are n ot part of sta n dar d - of-care f or t he 
partici pa nt’s disease.
1 6. Partici pa nt m ust be willi n g a n d a ble t o c o m pl y wit h st u d y  pr oce d ures, la b orat or y 
tests, a n d ot her re q uire me nts of t he st u d y. Partici pa nts wit h a k n o w n ps yc hiatric or 
s u bsta nce a b use dis or der t hat w o ul d i nterfere wit h t he partici pa nt’s a bility t o 
c o o perate wit h t he re q uire me nts of t he st u d y  are n ot eli gi ble.
1 7. F or partici pa nts wit h p ri or ce ntral ner v o us sys te m ( C N S)-directe d ra diati o n t hera p y, 
at least 7 d a y s m ust ha ve ela pse d fr o m pri or stere otactic ra di os ur ger y ( S R S) a n d at 
least 2 1 da ys m ust ha ve ela pse d fr o m pri or w h ole brai n ra diati o n t hera p y ( W B R T). 
Partici pa nts m ust ha ve rec o ve re d fr o m all ra diati o n-relate d t o xicities a n d n ot re q uire 
c ortic oster oi ds. F or n o n - C N S disease, partici pa nts m ust ha ve rec o vere d fr o m all 
ra diati o n-relate d t o xicities, n ot re q uire c ortic oster oi ds, a n d n ot ha ve ha d ra diati o n 
p ne u m o nitis. A 1 -wee k was h o ut i s per mitte d f or palliati ve ra diati o n (≤2 wee ks of 
ra di ot hera py)  t o n o n-C N S disease.
1 8. Partici pa nts i n t he p hase 2 1 L + C R C e x pa nsi o n ( C o h ort 2 B) m ust ha ve a R A S wil d -
t ype ge n ot y pe i n pri mar y or metastatic t u m or tiss ue, base d o n e x pa n de d R A S hist oric 
or l ocal testi n g i ncl u di n g K R A S e x o n 2 (c o d o ns 1 2 a n d 1 3), e x o n 3 (c o d o ns 5 9 a n d 
6 1), a n d e x o n 4 (c o d o ns 1 1 7 a n d 1 4 6), a n d N R A S e x o n 2 (c o d o ns 1 2 a n d 1 3), e x o n 3 
(c o d o ns 5 9 a n d 6 1), a n d e x o n 4 (c o d o ns 1 1 7 a n d 1 4 6).
1 9. Partici pa nts m ust be willi n g a n d a ble t o a d here t o a nti diarr heal pr o p h yl a xis, if 
re q uire d. 
6. 2. E xcl usi o n Criteri a
1.
Hist or y  of k n o w n h yperse nsiti vit y  t o pla n ne d st u d y treat me nt:
a
All c o h orts: trast uz u ma b or c o m p o u n ds c he micall y  or bi ol o gically si milar t o 
t ucati ni b 
b
All c o h orts e xce pt f or C o h ort 1 G: o xali plati n, fl u or o p yri mi di nes, or le uc o v ori n
c
F or C o h orts 1 E, 1 F, 1 G or 2 A: se vere h y perse nsiti vit y  (≥Gra de 3) t o 
pe m br oliz u ma b 
Partici pa nts w h o ha ve ha d Gra de 1 or 2 i nf usi o n- relate d reacti o ns (I R Rs) t o 
o xali plati n, pe m br oliz u ma b, a n d/ or trast uz u ma b t hat were s ucces sf ull y ma na ge d ma y 
e nr oll. Partici pa nts wit h k n o w n aller g y  t o a ny of t he e xci pie nts i n t he st u d y 
treat me nt(s) ma y e nr oll, u nless se vere h yperse nsiti vit y  (≥Gra de 3) t o e xci pie nts has 
occ urre d. Partici pa nts wit h k n o w n h y perse nsiti vit y  or aller g y t o re q uire d c o nc o mita nt 
me dicati o ns are e xcl u de d.
2.
Partici pa nts i n C o h orts 1 A, 1 B, 1 C, a n d 2 B: Treat me nt wit h o xali plati n i n e xcess of 
t he li mitati o ns s pecifie d i n i ncl usi o n criteri o n 2
3.
Maj or s ur ger y  < 2 8 da ys pri or t o C ycle 1, Da y 1
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 7 9 of 2 2 0
4.
Partici pa nts i n t he P hase 1 b c o h orts wit h k n o w n acti ve C N S metastasis (irra diate d or 
resecte d lesi o ns are per mitte d, pr o vi de d t he lesi o ns are f ully treate d a n d i nacti ve, 
partici pa nt is as y m pt o matic, a n d n o ster oi ds ha ve bee n a d mi nistere d f or at least 3 0 
da y s). Partici pa nts i n C o h orts 2 A a n d 2 B wit h k n o w n acti ve C N S lesi o ns ma y  be 
i ncl u de d b ut m ust n ot ha ve a ny of t he f oll o wi n g:
a
A n y  u ntreate d brai n lesi o ns > 2. 0 c m i n size, u nless a p pr o ve d b y t he me dical 
m o nit or
b
A n y  brai n lesi o n t h o u g ht t o re q uire i m me diate l ocal t hera p y, i ncl u di n g ( b ut n ot 
li mite d t o) a lesi o n i n a n a nat o mic site w here i ncrease i n size or p ossi ble 
treat me nt-relate d e de ma ma y p ose ris k t o partici pa nt (e g, brai n ste m lesi o ns). 
Partici pa nts w h o u n der g o l ocal treat me nt f or s uc h lesi o ns i de ntifie d b y  scree ni n g 
brai n ma g netic res o na n ce i ma gi n g ( M RI) ma y still be eli gi ble f or t he st u d y
c
K n o w n or s us pecte d le pt o me ni n geal disease as d oc u me nte d b y t he i n vesti gat or 
d
Ha ve p o orl y c o ntr olle d ( > 1/ wee k) ge neralize d or c o m ple x partial seiz ures, or 
ma nifest ne ur ol o gic pr o gressi o n d ue t o brai n lesi o ns n ot wit hsta n di n g C N S -
directe d t hera p y 
5.
A n y  t o xicit y relate d t o pri or ca ncer t hera pies t hat has n ot res ol ve d t o ≤Gra de 1, wit h 
t he f oll o wi n g e xce pti o ns:

Al o pecia

Cli nicall y  i nsi g nifica nt electr olyt e a b n or malities

He m o gl o bi n < 8 g/ d L
6.
Cli nicall y  si g nifica nt car di o p ul m o nar y disease s uc h as:

Ve ntric ular arr h yt h mia re q uiri n g t hera p y

S y m pt o matic h y perte nsi o n or u nc o ntr olle d as y m pt o matic h y perte nsi o n 
≥1 5 0/ ≥9 0 m m H g des pite sta n dar d me dical ma na ge me nt, as deter mi ne d b y t he 
i n vesti gat or

A n y  hist or y of sy m pt o matic c o n gesti ve heart fail ure ( C H F), left ve ntric ular 
s yst olic d ysf u ncti o n, or decrease i n ejecti o n fracti o n

Se vere d ys p nea at rest ( N CI  C T C A E v 5. 0 Gra de 3 or a b o ve) d ue t o c o m plicati o ns 
of a d va nce d mali g na nc y  or h yp o xia re q uiri n g s u p ple me ntar y  o x yge n t hera p y, 
e xce pt w he n t hera p y is nee de d f or o bstr ucti ve slee p a p nea
7.
K n o w n m y ocar dial i nfarcti o n or u nsta ble a n gi na wit hi n 6 m o nt hs pri or t o e nr oll me nt
8.
K n o w n t o be p ositi ve f or he patitis C i nfecti o n ( p ositi ve b y  p ol ymerase c hai n reacti o n 
[ P C R]). Partici pa nts w h o ha ve bee n treate d f or he patitis C i nfecti o n are per mitte d if 
t he y ha ve d oc u me nte d s ustai ne d vir ol o gic res p o nse of at least 1 2 wee ks. 
K n o w n t o be p ositi ve f or he patitis B ( H B V) b y s urface a nti ge n ( h Bs A g) e x pressi o n. 
Partici pa nts w h o are p ositi ve f or e it her he patitis B s urface a nti b o d y ( h Bs A B) or 
a nti b o dies t o t he he patitis B c ore a nti ge n ( h Bc A B) s h o ul d be scree ne d usi n g P C R 
meas ure me nt of he patitis B D N A le vels. Partici pa nts wit h he patitis B D N A le vels b y  
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 0 of 2 2 0
P C R t hat re q uire n ucle osi de a nal o g ue t hera p y ar e n ot eli gi ble f or t he trial. T he latest 
l ocal g ui deli nes s h o ul d be f oll o we d re gar di n g t he m o nit ori n g of he patitis B D N A 
le vels b y P C R f or partici pa nts o n st u d y treat me nt.
9.
Prese nce of k n o w n c hr o nic li ver disease
1 0. K n o w n di h y dr o p y ri mi di ne de hy dr o ge nase defici e nc y (f or all c o h orts e xce pt f or 
C o h ort 1 G)
1 1. Partici pa nts k n o w n t o be p ositi ve f or h u ma n i m m u n o deficie nc y  vir us ( HI V) are 
e xcl u de d if t he y meet a n y of t he f oll o wi n g criteria:

C D 4 + T -cell c o u nt of < 3 5 0 cells/ µ L

Detecta ble HI V viral l oa d

Hist or y  of a n o p p ort unistic i nfecti o n wit hi n t he past 1 2 m o nt hs

O n sta ble a ntiretr o viral t hera p y f or < 4 wee ks
N ote: N o testi n g f or HI V is re q uire d u nless ma n date d b y a l ocal healt h a ut h orit y.
1 2. Partici pa nts w h o are pre g na nt, breastfee di n g, or pla n ni n g t o bec o me pre g na nt fr o m 
ti me of i nf or me d c o nse nt u ntil 7 m o nt hs f oll o wi n g t he last d ose of st u d y treat me nt
1 3. U na ble t o s wall o w pills or re q uires e nteral fee di n g or pare nteral n utriti o n
1 4. Ha ve use d a str o n g C Y P P 4 5 0 2 C 8 i n hi bit or wit hi n 5 half -li ves of t he i n hi bit or or 
ha ve use d a str o n g C Y P 2 C 8 or C Y P 3 A 4 i n d ucer wit hi n 5 da y s pri or t o e nr oll me nt
1 5. Ot her me dical, s ocial, or ps y c h os ocial fact ors t hat, i n t he o pi ni o n of t he i n vesti gat or, 
c o ul d i m pact safet y or c o m plia nce wit h st u d y  pr oce d ures
1 6. Has a n acti ve i nfecti o n re q uiri n g s ys te mic t hera p y.
1 7. Re q uire t hera p y wit h warfari n or ot her c o u mari n deri vati ves if recei vi n g C A P O X 
( C o h orts 1 C, 1 F, 2 A) as part of t his st u d y ( n o n-c o u mari n a ntic oa g ula nts are all o we d)
1 8. C urre ntl y  partici pati n g i n a n ot her i nter ve nti o nal trial
1 9. Partici pa nts e nr olle d i n C o h orts 1 E , 1 F, 1 G, a n d 2 A w h o ha ve u nresecta ble or 
metastatic, gastric, es o p ha geal, a n d G EJ a de n ocarci n o ma ca n n ot ha ve ha d pre vi o us 
c he m ot hera p y f or metastatic/ u nresecta ble disease; a dj u va nt or ne oa dj u va nt 
c he m ot hera p y, or bi ol o gic t hera p y is per mitte d if m ore t ha n 6 m o nt hs ha ve ela pse d 
bet wee n t he e n d of t hera p y  a n d first rec urre nce
2 0. Partici pa nts e nr olle d i n C o h ort 2 A a n d C o h ort 2 B ca n n ot ha ve recei ve d pri or a nti -
H E R 2 t hera pies
2 1. Ha ve recei ve d a li ve vacci ne < 3 0 da y s of e nr oll me nt 
2 2. Has o n g oi n g ≥ Gra de 2 diarr hea of a n y eti ol o g y at scree ni n g
2 3. Partici pa nts i n C o h orts 1 E, 1 F, 1 G: Has k n o w n acti ve C N S metastases a n d/ or 
carci n o mat o us me ni n gitis. Partici pa nts wit h pre vi o usl y  treate d brai n metastases ma y 
partici pate pr o vi de d t he y are ra di ol o gicall y  sta ble, (ie, wit h o ut e vi de nce of 
pr o gressi o n) f or at least 4 wee ks b y re peat i ma gi n g ( N ote: T he re peat i ma gi n g s h o ul d 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 1 of 2 2 0
be perf or me d d uri n g st u d y  scree ni n g.), cli nically s ta ble a n d wit h o ut re q uire me nt of 
ster oi d treat me nt f or at least 3 0 da ys bef ore t he first d ose of st u d y i nter ve nti o n. 
2 4. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has recei ve d pri or t hera p y  wit h a n a nti-P D - 1, 
a nti-P D -L 1, or a nti P D L 2 a ge nt or wit h a n a ge nt directe d t o a n ot her sti m ulat or y  or 
c o-i n hi bit or y T-cell rece pt or (e g, C T L A -4, O X 4 0, C D 1 3 7), a n d was disc o nti n ue d 
fr o m t hat treat me nt d ue t o a Gra de 3 or hi g her i m m u ne-relate d a d verse e ve nt (ir A E).
2 5. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has ha d a n all o ge neic tiss ue/s oli d or ga n 
tra ns pla nt.
2 6. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has a dia g n osis of i m m u n o d eficie nc y 
(e xcl u di n g HI V) or is recei vi n g c hr o nic sys te mic ster oi d t hera py (i n d osi n g e xcee di n g 
1 0 m g dail y of pre d nis o ne e q ui vale nt) or a n y ot her f or m of i m m u n os u p pressi ve 
t hera py wit hi n 7 da ys pri or t o t he first d ose of st u d y  treat me nt.
2 7. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has a k n o w n a d diti o nal mali g na nc y  t hat is 
pr o gressi n g or has re q uire d acti ve treat me nt wit hi n t he past 3 y ears. 
N ote: Partici pa nts wit h basal cell carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of 
t he s ki n, or carci n o ma i n sit u (e g, breast carci n o ma, cer vical ca ncer i n sit u) t hat ha ve 
u n der g o ne p ote ntiall y c urati ve t hera p y are n ot e xcl u de d.
2 8. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has a n acti ve a ut oi m m u ne disease t hat has 
re q uire d sys te mic treat me nt i n past 2 years (ie, wit h use of di sease m o dif yi n g a ge nts, 
c ortic oster oi ds or i m m u n os u p pressi ve dr u gs). Re place me nt t hera p y (e g, t h yr o xi ne, 
i ns uli n, or p h ysi ol o gic c ortic oster oi d re place me nt t hera p y f or a dre nal or pit uitar y 
i ns ufficie nc y) is n ot c o nsi dere d a f or m of sys te mic treat me nt a n d is all o we d.
2 9. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has a hist or y  of ( n o n-i nfecti o us) 
p ne u m o nitis/i nterstitial l u n g disease t hat re q uire d ster oi ds or has c urre nt 
p ne u m o nitis/i nterstitial l u n g disease.
3 0. Partici pa nts i n C o h orts 1 E, 1 F, 1 G, 2 A: Has recei ve d ra d iati o n t hera p y t o t he l u n g 
t hat is > 3 0 gra y  ( G y) wit hi n 6 m o nt hs of t he first d ose of trial treat me nt.
6. 3. C hil d be ari n g P ote nti al
A pers o n of c hil d beari n g p ote ntial is a n y o ne b or n fe male w h o has e x perie nce d me narc he a n d 
w h o has n ot u n der g o ne s ur gical steriliz ati o n (e g, h ysterect o my, bilateral sal pi n gect o m y, 
bilateral o o p h orect o m y ) or has n ot c o m plete d me n o pa use. Me n o pa use is defi ne d cli nically as 
1 2 m o nt hs of a me n orr hea i n a pers o n o ver a ge 4 5 i n t he a bse nce of ot her bi ol o gical, 
p h y si ol o gical, or p har mac ol o gical ca uses.
A pers o n w h o ca n fat her c hil dre n is a n y o ne b or n male w h o has testes a n d w h o has n ot 
u n der g o ne s ur gical sterilizati o n (e g, vasect o m y f oll o we d b y a cli nical test pr o vi n g t hat t he 
pr oce d ure was effecti ve).
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 2 of 2 2 0
6. 4. Re m o v al of P artici p a nts fr o m T her a p y or As sess me nt
Pfizer or t heir desi g nee m ust be n otifie d if a partici pa nt is wit h dra w n fr o m st u d y  treat me nt or 
fr o m t he st u d y. T he reas o n(s) f or wit h dra wal m ust be d oc u me nte d i n t he partici pa nt’s 
me dical rec or ds a n d electr o nic case re p ort f or m (e C R F).
6. 4. 1. Disc o nti n u ati o n of St u d y Tre at me nt
A partici pa nt’s st u d y treat me nt ma y  be disc o nti n ue d f or a ny of t he f oll o wi n g reas o ns:

Pr o gressi ve disease (acc or di n g t o R E CI S T v 1. 1), as assesse d b y  i n vesti gat or

Cli nical disease pr o gressi o n

A E

Pre g na nc y  or be gi ns t o breastfee d w hile o n st u d y

I n vesti gat or decisi o n

Partici pa nt decisi o n, n o n -A E 
N ote: E ns ure t hat partici pa nts w h o deci de t o st o p treat me nt bec a use of a n A E are 
n ot i ncl u de d i n t his rati o nale.

St u d y  ter mi nati o n b y s p o ns or

N o n -c o m plia nce wit h st u d y re q uire me nts

Ot her, n o n -A E
Partici pa nts w h o disc o nti n ue fr o m st u d y treat me nt will re mai n o n st u d y f or f oll o w - u p u nless 
t he y wit h dra w c o nse nt.
6. 4. 2. P artici p a nt Wit h dr a w al fr o m St u d y
A partici pa nt ma y  wit h dra w fr o m t he st u d y at a ny ti me at t heir o w n re q uest. Reas o ns f or 
per ma ne nt disc o nti n uati o n of st u d y i nter ve nti o n ma y  i ncl u de t he f oll o wi n g:

Partici pa nt wit h dra wal of c o nse nt

St u d y  ter mi nati o n b y s p o ns or

L ost t o f oll o w - u p

Deat h

Ot her
If a partici pa nt wit h dra ws fr o m t he st u d y, t he y ma y re q uest destr ucti o n of a n y re mai ni n g 
sa m ples ta ke n a n d n ot teste d, a n d t he i n vesti gat or m ust d oc u me nt a n y s uc h re q uests i n t he 
site st u d y rec or ds a n d n otif y t he s p o ns or acc or di n gl y. 
If t he partici pa nt wit h dra ws fr o m t he st u d y a n d als o wit h dra ws c o nse nt f or c ollecti o n of 
f ut ure i nf or mati o n, n o f urt her e val uati o ns will be perf or me d, a n d n o a d diti o nal data will be 
c ollecte d e xce pt f or p u blicl y a vaila ble i nf or mati o n as a p pr o priatel y directe d i n acc or da nce 
wit h l ocal la w. T he s p o ns or ma y  retai n a n d c o nti n ue t o use a ny data c ollecte d bef ore s uc h 
wit h dra wal of c o nse nt.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 3 of 2 2 0
6. 4. 3. Wit h dr a w al of C o nse nt
Partici pa nts w h o re q uest t o disc o nti n ue recei pt of st u d y i nter ve nti o n or wit h dra w c o nse nt will 
tra nsiti o n t o e n d of st u d y. Partici pa nts s h o ul d n otif y t he in vesti gat or i n writi n g of t he 
decisi o n t o wit h dra w c o nse nt fr o m f ut ure f oll o w u p, w he ne ver p ossi ble. 
T he wit h dra wal of c o nse nt s h o ul d be e x plai ne d i n detail i n t he me dical rec or ds b y  t he 
i n vesti gat or.
7. T R E A T M E N T S
7. 1. 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
1.
T he i n vesti gat or or desi g nee m ust c o nfir m t hat a p pr o priate c o n diti o ns (e g, 
te m perat ure) ha ve bee n mai ntai ne d d uri n g tra nsit f or all st u d y i nter ve nti o ns recei ve d 
a n d a n y discre pa ncies are re p orte d a n d res ol ve d bef ore use of t he st u d y i nter ve nti o n. 
2.
O nl y  partici pa nts e nr olle d i n t he st u d y ma y recei ve st u d y i nter ve nti o n a n d o nl y 
a ut h orize d site staff ma y  s u p pl y, pre pare, a n d/ or a d mi nister st u d y i nter ve nti o n. 
3.
All st u d y  i nter ve nti o ns m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d 
m o nit ore d ( ma n ual or a ut o mate d rec or di n g) area i n acc or da nce wit h t he la bele d 
st ora ge c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h orize d site staff. At 
a mi ni m u m, dail y mi ni m u m a n d ma xi m u m te m perat ures f or all site st ora ge l ocati o ns 
m ust be d oc u me nte d a n d a vaila ble u p o n re q uest. Data f or n o n w or ki n g da y s m ust 
i n dicate t he mi ni m u m a n d ma xi m u m te m perat ures si nce pre vi o usly d oc u me nte d u p o n 
ret ur n t o b usi ness.
4.
A n y  e xc ursi o ns fr o m t he st u d y i nter ve nti o n la bel st ora ge c o n diti o ns s h o ul d be 
re p orte d t o Pfizer up o n disc o ver y  al o n g wit h acti o ns ta ke n. T he site s h o ul d acti vely 
p urs ue o pti o ns f or ret ur ni n g t he st u d y i nter ve nti o n t o la bele d st ora ge c o n diti o ns as 
s o o n as p ossi ble. O nce a n e xc ursi o n is i de ntifie d, t he st u d y i nter ve nti o n m ust be 
q uara nti ne d a n d n ot use d u ntil Pfizer pr o vi des per missi o n t o use t he st u d y  
i nter ve nti o n. S pecific details re gar di n g t he e xc ursi o n defi niti o n a n d i nf or mati o n t o 
re p ort f or eac h e xc ursi o n will be pr o vi de d t o t he site i n t he p har mac y i nstr ucti o ns/IP 
Ma n ual. Te m perat ure e xc ursi o ns s h o ul d be re p orte d o nl y  f or ce ntrally s o urce d st u d y 
i nter ve nti o ns.
5.
A n y  st ora ge c o n diti o ns state d i n t he S R S D will be s u perse de d b y t he st ora ge 
c o n diti o ns state d o n t he la bel. Site staff will i nstr uct partici pa nts o n t he pr o per st ora ge 
re q uire me nts f or ta ke- ho me st u d y  i nter ve nti o n. See t he p har mac y  i nstr ucti o ns/IP 
Ma n ual
f or st ora ge c o n diti o ns of t he st u d y i nter ve nti o n.
6.
St u d y  i nter ve nti o ns s h o ul d be st ore d i n t heir ori gi nal c o ntai ners.
7.
T he i n vesti gat or, i nstit uti o n, hea d of t he me dical i nstit uti o n, ( w here a p pl ica ble) or 
a ut h orize d site staff is res p o nsi ble f or st u d y  i nter ve nti o n acc o u nta bilit y, 
rec o nciliati o n, a n d rec or d mai nte na nce (ie, recei pt, rec o nciliati o n, a n d fi nal 
dis p ositi o n rec or ds). All ce ntrall y s o urce d st u d y i nter ve nti o ns will be acc o u nte d f or 
usi n g a st u d y i nter ve nti o n acc o u nta bilit y f or m/rec or d. All u n use d t ucati ni b st u d y 
i nter ve nti o n t hat is ta ke n h o me b y t he partici pa nt, m ust be ret ur ne d t o t he i n vesti gat or 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 4 of 2 2 0
b y  t he partici pa nt. Ret ur ne d t uc ati ni b st u d y i nter ve nti o n m ust n ot be re dis pe nse d 
t o t he p artici p a nts.
8.
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 ns are pr o vi de d i n t he p har mac y i nstr ucti o ns/IP Ma n ual. All destr ucti o n 
m ust be a de q uatel y d oc u me nte d. If destr ucti o n is a ut h orize d t o ta ke place at t he 
i n vesti gat or site, t he i n vesti gat or m ust e ns ure t hat t he materials are destr o ye d i n 
c o m plia nce wit h a p plica ble e n vir o n me ntal re g ulati o ns, i nstit uti o nal p olic y , a n d a n y 
s pecial i nstr ucti o ns pr o vi de d b y Pfizer.
U p o n i de ntificati o n of a pr o d uct c o m plai nt, n otif y t he s p o ns or wit hi n 1 b usi ness da y of 
disc o ver y .
7. 2. Si n gle Refere nce S afet y D oc u me nts
Si n gle refere nce safet y d oc u me nts ( S R S D) f or eac h of t he st u d y i nter ve nti o ns are 
s u m marize d i n Ta ble 6.
T a ble 6 . 
Si n gle Refere nce S afet y D oc u me nts f or St u d y I nter ve nti o ns
St u d y I nter ve nti o n
S R S D
T ucati ni b
I n vesti gat or’s br oc h ure
Le uc o v ori n or Le v ole uc o v ori n
Le uc o v ori n: U K S m P C 
or
Le v ole uc o v ori n: Fre nc h S m P C
O xali plati n
Iris h S m P C
5- Fl u or o uracil
Iris h S m P C
Ca pecita bi ne
E U S m P C
Trast uz u ma b
E U S m P C
Pe m br oliz u ma b
I n vesti gat or’s br oc h ure
L o pera mi de
Lit h ua nia n S m P C
7. 3. Tre at me nts A d mi nistere d
7. 3. 1. T uc ati ni b, Tr ast uz u m a b, a n d F O L F O X ( C o h orts 1 A, 1 B, 1 D, 2 B)
As s h o w n i n Ta ble 5 , partici pa nts i n t he st u d y will recei ve c o m bi nati o n t hera p y of t ucati ni b 
wit h trast uz u ma b a n d m F O L F O X 6 ( Ta ble 7 ) or m F O L F O X 7 i n 1 4-d a y  c ycles (Ta ble 8 ). I n 
C o h orts 1 A a n d 1 B, F O L F O X ma y  be a d mi nistere d usi n g eit her t he m F O L F O X 6 or 
m F O L F O X 7 re gi me n b ut s h o ul d re mai n c o nsiste nt t hr o u g h o ut st u d y partici pati o n. I n 
C o h orts 1 D a n d 2 B, partici pa nt s will recei ve m F O L F O X 6. I n C o h orts 1 A a n d 1 B, 
partici pa nts will recei ve trast uz u ma b a n d F O L F O X starti n g o n C ycle 1 Da y 1, w hile t he first 
d ose of t ucati ni b will be a d mi nistere d o n C y cle 1 Da y 8. I n C o h orts 1 D a n d 2 B, t ucati ni b, 
trast uz u ma b a n d F O L F O X will be a d mi nistere d starti n g o n C ycl e 1 Da y 1. T he starti n g d ose 
of t ucati ni b i n C o h ort 1 A is 1 5 0 m g P O BI D i n 1 4- d a y c y cles. T he starti n g d ose of t ucati ni b 
i n C o h ort 1 B is 3 0 0 m g P O BI D or a n alter nati ve d ose le vel as rec o m me n de d b y t he S M C. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 5 of 2 2 0
T he d ose of t uca ti ni b i n C o h orts 1 D a n d 2 B will be deter mi ne d b y S M C re vie w of data fr o m 
C o h ort 1 A a n d 1 B.
T a ble 7 . 
T uc ati ni b a n d m F O L F O X 6 A d mi nistere d i n 1 4- d a y C ycles Wit h 
Tr ast uz u m a b ( C o h orts 1 A, 1 B, 1 D, 2 B)
Dr u g
D ose/ R o ute
A d mi nistrati o n
Da y s
T ucati ni b
1 5 0 -3 0 0 m g a P O 
BI D
Dail y
O xali plati n
8 5 m g/ m 2 I V
A d mi nister o ver 2 h
Da y  1
Le uc o v ori n b
4 0 0 m g/ m 2 I V
A d mi nister o ver 2 h 
c o nc urre nt wit h 
o xali plati n
Da y  1
Fl u or o uracil
4 0 0 m g/ m 2 I V
B ol us
Da y  1
Fl u or o uracil
2 4 0 0 m g/ m 2 I V
A d mi nister o ver 4 6 h
Da y  1
Trast uz u ma b Q 2 W: 
C o h orts 1 A a n d 1 B
6 m g/ k g I V (l oa di n g 
d ose)
A d mi nister o ver 9 0 mi n
Da y  1 ( C ycle 1 o nl y)
4 m g/ k g I V
A d mi nister o ver 3 0 mi n
Da y  1 of e ver y 
s u bse q ue nt c ycle
Trast uz u ma b : Q 3 W:
C o h orts 1 D a n d 2 B
8 m g/ k g I V (l oa di n g 
d ose)
A d mi nister o ver 9 0 mi n
Da y  1 ( C ycle 1 o nl y)
6 m g/ k g I V
A d mi nister o ver 3 0 mi n
Da y  1 of e ver y 
s u bse q ue nt c ycle
a D ose t o be base d o n t he R P 2 D fr o m d ose escalati o n
b Le v ole uc o v ori n ( 2 0 0 m g/ m 2) ca n be s u bstit ute d base d o n i n vesti gat or prefere nce i n cases of s u p pl y 
s h orta ges. Le v ole uc o v ori n is d ose d at 1-half t he us ual d ose of race mic d,l -le uc o v ori n.
T a ble 8 .
T uc ati ni b, m F O L F O X 7 , a n d Tr ast uz u m a b A d mi nistere d i n 1 4-d a y 
C ycles ( C o h orts 1 A a n d 1 B O nl y)
Dr u g
D ose/ R o ute
A d mi nistrati o n
Da y s
T ucati ni b
1 5 0 -3 0 0 m g a P O 
BI D
Dail y starti n g fr o m 
C y cle 1 Da y 8
O xali plati n
8 5 m g/ m 2 I V
A d mi nister o ver 2 h
Da y  1
Le uc o v ori n b
2 0 0 m g/ m 2 I V
A d mi nister o ver 2 h 
c o nc urre nt wit h 
o xali plati n
Da y  1
Fl u or o uracil
2 4 0 0 m g/ m 2 I V
A d mi nister o ver 4 6 h
Da y  1
Trast uz u ma b
6 m g/ k g I V (l oa di n g 
d ose)
A d mi nister o ver 9 0 mi n
Da y  1 ( C ycle 1 o nl y)
Trast uz u ma b
4 m g/ k g I V
A d mi nister o ver 3 0 mi n
Da y  1 of e ver y 
s u bse q ue nt c ycle
a D ose t o be base d o n t he R P 2 D fr o m d ose escalati o n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 6 of 2 2 0
T a ble 8 .
T uc ati ni b, m F O L F O X 7 , a n d Tr ast uz u m a b A d mi nistere d i n 1 4-d a y 
C ycles ( C o h orts 1 A a n d 1 B O nl y)
Dr u g
D ose/ R o ute
A d mi nistrati o n
Da y s
b Le v ole uc o v ori n ( 1 0 0 m g/ m 2) ca n be s u bstit ute d base d o n i n vesti gat or prefere nce i n cases of s u p pl y 
s h orta ges. Le v ole uc o v ori n is d ose d at 1-half t he us ual d ose of race mic d,l -le uc o v ori n.
7. 3. 2. T uc ati ni b, Tr ast uz u m a b, a n d C A P O X ( C o h ort 1 C)
Partici pa nts i n C o h ort 1 C will recei ve c o m bi nati o n t hera p y of t ucati ni b wit h trast uz u ma b a n d 
C A P O X i n 2 1 -da y  c ycles (Ta ble 9). T he first d ose of t ucati ni b will be a d mi nistere d o n 
C y cle 1 Da y  1. T he d ose of t ucati ni b will be deter mi ne d b y S M C re vie w of data fr o m C o h ort 
1 A a n d 1 B.
T a ble 9 . 
T uc ati ni b, C A P O X, a n d Tr ast uz u m a b A d mi nistere d i n 2 1-d a y C yc les 
( C o h ort 1 C)
Dr u g
D ose/ R o ute
A d mi nistrati o n
Da y s
T ucati ni b
3 0 0 m g a P O 
BI D
Dail y starti n g fr o m C ycle 1 Da y 1
O xali plati n
1 3 0 m g/ m 2 I V
A d mi nister o ver 2 h
Da y  1
Ca pecita bi ne b
1 0 0 0 m g/ m 2, P O
BI D
C y cle 1: E ve ni n g of Da y 1 t o 
m o r ni n g of Da y 1 5
C y cle 2 a n d eac h s u bse q ue nt c ycle: 
Da y  1 - Da y  1 4
Trast uz u ma b
8 m g/ k g I V (l oa di n g 
d ose)
A d mi nister o ver 
9 0 mi n
Da y  1 ( C ycle 1 o nl y)
Trast uz u ma b
6 m g/ k g I V
A d mi nister o ver 
3 0 mi n
Da y  1 of e ver y s u bse q ue nt c ycle
a D ose t o be base d o n w hat t he R P 2 D fr o m d ose escalati o n
b Starti n g d ose of ca pecita bi ne ma y be re d uce d per i n vesti gat or prefere nce or i nstit uti o nal sta n dar ds u p o n 
a p pr o val b y me dical m o nit or b ut will n ot be l o wer t ha n 8 5 0 m g/ m 2 P O BI D.
7. 3. 3. T uc ati ni b, Tr ast uz u m a b, F O L F O X , a n d Pe m br oliz u m a b ( C o h orts 1 E, 2 A)
Partici pa nts i n C o h orts 1 E a n d 2 A will recei ve c o m bi nati o n t hera p y  wit h t ucati ni b a n d 
m F O L F O X 6 ( Ta ble 1 0 ) i n 1 4-d a y c y cles. Trast u z u ma b will be gi ve n i n 2 1 -d a y c y cles, a n d 
pe m br oliz u ma b i n 4 2 -da y c y cles. T he first d ose of t ucati ni b will be a d mi nistere d o n C ycle 1 
D a y  1. T he d ose of t ucati ni b will be deter mi ne d b y S M C re vie w of data fr o m C o h ort 1 A a n d 
1 B.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 7 of 2 2 0
T a ble 1 0 .
T uc ati ni b a n d m F O L F O X 6 A d mi nistere d i n 1 4- d a y C ycles Wit h 
Tr ast uz u m a b ( Q 3 W) a n d Pe m br oliz u m a b ( Q 6 W) ( C o h orts 1 E, 2 A)
Dr u g
D ose/ R o ute
A d mi nistrati o n
Da y s
T ucati ni b
3 0 0 m g a P O 
BI D
Dail y
O xali plati n
8 5 m g/ m 2 I V
A d mi nister o ver 2 h
Da y  1
Le uc o v ori n b
4 0 0 m g/ m 2 I V
A d mi nister o ver 2 h 
c o nc urre nt wit h 
o xali plati n
Da y  1
Fl u or o uracil
4 0 0 m g/ m 2 I V
B ol us
Da y  1
Fl u or o uracil
2 4 0 0 m g/ m 2 I V
A d mi nister o ver 4 6 h
Da y  1
Trast uz u ma b
8 m g/ k g I V (l oa di n g 
d ose)
A d mi nister o ver 9 0 mi n
Da y  1 ( C ycle 1 o nl y)
Trast uz u ma b
6 m g/ k g I V
A d mi nister o ver 3 0 mi n
Q 3 W after l oa di n g d ose
Pe m br oliz u ma b
4 0 0 m g I V
A d mi nister o ver 3 0 mi n
C y cle 1: Da y 1, t he n 
Q 6 W
a D ose t o be base d o n t he R P 2 D fr o m d ose escalati o n
b Le v ole uc o v ori n ( 2 0 0 m g/ m 2) ca n be s u bstit ute d base d o n i n vesti gat or prefere nce i n cases of s u p pl y 
s h orta ges. Le v ole uc o v ori n is d ose d at 1-half t he us ual d ose of race mic d,l -le uc o v ori n.
7. 3. 4. T uc ati ni b, Tr ast uz u m a b, C A P O X, a n d Pe m br oliz u m a b ( C o h orts 1 F, 2 A)
Partici pa nts i n C o h ort 1 F a n d 2 A will recei ve c o m bi nati o n t hera p y wit h t ucati ni b, 
trast uz u ma b, a n d C A P O X i n 2 1-d a y c y cles (Ta ble 1 1 ). Pe m br oliz u ma b will be gi ve n i n 4 2-
da y  c ycles. T he first d ose of t ucati ni b will be a d mi nistere d o n C y cle 1 Da y 1 i n C o h ort 1 F. 
T he first d ose of t ucati ni b i n C o h ort 2 A will be a d mi nistere d o n C y cle 1 Da y 1.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 8 of 2 2 0
T a ble 1 1 .
T uc ati ni b, C A P O X, a n d tr ast uz u m a b, a n d a d mi nistere d i n 2 1-d a y c ycles 
wit h Pe m br oliz u m a b ( Q 6 W) ( C o h orts 1 F, 2 A)
Dr u g
D ose/ R o ute
A d mi nistrati o n
Da y s
T ucati ni b
3 0 0 m g a P O 
BI D
Dail y
O xali plati n
1 3 0 m g/ m 2 I V
A d mi nister o ver 2 h
Da y  1
Ca pecita bi ne b
1 0 0 0 m g/ m 2, P O
BI D
C y cle 1: E ve ni n g of Da y 1 t o 
m o r ni n g of Da y 1 5
C y cle 2 a n d eac h s u bse q ue nt c ycle: 
Da y  1 - Da y  1 4
Trast uz u ma b
8 m g/ k g I V (l oa di n g 
d ose)
A d mi nister o ver 
9 0 mi n
Da y  1 ( C ycle 1 o nl y)
Trast uz u ma b
6 m g/ k g I V
A d mi nister o ver 
3 0 mi n
Da y  1 of e ver y s u bse q ue nt c ycle
Pe m br oliz u ma b
4 0 0 m g I V
A d mi nister o ver 
3 0 mi n
C y cle 1 Da y 1, t he n Q 6 W
a D ose t o be base d o n t he R P 2 D fr o m d ose escalati o n
b Starti n g d ose of ca pecita bi ne ma y be re d uce d per i n vesti gat or prefere nce or i nstit uti o nal sta n dar ds u p o n 
a p pr o val b y me dical m o nit or b ut will n ot be l o wer t ha n 8 5 0 m g/ m 2 P O BI D.
7. 3. 5. T uc ati ni b, Tr ast uz u m a b, a n d Pe m br oliz u m a b ( C o h ort 1 G)
Partici pa nts i n C o h ort 1 G will recei ve c o m bi nati o n t hera p y wit h t ucati ni b a n d trast uz u ma b i n 
2 1 -d a y c y cles (Ta ble 1 2 ). Pe m br oliz u ma b will be gi ve n i n 4 2-d a y  c ycles. T he first d ose of 
t ucati ni b will be a d mi nistere d o n Cycle 1 Da y 1.
T a ble 1 2 .
T uc ati ni b, tr ast uz u m a b a d mi nistere d i n 2 1-d a y c ycles a n d 
pe m br oliz u m a b ( C o h ort 1 G)
Dr u g
D ose/ R o ute
A d mi nistrati o n
Da y s
T ucati ni b
3 0 0 m g a P O 
BI D
Dail y
Trast uz u ma b
8 m g/ k g I V (l oa di n g d ose)
A d mi nister o ver 9 0 mi n
Da y  1 ( C ycle 1 o nl y)
Trast uz u ma b
6 m g/ k g I V
A d mi nister o ver 3 0 mi n
Da y  1 of e ver y s u bse q ue nt 
c ycle
Pe m br oliz u ma b
4 0 0 m g I V
A d mi nister o ver 3 0 mi n
C y cle 1 Da y 1, t he n Q 6 W
a D ose t o be base d o n t he R P 2 D fr o m d ose escalati o n
7. 4. I n vesti g ati o n al Pr o d uct ( T uc ati ni b)
Detaile d i nf or mati o n descri bi n g t he pre parati o n, a d mi nistrati o n, a n d st ora ge of t ucati ni b is 
l ocate d i n t he P har mac y I nstr ucti o ns/IP Ma n ual.
St u d y  pers o n nel s h o ul d i nstr uct partici pa nts o n t ucati ni b a d mi nistrati o n tec h ni q ues a n d dr u g 
diar y  pri or t o t he first d ose of t ucati ni b a n d e ns ure t hat t he partici pa nt u n dersta n ds t hese 
i nstr ucti o ns bef ore gra nti n g treat me nt i n de pe n de nce. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 8 9 of 2 2 0
7. 4. 1. Descri pti o n
T ucati ni b dr u g pr o d uct is s u p plie d as b ot h a c oate d y ell o w o val -s ha pe d ta blet i n a 1 5 0 m g 
d osa ge stre n gt h a n d a c oate d yell o w r o u n d c o n ve x ta blet i n a 5 0 m g d osa ge stre n gt h. T he 
ta blets are ma n ufact ure d fr o m a dr u g pr o d uct
of t ucati ni b 
i n 
c o p ol y m er, w hic h is t he n c o m bi ne d wit h t he 
p har mace utical e xci pie nts ( micr ocr y stalli ne cell ul ose, s o di u m c hl ori de, p otassi u m c hl ori de, 
s o di u m bicar b o nate, silic o n di o xi de, cr os p o vi d o ne, a n d ma g nesi u m stearate), a n d 
c o m presse d i nt o ta blets.
7. 4. 2.
Met h o d of Pr oc ure me nt
T he i n vesti gati o nal st u d y i nter ve nti o n (t ucati ni b) will be pr o vi de d b y  t he s p o ns or.
7. 4. 3. D ose a n d A d mi nistr ati o n
T he i n vesti gati o nal st u d y i nter ve nti o n (t ucati ni b) will be a d mi nistere d P O BI D. Partici pa n ts 
will be i nstr ucte d b y  t he p har macist or i n vesti gat or as t o t he s pecific n u m ber of ta blets 
re q uire d f or eac h d ose. At eac h visit d uri n g st u dy t reat me nt, partici pa nts will be s u p plie d 
wit h t he a p pr o priate n u m ber of ta blets f or t he n u m ber of d oses t o be ta ke n pri or t o t he ne xt 
sc he d ule d visit. 
Partici pa nts will be i nstr ucte d t o ta ke t ucati ni b ta blets t wice eac h da y  ( o nce i n t he m or ni n g, 
a n d o nce i n t he e ve ni n g) a p pr o xi matel y  8 t o 1 2 h o urs bet wee n d oses i n t he sa me cale n dar 
da y . It is rec o m me n de d t hat if a partici pa nt misses a sc he d ule d d ose of t ucati ni b a n d less t ha n 
6 h o urs ha ve passe d si nce t he sc he d ule d d osi n g ti me, t he d ose s h o ul d be i m me diatel y  ta ke n. 
It is rec o m me n de d t hat if m ore t ha n 6 h o urs ha ve passe d si nce t he sc he d ule d d osi n g ti me, t he 
partici pa nt s h o ul d n ot ta ke t he misse d d ose b ut s h o ul d wait a n d ta ke t he ne xt re g ularl y 
sc he d ule d d ose. Ta blets ma y be ta ke n wit h or wit h o ut f o o d. Ta blets m ust be s wall o we d 
w h ole a n d ma y  n ot be cr us he d, c he we d or diss ol ve d i n li q ui d. O n t he da y of d osi n g, t he 
i n di vi d ual u nit d ose of t he t ucati ni b ta blet ma y be e x p ose d t o a m bie nt te m perat ure f or u p t o 6 
h o urs pri or t o d ose. 
C o m plete d osi n g i nstr ucti o ns will be pr o vi de d t o t he p har macist pri or t o t he i nitiati o n of t he 
st u d y. C o m plete d osi n g i nstr ucti o ns will als o be pr o vi de d t o st u d y  partici pa nts a n d will 
i ncl u de t he mi ni m u m ti mes bet wee n d oses, d osi n g i n relati o n t o meals, a n d i nstr ucti o ns f or 
misse d d oses. Partici pa nts will be i nstr ucte d t o ta ke t heir m or ni n g d ose of t ucati ni b i n t he 
cli nic at t he start of t he o xali plati n i nf usi o n o n da ys w he n sa m ples will be c ollecte d f or P K 
a nal ys is ( Secti o n 9. 3 ). Partici pa nt c o m plia nce wit h i n vesti gati o nal st u d y i nter ve nti o n dosi n g 
i nstr ucti o ns will be assesse d wit h t he use of partici pa nt diaries a n d st u d y i nter ve nti o n 
acc o u nta bilit y.
D ose m o dificati o ns of t ucati ni b are descri be d i n Secti o n 7. 9 .
7. 4. 4. St or a ge a n d H a n dli n g
Ta blets of t ucati ni b are pac ka ge d i n r o u n d, hi g h -de nsit y  p olyet h yl e ne b ottles c o ntai ni n g a 
desicca nt, wit h a n i n d ucti o n seale d li ner a n d c hil d -resista nt plastic cl os ure ca p. B ottles of 
t ucati ni b ta blets are t o be st ore d u n der refri gerati o n at 2– 8° C i n a sec ure, access -li mite d 
l ocati o n.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)
C CI
C CI

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 0 of 2 2 0
T he ta blets are c oate d wit h a n o n -hazar d o us fil m t o pre ve nt a n y e x p os ure t o t he acti ve 
p har mace utical i n gre die nt d uri n g r o uti ne ha n dli n g. A v oi d brea ki n g or cr us hi n g ta blets. I n t he 
e ve nt t he ta blets are br o ke n or cr us he d, was h ha n ds a n d e x p ose d s ki n t h or o u g hl y wit h s oa p 
a n d water. 
Refer t o t he P har mac y  Instr ucti o ns/I P Ma n ual f or m ore i nf or mati o n.
7. 4. 5. P ac k a gi n g a n d L a beli n g
Eac h b ottle of i n vesti gati o nal st u d y  i nter ve nti o n will be la beled i n c o m plia nce wit h 
a p plica ble re g ulat or y re q uire me nts.
7. 4. 6. Pre p ar ati o n a n d Dis pe nsi n g
A q ualifie d staff me m ber will dis pe nse t he t ucati ni b st u d y  i nter ve nti o n via t he IR T s yste m i n 
t he b ottles pr o vi de d, i n q ua ntities a p pr o priate acc or di n g t o t he S O E. T he partici pa nt s h o ul d 
be i nstr ucte d t o mai ntai n t he pr o d uct i n t he b ottle pr o vi de d t hr o u g h o ut t he c o urse of d osi n g 
a n d ret ur n t he b ottle t o t he site at t he ne xt st u d y  visit.
7. 4. 7. St u d y I nter ve nti o n Acc o u nt a bilit y
T ucati ni b use d d uri n g t he c o urse of t he st u d y s h o ul d be ha n dle d acc or di n g t o t he P har mac y 
I nstr ucti o ns/IP Ma n ual. T ucati ni b ta blets are t o be trac ke d a n d d oc u me nte d fr o m t he ti me of 
recei pt at t he site, t hr o u g h partici pa nt d osi n g, a n d u ntil t he s p o ns or a p pr o ves of t he fi nal 
ret ur n or destr ucti o n. All s u p plies, i ncl u di n g partiall y use d or e m pt y b ottles, s h o ul d be 
trac ke d.
T he s p o ns or or desi g nee will c o n d uct dr u g acc o u nta bilit y  m o nit ori n g d uri n g t he c o urse of t he 
st u d y acc ordi n g t o t he St u d y  O perati o ns Ma n ual. All use d a n d u n use d b ottles of t ucati ni b 
s h o ul d be ha n dle d acc or di n g t o t he s p o ns or’s i nstr ucti o ns a n d dis p ose d acc or di n g t o t he 
P har mac y  Instr ucti o ns/I P ma n ual.
7. 5. F O L F O X Re gi me n ( C o h orts 1 A, 1 B, 1 D, 1 E, 2 A, a n d 2 B)
7. 5. 1. Descr i pti o n
O xali plati n is a plati n u m a nal o g t hat bl oc ks D N A re plicati o n. It is i n dicate d f or treat me nt of 
a d va nce d gastric ca ncer a n d C R C. Fl u or o uracil is a n i n hi bit or of n ucleic aci d s y nt hesis t hat is 
i n dicate d f or treat me nt of a d va nce d carci n o ma of t he c ol o n, rect u m, breast, st o mac h, a n d 
pa ncreas. Le uc o v ori n, als o k n o w n as f oli nic aci d, is a deri vati ve of f olic aci d i n dicate d f or 
treat me nt of a d va nce d gastric ca ncer a n d C R C i n c o m bi nati o n wit h fl u or o uracil. F O L F O X 
will be a d mi nistere d i n t his st u d y  usi n g eit her t he m F O L F O X 6 or m F O L F O X 7 re gi me n i n 
C o h orts 1 A a n d 1 B; o nl y m F O L F O X 6 will be use d i n C o h orts 1 D, 1 E, 2 A, a n d 2 B. 
7. 5. 2.
Met h o d of Pr oc ure me nt
Details re gar di n g s o urci n g of F O L F O X c he m ot hera p y  a ge nts ma y var y b y site a n d/ or re gi o n 
as o utli ne d i n ot her d oc u me nt s s uc h as Cli nical Trial A gree me nts. 
7. 5. 3. D ose a n d A d mi nistr ati o n
F or pre parati o n a n d c o m plete prescri bi n g i nf or mati o n f or F O L F O X c he m ot hera p y  a ge nts, 
please refer t o t he m ost c urre nt l ocal pr o d uct la beli n g.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 1 of 2 2 0
A d mi nistrati o n of F O L F O X will c o m me nce o n Da y  1 of eac h treat me nt c ycle a n d will be 
a d mi nistere d e ver y 2 wee ks as descri be d i n Ta ble 7 a n d Ta ble 8 . O xali plati n 8 5 m g/ m 2 a n d 
le uc o v ori n 4 0 0 m g/ m 2 ( F O L F O X 6) or 2 0 0 m g / m2 ( F O L F O X 7) will be a d mi nistere d I V o ver 
1 2 0 mi n ( ± 1 5 mi n). F or m F O L F O X 6, after c o m pleti o n of t he le uc o v ori n a n d o xali plati n 
i nf usi o ns, fl u or o uracil 4 0 0 m g/ m 2 (I V b ol us), t he n fl u or o uracil 2 4 0 0 m g / m2 will be 
a d mi nistere d I V o ver 4 6 h o urs ( ± 1 h o ur). F or m F O L F O X 7, after c o m pleti o n of t he 
le uc o v ori n a n d o xali plati n i nf usi o ns, fl u or o uracil 2 4 0 0 m g/ m 2 will be a d mi nist ere d I V o ver 
4 6 h o urs. F or b o d y wei g ht c ha n ges, d oses s h o ul d be recalc ulate d acc or di n g t o i nstit uti o nal 
sta n dar d of care. 
7. 5. 4. St or a ge a n d H a n dli n g
F O L F O X c he m ot hera p y a ge nts s h o ul d be st ore d i n acc or da nce wit h ma n ufact urer, s u p plier, 
a n d i nstit uti o nal pr oce d u res.
7. 5. 5. Pre p ar ati o n a n d Dis pe nsi n g
F or pre parati o n a n d c o m plete prescri bi n g i nf or mati o n f or F O L F O X c he m ot hera p y  a ge nts, 
please refer t o t he m ost c urre nt l ocal pr o d uct la beli n g.
St u d y  i nter ve nti o n s h o ul d be pre pare d a n d dis pe nse d b y a n a p pr o priately q ualifie d a n d 
e x perie nce d me m ber of t he st u d y  staff (e g, p h ysicia n, n urse, p h ysicia n’s assista nt, n urse 
practiti o ner, p har mac y  assista nt/tec h nicia n, or p har macist) as all o we d b y l ocal, state, a n d 
i nstit uti o nal g ui da nce. 
O nl y  q ualifie d pers o n nel w h o are fa miliar with pr oce d ures t hat mi ni mize u n d ue e x p os ure t o 
t he msel ves a n d t o t he e n vir o n me nt s h o ul d u n derta ke t he pre parati o n, ha n dli n g, a n d safe 
dis p osal of t he F O L F O X c he m ot hera p y a ge nts.
7. 6. C A P O X Re gi me n ( C o h orts 1 C, 1 F, a n d 2 A)
7. 6. 1. Descri pti o n
C A P O X c o nsists of ca pecita bi n e a n d o xali plati n. Ca pecita bi ne is a pr o dr u g of fl u or o uracil. I t 
u n der g oes h y dr ol ys is i n t he li ver a n d tiss ues t o f or m fl u or o uracil w hic h is t he acti ve m oiety. 
Fl u or o uracil is a fl u ori nate d p y ri mi di ne a nti meta b olite t hat i n hi bits t h ymi d y late s ynt hetase, 
bl oc ki n g t he met h yl ati o n of de o x yuri d yl ic aci d t o t h ymi d y lic aci d, i nterferi n g wit h D N A, a n d 
t o a lesser de gree, R N A s y nt hesis. O xali plati n is a plati n u m a nal o g t hat bl oc ks D N A 
re plicati o n.
7. 6. 2.
Met h o d of Pr oc ure me nt
Details re gar di n g s o urci n g of C A P O X c he m ot hera p y  a ge nts ma y var y b y site a n d/ or re gi o n 
as o utli ne d i n ot her d oc u me nts s uc h as Cli nical Trial A gree me nts. 
7. 6. 3. D ose a n d A d mi nistr ati o n
Ca pecita bi ne will be gi ve n at 1 0 0 0 m g/ m 2 P O BI D fr o m t he e ve ni n g of Da y 1 u ntil t he 
m or ni n g of Da y  1 5 ( Cycl e 1) a n d P O BI D D a y 1-Da y  1 4 f or all s u bse q ue nt c ycles. T he 
starti n g d ose of ca pecita bi ne ma y be re d uce d per i n vesti gat or prefere nce or i nstit uti o nal 
sta n dar ds u p o n a p pr o val b y t he me dical m o nit or b ut will n ot be l o wer t ha n 8 5 0 m g/ m 2 P O 
BI D. As ca pecita bi ne is a n oral dr u g a vaila ble i n fi xe d d oses, t he d ose a d mi nistere d ma y  n ot 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 2 of 2 2 0
e xactl y matc h t he calc ulate d d ose. Deter mi nati o n of t he r o u n di n g of ca pecita bi ne d oses f or 
a d mi nistrati o n s h o ul d be ma de acc or di n g t o l ocal i nstit uti o nal practices, wit h d oc u me ntati o n 
of b ot h t he cal c ulate d a n d a d mi nistere d d ose.
O xali plati n will be gi ve n at 1 3 0 m g/ m 2 I V o n Da y 1 of eac h 2 1-d a y  c ycle.
7. 6. 4. St or a ge a n d H a n dli n g
Ca pecita bi ne a n d o xali plati n s h o ul d be ha n dle d a n d st ore d acc or di n g t o t he l ocal pr o d uct 
la beli n g.
7. 6. 5. Pre p ar ati o n a n d Dis pe nsi n g
F or pre parati o n a n d c o m plete prescri bi n g i nf or mati o n f or C A P O X c he m ot hera p y  a ge nts, 
please refer t o t he m ost c urre nt l ocal pr o d uct la beli n g.
St u d y  i nter ve nti o n s h o ul d be pre pare d a n d dis pe nse d b y a n a p pr o priately q ualifie d a n d 
e x perie nce d me m ber of t he st u d y  staff (e g, p h ysicia n, n urse, p h ysicia n’s assista nt, n urse 
practiti o ner, p har mac y  assista nt/tec h nicia n, or p har macist) as all o we d b y l ocal, state, a n d 
i nstit uti o nal g ui da nce. 
O nl y  q ualifie d pers o n nel w h o are fa miliar wit h pr oce d ures t hat mi ni mize u n d ue e x p os ure t o 
t he msel ves a n d t o t he e n vir o n me nt s h o ul d u n derta ke t he pre parati o n, ha n dli n g, a n d safe 
dis p osal of t he C A P O X c he m ot hera p y a ge nts.
7. 7. Tr ast uz u m a b
7. 7. 1. Descri pti o n
Trast uz u ma b is a h u ma nize d I g- 1 ka p pa m o n ocl o nal a nti b o d y  t hat bi n ds t o t he e xtracell ular 
d o mai n of H E R 2; it me diates a nti b o d y -de pe n de nt cell ular c y t ot o xicit y b y i n hi biti n g 
pr oliferati o n of cells t hat o ver e x press H E R 2 pr otei n.
7. 7. 2.
Met h o d of Pr oc ure me nt
Details re gar di n g s o urci n g of trast uz u ma b ma y  var y b y site a n d/ or re gi o n as o utli ne d i n ot her 
d o c u me nts s uc h as Cli nical Trial A gree me nts.
7. 7. 3. D ose a n d A d mi nistr ati o n
I n C o h orts 1 A a n d 1 B, trast uz u ma b will be gi ve n as a l oa di n g d ose of 6 m g/ k g I V ( o ver 
9 0 mi n) f oll o we d b y  4 m g / k g ( o ver 3 0 mi n) e ver y 2 wee ks (Ta ble 7 , Ta ble 8 ). I n all ot her 
c o h orts, trast uz u ma b will be gi ve n as a l oa di n g d ose of 8 m g/ k g I V ( o ver 9 0 mi n) f oll o we d 
b y 6 m g / k g ( o ver 3 0 mi n) Q 3 W (Ta ble 7 , Ta ble 8 , Ta ble 9 , Ta ble 1 0 , Ta ble 1 1 a n d Ta ble 1 2 ). 
F or b o d y wei g ht c ha n ges, d oses s h o ul d be recalc ulate d acc or di n g t o i nstit uti o nal sta n dar d of 
care. Trast uz u ma b i nf usi o n rates ma y  be a dj uste d per i nstit uti o nal g ui deli nes. If d osi n g of 
trast uz u ma b has bee n hel d f or > 4 wee ks, t he I V l oa di n g d ose s h o ul d be gi ve n per a p pr o ve d 
d osi n g i nstr ucti o ns.
7. 7. 4. St or a ge a n d H a n dli n g
Refri gerati o n s h o ul d be set at 2 – 8° C f or st ora ge of vials c o ntai ni n g trast uz u ma b. F oll o w t he 
l ocal pr o d uct la beli n g f or m ore i nf or mati o n. Trast uz u ma b s h o ul d be st ore d acc or di n g t o t he
l ocal pr o d uct la beli n g.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 3 of 2 2 0
7. 7. 5. P ac k a gi n g a n d L a beli n g
Eac h vial of trast uz u ma b pr o vi de d b y t he s p o ns or will be la bele d i n c o m plia nce wit h 
a p plica ble re g ulat or y re q uire me nts.
7. 7. 6. Pre p ar ati o n a n d Dis pe nsi n g
Si n gle -d ose vial ( 1 5 0 m g/ vial) as a l y o p hilize d sterile p o w de r f or rec o nstit uti o n is 
c o m merciall y a vaila ble a n d s h o ul d be pre pare d a n d a d mi nistere d per i nstr ucti o ns i n t he 
trast uz u ma b l ocal pr o d uct la beli n g. Trast uz u ma b will be a d mi nistere d I V u n der t he directi o n 
of t he i n vesti gat or (s u bc uta ne o us a d mi nistrati o n is n ot all o we d o n st u d y ). 
St u d y  i nter ve nti o n s h o ul d be pre pare d a n d dis pe nse d b y a n a p pr o priately q ualifie d a n d 
e x perie nce d me m ber of t he st u d y  staff (e g, p h ysicia n, n urse, p h ysicia n’s assista nt, n urse 
practiti o ner, p har mac y  assista nt/tec h nicia n, or p har macist) as all o we d b y l ocal, state, a n d 
i nstit uti o nal g ui da nce.
7. 7. 7. St u d y Tre at me nt Acc o u nt a bilit y
Trast uz u ma b use d d uri n g t he c o urse of t he st u d y  s h o ul d be ha n dle d acc or di n g t o its l ocal 
pr o d uct la beli n g . S p o ns or-s u p plie d trast uz u ma b vials are t o be trac ke d a n d d oc u me nte d fr o m 
t he ti me of recei pt at t he site, t hr o u g h partici pa nt d osi n g, a n d u ntil t he s p o ns or a p pr o ves of 
t he fi nal ret ur n or destr ucti o n. All s u p plies, i ncl u di n g partiall y use d or e m pt y vials, s h o ul d be 
trac ke d.
T he s p o ns or or desi g nee will c o n d uct dr u g acc o u nta bilit y  m o nit ori n g d uri n g t he c o urse of t he 
st u d y. All use d a n d u n use d vials of trast uz u ma b s h o ul d be ha n dle d acc or di n g t o t he s p o ns or’s 
i nstr ucti o ns.
7. 8. Pe m br oliz u m a b ( C o h orts 1 E, 1 F, 1 G, a n d 2 A)
7. 8. 1. Descri pti o n
Pe m br oliz u ma b is a p ote nt a n d hi g hl y sele cti ve h u ma nize d m o n ocl o nal a nti b o d y  of t he 
I g G 4/ ka p pa is oty pe desi g ne d t o directl y bl oc k t he i nteracti o n bet wee n P D -1 a n d P D -L 1 a n d 
P D -L 2 .
7. 8. 2.
Met h o d of Pr oc ure me nt
Details re gar di n g s o urci n g of pe m br oliz u ma b ma y var y  b y site a n d/ or re gi o n as o utli ne d i n 
ot her d oc u me nts s uc h as Cli nical Trial A gree me nts. 
7. 8. 3. D ose a n d A d mi nistr ati o n
Pe m br oliz u ma b will be a d mi nistere d usi n g I V i nf usi o n o n Da y  1 of eac h 6-wee k treat me nt 
c ycle after all pr oce d ures a n d assess me nts ha ve bee n c o m plete d.
Pe m br oliz u ma b will be a d mi nistere d as a d ose of 4 0 0 m g usi n g a 3 0 -mi n ute I V i nf usi o n. 
Sites s h o ul d ma ke e ver y  eff ort t o tar get i nf usi o n ti mi n g t o be as cl ose t o 3 0 mi n utes as 
p ossi ble. H o we ver, gi ve n t he varia bilit y  of i nf usi o n p u m ps fr o m site t o site, a wi n d o w 
bet wee n -5 mi n utes a n d + 1 0 m i n utes is per mitte d (ie, i nf usi o n ti me is 3 0 mi n utes (- 5 
mi n/ + 1 0 mi n). 
T he pe m br oliz u ma b i nf usi o n s h o ul d be a d mi nistere d first, f oll o we d b y trast uz u ma b, 
o xali plati n, a n d ca pecita bi ne.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 4 of 2 2 0
7. 8. 4. St or a ge a n d H a n dli n g
T he i n vesti gat or or desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y  treat me nt recei ve d a n d a n y discre pa ncies are re p orte d 
a n d res ol ve d bef ore use of t he st u d y  treat me nt.
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 treat me nt an d o nl y  a ut h orize d site 
staff ma y s u p ply or a d mi nister st u d y treat me nt. All st u d y  treat me nts m ust be st ore d i n a 
sec ure, e n vir o n me ntally c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce 
wit h t he la bele d st ora ge c o n diti o ns wit h access li mi te d t o t he i n vesti gat or a n d a ut h orize d site 
staff.
7. 8. 5. P ac k a gi n g a n d L a beli n g
Refer t o t he P har mac y  Bi n der f or i nf or mati o n re gar di n g pac ka gi n g a n d la beli n g.
7. 8. 6. Pre p ar ati o n a n d Dis pe nsi n g 
St u d y  i nter ve nti o n s h o ul d be pre pare d a n d dis pe nse d b y a n a p pr o priately q ua lifie d a n d 
e x perie nce d me m ber of t he st u d y  staff (e g, p h ysicia n, n urse, p h ysicia n’s assista nt, n urse 
practiti o ner, p har mac y  assista nt/tec h nicia n, or p har macist) as all o we d b y l ocal, state, a n d 
i nstit uti o nal g ui da nce
T he P har mac y  Ma n ual c o ntai ns s pecific i nstr ucti o ns f or t he pre parati o n of t he 
pe m br oliz u ma b i nf usi o n a n d a d mi nistrati o n of i nf usi o n s ol uti o n.
7. 8. 7. St u d y Tre at me nt 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 dy treat me nt acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (ie, 
recei pt, rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds).
F or all st u d y sites, t he l ocal c o u ntr y S p o ns or pers o n nel or desi g nee will pr o vi de a p pr o priate 
d oc u me ntati o n t hat m ust be c o m plete d f or dr u g acc o u nta bilit y  a n d ret ur n, or l ocal discar d 
a n d destr ucti o n if a p pr o priate. W here l ocal discar d a n d destr ucti o n is a p pr o priate, t he 
i n vesti gat or is res p o nsi ble f or e ns uri n g t hat a l ocal discar d/ destr ucti o n pr oce d ure is 
d oc u me nte d.
T he st u d y  site is res p onsi ble f or rec or di n g t he l ot n u m ber, ma n ufact urer, a n d e x pir y  date f or 
a n y l ocally p urc hase d pr o d uct (if a p plica ble) as per l ocal g ui deli nes u nless ot her wise 
i nstr ucte d b y t he S p o ns or.
T he i n vesti gat or s hall ta ke res p o nsi bilit y  f or a n d s hall ta ke all ste ps t o mai ntai n a p pr o priate 
rec or ds a n d e ns ure a p pr o priate s u p pl y, st ora ge, ha n dli n g, distri b uti o n, a n d usa ge of st u d y 
treat me nts i n acc or da nce wit h t he pr ot oc ol a n d a ny a p plica ble la ws a n d re g ulati o ns
7. 9. D ose M o dific ati o ns
7. 9. 1. T uc ati ni b D ose M o dific ati o ns
D ose m o di ficati o ns of t ucati ni b will be ma de o n a per-partici pa nt basis. D ose re d ucti o ns will 
be ma de i n i ncre me nts of 5 0 m g ( Fi g ure 2 ). D ose re d ucti o ns t o bel o w 1 5 0 m g BI D are n ot 
all o we d u nless alter nati ve d ose le vels are rec o m me n de d b y t he S M C. Partici pa nts w h o, i n t he 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 5 of 2 2 0
o pi ni o n of t he i n vesti gat or, w o ul d re q uire a d ose re d ucti o n t o < 1 5 0 m g BI D s h o ul d 
disc o nti n ue st u d y  treat me nt. 
T he d ose of t ucati ni b s h o ul d n ot be re -escalate d after a d ose re d ucti o n is ma de. T ucati ni b 
s h o ul d be disc o nti n ue d if a dela y greater t ha n 6 wee ks is re q uire d d ue t o treat me nt-relate d 
t o xicit y u nless a l o n ger dela y is a p pr o ve d by t he st u d y  me dical m o nit or.
Fi g ure 2:
T uc ati ni b D ose Re d ucti o n Sc he d ule f or A Es B ase d o n St arti n g D ose
Ge neral d ose m o dificati o n g ui deli nes f or t ucati ni b are pr o vi de d i n Ta ble 1 3 . Inf or mati o n o n 
d ose m o dificati o ns d ue t o re nal t o xicit y  are disc usse d i n Secti o n 9. 5. 3. 1 .
T a ble 1 3 . T uc ati ni b D ose M o dific ati o ns f or A Es a
A d verse Re acti o ns, Se verit y b
T uc ati ni b D ose M o dific ati o n
He p at ot o xicit y (re g ar dless of rel ati o ns hi p t o t uc ati ni b)
A L T or A S T > 3 × t o ≤5 × U L N
N o d ose a dj ust me nt re q uire d
Bilir u bi n > 1. 5 × t o ≤3 × U L N
H ol d t ucati ni b u ntil rec o ver y t o ≤1. 5 × U L N. T he n res u me 
t ucati ni b at t he sa me d ose le vel
A L T or A S T > 5 × t o ≤2 0 × U L N
H ol d t ucati ni b u ntil rec o ver y t o ≤3 × U L N or u ntil ret ur n t o 
pretreat me nt le vel i n partici pa nts wit h k n o w n li ver 
metastasis. T he n res u me t uc ati ni b at t he ne xt l o wer d ose 
le vel
Bilir u bi n > 3 × t o ≤1 0 × U L N
H ol d t ucati ni b u ntil rec o ver y t o ≤1. 5 × U L N. T he n res u me 
t ucati ni b at t he ne xt l o wer d ose le vel
A L T or A S T > 2 0 × U L N
O R
Bilir u bi n > 1 0 × U L N
Per m a ne ntl y disc o nti n ue t ucati ni b
A L T or A S T > 3 × U L N
A N D
Bilir u bi n > 2 × U L N
Per m a ne ntl y disc o nti n ue t ucati ni b
Di arr he a rel ate d t o t uc ati ni b ( as assesse d b y t he i n vesti g at or)
Gra de 3 WI T H O U T a nti diarr heal treat me nt
I nitiate or i nte nsif y a p pr o priate me dical t hera p y. H ol d 
t ucati ni b u ntil rec o ver y t o ≤Gra de 1 or pretreat me nt le vel. 
T he n res u me t ucati ni b at t he sa me d ose le vel.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 6 of 2 2 0
T a ble 1 3 . T uc ati ni b D ose M o dific ati o ns f or A Es a
A d verse Re acti o ns, Se verit y b
T uc ati ni b D ose M o dific ati o n
Gra de 3 WI T H a nti diarr heal treat me nt
I nitiate or i nte nsif y a p pr o priate me dical t hera p y. H ol d 
t ucati ni b u ntil rec o ver y t o ≤Gra de 1 or pretreat me nt le vel. 
T he n res u me t ucati ni b at t he ne xt l o wer d ose le vel.
Gra de 4 (life -t hreate ni n g c o nse q ue nces; 
ur ge nt i nter ve nti o n i n dicate d)
Per m a ne ntl y disc o nti n ue t ucati ni b treat me nt.
N a use a a n d v o m iti n g rel ate d t o t uc ati ni b 
Gra de 3 na usea or v o miti n g WI T H O U T 
o pti mal use of a nti -e metics
H ol d u ntil se verit y ≤ Gra de 1 or pretreat me nt le vel. I nitiate 
a p pr o priate t hera p y.
Restart wit h o ut d ose re d ucti o n.
Gra de 3 na usea or v o miti n g WI T H o pti mal 
use of a nti -e metics
H ol d u ntil se verit y ≤ Gra de 1 or pretreat me nt le vel.
Restart at ne xt l o west d ose le vel.
Gra de 4 na usea or v o miti n g re gar dless of use 
of a nti -e metics
Per m a ne ntl y disc o nti n ue t ucati ni b treat me nt.
R as h rel ate d t o t uc ati ni b
Gra de 3 ras h WI T H O U T o pti mal use of t o pical 
c ortic oster oi ds or a nti -i nfecti ves
H ol d u ntil se verit y ≤ Gra de 1 or pretreat me nt le vel. I nitiate 
a p pr o priate t hera p y.
Restart wit h o ut d ose re d ucti o n.
Gra de 3 ras h WI T H o pti mal use of t o pical 
c ortic oster oi ds or a nti -i nfecti ves
H ol d u ntil se verit y ≤ Gra de 1 or pretreat me nt le vel.
Restart at ne xt l o west d ose le vel.
Gra de 4 ras h re gar dless of use of t o pical 
c ortic oster oi ds or a nti -i nfecti ves
Per m a ne ntl y disc o nti n ue t ucati ni b treat me nt.
Ot her a d verse re acti o ns t h at are rel ate d t o t uc ati ni b
Gra de 3 A Es ot her t ha n Gra de 3 fati g ue 
lasti n g ≤3 d a y s, al o peciac, na usea, v o miti n g, 
d iarr hea, ras h, c orrecta ble electr ol yte 
a b n or malities w hic h ret ur n t o ≤ Gra de 1 
wit hi n 7 da ys
H ol d t ucati ni b u ntil rec o ver y t o ≤ Gra de 1 or pretreat me nt 
le vel. T he n res u me t ucati ni b at t he ne xt l o wer d ose le vel.
Gra de 4
Per m a ne ntl y disc o nti n ue t ucati ni b.
a A E se verit y gra de d usi n g t he N CI C T C A E v 5. 0.
b If t he A E i n q uesti o n d oes n ot rec o ver t o t he gra de re q uire d f or restarti n g st u d y me dicati o n as o utli ne d i n 
t he ta ble, t he partici pa nt ma y nee d t o disc o nti n ue t he dr u g c o m pletel y. Partici pa nts re q uiri n g a h ol d of 
t ucati ni b f or > 6 we e ks m ust disc o nti n ue st u d y treat me nt u nless a l o n ger dela y is a p pr o ve d b y t he me dical 
m o nit or.
c N o d ose m o dificati o ns are re q uire d f or al o pecia
7. 9. 2. F O L F O X D ose M o dific ati o ns
D oses of fl u or o uracil, o xali plati n, a n d le uc o v ori n ma y  be a dj uste d de pe n di n g o n a n 
i n di vi d ual partici pa nt’s t olera nce. Ta ble 1 4 prese nts rec o m me n de d d ose re d ucti o n le v els f or 
o xali plati n ( n o n -ne ur ol o gical t o xicit y ) a n d fl u or o uracil. Ta ble 1 5 prese nts d ose m o dificati o n 
g ui deli nes f or A Es attri b ute d t o F O L F O X. Ta ble 1 6 prese nts d ose m o dificati o n g ui deli nes 
f or o xali plati n-ass ociate d ne ur ol o gical t o xicit y attri b ute d t o F O L F O X. D ose re d ucti o ns or 
treat me nt i nterr u pti o ns/ disc o nti n uati o n f or reas o ns ot her t ha n t h ose descri be d bel o w ma y be 
ma de b y t he i n vesti gat or per i nstit uti o nal practice a n d if dee me d i n t he best i nterest of 
partici pa nt safet y . W he ne ver p ossi ble, t hese decisi o ns s h o ul d first be disc usse d wit h t he 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 7 of 2 2 0
me dical m o nit or. D uri n g t he L T E P, i n v esti gat ors ma y c h o ose t o f oll o w i nstit uti o nal sta n dar d 
of care f or F O L F O X d ose m o dificati o ns.
T a ble 1 4 .
O x ali pl ati n ( N o n-ne ur ol o gic al T o xicit y) a n d Fl u or o ur acil D ose Re d ucti o n 
Le vels f or F O L F O X
Starti n g D ose
D ose Le vel - 1
D ose Le vel - 2
O xali plati n ( F O L F O X)
8 5 m g/ m 2
6 5 m g/ m 2
5 0 m g/ m 2
Fl u or o uracil
- m F O L F O X 6
    B ol us
    I nf usi o n
- m F O L F O X 7
    I nf usi o n
4 0 0 m g/ m 2
2 4 0 0 m g/ m 2
2 4 0 0 m g/ m 2
3 2 0 m g/ m 2
1 9 0 0 m g/ m 2
2 0 0 0 m g/ m 2
2 6 0 m g/ m 2
1 5 0 0 m g/ m 2
1 6 0 0 m g/ m 2
T a ble 1 5 . D ose M o dific ati o ns f or A Es Attri b ute d t o F O L F O X
T o xicit y C T C A E Gra de 
( v 5. 0)
S u bse q ue nt C ycles Base d o n I nter val 
T o xicit y
Pri or t o Eac h Treat me nt C ycle
Ne utr o pe nia a ( AN C)

