Conditions: Metastatic Colorectal Adenocarcinoma
Keywords: HER2 ERBB2 Colorectal cancer Seattle Genetics
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 117
Healthy volunteers: no

Brief summary:
This trial studies how well the drug tucatinib works when given with trastuzumab and when given by itself. The participants in this trial have HER2-positive (HER2+) metastatic colorectal cancer (mCRC). 'Metastatic' means that the cancer has spread to other parts of the body.

In the first part of this study, participants enrolled into Cohort A and received both tucatinib and trastuzumab. In the second part of this study, participants are randomly assigned to either Cohort B or Cohort C. Participants in Cohort B will receive tucatinib and trastuzumab. Participants in Cohort C will receive tucatinib. Participants in Cohort C who do not respond to therapy may have an option to receive tucatinib plus trastuzumab.

Detailed description:

Arms:
arm 1: Non-randomized cohort. Participants take tucatinib twice per day orally on Days 1-21 and trastuzumab intravenously (into the vein; IV) on Day 1. Cycles repeat every 21 days. arm 2: Randomized cohort. Participants take tucatinib twice per day orally on Days 1-21 and trastuzumab intravenously (into the vein; IV) on Day 1. Cycles repeat every 21 days. arm 3: Randomized cohort. Participants take tucatinib twice per orally every day. Participants who do not respond to therapy may have the option to receive tucatinib and trastuzumab.

Interventions: intervention 1: Trastuzumab intervention 2: Tucatinib
Intervention descriptions: intervention 1: Given intravenously (into the vein; IV) intervention 2: Given orally

Protocol document:
Prot_002.pdf: 
 
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)

SAP_003.pdf: 
 
P art or all of t he i nf or mati o n i n t his statistical a nal ysis pla n  a d de n d u m ma y be u n p u blis he d material. 
Acc or di n gl y, t his d oc u me nt is t o be treate d as c o nfi de ntial a n d restricte d t o its i nte n de d us e. T his material is t he 
pr o pert y of Sea ge n  I nc. a n d m ust n ot b e discl ose d or use d e xce pt as a ut h orize d i n writi n g b y Seage n  I nc. 
 
S T A TI S TI C A L A N A L Y SI S  P L A N  A D D E N D U M  
 
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 Patie nts wit h 
H E R 2 +  Metastatic C ol or ectal Ca ncer  
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  
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  
Versi o n : 
Versi o n 1  2 3 -O C T -2 0 2 3  
 
0 9 0 1 7 7 e 1 a 1 3 0f c d 5\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 3 2 2: 2 0 ( G M T)


 
St u d y S G N T U C -0 1 7  
Statistical A nal ysis Pla n  A d de n d u m  
Versi o n 1. 0 x x -J ul y-2 0 2 3  
T ucati ni b  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 2  of 7  
S P O N S O R A P P R O V A L P A G E  
 
D oc u me nt Title:  
Statistical A nal ysis Pla n  A d de n d u m  
Pr ot oc ol 
N u m ber / A me n d me nt: 
A C C R U -GI -1 6 1 7, S G N T U C -0 1 7  / A me n d me nt 1 2 
Versi o n:  
Versi o n 1  2 3 -O C T -2 0 2 3  
 
T he i n di vi d uals si g ni n g b el o w ha v e re vie we d a n d a p pr o ve of t his statistical a nal ysis pla n 
a d de n d u m . 
A p pr o v al ( s) 
 
 
 
, M D 
 
Sea ge n  I nc. 
 
Date  
 
 
 
, D O  
Sea ge n  I nc. 
 
Date  
 
 
 
, P h D 
 
Sea ge n  I nc. 
 
Date  
 
 
 
, P h D 
 
Sea ge n  I nc. 
 
Date  
0 9 0 1 7 7 e 1 a 1 3 0f c d 5\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 3 2 2: 2 0 ( G M T)
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
St u d y S G N T U C -0 1 7  
Statistical A nal ysis Pla n  A d de n d u m  
Versi o n 1. 0 x x -J ul y-2 0 2 3  
T ucati ni b  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 3  of 7  
T A B L E O F C O N T E N T S  
S P O N S O R A P P R O V A L P A G E  ............................................................................................................................. 2  
LI S T O F A B B R E VI A TI O N S  ................................................................................................................................ 4  
1  
I N T R O DU C TI O N  ........................................................................................................................................... 5  
2  
S T U D Y E N D P OI N T S  .................................................................................................................................... 5  
3  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  ......................................................................................... 6  
3. 1  
A nal ysis Sets  ........................................................................................................................................ 6  
3. 2  
Ti mi n g of A nal ys es  .............................................................................................................................. 6  
4  
S T A TI S TI C A L M E T H O D O L O G Y  ................................................................................................................ 6  
4. 1  
Trial Details  .......................................................................................................................................... 6  
4. 1. 1  
S u bj ect Dis p ositi o n  ................................................................................................................... 6  
4. 1. 2  
Pr ot oc ol De viati o ns  .................................................................................................................. 6  
4. 1. 3  
C o nc o mita nt T hera p y  ............................................................................................................... 6  
4. 1. 4  
E xte nt of E x p os ure  ................................................................................................................... 6  
4. 1. 5  
S u bse q ue nt A nti -Ca ncer Treat me nt  .......................................................................................... 7  
4. 2  
A nal ysis of Efficac y  ............................................................................................................................. 7  
4. 3  
A nal ysis of Safet y  ................................................................................................................................. 7  
4. 4  
C ha n ges i n t he Pla n ne d A nal ysis  .......................................................................................................... 7  
 
 
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St u d y S G N T U C -0 1 7  
Statistical A nal ysis Pla n  A d de n d u m  
Versi o n 1. 0 x x -J ul y-2 0 2 3  
T ucati ni b  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 4  of 7  
LI S T O F A B B R E VI A TI O N S  
A E  
A d verse E ve nt(s)  
A T C  
A nat o mical T her a pe utic C he mical  
BI C R  
Bli n de d I n de pe n de nt Ce ntral Re vie w  
C S R  
Cli nical St u d y Re p ort  
D o R  
D urati o n of Res p o nse  
E O S  
E n d of St u d y  
I T T 
I nte nt-to -treat 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
O S  
O verall S ur vi val  
P F S  
Pr o gressi o n Free S ur vi val  
P T  
Preferre d Ter m  
R E CI S T  
Res p o nse E val u ati o n Criteria i n S oli d T u m ors  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A nal ysis Pla n  
S M Q  
sta n dar d Me d D R A q uer y  
s S A P 
S u p ple me ntal Statistical A nal ysis Pla n  
S S Q  
S p o ns or S pecific Q uer y  
T E A E  
Treat me nt E mer ge nt A d verse E v e nt  
W H O  
W orl d Healt h Or ga nizati o n  
 
0 9 0 1 7 7 e 1 a 1 3 0f c d 5\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 3 2 2: 2 0 ( G M T)


