MOUNTAINEER: A Phase II, Open Label Study of Tucatinib Combined With Trastuzumab in Patients With HER2+ Metastatic Colorectal Cancer
Phase: PHASE2
Conditions: Metastatic Colorectal Adenocarcinoma
Sponsor: Seagen Inc.

 
T his d oc u me nt c o ntai ns i nf or mati o n pr o prietar y t o Sea ge n I nc. T he i nf or mati o n is bei n g pr o vi de d t o y o u f or t he 
p ur p ose of c o n d ucti n g a cli nic al trial f or Sea ge n I nc. Y o u ma y discl ose t he c o nte nts of t his d oc u me nt t o st u d y 
pers o n nel u n der y o ur s u per visi o n a n d t o y o ur I nstit uti o nal R e vie w B oar d (I R B) or Et hics C o m mittee ( E C) f or 
t he sa me p ur p ose. Y o u ma y n ot discl ose t he c o nte nts of t his d oc u me nt t o a n y ot her part y, u nless g o ver n me nt 
re g ulati o ns or la ws re q uire s uc h discl os ure, wit h o ut pri or writte n per missi o n fr o m Sea ge n I nc. A n y 
s u p ple me ntal i nf or mati o n t hat ma y be a d de d t o t his d oc u me nt is pr o prietar y t o Sea ge n I nc. a n d s h o ul d be 
ha n dle d usi n g t he discl os ure pr oce d ure descri be d a b o ve.  
 
 
 
Pr ot oc ol N u m ber:  
A C C R U -GI -1 6 1 7 , S G N T U C -0 1 7  
Versi o n:  
A me n d me nt 1 2  [0 9 -Mar -2 0 2 3 ] 
Pr ot oc ol Title:  
M O U N T AI N E E R: A  P hase 2 , O pe n La bel St u d y o f T ucati ni b 
C o m bi ne d w it h Trast uz u ma b in Patie nts w it h HE R 2 + 
Metastatic C ol orectal Ca ncer  
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 i n Patie nts wit h H E R 2 + C ol orectal 
Ca ncer  
P h ase:  
2  
I N D N u m ber: 
1 3 4 8 4 0  
E u dr a C T N u m ber  
2 0 2 0 -0 0 0 5 4 0 -6 0  
Cli nic al Tri als. g o v 
I de ntifier 
N C T 0 3 0 4 3 3 1 3  
S p o ns or:  
Sea ge n  I nc. 
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  
Me dic al M o nit or:  
, M D 
Tel : 
 
E mail: 
 
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 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)
P P D
P P D
P P D

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2  of 1 7 0  
S P O N S O R P R O T O C O L A P P R O V A L P A G E  
 
Pr ot oc ol N u m ber:  
A C C R U -GI -1 6 1 7, S G N T U C -0 1 7  
Pr ot oc ol Title:  
M O U N T AI N E E R: A P hase 2, O pe n La bel St u d y of T ucati ni b 
C o m bi ne d wit h Trast uz u ma b i n P atie nts wit h H E R 2 + Metast atic 
C ol orectal Ca ncer  
I n vesti g ati o n al Pr o d uct: 
T ucati ni b  
Versi o n:  
A me n d me nt 1 2 ; 0 9 -Mar -2 0 2 3  
T he s p o ns or a grees t o be res p o nsi ble f or i m ple me nti n g a n d mai ntai ni n g q ualit y c o ntr ol a n d 
q ualit y ass ur a nce s yste ms wit h writte n pr oce d ures t o e ns ure t hat t he cli nical trial is 
c o n d ucte d a n d d ata are ge nerat e d, d oc u me nte d, a n d re p orte d i n c o m plia n ce wit h t his 
pr ot oc ol, acce pte d sta n d ar ds of g o o d cli nical pr actice, a n d all a p plica ble fe deral, state, a n d 
l ocal la ws, r ules, re g ulati o ns, re q uire me nts, a n d g ui deli nes (i ncl u di n g all f orei g n l a ws a n d 
g o ver n me ntal re q uire me nts as a p plica ble) relati n g t o t he c o n d u ct  of t he cli nical trial.  
T he i n di vi d uals si g ni n g b el o w ha ve re vie we d a n d a p pr o ve t his pr ot oc ol.  
 
 
 
 
, M D 
 
 
Date   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)
P P D
P P D

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3  of 1 7 0  
P R O T O C O L S Y N O P SI S  
Pr ot oc ol N u m ber  
A C C R U -GI -1 6 1 7, S G N T U C -0 1 7  
Versi o n  
A me n d me nt 1 2 ; 0 9 -Mar -2 0 2 3  
P h ase  
2  
Pr o d uct N a me  
T ucati ni b  
S p o ns or  
Sea ge n  I nc. 
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  
M O U N T AI N E E R: A  P hase 2, O pe n  La b el St u d y of T ucati ni b C o m bi ne d wit h Trast uz u ma b i n P atie nts wit h 
H E R 2 + Metastatic C ol orectal Ca ncer  
St u d y O bjecti ves  
T his st u d y c o nsists of 3 c o h orts:  
•  
C o h ort A = ~ 4 0 s u bj ects d ose d wit h t ucati ni b a n d trast uz u ma b  
•  
Ra n d o mize d c o h orts:  
o  
C o h ort B = ~ 4 0 s u bj ects d ose d wit h t ucati ni b a n d trast uz u ma b  
o  
C o h ort C = ~ 3 0  s u bj ects d ose d wit h t ucati ni b m o n ot hera p y 
Pri m ary  O bjectives  
•  
T o deter mi ne t he a ntit 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 trast uz u ma b, i n C o h orts A + B, as 
meas ure d b y c o nfir me d o bj ecti ve res p o nse rate ( cO R R , 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] 1. 1 criteria ), acc or di n g t o bli n de d  i n de pe n de nt ce ntral re vie w (B I C R) assess me nt 
Sec o n d ary  O bjectives  
Effic acy  
•  
T o e val uate t he a ntit 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 trast uz u ma b , i n C o h orts A + B, b y 
o bj ecti ve res p o nse rate ( O R R ) b y 1 2 wee ks  of treat me nt  ( R E CI S T 1. 1), acc or di n g t o B I C R assess me nt 
•  
T o e val uate t he a ntit u m or acti vit y of t ucati ni b m o n ot hera p y , i n C o h ort C, as meas ure d b y O R R b y 1 2 
wee ks of treat me nt  ( R E CI S T 1. 1), acc or di n g t o B I C R assess me nt 
•  
T o assess t he d urati o n of res p o nse ( D O R) i n s u bj ects treate d wit h t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u ma b ( R E CI S T 1. 1), i n C o h orts A + B, acc or di n g t o B I C R assess me nt 
•  
T o assess t he D O R i n s u bj ects treate d wit h t ucati ni b m o n ot hera p y ( R E CI S T 1. 1), i n C o h ort C, acc or di n g t o 
B I C R assess me nt 
•  
T o assess t he pr o gressi o n -free s ur vi val ( P F S) i n s u bj ects treate d wit h t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u ma b ( R E CI S T 1. 1), i n C o h orts A + B, acc or di n g t o B I C R assess me nt 
•  
T o assess t he o verall s ur vi val ( O S) i n s u bj ects treate d wit h t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u ma b, i n C o h orts A + B 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4  of 1 7 0  
S afety  
•  
T o assess t he safet y 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, i n C o h orts A + B 
•  
T o assess t he safet y a n d t olera bilit y of t ucati ni b m o n ot hera p y , i n C o h ort C  
E x pl or at ory O bjectives  
•  
T o e val uate t he p har mac o ki netics ( P K) of t ucati ni b  
•  
T o e x pl ore a n y 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  
•  
T o assess t he P F S i n s u bj ects treate d wit h t ucati ni b m o n ot hera p y ( R E CI S T 1. 1),  i n C o h ort C, acc or di n g t o 
B I C R assess me nt  
•  
T o assess t he O S i n s u bj ects treate d wit h t ucati ni b m o n ot hera p y , i n C o h ort C 
•  
T o assess patie nt -re p orte d o utc o mes ( P R Os) ass ociate d wit h t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u ma b 
•  
T o e x pl ore healt h res o urce utilizati o n  
St u d y E n d p oi nts  
Pri m ary e n d p oi nts  
•  
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 ]), per R E CI S T  1. 1 , acc or di n g t o B I C R 
assess me nt , i n p o ole d C o h orts A + B.  
Sec o n d ary e n d p oi nts  
Effic acy  
•  
O R R  (R E CI S T  1. 1 ) b y  1 2 wee ks of treat me n t, acc or di n g t o B I C R assess me nt, i n C o h orts A + B 
•  
O R R ( R E CI S T  1. 1) b y 1 2 wee ks of treat me nt, acc or di n g t o B I C R assess me nt, i n C o h ort C 
•  
D O R (R E CI S T  1. 1 ), acc or di n g t o B I C R assess me nt, i n C o h orts A + B.   
•  
D O R ( R E CI S T  1. 1), acc or di n g t o B I C R assess me nt, in  C o h ort C  
•  
P F S ( R E CI S T  1. 1), acc or di n g t o B I C R assess me nt, i n C o h orts A + B 
•  
O S , i n C o h orts A + B  
S afety  
•  
Fre q ue nc y a n d se verit y, acc or di n g t o C o m m o n T er mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) 
versi o n  4. 0 3  criteria, of all treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) a n d treat me nt -relate d T E A Es, i n 
C o h orts A + B   
•  
Fre q ue nc y a n d se verit y, acc or di n g t o C T C A E  v 4. 0 3, of all T E A Es a n d treat me nt -relate d T E A Es, i n 
C o h ort  C  
•  
Fre q ue nc y of seri o us a d verse e ve nts ( S A Es) a n d deat hs d ue t o a d verse e ve nts ( A Es) , i n C o h orts A + B 
•  
Fre q ue nc y of S A Es a n d deat hs d ue t o A Es, i n C o h ort C  
•  
Fre q ue nc y of treat me nt m o difi cati o ns a n d per ma ne nt treat me nt disc o nti n uati o ns d ue t o A Es , i n C o h orts 
A + B  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5  of 1 7 0  
•  
Fre q ue nc y of treat me nt m o difi cati o ns a n d per ma ne nt treat me nt disc o nti n uati o ns d ue t o A Es, i n C o h ort C  
•  
Fre q u e nc y a n d se verit y of la b orat or y a b n or malities , i n C o h orts A + B 
•  
Fre q ue nc y a n d se verit y of la b orat or y a b n or malities, i n C o h ort C  
•  
V ital si g ns a n d ot her rele va nt safet y varia bles, i n C o h orts A + B 
•  
Vital si g ns a n d ot her rele va nt safet y varia bles, i n C o h ort C  
E x pl or at ory e n d p oi nts  
•  
P K para meters of t ucati ni b  
•  
T o e x pl ore p ote ntial bi o mar kers of res p o nse, resista nce or t o xicit y fr o m arc hi ve d paraffi n-e m be d de d t u m or 
sa m ples a n d circ ulati n g t u m or D N A ( ct D N A) is olate d fr o m plas ma sa m ples.  
•  
P F S ( R E CI S T  1. 1), acc or di n g t o B I C R assess me nt, i n C o h ort C 
•  
O S, i n C o h ort C  
•  
C ha n ge fr o m baseli ne i n P R O assess me nts of t he  E ur o pea n Q ualit y of Life 5 -Di me nsi o n 5 -Le vel  ( E Q-5 D -
5 L), a n d E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y -of -Li fe 3 0-ite m c ore 
q uesti o n naire ( E O R T C Q L Q-C 3 0)  
•  
C u m ulati ve i nci de nce of healt h res o urce utilizati o n, i ncl u di n g le n gt h of sta y, h os pitalizati o ns, a n d 
e mer ge nc y de p art me nt ( E D) visits  
St u d y P o p ul ati o n  
P atie nts wit h H E R 2 + , R A S wil d-t y pe, u nresecta ble or metast atic c ol orectal ca ncer ( m C R C ) w h o , u nless 
c o ntrai n dicate d,  ha ve  pre vi o usl y recei ve d s yste mic t hera p y wit h fl u or o p yri mi di nes, o xali plati n, iri n oteca n, a n 
a nti -vasc ular e n d ot helial gr o wt h fact or (V E G F ) m o n ocl o nal a nti b o d y ( m A b) ; patie nts  w h ose disease has 
deficie nt mis matc h re p air ( d M M R ) pr otei ns or is m icr osatellite i nsta bilit y-Hi g h  ( M SI-H)  m ust als o ha ve 
recei ve d a nti-P D -( L) 1 m Ab , if i n dicate d. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6  of 1 7 0  
 
N ote : S u bjects  e nr olle d i n C o h ort A or C o h ort B will be treate d wit h t u cati ni b a n d trast u z u ma b d o u blet c o m bi n a ti o n 
t h era p y, a n d s u bjects e nr olle d i n C o h ort C will be treate d wit h t ucati ni b m o n ot hera p y.  
C R = c o m plete res p o nse, E O T = e n d of treat me nt, P D = pr o gressi ve disease, P R = partial res p o nse  
a 
F or C o h ort A, ra di ol o gical disease assess me nts (c o m p uterize d t o m o gra p h y [ C T ] or ma g netic res o na nce i ma gi n g [ M RI ] 
sca ns of c hest, a b d o me n, a n d pel vis ) a n d  carci n oe m br y o nic a nti ge n ( C E A ) t u m or mar ker ass a ys  will be perf or me d  at 
t h e scree ni n g/ b aseli ne, e ver y 9 wee ks /3 c ycl es  (± 1 4 da ys ) d uri n g st u d y treat me nt (e ver y 1 2 wee ks / 4  c ycles [± 7 da ys ] 
after 1 2 m o nt hs of treat me nt , if t he s u bject is cli nicall y sta ble), a n d at t h e E O T visit . S u bjects  w h o  disc o nti n ue f or 
reas o ns ot h er t h a n d oc u me nte d P D  will c o nti n ue t o ha ve disease assess me nts a p pr o xi matel y e ver y 9 we e ks u ntil 
disease p r o gressi o n, deat h, wit h dra wal of c o nse nt, st u d y cl os ure, or alter nati ve t h era p y. H o we ver, s u bjects wit h 
d oc u me nte d P D w h o  ha ve c o nti n ue d o n st u d y treat me nt f or cli nical be nefit will n ot re q uire c o nti n ue d disease 
assess me nts after disc o nti n ui n g treat me nt.  
b  
F or C o h orts A a n d B, treat me nt will be a d mi nistere d i n 2 1 -da y c ycl es. T ucati ni b will be a d mi nistere d at 3 0 0 m g BI D 
pl us trast uz u ma b I V i nf usi o n at a l o a di n g d ose of 8 m g/ k g f oll o we d b y a mai nte na nce d ose of 6 m g/ k g e ver y 2 1 da ys.  
c 
F or C o h orts B a n d C,  a n o p ti o nal pre-scree ni n g is a vaila ble. Tiss ue base d H E R 2 testi n g ca n be perf or me d  wit hi n 
9 0  da ys pri or t o t h e a ntici pate d scree ni n g visit. C ollecti o n of tiss ue f or c o nfir mat or y H E R 2 + a n d bi o mar ker testi n g ca n 
be d o ne at pre-scree ni n g or screen i n g. R a di ol o gical  disease assess me nt  (C T or M RI of c hest, a b d o me n, a n d pel vis ) a n d 
C E A ass a ys will be perf or me d  at scree ni n g/ b aseli ne, e ver y 6 wee ks ( ± 7 da ys) d uri n g treat me nt (e ver y 1 2 we e ks [ ± 7 
da ys] aft er 1 2  m o nt hs of treat me nt , if t h e s u bject is cli nicall y sta ble), a n d  at t h e E O T visit . S u bjects  w h o  disc o nti n ue f or 
reas o ns ot h er t h a n d oc u me nte d P D  will c o nti n ue t o ha ve disease assess me nts a p pr o xi matel y e ver y 9 we e ks u ntil 
disease pr o gressi o n, deat h, wit h dra wal of c o nse nt, st u d y cl os ure , or alter nati ve t h era p y.  H o we ver, s u bjects wit h 
d oc u me nte d P D w h o  ha ve c o nti n ue d o n st u d y treat me nt f or cli nical be nefit will n ot re q uire c o nti n ue d disease 
assess me nts after disc o nti n ui n g treat me nt.  
d  
F or C o h ort C, treat me nt will be a d mi nistere d i n 2 1 -da y c ycles. T uc ati ni b will be a d mi nistere d at 3 0 0 m g BI D.  
e 
S u bjects ra n d o mize d t o C o h ort C will be all o we d t o cr oss o ver a n d recei v e d o u blet t ucati ni b + trast u z u ma b t h era p y if 
t h e y e x perie nce ra di o gra p hic pr o gressi o n at a n y ti me p oi nt, or if t he y ha ve n ot ac hie ve d a P R or C R  b y t h e W e e k 1 2 
assess me nt.  I n or der t o assess ra di o gra p hic res p o nse t o t h e d o u blet t h era p y, su bjects i n C o h ort C m ust ha ve a ne w 
baseli ne R E CI S T  assess me nt  pri or t o cr oss o ver fr o m m o n ot h era p y t o d o u blet t hera p y usi n g t h e  W ee k 1 2 sca ns or t h e 
first P D sca ns as a p plica ble. 
 
I ncl usi o n Criteri a 
S u bj ects  m ust meet t he f oll o wi n g criteria t o be eli gi ble f or t he st u d y:  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7  of 1 7 0  
1.  Ha ve hist ol o gicall y a n d/ or c yt ol o gicall y d oc u me nte d a de n ocarci n o ma of t he c ol o n or rect u m, w hic h is 
metastatic a n d/or u nresecta ble  
2.  U nless ot her wise  c o ntrai n dicate d, s u bj ects m ust ha ve recei ve d a n d faile d re gi me ns c o ntai ni n g t he f oll o wi n g 
a ge nts: fl u or o p yri mi di nes  (e. g., 5 -fl u or o uracil or ca pecita bi ne), o xali plati n, iri n oteca n, a n a nti-V E G F m A b  
( be vaciz u ma b, ra m ucir u ma b, or zi v-afli berce pt) , a n d a n a nti-P D -( L) 1 t hera p y ( ni v ol u ma b or 
pe m br oliz u ma b)  if t he t u m or has d M M R pr otei ns or is M SI-H  
3.  Ha ve pr o gressi o n of u nresecta ble or m C R C after last s yste mic t hera p y (as c o nfir me d b y i n vesti gat or), or be 
i nt olera nt of last s yste mic t her a p y 
4.  Ha ve R A S wil d -t 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 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)  
5.  S u bj ects  m ust b e willi n g a n d a ble t o pr o vi de t he m ost rece ntl y a vaila ble tiss ue bl oc ks (or sli des , wit h 
M e dical M o nit or’s a p pr o val) , o btai ne d pri or t o treat me nt i nitiati o n, t o a s p o ns or-desi g nate d ce ntral  
la b orat or y f or bi o mar ker a nal ysis. If arc hi val tiss ue is n ot a vaila ble, t he n a ne wl y-o btai ne d baseli ne bi o ps y 
of a n accessi ble t u m or lesi o n is re q uire d  
6.  Ha ve c o nfir me d  H E R 2 -p ositi ve m C R C , as defi ne d b y ha vi n g t u m or tiss ue  teste d at a Cli nic al La b orat or y 
I m pr o ve me nt A me n d me nts ( C LI A)-certifie d 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, meeti n g at least o ne of t he f oll o wi n g criteria:  
a. 
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]) b y a n F D A-a p pr o ve d or C o nf or mité 
E ur o pée n ne ( C E )-mar ke d H E R 2 I H C test f oll o wi n g t he pac ka ge i nsert’s i nter pretati o nal ma n ual f or 
breast ca ncer  
b.  H E R 2 2 + I H C is eli gi ble if t he t u m or is a m plifie d b y a n F D A -a p pr o ve d or C E -mar ke d H E R 2 i n sit u 
h y bri dizati o n assa y (fl u oresce nce i n sit u h y bri dizati o n [ FI S H] or c hr o m o ge nic i n sit u h y bri dizat i o n 
[ CI S H]) f oll o wi n g t he pac ka ge i nsert’s i nter pretati o nal ma n ual f or breast ca ncer 
c. 
H E R 2 ( E R B B 2 ) a m plificati o n b y C LI A-certifie d  or I S O -accr e dite d  Ne xt Ge nerati o n Se q ue nci n g 
(N G S ) se q ue nci n g assa y  
7.  A ge ≥1 8 years at ti me of c o ns e nt  
8.  Ha ve ra di o gra p hicall y me as ura ble disease assessa ble b y  R E CI S T 1. 1, wit h at least o ne sit e of disease t hat 
is meas ura ble a n d t hat has n ot bee n pre vi o usl y irra diate d; or,  if t he s u bj ect has ha d pre vi o us ra diati o n t o t he 
tar get lesi o n(s), t here m ust b e e vi de nce of pr o gressi o n si nce t he ra diati o n 
9.  Ha ve a n Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) P erf or ma nce Stat us ( P S) of 0, 1 , or 2  
1 0.  Life e x pecta nc y greater t ha n 3 m o nt hs , i n t he o pi ni o n of t he i n vesti gat or 
1 1.  Ha ve a d e q uate he mat ol o gical, he p atic, re nal, c oa g ulati o n, a n d car diac f u ncti o n as defi ne d bel o w, o btai ne d 
7 da ys pri or t o t he first st u d y treat me nt: 
a. 
A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 0  ×  1 0 3/µ L  
b.  Platelet c o u nt ≥7 5  ×  1 0 3/ µ L 
c. 
He m o gl o bi n 8 . 0 g/ d L  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8  of 1 7 0  
d.  T otal bilir u bi n ≤1. 5 × u p per li mit of n or mal ( U L N). S u bj ects  wit h k n o w n hist or y of Gil bert’s 
S y n dr o me a n d n or mal direct bilir u bi n, as partate a mi n otra nsferase  ( A S T), a n d ala ni ne a mi n otra nsferase 
( A L T) are eli gi ble 
e. 
A S T a n d A L T ≤2. 5 × U L N ( ≤5 × U L N if li ver m etastases ar e prese nt)  
f. 
Calc ulate d creati ni ne cleara nc e ≥5 0 m L / mi n usi n g t he C oc kcr oft-Ga ult f or m ula  
g.  I nter nati o nal n or malize d rati o (I N R) a n d acti vate d partial t hr o m b o plasti n ti me (a P T T) ≤1. 5 × U L N 
u nless o n me dicati o n k n o w n t o alter I N R a n d/ or a P T T  
h.  Left ve ntric ular ej ecti 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 ple -gate d ac q uisiti o n ( M U G A) sca n d oc u me nte d ≤2 8 da ys pri or t o st u d y treat me nt. 
1 2.  F or s u bj ects of c hil d beari n g p ote ntial , t he f oll o wi n g sti p ulati o ns a p pl y: 
a. 
M ust ha ve a ne gati ve ser u m pre g na nc y test ( mi ni m u m se nsiti vit y of 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 7  da ys pri or t o t he first d ose of st u d y 
treat me nt. A s u bj ect wit h a false p ositi ve res ult a n d d oc u me nte d verificati o n t hat t he s u bj ect is n ot 
pre g na nt is 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 dr u g a d mi nistrati o n  
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 dr u g a d mi nistrati o n 
d.  Ma y c h o ose t o practice c o m plete a bsti ne nce, if c o nsiste nt wit h t he s u bj ect’s preferre d lifest yle, as a n 
acce pta ble f or m of c o ntrace pti o n  
e. 
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 effe cti ve 
met h o ds of birt h c o ntr ol (i.e., met h o ds t hat ac hie ve a fail ure rate of < 1 % per year w he n use d 
c o nsiste ntl y a n d c orrectl y ) starti n g at t he ti me of i nf or me d c o nse nt an 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 d y dr u g a d mi nistrati o n  
1 3.  F or s u bj ects w h o ca n fat her c hil dre n, t he f oll o wi n g sti p ulati o ns a p pl y:  
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 st u d y dr u g a d mi nistrati o n  
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 hl y effecti ve met h o d s 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 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 dr u g 
a d mi nistrati o n  
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 d y dr u g a d mi nistr ati o n  
1 4.  S u bj ect  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 instit uti o nal re vie w 
b oar d/i n de p e n de nt et hics c o m mittee  (I R B/I E C) pri or t o i niti ati o n of a n y st u d y -relate d tests or pr oce d ures 
t hat are n ot p art of sta n dar d-of -care f or t he s u bj ect’s disease  
1 5.  S u bj ect  m ust b e 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  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9  of 1 7 0  
E xcl usi o n Criteri a  
S u bj ects  will be e xcl u de d fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns:  
1.  Ha ve pre vi o usl y bee n treate d wit h a nti -H E R 2 tar geti n g t her a p y  
2.  Ha ve recei ve d treat me nt wit h a n y s yste 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 p y), 
n o n -ce ntral ner v o us s yste m ( C N S) ra diati o n, or e x peri me ntal a ge nt ≤3 wee ks of first d ose of st u d y 
treat me nt or are c urre ntl y parti ci pati n g i n a n ot her i nter ve nti o nal cli nical trial  
3.  Ha ve 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:  
•  
A l o pecia a n d ne ur o pat h y, w hi c h m ust ha ve res ol ve d t o ≤ Gra de 2  
•  
C o n gesti ve heart fail ure ( C H F), w hic h m ust ha ve bee n ≤ Gr a de 1 i n se verit y at t he ti me of occ urre nce, 
a n d m ust ha ve res ol ve d c o m pl etel y  
•  
A ne mia, w hic h m ust ha ve res ol ve d t o ≤ Gra de 2  
•  
Decrease d A N C, w hic h m ust ha ve res ol ve d t o ≤ Gra de 2  
4.  Ha ve cli nicall y si g nifica nt car di o p ul m o nar y disease s uc h as:  
•  
V e 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 , as deter mi ne d b y t he 
i n vesti gat or 
•  
A n y hist or y of s y m pt o matic C H F , left ve ntric ular s yst olic d ysf u ncti o n or decrease i n ej ecti o n fracti o n 
•  
S e vere d ys p nea at rest ( C T C A E  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 nt ar y o x y ge n t hera p y  
•  
P rese nce of ≥ Gra d e 2 c orrecte d Q T i nter val ( Q T c ) pr ol o n gati o n o n scree ni n g  electr ocar di o gra m 
(E C G )  
5.  Ha ve k n o w n m y ocar di al i nfarcti o n, u nsta ble a n gi na, car diac or ot her vasc ular ste nti n g, a n gi o plast y, or 
car diac s ur ger y wit hi n 6 m o nt hs pri or t o first d ose of st u d y treat me nt  
6.  Maj or s ur gical pr oce d ure, o pe n bi o ps y, or si g nifica nt tra u matic i nj ur y ≤2 8 da ys pri or t o e nr oll me nt  
(≤5 6  da ys f or he p atect o m y, o pe n t h orac ot o m y,  or  maj or ne ur os ur ger y) or a ntici pati o n of ne e d f or maj or 
s ur gical pr oce d ure d uri n g t he c o urse of t he st u d y 
7.  Seri o us, n o n -heali n g w o u n d, ulcer, or b o ne fract ure  
8.  K n o w n t o be p ositi ve f or he p atitis B b y s urface a nti g e n e x pressi o n  
9.  K n o w n t o ha ve acti ve he p atitis C i nfecti o n ( p ositi ve b y p ol y merase c hai n reacti o n or o n a nti viral t hera p y 
f or he p atitis C wit hi n t he last 6 m o nt hs). S u bj ects  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 1 2 wee ks  
1 0.  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 ) 
1 1.  S u bj ects w h o a re pre g na nt, breastfee di n g, or pla n ni n g a pre g na nc y 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0  of 1 7 0  
1 2.  I na bilit y t o s wall o w pills or a n y si g nifica nt gastr oi ntesti nal disease w hic h w o ul d precl u de t he a de q uate oral 
a bs or pti o n of me dicati o ns  
1 3.  Ha ve use d a str o n g C Y P 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 first d ose of st u d y tr eat me nt.  
1 4.  Ha ve a n y 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 
safet y or c o m plia nce wit h st u d y pr oce d ures 
1 5.  Hist or y of a n ot her mali g na nc y wit hi n 3 years bef ore t he first d ose of st u d y dr u g, or a n y e vi de nce of 
resi d ual disease fr o m a pre vi o usl y dia g n ose d mali g na nc y. E xce pti o ns are mali g na ncies wit h a ne gli gi ble 
ris k of metastasis or deat h (e. g., 5-year O S  ≥9 0 %), s uc h as a de q uatel y treate d carci n o ma i n sit u of t he 
cer vi x, n o n -mela n o ma s ki n carci n o ma, l ocalize d pr ostate ca ncer, d uctal car ci n o ma i n sit u, or Sta ge I 
uteri ne ca ncer)  
1 6.  S u bj ects  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 ull y treate d a n d i nacti ve, s u bj ect is as y m pt o mati c, a n d n o ster oi ds ha ve bee n a d mi nistere d f or 
at least 3 0 da ys) 
1 7.  Ha ve a h y perse nsiti vit y t o t uc ati ni b or a n y of its e xci pie nts, t o trast uz u ma b or a n y of its e xci pie nts, or t o 
m uri ne pr otei ns.  
N u m ber of Pl a n ne d S u bjects  
A p pr o xi matel y 1 1 0  s u bj ects will be e nr olle d a n d treate d i n t his st u d y: a p pr o xi matel y 8 0 s u bj ects treate d i n t he 
t ucati ni b + trast uz u ma b c o h orts (C o h orts A + B ) a n d  a p pr o xi matel y  3 0 s u bj ects treate d i n t he t ucati ni b 
m o n ot hera p y c o h ort ( C o h ort C ). 
St u d y Desi g n  
T his is a m ultice nter, ra n d o mi ze d, o pe n -la bel, P hase 2 st u d y of t ucati ni b, a d mi niste re d as m o n ot hera p y a n d i n 
c o m bi nati o n wit h trast uz u ma b , i n patie nts  wit h H E R 2 -p ositi ve, R A S wil d -t y pe, u nresecta ble or metastatic C R C. 
Eli gi ble patie nts  are re q uire d t o ha ve pre vi o usl y recei ve d  a n d faile d , u nless c o ntrai n dicate d , s yste mic t hera p y 
wit h fl u o r o p yri mi di nes, o xali plati n, iri n oteca n, a n d a n a nti-V E G F m A b ; patie nts  wit h  d M M R or M SI -H  disease 
m ust als o ha ve recei ve d a n a nti -P D -( L) 1 m Ab , if i n dicate d. T he st u d y i nitiall y c o nsiste d of C o h ort A, w hic h 
i ncl u des a p pr o xi matel y 4 0 s u bj ects treate d wit h t he d o u blet re gi me n. As of Pr ot oc ol A me n d me nt  8, t he st u d y is  
e x pa n de d t o i ncl u de a p pr o xi matel y 4 0 a d diti o nal s u bj ects (C o h ort B) treate d wit h t he t ucati ni b  +  trast uz u ma b 
d o u blet  (f or a t otal of a p pr o xi matel y 8 0 s u bj ects i n C o h orts  A + B) , a n d a p pr o xi matel y  3 0 s u bj ects treate d wit h 
t ucati ni b m o n ot hera p y  ( C o h ort C) .  
Treat me nt will be a d mi nistere d i n c ycles of 2 1 da ys eac h. All s u bj ects e nr olle d i n t he e x pa nsi o n p orti o n of t he 
trial will be ra n d o mize d i n a 4: 3 rati o t o recei ve t ucati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b ( C o h ort  B) or 
t ucati ni b m o n ot hera p y (C o h ort C). E nr oll me nt will c o nti n ue u ntil a p pr o xi matel y  4 0 s u bj ects ha ve bee n 
ra n d o mize d t o a n d treate d i n C o h ort  B a n d  a p pr o xi matel y 3 0 s u bj ects ha ve bee n ra n d o miz e d t o a n d treate d i n 
C o h ort C . 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1  of 1 7 0  
Treat me nt will be a d mi nistere d i n c ycles of 2 1 da ys eac h . S u bj ects i n C o h orts A a n d B will be treate d wit h 
t ucati ni b at a d ose of 3 0 0 m g orall y t wice dail y ( P O  BI D ) a n d trast uz u ma b at a l oa di n g d ose of 8 m g/ k g 
i ntra ve n o us (I V) f oll o we d b y a d ose of 6 m g/ k g I V e ver y 3 wee ks. 
S u bj ects ra n d o mize d t o C o h ort C will be treate d wit h t ucati ni b at a d ose of 3 0 0 m g P O BI D.  
S u bj ects e nr olle d i n C o h ort A a n d t h ose ra n d o mize d t o C o h ort B will c o nti n ue o n t hera p y u ntil e vi de nce of 
ra di o gra p hic or cli nical pr o gressi o n, u n acce pta ble t o xicit y, wit h dra wal of c o nse nt, or st u d y cl os ure . S u bj ects 
ra n d o mize d t o C o h ort C will b e all o we d t o cr oss o ver a n d recei ve d o u blet t ucati ni b + trast uz u ma b t hera p y if 
t he y e x perie nce ra di o gra p hic pr o gressi o n at a n y ti me p oi nt, or if t he y ha ve n ot ac hie ve d a P R  or C R  b y t he 
W ee k 1 2 assess me nt.  S u bj ects i n C o h ort C m ust ha ve a ne w baseli ne R E CI S T assess me nt  pri or t o cr oss o ver 
fr o m m o n ot hera p y t o d o u blet t hera p y usi n g t he  Wee k 1 2  sca ns or t he first P D sca ns as a p plica ble.  
T he pri mar y efficac y a nal ysis set will c o m prise  all treate d s u bj ects i n C o h orts A + B. 
T he pri mar y e n d p oi nt of t he st u d y is t he c o nfir me d O R R. Ra di o gra p hic res p o nse will be assesse d b y a  B I C R, 
acc or di n g t o R E CI S T 1. 1, wit h c o nfir mati o n of res p o nse re q uire d ≥4 wee ks fr o m t he first d oc u me ntati o n of 
res p o nse. 
Sec o n dar y efficac y e n d p oi nts i ncl u de d urati o n of c o nfir me d res p o nse, P F S , a n d O S  f or all s u bj ects e nr olle d o n 
t he d o u blet re gi me n (C o h ort A + B) . I n a d diti o n, in or der t o assess t he c o ntri b uti o n of t ucati ni b t o t he d o u blet 
re gi me n, O R R b y 1 2 wee ks will  be assesse d i n C o h ort s A + B , as well as i n C o h ort C ; h o we ver, t here will be n o 
f or mal statistical c o m paris o ns bet wee n c o h orts. 
E n d  of  St u d y  
T he pri mar y a nal ysis f or t his trial was c o n d ucte d base d o n a data c ut -off date of 2 8  Marc h 2 0 2 2 . As t he pri mar y 
o bj ecti ve  was met, t he decisi o n was ma d e t o cl ose t he trial. F or s u bj ects re mai ni n g o n st u d y, a last visit  / c o ntact 
will o cc ur a n d s u bj ects w h o  are still recei vi n g treat me nt  will re vert t o p h ysicia n care. W he n a p plica ble, t he 
S p o ns or will assist wit h p ost -trial access t o t ucati ni b a n d trast uz u ma b. 
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  
T ucati ni b 3 0 0  m g P O BI D  o n Da y s 1 t o 2 1 of eac h 2 1 -da y c ycle.  
C o h orts A a n d B; S u bjects  fr o m C o h ort C W h o Cr oss over t o D o u blet T her a py 
Trast uz u ma b 8 m g/ k g will be a d mi nistere d b y I V i nf usi o n o ver 9 0 mi n utes o n Da y 1 of C ycle  1. I n s u bse q ue nt 
c ycles, trast uz u ma b 6  m g/ k g will b e a d mi nistere d I V o ver 3 0  mi n utes o n Da y  1 of eac h c ycle, e xce pt i n s pecific 
circ u msta nces w here 2  m g/ k g ma y be gi ve n wee kl y or 4  m g/ k g e ver y 2 wee ks t o c o m pe nsa te f or m o dificati o ns 
i n treat me nt sc he d ule. S u bj ects w h o are  cr ossi n g o ver fr o m C o h ort C will be a ble t o start d o u blet c o m bi nati o n 
t hera p y as s o o n as t he f or mal cr osso ver pr ocess occ urs, e ve n if it e ntails a br u pti o n i n a pre vi o us c ycle.  
O n da ys w he n trast uz u ma b is a d mi nistere d, t he t ucati ni b d ose ma y be ta ke n bef ore, d uri n g, or after t he 
trast uz u ma b i nf usi o n. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2  of 1 7 0  
D ur ati o n of Tre at me nt  
S u bj ects i n C o h orts A or B ma y c o nti n ue o n st u d y treat me nt u ntil pr o gressi ve disease ( P D ), deat h, A Es t hat are 
c o nsi dere d i nt ol era b le a n d u n ma na gea ble, l ost t o f oll o w-u p, t reat me nt-relate d a d verse e ve nts w hic h d o n ot 
res ol ve t o Gra d e ≤2 wit hi n 6  wee ks , re q uest b y re g ulat or y a ge ncies , d osi n g dela y greater t ha n 6 wee ks, 
i n vesti gat or decisi o n, pr ot oc ol n o nc o m plia nce, wit h dra wal of c onse nt, start of a s u bse q ue nt a ntica ncer t hera p y, 
pre g na nc y or breastfee di n g, or st u d y ter mi nati o n b y t he s p o ns or. All eff orts s h o ul d be ma de t o c o nti n ue 
treat me nt u ntil u ne q ui v ocal e vi de nce of ra di o gra p hic pr o gressi o n occ urs. 
S u bj ects ra n d o mize d t o C o h ort C , w h o ha ve e x perie nce d ra di o gra p hic pr o gressi o n at a n y ti me p oi nt, or if t he y 
ha ve n ot ac hie ve d a P R  or C R  b y t he W ee k 1 2 assess me nt,  ma y cr oss o ver t o recei ve d o u blet t hera p y . S u bj ects 
i n C o h ort C m ust ha ve a ne w baseli ne R E CI S T assess me nt  pri or t o cr oss o ver fr o m m o n ot hera p y t o d o u blet 
t hera p y usi n g t he  W ee k 1 2  sca ns or t he first P D sca ns as a p plica ble.  
S u bj ects wit h si g ns of cli nical be nefit (e. g., mi xe d res p o nse, s y m pt o m i m pr o ve me nt, de m o nstra ble sl o wi n g of 
pr o gressi o n , pr o gressi o n rate of < 2 0 % over 6 m o nt hs ) w h o are t olerati n g treat me nt ma y be all o we d t o c o nti n ue 
treat me nt p ast f or mal ra di ol o gic pr o gressi o n (per  R E CI S T  1. 1 ) if s uc h treat me nt is c o nsi dere d i n t he s u bj ect's 
best i nterest b y t he s u bj ect, t he treati n g p h ysicia n, a n d t he Me dical M o nit or.  I n t his sce nari o, s u bj ects ma y 
c o nti n ue u ntil cli nical pr o gressi o n.  
Effic ac y Assess me nts  
Ra di ol o gical disease assess me nts (c o m p uterize d t o m o gra p h y [ C T] or ma g netic res o na nce i ma gi n g [ M RI] sca ns 
of c hest, a b d o me n, a n d pel vis) a n d carci n oe m br y o nic a nti ge n ( C E A) t u m or mar ker assa ys will be u n derta ke n o n 
t he f oll o wi n g sc he d ule: 
1.  C o h ort A:  at scree ni n g/ baseli ne, e ver y 9  wee ks ( ± 1 4  da ys) d uri n g treat me nt (e ver y 1 2  wee ks [ ± 7 da ys] 
after 1 2  m o nt hs of treat me nt , if t he s u bj ect is cli nicall y sta bl e), a n d at t he e n d of treat me nt ( E O T ) visit . 
S u bj ects  w h o disc o nti n ue f or reas o ns ot her t ha n d oc u me nte d P D  will c o nti n ue t o ha ve dise ase assess me nts  
a p pr o xi matel y e ver y 9  wee ks u ntil P D,  deat h, wit h dra wal of c o nse nt, st u d y cl os ure, or alter nati ve t hera p y. 
2.  C o h ort s B a n d C:  at scree ni n g/ baseli ne, e ver y 6 wee ks ( ± 7 da ys) d uri n g treat me nt (e ver y 1 2  wee ks 
[ ± 7 da ys] after 1 2  m o nt hs of treat me nt , if t he s u bj ect is cli nic all y sta ble), a n d at t he E O T visit . S u bj ects  
w h o disc o nti n ue f or reas o ns ot her t ha n d oc u me nte d P D  will  c o nti n ue t o ha ve disease assess me nts  
a p pr o xi matel y e ver y 9  wee ks  u ntil P D,  deat h, wit h dra wal of c o nse nt, st u d y cl os ure, or alter nati ve t hera p y. 
N ote:  S u bj ects wit h d oc u me nte d P D w h o  ha ve c o nti n ue d o n st u d y treat me nt f or cli nical be nefit will n ot re q uire 
c o nti n ue d disease assess me nts after disc o nti n ui n g treat me nt.  
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 bj ecti ve res p o nse  assess me nts as defi ne d 
b y R E CI S T 1. 1. Disease assess me nts will be e val uate d b y b ot h t he B I C R a n d i n vesti gat ors. T he i n vesti gat or 
will ma ke treat me nt d ecisi o ns base d o n site assess me nts of s ca ns. F or C o h ort A, c o nfir mati o n of res p o nse was 
i nitiall y n ot re q uire d per pr ot oc ol. F or t he p ur p oses of t he pri mar y a nal ysis, t he disease assess me nt ti me p oi nt 
after t he firs t res p o nse d oc u me nte d b y t he B I C R will be use d t o deter mi ne c o nfir me d res p o nse . F or C o h ort A, 
res p o nses ( C R or P R) will be c o nfir me d at t he ne xt re -sta gi n g ti me p oi nt, 9 wee ks ( ± 1 4 da ys) after first 
d oc u me ntati o n of res p o nse. F or C o h orts B a n d C, r es p o nses ( C R or P R) will be c o nfir me d at t he ne xt re -sta gi n g 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3  of 1 7 0  
ti me p oi nt, 6 wee ks ( ±7  da ys ) after first d oc u me ntati o n of res p o nse . S u bj ects will be f oll o we d f or s ur vi val e ver y 
1 2 wee ks ( ± 1 4 da ys) u ntil P D , deat h, or e n d  of  st u d y. 
P h ar m ac o ki netic Assess me nts  
P K  assess me nts of tr o u g h le vels of t ucati ni b dr u g le vels will be perf or me d o n  Da y  1 of C ycles 2  t o 6 pri or t o 
a d mi nistrati o n of t ucati ni b  i n b ot h C o h orts B a n d C o h ort C . O n Da y 1 of C ycle 3, P K  assess me nts of pea k 
le vels of t ucati ni b dr u g le vels will b e perf or me d 1 t o 4 h o urs after a d mi nistrati o n of t ucati ni b  i n b ot h C o h ort B 
a n d C o h ort C . S u bj ects i n C o h ort C w h o cr oss o ver t o t he t uc ati ni b + trast uz u ma b re gi me n s h o ul d c o nti n ue P K 
assess me nts, if cr oss o ver occ urs pri or t o C ycle 6. If t he cr oss o ver ha p pe ns aft er C ycle 6, n o P K c ollecti o ns are 
re q uire d. 
Bi o m ar ker Assess me nts  
Bi o mar ker assess me nts ma y i ncl u de t he c o nfir mati o n of H E R 2 stat us b y I H C, FI S H, a n d N G S as well as  a n 
e x pl orat or y assess me nt of H E R 2 m utati o ns or ot her m utati o ns as p ote ntial bi o mar kers of r es p o nse. H E R 2 stat us 
will b e verifie d b y ce ntral la b orat or y a nal ysis usi n g  I H C b y a n F D A -a p pr o ve d  or  C E -mar ke d  I H C test f oll o wi n g 
t he pac ka ge i nsert’s i nter pretati o nal ma n ual f or breast ca ncer. N G S  a nal ysis ma y be perf or me d t o i nterr o gate 
t he m utati o n status of a pa nel of o nc o ge nes a n d t u m or s u p press or ge nes 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 p e utics. T his assess me nt ma y e na ble t he c orrelati o n of treat me nt 
o utc o me t o eit her pree xisti n g or ac q uire d ca ncer ge ne m ut ati o ns 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 ge n ot y pe i n t he f ut ure.  
P atie nt -Re p orte d O utc o mes a n d He alt h Ec o n o mic Assess me nts  
P R O meas ures will b e c o m plete d at pr ot oc ol -s pecifie d ti me p oi nts usi n g t he E O R T C Q L Q -C 3 0. Healt h 
ec o n o mic assess me nts will be e x pl ore d wit h t he  E Q -5 D -5 L i nstr u me nt a n d healt h res o urce utilizati o n.  
E Q -5 D -5 L a n d E O R T C Q L Q -C 3 0 q uesti o n naires will be a d mi nistere d  f or C o h orts B a n d C at: pre -d ose  C ycle  1 
Da y 1 ( C 1 D 1 ), C 1 D 8, C 1 D 1 5, C 2 D 1, C 3 D 1, C 4 D 1, e ver y 3 c ycles t hereafter, u ntil treat me nt disc o nti n uati o n, 
P D , deat h, t o xicit y, wit h dra wal of c o nse nt or st u d y cl os ure, a n d at t he E O T. 
S afet y Assess me nts  
Safet y assess me nts will i ncl u d e 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, p h ysical e xa mi nati o n 
fi n di n gs, vital si g ns, 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 
ej ecti o n fracti o n will be perf or me d b y M U G A sca n or E C H O.  
C o nc o mit a nt T her a pies  
Use of i n vesti gati o nal dr u gs a n d de vices, a ntica ncer (i ncl u di n g b ut n ot li mite d t o c he m ot hera p y a n d h or m o nal 
t hera p y) a n d ra diati o n t hera p y (e xce pt f or palliati ve ra di ot hera p y at f ocal n o n-C N S sites w hic h are n ot 
c o nsi dere d tar get lesi o ns per R E CI S T  1. 1) s h o ul d be pr o hi bite d  d ur i n g t he st u d y. T ucati ni b m ust be hel d 7 da ys 
pri or t o a n d 7 da ys p ost ra diati o n t hera p y.  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 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. C o nc o mit a nt use of a se nsiti ve C Y P 3 A s u bstrate s h o ul d be a v oi de d 1 wee k pri or t o t he first 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4  of 1 7 0  
d ose of st u d y treat me nt a n d d uri n g t he st u d y. Use of m o derate or wea k i n hi bit ors of C Y P 2 C 8 are per mitte d b ut 
s h o ul d be use d wit h ca uti o n. 
St atis tic al M et h o ds 
Safet y a n d efficac y e n d p oi nts will b e s u m marize d wit h descri pti ve statistics.  
Data c ollecte d i n t his st u d y will be prese nte d usi n g s u m mar y ta bles, s u bj ect data listi n gs, a n d fi g ures. 
C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve s tatistics, s pecificall y t he mea n, me dia n, sta n dar d 
de viati o n, mi ni m u m, a n d ma xi m u m. Cate g orical varia bles will be s u m marize d b y fre q ue ncies a n d perce nta ges. 
C o nfi de nce i nter vals ( CI), 9 5 % 2 -si de d, will be prese nte d w here nee de d t o ga u ge t he str e n gt h of e vi de nce f or a 
c orres p o n di n g esti mate d treat me nt effect. F or ti me -t o-e ve nt e n d p oi nts, t he me dia n s ur vi val ti me will be 
esti mate d usi n g t he Ka pla n M eier met h o d; t he ass ociate d 9 5 % CI will be calc ulate d base d o n t he 
c o m ple me ntar y l o g -l o g tra nsf or mati o n. S u bj ect s fr o m t he i nitial, n o n-ra n d o mize d C o h ort A  a n d t h ose 
ra n d o mize d t o C o h ort B d uri n g t he e x pa nsi o n will be a nal yz e d t o get her ( C o h orts A + B) . De m o gra p hic a n d 
baseli ne c haracteristics will be s u m marize d se paratel y b y c o h ort.   
T he pri mar y a nal ysis of effica c y e n d p oi nts will be perf or me d per B I C R assess me nt usi n g R E CI S T 1. 1 criteria. 
S u p p orti ve a nal ysis per i n vesti gat or assess me nts will als o be perf or me d. Disc or da nce  bet wee n t he B I C R a n d 
i n vesti gat or’s assess me nt will be e val uate d.  
S a m ple Size C o nsi der ati o ns  
C o h ort A  
C o h ort A use d  a Fle mi n g 2 -st a ge p hase 2 desi g n, wit h a n ull h y p ot hesis of 2 0 % u nc o nfir me d O R R f or 
t ucati ni b+ trast uz u ma b, a n alter nati ve h y p ot hesis of 4 0 %, a o ne-si de d si g nifica nce le vel of 0. 1 1 5 3, a n d a p o wer 
of 8 3. 5 4 %. T e n e val ua ble s u bj ects were  t o be treate d i n t he first sta ge; if ≤1 res p o nse is o bser ve d t he re gi me n 
w o ul d  be c o nsi dere d i neffecti ve i n t his s u bj ect p o p ulati o n; if ≥5 s uccesses are o bser ve d t he n ull h y p ot hesis will 
be rej ecte d; ot her wise C o h or t A pr ocee ds t o t he sec o n d sta ge. Fiftee n e val ua ble s u bj ects were  t o be treate d i n 
t he sec o n d sta ge; if a t otal of ≤7 res p o nses are o bser ve d i n t he first 2 5 e val ua ble s u bj ects, t he re gi me n will be 
c o nsi dere d i neffecti ve; if ≥8  res p o nses are o bser ve d t he re gi me n ma y merit f urt her e val uati o n. Base d o n i nteri m 
efficac y res ults, C o h ort A has bee n e x pa n de d t o a p pr o xi matel y 4 0 s u bj ects.  
C o h orts B a n d C  
T he e x pa nsi o n C o h ort  B  is desi g ne d t o i ncrease t he size of t he st u d y p o p ulati o n e x p ose d t o t he d o u blet re gi me n 
i n or der t o all o w m ore precise esti mati o n of t he c o nfir me d O R R i n s u bj ects recei vi n g t ucati ni b wit h 
trast uz u ma b, as well as t o f ur nis h s u p ple me ntar y safet y data. T he pri mar y efficac y a nal ysis will be perf or me d 
b y pr o vi di n g t he p oi nt esti mat e a n d t he 2 -si de d 9 5 % e xact Cl o p per -P ears o n CI f or t he c o nfir me d O R R  ( p o ole d 
C o h orts A a n d B) . 
T he a d diti o n of C o h ort C is i nte n de d t o better c haracterize t he a ntit u m or acti vit y of t ucati ni b w he n use d as a 
m o n ot hera p y i n t his patie nt p o p ulati o n .  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5  of 1 7 0  
F or ill ustrati o n p ur p oses, a s u m mar y of t he e x pecte d 9 5 % CIs f or s u bj ects treate d i n C o h orts A + B a n d s u bj ects 
treate d i n C o h ort C  at t he pr o p ose d sa m ple sizes of 8 0 a n d 3 0 , res pecti vel y. N o f or mal statistical c o m paris o ns 
bet wee n c o h orts are pla n ne d.  
C o nfir me d O R R  
9 5 % E xact CI. ( C o h ort s A + B, N = 8 0)  
4 0 %  
( 2 9 %, 5 2 %) 
5 0 %  
( 3 9 %, 6 1 %) 
6 0 %  
( 4 8 %, 7 1 %) 
 
 
C o nfir me d O R R  
9 5 % E xact CI. ( C o h ort C, N = 3 0)  
1 0 %  
( 2 %, 2 7 %) 
1 5 %  
( 5 %, 3 3 %) 
2 0 %  
( 8 %, 3 9 %) 
Effic ac y A n al yses  
T he pri mar y e n d p oi nt of t his st u d y is t he c o nfir me d O R R per R E CI S T 1. 1 acc or di n g t o B I C R assess me nt. T he 
O R R is defi ne d as t he pr o p orti o n of s u bj ects wit h c o nfir me d C R or P R. T he O R R a n d its e xact 2 -si de d 9 5 % CI, 
usi n g t he Cl o p per -P ears o n met h o d, will be calc ulate d.  
T he ti mi n g of t he pri mar y a nal ysis will be base d o n t he ti me t o c o nfir me d  O R R  per BI C R . D O R acc or di n g t o 
BI C R assess me nt will als o be a nal yze d at t his ti me.  P F S a n d O S will als o be a nal yze d at t he ti me of t he pri mar y  
O R R a n d D O R a nal yses; a d diti o nal a nal ysis of t hese ti me-t o-e ve nt e n d p oi nts ma y be u n derta ke n w he n mat ure 
pr o gres si o n a n d s ur vi val data bec o me a vaila ble.  
O R R, D O R, a n d P F S acc or di n g t o i n vesti gat or assess me nt will als o be a nal yze d; disc or da nce bet wee n t he 
B I C R a n d i n vesti gat or’s assess me nt will be s u m marize d descri pti vel y. 
I nteri m F utilit y Effic ac y A n al yses 
I nteri m f utilit y efficac y a nal ys es of t he C o h ort A  will be u n d erta ke n after t he first 1 0 s u bj ects ha ve u n der g o ne 
disease assess me nt (first sta ge of Fle mi n g desi g n), a n d after t he first 2 5 s u bj ects ha ve u n der g o ne disease 
assess me nt (sec o n d sta ge of Fl e mi n g desi g n).  
P h ar m ac o ki netic A n al yses  
I n di vi d ual (s u bj ect) plas ma t ucati ni b 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 . A d diti o nal e x pl orat or y P K  a nal yses ma y be c o n d ucte d , i ncl u di n g ex pl orat or y a nal ys es 
i n vesti gati ng t he relati o ns hi p bet wee n t ucati ni b e x p os ure a n d efficac y a n d safet y e n d p oi nts . T hese a nal yses will 
be  descri be d i n a se p arate a nal ysis pla n.  
P atie nt -Re p orte d O utc o me s a n d He alt h Res o urce Utiliz ati o n A n al yses  
P R O assess me nts base d o n t he E Q -5 D -3 L a n d E O R T C Q L Q -C 3 0 will be s u m marize d usi n g descri pti ve 
statistics. P R O sc ores will be a nal yze d descri pti vel y. All s u bscales a n d i n di vi d ual ite m sc ores will be ta b ulate d. 
Descri pti ve s u m maries of o bs er ve d data at eac h s c he d ule d assess me nt ti me p oi nt ma y be prese nte d.  
S afet y A n al yses  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6  of 1 7 0  
Safet y will be assesse d t hr o u g h s u m maries of A Es, c ha n ges i n la b orat or y test res ults, c ha n ges i n vital si g ns, 
p h ysical e xa mi nati o n fi n di n gs, c ha n ges i n E C O G P S, a n d c ha n ges i n car diac ej ecti o n fracti o n res ults. A Es will 
be classifie d b y s yste m or ga n class ( S O C) a n d preferre d ter m usi n g t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A); A E se verities will be classifie d usi n g t he C T C A E v 4. 0 3  criteria. Se paratel y, all S A Es 
a n d A Es of s pe cial i nterest (e. g., a n y dr u g -i n d uce d li ver i nj ur y, a n d as y m pt o matic left ve ntric ular s yst olic 
d ysf u ncti o n) will als o be liste d.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 7  of 1 7 0  
T A B L E O F C O N T E N T S  
S P O N S O R P R O T O C O L A P P R O V A L P A G E  ....................................................................................................... 2  
P R O T O C O L S Y N O P SI S  ....................................................................................................................................... 3  
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  ....................................................................... 2 1  
1  
I N T R O D U C TI O N ......................................................................................................................................... 2 4  
1. 1  
H E R 2 + C ol o rectal Ca ncer .................................................................................................................. 2 4  
1. 2  
Treat me nt of H E R 2 + C R C  ................................................................................................................. 2 4  
1. 2. 1  
O n g oi n g Me dical Nee d i n H E R 2 + Metastatic C R C  ............................................................. 2 5  
1. 3  
T ucati ni b  ............................................................................................................................................. 2 6  
1. 3. 1  
Pr o d uct Descri pti o n a n d Mec ha nis m of Acti o n  ................................................................... 2 6  
1. 3. 2  
O ver vie w of N o ncli nical a n d Cli nical P har mac ol o g y St u dies  ............................................. 2 6  
1. 3. 3  
S u m mar y of t ucati ni b  ........................................................................................................... 3 1  
1. 4  
Trast uz u ma b  ....................................................................................................................................... 3 2  
1. 5  
N o ncli ni cal Rati o nale f or c o m bi nati o n of t ucati ni b wit h trast uz u ma b  ............................................... 3 2  
1. 6  
Cli nical Rati o nale f or c o m bi nati o n of t ucati ni b wit h trast uz u m a b  ..................................................... 3 2  
1. 7  
St u d y Rati o nale  .................................................................................................................................. 3 3  
1. 8  
Rati o nale f or Selecti o n of D os es  ........................................................................................................ 3 4  
2  
O BJ E C TI V E S A N D E N D P O I N T S ............................................................................................................... 3 5  
3  
I N V E S TI G A TI O N A L P L A N ....................................................................................................................... 3 8  
3. 1  
S u m mar y of St u d y Desi g n  .................................................................................................................. 3 8  
3. 1. 1  
Data & Safet y M o nit ori n g  .................................................................................................... 3 9  
3. 1. 2  
St o p pi n g Criteria  .................................................................................................................. 3 9  
3. 1. 3  
E n d of St u d y  ......................................................................................................................... 3 9  
3. 2  
Disc ussi o n a n d Rati o nale f or St u d y Desi g n ........................................................................................ 4 1  
3. 2. 1  
Rati o nale f or Selecti o n of D os es a n d Re gi me n  .................................................................... 4 1  
4  
S T U D Y P O P U L A TI O N ................................................................................................................................ 4 2  
4. 1  
I ncl usi o n Criteria ................................................................................................................................ 4 2  
4. 2  
E xcl usi o n Criteria  ............................................................................................................................... 4 4  
4. 3  
C hil d beari n g P ote ntial  ........................................................................................................................ 4 6  
4. 4  
Re m o val of S u bj ects fr o m T hera p y or Assess me nt  ............................................................................ 4 6  
4. 4. 1  
Disc o nti n uati o n of St u d y Treat me nt  .................................................................................... 4 6  
4. 4. 2  
S u bj ect Wit h dra wal fr o m St u d y  ........................................................................................... 4 7  
5  
T R E A T M E N T S  ............................................................................................................................................ 4 8  
5. 1  
Treat me nts A d mi nistere d .................................................................................................................... 4 8  
5. 1. 1  
I n vesti gati o nal St u d y Dr u g ( T ucati ni b) ................................................................................ 4 8  
5. 1. 2  
Trast uz u ma b  ......................................................................................................................... 5 0  
5. 2  
D ose M o dificati o ns ............................................................................................................................. 5 1  
5. 2. 1  
T ucati ni b D ose Re d ucti o ns  .................................................................................................. 5 1  
5. 2. 2  
Trast uz u ma b D ose M o dificati o ns ......................................................................................... 5 2  
5. 2. 3  
D ose M o dificati o ns f or A d verse E ve nts  ............................................................................... 5 3  
5. 3  
C o nc o mita nt T hera p y  ......................................................................................................................... 5 5  
5. 3. 1  
P ote ntial C o nc o mita nt Dr u g I nteracti o ns  ............................................................................. 5 6  
5. 3. 2  
Re q uire d C o nc o mita nt T hera p y  ........................................................................................... 5 6  
5. 3. 3  
All o we d C o nc o mita nt T hera p y  ............................................................................................ 5 6  
5. 3. 4  
C o nc o mita nt T hera pies t o be Use d wit h Ca uti o n  ................................................................. 5 7  
5. 3. 5  
Pr o hi bite d C o nc o mita nt T hera p y  ......................................................................................... 5 8  
5. 4  
Ma na ge me nt of O ver d ose  ................................................................................................................... 5 9  
5. 5  
Treat me nt C o m plia nce  ....................................................................................................................... 5 9  
6  
S T U D Y A C TI VI TI E S  ................................................................................................................................... 6 0  
6. 1  
Sc he d ule of E ve nts  ............................................................................................................................. 6 0  
6. 2  
Scree ni n g P eri o d  ................................................................................................................................. 6 0  
6. 2. 1  
Pre -scree ni n g ( U p t o 3 M o nt hs Bef ore A ntici pate d Scree ni n g Visit)  .................................. 6 0  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T uca ti ni b  
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 8  of 1 7 0  
6. 2. 2  
Scree ni n g Visit ( Da ys [ -2 8] t o [ -1])  ..................................................................................... 6 0  
6. 2. 3  
B aseli ne Visit ( Da ys [ -7] t o [ -1]) .......................................................................................... 6 1  
6. 3  
Treat me nt P eri o d ( 2 1 -da y c ycl es)  ....................................................................................................... 6 1  
6. 3. 1  
C ycle 1 Pre -d ose Da y 1  ........................................................................................................ 6 1  
6. 3. 2  
C ycle 1 Da ys 8 & 1 5 ( ± 3 da ys)  ............................................................................................ 6 2  
6. 3. 3  
C ycle 2 (a n d All S u bse q ue nt C ycles) Da y 1 ( ± 3 da ys)  ........................................................ 6 2  
6. 3. 4  
C ycle 2 (a n d All S u bse q ue nt C ycles) E ver y 6 or 9 wee ks ( ± 7 da ys)  ................................... 6 3  
6. 3. 5  
E ver y 1 2 wee ks ( ± 1 4 da ys)  .................................................................................................. 6 3  
6. 3. 6  
S u bj ects Cr ossi n g -O ver t o D o u blet Re gi me n  ....................................................................... 6 3  
6. 4  
E n d of Treat me nt Visit ( 3 0 t o 3 7 da ys After Last D ose of St u d y Dr u g)  ............................................ 6 4  
6. 5  
F oll o w -u p  ........................................................................................................................................... 6 4  
6. 6  
E n d of St u d y/ E n d of F oll o w -u p  .......................................................................................................... 6 4  
6. 7  
P ost -St u d y Care  .................................................................................................................................. 6 5  
7  
S T U D Y A S S E S S M E N T S  ............................................................................................................................. 6 6  
7. 1  
Scree ni n g/ Baseli ne Assess me nts  ........................................................................................................ 6 6  
7. 2  
Res p o nse/ Efficac y Assess me nts  ......................................................................................................... 6 6  
7. 2. 1  
Sc he d ule of E ve nts  ............................................................................................................... 6 7  
7. 2. 2  
Defi niti o ns of Meas ura ble a n d N o n -Meas ura ble Disease  .................................................... 6 7  
7. 2. 3  
G ui deli nes f or E val uati o n of Meas ura ble Disease ................................................................ 6 8  
7. 2. 4  
Meas ure me nt of Effect  ......................................................................................................... 6 9  
7. 3  
P har mac o ki netic Assess me nts  ............................................................................................................ 7 2  
7. 4  
Bi o mar ker St u dies  .............................................................................................................................. 7 2  
7. 4. 1  
Bi os peci me n C ollecti o n  ....................................................................................................... 7 3  
7. 4. 2  
Ret ur n of Ge netic T esti n g Res earc h Res ults  ........................................................................ 7 3  
7. 4. 3  
P at h ol o g y C o nsi derati o ns/ Tiss ue Bi os peci me ns  .................................................................. 7 3  
7. 5  
Bi os peci me n Re p osit or y  ..................................................................................................................... 7 4  
7. 6  
P atie nt -Re p orte d O utc o mes a n d Healt h Ec o n o mic Assess me nts  ....................................................... 7 4  
7. 7  
Safet y Assess me nts ............................................................................................................................. 7 4  
7. 7. 1  
A d verse E ve nts  ..................................................................................................................... 7 5  
7. 7. 2  
Vital Si g ns  ............................................................................................................................ 8 1  
7. 7. 3  
Cli nical La b orat or y T ests  ..................................................................................................... 8 1  
7. 7. 4  
P h ysical E xa mi nati o n  ........................................................................................................... 8 2  
7. 7. 5  
Pre g na nc y T esti n g  ................................................................................................................ 8 2  
7. 7. 6  
Car diac F u ncti o n  .................................................................................................................. 8 2  
7. 7. 7  
Treat me nt/ F oll o w -u p Decisi o n at E val uati o n of S u bj ect  ..................................................... 8 3  
7. 8  
A p pr o priate ness of Meas ure me nts ...................................................................................................... 8 5  
8  
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  ................................................................ 8 6  
8. 1  
Site Trai ni n g a n d M o nit ori n g Pr oce d ures  ........................................................................................... 8 6  
8. 2  
Data Ma na ge me nt Pr oce d ures  ............................................................................................................ 8 7  
8. 3  
Access t o S o urce Data  ........................................................................................................................ 8 7  
8. 4  
Acc urac y a n d Relia bilit y of D ata ........................................................................................................ 8 7  
8. 5  
Q ualit y Ass ura nce Pr oce d ures  ............................................................................................................ 8 7  
8. 6  
Data Ha n dli n g a n d Rec or d Kee pi n g  ................................................................................................... 8 7  
8. 6. 1  
Data Ha n dli n g  ...................................................................................................................... 8 8  
8. 6. 2  
I n vesti gat or Rec or d Rete nti o n .............................................................................................. 8 8  
8. 7  
Res ults Re p orti n g o n Cli nical Trials. g o v  ............................................................................................. 8 8  
9  
D A T A A N A L Y SI S M E T H O D S  ................................................................................................................... 8 9  
9. 1  
Deter mi nati o n of Sa m ple Size  ............................................................................................................ 9 4  
9. 2  
St u d y E n d p oi nt Defi niti o ns  ................................................................................................................ 9 5  
9. 2. 1  
O bj ecti ve Res p o nse Rate  ...................................................................................................... 9 5  
9. 2. 2  
O bj ecti ve Res p o nse Rate b y Wee k 1 2  .................................................................................. 9 5  
9. 3  
Statistical a n d A nal ytical Pla ns  .......................................................................................................... 9 6  
9. 3. 1  
Ge neral C o nsi derati o ns  ........................................................................................................ 9 6  
9. 3. 2  
S u bj ect Dis p ositi o n  .............................................................................................................. 9 8  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 9  of 1 7 0  
9. 3. 3  
S u bj ect C haracteristics  ......................................................................................................... 9 8  
9. 3. 4  
Treat me nt C o m plia nce  ......................................................................................................... 9 8  
9. 3. 5  
Efficac y A nal yses  ................................................................................................................. 9 8  
9. 3. 6  
P har mac o ki netic A nal yses  ................................................................................................... 9 9  
9. 3. 7  
Bi o mar ker A nal yses  ............................................................................................................. 9 9  
9. 3. 8  
P atie nt -Re p orte d O utc o mes a n d Healt h Res o urce Utilizati o n A nal yses  .............................. 9 9  
9. 3. 9  
Safet y A nal yses  .................................................................................................................... 9 9  
9. 3. 1 0  
I nteri m A nal yses ................................................................................................................ 1 0 1  
1 0  I N F O R M E D C O N S E N T, E THI C A L R E VI E W, A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ............... 1 0 2  
1 0. 1  I nf or me d C o nse nt ............................................................................................................................. 1 0 2  
1 0. 2  E t hical Re vie w .................................................................................................................................. 1 0 2  
1 0. 3  Re g ulat or y C o nsi derati o ns ................................................................................................................ 1 0 3  
1 0. 4  I n vesti gat or I nf or mati o n ................................................................................................................... 1 0 3  
1 0. 4. 1  
Pr ot oc ol A me n d me nts a n d St u d y T er mi nati o n  .................................................................. 1 0 3  
1 0. 5  St u d y D oc u me ntati o n, Pri vac y a n d Rec or ds Rete nti o n  .................................................................... 1 0 3  
1 0. 6  Cli nical Trial A gree me nt  .................................................................................................................. 1 0 4  
1 1  R E F E R E N C E S  1 0 5  
A P P E N DI X A:  
S C H E D U L E O F E V E N T S  ................................................................................................. 1 1 0  
A P P E N DI X B:  
P E R F O R M A N C E S T A T U S S C A L E S C O N V E R SI O N  .................................................... 1 1 5  
A P P E N DI X C:  
G UI D A N C E O N C O N T R A C E P TI O N  .............................................................................. 1 1 6  
A P P E N DI X D:  
N E W Y O R K H E A R T A S S O C I A TI O N C L A S SI FI C A TI ON  ............................................ 1 1 7  
A P P E N DI X E:  
C Y P 3 A 4 I N D U C E R S A N D T H EI R E LI MI N A TI O N H A L F -LI V E S  ............................... 1 1 8  
A P P E N DI X F:  
C Y P 2 C 8 I N HI BI T O R S/I N D U C E R S A N D T H EI R E LI MI N A TI O N H A L F -LI V E S ........ 1 1 9  
A P P E N DI X G:  
P A TI E N T D R U G DI A R Y  ................................................................................................. 1 2 0  
A P P E N DI X H:  
E X A M P L E S O F C LI NI C A L  S U B S T R A T E S F O R C Y P 3 A -M E DI A T E D 
M E T A B O LI S M  ................................................................................................................. 1 2 2  
A P P E N DI X I:  
D E FI NI N G LI N E S O F T H E R A P Y  ................................................................................... 1 2 3  
A P P E N DI X J:  
I N V E S TI G A T O R SI G N A T UR E P A G E  ............................................................................ 1 2 4  
A P P E N DI X K:  
D O C U M E N T HI S T O R Y  ................................................................................................... 1 2 5  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 0  of 1 7 0  
LI S T O F I N-T E X T T A B L E S  
T a ble  1 -1:  
A nti -H E R 2 cli nical trials i n patie nts wit h refract or y H E R 2 + m C R C  ............................................ 2 4  
T a ble 1 -2:  
Cli nical trials i n patie nts wit h treat me nt refract or y m C R C  ........................................................... 2 6  
T a ble 1 -3:  
H E R 2 a n d H E R 1 I n hi biti o n  ........................................................................................................... 2 7  
T a ble 2 -1:  
O bj ecti ves a n d c orres p o n di n g e n d p oi nts  ....................................................................................... 3 5  
T a ble 5 -1:  
Treat me nt sc he d ule  ........................................................................................................................ 4 8  
T a bl e 5 -2:  
T ucati ni b: Rec o m me n de d d ose re d ucti o n sc he d ule f or A Es  ......................................................... 5 2  
T a ble 5 -3  
D ose m o dificati o ns f or i nf usi o n -relate d reacti o ns f or trast uz u ma b ............................................... 5 3  
T a ble 5 -4  
D ose m o dificati o ns f or cli nical A Es relate d t o eit her t ucati ni b or trast uz u ma b  ............................ 5 4  
T a ble 5 -5  
D ose m o dificati o ns of t ucati ni b f or li ver f u ncti o n a b n or malities  .................................................. 5 5  
T a ble 5 -6:  
Trast uz u ma b d ose m o dificati o ns g ui deli nes f or left ve ntric ul ar d ysf u ncti o n  ................................ 5 5  
T a ble 7 -1:  
E val uati o n of o verall o bj ecti ve stat us  ............................................................................................ 7 2  
T a ble  9 -1:  
O ver vie w of st u d y o utc o me meas ure me nts  ................................................................................... 9 0  
T a ble 9 -2:  
Esti mate d O R R  .............................................................................................................................. 9 4  
T a ble 1 1 -1:  
Sc he d ule of e ve nts  ....................................................................................................................... 1 1 0  
T a ble 1 1 -2:  
P har mac o ki netic a n d bi o mar ker sa m ple c ollecti o n ti me p oi nts –  C o h ort A  ................................ 1 1 4  
T a ble 1 1 -3:  
P har mac o ki netic a n d bi o mar ker sa m ple c ollecti o n ti me p oi nts –  C o h orts B a n d C  .................... 1 1 4  
 
