Clinical trial NCT02564900
Conditions: Advanced Solid Tumors
Keywords: Advanced solid tumors phase 1 oncology HER2 Antibody drug conjugate (ADC)
Sponsor: Daiichi Sankyo Co., Ltd.
Start date: 2015-09-01; Completion date: 2023-12-22
Enrollment: 292 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is an open-label, two-part, multicenter study to evaluate the safety and tolerability of DS-8201a in participants with advanced solid malignant tumors.

Detailed description:

Arms: arm 1: Part 1 is a dose escalation to identify the Maximum Tolerated dose (MTD) or the recommended phase 2 dose of DS-8201a guided by the modified continuous reassessment method using a Bayesian logistic regression model following escalation with overdose control principal. arm 2: Part 2 is a dose expansion to examine the safety and efficacy of DS-8201a and it is consist of multiple cohorts: in subjects with trastuzumab emtansine (T-DM1)-treated HER2 overexpressing breast cancer (Part 2a); trastuzumab-treated HER2 overexpressing gastric or gastroesophageal junction adenocarcinoma (Part 2b); HER2 low expressing breast cancer (Part 2c), HER2 expressing other solid malignant tumor (Part 2d); HER2 expressing breast cancer (Japan only; Part 2e)
Interventions: intervention 1: DS-8201a (DP1) intervention 2: DS-8201a (DP2) intervention 3: DS-8201a (DP)
Intervention descriptions: intervention 1: DS-8201a to be administered via intravenous (IV) dose. DS-8201a (DP1) was used for the Dose Escalation phase and for Dose expansion Parts 2a, 2b, 2c, and 2d. intervention 2: DS-8201a is to be administered via intravenous (IV) dose. DS-8201a (DP2) was used only used for Dose Expansion Part 2e. intervention 3: DS-8201a (DP) is to be administered via intravenous (IV) dose.

Protocol documents:
Prot_SAP_000.pdf: 
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
P H A S E 1, T W O- P A R T, M U L TI C E N T E R, N O N-
R A N D O MI Z E D, O P E N- L A B E L, M U L TI P L E D O S E 
FI R S T-I N- H U M A N S T U D Y O F D S- 8 2 0 1 A, I N S U B J E C T S 
WI T H A D V A N C E D S O LI D M A LI G N A N T T U M O R S
D S 8 2 0 1- A- J 1 0 1
I N D #: 1 2 7 5 5 3
V E R SI O N 1 2. 0, 2 6 A P R 2 0 1 9
Versi o n 1. 0 ( 0 3 J u n 2 0 1 5), Versi o n 2. 0 ( 2 6 J u n 2 0 1 5), Versi o n 3. 0 ( 1 4 J a n 2 0 1 6), 
Versi o n 4. 0 ( 2 9 Fe b 2 0 1 6), Versi o n 5. 0 ( 2 2 J ul 2 0 1 6), Versi o n 6. 0 ( 0 9 Se p 2 0 1 6),
Versi o n 7. 0 ( 1 6 N o v 2 0 1 6), Versi o n 8. 0 ( 0 7 M ar 2 0 1 7),
Versi o n 9. 0 ( 2 8 A pr 2 0 1 7, J a p a n-s pecific), Versi o n 1 0. 0 ( 1 4 Se p 2 0 1 7),
Versi o n 1 1. 0 ( 2 5 J a n 2 0 1 8)
D AII C HI S A N K Y O
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.  T he i nf or mati o n is 
pr o vi de d t o y o u i n c o nfi de nce w hic 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 veal 
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 ha n t h ose i n y o ur 
or ga nizati 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 per missi o n of a n a ut h orize d re prese ntati ve of 
Daiic hi Sa n k y o.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2
I N V E S TI G A T O R A G R E E M E N T
P H A S E 1, T W O- P A R T, M U L TI C E N T E R, N O N-
R A N D O MI Z E D, O P E N- L A B E L, M U L TI P L E D O S E 
FI R S T-I N- H U M A N S T U D Y O F D S- 8 2 0 1 A, I N S U B J E C T S 
WI T H A D V A N C E D S O LI D M A LI G N A N T T U M O R S
S p o ns or A p pr o v al:
T his cli nical st u d y pr ot oc ol has bee n re vie we d a n d a p pr o ve d b y t he Daiic hi Sa n k y o 
re prese ntati ve liste d bel o w.
Pri nt N a me
Si g n at ure
Cli nical St u d y Lea d
Title
D ate ( D D M M M Y Y Y Y)
I n vesti g at or’s Si g n at ure:
I ha ve f ull y disc usse d t he o bjecti ves 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 he S p o ns or’s re prese ntati ve.
I u n dersta n d t hat i nf or mati 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 discl 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 he 
et hical re vie w of t he 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, per 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 deli nes, a n d t o c o n d uct 
t he st u d y i n acc or da nce wit h t he Declarati o n of Helsi n ki, I nter nati o nal C o nfere nce o n 
Har m o nizati o n g ui deli nes o n G o o d Cli nical Practice (I C H E 6), a n d a p plica ble re gi o nal 
re g ulat or y re q uire me nts.
I a gree t o ma 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 
re g ulat or y a ut h orities, m y s u bjects’ st u d y rec or ds i n or der t o verif y t he data t hat I ha ve 
e ntere d i nt o t he case re p ort f or ms.  I a m a ware of m y res p o nsi bilities as a Pri nci pal 
I n vesti gat or as pr o vi de d b y t he S p o ns or.
I u n dersta n d t hat t he S p o ns or ma y deci de t o s us pe n d or pre mat urel y ter mi nate t he st u d y 
at a n y ti me f or w hate ver 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 he st u d y, I will c o m m u nicate 
m y i nte nti o n i m me 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)


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 3
P R O T O C O L S Y N O P SI S
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ 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-J 1 0 1
I n vesti gati o nal Pr o d uct:
D S- 8 2 0 1a
Acti ve I n gre die nt(s)/I N N:
I n vesti gati o nal ne w dr u g (I N N) is n ot deter mi ne d.
St u d y Title:
P hase 1, T w o- part, M ultice nter, N o n-ra n d o mize d, O pe n-la bel, 
M ulti ple D ose First-i n- h u ma n St u d y of D S- 8 2 0 1a, i n S u bjects 
wit h A d va nce d S oli d Mali g na nt T u m ors
St u d y P hase:
P hase 1
I n dicati o n U n der 
I n vesti gati o n:
D S- 8 2 0 1a will be e val uate d i n s u bjects wit h a d va nce d s oli d 
t u m ors.
St u d y O bjecti ves:
P art 1 ( D ose Esc al ati o n)
Pri mar y O bjecti ves:
1.
T o assess t he safet y a n d t olera bilit y of D S- 8 2 0 1a. 
2.
T o deter mi ne t he ma xi m u m t olerate d d ose ( M T D) or 
t he rec o m me n de d P hase 2 d ose ( R P 2 D) of D S- 8 2 0 1a.
Sec o n dar y O bjecti ves:
1.
T o assess t he p har mac o ki netic ( P K) pr ofile of D S-
8 2 0 1a, t otal a nti- h u ma n e pi der mal gr o wt h fact or 
rece pt or 2 ( H E R 2) a nti b o d y, a n d M A A A- 1 1 8 1.
2.
T o e val uate t he efficac y of D S- 8 2 0 1a.
3.
T o assess t he i nci de nce of a nti- dr u g a nti b o d y ( A D A) 
a gai nst D S- 8 2 0 1a.
E x pl orat or y O bjecti ves:
1.
T o assess t he bi o mar kers relate d t o D S- 8 2 0 1a.
P art 2 ( D ose E x p a nsi o n)
Pri mar y O bjecti ves:
1.
T o assess t he safet y a n d t olera bilit y of D S- 8 2 0 1a at 
t he M T D/t he R P 2 D.
2.
T o e val uate t he efficac y of D S- 8 2 0 1a at t he M T D/t he 
R P 2 D.
Sec o n dar y O bjecti ves:
1.
T o assess t he P K pr ofile of D S- 8 2 0 1a, 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.
2.
T o assess t he i nci de nce of A D A a gai nst D S- 8 2 0 1a.
E x pl orat or y O bjecti ves:
1.
T o assess t he bi o mar kers relate d t o D S- 8 2 0 1a.
St u d y Desi g n:
T his is a P hase 1, t w o- part, m ultice nter, n o n-ra n d o mize d, 
o pe n-la bel, m ulti ple d ose, first i n h u ma n st u d y of D S- 8 2 0 1a.  
T his 2- part st u d y will i ncl u de b ot h a D ose Escalati o n part, t o 
i de ntif y t he M T D or t he R P 2 D of D S- 8 2 0 1a, a n d a D ose 
E x pa nsi o n part, t o c o nfir m t he safet y, t olera bilit y a n d efficac y 
of D S- 8 2 0 1a at t he M T D/ R P 2 D.  D ose escalati o n of D S-


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 4
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
8 2 0 1a t o deter mi ne t he M T D/ R P 2 D will be g ui de d b y t he 
m o difie d c o nti n u o us reassess me nt met h o d ( m C R M) usi n g a 
Ba yesia n l o gistic re gressi o n m o del ( B L R M) f oll o wi n g 
escalati o n wit h o ver d ose c o ntr ol ( E W O C) pri nci ple.  
P art 1 ( D ose Esc al ati o n)
D ose escalati o n will be gi n i n s u bjects wit h a d va nce d breast 
ca ncer a n d gastric or gastr oes o p ha geal j u ncti o n 
a de n ocarci n o ma.  At least 1 8 s u bjects will be e nr olle d i n 
Part 1.  M ore t ha n 1 6 % of s u bjects (e g, 1 per 6 s u bjects) are 
e x pecte d t o be H E R 2 e x pressi o n (i m m u n o hist oc he mistr y 
[I H C] 2 + or 3 +).  T he pr o p ose d h u ma n starti n g d ose of D S-
8 2 0 1a is 0. 8 m g/ k g, base d o n 1/ 1 2 h u ma n e q ui vale nt d ose 
( H E D) of hi g hest n o n-se verel y t o xic d ose ( H N S T D) i n 
m o n ke y ( 3 0 m g/ k g).  
D uri n g Part 1, a n i nitial d ose of D S- 8 2 0 1a will be i nf use d 
i ntra ve n o usl y i nt o eac h s u bject f or a p pr o xi matel y 9 0 mi n utes 
o n Da y 1 of C ycle 1.  A 2 1- da y o bser vati o n peri o d ( C ycle 1) 
will t he n occ ur, at t he e n d of w hic h all rele va nt safet y data 
will be re vie we d.  U p o n c o m pleti o n of C ycle 1, s u bjects ma y 
c o nti n ue t o recei ve D S- 8 2 0 1a o nce e ver y 3 wee ks ( Q 3 W) ( 1 
c ycle) at t he discreti o n of t he I n vesti gat ors, u ntil u nacce pta ble 
t o xicit y, pr o gressi ve disease ( P D), or wit h dra wal of c o nse nt.  
If t here is n o i nf usi o n relate d reacti o n after i nitial d ose, t he 
ne xt d ose of D S- 8 2 0 1a will be i nf use d i ntra ve n o usl y i nt o eac h 
s u bject f or a p pr o xi matel y 3 0 mi n utes.  T he s u bject’s wei g ht at 
scree ni n g ( baseli ne) will be use d t o calc ulate t he i nitial d ose.  
If t he s u bject’s wei g ht c ha n ges b y ± 1 0 % of t he baseli ne 
wei g ht, t he d ose will be recalc ulate d.  
D ose le vel i ncre me nt d uri n g d ose esc al ati o n ( P art 1) b y 
m C R M wit h E W O C

T he d ose le vel i ncre me nt s h o ul d be n o less t ha n 3 0 % 
i n or der t o ha ve disti ncti o n a m o n g d ose le vels 
c o nsi deri n g t he i nter-s u bject varia bilit y i n e x p os ure.

T he d ose le vel i ncre me nt s h o ul d be n o m ore t ha n 
1 0 0 % e ve n if t he m o del s u g gests a hi g her d ose t ha n 
1 0 0 % f or t he ne xt c o h ort.
T he escalati o n b y m C R M wit h E W O C pri nci ple will be base d 
o n a B L R M.  T he l o gistic re gressi o n m o del f or t he d ose-
res p o nse ( d ose li miti n g t o xicit y [ D L T] rate) relati o ns hi ps will 
i ncl u de 2 para meters, t he i nterce pt, a n d sl o pe.  After at least 3 
s u bjects of eac h c o h ort c o m plete D L T e val uati o n d uri n g C ycle 
1, t he p osteri or distri b uti o ns of D L T rate are deri ve d f or all 
d ose le vels base d o n t he B L R M usi n g D L T o utc o me data fr o m 
all assesse d d oses a n d a pre-s pecifie d pri or distri b uti o n f or t he 
m o del para meters.  T he p osteri or pr o ba bilit y of D L T rate i n 
t he f oll o wi n g 4 i nter vals at eac h d ose le vel: [ 0 %, 1 6 %] as 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
D L T rate i nter val f or u n der- d osi n g, ( 1 6 %, 3 3 %] as tar get D L T 
rate i nter val, ( 3 3 %, 6 0 %] as D L T rate i nter val f or e xcessi ve 
t o xicit y, a n d ( 6 0 %, 1 0 0 %] as D L T rate i nter val f or 
u nacce pta ble t o xicit y will t he n be calc ulate d, a n d use d f or 
d ose rec o m me n dati o n f or t he ne xt c o h ort acc or di n g t o t he 
E W O C pri nci ple.  T he E W O C pri nci ple re q uires t hat t he 
m C R M rec o m me n de d d ose f or t he ne xt c o h ort of s u bjects is 
t he o ne wit h t he hi g hest p osteri or pr o ba bilit y of t he D L T rate 
i n t he tar get D L T rate i nter val of ( 1 6 %, 3 3 %] a m o n g all d oses 
f ulfilli n g t he o ver d ose c o ntr ol c o nstrai nt: t here is less t ha n 
2 5 % of pr o ba bilit y f or D L T rate > 3 3 % ( pr o ba bilit y f or 
e xcessi ve or u nacce pta ble t o xicit y).
T he d ose f or t he ne xt c o h ort will be c h ose n b y t he S p o ns or 
base d o n t he d ose rec o m me n dati o n b y t he m C R M, cli nical 
assess me nt of t o xicit y pr ofiles, a n d P K i nf or mati o n o bser ve d 
t h us far.
C o h orts of at least 3 D L T e val ua ble s u bjects will be e nr olle d 
a n d assesse d f or D L T d uri n g t he d ose escalati o n pr ocess.  As 
a n e xce pti o n, t he m o del will be ree val uate d bef ore e nr oll me nt 
of a n y a d diti o nal s u bjects t o t he c o h ort if 2 D L T e val ua ble 
s u bjects i n t he c o h ort e x perie nce D L T bef ore t he e nr oll me nt 
of t he t hir d s u bject.  E nr oll me nt of s u bjects t o a ne w c o h ort 
re q uires c o m pleti o n of D L T e val uati o n of at least 3 s u bjects 
treate d i n t he c urre nt c o h ort.  S u bjects w h o ha ve neit her 
c o m plete d D L T e val uati o n n or e x perie nce d D L T will be 
ce ns ore d a n d n ot i ncl u de d i n t he B L R M u p date.  I n t he e ve nt 
w he n s u bjects i n t he pre vi o us c o h ort e x perie nce D L T after 
e nr oll me nt of s u bjects t o a ne w c o h ort has be g u n, d ose le vel 
assi g n me nt of t he ne xt s u bject i n t he ne w c o h ort will be base d 
o n a n u p date d B L R M usi n g D L T o utc o me data fr o m all 
assesse d d oses.
T he R P 2 D will be deci de d base d o n c o nsi derati o ns of t he 
res pecti ve M T D esti mate d b y t he m C R M, a n d o n a n o verall 
assess me nt of safet y data fr o m s u bse q ue nt c ycles a n d 
efficac y/ P K i nf or mati o n c ollecte d at all differe nt d oses teste d.  
F or d ose deter mi nati o n, t he f oll o wi n g st o p pi n g r ules will be 
i m ple me nte d f or t he d ose escalati o n p hase: (a) at least 6 
e val ua ble s u bjects ha ve bee n e nr olle d at t he M T D/ R P 2 D le vel 
wit h at least 1 8 e val ua ble s u bjects i n t otal e nr olle d i n t he d ose 
escalati o n part, or ( b) at least 9 e val ua ble s u bjects ha ve bee n 
e nr olle d at a d ose le vel w hic h is t he m o del’s rec o m me n dati o n 
f or t he ne xt d ose c o h ort a n d f or w hic h t he p osteri or 
pr o ba bilit y of tar gete d t o xicit y is at least 5 0 %, or (c) t he i nitial 
d ose le vel ( 0. 8 m g/ k g) is t o o t o xic.
C o h orts ma y be e x pa n de d at a n y d ose le vel or at t he M T D f or 
f urt her ela b orati o n of safet y, or P K para meters as re q uire d.
P art 2 ( D ose E x p a nsi o n)


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
U p o n c o m pleti o n of d ose escalati o n ( Part 1) wit h 
deter mi nati o n of M T D/ R P 2 D, t he d ose e x pa nsi o n part will 
be gi n.  
Part 2 will c o nsist of m ulti ple c o h orts: i n s u bjects wit h 
trast uz u ma b e mta nsi ne ( T- D M 1)-treate d H E R 2 
o vere x pressi n g breast ca ncer ( Part 2a); trast uz u ma b-treate d 
H E R 2 o vere x pressi n g gastric or gastr oes o p ha geal j u ncti o n 
a de n ocarci n o ma ( Part 2 b); H E R 2 l o w e x pressi n g breast ca ncer 
( Part 2c), H E R 2 e x pressi n g ot her s oli d mali g na nt t u m or or a n y 
t u m or wit h H E R 2 m utati o n ( Part 2 d); a n d H E R 2 e x pressi n g 
breast ca ncer ( Part 2e).  A p pr o xi matel y 1 0 0 s u bjects will be 
e nr olle d i n Part 2a, a p pr o xi matel y 4 0 s u bjects will be e nr olle d 
i n Part 2 b, a p pr o xi matel y 2 0 t o 4 0 s u bjects will be e nr olle d i n 
Part 2c, a p pr o xi matel y 6 0 s u bjects will be e nr olle d i n Part 2 d, 
a n d a p pr o xi matel y 2 0 s u bjects will be e nr olle d i n Part 2e, 
res pecti vel y.
S u bjects will recei ve D S- 8 2 0 1a o n Da y 1 of a 2 1- da y c ycle.  
T he i nitial d ose of D S- 8 2 0 1a will be i nf use d i ntra ve n o usl y 
i nt o eac h s u bject f or a p pr o xi matel y 9 0 mi n utes o n Da y 1 of 
C ycle 1.  If t here is n o i nf usi o n relate d reacti o n after i nitial 
d ose, t he ne xt d ose of D S- 8 2 0 1a will be i nf use d i ntra ve n o usl y 
i nt o eac h s u bject f or a p pr o xi matel y 3 0 mi n utes.  T he s u bject’s 
wei g ht at scree ni n g ( baseli ne) will be use d t o calc ulate t he 
i nitial d ose.  If t he s u bject’s wei g ht c ha n ges b y ± 1 0 % of t he 
baseli ne wei g ht, t he d ose will be recalc ulate d. 
D ose Li miti n g T o xicit y Defi niti o n
A D L T is defi ne d as a n y treat me nt-e mer ge nt a d verse e ve nt 
( T E A E) n ot attri b uta ble t o disease or disease-relate d pr ocesses 
t hat occ urs d uri n g t he D L T e val uati o n peri o d ( Da y 1 t o Da y 
2 1 i n C ycle 1 of Part 1) a n d is gra de 3 or a b o ve acc or di n g t o 
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E ve nt ( N CI- C T C A E) versi o n 4. 0, wit h t he e xce pti o ns 
as defi ne d bel o w:  
F or he mat ol o gical t o xicities, a D L T is defi ne d as f oll o ws:

Gra de 4 ne utr o p hil c o u nt decrease d lasti n g > 7 da ys

Gra de ≥ 3 fe brile ne utr o pe nia

Gra de 4 a ne mia

Gra de 4 platelet c o u nt decrease d

Gra de ≥ 3 platelet c o u nt decrease d lasti n g > 7 da ys 

Gra de ≥ 3 platelet c o u nt decrease d wit h cli nicall y 
si g nifica nt he m orr ha ge

Gra de 4 l y m p h oc yte c o u nt decrease d lasti n g ≥1 4 da ys
F or he patic or ga n t o xicities, a D L T is defi ne d as f oll o ws:

Gra de 4 as partate a mi n otra nsferase ( A S T) or ala ni ne 
a mi n otra nsferase ( A L T) i ncrease d


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3

A S T or A L T > 5  u p per li mit of n or mal ( U L N), if 
acc o m pa nie d b y gra de ≥ 2 bl o o d bilir u bi n i ncrease d

I n s u bjects wit h o ut li ver metastases, A S T or A L T > 5 
 U L N lasti n g  > 3 da ys

I n s u bjects wit h li ver metastases, A S T or A L T > 5  
U L N lasti n g  > 3 da ys, if t he baseli ne le vel was ≤ 3  
U L N

I n s u bjects wit h li ver metastases, A S T or A L T > 8  
U L N lasti n g  > 3 da ys, if t he baseli ne le vel was > 3  
U L N
F or n o n- he mat ol o gical, n o n- he patic maj or or ga n t o xicities, a 
D L T is defi ne d as f oll o ws:

S y m pt o matic C o n gesti ve heart fail ure ( C H F)

Left ve ntric ular ejecti o n fracti o n ( L V E F) decli ne t o < 
4 0 % or > 2 0 % dr o p fr o m baseli ne

Ot her gra de ≥ 3 n o n- he mat ol o gical, n o n- he patic maj or 
or ga n t o xicities
T he f oll o wi n g T E A Es are N O T c o nsi dere d D L Ts:

Gra de 3 fati g ue lasti n g < 7 da ys 

Gra de 3 na usea, v o miti n g, diarr hea, or a n ore xia t hat 
has res ol ve d t o gra de ≤ 2 wit hi n 3 da ys 

Is olate d la b orat or y fi n di n gs n ot ass ociate d wit h si g ns 
or s y m pt o ms i ncl u di n g gra de 3/ 4 al kali ne p h os p hatase 
( A L P) i ncrease d, h y per urice mia, ser u m a m ylase 
i ncrease d, a n d li pase i ncrease d, a n d gra de 3 
h y p o natre mia lasti n g  < 7 2 h o urs de vel o pe d fr o m 
gra de 1 at baseli ne

Gra de 3 l y m p h oc yte c o u nt decrease d
If a n y of t he a b o ve t o xicities is o bser ve d d uri n g t he D L T 
e val uati o n peri o d, w het her or n ot t he t o xicit y is re gar de d as 
D L T will be deter mi ne d base d o n c o ns ultati o n bet wee n t he 
I n vesti gat or a n d S p o ns or.
I n a d diti o n, wit h re gar d t o ot her t o xicities t hat hi n der t he 
c o n d uct of t he sc he d ule d st u d y treat me nt or a ne mia wit h bl o o d 
tra nsf usi o n, w het her or n ot t he y are re gar de d as D L T will be 
deter mi ne d base d o n c o ns ultati o n bet wee n t he I n vesti gat or a n d 
S p o ns or.  
St u d y D urati o n:
Part 1 is e x pecte d t o last a p pr o xi matel y o ne a n d a half years 
fr o m t he ti me t he first s u bject is e nr olle d t o t he ti me t he last 
s u bject is off t he D L T e val uati o n peri o d.  
Part 2 is e x pecte d t o last a p pr o xi matel y o ne a n d a half years 
fr o m t he ti me t he first s u bject is e nr olle d t o t he ti me t he last 
s u bject is off t he st u d y.
T he n u m ber of treat me nt c ycles is n ot fi xe d i n t his st u d y.  
S u bjects w h o c o nti n ue t o deri ve cli nical be nefit fr o m t he st u d y 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 8
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
treat me nt i n t he a bse nce of wit h dra wal of c o nse nt, P D or 
u nacce pta ble t o xicit y ma y c o nti n ue t he st u d y treat me nt.
St u d y Sites a n d L ocati o n:
St u d y sites fr o m Ja pa n a n d t he U nite d States are pla n ne d f or 
t his st u d y.  Part 2e ( D ose E x pa nsi o n) will be c o n d ucte d at 
Ja pa nese sites o nl y.
Pla n ne d Sa m ple Size:
Part 1: At least 1 8 D L T-e val ua ble s u bjects are nee de d t o reac h 
a n acc urate esti mate of t he M T D.
Part 2: A p pr o xi matel y 2 6 0 s u bjects ( 1 0 0 s u bjects f or Part 2a, 
4 0 s u bjects f or Part 2 b, 2 0 t o 4 0 s u bjects f or Part 2c, 
p ote ntiall y a d diti o nal 2 0 s u bjects f or Part 2c, 6 0 s u bjects f or 
Part 2 d a n d 2 0 s u bjects f or Part 2e) will be e nr olle d. 
Part 2a
If tar get o bjecti ve res p o nse rate ( O R R) is m ore t ha n 1 5 % ( n ull 
h y p ot hesis: O R R  0. 1 5, alter nati ve h y p ot hesis: O R R > 0. 1 5), 
t he n t he pr o ba bilit y of less t ha n 9 res p o n ders o ut of 1 0 0 
s u bjects will be less t ha n 5 %.  T he pr o ba bilit y t hat m ore t ha n 
2 1 res p o n ders o ut of 1 0 0 s u bjects ( O R R > 2 1 %) are o bser ve d 
will be less t ha n 5 % u n der t he n ull h y p ot hesis wit h 
O R R  0. 1 5 b ut m ore t ha n 9 0 % u n der alter nati ve h y p ot hesis 
wit h O R R = 0. 3 5. 
Part 2 b
If tar get O R R is m ore t ha n 1 0 % ( n ull h y p ot hesis: O R R  0. 1 0, 
alter nati ve h y p ot hesis: O R R > 0. 1 0), t he n t he pr o ba bilit y of n o 
res p o nse o ut of 4 0 s u bjects will be less t ha n 5 %.  T he 
pr o ba bilit y t hat m ore t ha n 7 res p o n ders o ut of 4 0 s u bjects 
( O R R > 1 7. 5 %) are o bser ve d will be less t ha n 5 % u n der t he 
n ull h y p ot hesis wit h O R R  0. 1 0 b ut m ore t ha n 8 0 % u n der 
alter nati ve h y p ot hesis wit h O R R = 0. 2 5. 
Part 2c a n d Part 2e
If tar get O R R is m ore t ha n 1 5 % ( n ull h y p ot hesis: O R R  0. 1 5, 
alter nati ve h y p ot hesis: O R R > 0. 1 5), t he n t he pr o ba bilit y of n o 
res p o nse o ut of 2 0 s u bjects will be less t ha n 5 %.  T he 
pr o ba bilit y t hat m ore t ha n 4 res p o n ders o ut of 2 0 s u bjects 
( O R R > 2 0 %) are o bser ve d will be less t ha n 2 0 % u n der t he 
n ull h y p ot hesis wit h O R R  0. 1 5 b ut m ore t ha n 7 5 % u n der 
alter nati ve h y p ot hesis wit h O R R = 0. 3 0. 
Part 2 d
If tar get O R R is m ore t ha n 1 5 % ( n ull h y p ot hesis: O R R  0. 1 5, 
alter nati ve h y p ot hesis: O R R > 0. 1 5), t he n t he pr o ba bilit y of 
less t ha n 5 res p o n ders o ut of 6 0 s u bjects will be less t ha n 5 %.  
T he pr o ba bilit y t hat m ore t ha n 1 4 res p o n ders o ut of 6 0 
s u bjects ( O R R > 2 3. 3 %) are o bser ve d will be less t ha n 5 % 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 9
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
u n der t he n ull h y p ot hesis wit h O R R  0. 1 5 b ut m ore t ha n 8 0 % 
u n der alter nati ve h y p ot hesis wit h O R R = 0. 3 0.
T he pr o ba bilit y val ues f or t he sa m ple size are deri ve d base d 
o n bi n o mial distri b uti o n usi n g S A S ®  versi o n 9. 2.
S u bject Eli gi bilit y Criteria:
I ncl usi o n Criteri a
S u bjects m ust satisf y all of t he f oll o wi n g criteria t o be 
i ncl u de d i n t he st u d y:
C o m m o n I ncl usi o n Criteri a ( P art 1 a n d P art 2):
1.
A ge  2 0 years i n Ja pa n,  1 8 years i n t he U nite d 
States.
2.
Has a n Easter n C o o perati ve O nc ol o g y Gr o u p 
perf or ma nce stat us ( E C O G P S) 0- 1.
3.
Has L V E F  5 0 % b y eit her ec h ocar di o gra p h y 
( E C H O) or m ulti ple- gate d ac q uisiti o n ( M U G A) 
wit hi n 2 8 da ys bef ore re gistrati o n.
4.
Has a de q uate or ga n f u ncti o n wit hi n 7 da ys bef ore 
re gistrati o n, defi ne d as:
Ite m
L a b or at or y v al ue
Platelet c o u nt
 1 0 0 0 0 0/ m m 3
He m o gl o bi n ( H b)
≥ 8. 5 g/ d L
A bs ol ute ne utr o p hil 
c o u nt ( A N C)
 1 5 0 0/ m m 3
Creati ni ne
≤ 1. 5  U L N, or creati ni ne 
cleara nce ≥ 6 0 m L/ mi n as 
calc ulate d usi n g t he 
m o dificati o n C oc kcr oft- Ga ult 
e q uati o n
A S T/ A L T
≤ 3  U L N (if li ver metastases 
are prese nt, ≤ 5  U L N)
T otal bilir u bi n
≤ 1. 5  U L N or < 3 × U L N i n 
t he prese nce of d oc u me nte d 
Gil bert’s S y n dr o me or li ver 
metastases at baseli ne
Pr ot hr o m bi n ti me a n d 
acti vate d partial 
t hr o m b o plasti n ti me
≤ 1. 5 × U L N
5.
Has a de q uate treat me nt was h o ut peri o d bef ore 
re gistrati o n, defi ne d as:
Tre at me nt
W as h o ut peri o d
Maj or s ur ger y
 4 wee ks
Ra diati o n t hera p y
≥ 4 wee ks (if palliati ve 
stere otactic ra diati o n t hera p y 
wit h o ut a b d o mi nal, ≥ 2 wee ks)
A ut ol o g o us 
tra ns pla ntati o n
 3 m o nt hs 
H or m o nal t hera p y
 3 wee ks
C he m ot hera p y 
 3 wee ks ( 2 wee ks f or 5-


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 0
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
(i ncl u di n g a nti b o d y 
dr u g t hera p y)
fl u or o uracil- base d a ge nts, 
f oli nate a ge nts a n d/ or wee kl y 
Paclita xel.   6 wee ks f or 
nitr os o ureas or mit o m yci n C, 
> 1 wee k f or T KIs a p pr o ve d f or 
t he treat me nt of N S C L C - 
baseli ne C T sca n m ust be 
c o m plete d after disc o nti n uati o n 
of T KI)
I m m u n ot hera p y
 4 wee ks
C yt oc hr o me P 4 5 0 
( C Y P) 3 A 4 str o n g 
i n hi bit or
 3 eli mi nati o n half-li ves of t he 
i n hi bit or
Or ga nic a ni o n 
tra ns p orti n g 
p ol y pe pti de i n hi bit or
 3 eli mi nati o n half-li ves of t he 
i n hi bit or
6.
Is a ble t o pr o vi de writte n i nf or me d c o nse nt.  S u bject 
m ust be f ull y i nf or me d a b o ut t heir ill ness a n d t he 
i n vesti gati o nal nat ure of t he st u d y pr ot oc ol (i ncl u di n g 
f oreseea ble ris ks a n d p ossi ble t o xicities) a n d m ust 
si g n a n d date a n I nstit uti o nal Re vie w B oar d (I R B) 
a p pr o ve d i nf or me d c o nse nt f or m (I C F) (i ncl u di n g 
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
[ HI P A A] a ut h orizati o n, if a p plica ble) bef ore 
perf or ma nce of a n y st u d y-s pecific pr oce d ures or 
e xa mi nati o ns.
7.
Is willi n g t o pr o vi de pre-e xisti n g dia g n ostic or 
resecte d t u m or sa m ples.
8.
Has a life e x pecta nc y of ≥ 3 m o nt hs.
A d diti o n al I ncl usi o n Criteri a f or P art 1 ( D ose Esc al ati o n)
9.
Has a pat h ol o gicall y d oc u me nte d 
a d va nce d/ u nresecta ble or metastatic breast ca ncer or 
gastric or gastr oes o p ha geal j u ncti o n a de n ocarci n o ma 
t hat is refract or y t o or i nt olera ble wit h 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.
A d diti o n al I ncl usi o n Criteri a f or P art 2 a ( D ose E x p a nsi o n)
1 0.
Has a pat h ol o gicall y d oc u me nte d 
a d va nce d/ u nresecta ble or metastatic breast ca ncer 
wit h H E R 2 o vere x pressi o n (I H C 3 + or i n sit u 
h y bri dizati o n [I S H *] +) t hat is refract or y t o or 
i nt olera ble wit h 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.
* I S H: fl u oresce nce i n sit u h y bri dizati o n ( FI S H)  or 
d ual c ol or i n sit u h y bri dizati o n ( DI S H)
1 1. Treate d wit h T- D M 1.
1 2.
Has meas ura ble disease base d o n Res p o nse 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 1
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) 
versi o n 1. 1.
A d diti o n al I ncl usi o n Criteri a f or P art 2 b ( D ose E x p a nsi o n)
1 3.
Has a pat h ol o gicall y d oc u me nte d 
a d va nce d/ u nresecta ble or metastatic gastric or 
gastr oes o p ha geal j u ncti o n a de n ocarci n o ma wit h 
H E R 2 o vere x pressi o n (I H C 3 + or I H C 2 +/I S H * +) 
t hat is refract or y t o or i nt olera ble wit h 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.  It is rec o m me n de d t o o btai n H E R 2 stat us 
after c o m pleti n g t he last H E R 2-tar geti n g treat me nt.
* I S H: FI S H or DI S H
1 4. Treate d wit h trast uz u ma b.
1 5.
Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
A d diti o n al I ncl usi o n Criteri a f or P art 2c ( D ose E x p a nsi o n)
1 6.
Has a pat h ol o gicall y d oc u me nte d 
a d va nce d/ u nresecta ble or metastatic breast ca ncer 
wit h H E R 2 l o w e x pressi o n (I H C 2 +/I S H * –, I H C 
1 +/I S H * –, or I H C 1 +/I S H * u nteste d) t hat is 
refract or y t o or i nt olera ble wit h 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.  S u bjects 
wit h H E R 2 l o w e x pressi o n metastatic breast ca ncer 
w h o ha ve e x ha uste d treat me nts t hat ca n c o nfer a n y 
cli nicall y mea ni n gf ul be nefit (e g, ot her t hera pies s uc h 
as h or m o nal t hera p y f or patie nts w h o are h or m o ne 
rece pt or p ositi ve) are als o eli gi ble.
* I S H: FI S H or DI S H
1 7.
Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
A d diti o n al I ncl usi o n Criteri a f or P art 2 d ( D ose E x p a nsi o n)
1 8. Satisf y at least o ne of t he f oll o wi n g criteria. 

Has a pat h ol o gicall y d oc u me nte d 
a d va nce d/ u nresecta ble or metastatic s oli d 
mali g na nt t u m or wit h H E R 2 e x pressi o n 
( deter mi ne d b y I H C, FI S H, Ne xt Ge nerati o n 
Se q ue nci n g, or ot her a nal ysis tec h ni q ues as 
a p pr o priate) ot her t ha n breast ca ncer a n d gastric 
or gastr oes o p ha geal j u ncti o n a de n ocarci n o ma t hat 
is refract or y t o or i nt olera ble wit h 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.