 
St u d y S G N T U C -0 1 7  
Statistical A nal ysis Pla n  A d de n d u m  
Versi o n 1. 0 x x -J ul y-2 0 2 3  
T ucati ni b  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 5  of 7  
1  
I N T R O D U C TI O N 
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 was ma de t o cl ose t h e trial. F or 
s u bjects re mai ni n g o n st u d y, a l ast 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. 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 h e pr ot oc ol versi o n A me n d me nt 1 2 . 0 pr o vi de d 
“E n d of St u d y” rati o nale a n d pr oce d ure , a n d t his S A P a d de n d u m is t o pr o vi de  g ui d eli nes f or  
“ E n d of St u d y”  a nal yses .  
All pla n ne d a nal yses s pe cifie d i n t his d oc u me nt will be perf or me d. A n y c h a n ges will eit her 
be refl ecte d i n a me n d m e nts t o t his pla n or s pecificall y d o c u me nte d i n t he fi nal cli nical st u d y 
re p ort. A n y c h a n ges t o t his pla n, i n t he f or m of “ p ost h oc” or “ d ata dri ve n” a nal ys es will be 
i de ntifie d as s uc h i n t he fi nal cli nical st u d y re p ort.  
2  
S T U D Y E N D P OI N T S   
T he f oll o wi n g e n d p oi nts will be a nal yze d f or t he fi nal st u d y re p ort.  
Efficac y  
● 
D urati o n of Res p o nse  (D O R ) per BI C R, i n C o h orts A + B, a n d C o h ort C p ost -
cr oss o ver.  
● 
D O R per I n v esti gat or, i n C o h orts A + B, a n d C o h ort C p ost -cr oss o ver.  
● 
P F S per BI C R, i n C o h orts A + B.  
● 
P F S per I n vesti gat or, i n C o h orts A + B.  
● 
O S, i n C o h orts A + B, a n d C o h ort C .  
Safet y  
● 
Fre q u e nc y a n d se verit y, acc or di n g t o C o m m o n Ter mi n ol o g y Criteri a f or A d verse 
E ve nts ( C T C A E) versi o n 4. 0 3 criteria or hi g h er, 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, a n d C o h ort C p ost-
cr oss o ver  
● 
Fre q u e nc y of s eri o us a d v e rse e v e nts ( S A Es) a n d d eat hs d ue t o a d verse e v e nts ( A Es), 
i n C o h orts A + B, a n d C o h ort C p ost-cr oss o ver  
● 
Fre q u e nc y of treat me nt m o dificati 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, a n d C o h ort C p ost-cr oss o ver  
● 
Fre q u e nc y a n d se ver it y of la b orat or y a b n or malities, i n C o h orts A + B, a n d C o h ort C 
p ost -cr oss o ver  
● 
Vital si g ns a n d ot her rele va nt safet y varia bles, i n C o h orts A + B, a n d C o h ort C p ost -
cr oss o ver  
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St u d y S G N T U C -0 1 7  
Statistical A nal ysis Pla n  A d de n d u m  
Versi o n 1. 0 x x -J ul y-2 0 2 3  
T ucati ni b  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 6  of 7  
3  
G E N E R A L S T A TI S TI C A L C O N SI D E R A TI O N S  
T he ge neral statistical c o nsi derati o ns (f or i nsta nce, a nal ysis s ets, defi niti o n of e n d p oi nt a n d 
s u b gr o u p, ce ns ori n g r ul es, ha n dli n g of missi n g d ata, data c o n v e nti o ns a n d defi niti o ns) s h o ul d 
f oll o w t he st u d y S A P a n d s S A P u nless ot her wise s pecifie d i n t his d oc u me nt.  
3. 1  A n al y si s S et s  
T he  a nal ysis set s f oll o w t he st u d y S A P u nless ot her wise s pecifi e d i n t his d oc u me nt. 
3. 2  Ti mi n g of A n al y s e s  
T he  “ E n d of St u d y”  a n al ys es will be c o n d ucte d after t he fi nal data b ase l oc k of t his st u d y. 
4  
S T A TI S TI C A L M E T H O D O L O G Y  
4. 1  Tri al D et ail s  
4. 1. 1  S u bj e ct Di s p o siti o n  
Patie nt e nr oll me nt a n d dis p ositi o n will be s u m marize d b y c o h ort a n d t otal. T he ta ble will 
prese nt t he n u m ber a n d p erce nt a ge of patie nts w h o were e nr olle d or ra n d o mize d i n eac h 
c o h ort, recei ve d st u d y dr u g, a n d p artici pate d i n l o n g -ter m f oll o w-u p. T he n u m ber a n d 
perce nt a ge of pati e nts w h o disc o nti n ue d treat me nt will be s u m marize d b y t he reas o n f or 
treat me nt disc o nti n uati o n. T he n u m ber a n d p erce nta ge of patie nts w h o disc o nti n ue d t he st u d y 
will be s u m mariz e d b y t h e pri mar y reas o n f or st u d y disc o nti n uati o n. T he s u m mar y of 
dis p ositi o n will be c o n d ucte d f or I T T a nal ysis set.  
4. 1. 2  Pr ot o c ol D e vi ati o n s  
I m p ort a nt pr ot oc ol de viati o ns are a s u bset of pr ot o c ol de viati o ns t hat ma y re prese nt a 
di ver ge nce fr o m t he pr ot oc ol t hat c o ul d ha ve a si g nifica nt effect o n t he i nte grit y of t he st u d y 
data, or o n t he s u bject’s ri g hts, safet y, or welf are. I m p ort a nt pr ot oc ol de viati o ns als o i ncl u de 
e x e m pti o ns t o t he st u d y i ncl usi o n/e xcl usi o n criteria a n d will be s u m marize d b y cate g or y. A 
list of s u bjects wit h i m p orta nt pr ot oc ol de viati o ns will be prese nte d. 
4. 1. 3  C o n c o mit a n t T h er a p y 
C o nc o mita nt me dicati o ns will be s u m marize d b y t he W H O Dr u g A T C class a n d preferre d 
na me. T he n u m ber a n d p erce nt a ge of s u bjects w h o ta ke c o nc o mita nt me di cati o ns will be 
ta b ulate d. M ulti ple occ urre nces of t he sa me m e dicati o n wit hi n a s u bject will be s u m marize d 
o nl y o nce. C o nc o mita nt me dicati o ns will be liste d b y s u bject.  C o nc o mita nt me dicati o ns will 
be c o de d usi n g W orl d Healt h Or ga nizati o n ( W H O) Dr u g Dicti o nar y ( versi o n: W H O Dr u g 
Gl o bal 2 0 2 3 Mar B 3 or hi g her).  
4. 1. 4  E xt e nt of E x p o s ur e  
All t he a nal ys es f or t reat me nt e x p os ure s pecifie d i n t he S A P will be c o n d ucte d f or C o h orts 
A + B a n d C o h ort C p ost -cr oss o ver. 
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St u d y S G N T U C -0 1 7  
Statistical A nal ysis Pla n  A d de n d u m  
Versi o n 1. 0 x x -J ul y-2 0 2 3  
T ucati ni b  
Sea ge n  I nc. - C o nfi de ntial  
P a ge 7  of 7  
4. 1. 5  S u b s e q u e nt A nti -C a n c er T r e at m e nt 
T he n u m ber a n d p erce nta ge of s u bjects w h o recei ve s u bse q ue nt a ntica ncer t hera pies will be 
s u m marize d f or t he F A S.  
4. 2  A n al y si s of Effi c a c y   
P F S b y i n vesti gat or  a n d b y BI C R  will be s u m marize d per st u d y S A P  f or C o h orts A + B. D o R 
b y i n vesti gat or  a n d b y BI C R will be s u m marize d per st u d y S A P  f or C o h orts A + B a n d C o h ort 
C p ost -cr oss o ver. O S will be s u m marize d f or C o h orts A + B a n d C o h ort C  per st u d y S A P.  
4. 3  A n al y si s of S af et y  
T he  safet y a nal yses at t h e e n d of st u d y will be t he sa me as f or t h e pri mar y C S R, e x ce pt f or 
t he f oll o wi n g c h a n ges: 
1.  A d verse e ve nts will be c o de d usi n g Me di cal Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A, Versi o n 26. 0 or hi g her).  
2.  T he preferre d ter m " S us pecte d dr u g -i n d uce d li ver i nj ur y" will be a d d e d t o t he 
he pat ot o xicit y S S Q list use d i n t he pri mar y C S R. T h is preferre d ter m was ne wl y 
a d de d i n Me d D R A 2 6.  
3.  S u m mar y ta bles , fi g ures a n d listi n gs will n ot be u p date d f or C o h ort C pre -cr oss o ver 
beca use all patie nts i n C o h ort C eit her cr osse d o v er or ha d E O S b y t he pri m ar y 
data base l oc k .  
4. 4  C h a n g e s i n t h e Pl a n n e d A n al y si s  
T here f oll o wi n g a n al yses were n ot s pecifie d i n t he pr ot oc ol f or t his trial. 
S u m mar y of d urati o n of res p o ns e ( D o R) per BI C R a n d per I N V f or C o h ort C p ost -cr oss o ver.  
S u m mar y of a d diti o nal ris k cate g ories he pat ot o xicit y ( S M Q), he pat ot o xicit y ( S M Q), Diarr hea 
( P T), ser u m creati ni ne b y la b, bl o o d urea nitr o ge n b y la b, i nf usi o n relate d reacti o ns/I nf usi o n relate d 
h y p erse nsiti vit y reacti o ns  
 
0 9 0 1 7 7 e 1 a 1 3 0f c d 5\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 3 2 2: 2 0 ( G M T)


Si g nat ure Pa ge f or S G N- C LI N- 0 2 9 7 3 7 v 1. 0
Si g nat ure Pa ge f or S G N- C LI N- 0 2 9 7 3 7 v 1. 0
e Si g nat ure A p pr o val
Bi ostatistics
2 4- Oct- 2 0 2 3 1 7: 5 2: 4 3 G M T + 0 0 0 0
e Si g nat ure A p pr o val
Cli nical De vel o p me nt
2 4- Oct- 2 0 2 3 2 0: 4 3: 3 8 G M T + 0 0 0 0
e Si g nat ure A p pr o val
Bi ostatistics
2 5- Oct- 2 0 2 3 1 8: 2 4: 5 3 G M T + 0 0 0 0
e Si g nat ure A p pr o val
Cli nical De vel o p me nt
2 5- Oct- 2 0 2 3 2 1: 0 5: 4 1 G M T + 0 0 0 0
0 9 0 1 7 7 e 1 a 1 3 0f c d 5\ A p pr o v e d\ A p pr o v e d O n: 2 3- O ct- 2 0 2 3 2 2: 2 0 ( G M T)
P P D
P P D
P P D
P P D

SAP_001.pdf: 
 
Part or all of the information in this statistical analysis plan may be unpublished material. Accordingly, this 
document is to be treated as confidential and restricted to its intended use. This material is the property of 
Seagen, Inc. and must not be disclosed or used except as authorized in writing by Seagen, Inc. 
 
STATISTICAL ANALYSIS PLAN  
 
Protocol Number: 
ACCRU-GI-1617, SGNTUC-017 
SAP Version: 
Version 2 11-May-2022 
Protocol Title: 
MOUNTAINEER: A Phase 2, Open Label Study of Tucatinib 
Combined with Trastuzumab in Patients with HER2+ 
Metastatic Colorectal Cancer 
 
Sponsor: 
Seagen Inc. 
21823 30th Drive SE 
Bothell, WA 98021, USA 
 


Study SGNTUC-017
Statistical Analysis Plan
Version 2.0 11-May-2022
Tucatinib
Seagen, Inc. - Confidential
Page 2 of 40
APPROVAL SIGNATURES
Product:
Tucatinib
Protocol Number/Amendment:
ACCRU-GI-1617, ACCRU-GI-1617, SGNTUC-
017 / Amendment 11
SAP Version:
Version 2
Version Date:
11-May-2022
The individuals signing below have reviewed and approve this statistical analysis plan.
Date
Date
Date
Date
Date


Study SGNTUC-017 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ................................................................................................................................ 5 
1 
INTRODUCTION ........................................................................................................................................... 7 
2 
STUDY OBJECTIVES ................................................................................................................................... 7 
2.1 
Primary Objective ................................................................................................................................. 7 
2.2 
Secondary Objectives ............................................................................................................................ 7 
2.3 
Exploratory Objectives .......................................................................................................................... 8 
3 
STUDY ENDPOINTS .................................................................................................................................... 8 
3.1 
Primary Endpoint .................................................................................................................................. 8 
3.2 
Secondary Endpoints ............................................................................................................................. 8 
3.3 
Exploratory Endpoints ........................................................................................................................... 9 
4 
STUDY DESIGN ............................................................................................................................................ 9 
5 
ANALYSIS SETS ......................................................................................................................................... 10 
5.1 
Intent-to-Treat Analysis Set ................................................................................................................ 10 
5.2 
Full Analysis Set ................................................................................................................................. 11 
5.3 
Safety Analysis Set .............................................................................................................................. 11 
5.4 
Patient Reported Outcome Set............................................................................................................. 11 
5.5 
Pharmacokinetics (PK) Analysis Set ................................................................................................... 11 
6 
STATISTICAL CONSIDERATIONS .......................................................................................................... 11 
6.1 
General Principles ............................................................................................................................... 11 
6.2 
Determination of Sample Size ............................................................................................................. 12 
6.3 
Randomization and Blinding ............................................................................................................... 12 
6.4 
Data Transformations and Derivations ................................................................................................ 13 
6.4.1 
General ................................................................................................................................... 13 
6.4.2 
Best Overall Response ............................................................................................................ 13 
6.4.4 
Response Assessment Dates ................................................................................................... 13 
6.4.5 
Adequate Response Assessment ............................................................................................. 14 
6.4.6 
Action Taken with Study Treatment ...................................................................................... 14 
6.5 
Handling of Dropouts and Missing Data ............................................................................................. 14 
6.6 
Multicenter Studies ............................................................................................................................. 15 
6.7 
Multiple Comparison/Multiplicity....................................................................................................... 15 
6.8 
Examination of Subgroups .................................................................................................................. 15 
6.9 
Covariates ............................................................................................................................................ 16 
6.10 Timing of Analyses ............................................................................................................................. 16 
7 
PLANNED ANALYSES .............................................................................................................................. 16 
7.1 
Disposition .......................................................................................................................................... 16 
7.2 
Demographic and Baseline Characteristics ......................................................................................... 16 
7.3 
Protocol Deviations ............................................................................................................................. 17 
7.4 
Treatment Administration ................................................................................................................... 17 
7.5 
Efficacy Analyses ................................................................................................................................ 18 
7.5.1 
Primary Endpoint: Confirmed Objective Response Rate (cORR) per BICR ......................... 18 
7.5.2 
Secondary Endpoints .............................................................................................................. 19 
7.5.3 
Special considerations for Efficacy Analyses for Cohort C ................................................... 21 
7.6 
Safety Analyses ................................................................................................................................... 21 
7.6.1 
Adverse Events ....................................................................................................................... 22 
7.6.2 
Serious Adverse Events .......................................................................................................... 23 
7.6.3 
Adverse Events of Special Interest and Additional Risks ...................................................... 23 
7.6.4 
Clinical Laboratory Parameters .............................................................................................. 25 
7.6.5 
Left Ventricular Ejection Fraction .......................................................................................... 26 
7.6.6 
Vital Signs .............................................................................................................................. 26 
7.6.7 
ECOG ..................................................................................................................................... 26 
7.6.8 
Deaths ..................................................................................................................................... 26 