Gra de 1

Gra de 2

Gra de 3

Gra de 4

Mai ntai n d ose le vel

Mai ntai n d ose le vel

Decrease b ot h 5 -F U a n d o xali plati n 
1 d ose le vel

Decrease b ot h 5 -F U a n d o xali plati n 
1 d ose le vel

If A N C < 1. 5 × 1 09 / L at start of 
c ycle, h ol d a n d c hec k wee kl y 
t he n treat base d o n i nter val 
t o xicit y

If A N C < 1. 5 × 1 09 / L after 
4 we e ks, disc o nti n ue t hera p y
T hr o m b oc yt o pe nia a

Gra de 1

Gra de 2

Gra de 3

Gra de 4

Mai ntai n d ose le vel

Mai ntai n d ose le vel

Decrease b ot h 5 -F U a n d o xali plati n 
1 d ose le vel

Decrease b ot h 5 -F U a n d o xali plati n 
1 d ose le vel

If P L T < 7 5 × 1 0 9 / L at start of 
c ycle, h ol d a n d c hec k wee kl y 
t he n treat base d o n i nter val 
t o xicit y

If P L T < 7 5 × 1 09 / L after 4 we e ks, 
disc o nti n ue t hera p y
Fe brile ne utr o pe nia
Decrease b ot h 5 -F U a n d o xali plati n 1 
d ose le vel
Diarr hea b

Gra de 1

Gra de 2

Gra de 3

Gra de 4

Mai ntai n d ose le vel

Mai ntai n d ose le vel

Decrease b ot h 5 -F U a n d o xali plati n 
1 d ose le vel

Decrease b ot h 5 -F U a n d o xali plati n 
1 d ose le vel
If Gra de ≥2 diarr hea at start of c ycle, 
h ol d a n d c hec k wee kl y t he n treat 
base d o n i nter val t o x icit y
Ot her n o n he mat ol o gic 
t o xicitiesc
D ose m o dificati o ns f or ot her n o n he mat ol o gic A Es relate d t o t hera p y t hat are 
o bser ve d at t he start of s u bse q ue nt c o urse a n d at t he ti me of retreat me nt are 
base d o n C T C A E v 5. 0 a n d f oll o w t he sa me criteria as diarr hea a b o ve.
Le uc o v ori n ( or le v ole uc o v ori n) d ose m o dificati o ns ma y be ma de at t he i n vesti gat or’s discreti o n a n d per 
i nstit uti o nal sta n dar ds.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 8 of 2 2 0
T a ble 1 5 . D ose M o dific ati o ns f or A Es Attri b ute d t o F O L F O X
T o xicit y C T C A E Gra de 
( v 5. 0)
S u bse q ue nt C ycles Base d o n I nter val 
T o xicit y
Pri or t o Eac h Treat me nt C ycle
a La b orat or y val ues fr o m Da y 1 of eac h c ycle s h o ul d be use d t o deter mi ne d ose m o dificati o ns t o F O L F O X 
f or ne utr o pe nia a n d t hr o m b oc yt o pe nia
b m F O L F O X 6 ma y ca use se vere diarr hea; disc o nti n uati o n of t he 5 -F U b ol us d ose ma y be c o nsi dere d pri or t o 
m o dificati o n of t ucati ni b d osi n g (refer t o Secti o n 7. 9. 1 0 ).
c F or ot her n o n he mat ol o gic t o xicities, t he ne xt c ycle of t hera p y ma y be starte d des pite t he occ urre nce of a 
Gra de 2 A E, if c o nsiste nt wit h l ocal sta n dar ds.
T a ble 1 6 .
D ose M o dific ati o n f or O x ali pl ati n- ass oci ate d Ne ur ot o xicit y Attri b ute d t o 
F O L F O X
Parest hesia a n d Peri p heral Se ns or y 
Ne ur o pat h y ( Gra de a)
D urati o n of Ne ur ot o xicit y
1 – 7 Da ys
> 7 Da ys
Persiste nt ( N ot 
Res ol ve d Bet w ee n 
C y cles)
Parest hesias/ d ysest hesias of s h ort 
d urati o n t hat res ol ve a n d d o n ot 
i nterfere wit h f u ncti o n ( Gra de 1)
N o C ha n ge
N o C ha n ge  
N o C ha n ge
Parest hesias/ d ysest hesias 
i nterferi n g wit h i nstr u me ntal 
acti vities of dail y li vi n g ( Gra de 2)
N o C ha n ge
N o C ha n ge
F O L F O X: Decrease 
o xali plati n t o 
6 5 m g/ m 2
Parest hesias/ d ysest hesias wit h 
pai n or w it h f u ncti o nal i m pair me nt 
t hat i nterfere wit h self-care 
acti vities of dail y li vi n g ( Gra de 3)
1st ti me: 
F O L F O X: Decrease 
o xali plati n t o 6 5 m g/ m 2
2 nd ti me: 
F O L F O X: Decrease 
o xali plati n t o 4 0 m g/ m 2
S T O P
S T O P
Persiste nt 
parest hesias/ d ysest hesias t hat are 
life-t hreate ni n g ( Gra de 4)
S T O P
S T O P
S T O P
P har y n g o -lar y n geal d ysest hesias
N o C ha n ge
I ncrease d urati o n of 
i nf usi o n t o 6 h o urs
I ncrease d urati o n of 
i nf usi o n t o 6 h o urs
a A E se verit y gra de d usi n g t he N CI C T C A E v 5. 0.
A ne w c y cle of F O L F O X will be re peate d e ver y 2 wee ks b ut ma y n ot be a d mi nistere d if t he 
A N C < 1. 5 × 1 0 9/ L, platelets < 7 5. 0 × 1 09/ L, w hite bl o o d cells < 3. 0 × 1 0 9/ L, or diarr hea ha ve n ot 
rec o vere d t o ≤ Gra de 1. U p t o a 4 -wee k dela y  is all o we d i n t he i nitiati o n of a ne w c ycle of 
treat me nt f or res ol uti o n of t o xicities. A treat me nt dela y of 1 c o m p o ne nt of t he F O L F O X 
re gi me n (ie, fl u or o uracil/le uc o v ori n, or o xali plati n) res ults i n a si milar dela y  of t he ot her 
c o m p o ne nt t o all o w b ot h t hera pies t o be gi ve n t o get her o n Da y  1 of eac h 2-wee k c y cle. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 9 9 of 2 2 0
Trast uz u ma b, t ucati ni b a n d pe m br oliz u ma b (as a p plica ble) ma y  be c o nti n ue d d uri n g peri o ds 
of F O L F O X treat me nt dela y .
I n t he e ve nt t hat o xali plati n a d mi nistrati o n is disc o nti n ue d f or a ny reas o n pri or t o disease 
pr o gressi o n, fl u or o uracil/le uc o v ori n, trast uz u ma b, a n d t ucati ni b t hera p y ma y be c o nti n ue d 
u ntil disease pr o gressi o n. I n t he e ve nt t hat F O L F O X c he m ot hera p y  a d mi nistrati o n is 
disc o nti n ue d f or a n y reas o n pri or t o disease pr o gressi o n, trast uz u ma b a n d t ucati ni b t hera p y 
ma y  be c o nti n ue d u ntil disease pr o gressi o n. 
At t he discreti o n of t he PI, partici pa nts e nr olle d i n C o h ort 1 A at a t ucati ni b d ose bel o w t hat 
rec o m me n de d b y  t he S M C f or s u bse q ue nt c o h orts ma y i ncrease t o t he hi g her t ucati ni b d ose 
at a n y ti me f oll o wi n g S M C a p pr o val.
If F OL F O X c he m ot hera p y i nterr u pti o ns are ≤6 wee ks fr o m t he pre vi o us c ycle a n d t he 
partici pa nt has rec o vere d fr o m t o xicities as s pecifie d a b o ve, a n d t he partici pa nt’s disease has 
n ot pr o gresse d, F O L F O X s h o ul d be restarte d at d oses acc or di n g t o t he ta bles a b o ve. If t he 
F O L F O X c he m ot hera p y i nterr u pti o n is > 6 wee ks, b ut t he partici pa nt has rec o vere d fr o m 
t o xicit y a n d t he partici pa nt’s disease has n ot pr o gresse d, t he n t he partici pa nt ma y  c o nti n ue 
F O L F O X t hera p y after c o ns ultati o n wit h a n d a p pr o val b y t he s p o ns or’s me dical m o nit or. 
7. 9. 3. C A P O X D ose M o dific ati o ns
D oses of o xali plati n a n d ca pecita bi ne ma y  be a dj uste d de pe n di n g o n a n i n di vi d ual 
partici pa nt’s t olera nce. Ta ble 1 7 prese nts rec o m me n de d d ose re d ucti o n le vels f or o xal i plati n 
( n o n-ne ur ol o gical t o xicit y ) a n d ca pecita bi ne. Ta ble 1 8 prese nts d ose m o dificati o n g ui deli nes 
f or A Es attri b ute d t o C A P O X, a n d Ta ble 1 9 prese nts d ose m o dificati o n g ui deli nes f or 
o xali plati n -ass ociate d ne ur ol o gical t o xicit y attri b ute d t o C A P O X. D ose re d ucti o ns or 
treat me nt i nterr u pti o ns/ disc o nti n uati o n f or reas o ns ot her t ha n t h ose descri be d bel o w ma y be 
ma de b y t he i n vesti gat or per i nstit uti o nal practice a n d if dee me d i n t he best i nterest of 
partici pa nt safet y . W he ne ver p ossi ble, t hese decisi o ns s h o ul d first be disc usse d wit h t he 
me dical m o nit or.
Ca pecita bi ne m ust be hel d f or a n y partici pa nt w h o e x perie nces a Gra de 2 or greater A E 
c o nsi dere d relate d t o ca pecita bi ne or t o t he c o m bi nati o n of t ucati ni b a n d ca pecita bi ne a n d/ or 
trast uz u ma b (as deter mi ne d b y t he i n vesti gat or). Hel d d oses of ca pecita bi ne s h o ul d n ot be 
ma de u p wit hi n eac h c ycle. 
D uri n g t he L T E P, i n vesti gat ors ma y  c h o ose t o f oll o w i nstit uti o nal sta n dar d of care f or 
C A P O X d ose m o dificati o ns.
Ca pecita bi ne d ose s h o ul d n ot be re -escalate d after a d ose re d ucti o n is ma de.
I n t he e ve nt t hat o xali plati n a d mi nistrati o n is disc onti n ue d f or a n y reas o n pri or t o disease 
pr o gressi o n, ca pecita bi ne, trast uz u ma b, t ucati ni b, a n d pe m br oliz u ma b (as a p plica ble) t hera p y 
ma y  be c o nti n ue d u ntil disease pr o gressi o n. I n t he e ve nt t hat C A P O X c he m ot hera p y 
a d mi nistrati o n is disc o nti n ue d f or a n y reas o n pri or t o disease pr o gressi o n, trast uz u ma b a n d 
t ucati ni b t hera py ma y be c o nti n ue d u ntil disease pr o gressi o n.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 0 of 2 2 0
T a ble 1 7 .
O x ali pl ati n ( N o n-ne ur ol o gic al T o xicit y) a n d C a pecit a bi ne D ose Re d ucti o n 
Le vels f or C A P O X
Starti n g D ose
D ose Le vel – 1
D ose Le vel – 2
O xali plati n ( C A P O X)
1 3 0 m g/ m 2
1 0 0 m g/ m 2
8 5 m g/ m 2
Ca pecita bi ne a
1 0 0 0 m g/ m 2
7 5 0 m g/ m 2
5 0 0 m g/ m 2
a Starti n g d ose of ca pecita bi ne ma y be re d uce d per i n vesti gat or prefere nce or i nstit uti o nal sta n dar ds u p o n 
a p pr o val b y me dical m o nit or b ut will n ot be l o wer t ha n 8 5 0 m g/ m 2 P O BI D. F or partici pa nts wit h starti n g 
d oses of ca pecita bi ne < 1 0 0 0 m g/ m 2, d ose re d ucti o ns of ca pecita bi ne s h o ul d be 2 5 % of t he starti n g d ose f or 
d ose le vel 1 a n d 5 0 % of t he starti n g d ose f or d ose le vel 2. 
T a ble 1 8 .
D ose M o dific ati o ns f or A Es attri b ute d t o C A P O X
C A P O X 
Dr u g(s)
T o xicit y C T C A E 
Gra de ( v 5. 0)
S u bse q ue nt C ycles Base d o n I nter val 
T o xicit y
Pri or t o Eac h Treat me nt C ycle
O xali plati n
Ne utr o pe nia ( A N C) a

Gra de 1

Gra de 2

Gra de 3

Gra de 4

Mai ntai n d ose le vel

Mai ntai n d ose le vel

Decrease o xali plati n 1 d ose le vel

Decrease o xali plati n 1 d ose le vel

If A N C < 1. 5 × 1 09/ L at start of 
c ycle, h ol d a n d c hec k wee kl y 
t he n treat base d o n i nter val 
t o xicit y

If A N C < 1. 5 × 1 09/ L after 
4 wee ks, disc o nti n ue t hera p y
T hr o m b oc yt o pe nia a

Gra de 1

Gra de 2

Gra de 3

Gra de 4

Mai ntai n d ose le vel

Mai ntai n d ose le vel

Decrease o xali plati n 1 d ose le vel

Decrease o xali plati n 1 d ose le vel

If P L T < 7 5 × 1 09/ L at start of 
c ycle, h ol d a n d c hec k wee kl y 
t he n treat base d o n i nter val 
t o xicit y

If P L T < 7 5 × 1 09/ L after 
4 wee ks, disc o nti n ue t hera p y
Le u k o pe nia

Gra de 1

Gra de 2

Gra de 3

Gra de 4

Mai ntai n d ose le vel

Mai ntai n d ose le vel

Decrease o xali plati n 1 d ose le vel

Decrease o xali plati n 1 d ose le vel

If W B C < 3. 0 × 1 09/ L at start of 
c ycle, h ol d a n d c hec k wee kl y 
t he n treat base d o n i nter val 
t o xicit y

If W B C < 3. 0 × 1 09/ L after 
4 wee ks, disc o nti n ue t hera p y
Diarr hea

Gra de 1

Gra de 2

Gra de 3

Gra de 4

Mai ntai n d ose le vel

Mai ntai n d ose le vel

Decrease o xali plati n 1 d ose le vel

Decrease o xali plati n 1 d ose le vel

If Gra de ≥2 diarr hea at start of 
c ycle, h ol d a n d c hec k wee kl y 
t he n treat base d o n i nter val 
t o xicit y
Ot her 
n o n he mat ol o gic 
t o xicities
O xali plati n d ose m o dificati o ns f or ot her n o n he mat ol o gic A Es relate d t o 
C A P O X t hat are o bser ve d at t he start of s u bse q ue nt c o urse a n d at t he ti me of 
retreat me nt are base d o n C T C A E v 5. 0 a n d f oll o w t he sa me criteria as diarr hea 
a b o ve.
O xali plati n 
a n d 
Ca pecit a bi ne
Fe brile ne utr o pe nia
Decrease o xali plati n 1 d ose le vel a n d 
ca pecita bi ne t o 7 5 % of starti n g d ose

If A N C < 1. 5 × 1 09/ L at start of 
c ycle, h ol d a n d c hec k wee kl y 
t he n treat base d o n i nter val 
t o xicit y

If A N C < 1. 5 × 1 09/ L after 
4 wee ks, disc o nti n ue t hera p y

If Gra de ≥3 se psis occ urs, 
disc o nti n ue ca pecita bi ne a n d 
o xali plati n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 1 of 2 2 0
T a ble 1 8 .
D ose M o dific ati o ns f or A Es attri b ute d t o C A P O X
C A P O X 
Dr u g(s)
T o xicit y C T C A E 
Gra de ( v 5. 0)
S u bse q ue nt C ycles Base d o n I nter val 
T o xicit y
Pri or t o Eac h Treat me nt C ycle
Ca pecita bi ne
Ha n d a n d F o ot S y n dr o me 

If Gra de ≥2 ha n d -f o ot 
s yn dr o me occ urs, 
a d mi nistrati o n of ca pecita bi ne 
s h o ul d be i m me diatel y 
i nterr u pte d u ntil t he e ve nt 
res ol ves or decreases i n 
i nte nsit y t o Gra de ≤1

Gra de 1

Gra de 2

Gra de 3

Mai ntai n d ose le vel

1st ti me: Mai ntai n d ose le vel

2 n d ti me: Decrease ca pecita bi ne t o 
7 5 % of starti n g d ose

3r d ti me: Decrease ca pecita bi ne t o 
5 0 % of starti n g d ose

4t h ti me: Disc o nti n ue ca pecita bi ne 
per ma ne ntl y

1st ti me: Decrease ca pecita bi ne t o 
7 5 % of starti n g d ose

2 n d ti me: Decrease ca pecita bi ne t o 
5 0 % of starti n g d ose

3r d ti me: Disc o nti n ue ca pecita bi ne 
per ma ne ntl y
Ca pecita bi ne 
( C o nti n ue d)
St o matitis

Gra de 1

Gra de 2

Gra de 3

Gra de 4

Mai ntai n d ose le vel

1st ti me: Mai ntai n d ose le vel

2 n d ti me: Decrease ca pecita bi ne t o 
7 5 % of starti n g d ose 

3r d ti me: Decrease ca pecita bi ne t o 
5 0 % of starti n g d ose 

4t h ti me: Disc o nti n ue ca pecita bi ne 
per ma ne ntl y

1st ti me: Decrease ca pecita bi ne t o 
7 5 % of starti n g d ose

2 n d ti me: Decrease ca pecita bi ne t o 
5 0 % of starti n g d ose 

3r d ti me: Disc o nti n ue ca pecita bi ne 
per ma ne ntl y

Disc o nti n ue ca pecita bi ne 
per ma ne ntl y

If Gra de ≥2 st o matitis occ urs, 
a d mi nistrati o n of ca pecita bi ne 
s h o ul d be i m me diatel y 
i nterr u pte d u ntil t he e ve nt 
res ol ves or decreases i n 
i nte nsit y t o Gra de ≤1
Car di ot o xicit y b

Gra de 1

Gra de 2

Mai ntai n d ose le vel

Disc o nti n ue ca pecita bi ne 
per ma ne ntl y

If Gra de ≥2 car di ot o xicit y is 
attri b uta ble t o ca pecita bi ne, 
per ma ne ntl y disc o nti n ue 
t hera p y
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 2 of 2 2 0
T a ble 1 8 .
D ose M o dific ati o ns f or A Es attri b ute d t o C A P O X
C A P O X 
Dr u g(s)
T o xicit y C T C A E 
Gra de ( v 5. 0)
S u bse q ue nt C ycles Base d o n I nter val 
T o xicit y
Pri or t o Eac h Treat me nt C ycle
Ca pecita bi ne
( C o nti n ue d)
Ot her A d verse E ve nts Rel ate d t o C a pecit a bi ne
T o xicit y C T C A E 
Gr a de ( v 5. 0)
D uri n g a C o urse of T her a p y
D ose A dj ust me nt f or Ne xt 
Tre at me nt ( %  of St arti n g D ose)c
Gra de 1
Mai ntai n d ose le vel
Mai ntai n d ose le vel
Gra de 2 d
1st a p peara nce
2 n d a p peara nce
3r d a p peara nce
4t h a p peara nce
I nterr u pt u ntil res ol ve d t o Gra de ≤ 1
I nterr u pt u ntil res ol ve d t o Gra de ≤ 1
I nterr u pt u ntil res ol ve d t o Gra de ≤ 1
Disc o nti n ue per ma ne ntl y
1 0 0 %
7 5 %
5 0 %
N A
Gra de 3
1st a p peara nce
2 n d a p peara nce
3r d a p peara nce
I nterr u pt u ntil res ol ve d t o Gra de ≤ 1
I nterr u pt u ntil res ol ve d t o Gra de ≤ 1
Disc o nti n ue per ma ne ntl y
7 5 %
5 0 %
N A
Gra de 4
1st a p peara nce
Disc o nti n ue per ma ne ntl y
N A
N A = n ot a p plica ble
a La b orat or y val ues fr o m Da y 1 of eac h c ycle s h o ul d be use d t o deter mi ne d ose m o dificati o ns t o C A P O X f or 
ne utr o pe nia a n d t hr o m b oc yt o pe nia
b Car di ot o xicit y o bser ve d wit h ca pecita bi ne i ncl u des m y ocar dial i nfarcti o n/isc he mia, a n gi na, d ysr h yt h mias, 
car diac arre st, car diac fail ure, s u d de n deat h, electr ocar di o gra p hic c ha n ges, a n d car di o m y o pat h y ( X E L O D A 
pr o d uct l a beli n g, Ge ne ntec h, I nc., Fe b 2 0 1 9)
c D ose m o dificati o n ta ble is base d u p o n ca pecita bi ne pr o d uct la beli n g ; d ose r o u n di n g s h o ul d be perf or me d 
per i nstit uti o nal g ui deli nes
d I n certai n i nsta nces of as y m pt o matic or mil dl y s y m pt o matic Gra de 2 la b orat or y a b n or malities (f or e xa m ple, 
a ne mia), i n vesti gat ors ma y c h o ose t o mai ntai n ca pecita bi ne d ose le vel a n d/ or t o res u me ca pecita bi ne pri or 
t o res ol uti o n t o Gra de 1. T his s h o ul d be d o ne o nl y w he n t he ris k t o patie nt fr o m ca pecita bi ne d ose 
i nterr u pti o n a n d/ or re d ucti o n o ut wei g hs t he ris k t o t he patie nt fr o m t he A E, a n d w he n t he acti o n is 
c o nsiste nt wit h us ual a n d c ust o mar y cli nical practice.
T a ble 1 9 .
D ose M o dific ati o n f or O x ali pl ati n- ass oci ate d Ne ur ot o xicit y Attri b ute d t o 
C A P O X a
Parest hesia a n d Peri p heral 
Se ns or y Ne ur o pat h y ( Gra de b)
D urati o n of Ne ur ot o xicit y a
1 – 7 Da ys
> 7 Da ys
Persiste nt ( N ot 
Res ol ve d Bet w ee n 
C y cles)
Parest hesias/ d ysest hesias of s h ort 
d urati o n t hat res ol ve a n d d o n ot 
i nterfere wit h f u ncti o n ( Gra de 1)
N o C ha n ge
N o C ha n ge  
N o C ha n ge
Parest hesias/ d ysest hesias 
i nterferi n g wit h i nstr u me ntal 
N o C ha n ge
N o C ha n ge
C A P O X: Decrease 
o xali plati n t o 
1 0 0 m g/ m 2
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 3 of 2 2 0
T a ble 1 9 .
D ose M o dific ati o n f or O x ali pl ati n- ass oci ate d Ne ur ot o xicit y Attri b ute d t o 
C A P O X a
Parest hesia a n d Peri p heral 
Se ns or y Ne ur o pat h y ( Gra de b)
D urati o n of Ne ur ot o xicit y a
1 – 7 Da ys
> 7 Da ys
Persiste nt ( N ot 
Res ol ve d Bet w ee n 
C y cles)
acti vities of dail y li vi n g ( Gra de 
2)
Parest hesias/ d ysest hesias wit h 
pai n or w it h f u ncti o nal 
i mpair m e nt t hat i nterfere wit h 
self-care acti vities of dail y li vi n g 
A D L ( Gra de 3)
1st ti me: 
C A P O X: Decrease 
o xali plati n t o 
1 0 0 m g/ m 2
2 nd ti me: 
C A P O X: Decrease 
o xa li plati n t o 
6 5 m g/ m 2
S T O P
S T O P
Persiste nt 
parest hesias/ d ysest hesias t hat are 
life-t hreate ni n g ( Gra de 4)
S T O P
S T O P
S T O P
P har y n g o -lar y n geal d ysest hesias
N o C ha n ge
I ncrease d urati o n 
of i nf usi o n t o 
6 h o urs
I ncrease d urati o n of 
i nf usi o n t o 6 h o urs
a Ne ur ot o xicit y attri b ute d t o ca pecita bi ne s h o ul d be ma na ge d f oll o wi n g t he g ui deli nes f or ot her a d verse 
e ve nts relate d t o ca pecita bi ne liste d i n Ta ble 1 8 .
b A E se verit y gra de d usi n g t he N CI C T C A E v 5. 0.
7. 9. 4. Tr ast uz u m a b D ose M o dific ati o ns
I n t he e ve nt of Gra de ≥3 trast uz u ma b -relate d A Es ot her t ha n I R Rs ( Secti o n 7. 9. 6 ), h ol d 
trast uz u ma b u ntil t he A E res ol ve d t o Gra de ≤1 or pretreat me nt le vels a n d i nitiate or i nte nsif y  
a p plica ble me dical t hera p y, as a p pr o priate. Res u me trast uz u ma b at t he sa me d ose; t he 
trastuz u ma b d ose ma y  n ot be re d uce d. If d osi n g of trast uz u ma b is hel d f or > 4 wee ks a n d t he 
me dical m o nit or has a gree d t o restart trast uz u ma b, t he I V l oa di n g d ose of 6 m g/ k g f or 
C o h orts 1 A a n d 1 B or 8 m g/ k g f or all ot her c o h orts s h o ul d be gi ve n per a p pr o ve d d osi n g 
i nstr ucti o ns. Trast uz u ma b ma y als o be gi ve n o n a wee kly basis at 2 m g / k g I V o nce wee kly, 
i n or der t o resy n c hr o nize a d mi nistrati o n t o Da y 1 of eac h c ycle after disc ussi o n wit h t he 
me dical m o nit or. Trast uz u ma b s h o ul d be disc o nti n ue d if a dela y  greater t han 6 wee ks is 
re q uire d d ue t o treat me nt-relate d t o xicit y, u nless a l o n ger dela y is a p pr o ve d b y t he st u d y 
me dical m o nit or. I n t he e ve nt t hat trast uz u ma b is disc o nti n ue d f or a n y reas o n pri or t o disease 
pr o gressi o n, t ucati ni b, C A P O X, or F O L F O X t hera p y  m a y be co nti n ue d u ntil disease 
pr o gressi o n. Trast uz u ma b d ose m o dificati o n g ui deli nes f or left ve ntric ular d y sf u ncti o n a n d 
car di o m y o pat h y are prese nte d i n Secti o n 7. 9. 4. 1 f or IR R i n Secti o n 7. 9. 6 a n d f or 
h y perse nsiti vit y  reacti o n i n Secti o n 7. 9. 7 .
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 4 of 2 2 0
7. 9. 4. 1. D ose M o dific ati o ns f or Left Ve ntric ul ar D ysf u ncti o n
Trast uz u ma b ca n ca use left ve ntric ular car diac d ysf u ncti o n, arr h yt h mias, h y perte nsi o n, 
disa bli n g car diac fail ure, car di o m y o pat h y, a n d car diac deat h. Trast uz u ma b ca n als o ca use 
as ym pt o matic decli ne i n L V E F.
Trast uz u ma b d ose m o dificati o n g ui deli nes f or left ve ntric ular d ys f u ncti o n, re gar dless of 
relati o ns hi p t o st u d y i nter ve nti o n, are pr o vi de d i n Ta ble 2 0.
T a ble 2 0 .
Tr ast uz u m a b D ose M o dific ati o n G ui deli nes f or Left Ve ntric ul ar D ysf u ncti o n
L V E F at Assess me nt
Acti o n
S y m pt o matic C H F
Disc o nti n ue trast uz u ma b
L V E F ≥5 0 %
C o nti n ue treat me nt wit h trast uz u ma b
L V E F 4 5 % t o < 5 0 % w it h < 1 0 perce nta ge p oi nts decrease fr o m 
baseli ne
C o nti n ue treat me nt wit h trast uz u ma b
L V E F < 4 5 % or 4 5 % t o < 5 0 % wit h ≥1 0 perce nta ge p oi nts 
decrease fr o m baseli ne
H ol d trast uz u ma b, re peat L V E F i n 3 -4 wee ks

Re peat L V E F at 3 -4 w ee ks:
o
L V E F ≥5 0 %
Res u me treat me nt wit h trast uz u ma b
o
L V E F 4 5 % t o 4 9 %

< 1 0 perce nta ge p oi nts decrease fr o m baseli ne
Res u me treat me nt wit h trast uz u ma b

≥1 0 perce nta ge p oi nts decrease fr o m baseli ne
Disc o nti n ue trast uz u ma b
o
L V E F < 4 5 %
Disc o nti n ue trast uz u ma b
C H F = C o n gesti ve Heart Fail ure; L V E F = Left Ve ntric ular Ejecti o n Fracti o n
7. 9. 5. Pe m br oliz u m a b D ose M o dific ati o ns
7. 9. 5. 1. I m m u ne- Rel ate d E ve nts a n d D ose M o dific ati o n ( Wit h h ol d, Tre at, Disc o nti n ue)
D ose M o dific ati o n a n d T o xicit y M a n a ge me nt f or I m m u ne- rel ate d A Es (ir A Es)
Ass oci ate d wit h Pe m br oliz u m a b C o m bi n ati o n Tre at me nt
A Es ass ociate d wit h pe m br oliz u ma b c o m bi nati o n e x p os ure ma y  re prese nt a n i m m u ne-relate d 
res p o nse. T hese ir A Es ma y occ ur s h ortl y after t he first d ose or se veral m o nt hs after t he last 
d ose of pe m br oliz u ma b c o m bi nati o n treat me nt a n d ma y affect m ore t ha n o ne b o d y sys te m 
si m ulta ne o usl y. T heref ore, early rec o g niti o n a n d i nitiati o n of treat me nt is critical t o re d uce 
c o m plicati o ns. Base d o n e xisti n g cli nical st u d y  data, m ost ir A Es were re versi ble a n d c o ul d 
be ma na ge d wit h i nterr u pti o ns of pe m br oliz u ma b c o m bi nati o n a d mi nistrati o n of 
c ortic oster oi ds a n d/ or ot her s u p p orti ve care. F or s us pecte d ir A Es, e ns ure a de q uate e val uati o n 
t o c o nfir m eti ol o g y or e xcl u de ot her ca uses. A d diti o nal pr oce d ures or tests s uc h as 
br o nc h os c o p y, e n d osc o p y, s ki n bi o ps y ma y  be i ncl u de d as part of t he e val uati o n. D ose 
re d ucti o ns of pe m br oliz u ma b are n ot all o we d.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 5 of 2 2 0
Attri b uti o n of T o xicit y:
W he n st u d y  treat me nts are a d mi nistere d i n c o m bi nati o n, attri b uti o n of a n A E t o a si n gle 
c o m p o ne nt is li kel y to be diffic ult. T heref ore, w hile t he i n vesti gat or ma y  attri b ute a t o xicit y 
e ve nt t o c o m bi nati o ns, pe m br oliz u ma b m ust be hel d acc or di n g t o t he criteria i n t he D ose 
M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or ir A Es.
I n t hese cases w here t he t o xicit y is attri b ute d t o c o m bi nati o ns, re-i nitiati o n of pe m br oliz u ma b 
as a m o n ot hera p y m a y be c o nsi dere d after c o m m u nicati o n wit h a n d a gree me nt b y t he 
S p o ns or.
H ol di n g St u d y Tre at me nts: 
W he n st u d y  treat me nts are a d mi nistere d i n c o m bi nati o n a n d if t he A E is c o nsi dere d i m m u ne-
relate d, pe m br oliz u ma b s h o ul d be hel d acc or di n g t o rec o m me n de d D ose M o dificati o n 
criteria.
If t he t o xicit y d oes n ot res ol ve or t he criteria f or res u mi n g treat me nt are n ot met, t he 
partici pa nt m ust be disc o nti n ue d fr o m c o m bi nati o n t hera p y.
Rest a rti n g St u d y Tre at me nts:
Partici pa nts ma y  restart pe m br oliz u ma b c o m bi nati o n treat me nts as descri be d bel o w:
If t he t o xicities d o res ol ve a n d c o n diti o ns are ali g ne d wit h w hat is defi ne d i n t he D ose 
M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes f or ir A Es, c o m bi nati o n treat me nt ma y  be 
restarte d at t he discreti o n of t he i n vesti gat or.
D ose M o dificati o n a n d T o xicit y  Ma na ge me nt G ui deli nes f or ir A Es ass ociate d wit h 
pe m br oliz u ma b are pr o vi de d i n Ta ble 2 1 .
Tre at me nt of I m m u ne -rel ate d A d verse E ve nts
F or i m m u n ot hera pe utic a ge nts, treat me nt of ir A Es is mai nl y  de pe n de nt u p o n se verity ( N CI 
C T C A E gra de versi o n 5. 0) . I n ge neral, Gra de 1 or 2 ir A Es are treate d s y m pt o maticall y , a n d 
persiste nt Gra de 2, Gra de 3, or Gra de 4 ir A Es are ma na ge d wit h m o derate t o hi g h 
c ortic oster oi ds.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 6 of 2 2 0
T a ble 2 1 .
D ose M o dific ati o n a n d T o xicit y M a n a ge me nt G ui deli nes f or I m m u ne-rel ate d A Es Ass o ci ate d wit h 
Pe m br oliz u m a b
Ge neral i nstr ucti o ns:
1.   Se vere a n d life -t hreate ni n g ir A Es s h o ul d be treate d wit h I V c ortic oster oi ds f oll o we d b y oral ster oi ds. Ot her i m m u n os u p pressi ve treat me nt s h o u l d be gi n if 
t he ir A Es are n ot c o ntr olle d b y c ortic oster oi ds.
2.   Pe m br oliz u ma b c o m bi nati o n treat me nts m ust be per ma ne ntl y disc o nti n ue d if t he ir A E d oes n ot res ol ve or t he c ortic oster oi d d ose is n ot ≤1 0 m g / da y wit hi n 
1 2 w ee ks of t he last treat me nt.
3.   T he c ortic oster oi d ta per s h o ul d be gi n w he n t he ir A E is ≤ Gra de 1 a n d c o nti n ue at least 4 w ee ks.
4.   If pe m br oliz u ma b c o m bi nati o n treat me nts ha ve bee n wit h hel d, treat me nt ma y res u me after t he ir A E decrease d t o ≤ Gra de 1 a fter c ortic oster oi d ta per.
ir A Es
T o xicit y Gr a de 
( C T C A E v 5. 0)
Acti o n Wit h 
Pe m br oliz u m a b 
M o n ot her a p y, 
C of or m ul ati o ns or I O 
C o m bi n ati o ns
C ortic oster oi d a n d/ or 
Ot her T her a pies
M o nit ori n g a n d F oll o w -u p
P ne u m o nitis
Gra de 2
Wit h h ol d 

A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 1 t o 
2 m g/ k g 
pre d nis o ne or 
e q ui vale nt) 
f oll o we d b y ta per

A d d pr o p h ylactic 
a nti bi otics f or 
o p p ort u nistic 
i nfecti o ns

M o nit or partici pa nts f or si g ns a n d s y m pt o ms 
of p ne u m o nitis

E val uate partici pa nts wit h s us pecte d 
p ne u m o nitis wit h ra di o gra p hic i ma gi n g a n d 
i nitiate c ortic oster oi d treat me nt
Rec urre nt Gra de 2, 
Gra de 3 or 4 
Per m a ne ntl y disc o nti n ue
Diarr hea/ C olitis 
Gra de 2 or 3
Wit h h ol d

A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 1 t o 
2 m g/ k g 
pre d nis o ne or 

M o nit or partici pa nts f or si g ns a n d s y m pt o ms 
of e nter oc olitis (ie, diarr hea, a b d o mi nal 
pai n, bl o o d or m uc us i n st o ol wit h or 
wit h o ut fe ver) a n d of b o w el perf orati o n (ie, 
perit o neal si g ns a n d ile us)
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 7 of 2 2 0
Rec urre nt Gra de 3 
or Gra de 4
Per m a ne ntl y disc o nti n ue
e q ui vale nt) 
f oll o we d b y ta per

Partici pa nts wit h ≥Gra de 2 diarr hea 
s us pecti n g c olitis s h o ul d c o nsi der GI 
c o ns ultati o n a n d perf or mi n g e n d o sc o p y t o 
r ule o ut c olitis

Partici pa nts wit h diarr hea/c olitis s h o ul d be 
a d vise d t o dri n k li beral q ua ntities of clear 
fl ui ds. If s ufficie nt oral fl ui d i nta ke is n ot 
feasi ble, fl ui d a n d electr ol ytes s h o ul d be 
s u bstit ute d via I V i nf usi o n
A S T or A L T Ele vati o n or 
I ncrease d Bilir u bi n
Gra de 2 a
Wit h h ol d

A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 0. 5 
t o 1 m g/ k g 
pre d nis o ne or 
e q ui vale nt) 
f oll o we d b y ta per

M o nit or w it h li ver f u ncti o n tests (c o nsi der 
wee kl y or m ore fre q ue ntl y u ntil li ver 
e nz y me val ue ret ur ne d t o baseli ne or is 
sta ble)
Gra de 3 b or 4 c
Per m a ne ntl y disc o nti n ue

A d mi nister 
c ortic oster oi ds 
(i nitial d ose of 1 t o 
2 m g/ k g 
pre d nis o ne or 
e q ui vale nt) 
f oll o we d b y ta per
T 1 D M or H y per gl yce mia
N e w  o nset T 1 D M 
or Gra de 3 or 4 
h y per gl yce mia 
ass ociate d wit h 
e vi de nce of β -cell 
fail ure
Wit h h ol d
d

I nitiate i ns uli n 
re place me nt 
t hera p y f or 
partici pa nts wit h 
T 1 D M

A d mi nister 
a nti h y per gl yce mic 
i n partici pa nts 
wit h 
h y per gl yce mia

M o nit or partici pa nts f or h y per gl yce mia or 
ot her si g ns a n d s y m pt o ms of dia betes
H y p o p h ysitis
Gra de 2
Wit h h ol d

A d mi nister 
c ortic oster oi ds a n d 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 8 of 2 2 0
Gra de 3 or 4
Wit h h ol d or per ma ne ntl y 
disc o nti n ue d
i nitiate h or m o nal 
re place me nts as 
cli nicall y i n dicate d

M o nit or f or si g ns a n d s y m pt o ms of 
h y p o p h ysitis (i ncl u di n g h y p o pit uitaris m a n d 
a dre nal i ns ufficie nc y)
H y pert h yr oi dis m  
Gra de 2
C o nti n ue

Treat w it h 
n o nselecti ve beta -
bl oc kers (e g, 
pr o pra n ol ol) or 
t hi o na mi des as 
a p pr o priate

M o nit or f or si g ns a n d s y m pt o ms of t h yr oi d 
dis or ders
Gra de 3 or 4
Wit h h ol d or per ma ne ntl y 
disc o nti n ue d
H y p ot h yr oi dis m
Gra de 2, 3 or 4
C o nti n ue

I nitiate t h yr oi d 
re place me nt 
h or m o nes (e g, 
le v ot h yr o xi ne or 
li ot h yr o ni ne) per 
sta n dar d of care

M o nit or f or si g ns a n d s y m pt o ms of t h yr oi d 
dis or ders
Ne p hritis:
gra di n g acc or di n g t o 
i ncrease d creati ni ne or 
ac ute ki d ne y i nj ur y
Gra de 2
Wit h h ol d

A d mi nister 
c ortic oster oi ds 
( pre d nis o ne 1 t o 
2 m g/ k g or 
e q ui vale nt) 
f oll o we d b y ta per

M o nit or c ha n ges of re nal f u ncti o n
Gra de 3 or 4
Per m a ne ntl y disc o nti n ue
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 0 9 of 2 2 0
Ne ur ol o gical T o xicities
Gra de 2
Wit h h ol d

Base d o n se verit y 
of A E a d mi nister 
c ortic oster oi ds

E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y a n d/ or e xcl u de ot her ca uses
Gra de 3 or 4
Per m a ne ntl y disc o nti n ue
M y ocar ditis
Gra de 1
Wit h h ol d

Base d o n se verit y 
of A E a d mi nister 
c ortic oster oi ds

E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y a n d/ or e xcl u de ot her ca uses
Gra de 2, 3 or 4
Per m a ne ntl y disc o nti n ue
E xf oliati ve Der mat ol o gic 
C o n diti o ns
S us pecte d SJ S, 
T E N, or D R E S S
Wit h h ol d

Base d o n se verit y 
of A E a d mi nister 
c ortic oster oi ds

E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y or e xcl u de ot her ca uses
C o nfir me d SJ S, 
T E N, or D R E S S
Per m a ne ntl y disc o nti n ue
All Ot her ir A Es
Persiste nt Gra de 2
Wit h h ol d

Base d o n se verit y 
of A E a d mi nister 
c ortic oster oi ds

E ns ure a de q uate e val uati o n t o c o nfir m 
eti ol o g y or e xcl u de ot her ca uses
Gra de 3
Wit h h ol d or disc o nti n ue 
base d o n t he e ve nt e
Rec urre nt Gra de 3 
or Gra de 4 
Per m a ne ntl y disc o nti n ue
a A S T/ A L T: > 3. 0 t o 5. 0 × U L N if baseli ne n or mal; > 3. 0 t o 5. 0 × baseli ne if baseli ne a b n or mal; bilir u bi n: > 1. 5 t o 3. 0 × U L N if baseli ne n or mal; > 1. 5 t o 
3. 0 × baseli ne if baseli ne a b n or mal.
b A S T/ A L T: > 5. 0 t o 2 0. 0 × U L N, if baseli ne n or mal; > 5. 0 t o 2 0. 0 × baseli ne, if baseli ne a b n or mal; bilir u bi n: > 3. 0 t o 1 0. 0 × U L N if baseli ne n or mal; > 3. 0 t o 
1 0. 0 × baseli ne if baseli ne a b n or mal.
c A S T/ A L T: > 2 0. 0 × U L N, if baseli ne n or mal; > 2 0. 0 × baseli ne, if baseli ne a b n or mal; bilir u bi n: > 1 0. 0 × U L N if baseli ne n or mal; > 1 0. 0 × baseli ne if baseli ne 
a b n or mal.
d T he decisi o n t o w it h h ol d or per ma ne ntl y disc o nti n ue pe m br oliz u ma b c o m bi nati o n treat me nt is at t he discreti o n of t he i n vesti gat or or treati n g p h ysicia n. If 
c o ntr ol ac hie ve d or ≤Gra de 2, pe m br oliz u ma b c o mbi nati o n treat me nt ma y be res u me d.
e E ve nts t hat re q uire disc o nti n uati o n i ncl u de b ut are n ot li mite d t o: e nce p halitis a n d ot her cli nicall y i m p orta n t ir A Es (e g, vasc ulitis a n d scler osi n g c h ola n gitis).
A E(s) =a d verse e ve nt(s); A L T =ala ni ne a mi n otra nsferase; A S T =as partate a mi n otra nsferase; C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; 
D R E S S = Dr u g Ras h wit h E osi n o p hilia a n d S yste mic S y m pt o m; GI = gastr oi ntesti nal; I O =i m m u n o -o nc ol o g y; ir =i m m u ne relate d; I V =i ntra ve n o us; 
SJ S = Ste ve ns -J o h ns o n S y n dr o me; T 1 D M =t y pe 1 dia betes mellit us; T E N = T o xic E pi der mal Necr ol ysis; U L N = u p per li mit of n or mal.
N ote: N o n -ir A E will be ma na ge d as a p pr o priate, f oll o wi n g cli nical practice rec o m me n dati o ns.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 0 of 2 2 0
7. 9. 5. 2. D ose M o dific ati o n a n d T o xicit y M a n a ge me nt of I nf usi o n Re acti o ns Rel ate d t o 
Pe m br oliz u m a b
Pe m br oliz u ma b c o m bi nati o n treat me nt ma y  ca use se vere or life-t hreate ni n g i nf usi o n reacti o ns 
i ncl u di n g se vere hy p erse nsiti vit y or a na p hyl a xis. Si g ns a n d s y m pt o ms us uall y  de vel o p d uri n g or 
s h ortl y after dr u g i nf usi o n a n d ge nerall y res ol ve c o m pletel y wit hi n 24 h o urs of c o m pleti o n of 
i nf usi o n. D ose m o dificati o n a n d t o xicit y ma na ge me nt g ui deli nes o n pe m br oliz u ma b c o m bi nati o n 
treat me nt-ass ociate d i nf usi o n reacti o ns are pr o vi de d i n Ta ble 2 2.
T a ble 2 2 . Pe m br oliz u m a b I nf usi o n Re acti o n D ose M o dific ati o n a n d Tre at me nt 
G ui deli nes
N CI C T C A E Gr a de
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt 
D osi n g
Gra de 1
Mil d reacti o n;
i nf usi o n 
i nterr u pti o n n ot i n dicate d; 
i nter ve nti o n n ot i n dicate d
I ncrease m o nit ori n g of vital si g ns as me dicall y i n dicate d 
u ntil t he partici pa nt is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or
N o ne
Gra de 2
Re q uires t hera p y or i nf usi o n 
i nterr u pti o n b ut res p o n ds 
pr o m ptl y t o s y m pt o matic 
treat me nt (e g, a nti hista mi nes, 
N S AI Ds, narc otics, I V fl ui ds); 
pr o p h ylactic me dicati o ns 
i n dicate d f or ≤2 4 h
St o p I nf usi o n
A d diti o nal a p pr o priate me dical t hera p y ma y i ncl u de b ut 
is n ot li mite d t o:

I V fl ui ds

A nti hista mi nes

N S AI Ds

Aceta mi n o p he n

Narc otics
I ncrease m o nit ori n g of vital si g ns as me dicall y i n dicate d 
u ntil t he partici pa nt is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or.
If s y m pt o ms res ol ve wit hi n 1 h o ur of st o p pi n g dr u g 
i nf usi o n, t he i nfusi o n ma y be restarte d at 5 0 % of t he 
ori gi nal i nf usi o n rate (e g, fr o m 1 0 0 m L/ h t o 5 0 m L/ h). 
Ot her wise d osi n g will be hel d u ntil s y m pt o ms res ol ve 
a n d t he partici pa nt s h o ul d be pre me dicate d f or t he ne xt 
sc he d ule d d ose.
Partici pa nts w h o de vel o p Gra de 2 t o xici t y des pite 
a de q uate pre me dicati o n s h o ul d be per ma ne ntl y 
disc o nti n ue d fr o m f urt her st u d y i nter ve nti o n.
Partici pa nt ma y be 
pre me dicate d 1. 5 h 
( ± 3 0 mi n) pri or t o 
i nf usi o n of st u d y 
i nter ve nti o n wit h:
Di p he n h y dra mi ne 
5 0 m g P O ( or 
e q ui vale nt d ose of 
a nti hista mi ne).
Aceta mi n o p he n 
5 0 0 t o 1 0 0 0 m g P O 
( or e q ui vale nt d ose 
of a nal gesic).
Gra des 3 or 4
Gra de 3:
Pr ol o n ge d (ie, n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
me dicati o n a n d/ or brief 
i nterr u pti o n of i nf usi o n); 
rec urre nce of s y m pt o ms after 
i nitial i m pr o ve me nt; 
h os pitalizati o n i n dicate d f or 
ot her cli nical se q uelae (e g, 
St o p I nf usi o n.
A d diti o nal a p pr o priate me dical t hera p y ma y i ncl u de b ut 
is n ot li mited t o:

E pi ne p hri ne * *

I V fl ui ds

A nti hista mi nes

N S AI Ds

Aceta mi n o p he n

Narc otics

O x y ge n

Press ors
N o s u bse q ue nt 
d osi n g
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 1 of 2 2 0
T a ble 2 2 . Pe m br oliz u m a b I nf usi o n Re acti o n D ose M o dific ati o n a n d Tre at me nt 
G ui deli nes
N CI C T C A E Gr a de
Tre at m e nt
Pre m e dic ati o n at 
S u bse q ue nt 
D osi n g
re nal i m pair me nt, p ul m o nar y 
i nfiltrates)
Gra de 4:
Life -t hreate ni n g; press or or 
ve ntilat or y s u p p ort i n dicate d

C ortic oster oi ds
I ncrease m o nit ori n g of vital si g ns as me dicall y i n dicate d 
u ntil t he partici pa nt is dee me d me dicall y sta ble i n t he 
o pi ni o n of t he i n vesti gat or.
H os pitalizati o n ma y be i n dicate d.
* *I n cases of a na p h yla xis, e pi ne p hri ne s h o ul d be use d 
i m me diatel y.
Partici pa nt is per ma ne ntl y disc o nti n ue d fr o m f urt her 
st u d y i nter ve nti o n.
C T C A E = C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts; h = h o ur; I V =i ntra ve n o us; N CI = Nati o nal Ca ncer 
I nstit ute; N S AI Ds = n o nster oi dal a nti-i nfla m mat or y dr u gs.
N ote: A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble at t he be dsi de a n d a p h ysicia n rea dil y a vaila ble 
d uri n g t he peri o d of dr u g a d mi nistrati o n.
F or f urt her i nf or mati o n, please refer t o t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts v 5. 0 ( C T C A E) at 
htt p://cte p.ca ncer. g o v
7. 9. 5. 3. Ot her All o we d D ose I nterr u pti o n f or Pe m br oliz u m a b
Pe m br oliz u ma b c o m bi nati o n treat me nt ma y be i nterr u pte d f or sit uati o ns ot her t ha n 
treat me nt-relate d A Es s uc h as me dical or s ur gical e ve nts a n d/ or u nf oresee n circ u msta nces n ot 
relate d t o st u dy i nter ve nti o n. H o we ver, st u d y i nter ve nti o n is t o be restarte d wit hi n 4 2 da ys of t he 
ori gi nall y sc he d ule d d ose a n d wit hi n 8 4 da ys of t he pre vi o usl y a d mi nistere d d ose, u nless 
ot her wise disc usse d wit h t he S p o ns or. T he reas o n f or st u d y i nter ve nti o n i nterr u pti o n is t o be 
d oc u me nte d i n t he partici pa nt's st u d y rec or d.
7. 9. 6. I nf usi o n-rel ate d Re acti o ns
S y m pt o ms of I R R occ urri n g after a d mi nistrati o n of tr ast uz u ma b, o xali plati n, le uc o v ori n, or 
fl u or o uracil i ncl u de fe ver a n d c hills, a n d o n occasi o n i ncl u de d na usea, v o miti n g, pai n (i n s o me 
cases at t u m or sites), hea dac he, dizzi ness, d y s p nea, h yp ote nsi o n, ras h, a n d ast he nia. I n se vere 
cases, s y m pt o ms ha ve i ncl u de d br o nc h os pas m, a na p h y la xis, a n gi oe de ma, h yp o xia, a n d se vere 
h y p ote nsi o n, us uall y re p orte d d uri n g or i m me diatel y f oll o wi n g t he i nitial i nf usi o n. H o we ver, t he 
o nset a n d cli nical c o urse are varia ble, i ncl u di n g pr o gressi ve w orse ni n g, i nitial i m pr o ve me nt 
f oll o we d by cli nical deteri orati o n, or dela ye d p ost -i nf usi o n e ve nts wit h ra pi d cli nical 
deteri orati o n. F or fatal e ve nts, deat h occ urre d wit hi n h o urs t o da y s f oll o wi n g a seri o us i nf usi o n 
reacti o n. 
I nterr u pt i nf usi o n i n all partici pa nts e x perie nci n g d ys p nea or cli nicall y si g nifica nt h yp ote nsi o n, 
a n d a d mi nister s u p p orti ve t hera p y ( w hic h ma y i ncl u de e pi ne p hri ne, c ortic oster oi ds, 
di p he n h y dra mi ne, br o nc h o dilat ors, a n d o x y ge n). A n y  IR R relate d t o st u d y treat me nt wit h a n y  IV 
a d mi nistere d a ge nt s h o ul d be ma na ge d acc o r di n g t o t he prescri bi n g i nf or mati o n a n d/ or 
i nstit uti o nal sta n dar d of care f or t he ca usati ve a ge nt. Partici pa nts s h o ul d be e val uate d a n d 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 2 of 2 2 0
caref ull y m o nit ore d u ntil c o m plete res ol uti o n of si g ns a n d sy m pt o ms. I n s u bse q ue nt i nf usi o ns, 
pre me dicate partici pa nts wit h a nti hista mi nes a n d/ or c ortic oster oi ds.
Disc o nti n ue t he ca usati ve a ge nt(s) i n partici pa nts wit h Gra de 3 -4 i nf usi o n reacti o ns.
7. 9. 7. Aller gic/ H y perse nsiti vit y Re acti o ns
Aller gic/ h y perse nsiti vit y  reacti o ns are c haracterize d b y a d verse l ocal or ge neral res p o nses fr o m 
e x p os ure t o a n aller ge n ( N CI C T C A E v 5. 0). F or p ur p oses of t his st u d y, aller gic/ hy p erse nsiti vit y 
reacti o ns are differe ntiate d fr o m IR Rs b y  bei n g defi ne d as occ urri n g > 2 4 h o urs after i nf usi o n of 
st u d y treat me nt. Aller gic/ h yperse nsiti vit y  reacti o ns ma y ma nifest i n t he sa me ma n ner as I R Rs, 
ie, a c o m bi nati o n of si g ns or s ym pt o ms i ncl u di n g fe ver, ri g ors, fl us hi n g, itc hi n g, vari o us t y pes of 
ras h, urticaria, dys p nea, na usea, v o miti n g, bac k or a b d o mi nal pai n, a n d/ or h y p ote nsi o n.
S u p p ortive C are f or Hy perse nsi tivity Re acti o ns Ty pes 1 a n d 3:
T y pe 1 h y perse nsiti vit y  or aller gic (e g, s h ort ness of breat h, urticaria, a na p h yla xis, a n gi oe de ma) 
reacti o ns are t he oreticall y p ossi ble i n res p o nse t o a n y i njecte d pr otei n. Im m u ne c o m ple x 
me diate d T y pe 3 h y perse nsiti vit y  reacti o ns are si milar t o t he A Es of T ype 1 reacti o ns b ut are 
li kel y t o be dela ye d fr o m t he ti me of i nf usi o n a n d ma y  i ncl u de s ym pt o ms s uc h as ras h, urticaria, 
p ol y art hritis, m yal gia, p ol ys yn o vitis, fe ver, a n d, if se vere, gl o mer ul o ne p hritis. 
All partici pa nts s h o ul d be cl osel y o bser ve d w hile recei vi n g st u d y i nter ve nti o n i nf usi o ns a n d 
m o nit ori n g f or cli nical si g ns of a s ys te mic reacti o n will c o nti n ue t hereafter f or cli nical si g ns of 
aller gic reacti o ns/ h y perse nsiti vit y . 
I n t he case of a hy p erse nsiti vit y reacti o n, t he partici pa nt will be treate d sy m pt o maticall y  wit h 
s u p p orti ve care, f urt her m o nit ori n g, a n d treat me nt wit h a nti hista mi nes a n d/ or c ortic oster oi ds. 
St u d y  i nf usi o ns ma y be st o p pe d a n d t he partici pa nt will be f oll o we d u ntil t he e n d of t he st u d y.
7. 9. 8. A n a p h yl a xis
A na p h yl a xis is a se vere, life -t hreate ni n g, ge neralize d or s yste mic aller gic/ h yperse nsiti vit y  
reacti o n. A na p hyl a xis is c haracterize d b y a n ac ute i nfla m mat or y reacti o n res ulti n g fr o m t he 
release of hista mi ne a n d hista mi ne-li ke s u bsta nces fr o m mast cells, ca usi n g a hy p erse nsiti vit y 
i m m u ne res p o nse. Cli nicall y, it prese nts wit h breat hi n g diffic ulty, dizzi ness, h y p ote nsi o n, 
c ya n osis, a n d l oss of c o nsci o us ness a n d ma y lea d t o deat h. ( N CI C T C A E v 5. 0; R osell o 2 0 1 7 ).
If a na p hyl a xis occ urs, a d mi nistrati o n of t he ca usati ve a ge nt (s) s h o ul d be i m me diatel y  a n d 
per ma ne ntl y disc o nti n ue d.
7. 9. 9.
M a n a ge me nt of Di arr he a
Perf or m dia g n ostic tests as cli nicall y  i n dicate d t o e xcl u de ot her ca uses of diarr hea. If a n alter nate 
ca use o f diarr hea is s us pecte d a n d/ or i de ntifie d, treat acc or di n gly.
F or partici pa nts w h o are recei vi n g pri mar y  a nti diarr heal pr o p hyl a xis, please refer t o 
Secti o n 7. 1 1. 2 f or d osi n g g ui da nce. A nti diarr heal pr o p h yla xis s h o ul d be hel d i n sit uati o ns w here 
use is c o ntrai n dicate d (e g, i m m u ne me diate d c olitis/ diarr hea, bacterial e nter oc olitis), u ntil 
res ol uti o n of t he c o ntrai n dicati o n.
I n partici pa nts recei vi n g a nti diarr heals f or s y m pt o matic c o ntr ol of treat me nt -ass ociate d diarr hea:
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 3 of 2 2 0

E arl y Detecti o n: I nstr uct partici pa nts t o re p ort diarr hea o n t he first sy m pt o m/si g n of 
diarr hea.