Has a pat h ol o gicall y d oc u me nte d 
a d va nce d/ u nresecta ble or metastatic s oli d 
mali g na nt t u m or wit h H E R 2 m utati o n 
( deter mi ne d b y Ne xt Ge nerati o n Se q ue nci n g or 
ot her a nal ysis tec h ni q ues as a p pr o priate) t hat is 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
refract or y t o or i nt olera ble wit h 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.
2 3. Is a ble t o pr o vi de fres h t u m or bi o ps y s peci me n.
1 9.
Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
A d diti o n al I ncl usi o n Criteri a f or P art 2e ( D ose E x p a nsi o n)
2 0.
Has a pat h ol o gicall y d oc u me nte d 
a d va nce d/ u nresecta ble or metastatic breast ca ncer 
wit h H E R 2 e x pressi o n (I H C 1 +, I H C 2 +, I H C 3 + 
a n d/ or I S H * +) t hat is refract or y t o or i nt olera ble wit h 
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. 
2 1. Treate d wit h T- D M 1 ( patie nts wit h H E R 2 
o vere x pressi o n o nl y).
2 2.
Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
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 criteria will be 
dis q ualifie d fr o m e nteri n g t he st u d y:
1.
Has a me dical hist or y of s y m pt o matic C H F ( Ne w 
Y or k Heart Ass ociati o n [ N Y H A] classes II-I V) or 
seri o us car diac arr h yt h mia re q uiri n g treat me nt.
2.
Has a me dical hist or y of m y ocar dial i nfarcti o n or 
u nsta ble a n gi na wit hi n 6 m o nt hs bef ore re gistrati o n or 
tr o p o ni n le vels c o nsiste nt wit h m y ocar dial i nfarcti o n 
as defi ne d acc or di n g t o ma n ufact urer.
3.
Has a Q Tc pr ol o n gati o n t o > 4 5 0 millisec o n d ( ms) i n 
males a n d > 4 7 0 ms i n fe males base d o n a 1 2-lea d 
electr ocar di o gra m ( E C G) i n tri plicate.
4.
Has a hist or y of ( n o n-i nfecti o us) i nterstitial l u n g 
disease (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 ne 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 
scree ni n g.
5.
Has a n u nc o ntr olle d i nfecti o n re q uiri n g i ntra ve n o us 
i njecti o n (I V) of a nti bi otics, a nti virals, or a ntif u n gals.
6.
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.
7.
Is a lactati n g m ot her ( W o me n w h o are willi n g t o 
te m p oraril y i nterr u pt breastfee di n g will als o be 
e xcl u de d), or pre g na nt as c o nfir me d b y pre g na nc y 
tests perf or me d wit hi n 7 da ys bef ore re gistrati o n.
8.
Male a n d fe male s u bjects w h o are u n willi n g t o use 
a de q uate c o ntrace pti ve met h o ds (e g, c o nc o mita nt use 
of a s per mat oci dal a ge nt a n d barrier c o ntrace pti ve, 
i ntra uteri ne c o ntrace pti ve, w hic h are a p pr o ve d or 
certificate d i n Ja pa n [f or Ja pa nese s u bjects] a n d U S 




Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 4
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
m g/ k g of D S- 8 2 0 1a Q 3 W a n d a n ot her a p pr o xi matel y 2 0 
s u bjects will recei ve 5. 4 m g/ k g of D S- 8 2 0 1a Q 3 W.  I n Part 2c, 
first a p pr o xi matel y 2 0 s u bjects will recei ve 6. 4 m g/ k g of D S-
8 2 0 1a Q 3 W b ut a d diti o nal a p pr o xi matel y 2 0 s u bjects ma y 
recei ve a n ot her d ose le vel of D S- 8 2 0 1a Q 3 W.  I n Part 2 d a n d 
Part 2e, all s u bjects will recei ve 6. 4 m g/ k g of D S- 8 2 0 1a Q 3 W.  
St u d y E n d p oi nts:
Safet y e n d p oi nts:
Safet y e n d p oi nts will i ncl u de D L Ts, seri o us a d verse e ve nts 
( S A Es), T E A Es, p h ysical e xa mi nati o n fi n di n gs (i ncl u di n g 
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 para meters, E C G para meters, E C H O/ M U G A 
fi n di n gs, a n d o p ht hal m ol o gic fi n di n gs.  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 4. 0.
P har mac o ki netic e n d p oi nts:
Ser u m P K para meters (area u n der t he c o nce ntrati o n- vers us-
ti me c ur ve, fr o m ti me 0 t o t he last meas ura ble c o nce ntrati o n as 
calc ulate d b y t he li near- u p l o g- d o w n tra pez oi dal met h o d 
[ A U Clast], A U C d uri n g d osi n g i nter val [ A U Cta u], ma xi m u m 
( pea k) o bser ve d c o nce ntrati o n [ C ma x], ti me of ma xi m u m 
o bser ve d c o nce ntrati o n [ T ma x] a n d tr o u g h ser u m 
c o nce ntrati o ns [ Ctr o u g h]) of D S- 8 2 0 1a f or eac h s u bject will 
be esti mate d usi n g sta n dar d n o nc o m part me ntal met h o ds.  F or 
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, all para meters 
liste d a b o ve will be esti mate d.  Descri pti ve statistics will be 
pr o vi de d f or all ser u m c o nce ntrati o n data a n d P K para meter 
val ues, wit h a brea k d o w n b y d ose le vel/c o h ort wit hi n eac h 
Part a n d st u d y da y as a p pr o priate. 
Efficac y e n d p oi nts:
T u m or res p o nse will be e val uate d usi n g R E CI S T versi o n 1. 1.  
O R R (t he s u m of c o m plete res p o nse [ C R] rate a n d partial 
res p o nse [ P R] rate), disease c o ntr ol rate ( D C R, t he s u m of C R 
rate, P R rate, a n d sta ble disease [ S D] rate), res p o nse d urati o n, 
d urati o n of S D, ti me t o res p o nse ( T T R), a n d pr o gressi o n free 
s ur vi val ( P F S), o verall s ur vi val ( O S), perce nt c ha n ge i n tar get 
lesi o n, ti me o n t hera p y of t he m ost rece nt pri or re gi me n t he 
s u bject recei ve d a n d t hat of D S- 8 2 0 1a.  T he Efficac y 
Varia ble(s) will be als o e val uate d at 1 8 wee ks after Da y 1 of 
C ycle 1.
Statistical A nal yses:
T he data c ut off f or t he pri mar y a nal ysis will occ ur after all 
s u bjects ha ve eit her disc o nti n ue d t he st u d y or t he last s u bject 
e nr olle d i n Part 2 of t he st u d y has c o m plete d at least 6 m o nt hs 
of st u d y dr u g treat me nt.  After t he pri mar y a nal ysis, t he mai n 
st u d y will be cl ose d a n d t he data will be f oll o we d u ntil 
c o m pleti o n.  
Descri pti ve statistics will be pr o vi de d f or selecte d 
de m o gra p hic, safet y, a n d P K data b y d ose le vel/c o h ort wit hi n 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 5
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
eac h Part a n d ti me as a p pr o priate.  Descri pti ve statistics o n 
c o nti n u o us data will i ncl u de mea ns, me dia ns, sta n dar d 
de viati o ns, a n d ra n ges (as well as ge o metric mea ns a n d 
ge o metric c oefficie nt of variati o n f or C ma x a n d A U C P K 
para meters), w hile cate g orical data will be s u m marize d usi n g 
fre q ue nc y c o u nts a n d perce nta ges.  Gra p hical s u m maries of 
t he data ma y be prese nte d.  
Safet y A nal yses:
T he safet y pr ofile will be base d o n a d verse e ve nts ( A Es), 
p h ysical e xa mi nati o n fi n di n gs, vital si g n meas ure me nts, 
cli nical la b orat or y meas ure me nts, E C G rec or di n gs, 
E C H O/ M U G A fi n di n gs, a n d o p ht hal m ol o gic fi n di n gs.  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 4. 0.  I n 
t he D ose Escalati o n part, t he i nci de nce of D L Ts will als o be 
e val uate d.
Safet y a nal yses i n ge neral will be descri 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.  I n t he D ose Escalati o n part, t he n u m ber of D L Ts 
i de ntifie d a m o n g t he D L T-e val ua ble s u bjects i n t he D L T-
e val ua ble set will be liste d a n d s u m marize d f or eac h c o h ort of 
D S- 8 2 0 1a.
Efficac y A nal yses:
Efficac y varia bles will i ncl u de O R R (t he s u m of C R a n d P R 
rates); D C R (t he s u m of C R rate, P R rate, a n d S D rate f or a 
mi ni m u m of 5 wee ks fr o m t he first d osi n g date), res p o nse 
d urati o n, d urati o n of S D, T T R, a n d P F S, usi n g R E CI S T 1. 1.
T he efficac y varia bles will be liste d a n d s u m marize d.  F or 
O R R a n d D C R, p oi nt esti mates a n d 9 5 % e xact bi n o mial 
c o nfi de nce i nter vals will be pr o vi de d.  Ti me t o e ve nt varia bles 
i ncl u di n g P F S, O S, T T R, res p o nse d urati o n, a n d d urati o n of 
S D will be s u m marize d descri pti vel y usi n g t he Ka pla n- Meier 
met h o d.  P F S is defi ne d as t he ti me fr o m t he date of t he first 
d ose t o t he earlier of t he dates of t he first o bjecti ve 
d oc u me ntati o n of ra di o gra p hic P D or deat h d ue t o a n y ca use.  
Ce ns ori n g r ules f or t he P F S a nal ysis will be s pecifie d i n t he 
statistical a nal ysis pla n ( S A P).  T he gr o wt h m o d ulati o n 
i n dices (t he i ntras u bject rati o of P F S p ost-st u d y treat me nt 
vers us P F S p ost t he m ost rece nt pri or t hera pe utic re gi me n) 
will be s u m marize d.
Descri pti ve statistics f or t he best perce nt c ha n ge i n t he s u m of 
l o n gest di me nsi o ns ( S L D) of meas ura ble t u m ors will be 
pr o vi de d.  A waterfall pl ot of t he best perce nt c ha n ge fr o m 
scree ni n g i n t he S L D f or eac h s u bject will be prese nte d f or 
s u bjects wit h a d va nce d s oli d mali g na ncies.
P har mac o ki netic A nal yses:


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 6
E u dr a C T/I N D N u m ber:
E u dr a C T: N ot o bt ai ne d/ I N D N u m ber: 1 2 7 5 5 3
P K a nal yses will be perf or me d o n t he P K a nal ysis set.  Ser u m 
c o nce ntrati o n-ti me data f or D S- 8 2 0 1a, 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 will be liste d, pl otte d, a n d 
s u m marize d usi n g descri pti ve statistics b y d ose le vel/c o h ort 
wit hi n eac h Part at eac h p oi nt a n d i n st u d y peri o d ( Part 1 a n d 
Part 2). 
P K para meters will be liste d a n d s u m marize d usi n g 
descri pti ve statistics b y d ose le vel/c o h ort wit hi n eac h Part.
Bi o mar ker a n d E x pl orat or y A nal yses:
E x pl orati ve a nal yses f or bi o mar kers will be liste d a n d 
s u m marize d usi n g descri pti ve statistics.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 7
T A B L E O F C O N T E N T S
I N V E S TI G A T O R A G R E E M E N T................................................................................... 2
P R O T O C O L S Y N O P SI S.................................................................................................. 3
LI S T O F A B B R E VI A TI O N S......................................................................................... 2 7
1. 
I N T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N.................. 3 1
1. 1.  
Data S u m mar y................................................................................................ 3 1
1. 1. 1. 
I n vesti gati o nal Pr o d uct(s)............................................................................... 3 1
1. 1. 1. 1.  
Na me............................................................................................................... 3 1
1. 1. 1. 2.  
Descri pti o n...................................................................................................... 3 1
1. 1. 1. 3. 
I nte n de d Use U n der I n vesti gati o n.................................................................. 3 1
1. 1. 1. 4.  
N o ncli nical St u dies......................................................................................... 3 1
1. 1. 1. 5. 
Cli nical E x perie nce......................................................................................... 3 5
1. 2. 
St u d y Rati o nale............................................................................................... 3 5
1. 3. 
Ris ks a n d Be nefits f or St u d y S u bjects............................................................ 3 7
1. 4. 
P o p ulati o n, R o ute, D osa ge, D osa ge Re gi me n, Treat me nt Peri o d.................. 3 7
1. 5. 
C o m plia nce State me nt, Et hics a n d Re g ulat or y C o m plia nce.......................... 3 7
1. 5. 1. 
S u bject C o nfi de ntialit y................................................................................... 3 7
1. 5. 2. 
I nf or me d C o nse nt Pr oce d ure.......................................................................... 3 8
1. 5. 3. 
Re g ulat or y C o m plia nce.................................................................................. 3 9
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 S E S........................................... 4 0
2. 1. 
St u d y O bjecti ves............................................................................................. 4 0
2. 1. 1. 
Pri mar y O bjecti ves ......................................................................................... 4 0
2. 1. 1. 1. 
Part 1 ( D ose Escalati o n) ................................................................................. 4 0
2. 1. 1. 2. 
Part 2 ( D ose E x pa nsi o n)................................................................................. 4 0
2. 1. 2. 
Sec o n dar y O bjecti ves ..................................................................................... 4 0
2. 1. 2. 1. 
Part 1 ( D ose Escalati o n) ................................................................................. 4 0
2. 1. 2. 2. 
Part 2 ( D ose E x pa nsi o n)................................................................................. 4 0
2. 1. 3. 
E x pl orat or y O bjecti ves: Part 1 ( D ose Escalati o n) a n d Part 2 ( D ose 
E x pa nsi o n)...................................................................................................... 4 0
2. 2. 
St u d y H y p ot hesis............................................................................................ 4 0
3. 
S T U D Y D E SI G N .......................................................................................... 4 1
3. 1.  
O verall Pla n.................................................................................................... 4 1


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 8
3. 1. 1. 
St u d y T y pe...................................................................................................... 4 1
3. 1. 2. 
Treat me nt Gr o u ps........................................................................................... 4 1
3. 1. 3. 
St u d y E n d p oi nts.............................................................................................. 4 3
3. 1. 4.  
D urati o n of t he St u d y...................................................................................... 4 3
3. 1. 5.  
D urati o n of S u bject Partici pati o n ................................................................... 4 3
3. 1. 6. 
St o p pi n g R ules................................................................................................ 4 3
3. 1. 7.  
D ose-li miti n g T o xicities................................................................................. 4 4
3. 1. 8.  
Ma xi m u m T olerate d D ose a n d Rec o m me n de d P hase 2 D ose Defi niti o n ...... 4 5
3. 1. 9.  
Ma na ge me nt of S u bjects Wit h A d verse E ve nts of I nterests .......................... 4 5
3. 1. 9. 1. 
I nf usi o n Relate d Reacti o ns............................................................................. 4 5
3. 1. 9. 2. 
Car diac T o xicit y ............................................................................................. 4 6
3. 1. 9. 3. 
P ul m o nar y T o xicit y........................................................................................ 4 7
3. 2. 
Selecti o n of D oses .......................................................................................... 4 8
3. 2. 1. 
E x peri me ntal Treat me nts................................................................................ 4 8
3. 2. 1. 1. 
F or t he St u d y................................................................................................... 4 8
3. 2. 1. 2. 
F or I n di vi d ual S u bjects................................................................................... 4 8
3. 2. 2. 
C o ntr ol Treat me nts......................................................................................... 5 2
4. 
S T U D Y P O P U L A TI O N............................................................................... 5 3
4. 1. 
E nr oll me nt ...................................................................................................... 5 3
4. 1. 1. 
I ncl usi o n Criteria............................................................................................ 5 3
4. 1. 1. 1. 
C o m m o n I ncl usi o n Criteria ( Part 1 a n d Part 2).............................................. 5 4
4. 1. 1. 2.  
A d diti o nal I ncl usi o n Criteria f or Part 1 ( D ose Escalati o n) ............................ 5 5
4. 1. 1. 3.  
A d diti o nal I ncl usi o n Criteria f or Part 2a ( D ose E x pa nsi o n) .......................... 5 5
4. 1. 1. 4.  
A d diti o nal I ncl usi o n Criteria f or Part 2 b ( D ose E x pa nsi o n).......................... 5 5
4. 1. 1. 5.  
A d diti o nal I ncl usi o n Criteria f or Part 2c ( D ose E x pa nsi o n) .......................... 5 5
4. 1. 1. 6.  
A d diti o nal I ncl usi o n Criteria f or Part 2 d ( D ose E x pa nsi o n).......................... 5 5
4. 1. 1. 7.  
A d diti o nal I ncl usi o n Criteria f or Part 2e ( D ose E x pa nsi o n) .......................... 5 6
4. 1. 2. 
E xcl usi o n Criteria........................................................................................... 5 6
4. 1. 2. 1.  
A d diti o nal E xcl usi o n Criteria f or Part 2 ( D ose E x pa nsi o n)........................... 5 7
4. 2. 
Re m o val of S u bjects Fr o m T hera p y............................................................... 5 7
4. 2. 1. 
Reas o ns f or Wit h dra wal/ Earl y Disc o nti n uati o n............................................. 5 7
4. 2. 2.  
Wit h dra wal Pr oce d ures................................................................................... 5 8


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 9
4. 2. 3. 
S u bject Re place me nt ...................................................................................... 5 8
4. 2. 4. 
S u bject Re-scree ni n g Pr oce d ures ................................................................... 5 8
5. 
T R E A T M E N T S A D MI NI S T E R E D............................................................ 5 9
5. 1. 
I n vesti gati o nal Pr o d ucts.................................................................................. 5 9
5. 1. 1.  
Met h o d of Assi g ni n g S u bjects t o Treat me nts a n d Bli n di n g........................... 5 9
5. 1. 1. 1. 
Ra n d o mizati o n................................................................................................ 5 9
5. 1. 1. 2. 
Bli n di n g.......................................................................................................... 5 9
5. 1. 2.  
Met h o d of Assessi n g Treat me nt C o m plia nce................................................. 5 9
5. 1. 3. 
La beli n g a n d Pac ka gi n g.................................................................................. 5 9
5. 1. 4. 
Pre parati o n...................................................................................................... 5 9
5. 1. 5. 
St ora ge............................................................................................................ 6 0
5. 1. 6.  
Dr u g Acc o u nta bilit y ....................................................................................... 6 0
5. 1. 7. 
Rete nti o n Sa m ples.......................................................................................... 6 0
5. 2. 
C o nc o mita nt Me dicati o ns............................................................................... 6 0
5. 2. 1. 
Pr o hi bite d C o nc o mita nt Me dicati o ns/ Acti vities............................................. 6 0
6. 
S T U D Y P R O C E D U R E S.............................................................................. 6 2
6. 1. 
Scree ni n g ........................................................................................................ 6 2
6. 2. 
Ra n d o mizati o n................................................................................................ 6 3
6. 3. 
Treat me nt Peri o d ............................................................................................ 6 3
6. 3. 1. 
T u m or assess me nt........................................................................................... 6 4
6. 3. 2. 
C ycle 1, Da y 1 ................................................................................................ 6 4
6. 3. 2. 1. 
Bef ore I nf usi o n............................................................................................... 6 4
6. 3. 2. 2.  
A d mi nistrati o n a n d after I nf usi o n................................................................... 6 4
6. 3. 3. 
C ycle 1, Da y 2 ................................................................................................ 6 5
6. 3. 4. 
C ycle 1, Da y 4 ................................................................................................ 6 6
6. 3. 5. 
C ycle 1, Da y 8 ................................................................................................ 6 6
6. 3. 6. 
C ycle 1, Da y 1 5 .............................................................................................. 6 6
6. 3. 7. 
C ycle 1, Da y 2 2 .............................................................................................. 6 7
6. 3. 8. 
C ycle 2, Da y 1 ................................................................................................ 6 7
6. 3. 8. 1. 
Bef ore I nf usi o n............................................................................................... 6 7
6. 3. 8. 2.  
A d mi nistrati o n a n d after I nf usi o n................................................................... 6 8
6. 3. 9. 
C ycle 2, Da y 8 a n d Da y 1 5............................................................................. 6 9


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 0
6. 3. 1 0. 
C ycle 2, Da y 2 2 .............................................................................................. 6 9
6. 3. 1 1. 
C ycle 3, Da y 1 ................................................................................................ 6 9
6. 3. 1 1. 1. 
Bef ore I nf usi o n............................................................................................... 6 9
6. 3. 1 1. 2.  
A d mi nistrati o n a n d after I nf usi o n................................................................... 7 0
6. 3. 1 2. 
C ycle 3, Da y 8 a n d Da y 1 5............................................................................. 7 1
6. 3. 1 3. 
C ycle 3, Da y 2 2 .............................................................................................. 7 1
6. 3. 1 4. 
C ycle 4 a n d S u bse q ue nt C ycles, Da y 1.......................................................... 7 2
6. 3. 1 4. 1. 
Bef ore I nf usi o n............................................................................................... 7 2
6. 3. 1 4. 2.  
A d mi nistrati o n a n d after I nf usi o n................................................................... 7 3
6. 4. 
E n d of Treat me nt............................................................................................ 7 4
6. 5. 
F oll o w- u p........................................................................................................ 7 5
6. 6.  
Ne w Ca ncer Treat me nt a n d S ur vi val F oll o w- u p............................................ 7 5
6. 7. 
Pr ot oc ol De viati o ns ........................................................................................ 7 6
6. 8. 
P har mac o ki netic ( P K), P har mac o d y na mic ( P D y), E x pl orat or y Bi o mar ker 
a n d H u ma n A nti- h u ma n A nti b o dies............................................................... 7 6
6. 8. 1. 
Ser u m Sa m pli n g.............................................................................................. 7 6
6. 8. 2. 
T u m or Sa m pli n g............................................................................................. 7 6
6. 8. 2. 1. 
T u m or Sa m ples ( F or all s u bjects)................................................................... 7 6
6. 8. 2. 2. 
T u m or Sa m ples f or E x pl orat or y Bi o mar ker ( A d diti o nal f or Part 2 d o nl y).... 7 7
6. 8. 3. 
P har mac o ki netic ( P K)..................................................................................... 7 7
6. 8. 4. 
P har mac o d y na mic ( P D y)................................................................................ 7 9
6. 8. 5. 
E x pl orat or y Bi o mar ker................................................................................... 7 9
6. 8. 6.  
A nti- dr u g A nti b o d y ........................................................................................ 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. 
Pri mar y Efficac y Varia ble(s).......................................................................... 8 2
7. 2. 
Sec o n dar y Efficac y Varia ble(s)...................................................................... 8 2
7. 3. 
E x pl orat or y Efficac y Varia ble(s).................................................................... 8 2
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 3
8. 1. 
P har mac o ki netic ( P K) Varia ble(s).................................................................. 8 3
8. 2. 
P har mac o d y na mic ( P D y) Varia ble(s)............................................................. 8 3
8. 3. 
Bi o mar ker a n d E x pl orat or y Varia ble(s) ......................................................... 8 3
9. 
S A F E T Y A S S E S S M E N T S........................................................................... 8 4
9. 1.  
A d verse E ve nts............................................................................................... 8 4


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 1
9. 2. 
Safet y E n d p oi nts............................................................................................. 8 4
9. 3. 
E ve nts of S pecial I nterest ............................................................................... 8 5
9. 3. 1. 
Car di ot o xicit y ( Car diac-relate d e ve nts i ncl u di n g Q T Pr ol o n gati o n a n d L V E F 
Decrease) ........................................................................................................ 8 5
9. 3. 2. 
I nterstitial L u n g Disease/ P ne u m o nitis............................................................ 8 5
9. 3. 2. 1. 
I nterstitial L u n g Disease A dj u dicati o n C o m mittee ........................................ 8 6
9. 3. 3. 
I nf usi o n-relate d reacti o ns ............................................................................... 8 6
9. 4.  
Defi niti o ns ...................................................................................................... 8 6
9. 4. 1.  
A d verse E ve nt ( A E)........................................................................................ 8 6
9. 4. 2. 
Seri o us A d verse E ve nt ( S A E) ........................................................................ 8 7
9. 4. 3.  
A E Se verit y..................................................................................................... 8 7
9. 4. 4. 
Ca usalit y Assess me nt..................................................................................... 8 8
9. 4. 5.  
Acti o n Ta ke n Re gar di n g t he St u d y Pr o d uct................................................... 8 8
9. 4. 6.  
A d verse E ve nt O utc o me................................................................................. 8 8
9. 4. 7.  
Ot her Acti o n Ta ke n f or E ve nt ........................................................................ 8 9
9. 5. 
Seri o us A d verse E ve nt a n d A d verse E ve nts of S pecial I nterest Re p orti n g –
Pr oce d ure F or I n vesti gat ors............................................................................ 8 9
9. 6.  
N otif yi n g Re g ulat or y A ut h orities, I n vesti gat ors, I R B/ E C, a n d C o m pete nt 
A ut h orities ...................................................................................................... 9 0
9. 7. 
E x p os ure I n Uter o D uri n g Cli nical St u dies.................................................... 9 0
9. 8. 
Cli nical La b orat or y E val uati o ns..................................................................... 9 0
9. 9.  
Vital Si g ns ...................................................................................................... 9 1
9. 1 0. 
Electr ocar di o gra ms......................................................................................... 9 1
9. 1 1. 
P h ysical Fi n di n gs............................................................................................ 9 1
9. 1 2.  
Ot her Safet y Assess me nts............................................................................... 9 2
1 0.  
O T H E R A S S E S S M E N T S............................................................................ 9 3
1 1. 
S T A TI S TI C A L M E T H O D S........................................................................ 9 4
1 1. 1.  
A nal ysis Sets................................................................................................... 9 4
1 1. 1. 1. 
E nr olle d A nal ysis Set ..................................................................................... 9 4
1 1. 1. 2. 
Efficac y A nal ysis Set...................................................................................... 9 4
1 1. 1. 3.  
D ose- Li miti n g T o xicit y E val ua ble Set........................................................... 9 4
1 1. 1. 4. 
Safet y A nal ysis Set......................................................................................... 9 4
1 1. 1. 5. 
P har mac o ki netic A nal ysis Set ........................................................................ 9 4


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 2
1 1. 1. 6. 
Bi o mar ker A nal ysis Set.................................................................................. 9 4
1 1. 2.  
Ge neral Statistical C o nsi derati o ns.................................................................. 9 4
1 1. 3. 
St u d y P o p ulati o n Data.................................................................................... 9 5
1 1. 4. 
Efficac y A nal yses........................................................................................... 9 5
1 1. 4. 1. 
Pri mar y Efficac y A nal yses............................................................................. 9 6
1 1. 4. 2. 
Sec o n dar y Efficac y A nal yses......................................................................... 9 6
1 1. 4. 3. 
E x pl orat or y Efficac y A nal yses....................................................................... 9 6
1 1. 5. 
P har mac o ki netic/ P har mac o d y na mic A nal yses............................................... 9 6
1 1. 5. 1. 
P har mac o ki netic A nal yses.............................................................................. 9 6
1 1. 5. 2. 
P har mac o d y na mic A nal yses........................................................................... 9 6
1 1. 5. 3. 
Bi o mar ker a n d E x pl orat or y A nal yses............................................................. 9 6
1 1. 6. 
Safet y A nal yses .............................................................................................. 9 6
1 1. 6. 1.  
A d verse E ve nt A nal yses................................................................................. 9 7
1 1. 6. 2. 
Cli nical La b orat or y E val uati o n A nal yses....................................................... 9 7
1 1. 6. 3.  
Vital Si g n A nal yses ........................................................................................ 9 7
1 1. 6. 4. 
Electr ocar di o gra m A nal yses........................................................................... 9 7
1 1. 6. 5. 
P h ysical Fi n di n g A nal yses.............................................................................. 9 7
1 1. 6. 6.  
Ot her Safet y A nal yses .................................................................................... 9 8
1 1. 7.  
Ot her A nal yses................................................................................................ 9 8
1 1. 8. 
I nteri m A nal yses............................................................................................. 9 8
1 1. 9.  
Data a n d Safet y M o nit ori n g B oar d................................................................. 9 8
1 1. 1 0. 
Sa m ple Size Deter mi nati o n ............................................................................ 9 8
1 1. 1 1. 
S pecificati o n of M o difie d C o nti n u o us Reassess me nt Met h o d Wit h 
Escalati o n Wit h O ver d ose C o ntr ol................................................................. 9 9
1 1. 1 1. 1. 
Ba yesia n L o gistic Re gressi o n M o del f or M o difie d C o nti n u o us Reassess me nt 
Met h o d............................................................................................................ 9 9
1 1. 1 1. 2. 
Pri or S pecificati o n f or Ba yesia n L o gistic Re gressi o n M o del Para meters...... 9 9
1 1. 1 1. 3. 
Escalati o n Wit h O ver d ose C o ntr ol Pri nci ple................................................ 1 0 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............................ 1 0 1
1 2. 1.  
M o nit ori n g a n d I ns pecti o ns.......................................................................... 1 0 1
1 2. 2.  
Data C ollecti o n............................................................................................. 1 0 1
1 2. 3.  
Data Ma na ge me nt......................................................................................... 1 0 1
1 2. 4. 
St u d y D oc u me ntati o n a n d St ora ge ............................................................... 1 0 2


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 3
1 2. 5. 
Rec or d Kee pi n g............................................................................................ 1 0 3
1 3. 
FI N A N CI N G A N D I N S U R A N C E............................................................. 1 0 4
1 3. 1. 
Fi na nces........................................................................................................ 1 0 4
1 3. 2. 
Rei m b urse me nt, I n de m nit y, a n d I ns ura nce.................................................. 1 0 4
1 4. 
P U B LI C A TI O N P O LI C Y.......................................................................... 1 0 5
1 5. 
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 0 6
1 5. 1. 
Pr ot oc ol A me n d me nts .................................................................................. 1 0 6
1 5. 2. 
S u p pl y of Ne w I nf or mati o n Affecti n g t he C o n d uct of t he St u d y................. 1 0 6
1 5. 3.  
A d dress List.................................................................................................. 1 0 6
1 5. 3. 1. 
S p o ns or......................................................................................................... 1 0 6
1 5. 3. 1. 1. 
S p o ns or’s Res p o nsi ble Me dical E x pert / Me dical M o nit or.......................... 1 0 7
1 5. 3. 1. 2. 
S p o ns or Cli nical St u d y Lea der..................................................................... 1 0 7
1 5. 3. 2. 
C R O.............................................................................................................. 1 0 7
1 5. 3. 2. 1. 
C R O Me dical M o nit or f or U S...................................................................... 1 0 7
1 5. 3. 2. 2. 
C R O Pr oject Ma na ger................................................................................... 1 0 7
1 5. 3. 3.  
Dr u g Safet y................................................................................................... 1 0 7
1 5. 3. 3. 1. 
S p o ns or......................................................................................................... 1 0 7
1 5. 3. 3. 2. 
C R O.............................................................................................................. 1 0 8
1 5. 3. 4.  
Data Ma na ge me nt......................................................................................... 1 0 8
1 5. 3. 4. 1. 
S p o ns or......................................................................................................... 1 0 8
1 5. 3. 4. 2. 
C R O f or Bi ostatistics a n d Data Ma na ge me nt............................................... 1 0 8
1 5. 3. 4. 3. 
E D C Ve n d or ................................................................................................. 1 0 8
1 5. 3. 4. 4. 
E D C S yste m S u p p ort.................................................................................... 1 0 8
1 5. 3. 5. 
Bi ol o gical S peci me ns ................................................................................... 1 0 9
1 5. 3. 5. 1. 
I H C a n d FI S H Assess me nt........................................................................... 1 0 9
1 5. 3. 5. 2.  
H E R 2 E C D Test ............................................................................................ 1 0 9
1 5. 3. 5. 3.  
H E R 2 b y H E R mar k Test.............................................................................. 1 0 9
1 5. 3. 5. 4. 
Bi ol o gical S peci me ns Ma na ge me nt f or Part 1 i n Ja pa n a n d c T nI Test........ 1 0 9
1 5. 3. 5. 5. 
Bi ol o gical S peci me ns Ma na ge me nt f or Part 1 i n U S a n d Part 2.................. 1 0 9
1 5. 3. 5. 6.  
H E R 2 Assess me nt Usi n g Fres h T u m or Sa m ples f or Part 2 d S u bjects a n d 
H E R 2 E C D Test ............................................................................................ 1 0 9
1 5. 3. 5. 7. 
cf D N A A nal ysis............................................................................................ 1 0 9
1 5. 3. 5. 8. 
I m m u ne Pr ofili n g a n d M o nit ori n g................................................................ 1 1 0


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 4
1 5. 3. 6. 
I nteracti ve Res p o nse Tec h n ol o g y (I R T)....................................................... 1 1 0
1 5. 3. 7.  
Ge n o mics La b orat or y ................................................................................... 1 1 0
1 5. 3. 8. 
Bi oa nal ytical La b orat or y ( P K a n d A D A assess me nt).................................. 1 1 0
1 5. 3. 9. 
Ce ntral I ma gi n g............................................................................................ 1 1 0
1 5. 3. 1 0.  
Ot her............................................................................................................. 1 1 0
1 5. 3. 1 0. 1.
Safet y A d vis or.............................................................................................. 1 1 0
1 6.  
R E F E R E N C E S ........................................................................................... 1 1 1
1 7.  
A P P E N DI C E S............................................................................................. 1 1 3
1 7. 1. 
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma nce Stat us Scale................ 1 1 3
1 7. 2. 
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 1 4
1 7. 2. 1.  
Meas ura bilit y of T u m or at Baseli ne............................................................. 1 1 4
1 7. 2. 1. 1.  
Defi niti o ns .................................................................................................... 1 1 4
1 7. 2. 1. 2. 
S pecificati o ns b y Met h o ds of Meas ure me nts............................................... 1 1 5
1 7. 2. 2. 
T u m or Res p o nse E val uati o n......................................................................... 1 1 5
1 7. 2. 2. 1.  
Assess me nt of O verall T u m or B ur de n a n d Meas ura ble Disease.................. 1 1 5
1 7. 2. 2. 2. 
Baseli ne D oc u me ntati o n of “ Tar get” a n d “ N o n-tar get” Lesi o ns ................. 1 1 6
1 7. 2. 2. 3. 
Res p o nse Criteria.......................................................................................... 1 1 6
1 7. 2. 2. 4. 
E val uati o n of Best O verall Res p o nse........................................................... 1 1 9
1 7. 2. 2. 5. 
Fre q ue nc y of T u m or Re-e val uati o n.............................................................. 1 2 1
1 7. 3.  
Ne w Y or k Heart Ass ociati o n F u ncti o nal Classificati o n............................... 1 2 1
1 7. 4. 
Electr o nic Data Ca pt ure S yste m................................................................... 1 2 1
1 7. 5. 
S u p ple me nt List............................................................................................ 1 2 3
1 7. 6. 
Sc he d ule of E ve nts ( Part 1 a n d Part 2)......................................................... 1 2 4


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 5
LI S T O F T A B L E S
Ta ble 3. 1:
Acti o ns Ta ke n f or I nf usi o n Relate d Reacti o n ................................................ 4 5
Ta ble 3. 1:
Acti o ns Ta ke n f or I nf usi o n Relate d Reacti o n ( C o nti n ue d)............................ 4 6
Ta ble 3. 2:
Acti o ns Ta ke n f or Car diac T o xicit y............................................................... 4 6
Ta ble 3. 3:
Acti o ns Ta ke n f or St u d y Dr u g I n d uce d I L D or p ne u m o nitis......................... 4 8
Ta ble 3. 4:
D ose I nterr u pti o n Criteria a n d D ose Res u m pti o n R ules ................................ 5 1
Ta ble 3. 5:
Refere nce Sc he me of D ose Re d ucti o n at Pr o visi o nal D oses f or Part 1 ......... 5 1
Ta ble 3. 6:
Sc he me of D ose Re d ucti o n f or Part 2............................................................. 5 2
Ta ble 6. 1:
P har mac o ki netic Sa m pli n g Ti me P oi nts ( Part 1 a n d Part 2) .......................... 7 8
Ta ble 6. 1:
P har mac o ki netic Sa m pli n g Ti me P oi nts ( Part 1 a n d Part 2) ( C o nti n ue d)...... 7 9
Ta ble 6. 2:
H E R 2 E C D Sa m pli n g Ti me P oi nts.................................................................. 7 9
Ta ble 6. 3:
c T nI Sa m pli n g Ti me P oi nts............................................................................ 7 9
Ta ble 6. 4: I m m u ne M o nit ori n g Sa m pli n g Ti me P oi nts (Ja pa nese s u bjects i n Part 2 d 
o nl y)........................................................................................................... 8 0
Ta ble 6. 5:
Cell Free D N A Sa m pli n g Ti me P oi nts ( O pti o nal) ......................................... 8 0
Ta ble 6. 6:
A D A Sa m pli n g Ti me P oi nts........................................................................... 8 1
Ta ble 8. 1:
P har mac o ki netic Para meters........................................................................... 8 3
Ta ble 1 7. 1: O verall Res p o nse: S u bjects wit h Tar get ( +/ – N o n-tar get) Disease............... 1 1 9
Ta ble 1 7. 2: O verall Res p o nse: S u bjects wit h N o n-tar get Disease O nl y ......................... 1 2 0


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 6
LI S T O F FI G U R E S
Fi g ure 1. 1:
A nti-t u m or Effect of D S- 8 2 0 1a, M A A L- 9 0 0 1, a n d T- D M 1 a gai nst S T 2 2 5 
a n d S T 9 1 0 Patie nt- Deri ve d Breast Ca ncer Xe n o graft M o del.................... 3 2
Fi g ure 1. 2: Pre dicte d Plas ma C o nce ntrati o n Pr ofiles of D S- 8 2 0 1a i n M o n ke ys after 
Re peate d I ntra ve n o us A d mi nistrati o n E ver y 3 Wee ks f or 3 C ycles.......... 3 5
Fi g ure 3. 1: St u d y Desi g n Sc he ma of D S 8 2 0 1- A-J 1 0 1 ..................................................... 4 2


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 7
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 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 L P
al kali ne p h os p hatase
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
BI
bef ore i nf usi o n
B L R M
Ba yesia n l o gistic re gressi o n m o del
cf D N A
cell free D N A
C F R
C o de of Fe deral Re g ulati o ns
C H F
c o n gesti ve heart fail ure
C R
c o m plete res p o nse
C R F
case re p ort f or m
C R O
c o ntract researc h or ga nizati o n
C S F
c ol o n y sti m ulati n g fact or
C S P V
Cli nical Safet y a n d P har mac o vi gila nce
C T
c o m p ute d t o m o gra p h y
c T nI
car diac tr o p o ni n I
C Y P
c yt oc hr o me P 4 5 0
D A R
dr u g-t o-a nti b o d y rati o
D C R
disease c o ntr ol rate
DI S H
d ual c ol or i n sit u h y bri dizati o n
D L T
d ose li miti n g t o xicit y
D N A
de o x yri b o n ucleic aci d
E C D
e xtracell ular d o mai n
E C G
Electr ocar di o gra m
E C H O
Ec h ocar di o gra p h y
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p
e C R F
electr o nic case re p ort f or m
E D C
electr o nic data ca pt ure
EI U
e x p os ure i n uter o
E OI
e n d of i nf usi o n
E O T
e n d of treat me nt
E W O C
escalati o n wit h o ver d ose c o ntr ol
F/ U
f oll o w- u p
FI S H
fl u oresce nt i n sit u h y bri dizati o n
G C P
G o o d Cli nical Practice
H E D
h u ma n e q ui vale nt d ose
H E R 2
h u ma n e pi der mal gr o wt h fact or rece pt or 2


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 2 8
A B B R E VI A TI O N
D E FI NI TI O N
h E R G
h u ma n et her-a- g o- g o-relate d ge ne
HI P A A
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
HI V
h u ma n i m m u n o deficie nc y vir us
H N S T D
hi g hest n o n-se verel y t o xic d ose
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 nfere nce o n Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I g G 1
i m m u n o gl o b uli n G 1
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 N D
i n vesti gati o nal ne w dr u g
I N N
I nter nati o nal N o n- pr o prietar y Na me
I R B
i nstit uti o nal re vie w b oar d
I R T
i nteracti ve res p o nse tec h n ol o g y
I S H
i n sit u h y bri dizati o n
I V
i ntra ve n o us i njecti o n
I V R S
i nteracti ve v oice res p o nse s yste ms
I W R S
i nteracti ve we b res p o nse s yste m
L V E F
left ve ntric ular ejecti o n fracti o n
m C R M
m o difie d c o nti n u o us reassess me nt met h o d
M RI
ma g netic res o na nce i ma gi n g
M T D
ma xi m u m t olerate d d ose
M U G A
m ulti ple- gate d ac q uisiti o n
N CI- C T C A E
Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nt
N E
i ne val ua ble
N S AI Ds
n o nster oi dal a nti-i nfla m mat or y dr u gs
N Y H A
Ne w Y or k Heart Ass ociati o n
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 bjecti ve res p o nse rate
O S
o verall s ur vi val
O T C
o ver t he c o u nter
P A D
p har mac ol o gicall y acti ve d ose
P D
pr o gressi ve disease
P D y
p har mac o d y na mic(s)
P F S
pr o gressi o n free s ur vi val
P K
p har mac o ki netic(s)
P R
partial res p o nse
P S
perf or ma nce stat us
Q 3 W
o nce e ver y 3 wee ks


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
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
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m ors
R P 2 D
rec o m me n de d P hase 2 d ose
S A E
seri o us a d verse e ve nt
S A P
statistical a nal ysis pla n
S A V E R
seri o us a d verse e ve nt re p ort
S C R
scree ni n g
S D
sta ble disease
S L D
s u m of l o n gest di me nsi o ns
S O C
S yste m Or ga n Class
S O P
sta n dar d o perati n g pr oce d ure
S U S A R
s us pecte d u ne x pecte d seri o us a d verse e ve nt reacti o n
T- D M 1
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 T R
ti me t o res p o nse
U L N
u p per li mit of n or mal


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 0
List of P h ar m ac o ki netic P ar a meters
A B B R E VI A TI O N
D E FI NI TI O N
A U C
area u n der t he ser u m c o nce ntrati o n-ti me c ur ve
A U Ci nf
area u n der t he ser u m c o nce ntrati o n-ti me c ur ve u p t o i nfi nit y
A U Clast
area u n der t he ser u m c o nce ntrati o n-ti me c ur ve u p t o t he last 
q ua ntifia ble ti me
A U Cta u
A U C d uri n g d osi n g i nter val
C L
t otal b o d y cleara nce 
C ma x
ma xi m u m ser u m c o nce ntrati o n 
Ctr o u g h
tr o u g h ser u m c o nce ntrati o n 
Kel
eli mi nati o n rate c o nsta nt ass ociate d wit h t he ter mi nal p hase
T ma x
ti me t o reac h ma xi m u m ser u m c o nce ntrati o n
T 1/ 2
ter mi nal eli mi nati o n half-life
Vss
v ol u me of distri b uti o n at stea d y state
Vz
v ol u me of distri b uti o n base d o n t he ter mi nal p hase
List of Defi niti o ns of Ter ms
A B B R E VI A TI O N
D E FI NI TI O N
F L- D P 1
F L- D P 2
M A A A- 1 1 8 1
T he dr u g c o m p o ne nt of D S- 8 2 0 1a – a deri vati ve of e xateca n, a 
t o p ois o merase I i n hi bit or
M A A L- 9 0 0 1
T he a nti b o d y c o m p o ne nt of D S- 8 2 0 1a – a h u ma nize d I g G 1 
m o n ocl o nal a nti b o d y pr o d uce d i n- h o use wit h refere nce t o t he sa me 
a mi n o aci d se q ue nce of trast uz u ma b


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 1
1. 
I N T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N
1. 1.  
D at a S u m m ar y
1. 1. 1. 
I n vesti g ati o n al Pr o d uct(s)
1. 1. 1. 1.  
N a me
D S- 8 2 0 1a
1. 1. 1. 2.  
Descri pti o n
D S- 8 2 0 1a is a n a nti b o d y- dr u g c o nj u gate ( A D C) t hat tar gets H E R 2.  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" hereafter), w hic h is a h u ma nize d i m m u n o gl o b uli n G 1 
(I g G 1) m o n ocl o nal a nti b o d y pr o d uce d i n h o use wit h refere nce t o t he a mi n o aci d se q ue nce of 
trast uz u ma b, t hat is b o u n 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, w hic h is a n 
e xateca n deri vati ve t hat is a t o p ois o merase I i n hi bit or (" M A A A- 1 1 8 1" hereafter).  
T w o t y pes of D S- 8 2 0 1a dr u g pr o d uct, D S- 8 2 0 1a f or I njecti o n 
 ( F L- D P 1 hereafter) 
a n d D S- 8 2 0 1a f or I njecti o n 
 ( F L- D P 2 hereafter), will be s u p plie d i n t his st u d y.  F L-
D P 2 dr u g pr o d uct is a d de d t o be e val uate d i n s u bjects e nr olle d i n t he ne wl y a d de d c o h ort of Part 
2e.  
1. 1. 1. 3. 
I nte n de d Use U n der I n vesti g ati o n
D S- 8 2 0 1a will be e val uate d i n s u bjects wit h a d va nce d s oli d t u m ors
1. 1. 1. 4.  
N o ncli nic al St u dies
1. 1. 1. 4. 1. 
P h ar m ac ol o g y
T he fact t hat D S- 8 2 0 1a bi n ds s pecificall y t o t he H E R 2 e xtracell ular d o mai n ( E C D) a n d d oes n ot 
bi n d t o ot her H E R fa mil y pr otei ns has bee n c o nfir me d b y e nz y me-li n ke d i m m u n os or be nt assa y 
( E LI S A) usi n g rec o m bi na nt pr otei ns.  I n a d diti o n, si nce t he bi n di n g affi nit y of D S- 8 2 0 1a t o 
H E R 2 was c o m para ble t o t hat of M A A L- 9 0 0 1, t he a nti b o d y c o m p o ne nt of D S- 8 2 0 1a – a 
h u ma nize d I g G 1 m o n ocl o nal a nti b o d y pr o d uce d i n- h o use wit h refere nce t o t he sa me a mi n o aci d 
se q ue nce of trast uz u ma b, it is n ot c o nsi dere d t hat t he c o nj u gati o n of M A A A- 1 1 8 1 wit h M A A L-
9 0 0 1 has a n y effect o n t he bi n di n g affi nit y of M A A L- 9 0 0 1.
T he res ults of i n vitr o cell gr o wt h i n hi biti o n st u dies c o n d ucte d usi n g se veral ca ncer cell li nes 
ha ve s h o w n t hat D S- 8 2 0 1a has a m ore p ote nt gr o wt h i n hi biti o n a gai nst H E R 2- p ositi ve cells t ha n 
M A A L- 9 0 0 1, s u g gesti n g t hat t he c o nj u gati o n of M A A A- 1 1 8 1 e n ha nces t he gr o wt h i n hi biti o n of 
D S- 8 2 0 1a.  M ore o ver, n o gr o wt h i n hi biti o n was c o nfir me d i n H E R 2- ne gati ve cells, t h us 
c o nfir mi n g t he H E R 2 s pecificit y of D S- 8 2 0 1a.
Si milarl y, w he n t he i n vi v o a ntit u m or acti vit y of D S- 8 2 0 1a i n a t u m or- beari n g m o use m o del of a 
H E R 2- p ositi ve gastric ca ncer cell li ne was st u die d, it was c o nfir me d t hat D S- 8 2 0 1a e x hi bite d 
p ote nt, d ose- de pe n de nt a ntit u m or acti vit y wit h t u m or re gressi o n, a n d t hat t his acti vit y was e ve n 
str o n ger t ha n t hat of M A A L- 9 0 0 1.




Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 3
1. 1. 1. 4. 3. 
P h ar m ac o ki netics a n d Dr u g Met a b olis m
T he plas ma D S- 8 2 0 1a c o nce ntrati o ns decrease d e x p o ne ntiall y f oll o wi n g a si n gle i ntra ve n o us 
a d mi nistrati o n of D S- 8 2 0 1a at 0. 1 m g/ k g t o 3. 0 m g/ k g t o c y n o m ol g us m o n ke ys.  T he Vss was 
cl ose t o t he plas ma v ol u me.  T he C L decrease d as t he d ose i ncrease d, a n d t he p har mac o ki netics 
were f o u n d t o be n o n-li near.  B ot h D S- 8 2 0 1a a n d t he t otal a nti b o d y, b o u n d a n d u n b o u n d 
a nti b o d y c o m bi ne d, e x hi bite d si milar plas ma c o nce ntrati o n-ti me pr ofiles at all d ose le vels, as 
well as si milar A U C.  All i n di vi d ual plas ma c o nce ntrati o ns of M A A A- 1 1 8 1, t he release d dr u g 
fr o m D S- 8 2 0 1a, were bel o w t he l o wer li mit of q ua ntificati o n ( 0. 1 0 0 n g/ m L) at 0. 1 a n d 0. 3 
m g/ k g.  A l o w- plas ma le vel of M A A A- 1 1 8 1 was detecte d at li mite d ti me p oi nts at 1. 0 a n d 3. 0 
m g/ k g. N o a nti- D S- 8 2 0 1a a nti b o d y was detecte d i n a n y a ni mals.
T he mea n plas ma pr otei n bi n di n g rati os of M A A A- 1 1 8 1 at 1 0 n g/ m L t o 1 0 0 n g/ m L were fr o m 
9 0. 3 % t o 9 2. 5 % i n mice, 9 4. 2 % t o 9 6. 7 % i n rats, 8 6. 5 % t o 8 9. 1 % i n m o n ke ys, a n d 9 6. 8 % t o 
9 8. 0 % i n h u ma ns.  
T he release rates of M A A A- 1 1 8 1 fr o m D S- 8 2 0 1a i ncrease d gra d uall y t hr o u g h o ut t he i nc u bati o n 
peri o d i n m o use, rat, a n d m o n ke y plas ma wit h t he release rates fr o m 1. 2 % t o 3. 9 % o n Da y 2 1.  
O n t he ot her ha n d, t he release rate reac he d a platea u o n Da y 1 4 i n h u ma n plas ma wit h t he release 
rates fr o m 2. 2 % t o 2. 4 %.  T hese res ults i n dicate t hat m ost D S- 8 2 0 1a is sta ble i n plas ma.
N o maj or differe nces were f o u n d a m o n g t he meta b olite pr ofiles of D S- 8 2 0 1a i n rat, m o n ke y, a n d 
h u ma n he pat oc ytes.  M A A A- 1 1 8 1 was meta b olize d b y C Y P e nz y mes; C Y P 3 A 4 was t he pri mar y 
C Y P e nz y me i n t he meta b olis m, C Y P 3 A 5 a n d C Y P 2 D 6 were als o i n v ol ve d i n t he meta b olis m.
T he plas ma c o nce ntrati o n ti me pr ofiles f oll o wi n g re peate d a d mi nistrati o n of D S- 8 2 0 1a Q 3 W f or 
3 c ycles ( Q 3 W × 3) t o h u ma ns were si m ulate d o n t he basis of t he p har mac o ki netics of D S- 8 2 0 1a 
i n c y n o m ol g us m o n ke ys.  T hese esti mates were c o m pare d t o t he plas ma c o nce ntrati o ns of D S-
8 2 0 1a i n t he st u dies i n t u m or- beari n g mice.  As a res ult, t he mi ni m u m effecti ve d ose a n d t he 
p har mac ol o gicall y acti ve d ose ( P A D) were e x pecte d t o be 0. 8 a n d 4. 8 m g/ k g, res pecti vel y, wit h 
a d osa ge Q 3 W i n h u ma ns.
1. 1. 1. 4. 4. 
T o xic ol o g y
I n a st u d y of i nter mitte nt i ntra ve n o us d osi n g of D S- 8 2 0 1a i n rats ( Q 3 W d osi n g f or 6 wee ks), n o 
deat hs or m ori b u n d a ni mals were f o u n d at d ose le vels u p t o 1 9 7 m g/ k g, t he ma xi m u m d ose.  T he 
maj or o bser ve d fi n di n gs i ncl u de d testic ular a n d i ntesti nal t o xicit y at d ose le vels of 2 0 m g/ k g a n d 
greater, a n d l y m p hatic/ he mat o p oietic, s ki n, a n d i ncis or t o ot h, a n d re nal t o xicit y at d ose le vels of 
6 0 m g/ k g a n d greater.  E xce pt f or t he testic ular a n d i ncis or t o ot h c ha n ges, t hese c ha n ges were all 
f o u n d t o rec o ver.
I n a n i nter mitte nt i ntra ve n o us d osi n g st u d y of D S- 8 2 0 1a i n c y n o m ol g us m o n ke ys ( Q 3 W, 6 
wee ks), o ne fe male was sacrifice d m ori b u n d at 7 8. 8 m g/ k g, t he hi g hest d ose le vel.  T he maj or 
t o xicit y fi n di n gs i n t his m ori b u n d a ni mal were o bser ve d i n t he i ntesti ne, he mat o p oietic s yste m, 
s ki n, a n d ki d ne y.  T he ca use of t he m ori b u n dit y a p peare d t o be t he deteri orate d c o n diti o n of t he 
a ni mal w hic h i ncl u de d decrease d b o d y wei g ht a n d f o o d c o ns u m pti o n, as well as b o ne marr o w 
t o xicit y a n d i ntesti nal t o xicit y.  T he maj or fi n di n gs of t o xicit y i n t he s ur vi vi n g a ni mals were 
o bser ve d i n t he i ntesti ne at d ose le vels of 1 0 m g/ k g a n d greater, a n d i n t he l u n g, testes, a n d s ki n 
at d ose le vels of 3 0 m g/ k g a n d greater.  I n a d diti o n, he mat o p oietic s yste m t o xicit y, re nal t o xicit y, 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 4
a n d E C G a b n or malities (s h orte ne d P R i nter val a n d Q Tc pr ol o n gati o n) were f o u n d at 7 8. 8 m g/ k g.  
E xce pt f or t he p ul m o nar y a n d s ki n t o xicit y ( pi g me ntati o n), t hese fi n di n gs te n de d t o rec o ver.
T h us, as descri be d a b o ve, t he se verel y t o xic d ose i n 1 0 % of t he a ni mals ( S T D 1 0) i n a rat 
i nter mitte nt i ntra ve n o us d osi n g st u d y of D S- 8 2 0 1a was f o u n d t o be greater t ha n 1 9 7 m g/ k g. I n 
t he m o n ke y st u d y, d ue t o o bser ve d m ori b u n dit y at 7 8. 8 m g/ k g a n d e vi de nce of critical 
p ul m o nar y t o xicit y (e g, i nterstitial i nfla m mati o n a n d/ or al ve olar e de ma) i n t he s ur vi vi n g a ni mals, 
it was c o ncl u de d t hat t he H N S T D is 3 0 m g/ k g.  
I n a n i nter mitte nt i ntra ve n o us d ose t o xicit y st u d y of M A A A- 1 1 8 1 ( q w d osi n g f or 4 wee ks), 
fi n di n gs i n t he l y m p hatic/ he mat o p oietic s yste m, i ntesti nal tract, a n d t he c or nea of t he e ye were 
o bser ve d at 3 m g/ k g a n d greater i n rats a n d t here was n o deat h or m ori b u n dit y at u p t o 3 0 m g/ k g.  
Fi n di n gs si milar t o t h ose i n rats were o bser ve d i n c y n o m ol g us m o n ke ys at d ose le vels of 1 m g/ k g 
a n d greater.  I n a d diti o n, 1 fe male m o n ke y die d a n d 1 male m o n ke y was sacrifice d m ori b u n d at 
1 2 m g/ k g.  Alt h o u g h effects o n t he heart (f ocal m y ocar dial cell de ge nerati o n/ necr osis) were 
f o u n d i n t he m ori b u n d male al o n g wit h t he a b o ve me nti o ne d t o xicities, t here were n o a b n or mal 
heart fi n di n gs i n t he fe male t hat die d e ve n t h o u g h b ot h a ni mals e x hi bite d w orse ni n g cli nical 
c o n diti o ns ass ociate d wit h s ustai ne d decreases i n f o o d c o ns u m pti o n, b o ne marr o w t o xicit y, a n d 
i ntesti nal t o xicit y. T hese c ha n ges were c o nsi dere d t o be t he ca use of t he deat h a n d m ori b u n dit y.  
T he c o m m o n a d verse fi n di n gs wit h b ot h D S- 8 2 0 1a a n d M A A A- 1 1 8 1 st u dies were i ntesti nal a n d 
l y m p hatic/ he mat o p oietic s yste m t o xicities.  F or D S- 8 2 0 1a treat me nt, p ul m o nar y, testic ular, s ki n 
a n d re nal t o xicities were o bser ve d w hile heart, li ver, a n d c or neal t o xicities were f o u n d o nl y w he n 
M A A A- 1 1 8 1 was a d mi nistere d.  
I n a h u ma n cr oss-reacti vit y st u d y of D S- 8 2 0 1a wit h a pa nel of h u ma n tiss ues, D S- 8 2 0 1a-relate d 
cell me m bra ne stai ni n g was f o u n d o nl y i n t he place nta.  I n a cr oss-reacti vit y st u d y of D S- 8 2 0 1a 
wit h selecte d c y n o m ol g us m o n ke y tiss ues (e g, brai n, li ver, ki d ne y, l u n g, heart, i ntesti nes, 
l y m p h oi d or ga ns, testis, a n d s ki n), neit her me m bra n o us n or c yt o plas mic stai ni n g was n ote d i n 
a n y tiss ues.  
I n a n i n vitr o 3 T 3 N R U p h ot ot o xicit y st u d y, M A A A- 1 1 8 1 was f o u n d t o be p h ot ot o xic t o Bal b/c 
3 T 3 m o use fi br o blasts.  H o we ver, i n a n i n vi v o si n gle d ose p h ot ot o xicit y st u d y wit h M A A A-
1 1 8 1 i n pi g me nte d rats, n o p h ot ot o xic reacti o n was n ote d at 3 m g/ k g, t he hi g hest d ose teste d.
1. 1. 1. 4. 5.  
H u m a n St arti n g D ose
T he i nitial h u ma n starti n g d ose is deter mi ne d b y usi n g t he H N S T D i n c y n o m ol g us m o n ke ys, 
w hic h e x hi bit a hi g her le vel of t o xic ol o gical se nsiti vit y t ha n rats a n d w hic h e x hi bit a le vel of 
cr oss-reacti vit y si milar t o t hat of h u ma ns.  F or t he H N S T D i n c y n o m ol g us m o n ke ys, t he H E D is 
use d.  It was c o n verte d s o t hat t he d ose per b o d y s urface area ( m g/ m 2) was t he sa me i n t he 
e x peri me ntal a ni mals a n d i n h u ma ns, i n acc or da nce wit h t he e xtra p olati o n met h o d t hat is wi del y 
use d f or dr u g pr o d ucts t hat e x hi bit c yt ot o xicit y.  
T he H E D of H N S T D was calc ulate d t o be 9. 7 m g/ k g b y di vi di n g t he H N S T D i n c y n o m ol g us 
m o n ke ys, 3 0 m g/ k g, b y t he c orrecti o n fact or f or c y n o m ol g us m o n ke ys of 3. 1.  I n acc or da nce 
wit h t he N o ncli nical E val uati o n f or A ntica ncer P har mace uticals (t he I C H S 9 g ui deli nes), t he 
esti mate d ma xi m u m starti n g d ose f or a P hase 1 cli nical st u d y w o ul d be 1. 6 0 m g/ k g as o ne-si xt h 
of t he H E D of H N S T D.  H o we ver, as a c o nser vati ve a p pr oac h, t he h u ma n starti n g d ose of 0. 8 




Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 6
H E R 2 is a me m ber of t he H E R s u perfa mil y, a n d i nitiates si g nal tra ns d ucti o n via t he PI 3 K/ A K T 
a n d R A S/ M A P K pat h wa ys. 1, 2  I n h u ma n a d va nce d s oli d t u m ors, e x pressi o n of H E R 2 pr otei n 
has bee n re p orte d i n vari o us t u m or tiss ues a n d a variet y of c ult ure d t u m or cell li nes i ncl u di n g 
breast ca ncer, 3 gastric ca ncer,4, 5 pa ncreatic ca ncer,6 l u n g ca ncer,7 c ol orectal ca ncer,8 a n d o varia n 
ca ncer. 9  T here are als o ma n y re p orts de m o nstrati n g a n ass ociati o n bet wee n e x pressi o n of H E R 2 
pr otei n a n d cli nical p o or pr o g n osis.  I n n or mal h u ma n tiss ue, l o w e x pressi o n of H E R 2 pr otei n 
has bee n re p orte d o n cell me m bra nes of e pit helial cells i n t he gastr o-i ntesti nal, res pirat or y, 
re pr o d ucti ve, a n d uri nar y tract as well as i n t he s ki n, breast a n d place nta.1 0 
As a n a nti b o d y tar geti n g H E R 2, Trast uz u ma b has bee n a p pr o ve d i n t he U nite d States f or t he 
i n dicati o n of H E R 2 o vere x pressi n g breast ca ncer a n d H E R 2- o vere x pressi n g metastatic gastric or 
gastr oes o p ha geal j u ncti o n a de n ocarci n o ma, 1 1 i n E ur o pe f or H E R 2 p ositi ve metastatic breast 
ca ncer a n d H E R 2 p ositi ve metastatic a de n ocarci n o ma of t he st o mac h or gastr oes o p ha geal 
j u ncti o n,1 2 a n d i n Ja pa n f or H E R 2- o vere x pressi n g breast ca ncer a n d H E R 2- o vere x pressi n g 
u nresecta ble or a d va nce d/rec urre nt gastric or gastr oes o p ha geal j u ncti o n a de n ocarci n o ma. 1 3  T-
D M 1 is a n A D C tar geti n g H E R 2 t hat has bee n a p pr o ve d i n t he U nite d States f or t he i n dicati o n of 
H E R 2- p ositi ve metastatic breast ca ncer, 1 4 i n E ur o pe f or t he i n dicati o n of H E R 2- p ositi ve 
u nresecta ble l ocall y a d va nce d or metastatic breast ca ncer, 1 5 a n d i n Ja pa n f or H E R 2- p ositi ve 
u nresecta ble or a d va nce d breast ca ncer. 1 6
I n n o ncli nical st u dies, t he fact t hat D S- 8 2 0 1a bi n ds s pecificall y t o t he H E R 2 E C D a n d d oes n ot 
bi n d t o ot her H E R fa mil y pr otei ns has bee n c o nfir me d.  I n vitr o st u dies i n dicate t hat D S- 8 2 0 1a 
e x hi bits H E R 2 e x pressi o n- de pe n de nt cell gr o wt h i n hi biti o n acti vit y, m ore o ver, n o gr o wt h 
i n hi biti o n was c o nfir me d i n H E R 2- ne gati ve cells, t h us c o nfir mi n g t he H E R 2 s pecificit y of D S-
8 2 0 1a.  I n vi v o st u dies usi n g a t u m or- beari n g m o use m o del s u g gest t hat a d mi nistrati o n of D S-
8 2 0 1a res ults i n t he re gressi o n of H E R 2- p ositi ve t u m ors.  E mta nsi ne, w hic h has a t u b uli n 
p ol y merizati o n i n hi biti o n acti vit y, is use d as t he dr u g c o m p o ne nt i n T- D M 1.  Si nce M A A A- 1 1 8 1 
t hat i n hi bits t o p ois o merase I is use d i n D S- 8 2 0 1a, D S- 8 2 0 1a is e x pecte d t o be effecti ve e ve n i n 
t u m ors t hat d o n ot res p o n d or are resista nt t o T- D M 1.  D S- 8 2 0 1a e x hi bits a nti-t u m or effect wit h 
t u m or re gressi o n i n t u m ors t hat e x press l o w le vels of H E R 2, a gai nst w hic h T- D M 1 has little 
effect, a n d is t heref ore als o e x pecte d t o be effecti ve a gai nst t u m ors t hat e x press l o w le vels of 
H E R 2, f or w hic h H E R 2 t hera p y i ncl u di n g T- D M 1 has n ot bee n a p pr o ve d.  O ne reas o n f or t his 
ma y be t hat t he dr u g-t o-a nti b o d y rati o ( D A R) f or D S- 8 2 0 1a is a p pr o xi matel y 8, c o m pare d t o a 
D A R of a vera ge 3. 5 f or T- D M 1, 1 4 mea ni n g t hat D S- 8 2 0 1a ca n deli ver m ore dr u gs i nt o t he cell 
t ha n T- D M 1. 
I n s u m mar y, D S- 8 2 0 1a has a differe nt dr u g c o m p o ne nt fr o m t hat of T- D M 1 a n d is e x pecte d t o 
s h o w acti vit y i n t he t u b uli n i n hi bit or i nse nsiti ve t u m ors a n d i n l o w H E R 2-e x pressi n g t u m ors.  
T h us, D S- 8 2 0 1a will be a be nefit t o a br oa der patie nt p o p ulati o n t ha n T- D M 1.  T heref ore, D S-
8 2 0 1a is bei n g de vel o pe d as a n A D C tar geti n g H E R 2.  T his cli nical trial is t he first-i n- h u ma n 
st u d y desi g ne d t o e val uate t he safet y, t olera bilit y, P K, a n d efficac y of D S- 8 2 0 1a d oses usi n g F L-
D P 1 dr u g pr o d uct i n t he d ose escalati o n Part 1 of t he trial; after t he d ose f or e x pa nsi o n is 
selecte d fr o m Part 1, t he safet y, t olera bilit y, efficac y a n d P K, will be f urt her e val uate d i n 
de dicate d c o h orts of s u bjects wit h s oli d t u m ors a d mi nistere d F L- D P 1 dr u g pr o d uct ( Parts 2a, 2 b, 
2c, a n d 2 d) a n d i n s u bjects a d mi nistere d F L- D P 2 dr u g pr o d uct ( Part 2e).  T he P K pr ofile 
bet wee n F L- D P 1 a n d F L- D P 2 dr u g pr o d uct will be assesse d f or bri d gi n g i n cli nical use.  


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 3 7
1. 3.  
Ris ks a n d Be nefits f or St u d y S u bjects
N o n-cli nical st u dies ha ve de m o nstrate d t he p ote nt a nti-t u m or acti vit y of D S- 8 2 0 1a i n t u m or-
beari n g m o use m o dels.  T h us, si milar t o ot her H E R 2-tar gete d pr o d ucts, D S- 8 2 0 1a is e x pecte d t o 
de m o nstrate efficac y i n treati n g H E R 2-e x pressi n g t u m ors.
I n n o ncli nical t o xic ol o g y st u dies, t he i ntesti nal t o xicit y, he mat o p oietic s yste m t o xicit y, 
p ul m o nar y t o xicit y, testic ular t o xicit y, s ki n t o xicit y, a n d re nal t o xicit y were f o u n d i n ass ociati o n 
wit h t he a d mi nistrati o n of D S- 8 2 0 1a.  I n a d diti o n t o t hese t o xicities, si milar t o ot her pr o d ucts of 
t he sa me class, t he p ossi bilit y of car di ot o xicit y, he pat ot o xicit y, e m br y o-fetal t o xicit y, or 
p h ot ot o xicit y occ urri n g i n s u bjects recei vi n g D S- 8 2 0 1a ca n n ot be e xcl u de d.  As wit h a n y 
t hera pe utic a nti b o dies, t here is a p ossi bilit y of i nf usi o n relate d reacti o ns, i m m u ne res p o nses 
ca usi n g aller gic or a na p h ylactic reacti o ns of D S- 8 2 0 1a.
Base d o n t he efficac y a n d safet y data o bser ve d i n t he n o ncli nical st u dies a n d t he i nf or mati o n 
fr o m ot her pr o d ucts of t he sa me class, t he be nefit-ris k bala nce s u p p orts cli nical de vel o p me nt of 
D S- 8 2 0 1a.
1. 4. 
P o p ul ati o n, R o ute, D os a ge, D os a ge Re gi me n, Tre at me nt Peri o d
D S- 8 2 0 1a will be a d mi nistere d as a n I V s ol uti o n.  S u bjects wit h s oli d mali g na nt t u m ors will 
recei ve D S- 8 2 0 1a o n Da y 1 of Q 3 W.  A n alter nati ve dr u g a d mi nistrati o n sc he d ule f or d ose 
escalati o n ma y be c o nsi dere d after esta blis hi n g t he M T D a n d/ or R P 2 D of D S- 8 2 0 1a usi n g t he 
a b o ve sc he d ule, a n d u p o n re vie w of t he h u ma n safet y, a n d P K para meters b y t he I n vesti gat ors 
a n d S p o ns or ( Refer t o Secti o n 3  a n d 4  f or details.).  
S u bjects e nr olle d i n Part 1, Part 2a, Part 2 b, Part 2c a n d Part 2 d will recei ve F L- D P 1 dr u g 
pr o d uct, a n d t h ose e nr olle d i n Part 2e will recei ve F L- D P 2 dr u g pr o d uct.
1. 5.  
C o m pli a nce St ate me nt, Et hics a n d Re g ul at or y C o m pli a nce
T his st u d y will be c o n d ucte 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 nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) 
c o ns oli date d G ui deli ne E 6 f or G o o d Cli nical Practice ( 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 ncl u di n g 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 ( F D A) G C P Re g ulati o ns: C o de of Fe deral 
Re g ulati o ns ( C F R) Title 2 1, parts 1 1, 5 0, 5 4, 5 6 a n d 3 1 2, as a p pr o priate.

Ja 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 Marc h, 
1 9 9 7.

T he Act o n Sec uri n g Q ualit y, Efficac y a n d Safet y of P har mace uticals, Me dical 
De vices, Re ge nerati ve a n d Cell ular T hera p y Pr o d ucts, Ge ne T hera p y Pr o d ucts, a n d 
C os metics.

Ot her a p plica ble l ocal re g ulati o ns.
1. 5. 1. 
S u bject C o nfi de nti alit y
T he I n vesti gat ors a n d t he S p o ns or will preser ve t he c o nfi de ntialit y of all s u bjects ta ki n g part 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 ulati o ns.


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T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y is mai ntai ne d.  O n t he Electr o nic Case 
Re p ort F or ms (e C R F) or ot her d oc u me nts s u b mitte d t o S p o ns or a n d/ or its c o ntract researc h 
or ga nizati o n ( 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 N u m ber as desi 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 S p o ns or or C R O (e g, si g ne d I C F) s h o ul d 
be ke pt i n strict c o nfi de nce b y t he I n vesti 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 nc y(s), a n d t he 
I n de pe n de nt Et hics C o m mittee (I E C) or I nstit uti o nal Re vie w B oar d (I R B) 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 data.  T he 
I n vesti 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 b o ve na me d re prese 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. 2. 
I nf or me d C o nse nt Pr oce d ure
Bef ore a s u bject’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 de 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 bef ore a n y pr ot oc ol-s pecific 
scree ni n g pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  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 oc u me nti n g i nf or me d 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 
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 pri or t o bei n g pr o vi de 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 o btai ne d pri or t o his/ her partici pati o n i n t he 
st u d y, a n d 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 date 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 ucte d t he i nf or me d c o nse nt 
disc ussi o n ( n ot necessaril y t he I n vesti gat or).  T he ori gi nal si g ne d I C F s h o ul d be retai ne d i n 
acc or da nce wit h i nstit uti o nal p olic y, a n d a c o p y of t he 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 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.
If t he s u bject ca n n ot rea d, t he n acc or di n g t o I C H G C P G ui deli ne, Secti o n 4. 8. 9, a n i m partial 
wit ness s h o ul d be prese nt d uri n g t he e ntire i nf or me d c o nse nt disc ussi o n.  T his wit ness s h o ul d 
si g n t he I C F after t he s u bject has orall y c o nse nte d t o t he s u bject’s partici pati o n a n d, if p ossi ble, 
si g ne d t he I C F.  B y si g ni n g t he I C F, t he wit ness attests t hat t he i nf or mati o n i n t he I C F a n d a n y 
ot her writte n i nf or mati o n was a de q uatel y e x plai ne d t o a n d a p pare ntl y u n derst o o d b y t he s u bject 
a n d t hat i nf or me d c o nse nt was freel y gi ve n b y t he s u bject.
F or st u dies i n t he U nite d States, a n a d diti o nal c o nse nt is re q uire d f or t he HI P A A.
S u g geste d m o del te xt f or t he I C F f or t he st u d y a n d a n y a p plica ble s u b parts ( ge n o mic, P K, etc) is 
pr o vi de d i n t he S p o ns or I C F te m plate f or t he I n vesti gat or t o pre pare t he d oc u me nts t o be use d at 
his or her site.  
T he c o nse nt f or m s h o ul d be si g ne d a n d pers o nall y date d b y t he s u bject or le gall y acce pta ble 
re prese ntati ve pri or t o his/ her partici pati o n i n t he st u d y.


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1. 5. 3.  
Re g ul at or y C o m pli a nce
T he st u d y pr ot oc ol, s u bject i nf or mati o n a n d c o nse nt f or m, t he I n vesti gat or br oc h ure, a n y writte n 
i nstr ucti o ns t o be gi ve n t o t he s u bject, a vaila ble safet 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 nsati 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 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 ocal re g ulati 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 na me 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 nal ysis will be d oc u me nte 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 m ust s u b mit a n d, w here necessar y, o btai n a p pr o val fr o m t he I R B a n d/ or 
S p o ns or 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 nf or me d c o nse nt d oc u me nt 
or c ha n ges of t he i n vesti gati o nal site, facilities or pers o n nel.  T he I n vesti gat or s h o ul d n otif y t he 
I R B of de viati o ns fr o m t he pr ot oc ol or S A Es occ urri n g at t he site a n d ot her A E re p orts recei ve d 
fr o m S p o ns or or C R O, i n acc or da nce wit h l ocal pr oce d ures.
As re q uire d b y l ocal 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 i ns ure all le gal as pects are c o vere d, a n d 
a p pr o val of t he a p pr o priate re g ulat or y b o dies o btai ne d, pri or t o st u d y i nitiati o n, a n d t hat 
i m ple me ntati o n of c ha n ges t o t he i nitial pr ot oc ol a n d ot her rele va nt st u d y d oc u me nts ha p pe n 
o nl y after t he a p pr o priate n otificati o n of or a p pr o val b y t he rele va nt re g ulat or y b o dies.
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 t o 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 ual seri o us G C P n o n-c o m plia nce t hat t he I n vesti gat or bec o mes a ware of.


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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 S E S
2. 1. 
St u d y O bjecti ves
2. 1. 1. 
Pri m ar y O bjecti ves
2. 1. 1. 1. 
P art 1 ( D ose Esc al ati o n)
T he pri mar y o bjecti ves are as f oll o ws:
1.
T o assess t he safet y a n d t olera bilit y of D S- 8 2 0 1a. 
2.
T o deter mi ne t he M T D or t he R P 2 D of D S- 8 2 0 1a.
2. 1. 1. 2. 
P art 2 ( D ose E x p a nsi o n)
T he pri mar y o bjecti ves are as f oll o ws:
1.
T o assess t he safet y a n d t olera bilit y of D S- 8 2 0 1a at t he M T D/t he R P 2 D.
2.
T o e val uate t he efficac y of D S- 8 2 0 1a at t he M T D/t he R P 2 D.
2. 1. 2. 
Sec o n d ar y O bjecti ves
2. 1. 2. 1. 
P art 1 ( D ose Esc al ati o n)
T he sec o n dar y o bjecti ves are as f oll o ws:
1.
T o assess t he P K pr ofile of D S- 8 2 0 1a, 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.
2.
T o e val uate t he efficac y of D S- 8 2 0 1a.
3.
T o assess t he i nci de nce of a nti- dr u g a nti b o d y ( A D A) a gai nst D S- 8 2 0 1a.
2. 1. 2. 2. 
P art 2 ( D ose E x p a nsi o n)
T he sec o n dar y o bjecti ves are as f oll o ws:
1.
T o assess t he P K pr ofile of D S- 8 2 0 1a, 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.
2.
T o assess t he i nci de nce of A D A a gai nst D S- 8 2 0 1a.
2. 1. 3. 
E x pl or at or y O bjecti ves: P art 1 ( D ose Esc al ati o n) a n d P art 2 ( D ose E x p a nsi o n)
T he e x pl orat or y o bjecti ves are as f oll o ws:
1.
T o assess t he bi o mar kers relate d t o D S- 8 2 0 1a.
2. 2. 
St u d y H y p ot hesis
D S- 8 2 0 1a will be safe a n d well-t olerate d a n d e x hi bit acce pta ble P K pr o perties i n s u bjects wit h 
a d va nce d s oli d mali g na nt t u m ors.  See Secti o n 1 1. 1 0  f or sa m ple size deter mi nati o n.  


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3. 
S T U D Y D E SI G N
3. 1.  
O ver all Pl a n
3. 1. 1. 
St u d y T y pe
T his is a P hase 1, t w o- part, m ultice nter, n o n-ra n d o mize d, o pe n-la bel, m ulti ple d ose, first i n 
h u ma n st u d y of D S- 8 2 0 1a.  St u d y sites fr o m Ja pa n a n d t he U nite d States are pla n ne d f or t his 
st u d y.  Part 2e ( D ose E x pa nsi o n) will be c o n d ucte d at Ja pa nese sites o nl y.
3. 1. 2. 
Tre at me nt Gr o u ps
T his 2- part st u d y will i ncl u de b ot h a D ose Escalati o n part, t o i de ntif y t he M T D or t he R P 2 D of 
D S- 8 2 0 1a, a n d a D ose E x pa nsi o n part, t o c o nfir m t he safet y, t olera bilit y a n d efficac y of D S-
8 2 0 1a at t he M T D/ R P 2 D.  I n Part 1, m ore t ha n 1 6 % of s u bjects (e g, 1 per 6 s u bjects) are 
e x pecte d t o be H E R 2 e x pressi o n (I H C 2 + or 3 +).  I n Part 2, s u bjects wit h H E R 2 e x pressi o n, 
i ncl u di n g H E R 2 l o w, will be e nr olle d.  I n or der t o assess t he safet y, efficac y a n d P K pr ofile of 
F L- D P 1 a n d F L- D P 2 dr u g pr o d ucts i n eac h c o h ort, at least 2 0 s u bjects will be e nr olle d i n eac h 
Part.  T he St u d y Desi g n Sc he ma is as s h o w n bel o w:




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3. 1. 3. 
St u d y E n d p oi nts
T he e n d p oi nts f or t he st u d y i ncl u de t he f oll o wi n g:

Safet y e n d p oi nts:
Safet y e n d p oi nts will i ncl u de D L Ts, S A Es, T E A Es, p h ysical e xa mi nati o n fi n di n gs (i ncl u di n g 
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 para meters, E C G para meters, 
E C H O/ M U G A fi n di n gs, a n d o p ht hal m ol o gic fi n di n gs.  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 4. 0.

P har mac o ki netic e n d p oi nts:
Ser u m P K e n d p oi nts (area u n der t he c o nce ntrati o n- vers us-ti me c ur ve, fr o m ti me 0 t o t he last 
meas ura ble c o nce ntrati o n as calc ulate d b y t he li near- u p l o g- d o w n tra pez oi dal met h o d [ A U Clast], 
A U C d uri n g d osi n g i nter val [ A U Cta u], ma xi m u m ( pea k) o bser ve d c o nce ntrati o n [ C ma x], ti me 
of ma xi m u m o bser ve d c o nce ntrati o n [ T ma x] a n d tr o u g h ser u m c o nce ntrati o ns [ Ctr o u g h]) of D S-
8 2 0 1a f or eac h s u bject will be esti mate d usi n g sta n dar d n o nc o m part me ntal met h o ds.  F or 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, all para meters liste d a b o ve will be esti mate d.  

Efficac y e n d p oi nts:
T u m or res p o nse will be e val uate d usi n g R E CI S T versi o n 1. 1.  O R R (t he s u m of C R rate a n d P R 
rate), D C R (t he s u m of C R rate, P R rate, a n d S D rate), res p o nse d urati o n, d urati o n of S D, T T R, 
P F S, O S, perce nt c ha n ge i n tar get lesi o n, ti me o n t hera p y of t he m ost rece nt pri or re gi me n t he 
s u bject recei ve d a n d t hat of D S- 8 2 0 1a.  T u m or assess me nt will be perf or me d b y b ot h t he 
i n vesti gat or a n d i n de pe n de nt ce ntral i ma gi n g facilit y.  T he Efficac y Varia ble(s) will be als o 
e val uate d at 1 8 wee ks after Da y 1 of C ycle 1.
3. 1. 4.  
D ur ati o n of t he St u d y
Part 1 is e x pecte d t o last a p pr o xi matel y o ne a n d a half years fr o m t he ti me t he first s u bject is 
e nr olle d t o t he ti me t he last s u bject is off t he D L T e val uati o n peri o d.  Part 2 is e x pecte d t o last 
a p pr o xi matel y o ne a n d a half years fr o m t he ti me t he first s u bject is e nr olle d t o t he ti me t he last 
s u bject is off t he st u d y.
3. 1. 5.  
D ur ati o n of S u bject P artici p ati o n
T he n u m ber of treat me nt c ycles is n ot fi xe d i n t his st u d y.  S u bjects w h o c o nti n ue t o deri ve 
cli nical be nefit fr o m t he st u d y treat me nt i n t he a bse nce of wit h dra wal of c o nse nt, P D, or 
u nacce pta ble t o xicit y ma y c o nti n ue t he st u d y treat me nt.
3. 1. 6. 
St o p pi n g R ules
T he st u d y treat me nt will be c o nti n ue d acc or di n g t o t he d osi n g criteria t o deri ve cli nical be nefit i n 
t he a bse nce of wit h dra wal of s u bject c o nse nt, P D, or u nacce pta ble t o xicit y.  If t he st u d y 
treat me nt is dela ye d m ore t ha n 4 wee ks 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 ( See secti o ns  3. 2. 1. 2. 1, 3. 2. 1. 2. 3. 1  a n d 4. 2. 1 ).  
T he st u d y ma y be ter mi nate d a n y ti me at S p o ns or’s discreti o n.


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3. 1. 7.  
D ose-li miti n g T o xicities
A D L T is defi ne d as a n y T E A E n ot attri b uta ble t o disease or disease-relate d pr ocesses t hat 
occ urs d uri n g t he D L T e val uati o n peri o d ( Da y 1 t o Da y 2 1 i n C ycle 1 of Part 1) a n d is gra de 3 or 
a b o ve acc or di n g t o N CI- C T C A E versi o n 4. 0, wit h t he e xce pti o ns as defi ne d bel o w:  
F or he mat ol o gical t o xicities, a D L T is defi ne d as f oll o ws:

Gra de 4 ne utr o p hil c o u nt decrease d lasti n g > 7 da ys, ne utr o p hil c o u nt decrease d t hat 
re q uires sta n dar d t hera pies, s uc h as c ol o n y sti m ulati n g fact or ( C S F)

Gra de ≥ 3 fe brile ne utr o pe nia

Gra de 4 a ne mia

Gra de 4 platelet c o u nt decrease d

Gra de ≥ 3 platelet c o u nt decrease d lasti n g > 7 da ys

Gra de ≥ 3 platelet c o u nt decrease d wit h cli nicall y si g nifica nt he m orr ha ge

Gra de 4 l y m p h oc yte c o u nt decrease d lasti n g ≥ 1 4 da ys
F or he patic or ga n t o xicities, a D L T is defi ne d as f oll o ws:

Gra de 4 A S T or A L T i ncrease d

A S T or A L T > 5  U L N ( Gra de 3), if acc o m pa nie d b y Gra de ≥ 2 bl o o d bilir u bi n 
i ncrease d

I n s u bjects wit h o ut li ver metastases, A S T or A L T > 5  U L N ( Gra de 3) lasti n g > 3 da ys

I n s u bjects wit h li ver metastases, A S T or A L T > 5  U L N ( Gra de 3) lasti n g > 3 da ys, if 
t he baseli ne le vel was ≤ 3  U L N ( Gra de ≤ 1)

I n s u bjects wit h li ver metastases, A S T or A L T > 8  U L N lasti n g > 3 da ys, if t he baseli ne 
le vel was > 3  U L N ( Gra de ≥ 2)
F or n o n- he mat ol o gical, n o n- he patic maj or or ga n t o xicities, a D L T is defi ne d as f oll o ws:

S y m pt o matic C H F

L V E F decli ne t o < 4 0 % or > 2 0 % dr o p fr o m baseli ne

Ot her gra de ≥ 3 n o n- he mat ol o gical, n o n- he patic maj or or ga n t o xicities
T he f oll o wi n g T E A Es are N O T c o nsi dere d D L Ts:

Gra de 3 fati g ue lasti n g < 7 da ys 

Gra de 3 na usea, v o miti n g, diarr hea, or a n ore xia t hat has res ol ve d t o gra de ≤ 2 wit hi n 3 
da ys 

Is olate d la b orat or y fi n di n gs n ot ass ociate d wit h si g ns or s y m pt o ms i ncl u di n g Gra de 3/ 4 
A L P i ncrease d, h y per urice mia, ser u m a m ylase i ncrease d, a n d li pase i ncrease d, a n d 
Gra de 3 h y p o natre mia lasti n g < 7 2 h o urs de vel o pe d fr o m gra de 1 at baseli ne

Gra de 3 l y m p h oc yte c o u nt decrease d


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If a n y of t he a b o ve t o xicities is o bser ve d d uri n g t he D L T e val uati o n peri o d, w het her t he t o xicit y 
is re gar de d as D L T will be deter mi ne d base d o n c o ns ultati o n bet wee n t he I n vesti gat or a n d 
S p o ns or.
I n a d diti o n, wit h re gar d t o ot her t o xicities t hat hi n der t he c o n d uct of t he sc he d ule d st u d y 
treat me nt or a ne mia wit h bl o o d tra nsf usi o n, w het her t he y are re gar de d as D L T will be 
deter mi ne d base d o n c o ns ultati o n bet wee n t he I n vesti gat or a n d S p o ns or.  
T he pre me dicati o n, w hic h is a treat me nt bef ore st u d y dr u g a d mi nistrati o n t o a v oi d A E, is 
pr o hi bite d d uri n g t he D L T e val uati o n peri o d.  
H o we ver, t he s u p p orti ve t hera p y f or t he treat me nt is per mitte d after st u d y dr u g a d mi nistrati o n:
F or e xa m ple: 

Ne utr o p hil c o u nt decrease d: C S F a d mi nistrati o n

Na usea, v o miti n g: A ntie metics
3. 1. 8.  
M a xi m u m T oler ate d D ose a n d Rec o m me n de d P h ase 2 D ose Defi niti o n
O nce t he d ose escalati o n st o p pi n g criteria are met, t he M T D esti mate d b y m C R M + E W O C will 
be t he d ose wit h t he hi g hest p osteri or pr o ba bilit y of t he D L T rate i n t he tar get D L T rate i nter val 
of ( 1 6 %, 3 3 %] a m o n g all d oses f ulfilli n g t he o ver d ose c o ntr ol c o nstrai nt: t here is less t ha n 2 5 % 
pr o ba bilit y of a D L T rate  3 3 % ( pr o ba bilit y f or e xcessi ve or u nacce pta ble t o xicit y) 
( Secti o n 3. 2. 1. 2. 1 ).  T he fi nal M T D f or eac h d osi n g sc he d ule will be deci de d base d o n 
c o nsi derati o ns of t he res pecti ve M T Ds esti mate d b y t he m C R M a n d o n a n o verall assess me nt of 
safet y data fr o m s u bse q ue nt c ycles a n d P K i nf or mati o n c ollecte d at all differe nt d oses teste d.  
U p o n deter mi ni n g t he fi nal M T D of t he ori gi nal Q 3 W a n d/ or alter nati ve d osi n g sc he d ules, 
d osi n g re gi me n(s) will be selecte d f or f urt her e val uati o n i n Part 2 ( D ose E x pa nsi o n).  T his 
re gi me n gi ve n at t he fi nal M T D deter mi ne d i n Part 1 is referre d t o as t he “ R P 2 D.”  R P 2 D ca n be 
se veral d ose le vels de pe n di n g o n t he ris k- be nefit of st u d y dr u g.
3. 1. 9.  
M a n a ge me nt of S u bjects Wit h A d verse E ve nts of I nterests
3. 1. 9. 1. 
I nf usi o n Rel ate d Re acti o ns
If a n i nf usi o n relate d reacti o n is o bser ve d d uri n g D S- 8 2 0 1a a d mi nistrati o n, t he i nf usi o n s pee d 
s h o ul d be re d uce d or t he i nf usi o n s h o ul d be i nterr u pte d or disc o nti n ue d base d o n t he s y m pt o ms.  
Acti o n ta ke n f or t he i nf usi o n relate d reacti o n is referre d acc or di n g t o t he f oll o wi n g Ta ble 3. 1 .  
Please see Secti o n 9. 3. 3  f or cli nical s u m mar y a n d f urt her ma na ge me nt g ui da nce.
T a ble 3. 1:
Acti o ns T a ke n f or I nf usi o n Rel ate d Re acti o n
N CI- C T C A E Gr a de
Acti o ns
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 is o bser ve d d uri n g 
a d mi nistrati o n, t he i nf usi o n s pee d 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 s pee d 
c o ul d be res u me d at t he i nitial pla n ne d s pee d.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 6
T a ble 3. 1:  
Acti o ns T a ke n f or I nf usi o n Rel ate d Re acti o n ( C o nti n ue d)
N CI- C T C A E Gr a de
Acti o ns
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 o nster oi dal a nti-
i nfla m mat or y dr u gs ( 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 D S- 8 2 0 1a s h o ul d be i nterr u pte d briefl y.

