Clinical trial NCT03366428
Conditions: Malignant Neoplasm of Breast
Keywords: HER2 Breast cancer Oncology Antibody drug conjugate ADC
Sponsor: Daiichi Sankyo Co., Ltd.
Start date: 2017-12-26; Completion date: 2021-02-19
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will look at the effect on the QTc interval and pharmacokinetics after multiple dosing in subjects with HER2-expressing metastatic and/or unresectable breast cancer.

Detailed description:

Arms: arm 1: All participants will receive DS-8201a by intravenous infusion
Interventions: intervention 1: DS-8201a
Intervention descriptions: intervention 1: DS-8201a is supplied as a lyophilized powder which is reconstituted for infusion

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, M U L TI C E N T E R , O P E N-L A B E L, 
M U L TI P L E -D O S E S T U D Y O F D S -8 2 0 1 A T O A S S E S S 
T H E  E F F E C T O N T H E Q T I N T E R V A L A N D 
P H A R M A C O KI N E TI C S I N S U B J E C T S WI T H H E R 2 -
E X P R E S SI N G M E T A S T A TI C A N D/ O R 
U N R E S E C T A B L E B R E A S T C A N C E R  
 
D S 8 2 0 1 -A -J 1 0 2  
 
I N D N U M B E R : 1 2 7 5 5 3 
 
V E R SI O N 7 . 0, 0 3  J U L  2 0 2 0  
V E R SI O N 1. 0, 0 4  S E P 2 0 1 7  
V E R SI O N 2. 0, 0 9 N O V 2 0 1 7  
V E R SI O N 3. 0, 2 5 J A N  2 0 1 8  
V E R SI O N 4. 0, 0 1 J U N 2 0 1 8  
V E R SI O N 5. 0, 0 1 S E P  2 0 1 8   
V E R SI O N 6 . 0, 2 6 A P R 2 0 1 9 
 
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 hi c h is re q uest e 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 priet ar y i nf or mati o n c o ntai ne d i n it t o a n y t hir d p art 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 m e nt) wit h o ut t he pri or writte n per missi o n of a n a ut h orize d 
re pres e ntati ve of Daiic hi Sa n k y o . 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
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 EN T  
P H A S E 1, M U L TI C E N T E R, O P E N -L A B E L, M U L TI P L E -D O S E S T U D Y O F D S -8 2 0 1 A 
T O A S S E S S T H E E F F E C T O N T H E Q T I N T E R V A L A N D P H A R M A C O KI N E TI C S I N 
S U BJ E C T S WI T H H E R 2 -E X P R E S SI N G M E T A S T A TI C A N D/ O R U N R E S E C T A B L E 
B R E A S T C A N C E R  
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 pres e ntati ve liste d bel o w. 
 
 
  
 
  
Pri nt N a me  
  
Si g n at ure  
 
  
Cli nical St u d y Lea der   
  
 
  
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 h a 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 pres e ntati ve.  
I u n d ersta n d t hat i nf or m ati o n c o ntai ne d i n or pertai ni n g t o t his pr ot oc ol is c o nfi de ntial a n d 
s h o ul d n ot be 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 x ec uti o n or t he et hical 
re vie w of t h e st u d y, wit h o ut writte n a ut h orizati o n fr o m t he S p o ns or.  It is, h o we ver, 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 u ncil  f or Har m o ni sati 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 d er t o verif y t he dat a t hat I ha v e 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 d ersta n d t hat t he S p o ns or ma y d eci de t o s us pe n d or pre mat urel y t er mi n ate 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 dr a w fr o m e x ec 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)  
 
P P D


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
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 dra C T:  
N ot a p plica ble  
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 -J1 0 2  
I n v esti gati o nal Pr o d uct:  
D S -8 2 0 1a  
Acti ve I n gre die nt(s)/I N N:  T rast uz u ma b der u xteca n 
St u d y Title:  
P hase  1, m ultice nter , o pe n -la bel, m ulti ple -d ose  st u d y of  D S -
8 2 0 1 a t o assess the  e ffect o n  the  Q T I nter v al a n d  
p har mac o ki netics  i n su bj ects  w it h H E R 2 -e x pressi n g 
m etastatic a n d/ or u nresecta ble  b reast ca ncer. 
St u d y P has e:  
P hase 1  
I n dicati o n U n der 
I n v esti gati o n: 
D S -8 2 0 1a will be assesse d i n su bjects w it h h u ma n e pi der mal 
gr o wt h  fact or rece pt or 2 ( H E R 2)-e x pressi n g m etastatic a n d/ or 
u nresect a ble b reast ca n cer. 
St u d y O bjecti ves:   
Pri mar y O bj ecti ves  
 
T o assess t he effect of D S -8 2 0 1a o n t he c orrecte d Q T 
i nter val (Q Tc i nter val ) 
 
T o assess p har mac o ki netics ( P K) after m ulti ple d osi n g of 
D S -8 2 0 1a  
Ke y Sec o n dar y O bjecti ves  
 
T o assess t he safet y of D S -8 2 0 1a  
 
T o assess t he ser u m c o nce nt rati o ns of D S-8 2 0 1a at t he 
ti me of electr ocar di o gra m (E C G ) meas ure me nt  
Ot her Sec o n d ar y O bjecti ves  
 
T o e val uate t he effi cac y of D S -8 2 0 1a  
St u d y Desi g n:  
T his is a P hase 1, m ultice nter, o pe n -la bel, m ulti ple d ose st u d y 
of D S -8 2 0 1a desi g ne d t o assess t he effect o n t he Q Tc i nter val 
a n d p har mac o ki netics after m ulti ple d osi n g i n s u bjects wit h 
H E R 2 -e x pressi n g metast atic a n d/ or u nresecta bl e breast 
ca ncer.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4  
T he data c ut off f o r 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 c o m plete d at 
least 3 c ycles, w hi c he ver c o mes first.  After t he pri mar y 
a nal ysis, t he m ai n st u d y will be cl ose d a n d tra nsiti o n t o t he 
e xte nsi o n peri o d.  
St u d y D urati o n:  
E nr oll me nt is pla n ne d t o occ ur o ver a p pr o xi matel y 7 m o nt hs , 
wit h t he data c ut off f or t he pri mar y a n al ysis pr ojecte d t o be 
c o m plete d wit hi n a p pr o xi matel y 3 m o nt hs t hereafter.  S u bjects 
e x perie nci n g cli nical be nefit will c o nti n ue t o recei ve st u d y 
treat me nt i n t he e xte nsi o n peri o d of t he st u d y. T he f oll o w-u p ( F/ U) 
f or p ost treat me nt s u bjects will als o c o nti n ue at t he s p o ns or’s 
discreti o n t o c ollect m ore data.    T h us, t he a ntici pate d d urati o n of 
t he st u d y is 2 years a n d 6  m o nt hs . 
T he scree ni n g peri o d  is u p t o 2 8 da ys.  E ac h c ycle of 
treat me nt will be 2 1 da ys.  T he n u m ber of treat me nt c ycl es 
wit h D S -8 2 0 1a is n ot fi xe d.  
St u d y Sites  a n d L o cati o n:  T his  st u d y is pla n ne d t o be c o n d ucte d at a p pr o xi matel y se v e n 
st u d y sites i n J a pa n. 
S u bject Eli gi bilit y Crit eri a: Ke y i ncl usi o n criteria  
 
Ma n or W o ma n ≥ 2 0 years ol d.  
 
Has a pat h ol o gicall y d oc u me nte d u nresecta ble or 
metastatic breast ca ncer wit h H E R 2 e x pressi o n  
(i m m u n o hist oc he mistr y [I H C] 3 +, I H C 2 +, I H C 1 + 
a n d/ 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 nt i n sit u h y bri dizati o n ( FI S H) or d ual i n 
sit u h y bri dizati o n ( DI S H) 
 
L eft ve ntric ular ejecti o n fracti o n ( L V E F) ≥ 5 0 %.  
Ke y e x cl usi o n criteria  
 
Has a me dical hist or y of m y ocar dial i nfarcti o n wit hi n 6 
m o nt hs bef ore e nr oll me nt . 
 
Has a me dical hist or y of ve ntric ular arr h yt h mias, ot her 
t ha n rare, occasi o nal pre mat ure ve ntric ular c o ntracti o ns. 
 
Has u nc o ntr olle d or si g nifica nt car di o vasc ular disease, 
i ncl u di n g: 
- 
S y m pt o matic c o n gesti ve heart fail ure  (Ne w Y or k 
Heart Ass o ciati o n [ N Y H A]  class II-I V, Secti o n 
1 7. 4 ). 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5  
- 
Tr o p o ni n le vels c o nsiste nt wi t h m y o car dial 
i nfarcti o n as defi ne d acc or di n g t o ma n ufact urer. 
- 
U nsta ble a n gi na or s eri o us car diac arr h yt h mia 
re q uiri n g treat me nt. 
- 
Cli nicall y si g nifica nt bra d ycar dia.  
- 
U nc o ntr olle d h y perte nsi o n.  
- 
C orrecte d Q T i nter val b y Fri dericia's f or m ula ( Q Tc F 
i nter val) pr ol o n gati o n t o > 4 5 0  ms , heart rate of > 
1 0 0 beats per mi n ute  or  h eart rate of < 5 0 b eats per 
mi n ute  base d o n a vera ge of t he scree ni n g tri plicate 
1 2 -lea d E C G. 
- 
A n y a b n or mal E C G fi n di n gs i de ntifie d b y ce ntral 
assess me nt.  
- 
Atrial fi brillati o n or fl utter.  
- 
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 3 g ra de ≥2 atri o v e ntri c ular bl oc k, left b u n dle 
bra nc h bl oc k or pr ol o n ge d Q R S.  
- 
P ul m o nar y e m b olis m or dee p vei n t hr o m b osis.  
 
Has a n i m pla nta ble pace ma ker or a ut o mat ic i m pla nta ble 
car di o verter defi brillat or  or car diac res y nc hr o nizati o n 
t hera p y de vice. 
 
Has a c o n ge nital l o n g Q T s y n dr o me , fa mil y hist or y of 
l o n g Q T s y n dr o me or u n e x plai ne d s u d de n deat h . 
 
Has recei ve d ≥ 5 0 0 m g / m2 of c u m ulati ve a nt hrac ycli nes 
as d o x or u bici n -eq ui vale nt  d ose . 
 
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 n e u m o nitis, or w here s us pecte d I L D/ p ne u m o nitis 
ca n n ot be r ule d o ut b y i ma gi n g at scree ni n g . 
D osa ge F or m, D ose a n d 
R o ute of A d mi nistrati o n:  
D S -8 2 0 1a will be a d mi nistere d as a st erile i ntra v e n o us (I V) 
i njecti o n s ol uti o n at 6. 4  m g/ k g  o nce e ver y 3 wee ks.   
St u d y E n d p oi nts:   
Pri mar y E n d p oi nts  
 
Baseli ne -a dj uste d Q Tc F i nter val  
 
Ser u m c o nce ntrati o n a n d 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 a 
Ke y Sec o n dar y E n d p oi nts  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6  
 
S eri o us a d verse e ve nt s (S A Es ) 
 
T reat me nt e mer ge nt a d verse e ve nts (T E A Es )  
 
P h ysical e xa mi nati o n fi n di n gs (i ncl u di n g 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 ]) 
 
Vital si g n meas ure me nts  
 
Sta n dar d cli nical la b orat or y p ara m eters  
 
1 2 -lea d E C G para meters s uc h as R R, P R a n d Q R S 
d urati o n  
 
E c h ocar di o gra m (E C H O )/m ulti ple -gate d ac q uisiti o n 
(M U G A ) fi n di n gs 
 
O p ht hal m ol o gic fi n di n gs  
 
A nti -dr u g a nti b o d y (A D A ) 
Ot her Sec o n d ar y E n d p oi nts  
 
C o nce ntrati o n -Q T  
 
O bjecti ve res p o ns e rat e ( O R R)  
 
Disease c o ntr ol rate ( D C R)  
 
D urati o n of res p o ns e ( D o R) 
 
D urati o n of sta ble d isease ( S D) 
 
Cli nical be nefit rate ( C B R)  
 
Ti me t o res p o nse ( T T R)  
 