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7.6.9 
Concomitant Medications ....................................................................................................... 26 
7.7 
Additional Analyses ............................................................................................................................ 26 
7.7.1 
HER2 Status ........................................................................................................................... 26 
7.7.2 
Pharmacokinetics .................................................................................................................... 27 
7.7.3 
Patient Reported Outcomes .................................................................................................... 27 
7.7.4 
Health Resource Utilization.................................................................................................... 28 
7.7.5 
Subsequent Anticancer Therapy ............................................................................................. 29 
7.7.6 
Efficacy Analyses for Cohort C post-crossover ..................................................................... 29 
7.7.7 
Duration of Follow-up ............................................................................................................ 29 
7.7.8 
Biomarker related exploratory endpoint(s) ............................................................................. 29 
8 
INTERIM ANALYSIS.................................................................................................................................. 29 
9 
CHANGES FROM PLANNED ANALYSES .............................................................................................. 29 
9.1 
Changes from the Protocol .................................................................................................................. 29 
9.1.1 
Additional analyses for Cohort C Post-Crossover .................................................................. 29 
9.1.2 
Additional analyses for Adverse Event of Interest ................................................................. 29 
9.2 
Changes from the Original SAP .......................................................................................................... 29 
10 REFERENCES .............................................................................................................................................. 33 
11 APPENDICES ............................................................................................................................................... 34 
APPENDIX A: IMPUTATION OF PARTIALLY UNKNOWN ADVERSE EVENT DATES ......................... 34 
APPENDIX B: DEFINITION OF THE TERM “TREATMENT-EMERGENT” WITH RESPECT TO AE 
CLASSIFICATION ...................................................................................................................................... 36 
APPENDIX C: IMPUTATION OF PARTIAL MISSING PRIOR THERAPY DATES ..................................... 37 
APPENDIX D: IMPUTATION OF PARTIAL MISSING SUBSEQUENT ANTICANCER THERAPY DATES 
AND HOSPITALIZATION DATES ............................................................................................................ 38 
APPENDIX E: IMPUTATION OF PARTIAL MISSING DISEASE DIAGNOSIS DATES ............................. 39 
APPENDIX F: IMPUTATION OF PARTIAL MISSING DEATH DATES ....................................................... 40 
 


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LIST OF ABBREVIATIONS  
AE 
adverse event 
AESI 
adverse event of special interest 
BICR 
blinded independent central review  
BID 
twice daily 
CDISC 
clinical data interchange standards consortium 
CI 
confidence interval 
cORR 
confirmed objective response rate 
CPI 
checkpoint inhibitor 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCO 
data cutoff 
DOR 
duration of response 
ECOG 
Eastern Cooperative Oncology Group 
ED 
emergency department 
EGFR 
epidermal growth factor receptor 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer  
 
Quality of Life 30-item Core Questionnaire 
EOS 
end of study 
EOT 
end of treatment 
EQ-5D 
EuroQol five dimensions                                                                         
ITT i
i
HER2 
human epidermal growth factor receptor 2 
IRR 
infusion-related reaction 
FAS 
Full analysis Set 
IV 
intravenous 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NCI 
National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PO 
orally 
PP 
per protocol 
PR 
partial response 
PRO 
patient reported outcome 
PT 
preferred term 
QoL 
quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAP 
statistical analysis plan 


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SAE 
serious adverse event 
SMQ 
standard MedDRA query 
SMC 
Safety Monitoring Committee 
SSQ 
sponsor specific query 
TEAE 
treatment emergent adverse event 
SD 
stable disease 
SOC 
system organ class 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WHO 
World Health Organization 


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1 
INTRODUCTION  
This document outlines the statistical methods to be implemented within the scope of 
Protocol SGNTUC-017, entitled “MOUNTAINEER: A Phase 2, Open Label Study of 
Tucatinib Combined with Trastuzumab in Patients with HER2+ Metastatic Colorectal 
Cancer”. Results of the proposed analyses will become the basis of the clinical study report 
(CSR) for this protocol. 
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed. All planned analyses specified in this document will be performed. Any changes to 
this plan, in the form of “post hoc” or “data driven” analyses will be identified as such in the 
final CSR. Any changes will either be reflected in amendments to this plan before the 
database lock or specifically documented in the CSR. 
2 
STUDY OBJECTIVES  
The study consists of 3 cohorts. Cohort A includes approximately 40 subjects treated with the 
doublet regimen (tucatinib + trastuzumab). All subjects enrolled in the randomization cohorts 
of the trial will be randomized in a 4:3 ratio to receive tucatinib given in combination with 
trastuzumab (Cohort B) or tucatinib monotherapy (Cohort C). Enrollment will continue until 
approximately 30 subjects have been randomized to and treated in Cohort C, and 
approximately 40 subjects have been randomized to and treated in Cohort B.  
2.1 Primary Objective  
● 
To determine the antitumor activity of tucatinib given in combination with trastuzumab, 
in Cohorts A+B, as measured by confirmed objective response rate (cORR, per Response 
Evaluation Criteria in Solid Tumors [RECIST] 1.1 criteria), according to blinded 
independent central review (BICR) assessment 
2.2 Secondary Objectives  
Efficacy 
● 
To evaluate the antitumor activity of tucatinib given in combination with 
trastuzumab, in Cohorts A+B, as measured by ORR by 12 weeks of treatment 
(RECIST 1.1), according to BICR assessment. 
● 
To evaluate the antitumor activity of tucatinib monotherapy, in Cohort C, as 
measured by ORR by 12 weeks of treatment (RECIST 1.1), according to BICR 
assessment. 
● 
To assess the duration of response (DOR) in subjects treated with tucatinib given in 
combination with trastuzumab (RECIST 1.1), in Cohorts A+B, according to BICR 
assessment. 
● 
To assess the DOR in subjects treated with tucatinib monotherapy (RECIST 1.1), in 
Cohort C, according to BICR assessment. 


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● 
To assess the progression-free survival (PFS) in subjects treated with tucatinib given 
in combination with trastuzumab (RECIST 1.1), in Cohorts A+B, according to BICR 
assessment. 
● 
To assess the overall survival (OS) in subjects treated with tucatinib given in 
combination with trastuzumab, in Cohorts A+B 
Safety  
● 
To assess the safety and tolerability of tucatinib given in combination with 
trastuzumab, in Cohorts A+B  
● 
To assess the safety and tolerability of tucatinib monotherapy, in Cohort C  
2.3 Exploratory Objectives  
● 
To evaluate the pharmacokinetics (PK) of tucatinib 
● 
To explore any correlations between tissue and blood-based biomarkers and clinical 
outcomes 
● 
To assess the PFS in subjects treated with tucatinib monotherapy (RECIST 1.1), in 
Cohort C, according to BICR assessment. 
● 
To assess the OS in subjects treated with tucatinib monotherapy, in Cohort C. 
● 
To assess patient-reported outcomes (PRO) associated with tucatinib given in 
combination with trastuzumab. 
● 
To explore health resource utilization. 
3 
STUDY ENDPOINTS  
3.1 Primary Endpoint  
The primary efficacy endpoint of this study is confirmed objective response rate (cORR, 
confirmed complete response [CR] or partial response [PR] per Response Evaluation Criteria 
in Solid Tumors [RECIST] 1.1 criteria) according to blinded independent central review 
(BICR) assessment, in pooled Cohorts A+B. 
 
3.2 Secondary Endpoints  
Efficacy 
● 
ORR by 12 weeks of treatment, per BICR, in Cohorts A+B, and Cohort C 
● 
DOR (confirmed CR or PR) per BICR, in Cohorts A+B, and Cohort C. 
● 
PFS per BICR, in Cohorts A+B 
● 
OS, in Cohorts A+B 


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Safety  
● 
Frequency and severity, according to Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 criteria or higher, of all treatment-emergent adverse 
events (TEAEs) and treatment-related TEAEs, in Cohorts A+B, and Cohort C  
● 
Frequency of serious adverse events (SAEs) and deaths due to adverse events (AEs), 
in Cohorts A+B, and Cohort C 
● 
Frequency of treatment modifications and permanent treatment discontinuations due 
to AEs, in Cohorts A+B, and Cohort C  
● 
Frequency and severity of laboratory abnormalities, in Cohorts A+B, and Cohort C 
● 
Vital signs and other relevant safety variables, in Cohorts A+B, and Cohort C  
3.3 Exploratory Endpoints  
● 
Plasma concentrations of tucatinib 
● 
To explore potential biomarkers of response, resistance or toxicity from archived 
paraffin-embedded tumor samples and circulating tumor DNA (ctDNA) isolated from 
plasma samples. 
● 
PFS per BICR, in Cohort C 
● 
OS, in Cohort C 
● 
PRO per EQ-5D-5L, in Cohorts B and C 
● 
PRO per EORTC QLQ-C30, in Cohorts B and C 
● 
Cumulative incidence of health resource utilization, including length of stay, 
hospitalizations, and emergency department (ED) visits in Cohorts A+B, and Cohort 
C 
4 
STUDY DESIGN  
This is a randomized, open-label, multicenter Phase 2 study of tucatinib, administered as 
monotherapy and in combination with trastuzumab, in patients with human epidermal growth 
factor receptor 2 (HER2)-positive, RAS wild-type, unresectable or metastatic CRC. Eligible 
patients are required to have previously received and failed, unless contraindicated, systemic 
therapy with fluoropyrimidines, oxaliplatin, irinotecan, and an anti-VEGF mAb; patients 
with dMMR or MSI-H disease must also have received an anti-PD-(L)1 mAb, if indicated. 
Treatment will be administered in cycles of 21 days each. Subjects in Cohorts A and B will 
be treated with tucatinib at a dose of 300 mg orally twice daily (PO BID) and trastuzumab at 
a loading dose of 8 mg/kg intravenous (IV) followed by a dose of 6 mg/kg IV every 3 weeks. 
Subjects randomized to Cohort C will be treated with tucatinib at a dose of 300 mg PO BID.  