LI S T O F I N -T E X T FI G U R E S  
Fi g ure  1 -1:  
S u bj ect wit h E R B B 2 a m plifie d, E G F R -refract or y metastatic C R C treate d wit h off-la bel la pati ni b 
a n d trast uz u ma b  ............................................................................................................................. 2 5  
Fi g ure 3 -1:  
St u d y sc he matic  ............................................................................................................................. 4 0  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 1  of 1 7 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  
A E  
a d verse e ve nt  
A E SI  
a d verse e ve nt s 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  
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 
β -h C G  
beta h u ma n c h ori o nic g o na d otr o pi n  
B C R P  
breast ca ncer resista nce pr otei n  
BI C R  
bli n de d i n de p e n de nt ce ntral re vie w  
BI D  
t wice dail y  
B S D  
B aseli ne s u m of dia meters B S D  
C B C  
c o m plete bl o o d c o u nt  
C C G  
Case Re p ort F or m C o m pleti o n G ui deli nes  
C E  
C o nf or mité E ur o pée n ne  
C E A  
carci n oe m br y o nic a nti ge n  
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 ma x  
ma xi m u m c o nce ntrati o n o bser ve d  
C N S  
ce ntral ner v o us s yste m  
c O R R  
c o nfir me d o bj ecti ve res p o nse rate 
C R  
c o m plete res p o nse  
C R F  
case re p ort f or m  
C T  
c o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  
ct D N A 
circ ulati n g t u m or D N A  
C Y P  
c yt oc hr o me P 4 5 0  
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 M M R  
deficie nt mis matc h re pair  
D O R  
d urati o n of res p o nse  
E D  
e mer ge nc y de p art me nt  
E E A  
E ur o pea n Ec o n o mic Area  
E C G  
electr ocar di o gra m  
E C H O  
ec h ocar di o gra m  
E C O G  P S  
Easter n C o o perati ve O nc ol o g y Gr o u p  P erf or ma nce Stat us  
e C R F  
electr o nic case re p ort f or m  
E G F R  
e pi der mal gr o wt h fact or rece pt or  
E O R T C Q L Q -C 3 0  
E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca nc er Q ualit y -of -Life 3 0 -ite m 
C ore Q uesti o n naire  
E O T  
e n d of treat me nt  
E Q -5 D -5 L  
E ur o pea n Q ualit y of Life 5 -Di me nsi o n 5 -Le vel  
E U  
E ur o pea n U ni o n  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 2  of 1 7 0  
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F 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  
G L P  
G o o d La b orat or y Practice  
h E R G  
h u ma n et her a -g o -g o relate d ge ne  
H E R 2  
h u ma n e pi der mal gr o wt h fact or rece pt or 2  
H R  
hazar d rati o  
HI V  
h u ma n i m m u n o deficie nc y vir us  
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n  
I C5 0 
half ma xi mal i n hi bit or y c o nce ntrati o n  
I E C 
i n de p e n de nt et hics c o m mittee 
I H C 
i m m u n o hist oc he mistr y  
I M 
i ntra m usc ular 
I N D 
I n vesti gati o nal Ne w Dr u g 
I N R 
i nter nati o nal n or malize d rati o 
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 H 
i n sit u h y bri dizati o n 
I S O 
I nter nati o nal Or ga nizati o n f or Sta n dar dizati o n 
I S T 
i n vesti gat or-s p o ns ore d trial 
I T T 
i nte nt-t o-treat 
I V 
i ntra ve n o us 
H R  
hazar d rati o  
L F T  
li ver f u ncti o n test 
L V E F  
left ve ntric ular ej ecti o n fracti o n 
Me d D R A  
Me dical Dicti o nar y f or Re g ul at or y Acti vities  
m A b  
m o n ocl o nal a nti b o d y  
m C R C  
metastatic c ol orectal ca ncer  
M RI  
ma g netic res o na nce i ma gi n g  
M S D  
mi ni m u m s u m of t he dia meters  
M SI -H  
Micr osatellite i nsta bilit y -Hi g h  
M U G A  
m ulti ple -gate d ac q uisiti o n  
N CI  
Nati o nal Ca ncer I nstit ute  
N G S  
Ne xt Ge nerati o n Se q ue nci n g  
O R R  
o bj ecti ve res p o nse rate  
O S  
o verall s ur vi val 
P B P K  
p h ysi ol o gicall y base d p har ma c o ki netic  
P B S D  
P ost -B aseli ne S u m of t he Dia meters  
P D  
pr o gressi ve disease  
P E T  
p ositr o n e missi o n t o m o gra p h y  
P -g p  
P -gl yc o pr otei n  
P F S  
pr o gressi o n -free s ur vi val 
P K  
p har mac o ki netic(s)  
P O  
orall y  
P R  
partial res p o nse 
P R O  
patie nt -re p orte d o utc o me 
P T  
pr ot hr o m bi n ti me  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 3  of 1 7 0  
P T T  
partial t hr o m b o plasti n ti me  
Q o L  
q ualit y of life  
Q T c  
correcte d Q T i nter val  
R E CI S T  
Res p o nse E val uati o n Criteria i n S oli d T u m ors  
R P 2 D  
rec o m me n de d p hase 2 d ose 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S D  
sta ble disease 
S G O T  
ser u m gl uta mic o x ol oacetic tr a nsa mi nase 
S G P T  
ser u m gl uta mic p yr u vic tra nsa mi nase 
S M C  
Safet y M o nit ori n g C o m mittee  
S O C  
S yste m Or ga n Class  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o ns  
T -D M 1  
a d o -trast uz u ma b e mta nsi ne 
T E A E  
treat me nt-e mer ge nt a d verse e ve nts  
T GI  
t u m or gr o wt h i n hi biti o n  
T KI  
t yr osi ne ki nase i n hi bit or 
T T P  
ti me-t o-pr o gressi o n  
U L N  
u p per li mit of n or mal  
U S  
U nite d States  
V E G F  
vasc ular e n d ot helial gr o wt h fa ct or  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 4  of 1 7 0  
1  
I N T R O D U C TI O N 
1. 1  H E R 2 + C ol or e ct al C a n c er  
C ol orectal ca n cer ( C R C) is t he sec o n d lea di n g ca use of ca n cer deat h i n t he U nite d States  
( U S), wit h nearl y 5 0, 0 0 0 deat hs a n n uall y (J e mal 2 0 1 0). Bas e d o n c urre nt treat me nt 
al g orit h ms, s ur vi v al f or patie nts wit h metastatic C R C  ( m C R C) is a p pr o xi matel y 2-3 years  
(Va n C utse m 2 0 1 1 ; D o uillar d 2 0 1 3a ; D o uillar d 2 0 1 3 b ; Cre m oli ni 2 0 1 5 ). Nearl y half of all 
patie nts wit h m C R C  ha ve K R A S  or N R A S  ( R A S) wil d-t y pe t u m ors (D o uillar d 2 0 1 3a ). I n 
u nselecte d patie nts, t he pre vale n c e of E R B B 2  a m plificati o n is 3. 5 %  (Ca ncer Ge n o me Atlas 
2 0 1 2 ); h o we ver, a m o n g patie nts wit h K R A S /N R A S /B R A F  wil d -t y pe C R C t u m ors, t he 
pre vale n ce of E R B B 2  a m plificati o n i ncreas es  t o 6-1 0 %  (Sie na 2 0 1 5 ; Ra g ha v 2 0 1 6 ). T here 
are c urre ntl y n o a p pr o ve d t hera pies f or patie nts wit h E R B B 2  a m plifie d metastatic C R C.  
E nc o de d b y t he E R B B 2  ge ne, H E R 2 is part of a fa mil y of 4  rel ate d rece pt or t yr osi ne ki nas es, 
w hic h i ncl u de H E R 1 (als o k n o w n as e pi der m al 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 si n gle -pass tra ns m e m bra ne gl yc 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 ntrac ell 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. 
H E R 2 h o m o - or heter o di meriz ati o n res ults i n t he acti vati o n of m ulti ple si g nali n g casca d es, 
i ncl u di n g t he Ras/ Raf/ M E K/ M A P K, PI 3 K/ A K T, Src, a n d S T A T pat h w a ys. T hese si g nali n g 
pat h wa ys lea d t o c ell 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 yi 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 n es 2 0 0 5 ) 
1. 2  Tr e at m e nt of H E R 2 + C R C  
A nti -H E R 2 t hera pies are acti ve i n patie nts wit h hea vil y pre -treate d, H E R 2 + m C R C 
(Ta ble  1 -1 ). I n a si n gle-ar m, p hase 2  trial c o n d ucte d i n patie nts wit h refract or y H E R 2 + 
m C R C, d ual H E R 2 -bl oc ka de wit h la pati ni b a n d trast uz u ma b res ulte d i n a 3 0 % res p o nse rate, 
a n d a nearl y 5 m o nt h me dia n ti me -t o-pr o gressi o n ( T T P) (Sart ore -Bia nc hi 2 0 1 6 ). I n a d diti o n, 
t he M y Pat h w a y bas ket trial, w hic h e val uat e d trast uz u ma b pl us pert uz u ma b i n patie nts wit h 
H E R 2 + m C R C, re p orte d a 3 2 % res p o ns e rat e  (Hai ns w ort h 2 0 1 6 ) a n d a 2. 9 m o nt h me dia n 
pr o gressi o n -free s ur vi val (P F S) (Meri c -Ber nsta m 2 0 1 9 ). “ Pert uz u ma b pl us trast uz u ma b f or 
H E R 2 -a m plifie d metastatic c ol orectal ca ncer ( M y Pat h wa y): A n U p dat e d Re p ort fr o m a 
M ultice nter, O pe n -l a bel, P hase 2a, m ulti ple bas ket trial.”( 4): 5 1 8-5 3 0. d oi: 
1 0. 1 0 1 6/ S 1 4 7 0 -2 0 4 5( 1 8) 3 0 9 0 4 -5. Des pite t hese f a v ora ble res ults, access t o a nti -H E R 2 
t hera pies is restri cte d t o cli nical trials a n d off-la bel use.  
T a bl e  1 -1 : 
A nti -H E R 2 c li ni c al tri al s i n p ati e nt s wit h refr a ct or y H E R 2 + m C R C  
Cli nical Trial  
T hera pies  
P atie nts ( N)  
Res p o nse Rate  
T T P/ P F S ( me dia n)  
H E R A C L E S  
La p ati ni b + Trast uz u ma b  
2 7  
3 0 %  
4. 9 m o nt hs  
M y P at h wa y  
P ert uz u ma b + Trast uz u ma b  
5 7  
3 2 % a 
2. 9 m o nt hs  
T T P = ti me -t o-pr o gressi o n; W T = wil d -t y pe 
a 
O R R 3 2 % ; O R R 4 0 % ( 1 7/ 4 3) i n K R A S W T; O R R 8 % ( 1/ 1 3) i n K R A S m utate d  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 5  of 1 7 0  
As part of a n i n v esti gat or -i nitiate d trial at D u ke U ni versit y ( N C T 0 2 0 0 8 3 8 3), c o m pre h e nsi ve 
m olec ular pr ofili n g is bei n g perf or me d o n patie nts wit h E G F R -refract or y, R A S wil d-t y p e 
m C R C. T hree o ut  of t he first 2 4 patie nts ( 1 2. 5 %) ha d E R B B 2  a m plificati o n c o nf ir me d b y 
fl u oresce n ce i n sit u h y bri diz ati o n ( FI S H). O ne of t hese hea vil y pretreate d patie nts recei ve d 
off -la bel la p ati ni b a n d trast uz u ma b a n d e x perie nce d si g nifica nt cli nical res p o nse ( See 
Ta ble  1 -1 ). 
Fi g ur e  1 -1 : 
S u bj e ct wit h E R B B 2 a m plifi e d, E G F R -r efr a ct or y m et a st ati c C R C tr e at e d wit h 
off -l a b el l a p ati ni b a n d tr a st u z u m a b 
 
W it h m o u nti n g e vi de nce t hat E R B B 2  a m plifie d t u m ors are resista nt t o a nti -E G F R t hera pies  
(Vlacic h 2 0 1 1 ; Y o n esa ka 2 0 1 1 ; Bert otti 2 0 1 5 ), H E R 2 testi n g f or patie nts wit h m C R C is 
i ncreasi n gl y r o uti ne. I n crease d access t o a nti-H E R 2 cli nical trials will f urt her facilitate H E R 2 
testi n g a n d pers o nalize d treat me nt strate gi es. 
1. 2. 1  O n g oi n g M e di c al N e e d i n H E R 2 + M et a st ati c C R C  
After pr o gressi o n o n first a n d sec o n d li ne c h e m ot hera p y ( F O L F O X a n d F O L FI RI), t h e 
cli nical be nefit of a p pr o ve d t hera pies is li mite d. F or patie nts wit h R A S wil d -t y pe m C R C, 
a nti b o dies tar geti n g E G F R offer a m o n ot hera p y res p o nse rate of a p pr o xi matel y 2 0 % a n d a 
P F S of 4 m o nt hs  (Price 2 0 1 4 ). N o net heless, si nce E R B B 2  a mplificati o n is c o nsi dere d a dri v er 
of pri mar y E G F R treat m e nt resista nce  (Bert otti 2 0 1 1 ; Marti n 2 0 1 3 b ; Ra g h a v 2 0 1 6 ), t he r ole 
f or a nti-E G F R t hera pi es i n t he H E R 2 + C R C patie nt p o p ulati o n is i ncreasi n gl y q uesti o ne d  
(Sc h m oll 2 0 1 6 ). 
O nce patie nts wit h m C R C ha ve pr o gress e d o n all sta n dar d c h e m ot hera p y a n d b i ol o gical 
t hera pies, c urre nt a p pr o ve d treat me nt o pti o ns i ncl u de re g orafe ni b a n d trifl uri di ne/ti piracil 
( T A S-1 0 2). B ot h t hera pi es offer a res p o nse rate less t ha n 2 %, a n d a s ur vi v al be nefit of less 
t ha n 2 m o nt hs c o m pare d t o place b o (see Ta ble 1 -2 ) (Gr ot he y 2 0 1 3 ; Ma yer 2 0 1 5 ). T o 
i m pr o ve cli nical o utc o mes, eff orts are nee de d t o i d e ntif y a n d treat patie nts wit h acti o na ble 
ge n o mic alterati o ns.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)
P P D
P P D

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 6  of 1 7 0  
T a bl e 1 -2 : 
Cli ni c al tri al s i n p ati e nt s wit h tr e at m e nt refr a ct or y m C R C  
Cli nical T rial 
T hera pies  
P atie nts ( N)  
O R R ( %)  
Me dia n P F S ( m o nt hs)  
Me dia n O S ( m o nt hs)  
C O R R E C T  
Re g orafe ni b  
Place b o  
5 0 5  
2 5 5  
1. 0 %  
0. 4 %  
1. 9  
1. 7  
6. 4  
5. 0  
R E C O U R S E  
T A S -1 0 2  
Place b o  
5 3 4  
2 6 6  
1. 6 %  
0. 4 %  
2. 0  
1. 7  
7. 1  
5. 3  
1. 3  T u c ati ni b  
1. 3. 1  Pr o d u ct D e s cri pti o n a n d M e c h a ni s m of A cti o n  
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 Y -3 8 0) is a n oral, p ot e nt, H E R 2 -s pecific 
t yr osi ne ki nas e i n hi bit or ( T KI) t hat is bei n g de v el o pe d b y Sea ge n  ( 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 u al -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 
(Ta ble 1 -3 ). 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 h e E G F R -relat e d si de effects i ncl u di n g s e vere s ki n ras h a n d gastr oi ntesti nal 
t o xicit y. 
1. 3. 2  O v er vi e w of N o n cl i ni c al a n d Cli ni c al P h ar m a col o g y  St u di e s  
T he p har mac o ki netics ( P K ), t o xic o ki netics, distri b uti o n, meta b olis m, e x creti o n, a n d P K dr u g 
i nteracti o ns of t ucati ni b were assesse d i n i n vitr o s yste ms, a n d i n viv o i n mice, rats, a n d 
c y n o m ol g us m o n ke ys. M eta b olis m a n d e x creti o n st u dies were als o c o n d uct e d i n h u ma ns.  I n 
a d diti o n, m ulti ple cli nical trials ha ve bee n c o m plete d, or are c urre ntl y e nr olli n g t o e val uat e 
t ucati ni b i n s u bjects wit h H E R 2 + metastatic breast ca ncer.   
1. 3. 2. 1  Pr e cli ni c al St u di e s  
F or f ull details of precli nical st u dies of t ucati ni b, refer t o t he t u cati ni b I n vesti gat or’s 
Br oc h ure. O n e of t he k e y feat ur es of t ucati ni b is t he hi g hl y p ote nt a n d s electi ve i n hi biti o n of 
t he rece pt or t yr osi ne ki nase H E R 2. A c o m bi nati o n of bi oc he mical a n d cell bi ol o gical ass a ys 
ha ve bee n use d t o de m o nstrate t he selecti ve i n hi biti o n of H E R 2 wit h li mite d acti vit y a gai nst 
str uct urall y relate d pr otei n ki nases, i ncl u di n g E G F R a n d h u ma n e pi der mal gr o wt h fact or 
rece pt or 4 ( H E R 4). 
Usi n g a p a nel of 2 2 3 pr otei n ki nas es, t he o nl y e nz y m es i n hi bite d b y t ucati ni b b y 7 5 % w he n 
teste d at eit her 1 or 1 0 µ M were me m b ers of t he Er b B ki nas e fa mil y ( H E R 2, E G F R, H E R 4). 
F urt her a nal ysis of t his fa mil y of ki nases usi n g bi o c he mical ass a ys d e m o nstrate d t hat 
t ucati ni b i n hi bite d H E R 2 wit h a half ma xi mal i n hi bit or y c o n ce ntr ati o n (I C5 0) of 2 2 n M a n d 
was less acti ve a gai nst E G F R (I C 5 0 = 9 4  n M) a n d H E R 4 (I C 5 0 =  3 7 0  n M). T he selecti vit y of 
t ucati ni b f or H E R 2 is better e x e m plifie d i n assa ys desi g ne d t o meas ure t h e i n hi biti o n of 
H E R 2 a n d E G F R a ut o p h os p h or ylati o n usi n g t u m or deri ve d cell li nes. I n t he H E R 2 
o vere x pressi n g cell li ne B T -4 7 4, t ucati ni b i n hi bite d t he p h os p h or ylati o n of H E R 2 wit h a n 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 7  of 1 7 0  
I C5 0 = 8 n M a n d i n hi bite d t he p h os p h or yl ati o n of A kt, a d o w nstrea m effect or of H E R 2, wit h 
a n I C 5 0 = 3  n M. C o nsiste nt wit h t he p ote nt i n hi biti o n of H E R 2 p h os p h or yl ati o n i n t his cell 
li ne, t ucati ni b bl oc ke d t he pr oliferati o n of B T -4 7 4 cells wit h a n I C 5 0 = 1 1  n M. I n c o ntrast, 
t ucati ni b o nl y wea kl y i n hi bite d t he p h os p h or ylati o n of E G F R i n t he o vere x pressi n g cell li ne 
A 4 3 1, pr o d uci n g a n I C 5 0 =  4 0 0 0  n M a n d o nl y i n hi bite d pr oliferati o n of A 4 3 1 cells at dr u g 
c o nce ntr ati o ns greater t h a n 1 m M. T hese data de m o nstrate a hi g h de g ree of selecti vit y 
( 5 0 0-f ol d) f or H E R 2 rel ati ve t o E G F R a n d are c o nsiste nt wit h t he i dea t hat t ucati ni b has t he 
ca pacit y t o bl oc k H E R 2 si g nali n g wit h o ut t he c o ntri b uti n g t o xicities of E G F R i n hi biti o n.  
T a bl e 1 -3 : 
H E R 2 a n d H E R 1 I n hi biti o n  
 
H E R 2  
I C5 0 ( n M) 
H E R 1 ( E G F R)  
I C5 0 ( n M) 
Tr u ncate d p 9 5 H E R 2 I C 5 0 
( n M) 
T ucati ni b  
8  
> 1 0 0 0  
7  
Nerati ni b  
7  
8  
N ot teste d  
La p ati ni b  
4 9  
3 1  
2 5  
I n Vi v o P h ar m ac ol o g y  
T ucati ni b has bee n st u die d i n a variet y of n o n cli nical p har mac ol o g y st u dies t o meas ure its 
effic ac y as a si n gl e -a ge nt a n d i n dr u g c o m bi nati o ns usi n g H E R 2 -dri ve n t u m or m o dels. As a 
si n gle-a ge nt, t ucati ni b i n hi bite d t u m or gr o wt h w h e n d ose d at 2 5, 5 0 a n d 1 0 0 m g/ k g. 
At eac h of t h ese d ose le v els, t ucati ni b si g nifica ntl y i n hi bite d t u m or gr o wt h i n s u bc uta ne o us 
t u m or m o dels deri ve d fr o m B T-4 7 4 ( h u ma n breast carci n o ma) a n d N 8 7 ( h u ma n gastric 
carci n o ma) cells. I n t h e B T -4 7 4 m o del, t u m or gr o wt h i n hi biti o n ( T GI) b y t ucati ni b was 8 1 % 
at 5 0 m g/ k g a n d w as greater t ha n  t he T GI o bser ve d wit h trast uz u ma b ( 2 0 m g/ k g). I n t he 
N 8 7  m o del, t ucati ni b i n hi bite d t u m or gr o wt h m ore t ha n 7 0 % w he n d ose d at 5 0 m g/ k g. 
T ucati ni b has als o bee n e val uate d i n c o m bi nati o n wit h trast uz u ma b or d oceta xel i n 
s u bc uta ne o us H E R 2 t u m or m o dels. I n t hese c o m bi nati o n st u dies, t he dr u g d o u blets were 
well -t olerate d a n d m ore effic aci o us t ha n a n y si n gle-a ge nt. W he n t ucati ni b was c o m bi ne d 
wit h trast uz u ma b ( 2 0 m g/ k g ) i n t he B T-4 7 4 m o del, t he a nti t u m or acti vit y e x cee de d eit her 
dr u g w he n d ose d as a si n gle -a ge nt. Si milarl y, t he c o m bi nati o n of t ucati ni b wit h d oceta xel 
( 1 0 m g/ k g) i n t he B T -4 7 4 m o del was als o m ore effecti ve t h a n eit her si n gle -a ge nt.  
N o ncli nic al S afet y  
G o o d La b orat or y Practice ( G L P) t o xic ol o g y, safet y p har mac ol o g y, a n d t olera bilit y st u dies 
wit h t ucatini b ha ve bee n c o n d ucte d i n rats a n d c y n o m ol g o us m o n ke ys t o e xtra p olate t he 
safet y of a d mi nisteri n g t he dr u g t o h u ma ns. Ta ke n t o get her, t hese st u dies ha ve de m o nstrat e d 
t hat t ucati ni b has a satisf act or y safet y pr ofile a n d prese nts li mite d ris k i n h u ma ns. I n G L P 
t o xic ol o g y st u dies c o n d u cte d b y a d mi nistrati o n of t ucati ni b dail y o ver a 2 8 -da y peri o d, d os es 
of 3 0  m g/ k g BI D i n rats a n d 1 0  m g/ k g BI D  i n m o n ke ys were ge nerall y well-t olerate d o ver 
t he testi n g peri o d. Safet y p har mac ol o g y st u dies w ere c o n d u cte d t o e x a mine t he effect of 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 8  of 1 7 0  
t ucati ni b o n car di o vas c ular f u ncti o n usi n g i n vitr o h u ma n et her  a-g o -g o -relate d ge ne ( h E R G) 
i n hi biti o n assa ys, a n d b y i n vi v o tele metr y usi n g c y n o m ol g o us m o n ke ys. Titrati o n of 
t ucati ni b i n t he h E R G assa y pr o d uce d a n I C5 0 =  1 3. 5  µ M a n d t her e were n o si g nifica nt 
effects n ote d i n mea n art erial bl o o d press ur e, heart rate or el ectr ocar di o gra m ( E C G) 
wa vef or ms or i n Q T a n d c orrecte d Q T ( Q T c) meas ure me nts i n t he i n vi v o st u d y. T here were 
als o n o effects n ote d i n GI (secreti o n a n d pr o p ulsi o n), ne ur o be h a vi oral, or res pirat or y 
f u ncti o n st u dies perf or m e d i n rats. 
I n a d diti o n t o t hese precli nical safet y assess me nts, t ucati ni b was als o s h o w n t o ha ve a l o w 
ris k of m uta ge nicit y. I n vitr o st u dies de m o nstrate d t ucati ni b is n o n-m uta ge nic w he n teste d 
usi n g bact erial r e vers e m utati o n ( A mes test) or L 5 1 7 8 Y/ T K +/ - m o use l y m p h o ma cell assa ys. 
I n a d diti o n, at d oses u p t o 2 0 0 0 m g/ k g, t ucati ni b was ne gati ve f or t he i n d u cti o n of 
micr o n ucleate d p ol yc hr o matic er yt hr oc ytes i n mice.  
1. 3. 2. 2  A b s or pti o n, Di stri b uti o n, M et a b oli s m, a n d E x cr eti o n St u di e s  
T ucati ni b was meta b olize d b y c yt oc hr o me P 4 5 0 2 C 8 ( C Y P 2 C 8 ) a n d C Y P 3 A i n he patic i n 
vitr o  s yste ms. Cli nical dr u g -dr u g i nteracti o n ( D DI ) st u dies ( O N T-3 8 0 -0 1 2, O N T -3 8 0 -0 0 8 ) 
a n d p h ysi ol o gicall y bas e d p har mac o ki netic ( P B P K ) m o deli n g (P B P K Re p ort ) i n dicate 
C Y P 2 C 8 is t he pri mar y r o ute of meta b olis m ( ~ 7 0 %), w hereas C Y P 3 A pla ys a mi n or r ole 
( ~ 1 0 %) i n t ucati ni b meta b olis m.  
I n vitr o, t uc ati ni b was s h o w n t o be a c o m petiti ve i n hi bit or of C Y P 2 C 8, C Y P 2 C 9, a n d 
C Y P 3 A wit h K i val ues of 0. 1 7 0, 4. 5 7, a n d 0. 8 0 5 µ M, res pecti vel y, a n d ca use d 
meta b olis m -de pe n de nt i n acti vati o n of C Y P 3 A wit h K I v al ue of 0. 5 4 µ M. Cli nical D DI 
st u dies i n dicate d t ucati ni b is a wea k i n hi bit or of C Y P 2 C 8 a n d a str o n g i n hi bit or of C Y P 3 A 
b ut n ot a n i n hi bit or of C Y P 2 C 9.  
T ucati ni b is a s u bstrate a n d a n i n hi bit or of P -gl yc o pr otei n ( P -g p ) a n d breast ca ncer resista nce 
pr otei n ( B C R P),  wit h I C 5 0 val ues of 1 0 μ M t o ~  3 0 a n d ~ 9 μ M , res pecti vel y. Cli nical  D DI 
st u dies (O N T -3 8 0 -0 1 2 ) i n dicate t ucati ni b is a wea k i n hi bit or of P -g p.  T ucati ni b i n hi bite d 
ki d ne y pr o xi mal t u b ule tra ns p orters O C T 2, M A T E 1 a n d M A T E 2 -K me di ate d tra ns p ort of 
metf or mi n a n d creati ni ne i n vitr o. Res ults fr o m a cli nical dr u g i nteracti o n st u d y 
(O N T -3 8 0 -0 2 0 ) wit h metf or mi n s h o we d t hat c o -a d mi nistrati o n of t ucati ni b wit h metf or mi n 
i ncreas e d t he metf or mi n plas ma e x p os ure b y 4 8 % a n d ca use d tra nsie nt i ncrease i n ser u m 
creati ni ne le v el wit h o ut i m pacti n g re nal f u n cti o n.  
T he cli nical a n d n o n -cli nical data i n dicate t h at t here are n o cir c ulati n g m eta b olites of 
t ucati ni b t hat e x cee d 1 0 % of t otal dr u g-relate d e x p os ure i n healt h y v ol u nteers a n d m etastatic 
breast c a ncer patie nts . I n cli nical st u dies, t he p ote nc y a dj uste d e x p os ure of t he pre d o mi na nt 
meta b olite of t ucati ni b ( O N T -9 9 3 ) was  < 1 0 % , i n dicati n g t he p h ar mac ol o g y  of t ucati ni b  is 
pri maril y dri v e n b y  t he p are nt dr u g. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 2 9  of 1 7 0  
Plas ma pr otei n bi n di n g of t ucati ni b was 9 7. 1 % at 1 µ M ( 4 8 0 n g/ m L) a n d was c o nsiste nt 
bet wee n 0. 1 a n d 5 0 µ M.  
1. 3. 2. 3  Cli ni c al St u di e s  
A s u m mar y of c o m plete d  a n d o n g oi n g cli nical st u dies , w hic h pr o vi de i nf or mati o n o n t he P K 
a n d p har mac o d y na mic pr o perties of t ucati ni b , is pr o vi de d i n t he I n vesti gat or’s Br oc h ure.  
T he p har mac o ki netics  ( P K) of t ucati ni b ha ve bee n e val uate i n m ulti ple P hase 1 a n d P hase 
2  st u dies i n healt h y v ol u nteers a n d i n s u bjects wit h metastatic breast ca ncer. At t he 
rec o m me n de d p h ase 2 d ose (R P 2 D ) ( 3 0 0 m g BI D), t ucati ni b as a d mi nistere d as a ta blet was 
ra pi dl y a bs or be d wit h a me dia n ti me of ma xi m u m c o nce ntrati o n o bser ve d (T ma x ) of 2 h o urs 
(ra n ge 1 t o 4 h o urs), a n d a half-life of a p pr o xi matel y 8 h o urs. T ucati ni b e x hi bite d less t ha n 
2 -f ol d acc u m ulatio n after m ulti ple d osi n g t o stea d y -stat e. E val uati o n of t he i m pact of f o o d o n 
t he P K  of t ucati ni b i n dicate d c o -a d mi nistrati o n wit h f o o d i ncreas e d t he e x p os ure  area u n der 
t he c ur ve ( A U C) less t ha n 2-f ol d wit h n o effect o n ma xi m u m c o nce ntrati o n o bser ve d ( C ma x ). 
A ra di ola bele d m ass bala nce st u d y has i n dicate d t hat after a si n gl e d ose, t h e maj orit y of t otal 
ra di oacti vit y was r ec o vere d i n t he feces, w hereas l ess t ha n 5 % of t otal ra di o acti vit y was 
rec o vere d i n t he uri n e ( O N T-3 8 0 -0 0 8) . A t h or o u g h Q T st u d y i n dicat e d t ucati ni b has n o effect 
o n Q T pr ol o n gati o n  ( O N T-3 8 0 -0 1 1) . Cli nical D DI st u dies h a ve i n dicate d t hat t ucati ni b is a 
str o n g i n hi bit or of C Y P 3 A a n d a wea k i n hi bit or of C Y P 2 C 8, P -g p a n d M A T E 1/ 2 -K (see 
Secti o n 5. 3. 5 ).  
T he d ata fr o m a c o m plet e d  D DI st u d y ( O N T -3 8 0 -0 1 2 ) i n dicate t hat c o-a d mi nistrati o n of 
m ulti ple d oses of t ucati ni b ( 3 0 0 m g BI D) wit h mi daz ola m (a se nsiti ve C Y P 3 A s u bstrate) 
i ncreas e d t he ge o metri c mea n mi daz ola m e x p os ure ( A U C) a p pr o xi matel y 5. 8 5 -f ol d 
( 9 0 % CI  5. 1 4 , 6. 6 6) i n he alt h y s u bjects, c o m pare d wit h a d mi nistrati o n of mi daz ola m al o ne. 
T he fi n di n gs i n dicate a p ote ntial safet y ris k t o h u ma ns e x p ose d t o t ucati ni b w h o are ta ki n g 
c o nc o mita nt me dicati o ns t hat are se nsiti ve C Y P 3 A s u bstrates, as a d mi nistrati o n of t ucati ni b 
ma y p ote ntiall y i ncrease e x p os ure t o t he c o nc o mita nt me dicati o n. 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 (see A P P E N DI X H ). 
C o nsi der usi n g a n alter nate me dicati o n w hic h is n ot a se nsiti ve C Y P 3 A s u bstrate. If t he us e 
of se nsiti ve C Y P 3 A s u bstrates is u na v oi da ble, c o nsi der d o se re d u cti 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 ncreas e 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 m e dic ati o n’s prescri bi n g i nf or mati o n.  
M ulti ple cli nical trials ha ve bee n c o n d ucte d or are o n g oi n g wit h t ucati ni b i n  s u bjects wit h 
H E R 2 + metastatic breast ca ncer . T ucati ni b has bee n st u die d as a si n gle a ge nt i n St u d y 
A R R A Y -3 8 0 -1 0 1, a P hase 1, o pe n -la bel, d ose-es calati o n a n d e x pa nsi o n st u d y of t u cati ni b 
gi ve n as a dail y oral ( P O) re gi me n t o patie nts wit h a d va nce d s ol i d t u m ors. T w o P hase 1 b 
st u dies were c o m plete d t o i n vesti gate t ucati ni b as a p ote ntial ne w treat me nt f or patie nts  wit h 
a d va nce d H E R 2 + breast ca ncer, wit h a f oc us o n c o m bi nati o n wit h ot her ca ncer t hera pe utics, 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 0  of 1 7 0  
i ncl u di n g c o m bi nati o n wit h a d o-trast uz u ma b e mtansi ne ( T-D M 1, St u d y O N T -3 8 0 -0 0 4), a n d 
ca pecita bi ne, trast uz u ma b or ca pecita bi ne a n d trast uz u ma b ( St u d y O N T -3 8 0 -0 0 5). I n 
a d diti o n, St u d y O N T -3 8 0 -2 0 6 ( H E R 2 C LI M B) is a n o n g oi n g, P has e 2, ra n d o mize d, d o u ble-
bli n de d, place b o -c o ntr olle d cli nical trial t hat  c o m p ares t ucati ni b vers us place b o i n 
c o m bi nati o n wit h ca pecit a bi ne a n d trast uz u ma b i n patie nts wit h pr o gressi ve, u nresecta ble 
l ocall y a d va nce d or metastatic H E R 2 + breast ca ncer w h o ha v e ha d pri or treat me nt wit h 
trast uz u ma b, pert uz u ma b, a n d T-D M 1. T his tria l r ece ntl y re p orte d t o pli ne res ults w hic h 
s h o we d a 4 6 % re d ucti o n i n t he ris k of disease pr o gressi o n or deat h ( hazar d rati o [H R ]= 0. 5 4; 
p < 0. 0 0 0 0 1), a n i m pr o ve me nt i n o verall s ur vi val wit h a 3 4 % re d u cti o n i n t he ris k of deat h 
( H R = 0. 6 6; p = 0. 0 0 4 8) a n d a 5 2%  re du cti o n i n t he ris k of disease pr o gressi o n or deat h i n 
patie nts wit h brai n metastases at baseli ne ( H R = 0. 4 8; p < 0. 0 0 0 0 1)  (M urt h y 2 0 2 0 ). 
A d diti o nall y , a ra n d o mize d, d o u ble -bli n d, P hase 3 st u d y of t ucati ni b vers us place b o i n 
c o m bi nati o n wit h T -D M 1 i n patie nts  wit h u nresecta ble l ocall y a d va n ce d or metastatic 
H E R 2 + breast ca ncer is o n g oi n g  ( S G N T U C-0 1 6 ; H E R 2 C LI M B-0 2 ). 
Se veral c li nical trials e val uati n g t ucati ni b i n m ulti ple gastr oi ntesti nal ca ncers ha ve rece ntl y 
bee n i nitiate d . S G N T U C -0 2 2 ( M O U N T AI N E E R -0 2)  is a ran d o mize d, d o u ble -bli n d 
p hase  2/ 3 st u d y  e val uati n g t uc ati ni b i n c o m bi nati o n wit h trast uz u ma b, ra m ucir u ma b, a n d 
paclita x el i n H E R 2 + gastric or gastr o es o p ha geal j u ncti o n a de n ocarci n o ma ; S G N T U C -0 2 4 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 n i b i n c o m bi nati o n wit h 
trast uz u ma b a n d o x ali plati n-base d c he m ot hera p y i n H E R 2 + gastr oi ntesti nal ca ncers ; a n d 
S G N T U C -0 1 9 is a p hase  2 b as ket st u d y e val uati n g t ucati ni b a n d trast uz u ma b i n soli d tu m ors 
d ri ve n b y H E R 2 alterati o ns.  
T he S G N T U C -0 1 7 (M O U N T AI N E E R ) st u d y was i nitiate d o n 2 9-Mar -2 0 1 7 as a n 
i n vesti gat or-s p o ns ore d trial (I S T) i n w hic h a p pr o xi matel y 4 0 s u bjects w ere t o be e nr olle d a n d 
treate d wit h t ucati ni b i n c o m bi nati o n wit h trast uz u ma b ( C o h ort A). T he st u d y was tra nsferre d 
t o Sea ge n I nc. o n 1 7 Se p-2 0 1 9, a n d at t hat ti me, 3 7 s u bjects were e nr olle d. A n a d diti o nal 8 
s u bjects were e nr olle d i nt o C o h ort A after t he I n v esti gati o nal N e w Dr u g (I N D) tra nsfer a n d 
pri or t o e x pa nsi o n of t he trial. A t otal of 4 5 s u bjects were e nr olle d t o C o h ort A ( 4 4 s u bjects 
treate d wit h t ucati ni b +trast uz u ma b, a n d 1 s u bject treate d wit h tr ast uz u ma b o nl y pri or t o 
disc o nti n uati o n fr o m all st u d y treat me nt). F oll o wi n g disc ussi o n wit h t he F D A i n Se pte m ber 
2 0 1 9, t he pr ot oc ol was a me n de d ( Pr ot oc ol A me n d me nt 8) t o n ot o nl y e x pa n d e nr oll me n t t o 
i ncl u de a n a d diti o nal 4 0 s u bjects ( C o h ort B) treat e d wit h t ucati ni b +trast uz u ma b (f or a t otal of 
a p pr o xi matel y 8 0 s u bjects i n C o h orts A + B) b ut als o t o i ncl u de ra n d o mizati o n of 
a p pr o xi matel y 3 0 s u bjects treate d wit h t ucati ni b m o n ot hera p y ( C o h ort C).  
E nr oll me nt was c o nti n u o us; t here was n o p a use i n e nr oll me nt w he n t he trial was tra nsferre d 
t o Sea ge n a n d t here was n o pa use bet w ee n c o m pl eti o n of e nr oll me nt o n C o h ort A a n d 
i nitiati o n of ra n d o mizati o n t o C o h orts B a n d C. All s u bjects e nr olle d i n t he e x pa nsi o n  p orti o n 
of t he trial were ra n d o mize d i n a 4: 3 rati o t o recei ve t ucati ni b +trast uz u ma b ( C o h ort B) or 
t ucati ni b m o n ot hera p y ( C o h ort C). E nr oll me nt c o nti n ue d u ntil 4 1 s u bjects were ra n d o mize d 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 1  of 1 7 0  
t o C o h ort B ( 4 1 s u bjects treate d wit h t ucati ni b +trast uz u ma b) a n d 3 1 s u bjects were 
ra n d o mize d t o C o h ort C ( 3 0 s u bjects treat e d wit h t ucati ni b m o n ot hera p y, a n d 1 s u bject 
wit h dre w c o nse nt pri or t o treat me nt).  
Patie nts wit h H E R 2 + m C R C ha ve a si g nifi ca nt u n met nee d f or effi caci o us a n d well -t olerate d 
treat me nt o pti o ns. Data fro m t he M O U N T AI N E E R st u d y, e val uati n g a d u al H E R 2 -tar gete d 
re gi me n f or s u bjects wit h H E R 2 + C R C w h o ha d recei ve d at least o ne pri or treat me nt 
re gi me n f or u nresecta ble or metastatic diseas e, de m o nstrate d t hat 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 res ulte d i n cli nicall y mea ni n gf ul a n d d ura ble res p o nses i n t his 
p o p ulati o n. A r o b ust i n de pe n de ntl y assesse d c O R R of 3 8. 1 % ( 9 5 % CI: 2 7. 7 %, 4 9. 3 %) was 
o bser ve d i n s u bjects treat e d wit h t ucati ni b i n c o m bi nati o n wit h trast uz u ma b. Res p o nses were 
d ura ble,  wit h a me dia n d urati o n of 1 2. 4  m o nt hs. Be nefit was c o nsiste nt acr oss pres pecifie d 
s u b gr o u ps. T h e me dia n P F S a m o n g s u bj ects treat e d wit h t ucati ni b i n c o m bi nati o n wit h 
trast uz u ma b was 8. 2 m o nt hs a n d t he me dia n O S was 2 4. 1  m o nt hs.  
M O U N T AI N E E R s h o we d t ucati ni b +trast uz u ma b t o be safe a n d well t olerate d i n t his patie nt 
p o p ulati o n wit h hi g h u n met nee d. Disc o nti n uati o ns d ue t o T E A Es were i nfre q ue nt ( 5. 8 % a n d 
3. 5 % f or t ucati ni b a n d trast uz u ma b, res pecti vel y). M ost re p orte d e v e nts were l o w gra d e a n d 
ma na gea bl e, a n d t he t y pes a n d rates of o bs er ve d T E A Es were c o nsiste nt wit h t he esta blis he d 
safet y pr ofile of t ucati ni b i n t he a p pr o ve d i n dicati o n. T here were n o T E A Es lea di n g t o d eat h, 
a n d n o ne w safet y ris ks were i de ntifi e d.  
O verall, t he res ults of t his st u d y de m o nstrate d a p ositi ve be nefit:ris k f or t u cati ni b i n 
c o m bi nati o n wit h trast uz u ma b a n d ma y re prese nt a ne w sta n dar d of care f or patie nts wit h 
H E R 2 + m C R C w h o ha ve recei v e d at least o ne pri or treat me nt r e gi me n i n t he metastatic 
setti n g. 
1. 3. 3  S u m m ar y of t u c ati ni b 
O verall, t ucati ni b has b ee n well -t olerate d a n d has de m o nstrate d si n gl e-a ge nt a nti t u m or 
acti vit y, i ncl u di n g partial res p o nse ( P R ) i n s u bjects w h o ha d pr o gresse d aft er 2  pri or H E R 2 -
directe d t hera pies. N ota bl y, t o xicities ass ociate d wit h d ual  E G F R/ H E R 2 i n hi bit ors ha ve bee n 
u nc o m m o n, wit h Gra de 3 diarr hea a n d ras h re p orte d i n o nl y 1 s u bject eac h i n t he si n gle -
a ge nt st u d y ( A R R A Y-1 0 1) . T he data fr o m 2 p has e 1 b  cli nical trials de m o nstrate d t hat t he 
d o u blet c o m bi nati o n  of t ucati nib  wit h T -D M 1 (O N T -3 8 0 -0 0 4) a n d t he tri plet c o m bi nati o n 
wit h ca pecita bi ne a n d trast uz u ma b  (O N T -3 8 0 -0 0 5)  was well -t olerate d, de m o nstrati n g 
preli mi nar y acti vit y wit h acce pta ble t o xicit y, i n s u bjects wit h H E R 2 + metastatic breast 
ca ncer, incl u di n g s u bjects wit h brai n metastases.  Base d u p o n t h e precli nical a n d cli nical 
pr ofile o bser ve d t o date, t ucati ni b ma y b e a ble t o a d dress s o me of t h e u n met nee ds i n t he 
treat me nt of H E R 2 + ca n cers, partic ularl y wit h re gar d t o c o m bi nati o n a p pr oac hes wit h ot her 
H E R 2 a ge nts.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 2  of 1 7 0  
1. 4  Tr a st u z u m a b  
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 ntra ve n o us (I V) 
of t he H E R 2 e xtracell ular d o mai n a n d e x erts 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 diate 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 di ate d mit o ge ni c si g n ali n g  (Artea ga 2 0 1 2 ).  
H E R 2 is a vali date d tar get i n m ulti ple s oli d t u m ors, wi t h a nti-H E R 2 bi ol o gics (i ncl u di n g 
trast uz u ma b) 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 ncers. I n t hes e t u m or t y p es, 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 is c o m m o n.  
Trast uz u ma b is n ot a p pr o ve d f or use i n C R C . Cli nical trial data  i n H E R 2 + m C R C patie nts 
(see Secti o n 1. 6 ) d o s u p p ort a cate g or y 2 B rec o m me n dati o n f or t he treat me nt of patie nts  wit h 
H E R 2 -a m plifie d, R A S wil d -t y pe m C R C wit h eit her pert uz u ma b +  tr ast uz u ma b or la pati ni b +  
trast uz u ma b i n t he 2 L or 3 L setti n g wit h i n t he wi d el y a d o pte d nati o nal ( U S) g ui deli nes f or 
t he treat me nt of c ol o n ca ncer.  
1. 5  N o n cli ni c al R ati o n al e f or c o m bi n ati o n of  t u c ati ni b wit h tr a st u z u m a b 
Data fr o m x e n o graft m o dels acr oss m ulti ple t u m or t y pes, i ncl u di n g C R C, pr o vi de str o n g  
precli nical e vi d e nce s u p p orti n g t he i ncreas e d acti vit y of t ucati ni b + trast uz u ma b relati ve t o 
t he i n di vi d ual a ge nts. O verall, t hese m o dels de mo nstrate d t u m or re gressi o n rates i n t he 
t ucati ni b a n d trast uz u ma b m o n ot hera p y ar ms of 2 7 % a n d 1 7 %, res pecti vel y, c o m p are d t o 
6 7 % w he n a d mi nistere d i n c o m bi nati o n (see I n v esti gat or’s Br oc h ure). Si milar tre n ds ha v e 
bee n o bser ve d i n precli nical m o dels of ot he r a ge nts ( pert uz u ma b, la pati ni b, trast uz u ma b, a n d 
nerati ni b) c o m pari n g m o n ot hera p y wit h d ual H E R 2 -i n hi biti o n (Ha q ue 2 0 1 2 ; A merica n 
Ca ncer S ociet y ( A C S) 2 0 1 8 ).  
1. 6  Cli ni c al R ati o n al e f or c o m bi n ati o n of t u c ati ni b wit h tr a st u z u m a b  
Si n gle -a ge nt cli nical a cti vit y of trast uz u ma b i n H E R 2 + m C R C has n ot bee n esta blis he d, as 
d ual i n hi biti o n a p pr oac hes ha ve bee n c h ose n i n cli nical trials t o date base d u p o n e xisti n g 
cli nical data fa v ori n g c o m bi nati o n a p pr oac hes. H o we ver, hist orical data f or b ot h a nti -H E R 2 
m o n ot hera p y a n d d ual tr ast uz u ma b-c o ntai ni n g t h era p y is a v aila ble i n t he s etti n g of H E R 2 + 
breas t c a ncer, w here greater acti vit y h as bee n see n i n t he setti n g of d ual i n hi biti o n.  
H E R 2 + Met ast atic Bre ast C a ncer  setti n g 
Hist orical data f or trast uz u ma b m o n ot hera p y i n br east ca n cer de m o nstrate m o dest 
ra di o gra p hic res p o nse rat es of 1 4 % (C o blei g h 1 9 9 9 ; B urstei n 2 0 0 8 ; C ortes 2 0 1 2 ; Marti n 
2 0 1 3a ). H o we ver, w h e n a nti -H E R 2 a ge nts s uc h as la pati ni b or pert uz u ma b are a d d e d t o 
trast uz u ma b-base d re gi m e ns i n H E R 2 + breast ca n cer, res p o nse rates n ot o nl y i ncrease  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 3  of 1 7 0  
(2 4 % – 3 1 %) , b ut si g nifica nt gai ns i n P F S a n d O S are als o ac hie ve d (Basel ga 2 0 1 2 ; J o h nst o n 
2 0 1 8 ). 
St u d y O N T -3 8 0 -2 0 6  ( H E R 2 C LI M B) e v al uate d t ucati ni b vers us place b o i n c o m bi nati o n wit h 
ca pecita bi ne a n d tr ast uz u ma b i n patie nts wit h pr o gressi ve, u nres ecta ble l o call y a d va n ce d or 
metastatic H E R 2 + breast ca ncer w h o ha d pri or treat me nt wit h trast uz u ma b, pert uz u ma b, a n d 
T -D M 1. T o pli ne res ults fr o m t his trial  s h o we d a 4 6 % re d ucti o n i n t he ris k of disease 
pr o gressi o n or deat h ( H R = 0. 5 4; p < 0. 0 0 0 0 1), a n i m pr o ve me nt i n o verall s ur vi val wit h a 3 4 % 
re d ucti o n i n t he ris k of d eat h ( H R = 0. 6 6; p = 0. 0 0 4 8), a n d a 5 2% re d u cti o n i n t he ris k of 
disease pr o gressi o n or d eat h i n patie nts wit h brai n metastases at bas eli ne ( H R = 0. 4 8; 
p < 0. 0 0 0 0 1)  (M urt h y 2 0 2 0 ). 
H E R 2 + m C R C  setti n g 
As disc usse d a b o ve  (see Secti o n 1. 2 ), d ual H E R 2-i n hi biti o n wit h trast uz u ma b -c o ntai ni n g 
re gi me ns ha ve  b ee n e x a mi ne d i n t he setti n g of H E R 2 + m C R C , a n d t he res p o nse rates see n i n 
t he H E R A C L E S a n d M y Pat h wa y trials (Ta ble  1 -1 ) ha ve le d t o a c ha n ge i n t he wi del y 
a d o pte d nati o n al ( U S) g ui deli nes f or t he treat me nt of c ol o n ca n cer , w hic h n o w rec o m me n d 
( Cate g or y 2 B) d ual H E R 2-i n hi biti o n f or treat me nt of H E R 2-a m plifie d, R A S  wil d -t y pe, 
m C R C patie nts. W hile t here are n o m o n ot hera p y ar ms i ncl u de d i n t he H E R A C L E S a n d 
M y Pat h wa y tri als  (Ta ble  1 -1 ), it is w ort h n oti n g t h at res p o nse rates are hi g h er t ha n w hat h as 
hist oricall y bee n o bser ve d wit h a nti-H E R 2 a ge nts use d as m o n ot hera p y i n metast atic breast 
ca ncer, a n d c o m pare fa v ora bl y wit h res p o nse rates see n wit h d ual i n hi biti o n i n t hat setti n g. 
I nteri m data fr o m t he i nitial 2 6 s u bjects e nr olle d i n t he c urre nt M OU N T AI N E E R pr ot oc ol 
(t ucati ni b +  trast uz u ma b) was rece ntl y pres e 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 bjecti ve res p o nse rate ( O R R ) of 
5 2. 2 % ( 1 2 of 2 3  s u bjects; 9 5 % CI : 3 0. 6 , 7 3. 2) t hat c o nsiste d of 1 2 P Rs  i n 2 3 e val ua ble 
s u bjects, 1 1 of w hic h w ere c o nfir m e d at a s ec 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 ns e was 1 0. 4 m o nt hs ( 6. 0 -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) . 
1. 7  St u d y R ati o n al e  
Pat ie nts wit h H E R 2 + m C R C ha ve li mite d access t o a nti -H E R 2 t hera pies. T ucati ni b is a 
p ote nt H E R 2 -s pecific T KI  t hat is acti ve i n metastatic breast c a ncer  as a si n gle -a ge nt a n d i n 
c o m bi nati o n wit h trast uz u ma b  (B or ges 2 0 1 3 ; Ha milt o n 2 0 1 4 ). A d diti o nall y, trast uz u ma b is 
a p pr o ve d as a si n gle -a ge nt a n d i n c o m bi nati o n wit h eit her c he m ot hera p y or pert uz u ma b.  
T he acti vit y of t ucati ni b m o n ot hera p y i n H E R 2 + metastatic breast ca ncer  patie nts t hat ha d 
faile d pri or H E R 2 dir ecte d thera pies has b ee n e x a mi ne d, wit h a n O R R of 1 4 % o bser ve d. 
T ucati ni b has als o s h o w n si n gle -a ge nt acti vit y i n H E R 2 + C R C precli nical t u m or m o dels. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 4  of 1 7 0  
H o we ver, t he acti vit y of t ucati ni b m o n ot hera p y i n patie nts  wit h m C R C is c urre ntl y u n k n o w n. 
T heref ore, a t ucati ni b  m o n ot hera p y c o h ort has bee n i ncl u de d i n or der t o e x pl ore t his acti vit y.  
I n p atie nt-deri v e d x e n o grafts of E R B B 2  a m plifie d metastatic C R C , i ncrease d a ntit u m or 
acti vit y wit h d ual H E R 2 bl oc ka de  vers us si n gle -a ge nt acti vit y h as bee n d escri be d  (Bert otti 
2 0 1 1 ). F urt her m ore, n o n-ra n d o mize d st u dies c o n d ucte d i n patie nts wit h H E R 2 + metastatic 
C R C ha ve c o nfir me d t he effic ac y a n d t olera bilit y of d ual H E R 2- bl oc ka d e  (D o uillar d 2 0 1 3a ; 
Sart ore -Bia nc hi 2 0 1 6 ). T his trial is desi g ne d t o est a blis h t he efficac y of t u cati ni b i n 
c o m bi nati o n wit h trast uz u ma b i n patie nts wit h H E R 2 + m C R C.  
1. 8  R ati o n al e f or S el e cti o n of D o s e s  
Selecti o n of t he  t ucati ni b d osi n g re gi me n f or t he c urre nt st u d y was bas e d u p o n t he f oll o wi n g:  
•  P K st u dies ( A R R A Y-3 8 0 -1 0 2 a n d A R R A Y -3 8 0 -1 0 3)  
•  Res ults of t he P hase 1 d ose -escalati o n st u d y of si n gle -a ge nt t ucati ni b i n s u bjects wit h 
a d va nce d s oli d t u m ors ( A R R A Y -3 8 0 -1 0 1)  
•  Res ults of a P hase I b st u d y of t ucati ni b c o m bi ne d wit h T -D M 1 ( O N T -3 8 0 -0 0 4)  
•  Res ults of a P hase I b  st u d y of t ucati ni b c o m bi ne d wit h eit her ca p ecita bi ne a n d/ or 
trast uz u ma b ( O N T-3 8 0 -0 0 5); t his st u d y d eclare d a R P 2 D of 3 0 0 m g BI D i n t he ta blet 
f or m ulati o n, e q ui vale nt t o t he si n gle-a ge nt d ose of t ucati ni b  
Trast uz u ma b will be gi ve n at t he d ose a p pr o ve d f or si n gle-a ge nt use w he n a d mi nistere d o n a 
Q 3 wee k c ycle. Trast uz u ma b ma y als o be gi ve n o n a wee kl y b asis at 2  m g/ k g I V or Q 2 wee k 
basis at 4 m g/ k g I V, b ut o nl y i n circ u msta n ces w h ere t he trast uz u ma b i nf usi o n sc he d ule has 
bee n i nterr u pt e d or s us pe n de d, a n d t h ese i nf usi o ns are re q uire d t o r es y nc hr o nize t he c ycl e 
le n gt h t o 2 1 da ys. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 5  of 1 7 0  
2  
O B J E C TI V E S  A N D E N D P OI N T S   
T his st u d y will e val uate t he effi cac y a n d safet 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 i n patie 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 +), 
R A S wil d -t y p e, u nresect a ble or metastatic C R C w h o ha ve pre vi o usl y recei ve d  a n d faile d, 
u nless c o ntrai n dicate d,  s yste mic t hera p y wit h fl u or o p yri mi di nes, o x ali plati n, iri n oteca n, a n 
a nti-vasc ular e n d ot helial gr o wt h fact or ( V E G F) m o n ocl o nal  a nti b o d y ( m A b ); patie nts  w h ose 
disease has deficie nt mis matc h re pair ( d M M R) pr otei ns o r is Micr osatellite i nsta bilit y-Hi g h 
( M SI-H ) m ust als o ha ve recei v e d a n a nti -pr o gra m me d deat h li ga n d 1 ( P D -[ L] 1) m Ab , if 
i n dicate d. S pecific o bje cti 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 i n 
Ta ble 2 -1 . 
T a bl e 2 -1 : 
O bj e cti v e s a n d c orr e s p o n di n g e n d p oi nt s  
O bj ecti ve  
C orres p o n di n g E n d p oi nt a 
Pri mar y  
 
● T o deter mi ne t he a ntit 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 trast uz u ma b, i n C o h orts A + B, as 
meas ure d b y c o nfir me d o bj ecti ve res p o nse rate 
(cO R R , 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] 1. 1 criteria ), acc or di n g t o bli n de d  
i n de p e n de nt ce ntral re vie w (B I C R) assess me nt  
● cO 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]), per R E CI S T 1. 1, acc or di n g 
t o B I C R assess me nt, i n p o ole d C o h ort s A + B  
Sec o n dar y Efficac y  
 
● T o e val uate t he a ntit 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 trast uz u ma b, i n C o h orts A + B, b y 
O R R b y  1 2  wee ks of treat me nt  ( R E CI S T 1. 1), 
acc or di n g t o B I C R assess me nt 
● O R R ( R E CI S T 1. 1)  b y  1 2 wee ks of treat me nt, 
acc or di n g t o  B I C R assess me nt, i n C o h or ts A + B  
● T o e val uate t he a ntit u m or acti vit y of t ucati ni b 
m o n ot hera p y , i n C o h ort C, as meas ure d b y O R R b y  
1 2 wee ks of treat me nt  ( R E CI S T 1. 1), acc or di n g t o 
B I C R assess me nt 
● O R R (R E CI S T 1. 1 ) b y  1 2 wee ks of treat me nt, 
acc or di n g t o  B I C R assess me nt, i n C o h ort C  
● T o assess t he d urati o n of res p o nse ( D O R)  i n s u bj ects 
treate d wit h t ucati ni b gi ve n i n c o m bi nati o n wit h  
trast uz u ma b ( R E CI S T 1. 1), i n C o h orts A + B, 
acc or di n g t o B I C R assess me nt  
● D O R ( R E CI S T  1. 1), acc or di n g t o B I C R 
assess me nt, i n C o h orts A + B  
● T o assess t he D O R i n s u bj ects treate d wit h t ucati ni b 
m o n ot hera p y ( R E CI S T 1. 1) , i n C o h ort C, acc or di n g 
t o B I C R assess me nt  
● D O R ( R E CI S T 1. 1), acc or di n g t o B I C R 
assess me nt, i n C o h ort  C  
● T o assess t he pr o gressi o n -free s ur vi val ( P F S) i n 
s u bj ects treate d wit h t ucati ni b gi ve n i n c o m bi nati o n 
wit h  trast uz u ma b ( R E CI S T 1. 1), i n C o h orts A + B, 
acc or di n g t o B I C R assess me nt 
● P F S ( R E CI S T  1. 1), acc or di n g t o B I C R assess me nt, 
i n C o h orts A + B 
● T o assess t he o verall s ur vi val ( O S) i n s u bj ects treate d 
wit h t ucati ni b gi ve n i n c o m bi nati o n wit h  
trast uz u ma b, i n C o h orts A + B 
● O S, i n C o h orts A + B  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 6  of 1 7 0  
O bj ecti ve  
C orres p o n di n g E n d p oi nt a 
Sec o n dar y  Safet y   
 