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 
Pla n ne d Sa m ple Size:   
A t otal of 5 0 s u bjects are e x pecte d t o partici pate i n t his st u d y.  
Statistical A nal yses:   
Q Tc pr ol o n gati o n a n al ys es  
Q Tc pr ol o n gati o n a n al ys es  will be perf or me d f or car diac 
safet y a n al ysis set.  T he baseli ne Q Tc F i nter val f or eac h 
s u bject will be s u btracte d fr o m Q Tc F i nter val t o create a 
baseli ne -a dj uste d Q Tc F i nter val f or eac h s u bj ect at eac h ti me 
p oi nt. T he baseli ne -a dj uste d Q Tc F will be a vera ge d acr oss 
s u bjects at eac h ti me p oi nt a n d a p oi nt wise t w o-si de d 9 0 % 
c o nfi de nce i nter val ( CI)  will als o be calc ulate d.  
P har mac o ki netic A n al ys es  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7  
P K  a nal ysis will be perf or me d f or P K a n al 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 a will be liste d, pl otte d, a n d 
s u m marize d usi n g descri pti ve statistics at eac h ti me p oi nt. 
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 a will be liste d a n d s u m marize d usi n g 
descri pti ve statistics.  
Safet y A nal yses  
Safet y e n d p oi nts will be base d o n A Es, p h ysical e x a 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, A D A , 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 3 .   
Safet y a nal yses i n ge n eral will be descri pti ve a n d will be 
prese nte d i n ta b ular f or mat wit h t he a p pr o priat e s u m mar y 
statistics. 
Descri pti ve statistics will be pr o vi de d f or E C G para meters 
s uc h as R R, P R a n d Q R S d urati o n a n d c ha n ges fr o m ti me -
matc he d baseli ne b y s c he d ule d ti me of e val uati o n, i ncl u di n g 
t he e n d of treat me nt ( E O T)  visit a n d t he ma xi m u m p ost -
treat me nt val ue.  I n a d diti o n, t he n u m ber a n d perce nta ge of 
s u bjects wit h E C G i nter val val ues meeti n g t he criteria will be 
ta b ulate d (e g, Q Tc ≤ 4 5 0 ms, > 4 5 0 t o ≤ 4 8 0 ms, > 4 8 0 ms t o 
≤ 5 0 0 ms, a n d > 5 0 0 m s).   
Efficac y A nal yses  
Efficac y e n d p oi nts will i ncl u de O R R (t he s u m of c o m plete 
res p o nse [C R ] a n d partial res p o nse [ 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 d ate), D o R , d urati o n of S D, C B R, T T R, 
P F S, O S, a n d perce nt c ha n ge i n tar get lesi o n usi n g Res p o nse 
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.  
 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8  
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 EN T ......................................................................... 2  
P R O T O C O L S Y N O P SI S  ...................................................................................... 3  
T A B L E O F C O N T E N T S  ....................................................................................... 8  
LI S T O F T A B L E S  ............................................................................................... 1 5  
LI S T O F FI G U R E S  ............................................................................................. 1 6  
LI S T O F A B B R E VI A TI O N S  .............................................................................. 1 7  
LI S T O F P H A R M A C O KI N E TI C P A R A M E T E R S  ............................................ 2 1  
LI S T O F D E FI NI TI O N S O F T E R M S  ................................................................. 2 2  
1.  
I N T R O D U C TI O N ................................................................................. 2 3  
1. 1.  
Bac k gr o u n d  ............................................................................................ 2 3  
1. 1. 1.  
St u d y Dr u g  ............................................................................................. 2 3  
1. 1. 1. 1.  Na me  ...................................................................................................... 2 3  
1. 1. 1. 2.  Descri pti o n  ............................................................................................ 2 3  
1. 1. 1. 3.  N o n cli nical St u dies  ................................................................................ 2 4  
1. 1. 1. 4.  Cli nical St u d y  ........................................................................................ 2 6  
1. 2.  
St u d y R ati o nale  ..................................................................................... 2 9  
1. 3.  
Ris ks a n d Be nefits f or St u d y S u bjects  ................................................... 3 0  
2.  
S T U D Y O BJ E C TI V E S A N D  H Y P O T H E SI S  ...................................... 3 2  
2. 1.  
St u d y O bjecti ves  .................................................................................... 3 2  
2. 1. 1.  
Pri ma r y O bj ecti ves ................................................................................ 3 2  
2. 1. 2.  
Sec o n dar y O bj ecti ves  ............................................................................ 3 2  
2. 1. 2. 1.  Ke y Sec o n dar y O bjecti ves  .................................................................... 3 2  
2. 1. 2. 2.  Ot her Sec o n d ar y O bjecti ves  .................................................................. 3 2  
2. 2.  
St u d y H y p ot heses  .................................................................................. 3 2  
2. 3.  
St u d y E n d p oi nts  ..................................................................................... 3 2  
2. 3. 1.  
Pri mar y E n d p oi nts  ................................................................................. 3 2  
2. 3. 2.  
S ec o n dar y E n d p oi nts  ............................................................................. 3 2  
2. 3. 2. 1.  Ke y Sec o n dar y E n d p oi nts  ..................................................................... 3 2  
2. 3. 2. 2.  Ot her Sec o n d ar y E n d p oi nts  ................................................................... 3 3  
3.  
S T U D Y D E SI G N  .................................................................................. 3 4  
3. 1.  
O ver all Desi g n ....................................................................................... 3 4  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9  
3. 1. 1.  
O ver vie w  ............................................................................................... 3 4  
3. 1. 2.  
D urati o n of  t he St u d y ............................................................................ 3 4  
3. 1. 3.  
D urati o n of S u bject Parti ci pati o n  .......................................................... 3 4  
3. 1. 4.  
Pla n ne d St u d y peri o d  ............................................................................. 3 4  
3. 2.  
D isc ussi o n of St u d y Desi g n ................................................................... 3 5  
3. 2. 1.  
Selecti o n of D ose  ................................................................................... 3 5  
4.  
S T U D Y P O P U L A TI O N  ........................................................................ 3 6  
4. 1.  
I n cl usi o n Criteria  ................................................................................... 3 6  
4. 2.  
E x cl usi o n Criteria  .................................................................................. 3 9  
5.  
S T U D Y T R E A T M E N T( S)  .................................................................... 4 1  
5. 1.  
Assi g ni n g S u bjects t o Treat me nts a n d Bli n di n g  ................................... 4 1  
5. 1. 1.  
Treat me nt Gr o u p(s)/ Se q ue nces  ............................................................. 4 1  
5. 1. 2.  
Met h o d of Treat me nt All ocati o n  ........................................................... 4 1  
5. 1. 2. 1.  S u bject N u m ber Assi g n me nt  ................................................................. 4 1  
5. 1. 2. 2.  E nr oll me nt  ............................................................................................. 4 1  
5. 1. 3.  
Bli n di n g  ................................................................................................. 4 2  
5. 1. 4.  
E mer ge nc y U n b li n di n g Pr oce d ure  ........................................................ 4 2  
5. 2.  
St u d y Dr u g (s) ........................................................................................ 4 2  
5. 2. 1.  
Descri pti o n  ............................................................................................ 4 2  
5. 2. 2.  
La b eli n g a n d Pac k a gi n g  ........................................................................ 4 2  
5. 2. 3.  
Pre parati o n  ............................................................................................. 4 2  
5. 2. 4.  
A d mi nistrati o n  ....................................................................................... 4 3  
5. 2. 5.  
St ora ge  ................................................................................................... 4 3  
5. 2. 6.  
Dr u g Acc o u nta bilit y  .............................................................................. 4 3  
5. 3.  
C o ntr ol Treat me nt  ................................................................................. 4 4  
5. 4.  
D ose I nterr u pti o ns a n d Re d ucti o ns  ....................................................... 4 4  
5. 5.  
Met h o d of Assessi n g Treat me nt C o m plia nce  ........................................ 5 1  
5. 6.  
Pri or a n d C o nc o mita nt Me dicati o ns  ...................................................... 5 1  
5. 6. 1.  
C o nc o mita nt Me dicati o ns  ...................................................................... 5 1  
5. 6. 2.  
Pr o hi bite d C o nc o mita nt Me dicati o ns/ Acti vities  ................................... 5 2  
5. 7.  
S u bject Wit h dra wal/ Disc o nti n uati o n  ..................................................... 5 3  
5. 7. 1.  
Reas o ns f or Wit h dra wal fr o m St u d y Treat me nt  .................................... 5 3  
5. 7. 2.  
Reas o ns f or Wit h dra wal fr o m St u d y Partici pati o n  ................................ 5 3  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0  
5. 7. 3.  
Wit h dra wal Pr oce d ures  ......................................................................... 5 4  
5. 7. 4.  
S u bject Re place me nt  ............................................................................. 5 4  
5. 7. 5.  
S u bject Re -scree ni n g Pr oce d ures .......................................................... 5 4  
6.  
S T U D Y P R O C E D U R E S  ....................................................................... 5 5  
6. 1.  
Scree ni n g  ............................................................................................... 5 5  
6. 2.  
Ra n d o mizati o n  ....................................................................................... 5 6  
6. 3.  
Treat me nt Peri o d  ................................................................................... 5 6  
6. 3. 1.  
T u m or A ssess me nt ................................................................................ 5 6  
6. 3. 2.  
Ot her St u d y Pr oce d ure i n Treat me nt Peri o d  ......................................... 5 7  
6. 3. 2. 1.  C ycle 1, Da y 0  ....................................................................................... 5 7  
6. 3. 2. 2.  C ycle 1, Da y 1  ....................................................................................... 5 7  
6. 3. 2. 3.  C ycle 1, Da y 2  ....................................................................................... 5 9  
6. 3. 2. 4.  C ycle 1, Da y 4  ....................................................................................... 5 9  
6. 3. 2. 5.  C ycle 1, Da y 8  ....................................................................................... 6 0  
6. 3. 2. 6.  C ycle 1, Da y 1 5  ..................................................................................... 6 0  
6. 3. 2. 7.  C ycle 1, Da y 2 2  ..................................................................................... 6 0  
6. 3. 2. 8.  C ycle 2, Da y 1  ....................................................................................... 6 0  
6. 3. 2. 9.  C ycle 2, Da y 8  ....................................................................................... 6 2  
6. 3. 2. 1 0.  C ycle 2, Da y 1 5  ..................................................................................... 6 2  
6. 3. 2. 1 1.  C ycle 2, Da y 2 2  ..................................................................................... 6 2  
6. 3. 2. 1 2 . C ycle 3, Da y 1  ....................................................................................... 6 3  
6. 3. 2. 1 3.  C ycle 3, Da y 2  ....................................................................................... 6 4  
6. 3. 2. 1 4.  C ycle 3, Da y 4  ....................................................................................... 6 5  
6. 3. 2. 1 5.  C ycle 3, Da y 8  ....................................................................................... 6 5  
6. 3. 2. 1 6 . C ycle 3, Da y 1 5  ..................................................................................... 6 5  
6. 3. 2. 1 7.  C ycle 3, Da y 2 2  ..................................................................................... 6 6  
6. 3. 2. 1 8.  C ycle 4 a n d S u bse q ue nt C ycles, Da y 1  ................................................. 6 6  
6. 4.  
E n d of Treat me nt  ................................................................................... 6 7  
6. 5.  
4 0 -Da y F oll o w -u p  ................................................................................. 6 8  
6. 6.  
Ne w Ca ncer Treat me nt a n d S ur vi val F oll o w -u p  ................................... 6 9  
7.  
E F FI C A C Y A S S E S S M E N T S  ............................................................... 7 0  
7. 1.  
Assess me nts f or Effi cac y E n d p oi nt(s)  ................................................... 7 0  
7. 2.  
A p pr o priate ness of Selecte d Efficac y Assess me nt(s)  ........................... 7 0  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1  
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  . 7 1  
8. 1.  
Bl o o d Sa m pli n g  ..................................................................................... 7 1  
8. 2.  
T u m or Sa m pli n g  .................................................................................... 7 1  
8. 3.  
P har mac o ki netic ( P K) Assess me nt (s) ................................................... 7 1  
8. 4.  
P har mac o d y na mic ( P D) Assess me nt (s) ................................................ 7 3  
8. 5.  
Bi o mar ker Assess me nt(s)  ...................................................................... 7 3  
8. 5. 1.  
H E R 2 Stat us Assesse d b y Ce ntral La b orat or y  ...................................... 7 3  
8. 5. 2.  
Tr o p o ni n -T Assesse d  ............................................................................. 7 4  
8. 6.  
I m m u n o ge nicit y ( A nti-dr u g a nti b o d y)  .................................................. 7 5  
8. 7.  
S A R S -C o V -2 Ser u m sa m ples c ollecti o n  ............................................... 7 5  
8. 8.  
P har mac o ge n o mic A nal ysis  .................................................................. 7 5  
9.  
S A F E T Y E V A L U A TI O N A N D R E P O R TI N G  .................................... 7 6  
9. 1.  
Assess me nt of Safet y E n d p oi nt(s)  ......................................................... 7 6  
9. 2.  
A d verse E v e nt C ollecti o n a n d Re p orti n g  .............................................. 7 6  
9. 3.  
A d verse E v e nts of S peci al I nt erest  ........................................................ 7 7  
9. 3. 1.  
I nterstitial L u n g Disease/ P ne u m o nitis ................................................... 7 7  
9. 3. 1. 1.  I nterstitial L u n g Disease A dj u dicati o n C o m mittee ............................... 7 8  
9. 3. 2.  
L V E F Decrease  ..................................................................................... 7 8  
9. 4.  
A d verse E v e nt  ....................................................................................... 7 9  
9. 4. 1.  
Defi niti o n of A d verse E v e nt  .................................................................. 7 9  
9. 4. 2.  
Seri o us A d verse E v e nt  .......................................................................... 7 9  
9. 4. 3.  
Se verit y Assess me nt  .............................................................................. 8 0  
9. 4. 4.  
Ca usalit y Assess me nt  ............................................................................ 8 0  
9. 4. 5.  
Acti o n Ta ke n Re gar di n g St u d y Dr u g (s) ................................................ 8 1  
9. 4. 6.  
Ot her Acti o n Ta k e n f or E ve nt  ............................................................... 8 1  
9. 4. 7.  
A d verse E v e nt O utc o me  ........................................................................ 8 1  
9. 5.  
Seri o us A d verse E v e nts Re p orti n g – Pr oce d ure F or I n v esti gat ors  ......... 8 2  
9. 6.  
N otif yi n g Re g ulat or y A ut h orities, I n vesti gat ors, a n d Instit uti o nal 
R e vie w B o ar d / Et hics C o m mittee  .......................................................... 8 3  
9. 7.  
E x p os ure I n Uter o D uri n g Cli nical St u dies  ........................................... 8 3  
9. 8.  
Cli nical La b orat or y E val uati o ns  ............................................................ 8 4  
9. 9.  
Vital Si g ns  ............................................................................................. 8 5  
9. 1 0.  
Electr ocar di o gra ms  ................................................................................ 8 5  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2  
9. 1 0. 1.  Ce ntral re vie w  ....................................................................................... 8 6  
9. 1 1.  
P h ysical E x a mi nati o ns  ........................................................................... 8 6  
9. 1 2.  
Ot her E x a mi nati o ns  ............................................................................... 8 6  
1 0.  
O T H E R A S S E S S M E N T S  ..................................................................... 8 7  
1 1.  
S T A TI S TI C A L M E T H O D S  ................................................................. 8 8  
1 1. 1.  
Ge neral Statistical C o nsi derati o ns  ......................................................... 8 8  
1 1. 2.  
A nal ysis Sets  ......................................................................................... 8 8  
1 1. 2. 1.  E nr oll e d A nal ysis Set  ............................................................................ 8 8  
1 1. 2. 2.  Efficac y A nal ysis Set  ............................................................................ 8 8  
1 1. 2. 3.  Safet y A nal ysis Set  ................................................................................ 8 8  
1 1. 2. 4.  Car diac Safet y A nal ysis Set  .................................................................. 8 9  
1 1. 2. 5.  P har mac o ki netic A n al ysis Set  ............................................................... 8 9  
1 1. 2. 6.  Bi o mar ker A nal ysis Set  ......................................................................... 8 9  
1 1. 3.  
St u d y P o p ulati o n Dat a  ........................................................................... 8 9  
1 1. 4.  
Statistical A nal ysis  ................................................................................ 8 9  
1 1. 4. 1.  Pri mar y A nal yses  ................................................................................... 8 9  
1 1. 4. 1. 1.  Q Tc Pr ol o n gati o n A nal yses  ................................................................... 8 9  
1 1. 4. 1. 2.  P har mac o ki netic A n al ys es  ..................................................................... 9 0  
1 1. 4. 2.  Safet y A nal yses  ..................................................................................... 9 0  
1 1. 4. 2. 1.  A d verse E v e nt A nal yses  ........................................................................ 9 0  
1 1. 4. 2. 2.  Cli nical La b orat or y E val uati o n A nal ys es  .............................................. 9 1  
1 1. 4. 2. 3.  Vital Si g n A nal yses  ............................................................................... 9 1  
1 1. 4. 2. 4.  A nti -dr u g A nti b o dies A n al yses  ............................................................. 9 1  
1 1. 4. 2. 5.  Ot her Safet y  A nal yses  ........................................................................... 9 1  
1 1. 4. 3.  Efficac y A nal yses  .................................................................................. 9 1  
1 1. 4. 4.  P har mac o d y na mic/ Bi o mar ker A nal yses  ............................................... 9 2  
1 1. 4. 4. 1.  P har mac o d y na mic A nal yses  .................................................................. 9 2  
1 1. 4. 4. 2.  Bi o mar ker A nal yses  .............................................................................. 9 2  
1 1. 4. 4. 3.  P har mac o ge n o mic  A nal yses  .................................................................. 9 2  
1 1. 5.  
I nteri m A nal yses .................................................................................... 9 2  
1 1. 6.  
Sa m ple Size Deter mi nati o n  ................................................................... 9 2  
1 1. 7.  
Statistical A nal ysis Pr ocess  ................................................................... 9 3  
1 2.  
D A T A  IN T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  ........................ 9 4  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 3  
1 2. 1.  
M o nit ori n g a n d I ns p ecti o ns  ................................................................... 9 4  
1 2. 2.  
Data C ollecti o n  ...................................................................................... 9 4  
1 2. 3.  
Electr o nic Data Ca pt ure S yste m  ............................................................ 9 5  
1 2. 4.  
Data Ma na ge me nt  .................................................................................. 9 5  
1 2. 5.  
St u d y D oc u me ntati o n a n d St ora ge  ........................................................ 9 6  
1 2. 6.  
Rec or d Kee pi n g  ..................................................................................... 9 6  
1 3.  
FI N A N CI N G A N D IN S U R A N C E  ........................................................ 9 8  
1 3. 1.  
Fi na nces  ................................................................................................. 9 8  
1 3. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ura n ce  ........................................... 9 8  
1 4.  
P U B LI C A TI O N P O LI C Y  ..................................................................... 9 9  
1 5.  
E T HI C S A N D S T U D Y  A D MI NI S T R A TI V E  IN F O R M A TI O N  ....... 1 0 0  
1 5. 1.  
C o m plia nce State me nt, Et hics, a n d Re g ul at or y C o m plia nce  .............. 1 0 0  
1 5. 2.  
S u bject C o nfi de ntialit y  ........................................................................ 1 0 0  
1 5 . 3. 
I nf or me d C o nse nt ................................................................................ 1 0 1  
1 5. 4.  
Re g ulat or y C o m plia nce  ....................................................................... 1 0 1  
1 5. 5.  
Pr ot oc ol De viati o ns  ............................................................................. 1 0 2  
1 5. 6.  
S u p pl y of Ne w I nf or m ati o n Affecti n g t he C o n d uct of t he St u d y  ....... 1 0 2  
1 5. 7.  
Pr ot oc ol A me n d me nts  ......................................................................... 1 0 3  
1 5. 8.  
St u d y Ter mi nati o n  ............................................................................... 1 0 3  
1 5. 9.  
Data a n d Safet y M o nit ori n g B oar d  ...................................................... 1 0 3  
1 5. 1 0.  
A d dress List  ......................................................................................... 1 0 3  
1 5. 1 0. 1.  S p o ns or’s Res p o nsi ble Me dical Offi cer  .............................................. 1 0 4  
1 5. 1 0. 2.  S p o ns or’s Cli nical St u d y Lea der  ......................................................... 1 0 4  
1 5. 1 0. 3.  S p o ns or’s Safet y C o ntacts  ................................................................... 1 0 4  
1 5. 1 0. 4.  A R O  ..................................................................................................... 1 0 4  
1 5. 1 0. 5.  C R O s ................................................................................................... 1 0 4  
1 5. 1 0. 6.  I X R S Ve n d or ....................................................................................... 1 0 4  
1 5. 1 0. 7.  E D C  Ve n d or  ........................................................................................ 1 0 5  
1 5. 1 0. 8.  E D C S yste m S u p p ort  ........................................................................... 1 0 5  
1 5. 1 0. 9.  Ce ntral La b orat or y  ............................................................................... 1 0 5  
1 5. 1 0. 1 0.  Bi oa nal ytical La b orat or y ( P K a n d A D A)  ....................................... 1 0 5  
1 5. 1 0. 1 1.  E C G Ce ntral La b orat or y  ................................................................. 1 0 5  
1 5. 1 0. 1 2.  S p o ns or’s Bi ostatisticia n  ................................................................ 1 0 5  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 4  
1 5. 1 0. 1 3.  Data Safet y M o nit ori n g B oar d  ........................................................ 1 0 5  
1 5. 1 0. 1 4.  S A R S -C o V -2 Assess me nt ( R T -P C R test)  ...................................... 1 0 6  
1 6.  
R E F E R E N C E S  .................................................................................... 1 0 7  
1 7.  
A P P E N DI C E S  ..................................................................................... 1 0 9  
1 7. 1.  
C oc kcr oft -G a ult E q uati o n  ................................................................... 1 0 9  
1 7. 2.  
Easter n C o o perati ve O nc ol o g y Gr o u p Perf or ma n ce Stat us Scale  ....... 1 0 9  
1 7. 3.  
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 0  
1 7. 3. 1.  Meas ura bilit y of T u m or  at Bas eli ne  .................................................... 1 1 0  
1 7. 3. 1. 1.  Defi niti o ns  ........................................................................................... 1 1 0  
1 7. 3. 1. 2.  S pecificati o ns b y Met h o ds of Meas ure me nts  ...................................... 1 1 1  
1 7. 3. 2.  T u m or Res p o nse E val uati o n  ................................................................ 1 1 2  
1 7. 3. 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 2  
1 7. 3. 2. 2.  Baseli ne D oc u me ntati o n of “ Tar get” a n d “ N o n -t ar get ” Lesi o ns ........ 1 1 2  
1 7. 3. 2. 3.  Res p o nse Criteria  ................................................................................. 1 1 3  
1 7. 3. 2. 4.  E val uati o n of Best O verall Res p o nse  .................................................. 1 1 5  
1 7. 3. 2. 5.  Fre q u e nc y of T u m or Re -e val uati o n  ..................................................... 1 1 7  
1 7. 4.  
Ne w Y or k Heart Ass ociati o n F u ncti o nal Classificati o n  ..................... 1 1 8  
1 7. 5.  
S u p ple me nt List  ................................................................................... 1 1 8  
1 7. 6.  
I nstr u cti o ns relate d t o Se vere Ac ute Res pirat or y S y n dr o me C or o na vir us 
2 ( S A R S -C o V -2)  ................................................................................. 1 1 9  
1 7. 6. 1.  D ose m o dificati o n criteria f or s us pecte d or c o nfir me d C O VI D -1 9  .... 1 1 9  
1 7. 6. 2.  Pri or a n d C o nc o mita nt Me dicati o ns  .................................................... 1 2 0  
1 7. 6. 3.  P K Assess me nt(s) if C hl or o q ui ne or H y dr o x yc hl or o q ui ne is 
A d mi nistere d  ....................................................................................... 1 2 0  
1 7. 6. 4.  S A R S -C o V -2 Assess me nt(s)  ............................................................... 1 2 1  
1 7. 6. 5.  Statistical A nal ysis - Ass ess me nt of t he I m pact of S A R S -C o V -2  ...... 1 2 1  
1 7. 7.  
Sc he d ule of E ve nts  .............................................................................. 1 2 2  
 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 5  
LI S T O F T A B L E S  
Ta ble  1. 1:  P har mac o ki netic Para meters of D S -8 2 0 1a  ....................................... 2 8  
Ta ble  1. 2:  P har mac o ki netic Para meters of T otal A nt i-H E R 2 A nti b o d y  ........... 2 9  
Ta ble  1. 3:  P har mac o ki netic Para meters of M A A A -1 1 8 1a  ................................ 2 9  
Ta ble  5. 1:  D ose Re d ucti o n Le vels of D S -8 2 0 1a  ............................................... 4 4  
Ta ble  5. 2:  D ose or Sc he d ule M o difi cati o n f or D S -8 2 0 1 a  ................................. 4 5  
Ta ble  8. 1:  P har mac o ki netic Sa m pli n g Ti me P oi nts  ........................................... 7 1  
Ta ble  8. 2:  Sc he d ule of P K Sa m ple C ollecti o n f or S u bjects A d mi nistere d 
C hl or o q ui ne or H y dr o x yc hl or o q ui ne  ................................................ 7 3  
Ta ble  8. 3:  Tr o p o ni n Sa m pli n g Ti me P oi nts  ....................................................... 7 4  
Ta ble  8. 4:  A D A Sa m pli n g Ti me P oi nts  ............................................................. 7 5  
Ta ble  9. 1:  E C G Meas ure m e nt Ti me P oi nts  ....................................................... 8 5  
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 6  
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 1 6  
Ta ble  1 7. 3:  S A R S -C o V -2 D ose M o dificati o n Criteria  ...................................... 1 2 0  
Ta ble  1 7. 4 : Sc he d ule of E ve nts  ......................................................................... 1 2 3  
 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 6  
LI S T O F FI G U R E S  
Fi g ure  5. 1:  Pr ocess f or S u bject N u m ber Assi g n me nt a n d E nr oll me nt  ............... 4 2  
 
 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 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 C  
A dj u dicati o n C o m mittee  
A D A  
a nti-dr u g a nti b o d y  
A D C  
a nti b o d y-dr u g c o nj u gate  
A E  
a d verse e ve nt 
A 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 
C B R  
cli nical b e nefit rati o 
C H F  
c o n gesti ve heart fail ure  
CI  
c o nfi de nce inter val  
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 T  
c o m p ute d  t o m o gra p h y 
C Y P  
cyt oc hr o me P 4 5 0  
D C R  
d isease c o ntr ol rate 
DI S H  
d ual i n sit u h y bri dizati o n  
D N A  
de o x yri b o n ucleic aci d  
D o R  
d urati o n of res p o nse 
E C  
 E t hics C o m mittee  
E C G  
electr ocar di o gra m  
E C H O  
ec h ocar di o gra m 
E C O G  P S   
Easter n C o o perati ve O nc ol o g y Gr o u p  perf or ma nce stat us  
e C R F 
electr o nic  case re p ort f or m 
E D C  
electr o nic data ca pt ure  
EI U  
e x p os ure i n uter o 
E OI  
e n d of i nf usi o n  
E O T  
e n d of treat me nt  
FI S H  
fl u oresce nt i n sit u h y bri dizati o n 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 8  
A B B R E VI A TI O N  
D E FI NI TI O N  
F/ U  
f oll o w-u p  
G C P  
G o o d Cli nical Practice  
G EJ  
gastr oes o p ha geal j u ncti o n  
H b  
h e m o gl o bi n 
H E R 2  
h u ma n e pi der mal gr o wt h fact or rece pt or 2  
h E R G  
h u ma n et her -a-g o -g o -relate d ge ne 
HI V  
h u ma n  i m m u n o deficie nc y vir us 
H R T  
h or m o ne re place me nt t hera p y  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil  f or Har m o nisati o n  
I 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 
inter nati o nal n o n -pr o prietar y n a me 
I R B 
Instit uti o nal R e vie w B oar d  
I S H 
i n sit u h y bri dizati o n 
I V 
i ntra ve n o us 
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 
I X R S 
i nteracti ve we b/ v oice res p o nse s yste m 
L V E F  
left ve ntric ular ejecti o n fracti o n 
Me d D R A   
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M H L W  
Mi nistr y of Healt h, La b o ur a n d Welfare  
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 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 T er mi n ol o g y Criteria f or 
A d verse E ve nt  
N E  
n ot e val ua ble  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 9  
A B B R E VI A TI O N  
D E FI NI TI O N  
N R U  
ne utral re d u pta ke  
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 bj ecti 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 D  
pr o gressi ve disease  
P F S  
P r 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  
P T  
Preferre d T er m  
Q 3 W  
o nce e ver y 3 wee ks  
Q T c  i nter val  
c orrecte d Q T i nter val  
Q T c F i nter val   
c orrecte d Q T i nter val b y Fri dericia's f or m ula  
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 T -P C R   
re verse tra nscri pti o n p ol y merase c hai n reacti o n 
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S A R S -C o V -2   
se vere ac ute res pirat or y s y n dr o me c or o na vir us 2, ie C O VI D -1 9  
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 M Q  
Sta n dar dise d Me d D R A Q uer y  
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 p O 2 
peri p heral o x y ge n sat urati o n  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse e ve nt reacti o n 
S D  
sta n dar d de viati o n 
T B L  
total bilir u bi n  
T -D M 1  
trast uz u ma b e mta nsi ne 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 0  
A B B R E VI A TI O N  
D E FI NI TI O N  
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  
W H O D R U G   
W orl d Healt h Or ga nizati o n Dr u g Refere nce  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 1  
LI S T O F P H A R M A C O KI N E TI C P A R A M E T E R S  
P A R A M E T E R  
D E FI NI TI O N  
A U C  
area u n der t he plas ma /ser u m c o nce ntrati o n-ti me c ur ve 
A U C 2 1 d 
area u n der t he plas ma /ser u m c o nce ntrati o n-ti me c ur ve fr o m t he 
ti me of d osi n g t o 2 1 da y 
A U Ci nf  
area u n der t he plas ma /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 plas ma 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  
area u n der t he plas ma /ser u m c o nce ntrati o n -ti me c ur ve 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 plas ma /ser u m c o nce ntrati o n  
Ctr o u g h  
tr o u g h plas ma /ser u m c o nce ntrati o n  
T ma x  
ti me t o reac h ma xi m u m plas ma /ser u m c o nce ntrati o n 
t1/ 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  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 2  
LI S T O F D E FI NI TI O N S O F T E R M S  
T E R M  
D E FI NI TI O N  
M A A A -1 1 8 1 a 
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, free f or m 
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 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 3  
1.   
I N T R O D U C TI O N 
1. 1.   
B ac k gr o u n d  
H u ma n e pi der mal gr o wt h fact or  rece pt or 2 ( H E R 2) is a me m ber of t h e H E R s u perfa mil y 
t hat 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 n cer,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 we e 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 m al 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 the 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 nit e d States f or 
t he i n dicati o n of H E R 2 o vere x pressi n g breast ca n cer 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 ( G EJ) 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 c a ncer a n d H E R 2 p ositi ve metastatic a de n o carci n o ma of 
t he st o mac h or G EJ ,1 2 a n d i n J a 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 n ce d/rec urre nt gastri c  ca n cer.1 3  T rast uz u ma b 
e mta nsi ne (T -D M 1 ) is a n a nti b o d y-dr u g c o nj u gate ( 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 h e i n dicati o n of H E R 2-p ositi ve u nresecta ble l o call y a d v a nce d or 
metastatic breast ca ncer ,1 5 a n d i n J a pa n f or H E R 2 -p ositi ve u nresecta ble or a d va nce d 
breast c a ncer .1 6 
D S -8 2 0 1a is  a n A D C  tar geti n g H E R 2.  D S-8 2 0 1 a is c urre ntl y u n der i n vesti gati o n i n a 
t w o-part P hase 1 st u d y ( D S 8 2 0 1-A -J 1 0 1): Part 1 is t he d ose escalati o n st u d y i n patie nts 
wit h eit her a d va n ce d breast ca ncer or gastric/ G EJ  a de n ocarci n o ma.  Part 2 is t he 
e x pa nsi o n p hase  a n d f oc uses o n H E R 2 -e x pressi n g breast a n d gastric/ G EJ  
a de n ocarci n o ma, as well as ot her H E R 2 -e x pressi n g s oli d t u m ors.  
1. 1. 1.   
St u d y Dr u g  
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 c o nsists of a n a nti b o d y c o m p o n e nt, M A A L -9 0 0 1, c o v ale ntl y c o nj u gate d vi a a 
malei mi de tetra pe p ti de li n ker, t o a dr u g c o m p o ne nt M A A A-1 1 8 1 a.  M A A L-9 0 0 1 is a n 
i n-h o use 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 h a vi n g t he sa me 
a mi n o aci d se q ue n ce as trast uz u ma b.  M A A A -1 1 8 1 a, a n e x ateca n deri vati ve,1 7 ,1 8 ,1 9 is a 
t o p ois o merase I i n hi bit or, cell-me m bra n e per mea ble, a n d m ore p ote nt t ha n S N -3 8 (acti ve 
meta b olite of iri n oteca n).  T his A D C ac hie ves a hi g h dr u g -t o-a nti b o d y rati o ( 7 t o 8) wit h 
h o m o ge n e o us c o nj u gati o n wit h M A A A -1 1 8 1 a.2 0  D S -8 2 0 1a is clea v e d b y l ys os o mal 
e nz y mes a n d releases M A A A -1 1 8 1 a i n t he c yt o plas m after it bi n ds t o H E R 2 rece pt or a n d 
gets i nter n alize d i n t u m or c ells.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 4  
1. 1. 1. 3.  
N o ncli nic al St u dies  
1. 1. 1. 3. 1.  P h ar m a c ol o g y  
D S -8 2 0 1a i n hi bits t u m or gr o wt h b y m ai nl y t o p ois o merase I i n hi biti o n -deri ve d D N A 
da ma ge a n d a p o pt osis b y t he M A A A -1 1 8 1 a t h at is releas e d fr o m D S-8 2 0 1 a after 
i nter nalizati o n i n ca ncer cells via H E R 2.  I n vitr o n o ncli nical p har mac ol o g y st u dies ha v e 
c o nfir me d 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, 
a n d i n vi v o st u dies usi n g t u m or -beari n g m o use  m o dels s u g gest t hat t he a d mi nistrati o n of 
D S -8 2 0 1a res ults i n t he re gressi o n of a br oa d arra y of H E R 2 -e x pressi n g t u m ors, 
i ncl u di n g m ulti ple m o dels u nres p o nsi ve t o T-D M 1.  I n a d diti o n, i n vi v o st u dies i n t u m or -
beari n g m o use m o dels ha ve c o nfir me d t h at D S -8 2 0 1a has a ntit u m or acti vit y e v e n a gai nst 
H E R 2 l o w -e x pressi n g t u m ors w hic h are i nse nsiti ve t o T -D M 1.  D S -8 2 0 1a is t heref ore 
e x pecte d t o be effecti ve a gai nst H E R 2 l o w -e x pressi n g t u m ors w hic h are i ns e nsiti ve t o T -
D M 1, a n d is als o e x pecte d t o be effecti ve a gai n st T-D M 1 -i nse nsiti ve t u m ors wit h H E R 2 
hi g h -e x pressi n g a n d H E R 2 l o w -e x pressi n g t u m ors f or w hic h T -D M 1 has n ot bee n 
a p pr o ve d. M ore o ver, D S -8 2 0 1a de m o nstrate d p ot e nt efficac y  i n mice i n oc ulate d wit h a 
mi xt ure of H E R 2 -p ositi ve a n d -ne gati ve cells w hile T -D M 1 d i d n ot, d ue t o m ore p ote nt 
b ysta n der killi n g effect a n d hi g her cell me m bra ne per mea bilit y of t he c o nj u gat e d t o xi n.   
T he effect t heref ore s u p p orts t he efficac y of D S -8 2 0 1a a gai nst t u m ors wit h H E R 2 
heter o ge n eit y.  
1. 1. 1. 3. 2.  S afet y P h ar m ac ol o g y  
I n a safet y p h ar mac ol o g y st u d y i n m o n ke ys treat e d wit h si n gle i ntra ve n o us (I V) d oses of 
D S -8 2 0 1a, n o effects o n t he car di o vas c ular s yste m, t he res pirat or y s yste m, or t he ce ntral 
ner v o us s yst e m were o bs er ve d u n der t he st u d y c o n diti o n.  I n a d diti o n, i n h u ma n et her -a-
g o -g o -relat e d gene (h E R G ) st u dies of M A A A-1 1 8 1 a, t he dr u g c o m p o ne nt, M A A A-1 1 8 1 a 
di d n ot i n hi bit t he h E R G c ha n nel c urre nt.  
1. 1. 1. 3. 3.  P h ar m a c 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 V 
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 h e Vss  
was cl ose t o t he plas ma v ol u me.  T he C L d ecrease d as t he d ose i ncrease d, a n d t he 
p har mac o ki netics ( P K) were f o u n d t o b e n o n -li near.  B ot h D S-8 2 0 1a a n d t h e t otal a nti-
H E R 2 a nti b o d y , b o u n d a n d u n b o u n d a ntib o d y c o m bi ne d, e x hi bite d si milar plas ma 
c o nce ntr ati 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 a, t he release d dr u g fr o m D S-8 2 0 1 a, were b el 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 a was d etecte 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 a 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 a 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 pl as ma wit h t he releas e rat es fr o m 1. 2 % t o 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 5  
3. 9 % o n Da y 2 1.  O n t he ot her ha n d, t he releas e rate reac he d a pl atea 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 m eta 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 p at oc yt es.  M A A A -1 1 8 1 a was meta b olize d b y  c yt o c hr o me P 4 5 0  
(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 m e 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 n ce ntrati o n ti me pr ofiles f oll o wi n g re peat e d a d mi nistrati o n of D S -8 2 0 1a 
o nce e v er y 3 wee ks (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 K  of D S -8 2 0 1a i n c y n o m ol g us m o n k e ys.  T h ese est i 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 os e 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. 3. 4.  T o xic ol o g y  
I n a st u d y of i nter mitte nt I V 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 m als 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 v els of 6 0 m g/ k g a n d great er.  E x ce 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. 
In a n i nter mitte nt I V d osi n g st u d y of D S -8 2 0 1 a i n c y n o m ol g us m o n ke ys ( Q 3 W, 6 
wee ks), o ne fe mal e was s acrifice d m ori b u n d at 7 8. 8 m g/ k g, t he hi g hest d os e 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 yst e m, s ki n, a n d ki d ne y.  T he ca us e of t he m ori b u n dit y a p p eare d t o b e t he 
deteri orat e 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 xi cit y i n t he s ur vi vi n g a ni mals w ere o bs er 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 m at o p oietic s yste m t o xicit y, re nal t o xicit y, a n d electr ocar di o gra m  
(E C G ) a b n or m alities (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 x ce 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 b e d a b o ve, t he se verel y t o xic d ose i n 1 0 % of t he a ni ma ls i n a rat 
i nter mitte nt I V 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 d e 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 hi g hest n o n -s e verel y t o xic d ose is 3 0 m g/ k g.  
I n a n i nter mitte nt I V d os e t o xicit y st u d y of M A A A -1 1 8 1 a (o n ce wee kl y  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 bs er 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 bs er 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 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 6  
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 n erati 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 v e 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 xi cit y, a n d 
i ntesti nal t o xicit y.  T h ese c ha n ges were c o nsi dere d t o be t he ca use of t he d eat 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 a 
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 n al 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 a 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 st ai 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 y t o pl as 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 ne utral re d u pta ke ( N R U)  p h ot ot o xicit y st u d y, M A A A -1 1 8 1 a 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 a in 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 h e hi g h est d ose teste d.  
F or a d diti o nal n o ncli nical data s u p p orti n g D S -8 2 0 1a use i n n o ncli nical st u dies, please 
refer t o t he c urre nt I n v esti gat or’s Br oc h ure (I B). 
1. 1. 1. 4.  
Cli nic al St u d y  
1. 1. 1. 4. 1.  Cli nic al E x perie nce  
T he D S -8 2 0 1a first -i n-h u ma n st u d y ( D S 8 2 0 1 -A -J 1 0 1) is a n o pe n-la bel, d ose fi n di n g 
st u d y t o assess t he safet y a n d t olera bilit y of D S-8 2 0 1a i n s u bjects wit h a d v a nce d s oli d 
t u m ors.  T he st u d y is bei n g c o n d u cte d i n 2 parts; d ose escal ati o n ( Part 1) an d d ose 
e x pa nsi o n ( Part 2): Part 1 was a d ose escalati o n p h ase i n patie nts wit h eit her a d va nce d 
breast c a ncer or gastri c/ G EJ  a de n ocarci n o ma.  P art 2 is t he e x pa nsi o n p hase a n d f oc us es 
o n H E R 2 e x pressi n g breast ( pre vi o usl y treat e d T -D M 1 H E R 2 p ositi ve breas t ca ncer) a n d 
gastri c/ G EJ j u ncti o n a de n ocarci n o ma, as well as ot her H E R 2 e x pressi n g s oli d ca ncers.  
Preli mi nar y res ults fr o m Part 1 i n dicate t hat D S -8 2 0 1a has a fa v ora ble safet y a n d P K 
pr ofile a n d r o b ust a ntit u m or acti vit y i n breast ca n cer patie nts, wit h t u m ors t hat were 
pre vi o usl y tr eate d wit h T -D M 1.   A d verse e ve nts of s pecial i nterest detaile d i n t he P hase 1 
st u d y ( D S 8 2 0 1-A -J 1 0 1) i ncl u de d i nf usi o n reacti o ns, car diac e ve nts, a n d p ne u m o nitis.  
Peri o dic car di ac ass ess me nts are p erf or me d i ncl u di n g ec h ocar di o gra m (E C H O ) or 
m ulti gate d ac q uisiti o n  (M U G A ) perf or me d at e ver y 2 c ycl es ( 4 2 da ys) a n d 1 2 -lea d 
tri plicate E C Gs perf or me d at least e ver y c ycle ( 2 1 da ys).   
As of 0 8 J u n 2 0 1 7,  a t otal of 1 4 8 s u bjects, 2 4 i n Part 1 a n d 1 2 4 i n Part 2, ha ve recei ve d 
D S -8 2 0 1a i n t his st u d y.  I n Part 1, n o d ose li miti n g t o xicities were re p orte d a n d t he 
ma xi m u m t olerate d d ose (M T D ) was n ot reac he d.  T w o d oses were c h os e n f or e x pa nsi o n 
i n Part 2: 5. 4 m g/ k g a n d 6. 4 m g/ k g.   