E arl y I nter ve nti o n: 
o
F or partici pa nts w h o are n ot recei vi n g pr o p h yl a xis, pr o vi de partici pa nts wit h 
prescri pti o n f or l o pera mi de ( or ot her i nstr ucti o ns f or o btai ni n g l o pera mi de) 
a n d i nstr uct t he m t o start treat me nt as s o o n as first u nf or me d st o ol occ urs. T he 
rec o m me n de d d ose of l o pera mi de is 4 m g at first u nf or me d st o ol, f oll o we d b y 
2 m g e ver y 2 t o 4 h o urs u ntil diarr hea free ( ma xi m u m 1 6 m g/ da y ).
o
I n partici pa nts w h o ha ve persiste nt Gra de 1 diarr hea des pite l o pera mi de 
(i ncl u di n g partici pa nts recei vi n g a nti diarr heal pr o p h yla xis), c o nsi der 
treat me nt wit h L o m otil ( di p he n o x ylate h ydr oc hl ori de a n d atr o pi ne s ulfate) 
2. 5 m g/ 0. 0 2 5 m g e ver y  6 t o 8 h o urs
o
I nstr uct partici pa nts t o call site if diarr hea persists > 4 8 h o urs or t here is a n 
i ncrease of ≥7 st o ols per da y  o ver baseli ne ( Gra de 3 Diarr hea per C T C A E 
v 5. 0), or wit h ot her war ni n g si g ns s uc h as fe v er, bl o o d y st o ols, or se vere 
a b d o mi nal pai n.
o
I nstr uct partici pa nts t o mai ntai n oral hy drati o n. I nter ve nti o n wit h I V fl ui ds 
a n d electr ol yt e re place me nt s h o ul d be c o nsi dere d as cli nicall y  i n dicate d.
o
I nstr uct partici pa nts t o see k me dical atte nti o n if u na ble to mai ntai n oral 
h y drati o n d ue t o diarr hea or wit h ot her war ni n g si g ns as n ote d a b o ve. If 
diarr hea is se vere (ie, re q uiri n g I V re h y drati o n) a n d/ or ass ociate d wit h fe ver 
or se vere ne utr o pe nia ( Gra de 3 or 4), br oa d -s pectr u m a nti bi otics s h o ul d be 
prescri be d. In partici pa nts wit h se vere diarr hea, or a n y diarr hea ass ociate d 
wit h se vere na usea or v o miti n g, h os pitalizati o n s h o ul d be c o nsi dere d f or I V 
h y drati o n a n d c orrecti o n of electr ol yt e i m bala nces.
7. 9. 1 0. D ose M o dific ati o ns f or Di arr he a
T ucati ni b s h o ul d be m o difie d bef ore c he m ot hera p y  or pe m br oliz u ma b ( w here a p plica ble), e xce pt 
i n i nsta nces w here partici pa nts are recei vi n g m F O L F O X 6, w here disc o nti n uati o n of t he 
fl u or o uracil b ol us d ose ma y first be c o nsi dere d. See Ta ble 1 3 f or d ose m o dificati o n g ui deli nes of 
t ucati ni b f or diarr hea. D ose m o dificati o ns f or c he m ot hera py s h o ul d als o be c o nsi dere d w here 
a p pr o priate (see Ta ble 1 5 a n d Ta ble 1 8 ). F or partici pa nts recei vi n g treat me nt wit h 
pe m br oliz u ma b, i nterr u pti o n of pe m br oliz u ma b s h o ul d be c o nsi dere d if n o i m pr o ve me nt i n t he 
partici pa nt’s c o n diti o n is ac hie ve d after i nitiati o n of s u p p orti ve care meas ures a n d d ose 
m o dificati o ns t o t ucati ni b a n d/ or c he m ot hera p y ( w here a p pr o priate). Dia g n ostic w or k -u p f or 
ir A Es (ie, c olitis) s h o ul d be als o i nitiate d (see Ta ble 2 1 ). W he n diarr hea is u n der c o ntr ol, 
treat me nt wit h t ucati ni b, pe m br oliz u ma b, a n d c he m ot hera py ma y be rei nstate d w he n a p plica ble. 
Use of pr o p h yl actic a nti diarr heals ma y als o be c o nsi dere d w here cli nicall y  i n dicate d.
7. 1 0. Re q uire d Pre me dic ati o n a n d P ost me dic ati o n
Pre me dicati o n a n d p ost me dicati o n s h o ul d be a d mi nistere d i n acc or da nce wit h l ocal pr o d uct 
la beli n g a n d per i nstit uti o nal sta n dar d of care.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 4 of 2 2 0
7. 1 1. C o nc o mit a nt T her a p y
All c o nc o mita nt me dicati o ns, bl o o d pr o d ucts, a n d ra di ot hera p y a d mi nistere d will be rec or de d 
fr o m Da y 1 ( pre d ose) t hr o u g h t he safety re p orti n g peri o d. A n y c o nc o mita nt me dicati o n gi ve n f or 
a st u d y pr ot oc ol-relate d A E s h o ul d be rec or de d fr o m t he ti me of i nf or me d c o nse nt t hro u g h t he 
safety re p orti n g peri o d.
7. 1 1. 1. P ote nti al C o nc o mit a nt Dr u g I nter acti o ns
7. 1 1. 1. 1. T uc ati ni b
T ucati ni b is cleare d pre d o mi na ntl y  b y C Y P 2 C 8 a n d t o a lesser e xte nt b y C Y P 3 A 4. Str o n g 
C Y P 2 C 8 i n hi bit ors a n d str o n g C Y P 2 C 8 or C Y P 3 A 4 i n d ucers are pr o hi bite d as c o nc o mita nt 
m e dicati o ns d uri n g st u d y treat me nt a n d wit hi n 1 wee k of disc o nti n uati o n of t ucati ni b treat me nt. 
T ucati ni b e x hi bits i n hi biti o n of h u ma n C Y P 3 A e nz y mes, a n d t heref ore has t he p ote ntial t o 
i nteract wit h ot her me dicati o ns t hat are s u bstrates of C Y P 3 A. Use of sensiti ve C Y P 3 A s u bstrates 
s h o ul d be a v oi de d 1 wee k pri or t o e nr oll me nt a n d d uri n g st u d y treat me nt. C o nsi der usi n g a n 
alter nate me dicati o n t hat is n ot a se nsiti ve C Y P 3 A s u bstrate. If u na v oi da ble, c o nsi der d ose 
re d ucti o n of C Y P 3 A s u bstrates wit h narr o w t hera pe utic i n dices a n d/ or i ncrease d m o nit ori n g f or 
p ote ntial a d verse reacti o ns as descri be d i n t he me dicati o n’s prescri bi n g i nf or mati o n.
Treat me nt wit h t ucati ni b is ass ociate d wit h mil d i ncreases i n ser u m creati ni ne t hat were 
re versi ble u p o n treat me nt disc o nti nuati o n. A de dicate d D DI st u d y de m o nstrate d n o i m pact o n 
re nal f u ncti o n.
7. 1 1. 1. 2. Tr ast uz u m a b
Please refer t o t he l ocal pr o d uct la beli n g f or trast uz u ma b p ote ntial dr u g i nteracti o ns.
I n P K st u dies, trast uz u ma b (a m o n ocl o nal a nti b o d y) di d n ot alter t he plas ma c o nce ntrati o ns of 
s mall m olec ules s uc h as paclita xel, d oceta xel, or d o x or u bici n. It is t heref ore ver y u nli kely t hat 
trast uz u ma b w o ul d ha ve a n effect o n t he P K of t ucati ni b. T here was n o D DI bet wee n t ucati ni b 
a n d trast uz u ma b o bser ve d i n St u d y  O N T- 3 8 0-0 0 5, a c o m bi nati o n st u d y  of t ucati ni b wit h 
ca pecita bi ne a n d trast uz u ma b.
7. 1 1. 1. 3. F O L F O X
Please refer t o t he l ocal pr o d uct la beli n g f or F O L F O X p ote ntial dr u g i nteracti o ns.
7. 1 1. 1. 4. C A P O X
Please refer t o t he l ocal pr o d uct la beli n g f or C A P O X p ote ntial dr u g i nteracti o ns.
7. 1 1. 1. 5. Pe m br oliz u m a b
As pe m br oliz u ma b is a n I g G 4 a nti b o d y t hat is a d mi nistere d pare nterall y a n d cleare d b y 
cata b olis m, f o o d a n d D DI are n ot a ntici pate d t o affect e x p os ure. N o de dica te d D DI st u dies ha ve 
t heref ore bee n perf or me d. As s yste mic c ortic oster oi ds ma y be use d t o treat i m m u ne me diate d 
A Rs c o nc o mita nt wit h pe m br oliz u ma b, t he p ote ntial f or a P K D DI wit h pe m br oliz u ma b was, 
h o we ver, assesse d. N o relati o ns hi p was o bser ve d bet wee n p r ol o n ge d use of s yste mic 
c ortic oster oi ds a n d pe m br oliz u ma b e x p os ure. Si milarl y, t he p ote ntial of D DI bet wee n 
pe m br oliz u ma b a n d c he m ot hera p y a ge nts as well as ot her s mall m olec ules is e x pecte d t o be l o w. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 5 of 2 2 0
N o effect of c oa d mi nistere d pe metre xe d a n d car b o plati n, e paca d ostat, or a xiti ni b o n 
pe m br oliz u ma b P K was o bser ve d. 
7. 1 1. 2. Re q uire d C o nc o mit a nt T her a p y
All partici pa nts e nr olle d i n C o h orts 1 D, 1 E, a n d 2 B, a n d all partici pa nts e nr olle d i n C o h ort 2 A 
w h o are treate d wit h t ucati ni b + trast uz u ma b + pe m br oliz u ma b + m F O L F O X 6 m ust als o recei ve 
pri mar y  pr o p hyl a xis wit h a nti diarr heal me dicati o n be gi n ni n g c o nc o mita ntl y wit h t he first d ose of 
t ucati ni b o n C ycle 1 Da y 1, as f oll o ws: l o pera mi de 4 m g t hree ti mes dail y ( Da y s 1 t o 1 4) f or t he 
first 1 4 da ys f oll o we d b y 4 m g t wice dail y ( Da y 1 5 t hr o u g h Da y 4 2). F oll o wi n g t his i nitial 
4 2 -d a y  peri o d, partici pa nts ma y c o nti n ue o n a nti diarr heal pr o p h yla xis at a d ose of 2 t o 4 m g as 
nee de d, n ot t o e xcee d 1 6 m g per da y  (see Secti o n 7. 9. 9 ). T he I n vesti gat or m ust e ns ure t hat all 
partici pa nts w h o are sc he d ule d t o recei ve t ucati ni b ha ve a n a de q uate s u p pl y of l o pera mi de pri or 
t o C ycle 1 Da y 1 of treat me nt.

T he first d ose of l o pera mi de m ust be a d mi nistere d c o nc o mita ntl y  wit h t he first d ose 
of t ucati ni b. T he d osi n g of l o pera mi de s h o ul d be titrate d s uc h t hat partici pa nts ha ve 
1 - 2 st o ols per da y t hr o u g h o ut Da ys 1-4 2 a n d after war ds, as necessar y . T he d ose of 
l o pera mi de ca n be m o difie d, or l o pera mi de ca n be hel d at a n y p oi nt d uri n g t he st u d y 
as per i n vesti gat or discreti o n if partici pa nt has c o nsti pati o n or < 1 st o ol per da y .

A nti diarr heal pr o p h yl a xis s h o ul d be hel d i n sit uati o ns w here use is c o ntrai n dicate d 
(e g, i m m u ne me diate d c olitis/ diarr hea, bacterial e nter oc olitis), u ntil res ol uti o n of t he 
c o ntrai n dicati o n.

If t ucati ni b is disc o nti n ue d d uri n g t he first 4 2 da ys of treat me nt, a nti diarr heal 
pr o p h y la xis is n o l o n ger re q uire d, b ut s h o ul d be use d as nee de d (see Secti o n 7. 9. 9 ).

T he I n vesti gat or m ust e ns ure t hat all partici pa nts w h o are sc he d ule d t o recei ve 
t ucati ni b ha ve a n a de q uate s u p pl y of l o pera mi de pri or t o C ycle 1 Da y 1 of treat me nt. 
Details re gar di n g s o urci n g of l o pera mi de ma y  var y b y site a n d/ or re gi o n as o utli ne d 
i n ot her d oc u me nts s uc h as Cli nical Trial A gree me nts.

T he I n vesti gat or m ust re vie w t he Patie nt I nstr ucti o ns f or t he pr o p h yl a xis a n d 
ma na ge me nt of diarr hea wit h t he partici pa nt pri or t o treat me nt o n C ycle 1 Da y 1.

T he I n vesti gat or m ust e ns ure t hat all partici pa nts ha ve recei ve d a n d a gree d t o use a 
diar y  t o rec or d t he n u m ber of st o ols a n d t he a m o u nt of l o pera mi de a n d/ or ot her 
a nti diarr heals use d a n d m ust re vie w t he res ults of t he diar y  with patie nts d uri n g eac h 
visit i n t he first 6 wee ks of st u d y  treat me nt. I n vesti gat ors s h o ul d re vie w t he data i n 
or der t o acc uratel y rec or d diarr hea A Es a n d t he gra des f or t he e ve nts t hat occ ur 
d uri n g t he first 6 wee ks of st u d y  treat me nt ( Da ys 1-4 2).
A nti diar r heal pr o p hyl a xis will n ot be re q uire d f or partici pa nts e nr olle d i n C o h orts 1 C, 1 F, 1 G, or 
f or partici pa nts i n C o h ort 2 A w h o are treate d wit h t ucati ni b + trast uz u ma b + pe m br oliz u ma b + 
C A P O X, u nless rec o m me n de d b y t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he 
data fr o m t hese c o h orts d uri n g t he c o urse of t he st u d y . S h o ul d a nti diarr heal pr o p h yla xis be 
re q uire d, t he d ose a n d sc he d ule of l o pera mi de as descri be d a b o ve will be f oll o we d. Partici pa nts 
m ust be i nstr ucte d o n t he o pti mal use of a nti diarr heals f or s y m pt o matic c o ntr ol of treat me nt -
ass ociate d diarr hea as descri be d i n Secti o n 7. 9. 9 . 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 6 of 2 2 0
7. 1 1. 3. All o we d C o nc o mit a nt T her a p y
Partici pa nts ma y  c o nti n ue t o use a n y o n g oi n g me dicati o ns n ot pr o hi bite d b y  t he 
i ncl usi o n/e xcl usi o n criteria. H o we ver, eff orts s h o ul d be ma de t o mai ntai n sta ble d oses of 
c o nc o mita nt me dicati o ns d uri n g t he c o urse of st u d y  treat me nt. All bl o o d pr o d ucts a n d 
c o nc o mita nt me dicati o ns recei v e d fr o m Da y 1 ( pre d ose) t hr o u g h t he safety re p orti n g peri o d are 
t o be rec or de d i n t he me dical rec or ds.

D uri n g st u d y treat me nt, partici pa nts ma y  recei ve s u p p orti ve care, i ncl u di n g 
bis p h os p h o nates, he mat ol o gic a n d a nti -i nfecti o us s u p p ort, pai n ma na ge me nt, 
a ntaci ds, la xati ves, a n d treat me nt of ot her ne wl y dia g n ose d or c o nc urre nt me dical 
c o n diti o ns 

A nti diarr he als are re q uire d f or C o h orts 1 D, 1 E, 2 B, a n d all partici pa nts e nr olle d i n 
C o h ort 2 A w h o are treate d wit h t ucati ni b + trast uz u ma b + pe m br oliz u ma b + 
m F O L F O X 6 (see Secti o n 7. 1 1. 2 ). F or ot her c o h orts, pr o p h y lactic use of 
a nti diarr heals is per mitte d at t he discreti o n of t he i n vesti gat or. S y m pt o matic treat me nt 
of diarr hea s h o ul d f oll o w rec o m me n dati o ns as descri be d i n Secti o n 7. 9. 9 . 
Pr o p h y lactic a n d sy m pt o matic treat me nt of na usea a n d v o miti n g ma y  be use d per 
sta n dar d- of-care

T h orace ntesis or parace ntesis ma y  be perf or me d, if nee de d f or c o mf ort, f oll o wi n g 
co ns ultati o n wit h t he me dical m o nit or 

If s ur gical i nter ve nti o n or l ocalize d ra diati o n bec o me i n dicate d (eit her f or palliati o n 
or d o w n -sta gi n g of pre vi o usl y u nresecta ble t u m or), t hese i nter ve nti o ns s h o ul d be 
a v oi de d if cli nicall y feasi ble u ntil after t he se c o n d res p o nse assess me nt a n d t he 
me dical m o nit or s h o ul d be c o ns ulte d pri or t o t he i nter ve nti o n occ urri n g

Bl o o d pr o d ucts a n d gr o wt h fact ors s h o ul d be utilize d as cli nicall y i n dicate d a n d 
f oll o wi n g i nstit uti o nal p olicies a n d rec o m me n dati o ns 

R o uti ne pr o p h y laxis wit h vacci nes is per mitte d, if vacci nes use d d o n ot c o ntai n li ve 
micr o -or ga nis ms

S y ste mic gl uc oc ortic oi ds are per mitte d o nl y f or t he f oll o wi n g p ur p oses:
o
T o m o d ulate s y m pt o ms of a n A E t hat is s us pecte d t o ha ve a n i m m u n ol o gic 
eti ol o g y
o
As nee de d f or t he p re ve nti o n of e mesis
o
Pre me dicati o n f or I V c o ntrast aller gies
o
S h ort -ter m oral or I V use i n d oses > 1 0 m g/ da y  pre d nis o ne e q ui vale nt f or 
C O P D e xacer bati o ns
o
F or c hr o nic s ys te mic re place me nt n ot t o e xcee d 1 0 m g/ da y  pre d nis o ne 
e q ui vale nt

I n a d diti o n, t he f oll o wi n g gl uc oc ortic oi d use is all o we d:
o
F or t o pical use or oc ular use
o
I ntraartic ular j oi nt use
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 7 of 2 2 0
o
F or i n halati o n i n t he ma na ge me nt of ast h ma or c hr o nic o bstr ucti ve p ul m o nar y  
disease
7. 1 1. 4. C o nc o mit a nt T her a pies t o be Use d wit h C a uti o n
Partici pa nts o n a nti -c oa g ula nt treat me nt s h o ul d be cl osel y m o nit ore d d uri n g st u d y treat me nt.
Se nsiti ve s u bstrates of C Y P 3 A ( A p pe n di x F ); t ucati ni b e x hi bits i n hi biti o n of h u ma n C Y P 3 A 
e nz ymes, a n d t heref o re has t he p ote ntial t o i nteract wit h ot her me dicati o ns t hat are s u bstrates of 
C Y P 3 A. T heref ore, c o nc o mita nt use of t ucati ni b wit h se nsiti ve C Y P 3 A s u bstrates s h o ul d be 
a v oi de d 1 wee k pri or t o t he first d ose of t ucati ni b a n d w hile o n st u d y  treat me nt. C o nsi der usi n g 
a n alter nate me dicati o n t hat is n ot a se nsiti ve C Y P 3 A s u bstrate. If u na v oi da ble, c o nsi der d ose 
re d ucti o n of C Y P 3 A s u bstrates wit h narr o w t hera pe utic i n dices a n d/ or i ncrease d m o nit ori n g f or 
p ote ntial a d verse reacti o ns as descri be d i n t he me dicati o n’s prescri bi n g i nf or mati o n.
C o nc o mita nt use of t ucati ni b wit h di g o xi n, a P -gl yc o pr otei n ( P - g p) s u bstrate, i ncreases di g o xi n 
c o nce ntrati o ns, w hic h ma y i ncrease t he ris k f or di g o xi n relate d a d verse reacti o ns. C o nc o mita nt 
use of t ucati ni b wit h di g o xi n or P -g p s u bstrates wit h a narr o w t hera pe utic i n de x (s uc h as, b ut n ot 
li mite d t o, da bi gatra n, fe x ofe na di ne, a n d c ycl os p ori ne) s h o ul d be use d wit h ca uti o n. Refer t o t he 
prescri bi n g i nf or mati o n of di g o xi n or ot her P -g p s u bstrates f or d osa ge a dj ust me nt 
rec o m me n dati o ns d ue t o dr u g i nteracti o ns.
7. 1 1. 5. Pr o hi bite d C o nc o mit a nt T her a p y
T he f oll o wi n g t hera pies are pr o hi bite d d uri n g t he st u d y  ( u nless ot her wise n ote d):

I n vesti gati o nal dr u gs a n d de vices

A ntica ncer t hera p y, i ncl u di n g b ut n ot li mite d t o c he m ot hera p y, h or m o nal t hera p y, 
a n d a nti -V E G F a nti b o dies

I m m u n ot hera py n ot s pecifie d i n t his pr ot oc ol; if t he i n vesti gat or deter mi nes 
partici pa nt re q uires treat me nt wit h t he af ore me nti o ne d t hera p y f or a ny reas o n, 
pe m br oliz u ma b m ust be disc o nti n ue d.

Ra diati o n t hera p y, e xce pt f or palliati v e ra di ot hera p y at f ocal n o n-ce ntral ner v o us 
s yste m sites t hat are n ot c o nsi dere d tar get lesi o ns acc or di n g t o R E CIS T v 1. 1, w hic h 
ma y  be gi ve n after c o ns ultati o n wit h t he me dical m o nit or. Ra diati o n t hera p y directe d 
at tar get lesi o ns acc or di n g t o R E CIS T v 1. 1 re q uires pri or a p pr o val by t he me dical 
m o nit or. T ucati ni b, C A P O X, a n d F O L F O X m ust be hel d 7 da y s pri or t o a n d 7 da ys 
p ost ra diati o n t hera p y.

Li ve or li ve atte n uate d vacci nes wit hi n 3 0 da y s bef ore t he first d ose of st u d y 
i nter ve nti o n, w hile partici pati n g i n t he st u d y, a n d f or at least 3 m o nt hs after last d ose 
of c he m ot hera p y. if t he i n vesti gat or deter mi nes partici pa nt re q uires treat me nt wit h t he 
af ore me nti o ne d t hera p y f or a n y reas o n, pe m br oliz u ma b m ust be disc o nti n ue d. N ote: 
Kille d vacci nes are all o we d. 

Str o n g i n d ucers of C Y P 3 A 4 are pr o hi bite d as c o nc o mita nt me dicati o ns d uri n g st u d y 
treat me nt a n d wit hi n 1 wee k of disc o nti n uati o n of st u d y treat me nt (see A p pe n di x D )
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 8 of 2 2 0

Str o n g i n hi bit ors or i n d ucers of C Y P 2 C 8 are pr o hi bite d as c o nc o mita nt me dicati o ns 
d uri n g st u d y treat me nt a n d wit hi n 1 wee k of disc o nti n uati o n of t ucati ni b treat me nt 
(A p pe n di x E ). M o derate i n hi bit ors of C Y P 2 C 8 s h o ul d be use d wit h ca uti o n. 

Warfari n t hera p y, or t hera p y wit h ot her c o u mari n deri vati ves is n ot per mitte d o n t he 
st u d y f or a n y partici pa nt recei vi n g C A P O X ( C o h orts 1 C, 1 F, a n d 2 A).

Partici pa nts ma y  n ot recei ve i m m u n os u p pressi ve me dicati o ns d uri n g t he st u d y. If t he 
i n vesti gat or deter mi nes partici pa nt re q uires treat me nt wit h t he af ore me nti o ne d 
t hera py f or a n y reas o n, pe m br oliz u ma b m ust be disc o nti n ue d.
7. 1 2. M a n a ge me nt of O ver d ose
7. 1 2. 1. T uc ati ni b
I n t he e ve nt of a n o ver d ose of t ucati ni b, defi ne d as a n y  d ose greater t ha n t he prescri be d d ose, 
st u d y pers o n nel s h o ul d:

Care f or a n d me dicall y  sta bilize t he partici pa nt u ntil t here is n o i m me diate ris k of 
c o m plicati o ns or deat h, if a p plica ble. T here is c urre ntl y n o k n o w n a nti d ote f or a n 
o ver d ose of t ucati ni b.

N otif y  t he me dical m o nit or as s o o n as t he y bec o me a ware of t he o ver d ose, t o disc uss 
details of t he o ver d ose (e g, e xact a m o u nt of t ucati ni b a d mi nistere d, partici pa nt 
wei g ht) a n d A Es, if a n y.
O ver d ose e ve nts ( wit h or wit h o ut ass oci ate d A Es) are t o be ca pt ure d o n t he A E e C R F.
O ver d ose is re p orta ble t o Pfizer Safet y  o nly w he n ass ociate d wit h a n S A E.
7. 1 2. 2. Pe m br oliz u m a b
F or t his st u d y , a n o ver d ose of pe m br oliz u ma b will be defi ne d as a n y d ose of 1 0 0 0 m g or greater. 
N o s pecific i nf or mati o n is a vaila ble o n t he treat me nt of o ver d ose of pe m br oliz u ma b. I n t he e ve nt 
of o ver d ose, t he partici pa nt s h o ul d be o bser ve d cl osel y  f or si g ns of t o xicit y. A p pr o priate 
s u p p orti ve treat me nt s h o ul d be pr o vi de d if cli nicall y i n dicate d. 
O v er d ose is re p orta ble t o Pfizer Safet y  o nly w he n ass ociate d wit h a n S A E.
7. 1 2. 3. Tr ast uz u m a b, O x ali pl ati n, C a pecit a bi ne, Le uc o v ori n, a n d Fl u or o ur acil
Refer t o t he l ocal pr o d uct la beli n g f or o ver d ose i nf or mati o n f or trast uz u ma b, o xali plati n, 
ca pecita bi ne, le uc o v ori n , a n d fl u or o uracil. 
7. 1 3. Tre at me nt C o m pli a nce
St u d y  treat me nt a d mi nistrati o n will be perf or me d b y st u d y site staff a n d d oc u me nte d i n s o urce 
d oc u me nts a n d t he e C R F.
St u d y -dr u g c o m plia nce will be assesse d o n a partici pa nt -b y - partici pa nt basis usi n g partici pa nt 
d iaries. T he p har macist or desi g nee will rec or d t he n u m ber of t ucati ni b ta blets dis pe nse d t o eac h 
i n di vi d ual partici pa nt, a n d t he n u m ber of ta blets ret ur ne d t o t he cli nic at t he e n d of eac h c ycle.
Data re gar di n g t he a d mi nistrati o n a n d d ose of trast uz u ma b, p e m br oliz u ma b, o xali plati n, 
le uc o v ori n, ca pecita bi ne, a n d fl u or o uracil will als o be c ollecte d by t he site after eac h c y cle. D ose 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 1 9 of 2 2 0
m o dificati o ns a n d i nterr u pti o ns of a n y  st u d y treat me nt will be d oc u me nte d i n t he s o urce 
d oc u me nts a n d t he e C R F.
F oll o wi n g i m ple m e ntati o n of A me n d me nt 5 a n d e ntr y  of re mai ni n g o n-treat me nt partici pa nts 
i nt o t he LT E P, treat me nt a d mi nistrati o n data will n o l o n ger be c ollecte d i n e C R Fs. Please refer 
t o Secti o n 1 0. 2 f or f urt her detail o n L T E P data c ollecti o n re q uire me nts.
8. S T U D Y A C TI VI TI E S
8. 1. Sc he d ule of E ve nts
A Es a n d c o nc o mita nt me dicati o ns will be rec or de d fr o m Da y  1 ( pre d ose) t hr o u g h t he safet y 
re p orti n g peri o d (see Secti o n 9. 5. 1. 7 ). A n y st u d y pr ot oc ol-relate d A E ( defi ne d i n Secti o n 9. 5. 1. 1 ) 
as well as a n y c o nc o mita nt me dicati o ns gi ve n f or treat me nt of t he A E s h o ul d be rec or de d fr o m 
t he ti me of i nf or me d c o nse nt.
Cli nical la b orat or y  assess me nts (ser u m/ plas ma c he mistr y pa nel, c oa g ulati o n pa nel, ser u m 
c ystati n C, C B C wit h differe ntial [ ma n ual differe ntial if cli nicall y  i n dicate d, see Secti o n 9. 5. 3 ], 
uri nal y sis [i ncl u di n g uri ne pr otei n a n d creati ni ne, wit h micr osc o p y if cli nicall y i n dicate d], 
p h y sical e xa m, vital si g ns, wei g ht, a n d perf or ma nce stat us) ma y be perf or me d wit hi n 1 da y pri or 
t o a d mi nistrati o n of st u d y treat me nt. T he res ults fr o m all rele va nt cli nical la b orat or y assess me nts 
m ust be re vie we d pri or t o d os i n g.
Partici pa nts still recei vi n g cli nical be nefit a n d re mai ni n g o n st u d y treat me nt as of A me n d me nt 5 
ma y  c o nti n ue recei vi n g st u d y i nter ve nti o n d uri n g t he LT E P. D uri n g t his p hase of t he st u d y , o nly 
i nf or mati o n relate d t o pre g na ncies a n d S A Es will be re p ort e d t o t he S p o ns or. All safet y a n d 
efficac y assess me nts will be perf or me d per i nstit uti o nal g ui deli nes a n d i n vesti gat or-deter mi ne d 
us ual a n d c ust o mar y  cli nical care, wit h t he e xce pti o n of pre g na nc y testi n g w hic h will c o nti n ue as 
o utli ne d i n t he sc he d ule of e ve nts f or partici pa nts of c hil d beari n g p ote ntial.
A sc he d ule of e ve nts is pr o vi de d i n A p pe n di x A . St u d y acti vities are liste d b y visit i n t his secti o n 
a n d descri p ti o ns of all st u d y assess me nts are prese nte d i n Secti o n 9 .
8. 2. Scree ni n g Visit ( D a ys – 2 8 t o – 1)

I nf or me d c o nse nt

St u d y  eli gi bilit y per i ncl usi o n/e xcl usi o n criteria

Me dical hist or y  (i ncl u di n g assess me nt of diarr hea a n d a nti diarr heal usa ge)

He patitis B a n d C scree ni n g

Ra di ol o gical disease assess me nt (c o m p ute d t o m o gra p h y [ C T], p ositr o n e missi o n 
t o m o gra p hy [ P E T] -C T, a n d/ or M RI )

C o nc o mita nt me dicati o ns a n d A E s 

Electr ocar di o gra m ( E C G)

E C H O/ M U G A

Bl o o d sa m ple f or bi o mar ker a nal ys is
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 0 of 2 2 0

C ollecti o n of m ost rece ntl y  a vaila ble tiss ue, if a vaila ble. F or partici pa nts e nr olle d i n 
C o h orts 2 A a n d 2 B, c ollecti o n of m ost rece ntl y a vaila ble tiss ue is re q uire d.

T h y r oi d f u ncti o n tests f or C o h orts 1 E, 1 F, 1 G, a n d 2 A
8. 2. 1. B aseli ne Visit ( D a y – 7 t o D a y – 1) *

I ncl usi o n/e xcl usi o n criteria

Vital si g ns, wei g ht, hei g ht

P h y sical e xa m

E C O G Perf or ma nce stat us

C o nfir mati o n of last bl o o d tra nsf usi o n

C B C wit h differe ntial

Ser u m/ plas m a c he mistr y pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D LTs 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

C oa g ulati o n pa nel

Uri nal y sis

Uri ne pr otei n/creati ni ne rati o

C o nc o mita nt me dicati o ns a n d A Es

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial wit hi n 2 4 h o urs of treat me nt

Ra di ol o gical disease assess me nt ( C T, P E T- C T, a n d/ or M RI) f or partici pa nts 
recei vi n g o xali plati n d uri n g scree ni n g peri o d
* Baseli ne visit s h o ul d be sc he d ule d t o e ns ure t hat deter mi nati o n of esti mate d G F R ca n occ ur 
wit hi n 7 da y s of e nr oll me nt. 
8. 3. F O L F O X Tre at me nt Peri o d ( 1 4 -d a y c ycles) P h ase 1 b T uc ati ni b D ose Esc al ati o n 
( C o h orts 1 A a n d 1 B), J a p a n-s pecific C o h ort 1 D, Pe m br oliz u m a b C o h ort 1 E, a n d P h ase 2 
T u m or S pecific E x p a nsi o n C o h orts ( C o h orts 2 A a n d 2 B)
8. 3. 1. C ycle 1 D a y 1 – F O L F O X

Vital si g ns, i ncl u di n g wei g ht *

P h y sical e xa m*

E C O G Perf or ma nce stat us *

C o nfir mati o n of last bl o o d tra nsf usi o n

C B C wit h dif fere ntial*

Ser u m/ plas ma c he mistr y  pa nel*

Ser u m c y stati n C * (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D LTs 
ha ve bee n see n d uri n g d ose escalati o n, c y stati n C will n ot be c ollecte d)
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 1 of 2 2 0

Uri nal y sis*

Uri ne pr otei n/creati ni ne rati o

Bl o o d sa m ples f or o xali plati n P K ( pre d ose a n d p ost d ose; C o h orts 1 A a n d 1 B o nl y, 
see Ta ble 2 3 )

Bl o o d sa m ples f or t ucati ni b P K ( pre d ose a n d p ost d ose f or C o h ort 1 D o nl y,  see 
Ta ble 2 5 )

Uri ne sa m ples f or o xali plati n P K ( pre d ose a n d p ost d ose; C o h orts 1 A a n d 1 B o nl y, see 
Ta ble 2 4 )

Pre g na n c y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt

C o nc o mita nt me dicati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts a n d 
a nti diarr heal usa ge)

E ns ure partici pa nt has a de q uate s u p pl y of l o pera mi de pri or t o C yc le 1 Da y 1 a n d 
a d mi nister 1 st d ose of l o pera mi de c o nc o mita ntl y  wit h t he first d ose of t ucati ni b ( n ot 
a p plica ble t o C o h ort 1 A a n d C o h ort 1 B). 

A d mi nister o xali plati n, le uc o v ori n, fl u or o uracil Q 2 W

A d mi nister trast uz u ma b a n d c o nti n ue Q 2 W i n C o h orts 1 A a n d 1 B

A d mi nister trast uz u ma b a n d c o nti n ue Q 3 W i n C o h orts 1 D, 1 E, 2 A, a n d 2 B

A d mi nister pe m br oliz u ma b a n d c o nti n ue Q 6 W i n C o h orts 1 E a n d 2 A
C o h orts 1 D, 1 E, 2 A, a n d 2 B:

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n ( Partici pa nt will self -a d mi nister t he 
re mai n der of t ucati ni b d oses d uri n g t he treat me nt c y cle a n d d oc u me nt i n t he diar y.)

A d mi nistrati o n of first d ose of l o pera mi de c o nc o mita nt wit h first d ose of t ucati ni b 
( Partici pa nt will self-a d mi nister t he re mai n der of l o pera mi de d oses d uri n g t he 
treat me nt c ycle a n d d oc u me nt i n t he diar y .)
N ote: F or partici pa nts e nr olle d i n C o h orts 1 D, 1 E, a n d 2 B, a n d f or partici pa nts e nr olle d i n 
C o h ort 2 A w h o recei ve m F O L F O X 6, be gi n ni n g wit h t he first d ose of t ucati ni b, l o pera mi de 
s h o ul d be ta ke n as f oll o ws: 4 m g t hree ti mes dail y ( Da ys 1 t o 1 4) d uri n g C ycle 1 f oll o we d b y 4 
m g t wice dail y  ( Da y 1 5 t hr o u g h Da y 4 2). T he first d ose of l o pera mi de m ust be a d mi nistere d 
c o nc o mita ntl y wit h t he first d ose of t ucati ni b. T he d osi n g of l o pera mi de s h o ul d be titrate d s uc h 
t hat partici pa nts ha ve 1- 2 st o ols per da y t hr o u g h o ut Da ys 1-4 2 a n d after war ds, as necessar y . T he 
d ose of l o pera mi de ca n be m o difie d, or l o pera mi de ca n be hel d at a n y p oi nt d uri n g t he st u d y as 
per i n vesti gat or discreti o n if partici pa nt has c o nsti pati o n or < 1 st o ol per da y. Use of 
a nti diarr heals will be c ollecte d. F oll o wi n g t his i nitial 4 2-d a y  peri o d, partici pa nts ma y c o nti n ue 
o n a nti diarr heal pr o p h yl a xis at a d ose of 2 t o 4 m g as nee de d, n ot t o e xcee d 1 6 m g per da y  (see 
Secti o n 7. 1 1. 2 f or m ore details). 
* Pre d ose assess me nts d o n ot nee d t o be re peate d if perf or me d wit hi n 1 da y pri or t o d ose 
a d mi nistrati o n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 2 of 2 2 0
8. 3. 2. C ycle 1 D a y 3 ( ± 1 d) – F O L F O X ( C o h orts 1 A a n d 1 B o nl y)

Ser u m/ plas ma c he mistr y  panel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

C o nc o mita nt me dicati o ns a n d A Es 
8. 3. 3. C ycle 1 D a y 8 ( ± 1 d) – F O L F O X ( C o h orts 1 A, 1 B, 1 D, 1 E, 2 A a n d 2 B )

Vital si g ns, i ncl u di n g wei g ht 

C B C wit h differe ntial

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

C o nc o mita nt me dic ati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

Assess a nti diarr heal me dicati o n usa ge ( n ot a p plica ble t o C o h orts 1 A a n d 1 B) 
T uc ati ni b p h ase 1 b d ose esc al ati o n c o h orts utilizi n g F O L F O X o nl y ( C o h orts 1 A a n d 1 B):

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self- a d mi nister t he 
re mai n der of d oses d uri n g t he treat me nt c ycle a n d d oc u me nt i n t he diar y.)
8. 3. 4. C ycle 2 a n d C ycle 3 D a y 1 ( ± 1 d) – F O L F O X ( C o h orts 1 A, 1 B, 1 D, 1 E, 2 A, a n d 2 B)

Vital si g ns, i ncl u di n g wei g ht

P h y sical e xa m

E C O G Perf or ma nce stat us

C B C wit h differe ntial 

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

Uri nal y sis

Uri ne pr otei n/crea ti ni ne rati o

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt

C o nc o mita nt me dicati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

D oc u me ntati o n of c o nc o mita nt me dicati o ns, i ncl u di n g assess me nt of a nti diarr heal 
me dicati o n usa ge fr o m pre vi o us c y cle ( n ot a p plica ble t o C o h orts 1 A a n d 1 B). Use of 
all a nti diarr heals is t o be d oc u me nte d i n t he partici pa nt’s diar y .
N ote: F or partici pa nts e nr olle d i n C o h orts 1 D, 1 E, 2 B, a n d f or partici pa nts e nr olle d i n C o h ort 2 A
w h o recei ve m F O L F O X 6, be gi n ni n g wit h t he first d ose of t ucati ni b, l o pera mi de s h o ul d be ta ke n 
as f oll o ws: 4 m g t hree ti mes dail y  ( Da ys 1 t o 1 4) d uri n g Cycle 1 f oll o we d b y 4 m g t wice dail y 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 3 of 2 2 0
( Da y 1 5 t hr o u g h Da y 4 2). T he first d ose of l o pera mi de m ust be a d mi nistere d c o nc o mita ntly wit h 
t he first d ose of t ucati ni b. T he d osi n g of l o pera mi de s h o ul d be titrate d s uc h t hat partici pa nts ha ve 
1 - 2 st o ols per da y t hr o u g h o ut Da ys 1-4 2 a n d after war ds, as necessar y . T he d ose of l o pera mi de 
ca n be m o difie d, or l o pera mi de ca n b e hel d at a n y p oi nt d uri n g t he st u d y as per i n vesti gat or 
discreti o n if partici pa nt has c o nsti pati o n or < 1 st o ol da y . Use of a nti diarr heals will be c ollecte d. 
F oll o wi n g t his i nitial 4 2- da y  peri o d, partici pa nts ma y c o nti n ue o n a nti diarr heal pr o p h yla xis at a 
d ose of 2 t o 4 m g as nee de d, n ot t o e xcee d 1 6 m g per da y (see Secti o n 7. 1 1. 2 f or m ore details). 

A d mi nister o xali plati n, le uc o v ori n, fl u or o uracil Q 2 W

A d mi nister trast uz u ma b Q 2 W i n C o h orts 1 A a n d 1 B

A d mi nister trast uz u ma b Q 3 W i n C o h orts 1 D, 1 E, 2 A, a n d 2 B

A d mi nister pe m br oliz u ma b Q 6 W i n C o h orts 1 E a n d 2 A

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self -a d mi nister t he 
re mai n der of t ucati nib d oses d uri n g t he treat me nt c y cle a n d d oc u me nt i n t he diar y.)

Bl o o d sa m ples f or t ucati ni b P K ( pre d ose a n d p ost d ose i n C y cle 2 o nl y f or C o h orts 
1 A a n d 1 B o nl y;  pre d ose o nl y i n C ycle 3; see Ta ble 2 3 ; pre d ose o nly i n C ycles 2 a n d 
3 f or C o h orts 1 D, 1 E, 2 A, a n d 2 B; see Ta ble 2 5 a n d Ta ble 2 6 ) 

Bl o o d sa m ples f or o xali plati n P K ( pre d ose a n d p ost d ose, C y cle 2 o nl y, C o h orts 1 A 
a n d 1 B o nl y;  see Ta ble 2 3 )

Uri ne sa m ples f or o xali plati n P K ( pre d ose a n d p ost d ose, C ycle 2 o nl y;  C o h orts 1 A 
a n d 1 B o nl y, see Ta ble 2 4 )
8. 3. 5. C ycle 2 a n d C ycle 3 D a y 3 ( ± 1 d) – F O L F O X ( C o h orts 1 A a n d 1 B o nl y)

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

A Es 
8. 3. 6. C ycle 2 a n d C ycle 3 D a y 8 ( ± 1 d) – F O L F O X ( C o h orts 1 A, 1 B, 1 D, 1 E, 2 A a n d 2 B)

Vital si g ns, i ncl u di n g wei g ht ( n ot a p plica ble t o C o h orts 2 A a n d 2 B) 

C B C wit h differe ntial ( n ot a p plica ble t o C o h orts 2 A a n d 2 B) 

Ser u m/ plas ma c he mistr y  pa nel ( n ot a p plica ble t o C o h orts 2 A a n d 2 B) 

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c y stati n C will n ot be c ollecte d) ( n ot 
a p plica ble t o C o h orts 2 A a n d 2 B) 

C oa g ulati o n pa nel ( n ot a p plica ble t o C o h orts 2 A a n d 2 B) 

Uri nal y sis ( n ot a p plica ble t o C o h orts 2 A a n d 2 B) 

Uri ne pr otei n/creati ni ne rati o ( n ot a p plica ble t o C o h orts 2 A a n d 2 B) 

C o nc o mita nt me dicati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts)
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 4 of 2 2 0

Assess a nti diarr heal me dicati o n usa ge ( n ot a p plica ble t o C o h orts 1 A a n d 1 B) 
8. 3. 7. C ycle 4 ( a n d All S u bse q ue nt C ycles ) D a y 1 ( ± 1 d) – F O L F O X

Vital si g ns, i ncl u di n g wei g ht

P h y sical e xa m

E C O G Perf or ma nce stat us

C B C wit h differe ntial 

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose esc alati o n, c ystati n C will n ot be c ollecte d) 

Uri nal y sis

Uri ne pr otei n/creati ni ne rati o

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt

A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

Assess a nti diarr heal me di cati o n usa ge ( n ot a p plica ble t o C o h orts 1 A a n d 1 B). Use of 
all a nti diarr heals is t o be d oc u me nte d i n t he partici pa nt’s diar y .

D oc u me ntati o n of c o nc o mita nt me dicati o ns, i ncl u di n g assess me nt of a nti diarr heal 
me dicati o n usa ge fr o m pre vi o us c y cle; Use of all a nti diarr heals is t o be d oc u me nte d 
i n t he partici pa nt’s diar y ( n ot a p plica ble t o C o h orts 1 A a n d 1 B).

A d mi nister o xali plati n, le uc o v ori n, fl u or o uracil Q 2 W

A d mi nister trast uz u ma b Q 2 W i n C o h orts 1 A a n d 1 B

A d mi nister trast uz u ma b Q 3 W i n C o h orts 1 D, 1 E, 2 A, a n d 2 B

A d mi nister pe m br oliz u ma b Q 6 W i n C o h orts 1 E a n d 2 A

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self -a d mi nister t he 
re mai n der of d oses d uri n g t he treat me nt c ycle a n d d oc u me nt i n t he diar y.)

Bl o o d sa m ples f or t ucati ni b P K t hr o u g h C y cle 6, onl y  pre d ose ( C o h orts 1 A, 1 B, 1 D, 
1 E, 2 A, a n d 2 B; see Ta ble 2 3 , Ta ble 2 5 , a n d Ta ble 2 6 )
8. 3. 8. E ver y 6 Wee ks * or 8 Wee ks † ( ± 7 d) – F O L F O X

Ra di ol o gical disease assess me nt ( C T, P E T- C T , a n d/ or M RI)

T h y r oi d f u ncti o n tests f or C o h orts 1 E a n d 2 A Q 6 W 
* Sca ns occ ur e ver y  6 wee ks f or C o h orts 1 D, 1 E, 2 A, a n d 2 B f or t he first 2 4 wee ks, t he n e ver y 
9 wee ks
† Sca ns occ ur e ver y  8 wee ks f or p hase 1 b c o h orts utilizi n g F O L F O X ( C o h orts 1 A a n d 1 B) f or 
t he first 2 4 wee ks, t he n e ver y 1 2 wee ks
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 5 of 2 2 0
8. 3. 9. E ver y 1 2 Wee ks ( ± 7 d) – F O L F O X

E C H O or M U G A sca n
8. 4. C A P O X Tre at me nt Peri o ds ( 2 1 -d a y c ycles) – P h ase 1 b C A P O X C o h ort ( C o h ort 1 C), 
P h ase 1 b Pe m br oliz u m a b ( C o h ort 1 F), a n d P h ase 2 T u m or -S pecific E x p a nsi o n C o h ort 
( C o h ort 2 A)
N ote: F or partici pa nts e nr olle d i n C o h orts 1 C a n d 1 F a n d partici pa nts e nr olle d i n C o h ort 2 A w h o 
are treate d wit h C A P O X, a nti diarr heal pr o p h yl a xis is n ot re q uire d, u nless rec o m me n de d b y t he 
S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w of t he data d ur i n g t he c o urse of t he st u dy. 
S h o ul d a nti diarr heal pr o p h y la xis wit h l o pera mi de be re q uire d, t he d ose a n d sc he d ule d will be as 
f oll o ws: be gi n ni n g wit h t he first d ose of t ucati ni b: 4 m g t hree ti mes dail y ( D a ys 1 t o 1 4) d uri n g 
C y cle 1 f oll o we d b y 4 m g t wice dail y ( Da y 1 5 t hr o u g h Da y 4 2). T he d osi n g of l o pera mi de 
s h o ul d be titrate d s uc h t hat partici pa nts ha ve 1-2 st o ols per da y  t hr o u g h o ut Da ys 1-4 2 a n d 
after war ds, as necessar y . T he d ose of l o pera mi de ca n be m o difie d, or l o pera mi de ca n be hel d at 
a n y p oi nt d uri n g t he st u d y as per i n vesti gat or discreti o n if partici pa nt has c o nsti pati o n or < 1 st o ol 
per da y . F oll o wi n g t his i nitial 4 2 -da y  peri o d, partici pa nts ma y c o nti n ue o n a nti diarr heal 
pr o p h y la xis at a d ose of 2 t o 4 m g as nee de d, n ot t o e xcee d 1 6 m g per da y (see Secti o n 7. 1 1. 2 f or 
m ore details)
8. 4. 1. C ycle 1 D a y 1 – C A P O X

Vital si g ns, i ncl u di n g wei g ht *

P h y sical e xa m*

E C O G Perf or ma nce stat us *

C o nfir mati o n of last bl o o d tra nsf usi o n

C B C wit h differe ntial *

Ser u m/ plas ma c he mistr y  pa nel*

Ser u m c y stati n C * (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

Uri nal y sis*

Uri ne pr otei n/creati ni ne rati o

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt

C o nc o mita nt me dicati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

Assess a nti diarr heal me dicati o n usa ge. Use of all a nti diarr heals is t o be d oc u me nte d 
i n t he partici pa nt’s diar y.

E ns ure partici pa nts ha ve l o pera mi de t o use as nee de d f or s y m pt o mat ic diarr hea, as 
descri be d i n Secti o n 7. 9. 9 . If nee de d, partici pa nts will self-a d mi nister l o pera mi de 
d uri n g t he treat me nt c y cle a n d d oc u me nt i n t he diar y.

A d mi nister o xali plati n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 6 of 2 2 0

A d mi nister ca pecita bi ne † ( Partici pa nt will self-a d mi nister t he re mai n der of d oses 
d uri n g t he treat me nt c y cle a n d d oc u me nt i n t he diar y.)

A d mi nister trast uz u ma b a n d c o nti n ue Q 3 W

A d mi nister pe m br oliz u ma b a n d c o nti n ue Q 6 W ( C o h ort 1 F a n d 2 A)

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self -a d mi nister t he 
re mai n der of d oses d uri n g t he treat me nt c ycle a n d d oc u me nt i n t he diar y.) 
* Pre d ose assess me nts d o n ot nee d t o be re peate d if perf or me d wit hi n 1 da y  pri or t o d ose 
a d mi nistrati o n
† Ca pecita bi ne is a d mi nistere d BI D be gi n ni n g t he e ve ni n g of Da y 1 t o t he m or ni n g of Da y 1 5 of 
C y cle 1.
8. 4. 2. C ycle 1 D a y 8 ( ± 1 d) – C A P O X

Vital si g ns, i ncl u di n g wei g ht 

C B C wit h differe ntial

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

C o nc o mita nt me dicati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

Assess a nti diarr heal me dicati o n usa ge. Use of all a nti diarr heals is t o be d oc u me nte d 
i n t he partici pa nt’s diar y.
8. 4. 3. C ycle 2 D a y 1 ( ± 1 d) – C A P O X

Vital si g ns, i ncl u di n g wei g ht

P h y sical e xa m

E C O G Perf or ma nce stat us

C B C wit h differe ntial 

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

Uri nal y sis

Uri ne pr otei n/creati ni ne rati o

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt

A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

D oc u me ntati o n of c o nc o mita nt me dicati o ns, i ncl u di n g assess me nt of a nti diarr heal 
me dicati o n usa ge fr o m pre vi o us c y cle. Use of all a nti diarr heals is t o be d oc u me nte d 
i n t he partici pa nt’s diar y .
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 7 of 2 2 0

E ns ure partici pa nts ha ve l o pera mi de t o use as nee de d f or s y m pt o matic diarr hea, as 
descri be d i n Secti o n 7. 9. 9 . 

A d mi nister o xali pl ati n

A d mi nister ca pecita bi ne †

A d mi nister trast uz u ma b a n d c o nti n ue Q 3 W

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self -a d mi nister t he 
re mai n der of d oses d uri n g t he treat me nt c ycle a n d d oc u me nt i n t he diar y.) 

Bl o o d sa m ples f or t ucati ni b P K ( pre d ose; see Ta ble 2 6 )
† Ca pecita bi ne is a d mi nistere d BI D Da y  1 t hr o u g h Da y 1 4 of Cycle 2.
8. 4. 4. C ycle 2 D a y 8 ( ± 1 d) – C A P O X

Vital si g ns, i ncl u di n g wei g ht ( n ot a p plica ble t o C o h ort 2 A)

C B C wit h differe ntial ( n ot a p plica ble t o C o h ort 2 A)

Ser u m/ plas ma c he mistr y  pa nel ( n ot a p plica ble t o C o h ort 2 A)

Bl o o d f or ser u m c ystati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal 
D L Ts ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d) ( n ot 
a p plica ble t o C o h ort 2 A)

C oa g ulati o n pa nel ( n ot a p plica ble t o C o h ort 2 A)

Uri nal y sis ( n ot a p plica ble t o C o h ort 2 A)

Uri ne pr otei n/creati ni ne rati o ( n ot a p plica ble t o C o h ort 2 A)

C o nc o mita nt me dicati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

Assess a nti diarr heal me dicati o n usa ge
8. 4. 5. C ycle 3 ( a n d All S u bse q ue nt C ycles) D a y 1 ( ± 1 d) – C A P O X

Vital si g ns, i ncl u di n g wei g ht

P h y sical e xa m

E C O G Perf or ma nce stat us

C B C wit h differe ntial 

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

Uri nal y sis

Uri ne pr otei n/creati ni ne rati o

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt

A Es (i ncl u di n g assess me nt of diarr hea e ve nts)
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 8 of 2 2 0

D oc u me ntati o n of c o nc o mita nt me dicati o ns, i ncl u di n g assess me nt of a nti diarr heal 
me dicati o n usa ge fr o m pre vi o us c y cle. Use of all a nti diarr heals is t o be d oc u me nte d 
i n t he partici pa nt’s diar y.

A d mi nister o xali plati n

A d mi nister ca pecita bi ne †

A d mi nister trast uz u ma b Q 3 W

A d mi nister pe m br oliz u ma b Q 6 W

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self -a d mi nister t he 
re mai n der of d oses d uri n g t he treat me nt c ycle a n d d oc u m e nt i n t he diar y.) 