● T o assess t he safet y 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, i n C o h orts A + B 
● Fre q ue nc y a n d se verit y, acc or di n g t o C o m m o n 
T er mi n ol o g y  Criteria f or A d verse E ve nts ( C T C A E) 
versi o n  4. 0 3 criteria, of all treat me nt -e mer ge nt 
a d verse e ve nts ( T E A Es) a n d tr eat me nt -relate d 
T E A Es , i n C o h orts A + B  
● Fre q ue nc y of seri o us a d verse e ve nts ( S A Es) a n d 
deat hs d ue t o a d verse e ve nts ( A Es) , i n C o h orts 
A + B  
● Fre q ue nc y of treat me nt m o difi cati o ns a n d 
per ma ne nt treat me nt disc o nti n uati o ns d ue t o A Es , 
i n C o h orts A + B 
● Fre q ue nc y a n d se verit y of la b orat or y a b n or malities , 
i n C o h orts A + B 
● Vital si g ns a n d ot her rele va nt safet y varia bles , i n 
C o h orts A + B  
● T o assess t he safet y a n d t olera bilit y of t ucati ni b 
m o n ot hera p y , i n C o h ort C 
● Fre q ue nc y a n d se verit y, acc or di n g t o 
C T C A E  v 4. 0 3, of all T E A Es a n d treat me nt -relate d 
T E A Es, i n C o h ort C  
● Fre q ue nc y of S A Es a n d deat hs d ue t o A Es, i n 
C o h ort C  
● Fre q ue nc y of treat me nt m o difi cati o ns a n d 
pe r ma ne nt treat me nt disc o nti n uati o ns d ue t o A Es, 
i n C o h ort C 
● Fre q ue nc y a n d se verit y of la b orat or y a b n or malities, 
C o h ort C  
● Vital si g ns a n d ot her rele va nt safet y varia bles, i n 
C o h ort C  
E x pl orat or 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 
● T o e x pl ore a n y 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  
● T o e x pl ore p ote ntial bi o mar kers of res p o nse, 
resista nce or t o xicit y fr o m arc hi ve d paraffi n-
e m be d de d t u m or sa m ples a n d  circ ulati n g t u m or  
D N A ( ct D N A) is olate d fr o m plas ma sa m ples.  
● T o assess t he P F S  i n s u bj ects treate d wit h t ucati ni b 
m o n ot hera p y ( R E CI S T 1. 1), i n C o h ort C, acc or di n g 
t o BI C R assess me nt 
● P F S ( R E CI S T  1. 1), acc or di n g t o B I C R assess me nt, 
i n C o h ort C 
● T o assess t he O S i n s u bj ects treate d wit h t ucati ni b 
m o n ot hera p y , i n C o h ort C 
● O S, i n C o h ort C  
● T o assess patie nt -re p orte d o utc o mes ( P R Os) 
ass ociate d wit h t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u ma b 
● C ha n ge fr o m baseli ne i n P R O assess me nts of t he 
E ur o pea n Q ualit y of Life 5 -Di me nsi o n 5 -Le vel  
( E Q-5 D -5 L), a n d E ur o pea n Or ga nizati o n f or 
Researc h a n d Treat me nt of Ca ncer Q ualit y -of -Life 
3 0 -ite m C ore Q uesti o n naire ( E O R T C Q L Q -C 3 0)  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 7  of 1 7 0  
O bj ecti ve  
C orres p o n di n g E n d p oi nt a 
● T o e x pl ore healt h res o urce utilizati o n  
● C u m ulati ve i nci de nce of healt h res o urce utilizati o n, 
i ncl u di n g le n gt h of sta y, h os pitalizati o ns, a n d 
e mer ge nc y de part me nt ( E D) visits  
a 
F or t he defi niti o ns of st u d y e n d p oi nts refer t o Secti o n 9. 2 .  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 8  of 1 7 0  
3  
I N V E S TI G A TI O N A L P L A N 
3. 1  S u m m ar y of St u d y D e si g n  
T his is a P hase 2, ra n d o mize d, o pe n -la bel, m ultice nter st u d y of t ucati ni b a d mi nistere d as 
m o n ot hera p y  a n d i n c o m bi nati o n wit h trast uz u ma b i n patie nts  wit h H E R 2 -p ositi ve, R A S 
wil d -t y pe, u nresecta ble or metastatic C R C. Eli gi ble patie nts  are re q uir e d t o ha ve pre vi o usl y 
recei v e d a n d faile d, u nless c o ntrai n dicate d , s yste mic t hera p y wit h fl u or o p yri mi di nes, 
o x ali plati n, iri n oteca n, a n d a n a nti -V E G F m A b ; patie nts  w h ose disease has d M M R pr otei ns 
or is M SI -H m ust als o ha ve recei ve d a n a nti -P D -( L) 1 m Ab , if i n dicate d. T he st u d y i nitiall y 
c o nsiste d of C o h ort A, w hic h i ncl u des a p pr o xi matel y 4 0 s u bjects treate d wit h t he d o u blet 
re gi me n. As of Pr ot oc ol A me n d me nt 8, t he st u d y is e x pa n de d t o i ncl u de a p pr o xi matel y 
4 0  a d diti o nal s u bjects ( C o h ort B) treate d  wit h t he t ucati ni b + trast uz u ma b d o u blet (f or a t otal 
of a p pr o xi matel y 8 0 s u bj ects i n C o h orts A + B), a n d a p pr o xi matel y 3 0 s u bjects treate d wit h 
t ucati ni b m o n ot hera p y ( C o h ort C).  
All s u bjects  e nr olle d i n t he e x pa nsi o n p orti o n of t he trial will be ra n d o mize d i n a 4: 3 rati o t o 
recei v e t ucati ni b gi ve n  i n c o m bi nati o n wit h trast uz u ma b (C o h ort B) or t ucati ni b 
m o n ot hera p y ( C o h ort C). E nr oll me nt will c o nti n ue u ntil a p pr o xi matel y 4 0 s u bjects ha ve bee n 
ra n d o mize d t o a n d treate d i n C o h ort B a n d a p pr o xi matel y 3 0 s u bjects h a ve bee n ra n d o mize d 
t o a n d treate d i n C o h ort C . 
Treat me nt will be a d mi nistere d i n c y cl es of 2 1 da ys eac h. S u bjects  i n C o h orts A a n d B will 
be treate d wit h t ucati ni b at a d ose of 3 0 0 m g P O BI D a n d trast uz u ma b at a l oa di n g d ose of 
8  m g/ k g I V f oll o w e d b y a  d ose of 6 m g/ k g I V e ver y 3 wee ks.  S u bjects  ra n d o mize d t o 
C o h ort  C will be treate d wit h t ucati ni b at a d ose of 3 0 0 m g P O BI D.  
S u bjects  e nr olle d i n C o h ort A a n d t h ose ra n d o mize d t o C o h ort B will c o nti n ue o n t hera p y 
u ntil e vi de nce of ra di o gra p hic or cli nical  pr o gressi o n , u nacce pt a ble t o xicit y, wit h dr a wal of 
c o nse nt, or st u d y cl os ure . S u bjects ra n d o mize d t o C o h ort C will be all o we d t o cr oss o ver a n d 
recei v e d o u blet t ucati ni b + trast uz u ma b t hera p y, if t he y e x perie nce ra di o gra p hic pr o gressi o n 
at a n y ti me p oi nt, o r if t he y h a ve n ot ac hie ve d a P R  or C R  b y t h e W ee k 1 2 assess me nt  (f or 
details see Secti o n 6. 3. 6 ). 
D ose m o dificati o ns of t u cati ni b will be all o we d. D ose m o dificati o ns of trast uz u ma b  will n ot 
be all o we d; if  trast uz u ma b ca n n ot be restarte d after bei n g h el d f or a n A E , it m ust be 
disc o nti n ue d . If trast uz u ma b is disc o nti n ue d, t he s u bject ca n c o nti n ue t o recei ve t ucati ni b 
m o n ot hera p y.  N otif y t he s p o ns or of a n y c h a n ges ma de t o t he s u bject’s st u d y treat me nt.  
T he pri mar y e n d p oi nt of t he st u d y is a p oi nt esti mate of c o nf ir me d O R R. Ra di o gra p hic 
res p o nse will be ass esse d b y a B I C R ( per R E CI S T  1 . 1), wit h c o nfir mati o n of res p o nse 
re q uire d ≥4  w ee ks fr o m t he first d oc u me ntati o n of res p o nse.  T he pri mar y efficac y a nal ysis 
set will c o nsist  of all treate d s u bjects i n C o h ort s A + B.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 3 9  of 1 7 0  
Sec o n dar y effic ac y e n d p oi nts i ncl u de d urati o n of c o nfir me d res p o nse, P F S,  a n d O S  f or all 
s u bjects e nr olle d o n t he d o u blet re gi me n ( C o h ort A + B) . In a d diti o n, i n or der t o assess t he 
c o ntri b uti o n of t ucati ni b t o t he d o u blet re gi me n, O R R b y 1 2 wee ks will be assesse d i n 
C o h ort s A + B, as well as i n C o h ort C . T here will be n o f or mal statistical c o m paris o ns 
bet wee n c o h orts.  
P K  assess me nts of t ucati ni b will be perf or me d  i n s u bjects i n C o h orts B a n d C . Bl o o d sa m ples 
will als o be ta ke n f or p ossi ble e val uati o n of p ote ntial bi o mar kers of res p o ns e , i ncl u di ng 
ct D N A. 
Healt h -relate d q ualit y of life a n d healt h care ec o n o mics will be assesse d b y use of t he 
E Q -5 D -5 L a n d E O R T C Q L Q -C 3 0  q ualit y of life i nstr u me nts a n d c ollecti o n of healt h care 
res o urce utilizati o n data. 
A st u d y sc h e ma is pr o vi d e d i n  Fi g ure 3 -1 . See  A P P E N DI X A  f or a sc h e d ule of e ve nts . 
3. 1. 1  D at a & S af et y M o nit ori n g  
Assess me nt of s afet y will be  perf or m e d b y c ollecti n g a n d e val uati n g i nf or mati o n re gar di n g 
A Es a n d la b orat or y test r es ults. A Safet y M o nit ori n g C o m mittee ( S M C) will e val uate t he 
safet y of c o m bi nati o n t hera p y a n d m o n ot hera p y o ver t he c o urse of t he st u d y. Peri o dic 
c u m ulati ve data re vie w meeti n gs will  be hel d e ver y 6 m o nt hs . T he meeti n gs will ser ve t o 
e val uate a g gre gate safet y data of all s u bjects ( C o h orts A + B + C) a n d pr o vi d e a f or u m f or 
decisi o ns re gar di n g w het her t o c o nti n ue wit h t he st u d y as -is, t o c o nti n ue t h e st u d y wit h 
m o dificati o ns, t o s us pe n d e n r oll me nt, or t o ter mi nate t he st u d y. 
3. 1. 2  St o p pi n g Crit eri a  
Reas o ns f or pre mat urel y ter mi nati n g t he st u d y ma y i ncl u de b ut are n ot li mite d t o t he 
f oll o wi n g: 
•  T he i nci de nce or se v erit y of A Es i n t his or ot her st u dies i n dicates a p ote ntial healt h 
hazar d t o s u bjects , eit her t hr o u g h a safet y re vie w b y t he s p o ns or or a n S M C. 
•  S u bject e nr oll me nt is u nsatisfact or y.  
3. 1. 3  E n d of St u d y  
T he pri mar y a n al ysis f or t his trial was c o n d ucte d base d o n a dat a c ut -off dat e of 2 8 Marc h 
2 0 2 2. As t he pri mar y o bj ecti ve was met, t he d ecisi o n wa s ma de t o cl ose t h e st u d y. E n d of 
st u d y will be defi n e d as l ast patie nt, last visit. I n a d diti o n, t he s p o ns or ma y ter mi nate t he 
st u d y at a n y ti me (s ee Secti o n 1 0. 4. 1 ).  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 0  of 1 7 0  
Fi g ur e 3 -1 : 
St u d y s c h e m ati c  
 
N ote : S u bjects e nr olle d i n C o h ort A or C o h ort B will be treate d wit h t u cati ni b a n d trast u z u ma b d o u blet c o m bi n ati o n 
t h era p y, a n d s u bjects e nr olle d i n C o h ort C will be treate d wit h t ucati ni b m o n ot hera p y.  
C R = c o m plete res p o nse, E O T = e n d of treat me nt, P D = pr o gressi ve disease, P R = partial res p o nse  
a 
F or C o h ort A, ra di ol o gical disease assess me nts (c o m p uterize d t o m o gra p h y [ C T] or ma g netic res o na nce i ma gi n g [ M RI] 
sca ns of c hest, a b do me n, a n d pel vis)  a n d carci n oe m br y o nic a nti ge n ( C E A) t u m or mar ker ass a ys will be perf or me d at 
t h e scree ni n g/ b aseli ne, e ver y 9 wee ks/ 3 c ycl es ( ± 1 4 da ys) d uri n g st u d y treat me nt (e ver y 1 2 wee ks/ 4 c ycles [ ± 7 da ys] 
after 1 2 m o nt hs of treat me nt, if t he s u bject is cli nicall y sta ble), a n d at t h e E O T visit . S u bjects w h o  disc o nti n ue f or 
reas o ns ot h er t h a n d oc u me nte d P D will c o nti n ue t o ha ve disease assess me nts a p pr o xi matel y e ver y 9 we e ks u ntil 
disease pr o gressi o n, deat h, wit h dra wal of c o nse nt, st u d y cl os ure , or alter nati ve t h era p y. H o we ver, s u bjects wit h 
d oc u me nte d P D w h o  ha ve c o nti n ue d o n st u d y  treat me nt f or cli nical be nefit will n ot re q uire c o nti n ue d disease 
assess me nts after disc o nti n ui n g treat me nt .  
b  
F or C o h orts A a n d B, treat me nt will be a d mi nistere d i n 2 1 -da y c y cl es. T ucati ni b will be a d mi nistere d at 3 0 0 m g BI D 
pl us trast uz u ma b I V i nf usi o n at a l o a di n g d ose of 8 m g/ k g f oll o we d b y a mai nte na nce d ose of 6 m g/ k g e ver y 2 1 da ys.  
c 
F or C o h orts B a n d C, a n o pti o nal pre -scree ni n g is a vaila ble. Tiss ue base d H E R 2 testi n g ca n be perf or me d wit hi n 
9 0  da ys pri or t o t h e a ntici pate d scree ni n g visit. C ollecti o n of tiss ue f or c o nfir mat or y H E R 2 + a n d bi o mar ker testi n g ca n 
be d o ne at pre -scree ni n g or screen i n g. R a di ol o gical disease assess me nt ( C T or M RI of c hest, a b d o me n, a n d pel vis) a n d 
C E A ass a ys will be perf or me d at scree ni n g/ b aseli ne, e ver y 6 wee ks ( ± 7 da ys) d uri n g treat me nt (e ver y 1 2 we e ks [ ± 7 
da ys] aft er 1 2  m o nt hs of treat me nt , if t h e s u bject is cli nicall y sta ble), a n d at t h e E O T visit. S u bjects w h o  disc o nti n ue f or 
reas o ns ot h er t h a n d oc u me nte d P D will c o nti n ue t o ha ve disease assess me nts a p pr o xi matel y e ver y 9 we e ks u ntil 
disease pr o gressi o n, deat h, wit h dra wal of c o nse nt, st u d y cl os ure , or alter nati ve t h era p y.  H o we ver, s u bjects wit h 
d oc u me nte d P D w h o  ha ve c o nti n ue d o n st u d y treat me nt f or cli nical be nefit will n ot re q uire c o nti n ue d disease 
assess me nts after disc o nti n ui n g treat me nt.  
d  
F or C o h ort C, treat me nt will be a d mi nistere d i n 2 1 -da y c ycles. T uc ati ni b will be a d mi nistere d at 3 0 0 m g BI D.  
e 
S u bjects ra n d o mize d t o C o h ort C will be all o we d t o cr oss o ver a n d recei v e d o u blet t ucati ni b + trast u z u ma b t h era p y if 
t h e y e x perie nce ra di o gra p hic pr o gressi o n at a n y ti me p oi nt, or if t he y ha ve n ot ac hie ve d a P R or C R b y t h e W e e k 1 2 
assess me nt.  I n or der t o assess ra di o gra p hic res p o nse t o t h e d o u blet t h era p y, su bjects i n C o h ort C m ust ha ve a ne w 
baseli ne R E CI S T assess me nt , as d escri b e d i n Secti o n 6. 3. 6 , pri or t o cr oss o ver fr o m m o n ot h era p y t o d o u blet t hera p y 
usi n g t h e  W ee k 1 2  sca ns or first P D sca n s as a p plica ble. 
 
M ore  details o n t he sc h e d ule of e ve nts  are re p orte d i n Ta ble 1 1 -1 .  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 1  of 1 7 0  
3. 2  Di s c u s si o n a n d R ati o n al e f or St u d y D e si g n  
3. 2. 1  R ati o n al e f or S el e cti o n of D o s e s  a n d R e gi m e n  
Res p o nse rates t o d ual H E R 2 -bl oc ka de a m o n g pre vi o usl y -treate d s u bjects wit h H E R 2 +, 
refract or y, m C R C of 3 0 % a n d 3 5 % ha v e bee n re p orte d, w hil e a nti-E G F R m o n ot hera p y 
res ults i n a res p o nse rate of 2 0 % a m o n g t hese s u bj ects (Ola yi o ye 2 0 0 0 ; H ol br o 2 0 0 4 ; 
H ur witz 2 0 1 6 ). T he a d diti o n of t ucati ni b t o trast uz u ma b i n C o h orts A a n d B will pr o vi de 
d ual -i n hi biti o n of H E R 2 wit h t he p ote ntial t o i m pr o ve effi cac y a n d pr o vi de be nefit o ver 
si n gle-a ge nt bl ock a d e f or s u bjects pre vi o usl y tr eat e d i n 3 L + re gi me ns f or m C R C.  
Selecti o n of t he t ucati ni b d osi n g re gi me n f or t he c urre nt st u d y was bas e d u p o n t he R P 2 D 
deri ve d fr o m t w o P has e 1 b st u dies i n H E R 2 + metastatic breast ca ncer  t hat e val uate d 
t ucati ni b i n c o m bi nati o n wit h T-D M 1 ( O N T -3 8 0 -0 0 4), or ca p ecita bi ne a n d trast uz u ma b 
( O N T-3 8 0 -0 0 5). I n t h ose st u dies, t ucati ni b 3 0 0 m g was ge nerall y well-t olerate d, a n d A Es  
were ma n a gea ble b y pr ot oc ol -s pecifie d d os e m o dificati o ns a n d d ose re d ucti o ns. I n a d diti o n, 
t he efficac y a n d safet y of t ucati ni b  is c urre ntl y bei n g e x pl ore d i n a pi v otal st u d y i n H E R 2 + 
m etastatic breast ca ncer  ( O N T-3 8 0 -2 0 6 , H E R 2 C LI M B), at 3 0 0 m g BI D i n c o m bi nati o n wit h 
ca pecita bi ne a n d tr ast uz u ma b a n d a n a d diti o nal pi v otal st u d y i n 2 L metastatic breast c a ncer  
( S G N T U C-0 1 6) at 3 0 0 m g  BI D i n c o m bi nati o n wit h T -D M 1.   
I nteri m data fr o m t he i nitial 2 6 s u bjects e nr olle d i n t he c urre nt M OU N T AI N E E R pr ot oc ol 
(t ucati ni b +  trast uz u ma b) was rece ntl y pres e 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. A n O R R  of 5 2. 2 % ( 1 2 of 2 3  su bjects ; 9 5 % CI: 3 0. 6 , 7 3. 2) was 
o bser ve d i n t he e v al ua ble p o p ulati o n . C o m bi nati o n treat me nt wit h t ucati ni b + trast uz u ma b 
a p pears t o b e efficaci o us a n d well -t olerate d i n t he s u bjects e nr olle d t o date. T here is a n 
u n met me dical nee d i n H E R 2 + m C R C patie nts w h o ha ve faile d pri or t hera p y . T he A E pr ofile 
of t ucati ni b gi ve n  i n c o m bi nati o n wit h trast uz u ma b i n t his setti ng is e x pecte d t o be 
a de q uatel y ma n a ge d b y pr ot oc ol -s pecifi e d d ose m o dificati o ns a n d d ose re d ucti o ns. 
T he d ose of trast uz u ma b a d mi nistere d o n a q 2 1 -d a y c ycle is t he f ull d ose a p pr o ve d f or 
si n gle-a ge nt use i n br east ca ncer. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 2  of 1 7 0  
4  
S T U D Y P O P U L A TI O N  
Patie nts wit h H E R 2 -p ositi ve, R A S wil d -t y pe, u nresecta ble or m etastatic C R C w h o, u nless 
c o ntrai n dicate d, h a ve pre vi o usl y recei ve d s yste mi c t hera p y wit h fl u or o p yri m i di nes, 
o x ali plati n, iri n oteca n, a n d a n a nti -V E G F m A b ; patie nts w h ose disease has d M M R pr otei ns 
or is M SI -H m ust als o ha ve recei ve d a n a nti -P D -( L) 1 m Ab , if i n dicate d. 
Patie nts m ust meet all of t he e nr oll me nt criteri a t o be eli gi ble f or t his st u d y. Eli gi bil it y 
criteria ma y n ot b e wai ve d b y t he i n vesti gat or a n d are s u bject t o re vie w i n t he e ve nt of a 
g o o d cli nic al practice a u dit a n d/ or healt h re g ulat or y a ut h orit y i ns pe cti o n.  
4. 1  I n cl u si o n Crit eri a 
S u bjects m ust meet t he f oll o wi n g criteria t o be eli gi ble f or t he s t u d y: 
1.  Ha ve h ist ol o gic all y a n d/ or c yt ol o gicall y d o c u me nte d  a de n ocarci n o ma of t h e c ol o n or 
rect u m, w hic h is metastatic a n d/ or u nres ecta ble.  
2.  U nless ot her wise c o ntrai n dicate d, s u bjects m ust ha ve recei ve d a n d faile d re gi me ns 
c o ntai ni n g t he f oll o wi n g a ge nts: fl u or o p yri mi di ne (e. g., 5-fl u or o uracil or ca pecita bi ne), 
o x ali plati n, iri n oteca n, a n a nti -V E G F m A b  ( be v aci z u ma b, ra m ucir u ma b, or zi v-
afli berce pt), a n d a n a nti -P D -( L) 1 t hera p y ( ni v ol u ma b or pe m br oliz u ma b) if t he t u m or has 
d M M R pr otei ns or is M SI -H.  
1.  Ha ve pr o gressi o n of u nresecta ble or m etastatic C R C after last s yste mic t hera p y (as 
c o nfir me d b y i n vesti gat or), or be i nt olera nt of last s yste mic t hera p y  
2.  Ha ve R A S  wil d -t y p e 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 
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)   
3.  S u bjects  m ust be willi n g a n d a ble t o pr o vi de  t he m ost rece ntl y a v aila ble tiss ue bl oc ks ( or 
sli des, wit h M e dical M o nit or’s a p pr o val) , o btai n e d pri or t o treat me nt i nitiati o n, t o a 
s p o ns or-desi g nate d ce ntr al  la b orat or y f or bi o mar ker a nal ysis. If arc hi val tiss ue is n ot 
a vaila ble, t he n a n e wl y-o btai ne d baseli ne bi o ps y of a n accessi ble t u m or lesi o n is 
re q uire d. 
4.  Ha ve c o nfir me d  H E R 2 -p ositi ve m C R C, as defi ne d b y ha vi n g t u m or tiss ue teste d at a 
Cli nical La b orat or y I m pr o ve me nt A me n d me nts ( C LI A) -certifie d or I nter n ati o nal 
Or ga niz ati o n f or Sta n dar diz ati o n ( I S O)-accre dit e d  la b orat or y, meeti n g at least o ne of t he 
f oll o wi n g criteria:  
a. 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]) b y a n F D A -a p pr o ve d or 
C o nf or mité E ur o pée n n e (C E )-mar ke d H E R 2 I H C test f oll o wi n g t he pac ka ge i nsert’s 
i nter pretati o nal ma n ual f or breast c a ncer  
b.  H E R 2 2 + I H C is eli gi ble if t he t u m or is a m plifie d b y  a n F D A -a p pr o ve d or 
C E -mar ke d H E R 2 i n sit u h y bri dizati o n assa y ( FI S H  or c hr o m o ge ni c i n sit u 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 3  of 1 7 0  
h y bri dizati o n [ CI S H ]) f oll o wi n g t he pac ka ge i nsert’s i nter pretati o nal ma n ual f or 
breast c a ncer  
c. H E R 2 ( E R B B 2 ) am plificati o n b y C LI A -certifie d or I S O -accre dit e d Ne xt Ge nerati o n 
Se q ue nci n g ( N G S) s e q ue nci n g assa y.  
5.  A ge  ≥1 8 years at ti me of c o nse nt  
6.  Ha ve ra di o gra p hic all y m eas ura bl e disease assessa ble b y R E CI S T  1. 1,  wit h at least o ne 
site of disease t hat is meas ura ble a n d t hat h as n ot bee n pre vi o usl y irra diate d; or,  if t he 
s u bject has ha d pre vi o us ra diati o n t o t he tar get lesi o n(s), t here m ust be e vi de nce of 
pr o gressi o n si nce t he ra diati o n  
7.  Ha ve a n E aster n C o o perati ve O nc ol o g y Gr o u p ( E C O G ) Perf or m a nce Stat us ( P S) of 0, 1, 
or 2.  
8.  Lif e e x pecta nc y great er t ha n 3 m o nt hs  i n t he o pi ni o n of t he in vesti gat or  
9.  Ha ve a d e q uate h e mat ol o gic al, he patic, re nal, c oa g ulati o n, a n d car diac f u ncti o n 
(A P P E N DI X D ) as defi n e d bel o w, o btai ne d 7 da ys pri or t o t he first st u d y treat me nt: 
a. A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1 .0  ×  1 0 3/ µ L 
b.  Platelet c o u nt ≥7 5  ×  1 0 3/ µ L 
c. He m o gl o bi n 8 . 0 g/ d L 
d.  T otal bilir u bi n ≤1. 5 × u p per  li mit of n or mal ( U L N). S u bjects  wit h k n o w n hist or y of 
Gil bert ’s S y n dr o m e a n d  n or mal direct  bilir u bi n , as partate a mi n otra nsferase  ( A S T), 
a n d ala ni ne a mi n otra nsferase  ( A L T) are eli gi ble  
e. A S T a n d A L T ≤2. 5 × U L N ( ≤5 × U L N if li ver met astases are pres e nt)  
f. Calc u late d creati ni ne cle ara nce ≥5 0 m L / mi n usi n g t he C oc k cr oft-Ga ult f or m ula  
g.  I nter nati o nal n or malize d rati o (I N R) a n d acti vate d partial t hr o m b o plasti n ti me (a P T T) 
≤1. 5 × U L N u nless o n m e dicati o n k n o w n t o alter I N R a n d/ or a P T T  
h.  Left ve ntric ular eje cti 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 ple-gate d ac q uisiti o n ( M U G A) sca n d oc u me nte d ≤2 8 da ys pri or t o 
st u d y treat me nt  
1 0.  F or s u bjects of c hil d beari n g p ote ntial, as d efi ne d i n Secti o n  4. 3 , t he f oll o wi n g 
sti p ulati o ns a p pl y: 
a. M ust ha ve a ne gati ve ser u m pre g n a nc y test ( mi ni m u m se nsiti vit y of 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 7  da ys 
pri or t o t he first d ose of st u d y treat me nt. A s u bject wit h a false p ositi ve res ult a n d 
d oc u me nte d verificati o n t hat t he s u bject is n ot pre g na nt is eli gi ble f or p arti ci pati o n.  
b.  M ust a gree n ot t o tr y t o b ec 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 dr u g a d mi nistrati o n  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 4  of 1 7 0  
c. M ust a gree n ot t o breastf ee d or d o nat e 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 n al d ose of st u d y dr u g a d mi nistrati o n  
d.  Ma y c h o ose t o pr actice c o m plete a b sti ne nce, if c o nsiste nt wit h t he s u bject’s preferre d 
lifest yle, as a n acce pt a ble f or m of c o ntr ace pti o n  
e. If se x uall y acti ve i n a wa y t hat c o ul d lea d t o pre g n a nc y, m ust c o nsiste ntl y use 
2  hi g hl y effecti ve m et h o ds of birt h c o ntr ol, as defi ne d i n A P P E N DI X C , st arti 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 a n y st u d y dr u g . 
1 1.  F or s u bjects w h o ca n fat her c h il dre n, t h e f oll o wi n g sti p ulati o ns a p pl y: 
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 st u d y dr u g 
a d mi nistrati o n  
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 hl y effecti v e met h o ds of birt h c o ntr ol, as 
defi ne d i n A P P E 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 d y a n d f or at least 7 m o nt hs after t he fi nal d ose of a n y st u d y dr u g  
c. If se x uall y acti ve wit h a pers o n w h o is pre g n a nt or breastf ee 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 P E 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 d y a n d f or at least 7 m o nt hs after 
t he fi nal d ose of a n y st u d y dr u g.  
1 2.  S u bject  m ust pr o vi de si g ne d i nf or me d c o ns e nt d oc u me nt t hat has bee n a p pr o ve d b y a n 
instit uti o nal re vie 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 t ests or pr oce d ures t hat are n ot p art of sta n dar d-of -care f or t he s u bject’s 
disease  
1 3.  S u bject  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  
4. 2  E x cl u si o n Crit eri a  
S u bjects  will be e x cl u de d fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns:  
1.  Ha ve pre vi o usl y b ee n treate d wit h a nti-H E R 2 tar geti n g t hera p y  
2.  Ha ve recei v e d treat me nt wit h a n y s yste 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 p y), n o n -ce ntral ner v o us s yste m ( C N S) ra diati o n, or e x peri me ntal a ge nt 
≤3  wee ks of first d ose of st u d y treat me nt or are c urre ntl y partici pati n g i n a n ot her 
i nter ve nti o nal cli nical tri al  
3.  Ha ve 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 x ce pti o ns:  
A l o pecia a n d n e ur o pat h y, w hic h m ust ha ve res ol v e d t o ≤ Gra de 2  
C o n gesti ve heart fail ure ( C H F), w hic h m ust ha v e bee n ≤ Gra de 1 i n se verit y at t he ti me of 
occ urre nce, a n d m ust ha v e res ol ve d c o m pletel y  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T uc ati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 5  of 1 7 0  
A ne mia,  w hic h m ust ha v e res ol ve d t o ≤ Gra de 2  
Decrease d A N C, w hic h m ust ha ve res ol ve d t o ≤ Gra de 2  
4.  Ha ve cli nic all y si g nifica nt car di o p ul m o nar y disease s uc h as:  
V e ntric ular arr h yt h mia re q uiri n g t hera p y  
S y m pt o matic h y p erte nsi o n or u nc o ntr olle d as y m pt o matic h y perte nsi o n , as deter mi ne d b y t he 
i n vesti gat or 
A n y hist or y of s y m pt o m atic C H F , left v e ntric ular s yst olic d ysf u ncti o n or d ecrease i n ej ecti o n 
fracti o n 
S e vere d ys p nea at r est ( C T C A E Gra de 3 or a b o v e) d ue t o c o m plicati o ns of a d va nce d 
mali g na n c y or h y p o xia re q uiri n g s u p ple m e ntar y o x y ge n t h era p y  
P rese nce of ≥ Gra de 2 Q Tc pr ol o n gati o n o n scree ni n g E C G  
5.  Ha ve k n o w n m y ocar dial i nfarcti o n, u nsta ble a n gi n a, car di ac or ot h er vas c ular ste nti n g, 
a n gi o plast y, or car di ac s ur ger y wit hi n 6 m o nt hs p ri or t o first d ose of st u d y tr eat me nt 
6.  Maj or s ur gical pr o ce d ure, o pe n bi o ps y, or si g nifica nt tra u matic i nj ur y ≤2 8 da ys pri or t o 
e nr oll me nt  (≤5 6 da ys f or he patect o m y, o pe n t h or ac ot o m y,  or  maj or ne ur os ur ger y) or 
a ntici pati o n of nee d f or maj or s ur gical pr o ce d u re d uri n g t he c o urse of t he st u d y  
7.  Seri o us, n o n -heali n g  w o u n d, ulcer, or b o n e fract ure  
8.  K n o w n t o be p ositi ve f or he patitis B b y s urface a nti ge n e x pressi o n 
9.  K n o w n t o ha ve acti ve he patitis C i nfecti o n  ( p ositi ve b y p ol y merase c hai n r eacti o n or o n 
a nti viral t hera p y f or he p atitis C wit hi n t he last 6 m o nt hs). S u bjects  w h o ha v e bee n tr eate d 
f or he patitis C i nfecti o n are per mitte d if t he y h a ve d oc u me nte d s ustai ne d vir ol o gic 
res p o nse of 1 2 w ee ks 
1 0.  K n o w n t o be p o siti ve f or h u ma n i m m u n o deficie nc y vir us  (HI V ) 
1 1.  S u bjects w h o are pre g na nt, breastfee di n g, or pla n ni n g a pre g na n c y  
1 2.  I n a bilit y t o s wall o w pills or a n y si g nifica nt gastr oi ntesti nal disease w hic h w o ul d precl u de 
t he a de q uat e oral a bs or pti o n of me dicati o ns  
1 3.  Ha ve use d a str o n g C Y P 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 first d ose of st u d y treat me nt 
(see A P P E N DI X E  a n d A P P E N DI X F ).  
1 4.  Ha ve a n y ot h er me dic al, 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 safet y or c o m plia nce wit h st u d y pr oce d ures 
1 5.  Hist or y of a n ot her mali g na nc y wit hi n 3 years bef ore t he first d ose of st u d y dr u g, or a n y 
e vi de nce of resi d ual disease fr o m a pre vi o usl y dia g n ose d m ali g na n c y. E x ce pti o ns are 
mali g na n cies wit h a ne gli gi ble ris k of metast asis or deat h ( e. g., 5 -year O S ≥9 0 %), s uc h as 
a de q uatel y tr eate d carci n o ma i n sit u of t he cer vi x, n o n-mela n o ma s ki n carci n o ma, 
l ocalize d pr ostate ca n cer, d uctal carci n o ma i n sit u, or Sta ge I uteri ne ca n cer) 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 6  of 1 7 0  
1 6.  S u bjects  wit h k n o w n acti ve C N S metastasis (irra diate d or res ecte d lesi o ns are per mitte d, 
pr o vi de d t he lesi o ns are f ull y trea t e d a n d i nacti ve, s u bject 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 ys) 
1 7.  Ha ve a h y p erse nsiti vit y t o t ucati ni b or a n y of its e x ci pie nts, t o trast uz u ma b or a n y of its 
e x ci pie nts, or t o m ur ine pr otei ns.   
4. 3  C hil d b e ari n g P ot e 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 gic al steriliz ati 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 us e is 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 mal e o ver a ge 4 5 i n t he a bse n ce of ot her 
bi ol o gical, p h ysi ol o gi cal, or p har mac ol o gi cal 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 gi cal steriliz ati o n (e. g. vas ect 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).  
4. 4  R e m o v al of S u bj e ct s  fr o m T h er a p y or A s s e s s m e nt 
Sea ge n  or t heir d esi g n ee m ust be n otifie d if a s u bject 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 h e reas o n(s) f or wit h dr a wal m ust be d oc u me nte d i n t he s u bject’s me dical 
rec or ds a n d cas e re p ort f or m ( C R F). 
4. 4. 1  Di s c o nti n u ati o n of St u d y Tr e at m e nt  
A s u bject’s st u d y treat me nt ma y be disc o nti n ue d f or a n y of  t he f oll o wi n g reas o ns: 
● 
P D ( per R E CI S T 1. 1), as assesse d b y i n vesti gat or 
● 
Cli nical disease pr o gressi o n  
● 
A E  
● 
Pre g n a nc y  or be gi ns breastfe e di n g w hile o n trial  
● 
I n v esti gat or decisi o n ( ot h er)  
N ote: E ns ure t hat s u bjects w h o are rec o m me n d e d  t o st o p treat me nt bec a us e of a n A E 
or dise ase pr o gressi o n  are n ot i ncl u de d i n t his rati o nale.  
● 
S u bject  decisi o n, n o n -A E  
N ote: E ns ure t hat s u bjects w h o deci de t o st o p treat me nt bec a use of a n A E  or dise ase 
pr o gressi o n  are n ot i ncl u de d i n t his rati o nale.  
● 
St u d y t er mi nati o n b y s p o ns or  
● 
Ot her, n o n -A E  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 7  of 1 7 0  
N O T E: S u bjects wit h si g ns of cli nical be nefit (e. g., mi x e d res p o nse, s y m pt o m i m pr o ve me nt, 
de m o nstra ble sl o wi n g of pr o gressi o n, pr o gressi o n rate of < 2 0 % o ver 6 m o nt hs) w h o are 
t olerati n g tr eat me nt ma y be all o we d t o c o nti n ue treat me nt past f ormal ra di ol o gic pr o gressi o n 
(i.e., R E CI S T  1. 1 ) if s u c h treat me nt is c o nsi dere d i n t he s u bject's b est i nterest b y t he s u bject, 
t he treati n g p h ysicia n, a n d t he M e dical M o nit or . I n t his sce nari o, s u bjects ma y c o nti n ue o n 
treat me nt, wit h ra di o gra p hic assess me nts perf or me d per t he pr ot oc ol d efi ne d assess me nt 
sc he d ule u ntil cli nical pr o gressi o n.  
S u bjects  w h o disc o nti n ue fr o m st u d y tr eat 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 dr a w c o ns e nt. 
4. 4. 2  S u bj e ct  Wit h dr a w al fr o m St u d y 
A n y s u bject ma y be w it h dra w n fr o m t he st u d y f or a n y of t he f oll o wi n g reas o ns: 
● 
S u bject  wit h dra wal of c o nse nt  
● 
St u d y t er 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  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 8  of 1 7 0  
5  
T R E A T M E N T S  
5. 1  Tr e at m e nt s A d mi ni st er e d  
S u bjects  i n t he st u d y will recei v e d o u blet c o m bi nati o n t hera p y of t ucati nib wit h trast uz u ma b  
( C o h orts A a n d B) or  t uc ati ni b m o n ot hera p y ( C o h ort C) . F or C o h orts A a n d B, t ucati ni b will 
be gi v e n o n a 2 1 -d a y c ycle , wit h trast uz u ma b o n da y 1 of eac h c ycl e. F or C o h ort C, t ucati ni b 
will be gi ve n o n a 2 1 -da y c ycle . Su bjects i n C o h ort C are all o we d t o cr oss o ver t o start 
d o u blet c o m bi nati o n t hera p y  wit h Me dical M o nit or’s a p pr o val,  if, b y i n vesti gat or assess me nt 
( per R E CI S T 1. 1), t he y e x perie nce ra di o gra p hic pr o gressi o n at a n y ti me p oi nt, or if t he y h a ve 
n ot ac hie ve d P R or C R  b y t he 1 2 -wee k assess me nt , at w hic h p oi nt t he m o n ot hera p y-c ycle 
will be a br u pte d a n d t he c o m bi nati o n t hera p y -c ycle will start (f or details see Secti o n 6. 3. 6 ). 
T a bl e 5 -1 : 
Tr e at m e nt s c h e d ul e  
A ge nt  
D ose 
Le vel  
R o ute  
Da y(s)  
C ycle(s)  
Fre q ue nc y  
Dr u g A d mi nistrati o n i n Eac h 
C o h ort ( Y/ N)  
C o h ort 
A  
C o h ort 
B  
C o h ort 
C  
T ucati ni b  
3 0 0 m g  
P O  
Da ys 1 -
2 1  
All  
T wice 
dail y  
Y  
Y  
Y  
Trast uz u ma b a 
8 m g/ k g 
b o d y 
wei g ht  
I V 
Da y 1  
C ycle 1  
(l oa di n g 
d ose)  
O nce  
Y  
Y  
N  
Trast uz u ma b a b 
6 m g/ k g 
b o d y 
wei g ht  
I V 
Da y 1  
C ycle 2 
a n d be y o n d  
O nce  
Y  
Y  
N  
a 
Use act u al wei g ht or esti mate d dr y wei g ht if fl ui d rete nti o n  
b  
Trast uz u ma b ma y als o be gi ve n o n a wee kl y basis at 2 m g/ k g I V or  Q 2 wee k basis at 4  m g/ k g I V, b ut o nl y i n 
circ u mst a nce s w here t h e trastuz u ma b i nf usi o n sc he d ule has b ee n i nterr u pte d or s us pe n de d , a n d t h ese i nf usi o ns are 
re q uire d t o res y nc hr o nize t he c ycle le n gt h t o 2 1 da ys.  
 
It is a re q uire m e nt of t he n urse t o perf or m i nstr ucti o n 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 C ycl e 1  D a y 1  ( C 1 D 1) (A P P E N DI X G ). T he n urse will nee d t o e ns ure 
t hat t he s u bject 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 n ce. It is 
n ot a re q uire m e nt t hat t he first d ose be gi ve n i n cli nic.  
5. 1. 1  I n v e sti g ati o n al St u d y Dr u g ( T u c ati ni b) 
T ucati ni b, t he i n vesti gati o nal a ge nt u n der st u d y i n t his pr ot oc ol, is a ki nase i n hi bit or t hat 
selecti vel y i n hi bits H E R 2, a n d dis pla ys li mite d acti vit y a gai nst t he relat e d ki nase E G F R.  
T ucati ni b is s u p plie d as yell o w o val ( 1 5 0 m g) or r o u n d ( 5 0 m g) ca ps ule -s h a pe d ta blets for 
oral a d mi nistrati o n.  
Detaile d i nf or mati o n des cri bi n g a d mi nistrati o n,  ha n dli n g  a n d st ora ge of t h e i n vesti gati o nal 
st u d y dr u g (t u cati ni b) is l ocate d i n t he P har mac y I nstr ucti o ns. 
5. 1. 1. 1  D e s cri 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 yell o w o v al -s ha pe d t a blet i n a 1 5 0 m g 
d osa ge stre n gt h a n d a c o ate d yell o w r o u n d c o n v e x ta blet i n a  5 0 m g d osa ge stre n gt h. T he 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 4 9  of 1 7 0  
ta blets are ma n ufact ur e d fr o m a dr u g pr o d u ct i nter me diate a m or p h o us dis persi o n of t ucati ni b 
i n p ol y vi n yl p yrr oli d o ne-vi n yl acetate 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 x ci pie nts ( micr ocr ystalli 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.  
5. 1. 1. 2  M et h o d of Pr o c ur e m e nt  
T he i n vesti gati o nal st u d y dr u g (t ucati ni b) will be pr o vi de d b y t he s p o ns or.  
5. 1. 1. 3  D o s e a n d A d mi ni str ati o n  
T he i n vesti gati o nal st u d y dr u g ( tucati ni b) will be a d mi nistere d P O BI D a n d ma y b e ta ke n 
wit h or wit h o ut f o o d. D ose m o dificati o ns of t ucati ni b are des cri be d i n Secti o n 5. 2 . S u bjects 
will be i nstr ucte d b y t h e p har macist or i n vesti gat or as t o t he s pecifi c 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 d y treat me nt, s u bjects will be s u p plie d wit h 
t he a p pr o priat e 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.  
S u bjects 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 nd 
o nce i n t he e v e 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 s a me cale n dar da y. It 
is rec o m me n de d t hat if a s u bject 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 n ce t he sc h e d ule d d osi n g ti me, t he d ose s h o ul d be i m me di atel y ta ke n. It is 
rec o m me n de d t h at if m ore t ha n 6 h o urs ha v e passe d si nce t he sc he d ul e d d osi n g ti me, t he 
s u bject 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 s c he d ule d 
d ose. Ta blets ma y be ta k e 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 w e d , or diss ol ve d i n li q ui d. T ucati ni b b ottes s h o ul d be st ore d u n der 
refri gerati o n. The i n di vi d ual u nit d ose of t he t ucati ni b ta blet ma y b e e x p ose d t o a m bie nt 
te m perat ur e 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 s u bjects 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 instr ucti o ns f or misse d 
d oses. S u bject c o m plia nce wit h i n vesti gati o nal st u d y dr u g d osi n g i nstr ucti o ns will be 
assesse d wit h t he use of s u bject diaries a n d st u d y dr u g acc o u nt a bilit y.    
5. 1. 1. 4  St or a g e a n d H a n dli n g  
Ta blets of t ucati ni b are p ac ka ge d i n r o u n d, hi g h -d e n sit y p ol yet h yle ne b ottl es 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. 
T he ta blets are c oat e 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 h a 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.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 0  of 1 7 0  
Refer t o t he P har m ac y I nstr ucti o ns f or m ore i nf or mati o n.  
5. 1. 1. 5  P a c k a gi n g a n d L a b eli n g  
Eac h b ottle of i n vesti gati o nal st u d y dr u g 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. 
5. 1. 1. 6  St u d y Dr u g A c c o u nt a bilit y  
T ucati ni b use d d uri n g t he c o urs e 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 u cti o ns. 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 s u bject 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 k e 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 or di n g t o t he St u d y O p erati o ns Ma n ual . All use d a n d u n use d b ottles of t ucati ni b 
sh 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 I nstr u cti o ns.  
5. 1. 2  Tr a st u z u m a b  
5. 1. 2. 1  D e s cri pti o n  
Trast uz u ma b is a h u ma nize d I g G -1 ka p pa m o n o cl o nal a nti b o d y w hi c h bi n ds t o t he 
e xtracell ular d o mai n of t he h u ma n e pi der m al  gr o wt h fact or rece pt or 2 pr ot ei n ( H E R 2); it 
me diates a nti b o d y -de p e n de nt cell ular c yt ot o xicit y b y i n hi biti n g pr oliferati o n of cells w hic h 
o ver e x press H E R 2 pr otei n.  
5. 1. 2. 2  M et h o d of Pr o c ur e m e nt  
T he i n vesti gati o nal st u d y dr u g (trast uz u ma b) will be pr o vi de d b y t he s p o ns or. 
5. 1. 2. 3  D o s e, Pr e p ar ati o n, a n d A d mi ni str ati o n  
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 f oll o we d b y 6 m g/ k g o nce e ver y 
2 1 da ys. Trast uz u ma b ma y als o be gi ve n o n a wee kl y b asis at 2 m g/ k g I V q 7 da ys, b ut o nl y 
i n t he circ u msta nce t hat trastuz u ma b i nf usi o n has bee n dela ye d, a n d wee kl y i nf usi o ns are 
re q uire d t o r es y nc hr o nize t he c ycle le n gt h t o 2 1 da ys, after disc ussi o n wit h t he Me dical 
M o nit or. Trast uz u ma b i nf usi o n rates will be 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 os e of 8 m g/ k g 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.  
Si n gle -d ose vial ( 1 5 0 m g/ vial) as a l y o p hilize d sterile p o w der f or rec o nstit uti o n  is 
c o m merciall y a v aila ble a n d s h o ul d  be pre pare d a n d a d mi nistere d per i nstr u cti o ns i n t he 
trast uz u ma b ( Herce pti n ®) pac ka ge i nsert f or a d mi nistrati o n i nstr ucti o ns. Trast uz u ma b will 
be a d mi nistere d I V u n d er t he directi o n of t he i n vesti gat or.  
Trast uz u ma b s h o ul d be st ore d acc or di n g t o t he pac ka g e i nsert.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 1  of 1 7 0  
5. 1. 2. 4  Ri s k A s s o ci at e d wit h Tr a st u z u m a b  
Ris ks ass ociate d wit h trast uz u ma b i ncl u de fe ver, na usea, v o miti n g, i nf usi o n reacti o ns, 
diarr hea, i nfecti o ns, i ncrease d c o u g h, h ea dac he, fati g ue, d ys p nea, ras h, n e utr o pe nia, a n e mia, 
m yal gia, a n d C H F. Pleas e see t he trast uz u ma b ( Herce pti n® ) pac ka ge i nsert/ nati o nal 
prescri bi n g i nf or mati o n f or m ore details.  
● 
Ma na ge me nt of car di ac, gastr oi ntesti nal, a n d s ki n/s u bc uta ne o us tiss ue dis or ders ma y 
re q uire te m p orar y i nterr u pti o n or treat me nt disc o nti n uati o n of trast uz u ma b as per 
g ui deli nes pr o vi d e d i n t he p ac k a ge inser t a n d of i nf usi o n-relate d reacti o ns (I R R) i n 
Ta ble 5 -3 . 
5. 1. 2. 5  St or a g e 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 tr ast uz u ma b. F oll o w t he  
pac ka ge i nsert f or m or e i nf or mati o n.  
5. 1. 2. 6  P a c k a gi n g a n d L a b eli n g  
Eac h vial of tr ast uz u ma b 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. 
5. 1. 2. 7  St u d y Dr u g A c c o u nt a bilit y  
Trast uz u ma b use d d uri n g t he c o urse of t h e st u d y s h o ul d be ha n dle d acc or di n g t o its pac ka ge 
i nsert. Trast uz u ma b vials are t o be trac k e d a n d d o c u me nte d fr o m t he ti me of recei pt at t he 
site, t hr o u g h s u bject d osi n g, a n d u ntil t he s p o ns or a p pr o ves of t h e fi nal ret ur n or destr ucti o n. 
All s u p plies, i ncl u di n g partiall y us e d or e m pt y vi als, 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 us e 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. 
5. 2  D o s e M o difi c ati o n s  
5. 2. 1  T u c ati ni b D o s e R e d u cti o n s   
Refer t o Ta bl e 5 -2  f or t h e t ucati ni b d ose re d u cti o n le vels. D ose re d ucti o ns lar ger t ha n t h ose 
re q uire d b y t hes e ta bles ma y b e ma de at t he discreti o n of t he i n vesti gat or. U p t o 3 d ose 
re d ucti o ns of t ucati ni b are all o we d, b ut 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. Patie nts w h o, i n t he 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, or w h o w o ul d re q uire a p ot e ntial f o urt h d ose re d u cti o n of t ucati ni b, 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 -es calate d after a d ose re d ucti o n is ma de. F or f urt h er 
g ui deli nes re gar di n g d os e m o dificati o n of t ucati ni b d ue t o A Es, please s ee  Ta ble 5 -4 . 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 2  of 1 7 0  
T a bl e 5 -2 : 
T u c ati ni b: R e c o m m e n d e d d o s e r e d u cti o n s c h e d ul e f or A E s  
D ose  Re d ucti o n Sc he d ule  
T ucati ni b  D ose Le vel  
Starti n g d ose  
3 0 0 m g P O BI D  
1s t d ose re d ucti o n 
2 5 0 m g P O BI D  
2 n d  d ose re d ucti o n  
2 0 0 m g P O BI D  
3r d  d ose re d ucti o n  
1 5 0 m g P O BI D  
Re q uire me nt f or f urt her d ose re d ucti o n  
Disc o nti n ue treat me nt  
N ote: T ucati ni b d ose le vels are base d o n A Es liste d  i n Ta ble 5 -4 . D ose re d ucti o ns of greater i ncre me nts t ha n t h ose liste d i n 
t his ta ble (i.e., m ore t h a n 5 0 m g per d ose re d ucti o n) ma y be ma de if c o nsi dere d cli nicall y a p pr o priate b y t h e i n vesti gat or. 
H o we ver, t u cati ni b ma y n ot be d ose re d uce d bel o w 1 5 0 m g BI D  
5. 2. 2  T r a stu z u m a b  D o s e M o difi c ati o n s   
T here are n o d os e re d u cti o ns f or trast uz u ma b. G ui deli nes re gar di n g d os e dela ys a n d 
disc o nti n uati o n of trast uz u ma b d ue t o A Es are gi ve n i n  Ta ble 5 -4  a n d Ta bl e 5 -6 . 
Trast uz u ma b ma y als o be gi v e n o n a wee kl y basis at 2 m g/ k g I V q  7  d a ys  or bi wee kl y at 
4 m g/ k g I V , b ut o nl y i n t he circ u msta n ce t hat trast u z u ma b i nf usi o n has bee n dela ye d, a n d 
t hese i nf usi o ns are re q uir e d t o res y nc hr o nize t he c ycl e le n gt h t o 2 1 da ys, after disc ussi o n 
wit h t he Me dical M o nit or. If trast uz u ma b ca n n ot be restart e d at t he sa m e d ose after bei n g 
hel d f or a n A E, it m ust be disc o nti n ue d. 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 of 8 m g/ k g 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. As 
trast uz u ma b ma y be gi v e n as a n I V i nf usi o n, i nf usi o n-relate d reacti o ns (IR Rs), ma y o cc ur.  
5. 2. 2. 1  I nf u si o n-r el at e d R e a cti o n a n d it s M a n a g e m e nt  
A n I R R is c haracteri ze d b y a n a d verse reacti o n t o t he i nf usi o n of p har mac ol o gical or 
bi ol o gical s u bsta nces. I R Rs occ ur wit hi n 2 4 h o urs of i nf usi o n a n d ma y ma nifest as a 
c o m bi nati o n of si g ns or s y m 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 p es of 
ras h, urticaria, d ys p nea, na usea, v o miti n g, b ac k or a b d o mi nal pai n a n d/ or h y p ote nsi o n (Ka n g 
2 0 0 7 ). 
I R R ma y occ ur d uri n g t h e i nf usi o n of st u d y tr eat me nt. T he i nf usi o n s h o ul d be a d mi nistere d 
at a site pr o perl y e q ui p pe d a n d staffe d t o ma n a ge a na p h yla xis s h o ul d it occ ur. All s u p p orti ve 
meas ures c o nsiste nt wit h o pti mal s u bject care s h o ul d be g i ve n t hr o u g h o ut t he st u d y 
acc or di n g t o i nstit uti o nal sta n dar ds. S u p p orti ve meas ures ma y i n cl u de e xte n di n g t he i nf usi o n 
ti me a n d/ or a d mi nisteri n g me dicati o ns f or I R R. 
I R R rel ate d t o trast uz u ma b ha ve b ee n o bser ve d. Refer t o Ta bl e 5 -3  f or I R R-s pecific d ose 
m o dificati o n of trast uz u ma b. If a si g nifica nt IR R occ urs, t he i nf usi o n s h o ul d be i nterr u pte d 
a n d a p pr o pri ate me dic al t hera pies s h o ul d be a d mi n istere d (see Ta ble 5 -3 ). Per ma ne nt 
disc o nti n uati o n s h o ul d be c o nsi dere d i n s u bjects wit h se vere I R R. T his cli nical assess me nt 
s h o ul d be base d o n t he se verit y of t he prece di n g reacti o n a n d res p o ns e t o a d mi nistere d 
treat me nt f or t he a d vers e reacti o n. T h e se verit y of I R Rs s h o ul d be gra d e d acc or di n g t o N CI 
C T C A E v 4. 0 3 g ui deli nes.  
N o sta n dar d pre me dicati o n is re q uire d f or f ut ure treat me nts if s u bjects ha v e de ve l o pe d a n 
i nf usi o n s y n dr o me. S u bj ects ma y be gi ve n acet a mi n o p he n pri or t o treat m e nts. Seri o us 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 3  of 1 7 0  
reacti o ns ha v e bee n treat e d wit h s u p p orti ve t hera p y s uc h as o x y ge n, bet a-a g o nists, 
c ortic oster oi ds , a n d wit h dra wal of st u d y a ge nt as i n dicate d.  
T a bl e 5 -3  
D o s e m o difi c ati o n s f or i nf u si o n -r el at e d r e a cti o n s f or tr a st u z u m a b  
I nf usi o n-relate d reacti o ns 
D ose M o dificati o n  
Gra d e 2   
I N T E R R U PT  trast uz u ma b i nf usi o n i m me diatel y. 
S u bj ects  s h o ul d be treate d acc or di n g t o t he f oll o wi n g g ui deli nes, or acc or di n g t o 
i nstit uti o nal g ui deli nes, at discreti o n of t he st u d y p h ysicia n: 
St o p i nf usi o n a n d n otif y p h ysi cia n.  
Assess vital si g ns.  
A d mi nister aceta mi n o p he n 6 5 0 m g P O.  
C o nsi der a d mi nistrati o n of  me peri di ne 5 0 m g i ntra m usc ular (I M) or e q ui vale nt, 
di p he n h y dra mi ne 5 0 m g I V, ra niti di ne 5 0 m g I V or ci meti di ne 3 0 0 m g I V, 
de xa met has o ne 1 0 m g I V or fa m oti di ne 2 0 m g I V.  
If vital si g ns sta ble, R E S T A R T  trast uz u ma b at t he sa me d ose. 
N o sta n dar d pre me dicati o n  is re quire d f or f ut ure treat me nts if s u bj ects  ha ve 
de vel o pe d a n i nf usi o n s y n dr o me. S u bj ects  ma y be gi ve n ac eta mi n o p he n pri or t o 
treat me nts. 
Seri o us reacti o ns ha ve bee n tr eate d wit h s u p p orti ve t hera p y s uc h as o x y ge n, 
beta -a g o nists, c ortic oster oi ds a n d wit h dra wal of st u d y a ge nt as i n dicate d.  
≥ Gra d e 3   
I N T E R R U P T i nf usi o n i m me diatel y 
A d mi nister a p pr o priate me dic al t hera pies.  
DI S C O N TI N U E treat me nt. 
5. 2. 2. 2  All er gi c/ H y p er s e n siti vit y R e a cti o n   
Aller gi c/ h y p erse nsiti vit y reacti o ns are c h aracterize d b y a d v erse l o cal or ge n eral r es 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 4. 0 3). F or p ur p oses of t his st u d y, 
aller gic/ h y pers e nsiti vit y reacti o ns are differe ntiate d fr o m I R Rs b y bei n g d efi ne d as occ urri n g 
> 2 4 h o urs aft er i nf usi o n of trast uz u ma b. Aller gic/ h y perse nsiti vit y reacti o ns ma y ma nifest i n 
t he sa me ma n ner as I R Rs, i.e., a c o m bi nati o n of si g ns or s y m 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, d ys 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.  
5. 2. 2. 3  A n a p h yl a xi s   
A na p h yl a xis is a se vere, life -t hreat e ni n g, ge neralize d or s yste mic aller gic/ h y perse nsiti vit y 
reacti o n. A n a p h yl 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 
releas e of hista mi ne a n d hista mi ne-li ke s u bsta nces fr o m mast cells, ca usi ng a h y p erse nsiti vit y 
i m m u ne res p o nse. Cli nicall y, it pres e nts wit h breat hi n g diffic ult y, 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 4. 0 3 a n d (R osell o 
2 0 1 7 ). 
If a na p h yl a xis occ urs, a d mi nistrati o n of trast uz u ma b s h o ul d be i m me diatel y a n d p er ma n e ntl y 
disc o nti n ue d.  
5. 2. 3  D o s e M o difi c ati o n s f or A d v er s e E v e nt s  
Ge neral d ose m o dificati o n g ui deli nes f or t ucati ni b a n d trast uz u ma b are pr o vi de d i n  Ta ble 5 -4  
f or cli nical A Es. D os e m o dificati o ns f or he p at ot o xicit y  a n d left ve ntric ular d ysf u ncti o n are 
pr o vi de d i n Ta ble 5 -5  a n d Ta ble 5 -6 , acc or di n gl y. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 4  of 1 7 0  
A Es ≥ Gra de 3 n ot s p ecificall y me nti o ne d i n t he f oll o wi n g ta bles b ut  t hat are assess e d as 
bei n g relate d t o t ucati ni b or trast uz u ma b s h o ul d be ma na ge d b y H O L DI N G treat me nt u ntil 
e ve nt res ol uti o n t o ≤ Gra de 1 or pre -treat me nt le v el. Treat me nt s h o ul d be R E-S T A R T E D at 
ne xt l o wer d ose le vel.  
T a bl e 5 -4  
D o s e m o difi c ati o n s f or cli ni c al A E s r el at e d t o eit h er t u c ati ni b or tr a st u z u m a b   
Cli nical A d verse E ve nt  
T ucati ni b  
Trast uz u ma b  
Relate d t o t ucati ni b  
Relate d t o trast uz u ma b  
≥ Gra d e 3 A Es ot her t ha n Gra de 3 
fati g ue lasti n g ≤ 3 da ys;  al o pe cia a; 
na usea; v o miti n g; diarr hea; ras h; 
c orrecta ble electr ol yte a b n or malities  
w hic h ret ur n t o ≤ Gra d e 1 wit hi n 7 
da ys   
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. 
D o n ot a d mi nister u ntil se verit y  
≤ G ra de 1 or pretreat me nt le vel. 
Restart wit h o ut d ose re d ucti o n.  
Gra d e 3 na usea, v o miti n g, or 
diarr hea WI T H O U T o pti mal use of 
a nti -e metics or a nti -diarr heals  
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 . 
D o n ot a d mi nister 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 d e 3 na usea, v o miti n g, or 
diarr hea WI T H o pti mal use of a nti -
e metics or a nti -diarr heals  
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. 
D o n ot a d mi nister u ntil se verit y  
≤ Gra de 1 or pretreat me nt le vel.  
Restart wit h o ut d ose re d ucti o n.  
Gra d e 4 v o miti n g, or diarr hea 
re gar dless of use of a nti-e meti cs or 
a nti -diarr heals  
D o n ot a d mi nister u ntil se verit y  
≤ Gra de 1 . 
Re d uce t o ne xt l o west d ose 
le vel. 
D o n ot a d mi nister u ntil se verit y ≤ 
Gra de 1. Restart wit h o ut d ose 
re d ucti o n. 
Gra d e 3 ras h WI T H O U T ma xi 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.  
D o n ot a d mi nister 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 d e 3 ras h WI T H ma xi 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. 
D o n ot a d mi nister u ntil se verit y  
≤ Gra de 1 or pretreat me nt le vel.  
Restart wit h o ut d ose re d ucti o n.  
Gra d e 4 ras h re gar dless of 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. 
D o n ot a d mi nister u ntil se verit y  
≤ Gra de 1 or pretreat me nt le vel.  
Restart wit h o ut d ose re d ucti o ns.  
a 
N o d ose m o difi cati o ns are re q uire d f or al o pecia  
5. 2. 3. 1  D o s e M o difi c ati o n s f or H e p at ot o xi cit y  
D ose m o dificati o n ma y b e re q uir e d i n t he cas e of li ver f u ncti o n a b n or m alities. F or d os e 
m o dificati o ns of t ucati ni b  f or li ver f u n cti o n a b n or malities see Ta ble 5 -5 . D ose m o dificati o n 
of trast uz u ma b is n ot re q uire d b ut d osi n g ca n be h el d at i n vesti gat or ’s discreti o n. F or s u bjects 
wit h d oc u me nte d Gil bert’s disease, please c o ntact t he M e dical M o nit or f or g u i da nce 
re gar di n g d os e m o dificati o ns i n t hese s u bjects. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 5  of 1 7 0  
T a bl e 5 -5  
D o s e m o difi c ati o n s of t u c ati ni b f or li v er f u n cti o n a b n or m aliti e s  
Li ver F u ncti o n A b n or malities  
Acti o n f or t ucati ni b, Re gar dless of Relati o ns hi p t o 
Dr u g  
Gra d e 3 ele vati o n of A L T a n d/ or A S T  
( > 5 t o 2 0 × U L N) 
H ol d u ntil se verit y ≤ Gra de 1 or u ntil ret ur n t o 
pretreat me nt le vel i n s u bj ects wit h k n o w n li ver 
metastases  
Restart at ne xt l o west d ose le vel  
Gra d e 4 ele vati o n of A L T a n d/ or A S T  
( > 2 0 × U L N) 
D isc o nti n ue dr u g 
Ele vati o n of A L T a n d/ or A S T ( >  3 × U L N)  
A N D  
Bilir u bi n ( > 2 × U L N)  
Disc o nti n ue dr u g   
Gra d e 3 ele vati o n of bilir u bi n  
( > 3 t o ≤ 1 0 × U L N) a n d  
b ot h A L T a n d A S T < 3. 0  ×  U L N  
H ol d u ntil se verit y ≤ Gra de 1 or u ntil ret ur n t o 
pretreat me nt le vel i n  s u bj ects wit h k n o w n li ver 
metastases  
Restart at ne xt l o west d ose le vel  
Gra d e 4 ele vati o n of bilir u bi n ( > 1 0 x U L N)  
Disc o nti n ue dr u g  
A L T = ala ni n e a mi n otra nsferase; A S T = as partate a mi n otra nsfer ase; U L N = u p per li mit of n or mal  
5. 2. 3. 2  D o s e M o difi c ati o n s f or L ef t V e ntri c ul ar D y sf u n cti o n 
Trast uz u ma b ca n ca use l eft ve ntric ular car diac d ysf u ncti o n, arr h yt h mias, h y p erte 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 c a use 
as y m pt o matic decli ne i n L V E F.  
T rast uz u ma b d ose m o dificati o n g ui d eli nes f or left ve ntric ular d ysf u ncti o n are pr o vi de d i n 
Ta ble 5 -6 . 
T a bl e 5 -6 : 
Tr a st u z u m a b d o s e m o difi c ati o n s g ui d eli n e s f or l eft v e ntri c ul ar d y sf u n cti 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 % wit h < 1 0 % 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 % decrease fr o m bas eli ne   H ol d trast uz u ma b, re peat L V E F i n 3 wee ks  
 
Re p eat L V E F at 3 wee ks:   
 
 
 
- L V E F 5 0 %  
Res u me treat me nt wit h trast uz u ma b  
 
 
- L V E F 4 5 % t o 4 9 %  
 
 
 
 
< 1 0 % decrease fr o m baseli ne  
Res u me treat me nt wit h trast uz u ma b  
 
 
 