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 7  
F or 1 4 8 s u bjects w h o h a ve recei ve d D S -8 2 0 1 a i n t he  st u d y, t he m ost c o m m o n A Es 
( > 2 0 %) of a n y gra des w ere na usea ( 6 5 %), decrease d a p petite ( 5 3 %), v o miti n g ( 3 4 %), 
platelet c o u nt decreas e d ( 3 1 %), a ne mia ( 2 8 %), al o pecia ( 2 6 %), diarr hea ( 2 4 %), 
c o nsti pati o n ( 2 4 %), ne utr o p hil c o u nt decrease d ( 2 4 %), w hite bl o o d ce ll c o u nt decrease d 
( 2 4 %), a n d m alaise ( 2 2 %).  T he maj orit y of t he A Es were of Gra de 1 or 2 s e verit y; 5 2 
( 3 5. 1 %) of 1 4 8 s u bjects e x perie nce d Gra de 3 A Es a n d 1 0 s u bjects ( 6. 8 %) e x perie nce d 
Gra de 4 A Es as t he w orst gra de e x perie n ce d.   A t otal of 3 s u bjects di e d d ue t o a n A E; 1 
d ue t o mec ha nical ile us, 1 d ue t o e xtra d ural he mat o ma/tra u matic i ntracra ni al 
hae m orr h a ge occ urri n g m ore t ha n 2 8 da ys after last d ose of st u d y dr u g, a n d 1 d ue t o 
disease pr o gressi o n re p orte d as a n A E.  All t hese fatal e ve nts were c o nsi der e d n ot relate d 
t o st u d y dr u g b y t he I n v esti gat ors. 
As of 0 8 J u n 2 0 1 7 , 1 3 (8. 7 % ) of 1 4 8 s u bjects e x perie nce d treat me nt-e mer ge nt a d verse 
e ve nts ( T E A Es)  relati n g t o car di ot o xicit y i n t he o n-g oi n g st u d y.  Of t h ese 1 3 s u bjects, 9 
e x perie nce d Q T pr ol o n gati o n ( 7 Gra de 1 a n d 2 Gra de 2, all n o n -seri o us), all c o nsi dere d 
relate d t o t he st u d y t hera p y. T w o s u bjects e x perie nce d ejecti o n fracti o n decreas e d ( Gra de 
2, n o n -seri o us, rel ate d), 1 s u bject e x perie nce d Gra de 2 tac h ycar dia a n d 1 s u bject 
e x perie nce d heart rate decreas e d (relate d).  N o acti o n was ta ke n re gar di n g t he st u d y dr u g 
t hera p y a n d n o s u bjects disc o nti n ue d st u d y t hera p y.   
Irres p ecti ve of t he I n vesti gat or/s p o ns or ca usalit y, of t he 1 4 8 treat e d s u bjects, t here were 3 
s u bjects ( w here o ne recei ve d 8. 0 m g/ k g a n d t h e ot her 2 recei ve d 6. 4 m g/ k g) w h o ha d 
e x perie nce d o ne s eri o us a n d 2 n o n -seri o us p ne u m o nitis ( o ne was Gra d e 1 a n d t he ot her as 
Gra de 2).   T here were al s o 2 s u bjects w h o e x perie nce d i nterstitial l u n g disease ( 1 seri o us 
a n d Gra d e 3 i n se verit y, a n d t he ot her n o n -s eri o us; wit h Gra de 1 se v erit y).   
Of t he 1 4 8 s u bjects, a t ot al of 2 s u bjects ( 1. 4 %) e x perie nce d i nf usi o n relat e d reacti o ns 
( b ot h Gra de 1, n o n -seri o us) a n d 1 s u bject e x perie nce d i nf usi o n site e xtra vasati o n ( Gra d e 
1, n o n -seri o us).  St u d y dr u g a d mi nistrati o n was i nt err u pte d f or 1 of 3 re p orte d e ve nts.  
T he  o utc o me was re p ort e d as res ol ve d i n all s u bjects.  
O verall efficac y res ults fr o m all c o h orts i n P art 1 de m o nstrate d a n o bjecti ve res p o nse rate 
( O R R) of 3 4. 8 % a n d disease c o ntr ol rate ( D C R) of 9 1. 3 %.  S u bjects i n t he hi g her d ose 
le vels ( ≥5. 4 m g/ k g, 1 5 s u bjects) s h o we d O R R of 5 3. 3 %.  O verall efficac y res ults fr o m all 
c o h orts i n Part 2 de m o nstrate d a n O R R of 4 8. 8 % a n d D C R of 8 5. 7 %.  Breast ca ncer 
c o h orts wit h H E R 2 p ositi ve a n d l o w e x pressi o n, Part 2a a n d 2 c, s h o we d O R R of 6 1. 5 % 
a n d 5 0. 0 %, a n d D C R of 9 6. 2 % a n d 9 0. 0 % res pecti vel y.  T he H E R 2 p ositi ve gastric 
ca ncer c o h ort s h o we d O R R of 4 8. 4 % a n d D C R of 8 0. 6 % . 
Please refer t o t he c urre nt I B f or a d diti o nal i nf or m ati o n.  
1. 1. 1. 4. 2.  S u m m ar y of Cli nic al P h ar m a c o ki netics  
As of 0 8 J u n 2 0 1 7, p reli mi nar y P K data are a v aila ble fr o m t he 2 4 s u bjects i n t he 0. 8 
m g/ k g t o 8. 0  m g/ k g c o h orts i n Part  1.   T he P K para meters of D S -8 2 0 1 a  are s h o w n i n  
Ta ble  1 .1 , Ta ble  1 .2  a n d Ta ble  1 .3 .  F oll o wi n g a si n gle I V a d mi nistrati o n of D S -8 2 0 1a at 
6. 4 m g/ k g, pea k s er u m c o nce ntrati o n ( C ma x) of D S -8 2 0 1a was ac hie ve d wit h a me dia n 
T ma x of 2. 1 6 h a n d mea n t1/ 2 of 7. 3 3 da ys.  T he Vss  f or D S-8 2 0 1a was a p pr o xi matel y 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 8  
4 5  m L/ k g t o 7 0  m L/ k g (a p pr o xi mati n g plas ma/ser u m v ol u me), s u g gesti n g t hat D S -8 2 0 1a 
is pri maril y li mite d t o t he vasc ular c o m part me nt. 
T he t otal a nti-H E R 2 a nti b o d y pr ofile is si milar t o t he P K  pr ofile f or D S -8 2 0 1a, a n d t he 
P K para meters of t otal a nti b o d y were c o m para ble t o t h ose of D S -8 2 0 1a.  
Ser u m M A A A -1 1 8 1a c o nce ntr ati o ns gra d u all y i n creas e d a n d reac he d pea k 
c o nce ntr ati o ns wit h l o n ger T ma x ( 6  h t o  7  h, me dia n T ma x) c o m pare d t o t h ose f or D S -
8 2 0 1a.  T he s yste mic e x p os ure ( C ma x a n d A U Cs as re p orte d i n n g/ m L a n d n g ·da y/ m L, 
res pecti vel y) t o M A A A-1 1 8 1a was m uc h l o wer t ha n t hat of D S-8 2 0 1a (as re p orte d i n 
μ g/ m L a n d μ g ·da y/ m L, res pecti vel y), w h ere D S -8 2 0 1a e x p os ure was > 1 0, 0 0 0 -f ol d t o t hat 
of M A A A -1 1 8 1 a.  T he eli mi nati o n ( t1/ 2) a p peare d t o be si milar t o t hat of D S-8 2 0 1a.  T his 
reflects t he i ntri nsic sta bilit y of t he li n ker w he n D S -8 2 0 1a is i n circ ulati o n s yste micall y.  
T a ble  1 .1 :  
P h ar m a c o ki netic P ar a meters of D S -8 2 0 1 a  
 
C m a x  
(g/ m L)  
T m a x a 
( h) 
A U Cl ast  
(g d/ m L)  
A U Ci nf  
(g d/ m L)  
t1/ 2 
( d a y) 
C L  
( m L/ d/ k g) 
Vss  
( m L/ k g) 
0. 8 m g/ k g 
( N = 3) 
2 2. 9  
( 3. 7 6) 
1. 9 2  
( 1. 6 8, 
1. 9 2)  
5 1. 7  
( 1 3. 1) 
5 5. 0  
( 1 1. 9) 
2. 1 8  
( 0. 6 7 1) 
1 5. 0  
( 2. 8 9) 
4 5. 0  
( 8. 9 6) 
1. 6 m g/ k g 
( N = 3) 
3 6. 2  
( 4. 9 8) 
4. 0 8  
( 1. 9 2, 
4. 0 8)  
1 1 6  
( 5 8. 7) 
1 2 1  
( 5 8. 9) 
3. 0 7  
( 1. 2 2) 
1 6. 1  
( 9. 2 7) 
5 8. 3  
 ( 1 0. 0) 
3. 2 m g/ k g  
( N = 3)  
7 8. 2  
( 1 6. 1) 
4. 0 8  
( 1. 9 2, 
6. 9 6)  
3 2 5  
( 1 4 2) 
3 4 0  
( 1 5 0) 
4. 2 3  
( 1. 2 4) 
1 1. 3  
( 6. 5 2) 
5 6. 8  
 ( 1 4. 4) 
5. 4 m g/ k g  
( N = 6) 
1 2 7  
( 1 7. 2) 
1. 9 2  
( 1. 9 2, 
2. 1 6)  
5 4 4  
( 1 6 5) 
5 9 0  
( 1 8 6) 
6. 0 3  
( 0. 6 0 3) 
1 0. 1  
( 3. 9 0) 
7 5. 2  
 ( 2 4.2 ) 
6. 4 m g/ k g  
( N = 6) 
1 8 1  
( 3 3. 1) 
2. 1 6  
( 1. 4 4, 
4. 0 8)  
9 0 1  
( 1 5 5) 
1 0 3 0  
( 2 0 9) 
7. 3 3  
( 1. 6 4) 
6. 4 1  
( 1. 1 2) 
5 8. 6  
 ( 1 1. 0) 
8. 0 m g/ k g  
( N = 3) 
2 1 6  
( 5 2. 0) 
1. 9 2  
( 1. 9 2, 
2. 1 6)  
9 1 4  
( 2 3 5) 
1 0 2 0  
( 2 7 9) 
6. 9 7  
( 0. 3 5 7) 
8. 1 7  
( 1. 9 3) 
6 9. 7  
( 1 3. 1) 
Mea n ( S D)  
a: T ma x re p orte d as me dia n ( mi n, ma x)  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 2 9  
T a ble  1 .2 :  
P h ar m a c o ki netic P ar a meters of T ot al A nti -H E R 2 A nti b o d y  
 
C m a x  
(g/ m L)  
T m a x a 
( h) 
A U Cl ast  
(g d/ m L)  
A U Ci nf  
(g d/ m L)  
t1/ 2 
( d a y) 
0. 8 m g/ k g 
( N = 3) 
1 9. 3  
( 4. 3 0) 
1. 6 8  
( 1. 6 8, 1. 9 2) 
8 3. 8  
( 7 3. 4) 
9 3. 5  
( 8 2. 1) 
3. 4 9  
( 2. 5 1) 
1. 6 m g/ k g 
( N = 3) 
4 1. 2  
( 1 2. 7) 
1. 9 2  
( 1. 6 8, 4. 0 8) 
2 0 0  
( 1 9 1) 
2 2 7  
( 2 2 5) 
4. 3 5  
( 2. 7 7) 
3. 2 m g/ k g  
( N = 3) 
6 7. 5  
 ( 1 3. 8) 
4. 0 8  
( 4. 0 8, 6. 9 6) 
3 0 2  
( 9 7. 8) 
3 1 3  
( 1 0 2) 
3. 9 3  
( 0. 8 6 3) 
5. 4 m g/ k g  
( N = 6) 
1 1 6  
 ( 1 3. 9) 
1. 9 2  
( 1. 9 2, 6. 9 6) 
6 0 9  
( 1 5 1) 
6 8 2  
( 1 7 2) 
6. 7 8  
( 2. 3 9) 
6. 4 m g/ k g  
( N = 6) 
1 4 6  
 ( 1 8. 9) 
3. 8 4  
( 2. 1 6, 6. 9 6) 
8 7 8  
( 9 7. 1) 
1 0 5 0  
( 1 4 9) 
8. 2 5  
( 2. 1 6) 
8. 0 m g/ k g  
( N = 3) 
1 7 8  
 ( 1 8. 5) 
2. 1 6  
( 1. 9 2, 6. 7 2) 
1 0 9 0  
( 2 1 3) 
1 2 7 0  
( 2 9 6) 
7. 3 5  
( 0. 4 1 7) 
Mea n ( S D)  
a: T ma x re p orte d as me dia n ( mi n, ma x)  
 