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)

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 s pee d.

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 s pee d.
Gra de 3
Pr ol o n ge d (e g, n ot ra pi dl y res p o nsi ve 
t o s y m pt o matic me dicati o n a n d/ or 
brief i nterr u pti o n of i nf usi o n):
rec urre nce of s y m pt o ms f oll o wi n g 
i nitial i m pr o ve me nt: 
h os pitalizati o n i n dicate d f or cli nical 
se q uelae
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

A d mi nistrati o n of D S- 8 2 0 1a s h o ul d be disc o nti n ue d 
i m me diatel y a n d per ma 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 ntra ve n o us 
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.
3. 1. 9. 2.  
C ar di ac T o xicit y
Ta ki n g i nt o c o nsi derati o n of t he res ults of t he n o ncli nical t o xic ol o g y st u dies of D S- 8 2 0 1a a n d 
M A A A- 1 1 8 1 a n d t he n o ncli nical a n d cli nical i nf or mati o n t hat are a vaila ble f or trast uz u ma b a n d 
T- D M 1, t he I n vesti gat or will c hec k t he L V E F t o m o nit or f or car diac t o xicit y.
L V E F will be m o nit ore d b y eit her E C H O or M U G A at t he scree ni n g, BI of c ycle 2, 3, a n d e ver y 
2 c ycles t hereafter u ntil t he e n d of treat me nt ( E O T) (e g, Da y 1 i n C ycle 3, 5, 7, 9, 1 1...).  
S u bjects wit h c o nfir me d s y m pt o matic car diac d ysf u ncti o n will be disc o nti n ue d fr o m t he st u d y.  
A s y m pt o matic decli ne i n L V E F will be ha n dle d wit h t he al g orit h m s h o w n i n Ta ble 3. 2 .
Please see Secti o n 9. 3. 1  f or cli nical s u m mar y a n d f urt her ma na ge me nt g ui da nce.
T a ble 3. 2:  
Acti o ns T a ke n f or C ar di ac T o xicit y
S y m pt o m atic 
C H F 
L V E F < 4 0 % or 
> 2 0 % dr o p fr o m 
b aseli ne 
L V E F 4 0 % t o 
≤ 4 5 % a n d 
decre ase is ≥ 1 0 % 
fr o m b aseli ne
L V E F 4 0 % t o 
≤ 4 5 % a n d 
decre ase is < 1 0 % 
fr o m b aseli ne 
L V E F 
> 4 5 % 
Disc o nti n ue 
D S- 8 2 0 1a
I nterr u pt D S- 8 2 0 1a 
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 
I nterr u pt D S- 8 2 0 1a 
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 
C o nti n ue treat me nt 
wit h D S- 8 2 0 1a
Re peat L V E F 
assess me nt wit hi n 3 
wee ks.
C o nti n ue 
treat me nt 
wit h D S-
8 2 0 1a


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 7
S y m pt o m atic 
C H F 
L V E F < 4 0 % or 
> 2 0 % dr o p fr o m 
b aseli ne 
L V E F 4 0 % t o 
≤ 4 5 % a n d 
decre ase is ≥ 1 0 % 
fr o m b aseli ne
L V E F 4 0 % t o 
≤ 4 5 % a n d 
decre ase is < 1 0 % 
fr o m b aseli ne 
L V E F 
> 4 5 % 
baseli ne is 
c o nfir me d, 
disc o nti n ue D S-
8 2 0 1a.
1 0 % fr o m baseli ne, 
disc o nti n ue D S-
8 2 0 1a.
C H F = C o n gesti ve Heart Fail ure; L V E F = Left Ve ntric ular Ejecti o n Fracti o n
3. 1. 9. 3. 
P ul m o n ar y T o xicit y
I L D/ p ne u m o nitis is c o nsi dere d 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 vaila ble safet y data fr o m t he D S 8 2 0 1- A-J 1 0 1 cli nical st u d y as well as 
t he res ults of p ote ntial I L D/ p ne u m o nitis cases re vie we d b y t he i n de pe n de nt I L D A dj u dicati o n 
C o m mittee ( A C), a vaila ble data 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 
safet 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 s u m mar y of 
preli mi nar y cli nical st u d y data.
If a s u bject 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 nterstitial l u n g disease (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 s us 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

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)

arterial 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 a n d e x pl orat or y bi o mar ker 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. 
As s o o n as I L D/ p ne u m o nitis is s us pecte d, c ortic oster oi d treat me nt s h o ul d be starte d pr o m ptl y as 
per cli nical treat me nt g ui deli nes ( K u b o K, et al 2 0 1 3 f or g ui da nce).  1 8
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 me nt g ui da nce as o utli ne d i n 
Ta ble 3. 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 disc o nti n uati o n.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 8
Please see Secti o n 9. 3. 2  f or cli nical s u m mar y a n d f urt her ma na ge me nt g ui da nce.
T a ble 3. 3:  
Acti o ns T a ke n f or St u d y Dr u g I n d uce d I L D or p ne u m o nitis
N CI- C T C A E Gr a de
Acti o ns
Gra de 1
T he a d mi nistrati o n of D S- 8 2 0 1a 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.
F or Gra de 1 e ve nts, D S- 8 2 0 1a 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:

If res ol ve d i n ≤ 2 8 da ys fr o m date of o nset, mai ntai n d ose

If res ol ve d i n > 2 8 da ys fr o m date of o nset, re d uce d ose 1 le vel
Gra de 2, 3 or 4
Per ma ne ntl y disc o nti n ue s u bject fr o m st u d y treat me nt.
3. 2. 
Selecti o n of D oses
3. 2. 1. 
E x peri me nt al Tre at me nts
T he st u d y will e nr oll s u bjects i nt o c o h orts wit h d ose escalati o n b y m C R M wit h E W O C pri nci ple 
as o utli ne d i n Secti o n 3. 2. 1. 2 .  T he starti n g d ose will be 0. 8 m g/ k g ( See Secti o n 1. 1. 1. 4. 5  f or 
j ustificati o n of t he h u ma n starti n g d ose).  
U p o n c o m pleti o n of C ycle 1 of Part 1 ( D ose Escalati o n) a n d deter mi nati o n of t he M T D/ R P 2 D, 
Part 2 ( D ose E x pa nsi o n) will be gi n.  I n Part 1, t he sec o n d s u bject i n eac h d osi n g le vel s h o ul d 
start d osi n g at least 2 4 h o urs after t he i nitial d osi n g of t he first s u bject t o c hec k t he ac ute t o xicit y 
s uc h as i nf usi o n-relate d reacti o n.  S u bjects i n Part 2 will recei ve D S- 8 2 0 1a at t he M T D/ R P 2 D 
defi ne d i n Secti o n 3. 2. 1. 2 .
S u bjects i n Part 1, Part 2a, Part 2 b, Part 2c a n d Part 2 d will recei ve F L- D P 1 dr u g pr o d uct, a n d 
t h ose i n Part 2e will recei ve F L- D P 2 dr u g pr o d uct.
3. 2. 1. 1. 
F or t he St u d y
See Secti o ns 1. 1. 1. 4. 5  a n d 1. 2 .
3. 2. 1. 2. 
F or I n di vi d u al S u bjects
3. 2. 1. 2. 1. 
P art 1 ( D ose Esc al ati o n)
D ose escalati o n of D S- 8 2 0 1a t o deter mi ne t he M T D/ R P 2 D will be g ui de d b y t he m C R M usi n g a 
B L R M f oll o wi n g E W O C pri nci ple.  D ose escalati o n will be gi n i n s u bjects wit h a d va nce d breast 
ca ncer a n d gastric or gastr oes o p ha geal j u ncti o n a de n ocarci n o ma.  At least 1 8 s u bjects will be 
e nr olle d i n Part 1.  M ore t ha n 1 6 % of s u bjects (e g, 1 per 6 s u bjects) are e x pecte d t o be H E R 2 
e x pressi o n (I H C 2 + or 3 +).  T he pr o p ose d h u ma n starti n g d ose of D S- 8 2 0 1a is 0. 8 m g/ k g, base d 
o n 1/ 1 2 H E D of H N S T D i n m o n ke y ( 3 0 m g/ k g).  
D uri n g Part 1, a n i nitial d ose of D S- 8 2 0 1a will be i nf use d i ntra ve n o usl y i nt o eac h s u bject f or 
a p pr o xi matel y 9 0 mi n utes o n Da y 1 of C ycle 1.  A 2 1- da y o bser vati o n peri o d ( C ycle 1) will t he n 
occ ur, at t he e n d of w hic h all rele va nt safet y data will be re vie we d.  U p o n c o m pleti o n of C ycle 1, 
s u bjects ma y c o nti n ue t o recei ve D S- 8 2 0 1a Q 3 W( 1 c ycle) at t he discreti o n of t he I n vesti gat ors, 
u ntil u nacce pta ble t o xicit y, P D, or wit h dra wal of c o nse nt.  If t here is n o i nf usi o n relate d reacti o n 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 4 9
after i nitial d ose, t he ne xt d ose of D S- 8 2 0 1a will be i nf use d i ntra ve n o usl y i nt o eac h s u bject f or 
a p pr o xi matel y 3 0 mi n utes.  T he s u bject’s wei g ht at scree ni n g ( baseli ne) will be use d t o calc ulate 
t he i nitial d ose.  If t he s u bject’s wei g ht c ha n ges b y ± 1 0 % of t he baseli ne wei g ht, t he d ose will 
be recalc ulate d.
D ose le vel i ncre me nt d uri n g d ose esc al ati o n ( P art 1) b y m C R M wit h E W O C

T he d ose le vel i ncre me nt s h o ul d be n o less t ha n 3 0 % i n or der t o ha ve disti ncti o n 
a m o n g d ose le vels c o nsi deri n g t he i nter-s u bject varia bilit y i n e x p os ure.

T he d ose le vel i ncre me nt s h o ul d be n o m ore t ha n 1 0 0 % e ve n if t he m o del s u g gests a 
hi g her d ose t ha n 1 0 0 % f or t he ne xt c o h ort.
T he escalati o n b y m C R M wit h E W O C pri nci ple will be base d o n a B L R M.  T he l o gistic 
re gressi o n m o del f or t he d ose-res p o nse ( D L T rate) relati o ns hi ps will i ncl u de 2 para meters, t he 
i nterce pt, a n d sl o pe.  After at least 3 s u bjects of eac h c o h ort c o m plete D L T e val uati o n d uri n g 
C ycle 1, p osteri or distri b uti o ns of D L T rate are deri ve d f or all d ose le vels base d o n t he B L R M 
usi n g D L T o utc o me data fr o m all assesse d d oses a n d a pre-s pecifie d pri or distri b uti o n f or t he 
m o del para meters.  T he p osteri or pr o ba bilit y of D L T rate i n t he f oll o wi n g 4 i nter vals at eac h 
d ose le vel: [ 0 %, 1 6 %] as D L T rate i nter val f or u n der- d osi n g, ( 1 6 %, 3 3 %] as tar get D L T rate 
i nter val, ( 3 3 %, 6 0 %] as D L T rate i nter val f or e xcessi ve t o xicit y, a n d ( 6 0 %, 1 0 0 %] as D L T rate 
i nter val f or u nacce pta ble t o xicit y will t he n be calc ulate d, a n d use d f or d ose rec o m me n dati o n f or 
t he ne xt c o h ort acc or di n g t o t he E W O C pri nci ple.  T he E W O C pri nci ple re q uires t hat t he m C R M 
rec o m me n de d d ose f or t he ne xt c o h ort of s u bjects is t he o ne wit h t he hi g hest p osteri or 
pr o ba bilit y of t he D L T rate i n t he tar get D L T rate i nter val of ( 1 6 %, 3 3 %] a m o n g all d oses 
f ulfilli n g t he o ver d ose c o ntr ol c o nstrai nt: t here is less t ha n 2 5 % of pr o ba bilit y f or D L T rate > 
3 3 % ( pr o ba bilit y f or e xcessi ve or u nacce pta ble t o xicit y).
T he d ose f or t he ne xt c o h ort will be c h ose n b y t he S p o ns or base d o n t he d ose rec o m me n dati o n 
b y t he m C R M, cli nical assess me nt of t o xicit y pr ofiles, a n d P K i nf or mati o n o bser ve d t h us far.
C o h orts of at least 3 D L T e val ua ble s u bjects will be e nr olle d a n d assesse d f or D L T d uri n g t he 
d ose escalati o n pr ocess.  As a n e xce pti o n, t he m o del will be ree val uate d bef ore e nr oll me nt of 
a n y a d diti o nal s u bjects t o t he c o h ort if 2 D L T e val ua ble s u bjects i n t he c o h ort e x perie nce D L T 
bef ore t he e nr oll me nt of t he t hir d s u bject.  E nr oll me nt of s u bjects t o a ne w c o h ort re q uires 
c o m pleti o n of D L T e val uati o n of at least 3 s u bjects treate d i n t he c urre nt c o h ort.  S u bjects w h o 
ha ve neit her c o m plete d D L T e val uati o n n or e x perie nce d D L T will be ce ns ore d a n d n ot i ncl u de d 
i n t he B L R M u p date.  I n t he e ve nt w he n s u bjects i n t he pre vi o us c o h ort e x perie nce D L Ts after 
e nr oll me nt of s u bjects t o a ne w c o h ort has be g u n, d ose le vel assi g n me nt of t he ne xt s u bject i n t he 
ne w c o h ort will be base d o n a n u p date d B L R M usi n g D L T o utc o me data fr o m all assesse d d oses.
T he R P 2 D will be deci de d base d o n c o nsi derati o ns of t he res pecti ve M T D esti mate d b y t he 
m C R M, a n d o n a n o verall assess me nt of safet y data fr o m s u bse q ue nt c ycles a n d efficac y/ P K 
i nf or mati o n c ollecte d at all differe nt d oses teste d.  F or d ose deter mi nati o n, Part 1 will be st o p pe d 
acc or di n g t o t he f oll o wi n g r ules: (a) at least 6 e val ua ble s u bjects ha ve bee n e nr olle d at t he 
M T D/ R P 2 D le vel wit h at least 1 8 e val ua ble s u bjects i n t otal e nr olle d i n t he d ose escalati o n part, 
or ( b) at least 9 e val ua ble s u bjects ha ve bee n e nr olle d at a d ose le vel w hic h is t he m o del’s 
rec o m me n dati o n f or t he ne xt d ose c o h ort a n d f or w hic h t he p osteri or pr o ba bilit y of tar gete d 
t o xicit y is at least 5 0 %, or (c) t he i nitial d ose le vel is t o o t o xic.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 0
C o h orts ma y be e x pa n de d at a n y d ose le vel or at t he M T D f or f urt her ela b orati o n of safet y, or 
P K para meters as re q uire d.
3. 2. 1. 2. 2. 
P art 2 ( D ose E x p a nsi o n)
U p o n c o m pleti o n of d ose escalati o n ( Part 1) wit h deter mi nati o n of M T D/ R P 2 D, t he D ose 
e x pa nsi o n part will be gi n.  
Part 2 will c o nsist of m ulti ple c o h orts: i n s u bjects wit h T- D M 1-treate d H E R 2 o vere x pressi n g 
breast ca ncer ( Part 2a); trast uz u ma b-treate d H E R 2 o vere x pressi n g gastric or gastr oes o p ha geal 
j u ncti o n a de n ocarci n o ma ( Part 2 b); H E R 2 l o w e x pressi n g breast ca ncer ( Part 2c); H E R 2 
e x pressi n g ot her s oli d mali g na nt t u m or or a n y t u m or wit h H E R 2 m utati o n ( Part 2 d); a n d H E R 2 
e x pressi n g breast ca ncer ( Part 2e).  A p pr o xi matel y 1 0 0 s u bjects will be e nr olle d i n Part 2a, 
a p pr o xi matel y 4 0 s u bjects will be e nr olle d i n Part 2 b, a p pr o xi matel y 2 0 t o 4 0 s u bjects will be 
e nr olle d i n Part 2c, a p pr o xi matel y 6 0 s u bjects will be e nr olle d i n Part 2 d a n d a p pr o xi matel y 2 0 
s u bjects will be e nr olle d i n Part 2e, res pecti vel y.
S u bjects will recei ve D S- 8 2 0 1a o n Da y 1 of a 2 1- da y c ycle.  T he i nitial d ose of D S- 8 2 0 1a will 
be i nf use d i ntra ve n o usl y i nt o eac h s u bject f or a p pr o xi matel y 9 0 mi n utes o n Da y 1 of C ycle 1.  If 
t here is n o i nf usi o n relate d reacti o n after i nitial d ose, t he ne xt d ose of D S- 8 2 0 1a will be i nf use d 
i ntra ve n o usl y i nt o eac h s u bject f or a p pr o xi matel y 3 0 mi n utes.  T he s u bject’s wei g ht at scree ni n g 
( baseli ne) will be use d t o calc ulate t he i nitial d ose.  If t he s u bject’s wei g ht c ha n ges b y ± 1 0 % of 
t he baseli ne wei g ht, t he d ose will be recalc ulate d.
R P 2 D
Deter mi ne d R P 2 D of D S- 8 2 0 1a is 6. 4 m g/ k g Q 3 W or 5. 4 m g/ k g Q 3 W.  I n Part 2a, 
a p pr o xi matel y 5 0 s u bjects will recei ve 6. 4 m g/ k g of D S- 8 2 0 1a Q 3 W a n d a n ot her a p pr o xi matel y 
5 0 s u bjects will recei ve 5. 4 m g/ k g of D S- 8 2 0 1a Q 3 W.  I n Part 2 b, a p pr o xi matel y 2 0 s u bjects 
will recei ve 6. 4 m g/ k g of D S- 8 2 0 1a Q 3 W a n d a n ot her a p pr o xi matel y 2 0 s u bjects will recei ve 5. 4 
m g/ k g of D S- 8 2 0 1a Q 3 W.  I n Part 2c, first a p pr o xi matel y 2 0 s u bjects will recei ve 6. 4 m g/ k g of 
D S- 8 2 0 1a Q 3 W b ut a d diti o nal a p pr o xi matel y 2 0 s u bjects ma y recei ve a n ot her d ose le vel of D S-
8 2 0 1a Q 3 W.  I n Part 2 d a n d Part 2e, all s u bjects will recei ve 6. 4 m g/ k g of D S- 8 2 0 1a Q 3 W.
3. 2. 1. 2. 3.  
D ose I nterr u pti o ns a n d Re d ucti o ns
3. 2. 1. 2. 3. 1.  
D ose I nterr u pti o ns
I n vesti gat ors s h o ul d c o nfir m w het her s u bjects satisf y t he f oll o wi n g d ose i nterr u pti o n criteria 
bef ore a d mi nistrati o n of t he st u d y dr u g (latest date wit hi n 3 da ys bef ore a d mi nistrati o n).  If a 
s u bject satisfies t he d ose i nterr u pti o n criteria, t he d osi n g of D S- 8 2 0 1a m ust be i nterr u pte d u ntil 
t he s u bject rec o vers fr o m all t o xicities, after w hic h, t he D ose Res u m pti o n R ules s h o w n i n 
Ta ble 3. 4  s h o ul d be f oll o we d.
T he d ose ca n be i nterr u pte d f or u p t o 4 wee ks 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 ose dela y l o n ger t ha n 4 wee ks, t he s u bject will be wit h dra w n 
fr o m t he st u d y.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 1
T a ble 3. 4:  
D ose I nterr u pti o n Criteri a a n d D ose Res u m pti o n R ules
T o xicities
D ose I nterr u pti o n criteri a
( wit hi n 3 d a ys bef ore 
a d mi nistr ati o n)
D ose Res u m pti o n R ules
Ne utr o p hil c o u nt decrease d
< 1 0 0 0/ m m 3
Res ol ve d t o  1 0 0 0/ m m3
Platelet c o u nt decrease d
< 5 0 0 0 0/ m m 3.
Res ol ve d t o  5 0 0 0 0/ m m3
Car diac T o xicit y
See Secti o n 3. 1. 9. 2 .
P ul m o nar y T o xicit y
See Secti o n 3. 1. 9. 3 .
All ot her n o n- he mat ol o gical 
t o xicities, e xce pt al o pecia 
N CI- C T C A E versi o n 4. 0 gra de  
3 a n d Gra de  3 fati g ue lasti n g  
4 8 h o urs.
Res ol ve d t o gra de  1 or 
baseli ne val ues.
All ot her la b orat or y 
a b n or malities t hat are n ot D L Ts
N CI- C T C A E versi o n 4. 0 gra de  3; t he treat me nt i nterr u pti o n a n d 
res u m pti o n wit h D S- 8 2 0 1a will be at t he discreti o n of t he 
I n vesti gat or.
T he I n vesti gat or ma y c o nsi der d ose i nterr u pti o ns or disc o nti n uati o n of t he st u d y dr u g base d o n 
ot her e ve nts n ot liste d i n Ta ble 3. 4  acc or di n g t o t he c o n diti o n of s u bject.
3. 2. 1. 2. 3. 2.  
D ose Re d ucti o ns
F or Part 1
If t he d ose is i nterr u pte d d ue t o t o xicities meeti n g t he D L T defi niti o n ( See Secti o n 3. 1. 7  f or D L T 
defi niti o ns) d uri n g treat me nt peri o d, d ose re d ucti o n s h o ul d be c o n d ucte d o n t he ne xt 
a d mi nistrati o n.  
W he n t he st u d y treat me nt is res u me d, t he ne xt d ose s h o ul d be re d uce d t o t he d ose of t he pre vi o us 
c o h ort.  
T he d ose le vel will n ot be bel o w 0. 8 m g/ k g.  After t w o re d ucti o ns, f urt her re d ucti o n s h o ul d n ot 
be c o n d ucte d a n d a d mi nistrati o n s h o ul d be disc o nti n ue d.  H o we ver, f urt her d ose re d ucti o n ma y 
be c o n d ucte d base d o n c o ns ultati o n bet wee n t he I n vesti gat or a n d S p o ns or.  O nce t he d ose of D S-
8 2 0 1a is re d uce d, n o escalati o n is per mitte d.
T he refere nce sc he me of d ose re d ucti o n at pr o visi o nal d oses is s h o w n i n Ta ble 3. 5 .
T a ble 3. 5:  
Refere nce Sc he me of D ose Re d ucti o n at Pr o visi o n al D oses f or P art 1
D ose le vel bef ore d ose 
i nterr u pti o n
D ose le vel after first d ose 
re d ucti o n
D ose le vel after sec o n d 
d ose re d ucti o n
0. 8 m g/ k g
- >
Disc o nti n uati o n
- >
-
1. 6 m g/ k g
- >
0. 8 m g/ k g
- >
Disc o nti n uati o n
3. 2 m g/ k g
- >
1. 6 m g/ k g
- >
0. 8 m g/ k g
5. 0 m g/ k g
- >
3. 2 m g/ k g
- >
1. 6 m g/ k g


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 2
D ose le vel bef ore d ose 
i nterr u pti o n
D ose le vel after first d ose 
re d ucti o n
D ose le vel after sec o n d 
d ose re d ucti o n
6. 4 m g/ k g
- >
3. 2 m g/ k g
- >
1. 6 m g/ k g
8. 0 m g/ k g
- >
6. 4 m g/ k g
- >
5. 4 m g/ k g 
T he I n vesti gat or ma y c o nsi der d ose re d ucti o ns or disc o nti n uati o n of t he st u d y dr u g acc or di n g t o 
t he c o n diti o n of s u bject.
F or Part 2
If t he d ose is i nterr u pte d d ue t o t o xicities meeti n g t he D L T defi niti o n ( See Secti o n 3. 1. 7  f or D L T 
defi niti o ns) d uri n g treat me nt peri o d, d ose re d ucti o n s h o ul d be c o n d ucte d o n t he ne xt 
a d mi nistrati o n.  
W he n t he st u d y treat me nt is res u me d, t he ne xt d ose s h o ul d be re d uce d acc or di n g t o Ta ble 3. 6 .
After t w o re d ucti o ns, f urt her re d ucti o n s h o ul d n ot be c o n d ucte d a n d a d mi nistrati o n s h o ul d be 
disc o nti n ue d.  H o we ver, f urt her d ose re d ucti o n ma y be c o n d ucte d base d o n c o ns ultati o n bet wee n 
t he I n vesti gat or a n d S p o ns or.  O nce t he d ose of D S- 8 2 0 1a is re d uce d, n o escalati o n is per mitte d.
T a ble 3. 6: 
Sc he me of D ose Re d ucti o n f or P art 2
D ose le vel bef ore d ose 
i nterr u pti o n
D ose le vel after first d ose 
re d ucti o n
D ose le vel after sec o n d 
d ose re d ucti o n
8. 0 m g/ k g
- >
6. 4 m g/ k g
- >
5. 4 m g/ k g
6. 4 m g/ k g
- >
5. 4 m g/ k g
- >
4. 4 m g/ k g
5. 4 m g/ k g
- >
4. 4 m g/ k g
- >
3. 2 m g/ k g
T he I n vesti gat or ma y c o nsi der d ose re d ucti o ns or disc o nti n uati o n of t he st u d y dr u g acc or di n g t o 
t he c o n diti o n of s u bject.
3. 2. 2.  
C o ntr ol Tre at me nts
N ot a p plica ble.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 3
4. 
S T U D Y P O P U L A TI O N
4. 1. 
E nr oll me nt
I n vesti 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 li mite d i nf or mati o n of t he s u bjects (i nitials, a ge, se x) date a n d o utc o me of scree ni n g 
pr ocess (e g, e nr oll i n t he st u d y, reas o n f or i neli gi bilit y, ref use d t o partici pate).
I n vesti 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 S u bject N u m ber.  T he u ni q ue S u bject N u m ber f or all s u bjects w h o 
pr o vi de writte n i nf or me d c o nse nt will be assi g ne d b y i nteracti ve res p o nse tec h n ol o g y (I R T), 
e nc o m passi n g b ot h i nteracti ve v oice res p o nse s yste ms (I V R S) utilizi n g t he tele p h o ne or t o ne 
dialers a n d i nteracti ve we b res p o nse s yste ms (I W R S) utilizi n g t he i nter net.  T he date of 
re gistrati o n is defi ne d as t he date t hat s u bject is s uccessf ull y e nr olle d as eli gi ble i n t he I R T 
s yste m.  T he date of scree n fail ure is defi ne d as t he date t hat s u bject is s uccessf ull y e nr olle d as 
i neli gi ble i n t he I R T s yste m.
I n vesti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n c o de list.  T his c o nfi de ntial list of 
na mes of all s u bjects all ocate d t o S u bject 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 vesti gat or t o re veal t he i de ntit y of a n y s u bject w he n necessar y.
Eac h s u bject will be pr o vi de d wit h i nf or mati o n a b o ut t he st u d y, will ha ve all q uesti o ns a ns were d 
t o t heir satisfacti o n, a n d will si g n a n d date a n I C F.  T his will be c o m plete d bef ore a n y st u d y-
s pecific pr oce d ures are perf or me d.  A d diti o nal i nf or mati o n a b o ut i nf or me d c o nse nt pr oce d ures is 
pr o vi de d i n Secti o n  1. 5. 2.
A s u bject i s c o nsi dere d t o be e nr olle d as eli gi ble i n t he st u d y u p o n t he I n vesti gat or’s or 
desi g nee’s o btai 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. 2 ) a n d u p o n 
deter mi nati o n of all i ncl usi o n a n d e xcl usi o n criteria ha vi n g bee n satisfie d.  After assi g ni n g Site 
S u bject I de ntifier t o eac h s u bject at t he ti me of scree ni n g i n eac h site, I n vesti gat ors will assess 
t he eli gi bilit y of a s u bject base d o n t he i ncl usi o n a n d e xcl usi o n criteria after o btai ni n g writte n 
i nf or me d c o nse nt fr o m t he s u bject.  After assess me nt b y I n vesti gat ors, s u bject e nr oll me nt is 
c o n d ucte d at ce ntral I R T.  I n Part 1 ( D ose Escalati o n), m ore t ha n 1 6 % of t he eli gi ble s u bjects 
(e g, 1 per 6 s u bjects) are e x pecte d t o be H E R 2 e x pressi o n (I H C 2 + or 3 +).  I n Part 2 ( D ose 
E x pa nsi o n), t he eli gi ble s u bjects will be e nr olle d i n t he fi ve ar ms ( Part 2a t o Part 2e), 
res pecti vel y, acc or di n g t o t he f oll o wi n g A d diti o nal I ncl usi o n Criteria ( See Secti o ns 4. 1. 1. 3, 
4. 1. 1. 4, 4. 1. 1. 5 a n d 4. 1. 1. 6).  
Data f or al l st u d y visits will be rec or de d o n t he e C R F f or s u bjects w h o recei ve st u d y dr u g.  O nl y 
mi ni mal data will be rec or de d as scree ni n g fail ures o n t he e C R F f or s u bjects w h o d o n ot meet 
eli gi bilit y a n d/ or d o n ot recei ve st u d y dr u g.  F urt her data, s uc h as A Es, will n ot be c ollecte d fr o m 
s u bjects o nce t he y are c o nsi dere d scree n fail ures or ha ve deci de d t o wit h dra w pri or t o recei vi n g 
st u d y dr u g.
4. 1. 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 criteria t o be i ncl u de d i n t he st u d y:


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 4
4. 1. 1. 1.  
C o m m o n I ncl usi o n Criteri a ( P art 1 a n d P art 2)
1.
A ge  2 0 years i n Ja pa n,  1 8 years i n t he U nite d States.
2.
Has a n E C O G P S 0- 1.
3.
Has L V E F  5 0 % b y eit her E C H O or M U G A wit hi n 2 8 da ys bef ore re gistrati o n.
4.
Has a de q uate or ga n f u ncti o n wit hi n 7 da ys bef ore re gistrati o n, defi ne d as:
Ite m
L a b or at or y v al ue
Platelet c o u nt
 1 0 0 0 0 0/ m m3
He m o gl o bi n ( H b)
≥ 8. 5 g/ d L
A bs ol ute ne utr o p hil c o u nt 
( A N C)
 1 5 0 0/ m m3
Creati ni ne
≤ 1. 5  U L N, or creati ni ne cleara nce ≥ 6 0 m L/ mi n as 
calc ulate d usi n g t he m o dificati o n C oc kcr oft- Ga ult e q uati o n
A S T/ A L T
≤ 3  U L N (if li ver metastases are prese nt, ≤ 5  U L N)
T otal bilir u bi n
≤ 1. 5  U L N or < 3 × U L N i n t he prese nce of d oc u me nte d 
Gil bert’s S y n dr o me or li ver metastases at baseli ne
Pr ot hr o m bi n ti me a n d acti vate d 
partial t hr o m b o plasti n ti me
≤ 1. 5 × U L N
5.
Has a de q uate treat me nt was h o ut peri o d bef ore re gistrati o n, defi ne d as:
Tre at me nt
W as h o ut peri o d
Maj or s ur ger y
 4 wee ks
Ra diati o n t hera p y
≥ 4 wee ks (if palliati ve stere otactic ra diati o n 
t hera p y wit h o ut a b d o mi nal, ≥ 2 wee ks)
A ut ol o g o us tra ns pla ntati o n
 3 m o nt hs 
H or m o nal t hera p y
 3 wee ks
C he m ot hera p y (i ncl u di n g a nti b o d y dr u g 
t hera p y)
 3 wee ks ( 2 wee ks f or 5-fl u or o uracil- base d 
a ge nts, f oli nate a ge nts a n d/ or wee kl y Paclita xel.  
 6 wee ks f or nitr os o ureas or mit o m yci n C, 
> 1 wee k f or T KIs a p pr o ve d f or t he treat me nt of 
N S C L C - baseli ne C T sca n m ust be c o m plete d 
after disc o nti n uati o n of T KI)
I m m u n ot hera p y
 4 wee ks
C Y P 3 A 4 str o n g i n hi bit or
 3 eli mi nati o n half-li ves of t he i n hi bit or
Or ga nic a ni o n tra ns p orti n g p ol y pe pti de 
( O A T P) i n hi bit or
 3 eli mi nati o n half-li ves of t he i n hi bit or
6. Is a ble t o pr o vi de writte n i nf or me d c o nse nt.  S u bject m ust be f ull y i nf or me d a b o ut t heir 
ill ness a n d t he i n vesti gati o nal nat ure of t he st u d y pr ot oc ol (i ncl u di n g f oreseea ble ris ks 
a n d p ossi ble t o xicities) a n d m ust si g n a n d date a n I R B a p pr o ve d I C F (i ncl u di n g HI P A A 
a ut h orizati o n, if a p plica ble) bef ore perf or ma nce of a n y st u d y-s pecific pr oce d ures or 
e xa mi nati o ns.
7. Is willi n g t o pr o vi de pre-e xisti n g dia g n ostic or resecte d t u m or sa m ples.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 5
8.
Has a life e x pecta nc y of ≥ 3 m o nt hs.
4. 1. 1. 2.  
A d diti o n al I ncl usi o n Criteri a f or P art 1 ( D ose Esc al ati o n)
9.
Has a pat h ol o gicall y d oc u me nte d a d va nce d/ u nresecta ble or metastatic breast ca ncer or 
gastric or gastr oes o p ha geal j u ncti o n a de n ocarci n o ma t hat is refract or y t o or i nt olera ble 
wit h 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.
4. 1. 1. 3.  
A d diti o n al I ncl usi o n Criteri a f or P art 2 a ( D ose E x p a nsi o n)
1 0. Has a pat h ol o gicall y d oc u me nte d a d va nce d/ u nresecta ble or metastatic breast ca ncer wit h 
H E R 2 o vere x pressi o n (I H C 3 + or I S H * +) t hat is refract or y t o or i nt olera ble wit h 
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.
* I S H: FI S H or DI S H 
1 1. Treate d wit h T- D M 1.
1 2. Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
4. 1. 1. 4.  
A d diti o n al I ncl usi o n Criteri a f or P art 2 b ( D ose E x p a nsi o n)
1 3. Has a pat h ol o gicall y d oc u me nte d a d va nce d/ u nresecta ble or metastatic gastric or 
gastr oes o p ha geal j u ncti o n a de n ocarci n o ma wit h H E R 2 o vere x pressi o n (I H C 3 + or I H C 
2 +/I S H * +) t hat is refract or y t o or i nt olera ble wit h 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.  It is rec o m me n de d t o o btai n H E R 2 stat us after 
c o m pleti n g t he last H E R 2-tar geti n g treat me nt.
* I S H: FI S H or DI S H
1 4. Treate d wit h trast uz u ma b.
1 5. Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
4. 1. 1. 5.  
A d diti o n al I ncl usi o n Criteri a f or P art 2c ( D ose E x p a nsi o n)
1 6. Has a pat h ol o gicall y d oc u me nte d a d va nce d/ u nresecta ble or metastatic breast ca ncer wit h 
H E R 2 l o w e x pressi o n (I H C 2 +/I S H * –, I H C 1 +/I S H * –, or I H C 1 +/I S H * u nteste d) t hat is 
refract or y t o or i nt olera ble wit h 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.  S u bjects wit h H E R 2 l o w e x pressi o n metastatic breast ca ncer w h o ha ve 
e x ha uste d treat me nts t hat ca n c o nfer a n y cli nicall y mea ni n gf ul be nefit (e g, ot her 
t hera pies s uc h as h or m o nal t hera p y f or patie nts w h o are h or m o ne rece pt or p ositi ve) are 
als o eli gi ble.
* I S H: FI S H or DI S H
1 7. Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
4. 1. 1. 6.  
A d diti o n al I ncl usi o n Criteri a f or P art 2 d ( D ose E x p a nsi o n)
1 8. Satisf y at least o ne of t he f oll o wi n g criteria. 

Has a pat h ol o gicall y d oc u me nte d a d va nce d/ u nresecta ble or metastatic s oli d mali g na nt 
t u m or wit h H E R 2 e x pressi o n ( deter mi ne d b y I H C, FI S H, Ne xt Ge nerati o n 
Se q ue nci n g, or ot her a nal ysis tec h ni q ues as a p pr o priate) ot her t ha n breast a n d gastric 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 6
or gastr oes o p ha geal j u ncti o n a de n ocarci n o ma t hat is refract or y t o or i nt olera ble wit h 
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. 