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Subjects enrolled in Cohort A and those randomized to Cohort B will continue to receive 
study treatment until evidence of radiographic or clinical progression, unacceptable toxicity, 
withdrawal of consent, or study closure. Subjects randomized to Cohort C will be allowed to 
crossover and receive doublet (tucatinib + trastuzumab therapy), if they experience radiographic 
progression at any time point (as determined by investigator assessment using RECIST 1.1), or if 
they have not achieved a PR or CR by the week 12 assessment.   
Measures of anticancer activity will be assessed by either CT with contrast or MRI scans at 
protocol-specified time points. Subjects must be evaluated using the same imaging method 
throughout the study for efficacy assessments. Tumor response will be assessed by BICR as 
well as by investigator per RECIST v1.1 (Eisenhauer 2009). Clinical response of CR, PR, 
SD, or PD will be determined at each assessment. Responses (CR or PR) will be confirmed 
with repeat scans at least 4 weeks after first documentation of response. Tumor assessments 
will continue until the subject has radiologically confirmed disease progression per RECIST 
1.1 by the investigator, initiates a new anticancer therapy, dies, withdraws consent, or the 
study closes, whichever comes first.  
Subjects that discontinue treatment for reasons other than disease progression per RECIST 
v1.1 will continue to have disease assessments approximately every 9 weeks until disease 
progression, death, withdrawal of consent, study closure, or alternative therapy. 
Following progression or initiation of new anticancer therapy, subjects will be contacted 
every 12 weeks (±2 weeks) to obtain information on subsequent anticancer therapy, and 
survival status until death, study closure, withdrawal of consent, or subject is lost to follow-
up, whichever occurs first. 
Safety assessments will consist of the surveillance and recording of AEs including SAEs, 
vital signs, pregnancy testing, recording of concomitant medication, medical history, 
measurements of protocol-specified physical examination findings and laboratory tests.  
On a periodic basis, approximately every 6 months starting from the first patient enrollment, 
a safety monitoring committee (SMC) will monitor the safety of subjects participating in this 
trial. The SMC will be guided by an independent charter and will focus on the aggregate 
safety evaluation of all enrolled and treated patients. The SMC will make recommendations 
to either continue the study as planned, to continue the study with modifications, to suspend 
the enrollment, or to terminate the study. The final decision to act on the SMC 
recommendations will be made by Seagen. An ongoing real-time review of subject safety and 
SAEs will also be conducted by the sponsor’s Drug Safety Department. 
 
5 
ANALYSIS SETS  
5.1 Intent-to-Treat Analysis Set  
The intent-to-treat (ITT) analysis set will include all enrolled subjects in Cohort A and all 
randomized subjects in Cohort B and C. Subjects will be analyzed according to the cohort 
assigned at enrollment (Cohort A) or randomization (Cohort B and C) regardless of any 
actual treatment received.  


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5.2 Full Analysis Set  
The full analysis set (FAS) will include all subjects who are enrolled and have received any 
amount of study treatment and have HER2+ tumors as defined by one or more protocol 
required local tests.  
 
5.3 Safety Analysis Set  
The safety analysis set will include all subjects who are enrolled and have received any 
amount of study treatment. 
5.4 Patient Reported Outcome Set  
The patient reported outcome (PRO) analysis set will include subjects in the FAS who have 
an evaluable (i.e., complete a PRO instrument and at least one domain or single item can be 
computed) baseline PRO score and at least one post-baseline evaluable PRO assessment in 
Cohorts B or C. 
5.5 Pharmacokinetics (PK) Analysis Set  
The pharmacokinetic analysis set will include all randomized subjects who received at least 
one dose of tucatinib and have at least one evaluable PK assessment in Cohorts B or C. 
 
6 
STATISTICAL CONSIDERATIONS  
6.1 General Principles  
Descriptive statistics will be presented that include the number of observations, mean, 
median, standard deviation, minimum and maximum for continuous variables, and the 
number and percentages per category for categorical variables. 
Unless otherwise specified, confidence intervals (CIs) will be calculated at two-sided 95% 
level. 
The two-sided 95% exact CI using the Clopper-Pearson method will be calculated for the 
response rates where applicable (e.g., ORR) (Clopper 1934). 
For time-to-event endpoints, the median survival time will be estimated using the Kaplan-
Meier method; the associated 95% CI will be calculated based on the complementary log-log 
transformation (Collett 1994). 
Any analysis not described in this plan will be considered exploratory and will be 
documented in the CSR as a post hoc analysis. 
All statistical Tables, Listings and Figures will be produced using SAS®, version 9.3 or 
higher. Sample size calculations were performed using EAST®, version 6.0. Other statistical 
software, if used, will be described in the CSR. 


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6.2 Determination of Sample Size  
Approximately 110 subjects will be enrolled in the study. Subjects are considered enrolled if 
they give informed consent and meet all eligibility criteria. Approximately 40 subjects will 
be enrolled in Cohort A. Approximately 70 subjects, enrolled in the expansion portion of the 
trial, will be randomized in a 4:3 ratio to receive tucatinib given in combination with 
trastuzumab (Cohort B) or tucatinib monotherapy (Cohort C). Enrollment will continue until 
approximately 40 subjects have been randomized to and treated in Cohort B, and 
approximately 30 subjects have been randomized to and treated in Cohort C. 
The primary efficacy analysis will be performed by providing the point estimate and the 2-
sided 95% exact Clopper Pearson CI for the confirmed ORR (pooled Cohorts A and B). 
Cohort C is intended to better characterize the antitumor activity of tucatinib when used as a 
monotherapy in this patient population.  
For illustration purposes, Table 6-1 summarizes the expected 95% CIs for subjects treated 
with tucatinib given in combination with trastuzumab (Cohorts A+B) and subjects treated 
with tucatinib monotherapy (Cohort C) at the proposed sample sizes of 80 and 30 
respectively. No formal statistical comparisons between cohorts are planned. 
Table 6-1: 
Estimated ORR 
Confirmed ORR 
95% Exact CI. (Cohorts A+B, N=80) 
40% 
(29%, 52%) 
50% 
(39%, 61%) 
60% 
(48%, 71%) 
 
 
ORR 
95% Exact CI. (Cohort C, N=30) 
10% 
(2%, 27%) 
15% 
(5%, 33%) 
20% 
(8%, 39%) 
 
6.3 Randomization and Blinding  
All subjects enrolled in the expansion portion of the trial will be randomized in a 4:3 ratio to 
receive tucatinib given in combination with trastuzumab (Cohort B) or tucatinib 
monotherapy (Cohort C). Randomization will be stratified by:  
● 
Left sided primary versus all other primary types (i.e., right, transverse, overlapping 
primary) 
This is an open label study.  


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6.4 Data Transformations and Derivations  
6.4.1 General  
Reported age in years will be used; if not available, age at informed consent in years will be 
calculated with the SAS® INTCK function (with method specified as “continuous”) using 
informed consent date and birth date. 
Study Day will be calculated as (Date – First Dose Date + 1) for dates on or after the first 
dose date. The date of first dose will be Study Day 1. For dates prior to the first dose date, 
Study Day will be calculated as (Date – First Dose Date). For example, the date before the 
first dose date will be Study Day -1. 
Other time variables based on two dates, e.g., Start Date and End Date, will be calculated as 
(End Date – Start Date + 1) (in days) unless otherwise specified in the planned analysis 
section. 
The following unit conversion will be implemented unless otherwise specified: 
Months=Days/30.4375 
Years=Days/365.25 
Unless otherwise specified, baseline values used in all analyses will be the most recent non-
missing measurement prior to the first dose of study drug. 
6.4.2 Best Overall Response  
The subject’s best overall response per BICR will be the best response to date that has been 
confirmed, (i.e., for PR and CR). Response after the start of subsequent anticancer therapy 
will not be included in the derivation of best overall response. The subject’s best overall 
response will be used in determining the ORR per BICR.  
A response (CR or PR) will be considered confirmed if the subsequent response assessment 
(at least 4 weeks after the initial response) still shows response (CR or PR). A subject will 
have a best response of non-CR/non-PD or SD if there is at least one non-CR/non-PD or SD 
assessment (or better) ≥ 5 weeks after the efficacy start date (treatment start date for Cohort 
A; randomization date for Cohort B and Cohort C) and the subject does not qualify for 
confirmed CR or PR.  
6.4.4 Response Assessment Dates  
At each response assessment time point, scans could be performed on multiple dates. If the 
time point response is CR or PR, then the latest date of all radiologic scans at the given 
response assessment time point will be the date of response. If the time point response is SD 
or non-CR/non-PD, then the earliest date of all radiologic scans at the given response 
assessment time point will be the date of response. If the time point response is PD, then the 
earliest date that PD has been documented will be the date of PD, i.e., the earliest of: 


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x Date of target lesion assessments when the target lesion response is PD. 
x Date of non-target lesion assessments when the lesion status is unequivocal 
progression. 
x Date of documenting new lesions 
For subjects whose best overall response is a confirmed CR or PR, the date of objective 
response will be the date of initial documentation of response (i.e., CR or PR that is 
subsequently confirmed).  
6.4.5 Adequate Response Assessment  
An adequate tumor assessment must include a radiologic scan with the overall disease 
response of CR, PR, non-CR/non-PD, SD, or PD.   
6.4.6 Action Taken with Study Treatment  
Action taken with study treatment includes dose modification and drug withdrawn. For 
tucatinib, dose modification includes dose held (i.e., dose delay), dose reduced, or dose error. 
For trastuzumab, dose modification includes dose held (i.e., dose elimination or dose delay) 
and unplanned dose adjustment. For trastuzumab, unplanned dose adjustment includes dose 
error not leading to interruption or stoppage of dose, infusion interrupted due to AE (received 
full dose w/in 24hrs), infusion interrupted for other reason (received full dose w/in 24hrs), 
infusion stopped early due to AE (full dose not received), or infusion stopped early due to 
other reason (full dose not received). Drug withdrawn includes tucatinib discontinuation and 
trastuzumab discontinuation. 
6.5 Handling of Dropouts and Missing Data  
Missing data will not be imputed unless otherwise specified. 
For time-to-event endpoints (e.g., duration of response, PFS, and OS), subjects who have no 
specified event will be censored as specified for each respective endpoint in Section 7.5. 
Missing or partial AE dates will be imputed for the purpose of calculating treatment-
emergent status (see Appendix A for imputation details and Appendix B for treatment-
emergent definition).   
Partial prior therapy dates will be imputed (see Appendix C for details) for the purpose of 
deriving time since last prior therapy to study start. 
Partial subsequent anticancer therapy start and end dates will be imputed for the purpose of 
deriving the time-to-event endpoints as applicable. Partial missing hospitalization dates will 
be imputed for the purpose of deriving total length of hospitalization stays. (see Appendix D 
for details). 