T a ble  1 .3 :  
P h ar m a c o ki netic P ar a meters of M A A A -1 1 8 1 a  
 
C m a x  
( n g/ m L) 
T m a x a 
( h) 
A U Cl ast  
( n gd/ m L)  
A U Ci nf  
( n gd/ m L)  
t1/ 2 
( d a y) 
0. 8 m g/ k g 
( N = 3) 
1. 1 7  
( 0. 7 5 7) 
6. 7 2  
( 6. 7 2, 2 2. 3 2) 
4. 8 4  
( 1. 8 9) 
4. 8 9  
( 1. 8 9) 
2. 5 0  
( 0. 5 7 9) 
1. 6 m g/ k g 
( N = 3) 
1. 7 2  
( 0. 1 9 3) 
6. 9 6  
( 6. 7 2, 2 4. 0 0) 
8. 5 3  
( 2. 1 5) 
8. 7 6  
( 2. 3 4) 
3. 4 8  
 ( 1. 0 9) 
3. 2 m g/ k g  
( N = 3) 
5. 6 9  
 ( 0. 5 3 0) 
6. 9 6  
( 4. 0 8, 6. 9 6) 
2 4. 0  
( 7. 5 8) 
2 4. 9  
( 7. 9 8) 
4. 6 8  
 ( 0. 9 6 9) 
5. 4 m g/ k g  
( N = 6) 
1 0. 8  
 ( 7. 5 6) 
5. 2 8  
( 3. 8 4, 2 3. 7 6)  
4 0. 6  
( 1 9. 8) 
4 3. 6  
( 2 1. 2) 
6. 1 1  
 ( 0. 8 1 1) 
6. 4 m g/ k g  
( N = 6) 
6. 8 0  
( 1. 7 2) 
6. 7 2  
( 4. 0 8, 7. 2 0) 
3 1. 0  
( 5. 1 1) 
3 4. 2  
( 5. 6 3) 
6. 2 8  
 ( 1. 1 7) 
8. 0 m g/ k g  
( N = 3) 
9. 2 5  
( 3. 1 8) 
6. 7 2  
( 6. 7 2, 6. 9 6) 
3 9. 4  
( 6. 4 3) 
4 3. 4  
( 9. 1 6) 
6. 3 6  
 ( 1. 5 3) 
Mea n ( S D)  
a: T ma x re p orte d as me dia n ( mi n, ma x) 
1. 2.   
St u d y R ati o n ale  
D S -8 2 0 1a is a n A D C t hat tar gets H E R 2.  A h u ma nize d I g G 1 m o n ocl o nal a nti b o d y wit h 
refere nce t o t he a mi n o aci d se q ue nce of trast uz u ma b is use d as t he a nti b o d y c o m p o n e nt 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 0  
a n d a deri v ati ve of e x ateca n, a t o p ois o merase I i n hi bit or, is use d as t he dr u g c o m p o n e nt .  
T he res ults of n o ncli nical st u dies ha ve n ot i n dicate d a n effect of D S -8 2 0 1 a  o n car diac 
ve ntric ular  re p olarizati o n. 
T he detaile d st u d y of dr u g -i n d uce d car diac arr h yt h mias is a d dresse d i n t he c urre nt I C H-
E 1 4 g ui deli nes, w hi c h rec o m me n d e val uati o n of t he effect of n o n-a ntiarr h yt h mic dr u gs i n 
cli nical de vel o p me nt o n Q T i nter vals a n d Q Tc.   T his g ui da nce has bee n pr o vi de d d ue t o 
t he p ote ntiall y fatal c o m plicati o n of t orsa des de p oi ntes res ulti n g fr o m pr ol o n gati o n of 
t he Q T i nter val, a n effect see n i n a wi de variet y of dr u gs.  I n t his st u d y, Q T pr ol o n gati o n 
will be assesse d i n breast ca ncer patie nts  bas e d o n t he I C H-E 1 4 g ui da nce b eca use D S -
8 2 0 1 a is a n a nti-ca ncer dr u g a n d ca n n ot b e st u die d i n healt h y v ol u nteer d ue t o t he 
p ossi bilit y t hat M A A A-1 1 8 1 a has ge n ot o xicit y.  
I n t he P h ase 1 st u d y ( D S 8 2 0 1-A -J 1 0 1), P K  para m eters after si n gle d osi n g were assesse d  
b ut n ot t h ose after m ulti ple d osi n g .  The p ea k plas ma c o nce ntrati o ns of D S -8 2 0 1a a n d 
M A A A -1 1 8 1 a were o bser ve d at a p pr o xi matel y 1. 4 4  h t o 4. 0 8  h  a n d 3. 8 4  h t o 2 3. 7 6  h  
after si n gle d ose, res pecti vel y  (see Secti o n 1. 1. 1. 4. 2 ).  E x p os ure of M A A A-1 1 8 1 a, t he 
dr u g c o m p o ne nt of D S -8 2 0 1a, was q uite l o w a n d t1/ 2 of M A A A -1 1 8 1 a was si milar t o t hat 
of D S -8 2 0 1a  (see Secti o n  1. 1. 1. 4. 2 ).  I n t his st u d y, P K para meters after m ulti ple d osi n g 
will be assesse d , th o u g h t he C ma x will be s o me differe nt  bet wee n C ycle 1 a n d 
s u bse q ue nt c ycles d u e t o t he differe nce of i nf usi o n rate.   
1. 3.   
Ris ks a n d Be nefits f or St u d y S u bjects  
O ne st u d y (D S 8 2 0 1 -A -J 1 0 1) wit h D S -8 2 0 1a is c urre ntl y o n g oi n g.  D S 8 2 0 1 -A -J 1 0 1 is a 
t w o-part P hase 1 trial e x pl ori n g t he d ose a n d safet y/efficac y pr ofile of D S -8 2 0 1a (see 
Secti o n  1. 1. 1. 4 ). 
O verall, t he re p orte d a d v erse e v e nts ( A Es)  were c o nsiste nt wit h t he safet y pr ofile of D S -
8 2 0 1a e x pecte d base d o n t he n o ncli nical t o xic ol o g y dat a  (see Secti o n  1. 1. 1. 4. 1 ).  S u bjects 
recei vi n g D S-8 2 0 1 a s h o ul d be m o nit ore d f or si g ns a n d s y m pt o ms of a n y of t he t o xicities 
o bser ve d i n n o ncli nical st u dies a n d t o ot her pr o d u cts of t he sa me cl ass w hic h is disc usse d 
b el o w.   
I n n o n cli nical t o xic ol o g y st u dies, i ntesti nal, he mat o p oietic, p ul m o nar y (i nterstitial 
i nfla m mati o n a n d/ or al ve olar e de ma), testic ular, s ki n ( p h ot ot o xicit y), a n d re nal t o xicities 
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.  O p ht ha l m ol o gic safet y 
m o nit ori n g, w hic h i ncl u d es vis ual ac uit y, slit la m p e xa m, a n d f u n d osc o p y will als o be 
part of t he o verall e val u ati o n.  T hese assess me nts will be perf or me d at baseli ne a n d 
s pecific i nter vals descri b e d wit hi n t he pr ot oc ol a n d at t he e n d of treat me nt ( E O T), w he n 
a n a d diti o nal e x a m will als o be perf or me d.  I n a d diti o n, at t he discreti o n of t he 
I n v esti gat or, o p ht hal m ol o gic testi n g ca n be perf or me d at a n y ti me d uri n g t he st u d y. 
As of 0 8 J u n 2 0 1 7, 1 3 ( 8. 7 %) of 1 4 8 s u bjects e x perie nce d T E A Es rel ati n g t o 
car di ot o xicit y i n t he P has e 1 st u d y ( D S 8 2 0 1-A -J 1 0 1, see Secti o n  1. 1. 1. 4. 1 ).  Si milar t o 
ot her pr o d ucts of t he s a me class, t he p ossi bilit y of ca r di ot o xicit y, relati ve t o t he p ote ntial 
f or Q T pr ol o n gati o n 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 a n d 
ca n n ot be e x cl u de d.  L eft ve ntric ular ejecti o n fracti o n  (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 h e I n v esti gat or or 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 1  
dele gate d p h ysicia n f or m o nit ori n g car diac f u ncti o n.  P ul m o nar y t o xicit y were o bs er ve d 
i n ass ociati o n wit h t he a d mi nistrati o n of D S-8 2 0 1a a n d ca n n ot b e e x cl u de d . 
A d diti o nal safet y assess me nts s h o ul d be c o n d uct e d as nee d e d, at t he I n vesti gat or’s 
discreti o n.  He pat ot o xicit y, e m br y o -fet al t o xicit y, vis ual dist ur ba nces/c or n eal t o xicit y or 
p h ot ot o xicit y o cc urri n g i n s u bjects recei vi n g D S -8 2 0 1a als o ca n n ot be  e x cl u de d.  As wit h 
a n y t h era p e 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 gi c or a na p h yl actic reacti o ns of D S-8 2 0 1a.  S u bjects recei vi n g 
D S -8 2 0 1a s h o ul d be m o nit ore d f or si g ns a n d s y m pt o ms of a n y of  t he t o xicities o bser ve d 
i n n o ncli nical st u dies (see secti o n 6. 1 3 of t he I B) a n d cli nical st u dies wit h ot her pr o d ucts 
of t he sa me cl ass.  
Base d o n t h e efficac y a n d safet y data o bser ve d i n t he n o ncli nical st u dies, t he c urre nt 
P hase 1 st u d y  (D S 8 2 0 1 -A -J 1 0 1), an 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 bal a nce s u p p orts cli nical de vel o p me nt of D S-8 2 0 1a i n t his patie nt 
p o p ulati o n.   
F or u p -t o-d ate ass ess me nts of ris ks a n d be nefits t o s u bjects, please refer t o t he c urre nt I B 
f or D S-8 2 0 1a.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 2  
2.   
S T U D Y O B J E C TI V E S A N D  H Y P O T H E SI S  
2. 1.   
St u d y O bjecti ves  
2. 1. 1.   
Pri m ar y O bjecti ves  
 T o assess t he effect of D S -8 2 0 1a o n t he Q Tc i nter val  
 T o assess P K  after m ulti ple d osi n g of D S -8 2 0 1 a  
2. 1. 2.   
Sec o n d ar y O bjecti ves  
2. 1. 2. 1.  
Ke y Sec o n d ar y O bjecti ves  
 T o assess t he safet y of D S -8 2 0 1a  
 T o assess t he ser u m c o nce ntrati o ns of D S -8 2 0 1a at t he ti me of E C G 
meas ure me nt  
2. 1. 2. 2.  
Ot her Sec o n d ar y O bjecti ves  
 T o e val uate t he effi cac y of D S -8 2 0 1a  
2. 2.   
St u d y H y p ot hes es 
D S -8 2 0 1a will n ot s h o w a n effect o n t he Q Tc i nter val (baseli ne -a dj uste d c orrect e d Q T 
i nter val b y Fri d ericia's f or m ula [Q Tc F  i nter val] < 1 0  ms ) i n H E R 2-e x pressi n g breast 
ca ncer s u bjects.  
2. 3.   
St u d y E n d p oi nts  
2. 3. 1.   
Pri m ar y E n d p oi nt s 
 Baseli ne -a dj uste d Q Tc F i nter val  
 Ser u m c o nce ntr ati o n a n d 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 a 
2. 3. 2.   
Sec o n d ar y E n d p oi nts  
2. 3. 2. 1.  
Ke y Sec o n d ar y E n d p oi nts  
Ke y sec o n d ar y e n d p oi nts are t he f oll o wi n g safet y e n d p oi nts.  
 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 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 ]) 
 Vital si g n meas ure me nts  
 Sta n dar d cli nical la b orat or y p ara m eters  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 3  
 1 2 -lea d E C G para meters  s uc h as R R, P R a n d Q R S d urati o n 
 E C H O/ M U G A fi n di n gs  
 O p ht hal m ol o gic fi n di n gs  
 A nti -dr u g a nti b o d y ( A D A ) 
2. 3. 2. 2.  
Ot her Sec o n d ar y E n d p oi nts  
Ot her  sec o n d ar y e n d p oi nts are t he f oll o wi n g e n d p oi nts. 
 C o nce ntrati o n -Q T  
 O R R  
 D C R  
 D urati o n of res p o ns e (D o R ) 
 D urati o n of sta ble d ise ase (S D ) 
 Cli nical be nefit rati o ( C B R) 
 T i me t o res p o nse (T T R ) 
 P r 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  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 4  
3.   
S T U D Y D E SI G N  
3. 1.   
O ver a ll Desi g n 
3. 1. 1.   
O ver vie w  
T his is a P hase 1, m ultice nter, o pe n -la bel, m ulti ple d ose st u d y of D S-8 2 0 1a desi g ne d t o 
assess t he effect o n t he Q Tc i nter val  a n d P K  after m ulti ple d osi n g i n s u bjects wit h H E R 2 -
e x pressi n g metastatic a n d/ or u nresect a ble breast ca ncer.  A t otal of 5 0 s u bjects are 
e x pecte d t o partici pate i n t his st u d y.  
D S -8 2 0 1a will be a d mi nistere d as a st erile I V s ol uti o n at 6. 4  m g/ k g Q 3 W .  T he st u d y 
treat me nt will be c o nti n u e d acc or din g t o t he d osi n g criteria ( See Secti o n  5. 4 ) t o deri ve 
cli nical be nefit i n t he a bs e nce of wit h dra wal of s u bject c o nse nt, pr o gressi ve disease ( 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 h a 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.  
T he data c ut off f or t h e 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 c o m plete d at least 3 c ycl es , w hic he ver c o m es first .  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 tra nsiti o n t o t he e xte nsi o n peri o d . 
3. 1. 2.   
D ur ati o n of t he St u d y  
E nr oll me nt is pla n ne d t o occ ur o ver a p pr o xi matel y 7 m o nt hs , wit h t he data c ut off f or t h e 
pri mar y a nal ysis pr ojecte d t o be c o m plete d wit hi n a p pr o xi matel y 3 m o nt hs t hereafter.   
S u bjects e x perie nci n g cli nical be nefit will  c o nti n u e t o recei ve st u d y treat m e nt i n t he 
e xte nsi o n peri o d of t he st u d y. T he  f oll o w-u p ( F/ U) f or p ost treat me nt s u bjects will  als o 
c o nti n ue at t he s p o ns or’s discreti o n t o c ollect m ore data .  D uri n g t he e xte nsi o n peri o d, t he 
n u m ber a n d fre q ue n c y of n o n -safet y st u d y pr oce d ures ma y be re d uce d.  I n a d diti o n, t he 
e xte nt of data c ollecti o n will be re d uce d.  T he  st u d y ma y b e ter mi nate d at a n y ti me at t he 
s p o ns or’s discreti o n.  
T h us, t he a ntici pate d d urati o n of t he st u d y is 2 years a n d 6  m o nt hs . 
3. 1. 3.   
D ur ati o n of S u bject P a rtici p ati o n  
T he scree ni n g peri o d is u p t o 2 8 da ys.  E ac h c ycle of treat me nt will be 2 1 da ys. T h e 
n u m ber of treat me nt c ycl es  wit h D S -8 2 0 1a is n ot fi x e d.  U p o n c o m me nci n g st u d y 
treat me nt, s u bjects ma y c o nti n ue recei vi n g st u d y dr u g u ntil t he occ urre nce of a n y of t he 
e ve nts defi ne d i n Secti o n  5. 7. 1 .   
After disc o nti n uati o n fr o m st u d y treat me nt, all s u bjects, re gar dless of w h et her t he y 
disc o nti n ue d pri or t o or s u bse q ue nt t o disease pr o gressi o n, ma y be c o ntact e d e ver y 3 
m o nt hs u ntil deat h or u ntil F/ U  data c ollecti o n is n o l o n g er of scie ntific v al ue or 
ot her wise nee de d (at t he s p o ns or’s discreti o n), t o o btai n i nf or mati o n a b o ut s u bse q ue nt 
treat me nt(s) a n d s ur vi val stat us. 
3. 1. 4.   
Pl a n ne d St u d y peri o d  
0 1 Oct 2 0 1 7 t o 3 1 Mar  2 0 2 1 . 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 5  
3. 2.   
Disc ussi o n of St u d y Desi g n  
3. 2. 1.   
Selecti o n of D ose  
D S -8 2 0 1a was a d mi nistere d i n 0. 8  m g/ k g t o 8. 0  m g/ k g o nce e ver y 3 wee ks i n t he pri or 
P hase 1 st u d y ( D S 8 2 0 1 -A -J 1 0 1) a n d t he M T D was n ot reac he d u p t o 8. 0 m g/ k g.  
H o we ver, t he hi g hest d os e 8. 0 m g/ k g is c o nsi dere d n ot t o be a p pr o priate t o assess t he Q T 
i nter val at t he stead y stat e beca use t he d ose re d ucti o n rate at t he earlier ti m e p oi nt was 
hi g h ( 6 7 %).  I n a d diti o n, d ue t o t he p ossi bilit y t hat  M A A A -1 1 8 1 a h as ge n ot o xicit y, Q T 
assess me nt of D S -8 2 0 1a is n ot a ble t o be c o n d ucte d at a s u pra t hera pe utic d ose , a n d will 
be st u die d i n breast c a ncer s u bjects,  n ot healt h y v ol u nteers.    
O n t he basis of efficac y , t olera bilit y a n d P K pr ofile  esta blis he d i n t he P hase 1 st u d y  a n d 
pre -cli nical  st u dies, 6. 4  m g/ k g  ha ve b ee n c o nsi dere d as t he d os a ge f or t his st u d y . 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 6  
4.   
S T U D Y P O P U L A TI O N  
4. 1.   
I ncl usi o n Criteri a 
S u bjects m ust satisf y all of t he f oll o wi n g criteria t o be i ncl u de d i n t he st u d y:  
 N o. 1:  Ma n or w o ma n ≥ 2 0 years ol d.  
 N o. 2:  Has a pat h ol o gicall y d oc u m e nte d u nres ecta ble or metastatic breast 
ca ncer wit h H E R 2 e x pressi o n ( i m m u n o hist oc he mistr y [I H C] 3 +, I H C 2 +, I H C 
1 + a n d/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 d ar d treat me nt is a vaila ble.  
*I S H: fl u oresce nt i n sit u h y bri dizati o n ( FI S H) or d ual i n si t u h y bri dizati o n 
( DI S H) 
 N o. 3:  L V E F ≥ 5 0 %.  
 N o. 4:  Has a n E C O G  P S 0 or 1.  
 N o. 5:  Has a de q u ate or ga n f u ncti 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  
( Platelet tra nsf usi o n is n ot all o we d wit hi n 1 
wee k pri or t o scree ni n g assess me nt)  
He m o gl o bi n ( H b)  
≥ 9. 0  g/ d L  
( Re d bl o o d cell tra nsf usi o n is n ot all o we d 
wit hi n 1 wee k pri or t o scree ni n g assess me nt)  
A bs ol ute ne utr o p hil c o u nt  ( A N C) 
 1 5 0 0/ m m 3  
( G-C S F a d mi nistrati o n is n ot all o we d wit hi n 
1 wee k pri or t o scree ni n g assess me nt)  
Creati ni ne  
C reati ni ne cleara nce ≥ 3 0  m L/ mi n  as 
calc ulate d usi n g t he C oc kcr oft -Ga ult 
e q uati o n  (see Secti o n  1 7. 1 ) 
A S T /A L T  
≤ 3  u p per li mit of n or mal ( U L N)  (if li ver 
metastases are prese nt,  ≤ 5  U L N)  
T otal b ilir u bi n ( T B L) 
≤ 1. 5  U L N  if n o li ver metastases 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 (u nc o nj u gate d 
h y per bilir u bi ne mia ) 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  
Ser u m Ca, K a n d M g  
Wit hi n n or mal ra n ge  
 N o. 6:  Has a de q u ate treat me nt was h o ut peri o d bef ore e nr oll me nt , defi ne d as: 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 7  
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  
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 , 
reti n oi d t hera p y a n d 
h or m o nal t hera p y ) 
 3 wee ks  
( 2 wee ks or 5 half -li ves bef ore st u d y dru g 
treat me nt, w hic he ver is l o n ger, f or s mall-
m olec ule tar gete d a ge nts s uc h as 5 -fl u or o uracil-
base d a ge nts, f oli nate a ge nts, wee kl y paclita xel; 
> 6 wee ks f or nitr os ureas or mit o m yci n C ) 
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 
( See S u p ple me nt 4) 
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 
( See S u p ple me nt 4) 
 N o. 7:  Is a ble t o pr o vi de writte n i nf or me d c o ns e 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 ores eea 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 o ar d (I R B) a p pr o ve d I C F b ef ore 
perf or ma n ce of a n y st u d y -s p ecific pr oce d ures or e x a mi nati o ns. 
 N o. 8:  Is willi n g t o pr o vi d e o ne of t he f oll o wi n g:  
 P re-e xisti n g dia g n ostic or resecte d t u m or sa m ples.  
 H E R 2 stat us data c o nfir me d b y a ce ntral la b orat or y i n an ot h er D S -8 2 0 1 a 
cli nical st u d y.  
 N o. 9:  Has a life e x pecta nc y of ≥ 3 m o nt hs.  
 N o. 1 0:  Is a ble a n d willi n g t o c o m pl y wit h pr ot oc ol visits a n d pr oce d ures . 
 Male a n d fe male s u bjects of re pr o d ucti ve/c hil d beari n g p ote ntial m ust 
a gree t o us e a hi g hl y effecti ve f or m of c o ntrace pti o n or a v oi d i nterc o urse 
d uri n g a n d u p o n c o m pleti o n of t he st u d y a n d f or at least 7 m o nt hs f or 
fe males a n d 4 m o nt hs f or males after t he l ast d ose of st u d y dr u g.  M et h o ds  
c o nsi dere d as hi g hl y effecti ve met h o ds of c o ntrace pti o n i ncl u de: 
o  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n:   
 
Oral  
 
I ntr a va gi nal 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 8  
 
Tra ns der m al  
o  Pr o gest o ge n -o nl y  h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n 
of o v ulati o n:  
 
Oral  
 
I njecta ble 
 
I m pla nta bl e  
o  I ntr a uteri ne de vice  
o  I ntr a uteri ne h or m o ne-rel easi n g s yst e m  
o  Bilateral t u bal occl usi o n  
o  Vasect o mize d part ner  
o  C o m plete se x ual a bsti ne nce  defi ne d as refrai ni n g fr o m h eter os e x ual 
i nterc o urse d uri n g a n d u p o n c o m pleti o n of t he st u d y a n d f or at least 7 
m o nt hs f or fe males a n d 4 m o nt hs f or males  after t he last d ose of st u d y 
dr u g.  Peri o dic a bsti ne nce (cal e n dar, s y m pt ot her m al, p ost -o v ulati o n 
met h o ds) is n ot a n acce pta ble met h o d of c o ntrace pti o n.    
N o n -c hil d-beari n g p ote ntial defi ne d as pre -me n o pa usal fe mal es wit h a 
d oc u me nte d t u bal li gati o n or h ysterect o m y; or p ost me n o pa usal defi ne d as 
1 2 m o nt hs of s p o nta ne o us a me n orr hea (i n q uesti o na ble cas es, a bl o o d 
sa m ple wit h si m ulta ne o us f ollicle-sti m ulati n g h or m o ne > 4 0 mI U/ m L a n d 
estra di ol < 4 0 p g/ m L [ < 1 4 7 p m ol/ L] is c o nfir mat or y).  Fe males o n 
h or m o ne re place me nt t hera p y ( H R T) a n d w h ose m e n o pa usal stat us is i n 
d o u bt will be re q uire d t o use o ne of t he c o ntrace pti o n met h o ds o utli ne d f or 
w o me n of c hil d -beari n g p ote ntial if t he y wis h t o c o nti n ue t heir H R T 
d uri n g t he st u d y.  Ot her wise, t he y m ust disc o nti n ue H R T t o all o w 
c o nfir mati o n of p ost -me n o pa usal stat us pri or t o st u d y e nr oll me nt.  F or 
m ost f or ms of H R T, at least 2  wee ks t o 4 wee ks will ela pse bet wee n t h e 
cessati o n of t hera p y a n d t he bl o o d dra w; t his i nter val de pe n ds o n t he t y pe 
a n d d osa ge of H R T.  F oll o wi n g c o nfir mati o n of t h eir p ost -me n o pa usal 
stat us, t he y ca n res u m e use of H R T d uri n g t he st u d y wit h o ut use of a 
c o ntrace pti ve met h o d.  
 Mal e s u bjects m ust n ot freeze or d o nate s per m starti n g at Scree ni n g a n d 
t hr o u g h o ut t he st u d y peri o d, a n d at least 4 m o nt hs  after t he fi nal st u d y 
dr u g a d mi nistrati o n.   Preser vati o n of s per m s h o ul d be c o nsi dere d pri or t o 
e nr ollme nt i n t his st u d y.  
 Fe male s u bjects m ust n ot d o nate, or retrie ve f or t h eir o w n use, o va fr o m 
t he ti me of Scree ni n g a n d t hr o u g h o ut t he st u d y treat me nt peri o d, a n d f or at 
least 7  m o nt hs  after t he fi nal st u d y dr u g a d mi nistrati o n.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 3 9  
4. 2.   
E xcl usi o n Criteri a  
S u bjects w h o meet a n y of t he f oll o wi n g criteria will be dis q ualifie d fr o m e nteri n g t he 
st u d y: 
 N o. 1:  Has a me dical hist or y of  m y o car dial i nfarcti o n wit hi n 6 m o nt hs bef ore 
e nr oll me nt . 
 N o. 2 : Has a me dical hist or y of ve ntric ular arr h yt h mias, ot her t ha n rare, 
occasi o nal pre mat ure  v e ntric ula r c o ntracti o ns. 
 N o. 3 : Has u nc o ntr olle d or si g nifica nt car di o vasc ul ar disease, i n cl u di n g:  
 S y m pt o matic c o n gesti ve heart fail ure (C H F ) (Ne w Y or k Heart 
Ass ociati o n [ N Y H A]  class II-I V, Secti o n  1 7. 4 ). 
 T r o p o ni n le vels c o nsiste nt wit h m y o car dial i nfarcti o n as defi ne d acc or di n g 
t o ma n ufact ur er . 
 U nsta ble a n gi na or s eri o us car diac arr h yt h mia re q uiri n g treat me nt. 
 C li nicall y si g nifica nt bra d ycar dia. 
 U nc o ntr olle d h y perte nsi o n.  
 Q Tc F i nter val  pr ol o n gati o n t o > 4 5 0  ms , heart rat e of > 1 0 0 b eats per 
mi n ute  or  heart rate of < 5 0 beats per mi n ute  bas e d o n a vera ge of t he 
scree ni n g tri plicat e 1 2 -lea d E C G. 
 A n y a b n or mal E C G fi n di n gs i de ntifie d b y ce ntral assess me nt.  
 Atrial fi brillati o n or fl utter.  
 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) v ersi o n 4. 0 3  g ra d e ≥2 atri o v e ntric ular bl oc k, l eft 
b u n dle bra nc h bl oc k or pr ol o n ge d Q R S.  
 P ul m o nar y e m b olis m or dee p vei n t hr o m b o sis. 
 N o. 4:  Has a n i m pla nta ble pace ma ker or a ut o matic i m pla nta ble car di o verter 
defi brillat or  or  car diac res y nc hr o nizati o n t hera p y de vice . 
 N o. 5 : Has a c o n ge nital l o n g Q T s y n dr o me , fa mil y hist or y of l o n g Q T 
s y n dr o me or u ne x plai ne d s u d de n deat h . 
 N o. 6 : Has recei ve d ≥ 5 0 0 m g / m2 of c u m ulati ve a nt hrac ycli nes as d o x or u bici n -
e q ui vale nt d ose . 
 N o. 7 : Has a hist or y of ( n o n -i nfecti o us) interstitial l u n g diseas e (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 n e u m o nitis ca n n ot be r u le d o ut b y i ma gi n g at scree ni n g. 
 N o. 8 : Has a n u nc o ntr olle d i nfecti o n re q uiri n g I V a nti bi otics, a nti virals, or 
a ntif u n gals.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 0  
 N o. 9 : Has 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 p atitis 
B or C i nfecti o n.  
 N o. 1 0 : 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 x cl u de d), pla n ni n g t o bec o me pre g na nt  or pre g na nt 
as c o nfir me d b y pre g na n c y t ests perf or me d wit hi n 7 da ys b ef ore e nr oll me nt . 
 N o. 1 1 : Has m ulti ple pri mar y m ali g n a ncies wit hi n 3 years , e x ce pt a de q uat el y 
resect e d n o n -mela n o ma s ki n ca ncer, c urati vel y treate d i n -sit u disease, ot her 
s oli d t u m ors c urati vel y treate d, or c o ntralateral breast ca ncer . 
 N o. 1 2 : Has s pi nal c or d c o m pressi o n or cli nicall y acti ve ce ntral ner v o us 
s yste m metastas es, defi 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 cli nicall y i nacti ve brai n metastases ma y b e i ncl u de d i n t he st u d y.   
S u bjects wit h treate d brai n me tastases t hat are n o l o n ger s y m pt o matic a n d 
w h o re q uire n o treat me nt wit h c ortic oster oi ds or a ntic o n v ulsa nts  ma y be 
i ncl u de d i n t he st u d y if t he y h a ve rec o v ere d fr o m t he ac ute t o xic effect of 
ra di ot hera p y.  A mi ni m u m of 2 wee ks m ust ha ve ela pse d bet w ee n t h e e n d of 
w h ole brai n r a di ot hera p y a n d e nr oll me nt . 
 N o. 1 3 : Has u nres ol ve d t o xicities fr o m pre vi o us a ntica ncer t hera p y, d efi ne d as 
t o xicities ( ot her t ha n al o pecia) n ot yet res ol ve d t o gra de ≤ 1 or 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 v esti gat or after c o ns ultati o n wit h t he S p o ns or (e g, Gra de 2 
c he m ot hera p y-i n d uce d n e ur o pat h y). 
 N o. 1 4 : Has a cli nicall y si g nifica nt c or n eal diseas e  i n t he o pi ni o n of t he 
I n v esti gat or. 
 N o. 1 5 : Pri or treat me nt wit h a n A D C w hic h  c o nsists of a n e x ateca n d eri vati ve 
t hat is a t o p ois o merase I i n hi bit or. 
 N o. 1 6 : Has a c o n c o mita nt me dical c o n diti o n t hat w o ul d i n d uce Q Tc 
pr ol o n gati o n  a n d i n creas e t he ris k of t o xicit y i n t h e o pi ni o n of t he 
I n v esti gat or. 
 N o. 1 7 : Has hist or y of se vere h y pers e nsiti vit y reacti o ns  t o t he dr u g s u bsta n ces 
or i nacti ve i n gre di e nts i n t he dr u g pr o d uct , or ot her m o n ocl o nal a nti b o dies. 
 N o. 1 8 : Has s u bsta nce a b use or a n y ot her me dical c o n diti o ns t hat w o ul d 
i ncreas e t he safet y ris k t o t he s u bject or i nterfere wit h participati o n of t he 
s u bject or e val u ati o n of t he cli nical st u d y i n t he o pi ni o n of t he I n v esti gat or.  
 