Has a pat h ol o gicall y d oc u me nte d a d va nce d/ u nresecta ble or metastatic t u m or wit h 
H E R 2 m utati o n ( deter mi ne d b y Ne xt Ge nerati o n Se q ue nci n g or ot her a nal ysis 
tec h ni q ues as a p pr o priate) t hat is refract or y t o or i nt olera ble wit h 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.
2 3. Is a ble t o pr o vi de fres h t u m or bi o ps y s peci me n.
1 9. Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
4. 1. 1. 7.  
A d diti o n al I ncl usi o n Criteri a f or P art 2e ( D ose E x p a nsi o n)
2 0. Has a pat h ol o gicall y d oc u me nte d a d va nce d/ u nresecta ble or metastatic breast ca ncer wit h 
H E R 2 e x pressi o n (I H C 1 +, I H C 2 +, I H C 3 + a n d/ or I S H * +) t hat is refrac t or y t o or 
i nt olera ble wit h 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.
* I S H: FI S H or DI S H
2 1. Treate d wit h T- D M 1 ( patie nts wit h H E R 2 o vere x pressi o n o nl y).
2 2. Has meas ura ble disease base d o n R E CI S T versi o n 1. 1.
4. 1. 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 criteria will be dis q ualifie d fr o m e nteri n g t he st u d y:
1.
Has a me dical hist or y of s y m pt o matic C H F ( N Y H A classes II-I V) or seri o us car diac 
arr h yt h mia re q uiri n g treat me nt. 1)
2.
Has a me dical hist or y of m y ocar dial i nfarcti o n or u nsta ble a n gi na wit hi n 6 m o nt hs bef ore 
re gistrati o n or tr o p o ni n le vels c o nsiste nt wit h m y ocar dial i nfarcti o n as defi ne d acc or di n g 
t o ma n ufact urer. 1)
3.
Has a Q Tc pr ol o n gati o n t o > 4 5 0 millisec o n d ( ms) i n males a n d > 4 7 0 ms i n fe males 
base d o n 1 2-lea d E C G i n tri plicate. 1)
4.
Has a hist or y of ( n o n-i 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 ne 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 
scree ni n g. 1)
5.
Has a n u nc o ntr olle d i nfecti o n re q uiri n g I V of a nti bi otics, a nti virals, or a ntif u n gals. 1)
6.
K n o w n HI V i nfecti o n, or acti ve he patitis B or C i nfecti o n. 1)
7. Is a lactati n g m ot her ( W o me n w h o are willi n g t o te m p oraril y i nterr u pt breastfee di n g will 
als o be e xcl u de d), or pre g na nt as c o nfir me d b y pre g na nc y tests perf or me d wit hi n 7 da ys 
bef ore re gistrati o n. 1)
8.
Male a n d fe male s u bjects w h o are u n willi n g t o use a de q uate c o ntrace pti ve met h o ds (e g, 
c o nc o mita nt use of a s per mat oci dal a ge nt a n d barrier c o ntrace pti ve, i ntra uteri ne 
c o ntrace pti ve, w hic h are a p pr o ve d or certificate d i n Ja pa n [f or Ja pa nese s u bjects] a n d U S 
[f or U S s u bjects]) d uri n g t he st u d y a n d f or at least 7 m o nt hs after t he last d ose of D S-
8 2 0 1a. 2)


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 7
9.
Has cli nicall y acti ve brai n metastases, defi ne d as u ntreate d a n d s y m pt o matic, or re q uiri n g 
t hera p y wit h ster 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 treat me nt 
wit h ster oi ds ma y be i ncl u de d i n t he st u d y if t he y ha ve rec o vere d fr o m t he ac ute t o xic 
effect of ra di ot hera p y. 1)
1 0. Has u nres ol ve d t o xicities fr o m pre vi o us a ntica ncer t hera p y, defi ne d as t o xicities ( ot her 
t ha n al o pecia) n ot yet res ol ve d t o N CI- C T C A E versi o n 4. 0, gra de ≤ 1 or baseli 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 vesti gat or. 1)
1 1. Has a c o nc o mita nt me dical c o n diti o n t hat w o ul d i ncrease t he ris k of t o xicit y, i n t he 
o pi ni o n of t he I n vesti gat or. 1)
1 2. Has k n o w n h y perse nsiti vit y t o eit her t he dr u g s u bsta nces or i nacti ve i n gre die nts i n t he 
dr u g pr o d uct. 1)
1 4. Has a hist or y of se vere h y perse nsiti vit y reacti o ns t o ot her m o n ocl o nal a nti b o dies.
4. 1. 2. 1.  
A d diti o n al E xcl usi o n Criteri a f or P art 2 ( D ose E x p a nsi o n)
1 3. Has m ulti ple pri mar y mali g na ncies wit hi n 3 years, e xce pt a de q uatel y resecte d n o n-
mela n o ma s ki n ca ncer, c urati vel y treate d i n-sit u disease, ot her s oli d t u m ors c urati vel y 
treate d, or c o ntralateral breast ca ncer. 3)
R ati o n ale f or E xcl usi o n Criteri a a n d A d diti o n al E xcl usi o n Criteri a:  
T hese criteria are i ncl u de d t o 
1) Mi ni mize t he ris k f or s u bject safet y
2) Pre ve nt pre g na nc y d uri n g treat me nt
3) E ns ure e nr oll me nt of re prese ntati ve s u bjects f or t he pla n ne d i n dicati o n
4. 2.  
Re m o v al of S u bjects Fr o m T her a p y
4. 2. 1.  
Re as o ns f or Wit h dr a w al/ E arl y Disc o nti n u ati o n
A n y s u bject w h o disc o nti n ues fr o m t he st u d y treat me nt f or a n y reas o n will ha ve t heir st u d y 
treat me nt disc o nti n uati o n rec or de d.
S u bjects ma y be wit h dra w n fr o m t he st u d y after si g ni n g i nf or me d c o nse nt f or t he f oll o wi n g 
reas o ns:

P D [ per R E CI S T]

Cli nical Pr o gressi o n ( pr o vi de date) 

A E

Deat h

Wit h dra wal b y s u bject 

L ost t o f oll o w- u p ( F/ U)


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 5 8

Pr ot oc ol vi olati o n (s pecif y)

St u d y ter mi nate d b y S p o ns or

Ot her, s pecif y (e g, discreti o n of t he I n vesti gat or) 
If a s u bject wit h dra ws 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 date of last treat me nt a n d t he 
reas o n f or wit h dra wal.
If t he s u bject is wit h dra w n d ue t o 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 bilize d as p ossi ble.
All s u bjects w h o are wit h dra w n fr o m t he st u d y a n d recei ve d st u d y treat me nt s h o ul d c o m plete 
pr ot oc ol s pecifie d wit h dra wal pr oce d ures ( Secti o n 4. 2. 2 ).  
4. 2. 2.  
Wit h dr a w al Pr oce d ures
Pr ot oc ol-s pecifie d wit h dra wal pr oce d ures will i n v ol ve a n E O T visit a n d a F/ U visit 2 8 da ys 
( - 7 da ys) after t he last a d mi nistrati o n of D S- 8 2 0 1a.  Pr ot oc ol-s pecifie d wit h dra wal pr oce d ures 
are t he sa me as t h ose t o be perf or me d at t he E O T visit a n d t he F/ U visit ( Secti o ns 6. 4  a n d 6. 5 ).
4. 2. 3. 
S u bject Re pl ace me nt
S u bject re place me nt is n ot all o we d f or t his st u d y. 
4. 2. 4. 
S u bject Re-scree ni n g Pr oce d ures
T he st u d y will all o w re-scree ni n g 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.  F or Part 1 a n d Part 2, t he Site S u bject I de ntifier m ust re mai n t he sa me at t he 
ti me of re-scree ni n g.  T he i nitial scree ni n g i nf or mati o n a n d t he reas o n w h y t he s u bject was 
i neli gi ble f or t he i nitial e val uati o n will be rec or de d o n t he Scree ni n g L o g. 




Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 0
5. 1. 5. 
St or a ge
Dr u g s u p plies m ust be st ore d i n a sec 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 bel o w - 1 5° C ( pr otecte d fr o m li g ht).
If st ora ge c o n diti o ns are n ot mai ntai ne d per s pecifie d re q uire me nts, S p o ns or or C R O s h o ul d be 
c o ntacte d.
5. 1. 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 ve d, t he I n vesti gat or or desi 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 ua ge i n t he la bel, dr u g e x pirati o n date, a n d 
si g n t he Recei pt of S hi p me nt F or m pr o vi de d.  T he Recei pt of S hi p me nt F or m s h o ul d be si g ne d 
a n d t he ori gi nal F or m will be retai ne d at t he site.  I n a d diti o n, t he I n vesti gat or or desi g nee s hall 
c o ntact 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 Rec or d will be pr o vi de d f or t he i n vesti gati o nal pr o d uct.  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 dates a n d q ua ntities of dr u g recei ve d, s u bject’s 
(i de ntificati o n n u m ber a n d/ or i nitials or s u p pl y n u m ber as a p plica ble), f or w h o m t he 
i n vesti gati o nal pr o d uct was dis pe nse d, t he date a n d q ua ntit y of i n vesti gati o nal pr o d uct dis pe nse d 
a n d re mai ni n g, if fr o m i n di vi d ual s u bject dr u g u nits as well as t he i nitials/seal of t he dis pe nser.
At t he e n d of t he st u d y, or as directe d, all u n use d D S- 8 2 0 1a will be ret ur ne d t o a desi g nee as 
i nstr ucte d b y S p o ns or.  I n vesti gati o nal Pr o d uct will be ret ur ne d o nl y after t he st u d y m o nit or has 
c o m plete d a fi nal i n ve nt or y t o verif y t he q ua ntit y t o be ret ur ne d.  T he ret ur n of I n vesti gati o nal 
Pr o d uct m ust be d oc u me 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 t he e n d of t he 
st u d y, a fi nal I n vesti gati o nal Pr o d uct rec o nciliati o n state me nt m ust be c o m plete d b y t he 
I n vesti gat or or desi g nee a n d pr o vi de d t o t he S p o ns or.  U n use d dr u g s u p plies ma y be destr o ye d 
b y t he s u per vis or of i n vesti gati o nal pr o d ucts i n Ja pa n a n d I n vesti gat or i n t he U nite d States w he n 
a p pr o ve d i n writi n g b y S p o ns or a n d S p o ns or has recei ve d c o pies of t he site’s dr u g ha n dli n g a n d 
dis p ositi o n S O Ps.
All i n vesti gati o nal pr o d uct i n ve nt or y f or ms m ust be ma de a vaila ble f or i ns pecti o n b y a S p o ns or 
a ut h orize d re prese ntati ve or desi g nee a n d re g ulat or y a ge nc y i ns pect ors.  T he s u per vis or of 
i n vesti gati o nal pr o d ucts i n Ja pa n a n d I n vesti gat or i n t he U nite d States is res p o nsi ble f or t he 
acc o u nta bilit y of all use d a n d u n use d st u d y s u p plies at t he site.
5. 1. 7.  
Rete nti o n S a m ples
N ot a p plica ble.
5. 2.  
C o nc o mit a nt Me dic ati o ns
Me dicati o ns use d fr o m Da y 1 of C ycle 1 t o 2 8 da ys ( – 7 da ys) after t he last a d mi nistrati o n of 
D S- 8 2 0 1a will be rec or de d.  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.
5. 2. 1. 
Pr o hi bite d C o nc o mit a nt Me dic ati o ns/ Acti vities
T he f oll o wi n g me dicati o ns a n d pr o d ucts will be pr o hi bite d:


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 1

Ot her a ntica ncer t hera p y, i ncl u di n g c yt ot o xics, tar gete d a ge nts, i m m u n ot hera p y or 
e n d ocri ne t hera p y.  

Ot her i n vesti gati o nal a ge nts.

C Y P 3 A 4 str o n g i n hi bit ors liste d i n S u p ple me nt 6.
If c o nc o mita nt use of str o n g C Y P 3 A 4 i n hi bit ors is u na v oi da ble, c o nsi der dela yi n g 
D S- 8 2 0 1a treat me nt u ntil t he str o n g C Y P 3 A 4 i n hi bit ors ha ve cleare d fr o m t he 
circ ulati o n (a p pr o xi matel y 3 eli mi nati o n half-li ves of t he i n hi bit ors) w he n p ossi ble.  
If a str o n g C Y P 3 A 4 i n hi bit or is c o-a d mi nistere d a n d D S- 8 2 0 1a treat me nt ca n n ot be 
dela ye d, patie nts s h o ul d be cl osel y m o nit ore d f or a d verse reacti o ns.

F o o ds c o ntai ni n g h y peric u m perf orat u m ( Sai nt J o h n's w ort). 

F o o ds or be vera ges c o ntai ni n g gra pefr uit.

A v oi d str o n g i n d ucers of C Y P 3 A 4 liste d i n S u p ple me nt 6 i n Part 1.

O A T P i n hi bit ors liste d i n S u p ple me nt 6.
If c o nc o mita nt use of O A T P i n hi bit ors is u na v oi da ble, c o nsi der dela yi n g D S- 8 2 0 1a 
treat me nt u ntil t he O A T P i n hi bit ors ha ve cleare d fr o m t he circ ulati o n (a p pr o xi matel y 
3 eli mi nati o n half-li ves of t he i n hi bit ors) w he n p ossi ble.  If a O A T P i n hi bit or is c o-
a d mi nistere d a n d D S- 8 2 0 1a treat me nt ca n n ot be dela ye d, patie nts s h o ul d be cl osel y 
m o nit ore d f or a d verse reacti o ns.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 2
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 1 7. 6 ( Part 1 a n d Part 2).
6. 1. 
Scree ni n g 
O btai n of a si g ne d a n d date d I C F bef ore a n y st u d y-relate d pr oce d ures or assess me nts are 
c o n d ucte d.  I n t his st u d y, re gistrati o n will be perf or me d ( See Secti o n 4. 1 ).
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 scree ni n g peri o d:
Bef ore re gistrati o n

Assi g n a Site S u bject I de ntifier.

Rec or d de m o gra p hic (e g, birt h date, se x, race, et h nicit y [s pecificall y f or U nite d States 
resi de nts]), pri mar y ca ncer hist or y, si g nifica nt me dical hist or y i nf or mati o n a n d pri or 
treat me nt hist or y i nf or mati o n f or ca ncer.

Rec or d hist orical H E R 2 stat us.  
F or Part 2 b o nl y: H E R 2 stat us s h o ul d be e val uate d base d o n a H E R 2 assess me nt t hat 
is ta ke n after t he last H E R 2-tar geti n g treat me nt if t u m or is a vaila ble.

Assess s u bjects f or A Es.
Wit hi n 7 da ys bef ore re gistrati o n

Perf or m a c o m plete p h ysical e xa mi nati o n a n d rec or d wei g ht.

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

Assess f u ncti o nal stat us usi n g t he E C O G Perf or ma nce Stat us Scale ( Secti o n 1 7. 1 ).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ), pr ot hr o m bi n ti me a n d 
acti vate d partial t hr o m b o plasti n ti me, H E R 2 E C D, 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 b y st u d y site, a n d car diac tr o p o ni n I (c T nI) testi n g b y 
ce ntral la b ( Secti o n 6. 8. 5 ).

Perf or m a 1 2-lea d E C G i n tri plicate *.
*: E C Gs will be ta ke n i n cl ose s uccessi o n, a fe w mi n utes a part, after bei n g i n a 
s u pi ne/se mi-rec u m be nt p ositi o n f or 5 mi n utes.

O btai n a ser u m or uri ne sa m ple f or pre g na nc y testi n g i n w o me n of c hil d beari n g 
p ote ntial.  F or p ost me n o pa usal s u bjects ( n o c hil d beari n g p ote ntial, as i n dicate d b y a n 
ela pse of at least 1 2 m o nt hs after t he last me nstr uati o n) or fe male s u bjects w h o ha ve 
n o p ossi bilit y of pre g na nc y d ue t o sterilizati o n s ur ger y, etc., n o pre g na nc y test will be 
re q uire d.  Fe male s u bjects w h o ha ve bee n a me n orr heic f or 1 2 m o nt hs or l o n ger f or 
me dical reas o ns ot her t ha n sterilizati o n s ur ger y (e g, effect of me dicati o n) will be 
re gar de d as w o me n of c hil d- beari n g p ote ntial a n d re q uire d t o u n der g o t he pre g na nc y 
test.
Wit hi n 9 0 da ys bef ore re gistrati o n


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 3

Perf or m a HI V a nti b o d y test.  HI V a nti b o d y test m ust be perf or me d f or Ja pa nese 
s u bjects, a n d is o pti o nal f or U S s u bjects u nless re q uire d b y l ocal re g ulati o ns or I R B.
Bef ore t he first d ose of st u d y dr u g a d mi nistrati o n

Perf or m a c o m plete p h ysical e xa mi nati o n a n d rec or d hei g ht.

If t here is n o arc hi ve d sa m ple, I n vesti gat or perf or ms a t u m or bi o ps y bef ore t he first 
d ose of st u d y dr u g.  Te n t u m or sli des f or assess me nt of H E R 2 b y I H C/ FI S H a n d 
H E R mar k are nee de d.  T he detaile d pr oce d ures f or pre pari n g a n d s u b mitti n g t u m or 
sa m ples will be pr o vi de d i n Secti o n 6. 8. 2 .  

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).  I n vesti gat ors 
ma y o pt o ut of o btai ni n g bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis de pe n di n g 
o n a s u bject’s c o n diti o n.

F or Part 2 d o nl y:
Perf or m a t u m or bi o ps y bef ore t he first d ose of st u d y dr u g.  T u m or tiss ue will be se nt 
t o t he ce ntral la b orat or y f or a n e x pl orat or y bi o mar ker a nal ysis.  F urt her details will be 
pr o vi de d i n t he la b orat or y ma n ual ( Secti o n 6. 8. 2. 2 ).
If t u m or is n ot accessi ble f or bi o ps y, t he I n vesti gat ors s h o ul d disc uss wit h t he 
S p o ns or w het her a patie nt ca n be e nr olle d or n ot.

[ O pti o nal] O btai n bl o o d sa m ples f or cell free D N A (cf D N A) a nal ysis ( Secti o n 6. 8. 5 ).
Wit hi n 2 8 da ys bef ore re gistrati o n 

O p ht hal m ol o gic assess me nts.  T he assess me nts will i ncl u de 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.

Perf or m eit her E C H O or M U G A ( L V E F). 

Perf or m t u m or assess me nt b y C T or ma g netic res o na nce i ma gi n g ( M RI) sca ns of t he 
brai n, c hest, a b d o me n, pel vis, a n d a n y ot her sites of disease ( Secti o n 1 7. 2 ).
6. 2.  
R a n d o miz ati o n
N ot a p plica ble.   
6. 3. 
Tre at me nt Peri o d
I n c o nsi derati o n of t he s u bject’s safet y, t he s u bjects will be h os pitalize d fr o m Da y 1 t o Da y 2 1 
o n C ycle 1 of Part 1 t o all o w f or caref ul safet y m o nit ori n g.  H o we ver, te m p orar y sta y o ver 
o utsi de t he h os pital is per mitte d at t he I n vesti gat or’s discreti o n. I n vesti gat or s h o ul d e xa mi ne t he 
s u bject caref ull y bef ore per missi o n a n d t he st u d y site s h o ul d trai n t he s u bject a b o ut a n 
e mer ge nc y c o ntact.  
I nstr uct s u bject t o refrai n fr o m pr ol o n ge d e x p os ure t o ultra vi olet ra ys.  A d diti o nal safet y 
assess me nts s h o ul d be c o n d ucte d as nee de d, at t he I n vesti gat or’s discreti o n.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 4
F or Part 2 d, it is rec o m me n de d t o perf or m a t u m or bi o ps y o ne ti me d uri n g Da y 8 t o 2 2 ( pri or t o 
t he s u bse q ue nt st u d y dr u g a d mi nistrati o n) of a n y c ycle.  I n vesti gat ors ma y o pt o ut of o btai ni n g 
bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis de pe n di n g o n a s u bject’s c o n diti o n.
6. 3. 1. 
T u m or assess me nt
T he sa me i ma gi n g t u m or assess me nt as at t he ti me of scree ni n g b y C T or M RI sca ns will be 
perf or me d e ver y 6 wee ks ( ± 7 da ys) i n t he first 2 4 wee ks after Da y 1 of C ycle 1 a n d t hereafter 
e ver y 1 2 wee ks ( ± 7 da ys) re gar dless of dela y i n d osi n g.  T he assess me nt will be c o n d ucte d 
bef ore Da y 1 of eac h C ycle as p ossi ble.  C T or M RI sca ns of t he c hest, a b d o me n a n d pel vis are 
ma n dat or y.  H o we ver, if t here is n o brai n metastasis at t he ti me of scree ni n g, C T or M RI s h o ul d 
o nl y be d o ne w he n s y m pt o ms ass ociate d wit h brai n metastasis occ ur.  If n o cli nical s y m pt o ms 
are o bser ve d, brai n C T or M RI is n ot ma n dat or y. ( Secti o n 1 7. 2 ).
I n a d diti o n t o t he i n vesti gat or’s t u m or assess me nt, re vie w b y i n de pe n de nt ce ntral i ma gi n g 
facilit y will be perf or me d.  T he detail i nstr ucti o ns f or t he ha n dli n g of i ma ges are i ncl u de d i n a 
se parate d oc u me nt.
6. 3. 2.  
C ycle 1, D a y 1
6. 3. 2. 1. 
Bef ore I nf usi o n
T he f oll o wi n g pr oce d ures will be c o m plete d at pre- d ose o n Da y 1.  If assess me nts at scree ni n g 
are perf or me d wit hi n t his peri o d, t he y ca n be c o nsi dere d t o be Da y 1 data a n d t here is n o nee d t o 
re peat t he m.

Assess s u bjects f or A Es.
Wit hi n 8 h o urs bef ore a d mi nistr ati o n

O btai n P K bl o o d sa m ple ( Secti o n 6. 8. 3 ).

O btai n bl o o d sa m ple f or A D A ( Secti o n 6. 8. 6 ).
L atest d at a wit hi n 3 d a ys  bef ore a d mi nistr ati o n

Perf or m a c o m plete p h ysical e xa mi nati o n a n d rec or d wei g ht.

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate, 
b o d y te m perat ure a n d S p O 2).

Assess f u ncti o nal stat us usi n g t he E C O G Perf or ma nce Stat us Scale ( Secti o n 1 7. 1 ).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

Perf or m a 1 2-lea d E C G i n tri plicate.  
6. 3. 2. 2.  
A d mi nistr ati o n a n d after I nf usi o n

A d mi nister D S- 8 2 0 1a per Secti o n 3. 1. 2 .
T he f oll o wi n g pr oce d ures will be c o m plete d at p ost- d ose o n Da y 1.

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 5

Perf or m a 1 2-lea d E C G i n tri plicate wit hi n 3 0 mi n utes after e n d of i nf usi o n ( E OI), 
a n d 2 t o 4 h o urs after t he start of a d mi nistrati o n.

O btai n P K bl o o d sa m ples at t he f oll o wi n g ti me p oi nts: wit hi n 1 5 mi n utes after E OI, 
2, 4 a n d 7 h o urs ( ± 1 5 mi n utes) after t he start of a d mi nistrati o n ( Secti o n 6. 8. 3 ).

O btai n bl o o d sa m ples f or c T nI testi n g b y ce ntral la b ( Secti o n 6. 8. 5 ).

O btai n 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 b y 
st u d y site 2 t o 3 h o urs after E OI ( Secti o n 6. 8. 5 ).  If re peat testi n g is c o n d ucte d, 
I n vesti gat or o btai ns bl o o d sa m ples f or b ot h tr o p o ni n testi n g b y st u d y site a n d c T nI 
testi n g b y ce ntral la b. 

If tr o p o ni n le vels are c o nsiste nt wit h m y ocar dial i nfarcti o n as defi ne d acc or di n g 
t o ma n ufact urer ( C T C A E Gra de 3), perf or m a 1 2-lea d E C G i n tri plicate, re peat 
tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) a n d 1 2 h o urs ( ± 1 h o ur) after i nitial tr o p o ni n 
test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes. 

If tr o p o ni n le vels 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 vel of 
m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), re peat 
tr o p o ni n testi n g 3 h o urs ( ± 1 h o ur) after i nitial tr o p o ni n test was dra w n.
If tr o p o ni n le vels are a b o ve t he u p per li mit of n or mal at baseli ne a n d bel o w t he 
le vel of m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), 
n o re peat testi n g is re q uire d after t he first E OI 3- h o ur tr o p o ni n test if t he tr o p o ni n 
le vel is n ot Gra de 3.  
If t he tr o p o ni n le vel at 3 h o urs ( 6 h o urs p ost i nf usi o n):

Si g nifica ntl y i ncreases, t he n re peat tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) after 
i nitial tr o p o ni n test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes.

Ot her wise, t he n re peat tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) or 2 4 h o urs ( ± 2 
h o urs) after i nitial tr o p o ni n test was dra w n.

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.
6. 3. 3.  
C ycle 1, D a y 2
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 2.  

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

O btai n P K bl o o d sa m ples at t he 2 4 h o urs ( ± 2 h o urs)  after t he start of Da y 1 
a d mi nistrati o n ( Secti o n 6. 8. 3 ).

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).

Perf or m a 1 2-lea d E C G i n tri plicate.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 6

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.
6. 3. 4.  
C ycle 1, D a y 4
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 4 ( ± 1 da y f or Part 2).  

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

O btai n P K bl o o d sa m ples at t he 7 2 h o urs ( ± 2 h o urs f or Part 1, ± 1 da y f or Part 2) 
after t he start of Da y 1 a d mi nistrati o n ( Secti o n 6. 8. 3 ).

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.
6. 3. 5.  
C ycle 1, D a y 8
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 8 ( ± 1 da y).  

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

O btai n P K bl o o d sa m ples o n Da y 8 ( Secti o n 6. 8. 3 ).

O btai n a bl o o d sa m ple f or A D A ( Secti o n 6. 8. 6 ).

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).

Perf or m a 1 2-le a d E C G i n tri plicate.

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
6. 3. 6.  
C ycle 1, D a y 1 5
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 1 5 ( ± 1 da y).  

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

O btai n P K bl o o d sa m ples o n Da y 1 5 ( Secti o n 6. 8. 3 ).

Perf or m a 1 2-lea d E C G i n tri plicate.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 7

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
6. 3. 7.  
C ycle 1, D a y 2 2
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is dela ye d f or 3 da ys or m ore, i ncl u di n g if t he s u bject 
ca n n ot c o nti n ue o nt o t he ne xt c ycle, t he f oll o wi n g pr oce d ures will be perf or me d o n Da y 2 2 ( ± 2 
da ys).  

O btai n P K bl o o d sa m ples o n Da y 2 2 ( Secti o n 6. 8. 3 ).

F or Ja pa nese s u bject s i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
6. 3. 8.  
C ycle 2, D a y 1
6. 3. 8. 1. 
Bef ore I nf usi o n
T he f oll o wi n g pr oce d ures will be c o m plete d at pre- d ose o n Da y 1.  

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).  T his is n ot 
necessar y if bl o o d sa m ples are o btai ne d o n C ycle 1, Da y 2 2.

Rec or d c o nc o mita nt me dicati o ns.  

Assess s u bjects f or A Es.

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
Wit hi n 8 h o urs bef ore a d mi nistr ati o n

O btai n P K bl o o d sa m ple ( Secti o n 6. 8. 3 ).
If bl o o d sa m ple is c ollecte d o n Da y 2 2 of C ycle 1, t he bl o o d sa m ple will be c ollecte d 
at BI o n Da y 1 of C ycle 2 if p ossi ble.

O btai n a bl o o d sa m ple f or A D A ( Secti o n 6. 8. 6 ).
L atest d at a wit hi n 3 d a ys bef ore a d mi nistr ati o n

O p ht hal m ol o gic assess me nts.  T he assess me nts will i ncl u de 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.  If t he pla n ne d date of st u d y dr u g a d mi nistrati o n 
is dela ye d after e xa mi nati o n of o p ht hal m ol o gic assess me nts, a n d t here are n o 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 8
a b n or mal fi n di n gs o n t he e xa mi nati o n, o p ht hal m ol o gic assess me nts ma y n ot be 
re peate d at t he i n vesti gat or’s j u d g me nt.

Perf or m a c o m plete p h ysical e xa mi nati o n a n d rec or d wei g ht.

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate, 
b o d y te m perat ure a n d S p O 2).

Assess f u ncti o nal stat us usi n g t he E C O G Perf or ma nce Stat us Scale ( Secti o n 1 7. 1 ).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

Perf or m eit her E C H O or M U G A ( L V E F).  If t he pla n ne d date of st u d y dr u g 
a d mi nistrati o n is dela ye d after e xa mi nati o n of E C H O or M U G A, a n d t here are n o 
a b n or mal fi n di n gs o n t he e xa mi nati o n, E C H O or M U G A ma y n ot be re peate d at t he 
i n vesti gat or’s j u d g me nt.

Perf or m a 1 2-lea d E C G i n tri plicate. 
6. 3. 8. 2.  
A d mi nistr ati o n a n d after I nf usi o n
T he f oll o wi n g pr oce d ures will be c o m plete d o n Da y 1 ( + 2 da ys).

A d mi nister D S- 8 2 0 1a per Secti o n 3. 1. 2 .
T he f oll o wi n g pr oce d ures will be c o m plete d at p ost- d ose o n Da y 1:

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

O btai n P K bl o o d sa m ples at t he e n d of a d mi nistrati o n wit hi n 1 5 mi n utes after E OI 
( Secti o n 6. 8. 3 ).

O btai n bl o o d sa m ples f or c T nI testi n g b y ce ntral la b ( Secti o n 6. 8. 5 ).

Perf or m a 1 2-lea d E C G i n tri plicate.

O btai n 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 b y 
st u d y site 2 t o 3 h o urs after E OI ( Secti o n 6. 8. 5 ).  If re peat testi n g is c o n d ucte d, 
I n vesti gat or o btai ns bl o o d sa m ples f or b ot h tr o p o ni n testi n g b y st u d y site a n d c T nI 
testi n g b y ce ntral la b.

If tr o p o ni n le vels are c o nsiste nt wit h m y ocar dial i nfarcti o n as defi ne d acc or di n g 
t o ma n ufact urer ( C T C A E Gra de 3), perf or m a 1 2-lea d E C G i n tri plicate, re peat 
tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) a n d 1 2 h o urs ( ± 1 h o ur) after i nitial tr o p o ni n 
test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes. 

If tr o p o ni n le vels 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 vel of 
m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), re peat 
tr o p o ni n testi n g 3 h o urs ( ± 1 h o ur) after i nitial tr o p o ni n test was dra w n.  
If tr o p o ni n le vels are a b o ve t he u p per li mit of n or mal at baseli ne a n d bel o w t he 
le vel of m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), 
n o re peat testi n g is re q uire d after t he first E OI 3- h o ur tr o p o ni n test if t he tr o p o ni n 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 6 9
le vel is n ot Gra de 3.
If t he tr o p o ni n le vel at 3 h o urs ( 6 h o urs p ost i nf usi o n):

Si g nifica ntl y i ncreases, t he n re peat tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) after 
i nitial tr o p o ni n test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes.

Ot her wise, t he n re peat tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) or 2 4 h o urs ( ± 2 
h o urs) after i nitial tr o p o ni n test was dra w n.

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.
6. 3. 9.  
C ycle 2, D a y 8 a n d D a y 1 5
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 8 a n d Da y 1 5 ( ± 2 da ys).  

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
6. 3. 1 0.  
C ycle 2, D a y 2 2
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is dela ye d f or 3 da ys or m ore, i ncl u di n g if t he s u bject 
ca n n ot c o nti n ue o nt o t he ne xt c ycle, t he f oll o wi n g pr oce d ures will be perf or me d o n Da y 2 2 ( ± 2 
da ys).  

O btai n P K bl o o d sa m ples d uri n g t he C ycle 2, Da y 2 2 ( Secti o n 6. 8. 3 ).

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
6. 3. 1 1.  
C ycle 3, D a y 1
6. 3. 1 1. 1.
Bef ore I nf usi o n
T he f oll o wi n g pr oce d ures will be c o m plete d at pre- d ose o n Da y 1.  

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).  T his is n ot 
necessar y if bl o o d sa m ples are o btai ne d o n C ycle 2, Da y 2 2.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 0

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
Wit hi n 8 h o urs bef ore a d mi nistr ati o n

O btai n P K bl o o d sa m ple ( Secti o n 6. 8. 3 )
If bl o o d sa m ple is c ollecte d o n Da y 2 2 of C ycle 2, t he bl o o d sa m ple will be c ollecte d 
at BI o n Da y 1 of C ycle 3 if p ossi ble.

O btai n bl o o d sa m ple f or H E R 2 E C D ( Secti o n 6. 8. 5 ).
L atest d at a wit hi n 3 d a ys bef ore a d mi nistr ati o n

Perf or m a c o m plete p h ysical e xa mi nati o n a n d rec or d wei g ht.

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate, 
b o d y te m perat ure a n d S p O 2).

Assess f u ncti o nal stat us usi n g t he E C O G Perf or ma nce Stat us Scale ( Secti o n 1 7. 1 ).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

Perf or m eit her E C H O or M U G A ( L V E F).   If t he pla n ne d date of st u d y dr u g 
a d mi nistrati o n is dela ye d after e xa mi nati o n of E C H O or M U G A, a n d t here are n o 
a b n or mal fi n di n gs o n t he e xa mi nati o n, E C H O or M U G A ma y n ot be re peate d at t he 
i n vesti gat or’s j u d g me nt.

Perf or m a 1 2-lea d E C G i n tri plicate.
6. 3. 1 1. 2.
A d mi nistr ati o n a n d after I nf usi o n
T he f oll o wi n g pr oce d ures will be c o m plete d o n Da y 1 ( + 2 da ys).

A d mi nister D S- 8 2 0 1a per Secti o n 3. 1. 2 .
T he f oll o wi n g pr oce d ures will be c o m plete d at p ost- d ose o n Da y 1:

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

O btai n P K bl o o d sa m ples at t he f oll o wi n g ti me p oi nts: 
I n P art 1 D ose Esc al ati o n, wit hi n 1 5 mi n utes after E OI a n d 4 h o urs ( ± 1 5 mi n utes) 
after t he start of a d mi nistrati o n ( Secti o n 6. 8. 3 ).
I n P art 2 D ose E x p a nsi o n, wit hi n 1 5 mi n utes after E OI ( Secti o n 6. 8. 3 ).

O btai n bl o o d sa m ples f or c T nI testi n g b y ce ntral la b ( Secti o n 6. 8. 5 ).

O btai n 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 b y 
st u d y site 2 t o 3 h o urs after E OI ( Secti o n 6. 8. 5 ).  If re peat testi n g is c o n d ucte d, 
I n vesti gat or o btai ns bl o o d sa m ples f or b ot h tr o p o ni n testi n g b y st u d y site a n d c T nI 
testi n g b y ce ntral la b.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 1

If tr o p o ni n le vels are c o nsiste nt wit h m y ocar dial i nfarcti o n as defi ne d acc or di n g 
t o ma n ufact urer ( C T C A E Gra de 3), perf or m a 1 2-lea d E C G i n tri plicate, re peat 
tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) a n d 1 2 h o urs ( ± 1 h o ur) after i nitial tr o p o ni n 
test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes. 

If tr o p o ni n le vels 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 vel of 
m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), re peat 
tr o p o ni n testi n g 3 h o urs ( ± 1 h o ur) after i nitial tr o p o ni n test was dra w n.
If tr o p o ni n le vels are a b o ve t he u p per li mit of n or mal at baseli ne a n d bel o w t he 
le vel of m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), 
n o re peat testi n g is re q uire d after t he first E OI 3- h o ur tr o p o ni n test if t he tr o p o ni n 
le vel is n ot Gra de 3.  
If t he tr o p o ni n le vel at 3 h o urs ( 6 h o urs p ost i nf usi o n):

Si g nifica ntl y i ncreases, t he n re peat tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) after 
i nitial tr o p o ni n test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes.

Ot her wise, t he n re peat tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) or 2 4 h o urs ( ± 2 
h o urs) after i nitial tr o p o ni n test was dra w n.

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.
6. 3. 1 2.  
C ycle 3, D a y 8 a n d D a y 1 5
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 8 a n d Da y 1 5 ( ± 2 da ys).  

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

O btai n P K bl o o d sa m ples d uri n g t he C ycle 3, Da y 8 a n d Da y 1 5  visit ( Secti o n 6. 8. 3 ).

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
6. 3. 1 3.  
C ycle 3, D a y 2 2
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is dela ye d f or 3 da ys or m ore, i ncl u di n g if t he s u bject 
ca n n ot c o nti n ue o nt o t he ne xt c ycle, t he f oll o wi n g pr oce d ures will be perf or me d o n Da y 2 2 ( ± 2 
da ys).  

O btai n P K bl o o d sa m ples o n Da y 2 2 ( Secti o n 6. 8. 3 ).

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 2

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
6. 3. 1 4.  
C ycle 4 a n d S u bse q ue nt C ycles, D a y 1
6. 3. 1 4. 1.
Bef ore I nf usi o n
T he f oll o wi n g pr oce d ures will be c o m plete d at pre- d ose o n Da y 1.  

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis o ne ti me d uri n g treat me nt 
peri o d ( Secti o n 6. 8. 5 ).

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y o ne ti me d uri n g treat me nt peri o d 
( Secti o n 6. 8. 2. 2 ).
Wit hi n 8 h o urs bef ore a d mi nistr ati o n
At Da y 1 i n C ycle 4, 6, a n d 8 .

O btai n P K bl o o d sa m ple ( Secti o n 6. 8. 3 ).
If bl o o d sa m ple is c ollecte d o n Da y 2 2 of C ycle 3, t he bl o o d sa m ple will be c ollecte d 
at BI o n Da y 1 of C ycle 4 if p ossi ble.
At Da y 1 e ver y 2 c ycles fr o m C ycle 3 t o t he E O T (e g, Da y 1 i n C ycle 3, 5, 7, 9, 1 1...)

O btai n bl o o d sa m ples f or H E R 2 E C D ( Secti o n 6. 8. 5 ).  T his is a p plica ble u ntil 
pr ot oc ol versi o n 1 1. 0.  N o f urt her bl o o d sa m pli n g f or H E R 2 E C D is necessar y o nce 
pr ot oc ol versi o n 1 2. 0 is a p plie d f or a s u bject. 
At Da y 1 e ver y 2 c ycles fr o m C ycle 4 t o t he E O T (e g, Da y 1 i n C ycle 4, 6, 8, 1 0 ・・・)

O btai n a n bl o o d sa m ple f or A D A ( Secti o n 6. 8. 6 )
L atest d at a wit hi n 3 d a ys bef ore a d mi nistr ati o n

Perf or m a c o m plete p h ysical e xa mi nati o n a n d rec or d wei g ht.

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate, 
b o d y te m perat ure a n d S p O 2).

Assess f u ncti o nal stat us usi n g t he E C O G Perf or ma nce Stat us Scale ( Secti o n 1 7. 1 ).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ).

Perf or m a 1 2-lea d E C G i n tri plicate.
At Da y 1 e ver y 2 c ycles fr o m C ycle 3 t o t he E O T (e g, Da y 1 i n C ycle 3, 5, 7, 9, 1 1...)

Perf or m eit her E C H O or M U G A ( L V E F).  
If t he pla n ne d date of st u d y dr u g a d mi nistrati o n is dela ye d after e xa mi nati o n of 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 3
E C H O or M U G A, a n d t here are n o a b n or mal fi n di n gs o n t he e xa mi nati o n, E C H O or 
M U G A ma y n ot be re peate d at t he i n vesti gat or’s j u d g me nt.
At Da y 1 e ver y 4 c ycles fr o m C ycle 5 t o t he E O T (e g, Da y 1 i n C ycle 5, 9, 1 3...)

O p ht hal m ol o gic assess me nts.  
T he assess me nts will i ncl u de 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. If t he pla n ne d date of st u d y dr u g a d mi nistrati o n is dela ye d after 
e xa mi nati o n of o p ht hal m ol o gic assess me nts, a n d t here are n o a b n or mal fi n di n gs o n 
t he e xa mi nati o n, o p ht hal m ol o gic assess me nts ma y n ot be re peate d at t he 
i n vesti gat or’s j u d g me nt.
6. 3. 1 4. 2.
A d mi nistr ati o n a n d after I nf usi o n
T he f oll o wi n g pr oce d ures will be c o m plete d o n Da y 1 ( + 2 da ys).

A d mi nister D S- 8 2 0 1a per Secti o n 3. 1. 2 .
T he f oll o wi n g pr oce d ures will be c o m plete d at p ost- d ose o n Da y 1.

O btai n bl o o d sa m ples f or c T nI testi n g b y ce ntral la b ( Secti o n 6. 8. 5 ).

O btai n 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 b y 
st u d y site 2 t o 3 h o urs after E OI ( Secti o n 6. 8. 5 ).  If re peat testi n g is c o n d ucte d, 
I n vesti gat or o btai ns bl o o d sa m ples f or b ot h tr o p o ni n testi n g b y st u d y site a n d c T nI 
testi n g b y ce ntral la b.

If tr o p o ni n le vels are c o nsiste nt wit h m y ocar dial i nfarcti o n as defi ne d acc or di n g 
t o ma n ufact urer ( C T C A E Gra de 3), perf or m a 1 2-lea d E C G i n tri plicate, re peat 
tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) a n d 1 2 h o urs ( ± 1 h o ur) after i nitial tr o p o ni n 
test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes. 

If tr o p o ni n le vels 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 vel of 
m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), re peat 
tr o p o ni n testi n g 3 h o urs ( ± 1 h o ur) after i nitial tr o p o ni n test was dra w n.  
If tr o p o ni n le vels are a b o ve t he u p per li mit of n or mal at baseli ne a n d bel o w t he 
le vel of m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), 
n o re peat testi n g is re q uire d after t he first E OI 3- h o ur tr o p o ni n test if t he tr o p o ni n 
le vel is n ot Gra de 3.
If t he tr o p o ni n le vel at 3 h o urs ( 6 h o urs p ost i nf usi o n):

Si g nifica ntl y i ncreases, t he n re peat tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) after 
i nitial tr o p o ni n test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes.

Ot her wise, t he n re peat tr o p o ni n testi n g 6 h o urs ( ± 1 h o ur) or 2 4 h o urs ( ± 2 
h o urs) after i nitial tr o p o ni n test was dra w n.