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Partial diagnosis date will be imputed for the purpose of calculating the time from initial 
diagnosis, the time from first diagnosis of metastatic or unresectable diseases (see Appendix 
E for details). 
Partial missing death dates will be imputed for the purpose of deriving the time-to-event 
endpoints as applicable (see Appendix F). 
Unless otherwise specified, if the numeric value of a laboratory test is not available because 
it is below the lower limit of quantification (LLOQ), the result will be analyzed as equal to 
LLOQ when a numeric value is required (e.g., calculating the mean) and be listed as “< 
LLOQ” in the listings. 
For PK analysis, if the numeric value is not available because it is below the lower limit of 
qualification (LLOQ), the result will be analyzed as equal to half of the LLOQ (i.e., 
LLOQ/2) when a numeric value is required (e.g., calculating the mean, geometric mean, 
geometric coefficient of variation) and be listed as “<LLOQ” in the listings. The summary 
statistics for a timepoint will not be calculated if more than 50% of the results are <LLOQ. 
6.6 Multicenter Studies  
Approximately 110 subjects will be enrolled to the study from approximately 55 sites 
worldwide. 
6.7 Multiple Comparison/Multiplicity  
No multiple comparisons are planned and no alpha adjustment is needed.  
6.8 Examination of Subgroups  
As exploratory analyses, subgroup analyses may be conducted for selected endpoints 
(primary and secondary efficacy endpoints). Subgroups may include but are not limited to the 
following: 
● 
Age (<65, ≥65 years old) 
● 
ECOG performance score at baseline (0, 1-2) 
● 
Primary site of disease: 
o Left sided primary (rectum, rectosigmoid junction, sigmoid colon, splenic 
flexure, descending colon) 
o All other primary types (transverse colon, right sided, multiple/overlapping 
sites) 
● 
Geographic Region: North America, Europe 
A subgroup analysis may not be performed if the number of subjects in the subgroup is not 
sufficiently large (e.g., <10%).  


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6.9 Covariates  
No adjustment for covariates is planned in the analyses. 
6.10 Timing of Analyses  
The final analysis of the primary endpoint and secondary endpoints will be conducted when 
all treated subjects have been followed for at least 6 months or have been discontinued from 
study treatment.  
Additional cutoff dates may be defined and corresponding database locks may occur to allow 
for more precise estimates of time-to-event endpoints. 
7 
PLANNED ANALYSES  
7.1 Disposition  
Patient enrollment and disposition will be summarized by cohort and total. The table will 
present the number and percentage of patients who were enrolled or randomized in each 
cohort, received study drug, and participated in long-term follow-up. The number and 
percentage of patients who discontinued treatment will be summarized by the reason for 
treatment discontinuation. The number and percentage of patients who discontinued the study 
will be summarized by the primary reason for study discontinuation. The summary of 
disposition will be conducted for ITT analysis set. 
Number of patients who signed informed consent and number of patients in each analysis set 
will be summarized by cohort and total. 
Number of screen failures and the percentage relative to the total number of subjects 
screened will be summarized. A listing of subjects who failed screening will also be 
produced, with reasons for screen failure and available demographic information. 
The number of patients enrolled in each country and at each site will be summarized by 
cohort and total.  
7.2 Demographic and Baseline Characteristics  
Demographics and baseline characteristics, including age at consent, sex, ethnicity, race, 
ECOG performance status will be listed and summarized with descriptive statistics for the 
FAS by cohort. In addition, these may also be summarized for Cohort A and Cohorts B+C to 
show comparability between the non-randomized cohort and randomized cohorts. 
Disease specific characteristics, including primary tumor site, RAS mutation status, HER2 
result by IHC, HER2 status by FISH/CISH and HER2 result by NGS, time from initial 
diagnosis, time from first diagnosis of metastatic or unresectable disease will be listed and 
summarized for the FAS. 
Summary of prior cancer-related therapies, including number of prior therapies, therapy type, 
setting of prior therapies will be presented for the FAS. 


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In addition, the pre-existing condition of diarrhea that are ongoing at baseline, 
gastrointestinal-related history of prior surgical treatment and prior radiation therapy will be 
summarized using the Safety Analysis Set. 
7.3 Protocol Deviations  
Important protocol deviations are a subset of protocol deviations that may represent a 
divergence from the protocol that could have a significant effect on the integrity of the study 
data, or on the subject’s rights, safety, or welfare. Important protocol deviations also include 
exemptions to the study inclusion/exclusion criteria and will be summarized by category. A 
list of subjects with important protocol deviations will be presented. 
7.4 Treatment Administration  
Treatment administration will be summarized for the safety analysis set separately for 
Cohorts A+B and Cohort C.  
The following information will be summarized separately for trastuzumab and tucatinib: 
● 
Total number of treatment cycles per subject 
● 
Duration of treatment 
● 
Percentage of subjects with reduced, interrupted, and withdrawn infusions/doses 
overall and by reason.  
Dose reduction, absolute dose intensity (ADI) and relative dose intensity (RDI) will only be 
summarized for tucatinib. 
For tucatinib, the type, reason and time to first dose modification will be summarized. The 
number of subjects with dose modifications due to AE will also be summarized. 
Duration of treatment (except when calculating exposure) is defined as the time from first 
dose date to the earliest of the following dates: 
o The exposure end date: 
x For tucatinib, the date of last dose 
x For trastuzumab, date of last dose + 20 
o Date of death 
o End of study date 
o Analysis data cutoff (DCO) date if the subject is still on study at the time of DCO. 
Intended dose intensity (IDI) is defined as the intended dose of study drug per unit of time 
according to the protocol. 


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ADI is defined as the actual dose of study drug per unit of time that a subject received over 
the entire exposure period, i.e., ADI = cumulative dose/(exposure end date – first dose 
date+1).  
RDI is defined as the ADI over the IDI (i.e., RDI = ADI/IDI * 100%). 
7.5 Efficacy Analyses  
The analyses for efficacy endpoints, including the primary endpoint of cORR, the secondary 
endpoints of ORR by 12 weeks of treatment, DOR, PFS and OS will be performed for the 
FAS by for cohort A+B and cohort C separately, unless otherwise specified.  
Sensitivity analyses of cORR and DOR for cohort A+B may be performed for subjects in: 
(1) FAS with HER2+ tumors centrally confirmed by IHC breast algorithm; 
(2) FAS with HER2+ tumors centrally confirmed by IHC breast algorithm including 
samples analyzed outside the stability window that meet scientific justification 
criteria;  
(3) Safety Analysis Set.  
7.5.1 Primary Endpoint: Confirmed Objective Response Rate (cORR) per 
BICR  
The primary endpoint of this study is the cORR per BICR in pooled Cohorts A+B. cORR is 
defined as the proportion of subjects whose best overall response is a confirmed CR or PR 
according to RECIST v1.1 (Eisenhauer 2009). Only tumor assessments before first 
documented PD or new anti-cancer therapies will be considered. For a response to be 
considered as confirmed, the subsequent response needs to be at least 4 weeks after the initial 
response. Subjects who do not have at least two (initial response and confirmation scan) post-
baseline response assessments will be considered non-responders. 
The cORR per BICR and its exact two-sided 95% CI will be calculated for the FAS in 
Cohorts A+B.  
In addition, the cORR per BICR will be summarized by the subgroups defined in Section 6.8. 
The maximum percent reduction from baseline in the sum of diameters per BICR will be 
calculated for subject with baseline and post-baseline target lesion measurement and 
presented graphically with a waterfall plot. 
Time to response per BICR will be calculated as the time from the start of study treatment 
(Cohort A) or date of randomization (Cohorts B and C) to the first documentation of 
objective response (CR or PR that is subsequently confirmed). Time to response per BICR 
will be summarized for the responders only. For Cohort C pre-crossover, time to response 
will be summarized for the responders defined in Section 7.5.2.1. 


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All above analyses for cORR per BICR will also be performed for cORR per investigator, as 
sensitivity analysis.   
A summary of the concordance between investigator and BICR assessment will be provided. 
The percent agreement will be calculated as the proportion of subjects whose best overall 
response (responder vs. non-responder) per BICR match the best overall response (responder 
vs. non-responder) per investigator.  
Percent agreement = (Number of matched responders + Number of matched non-responders) 
/ Total number of subjects assessed. 
7.5.2 Secondary Endpoints  
7.5.2.1 Objective Response Rate (ORR) by 12 Weeks of Treatment  
ORR by 12 weeks of treatment is defined as the proportion of subjects with CR or PR by 12 
weeks of treatment or time of crossover, whichever comes earlier, as determined per RECIST 
v1.1. Responses do not need to be confirmed to be scored as responders for the purpose of 
determining ORR by 12 weeks of treatment. Subjects who do not have at least one post-
baseline response assessment by 12 weeks of treatment will be considered non-responders. 
The ORR by 12 weeks per BICR and its exact two-sided 95% CI will be calculated for the 
FAS in Cohorts A+B. The analyses will be performed per INV as sensitivity analyses.  
A summary of the concordance between investigator and BICR assessment will be provided 
only for Cohort C.  
7.5.2.2 Duration of Response (DOR)  
DOR is defined as the time from the date of first documented response (CR or PR that is 
subsequently confirmed) to the date of first documented PD per RECIST v1.1 or death due to 
any cause, whichever comes first.   
DOR will be censored as described below: 
● 
Subjects who do not have PD and are still on study at the time of an analysis will be 
censored at the date of the last adequate response assessment documenting absence of 
PD 
● 
Subjects who have started a new anticancer treatment prior to documentation of PD 
will be censored at the date of the last adequate response assessment prior to start of 
new treatment 
● 
Subjects who discontinue from the study prior to documentation of PD will be 
censored at the date of the last adequate response assessment documenting absence of 
PD. 
● 
Subjects who progressed or died after an extended loss to follow up (i.e., ≥2 
consecutive missed response assessments) will be censored at the date of the last 
adequate response assessment prior to the missed visits. 