1 0 % decrease fr o m baseli ne  
Disc o nti n ue trast uz u ma b   
 
 
- 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 V e ntric ular Ejecti o n Fracti o n  
5. 3  C o n c o mit a nt T h er 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 os e) t hr o u g h t he safet y re p orti n g peri o d. A n y c o n c 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 b e rec or de d fr o m t he ti me of i nf or me d c o ns e nt. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 6  of 1 7 0  
5. 3. 1  P ot e nti al C o n c o mit a nt Dr u g I nt er a cti o n s  
5. 3. 1. 1  T u c 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 
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. Use of s e 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 first d ose of 
st u d y treat me nt a n d d uri n g st u d y 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 m es, a n d t heref ore has t he p ot e 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. C o nsi der usi n g a n alter nat e 
me dicati o n w hic h is n ot a se nsiti ve C Y P 3 A s u bstrate. If u na v oi da b le, 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 pres cri 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 -g p s u bstrat e, i ncreases di g o xi n 
c o nce ntr ati o ns, w hic h ma y i n crease t he ris k f or di g o xi n relate d a d v erse 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 pres cri 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 os a 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.  
Treat me nt wit h t ucati ni b is ass ociate d wit h mil d i ncreas es i n ser u m creati ni ne w hic h were 
re versi ble u p o n treat me nt disc o nti n uati o n. A de dicate d D DI st u d y de m o nstr ate d n o i m pact o n 
re nal f u n cti o n. 
5. 3. 1. 2  Tr a st u z u m a b  
Please refer t o t he p ac ka ge i nsert 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 t hera pe utic, di d n ot alter t he plas ma 
c o nce ntr ati o ns of ot her s mall m olec ule t hera p e utics 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 kel y t hat tr ast uz u ma b w o ul d ha ve a n effect o n t he 
p har mac o ki netics of t ucati ni b. T her e 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 ies O N T -3 8 0 -0 0 5  a n d O N T-3 8 0 -2 0 6 ( H E R 2 C LI M B) , w hic h e val uat e d t he  
c o m bi nati o n of t ucati ni b wit h ca pecita bi ne a n d trast uz u ma b.  
5. 3. 2  R e q uir e d C o n c o mit a nt T h er a p y  
T here is n o re q uire d c o n c o mita nt t hera p y.  
5. 3. 3  All o w e d C o n c o mit a nt T h er a p y  
S u bjects  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 x cl 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 . 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 7  of 1 7 0  
•  D uri n g st u d y tr eat me nt, s u bjects ma y recei ve s u p p orti ve care t o i ncl u de 
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 a n d pai n ma na ge me nt 
•  S u p p orti ve care m e dicati o ns s uc h as a nti -diarr heals, a nti -e metics, a ntaci ds, a n d 
la x ati ves are per mitte d. Pr o p h ylactic use of a nti -di arr heals are per mitte d at t he 
discreti o n of t he i n vesti gat or  
•  Pr o p h yla ctic a n d s y m pt o matic treat me nt of na us ea a n d v o miti n g ma y b e use d per 
sta n dar d-of -care  
•  T h orace ntesis or parace ntesis ma y be p erf or me d, if nee de d f or c o mf ort  
•  If s ur gical i nter v e 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 n o nres ecta 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 sec o n d res p o nse ass ess me nt a n d t he 
Me dica l Mo 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 warra nt e 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. T he use of gr o wt h fact ors 
s h o ul d f oll o w p u blis he d g ui deli nes of t h e A merica n S ociet y of Cli nical O n c ol o g y 
( A S C O) U p date of R ec o m me n dati o ns f or t he Use of W hite Bl o o d Cell Gr o wt h 
Fact ors: A n E vi de nce -Base d Cli nical Practice G ui deli ne (S mit h 2 0 0 6 ). 
•  S u bjects  s h o ul d recei ve f ull s u p p orti ve care w hile o n t his st u d y. T his i ncl u d es bl o o d 
pr o d uct s u p p ort, a nti bi otic treat me nt, 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. All bl o o d pr o d ucts a n d c o nc o mita nt me dicati o ns s uc h 
as a nti -diarr heals, a n al gesics, a n d/ or a ntie metics recei ve d fr o m t he first da y of st u d y 
treat me nt a d mi nistrati o n u ntil 3 0 da ys aft er t he fi n al d ose will be rec or de d i n t he 
me dical rec or ds.  
•  Diarr hea: T his c o ul d  be ma na ge d c o ns er vati vel y wit h l o pera mi de. T he rec o m me n de d 
d ose of l o pera mi de is 4 m g at first o nset, f oll o we d b y 2 m g e v er y 2 t o 4 h o urs u ntil 
diarr hea free ( ma xi m u m 1 6 m g/ da y).  
● 
I n t he e ve nt of G ra d e 3 or 4 diarr hea, t he f oll o wi n g s u p p orti ve meas ures are all o we d: 
h y drati o n, o ctre oti de, a n d a nti -diarr heals.  
● 
If diarr hea is se v ere (re q uiri n g i ntra v e n o us re h y drati o n) a n d/ or ass oci ate d wit h fe ver 
or se vere ne utr o p e nia ( Gra de 3 or 4), br oa d -s pectr u m a nti bi otics m ust be prescri be d. 
S u bjects  wit h se vere diarr hea or a n y diarr hea ass o ciate d wit h se vere  na us ea or 
v o miti n g s h o ul d be h os pitalize d f or i ntra ve n o us h y drati o n a n d c orrecti o n of 
electr ol yte i m bala n ces. 
5. 3. 4  C o n c o mit a nt T h er a pi e s t o b e U s e d wit h C a uti o n  
S u bjects 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. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 8  of 1 7 0  
Se nsiti ve  s u bstrates of C Y P 3 A (A P P E N DI X H ); 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 m es, a n d t h eref ore has t h e 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 h eref ore, c o n c 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. C o nsi der usi n g a n alter nate me dicati o n w hic h  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 pres cri bi n g i nf or mati o n. 
M o derate C Y P 2 C 8 i n hi bit ors s h o ul d be use d wit h ca uti o n . 
C o nc o mita nt use of t ucati ni b wit h di g o xi n, a P -g p s u bstrate,  i ncreases di g o xi n 
c o nce ntr ati o ns, w hic h ma y i n crease t he ris k f or di g o xi n relate d  a d v erse 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 pres cri 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 os a 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. 
5. 3. 5  Pr o hi bit e d C o n c o mit a nt T h er a p y  
T he f oll o wi n g t h era 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 v esti gati o nal dr u gs a n d de vices 
•  A nti -ca 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 a n d h or m o nal t hera p y  
•  Ra diati o n t hera p y, e x ce pt f or palliati ve ra di ot hera p y at f o cal n o n -C N S sites w hic h are 
n ot c o nsi dere d tar get lesi o ns per R E CI S T 1. 1, w hi c 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 dir ecte d at tar get lesi o ns per R E CI S T 
1. 1 re q u ires pri or a p pr o val b y t he M e dical Mo nit or.  T ucati ni b m ust be hel d 7 da ys 
pri or t o a n d 7 da ys p os t r a diati o n t hera p y. 
•  Vacci n ati o n wit h li ve vacci nes  
•  Str o n g i n d ucers of C Y P 3 A 4 are pr o hi bite d as c o n c 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  w ee k  of disc o nti n uati o n of st u d y treat me nt (see  A P P E N DI X 
E ) 
•  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 
(see A P P E N DI X F ) 
•  Use of 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 first d ose of 
st u d y treat me nt a n d d uri n g st u d y treat me nt (see A P P E N DI X H ). C o nsi der usi n g a n 
alter nate me di cati o n w hi c h 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 di ces a n d/ or 
i ncreas e 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 m e dicati o n’s 
prescri bi n g i nf or mati o n.  
S u bjects  ma y n ot r ecei v e ot her i n vesti gati o nal dr u gs, i m m u n os u p pressi ve me dicati o ns, 
ra di ot hera p y, or s yste mic a nti-ne o plas tic t hera p y d uri n g t he st u d y. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 5 9  of 1 7 0  
5. 4  M a n a g e m e nt of O v er d o s e   
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 os e greater t ha n t h e prescri be d d ose, 
st u d y pers o n n el s h o ul d: 
Care f or a n d me dicall y st a biliz e t he s u bject 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 v er d ose of t ucati ni b.  
N otif y t he M e dical M o nit or as s o o n as t he y bec o me a ware of t he o v er d ose, t o disc uss details 
of t he o ver d os e (e. g., e x act a m o u nt of t ucati ni b a d mi nister e d, s u bject 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 ociate d A Es) are t o be ca pt ur e d o n t he A E  electr o ni c 
case re p ort f or m ( e C R F) 
Refer t o t he  pac ka ge i nsert  f or o ver d ose i nf or mati o n f or trast uz u ma b. 
5. 5  Tr e at m e nt C o m pli a n c e  
St u d y dr u g a d mi nistrati o n will be d oc u me nte d i n s o urce d oc u m e nts a n d t he C R F.  
St u d y -dr u g c o m plia n ce will be assesse d o n a s u bject -b y -s u bject b asis usi n g s u bject diaries. 
T he p har macist or desi g n ee 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 s u bject, a n d t he n u m ber of ta bl ets 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 will als o be c ollecte d b y t he site 
after eac h c ycle. D ose m o dificati o ns a n d i nterr u pti o ns of a n y st u d y dr u g wil l be d oc u me nte d 
i n t he s o urce d oc u m e nts a n d t he C R F. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 0  of 1 7 0  
6  
S T U D Y A C TI VI TI E S  
6. 1  S c h e d ul e of E v e nt s  
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 os e) t hr o u g h t he s afet y 
re p orti n g peri o d (s ee Secti o n 7. 7. 1. 3 ). A n y st u d y pr ot oc ol-relat e d A E  ( defi ne d i n 
Secti o n  7. 7. 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 c he mistr y pa nel,  li ver f u n cti o n tests ( L F Ts), c o m plete 
bl o o d c o u nt [ C B C] wit h differe ntial [ ma n ual differe ntial if cli nicall y i n dicate d, see Secti o n 
7. 7. 3 ], uri nal ysis, p h ysic al e x a m, wei g ht, a n d perf or ma nce stat us) m a y be p erf or me d wit hin 1 
da y pri or t o a d mi nistrati o n of st u d y dr u g. T h e res ults fr o m all rele va nt cli ni cal la b orat or y 
assess me nts m ust be re vi e we d pri or t o d osi n g.  
T u m or bi o psies perf or me d d uri n g t he st u d y s h o ul d be ma de a v aila ble t o t he sp o ns or if 
feasi ble (s ee Secti o n  7. 1 ). 
A sc he d ule of e ve nts is pr o vi de d i n A P P E 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 pti o ns of all st u d y ass ess me nts are prese nte d i n Secti o n 7 . 
6. 2  S cr e e ni n g P eri o d  
6. 2. 1  Pr e -s cr e e ni n g ( U p t o 3 M o nt h s B ef or e A nti ci p at e d S cr e e ni n g Vi sit)  
If H E R 2 o vere x pressi o n/a m plificati o n stat us is u n k n o w n i n pre-st u d y assess me nts, s u bjects 
ma y c o nse nt t o s u b mit a n arc hi val t u m or s peci me n or ne w lesi o n bi o ps y f or l ocal I H C /in sit u 
h y bri diz ati o n (I S H) testi n g f or assess me nt of H E R 2 stat us. S u bjects s h o ul d be k n o w n 
wil dt y pe b y e x pa n de d R A S testi n g a n d s h o ul d be e x pecte d t o be eli gi ble f or 
M O U N T AI N E E R after c o m pleti o n of t heir c urre nt c he m ot hera p y re gi me n. S u bjects m ust be 
i nf or me d t hat H E R 2 testi n g c o ns e nt is n ot i nf or me d c o nse nt f or t he st u d y a n d partici pati o n i n 
H E R 2 testi n g d oes n ot g uara nte e st u d y eli gi bilit y.  
H E R 2 alterati o ns testi n g i nf or me d c o nse nt  
S u b missi o n  of arc hi val tiss ue f or l ocal I H C/I S H t esti n g f or H E R 2 stat us f oll o wi n g t he 
pac ka ge i nsert ’s i nter pret ati o nal ma n ual f or breast ca ncer; if arc hi val tiss ue bl oc ks are 
n ot a vaila ble, a fres h t u m or bi o ps y ma y  b e o btai ne d f or H E R 2 pre -scree ni n g. 
6. 2. 2  S cr e e ni n g Vi sit ( D a y s [ -2 8] t o [-1] ) 
•  I nf or me d c o ns e nt 
•  St u d y eli gi bilit y p er i ncl usi o n/e xcl usi o n criteria  
•  D oc u me nte d diseas e  hist or y ( See Secti o n 7. 1 ) 
•  Ra di ol o gical Dise ase  Ass ess me nt  ( C T/ M RI) 
•  Bl o o d T u m or Mar ker ( carci n oe m br y o nic a nti ge n [ C E A ]) 
•  He patitis B a n d C scree ni n g (a nti-H C V will o nl y b e c ollecte d f or C o h orts B a n d C)   
•  C o nc o mita nt me dicati o ns  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 1  of 1 7 0  
•  A Es  
•  E C H O/ M U G A  
•  C o nfir m a vaila bilit y  of arc hi v al tiss ue f or s u b missi o n t o ce ntral la b orat or y (f or mali n 
fi x e d paraffi n-e m be d de d [ F F P E ]); if arc hi val tiss ue bl oc ks t hat meet r e q uir e me nts are 
n ot a vaila ble, a fres h t u m or bi o ps y m ust be o btai n e d a n d s u b mitte d f or H E R 2 testi n g 
(see Secti o n 7. 1 ). 
•  Bi o mar ker Plas ma c ollecti o n f or C o h orts B a n d C (Ta ble 1 1 -3 ) 
6. 2. 3  B a s eli n e Vi sit ( D a y s [-7 ] t o [-1 ]) 
P h ysic al e x a mi nati o n, i ncl u di n g hei g ht  
Vital si g ns  (w ei g ht, b o d y te m perat ur e, heart  rate, s yst olic a n d diast olic bl o o d 
press ure, p ulse, a n d o x y g e n sat urati o n)  
E C O G P S  (A P P E N DI X B ) 
Uri nal ysis  
Bl o o d sa m ples f or la b orat or y testi n g (as liste d i n Secti o n 7. 7. 3 ) 
○ 
Bl o o d c he mistries a n d L F T s 
○ 
C B C wit h differe ntial  a n d platelets  
○ 
C oa g ulati o n pa n el (i ncl u di n g I N R, pr ot hr o m bi n ti me ( P T ), a n d a P T T) 
F or pers o ns of c hil d beari n g p ote ntial, ser u m β -h C G  pre g na n c y test wit hi n 7 da ys of 
first st u d y treat me nt 
1 2 -lea d E C G 
C o nc o mita nt me dicati o ns  
A Es  
S u b mit  Eli gi bilit y W or ks heet t o s p o ns or f or a p pr o val t o e nr oll  
Wit h s p o ns or’s a p pr o val, access ra n d o mizati o n s yste m f or treat me nt assi g n me nt 
( C o h orts B a n d C o nl y) 
6. 3  Tr e at m e nt P eri o d ( 2 1 -d a y c y cl e s)  
6. 3. 1  C y cl e 1 Pr e -d o s e D a y 1  
P h ysical E x a mi nati o n  ( pre-d ose, ma y n ot be  p erf or me d if d o ne wit hi n 1 da y pri or t o 
C 1 D 1)   
Vital si g ns : wei g ht, b o d y te m perat ur e, heart  rate, s yst olic a n d diast olic bl o o d 
press ure, p ulse, a n d o x y g e n sat urati o n  (pre -d ose,  ma y n ot be perf or me d if d o ne 
wit hi n 1  da y pri or t o C 1 D 1)  
Dr u g Diar y Re vi e w  
E Q -5 D -5 L q u esti o n naire  ( C o h orts B a n d C o nl y) 
E O R T C Q L Q -C 3 0 q uesti o n naire  ( C o h orts B a n d C o nl y) 
E C O G  P S  (pre -d ose, ma y n ot be perf or me d if d o ne wit hi n 1  da y pri or t o C 1 D 1)  
C o nc o mita nt me dicati o ns  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 2  of 1 7 0  
A E s 
Bi o mar ker Plas ma  a n d S er u m  C ollecti o n ( C o h ort A o nl y) (Ta ble  1 1 -2 ) (pre -d ose, 
ma y n ot be p erf or me d if d o ne wit hi n 1  da y pri or t o C 1 D 1)  
Bl o o d c he mistries a n d L F Ts  (pre -d ose, ma y n ot b e perf or me d if d o ne wit hi n  7  da ys 
pri or t o C 1 D 1)  
C B C wit h differe ntial a n d platelets (pre -d ose, ma y n ot be perf or me d if d o ne wit hi n 
7  da ys pri or t o C 1 D 1)  
Ser u m pre g na n c y test  (pre -d ose, ma y n ot be perf or me d if d o ne wit hi n 7 da ys pri or t o 
C 1 D 1)  
Trast uz u ma b a d mi nistrati o n  (f or C o h orts A, B , a n d s u bjects fr o m C o h ort C w h o 
cr oss o ver t o d ual c o m bi nati o n  t hera p y)*  
T ucati ni b a d mi nistrati o n a n d dis pe nsati o n  (all c o h orts )*  
*  St u d y dr u gs ma y be a d mi nistere d i n a n y or der a n d ca n be gi ve n si m ulta n e o usl y   
6. 3. 2  C y cl e 1 D a y s 8  & 1 5 ( ± 3 d a y s ) 
Bl o o d c he mistr y  a n d L F Ts    
C B C wit h differe ntial a n d platelets   
E Q -5 D -5 L q u esti o n naire  ( C o h orts B a n d C o nl y) 
E O R T C Q L Q -C 3 0 q uesti o n naire  ( C o h orts B a n d C o nl y) 
C o nc o mita nt me dicati o ns  
A Es  
6. 3. 3  C y cl e 2 ( a n d All S u b s e q u e nt C y cl e s) D a y 1  ( ±3 d a y s)  
P h ysical E x a mi nati o n  
Vital Si g ns  (wei g ht, b o d y te m perat ur e, heart  rate, s yst olic a n d diast olic bl o o d 
press ure, p ulse, a n d o x y g e n sat urati o n ) 
Dr u g Diar y Re vi e w  
E C O G  P S  
C o nc o mita nt me dicati o ns  
A Es  
Bl o o d c he mistr ies a n d C B C wit h differe ntial a n d platelets  
Ser u m β -H C G  pre g n a nc y test f or fe mal es of c hild beari n g p ote ntial  
P K sa m ples f or C o h orts B a n d C o nl y ( pre-d ose C ycles 2, 3, 4, 5, & 6 a n d p ost -d ose 
C ycle 3) ( Ta bl e 1 1 -3 ) 
O nl y o n C ycles 2, 3 , a n d 4; a n d e ver y 3 c ycles t hereaft er 
○ 
E Q -5 D -5 L q u esti o n naire  ( C o h orts B a n d C o nl y) 
○ 
E O R T C Q L Q -C 3 0 q uesti o n naire  ( C o h orts B a n d C o nl y) 
Bi o mar ker Plas ma a n d S er u m c ollecti o ns (f or C o h ort A o nl y) at  C ycl e 4 a n d e ver y 3 
c ycles t hereaft er (i.e., C yc les 4, 7, 1 0, etc.) (Ta ble 1 1 -2 ) 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 3  of 1 7 0  
Trast uz u ma b a d mi nistrati o n  ( C o h orts A, B, a n d s ubjects fr o m C o h ort C w h o 
cr oss o ver t o d ual c o m bi nati o n t hera p y) *  
T ucati ni b a d mi nistrati o n a n d dis pe nsati o n  (all c o h orts) *  
* St u d y dr u gs ma y be a d mi nistere d i n a n y or der a n d ca n be gi ve n si m ulta n e o usl y.  
6. 3. 4  C y cl e 2 ( a n d All S u b s e q u e nt C y cl e s) E v er y 6 or 9 w e e k s ( ±7  d a y s)  
Ra di ol o gical Dise ase  A ss ess me nt 
○ 
C o h ort A: e ver y 9 w ee ks ( ± 1 4 da ys) d uri n g treat me nt; e ver y 1 2 wee ks after 
1 2  m o nt hs of tr eat me nt if cli nicall y sta ble ( ±  7 da ys). S u bjects w h o  disc o nti n ue f or 
reas o ns ot her t h a n d oc u me nte d P D will c o nti n ue t o ha ve disease assess me nts 
a p pr o xi matel y e ver y 9 wee ks u ntil disease pr o gressi o n, deat h, wit h dra wal of 
c o nse nt, st u d y cl os ure, or alter nati ve t hera p y.  
○ 
C o h orts B a n d C: e ver y 6 wee ks ( ± 7 d a ys) d uri n g treat me nt; e ver y 1 2 wee ks after 
1 2  m o nt hs of tr eat me nt if cli nicall y sta ble ( ± 7 da ys).  S u bjects w h o  disc o nti n ue f or 
reas o ns ot her t h a n d oc u me nte d P D will c o nti n ue t o ha ve disease assess me nts 
a p pr o xi matel y e v er y 9 wee ks u ntil disease pr o gressi o n, deat h, wit h dra wal of 
c o nse nt, st u d y cl os ure, or alter nati ve t hera p y.  
Bl o o d T u m or Mar ker ( C E A)  
o  
C E A assa ys will be perf or me d  o n t he sa me sc h e d ule as ra di o gra p hic sca n ni n g . 
6. 3. 5  E v er y 1 2 w e e k s ( ± 1 4  d a y s)  
•  E C H O/ M U G A  
6. 3. 6  S u bj e ct s Cr o s si n g -O v er t o D o u bl et R e gi m e n  
S u bjects ra n d o mize d t o t ucati ni b m o n ot hera p y (C o h ort C ) will be all o we d t o cr oss o ver a n d 
recei v e d o u blet t ucati ni b + trast uz u ma b t hera p y, if t he y e x perie nce ra di o gra p hic pr o gressi o n 
at a n y ti me p oi nt (as deter mi ne d b y i n vesti gat or assess me nt usi n g R E CI S T 1. 1), or if t he y 
ha ve n ot ac hi e ve d a P R or C R  b y t he W ee k 1 2 ass ess me nt.  
•  S u b mit Re q uest f or A p pr o val t o C ha n ge Treat me nt Re gi me n f or m t o s p o ns or  
•  Wit h s p o ns or’s a p pr o val, access ra n d o mizati o n s yste m t o re gister t he c h a n ge i n 
treat me nt assi g n me nt 
I m me diat el y pr ocee d wit h ne w st u d y tr eat me nt r e gi me n a n d c o nti n ue t o f oll o w st u d y 
pr oce d ures o utli ne d i n  Secti o n  6. 3. 3 . 
I n v esti gat ors m ust d o a ne w baseli ne R E CI S T ass ess me nt o n  C o h ort C s u bjects w h o 
cr oss o ver fr o m m o n ot hera p y t o d o u blet t hera p y. I n vesti gat ors m ust use t he R E CI S T sca ns 
t hat were us e d t o q ualif y t he s u bject f or cr ossi n g o ver (W ee k 1 2 sca ns or first P D sca n s as 
a p plica ble) t o esta blis h a ne w baseli ne. I n vesti gat ors m ust select tar get a n d n o n -tar get lesi o ns 
per R E CI S T v 1. 1 g ui da n ce. Selecti o n of tar get a n d n o n -tar get lesi o ns will be base d s olel y 
u p o n t he cr oss o ver s ca ns, a n d , t heref ore, ma y i n cl u de ne w lesi o ns t hat a p p eare d w hile t he 
s u bject was o n m o n ot hera p y. Est a blis hi n g a n e w baseli ne at t he ti me of cr oss o ver will all o w 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 4  of 1 7 0  
t hese s u bjects t o ac hie v e a n o bjecti ve res p o nse ( C R/ PR) per R E CI S T w hile o n d o u blet  
t hera p y, w hic h is r elati ve t o t he ne w baseli ne. S u bjects  w h o  ha ve ra di o gra p hic pr o gressi ve 
disease w hile o n d o u blet  t hera p y per t he ne w baseli ne s h o ul d disc o nti n ue t hera p y u nless t he 
i n vesti gat or b elie ves t he s u bject has si g ns of cli nical be nefit, as descri be d i n S ecti o n 7. 7. 7. 1 .    
6. 4  E n d of Tr e at m e nt Vi sit ( 3 0 t o 3 7 d a y s Aft er L a st D o s e of St u d y D r u g) 
E O T  visits s h o ul d occ ur 3 0 t o 3 7 da ys after t he l ast d ose of st u d y dr u g u nl ess dela ye d d u e t o 
a n A E. 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 ys. 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 her a p y. 
If E O T e v al uati o ns are c o m plete d bef ore 3 0 da ys after t he l ast st u d y treat me nt, t he s u bject 
will be c o ntacte d 3 0 t o 3 7 da ys f oll o wi n g t he l ast treat me nt t o assess f or A Es .  
•  P h ysical E x a mi nati o n  
•  Vital Si g ns  (wei g ht, b o d y te m perat ur e, heart  rate, s yst olic a n d diast olic bl o o d 
press ure, p ulse, a n d o x y g e n sat urati o n ) 
•  E C O G  P S   
•  C B C wit h differe ntial a n d platelets  
•  Ser u m bl o o d c he mistries  
•  C oa g ulati o n tests  
•  E C H O/ M U G A ( ma y n ot be perf or me d if d o ne o n -treat me nt 1 2 wee ks pre vi o usl y) 
•  Ra di ol o gical Dise ase Ass es s me nts  
•  Bl o o d T u m or Mar ker ( C E A ) 
•  E Q -5 D -5 L  ( C o h orts B a n d C o nl y) 
•  E O R T C Q L Q -C 3 0 q uesti o n naire  ( C o h orts B a n d C o nl y) 
•  C o nc o mita nt me dicati o ns  
•  A Es  
•  Bl o o d sa m ples f or bi o mar ker a n al ys es: 
o  C o h ort A: Bi o mar ker Plas ma a n d Ser u m  (Ta bl e 1 1 -2 ) 
o  C o h ort s B  a n d C: Bi o mar ker Plas ma  (Ta bl e 1 1 -3 ) 
6. 5  F oll o w -u p  
•  F urt her a nti -ca n cer t hera p y a n d  s ur vi val (ev er y 1 2 wee ks ± 1 4 da ys)  
•  If a s u bject disc o nti n ues trast uz u ma b f or a n y reas o n, assess me nt of car diac f u ncti o n 
( E C H O or M U G A) m ust be c o n d ucte d e ver y 6 m o nt hs ( ± 1 4 da ys) u ntil 2 4 m o nt hs 
fr o m t he last a d mi nistrati o n of trast uz u ma b 
6. 6  E n d of St u d y/ E n d of F oll o w -u p  
T he date t he s u bject met criteria f or st u d y dis c 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.  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 5  of 1 7 0  
6. 7  P o st -St u d y C ar e  
At t he ti me of st u d y cl os ure, s u bjects w h o are still recei vi n g tr eat me nt  will re vert t o 
p h ysicia n care. W he n a p plica ble, t he S p o ns or will assist wit h p ost -trial access t o t ucati ni b 
a n d trast uz u ma b . 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 6  of 1 7 0  
7  
S T U D Y A S S E S S M E N T S  
7. 1  S cr e e ni n g/ B a s eli n e A s s e s s m e nt s  
Scree ni n g / Baseli ne ass ess me nts will be c o n d ucte d t o esta blis h st u d y b aseli ne stat us a n d 
deter mi ne st u d y eli gi bilit y. O nl y s u bjects w h o meet all i ncl usi o n a n d e x cl usi o n criteria 
s pecifie d i n Secti o n 4. 1  a n d Secti o n  4. 2  will be e nr olle d i n t his st u d y.  
T u m or tiss ue m ust be s u b mitte d t o t he s p o ns or -desi g nate d ce ntr al  la b orat or y f or 
c o nfir mat or y H E R 2 testi n g  ( b y a n F D A-a p pr o ve d or C E -mar ke d H E R 2 I H C test f oll o wi n g 
t he pac ka ge i nsert’s i nter pretati o nal ma n ual f or breast ca n cer). Co nfir mat or y H E R 2 testi n g 
ma y b e perf or me d o n arc hi val tiss ue or a ne wl y -o btai ne d bas eli ne bi o ps y of a n accessi ble 
t u m or lesi o n t hat has n ot bee n pre vi o usl y irra diate d. 
S u bject  me dical hist or y i ncl u des a t h or o u g h re vie w of si g nifi ca nt past me dical hist or y, 
c urre nt c o n diti o ns, a n y tr eat me nt f or pri or mali g n a 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 ysic al e x a m, hei g ht, vital si g ns, C T wit h c o ntr ast/ M RI sca n f or b aseli ne res p o nse 
effic ac y ass ess me nt, bi o ps y c ollecti o n, C B C wit h differe ntial a n d platelets, u ri nal ysis, 
E C H O / M U G A, He p atitis B a n d C scree ni n g, bi o m ar ker s er u m c h e mistr y p a nel, c oa g ulati o n 
tests i ncl u di n g, I N R, P T, a n d a P T T, E C O G P S , E CG a n d ser u m pre g n a nc y test (f or fe m ales 
of c hil d beari n g p ote ntial) are re q uire d f or all s u bjects at scree ni n g a n d/ or baseli ne as 
descri be d i n  Secti o n  6. 2  a n d A P P E N DI X A . 
Tiss ue  C ollecti o n  
T he a vaila bilit y of arc hi v al tiss ue is t o be c o nfir me d  at pre -scree ni n g or scree ni n g. If arc hi val 
tiss ue bl oc ks t hat meet re q uire me nts are n ot a vaila ble, a fres h t u m or bi o ps y m ust be o btai ne d 
a n d s u b mitte d f or H E R 2 testi n g . F or fres h ti ss ue, core nee dle or e x cisi o nal bi o ps y is 
preferre d.  If neit her is p ossi ble, disc uss wit h s p o ns or w het her bi o ps y o btai n e d via alter nati v e 
met h o ds ma y be a p pr o pri ate.  
7. 2  R e s p o n s e/ Effi c a c y A s s e s s m e nt s  
T he deter mi nati o n of a ntit u m or acti vit y will be bas e d o n c o nfir me d o bj ecti v e res p o nse 
assess me nts ma de b y a B I C R acc or di n g t o t he R E CI S T 1. 1 (Eise n ha uer 2 0 0 9 ). T reat me nt 
decisi o ns will be base d o n o bjecti ve res p o nse assess me nts ma de b y t he i n v esti gat or. Cli nical 
res p o nse of C R, P R, S D, or P D will be deter mi ne d at eac h assess me nt. I n a d diti o n, i ma ges 
will be c ollecte d b y a n i n de pe n de nt r e vie w facilit y.  
Meas u res of a ntica n cer acti vit y will be assesse d b y eit her C T wit h c o ntrast or M RI s ca ns at 
pr ot oc ol -s pecifi e d ti me p oi nts. S u bjects  m ust be e v al u ate d usi n g t he s a me i m a gi n g 
met h o d t hr o u g h o ut t he st u d y f or effic ac y assess me nts.   
F or C o h ort A, r es p o nses ( C R or P R) will be c o nfir me d at t he ne xt re-sta gi n g ti me p oi nt, 
9  wee ks ( ± 1 4 d a ys) aft er first d oc u me ntati o n of res p o nse. F or C o h orts B a n d C, res p o nses 
( C R or P R) will be c o nfir me d at t he ne xt re-sta gi n g ti me p oi nt, 6 wee ks ( ± 7 da ys) after first 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 7  of 1 7 0  
d o c u me ntati o n of res p o nse . T u m or i ma gi n g s h o ul d als o be perf or me d w he ne ver disease 
pr o gressi o n is s us pecte d.  
S u bjects w h o  disc o nti n ue f or reas o ns ot her t ha n d o c u me nte d P D will c o nti n ue t o ha ve 
disease assess me nts ( C T/ M RI sca ns) a p pr o xi matel y e v er y 9 wee ks u n til disease pr o gressi o n, 
deat h, wit h dra w al of c o nse nt, st u d y cl os ur e,  or  alt er nati ve t hera p y (see A P P E N DI X A ). 
H o we ver, s u bjects wit h d oc u me nte d P D w h o  ha v e c o nti n ue d o n st u d y tr eat me nt f or cli nical 
be nefit will n ot re q uire c o nti n ue d disease assess m e nts after disc o nti n ui n g treat me nt . 
S u bjects ’ cli nical data m ust be a vaila ble f or C R F s o urce verificati o n. C o pies of t u m or i ma ges 
m ust be ma de a vaila ble f or re vie w b y t h e s p o ns or ( or its desi g n ee), u p o n re q uest.  
7. 2. 1  S c h e d ul e of E v e nt s  
F or t he p ur p os es of t his st u d y, s u bjects s h o ul d be re-e val u ate d as f oll o ws:  
C o h ort A: at scree ni n g/ b aseli ne, e ver y 9 wee ks ( ± 1 4 da ys) d uri n g treat me nt (e ver y 1 2 wee ks 
[ ± 7 da ys] after 1 2  m o n t hs of treat me nt, if t he s u bj ect is cli nicall y sta bl e), a n d at t he E O T 
visit . S u bjects w h o  disc o nti n ue f or reas o ns ot her t ha n d oc u me nte d P D will c o nti n ue t o ha ve 
disease assess me nts a p pr o xi matel y e v er y 9 wee ks u ntil P D , deat h, wit h dra wal of c o nse nt, 
st u d y cl os ur e, or alter nati ve t hera p y.   
C o h ort s B a n d C: at scree ni n g/ bas eli ne, e ver y 6 wee ks ( ± 7 da ys) d uri n g treat me nt (e ver y 
1 2  wee ks [ ± 7 da ys] aft er 1 2  m o nt hs of treat me nt , if t he s u bject is cli nicall y sta ble), a n d at t he 
E O T visit . S u bjects  w h o  disc o nti n ue f or reas o ns ot her t ha n d oc u me nte d P D  will c o nti n ue t o 
ha ve diseas e assess me nts e ver y 9  wee ks u ntil P D, deat h, wit h dra wal of c o nse nt, st u d y 
cl os ure, or  alter nati ve t hera p y.  
Ra di o gra p hic  diseas e  ass ess me nts f or s u bjects wit h d oc u me nte d P D w h o h a ve c o nti n ue d o n 
st u d y treat me nt f or cli nic al be nefit m ust c o nti n ue per t he pr ot oc ol d efi ne d assess me nt 
sc he d ule; co nti n ue d dise ase assess me nts will n ot be re q uir e d after treat me nt is disc o nti n ue d .  
7. 2. 2  D efi nit i o n s of M e a s ur a bl e a n d N o n-M e a s ur a bl e Di s e a s e  
1.  Meas ura ble Diseas e  
•  A n o n -n o dal lesi o n is c o nsi dere d meas ura ble if its l o n gest dia meter ca n b e acc uratel y 
meas ure d as 2. 0 c m wit h c hest x -ra y, or as ≥1. 0 c m wit h c o m p ute d t o m o gra p h y 
(C T ) sca n, C T c o m p o ne nt of a p ositr o n e missi o n t o m o gra p h y ( P E T)/ C T, or M RI.  
•  A s u perficial n o n -n o dal l esi o n is meas ura ble if its l o n gest dia meter is ≥1. 0  c m i n 
dia meter as assesse d usi n g cali pers (e. g. s ki n n o d ules) or i ma gi n g. I n t he case of s ki n 
lesi o ns, d oc u me ntati o n b y c ol or p h ot ogra p h y, i ncl u di n g a r uler t o esti mate t he size of 
t he lesi o n, is rec o m me n d e d 
•  A mali g na nt l y m p h n o de is c o nsi dere d meas ura ble if its s h ort a xis is ≥1. 5  c m w he n 
assesse d b y C T sca n ( C T sca n slice t hic k ness r ec o m me n de d t o be ≤5 m m).  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 8  of 1 7 0  
● 
T u m or lesi o ns i n a pre vi o usl y irra diate d area are n ot c o nsi dere d meas ura bl e disease.  
2.  N o n -Meas ur a ble Dise ase  
•  All ot her lesi o ns ( or sites of disease) are c o nsi dere d n o n -meas ura ble diseas e, 
i ncl u di n g pat h ol o gical n o des (t h ose wit h a s h ort a xis ≥1. 0 t o < 1. 5 c m). B o ne lesi o ns, 
lept o me ni n geal disease, ascites, ple ural/ pericar dial eff usi o ns, l y m p ha n gitis 
c utis/ p ul m o nis, i nfla m mat or y breast diseas e, a n d a b d o mi nal masses ( n ot f oll o we d b y 
C T or M RI), are c o nsi dere d as n o n -meas ura ble as well.  
● 
N O T E: ‘ C ystic lesi o ns’ t h o u g ht t o re prese nt c ysti c metastases ca n be c o nsi dere d as 
meas ura ble l esi o ns, if t he y meet t he defi niti o n of meas ura bilit y d escri b e d a b o ve. 
H o we ver, if n o n -c ystic lesi o ns are pres e nt i n t he sa me s u bject, t hese are preferre d f or 
selecti o n as tar get lesi o ns. I n a d diti o n, l y m p h n o des t hat ha ve a s h ort a xis < 1. 0 c m are 
c o nsi dere d n o n -pat h ol o gi cal (i.e., n or m al) a n d s h o ul d n ot be rec or de d or f oll o we d.  
7. 2. 3  G ui d eli n e s f or E v al u ati o n of M e a s ur a bl e Di s e a s e  
1.  Meas ure me nt M et h o ds  
•  All meas ure me nts s h o ul d be rec or de d i n metric n otati o n (i.e., d eci mal fracti o ns of 
ce nti meters) usi n g a r uler or cali pers.  
•  T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue m ust be use d t o c haract erize 
eac h i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g f oll o w -u p. F or s u bjects 
ha vi n g o nl y lesi o ns meas uri n g ≥1 c m t o < 2 c m m ust use C T i ma gi n g f or b ot h pre - 
a n d p ost -treat me nt t u m or assess me nts. 
•  I ma gi n g-base d e val uati o n is preferre d t o e val uati o n b y cli nical e xa mi nati o n w he n 
b ot h met h o ds ha ve bee n use d at t he sa me e val uati o n t o assess t he a ntit u m or effect of 
a treat me nt.  
2.  Acce pt a ble M o dalities f or Meas ura ble Dise ase  
•  C o n ve nti o nal C T a n d M RI  
● 
T his g ui deli ne has d efi ne d meas ura bilit y of lesi o ns o n C T sca n base d o n t h e 
ass u m pti o n t hat C T slice t hic k ness is ≤5 m m. If C T sca ns ha ve slice t hic k n ess 
> 5  m m, t he mi ni m u m size f or a m eas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness. 
● 
As wit h C T, if a n M RI is perf or me d, t h e tec h nical s pecificati o ns of t he s ca n ni n g 
se q ue nces us e d s h o ul d be o pti mize d f or t he e val u ati o n of t he t y p e a n d site of disease. 
T he lesi o ns s h o ul d be me as u re d o n t he s a me p ulse se q ue nce. I deall y, t he s a me t y pe of 
sca n ner s h o ul d b e use d a n d t he i ma ge ac q uisiti o n pr ot oc ol s h o ul d be f oll o we d as 
cl osel y as p ossi ble t o pri or sca ns. B o d y sca ns s h o ul d be perf or m e d wit h br eat h -h ol d 
sca n ni n g t ec h ni q ues, if p ossi ble. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 6 9  of 1 7 0  
•  P E T -C T  
● 
If t he site ca n d o c u me nt t hat t he C T perf or m e d as part of a P E T-C T is of i d e ntical 
dia g n ostic q ualit y t o a di a g n ostic C T ( wit h I V a n d oral c o ntrast), t h e n t he C T p orti o n 
of t he P E T -C T ca n b e use d f or R E CI S T meas ure me nts a n d ca n be us e d 
i nterc ha n gea bl y wit h c o n ve nti o nal C T i n acc uratel y meas uri n g ca n cer l esi o ns o ver 
ti me. 
3.  Meas ure me nt at F oll o w -u p E val uati o n  
I n t he cas e of S D , f oll o w-u p meas ure m e nts m ust ha ve met t he S D criteria at least o nce 
after st u d y e ntr y at a mi ni m u m i nter val of 9  wee ks (see Secti o n 7. 2. 4. 3 ). 
7. 2. 4  M e a s ur e m e nt of Eff e ct  
T ar get Lesi o ns & T ar get L y m p h N o des  
•  Meas ura ble l esi o ns (as d efi ne d i n Secti o n 7. 2. 2 ) u p t o a ma xi m u m of 5 lesi o ns, 
re pres e ntati ve of all i n v ol ve d or ga ns, s h o ul d be i d e ntifie d as “ T ar get Lesi o ns” a n d 
rec or de d a n d me as ure d at baseli ne. T hese lesi o ns ca n be n o n-n o dal or n o dal ( see 
Secti o n 7. 2. 2 ), w here ≤2 lesi o ns are fr o m t he s a me or ga n a n d ≤2 mali g na nt n o dal 
lesi o ns are sele cte d. N O T E: If fe w er t ha n 5  t ar get lesi o ns a n d tar get l y m p h n o des are 
i de ntifie d (as t here ofte n will be), t here is n o reas o n t o perf or m a d diti o nal st u dies 
be y o n d t h os e s pecifie d i n t he pr ot oc ol t o disc o ver ne w lesi o ns.  
•  Tar get lesi o ns a n d tar get l y m p h n o des s h o ul d be s electe d o n t he b asis of t heir size, be 
re pres e ntati ve of all i n v ol ve d sites of disease, b ut i n a d diti o n s h o ul d be t h ose t hat le n d 
t he msel ves t o re pr o d uci ble re peate d meas ure me nts. It ma y b e t he case t hat, o n 
occasi o n, t he lar gest lesi o n ( or mali g n a nt l y m p h n o de) d oes n ot le n d itself t o 
re pr o d uci ble m eas ur e me nts i n w hic h circ u msta nce t he ne xt lar gest lesi o n ( or 
mali g na nt l y m p h n o de) w hic h ca n b e meas ure d re pr o d uci bl y s h o ul d be selecte d.  
•  Baseli ne su m of d i a meters ( B S D): A s u m of t he l o n gest dia met er f or all tar get lesi o ns 
pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o des will be calc ulat e d a n d 
re p orte d as t he baseli ne s u m of dia meters ( B S D). T he B S D will be use d as refere nce 
t o f urt her c h aracteriz e a n y o bjecti ve t u m or res p o nse i n t he meas ura bl e di me nsi o n of 
t he disease. 
•  P ost -Baseli ne S u m of t he Dia meters ( P B S D): A s u m of t he l o n gest dia m eter f or all 
tar get lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o d es will be 
calc ulate d a n d re p orte d as t he P B S D. If t he ra di ol o gist is a ble t o p r o vi de a n act ual 
meas ure f or t he tar get lesi o n ( or tar get l y m p h n o de), t hat s h o ul d be rec or de d, e ve n if 
it is < 0. 5 c m. If t h e tar get lesi o n ( or tar get l y m p h n o de) is belie ve d t o be prese nt a n d 
is fai ntl y see n b ut t o o s m all t o meas ure, a d efa ult val ue of 0.5 c m s h o ul d b e assi g n e d. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 0  of 1 7 0  
If it is t he o pi ni o n of t he ra di ol o gist t hat t he tar get lesi o n or tar get l y m p h n o de has 
li kel y disa p peare d, t h e meas ure m e nt s h o ul d be rec or de d as 0 c m. 
•  T he mi ni m u m s u m of t he dia meters ( M S D) is t he mi ni m u m of t he B S D a n d t he 
P B S D.  
N o n -T ar get Lesi o ns & N o n -T ar get L y m p h N o des  
N o n -meas ur a ble sites of disease ( see Secti o n 7. 2. 2 ) are classifie d as n o n- tar get lesi o ns or 
n o n -tar get ly m p h n o des a n d s h o ul d als o be rec or de d at baseli ne. T hes e lesi o ns a n d l y m p h 
n o des s h o ul d be f oll o we d i n acc or d a nce wit h Secti o n 7. 2. 4. 2 . 
7. 2. 4. 1  E v al u ati o n of  T ar g et L e si o n s  
All tar get lesi o ns a n d tar get l y m p h n o des f oll o we d b y C T/ M RI/ P E T -C T/ C hest 
X -ra y/ p h ysical e x a mi nati o n m ust be meas ure d o n re-e v al uati o n at e val u ati o n ti mes s pecifie d 
i n Secti o n 7. 2. 1 . S pecificall y, a c ha n ge i n o bjecti ve stat us t o eit her a P R or C R ca n n ot be 
d o ne wit h o ut re -me as uri n g tar get lesi o ns a n d tar get l y m p h n o des.  
● 
C R : All of t he f oll o wi n g m ust be tr ue: 
○ 
Disa p peara nce of all tar get l esi o ns. 
○ 
Eac h tar get l y m p h n o d e m ust ha ve re d ucti o n i n s h ort a xis t o < 1. 0 c m.  
● 
P R : At least a 3 0 % decrease i n P B S D (s u m of t he l o n gest dia meter f or all tar get 
lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o des at c urre nt 
e val uati o n) ta ki n g as r efere nce t h e B S D (see Secti o n 7. 2. 4 ). 
● 
P D: At least o ne of t he f oll o wi n g m ust be tr ue:  
○ 
At least o ne ne w mali g na nt lesi o n, w hic h als o i ncl u des a n y l y m p h n o d e  t hat was 
n or mal at baseli ne ( < 1. 0 c m s h ort a xis) a n d i ncrease d t o ≥1. 0 c m s h ort a xis d uri n g 
f oll o w-u p.  
○ 
At least a 2 0 % i ncreas e i n P B S D (s u m of t he l o n gest dia meter f or all tar get 
lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o des at c urre nt 
e val uati o n) ta ki n g as r efere nce t h e M S D ( see Secti o n 7. 2. 4 ). I n a d diti o n, t he 
P B S D m ust als o de m o nstrate a n a bs ol ute i ncrease o f at least 0. 5 c m fr o m t he 
M S D.  
● 
S D:  Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncreas e t o q ualif y 
f or P D ta ki n g as refere nce t he M S D. 
7. 2. 4. 2  E v al u ati o n of N o n -T ar g et L e si o n s & N o n -T ar g et L y m p h N o d e s  
N o n -tar get lesi o ns a n d n o n-tar get l y m p h n o des s h o ul d be e val uate d at eac h assess me nt, 
es peciall y i n t he case of first res p o nse or c o nfir mati o n of res p o nse. I n sel ecte d circ u msta nces, 
certai n n o n -t ar get or ga ns ma y b e e val u ate d less fre q ue ntl y. F or e x a m ple, b o ne sca ns ma y 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 1  of 1 7 0  
nee d t o be re peat e d o nl y w he n c o m plete res p o nse is i de ntifie d i n tar get disease or w h e n 
pr o gressi o n i n b o ne is s us pecte d.  
● 
C R : All of t he f oll o wi n g m ust be tr ue: 
○ 
Disa p pear a nce of all n o n -tar get lesi o ns. 
○ 
Eac h n o n -tar get l y m p h n o de m ust ha ve a re d ucti o n i n s h ort a xis t o < 1. 0 c m. 
● 
N o n -C R/ N o n -P D: Per siste nce of o ne or m ore n o n-tar get lesi o ns or n o n-tar get l y m p h 
n o des.  
● 
P D : At least o ne of t he f oll o wi n g m ust be tr ue: 
○ 
At least o ne ne w mali g na nt lesi o n, w hic h als o i ncl u des a n y l y m p h n o d e t hat was 
n or mal at baseli ne ( < 1. 0 c m s h ort a xis) a n d i ncrease d t o ≥1. 0 c m s h ort a xis d uri n g 
f oll o w-u p.  
○ 
U ne q ui v ocal pr o gressi o n of e xisti n g n o n -tar get lesi o ns a n d n o n-tar get l y m p h 
n o des. ( N O T E: U n e q ui v ocal pr o gressi o n s h o ul d n ot n or mall y tr u m p tar get lesi o n 
a n d tar get l y m p h n o de st at us. It m ust be re pres e nt ati ve of o veral l disease st at us 
c ha n ge.)  
7. 2. 4. 3  O v er all O bj e cti v e St at u s  
T he o verall o bjecti ve stat us f or a n e v al uati o n is deter mi ne d b y c o m bi ni n g t he s u bject’s stat us 
o n tar get lesi o ns, tar get l y m p h n o des, n o n -t ar get l esi o ns, n o n-tar get l y m p h n o des, a n d ne w 
disease as d efi ne d i n t he f oll o wi n g ta bles: 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T u cati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 2  of 1 7 0  
T a bl e 7 -1 : 
E v al u ati o n of o v er a ll o bj e cti v e st at u s 
T ar get Lesi o ns &  
T ar get L y m p h N o des  
N o n -T ar get Lesi o ns  &  
N o n -T ar get L y m p h  
N o des  
Ne w  
Sites of Disease  
O verall O bj ecti ve 
Stat us  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ N o n -P D  
N o  
P R  
P R  
C R  
N o n -C R/ N o n -P D  
N o  
P R  
C R/ P R  
N ot All E val uate d a 
N o  
P R b 
S D  
C R  
N o n -C R/ N o n -P D  
N ot All E val uate d a 
N o  
S D  
N ot all E val uate d  
C R  
N o n -C R/ N o n -P D  
N ot All E val uate d a 
N o  
N ot E val uate d ( N E)  
P D  
U ne q ui v ocal P D  
C R  
N o n -C R/ N o n -P D  
N ot All E val uate d a 
Yes or N o  
P D  
C R/ P R/ S D/ P D/ N ot all 
E val uate d  
U ne q ui v ocal P D  
Yes or N o  
P D  
C R/ P R/ S D/ P D/ N ot all 
E val uate d  
C R  
N o n -C R/ N o n -P D  
N ot All E val uate d a 
Yes  
P D  
a 
See Secti o n 7. 2. 4. 1  
N O T E: T his st u d y uses t h e pr ot o c ol R E CI S T 1. 1 te m plate date d 2/ 1 6/ 2 0 1 1. F or data c ollecti o n a n d a nal ysis p ur p oses t h e 
o bjecti ve stat us c ha n ge d fr o m S D t o P R i n t h e pr ot oc ol R E CI S T 1. 1 te m plate  as of 2/ 1 6/ 2 0 1 1 a n d t o matc h R E CI S T 1. 1 
re q uire me nts. 
7. 3  P h ar m a c o ki n eti c A s s e s s m e nt s  
I n s u bjects ra n d o mize d t o C o h orts B or C, P K ass ess me nts of tr o u g h dr u g l e vels will be  
perf or me d o n Da y 1 of C ycl es 2 t o 6 pri or t o a d mi nistrati o n of t ucati ni b. O n Da y 1 of 
C ycle  3, P K assess me nts of pea k le vels of t ucati ni b dr u g le vels will be perf or me d 1  t o 4 
h o urs after a d mi nistrati o n of t ucati ni b (Ta ble 1 1 -3 ).  
Tr o u g h P K  s a m ples s h o ul d c o nti n ue t o be c ollecte d o n sc he d ule re gar dless of d ose h ol ds or 
i nterr u pti o ns. T he Da y 1 C ycle 3 p ost -d os e sa m ple s h o ul d n ot be c ollecte d d uri n g d ose h ol d 
or i nterr u pti o ns.  
S u bjects i n C o h ort C w h o cr oss o ver t o t he t ucati ni b + trast uz u ma b re gi me n s h o ul d c o nti n ue 
P K assess me nts per Ta bl e 1 1 -3 , if cr oss o v er occ urs pri or t o C ycle 6. If t he cr oss o ver ha p pe ns 
after C ycle 6, n o P K c ollecti o ns are re q uir e d.   
7. 4  Bi o m ar k er St u di e s  
Bi o mar ker assess me nts ma y i ncl u d e t he c o nfir mati o n of H E R 2 sta t us b y I H C, FI S H, a n d 
N G S as well as a n e x pl orat or y assess me nt of H E R 2 m utati o ns or ot her m utati o ns as p ote ntial 
bi o mar kers of res p o nse. H E R 2 stat us will be verifie d b y ce ntral la b orat or y a nal ysis usi n g 
I H C b y a n F D A-a p pr o ve d or C E -mar ke d I H C test f oll o wi ng t he pac ka ge i nsert’s 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 3  of 1 7 0  
i nter pretati o nal ma n ual f or breast c a ncer. Ne xt ge nerati o n D N A s e q ue nce a nal ysis ma y b e 
perf or me d t o i nterr o gate t he m utati o n stat us of a pa nel of o nc o ge nes a n d t u m or s u p press or 
ge n es t hat are ass oci ate 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 p e utics. 
T his assess me nt ma y e na ble t he c orrelati o n of treat me nt o utc o me t o eit her pree xisti n g or 
ac q uire d ca ncer ge ne m utati o ns a n d ma y ulti matel y g ui de or refi n e patie nt selecti o n 
strate gies t o better matc h t ucati ni b re gi mens wit h t u m or ge n ot y p e i n t he f ut ure.  
Sa m pli n g ti me p oi nts  f or b o d y fl ui d bi os peci me ns are liste d i n A P P E N DI X A  (Ta ble 1 1 -2  
a n d Ta ble 1 1 -3 ). 
7. 4. 1  Bi o s p e ci m e n C oll e cti o n  
Bl o o d  a n d bl o o d pr o d uct sa m ples c olle cte d f or t his st u d y are t he f oll o wi n g: 
4.  S ol u ble pr otei n ( bl o o d -base d) bi o mar k ers  
Bl o o d ( platelet p o or pl as ma, ser u m, a n d w hite bl o o d cells [b uff y c oat ]) will be c ollecte d 
as s u m mariz e d i n Ta ble 1 1 -2  a n d Ta ble 1 1 -3 . A nal yses m a y i ncl u de, b ut are n ot li mite d 
t o s ol u ble H G F, c-M E T, E G F, H B E G F, H E R 1 -3, V E G F A -D, Pl G F, V E G F R 2, G A S 6, 
A X L, S D F 1, A n g 2, a n d TI E -2. A d diti o nal bi o mar kers ma y als o b e e x pl ore d usi n g 
m ulti ple x arra y tec h n ol o g y. Fi nal bi o mar ker selecti o n will reflect t he best s cie nce at t he 
ti me of a nal ysis. 
5.  Bi o mar ker Plas ma (M utati o nal a n d Bl o o d N G S ) a na lyses  
Bl o o d ( platelet p o or pl as ma) t o assess t he m olec ul ar pr ofile of ct D N A will be c ollecte d as 
s u m marize d i n Ta ble 1 1 -2  a n d Ta ble 1 1 -3 . A nal ys es ma y i n cl u de, b ut are n ot li mite d t o 
H E R 2 a m plificati o n, E G F R a m plificati o n, B R A F  m utati o ns, a n d e xte n de d K R A S/ N R A S 
testi n g (e x o ns 2, 3, a n d 4). Fi nal bi o mar ker selecti o n will reflect t he b est scie nce at t he 
ti me of a nal ysis. 
7. 4. 2  R et ur n of G e n eti c T e sti n g R e s e ar c h R e s ult s  
Beca use t he res ults ge nerate d b y t he ge n etic testi n g i ncl u de d i n t his secti o n are n ot c urre ntl y 
a ntici pate d t o ha ve cli nical rele va n ce t o t he s u bjects or t heir fa mil y m e m bers, t he ge n etic 
res ults will n ot be discl ose d t o t he s u bjects or t heir p h ysicia ns.  
If at a n y ti me, ge n etic res ults are o btai ne d t hat ma y ha v e cli nical r ele va n ce, I R B/I E C re vie w 
a n d a p pr o val will be s o u g ht re gar di n g t he m ost a p pr o priate ma n ner of discl os ure a n d w het her 
or n ot vali dati o n i n a C LI A -certifie d setti n g will be re q uir e d. S hari n g  of res earc h d ata wit h 
i n di vi d ual s u bjects s h o ul d o nl y occ ur w h e n data ha ve bee n vali date d b y m ulti ple st u dies a n d 
testi n g has bee n d o ne i n C LI A-a p pr o ve d la b orat ories.  
7. 4. 3  P at h ol o g y C o n si d er ati o n s / Ti s s u e Bi o s p e ci m e n s 
S u b missi o n of t he m ost rece ntl y a v aila ble tu m or bl oc k is necessar y  t o s u p p ort H E R 2 
c o nfir mati o n. C o nfir mat or y H E R 2 testi n g will be d o ne i n t he ce ntr al la b orat or y f or I H C 
f oll o wi n g t he pac ka ge i nsert’s i nter pretati o nal ma n ual f or breast ca n cer. A d diti o nall y, t esti n g 
will i ncl u de N G S a n d FI S H f or m ut ati o nal stat us i ncl u di n g b ut n ot li mite d t o H E R 2.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 4  of 1 7 0  
Tiss ue Bi os peci me n S u b missi o n  
F F P E tiss ue bl oc k wit h l ar gest a m o u nt  of i n vasi v e t u m ors fr o m pri mar y t u m ors prese nt pri or 
t o st u d y e ntr y (if a vaila bl e) m ust be s u b mitte d u p o n e nr oll me nt . If n o pri mar y t u m or tiss ue is 
a vaila ble, metastatic bi o psies s h o ul d be use d.  
If t here is n o s uita ble F F P E bl oc k a vaila ble, c o ntact t he Me dical M o nit or.  
Bl oc ks re q ueste d t o acc o m m o date i n di vi d ual s u bject ma na ge me nt will be ret ur ne d pr o m ptl y 
u p o n re q uest.  
Refer t o t he Ce ntr al  La b orat or y Ma n ual f or i nstr ucti o ns o n pre parati o n a n d s u b missi o n of 
tiss ue bi os peci me ns. 
7. 5  Bi o s p e ci m e n R e p o sit or y  
I n t he U S o nl y, f or s u bjects w h o pr o vi de a d diti o n al c o nse nt, re m ai ni n g d e -i de ntifie d u n use d 
bl o o d a n d/ or tiss ue will be retai ne d b y Sea ge n  a n d use d f or f ut ure res earc h, i ncl u di n g b ut n ot 
li mite d t o t he e val uati o n of tar gets f or n o vel t hera pe utic a ge nts, t he bi ol o g y of a nti b o d y-dr u g 
c o nj u gate se nsiti vit y a n d resista nce mec ha nis ms, a n d t he i de ntificati o n of bi o mar kers of 
A D Cs. Bl o o d a n d tiss ue sa m p les d o nate d f or f ut ure res earc h will be ret ai ne d f or a p eri o d of 
u p t o 2 5 years. If a d diti o nal c o nse nt is n ot pr o vi de d, a n y re m ai ni n g bi ol o gical sa m ples will 
be destr o ye d after t h e st u d y has b ee n c o m plete d a n d all a p plica ble re g ulat or y o bli gati o ns 
ha ve bee n met.  
7. 6  P ati e nt -R e p ort e d O ut c o m e s a n d H e alt h E c o n o mi c A s s e s s m e nt s  
P R Os  meas ures will be c o m plete d at pr ot oc ol -s pecifie d ti me p oi nts usi n g t he E O R T C 
Q L Q -C 3 0 . Healt h ec o n o mic assess me nts will be e x pl ore d wit h t he E Q-5 D -5 L i nstr u me nt a n d 
healt h res o ur ce utilizati o n.  E Q -5 D -5 L a n d E O R T C Q L Q -C 3 0 q uesti o n nair es will be 
a d mi nistere d f or C o h orts B a n d C at: pre -d ose C ycle 1 Da y 1 ( C 1 D 1), C 1 D 8, C 1 D 1 5, C 2 D 1, 
C 3 D 1, C 4 D 1, e ver y 3 c ycles t hereafter, u ntil treat me nt disc o nti n uati o n, P D, deat h, t o xicit y, 
wit h dra wal of  c o nse nt or st u d y cl os ur e, a n d at t he E O T.  
7. 7  S af et y A s s e s s m e nt s  
T he assess me nt of s afet 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, vital si g ns, a n d pre g na nc y t esti n g rec or di n g of 
c o nc o mita nt me dicat i o n, a n d meas ure me nts of pr ot oc ol-s pecifie d p h ysic al e x a mi nati o n 
fi n di n gs a n d la b orat or y t ests.  
S afet y of all c o h orts  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.  Peri o dic 
c u m ulati ve data ( A Es a n d la b orat or y res ults) re vi e w meeti n gs will be h el d e ver y 6 m o nt hs. 
T he meeti n gs will pr o vi de a f or u m f or decisi o ns re gar di n g w het h er t o c o nti n ue wit h t he st u d y 
as-is, t o c o nti n ue t he st u d y wit h m o dificati o ns, t o s us pe n d e nr oll me nt, or t o ter mi nate t he 
st u d y. 
T he site pri nci pal i n vesti gat or is r es p o nsi ble f or re p orti n g a n y/all A Es  t o t h e s p o ns or as 
descri be d wit hi n t he pr ot oc ol. Refer t o  Secti o n  7. 7. 1  f or detaile d i nf or mati o n.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 5  of 1 7 0  
7. 7. 1  A d v er s e E v e nt s  
7. 7. 1. 1  D efi niti o n s  
A d verse E ve nt  
Acc or di n g t o t he I nt er nati o nal C o u ncil f or Har m o nisati o n (I C H) E 2 A g ui d eli ne Defi niti o ns 
a n d Sta n dar 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 v esti gati o nal Ne w Dr u g (I N D) Safet y 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 patie nt  or cli nical i n vesti gati o nal s u bject a d mi nistere d a me dici nal pr o d uct 
a n d w hic h d oes n ot necessaril y h a 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 C R F: 
● 
Fr o m t he ti me of i nf or m e d c o nse nt t hr o u g h t he da y pri or t o st u d y Da y 1 , o nl y st u d y 
p r ot oc ol-relat e d A Es s h o ul d be rec or de d. A pr ot oc ol -relat e 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 o ce d ure.  
● 
All me dical c o n diti o ns prese nt or o n g oi n g pre -d os e o n st u d y Da y 1  t hat i ncrease i n 
C T C A E gra de s h oul 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 h at w orse n i n 
se verit y, i ncrease i n fre q ue nc y, bec o me rel ate d t o st u d y dr u g, or w orse n i n a n y ot h er 
wa y b ut d o n ot meet t he t hres h ol d f or i ncreas e i n C T C A E gra de s h o ul d be rec o r de d. 
● 
All A Es (re gar dless of relati o ns hi p t o st u d y dr u g) s h o ul d be rec or de d fr o m st u d y 
Da 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 
Secti o n 7. 7. 1. 3 ). 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 pr ot o c ol 
ma n date d.  
● 
I n ge neral, a n a b n or mal la b orat or y v al ue s h o ul d n ot be rec or de d as an 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 uir es a n 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 n ati 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 l a b orat or y a b n or malit y, t he res ulti n g me dical 
c o n diti o n rat her t ha n t he a b n 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”). 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 6  of 1 7 0  
Seri o us A d verse E ve nts  
A n A E s h o ul d be classifi e 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 s u bj ect 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 hetic all 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 ge d  a n e xisti n g i n patie nt 
h os pitalizati o n. 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 missi o n t o a palliati ve u n it 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 pit alizati 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 nc er or st u d y tar get 
disease nee d n ot be ca pt ure d as S A Es.  
Disa bli n g/  
i nca pacitati n g: 
A n A E t ha t 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 s u bj ect’s a bilit y t o c o n d uct n or mal life f u ncti o ns. 
C o n ge nital a n o mal y or 
birt h defect:  
A n a d verse o u tc o me i n a c hil d or fet us of a s u bj ect e x p ose d t o t he m olec ule or 
stu d y treat me nt re gi me n bef or e c o nce pti o n or d uri n g pre g na nc y.  
Me dicall y 
si g nifica nt/i m p orta 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 j e o par dize d t he 
s u bj ect a n d mi g ht ha ve re q uir e 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 nifi ca nt e ve nt (see Secti o n 7. 7. 1. 2  f or t he defi niti o n of 
p ote ntial DI LI.)  
A d verse E ve nt C h ar a cteristics  
A d verse e ve nt m o nit ori n g a n d re p orti n g is a r o uti ne part of e ver y cli nical trial.  
A E c haracteristics s h o ul d be defi ne d usi n g t he f oll o wi n g criteria:  
a. I d e ntif y t he se verit y gra d e of t he e v e nt ( Secti o n 7. 7. 1. 1 ). 
b.  Deter mi ne if t he A E  is relate d t o t he st u d y i nter ve nti o n (a ge nt, treat me nt or 
pr oce d ure)  
c. Deter mi ne if A E  is seri o us or n o n-seri o us ( Secti o n 7. 7. 1. 1 ).  
d.  Deter mi ne t he a p pr o priat e  ti mefra me a n d mec h a nis m of re p orti n g ( Secti o ns 7. 7. 1. 3  
a n d 7. 7. 1. 4 ).  
A d verse E ve nts of S peci al I nterest  
A d verse E v e nts  of S peci al I nt erest  ( A E SI) are defi ne d b y Sea ge n  as a p ote ntial safet y 
pr o ble m i de ntifie d as a res ult of o n g oi n g safet y 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 SIs M U S T be u n derta ke n at eac h treat me nt e val u ati o n. De vel o p me nt 
of o ne of t hes e A E SIs ( ≥ Gra de 1 u nless ot h er wise n ote d) M U S T be re p orte d i n ter ms of 
C T C A E v 4. 0 3 gra de a n d attri b uti o n.  
T he A E SIs will nee d t o b e re p ort e d t o t he s p o ns or  irres pecti ve of re g ul at or y seri o us ness 
criteria or ca us alit y wit hi n 2 4 h o urs.  
A E SIs f or t his st u d y are:  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 7  of 1 7 0  
1.  P ote ntial dr u g -i n d uc e d li ver i nj ur y 
A n y p ote ntial case of dr u g -i n d uc e d li ver i nj ur y as assesse d b y la b orat or y criteria f or H y’s 
La w will be c o nsi dere d as a pr ot oc ol -defi ne d e v e nt of s pecial i nterest. T h e f oll o wi n g 
la b orat or y a b n or malities defi ne p ote ntial H y’s La w cases:   
A S T or A L T ele v ati o n s t hat are > 3 X U L N wit h c o nc urre nt ele v ati o n ( wit hi n 2 1 da ys of 
A S T a n d/ or A L T ele v ati o ns) of t otal bilir u bi n > 2 X t he U L N, e x ce pt i n s u bjects wit h 
d oc u me nte d Gil bert’s s y n dr o me. Meas ure me nt of c o nj u gate d a n d u n c o nj u gat e d bilir u bi n 
s h o ul d be c o nsi dere d i n c ases 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. 
2.  As y m pt o matic left v e ntric ular s yst olic d ysf u ncti o n  
I n ge neral, a n as y m pt o m atic decli ne i n L V E F lea di n g t o a c h a 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 is c o nsi dere d a n e ve nt of s pecial i nterest a n d m ust be 
re p orte d as an A E  t o t he sp o ns or ≤1 b usi ness da y of disc o ver y of t h e e ve nt.  
A d verse E ve nt Se verit y  
A E se verit y s h o ul d be gra de d usi n g t he N CI C T C A E  v 4. 0 3. T hese criteria are pr o vi d e d i n t he 
st u d y ma n ual. 
A E se verit y a n d s eri o us n ess are assesse d i n de pe n de ntl y. ‘ Se verit y’ c h aract erizes t he i nte nsit y 
of a n A E. ‘ Seri o us’ is a re g ul at 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 (s ee defi niti o n f or S A Es, a b o ve). 
N O T E: A se vere A E, as defi ne d b y t he a b o v e gra di n g scal e, is N O T t he sa me as seri o us A E 
w hic h is defi ne d i n Secti o n  7. 7. 1. 1 . 
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 a n d trast uz u ma b) s h o ul d be 
e val uate d b y t he i n v esti gat or usi n g t he f oll o wi n g criteria:  
Relate d:  
T here is e vi de n ce t o s u g gest a ca us al relati o ns hi p bet wee n t he d r 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 o cc urre n ces of a n e ve nt t hat is n ot c o m m o nl y 
ass ociated 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., t e n d o n r u pt ure)  
U nrelate d:  
A n ot her ca us e 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 ul ati 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  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 8  of 1 7 0  
7. 7. 1. 2  Pr o c e d ur e s f or Eli citi n g a n d R e c or di n g A d v er s e E v e nt s  
I n v esti 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 
s u bject q uesti o ni n g, disc o vere d d uri n g p h ysic al e x a 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 C R F a n d/ or S A E f or m, as a p pr o priate.  
Eliciti n g A d verse E ve nts  
A n o pe n -e n d e d or n o n -d irecte 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 C R F:  
•  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 tr eat 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 y m pt o ms. Gr o u pi n g of s y m pt o ms i nt o a dia g n osis sh o ul d o nl y b e d o ne if eac h c o m p o ne nt 
si g n a n d/ or s y m 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 dic al te xt b o o ks. If a n y as p ect 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, r e p ort t he i n di v i d ual s y m pt o m as a se parate a d v erse e ve nt. 
I m p ort a nt e x ce 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 dr u g. R ec or d eac h si g n or s y 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 u r wit h a gi ve n i nf usi o n-relate d e v e nt, eac h si g n or s y m pt o m 
s h o ul d be rec or de d se p aratel y wit h its le vel of se v erit y. 
Rec or di n g Seri o us A d verse E ve nts  
F or S A Es, rec or d t he e ve nt(s) o n b ot h t he C R F a n d a n S A E f or m.  
T he f oll o wi n g s h o ul d be c o nsi dere d w he n re c 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 v e 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 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 gic al or dia g n ostic pr oce d ure s h o ul d b e 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 n arrati ve as part of t he acti o n ta ke n i n 
res p o nse t o t he ill ness. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 7 9  of 1 7 0  
Pr o g ressi 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 d erl yi n g mali g na n c y is bei n g ass esse 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 t er 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 ot be use d t o 
descri be a n A E or S A E.  S y m pt o mati c cli nical det eri orati o n d ue t o diseas e pr o gressi o n as 
deter mi ne d b y t he i n vesti gat or will n o t be re p orte d as 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 b e re p orte d as A Es or S A Es if t he s y m pt o m ca n n ot be 
deter mi ne d as e x cl usi vel y d ue t o p r o gressi o n of t he u n derl yi n g mali g n a nc y or d oes n ot fit t he 
e x pecte d patter n of pr o gressi o n f or t he diseas e u n der st u d y.  I n a d diti o n, c o m plicati o ns fr o m 
pr o gressi o n of t he u n d erl yi n g mali g na nc y s h o ul d be re p ort e d as A Es or S A Es.  
Pre g n a nc y  
N otific ati o n t o D r u g S afety 
C o m plete a Pre g na nc y R e p ort F or m f or all pre g n a ncies t hat occ ur fr o m t he ti me of first st u d y 
dr u g d os e u ntil 7 m o nt hs after t he l ast d ose of st u d y dr u g(s) i ncl u di n g a n y pre g na nci es t hat 
occ ur i n t he part ner of a st u d y s u bject w h o is a bl e t o fat h er a c hil d. O nl y re p ort pre g na n cies 
t hat occ ur i n a s u bject’s part ner if t he esti mate d d ate of c o n ce pti o n is after t he s u bject’s first 
st u d y dr u g d ose. E m ail or fa x t o t he s p o ns or’s Dr u g Safet y De p art me nt wit hi n 4 8 h o urs of 
bec o mi n g a ware of a pre g na n c y. A ll pre g n a ncies will be m o nit ore d f or t he f ull d urati o n; all 
peri natal a n d n e o natal o utc o mes s h o ul d be re p ort e d. I nfa nts s h o ul d be f oll o we d f or a 
mi ni m u m of 8 wee ks.  
C ollecti o n of d at a o n t he C R F  
All pre g n a ncies (as des cri be d a b o ve) t hat o cc ur wit hi n 3 0 da y s of t he l ast d ose of st u d y 
dr u g(s) will als o be rec or de d o n t he A d verse E ve nts C R F.  
A b orti o n, w het her acci d e ntal, t hera pe utic, or s p o nta ne o us, s h o ul d be re p orte d as a n S A E. 
C o n ge nital a n o malies or birt h defects, as d efi ne d b y t he ‘s eri o us’ criteri o n a b o ve  (see 
defi niti o ns Secti o n 7. 7. 1. 1 ) s h o ul d be re p ort e d as S A Es. 
P ote nti al Dr u g -I n d uce d Liver I nj ury 
H y’s La w ca n be us e d t o esti mate se verit y a n d t h e li keli h o o d t hat a st u d y dr u g ma y ca use a n 
i ncreas e d i nci de nce of se vere he p at ot o xicit y. 
T he a bse n ce 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) b ei n g st u die d. H o we ver, 
fi n di n g 1 H y’s La w case i n cli nical trials is o mi n o us; fi n di n g 2 cas es is hi g hl y pre di cti 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 cas es i ncl u de t he f oll o wi n g 3 c o m p o n e nts:  
1.  A mi n otra nsfera se ( A L T a n d/ or A S T) ele vati o n > 3 x U L N  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 0  of 1 7 0  
A N D  
2.  T otal bilir u bi n > 2 x U L N, wit h o ut i nitial fi n di n gs of c h olestasis (i.e., el e vat e d ser u m 
al kali ne p h os p hatase),  
A N D  
3.  N o ot her i m me diatel y a p pare nt p ossi ble ca us es of a mi n otra nsferase el e vati o n a n d 
h y per bilir u bi ne mia, i ncl u di n g, b ut n o t li mite d t o, viral he patitis, pre-e xisti n g c hr o nic or 
ac ute li ver dise ase, or t h e 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 m e 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 seri o us a d verse e v e nt ( S A E) a n d 
re p orte d pr o m ptl y t o t he sp 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 h e 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 or m al L a b or a t or y Res ults S u g gesti n g P ote nti al DI LI 
I n ge neral, a n i ncreas e 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 p eat 
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. Meas ure me nt of 
c o nj u gate d a n d u n c o nj u gate d bilir u bi n s h o ul d be c o nsi dere d i n cas es of h y p er bilir u bi ne mia 
t o assist i n deter mi nati o n of its eti ol o g y. 
A p pr o priate me di cal assess me nt s h o ul d be i nitiate d t o i n vesti gate p ote nti al 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 dr u g.  
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 tr eat me nt or 
disc o nti n u ati 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 verit y Gra d es 2 t o 4 us e d t o re p ort as y m pt o mati c L V E F d ecreas e.  
F or s y m pt o matic C H F, t he ter m “ heart fail ure” s h o ul d be use d, a n d se v erit y Gra des 2 t o 5 
use d t o re p ort s y m pt o matic C H F.  
7. 7. 1. 3  R e p orti n g P eri o d s f or A d v er s e E v e nt s a n d S eri o u s A d v er s e E v e nt s  
T he safet y re p orti n g peri o d f or all A Es a n d 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  da ys after t h e last st u d y treat me nt (t ucati ni b or trast uz u ma b ). H o we v er, all st u d y 
pr ot oc ol -relat e 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 ns e nt. All S A Es t hat 
occ ur after t he s afet 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.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 1  of 1 7 0  
S A Es will b e 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 v eri 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 b y t he i n vesti gat or, or 
t he s u bject dies or wit h dr a 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 
safet y re p orti n g p eri 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 ur e. 
7. 7. 1. 4  S eri o u s A d v er s e E v e nt s R e q uir e I m m e di at e R e p orti n g  
Wit hi n 2 4 h o urs of o bser vi n g or lear ni n g  of a n S A E, i n vesti gat ors are t o r e p ort t he e ve nt t o 
t he s p o ns or, re gar dless of t he relati o ns hi p of t he e v e nt t o t he st u d y treat me nt re gi me n. 
F or i nitial S A E re p orts, a vaila ble cas e 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:  
•  S u bject  n u m ber  
•  Date of e v e nt o nset  
•  Descri pti o n of t he e v e nt  
•  St u d y treat me nt, if k n o w n  
•  I n v esti gat or’s ca usalit y assess me nt 
T he c o m plete d S A E f or m is t o be e maile d or fa x e d t o t he s p o ns or’s Dr u g Safet y De part me nt 
wit hi n 2 4 h o urs (see e mail o r fa x n u m ber s pecifie d o n t he S A E re p ort f or m). 
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.  
7. 7. 1. 5  S p o n s or S af et y R e p orti n g t o R e g ul at or y A ut h oriti e s  
I n v esti gat ors are re q uir e d t o re p ort all S A Es t o t he s p o ns or (see Secti o n 7. 7. 1. 4).  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 ul at or y a ut h orities as re q uir e d per l ocal le gislati o n or re g ulat or y re p orti n g 
re q uire me nts. 
7. 7. 2  Vit al Si g n s  
Vital si g n meas ur e m e nts are t o i ncl u de wei g ht, b o d y te m perat ur e, heart rat e, s yst olic a n d 
diast olic bl o o d press ure, p ulse, a n d o x y ge n sat ur ati o n . Vital si g ns s h o ul d be meas ure d after 
t he s u bject has bee n sitti n g/resti n g. 
7. 7. 3  Cli ni c al L a b or at or y T e st s  
T he f oll o wi n g l a b orat or y ass ess me nts will be perf or me d b y t h e l ocal la b orat or y t o e val uate 
safet y at sc h e d ule d ti me p oi nts (see A P P E N DI X A ) a n d ma ke cli nical decisi o ns d uri n g t he 
c o urse of t he st u d y: 
● 
T he ser u m c h e mistr y p a n el is t o i ncl u de t he f oll o wi n g tests: al b u mi n, bicar b o nate, 
bl o o d urea nitr o ge n, calci u m, c hl ori de, creati ni ne,  calc ulate d creati ni ne cleara nce 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 2  of 1 7 0  
usi n g C oc kcr oft -G a ult (at baseli ne a n d as cli nicall y i n dicat e d),  gl uc ose, p ot assi u m, 
s o di u m, t otal pr otei n. 
● 
He patitis B a n d C scree ni n g (a nti-H C V will o nl y b e c ollecte d f or C o h orts B a n d C 
o nl y)  
● 
L F Ts  i ncl u de A L T/s er u m gl uta mic p yr u vic tr a ns a mi nase (S G P T ), A S T/ ser u m 
gl uta mic o x ol oacetic tra nsa mi nase ( S G O T ), al kali ne p hos p hatase, a n d t otal bilir u bi n 
(a n d direct bilir u bi n w he n t otal bilir u bi n is > U L 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: C B C wit h differe ntial t hat 
i ncl u des he m o gl o bi n, he mat ocrit, platelet c o u nt, re d bl o o d cell c o u nt, a n d w hite bl o od 
cell c o u nt wit h 5 -part differe ntial ( b as o p hils, e osi n o p hils, l y m p h oc yt es, m o n oc yt es, 
a n d ne utr o p hils)  
● 
T he c oa g ulati o n pa n el is t o i ncl u de t he f oll o wi n g t ests: I N R, P T , a n d P T T 
● 
T he uri nal ysis is t o i ncl u de t he f oll o wi n g t ests: c ol or, a p peara nce, p H, pr ot e i n, 
gl uc ose, ket o nes, bl o o d, s pecific gra vit y, bilir u bi n, le u k oc yt e esterase, nitrites, 
ur o bili n o ge n   
● 
A ser u m β -h C G pre g n a n c y t est ( mi ni m u m se nsiti vit y of 2 5  mI U/ m L or e q ui vale nt 
u nits) f or s u bjects of c hil d beari n g p ote ntial  
7. 7. 4  P h y si c al E x a mi n ati o n  
P h ysical e x a 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 d y p arts/s yste 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 s u bjects o nl y, 
meas ure me nts of h ei g ht o btai ne d wit hi n t he pri or 1 2 m o nt hs ma y be utilize d.  
7. 7. 5  Pr e g n a n c y T e sti n g  
F or s u bjects of c hil d beari n g p ote ntial, a s er u m β -h C G pre g na nc y t est wit h se nsiti vit y of at 
least 2 5 mI U/ m L will be perf or me d at baseli ne a n d wit hi n 7  da ys pri or t o Da y  1 of eac h 
treat me nt c ycl e. A ne gati ve pre g na n c y res ult is re q uire d bef ore t he su bject ma y recei ve st u d y 
dr u g. Pre g na nc y t ests ma y als o be re p eate d as re q ueste d per I R B/I E C or if re q uire d b y l ocal 
re g ulati o ns. 
7. 7. 6  C ar di a c F u n cti o n  
7. 7. 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 nc e e ver y 1 2 wee ks t hereaft er 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 di ac E C H O or M U G A s h o ul d be perf or me d 
e ver y 1 2 w ee ks as d eter mi ne d b y t he date of t he m ost rece nt i nteri m assess me nt.  
A d diti o nall y,  if a s u bject disc o nti n ues trast uz u ma b f or a n y reas o n, ass ess me nt of car diac 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 3  of 1 7 0  
f u ncti o n ( E C H O or M U G A) m ust be c o n d uct e d e ver y 6 m o nt hs u ntil 2 4 m o nt hs fr o m t he last 
a d mi nistrati o n of trast uz u ma b. T he m o dalit y c h os e 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 ass ess me nts t hr o u g h o ut t he st u d y f or c o m paris o n.  
7. 7. 6. 2  El e ctr o c ar di o gr a m  
E C Gs will be perf or me d at baseli ne . 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 d ericia f or m ula.  
7. 7. 7  Tr e at m e nt/ F oll o w -u p D e ci si o n at E v al u ati o n of S u bj e ct  
7. 7. 7. 1  Tr e at m e nt  
S u bjects will c o nti n ue t o recei v e st u d y tr eat me nt p er pr ot oc ol u ntil disc o nti n uati o n f or o ne of 
t he reas o ns liste d bel o w. H o we ver, s u bjects ma y disc o nti n ue st u d y treat me nt or wit h dra w 
t heir c o nse nt t o partici pat e i n t he st u d y at a n y ti me wit h o ut prej u dice. All reas o ns f or 
disc o nti n uati o n fr o m trial will be rec or de d.  
N O T E: S u bjects wit h si g ns of cli nical be nefit (e. g., mi x e d res p o nse, s y m pt o m i m pr o ve me nt, 
de m o nstra ble sl o wi n g of pr o gressi o n, pr o gressi o n rate of < 2 0 % o ver 6 m o nt hs) w h o are 
t olerati n g tr eat me nt ma y be all o we d t o c o nti n ue treat me nt past f or mal ra di ol o gic pr o gressi o n 
(i.e., R E CI S T  1. 1 ) if s u c h treat me nt is c o nsi dere d i n t he s u bject's b est i nterest b y t he s u bject, 
t he treati n g p h ysicia n, a n d t he Me dical M o nit or  I n t his sce nari o, treat me nt ma y c o nti n ue u ntil 
cli nical pr o gressi o n.  
Reas o ns f or s u bject disc o nti n uati o n ma y i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  Deat h  
•  P D /treat me nt fail ure wit h o ut o n g oi n g cli nical be nefit 
•  Si g nifica nt n o nc o m plia n ce b y s u bject or treati n g p h ysicia n  
•  A Es  t hat are c o nsi dere d i nt olera ble a n d u n ma na gea ble (relati o n t o all dr u gs s h o ul d be 
n ote d)  
•  I n v esti gat or deter mi nati o n t hat it is n o l o n ger safe a n d/ or n o l o nger i n t he s u bject’s 
best i nterest t o c o nti n ue partici pati o n  
•  L ost t o f oll o w -u p  
•  Necessit y f or treat me nt wit h ot her a ntica ncer treat me nt pr o hi bite d b y pr ot oc ol  
•  Se x uall y acti ve s u bjects w h o ref use t o use me dicall y acce pte d barrier met h o ds of 
c o ntrace pti o n (e. g., male c o n d o m, fe male c o n d o m) d uri n g t h e c o urse of t he st u d y a n d 
f or 7 m o nt hs f oll o wi n g disc o nti n uati o n of st u d y tr eat me nt 
•  W o me n w h o bec o me pre g na nt or are breast fee di n g  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 4  of 1 7 0  
•  Treat me nt -relate d a d vers e e ve nts w hic h d o n ot r es ol ve t o Gra de ≤2 wit hi n 6  wee ks, i n 
w hic h case t h e s u bject will ha ve st u d y tr eat me nt disc o nti n ue d u nless t here is 
u ne q ui v ocal e vi de n ce t hat t he s u bject is be nefiti n g  
•  D osi n g del a y greater t ha n 6 wee ks  
•  Re q uest b y re g ulat or y a ge ncies f or t er mi nati o n of treat me nt of a n i n di vi d ual s u bject 
or a ll s u bjects u n der t he pr ot oc ol 
•  Wit h dra wal of c o nse nt  
•  St u d y t er mi nati o n b y s p o ns or  
7. 7. 7. 2  O b s er v ati o n  a n d F oll o w -u p ( C o h ort A)  
O bser v ati o n  
If s u bject disc o nti n ues tr eat me nt beca use of disease pr o gressi o n, t he y will ha ve 1  
O bser vati o n visit 3 0 ( ± 7) da ys p ost last st u d y i nter ve nti o n. After t his ti me, s u bject will e nter 
foll o w -u p . 
F or s u bjects w h o g o off st u d y treat me nt wit h n o d oc u me nte d diseas e pr o gressi o n a n d n o 
s u bse q ue nt a ntica n cer treat me nt, t he s u bject will be o bser ve d  e ver y 1 2 wee ks ( ± 1 4 da ys) or 
as cli nicall y i n dicate d u ntil P D, at w hic h ti me t he y will e nter foll o w -u p . S u bjects re mai ni n g 
i n o bser vati o n f or ≥5 years fr o m first st u d y treat m e nt will g o off st u d y wit h o ut e nteri n g 
foll o w -u p . 
F oll o w -u p  
S u bjects i n foll o w -u p  will ha ve stat us e val uati o n e ver y 1 2 wee ks ( ± 1 4 da ys) u ntil P D , deat h, 
or  e n d of st u d y. E val uati o n ma y b e b y tele p h o ne call, e mail, or i n -pers o n assess me nt. Re vie w 
of me dical r ec or ds ma y b e use d t o o btai n t his i nf or mati o n if re as o na ble eff orts t o ma ke 
p h o ne/ pers o nal c o nt act are u ns uccessf ul.  F or s u bjects re mai ni n g o n st u d y  at t he ti me of st u d y 
cl os ure, a last visit / c o ntact will occ ur a n d s u bjects w h o are still recei vi n g treat me nt will 
re vert t o p h ysicia n care. 
F oll o w -u p is t he ti me peri o d w he n t he s u bject is n o l o n ger f oll o wi n g t h e pr ot oc ol test 
sc he d ule. D uri n g foll o w -u p , t he data c ollecti o n sc he d ule is dictate d b y t he pr ot oc ol, b ut t he 
s u bject visit sc he d ule is deter mi ne d b y cli nical pr actice at eac h partici pati n g site.  
D uri n g t h e foll o w -u p p has e of t he st u d y, t he partici pa nt is bei n g m o nit ore d f or ke y st u d y 
e ve nts s uc h as pr o gressi o n, ne w pri maries, a n d deat h.  
S u bjects ca n n ot be re q uir e d t o ret ur n t o t he c o ns e nti n g site f or st u d y -relate d reas o ns or b e 
re q uire d t o ha v e res earc h-relate d t ests perfor m e d. Sa m ples fr o m bi os peci me ns c ollecte d i n 
t he c o urse of cli nical c are ma y be re q ueste d b ut ca n n ot be re q uir e d of t he partici pa nt. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 5  of 1 7 0  
Pr o g ressi o n of Dise ase  ( P D) 
S u bjects i n C o h ort A w h o de vel o p P D at a n y ti me will  ha ve o ne  o bser vati o n visit 
3 0  ( ± 7) da ys p ost last st u d y i nter ve nti o n a n d t he n t o foll o w -u p . T hese s u bjects s h o ul d be 
treate d wit h alter nati ve c he m ot hera p y if t heir cli nical stat us is g o o d e n o u g h t o all o w f urt her 
t hera p y. 
7. 7. 7. 3  F oll o w -u p Di s e a s e A s s e s s m e nt  
S u bjects i n all c o h orts  will u n der g o : 
● 
F urt her a nti-ca n cer t hera p y a n d s ur vi val  
7. 8  A p pr o pri at e n e s s of M e a s ur e m e nt s  
T he safet y me as ures t h at 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 1. 1 (Eise n ha uer 2 0 0 9 ), w hic h are 
sta n dar dize d criteria f or e val uati n g res p o nse i n s oli d t u m ors. T he sc he d ule f or t u m or i ma gi n g 
is c o nsiste nt wit h ge neral o nc ol o gical practice a n d a p pr o priatel y b ala nces meas ure me nt of 
t u m or c o ntr ol wit h t he e x pe nse a n d s u bject i nc o n v e nie nce ass ociate d wit h C T a n d P E T 
sca n ni n g. 
T he safet y me as ures t h at 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. A Es a n d cli ni cal la b orat or y 
data will be gra d e d usi n g sta n dar dize d criteria f or o nc ol o g y ( N CI C T C A E v 4. 0 3).  
T he Q L Q -C 3 0 ( Versi o n 3. 0) is a vali date d q uesti o n naire de v el o pe d b y t he E O R T C t o assess 
t he q ualit y of lif e  of ca ncer s u bjects (Aar o ns o n 1 9 9 3 ; S nee u w 1 9 9 8 ). T he E Q-5 D -5 L is a 
vali date d i nstr u me nt f or use as a meas ure of healt h -relate d Q o L. T hese P R Os ha ve bee n 
i nc or p orate d i nt o pr e vi o us cli nical trials t hat see k t o q ua ntif y t he Q o L i n s u bjects. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 6  of 1 7 0  
8  
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  
8. 1  Sit e Tr ai ni n g a n d M o nit ori n g Pr o c e d ur e s  
A st u d y ma n u al wit h i nstr ucti o ns f or st u d y c o m plia nce a n d 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 s u bjects at t he site, Sea ge n  or its desi g n ate d cli nical a n d 
me dical pers o n n el 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 bj ecti ves, eli gi bilit y re q uire m e nts, ra n d o mizati o n, st u d y 
pr oce d ures,  a n d wit h dr a wal pr ocess es  
● 
C urre nt I n vesti gat or’s Br oc h ure/ pac ka ge i ns ert  
● 
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  
● 
T he C R F c o m pleti o n pr o cess a n d s o urce d oc u m e ntati o n re q uire me nts  
● 
M o nit ori n g re q uir e me nts  
● 
I R B/I E C re vie w a n d a p pr o val pr ocess 
● 
I nf or me d c o ns e nt pr ocess 
● 
G o o d cli nical practice g ui deli nes a n d relate d re g ul at or y d o c u me ntati o n re q uire me nts  
● 
Ke y st u d y t ea m r oles a n d res p o nsi bilities  
● 
I n v esti gati o nal pr o d uct st ora ge, acc o u nta bilit y, la beli n g, dis pe nsi n g a n d rec or d 
kee pi n g  
● 
Scree ni n g a n d e nr oll me nt  
● 
St u d y s a 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 p e 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 Sea ge n  re pres e ntati ve will t y picall y 
re vie w re g ulat or y d oc u m e ntati o n, 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 u ct 
st ora ge, pre p arati o n, a n d acc o u nta bilit y. T he C R Fs will be re vie we d f or c o m plete ness, 
a d here n ce t o t he pr o vi de d g ui deli nes, a n d acc urac y c o m p are d t o t he s o urce d oc u me nts. 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 s u bjects, 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 h e trial are res ol ve d. T he i n vesti gat or m ust mai ntai n a c o m pre h e nsi ve 
a n d ce ntr alize d fili n g s yste 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 
b y Sea ge n  or its desi g nat e d m o nit ors a n d b y q u alit y ass ura nce  a u dit ors, or re prese nt ati ves of 
re g ulat or y a ut h orities. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 7  of 1 7 0  
8. 2  D at a M a n a g e m e nt Pr o c e d ur e s  
Sea ge n  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 dat a 
ma na ge me nt pr o ce 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 d ata verifi cati o n pr oce d ures will be p oste d electr o nicall y i n t he 
e C R F. 
8. 3  A c c e s s t o S o ur c e D at a  
T he i n vesti gat or will per mit t he s p o ns or’s re pres e ntati ves t o m o nit or t he st u d y as fre q u e ntl y 
as t he s p o ns or dee ms n ecessar y t o deter mi ne t hat pr ot oc ol a d here nce a n d d ata rec or di n g are 
satisfact or y. A p pr o priate meas ures t o pr otect s u bject c o nfi de ntialit y are t o b e e m pl o ye d 
d uri n g m o nit ori n g. T he C R Fs a n d relate d s o urce d oc u me nts will t y picall 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 m e nts or certifie d c o pies are 
nee de d f or re vi e w. T his r e 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 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 o ntai ne d i n t he C R Fs, s uc h as diseas e assess me nts, A Es, a n d c o nc o mita nt 
me dicati o ns, is c o m plete a n d c orrect. Ot her st u d y rec or ds, s u c 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 ur ce 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 nt ati ves of 
re g ulat or y a ut h orities a n d t he I R B/I E C. 
8. 4  A c c ur a c y a n d R eli 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 d e:  
•  T he selecti o n of q u alif ie 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 o ce d ures wit h t he i n vesti gat ors a n d ass ociat e 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 n ate d m o nit or(s).  
•  C R Fs will be re vie we d f or acc urac y a n d c o m plet e ness d uri n g m o nit ori n g visits t o t he 
st u d y ce nt ers a n d/ or b y ce ntralize d m o nit ori n g. A n y discre pa n cies will be res ol ve d 
wit h t he i n vesti gat or or d esi g nees as a p pr o priate.  
8. 5  Q u alit y A s s ur a n c e Pr o c e d ur e s  
T he Researc h a n d De vel o p me nt Q ualit y gr o u p or its desi g nee m a 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 Res earc h a n d D e v el o p me nt Q ualit y gr o u p of Sea ge n  as p art of t he writte n rec or d.  
8. 6  D at a H a n dli n g a n d R e c or d K e e pi n g  
Refer t o t he C ase R e p ort F or m C o m pleti o n G ui deli nes ( C C G) f or t he met h o ds of data 
c ollecti o n.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 8  of 1 7 0  
8. 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, l e 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 C R Fs a n d i n all re q uir e d re p orts. Dat a 
re p orte d o n t he C R F t h at is deri ve d fr o m s o urce d o c u me nts s h o ul d be c o nsiste nt wit h t he 
s o urce d oc u m e nts or t he discre pa n cies 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 C R F will be mai ntai ne d i n a n a u dit trail wit hi n t he el ectr o nic 
data ca pt ur e s yste m. Dat a c ha n ges ma y o nl y b e m a 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 r etai n rec or ds of t he c h a n ges a n d c orrecti o ns, writte n a n d/ or electr o nic. 
8. 6. 2  I n v e sti g at or R e c or d R et e nti o n 
T he i n vesti gat or s hall ret ai n st u d y dr u g dis p ositi o n rec or ds a n d 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 p atie 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 s t u d y will be 
c o n d ucte d, or f or t he peri o d s pecifie d b y Sea ge n , w hic he ver is l o n ger. T he i n vesti gat or m ust 
c o ntact Sea ge n  pri or t o d estr o yi n g a n y 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 p o n desi g nee, s uc h as a n ot h er i n vesti gat or or I R B/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 Sea ge n . 
8. 7  R e s ult s R e p orti n g o n Cli ni c al Tri al s. g o v  
At st u d y acti vati o n, t his st u d y wil l ha ve b ee n re gistere d wit hi n t he “ Cli ncial Trials. g o v ” 
we bsite. T he Pri mar y a n d Sec o n dar y E n d p oi nts (i.e., “ O utc o me M eas ures”) al o n g wit h ot her 
re q uire d i nf or mati o n f or t his st u d y will be re p orte d o n Cli nical Trials. g o v. 
F or p ur p os es of ti mi n g of t he Res ult s Re p orti n g, t he esti mate d c o m pleti o n d ate f or t he 
Pri mar y E n d p oi nt of t his st u d y is a p pr o xi matel y 5 0 m o nt hs after t he st u d y o pe ns t o 
e nr oll me nt.  
T he defi niti o n of “ Pri mar y E n d p oi nt C o m pleti o n Date” f or t his st u d y is 8 m o nt hs fr o m t he 
ti me t he last s u bject is re gistere d. 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 8 9  of 1 7 0  
9  
D A T A A N A L Y SI S M E T H O D S  
A n o ver vie w of st u d y o ut c o me meas ure me nts is pr o vi de d  i n Ta ble  9 -1 . 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 0  of 1 7 0  
T a bl e  9 -1 :  
O v er vi e w of st u d y o ut c o m e m e a s ur e m e nt s  
O bj ecti ve  
C orres p o n di n g E n d p oi nt  
C orres p o n di n g Meas ure me nt  
Ti mefra me  
Pri mar y  
 