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.
After C ycle 4 at e ver y 2 c ycles u ntil C ycle 8 at t he m a xi m u m (e g, D a y 1 of c ycle 4, 6, 8)


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 4

O btai n P K bl o o d sa m ple at t he e n d of a d mi nistrati o n wit hi n 1 5 mi n utes after E OI 
( Secti o n 6. 8. 3 ).
6. 4. 
E n d of Tre at me nt
T he date of disc o nti n uati o n of treat me nt is defi ne d as t he date of decisi o n b y I n vesti gat or.  T he 
f oll o wi n g assess me nts will be perf or me d at E O T visit ( wit hi n 7 da ys after t he date of 
disc o nti n uati o n).  If assess me nt at E O T are perf or me d i n t he treat me nt peri o d, t he y ca n be 
c o nsi dere d t o be t he E O T data a n d t here is n o nee d t o re peat t he m base d o n c o ns ultati o n bet wee n 
t he I n vesti gat ors a n d t he S p o ns or. 
F or Part 2 d, it is rec o m me n de d t o perf or m a t u m or bi o ps y if t he s u bject disc o nti n ues fr o m t he 
st u d y treat me nt d ue t o P D.  It is als o rec o m me n de d t o o btai n bl o o d sa m ples f or cf D N A a nal ysis.

O p ht hal m ol o gic assess me nts.  T he assess me nts will i ncl u de 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.

Perf or m a c o m plete p h ysical e xa mi nati o n a n d rec or d wei g ht.

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate, 
b o d y te m perat ure a n d S p O 2).

Assess f u ncti o nal stat us usi n g t he E C O G Perf or ma nce Stat us Scale ( Secti o n 1 7. 1 ).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ) a n d A D A ( Secti o n 6. 8. 6 ).

O btai n bl o o d sa m ples f or H E R 2 E C D ( Secti o n 6. 8. 5 ).  T his is a p plica ble u ntil 
pr ot oc ol versi o n 1 1. 0.  N o f urt her bl o o d sa m pli n g f or H E R 2 E C D is necessar y o nce 
pr ot oc ol versi o n 1 2. 0 is a p plie d f or a s u bject.

O btai n bl o o d sa m ples f or c T nI testi n g b y ce ntral la b a n d 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 b y st u d y site ( Secti o n 6. 8. 5 ).

O btai n a ser u m or uri ne sa m ple f or pre g na nc y testi n g i n w o me n of c hil d beari n g 
p ote ntial.  F or p ost me n o pa usal s u bjects ( n o c hil d beari n g p ote ntial, as i n dicate d b y a n 
ela pse of at least 1 2 m o nt hs after t he last me nstr uati o n) or fe male s u bjects w h o ha ve 
n o p ossi bilit y of pre g na nc y d ue t o sterilizati o n s ur ger y, etc., n o pre g na nc y test will be 
re q uire d.  Fe male s u bjects w h o ha ve bee n a me n orr heic f or 1 2 m o nt hs or l o n ger f or 
me dical reas o ns ot her t ha n sterilizati o n s ur ger y (e g, effect of me dicati o n) will be 
re gar de d as w o me n of c hil d- beari n g p ote ntial a n d re q uire d t o u n der g o t he pre g na nc y 
test.

Perf or m a 1 2-lea d E C G i n tri plicate.

Perf or m eit her E C H O or M U G A ( L V E F).

Perf or m sa me i ma gi n g t u m or assess me nt as at t he ti me of scree ni n g b y C T or M RI 
sca ns.  C T or M RI sca ns of t he c hest, a b d o me n a n d pel vis are ma n dat or y.  H o we ver, 
if t here is n o brai n metastasis at t he ti me of scree ni n g, C T or M RI s h o ul d o nl y be 
d o ne w he n s y m pt o ms ass ociate d wit h brai n metastasis occ ur.  If n o cli nical s y m pt o ms 
are o bser ve d, brai n C T or M RI is n ot ma n dat or y ( Secti o n 1 7. 2 ).  If pr o gressi o n is 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 5
i de ntifie d i n a pri or e xa mi nati o n, o nl y t he c hest is e xa mi ne d b y C T t o m o nit or t he 
p ul m o nar y stat us.

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.

Rec or d reas o n f or treat me nt disc o nti n uati o n.

F or Ja pa nese s u bjects i n Part 2 d o nl y:
O btai n bl o o d sa m ples f or i m m u ne m o nit ori n g a nal ysis ( Secti o n 6. 8. 5 ).

[ O pti o nal] O btai n bl o o d sa m ples f or cf D N A a nal ysis ( Secti o n 6. 8. 5 ).

[ O pti o nal] F or Part 2 d o nl y: Perf or m a t u m or bi o ps y ( Secti o n 6. 8. 2. 2 ).
6. 5. 
F oll o w- u p
T he F/ U visit s h o ul d occ ur 2 8 da ys ( – 7 da ys) after t he last a d mi nistrati o n of D S- 8 2 0 1a.  If t he 
s u bject be gi ns a n ot her a ntica ncer t hera p y bef ore t he e n d of t he 2 8 da ys ( – 7 da ys), e ver y eff ort 
will be ma de t o c o m plete all t he F/ U assess me nts pri or t o c o m me nci n g t he ne w t hera p y.  I n case 
of u nres ol ve d A Es, t he I n vesti gat or will f oll o w t he A Es u ntil t he e ve nt has res ol ve d or t he 
c o n diti o n has sta bilize d as p ossi ble.  If assess me nts at E O T or treat me nt peri o d are perf or me d 
wit hi n t his peri o d, t he y ca n be c o nsi dere d t o be t he F/ U data a n d t here is n o nee d t o re peat t he m.  
If disc o nti n uati o n of treat me nt is deci de d later t ha n 2 8 da ys after t he last a d mi nistrati o n of D S-
8 2 0 1a, t here is n o nee d t o perf or m t he F/ U assess me nts.
T he f oll o wi n g i nf or mati o n will be c ollecte d at t his F/ U visit:

O btai n vital si g n meas ure me nts (s yst olic a n d diast olic bl o o d press ure a n d p ulse rate 
a n d b o d y te m perat ure).

Perf or m a c o m plete p h ysical e xa mi nati o n a n d rec or d wei g ht.

Assess f u ncti o nal stat us usi n g t he E C O G Perf or ma nce Stat us Scale ( Secti o n 1 7. 1 ).

O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n 9. 8 ) a n d A D A ( Secti o n 6. 8. 6 ).  
F or s u bjects wit h p ositi ve A D A at F/ U visit, 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, or 
if t he A D A bec o mes ne gati ve, or if 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), or if 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 t he st u d y, w hic he ver occ urs first.

O btai n bl o o d sa m ples f or c T nI testi n g b y ce ntral la b a n d 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 b y st u d y site ( Secti o n 6. 8. 5 ).

Rec or d c o nc o mita nt me dicati o ns.

Assess s u bjects f or A Es.
6. 6.  
Ne w C a ncer Tre at me nt a n d S ur vi v al F oll o w- u p
After c o m pleti n g t he F/ U visit, a s u bject will be f oll o we d via a p h o ne call or site visit t o c o nfir m 
ne w ca ncer treat me nts a n d s ur vi val stat us e ver y 3 m o nt hs ( ± 1 m o nt h) u ntil deat h or t he data c ut-


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 6
off date, w hic he ver c o mes first.  E ve n if t he s u bject m o ves t o a n ot her h os pital, t he I n vesti gat or 
will c o nfir m ne w a ntica ncer t hera p y a n d s ur vi val stat us, if p ossi ble. 
6. 7. 
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 uire d, b y t he re g ulat or y a ut h orit y(ies), a n d w hic h was gi ve n a p pr o val/fa v ora ble 
o pi ni o n b y t he I R B/I E C.
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 state d criteria will n ot be all o we d i n t his 
st u d y e xce 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 pers o n desi g nate d b y t he I n vesti gat or, s h o ul d d oc u me 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 was i neli gi ble or recei ve d t he i nc orrect d ose or i n vesti gati o nal treat me nt, a n d ha d at 
least o ne a d mi nistrati o n of i n vesti gati o nal pr o d uct, data s h o ul d be c ollecte d f or safet y p ur p oses.
T he I n vesti gat or s h o ul d n otif y t he I R B/I E C 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.
6. 8. 
P h ar m ac o ki netic ( P K), P h ar m ac o d y n a mic ( P D y), E x pl or at or y Bi o m ar ker a n d 
H u m a n A nti- h u m a n A nti b o dies
6. 8. 1. 
Ser u m S a m pli n g
Bl o o d sa m ples f or P K, E x pl orat or y Bi o mar ker (e g, H E R 2 E C D, c T nI testi n g b y ce ntral la b, 
i m m u ne m o nit ori n g a n d cf D N A) a n d A D A will be c ollecte d i nt o bl o o d sa m pli n g t u bes s u p plie d 
b y t he S p o ns or.  T he c ollecte d bl o o d will be ce ntrif u ge d t o se parate t he ser u m.  T he ser u m 
sa m ples will be s hi p pe d t o a ce ntral la b orat or y.
T he detail i nstr ucti o ns f or t he ha n dli n g of bl o o d sa m ples a n d s hi p pi n g of ser u m sa m ples are 
i ncl u de d i n a se parate d oc u me nt (e g, la b orat or y ma n ual). 
6. 8. 2. 
T u m or S a m pli n g
6. 8. 2. 1. 
T u m or S a m ples ( F or all s u bjects)
Te n sli des of t u m or tiss ue secti o ns ( 4 μ m t o 5 μ m t hic k) w hic h are o btai ne d bef ore t he first st u d y 
dr u g a d mi nistrati o n f or Bi o mar ker (e g, H E R 2 assess me nt b y I H C, FI S H, a n d H E R mar k) will be 
s u b mitte d t o a ce ntral la b orat or y f or e x pl orat or y assess me nt of t he bi o mar ker.  
Arc hi ve d t u m or sa m ples i ncl u di n g tiss ue sa m ples fr o m s ur ger y, e n d osc o p y or nee dle bi o ps y 
alrea d y c ollecte d a n d f or mali n-fi xe d paraffi n-e m be d de d will be use d.  If t he b ot h of s ur ger y a n d 
bi o ps y sa m ples are a vaila ble f or o ne patie nt, it is rec o m me n de d t o s u b mit s ur ger y sa m ples t o t he 
ce ntral la b orat or y.  
If t he size of arc hi ve d tiss ue sa m ple is t o o s mall, t u m or tiss ue ne wl y c ollecte d b y nee dle bi o ps y 
or e n d osc o p y s h o ul d be s u b mitte d.  


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 7
Paraffi n-e m be d de d tiss ue bl oc ks of f or mali n-fi xe d tiss ue s peci me ns will be pre pare d b y t he 
sta n dar d pr oce d ure at t he st u d y ce nter a n d t he u nstai ne d sli des wit h tiss ue secti o ns ( 4 μ m t o 5 μ m 
t hic k) will be s u b mitte d t o t he c o urier assi g ne d b y t he S p o ns or.
T he detail i nstr ucti o ns f or t he ha n dli n g of t u m or sa m ples a n d s hi p pi n g of t u m or sa m ples are 
i ncl u de d i n a se parate d oc u me nt (e g, la b orat or y ma n ual).  
6. 8. 2. 2. 
T u m or S a m ples f or E x pl or at or y Bi o m ar ker ( A d diti o n al f or P art 2 d o nl y)
Fres h bi o ps y sa m ples w hic h are o btai ne d d uri n g t he st u d y will be e xa mi ne d f or e x pl orat or y 
bi o mar kers (e g, H E R 2 m utati o ns a n d e x pressi o n, i m m u n o pr ofili n g).  Re mai ni n g sa m ples will be 
retai ne d f or u p t o 1 5 years or u ntil it is e x ha uste d.
T he detail i nstr ucti o ns f or t he ha n dli n g of t u m or sa m ples a n d s hi p pi n g are i ncl u de d i n a se parate 
d oc u me nt (e g, la b orat or y ma n ual).  
6. 8. 3. 
P h ar m ac o ki netic ( P K) 
Bl o o d sa m ples of a p pr o xi matel y 7 m L f or P Ks a nal yses will be c ollecte d at t he ti me p oi nts 
s pecifie d i n Ta ble 6. 1 .
T he act ual ti me of st u d y dr u g a d mi nistrati o n a n d t he e xact ti me of bl o o d sa m pli n g m ust be 
rec or de d i n s o urce d oc u me nt a n d t he e C R F. 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 8
T a ble 6. 1: 
P h ar m ac o ki netic S a m pli n g Ti me P oi nts ( P art 1 a n d P art 2)
C ycle
D a y
S a m pli n g Ti me P oi nt ( Acce pt a ble R a n ge)
Da y 1
BI ( – 8 h o urs) 
E OI: Wit hi n 1 5 mi n utes after E OI
2 h o urs after t he start of a d mi nistrati o n ( ± 1 5 mi n utes)
4 h o urs after t he start of a d mi nistrati o n ( ± 1 5 mi n utes)
7 h o urs after t he start of a d mi nistrati o n ( ± 1 5 mi n utes)
Da y 2
2 4 h o urs after t he start of a d mi nistrati o n ( ± 2 h o urs)
Da y 4
7 2 h o urs after t he start of a d mi nistrati o n ( ± 2 h o urs f or 
Par 1, ± 1 da y f or Part 2)
Da y 8
7 da ys after t he start of a d mi nistrati o n ( ± 1 da y)
Da y 1 5
1 4 da ys after t he start of a d mi nistrati o n ( ± 1 da y)
C ycle 1
Da y 2 2
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is dela ye d 
f or 3 da ys or m ore, i ncl u di n g if t he s u bject ca n n ot 
c o nti n ue o nt o t he ne xt c ycle, c ollect bl o o d sa m ple 2 1 
da ys after t he start of a d mi nistrati o n ( ± 2 da ys)
Da y 1
BI ( – 8 h o urs)
If bl o o d sa m ple is c ollecte d o n Da y 2 2 of C ycle 1, t he 
bl o o d sa m ple will be c ollecte d at BI o n Da y 1 of C ycle 
2 if p ossi ble.
E OI: Wit hi n 1 5 mi n utes after E OI
C ycle 2
Da y 2 2
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is dela ye d 
f or 3 da ys or m ore, i ncl u di n g if t he s u bject ca n n ot 
c o nti n ue o nt o t he ne xt c ycle, c ollect bl o o d sa m ple o n 
2 1 da ys after t he start of a d mi nistrati o n ( ± 2 da ys)
Da y 1
BI ( – 8 h o urs) 
If bl o o d sa m ple is c ollecte d o n Da y 2 2 of C ycle 2, t he 
bl o o d sa m ple will be c ollecte d at BI o n Da y 1 of C ycle 
3 if p ossi ble.
E OI:
P art 1 ( D ose esc al ati o n)
 Wit hi n 1 5 mi n utes after E OI
 4 h o urs after t he start of a d mi nistrati o n ( ± 1 5 mi n utes)
P art 2 ( D ose e x p a nsi o n)
 Wit hi n 1 5 mi n utes after E OI
Da y 8
7 da ys after t he start of a d mi nistrati o n ( ± 2 da ys)
Da y 1 5
1 4 da ys after t he start of a d mi nistrati o n ( ± 2 da ys)
C ycle 3
Da y 2 2
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is dela ye d 
f or 3 da ys or m ore, i ncl u di n g if t he s u bject ca n n ot 
c o nti n ue o nt o t he ne xt c ycle, c ollect bl o o d sa m ple o n 
2 1 da ys after t he start of a d mi nistrati o n ( ± 2 da ys)


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 7 9
T a ble 6. 1: 
P h ar m ac o ki netic S a m pli n g Ti me P oi nts ( P art 1 a n d P art 2) ( C o nti n ue d)
C ycle
D a y
S a m pli n g Ti me P oi nt ( Acce pt a ble R a n ge)
C ycle 4, 6, 8
Da y 1
BI ( – 8 h o urs) 
If bl o o d sa m ple is c ollecte d o n Da y 2 2 of C ycle 3, t he 
bl o o d sa m ple will be c ollecte d at BI o n Da y 1 of C ycle 
4 if p ossi ble.
E OI: Wit hi n 1 5 mi n utes after E OI
6. 8. 4. 
P h ar m ac o d y n a mic ( P D y)
N ot a p plica ble.
6. 8. 5. 
E x pl or at or y Bi o m ar ker
Base d o n t he e val uati o n of pre-treat me nt t u m or sa m ple, t he le vels of H E R 2 will be assesse d b y 
I H C a n d FI S H.  T he e x pl orat or y bi o mar kers (e g, H E R 2 E C D, H E R 2 b y H E R mar k, c T nI testi n g 
b y ce ntral la b) will be meas ure d.  
Bl o o d sa m ples of a p pr o xi matel y 6 m L f or H E R 2 E C Ds a nal yses will be c ollecte d at t he ti me 
p oi nts s pecifie d i n Ta ble 6. 2 .  T his is a p plica ble u ntil pr ot oc ol versi o n 1 1. 0.  N o f urt her bl o o d 
sa m pli n g f or H E R 2 E C D is necessar y o nce pr ot oc ol versi o n 1 2. 0 is a p plie d f or a s u bject.
T a ble 6. 2:  
H E R 2 E C D S a m pli n g Ti me P oi nts
C ycle
D a y
S a m pli n g Ti me P oi nt ( Acce pt a ble R a n ge)
Scree ni n g
-
Wit hi n 7 da ys bef ore re gistrati o n
After C ycle 3 at e ver y 2 c ycles 
(e g, C ycle 3, 5, 7, 9, 1 1...)
Da y 1
BI ( – 8 h o urs)
E O T
-
T he date I n vesti gat or deci des t he disc o nti n uati o n 
of t he st u d y treat me nt ( + 7 da ys).  
I n a d diti o n t o tr o p o ni n testi n g b y st u d y site, bl o o d sa m ples of a p pr o xi matel y 6 m L f or c T nIs 
a nal yses b y ce ntral la b will be c ollecte d at t he ti me p oi nts s pecifie d i n Ta ble 6. 3 .
T a ble 6. 3: 
c T nI S a m pli n g Ti me P oi nts
C ycle
D a y
S a m pli n g Ti me P oi nt ( Acce pt a ble R a n ge)
Scree ni n g
-
Wit hi n 7 da ys bef ore re gistrati o n
E ver y C ycle
Da y 1
E OI
E O T
-
T he date I n vesti gat or deci des t he disc o nti n uati o n 
of t he st u d y treat me nt ( + 7 da ys).
F/ U
-
2 8 da ys ( – 7 da ys) after t he last a d mi nistrati o n of 
D S- 8 2 0 1a.
Bl o o d sa m ples of a p pr o xi matel y 2 0 m L f or i m m u ne m o nit ori n g a nal ysis will be c ollecte d fr o m 
Ja pa nese s u bjects i n Part 2 d at t he ti me p oi nts s pecifie d i n Ta ble 6. 4 .


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 0
T a ble 6. 4: 
I m m u ne M o nit ori n g S a m pli n g Ti me P oi nts ( J a p a nese s u bjects i n P art 2 d 
o nl y)
C ycle
D a y
S a m pli n g Ti me P oi nt ( Acce pt a ble R a n ge)
Scree ni n g – BI at C ycle 1 Da y 1
-
-
Da y 2
-
Da y 4
-
Da y 8
-
C ycle 1 
Da y 2 2
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is 
dela ye d f or 3 da ys or m ore, i ncl u di n g if t he s u bject 
ca n n ot c o nti n ue o nt o t he ne xt c ycle, c ollect bl o o d 
sa m ple 2 1 da ys after t he start of a d mi nistrati o n ( ± 
2 da ys)
Da y 1
BI.  T his is n ot necessar y if bl o o d sa m ples are 
o btai ne d o n C ycle 1, Da y 2 2.
C ycle 2
Da y 2 2
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is 
dela ye d f or 3 da ys or m ore, i ncl u di n g if t he s u bject 
ca n n ot c o nti n ue o nt o t he ne xt c ycle, c ollect bl o o d 
sa m ple 2 1 da ys after t he start of a d mi nistrati o n ( ± 
2 da ys)
C ycle 3
Da y 1
BI.  T his is n ot necessar y if bl o o d sa m ples are 
o btai ne d o n C ycle 2, Da y 2 2.
C ycle 4 a n d s u bse q ue nt c ycles 
Da y 1
BI.  O ne ti me d uri n g treat me nt peri o d.
E O T
-
T he date I n vesti gat or deci des t he disc o nti n uati o n 
of t he st u d y treat me nt ( + 7 da ys).  
Bl o o d sa m ples of a p pr o xi matel y 2 0 m L f or cf D N A a nal ysis will be c ollecte d at t he ti me p oi nts 
s pecifie d i n Ta ble 6. 5 .
T a ble 6. 5:  
Cell Free D N A S a m pli n g Ti me P oi nts ( O pti o n al)
C ycle
D a y
S a m pli n g Ti me P oi nt ( Acce pt a ble R a n ge)
Scree ni n g – BI at C ycle 1 Da y 1
-
-
E O T
-
T he date I n vesti gat or deci des t he disc o nti n uati o n 
of t he st u d y treat me nt ( + 7 da ys).  
I nstr ucti o ns f or t he ha n dli n g a n d s hi p pi n g of sa m ples are i ncl u de d i n a se parate d oc u me nt (e g, 
la b orat or y ma n ual).
6. 8. 6.  
A nti- dr u g A nti b o d y
Bl o o d sa m ples f or A D A of a p pr o xi matel y 4 m L a nal yses will be c ollecte d at t he ti me p oi nts 
s pecifie d i n Ta ble 6. 6 .  Ser u m c o nce ntrati o ns of D S- 8 2 0 1a 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 ose of a nti- dr u g a nti b o d y assess me nt. 
I nstr ucti o ns f or t he ha n dli n g a n d s hi p pi n g of ser u m sa m ples are i ncl u de d i n a se parate d oc u me nt 
(e g, la b orat or y ma n ual).


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 1
T a ble 6. 6:  
A D A S a m pli n g Ti me P oi nts
C ycle
D a y
S a m pli n g Ti me P oi nt ( Acce pt a ble R a n ge)
Da y 1
BI ( – 8 h o urs) 
C ycle 1
Da y 8
± 1 da y
C ycle 2
Da y 1
BI ( – 8 h o urs)
After C ycle 4 at e ver y 2 c ycles 
(e g, C ycle 4, 6, 8, 1 0, 1 2...)
Da y 1
BI ( – 8 h o urs)
E O T
-
T he date I n vesti gat or deci des t he disc o nti n uati o n 
of t he st u d y treat me nt ( + 7 da ys).  
F/ U *
-
2 8 da ys ( − 7 da ys) after t he last st u d y dr u g 
a d mi nistrati o n or u ntil starti n g ne w a ntica ncer 
treat me nt, w hic he ver c o mes first.
* F or s u bjects wit h p ositi ve A D A at F/ U visit, 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, or if t he A D A bec o mes 
ne gati ve, or if 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), or if 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 t he 
st u d y, w hic he ver occ urs first.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 8 2
7. 
E F FI C A C Y A S S E S S M E N T S
Efficac y assess me nts will be base d o n t u m or assess me nts t o be perf or me d at scree ni n g a n d e ver y 
6 wee ks i n t he first 2 4 wee ks after Da y 1 of C ycle 1 a n d t hereafter e ver y 1 2 wee ks w hile t he 
s u bject re mai ns o n st u d y dr u g.  T he cli nical acti vit y of D S- 8 2 0 1a will be assesse d b y e val uati n g 
t u m or res p o nse.  T u m or res p o nse will be e val uate d usi n g R E CI S T versi o n 1. 1 ( Secti o n 1 7. 2 ).  
C T or M RI (s piral C T or M RI wit h  5 m m c uts) of brai n, 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 assess me nt is necessar y f or t he 
lesi o ns at scree ni n g peri o d.  E ver y eff ort s h o ul d be ma de t o use t he sa me assess me nt m o dalit y 
f or all assess me nts f or eac h s u bject.  H o we ver, if t here is n o brai n metastasis at t he ti me of 
scree ni n g, C T or M RI s h o ul d o nl y be d o ne w he n s y m pt o ms ass ociate d wit h brai n metastasis 
occ ur d uri n g st u d y peri o d.  If n o cli nical s y m pt o ms are o bser ve d, brai n C T or M RI is n ot 
ma n dat or y d uri n g st u d y peri o d.
T he f oll o wi n g efficac y varia bles will be assesse d.  T he Efficac y Varia ble(s) will be als o 
e val uate d at 1 8 wee ks after Da y 1 of C ycle 1.

O R R (t he s u m of C R rate a n d P R rate)

D C R (t he s u m of C R rate, P R rate, a n d S D rate)

Res p o nse d urati o n

D urati o n of S D

T T R

P F S

O S

Perce nt c ha n ge i n tar get lesi o n 

Ti me o n t hera p y of t he m ost rece nt pri or re gi me n t he s u bject recei ve d a n d t hat of D S-
8 2 0 1a. 
7. 1. 
Pri m ar y Effic ac y V ari a ble(s)
N ot a p plica ble.
7. 2. 
Sec o n d ar y Effic ac y V ari a ble(s)
N ot a p plica ble.
7. 3. 
E x pl or at or y Effic ac y V ari a ble(s)
N ot a p plica ble.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 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. 1. 
P h ar m ac o ki netic ( P K) V ari a ble(s)
T he ser u m P K para meters liste d i n Ta ble 8. 1  of D S- 8 2 0 1a, 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 f or eac h s u bject will be esti mate d usi n g sta n dar d n o nc o m part me ntal met h o ds.  T he 
ot her P K para meter ( A U Ci nf, Kel, T 1/ 2, C L, Vz a n d, Vss) will be calc ulate d if data per mits.  T he 
details of P K a nal ysis are t o be s pecifie d i n t he P har mac o ki netic A nal ysis Pla n.
T a ble 8. 1: 
P h ar m ac o ki netic P ar a meters
P K p ar a meters
D S- 8 2 0 1a, 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 U Clast, A U Cta u, C ma x, T ma x, Ctr o u g h
8. 2. 
P h ar m ac o d y n a mic ( P D y) V ari a ble(s)
N ot a p plica ble.
8. 3. 
Bi o m ar ker a n d E x pl or at or y V ari a ble(s)
T u m or sa m ples will be e xa mi ne d f or H E R 2 stat us (e g m utati o ns a n d e x pressi o n).  E x pl orat or y 
bi o mar ker researc h ma y be c o n d ucte d o n a n y 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 rele va nt t o t he effects of D S- 8 2 0 1a, ca ncer a n d/ or t he resista nce t o 
t he treat me nt.  T his ma y i ncl u de t he de vel o p me nt of wa ys t o detect, m o nit or or treat ca ncer. 
T hese a d diti o nal i n vesti gati o ns w o ul d be de pe n de nt u p o n cli nical o utc o me, rea ge nt a n d sa m ple 
a vaila bilit y.


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9. 
S A F E T Y A S S E S S M E N T S
9. 1.  
A d verse E ve nts
All cli nical A Es occ urri n g after t he s u bject si g ns t he I C F a n d u p t o F/ U visit after t he last d ose of 
st u d y me dicati o n, w het her o bser ve d b y t he I n vesti gat or or re p orte d b y t he s u bject, will be 
rec or de d o n t he A E case re p ort f or m ( C R F) pa ge.  Me dical c o n diti o ns (i ncl u di n g la b orat or y 
val ues/ vital si g ns t hat are o ut of ra n ge) t hat were dia g n ose 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.  All S A Es are t o be re p orte d acc or di n g t o t he 
pr oce d ures i n Secti o n 9. 5  S A E Re p orti n g- Pr oce d ure f or I n vesti gat ors.  Al wa ys re p ort 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, re p ort t he pri mar y si g n or s y m pt o m 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 vaila 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, re p ort 
t he m as i n di vi d ual e ntries of A E or S A E.  F or e ve nts t hat are seri o us d ue t o 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 he 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 ure or treat me nt re q uiri n g 
h os pitalizati o n f or pre-e xisti n g c o n diti o ns w hic h d o n ot w orse n i n se verit y s h o ul d n ot be 
re p orte d as S A Es (see Secti o n 9. 4  f or Defi niti o ns).  F or deat hs, t he u n derl yi n g or i m me diate 
ca use of deat h s h o ul d al wa ys be re p orte d as a n S A E.  Pr o gressi ve disease is a st u d y e n d p oi nt a n d 
c o nse q ue ntl y, 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 
pr o gressi ve disease wit h n o ot her i m me diate ca uses, “ Pr o gressi ve disease” s h o ul d be re p orte d as 
a n S A E.  I n a d diti o n, a n y seri o us, u nt o war d e ve nt t hat ma y occ ur s u bse q ue nt t o t he re p orti n g 
peri o d t hat t he I n vesti gat or assesses as relate 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 
ma na ge d as a n S A E.
At eac h visit, t he I n vesti gat or will deter mi ne w het her a n y A Es ha ve occ urre d b y e val uati n g t he 
s u bject.  A Es ma y be directl y o bser ve d, re p orte 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 neral wa y, wit h o ut as ki n g 
a b o ut t he occ urre nce of a n y s pecific 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 verit 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 ust be clearl y d oc u me nte d i n t he site’s s o urce d oc u me ntati o n 
wit h t he I n vesti gat or’s si g nat ure.  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.  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 m ust be rec or de d as a n A E o n t he C R F, a n d if seri o us, re p ort as a n S A E f oll o wi n g 
t he pr oce d ures i n Secti o n 9. 5.
I n vesti gat or s h o ul d f oll o w s u bjects wit h A Es u ntil t he e ve nt has res ol ve d or t he c o n diti o n has 
sta bilize d as p ossi ble.  I n case of u nres ol ve d A Es i ncl u di n g si g nifica nt a b n or mal la b orat or y 
val ues at t he e n d of st u d y assess me nt, t hese e ve nts will be f oll o we d u p u ntil res ol uti o n or u ntil 
t he y bec o me cli nicall y n ot rele va nt.
9. 2. 
S afet y E n d p oi nts
Safet y e n d p oi nts will i ncl u de D L Ts, S A Es, T E A Es, p h ysical e xa mi nati o n fi n di n gs (i ncl u di n g 
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 para meters, E C G para meters, 
E C H O/ M U G A fi n di n gs, a n d o p ht hal m ol o gic assess me nts.  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 4. 0.  D ose escalati o n will be deter mi ne d b y t he i nci de nce of D L Ts.


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9. 3. 
E ve nts of S peci al I nterest
Rele va nt I nf or mati o n re gar di n g t he A d verse E ve nts of S pecial I nterest ( A E SIs) s pecifie d bel o w 
f or t he D S- 8 2 0 1a cli nical pr o gra m re gar dless of seri o us ness will be c ollecte d t hr o u g h t he 
tar gete d q uesti o n naires, b uilt wit hi n t he a p plica ble e C R Fs i n t he cli nical st u d y data base.
Please refer t o t he I B f or a d diti o nal i nf or mati o n.
9. 3. 1.  
C ar di ot o xicit y ( C ar di ac-rel ate d e ve nts i ncl u di n g Q T Pr ol o n g ati o n a n d L V E F 
Decre ase)
Cli nic al S u m m ary: 
Car di ot o xicit y i n ass ociati o n wit h D S- 8 2 0 1a is c o nsi dere d t o be a n i m p orta nt p ote ntial ris k base d 
o n t he a vaila ble pre-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.  Refer t o t he c urre nt I B f or a s u m mar y of preli mi nar y cli nical trial data.
M a n a ge me nt G ui d a nce:
L V E F 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 ysicia n f or m o nit ori n g car diac f u ncti o n.  Tr o p o ni n will be 
meas ure d at scree ni n g a n d after eac h i nf usi o n a n d as nee de d base d o n s u bject re p orte d car diac 
s y m pt o ms.  Tri plicate E C Gs will be perf or me d a n d sta n dar d E C G para meters 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 ysicia n f or t he prese 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. 3. 2. 
I nterstiti al L u n g Dise ase/ P ne u m o nitis
Cli nic al S u m m ary: 
As of 1 3 Dec 2 0 1 7, t hree cli nical st u dies ha ve s u bjects d ose d wit h D S- 8 2 0 1a: D S 8 2 0 1- A-J 1 0 1, 
D S 8 2 0 1- A- U 2 0 1, a n d D S 8 2 0 1- A-J 2 0 2.  T here ha ve bee n n o e ve nts of I L D/ p ne u m o nitis re p orte d 
i n t he D S 8 2 0 1- A- U 2 0 1 a n d D S 8 2 0 1- A-J 2 0 2 st u dies.  D ue t o t he li mite d n u m ber of s u bjects 
d ose d a n d s h ort treat me nt d urati o n i n t hese t w o st u dies, I L D/ p ne u m o nitis data has bee n 
s u m marize d fr o m t he D S 8 2 0 1- A-J 1 0 1 st u d y. 
I L D/ p ne u m o nitis is c o nsi dere d 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 vaila ble safet y data fr o m t he D S 8 2 0 1- A-J 1 0 1 cli nical st u d y as well as 
t he res ults of p ote ntial I L D/ p ne u m o nitis cases re vie we d b y t he i n de pe n de nt I L D A dj u dicati o n 
C o m mittee ( A C), a vaila ble data 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 
safet 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 s u m mar y of 
preli mi nar y cli nical st u d y data.
M a n a ge me nt G ui d a nce:
I L D/ 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 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.  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 desi g nate d “ All ot her n o n- he mat ol o gical t o xicities, e xce pt al o pecia” d ose 
m o dificati o n secti o n of t he st u d y pr ot oc ol. 


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If t he A E is s us 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, 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), arterial bl o o d gases 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 a n d e x pl orat or y bi o mar ker 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.  As s o o n as I L D/ p ne u m o nitis is s us pecte d, 
c ortic oster oi d treat me nt s h o ul d be starte d pr o m ptl y as per cli nical treat me nt g ui deli nes ( K u b o K, 
et al 2 0 1 3 f or g ui da nce).  1 8
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 me nt g ui da nce o utli ne d i n 
Secti o n 3. 1. 9. 3  of t he st u d y pr ot oc ol.
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.
9. 3. 2. 1. 
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 dj u dicati o n C o m mittee f or t he D S- 8 2 0 1a 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 ne u m o nitis.  T o e ns ure a de q uate a n d rele va nt i n de pe n de nt 
e val uati o n, s yste 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 hese a d diti o nal data c ollecti o n will c o ver a m ore 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 O P D 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 ve nt. T his data c ollecti o n will be tri g gere d f or a d verse 
e ve nts re p orte d usi n g Me d D R A preferre d ter ms ( P T) fr o m t he c urre nt I L D Sta n dar d Me d D R A 
Q uer y ( S M Q).
9. 3. 3. 
I nf usi o n-rel ate d re acti o ns
Cli nic al S u m m ary: 
As wit h a n y t hera pe utic a nti b o dies, t here is a p ossi bilit y of i nf usi o n-relate d reacti o ns a n d 
i m m u ne res p o nses ca usi n g aller gic or a na p h ylactic reacti o ns f oll o wi n g t he a d mi nistrati o n of D S-
8 2 0 1a.  I m m u ne res p o nses ca usi n g aller gic or a na p h ylactic reacti o ns are c o nsi dere d t o be a n 
a d verse e ve nt of s pecial i nterest f or t he D S- 8 2 0 1a cli nical pr o gra m.  Refer t o t he c urre nt I B f or a 
s u m mar y of preli mi nar y cli nical trial data.
M a n a ge me nt G ui d a nce: 
S u bjects recei vi n g D S- 8 2 0 1a s h o ul d be m o nit ore d b y mea ns of vital si g ns, p h ysical e xa mi nati o n, 
a n d si g ns a n d s y m pt o ms of i nf usi o n relate d reacti o n: fe ver, c hills, na usea, v o miti n g, hea dac he, 
c o u g h, dizzi ness, ras h, a n d/ or l o wer bac k pai n us uall y of mil d t o m o derate se verit y a n d ma y lea d 
t o s h ort ness of breat h a n d se vere l o weri n g of bl o o d press ure.
9. 4.  
Defi niti o ns
9. 4. 1.  
A d verse E ve nt ( A E)
A n y u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n s u bject a d mi nistere d a 
p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha ve t o ha ve a ca usal 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 la b orat or y fi n di n g, f or e xa m ple), s y m pt o m, or disease te m p orall y ass ociate 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 nal pr o d uct (I C H E 2 A 


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G ui deli ne.  Cli nical Safet y Data Ma na 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, Oct 1 9 9 4).
It is t he res p o nsi bilit y of I n vesti gat ors, base d o n t heir k n o wle d ge a n d e x perie nce, t o deter mi ne, 
t h ose circ u msta nces or a b n or mal la b fi n di n gs w hic h s h o ul d be c o nsi dere d A Es.
9. 4. 2. 
Seri o us A d verse E ve nt ( S A E)
A n y u nt o war d me dical occ urre nce 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 nca pacit 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 he ter m “life-t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d deat h if it were m ore se vere (I C H E 2 A G ui deli ne.  Cli nical 
Safet y Data Ma na 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, Oct 1 9 9 4).
Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her e x pe dite d re p orti n g is 
a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y 
life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize t he s u bject or ma y re q uire 
i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti o n a b o ve.  E xa m ples 
i ncl u de aller gic 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 
de pe n de nc y or dr u g a b use.
N ote:

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 re q uiri n g 
h os pitalizati o ns f or pre-e xisti n g c o n diti o ns w hic h d o n ot w orse n i n se verit y are n ot 
S A Es.
9. 4. 3.  
A E Se verit y
All A Es will be gra de d ( 1 t o 5; see bel o w) acc or di n g t o t he N CI- C T C A E versi o n 4. 0:

Gra de 1 Mil d A E

Gra de 2 M o derate A E

Gra de 3 Se vere A E

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

Gra de 5 Deat h relate d t o A E


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Se verit y vs. Seri o us ness: Se verit y is use d t o descri be t he i nte nsit y of a s pecific e ve nt w hile t he 
e ve nt itself, h o we ver, ma y be of relati vel y mi n or me dical si g nifica nce (s uc h as se vere hea dac he).  
T his is n ot t he sa me as "seri o us ness," w hic h is base d o n patie nt/e ve nt o utc o me at t he ti me of t he 
e ve nt.  F or e xa 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 nter 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 criteria 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 base d o n t he N CI- C T C A E gra des ma y or ma y n ot be assesse d as seri o us 
base d o n t he seri o us ness criteria.
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 relati o ns hi p bet wee n a n A E a n d t he st u d y pr o d uct o n t he 
basis or 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 s h o ul d 
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 ne w i nf or mati o n bec o mes 
a vaila ble.

1 = Relate d:

T he A E f oll o ws a reas o na ble te m p oral se q ue 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 na bl y e x plai ne d b y t he s u bject’s cli nical 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).

T he A E f oll o ws a reas o na ble te m p oral se q ue 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 har mac ol o g y.

2 = N ot Relate d:

T he A E d oes n ot f oll o w a reas o na ble se q ue nce fr o m st u d y pr o d uct a d mi nistrati o n, 
or ca n be reas o na bl y e x plai ne d b y t he s u bject’s cli nical 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).
9. 4. 5.  
Acti o n T a ke n Re g ar di n g t he St u d y Pr o d uct

1 = 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.

2 = Dr u g Wit h dra w n: T he st u d y pr o d uct was per ma ne ntl y st o p pe d.

3 = D ose Re d uce d: T he d osa ge of st u d y pr o d uct was re d uce d.

4 = Dr u g I nterr u pte d: T he st u d y pr o d uct was te m p oraril y st o p pe d.

5 = D ose I ncrease d: T he d osa ge of st u d y pr o d uct was i ncrease d.
9. 4. 6.  
A d verse E ve nt O utc o me

1 = 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.

2 = Rec o veri n g/ Res ol vi n g

T he A E i m pr o ve d b ut has n ot f ull y res ol ve d.


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
3 = 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 ble.

I ncl u de se q uelae/resi d ual effects.

4 = 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.

5 = Fatal

Fatal s h o ul d be use d w he n deat h is a direct o utc o me of t he a d verse e ve nt.

6 = U n k n o w n
9. 4. 7.  
Ot her Acti o n T a ke n f or E ve nt

1 = N o ne.

N o treat me nt was re q uire d.

2 = Me dicati o n re q uire d.

Prescri pti o n a n d/ or O T C me dicati o n was re q uire d t o treat t he A E.

3 = H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n re q uire d.

H os pitalizati o n was re q uire d or pr ol o n ge d d ue t o t he A E, w het her or n ot 
me dicati o n was re q uire d.