Bl o o d sa m ples f or t ucati ni b P K (t hr o u g h C ycle 6), o nl y  pre d ose (see Ta ble 2 6 )
† Ca pecita bi ne is a d mi nistere d BI D Da y  1-D a y  1 4 of eac h c ycle.
8. 4. 6. E ver y 6 Wee ks ( ± 7 d) C A P O X u p t o 2 4 Wee ks a n d E ver y 9 Wee ks T here after

Ra di ol o gical disease assess me nt ( C T, P E T- C T, a n d/ or M RI )

T h y r oi d f u ncti o n tests Q 6 W f or C o h orts 1 F a n d 2 A
8. 4. 7. E ver y 1 2 Wee ks ( ± 7 d) - C A P O X

E C H O or M U G A sca n
8. 5. Pe m br oliz u m a b ( C he m ot her a p y -free) Tre at me nt Peri o ds ( 2 1-d a y c ycles) –
Pe m br oliz u m a b C o h ort 1 G
N ote: F or partici pa nts e nr olle d i n C o h ort 1 G, a nti diarr heal pr o p h yl a xis is n ot re q uire d, u nless 
rec o m me n de d by t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vi e w of t he data d uri n g t he 
c o urse of t he st u d y. S h o ul d a nti diarr heal pr o p h yl a xis wit h l o pera mi de will be re q uire d, t he d ose 
a n d sc he d ule will be as f oll o ws: be gi n ni n g wit h t he first d ose of t ucati ni b: 4 m g t hree ti mes dail y  
( Da ys 1 t o 1 4) d uri n g Cycle 1 f ol l o we d by 4 m g t wice dail y ( Da y  1 5 t hr o u g h Da y 4 2). T he 
d osi n g of l o pera mi de s h o ul d be titrate d s uc h t hat partici pa nts ha ve 1 -2 st o ols per da y  t hr o u g h o ut 
D a y s 1-4 2 a n d after war ds, as necessar y . T he d ose of l o pera mi de ca n be m o difie d, or l o pera mi de 
ca n be hel d at a ny p oi nt d uri n g t he st u d y as per i n vesti gat or discreti o n if partici pa nt has 
c o nsti pati o n or < 1 st o ol per da y . F oll o wi n g t his i nitial 4 2-da y  peri o d, partici pa nts ma y c o nti n ue 
o n a nti diarr heal pr o p h yl a xis at a d ose of 2 t o 4 m g as nee de d, n ot t o e xcee d 1 6 m g per da y  (see 
Secti o n 7. 1 1. 2 f or m ore details) 
8. 5. 1. C ycle 1 D a y 1

Vital si g ns, i ncl u di n g wei g ht *

P h y sical e xa m*

E C O G Perf or ma nce stat us *

C o nfir mati o n of last bl o o d tra nsf usi o n

C B C wit h differe ntial *

Ser u m/ plas ma c he mistr y  pa nel*
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 2 9 of 2 2 0

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n ide ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

Uri nal y sis*

Uri ne pr otei n/creati ni ne rati o

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt

C o nc o mita nt me dicati o ns a n d A Es 

E ns ure partici pa nts ha ve l o pera mi de t o use as nee de d f or s y m pt o matic diarr hea as 
descri be d i n Secti o n 7. 9. 9 . 

A d mi nister trast uz u ma b a n d c o nti n ue Q 3 W 

A d mi nister pe m br oliz u ma b a n d c o nti n ue Q 6 W 

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self -a d mi nister t he 
re mai n der of d oses d uri n g t he treat me nt c ycle a n d d oc u me nt i n t he diar y.) 
* Pre d ose as sess me nts d o n ot nee d t o be re peate d if perf or me d wit hi n 1 da y pri or t o d ose 
a d mi nistrati o n
8. 5. 2. C ycle 1 D a y 8 ( ± 1 d)

Vital si g ns, i ncl u di n g wei g ht

C B C wit h differe ntial

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntified a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

C o nc o mita nt me dicati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

Assess usa ge of a nti diarr heal me dicati o n
8. 5. 3. C ycle 2 D a y 1 ( ± 1 d)

Vital si g ns, i ncl u di n g wei g ht

P h y sical e xa m

E C O G Perf or ma nce stat us

C B C wit h differe ntial 

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

Uri nal y sis

Uri ne pr otei n/creati ni ne rati o

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 0 of 2 2 0

A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

D oc u me ntati o n of c o nc o mita nt me dicati o ns, i ncl u di n g assess me nt of a n ti diarr heal 
me dicati o n usa ge fr o m pre vi o us c y cle. Use of all a nti diarr heals is t o be d oc u me nte d 
i n t he partici pa nt’s diar y.

E ns ure partici pa nts ha ve l o pera mi de t o use as nee de d f or s y m pt o matic diarr hea as 
descri be d i n Secti o n 7. 9. 9 . 

A d mi nister trast uz u ma b a n d c o nti n ue Q 3 W

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self -a d mi nister t he 
re mai n der of d oses d uri n g t he treat me nt c ycle a n d d oc u me nt i n t he diar y .) 

Bl o o d sa m ples f or t ucati ni b P K ( pre d ose, see Ta ble 2 6 )
8. 5. 4. C ycle 2 D a y 8 ( ± 1 d)

Vital si g ns, i ncl u di n g wei g ht

C B C wit h differe ntial 

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, c y stati n C will n ot be c ollecte d)

C oa g ulati o n pa nel

Uri nal y sis

Uri ne pr otei n/creati ni ne rati o

C o nc o mita nt me dicati o ns a n d A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

Assess usa ge of a nti diarr heal me dicati o n

E ns ure partic i pa nts ha ve l o pera mi de t o use as nee de d f or sy m pt o matic diarr hea as 
descri be d i n Secti o n 7. 9. 9 .
8. 5. 5. C ycle 3 ( a n d All S u bse q ue nt C ycles) D a y 1 ( ± 1 d)

Vital si g ns, i ncl u di n g wei g ht

P h y sical e xa m

E C O G Perf or ma nce stat us

C B C wit h differe ntial 

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

Uri nal y sis

Uri ne pr otei n/creati ni ne rati o

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial, t o be d o ne wit hi n 2 4 h o urs 
of treat me nt
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 1 of 2 2 0

A Es (i ncl u di n g assess me nt of diarr hea e ve nts)

D oc u me ntati o n of c o nc o mita nt me dicati o ns, i ncl u di n g assess me nt of a nti diarr heal 
me dicati o n usa ge fr o m pre vi o us c y cle. Use of all a nti diarr heals is t o be d oc u me nte d 
i n t he partici pa nt’s diar y.

E ns ure partici pa nts ha ve l o pera mi de t o use as nee de d f or s y m pt o matic diarr hea as 
descri be d i n Secti o n 7. 9. 9 . 

A d mi nister trast uz u ma b Q 3 W

A d mi nister pe m br oliz u ma b Q 6 W

T ucati ni b dis pe nsati o n a n d a d mi nistrati o n. ( Partici pa nt will self- a d mi nister t he 
re mai n der of d oses d uri n g t he treat me nt c ycle a n d d oc u me nt i n t he diar y.) 

Bl o o d sa m ples f or t ucati ni b P K (t hr o u g h C ycle 6), o nl y  pre d ose (Ta ble 2 6 )
8. 5. 6. E ver y 6 Wee ks ( ± 7 d) u p t o 2 4 Wee ks a n d E ver y 9 Wee ks T here after

Ra di ol o gical disease assess me nt ( C T, P E T- C T, a n d/ or M RI )

T h y r oi d f u ncti o n tests Q 6 W
8. 5. 7. E ver y 1 2 Wee ks ( ± 7 d)

E C H O or M U G A sca n
8. 6. L o n g -ter m E xte nsi o n P h ase – Be gi n ni n g of e ac h C ycle a n d E n d of Tre at me nt
Partici pa nts still recei vi n g cli nical be nefit a n d re mai ni n g o n st u d y treat me nt as of A me n d me nt 5 
ma y  c o nti n ue recei vi n g st u d y i nter ve nti o ns d uri n g t he LT E P. 

O nl y  i nf or mati o n relate d t o pre g na ncies a n d S A Es ( Secti o n 9. 5. 1. 1 a n d Secti o n 
9. 5. 1. 4. 2 ) will be re p orte d t o t he S p o ns or

All sa fety a n d efficac y assess me nts will be perf or me d per us ual a n d c ust o mar y 
cli nical practice, wit h t he e xce pti o n of pre g na nc y  testi n g 

Pre g na nc y  testi n g will c o nti n ue t o be perf or me d as o utli ne d i n t he sc he d ule of e ve nts
i n partici pa nts of c hil d beari n g p ote ntial
8. 7. E n d of Tre at me nt Visit ( 3 0 t o 3 7 D a ys After L ast D ose of St u d y Tre at me nt)
E n d of Treat me nt ( E O T) visits s h o ul d occ ur 3 0 t o 3 7 da y s after t he last d ose of st u d y treat me nt 
u nless dela y e d d ue t o a n A E. Partici pa nts are c o nsi dere d t o be recei vi n g st u d y  treat me nt u ntil all 
st u d y treat me nts ( o xali plati n, ca pecita bi ne, fl u or o uracil, le uc o v ori n, trast uz u ma b, 
pe m br oliz u ma b, a n d t ucati ni b) are disc o nti n ue d, or if a n y  ne w a ntica ncer treat me nt is gi ve n. 
N ote: T he ti me t o E O T visit ma y  be l o n ger t ha n 3 7 da ys, b ut i n n o case s h o ul d it be < 3 0 da y s. 
H o we ver, E O T e val uati o ns m ust be perf or me d bef ore i nitiati o n of a ne w t hera p y. If E O T 
e val uati o ns are c o m plete d bef ore 3 0 da y s after t he last st u d y treat me nt, t he partici pa nt will be 
c o ntacte d 3 0 t o 3 7 da ys f oll o wi n g t he last treat me nt t o assess f or A Es.

Vital si g ns, i ncl u di n g wei g ht

P h y sical e xa m

E C O G Perf or ma nce stat us
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 2 of 2 2 0

C B C wit h differe ntial 

Ser u m/ plas ma c he mistr y  pa nel

Ser u m c y stati n C (If after t he P hase 2 d ose has bee n i de ntifie d a n d n o re nal D L Ts
ha ve bee n see n d uri n g d ose escalati o n, c ystati n C will n ot be c ollecte d)

C oa g ulati o n pa nel

Uri nal y sis

Uri ne pr otei n/creati ni ne rati o

E C G

E C H O or M U G A sca n

Pre g na nc y  test f or partici pa nts of c hil d beari n g p ote ntial

A Es (i ncl u di n g assess me nt of diarr hea e ve n ts)

D oc u me ntati o n of c o nc o mita nt me dicati o ns, i ncl u di n g assess me nt of a nti diarr heal 
me dicati o n usa ge fr o m pre vi o us c y cle. Use of all a nti diarr heals is t o be d oc u me nte d 
i n t he partici pa nt’s diar y.

Ra di ol o gical disease assess me nt ( C T, P E T- C T, a n d/ or M RI )

Bl o o d sa m ple f or bi o mar ker a nal ys is ( will n ot be c ollecte d after i m ple me ntati o n of 
A me n d me nt 5)

Bl o o d sa m ples f or t ucati ni b P K ( C o h ort 1 D o nl y , see Ta ble 2 5 ; will n ot be c ollecte d 
after i m ple me ntati o n of A me n d me nt 5)
8. 8. F oll o w -u p ( E ver y 9 or 1 2 Wee ks ± 1 4 D a ys)
As of A me n d me nt 5, l o n g ter m f oll o w - u p will be disc o nti n ue d. Partici pa nts i n l o n g ter m f oll o w-
u p as of A me n d me nt 5 will tra nsiti o n t o e n d of st u d y . 
Partici pa nts w h o disc o nti n ue st u d y  treat me nt will re mai n o n st u d y f or f oll o w- u p (assess me nt of 
a ntica ncer t hera p y a n d s ur vi val) u ntil wit h dra wal of c o nse nt fr o m t he st u d y, deat h, or 
a d mi nistrati ve st u d y cl os ure w hic he ver occ urs first.
Partici pa nts t hat disc o nti n ue st u d y  treat me nt f or reas o ns ot her t ha n d oc u me nte d pr o gressi ve 
disease per R E CI S T will c o nti n ue t o ha ve disease assess me nts ( C T, P E T -C T, a n d/ or M RI sca ns) 
a p pr o xi matel y e ver y 9 wee ks ( ± 1 4 da ys) u ntil ra di o gra p hic disease pr o gressi o n (see 
A p pe n di x A ). 
After t he occ urre nce of d oc u me nte d disease pr o gressi o n, partici pa nts will be f oll o we d f or 
s ur vi val a p pr o xi matel y e ver y 1 2 wee ks ( ± 1 4 da ys) u ntil deat h, wit h dra wal of c o nse nt, st u d y 
cl os ure.
8. 9. E n d of St u d y
T he date t he partici pa nt met criteria f or st u d y  disc o nti n uati o n a n d t he reas o n f or st u d y 
disc o nti n uati o n will be rec or de d.
F or partici pa nts of c hil d beari n g p ote ntial:
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 3 of 2 2 0

C o nfir m wit h t he partici pa nt t hat m o nt hl y  pre g na nc y tests ha ve bee n perf or me d a n d 
ha ve bee n ne gati ve

Re mi n d partici pa nt t hat m o nt hl y  pre g na nc y tests will be perf or me d f or 7 m o nt hs after 
t he last d ose of st u d y treat me nt 
9. S T U D Y A S S E S S M E N T S
9. 1. Scree ni n g/ B aseli ne Assess me nts
Scree ni n g/ Baseli ne assess me nts will be c o n d uct e d t o esta blis h st u d y baseli ne stat us a n d 
deter mi ne st u d y eli gi bilit y. O nl y partici pa nts w h o si g n a n i nf or me d c o nse nt a n d meet all 
i ncl usi o n a n d e xcl usi o n criteria s pecifie d i n Secti o n 6 will be e nr olle d i n t his st u d y .
Partici pa nt me dical hist or y  i ncl u des a t h or o u g h re vie w of si g nifica nt past me dical hist or y, 
c urre nt c o n diti o ns, a n y treat me nt f or pri or mali g na ncies a n d res p o nse t o pri or treat me nt, a n d a n y 
c o nc o mita nt me dicati o ns. 
A p h y sical e xa m, hei g ht, vital si g ns, wei ght, disease assess me nt ( C T, P E T- C T, or M RI  sca n) f or 
baseli ne res p o nse efficac y  assess me nt, C B C wit h differe ntial, uri nalys is, E C H O/ M U G A, 
he patitis B a n d C scree ni n g, ser u m/ plas ma c he mistr y  pa nel, ser u m c ystati n C, c oa g ulati o n tests, 
E C O G perf or ma nce sta t us, E C G, bl o o d sa m ple f or bi o mar ker a nalys is, c ollecti o n of m ost 
rece ntly a vaila ble tiss ue, uri ne pr otei n/creati ni ne rati o, c o nfir mati o n of last bl o o d tra nsf usi o n, 
re vie w of A Es a n d c o nc o mita nt me dicati o ns, a n d ser u m/ plas ma pre g na nc y test (f or fe males of 
c hil d beari n g p ote ntial) are re q uire d f or all partici pa nts at scree ni n g a n d/ or baseli ne as descri be d 
i n Secti o n 8. 2 a n d A p pe n di x A .
9. 2. Res p o nse/ Effic ac y Assess me nts
T he deter mi nati o n of a ntit u m or acti vit y  will be base d o n c o nfir me d o bjecti ve res p o nse 
assess me nts as defi ne d b y R E CIS T v 1. 1 (Eise n ha uer 2 0 0 9 ). Disease res p o nse will be assesse d b y 
t he i n vesti gat or. Treat me nt decisi o ns will be ma de base d u p o n l ocal assess me nt of ra di ol o gic 
sca ns. Ra di o gra p hic disease assess me nts will e val uate all k n o w n sites of disease, prefera bl y 
usi n g hi g h q ualit y  s piral c o ntrast C T, a n d c o veri n g, at a mi ni m u m, t he c hest, a b d o me n, a n d 
pel vis. P E T -C T sca ns (if hi g h q ualit y C T sca n is i ncl u de d) a n d/ or M RI sca ns ma y  als o be use d as 
a p pr o priate, as well as a d diti o nal i ma gi n g of a n y ot her k n o w n sites of disease (e g, n uclear b o ne 
sca n i ma gi n g f or b o ne lesi o ns). F or eac h partici pa nt, t he sa me i ma gi n g m o dalit y as use d at 
scree ni n g/ baseli ne s h o ul d be used t hr o u g h o ut t he st u d y . Disease assess me nts will be perf or me d 
at pr ot oc ol -s pecifie d ti me p oi nts o utli ne d i n Secti o n 8 a n d A p pe n di x A .
Partici pa nts’ cli nical data m ust be a vaila ble f or e C R F s o urce verificati o n. I ma ges ma y  be 
c ollecte d b y a n i n de pe n de nt ce ntral re vie w facilit y f or p ossi ble f ut ure a nal ysis. C o pies o f t u m or 
i ma ges m ust be ma de a vaila ble f or re vie w by t he S p o ns or ( or its desi g nee) u p o n re q uest.
D uri n g t he L T E P, efficac y assess me nts will be perf or me d per i nstit uti o nal g ui deli nes a n d 
i n vesti gat or-deter mi ne d us ual a n d c ust o mar y  cli nical care.
9. 3. P h ar m ac o ki ne tic Assess me nts
Bl o o d ( o xali plati n a n d t ucati ni b) a n d uri ne ( o xali plati n) sa m ples f or P K assess me nts will be 
c ollecte d at pr ot oc ol -defi ne d ti me p oi nts ( Ta ble 2 3 , Ta ble 2 4 , Ta ble 2 5 , a n d Ta ble 2 6 ). Plas ma 
c o nce ntrati o ns of t ucati ni b will be a nal yz e d usi n g vali date d mass s pectr o metr y  met h o ds. 
C o nce ntrati o ns of t otal plati n u m i n plas ma, free plati n u m i n plas ma ultrafiltrates, a n d plati n u m i n 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 4 of 2 2 0
uri ne will be deter mi ne d usi n g vali date d met h o ds. Re mai ni n g P K sa m ples will be arc hi ve d a n d 
ma y  be use d f or t he a nal ysis of a d mi nistere d c o m p o u n ds or relate d s pecies wit h e x pl orat or y, 
n o n -vali date d assa y s. 
P K para meters will be calc ulate d usi n g sta n dar d n o n -c o m part me ntal met h o ds. P K para meters t o 
be esti mate d f or C o h orts 1 A, 1 B, a n d 1 D i ncl u de b ut are n ot li mite d t o area u n der t he plas ma 
c o nce ntrati o n-ti me c ur ve t o t he ti me of t he last q ua ntifia ble c o nce ntrati o n ( A U Clast), ma xi m u m 
o bser ve d c o nce ntrat i o n ( Cma x ), o bser ve d tr o u g h c o nce ntrati o n i n plas ma ( Ctr o u g h;t ucati ni b o nl y), 
a n d ti me of C ma x ( Tma x ). F or t he ot her c o h orts, P K para meters i ncl u de, b ut are n ot li mite d t o, 
o bser ve d tr o u g h c o nce ntrati o n i n plas ma ( C tr o u g h;t ucati ni b o nl y).
F oll o wi n g i m ple me ntati o n of A me n d me nt 5, n o P K sa m ples will be c ollecte d at E O T.
T a ble 2 3 .
Pl as m a P h ar m ac o ki netic S a m ple C ollecti o n i n F O L F O X P h ase 1 b C o h orts 
( C o h orts 1 A, 1 B)
St u d y Da y
Ti m e
Relati ve Ti me
O xali plati n a
T ucati ni b
C y cle 1 Da y 1
Pre d ose ( w it hi n 2 4 h) 
Start of o xali plati n 
i nf usi o n ( 2 h), first 
d ose
X
-
1 h i ntra -d ose ( ± 1 5 mi n)
X
-
E OI ( w it hi n 1 5 mi n)
X
-
C y cle 1 Da y 1
1 h ( ± 1 5 mi n)
E n d of o xali plati n 
i nf usi o n ( 2 h), first 
d ose
X
-
2 h ( ± 1 5 mi n)
X
-
4 h ( ± 1 5 mi n)
X
-
6 h ( ± 3 0 mi n)
X
-
C y cle 2 Da y 1
Pre d ose ( w it hi n 2 h)
Start of o xali plati n 
i nf usi o n ( 2 h), 
sec o n d d oseb
X
X
1 h i ntra -d ose ( ± 1 5 mi n)
X
X
E OI ( w it hi n 1 5 mi n)
X
X
C y cle 2 Da y 1
1 h ( ± 1 5 mi n)
E n d of o xali plati n 
i nf usi o n ( 2 h), 
sec o n d d ose
X
X
2 h ( ± 1 5 mi n)
X
X
4 h ( ± 1 5 mi n)
X
X
6 h ( ± 3 0 mi n) 
X
X
C y cles 3 -6 Da y 1
Pre d ose ( w it hi n 2 h o urs) 
Pri or t o ti me of A M 
t ucati ni b 
a d mi nistrati o n b
X
a Bl o o d sa m ples f or o xali plati n P K ( pre d ose a n d p ost d ose) ( C o h ort 1 A a n d 1 B o nl y)
b Partici pa nts s h o ul d be i nstr ucte d t o ta ke t heir m or ni n g d ose of t ucati ni b i n t he cli nic at t he start of t he 
o xali plati n i nf usi o n.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 5 of 2 2 0
T a ble 2 4 .
Uri ne P h ar m ac o ki netic S a m ple C ollecti o n i n F O L F O X P h ase 1 b C o h orts 
( C o h orts 1 A, 1 B)a
St u d y Da y
C ollecti o n Wi n d o w  Start 
Ti m e a
C ollecti o n Wi n d o w  
E n d Ti me a
Relati ve Ti me
O xali plati n i n 
Uri ne
C y cles 1 a n d 2 
D a y  1 
Start of o xali plati n 
i nf usi o n ( wit hi n 1 5 mi n)
E OI ( w it hi n 3 0 mi n)
Start of o xali plati n 
i nf usi o n ( 2 h), first d ose
X
C y cles 1 a n d 2 
D a y  1
E OI ( w it hi n 3 0 m i n)
2 h o urs ( ± 3 0 mi n) 
E n d of o xali plati n 
i nf usi o n ( 2 h), first d ose
X
2 h o urs ( ± 3 0 mi n)
6 h o urs ( ± 1 h o ur)
X
6 h o urs ( ± 1 h o ur) 
2 4 h o urs ( ± 2 h o urs)
X
a 2 4 -h o ur uri ne sa m pli n g ( S T A R T of o xali plati n i nf usi o n t o E OI, E OI t o 2 h o urs p ost -E OI, 2 t o 6 h o urs p ost -E OI, 
6 t o 2 4 h o urs p ost -E OI) will be perf or me d fr o m start of o xali plati n i nf usi o n o n D 1 of C ycles 1 -2. T he p ost d ose 
c o nti n u o us uri ne c ollecti o n will be ta ke n at t he e n d of eac h c ollecti o n peri o d ( E OI, 2, 6, a n d 2 4 h o urs p ost -E OI) 
a n d t he ne xt c ollecti o n ti me peri o d will be gi n. Partici pa nts s h o ul d be e nc o ura ge d t o sta y h y drate d t o facilitate 
uri ne c ollecti o n f or P K a nal ysis.
T a ble 2 5 .
Pl as m a P h ar m ac o ki netic S a m ple C ollecti o n Ti me p oi nts: J a p a n-s pecific 
C o h ort ( 1 D)
C y cle
C y cle 
D a y
Ti m e
Wi n d o w
Relati ve Ti me
T ucati ni b 
P K
1 
1
Pre d ose
Wit hi n 2 4 hrs
Ti m e of first t ucati ni b a d mi nistrati o n
X
1 hr p ost -d ose
± 5 mi n
X
2 hrs p ost -d ose
± 5 mi n
X
3 hrs p ost -d ose
± 1 5 mi n
X
4 hrs p ost -d ose
± 1 5 mi n
X
6 hrs p ost -d ose
± 1 5 mi n
X
8 hrs p ost -d ose
± 1 5 mi n
X
1 0 hrs p ost -d ose
± 3 0 mi n
X
1 2 hrs p ost -d ose
± 1 5 mi n
Pri or t o sec o n d t ucati ni b Da y 1 
a d mi nistrati o n
X
2- 6 
1
Pre d ose
Wit hi n 2 hrs 
Pri or t o ti me of A M t ucati ni b a d mi nistrati o n
X
E O T
3 0 t o 3 7 da ys
X
T a ble 2 6 . Pl as m a P h ar m ac o ki netic S a m ple C ollecti o n f or C o h orts 1 C, 1 E, 1 F, 1 G, 2 A, 
2 B
St u d y Da y
Ti m e
Relati ve Ti me
T ucati ni b
C y cles 2 -6 Da y 1
Pre d ose ( w it hi n 2 h)
Pri or t o ti me of A M 
t ucati ni b a d mi nistrati o n
X
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 6 of 2 2 0
9. 4. Bi o m ar ker Assess me nts
Partici pa nts eli gi ble f or e nr oll me nt will ha ve H E R 2 stat us deter mi ne d b y hist oric/l ocal I H C, 
FI S H, N G S, or cell -free D N A i n sa m ples pri or t o scree ni n g. W he n a vaila ble, arc hi val or fres h 
t u m or bl oc ks are t o be c ollecte d at scree ni n g. Bl o o d sa m ples f or bi o mar ker assa y will be dra w n 
at scree ni n g a n d at E O T. 
Bi o mar ker assess me nts ma y  i ncl u de a n e x pl orat or y assess me nt of m utati o ns as p ote ntial 
bi o mar kers of res p o nse. A d diti o nal a nal y ses i ncl u di n g b ut n ot li mite d t o I H C a n d N G S ma y be 
perf or me d t o i nterr o gate bi o mar kers t hat are ass ociate d wit h t u m or gr o wt h, s ur vi val, a n d 
resista nce t o tar gete d t hera pe utics. T his assess me nt ma y e na ble t he c orrelati o n of a dditi o nal 
bi o mar kers wit h treat me nt o utc o me a n d ma y  ulti matel y g ui de or refi ne patie nt selecti o n 
strate gies t o better matc h t ucati ni b re gi me ns wit h t u m or p he n ot ype/ ge n ot y p e i n t he f ut ure.
Refer t o t he Ce ntral La b orat or y  Ma n ual f or i nf or mati o n o n c ollecti o n, pr ocessi n g, st ora ge, a n d 
s hi p me nt of sa m ples.
F oll o wi n g i m ple me ntati o n of A me n d me nt 5, n o bl o o d sa m ples f or bi o mar ker assess me nts will 
be dra w n at E O T.
9. 5. S afet y Assess me nts
T he assess me nt of safet y d uri n g t he c o urse of t his st u d y  will c o nsist of t he s ur veilla nce a n d 
rec or di n g of A Es i ncl u di n g S A Es, rec or di n g of c o nc o mita nt me dicati o n, a n d meas ure me nts of 
pr ot oc ol -s pecifie d p h ysical e xa mi nati o n fi n di n gs a n d la b orat or y tests. Assess me nt of car diac 
ejecti o n fracti o n will be perf or me d usi n g M U G A sca n or E C H O.
D u ri n g t he L T E P, all safet y a n d efficac y assess me nts ot her t ha n pre g na nc y testi n g will be 
perf or me d per i nstit uti o nal g ui deli nes a n d i n vesti gat or- deter mi ne d us ual a n d c ust o mar y  cli nical 
care. Pre g na nc y testi n g will c o nti n ue t o be perf or me d as o utli ne d i n t he sc he d ule of e ve nts. 
F oll o wi n g i m ple me ntati o n of A me n d me nt 5, o nl y  i nf or mati o n relate d t o pre g na ncies ( defi ne d i n 
Secti o n 9. 5. 1. 4. 2 ), a n d S A Es a n d A E SIs ( defi ne d i n Secti o n 9. 5. 1. 1) will be re p orte d t o t he 
S p o ns or. 
Safet y  will be m o nit ore d o ver t he c o urse of t he st u d y b y a n S M C as descri be d i n Secti o n 5. 1. 7 .
9. 5. 1. A d verse E ve nts
See A p pe n di x G f or a d diti o nal details o n rec or di n g a n d re p orti n g A Es a n d S A Es.
9. 5. 1. 1. Defi niti o ns
A d verse E ve nt
Acc or di n g t o t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) E 2 A g ui deli ne Defi niti o ns a n d 
Sta n da r ds f or E x pe dite d Re p orti n g, a n d 2 1 C o de of Fe deral Re g ulati o ns ( C F R) 3 1 2. 3 2, 
i n vesti gati o nal ne w dr u g (I N D) Safety Re p orti n g, a n A E is a n y u nt o war d me dical occ urre nce i n 
a partici pa nt or cli nical i n vesti gati o nal partici pa nt a d mi nistere d a me dici nal pr o d uc t a n d w hic h 
d oes n ot necessaril y  ha ve a ca usal relati o ns hi p wit h t his treat me nt.
T he f oll o wi n g i nf or mati o n s h o ul d be c o nsi dere d w he n deter mi ni n g w het her or n ot t o rec or d a 
test res ult, me dical c o n diti o n, or ot her i nci de nt o n t he A d verse E ve nts e C R F:
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 7 of 2 2 0

Fr o m t he ti me of i nf or me d c o nse nt t hr o u g h t he da y  pri or t o st u d y D a y 1, o nl y st u d y 
pr ot oc ol -relate d A Es s h o ul d be rec or de d. A pr ot oc ol-relate d A E is defi ne d as a n 
u nt o war d me dical e ve nt occ urri n g as a res ult of a pr ot oc ol ma n date d pr oce d ure.

All me dical c o n diti o ns prese nt or o n g oi n g pre d ose o n st u d y  Da y 1 t hat i ncrease i n 
C T C A E gra de s h o ul d be rec or de d.

Me dical c o n diti o ns prese nt or o n g oi n g pre d ose o n st u d y  Da y 1 t hat w orse n i n 
se verity, i ncrease i n fre q ue nc y, bec o me relate d t o st u d y  treat me nt, or w orse n i n a n y 
o t her wa y b ut d o n ot meet t he t hres h ol d f or i ncrease i n C T C A E gra de s h o ul d be 
rec or de d.

All A Es (re gar dless of relati o ns hi p t o st u d y  treat me nt s h o ul d be rec or de d fr o m st u d y 
D a y 1 ( d uri n g a n d p ost -d ose) t hr o u g h t he e n d of t he safet y re p orti n g peri o d (see 
Sec ti o n 9. 5. 1. 7 ). C o m plicati o ns t hat occ ur i n ass ociati o n wit h a n y pr oce d ure (e g, 
bi o ps y ) s h o ul d be rec or de d as A Es w het her or n ot t he pr oce d ure was prot oc ol 
ma n date d.

I n ge neral, a n a b n or mal la b orat or y val ue (e g, he mat ol o g y, cli nical c he mistr y, or 
uri nal y sis) s h o ul d n ot be rec or de d as a n A E u nless it is ass ociate d wit h cli nical si g ns 
or s y m pt o ms, re q uires a n i nter ve nti o n, re q uires a d diti o nal dia g n ostic testi n g or 
me dical/s ur gical i nter ve nti o n, res ults i n a S A E, or res ults i n st u d y  ter mi nati o n or 
i nterr u pti o n/ disc o nti n uati o n of st u d y treat me nt. W he n rec or di n g a n A E res ulti n g fr o m 
a la b orat or y a b n or mality,  t he res ulti n g me dical c o n diti o n rat her t ha n t he a bn or malit y  
itself s h o ul d be rec or de d (e g, rec or d “a ne mia” rat her t ha n “l o w he m o gl o bi n”).
D uri n g t he L T E P, S A Es will be re p orte d t o t he S p o ns or s olel y  o n t he S A E f or m 
f oll o wi n g t he sa me re p orti n g g ui deli nes as o utli ne d i n Secti o n 9. 5. 1. 3 , a n d will n ot be 
rec or de d wit hi n t he e C R F.

Ne w c o n diti o n 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 have 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 y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y  
i nter ve nti o n or a c o nc o mita nt me dicati o n. O ver dose per se will n ot be re p orte d as a n 
A E or S A E u nless it is a n i nte nti o nal o ver d ose ta ke n wit h p ossi ble 
s uici dal/self- har mi n g i nte nt. S uc h o ver d oses s h o ul d be re p orte d re gar dless of 
se q uelae
E ve nts N O T Meeti n g t he A E Defi niti 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 or ot her a b n or mal safety 
assess me nts t hat are ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y  t he 
i n vesti 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.

T he disease/ dis or der bei n g st u die d or e x pe cte d pr o gressi o n, si g ns, or s y m pt o ms of t he 
disease/ dis or der bei n g st u die d, u nless 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.

Disease pr o gressi o n assesse d b y  meas ure me nt of mali g na nt lesi o ns o n ra di o gra p hs or 
ot her met h o ds s h o ul d n ot be re p orte d as A Es
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 8 of 2 2 0

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 pree 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.
Seri o us A d verse E ve nts
A n A E s h o ul d be classifie d as a n S A E if it meets o ne of t he f oll o wi n g criteria:
Fatal:
A E res ulte d i n deat h
Life t hreate ni n g:
T he A Es place d t he partici pa nt at i m me diate ris k of deat h. T his classificati o n d oes n ot 
a p pl y t o a n A E t hat h y p ot heticall y mi g ht ca use deat h if it were m ore se vere.
H os pitalizati o n:
T he A E res ulte d i n h os pitalizati o n or pr ol o n g e d a n e xisti n g i n patie nt h os pitalizati 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 ysicia n’s office or 
o ut patie nt setti n g. H os pitalizati o ns f or electi ve me dical or s ur gical pr oce d ures or 
treat me nts pla n ne d bef ore t he si g ni n g of i nf or me d c o nse nt i n t he st u d y or r o uti ne 
c hec k- u ps are n ot S A Es b y t his criteri o n. A d mis si o n t o a palliati ve u nit or h os pice 
care facilit y is n ot c o nsi dere d t o be a h os pitalizati o n. H os pitalizati o ns or pr ol o n ge d 
h os pitalizati o ns f or sc he d ule d t hera p y of t he u n derl yi n g ca ncer or st u d y tar get disease 
nee d n ot be ca pt ure d as S A Es. C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are 
A E s. 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 whet her “ h os pitalizati o n” occ urre d or w as 
necessar y, t he A E s h o ul d be c o nsi dere d seri o us
Disa bli n g/
i nca pacitati n g:
A n A E t hat res ulte d i n a persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n 
of t he partici pa nt’s a bilit y t o 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), t hat ma y i nterfere wit h or pre ve nt e ver y da 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.
C o n ge nital a n o mal y or 
birt h defect:
A n a d verse o utc o me i n a c hil d or fet us of a partici pa nt e x p ose d t o t he m olec ule or 
st u d y treat me nt re gi me n bef ore c o nce pti o n or d uri n g pre g na nc y.
Me dicall y si g nifica nt:
T he A E di d n ot meet a n y of t he a b o ve criteria b ut c o ul d ha ve je o par dize d t he 
partici pa nt a n d mi g ht ha ve re q uire d me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of 
t he o utc o mes liste d a b o ve or i n v ol ves s us pecte d tra ns missi o n via a me dici nal pr o d uct 
of a n i nfecti o us a ge nt. P ote ntial dr u g -i n d uce d li ver i nj ur y ( DI LI) als o is c o nsi dere d a 
me dicall y si g nifica nt e ve nt (see Secti o n 9. 5. 1. 6 f or t he defi niti o n of p ote ntial DI LI).
If t he i n vesti gat or d oes n ot k n o w w het her or n ot t he stu d y  i nter ve nti o n ca use d t he e ve nt, t he n t he 
e ve nt will be ha n dle d as “relate d t o st u d y i nter ve nti o n” f or re p orti n g p ur p oses, as defi ne d b y t he 
s p o ns or. In a d diti o n, if t he i n vesti gat or deter mi nes t hat a n S A E is ass ociate d wit h st u d y  
pr oce d ures, t he i n vesti gat or m ust rec or d t his ca usal relati o ns hi p i n t he s o urce d oc u me nts a n d 
re p ort s uc h a n assess me nt i n t he de dicate d secti o n of t he Pfizer S A E s u b missi o n assista nt 
( P S S A) a n d i n acc or da nce wit h t he S A E re p orti n g re q uire me nts.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 3 9 of 2 2 0
A d verse E ve nt Se verit y
A E se verity s h o ul d be gra de d usi n g t he Nati o nal Ca ncer I nstit ute ( N CI) C o m m o n Ter mi n ol o g y 
Criteria f or A d verse E ve nts ( C T C A E) Versi o n 5. 0. T hese criteria are pr o vi de d i n t he st u d y  
ma n ual.
A E se verit y a n d seri o us ness are assesse d i n de pe n de ntl y . ‘ Se verity’ c har acterizes t he i nte nsit y of 
a n A E. ‘ Seri o us’ is a re g ulat or y  defi niti o n a n d ser ves as a g ui de t o t he s p o ns or f or defi ni n g 
re g ulat or y re p orti n g o bli gati o ns (see defi niti o n f or S A Es, a b o ve).
Rel ati o ns hi p of t he A d verse E ve nt t o St u d y Tre at me nt
T he relati o ns hi p of eac h A E t o eac h st u d y treat me nt (t ucati ni b, trast uz u ma b, le uc o v ori n, 
fl u or o uracil, ca pecita bi ne, o xali plati n) s h o ul d be e val uate d b y t he i n vesti gat or usi n g t he 
f oll o wi n g criteria:
Relate d:
T here is e vi de nce t o s u g gest a ca usal relati o ns hi p bet w ee n t he dr u g a n d t he A E, s uc h 
as:
A si n gle occ urre nce of a n e ve nt t hat is u nc o m m o n a n d k n o w n t o be str o n gl y 
ass ociate d wit h dr u g e x p os ure (e g, a n gi oe de ma, he patic i nj ur y, Ste ve ns -J o h ns o n 
S y n dr o me)
O ne or m ore occ urre nces of a n e ve nt t hat is n ot c o m m o nl y ass ociate d wit h dr u g 
e x p os ure, b ut is ot her wise u nc o m m o n i n t he p o p ulati o n e x p ose d t o t he dr u g (e g, 
te n d o n r u pt ure)
U nrelate d:
A n ot her ca use of t he A E is m ore pla usi ble (e g, d ue t o u n derl yi n g disease or occ urs 
c o m m o nl y i n t he st u d y p o p ulati o n), or a te m p oral se q ue nce ca n n ot be esta blis he d wit h 
t he o nset of t he A E a n d a d mi nistrati o n of t he st u d y treat me nt, or a ca usal relati o ns hi p 
is c o nsi dere d bi ol o gicall y i m pla usi ble
9. 5. 1. 2. A d verse E ve nts of S peci al I nterest
A d verse E ve nts of S pecial I nterest ( A E SI) are defi ne d b y  t he sp o ns or as a p ote ntial safet y iss ue 
i de ntifie d as a res ult of o n g oi n g safety m o nit ori n g of t heir pr o d ucts. As s uc h, s ur veilla nce f or t he 
A E SI s M U S T be u n derta ke n at eac h treat me nt e val uati o n. De vel o p me nt of o ne of t hese A E SIs 
( ≥ Gra de 1 u nless ot her wise n ote d) M U S T be re p orte d i n ter ms of N CI C T C A E v 5. 0 gra de a n d 
attri b uti o n. 
All A E SI s m ust be re p orte d as a n A E or S A E f oll o wi n g t he pr oce d ures descri be d i n 
Secti o n 9. 5. 1. 3 , Secti o n 9. 5. 1. 7 , a n d Secti o n 9. 5. 1. 8 . In a d diti o n, a n A E SI t hat is als o a n S A E 
m ust be re p orte d us i n g t he P S S A ( Secti o n 9. 5. 1. 8 ). D uri n g t he L T E P, o nl y seri o us A E SIs will be 
re p orte d via P S S A..
A E SI s f or t his st u d y are:
1.
He pat ot o xicit y :

A S T or A L T ele vati o ns t hat are > 3 × U L N wit h c o nc urre nt ele vati o n ( wit hi n 2 1 da y s 
of A S T a n d/ or A L T ele vati o ns) of t otal bilir u bi n > 2 × U L N, e xce pt i n partici pa nts 
wit h d oc u me nte d Gil bert’s s y n dr o me

A S T or A L T ele vati o ns > 2 0 ╳U L N 

Bilir u bi n ele vati o ns > 1 0. 0 ╳U L N
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 0 of 2 2 0
Meas ure me nt of c o nj u gate d a n d u nc o nj u gate d bilir u bi n s h o ul d be c o nsi dere d i n cases 
of h y per bilir u bi ne mia t o assist i n deter mi nati o n of its eti ol o g y . T he s p o ns or will 
s u bse q ue ntl y deter mi ne w het her t he ele vati o ns are ass ociate d wit h ot her p ossi ble 
ca uses of a mi n otra nsferase ele vati o n a n d h y p er bilir u bi ne mia, s uc h as viral he patitis, 
pre -e xisti n g c hr o nic or ac ute li ver disease, or t he a d mi nistrati o n of ot her dr u g(s) 
k n o w n t o be he pat ot o xic.
2.
I ncrease of ser u m c ystati n C > 1. 5 × baseli ne
3.
≥ Gra de 3 diarr hea 
9. 5. 1. 3. P r oce d ures f or Eliciti n g a n d Rec or di n g A d verse E ve nts
I n vesti gat or a n d st u d y pers o n nel will re p ort all A Es a n d S A Es w het her elicite d d uri n g partici pa nt 
q uesti o ni n g, disc o vere d d uri n g p h ys ical e xa mi nati o n, la b orat or y testi n g, a n d/ or ot her mea ns b y 
rec or di n g t he m o n t he e C R F a n d/ or S A E f or m, as a p pr o priate. Diaries ma y be use d f or rec or di n g 
t he n u m ber of st o ols per da y t o ai d wit h acc uratel y d oc u me nti n g a n d gra di n g diarr hea A Es. 
Eliciti n g A d verse E ve nts
A n o pe n -e n de d or n o n- directe d met h o d of q uesti o ni n g s h o ul d be use d at eac h st u d y visit t o elicit 
t he re p orti n g of A Es.
Rec or di n g A d verse E ve nts
T he f oll o wi n g i nf or mati o n s h o ul d be rec or de d o n t he A d verse E ve nts e C R F ( See Ta ble 2 7 f or 
m ore details):

Descri pti o n i ncl u di n g o nset a n d res ol uti o n dates

W het her it met S A E criteria

Se verit y

Relati o ns hi p t o st u d y  treat me nt or ot her ca usalit y

O utc o me
Di a g n osis vs. Si g ns or S y m pt o ms
I n ge neral, t he use of a u nif yi n g dia g n osis is preferre d t o t he listi n g o ut of i n di vi d ual s ym pt o ms. 
Gr o u pi n g of s y m pt o ms i nt o a dia g n osis s h o ul d o nl y  be d o ne if eac h c o m p o ne nt si g n a n d/ or 
s ym pt o m is a me dicall y c o nfir me d c o m p o ne nt of a dia g n osis as e vi de nce d b y sta n dar d me dical 
te xt b o o ks. If a ny as pect of a si g n or s y m pt o m d oes n ot fit i nt o a classic patter n of t he dia g n osis, 
re p ort t he i n di vi d ual s ym pt o m as a se parate A E.
I m p orta nt e xce pti o ns f or t his st u d y are a d verse reacti o ns ass ociate d wit h t he i nf usi o n of st u d y 
treat me nt. Rec or d eac h si g n or sy m pt o m as a n i n di vi d ual A E i n a d diti o n t o t he I R R ter m. If 
m ulti ple si g ns or s y m pt o ms occ ur wit h a gi ve n i nf usi o n -relate d e ve nt, eac h si g n or sy m pt o m 
s h o ul d be rec or de d se paratel y wit h its le vel of se verit y. 
Rec or di n g Seri o us A d verse E ve nts
T he S A E s h o ul d be re p orte d t o Pfizer Safet y usi n g t he P S S A (see A p pe n di x G f or m ore details). 
H o we ver, d uri n g t he L T E P, S A Es will be re p orte d t o t he S p o ns or via P S S A f oll o wi n g t he sa me 
re p orti n g g ui deli nes as o utli ne d bel o w a n d will n ot be rec or de d wit hi n t he e C R F.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 1 of 2 2 0
T he f oll o wi n g s h o ul d be c o nsi dere d w he n rec or di n g S A Es:

Deat h is a n o utc o me of a n e ve nt. T he e ve nt t hat res ulte d i n t he deat h s h o ul d be 
rec or de d a n d re p orte d o n b ot h a n S A E f or m a n d e C R F.

F or h os pitalizati o ns, s ur gical, or dia g n ostic pr oce d ures, t he ill ness lea di n g t o t he 
s ur gical or dia g n ostic pr oce d ure s h o ul d be rec or de d as t he S A E, n ot t he pr oce d ure 
itself. T he pr oce d ure s h o ul d be ca pt ure d i n t he narrati ve as part of t he acti o n ta ke n i n 
res p o nse t o t he ill ness.
Pr o gressi o n of U n derl yi n g M ali g n a nc y
Si nce pr o gressi o n of u n derl y i n g mali g na nc y is bei n g assesse d as a n efficac y varia ble, it s h o ul d 
n ot be re p orte d as a n A E or S A E. T he ter ms “ Disease Pr o gressi o n”, “ Pr o gressi o n of Disease”, or 
“ Mali g na nt disease pr o gressi o n” a n d ot her si milar ter ms s h o ul d n o t be use d t o descri be a n A E or 
S A E. H o we ver, cli nical s y m pt o ms of pr o gressi o n ma y  be re p orte d as A Es or S A Es if t he 
s ym pt o m ca n n ot be deter mi ne d as e xcl usi vel y  d ue t o pr o gressi o n of t he u n derl yi n g mali g na nc y 
or d oes n ot fit t he e x pecte d patter n of pr o gress i o n f or t he disease u n der st u d y. In a d diti o n, 
c o m plicati o ns fr o m pr o gressi o n of t he u n derl yi n g mali g na nc y  s h o ul d be re p orte d as A Es or 
S A Es.
9. 5. 1. 4. E n vir o n me nt al E x p os ure, E x p os ure D uri n g Pre g n a nc y or Bre astfee di n g, a n d 
Occ u p ati o n al E x p os ure
Refer t o A p pe n di x G f or g ui da nce o n re p orti n g/rec or di n g e n vir o n me ntal e x p os ure, e x p os ure 
d uri n g pre g na nc y  ( E D P), e x p os ure d uri n g breastfee di n g ( E D B), a n d occ u pati o nal e x p os ures.
9. 5. 1. 4. 1. E n vir o n me nt al E x p os ure
E n vir o n me ntal e x p os ure occ urs w he n a pers o n n ot e nr olle d i n t he st u d y as a partici pa nt recei ves 
u n pla n ne d direct c o ntact wit h or e x p os ure t o t he st u d y  i nter ve nti o n. S uc h e x p os ure ma y or ma y 
n ot lea d t o t he occ urre nce of a n A E or S A E. Pers o n s at ris k f or e n vir o n me ntal e x p os ure i ncl u de 
healt hcare pr o vi ders, fa mil y  me m bers, a n d ot hers w h o ma y be e x p ose d. A n e n vir o n me ntal 
e x p os ure ma y i ncl u de E D P, E D B, a n d occ u pati o nal e x p os ure.
A n y  s uc h e x p os ure t o t he st u d y i nter ve nti o n u n der st u d y are re p ortable t o Pfizer Safet y wit hi n 2 4 
h o urs of i n vesti gat or a ware ness. Refer t o A p pe n di x G f or g ui da nce o n re p orti n g/rec or di n g 
e n vir o n me ntal e x p os ure.
9. 5. 1. 4. 2. E x p os ure D uri n g Pre g n a nc y
A n E D P occ urs if: 

A partici pa nt is f o u n d t o be pre g na nt w hile recei vi n g or after disc o nti n ui n g st u d y  
i nter ve nti o n. 

A partici pa nt w h o is recei vi n g or has disc o nti n ue d st u d y i nter ve nti o n i nse mi nates a 
part ner. 

A n o n partici pa nt is f o u n d t o be pre g na nt w hile bei n g e x p ose d or ha vi n g bee n e x p ose d 
t o st u d y i nter ve nti o n beca use of e n vir o n me ntal e x p os ure. Bel o w are e xa m ples of 
e n vir o n me ntal E D P: 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 2 of 2 2 0

A fa mil y  me m ber or healt hcare pr o vi der re p orts t hat t he y are pre g na nt after 
e x p os ure t o st u d y i nter ve nti o n, f or e xa m ple, b y i n gesti o n or s ki n c o ntact. 

A fa mil y  me m ber or healt hcare pr o vi der w h o has bee n e x p ose d t o t he st u d y 
i nter ve nti o n, f or e xa m ple, b y i n gesti o n or s ki n c o ntact a n d t he n i nse mi nates t heir 
part ner pri or t o or a r o u n d t he ti me of c o nce pti o n. 
T he i n vesti gat or m ust re p ort E D P t o Pfizer Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s 
a ware ness, irres pecti ve of w het her a n S A E has occ urre d. T he i nitial i nf or mati o n s u b mitte d 
s h o ul d i ncl u de t he a ntici pate d date of deli ver y (see bel o w f or i nf or mati o n relate d t o ter mi nati o n 
of pre g na nc y ). Refer t o A p pe n di x G f or g ui da nce o n re p orti n g/rec or di n g E D P.

If E D P occ urs i n a partici pa nt or a partici pa nt’s part ner after t he start of st u d y  
i nter ve nti o n a n d u ntil 7 m o nt hs after t he last d ose of t he last st u d y i nter ve nti o n, t he 
i n vesti gat or m ust re p ort t his i nf or mati o n t o Pfizer Safet y o n t he P S S A a n d a n E D P 
s u p ple me ntal F or m, re gar dless of w het her a n S A E has occ urre d. Details of t he pre g na nc y 
will be c ollecte d after t he start of st u d y  i nter ve nti o n a n d u ntil 7 m o nt hs after t he last d ose 
of t he last st u d y  i nter ve nti o n.

If E D P occ urs i n t he setti n g of e n vir o n me ntal e x p os ure, t he i n vesti gat or m ust re p ort 
i nf or mati o n t o Pfizer Safet y via P S S A. Si nce t he e x p os ure i nf or mati o n d oes n ot pertai n t o 
t he partici pa nt e nr olle d i n t he st u d y, t he i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, 
a c o p y of t he c o m plete d P S S A is mai ntai ne d i n t he i n vesti gat or site file.
F oll o w -u p is c o n d ucte d t o o btai n ge neral i nf or mati o n o n t he pre g na nc y  a n d its o utc o me f or all 
E D P re p orts wit h a n u n k n o w n o utc o me. T he i n vesti gat or will f oll o w t he pre g na nc y  u ntil 
c o m pleti o n ( or u ntil pre g na nc y  ter mi nati o n) a n d n otif y Pfizer Safet y of t he o utc o me as a 
f oll o w-u p t o t he i nitial E D P. I n t he case of a li ve birt h, t he str uct ural i nte grit y  of t he ne o nate ca n 
be assesse d at t he ti me of birt h. I n t he e ve nt of a ter mi nati o n, t he reas o n(s) f or ter mi nati o n s h o ul d 
be s pecifie d a n d, if cli nicall y p ossi ble, t he str uct ural i nte grity of t he ter mi nate d fet us s h o ul d be 
assesse d b y gr oss vis ual i ns pecti o n ( u nless pre pr oce d ure test fi n di n gs are c o ncl usi ve f or a 
c o n ge nital a n o mal y a n d t he fi n di n gs are re p orte d).
A b n or mal pre g na nc y  o utc o mes are c o nsi dere d S A Es. If t he o utc o me of t he pre g na nc y  meets t he 
criteria f or a n S A E (ie, ect o pic pre g na nc y , s p o nta ne o us a b orti o n, i ntra uteri ne fetal de mise, 
ne o natal deat h, or c o n ge nital a n o mal y  i n a li ve-b or n ba b y , a ter mi nate d fet us, a n i ntra uteri ne 
fetal de mise, or a ne o natal deat h), t he i n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g 
S A Es. A d diti o nal i nf or mati o n a b o ut pre g na nc y o utc o mes t hat are re p orte d t o Pfizer Safet y  as 
S A Es f oll o ws: 

S p o nta ne o us a b orti o n i ncl u di n g miscarria ge a n d misse d a b orti o n s h o ul d be re p orte d 
as a n S A E;

Ne o natal deat hs t hat occ ur wit hi n 1 m o nt h of birt h s h o ul d be re p orte d, wit h o ut re gar d 
t o ca usalit y, as S A Es. I n a d diti o n, i nfa nt deat hs after 1 m o nt h s h o ul d be re p orte d as S A Es 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 3 of 2 2 0
w he n t he i n vesti gat or assesses t he i nfa nt deat h as relate d or p ossi bl y relate d t o e x p os ure 
t o t he st u d y i nter ve nti o n. 
A d diti o nal i nf or mati o n re gar di n g t he E D P ma y  be re q ueste d b y t he s p o ns or. F urt her f oll o w-u p of 
birt h o utc o mes will be ha n dle d o n a case- b y -case basis (e g, f oll o w- u p o n preter m i nfa nts t o 
i de ntif y de vel o p me ntal dela ys). I n t he case of pater nal e x p os ure, t he i n vesti gat or will pr o vi de t he 
partici pa nt wit h t he Pre g na nt Part ner Release of I nf or mati o n F or m t o deli ver t o t heir part ner. T he 
i n vesti gat or m ust d oc u me nt i n t he s o urce d oc u me nts t hat t he partici pa nt was gi ve n t he Pre g na nt 
Part ner Release of I nf or mati o n F or m t o pr o vi de t o t heir part ner.
9. 5. 1. 4. 3. E x p os ure D uri n g Bre astfee di n g
A n E D B occ urs if: 

A partici pa nt is f o u n d t o be breastfee di n g w hile recei vi n g or after disc o nti n ui n g st u d y  
i nter ve nti o n ( u ntil 7 m o nt hs after t he last d ose of t he last st u d y i nter ve nti o n).

A n o n partici pa nt is f o u n d t o be breastfee di n g w hile bei n g e x p ose d or ha vi n g bee n 
e x p ose d t o st u d y i nter ve nti o n (ie, e n vir o n me ntal e x p os ure). A n e xa m ple of 
e n vir o n me ntal E D B is a fa mil y me m ber or healt hcare pr o vi der w h o re p orts breastfee di n g 
after ha vi n g bee n e x p ose d t o st u d y i nter ve nti o n, f or e xa m ple, b y  i n gesti o n or s ki n 
c o ntact. Refer t o A p pe n di x G f or g ui da nce o n re p orti n g/rec or di n g E D B.
T he i n vesti gat or m ust re p ort E D B t o Pfizer Safet y wit hi n 2 4 h o urs of t he i n vesti gat or’s 
a ware ness, irres pecti ve of w het her a n S A E has occ urre d. T he i nf or mati o n m ust be re p orte d usi n g
t he P S S A. W he n E D B occ urs i n t he setti n g of e n vir o n me ntal e x p os ure, t he e x p os ure i nf or mati o n 
d oes n ot pertai n t o t he partici pa nt e nr olle d i n t he st u d y , s o t he i nf or mati o n is n ot rec or de d o n a 
C R F. H o we ver, a c o p y of t he c o m plete d P S S A is mai ntai ne d i n t he i n vesti gat or site file.
9. 5. 1. 4. 4. Occ u p ati o n al E x p os ure
T he i n vesti gat or m ust re p ort a n y  i nsta nce of occ u pati o nal e x p os ure t o Pfizer Safety wit hi n 
2 4 h o urs of t he i n vesti gat or’s a ware ness usi n g t he P S S A re gar dless of w het her t here is a n 
ass ociate d S A E. Si nce t he i nf or mati o n a b o ut t he occ u pati o nal e x p os ure d oes n ot pertai n t o a 
partici pa nt e nr olle d i n t he st u d y, t he i nf or mati o n is n ot rec or de d o n a C R F; h o we ver, a c o p y  of 
t he c o m plete d P S S A m ust be mai ntai ne d i n t he i n vesti gat or site file.
9. 5. 1. 5. L ac k of Effic ac y
T he i n vest i gat or m ust re p ort si g ns, sy m pt o ms, a n d/ or cli nical se q uelae res ulti n g fr o m lac k of 
efficac y. L ac k of effic ac y or f ail ure of e x pecte d p h ar m ac ol o gic al acti o n is re p ort a ble t o 
Pfizer S afet y o nl y if ass oci ate d wit h a n S A E .
9. 5. 1. 6. P ote nti al Dr u g -i n d uce d Li ver I nj ur y
H y ’s La w ca n be use d t o esti mate se verit y a n d t he li keli h o o d t hat a st u d y treat me nt ma y ca use a n 
i ncrease d i nci de nce of se vere he pat ot o xicit y.
T he a bse nce of he pat ot o xicit y  i n cli nical trials pr o vi des a li mite d pre dicti ve val ue f or p ote ntial 
dr u g -i n d uce d li ver i nj ur y ( DI LI) i n t he cli nical setti n g(s) bei n g st u die d. H o we ver, fi n di n g 1 H y’s 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 4 of 2 2 0
La w case i n cli nical trials is o mi n o us; fi n di n g 2 cases is hi g hl y pre dicti ve of a p ote ntial f or 
se vere DI LI.
Defi niti o n
Briefl y, p ote ntial H y’s La w cases i ncl u de t he f oll o wi n g 3 c o m p o ne nts:

A mi n otra nsferase ( A L T a n d/ or A S T) ele vati o n > 3 × U L N
A N D

T otal bilir u bi n > 2 × U L N, wit h o ut i nitial fi n di n gs of c h olestasis (ie, ele vate d ser u m 
al kali ne p h os p hatase),
A N D

N o ot her i m me diatel y a p pare nt p ossi ble ca uses of a mi n otra nsferase ele vati o n a n d 
h y per bilir u bi ne mia, i ncl u di n g, b ut n ot li mite d t o, viral he patitis, pre -e xisti n g c hr o nic 
or ac ute li ver disease, or t he a d mi nistrati o n of ot her dr u g(s) k n o w n t o be he pat ot o xic.
Re p orti n g Re q uire me nts
A n y p ote nti al H y’s L a w c ase s h o ul d be h a n dle d as a n S A E a n d re p orte d pr o m ptl y t o t he 
S p o ns or .
Re p orti n g s h o ul d i ncl u de all a vaila ble i nf or mati o n a n d s h o ul d i nitiate cl ose f oll o w -u p u ntil 
c o m plete res ol uti o n of t he pr o ble m a n d c o m pleti o n of all atte m pts t o o btai n s u p ple me ntar y  data.
F oll o w -u p f or A b n o r m al L a b or at or y Res ults S u g gesti n g P ote nti al DI LI
I n ge neral, a n i ncrease of ser u m A L T or A S T t o > 3 × U L N s h o ul d be f oll o we d b y re peat testi n g 
wit hi n 4 8 t o 7 2 h o urs of ser u m A L T, A S T, al kali ne p h os p hatase, a n d t otal bilir u bi n, t o c o nfir m 
t he a b n or malities a n d t o deter mi ne w het her t he y are w orse ni n g.
A p pr o priate me dical assess me nt s h o ul d be i nitiate d t o i n vest i gate p ote ntial c o nf o u n di n g fact ors 
a n d alter nati ve ca uses of he pat ot o xicit y . D uri n g t his i n vesti gati o n, c o nsi der wit h h ol di n g st u d y 
treat me nt.
Left Ve ntric ul ar Ejecti o n Fr acti o n Decre ase d
F or as y m pt o matic decli nes i n L V E F lea di n g t o a c ha n ge i n st u d y  treat me nt or disc o nti n uati o n of 
st u d y treat me nt, t he ter m “ejecti o n fracti o n decrease d” s h o ul d be use d, a n d se verity Gra des 2 t o 
4 use d t o re p ort as y m pt o matic L V E F decrease.
F or s y m pt o matic c o n gesti ve heart fail ure ( C H F), t he ter m “ heart fail ure” s h o ul d be use d , a n d 
se verity Gra des 2 t o 5 use d t o re p ort s y m pt o matic C H F.
9. 5. 1. 7. Re p orti n g Peri o ds f or A d verse E ve nts a n d Seri o us A d verse E ve nts
T he safet y re p orti n g peri o d f or all A Es is fr o m st u d y D a y 1 ( pre d ose) t hr o u g h 3 0 d a y s after t he 
last st u d y treat me nt. H o we ver, all st u d y pr ot oc ol-relate d A Es are t o be rec or de d fr o m t he ti me of 
i nf or me d c o nse nt. F or C o h orts 1 A, 1 B, 1 C, 1 D, a n d 2 B, t he safety re p orti n g peri o d f or all S A Es 
is fr o m st u d y Da y 1 ( pre d ose) t hr o u g h 3 0 d a y s after t he last st u d y treat me nt. F or C o h orts 1 E, 1 F, 
1 G, a n d 2 A, all A Es meeti n g seri o us criteria, fr o m t he ti me of treat me nt all ocati o n t hr o u g h 
9 0 da y s f oll o wi n g cessati o n of st u d y treat me nt, or 3 0 da ys f oll o wi n g cessati o n of st u d y treat me nt 
if t he partici pa nt i nitiates ne w a ntica ncer t hera py, w hic he ver is earlier m ust be re p orte d b y t he 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 5 of 2 2 0
i n vesti gat or. All S A Es t hat occ ur after t he safet y  re p orti n g peri o d a n d are c o nsi dere d st u d y 
treat me nt-relate d i n t he o pi ni o n of t he i n vesti gat or s h o ul d als o be re p orte d t o t he s p o ns or.
I n vesti gat ors are n ot o bli gate d t o acti vely see k i nf or mati o n o n A Es or S A Es after t he partici pa nt 
has c o ncl u de d 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 S A E, i ncl u di n g a 
deat h, at a n y ti me after a partici pa nt has c o ncl u de d st u d y partici pati o n, a n d t he y c o nsi der t he 
e ve nt t o be reas o na bly relate d t o t he st u d y  i nter ve nti o n, t he i n vesti gat or m ust pr o m ptl y re p ort t he 
S A E t o Pfizer usi n g P S S A.
S A Es will be f oll o we d u ntil si g nifica nt c ha n ges ret ur n t o baseli ne, t he e ve nt sta bilizes 
(rec o veri n g/res ol vi n g) or is n o l o n ger c o nsi dere d cli nicall y si g nifica nt by t he i n vesti gat or, or t he 
partici pa nt dies or wit h dra ws c o nse nt. All n o n -seri o us A Es will be f oll o we d t hr o u g h t he safety 
re p orti n g peri o d. Certai n n o n-seri o us A Es of i nterest ma y be f oll o we d u ntil res ol uti o n, ret ur n t o 
baseli ne , or st u d y cl os ure. 
If a partici pa nt be gi ns a ne w a ntica ncer t hera p y, t he rec or di n g peri o d f or n o nseri o us A Es e n ds at 
t he ti me t he ne w treat me nt is starte d. S A Es occ urri n g d uri n g t he safety re p orti n g peri o d m ust still 
be re p orte d t o Pfizer Safet y  irres pecti ve of a n y i nter ve ni n g treat me nt. N ote t hat a s witc h t o a 
c o m merciall y a vaila ble versi o n of t he st u d y i nter ve nti o n is c o nsi dere d as a ne w a ntica ncer 
t hera py f or p ur p oses of S A E re p orti n g.
9. 5. 1. 8. Seri o us A d verse E ve nts Re q uire I m me di ate Re p orti n g
All S A Es occ urri n g i n a partici pa nt d uri n g t he safet y  re p orti n g peri o d are re p orte d t o Pfizer 
Safet y  o n t he P S S A i m me diately u p o n a ware ness a n d u n der n o circ u msta nce s h o ul d t his e xcee d 
2 4 h o urs. 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 ours of 
its bei n g a vaila ble.
F or i nitial S A E re p orts, a vaila ble case details are t o be rec or de d o n a n S A E f or m. At a mi ni m u m, 
t he f oll o wi n g s h o ul d be i ncl u de d:

Partici pa nt n u m ber

Date of e ve nt o nset

Descri pti o n of t he e ve nt

St u d y  treat me nt, if k n o w n

I n vesti gat or ca usalit y assess me nt
Rele va nt f oll o w - u p i nf or mati o n is t o be s u b mitte d t o t he s p o ns or as s o o n as it bec o mes a vaila ble. 
9. 5. 1. 9. S p o ns or S afet y Re p orti n g t o Re g ul at or y A ut h orities
I n vesti gat ors are re q uire d t o re p ort all S A Es t o t he s p o ns or (see Sectio n 9. 5. 1. 8 ). T he s p o ns or 
will re p ort all S A Es, i ncl u di n g s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) t o 
re g ulat or y a ut h orities as re q uire d per l ocal le gislati o n or re g ulat or y  re p orti n g re q uire me nts. A n 
i n vesti gat or w h o recei ves S U S A Rs or ot her s pecific safety i nf or mati o n (e g, s u m mar y or listi n g 
of S A Es) 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 S R S D(s) f or t he st u d y  a n d 
will n otif y  t he I R B/ E C, if a p pr o priate acc or di n g t o l ocal re q uire me nts.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 6 of 2 2 0
9. 5. 2. Vit al Si g ns
Vital si g ns meas ures are t o i ncl u de heart rate, bl o o d press ure, te m perat ure, a n d res pirat or y  rate.
9. 5. 3. Cli nic al L a b or at or y Tests
Sa m ples will be dra w n f or ce ntral a n d l ocal la b s. L ocal la b orat or y testi n g will i ncl u de 
i nstit uti o nal sta n dar d tests f or e val uati n g safety a n d ma ki n g cli nical decisi o ns. T he f oll o wi n g 
la b orat or y assess me nts will be perf or me d t o e val uate safet y at sc he d ule d ti me p oi nts (see 
A p pe n di x A ) d uri n g t he c o urse of t he st u dy:

T he c he mistr y  pa nel is t o i ncl u de t he f oll o wi n g tests: al b u mi n, al kali ne p h os p hatase, 
A L T, A S T, bl o o d urea nitr o ge n ( B U N), calci u m, creati ni ne, c hl o ri de, lactate 
de h y dr o ge nase, p h os p h or us, p otassi u m, s o di u m, a n d t otal bilir u bi n.