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DOR per BICR will only be calculated for subjects achieving a confirmed CR or PR per 
BICR. DOR will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will 
be provided if there are at least 5 events. The median DOR and its two-sided 95% CI will be 
calculated. In addition, the DOR at different timepoints (for instance, 6 and 12 months) will 
be summarized. 
DOR per investigator will be analyzed in the same way as the DOR per BICR, as sensitivity 
analysis. 
For Cohort C pre-crossover, DoR will be summarized for the responders defined in Section 
7.5.2.1. 
7.5.2.3 Progression-free Survival (PFS)  
PFS is defined as the time from start of study treatment (Cohort A) or date of randomization 
(Cohorts B and C) to first documentation of PD per RECIST v1.1 or death due to any cause, 
whichever comes first.  
The same censoring rules as outlined in Section 7.5.2.2 for DOR will be applied to PFS. In 
addition, subjects who have no post-baseline response assessment will be censored at the date 
of start of study treatment (Cohort A) or the date of randomization (Cohort B and C).  
PFS per BICR for Cohorts A+B will be analyzed using Kaplan-Meier methodology and 
Kaplan-Meier plots will be provided. The median PFS and its two-sided 95% CI will be 
calculated. In addition, the probability of PFS at different timepoints (for instance, 6 and 12 
month) will be summarized. 
A sensitivity analysis may be conducted by not considering new anti-cancer treatment as a 
censoring reason. Additional sensitivity analysis may be conducted by considering new anti-
cancer treatment as an event.    
All the analyses for PFS per BICR will also be performed for PFS per investigator, as 
sensitivity analysis. 
7.5.2.4 Overall Survival (OS)  
OS is defined as the time from start of study treatment (Cohort A) or date of randomization 
(Cohorts B and C) to date of death due to any cause. In the absence of death, OS will be 
censored at the date the subject is last known to be alive. Subjects lacking data beyond start 
of study treatment will have their survival time censored at the date of start of study 
treatment (Cohort A) or the date of randomization (Cohort B and C). 
OS will be analyzed using Kaplan-Meier methodology and Kaplan-Meier plots will be 
provided. The median OS and its two-sided 95% CI will be calculated. In addition, the 
probability of OS at different timepoints (for instance, 6 and 12 months) will be summarized. 


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7.5.3 Special considerations for Efficacy Analyses for Cohort C  
Subjects randomized to Cohort C will be allowed to crossover and receive doublet tucatinib + 
trastuzumab therapy if they experience radiographic progression at any time point, or if they 
have not achieved a PR or CR by 12 weeks of treatment. Crossover start date is the date of 
first dose of tucatinib or trastuzumab (whichever came first) in the first cycle of trastuzumab. 
Subjects who crossover will have new baseline assessment per RECIST 1.1. The re-baseline 
visit time point is defined as following: 
x If subject crossover due to PD per RECIST 1.1, the re-baseline timepoint is the 
assessment of PD.  
x If subject had no PD and have not achieved a PR or CR per RECIST 1.1 by 12 weeks 
and crossover, then the re-baseline time point is the last response assessment before 
crossover. 
In addition to the analyses described for the overall study in previous sections, the efficacy 
analyses for Cohort C that need special consideration due to the potential crossover are 
described in this section. 
7.5.3.1 ORR by 12 Weeks of Treatment  
Subjects who experience radiographic progression and crossover before 12 weeks of 
treatment will be analyzed using best overall response before crossover. Any response 
assessment before 12 weeks of treatment but after crossover will not be counted. 
7.5.3.2 PFS  
Besides the censoring rules specified in Section 7.5.2.3, subjects who do not have PFS event 
by 12 weeks of treatment and crossover to receive doublet regimen will be censored at the 
time of re-baseline.  
7.5.3.3 DOR  
For the summary of DOR in cohort C pre crossover, all responders by 12 weeks of treatment 
will be included in the analysis, regardless if the responses are confirmed or not. 
7.6 Safety Analyses  
The safety analysis set will be used to summarize all safety endpoints. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 24.0 or higher). 
Laboratory values will be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE version 4.03 or higher). 
Concomitant medications will be coded using World Health Organization (WHO) Drug 
Dictionary (version: WHODrug Global 2021Mar B3 or higher). 


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Safety analyses will be performed for Cohorts A+B and Cohort C. For subjects in Cohort C 
who crossover, safety analyses will be performed separately before and after crossover. 
Crossover start date is the date of first dose of tucatinib or trastuzumab (whichever came 
first) in the first cycle of trastuzumab.  
Summary of adverse events (AEs), clinical laboratory parameters, left ventricular ejection 
fraction, ECOG, and vital signs includes post-baseline data collected up through 30 days 
after the last dose of study treatment (tucatinib or trastuzumab). 
7.6.1 Adverse Events  
Adverse events (AEs) will be summarized by MedDRA preferred term (PT) in descending 
frequency of occurrence unless otherwise specified. For incidence reporting, if a subject 
reports more than one AE that was coded to the same system organ class (SOC) or PT, the 
subject will be counted only once for that specific SOC or PT. 
A treatment-emergent adverse event (TEAE) is defined as a newly occurring or worsening 
AE after the first dose of study treatment (tucatinib or trastuzumab). See for details regarding 
treatment-emergent classification.   
An overall summary of TEAEs will be provided. Summaries of TEAEs by MedDRA 
classification will also be provided for the following: 
● 
TEAEs  
● 
Grade 3 or higher TEAEs 
● 
Serious TEAEs 
● 
TEAEs leading to dose reduction/dose hold/drug withdrawal 
● 
TEAEs leading to death 
● 
Treatment-related TEAEs 
● 
Treatment-related grade 3 or higher TEAEs 
● 
Treatment-related serious TEAEs 
● 
Treatment-related TEAEs leading to dose reduction/dose hold/drug withdrawal 
● 
Treatment-related TEAEs leading to death 
● 
TEAEs by SOC, PT and maximum severity. At each SOC or PT, multiple 
occurrences of the same event within a subject are counted only once at the highest 
severity 
● 
TEAEs by SOC and PT 
All TEAEs, grade 3 or higher TEAEs, serious TEAEs, TEAEs leading to treatment 
discontinuation, and TEAEs leading to death will be listed. 


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7.6.2 Serious Adverse Events  
Serious adverse events (SAEs) will be summarized by preferred term and SOC using counts 
and percentages. The following summaries of SAEs will be produced. 
● 
Incidence of treatment emergent SAEs (TESAEs) by decreasing frequency of 
preferred term 
● 
Incidence of TESAEs by decreasing frequency of SOC and preferred term 
● 
Incidence of treatment related TESAEs by decreasing frequency of preferred term 
In addition to summary tables, listings of SAEs will be produced. 
7.6.3 Adverse Events of Special Interest and Additional Risks  
The incidence of treatment emergent adverse events of special interest (AESI) will be 
summarized by PT or lab values and listings will also be produced. The following AESIs to 
be summarized are described in the protocol Section 7.7.1 and are as the following: 
1. Potential drug-induced liver injury 
Any potential case of drug-induced liver injury as assessed by laboratory criteria for Hy’s 
Law will be considered as a protocol-defined event of special interest. The following 
laboratory abnormalities define potential drug-induced liver injury cases: 
Laboratory Test 
Laboratory Value 
AST 
>3 × ULN with concurrent elevation (within 21 days of AST and/or ALT 
elevations) of total bilirubin > 2 × ULN 
ALT 
>3 × ULN with concurrent elevation (within 21 days of AST and/or ALT 
elevations) of total bilirubin > 2 × ULN 
 
2. Asymptomatic left ventricular systolic dysfunction 
Treatment-emergent asymptomatic left ventricular systolic dysfunction will be 
considered as another event of special interest. The search strategy for asymptomatic 
decline in LVEF is defined as follows: 
1- TEAEs captured on the “AESI-Asymptomatic LVEF Decline” CRF form and leading 
to a change in study treatment or discontinuation of study treatment belong to this 
category. 
2- TEAEs with preferred terms defined by cardiomyopathy SMQ (narrow) and cardiac 
failure SMQ (narrow) leading to a change in study treatment or discontinuation of 
study treatment belong to this category. 
In addition to the protocol defined AESIs, the incidence of treatment emergent adverse 
events for additional risks will be summarized by PT or lab values and listings will also be 
produced. The TEAEs for the following additional risks to be summarized are: 
1. Hepatotoxicity 


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Treatment emergent hepatotoxicity events will be summarized using SMQ and SSQ 
search strategies defined below: 
Hepatotoxicity 
Two set of outputs for the following: 
1. Drug related hepatic disorders - 
comprehensive search SMQ (Narrow) 
2. Cluster of the following PTs (SSQ): 
x Acute hepatic failure 
x Acute on chronic liver failure 
x Alanine aminotransferase abnormal 
x Alanine aminotransferase increased 
x Aspartate aminotransferase 
abnormal 
x Aspartate aminotransferase 
increased 
x Bilirubin conjugated increased 
x Blood bilirubin abnormal 
x Blood bilirubin increased 
x Coma hepatic 
x Drug-induced liver injury 
x Gamma-glutamyltransferase 
abnormal 
x Gamma-glutamyltransferase 
increased 
x Hepatic cytolysis 
x Hepatic encephalopathy 
x Hepatic enzyme abnormal 
x Hepatic enzyme increased 
x Hepatic failure 
x Hepatic necrosis 
x Hepatitis 
x Hepatitis acute 
x Hepatitis fulminant 
x Hepatitis toxic 
x Hepatocellular injury 
x Hepatorenal failure 
x Hepatotoxicity 
x Hyperbilirubinaemia 
x Hypertransaminasaemia 
x Jaundice hepatocellular 
x Liver function test increased 
x Liver injury 
x Mitochondrial aspartate 
aminotransferase increased 


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x Mixed liver injury 
x Subacute hepatic failure 
x Transaminases abnormal 
x Transaminases increased 
 
2. Diarrhea 
Treatment emergent diarrhea events will be summarized using search strategy defined by 
single PT term “Diarrhoea”. 
3. Serum Creatinine and Blood Urea Nitrogen (BUN)  
Boxplots of serum creatinine and blood urea nitrogen by visits will be produced. 
4. Infusion/injection Related Hypersensitivity Reactions (IHR) and Infusion Related 
Reactions (IRR). 
Treatment emergent IHR/IRR events will be summarized by PT and by maximum 
severity. 
In addition, treatment-emergent AESI leading to dose modification and study treatment 
discontinuation that are related to study drug will be summarized. 
For selected AESI, time to first onset or resolution will be analyzed as appropriate.  
Time to first onset of a specific AESI will be calculated as time from the first dose of study 
drug to the start of first treatment-emergent event that meets the respective search criteria.  
Resolution is defined as event outcome of ‘recovered/resolved’ or ‘recovered/resolved with 
sequelae’. For events with an outcome of ‘recovered/resolved’ or ‘recovered/resolved with 
sequelae’, time to resolution will be calculated as time from the event start date to end date.  
Time to first onset will be summarized at the subject level. Time to resolution will be 
summarized at the event level. 
7.6.4 Clinical Laboratory Parameters  
All laboratory results (hematology and serum chemistry) up to the date of last dose of any 
study treatment + 30 days will be presented in standardized units. The incidence of 
laboratory toxicities by grade will be summarized. Shift from baseline to maximum post-
baseline NCI CTCAE (version 4.03 or higher) grade will be summarized for each lab test. 
Serum creatinine will be graded using NCI CTCAE version 5.0. Treatment-emergent 
laboratory abnormalities will also be summarized. 
Laboratory results and NCI CTCAE (version 4.03 or higher) grades for hematology and 
serum chemistry will be presented in data listings. Serum creatinine will be graded using NCI 
CTCAE version 5.0. Normal ranges will be documented and out-of-range values will be 