4 = Ot her.
9. 5. 
Seri o us A d verse E ve nt a n d A d verse E ve nts of S peci al I nterest Re p orti n g –
Pr oce d ure F or I n vesti g at ors
All A Es, S A Es a n d A E SIs will be re p orte d i n t he C R F.
T he f oll o wi n g t y pes 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)

He patic e ve nts ( b ot h seri o us a n d n o n-seri o us) w hic h meet t he p ote ntial H y’s La w 
criteria defi ne d as a n ele vate d ( A L T or A S T) ≥ 3 x U L N a n d a n ele vate d T B L ≥ 2 x 
U L N t hat ma y occ ur at differe nt ti me p oi nts d uri n g t he st u d y c o n d uct. 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 rele va nt a d diti o nal i nf or mati o n f or 
t hese p ote ntial cases.
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 ness, 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 he 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 dates of e ve nt o nset, 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 dical hist or y, c o nc o mita nt me dicati o ns, a n d la b orat or y data t hat are rele va nt t o t he 
e ve nt s h o ul d als o be s u m marize d i n t he narrati ve.  F or fatal e ve nts, t he narrati ve s h o ul d state 
w het her a n a ut o ps y was or will be perf or me d, a n d i ncl u de t he res ults if a vaila ble.  S o urce 


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d oc u me nts (i ncl u di n g me dical re p orts) will be retai ne d at t he st u d y ce nter 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 oses.
Ur ge nt safet y q ueries m ust be f oll o we d u p a n d a d dresse d pr o m ptl y.  F oll 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 ueries s h o ul d be c o m bi ne d f or re p orti n g t o 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 o n a Seri o us A d verse E ve nt Re p ort ( S A V E R) 
f or m ( S u p ple me nt 1).  All c o m plete d S A V E R f or ms m ust be si g ne d b y t he I n vesti gat or, a n d e-
maile d or fa xe d t o t he S p o ns or or t he C R O usi n g t he pr o vi de d fa x tra ns mittal f or m 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 mes a vaila ble, please e nter 
S A Es i nt o e C R F.
Please call t he l ocal S A E H otli ne (see St u d y Ma n ual) or y o ur st u d y m o nit or f or a n y q uesti 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, I R B/ E C, a n d C o m pete nt 
A ut h orities
Daiic hi Sa n k y o a n d/ or C R O will i nf or m I n vesti gat ors, I R Bs (I nstit uti o nal Re vie w B oar d)/ E Cs 
( Et hics C o m mittees), 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 Seri o us A d verse 
E ve nt Reacti o ns ( S U S A Rs) occ urri n g i n ot her st u d y ce nters or ot her Daiic hi Sa n k y o st u dies of 
t he i n vesti gati o nal pr o d uct, as a p pr o priate per l ocal re p orti n g re q uire me nts.
I n t he U S, u p o n recei pt of t he 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 
i n vesti gati o nal pr o d uct, 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 Ja pa n, it is t he S p o ns or’s res p o nsi bilit y t o re p ort all t he fatal/life-t hreate ni n g a d verse dr u g 
reacti o ns t o t he re g ulat or y a ut h orities a n d I R Bs/ E Cs re gar dless of e x pecte d ness.
9. 7. 
E x p os ure I n 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 or fe male part ner of a male s u bject w h o bec o mes 
pre 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 i n vesti gati o nal pr o d uct.  
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 ncies 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 blic 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 or fe male part ner of a male s u bject usi n g t he E x p os ure I n Uter o ( EI U) Re p orti n g 
f or m ( S u p ple me nt 2).  Re p orti n g after f oll o w- u p visit or earl y ter mi nati o n is d o ne v ol u ntaril y b y 
t he i n vesti gat or.  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 
lear ni n g of a pre g na 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.  If t he o utc o me of t he pre g na nc 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 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 vesti gat or s h o ul d f oll o w 
t he pr oce d ures f or re p orti n g S A Es 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:


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L a b or at or y tests
P ar a meters
He mat ol o g y
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, 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)
C he mistr y
T otal pr otei n, al b u mi n, A L P, A L T, A S T, t otal bilir u bi n,  
B U N, Ca, Cl, ser u m creati ni ne, L D H, K, Na, M g) 
I n a d diti o n, t he f oll o wi n g para meters will be a nal yze d at t he visits i n dicate d i n a p pe n di x Secti o n 
1 7. 6 .

Pre g na nc y test (ser u m or uri ne) f or all fe male s u bjects of c hil d beari n g p ote ntial m ust 
be perf or me d d uri n g t he Scree ni n g Peri o d.  A p ositi ve uri ne pre g na nc 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.

HI V a nti b o d y test m ust be perf or me d d uri n g t he Scree ni n g Peri o d f or Ja pa nese 
s u bjects.  HI V a nti b o d y test is o pti o nal f or U S s u bjects u nless re q uire d b y l ocal 
re g ulati o ns or I R B. 
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 pa ge of t he e C R F.  If t he 
a b n or mal la b orat or y val ue c o nstit utes a n S A E, a S A V E R f or m s h o ul d be s u b mitte d a n d ot her 
rele 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 la b orat or y val 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 res 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
Vital si g n meas ure me nts will i ncl u de s yst olic a n d diast olic bl o o d press ure a n d p ulse rate a n d 
b o d y te m perat ure.  A d diti o nall y, S p O 2 will be meas ure d bef ore a d mi nistrati o n o n Da y 1 of eac h 
c ycle a n d E O T.
9. 1 0. 
Electr oc ar di o gr a ms
Sta n dar d s u pi ne 1 2-lea d E C Gs i n tri plicate will be perf or me d i n t he sc he d ule of e ve nts.  Sta n dar d 
E C G para meters 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 ysicia n f or t he prese nce of 
a b n or malities.
9. 1 1. 
P h ysic al Fi n di n gs
P h ysical e xa mi nati o n fi n di n gs i ncl u di n g E C O G P S will e val uate t he f oll o wi n g b o d y 
s yste ms/ or ga ns: ge neral a p peara nce; der mat ol o gical; hea d a n d e yes; ears, n ose, m o ut h, a n d 
t hr oat; p ul m o nar y; car di o vasc ular; 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 pecti vel y.


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9. 1 2.  
Ot her S afet y Assess me nts
Eit her E C H O or M U G A, a n d o p ht hal m ol o gic assess me nts will be perf or me d as descri be d i n t he 
sc he d ule of e ve nts.  L V E F will be meas ure d b y eit her E C H O or M U G A.  O p ht hal m ol o gic 
assess me nts will i ncl u de 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.  All 
E C H Os/ M U G As, a n d t he o p ht hal m ol o gic assess me nts m ust be e val uate d b y t he I n vesti gat or or 
dele gate d p h ysicia n.  A d diti o nal safet y assess me nts s h o ul d be c o n d ucte d as nee de d, at t he 
I n vesti gat or’s discreti o n.
P ul m o nar y Assess me nts
P ul m o nar y assess me nt will i ncl u de C T or M RI of t he c hest, a n d S p O 2 will be perf or me d as 
descri be d i n sc he d ule of e ve nts.  F or m ore details please refer t o Secti o n 6  of t he pr ot oc ol.  
A d diti o nal safet y assess me nts s h o ul d be c o n d ucte d as nee de d, at t he I n vesti gat or’s discreti o n.  


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1 0.  
O T H E R A S S E S S M E N T S
N ot a p plica ble.


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1 1. 
S T A TI S TI C A L M E T H O D S
1 1. 1.  
A n al ysis Sets
1 1. 1. 1. 
E nr olle d A n al ysis Set
T he e nr olle d a nal ysis set will i ncl u de all s u bjects w h o si g ne d a n I C F a n d were e nr olle d i n eit her 
t he D ose Escalati o n part or D ose E x pa nsi o n part of t he st u d y.
1 1. 1. 2. 
Effic ac y A n al ysis Set
T he efficac y a nal ysis set will i ncl u de all s u bjects e nr olle d i n t he D ose Escalati o n part or t he D ose 
E x pa nsi o n part w h o recei ve d at least o ne d ose of D S- 8 2 0 1a a n d w h o ha d pre- a n d p ost-treat me nt 
efficac y data.
1 1. 1. 3.  
D ose- Li miti n g T o xicit y E v al u a ble Set 
T he D L T-e val ua ble set will i ncl u de all s u bjects w h o recei ve d at least o ne d ose of D S- 8 2 0 1a , 
wit h t he e xce pti o n of t h ose s u bjects f or w h o m D L T e val uati o n c o ul d n ot be a de q uatel y 
c o n d ucte d.  
1 1. 1. 4. 
S afet y A n al ysis Set
T he safet y a nal ysis set will i ncl u de all s u bjects w h o recei ve d at least o ne d ose of D S- 8 2 0 1a.  
S u bjects will be s u m marize d acc or di n g t o treat me nt act uall y recei ve d.  
T hree gr o u ps of s u bjects will be i de ntifie d wit hi n t he safet y a nal ysis set: ( 1) s u bjects i n t he D ose 
Escalati o n part, ( 2) s u bjects i n t he D ose E x pa nsi o n part, a n d ( 3) all s u bjects i n t he st u d y.
1 1. 1. 5. 
P h ar m ac 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 i n t he e nr olle d a nal ysis set w h o recei ve d at least o ne 
d ose of D S- 8 2 0 1a a n d ha d meas ura ble ser u m c o nce ntrati o ns of D S- 8 2 0 1a.  
1 1. 1. 6. 
Bi o m ar ker A n al ysis Set
T he bi o mar ker a nal ysis set will i ncl u de all s u bjects i n t he e nr olle d a nal ysis set w h o recei ve d at 
least o ne d ose of D S- 8 2 0 1a a n d w h o ha d t he baseli ne assess me nt a n d w here a p plica ble, at least 
o ne p ost- baseli ne assess me nt f or bi o mar kers.
1 1. 2.  
Ge ner al St atistic al C o nsi der ati o ns
T he pri mar y a nal ysis is t o assess t he safet y a n d t olera bilit y of D S- 8 2 0 1a i n s u bjects wit h 
a d va nce d s oli d mali g na nt t u m ors a n d t o deter mi ne t he M T D/ R P 2 D or esta blis h t he safet y a n d 
t olera bilit y of t he ma xi m u m a d mi nistere d d ose of D S- 8 2 0 1a.
T he data c ut off f or t he pri mar y a nal ysis will occ ur after all s u bjects ha ve eit her disc o nti n ue d t he 
st u d y or t he last s u bject e nr olle d i n Part 2 of t he st u d y has c o m plete d at least 6 m o nt hs of st u d y 
dr u g treat me nt.  After t he pri mar y a nal ysis, t he mai n st u d y will be cl ose d a n d t he data will be 
f oll o we d u ntil c o m pleti o n.  
T he data a nal yses will als o be c o n d ucte d d uri n g Part 1.


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Descri pti ve statistics will be pr o vi de d f or selecte d de m o gra p hic, safet y, a n d P K data b y d ose 
le vel/c o h ort wit hi n eac h Part a n d ti me as a p pr o priate.  Descri pti ve statistics o n c o nti n u o us data 
will i ncl u de mea ns, me dia ns, sta n dar d de viati o ns, a n d ra n ges (as well as ge o metric mea ns a n d 
ge o metric c oefficie nt of variati o n f or C ma x a n d A U C P K para meters), w hile cate g orical data 
will be s u m marize d usi n g fre q ue nc y c o u nts a n d perce nta ges.  Gra p hical s u m maries of t he data 
ma y be prese nte d.
Assess me nts 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 varia ble ta ke n bef ore t he first d ose of st u d y dr u g will be use d as t he 
baseli ne val ue, u nless ot her wise s pecifie d.  I n ge neral, missi n g or dr o p o ut data will n ot be 
i m p ute d f or t he p ur p ose of data a nal ysis, u nless ot her wise s pecifie d.  
Safet y a nal yses will be perf or me d base d o n t he safet y a nal ysis set.  A nal ysis of P K para meters 
will be base d o n t he P K a nal ysis sets a n d bi o mar ker a nal yses will be base d o n t he bi o mar ker 
a nal ysis sets.  Efficac y e n d p oi nts will be a nal yze d base d o n t he efficac y a nal ysis set.  Data will 
be s u m marize d b y d ose le vel/c o h ort wit hi n eac h Part a n d o verall.  
A detaile d S A P descri bi n g t he met h o d ol o g y t o be use d i n t he fi nal a nal ysis will be pre pare d a n d 
fi nalize d bef ore data base l oc k.  Statistical met h o ds descri be d wit hi n t his d oc u me nt ma y be 
c ha n ge d base d o n a d va nces i n researc h.
1 1. 3. 
St u d y P o p ul ati o n D at a
Dis p ositi o n a n d reas o ns f or e n di n g t he treat me nt a n d disc o nti n ui n g fr o m t he st u d y will be 
s u m marize d a n d liste d f or s u bjects i n t he e nr olle d a nal ysis sets.
De m o gra p hic a n d baseli ne c haracteristics s uc h as a ge, se x, race, et h nicit y, baseli ne E C O G P S, 
hist ol o g y, ca ncer sta ge, best res p o nse t o pri or c he m ot hera p y, li nes of pri or re gi me ns, a n d pri or 
treat me nt t y pe will be s u m marize d f or t he e nr olle d a nal ysis sets, efficac y a nal ysis sets, a n d 
safet y a nal ysis sets.  If 2 a nal ysis sets wit hi n a part of t he st u d y are i de ntical t o eac h ot her, t he 
ta ble will be prese nte d o nl y o nce.
1 1. 4. 
Effic ac y A n al yses
Efficac y varia bles will i ncl u de O R R (t he s u m of C R a n d P R rates); D C R (t he s u m of C R rate, 
P R rate, a n d S D rate f or a mi ni m u m of 5 wee ks fr o m t he first d osi n g date), res p o nse d urati o n, 
d urati o n of S D, T T R, a n d P F S, usi n g R E CI S T 1. 1.  T u m or assess me nt will be perf or me d b y b ot h 
t he i n vesti gat or a n d i n de pe n de nt ce ntral i ma gi n g facilit y.
T he efficac y varia bles will be liste d a n d s u m marize d.  F or O R R a n d D C R, p oi nt esti mates a n d 
9 5 % e xact bi n o mial c o nfi de nce i nter vals will be pr o vi de d.  Ti me t o e ve nt varia bles i ncl u di n g 
P F S, T T R, res p o nse d urati o n, a n d d urati o n of S D will be s u m marize d descri pti vel y usi n g t he 
Ka pla n- Meier met h o d.  P F S is defi ne d as t he ti me fr o m t he date of t he first d ose t o t he earlier of 
t he dates of t he first o bjecti ve d oc u me ntati o n of ra di o gra p hic P D or deat h d ue t o a n y ca use.  
Ce ns ori n g r ules f or t he P F S a nal ysis will be s pecifie d i n t he S A P.  T he gr o wt h m o d ulati o n 
i n dices (t he i ntras u bject rati o of P F S p ost-st u d y treat me nt vers us P F S p ost t he m ost rece nt pri or 
t hera pe utic re gi me n) will be s u m marize d.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
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Pa ge 9 6
Descri pti ve statistics f or t he best perce nt c ha n ge i n t he S L D of meas ura ble t u m ors will be 
pr o vi de d.  A waterfall pl ot of t he best perce nt c ha n ge fr o m scree ni n g i n t he S L D f or eac h s u bject 
will be prese nte d f or s u bjects wit h a d va nce d s oli d mali g na ncies.
1 1. 4. 1. 
Pri m ar y Effic ac y A n al yses
N ot a p plica ble.
1 1. 4. 2. 
Sec o n d ar y Effic ac y A n al yses
N ot a p plica ble.
1 1. 4. 3. 
E x pl or at or y Effic ac y A n al yses
N ot a p plica ble.
1 1. 5. 
P h ar m ac o ki netic/ P h ar m ac o d y n a mic A n al yses
1 1. 5. 1. 
P h ar m ac o ki netic A n al yses
P K a nal yses will be perf or me d o n t he P K a nal ysis set.  Ser u m c o nce ntrati o n-ti me data f or D S-
8 2 0 1a, 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 will be liste d, pl otte d, a n d s u m marize d usi n g 
descri pti ve statistics b y d ose le vel/c o h ort wit hi n eac h Part at eac h p oi nt a n d i n st u d y peri o d ( Part 
1 a n d Part 2). 
P K para meters of D S- 8 2 0 1a, 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 will be liste d a n d 
s u m marize d usi n g descri pti ve statistics b y d ose le vel/c o h ort wit hi n eac h Part.
T he c o m paris o n of t he P K pr ofile bet wee n eac h dr u g pr o d uct ( F L- D P 1 a n d F L- D P 2) will be 
assesse d.  T he c o m paris o n of t he P K pr ofile bet wee n eac h re gi o n (Ja pa n a n d t he U nite d States) 
will als o be assesse d.
Ser u m c o nce ntrati o n data will be use d t o perf or m a p o p ulati o n P K m o deli n g.  T he i nfl ue nces of 
i ntri nsic or e xtri nsic fact or will be assesse d i n t he p o p ulati o n P K a nal ysis.  If perf or me d, res ults 
of p o p ulati o n P K a nal yses will be re p orte d se paratel y (ie, n ot i n t he Cli nical St u d y Re p ort).
1 1. 5. 2. 
P h ar m ac o d y n a mic A n al yses
N ot a p plica ble. 
1 1. 5. 3. 
Bi o m ar ker a n d E x pl or at or y A n al yses
E x pl orati ve a nal yses f or bi o mar kers will be liste d a n d s u m marize d usi n g descri pti ve statistics.
1 1. 6. 
S afet y A n al yses
T he safet y pr ofile will be base d o n A Es, p h ysical e xa mi nati o n fi n di n gs, vital si g n meas ure me nts, 
cli nical la b orat or y meas ure me nts, E C G rec or di n gs, E C H O/ M U G A fi n di n gs, a n d o p ht hal m ol o gic 
fi n di n gs.  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 4. 0.  I n t he D ose Escalati o n 
part, t he i nci de nce of D L Ts will als o be e val uate d.
Safet y a nal yses i n ge neral will be descri 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.  I n t he D ose Escalati o n part, t he n u m ber of D L Ts i de ntifie d 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
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Pa ge 9 7
a m o n g t he D L T-e val ua ble s u bjects i n t he D L T-e val ua ble set will be liste d a n d s u m marize d f or 
eac h c o h ort of D S- 8 2 0 1a.
1 1. 6. 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 e mer ges d uri n g t he treat me nt peri o d (fr o m first d ose date u ntil 
F/ U visit after t he last d ose of st u d y me dicati o n), ha vi n g bee n a bse nt at pre-treat me nt; or 
ree mer ges d uri n g treat me nt, ha vi n g bee n prese nt at baseli ne b ut st o p pe d pri or t o treat me nt; or 
w orse ns i n se verit y after starti n g treat me nt relati ve t o t he pre-treat me nt state, w he n t he A E is 
c o nti n u o us.
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 t he w orst N CI-
C T C A E gra de, S yste m Or ga n Class ( S O C), a n d preferre d ter m.  
Si milarl y, t he n u m ber a n d perce nta ge of s u bjects re p orti n g treat me nt-e mer ge nt S A Es will be 
ta b ulate d, as well as T E A Es/ S A Es c o nsi dere d relate d t o D S- 8 2 0 1a.  
A b y-s u bject A E (i ncl u di n g T E A E) data listi n g will be pr o vi de d i ncl u di n g, b ut n ot li mite d t o, 
ver bati m ter m, preferre d ter m, S O C, N CI- C T C A E gra de, a n d relati o ns hi p t o st u d y dr u g.
Deat hs, ot her S A Es, 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 per ma ne nt 
disc o nti n uati o n fr o m D S- 8 2 0 1a, will be liste d.
1 1. 6. 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 selecte d cli nical la b orat or y test res ults ( he mat ol o g y 
a n d c he mistr y) a n d c ha n ges fr o m baseli ne b y sc he d ule d ti me of e val uati o n, i ncl u di n g t he E O T 
visit, 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 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 4. 0, if a p plica ble.  
A s hift ta ble, prese nti n g t he 2- wa y fre q ue nc 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 t he N CI- C T C A E gra de, will be pr o vi de d f or selecte d cli nical la b orat or y tests.  
A b n or mal cli nical la b orat or y test res ults t hat are dee me d of cli nical si g nifica nce or of Gra de 3 or 
4 will be liste d.
1 1. 6. 3.  
Vit al Si g n A n al yses
Descri pti ve statistics will be pr o vi de d f or t he vital si g ns 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 val uati o n, i ncl u di n g t he E O T visit 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.
1 1. 6. 4. 
Electr oc ar di o gr a m A n al yses
A s hift ta ble, prese nti n g t he 2- wa y fre q ue nc y ta b ulati o n f or baseli ne a n d eac h sc he d ules ti me, 
i ncl u di n g t he E O T Visit acc or di n g t o t he cate g ories f or E C G ( n or mal a n d a b n or mal) will be 
pr o vi de d.
1 1. 6. 5. 
P h ysic al Fi n di n g A n al yses
P h ysical e xa mi nati o n fi n di n gs i ncl u di n g E C O G P S will be liste d.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 8
1 1. 6. 6.  
Ot her S afet y A n al yses
T he E C H O/ M U G A fi n di n gs a n d o p ht hal m ol o gic fi n di n gs will be liste d.  
1 1. 7.  
Ot her A n al yses
N ot a p plica ble.
1 1. 8. 
I nteri m A n al yses
N o f or mal i nteri m a nal ysis is pla n ne d, e xce pt f or t he assess me nt of t he M T D after eac h 
escalati o n c o h ort i n t he D ose Escalati o n part.
1 1. 9.  
D at a a n d S afet y M o nit ori n g B o ar d
N ot a p plica ble.
1 1. 1 0. 
S a m ple Size Deter mi n ati o n
T he D ose Escalati o n part of t his st u d y ( Part 1) c o nsists of m C R M wit h E W O C desi g n wit h at 
least 3 D L T-e val ua ble s u bjects per d ose le vel.  At least 1 8 D L T-e val ua ble s u bjects are nee de d t o 
reac h a n acc urate esti mate of t he M T D.
Sa m ple size has bee n deter mi ne d b y practical c o nsi derati o ns f or t he D ose Escalati o n part of t he 
st u d y.  N o f or mal statistical assess me nt has bee n perf or me d.
F or t he D ose E x pa nsi o n part ( Part 2), a p pr o xi matel y 2 6 0 s u bjects ( 1 0 0 s u bjects f or Part 2a, 4 0 
s u bjects f or Part 2 b, 2 0 t o 4 0 s u bjects f or Part 2c, 6 0 s u bjects f or Part 2 d a n d 2 0 s u bjects f or Part 
2e) will be e nr olle d. 
Part 2a
If tar get O R R is m ore t ha n 1 5 % ( n ull h y p ot hesis: O R R  0. 1 5, alter nati ve h y p ot hesis: 
O R R > 0. 1 5), t he n t he pr o ba bilit y of less t ha n 9 res p o n ders o ut of 1 0 0 s u bjects will be less t ha n 
5 %.  T he pr o ba bilit y t hat m ore t ha n 2 1 res p o n ders o ut of 1 0 0 s u bjects ( O R R > 2 1 %) are 
o bser ve d will be less t ha n 5 % u n der t he n ull h y p ot hesis wit h O R R  0. 1 5 b ut m ore t ha n 9 0 % 
u n der alter nati ve h y p ot hesis wit h O R R = 0. 3 5. 
Part 2 b
If tar get O R R is m ore t ha n 1 0 % ( n ull h y p ot hesis: O R R  0. 1 0, alter nati ve h y p ot hesis: 
O R R > 0. 1 0), t he n t he pr o ba bilit y of n o res p o nse o ut of 4 0 s u bjects will be less t ha n 5 %.  T he 
pr o ba bilit y t hat m ore t ha n 7 res p o n ders o ut of 4 0 s u bjects ( O R R > 1 7. 5 %) are o bser ve d will be 
less t ha n 5 % u n der t he n ull h y p ot hesis wit h O R R  0. 1 0 b ut m ore t ha n 8 0 % u n der alter nati ve 
h y p ot hesis wit h O R R = 0. 2 5. 
Part 2c a n d Part 2e
If tar get O R R is m ore t ha n 1 5 % ( n ull h y p ot hesis: O R R  0. 1 5, alter nati ve h y p ot hesis: 
O R R > 0. 1 5), t he n t he pr o ba bilit y of n o res p o nse o ut of 2 0 s u bjects will be less t ha n 5 %.  T he 
pr o ba bilit y t hat m ore t ha n 4 res p o n ders o ut of 2 0 s u bjects ( O R R > 2 0 %) are o bser ve d will be 
less t ha n 2 0 % u n der t he n ull h y p ot hesis wit h O R R  0. 1 5 b ut m ore t ha n 7 5 % u n der alter nati ve 
h y p ot hesis wit h O R R = 0. 3 0. 


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 9 9
Part 2 d
If tar get O R R is m ore t ha n 1 5 % ( n ull h y p ot hesis: O R R  0. 1 5, alter nati ve h y p ot hesis: O R R > 
0. 1 5), t he n t he pr o ba bilit y of less t ha n 5 res p o n ders o ut of 6 0 s u bjects will be less t ha n 5 %.  T he 
pr o ba bilit y t hat m ore t ha n 1 4 res p o n ders o ut of 6 0 s u bjects ( O R R > 2 3. 3 %) are o bser ve d will be 
less t ha n 5 % u n der t he n ull h y p ot hesis wit h O R R  0. 1 5 b ut m ore t ha n 8 0 % u n der alter nati ve 
h y p ot hesis wit h O R R = 0. 3 0.
T he pr o ba bilit y val ues f or t he sa m ple size are deri ve d base d o n bi n o mial distri b uti o n usi n g S A S ®  
versi o n 9. 2.
1 1. 1 1. 
S pecific ati o n of M o difie d C o nti n u o us Re assess me nt Met h o d Wit h Esc al ati o n 
Wit h O ver d ose C o ntr ol 
1 1. 1 1. 1. 
B a yesi a n L o gistic Re gressi o n M o del f or M o difie d C o nti n u o us Re assess me nt 
Met h o d
T he d ose-t o xicit y relati o ns hi p f or m C R M wit h E W O C pri nci ple will be descri be d b y f oll o wi n g 
2- para meter B L R M:
l o git( π( d)) = l o g( α) + β l o g( d/ d *), α > 0, β > 0
w here l o git( π( d)) = l n ( π( d)/( 1- π( d))), π( d) is t he pr o ba bilit y of a D L T or t he D L T rate at d ose d.  
D oses are rescale d as d/ d * wit h t he refere nce d ose d * = 9. 7 m g/ k g.  As a c o nse q ue nce l o g( α) is 
e q ual t o l o git( π( d *)) at d ose d *.  N ote t hat f or a d ose e q ual t o zer o, t he pr o ba bilit y of t o xicit y is 
zer o.
1 1. 1 1. 2. 
Pri or S pecific ati o n f or B a yesi a n L o gistic Re gressi o n M o del P ar a meters
T he Ba yesia n a p pr oac h re q uires t he s pecificati o n of a pri or distri b uti o n f or t he B L R M 
para meters.  A mi ni mall y-i nf or mati ve bi variate n or mal pri or f or t he m o del para meters 
(l o g( α),l o g( β)) is o btai ne d as f oll o ws1 7:

Base d o n e xtra p olati o n of n o ncli nical t o xic ol o g y st u dies i n m o n ke ys, t he M T D is 
pr ojecte d t o be greater t ha n 9. 7 m g/ k g i n h u ma ns (t he H N S T D of m o n ke ys is 3 0 
m g/ k g a n d ass u mi n g h u ma ns a n d m o n ke ys are e q uall y se nsiti ve, t he M T D is 
pr ojecte d t o be greater t ha n 9. 7 m g/ k g i n h u ma ns).  T he me dia n pri or pr o ba bilities of 
D L T are set t o be a p pr o xi matel y 8. 0 % a n d 2 4. 5 % at 0. 8 m g/ k g ( pr ojecte d starti n g 
d ose f or d ose escalati o n usi n g m C R M) a n d at 9. 7 m g/ k g, res pecti vel y.

F or t he re mai ni n g d oses, t he me dia ns of pr o ba bilit y of D L T are ass u me d li near i n 
l o g- d ose o n t he l o git-scale.

Base d o n t he a b o ve me dia ns f or t he pr o ba bilit y of D L T at eac h d ose a n d wi de pri or 
cre di ble i nter vals ( o btai ne d fr o m mi ni mall y i nf or mati ve Beta distri b uti o ns), t he 
o pti mal para meters of t he bi variate n or mal distri b uti o n ca n be o btai ne d as f oll o ws:
P ar a meters
Me a ns
St a n d ar d de vi ati o ns
C orrel ati o n
l o g( α), l o g( β)
(- 1. 1 5 0 2, - 0. 8 9 5 1)
( 2. 0 9 2 4, 1. 1 1 8 3)
- 0. 3 4 4 8


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 0 0
1 1. 1 1. 3. 
Esc al ati o n Wit h O ver d ose C o ntr ol Pri nci ple
D ose rec o m me n dati o n f or t he ne xt c o h ort will be base d o n s u m maries of t he p osteri or 
pr o ba bilit y of t he D L T rate f or pr o visi o nal d oses: 0. 8, 1. 6, 3. 2, 5. 0, 6. 4, a n d 8. 5 m g/ k g.  After 
s u bjects of eac h c o h ort c o m plete  D L T e val uati o n d uri n g C ycle 1, t he p osteri or distri b uti o ns of 
t he D L T rate are deri ve d f or all pr o visi o nal d ose le vels base d o n t he B L R M usi n g t he D L T 
o utc o me data fr o m all assesse d d oses a n d a pre-s pecifie d pri or distri b uti o n f or t he m o del 
para meters.  T he p osteri or pr o ba bilit y of t he D L T rate i n t he f oll o wi n g 4 i nter vals at eac h d ose 
le vel will t he n be calc ulate d: [ 0 %, 1 6 %] as t he D L T rate i nter val f or u n der- d osi n g, ( 1 6 %, 3 3 %] 
as t he tar get D L T rate i nter val, ( 3 3 %, 6 0 %] as t he D L T rate i nter val f or e xcessi ve t o xicit y, a n d 
( 6 0 %, 1 0 0 %] as t he D L T rate i nter val f or u nacce pta ble t o xicit y, a n d use d f or d ose 
rec o m me n dati o n f or t he ne xt c o h ort acc or di n g t o t he E W O C pri nci ple.  T he a b o ve pr o visi o nal 
d oses are base d o n a n i nitial esti mate of t he h u ma n M T D of 9. 7 m g/ k g usi n g t he H N S T D of 
m o n ke ys i n n o ncli nical t o xic ol o g y st u dies ( 3 0 m g/ k g).  It is t heref ore c o ncei va ble t hat t he 
p osteri or pr o ba bilit y of D L T rate f or d ose rec o m me n dati o n ma y be ge nerate d usi n g alter nati ve 
pr o visi o nal d oses as l o n g as t he pre dicte d e x p os ure i ncre me nts are bet wee n 3 0 % a n d 1 0 0 % 
( Secti o n 3. 2. 1. 2. 1 ).
T he E W O C pri nci ple re q uires t hat t he m C R M rec o m me n de d d ose f or t he ne xt c o h ort of s u bjects 
is t he o ne wit h t he hi g hest p osteri or pr o ba bilit y of t he D L T rate i n t he tar get D L T rate i nter val of 
( 1 6 %, 3 3 %] a m o n g all d oses f ulfilli n g t he o ver d ose c o ntr ol c o nstrai nt: t here is less t ha n 2 5 % of 
pr o ba bilit y f or t he D L T rate > 3 3 % ( pr o ba bilit y f or e xcessi ve or u nacce pta ble t o xicit y).


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 0 1
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/I E 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 data/ d oc u me nts.  Direct 
access i ncl u des per missi o n t o e xa mi ne, a nal yze, verif 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 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 ose of i ns pecti n g t he facilities a n d, u p o n re q uest, 
i ns pecti n g t he vari o us rec or ds of t he st u d y (e g, C R Fs, s o urce data, a n d ot her perti ne nt 
d oc u me nts).
T he m o nit or is res p o nsi ble f or visiti n g site(s) at re g ular i nter vals t hr o u g h o ut t he st u d y t o verif y 
a d here nce t o t he pr ot oc 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 here nce t o 
I C H G C P a n d l ocal re g ulati o ns o n t he c o n d uct of cli nical researc h.  T he m o nit or is res p o nsi ble 
f or i ns pecti n g t he C R Fs a n d e ns uri n g c o m plete ness of t he st u d y esse 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 he e ntries o n t he C R Fs.
T he m o nit or will c o m m u nicate de viati o ns fr o m t he 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 hat a p pr o priate acti o n desi g ne d t o pre ve nt 
rec urre nce of t he detecte 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 perate 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 hese m o nit ori n g visits are a d dresse d a n d d oc u me nte d.
I n acc or da nce 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 selecte d f or a u dit 
b y re prese ntati ves fr o m S p o ns or.  I ns pecti o n of site facilities (e g, p har mac y, dr u g st ora ge areas, 
la b orat ories etc) a n d re vie w of st u d y relate d rec or ds will occ ur i n or der t o e val uate t he st u d y 
c o n d uct a n d c o m plia nce wit h t he pr ot oc ol, I C H G C P, a n d a p plica ble re g ulat or y re q uire me nts.
1 2. 2.  
D at a C ollecti o n
T he I n vesti gat or or st u d y staff will e nter t he data i n t he e C R F ( See Secti o n 1 7. 4 ) i n acc or da nce 
wit h t he C R F C o m pleti o n G ui deli nes t hat are pr o vi de d b y t he S p o ns or.
e C R F c o m pleti o n s h o ul d be ke pt c urre nt t o e na 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 he st u d y.  e C R F will be c o m plete d, re vie we d a n d si g ne d off or e-
si g ne d b y t he I n vesti gat or after all q ueries ha ve bee n satisfact oril y res ol ve d.
T he I n vesti gat or e-si g ns acc or di n g t o t he st u d y data fl o w.
A n y data rec or de d o n t he st u d y C R F will be c ollecte d a n d i ncl u de d i n t he data base acc or di n g t o 
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m ( C DI S C) sta n dar ds a n d s u bjecte d t o t he sa me 
pr oce d ures as ot her data.
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 N u m ber as defi ne d b y t he 
S p o ns or.


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T o e ns ure t he q ualit y of cli nical data acr oss all s u bjects a n d 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 pecificati o ns gi ve n t o S p o ns or or C R O.  
Data will be vette d b ot h electr o nicall y a n d ma n uall y f or e C R Fs t he 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 nerate d b y r ules a n d raise d 
b y re vie wers will be ge nerate 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 ke d f or c o nsiste nc y, o missi o ns, a n d a n y a p pare nt discre pa ncies.  T o res ol ve a n y q uesti o ns 
arisi n g fr o m t he Cli nical Data Ma na ge me nt re vie w pr ocess,  e C R Fs q ueries will be raise d a n d 
res ol ve d wit hi n t he E D C a p plicati o n.
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntral la bs will be rec o ncile d t o t he cli nical 
data base.
S A Es i n t he cli nical data base will be rec o ncile d wit h t he safet y data base.
All A Es will be c o de d usi n g Me d D R A.
All pri or ca ncer t hera p y a n d pri or/c o nc o mita nt me dicati o ns e ntere d i nt o t he data base will be 
c o de d b y usi n g t he latest versi o n of W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y.
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 ure List of a p pr o priatel y q ualifie d pers o ns t o w h o m 
he/s he has dele gate 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 
C 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 me nts, data, a n d rec or ds fr o m w hic h t he s u bject’s C R F data 
are o btai ne d.  T hese i ncl u de b ut are 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 har mac y rec or ds, diaries, micr ofic hes, X-ra ys, a n d c orres p o n de nce.
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 ntralize d 
fili n g s yste m ( Trial Master File) of all st u d y-relate d (esse ntial) d oc u me ntati o n, s uita ble f or 
i ns pecti o n at a n y ti me b y re prese ntati ves fr o m t he S p o ns or a n d/ or a p plica ble re g ulat 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 C R Fs, i nf or me d c o nse nts, 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 he pr ot oc ol wit h all a me n d me nts, I n vesti gat or’s Br oc h ure, 
c o pies of rele 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 de nce t o a n d fr o m t he I E C/I R B a n d t he S p o ns or.

Rec or ds relate d t o t he I n vesti gati o nal Pr o d uct(s) i ncl u di n g ac k n o wle d g me nt of 
recei pt at 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 me nts s u p p orti n g e ntries i n t he C R Fs m ust be mai ntai ne d a n d 
be rea dil y a vaila ble.
All esse ntial d oc u me ntati o n will be retai ne d b y t he I n vesti gat or u ntil at least 3 years after t he last 
a p pr o val of a mar keti 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 3 years ha ve la pse d si nce t he 
f or 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 pr o d uct.  T hese d oc u me nts 


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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 uire 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 bilit y 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 oc u me nts n o l o n ger nee d t o be retai ne d.
N o st u d y d oc u me nt s h o ul d be destr o ye d wit h o ut pri or writte n a gree me nt bet wee n S p o ns or a n d 
t he I n vesti gat or.  S h o ul d t he I n vesti 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 ocati o n, he/s he m ust n otif y 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 ne w l ocati o n.
1 2. 5.  
Rec or d Kee pi n g
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, data c orrecti o n f or ms, C R Fs, 
i n ve nt or y of st u d y pr o d uct, re g ulat or y d oc u me nts (e g, pr ot oc ol a n d a me n d me nts, I R B/ E C 
c orres p o n de nce a n d a p pr o vals, a p pr o ve d a n d si g ne d I C F, I n vesti 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 pertai ni n g 
t o 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 site.  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 
necessar y f or t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y.  T hese 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 site p olic y.  Pri or t o tra nsfer 
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 ort u nit y t o f urt her st ore s uc h rec or ds.


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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 me nt wit h S p o ns or or a 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 he 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 s hall 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 he parties.




