A Phase 3, Multicenter, Randomized, Open-label, Active Controlled Trial of DS-8201a, an Anti-HER2-antibody Drug Conjugate (ADC), Versus Treatment of Physician's Choice for HER2-low, Unresectable and/or Metastatic Breast Cancer Subjects
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Daiichi Sankyo

Pr o prietar y a n d C o nfi de ntial  
Pa ge 1  
C LI NI C A L S T U D Y P R O T O C O L  
 
A P H A S E 3, M U L TI C E N T E R, R A N D O MI Z E D, O P E N -
L A B E L, A C TI V E -C O N T R O L L E D T RI A L O F  
T R A S T U Z U M A B D E R U X T E C A N  (T -D X d ), A N A N TI-
H E R 2 -A N TI B O D Y D R U G C O N J U G A T E ( A D C), V E R S U S 
T R E A T M E N T O F P H Y SI CI A N’ S C H OI C E F O R H E R 2 -
L O W, U N R E S E C T A B L E A N D/ O R M E T A S T A TI C 
B R E A S T C A N C E R S U B J E C T S  
( D E S TI N Y-Bre ast 0 4 ) 
 
D S 8 2 0 1 -A -U 3 0 3  
 
I N D N U M B E R 1 2 7 5 5 3 
E u dr a C T N U M B E R 2 0 1 8 -0 0 3 0 6 9 -3 3  
 
V E R SI O N 5 . 0, 1 2  Oct o ber  2 0 2 0  
 
D aiic hi S a n k y o I nc.  
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
I nf or mati o n c o ntai ne d i n t his d oc u me nt is pr o prietar y t o Daiic hi Sa n k y o I n c.  T he i nf or mati o n is 
pr o vi de d t o y o u i n c o nfi d e nce w hi c h is re q ueste d u n der a n a gree d u p o n a n d si g ne d 
C o nfi de ntialit y a n d Discl os ure A gree me nt.  D o n ot gi ve t his d oc u me nt  or a n y c o p y of it or re v eal 
a n y pr o prietar y i nf or mati o n c o ntai ne d i n it t o a n y t hir d part y ( ot her t h a n t h ose i n y o ur 
or ga niz ati o n w h o are assisti n g y o u i n t his w or k a n d are b o u n d b y t he C o nfi de ntialit y a n d 
Discl os ure A gree me nt) wit h o ut t he pri or writte n p er missi o n of a n a ut h orize d re prese ntati ve of 
Daiic hi Sa n k y o I nc.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2  
D O C U M E N T HI S T O R Y  
Ve rsi o n N u m be r  
Ve rsi o n D ate  
5. 0  
1 2  Oct o ber 2 0 2 0  
4. 0  
2 3  A pril 2 0 2 0  
3. 0  
2 4  A pril  2 0 1 9  
2. 0  
2 3  N o ve m ber  2 0 1 8  
1. 0  
2 3 A u g ust  2 0 1 8  
 

Pr ot oc ol D S 8 2 0 1- A- U 3 0 3 
Versi o n 5. 0, 1 2 Oct 2 0 2 0
Pr o prietar y a n d C o nfi de nti al 
Pa ge 3 
I N V E S TI G A T O R A G R E E M E N T 
A P h ase 3, m ultice nter, r a n d o mize d, o pe n-l a b el, acti ve-c o ntr oll e d tri al of tr ast uz u m a b 
der u xtec a n ( T- D X d), a n a nti- H E R 2- a nti b o d y dr u g c o nj u g ate ( A D C), vers us tre at me nt of 
-l o w, u nresect a bl e a n d/ or met ast atic bre ast c a n cer s u bjects 
( D E S TI N Y- Bre ast 0 4) 
S p o ns or A p pr o v al: 
T his cli nical st u d y pr ot o c ol has bee n re vie we d a n d a p pr o ve d b y t he D aii c hi Sa n k y o I n c. 
re pres e ntati ve liste d bel o w. 
 
 
  
  
Pri nt N a me 
  
Si g n at ure 
 
Se ni or Direct or, Gl o bal O nc ol o g y R & D  
  
  
Title 
  
D ate ( D D M M M Y Y Y Y) 
 
 
I h a ve f ull y disc usse d t he o bjecti v es of t his st u d y a n d t he c o nte nts of t his pr ot oc ol wit h t h e 
 
I u n d ersta n d t hat i nf or m ati o n c o ntai ne d i n or pertai ni n g t o t his pr ot oc ol is c o nfi de ntial a n d 
s h o ul d n ot be dis cl ose d, ot her t ha n t o t h ose directl y i n v ol ve d i n t he e xec uti o n or t h e et hical 
re vie w of t h e st u d y, wit h o ut writte n a ut h orizati o n fr o m t he S p o ns or.  It is, h o we ver, p er missi ble 
t o pr o vi de i nf or mati o n t o a s u bject i n or der t o o btai n c o nse nt. 
I a gree t o c o n d uct t his st u d y acc or di n g t o t his pr ot oc ol a n d t o c o m pl y wit h its re q uire me nts, 
s u bject t o et hical a n d safet y c o nsi derati o ns a n d g ui d eli nes, a n d t o c o n d uct t he st u d y i n 
acc or d a nce wit h t he et hical pri nci ples t hat ha ve t h eir ori gi n i n t he Decl arati o n of Helsi n ki, 
I nter nati o nal C o nfere nce o n H ar m o nisati o n g ui d eli n es o n G o o d Cli nical Practi ce (I C H E 6), a n d 
a p plica ble re gi o nal re g ul at or y re q uir e me nts. 
I a gree t o m a ke a vaila ble t o S p o ns or pers o n nel, t heir re prese ntati ves, a n d rele va nt R e g ulat or y 
case re p ort f or ms.  I a m a ware of m y res p o nsi biliti es as a Pri nci p al I n v esti gat or as pr o vi de d b y 
t he S p o ns or. 
I u n d ersta n d t hat t he S p o ns or ma y deci d e t o s us pe n d or pre mat urel y ter mi n ate t he st u d y at a n y 
ti m e f or w hate v er reas o n; s uc h a decisi o n will be c o m m u nicate d t o me i n writi n g.  C o n versel y, 
s h o ul d I deci de t o wit h dra w fr o m e xec uti o n of t h e st u d y, I will c o m m u nicate m y i nt e nti o n 
i m m e diatel y i n writi n g t o t he S p o ns or. 
  
  
 
  
Pri nt N a me 
  
Si g n at ure 
 
  
  
 
  
Title 
  
D ate ( D D M M M Y Y Y Y) 
 
P P D
P P D

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4  
S U M M A R Y O F C H A N G E S  
Please refer t o t he c o m paris o n d oc u me nt f or pr ot o c ol Versi o n 5 . 0 ( date d 1 2  Oct  2 0 2 0 ) vs. 
pr ot oc ol Versi o n 4 . 0 ( date d 2 3  A pr  2 0 2 0 ) f or act ual c ha n ges i n te xt.  T he s u m mar y of c ha n ges 
bel o w is a t o p -li ne s u m mar y of maj or c ha n ges i n t he c urre nt D S 8 2 0 1 -A -U 3 0 3  cli nical st u d y 
pr ot oc ol ( Versi o n 5 . 0) b y secti o n. 
A me n d me nt R ati o n ale:  
T his a me n d me nt ( V ersi o n 5 . 0) i ncl u des t he a d diti o n of ne w ti me p oi nts f or o verall s ur vi val ( O S) 
a nal ys es.  T he st u d y w as ori gi nall y desi g ne d t o p erf or m O S a nal ysis at t he sa me ti me as  t he fi nal 
pr o gressi o n -free s ur vi val (P F S ) a nal ysis.  T his earl y a n al ysis w o ul d n ot ha ve pr o vi de d a d e q uate 
f oll o w u p a n d statistical p o wer t o dete ct a statisticall y si g nifica nt differe nce i n O S.  T he pr ot oc ol 
is n o w ame n de d t o i ncl u de O S as a ke y s ec o n dar y e n d p oi nt wit h a de q uate f oll o w -u p t o pr o vi de 
statistical p o wer t o detect mea ni n gf ul i m pr o ve me nt i n o verall s ur vi val bet wee n t he 2 treat me nt 
ar ms. 
I n a d diti o n, pr o gressi o n-free s ur vi val o n t he n e xt li ne of t hera p y ( P F S2 ) is a d de d as a n 
e x pl orat or y o bje cti ve  a n d e n d p oi nt .   
T o e val uate t he i m pa ct of t he gl o bal p a n de mic ca use d b y c or o na vir us  disease  2 0 1 9  (C O VI D -1 9 ), 
bi o mar ker a n al ysis is a d d e d t o i de ntif y p atie nts affecte d b y C O VI D -1 9,  a n d t he a nal ysis pla n is 
u p date d t o i de ntif y t h e i m pact of C O VI D-1 9 o n s afet y, efficac y , a n d st u d y c o n d uct .  Ot her 
c ha n ges  a n d rati o nale f or eac h c ha n ge  are n ot e d i n t he ta ble bel o w . 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Artic le 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
C O N V E N TI O N S U S E D I N T HI S S U M M A R Y O F C H A N G E S  
All l ocati o ns ( Secti o n n u m bers a n d/ or para gra p h/ b ullet n u m bers) refer t o t he c urre nt pr ot oc ol 
versi o n, w hic h i nc or p orates t he ite ms s pe cifie d i n t h e S u m mar y of C ha n ges.  
Mi n or e dits, s uc h as a n u p date t o la n g ua ge t h at d oes n ot alter ori gi nal mea ni n g, a n u p d ate t o 
versi o n n u m beri n g, f or m atti n g, a c ha n ge i n f o nt c ol or, a c orrecti o n t o a t y p o gra p hical err or, t h e 
use of a b bre viati o ns, m o vi n g v er bi a ge wit hi n a secti o n or ta ble, a c h a n ge i n st yl e  or n u m beri n g , 
or a c ha n ge i n cas e, are n ot n ote d i n t he ta ble bel o w.  
Secti o n # a n d Title  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
T hr o u g h o ut all secti o ns  
U p date d t he i n vesti gati o nal 
pr o d uct na me  fr o m trast uz u ma b 
der u xteca n  t o T-D X d.   
T o ali g n wit h t he pr o gra m  
c o m p o u n d ter mi n ol o g y . 
Title  P a ge  
I n vesti gat or A gree me nt 
Pr ot oc ol S y n o psis  
A d de d  “ D E S TI N Y -Breast 0 4” t o 
t he st u d y na me. 
T o pr o vi de clarificati o n . 
I n vesti gat or A gree me nt  
U p date d t he Daiic hi Sa n k y o I nc.  
st u d y re prese ntati ve. 
T he Daiic hi Sa n k y o I nc.  st u d y 
re prese ntati ve was u p date d. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5  
Secti o n # a n d Title  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
Pr ot oc ol S y n o psis  
2. 1. 2.  Ke y Sec o n dar y O bj ecti ve s 
2. 1. 3.  Ot her Sec o n dar y O bj ecti ves  
2. 3. 2.  Ke y Sec o n dar y Efficac y 
E n d p oi nt s 
2. 3. 3.  Ot her Sec o n dar y Efficac y 
E n d p oi nts  
3. 2. 1.  D urati o n of t he St u d y  
3. 2. 3.  Defi niti o n of t he E n d of t he 
St u d y  
7. 1. 2.  Ke y Sec o n dar y Efficac y 
E n d p oi nt s 
7. 1. 3.  Ot her Sec o n dar y Efficac y 
E n d p oi nts  
7. 2.  A p pr o priate ness of Selecte d 
Efficac y Assess me nts  
1 1. 1  Ge neral Statistical 
C o nsi derati o ns  
1 1. 4. 2 Ke y Sec o n dar y Efficac y 
A nal yses  
1 1. 6.  I nteri m A nal yses 
1 1. 7.  Sa m ple Size Deter mi nati o n  
1 7. 9. 1.  S we d e n O nl y  
U p date d t o i ncl u de o verall s ur vi val 
(O S ) p o wer c o nsi derati o n a n d 
pla n ne d a nal ys es . 
T he s t u d y was  ori gi nall y  desi g ne d 
t o perf or m O S a nal ysis at t he 
sa me ti me as fi nal P F S a nal ysis.  
T his earl y a nal ysis w o ul d n ot 
ha ve pr o vi de d a de q uate f oll o w u p 
a n d statistical p o wer t o detect a  
statisticall y si g nifica nt differe nce 
i n O S.  T he pr ot oc ol is n o w 
a me n de d t o i ncl u de  O S as a ke y 
sec o n dar y e n d p oi nt wit h a de q uate 
f oll o w-u p t o pr o vi de statistical 
p o wer t o detect mea ni n gf ul 
i m pr o ve me nt i n o verall s ur vi val 
bet wee n t he 2 treat me nt ar ms.  
T he rele va nt secti o ns of t he 
pr ot oc ol we re u p date d t o descri be 
t he c ha n ges. 
Pr ot oc ol S y n o psis  
2. 1. 4.  E x pl orat or y O bj ecti ves  
2. 3. 4.  E x pl orat or y Efficac y E n d p oi nts  
7. 1. 4 . E x pl orat or y Efficac y E n d p oi nts  
1 1. 4. 5 . 2. A nal yses of E x pl orat or y 
Efficac y E n d p oi nts  
1 7. 9. 1.  S we d e n O nl y  
Pr o gressi o n -free s ur vi val o n t he 
ne xt li ne of t hera p y  ( P F S 2) was 
a d de d as a n o bj ecti ve  a n d 
e n d p oi nt . 
P F S 2 wa s a d de d t o pr o vi de 
a d diti o nal i nf or mati o n o n t he 
i m pact of st u d y i nter ve nti o n o n 
t he s u bse q ue nt t hera p y i n ter ms 
of a sec o n d pr o gressi o n e ve nt as 
ca pt ure d b y t he P F S 2 e n d p oi nt . 
Pr ot oc ol S y n o psis  
U p dat e d t he ti mi n g of t he pri mar y 
a nal yses fr o m 1 8  m o nt hs t o n o w 
occ ur at a p pr o xi matel y 2 8  m o nt hs.  
Base d o n u p date d e nr oll me nt 
i nf or mati o n. 
5. 4. 1 . 1. D ose I nterr u pti o ns a n d 
Re d ucti o ns  f or T-D X d , 
T a ble  5. 3  
1 7. 1.  Sc he d ule of E ve nts, T a ble 1 7. 1  
1 7. 1.  Sc he d ule of E ve nts, T a ble 1 7. 2  
Re m o ve d d ose m o dificati o n 
g ui deli nes f or tr o p o ni n.  
T he re m o val of t he d ose 
m o dificati o n g ui deli nes f or 
ele vate d tr o p o ni n was dri ve n b y 
u p date d safet y data fr o m T -D X d  
cli nical st u dies, s h o wi n g n o 
ass ociati o n bet wee n 
as y m pt o matic tr o p o ni n i ncrease 
wit h left ve ntric ular d ysf u ncti o n 
or a n y ot her car diac e ve nts 
re p orte d i n t he pr o gra m. 
6. 2.  Scree ni n g  
U p date d h u ma n i m m u n o defici e nc y 
vir us ( HI V) testi n g la n g ua ge f or 
scree ni n g t o clearl y state t he t est is 
Clarificati o n of HI V testi n g 
la n g ua ge. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6  
Secti o n # a n d Title  
Descri pti o n of C h a n ge  
Brief R ati o n ale  
n ot ma n dat or y  u nless re q uire d b y 
l ocal re g ulati o ns or I nstit uti o nal 
Re vie w B oar d /I nstit uti o nal Et hics 
C o m mittee . 
6. 2.  Scree ni n g  
A d de d clarificati o n t hat s u bj ects  
w h o ha ve a p ositi ve  he patitis C  
vir us  (H C V ) a nti b o d y test will 
re q uire a ne gati ve p ol y merase 
c hai n reacti o n f or H C V R N A . 
Clarificati o n of H C V testi n g.  
6. 2.  Scree ni n g  
6. 4. 1. 2 . Da y 1 B ef ore D osi n g ( All 
C ycles, U nless Ot her wise 
N ote d).  
6. 5.  E n d of St u d y Treat me nt  
1 7. 1.  Sc he d ule of E ve nts, T a ble  1 7. 1 
a n d T a ble  1 7. 2  
1 7. 8.  I nstr ucti o ns Relate d t o 
C or o na vir us Disease 2 0 1 9 
( C O VI D-1 9)  
C O VI D -1 9 ser ol o g y testi n g  
g ui da nce  was a d de d.  
T o pr o vi de g ui da nce o n ser u m 
sa m ple c ollecti o n relate d t o 
C O VI D -1 9.  
6. 6. 2.  L o n g -ter m/ S ur vi val F oll o w-u p  
1 0. 1. 1.  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 
Q uesti o n naires C 3 0 a n d B R 4 5  
Ti mi n g of c o m pleti o n of s pecific 
H E O R o utc o mes q uesti o n nair es 
was s pecifie d . 
T o pr o vi de clarificati o n . 
8. 1  
P har mac o ki netic Assess me nts  
1 7. 1.  Sc he d ule of  E ve nts, T a ble 1 7. 2  
1 7. 8.  I nstr ucti o ns Relate d t o 
C or o na vir us Disease 2 0 1 9 
( C O VI D-1 9)  
Sc he d ule of P K Sa m ple C olle cti o n 
i n Case of C hl or o q ui ne or 
H y dr o x yc hl or o q ui ne Treat me nt 
a n d descri pti o ns of testi n g 
c o n diti o ns were a d de d . 
T o m o nit or p ote ntial dr u g -dr u g 
i nteracti o ns bet wee n 
i n vesti gati o nal/st u d y dr u g 
treat me nt a n d C O VI D 1 9 s pecific 
treat me nt. 
9. 5.  A d verse E ve nts a n d A d verse 
E ve nt of S pecial I nterest 
Re p orti n g – Pr oce d ures F or 
I n vesti gat ors 
Clarificati o n a d de d re gar di n g 
re p orti n g of ur ge nt safet y q uer y 
f oll o w-u p i nf or mati o n.  
T o p r o vi de clarificati o n re gar di n g 
ur ge nt safet y q uer y re p orti n g.  
1 1. 5. 7.  I m m u n o ge nicit y ( A nti-Dr u g 
A nti b o d y) A nal ys es  
Clarificati o n a d de d f or t he 
i m m u n o ge nicit y (a nti-dr u g 
a nti b o d y) a nal yses.  
T o f urt her defi ne t he a nal yses.  
1 7. 8.  I nstr ucti o ns Relate d t o 
C or o na vir us Disease 2 0 1 9 
( C O VI D-1 9)  
U p date d ma na ge me nt g ui da nc e.  
T o ali g n wit h t he latest 
ma na ge me nt g ui deli nes f or 
C O VI D -1 9 . 
1 7. 8.  I nstr ucti o ns Relate d t o 
C or o na vir us Disease 2 0 1 9 
( C O VI D-1 9)  
A d de d statistical a nal ysis t o assess 
t he i m pact of C O VI D -1 9, if 
dee me d a p pr o priate.  
T o assess t he i m pact of 
C O VI D -1 9.  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7  
P R O T O C O L S Y N O P SI S  
E u dra C T:  
2 0 1 8 -0 0 3 0 6 9 -3 3  
I N D N u m ber: 
1 2 7 5 5 3  
Pr ot oc ol N u m ber:  
D S 8 2 0 1 -A -U 3 0 3  ( D E S TI N Y-Breast 0 4)  
I n v esti gati o nal Pr o d uct: T rast uz u ma b der u xteca n (T -D X d ; D S -8 2 0 1a ; als o k n o w n as fa m-
trast uz u ma b der u xteca n-n x ki ) 
Acti ve I n gre die nts:  
T rast uz u ma b der u xteca n ( T-D X d ; D S-8 2 0 1a)  c o nsists of a n a nti b o d y 
c o m p o ne nt, M A A L-9 0 0 1, c o vale ntl y c o nj u gate d via a malei mi de 
tetra pe pti de li n ker, t o a dr u g c o m p o ne nt M A A A-1 1 8 1a  
St u d y Title:  
A P hase 3, m ultice nter, ra n d o mize d, o pe n -la bel, acti ve-c o ntr olle d trial 
of trast uz u ma b der u xteca n (T -D X d ), a n a nti-H E R 2 -a nti b o d y dr u g 
c o nj u gate ( A D C), vers us treat me nt of p h ysicia n’s c h oice f or H E R 2 -l o w, 
u nresect a ble a n d/ or met astatic breast ca ncer s u bjects   
( D E S TI N Y-Breast 0 4)  
St u d y P has e:  
P hase 3  
I n dic ati o n U n der 
I n v esti gati o n: 
U nresecta ble a n d/ or m etastatic breast c a ncer t hat is h u ma n e pi der mal 
gr o wt h fact or rece pt or 2 ( H E R 2) -l o w  
St u d y O bjecti ves:  
Pri mar y O bj ecti ve : 
 T o c o m pare t h e pr o gressi o n -free s ur vi val ( P F S) be nefit of T -D X d  t o 
p h ysicia n’s c h oice  i n H E R 2-l o w, h or m o ne rece pt or ( H R )-p ositi ve 
breast c a ncer, base d o n bli n de d i n de pe n de nt ce ntr al re vie w ( BI C R)  
Ke y Sec o n dar y O bjecti ve s: 
 T o c o m pare t h e P F S be n efit of T -D X d  t o p h ysicia n’s c h oice i n all 
ra n d o mize d s u bjects (H E R 2 -l o w, H R -p ositi ve , a n d H R -ne gati ve 
breast c a ncer ), bas e d o n BI C R 
 T o c o m pare t h e o verall s ur vi val ( O S) be n efit of T -D X d  t o 
p h ysicia n’s c h oice i n H E R 2 -l o w, H R-p ositi ve breast ca ncer  
 T o c o m pare t h e O S be nefit of T -D X d  t o p h ysicia n’s c h oice i n all 
ra n d o mize d s u bjects (H E R 2 -l o w, H R -p ositi ve a n d H R -ne gati ve 
breast c a ncer ) 
I n S w e de n o nl y, ple ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites 
i n S w e de n. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
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Pr o prietar y a n d C o nfi de ntial  
Pa ge 8  
Ot her Sec o n d ar y O bjecti ves : 
 T o e val uate efficac y of T -D X d  c o m pare d t o p h ysi cia n’s c h oice o n 
t he f oll o wi n g para met ers: 
 Pr o gressi o n -free s ur vi val (P F S ) i n H R-p ositi ve s u bjects, base d 
o n I n v esti gat or assess me nt  
 C o nfir me d o bjecti ve res p o nse rate ( O R R), base d o n BI C R a n d 
I n v esti gat or assess me nt i n H R-p ositi ve s u bjects  
 D urati o n of res p o ns e ( D o R), base d o n BI C R i n H R -p ositi ve 
s u bjects 
 C o nfir me d O R R, a n d D o R i n all s u bjects, re gar dless of H R 
stat us. 
 T o deter mi ne p har mac o ki netics ( P K) of T -D X d  
 T o e val uate s afet y of T -D X d  c o m pare d t o p h ysi cia n’s c h oice of 
treat me nt 
 T o e val uate Healt h Ec o n o mics a n d O utc o mes Res earc h ( H E O R) 
e n d p oi nts f or T -D X d  c o m pare d t o p h ysicia n’s c h oice  
I n S w e de n o nl y, ple ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites 
i n S w e de n. 
E x pl orat or y O bjecti ves : 
 T o e val uate cli nical be nefit rate ( C B R; t he s u m of c o m plete 
res p o nse [ C R] rate, partial res p o nse [ P R] rate, a n d greater t ha n or 
e q ual t o 6  m o nt hs’ sta ble disease rat e) bas e d o n BI C R   
 T o e val uate dise ase c o ntr ol rate ( D C R), bas e d o n BI C R  
 T o e val uate ti me t o res p o nse ( T T R), bas e d o n BI C R  
 T o e val uate  pr o gressi o n -free s ur vi val o n t he ne xt li ne of t hera p y 
( P F S 2) 
 T o e val uate p ote ntial bi o mar kers of res p o nse/resista nce  
 T o e val uate e x p os ure -res p o nse relati o ns hi ps f or efficac y a n d safet y 
e n d p oi nts  
 T o e val uate P F S, O S, c o nfir me d O R R, a n d D o R i n H R -ne gati ve 
s u bjects 
St u d y Desi g n:  
T his is a ra n d o mize d, 2 -ar m, P hase 3, o pe n -la bel, m ultice nter st u d y t o 
c o m pare t he s afet y a n d efficac y of T -D X d  vers us t he p h ysicia n’s c h oice 
i n H E R 2-l o w, u nresecta ble a n d/ or metastatic breast ca ncer s u bjects.   
S u bjects  t o be e nr olle d:  

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Pa ge 9  
 N ot m ore t ha n  2 4 0 H R -p ositi ve s u bjects w h o ha ve n ot ha d 
pri or t hera p y wit h a c ycli n -de pe n de nt ki nas e ( C D K) 4/ 6 
i n hi bit or 
 A t least 2 4 0 H R-p ositi ve s u bjects w h o ha ve h a d pri or 
t hera p y wit h a C D K 4/ 6 i n hi bit or  
 ~ 6 0 H R -ne gati ve s u bjects.  
T he ~ 5 4 0  s u bjects will be ra n d o mize d 2: 1 t o T -D X d  ( ~ 3 6 0) vers us t he 
p h ysicia n’s c h oice ( ~ 1 8 0) wit h o ne of t he f oll o wi n g dr u gs:  
 Ca pecita bi ne  
 Eri b uli n  
 Ge mcita bi ne  
 Paclita x el  
 Na b -paclita xel  
 
Ra n d o mizati o n will be stratifie d b y:  
 H E R 2 i m m u n o hist oc he mistr y (I H C) stat us of tiss ue sa m ples 
assesse d b y a ce ntr al la b orat or y:  H E R 2 I H C  1 + vs. H E R 2 
I H C 2 +/i n sit u h y bri dizati o n [I S H] - 
 N u m ber of pri or li nes of c he m ot hera p y:  1 vs. 2  
 H R/ C D K stat us:  H R -p ositi ve wit h pri or C D K 4/ 6 i n hi bit or treat me nt 
vs. H R -p ositi ve wit h o ut pri or C D K 4/ 6 i n hi bit or treat me nt vs. H R -
ne gati ve.  
 
St u d y Desi g n Sc he m a of D S 8 2 0 1 -A -U 3 0 3  
 
C D K = c ycli n -de pe n de nt ki nase, H E R 2 = h u ma n e pi der mal gr o wt h fact or rece pt or 2, 
I H C =  i m m u n o hist oc he mistr y, T P C =  treat me nt of p h ysicia n’s c h oice 
* S ee Secti o n  6. 1  a n d Secti o n  6. 2  f or details. 
T here will be f oll o w -u p visits after per ma n e nt disc o nti n uati o n of st u d y 
treat me nt t o o btai n i nf or mati o n a b o ut s u bse q ue nt treat me nt(s) a n d 
s ur vi val stat us. 

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0  
St u d y D urati o n:  
E nr oll me nt is pla n ne d t o occ ur o ver a p pr o xi matel y 1 6  m o nt hs  fr o m t he 
ra n d o mizati o n date of t he first s u bject.  T he d ata c ut off f or t h e pri mar y 
a nal ysis of P F S is pla n ne d w he n a p pr o xi matel y 3 1 8  P F S e ve nts per 
BI C R ha ve b ee n o bser ve d i n t he H R -p ositi ve s u bjects , a n d data c ut f or 
t he fi nal a nal ysis of t he k e y s ec o n dar y e n d p oi nt of O S is pla n ne d w he n 
a p pr o xi matel y 3 3 3 O S e ve nts ha ve bee n d oc u me nte d i n t he H R -p ositi ve 
s u bjects. 
T here will be a 4 0 -Da y ( +7 d a ys) F oll o w -u p aft er t he last st u d y 
treat me nt a d mi nistrati o n or bef ore starti n g ne w a ntica ncer treat me nt, 
w hic he ver c o mes first, f oll o we d b y L o n g -ter m/ S ur vi val F oll o w-u p 
e ver y 3 m o nt hs  ( ±1 4 d a ys) fr o m t he date of t he 4 0 -Da y ( +7 d a ys) 
F oll o w -u p, u ntil deat h, wit h dra wal of c o ns e nt, l oss t o f oll o w -u p, or  
st u d y cl os ur e, w hic he v er occ urs first. 
St u d y C e nter s a n d 
L ocati o n:  
A p pr o xi matel y 2 2 5  sites, i ncl u di n g b ut n ot li mite d t o, N ort h A merica, 
Wester n E ur o pe, a n d Asia.  
S u bject Eli gi bilit y 
Criteria:  
Ke y I ncl usi o n Criteria   
T he I n vesti gat or s h o ul d f oll o w t he la bel a p pr o ve d i n t he c o u ntr y of dr u g 
a d mi nistrati o n  f or t he i n di vi d ual treat me nt o pti o ns (ca pecita bi ne, 
eri b uli n, ge m cita bi ne, paclita xel, or na b -paclita xel)  f or eli gi bilit y criteria 
if t he s u bject is ra n d o mize d t o t he ar m of tr eat me nt of p h ysicia n’s 
c h oice. T he i n cl usi o n criteria i ncl u de : 
 Me n or w o me n ≥1 8 years ol d.  ( Please f oll o w l ocal re g ulat or y 
re q uire me nts if t he l e gal a ge of c o ns e nt f or st u d y partici pati o n is 
> 1 8 years ol d.)  
 Pat h ol o gicall y d oc u me nt e d breast ca ncer t hat:  
 Is u nresecta ble or met astatic. 
 Has a hist or y of l o w H E R 2 e x pressi o n, defi ne d as I H C 2 +/I S H - 
or I H C 1 + (I S H - or u nteste d).  
 Is assesse d as l o w H E R 2 e x pressi o n, defi ne d as I H C 2 +/I S H- or 
I H C 1 + acc or di n g t o A S C O-C A P  2 0 1 8  H E R 2 testi n g  g ui deli nes  
(a da pte d b y Daiic hi Sa n k y o I n c. a n d Ve nta na) e val uate d at a 
ce ntral la b orat or y.  
 Is H R-p ositi ve or H R -ne gati ve.  A p pr o xi matel y 6 0 H R -ne gati ve 
s u bjects are t o be e nr olle d ; t he re mai ni n g s u bj ects will be H R -
p ositi ve .  
 If H R-p ositi ve, i s d oc u me nte d refract or y t o e n d ocri ne t hera p y, 
defi ne d as h a vi n g pr o gresse d o n at least 1 e n d ocri ne t hera p y a n d 
deter mi ne d b y t he I n v esti gat or t h at s u bject w o ul d n o l o n ger 
be nefit fr o m f urt her treat me nt fr o m e n d ocri n e t hera p y.  

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Pa ge 1 1  
 If H R-p ositi ve, has or has n ot bee n treat e d wit h a C D K 4/ 6 
i n hi bit or.   N ot m ore t ha n  2 4 0 H R -p ositi ve s u bjects w h o ha ve 
n ot ha d pri or t hera p y wit h a C D K 4/ 6 i n hi bit or  a n d at least 2 4 0  
H R -p ositi ve s u bjects w h o ha ve ha d pri or t hera p y wit h a C D K 4/ 6 
i n hi bit or will be e nr olle d . 
 Has bee n tr eate d wit h at least 1 a n d at m ost 2 pri or li nes of 
c he m ot hera p y i n t he m etastatic setti n g.  If rec urre nce occ urre d 
wit hi n 6  m o nt hs of a dj u va nt c he m ot hera p y, a dj u v a nt t hera p y 
w o ul d c o u nt as 1 li ne of c he m ot hera p y.  
 Was ne ver pre vi o usl y H E R 2 -p ositi ve (I H C  3 + or 
I H C 2 +/I S H +) o n pri or pat h ol o g y testi n g ( per A S C O-
C A P  - g ui d eli nes) or was hist oricall y H E R 2 I H C 0 o nl y . 
 Was ne ver pre vi o usl y treate d wit h a nti -H E R 2 t hera p y.  
 D oc u me nte d ra di ol o gic pr o gressi o n ( d uri n g or after m ost rece nt 
treat me nt). 
 M ust ha ve a n a d e q uate arc hi val t u m or  tiss ue sa m ple a vaila ble f or 
assess me nt of H E R 2  stat us b y ce ntral la b orat or y ( base d o n m ost 
rece nt a vaila ble t u m or tiss ue sa m ple).  If arc hi val t u m or tiss ue is n ot 
a vaila ble, a fres h  t u m or tiss ue bi o ps y is re q uir e d.   See Secti o n  6. 1  
f or details.    
 All s u bjects m ust ha ve a rece nt t u m or  tiss ue sa m ple after t h e m ost 
rece nt treat me nt r e gi me n or a gree t o u n der g o a tiss ue bi o ps y pri or t o 
ra n d o mizati o n.  See Secti o n  6. 2  f or details. 
 Prese nce of at least 1 meas ura ble lesi o n bas e d o n c o m p ute d 
t o m o gra p h y ( C T) or ma g netic res o na n ce i ma gi n g ( M RI), per 
m o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors ( m R E CI S T) 
versi o n  1. 1 .   
 Brai n lesi o ns will be c o nsi dere d as n o n -t ar get lesi o ns o nl y. 
 Left ve ntric ular eject i o n fracti o n ( L V E F) ≥5 0 % 
 A de q uate re nal f u n cti o n, defi ne d as:  
 Creati ni ne cleara n ce ≥3 0  m L/ mi n, as cal c ulate d usi n g t he 
C oc kcr oft -Ga ult e q uati o n  
 A de q uate he patic f u ncti o n, defi ne d as:  
 As partate a mi n otra nsferase ( A S T)/ ala ni ne a mi n otra nsferase 
( A L T) ≤5 × u p p er li mit of n or mal ( U L N) 
 T otal bilir u bi n ≤1. 5 × U L N) if n o li ver metastas es or < 3  ×  U L N 
i n t he prese nce of d oc u m e nte d Gil bert’s s y n dr o me 

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( u nc o nj u gate d h y per bilir u bi ne mia) or li ver metast ases at 
baseli ne  
 Males a n d fe m ales of re pr o d ucti ve/c hil d beari n g p ote ntial m ust a gree 
t o f oll o w i nstr ucti o ns f or met h o d(s) of c o ntr ace pti o n 
Ke y E x cl usi o n Criteria   
T he I n vesti gat or s h o ul d f oll o w t he la bel a p pr o ve d i n t he c o u ntr y of dr u g 
a d mi nistrati o n  f or t he i n di vi d ual treat me nt o pti o ns (ca pecita bi ne, 
eri b uli n, ge m cita bi ne, paclita xel, or na b -paclita xel) if t he s u bject is 
ra n d o mize d t o t he ar m of treat me nt of p h ysicia n’s c h oice. T he e x cl usi o n 
criteria i ncl u de:  
 I n eli gi ble f or t he declare d  p h ysicia n’s c h oice c o m parat or  b eca us e of 
pre vi o usl y recei vi n g tr eat me nt  wit h t he sa me c o m parat or  i n t he 
metastatic setti n g or t h e c o m parat or is c o ntr ai n dicat e d.  S u bjects are 
eli gi ble if t here is a c o m p arat or wit h w hic h t h e y ha ve n ot pre vi o usl y 
bee n treate d.  
 Has me dical hist or y of m y o car dial i nfarcti o n wit hi n 6  m o nt hs bef ore 
ra n d o mizati o n 
 Has hist or y of s y m pt o matic c o n gesti ve heart fail ure ( Ne w Y or k 
Heart Ass o ciati o n Class II t o I V)  
 Has c orrecte d Q T i nter val ( Q Tc) pr ol o n gati o n t o > 4 7 0  ms (fe males) 
or > 4 5 0 ms ( male) b ase d o n a vera ge of Scree ni n g tri plicate 1 2 -lea d 
electr ocar di o gra ms ( E C Gs)  
 Has a hist or y of ( n o ni nf ecti o us) i nterstitial l u n g disease 
(I L D)/ p ne u m o nitis t hat r e q uire d ster oi ds, has c urre nt 
I L D/ p n e u m o nitis, or w here s us pecte d IL D/ p ne u m o nitis ca n n ot be 
r ule d o ut b y i ma gi n g at S cree ni n g. 
 Has s pi nal c or d c o m pressi o n or cli nicall y acti ve ce ntral ner v o us 
s yste m metastas es, defi n e d as u ntreate d or s y m pt o matic, or re q uiri n g 
t hera p y wit h c ortic oster oi ds or a ntic o n v ulsa nts t o c o ntr ol associate d 
s y m pt o ms. 
 S u bjects wit h treate d brai n metastases t hat are n o l o n ger 
s y m pt o matic a n d w h o re q uire n o treat me nt wit h c ortic oster oi ds 
or a ntic o n v ulsa nts ma y b e i ncl u de d i n t he st u d y if t he y h a ve 
rec o vere d fr o m t he ac ute t o xic effect of ra di ot hera p y.  A 
mi ni m u m of 2  wee ks m ust ha ve ela pse d b et wee n t he e n d of 
w h ole brai n r a di ot hera p y a n d st u d y e nr oll me nt.  
D osa ge F or m, D ose, 
a n d R o ute of 
A d mi nistrati o n:  
T -D X d  f or i njecti o n 1 0 0 m g, L y o-D P: A T -D X d  l y o p hilize d p o w der 
c o ntai ni n g 1 0 0 m g of T -D X d  i n a glass vial.   

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3  
T -D X d  f or i ntra ve n o us (I V) i nf usi o n is pre pare d b y dil uti o n of t he 
re q uire d v ol u me of t h e dr u g pr o d u ct calc ul ate d bas e d o n t he s u bject’s 
b o d y w ei g ht.  T h e st u d y treat me nt will be a d mi nistere d  at a d ose of 
5 . 4 m g/ k g  as a n I V i nf usi o n e ver y 2 1  d a ys, i nitiall y f or a p pr o xi matel y 
9 0  mi n utes, t he n, if t here is n o i nf usi o n  relate d reacti o n, f or a mi ni m u m 
of 3 0  mi n utes t hereafter.  
P h ysicia n’s c h oice c o m p arati ve t hera p y will be a d mi nistere d i n 
acc or da nce wit h t he la bel a p pr ove d i n t he c o u ntr y of dr u g 
a d mi nistrati o n  or t he N C C N g ui deli nes 1 (see T a ble  5 .1 ).  T he p h ysicia n’s 
c h oice nee ds t o be pre defi ne d, pri or t o ra n d o mizati o n, fr o m t he 
f oll o wi n g o pti o ns: 
 Ca pecita bi ne  
 Eri b uli n  
 Ge mcita bi ne  
 Paclita x el  
 Na b -paclita xel  
St u d y E n d p oi nts:  
Pri mar y Efficac y E n d p oi nt:  
 P F S, base d o n BI C R , i n H R-p ositi ve breast ca n cer  s u bjects 
Ke y Sec o n dar y Effi cac y E n d p oi nt:  
 P F S , base d o n BI C R , i n all ra n d o mize d s u bjects  
 O S i n H R-p ositi ve breast ca ncer  s u bjects 
 O S i n all ra n d o mize d s u bjects  
I n S w e de n o nl y, ple ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites 
i n S w e de n. 
Ot her Sec o n d ar y Efficac y E n d p oi nts:  
 P F S, base d o n I n vesti gat or asses s me nt 
 C o nfir me d O R R, base d o n BI C R a n d I n v esti gat or assess me nt  
 D o R, base d o n BI C R  
I n S w e de n o nl y, ple ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites 
i n S w e de n. 
E x pl orat or y Effi cac y E n d p oi nts:  
 C B R , base d o n BI C R  
 D C R, base d o n BI C R  
 T T R, base d o n BI C R  

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 P F S 2  
Healt h Ec o n o mic a n d O utc o mes Researc h E n d p oi nts:   
 E ur o pea n Or ga nizati o n f or Researc h a n d Treat me nt of Ca ncer 
( E O R T C) q ualit y of life q uesti o n naire ( Q L Q)  
o  C 3 0  
o  B R 4 5  
 E ur o Q ol 5 di me nsi o ns 5 le vels [ of se verit y] ( E Q -5 D -5 L)  
 H os pitalizati o n -relate d e n d p oi nts 
P har mac o ki netic E n d p oi nts:  
 Ser u m c o nce ntr ati o ns of T -D X d , t otal a nti-H E R 2 a nti b o d y , a n d 
M A A A -1 1 8 1a  
Bi o mar ker E n d p oi nts:  
 Ser u m bi o mar kers (e g, H E R 2 e xtracell ular d o mai n)  
 Ot her p ote ntial bi o mar kers  of res p o nse/resista nce  (e g, 
de o x yri b o n ucleic aci d [ D N A] pr ofili n g i n cell free D N A , R N A 
e x pressi o n pr ofili n g, m utati o ns)  
Safet y E n d p oi nts:  
 Seri o us a d verse e ve nts ( S A Es)  
 Treat me nt -e mer ge nt a d v erse e v e nts ( T E A Es), gra de d acc or di n g t o 
t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nts ( N CI C T C A E) versi o n 5. 0  
 A d verse e ve nts of s pecial i nterest ( A E SIs)  
 Disc o nti n uati o ns ass ociate d wit h  a d verse e ve nts  
 P h ysical e x a mi nati o n fi n di n gs  
 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 O G 
P S)  
 Vital si g n meas ure me nts  
 Sta n dar d cli nical la b orat or y p ara m eters  
 E C G para meters  
 Ec h ocar di o gra m ( E C H O)/ m ulti gate d ac q uisiti o n ( M U G A) sca n 
fi n di n gs  
 A nti -dr u g a nti b o dies  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5  
Pla n ne d Sa m ple  
Siz e:  
T he tar get sa m ple siz e will be a p pr o xi matel y 5 4 0 s u bjects, ra n d o mize d 
i n a 2: 1 rati o i nt o 2 treat me nt ar ms (T -D X d  vs. p h ysicia n’s c h oice).  U p 
t o ~ 4 0 T -D X d  s u bjects a n d u p t o ~ 2 0 p h ysicia n’s c h oice s u bjects will be 
H R -ne gati ve . 
Stat istical  
A nal ys es:  
T he pri mar y a n al yses f or P F S will be perf or me d w he n ~ 3 1 8  P F S e ve nts 
per BI C R h a ve bee n  o bser ve d  i n t he H R-p ositi ve p o p ulati o n , w hic h is 
e x pecte d t o occ ur i n ~ 2 8 m o nt hs  fr o m t he ra n d o mizati o n date of t he first 
s u bject. 
Efficac y A nal yses  
T he pri mar y efficac y e n d p oi nt is P F S per BI C R. T he pri mar y efficac y 
a nal ys es of P F S per BI C R will be perf or me d f or t he H R -p ositi ve c o h ort 
of t he F ull  A nal ysis Set  ( F A S).   
Pr o gressi o n -free s ur vi val per  BI C R is defi ne d as t he ti me fr o m t he date 
of ra n d o mizati o n t o t he earliest date of t he first o bjecti ve d oc u me ntati o n 
of ra di o gra p hi c disease pr o gressi o n base d o n BI C R or deat h d ue t o a n y 
ca use.  S u bjects w h o are ali ve wit h n o o bjecti ve d oc u me ntati o n of 
(ra di o gra p hi c) diseas e pr o gressi o n b y t h e data c ut off date f or P F S 
a nal ysis will be ce ns ore d at t he date of t heir last e val ua ble t u m or 
assess me nt.  
T he pri mar y efficac y a n al ysis will c o m pare P F S of H R -p ositi ve s u bjects 
bet wee n t he 2 treat me nt ar ms usi n g a str atifie d l o g-ra n k test.  
Stratificati o n fact ors us e d f or pri mar y a nal ysis will be fr o m t he 
ra n d o mizati o n.  T he P F S will be teste d f or statistical si g nifi ca nce at a 2 -
si de d al p ha of 0. 0 5.  Ka pla n-Meier esti mates a n d s ur vi val c ur ves will 
als o be prese nt e d f or  eac h treat me nt ar m.  T h e me dia n e ve nt ti mes a n d 
2 -si de d 9 5 % c o nfi d e nce i nter vals ( CIs) f or t he me dia ns will be pr o vi de d 
usi n g Br o o k me yer a n d Cr o wle y met h o d f or eac h treat me nt ar m.  T he 
hazar d rati os a n d t heir 9 5 % CIs will be esti mate d, usi n g stratifie d C o x 
pr o p orti o nal hazar ds re gressi o n m o dels.  
Gr o u p se q ue ntial testi n g will be use d t o c o m pare O S bet wee n t he 
2  treat me nt gr o u ps hierarc hicall y, pr o vi de d t he P F S a nal ysis is 
statisticall y si g nifica nt.  Ka pla n-Mei er esti mates a n d s ur vi val c ur v es 
will als o be p rese nte d f or eac h tr eat me nt gr o u p.  T he me dia n s ur vi val 
ti mes a n d 2-si de d 9 5 % CIs f or t he me dia ns will be pr o vi de d usi n g 
Br o o k me yer a n d Cr o wle y met h o d f or eac h treat me nt ar m.  I n a d diti o n, 
Ka pla n -Mei er esti mates at fi x e d ti me p oi nts , al o n g wit h t heir 2 -si de d 
9 5 % C Is, will be pr o vi de d f or eac h treat me nt ar m.  T he H R a n d its 9 5 % 
CI will be esti mate d, usi n g stratifie d C o x pr o p orti o nal hazar ds 
re gressi o n m o del stratifie d b y stratificati o n fact ors per I nteracti ve 
We b/ V oice Res p o nse S yste m .  U p t o 3 a nal ys es of O S will  be 
perf or me d:  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 6  
 First i nteri m a nal ysis at t he ti me of t he fi nal a n al ysis f or P F S 
( pr o vi de d P F S is si g nifica nt), at w hic h p oi nt a t otal of a p pr o xi matel y 
1 6 2 O S e ve nts ( 4 9 % i nf or mati o n fracti o n)  i n H R-p ositi ve s u bjects  
are e x pecte d.  
 If t he first O S i n teri m a n al ysis is n ot si g nifica nt, a sec o n d i nteri m 
a nal ysis f or O S is pla n ne d w he n a p pr o xi matel y 2 3 3 O S e ve nts ( 7 0 % 
i nf or mati o n fracti o n) i n H R-p ositi ve s u bjects  ha ve bee n 
d oc u me nte d .   
 If t he sec o n d O S i nteri m a nal ysis is n ot si g nifi ca nt, a fi nal a nal ysis 
f or O S after a p pr o xi matel y 3 3 3 O S e ve nts i n H R-p ositi ve s u bjects  
ha ve bee n d oc u me nte d .  
D urati o n of res p o ns e is defi ne d as t he ti me fr o m t he date of t he first 
d oc u me ntati o n of o bjecti ve res p o nse ( C R or P R) t o t he date of t he first 
d oc u me ntati o n of disease pr o gressi o n, base d o n BI C R, or deat h.  
D urati o n of res p o ns e will be meas ure d f or res p o n d i n g s u bjects ( P R or 
C R) o nl y.  S u bjects w h o are pr o gressi o n -free a n d ali ve at t he ti me of t he 
a nal ys es will be ce ns ore d at t he date of t he l ast e val ua ble t u m or 
assess me nt.  
D urati o n of res p o ns e will be s u m marize d wit h me dia n e ve nt ti mes a n d 
its 2-si de d 9 5 % CIs usi n g Br o o k me yer a n d Cr o wle y m et h o d f or eac h 
treat me nt ar m.  
T he C oc hra n – M a ntel – Hae nszel  test will be use d t o c o m pare c o nfir me d 
O R R  bet wee n t he treat me nt ar ms .  T he esti mates of c o nfir me d O R R  a n d 
its 2 -si de d 9 5 % e x act CI will be pr o vi de d usi n g t h e Cl o p per -Pears o n 
met h o d .   
Healt h Ec o n o mic a n d O utc o mes Researc h A nal ys es  
Healt h ec o n o mic a n d o ut c o mes researc h e n d p oi nts base d o n t he 
h os pitaliz ati o n -relate d data c ollecti o n f or m a n d t h e f oll o wi n g P R O 
q uesti o n naires will be s u m marize d b y treat me nt ar m: E O R T C Q L Q -
C 3 0, E O R T C Q L Q -B R 4 5, a n d E Q -5 D -5 L.  A d et aile d a nal ysis pla n of 
Q o L e n d p oi nts, i ncl u di n g c o ntr ol of t y p e I err or re gar di n g Q o L 
a nal ys es, will be pr o vi de d i n t he S A P.   
P har mac o ki netic A n al ys es  
Descri pti ve statistics will be pr o vi de d f or all ser u m c o nce ntrati o n dat a 
(T -D X d , t otal a nti-H E R 2 a nti b o d y, a n d M A A A -1 1 8 1a) at eac h ti me.  
T he p o p ulati o n -P K  ( p o p-P K) a nal ysis t o e val uate t he effect of i ntri nsic 
a n d e xtri nsic fact ors of T -D X d , a n d if a p pr o priat e, t otal a nti-H E R 2 
a nti b o d y a n d M A A A -1 1 8 1a, will be c haracterize d , i ncl u di n g a v aila ble 
P K data fr o m ot her T -D X d  st u dies.  After est a blis h me nt of t he p o p -P K 
m o del, a p o p -P K/ p har mac o d y n a mic m o del ma y b e de vel o pe d t o 
e val uate t he relati o ns hi p bet wee n e x p os ure a n d efficac y a n d safet y 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 7  
e n d p oi nts .  T he res ults of t he n o nli near mi x e d effects p o p-P K  a n d p o p-
P K/ p har mac o d y na mic  m o dels ma y b e re p orte d se paratel y fr o m t he 
cli nical st u d y re p ort.  
Bi o mar ker A nal yses  
A  t u m or tiss ue bi o ps y aft er t he c o m pleti o n of t he s u bject’s m ost rece nt 
treat me nt re gi me n is r e q uire d f or retr os pecti ve assess me nt. If t he t u m or 
tiss ue sa m ple pr o vi de d f or H E R 2 stat us testi n g was c ollecte d after 
c o m pleti o n of t he last treat me nt re gi me n, a n a d diti o nal  ne w bi o ps y  is 
n ot re q uire d.  If t he t u m or tiss ue sa m ple pr o vi de d f or H E R 2 stat us 
testi n g was c ollecte d bef ore c o m pleti o n of t he last treat me nt re gi me n, a n 
a d diti o nal ne w bi o ps y  is re q uire d.  O pti o nal fres h tiss ue sa m ples ma y 
a d diti o nall y be o btai ne d d uri n g a n d after st u d y tr eat me nt . 
Bi o mar kers will be s u m marize d b y tr eat me nt ar m usi n g descri pti ve 
statistics, w he n a p plica bl e. 
Safet y A nal yses  
Safet y e n d p oi nts will i ncl u de S A Es, T E A Es, A E SIs, disc o nti n uati o ns 
ass ociate d wit h  A Es, p h ysical e xa mi nati o n fi n di n gs, E C O G P S, vital 
si g ns meas ur e me nts, sta n dar d cli nical la b orat or y p ara meters, E C G 
para meters, E C H O/ M U G A sca n fi n di n gs, a n d a nti -dr u g a nti b o dies.  T he 
T E A Es will be gra de d acc or di n g t o t he N CI C T C A E versi o n 5. 0.  Safet y 
a nal ys es i n ge neral will be desc ri pti ve a n d will be prese nte d i n ta b ular 
f or mat wit h t he a p pr o priate s u m mar y statistics. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 8  
T A B L E O F C O N T E N T S  
D O C U M E N T HI S T O R Y .................................................................................................................2  
I N V E S TI G A T O R A G R E E M EN T ...................................................................................................3  
S U M M A R Y O F C H A N G E S  ...........................................................................................................4  
P R O T O C O L S Y N O P SI S  ................................................................................................................7  
LI S T O F A B B R E VI A TI O N S  ........................................................................................................2 8  
1.  
I N T R O D U C TI O N ...........................................................................................................3 2  
1. 1.  
Bac k gr o u n d  ......................................................................................................................3 2  
1. 1. 1.  
I n v esti gati o nal Pr o d uct ....................................................................................................3 3  
1. 1. 1. 1.  Na me  ................................................................................................................................3 3  
1. 1. 1. 2.  Descri pti o n  ......................................................................................................................3 3  
1. 1. 1. 3.  I nte n d e d Use U n der I n vesti gati o n  ...................................................................................3 3  
1. 1. 1. 4.  C o m parat ors ( P h ysi cia n’s C h oice)  ..................................................................................3 4  
1. 1. 1. 5.  N o ncli nical St u dies of T -D X d  .........................................................................................3 4  
1. 1. 1. 6.  Cli nical E x perie nce  .........................................................................................................3 5  
1. 1. 1. 7.  Be nefit / Ris k Assess me nt .................................................................................................3 8  
1. 1. 1. 8.  S u m mar y of Cli nical P har mac o ki netics  ..........................................................................3 9  
1. 2.  
St u d y R ati o nale  ...............................................................................................................4 0  
2.  
S T U D Y O BJ E C TI V E S A N D  H Y P O T H E SI S  ................................................................4 2  
2. 1.  
St u d y O bjecti ves  ..............................................................................................................4 2  
2. 1. 1.  
Pri mar y O bj ecti ve  ............................................................................................................4 2  
2. 1. 2.  
Ke y Sec o n dar y O bjecti ves  ..............................................................................................4 2  
2. 1. 3.  
Ot her Sec o n d ar y O bjecti ves  ............................................................................................4 2  
2. 1. 4.  
E x pl orat or y O bjecti ves  ....................................................................................................4 2  
2. 2.  
St u d y H y p ot hesis  .............................................................................................................4 3  
2. 3.  
St u d y E n d p oi nts  ...............................................................................................................4 3  
2. 3. 1.  
Pri mar y Efficac y E n d p oi nt  ..............................................................................................4 3  
2. 3. 2.  
Ke y Sec o n dar y Effi cac y E n d p oi nts  .................................................................................4 3  
2. 3. 3.  
Ot her Sec o n d ar y Efficac y E n d p oi nts  ..............................................................................4 3  
2. 3. 4.  
E x pl orat or y Effi cac y E n d p oi nt s ......................................................................................4 3  
2. 3. 5.  
Healt h Ec o n o mic a n d O utc o mes Researc h E n d p oi nts  ....................................................4 4  
2. 3. 6.  
P har mac o ki netic/ Bi o mar ker E n d p oi nts  ...........................................................................4 4  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 9  
2. 3. 6. 1.  P har mac o ki netic E n d p oi nts  .............................................................................................4 4  
2. 3. 6. 2.  Bi o mar ker E n d p oi nts  .......................................................................................................4 4  
2. 3. 7.  
Safet y E n d p oi nts  ..............................................................................................................4 4  
3.  
S T U D Y D E SI G N  ............................................................................................................4 5  
3. 1.  
O ver all Desi g n .................................................................................................................4 5  
3. 2.  
Disc ussi o n of St u d y Desi g n  .............................................................................................4 6  
3. 2. 1.  
D urati o n of t he St u d y  ......................................................................................................4 7  
3. 2. 2.  
D urati o n of S u bject Parti ci pati o n  ....................................................................................4 7  
3. 2. 3.  
Defi niti o n of t he E n d of t h e St u d y ..................................................................................4 7  
4.  
S T U D Y P O P U L A TI O N  ..................................................................................................4 8  
4. 1.  
I n cl usi o n Criteria .............................................................................................................4 8  
4. 2.  
E x cl usi o n Criteria  ............................................................................................................5 1  
4. 3.  
S u bject Re place me nt  .......................................................................................................5 3  
4. 4.  
S u bject Re -scree ni n g Pr oce d ures ....................................................................................5 3  
5.  
S T U D Y T R E A T M E N T S  ................................................................................................5 4  
5. 1.  
Assi g ni n g S u bjects t o Treat me nts a n d Bli n di n g  .............................................................5 4  
5. 1. 1.  
Treat me nt Gr o u ps  ............................................................................................................5 4  
5. 1. 2.  
Met h o d of Treat me nt All ocati o n  .....................................................................................5 4  
5. 1. 3.  
Bli n di n g  ...........................................................................................................................5 4  
5. 1. 4.  
E mer ge nc y U n b li n di n g Pr oce d ure  ..................................................................................5 5  
5. 2.  
St u d y Dr u g  .......................................................................................................................5 5  
5. 2. 1.  
Descri pti o n  ......................................................................................................................5 5  
5. 2. 2.  
La b eli n g a n d Pac k a gi n g  ..................................................................................................5 5  
5. 2. 3.  
Pre parati o n  .......................................................................................................................5 5  
5. 2. 4.  
A d mi nistrati o n  .................................................................................................................5 5  
5. 2. 5.  
St ora ge  .............................................................................................................................5 6  
5. 2. 6.  
Dr u g Acc o u nta bilit y  ........................................................................................................5 6  
5. 3.  
C o ntr ol Treat me nt  ...........................................................................................................5 6  
5. 4.  
G ui deli nes f or D ose M o dificati o n  ...................................................................................5 7  
5. 4. 1.  
D ose I nterr u pti o ns a n d Re d ucti o ns  .................................................................................5 7  
5. 4. 1. 1.  D ose I nterr u pti o ns a n d Re d ucti o ns f or T -D X d  ...............................................................5 8  
5. 4. 1. 2.  D ose I nterr u pti o ns a n d Re d ucti o ns f or P h ysi cia n’s C h oice  ............................................6 6  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 0  
5. 5.  
Met h o d of Assessi n g Treat me nt C o m plia nce  ..................................................................6 6  
5. 6.  
Pri or a n d C o nc o mita nt Me dicati o ns a n d Treat me nts  ......................................................6 6  
5. 6. 1.  
Pr o hi bite d Me dicati o ns a n d Treat me nts  ..........................................................................6 7  
5. 7.  
St u d y Dr u g Disc o nti n uati o n a n d Disc o nti n uati o n fr o m t he St u d y  ..................................6 8  
5. 7. 1.  
Disc o nti n uati o n of St u d y Dr u g  ........................................................................................6 8  
5. 7. 2.  
S u bject Wit h dra wal/ Disc o nti n uati o n fr o m t he St u d y  ......................................................6 9  
6.  
S T U D Y P R O C E D U R E S  .................................................................................................7 1  
6. 1.  
Tiss ue Scree ni n g  ..............................................................................................................7 1  
6. 2.  
Scree ni n g  .........................................................................................................................7 2  
6. 3.  
Ra n d o mizati o n  .................................................................................................................7 4  
6. 4.  
Treat me nt Peri o d  .............................................................................................................7 4  
6. 4. 1.  
C ycle 1 t o 4 a n d S u bse q u e nt C ycles  ................................................................................7 4  
6. 4. 1. 1.  Bet wee n -3 D a ys Bef ore D osi n g T hr o u g h I m m e diatel y Bef ore D osi n g ( All 
C ycles)  .............................................................................................................................7 4  
6. 4. 1. 2.  Da y 1 Bef ore D osi n g ( All C ycles, U nless Ot h er wise N ote d)  .........................................7 5  
6. 4. 1. 3.  Da y  1 D osi n g a n d E n d of D osi n g ( All C ycles, U nl ess Ot her wise N ot e d)  ......................7 6  
6. 4. 1. 4.  Da y 8 ( ± 1 da y) a n d D a y 1 5 ( ± 1 da y) ( C ycle 1 O nl y)  ......................................................7 7  
6. 4. 2.  
E ver y 4 C ycles ( ± 7 d a ys) After C ycle 1  ..........................................................................7 7  
6. 4. 3.  
E ver y 6 Wee ks ( ± 7 da ys)  ................................................................................................7 7  
6. 5.  
E n d of St u d y Treat me nt  ...................................................................................................7 8  
6. 6.  
F oll o w -u p  ........................................................................................................................7 9  
6. 6. 1.  
4 0 -Da y ( + 7 da ys) F oll o w -u p  ...........................................................................................7 9  
6. 6. 2.  
L o n g -t er m/ S ur vi val F oll o w-u p  ........................................................................................8 0  
7.  
E F FI C A C Y A S S E S S M E N T S  .........................................................................................8 2  
7. 1.  
Assess me nts f or Effi cac y E n d p oi nts  ...............................................................................8 2  
7. 1. 1.  
Pri mar y Efficac y E n d p oi nt  ..............................................................................................8 2  
7. 1. 2.  
Ke y Sec o n dar y Effi cac y E n d p oi nts  .................................................................................8 2  
7. 1. 3.  
Ot her Sec o n d ar y Efficac y E n d p oi nt s ..............................................................................8 2  
7. 1. 4.  
E x pl orat or y Effi cac y E n d p oi nts  ......................................................................................8 2  
7. 2.  
A p pr o priate n ess of Selecte d Efficac y Assess me nts  ........................................................8 3  
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S  ...........................8 5  
8. 1.  
P har mac o ki netic Assess me nt s .........................................................................................8 5  
8. 2.  
P har mac o d y na mic Ass ess me nt (s) ...................................................................................8 5  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 1  
8. 3.  
Bi o mar ker Assess me nts  ...................................................................................................8 5  
8. 3. 1.  
T u m or Tiss ue Sa m pli n g  ..................................................................................................8 6  
8. 3. 2.  
Bl o o d Sa m pli n g  ...............................................................................................................8 6  
8. 3. 3.  
A d diti o nal Bi o mar ker Assess me nts  ................................................................................8 6  
8. 3. 4.  
Discl os ure of t he Res ults of A d diti o nal Bi o mar ker Assess me nts  ...................................8 6  
8. 4.  
I m m u n o ge nicit y ...............................................................................................................8 6  
8. 5.  
P har mac o ge n o mic A n al ysis  ............................................................................................8 7  
8. 5. 1.  
Ge n o mic or Ge netic Ba n ki n g a n d A nal ysis  ....................................................................8 7  
8. 5. 1. 1.  Discl os ure of t he Res ults of Ge n o mic or Ge netic A nal ysis  ............................................8 7  
8. 5. 1. 2.  St ora ge a n d Dis p osal of S peci me ns f or Ge n o mic or Ge netic A nal ysis  ..........................8 7  
9.  
S A F E T Y E V A L U A TI O N A N D R E P O R TI N G  ..............................................................8 8  
9. 1.  
Assess me nt of Safet y E n d p oi nt(s)  ...................................................................................8 8  
9. 2.  
A d verse E v e nt C ollecti o n a n d Re p orti n g  ........................................................................8 8  
9. 3.  
A d verse E v e nts of S peci al I nt erest  ..................................................................................8 9  
9. 3. 1.  
I nterstitial L u n g Disease/ P ne u m o nitis .............................................................................8 9  
9. 3. 1. 1.  Cli nical S u m mar y  ............................................................................................................8 9  
9. 3. 1. 2.  Ma na ge me nt G ui da n ce  ....................................................................................................8 9  
9. 3. 1. 3.  I nterstitial L u n g Disease A dj u dicati o n C o m mittee .........................................................9 0  
9. 3. 2.  
Left Ve ntric ul ar Eje cti o n Fracti o n Decreas e  ...................................................................9 0  
9. 3. 2. 1.  Cli nical S u m mar y  ............................................................................................................9 0  
9. 3. 2. 2.  Ma na ge me nt G ui da n ce  ....................................................................................................9 0  
9. 4.  
A d verse E v e nt  .................................................................................................................9 0  
9. 4. 1.  
Defi niti o n of A d vers e E v e nt  ............................................................................................9 0  
9. 4. 2.  
Seri o us A d verse E v e nt  ....................................................................................................9 1  
9. 4. 3.  
Gra de Assess me nt  ...........................................................................................................9 1  
9. 4. 4.  
Ca usalit y Assess me nt  ......................................................................................................9 2  
9. 4. 5.  
Acti o n Ta ke n Re gar di n g St u d y Dr u g (s) ..........................................................................9 2  
9. 4. 6.  
Ot her Acti o n Ta k e n f or E ve nt  .........................................................................................9 3  
9. 4. 7.  
A d verse E v e nt O utc o me  ..................................................................................................9 3  
9. 5.  
A d verse E v e n ts a n d A d v erse E ve nt of S pecial I nt erest Re p orti n g– Pr oce d ures 
F or I n v esti gat ors  ..............................................................................................................9 3  
9. 6.  
N otif yi n g Re g ulat or y A ut h orities, I n vesti gat ors, a n d I nstit uti o nal Re vie w 
B oar d/I nstit uti o nal Et hics C o m mittee  .............................................................................9 5  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 2  
9. 7.  
E x p os ure i n Uter o D uri n g Cli nical St u dies  .....................................................................9 5  
9. 8.  
Cli nical La b orat or y E val uati o ns  ......................................................................................9 5  
9. 9.  
Vital Si g ns  .......................................................................................................................9 6  
9. 1 0.  
Electr ocar di o gra ms  ..........................................................................................................9 6  
9. 1 1.  
P h ysical E x a mi nati o ns  .....................................................................................................9 7  
9. 1 2.  
Ot her E x a mi nati o ns  .........................................................................................................9 7  
9. 1 2. 1.  Car diac Assess me nts  .......................................................................................................9 7  
9. 1 2. 2.  P ul m o nar y Assess me nts  ..................................................................................................9 7  
1 0.  
O T H E R A S S E S S M E N T S  ...............................................................................................9 8  
1 0. 1.  
Patie nt Re p orte d O utc o m es  .............................................................................................9 8  
1 0. 1. 1.  E ur o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naires C 3 0 a n d B R 4 5  ........................................................................................9 8  
1 0. 1. 2.  E ur o Q o L Fi v e Di me nsi o ns Fi ve Le v els Patie nt Re p orte d O utc o me 
Q uesti o n naire  ...................................................................................................................9 9  
1 0. 2.  
Healt h -relate d Q o L E n d p oi nts .........................................................................................9 9  
1 0. 2. 1.  E ur o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire E n d p oi nts  .................................................................................................9 9  
1 0. 2. 2.  E ur o Q o L Fi v e Di me nsi o ns Fi ve Le v els  E n d p oi nts  .......................................................1 0 0  
1 0. 3.  
P har mac oec o n o mic Assess me nts  ..................................................................................1 0 0  
1 0. 3. 1.  H os pitalizati o n -Relate d E n d p oi nt  .................................................................................1 0 0  
1 1.  
S T A TI S TI C A L M E T H O D S  .........................................................................................1 0 1  
1 1. 1.  
Ge neral Statistical C o nsi derati o ns  .................................................................................1 0 1  
1 1. 2.  
A nal ysis Sets  .................................................................................................................1 0 1  
1 1. 2. 1.  F ull A nal ysis Set  ............................................................................................................1 0 1  
1 1. 2. 2.  Safet y A nal ysis Set  ........................................................................................................1 0 1  
1 1. 2. 3.  Per -pr ot oc ol A n al ysis Set  ..............................................................................................1 0 1  
1 1. 2. 4.  P har mac o ki netic A n al ysis Set  .......................................................................................1 0 1  
1 1. 3.  
St u d y P o p ulati o n Dat a  ...................................................................................................1 0 2  
1 1. 4.  
Efficac y A nal yses  ..........................................................................................................1 0 2  
1 1. 4. 1.  Pri mar y Efficac y A nal ys es  ............................................................................................1 0 2  
1 1. 4. 2.  Ke y Sec o n dar y Effi cac y A nal ys es  ................................................................................1 0 2  
1 1. 4. 3.  Ot her Sec o n d ar y Efficac y A n al ys es  ..............................................................................1 0 3  
1 1. 4. 4.  A nal ys es of Healt h Ec o n o mic a n d O utc o mes Researc h E n d p oi nts  ..............................1 0 3  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 3  
1 1. 4. 4. 1.  E ur o Q o L Fi v e Di me nsi o ns Fi ve Le v els  ........................................................................1 0 3  
1 1. 4. 4. 2.  E ur o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire C 3 0 a n d B R 4 5  ........................................................................................1 0 3  
1 1 . 4. 4. 3. H os pitalizati o n -Relate d E n d p oi nts  ................................................................................1 0 4  
1 1. 4. 5.  E x pl orat or y Effi cac y A n al yses  ......................................................................................1 0 4  
1 1. 4. 5. 1.  S u b gr o u p A n al ys es  ........................................................................................................1 0 4  
1 1. 4. 5. 2.  A nal ys es of E x pl orat or y Efficac y E n d p oi nts  ................................................................1 0 4  
1 1. 4. 6.  P har mac o ki netic a n d P har mac o d y na mic A nal yses  .......................................................1 0 5  
1 1. 4. 6. 1.  P har mac o ki netic A n al ys es  .............................................................................................1 0 5  
1 1. 4. 6. 2.  P har mac o d y na mic A n al yses  ..........................................................................................1 0 5  
1 1. 4. 7.  Bi o mar ker A nal yses  ......................................................................................................1 0 5  
1 1. 5.  
Safet y A nal yses  .............................................................................................................1 0 5  
1 1. 5. 1.  A d verse E v e nt A nal yses  ................................................................................................1 0 6  
1 1. 5. 2.  Cli nical La b orat or y E val uati o n A nal ys es  ......................................................................1 0 6  
1 1. 5. 3.  Vital Si g n A nal yses  .......................................................................................................1 0 6  
1 1. 5. 4.  Electr ocar di o gra m A n al yses  ..........................................................................................1 0 6  
1 1. 5. 5.  P h ysical E x a mi nati o n A nal yses  ....................................................................................1 0 7  
1 1. 5. 6.  C o nc o mita nt Me dicati o n A nal ys es  ................................................................................1 0 7  
1 1. 5. 7.  I m m u n o ge nicit y ( A nti-Dr u g A nti b o d y) A nal yses  .........................................................1 0 7  
1 1. 5. 8.  Ot her Safet y A n al yses  ...................................................................................................1 0 7  
1 1. 6.  
I nteri m A nal yses ............................................................................................................1 0 7  
1 1. 7.  
Sa m ple Siz e Deter mi nati o n  ...........................................................................................1 0 8  
1 1. 8.  
Statistical A nal ysis Pr ocess  ...........................................................................................1 0 9  
1 2.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  ................................................1 1 0  
1 2. 1.  
M o nit ori n g a n d I ns p ecti o ns  ...........................................................................................1 1 0  
1 2. 2.  
Data C ollecti o n  ..............................................................................................................1 1 0  
1 2. 3.  
Data Ma na ge me nt  ..........................................................................................................1 1 1  
1 2. 4.  
St u d y D oc u me ntati o n a n d St ora ge  ................................................................................1 1 1  
1 2. 5.  
Rec or d Kee pi n g  .............................................................................................................1 1 2  
1 3.  
FI N A N CI N G A N D I N S U R A N C E  ................................................................................1 1 3  
1 3. 1.  
Fi na nces  .........................................................................................................................1 1 3  
1 3. 2.  
Rei m b urse me n t, I n de m nit y, a n d I ns ura n ce ...................................................................1 1 3  
1 4.  
P U B LI C A TI O N P O LI C Y  .............................................................................................1 1 4  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 4  
1 5.  
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E  I N F O R M A TI O N .................................1 1 5  
1 5. 1.  
C o m plia nce State me nt, Et hics, a n d Re g ul at or y C o m plia nce  ........................................1 1 5  
1 5. 2.  
S u bject C o nfi de ntialit y  ..................................................................................................1 1 5  
1 5 . 3. 
I nf or me d C o nse nt ..........................................................................................................1 1 5  
1 5. 4.  
Re g ulat or y C o m plia nce  .................................................................................................1 1 6  
1 5. 5.  
Pr ot oc ol De viati o ns  .......................................................................................................1 1 6  
1 5. 6.  
S u p pl y of Ne w I nf or m ati o n Affecti n g t he C o n d uct of t he St u d y  .................................1 1 7  
1 5. 7.  
Pr ot oc ol A me n d me nts  ...................................................................................................1 1 7  
1 5. 8.  
St u d y Ter mi nati o n  .........................................................................................................1 1 8  
1 5. 9.  
Data M o nit ori n g C o m mittee  ..........................................................................................1 1 8  
1 5. 1 0.  
A d dress List  ...................................................................................................................1 1 8  
1 6.  
R E F E R E N C E S  ..............................................................................................................1 1 9  
1 7.  
A P P E N DI C E S  ...............................................................................................................1 2 3  
1 7. 1.  
Sc he d ule of E ve nts  ........................................................................................................1 2 3  
1 7. 2.  
C oc kcr oft -G a ult E q uati o n  .............................................................................................1 3 2  
1 7. 3.  
Ne w Y or k Heart Ass ociati o n  .........................................................................................1 3 3  
1 7. 4.  
Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) Perf or ma nce Stat us  ............................1 3 4  
1 7. 5.  
M o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors ( versi o n 1. 1) ........................1 3 5  
1 7. 5. 1.  Meas ura bilit y of T u m or at Bas eli ne  ..............................................................................1 3 5  
1 7. 5. 1. 1.  Defi niti o ns  .....................................................................................................................1 3 5  
1 7. 5. 1. 2.  S pecificati o ns b y Met h o ds of Meas ure me nt s ................................................................1 3 6  
1 7. 5. 2.  T u m or Res p o nse E val uati o n  ..........................................................................................1 3 6  
1 7. 5. 2. 1.  Assess me nt of O verall T u m or B ur de n a n d Meas ura ble Dise ase  ..................................1 3 6  
1 7. 5. 2. 2.  Baseli ne D oc u me ntati o n of ‘ Tar get’ a n d ‘ N o ntar get’ Lesi o ns  .....................................1 3 6  
1 7. 5. 2. 3.  Res p o nse Crite ria ...........................................................................................................1 3 7  
1 7. 5. 2. 4.  E val uati o n of Tar get Lesi o ns  .........................................................................................1 3 7  
1 7. 5. 2. 5.  E val uati o n of N o n -tar get Lesi o ns ..................................................................................1 3 8  
1 7. 5. 2. 6.  Ne w Lesi o ns  ..................................................................................................................1 3 9  
1 7. 5. 2. 7.  E val uati o n of Best O verall Res p o nse  ............................................................................1 4 0  
1 7. 5. 2. 8.  Fre q u e nc y of T u m or Re -e val uati o n  ...............................................................................1 4 1  
1 7. 6.  
E ur o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire  C 3 0 a n d B R 4 5  ........................................................................................1 4 3  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 5  
1 7. 6. 1.  E u r o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire  C 3 0 ( versi o n 3. 0)  ....................................................................................1 4 3  
1 7. 6. 2.  E ur o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire  B R 4 5  ......................................................................................................1 4 5  
1 7. 7.  
E ur o Q o L Fi v e Di me nsi o ns Fi ve Le v els  ........................................................................1 4 8  
1 7. 8.  
I nstr u cti o ns Relate d t o C or o na vir us Diseas e 2 0 1 9 ( C O VI D-1 9)  ..................................1 5 1  
C O VI D -1 9 Ser u m Bi o mar ker Assess me nt(s)  ..............................................................................1 5 2  
1 7. 9.  
C o u ntr y -S pecific Pr ot oc ol Te xt  .....................................................................................1 5 3  
1 7. 9. 1.  S we de n O nl y  .................................................................................................................1 5 3  
1 7. 9. 2.  P ort u gal O nl y  .................................................................................................................1 5 4  
1 7. 9. 3.  Ger ma n y O nl y  ...............................................................................................................1 5 6  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 6  
LI S T O F T A B L E S  
Ta ble  1. 1:  Efficac y Res ults i n H E R 2 -p ositi ve a n d H E R 2 -l o w Breast Ca ncer S u bjects 
fr o m D S 8 2 0 1-A -J 1 0 1 ( 5. 4 m g/ k g or 6. 4 mg/ k g T -D X d) as of 0 1  Fe b 2 0 1 9  ..............3 6  
Ta ble  1. 2:  Mea n P har mac o ki netic Para meters of T -D X d ( ± Sta n dar d De vi ati o n)  ......................3 9  
Ta ble  1. 3:  Mea n P har mac o ki netic Para meters of T otal A nti b o d y ( ± Sta n dar d De viati o n)  .........3 9  
Ta ble  1. 4:  Mea n P har mac o ki netic Para meters of M A A A -1 1 8 1a ( ± Sta n dar d De viati o n)  ..........4 0  
Ta ble  5. 1:  D ose Re gi me ns f or P h ysicia n’s C h oice per t he N C C N G ui deli nes 1 ..........................5 7  
Ta ble  5. 2:  D ose Re d ucti o n Le vels of T -D X d  ..............................................................................5 8  
Ta ble  5. 3:  D ose M o dificati o n f or T -D X d  ....................................................................................5 9  
Ta ble  8. 1:  Bl o o d Sa m pli n g f or P h ar mac o ki netic A nal ysis  ..........................................................8 5  
Ta ble  1 1. 1:  St o p pi n g B o u n daries at O S I nteri m a n d Fi nal A nal yses  ..........................................1 0 8  
Ta ble  1 7. 1 : Sc he d ule of E ve nts –  Tiss ue Scree ni n g a n d Scree ni n g Peri o d  .................................1 2 4  
Ta ble  1 7. 2:  Sc he d ule of E ve nts –  Treat me nt a n d F oll o w -u p Peri o d  ...........................................1 2 7  
Ta ble  1 7. 3:  Ne w Y or k Heart Ass ociati o n F u ncti o nal Classificati o n  ...........................................1 3 3  
Ta ble  1 7. 4:  Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us Scale Gra d e 
Descri pti o n  ................................................................................................................1 3 4  
Ta ble  1 7. 5:  Ti me P oi nt Res p o nse: S u bjects wit h Tar get ( +/ – N o n -tar get) Dis ease .....................1 4 0  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 7  
LI S T O F FI G U R E S  
Fi g ure  1. 1:  A nti -t u m or Effect of T-D X d A gai nst Patie nt -deri v e d Breast Ca ncer 
Xe n o graft i n N u de Mice: S T 9 1 0 ( H E R 2 I H C 1 +, FI S H Ne gati ve)  ...........................3 4  
Fi g ure  3. 1:  St u d y Desi g n Sc he ma  .................................................................................................4 6  
 