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flagged. A separate listing of laboratory results with CTCAE grade 3 or higher will be 
presented. 
7.6.4.1 Liver Safety Assessment  
The incidence of potential drug-induced liver injury will be summarized. In addition to the 
laboratory abnormalities defined for AESI in Section 7.6.3, (AST and/or ALT) > 3 × ULN + 
Total Bilirubin > 2 × ULN + Alkaline Phosphatase < 1.5 × ULN and (AST and/or ALT) > 3 
× ULN, 5 × ULN, 10 × ULN, and 20 × ULN will also be summarized. 
7.6.5 Left Ventricular Ejection Fraction  
The minimal post baseline ejection fraction and the maximum decrease from baseline will be 
summarized for each treatment group. Time to minimal post baseline ejection fraction may 
also be tabulated. 
7.6.6 Vital Signs  
Vital signs (weight, body temperature, heart rate, systolic and diastolic blood pressure, and 
oxygen saturation) will be listed. The frequency and percentage of patients with post baseline 
clinically significant vital signs will be summarized. The clinically significant vital signs are 
defined as: heart rate >100 bpm; Temperature >=38.0 degrees C (100.4 F), and oxygen 
saturation <88%. Blood pressure will be summarized both for subjects with systolic blood 
pressure >=120 mmHg or diastolic blood pressure >=80 mmHg, as well as for subjects with 
systolic blood pressure >=140 mmHg or diastolic blood pressure >=90 mmHg, and subjects 
with systolic blood pressure >=160 mmHg or diastolic blood pressure >=100 mmHg.  
7.6.7 ECOG  
Shift from baseline ECOG status to worst post-baseline ECOG status up to the date of last 
dose of any study treatment + 30 days will be provided. 
7.6.8 Deaths  
Death information will be summarized and listed by subjects. 
7.6.9 Concomitant Medications  
Concomitant medications will be summarized by the WHO Drug ATC class and preferred 
name. The number and percentage of subjects who take concomitant medications will be 
tabulated. Multiple occurrences of the same medication within a subject will be summarized 
only once. Concomitant medications will be listed by subject. 
7.7 Additional Analyses  
7.7.1 HER2 Status  
Central confirmation of HER2 status by IHC analysis will be performed with IHC scoring of 
samples using the breast and gastric criteria. Subjects with an IHC 3+ result or an IHC 2+ 
with a Fluorescence In Situ Hybridization (FISH) positive result were classified as HER2 
positive per the package insert for HER2 testing.  


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Concordance between the two IHC scoring algorithms (breast and gastric) will be assessed 
by overall HER2 status and HER2 IHC score. Additional analyses may be performed and 
described in a separate biomarker analysis plan.  
7.7.2 Pharmacokinetics  
The analyses described in this section will be produced for the pharmacokinetics analysis set. 
Tucatinib levels will be summarized with descriptive statistics at each PK sampling time 
point. Additional PK and PK/PD analyses may be performed and described in a separate 
pharmacometric analysis plan. 
7.7.3 Patient Reported Outcomes  
7.7.3.1 EORTC QLQ-C30  
The EORTC QLQ-C30, Version 3.0 (Aaronson 1993) comprises nine multiple-item scales 
and six single-item scales. The multiple-item scales include five functional scales (Physical, 
Role, Emotional, Cognitive, and Social), three symptom scales (Fatigue, Nausea and 
Vomiting, Pain), and a global health status/QOL score. The single-item scales of the EORTC 
QLQ-C30 include Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, and 
Financial Difficulties. Patients assessed how true each statement in the questionnaire is for 
them on a four-point scale (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much), whereas 
Global Health Status or QOL was assessed using a seven-point Likert scale (ranging from 
“poor” to “excellent”) for two items. 
 
Scale scores are calculated by averaging items within scales and transforming average scores 
linearly. All the scales range in score from 0 to 100. High scores for global health status/QOL 
and functional scales represent high/healthy level of QOL or functioning; whereas high 
scores for symptom scales or items represent higher level of symptomatology. 
For each QLQ-C30 scale, score will be calculated and missing data will be accounted for 
according to the EORTC QLQ-C30 scoring manual. Descriptive summary of actual value 
and change from baseline will be presented by visit for subjects who have a baseline and at 
least one post baseline assessment. Line graphs for mean change from baseline in EORTC 
QLQ-C30 scores with 95% confidence intervals will be prepared. Visits with less than 5 
subjects with assessment will not be displayed in line graphs. 
The absolute change from baseline of 10 points in QLQ-C30 scale score is considered 
conventionally as a minimum important difference (Osoba et al., 1998). For the global health 
status/QoL and functioning scales, the scale score change from baseline will be categorized 
as follows: 
x Improved: change from baseline ≥ 10 
x Stable: -10 < change from baseline < 10 
x Worsened: change from baseline ≤ -10 or “Patient was too ill” is answered as the 
reason for not completing the QLQ-C30 form at visit 
 


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For QLQ-C30 symptom scales/item (i.e. Fatigue, Nausea and Vomiting, Pain, Appetite Loss) 
the scale score change from baseline will be categorized as follows: 
x Improved: change from baseline ≤ -10 
x Stable: -10 < change from baseline < 10 
x Worsened: change from baseline ≥ 10 or “Patient was too ill” is answered as the 
reason for not completing the QLQ-C30 form at visit 
 
The number and percentage of subjects who have a response of Improved, Stable, or 
Worsened will be summarized by visit and by cohort. In the reporting of the proportion of 
patients who have a response of Improved, Stable, or Worsened, the denominator will be all 
patients with non-missing corresponding QLQ-C30 scale scores at baseline and at each 
corresponding visit. 
 
The compliance and completion rate of EORTC QLQ-C30 will be summarized for each visit 
and by cohort. Compliance rate is defined as the proportion of subjects who completed the 
instrument among those who are expected to complete at a given visit. Completion rate is 
defined as the proportion of subjects who completed the instrument among the PRO analysis 
set. 
7.7.3.2 EuroQol-5D-5L  
The EQ-5D-5L is a widely used, self-administered questionnaire designed to assess health 
status in adults (Herdman et al., 2011). The measure is divided into two distinct sections. The 
first section includes one item addressing each of five dimensions (mobility, self-care, usual 
activity, pain/discomfort, and anxiety/depression). Respondents rate their perceived health 
state today as presenting “no problems,” “slight problems,” “moderate problems,” “severe 
problems,” or “unable to/extreme problems.” The second section of the questionnaire, the 
visual analog scale (EQ-VAS), measures self-rated Global Health Status using a vertically 
oriented visual analog scale (VAS), where 100 represents the “best imaginable health state” 
and 0 represents the “worst imaginable health state.” Respondents are asked to rate their 
current health by placing a mark along this continuum. The recall period of the questionnaire 
is “today.” 
A distribution (numbers and percentages of subjects) for the EQ-5D-5L responses for each of 
the five dimensions will be summarized for each visit and by cohort.  
Visual analogue scale (VAS) actual value and change from baseline will be summarized with 
descriptive statistics by visit for subjects who have a baseline and at least one post baseline 
assessment.   
The compliance and completion rate of EQ-5D will be summarized for each visit and by 
cohort. 
7.7.4 Health Resource Utilization  
Descriptive summary of health resource utilization, including type of hospitalization (i.e. 
inpatient or outpatient), length of stay, ED visits, and reason for hospitalization will be 


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summarized by cohort in safety analysis set from the date of first dose of study treatment to 
the date of last dose of study treatment + 37 days. 
7.7.5 Subsequent Anticancer Therapy  
The number and percentage of subjects who receive subsequent anticancer therapies will be 
summarized for the FAS.  
7.7.6 Efficacy Analyses for Cohort C post-crossover  
cORR and DOR per BICR and per INV will be summarized for subjects in cohort C post-
crossover. The baseline for response post-crossover is the re-baseline timepoint as described 
in section 7.5.3. 
7.7.7 Duration of Follow-up  
Duration of study follow-up will be summarized using reverse KM method (Schemper and 
Smith, 1996) for FAS by cohort. 
7.7.8 Biomarker related exploratory endpoint(s)  
The analyses for biomarker related exploratory endpoint(s) maybe specified in a separate 
biomarker analysis plan and reported outside of the clinical study report. 
8 
INTERIM ANALYSIS  
No interim analysis for the primary endpoint is planned. 
9 
CHANGES FROM PLANNED ANALYSES  
9.1 Changes from the Protocol  
9.1.1 Additional analyses for Cohort C Post-Crossover  
Summary of confirmed objective response rate (cORR) and duration of response (DoR) per 
BICR and per INV for Cohort C post-crossover will be provided. 
9.1.2 Additional analyses for Adverse Event of Interest  
Summary of additional risk categories hepatotoxicity (SMQ), hepatotoxicity (SMQ), 
Diarrhea (PT), serum creatinine by lab, blood urea nitrogen (BUN) by lab, infusion related 
reactions(IRR)/Infusion related hypersensitivity reactions (IHR) will be provided. 
9.2 Changes from the Original SAP  
Section 
Changes to Original SAP 
Global 
change 
The Sponsor name "Seattle Genetics" was updated with 
"Seagen". 
2 
Language of enrollment objective was updated per Protocol 
SGNTUC-017 Amendment 11. 


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4 
"Subjects that discontinue for reasons other than disease 
progression per RECIST v1.1..." was updated with "Subjects 
that discontinue treatment..." for clarification. 
5 
Added and modified the definition of analysis sets 
6.4.2 
Replaced "start of treatment" with "efficacy start date 
(treatment start date for Cohort A; randomization date for 
Cohort B and Cohort C)" when deriving valid SDs. 
6.4.6 
Language concerning the definition of treatment modification 
was updated to make it more explicit and clearer. 
6.5 
Imputations of partially missing dates were clarified. 
Handling of lab and PK values below LLOQ was clarified. 
6.10 
Timing of analyses was updated to "…at least 6 months or have 
been discontinued from study treatment" per Protocol 
SGNTUC-017 Amendment 11. 
7.2 
Summary of demographic and baseline characteristics was 
updated to use FAS (instead of using ITT). 
Baseline weight, height and body mass index were removed 
from summary. 
Summary of pre-existing conditions were clarified. 
7.2 
Best response to prior therapy and time from most recent pior 
therapy to first does of study drug were removed. 
 
Time from initial diagnosis and time from first diagnosis of 
metastatic or unresectable disease were added. 
7.4 
1. Summary of "total cumulative dose" was removed; 
2. Language for ADI, RDI was clarified. 3. Duration of 
treatment and exposure end date derivation rule was updated 
7.5 
Efficacy analyses was updated to use FAS (instead of using 
ITT). 
Sensitivity analysis for cohort A+B were specified. 
7.5.1 
Summary of maximum percent reduction from baseline in the 
sum of diameters per BICR were clarified. 
7.5.2.1 
The “by Week 12 of Treatment” efficacy summaries were 
clarified. 
7.5.2.2 
Language was added to clarify DoR derivation for Cohort C 
pre-crossover. 
7.5.2.2 
“KaplanMier plot will be produced if there are at least 5 events” 
was added. 
7.5.2.3 
Sensitivity analysis by treating new anti-cancer therapy as PFS 
events was added. 
7.5.2.4 
Derivation of overall survival date was updated. 
Text “in Cohorts A+B” were removed. Overall survival for 
Cohort C will also be summarized. 