 
 
● T o deter mi ne t he a ntit 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  
trast uz u ma b, i n C o h orts A + B, as 
meas ure d b y c O R R ( per R E CI S T 1. 1), 
acc or di n g t o BI C R assess me nt  
● cO R R (c o nfir me d C R or P R), per 
R E CI S T 1. 1, acc or di n g t o B I C R 
assess me nt, i n p o ole d C o h ort s A + B  
● O R R, per R E CI S T 1. 1, b y BI C R 
assess me nt  
● U p t o a p pr o xi matel y 5 years  
Sec o n dar y Efficac y  
 
 
 
● T o e val uate t he a ntit 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 
trast uz u ma b, i n C o h orts A + B, b y O R R 
b y  1 2 wee ks of treat me nt  ( R E CI S T 
1. 1), acc or di n g t o BI C R assess me nt  
● O R R ( R E CI S T 1. 1)  b y 1 2 wee ks of 
treat me nt, acc or di n g t o B I C R 
assess me nt, i n C o h ort s A +B  
● O R R, per R E CI S T 1. 1, b y BI C R 
assess me nt  
● U p t o a p pr o xi matel y  5 years  
● T o e val uate t he a ntit u m or acti vit y of 
t ucati ni b m o n ot hera p y, i n C o h ort C,  as 
meas ure d b y O R R b y 1 2 wee ks of 
treat me nt ( R E CI S T 1. 1), acc or di n g t o 
BI C R assess me nt  
● O R R ( R E CI S T 1. 1) b y 1 2 wee ks of 
treat me nt, acc or di n g t o B I C R 
assess me nt, i n C o h ort C  
● O R R, per R E CI S T 1. 1, b y BI C R 
assess me nt  
● U p t o a p pr o xi matel y 5 years  
● T o assess t he d urati o n of res p o nse 
( D O R) i n s u bj ects treate d wit h 
t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u ma b ( R E CI S T 1. 1), i n C o h orts 
A + B, acc or di n g t o BI C R assess me nt  
● D O R ( R E CI S T  1. 1), acc or di n g t o 
BI C R assess me nt, i n C o h orts A + B  
● D O R, per R E CI S T 1. 1, b y BI C R 
assess me nt  
● U p t o a p pr o xi matel y 5 years  
● T o assess t he D O R i n s u bj ects treate d 
wit h t ucati ni b m o n ot hera p y ( R E CI S T 
1. 1), i n C o h ort C, acc or di n g t o BI C R 
assess me nt  
● D O R  ( R E CI S T 1. 1), acc or di n g t o 
B I C R assess me nt, i n C o h ort  C  
● D O R, per R E CI S T 1. 1, b y BI C R 
assess me nt  
● U p t o a p pr o xi matel y 5 years  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 1  of 1 7 0  
O bj ecti ve  
C orres p o n di n g E n d p oi nt  
C orres p o n di n g Meas ure me nt  
Ti mefra me  
● T o assess t he P F S i n s u bj ects treate d 
wit h t ucati ni b gi ve n i n c o m bi nati o n 
wit h  trast uz u ma b ( R E CI S T 1. 1), i n 
C o h orts A + B, acc or di n g  t o BI C R 
assess me nt  b  
● P F S ( R E CI S T  1. 1), acc or di n g t o 
BI C R assess me nt, i n C o h orts A + B  
● P F S, per R E CI S T 1. 1, b y BI C R 
assess me nt  
● U p t o a p pr o xi matel y 5 years  
● T o assess t he O S  i n s u bj ects treate d 
wit h t ucati ni b gi ve n i n c o m bi nati o n 
wit h trast uz u ma b, i n C o h orts A + B  
● O S, i n C o h orts A + B  
● O S  
● U p t o a p pr o xi matel y 5 years  
Sec o n dar y Safet y  
 
 
 
● T o assess t he safet y 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, i n C o h orts A + B 
● Fre q ue nc y a n d se verit y, acc or di n g t o 
C T C A E  v 4. 0 3 criteria, of all T E A Es 
a n d treat me nt -relate d T E A Es, i n 
C o h orts A + B  
● Fre q ue nc y of S A Es a n d deat hs d ue t o 
A Es, i n C o h orts A + B  
● Fre q ue nc y of treat me nt m o difi cati o ns 
a n d per ma ne nt treat me nt 
disc o nti n uati o ns d ue t o A Es, i n 
C o h orts A + B  
● Fre q ue nc y a n d se verit y of la b orat or y 
a b n or malities, i n C o h orts A + B  
● Vital si g ns a n d ot her rele va nt safet y 
varia bles, i n C o h orts A + B  
● I nci de nce of A Es  
● I nci de nce of d ose m o dificati o n a n d 
treat me nt disc o nti n uati o n 
● I nci de nce of la b orat or y 
ab n or malities  
● T hr o u g h 1 m o nt h f oll o wi n g last 
d ose; u p t o a p pr o xi matel y 
9  m o nt hs o verall per s u bj ect  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 2  of 1 7 0  
O bj ecti ve  
C orres p o n di n g E n d p oi nt  
C orres p o n di n g Meas ure me nt  
Ti mefra me  
● T o assess t he safet y a n d t olera bilit y of 
t ucati ni b m o n ot hera p y, i n C o h ort C 
● Fre q ue nc y a n d se verit y, acc or di n g t o 
C T C A E  v 4. 0 3, of all T E A Es a n d 
treat me nt-relate d T E A Es, i n C o h ort C  
● Fre q ue nc y of S A Es a n d deat hs d ue t o 
A Es, i n C o h ort C  
● Fre q ue nc y of treat me nt m o difi cati o ns 
a n d per ma ne nt treat me nt 
disc o nti n uati o ns d ue t o A Es, i n 
C o h or t C 
● Fre q ue nc y a n d se verit y of la b orat or y 
a b n or malities, C o h ort C  
● Vital si g ns a n d ot her rele va nt safet y 
varia bles, i n C o h ort C  
● I nci de nce of A Es  
● I nci de nce of d ose m o dificati o n a n d 
treat me nt disc o nti n uati o n 
● I nci de nce of la b orat or y 
a b n or malities  
● T hr o u g h 1 m o nt h f oll o wi n g last 
d ose; u p t o a p pr o xi matel y 9 
m o nt hs o verall per s u bj ect  
E x pl orat or y   
 
 
 
● T o e val uate t he P K of t ucati ni b  
● P K para meters of t ucati ni b 
● P K para meters of t ucati ni b 
● T hr o u g h C ycle 6  
● T o e x pl ore a n y 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  
● T o e x pl ore p ote ntial bi o mar kers of 
res p o nse, resista nce or t o xicit y fr o m 
arc hi ve d paraffi n -e m be d de d t u m or 
sa m ples a n d ct D N A is olate d fr o m 
plas ma sa m ples.  
● Bi o mar ker  rea d o uts fr o m li q ui d 
bi o psies  
● U p t o a p pr o xi matel y 3 years  
● T o assess t he P F S  i n s u bj ects treate d 
wit h t ucati ni b m o n ot hera p y ( R E CI S T 
1. 1), i n C o h ort C, acc or di n g t o BI C R 
assess me nt  
● P F S ( R E CI S T  1. 1), acc or di n g t o 
BI C R assess me nt, i n C o h ort C  
● P F S, per R E CI S T  1. 1, b y BI C R 
assess me nt  
● U p t o a p pr o xi matel y 5 years  
● T o assess t he O S i n s u bj ects treate d 
wit h t ucati ni b m o n ot hera p y , i n C o h ort 
C  
● O S, i n C o h ort C  
● O S  
● U p t o a p pr o xi matel y 5 years  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 3  of 1 7 0  
O bj ecti ve  
C orres p o n di n g E n d p oi nt  
C orres p o n di n g Meas ure me nt  
Ti mefra me  
● T o assess P R Os  ass ociate d wit h 
t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u mab  
● C ha n ge fr o m baseli ne i n P R O 
assess me nts of t he E ur o Q O L -5 
Di me nsi o ns ( E Q -5 D -5 L), a n d 
E ur o pea n Or ga nizati o n f or Researc h 
a n d Treat me nt of Ca ncer C ore Q o L 
Q uesti o n naire ( E O R T C Q L Q -C 3 0)  
● C ha n ges i n P R O sc ores  
● U p t o a p pr o xi matel y 3 years  
● T o e x pl ore healt h res o urce utilizati o n 
● C u m ulati ve i nci de nce of healt h 
res o urce utilizati o n, i ncl u di n g le n gt h 
of sta y, h os pitalizati o ns, a n d E D 
visits  
● I nci de nce of healt h care utiliz ati o n 
● U p t o a p pr o xi matel y 3 years  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 4  of 1 7 0  
9. 1  D et er mi n ati o n of S a m pl e Si z e  
A p pr o xi matel y 1 1 0 s u bj ects will be e nr olle d i n t he st u d y . S u bjects are c o nsi dere d e nr olle d if 
t he y gi ve i nf or me d c o ns e nt a n d meet all eli gi bilit y criteria. A p pr o xi matel y 4 0 s u bjects will 
be e nr olle d i n C o h ort A.  A p pr o xi matel y  7 0 s u bj ects, e nr olle d i n t he ex pa nsi o n p orti o n of t he 
trial, will be ra n d o mize d i n a 4: 3 rati o t o recei ve t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u ma b ( C o h ort B) or t ucati ni b m o n ot hera p y ( C o h ort C). E nr oll me nt will c o nti n ue u ntil 
a p pr o xi matel y 4 0 s u bjects ha ve bee n ra n d o mize d t o a n d treate d i n C o h ort B , a n d 
a p pr o xi matel y 3 0 s u bjects ha ve bee n ra n d o mize d t o a n d treate d i n C o h ort C . 
T he e x pa nsi o n C o h ort B is desi g ne d t o i ncreas e t he size of t he st u d y p o p ulati o n e x p ose d t o 
t he d o u blet re gi me n i n or der t o all o w m ore precise esti mati o n of t he c o nfir me d O R R i n 
s u bjects recei vi n g t uc ati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b, as wel l as t o f ur nis h 
s u p ple me ntar y safet y dat a. T he pri mar y effi cac y a nal ysis will be perf or me d b y pr o vi di n g t he 
p oi nt esti mate a n d t he 2 -si de d 9 5 % e x act Cl o p per Pears o n CI f or t he c o nfir me d O R R ( p o ole d 
C o h orts A a n d B).  
T he a d diti o n of C o h ort C is i nte n de d t o better c haracterize t he a ntit u m or acti vit y of t ucati ni b 
w he n use d as a m o n ot hera p y i n t his patie nt p o p ulati o n.  
F or ill ustrati o n p ur p oses, Ta ble 9 -2  s u m marizes t he e x pecte d 9 5 % C Is f or s u bjects treate d 
wit h t ucati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b ( C o h ort A + B) a n d s u bjects treate d 
wit h t ucati ni b m o n ot hera p y  ( C o h ort C) at t he pr o p ose d sa m ple sizes of 8 0 a n d 3 0 
res pecti vel y. N o f or mal statistical c o m paris o ns bet wee n c o h orts are pla n ne d.  
T a bl e 9 -2 : 
E sti m at e d O R R  
C o nfir me d O R R  9 5 % E xact C I. ( C o h orts A + B, N = 8 0)  
4 0 %  
( 2 9 %, 5 2 %) 
5 0 %  
( 3 9 %, 6 1 %) 
6 0 %  
( 4 8 %, 7 1 %) 
 
 
C o nfir me d O R R  
9 5 % E xact CI. ( C o h ort C, N = 3 0)  
1 0 %  
( 2 %, 2 7 %) 
1 5 %  
( 5 %, 3 3 %) 
2 0 %  
( 8 %, 3 9 %) 
Accr u al Ti me a n d St u d y D ur ati o n  
A p pr o xi matel y 2 s u bj ects per m o nt h will be e nr olle d o ver 4 2  m o nt hs. S u bjects ma y c o nti n ue 
t o recei ve st u d y tr eat me nt u ntil t he y e x perie nce u n acce pta ble dr u g-relat e d t o xicit y or disease 
pr o gressi o n. S u bjects  will be f oll o we d f or s ur vi val u p t o 5 years fr o m first st u d y treat me nt. 
T he fi nal a n al ysis ca n be gi n a p pr o xi matel y 5 0  m o nt hs after t he trial b e gi ns.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 5  of 1 7 0  
9. 2  St u d y E n d p oi nt D efi niti o n s  
9. 2. 1  O bj e cti v e R e s p o n s e R at e  
T he pri mar y e n d p oi nt i n t his st u d y  is t he c o nfir me d O R R  per B I C R. T he O R R is defi ne d as 
t he pr o p orti o n of s u bjects wit h c o nfir me d C R or P R , per  R E CI S T 1. 1 . S u bjects w h o d o n ot 
ha ve at least 2 (i nitial res p o nse a n d c o nfir mati o n sca n) p ost -bas eli ne res p o nse assess me nts as 
descri be d i n Secti o n 7. 2  of t he pr ot oc ol will be c o u nte d as n o n -res p o n ders. 
T here h a ve bee n mi ni mal c ha n ges t o eli gi bilit y crit eria  f or C o h ort A a n d C o h ort B,  a n d all 
patie nts will be ce ntrall y c o nfir me d as b ei n g H E R 2 + wit h t he sa me testi n g met h o d ol o g y 
(I H C/ breast criteria), t heref ore t h e pri mar y efficac y a n al ysis s et will be c o m prise d of all 
treate d s u bjects i n C o h orts A + B . 
9. 2. 2  O bj e cti v e R e s p o n s e R at e b y W e e k 1 2  
O R R  b y W ee k 1 2 per B I C R is defi ne d as t he pr o p orti o n of s u bjects wit h C R or P R b y 1 2 
wee ks of treat me nt, a n d bef ore ti me of cr oss o ver ( C o h ort C), w hic he ver c o mes  earlier, as 
deter mi ne d b y B I C R assess me nt per R E CI S T 1. 1 . Res p o nses d o n ot nee d t o be c o nfir me d t o 
be sc ore d as res p o n d ers f or t he p ur p ose of deter mi ni n g O R R  b y W ee k 1 2. S u bjects  w h ose 
disease res p o ns e ca n n ot be assesse d as C R, P R, or S D b y Wee k 1 2 or later will be sc ore d as 
n o n -res p o n ders f or calc ul ati n g t he O R R b y W ee k 1 2 . 
O R R  b y W ee k 1 2 will be s u m marize d f or s u bjects treate d s olel y wit h t ucati ni b m o n ot hera p y 
( C o h ort C) a n d s u bjects treate d s olel y wit h t ucati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b 
( C o h orts A + B).  
9. 2. 2. 1  D O R  
T he D O R is defi ne d as t he ti me fr o m first d oc u me ntati o n of o bjecti ve res p o nse ( C R or P R  
t hat is s u bse q ue ntl y c o nfir me d) t o t he first d oc u me ntati o n of P D ( per R E CI S T 1. 1) or t o 
deat h d ue t o a n y ca use, w hic he ver c o mes first.  
D O R will be calc ulate d f or t he s u bjects treate d s olel y wit h t ucati ni b gi ve n i n c o m bi nati o n 
wit h trast uz u ma b ( C o h ort s A + B) a n d s u bjects treate d s olel y w it h t ucati ni b m o n ot hera p y 
( C o h ort C). 
9. 2. 2. 2  P F S  
P F S is defi ne d as t he ti me fr o m start of st u d y treat me nt ( C o h ort A) or ra n d o mizati o n 
( C o h orts B  a n d C) t o first d oc u me ntati o n of t u m or pr o gressi o n (cli nical pr o gressi o n or P D 
per R E CI S T 1. 1), as deter mi ne d b y B I C R assess m e nt, or t o deat h d ue t o a n y ca use, 
w hic he ver c o mes first. P F S data will be ce ns ore d o n t he date of t he last dis ease ass ess me nt 
d oc u me nti n g a bse nce of P D f or s u bjects w h o d o n ot ha ve t u m or pr o gressi o n a n d are still o n 
st u d y at t he ti me of a n a n al ysis, are gi ve n a ntit u m or treat me nt ot her t h a n t he st u d y tr eat me nt, 
or are re m o ve d fr o m st u d y pri or t o d o c u me ntati o n of t u m or pr o gressi o n. S u bjects lac ki n g a n 
e val uati o n of t u m or res p o nse after t h eir start of st u d y treat me nt ( C o h ort A) or ra n d o mizati o n 
( C o h orts B  a n d C) will h a ve t heir e v e nt ti me ce ns ore d at 1  da y.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 6  of 1 7 0  
9. 2. 2. 3  O S  
O S is defi ne d as t he ti me fr o m start of st u d y treat me nt ( C o h ort A) or ra n d o mizati o n 
( C o h orts B  a n d C) t o dat e of deat h d u e t o a n y ca use. I n t he a bse nce of c o nfir mati o n of deat h, 
s ur vi val ti me will be ce ns ore d at t he last date t h e s u bject is k n o w n t o be ali ve. S u bjects 
lac ki n g d ata be y o n d t h eir start of st u d y tr eat me nt ( C o h ort A) or ra n d o mizati o n ( C o h orts B  
a n d C) w ill ha ve t heir s ur vi val ti me ce ns ore d at 1 da y.  
9. 3  St ati sti c al a n d A n al yti c al Pl a n s  
T he statistical a n d a nal ytical pla ns prese nt e 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 statistical a nal ysis pla n ( S A P). A c ha n ge t o t he data a nal ysis me t h o ds 
descri be d i n t he pr ot o c ol will re q uire a pr ot o c ol a me n d me nt o nl y if it alters a pri nci pal  
feat ur e of t he pr ot o c ol. T he S A P will be fi nalize d pri or t o data base l o c k. A n y c h a n ges t o t he 
met h o ds descri be d i n t he fi nal S A P will be descri be d a n d j ustifie d  i n t he cli nical st u d y re p ort. 
9. 3. 1  G e n er al C o n si d er ati o n s  
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 h e 
n u m ber a n d perce nt a g es ( of n o n -missi n g) per cate g or y f or cate g orical varia bles.  
U nless ot her wise s pecifie d, C Is will be calc ulate d at 2-si de d 9 5 % le vel. 
T he 2 -si de d 9 5 % e x act 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 ns e rat es w h ere a p plica ble (e. g., O R R).  
F or ti me -t o-e v e nt e n d p oi nts, t he me dia n s ur vi val ti me will be esti mate d usi n g t he 
Ka pla n -Mei er met h o d; t he ass ociate d  9 5 % CI will be calc ul ate d base d o n t h e c o m ple me ntar y 
l o g-l o g tra nsf or mati o n (C ollett 1 9 9 4 ). 
S u bjects  e nr olle d i n  t he i nitial C o h ort A  a n d t h ose ra n d o mize d t o C o h ort B d uri n g t he 
e x pa nsi o n will be a nal yz e d t o get her ( C o h ort s A + B) . De m o gra p hic a n d bas eli ne 
c haracteristics will  be s u m marize d b y c o h ort . 
9. 3. 1. 1  R a n d o mi z ati o n  a n d Bli n di n g   
All s u bjects e nr olle d i n t he e x pa nsi o n p orti o n of t he trial will be ra n d o mize d i n a 4: 3 rati o t o 
recei v e t ucati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b (C o h ort B) or t ucati ni b 
m o n ot hera p y ( C o h ort C).  Ra n d o mizati o n will be stratifie d b y:  
● 
Left si de d pri mar y v ers us all ot her pri mar y t y pes (i.e., ri g ht, tra ns verse, o v erla p pi n g 
pri mar y)  
Bli n di n g will n ot be perf or me d.  
9. 3. 1. 2  A dj u st m e nt s f or C o v ari at e s  
N o a dj ust me nt f or c o vari ates is pla n ne d i n t he a n al yses.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 7  of 1 7 0  
9. 3. 1. 3  H a n dli n g of Dr o p o ut s a n d Mi s si n g D at a  
Wit h t he e x ce pti o n of ti me -t o-e ve nt e n d p oi nts, 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 p ecifie d.  
9. 3. 1. 4  M ulti c e nt er St u di e s  
T his st u d y will be c o n d u cte 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 site-
t o-site variati o n will be a dj uste d i n t he a nal ys es.  
9. 3. 1. 5  M ulti pl e C o m p ari s o n s a n d M ulti pli cit y  
N o m ulti ple c o m paris o ns are pla n n e d a n d n o al p h a a dj us t me nt is nee de d b eca use o nl y 
1  pri mar y e n d p oi nt will be teste d i n t his si n gle ar m st u d y.  
9. 3. 1. 6  D at a Tr a n sf or m ati o n s a n d D eri v ati o n s  
Ti me varia bles bas e d o n t w o dates, e. g., Start Dat e a n d E n d Dat e, will be calc ulate d as ( E n d 
Date –  Start Date + 1) (i n da ys) u nless ot her wise s pe cifie d i n t he pla n ne d a nal ysis secti o n.  
U nless ot her wise s pecifie d, baseli ne val ues use d i n all a nal ys es will be t he m ost rece nt 
n o n missi n g meas ure m e nt pri or t o t he first d ose of st u d y dr u g.  
9. 3. 1. 7  A n al y si s S et s  
T he i nte nt -t o-treat (I T T) set will i ncl u de all e nr olle d s u bjects i n C o h ort A a n d all ra n d o mize d 
s u bjects i n C o h orts B  a n d C.  A s u bject is c o nsi dere d e nr olle d if h e/s he has met all criteria f or 
partici pati o n i n t he st u d y.  
T he f ull a nal ysis set ( F A S) set will i ncl u de all s u bjects w h o are e nr olle d a n d recei v e  a n y 
a m o u nt of st u d y treat me nt.  
T he safet y a nal ysis set will i ncl u de all s u bjects w h o recei v e a n y a m o u nt of st u d y treat me nt. 
T he safet y a nal ysis set will be use d f or all safet y a nal yses.  
T he P K a nal ysis set will i ncl u de all s u bjects i n C o h orts B a n d C w h o  recei ve d st u d y 
treat me nt a n d fr o m w h o m at least o ne P K assess me nt  was re p orte d. T he P K a nal ysis set will 
be use d f or P K a nal yses.  
A d diti o nal a nal ysis sets of s u bjects ma y be defi ne d i n t he S A P.  
9. 3. 1. 8  E x a mi n ati o n of S u b gr o u p s  
As e x pl orat or y a nal yses, s u b gr o u p a nal yses ma y b e 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.  
9. 3. 1. 9  Ti mi n g of A n al y s e s  
T he ti mi n g of t he pri mar y a n al ysis will be b ase d o n t he ti me t o c o nfir me d O R R  per BI C R.  
D O R acc or di n g t o BI C R assess me nt will als o be a na l yze d at t his ti me. Detaile d i nf or mati o n 
re gar di n g t he ti mi n g of t he a nal ysis will be pr o vi de d i n t he S A P.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 8  of 1 7 0  
9. 3. 2  S u bj e ct  Di s p o siti o n  
A n acc o u nti n g of st u d y s u bjects b y dis p ositi o n will be ta b ulate d a n d t he n u m ber of s u bjects 
i n eac h a n al ysis set will be s u m marize d. S u bjects  w h o disc o nti n ue st u d y tr eat me nt a n d 
s u bjects 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.  
9. 3. 3  S u bj e ct  C h ar a ct eri sti c s  
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.  
9. 3. 4  Tr e at m e nt C o m pli a n c e  
Treat me nt a d mi nistrati o n will be s u m marize d f or safet y a n al ysis set. S u m mar y statistics f or  
d urati o n of t hera p y ( wee ks) a n d t he n u m ber of c ycles per s u bject will be prese nte d, as well as  
t he n u m ber a n d perce nta ge of s u bjects w h o were treate d at eac h c ycl e a n d c o m plete d eac h  
c ycle. Details will be pr o vi de d i n t he S A P.  
9. 3. 5  Effi c a c y A n al y s e s  
9. 3. 5. 1  Pri m ar y Effi c a c y A n al y s e s  
T he pri mar y e n d p oi nt of t his st u d y is t he c o nfir me d O R R per B I C R. T he O R R is defi ne d as 
t he pr o p orti o n of s u bjects wit h c o nfir me d C R or P R acc or di n g t o R E CI S T 1. 1 . S u bjects  w h o 
d o n ot ha ve at least 2 (i nitial res p o nse a n d c o nfir m ati o n sca n) p ost -bas eli ne res p o nse 
assess me nts will be c o u nte d as n o n -res p o n d ers.  
T he O R R a n d its e x act  2 -si de d 9 5 % CI, usi n g t he Cl o p per-Pears o n met h o d  (Cl o p per 1 9 3 4 ), 
will be calc ulate d.  
T he pri mar y effic ac y a n al ysis will be perf or me d f or s u bjects treat e d s olel y wit h t ucati ni b i n 
c o m bi nati o n wit h trast uz u ma b ( C o h ort s A + B).  
9. 3. 5. 2  S e c o n d ar y Effi c a c y A n al y s e s  
T he a nal yses o n s ec o n dar y e n d p oi nt, O R R  b y 1 2 wee ks of treat me nt , a n d t he e x act 2 -si de d 
9 5 % C Is, usi n g t he Cl o p per -Pears o n met h o d (Cl o p per 1 9 3 4 ), will be calc ulate d.  
Sec o n dar y e n d p oi nts, s uc h as D O R per B IC R , P F S per B IC R , a n d O S, are ti me-t o-e ve nt 
e n d p oi nts, a n d t he y will b e a nal yz e d usi n g Ka pla n -Meier met h o d ol o g y a n d Ka pla n -Mei er 
pl ots will be pr o vi de d. Details o n t he ce ns ori n g  al g orit h m will be pr o vi de d i n t he S A P.  
O R R  b y W ee k 1 2 will  be s u m marize d f or s u bjects treate d s olel y wit h t ucati ni b m o n ot herap y 
( C o h ort C) a n d s u bjects treate d s olel y wit h t ucati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b 
( C o h orts A + B).  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 9 9  of 1 7 0  
9. 3. 5. 3  Ot h er Effi c a c y A n al y s e s  
O R R , D O R, a n d P F S acc or di n g t o i n vesti gat or ass ess me nt will als o be a nal yz e d; 
discre pa n cies bet wee n t h e B I C R a n d i n vesti gat or’s assess me nt will be s u m marize d 
descri pti vel y.  
9. 3. 6  P h ar m a c o ki n eti c A n al y s e s  
I n di vi d ual (s u bje ct) plas ma t ucati ni b c o nce ntr ati o ns at eac h s a m pli n g ti me will be liste d a n d 
s u m marize d wit h descri pti ve statistics. A d diti o nal e x pl orat or y P K  a n al ys es ma y b e 
c o n d ucte d, i ncl u di n g e x pl orat or y a nal yses i n v esti gati n g t he relati o ns hi p bet wee n t ucati ni b 
e x p os ure a n d effi cac 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 ysis pla n.  
9. 3. 7  Bi o m ar k er A n al y s e s  
Relati o ns hi ps of bi o mar ker para meters (e. g., bas eli ne val ues,  a bs ol ute a n d relati ve c ha n ges 
fr o m baseli ne) t o effic ac y, safet y, a n d P K para meters will be e x pl ore d. Relati o ns hi ps a n d 
ass ociate d dat a t hat are d eter mi ne d t o be of i nterest will be s u m marize d. Details will be 
descri be d se p aratel y i n t he S A P or bi o mar ker a nal ysis pla n.  
9. 3. 8  P ati e nt -R e p ort e d O ut c o m e s a n d H e alt h R e s o ur c e Utili z ati o n A n al y s e s  
P R O assess me nts base d o n t he E Q -5 D -3 L a n d E O R T C Q L Q -C 3 0 will be s u m marize d usi n g 
descri pti ve statistics. P R O sc ores will be a nal yze d descri pti vel y. All s u bscales a n d i n di vi d ual 
ite m sc ores will be ta b ulate d. Descri pti ve s u m mari es of o bser ve d data at eac h sc he d ule d 
assess me nt ti me p oi nt ma y b e pres e nte d. F urt her i n vesti gati o n of missi n g p atter ns a n d det ails 
of i m p utati o n will be pr o vi de d i n t he S A P. A d diti o nal statistic al m o deli n g f or P R O meas ures 
ma y b e perf or me d se p aratel y as e x pl orat or y a nal yses.  
9. 3. 9  S af et y A n al y s e s  
Safet y will be assesse d t hr o u g h s u m maries of A Es, c ha n ges i n la b orat or y test res ults, 
c ha n ges i n vital si g ns, p h ysical e x a mi nati o n fi n di n gs, c h a n ges i n E C O G P S , a n d c ha n ges i n 
car diac eje cti o n fracti o n res ults. A Es will be classifie d b y S O C  a n d preferre d ter m usi n g 
Me dical Dicti o nar y f or R e g ul at or y Acti vities (Me d D R A ); A E se verities will be classifie d 
usi n g t he C T C A E v 4. 0 3 criteria.  
9. 3. 9. 1  E xt e nt of E x p o s ur e  
D urati o n of treat me nt, n u m ber of c ycl es, t otal d ose a n d d ose i nte nsit y will be s u m marize d b y 
c o h ort usi n g t he s afet y a nal ysis set. D ose m o dificati o ns will als o be s u m marize d.  
Details will be pr o vi de d i n t he S A P.  
9. 3. 9. 2  A d v er s e E v e nt s  
A n o ver vie w of A Es will pr o vi de a ta b u lati 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 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 0  of 1 7 0  
be defi ne d as treat me nt e mer ge nt if t he y are ne wl y  occ urri n g or w orse n f oll o wi n g st u d y 
treat me nt. 
A Es will be liste d a n d s u m mariz e d b y Me d D R A preferre d t er m, se verit y, a n d relati o ns hi p t o 
st u d y dr u g. I n t h e e ve nt of m ulti ple occ urre n ces of t he sa me A E wit h t he sa me preferre d ter m 
i n 1 s u bject, t he A E will be c o u nte d o nce as t he o cc urre nce. T he i nci de n ce of A Es will be 
ta b ulate d b y preferre d ter m a n d c o h ort. A Es lea di n g t o pre m at ure disc o nti n uati o n of st u d y 
dr u g will be s u m mariz e d a n d liste d i n t he sa me ma n ner.  
All c ollecte d A E dat a will be liste d b y c o h ort , st u d y site, s u bject n u m ber, a n d c ycle. 
Se paratel y, all seri o us A Es a n d A Es of s pecial i nterest (e. g., a n y DI LI, a n d as y m pt o matic left 
ve ntric ular s yst olic d ysf u ncti o n) will be liste d.  A se parat e listi n g of all o n -st u d y deat hs will 
be prese nt e d.  
9. 3. 9. 3  D e at h s a n d S eri o u s A d v er s e E v e nt s  
S A Es will be liste d a n d s u m mariz e 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.  
9. 3. 9. 4  Cli ni c al L a b or at or y R e s ult s  
F or la b orat or y res ults, s u m mar y statistics f or act u al val ues a n d f or c ha n ge fr o m baseli ne ma y 
be ta b ulate d as a p pr o priate b y sc h e 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 4. 0 3 a n d fla g ge d w he n v al ues are o utsi de t he n or mal refere n ce ra n ge.  
9. 3. 9. 5  Ot h er S af et y A n al y s e s  
Vit al Si g ns  
T he fre q u e nc y a n d perce nta ge of s u bjects wit h p ost -baseli ne cli nicall y si g nifica nt vital si g ns 
will be s u m mariz e d. A b n or mal p h ysic al e xa mi nati o n fi n di n gs ma y be c ollecte d as A Es.   
E C O G St at us  
E C O G stat us will be s u m mariz e d f or eac h visit. S hifts fr o m baseli ne t o t he best a n d w orst 
p ost baseli ne sc ore m a y b e ta b ulate d.  
E C G  
E C G stat us ( n or mal, a b n or mal cli nicall y si g nifica nt, or a b n or mal n ot cli nicall y si g nifica nt) 
ma y b e s u m mariz e d f or eac h sc he d ul e d E C G, a n d s hifts fr o m baseli ne ma y be ta b ulate d.  
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 nc e e ver y 1 2 wee ks t hereaft er 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 di ac E C H O or M U G A s h o ul d be perf or me d 
e ver y 1 2 w ee ks as d eter mi ne d b y t he date of t he m ost rece nt i nteri m assess me nt.  
A d diti o nall y, if a s u bject disc o nti n ues trast uz u ma b f or a n y reas o n, ass ess me nt of car diac 
f u ncti o n ( E C H O or M U G A) m ust be c o n d uct e d e ver y 6 m o nt hs u ntil 2 4 m o nt hs fr o m t he last 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 1  of 1 7 0  
a d mi nistrati o n of trast uz u ma b. T he m o dalit y c h os e 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 ass ess me nts t hr o u g h o ut t he st u d y f or c o m paris o n.  
9. 3. 1 0  I nt eri m A n al y s e s 
C o h ort A  uses a Fle mi n g 2 -sta ge p hase 2 desi g n, wit h a n ull h y p ot hesis of 2 0 % u nc o nfir me d 
O R R f or t ucati ni b  +  trast uz u ma b, a n alter nati ve h y p ot hesis of 4 0 %, a o ne-si de d si g nifica n ce 
le vel of 0. 1 1 5 3, a n d a p o wer of 8 3. 5 4 %. Te n e v al ua ble s u bjects are t o be treate d i n t he first 
sta ge; if ≤1 res p o nse is o bser ve d t he re gi me n will be c o nsi dere d i neffecti ve i n t his patie nt 
p o p ulati o n; if ≥5 s uccesses are o bs er ve d t h e n ull h y p ot hesis will be rej ecte d; ot her wise t he 
i nitial c o h ort pr ocee ds t o t he sec o n d sta ge. Fiftee n e val ua ble s u bjects are t o be treate d i n t he 
sec o n d sta ge; if a t otal of ≤7 res p o nses are o bser ve d i n t he first 2 5 e val ua bl e s u bjects, t he 
re gi me n will be c o nsi dere d i neffecti ve; if ≥8 res p o nses are o bs er ve d t h e re gi me n ma y merit 
f urt her e v al uati o n. 
N o f or mal i nteri m a nal ys es a re pl a n ne d f or C o h ort s B a n d C .  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 2  of 1 7 0  
1 0  I N F O R M E D C O N S E N T, E THI C A L R E VI E W, A N D R E G U L A T O R Y 
C O N SI D E R A TI O N S  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he N ote f or G ui da nce o n G o o d Cli nical 
Practice (I C H Har m o nise d Tri partite G ui deli ne E 6 ( R 2); F D A C F R [ 2 1 C F R § 5 0, 5 6, 3 1 2]), 
Declarati o n of Helsi n ki (W orl d Me dical Ass ociati o n 2 0 1 3 ), a n d all a p plica ble re g ulat or y 
re q uire me nts. F or st u dies c o n d ucte d i n t he E ur o p ea n U ni o n ( E U )/E ur o pea n Ec o n o mic Area 
(E E A ) c o u ntri es, t he i n vesti gat or wil l e ns ure c o m plia nce wit h t he E U Cli nical Trial Directi ve 
( 2 0 0 1/ 2 0/ E C) or a p plica ble E ur o pea n l o cal re g ul ati o ns. 
1 0. 1  I nf or m e d C o n s e nt 
T he i n vesti gat or is res p o nsi ble f or pres e nti n g t he ris ks a n d be nefits of st u d y partici pati o n t o 
t he s u bject i n si m ple ter ms usin g t he I R B/I E C a p pr o ve d i nf or me d c o nse nt d oc u me nt a n d f or 
e ns uri n g s u bj ects are re -c o nse nte d w he n t he i nf or me d c o nse nt d oc u me nt is u p date d d uri n g 
t he st u d y, if re q uire d. T h e i n vesti gat or will e ns ure t hat writte n i nf or me d c o nse nt is o btai ne d 
fr o m eac h s u bject, or le gall y acce pta ble re pres e ntati ve, if a p plica ble t o t his st u d y, b y 
o btai ni n g t he si g nat ur e a n d date o n t he i nf or me d c o nse nt d oc u me nt pri or t o t he perf or m a nce 
of pr ot oc ol e val u ati o ns or pr oce d ures.  
It is prefera ble f or a s u bj ect t o pr o vi de c o ns e nt t he msel ves. If i nf or me d c o nse nt is o btai ne d 
fr o m a le gall y acce pt a ble re pres e ntati ve f or a s u bj ect w h o is u na ble t o pr o vi de i nf or me d 
c o nse nt at st u d y e ntr y (if a p plica ble), b ut t he s u bject is later a ble t o pr o vi de i nf or me d 
c o nse nt, t he i n vesti gat or m ust o btai n writte n i nf or me d c o nse nt fr o m t he s u bject. 
1 0. 2  Et hi c al R e vi e w  
T he i n vesti gat or will pr o vi de t he s p o ns or or its desi g nee wit h d oc u me ntati o n of t he I R B/I E C 
a p pr o val of t he pr ot oc ol a n d t he i nf or me d c o nse nt d oc u me nt bef ore t he st u d y ma y b e gi n at 
t he i n vesti gati ve site(s). T he na me a n d a d dress of t he re vie wi n g et hics c o m mittee are 
pr o vi de d i n t he i n vesti gat or file.  
T he i n vesti gat or will s u p pl y t he f oll o wi n g t o t he i n vesti gati ve site’s I R B/I E C:  
● 
Pr ot oc ol a n d a me n d me nts  
● 
I nf or me d c o ns e nt d oc u m e nt a n d u p dates 
● 
Cli nical I n vesti gat or’s Br oc h ure a n d u p dates  
● 
Rele va nt c urri c ula vitae, if re q uire d  
● 
Re q uire d safet y a n d S A E re p orts  
● 
A n y a d diti o nal s u b missi o ns re q uire d b y t he site’s I R B/I E C  
T he i n vesti gat or m us t pr o vi de t he f oll o wi n g d o c u me ntati o n t o t he s p o ns or or its desi g nee: 
● 
T he I R B/I E C peri o dic (e. g., q uarterl y, a n n u al) re -a p pr o val of t he pr ot oc ol.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 3  of 1 7 0  
● 
T he I R B/I E C a p pr o vals of a n y a me n d me nts t o t h e pr ot oc ol or re visi o ns t o t he 
i nf or me d c o nse nt d oc u m e nt. 
● 
T he I R B /I E C r ecei pt of safet y a n d S A E re p orts, as a p pr o priate. 
1 0. 3  R e g ul at or y C o n si d er ati o n s  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol a n d et hical pri nci ples state d i n 
t he a p plica ble g ui deli nes o n g o o d cli nical practice, a n d all a p plica ble l ocal a nd/ or re gi o nal 
la ws, r ules, a n d re g ulati o ns. 
1 0. 4  I n v e sti g at or I nf or m ati o n 
T he c o ntact i nf or mati o n a n d q ualificati o ns of t he pri nci pal i n vesti gat or a n d s u b -i n vesti gat ors 
a n d na me a n d a d dress of t he researc h facilities are i ncl u de d i n t he i n vesti gat or file.  
1 0. 4. 1  Pr ot o c ol A m e n d m e nt s a n d St u d y T er 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 o c ol ( wit h t he e x ce 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 s u bject) 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 R B/I E C, a n d pri o r t o i m ple me nti n g. T he i n vesti gat or is res p o nsi ble f or 
e nr olli n g s u bjects 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 n ce 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 I R 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. 
1 0. 5  St u d y D o c u m e nt ati o n, Pri v a c y a n d R e c or d s R et e nti o n  
T o pr otect t he safet y of partici pa nts i n t he st u d y a n d t o e ns ure acc urate, c o m plete, a n d 
relia ble data, t h e i n vesti gat or will kee p rec or ds of la b orat or y tests, cli nical n otes, a n d s u bject 
me dical rec or ds i n t he s u bject files as ori gi nal s o urce d oc u m e nts f or t he st u d y. If re q u este d, 
t he i n vesti gat or will pr o vi de t he s p o ns or, its lice nsees a n d c olla b orat ors, a p plica ble 
re g ulat or y a ge ncies, a n d a p plica ble I R B/I E C wit h direct access t o ori gi nal s o urce d oc u m e nts 
or certifie d c o pies.  
Rec or ds c o ntai ni n g s u bject me dical i nf or mati o n m ust be ha n dle d i n acc or da nce wit h l ocal 
a n d nati o nal la ws, r ules, a n d re g ulati o ns a n d c o nsiste nt wit h t he ter ms of t he s u bject 
a ut h orizati o n c o ntai ne d i n t he i nf or me d c o nse nt d oc u me nt f or t he st u d y (t h e A ut h orizati o n). 
Care s h o ul d be ta ke n t o e ns ure t hat s uc h rec or ds are n ot s hare d wit h a n y p ers o n or f or a n y 
p ur p ose n ot c o nte m plate d b y t he A ut h orizati o n. F urt her m ore, C R Fs a n d ot her d oc u me nts t o 
be tra nsferre d t o t he s p o ns or s h o ul d be c o m plete d i n strict acc or da nce wit h t he i nstr ucti o ns 
pr o vi de d b y t he s p o ns or, i ncl u di n g t he i nstr ucti o ns re gar di n g t he c o di n g of s u bject i de ntities. 
I n c o m plia nce wit h l ocal a n d/ or re gi o nal re g ulati o ns, t his trial ma y be re gistere d, a n d tri al 
res ults ma y b e p oste d o n p u blic re gistries, s uc h as Cli nical Trials. g o v. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 4  of 1 7 0  
1 0. 6  Cli ni c al Tri al A gr e e m e 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 n ce, t he p u blicati o n p olic y f or cli nical trial dat a, 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 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 5  of 1 7 0  
1 1  R E F E R E N C E S  
Aar o ns o n N K, A h me dzai S, Ber g ma n B, et al. T h e E ur o pea n Or ga nizati o n f or Researc h a n d 
Treat me nt of Ca n cer Q L Q -C 3 0: a q ualit y -of -life i nstr u me nt f or use i n i nter nati o nal 
cli nical trials i n o nc ol o g y. J Natl Ca ncer I nst. 1 9 9 3; 8 5( 5): 3 6 5 -7 6.  
 