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 8  
LI S T O F A B B R E VI A TI O N S  
A B B R E VI A TI O N  
D E FI NI TI O N  
A C  
A dj u dicati o n C o m mittee  
A D A  
a nti -dr u g a nti b o d y  
A D C  
a nti b o d y dr u g c o nj u gate  
A E  
a d verse e ve nt 
A E SI  
a d verse e ve nt of s pecial i nterest  
A L T  
ala ni ne a mi n otra nsferase  
A S C O -C A P  
A merica n S ociet y of Cli nical O nc ol o g y –  C olle ge of A merica n Pat h ol o gists  
A S T  
as partate a mi n otra nsferase  
A U C  
area u n der t he plas ma/ser u m c o nce ntrati o n -ti me c ur ve 
A U C 0 -2 1 d 
area u n der t he plas ma/ser u m c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 
2 1  da ys  
A U C ∞ 
area u n der t he plas ma/ser u m c o nce ntrati o n -ti me c ur ve fr o m ti me 0 
e xtra p olate d t o i nfi nit y 
BI  
bef ore i nf usi o n or d osi n g  
BI C R  
bli n de d i n de pe n de nt ce ntral re vie w  
C B R  
cli nical be nefit rate   
C D K  
c ycli n-de pe n de nt ki nase  
cf D N A 
cell free de o x yri b o n ucleic aci d  
C H O  
C hi nese ha mster o var y  
CI  
c o nfi de nce i nter val  
C ma x  
ma xi m u m plas ma/ser u m c o nce ntrati o n  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C O VI D -1 9  
c or o na vir us disease 2 0 1 9  
C R  
c o m plete res p o nse 
C R O  
c o ntract researc h or ga nizati o n  
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 Criteria f or A d verse E ve nts  
C Y P  
c yt oc hr o me P 4 5 0 
D C R  
disease c o ntr ol rate  
D M C  
d ata m o nit ori n g co m mittee  
D N A  
de o x yri b o n ucleic aci d  
D o R  
d urati o n of res p o nse  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 9  
A B B R E VI A TI O N  
D E FI NI TI O N  
E C G  
electr ocar di o gra m  
E C H O  
ec h ocar di o gra m 
E C O G P S  
Easter n C o o perati ve O nc ol o g y Gr o u p perf or ma nce stat us  
e C R F 
electr o nic case re p ort f or m 
E D C  
electr o nic data ca pt ure  
EI U  
E x p os ure i n U ter o  
E OI  
e n d of i nf usi o n  or d osi n g  
E O R T C Q L Q  
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 
q uesti o n naire(s)  
E O T  
en d of treat me nt 
E Q -5 D -5 L  
E ur o Q ol  5  di me nsi o ns  5 le vels  [of se verit y ] 
F A S  
F ull A nal ysis Set  
F N A  
Fi ne Nee dle As pirate  
G C P  
G o o d Cli nical Practice  
G EJ  
gastr oes o p ha geal j u ncti o n  
H C V  
h e patitis C vir us 
H E O R  
H ealt h E c o n o mics a n d O utc o mes R esearc h  
H E R 2  
h u ma n e pi der mal gr o wt h fact or rece pt or 2  
H E R 2 E C D  
e xtracell ular d o mai n of H E R 2  
HI V  
h u ma n i m m u n o deficie nc y vir us  
H R  
h or m o ne rece pt or  
H R T  
h or m o ne re place me nt t hera p y 
I B 
I n vesti gat or’s Br oc h ure 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I C U 
i nte nsi ve care u nit 
I E C 
I nstit uti o nal Et hics C o m mittee 
I H C 
i m m u n o hist oc he mistr y 
I L D 
i nterstitial l u n g disease 
I R B 
I nstit uti o nal Re vie w B oar d  
I S H 
i n sit u h y bri dizati o n 
I U O 
i n vesti gati o nal use o nl y 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 0  
A B B R E VI A TI O N  
D E FI NI TI O N  
I V 
i ntra ve n o us(l y) 
IX R S  
I nteracti ve We b/ V oice Res p o nse S yste m 
L V E F  
left ve ntric ular ejecti o n fracti o n 
L y o -D P  
l y o p hilize d p o w der 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m R E CI S T  
m o difie d Res p o nse E val uati o n Criteria i n S oli d T u m ors ( versi o n 1. 1)  
M RI  
ma g netic res o na nce i ma gi n g  
M U G A  
m ulti gate d ac q uisiti o n  
N C C N  
Nati o nal C o m pre he nsi ve Ca ncer Net w or k  
N CI  
Nati o nal Ca ncer I nstit ute  
N E  
n ot e val ua ble  
N S A B P  
Nati o nal S ur gical  A dj u va nt Breast a n d B o wel Pr oject  
N S AI D  
n o nster oi dal a nti -i nfla m mat or y dr u g 
O A T P  
or ga nic a ni o n tra ns p orti n g p ol y pe pti de  
O R R  
o bj ecti ve res p o nse rate  
O S  
o verall s ur vi val  
P C R  
p ol y merase c hai n reacti o n  
P D  
pr o gressi ve disease  
P F S  
pr o gressi o n -free s ur vi val 
P F S 2  
p r o gressi o n-free s ur vi val o n t he ne xt li ne of t hera p y 
P K  
p har mac o ki netic  
p o p -P K  
p o p ulati o n p har mac o ki netics  
P P S  
Per -pr ot oc ol A nal ysis Set  
P R  
partial res p o nse  
P R O  
patie nt re p orte d o utc o me  
P T  
preferre d ter m  
Q o L  
q ualit y of life  
Q T c  
c orrecte d Q T i nter val  
Q T c F  
Q T i nter vals c orrecte d f or heart rate b y Fri dericia’s f or m ula  
R T -P C R  
real-ti me p ol y merase c hai n reacti o n 
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 1  
A B B R E VI A TI O N  
D E FI NI TI O N  
S A V E R  
Seri o us A d verse E ve nt Re p ort  
S D  
sta ble disease 
SI D  
s u bj ect i de ntificati o n 
S M Q  
Sta n dar dise d Me d D R A Q uer y  
S O P  
sta n dar d o perati n g pr oce d ure 
S p O 2  
peri p heral o x y ge n sat urati o n  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
t½  
ter mi nal eli mi nati o n half-life 
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 nt  
T ma x  
ti me t o reac h ma xi m u m plas ma/ser u m c o nce ntrati o n ( Cma x ) 
T P C  
treat me nt of p h ysicia n’s c h oice 
U L N  
u p per li mit of n or mal  
U S  
U nite d States  
V A S  
vis ual a nal o g ue  scale 
V ss 
v ol u me of distri b uti o n at stea d y state  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 2  
1.  
I N T R O D U C TI O N 
1. 1.  
B ac k gr o u n d  
Breast ca n cer is a life -t hr eate ni n g diseas e a n d re mai ns t he m ost c o m m o n ca ncer a n d t h e first 
lea di n g ca use of ca ncer m ortalit y i n w o me n gl o b all y.2  E vi de nce o n t h e gl o bal b ur de n of 
metastatic breast ca ncer is li mite d, a n d statistics o n metastatic rec urre n ces, w hic h acc o u nt f or t he 
lar gest pr o p orti o n of met astatic breast ca ncer pati e nts, are n ot r o uti nel y c ollecte d.  T he f oll o wi n g 
e vi de nce t h eref ore relates t o esti mate d i nci de nce, m ortalit y, a n d pre vale nce rates f or breast 
ca ncer cases o verall.  
Breast ca n cer h as a hi g h er i n ci d e n ce rat e i n w o me n ( 4 3. 3 p er 1 0 0, 0 0 0) t ha n a n y ot h er ca n cer.  
T h ere w ere a n esti m at e d 1, 6 7 6, 6 3 3 n e w cas es ( 2 5 % of all ca n cers i n w o m e n) a n d 5 2 1, 8 1 7 
breast ca n cer d eat hs ( 1 5 % of all ca n cer d eat hs i n w o m e n) i n 2 0 1 2.  I n t er ms of pre v al e n ce 
rat es, acc or di n g t o t h e W orl d H ealt h Or ga ni z ati o n, breas t ca n cer is t h e m ost pre v al e nt ca n cer, 
wit h 6, 2 5 5, 3 9 1 s ur vi v ors di a g n os e d wit hi n t h e pre vi o us 5  years. 2 
I n a p pr o xi matel y 2 0 % of breast c a ncer cas es, o vere x pressi o n of h u ma n e pi der mal gr o wt h f act or 
rece pt or 2 ( H E R 2) occ urs.  Se veral a nti-H E R 2 tar get e d t hera pi es s uc h as tr ast uz u ma b, 
pert uz u ma b, a d o -trast uz u ma b e mta nsi ne ( T-D M 1), a n d la pati ni b ha ve i m pr o ve d o utc o mes i n 
H E R 2 -p ositi ve breast c a ncer patie nts.  O n t h e ot her ha n d, c urre nt preferre d Nati o nal 
C o m pre he nsi ve Ca ncer Net w or k ( N C C N) tr eat m e nt g ui deli nes f or H R -p ositi ve, H E R 2 -ne gati ve 
breast c a ncer are f or 3 r o u n ds of e n d ocri n e t hera p y wit h t he i ncl usi o n of a C D K  4/ 6 i n hi bit or.  
O nce a t u m or is e n d o cri n e refract or y, si n gle -a ge nt c he m ot hera pi es are rec o m me n de d. 1 
A m o n g H E R 2 -n e gati ve p atie nts, H E R 2 -l o w (i m m u n o hist oc he mistr y [I H C] 2 +, i n sit u 
h y bri dizati o n  [I S H]- or I H C 1 +) t u m ors c o m prise a p pr o xi matel y 4 5 % of all breast c a ncers a n d 
treat me nt o pti o ns f or H R-p ositi ve, H E R 2 -l o w metastatic breast ca ncer f oll o w H R-p ositi ve, 
H E R 2 -ne gati ve p o p ulati o n, t heref ore re mai n li mite d, wit h n o tar gete d t hera p y s p ecificall y 
a p pr ove d f or e n d o cri ne refract or y diseas e.  I n t his setti n g, rec o m me n de d tr eat me nt o pti o ns 
i ncl u de si n gle-a ge nt c he m ot hera pies wit h li mite d efficac y.  D ue t o t he lac k of clear s u peri orit y, 
n o s pecific a ge nt is c urre ntl y e n d ors e d b y t he N C C N g ui deli nes. 1  Of n ote, eri b uli n is t he m ost 
rece nt c he m ot hera p y a p pr o ve d f or t his patie nt p o p ulati o n.  A p pr o val was b ase d o n res ults of t he 
E M B R A C E trial i n w hic h s u bjects  pre vi o usl y tr eate d wit h 2 t o 5 pri or c he m ot hera p y re gi me ns 
were ra n d o mize d 2: 1 t o eri b uli n vers us treat me nt of p h ysici a n’s c h oice.  T he m ost c o m m o n 
a ge nts c h ose n as c o m parat ors were vi n or el bi ne, ge mcita bi ne, ca p ecita bi ne, ta xa nes, a n d 
a nt hrac ycli n es.  I n t his trial, effic ac y of eri b uli n vers us p h ysicia n’s c h oice s h o we d a n o bjecti ve 
res p o nse rate ( O R R) of 1 2 % vers us 5 %, pr o gressi o n-free s ur vi val ( P F S) 3. 7 vers us 2. 2  m o nt hs , 
a n d o verall s ur v i val ( O S) of 1 3. 1 vers us 1 0. 6 m o nt hs .3  I n a n earlier li ne s etti n g of 1 t o 3 pri or 
c he m ot hera p y re gi me ns, a P hase 3 trial c o m pari n g eri b uli n t o ca pecita bi n e s h o we d O R R 1 1 % 
vers us 1 1. 5 %, P F S of 4. 2 vers us 4. 1 m o nt hs , a n d O S of 1 5. 9 vers us 1 4. 5 m ont hs .4  Ot her trials 
ha ve s h o w n si milar res ults f or si n gle -a ge nt c he m ot hera pies i n t his setti n g.  T heref ore, a hi g h l y 
u n met me dical nee d e xists a n d ne w treat me nt o pti o ns nee d t o  be de v el o pe d t o i m pr o ve o utc o mes 
f or patie nts wit h disease pr o gressi o n f or H E R 2-l o w breast c a ncer.  
Trast uz u ma b der u xteca n  ( T-D X d ; D S-8 2 0 1a)  is a n a nti b o d y-dr u g c o nj u gat e  ( A D C) c o m p ose d of 
a n a nti -H E R 2 a nti b o d y c o nj u gate d t o a dr u g -li n ker carr yi n g a t o p ois o meras e I pa yl oa d. T -D X d  
was st u die d i n t he P hase 1  D S 8 2 0 1 -A -J 1 0 1 st u d y f or H E R 2 -e x pressi n g s oli d t u m ors a n d St u d y  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 4  
1. 1. 1. 4.  
C o m p ar at ors ( P h ysici a n’s C h oice)  
S u bjec ts e nr olle d i n t his trial ma y b e ra n d o mize d t o t he treat me nt of p h ysici a n’s c h oice ar m.  
T he treati n g p h ysicia n will s pecif y c h oice of c o m p arat or pri or t o ra n d o mizati o n b y selecti n g 1 of 
t he f oll o wi n g o pti o ns: 
 Ca pecita bi ne  
 Eri b uli n  
 Ge mcita bi ne  
 Paclita x el  
 N a b-paclita x el  
T he descri pti o n of t hes e ca n be f o u n d wit hi n t heir  la bel a p pr o ve d i n t he c o u ntr y of dr u g 
a d mi nistrati o n .  Please refer t o t he la bel a p pr o ve d i n t he c o u ntr y of dr u g a d mi nistrati o n or t he 
N C C N g ui deli nes 1 (see T a ble  5 .1 ) f or t h e d osi n g re gi me ns. 
1. 1. 1. 5.  
N o ncli nic al St u dies of  T -D X d  
T he p har mac ol o g y, safet y p har mac ol o g y, p har mac o ki netics ( P K), a n d t o xic ol o g y of T -D X d  h a ve 
bee n e x a mi ne d i n n o ncli nical st u dies.  O ne e x a m ple of n o ncli nical p har mac ol o g y st u d y res ults 
i n dicates t hat T -D X d  i n hi bits t u m or gr o wt h i n patie nt-deri ve d H E R 2 -l o w t u m or xe n o graft t hat is 
i nse nsiti ve t o T-D M 1.  
Fi g ure  1 .1 : 
A nti -t u m o r Effect of T -D X d  A g ai nst P atie nt -deri ve d Bre ast C a ncer 
Xe n o gr aft i n N u de Mice: S T 9 1 0 ( H E R 2 I H C 1 +, FI S H N e g ati v e)  
 
FI S H = fl u oresce nce i n -sit u h y bri dizati o n; H E R 2  =  h u ma n e pit helial gr o wt h fact or 2; I H C = i m m u n o hist oc he mistr y .  
Data re prese nt t he mea n + sta n dar d err or of t he mea n ( n  =  5).  
Mice were s u bc uta ne o usl y i m pla nte d wit h S T 9 1 0 patie nt -deri ve d xe n o grafts.  T -D X d , M A A L-9 0 0 1, or T -D M 1 at 
t he d ose of 1 0 m g/ k g was a d mi nistere d o n Da y  0.  
T he t u m or v ol u me of eac h m o use was calc ulate d acc or di n g t o t he f oll o wi n g e q uati o n:  
T u m or v ol u me ( m m 3) =  0. 5 2 ×  le n gt h ×  wi dt h 2 
F or details of t hes e e x peri me nts, please see t he l atest versi o n of t he I n v esti gat or’s Br oc h ure 
(I B).9 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 5  
1. 1. 1. 6.  
Cli nic al E x perie nce  
As of 0 8 J u n 2 0 1 9, T -D X d  has bee n e v al uate d i n 1 2 c o m pa n y -s p o ns ore d cli nical st u dies ( 1 1 
m o n ot hera p y st u dies a n d 1 c o m bi nati o n t hera p y st u d y), wit h a n esti mate d 1 0 3 6  s u bjects e x p ose d 
t o at least 1 d ose of T -D X d . 9  T hree st u dies are c o m plete ( ha ve fi nalize d cli nical st u d y re p orts 
re p orti n g t he res ults f or t he st u d y pri mar y o bjecti ve), a n d 9 st u dies are o n g oi n g.  9   F or u p date d 
res ults, please refer t o t he latest versi o n of t he I B.  9  
T he T -D X d  first-i n-h u ma n st u d y ( Pr ot oc ol D S 8 2 0 1 -A -J 1 0 1) is a n o pe n-la bel, d ose fi n di n g st u d y 
t o assess t he safet y a n d t olera bilit y of T -D X d  i n s u bjects wit h a d va nce d s oli d t u m ors.  Part 1 
( d ose escalati o n) e nr olle d su bjects wit h eit her a d v a nce d breast c a ncer or gastric/ gastr o es o p ha geal 
j u ncti o n ( G EJ) a de n ocarci n o ma t hat is refract or y or i nt olera nt t o sta n dar d treat me nt, or f or w hic h 
n o sta n dar d treat me nt is a vaila ble.  Part 2 is t he e x pa nsi o n p hase a n d f oc uses o n T -D M 1 -tr eate d 
H E R 2 -o vere x pressi n g breast ca n cer, trast uz u ma b -treate d H E R 2 -o v ere x pressi n g gastric/ G EJ 
a de n ocarci n o ma, a n d H E R 2 -l o w breast c a ncer, as well as ot her H E R 2 e x pressi n g s oli d ca n cers. 
F or t he latest e nr oll me nt i n t his a n d ot her T -D X d  st u dies, please refer t o t h e latest versi o n of t he 
I B.9 
R es ults fr o m breast ca n cer s u bj ects treat e d wit h 5. 4 a n d 6. 4 m g/ k g T -D X d  acr oss P arts 1 a n d 2 
of S t u d y D S 8 2 0 1-A -J 1 0 1 d e m o nstrat e d t h at t h e m aj orit y of s u bj ects e x peri e n ce d t u m or 
s hri n k a ge a n d d ura bl e treat m e nt d urati o n . E val ua ble s u bjects f or c o nfir me d res p o nse were t h ose 
w h o ha d 2 p ost -baseli ne sca ns or disc o nti n ue d treat me nt f or a n y reas o n pri or t o sec o n d p ost-
baseli ne sca n.  C o nfir m e d res p o ns es are s u m m arize d i n Ta ble  1 .1 .   
As of t he data c ut -off d ate of 0 1 Fe b 2 0 1 9, at d oses of 5. 4 m g/ k g or 6. 4 m g/ k g f or s u bjects wit h 
H E R 2 -p ositi ve breast c a ncer , m e dia n d urati o n of f oll o w -u p was 1 5. 5  m o nt hs (ra n ge: 0. 1 m o nt hs 
t o 3 4. 4 m o nt hs). 9  I n t he E nr olle d A nal ysis Set, a c o nfir me d O R R b y I C R of 5 2. 5 % was 
o bser ve d i n all s u bjects wit h H E R 2 -p ositi ve breast ca ncer  (Ta bl e  1 .1 ). I n all s u bjects wit h H E R 2-
p ositi ve breast ca n cer, 6 2 s u bjects ha d best o verall res p o nses  b y I C R  of c o m plete res p o nse ( 1 0 
[ 8. 5 %] s u bjects) or partial res p o nse ( 5 2 [ 4 4. 1 %] s u bjects).  T he me d ia n d urati o n of c o nfir m e d 
res p o nse b y I C R  is 1 3. 3  m o nt hs .  
As of t he data c ut off dat e of 0 1 Fe b 2 0 1 9, at d oses of 5. 4 m g/ k g or 6. 4 m g/ k g f or s u bjects wit h 
H E R 2 -l o w breast ca ncer, m e dia n d urati o n of f oll o w -u p was 6. 3 m o nt hs (ra n ge: 2. 5 m o nt hs t o 
2 9. 3 m o nt hs ). 9  I n t he E nr olle d A nal ysis Set, c o nfir me d O R R b y I C R of 3 7. 0 % was o bser ve d i n 
s u bjects wit h H E R 2-l o w breast c a ncer (Ta bl e  1 .1 ).  I n all s u bjects wit h H E R 2-p ositi ve breast 
ca ncer, 2 0  s u bjects ha d b est o verall res p o ns es b y I C R of partial res p o nse (2 0  [3 7. 0 %] s u bjects).  
T he me dia n d urati o n of c o nfir me d res p o ns e b y I C R is 1 0. 4  m o nt hs.   

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 6  
T a ble  1 .1 : 
Effic ac y Res ults  i n H E R 2-p ositi ve a n d H E R 2 -l o w Bre ast C a ncer S u bjects  
fr o m D S 8 2 0 1-A -J 1 0 1 ( 5. 4 m g/ k g or 6. 4 m g/ k g T -D X d ) as of 0 1  Fe b  2 0 1 9  
Effic ac y V ari a ble  
S u bjects wit h B re ast C a ncer  
H E R 2 -l o w B C 
( N =5 4)  
H E R 2 -p ositi ve B C  
( N = 1 1 8) 
C o nfir me d O R R n ( %) ( 9 5 % CI a) 
O R R b y I C R  
2 0 ( 3 7. 0)  ( 2 4. 3, 5 1. 3) 
6 2 ( 5 2. 5)  ( 4 3. 1, 6 1. 8) 
O R R b y I n vesti gat or  
2 4 ( 4 4. 4)  ( 3 0. 9, 5 8. 6) 
7 1 ( 6 0. 2)  ( 5 0. 7, 6 9. 1) 
O R R b y I C R, n/ N  
2 0/ 4 9 ( 4 0. 8) ( 2 7. 0, 5 5. 8)  
6 0/ 1 0 2  ( 5 8. 8) ( 4 8. 6, 
6 8. 5)  
C o nfir me d B est O verall Res p o nse b y I C R ( n, %)  
C R  
0  
1 0 ( 8. 5)  
P R  
2 0 ( 3 7. 0) 
5 2 ( 4 4. 1)  
S D  
2 7 ( 5 0. 0)  
4 7 ( 3 9. 8)  
P D  
6 ( 1 1. 1)  
5 ( 4. 2)  
N E  
1 ( 1. 9)  
4 ( 3. 4)  
C o nfir me d B est O verall Res p o nse b y I n vesti gat or ( n, %)  
C R  
0  
5 ( 4. 2)  
P R  
2 4 ( 4 4. 4)  
6 6 ( 5 5. 9)  
S D  
2 1 ( 3 8. 9)  
3 8 ( 3 2. 2)  
P D  
9 ( 1 6. 7)  
6 ( 5. 1)  
N E  
0  
3 ( 2. 5)  
C o nfir me d D o R Me dia n  M o nt hs
c ( 9 5 % CI) 
D o R b y I C R  
1 0. 4 ( 8. 8, -) 
1 3. 3  ( 9. 5, -) 
D o R b y I n vesti gat or  
1 1. 0 ( 4. 5, 1 2. 8)  
1 7. 1  ( 9. 8, 2 0. 0) 
C o nfir me d D C R b ( n, %) ( 9 5 % CIa) 
D C R b y I C R  
4 7 ( 8 7. 0) ( 7 5. 1, 9 4. 6)  
1 0 9 ( 9 2. 4)  ( 8 6. 0, 9 6. 5) 
D C R b y I n vesti gat or  
4 5 ( 8 3. 3) ( 7 0. 7, 9 2. 1)  
1 0 9 ( 9 2. 4) ( 8 6. 0, 9 6. 5) 
Ti me t o C o nfir me d Res p o nse b y I C R, Me dia n M o nt hs c 
( 9 5 % CI) 
2. 6 ( 1. 3, 3. 1)  
2. 8  ( 1. 5, 2. 8) 
D urati o n of C o nfir me d Sta ble Disease b y I C R, Me dia n 
M o nt hs
c ( 9 5 % CI) 
1 0. 9 ( 4. 2, -) 
1 0. 5  ( 8. 2, -) 
Pr o gressi o n -free S ur vi val ( P F S) 
P F S b y I C R  
 
 
E ve nts ( n, %) 
2 4 ( 4 4. 4)  
5 0 ( 4 2. 4)  
Me dia n M o nt hs
c ( 9 5 % CI) 
1 1. 1 ( 7. 6, -) 
1 3. 7  ( 9. 4, 1 9. 4) 
P F S b y I n vesti gat or  
 
 
E ve nts ( n, %) 
3 0 ( 5 5. 6)  
4 8 ( 4 0. 7)  
Me dia n M o nt hs
c ( 9 5 % CI) 
8. 0 ( 5. 6, 1 3. 9)  
1 6. 6  ( 1 1. 3, 2 2. 1) 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 7  
Effic ac y V ari a ble  
S u bjects wit h B re ast C a ncer  
H E R 2 -l o w B C 
( N =5 4)  
H E R 2 -p ositi ve B C  
( N = 1 1 8) 
O verall s ur vi val  
E ve nts ( n, %)  
1 5 ( 2 7. 8)  
2 3 ( 1 9. 5) 
Me dia n M o nt hs
c ( 9 5 % CI) 
2 9. 4 ( 1 2. 9, 2 9. 4)  
- ( 2 6. 4, -) 
S ur vi val at 6 m o nt hs, % ( 9 5 % CI d) 
8 6. 2 ( 7 3. 1, 9 3. 2)  
9 4. 7  ( 8 8. 7, 9 7. 6) 
S ur vi val at 1 2 m o nt hs, % ( 9 5 % CI d) 
7 7. 7 ( 6 1. 7, 8 7. 6)  
8 4. 4  ( 7 5. 7, 9 0. 2) 
S ur vi val at 1 8 m o nt hs, % ( 9 5 % CI d) 
6 6. 4 ( 4 7. 7, 7 9. 7)  
7 7. 6  ( 6 7. 3, 8 5. 0) 
S ur vi val at 2 4 m o nt hs, % ( 9 5 % CI d) 
5 3. 1 ( 2 4. 8, 7 5. 1)  
7 4. 8  ( 6 3. 1, 8 3. 2) 
B C = breast ca ncer; CI = c o nfi de nce i nter val; C R = c o m plet e res p o nse; D C R = disease c o ntr ol rate; D o R = d urati o n 
of res p o nse; H E R 2 = h u ma n e pi der mal gr o wt h fac t or rece pt or 2; I C R = i n de pe n de nt ce ntr al re vie w; O R R = 
o bj ecti ve res p o nse rate; N E = n o n -e val ua ble; P D = pr o gressi ve disease; P F S = pr o gressi o n -free s ur vi val; P R = 
partial res p o nse; S D = sta ble disease  
a 9 5 % e xact bi n o mial CI  
b D C R was calc ulate d as t he pr o p orti o n of s u bj ects de m o nstr ati n g C R, P R, or S D f or a mi ni m u m of 6 wee ks 
(± 1 wee k) fr o m t he first d osi n g date  
c Me dia n is fr o m Ka pla n -Meier Esti mate. CI f or me dia n was c o m p ute d usi n g t he Br o o k me yer -Cr o wle y met h o d.  
d CI f or t he rate at a fi xe d ti me p oi nt was c o m p ute d b y a p pl yi n g as y m pt otic n or malit y t o t he l o g -l o g tra nsf or mati o n 
of t he rate  
T he ra n ge i ncl u des t he ce ns ore d o bser vati o ns w here usi n g " +" after val ue i n dicates ce ns ori n g.  M o nt hs were 
calc ulate d as Da ys * 1 2/ 3 6 5. 2 5.  
P art 1 ( 5. 4 m g/ k g a n d 6. 4 m g/ k g ) a n d P art 2 s u bj ects are i ncl u de d. 
Data c ut off date: 0 1 Fe b r uar y 2 0 1 9  
T he safet y d ataset i ncl u d e d all s u bjects w h o  ha d  recei ve d at least 1  d ose of st u d y dr u g i n 
D S 8 2 0 1 -A -J 1 0 1 as of 0 1 Fe b  2 0 1 9  ( n =2 8 9 ). 9 N o d ose -li miti n g t o xicit y was o bser ve d, a n d t h e 
ma xi m u m t olerate d d ose was n ot reac he d i n t he d ose escal ati o n part of D S 8 2 0 1 -A -J 1 0 1. T he 
rec o m me n de d d os e le vels f or t he e x pa nsi o n were 5. 4 m g/ k g  a n d 6. 4 m g/ k g base d o n t olera bilit y, 
effic ac y, P K  data , a n d e x p os ure -res p o nse a n al ysis. 
As of 0 1 Fe b  2 0 1 9 , 2 8 8 (9 9. 7 %) s u bjects e x perie n ce d at least 1  treat me nt-e mer ge nt a d verse 
e ve nt ( T E A E). 9 T he m ost c o m m o n ( > 2 0 %) a d v erse e ve nts ( A Es) re p orte d were: na us ea (2 2 2  
s u bjects [7 6. 8 %]), decrease d a p petite ( 1 6 8 s u bjects [5 8 . 1 %]), v o miti n g (1 3 3  s u bjects [4 6 . 0 %]), 
al o pecia (1 2 0 s u bj ects [4 1. 5 %]), a ne mia ( 1 1 8 s u bj ects [4 0. 8 %]), fati g ue ( 1 1 1 s u bjects [ 3 8. 4 %]), 
diarr hea ( 1 0 2 s u bjects [3 5 . 3 %]), c o nsti pati o n a n d platelet c o u nt decreas e d  (1 0 0 s u bjects [3 4. 6 %]  
eac h), ne utr o p hil c o u nt d ecrease d (9 1 s u bj ects [3 1. 5 %]),  w hite bl o o d cell c o u nt decrease d ( 8 2 
[2 8 . 4 %]), as partate a mi n otra nsferase ( A S T; 6 3  s u bjects [2 1. 8 %]),  malaise ( 6 2 s u bjects [ 2 1.5 %]) , 
p yre xia  (6 0  s u bjects [2 0. 8 %]), a n d st o matitis (5 8  s u bjects [2 0. 1 %]) .  
A t otal of 1 6 8 s u bjects (5 8. 1 %) e x perie nce d at least 1  G ra de 3 or a b o ve T E A E, of w hic h 1 3 9  
(4 8. 1 %) were relate d t o T -D X d  per In vesti gat or assess me nt . T he m ost c o m m o n ( > 5 %) Gra de 3 
or hi g her T E A Es w ere a n e mia ( 6 0  s u bjects [2 0. 8 %]), ne utr o p hil c o u nt decrease d ( 5 3  s u bjects 
[1 8 .3 %]) , w hite bl o o d cell c o u nt decrease d ( 3 7  s u bjects [ 1 2.8 %]) , platelet c o u nt decrease d ( 33  
s u bjects [ 1 1.4 %]) , a n d h y p o kal e mia ( 1 8 s u bjects [ 6. 2 %]). 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
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1. 1. 1. 7.  
Be nefit / Ris k Assess me nt 
T -D X d  is u n der de vel o p me nt f or t he treat me nt of H E R 2-e x pressi n g ca ncers a n d H E R 2 -m uta nt 
t u m ors.  Base d o n t he preli mi nar y cli nical o bser vati o ns i n t he P hase 1 st u d y ( St u d y D S 8 2 0 1-A -
J 1 0 1), T -D X d  de m o nstrates a ntit u m or acti vit y i n H E R 2 -e x pressi n g ca ncers, i ncl u di n g breast 
ca ncer a n d gastric ca ncer  ( Secti o n 1. 1. 1. 6 ).  
As of 0 1 Fe b r uar y 2 0 1 9 , fr o m t he o n g oi n g st u d y D S 8 2 0 1 -A -J 1 0 1, t he o verall efficac y res ults in 
s u bjects wit h H E R 2-p ositi ve breast c a ncer at 5. 4 m g/ k g or 6. 4 m g/ k g de m o nstrate d a c o nfir me d 
O R R b y I C R of 5 2. 5 %.  A m o n g t he s u bjects wit h H E R 2 -l o w breast ca ncer, c o nfir me d O R R b y 
I C R was 3 7. 0 %.  T he o v erall efficac y res ults i n s u bjects wit h H E R 2-p ositi v e gastric/ G EJ ca ncer 
at 5. 4 m g/ k g or 6. 4 m g/ k g de m o nstr ate d a c o nfir me d O R R b y I C R of 2 9. 5 %.  T he o verall 
effic ac y res ults i n s u bjects wit h ot her ca ncers de m o nstrate d a c o nfir me d O R R b y I C R of 2 9. 5 %.  
As of 0 8 J u n 2 0 1 9, base d o n t he c u m ulati ve re vie w of t h e safet y data, i ncl u di n g a v aila ble 
n o ncli nical, cli nical, a n d e pi de mi ol o gic i nf or mati o n a n d scie ntific literat ur e ( p u blis he d a n d 
u n p u blis he d) a n d ta ki n g i nt o c o nsi derati o n bi ol o gi cal pla usi bilit y, I L D, a ne mia, ne utr o p hil c o u nt 
decrease i ncl u di n g fe bril e ne utr o pe nia, a n d platel et c o u nt decreas e are classifie d as i m p orta nt 
i de ntifie d ris ks.  L V E F d ecrease is classifi e d as a n i m p orta nt p ote ntial ris k.  I nf usi o n relate d 
reacti o ns, w hic h were pre vi o usl y classifi e d as a n i m p orta nt p ote ntial ris k, are reclassifie d as a n 
i de ntifie d ris k.  Q T pr ol o n gati o n is n o l o n ger c o nsi dere d a n i m p orta nt p ote ntial ris k a n d has bee n 
re m o ve d fr o m t he list of safet y c o n cer ns f or T -D X d . 
I n t he T -D X d  cli nical pr o gra m, t he i ncl usi o n/e xcl usi o n criteria a n d m o nit ori n g/ ma na ge me nt 
g ui deli n es are c urre ntl y i n place i n all pr ot oc ols t o miti gate t he i m p orta nt i d e ntifie d ris ks of I L D, 
a ne mia, ne utr o p hil c o u nt decrease i ncl u di n g fe bril e ne utr o pe nia, a n d platel et c o u nt decreas e, a n d 
i m p orta nt p ote ntial ris k of L V E F d ecrease.  
I L D is a k n o w n seri ous ris k of T -D X d , a n d cas es wit h fatal o utc o mes ha v e bee n re p orte d.  M ost 
e ve nts were Gra de 1 or Gra de 2 a n d were ma na gea ble b y d ose m o dificati o n a n d f oll o wi n g 
cli nical treat me nt g ui deli nes f or dr u g -i n d uce d I L D, wit h s pecific rec o m m e n dati o ns i ncl u di n g 
cl ose m o nit ori n g of si g ns/s y m pt o ms of I L D (e g, c o u g h, fe ver, a n d d ys p nea) t o i de ntif y p ote ntial 
I L D a n d pr o acti vel y ma n a gi n g I L D wit h d ose m o dificati o n a n d treat me nt (e g, ster oi ds).  I L D 
re q uires pr o p er m o nit ori n g, d ose m o dificati o n, a n d s u p p orti ve care i nstitute d i n a ti mel y fas hi o n.    
Ot her i de ntifie d ris ks of T -D X d  i n or der of des ce n di n g fre q ue n cies are na usea, decrease d 
a p petite, al o peci a, v o miti n g, fati g u e, c o nsti pati o n, diarr h oea, W B C c o u nt decreas e, st o matitis, 
as partate a mi n otra nsferas e i ncrease d, c o u g h, h ea d ac he, a b d o mi nal pai n, ala ni ne a mi n otra nsferase 
i ncreas e d, h y p o kala e mia, e pista xis, d ys p n oea, d ys pe psia, dizzi ness, dr y e ye, u p per res pir at or y 
tract i nfecti o n, ast he nia, a n d i nf usi o n relate d reacti o ns.   
T hese i de ntifie d ris ks w ere ge nerall y ma na gea b le t hr o u g h d ose m o dificati o n a n d r o uti ne cli nical 
practice.  
T -D X d  has d e m o nstrate d a ge nerall y acce pta ble s afet y pr ofile i n t he tr eate d p o p ulati o ns.  
I n c o ncl usi o n, gi ve n t he data a vaila ble o n t h e efficac y a n d safet y of T -D X d , t he o verall 
be nefit/ris k re m ai ns p ositi ve f or cli nical de vel o p me nt.  
F or f urt her det ails relate d t o t he effic ac y a n d s afet y of T -D X d  re p orte d fr o m cli nical st u dies, 
please see t he latest versi o n of t he I B.  9 

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disc or da nce bet wee n la b orat ories has als o bee n s h o w n t o occ ur wit h u p t o 8 % differe nce i n 
H E R 2 stat us e ve n w he n rea d b y ce ntral la b orat orie s.1 8  T o pre ve nt heter o ge neit y i n H E R 2 stat us , 
t he S p o ns or t heref ore pr o p oses t o e x cl u de p ote ntial s u bjects w h o ha ve pre vi o usl y teste d p ositi ve 
f or H E R 2 (I H C 3 + or I H C 2 +/I S H +) or bee n treate d wit h a nti -H E R 2 t hera p y.  
T o defi ne l o w H E R 2 e x pressi o n , it is necessar y t o clarif y t he b o u n dar y bet wee n I H C 0 a n d I H C 
1 +.  T he A S C O -C A P s u g gests a d efi niti o n f or I H C 1 + as i nc o m plete me m br a ne stai ni n g t h at is 
fai nt/ barel y perce pti ble an d wit hi n > 1 0 % of t he i n vasi ve t u m or cells.  T he I H C 0 is defi ne d as n o 
stai ni n g o bser ve d or me m bra ne stai ni n g t hat is i nc o m plete a n d is fai nt/ barel y p erce pti ble a n d 
wit hi n ≤1 0 % of t he i n vasi ve t u m or cells. 1 0  Beca use t here is n o differe n ce i n treat me nt al g orit h m 
f or s u bjects wit h I H C 0 an d I H C 1 + rea di n gs, se veral c o m mercial H E R 2 tests use alter nati ve 
c ut offs.  T o sta n dar dize t his b o u n dar y, t h e S p o ns or pr o p oses  t o use t he a da pte d  A S C O -C A P 
c ut offs t o pr o vi de t he l o wer b o u n dar y f or l o w H E R 2  e x pressi o n . 
H or m o n e R ece pt or S t at us 
T he ot her ke y d eter mi na nt of treat me nt pat h wa y i n breast c a ncer is H R stat us.  T he H R -p ositi ve 
breast c a ncers are ge nerall y l u mi nal t y pe w hereas H R -ne gati ve, H E R 2 -l o w t u m ors w o ul d 
c urre ntl y be c haracterize d as tri ple ne gati ve dise ase.  I n ter ms of pre vale nce, alt h o u g h H R 
p ositi vit y is ne gati vel y c orrelate d wit h H E R 2 p ositi vit y, H R is p ositi vel y c orrelate d wit h H E R 2 
stat us wit hi n t he H E R 2-ne gati ve s pectr u m.  C o m bi ne d wit h t he o verall l o w er i nci de nce of tri ple 
ne gati ve diseas e, t hese c orrelati o ns res u lt i n t he maj orit y of H E R 2-l o w breast ca n cers bei n g 
H R -p ositi ve.  I n t he N S A B P B -4 7 tri al, 8 2. 8 % of s u bjects were H R -p ositi ve. 1 4  Si milarl y, as of 
1 6  Fe b 2 0 1 8, of 3 3 H E R 2 -l o w s u bjects e nr olle d i n t he D S 8 2 0 1-A -J 1 0 1 st u d y, 2 9 ( 8 7. 9 %) were 
H R -p ositi ve.  I n a d diti o n t o a differe nce i n pre val e nce, si g nifica nt differe n ces are see n i n ge ne 
si g nat ur e bet wee n l u mi nal a n d tri ple ne gati ve dis ease, o utc o mes , a n d res p o nse t o t hera p y.   
F or b ot h H E R 2 -ne gati ve, H R -p ositi ve breast ca n cers refract or y t o e n d ocri ne t hera p y a n d H R -
ne gati ve breast ca n cers, g ui deli nes fr o m t he N C C N rec o m me n d s e q ue ntial treat ment wit h si n gle -
a ge nt c he m ot hera pies .1  T o deli neate t he u n met m e dical nee d of s u bjec ts i n t his trial, i ncl usi o n 
criteria re q uire at least 1 a n d at m ost 2  pri or li nes of c he m ot hera p y.  
T o best c haracterize t he u n met nee d a n d a d dress t he r ole of T -D X d  i n t his patie nt p o p ulati o n, t he 
S p o ns or rec o g niz es t hat t here are a relati vel y lar ge n u m ber of a ge nts a n d p ote ntial se q ue nces of 
treat me nt.  A n ot her i m p orta nt criteri o n is t o clearl y defi ne t he b o u n daries f or H E R 2 stat us.  T o 
e ns ure a h o m o ge n o us patie nt p o p ulati o n, t he S p o ns or will ta ke e xtra ste ps t o f ull y c h aracterize 
H E R 2 -l o w stat us a n d n u m ber of pri or t hera pies.    

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2.  
S T U D Y O B J E C TI V E S A N D  H Y P O T H E SI S  
2. 1.  
St u d y O bjecti ves  
2. 1. 1.  
Pri m ar y O bjecti ve  
T he pri mar y o bje cti ve is t o c o m pare t he P F S be n efit of T -D X d  t o p h ysicia n’s c h oice i n H E R 2-
l o w, H R-p ositi ve  breast c a ncer , b ase d o n bli n de d i n de pe n de nt ce ntral re vie w ( BI C R). 
2. 1. 2.  
Ke y Sec o n d ar y O bjecti ve s 
T he ke y sec o n dar y  o bje cti ve s are: 
 T o c o m pare t h e P F S be n efit of T -D X d  t o p h ysicia n’s c h oice i n all ra n d o mize d 
s u bjects (H E R 2 -l o w, H R -p ositi ve , a n d H R -ne gati ve  breast ca ncer ), b ase d o n BI C R  
 T o c o m pare t h e O S be nefit of T -D X d  t o p h ysicia n’s c h oice i n H E R 2-l o w, 
H R -p ositi ve breast ca n cer  
 T o c o m pare t h e O S be nefit of T -D X d  t o p h ysicia n’s c h oice i n all ra n d o mize d s u bjects  
(H E R 2 -l o w, H R -p ositi ve  a n d H R-ne gati ve  breast ca ncer ) 
I n S w e de n o nl y, ple ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites i n S we de n. 
2. 1. 3.  
Ot her Sec o n d ar y O bjecti ves  
T he ot her sec o n dar y o bj ecti ves are: 
 T o i n vesti gate t h e efficac y of T -D X d  c o m pare d t o p h ysicia n’s c h oice o n  t h e 
f oll o wi n g parameters ( defi niti o ns of t hese e n d p oi nts are i ncl u de d i n Secti o n  7. 1. 3 ): 
 P F S i n H R -p ositi ve  s u bjects, base d o n I n v esti gat or assess me nt 
 C o nfir me d  O R R , base d o n BI C R a n d I n v esti gat or assess me nt  i n H R-p ositi ve 
s u bjects 
 D o R , base d o n BI C R i n H R-p ositi ve s u bjects  
 C o nfir me d O R R, a n d D o R i n all s u bjects, re gar dless of H R stat us  
 T o deter mi ne P K of T -D X d  
 T o e val uate s afet y of T -D X d  c o m pare d t o p h ysi cia n’s c h oic e 
 T o e val uate H ealt h Ec o n o mics a n d O utc o mes Res earc h ( H E O R) e n d p oi nts f or 
T -D X d  c o m pare d t o p h ysicia n’s c h oice  
I n S w e de n o nl y , p le ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites i n S we de n. 
2. 1. 4.  
E x pl or at or y O bjecti ves  
T he e x pl orat or y o bj ecti v es are  t o e val uate t he f oll o wi n g: 
 Cli nical be nefit rate ( C B R ; t he s u m of c o m plete res p o nse [ C R ] rate, P R rate, a n d 
greater  t ha n or e q u al t o  6 m o nt hs’ sta ble disease [S D ] rate), base d o n BI C R i n H R -
p ositi ve s u bjects a n d all s u bjects re gar dless of H R stat us  

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 Disease c o ntr ol rate ( D C R), base d o n BI C R i n H R -p ositi ve s u bjects  a n d i n all 
s u bjects re gar dless of H R stat us  
 Ti me t o res p o nse  ( T T R) i n H R-p ositi ve s u bjects a n d all s u bjects re gar dless of H R 
stat us, base d o n BI C R  
 P r o gressi o n-free s ur vi val o n t he ne xt li ne of t hera p y ( P F S 2) 
 P ote ntial bi o mar kers of res p o nse/resista nce  
 E x p os ure -res p o nse relati o ns hi ps f or efficac y a n d safet y e n d p oi nts 
 P F S, O S, c o nfir me d O R R, a n d D o R i n H R -ne gati ve  s u bjects 
2. 2.  
St u d y H y p ot hesis  
T -D X d  c o nfers a si g nifi ca nt be nefit i n P F S i n H E R 2 -l o w, H R -p ositi ve breast ca ncer s u bjects  
c o m pare d t o p h ysicia n’s c h oice . 
2. 3.  
St u d y E n d p oi nts  
2. 3. 1.  
Pri m ar y E ffic ac y E n d p oi nt 
T he pri mar y effic ac y e n d p oi nt is P F S , base d o n BI C R , i n H R-p ositi ve breast ca ncer  s u bjects. 
2. 3. 2.  
Ke y Sec o n d ar y Effic ac y E n d p oi nt s 
T he ke y sec o n dar y effic ac y e n d p oi nts are: 
 P F S , base d o n BI C R, i n all ra n d o mize d s u bjects  
 O S i n H R -p ositi ve breast ca ncer s u bjects 
 O S i n all ra n d o mize d s u bjects  
I n S w e de n o nl y, ple ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites i n S we de n. 
2. 3. 3.  
Ot her Sec o n d ar y Effic ac y E n d p oi nts  
T he ot her sec o n dar y effi cac y e n d p oi nts are: 
 P F S , base d o n I n vesti gat or assess me nt  
 C o nfir me d  O R R , base d o n BI C R a n d I n v esti gat or assess me nt  
 D o R , base d o n BI C R  
I n S w e de n o nl y, ple ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites i n S we de n. 
2. 3. 4.  
E x pl or at or y Effic ac y E n d p oi nt s 
T he e x pl orat or y effi cac y e n d p oi nts are:  
 C B R , base d o n BI C R  
 D C R, base d o n BI C R  

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 T T R , base d o n BI C R  
 P F S 2  
2. 3. 5.  
He alt h Ec o n o mic a n d O utc o mes Res e arc h E n d p oi nts  
T he H E O R e n d p oi nts i ncl u de:  
 E ur o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer ( E O R T C ) q ualit y of 
life q uesti o n naires ( Q L Q) 
 C 3 0  
 B R 4 5  
 E ur o Q ol  5 di me nsi o n s 5 le vels [of se verit y ] ( E Q-5 D -5 L)  
 H os pitalizati o n -relate d e n d p oi nts  
2. 3. 6.  
P h ar m a c o ki netic/ Bi o m ar ker E n d p oi nts  
2. 3. 6. 1.  
P h ar m a c o ki netic E n d p oi nts  
T he P K e n d p oi nts i ncl u de:  
 Ser u m c o nce ntr ati o ns of T -D X d , t otal a nti-H E R 2 a nti b o d y , a n d M A A A -1 1 8 1a  
2. 3. 6. 2.  
Bi o m ar ker E n d p oi nts  
T he b i o mar ker e n d p oi nts i ncl u de:  
 Ser u m bi o mar kers (e g, e xtracell ular d o mai n of H E R 2 [ H E R 2 E C D])  
 Ot her p ote ntial bi o mar kers  of res p o nse/resista nce  (e g, de o x yri b o n u cleic aci d [ D N A] 
pr ofili n g i n c ell free D N A  [cf D N A], R N A e x pressi o n pr ofili n g, m utati o ns) 
2. 3. 7.  
S afet y E n d p oi nts  
T he safet y e n d p oi nts i ncl u de:  
 Seri o us  a d verse e ve nts ( S A Es)  
 T E A Es , gra de d acc or di n g t o t he Nati o nal Ca ncer I nstit ute ( N CI) C T C A E versi o n 5. 0  
 A E SI s 
 Disc o nti n uati o ns ass ociate d wit h  A Es  
 P h ysical e x a mi nati o n fi n di n gs  
 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 O G P S) 
 Vital si g n meas ur e me nts  
 Sta n dar d cli nical la b orat or y p ara m eters  
 Electr ocar di o gra m ( E C G) para m eters  
 Ec h ocar di o gra m ( E C H O )/ m ulti gate d ac q uisiti o n ( M U G A) sca n fi n di n gs  
 A nti -dr u g a nti b o dies ( A D A s) 

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3.  
S T U D Y D E SI G N  
3. 1.  
O ver a ll Desi g n 
T his is a ra n d o mize d, 2 -ar m, P hase 3, o pe n -la bel, m ultice nter st u d y t o c o m pare t he s afet y a n d 
effic ac y of T -D X d  vers us t he p h ysicia n’s c h oice i n H E R 2 -l o w, u nresecta bl e a n d/ or metastatic 
breast ca ncer s u bjects.  Fi g ure  3 .1  s h o ws t he st u d y desi g n. 
T -D X d  f or i njecti o n, 1 0 0 m g, will be a d mi nistere d I V at a d ose of 5 . 4 m g/ k g e v er y 3 wee ks.   
T he c o m parat or f or t his st u d y is calle d p h ysici a n’s c h oice.  A p pr o xi matel y 5 4 0  s u bjects will be 
ra n d o mize d i n a 2: 1 rati o t o T -D X d  or 1 of t he f oll o wi n g p h ysicia n’s c h oice treat me nts:  
 Ca pecita bi ne  
 Eri b uli n  
 Ge mcita bi ne  
 Paclita x el  
 Na b -paclita x el  
If a s u bject recei ves a c o m parat or wit h a re gi me n ot her t ha n a 2 1 -d a y  c ycl e , t he I n v esti gator 
s h o ul d e ns ure t hat t he s u bject f oll o ws t he st u d y-d efi ne d S c he d ule of E ve nt s per a 2 8 -d a y c ycl e 
(see Secti o n 1 7. 1 ).  H o we ver, tu m or ass ess me nts a n d C T/ M RI of t he b rai n m ust be perf or me d 
e ver y 6 w ee ks + 7 d a ys  fr o m ra n d o mizati o n date.  La b orat or y a n d safet y assess me nt bef ore dr u g 
a d mi nistrati o n s h o ul d be a p pr o priatel y p erf or m e d acc or di n g t o t he la bel a p pr o ve d i n t he c o u ntr y 
of dr u g a d mi nistrati o n.  
Ra n d o mizati o n will be stratifie d b y:  
 H E R 2 I H C stat us of tiss ue sa m ples assesse d  b y a ce ntral la b orat or y :  H E R 2  I H C 1 +  
vs . H E R 2 I H C  2 + /I S H- 
 N u m ber of pri or li nes of c he m ot hera p y :  1  vs . 2  
 H R/ C D K stat us:  H R -p ositi ve wit h pri or C D K 4/ 6 i n hi bit or treat me nt vs . H R -p ositi ve 
wit h o ut pri or C D K 4/ 6 i n hi bit or treat me nt vs . H R -ne gati ve  
T he st u d y tr eat me nt will be c o nti n ue d acc or di n g t o t he d osi n g criteria i n t h e a bse nce of 
wi t h dra wal of s u bje ct c o nse nt, pr o gressi ve dise as e ( P D), or u n acce pta ble t o xicit y (see 
Secti o n  5. 7  f or ot her reas o ns w h y a s u bject ma y b e wit h dra w n fr o m st u d y treat me nt).  If t he 
st u d y treat me nt is dela ye d m ore t ha n 2 8 d a ys fr o m t he pla n ne d date of a d mi nistrati o n, t he s u bject 
will be wit h dra w n fr o m t he st u d y  tr eat me nt (see Secti o n  5. 7 ). 

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Fi g ure  3 .1 : 
St u d y Desi g n Sc he m a  
 
C D K = c ycli n -de p e n de nt ki nase, H E R 2 = h u ma n e pi der mal gr o wt h fact or rece pt or 2, I H C  =  i m m u n o hist oc he mistr y, 
T P C  =  treat me nt of p h ysicia n’s c h oice.  
* See Secti o n  6. 1  a n d Secti o n 6. 2  f or details. 
 