T he C B C wit h differe ntial is t o i ncl u de t he f oll o wi n g tests: w hite bl o o d cell c o u nt 
wit h 5 -part differe ntial ( ne utr o p hils, l y m p h oc y tes, m o n oc ytes, e osi n o p hils, a n d 
bas o p hils), platelet c o u nt, he m o gl o bi n, a n d he mat ocrit. 

A c oa g ulati o n pa nel is t o i ncl u de t he f oll o wi n g tests: I N R, pr ot hr o m bi n ti me, a n d 
P T T/a P T T.

C y stati n C i n ser u m (ce ntral la b or at or y test).

T he esti mate d G F R s h o ul d be calc ulate d usi n g t he M D R D e q uati o n, wit h ser u m 
creati ni ne re p orte d i n m g/ d L . 
G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 ×(ser u m creati ni ne)-1. 1 5 4×( A ge) -0. 2 0 3×( 0. 7 4 2 if 
fe male) ×( 1. 2 1 2 if Africa n A merica n)

Uri nal y sis
o
Sta n dar d uri nal ys is ( wit h micr osc o py if cli nicall y i n dicate d)
o
Uri ne pr otei n a n d uri ne creati ni ne f or uri ne pr otei n/creati ni ne rati o
o
2 4 -h o ur uri ne c ollecti o n re q uire d i n c ycles w he n uri ne pr otei n/creati ni ne rati o 
> 2. 0

A ser u m/ plas ma or uri ne β -h C G pre g na nc y  test f or partici pa nts of c hil d beari n g 
p ote ntial

T h y r oi d f u ncti o n tests (trii o d ot h yr o ni ne [ T 3] or free trii o d ot h yr o ni ne [ F T 3], free 
t h yr o xi ne [ F T 4], t h yr oi d sti m ulati n g h or m o ne [ T S H])
D uri n g t he L T E P, all safet y  assess me nts ot her t ha n pre g na nc y testi n g will be perf or me d per 
i nstit uti o nal g ui deli nes a n d i n vesti gat or-deter mi ne d us ual a n d c ust o mar y  care. Pre g na nc y testi n g 
will c o nti n ue t o be perf or me d as o utli ne d i n t he sc he d ule of e ve nts i n partici pa nts of c hil d beari n g 
p ote ntial. 
9. 5. 3. 1. M o nit ori n g f or Re n al T o xicit y
D ose h ol ds or disc o nti n uati o n of t ucati ni b ma y  be re q uire d i n t he case of re nal f u ncti o n c ha n ges. 
T he al g orit h m f or assess me nt a n d treat me nt of re nal f u ncti o n a b n or malities is detaile d i n Fi g ure
3 .
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 7 of 2 2 0
Fi g ure 3:
Decisi o n Tree f or C h a n ges i n Re n al F u ncti o n
Ser u m B U N, creati ni ne, a n d c y stati n C will be dra w n at t he sa me ti me f or eac h ti me p oi nt w he n 
re nal f u ncti o n is bei n g assesse d. It is e x pecte d t hat t he B U N a n d creati ni ne res ults will be 
a vaila ble pri or t o t he c ystati n C, s o i nitial treat me nt decisi o ns will be ma de usi n g t hese res ults. 
E val uati o n of t he eti ol o g y of a b n or mal creati ni ne or c y stati n C val ues ma y i ncl ude a d diti o nal 
bl o o d w or k, uri nal ys is, i ma gi n g ( ultras o u n d or C T), a n d/ or c o ns ult wit h ne p hr ol o g y. T ucati ni b 
m ust be disc o nti n ue d i n partici pa nts wit h c o nfir me d c y stati n C i ncreases > 5 0 % fr o m baseli ne, 
t hat are n ot d ue t o pre or p ost re nal eti ol o gies or f or w hic h t here is n o alter nati ve cli nical 
e x pla nati o n (e g, clearl y relate d t o a n i nterc urre nt ill ness or disease pr o gressi o n). Is olate d 
pr otei n uria is n ot i n dicati ve of t u b ular i nj ur y  a n d s h o ul d n ot necessarily lea d t o disc o nti n uati o n 
of t ucati ni b.
9. 5. 4. P h ysic al E x a mi n ati o n
P h y sical e xa mi nati o ns s h o ul d i ncl u de assess me nts of t he f oll o wi n g b o dy parts/s y ste ms: 
a b d o me n, e xtre mities, hea d, heart, l u n gs, nec k, a n d ne ur ol o gical. F or a d ult partici pa nts o nl y , 
meas ure me nts of hei g ht o btai ne d wit hi n t he pri or 1 2 m o nt hs ma y  be utilize d.
9. 5. 5. Pre g n a nc y Testi n g
F or partici pa nts of c hil d beari n g p ote ntial, a ser u m/ plas ma or uri ne β -h C G pre g na nc y test wit h 
se nsiti vit y of at least 2 5 mI U/ m L will be perf or me d at t he ti mes liste d i n t he S O Es 
(A p pe n di x A ). A ne gati ve pre g na nc y res ult is re q uire d bef ore t he partici pa nt ma y recei ve st u d y 
treat me nt. Pre g na nc y tests ma y als o be re peate d as re q ueste d per i nstit uti o nal re vie w 
b oar d/i n de pe n de nt et hics c o m mi ttee (IR B/I E C) or if re q uire d b y  l ocal re g ulati o ns. 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.
Pre g na nc y  tests will be perf or me d o nce a m o nt h f or 7 m o nt hs after t he last d ose of st u d y 
treat me nt. Partici pa nts will d o m o nt hl y h o me pre g na nc y tests d uri n g t he f oll o w-u p peri o d a n d 
re p ort i nteri m m o nt hl y res ults at l o n g-ter m f oll o w-u p visits. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 8 of 2 2 0
D uri n g t he L T E P, pre g na nc y  testi n g will c o nti n ue t o be perf or me d as o utli ne d a b o ve a n d i n t he 
sc he d ule of e ve nts f or partici pa nts of c hil d beari n g p ote ntial. Pre g na nc y re p orti n g s h o ul d 
c o nti n ue a n d will be c ollecte d b y t he S p o ns or.
9. 5. 6. C ar di ac F u ncti o n
9. 5. 6. 1. M U G A or E C H O
Assess me nt of car diac ejecti o n fracti o n will be perf or me d b y M U G A or E C H O at scree ni n g a n d 
at least o nce e ver y  1 2 wee ks t hereafter u ntil st u d y disc o nti n uati o n, a n d at E O T ( u nless d o ne 
wit hi n 1 2 wee ks pri or t o t he E O T Visit, e xcl u di n g scree ni n g/ baseli ne assess me nt). If t here is a n 
i nteri m assess me nt, s u bse q ue nt car diac E C H O or M U G A s h o ul d be perf or me d e ver y 1 2 wee ks 
as deter mi ne d b y t he date of t he m ost rece nt i nteri m assess me nt. E C H O/ M U G A assess me nts 
s h o ul d als o be u n derta ke n e ver y 6 m o nt hs f or at least 2 ye ars f oll o wi n g trast uz u ma b 
disc o nti n uati o n. T he m o dalit y  c h ose n i n scree ni n g s h o ul d be use d f or all s u bse q ue nt car diac 
assess me nts t hr o u g h o ut t he st u d y  f or c o m paris o n.
I n t he L T E P, car diac f u ncti o n assess me nts will be perf or me d per i nstit uti o nal g ui deli nes a n d 
i n vesti gat or-deter mi ne d us ual a n d c ust o mar y  cli nical care.
9. 5. 6. 2. Electr oc ar di o gr a m
E C Gs will be perf or me d at baseli ne, at t he E O T visit, a n d as cli nicall y i n dicate d. T o c orrect f or 
heart rate, Q T i nter vals s h o ul d be calc ulate d usi n g t he Fri dericia f or m ula.
I n t he L T E P, E C G assess me nts will be perf or me d per i nstit uti o nal g ui deli nes a n d i n vesti gat or-
deter mi ne d us ual a n d c ust o mar y  cli nical care.
9. 6. A p pr o pri ate ness of Me as ure me nts
T he safet y meas ures t hat will be use d i n t his trial are c o nsi dere d sta n dar d pr oce d ures f or 
e val uati n g t he p ote ntial a d verse effects of st u d y me dicati o ns.
Res p o nse will be assesse d acc or di n g t o R E CI S T v 1. 1, w hic h is t he g ol d sta n dar d f or e val uati n g 
a ntica ncer t hera pies. T he i nter vals of e val uati o n i n t his pr ot oc ol are c o nsi dere d a p pr o priate f or 
disease ma na ge me nt.
P K assess me nts are als o c o m m o n i n cli nical st u dies t o hel p c haracterize 
d ose -e x p os ure -res p o nse relati o ns hi ps.
1 0. D A T A Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
1 0. 1. Site Tr ai ni n g a n d M o nit ori n g Pr oce d ures
A st u d y  ma n ual wit h i nstr ucti o ns f or st u d y c o m plia nce a n d e C R F c o m pleti o n will be pr o vi de d. 
Pri or t o t he e nr oll me nt of partici pa nts at t he site, Pfizer or its desi g nate d cli nical a n d me dical 
pers o n nel will re vie w t he f oll o wi n g ite ms wit h t he i n vesti gat or a n d cli nic staff:

T he pr ot oc ol, st u d y  o bjecti ves, eli gi bilit y re q uire me nts, st u d y pr oce d ures, 
re gistrati o n, a n d wit h dra wal pr ocesses

C urre nt I n vesti gat or’s Br oc h ure/ l ocal pr o d uct la beli n g

Rec or di n g a n d re p orti n g A Es a n d S A Es

E nr oll me nt g oals a n d st u d y  ti meli nes
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 4 9 of 2 2 0

T he e C R F c o m pleti o n pr ocess a n d s o urce d oc u me ntati o n re q uire me nts

M o nit ori n g re q uire me nts

I RB/I E C re vie w a n d a p pr o val pr ocess

I nf or me d c o nse nt pr ocess

G o o d cli nical practice g ui deli nes a n d relate d re g ulat or y  d oc u me ntati o n re q uire me nts

K e y  st u d y tea m r oles a n d res p o nsi bilities

I n vesti gati o nal pr o d uct st ora ge, acc o u nta bility, la beli n g, dis pe nsi n g, a n d rec or d 
kee pi n g

Partici pa nt c o di n g a n d ra n d o mizati o n (if a p plica ble)

St u d y  sa m ples/s peci me n c ollecti o n, ha n dli n g, a n d s hi p pi n g

Pr ot oc ol c o m plia nce

Cli nical st u d y rec or d kee pi n g, d oc u me nt rete nti o n, a n d a d mi nistrati ve re q uire me nts
M o nit ori n g visits will occ ur peri o dicall y , wit h fre q ue nc y de pe n de nt o n t he rate of e nr oll me nt a n d 
w or kl oa d at eac h site. D uri n g m o nit ori n g visits, t he Pfizer re prese ntati ve will t yp ically re vie w 
re g ulat or y d oc u me ntati o n, e C R Fs, s o urce d oc u me ntati o n, a n d i n vesti gati o nal pr o d uct st ora ge, 
pre parati o n, a n d acc o u nta bilit y . T he e C R Fs will be re vie we d f or c o m plete ness, a d here nce t o t he 
pr o vi de d g ui deli nes, a n d acc urac y c o m pare d t o t he s o urc e d oc u me nts u ntil t he fi nal data base 
l oc k occ urs. T he i n vesti gat ors m ust e ns ure t hat t he m o nit or is all o we d t o i ns pect all s o urce 
d oc u me nts perti ne nt t o st u d y  partici pa nts a n d m ust c o o perate wit h t he m o nit or t o e ns ure t hat a n y 
pr o ble ms n ote d i n t he c o urse of t he trial are res ol ve d. T he i n vesti gat or m ust mai ntai n a 
c o m pre he nsi ve a n d ce ntralize d fili n g s y ste m of all st u d y-relate d d oc u me ntati o n t hat is s uita ble 
f or i ns pecti o n by Pfizer or its desi g nate d m o nit ors a n d b y  q ualit y ass ura nce a u dit ors, or 
re prese ntati ves of re g ulat or y a ut h orities.
1 0. 2. D at a M a n a ge me nt Pr oce d ures
Pfizer will pr o vi de C R F C o m pleti o n G ui deli nes f or e C R F data e ntr y . St u d y s pecific data 
ma na ge me nt pr oce d ures will be mai ntai ne d i n t he data ma na ge me nt pla n. Q ueries res ulti n g fr o m 
e dit c hec ks a n d/ or data verificati o n pr oce d ures will be p oste d electr o nicall y  i n t he e C R F.
F oll o wi n g i m ple me ntati o n of A me n d me nt 5 a n d e ntr y  of re mai ni n g o n-treat me nt partici pa nts 
i nt o t he LT E P, data will n o l o n ger be c ollecte d i n e C R Fs. O nl y  pre g na ncies a n d S A Es will be 
re p orte d t o t he S p o ns or d uri n g t he L T E P, utilizi n g t he Pre g na nc y Re p ort F or m a n d S A E f or m 
(f or b ot h S A Es a n d A E SIs). Please see Secti o n 9. 5. 1. 3 a n d 9. 5. 1. 4. 2 f or f urt her detail o n 
pre g na nc y , S A E, a n d A E SI re p orti n g re q uire me nts.
1 0. 3. Access t o S o urce D at a
T he i n vesti gat or will per mit t he s p o ns or’s re prese ntati ves t o m o nit or t he st u d y  as fre q ue ntl y as 
t he s p o ns or dee ms necessar y t o deter mi ne t hat pr ot oc ol a d here nce a n d data rec or di n g are 
satisfact or y. A p pr o priate meas ures t o pr otect partici pa nt c o nfi de ntiality are t o be e m pl o ye d 
d uri n g m o nit ori n g. T he e C R Fs a n d relate d s o urce d oc u me nts will t ypicall y be re vie we d i n detail 
b y  t he m o nit or at eac h site visit. Ori gi nal s o urce d oc u me nts or certifie d c o pies are nee de d f or 
re vie w. T his re vie w i ncl u des i ns pecti o n of data ac q uire d as a re q uire me nt f or partici pati o n i n t his 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 0 of 2 2 0
st u d y a n d ot her me dical rec or ds as re q uire d t o c o nfir m t hat t he i nf or mati o n c ollecte d is c orrect. 
Ot her st u d y  rec or ds, s uc h as c orres p o n de nce wit h t he s p o ns or a n d t he I R B/I E C a n d scree ni n g 
a n d dr u g acc o u nta bilit y l o gs will als o be i ns pecte d. All s o urce data a n d st u d y rec or ds m ust als o 
be a vaila ble f or i ns pecti o n b y  re prese ntati ves of re g ulat or y a ut h orities a n d t he IR B/I E C.
1 0. 4. Acc ur ac y a n d Reli a bilit y of D at a
Ste ps t o be ta ke n t o ass ure t he acc urac y  a n d relia bilit y of data i ncl u de:

T he selecti o n of q ualifie d i n vesti gat ors a n d a p pr o priate st u d y  ce nters.

Re vie w of pr ot oc ol pr oce d ures wit h t he i n vesti gat ors a n d ass ociate d pers o n nel pri or 
t o t he st u d y.

Peri o dic m o nit ori n g visits b y  t he desi g nate d m o nit or(s).

e C R Fs will be re vie we d f or acc urac y  a n d c o m plete ness d uri n g m o nit ori n g visits t o 
t he st u d y ce nters a n d/ or b y ce ntralize d m o nit ori n g. A ny discre pa ncies will be 
res ol ve d wit h t he i n vesti gat or or desi g nees as a p pr o priate.

D uri n g t he L T E P, e C R Fs will n ot be c ollecte d. 
1 0. 5. Q u alit y Ass ur a nce Pr oce d ures
T he Researc h a n d De vel o p me nt Q ualit y  gr o u p of Pfizer or its desi g nee ma y  c o n d uct a u dits at t he 
cli nical site or ot her st u d y-relate d facilities a n d or ga nizati o ns. A u dit re p orts will be retai ne d b y 
t he Researc h a n d De vel o p me nt Q ualit y gr o u p of Pfizer as part of t he writte n r ec or d.
1 0. 6. D at a H a n dli n g a n d Rec or d Kee pi n g
1 0. 6. 1. D at a H a n dli n g
It is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t he acc urac y, c o m plete ness, le gi bilit y, a n d 
ti meli ness of t he data re p orte d t o t he s p o ns or i n t he e C R Fs a n d i n all re q uire d re p orts. Data 
re p orte d o n t he e C R F t hat is deri ve d fr o m s o urce d oc u me nts s h o ul d be c o nsiste nt wit h t he s o urce 
d oc u me nts or t he discre pa ncies s h o ul d be e x plai ne d.
A n y  c ha n ge or c orrecti o n t o a n e C R F will be mai ntai ne d i n a n a u dit trail wit hi n t he electr o nic 
data ca pt ure s ys te m. Data cha n ges ma y  o nl y be ma de b y t h ose i n di vi d uals s o a ut h orize d. T he 
i n vesti gat or s h o ul d retai n rec or ds of t he c ha n ges a n d c orrecti o ns, writte n a n d/ or electr o nic.
1 0. 6. 2. I n vesti g at or Rec or d Rete nti o n
T he i n vesti gat or s hall retai n st u d y  treat me nt dis p ositi o n rec or ds a nd all s o urce d oc u me ntati o n 
(s uc h as ori gi nal E C G traci n gs, la b orat or y re p orts, i n patie nt or office patie nt rec or ds) f or t he 
ma xi m u m peri o d re q uire d b y  t he c o u ntr y a n d i nstit uti o n i n w hic h t he st u d y will be c o n d ucte d, or 
f or t he peri o d s pecifie d b y Pfizer , w hic he ver is l o n ger. T he i n vesti gat or m ust c o ntact Pfizer pri or 
t o destr o yi n g a ny rec or ds ass ociate d wit h t he st u d y. If t he i n vesti gat or wit h dra ws fr o m t he st u d y 
( d ue t o rel ocati o n, retire me nt, etc), t he rec or ds s hall be tra nsferre d t o a m ut uall y a gree d u po n 
desi g nee, s uc h as a n ot her i n vesti gat or or I RB/I E C. N otice of s uc h tra nsfer will be pr o vi de d i n 
writi n g t o Pfizer .
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 1 of 2 2 0
1 1. D A T A A N A L Y SI S M E T H O D S
1 1. 1. Deter mi n ati o n of S a m ple Size
T he t ucati ni b d ose escalati o n will f oll o w a 3 + 3 sc he me. A p pr o xi matel y  6 D LT- e val ua ble 
pa rtici pa nts ma y be treate d i n eac h p hase 1 b d ose escalati o n c o h ort i n or der t o i de ntif y t he 
rec o m me n de d p hase 2 d ose of t ucati ni b i n c o m bi nati o n wit h trast uz u ma b a n d o xali plati n-base d 
re gi me ns. 
C o h ort 1 A ma y  e nr oll a p pr o xi matel y 5 partici pa nts i n or der t o ha ve at least 3 D L T- e val ua ble 
partici pa nts, a n d a p pr o xi matel y  8 partici pa nts i n C o h ort 1 B i n or der t o ha ve at least 6 
D L T- e val ua ble partici pa nts i n t he case a re nal D L T is o bser ve d i n t he first 3 D L T- e val ua ble 
partici pa nts. 
C o h orts 1 C, 1 E, 1 F, a n d 1 G ma y  e nr oll a p pr o xi matel y 8 partici pa nts i n eac h c o h ort t o e ns ure at 
least 6 partici pa nts i n eac h c o h ort c o m plete t he a p pr o priate D L T peri o d ( 2 1 da ys f or C o h orts 1 C, 
1 F a n d 1 G; 2 8 da y s f or C o h ort 1 E). E nr oll me nt ma y re mai n o pe n t o e ns ure at least 3 partici pa nts
fr o m Ja pa n are e nr olle d i nt o eac h c o h ort.
C o h ort 1 D (Ja pa n-s pecific c o h ort) will e nr oll a mi ni m u m of 3 partici pa nts t o recei ve t ucati ni b, 
trast uz u ma b, a n d m F O L F O X 6. 
P hase 2 T u m or S pecific E x pa nsi o n
T u m or s pecific e x pa nsi o n c o h orts ma y  be e nr olle d. F or e xa m ple, a 1 L gastric, es o p ha geal, a n d 
G EJ a de n ocarci n o ma e x pa nsi o n c o h ort ( C o h ort 2 A) ma y  e nr oll u p t o 4 0 partici pa nts, a n d a 1 L + 
C R C e x pa nsi o n c o h ort ( C o h ort 2 B) ma y  e nr oll u p t o 2 0 partici pa nts.
F or a sa m ple size of 4 0 partici pa nts, ass u mi n g c o nfir me d O R R is bet wee n 6 0 % a n d 8 0 %, t he 
2 -si de d 9 0 % e xact CIs are s u m marize d bel o w:
C o nfir me d O R R
9 0 % E xact CI. ( N = 4 0)
6 0 %
( 4 6 %, 7 3 %)
7 0 %
( 5 6 %, 8 2 %)
8 0 %
( 6 7 %, 9 0 %)
F or a sa m ple size of 2 0 partici pa nts, ass u mi n g c o nfir me d O R R is bet wee n 5 5 % a n d 6 5 %, t he 
2 -si de d 9 0 % e xact CI are s u m marize d bel o w:
C o nfir me d O R R
9 0 % E xact CI. ( N = 2 0)
5 5 %
( 3 5 %, 7 4 %)
6 0 %
( 3 9 %, 7 8 %)
6 5 %
( 4 4 %, 8 2 %)
1 1. 2. St u d y E n d p oi nt Defi niti o ns
1 1. 2. 1. O bjecti ve Res p o nse R ate
C o nfir me d O R R per i n vesti gat or is defi ne d as t he pr o p orti o n of partici pa nts wit h c o nfir me d C R 
or P R, acc or di n g t o R E CI S T v 1. 1. O nl y res p o nse assess me nts bef ore first d oc u me nte d 
pr o gressi ve disease or ne w a ntica ncer t hera pies will be c o nsi dere d.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 2 of 2 2 0
1 1. 2. 2. D ur ati o n of Res p o nse
D O R is defi ne d as t he ti me fr o m first d oc u me ntati o n of o bjecti ve res p o nse of c o nfir me d C R or 
c o nfir me d P R t o t he first d oc u me ntati o n of disease pr o gressi o n acc or di n g t o R E CI S T v 1. 1 or 
deat h fr o m a n y ca use, w hic he ver occ urs first. O nl y  partici pa nts wit h a n o bjecti ve res p o nse will 
be i ncl u de d i n t he a nal y sis of D O R. D O R per IC R ma y  be e val uate d i n selecte d c o h orts.
1 1. 2. 3. Pr o gressi o n -free S ur vi v al
P F S is defi ne d as t he ti me fr o m t he date of treat me nt i nitiati o n t o t he date of disease pr o gressi o n 
acc or di n g t o R E CIS T versi o n 1. 1 or deat h fr o m a n y ca use, w hic he ver occ urs first. Partici pa nts 
wit h o ut d oc u me ntati o n of pr o gressi o n or deat h at t he ti me of a nal ys is will be ce ns ore d at t he date 
of t he last disease assess me nt wit h a n o verall res p o nse of C R, P R, sta ble disease, or n o n -
C R/ n o n - pr o gressi ve disease. If t here is n o ra di o gra p hic p ost-baseli ne t u m or assess me nt, P F S will 
be ce ns ore d at t he date of treat me nt i nitiati o n. P F S per I C R ma y  be e val uate d i n selecte d c o h orts.
Detaile d met h o d ol o g y , i ncl u di n g ha n dli n g r ules f or missi n g assess me nts a n d ce ns ori n g 
a p pr oac hes f or t he a nal ys is of P F S, is pr o vi de d i n t he statistical a nalys is pla n ( S A P).
1 1. 2. 4. O ver all S ur vi v al
O S is defi ne d as t he ti me fr o m treat me nt i nitiati o n t o deat h d ue t o a n y ca use. F or a partici pa nt 
w h o is n ot k n o w n t o ha ve die d b y t he e n d of st u d y f oll o w - u p, o bser vati o n of O S is ce ns ore d o n 
t he date t he partici pa nt was last k n o w n t o be ali ve (ie, t he date of last c o ntact). Partici pa nts 
lac ki n g data be yo n d t he da y  of treat me nt i nitiati o n will ha ve t heir s ur vi val ti me ce ns ore d o n t he 
date of treat me nt i nitiati o n (ie, O S d urati o n of 1 da y ).
1 1. 3. St atistic al a n d A n al ytic al Pl a ns
T he statistical a n d a nal yt ical pla ns prese nte d bel o w s u m marize t he m ore c o m plete pla ns t o be 
detaile d i n t he S A P. A c ha n ge t o t he data a nal ys is met h o ds descri be d i n t he pr ot oc ol will re q uire 
a pr ot oc ol a me n d me nt o nl y if it alters site c o n d uct (e g, a d di n g baseli ne assess me nts t o defi ne a 
s u b gr o u p). T he S A P ma y m o dif y  w hat is o utli ne d i n t he pr ot oc ol w here a p pr o priate; h o we ver, 
a n y maj or m o dificati o ns of t he pri mar y e n d p oi nt defi niti o ns or t heir a nalys es will als o be 
reflecte d i n a pr ot oc ol a me n d me nt. T he S A P will be fi nalize d pri or t o fi nal data base l oc k. 
1 1. 3. 1. Ge ner al C o nsi der ati o ns
I n ge neral, descri pti ve statistics will be prese nte d t hat i ncl u de t he n u m ber of o bser vati o ns, mea n, 
me dia n, sta n dar d de viati o n, mi ni m u m a n d ma xi m u m f or c o nti n u o us varia bles, a n d t he n u m ber 
a n d perce nta ges ( of n o n -missi n g) per cate g or y  f or cate g orical variables. 
T he e xact CI  usi n g Cl o p per-Pears o n met h o d (Cl o p per 1 9 3 4 ) will be calc ulate d f or t he res p o nse 
rates w here a p plica ble.
1 1. 3. 1. 1. R a n d o miz ati o n a n d Bli n di n g
Bli n di n g will n ot be perf or me d.
1 1. 3. 1. 2. A dj ust me nts f or C o v ari ates
N o a dj ust me nt f or c o variates is pla n ne d i n t he a nal y ses.
1 1. 3. 1. 3. H a n dli n g of Dr o p o uts a n d Missi n g D at a
N o i m p utati o n will be c o n d ucte d f or missi n g data u nless ot her wise s pecifie d i n t he S A P.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 3 of 2 2 0
1 1. 3. 1. 4. M ultice nter St u dies
T his st u d y  will be c o n d ucte d at m ulti ple st u d y ce nters; h o we ver, it is n ot a ntici pate d t hat a n y 
ce nter will accr ue e n o u g h partici pa nts t o warra nt a n a nal ys is b y ce nter.
1 1. 3. 1. 5.
M ulti ple C o m p aris o ns a n d M ulti plicit y
N o m ulti ple c o m paris o ns are p la n ne d, a n d n o al p ha a dj ust me nt is nee de d beca use n o f or mal 
statistical testi n g will be perf or me d i n t his st u d y.
1 1. 3. 1. 6. D at a Tr a nsf or m ati o ns a n d Deri v ati o ns
Ti me varia bles base d o n 2 dates (e g, Start Date a n d E n d Date) will be calc ulate d as ( E n d Date –
Start Date + 1 [i n da y s]) u nless ot her wise s pecifie d i n t he pla n ne d a nalys is secti o n. 
U nless ot her wise s pecifie d i n t he a nal ys is pla n, baseli ne val ues use d i n all statistical a nal yses 
will be t he m ost rece nt n o n- missi n g meas ure me nt pri or t o t he first d ose of st u d y  treat me nt.
1 1. 3. 1. 7. A n al ysis Sets
P hase 1 b T ucati ni b D ose Escalati o n wit h F O L F O X ( C o h orts 1 A a n d 1 B) 
T he D L T -E v al u a ble A n al ysis set i ncl u des all partici pa nts i n C o h ort 1 A or 1 B w h o meet o ne of 
t he f oll o wi n g criteria: ( 1) ha d a re nal D L T or ( 2) ha d ta ke n at least 7 5% of pla n ne d o xali plati n 
a n d t ucati ni b d oses per c ycle a n d ha ve bee n f oll o we d f or at least 2 c ycles of st u d y treat me nt 
(t hr o u g h t he e n d of Cycl e 3 f or F O L F O X re gi me ns), i ncl usi ve of d ose.
P hase 1 b Safet y E val uati o n of T ucati ni b wit h Trast uz u ma b a n d C A P O X ( C o h ort 1 C) or wit h 
Trast uz u ma b a n d Pe m br oliz u ma b -C o ntai ni n g Re gi me ns ( C o h orts 1 E, 1 F, 1 G)
T he D L T -E v al u a ble A n al ysis Set f or C o h ort 1 C i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d ca pecita bi ne, 
o xali plati n, trast uz u ma b, a n d t ucati ni b f or t he first 2 1 -d a y s of st u d y treat me nt a n d ha ve bee n 
f oll o we d f or at 2 1 da ys of st u d y treat me nt.
T he D L T -E v al u a ble A n al ysis Set f or C o h ort 1 E i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d fl u or o uracil, 
o xali plati n, pe m br oliz u ma b, trast uz u ma b, a n d t ucati ni b f or t he first 2 8 da y s of st u d y treat me nt 
a n d ha ve bee n f oll o we d f or at 2 8 da y s of st u d y treat me nt.
T he D L T -E v al u a ble A n al ysis Set f or C o h ort 1 F i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d ca pecita bi ne, 
o xali plati n, pe m br oliz u ma b, trast uz u ma b, a n d t ucati ni b f or t he first 2 1 da y s of st u d y treat me nt 
a n d ha ve bee n f oll o we d f or at 2 1 da y s of st u d y treat me nt.
T he D L T -E v al u a ble A n al ysis Set f or C o h ort 1 G i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d pe m br oliz u ma b, 
trast uz u ma b, a n d t ucati ni b f or t he first 2 1 da ys of st u d y treat me nt a n d ha ve bee n f oll o we d f or at 
2 1 da y s of st u d y treat me nt. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 4 of 2 2 0
P hase 1 b T ucati ni b Ja pa n Safet y E val uati o n i n C o m bi nati o n wit h Trast uz u ma b a n d F O L F O X 
( C o h ort 1 D)
T he D L T -e v al u a ble a n al ysis set i n C o h ort 1 D i ncl u des all partici pa nts w h o meet o ne of t he 
f oll o wi n g criteria: ( 1) ha d a D L T or ( 2) ha d ta ke n at least 7 5 % of pla n ne d fl u or o uracil, 
o xali plati n, trast uz u ma b, a n d t ucati ni b d oses a n d ha ve bee n f oll o we d f o r at least 2 8 da ys.
T he F ull A n al ysis Set will i ncl u de all partici pa nts w h o are e nr olle d i n t he st u d y a n d recei ve a n y 
a m o u nt of st u d y treat me nt. T he F ull A n al ysis Set will be use d f or t he a nal y sis of P F S.
T he S afet y A n al ysis Set will i ncl u de all partici pa n ts w h o recei ve a ny a m o u nt of st u d y treat me nt. 
T he safet y a nal ys is set will be use d f or all safet y a nal yses.
T he P K A n al ysis Set will i ncl u de all partici pa nts i n t he safet y set fr o m w h o m at least 1 P K 
assess me nt was re p orte d. T he P K a nal ys is set will be used f or P K a nal ys is.
T he Res p o nse E v al u a ble A n al ysis Set will i ncl u de all partici pa nts w h o meet all f oll o wi n g 
criteria: ( 1) ha d meas ura ble disease at baseli ne, ( 2) recei ve d a n y a m o u nt of st u d y treat me nt, a n d 
( 3) ha d at least o ne p ost- baseli ne disease assess me nt of disc o nti n ue d d ue t o cli nical pr o gressi o n, 
t o xicit y, or deat h.
A d diti o nal a nal y sis sets of partici pa nts ma y be defi ne d i n t he S A P.
1 1. 3. 1. 8. E x a mi n ati o n of S u b gr o u ps
As e x pl orat or y  a nalys es, s u b gr o u p a nal ys es ma y be c o n d ucte d f or selecte d e n d p oi nts. Detaile d 
met h o d ol o g y  will be pr o vi de d i n t he S A P.
1 1. 3. 1. 9. Ti mi n g of A n al yses
Safet y  a nalys is d uri n g t he p hase 1 b p orti o n of t he st u d y will be u n derta ke n b y t he S M C w he n t he 
first 3 D L T-e val ua ble partici pa nts i n C o h ort 1 A ha ve bee n f oll o we d f or at least 2 c ycles. T he 
S M C will u n derta ke si milar a nal ys es w he n t he first 6 D LT- e valua ble partici pa nts i n C o h ort 1 B 
ha ve bee n f oll o we d f or at least 2 c ycles. O nce t he d ose escalati o n p hase is c o m plete d, t he S M C 
will e val uate t he safet y of st u d y re gi me n t hr o u g h o ut t he p hase 2.
F or C o h ort 1 D, partici pa nts will be e val uate d after 3 partici pa nts c o m plete 2 c y cles of treat me nt. 
F or C o h ort 1 E, partici pa nts will be e val uate d after 6 partici pa nts c o m plete 2 c y cles of treat me nt. 
F or C o h ort 1 F a n d 1 G, partici pa nts will be e val uate d after 6 partici pa nts c o m plete 1 c y cle of 
treat me nt. 
T he fi nal a nal y sis of t he pri mar y e n d p oi nt a n d sec o n dar y e n d p oi nts will be c o n d ucte d se paratel y 
f or eac h p hase 2 c o h ort ( C o h ort 2 A a n d C o h ort 2 B) w he n all treate d partici pa nts ha ve bee n 
f oll o we d f or at least 8 m o nt hs ( or all res p o n ders ha ve bee n f oll o we d f or a mi ni m u m of 6 m o nt hs 
after t heir i nitial res p o nse, w hic he ver c o mes first), ha ve disc o nti n ue d fr o m t he st u d y  or ha d 3 0 
da y s safety f oll o w -u p after pr o gressi ve disease, w hic he ver c o mes first, or f oll o wi n g st u d y  
ter mi nati o n b y t he s p o ns or. 
Safet y  i n Ja pa nese partici pa nts will be e val uate d after 1 c ycle of treat me nt as descri be d i n 
Secti o n 5. 1. 3 .
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 5 of 2 2 0
1 1. 3. 2. P artici p a nt Dis p ositi o n
A n acc o u nti n g of st u d y partici pa nts b y dis p osit i o n will be ta b ulate d a n d t he n u m ber of 
partici pa nts i n eac h a nal ysis set will be s u m marize d. Partici pa nts w h o disc o nti n ue st u d y 
treat me nt a n d partici pa nts w h o wit h dra w fr o m t he st u d y will be s u m marize d wit h reas o n f or 
disc o nti n uati o n or wit h dra wal.
1 1. 3. 3. P artic i p a nt C h ar acteristics
De m o gra p hics a n d ot her baseli ne c haracteristics will be s u m marize d. Details will be pr o vi de d i n 
t he S A P.
1 1. 3. 4. Tre at me nt C o m pli a nce
T he d ose a d mi nistere d at eac h c y cle f or eac h treat me nt a ge nt will be assesse d a n d d ose i nte nsit y 
will be s u m marize d. Details will be pr o vi de d i n t he S A P.
1 1. 3. 5. Effic ac y A n al yses
T he O R R will be s u m marize d usi n g t he res p o nse e val ua ble set. T he 2- si de d 9 0 % e xact Cl o p per 
Pears o n CI f or t he c o nfir me d O R R will be pr o vi de d (Cl o p per 1 9 3 4 ).
1 1. 3. 6. P h ar m ac o ki netic A n al yses
I n di vi d ual t ucati ni b plas ma a n d o xali plati n plas ma (t otal a n d free plati n u m) a n d uri ne ( plati n u m) 
c o nce ntrati o ns at eac h sa m pli n g ti me will be liste d a n d s u m marize d wit h descri pti ve statistics. 
T he P K para meter f or t ucati ni b a n d o xali plati n t o be calc ulat e d (if p ossi ble) ma y i ncl u de b ut is 
n ot li mite d t o C tr o u g h. 
A d diti o nal e x pl orat or y  P K a nalys es ma y be c o n d ucte d, i ncl u di n g e x pl orat or y a nalys es 
i n vesti gati n g t he relati o ns hi p bet wee n t ucati ni b a n d o xali plati n e x p os ure, efficac y a n d safet y 
e n d p oi nts. T hese a nal ys es will be descri be d i n a se parate a nal ys is pla n. 
1 1. 3. 7. Bi o m ar ker A n al yses
Relati o ns hi ps of bi o mar ker para meters (e g, baseli ne val ues, a bs ol ute a n d relati ve c ha n ges fr o m 
baseli ne) t o efficac y , safet y, a n d P K para meters ma y be e x pl ore d. Relati o ns hi ps a n d ass ociate d 
data t hat are deter mi ne d t o be of i nterest will be s u m marize d. Details will be descri be d se paratel y 
i n t he S A P or Bi o mar ker A nal ysis Pla n ( B A P).
1 1. 3. 8. S afet y A n al yses
1 1. 3. 8. 1. E xte nt of E x p os ure
D urati o n of treat me nt will be s u m marize d a n d liste d.
D urati o n of treat me nt, n u m ber of c ycles, t otal d ose, d ose i nte nsit y a n d d ose m o dificati o ns will be 
s u m marize d. Details will be pr o vi de d i n t he S A P.
1 1. 3. 8. 2. A d verse E ve nts
A n o ver vie w of A Es will pr o vi de a ta b ulati o n of t he i nci de nce of all A Es, treat me nt -e mer ge nt 
A Es, treat me nt-relate d A Es, Gra de 3 a n d hi g her A Es, S A Es, treat me nt- relate d S A Es, deat hs, a n d 
A Es lea di n g t o st u d y  treat me nt disc o nti n uati o n. A Es will be defi ne d as treat me nt e mer ge nt if 
t he y are ne wly occ urri n g or w orse n f oll o wi n g st u d y treat me nt.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 6 of 2 2 0
A Es will be liste d a n d s u m marize d b y  Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A), 
preferre d ter m, se verit y , a n d relati o ns hi p t o st u d y treat me nt. I n t he e ve nt of m ulti ple occ urre nces 
of t he sa me A E wit h t he sa me preferre d ter m i n 1 partici pa nt, t h e A E will be c o u nte d o nce as t he 
occ urre nce. T he i nci de nce of A Es will be ta b ulate d b y  preferre d ter m a n d treat me nt gr o u p. A Es 
lea di n g t o pre mat ure disc o nti n uati o n of st u d y treat me nt will be s u m marize d a n d liste d i n t he 
sa me ma n ner. A E SIs will be se parately s u m marize d a n d liste d.
1 1. 3. 8. 3. D ose -li miti n g T o xicit y
T he o bser ve d n u m ber a n d pr o p orti o n of partici pa nts e x perie nci n g a re nal D L T will be re p orte d 
b y  d ose le vels.
1 1. 3. 8. 4. De at hs a n d Seri o us A d verse E ve nts
S A Es will be liste d a n d s u m marize d i n t he sa me ma n ner as all A Es. E ve nts wit h a fatal o utc o me 
will be liste d.
1 1. 3. 8. 5. Cli nic al L a b or at or y Res ults
La b orat or y  val ues (e g, c he mistr y, he mat ol o g y, a n d uri nal ysis) ma y be prese nte d gra p hically b y 
visit. S u m mar y  statistics ma y be ta b ulate d as a p pr o priate b y sc he d ule d visit. La b orat or y val ues 
will be liste d wit h gra de per N CI C T C A E v 5. 0 a n d fla g ge d w he n val ues are o utsi de t he n or mal 
refere nce ra n ge.
1 1. 3. 8. 6. Gl o mer ul ar Filtr ati o n R ate
C ha n ge i n G F R (as esti mate d usi n g ser u m c y stati n C) fr o m baseli ne t hr o u g h 2 c ycles of 
c o m bi nati o n t hera p y will be s u m marize d.
1 1. 3. 8. 7. Ot her S afet y A n al yses
T he fre q ue nc y  a n d perce nta ge of partici pa nts wit h p ost-baseli ne cli nicall y s i g nifica nt vital si g ns 
will be s u m marize d. A b n or mal p h y sical e xa mi nati o n fi n di n gs ma y be c ollecte d as A Es. E C O G 
perf or ma nce stat us will be liste d .
Car diac ejecti o n fracti o n data a n d c ha n ge fr o m baseli ne will be s u m marize d.
1 1. 3. 9. I nteri m A n al yses
N o f or mal i nteri m a nal ys es are pla n ne d.
1 2. R E G U L A T O R Y, E T HI C A L, A N D S T U D Y O V E R SI G H T C O N SI D E R A TI O N S
1 2. 1. Pr ot oc ol A me n d me nts a n d St u d y Ter mi n ati o n
A n y  i n vesti gat or-i nitiate d c ha n ges t o t he pr ot oc ol ( wit h t he e xce pti o n of c ha n ges t o eli mi nate a n 
i m me diate hazar d t o a st u d y partici pa nt) m ust be a p pr o ve d b y t he s p o ns or pri or t o see ki n g 
a p pr o val fr o m t he I RB/I E C, a n d pri or t o i m ple me nti n g. T he i n vesti gat or is res p o nsi ble f or 
enr olli n g partici pa nts w h o ha ve met pr ot oc ol eli gi bilit y  criteria. Pr ot oc ol de viati o ns m ust be 
re p orte d t o t he s p o ns or a n d t he l ocal I R B/I E C i n acc or da nce wit h I R B/I E C p olicies.
T he s p o ns or ma y  ter mi nate t he st u d y at a n y ti me. T he IR B/I E C m ust be a d vise d i n writi n g of 
st u d y c o m pleti o n or earl y ter mi nati o n.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 7 of 2 2 0
1 2. 2. 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 wit h t he f oll o wi n g:

C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes, i ncl u di n g t he 
Declarati o n of Helsi n ki a n d 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, i ncl u di n g a p plica ble pri vac y  la ws.
T he pr o t oc ol, pr ot oc ol a me n d me nts, IC D, S R S D(s), a n d ot her rele va nt d oc u me nts 
(e g, a d vertise me nts) m ust be re vie we d a n d a p pr o ve d b y  t he s p o ns or, s u b mitte d t o a n IR B/ E C b y  
t he i n vesti gat or, a n d re vie we d a n d a p pr o ve d by t he I R B/ E C bef ore t he st u d y  is i nitiate d.
A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/ E C a p pr o val bef ore i m ple me ntati o n of 
c ha n ges ma de t o t he st u d y desi g n, e xce pt f or c ha n ges necessar y  t o eli mi nate a n i m me diate 
hazar d t o st u d y  partici pa nts.
Pr ot oc ols a n d a n y s u bsta ntial a me n d me nts t o t he pr ot oc o l will re q uire healt h a ut h orit y a p pr o val 
pri or t o i nitiati o n e xce pt f or c ha n ges necessar y  t o eli mi nate a n i m me diate hazar d t o st u d y 
partici pa nts.
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 t o t he I R B/ E C a n n uall y or m ore 
fre q ue ntly i n acc or da nce wit h t he re q uire me nts, p olicies, a n d pr oce d ures esta blis he d b y 
t he I R B/ E C.

N otif y i n g t he I R B/ E C of S A Es or ot her si g nifica nt safety fi n di n gs as re q uire d b y I RB/ E C 
pr oce d ures.

Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y 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 C P g ui deli nes, t he I R B/ 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, E ur o pea n M D R 2 0 1 7/ 7 4 5 f or cli nical de vice researc h, a n d all ot her a p plica ble 
l ocal re g ulati o ns.
1 2. 2. 1. Re p orti n g of S afet y Iss ues a n d Seri o us Bre ac hes of t he Pr ot oc ol or I C H G C P
I n t he e ve nt of a ny pr o hi biti o n or restricti o n i m p ose d (ie, cli nical h ol d) b y a n a p plica ble 
re g ulat or y a ut h ority i n a n y area of t he w orl d, or if t he i n vesti gat or is a ware of a n y ne w
i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of t he st u d y 
i nter ve nti o n, Pfizer s h o ul d be i nf or me d i m me diatel y.
I n a d diti o n, t he i n vesti gat or will i nf or m Pfizer i m me diatel y of a n y ur ge nt safety meas ures ta ke n 
b y  t he i n vesti gat or t o pr otect t he st u d y partici pa nts a gai nst a n y i m me diate hazar d, a n d of a n y 
seri o us breac hes of t his pr ot oc ol or of t he I C H G C P t hat t he i n vesti gat or bec o mes a ware of.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 8 of 2 2 0
1 2. 3. I nf or me d C o nse nt Pr ocess
T he i n vesti gat or or t he i n vesti gat or’s re prese ntati ve will e x p lai n t he nat ure of t he st u d y, 
i ncl u di n g t he ris ks a n d be nefits, t o t he partici pa nt a n d a ns wer all q uesti o ns re gar di n g t he st u dy. 
T he partici pa nt s h o ul d be gi ve n s ufficie nt ti me a n d o p p ort u nit y  t o as k q uesti o ns a n d t o deci de 
w het her or n ot t o partici pate i n t he trial.
Partici pa nts m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y . Partici pa nts 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, IC H G C P g ui deli nes, pri vac y  a n d data pr otecti o n re q uire me nts, w here a p plica ble, 
a n d t he I R B/ E C or st u d y ce nter.
T he i n vesti gat or m ust e ns ure t hat eac h st u d y  partici pa nt is f ull y i nf or me d a b o ut t he nat ure a n d 
o bjecti ves of t he st u d y, t he s hari n g of data relate d t o t he st u d y, a n d p ossi ble ris ks ass oci ate d wit h 
partici pati o n, i ncl u di n g t he ris ks ass ociate d wit h t he pr ocessi n g of t he partici pa nt’s pers o nal data. 
T he partici pa nt m ust be i nf or me d t hat t heir pers o nal st u d y -relate d data will be use d b y t he 
s p o ns or i n acc or da nce wit h l ocal data pr otecti o n law. T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he partici pa nt.
T he partici pa nt m ust be i nf or me d t hat t heir me dical rec or ds ma y  be e xa mi ne d b y Cli nical 
Q ualit y  Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he s p o ns or, b y 
a p pr o priate I RB/ E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities.
T he i n vesti gat or f urt her m ust e ns ure t hat eac h st u d y  partici pa nt is f ull y i nf or me d a b o ut his or her 
ri g ht t o access a n d c orrect t heir pers o nal data a n d t o wit h dra w c o nse nt f or t he pr ocessi n g of his 
or her pers o nal data.
T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt 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 a n d t he date o n w hic h t he writte n c o nse nt was o btai ne d. 
T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C D.
Partici pa nts m ust be rec o nse nte d t o t he m ost c urre nt I R B/ E C versi o n of t he I R B/ E C -a p pr o ve d 
I C D(s) d uri n g t heir partici pati o n i n t he st u d y as re q uire d per l ocal re g ulati o ns.
A c o p y of t he I C D(s) m ust be pr o vi de d t o t h e partici pa nt.
1 2. 4. D at a Pr otecti o n
All parties will c o m pl y  wit h all a p plica ble la ws, i ncl u di n g la ws re gar di n g t he i m ple me ntati o n of 
or ga nizati o nal a n d tec h nical meas ures t o e ns ure pr otecti o n of partici pa nt data.
Partici pa nts’ pers o nal data will be st ore d at t he st u d y  site i n electr o nic a n d/ or pa per f or m a n d will 
be sec ure d i n a l oc ke d r o o m t o e ns ure t hat o nl y  a ut h orize d st u d y staff ha ve access. T he st u d y site 
will i m ple me nt a p pr o priate tec h nical a n d or ga nizati o nal meas ures t o e ns ure t hat t he pers o nal 
data ca n be rec o vere d i n t he e ve nt of disaster. I n t he e ve nt of a p ote ntial pers o nal data breac h, t he 
st u d y site will be res p o nsi ble f or deter mi ni n g w het her a pers o nal data breac h has i n fact occ urre d 
a n d, if s o, pr o vi di n g breac h n otificati o ns as re q uire d b y la w.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 5 9 of 2 2 0
T o pr otect t he ri g hts a n d free d o ms of partici pa nts wit h re gar d t o t he pr ocessi n g of pers o nal data, 
partici pa nts will be assi g ne d a si n gle, partici pa nt- s pecific n u merical c o de. 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 n u merical c o de; partici pa nt 
na mes will n ot be tra nsferre d. All ot her i de ntifia ble data tra nsferre d t o t he s p o ns or will be 
i de ntifie d b y t his si n gle, partici pa nt-s pecific c o de. T he st u d y site will mai ntai n a c o nfi de ntial list 
of partici pa nts w h o par tici pate d i n t he st u d y, li n ki n g eac h partici pa nt’s n u merical c o de t o t heir 
act ual i de ntit y a n d me dical rec or d I D. I n case of data tra nsfer, t he s p o ns or will pr otect t he 
c o nfi de ntialit y of partici pa nts’ pers o nal data c o nsiste nt wit h t he cli nical st u d y a greeme nt a n d 
a p plica ble pri vac y la ws.
I nf or mati o n tec h n ol o g y s yste ms use d t o c ollect, pr ocess, a n d st ore st u d y-relate d data are sec ure d 
b y  tec h nical a n d or ga nizati o nal sec urit y meas ures desi g ne d t o pr otect s uc h data a gai nst 
acci de ntal or u nla wf ul l oss, alterat i o n, or u na ut h orize d discl os ure or access. 
T he s p o ns or mai ntai ns S O Ps o n h o w t o res p o n d i n t he e ve nt of u na ut h orize d access, use, or 
discl os ure of s p o ns or i nf or mati o n or s y ste ms.
1 2. 5. Disse mi n ati o n of Cli nic al St u d y D at a
Pfizer f ulfills its c o m mit me nt t o p u bli cl y discl ose cli nical st u d y res ults t hr o u g h p osti n g t he 
res ults of st u dies o n w w w.cli nicaltrials. g o v ( Cli nical Trials. g o v), a n d/ or w w w. pfizer.c o m, a n d 
ot her p u blic re gistries a n d we bsites i n acc or da nce wit h a p plica ble l ocal la ws/re g ulati o ns. I n 
a d diti o n, Pf izer re p orts st u d y res ults o utsi de of t he re q uire me nts of l ocal la ws/re g ulati o ns 
p urs ua nt t o its S O Ps.
I n all cases, st u dy res ults are re p orte d b y Pfizer i n a n o bjecti ve, acc urate, bala nce d, a n d c o m plete 
ma n ner a n d are re p orte d re gar dless of t he o utc o me of t he st u d y or t he c o u ntr y i n w hic h t he st u d y 
was c o n d ucte d.
w w w.cli nicaltrials. g o v
Pfizer p osts cli nical trial res ults o n w w w.cli nicaltrials. g o v f or Pfizer -s p o ns ore d i nter ve nti o nal 
st u dies (c o n d ucte d i n patie nts) t hat e val uate t he safet y a n d/ or efficac y of a pr o d uct, re gar dless of 
t he ge o gra p hical l ocati o n i n w hic h t he st u d y is c o n d ucte d. T hese res ults are s u b mitte d f or 
p osti n g i n acc or da nce wit h t he f or mat a n d ti meli nes set f ort h b y U S la w.
w w w. pfizer.c o m
Pfizer p osts C S R s y n o pses a n d plai n -la n g ua ge st u d y res ults s u m maries o n w w w. pfizer.c o m f or 
Pfizer -s p o ns ore d i nter ve nti o nal st u dies at t he sa me ti me t he c orres p o n di n g st u d y res ults are 
p oste d t o w w w.cli nicaltrials. g o v. C S R s y n o pses will ha ve pers o nall y i de ntifia ble i nf or mati o n 
a n o n ymize d.
D oc u me nts wit hi n m ar keti n g a p plicati o ns 
Pfizer c o m plies wit h a p plica ble l ocal la ws/re g ulati o ns t o p u blis h cli nical d oc u me nts i ncl u de d i n 
mar keti n g a p plicati o ns. Cli nical d oc u me nts i ncl u de s u m mar y  d oc u me nts a n d C S Rs i ncl u di n g t he 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 0 of 2 2 0
pr ot oc ol a n d pr ot oc ol a me n d me nts, sa m ple C R F s, a n d S A Ps. Cli nical d oc u me nts will ha ve 
pers o nall y i de ntifia ble i nf or mati o n a n o n y m ize d.
Data s hari n g
Pfizer pr o vi des researc hers sec ure access t o partici pa nt-le vel data or f ull C S Rs f or t he p ur p oses 
of “ b o na -fi de scie ntific researc h” t hat c o ntri b utes t o t he scie ntific u n dersta n di n g of t he disease, 
tar get, or c o m p o u n d class. Pfizer will ma ke data fr o m t hese trials a vaila ble 1 8 m o nt hs after st u d y  
c o m pleti o n. Partici pa nt -le vel data will be a n o ny m ize d i n acc or da nce wit h a p plica ble pri vac y 
la ws a n d re g ulati o ns. C S Rs will ha ve pers o nally i de ntifia ble i nf or mati o n a n o n y mize d.
Data re q uests are c o nsi dere d fr o m q ualifie d researc hers wit h t he a p pr o priate c o m pete ncies t o 
perf or m t he pr o p ose d a nal y ses. Researc h tea ms m ust i ncl u de a bi ostatisticia n. Data will n ot be 
pr o vi de d t o a p plica nts wit h si g nifica nt c o nflicts of i nterest, i ncl u di n g i n di vi d uals re q uesti n g 
access f or c o m mercial/c o m petiti ve or le gal p ur p oses.
1 2. 6. D at a Q u alit y Ass ur a nce
All partici pa nt data relati n g t o t he st u d y will be rec or de d o n electr o nic C R F u nless tr a ns mitte d t o 
t he s p o ns or or desi g nee electr o nically (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 acc urate a n d c orrect b y electr o nicall y si g ni n g t he C R F.
G ui da nce o n c o m pleti o n of eC R Fs will be pr o vi de d i n t he C R F C o m pleti o n G ui deli nes 
d oc u me nt.
T he i n vesti gat or m ust e ns ure t hat t he e C R Fs are sec urel y st ore d at t he st u d y site i n electr o nic 
f or m a n d are pass w or d-pr otecte d or sec ure d i n a l oc ke d r o o m t o pre ve nt access b y  u na ut h orize d 
t hir d parties.
T he i n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/ E C re vie w, a n d re g ulat or y 
a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce rec or ds a n d d oc u me nts. T his verificati o n 
ma y  als o occ ur after st u d y c o m pleti o n. It is i m p orta nt t hat t he i n vesti gat or(s) a n d t heir rele va nt 
pers o n nel are a vaila ble d uri n g t he m o nit ori n g visits a n d p ossi ble a u dits or i ns pecti o ns a n d t hat 
s ufficie nt ti me is de v ote d t o t he pr ocess.
M o nit ori n g details descri bi n g strate g y , i ncl u di n g defi niti o n of st u d y-critical data ite ms a n d 
pr oces ses (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 nal yt 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, 
virt ual, or o n -site m o nit ori n g), are pr o vi de d i n t he Cli nical M o nit ori n g Pla n, Ce ntralize d 
M o nit ori n g Pla n, a n d Data Ma na ge me nt Pla n mai ntai ne d a n d utilize d b y  t he s p o ns or or desi g nee.
T he s p o ns or or desi g nee is res p o nsi ble f or t he data ma n a ge me nt of t his st u d y, i ncl u di n g q uality 
c hec ki n g of t he data.
Rec or ds a n d d oc u me nts, i ncl u di n g si g ne d I C Ds, pertai ni n g t o t he c o n d uct of t his st u d y  m ust be 
retai ne d by t he i n vesti gat or f or 1 5 ye ars after st u d y c o m pleti o n u nless l ocal re g ulati o ns or 
i nstituti o nal p olicies re q uire a l o n ger rete nti o n peri o d. N o rec or ds ma y  be destr o ye d d uri n g t he 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 1 of 2 2 0
rete nti o n peri o d wit h o ut t he writte n a p pr o val of t he s p o ns or. N o rec or ds ma y be tra nsferre d t o 
a n ot her l ocati o n or part y wit h o ut writte n n otificati o n t o t he s p o ns or. T he i n vesti gat or m ust 
e ns ure t hat t he rec or ds c o nti n ue t o be st ore d sec urel y  f or as l o n g as t he y are mai ntai ne d.
W he n partici pa nt data are t o be delete d, t he i n vesti gat or will e ns ure t hat all c o pies of s uc h data 
are pr o m ptl y a n d irre v oca bl y delete d fr o m a ll s yste ms.
T he i n vesti gat or(s) will n otif y t he s p o ns or or its a ge nts i m me diatel y  of a n y re g ulat or y i ns pecti o n 
n otificati o n i n relati o n t o t he st u d y . F urt her m ore, t he i n vesti gat or will c o o perate wit h t he s p o ns or 
or its a ge nts t o pre pare t he i n vesti gat or si te f or t he i ns pecti o n a n d will all o w t he s p o ns or or its 
a ge nt, w he ne ver feasi ble, t o be prese nt d uri n g t he i ns pecti o n. T he i n vesti gat or site a n d 
i n vesti gat or will pr o m ptl y res ol ve a ny discre pa ncies t hat are i de ntifie d bet wee n t he st u d y data 
a n d t he partici pa nt's me dical rec or ds. T he i n vesti gat or will pr o m ptl y  pr o vi de c o pies of t he 
i ns pecti o n fi n di n gs t o t he s p o ns or or its a ge nt. Bef ore res p o nse s u b missi o n t o t he re g ulat or y 
a ut h orities, t he i n vesti gat or will pr o vi de t he s p o ns or or its a ge nts wit h a n o p p ort u n it y t o re vie w 
a n d c o m me nt o n res p o nses t o a n y  s uc h fi n di n gs.
1 2. 7. S o urce D oc u me nts
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he partici pa nt a n d s u bsta ntiate t he 
i nte grity of t he data c ollecte d. S o urce d oc u me nts are file d at t he i n vesti gat or site.
Data e ntere d i n t he e C R F t hat are fr o m s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o urce 
d oc u me nts or t he discre pa ncies m ust be e x plai ne d. T he i n vesti gat or ma 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 u rre nt me dical 
rec or ds m ust be a vaila ble.
A S o urce D oc u me nt I de ntificati o n L o g ( or e q ui vale nt) s h o ul d be mai ntai ne d wit h t he 
I n vesti gat or Site File o n site. Defi niti o n of w hat c o nstit utes a s o urce d oc u me nt a n d its ori gi n ca n 
be f o u n d i n t he S o urce D oc u me nt L o cat or or e q ui vale nt, w hic h is mai ntai ne d b y  t he site.
Descri pti o n of t he use of t he c o m p uterize d s yste m is d oc u me nte d i n t he Data Ma na ge me nt Pla n, 
w hic h is mai ntai ne d b y  t he s p o ns or. 
T he i n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce rec or d) t hat s u p p orts t he 
i nf or mati o n e ntere d o n t he e C R F.
T he s p o ns or or desi g nee will perf or m m o nit ori n g t o c o nfir m t hat data e ntere d i nt o t he e C R F b y 
a ut h orize d site pers o n nel are acc urate, c o m plete, a n d verifia ble fr o m s o urce d oc u me nts; 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 i n 
acc or da nce wit h t he c urre ntl y  a p pr o ve d pr ot oc ol a n d a ny ot her st u d y a gree me nts, t he I C H G C P 
g ui deli nes, a n d all a p plica ble re g ulat or y  re q uire me nts.
1 2. 8. Use of Me dic al Rec or ds
T here ma y  be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d b y Pfizer 
Safet y , w here et hicall y a n d scie ntifically j ustifie d a n d per mitte d b y l ocal re g ulati o ns, t o e ns ure 
partici pa nt safet y .
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 2 of 2 2 0
D ue t o t he p ote ntial f or a partici pa nt t o be rei de ntifie d fr o m t heir me dical rec or ds, t he f oll o wi n g 
acti o ns m ust be ta ke n w he n me dical rec or ds are se nt t o t he s p o ns or or s p o ns or desi g nee:

T he i n vesti gat or or site staff m ust re dact pers o nal i nf or mati o n fr o m t he me dical rec or d. 
T he pers o nal i nf or ma ti o n i ncl u des, b ut is n ot li mite d t o, t he f oll o wi n g: partici pa nt na mes 
or i nitials, partici pa nt dates (e g, birt h date, date of h os pital a d missi o n/ disc har ge, date of 
deat h), partici pa nt i de ntificati o n n u m bers (e g, S ocial Sec urit y  n u m ber, healt h i ns ura nce 
n u m ber, me dical rec or d n u m ber, h os pital/i nstit uti o n i de ntifier), partici pa nt l ocati o n 
i nf or mati o n (e g, street a d dress, city, c o u ntr y, p ostal c o de, I P a d dress), a n d partici pa nt 
c o ntact i nf or mati o n (e g, tele p h o ne/fa x n u m ber, e mail a d dress).