A merica n Ca n cer S oci et y. Breast ca n cer 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/r esearc h/ ca ncer -facts-a n d-
statistics/ breast-ca n cer -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 c a 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 2; 9( 1): 1 6 -3 2.  
 
Basel ga J, C ortes J, Ki m S B, et al. Pert uz u ma b pl us trast uz u ma b pl us d oceta xel f or 
metastatic breast ca ncer. N E n gl J Me d. 2 0 1 2; 3 6 6( 2): 1 0 9 -1 9.  
 
Bert otti A, Mi gliar di G, Gali mi F, et al. A m olec ularl y a n n otate d platf or m of patie nt -deri v e d 
x e n o grafts (" x e n o patie nts") i de ntifies H E R 2 as a n effecti ve t hera pe utic tar get i n 
cet u xi ma b -resista nt c ol or ectal ca ncer. Ca ncer Disc o v. 2 0 1 1; 1( 6): 5 0 8-2 3.  
 
Bert otti A, Pa p p E, J o nes S, et al. T he ge n o mic la n dsca pe of res p o nse t o E G F R bl oc ka de i n 
c ol orectal ca ncer. Nat ure. 2 0 1 5; 5 2 6( 7 5 7 2): 2 6 3 -7.  
 
B or ges V F, C hia S K L, Al oisi o S, et al. A R R Y -3 8 0, a n oral H E R 2 i n hi bit or: fi nal p hase 1 
res ults a n d c o ncl usi o ns. M ol Ca ncer Res. 2 0 1 3; 1 1( 1 0 S u p pl): A bstract A 0 5 0. 
 
B urstei n HJ, St or ni ol o A M, Fra n c o S, et al. A p hase II st u d y of la p ati ni b m o n ot hera p y i n 
c he m ot hera p y-refract or y H E R 2-p ositi ve a n d H E R 2 -ne gati ve a d v a nce d or metastatic 
breast c a ncer. A n n O n c ol. 2 0 0 8; 1 9( 6): 1 0 6 8 -7 4.  
 
Ca ncer Ge n o me Atlas N. C o m pre he nsi ve m olec ul ar c haracterizati o n of h u ma n c ol o n a n d 
rectal ca ncer. N at ure. 2 0 1 2; 4 8 7( 7 4 0 7): 3 3 0-7.  
 
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 h e 
bi n o mial. Bi o metri ka. 1 9 3 4; 2 6( 4): 4 0 4 -1 3.  
 
C o blei g h M A, V o gel C L, Tri pat h y D, et al. M ulti nati o nal st u d y of t he effi cac y a n d saf et y of 
h u ma nize d a nti -H E R 2 m o n ocl o nal a nti b o d y i n w o me n w h o ha ve H E R 2 -
o vere x pressi n g m etastatic breast ca ncer t hat has pr o gresse d after c he m ot hera p y f or 
metastatic disease. J Cli n O nc ol. 1 9 9 9; 1 7( 9): 2 6 3 9 -4 8.  
 
C ollett D. I nter v al -ce ns ore d s ur vi val data. M o d e lli n g s ur vi val dat a i n me dical res earc h. 
L o n d o n, C ha p ma n & H all. 1 9 9 4: 2 3 7 -5 1.  
 
C ortes J, F u m olea u P, Bia nc hi G V, et al. Pert uz u ma b m o n ot hera p y after trast uz u ma b -base d 
treat me nt a n d s u bse q u e nt rei ntr o d ucti o n of trast uz u ma b: acti vit y a n d t olera bilit y i n 
pati e nts wit h a d va nce d h u ma n e pi der mal gr o wt h fact or rece pt or 2 -p ositi ve breast 
ca ncer. J Cli n O nc ol. 2 0 1 2; 3 0( 1 4): 1 5 9 4-6 0 0.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 6  of 1 7 0  
 
Cre m oli ni C, L o u p a kis F, A nt o ni otti C, et al. F O L F O XI RI pl us be v aciz u ma b vers us 
F O L FI RI pl us be vaciz u ma b as first -li ne treat me nt of patie nts wit h metastatic 
c ol orectal ca ncer: u p date d o verall s ur vi val a n d m olec ular s u b gr o u p a nal yses of t he 
o pe n -la bel, p has e 3 T RI B E st u d y. La ncet O nc ol. 2 0 1 5; 1 6( 1 3): 1 3 0 6 -1 5.  
 
D o uillar d J Y, Oli ner K S, Sie na S, et al. Pa nit u m u ma b -F O L F O X 4 treat me nt a n d R A S 
m utati o ns i n c ol orectal ca ncer. N E n gl J Me d. 2 0 1 3a; 3 6 9( 1 1): 1 0 2 3 -3 4.  
 
D o uillar d J Y, Sie na S, Ta ber ner o J, et al. O verall s ur vi val ( O S) a nal ysis fr o m P RI M E: 
Ra n d o mize d p hase III st u d y of pa nit u m u ma b ( p ma b) wit h F O L F O X 4 f or first -li ne 
metastatic c ol orectal c a n cer ( m C R C). J Cli n O nc ol. 2 0 1 3 b; 3 1(s u p pl; a bstr 3 6 2 0).  
 
Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e v al uati o n criteria i n s oli d 
t u m o urs: re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5( 2): 2 2 8-4 7.  
 
Gr ot he y A, Va n C utse m E, S o brer o A, et al. Re g orafe ni b m o n ot hera p y f or pre vi o usl y tr eate d 
metastatic c ol orectal ca n cer ( C O R R E C T): a n i nter nati o nal, m ultice ntre, ra n d o mise d, 
place b o -c o ntr olle d, p has e 3 trial. La ncet. 2 0 1 3; 3 8 1( 9 8 6 3): 3 0 3 -1 2.  
 
Hac ha d H, Ra g ue n ea u -M ajlessi 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 Dat a base. 
H u m Ge n o mics. 2 0 1 0; 5( 1): 6 1 -7 2.  
 
Hai ns w ort h J D, Meric -Ber nsta m F, S wa nt o n C, et al. Tar get e d t hera p y f or a d va nce d s oli d 
t u m ors based o n m olec ul ar pr ofiles: Earl y res ults fr o m M y Pat h wa y, a n o pe n -la bel, 
p hase IIa u m brella b as ket st u d y. J Cli n O nc ol. 2 0 1 6; 3 4(s u p pl; a bstr L B A 1 1 5 1 1).  
 
Ha milt o n E, Yar dle y D, H ort o ba g yi G, et al. A p hase 1 b st u d y of O N T -3 8 0, a n oral H E R 2 -
s pecific i n hi bit or, c o m bi ne d wit h ca pecita bi ne a n d trast uz u ma b, i n H E R 2 + metastatic 
breast c a ncer ( M B C). J Cli n O nc ol. 2 0 1 4; 3 2( 5s s u p pl; a bstr T P S 6 6 3).  
 
Ha q ue R, A h me d S A, I n z ha k o va G, et al. I m pact of breast c a ncer s u bt y pes a n d treat me nt o n 
s ur vi val: a n a nal ysis s pa n ni n g t w o deca des. Ca n cer 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 ol br o T, H y nes N E. Er b B rece pt ors: directi n g k e 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.  
 
H ur witz H, Hai ns w ort h J, S wa nt o n C, et al. Tar get e d t hera p y f or gastr oi ntesti naI ( GI) t u m ors 
base d o n m olec ular pr ofiles: Earl y res ults fr o m M y P at h wa y, a n o pe n -la bel p hase IIa 
bas ket st u d y i n patie nts wit h a d va nce d s oli d t u m ors. J Cli n O nc ol. 2 0 1 6; 3 4(s u p pl 4 S; 
a bstr 6 5 3).  
 
H y n es N E, La n e H A. E R B B rece pt ors a n d ca ncer: t he c o m ple xit y of t ar get e d i n hi bit ors. Nat 
Re v Ca ncer. 2 0 0 5; 5( 5): 3 4 1 -5 4.  
 
J e mal A, Sie gel R, X u J, War d E. Ca ncer statistics, 2 0 1 0. C A: A Ca ncer J o ur nal f or 
Cli nicia ns. 2 0 1 0; 6 0( 5): 2 7 7 -3 0 0.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 7  of 1 7 0  
 
J o h nst o n S R D, He g g R, I m S A, et al. P hase III, ra n d o mize d stu d y of d ual h u ma n e pi der mal 
gr o wt h fact or rece pt or 2 ( H E R 2) bl oc ka d e wit h la pati ni b pl us trast uz u ma b i n 
c o m bi nati o n wit h a n ar o matase i n hi bit or i n p ost me n o pa usal w o me n wit h H E R 2 -
p ositi ve, h or m o ne rece pt or – p ositi ve metastatic breast ca n cer: A L T E R N A TI V E. J 
C li n O nc ol. 2 0 1 8; 3 6( 8): 7 4 1-8.  
 
Ka n g S P, Saif M W. I nf usi o n -relate d a n d h y p erse nsiti vit y reacti o ns of m o n ocl o nal a nti b o dies 
use d t o treat c ol orectal ca ncer --i de ntificati o n, pre v e nti o n, a n d ma na ge m e nt. J S u p p ort 
O nc ol. 2 0 0 7; 5( 9): 4 5 1 -7.  
 
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 -stat e 
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.  
 
Marti n M, B o n neterre J, Ge yer C E, Jr., et al. A p hase t w o ra n d o mise d tri al of nerati ni b 
m o n ot hera p y vers us la pati ni b pl us ca pecita bi ne c o m bi nati o n t hera p y i n p atie nts wit h 
H E R 2 + a d va n ce d breast ca ncer. E ur J Ca ncer. 2 0 1 3a; 4 9( 1 8): 3 7 6 3 -7 2.  
 
Marti n V, La n di L, M oli nari F, et al. H E R 2 ge ne c o p y n u m b er stat us ma y i nfl ue nce cli nical  
effic ac y t o a nti -E G F R m o n ocl o nal a nti b o dies i n metastatic c ol orectal ca n cer patie nts. 
Br J Ca ncer. 2 0 1 3 b; 1 0 8( 3): 6 6 8 -7 5.  
 
Ma yer RJ, Va n C utse m E, Falc o n e A, et al. Ra n d o mize d trial of T A S -1 0 2 f or refract or y 
metastatic c ol orectal ca n cer. N E n gl J Me d. 2 0 1 5; 3 7 2( 2 0): 1 9 0 9 -1 9.  
 
Meric -Ber nst a m F, H ur witz H, Ra g ha v K P S, et al. Pert uz u ma b pl us trast uz u ma b f or H E R 2 -
a m plifie d metastatic c ol orectal ca ncer ( M y Pat h w a y): a n u p date d re p ort fr o m a 
m ultice ntre, o pe n -la b el, p hase 2a, m ulti ple bas ket st u d y. La n cet O nc ol. 
2 0 1 9 ; 2 0( 4): 5 1 8-3 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 yi o ye M A, Ne v e R M, La n e H A, H y nes N E. T h e Er b B si g n ali n g n et w or k: rece pt or 
heter o di merizati o n i n de vel o p me nt a n d ca n cer. E M B O J. 2 0 0 0; 1 9( 1 3): 3 1 5 9 -6 7.  
 
Price TJ, Peeters M, Ki m T W, et al. Pa nit u m u ma b vers us cet u xi ma b i n patie nts wit h 
c he m ot hera p y-refract or y wil d-t y pe K R A S e x o n 2 metastatic c ol orectal ca n cer 
( A S P E C C T): a ra n d o mise d, m ultice ntre, o pe n-la bel, n o n-i nferi orit y p has e 3 st u d y. 
La n cet O n c ol. 2 0 1 4; 1 5( 6): 5 6 9 -7 9.  
 
Ra g ha v K P, O ver ma n MJ, Y u R, et al. H E R 2 a m plificati o n as a ne gati ve pre dicti ve 
bi o mar ker f or a nti -e pi der mal gr o wt h fact or rece pt or a nti b o d y t hera p y i n m etastatic 
c ol orectal ca ncer. J Cli n O nc ol. 2 0 1 6; 3 4(s u p pl; a bstr 3 5 1 7). 
 
Riese DJ, 2 n d, Ster n D F. S pecificit y wit hi n t he E G F fa mil y/ Er b B rece pt or fa mil y si g n ali n g 
net w or k. Bi o essa ys. 1 9 9 8; 2 0( 1): 4 1 -8.  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 8  of 1 7 0  
R osell o S, Blasc o I, Garcia Fa bre gat L, et al. Ma n a ge me nt of i nf usi o n r ea cti o ns t o s yst e mic 
a ntica ncer t hera p y: E S M O Cli nical Practice G ui d eli 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.  
 
Sart ore -Bia nc hi A, Tr us oli n o L, Marti n o C, et al. D ual -tar gete d t hera p y wit h trast uz u ma b a n d 
la pati ni b i n treat me nt-refract or y, K R A S c o d o n 1 2/ 13 wil d -t y pe, H E R 2-p ositi ve 
metastatic c ol orectal ca n cer ( H E R A C L E S): a pr o of -of -c o nce pt, m ultice ntr e, o pe n -
la bel, p hase 2 trial. La ncet O nc ol. 2 0 1 6; 1 7( 6): 7 3 8-4 6.  
 
Sc hlessi n ger J. Li 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.  
 
Sc h m oll HJ. Tar geti n g H E R 2: precisi o n o nc ol o g y f or c ol orectal ca ncer. La ncet O nc ol. 2 0 1 6.  
 
Sie na S, Sart ore -Bia nc hi A, L o n ar di S, et al. Trast uz u ma b a n d la pati ni b i n H E R 2 -a m plifie d 
metastatic c ol orectal ca n cer patie nts ( m C R C): T h e H E R A C L E S trial. J Cli n O nc ol. 
2 0 1 5; 3 3(s u p pl; a bstr 3 5 0 8).  
 
S mit h TJ, K hatc heressia n J, L y ma n G H, et al. 2 0 0 6 u p date of rec o m me n d ati o ns f or t he use 
of w hite bl o o d cell gr o wt h fact ors: a n e vi de nce -base d cli nical practice g ui d eli ne. J 
Cli n O nc ol. 2 0 0 6; 2 4( 1 9): 3 1 8 7 -2 0 5.  
 
S nee u w K C, Aar o ns o n N K, S pra n gers M A, et al. C o m paris o n of patie nt a n d pr o x y E O R T C 
Q L Q -C 3 0 rati n gs i n assessi n g t he q ualit y of life of ca ncer patie nts. J Cli n E pi de mi ol. 
1 9 9 8; 5 1( 7): 6 1 7 -3 1.  
 
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.  
 
Va n C utse m E, K o h ne C H, La n g I, et al. Cet u xi ma b pl us iri n oteca n, fl u or o uracil, a n d 
le uc o v ori n as first-li ne tr eat me nt f or metast atic c ol orectal ca ncer: u p date d a nal ysis of 
o verall s ur vi val a cc or di n g t o t u m or K R A S a n d B R A F m utati o n stat us. J Cli n O nc ol. 
2 0 1 1; 2 9( 1 5): 2 0 1 1 -9.  
 
Vlacic h G, C offe y RJ. Resista nce t o E G F R -tar gete d t hera p y: a fa mil y affair. Ca ncer C ell. 
2 0 1 1; 2 0( 4): 4 2 3 -5.  
 
W orl d Me dical Ass ociati o n. Declarati o n of Helsi n ki --et hical pri nci ples f or me dical res earc h 
i n v ol vi n g h u ma n s u bjects. 64t h W M A Ge neral Asse m bl y, F ortaleza, Brazil, Oct o ber 
2 0 1 3. htt ps:// w w w. w ma. net/ p olicies -p ost/ w ma -declarati o n -of -helsi n ki -et hi cal-
pri nci ples -f or-me dical -researc h-i n v ol vi n g-h u m a n -s u bjects/. Access e d: Fe b 1, 2 0 1 9. 
2 0 1 3.  
 
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 n alli n g n et 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 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 0 9  of 1 7 0  
Y o nesa ka K, Zej n ulla h u K, O ka m ot o I, et al. Acti vati o n of E R B B 2 si g n ali n g ca uses 
resista nce t o t he E G F R-directe d t hera pe utic a nti b o d y cet u xi ma b. Sci Tra nsl Me d. 
2 0 1 1; 3( 9 9): 9 9ra 8 6.  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 0  of 1 7 0  
A P P E N DI X A : S C H E D U L E O F E V E N T S   
T a bl e 1 1 -1 : 
S c h e d ul e of e v e nt s  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 1  of 1 7 0  
St u d y P eri o d/ Treat me nt C ycle  
Pre -scree ni n gv 
Scree ni n g/ Baseli ne  
Treat me nt  
E O T a 
F/ U b 
U p t o 3 
m o nt hs pri or 
t o scree ni n g 
 
C ycle 1  
C ycles > 1  
E ver y 6 or 
9  w ks  
E ver y 
1 2  w ks  
3 0 da ys p ost last 
d ose  
E ver y 
1 2  w ks  
Da y  
 
D – 2 8 t o – 1  D – 7 t o – 1  
Pre -d ose D 1  
D 8 a n d 1 5  
Pre -d ose D 1  
 
 
 
 
 
Visit Wi n d o w  
 
 
 
 
± 3 da ys  
± 3 da ys  
± 7 da ys  
± 1 4 da ys  
+ 7 da ys  
± 1 4 da ys  
H E R 2  alterati o ns  testi n g inf or me d c o nse nt v 
X  
 
 
 
 
 
 
 
 
 
St u d y i nf or me d c o nse nt c 
 
X  
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
 
X  
 
 
 
 
 
 
 
 
D oc u me nt disease hist or y  
 
X  
 
 
 
 
 
 
 
 
F F P E T u m or S peci me n d 
X  
X  
 
 
 
 
 
 
 
 
P h ysical e xa mi n ati o n e  
 
 
X  
X  
 
X  
 
 
X  
 
Hei g ht  
 
 
X  
 
 
 
 
 
 
 
Vital si g ns f 
 
 
X  
X  
 
X  
 
 
X  
 
Dr u g Diar y re vie w  
 
 
 
X  
 
X  
 
 
 
 
A d verse  e ve nt c ollecti o n  
 
Relate d t o st u d y 
pr oce d ures  
C ollect fr o m C 1 D 1 pre -d ose t hr o u g h safet y re p orti n g peri o d of st u d y dr u gs  
 
C o nc o mita nt me dicati o n  
 
 
E C O G P S  
 
 
X  
X  
 
X  
 
 
X  
 
C B C wit h differe ntial a n d platelets g 
 
 
X  
X  
X  
X  
 
 
X  
 
Bl o o d c he mistries a n d L F Ts h 
 
 
X  
X  
X  
X  
 
 
X  
 
C oa g ulati o n tests i 
 
 
X  
 
 
 
 
 
X  
 
Uri nal ysis  
 
 
X  
 
 
 
 
 
 
 
1 2 -lea d E C Gj 
 
 
X  
 
 
 
 
 
 
 
E C H O/ M U G A k 
 
X  
 
 
 
 
 
X  
X l 
X  
Ser u m β -H C G pre g na nc y test m  
 
 
X m  
X m  
 
X  
 
 
 
 
He patitis B a n d C scree ni n g n 
 
X  
 
 
 
 
 
 
 
 
Ra di ol o gical disease assess me nt o , u 
 
X  
 
 
 
 
X o 
 
X  
 
Bl o o d t u m or mar ker –  C E A p 
 
X  
 
 
 
 
X p 
 
X  
 
E Q -5 D -5 L/ E O R T C Q L Q C 3 0 q uesti o n naire q 
 
 
 
X  
X  
X  
 
 
X  
 
St u d y dr u g treat me nt –  T ucati ni b r 
 
 
 
X  
 
X  
 
 
 
 
St u d y dr u g treat me nt –  Trast uz u ma b s 
 
 
 
X  
 
X  
 
 
 
 
P K a n d Bi o mar ker s a m ple  
 
See  T a ble 1 1 -2  a n d T a ble 1 1 -3  f or P K a n d bi o mar ker sa m ples c ollecti o n sc he d ule 
F urt h er a ntica ncer t h era p y a n d s ur vi valt 
 
 
 
 
 
 
 
 
 
X  
a 
F or C o h ort A, if s u bject disc o nti n ues treat me nt beca use of P D, t h e y will ha ve 1 O bser vati o n visit 3 0 ( ± 7) da ys p ost last st u d y i nter ve nti o n. After t his ti me, s u bject will e nter f oll o w -u p. F or 
s u bjects w h o g o off st u d y treat me nt wit h n o d oc u me nte d disease pr o gressi o n a n d n o s u bse q ue nt a ntica ncer treat me nt, t h e s u bject will be o bser ve d e ver y 1 2 wee ks ( ± 1 4 da ys) or as cli nicall y 
i n dicate d u ntil P D, at w hic h ti me t h e y will e nter f oll o w-u p. S u bj ects re mai ni n g i n o bser vati o n f or ≥5 years fr o m first st u d y treat me nt will g o off st u d y wit h o ut e nteri n g f oll o w -u p.   
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 2  of 1 7 0  
b  
Treat me nt decisi o ns/ patie nt  care f or s u bjects w h o ha ve disc o nti n ue d st u d y treat me nt is at t h e discreti o n of t h e treati n g p h ysicia n.  
c 
I nf or me d c o nse nt m ust b e o btai ne d bef ore i nitiati o n of a n y cli nical scree ni n g pr oce d ure t hat is perf or me d s olel y f or t h e p ur p ose of deter mi ni n g eli gi bilit y f or t his st u d y. E val u ati o ns perf or me d as 
part of r o uti ne care bef ore i nf or me d c o nse nt ca n be c o nsi dere d as scree ni n g e val u ati o ns if d o ne wit hi n t h e defi ne d scree ni n g peri o d, a n d if per mitte d b y t h e site’s i n stit uti o nal re vie w b oar d 
(I R B)/i n de pe n de nt et hics c o m mittee (I E C) p olicies. 
d  
I nitiate c ollecti o n of tiss ue f or s u b missi o n f or c o nfir mator y H E R 2 + a n d b i o mar ker testi n g at pre -scr ee ni n g or screen i n g. If arc hi ve d tiss ue is n ot a vaila ble, a ne w bi o ps y of a t u m or lesi o n s h o ul d 
be o btai ne d, if me dicall y feasi ble. S u bjects wit h n o arc hi val tiss ue, a n d w h ose t u m ors are c o nsi dere d n ot accessi ble or a p pr o priate f or bi o ps y are n ot eli gi ble f or e nr oll me nt . 
e 
P re-d ose , ma y n ot be perf or me d if d o ne wit hi n 1 da y pri or t o C 1 D 1 
f 
Vital si g ns t o be c ollecte d are wei g ht, b o d y te m perat ure, heart  rate, s yst olic a n d diast olic bl o o d press ure, p ulse, a n d o x y ge n sat urati o n.  P re-d ose, ma y n ot be perf or me d if d o ne wit hi n 1 da y pri or 
to C 1 D 1 .  
g  
If C B C is perf or me d wit hi n 7 da ys pri or t o C 1 D 1, it d oes N O T nee d re peati n g o n C 1 D 1. 
h  
Creati ni n e, calc ulate d creati ni ne cleara nce usi n g C oc kcr oft -Ga ult (at baseli ne a n d as cli nicall y i n dicate d), t otal bilir u bi n  (a n d direct bilir u bi n w he n t otal bilir u bi n is > U L N), A L T, A S T, al kali ne 
p h os p hatase, al b u mi n, calci u m, s o di u m, p otassi u m, c hl ori de, bicar b o nate, B U N, gl u c ose, a n d t otal pr otei n. If c he mistries are perf or me d wit hi n 7 da ys pri or t o C 1 D 1, t he y d o N O T nee d t o be 
re peate d o n C 1 D 1. 
i 
P T, I N R, a P T T  
j 
E C G ass ess me nts will be perf or me d wit h sta n dar d 1 2 -lea d E C G e q ui p me nt acc or di n g t o sta n dar d i nstit uti o nal pr oce d ures. Pre-treat me nt E C Gs s h o ul d be perf or me d aft er vital si g ns are o btai ne d 
a n d bef ore a n y bl o o d dra ws.  
k  
Car diac ejecti o n fracti o n will be 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 we e ks u ntil treat me nt disc o nti n uati o n irres pecti ve of d ose del a ys or i nterr u pti o n, a n d at 
t h e E O T visit. E C H O is t h e 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 s ca n ma y be use d i n place of E C H O. If a s u bject disc o nti n ues trast uz u ma b f or a n y reas o n, 
assess me nt of car diac f u ncti o n ( E C H O or M U G A) m ust b e c o n d ucte d e ver y 6 m o nt hs u ntil 2 4 m o nt hs fr o m t h e last a d mi nistrati o n o f trast u z u ma b. T he sa me met h o d f or L V E F asse ss me nt s h o ul d 
be e m pl o ye d at eac h assess me nt.  
l 
T he E O T assess me nt of E C H O d oes n ot nee d t o be perf or me d if a n o n -treat me nt E C H O h a d bee n perf or me d wit hi n 1 2 wee ks pre vi o usl y. 
m  
W o me n of c hil d beari n g p ote ntial o nl y. If pre g na nc y test is p erf or me d wit hi n 7 da ys  pri or t o C 1 D 1, it d oes n ot nee d t o be re peate d o n C 1 D 1.  
n  
Bl o o d sa m ples f or He patitis B s urfa ce a nti ge n ( h Bs A g), a nti b o dies t o He patitis B c ore (a nti -H Bc), a n d a nti b o dies t o He patitis C (a nti -H C V  will o nl y be c ollecte d f or C o h orts B a n d C ). 
o  
C T or M RI of t h e  c hest, a b d o me n, a n d pel vis t o assess sites of meas ura ble disease as p er R E CI S T 1. 1. If c ycles are dela ye d f or a n y re as 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 h e ori gi n al sc he d ule. U nless cli nic all y i n dicate d, t he sa me met h o d f or t u m or assess me nt s h o ul d be e m pl o ye d at e ver y resta gi n g. F or C o h ort A, 
ra di ol o gical disease assess me nt will be perf or me d at t h e scree ni n g/ baseli ne, e ver y 9 we e ks/ 3 c ycl es ( ± 1 4 da ys) d uri n g st u d y t reat me nt (e ver y 1 2 wee ks/4 c ycles [ ± 7 da ys] after 1 2 m o nt hs of 
treat me nt, if t h e s u bject is cli nicall y sta ble), a n d at t h e E O T visit. F or C o h orts B a n d C, ra di ol o gical assess me nt will be perf or me d at scree ni n g/ b aseli ne, e ver y 6 we e ks ( ± 7 da ys) d uri n g treat me nt 
(e ver y 1 2 wee ks [ ± 7 da ys] after 1 2 m o nt hs of treat me nt, if t h e s u bject is cli nicall y sta ble), a n d at t he E O T visit. Ra di o gra p hic assess me nts f or s u bjects wit h d oc u me nte d P D w h o ha ve c o nti n ue d 
o n st u d y treat me nt f or cli nical be nefit m ust c o nti n ue t o be perf or me d per t he pr ot o c ol defi n e d assess me nt sc he d ul e; co nti n ue d disease assess me nts will n ot be re q uire d after treat me nt is 
disc o nti n ue d.  S u bjects w h o  disc o nti n ue f or reas o ns ot h er t ha n d oc u me nte d P D will c o nti n ue t o ha ve disease assess me nts a p pr o xi matel y e ver y 9 we e ks u ntil disease pr o gressi o n, deat h, 
wit h dra wal of c o nse nt, st u d y cl os ure, or alter nati ve t h era p y.   
p  
C E A  ass a ys  will be  perf or me d  o n t h e sa m e sc he d ule as ra di o gra p hic sca n ni n g. F or C o h ort  A , C E A assa ys will be perf or me d at t h e scree ni n g/ b aseli ne, e ver y 9 wee ks ( e ver y 3 c ycles , ±1 4 da ys) 
d uri n g st u d y treat me nt (e ver y 1 2 we e ks [ ± 7 da ys] after 1 2  m o nt hs of treat me nt, if t h e s u bject is cli nicall y sta ble), a n d at t he E O T visit. F or C o h orts  B a n d C , C E A assa ys will be perf or me d  at 
scree ni n g/ b aseli ne, e ver y 6 wee ks ( ±7 da ys ) d uri n g treat me nt (e ver y 1 2  we e ks [ ± 7 da ys] after 1 2  m o nt hs of treat me nt, if t h e s u bject is cli nicall y sta ble),  a n d  at t h e E O T visit . 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 me nt, C E A assa ys 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.  
q  
E Q -5 D -5 L a n d E O R T C Q L Q -C 3 0 q uesti o n naires will be a d mi nistere d  f or C o h orts B a n d C at: pre -d ose C 1 D 1 , C 1 D 8, C 1 D 1 5, C 2 D 1, C 3 D 1, C 4 D 1, e ver y 3 c ycles t h ereafter, u ntil treat me nt 
disc o nti n uati o n, P D , deat h, t o xicit y, wit h dra wal of c o nse nt or st u d y cl os ure, a n d at t h e E O T . 
r 
T ucati ni b is a d mi nistere d P O BI D, o n eac h 2 1 -da y c ycle.  
s 
Trast uz u ma b is a d mi nistere d I V, o nce e ver y 2 1 da ys f or C o h orts A a n d B , or s u bjects i n C o h ort C w h o are a p pr o ve d t o cr oss o ver t o d o u blet treat me nt.  
t 
F oll o wi n g pr o gressi o n or i nitiati o n of f urt h er a ntica ncer t h era p y, s u bjects will be c o ntacte d e ver y 1 2 we e ks ( ± 2 wee ks) t o o btai n i nf or mati o n o n s u bse q ue nt a ntica ncer t h era p y, a n d s ur vi val stat us 
u ntil deat h, st u d y cl os ure, or wit h dra wal of c o nse nt.  
u  
S u bjects fr o m C o h ort C  m ust h a ve a ne w baseli ne R E CI S T assess me nt , as d escri b e d i n  Secti o n 6. 3. 6 , pri or t o cr oss o ver fr o m m o n ot hera p y t o d o u blet t hera p y usi n g t h e  W ee k 1 2 sca ns or t h e first 
P D sca n s as a p plica ble. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 3  of 1 7 0  
v  
If H E R 2 o vere x pressi o n/a m plific ati o n stat us is u n k no w n i n pre -st u d y ass ess me nts, s u bjects ma y c o nse nt t o s u b mit a n arc hi val t u m or s peci me n or ne w lesi o n bi o ps y f or l o cal 
I m m u n o hist oc he mistr y/I n sit u h y bri dizati o n testi n g f or assess me nt of H E R 2 stat us. S u bjects m ust b e i nf or me d t h at H E R 2 testi n g c o nse nt is n ot i nf or me d c o nse nt f or t h e st u d y a n d partici pati o n i n 
H E R 2 testi n g d oes n ot g uara ntee st u d y eli gi bilit y.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 4  of 1 7 0  
T a bl e 1 1 -2 : 
P h ar m a c o ki n eti c a n d bi o m ar k er s a m pl e c oll e cti o n ti m e p oi nt s –  C o h ort A  
Visit  
St u d y da y   T i me 
Wi n d o w  
Relati ve Ti me  
Bl o o d Sa m ples  
T u m or  
Bi o mar ker  Plas ma  
(M utati o nal A nal ysis ) 
Bi o mar ker Ser u m  
F F P E T u m or S peci me n  
Scree ni n g  
-2 8 t o -1  
N/ A  
N/ A  
N/ A  
 
 
X a 
C ycle 1  
 
Da y 1  
Pre -d ose  
Wit hi n 2 4 h o urs  
Ti me of a d mi nistrati o n  
X  
X  
 
C ycle 4 a n d e ver y t hir d 
c ycle t hereafter  
Da y 1  
Pre -d ose  
Wit hi n 2 4 h o urs  
Ti me of a d mi nistrati o n  
X  
X  
 
E n d of Treat me nt  
X  
X  
 
a 
If arc hi ve d tiss ue is n ot a vaila ble, a ne w bi o ps y of a t u m or lesi o n s h o ul d be o btai ne d, if me dicall y fe asi ble. S u bjects wit h n o arc hi val tiss ue, a n d w h ose t u m ors are c o nsi dere d n ot accessi ble or 
a p pr o priate f or bi o ps y are n ot eli gi ble f or e nr oll me nt  
 
T a bl e 1 1 -3 : 
P h ar m a c o ki n eti c a n d b i o m ar k er s a m pl e c oll e cti o n ti m e p oi nt s –  C o h ort s  B  a n d C  
Visit  
St u d y da y   
Ti me  
Wi n d o w  
Relati ve Ti me  
Bl o o d Sa m ples  
T u m or  
P K  
Bi o mar ker  
Plas ma  
F F P E T u m or S peci me n  
Scree ni n g  
-2 8 t o -1  
N/ A  
N/ A  
N/ A  
 
X  
X a 
C ycle 2  
Da y 1  
Pre -d ose  
Wit hi n 2 h o urs  
Ti me of a d mi nistrati o n of t ucati ni b  
X  
 
 
C ycle 3  
Da y 1  
Pre -d ose  
Wit hi n 2 h o urs  
Ti me  of a d mi nistrati o n of t ucati ni b  
X  
 
 
P ost -d ose  
Wit hi n 1 -4 h o urs  
P ost -d ose  of t ucati ni b  
X  
 
 
C ycle 4, 5 & 6  
Da y 1  
Pre -d ose  
Wit hi n 2 h o urs  
Ti me of a d mi nistrati o n of t ucati ni b  
X  
 
 
E n d of Treat me nt  
 
X  
 
a 
If arc hi ve d tiss ue is n ot a vaila ble, a ne w bi o ps y of a t u m or lesi o n s h o ul d be o btai ne d, if me dicall y fe asi ble. S u bjects wit h n o arc hi val tiss ue, a n d w h ose t u m ors are c o nsi dere d n ot accessi ble or 
a p pr o priate f or bi o ps y are n ot eli gi ble f or e nr oll me nt  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 5  of 1 7 0  
A P P E N DI X B : P E R F O R M A N C E S T A T U S S C A L E S C O N V E R SI O N  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)
C O P Y RI G H T E D M A T E RI A L

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 6  of 1 7 0  
A P P E N DI X C : G UI D A N C E O N C O N T R A C E P TI O N  
F or t he p ur p os es of t his g ui da nce, c o m plete a bsti ne nce, if c o nsiste nt wit h t he s u bject’s preferre d 
lifest yle, is a n acce pta ble f or m of c o ntr ace 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 hro u g h o ut t he st u d y a n d u ntil t he e n d 
of s yste 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 dr u g  a d mi nistrati o n ; see 
Secti o n  4. 1 ).  
Acce pt a ble 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) 
S u bjects 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 he f oll o wi n g 
me t 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 o ciate 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 a z o os per mia)  
● B arrier met h o d/s ( male or fe male c o n d o m wit h or wit h o ut s p er 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 wit h o ut s per mici de)  
a 
A pers o n of c hil d beari n g p ote ntial is d efi n e d as  a n y o ne b or n fe mal e 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 is d efi n e d cli nicall y as 1 2 m o nt hs of a me n orr h ea 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 ma c 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  
S u bjects 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 v es i n O pti o n 1 or 2:  
● O pti o n 1: Male c o n d o m ( wit 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 ( wit h or wit h o ut s per mici de) a n d dia p hra g m  
U n acce pt a ble met h o ds of c o ntr ace pti o n  
● P eri o dic a bs ti ne nce 
● S per mici de o nl y  
● N o met h o d  
● Pr o gesti n -o nl y pills  
● Wit h dra wal  
● C o nc o mita nt use of fe male a n d male c o n d o ms  
● R h yt h m  
 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 7  of 1 7 0  
A P P E N DI X D : N E W Y O R K H E A R T A S S O C I A TI O N C L A S SI FI C A TI ON  
O n -li ne s o urce: htt p:// w w w. heart. or g/ H E A R T O R G/ C o n diti o ns/ Heart Fail ure/ A b o ut Heart Fail ure/ Classes -of -H eart -
Fail ure _ U C M _ 3 0 6 3 2 8 _ Article.js p  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)
C O P Y RI G H T E D M A T E RI A L

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 8  of 1 7 0  
A P P E N DI X E : 
C Y P 3 A 4 I N D U C E R S A N D T H EI R E LI MI N A TI O N H A L F -LI V E S  
C Y P 3 A 4 i n d ucers i ncl u d e b ut are n ot li mite d t o t he f oll o wi n g. T h ere c o ul d als o be a d diti o nal 
n e 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 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  
B ar 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 merci all y a vaila ble w hile t h e 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/ u c m 0 9 3 6 6 4. ht
m # p ote nc y ) 
b.  
E M A. “ G ui d eli ne o n t he i n vesti g ati 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/ Scientific _ g ui d eli ne/ 2 0 1 2/ 0 7/ W C 5 0 0 1 2 9 6 0 6. p d f) 
c. 
D r u g pac ka ge i nsert 
d.  
(Ker b 1 9 9 6 ) 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 1 9  of 1 7 0  
A P P E N DI X F : 
C Y P 2 C 8 I N HI BI T O R S/I N D U C E R S A N D T H EI R E LI MI N A TI O N H A L F -
LI V E S  
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 ma r 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  
T erifl 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 d e ntifie d or bec o me c o m merci all y a vaila ble w hile t h e 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/ u c m 0 9 3 6 6 4. ht
m # p ote nc y)  
b  
E M A. “ G ui d eli ne o n t he i n vesti g ati 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 d eli ne/ 2 0 1 2/ 0 7/ W C 5 0 0 1 2 9 6 0 6. p df )  
c 
Dr u g pac ka ge i nsert  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 0  of 1 7 0  
A P P E N DI X G : P A TI E N T D R U G DI A R Y   
T uc ati ni b  
C ycle:  
P atie nt I D N u m ber:  
Na me:  
Pill stre n gt h  dis pe nse d :  
 5 0 m g ta blets  
Y o u will ta ke _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ta blets i n t he M O R NI N G,  
 a n d _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ta blets i n t he E V E NI N G.  
 1 5 0 m g  ta blets 
O R A L M E DI C A TI O N DI A R Y  
Patie nt I nstr ucti o ns  
● 
St ore y o ur st u d y dr u g i n t he refri gerat or  a n d kee p o ut of t he r eac h of c hil dre n a n d pets. T he i n di vi d ual u nit d ose of t he t uc ati ni b ta blet ma y be e x p ose d 
t o r o o m te m perat ure f or u p t o 6 h o urs pri or t o d ose. If left o ut of refri gerati o n f or a l o n ger peri o d of ti me, please c o ntact y o ur st u d y tea m.    
● 
Please bri n g y o ur Me dicati o n Diar y a n d a n y e m pt y or u n use d me dicati o n c o ntai ner(s) wit h y o u t o e ver y a p p oi nt me nt  
● 
Please use a n i n k pe n w he n c o m pleti n g t he Me dicati o n Diar y as t hese will be retai ne d i n o ur researc h rec or d.  
● 
Please c o ntact y o ur p h ysicia n a n d st u d y c o or di nat or a n y ti me y o u g o i nt o t he h os pital. Y o ur p h ysicia n ca n a d vise if y o u s h o ul d st o p ta ki n g y o ur 
me dicati o n or c o nti n ue it.  
● 
T o c orrect a n err or or mista ke, please ma ke a si n gle li ne t hr o u g h t hat e ntr y a n d wri te y o ur i nitials a n d date ne xt t o t he err or or mista ke. 
● 
Please rec or d eac h d ose as s o o n as y o u ta ke it a n d fill i n t he date as directe d.  
● 
Please i n dicate o n t he cale n dar bel o w e ver y da y t hat y o u ta ke y o ur st u d y me dicati o n b y pl aci n g t he ti me d ose was ta ke n o n t he li ne u n der t he date.  
● 
Please d o n ot c o ns u me gra p efr uit, gra pefr uit j uice, star fr uit, or Se ville ora n ges w hile ta ki n g t ucati ni b.  
● 
T ucati ni b ta blets s h o ul d be ta ke n 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 8-1 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 d e d t hat if y o u miss 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, y o u 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. If y o u miss a d ose, place a c hec k “ 0” u n der t he d ate.  
● 
T a ke ta blets b y m o ut h t wice d ail y as prescri be d o n da ys 1 – 2 1 of  eac h c ycle  
● 
If y o u acci de ntall y ta ke m ore t ha n y o u are i nstr ucte d t o, c o ntact y o ur d oct or or t he e mer ge nc y r o o m i m me diatel y.  
● 
If y o u miss a d ose, d o n ot ma ke u p t he d ose or d o u ble u p t he ne xt d ose. 
● 
Pills m ust b e s wall o we d w h ol e. D o n ot cr us h, c he w, or diss o l ve pills i n li q ui d. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 1  of 1 7 0  
● 
If y o u v o mit a d ose, a n d t he pill is visi ble i n t he v o mit, y o u c a n ta ke a  re place me nt pill.  If t he pill is n ot visi ble i n t he v o mit, please wait u ntil y o ur ne xt 
sc he d ule d ti me bef ore ta ki n g t he me dicati o n a gai n.  
 
D a y 1  
D a y 2  
D a y 3  
D a y  4  
D a y 5  
D a y 6  
D a y 7  
Date:  
 
 
 
 
 
 
 
Ti me of M or ni n g 
D ose  
A M  
A M  
A M  
A M  
A M  
A M  
A M  
Ti me of E ve ni n g 
D ose  
P M  
P M  
P M  
P M  
P M  
P M  
P M  
 
D a y 8  
D a y 9  
D a y 1 0  
D a y 1 1  
D a y 1 2  
D a y 1 3  
D a y 1 4  
Date:  
 
 
 
 
 
 
 
Ti me of M or ni n g 
D ose  
A M  
A M  
A M  
A M  
A M  
A M  
A M  
Ti me of E ve ni n g 
D ose  
P M  
P M  
P M  
P M  
P M  
P M  
P M  
 
D a y 1 5  
D a y 1 6  
D a y 1 7  
D a y 1 8  
D a y 1 9  
D a y 2 0  
D a y 2 1  
Date:  
 
 
 
 
 
 
 
Ti me of M or ni n g 
D ose  
A M  
A M  
A M  
A M  
A M  
A M  
A M  
Ti me of E ve ni n g 
D ose  
P M  
P M  
P M  
P M  
P M  
P M  
P M  
Eac h c ycl e has 2 1 d a ys.  I n cases w here a patie nt is u na ble t o ret ur n t o cli ni c at t he 
e n d of a c ycle, a 3 -da y wi n d o w is all o we d i n t he st u d y.  T ucati ni b ta blets ta ke n 
d uri n g t his ti me will be rec or de d h ere.  
 
 
+ D ay  1  
 
 
+ D ay  2  
 
 
+ D ay 3  
Date:   
 
 
Ti me of M or ni n g D ose  
A M  
A M  
A M  
Ti me of E ve ni n g D ose  
P M  
P M  
P M  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 2  of 1 7 0  
A P P E N DI X H : E X A M P L E S O F C LI NI C A L  S U B S T R A T E S F O R C Y P 3 A -M E DI A T E D 
M E T A B O LI S M  
T he f oll o wi n g t a ble pr o vi des e x a m ples of cli nical s u bstrates f or C Y P 3 A -m e diate d meta b olis m 
a n d is n ot i nte n de d t o be a n e x ha usti ve list. 
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 n
d, mi daz ola m, 
nal o xe g ol, nis ol di pi ne, sa q ui na vir
c, si m vastati n
d, 
sir oli m us, tacr oli m us, ti pra na vir
c, 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 m ozi 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 vir
c, 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 h at de m o nstrate a n i n crease 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 h at de m o nstrate a n i n crease 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 h e das he d li ne. Ot her eli mi n ati o n 
pat h wa ys ma y als o c o ntri b ute t o t he eli mi n ati o n of t h e 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 w he n 
assessi n g t h e dr u g i nt eracti o n p ote ntial.  
D DI data were c ollecte d base d o n a searc h of t h e 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 ). 
O A T P 1 B 1  =  or ga nic a ni o n tra ns p orti n g p ol y pe pti de 1 B 1.  
d  
Liste d base d o n p har mac o ge netic st u dies.  
e 
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.  
f 
Us uall y a d mi n istere d t o patie nts i n c o m bi n ati o n wit h rit o na vir, a str o n g C Y P 3 A i n hi bit or. 
g  
Aci d f or m is a n O A T P 1 B 1 s u bstrate  
S o urce: 
htt p  s:// 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/ u c m 0 9 3 6 6 4. ht m #t
a ble 3 -1  
 
 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 3  of 1 7 0  
A P P E N DI X I: 
D E FI NI N G LI N E S O F T H E R A P Y  
A li ne of t hera p y is defi n e d as a c o urse of treat me nt at t he e n d of w hic h t here was disease 
pr o gressi o n, t o xicit y, or i n t he i n vesti gat or’s o pi ni o n, ma xi m u m be nefit has bee n ac hie ve d.  
Disease pr o gressi o n ca n be eit her cli nical or ra di o gra p hic a n d d o es n ot ha v e t o be base d o n a 
f or mal R E CI S T ass ess me nt. 
 
•  Mai nte na nce t h era p y (e .g ., c o nti n uati o n of 5 -fl u or o uracil [5 F U ] after disc o nti n uati o n of 
o x ali plati n or iri n oteca n) d oes n ot c o u nt as a se p arate li ne.  
 
•  He patic arterial i nf usi o n ( H AI) p u m p t hera p y c o u nts as a se parate li ne.  
 
•  Restarti n g a c he m ot hera p y bac k b o ne c o u nts as a li ne if:  
o  T here is a n a d diti o n of a bi ol o gic n ot pre vi o usl y use d  
o  T he patie nt pre vi o usl y ha d pr o gressi ve dise ase (cli nical or ra di o gra p hic) o n t his 
re gi me n 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 4  of 1 7 0  
A P P E N DI X J : 
I N V E S TI G A T O R SI G N A T UR E P A G E  
 
Pr ot oc ol N u m ber:  
St u d y S G N T U C -0 1 7  
Pr ot oc ol Title:  
A  P hase 2 , O pe n La bel St u d y o f T ucati ni b C o m bi ne d w it h 
Trast uz u ma b in P atie nts w it h HE R 2 + Metastatic C ol orectal Ca ncer  
(M O U N T AI N E E R ) 
I n vesti g ati o n al Pr o d uct:  
T ucati ni b ( O N T -3 8 0)  
Versi o n:  
A me n d me nt 1 2 ; 0 6 -Mar -2 0 2 3  
 
I n vesti g at or St ate me nt a n d Si g n at ure 
 
I h a ve rea d t he attac he d pr ot oc ol e ntitle d “A P has e 2, O pe n La b el St u d y of T ucati ni b C o m bi ne d 
wit h Trast uz u ma b i n Patie nts wit h H E R 2 + Metast atic C ol orectal Ca ncer  (M O U N T AI N E E R )” 
I u n d ersta n d a n d a gree t o t he pr o visi o ns of t he pr ot oc ol, a n d I acce pt t he res p o nsi bilities liste d 
a b o ve i n m y r ole as pri n ci pal i n vesti gat or f or t he st u d y.  
 
 
 
I n vesti gat or Si g nat ure 
 
Date  
 
 
 
 
 
 
 
 
 
I n vesti gat or Na me, Pri nte d 
 
 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 5  of 1 7 0  
A P P E N DI X K : D O C U M E N T HI S T O R Y  
Versi o n *  
Date  
Ori gi nal  
5 Ma y 2 0 1 7  
A me n d me nt  1  
2 3 J u ne 2 0 1 7  
A me n d me nt  2  
2 0 Oct o ber 2 0 1 7  
A me n d me nt  3  
0 2 Marc h 2 0 1 8  
A me n d me nt  4  
2 1 Se pte m ber 2 0 1 8  
A me n d me nt  5  
1 9 A pril 2 0 1 9  
A me n d me nt  6  
0 5 J ul y 2 0 1 9  
A me n d me nt  7  
1 0 Se pte m ber 2 0 1 9  
A me n d me nt 8  
0 1 N o ve m ber 2 0 1 9  
A me n d me nt 8. 1  
2 2  N o ve m ber 2 0 1 9  
A me n d me nt 8. 2  
1 4 Fe br uar y 2 0 2 0  
A me n d me nt 9  
1 0  Se pte m ber  2 0 2 0  
A me n d me nt 1 0  
2 1  Dece m ber 2 0 2 0  
A me n d me nt 1 1  
3 0  J un e 2 0 2 1  
A me n d me nt 1 2  
0 9  Marc h 2 0 2 3  
* U p t hr o u g h “A me n d me nt 6 ” t he i n vesti gat or-s p o ns ore d trial d oc u me nts were als o k n o w n as “A d de n d u ms ” i nstea d of “A me n d me nts. ”  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 6  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt  1  
Pr ot oc ol secti o n u p d ate d  
N at ure of c h a n ge 
Title P a ge  
•  
I N D n u m ber c orrecte d 
•  
Draft date re m o ve d  
•  
D oc u me nt hist or y u p date d t o reflect 
Acti vati o n/ A me n d me nt  1  
Pr ot oc ol Res o urce P a ge  
•  
Re m o ve d fr o m pr ot oc ol  
Sc he ma  
•  
C orrecti o n ma de t o T ucati ni b d osi n g sc he d ule  
•  
Clarificati o ns ma de t o st u d y s c he ma  
Secti o n 3. 0, P atie nt Eli gi bilit y  
•  
E dit orial c ha n ges  
•  
C ha n ge t o le n gt h of birt h c o ntr ol re q uire me nts  
Secti o n 4. 0, T est Sc he d ule  
•  
C ha n ges t o pre -re gistrati o n tests a n d pr oce d ures 
•  
C orrecti o n t o Cli nical F oll o w -u p a n d E ve nt F oll o w -u p 
visits  
•  
Clarificati o ns t o vis it ti mi n g 
•  
C o ns oli dati o n of li ke bi os peci me n c ollecti o ns  
•  
F o ot n otes u p date d t o reflect a b o ve -me nti o ne d e dits 
a n d t o a d d f urt her clarificati o ns  
Secti o n 1 3. 0, Treat me nt/ F oll o w -u p Decisi o n at 
E val uati o n of P atie nt  
•  
C ha n ge t o le n gt h of birt h c o ntr ol re q uire me nts  
Secti o n 1 4. 0, B o d y Fl ui d Bi os peci me ns  
•  
Bi os peci me n s u b missi o n ta ble u p date d t o reflect T est 
Sc he d ule c ha n ges  
•  
A d diti o nal g ui deli nes a d de d t o kit i nstr ucti o ns  
Secti o n 1 5. 0, Dr u g I nf or mati o n  
•  
I N D n u m ber c orrecte d 
•  
T ucati ni b secti o n u p date d base d o n P har mac y re vie w 
of te m plate  
•  
N ursi n g g ui deli nes a d de d  
Secti o n 1 7. 0, P at h ol o g y C o nsi derati o ns/ Tiss ue 
Bi os peci me ns  
•  
Re m o val of re d u n da nt i nf or mati o n  
•  
C orrecti o n of f or m na me  
Secti o n 1 8. 0, Rec or ds a n d Data C ollecti o n 
Pr oce d ures  
•  
I nitial Materials ta ble u p date d t o reflect fi nal f or ms 
b uil d  
•  
T est Sc he d ule Materials u p date d t o reflect fi nal f or ms 
b uil d  
•  
F oll o w -u p Materials ta ble u p date d t o reflect fi nal 
f or ms b uil d 
A p pe n di x I, I nf or me d C o nse nt T e m plate  
•  
Si de effects of T ucati ni b u p date d base d o n P har mac y 
re vie w of I B 
•  
Si de effects of Trast uz u ma b u p date d base d o n 
P har mac y re vie w of I B  
•  
C ha n ge t o le n gt h of birt h c o ntr ol re q uire me nts  
•  
Ris ks of T T E re m o ve d  
•  
Ti mefra me f or re p orti n g of pre g na nc y of part ner of 
male patie nt re vise d  
A p pe n di x VII, P atie nt Dr u g Diar y  
•  
C orrecti o n ma de t o d r u g st ora ge i nstr ucti o ns 
E dit orial a n d a d mi nistrati ve c ha n ges ha ve bee n ma de t hr o u g h o ut t he pr ot oc ol b ut d o n ot affect t he scie ntific 
c o nte nt or mea ni n g.  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 7  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt  2  
Pr ot oc ol secti o n u p d ate d  
N at ure of c h a n ge  
Title P a ge  
•  
E dit orial a n d a d mi nistrati ve c ha n ges ha ve bee n ma d e 
re gar di n g t he Pr ot oc ol Res o urce P a ge c o m m u nicati o n. 
Sc he ma, P a ge 3  
•  
T ucati ni b a n d Trast uz u ma b ha ve bee n u p date d wit h 
a d mi nistrati ve a n d e dit orial c ha n ges.  
Secti o n 3. 0, P atie nt Eli gi bilit y  
•  
3. 1 3 ha ve bee n u p date d wit h a n e dit orial c ha n ge.  
•  
3. 1 8 ha ve bee n u p date d wit h a d mi nistrati ve a n d 
e dit orial c ha n ges.  
•  
3. 1 9c has bee n u p date d wit h a n e dit orial c ha n ge a n d t o 
defi ne a me n orr hea as ≥1 2 c o nsec uti ve m o nt hs.  
•  
3. 1 9 d ha ve bee n u p date d wit h a d mi nistrati ve a n d 
e dit orial c ha n ge s. 
Secti o n 4. 0, T est Sc he d ule  
•  
U n der C ycle 1, da ys 8 & 1 5 was m o difie d as re q uire d.  
•  
U n der t he Acti ve Treat me nt s ecti o n, t he c ycles were 
m o difie d wit h e dit orial c ha n ges.  
•  
F o ot n ote 1 0 has bee n delete d; t h us re n u m beri n g 
f o ot n otes 1 0-1 3 has c ha n ge d.  
•  
T he ma n dat o r y tiss ue sa m ple was m o ve d t o t he 
o bser vati o n secti o n as re q uire d.  
Secti o n 7. 0, Pr ot oc ol Treat me nt  
•  
Secti o n 7. 1 Treat me nt Sc he d ule has bee n u p date d wit h 
a n a d mi nistrati ve c ha n ge.  
•  
Secti o n 7. 2 has bee n u p date d wit h a d mi nistrati ve a n d 
e dit orial c ha n ges.  
Secti o n 1 1. 0, R E CI S T Meas ure me nt 
G ui deli nes  
•  
Secti o n 1 1. 1 has bee n u p date d wit h a d mi nistrati ve a n d 
e dit orial c ha n ges.  
Secti o n 1 4. 0, B o d y Fl ui d Bi os peci me ns  
•  
Secti o n 1 4. 1 1 5 has bee n delete d re gar di n g t he da ys of 
s hi p me nt f or s peci me ns. 
Secti o n 1 5. 0, Dr u g I n f or mati o n 
•  
Secti o n 1 5. 1 4 has bee n u p date d wit h a d de d 
i nf or mati o n re gar di n g t he a d mi nistrati o n of T ucati ni b. 
•  
Secti o n 1 5. 1 6, a d diti o nal i nf or mati o n was a d de d t o t he 
P ote ntial Dr u g I nteracti o ns para gra p h.  
•  
Secti o ns 1 5. 2 9 7 -9 8 N ursi n g G ui deli nes ha ve bee n 
a d de d for Trast uz u ma b.  
Secti o n 1 8. 0, Rec or ds a n d Data C ollecti o n 
Pr oce d ures  
•  
Secti o n 1 8. 1 S u b missi o n Ti meta ble, t he s peci me n 
s u b missi o n tiss ue f or baseli ne has bee n m o ve d fr o m 
t he acti ve-m o nit ori n g p hase t o t he o bser vati o n p hase 
a n d f o ot n otes ha ve bee n u p dat e d t o  reflect t hese 
c ha n ges.  
Secti o n 1 9. 0, B u d get  
•  
Secti o n 1 9. 2 has bee n u p date d wit h e dit orial c ha n ges.  
A p pe n di x I, I nf or me d C o nse nt T e m plate  
•  
P a ges 7, 8, a n d 9 ha ve bee n u p date d t o reflect 
T ucati ni b t o be ta ke n t wice dail y.  
•  
P a ge 1 0 has bee n u p date d wit h a d mi nistrati ve a n d 
e dit orial c ha n ges.  
•  
P a ges 1 4, 1 5; Re pr o d ucti ve Ris ks ha ve bee n u p date d 
wit h a d mi nistrati ve a n d e dit orial c ha n ges.  
•  
P a ge 1 8; t he ver bia ge re gar di n g dr u g c ost has bee n 
u p date d.  
•  
P a ge 1 9; Tra vel Rei m b urse me nt la n g ua ge has bee n 
a d de d. 
A p pe n di x  I V 
•  
P a ge 1; A d mi nistrati ve a n d e dit orial c ha n ges ha ve 
bee n ma de.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 8  of 1 7 0  
Pr ot oc ol secti o n u p d ate d  
N at ure of c h a n ge  
E dit orial a n d a d mi nistrati ve c ha n ges ha ve bee n ma de t hr o u g h o ut t he pr ot oc ol b ut d o n ot affect t he scie ntific 
c o nte nt or mea ni n g.  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 2 9  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt  3  
Pr ot oc ol secti o n u p d ate d  
N at ure of c h a n ge  
Sc he ma  
•  
Trast uz u ma b a vaila bilit y has bee n c ha n ge d t o 
Bi ol o gics.  
Secti o n 7. 0, Pr ot oc ol Treat me nt  
•  
Secti o n 7. 3 was u p date d t o clarif y t hat t he patie nt d oes 
n ot necessaril y nee d t o get tre at me nt w here t he y 
si g ne d c o nse nt. 
Secti o n 9. 0, A ncillar y Treat me nt/ S u p p orti ve 
Care  
•  
Secti o n 9. 5 was u p date d wit h a n e dit orial c ha n ge.  
•  
Secti o n 9. 9a was u p date d t o clarif y ra diati o n a n d 
R E CI S T.  
Secti o n 1 4. 0, B o d y Fl ui d Bi os peci me ns  
•  
F o ot n ote # 2; c ycle n u m bers were c orrecte d.  
Secti o n 1 5. 0, Dr u g I nf or mati o n  
•  
Secti o n 1 5. 1 3 was u p date d t o clarif y t he s helf life of 
T ucati ni b.  
•  
Secti o n 1 5. 1 7; M ore ver bia ge has bee n a d de d t o t he 
t o xicities f or T ucati ni b. 
•  
Secti o n 1 5. 1 8; Dr u g pr oc ure me nt la n g ua ge has bee n 
a d de d f or T ucati ni b.  
•  
Secti o n 1 5. 1 9a; T e m perat ure E xc ursi o n la n g ua ge has 
bee n a d de d t o clarif y t he pr ocess f or sites.  
•  
Secti o n 1 5. 1 9 b; N ursi n g G ui d eli nes ha ve bee n 
c ha n ge d d ue t o t he u p date d I B f or T ucati ni b.  
•  
Secti o n 1 5. 1 9c; Dr u g Acc o u nt a bilit y has bee n u p date d 
f or sites clarit y. 
•  
Secti o n 1 5. 2 8 Dr u g pr oc ure me nt f or trast uz u ma b has 
bee n u p date d t o clarif y f u n di n g a n d t he u p date d 
pr ocess.  
A p pe n di x I, I nf or me d C o nse nt T e m plate  
•  
A p pe n di x I; P a ges 3, 5, 6, 8, 9, 1 0, 1 1, 1 8, 1 9 were 
u p date d wit h a n a d mi nistrati ve a n d e dit orial c ha n ges.  
A p pe n di x VII, Dr u g Diar y  
•  
T he P atie nt  Dr u g Diar y has be e n u p date d t o clarif y 
i nstr ucti o ns f or t he patie nt re gar di n g t he dr u g. 
E dit orial a n d a d mi nistrati ve c ha n ges ha ve bee n ma de t hr o u g h o ut t he pr ot oc ol b ut d o n ot affect t he scie ntific 
c o nte nt or mea ni n g.  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 0  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt  4  
Pr ot oc ol secti o n u p d ate d  
N at ure of c h a n ge  
Title P a ge  
•  
T he I N D H ol der has bee n c ha n ge d fr o m Dr.  
 
t o Dr. 
. 
•  
T he Statisticia n’s f or t his trial has bee n e dite d.  
I n de x 
•  
T he hea der was c ha n ge d t o reflect A me n d me nt  4.  
Sc he ma  
•  
Bi ol o gics was c ha n ge d t o Mc Kess o n o n t he 
a vaila bilit y f or t ucati ni b a n d trast uz u ma b.  
Secti o n 1. 0, B ac k gr o u n d  
•  
A d mi nistrati ve a n d e dit orial c ha n ges were ma de 
t hr o u g h o ut Secti o n 1. 0. 
Secti o n 3. 0, P atie nt Eli gi bilit y  
•  
A d mi nistrati ve a n d e dit orial c ha n ges were ma de 
t hr o u g h out Secti o n 3. 0.  
Secti o n 4. 0, T est Sc he d ule  
•  
F o ot n ote # 6 was c ha n ge d f or clarificati o n re gar di n g 
i ma gi n g. 
•  
F o ot n ote # 8 was m o difie d t o clarif y tiss ue s u b missi o n.  
Secti o n 8. 0, D osa ge M o dificati o n B ase d o n 
A d verse E ve nts  
•  
A d de d la n g ua ge was i nserte d f or clarificati o n 
re gar di n g A d verse E ve nt-S pecific D ose M o dificati o ns.  
Secti o n 1 0. 0, A d verse E ve nt ( A E) Re p orti n g 
a n d M o nit ori n g  
•  
Casca dia n was c ha n ge d t o Seattle Ge netics t hr o u g h o ut 
secti o n 1 0. 0. 
Secti o n 1 3. 0, Treat me nt/ F oll o w -u p Decisi o n at 
E val uati o n of P a tie nt 
•  
T he f oll o w -u p peri o d was c ha n ge d i n secti o n 1 3. 1 f or 
clarificati o n.  
•  
Ver bia ge re gar di n g d osi n g dela ys was a d de d f or 
clarificati o n.  
Secti o n 1 5. 0, Dr u g I nf or mati o n  
•  
Secti o n 1 5. 1 T ucati ni b; Casca dia n was c ha n ge d t o 
t heir ne w na me Seattle Ge neti cs. 
•  
T he te m perat ure e xc ursi o n e mail was m o difie d.  
•  
Secti o n 1 5. 2 Trast uz u ma b; ha d a d mi nistrati ve a n d 
e dit orial c ha n ges t hr o u g h o ut f or clarificati o n o n 
Casca dia n’s na me c ha n ge t o S eattle Ge netics a n d 
base d o n t he pac ka ge i nsert.  
•  
Secti o n 1 5. 2 6 la n g ua ge re m o ve d fr o m t he pr ot oc ol as 
it was n ot relate d t o t his st u d y. 
•  
Secti o n 1 5. 2 7 has e dit orial a n d a d mi nistrati ve c ha n ges 
f or clarificati o n. 
Secti o n 1 6. 0, Statistical C o nsi derati o ns a n d 
Met h o d ol o g y  
•  
Secti o n 1 6. 2 Pri mar y E n d p oi nt; has bee n e dite d f or 
clarificati o n.  
•  
Secti o n 1 6. 3 1 Decisi o n R ule; A d mi nistrati ve a n d 
e dit orial c ha n ges ha ve bee n ma de.  
•  
Secti o n 1 6. 3 4 P o wer a n d Si g nifica nce Le vel; 
a d mi nistrati ve a n d e dit orial c ha n ges ha ve bee n ma d e.  
A p pe n di x I, I nf or me d C o nse nt T e m plate  
•  
T he hea der has bee n c ha n ge d t o reflec t A me n d me nt  4  
•  
Casca dia n has bee n c ha n ge d t o Seattle Ge netics.  
•  
Ver bia ge re gar di n g st u d y testi n g was m o difie d f or 
clarificati o n.  
•  
Si de Effects ass ociate d wit h Trast uz u ma b were 
c ha n ge d base d o n t he pac ka ge i nsert.  
•  
T u m or assess me nts ha ve bee n m o difie d re gar di n g 
R E CI S T i ma gi n g.  
E dit orial a n d a d mi nistrati ve c ha n ges ha ve bee n ma de t hr o u g h o ut t he pr ot oc ol b ut d o n ot affect t he scie ntific 
c o nte nt or mea ni n g.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)
P P D
P P D

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 1  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt  5  
Pr ot oc ol secti o n u p d ate d  
N at ure of c h a n ge  
Title P a ge  
•  
A me n d me nt  5 has bee n a d de d t o t he title pa ge.  
Secti o n 1. 0, B ac k gr o u n d  
•  
Secti o n 1. 2 refere nces a n d la n g ua ge was c ha n ge d 
base d o n ne w fi n di n gs.  
•  
Secti o n 1. 3 2 3 was e dite d base d o n t he trast uz u ma b 
pac ka ge i nsert.  
Secti o n 4. 0, T est Sc he d ule  
•  
F o ot n ote 6, la n g ua ge ha d a d de d la n g ua ge f or 
clarificati o n.  
Secti o n 8. 0, D osa ge M o dificati o n B ase d o n 
A d verse E ve nts  
•  
8. 2; A d mi nistrati ve a n d e dit orial e dits ha ve bee n a d de d 
f or clarificati o ns. 
•  
E dits ha ve bee n ma de t o t he ta ble re gar di n g Left 
Ve ntric ular S yst olic D ysf u ncti o n.  
Sect i o n 1 1. 0, R E CI S T Meas ure me nt 
G ui deli nes  
•  
1 1. 2 1 3; A n e dit orial c ha n ge was ma de f or clarificati o n 
re gar di n g meas ura ble disease. 
Secti o n 1 4. 0, B o d y Fl ui d Bi os peci me ns  
•  
1 4. 0, F o ot n ote 1 ha d a n a d mi nistrati ve c ha n ge 
re gar di n g bl o o d c ollecti o n f or C 1 da y 1. 
Secti o n 1 8. 0, Rec or ds a n d Data C ollecti o n 
Pr oce d ures  
•  
N G S or FI S H/ CI S H are n o w a d de d as re p orts t o be 
u pl oa de d f or baseli ne.  
Secti o n 2 0. 0 Refere nces  
•  
A n o ut date d refere nce was re m o ve d a n d re place d.  
A p pe n di x I, I nf or me d C o nse nt T e m plate  
•  
Trast uz u ma b Re pr o d uc ti ve Ris ks; la n g ua ge was a d de d 
f or preca uti o nar y meas ures f or pre g na nt fe males. 
•  
Seattle Ge netics was a d de d t o recei ve data f or t his 
pr ot oc ol.  
E dit orial a n d a d mi nistrati ve c ha n ges ha ve bee n ma de t hr o u g h o ut t he pr ot oc ol b ut d o n ot affect t he scie ntific 
c o nte nt or mea ni n g.  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 2  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt  6  
Pr ot oc ol secti o n u p d ate d  
N at ure of c h a n ge  
Title P a ge  
•  
A me n d me nt  6 was c ha n ge d o n t he Title P a ge.  
Secti o n 1. 0, B ac k gr o u n d  
•  
Secti o n 1. 2 was m o difie d wit h t he c urre nt refere nce.  
•  
Secti o n 1. 2; la n g ua ge was re m o ve d a n d a n e dit orial 
c ha n ges was ma de.  
•  
Secti o n 1. 3 2 3; C Y P la n g ua ge was a d de d f or st u d y 
clarificati o n.  
•  
Secti o n 1. 6; A d mi nistrati ve c ha n ges were ma de f or 
clarificati o n.  
Secti o n 3. 0, P atie nt Eli gi bilit y  
•  
N u m beri n g was m o difie d d ue t o i nserti o n a n d deleti o n 
of la n g ua ge.  
•  
A d mi nistrati ve a n d e dit orial c ha n ges were ma de 
t hr o u g h o ut Secti o n 3. 0 
Secti o n 4. 0, T est Sc he d ule  
•  
F o ot n ote 6 & 7 ha d a n e dit orial c ha n ges f or st u d y 
clarificati o n.  
•  
T he ma n dat or y bl o o d sa m ple o n t he test sc he d ule was 
c ha n ge d fr o m baseli ne t o pr i or t o d osi n g o n Da y 1, per 
t he PI. 
Secti o n 7. 0, Pr ot oc ol Treat me nt  
•  
A d diti o nal la n g ua ge has bee n a d de d t o t he treat me nt 
sc he d ule f or st u d y p ur p oses. 
Secti o n 8. 0, D osa ge M o dificati o n B ase d o n 
A d verse  
E ve nts  
•  
E dit orial c ha n ges were ma de t o Secti o n 8. 1 f or 
clarificati o n.  
Secti o n 9. 0, A ncillar y Treat me nt/ S u p p orti ve 
Care  
•  
A d diti o nal la n g ua ge was i nserte d t hr o u g h o ut f or 
preca uti o nar y meas ures f or t his trial re gar di n g 
me dicati o ns a n d C Y P s u bstrat es.  
Secti o n 1 4. 0; B o d y Fl ui d S peci me ns  
•  
F o ot n ote 1; a d diti o nal la n g ua ge was a d de d f or 
clarificati o n.  
Secti o n 1 5. 0, Dr u g I nf or mati o n  
•  
Secti o n 1 5. 1 5; a n e dit orial c ha n ge was ma de.  
•  
Secti o n 1 5. 1 6; La n g ua ge was re m o ve d a n d re place d 
f or u p date d p ote ntial dr u g i nteracti o ns. 
•  
1 5. 1 7; a n e dit orial c ha n ge was ma de.  
Secti o n 1 6. 0, Sta tistical C o nsi derati o ns a n d 
Met h o d ol o g y  
•  
A d mi nistrati ve a n d e dit orial c ha n ges were ma de 
t hr o u g h o ut Secti o n 1 6. 0 f or st u d y clarificati o n. 
Secti o n 1 7. 0, P at h ol o g y C o nsi derati o ns/ Tiss ue 
Bi os peci me ns  
•  
T he ta ble a n d secti o ns were e dite d t o c ha n ge tiss ue 
i nf or mati o n nee de d f or st u d y p ur p oses. 
Secti o n 2 0. 0, Refere nces  
•  
A refere nce was e dite d t o refl ect t he m ost c urre nt 
i nf or mati o n. 
A p pe n di x I, I nf or me d C o nse nt T e m plate  
•  
A p pe n di x I was e dite d t o reflect t he m ost c urre nt 
a me n d me nt . 
A p pe n di x VIII, List of Sel ecte d S u bstrates or 
I n hi bit ors of P-g p a n d S u bstrates of B C R P 
Oral Dr u gs  
•  
T his a p pe n di x was a d de d f or st u d y p ur p oses.  
A p pe n di x I X, E xa m ples of Cli nical S u bstrates 
f or C Y P 3 A-Me diate d Meta b olis m  
•  
T his a p pe n di x was a d de d f or st u d y p ur p oses.  
A p pe n di x X, Dr u gs Acce pte d or P ossi bl y 
Ass ociate d wit h Ris k of Q T Pr ol o n gati o n or 
T orsa d e de P oi ntes  
•  
T his a p pe n di x was a d de d f or st u d y p ur p oses.  
A p pe n di x XI, List of Selecte d P ote ntial 
Se nsiti ve S u bstrates f or U G T 1 A 1  
•  
T his a p pe n di x was a d de d f or st u d y p ur p oses.  
E dit orial a n d a d mi nistrati ve c ha n ges ha ve bee n ma de t hr o u g h o ut t he pr ot oc ol b ut d o n ot affect t he scie ntific 
c o nte nt or mea ni n g.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 3  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt  7  
Secti o n(s)  
C ha n ge  
Rati o nale  
T hr o u g h o ut  
Re place d “ A C C R U” wit h “ Se attle Ge netics, I nc.” or “s p o ns or” 
S p o ns or na me c ha n ge  
T hr o u g h o ut  
A d de d ne w pr ot oc ol n u m ber:  
A C C R U -GI -1 6 1 7 , S G N T U C-0 1 7  
A d de d Seattle Ge netics pr ot oc ol 
n u m ber.  
C o ver P a ge  
•  
C ha n ge d t he na me of t he I N D H ol der fr o m “
, M D” t o “ Seattle 
Ge netics”  
•  
R e m o ve d st u d y c o -c hair  
•  
A d de d S p o ns or Me dical M o nit or  
•  
Re place d A C C R U Statist icia n wit h Seattle Ge netics Statisticia n 
•  
A d de d Seattle Ge netics  c o nfi d e ntialit y state me nt  
•  
Re m o ve d t he f oll o wi n g te xt:  
F or a ny c o m m u nic ati o ns re g ar di n g t his pr ot oc ol, ple ase c o nt act t he pers o n 
i n dic ate d o n t he Pr ot oc ol Res o urce P a ge. T his is a st a n d-al o ne d oc u me nt f o u n d o n 
t he A C C R U we b site ( w w w. A C C R U. or g)St u d y C hairs  
 
 St u d y c o ntri b ut or(s) n ot res p o nsi ble f or patie nt care.  
 