3. 2.  
Disc ussi o n of St u d y Desi g n  
T his trial is desi g ne d t o c o m pare t he use of T -D X d  vers us treat me nt of p h ysicia n’s c h oice f or 
u nresect a ble/ metastatic breast c a ncer t hat is H E R 2 -l o w.  
H E R 2 -l o w is a ne w cate g or y of H E R 2 stat us f or w hic h n o tar gete d t hera p y is c urre ntl y a p pr o ve d.  
T o defi ne t he u p p er b o u n dar y of l o w H E R 2 e x pressi o n, t he S p o ns or pla ns t o use t he a da pte d 
A S C O -C A P  2 0 1 8 H E R 2 testi n g  g ui deli nes (a d a pte d b y Daiic hi Sa n k y o I nc. a n d Ve nta na) .  T he 
disti ncti o n bet wee n I H C 2 + a n d 3 + h as bee n well defi ne d beca use of  t he differe nces i n treat me nt 
al g orit h m i n w hic h m ulti ple H E R 2 -tar get e d a ge nts ha ve bee n s h o w n t o be nefit H E R 2-p ositi ve 
patie nts.  H o we ver, partl y as a res p o ns e t o a nti -H E R 2 t hera p y, c ha n ges i n t u m or H E R 2 stat us 
ha ve bee n descri be d t o o cc ur o ver ti me. 1 7  I n a d diti o n, disc or da nce b et wee n la b orat ories has als o 
bee n s h o w n t o occ ur wit h u p t o 8 % differe nce i n H E R 2 stat us e ve n w he n rea d b y ce ntral 
la borat orie s.1 8  T o pre ve nt heter o ge neit y i n H E R 2 stat us , t he S p o ns or t herefore pr o p oses t o 
e x cl u de p ote ntial s u bjects w h o ha ve pre vi o usl y teste d p ositi ve f or H E R 2 or bee n tr eate d wi t h 
a nti-H E R 2 t hera p y.  
T o defi ne l o w H E R 2 e x pressi o n , it is necessar y t o clarif y t he b o u n dar y bet wee n I H C 0 a n d I H C 
1 +.  T he A S C O -C A P s u g gests a d efi niti o n f or I H C 1 + as i nc o m plete me m br a ne stai ni n g t h at is 
fai nt/ barel y perce pti ble a n d wit hi n > 1 0 % of t he i nvasi ve t u m or cells.  T he I H C 0 is defi ne d as n o 
stai ni n g o bser ve d or me m bra ne stai ni n g t hat is i nc o m plete a n d is fai nt/ barel y p erce pti ble a n d 
wit hi n ≤1 0 % of t he i n vasi ve t u m or cells. 1 0  Beca use t here is n o differe n ce i n treat me nt al g orit h m 
f or s u bjects wit h I H C 0 a n d I H C 1 + rea di n gs, se veral c o m mercial H E R 2 tests use alter nati ve 
c ut offs.  T o sta n dar dize t his b o u n dar y, t h e S p o ns or pr o p oses t o use t he  a da pte d  A S C O -C A P 
c ut offs t o pr o vi de t he l o wer b o u n dar y f or l o w H E R 2 e x pressi o n.  
T his st u d y will be c o n d u cte d i n a p pr o xi matel y 2 2 5  sites i ncl u di n g b ut n ot li mite d t o N ort h 
A merica, Wester n E ur o p e, a n d Asia.  
T he tar get sa m ple siz e will be a p pr o xi matel y 5 4 0 s u bjects ra n d o mize d i n a 2: 1 rati o i nt o 
2  treat me nt ar ms (T -D X d  vers us p h ysi cia n’s c h oi ce).  

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3. 2. 1.  
D ur ati o n of t he St u d y  
E nr oll me nt is pla n ne d t o occ ur o ver a p pr o xi matel y 1 6 m o nt hs  fr o m t he ra n d o mizati o n date of t he 
first s u bject.  T he data c ut off  f or t he pri mar y efficac y a n al ysis of P F S is pla n ne d w he n 
a p pr o xi matel y 3 1 8  P F S e ve nts per BI C R ha ve bee n o bser ve d  i n t he H R-p ositi ve s u bjects.  
T he S p o ns or  will m o nit or t he n u m ber of P F S e ve nts a n d will ma ke pr ojecti o ns of t he data c ut off 
date f or P F S a n al ysis.  T he pri mar y a n al ysis will use all e ve nts a ccr ue d o n or bef ore t he c ut off 
date.  All data bef ore or o n t he c ut off dat e will be use d f or a n al ysis.  
T he fi nal data c ut off f or t he ke y sec o n d ar y ef ficac y e n d p oi nt O S is pla n ne d w he n a p pr o xi matel y 
3 3 3 O S e ve nts ha ve b ee n o bser ve d i n H R -p ositi ve  s u bjects. 
F or eac h s u bject t here will be a 4 0 -Da y ( +7 d a ys ) F oll o w-u p aft er t he last st u d y dr u g tr eat me nt 
a d mi nistrati o n or bef ore starti n g ne w a ntica n cer trea t me nt, w hic he v er c o m es first, f oll o we d b y 
L o n g -t er m/ S ur vi val F oll o w-u p e ver y 3 m o nt hs  ( ±1 4 d a ys ) fr o m t he date of 4 0-Da y ( +7 d a ys) 
F oll o w -u p, u ntil deat h, wit h dra wal of c o ns e nt, l oss t o f oll o w -u p, or st u d y cl os ure, w hic he v er 
occ urs first.  
T he S p o ns or ma y ter mi n ate t he st u d y at a n y ti me a n d st u d y ter mi nati o n ma y als o be re q u este d b y 
(a) c o m p ete nt a ut h orit y(i es). 
3. 2. 2.  
D ur ati o n of S u bject P a rtici p ati o n  
T he Scree ni n g p eri o d is u p t o 2 8 d a ys.  F or T -D X d , eac h c ycle of treat me nt will be 2 1 d a ys.  T h e 
n u m ber of treat m e nt c ycl es wit h T -D X d  is n ot fi x e d.  U p o n c o m me nci n g st u d y treat me nt, 
s u bjects ma y c o nti n ue recei vi n g st u d y tr eat me nt u ntil t he occ urre n ce of a n y of t he e ve nts defi ne d 
i n Secti o n  5. 7 . 
F or t he p h ysicia n’s c h oic e c o m parat or ar m, if a s u bject recei ves a c o m parat or wit h a re gi me n 
ot her t ha n 2 1 da ys, t he I n vesti gat or s h o ul d e ns ure t hat t he s u bject f oll o ws t he st u d y -d efi ne d 
S c he d ule of E ve nt s per a 2 8 -da y c ycl e (see Secti o n 1 7. 1 ).  H o we v er, tu m or assess me nts a n d 
C T/ M RI of t he Brai n  m ust be perf or m e d e ver y 6 wee ks + 7 d a ys  fr o m r a n d o mizati on date .  
La b orat or y a n d safet y assess me nt bef ore dr u g a d mi nistrati o n s h o ul d be a p pr o priatel y perf or me d 
acc or di n g t o t he la b el a p pr o ve d i n t he c o u ntr y of dr u g a d mi nistrati o n.  
After st u d y treat me nt disc o nti n uati o n, all s u bjects ma y b e c o ntacte d at t he 4 0 -Da y ( +7 da ys) 
F oll o w -u p a n d e ver y 3 m o nt hs  u ntil deat h or u ntil f oll o w -u p data c ollecti o n is n o l o n ger of 
scie ntific val ue or ot h er wise nee de d (at t he S p o ns or’s discreti o n), t o o btai n i nf or mati o n a b o ut 
s u bse q ue nt treat me nt(s) a n d s ur vi val stat us ( Secti o n 5. 7. 1 ).  If a s u bject disc o nti n ues treat me nt 
f or reas o ns ot her t ha n dis ease pr o gressi o n or deat h , e ver y atte m pt s h o ul d be ma de t o c ollect 
t u m or assess me nts u ntil disease pr o gressi o n a n d t he sca ns be s e nt f or ce ntr al re vie w e ve n if t he 
s u bject has starte d a n ot her a nti-ne o pl astic t hera p y . 
3. 2. 3.  
Defi niti o n of t he E n d of t he St u d y  
T he st u d y cl os ure is defi ne d as t he date w he n t he last s u bject disc o nti n ues st u d y treat me nt a n d 
a p plica ble f oll o w -u p o cc urs, or t he st u d y is e n de d b y t he S p o ns or.  

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4.  
S T U D Y P O P U L A TI O N  
Eac h s u bject will si g n st u d y I nf or me d C o nse nt F or m(s) (I C F[s]) pr o vi de d b y t he site.  A s u bject 
is c o nsi dere d e nr olle d i n t he st u d y u p o n t he I n v esti gat or or desi g nee o bt ai ni n g writte n i nf or me d 
c o nse nt fr o m t he s u bject ( Secti o n 1 5. 3 ) at t he ti me of Scree ni n g a n d u p o n d eter mi nati o n t hat all 
i ncl usi o n a n d e x cl usi o n criteria ha v e bee n s atisfie d. 
I n v esti gat ors will mai ntai n a c o nfi de ntial Scree ni n g L o g of all p ote ntial st u d y ca n di dates t hat 
i ncl u des limite d s u bject i nf or mati o n a n d o utc o me of Scree ni n g pr ocess (i e, e nr oll me nt i n t he 
st u d y, reas o n f or i n eli gi bilit y, wit h dr e w c o ns e nt). 
I n v esti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n t he st u d y 
i n dicati n g t heir assi g ne d st u d y n u m ber.  
I n v esti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n ( SI D) c o de list.  T his c o nfi de ntial 
list of t he na mes of all s u bjects, all ocate d st u d y n u m bers o n e nr olli n g i n t he st u d y, all o ws t he 
I n v esti gat or t o re v eal t he i de ntit y of an y s u bject w he n necessar y.  
4. 1.  
I ncl usi o n Criteri a 
S u bjects m ust satisf y all of t he f oll o wi n g criteri a t o be i ncl u de d i n t he st u d y .  T he I n vesti gat or 
s h o ul d f oll o w t he la bel a p pr o ve d i n t he c o u ntr y of dr u g a d mi nistrati o n f or t he i n di vi d ual 
treat me nt o pti o ns (cap ecita bi ne, eri b uli n, ge mcita bi ne, paclita xel, or na b -paclita xel) f or 
eli gi bilit y criteria if t he s u bject is ra n d o mize d t o t he ar m of tr eat me nt of p h ysicia n’s c h oice.  T he 
i ncl usi o n criteria i ncl u de: 
1.  M ust be c o m pete nt a n d a ble t o c o m pre he n d, si g n, a n d date  a n I nstit uti o nal Re vie w B o ar d 
(I R B) or I nstit uti o nal Et hics C o m mittee ( I E C) a p pr o ve d I C F b ef ore perf or ma nce of a n y 
st u d y-s pecific pr oce d ures or tests. 
2.  Me n or w o me n ≥1 8 y ears  ol d.  ( Please f oll o w l ocal re g ulat or y re q uire m e nts if t he le gal 
a ge of c o ns e nt f o r st u d y partici pati o n is > 1 8 years  ol d.)  
3.  Pat h ol o gicall y d oc u me nt e d breast ca ncer t hat:  
a. Is u nresecta ble or met astatic. 
b.  Has a hist or y of l o w H E R 2 e x pressi o n, defi ne d as I H C 2 +/I S H - or I H C 1 + (I S H - or 
u nteste d)  
c. Assesse d as l o w H E R 2 e x pressi o n, defi ne d as I H C 2 +/I S H - or I H C 1 + acc or di n g t o 
A S C O -C A P  2 0 1 8  H E R 2 testi n g  g ui deli nes (a d a pte d b y Daiic hi Sa n k y o I nc. a n d 
Ve nta na) e val uat e d at a c e ntral la b orat or y.    
d.  Is H R -p ositi ve  or H R -ne gati ve.  A p pr o xi matel y 6 0 H R -ne gati ve s u bjects are  t o be 
e nr olle d, t he re mai ni n g s u bjects will be H R -p ositi ve ( p ositi ve f or estr o ge n rece pt or or 
pr o gester o ne rece pt or if fi n di n g of ≥1 % of t u m or cell n uclei are i m m u n oreacti ve). 
e. If H R-p ositi ve, i s d oc u me nte d refract or y t o e n d ocri ne t hera p y, d efi ne d as h a vi n g 
pr o gresse d o n at least 1  e n d ocri ne t hera p y a n d d eter mi ne d b y t he In v esti gat or t hat 
s u bject w o ul d n o l o n ger be nefit fr o m f urt her treat me nt wit h e n d ocri ne t hera p y . 
f. If H R-p ositi ve, h as or h as n ot bee n treat e d wit h a C D K 4/ 6 i n hi bit or.  N ot m ore t ha n 
2 4 0 H R -p ositi ve s u bjects w h o ha ve n ot ha d pri or t hera p y wit h a C D K 4/ 6 i n hi bit or  
a n d at least 2 4 0  H R -p ositi ve s u bjects w h o ha ve h a d pri or t hera p y wit h a C D K 4/ 6 
i n hi bit or will be e nr olle d . 

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g.  Has bee n tr eate d wit h at least 1 a n d at m ost 2 pri or li nes of c he m ot hera p y i n t he 
rec urre nt or met astatic s etti n g.  If rec urre nce occ urre d wit hi n 6 m o nt hs  of 
( ne o)a dj u v a nt c he m ot hera p y, ( ne o)a dj u va nt t hera p y w o ul d c o u nt as 1 li ne of 
c he m ot hera p y.   Tar gete d a ge nts (s uc h as m T O R i n hi bit ors , P A R P i n hi bit ors , P D-L  
i n hi bit ors, P D -L 1  i n hi bit ors, hist o ne deacet yl ase in hi bit ors, or C D K 4/ 6 i n hi bit ors ) 
a n d e n d ocri n e t hera pies o n t heir o w n d o n ot c o ntri b ute t o t he c o u nt of pri or li nes of 
c he m ot hera p y, alt h o u g h re gi me ns wit h s uc h a ge nts i n c o m bi nati o n wit h 
c he m ot hera p y w o ul d still c o u nt as 1 li ne of c h e m ot hera p y.  
h.  Was ne ver pre vi o usl y H E R 2 -p ositi ve (I H C  3 + or I H C2 +/ I S H +) o n pri or pat h ol o g y 
testi n g ( per A S C O-C A P g ui deli nes ) or  was  hist ori cal l y H E R 2 I H C 0  o nl y . 
i. Was ne ver pre vi o usl y treate d wit h a nti -H E R 2 t hera p y.  
4.  D oc u me nte d  ra di ol o gic pr o gressi o n ( d uri n g or after m ost rece nt treat me nt). 
5.  M ust  ha ve a n a d e q uate arc hi val t u m or  tiss ue sa m ple a vaila ble f or assess me nt  of H E R 2 
stat us b y ce ntral la b orat or y ( base d o n m ost r ece nt a vaila ble t u m or tiss ue sa m ple).   If 
arc hi val t u m or tiss ue is n ot a vaila ble, a fres h t u m or tiss ue bi o ps y is re q uir e d.   See 
Secti o n  6. 1  f or details. 
6.  All  su bjects m ust ha ve a rece nt t u m or  tiss ue sa m ple after t h e m ost rece nt treat me nt 
re gi me n or a gree t o u n d er g o a tiss ue bi o ps y pri or t o ra n d o mizati o n.  See Secti o n  6. 2  f or 
details.  
7.  Prese nce  of at  least 1 meas ura ble lesi o n bas e d o n c o m p ute d t o m o gra p h y ( C T) or 
ma g n etic res o n a nce i ma gi n g ( M RI)  p er m o difie d Res p o nse E val uati o n Criteria i n S oli d 
T u m ors ( m R E CI S T) versi o n 1. 1 (see Secti o n  1 7. 5 ).1 9   
 Brai n lesi o ns  will be c o nsi dere d as n o n -t ar get lesi o ns o nl y. 
8.  E C O G  P S 0 or 1.  
9.  L V E F  ≥5 0 % wit hi n 2 8  d a ys pri or t o ra n d o mizati o n.  
1 0.  A de q uate  b o n e marr o w f u ncti o n wit hi n 1 4  d a ys b ef ore ra n d o mizati o n, defi ne d as:  
 Platelet c o u nt ≥1 0 0 ,0 0 0/ m m 3 ( Platelet tra nsf usi o n is n ot all o we d wit hi n 1 wee k pri or 
t o Scree ni n g assess me nt) 
 He m o gl o bi n le v el ≥9. 0 g/ d L ( re d bl o o d cell tr a nsf usi o n is n ot all o we d wit hi n 1 wee k  
pri or t o Scree ni n g ass ess me nt)  
 A bs ol ute ne utr o p hil c o u nt ≥1 5 0 0/ m m 3 ( gra n ul o c yt e c ol o n y-sti m ulati n g fact or 
a d mi nistrati o n is n ot all o we d wit hi n 1 wee k  pri or t o Scree ni n g assess me nt)  
1 1.  A de q uate  re nal f u n cti o n wit hi n 1 4 d a ys bef ore ra n d o mizati o n, defi ne d as:  
 Creati ni ne cleara n ce ≥3 0  m L/ mi n, as cal c ulate d usi n g t he C oc kcr oft -Ga ult e q uati o n 
(see Sect i o n 1 7. 2 ; C Lcr ( m L/ mi n) =   
[ 1 4 0 - a ge ( years)] × wei g ht ( k g)
7 2 × ser u m creati ni ne ( m g/ d L)   { × 0. 8 5 f or fe males } ). 
1 2.  A de q uate  h e patic f u ncti o n wit hi n 1 4  d a ys bef ore ra n d o mizati o n, defi ne d as:  
 As partate a mi n otra nsferase  ( A S T)/ala ni ne a mi n otra nsferase  ( A L T) ≤5 × u p per li mit 
of n or mal ( U L N)  

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 T otal bilir u bi n ≤1. 5 × U L N if n o li ver metastases or < 3 × U L N i n t he pres e nce of 
d oc u me nte d Gil bert’s sy n dr o me ( u nc o nj u gat e d h y p er bilir u bi ne mia) or li v er 
metastases at bas eli ne  
1 3.  A de q uate  bl o o d cl otti n g f u ncti o n wit hi n 1 4  d a ys b ef ore ra n d o mizati o n, defi ne d as:  
 I nter nati o nal n or malize d rati o/ pr ot hr o m bi n ti me ≤1. 5 × U L N  a n d eit her partial 
t hr o m b o plasti n or acti vate d partial t hr o m b o plasti n ti me  
1 4.  Male  a n d fe male s u bjects of re pr o d ucti ve/c hil d beari n g p ote ntial m ust a gree t o use a 
hi g hl y effecti ve f or m of c o ntrace pti o n or a v oi d i nterc o urse d uri n g a n d u p o n c o m pleti o n 
of t he st u d y a n d after t he last d ose of T -D X d  f or at least 7 m o nt hs f or fe mal es or 4. 5 
m o nt hs f or males  or acc or di n g t o t he  la bel a p pr o v e d i n t he c o u ntr y of dr u g a d mi nistrati o n 
f or t he p h ysicia n’s c h oic e treat me nts.2 0  Male s u bjects m ust a gree t o i nf or m all fe male 
part ners t hat t he y are p artici pat i n g i n a cli nical trial t hat ma y ca use birt h defects.  
Met h o ds c o nsi dere d as hi g hl y effecti ve met h o ds of c o ntrace pti o n 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 ntr a va gi nal 
 Tra ns der m al  
 Pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n a ss ociate d wit h i n hi biti o n of o v ulati o n: 
 Oral  
 I nje cta ble 
 I m pla nta bl e 
 I ntr a uteri ne d e vice 
 I ntr a uteri ne h or m o ne-rel easi n g s yst e m 
 Bilateral t u bal occl usi o n  
 Vasect o miz e d part ner  
 T he relia bilit y of c o m plete se x ual a bsti ne nce nee ds t o be e val uate d i n r elati o n t o t he 
d urati o n of t he cli nical tri al a n d t he preferre d a n d us ual lifest yle of t he s u bject.  
S u bjects i n t his st u d y s h o ul d refrai n fr o m heter ose x ual i nterc o urse d uri n g a n d u p o n 
c o m pleti o n of t he st u d y a n d f or at least 7 m o nt hs f or fe males or 4. 5 m o nt hs f or ma les 
after t he l ast d ose of T -D X d  or acc or di n g t o t he la bel a p pr o ve d i n t he c o u ntr y of dr u g 
a d mi nistrati o n  f or t he p h ysicia n’s c h oice treat me nt. Peri o dic a bsti ne nce (e g, cale n dar, 
o v ulati o n, s y m pt ot her mal, p ost o v ulati o n met h o ds), declarati o n of a bsti ne nce f or t he 
d urati o n of e x p os ure t o st u d y dr u g, a n d wit h dra wal are n ot acce pta bl e met h o ds of 
c o ntrace pti o n.  
N o n -c hil d beari n g p ot e ntial is defi ne d as pre me n o pa usal fe mal es wit h a d oc u me nte d t u bal 
li gati o n or h ysterect o m y; or p ost me n o pa usal defi n e d as 1 2 m o nt hs  o f s p o nta ne o us 

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a me n orr hea (i n q uesti o na ble cases, a bl o o d sa m ple wit h si m ulta ne o us f ollicle -sti m ulati n g 
h or m o ne > 4 0 mI U/ m L a n d estra di ol < 4 0  p g/ m L [ < 1 4 7 p m ol/ L] is c o nfir mat or y).  
Fe males o n h or m o ne re pl ace me nt t hera p y ( H R T) a n d w h ose me n o pa usal stat us is i n 
d o u bt will be re q uire d t o use 1  of t he c o ntr ace pti o n met h o ds o utli ne d f or w o me n of 
c hil d beari n g p ote ntial if t he y wis h t o c o nti n ue t heir H R T d uri n g t h e st u d y.  Ot her wise, 
t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal stat us pri or t o st u d y 
e nr oll me nt.  F or m ost f or ms of H R T, at least 2 t o 4 wee ks  will ela pse b et w ee n t he 
cessati o n of t hera p y a n d t he bl o o d dra w; t his i nter val de pe n ds o n t he t y pe a n d d osa ge of 
H R T.  F oll o wi n g c o nfir mati o n of t heir p ost me n o pa usal stat us, t he y ca n res u me use  of 
H R T d uri n g t he st u d y wit h o ut use of a c o ntrace pti ve met h o d.  
I n P ort u g al  o nl y , p le ase see Secti o n  1 7. 9. 2  f or te xt a p plic a ble t o sites i n P ort u g al . 
1 5.  Male s u bjects m ust n ot freeze or d o nate s p er m starti n g at Scree ni n g a n d t hr o u g h o ut t he 
st u d y peri o d, a n d at least 4. 5 m ont hs  after t he fi nal st u d y treat me nt a d mi nistrati o n  or 
acc or di n g t o t he  la b el a p pr o ve d i n t he c o u ntr y of dr u g a d mi nistrati o n f or t he p h ysici a n’s 
c h oice treat me nts .  Preser vati o n of s per m s h o ul d be c o nsi dere d pri or t o e nr oll me nt i n t his 
st u d y. 
1 6.  Fe male  s u bjects m ust n ot d o nate o va , or retrie v e f or t heir o w n use, fr o m t he ti me of 
Scree ni n g a n d t hr o u g h o ut t he st u d y treat me nt peri o d, a n d f or at least 7  m o nt hs  after t he 
fi nal st u d y treat me nt a d mi nistrati o n or acc or di n g t o t he  la bel a p pr o ve d i n t he c o u ntr y of 
dr u g a d mi nistrati o n  f or t he p h ysici a n’s c h oice treat me nts. 
1 7.  Has a de q u ate treat me nt was h o ut peri o d bef ore ra n d o mizati o n/e nr oll me nt, defi ne d as  
chl or o q ui ne/ h y dr o x yc hl or o q ui ne > 1 4 da ys . 
4. 2.  
E xcl usi o n Criteri a  
S u bjects w h o meet a n y of t he f oll o wi n g criteri a will be dis q ualifie d fr o m e nteri n g t he st u d y .  T h e 
I n v esti gat or s h o ul d f oll o w t he la bel a p pr o v e d i n t he c o u ntr y of dr u g a d mi nistrati o n f or t he 
i n di vi d ual treat me nt o pti o ns (ca pecita bi ne, eri b uli n, ge m cita bi ne, paclita xel, or na b-paclita x el)  
f or eli gi bilit y criteri a if t he s u bject is ra n d o mize d t o t he ar m of treat me nt of p h ysici a n’s c h oice.  
T he e x cl usi o n criteria i ncl u de:  
1.  I n eli gi ble f or t he declare d p h ysicia n’s c h oice c o m parat or b eca us e of pre vi o usl y ha vi n g 
recei v e d treat me nt wit h t he sa me c o m parat or  i n t h e metastatic setti n g or t he c o m parat or 
is c o ntrai n dicat e d.  S u bje cts are eli gi ble  t o be treat e d wit h a c o m parat or wit h w hic h t he y 
ha ve n ot pre vi o usl y  bee n treate d.    
2.  Pri or treat me nt wit h a nti b o d y dr u g c o nj u gate t hat c o nsists of a n e x ateca n d eri vati ve t hat 
is a t o p ois o merase I i n hi bit or i ncl u di n g pri or partici pati o n i n a st u d y i n v ol vi n g a n A D C 
pr o d uce d b y D aiic hi Sa n k y o  a n d/ or Astra Ze neca . 
3.  U nc o ntr olle d  or si g nifica nt car di o vasc ul ar diseas e, i ncl u di n g a n y of t h e f oll o wi n g:  
a. Hist or y of m y o car dial i nfarcti o n wit hi n 6 m o nt hs  bef ore ra n d o mizati o n, tr o p o ni n 
le vels c o nsiste nt wit h m y ocar dial i nfarcti o n as d efi ne d acc or di n g t o t he m a n ufact ur er 
2 8 da ys pri or t o ra n d o mi zati o n 
b.  Hist or y of s y m pt o matic c o n gesti ve h eart fail ure ( Ne w Y or k Heart Ass ociati o n Class 
II t o I V) 

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c. C orrecte d Q T i nter val ( Q Tc) pr ol o n gati o n t o > 4 7 0  ms (fe males) or > 4 5 0  ms ( male) 
base d o n a vera ge of Scree ni n g tri plicat e 1 2 lea d E C Gs  
4.  Has a hist or y of  ( n o ni nfecti o us) I L D/ p ne u m o nitis t hat re q uire d ster oi ds, has c urre nt 
I L D/ p n e u m o nitis, or w here s us pecte d I L D/ p ne u m o nitis ca n n ot be r ule d o ut b y i ma gi n g at 
S cree ni n g.  
5.  Has s pi nal c or d c o m pressi o n or cli nicall y acti ve ce ntral ner v o us s yste m metastases, 
defi ne d as u ntreate d or s y m pt o matic, or re q uiri n g t hera p y wit h c ortic oster oi ds or 
a ntic o n v ulsa nts t o c o ntr ol ass ociate d s y m pt o ms.  
 S u bjects wit h treate d brai n metastases t hat are n o l o n ger s y m pt o matic a n d w h o 
re q uire n o tr eat me nt wit h c ortic oster oi ds or a ntic o n vulsa nts ma y be i n cl u de d i n t he 
st u d y if t he y ha v e rec o vere d fr o m t he ac ute t o xic effect of ra di ot hera p y.  A mi ni m u m 
of 2 w eek s m ust ha v e ela pse d bet wee n t h e e n d of w h ole brai n r a di ot hera p y a n d st u d y 
e nr oll me nt.  
6.  Has m ulti ple pri mar y m ali g na nci es wit hi n 3 y ears, e x ce pt a de q uatel y resect e d n o n-
mela n o ma s ki n ca ncer, c urati vel y treate d i n sit u disease, or c o ntralateral br east ca n cer.  
7.  Has a hist or y of se v ere h y p erse nsiti vit y reacti o ns t o eit her t he dr u g s u bsta n ces or i nacti ve 
i n gre di e nts i n t he dr u g pr o d uct. 
8.  Has a hist or y of se v ere h y p erse nsiti vit y reacti o ns t o ot her m o n ocl o nal a nti b o dies.  
9.  Has a n u nc o ntr olle d i nf ecti o n re q uiri n g I V a nti bi otics, a nti virals, or a ntif u n gals.  
1 0.  S u bsta nce a b use or me dical c o n diti o ns s uc h as cli nicall y si g nifica nt car di ac or p ul m o nar y 
di seases or ps yc h ol o gic al c o n diti o ns, t hat ma y , i n t he o pi ni o n of t he I n vesti gat or, 
i nterfere wit h t he s u bject’s partici pati o n i n t he cli nical st u d y or e val uati o n of t he cli nical 
st u d y res ults. 
1 1.  S ocial, fa milial, or ge o gra p hical fact ors t hat w o ul d i nterfere w it h st u d y p artici pati o n or 
f oll o w-u p.  
1 2.  Has k n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n or acti ve he patitis B or C 
i nfecti o n.  S u bject s p ositi ve f or he p atitis C ( H C V) a nti b o d y are eli gi ble o nl y if 
p ol y merase c h ai n reacti o n is ne gati ve f or H C V R N A .  S u bjects s h o ul d be teste d f or HI V 
pri or t o ra n d o mizati o n if re q uire d b y l ocal re g ulati o ns or I R B/ IE C .  
I n P ort u g al o nl y , p le ase see Secti o n 1 7. 9. 2  f or te xt a p plic a ble t o sites i n P ort u g al. 
1 3.  Has u nres ol ve d t o xicities fr o m pre vi o us a ntica ncer t hera p y, d efi ne d as t o xicities ( ot her 
t ha n al o pecia) n ot yet res ol ve d t o Gra de ≤1 or bas eli ne.  S u bjects wit h c hr o nic Gra de 2 
t o xicities ma y be eli gi ble per t he discreti o n of t he I n v esti gat or aft er c o ns ult ati o n wit h t he 
S p o ns or Me dical M o nit or or desi g nee (e g, Gra d e 2 c he m ot hera p y -i n d uce d ne ur o pat h y). 
1 4.  T hera p e utic ra diati o n t hera p y or maj or s ur ger y wit hi n 4 w eek s bef ore st u d y treat me nt or 
palliati ve stere otactic ra diati o n t hera p y wit hi n 2 w eek s bef ore st u d y treat me nt.  
1 5.  S yste mic treat me nt wit h a ntica ncer t hera p y  (i m m u n ot hera p y [ n o n-a nti b o d y-b ase d 
t hera p y], reti n oi d t hera p y,) or h or m o nal t hera p y wit hi n 3 wee ks  bef ore st u d y treat me nt;  
a nti b o d y-b ase d -a ntica ncer -t hera p y wit hi n 4 week s bef ore ra n d o mizati o n;  or treat me nt 

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wit h nitr os o ureas or mit o m yci n C wit hi n 6 wee ks  bef ore st u d y tr eat me nt; or treat me nt 
wit h s mall -m olec ule tar gete d a ge nts wit hi n 2 wee ks , or 5  half -li ves, w hic h e ver is l o n ger. 
1 7.  Partici pati o n i n a t hera pe utic cli nical st u d y wit hi n 3 wee ks  bef ore st u d y tr eat me nt (f or 
s mall-m olec ule tar get e d a ge nts, t his n o n partici pati o n peri o d is 2  w eek s or 5  half -li ves, 
w hic he ver is l o n ger), c urre nt partici pati o n  i n ot her t hera pe utic i n vesti gati o n al pr oce d ures 
or pri or partici p ati o n i n t his i n vesti gati o nal trial .  
1 8.  Is pre g na nt or breastfee di n g, or pla n ni n g t o bec o m e pre g na nt. 
1 9.  S u bject m ust n ot be st u d y site pers o n nel or S p o ns or e m pl o yee dir ectl y i n v ol ve d i n t he 
cli nical trial, or a n i m me diate fa mil y m e m ber of s o me o ne directl y i n v ol ve d.   
2 0.  Ot her wise c o nsi d ere d i na p pr o priate f or t he st u d y b y t he I n v esti gat or.   
2 1.  Cli nicall y s e vere p ul m o nar y c o m pr o mise res ulti n g fr o m i nterc urre nt p ul m o nar y ill nesses 
i ncl u di n g, b ut n ot li mite d t o, a n y u n d erl yi n g p ul m o nar y dis or der (ie , p ul m o nar y e m b oli 
wit hi n t hree m o nt hs of t he st u d y e nr oll me nt, se vere ast h ma, se vere chr o nic o bstr ucti ve 
p ul m o nar y dise ase  [C O P D ], restricti ve l u n g dise ase, ple ural eff usi o n etc), a n d a n y 
a ut oi m m u ne, c o n necti ve tiss ue or i nfla m mat or y dis or ders wit h p ul m o nar y i n v ol ve me nt 
(ie, rhe u mat oi d art hritis, Sj ö gre n’s , s arc oi d osis etc), or pri or p ne u m o n ect o m y.  
4. 3.  
S u bject Re pl ace me nt  
Ra n d o mize d s u bjects will n ot be re place d.  
4. 4.  
S u bject Re -scree ni n g Pr oce d ures 
Re -scree ni n g is per mitte d f or a n y s u bject w h o faile d t o meet eli gi bilit y criteria u p o n i nitial 
scree ni n g.  T h e SI D n u m ber m ust re m ai n t he s a me  at t he ti me of re -scree ni n g.  T h e i nitial 
scree ni n g i nf or mati o n a n d t he reas o n w h y t h e s u bject was i neli gi ble f or t h e i nitial e val uati o n will 
be rec or de d o n t he Scree ni n g L o g.  N o data fr o m t he i nitial e val uati o n will be e ntere d i nt o t he 
cli nical data bas e f or a s u bject w h o was re -scree ne d (see St u d y M a n ual f or details). 

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5.  
S T U D Y T R E A T M E N T S  
5. 1.  
Assi g ni n g S u bjects t o Tre at me n ts a n d Bli n di n g 
5. 1. 1.  
Tre at me nt Gr o u p s 
T here will be 2 tr eat me nt ar ms, T -D X d  a n d p h ysicia n’s c h oice.  T h ere are 5 o pti o ns w it hi n 
p h ysicia n’s c h oice:  
 Ca pecita bi ne  
 Eri b uli n  
 Ge mcita bi ne  
 Paclita x el  
 Na b -paclita x el  
T he o pti o n c h ose n m ust be declare d f or eac h i n di vi d ual s u bject bef ore ra n d o mizati o n.  O nce 
assi g ne d, s u bj ects will re mai n o n st u d y i n t heir treat me nt ar m a n d will n ot c ha n ge ar ms.  Wit hi n 
p h ysicia n’s c h oice, t h e s u bject m ust re mai n o n t he declare d o pti o n f or his/ her d urati o n wit hi n t he 
st u d y. 
5. 1. 2.  
Met h o d of Tre at me nt All oc ati o n  
Pri or t o ra n d o mizati o n of a s u bject, t he I C F m ust be si g ne d a n d all eli gi bilit y criteria m ust be 
met.  
S u bjects will be ra n d o mize d i nt o 1 of t he 2 treat me nt ar ms ( T -D X d  vers us p h ysicia n’s c h oice) i n 
a 2: 1 rati o.  T he ra n d o mizati o n will be stratifie d b y  
 H E R 2 I H C stat us of tiss ue sa m ples assesse d b y a ce ntral la b orat or y:  H E R 2  I H C 1+  
vs . H E R 2 I H C  2 + /I S H- 
 N u m ber of pri or li nes of c he m ot hera p y:  1 vs . 2  
 H R/ C D K stat us :  H R -p ositi ve wit h pri or C D K 4/ 6 i n hi bit or treat me nt vs. H R -p ositi ve 
wit h o ut pri or C D K 4/ 6 i n hi bit or treat me nt vs. H R -ne gati ve . 
Ra n d o mizati o n will be ma na ge d t hr o u g h a n I nteracti ve We b/ V oice Res p o nse S yste m (I X R S) f or 
s u bjects meeti n g all eli gi bilit y criteria.  T h e directi o ns o n h o w t o use t he s yste m will be pr o vi de d 
i n t he I X R S Q uic k Refere nce Ma n u al. 
All s u bjects will ha ve p h ysicia n’s c h oice treat me nt declare d a n d rec or de d i n t he I X R S pri or t o 
ra n d o mizati o n. 
5. 1. 3.  
Bli n di n g  
It is n ot feasi ble t o bli n d treat me nt all ocati o ns f or i n di vi d ual s u bjects beca use of differe nt r o utes 
of a d mi nistrati o n, differe nt treat me nt sc he d ules, a n d differe nt A E pr ofiles bet wee n T -D X d  a n d 
p h ysicia n’s c h oice t h era p y.  T he pri mar y e n d p oi nt of P F S will be base d o n BI C R.  T he st u d y 
tea m will n ot perf or m or ha ve access t o efficac y a nal ysis/s u m mar y d uri n g t he st u d y.  

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A n i n de pe n de nt bi ostatisticia n will ge n erat e t he ra n d o mizati o n sc he d ule  per t he ra n d o mizati o n 
s pecificati o n. 
5. 1. 4.  
E mer ge nc y U n b li n di n g Pr o ce d ure  
N ot a p plica ble as t he st u d y is o pe n la b el.  
5. 2.  
St u d y Dr u g  
5. 2. 1.  
Descri pti o n  
L y o p hiliz e d p o w der ( L y o -D P)  
T -D X d  f or i njecti o n 1 0 0 m g L y o -D P will be pr o vi de d as a l y o p hilize d p o w der c o ntai ni n g 
1 0 0  m g of T -D X d  i n a gl ass vial.  Eac h glass vial s h o ul d be rec o nstit ute d t o a c o nce ntrati o n of 
2 0  m g/ m L.  Eac h vi al is desi g ne d f or si n gle us e o nl y a n d is n ot t o be use d t o treat m ore t ha n 1 
s u bject.   
T he starti n g d os e of 5. 4 m g/ k g will be base d o n b o d y wei g ht.   
5. 2. 2.  
L a beli n g a n d P ac k a gi n g  
T -D X d  f or i njecti o n 1 0 0 m g L y o -D P will be s u p plie d b y t he S p o ns or.  T -D X d  f or i njecti o n 
1 0 0  m g will be pac ka g e d a n d la bele d i n c o m plia nce wit h re g ulat or y re q uir e me nts.  T he 
pac ka gi n g will cle arl y dis pla y t he n a me of t he st u d y treat me nt, t he l ot n u m ber, st ora ge c o n diti o n, 
a n d ot her re q uire d i nf or mati o n i n acc or da n ce wit h l ocal re g ulati o ns.  
5. 2. 3.  
Pre p ar ati o n  
T -D X d  f or I V i nf usi o n is pre pare d b y dil uti o n of t he re q uir e d v ol u me of t h e dr u g pr o d uct 
calc ulate d b ase d o n t he s u bject’s b o d y wei g ht.  Pre pare d st u d y tr eat me nt i nf usi o n s ol uti o ns 
s h o ul d be pre pare d a n d use d as direct e d i n t he p har mac y i nstr ucti o ns.  Pr oce d ures f or pr o per 
ha n dli n g a n d dis p osal of a ntica ncer dr u gs s h o ul d be f oll o we d i n c o m plia nce wit h t he sta n dar d 
o perati n g pr oce d ures ( S O Ps) of t he st u d y site.   
5. 2. 4.  
A d mi nistr ati o n  
T -D X d  will be a d mi nistere d  at a b o d y wei g ht – bas e d d ose of 5 . 4 m g/ k g i nitiall y as a n I V i nf usi o n 
o ver 3 0 t o 9 0 mi n utes  e v er y 2 1  d a ys ( ±2 d a ys).  T he i nitial d ose of T -D X d  will be i nf use d f or 
a p pr o xi matel y 9 0  mi n utes .  If t here is n o i nf usi o n relate d reacti o n, after t he i nitial d ose, t he ne xt 
d oses of T -D X d  will be i nf use d f or a mi ni m u m of 3 0 mi n utes .  T he s u bject’s wei g ht at Scree ni n g 
( baseli ne) will be us e d t o calc ulate t he i nitial d ose.  If d uri n g t he c o urse of treat me nt, t he 
s u bject’s wei g ht c ha n ges b y ≥± 1 0 % of t h e baseli n e wei g ht, t he s u bject’s d ose will be 
recal c ulate d bas e d o n t he s u bject’s u p date d wei g ht.  Refer t o t he p har mac y i nstr ucti o ns f or 
detaile d i nf or mati o n a b o ut a d mi nistrati o n of T -D X d . 
T -D X d  s h o ul d o nl y b e i nitiate d b y a p h ysici a n or healt hcare pr ofessi o nal e x perie nce d i n t he 
a d mi nistrati o n of c yt ot o xic c he m ot hera p y.  Me dici nal pr o d ucts t o treat aller gic/a n a p h ylactic 
i nf usi o n reacti o ns, as w ell as e mer ge n c y e q ui p me nt, s h o ul d be a vaila ble f or i m me diate use. 

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5. 2. 5.  
St or a ge  
T -D X d  f or i njecti o n 1 0 0 m g m ust be st ore d i n a s ec ure, li mite d-access st ora ge area u n der t he 
st ora ge c o n diti o ns liste d bel o w: 
 St ore d at 2° C t o 8° C ( pr otecte d fr o m li g ht) f or  l y o p hilize d p o w der   
If st ora ge c o n diti o ns are n ot mai ntai ne d per s pecifie d re q uire m e nts, t he S p o ns or or c o ntract 
researc h or ga niz ati o n ( C R O) s h o ul d be c o ntacte d. 
F or st ora ge of t he i nf usi o n s ol uti o ns, see p har mac y i nstr ucti o ns. 
5. 2. 6.  
Dr u g Acc o u nt a bilit y  
W he n a dr u g s hi p me nt is recei v e d  fr o m t he S p o ns or, t he I n vesti gat or or d esi g nee will c hec k t he 
a m o u nt a n d c o n diti o n of t he dr u g, c hec k f or a p pr o priate l ocal la n g u a ge i n t he la bel, c hec k  dr u g 
e x pirati o n date, a n d ac k n o wle d ge recei pt i n I X R S.  I n a d diti o n, t he I n vesti gat or or desi g nee will  
c o ntact t he S p o ns or as s o o n as p ossi ble if t here is a pr o ble m wit h t he s hi p me nt.  
A  Dr u g Acc o u nta bilit y R ec or d will be pr o vi d e d f or st u d y tr eat me nt ( T -D X d / p h ysicia n’s c h oice).  
T he rec or d m ust be ke pt c urre nt a n d s h o ul d c o ntai n t he f oll o wi n g:  
 D ates a n d q ua ntities of dr u g recei ve d  
 S u bject’s SI D a n d/ or i nitials or s u p pl y n u m ber (as a p plica ble)  
 T he date a n d q u a ntit y of st u d y treat me nt dis pe nse d a n d re ma i ni n g (if fr o m i n di vi d ual 
s u bject dr u g u nits)  
 Initials of t he dis pe ns er  
At t he st u d y cl os ur e, or as directe d, all st u d y treat me nt, i ncl u di n g u n use d, partiall y us e d, or 
e m pt y c o nt ai ners, will be ret ur ne d t o a desi g n ee as i nstr ucte d b y S p o ns or.  St u d y dr u g will be 
ret ur ne d o nl y after t he st u d y m o nit or has c o m plet e d a fi nal i n ve nt or y t o v erif y t h e q ua ntit y t o b e 
ret ur ne d.  T h e ret ur n of st u d y dr u g m ust be d oc u m e nte d a n d t he d oc u me ntati o n i ncl u de d i n t he 
s hi p me nt.  At st u d y cl os ure, a fi n al st u d y dr u g rec o nciliati o n state me nt m ust be c o m plete d b y t he 
I n v esti gat or or desi g nee a n d pr o vi de d t o t he S p o ns or.  See p har m ac y i nstr ucti o ns f or details. 
U n use d st u d y dr u g s u p plies ma y b e destr o ye d b y t he I n vesti gat or w h e n a p pr o ve d i n writi n g b y 
t he S p o ns or , t he S p o ns or has  recei ve d c o pi es of t h e st u d y site’s dr u g ha n dli n g a n d dis p ositi o n 
S O Ps , a n d it is ass ure d t hat t he S p o ns or will recei v e c o pies of t he certificate of destr ucti o n t hat is 
tracea ble t o t he st u d y treat me nt. 
All i n vesti gati o nal pr o d u ct i n ve nt or y f or ms m ust be ma de a v aila ble f or i ns pecti o n b y a S p o ns or -
a ut h orize d re pres e ntati ve or desi g n ee a n d Re g ulat or y A ge nc y i ns pe ct ors.  
5. 3.  
C o ntr ol Tre at me nt  
S u bjects ra n d o mize d t o p h ysicia n’s c h oice will be treate d wit h 1 of t he f oll o wi n g a ge nts:  
 Ca pecita bi ne  
 Eri b uli n  
 Ge mcita bi ne  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 7  
 Paclita x el  
 Na b -paclita x el  
Acc o u nta bilit y f or In v esti gat or’s c h oice m e dicati o ns will f oll o w t he T -D X d  pr oce d ures 
(Secti o n  5. 2. 6 ).  St ora ge f or all me dicati o ns m ust f oll o w st ora ge i nstr ucti o ns pri nte d o n t he 
pr o d uct la bel .  D osa ge, re gi me n, a n d d ose m o difi cati o n m ust f oll o w t he la bel a p pr o ve d i n t he 
c o u ntr y of dr u g a d mi nistrati o n  or t he N C C N g ui deli nes 1 (see Ta ble  5 .1 ).  A 2 1 -da y c ycl e 
re gi me n is rec o m me n d e d if t here are m ulti ple o pti o ns i n t he la bel a p pr o ve d i n t he c o u ntr y of 
dr u g a d mi nistrati o n  or t he N C C N g ui deli nes .1  If a s u bject recei ves a c o m p arat or wit h a re gi me n 
ot her t ha n 2 1 da ys, t he I n vesti gat or s h o ul d e ns ure t hat t he s u bject f oll o ws t he st u d y -d efi ne d 
sc he d ule of e ve nt (see Secti o n 1 7. 1 ) i nter val per a 2 8 -da y c ycl e. H o we ver, tu m or assess me nts 
a n d C T/ M RI of t he b rai n m ust be perf or me d e ver y 6 wee ks + 7 d a ys  fr o m r a n d o mizati o n date. 
La b orat or y a n d safet y assess me nt bef ore dr u g a d mi nistrati o n s h o ul d be a p pr o priatel y perf or me d 
acc or di n g t o t he la b el a p pr o ve d i n t he c o u ntr y of dr u g a d mi nistrati o n .  Treat me nt of p h ysi cia n’s 
c h oice will be s u p plie d b y t he l ocal p har mac y  or site  a n d rei m b u rse d b y t he S p o ns or w here 
necessar y .  Me dic ati o n will be ce ntrall y s u p plie d b y t he S p o ns or or d ele gate d ve n d or i n t he e ve nt 
t hat a partic ular c o u ntr y or site ca n n ot l ocall y s o urce t he a p pr o ve d m e dicati o ns . 
A d mi nistrati o n a n d d ose m o dificati o n s h o ul d be d o ne acc or di n g t o t he la bel a p pr o ve d i n t he 
c o u ntr y of dr u g a d mi nistrati o n  or t he N C C N g ui deli nes 1 (see Ta ble  5 .1 ). 
T a ble  5 .1 : 
D ose Re gi me ns f or P h ysici a n’s C h oice per t he N C C N G ui deli nes 1 
C o m p ar at or  
D osi n g Re gi me n  
Ca p ecita bi ne  
1 0 0 0 -1 2 5 0 m g/ m 2 P O t wice d ail y Da ys 1 -1 4; c ycle d e ver y 2 1 da ys  
Eri b uli n  
1. 4 m g a/ m2 I V Da ys 1 a n d 8; c ycle d e ver y 2 1 da ys 
Ge mcita bi ne  
8 0 0 -1 2 0 0 m g/ m 2 I V Da ys 1, 8, a n d 1 5; c ycle d e ver y 2 8 da ys 
P aclita xel  
O pti o n 1: 1 7 5 m g/ m 2 I V Da y 1; c ycle d e ver y 2 1 da ys 
O pti o n 2: 8 0 m g/ m 2 I V Da y 1 wee kl y  
Na b -paclita xel  
O pti o n 1: 2 6 0 m g/ m 2 I V; c ycl e d e ver y 2 1 da ys  
O pti o n 2: 1 0 0 m g/ m 2 or 1 2 5  m g/ m 2 I V Da ys 1, 8, a n d 1 5; c ycle d e ver y 2 8 da ys 
a Refers t o eri b uli n mes ylate. 1. 2 3 m g eri b uli n base = 1. 4 m g eri b uli n mes ylate  
5. 4.  
G ui deli nes f or D ose M o dific ati o n  
5. 4. 1.  
D ose I nterr u pti o ns a n d Re d ucti o ns  
T he I n vesti gat or will e v al uate w hic h t o xicities are attri b ute d t o t he st u d y tr eat me nt a n d a dj ust t he 
d ose of t he dr u g as rec o m me n de d i n Secti o n  5. 4. 1. 1  f or T -D X d  a n d as p er la bel a p pr o ve d i n t he 
c o u ntr y of dr u g a d mi nistrati o n f or p h ysicia n’s c h oice treat me nt (s ee Secti o n 5. 4. 1. 2 ).  All d ose 
m o dificati o ns s h o ul d be base d o n t he w orst prece di n g t o xicit y ( C o m m o n Ter mi n ol o g y Criteri a 
f or A d verse E ve nts [ C TC A E] versi o n 5 . 0).  All i nterr u pti o ns or m o dificati o ns m ust be rec or de d 
o n t he A E a n d dr u g a d mi nistrati o n electr o nic case re p ort f or m (e C R F).  A p pr o priate cli nical 
e x perts s h o ul d be c o ns ulte d as dee m e d necessar y.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 8  
I n v esti gat ors ma y c o nsi d er d ose re d ucti o ns or disc o nti n uati o ns of t he st u d y treat me nt acc or di n g 
t o t he s u bject’s c on diti o n a n d after disc ussi o n wit h a n d a p pr o val fr o m t he S p o ns or Me dical 
M o nit or or desi g n ee.  
F or Gra de 3 or Gra d e 4 e ve nts  assesse d as relate d t o use of T -D X d  b y t he I n vesti gat or(s) , 
m o nit ori n g (i ncl u di n g l ocal la b orat or y  tests w he n a p pr o priate) s h o ul d be perf or me d at i nter vals 
n o greater t ha n 7  da ys  u ntil t he A E is deter mi ne d t o be res ol vi n g.  
Pr o p h yla ctic or s u p p orti v e treat me nt f or e x pecte d t o xicities, i ncl u di n g ma na ge m e nt of st u d y 
treat me nt– i n d uce d A Es will be as per treati n g p h ysicia n discreti o n a n d i nstit uti o nal g ui deli nes.  
5. 4. 1. 1.  
D ose I nterr u pti o ns a n d Re d ucti o ns f or T -D X d  
N O T E:  T here will be n o d ose m o dificati o ns f or Gra de 1 or Gra d e 2 A Es u nless s pecifie d bel o w 
i n Ta ble  5 .3 . 
All d ose m o dificati o ns (i nterr u pti o n, re d ucti o n , a n d/ or disc o nti n uati o n) s h o ul d be base d o n t he 
w orst prece di n g t o xicit y ( C T C A E versi o n 5. 0).  
S pecific criteria f or i nterr u pti o n, re -i nitiati o n, d ose re d ucti o n, a n d/ or disc o nti n uati o n of T -D X d  
are a p plic a ble o nl y t o T E A Es t h at are assesse d as rel ate d  t o t he use of T -D X d  b y t he 
i n vesti gat or(s).  F or n o n-dr u g relate d T E A Es, f oll o w sta n dar d cli nical practice.  A p pr o priat e 
cli nical e x perts s h o ul d be c o ns ult e d as dee m e d necessar y.  
T w o d ose re d u cti o ns will be per mitte d. T he a dj ust me nt f or re d u ce d d osi n g of T -D X d  d e pe n d s o n 
t he i nitial starti n g d ose, as s h o w n i n Ta ble  5 .2 . 
T a ble  5 .2 : 
D ose Re d ucti o n Le vels of T -D X d   
St a rti n g D ose  
D ose Le vel -1  
D ose Le vel -2  
5. 4  m g/ k g  
4. 4  m g/ k g  
3. 2  m g/ k g  
O nce t he d ose of T -D X d  has bee n re d uce d beca us e of t o xicit y, all s u bse q ue nt c ycles s h o ul d be 
a d mi nistere d at t hat l o wer d ose le vel u nless f urt her d ose re d u cti o n is re q uir e d. If t o xicit y 
c o nti n ues after 2 d ose re d ucti o ns, t he s u bject will be wit h dr a w n fr o m t he st u d y tre at me nt.  
Refer t o Secti o n  5. 7  f or wit h dra wal/disc o nti n ua ti o n pr oce d ures.   
T -D X d  d ose i ncreas es are n ot all o we d i n t he st u d y.  
D ose I nterr u pti o n a n d M o dificati o n/ T o xicit y Ma n a ge me nt G ui deli nes: 
A d ose ca n b e dela ye d f or u p t o 2 8 da ys ( 4 9 da ys fr o m t he last i nf usi o n date) fr o m t he pla n ne d 
date of a d mi nistrati o n. If a s u bject is assesse d as re q uiri n g a d os e dela y of l o n ger t ha n 2 8 da ys, 
t he s u bject will be wit h dra w n fr o m t he st u d y.  Refer t o Secti o n  5. 7  f or 
wit h dr a w al/ disc o nti n u ati o n pr oce d ures.   
Treat me nt c ycl es f or a s u bject f or w h o m T -D X d  d osi n g is te m p oraril y wit h hel d f or a n y reas o n 
ma y h a ve f ut ure c ycl es s c he d ule d bas e d o n t he date t hat T -D X d  d osi n g was res u me d.  
All  c o nfir me d or s us pe cte d c or o na vir us disease 2 0 1 9 ( C O VI D -1 9 ) i nfecti o n e ve nts m ust be 
rec or de d i n t he e C R F.  Pl ease refer t o Secti o n  1 7. 8  f or a d diti o nal i nf or mati o n o n d ose 
m o dificati o n.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 9  
T a ble  5 .3 : 
D ose M o dific ati o n f or T -D X d  
W orst T o xicit y C T C A E v 5 . 0 Gr a de 
( u nless ot her wise s pecifie d) 
M a n a ge me nt G ui deli nes  f or T -D X d  
N o T o xicit y  
Mai ntai n d ose a n d sc he d ule  
I nf usi o n rel ate d Re acti o n 
Gra de 1  
( Mil d tra nsie nt reacti o n; i nf usi o n 
i nterr u pti o n n ot i n dicate d; i nter ve nti o n n ot 
i n dicate d) 
 
If i nf usi o n relate d reacti o n (s uc h as fe ver a n d 
c hills, wit h a n d wit h o ut na usea/ v o miti n g, pai n, 
hea dac he, dizzi ness, d ys p nea, h y p ote nsi o n) is 
o bser ve d d uri n g a d mi nistrati o n, t he i nf usi o n rate 
s h o ul d be re d uce d b y 5 0 % a n d s u bjects s h o ul d be 
cl osel y m o nit ore d.   
 
If n o ot her reacti o ns a p pear, t he s u bse q ue nt 
i nf usi o n rate c o ul d be res u me d at t he i nitial 
pla n ne d rate.  
Gra de 2  
( T hera p y or i nf usi o n i nterr u pti o n i n dicate d 
b ut res p o n ds pr o m ptl y t o s y m pt o matic 
treat me nt (e g, a nti hista mi nes, N S AI Ds, 
narc otics, I V fl ui ds); pr o p h ylactic 
me dicati o ns i n dicate d f or ≤2 4  h o urs ) 
 
A d mi nistrati o n of T -D X d  s h o ul d be i nterr u pte d 
a n d s y m pt o matic treat me nt starte d (e g, 
a nti hista mi nes, N S AI Ds, narc otics, I V fl ui ds).  
 
If t he e ve nt res ol ves or i m pr o ves t o Gra de 1, 
i nf usi o n ca n be re-starte d at a 5 0 % re d uce d 
i nf usi o n rate. 
 
S u bse q ue nt a d mi nistrati o ns s h o ul d be c o n d ucte d 
at t he re d uce d rate. 
Gra de 3 or 4  
( Pr ol o n ge d or life-t hreate ni n g 
c o nse q ue nces, ur ge nt i nter ve nti o n 
i n dicate d) 
 
A d mi nistrati o n of T -D X d  s h o ul d be disc o nti n ue d 
i m me diatel y a n d perma ne ntl y.  
 
Ur ge nt i nter ve nti o n i n dicate d.  A nti hista mi nes, 
ster oi ds, e pi ne p hri ne, br o nc h o dilat ors, 
vas o press ors, I V fl ui d t hera p y, o x y ge n i n halati o n , 
etc, s h o ul d be a d mi nistere d.  
He m at ol o gic T o xicit y  
Ne utr o p hil C o u nt Decre ase d  a n d/ or W hite Bl o o d Cell C o u nt Decre ase d  
Gra de 3  
 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2, t he n 
mai ntai n d ose  
Gra de 4  
 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2  
 
Re d uce d ose 1 le vel  
F e brile Ne utr o pe ni a  
(A bs ol ute ne utr o p hil c o u nt < 1 × 1 0 9/ L, 
fe ver > 3 8. 3° C or a s ustai ne d te m perat ure of 
≥3 8° C f or m ore t ha n 1  h o ur ) 
 
Dela y d ose u ntil res ol ve d  
 
Re d uce d ose b y 1 le vel  
L y m p h oc yte C o u nt Decre ase d  
Gra de 1 t o Gra de 3 l y m p h o pe nia  
 
N o d ose m o dificati o n  
Gra de 4 ( < 0. 2 × 1 0 9/ L) 
 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2:  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 0  
W orst T o xicit y C T C A E v 5 . 0 Gr a de 
( u nless ot her wise s pecifie d) 
M a n a ge me nt G ui deli nes  f or T -D X d  
 If res ol ve d i n ≤1 4 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 1 4 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
A n a e mi a 
Gra de 3  
(He m o gl o bi n < 8. 0  g/ d L); tra nsf usi o n 
i n dicate d 
 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2, t he n 
mai ntai n d ose  
Gra de 4  
Life -t hreate ni n g c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d 
 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2, t he n 
re d uce d ose 1 le vel 
Pl atelet C o u nt Decre ase d  
Gra de 3  
(P latelets < 5 0 t o 2 5 × 1 09/ L) 
 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1:  
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
Gra de 4  
(P latelets < 2 5 × 1 09/ L) 
 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1, t he n 
re d uce d ose 1 le vel 
C ar di ac T o xicit y  
S y m pt o matic c o n gesti ve heart fail ure  
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  
Decrease i n L V E F 1 0 %  t o 2 0 % (a bs ol ute 
val ue), b ut L V E F > 4 5 %  
 
C o nti n ue treat me nt wit h T -D X d  
L V E F 4 0 % t o ≤4 5 % a n d decrease is < 1 0 % 
(a bs ol ute val ue) fr o m baseli ne 
 
C o nti n ue treat me nt wit h T -D X d  
 
Re peat L V E F assess me nt wit hi n 3  wee ks  
L V E F 4 0 % t o ≤4 5 % a n d decrease is 
1 0 -2 0 % (a bs ol ute val ue) fr o m baseli ne  
 
I nterr u pt T -D X d  d osi n g  
 
Re peat L V E F assess me nt wit hi n 3 wee ks  
 
If L V E F has n ot rec o vere d t o wit hi n 1 0 % 
(a bs ol ute val ue) fr o m baseli ne, disc o nti n ue 
s u bj ect fr o m st u d y treatme nt  
 
If L V E F rec o vers t o wit hi n 1 0 % fr o m baseli ne, 
res u me st u d y dr u g treat me nt a n d mai ntai n d ose  
L V E F < 4 0 % or > 2 0 % (a bs ol ute val ue) 
decrease fr o m baseli ne 
 
I nterr u pt T -D X d  d osi n g  
 
Re peat L V E F assess me nt wit hi n 3 wee ks  
 
If L V E F < 4 0 % or > 2 0 % dr o p fr o m baseli ne is 
c o nfir me d, disc o nti n ue s u bject fr o m st u d y 
treat me nt 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 1  
W orst T o xicit y C T C A E v 5 . 0 Gr a de 
( u nless ot her wise s pecifie d) 
M a n a ge me nt G ui deli nes  f or T -D X d  
Electr o c ar di o gr a m  Q T Pr ol o n g e d 
Gra de 3  
(A vera ge Q T c  > 5 0 0  ms or > 6 0  ms c ha n ge 
fr o m baseli ne) 
 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1 ( Q T c 
≤4 8 0  ms) , deter mi ne if a n ot her me dicati o n t he 
s u bj ect was ta ki n g ma y be res p o nsi ble a n d ca n be 
a dj uste d or if t here are a n y c ha n ges i n ser u m 
electr ol ytes t hat ca n be c orrecte d , t he n 
 if attri b ute d  t o T -D X d , re d uce d ose 1 le vel 
Gra de 4  
( T orsa de de p oi ntes or p ol y m or p hic 
ve ntric ular tac h ycar dia or si g ns/s y m pt o ms 
of seri o us arr h yt h mia)  
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  
P ul m o n ar y T o xicit y  
If a s u bj ect de vel o ps ra di o gra p hic c ha n ges p ote ntiall y 
c o nsiste nt wit h I L D or de vel o ps a n ac ute o nset of ne w 
or w orse ni n g p ul m o nar y or ot her relate d 
si g ns/s y m pt o ms s uc h as d ys p nea, c o u g h, or fe ver, r ule 
o ut I L D/ p ne u m o nitis.  
If t he A E is c o nfir me d t o ha ve a n eti ol o g y ot her t ha n 
I L D/ p ne u m o nitis, f oll o w t he ma na ge me nt g ui da nce 
o utli ne d i n t he “ Ot her N o n -la b orat or y A d verse E ve nts” 
d ose m o dificati o n secti o n bel o w.  
If t he A E is sus pecte d t o be I L D/ p ne u m o nitis, treat me nt 
wit h st u d y dr u g s h o ul d be i nterr u pte d pe n di n g f urt her 
e val uati o ns.  
E val uati o ns s h o ul d i ncl u de:  
 
Hi g h res ol uti o n C T, 
 
P ul m o n ol o gist c o ns ultati o n  (infecti o us d isease 
c o ns ultati o n as cli nicall y i n dicate d)  
 
Bl o o d c ult ure a n d C B C. Ot her bl o o d  tests c o ul d 
be c o nsi dere d as nee de d  
 
C o nsi der br o nc h osc o p y a n d br o nc h oal ve olar 
la va ge if cli nicall y i n dicate d a n d feasi ble 
 
P ul m o nar y f u ncti o n tests a n d p ulse o xi metr y 
( S p O 2) 
 
A rterial bl o o d gases if cli nicall y i n dicate d 
 
O ne  bl o o d sa m ple c ollecti o n f or P K  (ce ntral 
la b orat or y) a nal ysis as s o o n as I L D/ p ne u m o nitis  is 
s us pecte d, if feasi ble. 
Ot her tests c o ul d be c o nsi dere d, as nee de d. 
If t he A E is c o nfir me d t o be I L D, f oll o w t he I L D 
ma na ge me nt g ui da nce as o utli ne d bel o w.  
All e ve nts of I L D re gar dless of se verit y or seri o us ness 
will be f oll o we d u ntil res ol uti o n i ncl u di n g after dr u g 
disc o nti n uati o n.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 2  
W orst T o xicit y C T C A E v 5 . 0 Gr a de 
( u nless ot her wise s pecifie d) 
M a n a ge me nt G ui deli nes  f or T -D X d  
Gra de 1  
T he a d mi nistrati o n of T -D X d  m ust be i nterr u pte d f or 
a n y I L D e ve nts re gar dless of gra de.  
 
M o nit or a n d cl osel y f oll o w -u p i n 2  t o 7 da ys f or 
o nset of cli nical s y m pt o ms a n d p ulse o xi metr y  
 
C o nsi der f oll o w -u p i ma gi n g i n 1 -2 wee ks ( or as 
cli nicall y i n dicate d). 
 
C o nsi der starti n g s yste mic ster oi ds (e g , at least 0. 5 
m g/ k g/ da y pre d nis o ne or e q ui vale nt) u ntil 
i m pr o ve me nt, f oll o we d b y gra dual ta per o ver at 
least 4 wee ks. 
 
If w orse ni n g of dia g n ostic o bser vati o ns des pite 
i nitiati o n of c ortic oster oi ds, t he n f oll o w Gra de 2 
g ui deli nes. *  
F or Gra de 1 e ve nts, T -D X d  ca n be restarte d o nl y if t he 
e ve nt is f ull y res ol ve d t o Gra de 0, t he n: 
 
If res ol ve d i n ≤2 8  da ys fr o m da y of o nset, 
mai ntai n d ose  
 
If res ol ve d i n > 2 8 da ys fr o m da y of o nset, re d uce 
d ose 1 le vel  
H o we ver, if t he e ve nt G ra de 1 I L D occ urs be y o n d c ycle 
da y 2 2 a n d has n ot res ol ve d wit hi n 4 9 da ys fr o m t he last 
i nf usi o n, t he dr u g s h o ul d be disc o nti n ue d. 
* If s u bject is as y m pt o matic, t he n s u bject s h o ul d still be 
c o nsi dere d as Gra de 1 e ve n if ster oi d treat me nt is gi ve n . 
Gra de 2  
Per ma ne ntl y d isc o nti n ue s u bj ect fr o m st u d y treat me nt. 
 