Eac h me dical rec or d m ust be tra ns mitte d t o t he s p o ns or or s p o ns or desi g nee usi n g 
s yste ms wit h tec h nical a n d or ga nizati o nal sec urit y meas ures t o e ns ure t he pr otecti o n of 
pers o nal data (e g, Fl ore nce is t he preferre d s ys te m if a vaila ble). 

T here ma y  be u n pla n ne d sit uati o ns w here t he s p o ns or ma y re q uest me dical rec or ds (e g, 
s hari n g me dical rec or ds s o t hat t he s p o ns or ca n pr o vi de st u d y-relate d a d vice t o t he 
i n vesti gat or). T he me dical rec or ds s h o ul d be s u b mitte d acc or di n g t o t he pr oce d ure 
descri be d a b o ve.
1 2. 9. St u d y a n d Site St art a n d C l os ure
T he st u d y  start date is t he date of t he first partici pa nt’s first visit.
T he s p o ns or desi g nee 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 
f or a ny reas o n at t he s ole discreti o n of t he s p o ns or, i ncl u di n g ( b ut n ot li mi te d t o) re g ulat or y 
a ut h orit y decisi o n, c ha n ge i n o pi ni o n of t he IR B/ E C, or c ha n ge i n be nefit -ris k assess me nt. St u d y 
sites will be cl ose d u p o n st u d y c o m pleti o n. A st u d y site is c o nsi dere d cl ose d w he n all re q uire d 
d oc u me nts a n d st u d y  s u p plies ha ve bee n c ollecte d a n d a st u d y-site cl os ure visit has bee n 
perf or me d.
T he i n vesti gat or ma y  i nitiate st u d y-site cl os ure at a n y ti me u p o n n otificati o n t o t he s p o ns or if 
re q ueste d t o d o s o by t he res p o nsi ble I R B/ E C or if s uc h ter mi nati o n is re q uire d t o pr otect t he 
healt h o f st u d y partici pa nts.
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 ma y i ncl u de b ut are n ot li mite d t o:

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 IR B/ E C 
or l ocal healt h a ut h orities, t he s p o ns or's pr oce d ures, or t he I C H 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 st u d y  i nter ve nti o n de vel o p me nt.
If t he st u dy is pre mat urel y ter mi nate d or s us pe n de d, t he s p o ns or s hall pr o m ptl y i nf or m t he 
i n vesti gat ors, t he E Cs/I R Bs, t he re g ulat or y a ut h orities, a n d a n y C R O(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 t he a p plica ble re g ulat or y re q uire me nts. T he 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 3 of 2 2 0
i n vesti gat or s hall pr o m ptl y i nf or m t he partici pa nt a n d s h o ul d ass ure a p pr opriate partici pa nt 
t hera py a n d/ or f oll o w - u p.
St u d y  ter mi nati o n is als o pr o vi de d f or i n t he cli nical st u d y a gree me nt. If t here is a n y c o nflict 
bet wee n t he c o ntract a n d t his pr ot oc ol, t he c o ntract will c o ntr ol as t o ter mi nati o n ri g hts.
1 2. 1 0. P u blic ati o n P olic y
F or m ultice nter trials, t he pri mar y  p u blicati o n will be a j oi nt p u blicati o n de vel o pe d by t he 
i n vesti gat or a n d Pfizer re p orti n g t he pri mar y e n d p oi nt(s) of t he st u d y c o veri n g all st u d y sites. 
T he i n vesti gat or a grees t o refer t o t he pri mar y  p u blicati o n i n a n y s ubse q ue nt p u blicati o ns. Pfizer 
will n ot pr o vi de a n y  fi na ncial c o m pe nsati o n f or t he i n vesti gat or’s partici pati o n i n t he pre parati o n 
of t he pri mar y  c o n gress a bstract, p oster, prese ntati o n, or pri mar y ma n uscri pt f or t he st u d y. 
I n vesti gat ors are free t o p u blish i n di vi d ual ce nter res ults t hat t he y  dee m t o be cli nicall y 
mea ni n gf ul after p u blicati o n of t he o verall res ults of t he st u d y  or 1 2 m o nt hs after pri mar y 
c o m pleti o n date or st u d y c o m pleti o n at all sites, w hic he ver occ urs first, s u bject t o t he ot her 
re q uire ments descri be d i n t his secti o n.
T he i n vesti gat or will pr o vi de Pfizer a n o p p ort u nit y  t o re vie w a n y pr o p ose d p u blicati o n or a n y 
ot her t y pe of discl os ure of t he st u d y  res ults (c ollecti vel y, “ p u blicati o n”) bef ore it is s u b mitte d or 
ot her wise discl ose d a n d will s u b mit all p u blicati o ns t o Pfizer 3 0 da y s bef ore s u b missi o n. If a n y 
pate nt acti o n is re q uire d t o pr otect i ntellect ual pr o pert y ri g hts, t he i n vesti gat or a grees t o dela y  t he 
discl os ure f or a peri o d n ot t o e xcee d a n a d diti o nal 6 0 da y s u p o n re q uest fr o m Pfizer. T his all o ws 
Pfizer 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, a n d t he i n vesti gat or will, o n 
re q uest, re m o ve a ny pre vi o usl y  u n discl ose d c o nfi de ntial i nf or mati o n bef ore discl os ure, e xce pt 
f or a ny st u d y- i nter ve nti o n or Pfizer-relate d i nf or mati o n necessar y f or t he a p pr o priate scie ntific 
prese ntati o n or u n dersta n di n g of t he st u d y res ults. F or j oi nt p u blicati o ns, s h o ul d t here be 
disa gree me nt re gar di n g i nter pretati o n a n d/ or prese ntati o n of s pecific a nal ysis res ults, res ol uti o n 
of, a n d res p o nsi bi lit y f or, s uc h disa gree me nts will be t he c ollecti ve res p o nsi bilit y of all a ut h ors 
of t he p u blicati o n.
F or all p u blicati o ns relati n g t o t he st u d y, t he i n vesti gat or a n d Pfizer will c o m pl y wit h rec o g nize d 
et hical sta n dar ds c o ncer ni n g p u blicati o ns a n d a ut h ors h i p, i ncl u di n g t h ose esta blis he d b y t he 
I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors. T he i n vesti gat or will discl ose a ny 
relati o ns hi p wit h Pfizer a n d a n y rele va nt p ote ntial c o nflicts of i nterest, i ncl u di n g a n y fi na ncial or 
pers o nal relati o ns hi p wit h P fizer, i n a n y p u blicati o ns. W he n a p plia ble, e dit orial or tec h nical 
s u p p ort pr o vi de d by a t hir d part y a n d pai d f or b y Pfizer, or pr o vi de d b y a Pfizer e m pl o yee, ma y 
be a re p orta ble tra nsfer of val ue u n der t he S u ns hi ne Act f or U S lice nse d p h ysicia ns or ot her 
healt hcare pr ofessi o nals . All a ut h ors will ha ve access t o t he rele va nt statistical ta bles, fi g ures, 
a n d re p orts (i n t heir ori gi nal f or mat) re q uire d t o de vel o p t he p u blicati 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 b y  t he i n vesti gat or after p u blicati o n of t he 
o verall st u d y res ults or 1 ye ar after t he e n d of t he st u d y ( or st u dy ter mi nati o n), w hic he ver c o mes 
first.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 4 of 2 2 0
1 2. 1 1. S p o ns or’s Me dic all y Q u alifie d I n di vi d u al
T he s p o ns or will desi g nate a me dicall y q ualifie d i n di vi d ual ( M QI, als o k n o w n as t he me dical 
m o nit or) t o a d vise t he i n vesti gat or o n st u d y- relate d me dical q uesti o ns. T he c o ntact i nf or mati o n 
f or t he st u dy me dical m o nit or is d oc u me nte d i n t he St u d y  Tea m C o ntact List l ocate d i n t he 
I n vesti gat or Site File or e q ui vale nt. 
Par tici pa nts are pr o vi de d wit h a Pfizer st u d y i nf or mati o n car d at t he ti me of i nf or me d c o nse nt, 
w hic h i ncl u des c o ntact i nf or mati o n f or t heir i n vesti gat or i n case of st u d y- relate d me dical 
q uesti o ns . T he st u d y i nf or mati o n car d c o ntai ns, at a mi ni m u m, (a) st u d y n u m ber, ( b) 
partici pa nt’s st u d y i de ntificati o n n u m ber, a n d (c) pri nci pal i n vesti gat or c o ntact i nf or mati o n. 
1 2. 1 2. Cli nic al Tri al A gree me nt
Pa y me nts b y  t he s p o ns or t o i n vesti gat ors a n d i nstit uti o ns c o n d ucti n g t he trial, re q uire me nts f or 
i n vesti gat ors’ i ns ura nce, t he p u blicati o n p olic y f or cli nical trial data, a n d ot her re q uire me nts are 
s pecifie d i n t he cli nical trial a gree me nt.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 5 of 2 2 0
1 3. LI S T O F R E F E R E N C E S
Al brec ht T, Ra usc h M, R oessler S, et al. H E R 2 ge ne ( E R B B 2 ) a m plificati o n is a l o w-fre q ue nc y 
dri ver wit h p ote ntial pre dicti ve val ue i n gall bla d der carci n o ma. Virc h o ws Arc h. 
2 0 2 0; 4 7 6( 6): 8 7 1 - 8 0.
A merica n Ca ncer S ociet y. Breast ca ncer facts & fi g ures ( 2 0 1 7 -2 0 1 8). 2 0 1 8. 
htt ps:// w w w.ca ncer. or g/c o nte nt/ da m/ca ncer- or g/researc h/ca ncer -facts-a n d-
statistics/ breast-ca ncer -facts-a n d-fi g ures/ breast-ca ncer-facts-a n d-fi g ures-2 0 1 7 - 2 0 1 8. p df. 
Accesse d: Dec 1 2, 2 0 1 9.
Artea ga C L, Sli w k o ws ki M X, Os b or ne C K, et al. Treat me nt of H E R 2- p ositi ve breast ca ncer: 
c urre nt stat us a n d f ut ure pers pecti ves. Nat Re v Cli n O nc ol. 2 0 1 1; 9( 1): 1 6 -3 2.
Ba n g YJ, Va n C utse m E, Fe y ereisl o va A, et al. Trast uz u ma b i n c o m bi nati o n wit h c he m ot hera p y 
vers us c he m ot hera p y al o ne f or treat me nt of H E R 2 -p ositi ve a d va nce d gastric or gastr o -
oes o p ha geal j u ncti o n ca ncer ( T o G A): a p hase 3, o pe n- la bel, ra n d o mise d c o ntr olle d trial. 
La ncet. 2 0 1 0; 3 7 6( 9 7 4 2 ): 6 8 7- 9 7.
Be ns o n A B, Ve n o o k A P, Al -Ha war y  M M, et al. C ol o n Ca ncer, Versi o n 2. 2 0 2 1, N C C N Cli nical 
Practice G ui deli nes i n O nc ol o g y . J Natl C o m pr Ca nc Net w. 2 0 2 1; 1 9( 3): 3 2 9- 5 9.
C ha ga nt y B K R, Qi u S, Gest A, et al. Trast uz u ma b u pre g ulates P D- L 1 as a p ote ntial mec ha nis m 
of trast uz u ma b resista nce t hr o u g h e n ga ge me nt of i m m u ne effect or cells a n d sti m ulati o n 
of I F Nγ secreti o n. Ca ncer Lett. 2 0 1 8; 4 3 0: 4 7 - 5 6.
Cl o p per CJ, Pears o n E S. T he use of c o nfi de nce or fi d ucial li mits ill ustrate d i n t he case of t he 
bi n o mial. Bi o me tri ka. 1 9 3 4; 2 6( 4): 4 0 4- 1 3.
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
re vise d R E CIS T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5( 2): 2 2 8 - 4 7.
Hac ha d H, Ra g ue nea u -Majlessi I , Le v y R H. A usef ul t o ol f or dr u g i nteracti o n e val uati o n: t he 
U ni versit y  of Was hi n gt o n Meta b olis m a n d Tra ns p ort Dr u g I nteracti o n Data base. H u m 
Ge n o mics. 2 0 1 0; 5( 1): 6 1 - 7 2.
Ha q ue R, A h me d S A, I nz ha k o va G, et al. I m pact of breast ca ncer s u bt y pes a n d treat me nt o n 
s ur vi val: a n a nalys is s pa n ni n g t w o deca des. Ca ncer E pi de mi ol Bi o mar kers Pre v. 
2 0 1 2; 2 1( 1 0): 1 8 4 8 - 5 5.
H oe hler T, v o n Wic hert G, Sc hi ma ns ki C, et al. P hase I/II trial of ca pecita bi ne a n d o xali plati n i n 
c o m bi nati o n wit h be vaciz u ma b a n d i mati ni b i n patie nts wit h metastatic c ol orectal ca ncer: 
AI O K R K 0 2 0 5. Br J Ca ncer. 2 0 1 3; 1 0 9( 6): 1 4 0 8 - 1 3.
H ol br o T, H y nes N E. Er b B rece pt ors: directi n g ke y  si g nali n g net w or ks t hr o u g h o ut life. A n n u 
Re v P har mac ol T o xic ol. 2 0 0 4; 4 4: 1 9 5 - 2 1 7.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 6 of 2 2 0
H y nes N E, La ne H A. E R B B rece pt ors a n d ca ncer: t he c o m ple xit y  of targete d i n hi bit ors. Nat Re v 
Ca ncer. 2 0 0 5; 5( 5): 3 4 1 -5 4.
Ja nji gia n Y Y, Ka waz oe A, Ya nez P E, et al. Pe m br oliz u ma b pl us trast uz u ma b a n d c he m ot hera p y 
f or H E R 2 + metastatic gastric or gastr oes o p ha geal j u ncti o n ( G/ G EJ) ca ncer: i nitial 
fi n di n gs of t he gl o bal p hase 3 K E Y N O T E- 8 1 1 st u d y . J Cli n O nc ol. 2 0 2 1; 3 9( 1 5 
S u p pl): A bstract 4 0 1 3.
Ja nji gia n Y Y, Mar o n S B, C hatila W K, et al. First-li ne pe m br oliz u ma b a n d trast uz u ma b i n 
H E R 2 - p ositi ve oes o p ha geal, gastric, or gastr o-oes o p ha geal j u ncti o n ca ncer: a n o pe n-
la bel, si n gle-ar m, p hase 2 trial. La ncet O nc ol. 2 0 2 0; 2 1( 6): 8 2 1 - 3 1.
Kell y  C M, Ja nji gia n Y Y. T he ge n o mics a n d t hera pe utics of H E R 2-p ositi ve gastric ca ncer -fr o m 
trast uz u ma b a n d be yo n d. J Gastr oi ntest O nc ol. 2 0 1 6; 7( 5): 7 5 0 - 6 2.
Ker b R , Br oc k m oller J, Staffel dt B, Pl oc h M, R o ots I. Si n gle-d ose a n d stea d y -state 
p har mac o ki netics of h y p erici n a n d pse u d o h y p erici n. A nti micr o b A ge nts C he m ot her. 
1 9 9 6; 4 0( 9): 2 0 8 7 - 9 3.
Lala M, L i M, Si n ha V, et al. A si x-wee kl y  ( Q 6 W) d osi n g sc he d ule f or pe m br olizu ma b base d o n 
a n e x p os ure- res p o nse ( E- R) e val uati o n usi n g m o deli n g a n d si m ulati o n. J Cli n O nc ol. 
2 0 1 8; 3 6( S u p pl 1 5): A bstract 3 0 6 2.
Li R, Sa nt S, Br o w n E, et al. T ucati ni b fa v o ura bl y m o d ulates t he i m m u ne micr oe n vir o n me nt a n d 
s yner gizes wit h a nti -P D 1 t hera p y i n a trast uz u ma b resista nt H E R 2 + m uri ne m o del. 
Ca ncer Res. 2 0 2 1; 8 1( 4 S u p pl): A bstract P S 1 0- 0 4.
L oi S, Gi o b bie -H ur der A, G o m b os A, et al. Pe m br oliz u ma b pl us trast uz u ma b i n trast uz u ma b -
resista nt, a d va nce d, H E R 2- p ositi ve breast ca ncer ( P A N A C E A): a si n gle-ar m, 
m ultice ntre, p hase 1 b -2 trial. La ncet O nc ol. 2 0 1 9; 2 0( 3): 3 7 1 - 8 2.
L oree J M, M ul der K E, G h os h S, S pratli n J L. Retr os pecti ve c o m paris o n of C A P O X a n d 
F O L F O X d ose i nte nsit y, t o xicit y , a n d cli nical o utc o mes i n t he treat me nt of metastatic 
c ol o n ca ncer. J Gastr o i ntest Ca ncer. 2 0 1 4; 4 5( 2): 1 5 4- 6 0.
Mic hael M, Zalc ber g J, Gi b bs P, et al. A p hase I trial of i mati ni b i n c o m bi nati o n wit h 
m F O L F O X 6 - be vaciz u ma b i n patie nts wit h a d va nce d c ol orectal ca ncer. Ca ncer 
C he m ot her P har mac ol. 2 0 1 3; 7 1( 2): 3 2 1- 3 0.
M o n daca S, Mar g olis M, Sa nc hez -Ve ga F, et al. P hase II st u d y of trast uz u ma b wit h m o difie d 
d oceta xel, cis plati n, a n d 5 fl u or o uracil i n metastatic H E R 2 - p ositi ve gastric ca ncer. 
Gastric Ca ncer. 2 0 1 9; 2 2( 2): 3 5 5- 6 2.
M orte ns o n E D, Par k S, Jia n g Z, Wa n g S, F u Y X.
Effecti ve a nti -ne u -i nitiate d a ntit u m or 
res p o nses re q uire t he c o m ple x r ole of C D 4 + T cells. Cli n Ca ncer Res. 2 0 1 3; 1 9( 6): 1 4 7 6-
8 6.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 7 of 2 2 0
M urt h y  R K, L oi S, O ki nes A, et al. T ucati ni b, trast uz u ma b, a n d ca pecita bi ne f or H E R 2-p ositi ve 
metastatic breast ca ncer. N E n gl J Me d. 2 0 2 0; 3 8 2( 7): 5 9 7- 6 0 9.
Ola y i o ye M A, Ne ve R M, La ne H A, H ynes N E. T he Er b B si g nali n g net w or k: rece pt or 
heter o di merizati o n i n de vel o p me nt a n d ca ncer. E M B O J. 2 0 0 0; 1 9( 1 3): 3 1 5 9 - 6 7.
Orla n d o L, Gi otta F, L or uss o V, et al. Bi wee kl y c o m bi nati o n of trast uz u m a b, d oceta xel a n d 
ge mcita bi ne f or H E R 2 - p ositi ve metastatic breast ca ncer: res ults of a p hase II G OI M 
st u d y. F ut ure O nc ol. 2 0 1 4; 1 0( 5): 7 2 5- 3 3.
Par k S, Jia n g Z, M orte ns o n E D, et al. T he t hera pe utic effect of a nti -H E R 2/ ne u a nti b o d y  de pe n ds 
o n b ot h i n nate a n d a da pti ve i m m u nit y. Ca ncer Cell. 2 0 1 0; 1 8( 2): 1 6 0- 7 0.
Qi u M Z, Li Q, Wa n g Z Q, et al. H E R 2 - p ositi ve patie nts recei vi n g trast uz u ma b treat me nt ha ve a 
c o m para ble pr o g n osis wit h H E R 2- ne gati ve a d va nce d gastric ca ncer patie nts: a 
pr os pecti ve c o h ort o bser vati o n. I nt J Ca ncer. 2 0 1 4; 1 3 4( 1 0): 2 4 6 8- 7 7.
Riese DJ, 2 n d, Ster n D F. S pecificit y  wit hi n t he E G F fa mily/ Er b B rece pt or fa mil y  si g nali n g 
net w or k. Bi oessa y s. 1 9 9 8; 2 0( 1): 4 1- 8.
Ri vera F, R o mer o C, Ji me nez -F o nseca P, et al. P hase II st u d y t o e val uate t he efficac y of 
trast uz u ma b i n c o m bi nati o n wit h ca pecita bi ne a n d o xali plati n i n first -li ne treat me nt of 
H E R 2 -p ositi ve a d va nce d gastric ca ncer: H E R X O trial. Ca ncer C he m ot her P har mac ol. 
2 0 1 9; 8 3( 6): 1 1 7 5 - 8 1.
R osell o S, Blasc o I, Garcia Fa bre gat L, et al. Ma na ge me nt of i nf usi o n rea cti o ns t o s yste mic 
a ntica ncer t hera p y:  E S M O Cli nical Practice G ui deli nes. A n n O nc ol. 2 0 1 7; 2 8( S u p pl 
4):i v 1 0 0 - 1 8.
Sc hlessi n ger J. L i ga n d-i n d uce d, rece pt or- me diate d di merizati o n a n d acti vati o n of E G F rece pt or. 
Cell. 2 0 0 2; 1 1 0( 6): 6 6 9 - 7 2.
Starli n g N, Ha w kes E A , C ha u I, et al. A d ose escalati o n st u d y of ge mcita bi ne pl us o xali plati n i n 
c o m bi nati o n wit h i mati ni b f or ge mcita bi ne -refract or y a d va nce d pa ncreatic 
a de n ocarci n o ma. A n n O nc ol. 2 0 1 2; 2 3( 4): 9 4 2- 7.
Stric kler J H, Ze mla T, O u F S, et al. Trast uz u ma b a n d t ucati ni b f or t he treat me nt of H E R 2 
a m plifie d metastatic c ol orectal ca ncer ( m C R C): i nitial res ults fr o m t he M O U N T AI N E E R 
trial. A n n O nc ol. 2 0 1 9; 3 0( S u p pl 5): v 2 0 0.
Ta ke ga wa N, Y o nesa ka K. H E R 2 as a n e mer gi n g o nc otar get f or c ol orectal ca ncer treat me nt after 
fail ure of a nti-e pi der mal gr o wt h fact or rece pt or t hera p y. Cli n C ol orectal Ca ncer. 
2 0 1 7; 1 6( 4): 2 4 7 - 5 1.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5/ S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 6 8 of 2 2 0
Ta y l or C, Hers h ma n D, S ha h N, et al. A u g me nte d H E R- 2 s pecific i m m u nit y d uri n g treat me nt 
wit h trast uz u ma b a n d c he m ot hera p y. Cli n Ca ncer Res. 2 0 0 7; 1 3( 1 7): 5 1 3 3 - 4 3.
V alt orta E, Marti n o C, Sart ore-Bia nc hi A, et al. Assess me nt of a H E R 2 sc ori n g s ys te m f or 
c ol orectal ca ncer: res ults fr o m a vali dati o n st u d y . M o d Pat h ol. 2 0 1 5; 2 8( 1 1): 1 4 8 1- 9 1.
Vara da n V, Gil m ore H, Mis ki me n K L , et al. I mm u ne si g nat ures f oll o wi n g si n gle d ose 
trast uz u ma b pre dict pat h ol o gic res p o nse t o pre o perati ve trast uz u ma b a n d c he m ot hera py 
i n H E R 2-p ositi ve earl y breast ca ncer. Cli n Ca ncer Res. 2 0 1 6; 2 2( 1 3): 3 2 4 9 - 5 9.
Wei n ber g B A, Xi u J, Li n d ber g M R, et al. M olec ular pr ofili n g of biliar y  ca ncers re veals disti nct 
m olec ular alterati o ns a n d p ote ntial t hera pe utic tar gets. J Gastr oi ntest O nc ol. 
2 0 1 9; 1 0( 4): 6 5 2 - 6 2.
Yar de n Y, Sli w k o ws ki M X. U nta n gli n g t he Er b B si g nalli n g net w or k. Nat Re v M ol Cell Bi ol. 
2 0 0 1; 2( 2): 1 2 7 - 3 7.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 6 9 of 2 2 0
A p pe n di x A. Sc he d ule of E ve nts: P h ase 1 b a n d P h ase 2 C o h orts Utilizi n g F O L F O X
Scree ni n g/
Baseli ne
Treat me nt Peri o d ( 1 4 -da y c ycles)
E O T
F oll o w
-u p F F
L T E P
D – 2 8 
t o D– 1
D – 7 t o 
D – 1 A
C y cle 1
C y cles 2 – 3
C y cle > 3
E ver y 6 D
or 8 E
Wee ks
F
E ver y 
1 2
Wee ks
F
3 0 da ys 
p ost
last d ose
E ver y 9 
or 1 2 
wee ks 
-
D 1  
D 3 B
D 8  
D 1  
D 3 B
D 8 C
D 1
Visit wi n d o w  ( da ys)
± 1 
± 1 
± 1 
± 1 
± 1 
± 1 
± 7 
± 7
+ 7
± 1 4
± 1 G G
Scree ni n g/
Baseli ne
I nf or me d c o nse ntG
X
I ncl usi o n/e xcl usi o n 
criteria
X  
X
Me dical hist or y 
(i ncl u di n g assess me nt of 
diarr hea a n d 
a nti diarr heal usa ge)
X
Hei g ht
X
Ser ol o g y f or he patitis B 
a n d C
X
T u m or s peci me n 
c ollecti o n if a vaila ble H
X
Safet y 
assess me nts
Vital si g ns, i ncl u di n g 
wei g ht I
X  
X
X  
X
X C
X
X
X C C
P h y sical e xa mJ
X  
X
X
X
X
X C C
E C O G perf or ma nce 
stat usJ
X  
X
X
X
X
X C C
C o nfir mati o n of last 
bl o o d tra nsf usi o n 
X  
X
X C C
C B C wit h differe ntial J
X  
X
X  
X
X C
X
X
X C C
Ser u m/ plas ma c he mistr y 
pa nel a n d ser u m c ystati n 
C J
X K
X K
X K
X K
X K
X K
X C, K
X K
X K
X C C
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 7 0 of 2 2 0
Scree ni n g/
Baseli ne
Treat me nt Peri o d ( 1 4 -da y c ycles)
E O T
F oll o w
-u p F F
L T E P
D – 2 8 
t o D– 1
D – 7 t o 
D – 1 A
C y cle 1
C y cles 2 – 3
C y cle > 3
E ver y 6 D
or 8 E
Wee ks
F
E ver y 
1 2
Wee ks
F
3 0 da ys 
p ost
last d ose
E ver y 9 
or 1 2 
wee ks 
-
D 1  
D 3 B
D 8  
D 1  
D 3 B
D 8 C
D 1
C oa g ulati o n pa nel J
X
X C
X
X C C
Uri nal ysis, wit h 
micr osc o p y if cli nicall y 
i n dicate dJ
X  
X
X
X C
X
X
X C C
Uri ne Pr otei n/ Creati ni ne 
( U P C) Rati oJ
X  
X
X
X C
X
X
X C C
E C G 
X
X
X C C
Ec h ocar di o gra m or 
M U G A sca n L
X
X  
X
X C C
T h yr oi d f u ncti o n test M
X
X
X C C
Ser u m/ plas ma or uri ne 
β- h C G pre g na nc y test 
(f or fe males of 
c hil d beari n g p ote ntial) N
X N
X
X
X
X O
X O
X N, O
A d verse e ve nts a n d 
c o nc o mita nt 
me dicati o ns P (i ncl u di n g 
diarr hea A Es a n d 
A nti diarr heal Usa ge)
C ollecte d t hr o u g h o ut st u d y re p orti n g peri o d fr o m scree ni n g t o E O T visit P
X B B, C C
Partici pa nt 
Diar y
Iss ue Partici pa nt Diaries
Iss ue partici pa nt a p pr o priate visit diar y a n d e ns ure site re q uire d fiel ds are 
c o m plete d; Partici pa nt diaries s h o ul d be re vie we d at eac h visit.
St u d y 
Treat me nt
O xali plati n Q
X
X
X
X
Le uc o v ori n Q
X
X
X
X
Fl u or o uracil Q
X
X
X
X
Trast uz u ma b R
C o h orts 1 A a n d 1 B: Trast uz u ma b is a d mi nistere d Q 2 W
All ot her C o h orts: Trast uz u ma b is a d mi nistere d Q 3 W
X
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 7 1 of 2 2 0
Scree ni n g/
Baseli ne
Treat me nt Peri o d ( 1 4 -da y c ycles)
E O T
F oll o w
-u p F F
L T E P
D – 2 8 
t o D– 1
D – 7 t o 
D – 1 A
C y cle 1
C y cles 2 – 3
C y cle > 3
E ver y 6 D
or 8 E
Wee ks
F
E ver y 
1 2
Wee ks
F
3 0 da ys 
p ost
last d ose
E ver y 9 
or 1 2 
wee ks 
-
D 1  
D 3 B
D 8  
D 1  
D 3 B
D 8 C
D 1
Pe m br oliz u ma b S
Pe m br oliz u ma b is a d mi nistere d Q 6 W
X
T ucati ni b
BI D fr o m C ycle 1 Da y 8 f or C o h orts 1 A a n d 
1 B T
X
BI D fr o m C ycle 1 Da y 1 f or C o h orts 1 D, 1 E, 2 A, a n d 2 B T
X
Disease
C T sca n, P E T -C T, 
a n d/ or M RI 
assess me nts U
X  
X V
X
X
X U
X C C
S ur vi val a n d a ntica ncer 
t hera p y
X
P K/ P D
( P har mac o-
ki netics/
P har m ac o -
d y na mics)
Bl o o d sa m ples f or 
o xali plati n P K ( pre d ose 
a n d p ost d ose) W
X
X X
Uri ne sa m ples f or 
o xali plati n P K ( pre d ose 
a n d p ost d ose) Y
X
X X
Bl o o d sa m ples f or 
t ucati ni b P K ( pre d ose 
a n d p ost d ose) Z
X
X A A
X A A
X D D
Bl o o d sa m ple f or 
bi o mar ker assa y
X
X E E
A.
Baseli ne visit s h o ul d be sc he d ule d t o e ns ure t hat deter mi nati o n of esti mate d G F R ca n occ ur w it hi n 7 da ys of e nr oll me nt.
B.
C o h orts 1 A a n d 1 B o nl y.
C.
P hase 1 b c o h orts m ust c o m plete all assess me nts; p hase 2 c o h orts o nl y nee d t o c o m plete t he assess me nts f or A Es a n d a nti diarr heal usa ge.
D.
F or C o h orts 1 D, 1 E, 2 A, a n d 2 B utilizi n g F O L F O X, sca ns will be o btai ne d e ver y 6 w ee ks.
E.
F or t he t ucati ni b p hase 1 b d ose escalati o n c o h orts utilizi n g F O L F O X ( C o h orts 1 A a n d 1 B) sca ns will be o btai ne d e ver y 8 w ee ks.
F.
Sc he d uli n g deter mi ne d b y C ycle 1 Da y 1 (e nr oll me nt).
G.
All partici pa nts m ust si g n i nf or me d c o nse nt f or t he st u d y bef ore Scree ni n g/ Baseli ne pr oce d ures are c o n d ucte d.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 7 2 of 2 2 0
H.
M ost rece ntl y c ollecte d tiss ue, if a vaila ble. F or partici pa nts e nr olle d i n C o h orts 2 A a n d 2 B,
c ollecti o n of m ost rece ntl y a vaila ble tiss ue is re q uire d.
I.
Vital si g ns t o be c ollecte d are s yst olic a n d diast olic bl o o d press ure, heart rate, te m perat ure, a n d res pirat or y rate.
J.
Assess me nt t o be d o ne pre d ose o n da ys w he n st u d y treat me nt(s) are a d mi nistere d. Pre d ose la bs ca n be d o ne w it hi n 1 da y pri or t o st u d y visit. C o nfir m 
la b res ults pri or t o a d mi nisteri n g st u d y treat me nt d osi n g. 
K.
Ser u m c ystati n C (after t he P hase 2 d ose has bee n i de ntifie d, if n o re nal D L Ts ha ve bee n o bser ve d d uri n g d ose escalati o n, c ystati n C will n ot be 
c ollecte d).
L.
Car diac ejecti o n fracti o n assesse d b y tra nst h oracic E C H O will be perf or me d at scree ni n g, e ver y 1 2 w ee ks u ntil treat me nt disc o nti n uati o n irres pecti ve of 
d ose dela ys or i nterr u pti o n, a n d at t he E O T visit. E C H O is t he preferre d m o dalit y f or assess me nt of L V E F. If cli nicall y i n dicate d, M U G A sca n ma y be 
use d i n place of E C H O. T he sa me met h o d f or L V E F assess me nt s h o ul d be e m pl o ye d at eac h assess me nt. A n E C H O or M U G A is n ot re q u ire d at E O T if 
o ne has bee n perf or me d i n t he pre vi o us 1 2 we e ks (e xcl u di n g t he Scree ni n g/ Baseli ne assess me nt). E C H O/ M U G A assess me nts s h o ul d als o be u n derta ke n 
e ver y 6 m o nt hs f or at least 2 years f oll o wi n g trast uz u ma b disc o nti n uati o n.
M.
T h yr oi d f u ncti o n tests Q 6 W i n C o h orts 1 E, 2 A.
N.
Partici pa nts of c hil d beari n g p ote ntial o nl y; pre g na nc y test m ust be perf or me d wit hi n 2 4 h o urs pri or t o st u d y treat me nt d osi n g o n Da y 1 of eac h c ycle. 
C o nfir m ne gati ve pre g na nc y test pri or t o c o nti n ui n g st u d y treat me nt d osi n g. 
O.
After last d os e of st u d y treat me nt, pre g na nc y tests will be perf or me d o nce a m o nt h f or 7 m o nt hs. 
P.
S A Es a n d A E SIs will be f oll o we d u ntil res ol uti o n of ac ute e ve nts. Treat me nt -relate d S A Es occ urri n g after t he E O T visit will be f oll o we d u ntil 
res ol uti o n of ac ute e ve nts. C onc o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures will be c ollecte d, i ncl u di n g a nti diarr heal me dicati o n usa ge ( n ot 
a p plica ble t o C o h orts 1 A a n d 1 B). A nti diarr heals s h o ul d be a d mi nistere d t o partici pa nts e nr olle d i n C o h orts 1 D a n d 1 E a n d par tici pa nts e nr olled i n 
C o h ort 2 A w h o recei ve t ucati ni b + trast uz u ma b + pe m br oliz u ma b + m F O L F O X 6 as descri be d i n Secti o n 7. 1 1. 2 . A nti diarr heal pr o p h yla xis, if re q uire d, 
w ill be f oll o we d as descri be d i n Secti o n 7. 1 1. 2 .
Q.
m F O L F O X 6:
O xali plati n 8 5 m g/ m 2 a n d le uc o v ori n 4 0 0 m g/ m 2 will be a d mi nistere d I V o ver 1 2 0 mi n ( ± 1 5 mi n ut es) t he n fl u or o uracil 4 0 0 m g/ m 2 (I V 
b ol us), t he n fl u or o uracil 2 4 0 0 m g/ m 2 will be a d mi nistere d I V o ver 4 6 h o urs ( ± 1 h o ur); m F O L F O X 7: O xali plati n 8 5 m g/ m 2 a n d le uc o v ori n 2 0 0 m g/ m 2
will be a d mi nistere d I V o ver 1 2 0 mi n ( ± 1 5 mi n utes) t he n fl u or o uracil 2 4 0 0 m g/ m 2 will be a d mi nistere d I V o ver 4 6 h o urs ( ± 1 h o ur).
R.
Trast uz u ma b Q 2 W i n C o h orts 1 A a n d 1 B a n d Q 3 W i n ot her c o h orts.
S.
Pe m br oliz u ma b Q 6 W C o h orts 1 E a n d 2 A f or a ma xi m u m of 1 8 d oses.
T.
Partici pa nts are t o be i nstr ucte d t o bri n g t heir m or ni n g d ose of t ucati ni b o n D a y 1 of C ycles ≥2 t o e ns ure c orrect ti mi n g of t he P K sa m pli n g f or C o h orts 
1 A a n d 1 B, a n d o n Da y 1 of C ycle 2 -6 f or C o h orts 2 A a n d 2 B.
U.
At mi ni m u m, disease assess me nts, prefera bl y usi n g C T sca ns, m ust i ncl u de t he c hest, a b d o me n, a n d pel vis, as we ll as a p pr o priate i ma gi n g of a n y ot her 
k n o w n sites of disease s uc h as b o ne i ma gi n g. Sca ns s h o ul d be perf or me d at scree ni n g, d uri n g st u d y treat me nt, a n d at t he E O T v isit. D uri n g st u d y 
treat me nt, sca ns s h o ul d be perf or me d e ver y 8 wee ks ± 7 da ys ( base d o n C ycle 1 Da y 1) for t he first 2 4 w ee ks a n d t he n e ver y 1 2 wee ks ± 7 da ys t hereafter 
i n C o h orts 1 A a n d 1 B. I n C o h orts 1 D, 1 E, 2 A, a n d 2 B, sca ns s h o ul d be perf or me d e ver y 6 wee ks ± 7 da ys f or t he first 2 4 w ee ks a n d t he n e ver y 9 wee ks 
± 7 da ys t hereafter. If c ycles are dela ye d f o r a n y reas o n or t here is a n i nteri m u nsc he d ule d assess me nt, sca ns s h o ul d c o nti n ue t o be perf or me d acc or di n g 
t o t he ori gi nal sc he d ule. Partici pa nts w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n d oc u me nte d pr o gressi ve disease per R E CI S T w ill c o nti n ue 
t o ha ve disease assess me nts ( C T, P E T-C T, a n d/ or M RI sca ns) a p pr o xi matel y e ver y 9 w ee ks ( ± 1 4 da ys) u ntil ra di o gra p hic disease pr o gressi o n. After t he 
occ urre nce of d oc u me nte d disease pr o gressi o n, partici pa nts will be f oll o we d a p pr o xi matel y e ver y 1 2 wee ks ( ± 1 4 da ys) u ntil deat h, wit h dra wal of 
c o nse nt, st u d y cl os ure. Disease s h o ul d be e val uate d usi n g t he sa me i ma gi n g m o dalit y as at scree ni n g/ baseli ne. If b o ne i ma gi n g is c ollecte d, a n y 
R E CI S T -a p pr o priate i ma gi n g m o dalit y ma y be use d. 
V.
Disease assess me nt will be re peate d o nl y f or t h ose partici pa nts recei vi n g o xali plati n d uri n g t he scree ni n g peri o d.
W.
O xali plati n plas ma P K sa m ples will be c ollecte d i n C ycles 1 a n d 2 f or C o h orts 1 A a n d 1 B o nl y.
X.
C y cle 2 o nl y.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 7 3 of 2 2 0
Y.
Partici pa nts s h o ul d be e nc o ura ge d t o sta y h y drate d t o fa cilitate uri ne c ollecti o n f or P K a nal ysis. Uri ne sa m ples f or o xali plati n P K are c ollecte d o nl y f or 
p hase 1 b C o h orts 1 A a n d 1 B.
Z.
T ucati ni b P K sa m ples will be c ollecte d fr o m C ycle 2 t o C ycle 6 f or C o h orts 1 A a n d 1 B ( Ta ble 2 3 ), C y cles 1 -6 a n d E O T f or C o h ort 1 D ( T a ble 2 5 ), a n d 
C y cles 2 -6 f or C o h orts 1 C, 1 E, 1 F, 1 G, a n d p hase 2 c o h orts acc or di n g t o Ta ble 2 6 .
A A. Pre d ose o nl y i n C ycle ≥3 t hr o u g h C ycle 6.
B B. O nl y S A Es, A E SIs, a n d pre g na nc y ca pt ure d b y t he S p o ns or.
C C. D uri n g t he L T E P, safet y a n d efficac y assess me nts t hat i ncl u de deter mi nati o n of disease pr o gressi o n will be perf or me d per i nstit uti o nal g ui deli nes a n d 
i n vesti gat or-deter mi ne d us ual a n d c ust o mar y cli nical care.
D D. F oll o w i n g i m ple me ntati o n of A me n d me nt 5, n o P K sa m ples will be c ollecte d at E O T.
E E. F ol l o wi n g i m ple me ntati o n of A me n d me nt 5, n o bl o o d sa m ples f or bi o mar ker assess me nts will be dra wn at E O T.
F F. As of A me n d me nt 5, l o n g ter m f oll o w -u p will be disc o nti n ue d. Partici pa nts disc o nti n ui n g st u d y treat me nt will o nl y be f oll o we d t hr o u g h t he c o ncl usi o n 
of t he safet y re p orti n g peri o d. Partici pa nts i n l o n g ter m f oll o w -u p as of A me n d me nt 5 w ill tra nsiti o n t o e n d of st u d y.
G G. T he ± 1 da y visit wi n d o w is o nl y a p plica ble t o dr u g a d mi nistrati o n a n d pre g na nc y testi n g d uri n g t he L T E P
Sc he d ule of E ve nts: P h ase 1 b a n d P h a se 2 C o h orts Utilizi n g C A P O X a n d Pe m br oliz u m a b C o h ort 1 G
Scree ni n g/
Baseli ne
Treat me nt Peri o d ( 2 1 -da y c ycles)
E O T
F oll o w -
u p W
L T E P
D – 2 8 
t o D– 1
D – 7 t o 
D – 1 A
C y cle 1
C y cle 2
C y cle > 2
E ver y 6
Wee ks
C
E ver y 1 2
Wee ks
C
3 0 da ys 
p ost
last d ose
E ver y 9 
or 1 2 
Wee ks
-
D 1  
D 8 B
D 1  
D 8 B
D 1
Visit wi n d o w  ( da ys)
± 1 
± 1 
± 1 
± 1 
± 7 
± 7
+ 7
± 1 4
± 1 X
Scree ni n g/
Baseli ne
I nf or me d c o nse ntD
X
I ncl usi o n/e xcl usi o n 
criteria
X  
X
Me dical hist or y 
(i ncl u di n g assess me nt of 
diarr hea a n d a nti diarr heal 
usa ge)
X
Hei g ht
X
Ser ol o g y f or he patitis B 
a n d C
X
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 7 4 of 2 2 0
Scree ni n g/
Baseli ne
Treat me nt Peri o d ( 2 1 -da y c ycles)
E O T
F oll o w -
u p W
L T E P
D – 2 8 
t o D– 1
D – 7 t o 
D – 1 A
C y cle 1
C y cle 2
C y cle > 2
E ver y 6
Wee ks
C
E ver y 1 2
Wee ks
C
3 0 da ys 
p ost
last d ose
E ver y 9 
or 1 2 
Wee ks
-
D 1  
D 8 B
D 1  
D 8 B
D 1
T u m or s peci me n 
c ollecti o n if a vaila ble
X
Safet y 
assess me nts
Vital si g ns, i ncl u di n g 
wei g ht E, F
X  
X  
X  
X  
X B
X
X
X U
P h y sical e xa mF
X  
X
X
X
X
X U
E C O G perf or ma nce 
stat usF
X  
X
X
X
X
X U
C o nfir mati o n of last 
bl o o d tra nsf usi o n 
X  
X
X U
C B C wit h differe ntial F
X  
X  
X  
X  
X B
X
X
X U
Ser u m/ plas ma c he mistr y 
pa nel a n d ser u m c ystati n 
C F
X G
X G
X G
X G
X B, G
X G
X G
X U
C oa g ulati o n pa nel F
X
X B
X
X U
Uri nal ysis, wit h 
micr osc o p y if cli nicall y 
i n dicate dF
X  
X
X  
X B
X
X
X U
Uri ne Pr otei n/ Creati ni ne 
( U P C) Rati oF
X  
X
X  
X B
X
X
X U
E C G 
X
X
X U
Ec h ocar di o gra m or 
M U G A sca n
H
X
X  
X
X U
T h yr oi d f u ncti o n test I
X
X
X U
Ser u m/ plas ma or uri ne β -
h C G pre g na nc y test f or 
X J
X
X
X
X K
X K
X J, K
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 7 5 of 2 2 0
Scree ni n g/
Baseli ne
Treat me nt Peri o d ( 2 1 -da y c ycles)
E O T
F oll o w -
u p W
L T E P
D – 2 8 
t o D– 1
D – 7 t o 
D – 1 A
C y cle 1
C y cle 2
C y cle > 2
E ver y 6
Wee ks
C
E ver y 1 2
Wee ks
C
3 0 da ys 
p ost
last d ose
E ver y 9 
or 1 2 
Wee ks
-
D 1  
D 8 B
D 1  
D 8 B
D 1
fe males of c hil d beari n g 
p ote ntial J 
A d verse e ve nts a n d 
c o nc o mita nt me dicati o ns 
(i ncl u di n g diarr hea A Es 
a n d A nti diarr heal Usa ge)
C ollecte d t hr o u g h o ut st u d y re p orti n g peri o d fr o m scree ni n g t o E O T visit L
X T, U
Partici pa nt 
Diar y
Iss ue Partici pa nt Diaries
Iss ue partici pa nt a p pr o priate visit diar y a n d e ns ure site re q uire d fiel ds 
are c o m plete d; Partici pa nt diaries s h o ul d be re vie we d at eac h visit.
St u d y 
Treat me nt
O xali plati n M
X
X
X
X
Ca pecita bi ne M
X
X
X
X
Trast uz u ma b N
X
X
X
X
Pe m br oliz u ma b O
Pe m br oliz u ma b is a d mi nistere d Q 6 W
X
T ucati ni b
BI D fr o m C ycle 1 Da y 1 P
X
Disease 
C T sca n, P E T -C T, a n d/ or 
M RI assess me nts
Q
X  
X R
X
X
X Q
X U
S ur vi val a n d a ntica ncer 
t hera p y
X
P K/ P D
( P har mac o-
ki netics/
P har m ac o -
d y na mics)
Bl o o d sa m ples f or 
t ucati ni b P K ( pre d ose)S
X S
X S
Bl o o d sa m ple f or 
bi o mar ker assa y
X
X V
A.
Baseli ne visit s h o ul d be sc he d ule d t o e ns ure t hat deter mi nati o n of esti mate d G F R ca n occ ur w it hi n 7 da ys of e nr oll me nt.
B.
F or C ycle 1 Da y 8, all c o h orts m ust c o m plete all assess me nts. F or C ycle 2 Da y 8, P hase 1 b c o h orts m ust c o m plete all assess me nts b ut P hase 2 c o h orts 
o nl y nee d t o c o m plete t he assess me nts f or A Es a n d a nti diarr heal usa ge.
C.
Sc he d uli n g deter mi ne d b y C ycle 1 Da y 1 (e nr oll me nt).
D.
All partici pa nts m ust si g n i nf or me d c o nse nt f or t he st u d y bef ore Scree ni n g/ Baseli ne pr oce d ures are c o n d ucte d. 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 7 6 of 2 2 0
E.
Vital si g ns t o be c ollecte d are s yst olic a n d diast olic bl o o d press ure, heart rate, te m perat ure, a n d res pirat or y rate.
F.
Assess me nt t o be d o ne pre d ose o n da ys w he n st u d y treat me nt(s) are a d mi nistere d. Pre d ose la bs ca n be d o ne w it hi n 1 da y pri or t o st u d y visit. C o nfir m 
la b res ults pri or t o a d mi nisteri n g st u d y treat me nt d osi n g. 
G.
Ser u m c ystati n C (after t he P hase 2 d ose has bee n i de ntifie d, if n o re nal D L Ts ha ve bee n o bser ve d d uri n g d ose escalati o n, c ys tati n C will n ot be 
c ollecte d).
H.
Car diac ejecti o n fracti o n assesse d b y tra nst h oracic E C H O will be perf or me d at scree ni n g, e ver y 1 2 w ee ks u ntil treat me nt disc o nti n uati o n irres pecti ve of 
d ose dela ys or i nterr u pti o n, a n d at t he E O T visit. E C H O is t he preferre d m o dalit y f or assess me n t of L V E F. If cli nicall y i n dicate d, M U G A sca n ma y be 
use d i n place of E C H O. T he sa me met h o d f or L V E F assess me nt s h o ul d be e m pl o ye d at eac h assess me nt. A n E C H O or M U G A is n ot re q u ire d at E O T if 
o ne has bee n perf or me d i n t he pre vi o us 1 2 we e ks (e xcl u di n g t he Scree ni n g/ Baseli ne assess me nt). E C H O/ M U G A assess me nts s h o ul d als o be u n derta ke n 
e ver y 6 m o nt hs f or at least 2 years f oll o wi n g trast uz u ma b disc o nti n uati o n.
I.
T h yr oi d f u ncti o n tests Q 6 W i n C o h orts 1 F, 1 G, a n d 2 A.
J.
Partici pa nts of c hil d beari n g p ote ntial o nl y; pre g na nc y test m ust be perf or me d wit hi n 2 4 h o urs pri or t o st u d y treat me nt d osi n g o n Da y 1 of eac h c ycle. 
C o nfir m ne gati ve pre g na nc y test pri or t o c o nti n ui n g st u d y treat me nt d osi n g. 
K.
After t he last d ose of st u d y treat me nt, pre g na nc y tests will be perf or me d o n ce a m o nt h f or 7 m o nt hs. 
L.
S A Es a n d A E SIs will be f oll o we d u ntil res ol uti o n of ac ute e ve nts. Treat me nt -relate d S A Es occ urri n g after t he E O T visit will be f oll o we d u ntil 
res ol uti o n of ac ute e ve nts. C o nc o mita nt me dicati o ns a n d c o nc o mita nt pr oce d ures will be collecte d, i ncl u di n g a nti diarr heal me dicati o n usa ge. Ma n dat or y 
a nti diarr heal pr o p h yla xis will n ot be re q uire d f or partici pa nts e nr olle d i n C o h orts 1 C, 1 F, 1 G, or f or partici pa nts i n C o h ort 2 A w h o are treate d w it h 
t ucati ni b + trast uz u ma b + pe m br oliz u ma b + C AP O X, u nless rec o m me n de d b y t he S M C a n d re q uire d b y t he S p o ns or base d o n a re vie w  of t he data fr o m 
t hese c o h orts. A nti diarr heal pr o p h yla xis, if re q uire d, will be f oll o we d as descri be d i n Secti o n 7. 1 1. 2 .
M.
O xali plati n 1 3 0 m g/ m 2 will be a d mi nistere d I V o ver 1 2 0 mi n ( ± 1 5 mi n utes). Ca pecita bi ne 1 0 0 0 m g/ m 2 will be a d mi nistere d P O BI D be gi n ni n g t he 
e ve ni n g of Da y 1 t o m or ni n g of Da y 1 5 ( C ycle 1) a n d P O BI D Da y 1 -Da y 1 4 f or all s u bse q ue nt c ycles.
N.
Trast uz u ma b Q 3 W.
O.
Pe m br oliz u ma b Q 6 W C o h orts 1 F, 1 G, a n d 2 A f or a ma xi m u m of 1 8 d oses.
P.
T he first d ose of t ucati ni b ( 3 0 0 m g P O BI D or a n i nter me diate d ose as rec o m me n de d b y t he S M C) ma y be a d mi nistere d o n C ycle 1 D a y  1. Partici pa nts 
are t o be i nstr ucte d t o bri n g t heir m or ni n g d ose of t ucati ni b o n Da y 1 of C ycles ≥2 t o e ns ure c orrect ti mi n g of t he P K sa m pli n g f or C o h orts 1 C a n d 1 F 
a n d o n Da y 1 of C ycle 2 -6 f or C o h ort 2 A.
Q.
At mi ni m u m, disease assess me nts, prefera bl y usi n g C T sca ns, m ust i ncl u de t he c hest, a b d o me n, a n d pel vis, as we ll as a p pr o priate i ma gi n g of a n y ot her 
k n o w n sites of disease s uc h as b o ne i ma gi n g. Sca ns s h o ul d be perf or me d at scree ni n g, d uri n g st u d y treat me nt, a n d at t he E O T visit. D uri n g st u d y 
treat me nt, sca ns s h o ul d be perf or me d e ver y 6 wee ks ± 7 da ys ( base d o n C ycle 1 Da y 1) f or t he first 2 4 wee ks t he n e ver y 9 wee ks ± 7 d a y s u ntil t he 
occ urre nce of d oc u me nte d disease pr o gressi o n. If c ycles are dela ye d f or a n y reas o n or t here is a n i nteri m u nsc he d ule d assess m e nt, sca ns s h o ul d c o nti n ue 
t o be perf or me d acc or di n g t o t he ori gi nal sc he d ule Partici pa nts w h o disc o nti n ue st u d y treat me nt f or reas o ns ot her t ha n d oc u me nte d pr o gressi ve disease 
per R E CI S T will c o nti n ue t o ha ve disease assess me nts ( C T, P E T -C T, a n d/ or M RI sca ns) a p pr o xi matel y e ver y 9 wee ks ( ± 1 4 da ys) u ntil ra di o gra p hic 
disease pr o gressi o n. After t he occ urre nce of d oc u me nte d diseas e pr o gressi o n, partici pa nts will be f oll o we d a p pr o xi matel y e ver y 1 2 wee ks ( ± 1 4 da ys) 
u ntil deat h, wit h dra wal of c o nse nt, st u d y cl os ure. Disease s h o ul d be e val uate d usi n g t he sa me i ma gi n g m o dalit y as at scree ni n g/ baseli ne. If b o ne 
i ma gi n g is c ollecte d, a n y R E CI S T -a p pr o priate i ma gi n g m o dalit y ma y be use d.
R.
Disease assess me nt will be re peate d o nl y f or t h ose partici pa nts recei vi n g o xali plati n d uri n g t he scree ni n g peri o d.
S.
T ucati ni b pre d ose P K sa m ples w ill be c ollecte d fr o m C ycle 2 t o C ycle 6 f or C o h orts 1 C, 1 E, 1 F, 1 G, a n d 2 A acc or di n g t o Ta ble 2 6 .
T.
O nl y S A Es, A E SIs, a n d pre g na nc y ca pt ure d b y t he S p o ns or.
U.
D uri n g t he L T E P, safet y a n d efficac y assess me nts t hat i ncl u de deter mi nati o n of disease pr o gressi o n will be perf or me d per i nstit uti o nal g ui deli nes a n d 
i n vesti gat or-deter mi ne d us ual a n d c ust o mar y cli nical care.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de nti al
Pa ge 1 7 7 of 2 2 0
V.
F oll o w i n g i m ple me ntati o n of A me n d me nt 5, n o bl o o d sa m ples f or bi o mar ker assess me nts will be dra wn at E O T.
W.
As of A me n d me nt 5, l o n g ter m f oll o w -u p will be disc o nti n ue d. Partici pa nts disc o nti n ui n g st u d y treat me nt will o nl y be f oll o we d t hr o u g h t he c o ncl usi o n 
of t he safet y re p orti n g peri o d. Partici pa nts i n l o n g ter m f oll o w -u p as of A me n d me nt 5 w ill tra nsiti o n t o e n d of st u d y.
X.
T he ± 1 da y visit wi n d o w is o nl y a p plica ble t o dr u g a d mi nistrati o n a n d pre g na nc y testi n g d uri n g t he L T E P
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 /S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 7 8 of 2 2 0
A p pe n di x B. Perf or m a nce St at us Sc ales C o n versi o n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)
C O P Y RI G H T E D M A T E RI A L

C 4 2 5 1 0 0 5 /S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 7 9 of 2 2 0
A p pe n di x C.
G ui d a nce O n C o ntr ace pti o n
F or t he p ur p oses of t his g ui da nce, c o m plete a bsti ne nce, if c o nsiste nt wit h t he partici pa nt’s 
preferre d lifest y le, is a n acce pta ble f or m of c o ntrace pti o n. C o m plete a bsti ne nce is defi ne d as 
a bsti ne nce starti n g fr o m t he ti me of i nf or me d c o nse nt a n d c o nti n ui n g t hr o u g h o ut t he st u d y 
a n d u ntil t he e n d of s ys te mic e x p os ure (at least 7 m o nt hs after t he fi nal d ose of st u d y 
treat me nt; see Secti o n 6. 1 ). 
Acce pt a bl e met h o ds f or hi g hl y effecti ve birt h c o ntr ol ( pre ve nti n g c o nce pti o n)
P artici p a nts w h o are of c hil d be ari n g p ote nti al a or w h ose p art ners are of c hil d be ari n g p ote nti al a a n d 
w h o are se x u all y acti ve i n a w a y t h at c o ul d le a d t o pre g n a nc y m a y c h o ose a n y T W O of t h e f oll o wi n g 
met h o ds:

H or m o nal met h o ds of c o ntrace pti o n (e xcl u di n g pr o gesti n -o nl y  pills; met h o d m ust be ass ociate d 
wit h i n hi biti o n of o v ulati o n), u nless c o ntrai n dicate d

I ntra uteri ne de vice wit h fail ure rate < 1 %

T u bal li gati o n

Vasect o m y (at least 9 0 da ys fr o m t he date of s ur ger y wit h a se me n a nal ysis d oc u me nti n g 
az o os per mia)

Barrier met h o d/s ( male or fe male c o n d o m wit h or wit h o ut s per mici de, cer vical ca p wit h or 
wit h o ut s per mici de, dia p hra g m wit h or w it h o ut s per mici de)
a A pers o n of c hil d beari n g p ote ntial is defi ne d as a n y o ne b or n fe male w h o has e x perie nce d me narc he a n d 
w h o has n ot u n der g o ne s ur gical sterilizati o n (e g, h ysterect o m y, bilateral sal pi n gect o m y, bilateral 
o o p h orect o m y) or has n ot c o m plete d me n o pa use. Me n o pa use i s defi ne d cli nicall y as 1 2 m o nt hs of 
a me n orr hea i n a pers o n b or n fe male o ver a ge 4 5 i n t he a bse nce of ot her bi ol o gical, p h ysi ol o gical, or 
p har mac ol o gical ca uses.
Acce pt a ble met h o ds f or pre ve nti n g sec o n d ar y e x p os ure t o se mi n al fl ui d
P artici p a nts b or n m ale a n d w h o are se x u all y acti ve wit h a pre g n a nt or bre astfee di n g pers o n, m ust use 
t he c o ntr ace pti ves i n O pti o n 1 or 2:

O pti o n 1: Male c o n d o m ( w it h or wit h o ut s per mici de) a n d cer vical ca p 

O pti o n 2: Male c o n d o m ( w it h or wit h o ut s per mici de) a n d dia p hra g m 
U n a cce pt a ble met h o ds of c o ntr ace pti o n

Peri o dic a bsti ne nce

N o m et h o d

Wit h dra w al

R h yt h m

S per m ici de o nl y

Pr o gesti n -o nl y pills

C o nc o mita nt use of fe male a n d male c o n d o ms
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 /S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 0 of 2 2 0
A p pe n di x D.
C Y P 3 A I n d ucers a n d T heir Eli mi n ati o n H alf- li ves
C Y P 3 A 4 i n d ucers i ncl u de b ut are n ot li mite d t o t he f oll o wi n g. T here c o ul d als o be a d diti o nal 
ne w dr u gs a n d mar kete d dr u gs t hat c o ul d be i de ntifie d as i n hi bit ors/i n d ucers wit h c o nti n ue d 
researc h.
Dr u g a, b
Eli mi nati o n Half -life c
( h o urs)
Str o n g I n d ucers
Bar bit urates
Varia ble
Car ba maze pi ne
2 5 – 6 5 h o urs (si n gle d ose), 1 2 – 1 7 h o urs (re peat d ose)
P he n yt oi n
7 – 4 2 h o urs
Rifa m pi n
3 – 4 h o urs (si n gle d ose), 2 – 3 h o urs (re peat d ose)
St. J o h n’s W ort
9 – 4 3 h o urs d
N ote: A n y a d diti o nal C Y P 3 A 4 i n d ucers t hat are i de ntifie d or bec o me c o m merciall y a vaila ble w hile t he 
cli nical trial is o n g oi n g are als o pr o hi bite d.
a F D A. “ Dr u g De vel o p me nt a n d Dr u g I nteracti o ns: Ta ble of S u bstrates, I n hi bit ors a n d I n d ucers” 
(htt p:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti o ns La beli
n g/ uc m 0 9 3 6 6 4. ht m # p ote nc y )
b E M A . “ G ui deli ne o n t he i n vesti gati o n of dr u g i nteracti o ns” 
(htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n _ G B/ d oc u me nt _li brar y/ Scie ntific _ g ui deli ne/ 2 0 1 2/ 0 7/ W C 5 0 0 1 2 9 6 0 6. p d
f)
c Dr u g pr o d uct la beli n g
d (Ker b 1 9 9 6 )
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 /S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 1 of 2 2 0
A p pe n di x E.
C Y P 2 C 8 i n hi bit ors/i n d ucers a n d T heir eli mi n ati o n H alf -li ves
C Y P 2 C 8 i n hi bit ors a n d i n d ucers i ncl u de b ut are n ot li mite d t o t he f oll o wi n g. T here c o ul d 
als o be a d diti o nal ne w dr u gs a n d mar kete d dr u gs t hat c o ul d be i de ntifie d as 
i n hi bit ors/i n d ucers wit h c o nti n ue d researc h.
Dr u g a, b
Eli mi nati o n Half -lifec
Str o n g i n hi bit ors
Ge mfi br ozil
1 – 2 h o urs
M o der ate i n hi bit ors
Cl o pi d o grel
6 h o urs
Deferasir o x
8- 1 6 h o urs
Terifl u n o mi de
1 8 -1 9 da ys
M o der ate i n d ucer
Rifa m pi n
3 – 5 h o urs
N ote: A n y a d diti o nal C Y P 2 C 8 i n hi bit ors/i n d ucers t hat are i de ntifie d or bec o me c o m merciall y a vaila ble 
w hile t he cli nical trial is o n g oi n g are als o pr o hi bite d.
a F D A. “ Dr u g De vel o p me nt a n d Dr u g I nteracti o ns: Ta ble of S u bstrates, I n hi bit ors a n d I n d ucers” 
(htt p:// w w w.f da. g o v/ Dr u gs/ De vel o p m e nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti o ns La beli
n g/ uc m 0 9 3 6 6 4. ht m # p ote nc y )
b E M A. “ G ui deli ne o n t he i n vesti gati o n of dr u g i nteracti o ns” 
(htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n _ G B/ d oc u me nt _li brar y/ Scie ntific _ g ui deli ne/ 2 0 1 2/ 0 7/ W C 5 0 0 1 2 9 6 0 6. p d
f) 
c Dr u g pr o d uct la beli n g
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 /S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 2 of 2 2 0
A p pe n di x F.
E x a m ples of Cli nic al S u bstr ates f or C Y P 3 A -me di ate d Met a b olis m
Se nsiti ve
( A U C i ncrease ≥5 -f ol d wit h str o n g i n de x i n hi bit or)
M o derate Se nsiti ve
( A U C i ncrease 2- t o 5-f ol d wit h str o n g i n de x 
i n hi bit or)
alfe nta nil, a va nafil, b us pir o ne, c o ni va pta n, darife naci n, 
dar u na vir c, e basti ne, e ver oli m us, i br uti ni b, l o mita pi de, 
l o vastati nd, mi daz ola m, nal o xe g ol, nis ol di pi ne, sa q ui na virc, 
si m vastati nd, sir oli m us, tacr oli m us, ti pra na virc, triaz ola m, 
var de nafil
al praz ola m, a pre pita nt, at or vastati n a, 
c olc hici ne, eli gl ustat b, pi mozi de, ril pi viri ne, 
ri var o xa ba n, ta dalafil
b u des o ni de, dasati ni b, dr o ne dar o ne, eletri pta n, e plere n o ne, 
fel o di pi ne, i n di na virc, l urasi d o ne, mara vir oc, q uetia pi ne, 
sil de nafil, tica grel or, t ol va pta n
N ote: Se nsiti ve s u bstrates are dr u gs t hat de m o nstrate a n i ncrease i n A U C of ≥5 -f ol d wit h str o n g i n de x 
i n hi bit ors of a gi ve n meta b olic pat h wa y i n cli nical D DI st u dies. M o derate se nsiti ve s u bstrates are dr u gs t hat 
de m o nstrate a n i ncrease i n A U C of ≥2 - t o <5- f ol d wit h str o n g i n de x i n hi bit ors of a gi ve n meta b olic pat h wa y 
i n cli nical D DI st u dies. Se nsiti ve s u bstrates of C Y P 3 A wit h ≥1 0 -f ol d i ncrease i n A U C b y c o-a d mi nistrati o n 
of str o n g i n de x i n hi bit ors are s h o w n a b o ve t he das he d li ne. Ot her eli mi nati o n pat h wa y s ma y als o c o ntri b ute 
t o t he eli mi nati o n of t he s u bstrates liste d i n t he ta ble a b o ve a n d s h o ul d be c o nsi dere d whe n assessi n g t he 
dr u g i nteracti o n p ote ntial.
T his ta ble is pre pare d t o pr o vi de e xa m ples of cli nical s u bstrates a n d n ot i nte n de d t o be a n e x ha usti ve list. 
D DI data w ere c ollecte d base d o n a searc h of t he U ni versit y of Was hi n gt o n Meta b olis m a n d Tra ns p ort Dr u g 
I nteracti o n Data base (Hac ha d 2 0 1 0 ).
a Liste d base d o n p har mac o ge netic st u dies.
b Se nsiti ve s u bstrate of C Y P 2 D 6 a n d m o derate se nsiti ve s u bstrate of C Y P 3 A.
c Us uall y a d mi nistere d t o patie nts i n c o m bi nati o n wit h rit o na vir, a str o n g C Y P 3 A i n hi bit or.
d Aci d f or m is a n O A T P 1 B 1 s u bstrate.
S o urce: 
htt ps:// w w w.f da. g o v/ Dr u gs/ De vel o p me nt A p pr o val Pr ocess/ De vel o p me nt Res o urces/ Dr u gI nteracti o n s La beli
n g/ uc m 0 9 3 6 6 4. ht m #ta ble 3 - 1
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 /S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 3 of 2 2 0
A p pe n di x G. Pr oce d ures f or Rec or di n g a n d Re p orti n g A E s a n d S A Es
A E a n d S A E Rec or di n g/ Re p orti n g
T he ta ble bel o w s u m marizes t he re q uire me nts f or re p orti n g S A Es via P S S A t o Pfizer Safet y  
t hr o u g h o ut t he safety re p orti n g peri o d. T hese re q uire me nts are deli neate d f or e x p os ure t o t he 
st u d y i nter ve nti o n u n der st u d y d uri n g pre g na nc y or breastfee di n g, a n d occ u pati o nal 
e x p os ure.
T a ble 2 7 .
Re p orti n g S A Es vi a P S S A
S afet y E ve nt
Re p orte d vi a P S S A t o Pfizer S afet y Wit hi n 2 4 
H o urs of A w are ness
S A E
All
N o nseri o us A E
N o ne
E x p os ure t o t he st u d y  i nter ve nti o n 
u n der st u d y  d uri n g pre g na nc y or 
breastfee di n g 
All i nsta nces of E D P are re p orte d ( w het her or 
n ot t here is a n ass ociate d S A E) *
All i nsta nces of E D B are re p orte d ( w het her or 
n ot t here is a n ass ociate d S A E) * *
E n vir o n me ntal or occ u pati o nal 
e x p os ure t o t he pr o d uct u n der st u d y t o 
a n o n- partici pa nt ( n ot i n v ol vi n g E D P or 
E D B)
T he e x p os ure ( w het her or n ot t here is a n 
ass ociate d A E or S A E) m ust be re p orte d * * *
* E D P ( wit h or wit h o ut a n ass ociate d S A E) is re p orte d t o Pfizer Safet y via P S S A. 
* * E D B is re p orte d t o Pfizer Safet y via P S S A, w hic h wo ul d als o i ncl u de details of a n y S A E t hat mi g ht be 
ass ociate d wit h t he E D B. 
* * * E n vir o n me nt al or occ u p ati o n al e x p os ure: A E s or S A Es ass ociate d wit h occ u pati o nal e x p os ure are 
re p orte d t o Pfizer Safet y via P S S A.