R ati o n ale f or E xcl usi o n Criteri a:  
T hese criteria are i ncl u de d t o m i ni mize t he ris k f or s u bject safet y. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 1  
5.   
S T U D Y T R E A T M E N T( S)  
5. 1.   
Assi g ni n g S u bjects t o Tre at me nts a n d Bli n di n g  
5. 1. 1.   
Tre at me nt Gr o u p (s)/ Se q ue nces 
St u d y treat me nt a n d pr oce d ure is t he sa me a m o n g all s u bjects e nr olle d i n t h is st u d y. 
5. 1. 2.   
Met h o d of Tre at me nt All oc ati o n  
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 h eir 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 o ce d ures is pr o vi de d i n Secti o n  1 5. 3 . 
I n v esti gat ors will mai ntai n a c o nfi de ntial scree ni n g l o g of all p ote ntial st u d y ca n di dates 
t hat i ncl u des li mite d i nf or mati o n of t he s u bjects (i nitials, a ge, ge n der), date a n d o utc o me 
of scre e 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 v esti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n 
t he st u d y i n dicati n g t heir assi g ne d S u bject N u m ber.  
I n v esti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n 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 v esti gat or t o re veal t he i de ntit y of a n y s u bject w h e n necessar y.  
5. 1. 2. 1.  
S u bject N u m ber Assi g n me nt  
T he u ni q ue S u bject N u m ber will be assi g ne d t o all s u bjects w h o pr o vi de writte n 
i nf or me d c o nse nt.  After o btai ni n g writte n i nf or me d c o nse nt, I n v esti gat ors will assi g n t he 
u ni q ue S u bject N u m ber t o t he s u bject b y i nteracti ve we b/ v oice res p o nse s yste m (I X R S), 
e nc o m passi n g b ot h i nteracti ve v oice res p o nse s yste ms 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 utilizi n g t he i nter net  (see Fi g ure  5 .1 ). 
5. 1. 2. 2.  
E nr oll me nt  
I n v esti 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 x cl 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.  
E nr oll me nt date is defi ne d as t he date st u d y dr u g a d mi nist rati o n is starte d u p o n t he 
I n v esti gat or’s or desi g n ee’s o btai ni n g writte n i nf or me d c o nse nt fr o m a s u bject (see 
Secti o n  1 5. 3 ) a n d u p o n d eter mi nati o n of all i ncl usi o n a n d e x cl usi o n criteria ha vi n g b ee n 
satisfie d.  T he date of scree n fail ure is defi ne d as t he date t hat I n v esti gat ors c o nfir m a 
s u bject ca n n ot be e nr oll e d i n t he st u d y (see Fi g ure  5 .1 ). 




Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 3  
me dici nal s ol uti o ns s h o ul d be use d i m me diatel y.  T he pre p arati o n will be c o n d ucte d i n 
acc or da nce wit h t he p har mac y i nstr ucti o ns pr o vi de d b y t h e S p o ns or.  Pr oce d ures f or  
pr o per ha n dli n g a n d dis p osal of a ntica n cer dr u gs s h o ul d be f oll o we d i n c o m plia nce wit h 
t he sta n dar d o perati n g pr oce d ures ( S O Ps) of t he st u d y site.  Refer t o t he p h ar mac y 
ma n ual f or det aile d i nf or mati o n a b o ut pre parati o n a n d a d mi nistrati o n of D S -8 2 0 1a.  
5. 2. 4.   
A d m i nistr ati o n 
T he st u d y dr u g will be a d mi nistere d at a d ose of 6. 4  m g/ k g . T he i nitial d ose of D S-8 2 0 1a 
will be i nf use d f or a p pr o xi matel y 9 0 mi n utes.  If t here is n o i nf usi o n relat e d reacti o n, 
after t he i nitial d ose, t he ne xt d ose of D S -8 2 0 1a will be i nf use d 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 will be us e d t o calc ulate t he i nitial d ose.  If d uri n g t he 
c o urse of treat me nt t he s u bject’s wei g ht c ha n ges b y m ore t h a n  1 0 % of t he baseli ne 
wei g ht, t he s u bject’s d os e will be recalc ulate d bas e d o n t he s u bject’s u p dat e d wei g ht.  
5. 2. 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 at 2° C t o 8° 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 m e nts, t he S p o ns or or 
c o ntract r esearc h or ga nizati o n ( C R O)  s h o ul d be c o ntacte d. 
5. 2. 6.   
Dr u g Acc o u nt a bilit y  
W he n a dr u g s hi p me nt is recei v e d, t he I n v esti 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 o cal 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  b y t he S p o ns or .  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 n al F or m will be retai ne d at t he 
site.  I n a d diti o n, t he I n v esti 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 R ec or d will be pr o vi d e d f or t he st u d y dr u g.  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 st u d y dr u g recei v e d, s u bject’s 
i nf or mati on (t he site s u bject i de ntifier a n d t h e s u bject n u m ber), f or w h o m t he st u d y dr u g 
was dis pe nse d, t he date a n d q ua ntit y of st u d y dr u g dis pe nse d a n d re mai ni n g,  as well as 
t he i nitials or seal of t he dis pe nser.  
At t he e n d of t he st u d y, or as direct e d  b y t he S p o ns or , all u n use d st u d y dr u g s will be 
ret ur ne d t o a desi g n ee as i nstr ucte d b y t h e S p o ns or.  St u d y dr u g  will be ret ur ne d o nl y 
after t he st u d y m o nit or h as 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 h e ret ur n of st u d y dr u g m ust be d oc u m e nte d a n d t he d oc u me ntati o n i ncl u de d 
i n t he s hi p me nt.  At t he e n d of t he st u d y, a fi nal st u d y dr u g rec o n ciliati o n state me nt m ust 
be c o m plete d b y t he I n v esti gat or or d esi g n ee a n d pr o vi de d t o t he S p o ns or.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 4  
5. 3.   
C o ntr ol Tre at me nt  
N ot a p plica ble.  
5. 4.   
D ose I nterr u pti o ns a n d Re d ucti o ns 
T he I n vesti gat or will e val uate w hic h t o xicities are attri b ute d t o t he st u d y dr u g a n d a dj ust 
t he d ose of t he dr u g as rec o m me n de d bel o w.  All d ose m o dificati o ns s h o ul d be base d o n 
t he w orst prece di n g t o xicit y (N CI -C T C A E  v ersi o n 4 . 03 ).  S pecific criteria f or 
i nterr u pti o n, re-i nitiati o n, d ose re d ucti o n a n d/ or disc o nti n uati o n of D S-8 2 0 1a are liste d i n  
Ta ble  5 .2 . F or Gra de 3 or Gra de 4 e ve nts, m o nit ori n g (i ncl u di n g l ocal la b tests w he n 
a p pr o priate) s h o ul d be perf or me d at i nter vals n o greater t ha n 7 da ys u ntil A E is 
deter mi ne d t o be res ol vi n g or disc o nti n u ati o n of st u d y treat me nt is deci de d. 
Pr o p h ylactic or s u p p orti v e treat me nt f o r e x pecte d t o xicities, i ncl u di n g ma na ge m e nt of 
st u d y-dr u g i n d u ce d a d v erse e ve nts will be as per t he treati n g p h ysicia n’s discreti o n a n d 
i nstit uti o nal g ui deli nes. 
I n a d diti o n, I n v esti gat ors ma y c o nsi der d ose re d ucti o ns or disc o nti n uati o ns of t he st u d y 
dr u g acc or di n g t o t he s u bject’s c o n diti o n a n d after disc ussi o n wit h t he S p o ns or . 
 
D ose Re d ucti o n G ui deli n es:  
N ote : T here will be n o d ose m o dificati o ns f or Gra de 1 or Gra de 2 A Es u nless s pecifie d i n 
Ta ble  5 .2 . 
T w o d ose re d u cti o ns will be per mitte d.  T he a dj ust me nt f or a re d uce d d osi n g of D S -
8 2 0 1a is as s h o w n i n  Ta ble  5 .1 . 
M ore t ha n 2 d ose re d ucti o ns are n ot all o we d a n d t he s u bject will be wit h dra w n fr o m t he 
st u d y treat me nt if f urt her t o xicit y meeti n g t he re q uire me nt f or d ose re d ucti o n occ urs.  
T a ble  5 .1 :  
D ose Re d ucti o n Le vels of D S -8 2 0 1 a  
St arti n g D ose   
D ose Le vel −1   
D ose Le vel −2  
6. 4 m g/ k g  
5. 4 m g/ k g  
4. 4 m g/ k g  
 
D ose I nterr u pti o n a n d Sc he d ule M o dific ati o n  G ui deli nes:  
A  d ose ca n b e dela ye d  f or u p t o 2 8 da ys  ( 4 9 da ys fr o m t he last i nf usi o n date) fr o m t he 
pla n ne d date of a d mi nistrati o n.  If a s u bject is ass esse d as re q uiri n g a d ose dela y of 
l o n ger t h a n 2 8 da ys , t he s u bject will be wit h dra w n fr o m t he st u d y. 
I n case D S-8 2 0 1a  d osi n g is te m p oraril y wit h hel d f or a n y reas o n, ne xt pla n ne d date of 
a d mi nistrati o n will be sc he d ule d base d o n t he dat e of d ose res u m pti o n.  
 
All  c o nfir me d or s us pecte d S A R -C o V -1 9  i nfecti o n e ve nts m ust be rec or de d i n t he e CR F.  
Please refer t o Secti o n 1 7. 6  f or a d diti o nal i nf or mati o n o n d ose m o dificati o n. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 5  
 
T a ble  5 .2 :  
D ose or Sc he d ule M o dific ati o n f or D S -8 2 0 1 a  
W orst t o xicit y N CI -
C T C A E v ersi o n 4. 0 3  
Gr a de ( u nless ot her wise 
s pecifie d) 
M a n a ge me nt G ui deli nes f or D S-8 2 0 1 a  
N o t o xicit y  
Mai ntai n d ose a n d sc he d ule . 
I nf usi o n-rel ate d  Re a cti o n  
Gra de 1  
( Mil d tra nsie nt reacti o n; 
i nf usi o n i nterr u pti o n n ot 
i n dicate d; i nter ve nti o n n ot 
i n dicate d) 
  
If i nf usi o n relate d reacti o n (s uc h as fe ver a n d c hills, wit h a n d 
wit h o ut na usea/ v o miti n g, pai n, hea dac he, dizzi ness, d ys p nea, 
h y p ote nsi o n) is o bser ve d d uri n g a d mi nistrati o n, t he i nf usi o n rate 
s h o ul d be re d uce d b y 5 0 % a n d s u bj ects s h o ul d be cl osel y 
m o nit ore d.  
  
If n o ot her reacti o ns a p pear, t he s u bse q ue nt i nf usi o n rate c o ul d 
be res u me d at t he i nitial pla n ne d rate.  
Gra de 2  
( T hera p y or i nf usi o n 
i nterr u pti o n i n dicate d b ut 
res p o n ds pr o m ptl y t o 
s y m pt o matic treat me nt (e g, 
a nti hista mi nes, N S AI Ds , 
narc otics, I V fl ui ds); 
pr o p h ylactic me dicati o ns 
i n dicate d f or ≤ 2 4 h) 
  
A d mi nistrati o n of D S -8 2 0 1a s h o ul d be i nterr u pte d a n d 
s y m pt o matic treat me nt starte d (e g, a nti hista mi nes, N S AI Ds, 
narc otics, I V fl ui ds).  
  
If t he e ve nt res ol ves or i m pr o ves t o gra de 1, i nf usi o n ca n be re-
starte d at a 5 0 % re d uce d i nf usi o n rate. 
  
S u bse q ue nt a d mi nistrati o ns s h o ul d be c o n d ucte d at t he re d uc e d 
rate. 
Gra de 3 or 4  
( Pr ol o n ge d or life-
t hreate ni n g c o nse q ue nces, 
ur ge nt i nter ve nti o n 
i n dicate d) 
  
A d mi nistrati o n of D S -8 2 0 1a s h o ul d be disc o nti n ue d i m me di a tel 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 V fl ui d t hera p y, 
o x y ge n i n halati o n etc., s h o ul d be a d mi nistere d.  
He m at ol o gic T o xicit y  
Ne utr o p hil C o u nt Decre ase d  a n d/ or W hite Bl o o d Cell C o u nt Decre ase d  
Gra de 3  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2 : 
  
M ai ntai n d ose  
Gra de 4  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2 : 
  
R e d uce d ose 1 le vel  
Fe brile Ne utr o pe ni a  
Gra de 3  
(a bs ol ute ne utr o p hil 
c o u nt <  1  x 1 0 9/ L, fe ver 
> 3 8. 3° C or a s ustai ne d 
te m perat ure of ≥ 3 8 ° C 
f or m ore t ha n o ne h o ur) 
Dela y d ose u ntil res ol ve d : 
  
R e d uce d ose 1 le vel  
Gra de 4  
Disc o nti n ue s u bj ect fr o m st u d y treat me nt.  
L y m p h oc yte C o u nt Decre as e d  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 6  
Gra de 1 t o 3  
N o d ose m o dificati o n.  
Gra de 4  
( < 0. 2 x  1 0 9/ L) 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2 : 
  
If res ol ve d i n ≤ 1 4 da ys fr o m da y of o nset, mai ntai n d ose 
  
If res ol ve d i n > 1 4 da ys fr o m da y of o nset, re d uce d ose 1 le vel 
A n a e mi a  
Gra de 3  
(H b  < 8. 0  g/ d L ; 
tra nsf usi o n i n dicate d) 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2 : 
  
M ai ntai n d ose  
Gra de 4  
(Life t hreate ni n g 
c o nse q ue nces; ur ge nt 
i nter ve nti o n i n dicate d) 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2 : 
  
R e d uce d ose 1 le vel  
Pl atelet C o u nt Decre ase d  
Gra de 3  
( < 5 0 t o 2 5 x 1 0 9/ L) 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1:  
  
If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose 
  
If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
Gra de 4  
( < 2 5 x 1 09/ L) 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1 : 
  
R e d uce d ose  1 le vel  
C ar di ac T o xicit y  
C H F  
Disc o nti n ue s u bj ect fr o m st u d y treat me nt . 
Decrease i n  L V E F  1 0 % t o 
2 0 % (a bs ol ute val ue), b ut 
L V E F >  4 5 %  
C o nti n ue treat me nt wit h D S -8 2 0 1a . 
L V E F 4 0 % t o ≤ 4 5 % a n d 
decrease is < 1 0 % 
(a bs ol ute val ue) fr o m 
baseli ne  
C o nti n ue treat me nt wit h D S -8 2 0 1a . 
Re peat L V E F assess me nt wit hi n 3 wee ks . 
L V E F 4 0 % t o ≤ 4 5 % a n d 
decrease is ≥ 1 0 -2 0 % 
(a bs ol ute val ue) fr o m 
baseli ne  
I nterr u pt 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 1 0 % (a bs ol ute val ue) fr o m 
baseli ne, disc o nti n ue s u bj ect fr o m st u d y treat me nt . 
If L V E F rec o vers t o wit hi n 1 0 % fr o m baseli ne, res u me st u d y dr u g 
treat me nt 
L V E F < 4 0 % or > 2 0 % 
(a bs ol ute val ue) dr o p fr o m 
baseli ne  
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 baseli ne is c o nfir me d, 
disc o nti n ue s u bj ect fr o m st u d y treat me nt. 
 Electr oc ar di o gr a m Q T pr ol o n ge d  
Gra de 3  
( Q T c > 5 0 0 ms o n 2 
se parate E C Gs) 
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1 ( Q T c ≤ 4 8 0 ms) . 
  
D eter mi ne if a n ot her me dicati o n t he s u bj ect was ta ki n g ma y be 
res p o nsi ble a n d ca n be a dj uste d or if t here are a n y c ha n ges i n 
ser u m electr ol ytes t hat ca n be c orrecte d, t he n if attri b ute d t o D S-
8 2 0 1a, re d uce d ose 1 le vel  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 7  
Gra de 4  
( Q T c > 5 0 0 or > 6 0 ms 
c ha n ge fr o m baseli ne a n d 
T orsa de de p oi ntes or 
p ol y m or p hic ve ntric ular 
tac h ycar dia or 
si g ns/s y m pt o ms of seri o us 
arr h yt h mia)  
Disc o nti n ue s u bj ect fr o m st u d y treat me nt . 
Tr o p o ni n  
Gra de 1  
( Le vels a b o ve t he u p pe r 
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)  
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 n d of i nf usi o n ( 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 tr o p o ni n le vels are n ot a b o ve t he u p per li mit of n or mal at baseli ne, 
f or ne w dia g n ose d gra de 1, re peat tr o p o ni n testi n g at 3 ± 1 h o urs ( ~ 6 
h o urs p ost -i nf usi on) after i nitial tr o p o ni n test.  
  
If re peat tr o p o ni n le vel at 3 ± 1 h o urs ( ~ 6 h o urs p ost -i nf usi o n) 
rises si g nifica ntl y per i nstit uti o nal g ui deli nes,  
-  
perf or m E C G i n tri plicate;  
-  
re peat tr o p o ni n testi n g at 6 ± 1 h o urs ( ~ 9 h o urs p ost-
i nf usi o n) after i nitial tr o p o ni n test; 
-  
f oll o w i nstit uti o nal g ui deli nes f or ma na ge me nt of 
detecta ble tr o p o ni n testi n g.  
  
If re peat tr o p o ni n le vel at 3 ± 1 h o urs ( ~ 6 h o urs p ost-i nf usi o n) 
d oes n ot rise si g nifica ntl y per i nstit uti o nal g ui deli nes,  
-  
re peat tr o p o ni n testi n g at 6 ± 1 h o urs ( ~ 9 h o urs p ost-
i nf usi o n) or at 2 4 ± 2 h o urs ( ~ 2 7 h o urs p ost-i nf usi o n) after 
i nitial tr o p o ni n test.  
C o nti n ue treat me nt wit h D S -8 2 0 1a  
Gra de 3  
( Le vels c o nsiste nt wit h 
m y ocar dial i nfarcti o n as 
defi ne d b y t he 
ma n ufact urer)  
P erf or m E C G i n tri plicate . 
Re peat tr o p o ni n testi n g at 6 ± 1 h o urs ( ~ 9 h o urs p ost -i nf usi o n) a n d 1 2  
± 1 h o ur s ( ~ 1 5 h o urs p ost -i nf usi o n) after i nitial tr o p o ni n test.  
F oll o w i nstit uti o nal g ui deli nes f or ma na ge me nt of detecta ble tr o p o ni n 
testi n g.  If ac ute m y ocar dial i nfarcti o n  c o nfir me d, disc o nti n ue s u bj ect 
fr o m st u d y t hera p y. 
O t her wise, dela y  d ose u ntil res ol ve d t o ≤ Gra de 1: 
  
If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose 
  
If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
P ul m o n ar y T o xicit y  
If a s u bj ect de vel o ps ra di o gra p hic c ha n ges p ote ntiall y c o nsiste nt wit h I L D/ p ne u m o nitis or de vel o ps 
a n ac ute o nset of ne w or w ors e ni n g p ul m o nar y or ot her relate d si g ns/s y m pt o ms s uc h as d ys p nea, 
c o u g h or fe ver, r ule o ut I L D/ p ne u m o nitis.  
If t he A E is c o nfir me d t o ha ve a n eti ol o g y ot her t ha n I L D/ p ne u m o nitis, f oll o w t he ma na ge me nt 
g ui da nce o utl i 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.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 8  
E val uati o ns s h o ul d i ncl u de:  
•   
hi g h res ol uti o n C T  
•   
p ul m o n ol o gist c o ns ultati o n  (infecti o us d isease c o ns ultati o n as cli nicall y i n dicate d) 
•   
b l o o d c ult ure a n d C B C. Ot her bl o o d  tests c o ul d be c o nsi dere d as nee de d 
•   
co nsi der br o nc h osc o p y a n d br o nc h oal ve olar la va ge if cli nic all y i n dicate d a n d feasi ble  
•   
p ul m o nar y f u nc ti o n tests a n d p ulse o xi metr y ( S p O2)  
•   
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 nal ysis as s o o n as I L D/ p ne u m o nitis is s us pecte d, if 
feasi ble. 
Ot her tests c o ul d be c o nsi dere d, as nee de d. 
If t he A E is c o nfir me d t o be I LD/ p ne u m o nitis, f oll o w t he I L D/ p ne u m o nitis ma na ge me nt g ui da nce as 
o utli ne d bel o w.  All e ve nts of I L D / p ne u m o nitis 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.  
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/ p ne u m o nitis e ve nts re gar dless of gra de.  
•  M o nit or a n d cl osel y f oll o w -u p i n 2 t o 7 da ys f or o nset of 
cli nical s y m pt o ms a n d p ulse o xi metr y  
 
•  C o nsi der f oll o w -u p i ma gi n g i n 1 -2 wee ks ( or as cli nicall y 
i n dicate d). 
 
•  C o nsi der starti n g s yste mic ster oi ds (e. g. at least 0. 5 
m g/ k g/ da y pre d nis o ne or e q ui vale nt) u ntil i m pr o ve me nt, 
f oll o we d b y gra d ual ta per o ver at least 4 wee ks. 
 
•  If w orse ni n g of dia g n ostic o bser vati o ns des pite i nitiati o n of 
c ortic oster oi ds, t he n f oll o w Gr a d e 2 g ui deli nes. *  
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 da y of o nset , mai ntai n d ose 
  
If res ol ve d i n > 2 8 da ys  fr o m da y of o nset, re d uce d ose 1 le vel 
 
H o we ver, if t he e ve nt  gra de 1 I L D / p ne u m o nitis occ urs be y o n d c ycle 
da y 2 2 a n d has n ot res ol ve d wit hi n 4 9 da ys fr o m t he last i nf usi o n, t he 
dr u g s h o ul d be disc o nti n ue d.  
 