Pr o m ptl y start  a n d treat wit h  s yste mic ster oi ds 
(e g, at least 1 m g/ k g/ da y pre d nis o ne or 
e q ui vale nt) f or at least 1 4 da ys or u ntil c o m plete 
res ol uti o n of cli nical a n d c hest C T fi n di n gs, t he n 
f oll o we d b y  a gra d ual ta per  o ver at least 4 wee ks.  
 
M o nit or s y m pt o ms cl osel y.  
 
Re -i ma ge as cli nicall y i n dicate d. 
 
If w orse ni n g or n o i m pr o ve me nt i n cli nical or 
dia g n ostic o bser vati o ns i n 5 da ys,  
 C o nsi der  i ncreasi n g d ose of ster oi ds (e g, 2 
m g/ k g/ da y pre d nis o ne or e q ui vale nt) a n d 
a d mi nistrati o n ma y be s witc he d t o 
i ntra ve n o us (e g, met h yl pre d nis ol o n e). 
 Re -c o nsi der  a d diti o nal w or k -u p f or alter nati ve 
eti ol o gies as descri be d a b o ve.  
 Escalate  care as cli nicall y i n dicate d. 
Gra de 3 a n d 4  
Per ma ne ntl y disc o nti n ue s u bj ect fr o m st u d y treat me nt.  
 
H os pitalizati o n re q uire d.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 3  
W orst T o xicit y C T C A E v 5 . 0 Gr a de 
( u nless ot her wise s pecifie d) 
M a n a ge me nt G ui deli nes  f or T -D X d  
 
Pr o m ptl y i nitiate e m piric hi g h -d ose 
met h yl pre d nis ol o ne I V treat me nt (e g, 5 0 0 -1 0 0 0 
m g/ da y f or 3 da ys), f oll o we d b y at least 1. 0 
m g/ k g/ da y of pre d nis o ne ( or e q ui vale nt) f or at 
least 1 4 da ys or u ntil c o m plete res ol uti o n of 
cli nical a n d c hest C T fi n di n gs, t he n  f oll o we d b y a 
gra d ual ta per  o ver at least 4 wee ks.  
 
Re -i ma ge as cli nicall y i n dicate d. 
 
If still n o i m pr o ve me nt wit hi n 3 t o 5 da ys,  
 Re -c o nsi der  a d diti o nal w or k -u p f or alter nati ve 
eti ol o gies as descri be d a b o ve.  
 C o nsi der  ot her i m m u n o -s u p pressa nts a n d/ or 
treat per l ocal practice.  
Oc ul ar  
Gra de 3  
 
Dela y d ose u ntil res ol ve d t o ≤Gra de 1:  
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
mai ntai n d ose.  
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel. 
Gra de 4  
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  
Bl o o d  Cre ati ni ne  I ncre ase d 
Gra de 3  
( > 3 t o 6 × U L N) 
 
Dela y d ose u ntil res ol ve d t o ≤Gra de 2 or baseli ne, 
t he n re d uce d ose 1 le vel 
Gra de 4  
( > 6 × U L N) 
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  
He p atic T o xicit y  
A S T or A L T Wit h Si m ult a ne o us T ot al Bilir u bi n  
A S T/ A L T ≥3. 0 × U L N wit h si m ulta ne o us 
t otal bilir u bi n > 2. 0 × U L N 
 
Dela y st u d y me dicati o n u ntil dr u g -i n d uce d li ver 
i nj ur y ca n be r ule d o ut.   
 
If dr u g-i n d uce d li ver i nj ur y is r ule d o ut, t he 
s u bj ect s h o ul d be treate d acc or di n gl y, a n d 
res u m pti o n of st u d y treat ment ma y occ ur after 
disc ussi o n bet wee n t he I n vesti gat or a n d S p o ns or.  
 
If dr u g-i n d uce d li ver i nj ur y ca n n ot be r ule d o ut 
fr o m dia g n ostic w or k u p, per ma ne ntl y disc o nti n ue 
st u d y treat me nt. 
 
M o nit or A S T/ A L T a n d t otal bilir u bi n t wice 
wee kl y u ntil res ol uti o n or ret u r n t o baseli ne. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 4  
W orst T o xicit y C T C A E v 5 . 0 Gr a de 
( u nless ot her wise s pecifie d) 
M a n a ge me nt G ui deli nes  f or T -D X d  
A S T or A L T I ncre ase d  
Gra de 2 ( > 3. 0 t o 5. 0 × U L N if baseli ne was 
n or mal; > 3. 0 t o 5. 0 × baseli ne if baseli ne 
was a b n or mal)  
 
N o acti o n f or Gra de 2 A S T/ A L T  
Gra de 3 ( > 5. 0 t o 2 0. 0 × U L N if baseli ne 
was n or mal; > 5. 0 t o 2 0. 0 × baseli ne if 
baseli ne was a b n or mal)  
I n s u bj ects wit h o ut li ver metastases a n d 
s u bj ects wit h li ver metastases a n d baseli ne 
le vel ≤3 × U L N 
 
Re peat testi n g wit hi n 3  d a ys.  Dela y d ose u ntil 
res ol ve d t o ≤Gra de 1 if baseli ne ≤ 3 ×  U L N, 
ot her wise dela y d ose u ntil res ol ve d t o ≤ baseli ne , 
t he n: 
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
Gra de 3 ( > 8. 0 t o 2 0. 0 × U L N if baseli ne 
was n or mal; > 8. 0 t o 2 0. 0 × baseli ne if 
baseli ne was a b n or mal)  
I n s u bj ects wit h li ver metastases, if t he 
baseli ne le vel was > 3 × U L N  
 
Re peat testi n g wit hi n 3  d a ys.  Dela y d ose u ntil 
res ol ve d t o ≤ baseli ne le vel, t he n:  
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
Gra de 4 ( > 2 0. 0 × U L N if baseli ne was 
n or mal; > 2 0. 0 × baseli ne if baseli ne was 
a b n or mal) 
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  
T ot al Bilir u bi n I ncre ase d  
Gra de 2 ( > 1. 5 t o 3. 0 × U L N if baseli ne was 
n or mal; > 1. 5 t o 3. 0 × baseli ne if baseli ne 
was a b n or mal)  
 
If n o d oc u me nte d Gil bert’s s y n dr o me or li ver 
metastases at baseli ne, dela y d ose u ntil res ol ve d t o 
≤Gra de 1:  
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
 
If d oc u me nte d Gil bert’s s y n dro me or li ver 
metastases at baseli ne, c o nti n ue st u d y treat me nt  
Gra de 3 ( > 3. 0 t o 1 0. 0 × U L N if baseli ne 
was n or mal; > 3. 0 t o 1 0. 0 × baseli ne if 
baseli ne was a b n or mal)  
 
If n o d oc u me nte d Gil bert’s s y n dr o me or li ver 
metastases at baseli ne, re peat testi n g wit hi n 
3  d a ys.  Dela y d ose u ntil res ol ve d t o ≤Gra de 1: 
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
disc o nti n ue T -D X d  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 5  
W orst T o xicit y C T C A E v 5 . 0 Gr a de 
( u nless ot her wise s pecifie d) 
M a n a ge me nt G ui deli nes  f or T -D X d  
 
If d oc u me nte d Gil bert’s s y n dr o me or li ver 
metastases at baseli ne, re peat testi n g wit hi n 
3  d a ys.  Dela y d ose u ntil res ol ve d t o ≤Gra de  2:  
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
disc o nti n ue T -D X d  
Gra de 4 ( > 1 0. 0 × U L N if baseli ne was 
n or mal; > 1 0. 0 × baseli ne if baseli ne was 
a b n or mal) 
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  
Bl o o d Al k ali ne P h os p h at ase I ncre ase d  
Gra de 3 ( > 5. 0 t o 2 0. 0 × U L N if baseli ne 
was n or mal; > 5. 0 t o 2 0. 0 × baseli ne if 
baseli ne was a b n or mal),  
or  
Gra de 4 ( > 2 0. 0 × U L N if baseli ne was 
n or mal; > 2 0. 0 × baseli ne if baseli ne was 
a b n or mal) 
 
N o m o dificati o n u nless deter mi ne d b y t he 
I n vesti gat or t o be cli nicall y si g nifica nt or life-
t hreate ni n g 
G astr oi ntesti n al  
N a use a  
Gra de 3  
 
Dela y d ose u ntil res ol ve d t o ≤Gra de 1  
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
Di arr he a/ C olitis  
Gra de 3  
 
Dela y d ose u ntil res ol ve d t o ≤Gra de 1  
 If res ol ve d i n ≤3 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 3 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
Gra de 4  
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  
Ot her L a b or at or y A Es  
Gra de 3  
 
Dela y d ose u ntil res ol ve d t o ≤Gra de 1 or baseli ne 
le vel:  
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel 
Gra de 4  
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 6  
W orst T o xicit y C T C A E v 5 . 0 Gr a de 
( u nless ot her wise s pecifie d) 
M a n a ge me nt G ui deli nes  f or T -D X d  
Ot her N o n -l a b or at or y A d verse E ve nts 
Gra de 3  
 
Dela y d ose u ntil res ol ve d t o ≤Gra de 1 or baseli ne:  
 If res ol ve d i n ≤7 da ys fr o m da y of o nset, 
mai ntai n d ose  
 If res ol ve d i n > 7 da ys fr o m da y of o nset, 
re d uce d ose 1 le vel  
Gra de 4  
 
Disc o nti n ue s u bject fr o m st u d y treat me nt  
All d ose m o dificati o ns s h o ul d be base d o n t he w orst prece di n g t o xicit y.   
A E  =  a d verse e ve nt; A L T  =  ala ni ne a mi n otra nsferase ; A S T =  as partate a mi n otra nsferase ; 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 Criteria f or A d verse E ve nts; E C G  =  electr ocar di o gra m; 
I L D =  i nterstitial l u n g disease; I V =  i ntra ve n o us; L V E F =  left ve ntric ular ej ecti o n fracti o n; N S AI D =  n o nster oi dal 
a nti -i nfla m mat or y dr u g; P K =  p har m ac o ki netic; Q T c  =  c orrecte d Q T i nter val; U L N  =  u p per li mit of n or mal.  
I n a d diti o n, I n v esti gat ors ma y c o nsi der d ose re d ucti o ns or disc o nti n uati o ns of t he st u d y 
treat me nt acc or di n g t o t he s u bject’s c o n diti o n a n d after disc ussi o n wit h t he S p o ns or Me dical 
M o ni t or or desi g n ee . 
5. 4. 1. 2.  
D ose I nterr u pti o ns a n d Re d ucti o ns f or P h ysici a n’s C h oice  
D ose a dj ust me nts f or p h ysicia n’s  c h oice treat me nt s h o ul d be ma de i n acc or da nce wit h t he la bel 
a p pr o ve d i n t he c o u ntr y of dr u g a d mi nistrati o n  or t he N C C N g ui deli nes. 1  C ha n ges i n me di cati o n 
d osa ge, ti mi n g, etc , will be d oc u me nte d i n t he e C R F.  P h ysicia n’s c h oice treat me nt ca n be 
i nterr u pte d f or u p t o 2 8 d a ys fr o m t he pla n ne d d at e of a d mi nistrati o n.  If a s u bject re q uires a d ose 
dela y l o n ger t ha n 2 8 d a ys  ( 4 9 d a ys fr o m t he last i nf usi o n date), t he s u bject will per ma ne ntl y 
disc o nti n ue st u d y treat me nt a n d will be f oll o we d f or s ur vi val.   
5. 5.  
Met h o d of Assessi n g Tre at me nt C o m pli a nce  
T -D X d  a n d p h ysici a n’s c h oice treat me nt will be a d mi nistere d t o s u bjects partici pati n g i n t he 
st u d y a n d u n d er t he s u per visi o n of cli nical st u d y p ers o n nel at t he site.  Start a n d st o p ti mes of 
d osi n g a n d a m o u nt of dr u g a d mi nistere d are t o be rec or de d b y cli nical st u d y pers o n nel.  
F or orall y a d mi nistere d p h ysicia n’s c h oice treat me nts, treat me nt c o m plia nce will be re p ort e d b y 
t he s u bject or cli nical st u d y pers o n nel. 
5. 6.  
Pri or a n d C o nc o mit a nt Me dic ati o ns a n d Tre at me nts  
Me dicati o ns use d fr o m t he ti me t he s u bject si g ns t he Mai n I C F t o 4 0 da ys ( +7 d a ys) after t he last 
a d mi nistrati o n of T -D X d  or c o ntr ol treat me nt will be rec or de d.  C o nc o mita nt me dicati o ns a n d 
t hera pies i ncl u de all pres cri pti o n, o ver-t he-c o u nter, a n d her bal re me di es.  All c o nc o mita nt 
me dicati o ns will be rec or de d o n t he e C R F.   
He mat o p oietic gr o wt h f act ors ma y be use d f or pr o p h y la xis or treat me nt bas e d o n t he cli nical 
j u d g me nt of t he I n vesti gat or, e x ce pt f or wit hi n 1 w eek pri or t o Scree ni n g (see Secti o n  4. 1 ). 
Pr o p h yla ctic or  s u p p orti v e treat me nt of st u d y tr eat me nt– i n d uce d A Es will be ot her wise as per 
I n v esti gat or’s discreti o n a n d i nstit uti o nal g ui deli nes. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 7  
Base d o n t h e c urre ntl y a v aila ble cli nical safet y dat a, it is rec o m me n de d t hat s u bjects recei ve 
pr o p h yla ctic a nti -e metic a g e nts pri or t o i nf usi o n of T -D X d  a n d o n s u bse q ue nt da ys.  A ntie metics 
s uc h as 5-h y dr o x ytr y pt a mi ne rece pt or a nta g o nists or Ne ur o ki ni n -1 rece pt or a nta g o nists a n d/ or 
ster oi ds (e g, de x a met has o ne) s h o ul d be c o nsi dere d a n d a d mi nistere d i n acc or da nce wit h t he 
pres cri bi n g i nf or mati o n or i nstit uti o nal g ui deli nes . 
C o nc o mita nt use of dietar y s u p ple m e nts, me dicati o ns n ot prescri be d b y t he I n v esti gat or, a n d 
alter nati ve/c o m ple me nt ar y treat me nts is disc o ura ge d b ut n ot pr o hi bite d.   C o nc o mita nt u se of 
e-ci garettes a n d v a pi n g  is str o n gl y disc o ura ge d b ut n ot pr o hi bite d. 
5. 6. 1.  
Pr o hi bite d Me dic ati o ns a n d Tre at me nts  
Wit h t he e x ce pti o n of me dicati o ns t hat are u n d er i n vesti gati o n i n t he st u d y (e g , sta n dar d of care, 
c o m parat ors, or c o m bi nati o n t hera pies ), the f oll o wi n g me dicati o ns, treat m e nt, a n d pr oce d ures 
will be pr o hi bite d d uri n g t he treat me nt peri o d (see Secti o n  4. 2  f or re q uir e d was h o ut peri o ds).  
T he S p o ns or  m ust be n otifie d if a s u bject recei v es a n y of t hese d uri n g t he st u d y. 
 Ot her a ntica n cer t hera p y, i ncl u di n g c yt ot o xic, tar gete d a ge nts, i m m u n ot hera p y, 
a nti b o d y, reti n oi d, or a ntica ncer h or m o nal tr eat me nt  (c o nc urre nt use of h or m o nes f or 
n o nca ncer -relate d c o nditi o ns [e g, i ns uli n f or dia betes a n d h or m o ne re place me nt 
t hera p y] is a cce pt a ble); 
 Use of bis p h os p h o nates or R A N K L pat h w a y i n hi bit ors f or t he pre v e nti o n or 
treat me nt of s kelet al-rel ate d e ve nts is acce pta ble. 
 C o nc o mita nt treat me nt wit h c hl or o q ui ne or h y dr o x yc hl or o q ui ne is n ot all o we d d uri n g 
t he st u d y treat me nt. Refer t o Secti o n  1 7. 8  f or f urt h er details.; 
 Ot her i n vesti gati o nal t hera pe utic a ge nts;  
 Ra di ot hera p y (e x ce pt f or palliati ve ra diati o n t o k n o w n metastatic sites as l o n g as it 
d oes n ot affect assess me nt of res p o nse or i nterr u pt treat me nt f or m or e t ha n t he 
ma xi m u m ti me s pecifie d i n d ose m o dificati o n secti o n);  
 Ra di ot hera p y t o t he t h ora x;  
 C o nc o mita nt use of c hr o nic s yste mic (I V or oral) c ortic oster oi ds or ot her 
i m m u n os u p pressi ve me dicati o ns e x ce pt f or ma na gi n g A Es (i n h ale d ster oi ds or i ntra-
artic ular ster oi d i njecti o ns are per mitte d i n t his st u d y) ; 
 S u bjects w it h br o nc h o p ul m o nar y dis or ders w h o re q uire i nter mitte nt use of 
br o nc h o dilat ors (s uc h as al b uter ol) will n ot be e x cl u de d fr o m t his st u d y.   
F or s u bjects r a n d o mize d t o In vesti gat or’s c h oice:  
 Refer t o t he a p pr o ve d la b el  i n t he c o u ntr y of dr u g a d mi nistrati o n o r t he N C C N 
g ui deli nes 1 f or ca pecita bi ne, eri b uli n, ge mcita bi ne, paclita xel, or na b-paclita x el  f or 
me dicati o ns pr o hi bite d d uri n g tr eat me nt wit h t he a p plica ble pr o d u ct.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 8  
5. 7.  
St u d y Dr u g Disc o nti n u ati o n a n d Disc o nti n u ati o n fr o m t he St u d y  
5. 7. 1.  
Disc o nti n u ati o n of  St u d y Dr u g  
S u bjects ma y be dis c o nti n ue d  fr o m st u d y treat me nt f or t he f oll o wi n g reas o ns: 
 P D per criter i a set f ort h i n m R E CI S T versi o n 1. 1 ( Secti o n  1 7. 5 ); 
 Cli nical pr o gressi o n ( defi niti ve cli nical si g ns of P D), b ut a rece nt r a di o gra p hic 
assess me nt di d n ot meet t he criteri a f or P D acc or di n g t o m R E CI S T versi o n 1. 1;  
 A E;  
 Deat h;  
 Pre g n a nc y;  
 Wit h dra wal b y s u bject ( t o disc o nti n ue st u d y dr u g) N ote: t his secti o n o nl y refers t o 
wit h dra wal fr o m treat me nt wit h st u d y dr u g, w hic h is n ot t he sa me t hi n g as a c o m plete 
wit h dra wal fr o m t he st u d y.  Disc uss wit h t he s u bject t hat t he y will re mai n i n t he st u d y 
(ie, c o nti n ue wit h st u d y visits a n d assess me nts, i ncl u di n g s ur vi val f oll o w-u p) ; 
 L os t t o f oll o w-u p;  
 Pr ot oc ol de viati o n;  
 P h ysicia n decisi o n;  
 St u d y t er mi nate d b y S p o ns or;  
 Ot her, s pecif y.  
Pr o ce d ures f or Disc o nti n u ati o n fr o m St u d y Dr u g  
If t here is e vi de nce t hat t he s u bject is recei vi n g b e nefit fr o m treat me nt e ve n t h o u g h t he s u bject 
has met a criteri o n f or disc o nti n uati o n as liste d a b o ve, t he s u bject ma y re m ai n o n st u d y treat me nt 
after disc ussi o n wit h a n d a p pr o val fr o m t he S p o ns or Me dical M o nit or.  
A ll s u bjects w h o are disc o nti n ue d fr o m st u d y tr eat me nt s h o ul d c o m plete pr ot oc ol-s pecifie d E O T 
assess me nts  (Secti o n  6. 5 ), wit h dra wal pr oce d ures a n d f oll o w -u p pr o ce d ures ( Secti o n  6. 6 ).  T he 
i n vesti gat or m ust disc uss wit h t he s u bject t hat e ve n t h o u g h st u d y treat me nt has st o p pe d, t he 
s u bject will c o nti n ue i nt o t he foll o w -u p p eri o d f or st u d y visits.  If a s u bject wit h dra ws c o nse nt 
fr o m st u d y tr eat me nt, t he i n vesti gat or m ust disc uss wit h t he s u bject t hat t heir decisi o n t o 
per ma ne ntl y disc o nti n ue st u d y treat me nt d oes n ot mea n f oll o w -u p visits s h o ul d be disc o nti n ue d 
as well. 
Rec or d t he last d ose d ate a n d reas o n f or a n y s u bj ect w h o disc o nti n ues st u d y treat me nt o n t he 
e C R F.  Disc o nti n ue d s u bjects will be f oll o we d f or s ur vi val, eit her t hr o u g h direct c o ntact or b y 
c ollecti n g p u blic rec or ds (e g, deat h certificates) as all o we d b y l ocal la ws.   If a s u bject 
disc o nti n ues treat m e nt f or reas o ns ot her t ha n disease pr o gressi o n  or deat h , e ver y atte m pt s h o ul d 
be ma de t o c ollect t u m or assess me nts u ntil disease pr o gressi o n a n d t he s ca ns be se nt f or ce ntral 
re vie w e v e n if t he s u bject has starte d a n ot her a nti-ne o plastic t hera p y.  
If t he s ubject is wit h dra w n beca use of a n A E, t he I n vesti gat or will f oll o w t he s u bject u ntil t he 
A E has res ol ve d or sta biliz e d.  

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If a s u bject d o es n ot a gree t o c o nti n ue t o c o me t o t he st u d y site, t he n a m o difie d f oll o w-u p m ust 
be arra n ge d t o e ns ure t he c o nti n ue d c ol lecti o n of e n d p oi nts a n d safet y i nf or mati o n.  O pti o ns f or 
m o difie d f oll o w -u p are n ote d bel o w.  
M o difie d F oll o w -u p O pti o ns  
T he f oll o wi n g m o difie d f oll o w -u p o pti o ns ca n be offere d t o t he s u bject w h o d oes n ot a gree t o 
st u d y visits at t he st u d y site. 
 St u d y p ers o n nel c o ntacti n g t he s u bject b y t ele p h o ne t o c ollect st u d y i nf or mati o n 
base d o n t he f oll o w -u p s c he d ule  
 St u d y p ers o n nel c o ntacti n g a n alter nati ve p ers o n (e g, fa mil y m e m ber, s p o use, part ner, 
le gal re prese ntati ve, p h ysicia n, or ot her h ealt hcare pr o vi der) 
 St u d y p ers o n nel accessi n g a n d re vie wi n g t he s u bj ect’s me dical i nf or mati o n (e g, 
d oct or’s n otes, h os pital rec or ds) at t he st u d y site or ot her l ocati o n ) 
Dates of t he m o difie d f oll o w -u p c o ntact(s) s h o ul d be rec or de d.  See Secti o n  5. 7. 2  f or defi niti o n 
of wit h dra wal b y s u bject fr o m t he st u d y (ie, wit h dra wal of c o nse nt ). 
5. 7. 2.  
S u bject  Wit h dr a w al / Disc o nti n u ati o n fr o m t he St u d y 
T he d urati o n of s u bject partici pati o n i n t he st u d y will be  u ntil 1 of t he f oll o wi n g occ urs:  
 S u bject dies;  
 St u d y t er mi nati o n;  
 Wit h dra wal b y s u bject ( fr o m t he st u d y) N O T E: t his i n dicates t hat t he s u bject 
wit h dra ws c o nse nt a n d ref uses t o u n der g o a n y f urt her st u d y pr oce d ures or be 
f oll o we d f or l o n g-ter m s ur vi val; 
 S u bject is l ost t o f oll o w -u p;  
 Ot her, s pecif y.  
O nl y s u bjects w h o ref us e all of t he f oll o wi n g m et h o ds of f oll o w -u p will be c o nsi dere d t o ha ve 
wit h dra w n c o nse nt fr o m st u d y partici p ati o n (ie, fr o m t he i nter ve nti o nal p orti o n a n d f oll o w -u p):  
 Atte n da nce at st u d y visits per pr ot oc ol  
 St u d y p ers o n nel c o ntacti n g t he s u bject b y t ele p h o ne  
 St u d y p ers o n nel accessi n g a n d re vie wi n g t he s u bj ect’s me dical i nf or mati o n (at st u d y 
site or ot her l ocati o n) 
If t he s u bject r ef uses all of t he a b o ve met h o ds of f oll o w-u p, t he i n vesti gat or s h o ul d pers o nall y 
s pea k t o t he s u bject t o e ns ure t he s u bject u n dersta n ds all of t he p ote ntial met h o ds of f oll o w -u p.  
If t he s u bject c o nti n ues t o ref use all p ote ntial met h o ds of f oll o w u p, t he i n vesti gat or will 
d oc u me nt t his as a wit h dra wal of c o nse nt (f r o m t he i nter ve nti o nal p orti o n a n d f oll o w-u p).   T he  
I n v esti gat or will c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he date of 
wit h dra wal, i ncl u di n g t he date of last tr eat me nt a n d t he reas o n f or wit h dra wal.  F or t h ese 

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s u bjects, s ur vival stat us i nf or mati o n will be c ollecte d b y p u blic rec or ds (e g deat h certificates) 
u nless pr o hi bite d b y l oc al la ws.  
Pr o ce d ures f or Wit h dr a w al /Disc o nti n u ati o n Fr o m St u d y  
Wit h dra wal fr o m t he st u d y will e ntail disc o nti n uati o n of all f oll o w -u p pr oce d ures.  
S u bjects will be f oll o we d f or s ur vi val  stat us b y c ollecti n g p u blic rec or ds (e g, deat h certificates) 
u nless pr o hi bite d b y l oc al la ws.  
If a s u bject is wit h dra w n fr o m t he st u d y, t he I n vesti gat or will c o m plete a n d re p ort t he 
o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he date of wit h dra wal, i ncl u di n g t he dat e of last 
treat me nt a n d t he reas o n f or wit h dra wal. 
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete pr ot oc ol -s p ecifie d wit h dr a wal 
pr oce d ures.  Pr ot oc ol -s pecifie d wit h dra wal pr oce d ures will be o btai ne d d uri n g t he E O T  
assess me nts  a n d t he 4 0-Da y ( + 7 d a ys) F oll o w -u p  assess me nts  c o n d ucte d after t he last 
a d mi nistrati o n of st u d y tr eat me nt  ( Secti o n 6. 5  a n d Secti o n  6. 6. 1 ). 

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6.  
S T U D Y P R O C E D U R E S  
A st u d y visit sc he d ule i n ta b ular f or mat is pr o vi de d i n Ta ble  1 7 .1  f or t he Tiss ue Scree ni n g a n d 
Scree ni n g peri o d a n d i n Ta ble  1 7 .2  f or t he treat m e nt a n d f oll o w-u p peri o ds.  
6. 1.  
Tiss ue Scree ni n g  
T o deter mi ne eli gi bilit y, s u bjects m ust ha ve breast ca ncer t hat has b ee n ass esse d as ha vi n g  l o w 
H E R 2 e x pressi o n as deter mi ne d b y t he F D A a p pr o ve d V E N T A N A P A T H W A Y A nti -H E R -
2/ n e u ( 4 B 5) I H C assa y, a d diti o nall y v ali date d t o i n vesti gati o nal use o nl y (I U O) f or t h e H E R 2 
I H C 1 + cat e g or y, acc or di n g t o A S C O -C A P  2 0 1 8  H E R 2 testi n g  g ui deli nes (a da pte d b y Daiic hi 
Sa n k y o I n c. a n d V e nta na) 1 0 e val uate d at a ce ntral la b orat or y.   T he assa y m et h o d ol o g y will be t he 
sa me as descri be d i n t he pac ka ge i nsert.  T he o nl y differe n ce b et wee n t h e I U O versi o n of t he 
assa y use d i n t his st u d y a n d t he a p pr o ve d assa y will be  t he i n vesti gati o nal s c ori n g al g orit h m f or 
t he l o wer c ut p oi nt b o u n d o n t he H E R 2 I H C 1 + cate g or y.  H E R 2 I S H testi n g  wi ll f oll o w t he 
sc ori n g criteri a s pecifi e d i n t he pac ka ge i nsert of Ve nta na I N F O R M D ual I S H kit . 
N ote:  S u bjects ma y c o nti n ue o n pri or t hera p y w hile tiss ue testi n g ta kes pl ace.   
A se q ue ntial scree ni n g pr ocess m ust  be f oll o we d.  Tiss ue scree ni n g m ust  be f oll o we d b y t he 
mai n scree ni n g  pr oce d ures  i n Secti o n 6. 2 . 
Please refer t o t he st u d y l a b orat or y ma n ual f or re q uire d t u m or sa m ple s pecificati o ns a n d 
s hi p pi n g i nstr ucti o ns.   
Fi ne Nee dle As pir ate  ( F N A) a n d b o n e bi o psies will n ot be acce pte d f or tiss ue sa m ples.  
T he f oll o wi n g pr oce d ures will be c o n d ucte d:  
 O btai n a si g n e d a n d dat e d writte n Tiss ue Scree ni n g I C F fr o m t he s u bject pri or t o 
c ollect i n g tiss ue.   
 O btai n a de q uat e arc hi ve d or rece nt t u m or tiss ue sa m ple f or H E R 2 testi n g.   T he 
bi o ps y use d f or ce ntral H E R 2 testi n g ca n b e a n arc hi ve d sa m ple t hat was o btai ne d 
pri or or aft er t he  last treat me nt re gi me n.  R efer t o t he st u d y la b orat or y ma n ual f or 
pre parati o n,  n u m ber of sli des re q uire d, st ora ge, a n d s hi p me nt pr oce d ures.  If t he m ost 
rece nt tiss ue sa m ple is u n a vaila ble: 
 D oc u me nt t he reas o n w h y t he m ost rece nt tiss ue s a m ple is u na vaila ble a n d s u b mit 
a n ot her pri or tiss ue s peci me n.  
 If arc hi val t u m or tiss ue is n ot a vaila ble, c ollect  a fres h t u m or tiss ue sa m ple. 
 If a t u m or bi o ps y is nee d e d, re p ort a n y S A Es directl y relate d t o tiss ue scree ni n g 
pr oce d ure (ie, t u m or bi o ps y) al o n g wit h a n y ass oci ate d treat me nt.  U nl ess 
d oc u me ntati o n of ot her A Es is re q uire d b y l ocal la w,  o nl y S A Es directl y relate d t o 
t u m or bi o ps y will be rec or de d d uri n g tiss ue scree ni n g. 
 Se n d t he sa m ples t o t he ce ntral la b orat or y t o assess  H E R 2 stat us.  
 Assi g n SI D.  

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6. 2.  
Scree ni n g  
A se q ue ntial scree ni n g pr ocess m ust  be f oll o we d.  Tiss ue scree ni n g  (see Secti o n  6. 1 ) m ust  be 
c o m plete bef ore t he  mai n scree ni n g pr oce d ures  bel o w . 
T he d urati o n of t he s cree ni n g/ baseli ne p eri o d is u p t o 2 8 d a ys.  I nf or me d co nse nt will be 
o btai ne d fr o m t he s u bject bef ore a n y st u d y -s pecific pr oce d ures are i nitiate d.   
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d wit hi n 2 8  d a ys  bef ore 
r a n d o miz ati o n  d uri n g t h e scree ni n g peri o d:  
 U nless re q uire d b y l o cal re g ulati o ns or I R B/ IE C, a n HI V a nti ge n/a nti b o d y test is n ot 
re q uire d pri or t o ra n d o mi zati o n/e nr oll me nt.  
I n P ort u g al o nl y , p le ase see Secti o n 1 7. 9. 2  f or te xt a p plic a ble t o sites i n P ort u g al. 
 Perf or m a he p atitis B s urface a nti ge n/ he patitis C a nti b o d y test.   S u bjec ts w h o ha ve a 
p ositi ve H C V a nti b o d y t est will re q uire a n e gati v e p ol y merase c hai n r eacti o n f or 
H C V R N A.  
 Perf or m o p ht hal m ol o gic assess me nts i ncl u di n g vis ual ac uit y t esti n g, slit la m p 
e x a mi nati o n, a n d f u n d osc o p y.  
 Perf or m a n E C H O or M U G A ( N ote:  T h e sa me test m ust be use d f or t he s u bject 
t hr o u g h o ut t he st u d y).  
I n Ger m a n y o nl y , p le ase see Secti o n 1 7. 9. 3  f or te xt a p plic a ble t o sites i n 
Ger m a n y . 
 Perf or m t u m or assess me nt b y C T or M RI sca ns of t he c hest, a b d o m e n, pel vis, a n d 
a n y ot h er sites of diseas e.  A C T or M RI of t he brai n is t o be i ncl u de d f or all s u bjects.  
 A t u m or tiss ue bi o ps y aft er t he c o m pleti o n of t he s u bject’s m ost rece nt treat me nt 
re gi me n is re q uir e d f or retr os pecti ve assess me nt.  If t he t u m or tiss ue pr o vi de d f or 
H E R 2 stat us testi n g was c ollecte d after c o m pleti o n of t he last treat me nt r e gi me n, a n 
a d diti o nal  ne w bi o ps y  is n ot re q uire d.  If t he t u m or tiss ue pr o vi de d f or H E R 2 stat us 
testi n g was c ollecte d b ef ore c o m pleti o n of t he last treat me nt re gi me n, a n a d diti o nal 
ne w bi o ps y  is r e q uire d.  T he detaile d pr o ce d ures f or pre pari n g a n d s u b mitti n g t u m or  
tiss ue sa m ples will be pr o vi de d i n t he la b orat or y ma n ual.  F N A a n d b o ne bi o psies 
will n ot be acce pt e d f or tiss ue sa m ples.  
 A d diti o nal tiss ue sa m ples f or e x pl orat or y bi o mar ker assess me nt are re q uire d u nless 
pr o hi bite d b y l oc al re g ul ati o ns (see t he st u d y la b orat or y ma n ual).   It is preferre d if t h e 
sli des are fr o m t he s a me bl oc k as t he tiss ue sa m ple se nt f or ce ntral la b orat or y H E R 2 
testi n g. 
If t here are scree ni n g pr oce d ures t h at are p erf or me d wit hi n 2 8 da ys of ra n d o mizati o n d uri n g t he 
sta n dar d treat me nt of t he s u bject, t hese pr oce d ure res ults ca n be use d f or t he trial e ve n if 
c o n d ucte d pri or t o c o nse nt as t he y were perf or me d d uri n g t he n or mal c o urse of s u bject care.  
N ote:  T o asse ss o bjecti v e res p o nse or f ut ure pr o gressi o n, it is necessar y t o esti mate t he o verall 
t u m or b ur de n at baseli ne a n d use it as c o m parat or f or s u bse q ue nt meas ure m e nt.  T heref ore, all 
lesi o ns (tar get a n d n o n -t ar get) ha v e t o be assess e d at Scree ni n g acc or di n g t o  m R E CI S T versi o n 
1. 1 ( Secti o n  1 7. 5 ). 

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T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d d uri n g t he s cree ni n g p eri o d 
wit hi n 1 4  d a ys  bef ore r a n d o miz ati o n  e x ce pt as i n dicate d : 
 C o nfir m s u bject eli gi bilit y.  
 O btai n:  
 De m o gra p hics (e g, birt h date, se x, race, et h nicit y);  
 Me dical  (i ncl u di n g s m o ki n g) a n d s ur gical hist or y, i ncl u di n g all pre vi o us, n o w 
res ol ve d, si g nifica nt me dical c o n diti o ns, date of di a g n osis, e xte nt of disease, 
disease sta gi n g, estr o ge n/ pr o gester o ne rece pt or stat us, a n d pre vi o us ca n cer 
t hera pies (i ncl u di n g pri or ra diati o n t hera p y); 
 O nc ol o g y s ur gical hist or y.  
 Perf or m a p h ysic al e x a mi nati o n (see Secti o n  9. 1 1 ), i ncl u di n g wei g ht a n d hei g ht. 
 Assess f u ncti o nal stat us usi n g  t he E C O G P S ( Secti o n 1 7. 4 ). 
 Rec or d c o n c o mita nt me dicati o ns, A Es, a n d h os pitalizati o n -relate d rec or ds at e ver y 
visit (fr o m t he ti me t h e s u bject si g ne d t h e Mai n I C F).  F or details o n A E c ollecti o n 
a n d re p orti n g, refer t o Secti o n  9. 2 . 
 O btai n vital si g ns (s yst olic a n d d iast olic bl o o d press ure, p ulse rat e, res pir at or y rate, 
b o d y te m perat ur e; Secti o n  9. 9 ) a n d peri p h eral o x y ge n s at urati o n ( S p O 2; 
Secti o n  9. 1 2. 2 ). 
 Perf or m tri plicate 1 2 -l ea d E C G.   
 T he E C Gs will be ta ke n i n cl ose s uccessi o n w hile i n a s u pi ne/se mi -rec u m b e nt 
p ositi o n.   T he E C Gs s h o ul d  prefera bl y  be perf or me d bef ore bl o o d dra ws at res pecti ve 
ti me p oi nts ( Secti o n 9. 1 0 ).   
 N ote t hat s u bse q ue nt E C Gs will be perf or m e d i n tri plicate o nl y if a n a b n or malit y 
is n ote d. 
 C ollect a n d se n d bl o o d sa m ples t o t he la b orat or y f or t he f oll o wi n g tests ( Secti o n  9. 8 ): 
 He mat ol o g y  
 C he mistr y  
 C oa g ulati o n (s h o ul d als o be perf or me d as cli nicall y i n dicat e d t hr o u g h o ut t he 
st u d y) 
 Tr o p o ni n ( prefera bl y hi g h -se nsiti vit y tr o p o ni n-T); t he test use d t o test tr o p o ni n 
s h o ul d be  t he sa me at Scree ni n g a n d at E O T.   I n a d diti o n to t he tr o p o ni n sa m ple 
t hat is teste d l ocall y, a s a m ple s h o ul d als o be s u b mitte d f or ce ntral la b orat or y 
tr o p o ni n-T testi n g.  If E C G is a b n or mal, f oll o w i nstit uti o nal g ui deli nes.  
 Ser u m bi o mar kers (e g, H E R 2 E C D) , e x pl orat or y bi o mar kers (e g, cf D N A i n 
plas ma), see Secti o n 8. 3. 2 , a n d C O VI D -1 9 s er ol o g y , see Secti o n  1 7. 8 . 

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 O btai n uri ne sa m ple f or uri nal ysis ( pr otei n, gl u c ose, bl o o d, micr osc o p y assess me nt [if 
i n dicate d], a n d s pecific gra vit y; Secti o n 9. 8 ).   
 F or w o me n of c hil d beari n g p ote ntial (criteria f or n o n -c hil d beari n g p ote nti al are 
defi ne d i n Secti o n  4. 1 ), wit hi n 7 2 h o urs bef ore ra n d o mizati o n perf or m a ser u m or 
uri ne pre g n a nc y test a n d d oc u me nt t he res ults ; a p ositi ve uri ne pre g na n c y test res ult 
m ust be i m me diatel y c o nfir me d usi n g a ser u m test .  
6. 3.  
R a n d o miz ati o n  
Eli gi ble s u bjects will be ra n d o mize d b y t he I X R S i n a 2: 1 rati o i nt o t he tre at me nt ar ms : T -D X d  
vs.  p h ysicia n’s c h oice, w hic h has 5 a vaila ble treat me nt para di g ms  (refer t o Secti o n 5. 1. 1 ).   
S u bjects t o be e nr olle d:  
 N ot m ore t ha n 2 4 0 H R -p ositi ve s u bjects w h o ha ve n ot ha d pri or t hera p y wit h a 
c ycli n -de pe n d e nt ki nase ( C D K) 4/ 6 i n hi bit or  
 A t least 2 4 0 H R-p ositi ve s u bjects w h o ha ve h a d pri or t hera p y wit h a C D K 4/ 6 
i n hi bit or  
 ~ 6 0 H R -ne gati ve s u bjects.  
Ra n d o mizati o n will be stratifie d b y  
 H E R 2 I H C stat us of tiss ue sa m ples assesse d b y a ce ntral la b orat or y:  H E R 2  I H C 1 +  
vs.  H E R 2 I H C  2 + /I S H- 
 N u m ber of pri or li nes of c he m ot hera p y:  1 vs. 2  
 H R/ C D K stat us:  H R -p ositi ve wit h pri or C D K 4/ 6 i n hi bit or treat me nt vs. H R -p ositi ve 
wit h o ut pri or C D K 4/ 6 i n hi bit or treat me nt vs. H R -ne gati ve . 
I n v esti gat ors will c h o ose 1 of t he c o ntr ol treat me nts f or e ver y s u bj ect bef ore ra n d o mizati o n.  
Treat me nt a n d pr oce d ur es perf or me d o n Da y 1 of C ycle 1 a n d be y o n d are s pecifie d i n Ta ble  1 7 .2  
a n d f urt her descri b e d bel o w.  Pr oce d ures are t o be perf or me d wit hi n 3  d a ys  of t he Da y 1 visit of 
eac h c ycle u nless ot her wise s pecifie d.  C ycles f or T -D X d  are 2 1 d a ys i n d urati o n; c ycles f or 
p h ysicia n’s c h oice s h o ul d be 2 1 da ys i n d urati o n if t here are m ulti ple o pti o ns i n t he la bel 
a p pr o ve d i n t he c o u ntr y of dr u g a d mi nistrati o n  or t he N C C N g ui deli nes .1 
A s u bject’s first d ose  at C ycle 1 Da y 1 s h o ul d occ ur wit hi n 7 d a ys after t h e date t he s u bject is 
ra n d o mize d. 
6. 4.  
Tre at me nt Peri o d  
6. 4. 1.  
C ycle 1 t o 4 a n d S u bse q ue nt C ycles  
6. 4. 1. 1.  
Bet wee n -3 D a ys Bef ore D osi n g T hr o u g h I m me di atel y Bef ore D osi n g ( All C ycles) 
 Perf or m a p h ysic al e x a mi nati o n ( Secti o n  9. 1 1 ), i ncl u di n g wei g ht.  M or e fre q ue nt 
e x a mi n ati o ns ma y b e perf or me d at t he discreti o n of t he I n vesti gat or a n d if me dicall y 
i n dicate d. 

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 Assess f u ncti o nal stat us usi n g t he E C O G P S ( Secti o n 1 7. 4 ). 
 Rec or d c o n c o mita nt me dicati o ns, A Es, a n d h os pitalizati o n -relate d rec or ds at e ver y 
visit.   F or details o n A E c ollecti o n a n d re p orti n g, refer t o Secti o n  9 . 2. 
 O btai n vital si g ns (s yst olic a n d diast olic bl o o d press ure, p ulse rat e, res pir at or y  rate, 
a n d b o d y t e m perat ure ; Secti o n 9. 9 ) a n d S p O 2 ( Secti o n 9. 1 2. 2 ).  M ore fre q ue nt 
e x a mi nati o ns ma y b e perf or me d at t he discreti o n of t he I n vesti gat or a n d if me dicall y 
i n dicate d. 
 Perf or m 1 2 -le a d E C G.  E C Gs will be perf or me d i n tri plicate if a n a b n or malit y is 
n ote d.   T he E C Gs will be ta ke n i n cl ose s uccessi o n w hile i n a s u pi ne/se mi -rec u m be nt 
p ositi o n.  T he E C Gs s h o ul d  prefera bl y  be perf or me d bef ore bl o o d dra ws at res pecti ve 
ti me p oi nts ( Secti o n 9. 1 0 ). 
 C ollect a n d se n d bl o o d sa m ples t o t he la b or at or y f or t he f oll o wi n g tests ( Secti o n  9. 8 ): 
 He mat ol o g y  
 C he mistr y  
 F or all fe male s u bjects of c hil d beari n g p ote ntial (as defi ne d i n Secti o n  4. 1 ), perf or m a 
ser u m or uri ne pre g na n c y test wit hi n 7 2 h o urs  pri or t o t he be gi n ni n g of d osi n g a n d 
d oc u me nt t he res ults.  A p ositi ve uri ne pre g na n c y test res ult m ust be c o nfir me d 
i m me diatel y usi n g a ser u m test, wit h a c o nfir me d ne gati ve test res ult wit hi n 7 2 h o urs 
pri or t o dr u g a d mi nistrati o n.  F or s u bjects w h o are of n o n -c hil d beari n g p ot e ntial (as 
defi ne d i n Secti o n 4. 1 ), n o pre g na nc y t est will be re q uire d.  
N ote: Vital si g ns (i ncl u di n g S p O 2) e v al uati o ns, cli nical la b orat or y tests, p h ysical e x a mi nati o n, 
wei g ht, E C G E C O G P S , a n d H E O R o utc o me q uesti o n naires  nee d n ot be re peate d if t he y were 
perf or me d wit hi n 3  da ys of t he first d ose i n eac h c ycl e.  
6. 4. 1. 2.  
D a y 1 Bef ore D osi n g ( All C ycles, U nless Ot her wise N ote d) 
 T he s u bject m ust c o m plete t he H E O R o utc o mes : E O R T C Q L Q -C 3 0, E O R T C Q L Q -
B R 4 5, a n d E Q -5 D -5 L q u esti o n naires bef ore a n y ot her assess me nts or pr o ce d ures are 
d o ne o n t he da y of cli nic visit (Secti o n  1 0. 1 ) at C ycle 1, C ycl e 2, a n d C ycl e 3 a n d 
t he n e ver y 2  c ycles d uri n g t he treat me nt peri o d . 
 O btai n bl o o d sa m ples f or:  
 P har mac o ge n etic assess me nt  ( Secti o n 8. 5 ), C ycl e 1 o nl y, if t he s u bj ect pr o vi des 
c o nse nt b y si g ni n g t he p har mac o ge netics sa m ple ba n ki n g I C F.  ( T his sa m pl e is 
n ot re q uire d f or st u d y p artici pati o n.)  
 Ser u m bi o mar kers (e g, H E R 2 E C D  [Sect i o n 8. 3. 2 ]; C O VI D-1 9 ser ol o g y 
[ Secti o n 1 7. 8 ]) assess me nts will be c ollecte d o n C ycl e  3 Da y 1 a n d e ver y 2 c ycles 
t hereafter (e g, C ycles 5, 7, 9, etc), see Secti o n 8. 3. 2 . 
 C O VI D -1 9 testi n g will be perf or me d o n t he ser ol o g y sa m ples  o nl y  starti n g 
fr o m C ycl e 5 a n d e v er y 4 c ycles t hereaft er.  
 O nl y s u bjects ra n d o mize d t o T -D X d : 

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 P K assess me nt bef ore i nf usi o n ( wit hi n 8 h o urs ) o n Da y 1  of eac h c ycle 
t hr o u g h C ycle 4 a n d t he n e ver y 2 c ycles u ntil C ycl e 8 (ie, C ycle 1, 2, 3, 4, 
6, 8) ; see Secti o n 8. 1 ; 
 A D A ( wit hi n 8 h o urs  bef ore i nf usi o n) at C ycles 1, 2 a n d 4, t he n e ver y 4 
c ycles (ie, C ycl es 8, 1 2, 1 6, etc); see Secti o n 8. 4 . 
 O btai n bl o o d sa m ples f or e x pl orat or y bi o mar kers, s uc h as cf D N A i n plas ma, bef ore 
treat me nt o n Da y 1 of C ycle 1 a n d e v er y 3 c ycles t hereafter (e g, C ycles 4, 7, etc) u ntil 
E O T; see Secti o n 8. 3. 2 . 
 A n o pti o nal fres h t u m or tiss ue bi o ps y ma y be c ollecte d at C ycle 3 Da y 1 ( ± 7 da ys) ; 
see Secti o n 8. 3. 1 . 
 Rec or d c o n c o mita nt me dicati o ns, A Es, a n d h os pitalizati o n -relate d rec or ds at e ver y 
visit.  
6. 4. 1. 3.  
D a y 1 D osi n g a n d E n d of D osi n g ( All C ycles, U nless Ot her wise N ote d) 
T -D X d  s h o ul d o nl y b e i nitiate d a n d a d mi nistere d b y a h ealt hcare pr ofessi o nal e x perie nce d i n t he 
a d mi nistrati o n of c yt ot o xic c he m ot hera p y. Me dici nal pr o d ucts t o treat aller gic/a n a p h ylactic 
i nf usi o n reacti o ns, as w ell as e mer ge n c y e q ui p me nt, s h o ul d be a vaila ble for i m me diate use. 
C o m parat or treat me nts s h o ul d be a d mi nistere d  a n d m o nit ore d  as per la bel a p pr o ve d i n t he 
c o u ntr y of dr u g a d mi nistrati o n  or t he N C C N g ui deli nes .1 
 F or T -D X d  treat me nt, ad mi nister st u d y treat me nt I V i nf usi o n a p pr o xi matel y 
9 0  mi n utes  f or t he i nitial d ose a n d, if n o i nf usi o n relate d reacti o n aft er t he i nitial d ose, 
i nf use s u bse q ue nt d oses over 3 0 mi n utes .  Rec or d start a n d st o p ti mes of a n y st u d y 
treat me nt a n d a m o u nt of dr u g a d mi nistere d.  T -D X d  a n d p h ysicia n’s c h oice 
treat me nts are t o be a d mi nistere d e ver y 2 1 d a ys ± 2 d a ys. 
 O btai n vital si g ns (s yst olic a n d diast olic bl o o d press ure, p ulse rat e, res pir at or y rate, 
a n d b o d y t e m perat ure ; Secti o n 9. 9 ) (all c ycles bef ore a n d  f or t he T -D X d  ar m o nl y 
after i nf usi o n ) a n d S p O 2 (all c ycles b ef ore a nd  f or t he T -D X d  ar m o nl y after 
i nf usi o n) ( Secti o n 9. 1 2. 2 ).  M ore fre q ue nt e x a mi nati o ns ma y be p erf or me d at t he 
discreti o n of t he I n v esti gat or a n d if me dicall y i n di cate d.  
 At C ycle 1 Da y 1, p erf or m E C G testi n g at 5 h o urs  after t he start of dr u g 
a d mi nistrati o n ( ± 2 ho urs ) f or T -D X d -treate d s u bjects. 
 If a n a b n or malit y is n ote d, perf or m tri plicat e E C G.  
 C ollect bl o o d sa m ples f or:  
 F or s u bjects r a n d o mize d t o T -D X d , P K a nal ysis o n Da y 1 of eac h c ycle t hr o u g h 
C ycle 4 a n d t he n e v er y 2 c ycles u ntil C ycl e 8 (ie,  C ycle 1, 2, 3, 4, 6, 8)  prefera bl y 
wit hi n 1 5  mi n utes  or as s o o n as p ossi ble  after e n d of i nf usi o n .  T he act u al ti me of 
sa m pli n g s h o ul d be acc uratel y rec or de d.  I n a d diti o n, f or C ycle 1 Da y 1 o nl y, 
c ollect sa m ple at 5  h o urs  after t he start of dr u g a d mi nist rati o n ( ± 2 h o urs ); see 
Secti o n  8. 1 . 

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 If at a n y ti me a s u bject re p orts si g ns or s y m pt o ms s u g gesti n g c o n gesti ve heart 
fail ure, m y ocar dial i nfarcti o n, or ot her ca uses of car diac m y oc yt e necr osis, c ollect 
bl o o d sa m ples f or tr o p o ni n  ( prefera bl y hi g h-se nsiti vit y tr o p o ni n-T) testi n g a n d 
perf or m E C G i n tri plicat e.  If E C G is a b n or m al, f oll o w i nstit uti o nal g ui deli nes.  
See details i n Ta ble  5 .3 . 
N ote t hat e n d of i nf usi o n assess me nts are n ot re q uire d f or s u bjects o n ca pecita bi ne. 
6. 4. 1. 4.  
D a y 8 ( ± 1  d a y)  a n d D a y 1 5 ( ± 1  d a y)  ( C ycle 1 O nl y) 
 O btai n vital si g ns (s yst olic a n d diast olic bl o o d press ure, p ulse rat e, res pir at or y rate, 
a n d b o d y t e m perat ure ; Secti o n 9. 9 ) ( bef ore a n d f or t he T -D X d  ar m o nl y aft er 
i nf usi o n) a n d S p O 2  (bef ore a n d  f or t he T -D X d  ar m o nl y after i nf usi o n ) ( S ecti o n 
9. 1 2. 2 ).  M ore fre q ue nt e x a mi nati o ns ma y be p erf or me d at t he discreti o n of t he 
I n v esti gat or a n d if me di call y i n dicate d. 
 C ollect a n d se n d bl o o d sa m ples t o t he la b orat or y f or t he f oll o wi n g tests ( Secti o n  9. 8 ): 
 He mat ol o g y  
 C he mistr y  
 Rec or d c o n c o mita nt me dicati o ns, A Es, a n d h os pitalizati o n -relate d rec or ds at e ver y 
visit.  
6. 4. 2.  
E ver y 4 C ycles ( ± 7 d a ys)  A fter C ycle 1 
 Perf or m a n E C H O or M U G A ( N ote:  T h e sa me test m ust be use d f or t he s u bject 
t hr o u g h o ut t he st u d y) bef ore i nf usi o n at C ycle 5, 9, 1 3, etc.  
I n Ger m a n y o nl y , p le ase see Secti o n  1 7. 9. 3  f or te xt a p plic a ble t o sites i n 
Ger m a n y.  
6. 4. 3.  
E ver y 6 Wee ks ( ± 7 d a ys)  
 T u m or assess me nts, base d o n sites of disease i de ntifie d at Scree ni n g a n d a n y 
a d diti o nal ne wl y s us p ect e d sites of P D, will be c o n d ucte d e ver y 6  w eek s ( ±7 d a ys) 
fr o m ra n d o mizati o n , i n de pe n de nt of treat me nt c ycl e.  A C T or M RI ( C T or M RI wit h 
≤5 m m c uts) of c hest, a b d o me n, a n d pel vis s h o ul d be use d f or t u m or assess me nt 
u nless a n ot her m o dalit y of disease ass ess me nt is necessar y f or t he l esi o ns.  T he sa me 
assess me nt m o dalit y s h o ul d be use d t hr o u g h o ut t he st u d y f or all assess me nts f or eac h 
s u bject u nless pri or a p pr o val is o btai ne d fr o m S p o ns or or its desi g n ee.  U nsc he d ule d 
t u m or assess me nts ma y b e perf or me d if pr o gressi o n is s us pecte d. 
 A C T or M RI of t he brai n is ma n dat or y f or all s u bjects w h o were e nr ol le d wit h 
baseli ne sta ble brai n metastases.  S u bjects wit h o ut brai n metastases d o n ot nee d 
a d diti o nal brai n sca ns f or s u bse q ue nt t u m or assess me nts u nless cli nicall y i n dicate d.  
I ma gi n g res ults will be re vie we d b y a n i n de pe n de nt ra di ol o gic facilit y. 

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6. 5.  
E n d of St u d y Tre at me nt  
T he E O T is defi ne d as t h e date t he I n v esti gat or deci des t o disc o nti n ue st u d y treat me nt a n d t he 
visit s h o ul d occ ur wit hi n 7 da ys of t he decisi o n .  All assess me nts re q uire d as part of E O T m ust 
occ ur wit hi n 7 da ys fr o m t he date t he I n v esti gat or deci des t o disc o nti n ue st u d y treat me nt.   T he 
f oll o wi n g pr oce d ures will be perf or m e d as s pecifi e d i n Ta ble  1 7 .2 .  If t h e E O T assess me nts ha v e 
bee n perf or m e d wit hi n 3 0  d a ys ( ±7  da ys)  of t h eir last treat me nt, t he y ca n b e c o nsi dere d t o be t he 
E O T data a n d t h ere is n o nee d t o re p eat t he m; ot her wise, t hese ass ess me nts nee d t o be re peat e d.  
 T he s u bject m ust c o m plete t he H E O R o utc o mes E O R T C Q L Q -C 3 0 , E O R T C Q L Q -
B R 4 5, a n d E Q -5 D -5 L q u esti o n naires bef ore a n y ot her assess me nts or pr o ce d ures are 
d o ne  o n t he da y of cli nic visit . 
 F or w o me n of c hil d beari n g p ote ntial (as defi ne d i n Secti o n  4. 1 ), perf or m a ser u m or 
uri ne pre g n a nc y test a n d d oc u me nt t he res ults.  F or s u bjects w h o are of n o n -
c hil d beari n g p ote ntial (as defi ne d i n Secti o n 4. 1 ), n o pre g na nc y t est will be re q uire d.  
 Perf or m a p h ysic al e x a mi nati o n ( Secti o n  9. 1 1 ), i ncl u di n g wei g ht. 
 Perf or m o p ht hal m ol o gic assess me nts i ncl u di n g vis ual ac uit y t esti n g, slit la m p 
e x a mi nati o n, a n d f u n d osc o p y.  
 Assess f u ncti o nal stat us usi n g t he E C O G P S ( Secti o n  1 7. 4 ). 
 Rec or d c o n c o mita nt me dicati o ns, A Es, a n d h os pitalizati o n -relate d rec or ds at e ver y 
visit.  
 O btai n vital si g ns (s yst olic a n d diast olic bl o o d p ress ure, p ulse rat e, res pir at or y rate, 
a n d b o d y t e m perat ure; Secti o n 9. 9 ) a n d S p O 2 ( Secti o n 9. 1 2. 2 ).   
 Perf or m 1 2 -le a d E C Gs.   
 If a n a b n or malit y is n ote d, perf or m tri plicat e E C G.  T he E C Gs will be ta k e n i n 
cl ose s uccessi o n w hile i n a s u pi ne/se mi -rec u m be nt p ositi o n.  T he E C Gs s h o ul d 
prefera bl y  be p erf or me d bef ore bl o o d dra ws at res pecti ve ti me p oi nts  
( Secti o n 9. 1 0 ). 
 Perf or m a n E C H O or M U G A ( N ote:  T h e sa me test m ust be use d f or t he s u bject 
t hr o u g h o ut t he st u d y). 
I n Ger m a n y o nl y , p le ase see Secti o n  1 7. 9. 3  f or te xt a p plic a ble t o sites i n 
Ger m a n y.  
 Bl o o d sa m ple f or tr o p o ni n ( prefera bl y hi g h -s e nsiti vit y tr o p o ni n-T).  I n a d diti o n t o t he 
tr o p o ni n sa m ple t hat is teste d l ocall y, a sa m ple s h o ul d als o be s u b mitte d f or ce ntr al 
la b orat or y tr o p o ni n-T testi n g.   If tr o p o ni n le v els are a b o ve t he u p per li mit of n or mal 
a n d bel o w t he le v el of m y o car dial i nfarcti o n as d efi ne d b y t h e ma n ufact urer ( C T C A E 
Gra de 1) at baseli ne, n o re peat testi n g is re q uir e d if t he tr o p o ni n le vel is n ot Gra de 3 . 
If Gra de 1:   
o  Re peat tr o p o ni n testi n g at 3 ± 1 h o urs after i nitial tr o p o ni n test.  If re peat 
tr o p o ni n le vel at 3 ± 1 h o urs rises si g nifi ca ntl y p er i nstit uti o nal g ui deli nes,  

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- 
P erf or m E C G i n tri plicat e;  
- 
R e peat tr o p o ni n testi n g at 6 ± 1 h o urs after i nitial tr o p o ni n test;  
- 
F oll o w i nstit uti o nal g ui deli nes f or ma na ge me nt of detecta ble tr o p o ni n 
testi n g. 
o  If re p eat tr o p o ni n le vel at 3 ± 1 h o urs d oes n ot rise si g nifica ntl y per 
i nstit uti o nal g ui deli nes, re peat tr o p o ni n testi n g at 6 ± 1 h o urs or at 2 4 ± 2 h o urs 
after i nitial tr o p o ni n test.  
If Gra de 3: 
o  Perf or m E C G i n tri plicat e.  
o  Re peat tr o p o ni n testi n g at 6 ± 1 h o urs a n d 1 2 ± 1 h o urs after i nitial tr o p o ni n test.  
o  F oll o w i nstit uti o nal g ui deli nes f or ma na ge me nt of detecta ble tr o p o ni n testi n g.    
 C ollect a n d se n d bl o o d sa m ples t o t he la b orat or y f or t he f oll o wi n g tests ( Secti o n  9. 8 ): 
 He mat ol o g y  
 C he mistr y  
 C oa g ulati o n  
 Ser u m bi o mar kers (e g, H E R 2 E C D [Secti o n  8. 3. 2 ]; C O VI D-1 9 ser ol o g y 
[ Secti o n 1 7. 8 ]). 
 Bl o o d sa m ple f or e x pl orat or y bi o mar kers, s uc h as cf D N A a nal ysis i n plas ma, will be 
c ollecte d.  
 A n o pti o nal fres h  t u m or tiss ue bi o ps y ma y be c ollecte d. 
 T u m or assess me nts  s h o ul d i ncl u de all sites of disease i de ntifie d at Scree ni n g a n d a n y 
ot her l ocati o ns w here P D is s us pecte d (e g, M RI of t he brai n if brai n met astases are 
s us pecte d) s h o ul d als o be i ma ge d, p er m R E CI S T v ersi o n 1. 1.  If t he pre vi o us sca n 
was wit hi n t he last 6 w ee k s ( ± 7 da ys)  fr o m t he d at e of E O T, t his assess me nt d oes n ot 
nee d t o be perf or me d at E O T.   If a s u bj ect disc o nti n ues treat me nt f or reas o ns ot her 
t ha n disease pr o gressi o n or deat h , e v er y atte m pt s h o ul d be ma de t o c ollect t u m or 
assess me nts u ntil disease pr o gressi o n a n d t he s ca ns be se nt f or ce ntral r e vie w  e ve n if 
t he s u bject has starte d a n ot her a nti -ne o plastic t hera p y.  
 A C T or M RI of t he brai n is ma n dat or y f or all s u bjects i ncl u de d wit h baseli ne sta ble 
brai n metastases.  S u bjects wit h o ut brai n metastases d o n ot nee d brai n sca n f or t u m or 
assess me nt u nless cli nicall y i n dicate d.   
6. 6.  
F oll o w -u p  
6. 6. 1.  
4 0 -D a y ( +7 d a ys)  F oll o w -u p  
F ort y d a ys (+ 7 d a ys) after last st u d y treat me nt a d mi nistrati o n or bef ore starti n g ne w a ntica n cer 
treat me nt, w hic he v er c o mes first, t he f oll o wi n g pr oce d ures will be perf or me d as s pecifie d i n 

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Ta ble  1 7 .2 .  If E O T is > 4 0 da ys ( +7 d a ys) aft er last treat me nt, t he n t he E O T assess me nts ca n als o 
f u ncti o n as t he 4 0-D a y ( +7 d a ys) F oll o w -u p assess me nts .   
 T he s u bject m ust c o m plete t he H E O R o utc o mes E O R T C Q L Q -C 3 0 , E O R T C Q L Q -
B R 4 5, a n d E Q -5 D -5 L q u esti o n naires bef ore a n y ot her assess me nts or pr o ce d ures are 
d o ne  o n t he da y of cli nic visit .   
 F or w o me n of c hil d beari n g p ote ntial (as defi ne d i n Secti o n  4. 1 ), perf or m a ser u m or 
uri ne pre g n a nc y test a n d d oc u me nt t he res ults.  F or s u bjects w h o are of n o n -
c hil d beari n g p ote ntial (as defi ne d i n Secti o n 4. 1 ), n o pre g na nc y t est will be re q uire d.  
 Perf or m a p h ysic al e x a mi nati o n ( Secti o n  9. 1 1 ), i ncl u di n g wei g ht.   
 Assess f u ncti o nal stat us usi n g t he E C O G P S ( Secti o n  1 7. 4 ).   
 Rec or d c o n c o mita nt me dicati o ns, A Es, a n d h os pitalizati o n -relate d rec or ds. 
 O btai n vital si g ns (s yst olic a n d diast olic bl o o d press ure, p ulse rat e, res pir at or y rate, 
a n d b o d y t e m perat ure; Secti o n 9. 9 ) a n d S p O 2 (Secti o n 9. 1 2. 2 ).   
 C ollect a n d se n d bl o o d sa m ples t o t he la b orat or y f or t he f oll o wi n g tests ( Secti o n  9. 8 ): 
 He mat ol o g y  
 C he mistr y  
 O btai n bl o o d sa m ples f or A D A, o nl y f or s u bjects r a n d o mize d t o T -D X d .  
See Secti o n  6. 6. 2  for i nf or mati o n o n s u bjects wit h p ositi ve A D A at t he 4 0 -Da y 
( + 7 d a ys) F oll o w -u p.  
6. 6. 2.  
L o n g -ter m/ S ur vi v al F oll o w-u p  
After c o m pleti o n of t he 4 0 -Da y ( +7 d a ys) F oll o w-u p assess me nts , t he L o n g-ter m/ S urvi val 
F oll o w -u p assess me nts will be perf or me d e ver y 3 m o nt hs  ( ±1 4 d a ys) fr o m t he date of 4 0-Da y 
( +7 d a ys) F oll o w-u p ass ess me nts u ntil deat h, wit h dra wal of c o nse nt  fr o m t he st u d y, l oss t o 
f oll o w-u p, or st u d y cl os ure, w hic he v er occ urs first.   
T he f oll o wi n g acti vities will ta ke place d uri n g L o n g -ter m/ S ur vi val F oll o w-u p at t he st u d y site or 
b y tele p h o n e c o nta ct:  
 T he s u bject m ust c o m plete t he H E O R o utc o mes E O R T C Q L Q -C 3 0 , E O R T C Q L Q -
B R 4 5, a n d E Q -5 D -5 L q u esti o n naires bef ore a n y ot her assess me nts or pr o ce d ures are 
d o ne  t hat da y ( o nl y at first 3 m o nt hs , w hic h will be t he last data c ollecti o n p oi nt f or 
H E O R q uesti o n naires).  
 F or s u bjects wit h p ositi ve A D A at t he 4 0 -Da y ( +7 d a ys) F oll o w -u p assess me nt , 
a d diti o nal ser u m A D A sa m ples ma y be c ollecte d e ver y 3 m o nt hs  ( ± 1 m ont h ) u p t o 
1  y ear fr o m t he last d ose of st u d y dr u g , u ntil t he A D A bec o mes n e gati ve, u ntil t he 
A D A titer bec o mes less t ha n baseli ne (a p plica ble w he n pre -e xisti n g A D A is 
o bser ve d), u ntil t he s u bject starts a n ot her t hera p y f or ca ncer or wit h dra ws c o nse nt 
fr o m the st u d y, w hic he ver occ urs first.  
 Rec or d s u bse q ue nt a ntica ncer treat me nts, t heir o ut c o mes, a n d s ur vi val.  