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1 5. 
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. 
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 see m t o be a p pr o priate 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 t he S p o ns or or 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 ulat 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 ce nters 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 ma de 
b y s uc h a me n d me nts will be d oc u me nte d i n a S u m mar y of C ha n ges d oc 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 vie 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 me nt will affect st u d y c o n d uct at a partic ular st u d y ce nter(s) a n d/ or i n a 
partic ular 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 clearl y d oc u me nte d.
A pr ot oc ol a me n d me nt ma y be i m ple me nte d after it has bee n a p pr o ve d b y t he I R B/ E C a n d b y 
re g ulat or y a ut h orities w here a p pr o priate, u nless i m me diate i m ple me ntati o n of t he c ha n ge is 
necessar y f or s u bject safet y.
1 5. 2. 
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 bec o mes a vaila ble t hat ma y a d versel y affect t he safet y of s u bjects 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, 
E 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 de 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 ver ne w i nf or mati o n bec o mes 
a vaila ble t hat ma y be rele 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 h o ul d be d oc u me nte d o n me dical 
rec or ds, f or e xa m ple, a n d it s h o ul d be c o nfir me d w het her 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 mati o n is re vise d, it m ust be re-a p pr o ve d b y t he I E C/I R B.  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 ue 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 bjects 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 pers 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. 3.  
A d dress List
1 5. 3. 1. 
S p o ns or
J a p a n:
Daiic hi Sa n k y o C o., Lt d.
3- 5- 1, Ni h o n bas hi - h o nc h o, C h u o- k u, T o k y o 1 0 3- 8 4 2 6, Ja pa n
U nite d St ates:
Daiic hi Sa n k y o P har ma De vel o p me nt
2 1 1 M o u nt Air y R oa d, Bas ki n g Ri d ge, NJ 0 7 9 2 0, U nite d States










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1 6.  
R E F E R E N C E S
1.
Arc her S G, Eli o p o ul os A, S pa n di d os D, et al. E x pressi o n of ras p 2 1, p 5 3 a n d c-er b B- 2 i n 
a d va nce d breast ca ncer a n d res p o nse t o first li ne h or m o nal t hera p y. Br J Ca ncer. 
1 9 9 5; 7 2( 5): 1 2 5 9- 6 6.
2.
Este va FJ, G u o H, Z ha n g S, et al. P T E N, PI K 3 C A, p- A K T, a n d p- p 7 0 S 6 K stat us: 
ass ociati o n wit h trast uz u ma b res p o nse a n d s ur vi val i n patie nts wit h H E R 2- p ositi ve 
metastatic breast ca ncer. A m J Pat h ol. 2 0 1 0; 1 7 7( 4): 1 6 4 7- 5 6.
3.
R oss J S, Sl o d k o ws ka E A, S y m ma ns W F, et al. T he H E R- 2 rece pt or a n d breast ca ncer: 
te n years of tar gete d a nti- H E R- 2 t hera p y a n d pers o nalize d me dici ne. O nc ol o gist. 
2 0 0 9; 1 4( 4): 3 2 0- 6 8.
4.
H of ma n n M, St oss O, S hi D, et al. Assess me nt of a H E R 2 sc ori n g s yste m f or gastric 
ca ncer: res ults fr o m a vali dati o n st u d y. Hist o pat h ol o g y. 2 0 0 8; 5 2( 7): 7 9 7- 8 0 5.
5.
Gra val os C, Ji me n o A. H E R 2 i n gastric ca ncer: a ne w pr o g n ostic fact or a n d a n o vel 
t hera pe utic tar get. A n n O nc ol. 2 0 0 8; 1 9( 9): 1 5 2 3- 9.
6.
Har der J, I h orst G, Hei ne ma n n V, et al. M ultice ntre p hase II trial of trast uz u ma b a n d 
ca pecita bi ne i n patie nts wit h H E R 2 o vere x pressi n g metastatic pa ncreatic ca ncer. Br J 
Ca ncer. 2 0 1 2; 1 0 6( 6): 1 0 3 3- 8.
7.
Y os hiza wa A, S u mi y os hi S, S o n o be M, et al. H E R 2 stat us i n l u n g a de n ocarci n o ma: a 
c o m paris o n of i m m u n o hist oc he mistr y, fl u oresce nce i n sit u h y bri dizati o n ( FI S H), d ual-
I S H, a n d ge ne m utati o ns. L u n g Ca ncer. 2 0 1 4; 8 5( 3): 3 7 3- 8.
8.
Bl o k EJ, K u p pe n PJ, va n Lee u we n J E, et al. C yt o plas mic o vere x pressi o n of H E R 2: a ke y 
fact or i n c ol orectal ca ncer. Cli n Me d I nsi g hts O nc ol. 2 0 1 3; 7: 4 1- 5 1.
9.
Verri E, G u gliel mi ni P, P u nt o ni M, et al. H E R 2/ ne u o nc o pr otei n o vere x pressi o n i n 
e pit helial o varia n ca ncer: e val uati o n of its pre vale nce a n d pr o g n ostic si g nifica nce. 
Cli nical st u d y. O nc ol o g y. 2 0 0 5; 6 8( 2- 3): 1 5 4- 6 1.
1 0. Press M F, C or d o n- Car d o C, Sla m o n DJ. E x pressi o n of t he H E R- 2/ ne u pr ot o- o nc o ge ne i n 
n or mal h u ma n a d ult a n d fetal tiss ues. O nc o ge ne. 1 9 9 0; 5( 7): 9 5 3- 6 2.
1 1. Herce pti n: f ull prescri bi n g i nf or mati o n, Re vise d: 0 4/ 2 0 1 5 ( U nite d States).  
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 5/ 1 0 3 7 9 2s 5 3 2 7l bl. p df
1 2. Herce pti n : E P A R - Pr o d uct I nf or mati o n, U p date d: 2 1/ 0 4/ 2 0 1 5 ( E ur o pe).  
htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n _ G B/ d oc u me nt _li brar y/ E P A R _-
_ Pr o d uct _I nf or mati o n/ h u ma n/ 0 0 0 2 7 8/ W C 5 0 0 0 7 4 9 2 2. p df
1 3. Herce pti n: Pac ka ge I nsert, Re vise d: 0 5/ 2 0 1 4 (Ja pa n).  
htt p:// w w w.i nf o. p m da. g o.j p/ g o/ pac k/ 4 2 9 1 4 0 6 D 3 0 2 1 _ 1 _ 0 1/
1 4. Ka dc yla: f ull prescri bi n g i nf or mati o n, Re vise d: 0 7/ 2 0 1 4  ( U nite d States).  
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 4/ 1 2 5 4 2 7s 0 3 3l bl. p df


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1 5. Ka dc yla: E P A R - Pr o d uct I nf or mati o n, U p date d: 0 3/ 1 2/ 2 0 1 4 ( E ur o pe).  
htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n _ G B/ d oc u me nt _li brar y/ E P A R _-
_ Pr o d uct _I nf or mati o n/ h u ma n/ 0 0 2 3 8 9/ W C 5 0 0 1 5 8 5 9 3. p df
1 6. Ka dc yla: Pac ka ge I nsert, Re vise d: 0 8/ 2 0 1 4  (Ja pa n).  
htt p:// w w w.i nf o. p m da. g o.j p/ g o/ pac k/ 4 2 9 1 4 2 6 D 1 0 2 6 _ 1 _ 0 1/
1 7. Ne ue nsc h wa n der B, Bra ns o n M, Gs p o ner T. Critical as pects of t he Ba yesia n a p pr oac h t o 
p hase I ca ncer trials. Stat Me d. 2 0 0 8; 2 7( 1 3): 2 4 2 0- 3 9.
1 8. K u b o K, Az u ma A, Ka naza wa M, et al. C o nse ns us state me nt f or t he dia g n osis a n d 
treat me nt of dr u g-i n d uce d l u n g i nj uries. Res pir I n vesti g. 5 1( 2 0 1 3) 2 6 0 – 2 7 7.


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1 7.  
A P P E N DI C E S
1 7. 1. 
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
G R A D E
D E S C RI P TI O N
0
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
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
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 ut m ore t ha n 5 0 % of wa ki n g h o urs
3
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
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 Easter 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.


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1 7. 2.  
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. 2. 1.  
Me as ur a bilit y of T u m or at B aseli ne
1 7. 2. 1. 1.
Defi niti o ns
At baseli ne, t u m or lesi o ns/l y m p h n o des will be cate g orize d meas ura ble or n o n- meas ura ble as 
f oll o ws:
1 7. 2. 1. 1. 1.  
Me as ur a ble

T u m or lesi o ns: M ust be acc uratel y meas ure d i n at least 1 di me nsi o n (l o n gest dia meter 
i n t he pla ne of meas ure me nt is t o be rec or de d) wit h a mi ni m u m size of:

1 0 m m b y C T sca n ( C T sca n slice t hic k ness n o greater t ha n 5 m m)

1 0 m m cali per meas ure me nt b y cli nical e xa m (lesi o ns w hic h ca n n ot be acc uratel y 
meas ure d wit h cali pers s h o ul d be rec or de d as n o n- meas ura ble)

2 0 m m b y c hest X-ra y

Meas ura ble mali g na 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 de m ust be  1 5 m m i n s h ort a xis w he n assesse d b y C T sca n 
( C T sca n slice t hic k ness rec o m me n de d t o be n o greater t ha n 5 m m).  At baseli ne a n d 
i n F/ U, o nl y t he s h ort a xis will be meas ure d a n d f oll o we d.  See als o n otes bel o w o n 
“ Baseli ne d oc 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. 2. 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 ble lesi o ns.  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 ysical e xa m t hat is n ot meas ura ble b y 
re pr o d uci ble i ma gi n g tec h ni q ues.
1 7. 2. 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 partic ular 
c o m me nt.
1 7. 2. 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 ( P E T) sca n or plai n fil ms are n ot 
c o nsi dere d a de q uate i ma gi n g tec h ni q ues t o meas ure b o ne lesi o ns.  H o we ver, t hese 
tec h ni q ues ca n be use d t o c o nfir m t he prese nce or disa p peara nce of b o ne lesi o ns.

L ytic b o ne lesi o ns or mi xe d l ytic- blastic lesi o ns, wit h i de ntifia ble s oft tiss ue 
c o m p o ne nts, t hat ca n be e val uate d b y cr oss-secti o nal i ma gi n g tec h ni q ues s uc h as C T 
or M RI ca n be c o nsi dere d as meas ura ble lesi o ns if t he s oft tiss ue c o m p o ne nt meets 
t he defi niti o n of meas ura bilit y descri be d a b o ve.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 1 5

Blastic b o ne lesi o ns are n o n- meas ura ble.
1 7. 2. 1. 1. 3. 2.
C ystic Lesi o ns

Lesi o ns t hat meet t he criteria 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 ura ble n or n o n- meas ura ble) si nce t he y 
are, b y defi niti o n, si m ple c ysts.

“ C ystic lesi o ns” t h o u g ht t o re prese nt c ystic metastases ca n be c o nsi dere d as 
meas ura ble lesi o ns, if t he y meet t he defi niti o n of meas ura bilit y descri be d a b o ve.  
H o we ver, if n o nc 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. 2. 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 diate 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 ble u nless t here has bee n 
de m o nstrate d pr o gressi o n i n t he lesi o n.  
1 7. 2. 1. 2.
S pecific ati o ns b y Met h o ds of Me as ure me nts
1 7. 2. 1. 2. 1.  
Me 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, usi n g cali pers if cli nicall y assesse d.  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 2 8 da ys of t he first d ose of st u d y dr u g a d mi nistrati o n.
1 7. 2. 1. 2. 2.  
Met 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 haracterize 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/ U.  I ma gi n g base d e val uati o n s h o ul d 
al wa ys be perf or me d rat her t ha n cli nical e xa mi nati o n u nless t he lesi o n(s) bei n g f oll o we d ca n n ot 
be i ma ge d b ut are assessa ble b y cli nical e xa m.
C T, M RI: C T is t he best c urre ntl y a vaila ble a n d re pr o d uci ble met h o d t o meas ure lesi o ns selecte d 
f or res p o nse assess me nt.  T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T sca n base d 
o n t he ass u m pti o n t hat C T slice t hic k ness is 5 m m or less.  W he n C T sca ns ha ve slice t hic k ness 
greater t ha n 5 m m, t he mi ni m u m size f or a meas ura ble lesi o n s h o ul d be t wice t he slice t hic k ness.  
M RI is als o acce pta ble i n certai n sit uati o ns (e g, f or b o d y sca ns).  
1 7. 2. 2. 
T u m or Res p o nse E v al u ati o n
1 7. 2. 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 mate t he o verall t u m or 
b ur de n at baseli ne a n d use t his as a c o m parat or f or s u bse q ue nt meas ure me nts.  
I n Part 2 D ose E x pa nsi o n of t his st u d y, o nl y s u bjects wit h meas ura ble disease at baseli ne s h o ul d 
be i ncl u de d i n t he st u d y.


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Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 1 6
1 7. 2. 2. 2.
B aseli ne D oc u me nt ati o n of “ T ar get ” a n d “ N o n-t 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 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) s h o ul d be i de ntifie d as tar 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 ve 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).
Tar get lesi o ns s h o ul d be selecte d o n t he basis of t heir size (lesi o ns wit h t he l o n gest dia meter), be 
re prese ntati ve of all i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o 
re pr o d uci ble re peate d meas ure me nts.  It ma y be t he case t hat, 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 ure me nt i n w hic h circ u msta nce t he ne xt lar gest lesi o n w hic h 
ca n be meas ure d re pr o d uci bl y s h o ul d be selecte d.
L y m p h n o des merit s pecial me nti o n si nce t he y are n or mal a nat o mical str uct ures w hic h 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, pat h ol o gical n o des w hic h are 
defi ne d as meas ura ble a n d ma y be i de ntifie d as tar get lesi o ns m ust meet t he criteri o n of a s h ort 
a xis of  1 5 m m b y C T sca n.  O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o t he baseli ne 
s u m.  T he s h ort a xis of t he n o de is t he dia meter n or mall y use d b y ra di ol o gists t o j u d ge if a n o de 
is i n v ol ve d b y s oli d t u m or.  N o dal size is n or mall y re p orte d as 2 di me nsi o ns i n t he pla ne i n 
w hic h t he i ma ge is o btai ne d (f or C T sca n t his is al m ost al wa ys t he a xial pla ne; f or M RI t he pla ne 
of ac q uisiti o n ma y be a xial, sa gittal, or c or o nal).  T he s maller of t hese meas ures is t he s h ort a xis.  
F or e xa m ple, a n a b d o mi nal n o de w hic h is re p orte d as bei n g 2 0 m m × 3 0 m m has a s h ort a xis of 
2 0 m m a n d q ualifies as a mali g na nt, meas ura ble n o de.  I n t his e xa m ple, 2 0 m m s h o ul d be 
rec or de d as t he n o de meas ure me nt.  All ot her pat h ol o gical n o des (t h ose wit h s h ort a xis  1 0 m m 
b ut < 1 5 m m) s h o ul d be c o nsi dere d n o n-tar get lesi o ns.  N o des t hat ha ve a s h ort a xis < 1 0 m m are 
c o nsi dere d n o n- pat h ol o gical a n d s h o ul d n ot be rec or de d or f oll o we d.
A s u m of t he dia meters (l o n gest f or n o n- n o dal lesi o ns, s h ort a xis f or n o dal lesi o ns) f or all tar get 
lesi o ns will be calc ulate d a n d re p orte d as t he baseli ne s u m dia meters.  If l y m p h n o des are t o be 
i ncl u de d i n t he s u m, t he n as n ote d a b o ve, o nl y t he s h ort a xis is a d de d i nt o t he s u m.  T he baseli ne 
s u m dia meters will be use d as refere nce t o f urt her c haracterise 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 ncl u di n g pat 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 re q uire d a n d 
t hese lesi o ns s h o ul d be f oll o we d as “ prese nt,” “a bse nt,” or i n rare cases “ u ne q ui v ocal 
pr o gressi o n.”  I n a d diti o n, it is p ossi ble t o rec or d m ulti ple n o n-tar get lesi o ns i n v ol vi n g t he sa me 
or ga n as a si n gle ite m o n t he case rec or d f or m (e g, “ m ulti ple e nlar ge d pel vic l y m p h n o des” or 
“ m ulti ple li ver metastases”).  
1 7. 2. 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. 2. 2. 3. 1. 
E v al u ati o n of T ar get Lesi o ns
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 tar get or n o n-
tar get) m ust ha ve re d ucti o n i n s h ort a xis t o < 1 0 m m.


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Pa ge 1 1 7
P R: At least a 3 0 % decrease i n t he s u m of dia meters of tar get lesi o ns, ta ki n g as refere nce t he 
baseli ne s u m dia meters.
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 nce 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 m ust als o de m o nstrate a n a bs ol ute i ncrease of at 
least 5 m m.  ( N ote: t he a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).
S D: Neit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt i ncrease t o q ualif y f or P D, 
ta ki n g as refere nce t he s mallest s u m dia meters w hile o n st u d y.
1 7. 2. 2. 3. 2. 
S peci al N otes o n t he Assess me nt of T ar get 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 ve t he act ual s h ort a xis 
meas ure me nt rec or de d ( meas ure d i n t he sa me a nat o mical pla ne as t he baseli ne e xa mi nati o n), 
e ve n if t he n o des re gress t o bel o w 1 0 m m o n st u d y.  T his mea ns t hat w he n l 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 de is defi ne d as ha 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 tar get lesi o ns.
T ar get lesi o ns t h at bec o me “t o o s m all t o me as ure ”: W hile o n st u d y, all lesi o ns ( n o dal a n d 
n o n- n o dal) rec or de d at baseli ne s h o ul d ha ve t heir act ual meas ure me nts rec or de d at eac h 
s u bse q ue nt e val uati o n, e ve 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 w hic h 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 he 
ra di ol o gist ma y n ot feel c o mf orta ble assi g ni n g a n e xact meas ure a n d ma y re p ort t he m as bei n g 
“t o o s mall t o meas ure.”  W he n t his occ urs, it is i 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 li 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 ue 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 de is 
belie ve d t o be prese nt a n d is fai ntl y see n b ut t o o s mall t o meas ure, a defa ult val ue of 5 m m 
s h o ul d be assi g ne d i n t his circ u msta nce as well).  T his defa ult val ue is deri ve d fr o m t he 5 m m 
C T slice t hic k ness ( b ut s h o ul d n ot be c ha n ge d wit h var 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 base d u p o n meas ure me nt err or.  T o reiterate, 
h o we ver, if t he ra di ol o gist is a ble t o pr o vi de a n act ual meas ure, t hat s h o ul d be rec or de d, e ve n if 
it is bel o w 5 m m.
Lesi o ns t h at s plit or c o alesce o n tre at me nt: W he n n o n- n o dal lesi o ns “fra g me nt,” t he l o n gest 
dia meters of t he fra g me nte d p orti o ns s h o ul d be a d de d t o get her t o calc ulate t he tar get lesi o n s u m.  
Si milarl y, as lesi o ns c oalesce, a pla ne bet wee n t he m ma y be mai ntai ne d t hat w o ul d ai d i n 
o btai ni n g ma xi mal dia meter meas ure me nts of eac h i n di vi d ual lesi o n.  If t he lesi o ns ha ve tr 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 o n gest dia meter i n t his 
i nsta nce s h o ul d be t he ma xi mal l o n gest dia meter f or t he “c oalesce d lesi o n.”


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Pr o prietar y a n d C o nfi de ntial
Pa ge 1 1 8
1 7. 2. 2. 3. 3. 
E v al u ati o n of N o n-t ar 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 be meas ura ble, t he y 
nee d n ot be meas ure d a n d i nstea d s h o ul d be assesse d o nl y q ualitati vel y at t he ti me p oi nts 
s pecifie d i n t he pr ot oc ol.  
C R: Disa p peara nce of all n o n-tar get lesi o ns a n d n or malizati o n of t u m or mar ker le vel.  All l y m p h 
n o des m ust be n o n- pat h ol o gical i n size ( < 1 0 m m s h ort a xis).
N o n- C R/ N o n- P D: Persiste nce of 1 or m ore n o n-tar get lesi o n(s) a n d/ or mai nte na nce of t u m or 
mar ker le vel a b o ve t he n or mal li mits.
P D: U ne q ui v ocal pr o gressi o n (see c o m me nts bel o w) of e xisti n g n o n-tar get lesi o ns ( N ote: t he 
a p peara nce of 1 or m ore ne w lesi o ns is als o c o nsi dere d pr o gressi o n).
1 7. 2. 2. 3. 4. 
S peci al N otes o n Assess me nt of Pr o gressi 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 h as me as ur a ble dise ase:   I n t his setti n g, t o ac hie ve “ u ne q ui v ocal 
pr o gressi o n” o n t he basis of t he n o n-tar get disease, t here m ust be a n o verall le vel of s u bsta ntial 
w orse ni n g i n n o n-tar get disease s uc h t hat, e ve n i n prese nce of S D or P R i n tar get disease, t he 
o verall t u m or b ur de n has i ncrease d s ufficie ntl y t o merit disc o nti n uati o n of t hera p y.  A m o dest 
“i ncrease” i n t he size of 1 or m ore n o n-tar get lesi o ns is us uall y n ot s ufficie nt t o q ualit y f or 
u ne q ui v ocal pr o gressi o n stat us.  T he desi g nati o n of o verall pr o gressi o n s olel y 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 e xtre mel y 
rare.  
W he n t he s u bject h as o nl y n o n- me as ur a ble dise ase:   T he sa me ge neral c o nce pts a p pl y here as 
n ote d a b o ve, h o we ver, i n t his i nsta nce t here is n o meas ura ble disease assess me nt t o fact or i nt o 
t he i nter pretati o n of a n i ncrease i n n o n- meas ura ble disease b ur de n.  Beca use w orse ni n g i n n o n-
tar get disease ca n n ot be easil y 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 disease is 
c o m para ble i n ma g nit u de t o t he i ncrease t hat w o ul d be re q uire d t o declare P D f or meas ura ble 
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 he 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 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 ble disease, t he ver y 
nat ure of t hat disease ma kes it i m p ossi ble t o d o s o, t heref ore t he i ncrease m ust be s u bsta ntial.
1 7. 2. 2. 3. 5.  
Ne w Lesi o ns
T he a p peara nce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me 
c o m me nts o n detecti o n of ne w lesi o ns are i m p orta nt.  T here are n o s pecific criteria f or t he 
i de ntificati o n of ne w ra di o gra p hic lesi o ns; h o we ver, t he fi n di n g of a ne w lesi o n s h o ul d be 
u ne q ui v ocal: ie, n ot attri b uta ble t o differe nces i n sca n ni n g tec h ni q ue, c ha n ge i n i ma gi n g 
m o dalit y or fi n di n gs t h o u g ht t o re prese nt s o met hi n g ot her t ha n t u m or (f or e xa m ple, s o me “ ne w” 
b o ne lesi o ns ma y be si m pl y heali n g or flare of pree xisti n g lesi o ns).  T his is partic ularl y 


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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 xa m ple, necr osis of a li ver 
lesi o n ma y be re p orte d o n a C T sca n re p ort as a “ ne w” c ystic lesi o n, w hic h it is n ot.
A lesi o n i de ntifie d o n a F/ U st u d y i n a n a nat 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 ne w lesi o n a n d will i n dicate disease pr o gressi o n.  A n e xa 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 brai n or dere d w hic h 
re veals metastases.  T he s u bject’s brai n metastases are c o nsi dere d t o be e vi de nce of P D e ve n if 
he/s he di d n ot ha ve brai n i ma gi n g at baseli ne.  
If a ne w lesi o n is e q ui v ocal, f or e xa m ple beca use of its s mall size, c o nti n ue d t hera p y a n d F/ U 
e val uati o n will clarif y if it re prese nts tr ul y ne w disease.  If re peat sca ns c o nfir m t here is 
defi nitel y a ne w lesi o n, t he n pr o gressi o n s h o ul d be declare d usi n g t he date of t he i nitial sca n.  
1 7. 2. 2. 4.
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.  N o c o nfir mat or y meas ure me nt f or C R, P R, or S D is re q uire d i n t he st u d y.
T he s u bject’s best o verall res p o nse assi g n me nt will de pe n d o n t he fi n di n gs of b ot h tar get a n d 
n o n-tar get disease a n d will als o ta ke i nt o c o nsi derati o n t he a p peara nce of ne w lesi o ns.
1 7. 2. 2. 4. 1. 
Ti me P oi nt Res p o nse
It is ass u me d t hat at eac h pr ot oc ol-s pecifie d ti me p oi nt, a res p o nse assess me nt occ urs.  
Ta ble 1 7. 1  pr 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 meas ura ble disease at baseli ne. 
W he n s u bjects ha ve n o n- meas ura ble (t heref ore n o n-tar get) disease o nl y, Ta ble 1 7. 2  is t o be use d.
T a ble 1 7. 1:  
O ver all Res p o nse: S u bjects wit h T ar get ( +/ – N o n-t ar get) Dise ase
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 get Lesi o ns
N o n-t ar get Lesi o ns
Ne w Lesi o ns
O ver all Res p o nse
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 ot e val uate d
N o
P R
P R
N o n- P D or n ot all e val uate d
N o
P R
S D
N o n- P D or n ot all e val uate d
N o
S D
N ot all E val uate d
N o n- P D
N o
N E
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
C R = c o m plete res p o nse; N E = i ne val ua ble; P D = pr o gressi ve disease; P R = partial res p o nse; 
S D = sta ble disease.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2 0
T a ble 1 7. 2:  
O ver all Res p o nse: S u bjects wit h N o n-t ar get Dise ase O nl y
Ti me P oi nt Res p o nse: S u bjects wit h N o n-t ar get Dise ase O nl y
N o n-t ar get Lesi o ns
Ne w Lesi o ns
O ver all Res p o nse
C R
N o
C R
N o n- C R/ N o n- P D
N o
N o n- C R/ N o n- P D
N ot all e val uate d
N o
N E
U ne q ui v ocal P D
Yes or N o
P D
A n y
Yes
P D
C R = c o m plete res p o nse; N E = i ne val ua ble; P D = pr o gressi ve disease.
1 7. 2. 2. 4. 2.  
Missi n g Assess me nts a n d I ne 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 perf or me d 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 case 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 be ma de t hat 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 ne 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 xa 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/ U o nl y 2 
lesi o ns were assesse 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. 2. 2. 4. 3. 
Best 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 is k n o w n.
Best res p o nse deter mi nati o n i n t his st u d y w here c o nfir mati o n of C R or P R I S N O T re q uire d: 
Best res p o nse i n t his st u d y is defi ne d as t he best res p o nse acr oss all ti me p oi nts (e g, a s u bject 
w h o has S D at first assess me nt, P R at sec o n d assess me nt, a n d P D o n last assess me nt has a best 
o verall res p o nse of P R).  W he n S D is belie ve d t o be best res p o nse, it m ust als o meet t he pr ot oc ol 
s pecifie d mi ni m u m ti me fr o m baseli ne, 6 wee ks ( ± 1 wee k).  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. 
1 7. 2. 2. 4. 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” 
size ( < 1 0 m m), t he y ma y still ha ve a meas ure me nt re p orte d o n sca ns.  T his meas ure me nt s h o ul d 
be rec or de d e ve n t h o u g h t he n o des are n or mal i n or der n ot t o o verstate pr o gressi o n s h o ul d it be 
base d o n i ncrease i n size of t he n o des.  As n ote d earlier, t his mea ns t hat s u bjects wit h C R ma y 
n ot ha ve a t otal s u m of “zer o” o n t he e C R F.
S u bjects wit h a gl o bal deteri orati o n of healt h stat us re q uiri n g disc o nti n uati o n of treat me nt 
wit h o ut o bjecti ve e vi de nce of disease pr o gressi o n at t hat ti me s h o ul d be re p orte d as 
“s y m pt o matic deteri orati o n.”  E ver y eff ort s h o ul d be ma de t o d oc u me nt o bjecti ve pr o gressi o n 
e ve n after disc o nti n uati o n of treat me nt.  S y m pt o matic deteri orati o n is n ot a descri pt or of a n 
o bjecti ve res p o nse: it is a reas o n f or st o p pi n g st u d y t hera p y.  T he o bjecti ve res p o nse stat us of 
s uc h s u bjects is t o be deter mi ne d b y e val uati o n of tar get a n d n o n-tar get disease.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2 1
F or e q ui v ocal fi n di n gs of pr o gressi o n (e g, ver y s mall a n d u ncertai n ne w lesi o ns; c ystic c ha n ges 
or necr osis i n e xisti n g lesi o ns), treat me nt ma y 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 he n pr o gressi o n was s us pecte d.
1 7. 2. 2. 5.
Fre q ue nc y of T u m or Re-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 ucte d e ver y 6 wee ks i n t he first 2 4 wee ks after 
Da y 1 of C ycle 1 a n d t hereafter e ver y 1 2 wee ks w hile t he s u bject re mai ns o n st u d y u ntil 
pr o gressi o n of disease, wit h dra wal of c o nse nt, deat h, or l oss t o F/ U.  Sca n dates s h o ul d n ot be 
a dj uste d or resc he d ule d d ue t o d ose i nterr u pti o n of a n y t y pe.
Baseli ne t u m or assess me nts m ust be perf or me d wit hi n 2 8 da ys of t he first d ose of st u d y dr u g 
a d mi nistrati o n. 
All eff orts s h o ul d be ma de t o e ns ure c o nsiste nc y bet wee n t he baseli ne meas ure me nts a n d all 
s u bse q ue nt meas ure 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 ness 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 val uati o n m ust i ncl u de C T or M RI sca n ni n g of t he brai n, c hest, a b d o me n, a n d 
pel vis at scree ni n g peri o d.  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 de t o use t he sa me assess me nt m o dalit y f or all assess me nts f or eac h 
s u bject.  H o we ver, if t here is n o brai n metastasis at t he ti me of scree ni n g, C T or M RI s h o ul d 
o nl y be d o ne w he n s y m pt o ms ass ociate d wit h brai n metastasis occ ur d uri n g st u d y peri o d.  If n o 
cli nical s y m pt o ms are o bser ve d, brai n C T or M RI is n ot ma n dat or y d uri n g st u d y peri o d.  All 
e val uati 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 val uate d at eac h ti me p oi nt of t u m or assess me nt. 
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
Cl ass
F u ncti o n al C a p acit y
I
N o 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 (s h ort ness of breat h).
II
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 
(s h ort ness of breat h).
III
Mar ke d li mitati o n of p h ysical acti vit y.  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, or d ys p nea.
I V
U na ble 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 at rest.  If a n y p h ysical acti vit y is 
u n derta ke n, disc o mf ort i ncreases.
S o urce: htt ps:// w w w. he art. or g/ H E A R T O R G/ C o n diti o ns/ He art F ail ure/ A b o ut He art F ail ure/ Cl asses- of-
He art- F ail ure _ U C M _ 3 0 6 3 2 8 _ Article.js p  ( U p date d: A pr 2 3, 2 0 1 4)
1 7. 4. 
Electr o nic D at a C a pt ure S yste m
T he E D C s yste m use d f or c o m pleti n g e C R F i n t his st u d y is s h o w n bel o w.


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2 2
N a me of E D C s yste m
Me di d at a R a ve
®
E D C s yste m de vel o per
Me di data S ol uti o ns I nc.
E ntr y met h o d
We b- base d data e ntr y
I n p ut ter mi nal
Des kt o p/la pt o p c o m p uter at t he st u d y site
I nc o m pati ble o perati n g 
s yste ms
N o ne
Rec o m me n de d br o wsers
T he Me di data Ra ve ®  s u p p orts a n y br o wser w hic h is H T M L 4, H T M L 
5, a n d C S S 2 c o m plia nt.  Br o wsers m ust ha ve Ja va Scri pt e na ble d.
Scree n Res ol uti o n
T he mi ni m u m scree n res ol uti o n re q uire d t o pr o perl y dis pla y Me di data 
Ra ve a p plicati o ns is 1 0 2 4 x 7 6 4.
C o n necti o n S pee d
1 2 8 k b ps is t he mi ni m u m c o n necti o n s pee d rec o m me n de d f or usi n g 
Me di data Ra ve.
Ot her
A d o be Flas h Pla yer : ver. 1 0 or a b o ve is re q uire d


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2 3
1 7. 5. 
S u p ple me nt List
S u p ple me nts are pri nte d se paratel y fr o m pr ot oc ol, a n d t heir versi o ns are i n de pe n de nt fr o m st u d y 
pr ot oc ol.  S o me s u p ple me nt will be a p plie d t o s pecific st u d y sites or s pecific c o u ntr y.  
S u p ple me nt 3, 4 a n d 5 is o nl y s u b mitte d f or Ja pa nese site’s I R B.
S u p ple me nts are liste d as f oll o w: 

S u p ple me nt 1: Seri o us A d verse E ve nt Re p ort ( S A V E R) f or m 

S u p ple me nt 2: EI U Re p orti n g F or m

S u p ple me nt 3: La beli n g a n d Pac ka gi n g of t he st u d y dr u g  (f or Ja pa nese St u d y Ce nter 
O nl y)

S u p ple me nt 4: T he list of St u d y Ce nters a n d I n vesti gat ors (f or Ja pa nese St u d y Ce nter 
O nl y)

S u p ple me nt 5: A d diti o nal I nf or mati o n (f or Ja pa nese St u d y Ce nter O nl y)

S u p ple me nt 6: T he list of C Y P 3 A 4 str o n g i n hi bit ors, C Y P 3 A 4 str o n g i n d ucers a n d 
O A T P i n hi bit ors


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2 4
1 7. 6. 
Sc he d ule of E ve nts ( P art 1 a n d P art 2)
C ycle 1
C ycle 2
C ycle 3
C ycle 4 
a n d 
s u bse q ue n
t c ycles
E O
T a
F/ U 
b
D a y 1
D a
y
2
D a
y
4
D a y
8
D a y
1 5
( D a y 
2 2)
D a y 1
D a y
8
D a y
1 5
( D a y 
2 2)
D a y 1
D a y
8
D a y
1 5
( D a y 
2 2)
D a y 1
S C
R
BI
E OI
( ± 
1 
d a y
)
( ± 
1 
d a y
)
( ± 2 
d a ys
)
BI
E O
I
( ± 2 
d a ys
)
( ± 2 
d a ys
)
( ± 2 
d a ys
)
BI
E OI
( ± 2 
d a ys
)
( ± 2 
d a ys
)
( ± 2 
d a ys
)
BI
E O
I
I nf or me d c o nse nt
X
A d mi nistrati o n 
D S- 8 2 0 1a
X
X u
X u
X u
De m o gra p hic 
i nf or mati o n
X
Vital si g n
X c
X d
X
X
X
X
X
X d
X
X
X
X d
X
X
X
X d
X
X
P h ysical 
e xa mi nati o n
X c
X d
X d
X d
X d
X
X
S p O 2
X d
X d
X d
X d
X
I/ E Criteria
X
Hei g ht
X
Wei g ht, 
E C O G P S
X c
X d
X d
X d
X d
X
X
La b orat or y tests
X c
X d
X
X
X
X d
X
X
X d
X
X
X d
X
X
P K
X e
X f, g
X h
X h
X
X
( X) i
X e
X f
( X) i
X e
X f,j 
X
X
( X) i
X e
X f
A D A
X k
X
X k
X k
X
X  q
HI V a nti b o d y test
X l
H E R 2 E C D 
( bl o o d)
X c
X m
X
Tr o p o ni n ( bl o o d)
X c
X  n
X  n
X n
X  n
X
X
E C H O or M U G A 
( L V F F) 
X o
X d
X d, m
X
1 2-lea d 
E C G i n 
tri plicate
X c
X d
X p
X
X
X
X d
X
X d
X d
X
Pre g na nc y test
X c
X


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2 5
C ycle 1
C ycle 2
C ycle 3
C ycle 4 
a n d 
s u bse q ue nt 
c ycles
E O T  
a
F/ U  
b
D a y 1
D a y
2
D a y
4
D a y
8
D a y
1 5
( D a y 
2 2)
D a y 1
D a y
8
D a y
1 5
( D a y 
2 2)
D a y 1
D a y
8
D a y
1 5
( D a y 
2 2)
D a y 1
S C
R
BI
E OI
( ± 1 
d a y)
( ± 1 
d a y)
( ± 2 
d a ys)
BI
E OI
( ± 2 
d a ys)
( ± 2 
d a ys)
( ± 2 
d a ys)
BI
E OI
( ± 2 
d a ys)
( ± 2 
d a ys)
( ± 2 
d a ys)
BI
E OI
T u m or 
assess me nt
X  o
E ver y 6 wee ks ( ± 7 da ys) i n t he first 2 4 wee ks after Da y 1 of C ycle 1, a n d t hereafter e ver y 1 2 wee ks ( ± 7 da ys)
X
O p ht hal m ol o gic 
assess me nts
X  o
X  d
At Da y 1 i n C ycle 2 a n d e ver y 4 c ycles fr o m C ycle 5 t o t he E O T (e g, Da y 1 i n C ycle 2, 5, 9, 1 3...) 
X
I H C/ FI S H, 
H E R mar k
(t u m or sa m ple)
X
cf D N A ( bl o o d)
( X)
( X)
F or Part 2 d o nl y: 
I m m u ne 
m o nit ori n g 
( bl o o d)
X
X
X
X
( X) s
X
( X) s
X
X  v
X
F or Part 2 d o nl y:
E x pl orat or y 
bi o mar ker
(t u m or sa m ple)
X
( X) t
O ne ti me d uri n g Da y 8 t o 2 2 ( pri or t o t he s u bse q ue nt st u d y dr u g a d mi nistrati o n) of a n y c ycle
( X) t
C o nc o mita nt 
me dicati o ns 
X
A Es
X  r
S C R: scree ni n g, F/ U: f oll o w- u p, BI: bef ore i nf usi o n, E OI: e n d of i nf usi o n, E O T: e n d of treat me nt
a
T he date I n vesti gat or deci des t he disc o nti n uati o n of t he st u d y treat me nt ( + 7 da ys)
b
2 8 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.
c
Latest data wit hi n 7 da ys bef ore re gistrati o n.  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 b y st u d y site a n d c T nI testi n g b y ce ntral la b.
d
Latest data wit hi n 3 da ys bef ore a d mi nistrati o n
e
Wit hi n 8 h o urs BI o n Da y 1 of eac h c ycle u ntil C ycle 4 a n d  t he n e ver y 2 c ycles u ntil C ycle 8 (e g, C ycle 1, 2, 3, 4, 6, 8).
f
Wit hi n 1 5 mi n utes at E OI o n Da y 1 of eac h c ycle u ntil C ycle 4 a n d  t he n e ver y 2 c ycles u ntil C ycle 8 (e g, C ycle 1, 2, 3, 4, 6, 8).
g
2, 4, 7 h o urs after t he start of a d mi nistrati o n ( ± 1 5 mi n utes)
h
2 4 ( ± 2 h o urs) a n d 7 2 h o urs ( ± 2 h o urs f or Part 1, ± 1 da y f or Part 2) after t he start of a d mi nistrati o n
i
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is dela ye d f or 3 da ys or m ore, i ncl u di n g if t he s u bject ca n n ot c o nti n ue o nt o t he ne xt c ycle, c ollect bl o o d sa m ple f or 
P K a nal ysis
j
Part 1 ( D ose escalati o n): Wit hi n 1 5 mi n utes at E OI, 4 h o urs after t he start of a d mi nistrati o n ( ± 1 5 mi n utes), Part 2 ( D ose e x pa nsi o n): Wit hi n 1 5 mi n utes at 
E OI


Pr ot oc ol D S 8 2 0 1- A-J 1 0 1
Versi o n 1 2. 0, 2 6 A pr 2 0 1 9
Pr o prietar y a n d C o nfi de ntial
Pa ge 1 2 6
k
Wit hi n 8 h o urs BI o n Da y 1 i n C ycle 1 a n d 2, a n d t he n e ver y 2 c ycles u ntil t he e n d (e g, C ycle 1, 2, 4, 6, 8, 1 0, 1 2...)
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Latest data wit hi n 9 0 da ys bef ore re gistrati o n.  HI V a nti b o d y test m ust be perf or me d f or Ja pa nese s u bjects, a n d is o pti o nal f or U S s u bjects u nless re q uire d b y 
l ocal re g ulati o ns or I R B.
m
Bef ore a d mi nistrati o n f or E C H O/ M U G A a n d wit hi n 8 h o urs BI f or H E R 2 E C D.  At e ver y 2 c ycles fr o m C ycle 3 (e g, C ycle 3, 5, 7, 9...).  F or H E R 2 E C D, t his 
is a p plica ble u ntil pr ot oc ol versi o n 1 1. 0.  N o f urt her bl o o d sa m pli n g f or H E R 2 E C D is necessar y o nce pr ot oc ol versi o n 1 2. 0 is a p plie d f or a s u bject.
n
E OI f or c T nI testi n g b y ce ntral la b a n d 2 t o 3 h o urs after E OI f or tr o p o ni n ( prefera bl y tr o p o ni n T) testi n g at st u d y site.  De pe n di n g o n t he res ult of tr o p o ni n 
testi n g at st u d y sites 2 t o 3 h o urs after E OI, a d diti o nal testi n g(s) is nee de d. 
If tr o p o ni n le vels are c o nsiste nt wit h m y ocar dial i nfarcti o n as defi ne d acc or di n g t o ma n ufact urer ( C T C A E Gra de 3), perf or m E C G testi n g i n tri plicate, re peat 
tr o p o ni n testi n g 6 h o urs ( ± 1 hr) a n d 1 2 h o urs ( ± 1 hr) after i nitial tr o p o ni n test was dra w n, a n d f oll o w i nstit uti o nal g ui deli nes.  If tr o p o ni n le vels 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 vel of m y ocar dial i nfarcti o n as defi ne d b y t he ma n ufact urer ( C T C A E Gra de 1), re peat tr o p o ni n testi n g at 3 h o urs ( ± 1 
hr) after i nitial tr o p o ni n test was dra w n.  If tr o p o ni n le vel at 3 h o urs ( 6 h o urs p ost-i nf usi o n): Si g nifica ntl y i ncreases per i nstit uti o nal g ui deli nes, t he n re peat 
tr o p o ni n testi n g at 6 h o urs ( ± 1 hr) a n d f oll o w i nstit uti o nal g ui deli nes. Ot her wise, re peat tr o p o ni n testi n g at 6 h o urs ( ± 1 hr) or at 2 4 h o urs ( ± 2 h o urs) after 
i nitial tr o p o ni n test.  If tr o p o ni n le vels are a b o ve t he u p per li mit of n or mal at baseli ne a n d bel o w t he le vel of m y ocar dial i nfarcti o n as defi ne d b y t he 
ma n ufact urer ( C T C A E Gra de 1), n o re peat testi n g is re q uire d after t he first E OI 3- h o ur tr o p o ni n test if t he tr o p o ni n le vel is n ot Gra de 3.
o
Latest data wit hi n 2 8 da ys bef ore re gistrati o n
p
Wit hi n 3 0 mi n utes after e n d of i nf usi o n ( E OI), a n d 2 t o 4 h o urs after t he start of a d mi nistrati o n
q
F or s u bjects wit h p ositi ve A D A at F/ U visit, 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, or if t he A D A bec o mes ne gati ve, or if 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), or if 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 t he st u d y, w hic he ver occ urs first.  
r
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:
•
hi g h res ol uti o n C T 
•
p ul m o n ol o gist c o ns ultati o n 
•
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) 
•
arterial 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 a n d e x pl orat or y bi o mar ker 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.
s
If t he sc he d ule o n Da y 1 of t he ne xt c ycle is dela ye d f or 3 da ys or m ore, i ncl u di n g if t he s u bject ca n n ot c o nti n ue o nt o t he ne xt c ycle, c ollect bl o o d sa m ple f or 
i m m u ne m o nit ori n g a nal ysis.
t
It is rec o m me n de d t o perf or m a t u m or bi o ps y o ne ti me d uri n g Da y 8 t o 2 2 ( pri or t o t he s u bse q ue nt st u d y dr u g a d mi nistrati o n), a n d E O T if t he s u bject 
disc o nti n ues fr o m t he st u d y treat me nt d ue t o P D.
u
2 1 da ys ( + 2 da ys) fr o m latest a d mi nistrati o n date.
v
O ne ti me o ne ti me d uri n g treat me nt peri o d.
F or s us pecte d I L D/ p ne u m o nitis, st u d y dr u g s h o ul d be i nterr u pte d pe n di n g e v al u ati o n.