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7.5.3 
Crossover start date was defined in efficacy analyses. 
7.5.3.3 
Language was added to clarify DOR derivation in Cohort C pre 
crossover. 
7.6 
MedDRA and WHODrug versions were updated. 
7.6 
1. Crossover start date was defined in safety analyses. 
2. safety summary ascertainment period was clarified. 
7.6.3 
1. Search strategy of AESI and risks were updated. 
2.Definition of AESI resolution was updated. 
3. Time to improvement was removed from analyses. 
4. “First” was added to clarify time to first onset. 
7.6.4 
1. The end date of lab summary ascertainment period "end of 
treatment" was replaced with "date of last dose of any study 
treatment + 30 days".  
2. "Serum creatinine will be graded using NCI CTCAE version 
5.0." was added. 
7.6.6 
Vital sign summary categories were updated. 
7.6.7 
Summary of shift from baseline ECOG status to worst post-
baseline ECOG status was added. 
7.7.1 
1. Central confirmation of HER2 status was specified. 
2. Concordance between 2 IHC scoring algorithms (breast and 
gastric) was added. 
7.7.3.2 
"The EQ-5D health state dimension scores will be converted 
into a health state index using the time trade-off valuation 
method and the US-based value set (Shaw 2005)." was 
removed. 
7.7.4 
Summary of health utilization was updated. 
7.7.5 
"Subsequent anticancer therapy" will be summarized using FAS 
(instead of ITT). 
7.7.6 
Efficacy analyses for Cohort C post-crossover were added. 
7.7.7 
Duration of follow-up was added. 
7.7.8 
Conduction of biomarker related exploratory endpoint(s) were 
specified. 
Appendix 
B 
Treatment emergent AE Cohort C pre-crossover and Cohort C 
post-crossover was defined.  
Appendix 
E 
Imputation of disease diagnosis was added. 


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Appendix 
F 
Imputation of partial missing death dates was added. 


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10 REFERENCES  
 
Aaronson, N. K., Ahmedzai, S., Bergman, B., Bullinger, M., Cull, A., Duez, N. J., Filiberti, A., Flechtner, H., 
Fleishman, S. B., & de Haes, J. C. (1993). The European Organization for Research and Treatment of 
Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in 
oncology. Journal of the National Cancer Institute, 85(5), 365–376. 
https://doi.org/10.1093/jnci/85.5.365 
Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case of the 
binomial. Biometrika 26: 404-413. 
Collett D (1991). Statistical inference for binary data. Modelling Binary Data. London, Chapman and Hall: 23-
26. 
Collett D (1994). Interval-censored survival data. Modelling survival data in medical research. London, 
Chapman & Hall: 237-251. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D and Verweij J (2009). New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45: 
228-47. 
Herdman, M., Gudex, C., Lloyd, A., Janssen, M., Kind, P., Parkin, D., Bonsel, G., & Badia, X. (2011). 
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of 
life research : an international journal of quality of life aspects of treatment, care and 
rehabilitation, 20(10), 1727–1736. https://doi.org/10.1007/s11136-011-9903-x 
Osoba, D., Rodrigues, G., Myles, J., Zee, B., & Pater, J. (1998). Interpreting the significance of changes in 
health-related quality-of-life scores. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology, 16(1), 139–144. https://doi.org/10.1200/JCO.1998.16.1.139 
Paules M, Casey M, Williams G, Swann RS, Murphy PS, Salazar VM, Foose D, Bailey B, and Therasse P 
(2011). Recommendations for capture, validation and summarization of data from studies using 
RECIST. Eur J Cancer 47: 697-7. 
Schemper, M., & Smith, T. L. (1996). A note on quantifying follow-up in studies of failure time. Controlled 
clinical trials, 17(4), 343–346. https://doi.org/10.1016/0197-2456(96)00075-x 
Shaw JW, Johnson JA and Coons SJ (2005). US valuation of the EQ-5D health states: development and testing 
of the D1 valuation model. Med Care 43: 203-20. 
 
 
 


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11 APPENDICES  
Appendix A: Imputation of Partially Unknown Adverse Event Dates  
For an adverse event (AE) with a partial start or end date, if it can be determined that the 
event occurred prior to the date of first dose of study treatment, the partial date will not be 
imputed; Otherwise, the partial date will be imputed using the rules described below. AE 
start dates should be imputed before imputation of AE condition end date in all cases.  
Incomplete AE Start Date: 
AE day only is missing 
If the month/year is the same as the month/year of first dose of any study treatment: 
AE start date will be imputed as the first dose date of any study treatment 
If the month/year is after the month/year of first dose of any study treatment: 
AE start date will be imputed as the first day of the month 
AE day and month are missing, or month only is missing 
If the year is the same as the year of first dose of any study treatment: 
AE start date will be imputed as the first dose date of any study treatment 
If the year is after the year of first dose of any study treatment: 
AE start date will be imputed as January 1st 
AE day, month and year are missing, or year only is missing 
AE start date will be imputed as the first dose date of any study treatment 
 
If AE condition end date* is not missing, and the imputed start date is after the end date, the 
start date will be set to the AE condition end date. 
* only use condition end date if known and full end date is available. 
Incomplete AE End Date: 
If AE outcome is “not recovered/resolved”, “unknown”, or blank: AE condition end date will 
not be imputed. 
If AE outcome is “recovering/resolving”, “recovered/resolved”, “recovered/resolved with 
sequelae”, or “fatal” apply the following:  
AE day only is missing 
AE condition end date will be imputed as the minimum of (death date, data extraction 
date, last day of the end date month/year, EOS date) 
AE day and month are missing, or month only is missing 
If the year is equal to the year of the last dose date: 
AE condition end date will be imputed as the minimum of (last dose date + 30, death 
date, data extraction date, December 31st of the end date year, EOS date) 
 


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If the year is not equal to the year of the last dose date: 
AE condition end date will be imputed as the minimum of (death date, data extraction 
date, December 31st of the end date year, EOS date) 
AE day, month and year are missing, or year only is missing 
AE condition end date will not be imputed 
Within a single record, if the imputed stop date is before the start date, then the imputed stop 
date will be equal to the start date. 
Example 
AE Number 4:  Condition/Event NAUSEA 
First dose date 02APR2012 
Prior to imputation 
Log Line 
Start date 
Condition end date 
Severity 
Outcome 
1 
25APR2012 
UNAPR2012 
2 
recovering/resolvin
g 
2 
UNAPR2012 
04MAY2012 
1 
recovered/resolved 
Post imputation 
Log Line 
Start date 
Condition end date 
Severity 
Outcome 
1 
25APR2012 
30APR2012 
2 
recovering/resolvi
ng 
2 
02APR2012 
04MAY2012 
1 
recovered/resolved 
 
 
 


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Appendix B: Definition of the Term “Treatment-Emergent” with Respect to AE 
Classification  
The algorithm below should be used to determine whether an adverse event (AE) is classified 
as a treatment-emergent adverse event (TEAE). A TEAE is defined as any AE which is 
newly occurring or worsening in severity, where newly occurring means that the AE was not 
present at baseline. For ease of reading, both pre-existing conditions and AEs will be referred 
to as AEs for the remainder of this document. AE dates should be imputed in accordance 
with the algorithm detailed in Appendix A prior to determination of TEAE classification. 
Details of the TEAE classification are as follows: 
¾ For each subject, determine the first dose date, which is the earliest date the subject 
receives any amount of study drug (trastuzumab or tucatinib). 
¾ An AE record from AE page will be classified as a TEAE if it meets all the following 
three conditions: 
1. Onset period = Started after first dose of any study treatment (i.e., tucatinib or 
trastuzumab) 
2. AE Start Date on or after first dose date of study treatment (i.e., tucatinib or 
trastuzumab) 
3. AE Start Date before last dose date of study treatment (i.e., trastuzumab or tucatinib) + 
30 days 
 
¾ TEAEs pre-crossover are defined as AEs that are newly onset or worsened (increase in 
AE grade, AE becoming serious, or related to study drug) on or after receiving the first 
dose of tucatinib and up to 30 days after last dose of tucatinib for patients who didn’t 
crossover,  or the day before cross-over for patients who crossed over. 
 
¾ TEAEs post-crossover are defined as AEs that are newly onset or worsened (increase in 
AE grade, AE becoming serious, or related to study drug) on or after crossover (date of 
first dose of tucatinib or trastuzumab (whichever came first) in the first cycle of 
trastuzumab) and up to 30 days after the last dose of study treatment (tucatinib or 
trastuzumab). 
NOTE: 
¾ For summaries which include only treatment emergent AEs include all AEs 
which are classified as TEAEs as well as those AEs for which TEAE status could 
not be determined (e.g., the value of the TEAE variable may be missing if onset 
period is not known - missing information on the AE CRF should be queried). 
Only exclude those AEs which were determined to not be treatment emergent. 
 
 


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Appendix C: Imputation of Partial Missing Prior Therapy Dates  
Prior therapy dates will be imputed if both month and year are present and only day is 
missing. 
x For prior therapy start date, impute the first day of the month.  
x For prior therapy end date, impute the last day of the month or the date of first dose of 
any study drug, whichever is earlier.  
 
 
 


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Appendix D: Imputation of Partial Missing Subsequent Anticancer Therapy 
Dates and Hospitalization Dates 
Subsequent anticancer therapy and hospitalization start date and end date will be imputed if 
both month and year are present and only day is missing. 
x For start date, impute to first day of the month or the date of first dose of any study 
drug, whichever is later. 
x For end date, impute to last day of the month or the end of study, date of death, data 
cutoff date whichever is earlier. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix E: Imputation of Partial Missing Disease Diagnosis Dates  
Disease diagnosis dates (i.e. initial diagnosis date, date of first diagnosed with metastatic 
disease, date of first diagnosed with unresectable disease) will be imputed to the 1st day of 
the month if both month and year are present and only day is missing. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix F: Imputation of Partial Missing Death Dates  
Death dates are imputed if only the day is missing.  
The imputation of partial missing death date depends on the last-know-alive date derived 
from eCRF. 
If the last-known-alive date is in the same month and year of the partial missing death date, 
then the partial missing death date is imputed as the later of the following dates,  
x The last-known-alive date. 
x Day 15 of the month and year.  
If the last-known-alive date is not in the same month and year of the partial missing death 
date, then the partial missing death date is imputed as day 15 of the month and year. 
 


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