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 F urt her f oll o w -u p ma y b e re q uir e d f or o n g oi n g A Es (see Secti o n  9. 2 ). 
 All s u bjects will be f oll o we d f or s ur vi v al u ntil deat h, wit h dra wal of c o nse nt, l oss t o 
f oll o w-u p, or st u d y cl os ure , w hic he v er occ urs first. 
If direct c o ntacts are n ot p ossi ble beca use of  wit h dra wal of c o nse nt or t he s u bject bec o mes l ost t o 
f oll o w-u p, t he site m ust ma ke e ver y eff ort t o c oll ect s ur vi val stat us fr o m p u blic rec or ds (e g, 
deat h certificates) i n acc or da nce wit h l ocal la ws.  See Secti o n  5. 7. 1  f or f urt her details o n h o w 
s u bjects will be f oll o we d f or s ur vi val stat us if t he y wit h dra w c o nse nt.  
N o te t hat if a s u bject disc o nti n ues treat me nt f or reas o ns ot her t ha n diseas e pr o gressi o n  or deat h , 
e ver y atte m pt s h o ul d be ma de t o c ollect t u m or ass ess me nts u ntil disease pr o gressi o n a n d t he 
sca ns be se nt f or ce ntral r e vie w e v e n if t he s u bject has starte d a n ot her a nt i-n e o plastic t hera p y.  

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7.  
E F FI C A C Y A S S E S S M E N T S  
7. 1.  
Assess me nts f or Effic ac y E n d p oi nts  
7. 1. 1.  
Pri m ar y Effic ac y E n d p oi nt  
T he pri mar y effic ac y e n d p oi nt is P F S , base d o n BI C R , i n H R-p ositi ve  breast ca ncer  s u bjects.  
Pr o gressi o n -free s ur vi val base d o n BI C R is defi ne d as t he ti me fr o m t he dat e of ra n d o mizati o n t o 
t he earliest date of t he first o bjecti ve d oc u me ntati o n of ra di o gra p hic diseas e pr o gressi o n via 
BI C R acc or di n g t o m R E CI S T versi o n 1. 1 or d eat h d ue t o a n y ca us e.   S u bjects w h o are ali ve wit h 
n o o bjecti ve d oc u me ntati o n of (ra di o gra p hic) dise ase pr o gressi o n b y t h e data c ut off dat e f or P F S 
a nal ysis will be ce ns or e d at t he date of t heir last e val ua ble t u m or assess me nt.  Detaile d ce ns ori n g 
r ules f or P F S bas e d o n BI C R will be s pecifi e d i n t he Statistical A nal ysis Pla n ( S A P). 
7. 1. 2.  
Ke y S ec o n d ar y Effic ac y E n d p oi nt s 
T he ke y s ec o n dar y effic ac y e n d p oi nt s are:  
 P F S, base d o n BI C R, i n  all ra n d o mize d s u bjects  
 O S i n H R -p ositi ve breast ca ncer  s u bjects 
 O S i n all ra n d o mize d s u bjects  
I n S w ede n o nl y, ple ase see Secti o n 1 7. 9. 1  f or te xt a p plic a ble t o sites i n S we de n. 
O S  is defi ne d as t he ti me fr o m t he date of ra n d o mizati o n t o t he date of deat h f or a n y ca use.  If 
t here is n o deat h r e p orte d f or a s u bject b ef ore t he data c ut off f or O S a nal ysis, O S will be 
ce ns ore d at t he last c o nta ct date at w hic h t h e s u bject is k n o w n t o be al i ve. 
7. 1. 3.  
Ot her Sec o n d ar y Effic ac y E n d p oi nt s 
Ot her s ec o n d ar y effic ac y e n d p oi nts i ncl u de:  
 P F S, base d o n I n vesti gat or assess me nt 
 C o nfir me d O R R, defi ne d as t he s u m of C R rate  a n d P R rate, base d o n BI C R a n d  
I n v esti gat or assess me nt, a n d c o nfir me d b y a sec o n d assess m e nt. 
 D o R, defi ne d as t he ti me fr o m t he date of t h e first d oc u me ntati o n of o bjecti ve 
res p o nse ( C R or P R) t o t he date of t he first d oc u me ntati o n of disease pr o gressi o n, 
base d o n BI C R,  or deat h .  D urati o n of res p o nse will be meas ure d f or res p o n di n g 
s u bjects (P R or C R) o nl y.  S u bjects w h o are pr o gressi o n -free at t he ti me of t he 
a nal ys es will be ce ns ore d at t he date of t he l ast e val ua ble t u m or assess me nt.   
I n S w e de n o nl y , p le ase see Secti o n 1 7. 9. 1  for te xt a p plic a ble t o sites i n S we de n.  
Detaile d ce ns ori n g r ules f or a p plica bl e sec o n d ar y efficac y e n d p oi nts will be s pecifie d i n t he 
S A P.  
7. 1. 4.  
E x pl or at or y Effic ac y E n d p oi nt s 
T he e x pl orat or y effi ca c y e n d p oi nts i ncl u de: 

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 C B R , defi ne d as t he s u m of C R rate, P R rate, a n d greater t ha n or e q u al t o  6  m o nt hs’ 
S D rate, base d o n  BI C R . 
 D C R, defi ne d as t he s u m of C R rate, P R rate, a n d S D rate, base d o n  BI C R  
 T T R, defi ne d as t he ti me fr o m t he date of ra n d o mi zati o n t o t he date of t he first 
d oc u me ntati o n of o bjecti ve res p o nse ( C R or P R), base d o n BI C R.  Ti me t o res p o nse 
will be meas ure d f or res p o n di n g s u bjects ( C R or P R) o nl y.  
 P F S 2, defi ne d as t he ti m e fr o m date of ra n d o mizati o n t o t he first d oc u me nte d 
p r o gressi o n o n ne xt-li ne t hera p y * or deat h d ue t o a n y ca use, w hic he v er occ urs first.  
T he first d oc u me nte d pr o gressi o n o n ne xt -li ne t hera p y is bas e d o n i n vesti gat or 
assess me nt of P D.  P F S 2 will be ce ns ore d if n o P F S 2 e ve nt is o bser ve d d uri n g ne xt 
li ne t herap y bef ore t he a n al ysis c ut off date; t he ce ns ori n g dat e will be t he last c o ntact 
date i n cases w here t here is n o ne xt-li ne t hera p y.  I n t he cas e t hat a sec o n d a nti-ca ncer 
t hera p y is i ntr o d uce d pri or t o a P F S 2 e ve nt, t he n P F S 2 date will be ce ns ore d at t he 
e nd date of t he first ne xt -li ne t hera p y. 
 A n y d eat h oc c urri n g pri or t o t he start of ne xt -li ne t hera p y will be c o nsi d ere d a 
P F S 2 e ve nt.  
 A n y d eat h f oll o wi n g t he ne xt li ne of t hera p y will be a P F S 2 e ve nt if n o s ec on d 
ne w li ne of t hera p y is i nitiate d.  
 P F S a n d P F S 2 ma y b e i de ntical i n t he cas e t hat a s u bject starts t he ne xt li ne 
a nti-ne o plastic t hera p y pri or t o pr o gressi o n o n t he trial t hera p y a n d t u m or 
assess me nts c o nti n ue aft er start of t he ne w t hera p y.  
* Ne xt -li ne t hera p y is defi ne d as t he first ne w s yst e mic a ntica ncer t hera p y i nitiate d 
after disc o nti n uati o n of st u d y treat me nt re gar dless of E O T reas o n.  
7. 2.  
A p pr o pri ate ness of Selecte d Effic ac y Assess me nts  
T he pri mar y e n d p oi nt of t his st u d y is P F S  base d o n m R E CI S T versi o n  1. 1 , w hic h will be 
deter mi ne d b y i n de pe n d e nt re vie w of baseli ne a n d f oll o w -u p assess me nts o btai ne d e ver y 
6  wee ks  fr o m ra n d o mizati o n date.  Pr o gressi o n -free s ur vi val has ser ve d as t he basis of se veral 
rece nt a p pr o vals i n t he m etastatic breast ca n cer setti n g i ncl u di n g p ert uz u ma b ( C L E O P A T R A 
st u d y),1 2 p al b ocicli b ( P A L O M A st u dies), 2 1 ,2 2 ri b ocicli b ( M O N A L E E S A-2), 2 3 a n d a be macic li b 
( M O N A R C H 2).2 4  Sa m ple size has bee n calc ulate d t o e ns ure t he st u d y is a de q uate l y p o were d t o 
detect a cli nicall y me a ni n gf ul P F S be n efit . 
S ur vi val is c o nsi dere d t h e m ost relia ble ca ncer e n d p oi nt, a n d w he n st u dies ca n be c o n d ucte d t o 
a de q uatel y assess o verall s ur vi val, it is us uall y t h e preferre d e n d p oi nt. 2 5 ,2 6  T he g ui d eli nes 
rec o m me n d esti mati n g t he treat me nt effect o n O S w he n t he pri mar y e n d p oi nt is s o met hi n g ot her 
t ha n O S.  A d diti o n of O S as a ke y sec o n dar y e n d p oi nt is e x pecte d t o hel p de m o nstrate t he 
o verall fa v ora ble ris k -be nefit  pr ofile  of t he st u d y  treat me nt.  
Patie nts wit h metastatic breast c a ncer face a n ill ness ass ociate d wit h si g nifica nt s y m pt o ms.  
M ore o ver, t he y are als o a ware t hat d es pite t he a v aila bilit y of vari o us tr eat me nts, it is ult i matel y 
i nc ura ble.  T h e s uccess of m o der n t hera pies i n ac hie vi n g better disease c o ntr ol a n d pr ol o n ge d 
s ur vi val mea ns t hat m ore w o me n wit h metastatic breast c a ncer  ca n recei ve se veral li nes of 

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treat me nt a n d i n t he pr o cess t he ke y g oals are t o pr ol o n g s ur vi val a n d t o i m pr o ve healt h -relate d 
q ualit y of life ( Q o L).  T h at is w h y it is partic ularl y val ua ble t o i n v ol ve s u bjects i n cli nical st u dies 
b y as ki n g t he m t o pr o vi d e assess me nt of t heir h ealt h a n d Q o L.  I n rece nt years , a gr o wi n g 
n u m ber of cli nical st u dies i n  metastatic breast c a n cer  ha v e bee n re p orti n g o n healt h -rel ate d Q o L, 
t he m ost c o m m o n patie nt re p orte d o utc o m e ( P R O) bei n g us e d is t he E O R T C Q L Q-C 3 0 wit h or 
wit h o ut t he breast ca n cer s u p ple me nt E O R T C Q L Q -B R 4 5, f oll o we d b y F A C T -B. 2 7 
T he i n de x sc ores fr o m t h e P R Os will be use d t o s h o w c ha n ges i n o v erall h ealt h re late d q u alit y of 
life a n d cli nicall y mea ni n gf ul c h a n ges i n s pecific as pects of s u bject’s well bei n g o v er ti me.  I n 
a d diti o n, t he o utc o mes will be use d i n f urt her a n al ys es a n d ec o n o mic m o d els t o ge nerate 
e vi de nce t o s u p p ort access a n d  rei m b urse me nt. 

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8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S  
8. 1.  
P h ar m ac o ki netic Assess me nt s 
Bl o o d sa m ples f or P K assess me nts will be c ollect e d fr o m s u bjects r a n d o mize d t o T -D X d  at 
m ulti ple ti me p oi nts i n t he st u d y, as o utli ne d i n Ta ble  8 .1  a n d Ta ble  1 7 .2 .  I n a d diti o n, if feasi ble, 
a bl o o d sa m ple s h o ul d be c ollecte d f or P K a nal ysis as s o o n as p ossi ble w he n a s u bject is 
sus pecte d of h a vi n g I L D/ p ne u m o nitis . 
T a ble  8 .1 : 
Bl o o d S a m pli n g f or P h ar m ac o ki netic A n al ysis  
C ycle  
D a y  
S a m pli n g Ti me P oi nt ( Acce pt a ble R a n ges)  
C ycle 1  
Da y 1  
BI ( wit hi n 8 h o urs )  
E OI: Prefera bl y  w it hi n 1 5 mi n utes  or as s o o n as p ossi ble  after 
E OI  
5 h o urs  after t he start of dr u g a d mi nistrati o n ( ± 2 h o urs ) 
C ycles 2, 3, 4, 6, 
a n d 8 
Da y 1  
BI ( wit hi n 8 h o urs ) 
E OI: Prefera bl y w it hi n 1 5 mi n utes  or as s o o n as p ossi ble  after 
E OI  
BI = bef ore i nf usi o n; E OI = e n d of i nf usi o n  
At eac h ti me p oi nt, bl o o d will be c ollecte d f or T -D X d , t otal a nti-H E R 2 a nti b o d y, a n d 
M A A A -1 1 8 1a P K a nal ysis.  T he act ual ti me of st u d y treat me nt a d mi nistrati o n a n d t he e x act ti me 
of bl o o d sa m pli n g f or P K a nal ysis m ust be rec or de d o n t he e C R F.  
Details f or bl o o d sa m pli n g, pr ocessi n g, st ora ge , a n d s hi p me nt  t o ce ntral la b orat or y f or P K 
sa m ples will be pr o vi de d i n t he st u d y la b orat or y ma n ual. 
Ser u m c o nce ntr ati o ns of T -D X d , t otal a nti-H E R 2 a n ti b o d y, a n d M A A A-1 1 8 1a will be meas ure d 
usi n g vali date d assa ys at t he bi oa nal yti cal la b orat or y.  
If c hl or o q ui ne or h y dr o x yc hl or o q ui ne is a d mi nistere d f or C O VI D-1 9  i nfecti o n, a d diti o nal P K 
ser u m sa m ples s h o ul d be c ollecte d fr o m eac h s u bj ect w h o pr o vi des c o nse nt as descri be d i n  
Secti o n  1 7. 8  a n d at t he ti me p oi nts s pecifie d i n t he Sc he d ule of E v e nts ( Ta ble  1 7 .2 ). 
8. 2.  
P h ar m ac o d y n a mic Assess me nt (s) 
N ot a p plica ble . 
8. 3.  
Bi o m ar ker Assess me nts  
I n t his st u d y, bi o mar ker a nal ys es will be use d t o i n vesti gate t h e effect of T -D X d  at t he m olec ul ar 
a n d cell ular le v el as well as t o deter mi ne h o w c ha n ges i n t he mar kers m a y relate t o e x p os ure a n d 
cli nical o utc o mes.  T he s a m ple c ollecti o n i nf or mati o n as re q uire d s h o ul d b e rec or de d o n t he 
e C R F pa ge(s) a n d ce ntral la b orat or y re q uisiti o n f or m(s).  Detaile d i nstr ucti o ns f or t he c ollecti o n, 
ha n dli n g, a n d s hi p pi n g of bi o mar ker sa m ples are o utli ne d i n t he st u d y l a b orat or y m a n ual.  

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8. 3. 1.  
T u m or  Tiss ue  S a m pli n g  
I n a d diti o n t o t he t u m or tiss ue sa m ple re q uire d f or assess me nt  of H E R 2 stat us, a n a d diti o nal 
tiss ue sa m ple f or e x pl orat or y bi o mar ker a n al ysis nee ds t o be s u b mitte d, if all o we d b y l ocal la ws.  
A n a d diti o nal  t u m or tiss ue bi o ps y after t he c o m pleti o n of t he s u bject’s m ost rece nt treat me nt 
re gi me n is re q uir e d f or retr os pecti ve assess me nt. If t his t u m or tiss ue sa m ple was c ollecte d after 
c o m pleti o n of t he last treat me nt re gi me n, a n a d diti o nal t u m or tiss ue bi o ps y is n ot re q uire d.  If 
t his t u m or tiss ue sa m ple was c ollecte d bef ore c o m pleti o n of t he last treat me nt re gi me n, a n 
a d diti o nal t u m or tiss ue bi o ps y is re q uir e d.  O pti o n al fres h tiss ue sa m ples m a y a d diti o nall y b e 
o btai ne d d uri n g a n d after st u d y treat me nt.  T he det aile d  i nstr ucti o ns f or t he ha n dli n g a n d 
s hi p pi n g of t u m or sa m pl es are i n cl u de d i n t he st u d y la b orat or y ma n ual.  F N A a n d b o ne bi o psies 
will n ot be acce pt e d f or tiss ue sa m ples.  
8. 3. 2.  
Bl o o d S a m pli n g  
T he H E R 2 E C D i n ser u m ma y b e meas ure d b y a ce ntral la b orat or y.  Ot her e x pl orat or y 
bi o mar kers, s uc h as cf D N A i n plas ma, ma y be m eas ure d.  
8. 3. 3.  
A d diti o n al Bi o m ar ker Assess me nts  
D uri n g t h e st u d y, i n a d diti o n t o t he bi o mar kers s pecifie d a b o v e, o pti o nal e x pl orat or y bi o mar ker 
researc h ma y b e c o n d uct e d o n a vaila ble a d diti o nal sa m ples.  T hese st u dies w o ul d e xte n d t he 
searc h f or ot her p ote ntial bi o mar kers of res p o nse/resista nce t hat ma y c orrelate wit h cli nical 
be nefit .  T his ma y i ncl u d e t he de vel o p me nt of wa ys t o detect, m o nit or, or treat ca ncer.  T hes e 
a d diti o nal i n vesti gati o ns w o ul d be de pe n d e nt u p o n cli nical o utc o me, rea ge nt , a n d sa m ple 
a vaila bilit y.  If t he s u bject a grees, t he re mai ni n g sa m ples (t u m or tiss ues, bl o o d , a n d plas ma) ma y 
be st ore d f or u p t o 1 5 y ears at t he l o n gest,  acc or di n g t o t he re g ulati o n i n eac h c o u ntr y or re gi o n , 
res pecti vel y, a n d f urt her a nal yze d t o a d dress sci e ntific q uesti o ns relate d t o T -D X d  a n d/ or ca n cer.  
8. 3. 4.  
Discl os ure of t he Res ults of A d diti o n al Bi o m ar ker Assess me nts  
See I C F f or details o n discl os ure.  
8. 4.  
I m m u n o ge nicit y 
Bl o o d sa m ples f or A D A a nal ys es will be c ollecte d o nl y f or s u bj ects ra n d o mize d t o T -D X d  a n d at 
t he ti me p oi nts s pecifie d i n Ta ble  1 7 .2 .  A bl o o d sa m ple will be dra w n at eac h ti me p oi nt.  Ser u m 
c o nce ntr ati o ns of T -D X d  a n d/ or t otal a nti -H E R 2 a nti b o d y ma y be meas ure d usi n g t he sa me 
A D A sa m ples f or p ur p os e of A D A assess m e nt.  
Details f or A D A ser u m s a m pli n g, pr ocessi n g, st or a ge , a n d s hi p me nt f or A D A sa m ples will be 
pr o vi de d i n t he st u d y la b orat or y ma n ual.  
T he A D A testi n g will be perf or me d usi n g a vali date d A D A assa y f oll o wi n g tiere d assa y ste ps 
i ncl u di n g scree ni n g, c o nfir mat or y, a n d titer deter mi nati o n testi n g.  Sa m ples c o nfir me d A D A  
p ositi ve will be a nal yze d b y ne utr alizi n g a nti b o d y assa y.  

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8. 5.  
P h ar m ac o ge n o mic A n al ysis  
8. 5. 1.  
Ge n o mic o r Ge netic B a n ki n g a n d A n al ysis  
A si n gle bl o o d sa m ple f or p har mac o ge n o mics a n al ysis will be c ollecte d fr o m eac h s u bject w h o 
c o nse nts t o t his test, pre d ose o n C ycl e 1  Da y 1 .  P artici pati o n i n t his part of t he st u d y is o pti o nal 
f or all s u bjects. 
T he D N A sa m ples will be e xtracte d fr o m t he bl o o d sa m ple f or p har mac o ge n o mics a nal ysis.  T h e 
p har mac o ge n o mic sa m pl es ma y b e a n al yze d f or ge nes i n v ol ve d i n a bs or pti o n, distri b uti o n, 
meta b o lis m, eli mi nati o n, safet y, a n d efficac y of T -D X d .  A d diti o nall y, sa m ples ma y b e a nal yze d 
f or ge nes i n v ol ve d i n T -D X d  relate d si g n ali n g p at h wa ys or t o e x a mi ne diseases or p h ysi ol o gic 
pr ocesses relate d t o T -D X d .  T his i nf or mati o n ma y be us ef ul i n i ncreasi n g t he k n o wle d ge of 
differe n ces a m o n g i n di vi d uals i n t he wa y t he y res p o n d t o t he st u d y treat me nt, as well as hel pi n g 
i n t he de vel o p me nt of ne w dr u gs or i m pr o ve me nt of e xisti n g dr u gs. 
S peci me n s hi p pi n g a n d h a n dli n g det ails will be i ncl u de d i n t he st u d y la b orat or y m a n ual.  
8. 5. 1. 1.  
Discl os ure of t he Res ults of Ge n o mi c or Ge neti c A n al ysis  
See I C F f or details o n discl os ure.  
8. 5. 1. 2.  
St or a ge a n d Dis p os al of S peci me ns f or Ge n o mi c or Ge netic A n al ysis  
Sa m ples will be retai ne d f or u p t o 1 5 y ears at t he l o n gest, a cc or di n g t o t he re g ul ati o n i n eac h 
c o u ntr y or re gi o n res pecti vel y, or u ntil t he sa m ple has bee n e x ha uste d or u ntil t he S p o ns or 
i nstr ucts t he la b orat or y f or sa m ple st ora ge a n d/ or a nal ysis t o destr o y t h e sa m ple (i n acc or da nce 
wit h la b orat or y pr oce d ures).  D uri n g t he peri o d of st ora g e, t he sa m ples will n ot be i m m ortalize d 
or s ol d t o a n y o n e.  S u bjects will ha ve t he ri g ht t o wit h dra w c o nse nt a n d ha ve t heir sa m ple 
destr o ye d at a n y ti me.   
H o we ver, t he data will n ot be discar de d if t h e ge n etic a nal ysis has bee n c o m plete d bef ore t he 
s u bject wit h dra ws c o ns e nt.  

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9.  
S A F E T Y E V A L U A TI O N A N D R E P O R TI N G  
9. 1.  
Assess me nt of S afet y E n d p oi nt(s)  
Safet y e n d p oi nts will i ncl u de S A Es, T E A Es, A E SI s, disc o nti n uati o ns ass ociate d wit h  A Es , 
p h ysical e x a mi nati o n fi n di n gs , E C O G P S, vital si g n s meas ure me nts, sta n d ar d cli nic al la b orat or y 
para meters, E C G para meters, E C H O / M U G A fi n di n gs, a n d A D As.  All A Es will be cate g orize d 
usi n g t he Me dic al Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A).  A d verse e ve nts a n d 
a b n or mal la b orat or y test res ults, if a p plica ble, will be gra de d usi n g Nati o nal Ca ncer I nstit ute 
( N CI) C T C A E versi o n 5 . 0.  Safet y a nal yses i n ge n eral will be des cri pti ve a n d will be prese nte d 
i n ta b ular f or mat wit h t he a p pr o priate s u m mar y statistics. 
9. 2.  
A d verse E ve nt C ollecti o n a n d Re p orti n g  
All cli nical A Es (see Secti o n 9. 4. 1  f or defi niti o ns) occ urri n g after t h e s u bject si g ns t he Mai n I C F 
a n d u p t o 4 0 d a ys ( +7 d a ys) after l ast treat me nt (i e, t he f oll o w -u p per i o d), w het her o bser ve d b y 
t he I n v esti gat or or re p ort e d b y t h e s u bject, will be rec or de d o n t he A E e C R F pa ge.  All S A Es 
occ urri n g after s u bject si g ns t he Mai n I C F a n d u p t o 4 0 d a ys ( +7 d a ys) after last treat me nt will 
be rec or de d o n t he e C R F.  Me dical c o n dit i o ns (i ncl u di n g cli nical la b orat or y val u es/ vital si g ns 
t hat are o ut of ra n ge) t hat were dia g n os e d or k n o w n t o e xist pri or t o i nf or me d c o nse nt will be 
rec or de d as part of me dical hist or y. 
If a t u m or bi o ps y is nee d e d, re p ort a n y S A Es directl y relate d t o tissue scree ni n g pr oce d ure (ie, 
t u m or bi o ps y) al o n g wit h a n y ass ociate d treat me nt.  U nless d oc u me ntati o n of ot her A Es is 
re q uire d b y l oc al la w, o nl y S A Es directl y relate d t o t u m or bi o ps y will be rec or de d d uri n g tiss ue 
scree ni n g. 
All A Es, S A Es, a n d A E SI s are t o be re p ort e d acc or di n g t o t he pr oce d ures i n Secti o n  9. 5 . 
All cli nical la b orat or y res ults, vital si g ns, a n d E C G res ults or fi n di n gs  s h o ul d be a p praise d b y t h e 
I n v esti gat or t o deter mi ne t heir cli nical si g nifi ca nce.  Is olate d a b n or mal la b orat or y res ults, vital 
si g ns fi n di n gs, or E C G fi n di n gs (ie, n ot part of a re p orte d dia g n osis) s h o ul d be re p ort e d as A Es if 
t he y are s y m pt o matic, lea d to st u d y dr u g disc o nti n uati o n,  d ose  i nterr u pti o n or  re d ucti o n, re q uire 
c orrecti ve treat me nt, or c o nstit ute a n A E i n t he I n vesti gat or’s  cli nical j u d g me nt . 
At eac h visit, t he I n vesti gat or will deter mi ne w het her or n ot a n y A Es h a ve occ urre d b y 
e val uati n g t he s u bject.  A d verse e v e nts ma y be dir ectl y o bs er ve d, re p ort e d s p o nta ne o usl y b y t he 
s u bject or b y q uesti o ni n g t he s u bject at eac h st u d y visit.  S u bjects s h o ul d be q uesti o ne d i n a 
ge n eral w a y, wit h o ut as ki n g a b o ut t he o cc urre nce of a n y s pecifi c s y m pt o ms.  T he I n vesti gat or 
m ust assess all A Es t o deter mi ne seri o us ness, se v erit y, a n d ca usalit y, i n acc or da nce wit h t he 
defi niti o ns i n Secti o n  9. 4 .  T he I n vesti gat or’s assess me nt m us t be clearl y d oc u me nte d i n t he 
site’s s o urce d o c u me ntati o n wit h t he I n v esti gat or’s si g nat ur e.   
T he I n vesti gat or s h o ul d a l wa ys re p ort t he dia g n osis as t he A E or S A E ter m.  W he n a dia g n osis is 
u na vaila ble, t he pri mar y si g n or s y m pt o m s h o ul d be re p ort e d as t he A E or S A E ter m wit h 
a d diti o nal details i ncl u de d i n t he narrati ve u ntil t he dia g n osis bec o mes a v aila ble.  If t he si g ns a n d 
s y m pt o ms are disti nct a n d d o n ot s u g gest a c o m m o n dia g n osis, t he y s h o ul d be re p ort e d as 
i n di vi d ual e ntries of A E or S A E. 

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F or e v e nts t hat are c o nsi dere d seri o us beca use of  h os pitalizati o n, t he reas o n f or h os pitalizati o n 
m ust be re p orte d as t h e S A E ( dia g n osis or s y m pt o m re q uiri n g h os pitalizati o n).  A pr oce d ure is 
n ot a n A E or S A E, b ut t he reas o n f or t he  pr oce d ure ma y be a n A E or S A E.  Pre pla n ne d ( pri or t o 
si g ni n g t he I C F) pr oce d ures or treat me nt s re q uiri n g h os pitalizati o n f or pre-e xisti n g c o n diti o ns 
t hat d o n ot w orse n i n se v erit y s h o ul d n ot be re p ort e d as S A Es (see Secti o n  9. 4. 2  f or d efi niti o ns).  
F or deat hs, t he u n derl yi n g or i m me diate ca us e of deat h s h o ul d al wa ys be re p orte d as a n S A E.  
Disease pr o gress i o n is a st u d y e n d p oi nt a n d c o ns e q ue ntl y, s h o ul d n ot be re p orte d as a n A E or 
S A E.  H o we ver, w he n a s u bject dies fr o m P D wit h n o ot her i m me diate ca uses, “ disease 
pr o gressi o n” s h o ul d be re p orte d as a n S A E.  
A n y s eri o us, u nt o war d e ve nt t hat ma y o cc ur s u bs e q ue n t t o t he re p orti n g p eri o d t hat t he 
I n v esti gat or assess es as r elate d t o st u d y dr u g s h o ul d als o be re p orte d a n d m a na ge d as a n S A E. 
9. 3.  
A d verse E ve nts of S peci al I nterest   
F or t he T -D X d  cli nical pr o gra m, base d o n t he a vaila ble precli nical d ata, re vie w of t he 
c u m ulati ve literat ure, re p orte d t o xicities f or t he sa me class of a ge nts, a n d bi ol o gical pla usi bilit y,  
I L D a n d L V E F decrease are c o nsi d ere d t o be A E SI s. 
9. 3. 1.  
I nterstiti al L u n g Dise ase/ P ne u m o nitis 
9. 3. 1. 1.  
Cli nic al S u m m a r y  
I nterstitial l u n g diseas e/ p ne u m o nitis is c o nsi dere d to be a n i m p orta nt i de ntifie d ris k base d o n a 
c o m pre he nsi ve c u m ulati ve re vie w of t he a v aila bl e safet y d ata fr o m t he cli nical  de vel o p me nt 
pr o gra m  as w ell as t he res ults of p ote ntial I L D/ p n e u m o nitis cases re vie we d b y t he i n de p e n de nt 
I L D A C, a vaila ble d ata fr o m rece nt e pi de mi ol o g y/literat ure, bi ol o gical pla usi bilit y, a n d s afet y 
i nf or mati o n fr o m dr u gs of si milar class.  Refer t o t he c urre nt I B f or a su m mar y of preli mi nar y 
cli nical st u d y dat a. 9  
9. 3. 1. 2.  
M a n a ge me nt G ui d a nce  
I nterstitial l u n g diseas e/ p ne u m o nitis s h o ul d be r ule d o ut if a s u bject de vel o ps ra di o gra p hic 
c ha n ges p ote ntiall y c o nsiste nt wit h I L D or de vel o ps a n ac ute o ns et of ne w or w orse ni n g 
p ul m o nar y or ot her relate d si g ns/s y m pt o ms s uc h as d ys p nea, c o u g h , or fe ver.  If t he A E is 
c o nfir me d t o ha v e a n eti ol o g y ot her t ha n I L D/ p ne u m o nitis, f oll o w t he ma na ge m e nt g ui d a nce 
o utli ne d i n t he desi g nate d “ Ot her N o n -la b orat or y A d verse E v e nts” d ose m o dificati o n secti o n of 
t he st u d y pr ot oc ol ( Secti o n 5. 4 ).  
If t he A E is s us pect e d t o be I L D/ p ne u m o nitis, treat me nt wit h st u d y dr u g  s h o ul d be i nterr u pte d 
pe n di n g f urt her e val uati o n s.  E val uati o ns s h o ul d i ncl u de hi g h res ol uti o n C T, p ul m o n ol o gist 
c o ns ultati o n  (infecti o us disease c o ns ultati o n as cli nicall y i n dicat e d), bl o o d c ult ure a n d C B C 
( ot her bl o o d tests c o ul d b e c o nsi dere d as nee de d), br o nc h osc o p y a n d br o nc h oal ve olar la v a ge if 
cli nicall y i n dicat e d a n d feasi ble s h o ul d be c o nsi dere d , p ul m o nar y f u ncti o n tests a n d  p ulse 
o x i metr y (S p O 2 ), arterial bl o o d gas es if cli nicall y i n dicate d, a n d o ne bl o o d sa m ple  c ollecti o n  f or 
P K  (ce ntral la b orat or y) a nal ysis as s o o n as I L D/ p ne u m o nitis is s us pecte d, if feasi ble.  Ot her tests 
c o ul d be c o nsi dere d , as n ee de d.   

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If t he A E is c o nfir me d t o be I L D/ p ne u m o nitis, f oll o w t he ma na ge m e nt g ui d a nce o utli ne d i n t he 
desi g nat e d “ P ul m o nar y T o xicit y” d ose m o difi cati o n secti o n of t he st u d y pr ot oc ol ( Ta ble  5 .3 ). 
All e ve nts of I L D re gar dless of se verit y or seri o us ness will be f oll o we d u ntil res ol uti o n i ncl u di n g 
after dr u g dis c o nti n uati o n.  
9. 3. 1. 3.  
I nterstiti al L u n g Dise ase A dj u dic ati o n C o m mittee 
A n i n de pe n de nt I L D A C f or t he T -D X d  pr o gra m is res p o nsi ble f or re vie wi n g all cases of 
p ote ntial I L D/ p n e u m o nitis.  T o e ns ure a d e q uate a n d rele va nt i n de p e n de nt e val uati o n, s yst e matic 
a d diti o nal data c ollecti o n will be c o n d ucte d f or all cases t hat will be br o u g ht f or a dj u dicati o n.  
T his a d diti o nal data c ollecti o n will c o ver a m or e i n -de pt h rele va nt me dical hist or y (e g , s m o ki n g, 
ra diati o n, c hr o nic o bstr ucti ve p ul m o nar y disease , a n d ot her c hr o nic l u n g c o n diti o ns), dia g n ostic 
e val uati o n, treat me nt , a n d o utc o me of t he e v e nt.  T his data c ollecti o n will be tri g gere d f or A Es 
re p orte d usi n g t he sel ecte d 4 2 preferre d t er ms ( P Ts) (a ll fr o m t he I L D Sta n dar di se d Me d D R A 
Q uer y  [ S M Q]) pl us t he 2  P Ts of ac ute res pirat or y fail ure a n d res pirat or y fail ure . 
9. 3. 2.  
Left Ve n tric ul ar Ejecti o n Fr acti o n Decre ase  
9. 3. 2. 1.  
Cli nic al S u m m a r y  
L V E F decrease  i n ass o ciati o n wit h T -D X d  are c o nsi dere d t o be i m p orta nt p ote ntial ris k s base d 
o n t he a vaila ble n o n cli nical data, literat ure , a n d a vaila ble safet y i nf or mati o n f or dr u gs of si milar 
class.  R efer t o t he c urre nt I B f or a s u m mar y of preli mi nar y cli nical st u d y data. 9  
9. 3. 2. 2.  
M a n a ge me nt G ui d a nce  
Left ve ntric ular eje cti o n fracti o n will be meas ure d b y eit her E C H O or M U G A sca n.  All 
E C H Os / M U G As will be e val uate d b y t he I n vesti gat or or dele gate d p h ysici a n f or m o nit ori n g 
car diac f u ncti o n.   
I n Ger m a n y o nl y , p le ase see Secti o n 1 7. 9. 3  f or te xt a p plic a ble t o sites i n Ger m a n y. 
Tr o p o ni n will be meas ur e d at Scree ni n g a n d E O T a n d as nee d e d bas e d o n s u bject -re p orte d 
car diac si g ns a n d s y m pt o ms s u g gesti n g c o n gesti ve heart fail ure, m y ocar dial i nfarcti o n, or ot her 
ca uses of car di ac m y oc yt e necr osis .  E C Gs will be perf or me d , a n d sta n dar d E C G para meters will 
be meas ur e d, i ncl u di n g R R, P R, Q T i nter vals, a n d Q R S d urati o n.  All E C Gs m ust be e val uate d 
b y I n v esti gat or or del e gate d p h ysicia n f or t he pres e nce of a b n or malities.  W het her or n ot 
meas ure me nt is perf or me d, date perf or me d,  res ults, a n d fi n di n gs f or eac h para meter will be 
rec or de d i n t he e C R F. 
9. 4.  
A d verse E ve nt  
9. 4. 1.  
Defi niti o n of A d verse E ve nt  
A n A E is a n y u nt o war d me dical occ urre n ce i n a s u bject a d mi nistere d a p h ar mace utical pr o d uct  
a n d t hat d oes n ot necessaril y ha v e t o ha ve a ca us a l relati o ns hi p wit h t his treat me nt.  A n A E ca n 
t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal l a b orat or y fi n di n g, f or 
e x a m ple), s y m pt o m, or disease te m p orall y ass o ciate d wit h t he use of a me dici nal pr o d uct, 
w het her or n ot c o nsi dere d relate d t o t he me dici n al pr o d uct (I nter nati o nal C o nfere n ce o n 

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Har m o nisati o n [I C H] E 2 A G ui deli ne.  Cli nical Safet y Data M a na ge m e nt: Defi niti o ns a n d 
Sta n dar ds f or E x pe dite d Re p orti n g, O ct 1 9 9 4). 2 8 
It is t he res p o nsi bilit y of I n v esti gat ors, base d o n t h eir k n o wle d ge a n d e x peri e nce, t o det er mi ne 
t h ose circ u msta nces or a b n or mal la borat or y  fin di n gs t hat s h o ul d be c o nsi d ere d A Es. 
9. 4. 2.  
Seri o us A d verse E ve nt  
A n S A E is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose:  
 Res ults i n deat h,  
 Is life-t hreate ni n g, 
 Re q uires 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,  
 Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y,  
 Is a c o n ge nital a n o mal y/ birt h defect, or 
 Is a n i m p orta nt me dical e ve nt. 
N ote:  T h e ter m “lif e -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of d eat h at t he time of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat 
h y p ot hetic all y mi g ht ha v e ca use d d eat h if it were m ore se vere (I C H E 2 A G ui deli ne.  Cli nical 
Safet y Data M a na ge m e nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, Oct 1 9 9 4). 2 8  
Me dical a n d sci e ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her or n ot e x pe dite d 
re p orti n g is a p pr o priat e i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be 
i m me diatel y life t hr eate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he s u bject 
or ma y re q uir e i nter ve nti o n t o pre ve nt 1  of t he ot h er o utc o mes liste d i n t he  defi niti o n a b o ve.  
E x a m ples i ncl u de aller gi c br o nc h os pas m, c o n v ulsi o ns, a n d bl o o d d yscrasias or de vel o p me nt of 
dr u g d e pe n de nc y or dr u g a b use.  
N ote:   
 P r oce d ures are n ot A E s or S A E s, b ut t he reas o n f or t he pr oce d ure ma y b e a n A E or 
S A E.    
 Pre pla n ne d ( pri or t o si g ni n g t he I C F) pr o ce d ures or treat me nts re q uiri n g 
h os pitaliz ati o ns f or pre -e xisti n g c o n diti o ns t hat d o n ot w orse n i n se verit y are n ot 
S A Es.  
9. 4. 3.  
Gr a de Ass ess me nt  
T he se verit y of A Es will be gra de d usi n g t he  N CI  C T C A E versi o n 5. 0.  F or eac h e pis o de, t he 
hi g hest se v erit y gra d e att ai ne d s h o ul d be re p orte d.  
T he N CI  C T C A E g ui deli nes d o n ot all o w cert ai n gra des f or certai n A Es.  F or e x a m ple, pai n ca n 
be Gra d e 1 t o 3 o nl y (ie, ca n n ot be life -t hreat e ni n g or fatal), w h ereas se psis ca n o nl y be Gra de 4 
or 5 (ie, ca n o nl y b e life -t hreate ni n g or fatal).  I n a d diti o n, al o pecia ca n o nl y be Gra d e 1 o r 2.  
T he N CI  C T C A E g ui deli nes s h o ul d be f oll o we d cl osel y.  
 Gra de 1: Mil d A E  

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 Gra de 2: M o derate A E  
 Gra de 3: Se vere A E  
 Gra de 4: Lif e -t hreate ni n g c o nse q ue nces; ur ge nt i nt er ve nti o n i n dicate d 
 Gra de 5: D eat h r elate d t o A E  
Se verit y vs. Seri o us ness:  Se verit y is use d t o des cri be t he i nte nsit y of a s pecific e ve nt ; h o we v er, 
t he e ve nt itself ma y be of relati vel y mi n or me dical si g nifica n ce (s uc h as se vere hea dac he).  
Seri o us ness of a n e v e nt i s base d u p o n a u ni versal a n d gl o b al re g ulat or y d efi niti o n f or re p orti n g 
S A Es t o Re g ulat or y A ge ncies .  F or e x a m ple, t he N CI C T C A E Gra de 4 (life -t hreate ni n g 
c o nse q ue nces; ur ge nt i nt er ve nti o n i n dicate d) is assesse d base d o n u ni q ue cli nical descri pti o ns of 
se verit y f or eac h A E, a n d t hese criteri a ma y be differe nt fr o m t h ose use d f or t he assess me nt of 
A E seri o us ness.  A n A E assesse d as Gra de 4 b ase d o n t he N CI  C T C A E gra de ma y or ma y n ot b e 
assesse d as seri o us base d o n t he seri o us ness criteria.  O verall, t he s e verit y of a n e ve nt ma y b e 
gra de d b y t he I n vesti gat or as Gra de 1 or 2, b ut if t he s u bject pres e nts t o t he e mer ge n c y facilit y 
f or e val u ati o n a n d is h os pitaliz e d o ver ni g ht f or o bser vati o n t hat i m me diatel y ma kes t he e ve nt 
seri o us base d u p o n h os pitaliz ati o n wit h o ut re gar d t o t he I n v esti gat or assess me nt of se verit y. 
9. 4. 4.  
C a us alit y Assess me nt  
T he I n vesti gat or s h o ul d assess ca usal r elati o ns hi p bet wee n a n A E a n d t he st u d y dr u g o n t h e basis 
of  his/ her cli nical j u d g me nt a n d t he f oll o wi n g defi niti o ns.  T he ca usalit y assess me nt m ust  be 
ma de base d o n t he a vaila ble i nf or mati o n a n d ca n be u p date d as n e w i nf or mati o n bec o mes 
a vaila ble.  
 Relate d:  
 T he A E f oll o ws a reas o n a ble te m p oral se q u e nce fr o m st u d y dr u g a d mi nistrati o n, 
a n d ca n n ot be reas o n a bl y e x plai ne d b y t he s u bject’s cli nica l state or ot her fact ors 
(e g, disease u n der st u d y, c o nc urre nt diseases, a n d c o nc o mita nt me dicati o ns). 
or  
 T he A E f oll o ws a reas o n a ble te m p oral se q u e nce fr o m st u d y dr u g a d mi nistrati o n, 
a n d is a k n o w n reacti o n t o t he dr u g u n der st u d y or its c he mical gr o u p, or  is 
pre dicte d b y k n o w n p h ar mac ol o g y.  
 N ot Relate d:  
 T he A E d oes n ot f oll o w a reas o n a ble se q u e nce fr o m st u d y dr u g a d mi nistrati o n, or 
ca n be reas o n a bl y e x plai ne d b y t h e s u bject’s cli ni cal state or ot her fact ors (e g, 
disease u n der st u d y, c o nc urre nt diseas es, a n d c o n c o mita nt me dicati o ns).  
9. 4. 5.  
Acti o n T a ke n Re g ar di n g St u d y Dr u g (s) 
 D ose N ot C ha n ge d: N o c ha n ge i n st u d y dr u g d osa ge was ma de  
 Dr u g Wit h dra w n: T he st u d y dr u g was per ma ne ntl y st o p pe d  
 D ose Re d uce d: T h e d osa ge of st u d y dr u g was re d uce d  
 Dr u g I nterr u pte d: T he st u d y dr u g was te m p oraril y st o p pe d  

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 N ot A p plica ble : S u bject die d, st u d y treat me nt ha d bee n c o m plete d pri or t o 
reacti o n/e v e nt, or reacti o n/e ve nt occ urre d pri or t o start of treat me nt 
9. 4. 6.  
Ot her Acti o n T a ke n f or E ve nt  
 N o ne: N o treat me nt w as re q uire d  
 Me dicati o n re q uir e d : Prescri pti o n a n d/ or o ver -t h e-c o u nter me dicati o n was re q uire d t o 
treat t he A E 
 Ot her  
9. 4. 7.  
A d verse E ve nt O utc o me  
 Rec o vere d/ Res ol ve d: T he s u bject f ull y rec o vere d fr o m t he A E wit h n o resi d ual effect 
o bser ve d.  
 Rec o vere d/ Res ol ve d wit h Se q uelae: T he resi d ual effects of t he A E are still prese nt 
a n d o bser va bl e.  
 I n cl u de se q u elae/r esi d ual effects. 
 Rec o veri n g/ Res ol vi n g: T he A E has i m pr o ve d b ut has n ot f ull y res ol ve d.  
 N ot Rec o vere d/ N ot Res ol ve d: T he A E itself is still prese nt a n d o bser va ble.  
 Fatal: Fatal s h o ul d be use d w he n  deat h is a dir ect o utc o me of t he A E.  
 U n k n o w n : U n k n o w n s h o ul d be use d if s u bject is l ost t o f oll o w-u p bef ore a n o utc o me 
ca n be d eter mi ne d.  
9. 5.  
A d verse E ve n ts a n d A d verse E ve nt of S peci al I nterest Re p orti n g–
Pr oce d ure s F or I n vesti g at ors  
All A Es, S A Es, A E SI s, a n d o ver d oses will be re p orte d i n t he e C R F. 
A d diti o nal rele va nt i nf or mati o n re gar di n g t he A E SIs I L D/ p n e u m o nitis a n d L V E F  decrease  f or 
t he T -D X d  cli nic al pr o gra m , re gar dless of seri o us ness, is t o be c ollecte d t hr o u g h t he tar get e d 
q uesti o n naires b uilt wit h i n t he a p plica ble e C R Fs i n t he cli nical st u d y d ata base.  O nl y t he A E SIs 
I L D/ p n e u m o nitis tar gete d q uesti o n naire is t o be c ollecte d f or t he c o m parat or ar m.  
F or br o a d s ur veilla nce of L V E F decrease, rele va nt A Es u n der t he Me d D R A S M Qs of Car diac 
Fail ure  a n d M y ocar dial I nfarcti o n are  i ncl u de d f or e n ha nce d data c ollecti o n; a d diti o nal data f or 
t hese A Es are c ollecte d via tar gete d q uesti o n naires of heart fail ure or m y o car dial i nfarcti o n .  
F or br o a d s ur veilla nce of I L D, t he selecte d 4 2  P Ts (all fr o m t he I L DS M Q ) pl us  t he 2  P Ts of 
res pirat or y fail ure a n d ac ute res pirat or y fail ure are i ncl u de d f or e n h a nce d d ata c ollecti o ns. 
Seri o us e ve nts t hat are als o efficac y e n d p oi nts (e g, P D) a n d/ or safet y e n d p oi nts will be e x e m pte d 
fr o m S A E pr ocessi n g a n d e x pe dite d re p orti n g.  Disease pr o gressi o n s h o ul d n ot be re p orte d as a n 
A E/ S A E.  H o we ver, w he n a s u bject dies fr o m P D wit h n o ot her i m me diate ca uses, “ dise ase 
pr o gressi o n” s h o ul d be re p orte d as a n S A E a n d ca pt ure d o n desi g nat e d e C R F.  T hese e ve nts are 
cli nicall y a ntici p ate d e v e nts i n t he tar get treat me nt p o p ulati o n, a n d will be peri o dicall y re vie we d 

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b y t he Daiic hi Sa n k y o safet y t ea ms t o e ns ure pr o m pt i de ntificati o n of a n y cli nicall y c o n cer ni n g 
safet y iss ues. 
T he f oll o wi n g t y p es of e ve nts s h o ul d be re p orte d b y t he I n vesti gat or i n electr o nic data ca pt ure 
( E D C) wit hi n 2 4 h o urs  of a ware ness:  
 S A Es (see Secti o n 9. 4. 2  f or defi niti o n). 
 All p ote ntial I L D cases s h o ul d  be re p orte d wit hi n 2 4 h o urs; i ncl u di n g b ot h seri o us 
a n d n o n-seri o us p ote ntial I L D cas es ( p ote ntial I L D is defi ne d b y t he E ve nt 
A dj u dicati o n Site Ma n ual List of P Ts)  
 He patic e v e nts ( b ot h seri o us a n d n o n -seri o us) t hat meet t he p ote ntial H y’s La w 
criteria d efi ne d as a n ele vate d ( A L T or A S T) ≥3 × U L N a n d a n ele vate d t otal 
bilir u bi n > 2 × U L N t hat ma y o cc ur  eit her at differe nt ti me p oi nts  or si m ulta ne o usl y 
d uri n g t he st u d y.  A tar gete d q uesti o n naire is i n -b uilt as a n e C R F t o c ollect r ele va nt 
a d diti o nal i nf or mati o n f or t hese p ote ntial cases.  
 O ver d ose, d efi ne d as t he acci de nt al or i nte nti o nal a d mi nistrati o n of a n y d os e of a 
pr o d uct t hat is c o nsi dere d b ot h e xcessi ve a n d me dicall y i m p orta nt.  A n “e x cessi ve 
a n d me dicall y i m p orta nt” o ver d ose i ncl u des a n y o ver d ose i n w h ic h eit her a n S A E, a 
n o n -seri o us A E, or n o A E occ urs a n d is c o nsi dere d b y t he I n vesti gat or as cli nicall y 
rele va nt, ie, p os es a n act ual or p ote ntial ris k t o t he s u bject.  
 O ver d ose is al w a ys seri o us. B y defi niti o n a n o ver d ose is me dicall y i m p ort a nt, 
w hic h me ets t he seri o us n ess criteri o n of i m p orta nt me dical e ve nt. A n o v er d ose 
ca n occ ur wit h or wit h o ut a n A E. A Es ca n eit her be seri o us or n o n -s eri o us. 
Details of t he o ver d os e i ncl u di n g T -D X d  d osa ge, cli nical c o urse, ass ociate d A Es, 
a n d o utc o me m ust be ca pt ure d i n t he Narrati ve f or m of t he C R F wit hi n electr o nic 
data ca pt ur e . 
All e ve nts (seri o us a n d n o n -seri o us) m ust be re p orte d wit h I n vesti gat or’s assess me nt of t he 
e ve nt’s seri o us n ess, se verit y, a n d ca usalit y t o t he st u d y dr u g.  A detaile d narrati ve s u m marizi n g 
t he c o urse of t h e e ve nt, i ncl u di n g its e val uati o n, treat me nt, a n d o utc o me s h o ul d be pr o vi de d.  
S pecific or esti mate d d ates of e ve nt o ns et, treat me nt, a n d res ol uti o n s h o ul d be i ncl u de d w he n 
a vaila ble.  Me dic al hist or y, c o n c o mita nt me dicati o ns, a n d la b orat or y d ata t h at are rele va nt t o t he 
e ve nt s h o ul d als o be s u m mariz e d i n t he narrati ve.  F or fatal e ve nts, t he n arrati ve s h o ul d state 
w het her or n ot a n a ut o ps y w as or will be perf or m e d, a n d i ncl u de t he res ults if a vaila ble.  S o urce 
d oc u me nts (i ncl u di n g m e dical re p orts) will be retai ne d at t he st u d y site a n d s h o ul d n ot be 
s u b mitte d t o t he S p o ns or f or S A E re p orti n g p ur p os es. 
Ur ge nt safet y q ueries  a n d f oll o w -u p i nf or mati o n , s uc h as t h ose u p gra d e d t o a 
fatal/life-t hreate ni n g case,  m ust be f oll o we d a n d a d dresse d pr o m ptl y.  T he i n vesti gat or will 
s u b mit a n y u p date d S A E data t o t he C R O wit hi n 2 4 h o urs of recei pt of t he i nf or mati o n.  Ot her 
foll o w -u p i nf or mati o n a n d res p o nse t o n o n -ur ge nt safet y q ueri es s h o ul d be c o m bi ne d f or 
re p orti n g to pr o vi de t he m ost c o m plete data p ossi ble wit hi n eac h f oll o w -u p.  I n t he e ve nt t hat 
e C R F is u na vaila ble, re p ort S A Es b y fa xi n g t he pa per Seri o us A d v erse E v e nt Re p ort ( S A V E R) 
F or m t o t he C R O usi n g t he pr o vi de d fa x c o ver s heet a n d t he a p pr o priate fa x n u m ber pr o vi de d f or 
y o ur c o u ntr y.  O nce e C R F bec o m es a vaila ble, pl ease e nter S A Es re p ort e d o n t he S A V E R F or m 

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i nt o e C R F as s o o n as p ossi ble.  Please refer t o e C R F C o m pleti o n G ui de f or a d diti o nal 
i nstr ucti o ns. 
Please call t he l ocal S A E H otli ne (see St u d y M a n ual) or  y o ur st u d y m o nit or f or a n y q u esti o ns o n 
S A E re p orti n g.   
9. 6.  
N otif yi n g Re g ul at or y A ut h orities, I n vesti g at ors, a n d I nstit uti o n al 
Re vie w B o ar d/ I nstit uti o n al Et hics C o m mittee  
Daiic hi Sa n k y o a n d/ or t h e C R O will i nf or m I n vesti gat ors, I R Bs/ IE C s, a n d Re g ulat or y 
A ut h orities of a n y S us pecte d U ne x pecte d S eri o us A d verse R eacti o ns ( S U S A Rs) occ urri n g i n  
ot her st u d y sites or ot her st u dies of t he i n vesti gati o nal dr u g , as a p pr o priate per l ocal r e p orti n g 
re q uire me nts.  D aiic hi Sa n k y o a n d/ or t he C R O will c o m pl y wit h a n y a d diti o nal l ocal safet y 
re p orti n g re q uir e me nts. 
I n t he U nite d States ( U S ), u p o n recei pt of t h e S p o ns or’s n otificati o n of S U S A Rs t hat occ urre d 
wit h t he st u d y dr u g, u nless dele gate d t o t he S p o ns or, it is t he I n vesti gat or’s res p o nsi bilit y t o 
i nf or m t he I R B per S p o ns or’s i nstr ucti o n.  
I n t he E ur o pea n Ec o n o mic Area st ates, it is t he S p o ns or’s res p o nsi bilit y t o re p ort S U S A Rs t o all 
IE Cs  a n d R e g ulat or y A ut h orities . 
9. 7.  
E x p os ure in Uter o D uri n g Cli nic al St u dies  
Daiic hi Sa n k y o m ust be n otifie d of a n y s u bject w h o bec o mes pr e g na nt w hile recei vi n g or wit hi n 
7  m o nt hs  of disc o nti n ui n g t he st u d y dr u g.  
Alt h o u g h pre g na nc y is n ot tec h nicall y a n A E, all pre g na nci es m ust be f oll o we d t o c o ncl usi o n t o 
deter mi ne t heir o utc o me.  T his i nf or mati o n is i m p orta nt f or b ot h dr u g safet y a n d p u bl ic healt h 
c o ncer ns.  It is t he res p o nsi bilit y of t he I n vesti gat or, or desi g nee, t o re p ort a n y pre g na nc y i n a 
fe male s u bject usi n g t he E x p os ure in Uter o ( EI U) Re p orti n g F or m.  Please c o ntact y o ur st u d y 
m o nit or t o recei ve t he EI U Re p orti n g F or m u p o n l ear ni n g  of a pre g n a nc y.  T he I n vesti gat or 
s h o ul d ma ke e ver y eff ort t o f oll o w t he s u bject u ntil c o m pleti o n of t he pre g na nc y a n d c o m plete 
t he EI U Re p orti n g F or m wit h c o m plete pre g na n c y o utc o me i nf or mati o n, i ncl u di n g n or mal 
deli ver y a n d i n d uc e d a b orti o n.  T he a d vers e pre g n a nc y o utc o me, eit her seri o us or n o n seri o us, 
s h o ul d be re p orte d i n a cc or da nce wit h st u d y pr oce d ures.  If t he o ut c o me of t he pre g na n c y meets 
t he criteria f or i m me diate classificati o n as a S A E (ie, p ost part u m c o m plicati o ns, s p o nta ne o us or 
i n d uce d a b orti o n, still birt h, ne o natal deat h, or c o n ge nital a n o mal y, i ncl u di n g t hat i n a n a b orte d 
fet us), t he I n v esti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es o utli ne d i n Secti o n 9. 5 . 
9. 8.  
Cli nic al L a b or at or y E v al u ati o ns  
T he f oll o wi n g cli nical la b orat or y tests will be perf or me d:  
1.  He mat ol o g y t ests  
 Re d bl o o d cell c o u nt, he m o gl o bi n, he mat ocrit, w hite bl o o d cell c o u nt, differe ntial 
w hite bl o o d cell c o u nt ( n e utr o p hils, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, bas o p hils), 
a n d platelet c o u nt  