 * If s u bj ect is as y m pt o matic, t he n s u bj ect s h o ul d still be c o nsi dere d 
as Gra de 1 e ve n if ster oi d treat me nt is  gi ve n  
 
Gra de 2  
P er ma ne ntl y d isc o nti n ue s u bj ect fr o m st u d y treat me nt. 
 
•  Pr o m ptl y  start a n d treat wit h s yste mic ster oi ds (e. g., at least 
1  m g/ k g/ da y pre d nis o ne or e q ui vale nt) f or at least 1 4 da ys or 
u ntil c o m plete res ol uti o n of cli nical a n d c hest C T fi n di n gs, 
t he n f oll o we d b y a gra d ual ta p er  o ver at least 4 wee ks.  
•  M o nit or s y m pt o ms cl osel y.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 4 9  
•  Re -i ma ge as cli nicall y i n dicat e d. 
•  If w orse ni n g or n o i m pr o ve me nt i n cli nical or dia g n ostic 
o bser vati o ns i n 5 da ys,  
•  C o nsi der i ncreasi n g d ose of st er oi ds (e. g., 2 
m g/ k g/ da y pre d nis o ne or e q ui vale nt) a n d 
a d mi nistrati o n ma y be s witc he d t o i ntra ve n o us (e. g. 
met h yl pre d nis ol o ne).  
•  Re -c o nsi der a d diti o nal wor k -u p f or alter nati ve 
eti ol o gies as descri be d a b o ve.  
•  Escalate care as cli nicall y i n di cate d.  
 
Gra de 3 a n d 4  
P er ma ne ntl y d isc o nti n ue s u bj ect fr o m st u d y treat me nt. 
 
•  H os pitalizati o n re q uire d.  
•  Pr o m ptl y i nitiate e m piric hi g h -d ose met h yl pre d nis ol o ne I V 
treat me nt (e. g., 5 0 0-1 0 0 0 m g/ da y f or 3 da ys), f oll o we d b y at 
least 1 m g/ k g/ da y of pre d nis o ne ( or e q ui vale nt) f or at least 
1 4 da ys or u ntil c o m plete res ol uti o n of cli nical a n d c hest C T 
fi n di n gs, t he n f oll o we d b y a gra d ual ta per  o ver at least 4 
wee ks.  
•  Re -i ma ge as cli nicall y i n dicat e d. 
•  If still n o i m pr o ve me nt wit hi n 3 t o 5 da ys,  
•  Re -c o nsi der a d diti o nal w or k -u p f or alter nati ve 
eti ol o gies as descri be d a b o ve.  
•  C o nsi der ot her i m m u n o -s u p pressa nts a n d/or treat per 
l ocal practice. 
Oc ul ar  
Gra de 3  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1:  
•   If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose 
•   If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
Gra de 4  
Disc o nti n ue s u bj ect fr o m st u d y treat me nt . 
 Bl o o d cre ati ni ne i ncre ase d  
Gra de 3  
(> 3. 0 t o 6. 0 x U L N)  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 2 or baseli ne . 
•   R e d uce d ose 1 le vel  
Gra de 4  
( > 6. 0 x U L N) 
Disc o nti n ue s u bj ect fr o m st u d y treat me nt . 
He p atic T o xicit y  
As p art ate a mi n otr a ns a mi n ase ( A S T ) or al a ni ne a mi n otr a ns a mi n ase ( A L T )  wit h 
si m ult a ne o us T B L 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 0  
A S T/ A L T ≥ 3. 0 x U L N 
wit h si m ulta ne o us T B L 
>  2. 0 x U L N  
Dela y st u d y me dicati o n u ntil dr u g -i n d uce d li ver i nj ur y ca n be r ule d 
o ut.  
•   If dr u g-i n d uce d li ver i nj ur y is r ule d o ut, t he s u bj ect s h o ul d b e 
treate d acc or di n gl y, a n d res u m pti o n of st u d y dr u g ma y occ ur after 
disc ussi o n bet wee n t he I n vesti gat or a n d S p o ns or.  
•   If dr u g-i n d uce d li ver i nj ur y ca n n ot be r ule d o ut fr o m dia g n ostic 
w or k u p, pe r ma ne ntl y disc o nti n ue st u d y treat me nt. 
M o nit or A S T/ A L T a n d T B L t wice wee kl y u ntil res ol uti o n or ret ur n t o 
baseli ne.  
As p art ate a mi n otr a ns a mi n ase ( A S T ) or al a ni ne a mi n otr a ns a mi n ase ( A L T ) i ncre ase d 
Gra de 2  
(> 3. 0 t o 5. 0 x U L N ) 
N o acti o n f or Gra de 2 A S T/ A L T . 
Gra de 3  
( > 5. 0 t o 2 0. 0 x U L N ) 
I n s u bj ects wit h o ut li ver 
metastases a n d s u bj ects 
wit h li ver metastases 
a n d baseli ne le vel ≤ 3 x 
U L N  
Re peat testi n g wit hi n 3 da ys.  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1  if baseli ne ≤ 3 x U L N, 
ot her wise dela y d ose u ntil res ol ve d t o ≤ baseli ne, t he n:  
•   If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose 
•   If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
Gra de 3  
( > 8 . 0 t o 2 0. 0 x U L N ) 
I n s u bj ects wit h li ver 
metastases, if t he 
baseli ne le vel was > 3 x 
U L N  
Re peat testi n g wit hi n 3 da ys.  
Dela y d ose u ntil res ol ve d t o baseli ne le vel : 
•   If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose 
•   If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
Gra de 4  
( > 2 0. 0 x U L N)  
Disc o nti n ue s u bj ect fr o m st u d y treat me nt. 
T B L  i ncre ase d 
Gra de 2  
( > 1. 5 t o 3. 0 x U L N)  
If n o d oc u me nte d Gil bert’s s y n dr o me or li ver metastases at baseli ne, 
d ela y d ose u ntil res ol ve d t o ≤ Gra de 1:  
  
If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose 
  
If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
If d oc u me nte d Gil bert’s s y n dr o me or li ver metastases at baseli ne, 
c o nti n ue st u d y treat me nt  
Gra de 3  
( > 3. 0 t o 1 0. 0 x U L N)  
If n o d oc u me nte d Gil bert’s s y n dr o me or li ver metastases at baseli ne, 
re peat testi n g wit hi n 3 da ys.  Dela y d ose u ntil res ol ve d t o ≤ Gra de 1:  
  
If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, re d uce d ose 1 le vel 
  
If res ol ve d i n > 7 da ys fr o m d a y of o nset, disc o nti n ue D S-8 2 0 1a  
If d oc u me nte d Gil bert’s s y n dr o me or li ver metastases at baseli ne, 
re peat testi n g wit hi n 3 da ys. Dela y d ose u ntil res ol ve d t o < Gra de 2:  
  
If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, re d uce d ose 1 le vel 
  
If res ol ve d i n > 7 da ys fr o m d a y of o nset, disc o nti n ue D S-8 2 0 1a  
Gra de 4  
( > 1 0. 0 x U L N) 
Disc o nti n ue s u bj ect fr o m st u d y treat me nt . 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 1  
5. 5.   
Met h o d of Assessi n g Tre at me nt C o m pli a nce  
All dr u gs use d f or t he st u d y treat me nt will be a d mi nistere d b y t h e I n vesti gat or or ot her 
desi g nat e d st u d y p ers o n nel.  T heref ore, treat me nt c o m plia nce will be g uara ntee d as l o n g 
as t he s u bject atte n ds eac h visit f or t he a d mi nistrati o n of st u d y treat me nt.  Start a n d st o p 
date/ti me of i njecti o n, a m o u nt of dr u g a d mi nistere d, a n d reas o n f or d os e 
re d ucti o n/i nterr u pti o n (if a p plica ble) will be rec or de d i n me dical rec or d b y cli nical st u d y 
pers o n nel.   T hes e data will be rec or de d o n t he el ectr o nic case re p ort f or m (e C R F) . 
5. 6.   
Pri or a n d C o nc o mit a nt Me dic ati o ns  
5. 6. 1.   
C o nc o mit a nt Me dic ati o ns  
Me dicati o ns use d fr o m t he ti me t he s u bject si g ns t he I C F t o 4 0 -Da y F/ U  visit  ( +  7 da ys) 
will be rec or de d.  All c o nc o mita nt me dicati o ns will be rec or de d i n t he e C R F. 
Bl o o d Al k ali ne P h os p h at ase  ( A L P) I ncre ase d 
Gra de 3 t o 4  
(> 5. 0 x U L N ) 
N o m o dificati o n u nless deter mi ne d b y t he I n vesti gat or t o be cli nicall y 
si g nifica nt or life-t hreate ni n g. 
G astr oi ntesti n al  
N a use a  
Gra de 3  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1 :  
  
If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose 
  
If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
Di arr he a/ C olitis  
Gra de 3  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1 : 
  
If res ol ve d i n ≤ 3 da ys fr o m da y of o nset, mai ntai n d ose 
  
If res ol ve d i n > 3 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
Gra de 4  
Disc o nti n ue s u bj ect fr o m st u d y treat me nt . 
Ot her L a b or at or y A d verse E ve nts  
Gra de 3  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1 or baseli ne le vel:  
  
If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose 
  
If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel 
Gra de 4  
Disc o nti n ue s u bj ect fr o m st u d y treat me nt . 
Ot her N o n -l a b or at or y A d verse E ve nts 
Gra de 3  
Dela y d ose u ntil res ol ve d t o ≤ Gra de 1 or baseli ne:  
  
If res ol ve d i n ≤ 7 da ys fr o m da y of o nset, mai ntai n d ose  
  
If res ol ve d i n > 7 da ys fr o m d a y of o nset, re d uce d ose 1 le vel  
Gra de 4  
Disc o nti n ue s u bj ect fr o m st u d y treat me nt . 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 2  
5. 6. 2.   
Pr o hi bite d C o nc o mit a nt Me dic ati o ns/ Acti vities  
Wit h t he e x ce pti o n of me dicati o ns t hat are u n d er i n vesti gati o n i n t he st u d y (e. g. sta n dar d 
of care, c o m parat ors, or c o m bi nati o n t hera pies, the f oll o wi n g me dicati o ns, treat me nt a n d 
pr oce d ures will be pr o hi bite d  d uri n g t he treat me nt peri o d . T he S p o ns or m ust be n otifie d 
if a s u bject recei ves a n y of t hese d uri n g t he st u d y: 
 Ot her a ntica n cer t hera p y, i ncl u di n g c yt ot o xic, tar gete d a ge nts, 
i m m u n ot hera p y, a nti b o d y, reti n oi d, or h orm o n al treat me nt  [c o nc urre nt use of 
h or m o nes f or n o nca ncer -relate d c o n diti o ns (e. g. i ns uli n f or dia betes a n d 
h or m o ne re place me nt t h era p y) is acce pta bl e] .   
 Ot her i n vesti gati o nal t hera pe utic a ge nts.  
 Ra di ot hera p y (e x ce pt f or palliati ve ra diati o n t o k n o w n metastatic sites as l o n g 
as it d oes n ot affect assess me nt of res p o nse or i nterr u pt treat me nt f or m ore 
t ha n t he ma xi m u m ti me s pecifie d i n d ose m o dificati o n secti o n). 
 Ra di ot hera p y t o t he t h ora x.  
 C o nc o mita nt use of c hr o nic s yste mic  (I V or oral) c ortic oster oi ds or ot her 
i m m u n os u p pressi ve me dicati o ns e x ce pt f or ma na gi n g A Es ; I n h ale d ster oi ds or 
i ntra artic ular ster oi d i njecti o ns are per mitte d i n t his st u d y. 
 S u bjects wit h br o nc h o p ul m o nar y dis or ders w h o re q uire i nter mitte nt use of 
br o nc h o dilat ors (s uc h as al b uter ol) will n ot be e x cl u de d fr o m t his st u d y.  
 C o nc o mita nt treat me nt w it h c hl or o q ui ne or h y dr o x yc hl or o q ui ne is n ot 
all o we d d uri n g t he st u d y treat me nt. Refer t o 1 7. 6  f or f urt her details. 
 C o nc o mita nt use of dr u gs w hic h w o ul d i n d uce Q T pr ol o n gati o n  (see 
S u p ple me nt 3) . 
 
Per mitte d T her a pies/ Pr o d ucts  
 
He mat o p oietic gr o wt h fact ors m a y be use d f or pr o p h yla xis or treat me nt base d 
o n t he cli nical j u d g me nt of t he I n vesti gat or.  
 
Pr o p h ylactic or s u p p orti v e treat me nt of st u d y -dr u g i n d uce d A Es  will be 
ot her wise as p er I n v esti gat or’s discreti o n a n d i nstit uti o nal g ui deli nes. 
 
C o nc o mita nt use of d ietar y s u p ple m e nts, me dicati o ns n ot prescri be d b y t he 
I n v esti gat or, a n d alter nati ve/c o m ple me ntar y treat me nts is disc o ura ge d, b ut 
n ot pr o hi bit e d. 
 
Base d o n t h e c urre ntl y a v aila ble cli nical safet y dat a, it is rec o m me n de d t hat 
s u bjects recei ve pr o p h ylactic a nti-e metic a ge nts pri or t o i nf usi o n of T -D X d 
a n d o n s u bse q ue nt da ys. A ntie metics s uc h as 5 -h y dr o x ytr y pt a mi ne rece pt or 
( 5-H T 3) a nta g o nists or Ne ur o ki ni n -1 ( N K 1) rece pt or a nta g o nists a n d/ or 
ster oi ds (e. g. de x a met has o ne) s h o ul d be c o nsi dere d a n d a d mi nistere d  i n 
acc or da nce wit h t he pres cri bi n g i nf or mati o n or i nstit uti o nal g ui deli nes.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 3  
 
Restricte d Pr o d ucts  
 
Use of e -ci garettes a n d v a pi n g is str o n gl y disc o ura ge d b ut n ot pr o hi bite d.   
 