It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he partici pa nt’s me dical 
rec or ds t o Pfizer Safet y i n lie u of c o m pleti o n of t he Re p ort F or m.

T here ma y  be i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d b y 
Pfizer Safet y . In t his case, all partici pa nt i de ntifiers, wit h t he e xce pti o n of t he partici pa nt 
n u m ber, will be re dacte d o n t he c o pies of t he me dical rec or ds bef ore s u b missi o n t o Pfizer 
Safet y . 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 /S G N T U C -0 2 4
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 4 of 2 2 0
S A E Re p orti n g t o Pfizer S afet y Vi a Electr o nic D at a C ollecti o n T o ol ( D C T)
S A E Re p orti n g t o Pfizer S afet y vi a a n electr o nic D C T

T he pri mar y  mec ha nis m f or re p orti n g a n S A E t o Pfizer Safet y will be t he electr o nic D C T 
( P S S A).

If t he electr o nic s ys te m is u na vaila ble, t he n t he site will use t he pa per S A E re p ort f or m 
(see ne xt secti o n) t o re p ort t he e ve nt wit hi n 2 4 h o urs.

T he site will e nter t he S A E data i nt o t he electr o nic D C T ( P S S A) or pa per f or m (as 
a p plica ble) as s o o n as t he data bec o me a vaila ble.

After t he st u d y is c o m plete d at a gi ve n site, t he electr o nic D C T 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.

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 D C T 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 (see ne xt secti o n) or t o Pfizer Safet y 
b y  tele p h o ne.
S A E Re p orti n g t o Pfizer S afet y vi a t he C T S A E Re p ort F or m

Facs i mile tra ns missi o n of t he C T S A E Re p ort F or m is t he bac k u p met h o d t o tra ns mit t his 
i nf or mati o n t o Pfizer Safet y i n case P S S A is u na vaila ble f or m ore t ha n 2 4 h o urs.

I n circ u msta nces w he n t he facsi mile is n ot w or ki n g, a n alter nati ve met h o d s h o ul d be 
use d, e g , sec ure d ( Tra ns p ort La yer Sec urit y) or pass w or d -pr otecte d e mail. If n o ne of 
t hese met h o ds ca n be use d, n otificati o n b y tele p h o ne is acce pta ble wit h a c o p y of t he C T 
S A E Re p ort F or m se nt b y  o ver ni g ht mail or c o urier ser vice.

I nitial n otificati o n via tele p ho 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 C T S A E Re p ort F or m pa ges wit hi n t he desi g nate d re p orti n g ti me 
fra mes.
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C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 5 of 2 2 0
A p pe n di x H. S u m m ar y of C h a n ges f or Pri or Gl o b al A me n d me nts
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis
Re m o ve “as a p plica ble” fr o m esti mate d G F R i ncl usi o n criteri o n 
T here is n ot a sit uati o n w here it w ill n ot be 
a p plica ble.
S y n o psis
Li n ks t o a p pe n dices wit hi n t he b o d y of t he pr ot oc ol w ere 
r e mo ve d.
A d mi nistrati ve c ha n ge (i nter nal li n ks t o 
a p pe n dices or e xter nal li n ks t o ot her d oc u me nts 
s h o ul d n ot be i ncl u de d i n t he s y n o psis).
Secti o n 4. 1
Re m o ve “as a p plica ble” fr o m esti mate d G F R i ncl usi o n criteri o n 
T here is n ot a sit uati o n w here it w ill n ot be 
a p plica ble.
Secti o n 5. 4. 2
A d de d te xt t o i n dicate t hat F D A a p pr o ve d bi osi milars of 
trast uz u ma b are all o we d.
Clarificati o n
Secti o n 5. 5. 3
Re m o ve d “ Herce pti n” si nce trast uz u ma b bi osi milars will be 
all o we d
U p date
Secti o n 5. 5. 1
Te xt w as a d de d t o Ta ble 3: 
After He pat ot o xicit y hea di n g a d de d “(re gar dless of relati o ns hi p t o 
t ucati ni b)"; after Diarr hea hea di n g a d de d "relate d t o t ucati ni b (as 
assesse d b y t he i n vesti gat or)"
I n t he “ Ot her a d verse reacti o ns t hat are relate d t o t ucati ni b” 
u p date t ucati ni b d ose m o dificati o n te xt t o i n dicate f or Gra de 3 
A E s h ol d t ucati ni b u ntil rec o ver y t o ≤ Gra de 1 or pretreat me nt 
le vel.
T his ta ble has bee n u p date d t o be c o nsiste nt wit h 
all t ucati ni b cli nical trials i n gastr oi ntesti nal 
i n dicati o ns. D ose m o dificati o ns d ue t o 
he pat ot o xicit y are i nte n de d t o be re gar dless of 
ca usalit y, a n d t his was n ot s pecifie d i n t he trial. 
D ose m o dificati o ns f or ot her a d verse e ve nts are 
o nl y re q uire d if t he e ve nt is assesse d as bei n g 
relate d t o t ucati ni b. T his is n o w clearl y state d i n 
t he ta ble. 
Ot her a d verse reacti o n d ose m o dificati o n te xt was 
clarifie d beca use s u bjects wit h Gra de 2 a ne mia 
a n d Gra de 1 or h i g her cli nicall y i nsi g nifica nt 
electr ol yte a b n or malities are all o we d t o e nr oll s o 
rec o ver y t o pretreat me nt le vel w o ul d be 
acce pta ble i n t hese cases.
Secti o n 5. 5. 4
A d de d te xt a b o ut I R Rs relate d t o st u d y treat me nt.
Clarificati o n
Secti o n 5. 7. 3
A d de d te xt t o clarif y C Y P 3 A s u bstrates s h o ul d be a v oi de d 1 w ee k 
pri or t o t he first d ose of t ucati ni b a n d w hile o n st u d y treat me nt.
Clarificati o n
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C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 6 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 6. 5
Te xt a d de d t o i n dicate patie nts disc o nti n ui n g st u d y f or reas o ns 
ot her t ha n d oc u me nte d pr o gressi ve disease s h o ul d c o nti n ue sca ns 
u ntil disease pr o gressi o n, deat h, wit h dra w al of c o nse nt, or st u d y 
cl os ure
Clarificati o n
Secti o n 7. 2
A d de d “c o nfir me d” t o “ … o bjecti ve res p o nse assess me nts” t o be 
c o nsiste nt wit h 9. 2. 1
Clarificati o n
Secti o n 7. 5. 3
Re m o ve “as a p plica ble” fr o m esti mate d G F R b ullet
F or c o nsiste nc y wit h esti mate d G F R i ncl usi o n 
criteri o n u p date
Secti o n 7. 5. 3. 1
U p date d Fi g ure 3
Clarificati o n
A p pe n di x A
F o ot n ote F te xt was re place d wit h t he f oll o wi n g te xt (s h o w n i n 
u n derli ne): 
Car diac ejecti o n fracti o n asses se d b y tra nst h oracic E C H O will be 
perf or me d at scree ni n g, e ver y 1 2 wee ks u ntil treat me nt 
disc o nti n uati o n irres pecti ve of d ose dela ys or i nterr u pti o n, a n d at 
t he E O T visit. E C H O is t he preferre d m o dalit y f or assess me nt of 
L V E F. If cli nicall y i n dicate d, M U G A sca n ma y be use d i n place 
of E C H O. T he sa me met h o d f or L V E F assess me nt s h o ul d be 
e mpl o y e d at eac h assess me nt. A n E C H O or M U G A is n ot 
re q uire d at E O T if o ne has bee n perf or me d i n t he pre vi o us 1 2 
wee ks (e xcl u di n g t he Scree ni n g/ Baseli ne assess me nt). 
T he f oll o wi n g te xt (s h o w n i n stri ket hr o u g h) was re m o ve d fr o m 
F o ot n ote F:   Ec h ocar di o gra m or M U G A -sca n will be assesse d 
d uri n g treat me nt a n d at E O T o nl y. Sc he d uli n g is deter mi ne d b y 
date of m ost rece nt scree ni n g or o n -treat me nt 
ec h ocar di o gra m/ M U G A. N ot re q uire d at E O T visit if a n 
ec h ocar di o gra m or M U G A sca n was d o ne wit hi n t he pre vi o us 
1 2 we e ks (e xcl u di n g t he Scree ni n g/ Baseli ne assess me nt) .
Clarificati o n
A p pe n di x A
T he r o w  f or C T sca n, P E T-C T, a n d/ or M RI assess me nt was 
u p date d w it h a n X i n t he F oll o w-u p c ol u m n.
I ma gi n g f or patie nts w h o c o me off trial d ue t o 
n o n- ra di o gra p hic pr o gressi ve disease will be 
re q uire d t o c o nti n ue sca n ni n g u ntil pr o gressi ve 
disease. T his is a d dresse d i n t he c urre nt f o ot n ote 
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C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 7 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
K b ut was missi n g fr o m t he Sc he d ule of E ve nts 
ta ble.
T hr o u g h o u t pr ot oc ol
Mi n or c orrecti o ns, u p dates, f or matti n g, a n d c ha n ges
A d mi nistrati ve c ha n ges
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 8 of 2 2 0
S u m m ar y of C h a n ges i n A me n d me nt 2
Secti o n(s)
C ha n ge
Rati o nale
C o ver pa ge
U p date d na me a n d c o ntact i nf or mati o n f or me dical m o nit or 
U p date d title t o i n dicate st u d y will i ncl u de e x pa nsi o n c o h orts
Pr o vi de u p date d me dical c o ntact i nf or mati o n
S y n o psis, St u d y O bjecti ves
U p date d st u d y o bjecti ves t o i ncl u de ta b ular s u m mar y of P hase 1 b 
T ucati ni b D ose Escalati o n wit h O xali plati n -base d C he m ot hera p y 
o bjecti ves a n d e n d p oi nts
A d de d ta b ular s u m mar y f or t he a d de d P hase 2 T u m or S pecific 
E x pa nsi o n o bjecti ves a n d e n d p oi nts
C o nsiste nc y wit h st u d y desi g n c ha n ges
S y n o psis, I ncl usi o n criteri o n (I C) 2
Secti o n 4. 1, I C 2
A d de d te xt a b o ut per mitte d o xali plati n d oses pri or t o C ycle 1 Da y 
1 i n t he p hase 1 b p orti o n of t he st u d y f or C o h orts 1 A, 1 B, a n d 1 C 
a n d f or p hase 2 C o h ort 2 B
I ncl usi o n criteri o n u p date
S y n o psis, I C 3
Secti o n 4. 1, I C 3
F or C R C, c h ola n gi ocarci n o ma, a n d gall bla d der carci n o ma a d de d 
te xt I nter nati o nal Or ga nizati o n f or Sta n dar dizati o n te xt
F or Gastric, G EJ, a n d es o p ha geal a de n ocarci n o mas a d de d te xt 
a b o ut C o nf or mité E ur o pée n ne ( C E) -mar ke d H E R 2 I H C tests
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
S y n o psis, I C 4 
Secti o n 4. 1, I C 4
A d de d clarif yi n g te xt a b o ut re q uire me nt f or meas ura ble or 
n o n- meas ura ble disease f or t he vari o us c o h orts i n p hase 1 b a n d 
p hase 2 c o h orts
C o h ort s pecific clarificati o ns 
S y n o psis, I C 1 0
Secti o n 4. 1, I C 1 0
A d de d clarif yi n g te xt a b o ut esti mate d gl o mer ular filtrati o n rate 
f or p hase 1 b C o h ort 1 A a n d p hase 2 c o h orts
C o h ort s pecific clarificati o ns
S y n o psis, I C 1 1
Secti o n 4. 1, I C 1 1
A d de d n ote a b o ut pr o hi biti o ns of w arfari n a n d ot her c o u mari n 
deri vati ves f or s u bjects recei vi n g C A P O X
Safet y relate d clarificati o n
S y n o psis, I C 1 5
Secti o n 4. 1, I C 1 5
A dj uste d te xt a b o ut si g ne d i nf or me d c o nse nt t o i n dicate a p pr o val 
b y I R B/I E C 
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 8 9 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis, I C 1 7
Secti o n 4. 1, I C 1 7
A d de d ne w I C a b o ut stere otactic ra di os ur ger y a n d w h ole brai n 
ra diati o n t hera p y
Ra diati o n relate d i ncl usi o n criteri o n
S y n o psis, I C 1 8
Secti o n 4. 1, I C 1 8
A d de d ne w I C a b o ut R A S m utati o n stat us f or s u bjects i n t he 
p hase 2 1 L + C R C t u m or s pecific e x pa nsi o n c o h ort 
C o h ort s pecific clarificati o n
S y n o psis, E xcl usi o n Criteri o n ( E C) 
1
Secti o n 4. 2, E C 1
C ha n ge d “fl u or o u racil” t o br oa der ter m “fl u or o p yri mi di nes” a n d 
a d de d “ k n o w n h y perse nsiti vit y” i n place of “aller gic reacti o ns”
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
S y n o psis, E C 2
Secti o n 4. 2, E C 2
A dj uste d te xt a b o ut per missi ble o xali plati n treat me nts t o refer 
bac k t o details i n I C 2
Si m plificati o n of e xisti n g E C te xt a n d c o nsiste nc y 
wit h I C 2
S y n o psis, E C 3
Secti o n 4. 2, E C 3
A dj uste d te xt a b o ut s ur geries fr o m “ … < 2 8 da ys pri or t o 
e nr oll me nt” t o “ …. < 2 8 da ys pri or t o C ycle 1, Da y 1 
Clarificati o n of ti mi n g
S y n o psis, E C 4
Secti o n 4. 2, E C 4
A d de d te xt a b o ut C N S lesi o n stat us 
C o nsiste nc y wit h st u d y desi g n u p dates a n d ot her 
t ucati ni b pr ot oc ols
S y n o psis, E C 5
Secti o n 4. 2, E C 5
A d de d he m o gl o bi n ≥8 g/ d L as a n e xce pti o n
C o nsiste nc y wit h ot her pr ot oc ol secti o ns
S y n o psis, E C 1 1
Secti o n 4. 2, E C 1 1
U p date d te xt a b o ut e xcl usi o n of s u bjects wit h h u ma n 
i m m u n o deficie nc y vir us ( HI V)
C o nsiste nc y wit h c urre nt HI V g ui da nces a n d ot her 
t ucati ni b pr ot oc ols
S y n o psis, E C 1 7
Secti o n 4. 2, E C 1 7
A d de d E C as f oll o ws:  
Re q uire t hera p y wit h war fari n or ot her c o u mari n deri vati ves if 
recei vi n g C A P O X as part of t his st u d y ( n o n-c o u mari n 
a ntic oa g ula nts are all o we d)
N e w  E C a d diti o n f or c o h orts utilizi n g C A P O X 
a n d f or c o nsiste nc y wit h ca pecita bi ne la bel 
rec o m me n dati o ns
S y n o psis, E C 1 8
Secti o n 4. 2, E C 1 8
A d de d E C as f oll o ws: 
C urre ntl y partici pati n g i n a n ot her i nter ve nti o nal trial
N e w  E C a d diti o n 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 0 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis, E C 1 9
Secti o n 4. 2, E C 1 9
A d de d E C as f oll o ws:
S u bjects e nr olle d i n C o h ort 2 A ( 1 L gastric, es o p ha geal, a n d G EJ 
a de n ocarci n o ma) ca n n ot ha ve ha d pre vi o us c he m ot hera p y f or 
metastatic/ u nresecta ble disease; a dj u va nt or ne o -a dj u va nt 
c he m ot hera p y or bi ol o gic t hera p y is per mitte d if m ore t ha n 1 2 
m o nt hs ha ve el a pse d bet wee n t he e n d of t hera p y a n d first 
rec urre nce 
N e w  E C a d diti o n 
S y n o psis, E C 2 0 
Secti o n 4. 2, E C 2 0
A d de d E C as f oll o ws:
S u bjects e nr olle d i n C o h orts 2 A a n d 2 B e x pa nsi o n c o h orts ca n n ot 
ha ve recei ve d pri or a nti -H E R 2 t hera pies
N e w  E C a d diti o n f or e xpa nsi o n c o h orts s pecif yi n g 
n o pri or a nti -H E R 2 t hera pies
S y n o psis, N u m ber of Pla n ne d 
S u bjects
A dj uste d a p pr o xi mate n u m ber of s u bjects pla n ne d t o be e nr olle d 
fr o m “ 1 5 t o 3 0” t o “ 6 5”
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts
S y n o psis , St u d y Desi g n
Secti o ns 3. 1, 3. 1. 1, a n d 3. 1. 2
U p date d lea d -i n te xt sli g htl y t o reflect st u d y desi g n c ha n ges
A d de d ta b ular s u m mar y of t he c o h orts, treat me nts, p o p ulati o ns, 
a n d n u m ber of s u bjects 
A dj uste d te xt t o i ncl u de secti o ns f or p hase 1 b C o h orts 1 A, 1 B, 
a n d 1 C i n t he st u d y
A d de d secti o n a b o ut ne w p hase 2 e x pa nsi o n p orti o n of t he st u d y
A d de d st u d y desi g n gra p hic wit h re vise d st u d y desi g n
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts
S y n o psis, I n vesti gati o nal Pr o d uct, 
D ose, a n d M o de of A d mi nistrati o n 
( All C o h orts)
A dj uste d te xt t o reflect c ha n ges a n d u p dates nee de d t o be 
c o nsiste nt wit h re vise d st u d y desi g n
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts
S y n o psis, Efficac y Assess me nts
A dj uste d te xt a b o ut i ma ge c ollecti o n f or f ut ure a nal ysis
A dj uste d te xt a b o ut disease assess me nt
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts
S y n o psis, Bi o mar ker Assess me nts
Mi n or u p dates t o bi o mar ker te xt
Clarificati o ns
S y n o psis, Statistical Met h o ds
A dj uste d te xt t hr o u g h o ut t his secti o n t o be c o nsiste nt wit h re vise d 
st u d y desi g n
A d de d sa m ple size/c O R R esti mates f or t he t u m or s pecific 
e x pa nsi o n c o h orts
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 1 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 1. 3
A d de d rati o nale f or i ncl u di n g C A P O X i n t his st u d y
U p date d te xt t o be c o nsiste nt wit h ne w st u d y desi g n
U p date d te xt t o i n dicate b ot h F O L F O X a n d C A P O X will be use d
A d de d te xt a b o ut p hase 2 p orti o n of t he st u d y
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of i nf or mati o n a b o ut ne w c o h orts
Secti o n 2
A dj uste d te xt t o reflect p hase 1 b/ 2 desi g n a n d a d diti o n of C A P O X 
U p date d Ta ble 1 ( o bjecti ves a n d c orres p o n di n g e n d p oi nts) t o be 
c o nsiste nt wit h re vise d st u d y desi g n a n d re vise d st u d y o bjecti ves 
f or p hase 1 b
A d de d Ta ble 2 ( o bjecti ves a n d c o rres p o n di n g e n d p oi nts) p hase 2 
t u m or s pecific e x pa nsi o n o bjecti ves a n d c orres p o n di n g e n d p oi nts
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts
Secti o n 3. 1
U p date d te xt t o be c o nsiste nt wit h st u d y desi g n re visi o ns
A d de d ta b ular s u m mar y of t he c o h orts, treat me nts, p o p ulati o ns, 
a n d n u m ber of s u bjects 
C o nsiste nc y wit h st u d y desi g n u p dates
Secti o n 3. 1. 1
( T his i ncl u des t he s u bsecti o ns 
3. 1. 1. 1 t hr o u g h 3. 1. 1. 4)
U p date d te xt t o i ncl u de secti o ns f or eac h of t he p hase 1 b c o h orts
A dj uste d d ose -escalati o n pr ocess la n g ua ge t o be c o nsiste nt wit h 
re vise d st u d y desi g n
A dj uste d t o xicit y te xt t o reflect re visi o ns t o st u d y desi g n 
C o nsiste nc y wit h st u d y desi g n u p dates
Secti o n 3. 1. 2
A d de d te xt a b o ut t he p hase 2 c o h orts
A d de d re vise d st u d y desi g n gra p hic ( Fi g ure 1)
C o nsiste nc y wit h st u d y desi g n u p dates
Secti o n 3. 1. 3
A dj uste d re nal d ose -li miti n g t o xicit y la n g ua ge t o be c o nsiste nt 
wit h re vise d st u d y desi g n
C o nsiste nc y wit h st u d y desi g n u p dates
Secti o n 3. 1. 4
A dj uste d te xt i n safet y m o nit ori n g c o m mittee secti o n t o be 
c o nsiste nt wit h re vise d st u d y desi g n.
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts
Secti o n 3. 1. 5
A d de d E n d of St u d y secti o n
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
Secti o n 3. 2
A dj uste d te xt i n Di sc ussi o n a n d Rati o nale f or St u d y Desi g n t o be 
c o nsiste nt wit h re vise d st u d y desi g n
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts
Secti o n 3. 2. 1
U p date d te xt t o reflect c ha n ges i n st u d y desi g n
C o nsiste nc y wit h st u d y desi g n u p dates
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 2 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 3. 2. 2
A dj uste d Rati o nale f or Selecti o n of D oses secti o n t o i ncl u de 
i nf or mati o n a b o ut C A P O X
Ot her mi n or te xt a dj ust me nts base d o n st u d y desi g n u p dates
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts.
Secti o n 4. 4. 1
A d de d n o n- c o mplia nce wit h st u d y re q uire me nts as a reas o n f or 
p ossi ble disc o nti n uati o n of st u d y treat me nt
St u d y s pecific clarificati o n
Secti o n 5. 1. 1 
A dj uste d te xt t o reflect re visi o ns t o st u d y desi g n
A d de d ta ble f or m F O L F O X 6 re gi me n
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts.
Secti o n 5. 1. 2
A d de d te xt a n d ta ble a b o ut treat me nt wit h t ucati ni b, trast uz u ma b, 
a n d C A P O X 
C o nsiste nc y wit h st u d y desi g n u p dates a n d 
a d diti o n of ne w c o h orts.
Secti o n 5. 3. 1
A d de d te xt a b o ut use of m F O L F O X 6 or m F O L F O X 7 re gi me ns
Clarificati o n a b o ut use of F O L F O X re gi me ns
Secti o n 5. 3. 3 
A d de d te xt a b o ut m F O L F O X 6 re gi me n
C o nsiste nc y wit h st u d y u p dates
Secti o n 5. 4
(i ncl u des Secti o ns 5. 4. 1 t hr o u g h 
5. 4. 4)
A d de d te xt a b o ut C A P O X re gi me n i ncl u di n g descri pti o n ( 5. 4. 1), 
met h o d of pr oc ure me nt ( 5. 4. 2), d ose, pre parati o n, a n d 
a d mi nistrati o n ( 5. 4. 3), a n d st ora ge a n d ha n dli n g ( 5. 4. 4)
A d diti o n of C A P O X re gi me n relate d i nf or mati o n
Secti o n 5. 6. 1
A dj uste d te xt t o be c o nsiste nt wit h ne w st u d y desi g n, a dj uste d 
Ta ble 7 o n t ucati ni b d ose m o dificati o ns f or a d verse e ve nts t o 
i ncl u de i nf or mati o n a b o ut na usea a n d v o miti n g, a n d ras h, a dj uste d 
te xt a b o ut ot her a d verse reacti o ns relate d t o t ucati ni b, a d de d 
f o ot n otes, as a p pr o priate
C o nsiste nc y wit h d ose m o dificati o ns i n ot her 
t ucati ni b pr ot oc ols
Secti o n 5. 6. 2
A d de d te xt t o i n dicate i n vesti gat ors ca n escalate t ucati ni b d ose f or 
s u bjects e nr olle d i n C o h ort 1 A f oll o wi n g S M C a p pr o val of hi g her 
t ucati ni b d oses i n s u bse q ue nt c o h orts
A dj uste d c o nte nt i n ta bles i n t his secti o n t o reflect c ha n ges t o 
st u d y desi g ns
Clarificati o n f or C o h ort 1 A d ose escalati o ns a n d 
c o nsiste nc y wit h st u d y u p dates
Secti o n 5. 6. 3
A d de d te xt a n d ta b ular c o nte nt ( Ta ble 1 1) a b o ut ca pecita bi ne d ose 
m o dificati o ns
U p dates relate d t o a d diti o n of ca pecita bi ne as a 
c o m p o ne nt of C A P O X a n d re vise d st u d y desi g n
Secti o n 5. 6. 4
A d de d te xt a b o ut c o nti n ui n g treat me nt i n t he e ve nt trast uz u ma b is 
disc o nti n ue d
Clarificati o n a b o ut ot her st u d y dr u gs i n t he e ve nt 
trast uz u ma b is disc o nti n ue d
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 3 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 5. 6. 4. 1
A dj uste d Ta ble 1 2 c o nte nt a b o ut trast uz u ma b d ose m o dificati o n 
g ui deli nes f or left ve ntric ular ejecti o n fracti o n ( L V E F)/left 
ve ntric ular d ysf u ncti o n
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols a n d 
m o st rece nt d ose m o dificati o ns g ui deli nes
Secti o n 5. 8. 1. 1
Delete d te xt t hat is re peate d i n Secti o n 5. 8. 4
Re m o val of re peate d te xt
Secti o n 5. 8. 1. 4
A d de d te xt a b o ut C A P O X dr u g i nteracti o ns
U p date relate d t o a d diti o n of C A P O X
Secti o n 5. 8. 4
U p dates t o c yt oc hr o me ( C Y P) P 4 5 0 te xt 
A d de d te xt a b o ut warfari n/c o u mari n deri vati ves
C o nsiste nc y wit h c urre nt C Y P rec o m me n dati o ns 
a n d c o nsiste nc y wit h c o n me dicati o n e xcl usi o ns 
f or ca pecita bi ne/ C A P O X
Secti o n 5. 9
A d de d te xt a b o ut ca pt uri n g o ver d oses e ve nts o n t he A E e C R F a n d 
wit hi n t he safet y data base
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
Secti o n 6. 3. 1
U p date d C y cle 1 Da y 1 t o i ncl u de i nf o a b o ut t ucati ni b 
a d mi nistrati o n f or c o h orts utilizi n g F O L F O X
A d de d uri ne pr otei n/creati ni ne rati o b ullet p oi nt (t his was als o 
a d de d t o Secti o ns 6. 3. 4, 6. 3. 6, a n d 6. 3. 7)
C o nsiste nc y wit h st u d y desi g n u p dates
Secti o n 6. 3. 3
U p date d te xt t o clarif y t ucati ni b a d mi nistrati o n i n t he t ucati ni b 
d ose escalati o n utilizi n g F O L F O X
C o nsiste nc y wit h st u d y desi g n u p dates
Secti o n 6. 3. 4
Secti o n 6. 3. 7
A d de d te xt a b o ut t ucati ni b dis pe nsati o n a n d a d mi nistrati o n
Clarificati o n
Secti o n 6. 3. 8
U p date d te xt a b o ut ra di ol o gical disease assess me nt f or p hase 1 b 
a n d p hase 2 c o h orts utilizi n g F O L F O X t o i n dicate 6 wee ks f or 
p hase 2 c o h orts a n d 8 w ee ks f or p hase 1 b c o h orts
Clarificati o n relate d t o st u d y desi g n u p dates
Secti o n 6. 4 (i ncl u des s u bsecti o ns 
6. 4. 1 t hr o u g h 6. 4. 9)
A d de d st u d y acti vities i nf or mati o n f or p hase 1 b t ucati ni b d ose 
escalati o n utilizi n g C A P O X ( C o h ort 1 C) a n d p hase 2 t u m or 
e x pa nsi o n c o h ort utilizi n g C A P O X ( C o h ort 2 A)
U p dates t o be c o nsiste nt wit h st u d y desi g n 
u p dates
Secti o n 6. 5
A d de d ca pecita b i ne t o e n d of treat me nt te xt
U p date t o be c o nsiste nt wit h st u d y desi g n u p date 
a d di n g i n ca pecita bi ne as a c o m p o ne nt of C A P O X
Secti o n 7. 1
A d de d “ m ost rece ntl y a vaila ble” t o arc hi val tiss ue t o be s u p plie d. 
Pr o vi de fle xi bilit y i n t he e ve nt m ost rece nt 
sa m ples ha ve bee n de plete d or are u na vaila ble.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 4 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 7. 2
A d de d te xt: “I ma ges will be c ollecte d b y a n I C R facilit y f or 
p ossi ble f ut ure a nal ysis.”
Clarificati o n a b o ut i ma ge c ollecti o n
Secti o n 7. 3
U p date d Ta ble 1 3 a n d Ta ble 1 4 titles t o reflect a p plica ble c o h orts
A d de d Ta ble 1 5 f or P K relate d g oals f or p hase 2 t u m or s pecific 
e x pa nsi o n c o h orts
U p dates t o be c o nsiste nt wit h st u d y desi g n 
u p dates
Secti o n 7,. 4
Mi n or u p dates t o bi o mar ker te xt
A d de d t he f oll o wi n g state me nt: Refer t o t he Ce ntral La b orat or y 
Ma n ual f or i nf or mati o n o n c ollecti o n, pr ocessi n g, st ora ge, a n d 
s hi p me nt of sa m ples.
Clarificati o ns 
Secti o n 7. 5. 1. 2
A d de d te xt (at e n d of t he secti o n) a b o ut Left Ve ntric ular Ejecti o n 
Fracti o n Decrease d
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
Secti o n 7. 5. 1. 5
A d de d te xt a b o ut re p orti n g t o re g ulat or y a ut h orities
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
Secti o n 7. 5. 3 
A d de d clarificati o n a b o ut C ystati n C bei n g a ce ntral la b test
Clarificati o n 
Secti o n 7. 5. 3. 1
U p date d t he decisi o n tree f or c ha n ges i n re nal f u ncti o n gra p hic s o 
t hat C ystati n C < 5 0 % a b o ve baseli ne t o C ystati n C ≤5 0 % a b o ve 
baseli ne
A d de d te xt a b o ut is olate d pr otei n uria
Pre vi o us gra p hic left o ut t he p ossi bilit y of a n 
e xactl y 5 0 % i ncrease fr o m baseli ne
A d diti o nal g ui da nce a b o ut pr otei n uria
Secti o n 7. 5. 6. 1
A d de d te xt a b o ut c o nti n ui n g E C H O/ M U G A assess me nts e ver y 6 
m o nt hs f or at least 2 years f oll o w i n g trast uz u ma b disc o nti n uati o n
A d diti o nal g ui da nce f or trast uz u ma b t o be 
c o nsiste nt wit h ot her t ucati ni b pr ot oc ols a n d 
safet y rec o m me n dati o ns
Secti o n 9 
Re m o ve d O ver vie w of st u d y o utc o me meas ure me nts ta ble
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
Secti o n 9. 1
U p date d sa m ple size deter mi nati o n te xt t o be c o nsiste nt wit h 
re vise d st u d y desi g n
A d de d sa m ple size/c O R R esti mates f or t he t u m or s pecifi c 
e x pa nsi o n c o h orts
U p date t o be c o nsiste nt wit h st u d y desi g n u p dates 
a n d s y n o psis u p dates
Secti o n 9. 2
A d de d defi niti o ns of d urati o n of res p o nse, pr o gressi o n -free 
s ur vi val, a n d o verall s ur vi val
U p date d d ue t o st u d y desi g n u p dates t hat i ncl u de d 
t hese e n d p oi nts
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 5 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 9. 3(i ncl u des s u bsecti o ns 
9. 3. 1 t hr o u g h 9. 3. 9)
Mi n or te xt u p dates f or clarificati o n
U p dates t o defi niti o n of a nal ysis sets t o be c o nsiste nt wit h st u d y 
desi g n u p dates
U p dates t o ti mi n g of a nal ysis
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
C o ns iste nc y wit h u p dates i n ot her secti o ns of t he 
pr ot oc ol a n d u p dates t o st u d y desi g n
C o nsiste nc y wit h u p dates t o st u d y desi g n
Secti o n 1 0
A d de d te xt a b o ut E ur o pea n g ui deli nes.
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols
A p pe n di x A
Ori gi nal F O L F O X sc he d ule of e ve nts ( S O E) was u p date d 
i ncl u di n g:
I n dicate d 1 4-da y c ycles i n t he “ Treat me nt Peri o d” c ol u m n 
hea di n g
A d diti o n of li ne ite m f or uri ne pr otei n/creati ni ne rati o
U p date t o f o ot n ote E t o i n dicate 2 4 h o urs uri ne re q uire d if 
uri ne/ pr otei n creati ni ne rati o is > 2. 0.
U p date t o f o ot n ote F t o i ncl u de te xt a b o ut c o nti n ui n g 
E C H O/ M U G A assess me nts e ver y 6 m o nt hs f or 2 years f oll o w i n g 
trast uz u ma b disc o nti n uati o n. 
U p date t o f o ot n ote I a b o ut m F O L F O X 6 a n d m F O L F O X 7 
re gi me ns
U p date t o f o ot n ote J a b o ut t ucati ni b d oses.
A dj uste d te xt i n f o ot n ote K a b o ut i ma gi n g f or s u bjects w h o 
disc o nti n ue st u d y treat me nt 
U p dates t o C T sca n, P E T -C T, a n d/ or M RI assess me nt fre q ue nc y 
wa s a d de d via a d diti o n of f o ot n otes P a n d Q
Clarificati o ns t o li ne ite m a b o ut t ucati ni b st u d y treat me nt t o 
i ncl u de inf o o n C o h orts 2 A a n d 2 B
U p dates t o P K sa m pli n g were ma de via f o ot n otes R a n d S a n d 
a d diti o n t o f o ot n ote N
A d de d f o ot n ote K t o t he sa m pli n g f or C T sca n, P E T -C T, a n d/ or 
M RI assess me nts o n t he X i n t he “f oll o w -u p” c ol u m n
Re m o ve d “after disease pr o gressi o n” te xt fr o m t he F oll o w-u p 
c ol u m n
A ne w S O E f or c o h orts recei vi n g C A P O X was a d de d
U p dates t o be c o nsiste nt wit h st u d y desi g n 
u p dates
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 6 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
A p pe n di x E
U p date d C Y P i nf or mati o n t o matc h c urre nt C Y P g ui deli nes
C o nsiste nc y wit h c urre nt C Y P relate d te xt a n d 
ot her t ucat i ni b pr ot oc ols
A p pe n di x F
Re m o ve d state me nt a b o ut O A T P 1 B 1 t hat w as n o l o n ger rele va nt
A d mi nistrati ve u p date
T hr o u g h o ut d oc u me nt
Mi n or c orrecti o ns, u p dates, f or matti n g, a n d c ha n ges
U p date t o i n dicate l ocal la bs ma y be perf or me d o n plas ma or 
ser u m
A d mi nistrati ve c ha n ges
Clarificati o n base d o n site fee d bac k
S u m m ar y of C h a n ges i n A me n d me nt 2. 1
Secti o n(s)
C ha n ge
Rati o nale
5. 6. 2

U p date d hea di n g f or Secti o n 5. 6. 2 fr o m “ m F O L F O X 7 D ose 
M o dificati o ns” t o “ F O L F O X D ose M o dificati o ns.”

U p date d te xt i n Secti o n 5. 6. 2 t o m ore clearl y refer t o ta b ular 
c o nte nt i n t he secti o n. 

Mi n or clarificati o ns t o titles of Ta bles 8, 9 a n d 1 0 a n d mi n or 
clarificati o ns t o c o nte nt of Ta bles 8 a n d 1 0

U p date t o m ore acc uratel y reflect secti o n 
c o nte nt

U p dates f or clarit y.

Mi n or u p dates f or clarit y
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 7 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
5. 6. 3

U p date d te xt t o be c o nsiste nt wit h c ha n ges descri be d i n ta bles 
(see bel o w f or m ore details). 

A d de d Ta ble 1 1 c o ntai ni n g o xali plati n ( n o n -ne ur ol o gical 
t o xicit y) a n d ca pecita bi ne d ose re d ucti o n le vels 

Ta ble o n d ose m o dificati o n f or cli nical a d verse e ve nts 
c o nsi dere d relate d t o ca pecita bi ne was u p date d t o a d di n g 
d ose m o dificati o n i nf or mati o n a b o ut he mat ol o gic a n d 
n o n he mat ol o gic A Es f or o xali plati n a n d ca pecita bi ne. ( N ote 
t his was ori gi nall y Ta ble 1 1 b ut is n o w T able 1 2)

A d diti o n of Ta ble 1 3 c o ntai ni n g d ose m o dificati o n 
i nf or mati o n f or o xali plati n ass ociate d ne ur ot o xicit y attri b ute d 
t o C A P O X.

U p dates f or c o nsiste nc y wit h a d de d secti o n 
c o nte nt

A d diti o n of o mitte d d ose re d ucti o n le vel 
g ui da nce f or n o n -ne ur ol o gical t o xicit y

A d diti o n of d ose m o dificati o n g ui da nce f or 
o xali plati n a n d ca pecita bi ne as part of t he 
C A P O X re gi me n

A d diti o nal o mitte d d ose m o dificati o n 
g ui da nce f or o xali plati n ass ociate d 
ne ur ot o xicit y attri b ute d t o C A P O X.
T hr o u g h o ut d oc u me nt

U p date d ta ble n u m beri n g t hr o u g h o ut d oc u me nt t o 
acc o m m o date t he ta ble a d diti o ns descri be d i n Secti o n 5. 6. 3

A d mi nistrati ve c ha n ge
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 8 of 2 2 0
S u m m ar y of C h a n ges i n A me n d me nt 3. 0
Secti o n(s)
C ha n ge
Rati o nale
C o ver pa ge/ S y n o psis
C ha n ge d t he title t o reflect t he a d diti o n of 
pe m br oliz u ma b 
Clarificati o n
List of A b bre viati o ns 
a n d Defi niti o ns of 
T er m s
U p date d a b bre viati o n list
C o nsiste nc y wit h u p dates t hr o u g h o ut 
pr ot oc ol
S y n o psis / O bjecti ves 
/ Secti o n 2. 1
C ha n ge d hea di n g t o reflect d ose -escalati o n 
P hase 1 A / 1 B c o h orts
Clarificati o n of d ose -escalati o n 
c o h orts
S y n o psis / O bjecti ve s 
/ Secti o n 2. 2 
I de ntifie d s u b-secti o n f or P hase 1 b C o h orts 
1 C, 1 E, 1 F, a n d 1 G 
U p date d o bjecti ves t o reflect 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
treat me nt ar ms
A d de d “i ncl u di n g D L Ts” t o pri mar y 
e n d p oi nt.
Defi ne d P K e n d p oi nt f or t ucati ni b as 
i ncl u di n g b ut n ot li mite d t o C tr o u g h
T o i de ntif y o bjecti ves f or P hase 1 b 
C o h orts 1 C, 1 E, 1 F, a n d 1 G; C o h orts 
1 E, 1 F, a n d 1 G are ne w  c o h orts t o 
w hic h pe m br oliz u ma b has bee n 
a d de d.
S y n o psis / O bjecti ves 
/ Secti o n 2. 3 
A d de d Ja pa n -s pecific st u d y ( C o h ort 1 D) t o 
P hase 1 b 
T o i de ntif y t he o bjecti ves f or t he 
Ja pa n-s pecific c o h ort
S y n o psis / O bjecti ves 
/ Secti o n 2. 4
Clarifie d o bjecti ves f or 2 A wit h a d diti o n of 
pe m br oliz u ma b. 
A d de d “i ncl u di n g D L Ts” t o pri mar y 
e n d p oi nt
M o ve d P K a nal ysis t o e x pl orat or y 
T o a d d pe m br oliz u ma b t o t he 
treat me nt re gi me n f or C o h ort 2 A
P K data w ill n ot be a sec o n dar y 
o bjecti ve of t he P hase 2 p orti o n of 
t he st u d y.
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria: # 1
I de ntifie d c o h orts a n d ass ociate d 
i n dicati o ns
Clarificati o n
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria: # 2
Clarifie d c o h orts a n d w hic h ca n be 
recei vi n g a n o xali plati n-base d re gi me n 
d uri n g t he scree ni n g peri o d
Clarificati o n
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria: # 3
U p dates t o details o f H E R 2 testi n g 
pr oce d ures f or gastric, G EJ, a n d 
es o p ha geal a de n ocarci n o ma
Clarificati o n
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria # 5
A dj uste d te xt t o i ncl u de a ge of maj orit y i n 
t he ge o gra p hic re gi o n
Fle xi bilit y acr oss ge o gra p hic re gi o ns 
t o be c o nsiste nt wit h ge o gra p hic 
variati o ns i n a ge of le gal c o nse nt
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria: # 9
A d de d t hat s u bjects ca n be o n a sta ble d ose 
of er yt hr o p oieti n
Clarificati o n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 1 9 9 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria: 
# 1 0
A dj uste d te xt t o reflect i ncl usi o n of 
a d diti o nal c o h orts
Clarificati o n
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria: 
# 1 3
C ha n ge d ne gati ve pre g na nc y testi n g t o 
wit hi n 2 4 h o urs of first d ose fr o m wit hi n 7 
da ys of e nr oll me nt.
C o nsiste nc y wit h i ncl usi o n criteri o n 
use d i n Sea ge n a n d Merc k pr ot oc o ls 
t hat i ncl u de pe m br oliz u ma b rts 
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria: 
# 1 6
A d de d t hat s u bjects w it h a k n o w n 
ps y c hiatric or s u bsta nce a b use dis or der t hat 
w o ul d i nterfere wit h t he s u bject’s a bilit y t o 
c o o perate wit h t he re q uire me nts of t he 
st u d y are n ot eli gi ble.
Clarificati o n
S y n o psis / Secti o n 4. 1 
I ncl usi o n Criteria: 
# 1 7
A d de d t hat s u bjects w h o ha ve recei ve d 
C N S -directe d ra di ot hera p y m ust ha ve 
rec o vere d fr o m all ra diati o n-relate d 
t o xicities a n d n ot re q uire c ortic oster oi ds. 
Als o, a 1 -wee k was h o ut is per mitte d f or 
palliati ve ra diati o n ( ≤2 w ee ks of 
ra di ot hera p y) t o n o n-C N S disease.
T o ali g n wit h pe m br oliz u ma b 
i ncl usi o n criteria
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: # 1
Clarifie d c o h orts a n d h y perse nsiti vit y 
e xcl usi o n criteria
T o a d d e xcl usi o n crit eria f or s u bjects 
wit h h y perse nsiti vit y t o treat me nt
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: # 2
Clarifie d e xcl usi o n criteria f or e xcee di n g 
li mits of o xali plati n-base d re gi me n as part 
of t heir sta n dar d -of -care treat me nt
Clarificati o n f or ne w c o h orts
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: # 4
Clarifie d t hat s u bjects i n C o h orts 2 A a n d 
2 B w it h k n o w n acti ve C N S lesi o ns ma y be 
i ncl u de d u n der s pecifie d criteria.
Clarificati o n of criteria f or i ncl usi o n 
of s u bjects wit h k n o w n acti ve C N S 
lesi o ns i n C o h orts 2 A  a n d 2 B
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: # 8
I n dicate d t hat s u bjects w h o are p ositi ve f or 
eit her he patitis B s urface a nti b o d y 
( H Bs A B) or a nti b o dies t o t he he patitis B 
c ore a nti ge n ( H Bc A B) s h o ul d be scree ne d 
usi n g P C R meas ure me nt of he patitis B 
D N A le vels.
T o pr o vi de clarit y wit h re gar d t o 
he patitis B testi n g
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 1 1
Clarifie d t hat HI V testi n g is n ot re q uire d 
u nless ma n date d b y t he l ocal healt h 
a ut h orit y
T o pr o vi de fle xi bilit y i n w or di n g 
beca use s o me c o u ntries d o n ot all o w  
HI V testi n g 
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 1 6
A dj uste d E C w or di n g t o i n dicate s u bjects 
ca n n ot ha ve acti ve i nfecti o n re q uiri n g 
s yste mic t hera p y 
T o pr o vi de c o nsiste nc y wit h
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b 
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 1 8
I de ntifie d c o h orts recei vi n g C A P O X
Clarificati o n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 0 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 1 9
F or C o h orts 1 E, 1 F, 1 G, 2 A w h o ha ve 
u nresecta ble or metastatic, gastric, 
es o p ha geal, a n d G EJ a de n ocarci n o ma) 
ca n n ot ha ve ha d pre vi o us c he m ot hera p y 
f or metastatic/ u nresecta ble disease; 
a dj u va nt or ne oa dj u va nt c he m ot hera p y, or 
bi ol o gic t hera p y is per mitte d if m ore t ha n 
1 2 m o nt h s ha ve ela pse d bet wee n t he e n d of 
t hera p y a n d first rec urre nce
T o pr o vi de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b c o h orts
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 1
A d de d li ve vacci ne e xc l usi o n criteri o n
C o nsiste nc y wit h ot her t ucati ni b 
pr ot oc ols
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 2
A d de d o n g oi n g ≥ Gra de 2 diarr hea of a n y 
eti ol o g y at scree ni n g
T o r ule o ut s u bjects wit h p ote ntial 
s usce pti bilit y t o treat me nt reacti o ns
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 3
S u bjects i n C o h orts 1 E, 1 F, 1 G, 2 A: a d de d 
k n o w n acti ve C N S metastases a n d/ or 
carci n o mat o us me ni n gitis f or 
pe m br oliz u ma b c o h orts
T o pr o vi de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat
i ncl u de pe m br oliz u ma b c o h orts
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 4
F or C o h orts 1 E, 1 F, 1 G, 2 A, a d de d pri or 
t hera p y wit h a n a nti-P D -1, a nti -P D -L 1, or 
a nti P D-L 2 a ge nt or w it h a n a ge nt directe d 
t o a n ot her sti m ulat or y or c oi n hi bit or y T-
cell rece ptor
T o pr o vi de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b c o h orts
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 5
F or C o h orts 1 E, 1 F, 1 G, 2 A, a d de d 
all o ge neic tiss ue/s oli d or ga n tra ns pla nt
T o pr o v i de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b c o h orts
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 6
F or C o h orts 1 E, 1 F, 1 G, 2 A, a d de d f or a 
dia g n osis of i m m u n o deficie nc y (e xcl u di n g 
HI V) or is recei vi n g c hr o nic s yste mic 
ster oi d t hera p y (i n d osi n g e xcee di n g 1 0 m g 
dail y of pre d nis o ne e q ui vale nt) or a n y 
ot her f or m of i m m u n os u p pressi ve t hera p y 
wit hi n 7 da ys pri or t he first d ose of st u d y 
dr u g
T o pr o vi de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot h er 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b c o h orts
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 7
F or C o h orts 1 E, 1 F, 1 G, 2 A, a d de d k n o w n 
a d diti o nal mali g na nc y t hat is pr o gressi n g 
or has re q uire d acti ve treat me nt wit hi n t he 
past 3 years
T o p r o vi de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b c o h orts
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 8
F or C o h orts 1 E, 1 F, 1 G, 2 A, a d de d a n 
acti ve a ut oi m m u ne disease t hat has 
re q uire d s yste mic treat me nt i n past 2 years
T o pr o vi de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b c o h orts
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 2 9
F or C o h orts 1 E, 1 F, 1 G, 2 A, a d de d a 
hist or y of ( n o n -i nfecti o us) p ne u m o nitis / 
i nterstitial l u n g disease t hat re q uire d 
ster oi ds or has c urre nt p ne u m o nitis / 
i nterstitial l u n g disease
T o pr o vi de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b c o h orts
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 1 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis / Secti o n 4. 2 
E xcl usi o n Criteria: 
# 3 0
S u bjects i n C o h orts 1 E, 1 F, 1 G, 2 A: a d de d 
recei ve d ra diati o n t hera p y t o t he l u n g t hat 
is > 3 0 G y wit hi n 6 m o nt hs of t he first d ose 
of trial treat me nt.
T o pr o vi de c o nsiste nc y wit h 
e xcl usi o n criteria use d i n ot her 
Sea ge n a n d Merc k pr ot oc ols t hat 
i ncl u de pe m br oliz u ma b c o h orts
S y n o psis / N u m ber of 
Pla n ne d S u bjects / 
Secti o n 3. 1
U p date d t he t otal n u m ber of s u bjects 
e nr olle d i n t he gl o bal st u d y 
U p date d t he sa m ple size t o acc o u nt 
f or t he a d diti o nal patie nt p o p ulati o ns
S y n o p sis / St u d y 
Desi g n / Secti o n 3. 1
U p date d st u d y desi g n ta ble t o descri be 
c o h orts 1 A, 1 B, 1 C, 1 D, 1 E, 1 F, a n d 1 G 
a n d ass ociate d patie nt p o p ulati o ns; C o h ort 
1 C m o ve d fr o m d ose escalati o n t o safet y 
e val uati o n c o h orts, w hic h i ncl u de 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
C o h orts 1 E, 1 F, 1 G.
Delete d “ S u bjects wit h gastric a n d G EJ 
a de n ocarci n o ma s h o ul d als o be recei vi n g 
trast uz u ma b as part of t heir sta n dar d-of -
care re gi me n.”
A d de d t o t he d ose escalati o n pr ocess t hat 
t he S M C will re vie w t he t otalit y of t he 
safet y data.
U p date d D L T criteria f or C o h ort 1 D.
U p date d t o a d d 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
c o h orts; defi ne d C o h orts 1 C as safet y 
e val uati o n c o h ort; defi ne d Ja pa n -
s pecific C o h ort 1 D
S y n o psis / Secti o n 
3. 1. 1 / Secti o n 3. 1. 1. 1 
/ Secti o n 3. 1. 1. 2 / 
Secti o n 3. 1. 1. 3 
Descri be d t he d ose -escalati o n C o h orts i n 
P hase 1 b
U p date d t o descri be d ose -escalati o n 
gati n g r ules
S y n o psis / Secti o n 
3. 1. 2 / Secti o n 3. 1. 2. 1 
/ Secti o n 3. 1. 2. 2 / 
Secti o n 3. 1. 2 . 3 / 
Secti o n 3. 1. 2. 4 
Descri be d t he c o h orts c o m prisi n g t he 
safet y e val uati o n p orti o n of P hase 1 b; 
m o ve d C o h ort 1 C fr o m D ose Escalati o n t o 
Safet y E val uati o n; a d de d 
t ucati ni b/trast uz u ma b / pe m br oliz u ma b 
re gi me ns 1 E, 1 F, a n d 1 G
T o clarif y t he ne w st u d y desi g n
Secti o n 3. 1. 3. 
Pr o vi de d desi g n f or Ja pa n -s pecific st u d y as 
P hase 1 b
T o defi ne t he Ja pa n -s pecific st u d y as 
P hase 1 b.
S y n o psis / Secti o n 
3. 1. 4 
Defi ne d C o h ort 2 A as i ncl u di n g 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b. 
A d de d criteria f or S M C re vie w. A d de d t hat 
ex pl orat or y o bjecti ves will i ncl u de 
e val uati o n of t he P K of t ucati ni b gi ve n i n 
c o m bi nati o n wit h trast uz u ma b a n d 
o xali plati n -base d c he m ot hera p y a n d 
u p date d st u d y desi g n fi g ure.
T o descri be t he c o m p ositi o n of t he 
e x pa nsi o n c o h orts a n d u p date te xt 
a n d st u d y f i g ure t o be c o nsiste nt wit h 
c ha n ges ma de t o st u d y.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 2 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis / 
I n vesti gati o nal 
Pr o d uct, D ose, a n d 
M o de of 
A d mi nistrati o n ( All 
C o h orts)
I de ntifie d c o h orts ass ociate d wit h 
c he m ot hera p y re gi me ns; a d de d 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
treat me nt; c ha n ge d ad m i nistrati o n of t he 
first d ose of t ucati ni b fr o m Da y 8 t o Da y 1
A d de d treat me nt re gi me ns ass ociate d 
wit h t he 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
c o h orts 
S y n o psis / D urati o n of 
Treat me nt 
Secti o n 3. 1. 8 
I n dicate d t hat pe m br oliz u ma b will be 
gi ve n f or a ma xi m u m of 1 8 d oses
T o ali g n wit h pe m br oliz u ma b d osi n g 
g ui da nce
S y n o psis / Efficac y 
Assess me nts
U p date d t o a d d 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
c o h orts; a d de d i ma gi n g assess me nts t o be 
e ver y 6 wee ks f or first 2 4 wee ks a n d e ver y 
9 w ee ks t hereafter.
A d de d ti mi n g of efficac y assess me nts 
f or p ost-d ose -escalati o n c o h orts
S y n o psis / Statistical 
Met h o ds / Secti o n 9. 1. 
Defi ne d e val ua ble a nal ysis sets f or vari o us 
c o h orts
T o defi ne a nal ysis data set
Secti o n 1. 3. 
Refere nce d bac k gr o u n d i nf or mati o n f or 
pe m br oliz u m a b
T o c haracterize t he t hera pe utic 
pr ofile of pe m br oliz u ma b 
Secti o n 1. 4 
A dj uste d te xt a b o ut H E R 2 pr o g n ostic 
val ue a n d t he c o m bi nati o n of H E R 2 
tar geti n g a ge nts gi ve n wit h trast uz u ma b
Clarificati o n
Secti o n 1. 4. 
A d de d rati o nale f or pe m br oliz u ma b 
c o h orts, i ncl u di n g i nteri m res ults fr o m t he 
K E Y N O T E -8 1 1
T o pr o vi de t he rati o nale f or t he 
pe m br oliz u ma b c o h orts
Secti o n 3. 1. 5 
S pecifie d t hat re nal D L T a p plies t o t he 
d ose -escalati o n c o h orts ( 1 A a n d 1 B)
T o s pecif y t hat re nal D L T para meters 
a p pl y o nl y t o t he d ose escalati o n 
c o h orts ( 1 A a n d 1 B)
Secti o n 3. 1. 6. 
Defi ne d D L T criteria f or Safet y E val uati o n 
c o h orts
T o defi ne d ose -li miti n g criteria f or 
C o h orts 1 C, 1 D, 1 E, 1 F, a n d 1 G
Secti o n 3. 1. 7. 1.
U p date d r ole of S M C i n re vie wi n g f or 
d ose -escalati o n C o h orts 1 A a n d 1 B
T o descri be r ole of S M C i n re vie wi n g 
safet y data f or C o h orts 1 A a n d 1 B
Secti o n 3. 1. 7. 2
Defi ne d r ole of S M C i n re vie wi n g f or 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
C o h orts 1 C, 1 E, 1 F, 1 G 
T o descri be r ole of S M C i n re vie wi n g 
safet y data f or C o h orts 1 C, 1 E, 1 F, 
a n d 1 G
Secti o n 3. 1. 7. 3. 
A d de d secti o n f or S M C re vie w of safet y 
f or P hase 2 c o h orts
T o descri be r ole of S M C i n re vie wi n g 
safet y data f or C o h orts 2 A a n d 2 B
Secti o n 3. 2.
A d de d rati o nale f or i ncl u di n g 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
c o h orts
T o pr o vi de basis f or a d diti o n of 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
t o P hase 1 b.
Secti o n 3. 2. 2 
A d de d t he rati o nale f or t he pe m br oliz u ma b 
d ose, i ncl u di n g i nteri m res ults fr o m t he 
K E Y N O T E -8 1 1 
T o pr o vi de t he d ose j ustificati o n f or 
pe m br oliz u ma b
Secti o n 5. 1. 1 
Defi ne d treat me nts f or F O L F O X c o h orts; 
differe ntiate d trast uz u ma b Q 2 W a n d Q 3 W 
re gi me ns
Clarificati o n
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 3 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 5. 1. 2 
Defi ne d treat me nts f or C A P O X c o h orts
Clarificati o n 
Secti o n 5. 1. 3 
A d de d treat me nt re gi me n f or 
pe m br oliz u ma b a n d F O L F O X
T o pr o vi de treat me nt re gi me n of 
F O L F O X a n d pe m br oliz u ma b
Secti o n 5. 1. 4 
A d de d treat me nt re gi me n f or 
pe m br oliz u ma b a n d C A P O X
T o pr o vi de treat me nt re gi me n of 
C A P O X a n d pe m br oliz u ma b
Secti o n 5. 1. 5 
A d de d treat me nt re gi me n f or 
t ucati ni b/trast uz u ma b/ p e m br oliz u ma b 
wit h o ut c he m ot hera p y
T o pr o vi de treat me nt re gi me n of 
t ucati ni b/trast uz u ma b/ 
pe m br oliz u ma b wit h o ut 
c he m ot hera p y
Secti o n 5. 2
A d de d t hat st u d y pers o n nel s h o ul d i nstr uct 
s u bjects o n t ucati ni b a d mi nistrati o n 
tec h ni q ues
T o e ns ure s u bjects recei ve 
i nstr ucti o ns f or t ucati ni b 
a d mi nistrati o n 
Secti o n 5. 3 
I de ntifie d c o h orts recei vi n g t he F O L F O X 
re gi me n
Clarificati o n
Secti o n 5. 3. 1 
A d de d gastric ca ncer t o o nc ol o g y 
i n dicati o ns t hat use o xali plati n
C orrecti o n of o missi o n
Secti o n 5. 3. 2 
I n dicate d s o urci n g f or F O L F O X ma y var y 
b y site a n d/ or re gi o n as o utli ne d i n ot her 
d oc u me nts s uc h as Cli nical Trial 
A gree me nts.
T o clarif y s o urci n g f or F O L F O X
Secti o n 5. 4 
I de ntifie d c o h orts recei vi n g t he C A P O X 
re gi me n
Clarificati o n
Secti o n 5. 4. 2 
I n dicate d s o urci ng f or C A P O X ma y var y 
b y site a n d/ or re gi o n as o utli ne d i n ot her 
d oc u me nts s uc h as Cli nical Trial 
A gree me nts.
T o clarif y s o urci n g f or C A P O X
Secti o n 5. 4. 3 
A d de d t hat t he starti n g d ose of 
ca pecita bi ne ma y be re d uce d per 
i n vesti gat or prefere nce or i nstit uti o nal 
sta n dar ds u p o n a p pr o val b y t he me dical 
m o nit or, b ut will n ot be l o w er t ha n 
8 5 0 m g/ m 2 P O BI D
T o pr o vi de d osi n g i nstr ucti o ns f or 
ca pecita bi ne
Secti o n 5. 5. 2 
I n dicate d s o urci n g f or trast uz u ma b ma y 
var y b y site a n d/ or re gi o n as o utli ne d i n 
ot her d oc u me nts s uc h as Cli nical Trial 
A gree me nts.
T o clarif y s o urci n g of trast uz u ma b
Secti o n 5. 5. 3 
A d de d Q 2 W a n d Q 3 W re gi me ns f or 
trast uz u ma b
T o clarif y re gi me ns of trast uz u ma b 
base d o n treat me nt re gi me ns f or 
C o h orts 1 A a n d 1 B ( Q 2 W) vs 
C o h orts 1 C, 1 D, 1 E, 1 F, 1 G, 2 A, a n d 
2 B
Secti o n 5. 5. 6
St u d y Dr u g Acc o u nta bilit y was c ha n ge d t o 
St u d y Treat me nt Acc o u nta bilit y
C o nsiste nc y wit h c ha n ges t hr o u g h o ut 
pr ot oc ol t o clearl y i n dicate 
disti ncti o ns bet wee n st u d y dr u g a n d 
st u d y treat me nt
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 4 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 5. 6 / Secti o n 
5. 6. 1 / S ecti o n 5. 6. 2 / 
Secti o n 5. 6. 3 / Secti o n 
5. 6. 4 / Secti o n 5. 6. 5 / 
Secti o n 5. 6. 6 
Pr o vi de d pe m br oliz u ma b a d mi nistrati o n 
i nf or mati o n 
T o pr o vi de t he i nstr ucti o ns f or 
a d mi nistrati o n of pe m br oliz u ma b
Secti o n 5. 7. 2 / Secti o n 
5. 7. 3 
A d de d t hat d ose re d ucti o ns or treat me nt 
i nterr u pti o ns/ disc o nti n uati o n ma y be ma de 
b y t he i n vesti gat or per i nstit uti o nal practice 
a n d if dee me d i n t he best i nterest of s u bject 
safet y. 
T o pr o vi de i n vesti gat or discreti o n f or 
m o nit ori n g of s u bject safet y
Sec ti o n 5. 7. 4 
Re m o ve d 6 m g/ k g fr o m t he i nstr ucti o ns 
a b o ut restarti n g trast uz u ma b a n d i n dicate d 
i n vesti gat ors s h o ul d use t he l oa di n g d ose 
base d o n t he re gi me n
F O L F O X a n d C A P O X use differe nt 
l oa di n g d oses s o 6 m g/ k g d oes n ot 
a p pl y t o b ot h
Secti o n 5. 7. 4. 1
C ha n ge d perce nta ge decrease t o perce nta ge 
p oi nts decrease
Clarificati o n
Secti o n 5. 7. 5 / Secti o n 
5. 7. 5. 1  
Pr o vi de d d ose m o dificati o n g ui deli nes f or 
pe m br oliz u ma b i m m u ne -relate d e ve nts
T o descri be t he g ui deli nes f or t he 
ma na ge me nt of i m m u ne -relate d A Es 
associate d wit h pe m br oliz u ma b
Secti o n 5. 7. 5. 2
A d de d d ose m o dificati o n g ui deli nes f or 
pe m br oliz u ma b
T o pr o vi de g ui deli nes i n t he e ve nt of 
a d verse reacti o ns t o pe m br oliz u ma b
Secti o n 5. 7. 2 
A d de d a f o ot n ote t o 
ne utr o pe nia/t hr o m b oc yt o pe nia t o i n dicate 
t hat t he la bs fr o m D 1 of eac h c ycle s h o ul d 
be use d t o deter mi ne d ose m o dificati o ns 
f or F O L F O X; delete d d ose a dj ust me nts f or 
le u k o pe nia 
T o clarif y d ose m o dificati o n 
g ui deli nes wit h re gar d t o 
ne utr o pe nia/t hr o m b oc yt o pe nia f or 
F O L F O X
Secti o n 5. 7. 5. 3 
Pr o vi de d criteri a f or d ose i nterr u pti o n of 
pe m br oliz u ma b
Pr o vi de d d ose g ui deli nes f or 
i nterr u pti o n of pe m br oliz u ma b
Secti o n 5. 7. 6 
M o ve d t o after pe m br oliz u ma b d ose 
m o dificati o n g ui deli nes
T o c orrect or ga nizati o n
Secti o n 5. 7. 7 
M o ve d t o after pe m br oliz u ma b d ose 
m o dificati o n g ui deli nes
T o c orrect or ga nizati o n
Secti o n 5. 7. 8 
A d de d d ose m o dificati o n g ui deli nes f or 
diarr hea
T o pr o vi de g ui deli nes f or 
ma na ge me nt of diarr hea ass ociate d 
wit h treat me nt
Secti o n 5. 9. 1. 5 
A d de d t hat D DI are n ot e x pecte d w it h 
pe m br oliz u ma b
Clarifie d p ote ntial f or dr u g -dr u g 
i nteracti o ns wit h pe m br oliz u ma b
Secti o n 5. 9. 2 
Clarifie d gl uc oc ortic oi d use
T o clarif y c o nc o mita nt use of 
gl uc oc ortic oi ds
Secti o n 5. 9. 4 
A d d i nstr ucti o ns wit h re gar d t o rec or di n g 
of c o nc o mita nt treat me nt a n d 
disc o nti n uati o n (i ncl u di n g i nstr ucti o ns o n 
i m m u n ot hera p y n ot s pecifie d i n t his 
pr ot oc ol a n d li ve or li ve atte n uate d 
vacci nes)
T o pr o vi de f or t he rec or di n g of 
c o nc o mita nt treat me nt a n d t o clarif y 
t he criteria f or disco nti n uati o n of 
treat me nt i n t he e ve nt of use of 
pr o hi bite d me dicati o ns
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 5 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 5. 1 0 / Secti o n 
5. 1 0. 2 
Pr o vi de d i nf or mati o n wit h re gar d t o 
o ver d ose of pe m br oliz u ma b
T o defi ne a n o ver d ose of 
pe m br oliz u ma b a n d treat me nt 
i nstr ucti o ns
Secti o n 5. 1 0. 3 
Pr o vi de d o ver d ose i nf or mati o n f or 
trast uz u ma b, o xali plati n, ca pecita bi ne, 
le uc o v ori n, a n d fl u or o uracil
T o pr o vi de i nf or mati o n o n o ver d ose
T hr o u g h o ut Secti o n 6
A dj uste d te xt fr o m “ Bl o o d f or c ystati n C” 
t o “ Ser u m c ystati n C” a n d mi n or te xt 
c ha n ges
C o nsiste nc y wit h sc he d ule of e ve nts 
a n d te xt i n re mai n der of pr ot oc ol 
w hic h refers t o ser u m c ystati n 
Clarificati o ns, as nee de d, f or e xisti n g 
te xt
Secti o n 6. 2
Re m o ve d b ullet f or vital si g ns, w ei g ht, 
hei g ht 
A d de d b ullet a b o ut t h yr oi d f u ncti o n tests 
f or selecte d c o h orts
C o nsiste nc y wit h sc he d ule of e ve nts
Secti o n 6. 3
A d de d Ja pa n -s pecific ( 1 D) c o h ort a n d 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
C o h ort 1 E
T o a d d st u d y pr oce d ures f or Ja pa n -
s pecific c o h ort a n d F O L F O X/ 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
c o h ort
Se cti o n 6. 3. 1 / Secti o n 
6. 3. 4 / Secti o n 6. 3. 7 / 
Secti o n 6. 4. 1 / Secti o n 
6. 4. 4 / Secti o n 6. 4. 7 
Pre g na nc y test f or s u bjects of c hil d beari n g 
p ote ntial t o be d o ne w it hi n 2 4 h o urs of 
treat me nt
S pecifie d bl o o d sa m ples f or o xali plati n P K 
i n C o h orts 1 A a n d 1 B o nl y
S pecifie d trast uz u ma b Q 2 W i n C o h orts 1 A 
a n d 1 B a n d Q 3 W i n C o h orts 1 D, 1 E, 2 A, 
a n d 2 B
C o nsiste nc y wit h sc he d ule of e ve nts
Secti o n 6. 3. 1
A d de d pe m br oliz u ma b a d mi nistrati o n a n d 
u p date d i nf or mati o n f or trast uz u ma b 
a d mi nistrati o n
T o a d d a d mi nistrati o n of 
pe m b r oliz u ma b t o C ycle 1 
pr oce d ures f or t he F O L F O X 
c o m bi nati o n re gi me n
T o clarif y Q 2 W a n d Q 3 W 
trast uz u ma b d osi n g
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 6 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 6. 3. 1 
Secti o n 6. 3. 2 
Secti o n 6. 3. 3
Secti o n 6. 3. 4
Secti o n 6. 3. 5 
Secti o n 6. 3. 6
Secti o n 6. 3. 7 
Secti o n 6. 4. 1
Secti o n 6. 4. 2 
Secti o n 6. 4. 3
Secti o n 6. 4. 5 
Secti o n 6. 5. 3 
Secti o n 6. 6
A d de d f or c ystati n C, “If after t he P hase 2 
d ose has bee n i de ntifie d a n d n o re nal D L Ts 
ha ve bee n see n d uri n g d ose escalati o n, 
c ystati n C will n ot be c ollecte d”
T o q ualif y g ui deli nes f or c ystati n C 
testi n g i n t he e ve nt t he P hase 2 d ose 
has bee n i de ntifie d a n d n o re nal 
D L Ts ha ve bee n see n d uri n g d ose 
escalati o n
Secti o n 6. 3. 8 /
A p pe n di x A Sc he d ule 
of E ve nts
Clarifie d i ma gi n g assess me nts t o be e ver y 
6 w ee ks f or 2 4 wee ks a n d e ver y 9 wee ks 
t hereafter f or p ost-d ose escal ati o n c o h orts 
( 1 B, 1 C, 1 D, 1 E, 1 F, 1 G, 2 A, a n d 2 B
A d de d i nf or mati o n a b o ut t h yr oi d f u ncti o n 
tests f or c o h orts 1 E a n d 2 A
T o clarif y i ma gi n g sc he d ule f or p ost -
d ose escalati o n c o h orts
T o pr o vi de g ui da nce f or fre q ue nc y of 
t h yr oi d f u ncti o n tests
Secti o n 6. 4. 1 
A d de d a d mi nistrati o n of pe m br oliz u ma b t o 
C y cle 1 pr oce d ures f or t he C A P O X 
c o m bi nati o n re gi me n
T o a d d a d mi nistrati o n of 
pe m br oliz u ma b t o C ycle 1 
pr oce d ures f or t he C A P O X 
c o m bi nati o n re gi me n
Secti o n 6. 4. 1, 6. 4. 3
Delete d bl o o d sa m ples f or o xali plati n P K
P ote ntial dr u g -dr u g i nteracti o ns will 
be e val uate d d uri n g t he d ose -
escalati o n p hase ( C o h orts 1 A a n d 1 B)
Secti o n 6. 4. 6 
Clarifie d i ma gi n g assess me nts t o be e ver y 
6 w ee ks f or 2 4 wee ks a n d e ver y 9 wee ks 
t hereafter
A d de d i nf or mati o n a b o ut t h yr oi d f u ncti o n 
tests f or c o h orts 1 F a n d 2 A)
T o clarif y i ma gi n g sc he d ule f or 
C o h orts 1 C, 1 F, a n d 2 A
T o pr o vi de g ui da nce f or fre q ue nc y of 
t h yr oi d f u ncti o n tests
Secti o n 6. 5
Secti o n 6. 5. 1 
Secti o n 6. 5. 2 
Secti o n 6. 5. 3 
Secti o n 6. 5. 4 
Secti o n 6. 5. 5 
Secti o n 6. 5. 6
Secti o n 6. 5. 7 
A d de d treat me nt pr oce d ures f or 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
re gi me n ( C o h ort 1 G)
T o list treat me nt pr oce d ures b y ti me 
p oi nt f or 
t ucati ni b/trast uz u ma b/ pe m br oliz u ma b 
treat me nt ar m
Secti o n 6. 6
U p date d c o nte nt t o be c o nsiste nt wit h 
u p date s i n b o d y of pr ot oc ol
C o nsiste nc y
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 7 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 6. 7
A d de d f oll o w -u p i ma gi n g e ver y 9 wee ks 
u ntil disease pr o gressi o n a n d e ver y 1 2 
wee ks u ntil deat h, wit h dra wal of c o nse nt, 
st u d y cl os ure.
T o pr o vi de ti mi n g of f oll o w -u p 
i ma gi n g assess me nts
Secti o n 7. 1
A dj uste d te xt as s h o w n:
O nl y s u bjects w h o si g n a n i nf or me d 
c o nse nt a n d meet all i ncl usi o n a n d 
e xcl usi o n criteria s pecifie d i n Secti o n 4 
will be e nr olle d i n t his st u d y.
A d de d te xt:
“ …c o nfir mati o n of last bl o o d tra nsf usi o n, 
re vie w of a d verse e ve nts a n d c o nc o mita nt 
me dicati o ns , …”
C o nsiste nc y wit h S O E
Secti o n 7. 3.
Secti o n 9. 3. 6 
U p date d P K para meters f or c o h orts
T o defi ne t he P K para meters f or ne w  
c o h orts
Secti o n 7. 4 
Pr o vi de d i nstr ucti o ns f or c ollecti n g tiss ue 
f or bi o mar ker stat us
T o pr o vi de t he pr oce d ure f or 
c ollecti n g tiss ue sa m ples f or 
bi o mar ker a nal ysis
Secti o n 7. 5. 1. 1 
Defi ne d N CI C T A E
A dj uste d te xt i n sec o n d b ullet u n der 
He pat ot o xicit y fr o m: Gra de 4 A S T, A L T, 
or bilir u bi n fr o m gra de t o ele vati o ns – ne w 
te xt is: 