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2.  Bl o o d c he mistr y tests  
 T otal pr otei n, al b u mi n, al kali ne p h os p hatase, A L T, A S T, t otal bilir u bi n, bl o o d urea 
nitr o ge n/ ur ea, calci u m, c hl ori de, ser u m creati ni ne, lacta te de h y dr o ge nas e, p otassi u m, 
s o di u m, a n d ma g nesi u m. 
 Creati ni ne cleara n ce ( m L/ mi n) will be calc ulate d usi n g t he C oc kcr oft -Ga ult e q uati o n 
(Secti o n  1 7. 2 ). 
 A c oa g ulati o n test will be perf or me d ( i nter nati o nal n or malize d rati o/pr ot hr o m bi n ti me  
≤1. 5 × U L N  a n d eit her partial t hr o m b o plasti n or  acti vate d partial t hr o m b o plasti n 
ti me). 
 Tr o p o ni n will be a nal yz e d f or eac h sa m ple at Scree ni n g, E O T, a n d as n ee d e d base d 
o n s u bject -re p orte d si g ns or s y m pt o ms.  
3.  Uri nal ysis  
 Pr otei n, gl uc ose, bl o o d, micr osc o p y assess me nt (if i n dicate d), a n d s pecifi c gra vit y.  
I n a d diti o n, pre g na n c y test (ser u m or u ri ne) f or all fe male s u bjects of c hil d beari n g p ote ntial will 
be perf or me d at t he visits i n dicate d i n t he Sc he d ul e of E ve nts ( T a ble  1 7 .1  a n d Ta ble  1 7 .2 ).  A 
p ositi ve uri ne pre g na n c y test res ult m ust be c o nfir me d i m me diatel y usi n g a ser u m test.  
All la b orat or y val ues m ust be a p praise d b y t he I n vesti gat or as t o cli nical si g nifica nce a n d use d t o 
ta ke a p pr o priate cli nical ma na ge me nt meas ures.  All a b n or mal la b orat or y val ues c o nsi dere d 
cli nicall y si g nifica nt b y t he I n vesti gat or s h o ul d be rec or de d o n t he A E p a ge of t he e C R F.  If t he 
a b n or mal la b orat or y val u e c o nst it utes a n S A E, rel e va nt pr oce d ures m ust be f oll o we d (see 
Secti o n  9. 5 ).  A b n or mal l a b orat or y v al ues ( N CI C T C A E Gra de 3 or 4) occ urri n g d uri n g t he 
cli nical st u d y will be f oll o we d  u ntil re peat test r es ults ret ur n t o n or mal ( or baseli ne), sta bilize, or 
are n o l o n ger cli nicall y si g nifica nt.  
9. 9.  
Vit al Si g ns  
Bl o o d press ur e a n d p ulse rate will be meas ure d aft er t he s u bject h as reste d i n a rec u m b e nt 
p ositi o n f or 5 mi n utes or m ore.  
I nf or mati o n will be e ntere d i n t he e C R F o n w het h er or n ot meas ure d, dat e of meas ure m e nt, a n d 
meas ure me nt res ults f or t he f oll o wi n g ite ms: s yst olic bl o o d press ure, diast olic bl o o d press ure, 
p ulse rate, res pirat or y rat e, a n d b o d y te m perat ure.  
9. 1 0.  
Electr oc ar di o gr a ms  
E C Gs will be ta ke n i n tri plicate at scree ni n g.  T hereaft er, si n g ular E C Gs will be perf or me d. If a n 
a b n or malit y is n ote d, E C Gs s h o ul d t he n be perf or me d i n tri plicate.  Sta n dar d s u pi ne/se mi -
rec u m be nt 1 2-l ea d E C Gs s h o ul d pr efera bl y be ta ke n pri or t o bl o o d dra ws a n d  will be perf or me d 
as descri be d i n t he Sc h e d ule of E ve nts ( Ta bl e  1 7 .1  a n d Ta ble  1 7 .2 ).  W he n t a ke n i n tri plicate, 
E C Gs s h o ul d be ta ke n i n cl ose s uccessi o n .  Sta n dar d E C G para m eters will be meas ure d, 
i ncl u di n g R R, P R, Q T i nter vals, a n d Q R S d urati o n.  All E C Gs m ust be e val uate d b y I n vesti gat or 
or dele gate d p h ysi cia n f or t he prese n ce of a b n or m alities.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 7  
9. 1 1.  
P h ysic al E x a mi n ati o ns  
P h ysical e x a mi nati o n fi n di n gs will e val uate t h e f oll o wi n g b o d y s yst e ms/ or ga ns: ge n eral 
a p peara nce; der mat ol o gi cal; hea d; e ars, n ose, m o ut h, a n d t h r oat; p ul m o nar y; car di o vasc ul ar; 
a b d o mi nal; ge nit o uri nar y ( o pti o nal); l y m p hatic; m usc ul os keletal/e xtre mities; a n d ne ur ol o gical.  
Wei g ht a n d hei g ht will als o be rec or de d i n kil o gra ms a n d ce nti meters, res p ecti vel y.  
9. 1 2.  
Ot her E x a mi n ati o ns  
9. 1 2. 1.  
C ar di ac Assess me nts  
Eit h er E C H O or M U G A will be perf or me d as des cri be d i n t he Sc he d ule of E ve nts ( Ta ble  1 7 .1  
a n d Ta ble  1 7 .2 ); L V E F will be meas ure d.  
I n Ger m a n y o nl y , p le ase see Secti o n  1 7. 9. 3  for te xt a p plic a ble t o sites i n Ger m a n y.  
9. 1 2. 2.  
P ul m o n ar y Assess me nts  
T he S p O 2 will be c ollect e d as i n dicate d i n t he Sc he d ule of E ve nts ( T a ble  1 7 .1  a n d Ta ble  1 7 .2 ).  
F or m ore d etails , please refer t o Secti o n  6  of t he pr ot oc ol.  
A n I L D A C will re vie w all cases of ( p ote ntial) I L D / p ne u m o nitis o n a n o n g oi n g basis.  
Descri pti o n of t he I L D A C is a vaila ble i n Secti o n  9. 3. 1. 3 . 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
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Pa ge 9 8  
1 0.  
O T H E R A S S E S S M E N T S  
1 0. 1.  
P atie nt Re p orte d O utc o mes  
Patie nt re p orte d o utc o mes will be use d t o e val uate st u d y treat me nt.  T he i m pact of breast ca n cer 
s y m pt o ms will be assess e d base d u p o n t he E O R T C Q L Q -B R 4 5 a n d E O R T C Q L Q -C 3 0 ( versi o n 
3. 0), a n d E Q -5 D -5 L q uesti o n naires ( Secti o n  1 7. 6  a n d Secti o n  1 7. 7 , res pecti vel y). 
1 0. 1. 1.  
E ur o pe a n Or g a niz ati o n f or Rese arc h a n d Tre at me nt of C a ncer Q u alit y of Life 
Q uesti o n n aires C 3 0 a n d B R 4 5   
T he Q L Q -C 3 0 is a Q o L i nstr u me nt f or ca n cer patie nts de vel o pe d i n 1 9 8 7 b y E O R T C.  Si nce 
t he n it has u n der g o ne se v eral r e visi o ns a n d its c urre nt versi o n is 3. 0. 
T he Q L Q -C 3 0 is c o m p os e d of b ot h m ulti -ite m scales a n d si n gle-ite m meas ures.  T hese i n cl u de 5 
f u ncti o nal scales, 3 s y m pt o m scales, a gl o bal healt h stat us/ Q o L scale, a n d 6  si n gle ite ms.  Eac h 
of t he m ulti -ite m scales i ncl u des a differe nt set of ite ms - n o ite m occ urs i n m ore t ha n 1 scal e.  
All of t he scales a n d si n gle -ite m meas ures ra n ge i n sc ore fr o m 0 t o 1 0 0.  A hi g h scal e sc ore 
re pres e nts a hi g her res p o nse le vel. 
T h us , a hi g h s c ore f or a f u ncti o nal scale re pres e nts a hi g h/ healt h y le vel of f u ncti o ni n g, a hi g h 
sc ore f or t he gl o bal healt h stat us/ Q o L re pres e nts a hi g h Q o L, b ut a hi g h sc ore f or a s y m pt o m 
scale/ite m re prese nts a hi g h le v el of s y m pt o mat ol o g y/ pr o ble ms. 
D ue t o li mitati o ns i n here nt i n its ge neric f oc us, t h e E O R T C Q L Q -C 3 0 is s u p ple me nte d b y 
disease s pecific m o d ules s uc h as t he E O R T C Q L Q -B R 4 5, w hic h are d esi g n e d t o be a d mi nistere d 
i n a d diti o n t o t he c ore qu esti o n naire.  T he E O R T C Q L Q -B R 4 5 is s pecific f or breast c a ncer.  
T he E O R T C Q L Q -C 3 0 wit h E O R T C Q L Q -B R 4 5 will be use d i n t he st u d y  as t he dis ease -
s pecific i nstr u me nts t o assess t he healt h -relate d Q o L of s u bj ects.  T he y will be a d mi nistere d 
bef ore  a n y ot her assess m e nts or pr oce d ures are d o ne  t hat da y.  C o m plete be f ore i nf usi o n o n Da y 
1 of C ycl e 1 , C ycl e  2, a n d C ycle 3 a n d t he n  e v er y 2 c ycles  t hereaft er, a n d at t he E O T 
assess me nts .  S u bjects will be f oll o we d u p at Da y 4 0 ( +7 d a ys) a n d at t he first of t he L o n g -
ter m/ S ur vi val F oll o w-u p V isit 3  m o nt hs  after, w hic h will be t he last data c ollecti o n p oi nt f or t he 
q uesti o n naires .  Re p orti n g will f oll o w cl osel y t he C o ns oli date d Sta n dar ds of Re p orti n g Trials 
( C O N S O R T) e xte nsi o n o n re p orti n g P R Os.2 9 
C ha n ges fr o m bas eli ne o ver ti me will  be assesse d i n t he gl o bal Q o L s cale, eac h of t h e 
f u ncti o ni n g scales ( p h ysi cal, r ole, e m oti o nal, c o g niti ve, a n d s ocial), s y m pt o m scales (fati g u e, 
na usea/ v o miti n g, a n d p ai n), 6 si n gle -ite m scales ( d ys p nea, slee p dist ur ba n ce, a p p etite l oss, 
c o nsti pati o n, diarr hea, a n d fi na ncial i m pact) of t he E O R T C Q L Q -C 3 0 a n d i n eac h of t h e 
s u bscales ( breast s y m pt o ms, ar m s y m pt o ms, b o d y i ma ge, s e x ual f u ncti o ni n g, a n d s yste mic 
t hera p y si de effects) of t h e E O R T C Q L Q-B R 4 5.  
F urt her, ti me t o det eri orati o n o n t he “breast s y m pt o ms ” a n d “ar m s y m pt o ms ” s u bscales of t h e 
E O R T C Q L Q -B R 4 5 a n d t he pai n s y m pt o m s u bscale of t he E O R T C Q L Q -C 3 0 will be assesse d.  
O n t he b asis of pre vi o usl y p u blis he d researc h o n cli nicall y mea ni n gf ul c ha n ges i n t he E O R T C 
Q L Q -B R 4 5 a n d t he Q L Q -C 3 0, deteri orati o n is defi ne d as a n i ncrease of 1 0 p oi nts or m ore o n 
t hese s y m pt o m s u bscal e sc ores. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 9  
F urt her details o n t he sc ori n g of t h ese scales, i nc l u di n g missi n g ite ms, will be pr o vi de d i n t he 
S A P.  
1 0. 1. 2.  
E ur o Q o L Fi ve Di me nsi o ns Fi ve Le vels P ati e nt Re p orte d O utc o me Q uesti o n n aire  
St u d y s u bj ects will be as ke d t o c o m plete t he E Q -5 D -5 L q uesti o n naire, a ge neric meas ure of 
sta n dar dize d healt h stat us, bef ore a n y ot her st u d y pr oce d ures are perf or me d bef ore i nf usi o n o n 
Da y 1 of C ycles 1 , C ycle  2, a n d C ycl e 3 a n d t he n  e ver y 2 c ycles t hereafter, a n d at t he E O T 
assess me nts .  Data c ollecti o n will c o nti n ue at t he 4 0 -Da y ( +7 d a ys) F oll o w-u p assess me nts  a n d 
t he first L o n g -ter m/ S ur vi val F oll o w-u p ass ess me nts  3  m o nt hs  after, w hic h will be t he last data 
c ollecti o n p oi nt f or t he q uesti o n naires.  
T he E Q -5 D -5 L is self -a d mi nistere d a n d c o nsists of 2 parts, t he E Q -5 D -5 L descri pti ve s yste m, 
a n d t he E Q-5 D vis u al a n al o g u e scale ( V A S).  T h e descri pti ve s yste m c o m prises 5  di me nsi o ns 
( m o bilit y, s elf-care, us u al acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n).  Eac h di me nsi o n 
has 5 le vels  of se v erit y : n o pr o ble ms, sli g ht pr o ble ms, m o derate pr o ble ms, se vere pr o ble ms, a n d 
e xtre me pr o ble m s.3 0  T he res p o n de nt is as ke d t o i n dicate his/ her healt h state b y tic ki n g ( or 
placi n g a cr oss) i n t he b o x a gai nst t he m ost a p pr o priate state me nt i n eac h of t he 5 di me nsi o ns.  
T his decisi o n res ults i n a 1 -di git n u m ber e x pressi n g t he le v el select e d f or t h at di me nsi o n.  T he 
di gits f or 5 di me nsi o ns ca n be c o m bi ne d i n a 5 -di git n u m ber des cri bi n g t he res p o n de nt’s h ealt h 
state.  T he n u merals 1 t o 5 ha ve n o arit h metic pr o perties a n d s h o ul d n ot be use d as a car di nal 
sc ore.  
T he E Q -5 D V A S rec or ds t he res p o n de nt’s s elf -rate d healt h o n a 2 0 c m vertical V A S wit h 
e n d p oi nts la bele d “ t he b est healt h y o u ca n i ma gi ne” a n d “t he w orst healt h y o u ca n i ma gi ne.”  
T his i nf or mati o n ca n be use d as a q ua ntitati ve meas ure of healt h as j u d ge d b y t he i n di vi d ual 
res p o n de nts.  
T he E Q -5 D -5 L will be a d mi nistere d bef ore t he first c ycl e a n d e v er y 2 c ycl es  after t h at u ntil E O T 
as defi ne d i n t he pr ot o c ol.  S u bjects will be f oll o we d u p at Da y 4 0 ( ± 7 d a ys ) a n d at t he first 
L o n g -t er m/ S ur vi val F oll o w-u p V isit 3  m o nt hs  after t hat (last meas ure me nt) .  Re p orti n g will 
f oll o w cl osel y t h e C O N S O R T e xte nsi o n o n re p orti ng P R Os. 2 9  
1 0. 2.  
He alt h -rel ate d Q o L E n d p oi nts  
1 0. 2. 1.  
E ur o pe a n Or g a niz ati o n f or Rese arc h a n d Tre at me nt of C a ncer Q u alit y of Life 
Q uesti o n n aire E n d p oi nts  
 C ha n ges fr o m bas eli ne o ver ti me will be assesse d i n t he gl o bal Q o L s cale, eac h of t h e 
f u ncti o ni n g scales ( p h ysi cal, r ole, e m oti o nal, c o g niti ve, a n d s ocial), s y m pt o m scales 
(fati g ue, na us ea/ v o miti n g, a nd pai n), a n d t he 6  si n gle-ite m s cales ( d ys p n ea, slee p 
dist ur ba nce, a p p etite l oss, c o nsti pati o n, diarr hea, a n d fi na ncial i m pact) of t he E O R T C 
Q L Q -C 3 0.  
 Ti me t o deteri orati o n o n t he pai n s y m pt o m s u bscale of t he E O R T C Q L Q -C 3 0 will be 
assesse d.  
 C ha n ges fr o m bas eli ne o ver ti me will be assesse d i n eac h of t he s u bs cales ( breast 
s y m pt o ms, ar m s y m pt o ms, b o d y i ma ge, s e x ual f u ncti o ni n g, a n d s yste mic t h era p y si de 
effects) of t he E O R T C Q L Q -B R 4 5.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 0  
 Ti me t o deteri orati o n o n t he “breast s y m pt o ms ” a n d “ar m s y m pt o ms ” s u bscales of t he 
E O R T C Q L Q -B R 4 5 will be assesse d.  
 O n t he basis of pre vi o usl y p u blis he d researc h o n cli nicall y mea ni n gf ul c ha n ges i n t he 
E O R T C Q L Q -B R 4 5 a n d t he Q L Q -C 3 0, deteri orati o n is defi ne d as a n i ncrease of 1 0 
p oi nts or m ore o n t hese s y m pt o m s u b scale sc ores. 3 1 
1 0. 2. 2.  
E ur o Q o L Fi ve Di me nsi o ns Fi ve Le vels  E n d p oi nts  
 V A S as a meas ure of s e lf-rate d healt h stat us 
 Res p o nse b y di me nsi o n  
 I n d e x sc ore c ha n ge fr o m baseli ne usi n g Unite d K i n g d o m val ue s et  
 I n d e x sc ore b y diseas e state 
1 0. 3.  
P h ar m ac oec o n o mic Assess me nts  
1 0. 3. 1.  
H os pit aliz ati o n -Rel ate d E n d p oi nt  
Ti me t o h os pitaliz ati o n will be assesse d.  Eac h h os pitalizati o n e ve nt will pr o m pt t he c o m pleti o n, 
b y t he site, of a detaile d h os pitaliz ati o n e C R F c o ntai ni n g t he f oll o wi n g c o m p o ne nts:  
 Date of a d missi o n t o h os pital.  
 Date of disc h ar ge fr o m h os pital.  
 Pri mar y reas o n f or h os pitalizati o n.  
 Disc har ge stat us fr o m  h os pital ( die d, disc har ge d h o me, disc har ge d t o h o me healt h 
care, dis c har ge d t o n ursi n g h o me care, disc har ge d t o l o n g -ter m care, ot her). 
 Use of i nte nsi ve care u nit (I C U) ser vi ces i n h os pital ( Yes/ N o).  
 If yes, date of a d missi o n t o I C U. 
 If yes, date of disc har ge fr o m I C U.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
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Pa ge 1 0 1  
1 1.  
S T A TI S TI C A L M E T H O D S   
1 1. 1.  
Ge ner al St atistic al C o nsi der ati o ns  
T he pri mar y effic ac y a n al yses o f P F S per BI C R  will be perf or me d f or t he H R -p ositi ve c o h ort 
a n d F ull A nal ysis Set  ( F A S) w he n a p pr o xi matel y 3 1 8  P F S e ve nts per BI C R ha ve bee n  o bs er ve d  
i n t he H R -p ositi ve c o h ort of F A S .  U p t o 3  a n al ys es of O S c o ul d be perf or m e d  f or t he H R -
p ositi ve c o h ort a n d F A S w he n a p pr o xi matel y  1 6 2, 2 3 3, a n d  3 3 3 O S e ve nts , res pecti vel y, h a ve 
bee n o bser ve d i n t he H R -p ositi ve c o h ort , if t he P F S a nal yses are statisticall y si g nifica nt.  
C o nti n u o us varia bles will be s u m marize d b y t he n u m ber of o bser vati o ns, mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m, a n d ma xi m u m val ues (as w ell as ge o metric mea ns a n d ge o metric 
c oeffi cie nt of variati o n f or  t he P K para m eters of C ma x  a n d A U C).  Cate g orical varia bles will be 
s u m marize d usi n g fre q u e nc y c o u nts a n d perce nt a ges. 
Assess me nt of c ha n ge fr o m baseli ne t o p ost -treat me nt or t he rati o of p ost-treat me nt t o baseli ne 
will i ncl u de o nl y t h ose s u bjects wit h b ot h baseli ne a n d p ost -treat me nt meas ure me nts.  T he last 
n o n -missi n g val ue of a v aria ble ta k e n bef ore t he first d ose of t he st u d y tr eat me nt will be use d as 
t he baseli ne val ue, u nl ess ot her wise s pecifie d.  I n ge n eral, missi n g or dr o p o ut data will n ot be 
i m p uted f or t he p ur p ose of data a n al ysis, u nless ot her wise s pecifie d.  
Efficac y a nal ys es will be perf or me d o n t he H R -p ositi ve c o h ort a n d F A S .  S afet y a n al ys es will be 
perf or me d usi n g t he Safet y A nal ysis Set.  A nal ysis of P K para met ers will be base d o n t he P K 
A nal ysis Set.  A nal ys es f or a ll ot her e x pl orat or y e n d p oi nts  will be perf or m e d base d o n t he  H R -
p ositi ve  c o h ort. 
1 1. 2.  
A n al ysis Sets  
1 1. 2. 1.  
F ull  A n al ysis Set  
T he F A S  will i ncl u de all s u bjects ra n d o mize d i nt o t he st u d y, i ncl u di n g t h ose w h o di d n ot recei ve 
a d ose of st u d y tre at me nt.  S u bjects will be a nal yz e d acc or di n g t o t he treat me nts assi g ne d at 
ra n d o mizati o n. 
1 1. 2. 2.  
S afet y A n al ysis Set  
T he Safet y A n al ysis Set will i ncl u de all ra n d o mize d s u bjects w h o recei ve d at least 1 d ose of 
st u d y treat me nt.  S u bjects will be s u m marize d acc or din g t o treat me nt act uall y recei ve d.  
1 1. 2. 3.  
Per -pr ot oc ol A n al ysis Set  
T he P P S will i ncl u de all s u bjects i n t he F A S  w h o c o m plie d wit h t he pr ot oc ol s ufficie ntl y wit h 
res pect t o e x p os ure t o st u d y treat me nt, a vaila bilit y of t u m or assess me nt, a n d a bse nce of maj or 
pr ot oc ol vi olati o ns  li kel y t o i m pact efficac y o utc o me.  Details will be s pecifie d i n t he S A P. 
1 1. 2. 4.  
P h ar m a c o ki netic A n al ysis Set  
T he P K A nal ysis Set will i ncl u de all s u bjects w h o recei v e d at least 1 d ose of T -D X d  a n d ha d 
meas ura ble s er u m c o n ce ntrati o ns of T -D X d , t otal a nti-H E R 2 a nti b o d y, a n d M A A A -1 1 8 1a.  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 2  
1 1. 3.  
St u d y P o p ul ati o n D at a  
S u bject dis p ositi o n will be s u m mariz e d f or s u bjects i n t he F A S a n d H R -p ositi ve c o h ort of F A S .  
T he t otal n u m ber of s u bj ects f or eac h d efi ne d a nal ysis set will als o be ta b ul ate d.  T he 
de m o gra p hic a n d b aseli n e c haracteristics will be s u m marize d descri pti vel y f or t he H R -p ositi ve 
c o h ort, F A S , P P S, a n d Safet y A nal ysis Set.  St u d y treat me nt e x p os ure a n d treat me nt d urati o n 
will be s u m mariz e d usi n g des cri pti ve statistics f or t he Safet y A nal ysis Set.  
1 1. 4.  
Effic ac y A n al yses  
1 1. 4. 1.  
Pri m ar y Effic ac y A n al yses  
T he pri mar y effic ac y e n d p oi nt is P F S , base d o n  BI C R , i n H R-p ositi ve breast ca ncer  s u bjects.  
O ne a nal ysis f or t h e pri mar y e n d p oi nt is pla n ne d.  T he P F S a nal ysis will be perf or me d after 
o bser vi n g 3 1 8 BI C R -assesse d  P F S e ve nts.  
T he pri mar y effic ac y a n al ysis will c o m pare t he distri b uti o n of P F S bet wee n t he 2 treat me nt ar ms  
i n t he H R-p ositi ve  c o h ort usi n g a str atifie d l o g-ra n k test.  Stratificati o n fact ors use d f or pri mar y 
a nal ysis will be  fr o m t he ra n d o mizati o n.  T he P F S will be teste d  usi n g stratifie d l o g -ra n k test f or 
statistical si g nifica nce at a 2 -si de d al p ha of 0. 0 5.  Ka pla n-Mei er  ( K M) esti mates a n d K M c ur ves 
will als o be prese nte d f or eac h tr eat me nt ar m.  T h e me dia n s ur vi val ti mes a n d 2 -si de d 9 5 % 
c o nfi de nce i nter vals ( CIs) f or t he me dia ns  b ase d o n t he Br o o k me yer a n d Cr o wle y m et h o d  will be 
pr o vi de d f or eac h tr eat m e nt ar m.  T he h azar d rati os a n d t heir 9 5 % CIs will be esti mate d, usi n g 
stratifie d C o x pr o p orti o nal hazar ds re gressi o n m o dels wit h t he stratificati o n fact o rs per I X R S. 
1 1. 4. 2.  
Ke y Sec o n d ar y Effic ac y A n al yses  
T he s a me a n al ysis as  s pecifie d a b o ve f or pri mar y efficac y e n d p oi nt will be perf or me d f or t he ke y 
sec o n dar y e n d p oi nts: P F S base d o n  BI C R i n  t he F A S, O S  i n t he H R-p ositi ve c o h ort, a n d O S  i n 
t he F A S.   If t he t est of t he pri mar y e n d p oi nt, P F S base d o n BI C R, is statisticall y si g nifica nt, t he 
ke y s ec o n dar y e n d p oi nts will be teste d.  Gr o u p se q ue ntial testi n g wit h 2 i nteri m a nal ys es are 
pla n ne d f or O S a n al yses.  T he first O S i nteri m a nal ysis is pla n ne d at ti me of t he P F S  a nal ysis 
(e x pecti n g a p pr o xi matel y 1 6 2 O S e v e nts or 4 9 % of t he tar get e d 3 3 3 O S e ve nts ) a n d t he sec o n d 
O S i nteri m a nal ysis will be perf or me d w he n a p pr o xi matel y 2 3 3 O S e ve nts ha ve bee n 
d oc u me nte d  ( 7 0 % of t he pla n ne d 3 3 3 O S e ve nts) i n t he H R -p ositi ve c o h ort.  T he data c ut -off f or 
t he fi nal O S a nal ysis will occ ur after a p pr o xi matel y 3 3 3 O S e ve nts ha ve b ee n d oc u me nte d i n 
H R -p ositi ve c o h ort.  T he O S i nteri m a nal ysis will all o w t he st u d y t o st o p earl y f or o utsta n di n g 
effic ac y.  A d diti o nal details of t he i nteri m a n al ys es are i n Secti o n  1 1. 6 . 
T o c o ntr ol t he o verall fa mil y -wise t y pe -I err or, t h e pri mar y efficac y e n d p oi nt a n d t he ke y 
sec o n dar y effi cac y e n d p oi nts, will be teste d hierarc hicall y i n t he or der bel o w t o mai ntai n t he 
o verall 2 -si de d t y pe-I err or rate t o 0. 0 5 or less:   
1.  P F S base d o n  BI C R i n t h e  H R-p ositi ve c o h ort  
2.  P F S base d o n  BI C R i n t h e  F A S   
3.  O S i n t he  H R-p ositi ve c o h ort ( u p t o 3 a nal yses)   
4.  O S i n t he  F A S ( u p t o 3 a nal yses) 

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T he statistical testi n g f or a ke y sec o n d ar y e n d p oi nt will be perf or me d o nl y w he n t he a n al ys es i n 
t he hierarc h y a b o v e t he c urre nt e n d p oi nt ha ve de m o nstrate d statistical si g nifica n ce. 
1 1. 4. 3.  
Ot her Sec o n d ar y Effic ac y A n al yses  
D urati o n of res p o ns e will be s u m mariz e d wit h me dia n s ur vi val ti mes a n d its 2-si de d 9 5 % CIs 
usi n g Br o o k me yer a n d Cr o wle y met h o d f or eac h treat me nt ar m.  
T he C oc hra n – M a ntel – Hae nszel  test will be use d t o c o m pare c o nfir me d O R R  bet wee n t he 
treat me nt ar ms.  T h e esti mates of c o nfir m ed O R R  a n d its 2 -si de d 9 5 % e x act CI b ase d o n t he 
Cl o p per -Pears o n met h o d  will be pr o vi de d.   
A d diti o nal s e nsiti vit y a n al yses of P F S  per BI C R  a n d a nal ysis of P F S per i n vesti gat or assess me nt  
will be s pecifie d i n t he S A P.  
1 1. 4. 4.  
A n al yses of He alt h Ec o n o mic a n d O utc o me s R ese arc h E n d p oi nts 
Healt h ec o n o mic a n d o ut c o mes researc h e n d p oi nts base d o n t he h os pitalizati o n -relate d data 
c ollecti o n f or m a n d t he f oll o wi n g P R O q uesti o n naires will be s u m marize d b y treat me nt ar m: 
E O R T C Q L Q -C 3 0, E O R T C Q L Q -B R 4 5, a n d E Q -5 D -5 L.  A d etaile d a nal ysis pla n of Q o L 
e n d p oi nts, i ncl u di n g c o ntr ol of t y p e I err or re gar di n g Q o L a nal yses, will be pr o vi de d i n t he S A P.  
S o me descri pti ve a nal ysis will be perf or me d as f oll o ws.  
1 1. 4. 4. 1.  E ur o Q o L Fi ve Di me nsi o ns Fi ve Le vels  
Base d o n res ults of t he E Q -5 D -5 L assess me nt, t he E Q -5 D -5 L s u m mar y i n d e x sc ore acr oss 
disease states will be ass esse d.  Des cri pti ve statistics f or t he act ual val ue a n d c ha n ge fr o m 
baseli ne will be c o m p ute d f or t he E Q -5 D -5 L healt h pr ofile utilities a n d E Q -5 D V A S b y 
sc he d ule d ti me of e v al uati o n (i ncl u di n g E O T) f or all s u bjects.  Res ults of t he E Q-5 D V A S will 
be prese nt e d as a me as ur e of o verall self -rate d healt h stat us. 
1 1. 4. 4. 2.  E ur o pe a n Or g a niz ati o n f or Rese arc h a n d Tre at me nt of C a ncer Q u alit y of Life 
Q uesti o n n aire C 3 0 a n d B R 4 5  
C ha n ges fr o m bas eli ne o ver ti me will be assesse d i n t he gl o bal Q o L s cale, eac h of t h e 
f u ncti o ni n g scales ( p h ysi cal, r ole, e m oti o nal, c o g niti ve, a n d s ocial), s y m pt o m scales (fati g u e, 
na usea/ v o miti n g, a n d p ai n), a n d 6 si n gl e -ite m scal es ( d ys p nea, sle e p dist ur ba nce, a p petite l oss, 
c o nsti pati o n, diarr hea, a n d fi na ncial i m pact) of t he E O R T C Q L Q -C 3 0 a n d i n eac h of t h e 
s u bscales ( breast s y m pt o ms, ar m s y m pt o ms, b o d y i ma ge, s e x ual f u ncti o ni n g, a n d s yste mic 
t hera p y si de effects) of t h e E O R T C Q L Q-B R 4 5.   
Ti me t o deteri orati o n o n t he “breas t s y m pt o ms” a n d “ar m s y m pt o ms ” s u bscales of t he E O R T C 
Q L Q -B R 4 5 a n d t he pai n s y m pt o m s u bscale of t h e E O R T C Q L Q -C 3 0 will als o be assesse d.  O n 
t he basis of pre vi o usl y p u blis he d researc h o n cli nicall y mea ni n gf ul c ha n ges i n t he E O R T C Q L Q-
B R 4 5 a n d t he E O R T C Q L Q -C 3 0, deteri or ati o n is defi ne d as a n i ncrease of 1 0 p oi nts or m ore o n 
t hese s y m pt o m s u bscal e sc ores.  
F urt her details o n t he sc ori n g of t h ese scales, i ncl u di n g missi n g ite ms, will be pr o vi de d i n t he 
S A P.  

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1 1. 4. 4. 3.  H os pit aliz ati o n -Rel ate d E n d p oi nts  
F or h os pitalizati o n -relate d e n d p oi nts: ti me t o h os pitalizati o n as well as reas o n, disc har ge 
dia g n osis, I C U sta y, a n d le n gt h of sta y will be re p orte d.  
1 1. 4. 5.  
E x pl or at or y Effic ac y A n al yses  
1 1. 4. 5. 1.  S u b gr o u p A n al yses  
S u b gr o u p a n al ys es f or P F S  base d o n BI C R , a n d O S  will be perf or me d f or t he H R -p ositi ve  c o h ort 
a n d t he F A S .   
S u b gr o u ps will i ncl u de:  
 H E R 2 stat us ( H E R 2 I H C 1 +, H E R 2 I H C 2 +/I S H -) assesse d  b y a ce ntr al la b orat or y  
 N u m ber of pri or li nes of c he m ot hera p y ( 1, 2)  
 Pri or C D K 4/ 6 ( Yes, N o)  
 A ge ( < 6 5, ≥ 6 5 years)  
 Race ( Asia n, R est of W orl d)  
 Re gi o n ( Asi a, N ort h A m erica n, E ur o pe, R est o f W orl d ) 
 Li nes of e n d ocri ne t hera p y recei v e d i n t he metast atic setti n g ( 0, 1, 2, ≥3)  
 Best res p o ns e t o pri or ca ncer s yste mic t hera p y  
 Hist or y of C N S metastas es ( yes, n o)  
 Re nal i m pair me nt at baseli ne ( wit hi n n or mal  ra n ge, mil d/ m o derate i m pair me nt) 
 He patic i m pair me nt at b aseli ne ( wit hi n n or mal ra n ge, mil d i m pair me nt)  
 Hist or y of visceral diseas e ( yes, n o)  
 E C O G P S ( 0, 1)  
T he s u b gr o u ps are base d o n baseli ne val ues (i e, t he last n o n -missi n g val ue s bef ore t h e first dr u g 
a d mi nistrati o n ).  T hese res ults will be c o nsi dere d e x pl orat or y beca use of s maller sa m ple siz es.   
S u b gr o u p a n al ys es will be perf or me d o nl y if at least 1 0 rele va nt e v e nts i n eac h s u b gr o u p.   
Details a b o ut statistical met h o d f or s u b gr o u p  a n al yses will be s pecifie d i n S A P.  
1 1. 4. 5. 2.  A n al yses of E x pl or at or y Effic ac y E n d p oi nts  
T he f oll o wi n g e x pl orat or y effic ac y e n d p oi nts will be e val uat e d : 
 C B R  a n d D C R , base d o n BI C R  
 T T R , base d o n BI C R  
Rates a n d 9 5 % CIs f or C B R a n d D C R a n d d es cri pti ve statistics f or T T R ( base d o n BI C R) will be 
pr o vi de d b y treat me nt ar m.   A nal ys es will be c o n d ucte d base d o n t he H R -p ositi ve c o h ort a n d 
base d o n t he F A S , res pecti vel y. 

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T he s ur vi val distri b uti o n of P F S 2 will be esti mate d usi n g t he Ka pla n -Meier met h o d a n d will be 
prese nte d gra p hicall y b y treat me nt gr o u p.   T he m e dia n P F S 2 a n d its t w o -si de d 9 5 % CI usi n g 
Br o o k me yer a n d Cr o wle y met h o d will be pr o vi de d f or eac h treat me nt gr o u p.  P F S 2 rates at fi x e d 
ti me p oi nts (e g, 3, 6, 9, 1 2 m o nt hs) a n d t he t w o-si ded 9 5 % CIs will be pr o vi de d f or eac h 
treat me nt gr o u p.  T he treat me nt effect hazar d rati o a n d its t w o -si de d 9 5 % CI will be esti mate d 
usi n g stratifie d C o x pr o p orti o nal hazar ds re gressi o n m o del wit h t he treat me nt gr o u p as m o del 
fact or a n d t he ra n d o mizati o n stratificati o n fact ors fr o m I X R S as strata varia bles.  
E x p os ure -res p o nse relati o ns hi ps will be e x pl ore d. 
1 1. 4. 6.  
P h ar m a c o ki netic a n d P h ar m a c o d y n a mic A n al yses  
1 1. 4. 6. 1.  P h ar m a c o ki netic A n al yses  
Descri pti ve statistics will be pr o vi de d f or all ser u m c o nce ntrati o n dat a ( T -D X d , t otal a nti-H E R 2 
a nti b o d y, a n d M A A A -1 1 8 1a) at e ac h ti me.  
T he p o p ulati o n P K ( p o p-P K) a nal ysis t o e val uate t he effect of i ntri nsic a n d e xtri nsic fact ors of 
T -D X d , a n d, if a p pr o pri ate, t otal a nti-H E R 2 a nti b o d y a n d M A A A -1 1 8 1 a will be c haracteriz e d , 
i ncl u di n g a v ailable P K d ata fr o m ot her T -D X d  st u dies.  After est a blis h me nt of t he p o p-P K 
m o del, a p o p -P K/ p har mac o d y n a mic m o del ma y b e de vel o pe d t o e val uate t he relati o ns hi p 
bet wee n e x p os ure a n d efficac y a n d safet y e n d p oi nts.  T he res ults of t he n o nli near mi x e d effects 
p o p -P K a n d p o p -P K/ p har mac o d y na mic  m o dels ma y be re p ort e d se paratel y fr o m t he cli nical 
st u d y re p ort. 
1 1. 4. 6. 2.  P h ar m a c o d y n a mi c A n al yses  
N ot a p plica ble . 
1 1. 4. 7.  
Bi o m ar ker A n al yses  
A t u m or tiss ue bi o ps y aft er t he c o m pleti o n of t he s u bject’s m ost rece nt treat me nt re gi me n is 
re q uire d f or retr os pecti ve assess me nt. If t he t u m or tiss ue sa m ple pr o vi de d f or H E R 2 stat us 
testi n g was c ollecte d after c o m pleti o n of t he last treat me nt re gi me n, a n a d diti o nal ne w bi o ps y is 
n ot re q uire d.  If t he t u m or tiss ue sa m ple pr o vi de d f or H E R 2 stat us testi n g was c ollecte d bef ore 
c o m pleti o n of t he last treat me nt re gi me n, a n a d diti o nal ne w bi o ps y  is re q uir e d.  O pti o nal fres h 
tiss ue sa m ples ma y a d diti o nall y be o btai n e d d uri n g a n d after st u d y tr eat me nt. 
Bi o mar kers will be s u m marize d b y tr eat me nt ar m usi n g descri pti ve statistics , w he n a p plica ble . 
1 1. 5.  
S afet y A n al yses  
Safet y a nal ysis will be perf or me d usi n g t he Safet y A nal ysis Set a n d s u bjects will be a nal yze d 
acc or di n g t o t heir act ual treat me nt r ecei ve d.  
Safet y a nal yses i n ge n eral will be descri pti ve a n d will be prese nte d i n ta b ul ar f or mat wit h t he 
a p pr o priate s u m mar y statistics.  

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1 1. 5. 1.  
A d verse E ve nt A n al yses  
A T E A E is defi ne d as a n A E t hat occ urs , h a vi n g b ee n a bse nt b ef ore t he first d ose of st u d y dr u g, 
or has w orse n e d i n se verit y or seri o us ness aft er i nitiati n g st u d y dr u g u p u ntil 4 7 da ys after last 
d ose of t he st u d y dr u g.  S A Es wit h a n o nset 4 8 da ys or m ore aft er t he last d ose of st u d y dr u g, if 
c o nsi dere d relate d t o t he st u d y treat me nt, are als o T E A Es.  Treat me nt -e mer ge nt A Es will be 
c o de d usi n g Me d D R A a n d assi g ne d gra d e s base d o n versi o n 5. 0 of N CI  C T C A E.  T he n u m ber 
a n d perce nta ge of s u bjects re p orti n g T E A Es will be ta b ulate d b y s yste m or ga n class, P T, 
relati o ns hi p t o t he st u d y treat me nt, a n d t he w orst N CI  C T C A E gra de.  Si milarl y, t he n u m ber a n d 
perce nt a ge of s u bjects r e p orti n g seri o us T E A Es will be ta b ulate d b y tr eat m e nt ar m, as well as 
T E A Es lea di n g t o disc o nti n uati o n of t he st u d y treat me nts.    
A b y -s u bj ect A E (i n cl u di n g T E A E) data listi n g i n cl u di n g b ut n ot li mite d t o t he ver bati m ter ms, 
s yste m or ga n class, P T, N CI C T C A E gra de, a n d relati o ns hi p t o st u d y treat me nt will be pr o vi de d.  
Deat hs, ot her S A Es, A E SIs, a n d ot her si g nifica nt A Es, i ncl u di n g t h ose lea di n g t o disc o nti n uati o n 
of t he st u d y tr eat me nts, will be liste d.   
Treat me nt -e mer ge nt A Es will als o be s u m marize d b y t reat me nt ar m f or t he s u b gr o u ps descri be d 
i n t he S A P. 
1 1. 5. 2.  
Cli nic al L a b or at or y E v al u ati o n A n al yses  
Descri pti ve statistics will be pr o vi de d f or t he cli nical la b orat or y test res ults a n d c ha n ges fr o m 
baseli ne b y treat me nt ar m at eac h sc h e d ule d ti me of e val uati o n, i ncl u di n g E O T, ma xi m u m p ost -
treat me nt val ue, a n d mi ni m u m p ost-treat me nt val ue. 
A b n or mal cli nical la b orat or y res ults will be gra de d acc or di n g t o N CI  C T C A E versi o n  5 . 0, if 
a p plica ble, a n d t h e gra d e will be prese nte d i n a b y -s u bject data listi n g.  A s hift ta ble, prese nti n g 
2 -wa y fre q ue n c y ta b ulati o n f or baseli ne a n d t he w orst p ost -treat me nt val ue acc or di n g t o N CI 
C T C A E gra de, will be pr o vi de d f or cli nical la b orat or y tests.  
All cli nical la b orat or y test res ults a n d a b n or mal cli nical la b orat or y test res ults of Gra de 3 or 4 
will be liste d.  
1 1. 5. 3.  
Vit al Si g n A n al yses  
Descri pti ve statistics will be pr o vi de d b y treat me nt ar m f or t he vital si g n s meas ure me nts a n d 
c ha n ges fr o m baseli ne b y sc he d ule d ti me of e v al uati o n, i ncl u di n g E O T a n d t he ma xi m u m a n d 
mi ni m u m p ost -treat me nt val ues.  All vital si g ns data will als o be liste d.  
1 1. 5. 4.  
Electr oc a r di o gr a m A n al yses  
Descri pti ve statistics will be pr o vi de d b y treat me nt ar m f or E C G para meters a n d c ha n ges fr o m 
baseli ne b y sc he d ul e d ti me of e val uati o n, i ncl u di n g E O T a n d t he ma xi m u m p ost -treat me nt val ue.  
I n a d diti o n, t he n u m ber a n d perce nt a ge of s u bjects wit h t he ma xi m u m p ost-baseli ne  E C G 
i nter val val ues a n d c ha n ge fr o m baseli ne  m eeti n g t he  cate g orical  criteria p er I C H E 1 4 g ui d a nce 3 2 
will be ta b ulate d  (see det ails i n t he S A P) .   
T he Q T i nter vals c orrect e d b y Fri d ericia’s f or m ul a , Q Tc F = Q T/[ R R] 1/ 3, will be use d f or 
assessi n g t he effect of tr eat me nt o n Q T .  T he E C G data will als o be liste d.  

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1 1. 5. 5.  
P h ysic al E x a mi n ati o n A n al yses  
P h ysical e x a mi nati o n fi n di n gs a nd  E C O G P S  will be liste d.  
1 1. 5. 6.  
C o nc o mit a nt Me dic ati o n A n al yses  
C o nc o mita nt me dicati o ns will be c o de d usi n g t h e W orl d Healt h Or ga nizati o n Dr u g Refere nce 
List Dicti o nar y .  N u m b er a n d perce nta ge of s u bjects ta ki n g c o nc o mita nt me dicati o ns will be 
s u m marize d.  C o nc o mita nt me dicati o ns will als o be liste d.  
1 1. 5. 7.  
I m m u n o ge nicit y ( A nti-Dr u g A nti b o d y) A n al yses  
I m m u n o ge nicit y will be assesse d t hr o u g h c h aract erizati o n of i nci de nce a n d titer of A D A.  T h e 
n u m ber a n d perce nt a ge of s u bjects will be calc ul ate d f or t he prese n ce or a bse nce of de vel o p me nt 
of A D A after t he start of a d mi nistrati o n, defi ni n g s u bjects w h o are ne gati v e f or A D A at all ti me 
p oi nts as ne gati ve a n d s u bjects w h o are p ositi ve f or A D A at least 1  ti me p oi nt after dr u g 
treat me nt as p ositi ve.  T h e ra w v al ues a n d c han ge fr o m baseli ne f or A D A titers will be 
s u m marize d b y ti me p oi nt a n d treat me nt ar m usi n g descri pti ve statistics.  T he treat me nt -
e mer gi n g A D A i n ci de nce will be calc ulat e d.  A t reat me nt-e mer ge nt A D A -p ositi ve s u bject will 
be defi ne d as s u bjects w h o are A D A n e gati ve at baseli ne a n d bec o m e A D A p ositi ve p ost -
treat me nt, t h ose w h o are A D A p ositi ve at baseli ne a n d p ost -treat me nt b ut h a ve a n i ncreas e i n 
A D A titer fr o m b aseli ne t o p ost -treat me nt, or t h ose w h o ha ve missi n g A D A data at bas eli ne b ut 
bec o me A D A p ositi ve p osttreat me nt.  T he n u m ber a n d perce nta ge of s u bjects p ositi ve f or 
ne utralizi n g a nti -dr u g a nti b o d y of T -D X d  ma y  b e  re p orte d. 
1 1. 5. 8.  
Ot her S afet y A n al yses  
All ot her safet y e n d p oi nts (e g, E C H O / M U G A) will be liste d. 
1 1. 6.  
I nteri m A n al yses 
N o i nteri m a nal ysis is pla n ne d f o r P F S .  
U p t o 3  a nal yses of O S are pla n ne d:  
 First i nteri m a nal ysis at t he ti me of t he fi nal a n al ysis f or P F S ( pr o vi de d P F S is 
si g nifica nt), at w hic h p oi nt a t otal of a p pr o xi matel y1 6 2 O S e ve nts ( 4 9 % i nf or mati o n 
fracti o n) i n H R-p ositi ve s u bjects  are e x pecte d . 
 If t he first O S i nteri m a n al ysis is n ot si g nifica nt, a sec o n d i nteri m a nal ysis f or O S is 
pla n ne d w he n a p pr o xi matel y 2 3 3 O S e ve nts ( 7 0 % i nf or mati o n fracti o n)  i n 
H R -p ositi ve s u bjects  ha ve bee n d o c u me nte d .   
 If t he sec o n d O S i nteri m a nal ysis is n ot si g nifi ca nt, a fi nal a nal ysis f or O S after 
a p pr o xi matel y 3 3 3 O S e ve nts  i n H R-p ositi ve s u bjects  ha ve b ee n d oc u m e nte d .   
O S will be c o m pare d bet wee n t he 2 treat me nt gr o u ps  at eit her i nteri m or fi nal a nal ysis , pr o vi de d 
s u peri orit y i n P F S is de m o nstrate d f or b ot h t he H R -p ositi ve c o h ort a n d t he F A S.  A hierarc hical 
testi n g pr oce d ure, as des cri be d i n Secti o n 1 1. 4. 2 , will be a d o pte d i n t his st u d y.  
A gr o u p se q ue ntial desi g n, utilizi n g 3 -l o o k La n-De Mets al p ha s pe n di n g f u ncti o n wit h O’ Brie n -
Fle mi n g t y p e st o p b o u n dar y will be use d t o c o nstr uct t he effi cac y st o p pi n g b o u n daries 3 3 wit h a n 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 8  
o verall 2 -si de d si g nifica n ce le vel of 0. 0 5.  T he trial all o ws f or t he earl y st o p pi n g of t he st u d y f or 
a s u peri or O S, pr o vi de d t he l o g -ra n k test f or P F S has de m o nstrate d statistical si g nifi ca n ce i n 
b ot h H R -p ositi ve c o h ort a n d F A S.  T he s a me i nteri m efficac y st o p pi n g b o u n daries will be use d 
f or O S h y p ot h eses testi n g wit h H R-p ositi ve c o h ort a n d F A S.   If t he st u d y c o nti n ues t o fi nal 
a nal ysis, t he effi cac y st o p pi n g b o u n daries at t he fi nal O S a nal ysis t o c o n tr ol t he 2-si de d 
si g nifica n ce le v el of t he re peate d t esti n g at 0. 0 5 will be deri ve d se p aratel y f or H R -p ositi ve 
c o h ort a n d F A S base d o n t he act ual n u m ber of O S e ve nts d oc u me nte d at t he c ut -off d ate, a n d t h e 
act ual i nf or mati o n fracti o ns a n d t he al p ha alrea d y  s pe nt at t he i nteri m a nal yses.  T his will e ns ure 
t he o verall si g nifica n ce l e vel at 0. 0 5 ( 2-si de d) acr oss t he 2 O S h y p ot heses testi n g wit h H R 
p ositi ve c o h ort a n d F A S, a n d t he re p eate d testi n g of t he O S h y p ot h eses at t he i nteri m a n d t he 
fi nal a nal yses, pr o vi d e d t he l o g-ra n k test f or P F S has de m o nstrate d statistical si g nifi ca nce i n b ot h 
t he H R -p ositi ve c o h ort a n d F A S. 3 4 
T he st o p pi n g b o u n daries i n p -val ue a n d hazar d rati o scales , as w ell as t he mi ni mal detecta ble 
me dia n O S differe nces a n d t he c u m ulati ve statistical p o wers,  are s u m marize d i n Ta b le 1 1 .1 . 
T a b le 1 1 .1 : 
St o p pi n g B o u n d aries at O S  I nteri m a n d Fi n al A n al ys es 
A n al ysis 
T i me 
( m o nt hs)*  
N u m ber of 
O S E ve nts  
(inf o r m ati o n 
fr a cti o n) 
H R ( p -v al ue) 
S u peri orit y 
B o u n d ar y a 
Mi ni m al D etect a ble 
D iffere nce i n 
M e di a n O S vs 1 5 f or 
C o ntr ol A r m 
( m o nt hs)b  
C u m ul ati ve  
P o w er  w he n  
T r ue  
H R = 0. 7 2  
C u m ul ati ve  
P o w er  w he n  
T r ue  
H R = 0. 6 8  
2 8. 3 ( F A P F S)  
1 6 2 ( 0. 4 9)  
0. 6 0 5 ( 0. 0 0 1)  
9. 8  
0. 1 5 0  
0. 2 4 4  
3 5. 2 (I A O S)  
2 3 3 ( 0. 7 0)  
0. 7 1 1 ( 0. 0 0 7)  
6. 1  
0. 4 6 6  
0. 6 2 8  
4 9. 3 ( F A O S)  
3 3 3 ( 1. 0 0)  
0. 7 9 2 ( 0. 0 2 3)  
3. 9  
0. 8 0 0  
0. 9 0 9  
F A = fi nal a nal ysis; I A = i nteri m a nal ysis; H R = h azar d rati o ; O S = o verall s ur vi val; P F S = pr o gressi o n -free s ur vi val 
* F r o m ra n d o mizati o n date of t he first s u bj ect. 
a T he deri ve d O’ Brie n -Fle mi n g t y pe s u peri orit y st o p pi n g b o u n dar y.  
b Mi ni mal d etecta ble differe nces i n me dia n O S  are deri ve d base d o n t he hazar d rati o  b o u n daries a n d t he me dia n O S 
f or t he c o ntr ol ar m of 1 5 m o nt hs, ass u mi n g e x p o ne ntial distri b uti o ns f or O S . 
It is rec o g nize d t hat t he i nf or mati o n fracti o ns at t he i nteri m a nal ys es ma y n ot be as pla n ne d .  T h e 
st o p pi n g b o u n dar y will b e u p date d bas e d o n t he act ual i nf or mati o n fracti o n at t he i nteri m 
a nal ys es.  
A n i n de pe n de nt statisticia n fr o m t he desi g nat e d v e n d or will perf or m t he i nteri m a nal yses f or t h e 
data m o nit ori n g c o m mittee (D M C ) re vie w.  F or f urt her details , see t he D M C C harter. 
1 1. 7.  
S a m ple Size Deter mi n ati o n  
T his is a pr os pecti vel y ra n d o mize d o pe n -la bel trial t o c o m pare t he pri mar y e n d p oi nt  of  P F S  
bet wee n t he 2 treat me nt ar ms, T -D X d  a n d p h ysici a n’s c h oice  wit h a ra n d o mizati o n rati o of 2: 1 .  
Ass u mi n g a tr u e hazar d rati o of  0. 6 8 (c orres p o n di n g a n i m pr o ve me nt i n me dia n P F S fr o m t he 
p h ysicia n’s c h oice ar m of 4. 2 m o nt hs  [ N C T 0 0 3 3 7 1 0 3] t o a me dia n P F S i n T -D X d  ar m of 
6. 2  m o nt hs ), a t otal of 3 1 8  P F S e ve nts per BI C R i n H R -p ositi ve c o h ort will be nee de d t o e ns ure 
at least 9 0 % p o wer of l o g -ra n k test t o rej ect t he n ull h y p ot hesis of n o differe nce i n P F S 
distri b uti o ns  at 2 -si de d al p ha of 0. 0 5 i n H R-p ositi ve c o h ort ( pri mar y a n al ysis).  A t otal of 
~ 4 8 0  H R -p ositi ve s u bjects (~ 3 2 0 T -D X d  a n d ~ 1 6 0  p h ysicia n’s c h oice)  a n d ~ 6 0  H R -ne gati ve 

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 9  
s u bjects ( ~ 4 0 T -D X d  a n d ~ 2 0  p h ysicia n’s c h oice) will be ra n d o mize d, f or a t otal e nr oll me nt of 
~ 5 4 0 s u bjects  ( ~ 3 6 0 T -D X d  a n d ~ 1 8 0 p h ysicia n’s c h oice) . 
T he pri mar y effic ac y a n al yses will be e v e nt dri ve n, a n d t he pri mar y a nal yses f or P F S will be 
perf or me d w he n a p pr o xi matel y 3 1 8  P F S e v e nts p er BI C R h a ve bee n  o bser ve d  i n t he H R-p ositi ve 
p o p ulati o n .  T he e x pecte d data c ut off d at es f or t h e fi nal a nal ys es of P F S will be a p pr o xi matel y 
2 8. 3  m o nt hs  after t he first s u bject is ra n d o mize d , base d o n u p date d e nr oll me nt rates. 
T he ke y sec o n dar y e n d p oi nt of O S will be c o m pare d bet wee n t he 2  tr eat m e nt gr o u ps, pr o vi de d 
t hat t he l o g-ra n k tests f or c o m paris o n of P F S  i n b ot h t he H R-p ositi ve c o h ort a n d t he F A S 
de m o nstrat e statistical si g nifica nce.  Ass u mi n g a  me dia n O S of 1 5 m o nt hs  i n t he c o ntr ol 
ar m 3 5 ,3 6 ,3 7 ,3 8 ,3 9 ,4 0 a n d a hazar d rati o of 0. 7 2, a t otal of 3 3 3  O S e ve nts  is nee d e d t o e ns ure 8 0 % 
p o wer of a l o g -ra n k t est t o reject a n ull h y p ot hesis of n o differe nce i n O S distri b uti o ns at an  
o verall 2 -si de d si g nifica n ce le vel of 0. 0 5 u n d e r a 3 -l o o k gr o u p s e q ue ntial desi g n usi n g  La n -
De Mets al p ha s p e n di n g f u ncti o n wit h O’ Brie n -Fl e mi n g  t y p e s u peri orit y st o p pi n g b o u n dar y  
pr o vi de d P F S is statisticall y si g nifi ca nt .  F i n al O S a nal ysis  is pr ojecte d i n a p pr o xi matel y 
4 9. 3  m o nt hs fr o m t he date of first s u bject r a n d o mize d w he n 3 3 3  O S e ve nts ha ve bee n 
d oc u me nte d  i n t he H R-p ositi ve  c o h ort.  A p pr o xi matel y 1 6 2  ( 4 9 %) a n d 2 3 3  ( 7 0 %) o ut of t he 
tar get t otal O S e ve nts are pr ojecte d at t he first a n d t he sec o n d O S i nteri m a n al yses i n t he H R-
p ositi ve c o h ort .  
T he sa m ple siz e c o m p utati o n was  perf or m e d usi n g t he E A S T 6. 4. 
1 1. 8.  
St atistic al A n al ysis Pr ocess  
Statistical a nal yses of t he st u d y will be perf or me d b y t he d esi g n ate d  C R O.  
T he S A P will pr o vi de t he statistical met h o ds a n d defi niti o ns f or t he a nal ysis of t he effi cac y a n d 
safet y data, as well as d escri be t he a p pr oac h es t o be ta ke n f or s u m marizi n g ot her cli nical st u d y 
i nf or mati o n s uc h as s u bject dis p ositi o n, de m o gra p hic a n d baseli ne c haract eristics, st u d y dr u g 
e x p os ure, a n d pri or a n d c o nc o mita nt me dicati o ns.  T h e S A P will als o i ncl u de a descri pti o n of 
h o w missi n g, u n use d, a n d s p uri o us data will be a d dresse d.  
All statistical a nal yses will be perf or me d usi n g S A S ® versi o n 9. 3 or hi g h er ( S A S I nstit ute, Car y, 
N C 2 7 5 1 3).  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 0  
1 2.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  
T he I n vesti gat or/i n vesti gati o nal site will per mit st u d y -relate d m o nit ori n g, a u dits, I R B/IE C 
re vie w, a n d re g ulat or y i ns pecti o ns b y pr o vi di n g direct access t o s o urce dat a/ d oc u me nts.  Direct 
access i ncl u des per missi o n t o e x a mi ne, a nal yze, v erif y, a n d re pr o d uce a n y rec or ds a n d re p orts 
t hat are i m p orta nt t o t he e val uati o n of a cli nical st u d y. 
1 2. 1.  
M o nit ori n g a n d I ns pecti o ns  
T he S p o ns or/ C R O m o nit or a n d Re g ulat or y A ut h orit y i ns pect ors are res p o nsi ble f or c o ntacti n g 
a n d visiti n g t he I n vesti gat or f or t he p ur p os e of i ns pecti n g t h e f acilities a n d, u p o n re q uest, 
i ns pecti n g t he v ari o us rec or ds of t he st u d y (e g, e C R Fs, s o urce dat a, a n d ot her perti ne nt 
d oc u me nts).  
T he verific ati o n  of a d h ere nce t o t he pr ot o c ol; c o m plete ness, acc urac y, a n d c o nsiste nc y of t he 
data; a n d a d h ere n ce t o I C H  G o o d Cli nical Practice ( G C P) a n d l ocal r e g ulati o ns o n t he c o n d uct of 
cli nical researc h will be acc o m plis he d t hr o u g h a c o m bi nati o n of o nsite visits b y t he m o nit or a n d 
re vie w of st u d y d ata re m otel y.  T he fre q u e nc y of t he m o nit ori n g visit will var y base d o n t h e 
acti vit y at e ac h st u d y site.  T he m o nit or is res p o nsi ble f or i ns pecti n g t he e C R Fs a n d e ns uri n g 
c o m plete ness of t he st u d y ess e ntial d oc u me nts.  T he m o nit or s h o ul d ha ve access t o s u bject 
me dical rec or ds a n d ot her st u d y -relate d rec or ds nee de d t o verif y t h e e ntries o n t he e C R Fs.  
Detaile d i nf or mati o n is pr o vi de d i n t he m o nit ori n g pla n.  
T he m o nit or will c o m m u nicate de viati o ns fr o m t h e pr ot oc ol, S O Ps, G C P , a n d a p plica ble 
re g ulati o ns t o t he I n vesti gat or a n d will e ns ure t h at a p pr o priate acti o n(s) d esi g ne d t o pr e ve nt 
rec urre nce of t he d etecte d de viati o ns is ta ke n a n d d oc u me nte d. 
T he I n vesti gat or a grees t o c o o perat e wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n t he 
c o urse of t hes e m o nit ori n g visits are a d dress e d  t o t he satisfacti o n of t he S p o ns or a n d 
d oc u me nt e d.  
I n acc or da n ce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y ma y be s electe d f or a u dit 
b y re pres e ntati ves fr o m t he S p o ns or.  A u dit  of st u d y site facilities (e g, p har mac y, dr u g st ora ge 
areas, l a b orat ori es) a n d re vie w of st u d y -relate d rec or ds will occ ur i n or d er t o e val uate t he st u d y 
c o n d uct a n d c o m plia n ce wit h t he pr ot oc ol, I C H G C P, a n d a p plica ble re g ul at or y re q uir e me nts.   
T he I n vesti gat or s h o ul d r es p o n d t o a u dit fi n di n gs.  I n t he e ve nt t hat a R e g ulat or y A ut h orit y 
i nf or ms t he I n vesti gat or t hat it i nte n ds t o c o n d uct a n i ns pecti o n, t he S p o ns or will  be n otifie d 
i m me diatel y. 
1 2. 2.  
D at a C ollecti o n  
All rele va nt o bser vati o ns a n d data relate d t o t he st u d y, as p er t he st u d y pr ot oc ol, will be rec or de d 
o n e C R F pa ges.  A re prese ntati ve of Daiic hi Sa n k y o or t heir de si g nee will pr o vi de i nstr ucti o n f or 
c o m pleti n g t he e C R F.  A de q uate a n d acc urate cas e rec or ds s h o ul d be mai ntai ne d, i ncl u di n g t he 
e val uati o n of i ncl usi o n a n d e x cl usi o n criteria, me dical hist or y, p h ysic al e xa mi nati o ns, cli nical 
assess me nts, a rec or d of cli ni cal safet y la b orat or y sa m ple c ollecti o n dr u g a d mi nistrati o n, A Es, 
a n d fi nal e val u ati o n.   
T he e C R F s h o ul d be ke pt c urre nt t o e n a ble t he m o nit or t o re vie w t he s u bject’s stat us t hr o u g h o ut 
t he c o urse of t h e st u d y.   

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 1  
A n e C R F m ust be c o m pl ete d f or eac h s u bject w h o si g ns a n I C F a n d u n der g oes a n y scree ni n g 
pr oce d ures.  F or s u bjects w h o are s cree ne d b ut n ot ra n d o mize d, mi ni mal data will be rec or de d o n 
t he e C R F, i ncl u di n g d e m o gra p h y, s u bject stat us, a n d A Es ( or S A Es as a p pr o priate).  All st u d y-
relate d dat a f or t hes e s u bjects will be mai ntai ne d i n t he me dical rec or ds at t he site. 
T he I n vesti gat or will si g n a n d date t he i n dicate d places o n t he e C R F vi a t he E D C s yste m’s 
electr o nic si g nat ur e.  T hese si g nat ures will i n dicat e t hat t he I n vesti gat or i ns pecte d or re vie we d 
t he data o n t he e C R F, t h e data q ueries, a n d t he site n otificati o ns, a n d a grees wit h t he c o nte nt.  
All writte n i nf or mati o n a n d ot her material t o be us e d b y s u bj ects a n d i n vesti gati ve staff m ust use 
v oca b ular y a n d la n g ua ge t hat are cl earl y u n derst o o d.  
1 2. 3.  
D at a M a n a ge me nt  
Eac h s u bject will be i de ntifie d i n t he data base b y a u ni q ue s u bject i de ntifier as defi ne d b y t h e 
S p o ns or.  
T o e ns ure t he q u alit y of cli nical data acr oss all s u bjects a n d st u d y sites, a Cli nical Data 
Ma na ge me nt re vie w will be perf or me d o n s u bject data acc or di n g t o s pecifi cati o ns gi ve n t o 
S p o ns or or d esi g n ee.  D ata will be vette d b ot h electr o nicall y a n d ma n uall y f or e C R Fs a n d t h e 
data will be electr o nicall y vette d b y pr o gra m me d data r ules wit hi n t he a p plicati o n.  Q ueries 
ge n erat e d b y r ules a n d raise d b y re vie wers will be ge n erat e d wit hi n t he E D C a p plicati o n.  D uri n g 
t his re vie w, s u bject data will be c hec k e d f or c o nsiste nc y, c o m plete ness, a n d a n y a p pare nt 
discre pa n cies.  
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntr al la b orat ories will be rec o ncile d t o t he cli nical 
data base.  
Seri o us A Es i n t he cli nical data base will be rec o n cile d wit h t he safet y d ata base.  
All A Es will be c o de d usi n g Me d D R A.   
All c o nc o mita nt me dicati o ns a n d pri or ca ncer t hera pies will be c o de d usi n g t he W orl d Healt h 
Or ga niz ati o n Dr u g Refere nce List Dicti o nar y.  
Data t hat ma y p ote ntiall y u n bli n d t he treat me nt assi g n me nt (ie, st u d y treat me nt ser u m 
c o nce ntr ati o ns, A D A, treat me nt all ocati o n, a n d st u d y treat me nt pre p arati o n/acc o u nta bilit y d ata) 
will be ha n dle d wit h s pecial care d uri n g t he data clea ni n g a n d re vie w pr ocess.  T hese data will be 
ha n dle d i n s uc h a w a y t hat, pri or t o u n bli n di n g, a n y dat a t hat ma y u n bli n d st u d y tea m p ers o n nel 
will be prese nte d as bli n de d i nf or mati o n or ot her wise will n ot be ma de a vaila ble.  If a p plica ble, 
u n bli n de d data ma y be m a de a v aila ble t o q ualit y ass ura nce re prese ntati ves f or t he p ur p oses of 
c o n d ucti n g i n d e pe n de nt a u dits.  
1 2. 4.  
St u d y D oc u me nt ati o n a n d St or a ge  
T he I n vesti gat or will mai ntai n a Si g nat ur e List of a p pr o priatel y q u alifie d p ers o ns t o w h o m 
he/s he has dele g ate d st u d y d uties.  All pers o ns a ut h orize d t o ma ke e ntries a n d/ or c orrecti o ns o n 
eC R Fs will be i ncl u de d o n t he Si g nat ure List.  
S o urce d oc u me nts are ori gi nal d oc u m e nts, data, a n d rec or ds fr o m w hic h t he s u bject’s e C R F data 
are o btai ne d.  T hese i ncl u de b ut ar e n ot li mite d t o h os pital rec or ds, cli nical a n d office c harts, 
la b orat or y a n d p h ar mac y rec or ds, diaries, micr ofi c hes, X-ra ys, a n d c orres p o n de nce. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 2  
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, dat a c orrecti o n f or ms, e C R Fs, 
i n ve nt or y of st u d y dr u g, re g ulat or y d oc u m e nts (e g, pr ot oc ol a n d a me n d me nts, I R B/ IE C 
c orres p o n d e nce a n d a p pr o vals, a p pr o ve d a n d si g n e d I C Fs, I n v esti gat or’s A gree me nt, cli nical 
s u p plies recei pts, distri b uti o n, a n d ret ur n rec or ds), a n d ot her S p o ns or c orres p o n de nce p ertai ni n g 
to t he st u d y m ust be ke pt i n a p pr o priate st u d y files at t he st u d y site  ( Trial M aster File).  S o urce 
d oc u me nts i ncl u de all rec or di n gs a n d o bser vati o ns or n otati o ns of cli nical acti vities a n d all 
re p orts a n d rec or ds n ecessar y f or t he e val uati o n a n d rec o nstr ucti o n of t h e cli nical st u d y.  T hes e 
rec or ds will be retai ne d i n a sec ure file f or t he peri o d re q uire d b y t he i nstit uti o n or st u d y site 
p olic y.  Pri or t o tra nsf er or destr ucti o n of t hese rec or ds, t he S p o ns or m ust be n otifie d i n writi n g 
a n d be gi ve n t he o p p or t u nit y t o f urt her st or e s uc h rec or ds. 
1 2. 5.  
Rec or d Kee pi n g  
T he I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d ce ntr alize d 
fili n g s yste m ( Trial Mast er File) of all st u d y-relate d (esse ntial) d oc u m e ntati o n, s uita ble f or 
i ns pecti o n at a n y ti me b y re pres e ntati ves fr o m t he S p o ns or a n d/ or a p plica bl e Re g ul at or y 
A ut h orities.  Esse ntial d oc u me nts i ncl u de:  
 S u bject files c o ntai ni n g c o m plete d e C R Fs, I C Fs, a n d s u p p orti n g c o pies of s o urce 
d oc u me ntati o n (if ke pt).  
 St u d y files c o ntai ni n g t h e pr ot oc ol wit h all a me n d me nts, I B, c o pies of rel e va nt 
esse ntial d oc u me nts re q uire d pri or t o c o m me nci n g a cli nical st u d y, a n d all 
c orres p o n d e nce t o a n d fr o m t he I R B/I E C a n d t he S p o ns or.  
 Rec or ds rel ate d t o t he st u d y dr u g(s) i ncl u di n g ac k n o wle d g m e nt of recei pt at st u d y 
site, acc o u nta bilit y rec or ds, a n d fi nal rec o nciliati o n a n d a p plica ble c orres p o n de nce.  
I n a d diti o n, all ori gi nal s o urce d oc u m e nts s u p p orti n g e ntries i n t he e C R Fs m ust be mai ntai ne d 
a n d be rea dil y a vaila ble.  
All st u d y -relate d esse ntial d oc u me ntati o n will be retai ne d b y t he I n v esti gat or u ntil at least 
2  y ears after t he l ast a p pr o val of a mar k eti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o 
pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n a n I C H re gi o n or at least 2  y ears ha v e la pse d 
si nce t he for mal disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal dr u g .  T hese 
d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if re q uir e d b y t he a p plica ble 
re g ulat or y re q uire me nts or b y a n a gree me nt wit h t he S p o ns or.  It is t he res p o nsi bility of t he 
S p o ns or t o i nf or m t he I n vesti gat or/i nstit uti o n as t o w he n t hese d o c u me nts n o l o n ger nee d t o be 
retai ne d. 
S u bject me dical files s h o ul d be retai ne d i n acc or da nce wit h a p plica ble le gislati o n a n d i n 
acc or da nce wit h t he ma xi m u m peri o d of ti me per mitte d  b y t he h os pital, i nstit uti o n , or pri vate 
practice.  
N o st u d y d oc u m e nt s h o ul d be destr o ye d wit h o ut pri or writte n a gree me nt b et wee n t he S p o ns or 
a n d t he I n vesti gat or.  S h o ul d t he I n v esti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her part y or 
m o ve t he m t o a n ot her l oc ati o n, he/s he m ust n otif y t he S p o ns or i n writi n g of t he ne w res p o nsi ble 
pers o n a n d/ or t he n e w l o cati o n.  

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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 3  
1 3.  
FI N A N CI N G A N D I N S U R A N C E  
1 3. 1.  
Fi n a nces  
Pri or t o starti n g t he st u d y, t he Pri nci pal I n vesti gat or a n d/ or i nstit uti o n will si g n a cli nical st u d y 
a gree m e nt wit h t he S p o ns or or t he C R O.  T his a gree me nt will i ncl u de t he fi na ncial i nf or mati o n 
a gree d u p o n b y t h e parties.  
1 3. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce  
T he S p o ns or pr o vi des i ns ura nce f or st u d y s u bjects t o ma ke a vaila ble c o m pe nsati o n i n case of 
st u d y-relate d i nj ur y. 
Rei m b urse me nt, i n de m nit y a n d i ns ura nce will  be a d dresse d i n a se parate a gree me nt o n ter ms 
a gree d u p o n b y t h e parties.  