5. 7.   
S u bject Wit h dr a w al/ Disc o nti n u ati o n  
5. 7. 1.   
Re as o ns f or Wit h dr a w al  fr o m St u d y Tre at me nt 
S u bjects ma y be wit h dra w n fr o m t he st u d y treat m e nt after si g ni n g I C F f or t he f oll o wi n g 
reas o ns: 
 P D  per criteri a set f ort h i n Res p o nse 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  
 Cli nical pr o gressi o n ( defi niti ve cli nical si g ns of disease pr o gressi o n, b ut a 
rece nt ra di o gra p hi c assess me nt di d n ot meet t he criteria f or Pr o gressi ve 
Disease acc or di n g t o R E CI S T Versi o n 1. 1)  
 A d verse e ve nt  
 Wit h dra wal of c o nse nt t o st u d y treat me nt  
 P h ysicia n Decisi o n  
 Deat h  
 Pre g n a nc y  
 Pr ot oc ol vi olati o n  
 St u d y t er mi nate d b y t he s p o ns or 
 L ost t o F/ U  
 Ot her, s pecif y  
If t here is e vi de nce t hat t he s u bject is recei vi n g b e nefit fr o m treat me nt e ve n t h o u g h t he 
s u bject has met a criteri o n f or disc o nti n uati o n as liste d a b o ve, t he s u bject ma y re mai n o n 
st u d y treat me nt after disc ussi o n wit h t he S p o ns or .   
All s u bjects w h o are wit h dra w n fr o m 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 o ce d ures ( s ee Secti o n  6. 4 ) a n d F/ U  pr oce d ures ( see Secti o n  6. 5  a n d Secti o n  
6. 6 ). 
Rec or d t he reas o n f or a n y s u bject w h o disc o nti n ues st u d y treat me nt.  Disc o nti n ue d 
s u bjects will be f oll o we d f or s ur vi val, eit her t hr o u g h direct c o ntacts or b y c ollecti n g 
p u blic rec or ds (e g,  deat h certificates) as all o we d b y l ocal la ws.  
5. 7. 2.   
Re as o ns f or Wit h dr a w al fr o m St u d y P artici p ati o n  
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 C F f or t he f oll o wi n g reas o ns: 
 Wit h dra wal of c o nse nt t o partici pate i n st u d y pr oce d ures  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 4  
 Deat h  
 L ost t o F/ U  
 St u d y t er mi nate d b y t he s p o ns or 
 Ot her, s pecif y  
5. 7. 3.   
Wit h dr a w al Pr oce d ures  
If a s u bject is wit h dra w n fr o m t he st u d y, t he I n vesti gat or will c o m plete a n d re p ort t he 
o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he d ate 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 v esti 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.  
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete pr ot oc ol -s p ecifie d 
wit h dra wal pr o ce d ures.   Pr ot oc ol -s pecifie d wit hdra wal pr oce d ures will be perf or m e d 
d uri n g t he E O T  visit ( + 7 da ys , Secti o n  6. 4 ) a n d t h e 4 0-D a y F/ U  visit ( + 7 d a ys , Secti o n  
6. 5 ). 
5. 7. 4.   
S u bject Re pl ace me nt  
S u bjects t hat ha ve bee n e nr olle d a n d recei ve d st u d y dr u g  will n ot be re place d.  
5. 7. 5.   
S u bject Re -scree ni n g Pr oce d ures 
Re -scree ni n g is per mitte d f or a n y s u bject w h o faile d t o meet eli gi bilit y criteria u p o n 
i nitial scree ni n g.  T he u ni q ue S u bject N u m ber  m ust re mai n t he sa me at t he ti me of re -
scree ni n g.  T h e i nitial scree ni n g i nf or mati o n a n d t he reas o n w h y t he s u bject is 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 S cree ni n g L o g.  N o data fr o m t he i nit ial 
e val uati o n will be e ntere d i nt o t he cli nical data bas e f or a s u bject w h o is res cree n e d.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 5  
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 Secti o n  1 7. 7 . 
6. 1.   
Scree ni n g  
O btai n of a si g ne d a n d d ate d I C F b ef 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.  
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 e nr oll me nt  
 Assi g n a Site S u bject I de ntifier.  
 Assi g n a n u ni q ue S u bject N u m ber  b y I X R S  
 Rec or d de m o gra p hic (e g, birt h date, se x, race), pri mar y ca n cer hist or y, 
si g nifica nt me di cal hist or y i nf or m ati 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.   
 If a s u bject h as H E R 2 stat us data c o nfir me d b y a ce ntral la b orat or y i n a not h er 
D S -8 2 0 1a cli nical st u d y , i de ntif y t he u ni q ue S u bject N u m ber  f or t he st u dy a n d 
pr o vi de it t o t he ce ntral l a b orat or y of t h e D S 8 2 0 1 -A -J 1 0 2 st u d y. 
 R e vie w I ncl usi o n/ E x cl usi o n  criteria.  
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
Wit hi n 9 0 da ys bef ore e nr oll me nt  
 Perf or m a HI V a nti b o d y test.  
Wit hi n 2 8 da ys bef ore e nr oll me nt  
 O p ht hal m ol o gic ass ess 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 o m p ute d t o m o gra p h y ( C T)  or ma g netic 
res o na nce i ma gi n g ( M RI) sca ns of t he brai n, c hest, a b d o me n, pel vis, a n d a n y 
ot her sites of d isease (Secti o n  1 7. 3 ). 
Wit hi n 7 da ys bef ore e nr oll me nt  
 Perf or m a 1 2 -l ea d E C G i n tri plicate (Secti o n  9. 1 0 ).   
E C Gs will be ta ke n i n cl ose s uccessi o n, n o m ore t ha n a p pr o xi matel y 2 mi n 
a part, a n d after at least 1 0 mi n of q uiet rest i n t he s u pi ne p ositi o n.  A n y st u d y 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 6  
pr oce d ures s uc h as bl o o d sa m pli n g are n ot all o we d d uri n g q uiet rest a n d pri or 
t o E C G meas ure me nt. 
 Perf or m a c o m plet e 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 t e m perat ure).  
 Assess f u ncti o nal stat us usi n g t he E C O G P S  Scal e ( Secti o n  1 7. 2 ). 
 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 Secti o n 1 7. 1 ), 
pr ot hr o m bi n ti me a n d acti vate d partial t hr o m b o plasti 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 tr o p o ni n-T testi n g b y 
ce ntral la b (Secti o n  8. 5. 2 ). 
 O btai n a ser u m or uri ne s a m ple f or pre g na nc y t esti 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 us al  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 n c y d ue t o sterilizati o n s ur ger y, et c., n o 
pre g na nc y t est will be re q uire d.  Fe male s u bje cts w h o ha ve bee n a me n orr h eic 
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 m e n of c hil d-beari n g 
p ote ntial a n d re q uir e d t o u n der g o t he pre g na nc y t est.  
 Perf or m uri nal ysis test  (Secti o n  9. 8 ). 
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 plet e 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 s a m ple, I n v esti 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.  T u m or  sli des f or ass ess me nt of H E R 2 b y 
I H C/ FI S H are nee de d.  T he detaile d pr o ce d ures f or pre pari n g a n d s u b mitti n g 
t u m or sa m ples will be pr o vi de d i n Secti o n  8. 2 .  If a s u bject has H E R 2 stat us 
data c o nfir m e d b y a ce ntral la b orat or y i n  a n ot h er D S -8 2 0 1a cli nical st u d y , 
t here is n o nee d t o c ollect a n d s u b mit t u m or sa m ples. 
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  
6. 3. 1.   
T u m or A ssess 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 v er 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 v er y 1 2 wee ks ( ± 7 da ys) re gar dless of dela y i n d osi n g.  T h e assess me nt will 
be c o n d ucte d bef ore Da y 1 of eac h C ycl e as p ossi ble.  C T or M RI s ca 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 metast asis 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 ociat e d wit h brai n 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 7  
metastasis occ ur.  If n o cli nical s y m pt o ms are o bs er ve d, brai n C T or M RI is n ot 
ma n dat or y  (Secti o n  1 7. 3 ). 
6. 3. 2.   
Ot her St u d y Pr o ce d ure i n Tre at me nt Peri o d  
N O T E:  T he tri plicate 1 2 -lea d safet y E C Gs will be perf or me d at t he eac h ti me p oi nt i n 
cl ose s uccessi o n, n o m ore t ha n a p pr o xi matel y 2 mi n a part, a n d after at least 1 0 mi n of 
q uiet rest i n t he s u pi ne p ositi o n. A n y st u d y pr oce d ures s uc h as bl o o d sa m pli n g are n ot 
all o we d d uri n g q uiet rest a n d pri or t o E C G meas ure me nt.  
6. 3. 2. 1.  
C ycle 1, D a y 0  
T he f oll o wi n g pr oce d ures will be perf or me d o n Da y 0  (Wit hi n 3 da ys bef ore  Da y 0 ). 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
T he I n vesti gat or m ust c o nfir m a n y cli nicall y si g nifica nt A Es ha v e n ot bee n 
occ urre d bef ore p erf or mi n g a 1 2 -lea d E C G. 
 Perf or m a 1 2 -l ea d E C G i n tri plicate at t he f oll o wi n g ti me p oi nts (Secti o n  
9. 1 0 ):  
 1 5 mi n utes bef ore t he pla n ne d start ti me of a d mi nistrati o n o n  C ycle  1, Da y  
1 (Acce pta ble ra n ge of E C G meas ure me nt start ti me: ± 1 0 mi n utes)  
 3 0  mi n utes after t he pla n ne d start ti me of a d mi nistrati o n o n C ycl e 1, Da y  1  
( Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
 2 h o urs after t h e pla n ne d start ti me of a d mi nistrati o n o n  C ycle  1, Da y  1  
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
 4 h o urs after t h e pla n ne d start ti me of a d mi nistrati o n o n  C ycle  1, Da y  1  
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
 7 h o urs after t h e pla n ne d start ti me of a d mi nistrati o n o n  C ycle  1, Da y  1  
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
6. 3. 2. 2.  
C ycle 1, D a y 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 n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
Lat est data wit hi n 3 da ys bef ore a d mi nistrati o n  
P h ysical e xa m i nati o n, wei g ht, E C O G P S  Scale assess me nt, he mat ol o g y, bl o o d 
c he mistr y a n d vital si g ns e val uati o ns d o N O T nee d t o be re peate d if perf or me d wit hi n 
3 da ys b ef ore t he first d ose of st u d y dr u g.  
 Perf or m a c o m plet e p h ysical e xa mi nati o n a n d rec or d wei g ht.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 8  
 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 peri p heral o x y ge n sat urati o n [ S p O 2]). 
 Assess f u ncti o nal stat us usi n g t he E C O G P S  Scal e ( Secti o n  1 7. 2 ). 
 O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n  9. 8 ). 
Wit hi n 8 h o urs bef ore a d mi nistrati o n 
 O btai n b l o o d sa m ple f or A D A  (Secti o n  8. 6 ). 
1 5 mi n utes  bef ore a d mi nistrati o n  
 Perf or m a 1 2 -l ea d E C G i n tri plicate (Acce pta ble ra n ge  of E C G meas ure me nt 
start ti me: ± 1 0 mi n utes)  (Secti o n  9. 1 0 ). 
 O btai n P K bl o o d sa m ple ( Wit hi n 1 0 mi n utes after c o m pleti n g E C G 
meas ure me nt) (Secti o n  8. 3 ). 
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  5. 2. 4 . 
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 t e m perat ure).  
 Perf or m a 1 2 -l ead E C G i n tri plicate at t he f oll o wi n g ti me p oi nts  (Secti o n  
9. 1 0 ): 
 2 h o urs after t h e start of a d mi nistrati o n   
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
 4 h o urs after t h e start of a d mi nistrati o n  
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
 7  h o urs after t h e start of a d mi nistrati o n   
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
 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 ( Secti o n 8. 3 ): 
 E OI ( Wit hi n  1 0  mi n utes after  E OI ) 
 2 h o urs after t h e start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes after 
c o m pleti n g E C G meas ure me nt)  
 4 h o urs after t h e start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes after 
c o m pleti n g E C G meas ure me nt)  
 7 h o urs after t h e start of a d mi nistrati o n ( Wit hi n 1 0 mi n utes after 
c o m pleti n g E C G meas ure me nt)  
 O btai n bl o o d sa m ples f o r 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 tr o p o ni n-T testi n g b y ce ntral l a b 2 t o 3 h o urs after 
E OI  ( Secti o n 8. 5. 2 ). 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 5 9  
 If tr o p o ni n le vels are c o nsiste nt wit h m y o car dial i nfarcti o n as d efi ne d 
acc or di n g t o ma n ufact urer ( C T C A E Gra d e 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 v el 
of m y ocar dial i nfarcti o n as defi ne d b y t he m a n ufact urer ( C T C A E Gra d e 
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 d efi 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 r e 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 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 ncreas es per i nstit uti o nal g ui deli nes, t he n p erf or m a 1 2 -lea d E C G i n 
tri plicate, re peat tro p o ni n testi n g at 6 h o urs (  ±  1 h o u r) 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 h o u r) or at 2 4 h o urs 
( ±  2 h o u rs) aft er i nitial tr o p o ni n test. 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 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 t e m perat ure).  
 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 nistrat i o n (Secti o n  8. 3 ). 
 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 n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 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.  
 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 t e 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 ) after t he start of Da y 1 
a d mi nistrati o n ( Secti o n  8. 3 ). 
 Rec or d c o n c o mita nt me dicati o ns.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 0  
 Assess s u bjects f or A Es.  
6. 3. 2. 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 t e m perat ure).  
 Perf or m a 1 2 -l ea d E C G i n tri plicate (Secti o n  9. 1 0 ). 
 O btai n P K bl o o d sa m ples o n Da y 8 ( Wit hi n 1 0 mi n utes after c o m pleti n g E C G 
meas ure me nt) (Secti o n  8. 3 ). 
 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 a bl o o d sa m ple f or A D A  (Secti o n  8. 6 ). 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 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 t e m perat ure).  
 Perf or m a 1 2 -l ea d E C G i n tri plicate (Secti o n  9. 1 0 ). 
 O btai n P K bl o o d sa m ples o n Da y 1 5  ( Wit hi n 1 0 mi n utes after c o m pleti n g 
E C G meas ure me nt)  (Secti o n  8. 3 ). 
 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 n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 7.  
C ycle 1, D a y 2 2  
If t he sc he d ul e o n Da y 1 of t he ne xt c ycl e is dela ye d f or 3 da ys or m ore, i n cl u di n g if 
t he s u bject ca n n ot c o nti n ue ont o t he ne xt c ycl e, 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  8. 3 ). 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 8.  
C ycle 2, D a y 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  ( ± 2 da ys ).  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 1  
 Rec or d c o n c o mita nt me dicati o ns.   
 Assess s u bjects f or A Es.  
Lat est data wit hi n 3 da ys bef ore a d mi nistrati o n  
 O p ht hal m ol o gic ass ess 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 pl a n n e d date of st u d y dr u g a d mi nistrati o n is dela ye d after 
e x a mi nati o n of o p ht hal m ol o gic ass ess 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 x a 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 plet e 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 P S  Scal e ( Secti o n  1 7. 2 ). 
 Perf or m a 1 2 -l ea d E C G i n tri plicate (Secti o n  9. 1 0 ).  
 O btai n bl o o d sa m ples f or saf et 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 d ate of st u d y dr u g a d mi nistrati o n is dela ye d after e x a mi nati o n 
o f 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 x a 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. 
Wit hi n 8 h o urs bef ore a d mi nistrati o n  
 O btai n P K bl o o d sa m ple ( Secti o n  8. 3 ). 
E ve n 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 bef ore i nf usi o n ( BI) o n Da y 1 of C ycl e 2 if p ossi ble.  
 O btai n a bl o o d sa m ple f or A D A  (Secti o n  8. 6 ). 
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  5. 2. 4 . 
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 t e 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 3 0  mi n utes after 
E OI ( Secti o n  8. 3 ). 
 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 a n d tr o p o ni n-T testi n g b y ce ntral l a b 2 t o 3 h o urs after 
E OI ( Secti o n 8. 5. 2 ). 
 If tr o p o ni n le vels are c o nsiste nt wit h m y o car dial i nfarcti o n as d efi ne d 
acc or di n g t o ma n ufact urer ( C T C A E Gra d e 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 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 2  
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 v el 
of m y ocar dial i nfarcti o n as defi ne d b y t he m a n ufact urer ( C T C A E Gra d e 
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 d efi 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 r e 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 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 ncreas es per i nstit uti o nal g ui deli nes, t he n p erf or m a 1 2 -lea d E C G i n 
tri plicate, re peat tro p o ni n testi n g at 6 h o urs (  ±  1 h o u r) 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 h o u r) or at 2 4 h o urs 
( ±  2 h o u rs) aft er i nitial tr o p o ni n test. 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 9.  
C ycle 2, 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 ( ± 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 t e 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 n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 1 0.  C ycle 2, 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  ( ± 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 t e 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 n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 1 1.  C ycle 2, D a y 2 2  
If t he sc he d ul e o n Da y 1 of t he ne xt c ycl e is dela ye d f or 3 da ys or m ore, i n cl 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 ycl e, 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).  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 3  
 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 ( S ecti o n 8. 3 ). 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 1 2.  C ycle 3, D a y 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 p re-d ose o n Da y 1  ( ± 2 da ys ).   
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
Lat est data wit hi n 3 da ys bef ore a d mi nistrati o n  
 Perf or m a c o m plet e 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 P S  Scal e ( Secti o n  1 7. 2 ). 
 O btai n bl o o d sa m ples f or safe t 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 d ate of st u d y dr u g a d mi nistrati o n is dela ye d after e x a 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 x a 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. 
1 5 mi n utes  bef ore a d mi nistrati o n  
 Perf or m a 1 2-l ea d E C G i n tri plicate (Acce pta ble ra n ge of E C G meas ure me nt 
start ti me: ± 1 0 mi n utes)  (Secti o n  9. 1 0 ). 
 O btai n P K bl o o d sa m ple ( Wit hi n 1 0 mi n utes after c o m pleti n g E C G 
meas ure me nt) (Secti o n  8. 3 ). 
E ve n if bl o o d sa m ple i s 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 ycl e 3  if p ossi ble. 
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 S ecti o n 5. 2. 4 . 
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 ur e a n d 
p ulse rate a n d b o d y t e m perat ure).  
 Perf or m a 1 2 -l ea d E C G i n tri plicate at t he f oll o wi n g ti me p oi nts (Secti o n  
9. 1 0 ):  
 E OI ( Wit hi n 1 5  mi n utes after E OI)  
 2 h o urs after t h e start of a d mi nistrati o n   
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 4  
 4 h o urs after t h e start of a d mi nistrati o n   
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
 7  h o urs after t h e start of a d mi nistrati o n   
(Acce pta ble ra n ge of E C G meas ure m e nt start ti me: ± 1 0 mi n utes)  
 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  ( Secti o n 8. 3 ):  
 E OI (Wit hi n 1 0 mi n utes after c o m pleti n g E C G m eas ure m e nt ) 
 2 h o urs after t h e start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes after 
c o m pleti n g E C G mea s ure me nt) 
 4 h o urs after t h e start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes after 
c o m pleti n g E C G meas ure me nt)  
 7 h o urs after t h e start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes after 
c o m pleti n g E C G meas ure me nt)  
 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 a n d tr o p o ni n-T testi n g b y ce ntral l a b 2 t o 3 h o urs after 
E OI ( Secti o n 8. 5. 2 ). 
 If tr o p o ni n le vels are c o nsiste nt wit h m y o car dial i nfarcti o n as d efi ne d 
acc or di n g t o ma n ufact urer ( C T C A E Gra d e 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 nst it 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 v el 
of m y ocar dial i nfarcti o n as defi ne d b y t he m a n ufact urer ( C T C A E Gra d e 
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 d efi 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 r e 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 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 ncreas es per i nstit uti o nal g ui deli nes, t he n p erf 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 at 6 h o urs ( ±  1 h o u r) 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 h o u r) or at 2 4 h o urs 
( ±  2 h o u rs) aft er i nitial tr o p o ni n test. 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 1 3.  C ycle 3 , 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.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 5  
 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 t e m perat ure).  
 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  8. 3 ). 
 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 n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es. 
6. 3. 2. 1 4.  C ycle 3 , 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.  
 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 t e 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 ) after t he start of Da y 1 
a d mi nistrati o n ( Secti o n  8. 3 ). 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 1 5.  C ycle 3, D a y 8  
T he f oll o wi n g pr oce d ures will b e 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 t e m perat ure).  
 Perf or m a 1 2 -l ea d E C G i n tri plicate (Secti o n  9. 1 0 ). 
 O btai n P K bl o o d sa m ples o n  Da y 8  ( Wit hi n 1 0 mi n utes after c o m pleti n g E C G 
meas ure me nt) (Secti o n  8. 3 ). 
 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 n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 1 6.  C ycle 3, 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 dias t olic bl o o d press ure a n d 
p ulse rate a n d b o d y t e m perat ure).  
 Perf or m a 1 2 -l ea d E C G i n tri plicate (Secti o n  9. 1 0 ). 
 O btai n P K bl o o d sa m ples o n  Da y 1 5 ( Wit hi n 1 0 mi n utes after c o m pleti n g 
E C G meas ure me nt) (Secti o n  8. 3 ). 
 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 oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 6  
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 1 7.  C ycle 3, D a y 2 2  
If t he sc he d ul e o n Da y 1 of t he ne xt c ycl e is dela ye d f or 3 da ys or m ore, i n cl 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 ycl e, 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  8. 3 ). 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 3. 2. 1 8.  C ycle 4 a n d S u bse q ue nt C ycles, D a y 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  ( ± 2 da ys ).  
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
Lat est data wit hi n 3 da ys bef ore a d mi nistrati o n  
 Perf or m a c o m plet e 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 P S  Scal e ( Secti o n  1 7. 2 ). 
 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 -l ea d E C G i n tri plicate (Secti o n  9. 1 0 ). 
< At Da y 1 e v er y 2 c ycles fr o m  C ycl e 5  t o t he E O T (e g, Da y 1 i n C ycle 5, 7, 9...)>  
 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 d ate of st u d y dr u g a d mi nistrati o n is dela ye d after e x a 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 x a 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. 
Wit hi n 8 h o urs bef ore a d mi nistrati 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 8. 3 ).   
E ve n if  bl o o d sa m ple is c ollecte d o n Da y 2 2 of C ycle 3, 5 a n d/ or 7, 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, 6 a n d/ or 8 if p ossi ble. 
< At Da y 1 e v er y 2 c ycles fr o m C yc l e 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 bl o o d sa m ple f or A D A  ( Secti o n 8. 6 ). A p orti o n of A D A bl o o d 
sa m ple will be use d f or f ut ure ce ntral la b a nal ysis f or S A R S -C o V -2 testi n g 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 7  
o nce pr ot oc ol versi o n 7 . 0 is a p plie d f or a s u bject. S A R S -C o V -2 testi n g will be 
c o n d ucte d e v er y 4 c ycles fr o m C ycl e 4 ( C ycle 4, C ycle 8 etc.).  
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  5. 2. 4 . 
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.  
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
< E ver y  2 c ycles fr o m C ycle 4 u ntil C ycle 8 at t he ma xi m u m (e g, Da y 1 of c ycle 4, 6, 
8) >  
 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 3 0  mi n utes  after 
E OI ( Secti o n  8. 3 ). 
6. 3. 2. 1 8. 1.  C ycle 5 , D a y 2 2 a n d C ycle 7 , D a y 2 2 
If t he sc he d ul e o n Da y 1 of t he ne xt c ycl e is dela ye d f or 3 da ys or m ore, i n cl 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 ycl e, 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  8. 3 ). 
 Rec or d c o n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
6. 4.   
E n d of Tre at me nt  
T he E O T is defi ne d as t h e date t he I n v esti gat or deci des t o disc o nti n ue st u d y treat me nt.   
T he f oll o wi n g assess me nts will be perf or me d at E O T visit ( + 7 da ys).  H o we ver, if t h e 
f oll o wi n g ass ess me nts ha ve bee n p erf or me d wit hi n 3 0 da ys ( ±  9  da ys ) of t heir last 
treat me nt, 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, 
ot her wise t hese assess me nts nee d t o be re p eate d.  
 O p ht hal m ol o gic ass ess 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 plet e 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 ol ic 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 P S  Scal e ( Secti o n  1 7. 2 ). 
 Perf or m a 1 2 -l ea d E C G i n tri plicate (Secti o n  9. 1 0 ). 
 O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n  9. 8 ), A D A  (Secti o n  8. 6 ), 
tr o p o ni n ( prefera bl y hi g h -se nsiti vit y tr o p o ni n-T) t esti n g b y  st u d y site ( Secti o n 
8. 5. 2 ). A p orti o n of A D A bl o o d sa m ple will be use d f or f ut ure ce ntral la b 
a nal ysis f or S A R S -C o V -2 testi n g o nce pr ot oc ol v ersi o n 7. 0 is a p plie d f or a 
s u bject. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 8  
 O btai n a ser u m or uri ne s a m ple f or pre g na nc y t esti 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 m ale s u bjects w h o ha ve n o p ossi bilit y of pre g na n c y d ue t o 
sterilizati o n s ur ger y, et c., n o pre g na nc y t est will be re q uire d.  Fe male s u bjects 
w h o ha ve bee n a me n orr h eic f or 1 2 m o nt hs or l o n ger f or me di cal reas o ns ot her 
t ha n steriliz ati o n s ur ger y (e g, effect of me dicati o n) will be re gar de d as w o m e n 
of c hil d -beari n g p ot e ntial a n d re q uire d t o u n der g o t he pre g na n c y test.  
 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 s ca ns of t he c hest, a b d o m e n a n d pel vis are 
ma n dat or y.  H o we ver, if t here is n o brai n metast as is at t he ti me of scree ni n g, 
C T or M RI s h o ul d o nl y b e 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 bs er ve d, brai n C T or M RI is 
n ot ma n dat or y ( Secti o n  1 7. 3 ).  If pr o gressi o n is i de ntifie d i n a pri or 
e x a mi nati o n, o nl y t he c h est is e x a 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 n c o mita nt me dicati o ns.  
 Assess s u bjects f or A Es.  
 Rec or d reas o n f or treat m e n t disc o nti n uati o n. 
6. 5.   
4 0 -D a y F oll o w -u p  
F ort y da ys ( + 7 da ys) after last st u d y dr u g a d mi nistrati o n or bef ore starti n g n e w a ntica n cer 
treat me nt, w hic he v er c o mes first, t he f oll o wi n g pr oce d ures will be perf or me d.  If E O T 
visit is > 4 0 da ys aft er last treat me nt, t he n t he E O T assess me nts ca n als o f u n cti o n as t he 
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 t e m perat ure  a n d S p O 2). 
 Perf or m a c o m plet e 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 P S  Scal e ( Secti o n  1 7. 2 ). 
 O btai n bl o o d sa m ples f or safet y la b orat ories ( Secti o n  9. 8 ), A D A  (Secti o n  
8. 6 ).F or s u bjects wit h p ositi ve A D A  at 4 0 -Da y 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 h e A D A  b ec o mes ne gati ve, or if A D A  titer 
bec o mes less t ha n bas eli ne (a p plica bl e 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 ns e nt fr o m 
t he st u d y, w hic h e ver occ urs first. A p orti o n of A D A bl o o d sa m ple will be 
use d f or f ut ure ce ntral la b a nal ysis f or S A R S -C o V -2 testi n g o n ce pr ot oc ol 
versi o n 7. 0 is a p plie d f or a s u b ject. 
 O btai n a ser u m or uri ne s a m ple f or pre g na nc y t esti 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 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 6 9  
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 m ale s u bjects w h o ha ve  n o p ossi bilit y of pre g na n c y d ue t o 
sterilizati o n s ur ger y, et c., n o pre g na nc y t est will be re q uire d.  Fe male s u bjects 
w h o ha ve bee n a me n orr h eic f or 1 2 m o nt hs or l o n ger f or me di cal reas o ns ot her 
t ha n steriliz ati o n s ur ger y (e g, effect of me dicati o n) will be re gar de d as w o m e n 
of c hil d -beari n g p ot e ntial a n d re q uire d t o u n der g o t he pre g na n c y test.  
 Rec or d c o n c 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  
S u bjects will be assesse d e ver y 3  m o nt hs ( ± 1 4 da ys), fr o m t he date  of 4 0 -Da y F/ U visit , 
f or s ur vi val a n d s u bse q u e nt a ntica ncer t hera p y u ntil deat h, wit h dra wal of c o nse nt, l ost t o 
F/ U  or st u d y cl os ure, w hic he ver occ urs first.  T his i nf or mati o n ma y b e c ollecte d i n a visit 
or via p h o ne c o ntact, or (as necess ar y f or s ur vi val  stat us, i n t he case of wit h dra wal of 
c o nse nt or l oss t o F/ U ) fr o m p u blic rec or ds as all o we d b y la w. 
F urt her F/ U  ma y b e re q uire d f or o n g oi n g A Es.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 0  
7.   
E F FI C A C Y A S S E S S M E N T S  
7. 1.   
Assess me nts f or Effic ac y E n d p oi nt(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 ycl e 1 a n d t hereafter e ver y 1 2 
wee ks w hile t he s u bject r e 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 wi ll be 
assesse d b y e v al 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. 3 ). 
C T or M RI (s piral C T or M RI w it 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 h er m o dalit y of disease assess me nt is 
necessar y f or t he l esi o ns at scree ni n g p eri 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 v er, 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 b e 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 bs er 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 effi cac y v aria bles will be ass esse d.  
 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) 
 D C R (t he s u m of C R rate, P R rate, a n d S D rate)  
 D o R  
 D urati o n of S D  
 C B R  
 T T R  
 P F S  
 O S  
 Perce nt c ha n ge i n tar get lesi o n  
7. 2.   
A p pr o pri ate ness of Selecte d Effic ac y Assess me nt (s) 
T he effi cac y assess me nts were s electe d f or t his st u d y beca use R E CI S T is us e d wi del y 
a n d ge nerall y rec o g nize d as sta n dar d t u m or res p o nse criteria.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 1  
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.   
Bl o o d S a m pli n g  
Bl o o d sa m ples f or P K a n d A D A  will be c ollect e 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 ollect e 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 ntr al 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).  
8. 2.   
T u m or S a m pli n g  
Sli des  of t u m or tiss ue secti o ns w hic h are o btai ne d bef ore t h e 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 b y I H C a n d FI S H) 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 ass ess me nt of t he bi o mar ker.  If a s u bject has H E R 2 stat us data 
c o nfir m e d b y a ce ntr al la b orat or y i n a not her D S -8 2 0 1a cli nical st u d y , t h ere is n o nee d t o 
c ollect a n d s u b mit t u m or sa m ples.  
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 alr ea 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 s a m pl es are a v aila ble f or o ne patie nt, it is rec o m me n de d t o s u b mit 
t he m ost rece nt 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 n ee dle 
bi o ps y or e n d os c o p y s h o ul d be s u b mitte d.   
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 o ce 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 
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) . 
8. 3.   
P h ar m ac o ki netic ( P K) Assess me nt (s) 
Ser u m P K para meters  (A U Cta u, C ma x, T ma x a n d Ctr o u g h ) of D S-8 2 0 1a f or eac h s u bj ect 
will be esti mate d usi n g st a n dar d n o nc o m p art 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 a, all para m eters liste d a b o ve will be esti mate d. 
Bl o o d sa m ples of a p pr o xi matel y 4 m L  f or P Ks a n al yses will be c ollecte d at t he ti me 
p oi nts s pecifie d i n  Ta ble  8 .1  a n d Ta ble  8 .2 .  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 x act 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. 
T a ble  8 .1 :  
P h ar m a c o ki netic S a m pli n g Ti me P oi nts  
C ycle   
D a y   
S a m pli n g T i me P oi nt ( Acce pt a ble R a n ge)  
C ycle 1   
Da y 1   
BI ( Wit hi n 1 0 mi n utes after c o m pleti n g E C G meas ure me nt) 
E OI ( Wit hi n 1 0  mi n utes after E OI)  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 2  
C ycle   
D a y   
S a m pli n g T i me P oi nt ( Acce pt a ble R a n ge)  
2 h o urs after t he start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes 
after c o m pleti n g E C G meas ure me nt)  
4 h o urs after t he  start of a d mi nistrati o n ( Wit hi n 1 0 mi n utes 
after c o m pleti n g E C G meas ure me nt)  
7 h o urs after t he start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes 
after c o m pleti n g E C G meas ure me nt)  
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 ) 
Da y 8  
7 da ys after t he start of a d mi nistrati o n (  ±  1  da y ) ( Wit hi n 1 0 
mi n utes after c o m pleti n g E C G meas ure me nt)  
Da y 1 5  
1 4 da ys after t he start of a d mi nistrati o n (  ±  1  da y ) ( Wit hi n 
1 0  mi n utes after c o m pleti n g E C G meas ure me nt)  
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 y s) 
C ycle 2   
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 3 0  mi n utes after E OI  
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 y s) 
C ycle 3   
Da y 1   
BI  (Wit hi n 1 0 mi n utes after  c o m pleti n g E C G meas ure me nt ) 
E OI ( Wit hi n 1 0 mi n utes after c o m pleti n g E C G 
meas ure me nt ) 
2 h o urs after t he start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes 
after c o m pleti n g E C G meas ure me nt)  
4 h o urs after t he start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes 
after c o m pletin g E C G meas ure me nt)  
7 h o urs after t he start of a d mi nistrati o n  ( Wit hi n 1 0 mi n utes 
after c o m pleti n g E C G meas ure me nt)  
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 ) 
Da y 8  
7 da ys after t he start of a d mi nistrati o n (  ±  1 da y ) ( Wit hi n 1 0 
mi n utes after c o m pleti n g E C G meas ure me nt)  
Da y 1 5  
1 4 da ys after t he start of a d mi nistrati o n (  ±  1 da y ) ( Wit hi n 
1 0  mi n utes after c o m pleti n g E C G meas ure me nt)  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 3  
C ycle   
D a y   
S a m pli n g T i me P oi nt ( Acce pt a ble R a n ge)  
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 y s) 
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 , 5 a n d/ or 
7, t he bl o o d sa m ple will be c ollecte d at BI o n Da y 1 of ne xt 
C ycle if p ossi ble . 
E OI: Wit hi n 3 0  mi n utes after E OI  
BI = bef ore i nf usi o n, E C G = electr ocar di o gra m, E OI = e n d of i nf usi o n  
 
I n case of c hl or o q ui ne or h y dr o x yc hl or o q ui ne a d mi nistrati o n f or S A R S -C o V -2  i nfecti o n, 
a d diti o nal P K ser u m sa m ples s h o ul d be c ollecte d at t he ti me p oi nts s pecifie d i n  Ta ble  8 .2 . 
 