A S T or A L T ele vati o ns > 2 0 x U L N 

Bilir u bi n ele vati o ns > 1 0. 0 x U L N
C o nsiste nc y wit h ot her t ucati ni b 
pr ot oc ols
Secti o n 7. 5. 1. 1 
A d de d a n o ver d ose of t ucati ni b or 
pe m br oliz u ma b a n d ≥ Gra de 3 diarr hea as 
A E SI 
T o u p date defi niti o n of A E SIs
Secti o n 7. 5. 1. 3 
A d de d seri o us A E re p orti n g d uri n g a n d f or 
9 0 da ys after t he e n d of treat me nt f or 
C o h orts 1 E, 1 F, 1 G, a n d 2 A
T o defi ne t he re p orti n g peri o d f or 
seri o us A Es
Secti o n 7. 5. 3 
A d de d t h yr oi d tests 
T o ali g n wit h pe m br oliz u ma b testi n g 
re q uire me nts
Secti o n 7. 5. 5 
Mi n or a dj ust me nts t o t he te xt ar o u n d 
pre g na nc y testi n g t o be m ore well defi ne d 
a n d m ore c o nsiste nt wit h t he sc he d ule of 
e ve nts li ne ite m f or pre g na nc y testi n g.
Clarificati o ns t o be c o nsiste nt wit h 
S O E c o nte nt
Secti o n 9. 3. 1. 7 
Defi ne d D L T -e val ua ble a nal ysis sets f or 
vari o us c o h orts
T o defi ne e val ua ble a nal ysis sets f or 
ne w c o h orts
Secti o n 9. 3. 1. 9 
A d de d ti mi n g of e val uati o n of vari o us 
c o h orts.
T o pr o vi de t he ti mi n g of t he a nal yses 
f or t he new c o h orts
A p pe n di x A, 
Sc he d ule of E ve nts 
f or P hase 1 b a n d 
M o ve d Hei g ht assess me nt fr o m D -2 8 t o D -
1 cell t o D -7 t o D -1 cell
U p dates t o be c o nsiste nt wit h 
c ha n ges ma de t o t he b o d y of t he 
pr ot oc ol, e xisti n g c o nte nt i n t he 
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 8 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
P hase 2 C o h orts 
Utilizi n g F O L F O X
Delete d assess me nt of vital si g ns, 
i ncl u di n g wei g ht fr o m D-2 8 t o D -1 cell
A dj uste d f o ot n ote te xt o n pre g na nc y 
testi n g a n d a d de d a ne w f o ot n ote i n t he 
E O T a n d F oll o w -u p c ol u m n f or t he 
pre g na nc y test assess me nt r o w of t he 
sc he d ule of e ve nts.
A d de d f o ot n ote B f or Da y 3, C o h orts 1 A 
a n d 1 B o nl y
A d de d f o ot n ote C f or Da y 8, P hase 1 b 
c o h orts o nl y
U p date d f o ot n ote D f or C o h orts 1 D, 1 E, 
2 A, a n d 2 B utilizi n g F O L F O X: sca ns will 
be o btai ne d e ver y 6 w ee ks.
A d de d f o ot n ote H, F or P hase 1 b c o h orts, 
m o st rece ntl y c ollecte d tiss ue, if a vaila ble. 
F or s u bjects e nr olle d i n C o h orts 2 A a n d 
2 B, c ollecti o n of m ost rece ntl y a vaila ble 
tiss ue is re q uire d
U p date d f o ot n ote K: c ystati n C will n ot be 
c ollecte d if n o re nal D L Ts ha ve bee n 
o bser ve d d uri n g d ose escalati o n.
A d de d f o ot n ote R, trast uz u ma b Q 2 W i n 
C o h orts 1 A a n d 1 B a n d Q 3 W i n ot her 
c o h orts
A d de d f o ot n ote S, pe m br oliz u ma b t o be 
gi ve n f or a ma xi m u m of 1 8 d oses
U p date d f o ot n ote U o n ti mi n g of sca ns
Re or dere d se veral f o ot n otes t o be m ore 
se q ue ntiall y al p ha beticall y or dere d.
pr ot oc ol, a n d f or c o nsiste nc y wit h 
ot her t ucati ni b pr ot oc ols.
A p pe n di x A, 
Sc he d ule of E ve nts 
f or P hase 1 b a n d 
P hase 2 C o h orts 
Utilizi n g C A P O X a n d 
Pe m br oliz u ma b 
C o h ort 1 G
M o ve d Hei g ht assess me nt fr o m D -2 8 t o D -
1 cell t o D -7 t o D -1 cell
Delete d assess me nt of vital si g ns, 
i ncl u di n g wei g ht fr o m D-2 8 t o D -1 cell
U p dates t o be c o nsiste nt wit h 
c ha n ges ma de t o t he b o d y of t he 
pr ot oc ol, e xisti n g c o nte nt i n t he 
pr ot oc ol, a n d f or c o nsiste nc y wit h 
ot her t ucati ni b pr ot oc ols.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 0 9 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
A dj uste d f o ot n ote te xt o n pre g na nc y 
testi n g a n d a d de d a ne w f o ot n ote i n t he 
E O T a n d F oll o w -u p c ol u m n f or t he 
pre g na nc y test assess me nt r o w of t he 
sc he d ule of e ve nts.
U p date d f o ot n ote G, c ystati n C will n ot be 
c ollecte d if n o re nal D L Ts ha ve bee n 
o bser ve d d uri n g d ose escalati o n.
A d de d f o ot n ote N, trast uz u ma b Q 3 W 
A d de d f o ot n ote O, pe m br oliz u ma b t o be 
gi ve n f or a ma xi m u m of 1 8 d oses
Delete d P K sa m pli n g f or o xali plati n
U p date d f o ot n ote T f or t ucati ni b P K 
sa m pli n g t hr o u g h C ycle 6
U p date d f o ot n ote Q o n ti mi n g of sca ns
Re or dere d s e veral f o ot n otes t o be m ore 
se q ue ntiall y al p ha beticall y or dere d.
A p pe n di x A: 
Sc he d ule of E ve nts
A d de d pe m br oliz u ma b a d mi nistrati o n t o 
b ot h S O Es
T o i ncl u de ti mi n g of pe m br oliz u ma b 
a d mi nistrati o n
T hr o u g h o ut d oc u me nt 
Defi ne d C R C as c ol orectal 
a de n ocarci n o ma
Clarificati o n
T hr o u g h o ut d oc u me nt
C ha n ge d “ …t he first d ose of st u d y 
treat me nt” t o “e nr oll me nt ( C ycle 1 Da y 1)
A n d, w here a p pr o priate t hr o u g h o ut 
pr ot oc ol, pare nt heticall y i n dicate d 
i nterc ha n gea bilit y of C ycle 1 Da y 1 
(e nr oll me nt) or e nr oll me nt ( C ycle 1 Da y 1)
C o nsiste nc y wit h te xt i n e ntire 
pr ot oc ol a n d t o clearl y i n dicate 
e nr oll me nt a n d C ycle 1 Da y 1 are 
i nterc ha n gea ble 
T hr o u g h o ut d oc u me nt
C ha n ge d “ …st u d y dr u g(s) …” t o “ ….st u d y 
treat me nt(s)”
Clarificati o n. T ucati ni b is c o nsi dere d 
t o be t he i n vesti gati o nal st u d y dr u g. 
B ut all dr u gs bei n g use d are c o nsi der 
part of t he st u d y treat me nt.
T hr o u g h o ut d oc u me nt
Mi n or c orrecti o ns (clerical a n d/ or f or 
clarit y, a dj usti n g r u n -o n se nte nces, a n d 
f or matti n g relate d) a n d mi n or a dj ust me nts 
t o te xt t o be c o nsiste nt wit h c ha n ges 
descri be d a b o ve
A d mi nistrati ve c ha n ges a n d 
c o nsiste nc y
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 0 of 2 2 0
S u m m ar y of C h a n ges i n A me n d m e nt 3. 1
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis a n d Secti o n 2. 2 
( Ta ble 2)
M o ve d O R R o bjecti ve a n d e n d p oi nt 
fr o m e x pl orat or y t o sec o n dar y.
O R R m ust be a sec o n dar y 
o bjecti ve/e n d p oi nt f or t hese c o h orts 
si nce D O R, O S, a n d P F S are als o 
sec o n dar y e n d p oi nts.
S y n o psis, E xcl usi o n 
Criteri o n ( E C) 2 3 a n d 
Secti o n 4. 2 E C 2 3
Re m o ve d C o h ort 2 A fr o m E C 2 3.
C o nsiste nc y wit h E C 4. F or P hase 2 
c o h orts s u bjects wit h acti ve C N S 
metastases are all o we d if t he y meet 
certai n criteria.
Secti o n 5. 7. 2, Ta ble 1 4
Re m o ve d e xtra r o w
E m pt y  r o w was n ot nee de d
T hr o u g h o ut pr ot oc ol
U p date d f o oters a n d dates, as 
a p pr o priate
A d mi nistrati ve
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 1 of 2 2 0
S u m m ar y of C h a n ges i n A me n d me nt 4
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis, 
I ncl usi o n Criteria 
(I C) 1 9 a n d 
Secti o n 4. 1 I C 1 9 
A d de d i ncl usi o n criteri o n i n dicati n g s u bjects 
m ust be willi n g a n d a ble t o a d here t o 
a nti diarr heal pr o p h yla xis.
A nti diarr heals m ust be ta ke n if 
re q uire d.
S y n o psis, 
E xcl usi o n Criteria 
( E C) 1 a n d 
Secti o n 4. 2, E C 1 
A d de d te xt i n dicati n g s u bjects s h o ul d n ot ha ve 
aller g y or h y perse nsi ti vit y t o a n y re q uire d 
c o nc o mita nt me dicati o ns. 
E ns ure s u bjects d o n ot ha ve aller g y 
or h y perse nsiti vit y t o l o pera mi de
S y n o psis, St u d y 
Desi g n a n d 
Secti o n 3. 1, 
Secti o n 3. 1. 2. 1 
t hr o u g h Secti o n 
3. 2. 1. 4, a n d 
Secti o n 3. 1. 3 a n d 
Secti o n 3. 1. 4
A d de d te xt i n dicati n g a nti diarr heal pr o p h yla xis 
re q uire d f or all s u bjects i n C o h orts 1 D a n d 1 E 
a n d f or s u bjects i n C o h ort 2 A w h o recei ve 
t ucati ni b + trast uz u ma b + pe m br oliz u ma b + 
F O L F O X. Pr o vi de d i nf or mati o n o n l o pera mi de 
d osa ge a n d s u m mar y of preli mi nar y data fr o m 
the o n g oi n g st u d y ( S G N T U C -0 2 4).
I n secti o ns a b o ut details of eac h c o h ort – a d de d 
te xt a b o ut t he a nti diarr heal pr o p h yla xis 
a p pr oac h as a p pr o priate f or eac h c o h ort (ie, if 
re q uire or n ot, w he n s u bject will be e x pecte d t o 
use a nti diarr heal, titrati o n of l o per a mi de d oses, 
etc)
Pr o vi de d s u m mar y of h o w  S M C re vie w of 
safet y data will be d o ne f or c o h orts w here 
s u bjects are n ot re q uire d t o recei ve ma n dat or y 
a nti diarr heal pr o p h yla xis.
Base d o n preli mi nar y data fr o m 
C o h orts 1 A a n d 1 B a n d S M C 
rec o m me n dati o ns. a nti diarr heals will 
be gi ve n pr o p h ylacticall y f or C o h orts 
1 D a n d 1 E a n d f or s u bjects i n 
C o h orts 2 A w h o recei ve w h o recei ve 
t ucati ni b + trast uz u ma b + 
pe m br oliz u ma b + F O L F O X as 
s pecifie d. 
Als o pr o vi de d g ui da nce o n a p pr oac h 
f or a nti diarr heal pr o p h yla xis f or 
s u bjects i n ot her c o h orts. 
S y n o psis, St u d y 
Desi g n, Fi g ure 
a n d Secti o n 
3. 1. 4. 2, Fi g ure 1
U p date d C o h ort 1 C t o be N ≥6
C o nsiste nc y wit h u p dates t o b o d y of 
pr ot oc ol
S y n o psis,
Statistical 
Met h o ds a n d 
Secti o n 9. 1 
T he p hrase “ u p t o” has bee n re place d wit h 
“a p pr o xi matel y,” a n d t he p hrase “at least” has 
bee n a d de d i n relati o ns hi p t o D L T e val ua ble 
s u bjects.
U p date d t o i n dicate C o h ort 1 C w ill e nr oll 
a p pr o xi matel y 8 s u bjects t o ha ve 6 s u bjects 
t hat c o m plete t he D L T peri o d.
Mi n or a dj ust me nts t o la n g ua ge f or 
clar it y.
C o nsiste nc y wit h u p dates t o t he b o d y 
of t he pr ot oc ol.
Secti o n 3. 1. 4 
Se parate d te xt a b o ut C o h ort 2 A i nt o Secti o n 
3. 1. 4. 1 a n d C o h ort 2 B i nt o Secti o n 3. 1. 4. 2
F or clarit y
Secti o n 5. 1. 1 a n d 
Secti o n 5. 1. 3 
W here a p plica ble, u p date d ta ble f o ot n otes t o 
i ncl u de le v ole uc o v ori n d ose i nf or mati o n. 
Clarificati o n a b o ut le v ole uc o v ori n 
d ose t hat ca n be s u bstit ute d i n cases 
of s u p pl y s h orta ges (f or t he 
m F O L F O X 6 a n d m F O L F O X 7 
re gi me ns).
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 2 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 5. 7. 2 a n d 
Secti o n 5. 7. 3 
A d de d te xt i n dicati n g pe m br oliz u ma b ma y be 
c o nti n ue d d uri n g peri o ds of F O L F O X dela y i n 
s u bjects recei vi n g F O L F O X or d uri n g peri o ds 
of o xali plati n treat me nt dela y i n s u bjects 
recei vi n g C A P O X.
Ot her st u d y treat me nts ma y be 
c o nti n ue d i n t he e ve nt of F O L F O X 
or o xali plati n (as part of C A P O X) 
treat me nt dela y. 
Secti o n 5. 7. 8 
A d de d secti o n wit h te xt f or ma na ge me nt of 
diarr hea. I ncl u de d te xt a b o ut a nti diarr heal 
pr o p h yla xis, w he n a nti diarr heal pr o p h yla xis is 
c o ntrai n dicate d a n d te xt a b o ut earl y detecti o n 
a n d earl y i nter ve nti o n a p pr oac hes, a n d 
i nstr ucti o ns that s h o ul d be pr o vi de d b y t he 
i n vesti gat or. A d diti o n of t his secti o n m o ve d 
s u bse q ue nt secti o ns u p b y o ne le vel (t he ol d 
5. 7. 8 beca me 5. 7. 9, etc).
T o pr o vi de details o n a nti diarr heal 
usa ge pr o p h ylacticall y ( C o h orts 1 D 
a n d 1 E a n d f or s u bjects i n C o h ort 2 A 
w h o recei ve t ucati ni b + trast uz u ma b 
+ pe m br oliz u ma b + F O L F O X) a n d 
f or ot her c o h orts i n t he e ve nt of 
s y m pt o matic diarr hea e ve nts.
Secti o n 5. 9. 2 
A d de d Secti o n t o i n dicate l o pera mi de is a 
re q uire d c o nc o mita nt me dicati o n f or s u bjects 
e nr olle d i n C o h orts 1 D a n d 1 E a n d f or s u bjects 
i n c o h ort 2 A w h o recei ve t ucati ni b + 
trast uz u ma b + pe m br oliz u ma b + F O L F O X; 
i ncl u de d details a b o ut a d mi nistrati o n of 
l o pera mi de.
Base d o n preli mi nar y data fr o m 
C o h orts 1 A a n d 1 B a n d S M C 
rec o m me n dati o ns. a nti diarr heals will 
be gi ve n pr o p h ylacticall y, as 
s pecifie d, t o re d uce ris k of p ossi ble 
diarr hea a d verse e ve nts.
Secti o n 5. 9. 3 
U p date d te xt relate d t o a nti diarr heals i n 
all o we d c o nc o mita nt me dicati o n t hera p y t o be 
c o nsiste nt wit h ot her u p dates i n t he c urre nt 
a me n d me nt.
C o nsiste nc y bet we e n t his secti o n a n d 
ot her secti o ns t hat ha ve bee n u p date d 
wit hi n c urre nt a me n d me nt.
Secti o n 6. 2 
t hr o u g h Secti o n 
6. 6 a n d 
s u bsecti o ns 
t herei n. 
A dj uste d b ullets a n d a d de d te xt as nee de d t o 
pr o vi de details f or t he a p pr oac h f or t he 
ma n dat or y a nti diarr heal pr o p h yla xis i n C o h orts 
1 D a n d 1 E a n d f or s u bjects i n c o h ort 2 A w h o 
recei ve t ucati ni b + trast uz u ma b + 
pe m br oliz u ma b + F O L F O X, f or treat me nt of 
s y m pt o matic diarr hea i n ot her c o h orts, 
pr o vi de d g ui da nce o n usa ge of s u bject diaries, 
a n d f or assessi n g diarr hea e ve nts, as 
a p pr o priate, i n eac h secti o n/c o h ort. 
C o nsiste nc y wit hi n pr ot oc ol base d 
o n u p dates relate d t o re q uire me nt f or 
a nti diarr heal pr o p h yla xis.
Secti o n 7. 3 
U p date d relati ve ti me c ol u m n i n Ta ble 2 2 t o 
i n dicate d “ Pri or t o ti me of A M t ucati ni b 
a d mi nistrati o n” f or P K sa m ples f or C ycles 3 -6 
D a y  1.
U p date d te xt i n “ Ti me” c ol u m n f or c ycle 2 -6 i n 
Ta ble 2 4 t o i n dicate ti me of t ucati ni b P K is 
pre d ose. 
U p date d “ Relati ve Ti me” c ol u m n i n Ta ble 2 4 
a n d Ta ble 2 5 t o i n dicate “ Pri or t o ti me of A M 
t ucati ni b a d mi nistrati o n”
Clarificati o n t o be c o nsiste nt wit h 
rest of pr ot oc ol a n d sc he d ule of 
e ve nts
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 3 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 7. 5. 1. 2 
C ha n ge pre g na nc y re p orti n g fr o m wit h 4 8 
h o urs t o wit hi n 2 4 h o urs of bec o mi n g a ware of 
a pre g na nc y.
A d de d te xt t hat “ Diaries ma y be use d f or 
rec or di n g n u m ber of st o ols per da y t o ai d wit h 
acc uratel y d oc u me nti n g a n d gra di n g diarr hea 
A E s.”
C o nsiste nc y wit h c urre nt pre g na nc y 
re p orti n g g ui deli nes.
Pr o vi d e i nf or mati o n a b o ut diaries.
A p pe n di x A, 
Sc he d ule of 
E ve nts f or P hase 
1 b a n d P hase 2 
C o h orts Utilizi n g 
F O L F O X
Re m o ve d f o ot n ote t hat was o n Da y 8 t hat 
state d “ P hase 1 b c o h orts o nl y”. B ut ke pt 
f o ot n ote “ C” o n C ycle 2-3 Da y 8 a n d clarifie d 
te xt t o i n dicate assess me nts t hat a p plie d t o 
eac h of t he P hase 1 b a n d P hase 2 c o h orts 
utilizi n g F O L F O X. 
C o nsiste nc y wit h u p dates ma d e i n 
t his a me n d me nt.
O n t he A E a n d c o nc o mita nt me dicati o ns R o w, 
a d de d pare nt hetical te xt a b o ut diarr hea A Es 
a n d a nti diarr heal usa ge. 
T o clearl y i n dicate diarr hea A Es a n d 
a nti diarr heal usa ge s h o ul d be 
ca pt ure d.
A d de d r o w  f or “Iss ue S u bject Diaries” wit h 
a p pr o priate iss ue a n d c ollecti o n/re vie w 
i nf or mati o n. 
C o nsiste nc y wit h u p dates t o Secti o n 
8
A dj uste d h o w d osi n g f or trast uz u ma b ( Q 2 W or 
Q 3 W) a n d pe m br oliz u ma b ( Q 6 W) is prese nte d. 
Clarificati o n t o i n dicate trast uz u ma b 
d osi n g is Q 2 W f or C o h orts 1 A a n d 
1 B a n d Q 3 W f or all ot her c o h orts, 
a n d t hat pe m br oliz u ma b d osi n g is 
Q 6 W.
U p date f o ot n ote P wit h te xt a b o ut c o nc o mita nt 
me dici nes a n d a nti diarr heals.
C o nsiste nt wit h u p dates t o Secti o n 
7. 1. 1. 2 
U p date d f o ot n ote Z t o i ncl u de i nf or mati o n 
a b o ut sa m pli n g ti mes f or C o h ort 1 E a n d t o 
pr o vi de clarificati o ns a b o ut sa m pli n g ti mes f or 
C o h ort 1 D.
C orrecti o n of t y p o gra p hical o missi o n 
a n d c o nsiste nc y wit h ta bles cite d.
A p pe n di x A, 
Sc he d ule of 
E ve nts f or P hase 
1 b a n d P hase 2 
C o h orts Utilizi n g 
C A P O X a n d 
Pe m br oliz u ma b 
C o h ort 1 G
U p date d f o ot n ote B t o i n dicate w hic h 
assess me nts a p pl y t o w hic h c o h orts o n C ycle 1 
D a y  8 a n d C ycle 2 Da y 8.
C o nsiste nc y wit h u p dates t o t he b o d y 
of t he pr ot oc ol. 
O n t he A E a n d c o nc o mita nt me dicati o ns R o w, 
a d de d pare nt hetical te xt a b o ut diarr hea A Es 
a n d a nti diarr heal usa ge. 
T o clearl y i n dicate diarr hea A Es a n d 
a nti diarr heal usa ge s h o ul d be 
ca pt ure d.
A d de d r o w  f or S u bject Diaries wit h 
a p pr o priate iss ue a n d c ollecti o n/re vie w 
i nf or mati o n. 
C o nsiste nc y wit h u p dates t o Secti o n 
8.
A dj uste d h o w d osi n g f or pe m br oliz u ma b 
( Q 6 W) is prese nte d. 
D osi n g is Q 6 W f or pe m br oliz u ma b.
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 4 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Re m o ve d “ p ost d ose” fr o m pare nt hetical te xt 
o n r o w  f or “ Bl o o d sa m ples f or t ucati ni b P K”
C o nsiste nc y wit h t he pr ot oc ol b o d y
U p date f o ot n ote L wit h te xt a b o ut c o nc o mita nt 
me dici nes t o i n dicate t o refer t o secti o n 5. 9. 2.
C o nsiste nt wit h u p dates t o Secti o n 
7. 1. 1. 2 
U p date d f o ot n ote S t o i ncl u de C o h orts 1 E, a n d 
1 G, a n d i nc or p orate d pre d ose i nstr ucti o n 
pre vi o usl y i ncl u de d i n f o ot n ote T. Re m o ve d 
f o ot n ote T si nce it was n o l o n ger nee de d
C o ns oli dati o n of relate d i nf or mati o n 
pre vi o usl y c o ntai ne d i n 2 f o ot n otes 
i nt o 1 f o ot n ote.
T hr o u g h o ut 
d oc u me nt
Mi n or e dit orial a n d f or matti n g u p dates; 
u p date d f o oters a n d dates, as a p pr o priate
A d mi nistrati ve
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 5 of 2 2 0
S u m m ar y of C h a n ges i n A me n d me nt 5
Secti o n(s)
C ha n ge
Rati o nale
C o ver pa ge
A d de d 
 as St u d y 
Direct or a n d u p date d e mail a d dress 
c o ntact f or
 Me dical 
M o nit or.  
Pr o visi o n of St u d y Direct or c o ntact 
i nf or mati o n a n d u p date d Me dical M o nit or 
e mail a d dress.
C o ver pa ge
I n dicate d t hat Sea ge n I nc. has bee n 
ac q uire d b y Pfizer I nc.
Sea ge n is part of Pfizer as of 1 4 Dec 2 0 2 3
S y n o psis, St u d y 
O bjecti ves; Secti o n 
2. 4
T o e val uate t he P K of t ucati ni b gi ve n 
wit h pe m br oliz u ma b, trast uz u ma b, a n d 
o xali plati n -base d c he m ot hera p y as 1 L 
t hera p y f or u nresecta ble or metastatic 
H E R 2 + gastric, es o p ha geal, or G EJ 
a de n ocarci n o ma ( C o h ort 2 A) or a n d t o 
e val uate t he P K of t ucati ni b gi ve n
wit h trast uz u ma b a n d o xali plati n -
base d c he m ot hera p y as 1 L + t hera p y 
f or metastatic H E R 2 + C R C ( C o h ort 
2 B)
A d diti o n of te xt t o m ore clearl y i n dicate 
P K is als o e val uate d f or C o h ort 2 B
S y n o psis, N u m ber of 
Pla n ne d S u bjects; 
Secti o n 3. 1
E dite d te xt t o reflect altere d 
e nr oll me nt pr ojecti o n fr o m 
a p pr o xi matel y 1 2 0 t o a p pr o xi matel y 
4 0 s u bjects.
Pr o vi de u p date d e nr oll me nt pr ojecti o n 
u p o n i m ple me ntati o n of A me n d me nt 5 
S y n o psis, St u d y 
Desi g n; Secti o n 3. 1, 
Secti o n 3. 1. 8
A d de d f o ot n ote b t o ta ble i n s y n o psis 
a n d Sectio n 3. 1 s u m marizi n g c o h orts, 
treat me nts, p o p ulati o ns, a n d n u m ber 
of s u bjects t o i n dicate t hat n o 
a d diti o nal e nr oll me nt will occ ur f or 
a n y c o h ort as of A me n d me nt 5. T his 
te xt was als o i ncl u de d i n Secti o n 3. 1. 8
N o a d diti o nal e nr oll me nt will occ ur as of 
A me n d m e nt 5 d ue t o s p o ns or decisi o n 
S y n o psis, St u d y 
Desi g n
S pecificati o n of l o pera mi de 
pr o p h yla xis re gi me n f or C o h orts 1 D, 
1 E, a n d 2 B
Clearl y i n dicate w hic h c o h orts re q uire 
l o pera mi de pr o p h yla xis
S y n o psis, St u d y 
Desi g n; S y n o psis, 
P hase 2 T u m or -
S pecific E x pa nsi o n 
C o h orts ( C o h orts 2 A 
a n d 2 B); Secti o n 3. 1; 
Secti o n 3. 1. 4. 2; 
Secti o n 5. 9. 2; Secti o n 
5. 9. 3; Secti o n 6. 3. 1; 
Secti o n 6. 3. 4
E dite d te xt t o i n dicate t hat l o pera mi de 
pr o p h yla xis is n o w re q uire d f or C o h ort 
2 B
Base d o n re vie w  of C o h ort 2 B data as of 
1 2 -Dec -2 0 2 3, te xt w as u p date d t o 
i n dicate l o pera mi de pr o p h yla xis is n o w 
ma n dat or y f or C o h ort 2 B
S y n o psis, D urati o n of 
Treat me nt; Secti o n 6. 1
A d de d la n g ua ge descri bi n g t hat 
s u bjects still recei vi n g cli nical be nefit 
a n d re mai ni n g o n st u d y treat me nt as of 
A me n d me n t 5, ma y c o nti n ue t o 
recei ve st u d y dr u g d uri n g t he L T E P
S pecif y p ote ntial f or c o nti n ue d st u d y 
dr u g i n s u bjects recei vi n g cli nical be nefit 
as of A me n d me nt 5
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)
P P D
P P D

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 6 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
S y n o psis, Efficac y 
Assess me nts; Secti o n 
7. 2
A d de d te xt: “ D uri n g t he L T E P, 
efficac y assess me nts will be 
perf or me d per i nstit uti o nal g ui deli nes 
a n d i n vesti gat or -deter mi ne d us ual a n d 
c ust o mar y cli nical care ”
Clarif y c ollecti o n of efficac y assess me nts 
d uri n g t he L T E P
S y n o psis, 
P har m ac o ki netic 
Assess me nts
Clarifie d t hat n o P K assess me nts will 
be perf or me d f oll o wi n g 
i mple me ntati o n of A me n d me nt 5
S pecif y t hat P K sa m ples will n ot be 
c ollecte d at E O T f oll o wi n g 
i mple me ntati o n of A me n d me nt 5
S y n o psis, Bi o mar ker 
Assess me nts
Clarifie d t hat n o bl o o d sa m ples f or 
bi o mar ker assess me nts will be dra w n 
at E O T f oll o wi n g i m p le me ntati o n of 
A me n d me nt 5
A d diti o n of g ui da nce a b o ut bl o o d 
sa m ples at E O T f oll o wi n g 
i mple me ntati o n of A me n d me nt 5
S y n o psis, Safet y 
Assess me nts; Secti o n 
6. 1; Secti o n 7. 5
Pr o vi de d g ui da nce f or safet y 
assess me nts, i ncl u di n g pre g na nc y 
testi n g, a n d re p orti ng d uri n g t he 
L T E P.
Clarif y safet y assess me nts t o be c ollecte d 
d uri n g L T E P
Secti o n 3. 1. 8 ( ne w  
secti o n)
A d diti o n of Secti o n 3. 1. 8 L o n g -ter m 
E xte nsi o n P hase t o descri be L T E P 
desi g n
Pr o vi de details a b o ut a d diti o n of a n L T E P 
t o t he st u d y t hat are c o nsiste nt wit h L T E P 
relate d u p dates t hr o u g h o ut t he d oc u me nt
Secti o n 3. 1. 9
Clarificati o n of E n d of St u d y after 
i mple me ntati o n of L T E P
U p date e n d of st u d y te xt f or c o nsiste nc y 
wit h a d diti o n of t he L T E P
Secti o n 5. 3. 3; Secti o n 
5. 5. 3; Secti o n 5. 6. 3
Re m o ve d rec o m me n dati o n t o 
recalc ulate d oses if t here is a > 1 0 % 
c ha n ge i n baseli ne b o d y wei g ht
E dite d te xt t o i n dicate t hat f or b o d y 
wei g ht c ha n ges, d oses of trast uz u ma b 
a n d F O L F O X s h o ul d be recalc ulate d 
acc or di n g t o i nstit uti o nal sta n dar d of 
care
Clarif y d ose recalc ulati o n re q u ire me nts 
d uri n g t he L T E P 
Secti o n 5. 7. 2
A d de d te xt “ D uri n g t he L T E P, 
i n vesti gat ors ma y c h o ose t o f oll o w 
i nstit uti o nal sta n dar d of care f or 
F O L F O X d ose m o dificati o ns ”
Clearl y i n dicate i n vesti gat ors ma y f oll o w 
i nstit uti o nal S O C
Secti o n 5. 7. 2, Ta ble 
1 4
A d de d f o ot n ote b t o Ta ble 1 4 t o 
pr o vi de m ore i nf or mati o n a b o ut 
ma na ge me nt of diarr hea relate d t o 
m F O L F O X 6
5- F U b ol us ma y be disc o nti n ue d i n e ve nt 
of se vere diarr hea wit h m F O L F O X 6
Secti o n 5. 7. 2, Ta ble 
1 4
A d de d f o ot n ote c t o Ta ble 1 4 t o 
pr o vi de m ore i nf or mati o n a b o ut 
ma na ge me nt of ot her n o n he mat ol o gic 
t o xicities
G ui da nce a b o ut ne xt c ycle of t hera p y 
d uri n g Gra de 2 n o n he mat ol o gical 
t o xicities
Secti o n 5. 7. 3
Clarifie d t hat “ D uri n g t he L T E P, 
i n vesti gat ors ma y c h o ose t o f oll o w 
i nstit uti o nal sta n dar d of care f or 
C A P O X d ose m o dificati o ns ”
Clearl y i n dicate i n vesti gat ors ma y f oll o w 
i nstit uti o nal S O C
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 7 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 5. 7. 3, Ta ble 
1 7
A d de d f o ot n ote a t o Ta ble 1 7 t o clarif y 
deter mi nati o n of d ose m o dificati o ns t o 
C A P O X f or ne utr o pe nia a n d 
t hr o m b oc yt o pe nia. T his has s hifte d all 
s u bse que nt f o ot n otes
Pr o vi de g ui da nce relate d t o C A P O X d ose 
m o dificati o ns 
Secti o n 5. 1 1
I de ntifie d t hat treat me nt 
a d mi nistrati o n data will n o l o n ger be 
c ollecte d i n e C R Fs after L T E P 
i mple me ntati o n a n d refere nce d 
Secti o n 8. 2 f or L T E P data c ollecti o n 
re q uire me nts
U p date data c ollecti o n g ui da nce after 
L T E P i m ple me ntati o n
Secti o n 6. 3. 1
C orrecte d te xt t o clearl y i n dicate w he n 
bl o o d sa m ples f or t ucati ni b P K are 
c ollecte d, f or c o nsiste nc y acr oss 
pr ot oc ol
U p date t o e ns ure c o nsiste nc y acr oss 
pr ot oc ol
Secti o n 6. 6 ( ne w  
secti o n)
A d de d t he f oll o wi n g c o nte nt: 
S u bjects still recei vi n g cli nical be nefit 
a n d re mai ni n g o n st u d y treat me nt as of 
A me n d me nt 5 ma y c o nti n ue recei vi n g 
st u d y dr u gs d uri n g t he L T E P. 

O nl y i nf or mati o n relate d t o 
pre g na ncies, S A Es, a n d A E SIs 
( Secti o n 9. 5. 1. 1) will be re p orte d 
t o t he S p o ns or

All safet y a n d efficac y assess me nts 
will be perf or me d per us ual a n d 
c ust o mar y practice, wit h t he 
e xce pti o n of pre g na nc y testi n g

Pre g na nc y testi n g will c o nti n ue t o 
be perf or me d as o utli ne d i n t he 
sc he d ule of e ve nts i n s u bjects of 
c hil d-beari n g p ote ntial
S pecif y safet y i nf or mati o n, assess me nts, 
a n d pre g na nc y testi n g t o be c ollecte d 
d uri n g t he L T E P
Secti o n 6. 7
Clarifie d t hat bl o o d sa m ples f or 
bi o mar ker a nal ysis a n d t ucati ni b P K 
will n ot be c ollecte d after 
i mple me ntati o n of A me n d me nt 5
U p date t o e ns ure c o nsiste nc y acr oss 
pr ot oc ol
Secti o n 6. 8
A d de d te xt t o i n dicate t hat as of 
A me n d me nt 5, l o n g -ter m f oll o w u p 
will be disc o nti n ue d a n d t hat s u bjects 
i n l o n g ter m f oll o w-u p as of 
A me n d me nt 5 will tra nsiti o n t o e n d of 
st u d y
C o nsiste nc y wit h u p dates ma de acr oss t he 
pr ot oc ol d uri n g t his a me n d me nt
Secti o n 7. 3
Clarifie d t hat n o P K assess me nts will 
be perf or me d f oll o wi n g 
i mple me ntati o n of A me n d me nt 5
A dj uste d Ta ble 2 2 f o ot n ote or der
S pecif y t hat P K sa m ples will n ot be 
c ollecte d at E O T f oll o wi n g 
i mple me ntati o n of A me n d me nt 5
A d mi nistrati ve u p date
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 8 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 7. 4
Clarifie d t hat n o bl o o d sa m ples f or 
bi o mar ker assess me nts will be dra w n 
at E O T f oll o wi n g i m ple me ntati o n of 
A me n d me nt 5
A d diti o n of g ui da nce a b o ut bl o o d 
sa m ples at E O T f oll o wi n g 
i mple me ntati o n of A me n d me nt 5
Secti o n 7. 5. 1. 1, 
A d verse E ve nt
I de ntifie d t hat S A Es s h o ul d be 
re p orte d t o t he S p o ns or s olel y o n t he 
S A E f or m, f oll o wi n g t he re p orti n g 
g ui deli nes i n Secti o n 7. 5. 1. 2 a n d will 
n ot be rec or de d w it hi n t he e C R F
Clarificati o n of data c ollecti o n d uri n g 
L T E P
Secti o n 7. 5. 1. 1, 
A d verse E ve nts of 
S pecial I nterest
A d de d t he f oll o wi n g te xt: “ D uri n g t he 
L T E P, A E SIs will be re p orte d t o t he 
s p o ns or usi n g a n S A E f or m o nl y a n d 
will n ot be rec or de d w it hi n t he e C R F.”
Clarificati o n of data c oll ecti o n d uri n g 
L T E P
Secti o n 7. 5. 1. 2, 
Rec or di n g Seri o us 
A d verse E ve nts
A d de d t he f oll o wi n g te xt: “ H o we ver, 
d uri n g t he L T E P, S A Es will be 
re p orte d t o t he S p o ns or s olel y o n t he 
S A E f or m f oll o wi n g t he sa me 
re p orti n g g ui deli nes as o utli ne d bel o w, 
a n d will n ot b e rec or de d wit hi n t he 
e C R F.”
G ui da nce o n rec or di n g S A Es d uri n g t he 
L T E P
Secti o n 7. 5. 1. 2, 
C ollecti o n of Data o n 
t he e C R F
A d de d te xt t o clarif y pre g na nc y data 
c ollecti o n d uri n g t he L T E P
G ui da nce f or data c ollecti o n of 
pre g na ncies t hat occ ur d uri n g t he L T E P
Secti o n 7. 5. 3
Clarifie d t hat l ocal la b orat or y testi n g 
will be perf or me d per i nstit uti o nal 
g ui deli nes a n d i n vesti gat or -deter mi ne d 
us ual a n d c ust o mar y care, e xce pt f or 
pre g na nc y testi n g ( w hic h will c o nti n ue 
t o be c ollecte d as o utli ne d i n t he 
sc he d ule of e ve nts).
C o nsiste nc y wit h u p dates ma de i n t he 
b o d y of t he d oc u me nt
Secti o n 7. 5. 5
A d de d t he f oll o wi n g te xt: “ D uri n g t he 
L T E P, pre g na nc y testi n g will c o nti n ue 
t o be perf or me d as o utli ne d a b o ve i n 
t he sc he d ule of e ve nts f or s u bjects of 
c hil d-beari n g p ote ntia l. Pre g na nc y 
re p orti n g s h o ul d c o nti n ue a n d will be 
c ollecte d b y t he S p o ns or usi n g t he 
Pre g na nc y Re p ort F or m. Please see 
Secti o n 7. 5. 1. 2 f or f urt her details o n 
pre g na nc y re p orti n g re q uire me nts. ”
Pr o vi de d g ui da nce f or pre g na nc y testi n g 
a n d re p orti n g d uri n g t he L T E P
Secti o n 7. 5. 6. 1 a n d 
Secti o n 7. 5. 6. 2
Clarifie d car diac f u ncti o n a n d E C G 
assess me nts will be perf or me d per 
i nstit uti o nal g ui deli nes a n d 
i n vesti gat or-deter mi ne d us ual a n d 
c ust o mar y cli nical care d uri n g t he 
L T E P.
Pr o vi de u p date d g ui da nce re gar di n g E C G
assess me nts d uri n g t he L T E P
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 1 9 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
Secti o n 8. 1
Clarifie d t hat e C R Fs will be re vie we d 
f or c o m plete ness, a d here nce t o 
pr o vi de d g ui deli nes, a n d acc urac y 
c o m pare d t o s o urce d oc u me nts u ntil 
t he fi nal data base l oc k occ urs
Clarif y e C R F re vie w peri o d
Secti o n 8. 2
A d de d te xt t o i n dicate data c ollecti o n 
nee de d d uri n g L T E P 
G ui da nce f or data c ollecti o n d uri n g L T E P
Secti o n 8. 4
A d de d te xt t o i n dicate e C R Fs will n ot 
be c ollecte d d uri n g L T E P
e C R Fs will n ot be c ollecte d i n t he L T E P
Secti o n 9. 3. 1. 7
E dite d te xt as f oll o ws: T he F ull 
A nal ysis Set will be use d f or t he 
a nal ysis of efficac y e n d p oi nts. P F S.
A d de d t he f oll o wi n g te xt: “ T he 
Res p o nse E val ua ble A nal ysis Set will 
i ncl u de all s u bjects w h o meet all 
f oll o wi n g criteria: ( 1) ha d meas ura ble 
disease at baseli ne, ( 2) recei ve d a n y 
a mo u nt of st u d y treat me nt, a n d ( 3) ha d 
at least o ne p ost -baseli ne disease 
assess me nt of disc o nti n ue d d ue t o 
cli nical pr o gressi o n, t o xicit y, or 
deat h. ”
E ns ure s u bjects e val uate d f or O R R ha ve 
meas ura ble disease at baseli ne per 
R E CI S T v 1. 1 a n d are eli gi b le t o ac hie ve 
a n o bjecti ve res p o nse.
Secti o n 9. 3. 5
E dite d te xt as f oll o ws: T he O R R will 
be s u m marize d usi n g t he f ull a nal ysis
res p o nse e val ua ble set.
E ns ure s u bjects e val uate d f or O R R ha ve 
meas ura ble disease at baseli ne per 
R E CI S T v 1. 1 a n d are eli gi ble t o ac hie ve 
a n o bjecti ve res p o nse.
A p pe n di x A: Sc he d ule 
of E ve nts: P hase 1 b 
a n d P hase 2 C o h orts 
Utilizi n g F O L F O X
A d de d c ol u m n f or assess me nts nee de d 
d uri n g t he L T E P t o S O E ta bles. 
F o ot n otes B B, C C, D D, E E, F F, a n d 
G G w ere a d de d t o e ns ure g ui da nce 
a b o ut assess me nts, as of A me n d me nt 
5 a n d d uri n g t he L T E P, is clearl y 
descri be d i n t he F O L F O X relate d S O E 
ta ble.
U p date d f o ot n ote P t o reflect t hat 
l o pera mi de pr o p h yla xis is n o w 
re q uire d f or C o h ort 2 B.
U p date d f o ot n otes J t o re m o ve “ 2 4 
h o ur uri ne is re q uire d if uri ne 
pr otei n/creati ni ne rati o is > 2. 0”
U p date d f o ot n ote N t o reflect 
pre g na nc y testi n g re q uire me nts d uri n g 
t he L T E P
C ol u m n a d de d t o i n dicate ti mi n g of 
assess me nts t o be d o ne d uri n g t he L T E P. 
Clear descri pti o ns f or A E c ollecti o n, 
bl o o d bi o mar ker sa m pli n g, a n d ot her 
safet y a n d efficac y assess me nts d uri n g 
t he L T E P.
U p date t o e ns ure c o nsiste nc y acr oss 
pr ot oc ol
Re m o ve d te xt i nte n de d o nl y f or c o h orts 
1 A/ 1 B t hat was i na d verte ntl y n ot 
r e mo ve d i n a pre vi o us a me n d me nt. 
Pr o vi de d g ui da nce f or pre g na nc y testi n g 
a n d re p orti n g d uri n g t he L T E P
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)

C 4 2 5 1 0 0 5 ( S G N T U C -0 2 4)
Cli nical Pr ot oc ol
A me n d me nt 0 6, 0 6- N o v -2 0 2 4
T ucati ni b
Sea ge n I nc., a w h oll y o w ne d s u bsi diar y of Pfizer - C o nfi de ntial
Pa ge 2 2 0 of 2 2 0
Secti o n(s)
C ha n ge
Rati o nale
U p date d f o ot n ote Z 
T o e ns ure c o nsiste nc y wit h u p dates ma de 
i n t he b o d y of t he d oc u me nt.
A p pe n di x A: Sc he d ule 
of E ve nts - P hase 1 b 
a n d P hase 2 C o h orts 
Utilizi n g C A P O X a n d 
Pe m br oliz u ma b 
C o h ort 1 G
A d de d c ol u m n f or assess me nts nee de d 
d uri n g t he L T E P t o S O E ta bles. 
U p date d f o ot n ote F t o re m o ve “ 2 4 
h o ur uri ne is re q uire d if uri ne 
pr otei n/creati ni ne rati o is > 2. 0”
A d de d f o ot n otes T, U, V, W, a n d X t o 
e ns ure g ui da nce a b o ut assess me nts, as 
of A me n d me nt 5 a n d d uri n g t he 
L T E P, is clearl y descri be d i n t he 
C A P O X a n d Pe m br oliz u ma b relate d 
S O E ta ble.
U p date d f o ot n ote K t o reflect 
pre g na nc y testi n g re q uire me nts d uri n g 
t he L T E P
C ol u m n a d de d t o i n dicate ti mi n g of 
assess me nts t o be d o ne d uri n g t he L T E P. 
Re m o ve d te xt i nte n de d o nl y f or c o h orts 
1 A/ 1 B t hat was i na d verte ntl y n ot 
r e mo ve d i n a pre vi o us a me n d me nt.
Clear descri pti o ns f or A E c ollecti o n, 
bl o o d bi o mar ker sa m pli n g, a n d ot her 
safet y a n d efficac y assess me nts d uri n g 
t he L T E P
Pr o vi de d g ui da nce f or pre g na nc y testi n g 
a n d re p orti n g d uri n g t he L T E P
T hr o u g h o ut d oc u me nt
C orrecti o n of t y p o gra p hical err ors, 
f or matti n g err ors, a n d mi n or 
a d mi nistrati ve c orrecti o ns
A d mi nistrati ve u p dates
0 9 0 1 7 7 e 1 a 2 2 6 0 d 8 d\ A p pr o v e d\ A p pr o v e d O n: 1 1- N o v- 2 0 2 4 1 8: 5 5 ( G M T)