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V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 4  
1 4.  
P U B LI C A TI O N P O LI C Y  
Daiic hi Sa n k y o I nc. is c o m mitte d t o meeti n g t he hi g hest sta n dar ds of p u blicati o n a n d p u blic 
discl os ure of i nf or mati o n arisi n g fr o m cli nical st u dies s p o ns ore d b y t he c o m pa n y.  We will 
c o m pl y wit h U S, E ur o pea n U ni o n, a n d J a pa nese p olicies f or p u blic discl os ure of t he cli nical 
st u d y pr ot oc ol a n d cli nic al st u d y res ults, a n d f or s hari n g of cli nical st u d y d ata.  We f oll o w t he 
pri nci ples set f or war d i n “ G o o d P u blicati o n Practice f or C o m m u nicati n g C o m pa n y -S p o ns ore d 
Me dical Researc h ( G P P 3) ,” a n d p u blicati o ns will a d here t o t he “ Rec o m me n dati o ns f or t he 
C o n d uct, Re p orti n g, E diti n g, a n d P u blicati o n of S c h olarl y W o r k i n Me dical J o ur nals” 
esta blis he d b y t h e I nter n ati o nal C o u ncil of Me dical J o ur nal E dit ors. 4 1   
I n or der t o e ns ure t hat w e are i n c o m plia nce wit h t he p u blic discl os ure p olicies a n d t he 
I nter nati o nal C o u ncil of Me dical J o ur nal E dit ors rec o m me n dati o ns, a n d t o pr otect pr o priet ar y 
i nf or mati o n ge nerate d d uri n g t he st u d y, all p u blicati o ns ( ma n uscri pts, a bstracts, or ot her p u blic 
discl os ure) bas e d o n data ge n erat e d i n t his st u d y m ust be acce pt e d, re vi e we d, a n d a p pr o ve d i n 
writi n g b y t he S p o ns or pri or t o s u b missi o n.  

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V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 5  
1 5.  
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E  I N F O R M A TI O N 
1 5. 1.  
C o m pli a nce St ate me nt, Et hics , a n d Re g ul at or y C o m pl i a nce 
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat ha ve 
t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I C H c o ns oli date d G ui deli ne E 6 f or G C P 
( C P M P/I C H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y re q uire me nt(s) i n cl u di ng t he f oll o wi n g:  
 U S F o o d a n d Dr u g A d mi nistrati o n G C P Re g ulati o ns: C o de of Fe d eral Re g ulati o ns 
Title 2 1, parts 1 1, 5 0, 5 4, 5 6 , a n d 3 1 2 as a p pr o priate a n d/ or;  
 J a pa nese Mi nistr y of Healt h, La b or, a n d Welfare Or di na nce N o. 2 8 of 2 7  Mar  1 9 9 7 
a n d/ or; 
 Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d of t he C o u ncil o n t he 
a p pr o xi mati o n of t he la ws, re g ulati o ns , a n d a d mi nistrati ve pr o visi o ns of t he Me m ber 
States relati n g t o t he i m ple me ntati o n of G C P i n t he c o n d uct of cli nical trials o n 
me dici nal pr o d uct f or h u ma n use a n d/ or;  
 Ot her a p plica bl e l ocal r e g ulati o ns.  
1 5. 2.  
S u bject C o nfi de nti alit y  
T he I n vesti gat ors a n d t h e S p o ns or will preser ve t h e c o nfi de ntialit y of all s u bjects ta ki n g p art i n 
t he st u d y, i n acc or da nce wit h G C P a n d l ocal re g ul ati o ns. 
T he I n vesti gat or m ust e ns u re t hat t he s u bject’s a n o n y mit y is mai ntai ne d.  O n t he e C R Fs or ot her 
d oc u me nts s u b mitte d t o t he S p o ns or or t he C R O, s u bjects s h o ul d be i de ntifie d b y a u ni q ue 
s u bject i de ntifier as d esi g nate d b y t he S p o ns or.  D oc u me nts t hat are n ot f or s u b missi o n t o t he 
S p o ns or or t he C R O (e g, si g ne d I C F) s h o ul d be k e pt i n strict c o nfi de nce b y t he I n v esti gat or.  
I n c o m plia nce wit h I C H G C P G ui deli nes, it is re q uire d t hat t he I n vesti gat or a n d i nstit uti o n 
per mit a ut h orize d re prese ntati ves of t he c o m pa n y, of t he Re g ulat or y A ge n c y( ies), a n d t he 
I R B/IE C direct access t o re vie w t he s u bject’s ori gi nal me dical rec or ds f or verificati o n of st u d y -
relate d pr oce d ures a n d d ata.  T he I n v esti gat or is o bli gate d t o i nf or m t he s u bject t hat his/ her 
st u d y-relate d rec or ds will be re vie we d b y t he a bo v e na me d re pres e ntati ves wit h o ut vi olati n g t he 
c o nfi de ntialit y of t he s u bject.  
1 5. 3.  
I nf or me d C o nse nt  
Bef ore a s u bj ect’s partici pati o n i n t he st u d y, it is t he I n vesti gat or’s res p o nsi bilit y t o o btai n freel y 
gi ve n c o nse nt, i n writi n g, fr o m t he s u bject after a d e q uate e x pla nati o n of t he ai ms, met h o ds, 
a ntici pate d be nefits, a n d p ote ntial hazar ds of t he st u d y a n d b ef ore a n y pr ot oc ol -s pecific 
pr oce d ures or a n y st u d y treat me nts are a d mi nistere d.  S u bjects s h o ul d be gi ve n t he o p p ort u nit y 
t o as k q uesti o ns a n d recei ve satisfact or y a ns wers t o t heir i n q uiries, a n d s h o ul d ha ve a de q u ate 
ti me t o deci de w het her or n ot t o partici pate i n t he st u d y.  T he writte n I C F s h o ul d be pre pare d i n 
t he l ocal la n g ua ge(s) of t he p ote ntial s u bject p o p ulati o n. 
I n o btai ni n g a n d d o c u me nti n g i nf or med c o nse nt , t he I n vesti gat or s h o ul d c o m pl y wit h t he 
a p plica ble re g ulat or y re q uire me nts, a n d s h o ul d a d here t o G C P a n d t o t he et hical pri nci ples t hat 

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Pa ge 1 1 6  
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  T he c o nse nt f or m a n d a n y re visi o n(s) s h o ul d be 
a p pr o ve d b y t he I R B/I E C pri or t o bei n g pr o vi d e d t o p ote ntial s u bjects.  
T he s u bject’s writte n i nf or me d c o nse nt s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or ds.  
T he I C F s h o ul d be si g ne d a n d pers o nall y dat e d b y t he s u bject a n d b y t he pers o n w h o c o n d u cte d 
t he i nf or me d c o nse nt dis c ussi o n ( n ot necess aril y t he I n vesti gat or).  T h e ori gi nal si g ne d I C F 
s h o ul d be retai ne d i n a cc or da nce wit h i nstit uti o nal p olic y, a n d a c o p y of t h e si g ne d c o nse nt f or m 
s h o ul d be pr o vi de d t o t he s u bject.  T he date a n d ti me (if a p plica ble) t hat i nf or me d c o nse nt was 
gi ve n s h o ul d be rec or de d o n t he e C R F.  
1 5. 4.  
Re g ul at or y C o m pli a nce  
T he st u d y pr ot oc ol, s u bje ct i nf or mati o n a n d c o nse nt f or m, t he I B, a n y s u bject writte n 
i nstr ucti o ns t o be gi ve n t o t he s u bject, a vaila ble s afet y i nf or mati o n, s u bject recr uit me nt 
pr oce d ures (e g, a d vertise me nts), i nf or mati o n a b o ut pa y me nts a n d c o m pe ns ati o n a vaila ble t o t he 
s u bjects, a n d d oc u me ntati o n e vi de nci n g t he I n vesti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o 
t he IE C or I R B f or et hical re vie w a n d a p pr o val acc or di n g t o l o cal re g ul ati o ns, pri or t o t he st u d y 
start.  T he writte n a p pr o val s h o ul d i de ntif y all d oc u me nts re vie we d b y n a m e a n d versi o n.  
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a n al ysis will be d oc u me nt e d i n a pr ot oc ol 
a me n d me nt a n d/ or t he S A P.  
T he I n vesti gat or  a n d/ or S p o ns or m ust s u b mit a n d, w here n ecess ar y, o btai n a p pr o val fr o m t he 
IE C or I R B f or all s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he I C F.  T he I n v esti gat or 
s h o ul d n otif y t he IE C or I R B of de vi ati o ns fr o m t he pr ot oc ol or S A Es occ urri n g at t he st u d y site 
a n d ot her A E re p orts recei ve d fr o m t he S p o ns or/ C R O, i n acc or da n ce wit h l ocal pr oce d ures.  
As re q uire d b y l o cal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y Affairs gr o u p or re prese ntati ve 
t o w h o m t his res p o nsi bilit y has bee n dele gate d will e ns ure all le gal as p ects are c o v ere d, a n d 
a p pr o val fr o m t he a p pr o priate re g ul at or y b o dies o btai ne d, pri or t o st u d y i nitiati o n.  If c ha n ges t o 
t he i nitial pr ot oc ol a n d ot her rel e va nt st u d y d o c u m e nts are ma de, t his re pres e ntati ve will als o 
e ns ure t hat a n y re vise d d oc u me nts re q uire d f or s u b missi o n are s u b mitte d t o Re g ulat or y 
A ut h orities a n d i m ple me ntati o n of t hese c ha n ges are ma de o nl y after a p pr o val b y t he rele va nt 
re g ulat or y b o dies, as n ee de d. 
I n t he e ve nt of a n y pr o hi biti o n or restricti o n i m p ose d (e g, cli nical h ol d) b y a n a p plica ble 
Re g ulat or y A ut h orit y(i es) i n a n y area of t he w orl d, or if t he I n vesti gat or is a ware of a n y n e w 
i nf or mati o n t hat mi g ht i nfl ue nce t he e val uati o n of t he be nefits a n d ris ks of t he i n vesti gati o nal 
dr u g, t he S p o ns or s h o ul d be i nf or me d i m me diatel y.   
I n a d diti o n, t he I n vesti gat or will i nf or m t he S p o ns or i m me diatel y of a n y ur ge nt safet y meas ures 
ta ke n b y t he I n vesti gat or to pr otect t he st u d y s u bjects a gai nst a n y i m me diate hazar d, a n d of a n y 
s us pecte d/act u al seri o us G C P n o nc o m plia nce of w hic h  t he I n vesti gat or b ec o mes a ware. 
1 5. 5.  
Pr ot oc ol De vi ati o ns  
T he I n vesti gat or s h o ul d c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y S p o ns or 
a n d, if re q uir e d, b y t he R e g ul at or y A ut h orit y(ies), a n d w hic h was gi v e n a p pr o val/fa v ora ble 
o pi ni o n b y t he I R Bs/ E Cs.  

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V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
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Pa ge 1 1 7  
A de viati o n t o a n y pr ot oc ol pr oce d ure or wai ver t o a n y stat e d criteria will n ot be all o we d i n t his 
st u d y e x ce pt w here necessar y t o eli mi nate i m me diate hazar d(s) t o t he s u bject.  S p o ns or m ust be 
n otifie d of all i nte n de d or u ni nte n de d de viati o ns t o t he pr ot oc ol (e g, i ncl usi o n/e xcl usi o n criteria, 
d osi n g, misse d st u d y visits) o n a n e x pe dite d basis.  
T he I n vesti gat or, or p ers o n desi g n at e d b y t he I n v esti gat or, s h o ul d d oc u m e nt a n d e x plai n a n y 
de viati o n fr o m t he a p pr o ve d pr ot oc ol.  
If a s u bject w as i neli gi ble or recei ve d t h e i nc orrect d ose or st u d y tr eat me nt, a n d ha d at least 1 
a d mi nistrati o n of st u d y dr u g, d ata s h o ul d be c ollecte d f or safety p ur p os es.  
If a p plica bl e, the I n vesti gat or s h o ul d n otif y t he I R Bs/ E Cs of de viati o ns fr o m t he pr ot oc ol i n 
acc or da nce wit h l ocal pr oce d ures.  
1 5. 6.  
S u p pl y of Ne w I nf or m ati o n Affecti n g t he C o n d uct of t he St u d y  
W he n ne w i nf or mati o n b ec o mes a v aila ble t hat ma y a d v erse l y affect t he safet y of s u bj ects or t he 
c o n d uct of t he st u d y, t he S p o ns or will i nf or m all I n vesti gat ors i n v ol ve d i n t he cli nical st u d y, 
IE Cs/I R Bs, a n d Re g ulat or y A ut h orities of s uc h i nf or mati o n, a n d w he n nee d e d, will a me n d t he 
pr ot oc ol a n d/ or s u bject i nf or mati o n.  
T he I n vesti gat or s h o ul d i m me diatel y i nf or m t he s u bject w he ne v er ne w i nf or mati o n bec o mes 
a vaila ble t hat ma y be rel e va nt t o t he s u bject’s c o nse nt or ma y i nfl ue nce t he s u bject’s willi n g ness 
t o c o nti n ue partici pati o n i n t he st u d y.  T he c o m m u nicati o n s ho ul d be d oc u me nte d o n me dical 
rec or ds, f or e x a m ple, a n d it s h o ul d be c o nfir me d w het her or n ot  t he s u bject is willi n g t o re mai n 
i n t he st u d y.  
If t he s u bject i nf or m ati o n is re vise d, it m ust be re-a p pr o ve d b y t he I R B /I E C.  T he I n vesti gat or 
s h o ul d o btai n writte n i nf or me d c o nse nt t o c o nti n u e partici pati o n wit h t he re vise d writte n 
i nf or mati o n e ve n if s u bje cts were alrea d y i nf or me d of t he rele va nt i nf or mati o n.  T he I n vesti gat or 
or ot her res p o nsi ble p ers o n nel w h o pr o vi de d e x pla nati o ns a n d t he s u bject s h o ul d si g n a n d date 
t he re vise d I C F. 
1 5. 7.  
Pr ot oc ol A me n d me nts  
A n y a me n d me nts t o t he st u d y pr ot oc ol t hat se e m t o be a p pr o pri ate as t he st u d y pr o gresses will 
be c o m m u nicate d t o t he I n vesti gat or b y Daiic hi Sa n k y o or t h e C R O.  Als o, t he S p o ns or will 
e ns ure t he ti mel y s u b missi o n of a me n d me nts t o Re g ul at or y A ut h orities.  
A gl o bal pr ot oc ol a me n d me nt will affect st u d y c o n d uct at all st u d y sites i n all re gi o ns of t he 
w orl d.  S uc h a me n d me nts will be i nc or p orate d i nt o a re vise d pr ot oc ol d oc u me nt.  C ha n ges m a de 
b y s uc h a me n d me nts will b e d oc u me nte d i n a S u m mar y of C ha n ges d o c u me nt.  T hese pr ot oc ol 
a me n d me nts will u n der g o t he sa me re vi e w a n d a p pr o val pr ocess as t he ori gi nal pr ot oc ol.   
A l ocal pr ot oc ol a me n d m e nt will affect st u d y c o n d uct at a partic ul ar st u d y site(s) a n d/ or i n a 
partic ula r re gi o n/c o u ntr y.  S p o ns or a p pr o val of l ocal a me n d me nts will be cl earl y d oc u me nt e d. 
A pr ot oc ol a me n d me nt ma y b e i m ple me nte d aft er it has bee n a p pr o ve d b y t he I R B/ IE C a n d b y 
Re g ulat or y A ut h orities w here a p pr o priate, u nl ess i m me diate i m ple me ntati o n of t he c h a n ge is 
necessar y f or s u bject safet y.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 8  
1 5. 8.  
St u d y Ter mi n ati o n  
T he S p o ns or has t he ri g ht t o ter mi nate t he st u d y at a n y ti me a n d st u d y ter mi nati o n ma y als o be 
re q ueste d b y (a) c o m pete nt a ut h orit y(ies). 
1 5. 9.  
D at a M o nit ori n g C o m mittee  
A n i n de pe n de nt D M C will be creat e d t o f urt her pr otect t he ri g hts, safet y, a n d well -bei n g of 
s u bjects w h o will be partici pati n g i n t his st u d y b y m o nit ori n g t he pr o gress a n d res ults.  T he 
D M C will c o m prise q ualifie d p h ysici a ns a n d scie ntists w h o are n ot In vesti gat ors i n t he st u d y a n d 
n ot ot her wise directl y ass ociate d wit h t he S p o ns or.  
T he D M C will peri o dicall y re vi e w u n bli n de d safet y dat a i n t his st u d y.  T he details a b o ut t he 
re vie ws of t he st u d y d ata a n d ot her D M C pr ocesses will be descri be d i n t he D M C c harter. 
T he D M C ma y rec o m me n d m o dificati o n of t he st u d y pr ot o c ol or st u d y t o t he Steeri n g 
C o m mittee base d o n pre -s pecifie d r ules d escri b e d i n t he D M C c harter. 
1 5. 1 0.  
A d dress List  
A list of ke y st u d y pers o n nel (i ncl u di n g p ers o n nel at t he S p o ns or, C R O, la b orat ories, a n d ot her 
ve n d ors) a n d t h eir c o nta ct i nf or mati o n (a d dress, tele p h o ne, fa x, e mail) will be ke pt o n file a n d 
re g ularl y u p dat e d as necessar y. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 9  
1 6.  
R E F E R E N C E S  
1.  N ati o nal C o m pre he nsi ve Ca ncer Net w or k. Breast Ca ncer ( v ersi o n 2. 2 0 2 0). 0 5 Fe br uar y 
2 0 2 0. A vaila ble fr o m: htt ps:// w w w. ncc n. or g/ pr ofessi o nals/ p h ysi cia n _ gls/ p df/ breast. p df.  
2.  Ste wart B W, Wil d C P, e dit ors. W orl d Ca ncer Re p ort 2 0 1 4. Ge ne v a, S witzerla n d: W orl d 
Hea lt h Or ga niz ati o n, I nter nati o nal A ge nc y f or Res earc h o n C a ncer, W H O Press; 2 0 1 5. 
3.  C ortes J, O’ S ha u g h ness y J, L oes c h D, et al; E M B R A C E ( Eisai Metastatic Breast Ca ncer 
St u d y Assessi n g P h ysicia n’s C h oice Vers us E 7 3 8 9) i n vesti gat ors. Eri b uli n m o n ot hera p y 
vers us treat me nt of p h ysi cia n’s c h oice i n patie nts wit h metastatic breast c a ncer 
( E M B R A C E): a p h ase 3 o pe n-la bel r a n d o mise d st u d y. La n cet. 2 0 1 1; 3 7 7( 9 7 6 9): 9 1 4-2 3.  
4.  Ka uf ma n P A, A w a da A, T wel ves C, et al. P hase III o pe n -la bel ra n d o mize d st u d y of 
eri b uli n mes ylat e ver s us ca pecita bi ne i n patie nts wit h l ocall y a d v a nce d or metastatic 
breast c a ncer pre vi o usl y treate d wit h a n a nt hrac ycli ne a n d a ta xa ne. J Cli n O nc ol. 
2 0 1 5; 3 3( 6): 5 9 4 -6 0 1.  
5.  A b o u -Alfa G K, Let o ur n ea u R, Har ker G, et al. Ra n d o mize d p hase III st u d y of e x ateca n 
a n d ge mcita bi ne c o m pare d wit h ge mcita bi ne al o n e i n u ntreate d a d va nce d p a ncreatic 
ca ncer. J Cli n O nc ol. 2 0 0 6; 2 4( 2 7): 4 4 4 1 -7.  
6.  C he vert o n P, Friess H, A n dras C, et al. P hase III res ults of e x ateca n ( D X -8 9 5 1f) vers us 
ge m cita bi ne ( G e m) i n c h e m ot hera p y - n aï ve patie nts  wit h a d va nce d pa n creatic ca ncer 
( A P C). J Cli n O nc ol. 2 0 0 4;2 2 ( 1 4 S u p pl. ): A bstract 4 0 0 5. 
7.  De J a ger R, C he vert o n P, Ta ma n oi K, et al; D X -8 9 3 1f I n vesti gat ors. D X -8 9 5 1f: 
s u m mar y of p hase I cli nical trials. A n n N Y Aca d Sci. 2 0 0 0; 9 2 2: 2 6 0-7 3.  
8.  O gita ni Y, Ai d a T, Ha gi h ara K, et al. D S -8 2 0 1a, a n o vel H E R 2 -tar geti n g A D C wit h a 
n o vel D N A t o p ois o meras e I i n hi bit or, de m o nstrates a pr o misi n g a ntit u m or efficac y wit h 
differe ntiati o n fr o m T -D M 1. Cli n Ca ncer Res. 2 0 1 6; 2 2( 2 0): 5 0 9 7 -1 0 8.  
9.  Trast uz u ma b der u xteca n  I n v esti gat or’s Broc h ure. M ost c urre nt versi o n.  
1 0.  W olff A C, Ha m m o n d M E H, Allis o n K H, et al; H u ma n e pi der mal gr o wt h fact or rece pt or 
2 testi n g i n breast ca ncer: A merica n S ociet y of Cli nical O nc ol o g y/ C olle ge of A merica n 
Pat h ol o gists Cli nical Practice G ui deli ne f oc use d u p date. J Cli n O nc ol. 2 0 1 8; 3 6( 2 0): 2 1 0 5 -
2 2.  
1 1.  Ge yer C E, F orster J, Li n d q uist D, et al. La pati ni b pl us ca pecita bi ne f or H E R 2 -p ositi ve 
a d va nce d breast ca n cer. N E n gl J Me d. 2 0 0 6; 3 5 5( 2 6): 2 7 3 3 -4 3.  
1 2.  Basel ga J, C ortés J, Ki m S B, et al; C L E O P A T R A St u d y Gr o u p. Pert uz u ma b pl us 
trast uz u ma b pl us d oceta xel f or metastatic breast c a ncer. N E n gl J Me d. 2 0 1 2; 3 6 6( 2): 1 0 9-
1 9.  
1 3.  Ver ma S, Miles D, Gia n ni L, et al; E MI LI A St u d y Gr o u p. Trast uz u ma b e mt a nsi ne f or 
H E R 2 -p ositi ve a d va nce d breast c a ncer. N E n gl J Me d. 2 0 1 2; 3 6 7( 1 9): 1 7 8 3 -9 1.  
1 4.  Fe hre n bac h e r L, Cecc hi ni R S, Ge yer C E, et al. N S A B P B-4 7 ( N R G o nc ol o g y): P hase III 
ra n d o mize d trial c o m pari n g a dj u v a nt c he m ot hera p y wit h a dria m yci n ( A) a n d 
c ycl o p h os p ha mi de ( C) → wee kl y paclita xel ( W P), or d oceta xel ( T) a n d C wit h or wit h o ut 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 0  
a year of trast uz u ma b ( H)  i n w o me n wit h n o de-p ositi ve or hi g h -ris k n o de-n e gati ve 
i n vasi ve breast c a ncer (I B C) e x pressi n g H E R 2 stai ni n g i nte nsit y of I H C 1 + or 2 + wit h 
ne gati ve FI S H ( H E R 2 -L o w I B C). Oral pr ese ntati o n prese nte d at: 2 0 1 7 Sa n A nt o ni o 
Breast Ca ncer S y m p osi u m; 2 0 1 7 Dec 5 -9; Sa n A nt o ni o, T X: P u blicati o n n u m ber G S 6 -
0 7. A vaila ble fr o m: htt ps:// w w w.sa bcs. or g/ P ortals/ S A B C S 2 0 1 6/ D oc u me nts/ S A B C S -
2 0 1 7 -A bstracts. p df.  
1 5.  M o di S, Par k H, M urt h y R, et al. A ntit u m or acti vit y a n d safet y of trast uz u ma b  der u xt eca n 
i n patie nts wit h H E R 2-l o w-e x pressi n g a d va nce d breast c a ncer: res ults fr o m a p hase I b 
st u d y. J Cli n O nc ol. D OI: 1 0. 1 2 0 0/J C O. 1 9. 0 2 3 1 8. P u blis he d o nli ne 1 4 Fe b 2 0 2 0.  
1 6.  W olff, A. C., et al., H u ma n E pi der mal Gr o wt h Fact or Rece pt or 2 Testi n g i n Breast 
Ca ncer: A merica n S ociet y of Cli nical O n c o l o g y/ C olle ge of A meri ca n Pat h ol o gists 
Cli nical Practice G ui deli ne F oc us e d U p dat e. J Cli n O nc ol. 2 0 1 8. 3 6( 2 0): 2 1 0 5 -2 2.  
1 7.  Li n dstr ö m L S, Karlss o n E, Wil ki n g U M, et al. Cli nicall y use d breast ca ncer mar kers s u c h 
as estr o ge n rece pt or, pr o gester o ne rece pt or, a n d h u ma n e pi der mal gr o wt h fact or rece pt or 
2 are u nsta ble t hr o u g h o ut t u m or pr o gressi o n. J Cli n O nc ol. 2 0 1 2; 3 0( 2 1): 2 6 0 1 -8.  
1 8.  Perez E A, Press M F, D u ec k A C, et al. I m m u n o hist oc he mistr y a n d fl u ores ce nce i n sit u 
h y bri dizati o n assess me nt of H E R 2 i n cli nical trials of a dj u va nt t hera p y f or breast c a ncer 
( N C C T G N 9 8 3 1, B CI R G 0 0 6, a n d B CI R G 0 0 5). Breast Ca ncer Res Treat. 
2 0 1 3; 1 3 8( 1): 9 9 -1 0 8.  
1 9.  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.  
2 0.  U K M H R A. Rec o m me n dati o ns relate d t o c o ntrace pti o n a n d pre g na n c y testi n g i n cli nical 
trials. A d vis or y n o n bi n di n g g ui da nce s u p p orte d b y nati o nal c o m pete nt a ut h orities 
re pres e nte d at t he Cli nical Trial Facilitati o n Gr o u p ( C T FG) meeti n g i n R o m e 2 0 1 4 Se p 
1 5; 2 0 1 4. A vaila ble fr o m: htt p:// w w w. h ma.e u/filea d mi n/ dateie n/  
H u ma n _ Me dici nes/ 0 1 -A b o ut _ H M A/ W or ki n g _ Gr o u ps/ C T F G/ 2 0 1 4 _ 0 9 _ H M A _  
C T F G _ C o ntrace pti o n. p df.  
2 1.  Fi n n R S, Cr o w n J P, La n g I, et al. T he c ycli n -de p e n de nt ki nase 4/ 6 i n hi bit or pal b ocicli b i n 
c o m bi nati o n wit h letr oz ole vers us letr oz ole al o ne as first -li ne treat me nt of oestr o ge n 
rece pt or-p ositi ve, H E R 2 -ne gati ve, a d v a nce d breast ca ncer ( P A L O M A -1/ T RI O -1 8): a 
ra n d o mise d p hase 2 st u d y. La n cet O n c ol. 2 0 1 5 J a n; 1 6( 1): 2 5-3 5.  
2 2.  Fi n n R S, Marti n M, R u g o H S, et al. Pal b ocicli b a n d letr oz ole i n a d va nce d breast c a ncer. 
N E n gl J Me d. 2 0 1 6; 3 7 5( 2 0): 1 9 2 5 -3 6.  
2 3.  H ort o ba g yi G N, Ste m mer S M, B urris H A, et al. Ri b ocicli b as first -li ne t hera p y f or H R-
p ositi ve, a d va nce d breast ca ncer. N E n gl J Me d. 2 0 1 6; 3 7 5( 1 8): 1 7 3 8 -4 8.  
2 4.  Sle d ge G W Jr, T oi M, Ne ve n P, et al. M O N A R C H 2: a be maci cli b i n c o m bi nati o n wit h 
f ul vestra nt i n w o me n wit h H R +/ H E R 2- a d va n ce d breast c a ncer w h o ha d pr o gresse d 
w hile recei vi n g e n d ocri n e t hera p y. J Cli n O nc ol. 2 0 1 7; 3 5( 2 5): 2 8 7 5 -8 4.  
2 5.  F D A G ui da n ce f or I n d u str y. Cli nical trial en d p oi nts f or t he ap pr o val of ca n cer d r u gs a n d 
b i ol o gics. Dec 2 0 1 8 . [cite d 0 1 Oct 2 0 2 0].  A vaila ble at: 
htt ps:// w w w.f da. g o v/ me dia/ 7 1 1 9 5/ d o w nl oa d . 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 1  
2 6.  E M A. G ui deli ne o n t he e val uati o n  of a ntica n cer m e dici nal pr o d ucts i n ma n. 
E M A/ C M P/ 2 0 5/ 9 5 Re v 5. 2 2 Se p 2 0 1 7. [cite d 0 1 Oct 2 0 2 0] A vaila ble at: 
htt ps:// w w w.e ma.e ur o pa. e u/e n/ d oc u me nts/scie ntific -g ui d eli ne/ g ui d eli ne -e v al uati o n -
a ntica ncer -me dici n al -pr o d ucts -ma n -re visi o n-5 _e n. p df . 
2 7.  G hislai n I,  Zi k os E, C oe ns C, et al; E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of 
Ca ncer ( E O R T C) Q ualit y of Lif e Gr o u p; Breast Ca ncer Gr o u p; E O R T C Hea d q uarters. 
Healt h -relate d q ualit y of life i n l ocall y a d va nce d a n d metastatic breast ca ncer: 
met h o d ol o gical a n d  cli nical iss ues i n ra n d o mise d c o ntr olle d trials. La ncet O nc ol. 
2 0 1 6; 1 7( 7):e 2 9 4 -e 3 0 4.  
2 8.  I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) of Tec h nical Re q uire me nts f or 
Re gistrati o n of P har m ace uticals f or H u ma n Us e. I C H Har m o nise d Tri partite G ui deli ne. 
Cli nical  Safet y D ata Ma n a ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, 
E 2 A. 2 7 Oct 1 9 9 4. A vail a ble fr o m: 
htt ps:// w w w.ic h. or g/filea d mi n/ P u blic _ We b _ Site/I C H _ Pr o d ucts/ G ui deli nes/ Efficac y/ E 2 A
/ Ste p 4/ E 2 A _ G ui deli ne. p df. 
2 9.  Cal vert M, Br u n da ge M, J ac o bse n P B, et  al. T he C O N S O R T patie nt -re p orte d o utc o me 
( P R O) e xte nsi o n: i m plicati o ns f or cli nical trials a n d practice. Healt h Q ual Life O utc o mes. 
2 0 1 3; 1 1: 1 8 4.  
3 0.  Her d ma n M, G u d e x C, Ll o y d A, et al. De vel o p me nt a n d preli mi nar y testi n g of t he n e w 
fi ve-le vel v ersi o n of E Q-5 D  ( E Q-5 D -5 L). Q u al Life Res. 2 0 1 1; 2 0( 1 0): 1 7 2 7 -3 6.  
3 1.  Os o ba D, R o dri g ues G, M yles J, et al. I nter preti n g t he si g nifica nce of c ha n ges i n h ealt h -
relate d q ualit y-of -life sc ores. J Cli n O nc ol. 1 9 9 8; 1 6( 1): 1 3 9-4 4.  
3 2.  U S De part me nt of Healt h a n d H u ma n Ser vices. F o o d a n d Dr u g A d mi nistr ati o n. G ui da nce 
f or I n d ustr y. E 1 4 cli nic al e val uati o n of Q T/ Q Tc i nter val pr ol o n gati o n a n d pr oarr h yt h mic 
p ote ntial f or n o n -a ntiarr h yt h mic dr u gs. O ct o ber 2 0 0 5.  
3 3.  La n K K G a n d De Mets D L. Discrete s e q ue ntial b o u n daries f or cli nical trials. Bi o metri k a. 
1 9 8 3; 7 0( 3): 6 5 9 -6 3.  
3 4.  Gli m m E, Ma urer W, Bretz F ( 2 0 1 0) Hierarc hical testi n g of m ulti ple e n d p oi nts i n gr o u p - 
se q ue ntial trials. Statist Me d; 2 9: 2 1 9-2 8 . 
3 5.  T wel ves C, C ortes J, Va h dat L, et al. Efficac y of eri b uli n i n w o me n wit h metastatic 
breast c a ncer: a p o ole d a nal ysis of t w o p h ase 3 st u dies. Breast Ca ncer Res Treat. 
2 0 1 4; 1 4 8( 3): 5 5 3 -6 1.  P u blis he d c orrecti o n a p pears i n Breast Ca ncer R es Treat. 2 0 1 5 
J a n; 1 4 9( 1): 3 1 3. 
3 6.  Ka uf ma n P A, A w a da A, T wel ves C, et al. P hase III o pe n -la bel ra n d o mize d st u d y of 
eri b uli n mes ylat e vers us ca pecita bi ne i n patie nts wit h l ocall y a d v a nce d or metastatic 
breast c a ncer pre vi o usl y treate d wit h a n a nt hrac ycli ne a n d a ta xa ne. J Cli n O nc ol. 
2 0 1 5; 3 3( 6): 5 9 4 -6 0 1.  
3 7.  T wel ves C, A wa d a A, C ortes J, et al. S u b gr o u p anal yses fr o m a P has e 3, o pe n -la bel, 
ra n d o mize d st u d y of e ri b uli n m es yl ate v ers us ca p ecita bi ne i n p retr eate d p atie nts wit h 
ad va nce d or m etastatic b reast ca ncer. Breast Ca n cer ( A uc kl). 2 0 1 6; 1 0: 7 7 -8 4.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 2  
3 8.  Yar dle y D A, Ree ves J, Dees E C, et al. Ra m ucir u m a b w it h eri b uli n v ers us eri b uli n i n 
locall y rec urre nt or m et astatic b reast ca ncer p re vi o usl y treate d w it h ant hrac ycli ne a n d 
ta x a ne thera p y: A m ultice nter, ra n d o mize d, P hase II st u d y. Cli n Breast Ca n cer. 
2 0 1 6; 1 6( 6): 4 7 1 -4 7 9.e 1.  
3 9.  Y ua n P, H u X, S u n T, et al. Eri b uli n mesilate vers us vi n orel bi ne i n w o me n wit h l ocall y 
rec urre nt or met astatic breast ca n cer: A ra n d o mise d cli nical trial. E ur J Ca ncer. 
2 0 1 9; 1 1 2: 5 7 -6 5.  
4 0.  Bar ni S, Li vra g hi L, M orritti M, et al. Eri b uli n i n t he treat me nt of a d va nce d breast 
ca ncer: real -w orl d sc e nari o fr o m 3 9 It alia n ce nt ers - E S E M P i O st u d y. F ut ur e O nc ol. 
2 0 1 9; 1 5( 1): 3 3 -4 4.  P u blis he d c orrecti o n a p p ears i n F ut ure O nc ol. 2 0 1 9 J ul; 1 5( 2 1): 2 5 5 5.  
4 1.  I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors.  Rec o m me n dati o ns f or t he c o n d uct, 
re p orti n g, e diti n g, a n d p u blicati o n of sc h olarl y w or k i n me dical j o ur nals.  D ec 2 0 1 7.  
[cite d 1 7  Se p  2 0 2 0].  A vaila ble at: htt p:// w w w.ic mje. or g/rec o m me n d ati o ns/.  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 3  
1 7.  
A P P E N DI C E S  
1 7. 1.  
Sc he d ule of E ve nts  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n 5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 4  
T a ble  1 7 .1 : 
Sc he d ule of E ve nts –  Tiss ue Scree ni n g a n d Scree ni n g Peri o d  
Visit  
Tiss ue Scree ni n g  
Scree ni n g  
Wi n d o w ( D a ys)  
 
-2 8 t o -1  
-1 4 t o -1 or as n ote d  
Pr o ce d ures  
 
 
 
Tiss ue Scree ni n g I nf or me d C o nse nt a 
● 
 
 
T u m or Tiss ue Sa m ple f or H E R 2 Stat us  
● b 
 
 
Mai n I nf or me d C o nse nt 
a 
 
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T u m or Tiss ue Bi o ps y ( ma y c ollect sa m ple a n yti me bet wee n c o m pleti o n of m ost 
rece nt treat me nt re gi me n a n d r a n d o mizati o n) 
 
● c 
 
T u m or Tiss ue Ma n dat or y E x pl orat or y  Bi o mar ker  
 
● d 
 
I ncl usi o n/ E xcl usi o n 
 
 
● 
De m o gra p hics  
 
 
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Me dical  (i ncl u di n g s m o ki n g) a n d S ur gical Hist or y (i ncl u di n g tar get disease)  
 
 
● 
P h ysical E xa mi nati o n  
 
 
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W ei g ht  
 
 
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Hei g ht  
 
 
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E C O G P S  
 
 
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A d verse E ve nts  
● e 
 
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C o nc o mita nt Me dicati o ns  
 
 
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H os pitalizati o n -relate d Rec or ds 
 
 
● 
Vital Si g ns  
 
 
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S p O 2  
 
 
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1 2 -lea d E C G i n Tri plicate f 
 
 
● 
E C H O or M U G A ( L V E F)  g 
 
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O p ht hal m ol o gic Assess me nt h 
 
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Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n 5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 5  
Visit  
Tiss ue Scree ni n g  
Scree ni n g  
Wi n d o w ( D a ys)  
 
-2 8 t o -1  
-1 4 t o -1 or as n ote d  
Pr o ce d ures  
 
 
 
T u m or Assess me nt ( C T/ M RI of t he c hest, a b d o me n, pel vis, a n d a n y ot her sites of 
disease)  i 
 
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C T/ M RI of t he Brai n  
 
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He mat ol o g y, Cli nical C he mistr y j 
 
 
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C oa g ulati o n  
 
 
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Uri nal ysis  
 
 
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Tr o p o ni n  k 
 
 
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Sa m ple f or Ser u m Bi o mar kers (e g, H E R 2 E C D , C O VI D -1 9 s er ol o g y ) a n d 
E x pl orat or y Bi o mar kers (e g, cf D N A i n plas ma)  
 
 
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HI V A nti b o d y T est (as re q uire d b y l ocal re g ulati o ns or  I R Bs/I E Cs) 
I n P ort u g al o nl y , p le ase see Secti o n 1 7. 9. 2  f or te xt a p plic a ble t o sites i n 
P ort u g al  
 
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He p atitis B / C Ser ol o g y 
 
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Pre g na nc y T est ( uri ne or ser u m) l 
 
 
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Assi g n S u bj ect I de ntificati o n N u m ber  
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P h ysicia n Selecti o n of P h ysici a n’s C h oice P ara di g m, t he n Ra n d o mizati o n  
 
 
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A E = a d verse e ve nt;  C O VI D -1 9  = c or o na vir us disease 2 0 1 9;  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 Criteria f or A d verse E ve nts;  
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 perf or ma nce stat us;   H E R 2  =  h u ma n e pi der mal 
gr o wt h fact or rece pt or 2; H E R 2 E C D  =  e xtracell ular d o mai n of H E R 2; HI V  =  h u ma n i m m u n o deficie nc y vir us; L V E F = left ve ntric ular ej ecti o n fracti o n; 
M RI  =  ma g netic res o na nce i ma gi n g; M U G A  =  m ulti gate d a c q uisiti o n (sca n); S A E = seri o us a d verse e ve nt; S p O 2  =  peri p heral o x y ge n sat urati o n.  
a Tiss ue scree ni n g i nf or me d c o nse nt m ust b e si g ne d bef ore t u m or tiss ue scree ni n g assess me nts.  T he mai n i nf or me d c o nse nt f or m m ust b e si g ne d a n d ce ntral 
H E R 2 testi n g c o nfir me d H E R 2 -l o w stat us bef ore i nitia ti n g all ot her scree ni n g assess me nts.  See  Secti o n  6. 2 . 
b Arc hi ve d t u m or tiss ue sa m ple a p pr o priate f or ce ntral la b orat or y H E R 2 testi n g.  If arc hi ve d  t u mor  tiss ue is n ot a vaila ble, a fres h t u m or tiss ue bi o ps y is re q uire d.  
A se q ue ntial scree ni n g pr ocess s h o ul d be f oll o we d.  Tiss ue scree ni n g (see Secti o n  6. 1 ) s h o ul d be c o m plete bef ore t he mai n scree ni n g pr oce d ures. 
c A t u m or tiss ue bi o ps y after t he c o m pleti o n of t he s u bj ect’s m ost rece nt treat me nt re gi me n is re q uire d f or retr os pecti ve assess me nt. If t he t u m or tiss ue pr o vi de d 
f or H E R 2 stat us testi n g was c ollecte d after c o m pleti o n of t he last treat me nt re gi me n, a n a d diti o nal ne w bi o ps y  is n ot re q uire d.  If t he t u m or tiss ue sa m ple 
pr o vi de d  f or H E R 2 stat us testi n g was c ollecte d bef ore c o m pl eti o n of t he last treat me nt re gi me n, a n a d diti o nal ne w bi o ps y  is re q uire d.  See Secti o n  6. 2   f or 
details.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n 5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 6  
d A d diti o nal  sli des are re q uire d f or e x pl orat or y bi o mar ker a nal ysis.  It is preferre d if t he sli des are fr o m t he sa me bl oc k  as t he  tiss ue sa m ple se nt f or ce ntral 
la b orat or y H E R 2 testi n g.  
e F or s u bj ects w h o si g n o nl y t he I nf or me d C o nse nt F or m f or  t u m or tiss ue scree ni n g, o nl y S A Es directl y relate d t o tiss ue s cree ni n g pr oce d ure (ie, t u m or tiss ue 
bi o ps y) will b e re p orte d.  U nless d oc u me ntati o n of ot her A Es is re q uire d b y l ocal la w, o nl y S A Es directl y relate d t o t u m or  tiss ue bi o ps y will be rec or de d d uri n g  
t u m or tiss ue scree ni n g. 
f E C G will be ta ke n i n tri plicate at scree ni n g.  S u bse q ue nt E C Gs will be perf or me d i n tri plic ate if a n a b n or malit y is n ote d.  E C Gs will be ta ke n i n cl ose 
s uccessi o n w hile i n a s u pi ne/s e mi-rec u m be nt p ositi o n.  E C Gs s h o ul d prefera bl y be perf or me d bef ore bl o o d dra ws at res pecti ve ti me p oi nts. 
g E C H O or M U G A sca n assess me nts will b e perf or me d at Scree ni n g.  N ote t hat t he sa me test m ust be use d f or t he s u bj ect t hr o u g h o u t t he st u d y. 
I n Ger m a n y o nl y , p le ase see Secti o n  1 7. 9. 3  f or te xt a p plic a ble t o sites i n Ger m a n y. 
h O p ht hal m ol o gic assess me nts i ncl u d i n g vis ual ac uit y testi n g, slit la m p e xa mi nati o n, a n d f u n d osc o p y  will be perf or me d at scree ni n g a n d E O T a n d as cli ni call y 
i n dicate d. 
i A pre vi o us t u m or assess me nt sca n perf or me d acc or di n g t o sta n dar d of care after pr o gressi o n o n t he pre vi o us treat me nt ca n be u se d if perf or me d wit hi n 2 8 da ys 
of ra n d o mizati o n re gar dless of date of si g ne d i nf or me d c o ns e nt  
j He mat ol o g y tests i ncl u de re d bl o o d cell c o u nt, he m o gl o bi n, he mat ocrit, platelet c o u nt, w hite bl o o d cell c o u nt, a n d differe ntial w hite bl o o d cell c o u nt 
( ne utr o p hils, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, bas o p hils); cli nical che mistr y tests i ncl u de t otal pr otei n, al b u mi n, al kali ne p h os p hatase, ala ni ne 
a mi n otra nsferase, as partate a mi n otra nsferase, t otal bilir u bi n, bl o o d urea nitr o ge n/ urea, calci u m, c hl ori de, ser u m creati ni ne,  lactate de h y dr o ge nase, p ot assi u m, 
s o di u m, a n d ma g nesi u m.  
k C ollect bl o o d sa m ples f or tr o p o ni n ( prefera bl y hi g h -se nsiti vit y tr o p o ni n-T) at Scree ni n g , E O T, a n d if at a n y ti me a s u bj ect re p orts si g ns or s y m pt o ms 
s u g gesti n g c o n gesti ve heart fail ure, m y ocar dial i nfarcti o n, or ot her ca uses of m y oc yte necr osis.  A n a d diti o nal sa m ple s h o ul d be s u b mitte d f or ce ntral 
la b orat or y tr o p o ni n-T testi n g, a n d perf or m E C G.  If E C G is a b n or mal, f oll o w i nstit uti o nal g ui deli nes. 
l Wit hi n 7 2 h o urs bef ore ra n d o mizati o n f or all fe male s u bj ects of c hil d beari n g p ote ntial  (criteria f or n o n-c hil d beari n g p ote n tial are defi ne d i n Secti o n 4. 1 ) ; a 
p ositi ve uri ne pre g na nc y test r es ult  m ust b e i m me diatel y c o nfir me d usi n g a ser u m test.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n 5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 7  
T a ble  1 7 .2 : 
Sc he d ule of E ve nts –  Tre at me nt a n d F oll o w -u p Peri o d  
Visit/ C ycle  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4 a n d 
S u bse q ue nt C ycles  
E ver y 6 
w ee ks  
( ± 7 d) 
 
 
L o n g -ter m
/ 
St u d y D a y ( Wi n d o w) 
D a y 1  
D a y  8  
( ± 1 d)  
D a y  1 5  
( ± 1 d) 
D a y  1 ± 2  d  
D a y  1 ± 2  d  
D a y 1 ± 2 d  
 
4 0 -
D a y  
S ur vi v al 
F/ U  
BI a 
E OI  
BI  
E OI  
BI  
E OI  
BI  
E OI  
E O T b  
F/ U c 
( ± 1 4 d)d  
Fres h T u m or T iss ue 
B i o ps ye 
 
 
 
 
 
 
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H E O R O utc o mes:  
E O R T C Q L Q -C 3 0 ,  
E O R T C Q L Q -B R 4 5,  
a n d E Q -5 D -5 L  f 
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P h ysical  
E xa mi nati o n  
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W ei g ht  
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E C O G P S  
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A d verse E ve nts  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt  
Me dicati o ns  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H os pitalizati o n - 
relate d Rec or ds  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Si g ns  i 
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S p O 2  
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1 2 -lea d E C G k 
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E C H O or M U G A  
( L V E F) l 
 
 
 
 
 
 
 
 
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O p ht hal m ol o gic  
Assess me nt m  
 
 
 
 
 
 
 
 
 
 
 
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Pre g na nc y T est n 
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Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n 5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 8  
Visit/ C ycle  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4 a n d 
S u bse q ue nt C ycles  
E ver y 6 
w ee ks  
( ± 7 d) 
 
 
L o n g -ter m
/ 
St u d y D a y ( Wi n d o w) 
D a y 1  
D a y  8  
( ± 1 d)  
D a y  1 5  
( ± 1 d) 
D a y  1 ± 2  d  
D a y  1 ± 2  d  
D a y 1 ± 2 d  
 
4 0 -
D a y  
S ur vi v al 
F/ U  
BI a 
E OI  
BI  
E OI  
BI  
E OI  
BI  
E OI  
E O T b  
F/ U c 
( ± 1 4 d)d  
He mat ol o g y &  
Bl o o d C he mistr y  
T ests o 
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C oa g ulati o n  
 
 
 
 
 
 
 
 
 
 
 
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Tr o p o ni n p 
 
 
 
 
 
 
 
 
 
 
 
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P K Bl o o d  
( Ser u m) Sa m ple o nl y 
f or T -D X d  Ar m  
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P K Sa m pli n g f or 
C Q/ H C Q 
A d mi nistrati o n b b 
If C Q or H C Q is a d mi nistere d f or C O VI D-1 9, a d diti o nal P K bl o o d sa m ples s h o ul d be c ollecte d at 
t he f oll o wi n g visits: 
• 
Pri or t o t he first C Q or H C Q d ose ( Da y 1)  
• 
Da y 3 or Da y 4 of C Q or H C Q treat me nt, pri or t o C Q or H C Q  d ose ( wit hi n 4 h)  
• 
Last da y of t he C Q/ H C Q treat me nt pri or t o C Q/ H C Q d ose ( wit hi n 4 h)  
T he da y of T -D X d  res u m pti o n, after t he C Q/ H C Q was h o ut p eri o dcc, ( wit hi n 8 h BI of T -D X d ) 
 
 
 
A D A Bl o o d Sa m ple  
o nl y f or T -D X d  Ar m  
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Ser u m B i o mar kers  
(e g, H E R 2 E C D, 
C O VI D -1 9 ser ol o g y d d)  
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E x pl orat or y  
Bi o mar ker  
Bl o o d Sa m ples w  
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P har mac o ge n o mics  
Bl o o d Sa m ple x 
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Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n 5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 9  
Visit/ C ycle  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4 a n d 
S u bse q ue nt C ycles  
E ver y 6 
w ee ks  
( ± 7 d) 
 
 
L o n g -ter m
/ 
St u d y D a y ( Wi n d o w) 
D a y 1  
D a y  8  
( ± 1 d)  
D a y  1 5  
( ± 1 d) 
D a y  1 ± 2  d  
D a y  1 ± 2  d  
D a y 1 ± 2 d  
 
4 0 -
D a y  
S ur vi v al 
F/ U  
BI a 
E OI  
BI  
E OI  
BI  
E OI  
BI  
E OI  
E O T b  
F/ U c 
( ± 1 4 d)d  
A d mi nister St u d y  
Treat me nt, as  
A p pr o priate y 
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T u m or  
Assess me nt y, z 
 
 
 
 
 
 
 
 
 
 
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C T/ M RI of t he  
Brai n y, aa 
 
 
 
 
 
 
 
 
 
 
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S ur vi val F oll o w -u p  
 
 
 
 
 
 
 
 
 
 
 
 
 
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A D A = a nti -dr u g a nti b o d y ; BI =  bef ore i nf usi o n  or d osi n g ; cf D N A =  cell free de o x yri b o n ucleic aci d;  C O VI D -1 9 = c or o na vir us disease 2 0 1 9;  C Q  =   c hl or o q ui ne ; 
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 Criteria f or A d verse E ve nts;  d  =  da y; E C H O  =  ec h ocar di o gra m; E C G  =  electr ocar di o gra m; 
E C O G P S  =  Easter n C o o perati ve O nc ol o g y Gr o u p perf or ma nce stat us; E OI  =  e n d of i nf usi o n  or d osi n g ; E O R T C Q L Q  =  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 q uesti o n naire; E Q -5 D -5 L  =  E ur o Q o l 5 di me nsi o ns  5 le vels  [of se verit y ]; E O T =  e n d of treat me nt; F/ U  =  f oll o w-u p ; 
H C Q  =   h y dr o x yc hl or o q ui ne;  H E O R  =  Healt h Ec o n o mics a n d O utc o mes  Researc h ; H E R 2 =  h u ma n e pi der mal gr o wt h fa ct or rece pt or 2; 
H E R 2 E C D  =  e xtracell ular d o mai n of H E R 2;  I L D =  i nterstitial l u n g disease; L V E F  =  left ve ntric ular ej ecti o n fracti o n; m R E CI S T = m o difie d Res p o nse 
E val uati o n Criteria i n S oli d T u m ors; M RI  =  ma g netic res o na nce i ma gi n g; M U G A =  m ulti gate d ac q uisiti o n (sca n); P K  =  p har mac o ki netic; S p O 2  =  peri p heral 
o x y ge n sat urati o n.  
a First d ose at C ycle 1 Da y 1 s h o ul d occ ur wit hi n 7 da ys after t he date t he s u bj ect is ra n d o mi ze d.  
b All assess me nts re q uire d as part of E O T  m ust occ ur wit hi n 7 da ys fr o m t he date t he I n vesti gat or deci des t o disc o nti n ue st u d y treat me nt.   See Secti o n  6. 5   f or 
w het her ne w tests nee d t o be c o n d ucte d.  
c 4 0 da ys ( +7 da ys) after t he last st u d y dr u g a d mi nistrati o n or bef ore starti n g ne w a ntica ncer treat me nt, w hic he ver c o mes first.  See Secti o n  6. 6. 1   t o deter mi ne 
w het her ne w tests nee d t o be c o n d ucte d.  If E O T assess me nts oc cur  > 4 0 da ys ( +7 da ys) aft er last treat me nt, t he n t he E O T assess me nts ca n als o f u ncti o n as t he 
4 0 -Da y ( +7 da ys) F oll o w -u p assess me nts . 
d L o n g -ter m/ S ur vi val F oll o w-u p visits will be perf or me d e ver y 3 m o nt hs ( ± 1 4 da ys) fr o m t he date of 4 0 -Da y (+ 7 da ys) F oll o w -u p assess me nts u ntil d eat h, 
wit h dra wal of c o nse nt, l oss t o f oll o w -u p, or st u d y cl os ure, w hic he ver occ urs first.  
e P artici pati o n is o pti o nal f or all s u bj ects.  T he o pti o nal fres h t u m or tiss ue bi o ps y d uri n g treat me nt s h o ul d be perf or me d at C ycle 3 Da y 1 ( ± 7 da ys) a n d E O T . 
f D o ne  at C ycle 1, C ycle 2, a n d C ycle 3 a n d t he n  e ver y 2 c ycl es  (e g, C ycles 5, 7, 9 , etc) d uri n g t he treat me nt p eri o d.  S u bject m ust c o m plete t he H E O R o utc o mes 
q uesti o n naires bef ore a n y ot her assess me nts or pr oce d ures are d o ne  o n t he da y of cli nic visit . 
g P erf or me d o nl y 3 m o nt hs after t he 4 0 -Da y ( +7 da ys) F oll o w -u p assess me nts . 
h Wit hi n 7 2 h o urs bef ore a d mi nistrati o n.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n 5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3 0  
i Vital si g ns a n d S p O 2 will be d o ne at all c ycles bef ore a n d aft er a n i nf usi o n.  F or t he c o m parat or ar m, vital si g ns a n d  S p O 2  is re q uire d o nl y at Da y 1 of eac h 
c ycle .  F or ca pecita bi ne, n o e n d of i nf usi o n assess me nt is re q uire d.  
j T -D X d  ar m o nl y  
k At C ycle 1  D a y 1 f or T -D X d  s u bj ects o nl y, rec or d E C G 5 hr ( ± 2 h r) after start of dr u g a d mi nistrati o n.  If at a n y ti me d uri n g t he st u d y a n a b n or malit y is n ote d, 
perf or m E C G . E C Gs will be t a ke n i n cl ose s uccessi o n w hile s u bj ect is i n a s u pi ne/se mi -rec u m be nt p ositi o n.  E C Gs s h o ul d  prefera bl y  be perf or me d bef ore 
bl o o d dra ws at res pecti ve ti me p oi nts . 
l F or E C H O or M U G A sca n ass ess me nts  (N ote:  T he sa me test m ust be use d f or t he s u bj ect t hr o u g h o ut t he st u d y) will be perf or me d BI o n Da y 1 of e ver y 4 
c ycles ( ± 7 da ys ) ( C ycle 5, 9, 1 3, etc) . 
I n Ger m a n y o nl y , p le ase see Secti o n 1 7. 9. 3  f or te xt a p plic a ble t o sites i n Ger m a n y. 
m  O p ht hal m ol o gic assess me nts i ncl u d i n g vis ual ac u it y testi n g, slit la m p e xa mi nati o n, a n d f u n d osc o p y will be perf or me d at scree ni n g a n d E O T a n d as cli nicall y 
i n dicate d. 
n F or fe male s u bj ects of c hil d beari n g p ote ntial, perf or m a uri ne or ser u m pre g na nc y test.  A p ositi ve uri ne pre g na nc y test r es u lt m ust i mme diatel y be c o nfir me d 
usi n g a ser u m test.   M ust b e perf or me d wit hi n 7 2 h o urs of dr u g a d mi nistrati o n.  
o La b orat or y tests: He mat ol o g y tests i ncl u de re d bl o o d cell c o u nt, he m o gl o bi n, he mat ocrit, platelet c o u nt, w hite bl o o d cell c o u nt, a n d differe nti al w hite bl o o d 
cell c o u nt ( ne utr o p hils, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, bas o p hils), a n d c he mistr y tests i ncl u de t otal pr otei n, al b u mi n,  al kali ne p h os p hatase, ala ni ne 
a mi n otra nsferase, as partate a mi n otra nsferase, t otal bilir u bi n, bl o o d urea nitr o ge n/ urea, calci u m, c hl ori de, ser u m creati ni ne, lactate de h y dr o ge nase, p ot assi u m, 
s o di u m, a n d ma g nesi u m. 
p C ollect bl o o d sa m ples f or tr o p o ni n ( prefera bl y hi g h -se nsiti vit y tr o p o ni n-T) at Scree ni n g, E O T, a n d if at a n y ti me a s u bj ect re p orts si g ns or s y m pt o ms 
s u g gesti n g c o n gesti ve heart fail ure, m y ocar dial i nfarcti o n ( MI), or ot her ca uses of m y oc yte necr osis.  A n a d diti o nal sa m ple s h o ul d be s u b mit te d f or ce ntral 
la b orat or y tr o p o ni n-T testi n g.   P erf or m E C G.   If E C G is a b n or mal, f oll o w i nstit uti o nal g ui deli nes. 
q F or T -D X d  s u bjects o nl y, P K sa m ples s h o ul d be o btai ne d wit hi n 8 h o urs BI o n Da y 1 of C ycles 1, 2, 3, 4, 6, a n d 8.   
r F or T -D X d  s u bj ects o nl y, prefera bl y w it hi n 1 5 mi n utes or as s o o n as p ossi ble  after  E OI o n Da y 1 of C ycles 1, 2, 3, 4, 6, a n d 8.   
s F or T -D X d  s u bj ects o nl y, 5 h o urs ( ± 2 h o urs) after t he start of dr u g a d mi nistrati o n.  
t F or T -D X d  s u bj ects o nl y, A D A sa m ples s h o ul d be ta ke n wit hi n 8 h o urs BI o n Da y 1 i n C ycles 1, 2, a n d 4, a n d t he n e ver y 4 c ycles ( C ycles 8, 1 2, 1 6, etc)  
u F or s u bj ects wit h p ositi ve A D A at t h e 4 0 -Da y (+ 7 da ys) F/ U assess me nt , a d diti o nal ser u m A D A sa m ples ma y be c ollecte d e ver y 3 m o nt hs ( ± 1 m o nt h) u p t o 1 
year fr o m t he last d ose of st u d y dr u g, u ntil t he A D A bec o mes ne gati ve, u ntil t he A D A titer bec o mes less t ha n baseli ne (a p plic a ble w he n pre -e xisti n g A D A is 
o bser ve d), u ntil t he s u bj ect starts a n ot her t hera p y f or ca ncer or wit h dra ws c o nse nt fr o m t he st u d y, w hic he ver occ urs first.  
v B ef ore a d mi nistrati o n at e ver y 2 c ycles fr o m C ycle 3 ( C ycle 3, 5, 7, 9, etc).  
w  Sa m ples will be c ollecte d at C ycle 1 a n d t he n e ver y 3 c ycles ( C ycles 4, 7, etc) u ntil E O T f or e x pl orat or y bi o mar kers s uc h us cf D N A i n plas ma.  
x A si n gle bl o o d sa m ple f or p har mac o ge n o mics a nal ysis will be c ollecte d fr o m eac h s u bj ect w h o c o nse nts t o t his test, pre d ose o n  Da y 1 of C ycle 1  Da y 1.  
P artici pati o n i n t his part of t he st u d y is o pti o nal f or all s u bj ects.   
y T -D X d  is t o be a d mi nistere d e ver y 2 1 da ys ± 2 da ys u nless d ose i nterr u pti o n/ m o dificati o n or disc o nti n uati o n is re q uire d.   F or t he c o ntr ol treat me nt ar m, if a 
s u bj ect recei ves a c o m parat or wit h a re gi me n ot her t ha n  a 2 1 -da y  c ycle , t he I n vesti gat or s h o ul d e ns ure t hat t he s u bj ect f oll o ws t he st u d y-defi ne d S c he d ule of 
E ve nt s per a 2 8 -da y c ycle. H o we ver,  tu m or assess me nts a n d C T/ M RI of t he b rai n m ust be perf or me d e ver y 6 wee ks + 7 d a ys fr o m ra n d o mizati o n date. 
La b orat or y a n d safet y assess me nt b ef ore dr u g a d mi nistrati o n s h o ul d be a p pr o priatel y perf or me d acc or di n g t o la bel a p pr o ve d i n t he c o u ntr y of dr u g 
a d mi nistrati o n. 
z If a s u bj ect disc o nti n ues treat me nt f or reas o ns ot her t ha n disease pr o gressi o n  or deat h , e ver y atte m pt s h o ul d be ma d e t o c ollect t u m or assess me nts u ntil disease 
pr o gressi o n a n d t he sca ns be s e nt f or ce ntral re vie w e ve n if t he s u bj ect has starte d a n ot her a nti -ne o plastic t hera p y .  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n 5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3 1  
aa C T or M RI of t he brai n is ma n dat or y f or all s u bj ects w h o were e nr olle d wit h baseli ne sta bl e brai n metastases.  S u bj ects wit h o ut brai n metastases d o n ot  nee d 
a d diti o nal brai n sca ns f or t u m or assess me nt u nless cli nicall y i n dicate d.   C T/ M RI will be perf or me d e ver y 6 wee ks ± 7 da ys  fr o m ra n d o mizati o n date, a n d at 
E O T.  
b b  If s u bj ect pr o vi des c o nse nt, sa m ples s h o ul d be c ollecte d. 
cc A  was h o ut p eri o d of m ore t ha n 1 4 d a ys si nce last d ose of C Q/ H C Q is re q uire d bef ore restarti n g T -D X d .  See Secti o n 1 7. 8 . 
d d  If s u bj ect pr o vi des c o nse nt, sa m ples s h o ul d be c ollecte d pri or t o st u d y dr u g i nf usi o n.  F or s u bj ects wit h s us pecte d or c o nfir me d C O VI D -1 9, f oll o w t he d ose 
m o dificati o ns i n Secti o n  1 7. 8 . 
ee C O VI D -1 9 ser ol o g y testi n g t o be perf or me d starti n g at C ycl e 5, Da y 1 a n d e ver y 4 c ycles t hereafter . 
F or s us pecte d I L D/ p ne u m o nitis, treat me nt wit h st u d y dr u g s h o ul d be i nterr u pte d pe n di n g e val uati o n.   
E val uati o ns s h o ul d i ncl u de:  
 
H i g h res ol uti o n C T 
 
P ul m o n ol o gist c o ns ultati o n  (infecti o us d isease c o ns ultati o n as cli nicall y i n dicate d)  
 
Bl o o d c ult ure a n d C B C . Ot her bl o o d  tests c o ul d be c o nsi dere d as nee de d 
 
C o nsi der br o nc h osc o p y a n d br o nc h oal ve olar la va ge if cli nic all y i n dicate d a n d feasi ble  
 
P ul m o nar y f u ncti o n tests a n d p ulse o xi metr y ( S p O 2)  
 