Researc h C o or di nati n g Ce nter  
Aca de mic a n d C o m m u nit y Ca ncer Researc h U nite d  
2 0 0 First Street S o ut h west  
R oc hester, M N 5 5 9 0 5  
F A X # 5 0 7 -5 3 8 -0 9 0 6  
U p date d, as after t he I N D tra nsfer t o 
Seattle Ge netics , t he c o m pa n y 
ass u me d s p o ns ors hi p of t he st u d y a n d 
s pecific i nf or mati o n pertai ni n g t o 
A C C R U pr ocesses n o l o n ger a p plies.  
A d de d S p o ns or Me dical M o nit or a n d 
S p o ns or Statisticia n d ue t o c h a n ge i n 
res p o nsi bilities.  
T hr o u g h o ut  
Re m o ve d refere nces t o t he A C C R U we bsite.  
Re m o ve d, t o reflect t he u p date d 
res o urces. 
T hr o u g h o ut  
Mi n or e dit orial c orrecti o ns: s pelli n g, f or matti n g, a d diti o n of missi n g ite ms t o t he T O C 
(I n de x) ta ble 
T o pr o vi de m ore clarit y a n d 
c o nsiste nc y t hr o u g h o ut t he d oc u me nt . 
Sc he ma  
S witc he d t he n otes o n eac h si de of t he Sc he ma dia gra m: “ Off st u d y f or Disease 
Pr o gressi o n, Alter nati ve T hera p y, or Wit h dra wal/ Ref usal” was m o ve d t o t he ri g ht si de 
a n d “ Off st u d y f or a n y reas o n ot her t ha n Disease Pr o gressi o n, Alter nati ve T hera p y, or 
Wit h dra wal/ Ref usal” was m o ve d t o t he left si de.  
 
C ha n ge d “a vaila bilit y” of trast uz u ma b:  
 Mc Kess o n Seattle Ge netics  
C orrecte d misla beli n g.  
 
 
 
C orrecti o n ma d e t o reflect c ha n ges i n 
t he dr u g pr oc ure me nt 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)
P P D

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 4  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
3. 1 7  
E C O G P erf or ma nce Stat us ( P S) of 0, 1, or 2. ( F or m is a vail a ble o n t he A C C R U we b site 
htt ps:// w w w.accr u. or g/accr u/f or ms/ N o n Pr ot oc ol S pecific F or ms/i n de x. ht ml) A n e xa m ple 
f or m is a vaila ble i n t he St u d y O perati o ns Ma n ual.  
C orrecti o n ma d e t o s pecif y t he 
desi g nate d l ocati o n ( St u d y O perati o ns 
Ma n ual) of t he u p date d f or ms  
4. 0  
In t he T est Sc he d ule T a ble : 
1.  Re m o ve d “ Ma n dat or y bl o o d sa m ple –  w h ole bl o o d f or p har mac o ge n o mics a nal ysis” 
r o w  
2.  A me n de d te xt i n t he F o ot n ote 8: S u b missi o n will be o nce wit hi n 1 2 m o nt hs of t he 
a nal ysis of t he pri mar y e n d p oi nt w he n re q ueste d b y st u d y c hair or desi g nee  
d o ne u p o n e nr oll me nt . See secti o n 1 7. 0.  
C ha n ge ma d e t o reflect t he re d ucti o n 
i n bl o o d c ollecti o n. 
T he  f o ot n ote u p date was als o 
ca pt ure d i n Secti o n 1 7. 1 1 a n d was 
perf or me d t o reflect t he c ha n ges i n 
t he pr ocess. 
 
6. 1  
Pr oce d ures f or re gisteri n g patie nts are a vaila ble i n t he St u d y O perati o ns Ma n ual.  
T o re gister a patie nt, access t he A C C R U we b pa ge at 
htt ps:/ / w w w.accr u. or g/accr u/ gr o u p/cra. ht ml, g o t o t he Re m ote A p plicati o n secti o n, clic k 
o n “ Re gistrati o n” a n d e nter t he re gistrati o n/ra n d o mizati o n a p plicati o n. T he 
re gistrati o n/ra n d o mizati o n a p plicati o n is a vaila ble 2 4 h o urs a da y, 7 da ys a wee k. Bac k 
u p a n d/ or s yste m s u p p ort c o nt act i nf or mati o n is a vaila ble o n t he We b site. If u na ble t o 
access t he W e b site, call t he Aca de mic a n d C o m m u nit y Ca ncer Researc h U nite d 
( A C C R U) Re gistrati o n Office at ( 5 0 7) 2 8 4-4 1 3 0 bet wee n t he h o urs of 8 a. m. a n d 4: 3 0 
p. m. Ce ntral Ti me ( M o n da y t hr o u g h Fri da y).  
 
I nstr ucti o ns f or t he re gistrati o n/ra n d o mizati o n a p plicati o n ar e a vaila ble o n t he a b o ve we b 
pa ge u n der t he Re m ote A p plicati o n secti o n, “ Re m ote A p plic ati o n Trai ni n g.”  
 
Pri or t o i nitiati o n of pr ot oc ol st u d y i nter ve nti o n, t his pr ocess m ust be c o m plete d i n its 
e ntiret y a n d a n A C C R U s u bj ect I D n u m ber m ust be a vaila ble as n ote d i n t he i nstr ucti o ns. 
It is t he res p o nsi bilit y of t he i n di vi d ual a n d i nstit uti o n re gisteri n g t he patie nt t o c o nfir m 
t he pr ocess has bee n s uccessf ull y c o m plete d pri or t o release of t he st u d y a ge nt. P atie nt 
re gistrati o n via t he re gistrati o n/ra n d o mizati o n a p plicati o n c a n be c o nfir me d i n a n y of t he 
f oll o wi n g wa ys: 
 
• 
C o ntact t he A C C R U Re gistrati o n Office ( 5 0 7) -2 8 4 -4 1 3 0. If t he patie nt was f ull y 
re gistere d, t he Re gistrati on Office staff ca n access t he i nf or mati o n fr o m t he ce ntralize d 
data b ase a n d c o nfir m t he re gistrati o n.  
 
• 
Refer t o “ Re m ote Re gistrati o n, I nstallati o n & E ntr y I nstr ucti o ns” u n der “ Trai ni n g 
Material Ma n uals.”  
Re m o ve d , as s pecific details a b o ut 
pr oce d ures f or re gisteri n g pati e nts are 
o utli ne d i n t he St u d y O perati o ns 
Ma n ual.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 5  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
6. 3  
D oc u me ntati o n of I R B a p pr o val m ust be o n file wit h A C C R U  t he s p o ns or bef ore a n 
i n vesti gat or ma y re gister a n y patie nts. A p pr o vals s h o ul d be u pl o a de d t hr o u g h t he 
electr o nic A C C R U Re g ulat or y Ma na ge me nt S yste m ( A R M S) at 
htt ps://accr u. vaca va.c o m/.   
 
I n a d diti o n t o s u b mitti n g i nitial I R B a p pr o val d oc u me nts, o n g oi n g I R B a p pr o val 
d oc u me ntati o n m ust be o n file wit h A C C R U t he sp o ns or  n o l ess t ha n a n n uall y. A p pr o vals 
s h o ul d be u pl oa d e d t hr o u g h t he electr o nic A C C R U Re g ulat or y Ma na ge me nt S yste m 
( A R M S) at htt ps://accr u. vaca va.c o m /. 
 
If t he necessar y d oc u me ntati o n is n ot s u b mitte d i n a d va nce of atte m pti n g patie nt 
re gistrati o n, t he re gistrati o n will n ot be acce pte d a n d t he patie nt ma y n ot be e nr olle d i n 
t he pr ot oc ol u ntil t he sit uati o n is res ol ve d. 
 
A n n ual I R B a p pr o val m ust c o nti n ue t o be s u b mitte d t o  A C C R U  t he s p o ns or u ntil site 
recei ves n otificati o n fr o m A C C R U t he s p o ns or t hat I R B cl os ure ca n c o m me nce a n d 
a p pr o val of s uc h is gra nte d.  I R B a p pr o val of st u d y cl os ure s h o ul d be u pl oa de d t hr o u g h 
t he electr o nic A C C R U Re g ulat or y Ma na ge me nt S yste m ( A R M S) at 
htt ps://accr u. vaca va.c o m/.   
Re m o ve d s pecific i nf or mati o n 
re gar di n g A C C R U electr o nic 
re g ulat or y s yste m as it is n o l o n ger 
rele va nt. 
6. 4 t o 6. 9  
Re m o ve d Secti o ns 6. 4 t hr o u g h 6. 9.  
6. 4 Pri or t o acce pti n g t he patie nt re gistrati o n, t he re gistrati o n a p plicati o n will verif y t he 
f oll o wi n g: 
 
• 
I R B a p pr o val at t he re gisteri n g i nstit uti o n 
• 
P atie nt eli gi bilit y  
• 
E xiste nce of a si g ne d c o nse nt f or m  
• 
E xiste nce of a si g ne d a ut h orizati o n f or use a n d discl os ure of pr otecte d healt h 
i nf or mati o n  
 
6. 5  At t he ti me of re gistrati o n, t he f oll o wi n g will be rec or de d:  
 
• 
P atie nt has/ has n ot gi ve n per missi o n t o st ore a n d use his/ her sa m ple(s) f or f ut ure 
researc h t o lear n a b o ut, pre ve nt, or treat ca ncer. 
• 
P atie nt has/ has n ot gi ve n per missi o n f or A C C R U t o gi ve his/ her sa m ple(s) t o o utsi de 
researc hers. 
 
Re m o ve d as s pecific details a b o ut 
re gistrati o n pr ocesses are o utli ne d i n 
t he St u d y O perati o ns Ma n ual, as 
s pecifie d i n Secti o n 6. 1. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 6  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
6. 6  Treat me nt ca n n ot be gi n pri or t o re gistrati o n a n d m us t be gi n 7 da ys after 
re gistrati o n. 
 
6. 7  Pretreat me nt tests/ pr oce d ures (see Secti o n 4. 0) m ust be c o m plete d wit hi n t he 
g ui deli nes s pecifie d o n t he test sc he d ule.  
 
6. 8  All re q uire d baseli ne s y m pt o ms (see Secti o n 1 0. 6 2) m ust b e d oc u me nte d a n d 
gra d e d.  
 
6. 9a  Tr eat me nt o n t his pr ot oc ol m ust c o m me nce at a n A C C R U i nstit uti o n u n der t he 
s u per visi o n of a me dical o nc ol o gist. 
 
6. 9 b  St u d y dr u g is a vaila ble o n site.  
6. 9c  Bl o o d dra w kit is a vaila ble o n site.  
1 0. 0  
1 0. 0  A d verse E ve nt ( A E) Re p orti n g a n d M o nit ori n g  
T he site pri nci pal i n vesti gat or is res p o nsi ble f or re p orti n g a n y/all a d verse e ve nts t o 
A C C R U the s p o ns or as descri be d wit hi n t he pr ot oc ol. Refer t o t he a d verse e ve nt a n d 
seri o us a d verse e ve nt secti o ns of t he pr ot oc ol f or detaile d i nf or mati o n.  
A C C R U is res p o nsi ble f or n otif yi n g F D A a n d all partici pati n g i n vesti gat ors i n a writte n 
safet y re p ort of a n y of t he f oll o wi n g:  
• 
A n y s us pecte d a d verse reacti o n t hat is b ot h seri o us a n d u ne x pecte d.  
• 
A n y fi n di n gs fr o m la b orat or y a ni mal or i n vitr o testi n g t hat s u g gest a si g nifica nt ris k 
f or h u ma n s u bj ects, i ncl u di n g re p orts of m uta ge nicit y, terat o ge nicit y, or carci n o ge nicit y.  
• 
A n y fi n di n gs fr o m e pi de mi ol o gical st u dies, p o ole d a nal ysis of m ulti ple st u dies, or 
cli nical st u dies, w het her or n ot c o n d ucte d u n der a n I N D a n d w het her or n ot c o n d ucte d b y 
t he s p o ns or, t hat s u g gest a si g nifica nt ris k i n h u ma ns e x p ose d t o t he dr u g. 
• 
A n y cli nicall y i m p orta nt i ncre ase i n t he rate of a seri o us s us pecte d a d verse reacti o n 
o ver t he rate state d i n t he pr ot oc ol or I n vesti gat or’s Br oc h ur e (I B).  
Re m o ve d s pecific i nf or mati o n 
re gar di n g A C C R U’s pr ocesses, as 
f oll o wi n g u p date d s p o ns ors hi p, all 
re g ulat or y a ut h orit y re p orti n g is 
perf or me d per Seattle Ge netics 
Sta n dar d O perati n g Pr oce d ures 
( S O Ps).  
1 0. 1  
Re m o ve d t he f oll o wi n g defi niti o ns:  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n ( S U S A R)  
Re m o ve d, as i nf or mati o n relat e d t o 
S us pecte d U ne x pecte d Seri o us 
A d verse Reacti o ns ( S U S A R ), 
S us pecte d A d verse Reacti o n, a n d 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 7  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
A S U S A R is a seri o us a d verse reacti o n or e ve nt, t he nat ure a n d se verit y of w hic h is 
n ot c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n (e. g., I n vesti gat or’s Br oc h ure 
or pac ka ge i nsert). T he I n vesti gat or m ust deter mi ne t he relati o ns hi p of t he e ve nt t o 
st u d y a ge nt b ase d o n i nf or mati o n a vaila ble at t he ti me of t he i nitial re p ort i n g. T he 
i nitial assess me nt ma y be re vise d as ne w i nf or mati o n bec o mes a vaila ble. 
S o me u na ntici pate d pr o ble ms i n v ol ve s ocial or ec o n o mic har m i nstea d of t he 
p h ysical or ps yc h ol o gical har m ass ociate d wit h a d verse e ve nts. I n ot her cases, 
u na ntici pate d pr o ble m s place s u bj ects or ot hers at i ncrease d ris k of har m, b ut n o 
har m occ urs.  
N O T E: T he ter ms “se vere” a n d “seri o us” are n ot s y n o n y m o us. Se verit y refers t o t he 
i nte nsit y of a n a d verse e ve nt (rate d as mil d, m o derate, or se vere, or acc or di n g t o N CI 
C T C A E criteri a); t he e ve nt its elf ma y be of relati vel y mi n or me dical si g nifica nce 
(s uc h as se vere hea dac he wit h o ut a n y f urt her fi n di n gs). 
S us pecte d A d verse Reacti o n  
A n y a d verse e ve nt f or w hic h t here is a reas o na ble p ossi bilit y t hat t he dr u g ca use d t he 
a d verse e ve nt.  
E x pe dite d Re p orti n g  
E ve nts re p orte d t o s p o ns or wit hi n 2 4 h o urs, 5 da ys, or 1 0 da ys of st u d y tea m 
bec o mi n g a ware of t he e ve nt.  
R o uti ne Re p orti n g  
E ve nts re p orte d t o s p o ns or via case re p ort f or ms  
E ve nts of I nterest  
E ve nts t hat w o ul d n ot t y picall y be c o nsi dere d t o meet t he criteria f or e x pe dite d 
re p orti n g, b ut t hat f or a s pecifi c pr ot oc ol are bei n g re p orte d via e x pe dite d mea ns i n 
or der t o facilitate t he re vie w of safet y data ( ma y be re q ueste d b y t he F D A or t he 
s p o ns or). 
E x pe dite d a n d R o uti ne Re p orti n g are  
c o vere d b y Seattle Ge netics S O P s a n d 
are o utsi de of t he sc o pe of t he 
i n di vi d ual site(s). Re m o ve d E ve nts of 
I nterest as A C C R U’s defi niti o n d oes 
n ot ali g n wit h Seattle Ge netics’ 
defi niti o n.  
1 0. 2  
A d de d t he f oll o wi n g te xt:  
Dia g n osis vs. Si g ns or S y m pt o ms  
A d de d t he Seattle Ge netics sta n dar d 
la n g ua ge f or m ore clarit y. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 8  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
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 y m 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 y m 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 di cal te xt b o o ks. If a n y 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 y m pt o m as a 
se p arate a d verse e ve nt. 
If a p plica ble: 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 dr u g. F or i nf usi o n -relate d reacti o ns, d o n ot use t he N CI 
C o m m o n T er mi n ol o g y Criteri a f or A d verse E ve nts  ( C T C A E) ter ms of “c yt oki ne 
release s y n dr o me,” “ac ute i nf usi o n reacti o n,” or “aller gic or h y perse nsiti vit y 
reacti o n.” I nstea d, rec or d eac h si g n or s y m pt o m as a n i n di vi d ual A E. 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 s y 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.  
 
Pr o gressi o n of U n derl yi n g Mali g na nc y  
Si nce pr o gressi o n of u n derl yi n g mali g na nc y is bei n g assess e 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 seri o us a d vers e e ve nt ( 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 ot 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 y m pt om 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 gressi o n f or t he disease u n der 
st u d y. I n 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.  
 
Pri or 1 0. 4  
1 0. 4 E x pecte d ness  
Deter mi nati o n of w het her a n e ve nt is e x pecte d or u ne x pecte d s h o ul d be deter mi ne d 
as o utli ne d bel o w.  
1 0. 4 1  
E x pecte d e ve nts  
Re m o ve d, as assess me nt of 
e x pecte d ness will n ot b e perf or me d  
b y t he cli nical sites, b ut will be 
perf or me d b y Seattle Ge netics . 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 3 9  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
T h ose e ve nts descri be d wit hi n t he Secti o n 1 5. 0 of t he pr ot oc ol, t he st u d y -s pecific 
c o nse nt f or m, pac ka ge i nsert a n d/ or t he i n vesti gat or br oc h ur e, or ot her wise descri be d 
i n t he ge neral i n vesti gati o nal pla n. 
1 0. 4 2  
U ne x pecte d a d verse e ve nts  
T h ose e ve nts n ot liste d i n Sect i o n 1 5. 0 of t he pr ot oc ol, t he st u d y s pecific c o nse nt 
f or m, pac ka ge i nsert a n d/ or i n t he i n vesti gat or br oc h ure ( or are n ot liste d at t he 
s pecificit y or se verit y t hat has bee n o bser ve d), or is n ot c o nsiste nt wit h t he ris k 
i nf or mati o n descri be d i n t he ge neral i n vesti gati o nal pla n. 
U ne x pecte d als o refers t o a d verse e ve nts or s us pecte d a d verse reacti o ns t hat are 
me nti o ne d i n t he i n vesti gat or br oc h ure as occ urri n g wit h a class of dr u gs b ut ha ve 
n ot b ee n o bser ve d wit h t he dr u g u n der i n vesti gati o n.  
1 0. 4 3  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n ( S U S A R)  
A S U S A R is a seri o us a d verse reacti o n or e ve nt, t he nat ure a n d se verit y of w hic h is 
n ot c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n (e. g., I n vesti gat or’s Br oc h ure 
or pac ka ge i nsert). T he I n vesti gat or m ust deter mi ne t he relati o ns hi p of t he e ve nt t o 
st u d y a ge nt b ase d o n i nf or mati o n a vaila ble at t he ti me of t he i nitial re p orti n g. T he 
i nitial assess me nt ma y be re vise d as ne w i nf or mati o n bec o mes a vaila ble. S U S A Rs 
i ncl u de a n y i nci de nt, e x perie nce, or o utc o me t hat meets all of t he f oll o wi n g criteria:  
• 
U ne x pecte d (i n ter ms of nat ur e, se verit y, or fre q ue nc y) gi ve n (a) t he researc h 
pr oce d ures t hat are descri be d i n t he pr ot oc ol -relate d d oc u me nts s uc h as t he I R B-
a p pr o ve d researc h pr ot oc ol a n d i nf or me d c o nse nt d oc u me nt;  a n d ( b) t he 
c haracteristics of t he s u bj ect p o p ulati o n bei n g st u die d;  
• 
Relate d or p ossi bl y relate d t o partici pati o n i n t he researc h (i n t his g ui da nce 
d oc u me nt, p ossi bl y relate d me a ns t here is a reas o na ble p ossi bilit y t hat t he i nci de nt, 
e x perie nce, or o utc o me ma y ha ve bee n ca use d b y t he pr oce d ures i n v ol ve d i n t he 
researc h); a n d 
• 
S u g gests t hat t he researc h plac es s u bj ects or ot hers at a great er ris k of har m 
(i ncl u di n g p h ysical, ps yc h ol o gical, ec o n o mic, or s ocial har m) t ha n was pre vi o usl y 
k n o w n or rec o g nize d . 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 0  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
S o me u na ntici pate d pr o ble ms i n v ol ve s ocial or ec o n o mic har m i nstea d of t he 
p h ysical or ps yc h ol o gical har m ass ociate d wit h a d verse e ve nts. I n ot her cases, 
u na ntici pate d pr o ble ms place s u bj ects or ot hers at i ncrease d ris k of har m, b ut n o 
har m occ urs.  
If t he e ve nt meets t he criteria f or a S U S A R, s u b mit t o y o ur I R B as re q uire d b y y o ur 
i nstit uti o nal p olicies. 
1 0. 4 1  
I n vesti gati o nal A ge nts a n d C o m mercial A ge nts o n t he S A M E Ar m  
 
W he n c o m mercial a ge nts are use d o n t he sa me treat me nt ar m as t he i n vesti gati o nal 
a ge nt/i nter ve nti o n (als o, i n vesti gati o nal dr u g, bi ol o gic, cell ular pr o d uct, or ot her 
i n vesti gati o nal t hera p y u n der a n I N D), t he entire c o m bi nati o n (ar m) is t he n c o nsi dere d a n 
i n vesti gati o nal i nter ve nti o n f or re p orti n g. 
 
T hese aEs s h o ul d be assesse d as s pecifie d i n t he a p pr o priate I N D/I D E Re p orti n g T a ble i n 
Secti o n 1 0. 8 2 2.  
 
Relati o ns hi p of t he A d verse E ve nt t o St u d y Treat me nt  
 
T he re lati o ns hi p of eac h A E t o eac h st u d y treat me nt (t ucati ni b a n d trast uz u ma b) 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 wee 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 wis e 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 d erl 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 b e 
establis 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  
 
Re place d t he c o nte nt of t he Se cti o n 
1 0. 4 1 ( pri or 1 0. 5 1) , as relate d ness 
will b e re p orte d i n relati o ns t o eac h 
st u dy dr u g (t ucati ni b a n d 
trast uz u ma b) i n t he c o m bi nati o n 
treat me nt, as o p p ose d t o t he re gi me n 
i n ge neral.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 1  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
1 0. 5 1 1 1  
Re p orta ble cate g ories of deat h:  
 
• 
Deat h attri b uta ble t o a C T C A E ter m  
 
• 
Deat h Ne o natal: A dis or der c haracterize d b y cessati o n of life d uri n g t he first 
2 8  da ys of life  
 
• 
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 C R F. 
 
• 
Deat h N O S: A cessati o n of life t hat ca n n ot be attri b ute d t o a C T C A E ter m 
ass ociate d wit h Gra d e 5  
 
• 
S u d de n deat h N O S: A s u d de n ( defi ne d as i nsta nt or wit hi n o ne h o ur of t he o nset 
of s y m pt o ms) or a n u n o bser ve d cessati o n of life t hat ca n n ot be attri b ute d t o a 
C T C A E ter m ass ociate d wit h Gra de 5  
 
• 
Deat h d ue t o pr o gressi ve disease s h o ul d be re p orte d as Gra de 5 “ Ne o plas ms 
be ni g n, mali g na nt a n d u ns pecifie d (i ncl u di n g c ysts a n d p ol y ps) –  Ot her ( Pr o gressi ve 
Disease)” u n der t he s yste m or ga n class ( S O C) of t he sa me na me. E vi de nce t hat t he 
deat h was a ma nifestati o n of u n derl yi n g disease (e. g., ra di ol o gical c ha n ges 
s u g gesti n g t u m or gr o wt h or pr o gressi o n: cli nical deteri orati o n ass ociate d wit h a 
disease pr ocess) s h o ul d be s u b mitte d.  
U p date d t he la n g ua ge o n deat h t o 
ali g n wit h  t he Seattle Ge netics  
sta n dar d la n g ua ge. 
1 0. 5 1 3  
A n a d verse e ve nt t hat res ults i n i n pat ie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g 
h os pitalizati o n f or ≥2 4 h o urs  
 
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 a cti o n ta ke n i n res p o nse t o 
t he ill ness. 
A d de d  t he la n g ua ge o n re p orti n g of 
seri o us e ve nts t o ali g n wit h t he 
Seattle Ge netics  sta n dar d la n g ua ge. 
Pri or 1 0. 6 2 , 1 0. 6 2 1, 
a n d 1 0. 6 2 2  
1 0. 6 2  
N o n -Seri o us E ve nts  
A n o n -seri o us a d verse e ve nt is defi ne d as a n y of t he f oll o wi n g t hat d o n ot meet seri o us 
criteria as pre vi o usl y o utli ne d:  
1 0. 6 2 1  Gra d e 2 aEs dee me d p ossi bl y, pr o ba bl y, or defi nitel y relate d t o t he st u d y 
treat me nt or pr oce d ure. 
1 0. 6 2 2  Gra d e 3 a n d 4 aEs re gar dless of attri b uti o n t o t he st u d y treat me nt or pr oce d ure . 
Re m o ve d, as t his defi niti o n d oes n ot 
ali g n wit h Seattle Ge netics’ 
defi niti o n.  
1 0. 6 2  
I n ge neral, a n as y m pt o matic d ecli ne 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 is c o nsi dere d a n e ve nt of s pecial i nterest a n d m ust b e 
Re m o ve d s pecific i nf or mati o n 
re gar di n g A C C R U’s pr ocesses t o 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 2  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
re p orte d as a seri o us a d verse e ve nt t o A C C R U t he s p o ns or ≤1 b usi ness da y of disc o ver y 
of t he e ve nt. A C C R U will n otif y Seattle Ge netics ≤1 b usi ness da y of site n otific ati o n.  
reflect t he c ha n ges ass ociate d wit h 
t he u p date d s p o ns ors hi p. 
1 0. 7   
Re m o ve d t he ta ble f or Re p orti n g Ti mefra mes a n d Mec ha nis ms  a n d a d de d t he f oll o wi n g 
la n g ua ge: 
 
Wit hi n 2 4 h o urs of o bser vi n g  or lear ni n g of a n S A E, i n vesti gat ors are t o re p ort t he 
e ve nt t o t he s p o ns or, re gar dless of t he relati o ns hi p of t he e ve nt t o t he st u d y treat me nt 
re gi me n. 
 
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: 
● 
P atie 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’s ca usalit y assess me nt 
 
T he c o m plete d S A E f or m is t o be e maile d or fa xe d t o t he s p o ns or’s Dr u g Safet y 
De p art me nt wit hi n 2 4 h o urs (s ee e mail or fa x n u m ber s pecifi e d o n t he S A E re p ort 
f or m). 
 
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.  
 
Re m o ve d t he ta ble f or Re p orti n g 
Ti mefra mes a n d Mec ha nis ms a n d 
a d de d t he u p date d i nf or mati o n o n 
S A Es ( per Seattle Ge netics sta n dar d 
S A E re p orti n g la n g ua ge) i n Se cti o n 
1 0. 7 , o n A d verse E ve nts of S p ecial 
I nterest ( A E SI) i n Secti o n 1 0. 7 3 , a n d 
o n pre g na ncies i n Secti o n  1 0. 8 3.  
 
1 0. 7 2  ( pri or 1 0. 8 2)  
E x pe dite d Re p orti n g Ti mefra me a n d Mec ha n is m 
 
1 0. 8 2 1  E x pe dite d Re p orti n g Mec ha nis m  
 
F or a d verse e ve nts meeti n g criteria f or e x pe dite d re p orti n g a n d occ urri n g wit hi n 3 0 da ys 
of t he last d ose of i n vesti gati o nal a ge nt:  
 
• 
C o m plete t he A C C R U A d vers e E ve nt E x pe dite d Re p ort F or m, l ocate d o n t he 
A C C R U we bsite: 
( htt ps:// w w w. accr u. or g/accr u/f or ms/ N o n Pr ot oc ol S pecific F or ms/i n de x. ht ml) a n d s u b mit 
t he c o m plete d f or m t o t he A C C R U S A E C o or di nat or via fa x ( 5 0 7. 2 8 4. 9 6 2 8) wit hi n t he 
ti mefra me o utli ne d i n t he ta bl e(s) bel o w. 
 
Re m o ve d t he secti o n, as all E x pe dite d 
Re p orti n g.t o re g ulat or y a ut h orities 
will b e perf or me d b y Seattle Ge netics 
as per Seattle Ge netics S O P s. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 3  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
• 
T he A C C R U S A E C o or di nat or will n otif y  I n d ustr y P art ner via e mail t o 
Dr u g.safet y @sea ge n.c o m a n d A C C R U I N D C o or di nat or as re q uire d.  
 
• 
T he A C C R U I N D C o or di nat or will assist A C C R U s p o ns or -i n vesti gat or i n n otif yi n g 
F D A if re q uire d.  
 
• 
C o m plete all re q uire d site -s pe cific re p orti n g pr oce d ures. 
Pri or 1 0. 8 2 2  
1 0. 8 2 2 E x pe dite d Re p orti n g Ti meli nes f or I n vesti gati o nal A ge nts  
 
F D A R E P O R TI N G R E Q UI R E M E N T S F O R S E RI O U S  A D V E R S E 
E V E N T S ( 2 1 C F R P art 3 1 2)  
N O T E:  I n vesti gat ors M U S T  i m me diatel y re p ort t o t he s p o ns or A N Y Seri o us 
A d verse E ve nts, w het her or n ot t he y are c o nsi dere d relate d t o t he i n vesti gati o nal 
a ge nt(s)/i nter ve nti o n ( 2 1 C F R 3 1 2. 6 4)  
A n a d verse e ve nt is c o nsi dere d seri o us if it res ults i n A N Y  of t he f oll o wi n g 
o utc o mes:  
1.  Deat h  
2.  A life -t hreate ni n g a d verse e ve nt 
3.  A n a d verse e ve nt t hat res ults i n i n patie nt h os pitalizati o n or pr ol o n gati o n 
of e xisti n g h os pitalizati o n f or ≥ 2 4 h o urs  
4.  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 
a bilit y t o c o n d uct n or mal life f u ncti o ns  
5.  A c o n ge nital a n o mal y/ birt h defect.  
6.  I m p orta nt Me dical E ve nts (I M E) t hat ma y n ot res ult i n deat h, be life 
t hreate ni n g, or re q uire h os pitalizati o n ma y be c o nsi dere d seri o us w he n, 
base d u p o n me dical j u d g me nt, t he y ma y j e o par dize t he patie nt or 
s u bj ect a n d ma y re q uire me dic al 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 i n t his defi niti o n. ( F D A, 2 1 C F R 3 1 2. 3 2; I C H 
E 2 A a n d I C H E 6).  
A L L S E RI O U S  a d verse e ve nts t hat meet t he a b o ve criteria M U S T be 
i m me diatel y re p orte d t o t he s p o ns or wit hi n t he ti mefra mes d etaile d i n t he ta ble 
bel o w.  
Re m o ve d t he secti o n, as all E x pe dite d 
Re p orti n g t o re g ulat or y a ut h orities 
will b e perf or me d b y Seattle Ge netics 
as per  Seattle Ge netics S O P s. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 4  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
H os pit aliz ati o n  
Gr a de 1 a n d Gr a de 2 
Ti mefr a mes  
Gr a de 3 -5  
Ti mefr a mes  
Res ulti n g i n 
H os pitalizati o n 
≥2 4 hrs  
7 Cale n dar  Da ys  
2 4 -H o ur; 3 Cale n dar Da ys  
N ot res ulti n g i n 
H os pitalizati o n 
≥2 4 hrs  
N ot re q uire d  
E x pe dite d A E re p orti n g ti meli nes are defi ne d as : 
o  “ 2 4 -H o ur; 3 Cale n dar Da ys” – - T he A E m ust i nitiall y be re p orte d wit hi n 2 4 
h o urs of lear ni n g of t he A E, f oll o we d b y a c o m plete e x pe dit e d re p ort wit hi n 3 
cale n dar da ys of t he i nitial 2 4 -h o ur re p ort.  
o  “ 7 Cale n dar Da ys” – - A c o m pl ete e x pe dite d re p ort o n t he A E m ust be 
s u b mitte d wit hi n 7 cale n dar da ys of lear ni n g of t he A E.  
1Seri o us a d verse e ve nts t hat occ ur m ore t ha n 3 0 da ys after t he last a d mi nistrati o n 
of i n vesti gati o nal a ge nt/i nter ve nti o n a n d ha ve a n attri b uti o n of p ossi ble, 
pr o ba ble, or defi nite re q uire re p orti n g as f oll o ws:  
E x pe dite d 2 4 -h o ur n otific ati o n  f oll o w e d b y c o m plete re p ort wit hi n 3 
c ale n d ar d a ys f or:  
•  
All Gra de 3,  4, a n d Gra de 5 aEs  
E x pe dite d 7 c ale n d ar d a y  re p orts f or:  
1.  
Gra d e 2 aEs res ulti n g i n h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n  
2 F or st u dies usi n g P E T or S P E C T I N D a ge nts, t he A E re p orti n g peri o d is li mite d 
t o 1 0 ra di oacti ve half-li ves, r o u n de d U P t o t he nearest w h ole da y, after t he 
a ge nt/i nter ve nti o n was last a d mi nistere d. F o ot n ote “ 1” a b o ve a p plies after t his 
re p orti n g peri o d. 
Ef fecti ve Date: Ma y 5, 2 0 1 1 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 5  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
1 0. 7 3 ( pri or 1 0. 8 4 )  
1 0. 8 4 1  A E SI Re p orti n g Mec ha nis m  
 
Wit hi n 2 4 h o urs of o bser vi n g or  lear ni n g of a n e ve nt meeti n g criteria f or a n A E SI 
( Secti o n 1 0. 7), i n vesti gat ors are t o re p ort, e mail or fa 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), t he e ve nt t o t he s p o ns or’s Dr u g Safet y De p art me nt, re gar dless 
of t he relati o ns hi p of t h e e ve nt t o t he st u d y treat me nt re gi me n.  
 
F or e ve nts meeti n g criteria f or a d verse e ve nt of s pecial i nter est ( A E SI) re p orti n g a n d 
occ urri n g wit hi n 3 0 da ys of t he last d ose of i n vesti gati o nal a ge nt ( Secti o n 1 0. 7):  
1.  
C o m plete t he A C C R U A d vers e E ve nt E x pe dite d Re p ort F or m, l ocate d 
o n t he A C C R U we bsite: 
(htt ps:// w w w. accr u. or g/accr u/f or ms/ N o n Pr ot oc ol S pecific F or ms/i n de x.
ht ml ) a n d s u b mit t he c o m plete d f or m t o t he A C C R U S A E C o or di nat or 
via fa x ( 5 0 7. 2 8 4. 9 6 2 8) wit hi n t he ti mefra me o utli ne d bel o w.  
2.  
T he A C C R U S A E C o or di nat or will n otif y I n d ustr y P art ner via e mail t o 
Dr u g.safet y @sea ge n.c o m  wit hi n t he ti meli ne o utli ne d bel o w.  
 
N O T E: F or e ve nts t hat meet criteria f or b ot h a n A E SI a n d a se vere a d verse e ve nt 
( Secti o n 1 0. 6 1), o nl y t he S A E re p orti n g mec ha nism a n d ti meli ne s h o ul d be use d.  
1 0. 8 4 2  A E SI Re p orti n g Ti meli ne  
3.  
E ve nts meeti n g criteria f or A E SI s h o ul d be re p orte d t o A C C R U wit hi n 
2 1 da ys of lear ni n g of t he m.  
4.  
A C C R U will f or war d all A E SI f or ms t o Seattle Ge netics wit hi n 2 4 
h o urs of t heir recei pt.  
U p date d t he la n g ua ge o n re p orti n g of 
A E SIs t o ali g n wit h Seattle G e netics 
sta n dar d la n g ua ge. 
1 0. 8 3  
T he i n vesti gat or s h o ul d re p ort , e mail or fa 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),  all pre g na ncies, i ncl u di n g t h ose of t he part ners of male patie nts, 
wit hi n 2 4 h o urs t o A C C R U t he s p o ns or’s Dr u g Safet y De p art me nt usi n g Pre g na nc y 
Re p ort f or m. T he f u n di n g s p o ns or will be n otifie d b y A C C R U wit hi n 2 b usi ness da ys. 
T he s p o ns or ma y as k f or f oll o w u p e val uati o n of t he pre g na nc y, fet us, a n d c hil d.  
 
U p date d t he i nf or mati o n o n re p orti n g 
of pre g na ncies.  
T hr o u g h o ut  
Re place d C T C A E v 4. 0 t o C T C A E v ersi o n 4. 0 3  
 
U p date d t he  versi o n of C T C A E.   
1 3. 1  
N O T E: S u bj ects wit h si g ns of cli nical be nefit (e. g., mi x e d res p o nse, s y m pt o m 
i m pr o ve me nt, de m o nstra ble sl o wi n g of pr o gressi o n, pr o gressi o n rate of < 2 0 % o ver 6 
m o nt hs) w h o are t olerati n g tre at me nt ma y be all o we d t o c o nti n ue treat me nt past f or mal 
ra di ol o gic pr o gressi o n (i.e. R E CI S T) if s uc h treat me nt is c o nsi dered i n t he s u bj ect's best 
U p date d, t o reflect t he c ha n ges i n t he 
pr ocess.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 6  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
i nterest b y t he s u bj ect, t he treati n g p h ysicia n, a n d t he A C C R U st u d y c hair S p o ns or  
Me dical M o nit or . 
1 3. 7  
A patie nt is dee me d a ca ncel if he/s he is re m o ve d fr o m t he st u d y f or a n y reas o n  bef ore 
a n y st u d y treat me nt is gi ve n.  
O n -st u d y material a n d t he E n d of Acti ve Treat me nt/ Ca ncel N otificati o n F or m m ust b e 
s u b mitte d. 
T he patie nt will g o directl y t o t he e ve nt -m o nit ori n g p hase of t he st u d y, a n d e ve nt 
m o nit ori n g will be re q uire d per Secti o n 1 8. 0 of t he pr ot oc ol.  
Re m o ve d, as t he s pecific i nstr ucti o ns 
o n w hic h f or ms t o c o m plete f or t his 
p o p ulati o n are pr o vi de d i n C C Gs.  
1 4. 1  
1 4. 1 S u m mar y T a ble of Researc h Bl o o d/ Bl o o d Pr o d ucts t o Be C ollecte d f or T his 
Pr ot oc ol:  
1.  Re m o ve d “ Ma n dat or y - E D T A K 2 ( p ur pl e) - W h ole Bl o o d” r o w  
2.  C ha n ges i n t he f o ot n ote:  
4.  After all sa m ples ha ve bee n pr ocesse d acc or di n g t o kit i nstr ucti o ns, s hi p all 
s peci me ns acc or di n g t o s hi p pi n g i nstr ucti o ns f o u n d i n t he Ce ntral 
La b orat or y Ma n ual  (see Secti o n 1 4. 2 f or detaile d s hi p pi n g i nstr ucti o ns.) 
U p date d, t o reflect t he re d ucti o n i n 
t he bl o o d c ollecti o n a n d l ocati o n of 
s hi p pi n g i nstr ucti o ns. 
1 4. 1 1 1 t o 1 4. 1 1 4  
1 4. 1 1 1  T he kit c o ntai ns s u p plies a n d i nstr ucti o ns f or c ollecti n g, pr ocessi n g, a n d 
s hi p pi n g s peci me ns. Refer t o t he Ce ntral La b orat or y Ma n ual f or i nstr ucti o ns re gar di n g 
t he kit s u p pl y, re-or deri n g, s pe ci me n c ollecti o n, pr ocessi n g, a n d s hi p pi n g.  
1 4. 1 1 2  P artici pati n g i nstit uti o ns ma y o btai n kits b y c o m pleti n g a n d fa xi n g t he S u p pl y 
Or der F or m (f o u n d i n t he F or ms P ac ket) t o t he n u m ber  liste d o n t he f or m. Fill o ut t he site 
a d dress t o w here t he kits will be s hi p pe d o n t he Fa x S u p pl y f or m. A s mall b ut s ufficie nt 
s u p pl y of t he s peci me n c ollecti o n kits s h o ul d be or dere d pri or t o patie nt e ntr y. 
U n use d/e x pire d kits s h o ul d be dis p ose d of per i nstit uti o n p olic y. D o n ot se n d u n use d kits 
bac k t o B A P. S u p pl y Or der F or ms m ust be fille d i n c o m plet el y a n d le gi bl y f or q uic k 
pr ocessi n g.  
1 4. 1 1 3  Kits will be se nt via Fe d E x Gr o u n d at n o c ost t o t he partici p ati n g i nstit uti o ns. 
All o w u p t o t w o wee ks t o recei ve t he kits. Kits will arri ve i nsi de t he s hi p pi n g b o xes.  
1 4. 1 1 4  Kits will n ot be se nt via r us h d eli ver y ser vice u nless t he parti ci pati n g i nstit uti o n 
pr o vi des t heir o w n Fe d E x acc o u nt n u m ber or alter nate billi n g n u m ber f or e x press 
ser vice. A C C R U will n ot c o ver t he c ost f or r us h deli ver y of kits.  
Re m o ve d, as t he s pecific i nstr ucti o ns 
o n pr oc ure me nt of kits is liste d i n t he 
Ce ntral La b orat or y Ma n ual.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 7  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
1 4. 2  
1 4. 2 S hi p pi n g a n d Ha n dli n g  
Refer t o t he Ce ntral La b orat or y Ma n ual f or details o n s hi p pi n g a n d ha n dli n g.  
1 4. 2 1  
Verif y A L L secti o ns of t he Bl o o d S peci me n S u b missi o n F or m (see F or ms 
P ac ket), B A P Re q uisiti o n F or m ( pr o vi de d i n kit, a n d s peci me n c ollecti o n la bels are 
c o m plete d a n d fille d i n c orrectl y.  
1 4. 2 2  
S peci me ns m ust be s hi p pe d t he sa me da y t he y are dra w n.  
1 4 . 2 3 
S hi p t u bes wit h a pr o perl y pre pare d c ol d pac k. See kit i nstr ucti o ns f or s pecific 
details f or c ol d pac k pre parati o n (i.e., fr oze n or refri gerate d) a n d pr o per pac ki n g of bl o o d 
a n d c ol d pac k t o a v oi d freezi n g of s peci me n.  
1 4. 2 4  
S hi p s peci me ns via Pri orit y  O ver ni g ht ser vice, M o n da y –  T h urs da y, t o B A P 
Freezer acc or di n g t o kit i nstr ucti o ns. D o n ot se n d sa m ples o n wee ke n ds or j ust pri or t o 
fe d eral h oli da ys. If a patie nt c a n o nl y be see n o n Fri da ys, e mail t he Bi os peci me n 
Ma na ger (f o u n d o n res o urce pa ge) wit h t h e sa m ple i nf or mati o n a n d Fe d E x trac ki n g 
n u m ber.  
1 4. 2 5  
T he B A P kits will i ncl u de a s mart s hi p per la bel ( 3 x 5 w hite barc o de d la bel) 
affi xe d t o t he s hi p pi n g b o xes. T he s mart s hi p per la bel is a pre -a d dresse d ret ur n la bel, 
w hic h re places t he nee d f or a n air bill . S hi p pi n g c osts will be c o vere d b y A C C R U if t he 
s hi p pi n g b o x pr o vi de d wit h t he B A P kit is use d f or s hi p pi n g s peci me ns t o B A P Freezer.  
1 4. 2 6  
B A P Freezer will recei ve t he s a m ples a n d i m me diatel y f or war d s peci me ns t o 
t he A C C R U Researc h Base B A P S hare d Res o urce, Hilt o n S L -2 1, Atte nti o n: B A P 
S u per vis or.  
Re m o ve d s pecific i nf or mati o n 
re gar di n g s hi p pi n g a n d ha n dli n g of 
b o d y fl ui d bi os peci me ns as t he 
u p date d i nf or mati o n is pr o vi de d i n 
t he Ce ntral La b orat or y Ma n ual. 
1 4. 3 1 1 a n d 1 4. 3 1 2  
1 4. 3 1 1  W h ole bl o o d f or p har mac o ge n o mics  
D N A will be e xtracte d fr o m w h ole bl o o d a n d st ore d f or f ut ur e p har mac o ge netic assa ys 
(e. g., ge netic p ol y m or p his ms s uc h as t h ose k n o w n t o re g ulat e a n gi o ge nesis, 
i nfla m mati o n, i m m u nit y, a ut o-i m m u nit y, a n d a nti b o d y or dr u g acti o n of cleara nce) t hat 
ma y c orrelate wit h efficac y a n d t olera bilit y. T he D u ke P hase I Bi o mar ker La b orat or y 
l ocate d at D u ke U ni versit y ma y a nal yze t he D N A f or t he prese nce of mar kers of i nterest 
usi n g sta n dar d la b orat or y pr ot oc ols.  
1 4. 3 1 2 1  S ol u ble pr otei n ( bl o o d -base d) bi o mar kers  
C ha n ge ma d e t o reflect t he re d ucti o n 
i n bl o o d c ollecti o n.  
A nal yses of bi os peci me ns will be 
perf or me d b y t he ce ntral la b orat or y 
a n d n o l o n ger b y t he  D u ke  P hase I 
Bi o mar ker La b orat or y.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 8  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
Bl o o d ( platelet p o or plas ma, s er u m, a n d w hite bl o o d cells ( b uff y c oat)) will be c ollecte d 
at baseli ne, e ver y resta gi n g, a n d pr o gressi o n f or f ut ure a nal ysis. T he D u ke P hase I 
Bi o mar ker La b orat or y l ocate d at D u ke U ni versit y ma y a nal yze f or t he f oll o wi n g, 
A na l yses ma y i ncl u de, b ut are n ot li mite d t o s ol u ble H G F, c -M E T, E G F, H B E G F, 
H E R 1 -3, V E G F A -D, Pl G F, V E G F R 2, G A S 6, A X L, S D F 1, A n g 2, a n d TI E -2. A d diti o nal 
bi o mar kers ma y als o be e x pl ore d usi n g m ulti ple x arra y tec h n ol o g y. Fi nal bi o mar ker 
selecti o n will reflect the best s cie nce at t he ti me of a nal ysis.  
1 4. 3 1 3 2  Plas ma f or m utati o nal a nal ysis  
Bl o o d ( platelet p o or plas ma) t o assess t he m olec ular pr ofile of circ ulati n g t u m or D N A 
(ct D N A) will be c ollecte d at baseli ne, e ver y resta gi n g, a n d at t he 3 0-da y p ost -treat me nt 
v isit. T he D u ke P hase I Bi o mar ker La b orat or y l ocate d at D u ke U ni versit y ma y a nal yze 
f or t he f oll o wi n g, A nal ys es ma y i ncl u de, A nal ys es ma y i ncl u de,  b ut are n ot li mite d t o 
H E R 2 a m plificati o n, E G F R a m plificati o n, B R A F m utati o ns, a n d e xte n de d K R A S/ N R A S 
testi n g (e x o ns 2, 3, a n d 4). Fi nal bi o mar ker selecti o n will reflect t he best scie nce at t he 
ti me of a nal ysis. 
1 5. 0  
I n v esti gat or br oc h ure will be pr o vi de d t o partici pati n g sites a n d st ore d o n 
t he A C C R U we bsite. 
Re m o ve d,  t o reflect t he 
a d mi nistrati ve  c ha n ges. 
1 5. 1 8  
A n i nitial s u p pl y of t ucati ni b will be a ut o -s hi p pe d t o partici pati n g sites u p o n recei pt b y 
A C C R U of si g ne d P har mac y C o ntact F or m a n d i nitial I R B a p pr o val site acti vati o n b y t he 
s p o ns or. T hereafter, eac h partici pati n g A C C R U  treati n g l ocati o n will or der t he dr u g fr o m 
Seattle Ge netics. E mail t he Dr u g Or der Re q uest  I n vesti gati onal Dr u g Re q uest/ S hi p me nt 
Rec or d  F or m (f o u n d i n t he f or ms pac ket P har mac y Bi n der ) t o: 
 I S T @sea ge n.c o m m o u ntai neer @sea ge n.c o m  
Eac h partici pati n g A C C R U  treati n g l ocati o n will be res p o nsi ble f or m o nit ori n g t he 
s u p pl y of t ucati ni b a n d will us e t he Dr u g Or der Re q uest  I n vesti gati o nal Dr u g 
Re q uest/ S hi p me nt Rec or d F or m t o or der a d diti o nal s u p plies as nee de d.  
O ut date d E x pire d  or re mai ni n g dr u g is t o be destr o ye d  o n -sit e as per pr oce d ures i n place 
at eac h i nstit uti o n. C o ntact t he s p o ns or pri or t o destr o yi n g i n vesti gati o nal pr o d uct.  
U p dates ma d e t o reflect t he 
a d mi nistrati ve  c ha n ges i n t he  pr ocess 
of dr u g pr oc ure me nt . 
1 5. 1 9a  
T e m perat ure E xc ursi o ns  
T e m perat ure e xc ursi o ns t hat occ ur at t he site s h o ul d be re p orte d b y t he site usi n g t he 
I n vesti gati o nal Pr o d uct Q ualit y C o m plai nts a n d T e m perat ur e E xc ursi o ns F or m i nsert 
U p dates ma d e t o reflect t he 
a d mi nistrati ve  c ha n ges i n t he  pr ocess 
of dr u g pr oc ure me nt  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 4 9  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
s p o ns or de viati o n/te m perat ure e xc ursi o n f or m na me  f o u n d o n t he A C C R U we b site f or 
t his st u d y i n t he P har mac y Bi n dera n d e maile d t o:   I S T @sea ge n.c om  
 
1 5. 2 8  
Seattle Ge netics will pr o vi de f u n di n g f or t he pr oc ure me nt of trast uz u ma b b y Mc Kess o n. 
Eac h partici pati n g A C C R U treati n g l ocati o n will or der t he dr u g fr o m Mc Kess o n. Fa x t he 
Dr u g Or der Re q uest F or m (f o u n d o n t he A C C R U we b site) t o:  
 
Mc Kess o n  
Att n. Cli nical Researc h Ser vic es  
Fa x: ( 9 1 9) 2 5 6 -0 7 9 4  
 
Eac h partici pati n g A C C R U treati n g l ocati o n will be res p o nsi ble f or m o nit ori n g t he 
s u p pl y of trast uz u ma b a n d will use t he Dr u g Or der Re q uest F or m t o or der a d diti o nal 
s u p plies as nee de d. 
Eac h partici pati n g treati n g l oc ati o n will be res p o nsi ble f or m o nit ori n g t he s u p pl y of 
trast uz uma b a n d will use t he I n vesti gati o nal Dr u g Re q uest/ S hi p me nt Rec or d F or m 
(f o u n d i n t he P har mac y Bi n der) t o or der a d diti o nal s u p plies as nee de d. 
 
O ut date d E x pire d or re mai ni n g dr u g is t o be destr o ye d o n -sit e as per pr oce d ures i n place 
at eac h i nstit uti o n. C o nt act t he s p o ns or pri or t o destr o yi n g t he i n vesti gati o nal pr o d uct. 
U p dates ma d e t o reflect t he 
a d mi nistrati ve  c ha n ges i n t he  pr ocess 
of dr u g pr oc ure me nt  
1 6. 5 1  
T he st u d y c hair(s) a n d t he st u d y statisticia n will re vie w t he st u d y at least t wice a year t o 
i de ntif y accr ual, a d verse e ve nt, a n d a n y e n d p oi nt pr o ble ms t hat mi g ht be de vel o pi n g. T he 
Ma y o Cli nic Ca ncer Ce nter ( M C C C) Data Safet y M o nit ori n g B oar d ( D S M B) is 
res p o nsi ble f or re vie wi n g accr ual a n d safet y data f or t his trial at least t wice a year, base d 
o n re p orts pr o vi de d b y t he M C C C Statistical Office.  
Re m o ve d s pecific i nf or mati o n 
re gar di n g A C C R U’s pr ocesses of data 
m o nit ori n g t o reflect t he 
a d mi nistrati ve c ha n ge s ass oci ate d 
wit h t he u p date d s p o ns ors hi p.  
1 6. 7 3  
B ase d o n pri or A C C R U  st u dies i n v ol vi n g si milar disease sites, we e x pect a b o ut  it is 
esti mate d t hat  1 0 % of patie nts will be classifie d as mi n orities b y race a n d a b o ut 4 0 % of 
patie nts will be w o me n. E x pecte d sizes of racial b y ge n der s u bsets f or patie nts re gistere d 
t o t his st u d y are s h o w n i n t he f oll o wi n g ta ble: 
Re w or de d f or clarit y.  
1 7. 0 a n d 1 7. 1 1  
•  
A d de d la n g ua ge t o Secti o n 1 7: Refer t o t he Ce ntral La b orat or y Ma n ual f or 
i nstr ucti o ns o n pre parati o n a n d s u b missi o n of tiss ue bi os peci me ns. 
 
•  
C ha n ges ma d e t o t he S u m mar y T a ble of Tiss ue Bi os peci me ns f or T his Pr ot oc ol  
( Secti o n 1 7. 1 1): 
 
•  
T o t he “ T y pe of tiss ue bi os p eci me n t o s u b mit” c ol u m n: F F P E tiss ue bl oc k wit h 
c orres p o n di n g H & E sli de or u p t o fift y ( 5 0) 5 -micr o n, u nstai ne d sli des a n d u p t o 
t hree ( 3) c orres p o n di n g H & E sli des fr o m pri m ar y t u m ors prese nt pri or t o 
U p dates ma d e t o reflect t he c ha n ges 
i n t he pr ocesses. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 0  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
st u d y e ntr y (if a vaila ble). If n o pri mar y t u m or tiss ue is a vail a ble, metastatic 
bi o psies s h o ul d be  use d.  
•  
T o t he “ w he n t o s u b mit” c ol u m n: Wit hi n 1 2 m o nt hs of t he a nal ysis of t he 
pri mar y e n d p oi nt w he n re q ueste d b y st u d y c hair or desi g nee U p o n e nr oll me nt  
 
1 7. 2, 1 7. 2 1 t o 1 7. 2 9  
1 7. 2  P araffi n E m be d de d Tis s ue Bl oc ks/ Sli des 
1 7. 2 1  
S u b mit o ne f or mali n fi xe d paraffi n -e m be d de d ( F F P E) t u m or tiss ue bl oc k wit h 
lar gest a m o u nt of i n vasi ve t u m or (at least 1 c m of t u m or f or cases of s ur gical resecti o n) 
fr o m ori gi nal s ur ger y at t he ti me of dia g n osis. Bi o ps y material o btai ne d at t he ti me of 
met astatic dia g n osis ma y be s u b mitte d. A c orres p o n di n g H & E sli de f or eac h s u b mitte d 
bl oc k m ust b e pr o vi de d t o per mit q ualit y assess me nt of eac h tiss ue bl oc k. T he H & E sli de 
f or eac h bl oc k s h o ul d be re vie we d b y t he i nstit uti o n’s pat h ol o gist t o assess tiss ue q ualit y 
pri or t o s u b missi o n.  
 
If t here is n o s uita ble F F P E bl oc k a vaila ble, c o ntact t he me dical m o nit or.1 7. 2 2  T he 
F F P E tiss ue bl oc k is preferre d; h o we ver, if a n i nstit uti o n is u na ble t o pr o vi de a tiss ue 
bl oc k, c ut u p t o 5 0 (fift y) 5 -mi cr o n secti o ns a n d m o u nt o n c har ge d glass sli des. La bel t he 
sli des wit h A C C R U patie nt I D n u m ber, accessi o n n u m ber, a n d or der of secti o ns, a n d 
t hic k ness of secti o ns. N O T E: d o n ot place “stic k y” la bels directl y o n sli des. H & E stai n 
e ver y te nt h sli de (i.e., sli des la bele d 1, 1 1, 2 1, etc.). T he H & E sli des s h o ul d be re vie we d 
b y t he i nstit uti o n’s pat h ol o gist t o assess tiss ue q ualit y pri or t o s u b missi o n. F or sa m ples 
c o ntai ni n g less t ha n 7 s q uare milli meters of t u m or tiss ue, m ulti ple secti o ns s h o ul d be 
m o u nte d o nt o eac h sli de t o e ns ure t ha t t he a p pr o priate a m o u nt of t u m or tiss ue is 
a vaila ble. I deall y, eac h sli de s h o ul d ha ve a mi ni m u m of 7 5 % t u m or tiss ue o n t he sli de t o 
be dee me d a d e q uate f or st u d y. D o n ot ba ke or place c o vers sli ps o n t he sli des.  
 