A rterial bl o o d gases if cli nicall y i n dicate d 
 
O ne bl o o d sa m ple c ollect i o n f or P K (ce ntral la b orat or y) a nal ysis as s o o n as I L D/ p ne u m o nitis is s us pecte d, if feasi ble.   
Ot her tests c o ul d be c o nsi dere d, as nee de d.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3 2  
1 7. 2.  
C oc kcr oft -G a ult E q u ati o n  
T he esti mate d creati ni ne cleara nce ( Cr Cl) rate ( m L/ mi n) will be calc ulate d usi n g t he 
C oc kcr oft -G a ult e q uati o n base d o n act u al wei g ht ( 1  kil o gra m = 2. 2 p o u n ds):  
C o n ve nti o n al –  ser u m cre ati ni ne i n m g/ d L: 
Male:  
Cr Cl ( m L/ mi n) = 
7 2
 x 
mg/ d L)
(in 
 
creatinine
 
ser u m
k g)
(in 
 x weight 
years)]
(in 
 
a ge
 - 
[ 1 4 0
 
Fe male:  
Cr Cl ( m L/ mi n) = 
7 2
 x 
mg/ d L)
(in 
 
creatinine
 
ser u m
k g)
(in 
 x weight 
years)]
(in 
 
a ge
 - 
[ 1 4 0
  0. 8 5  
 
I nter n ati o n al S yste m of U nits –  ser u m cre ati ni ne i n μ m ol/ L: 
Male:  
Cr Cl ( m L/ mi n) = 
0. 0 1 1 3
 x 
7 2
 x 
mol/ L)
(in 
 
creatinine
 
ser u m
k g)
(in 
 x weight 
years)]
(in 
 
a ge
 - 
[ 1 4 0

 
Fe male:  
Cr Cl ( m L/ mi n) = 
0. 0 1 1 3
 x 
7 2
 x 
mol/ L)
(in 
 
creatinine
 
ser u m
k g)
(in 
 x weight 
years)]
(in 
 
a ge
 - 
[ 1 4 0

  0. 8 5  
 
S o urce: C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m ser u m creati ni ne. Ne p hr o n . 
1 9 7 6; 1 6: 3 1 -4 1.  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3 3  
1 7. 3.  
Ne w Y or k He art Ass oci ati o n  
T a ble  1 7 .3 : 
Ne w Y or k He art Ass oci ati o n F u ncti o n al Cl assific ati o n  
F u ncti o n al C a p acit y  
O bjecti ve Assess me nt  
Cl ass I.  Patie nts wit h car diac disease b ut wit h o ut res ulti n g li mitati o n of 
p h ysical acti vit y.  Or di nar y p h ysical acti vit y d oes n ot ca use u n d ue 
fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n. 
A.  N o o bj ecti ve e vi de nce 
of car di o vasc ular disease.  
Cl ass II.  Patie nts w it h car diac disease res ulti n g i n sli g ht li mitati o n of 
p h ysical acti vit y.  T he y are c o mf orta ble at rest.  Or di nar y p h ysical 
acti vit y res ults i n fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n.  
B.  O bjecti ve e vi de nce of 
mi ni mal car di o vasc ular 
disease.  
Cl ass III. Patie nts wit h car diac disease res ulti n g i n mar ke d li mitati o n of 
p h ysical acti vit y.  T he y are c o mf orta ble at rest.  Less t ha n or di nar y 
acti vit y ca uses fati g ue, pal pitati o n, d ys p nea, or a n gi nal pai n.  
C.  O bjecti ve e vi de nce of 
m o deratel y se vere 
car di o vasc ular disease.  
Cl ass I V.  Patie nts wit h car diac disease res ulti n g i n i na bilit y t o carr y o n 
a n y p h ysical acti vit y wit h o ut disc o mf ort.  S y m pt o ms of heart fail ure or 
t he a n gi nal s y n dr o me ma y be prese nt e ve n at rest.  If a n y p h ysical 
acti vit y is u n derta ke n, dis c o mf ort is i ncrease d.  
D.  O bjecti ve e vi de nce of 
se vere car di o vasc ular 
disease.  
S o urce: A merica n heart Ass ociati o n. Classificati o n of F u ncti o nal Ca pacit y a n d O bj ecti ve Assess me nt. A vaila ble 
fr o m: 
htt p:// m y.a merica n heart. or g/ pr ofessi o nal/ State me nts G ui deli nes / B y P u blicati o n Date/ Pre vi o us Years/ Classificati o n-of -
F u ncti o nal -Ca p acit y -a n d -O bj ecti ve -Assess me nt _ U C M _ 4 2 3 8 1 1 _ Article.js p   
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3 4  
1 7. 4.  
E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a nce St at us  
T a ble  1 7 .4 : 
E aster n C o o per ati ve O nc ol o g y Gr o u p Perf or m a nce St at us Sc ale Gr a de 
Descri pti o n  
0  
N or mal acti vit y.  F ull y acti ve, a ble t o carr y o n all pre disease perf or ma nce wit h o ut restricti o n.  
1  
S y m pt o ms, b ut a m b ulat or y.  Restricte d i n p h ysicall y stre n u o us acti vit y, b ut a m b ulat or y a n d 
a ble t o carr y o ut w or k of a li g ht or se de ntar y nat ure (e g, li g ht h o use w or k, office w or k).  
2  
I n be d < 5 0 % of t he ti me.  A m b ulat or y a n d ca pa ble of all self-care, b ut u na ble t o carr y o ut a n y 
w or k acti vities.  U p a n d a b o u t m ore t ha n 5 0 % of wa ki n g h o urs. 
3  
I n be d > 5 0 % of t he ti me.  Ca pa ble of o nl y li mite d self-care, c o nfi ne d t o be d or c hair m ore t ha n 
5 0 % of wa ki n g h o urs.  
4  
1 0 0 % be dri d de n.  C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -care.  T otall y c o nfi ne d t o be d 
or c hair. 
5  
Dea d.  
S o urce:  O ke n M M, Creec h R H, T or me y D C, et al. T o xicit y a n d res p o nse criteria of t he E aster n C o o perati ve 
O nc ol o g y Gr o u p. A m J Cli n O nc ol. 1 9 8 2; 5( 6): 6 4 9 -5 5.  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3 5  
1 7. 5.  
M o difie d Res p o nse E v al u ati o n Criteri a i n S oli d T u m ors ( versi o n 1. 1)  
1 7. 5. 1.  
Me as ur a bilit y of T u m or at B aseli ne  
1 7. 5. 1. 1.  Defi niti o ns  
At baseli ne, t u m or lesi o ns/l y m p h n o d es will be cat e g orize d meas ura bl e or n o n -meas ura bl e as 
f oll o ws: 
1 7. 5. 1. 1. 1.   
M e as ur a ble  
 T u m or lesi o ns: M ust be acc urat el y m eas ure d i n at least 1 di me nsi o n (l o n gest dia meter 
i n t he pla ne of meas ure m e nt is t o be rec or de d) wit h a mi ni m u m size of: 
 1 0 m m b y c o m p ute d t o m o gra p h y ( C T )/ ma g netic res o na nce i ma gi n g ( M RI) sca n 
( C T sca n slice t hic k ness n o greater t ha n 5 m m). 
 Meas ura ble m ali g n a nt l y m p h n o des: T o be c o nsi dere d pat h ol o gicall y e nlar ge d a n d 
meas ura ble,  a l y m p h n o d e m ust be ≥1 5 m m i n s h ort a xis w he n assesse d b y C T sca n 
( C T sca n slice t hic k ness rec o m me n de d t o b e n o greater t ha n 5 m m).  At bas eli ne a n d 
i n f oll o w-u p  (ie, all o n-st u d y meas ure me nts), o nl y t he s h ort a xis will be meas ure d a n d 
f oll o we d.  See also n otes bel o w o n “Baseli ne d o c u me ntati o n of tar get a n d n o n -tar get 
lesi o ns” f or i nf or mati o n o n l y m p h n o de meas ure me nt. 
1 7. 5. 1. 1. 2.   
N o n -me as ur a ble  
All ot her lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter < 1 0 m m or pat h ol o gical l y m p h n o des 
wit h ≥1 0 t o < 1 5 m m s h ort a xis) , as well as tr ul y n o n -meas ura bl e lesi o ns  are c o nsi dere d n o n -
meas ura ble .  Lesi o ns c o nsi dere d tr ul y n o n -meas ura ble i ncl u de: le pt o me ni n geal disease, ascites, 
ple ural or pericar dial eff usi o n, i nfla m mat or y breast disease, l y m p ha n gitic i n v ol ve me nt of s ki n or 
l u n g, a n d a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d b y p h ysi cal e xa m i nati o n t hat is 
n ot meas ura b le b y re pr o d uci ble i ma gi n g tec h ni q ues. 
1 7. 5. 1. 1. 3.   
S peci al C o nsi der ati o ns Re g ar di n g Lesi o n Me as ur a bilit y  
B o ne lesi o ns, c ystic lesi o ns, a n d lesi o ns pre vi o usl y treate d wit h l ocal t hera p y re q uire p artic ular 
c o m me nt:  
1 7. 5. 1. 1. 3. 1.  B o ne lesi o ns  
B o ne sca n, p ositr o n e missi o n t o m o gra p h y sca n or plai n fil ms are n ot c o nsi d ere d a d e q uate 
i ma gi n g tec h ni q u es t o meas ure b o n e lesi o ns.  H o we ver, t hes e tec h ni q u es ca n be use d t o c o nfir m 
t he prese n ce or disa p p eara nce of b o n e lesi o ns. 
L ytic b o ne l esi o ns or mi xe d l ytic -bl astic lesi o ns, wit h i de ntifia ble  s oft tiss ue c o m p o ne nts, t hat 
ca n be e val uate d b y cr oss secti o nal i ma gi n g tec h ni q ues s uc h as C T or M RI ca n be c o nsi dere d as 
meas ura ble l esi o ns if t he s oft tiss ue c o m p o ne nt meets t he defi niti o n of meas ura bilit y des cri be d 
a b o ve.  
Blastic b o ne lesi o ns are n o n -meas ura bl e.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3 6  
1 7. 5. 1. 1. 3. 2.  C ystic lesi o ns  
Lesi o ns t hat me et t he crit eria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d n ot be c o nsi dere d 
as mali g na nt lesi o ns ( neit her meas ur a ble n or n o n -meas ura ble) si nce t he y are, b y d efi niti o n, 
si m ple c ysts. 
‘ C ystic lesi o ns’ t h o u g ht t o re pres e nt c ystic metast ases ca n b e c o nsi dere d as meas ura ble l esi o ns, 
if t he y me et t he defi niti o n of meas ura bilit y descri be d a b o ve.  H o we ver, if n o n-c ystic lesi o ns are 
prese nt i n t he sa me s u bject, t hese are preferre d f or selecti o n as tar get lesi o ns.  
1 7. 5. 1. 1. 3. 3.  Lesi o ns wit h pri or l oc al tre at me nt  
T u m or lesi o ns sit uate d i n a pre vi o usl y irra di ate d area, or i n a n area s u bjecte d t o ot her l oc o -
re gi o nal t hera p y, are n ot c o nsi dere d meas ura bl e u nless t here has b ee n de m o nstrate d pr o gressi o n 
i n t he lesi o n si nce t he t hera p y. 
1 7. 5. 1. 2.  S pe cific ati o ns b y Met h o ds of Me as ure me nts  
1 7. 5. 1. 2. 1.   
M e as ure me nt of Lesi o ns  
All meas ure me nts s h o ul d be rec or de d i n metric n otati o n.  All baseli ne e val uati o ns s h o ul d be 
perf or me d as cl ose as p ossi ble t o t he treat me nt start a n d N E V E R m ore t ha n 4 w eek s bef ore 
ra n d o mizati on . 
1 7. 5. 1. 2. 2.   
M et h o d of Assess me nt  
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue s h o ul d be use d t o c 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.  I ma gi n g base d e val uati o n s h o ul d 
al wa ys be d o n e rat her t ha n cli nical e x a mi nat i o n. 
C T, M RI:  C T is t he best c urre ntl y a v aila ble a n d re pr o d uci ble met h o d t o m eas ure l esi o ns 
selecte d f or res p o ns e ass ess me nt.  T his g ui deli ne has defi 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 or less.  W he n C T sca ns  ha ve slice 
t hic k ness greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice 
t hic k ness.  T he M RI is als o acce pt a ble i n certai n sit uati o ns (e g , f or b o d y sca ns). 
1 7. 5. 2.  
T u m or R es p o nse E v al u ati o n  
1 7. 5. 2. 1.  Assess me nt of O ver all T u m or B ur de n a n d Me as ur a ble Dise ase  
T o assess o bjecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y t o esti mat e t he o verall t u m or 
b ur de n at bas eli ne a n d us e t his as a c o m parat or f or s u bse q ue nt meas ure me nts.  
I n t his st u d y, o nl y s u bjects wit h meas ura ble diseas e at baseli ne s h o ul d be i n cl u de d i n t he st u d y. 
1 7. 5. 2. 2.  B aseli ne D oc u me nt ati o n of ‘ T ar get’ a n d ‘ N o nt ar get’ Lesi o ns  
W he n m ore t ha n 1 meas ura ble lesi o n is prese nt at baseli ne all lesi o ns u p t o a t otal of 2  lesi o ns 
per or ga n a n d a ma xi m u m of 5 lesi o ns t otal (re prese ntati ve of all i n v ol ve d or ga ns, wit h a 
ma xi m u m of 2 per or ga n) s h o ul d be i de ntifie d as t ar get lesi o ns a n d will be rec or de d a n d 
meas ure d at baseli ne (t his mea ns i n i nsta nces w here s u bjects ha v e o nl y 1 or 2 or ga n sites 
i n v ol ve d a ma xi m u m of 2 a n d 4 lesi o ns res pecti vel y will be rec or de d).  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3 7  
Tar get lesi o ns s h o ul d be selecte d o n t he b asis of t heir size (lesi o ns wit h t he l o n gest dia meter), be 
re pres e ntati ve of all i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o 
re pr o d uci ble re peate d meas ure me nts.  It ma y b e t he case t h at, o n occasi o n, t he lar gest lesi o n d oes 
n ot le n d itself t o re pr o d uci ble meas ur e me nt i n w hic h circ u msta nce t he ne xt lar gest lesi o n t hat 
ca n be me as ure d re pr o d uci bl y s h o ul d be sel ecte d.  
L y m p h n o des merit s peci al me nti o n si nce t he y are n or ma l a nat o mical str uct ures t hat ma y be 
visi ble b y i ma gi n g e ve n if n ot i n v ol ve d b y t u m or.  As n ote d a b o ve, p at h ol o gical n o des t hat are 
defi ne d as me as ura bl e a n d ma y b e i de ntifie d as tar get lesi o ns m ust meet t he criteri o n of a s h ort 
a xis of ≥1 5 m m b y C T sca n.  O nl y t h e s h ort a xis of t hese n o des will c o ntri b ute t o t he baseli ne 
s u m of lesi o n dia meters .  T he s h ort a xis of t he n o de is t he dia meter n or m all y use d b y ra di ol o gists 
t o j u d ge if a n o d e is i n v ol ve d b y s oli d t u m or.  N o d al size is n or mall y re p ort e d as 2 di me nsi o ns i n 
t he pla ne i n w hic h t he i m a ge is o btai ne d (f or C T sca n t his is al m ost al wa ys t he a xial pla ne; f or 
M RI t he pla n e of ac q uisiti o n ma y be a xial, sa gittal , or c or o nal).  T he s maller of t hese meas ures is 
t he s h ort a xis.  F or e x a m ple, a n a b d o mi nal n o de t hat is re p orte d as b ei n g 2 0 m m × 3 0 m m has a 
s h ort a xis of 2 0 m m a n d q ualifies as a mali g na nt, meas ura ble n o de.  I n t his e x a m ple, 2 0  m m 
s h o ul d be rec or de d as t he n o de meas ure me nt.  U p t o 2 n o dal tar get lesi o ns ca n be rec or de d.  All 
ot her pat h ol o gi cal n o des (t h ose wit h s h ort a xis ≥1 0 m m b ut < 1 5 m m) s h o ul d be c o nsi dere d n o n -
tar get lesi o ns.  N o des t hat ha ve a s h ort a xis < 1 0 m m are c o nsi dere d n o n -p at h ol o gical a n d s h o ul d 
n ot be rec or de d . 
A s u m of t he dia meters (l o n gest dia met er f or n o n-n o dal lesi o ns, s h ort -a xis dia meter f or n o d al 
lesi o ns) f or all tar get lesi o ns will be calc ulate d a n d re p orte d as t he baseli ne s u m of dia meters.  If 
l y m p h n o des are t o be i n cl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o 
t he s u m.  T he baseli ne s u m of dia mete rs will be us e d as refere nce t o f urt her c haracterize a n y 
o bjecti ve t u m or re gressi o n i n t he meas ura ble di me nsi o n of t he disease.  
All ot her lesi o ns ( or sites of disease) i n cl u di n g p at h ol o gical l y m p h n o des s h o ul d be i de ntifie d as 
n o n -tar get lesi o ns a n d s h o ul d als o be rec or de d at baseli ne.  Meas ure me nts are n ot r e q uire d a n d 
t hese lesi o ns s h o ul d be f oll o we d as “prese nt, ” “a bse nt, ” or i n rare cases “ u ne q ui v ocal 
pr o gressi o n. ”  I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n -tar get lesi o ns i n v ol vi n g t he sa me 
or g a n as a si n gle ite m o n t he case re p ort f or m (e g, ‘ m ulti ple e nlar ge d pel vic l y m p h n o des’ or 
‘ m ulti ple li ver metastases’). 
1 7. 5. 2. 3.  Res p o nse Criteri a  
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne o bjecti ve t u m or res p o nse 
f or tar get lesi o ns. 
1 7. 5. 2. 4.  E v al u ati o n of T ar get Lesi o ns  
C o m plete Res p o nse ( C R):  Disa p peara nce of all tar get lesi o ns.  A n y pat h ol o gical l y m p h n o des 
( w het her t ar get or n o n -tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m. 
Partial Res p o nse ( P R): At least a 3 0 % decrease i n t he s u m o f dia meters of t ar get lesi o ns, ta ki n g 
as refere n ce t he b aseli ne s u m dia meters.  
Pr o gressi ve Diseas e ( P D): At least a 2 0 % i ncrease i n t he s u m of dia meters of tar get lesi o ns, 
ta ki n g as refere n ce t he s mallest s u m o n st u d y (t his i ncl u des t he baseli ne s u m if t hat is t he 
s mallest o n st u d y).  I n a d diti o n t o t he relati ve i ncrease of 2 0 %, t he s u m of dia meters m ust als o 

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de m o nstrate a n a bs ol ute i ncreas e of at least 5 m m . (N ote:  T he a p p eara nce of o ne or m ore ne w 
lesi o ns is als o c o nsi dere d pr o gressi o n.) 
Sta ble Disease ( S D): N eit her s ufficie nt s hri n k a ge t o q ualif y f or P R  (ta ki n g as refere n ce t he s u m 
of dia meters at b aseli ne)  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 
s mallest s u m of dia meters w hile o n st u d y ). 
1 7. 5. 2. 4. 1.   
S peci al N otes o n t he Assess me nt of T ar g et Lesi o ns  
L y m p h n o des: L y m p h n o des i de ntifie d as tar get lesi o ns s h o ul d al wa ys ha v e t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa m e a n at o mical pla ne as t he b as eli ne e x a mi nati o n), 
e ve n if t he n o des re gress t o bel o w 1 0 m m o n st u d y.  T his mea ns t hat w he n l y m p h n o des are 
i ncl u de d as tar get lesi o ns, t he ‘s u m’ of lesi o ns ma y n ot be zer o e ve n if C R criteria are met, si nce 
a n or mal l y m p h n o d e is defi ne d as h a vi n g a s h ort a xis of < 1 0  m m.  F or P R, S D, a n d P D, t he 
act ual s h ort a xis meas ure me nt of t he n o des is t o be i ncl u de d i n t he s u m of t ar get lesi o ns.  
Tar get lesi o ns t hat bec o me ‘t o o s mall t o meas ure’:  W hile o n st u d y, all lesi o ns ( n o dal a n d n o n -
n o dal) rec or de d at baseli ne s h o ul d ha ve t heir act u al meas ure m e nts rec or de d at eac h s u bs e q ue nt 
e val uati o n, eve n w he n ver y s mall (e g, 2 m m).  H o we ver, s o meti mes lesi o ns or l y m p h n o des t hat 
are rec or de d as tar get lesi o ns at baseli ne bec o me s o fai nt o n C T sca n t hat t h e ra di ol o gist ma y n ot 
feel c o mf orta ble assi g ni n g a n e x act meas ure a n d ma y re p ort t he m as b ei n g ‘t o o s mall t o 
meas ure .’  W he n t his occ urs, it is i m p orta nt t hat a val ue be rec or de d o n t he e C R F.  If it is t he 
o pi ni o n of t he ra di ol o gist t hat t he lesi o n has li kel y disa p peare d, t he meas ure me nt s h o ul d be 
rec or de d as 0 m m.  If t he lesi o n is belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o 
meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d ( N ote:  It is less u nli kel y t hat t his r ule will 
be use d f or l y m p h n o des si nce t he y us uall y ha ve a defi na ble size w he n n or mal a n d are fre q u e ntl y 
s urr o u n de d b y fat s uc h as i n t he retr o-perit o ne u m; h o we ver, if a l y m p h n o d e is belie ve d t o be 
prese nt a n d is f ai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m s h o ul d be assi g ne d 
i n t his circ u msta nce as w ell.  T his defa ult val ue is deri ve d fr o m t he 5 m m C T slice t hic k ness ( b ut 
s h o ul d n ot be c ha n ge d wit h var yi n g C T slice t hic k ness.)  T he meas ure me nt of t hese lesi o ns is 
p ote ntiall y n o n -re pr o d uci ble; t heref ore pr o vi di n g t his defa ult val ue will pre ve nt false res p o nses 
or pr o gressi o ns bas e d u p o n meas ure me nt err or.  T o reiterat e, h o we v er, if t h e ra di ol o gist is a ble t o 
pr o vi de a n act ual meas ur e, t hat s h o ul d be rec or de d, e ve n if it is bel o w 5 m m.  
Lesi o ns t hat s plit or c oal esce o n tr eat me nt:  W he n n o n -n o dal lesi o ns “fra g me nt,” t he l o n gest 
dia meters of t he fra g me nte d p ort i o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n s u m.  
Si milarl y, as lesi o ns c oal esce, a pl a ne bet w ee n t he m ma y be m ai ntai ne d t hat w o ul d ai d i n 
o btai ni n g ma xi mal dia meter meas ur e me nts of eac h i n di vi d ual lesi o n.  If t he lesi o ns ha ve tr ul y 
c oalesce d s uc h t hat t he y are n o l o n ger  se para ble, t he vect or of t he l on gest dia meter i n t his 
i nsta nce s h o ul d be t he m a xi mal l o n gest dia meter f or t he “c o alesce d lesi o n .” 
1 7. 5. 2. 5.  E v al u ati o n of N o n -tar get Lesi o ns  
T his secti o n pr o vi des t he defi niti o ns of t he criteria use d t o deter mi ne t he t u m or res p o nse f or t he 
gr o u p of n o n -tar get lesi o ns.  W hile s o me n o n -tar get lesi o ns ma y act uall y b e meas ura ble, t he y 
nee d n ot be meas ure d a n d i nstea d s h o ul d be assesse d o nl y q u alitati vel y at t he ti me p oi nts 
s pecifie d i n t he pr ot oc ol. 

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C o m plet e R es p o nse: Disa p peara nce of all n o n -tar get lesi o ns.  All l y m p h n o des m ust be n o n -
pat h ol o gic al i n size ( < 1 0 m m s h ort a xis).  
Pr o gressi ve Diseas e: U ne q ui v ocal pr o gressi o n (see c o m me nts bel o w) of e xisti n g n o n -tar get 
lesi o ns.  (N ote:  T h e a p p eara nce of o ne or m ore n e w lesi o ns is als o c o nsi dere d pr o gressi o n .) 
N o n -C R/ N o n -P D: Persiste nce of o ne or m ore n o n -tar get lesi o n(s). 
1 7. 5. 2. 5. 1.   
S peci al N otes o n Assess me nt of Pr o g ressi o n of N o n -t ar get Dise ase 
T he c o nce pt of pr o gressi o n of n o n -tar get disease re q uires a d diti o nal e x pla nati o n as f oll o ws:  
W he n t he s u bject als o has meas ura ble disease:  I n t his setti n g, t o ac hie ve ‘ u ne q ui v ocal 
pr o gressi o n’ o n t he b asis of t he n o n -tar get disease, t here m ust be a n o v erall le vel of s u bsta ntial 
w orse ni n g i n n o n -tar get disease s uc h t hat, e v e n i n prese nce of S D or P R i n tar get disease, t h e 
o verall t u m or b ur de n h as i ncreas e d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y.  A m o d est 
“i ncrease” i n t he siz e of 1 or m ore n o n -tar get lesi o ns is us uall y n ot s ufficie nt t o q ualif y f or 
u ne q ui v ocal pr o gressi o n stat us.  T he desi g n ati o n of o verall pr o gressi o n s olel y o n t he basis of 
c ha n ge i n n o n -tar get disease i n t he face of S D or P R of tar get disease will t heref ore be rare. 
W he n t he s u bject has o nl y n o n -me as ur a ble diseas e: T he  sa me ge neral c o nce pts a p pl y h ere as 
n ote d a b o ve ; h o we v er, i n t his i nsta nce t here is n o meas ura ble disease assess me nt t o fact or i nt o 
t he i nter pretati o n of a n i ncreas e i n n o n -meas ura ble disease b ur de n.  Beca us e w orse ni n g i n n o n -
tar get disease ca n n ot be easil y q ua ntifie d ( b y defi niti o n: if all lesi o ns are tr ul y n o n -meas ura ble) a 
usef ul test t hat ca n be a p plie d w he n assessi n g s u bjects f or u ne q ui v ocal pr o gressi o n is t o c o nsi der 
if t he i ncrease i n o verall disease b ur de n base d o n t he c ha n ge i n n o n -meas ura ble dise ase is 
c o m para ble i n ma g nit u de t o t he i ncreas e t hat w o ul d be re q uir e d t o declare P D f or meas ura ble 
disease (ie, a n i ncrease i n t u m or b ur de n re prese nti n g a n a d diti o nal 7 3 % i ncrease i n “v ol u me ” 
[ w hic h is e q ui vale nt t o a 2 0 % i ncrease dia meter i n a meas ura ble lesi o n]).  If ‘ u ne q ui v ocal 
pr o gressi o n’ is see n, t h e s u bject s h o ul d be c o nsi dere d t o ha ve ha d o verall P D at t hat ti me p oi nt.  
W hile it w o ul d be i deal t o ha ve o bjecti ve criteria t o a p pl y t o n o n -meas ura bl e disease, t he ver y 
nat ure of t hat disease ma kes it i m p ossi ble t o d o s o ; t heref ore, t he i ncrease m ust be s u bsta ntial. 
1 7. 5. 2. 6.  Ne w Lesi o ns  
T he a p peara n ce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me 
c o m me nts o n detecti o n of ne w lesi o ns are i m p orta nt.  T here are n o s pecific criteria f or t he 
i dentificati o n of ne w ra di o gra p hic lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be 
u ne q ui v ocal , ie, n ot attri b uta ble t o differe nces i n sca n ni n g t ec h ni q ue, c ha n ge i n i ma gi n g 
m o dalit y , or fi n di n gs t h o u g ht t o re prese nt s o met hi n g ot her t h a n t u m or (f or e x a m ple, s o me ‘ ne w’ 
b o ne lesi o ns ma y b e si m pl y heali n g or flare of pre -e xisti n g lesi o ns).  T his is partic ularl y 
i m p orta nt w he n t he s u bject’s baseli ne lesi o ns s h o w P R or C R.  F or e x a m ple, necr osis of a li ver 
lesi o n ma y be re p ort e d o n a C T sca n re p ort as a ‘ ne w’ c ystic lesi o n, w hic h it is n ot. 
A lesi o n i de ntifie d o n a f oll o w -u p st u d y i n a n a n at o mical l ocati o n t hat was n ot sca n ne d at 
baseli ne is c o nsi dere d a n e w lesi o n a n d will i n dicate disease pr o gressi o n.  A n e x a m ple of t his is 
t he s u bject w h o has visceral disease at baseli ne a n d w hile o n st u d y has a C T or M RI of brai n t hat 
re veals met astases.  T he s u bject’s brai n metastas es are c o nsi dere d t o be e vi de nce of P D e ve n if 
he/s he di d n ot ha ve brai n i ma gi n g at bas eli ne.  

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If a ne w lesi o n is e q ui v ocal, f or e x a m ple beca use of its s mall size, c o nti n ue d t hera p y a n d f oll o w -
u p e val uati o n will clarif y if it re prese nts tr ul y ne w disease.  If re peat sca ns c o nfir m t here is 
defi nitel y a ne w lesi o n, t he n pr o gressi o n s h o ul d b e declare d usi n g t he dat e of t he i nitial sca n t hat 
i n dicated its prese nce.  
1 7. 5. 2. 7.  E v al u ati o n of Best O ver all Res p o nse  
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he st u d y treat me nt u ntil 
t he E O T.  T he s u bject’s best o verall res p o ns e assi g n me nt will de pe n d o n t h e fi n di n gs of b ot h 
tar get a n d n o n -t ar get disease a n d will als o ta ke i nt o c o nsi derati o n t he a p p eara nce of ne w l esi o ns. 
1 7. 5. 2. 7. 1.   
T i me P oi nt Res p o nse 
It is ass u me d t hat at eac h pr ot oc ol-s pecifi e d ti me p oi nt, a res p o nse ass ess me nt occ urs.  
Ta ble  1 7 .5  p r o vi des a s u m mar y of t he o verall res p o nse stat us calc ulati o n at eac h ti me p oi nt f or 
s u bjects w h o ha ve me as ura ble diseas e at bas eli ne. 
T a ble  1 7 .5 : 
Ti me P oi nt Res p o nse: S u bjects wit h T ar get ( +/ – N o n -t ar get) Dise ase 
T ar g et L esi o ns  
N o n -t ar g et L esi o ns 
Ne w Le si o ns 
Ti me  P oi nt  R es p o nse 1  
C R  
C R  
N o  
C R  
C R  
N o n -C R/ n o n -P D  
N o  
P R  
C R  
N E  
N o  
P R 2 
P R  
N E  
N o  
P R 2 
P R  
C R  
N o  
P R  
P R  
N o n -C R/ N o n -P D  
N o  
P R  
S D  
N E  
N o  
S D 2 
S D  
C R  
N o  
S D  
S D  
N o n -C R/ N o n -P D  
N o  
S D  
P D   
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
N E  
N o n -P D  
N o  
N E  
C R  
N A 4 
N o  
C R  
P R  
N A 4 
N o  
P R  
S D  
N A 4  
N o  
S D  
N A 3  
N o n -C R/ N o n -P D  
N o  
N o n -C R/ N o n -P D  
N A 3  
C R  
N o  
C R  
N A 3  
N E  
N o  
N E  
N A 3  
N A 4  
N o  
N E  
C R = c o m plete res p o nse; N A = n ot a p plica ble; N E = n ot e val u a ble; P D = pr o gressi ve disease; P R = partial res p o nse; S D = sta ble  
disease  
1  I de ntificati o n of ne w lesi o ns at a p ost-Baseli ne ti me  p oi nt will res ult i n a ti me p oi nt res p o nse (T P R ) of P D. If a n i d e ntifie d ne w 
lesi o n s u bse q ue ntl y bec o mes N E, t h e T P R will be rec or de d as P D u nless t h e ne w lesi o n has pr o ve n t o ha ve res ol ve d. N ote: 
T P Rs assesse d after a pr o gressi o n e ve nt will n ot c o ntri b ute t o t he deter mi n ati o n o f t h e Best Res p o nse. 
2  If a n o n-tar get lesi o n is classifie d as N E, a desi g nati o n of P R or S D ma y be assi g ne d base d o n i nf or mati o n fr o m t h e tar get 
lesi o ns. 
3  N o tar get lesi o ns i de ntifie d at Baseli ne.  
4  N o n o n -tar get lesi o ns i d e ntifie d at Baseli ne. 

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1 7. 5. 2. 7. 2.   
M issi n g Assess me nts a n d N o n -e v al u a ble Desi g n ati o n  
W he n n o i ma gi n g/ meas ure me nt is d o ne at all at a partic ular ti me p oi nt, t he s u bject is n ot 
e val ua ble ( N E) at t hat ti me p oi nt.  If o nl y a s u bset of lesi o n meas ure me nts are ma de at a n 
assess me nt, us uall y t he ca se is als o c o nsi dere d N E at t hat ti me p oi nt, u nless a c o n vi nci n g 
ar g u me nt ca n b e ma de t h at t he c o ntri b uti o n of t he i n di vi d ual missi n g lesi o n(s) w o ul d n ot c ha n ge 
t he assi g n e d ti me p oi nt res p o nse.  T his w o ul d be m ost li kel y t o ha p pe n i n t he case of P D.  F or 
e x a m ple, if a s u bject ha d a baseli ne s u m of 5 0 m m wit h 3 meas ure d lesi o ns a n d at f oll o w -u p 
o nl y 2 lesi o ns were ass esse d, b ut t h ose ga ve a s u m of 8 0 m m, t he s u bject will ha ve ac hie ve d P D 
stat us, re gar dless of t he c o ntri b uti o n of t he missi n g lesi o n. 
1 7. 5. 2. 7. 3.   
B est O ver all Res p o nse: All Ti me P oi nts  
T he best o verall res p o nse is deter mi ne d o nce all t he data f or t he s u bject are k n o w n.  
T he best o verall res p o nse is t he best res p o nse rec or de d fr o m t he start of t he st u d y treat me nt u ntil 
t he E O T.  W he n S D is belie ve d t o be bes t res p o ns e, it m ust als o meet t he pr ot oc ol-s pecifi e d 
mi ni m u m ti me of 5 w eek s fr o m C ycl e 1 Da y 1.  If t he mi ni m u m ti me is n ot met w he n S D is 
ot her wise t he best ti me p oi nt res p o nse, t he s u bject’s best res p o nse de pe n ds o n t he s u bse q ue nt 
assess me nts.  F or e x a m ple, a s u bject w h o h as S D at first assess me nt, P D at sec o n d , a n d d o es n ot 
meet mi ni m u m d urati o n f or S D, will ha ve a b est r es p o nse of P D.  T he s a me s u bject l ost t o 
f oll o w-u p after t he first S D assess me nt w o ul d be c o nsi dere d n o n -e val ua ble.   
1 7. 5. 2. 7. 4.   
S peci al N otes o n Res p o nse Assess me nt  
W he n n o dal disease is i ncl u de d i n t he s u m of tar get lesi o ns a n d t he n o des decrease t o “n or mal ” 
siz e ( < 1 0 m m), t he y ma y still ha ve a meas ure m e nt re p orte d o n s ca ns.  T his meas ure me nt s h o ul d 
be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o verstat e pr o gressi o n s h o ul d it be 
base d o n i ncrease i n size of t he n o des.  As n ote d earlier, t his mea ns t hat s u bjects wit h C R mi g ht 
n ot ha ve a t otal s u m of di a meters of “zer o” o n t he e C R F.  
F or e q ui v o cal fi n di n gs of pr o gressi o n (e g, v er y s m a ll a n d u ncert ai n ne w lesi o ns; c ystic c h a n ges 
or necr osis i n e xisti n g lesi o ns), treat me nt ma y c o nti n ue u ntil t he ne xt sc he d ule d assess me nt.  If at 
t he ne xt sc he d ule d assess me nt, pr o gressi o n is c o nfir me d, t he date of pr o gressi o n s h o ul d be t he 
earlier date w h e n pr o gressi o n was s us pecte d.  
1 7. 5. 2. 8.  Fre q ue nc y of T u m or R e -e v al u ati o n  
I n t his st u d y, t u m or meas ure me nt will be c o n d uct e d at Scree ni n g, a n d t h e n at t he i nter vals 
s pecifie d or s o o n er if cli nicall y i n dicat e d.  T u m or meas ure me nt will be p erf or me d d uri n g t he 
E O T assess me nts if it was n ot d o ne wit hi n t he pre vi o us 6 wee ks  ( ±7 d a ys) or t he pre vi o us 
assess me nt de m o nstrate d disease pr o gressi o n.  
Baseli ne t u m or assess me nts m ust be perf or me d wit hi n 2 8  da ys of ra n d o mizati o n.  
All eff orts s h o ul d be ma d e t o e ns ure c o nsiste nc y b et wee n t he baseli ne meas ure me nts a n d all 
s u bse q ue nt meas ur e me nts i n refere nce t o utilizati o n of sca n ni n g met h o d, e q ui p me nt, tec h ni q ue 
(i ncl u di n g slice t hic k n ess a n d fiel d of vie w), a n d ra di o gra p hic i nter preter. 
T he ra di o gra p hic e v al uati o n m ust i ncl u de C T or M RI sca n ni n g of c h est, a b d o me n, a n d pel vis at 
Scree ni n g peri o d.  A C T or M RI of t he brai n is ma n dat or y f or all s u bjects i ncl u de d wit h baseli ne 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4 2  
sta ble brai n metastas es.  A n y a d diti o nal s us pecte d sites of disease s h o ul d als o be i ma ge d.  E ver y 
eff ort s h o ul d be ma d e t o use t he sa me ass ess me nt m o dalit y f or all assess me nts f or eac h s u bj ect.  
F oll o w -u p e v al uati o ns s h o ul d i ncl u de all sites of disease i de ntifie d at Scree ni n g a n d a n y ot her 
l ocati o ns if P D is s us pecte d (e g, M RI of t h e brai n if brai n metastases are s us pecte d) s h o ul d als o 
be i ma ge d.  All e val u ati o ns s h o ul d meet t he sta n dar d of care f or i ma gi n g of lesi o ns i n t he 
res pecti ve or ga n(s) a n d s h o ul d c o nf or m t o t he i ma ge ac q uisiti o n g ui deli nes acc or di n g t o 
i nstit uti o nal sta n dar ds.   
All tar get a n d n o n -tar get sites are e v al uate d at eac h ti me p oi nt of t u m or assess me nt. 
 
S o urce:  Eise n ha uer E A, T herasse P, B o gaerts J, et al. Ne w res p o nse e val uati o n criteria i n s oli d t u m o urs: 
re vise d R E CI S T g ui deli ne ( v ersi o n 1. 1). E ur J Ca ncer. 2 0 0 9; 4 5 ( 2): 2 2 8-4 7.  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4 3  
1 7. 6.  
E ur o pe a n Or g a niz ati o n f or Rese arc h a n d Tre at me nt of C a ncer 
Q u alit y of Life Q uesti o n n aire  C 3 0 a n d B R 4 5  
1 7. 6. 1.  
E ur o pe a n Or g a niz ati o n f or Rese arc h a n d Tre at me nt of C a ncer Q u alit y of Life 
Q uesti o n n aire  C 3 0 ( versi o n 3. 0)  
 

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V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4 4  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4 5  
1 7. 6. 2.  
E ur o pe a n Or g a niz ati o n f or Rese arc h a n d Tre at me nt of C a ncer Q u alit y of Life 
Q uesti o n n aire  B R 4 5  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4 6  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4 7  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4 8  
1 7. 7.  
E ur o Q o L  Fi ve Di me nsi o ns Fi ve Le vels  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4 9  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 0  
 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 1  
1 7. 8.  
I nstr ucti o ns R el ate d t o C or o n a vir us D ise ase 2 0 1 9 (C O VI D -1 9 ) 
I ncl usi o n criterio n  
 Has a de q u ate treat me nt was h o ut peri o d bef ore ra n d o mizati o n/ e nr oll me nt, defi ne d as  
chl or o q ui ne/ h y dr o x yc hl or o q ui ne: > 1 4 da ys  
Pri o r a n d C o nc o mit a nt Me dic ati o ns  
C o nc o mita nt treat me nt wit h c hl or o q ui ne or h y dr o x yc hl or o q ui ne is n ot all o we d d uri n g t he st u d y 
treat me nt.  If treat me nt wit h c hl or o q ui ne or h y dr o x yc hl or o q ui ne treat me nt is a bs ol utel y re q uire d 
f or C O VI D-1 9, st u d y tr eat me nt m ust be i nterr u pte d.   If c hl or o q ui ne or h y dr o x yc hl or o q ui ne is 
a d mi nistere d, t he n a w as h o ut peri o d of > 1 4 da ys is re q uire d bef ore restarti n g st u d y treat me nt . 
P K Assess me nt(s) if C hl or o q ui ne or H y dr o x yc hl or o q ui ne is A d mi nistere d  
A d diti o nal P K ser u m sa m ples s h o ul d be c ollecte d  fr o m eac h s u bject w h o pr o vi des c o nse nt, if 
c hl or o q ui ne or h y dr o x yc hl or o q ui ne is a d mi nistere d f or  C O VI D -1 9 , at t he ti me p oi nts s pecifie d 
i n t he Sc he d ule of E ve nts (Ta ble  1 7 .2 ). 
T he c hl or o q ui ne or h y dr o x yc hl or o q ui ne a d mi nistrati o n a n d t he e x act ti me of bl o o d sa m ple 
c ollecti o n f or P K a n al ysis m ust be rec or de d o n t he e C R F  (T a ble  1 7 .2 ). 
D ose m o dific ati o n criteri a f or s us pecte d or c o nfir me d C O VI D -1 9  
D ose m o dificati o ns will be base d o n t he w orst C T C A E gra de.  All i nterr u pti o ns or m o dificati o ns 
m ust be rec or de d o n t he A E a n d dr u g a d mi nistrati o n e C R Fs.  Pl e ase use C T C A E v 5. 0 ge ner al 
gr a di n g criteri a t o e v al u ate C O VI D -1 9.  
D ose m o dific ati o n criteri a  
If C OVI D -1 9 i nfecti o n is s us pecte d, i nterr u pt T -D X d  a n d r ule o ut C O VI D -1 9 per l ocal g ui da nce.  
 If C O VI D-1 9 is r ule d o ut, f oll o w d ose m o dificati o n a n d ma na ge m e nt g ui d a nce as 
o utli ne d i n  Ta ble  5 .3 . 
 If C O VI D-1 9 is c o nfir me d or dia g n osis is s us pecte d after e val uati o n, ma na ge 
C O VI D -1 9 per l ocal g ui da nce u ntil rec o ver y of C O VI D -1 9 , d efi ne d as n o 
si g ns/s y m pt o ms, at least 1 ne gati ve real-ti me p ol y merase c hai n  reacti o n (R T -P C R ) 
test res ult,a a n d nearl y or c o m pletel y res ol ve d c hest C T fi n di n gs.  T he n f oll o w bel o w 
d ose m o dificati o ns:  
 If G ra de 1, res u me T -D X d  at t he sa me d ose ; 
 If G ra de 2 , 
o  Mai ntai n sa me d ose if c h est C T fi n di n gs are c o m pletel y res ol ve d ;b 
o  Re d uce d ose 1 le v el if c h est C T fi n di n gs are nearl y res ol ve d.b  
 If G ra de 3 , 
o  Re d uce d ose 1 le v el if c h est C T fi n di n gs are c o m pletel y res ol ve d ;b 
o  D isc o nti n ue st u d y dr u g if c hest C T fi n di n gs are n ot  c o m pletel y res ol ve d;   
 If G ra de 4, disc o nti n ue st u d y treat me nt.  

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V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 2  
a All c o nfir me d or s us pecte d C O VI D -1 9 i nf ecti o n e ve nts m ust be rec or de d i n t he e C R F.  If a 
s u bject prese nts t o t he cli nic wit h s y m pt o ms s u g gesti ve of C O VI D-1 9, b ut t he real -ti me R T P C R 
test is n ot a vaila ble at t he site, t he partici pa nt m ust n ot ha ve a n y si gns or s y m pt o ms of C O VI D -
1 9 i nfecti o n f or at least 2 wee ks a n d n earl y or c o m pletel y res ol ve d c h est C T fi n di n gs.  
Alter nati vel y, a sa m ple kit ma y be pr o vi d e d f or s a m ple c ollecti o n t o be teste d at a ce ntral 
la b orat or y.  T he res ults will be pr o vi de d t o t he site fr o m t he ce ntral la b orat or y.  
b Cl osel y m o nit or si g ns/s y m pt o ms after restarti n g T -D X d , i nitiall y wit h a telep h o ne call e v er y 3 
da ys f or t he first wee k, a n d t he n wit h a wee kl y tel ep h o ne call t hereafter, f or a t otal of 6 wee ks.  
I n a d diti o n t o t he rec o m me n dati o ns o utli ne d a b o ve, I n vesti gat ors ma y c o nsi der d ose 
m o dificati o ns of t he st u d y dr u g acc or di n g t o t he s u bject’s c o n diti o n a n d aft er disc ussi o n wit h t he 
st u d y Me dic al M o nit or or desi g n ee.  If a n e ve nt is s us pecte d t o be a dr u g -relate d I L D, m a na ge 
per pr ot o c ol I L D ma na ge me nt g ui deli ne.  
C O VI D -1 9 Ser u m Bi o m a r ker Ass ess me nt(s)  
Ser u m sa m ples will be use d f or C O VI D -1 9 testi n g fr o m eac h s u bject w h o pr o vi des c o nse nt.  
Sa m ples will be c ollecte d pri or t o t he st u d y dr u g i nf usi o n, will be s hi p pe d t o a ce ntr al la b orat o r y 
a n d st ore d t here u ntil t he tests bec o me a v aila ble.  
If s u bjects c o ns e nt, t he re mai ni n g ser u m sa m ples will als o be st ore d f or f ut ure a nal ysis. 
Ser u m  sa m ple c ollecti o n, pre parati o n, ha n dli n g, st ora ge, a n d s hi p pi n g i nstr ucti o ns are pr o vi de d 
i n t he St u d y La borat or y Ma n ual.  
St atistic al A n al ysis - Assess me nt of t he I m p act of C O VI D -1 9  
If dee m e d a p pr o priate, a nal yses will be perf or me d t o e x pl ore t he i m pact of C O VI D-1 9 o n t he 
safet y, efficac y, a n d a n y ot her e n d p oi nts, as a p pr o priate, re p orte d f or t h e st u d y.  
As a res ult of t he i m pact of C O VI D-1 9 o n st u d y c o n d uct, a dj ust me nts t o t he statistical a nal ysis 
a n d i nter pret ati o n will be ma de, if re q uir e d.  T hes e will be descri b e d i n t he statistical a nal ysis 
pla n . 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 3  
1 7. 9.  
C o u ntr y -S pecific Pr ot oc ol Te xt  
T his a p pe n di x lists pr ot oc ol te xt italicize d, u n derli ne d , a n d b ol de d t hat a p plies o nl y t o 1  c o u ntr y 
as s pecifie d b el o w.  Pr ot oc ol te xt re m o ve d i n o nl y 1 c o u ntr y is s h o w n i n stri ket hr o u g h as 
s pecifie d bel o w. 
1 7. 9. 1.  
S w e de n O nl y  
T he  italicize d, u n derli ne d , a n d b ol de d te xt bel o w is a p plica ble to sites i n S we de n.  
I n eac h s ecti o n bel o w  i n t he sec o n dar y efficac y o bjecti ves a n d e n d p oi nts , H E R 2-l o w s u bjects are 
s pecifie d.  Te xt s pecific t o S we de n is s h o w n italicize d, u n derli ne d , a n d b ol d e d bel o w a n d all 
ot her te xt re mai ns t he sa me .   
Secti o n  2. 1. 2  Ke y Sec o n d ar y O bjecti ves  
T he ke y sec o n dar y  o bje cti ve s f or H E R 2-l o w (I H C 1 + or I H C 2 +/I S H-) s u bjects are:  
 T o c o m pare t h e P F S be n efit of T -D X d  t o p h ysicia n’s c h oice i n  all ra n d o mize d 
s u bjects (H E R 2 -l o w, H R -p ositi ve , a n d H R -ne gati ve  breast ca ncer ), b ase d o n BI C R 
 T o c o m pare t h e O S be nefit of T -D X d  t o p h ysicia n’s c h oice i n H E R 2-l o w, H R-
p ositi ve breast ca n cer  
 T o c o m pare t h e O S be nefit of T -D X d  t o p h ysicia n’s c h oice i n all ra n d o mize d s u bjects  
(H E R 2 -l o w, H R -p ositi ve , a n d H R-ne gati ve  breast ca ncer ) 
Secti o n  2. 1. 3  Ot her Sec o n d ar y O bjecti ves  
 T o i n vesti gate t h e efficac y of T -D X d  c o m pare d t o p h ysicia n’s c h oice f or H E R 2-l o w (I H C 
1 + or I H C 2 +/I S H -) s u bjects o n t he f oll o wi n g p ara meters:  
 P F S i n H R -p ositi ve s u bjects, base d o n I n v esti gat or assess me nt  
 C o nfir me d O R R, base d o n BI C R i n H R -p ositi ve s u bject s 
 D o R, base d o n BI C R i n H R -p ositi ve s u bjects  
 C o nfir me d D o R i n all s u bjects, re gar dless of H R stat us.  
Secti o n  2. 3. 2  Ke y Sec o n d ar y Effic ac y E n d p oi nt s 
T he  ke y sec o n dar y effic ac y e n d p oi nts f or H E R 2-l o w (I H C 1 + or I H C 2 +/I S H-) s u bjects are:  
 P F S, base d o n BI C R, i n all ra n d o mize d s u bjects  
 O S i n H R -p ositi ve breast ca ncer s u bjects  
 O S i n all ra n d o mize d s u bjects 
Secti o n  2. 3. 3  Ot her Sec o n d ar y Effic ac y E n d p oi nts  
T he ot her sec o n dar y effi cac y e n d p oi nts f or H E R 2-l o w (I H C 1 + or I H C 2 +/I S H-) s u bjects are: 
 P F S , base d o n I n vesti gat or assess me nt 
 C o nfir me d O R R , base d o n BI CR a n d I n v esti gat or assess me nt  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 4  
 D o R , base d o n BI C R  
Secti o n  7. 1. 2  Ke y Sec o n d ar y Effic ac y E n d p oi nt  
T he ke y s ec o n dar y effic ac y e n d p oi nt s f or H E R 2-l o w s u bjects are: 
 P F S, base d o n BI C R, i n all ra n d o mize d s u bjects  
 O S i n H R -p ositi ve breast ca ncer  s u bjects 
 O S i n all ra n d o mize d s u bjects 
Secti o n  7. 1. 3  Ot her Sec o n d ar y Effic ac y E n d p oi nts  
I n t he ot h er sec o n dar y efficac y e n d p oi nts, H E R 2-l o w s u bjects are s pecifie d.  Te xt s pecific t o 
S we de n is s h o w n italicize d, u n derli ne d, a n d b ol d e d bel o w a n d all ot her te xt re mai ns t he sa me . 
Ot her s ec o n d ar y effic ac y e n d p oi nts f or H E R 2-l o w s u bjects i ncl u de: 
 P F S, base d o n I n vesti gat or assess me nt  
 C o nfir me d O R R, defi ne d as t he s u m of C R r ate a n d P R rate, base d o n BI C R a n d 
I n v esti gat or assess me nt, a n d c o nfir me d b y a sec o n d assess me nt. 
 D o R, defi ne d as t he ti me fr o m t he date of t h e first d oc u me ntati o n of o bjecti ve 
res p o nse ( C R or P R) t o t he date of t he first d oc u me ntati o n of disease pr o gressio n, 
base d o n BI C R, or deat h.  D urati o n of res p o nse will be meas ure d f or res p o n di n g 
s u bjects ( P R or C R) o nl y.  S u bjects w h o are pr o gressi o n-free at t he ti me of t he 
a nal ys es will be ce ns ore d at t he date of t he l ast e val ua ble t u m or assess me nt.  
1 7. 9. 2.  
P ort u g al  O nl y  
T he italiciz e d, u n derli ne d, a n d b ol de d te xt bel o w is a p plica ble t o sites i n P ort u gal.   
Secti o n  4. 1  I ncl usi o n Criteri a 
I n cl usi o n criteri o n # 1 4 is a me n de d t o s pecif y t hat s u bjects wit h h or m o ne rece pt or ( H R) -p ositi ve 
t u m ors m ust n ot use h or m o nal c o ntrace pti ves t o pre ve nt pr e g na nc y a n d m ust c h o ose o ne of t he 
ot her met h o ds liste d .  Te xt s pecific t o P ort u gal is s h o w n italicize d, u n derli ne d , a n d b ol de d bel o w 
a n d all ot her te xt re mai ns t he sa me.   
1 4  Male a n d fe male s u bjects of re pr o d ucti ve/c hil d beari n g p ote ntial m ust a gree t o use a 
hi g hl y effecti ve f or m of c o ntrace pti o n or a v oi d i nterc o urse d uri n g a n d u p o n c o m pleti o n 
of t he st u d y a n d after t he last d ose of T -D X d  f or at least 7 m o nt hs f or fe mal es or 4. 5 
m o nt hs f or males  or acc or di n g t o t he la bel a p pr o v e d i n t he c o u ntr y of dr u g a d mi nistrati o n 
f or t he p h ysicia n’s c h oic e treat me nts.2 0  S u bjects wit h H R -p ositive t u m ors m ust n ot 
c h o ose h or m o n al c o ntr ace ptives t o pre ve nt pre g n a ncy a n d m ust c h o ose o ne of t he 
ot her m et h o ds liste d bel o w.   Male s u bjects m ust a gree t o i nf or m all fe mal e part ners t hat 
t he y are p artici pati n g i n a cli nical trial t hat ma y ca use birt h defects.  Met h o ds c o nsi dere d 
as hi g hl y effecti ve met h o ds of c o ntrace pti o n 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  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 5  
 I ntr a va gi nal 
 Tra ns der m al  
 Pr o gest o ge n -o nl y 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 nje cta ble 
 I m pla nta bl e 
 I ntr a uteri ne d e vice 
 I ntr a uteri ne h or m o ne-rel easi n g s yst e m 
 Bilateral t u bal occl usi o n  
 Vasect o miz e d part ner  
 T he relia bilit y of c o m plete se x ual a bsti ne nce nee ds t o be e val uate d i n r elati o n t o t he 
d urati o n of t he cli nical tri al a n d t he preferre d a n d us ual lifest yle of t he s u bject.  
S u bjects i n t his st u d y s h o ul d  refrai n fr o m heter ose x ual i nterc o urse d uri n g a n d u p o n 
c o m pleti o n of t he st u d y a n d f or at least 7 m o nt hs f or fe males or 4. 5 m o nt hs f or males 
after t he l ast d ose of T -D X d  or acc or di n g t o t he la bel a p pr o ve d i n t he c o u ntr y of dr u g 
a d mi nistrati o n f or t he p h ysicia n’s c h oice treat me nt. Peri o dic a bsti ne nce (e g, cale n dar, 
o v ulati o n, s y m pt ot her mal, p ost o v ulati o n met h o ds), declarati o n of a bsti ne nce f or t he 
d urati o n of e x p os ure t o st u d y dr u g, a n d wit h dra wal are n ot acce pta bl e met h o ds of 
c o ntrace pti o n.  
N o n -c hil d beari n g p ot e ntial is defi ne d as pre me n o pa usal fe mal es wit h a d oc u me nte d t u bal 
li gati o n or h ysterect o m y; or p ost me n o pa usal defi n e d as 1 2 m o nt hs of s p o nta ne o us 
a me n orr hea (i n q uesti o na ble cases, a bl o o d sa m ple wit h si m ulta ne o us f ollicle -sti m ulati n g 
h or m o ne > 4 0 mI U/ m L a n d estra di ol < 4 0  p g/ m L [ < 1 4 7 p m ol/ L] is c o nfir mat or y).  
Fe males o n h or m o ne re pl ace me nt t hera p y ( H R T) a n d w h ose me n o pa usal stat us is i n 
d o u bt will be re q uire d t o use 1  of t he c o ntr ace pti o n met h o ds o utli ne d f or w o me n of 
c hil d beari n g p ote ntial if t he y wis h t o c o nti n ue t heir H R T d uri n g t h e st u d y.  Ot her wise, 
t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal stat us pri or t o st u d y 
e nr oll me nt.  F or m ost f or ms of H R T, at least 2 t o 4 wee ks will ela pse b et w ee n t he 
cessati o n of t hera p y a n d t he bl o o d dra w; t his i nter val de pe n ds o n t he t y pe a n d d osa ge of 
H R T.  F oll o wi n g c o nfir mati o n of t heir p ost me n o pa usal stat us, t he y ca n res u me use of 
H R T d uri n g t he st u d y wit h o ut use of a c o ntrace pti ve met h o d.  
 
Secti o n  4. 2  E xcl usi o n Criteri a  
Testi n g f or h u ma n i m m u n o deficie nc y vir us ( HI V) is a me n de d t o s pecif y HI V  testi n g is r e q uire d.  
I n t he e x cl usi o n criteri o n # 1 2, te xt is re m o ve d as s h o w n i n stri ket hr o u g h b elo w a n d all ot her te xt 
re mai ns t he sa me. 

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 6  
1 2.  
Has k n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti o n or acti ve he patitis B or C 
i nfecti o n.  S u bjects s h o ul d be teste d f or HI V pri or t o ra n d o mizati o n as re q uire d b y 
l ocal re g ulati o ns or I R B/I E C. 
 
Secti o n  6. 2  Scree ni n g  
Testi n g f or h u ma n i m m u n o deficie nc y vir us ( HI V) is a me n de d t o s pecif y HI V testi n g is r e q uire d.  
I n t he s cree ni n g pr oce d ures, te xt is re m o ve d as s h o w n i n stri ket hr o u g h b el o w a n d all ot her te xt 
re mai ns t he sa me.   
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d wit hi n 2 8  d a ys bef ore 
r a n d o miz ati o n  d uri n g t h e scree ni n g peri o d:  
 Perf or m a n HI V a nti b o d y test U nless  re q uire d b y l ocal re g ulati o ns or I R B/I E C, a n 
HI V a nti ge n/a nti b o d y test is n ot re q uire d pri or t o r a n d o mizati o n/e nr oll me nt.  
 
Secti o n  1 7. 1  Sc he d ule of E ve nts   
Testi n g f or h u ma n i m m u n o deficie nc y vir us ( HI V) is a me n de d t o s pecif y  HI V  testi n g is r e q uire d.  
I n t he Ta ble  1 7 .1 , te xt is re m o ve d as s h o w n i n stri ket hr o u g h bel o w a n d all ot her te xt re mai ns t he 
sa me.   
HI V A nti b o d y T est (as re q uire d b y l ocal re g ulati o ns or 
I R Bs/I E Cs) 
 
● 
 
 
1 7. 9. 3.  
Ger m a n y  O nl y  
T he italiciz e d, u n derli ne d, a n d b ol de d te xt bel o w is a p plica ble t o sites i n Ger ma n y.    
I n eac h s ecti o n bel o w, clarificati o n is a d de d t h at ec h ocar di o gra m ( E C H O) is t he preferre d L V E F 
assess me nt m o dalit y.  A m ulti gate d ac q uisiti o n ( M U G A) sca n ma y be use d o nl y if E C H O 
e x a mi nati o n is n ot i n dicate d per s u bject’s cli nical c o n diti o n (e g , hi g h er acc urac y a n d 
re pr o d uci bilit y of assess me nt are re q uire d p er i n v esti gat or’s j u d ge me nt).   
Te xt s pecific t o Ger ma n y is s h o w n italicize d, u n derli ne d, a n d b ol de d .  Del ete d te xt is s h o w n i n 
stri ket hr o u g h.  A ll ot her te xt re mai ns t he sa me.   
Secti o n  6. 2  Scree ni n g  
 Perf or m a n E C H O  or M U G A .  N ote:  T he s a me t est m ust be use d f or t he s u bject 
t hr o u g h o ut t he st u d y.  E C H O will be t he preferre d L V E F assess m e nt m o d ality, as a 
less i nv asive pr oce d ure av oi di n g st u dy s u bjects’ e x p os ure t o i o nizi n g r a di ati o n.  
M U G A sc a n m ay be use d o nly if E C H O e x a mi n ati o n is n ot i n dic ate d per s u bject’s 
cli nic al c o n diti o n (e g , hi g her acc ur acy a n d re pr o d uci bility of assess m e nt are 
re q uire d per i nvesti g at or’s j u d ge m e nt).  I n case M U G A is t he assess m e nt m o d ality 
of c h oice, a s o u n d m e dic al r ati o n ale f or selecti n g it m ust be pr ovi de d a n d pr o perly 
d oc u m e nte d.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 7  
Secti o n  6. 4. 2  E ver y 4 C ycles ( ± 7 d a ys) After C ycle 1  
 Perf or m a n E C H O  or M U G A ( N ote:  T h e sa me test m ust be use d f or t he s u bject 
t hr o u g h o ut t he st u d y) bef ore i nf usi o n at C ycle 5, 9, 1 3, etc.  N ote: T he s a m e test 
m ust be use d f or t he s u bject t hr o u g h o ut t he st u dy.  E C H O will be  t he preferre d 
L V E F assess m e nt m o d ality, as a less i nv asive pr oce d ure av oi di n g st u dy s u bjects’ 
e x p os ure t o i o nizi n g r a di ati o n.  M U G A sc a n m ay be use d o nly if E C H O 
e x a mi n ati o n is n ot i n dic ate d per s u bject’s cli nic al c o n diti o n (e g , hi g her acc ur acy 
a n d re pr o d uci bility of assess m e nt are re q uire d per i nvesti g at or’s j u d ge m e nt).  I n 
c ase M U G A is t he assess m e nt m o d ality of c h oice, a s o u n d m e dic al r ati o n ale f or 
selecti n g it m ust be pr ovi de d a n d pr o perly d oc u me nte d. 
Secti o n  6. 5  E n d of St u d y Tre at me nt  
 Perf or m a n E C H O or M U G A .  N ote:  T he s a me t est m ust be use d f or t he s u bject 
t hr o u g h o ut t he st u d y.  E C H O will be t he preferre d L V E F assess m e nt m o d ality, 
as a less i nv asive pr oce d ure av oi di n g st u dy s u bjects’ e x p os ure t o i o nizi n g 
r a di ati o n.  M U G A sc a n m ay be use d o nly if E C H O e x a mi n ati o n is n ot i n dic ate d 
per s u bject’s cli nic al c o n diti o n (e g , hi g her acc ur acy a n d re pr o d uci bility of 
assess m e nt are re q uire d per i nvesti g at or’ s j u d ge m e nt).  I n c ase M U G A is t he 
assess m e nt m o d ality of c h oice, a s o u n d m e dic al r ati o n ale f or selecti n g it m ust 
be pr ovi de d a n d pr o perl y d oc u m e nte d.  
Secti o n  9. 3. 2. 2  M a n a ge me nt G ui d a nce  
Left ve ntric ular eje cti o n fracti o n will be meas ure d b y eit her E C H O or M U G A sca n.  All 
E C H Os/ M U G As will be e val uate d b y t he I n vesti gat or or dele gate d p h ysici a n f or m o nit ori n g 
car diac f u ncti o n.  N ote: T he s a m e test m ust be use d f or t he s u bject t hr o u g h o ut t he st u dy.  
E C H O will be t he preferre d L V E F assess m e nt m o d ality, as a less i nv asive pr oce d ure  a v oi di n g 
st u dy s u bjects’ e x p os ure t o i o nizi n g r a di ati o n.  M U G A sc a n m ay be use d o nly if E C H O 
e x a mi n ati o n is n ot i n dic ate d per s u bject’s cli nic al c o n diti o n (e g , hi g her acc ur acy a n d 
re pr o d uci bility of assess m e nt are re q uire d per i nvesti g at or’s j u d ge m e nt).  I n c ase M U G A is t he 
assess m e nt m o d ality of c h oice, a s o u n d m e dic al r ati o n ale f or s electi n g it m ust be pr ovi de d a n d 
pr o perly d oc u m e nte d.  
Secti o n  9. 1 2. 1  C ar di ac Assess me nts  
Eit her E C H O or M U G A will be perf or me d as des cri be d i n t he Sc he d ule of E ve nts ( Ta ble  1 7 .1  
a n d Ta ble  1 7 .2 ); L V E F will be meas ure d.  N ot e: T he s a m e test m ust be use d f or t he s u bject  
t hr o u g h o ut t he st u dy.  E C H O will be t he preferre d L V E F assess m e nt m o d ality, as a less 
i nv asive pr oce d ure av oi di n g st u dy s u bjects’ e x p os ure t o i o nizi n g r a di ati o n.  M U G A sc a n m ay 
be use d o nly if E C H O e x a mi n ati o n is n ot i n dic ate d per s u bject’s cli nic al c o n di ti o n (e g, hi g her 
acc ur acy a n d re pr o d uci bility of assess m e nt are re q uire d per i nvesti g at or’s j u d ge m e nt).  I n 
c ase M U G A is t he assess m e nt m o d ality of c h oice, a s o u n d m e dic al r ati o n ale f or selecti n g it 
m ust be pr ovi de d a n d pr o perly d oc u m e nte d.  

Pr ot oc ol D S 8 2 0 1 -A -U 3 0 3  
V ersi o n  5 . 0, 1 2  Oct  2 0 2 0  
 
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5 8  
Secti o n  1 7. 1  Sc he d ule of E ve nts  
Ta ble 1 7. 1 Sc he d ule of E ve nts –  Tiss ue Scree ni n g a n d Scree ni n g Peri o d  
e 
E C H O  or M U G A sca n  assess me nts will be perf or me d at Scree ni n g.  N ot e t hat t he sa me test 
m ust be use d f or t he s u bj ect t hr o u g h o ut t he st u d y.  E C H O will be t he preferre d L V E F 
assess m e nt m o d ality, as a less i nv asive pr oce d ur e av oi di n g st u dy s u bjects’ e x p os ure t o 
i o nizi n g r a di ati o n.  M U G A sc a n m ay be use d o nly if E C H O e x a mi n ati o n is n ot i n dic ate d 
per s u bject’s cli nic al c o n diti o n (e g , hi g her acc ur acy a n d re pr o d uci bility of assess m e nt 
are re q uire d per i nvesti g at or’s j u d ge m e nt).  I n c ase M U G A is t he assess me nt m o d ality of 
c h oice, a s o u n d m e dic al r ati o n ale f or selecti n g it m ust be pr ovi de d a n d pr o perly 
d oc u m e nte d.   
Ta ble 1 7. 2 Sc he d ule of E ve nts –  Treat me nt a n d F oll o w -u p Peri o d  
k 
E C H O or M U G A sca n  assess me nts will be perf or me d BI o n Da y 1 of e ver y 4 c ycles 
( ± 7 da ys) ( C ycle 5, 9, 1 3, et c).  N ote t hat t he s a me test m ust be use d f or t he s u bject 
t hr o u g h o ut t he st u d y.  E C H O will be t he preferre d L V E F assess m e nt m o d ality, as a less 
i nv asive pr oce d ure av oi di n g st u dy s u bjects’ e x p os ure t o i o nizi n g r a di ati o n.  M U G A sc a n 
m ay be use d o nly if E C H O e x a mi n ati o n is n ot i n dic ate d per s u bject’s cli nic al c o n diti o n 
(e g, hi g her acc ur acy a n d re pr o d uci bility of assess m e nt are re q uire d per i nvesti g at or’s 
j u d ge m e nt).  I n c ase M U G A is t he assess m e nt m o d ality of c h oice, a s o u n d m e dic al 
r ati o n ale f or selecti n g it m ust be pr ovi de d a n d pr o perly d oc u m e nte d.