1 7. 2 3  
T he f oll o wi n g materials bel o w are ma n dat or y ( u nless i n dicate d ot her wise) a n d 
re q uire d f or s hi p me nt: 
 
• 
P araffi n e m be d de d tiss ue bl oc ks wit h c orres p o n di n g H & E sli de(s) ( O R u p t o 5 0 
(fift y) u nstai ne d sli des wit h c orres p o n di n g H & E sli de(s).  
• 
S peci me n S u b missi o n: Tiss ue f or m  
• 
S ur gical P at h ol o g y Re p ort  
• 
O perati ve Re p ort ( o pti o nal)  
 
N O T E: Please i ncl u de t he A C C R U patie nt I D n u m ber o n all materials liste d a b o ve.  
 
Re m o ve d, as s pecific i nf or mati o n 
re gar di n g s hi p pi n g a n d ha n dli n g of 
tiss ue s peci me ns is pr o vi de d i n the 
Ce ntral La b orat or y Ma n ual , as 
s pecifie d i n Secti o n 1 7. 0. 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 1  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
1 7. 2 4  
T he bl oc k/sli des m ust be a p pr o priatel y pac ke d t o pre ve nt da ma ge (e. g., sli des 
s h o ul d be place d i n a p pr o priate sli de c o ntai ner) a nd place d i n a n i n di vi d ual plastic ba g. 
La b el t he ba g wit h t he pr ot oc ol n u m ber, A C C R U patie nt I D n u m ber, a n d patie nt i nitials.  
 
1 7. 2 5  
Tiss ue s peci me ns m ust be s hi p pe d ≤3 0 da ys fr o m date of s u b missi o n re q uest b y 
st u d y c hair or desi g nee. 
 
1 7. 2 6  
Verif y t hat t h e a p pr o priate secti o ns of t he S peci me n S u b missi o n: Tiss ue f or m 
are c o m plete d a n d fille d i n c orrectl y. E nter i nf or mati o n fr o m t he S peci me n S u b missi o n: 
Tiss ue f or m i nt o t he re m ote data e ntr y s yste m o n t he sa me d a y t he s peci me n is s u b mitte d 
(see F or ms P ac ket). 
 
1 7. 2 7  
S hi p all bl oc k/sli de tiss ue s peci me ns a n d acc o m pa n yi n g mat erials t o t he 
A C C R U Researc h B ase:  
 
A C C R U O perati o ns Office  
Att n: P C Office ( A C C R U -GI -1 6 1 7)  
R O _ F F _ 0 3 _ 2 4 -C C/ N W Cli ni c  
2 0 0 First Street S W  
R oc hester, M N 5 5 9 0 5  
 
1 7. 2 8  
W he n a n a p pr o priate re q uest is s u b mitte d, t he A C C R U O per ati o ns Office will 
f or war d t he bl oc k(s) t o t he A C C R U Researc h Base P R C, 2 9 1 5 Valle y hi g h Dri ve, Ma y o 
Cli nic R oc hester ( Att n: P R C S u per vis or) f or pr ocessi n g as o utli ne d i n Secti o n 1 7. 3.  
 
1 7. 2 9  
If a c orres p o n di n g H & E was n’t s u b mitte d b y t he i nstit uti o n wit h t he bl oc k, t he 
A C C R U O perati o ns Office will re q uest a sli de t o be pr ocesse d (i.e., c ut a n d H & E 
stai ne d) fr o m t he t u m or tiss ue bl oc k a n d will be f or war de d t o t he A C C R U Researc h B ase 
P R C f or re vie w u n der t he rese arc h base’ s pr ot oc ol f or assessi n g tiss ue q ualit y f or t he 
pr o p ose d c orrelati ve st u dies, u nless t he t u m or size is t o o s mall. If t he t u m or tiss ue is t o o 
s mall, assess me nt of tiss ue q ualit y will occ ur at t he ti me t he tra nslati o nal st u dies are 
perf or me d. After A C C R U res earc h base pat h ol o gist assesses t he tiss ue q ualit y, t he bl oc k 
a n d a p pr o priate pa p er w or k will be ret ur ne d t o t he A C C R U O perati o ns Office. O perati o ns 
Office.  
1 7. 3  
1 7. 3 1 At t he c o m pleti o n of t he st u d y, a n y u n use d/re mai ni n g material will be st ore d i n t he 
A C C R U Ce ntral O perati o ns Office or D u ke P hase I Bi o mar ker La b orat or y ( Att n.: 
P at h ol o g y C o or di nat or)  f or f ut ure researc h acc or di n g t o t he patie nt c o nse nt per missi o n 
(see Secti o n 6. 5). P ote ntial f ut ure researc h ma y i ncl u de i m m u n o hist oc he mistr y (I H C) 
a nal yses t o a nal yze pre dicti ve bi o mar kers, c ha n ges i n e x pressi o n patter n wit h t hera p y, 
U p date d t he bi os peci me n re p osit or y 
i nf or mati o n per Seattle Ge neti cs 
S O Ps.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 2  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
a n d c orrelati o n wit h res p o nse a n d/ or a d verse e ve nts. W he n a pr ot oc ol is de vel o pe d, it 
will b e prese nte d f or I R B re vie w a n d a p pr o val. 
 
1 7. 3 2  
F or patie nts w h o pr o vi de a d diti o nal c o nse nt, re mai ni n g de -i d e ntifie d u n use d 
bl o o d a n d/ or tiss ue will be retai ne d b y Seattle Ge netics a n d use d f or f ut ure researc h, 
i ncl u di n g b ut n ot li mite d t o t he e val uati o n of tar gets f or n o vel t hera pe utic a ge nts, t he 
bi ol o g y of se nsiti vit y a n d resista nce mec ha nis ms t o t ucati ni b, a n d t he i de ntificati o n of 
bi o mar kers of H E R 2 + metastatic c ol orectal disease a n d res p o nse/resista nce t o t hera p y. 
Bl o o d a n d tiss ue sa m ples d o nate d f or f ut ure researc h will be retai ne d f or a peri o d of u p 
t o 2 5 years. If a d diti o nal c o ns e nt is n ot pr o vi de d, a n y re mai ni n g bi ol o gical sa m ples will 
be destr o ye d after t he st u d y has bee n c o m plete d a n d all a p plica ble re g ulat or y o bli gati o ns 
ha ve bee n met. B a n ki n g of t u m or tiss ue, acc or di n g t o t he patie nt c o nse nt per missi o n (see 
Secti o n 6. 5), is f or f ut ure rese arc h. As pr ot oc ols are de vel o pe d, t he y will be prese nte d 
f or A C C R U a n d I R B re vie w a n d a p pr o val. ( T his c ollecti o n is part of a ge neral strate g y of 
i n vesti gati o n f or A C C R U st u dies). 
 
1 7. 3 3  
T he i nstit uti o nal pat h ol o gist will  be n otifie d b y t he P at h ol o g y C o or di nat or if t he 
bl oc k ma y be de plete d.  
1 8. 0  
Re m o ve d all 3  S u b missi o n Ti meta bles:  
•  
I nitial Material(s) 
•  
T est Sc he d ule Material(s)  
•  
F oll o w -u p Material(s)  
 
Re m o ve d ta bles were re place d wit h t he f oll o wi n g la n g ua ge:  
Refer t o t he Case Re p ort F or m C o m pleti o n G ui deli nes ( C C G) f or t he met h o ds  of  
data c ollecti o n.  
Re m o ve d, as s pecific i nf or mati o n 
re gar di n g met h o ds of  data c ollecti o n 
are pr o vi de d i n t he C C G.  
A p pe n di x I  
•  
Re m o ve d a sa m ple of I nf or me d C o nse nt T e m plate f or Ca ncer Treat me nt Trials  as 
A p pe n di x I , a n d  
•  
Ori gi nal A p pe n dices II t hr o u g h XI were re n u m bere d t o A p pe n di x I t hr o u g h X.  
•  
A d de d te xt t o t he A p pe n di x I ( A C C R U -GI -1 6 1 7, S G N T U C -0 1 7 
[ M O U N T AI N E E R] St u d y Assess me nt ) 
L ocal la b orat ories will perf or m all la b orat or y tests, a n d res ults will be pr o vi de d 
t o t he i n vesti gat or. Bl o o d a n d uri ne sa m ples f or he mat ol o g y, ser u m c he mistr y, 
a n d uri nal ysis will be pre pare d usi n g sta n dar d pr oce d ures. Wit h t he e xce pti o n of 
pre g na nc y test i n g, res ults of cli nical la b orat or y tests are t o be s u b mitte d t o t he 
ce ntral la b orat or y.  La b orat or y res ults will be re vie we d b y t he i n vesti gat or f or 
cli nical si g nifica nce.  
I C F te m plate was re m o ve d fr o m t he 
pr ot oc ol t o pr o vi de c o nsiste nc y wit h 
Seattle Ge net ics d oc u me nt 
de vel o p me nt.  
A d de d  te xt t o reflect t he 
a d mi nistrati ve c ha n ge i n  t he 
La b orat or y Assess me nt pr ocess.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 3  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
A p pe n di x II  
T u m or Assess me nts  
T u m or res p o nse will be assess e d usi n g R E CI S T 1. 1 Criteria. Ra di o gra p hic i ma gi n g will 
be perf or me d wit h C T or M RI . T he sa me met h o d f or t u m or assess me nt s h o ul d be 
e m pl o ye d at e ver y assess me nt. I ma gi n g will be perf or me d e ver y 9 wee ks (e ver y 3 
c ycles). If t he patie nt is cli nicall y sta ble after t w o years ( 3 4 c ycles)1 2 m o nt h of 
treat me nt, C T or M RI of t he c hest, a b d o me n, a n d pel vis ma y be perf or me d o nce e ver y 1 2 
wee ks (e ver y 4 c ycles +/ - 1 4 da ys).  
U p date d f or t he c o nsiste nc y wit h 
Secti o n 4 ( T est Sc he d ule).  
A p pe n di x VI  
•It is rec o m me n de d t hat if y o u miss 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 ul e 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, y o u 
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.  If y ou miss a d ose, place a c hec k “ 0” u n der t he date , b ut re me m ber t o ta ke y o ur 
prescri be d d ose at t he ne xt re g ularl y sc he d ule d ti me . 
A d de d  te xt t o t he P atie nt Dr u g Diar y 
t o pr o vi de m ore clarit y. 
A p pe n di x XI  
A d de d a p pe n di x XI  
A d de d t o ali g n wit h Seattle G e netics 
d oc u me nt d e vel o p me nt.  
A p pe n di x XII  
A d de d S u m mar y of C ha n ges f or A me n d me nt  2 t hr o u g h 7.  
A d de d t o ali g n wit h Seattle G e netics 
d oc u me nt d e vel o p me nt.  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 4  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt  8  
Secti o n(s)  
C ha n ge  
Rati o nale  
Title p a ge  
A d de d  a brief title.  
T o ali g n wit h pr ot oc ol te m plat e  
T hr o u g h o ut  
Re vise d A C C R U (I S T) la n g ua ge wit h t he sta n dar d Seattle G e netics te m plate 
la n g ua ge  
T o ha ve t he pr ot oc ol t hat better reflects 
c o m pa n y’s pr ocesses a n d t o a cc o m m o date 
c ha n ges d ue t o u p date d s p o ns ors hi p (t he I N D 
tra nsfer t o Seattle Ge netics oc c urre d o n t he 
1 7 -Se p -2 0 1 9), t he d oc u me nt was tra nsferre d i nt o 
t he Seattle Ge netics pr ot oc ol te m plate 
S y n o psis  
A d diti o n of s y n o psis  
T o ali g n wit h t he pr ot oc ol te m plate. T here was  
n o s y n o psis i n t he A C C R U te m plate ( ori gi nal 
pr ot oc ol t hr o u g h t he Pr ot oc ol A me n d me nt A 0 7)  
S y n o psis, 2, 3. 1, 4  
A d de d i n dicati o n:  
•  
P atie nts wit h H E R 2 -p ositi ve, R A S wil d -t y pe, u nresecta ble or metastatic 
C R C w h o, u nless c o ntrai n dicate d, ha ve pre vi o usl y recei ve d s yste mic 
t hera p y wit h fl u or o p yri mi di nes, o xali plati n, iri n oteca n, a n d a n a nti-
V E G F m A b; p atie nts w h ose disease has d M M R pr otei ns or is M SI -H 
m ust als o ha ve recei ve d a n a nti -P D -( L) 1 m A b, if i n dicate d. 
T o a d d clarit y  
T hr o u g h o ut  
A d diti o n of 2 c o h orts t o t he st u d y: t ucati ni b gi ve n i n c o m bi nati o n wit h 
trast uz u ma b ( C o h ort B) a n d t ucati ni b m o n ot hera p y ( C o h ort C). 
C o h ort B was  a d de d  to assess  efficac y 
(c o nfir me d O bj ecti ve Ress p o nse Rate [c O R R ]) 
a n d safet y of t he d ual t hera p y f or m C R C 
s u bj ects. C o h ort C was a d de d t o better 
c haracterize t he a ntit u m or acti vit y of t ucati ni b 
w he n use d as a m o n ot hera p y . 
1. 3. 2 a n d 1. 3. 3  
U p date d t he te xt  pertai ni n g t o t he o ver vie w of cli nical t ucati ni b st u dies.  
Reflect s t he latest u p dates f or t ucati ni b cli nical 
trials 
1. 4 a n d 1. 6  
A d diti o n of t he “wi del y a d o pte d nati o nal ( U S) g ui deli nes f or t he treat me nt of 
c ol o n ca ncer ”. 
Reflects a n u p date t o t he c urre nt g ui deli nes f or 
treat me nt of c ol o n ca ncer pati e nts  
1. 6  
A d diti o n of t he i nteri m data fr o m t he c urre nt M O U N T AI N E E R pr ot oc ol .  
Reflects t he latest data up date f or t he 
M O U N T AI N E E R  st u d y 
S y n o psis, 2, 9  
A me n d me nt of t he pri mar y o bj ecti ve ( t o c O R R) a n d a d diti o n  of ne w st u d y 
o bj ecti ves (sec o n dar y, a n d e x pl orat or y) f or t he c o m bi nati o n t hera p y a n d 
m o n ot hera p y c o h orts of t he st u d y as f oll o ws:  
•  
T o deter mi ne t he a ntit 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 trast uz u ma b, i n C o h orts A + B,  as meas ure d b y c O R R (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]   1. 1 criteria ), acc or di n g 
t o bli n de d i n de pe n de nt ce ntral re vie w ( BI C R) assess me nt 
E val uati o n 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 t ucati ni b m o n ot hera p y  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 5  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
•  
T o e val uate t he a ntit 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 
trast uz u ma b, i n C o h orts A + B, b y O R R b y 1 2 wee ks of treat me nt 
( R E CI S T 1. 1), acc or di n g t o BI C R assess me nt  
•  
T o e val uate t he a ntit u m or acti vit y of t ucati ni b m o n ot hera p y, i n C o h or t 
C,  as meas ure d b y O R R b y 1 2 wee ks of treat me nt ( R E CI S T  1. 1), 
acc or di n g t o BI C R assess me nt  
•  
T o assess t he D O R i n s u bj ects treate d wit h t ucati ni b m o n ot hera p y 
( R E CI S T 1. 1), i n C o h ort C, ac c or di n g t o BI C R assess me nt 
•  
T o assess t he safet y a n d t olera bilit y of t u cati ni b m o n ot hera p y , i n 
C o h ort  C  
•  
T o assess t he P F S i n s u bj ects treate d wit h t ucati ni b m o n ot hera p y 
( R E CI S T 1. 1), i n C o h ort C, ac c or di n g t o B I C R assess me nt  
•  
T o assess t he O S i n s u bj ects treate d wit h t ucati ni b m o n ot hera p y , i n 
C o h ort  C  
•  
T o assess patie nt -re p orte d o utc o mes ( P R Os) ass ociate d wit h t ucati ni b 
gi ve n i n c o m bi nati o n wit h trast uz u ma b, i n C o h orts A + B 
•  
T o e x pl ore healt h res o urce utilizati o n  
Re m o ve d cli nical be nefit rate ( C B R) fr o m t he o bj ecti ves.  
U p date d o bj ecti ves a n d e n d p oi nts t o s tate t hat all assess me nts will be d o ne 
b y BI C R.  
A me n d e d en d p oi nts t o reflect t he o bj ecti ves.  
S y n o psis, 3  
Pla n ne d e nr oll me nt was i ncre ase d fr o m 4 0 t o 1 1 0 s u bj ects . As  of 
A me n d me nt 8, 7 0  ne wl y  e nr olle d  s u bj ects will be ra n d o mize d t o eit her 
t ucati ni b gi ve n i n c o m bi nati o n wit h trast uz u ma b (4 0 s u bj ects ra n d o mize d t o 
C o h ort B) or t ucati ni b m o n ot hera p y ( 3 0 s u bj ects ra n d o mize d t o C o h ort C).  
E val uati o n 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 t ucati ni b m o n ot hera p y  
3. 1. 1, a n d 7. 7  
As of A me n d me nt 8, safet y o ver t he c o urse of t he st u d y will be e val uate d b y 
safet y m o nit ori n g c o m mittee ( S M C).  
Reflects tra nsfer of data a n d s a fet y m o nit ori n g 
f u ncti o n fr o m St u d y C hair t o S M C 
3. 1. 2  
A d diti o n of st o p pi n g criteria.  
Refle cts c ha n ges t o t he st u d y desi g n  
S y n o psis, 3. 1. 3  
U p date d t he st u d y sc he matic.  
Refle cts c ha n ges t o t he st u d y desi g n  
3. 2. 1  
Re w or de d t he rati o nale f or sel ecti o n of d oses a n d re gi me n . 
Clarificati o n  
S y n o psis,  4. 1, 7. 1, 
7. 4, 7. 4. 3, a n d 
A P P E N DI X A  
S pecifie d t hat:  
•  
I H C testi n g m ust be d o ne f oll o wi n g t he pac ka ge i nsert’s 
i nter pretati o nal ma n ual f or breast ca ncer.  
•  
C o nfir mat or y H E R 2 testi n g will be d o ne i n t he ce ntral la b orat or y . 
A d de d:  
Reflects c ha n ges t o t he st u d y desi g n.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 6  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
•  
If arc hi ve d tiss ue is n ot a vaila ble, t he n a ne wl y-o btai ne d bas eli ne 
bi o ps y of a n accessi ble t u m or lesi o n is re q uire d.  
S y n o psis, 4. 1  
T he baseli ne platelet c o u nt was c ha n ge d fr o m “ ≥7 5, 0 0 0/ m m 3” t o “≥1 0 0 x 
1 0 3/ µ L; s u bj ects wit h sta ble pl atelet c o u nt fr o m 7 5 -1 0 0 × 1 0 3/ µ L ma y be 
i ncl u de d wit h a p pr o val fr o m me dical m o nit or” 
Clarificati o n  
S y n o psis, 4. 1  
T he baseli ne la b orat or y he m o gl o bi n le vel was c ha n ge d fr o m “8. 0 g/ d L ” t o 
“9. 0 g/ d L ”  
A d de d fle xi bilit y  
S y n o psis, 4. 1  
T he i ncl usi o n criteria f or pre g na nc y was clarifie d t o i ncl u de a n a gree me nt 
f or fe males of c hil d beari n g p ote ntial n ot t o tr y t o bec o me pr e 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 dr u g, a n d 
a gree me nt t o n ot d o nate o va, start i 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 7 m o nt hs after t he fi nal d ose of st u d y dr u g.  
 
A d de d h or m o nal met h o ds of c o ntrace pti o n.  
 
I n a d diti o n, t he ti mi n g of males w h o a gree d n ot t o d o nate s p er m d uri n g t he 
st u d y was clarifie d t o “starti n g at t he ti me of i nf or me d c o nse nt, 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 7 m o nt hs after disc o nti n uati o n of st u d y 
dr u g.”  
A d de d fle xi bilit y , clarificati o n , a n d ali g n me nt 
wit h t he pr ot oc ol te m plate  
S y n o psis, 4. 2  
A d de d “ decrease d a bs ol ute ne utr o p hil c o u nt, w hic h m ust ha ve res ol ve d t o 
≤ Gra d e 2 ” cla use t o t he T o xicit y Relate d t o Pri or Ca ncer T hera pies 
criteri o n”  
Clarificati o n  
S y n o psis, 4. 2, 5. 2. 2. 1, 
5. 3. 4, A P P E N DI X E 
a n d A P P E N DI X F  
U p date d t he C o nc o mita nt Me dicati o n E xcl usi o n criteri o n t o as f oll o ws:  
Ha ve use d str o n g C Y P 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 C Y P 2 C 8 i n d uc er wit hi n 5 da ys pri or t o first d ose of st u d y 
treat me nt. C Y P 3 A 4 or C Y P 2 C 8 i n d ucers a n d str o n g C Y P 2 C 8 i n hi bit ors 
are als o pr o hi bite d as c o nc o mita nt me dicati o n s wit hi n 2 wee ks of 
disc o nti n uati o n of t ucati ni b treat me nt. Use of se nsiti ve C Y P 3 A 
s u bstrates s h o ul d be a v oi de d 2 wee ks bef ore e nr oll me nt a n d d uri n g 
st u d y treat me nt. 
 
Re m o ve d “ Re q uire t hera p y wit h warfari n or ot her c o u mari n deri vati ves 
( n o n-c o u mari n a ntic o a g ula nts are all o we d) ” criteri o n.  
 
U p date d i nf or mati o n o n C Y P 3 A 4 a n d C Y P 2 C 8 i n hi bit ors/i n d ucers, 
A p pe n di x E a n d A p pe n di x F, res pecti vel y.  
Reflects t he latest u p dates fr o m t ucati ni b cli nical 
st u dies 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 7  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
S y n o psis, 4. 2  
U p date d t he hist or y of a n ot her mali g na nc y e xcl usi o n criteri o n fr o m “ ≤2  
years pri or t o re gistrati o n w hi c h re q uire d s yste mic treat me nt” t o “ wit hi n 3 
years bef ore t he first d ose of st u d y dr u g, or a n y e vi de nce of resi d ual disease 
fr o m a pre vi o usl y dia g n ose d mali g na nc y” 
Ali g n me nt  wit h t he pr ot oc ol te m p late 
S y n o psis, 4. 2  
U p date d He p atitis C e xcl usi o n criteri o n t o as f oll o ws:  
K n o w n t o ha ve acti ve he patitis C i nfecti o n ( p ositi ve b y p ol y merase 
c hai n reacti o n or o n a nti viral t hera p y f or he patitis C wit hi n t he last 6 
m o nt hs). S u bj ects w h o ha ve bee n treate d f or he patitis C i nfe cti 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 1 2 
wee ks  
A d de d fle xi bilit y f or e nr oll me nt  
5. 1, 5. 2  
U p date d treat me nt a d mi nistrati o n t o i ncl u de C o h orts B a n d C  
Reflects c ha n ges t o t he st u d y desi g n  
5. 2. 3  
A E -s pecific D ose M o dificati o n ta ble f or t ucati ni b a n d trast uz u ma b was 
m o difie d t o reflect t he latest u p dates fr o m t he cli nical st u dies a n d se parate d 
i nt o 4  ta bles:  
•  
T a ble 5 -3  
D ose m o dificati o ns f or i nf usi o n -relate d reacti o ns f or 
trast uz u ma b 
•  
T a ble 5 -4  
D ose m o dificati o ns f or cli nical A Es relate d t o eit her 
t ucati ni b or trast uz u ma b 
•  
T a ble 5 -5  
D ose m o dificati o ns of t ucati ni b f or li ver f u ncti o n 
a b n or malities  
•  
T a ble 5 -6  
D ose m o dificati o ns g ui deli nes f or left ve ntric ular 
d ysf u ncti o n  
Clarificati o n  
5. 2. 3  
D ose m o dificati o n f or “ Bl o o d bilir u bi n i ncrease d at Gra de 2” was re m o ve d 
a n d at a n i nsta nce of “ Bl o o d bilir u bi n i ncrease d at Gra de 3” it is n o w 
rec o m me n de d t o “ H O L D u ntil se verit y ≤ Gra de 2”, i nstea d of “ ≤ Gra de 1”.  
C ha n ges t o t he d ose m o dificati o n were 
pe rf or me d t o reflect t he u p dates t o t he safet y 
practices  
5. 3. 3, 5. 3. 4  
U p date d t he la n g ua ge i n C o nc o mita nt T hera pies t o be Use d wit h Ca uti o n 
a n d Pr o hi bite d C o nc o mita nt T hera pies.  
Reflects t he latest u p dates fr o m t ucati ni b cli nical 
st u dies 
5. 4, 5. 5  
A d de d la n g ua ge f or Ma na ge me nt of Treat me nt -E mer ge nt A d verse E ve nts 
( T E A E) a n d Treat me nt C o m plia nce. 
Ali g n me nt wit h t he pr ot oc ol te m plate  
6, A P P E N DI X A  
A d de d: E Q -5 D -5 L a n d E O R T C Q L Q C 3 0 q ue sti o n naires ( C 1 D 1, C 1 D 8, 
C 1 D 1 5, C 2 D 1, C 3 D 1, C 4 D 1, e ver y 3 c ycles t hereafter,  u ntil treat me nt 
disc o nti n uati o n, disease pr o gr essi o n, deat h, t o xicit y, wit h dra wal of c o nse nt 
or st u d y cl os ure, a n d at t he E O T) . 
A d de d o nl y f or C o h orts B a n d C:  
•  
Bi o mar ker Plas ma c ollecti o n ( at scree ni n g)  
•  
Ra n d o mizati o n ( At scree ni n g)  
Reflects c ha n ges t o t he st u d y desi g n  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 8  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
•  
A nti b o dies t o He p atitis  C (a nti -H C V)  
•  
P K assess me nt ( pre -d ose C ycl es 2, 3, 4, 5, & 6 a n d p ost -d ose 
C ycle  3 ) 
•  
Ra di ol o gical assess me nt: e ver y 6 wee ks ( ± 7 da ys) d uri n g tre at me nt; 
e ver y 1 2 wee ks after 1 2  m o nt hs of tr eat me nt if cli nicall y sta ble 
( ±7  da ys). S u bj ects t hat disc o nti n ue f or  reas o ns ot her t ha n 
d oc u me nte d P D will c o nti n ue t o ha ve disease assess me nts 
a p pr o xi matel y e ver y 9 wee ks u ntil disease pr o gressi o n, deat h, 
wit h dra wal of c o nse nt, st u d y cl os ure , or alter nati ve t hera p y  
A d de d f or all c o h orts:  
•  
If arc hi ve d tiss ue is n ot a vailable, a ne w bi o ps y of a t u m or l esi o n 
s h o ul d be o btai ne d, if me dicall y feasi ble. S u bj ects wit h n o arc hi val 
tiss ue, a n d w h ose t u m ors are c o nsi dere d n ot accessi ble or 
a p pr o priate f or bi o ps y are n ot eli gi ble f or e nr oll me nt  
U p date d f or C o h ort A:  
•  
Ra di ol o gical ass ess me nt: e ver y 9 wee ks d uri n g treat me nt; e ver y 1 2 
wee ks after 1 2 m o nt hs of tr eat me nt if cli nicall y sta ble ( ± 7  da ys). 
S u bj ects t hat disc o nti n ue f or reas o ns ot her t ha n d oc u me nte d P D 
will c o nti n ue t o ha ve disease assess me nts a p pr o xi matel y e ver y 9 
wee ks u ntil disease pr o gressi o n, deat h, wit h dra wal of c o nse nt, st u d y 
cl os ure , or alter nati ve t hera p y. 
•  
Bi o mar ke r Plas ma a n d Ser u m c ollecti o ns at C ycle 1, C ycle 4 a n d 
e ver y 3 c ycles t hereafter (i.e., C ycles 4, 7, 1 0, etc.)  
A d de d: “ S u bj ects ra n d o mize d t o C o h ort C will be  all o we d t o cr oss o ver a n d 
recei ve d o u blet t ucati ni b + trast uz u ma b t hera p y, if t he y e x perie nce 
ra di o gra p hic pr o gressi o n at a n y ti me p oi nt (as deter mi ne d b y i n vesti gat or 
assess me nt usi n g R E CI S T 1. 1), or if t he y ha ve n ot ac hie ve d a P R or C R b y 
t he wee k 1 2 assess me nt. ”  
7. 3, A P P E N DI X A  
A d de d i nf or mati o n f or P K assess me nts f or C o h orts B a n d C, a n d f or s u bj ects 
i n C o h ort C w h o cr oss o ver t o t he t ucati ni b + trast uz u ma b re gi me n. 
Reflects c ha n ges t o t he st u d y desi g n  
7. 6, A P P E N DI X  A  
A d de d P atie nt -Re p orte d O utc o mes.  
Reflects c ha n ges t o t he st u d y desi g n  
7. 7, 7. 8, 8, 8. 1, 8. 2, 
8. 3, 8. 4, 8. 5, 8. 6, 8. 7  
T he sta n dar d Seattle Ge netics te m plate la n g ua ge was i nc or p orate d 
t hr o u g h o ut t he secti o n. 
Ali g n me nt wit h t he pr ot oc ol te m plate  
9. 1  
A d de d i nf or mati o n o n deter mi nati o n of sa m ple size of 1 1 0 s u bj ects.  
Reflects c ha n ges t o t he st u d y desi g n  
9. 2  
A d de d t he defi niti o ns f or c O R R a n d O R R b y Wee k 1 2  
Reflects c ha n ges t o t he st u d y desi g n  
9. 3  
A d de d a n d u p date d t he i nf or mati o n o n Statistical a n d A nal ytical Pla ns t o 
reflect c ha n ges i n t he o bj ecti ves. 
Reflects c ha n ges t o t he st u d y desi g n  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 5 9  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
1 0  
A d de d t he sta n dar d Seattle Ge netics la n g ua ge.  
Ali g n me nt wit h t he pr ot oc ol te m plate  
A P P E N DI X B  
A d de d t he La ns k y P erf or ma nc e Stat us scale  
Ali g n me nt wit h t he pr ot oc ol te m plate  
A P P E N DI X C  
A d de d t he a p pe n di x per Seattl e Ge netics te m plate.  
Ali g n me nt wit h t he pr ot oc ol te m plate  
A p pe n di x  I X 
(re m o ve d) 
Re m o ve d t he a p pe n di x title d Dr u gs Acce pte d or P ossi bl y Ass ociate d wit h 
Ris k of Q T Pr o l o n gati o n or T orsa de De P oi ntes. 
Res ults fr o m a cli nical p har ma c ol o g y t h or o u g h 
Q T st u d y i n healt h y v ol u nteers e val uati n g t he 
p ote ntial f or t ucati ni b t o pr ol o n g t he Q T i nter val 
i n dicate d t hat m ulti ple d oses of t ucati ni b 3 0 0 m g 
BI D di d n ot ha ve a si g nifica nt effect o n t he Q T 
i nter val i n healt h y v ol u nteers. 
5. 3. 3  a n d A p pe n di x X 
(re m o ve d) 
Re m o ve d “se nsiti ve s u bstrates f or t he U G T 1 A 1 tra ns p orter” fr o m t he list of 
C o nc o mita nt T hera pies t o be Use d wit h Ca uti o n.  
Re m o ve d t he a p pe n di x title d List of Selecte d P ote ntial Se nsiti ve S u bstrates 
f or U G T 1 A1.  
Reflects t he latest u p dates fr o m t ucati ni b  
cli nical st u dies  
T hr o u g h o ut  
A d mi nistrati ve c ha n ges ma de, as necessar y  
T o fi x err ors a n d e ns ure clarit y  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 0  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt 8. 1  
Secti o n(s)  
C ha n ge  
Rati o nale  
S y n o psis, 4. 2  
1 3.  Ha ve use d  a str o n g C Y P 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 C Y P 2 C 8 or C Y P 3 A 4  i n d ucer wit hi n 5 da ys  pri or t o 
first d ose of st u d y treat me nt. C Y P 3 A 4 or C Y P 2 C 8 i n d ucers a n d str o n g  
Str o n g  C Y P 2 C 8 i n hi bit ors a n d C Y P 2 C 8 or C Y P 3 A 4 i n d ucers  are als o  
pr o hi bite d as c o nc o mita nt me dicati o ns wit hi n 2 wee ks of  i n t he 2 wee ks 
f oll o wi n g disc o nti n uati o n of t ucati ni b treat me nt. Use of se nsiti ve C Y P 3 A 
s u bstrates s h o ul d be a v oi de d 2 wee ks bef ore e nr oll me nt  pri or t o first d ose of 
st u dy tre at m e nt a n d d uri n g st u d y treat me nt. 
Clarif y t he use of c o nc o mita nt dr u g t hat are 
s pecific C Y P i n hi bit ors or i n d ucers. 
S y n o psis, 5. 3. 1. 1  
Str o n g i n hi bit ors or i n d ucers of C Y P 2 C 8  i n hi bit ors a n d 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 me dicati o ns d uri n g st u d y 
treat me nt a n d wit hi n 2 wee ks of disc o nti n uati o n of t ucati ni b treat me nt. 
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 2 wee ks of disc o nti n uati o n  of st u d y 
treat me nt. 
Clarif y t he use of c o nc o mita nt dr u g t hat are 
s pecific C Y P i n hi bit ors or i n d ucers. 
5. 1. 1. 6  
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. T ucati ni b t a 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 r ecei pt at t he site, t hr o u g h s u bj ect 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.  
Clarif y t he c ollecti o n of t ucati ni b ta blets  
5. 1. 2. 7  
Trast uz u ma b use d d uri n g t he c o urse of t h e st u d y s h o ul d be ha n dle d 
acc or di n g t o its pac ka ge i nsert. Trast uz u ma b vi als are t o be trac ke d a n d 
d oc u me nte d fr o m t he ti me of r ecei pt at t he site, t hr o u g h s u bj ect 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.  
Clarif y t he c olle cti o n of trast uz u ma b vials  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 1  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt 8. 2  
Secti o n(s)  
C ha n ge  
Rati o nale  
Title p a ge  
A d de d E u dra C T n u m ber  
A d mi nistrati ve c ha n ge . 
S y n o psis , 4. 1 , 
A P P E N DI X  C  
A p pe n di x C was u p date d . T he i ncl usi o n criteria n u m ber 1 2 was u p date d t o 
ali g n wit h A p pe n di x C.  
d.  M a y c h o ose t o pr actice c o m plete a bsti ne nce, if c o nsiste nt wit h t he 
s u bject’s preferre d lifestyle, as a n acce pt a ble f or m of c o ntr ace pti o n  
d. e. 
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 hi g hl y effecti ve met h o ds of birt h c o ntr ol (i.e., met h o ds 
t hat ac hie ve a fail ure rate of < 1 % per year w he n use d c o nsiste ntl y a n d 
c orrectl y) starti n g at t he ti me of i nf or me d c o ns e 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 d y 
dr u g a d mi nistrati o n. F or t he f ull list of hi g hly effective m et h o ds of birt h 
c o ntr ol a n d g ui d a nce o n c o ntr ace pti o n r R efer t o A P P E N DI X C . f or 
g ui da nce o n c o ntrace pti o n.  
Hi g hl y effecti ve met h o ds of birt h c o ntr ol i ncl u de:  
● C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n ( oral, i ntra va gi nal, or 
tra ns der mal) 
● Pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass ocia te d wit h i n hi biti o n of 
o v ulati o n ( oral, i nj ecta ble, or i m pla nta ble)  
● I ntra uteri ne de vice 
● Bilateral t u bal occl usi o n/li gati o n  
● Vasect o mize d part ner  
● Se x ual a bsti ne nce w he n it is t he preferre d a n d us ual lifest yl e c h oice of 
t he s u bj ect 
 
Reflect s t he latest u p dates of Seattle Ge netics 
g ui da nce o n c o ntrace pti o n.  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 2  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
S y n o psis, 4. 1 , 7. 1, 7. 4 
H E R 2 stat us will b e verifie d b y ce ntral la b orat or y a nal ysis usi n g I H C b y a n 
F D A -a p pr o ve d or C E -m ar ke d  I H C test f oll o wi n g t he pac ka ge i nsert’s 
i nter pretati o nal ma n ual f or breast ca ncer.  
6.  Ha ve c o nfir me d H E R 2 -p ositi ve m C R C, as defi ne d b y ha vi n g t u m or 
tiss ue teste d at a Cli nical La b orat or y I m pr o ve me nt A me n d me nts 
( C LI A)-certifie d or I nter n ati o n al Or g a niz ati o n f or  St a n d ar diz ati o n 
(I S O)-accre di te d la b orat or y, meeti n g at least o ne of t he f oll o wi n g 
criteria:  
a. 
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]) b y a n 
F D A -a p pr o ve d or C o nf or mité E ur o pée n ne (C E )-m ar ke d  H E R 2 
I H C test f oll o wi n g t he pac ka ge i nsert’s i nter pretati o nal ma n ual f or 
breast ca ncer  
b.  H E R 2 2 + I H C is eli gi ble if t he t u m or is a m plifie d b y a n 
F D A -a p pr o ve d or C E -m ar ke d  H E R 2 i n sit u h y bri dizati o n assa y 
( FI S H or c hr o m o ge nic i n sit u h y bri dizati o n [ CI S H]) f oll o wi n g t he 
pac ka ge i nsert’s i nter pretati o nal ma n ual f or breast ca ncer  
c. H E R 2 ( E R B B 2 ) a m plificati o n b y C LI A-certifie d or I S O-accre di te d 
Ne xt Ge nerati o n Se q ue nci n g ( N G S) se q ue nci n g assa y.  
T u m or tiss ue m ust be s u b mitt e d t o t he s p o ns or -desi g nate d ce ntral la b orat or y 
f or c o nfir mat or y H E R 2 testi n g ( b y a n F D A-a p pr o ve d or C E -m ar ke d  H E R 2 
I H C test f oll o wi n g t he pac ka ge i nsert’s i nter pretati o nal ma n ual f or breast 
ca ncer).  
H E R 2 stat us will b e verifie d b y ce ntral la b orat or y a nal ysis usi n g I H C b y a n 
F D A -a p pr o ve d or C E -m ar ke d  I H C test f oll o wi n g t he pac ka ge i nsert’s 
i nter pretati o nal ma n ual f or breast ca ncer. 
A d de d E U -s pecific la n g ua ge f or t he l ocal I H C 
testi n g. 
7. 4. 2  
If at a n y ti me, ge netic res ults are o btai ne d t hat ma y ha ve cli nical rele va nce, 
I R B/I E C re vie w a n d a p pr o val will be s o u g ht re gar di n g t he m ost a p pr o priate 
ma n ner of discl os ure a n d w het her or n ot vali dati o n i n a C LI A -certifie d 
setti n g will be re q uire d. 
Ali g ne d wit h t he rest of t he pr ot oc ol . 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 3  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
1. 1, 1. 2. 1,  1. 7 , 1. 8 
Re m o ve d U S -s pecific la n g ua ge as a p pr o priate. 
T here are c urre ntl y n o F D A -a p pr o ve d t hera pies f or patie nts wit h E R B B 2 
a m plifie d metastatic C R C.  
After pr o gressi o n o n first a n d sec o n d li ne c he m ot hera p y ( F O L F O X a n d 
F O L FI RI), t he cli nical be nefit of F D A -a p pr o ve d t hera pies is li mite d.  
O nce patie nts wit h m C R C ha ve pr o gresse d o n all sta n dar d c he m ot hera p y 
a n d bi ol o gical t hera pies, c urre nt F D A -a p pr o ve d treat me nt o pti o ns i ncl u de 
re g orafe ni b a n d trifl uri di ne/ti piracil ( T A S-1 0 2).  
A d diti o nall y, trast uz u ma b is F D A -a p pr o ve d as a si n gle -a ge nt a n d i n 
c o m bi nati o n wit h eit her c he m ot hera p y or pert uz u ma b.  
Trast uz u ma b will be gi ve n at t he d ose a p pr o ve d b y t he F D A  f or si n gle-
a ge nt use w he n a d mi nistere d o n a Q 3 wee k c ycle.  
Re m o ve d U S -s pecific la n g ua g e t o acc o m m o date 
t he trial e x pa nsi o n i n t he E U. 
3. 1. 3 , 6. 6 
U p date d t he E n d o f St u d y defi niti o n 
T he st u d y e n ds w he n t he last s u bj ect c o m pletes t he last visit, or last 
c o ntact, disc o nti n ues fr o m t he st u d y, or is l ost t o f oll o w -u p, w hic he ver 
occ urs first.  T he st u dy will be cl ose d 5 ye ars after e nr oll m e nt of t he l ast 
s u bject, or w he n n o s u bjects r e m ai n i n l o n g -ter m f oll o w-u p, w hic hever 
occ urs first.  I n a d diti o n, t he s p o ns or m ay ter mi n ate t he st u dy at a ny ti m e 
(see Secti o n 1 0. 4. 1). 
Clarifies  t he defi niti o n of E n d of St u d y. 
4. 3  
Me n o pa use is 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 m ale  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.  
Clarif ies t he defi niti o n of me n o pa use. 
S y n o psis, 6. 3. 1 , 6. 3. 2, 
6. 3. 3,  6. 4, 7. 6, 
A P P E N DI X  A  
S pecifie d t hat E Q -5 D -5 L a n d E O R T C Q L Q -C 3 0 q uesti o n naires  a p pl y t o 
C o h orts B a n d C o nl y.  
E Q -5 D -5 L a n d E O R T C Q L Q -C 3 0 q uesti o n naires will be a d mi nistere d f or 
C o h orts B a n d C  at: pre -d ose C ycle 1 Da y 1 ( C 1 D 1), C 1 D 8, C 1 D 1 5, 
C 2 D 1, C 3 D 1, C 4 D 1, e ver y 3 c ycles t hereafter, u ntil treat me nt 
disc o nti n uati o n, P D, deat h, t o xicit y, wit h dra wal of c o nse nt or st u d y 
cl os ure, a n d at t he E O T.  
Clarif ies t he use of q uesti o n naires. 
1 0. 0  
F or st u di es c o n d ucte d i n t he E ur o pe a n U ni o n ( E U )/E ur o pe a n Ec o n o mic 
Are a ( E E A ) c o u ntries, t he i n vesti g at or will e ns ure c o m pli a nce wit h t he E U 
Cli nic al Tri al Directive ( 2 0 0 1/ 2 0/ E C) or a p plic a ble E ur o pe a n l oc al 
re g ul ati o ns. 
A d de d  re g ulat or y c o nsi derati o ns f or E U/ E E A 
c o u ntries.  
 
 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 4  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt 9  
Secti o n(s)  
C ha n ge  
Rati o nale  
S y n o psis, Secti o ns 3. 1. 3  
( Fi g ure 3-1 f o ot n otes a a n d 
c) , 6. 3. 4, 7. 2, 7. 2. 1, a n d 
A p pe n di x A f o ot n ote o.  
I n t hese secti o ns te xt was u p date d t o i n dicate s u bj ects wit h d oc u me nte d P D w h o 
ha ve c o nti n ue d o n st u d y treat me nt f or cli nical be nefit will n ot re q uire c o nti n ue d 
disease assess me nts after disc o nti n ui n g treat me nt. I n t he s y n o psis t his i ncl u de d 
u p date d te xt i n t he st u d y sc he ma f o ot n otes a a n d c, a n d  i n t he “ Efficac y 
A ssess me nts” secti o n. 
Pr oce d ural clarificati o n descri bi n g disease assess me nts 
f or s u bj ects wit h d oc u me nte d P D w h o ha ve c o nti n ue d 
o n st u d y treat me nt f or cli nical be nefit o nl y.  
C o nsiste nc y wit h detaile d u p dates i n Secti o n 6. 3. 6 a b o ut 
disease assess me nt pr oce d ures.  
 
 
S y n o psis, Secti o ns 3. 1. 3  
( Fi g ure 3-1, f o ot n ote e) ,  
7. 2. 1, a n d A p pe n di x A 
f o ot n ote u. 
 
I n t hese secti o ns te xt a b o ut re q uiri n g ne w baseli ne R E CI S T assess me nt f or 
s u bj ects fr o m C o h ort C w h o cr oss o ver fr o m m o n ot hera p y t o d o u blet t hera p y was 
a d de d.  I n t he s y n o psis t his i ncl u de d u p dates t o  te xt i n t he st u d y sc he ma (f o ot n ote 
e), st u d y desi g n, a n d d urati o n of treat me nt secti o ns. I n A p pe n di x A, f o ot n ote u 
was a d de d.  
 
C o nsiste nc y wit h detaile d  u p date a b o ut ne w baseli ne 
R E CI S T assess me nt a d de d t o Secti o n 6. 3. 6 (see bel o w).  
 
S y n o psis, Secti o ns 4. 1, a n d 
7. 4. 3  
I ncl usi o n criteri o n 5 a n d Secti o n 7. 4. 3:  A d de d te xt t o i n dicate s u bj ects m ust b e 
willi n g a n d a ble t o pr o vi de m ost rece ntl y a vaila ble  tiss ue bl oc ks.  
 
T o acc o u nt f or i nsta nces w here latest tiss ue bl oc k is 
e x ha uste d or n ot a vaila ble.  
 
S y n o psis, Secti o n 4. 1  
I ncl usi o n criteri o n 1 1 was a dj uste d as f oll o ws: 
•  
Platelet c o u nt c ha n ge fr o m 1 0 0 t o 7 5 ×  1 0 3/ u L a n d n ote t o c o ntact 
me dical m o nit or f or c o u nts fr o m 7 5 t o 1 0 0 ×  1 0 3/ u L was delete d as it is 
n o l o n ger rele v a nt.  
•  
He m o gl o bi n val ues were c ha n ge d  fr o m 9 t o 8 g/ d L 
 
A dj uste d t o ali g n wit h ori gi nal val ues use d i n t he 
i n vesti gat or-s p o ns ore d trial pr ot oc ol. 
 
S y n o psis, Secti o ns 4. 2, 
Secti o n 5. 3. 1. 1 , a n d 5. 3. 5 
E xcl usi o n criteri o n  ( E C) 1 3 , C o nc o mita nt T hera pies  (i n s y no psis), a n d Secti o n s 
5. 3. 1. 1 a n d 5. 3. 5 were  u p date d wit h  te xt a b o ut C Y P 2 C 8 a n d C Y P 3 A 4 i n d ucers 
t o i ncl u de t he q ualifier “str o n g” a n d a dj uste d pr o hi biti o n of use of str o n g 
C Y P 2 C 8 i n h ibit ors, str o n g C Y P 2 C 8 or C Y P 3 A 4 i n d ucers, or se nsiti ve C Y P 3 A 
s u bstrates f oll o wi n g disc o nti n uati o n fr o m 2 wee ks t o 1 wee k.  
 
I n S y n o psis a n d Secti o n 4. 2 E C  1 3 , re m o ve d C Y P relate d te xt t hat was c o vere d  
i n Secti o n 5. 3. 1. 1. 
 
I n Secti o n 5. 3. 1. 1 a d de d te xt a b o ut a v oi di n g se nsiti ve C Y P 3 A s u bstrates 1 wee k 
pri or t o first d ose of st u d y treat me nt a n d d uri n g st u d y treat me nt.  
 
I n Secti o n 5. 3. 5 ad de d ne w b ullet: Use of 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 first  d ose of st u d y treat me nt a n d d uri n g st u d y treat me nt 
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols  a n d c urre nt 
har m o nize d dr u g -dr u g i nteracti o n  rec o m me n dati o ns. 
 
 
 
 
 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 5  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
(see A P P E N DI X H ). C o nsi der usi n g a n alter nate me dicati o n w hic h 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. 
S y n o psis, Secti o n 4. 2  
E xcl usi o n criteri o n 1 7 was a d de d:  
Ha ve a h y perse nsiti vit y t o t uc ati ni b or a n y of its e xci pie nts, t o trast uz u ma b or 
a n y of its e xci pie nts, or t o m uri ne pr otei ns.  
Ne w te xt t o ali g n wit h u p dates ma d e i n t ucati ni b 
res p o nses t o re q uests f or i nf or mati o n. 
Secti o ns 3. 1, 5. 1,  
A d de d cr oss -refere nce t o Secti o n 6. 3. 6 
Cl arificati o n t o ali g n wit h c ha n ges ma d e i n Secti o n 
6. 3. 6  
Secti o n 5. 2. 3. 2  
I n T a ble 5-6, re m o ve d t ucati ni b fr o m d ose m o dificati o n g ui d eli nes f or left 
ve ntric ular ej ecti o n fracti o n  
B ase d o n e val uati o n of H E R 2 C LI M B data, a ca usal 
ass ociati o n bet wee n t ucati ni b a n d decrease d L V E F was 
n ot esta blis he d  
 
Secti o n 5. 3. 4  
A d de d te xt i n dicati n g m o derat e C Y P 2 C 8 i n hi bit ors s h o ul d be use d wit h ca uti o n.  
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols  a n d c urre nt 
har m o nize d dr u g -dr u g i nteracti o n rec o m me n dati o ns.  
Secti o n 5. 4  
A d de d  te xt t o be c o nsiste nt wit h ot her t ucati ni b pr ot oc ols i n dicati n g o ver d ose 
e ve nts s h o ul d be ca pt ure d o n a d verse e ve nt e C R F per Secti o n 5. 4 a n d re p orte d as 
disc usse d i n Secti o n 7. 7. 1. 2.  
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols  
Secti o ns 6. 2. 2, 6. 3. 1, 6. 3. 3 , 
6. 4, 7. 7. 2, A p pe n di x A 
f o ot n ote f 
Ali g ne d vital si g n te xt bet wee n t hese secti o ns.  
C o nsiste nc y bet wee n secti o ns  
Secti o n 6. 3. 6  ( See R o w 2 
a b o ve as well f or relate d 
u p dates)  
A d de d  clarificati o n a b o ut t ucati ni b m o n ot hera p y a n d a d de d m ore detaile d te xt 
a b o ut re q uiri n g ne w baseli ne R E CI S T assess me nt f or s u bj ects fr o m C o h ort C 
w h o cr oss o ver fr o m m o n ot her a p y t o d o u blet t hera p y.  
As me nti o ne d o n R o w 2, u p dates were ma de t hr o u g h o ut t he pr ot oc ol w here 
cr oss o ver was disc usse d t o eit her refer bac k t o t his secti o n (Sec ti o n 6. 3. 6) a n d/ or 
t o me nti o n re q uire me nt f or ne w baseli ne R E CI S T assess me nt f or s u bj ects fr o m 
C o h ort C w h o cr oss o ver fr o m m o n ot hera p y t o d o u blet t hera p y.  
 
Detaile d pr oce d ural c larificati o ns a b o ut ne w baseli ne 
assess me nts f or s u bj ects i n C o h ort C w h o cr oss o ver 
fr o m m o n ot hera p y t o d o u blet t hera p y. C o nsiste nc y wit h 
u p dates i n  S y n o psis, Secti o ns 3. 1. 3  ( Fi g ure 3-1, 
f o ot n ote e), 7. 2. 1, a n d A p pe n di x A f o ot n ote u . 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 6  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
Secti o n 7. 7. 1. 1  
A d de d te xt t o ma n date t hat A E SIs be re p orte d wit hi n 2 4 h o urs t o be c o nsiste nt 
wit h ot her t ucati ni b st u dies.  
 
Clarifie d DI LI relate d te xt  –  re wr ote i nt o te xt f or m beca use ta ble f or m was 
p ote ntiall y a m bi g u o us . 
 
A d de d state m e nt a b o ut meas uri n g  c o nj u gate d a n d u nc o nj u gate d bilir u bi n i n 
cases of h y per bilir u bi ne mia . 
Clarificati o ns t o be c o nsist e nt wit h ot her t ucati ni b 
pr ot oc ols  
 
Clarificati o n o nl y  
 
 
Clarificati o n t o assist i n deter mi ni n g eti ol o g y i n cases of 
h y per bilir u bi ne mia.  
Secti o n 7. 7. 1. 2  
T o “ F oll o w -u p f or A b n or mal La b orat or y Res ults S u g gesti n g P ote ntial DI LI”, 
a d de d te xt a b o ut meas uri n g c o nj u gate d a n d u nc o nj u gate d bilir u bi n  
 
A d de d te xt i n secti o n calle d “ D osi n g Err ors” a b o ut t ucati ni b d osi n g err ors a n d 
cr oss-refere nce d t o Secti o n 5. 4 Ma na ge me nt of O ver d ose 
 
A d de d te xt  i n secti o n calle d “Left Ve ntric ular E j ecti o n Fracti o n Decrease d” t o 
a d dress re p orti n g f or left ve ntric ular ej ecti o n fracti o n decrease a n d c o n gesti ve 
heart fail ure.  
C o nsiste nc y wit h u p dates t o S ecti o n 7. 7. 1. 1  
 
 
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ols  
 
 
C o nsiste nc y wit h ot her t ucati ni b pr ot o c ols 
A p pe n di x A  
T a ble 1 1 -2:  A d de d f o ot n ote c  ‘ Bi o mar ker sa m ples c ollecte d pri or t o d osi n g o n 
Da y 1 of C ycle 3 a n d e ver y 3 c ycles t hereafter (i.e., C ycle 3, 6, 9 etc.) pri or t o 
Pr ot oc ol A d de n d u m 2 (effecti ve date: 2 0 O C T 2 0 1 7).’  
 
A d de d t o i n dicate t hat bi o mar ker sa m ple c ollecti o n 
ti mes i n pri or a me n d me nts were differe nt. T he a d de d 
te xt ma kes it clear t hat u n der pre vi o us a me n d me nts 
pr oce d ures were d o ne per pr ot oc ol.  
A p pe n di x E  
Re m o ve d te xt a b o ut C Y P 3 A 4 i n hi bit ors  
C o nsiste nc y wit h ot her t ucati ni b pr ot oc ol s 
A p pe n di x F  
T he f oll o wi n g c ha n ges were ma de:  
•  Str o n g I n hi bit ors list: re m o ve d cl o pi d o grel  
•  M o derate I n hi bit ors List: a d de d cl o pi d o grel, deferasir o x, terifl u n o mi de  
Rifa m pi n was c ha n ge d t o a m o derate i n d ucer (i nstea d of str o n g i n d ucer)  
C ha n ges t o ali g n wit h  c urre nt C Y P rec o m me n dati o ns.  
A p pe n di x G  
A d de d r o w f or 5 0 a n d 1 5 0 m g pills i n I nstr ucti o ns hea der  
 
A d de d  + 3 da y wi n d o w f or e n d of c ycle cli nic visit  
 
Clarifie d te xt a b o ut missi n g/re placi n g a d ose d ue t o v o miti n g.  
C ha n ges t o ma ke t he P atie nt Dr u g Diar y m o re 
f u ncti o nal a n d t o clarif y missi n g/re place d d oses d ue t o 
v o miti n g.  
A p pe n di x H  
Re m o ve d c o nte nt a b o ut P -g p i n hi bit ors ( T his was i n A p pe n di x H c o nte nt).  
 
T he f or mer A p pe n di x I “ E xa m ples of Cli nical S u bstrates f or C Y P 3 A -Me diate d 
Meta b olis m n o w bec o mes A p pe n di x H.   
 
T hese are n o l o n ger pr o hi bite d c o nc o mita nt 
me dicati o ns.  
 
 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 7  of 1 7 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
A p pe n di x I  
A d de d a ne w a p pe n di x t o i ncl u de i nf or mati o n a b o ut Defi ni n g Li nes of T hera p y.  
 
T his a d diti o n mea ns t he I n vesti gat or’s Si g nat ure P a ge bec o mes A p pe n di x J  
A d diti o n t o pr o vi de clarificati o ns a b o ut pr ot oc ol 
s pecific defi niti o ns relate d t o li nes of t hera p y.  
T hr o u g h o ut  
A d mi nistrati ve c ha n ges ma de, as necessar y  
T o fi x err ors a n d e ns ure clarit y  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 8  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt 1 0  
Secti o n(s)  
C ha n ge  
Rati o nale  
T hr o u g h o ut  
Seattle Ge netics c ha n ge d t o S ea ge n  t hr o u g h o ut 
C or p orate na me c ha n ge  
Secti o n 1. 3. 2. 3 a n d 
Secti o n  1. 6 , Secti o n 5. 3. 1. 2 
A d de d ne w o n g oi n g st u dies wit h t ucati ni b  a n d H E R 2 C LI M B ( O N T -3 8 0 -2 0 6) 
pri mar y res ults  
T o pr o vi de u p date d t ucati ni b cli nical de vel o p me nt  
i nf or mati o n 
S y n o psis , Secti o n 3. 1, 
Secti o n 9. 1,  
Clarifie d  ‘a p pr o xi matel y’ 3 0 s u bj ects will be ra n d o mize d t o a n d treate d i n 
C o h ort C  
Clarificati o n a n d c o nsiste nc y wit h C o h orts A  a n d B  
S y n o psis Secti o n 3. 1  a n d  
Secti o n 9. 2. 1  
U p date d pri mar y efficac y a nal ys is set 
T o clarif y t hat t he pri mar y effi cac y a nal ysis set will 
c o nsist of all patie nts i n C o h orts A + B.  
S y n o psis a n d Secti o n  4. 1  
U p date d c o ntrace pti o n la n g ua ge  
F or c o nsiste nc y wit h A p pe n di x C  
Secti o n 4. 4. 1 , Secti o n 6. 3. 4, 
Secti o n 7. 2. 1 , Secti o n 
7. 7. 7. 1  a n d A p pe n di x A  
Clarifie d ti mi n g of ra di o gra p hic assess me nts f or s u bj ects wit h d oc u me nte d P D 
w h o  c o nti n ue o n treat me nt  
T o e ns ure t hat assess me nts c o nti n ue t o be  perf or me d per 
t he pr ot oc ol d efi ne d assess me nt sc he d ule 
Secti o n 5. 4  a n d Secti o n 
7. 7. 1. 2  
Re m o ve d  re q uire me nt t o re p ort o ver d ose e ve nts or d osi n g err ors f oll o wi n g t he 
S A E re p orti n g pr ocess  
O ver d ose a n d d osi n g err ors will n o l o n ger be ca pt ure d 
i n t he safet y data b ase. 
Secti o n 5. 2. 3. 2  
Re vise d trast uz u ma b d ose m o dificati o ns g ui deli nes f or L V E F  
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 3. 1. 3, 
Secti o n 6. 2. 1 , Secti o n 7. 1, 
A p pe n di x A  
A d de d a pre -scree ni n g peri o d 
T o all o w patie nts o n a c urre nt c he m ot hera p y re gi me n 
w h o are e x pecte d t o be eli gi ble f or M O U N T AI N E E R 
t he o pti o n t o s u b mit a t u m or s peci me n f or assess me nt of 
H E R 2 stat us  
Secti o n 6. 5, Secti o n 7. 7. 6. 1, 
Secti o n 9. 3. 9. 5, A p pe n di x A  
A d de d e ver y 6 -m o nt h assess me nt of car diac f u ncti o n ( E C H O or M U G A) u ntil 
2 4  m o nt hs fr o m t he last a d mi nistrati o n of trast uz u ma b  
F or ali g n me nt wit h t he trast uz u ma b  s u m mar y of pr o d uct 
c haracteristics  
Secti o n 7. 7. 1. 5  
A d de d re q uire me nt f or i n vesti gat or t o re p ort S A Es t o s p o ns or 
T o satisf y S U S A R re p orti n g re g ulati o ns  
A p pe n di x G  
Re vise d Oral Me dicati o n Diar y  
F or clarit y  
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 6 9  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt 1 1  
Secti o n(s)  
C ha n ge  
Rati o nale  
Pr ot oc ol S y n o psis , Secti o n 
9. 3. 1. 9  
T he ti mi n g of t he pri mar y a nal ysis will be base d o n t he ti me t o c o nfir me d O R R  
per BI C R.  D O R acc or di n g t o BI C R assess me nt will als o be a nal yze d at t his 
ti me.T he fi nal a nal ysis of c O R R a n d D O R will be c o n d ucte d w he n all treate d 
s u bj ects 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 ys safet y f oll o w -u p 
after disease pr o gressi o n, w hi c he ver c o mes first.  Detaile d i nf or mati o n re gar di n g 
t he ti mi n g of t he a nal ysis will be pr o vi de d i n t he S A P. 
T his c ha n ge all o ws t he pri mar y a nal ysis t o be 
perf or me d at a ti me w he n s ufficie nt f oll o w-u p has 
occ urre d t o e ns ure t hat all s u bj ects e nr olle d will ha ve 
t he o p p ort u nit y t o ac hie ve a c o nfir me d res p o nse. T he 
S A P will o utli ne ti mi n g of t he a nal ysis base d u p o n data 
mat urit y , ta ki n g i nt o acc o u nt t he fact t hat at 6 m o nt hs 
after L PI (last patie nt e nr olle d), ~ 9 0 % of s u bj ects are 
e x pecte d t o ha ve at least 8 m o nt hs f oll o w -u p.  T his 
a p pr oac h t o t he ti mi n g of t he pri mar y a nal ysis will 
mi ni mize t he ris k of e xcl u di n g c o nfir me d res p o nses 
fr o m s u bj ects e nr olle d at t he e n d of t he st u d y .  
 
A P P E N DI X A:  
S C H E D U L E O F E V E N T S  
b  
At ti me of ra di o gra p hic assess me nts (i.e., pri or t o C ycle 4, pri or t o C ycle 7 
etc.) w hic h ma y occ ur ≤1 4 da ys pri or t o Da y 1 of ne w c ycle.  
c 
Bi o mar ker sa m ples c ollecte d pri or t o d osi n g o n Da y 1 of C ycle 3 a n d e ver y 
3 c ycles t hereafter (i.e., C ycle 3, 6, 9 etc.) pri or t o Pr ot oc ol A d de n d u m 2 
(effecti ve date: 2 0 O C T 2 0 1 7). 
F o ot n otes n o l o n ger a p pl y  si nce all C o h ort A s u bj ects 
ha ve rec o nse nte d t o a pr ot oc ol versi o n after A d de n d u m 
2.  
- 
 
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)

 
,
St u d y A C C R U -GI -1 6 1 7; S G N T U C -0 1 7   
Cli nical Pr ot oc ol  
 A me n d me nt 1 2 , 0 9 -Mar -2 0 2 3  
T ucati ni b   
Sea ge n I nc. - C o nfi de ntial  
 P a ge 1 7 0  of 1 7 0  
S u m m ar y of C h a n ges i n A me n d me nt 1 2  
Secti o n(s)  
C ha n ge  
Rati o nale  
S y n o psis  
A d de d  ne w s u b -secti o n “ E n d of St u d y” : 
T he pri mar y a nal ysis f or t his trial was c o n d ucte d base d o n a data c ut -off date of 
2 8 Marc h 2 0 2 2 . As t he pri mar y o bj ecti ve  was met, t he decisi o n was ma de t o 
cl ose t he trial. F or s u bj ects re mai ni n g o n st u d y, a last visit c o ntact will occ ur a n d 
s u bj ects w h o are still recei vi n g treat me nt will re vert t o p h ysicia n care. W he n 
a p plica ble, t he S p o ns or will assist wit h p ost -trial access t o t ucati ni b a n d 
trast uz u ma b. 
T o defi ne t he basis  f or en di n g t he  st u d y a n d pla n f or last 
s u bj ect visit 
S y n o psis  
C larifie d t hat s u bj ects will ha ve stat us e val uati o n e ver y 1 2 wee ks u ntil P D, 
deat h, or e n d of st u d y.  
T o clarif y t he ti mi n g of f oll o w -u p e val uati o ns  
Secti o n 1. 3. 2. 3 Cli nical 
St u dies  
A d de d res ults of a nal ysis f or pri mar y e n d p oi nt.  
T o d oc u me nt t he c o m pleti o n of t he pri mar y a nal ysis of 
t he M O U N T AI N E E R st u d y 
Secti o n 3. 1. 3 E n d of St u d y  
Delete d: “ T he st u d y will be cl ose d 5  years after e nr oll me nt of t he last s u bj ect, or 
w he n n o s u bj ects re mai n i n l o n g -ter m f oll o w-u p, w hic he ver occ urs first. ” 
A d de d: “T he pri mar y a nal ysis f or t his trial was c o n d ucte d b ase d o n a data c ut -off 
date of 2 8 Marc h 2 0 2 2. As t he pri mar y o bj ecti ve was met, t he decis i o n was ma d e 
t o cl ose t he st u d y. E n d of st u d y will be defi ne d as last patie nt , last visit.”  
T o defi ne e n d of st u d y  
Secti o n 6. 6 E n d of 
St u d y/ E n d of F oll o w -u p  
Delete d: “ T he st u d y will be cl ose d 5 years after e nr oll me nt of t he last s u bj ect, or 
w he n n o s u bj ects re mai n i n l o n g -ter m f oll o w-u p, w hic he ver occ urs first. I n 
a d diti o n, t he s p o ns or ma y ter mi nate t he st u d y at a n y ti me (s ee Secti o n 1 0. 4. 1 ).” 
M o ve d t he e n d -of st u d y defi niti o n t o Secti o n 3. 1. 3. E n d 
of St u d y.  
Secti o n 6. 7 P ost -St u d y Care  
A d de d secti o n: “ At t he ti me of st u d y cl os ure, s u bj ects w h o are still recei vi n g 
treat me nt will re vert t o p h ysicia n care. W he n a p plica ble, t he S p o ns or will assist 
wit h p ost -trial access t o t ucati ni b a n d trast uz u ma b .”  
T o e ns ure s u bj ects c o nti n ue t o recei ve care as nee de d 
Secti o n 7. 7. 7. 2  O bser vati o n  
a n d F oll o w-u p ( C o h ort A)  
U n der F o ll o w-u p, clarifie d t hat s u bj ects will ha ve stat us e val uati o n  e ver y 1 2 
wee ks u ntil  P D, deat h, or e n d of st u d y. 
A d de d: “ F or s u bj ects re mai ni n g o n st u d y  at t he ti me of st u d y cl os ure , a last visit 
/ c o ntact will occ ur a n d s u bjects w h o are still recei vi n g treat me nt will re vert t o 
p h ysicia n care. ”  
T o clarif y t he ti mi n g of f oll o w -u p e val uati o ns  
 
0 9 0 1 7 7 e 1 a 1 3 6 6 5 3 b\ A p pr o v e d\ A p pr o v e d O n: 1 0- M ar- 2 0 2 3 0 4: 5 5 ( G M T)