T a ble  8 .2 :  
Sc he d ule of P K S a m ple C ollecti o n f or S u bjects A d mi nistere d 
C hl or o q ui ne or H y dr o x yc hl or o q ui ne  
D a y of C Q or H C Q A d mi nistr ati o n  
S a m pli n g Ti me P oi nt ( Acce pt a ble 
R a n ges)  
Da y 1  
Pri or t o C Q/ H C Q d ose  
Da y 3 or Da y 4  
Pri or t o C Q/ H C Q d ose ( wit hi n 4 hrs)  
E n d of C Q or H C Q treat me nt  
Pri or t o C Q/ H C Q d ose ( wit hi n 4 hrs)  
Pri or t o res u m pti o n of D S -8 2 0 1a (after C Q/ H C Q 
was h -o ut peri o d) a 
Bef ore i nf usi o n of  st u d y trea me nt ( wit hi n 
8  hrs)  
C Q = c hl or o q ui ne; H C Q = h y dr o x yc hl or o q ui ne.  
a Was h o ut peri o d of ≥1 4 da ys is re q uire d bef ore restarti n g st u d y treat me nt.  
 
8. 4.   
P h ar m ac o d y n a mic ( P D) Assess me nt (s) 
N ot a p plica ble.  
8. 5.   
Bi o m ar ker Assess me nt (s) 
8. 5. 1.   
H E R 2 S t at us A ssesse d b y C e ntr al L a b or at or y  
H E R 2 stat us i n pre-treat me nt t u m or sa m ple will be assesse d b y ce ntral la b orat or y.  T he 
stat us will be assesse d b y I H C a n d/ or FI S H.   If a s u bject has H E R 2 stat us data c o nfir me d 
b y a ce ntr al la b orat or y i n a not her D S -8 2 0 1a cli nical st u d y , it will be als o use d f or t he 
D S 8 2 0 1 -A -J 1 0 2 st u d y a n d t here is n o nee d t o assess H E R 2 stat us a gai n. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 4  
8. 5. 2.   
Tr o p o ni n -T Assesse d  
Bl o o d sa m ples f or tr o p o ni n-T testi n g will be c ollecte d at t he ti me p oi nts s pecifie d i n  
Ta ble  8 .3 .  Tr o p o ni n ( prefera bl y hi g h -s e nsiti ve tr o p o ni n-T)  testi n g will be c o n d ucte d als o 
b y  st u d y site at t he time p oi nts s pecifie d i n  Ta ble  8 .3 . 
 
T a ble  8 .3 :  
Tr o p o ni n S a m pli n g Ti me P oi nts  
C ycle  
D a y   
S a m pli n g T i me P oi nt ( Acce pt a ble R a n ge)  
Scree ni n g  
-  
W it hi n 7 da ys bef ore e nr oll me nt  
C ycle 1 -3  
Da y 1   
2 t o 3 h o urs after  E OI  
  
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 draw 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 t r o p o ni n le vel is 
n ot Gra de 3.  
  
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 
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 at 6 h o urs ( ± 1 
h o ur) a n d f oll o w i nstit uti o nal 
g ui d eli nes. 
  
Ot her wise, re peat tr o p o ni n testi n g at 6 
h o urs ( ± 1 h o ur) or at 2 4 h o urs ( ± 2 
h o urs) after i nitial tr o p o ni n test.  
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) .   
E OI = e n d of i nf usi o n, E O T = e n d of treat me nt. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 5  
I nstr u cti 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).  
8. 6.   
I m m u n o ge nicit y (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  8 .4 .  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 ntib o d y ma y b e meas ure d usi n g t he sa me A D A  s a m ples f or p ur p os e of A D A  
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 m e nt (e g, la b orat or y ma n ual).  
T a ble  8 .4 :  
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 T i me P oi nt ( Acce pt a ble R a n ge)  
C ycle 1  
Da y 1   
BI ( –  8 h o urs)  
Da y 8   
± 1 da y  
C ycle 2  
Da y 1   
BI ( –  8 h o urs)  
E ver y  2 c ycles fr o m C ycle 4 
(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) .   
4 0 -Da y F/ U *  
- 
4 0  da ys (  +  7 da ys) after t he last st u d y dr u g 
a d mi nistrati o n or u ntil starti n g ne w a ntica ncer 
treat me nt, w hic he ver c o mes first. 
BI = bef ore i nf usi o n, E O T = e n d of treat me nt, F/ U = f oll o w -u p.  
F or s u bj ects wit h p ositi ve A D A  at 4 0 -Da y 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  b ec 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 bj ect starts a n ot her t hera p y f or ca ncer, or wit h dra ws c o nse nt fr o m t he st u d y, w hic he ver occ urs first.  
8. 7.   
S A R S -C o V -2 Ser u m s a m ples c ollecti o n 
P orti o n of A D A bl o o d sa m ple will be use d f or f ut ure ce ntral la b a n al ysis f or S A R S -C o V -
2 testi n g o nce pr ot oc ol v ersi o n 7 . 0 is a p plie d f or a s u bject. Sa m ples will be se nt t o t he 
ce ntral la b orat or y a n d st ore d u ntil t he tests will bec o me a vaila ble.  
8. 8.   
P h ar m ac o ge n o mic  A n al ysis  
N ot a p plica ble.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 6  
9.   
S A F E T Y E V A L U A TI O N A N D R E P O R TI N G  
9. 1.   
Assess me nt of S afet y E n d p oi nt(s)  
Safet y e n d p oi nts will i ncl u de S A Es, T E A Es, 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 p ara m eters, E C G 
para meters, E C H O/ M U G A fi n di n gs, a n d o p ht h al m ol o gic ass ess 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 3 . 
9. 2.   
A d verse E ve nt C ollecti o n a n d Re p orti n g  
All cli nical A Es (see Secti o n  9. 4. 1  f or defi niti o ns) occ urri n g after t he s u bject si g ns t he 
I nf or me d C o nse nt F or m a n d u p t o t he 4 0 -Da y F/ U  visit  ( + 7 da ys), w het h er o bser ve d b y 
t he In v esti gat or or re p ort e d b y t h e s u bject,  will be rec or de d o n t he A d v erse E ve nt C R F 
pa ge.  Me dical c o n diti o ns (i ncl u di n g la b orat or y v al ues/ vital si g ns t hat are o ut of ra n ge) 
t hat were dia g n os e d or k n o w n t o e xist pri or t o I nf or me d C o nse nt will be rec or de d as p art 
of me dical hist or y.  
All A Es  a n d S A Es  are t o be re p ort e d acc or di n g t o t he pr oce d ures i n Secti o n  9. 5 .   
All cli nical la b orat or y res ults, vital si g ns, a n d E C G res ults or fi n di n gs  s h o ul d be 
a p praise d b y t he I n vesti gat or t o deter mi ne t heir cli nical si g nifica nce .  Is olat e d a b n or mal 
la b orat or y res ults, vital si g n fi n di n gs, or E C G fi n di n gs (ie, n ot part of a re p orte d 
dia g n osis) s h o ul d be re p orte d as A Es if t he y are s y m pt o matic, lea d t o  st u d y dr u g 
disc o nti n uati o n,  d ose re d ucti o n,  re q uire c orrecti ve treat me nt, or c o nstit ute a n A E i n t he 
In v esti gat or ’s cli nical j u d g me nt . 
At eac h visit, t he I n vesti gat or will deter mi ne w het her a n y A Es h a ve occ urre d b y 
e val uati n g t he s u bject.  A d verse e v e nts ma y be directl y o bs er 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 w a y, wit h o ut as ki n g a b o ut t he occ urre nce of a n y s p ecific 
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 n ess, 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 nt e d i n t he site’s s o urce d o c u me ntati o n wit h t he 
I n v esti gat or’s si g nat ure.   
Al wa ys re p ort t he dia g n osis as t he A E or S A E ter m.  W he n a dia g n osis is u na vaila ble, 
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 v e nts t hat are s eri 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 o ce d ure m a y b e a n A E or S A E.  Pre -pla n ne d 
( pri or t o si g ni n g t he I nf or me d C o nse nt F or m) pr oce d ures or treat me nt s re q uiri n g 
h os pitalizati o n f or pre -e xisti n g c o n diti o ns t hat d o n ot w orse n i n se verit y s h o ul d n ot be 
re p orte d as S A Es (see Secti o n  9. 4. 2  f or Defi niti o ns).   


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 7  
F or deat hs, t he u n derl yi n g or i m me diate ca us e of deat h s h o ul d al wa ys be re p orte d as a n 
S A E.  Pr o gressi o n of a n u n derl yi n g disease (t u m or) will be ha n dle d as f oll o ws:  
 Disea se pr o gressi o n (e nl ar ge me nt of m eas ura ble/ n o n-meas ura bl e lesi o ns, 
a p peara nce of ne w lesi o ns) will n ot be ha n dle d as a n A E. H o we ver w h e n a 
s u bject dies a n d n o pr o xi mal ca use of deat h ot her t ha n disease pr o gressi o n ca n 
be deter mi ne d, " dise ase pr o gressi o n" s h o ul d b e re p orte d as a n S A E wit h a 
fatal o utc o me.  If a fatal e ve nt is i de ntifie d d ue t o disease pr o gressi o n, t he 
e ve nt s h o ul d be ca pt ure d.  
 A n i ncreas e i n t he val ue of a t u m or mar ker will n ot be re gar de d as a n 
A E/ S A E.  
A n y s eri o us, u nt o war d e ve nt t hat ma y o c c ur s u bse q ue nt t o t he re p orti n g p eri o d t hat t he 
I n v esti gat or assess es as 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 m a na ge d as a n 
S A E.  
9. 3.   
A d verse E ve nts of S peci al I nterest  
F or t he D S -8 2 0 1 a cli nical pr o gra m, base d o n t he a vaila ble pre -cli nical data, revie w of t h e 
c u m ulati ve literat ure, re p orte d t o xicities f or t he sa me class of a ge nts a n d bi ol o gical 
pla usi bilit y,  I nt erstitial l u n g diseas e a n d L V E F d ecreases are c o nsi dere d t o be a d verse 
e ve nts of s peci al i nterest ( A E SI).  
A d diti o nal rele va nt i nf or mati o n r e gar di n g t he A E SIs f or t h e D S -8 2 0 1a cli nical pr o gra m 
re gar dl ess of seri o us ness is t o 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 e C R F i n t he cli nical st u d y data base.  I n t he e ve nt t hat e C R F is u n a vaila ble, 
re p ort A E SI s o n a p a per f or m .  O nce e C R F bec o mes a vaila ble, please e nt er A E SI s 
re p orte d o n t he p a per f or m i nt o e C R F as s o o n as p ossi ble.  
F or br o a d s ur veilla nce of L V E F decrease, rele va nt A Es u n der t he Me d D R A S M Qs of 
Car diac Fail ure is i ncl u d e d f or e n h a nce d data c ollecti o n; a d diti o nal  data f or t hese A Es are 
c ollecte d via T Qs of heart fail ure.  
F or br o a d s ur veilla nce of I L D / p n e u m o nitis, select e d 4 2 Preferre d Ter ms  ( P T) [all fr o m 
t he I L D Sta n dar d Me d D R A Q uer y ( S M Q)] pl us 2 P Ts of ac ute res pirat or y fail ure a n d 
res pirat or y fail ure are i ncl u de d f or e n h a nce d d ata c ollecti o ns. 
9. 3. 1.   
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 o se 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 b ee n n o e ve nts of 
I L D/ p n e 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 wo st u dies, 
I L D/ p n e 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 n e 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 
w ell as t he res ults of p ote ntial I L D/ p n e u m o nitis cases re vie we d b y t he i n de 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 d e mi ol o g y/literat ure, 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 8  
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 cl ass.  Refer t o t h e 
c urre nt I B f or a s u m mar y of preli mi nar y cli nical st u d y dat a.  
M a n a ge me nt G ui d a n ce:  
I L D/ p n e u m o nitis s h o ul d be r ule d o ut if a s u bject de vel o ps ra di o gra p hic c h a n ges 
p ote ntiall y c o nsiste nt wit h I L D / p n e u m o nitis or de vel o ps a n ac ute o nset of ne w or 
w orse ni n g p u l m o nar y or ot her relat e d si g ns/s y m pt o ms s uc h as d ys p n ea, 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 h a 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 “ 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 of t he st u d y pr ot oc ol.  
If t he A E is s us pect e d t o be I L D/ p ne u m o nitis, treat me nt wit h st u d y dr u g s h o ul d be 
i nterr u pte d pe n di n g f urt her e val u ati o n s. E val uati o ns s h o ul d i ncl u de hi g h res ol uti o n C T, 
p ul m o n ol o gist c o ns ultati o n  (i nfecti o us disease c o ns ultati o n as cli nicall y i n dicate d), bl o o d 
c ult ure a n d C B C ( ot h er bl o o d tests c o ul d be c o nsi dere d as n ee d e d), br o n c h osc o p y a n d 
br o nc h oal ve olar la va ge if cli nicall y i n dicat e d a n d feasi ble s h o ul d be c o nsi dere d , 
p ul m o nar y f u ncti o n tests a n d p ulse o xi metr y ( S p O 2), arterial bl o o d gases if cli nicall y 
i n dicate d, a n d one bl o o d sa m ple c ollecti o n f or P K  a nal ysis as s o o n as I L D/ p ne u m o nitis 
is s us pecte d, if feasi ble. Ot her tests c o ul d be c o nsi dere d, as n ee de d.   
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 mana ge m e nt g ui d a nce o utli ne d 
i n t he desi g nat e d “ P ul m o nar y T o xicit y” d ose m o dificati o n secti o n of t he st u d y pr ot oc ol. 
All e ve nts of I L D / p ne u m o nitis re gar dless of se v erit y or seri o us n ess will be f oll o we d u ntil 
res ol uti o n i ncl u di n g aft er dr u g disc o nti n uati o n. 
9. 3. 1. 1.  
Interstiti al L u n g Dise ase A dj u dic ati o n C o m mittee  
A n i n de pe n de nt I L D A C  f or t he 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 u ate a n d rel e va nt i n de pe n d e nt e val uati o n, 
s yste matic a d diti o nal data c ollectio 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 hes e 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 di ati on, 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 v al uati o n, treat me nt a n d o utc o me of t h e e ve nt.  T his data c ollecti o n will be 
tri g gere d f or a d verse e v e nts re p orte d usi n g  select e d 4 2 P Ts  [all fr o m t he I L D Sta n dar d 
Me d D R A Q uer y ( S M Q) ] pl us 2 P Ts of ac ute res pirat or y fail ure a n d res pirat or y fail ure. 
9. 3. 2.   
L V E F Decre ase  
Cli nic al S u m m ary:  
L V E F decrease i n ass o ciati 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 v aila ble pre-cli nical data, literat ure a n d a v aila 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 n ce:  
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 ysici a n f or m o nit ori n g car diac f u ncti o n.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 7 9  
Tr o p o ni n will be meas ure d at scree ni n g a n d E O T  a n d as nee d e d bas e d o n s u bject 
re p orte d car diac 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 v esti gat or or del e gate d ph 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. 4.   
A d verse E ve nt  
9. 4. 1.   
Defi niti o n of A d verse E ve nt  
A n A E  is an y u nt o war d me dical occ urre n ce i n a s u bject a d mi nistere d a p h ar mace utical 
pr o d uct  a n d t hat d oes n ot necessaril y h a 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 h eref 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 x a m ple), s y m pt o m, or disease te m p orall y ass o ciate d 
wit h t he use of a me dici n al pr o d uct, w het her or n ot c o nsi dere d relate d t o t h e me dici nal 
pr o d uct (I C H E 2 A G ui deli ne.  Cli nical Safet y Data Ma na ge m e nt: Defi niti o ns a n d 
Sta n dar ds f or E x pe dite d Re p orti n g, Oct 1 9 9 4).  
It is t he res p o nsi bilit y of I n v esti gat ors, base d o n t h eir k n o wle d ge a n d e x perie nce, t o 
deter mi ne t h ose cir c u msta nces or a b n or mal la b orat or y  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  
A S A E  is an y u nt o w ar d me dical occ urre n ce t hat at a n y d ose:  
 Res ults i n deat h,  
 Is life-t hreate ni n g, 
 Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,  
 Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y,  
 Is a c o n ge nital a n o mal y/ birt h defect, or 
 Is a n i m p orta nt me dical e ve nt. 
N ote:  T h e ter m “lif e -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n 
w hic h t he s u bject was at ris k of 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 h eticall y mi g ht ha ve ca us e 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 sci e ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g w het her e x pe dite d 
re p orti n g is a p pr o priat e i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y n ot 
be i m me diatel y life -t 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 uir e i nter ve nti o n t o pre v e nt o ne  of t he ot her o ut c o mes liste d i n t he 
defi niti o n a b o ve.  E x a m ples i ncl u de aller 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 d e vel o p me nt of dr u g d e pe n d e nc y or dr u g a b use.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 0  
N ote:   
 P r oce d ures are n ot A E s or S A E s, b ut t he reas o n f or t he pr oce d ure ma y b e a n 
A E or S A E.    
 Pre -pla n ne d ( pri or t o si g ni n g t he I nf or me d C o nse nt F or m) pr oce d ure s or 
treat me nts re q uiri n g h os pitalizati o ns f or pre-e xisti n g c o n diti o ns t hat d o n ot 
w orse n i n se verit y are n ot S A Es.  
9. 4. 3.   
Se verit y Assess me nt  
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 3 : 
 Gra de 1 Mil d A E  
 Gra de 2 M o d erate A E  
 Gra de 3 Se v ere A E  
 Gra de 4 Lif e -t hr eate ni n g c o nse q ue nces; ur ge nt i nt er ve nti o n i n dicate d 
 Gra de 5 Deat h r elate d t o A E  
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 b e of relati vel y mi n or me dical si g nifica nce (s uc h as 
se vere h ea d ac he).  Seri o us ness of a n e v e nt is base d u p o n a u ni versal a n d gl o bal 
Re g ulat or y d efi niti o n f or re p orti n g S A Es t o re g ulat or y a ge ncies.   F or e x a m ple, t he N CI -
C T C A E gra de 4 (life -t hr eate ni n g c o nse q u e nces; ur ge nt i nter ve nti o n i n dicat e 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 s eri o us base d o n t he 
seri o us ness criteria.  O verall, t he se verit y of a n e v e nt ma y b e gra d e d b y t he I n v esti gat or 
as Gra d e 1 or 2, b ut if t he s u bject prese nts t o t he e mer ge nc y facilit y f or e val uati o n a n d is 
h os pitalize d o ver ni g ht f or o bser vati o n t hat i m me diatel y ma kes t he e v e nt seri o us base d 
u p o n h os pitalizati o n wit h o ut re gar d t o t he I n v esti gat or assess me nt of s e verit y.  
9. 4. 4.   
C a us alit y Assess me nt  
T he In vesti gat or s h o ul d a ssess ca usal relati o ns hi p bet wee n a n A E  a n d t he st u d y dr u g o n 
t he basis of  his/ her cli nical j u d g me nt a n d t h e f oll o wi n g defi niti o ns.  T he ca usalit y 
assess me nt m ust  be ma de base d o n t he a vaila ble i nf or mati o n a n d ca n be u p date d as ne w 
i nf or mati o n bec o mes a v aila ble. 
 Relate d:  
 T he A E f oll o ws a reas o n a 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 n a 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, diseas e u n der st u d y, c o n c urre nt diseases, 
a n d c o nc o mita nt me dicati o ns).  
o r 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 1  
 T he A E f oll o ws a reas o n a 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.  
 N ot Relate d:  
 T he A E d oes n ot f oll o w a reas o n a ble se q u e nce fr o m st u d y dr u g 
a d mi nistrati o n, or ca n be reas o 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 diseas es, 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 St u d y Dr u g (s) 
 D ose N ot C ha n ge d: N o c ha n ge i n st u d y dr u g d osa ge was ma de.  
 Dr u g Wit h dra w n: T he st u d y dr u g was per ma ne ntl y st o p pe d.  
 D ose Re d uce d: T h e d osa ge of st u d y dr u g was re d uce d.  
 Dr u g I nterr u pte d: T he st u d y dr u g was te m p oraril y st o p pe d.  
9. 4. 6.   
Ot her Acti o n T a ke n f or E ve nt  
 N o ne.  
 N o treat me nt was re q uire d.  
 Me dicati o n re q uir e 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 . 
 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.  
 Ot her.  
9. 4. 7.   
A d verse E ve nt O utc o me  
 Rec o vere d/ Res ol ve d  
 T he s u bject f ull y rec o vere d fr o m t he A E  wit h n o resi d ual effect o bser v e d.  
 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.  
 N ot Rec o vere d/ N ot Res ol ve d  
 T he a d v erse e v e nt itself is still prese nt a n d o bser va ble.  
 Rec o vere d/ Res ol ve d wit h Se q uelae  
 T he resi d ual effects of t h e a d verse e v e nt are still prese nt a n d o bser va ble.  
 I n cl u de se q u elae/r esi d ual effects. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 2  
 Fatal  
 Fatal s h o ul d be use d w he n d eat h is a direct o utc o me of t he a d verse e v e nt. 
 U n k n o w n  
9. 5.   
Seri o us A d verse E ve nts  Re p orti n g – Pr oce d ure F or 
I n vesti g at ors 
All A Es , S A Es , A Es of s pecial i nterest  a n d me dicati o n err ors i ncl u di n g o v er d ose  will be 
re p orte d i n t he C R F. 
T he f oll o wi n g t y p es of e ve nts s h o ul d be re p orte d b y t he I n vesti gat or i n electr o nic data 
ca pt ure ( E D C ) wit hi n 2 4 h o urs of a ware n ess:  
 
 S A Es (see Secti o n  9. 4. 2  f or defi niti o n) 
 All p ote ntial I L D / p n e u m o nitis cases s h o ul d be re p orte d wit hi n 2 4 h o urs; 
i ncl u di n g b ot h seri o us a n d n o n-seri o us p ote ntial I L D/ p ne u m o nitis cas es 
( p ote ntial I L D/ p ne u m o nitis is defi ne d b y t he E v e nt A dj u dicati o n Site Ma n ual 
List of P Ts).  
 He patic e v e nts ( b ot h seri o us a n d n o n -seri o us) w hi c 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 vat e d 
T B L >  2 x U L N t hat ma y occ ur eit her at differe nt ti me p oi nts or 
si m ulta ne o usl y d uri n g t he st u d y.  A t ar gete d q uesti o n naire is 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.   
 O ver d ose, d efi ne d as t he acci de nt al or i nte nti o nal a d mi nistrati o n of a n y d os e 
of a  pr o d uct t hat is c o nsi dere d b ot h e xcessi ve a n d me dicall y i m p orta nt.  A n 
“e x cessi ve a n d me dicall y i m p orta nt” o ver d ose i ncl u des a n y o ver d ose i n w hi c h 
eit her a seri o us a d verse e ve nt, a n o n -seri o us a d verse e ve nt, or n o a d verse 
e ve nt occ urs a n d is c o nsi dere d b y  t he I n vesti gat or as cli nicall y rele va nt, i.e. 
p oses a n act u al or p ote ntial ris k t o t he s u bject.  
 O ver d ose is al w a ys seri o us. B y defi niti o n a n o ver d ose is me dicall y 
i m p orta nt, w hic h meets t he seri o us ness criteri o n of i m p orta nt me dical 
e ve nt. A n o ver d ose ca n  o cc ur wit h or wit h o ut a n A E. A Es ca n eit her be 
seri o us or n o n-seri o us. Details of t he o ver d ose i ncl u di n g trast uz u ma b 
der u xteca n  d osa ge, cli nical c o urse, ass ociate d A Es, a n d o utc o me m ust be 
ca pt ure d i n t he Narrati ve f or m of t he C R F wit hi n E D C.  
 
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 In 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 oul d be pr o vi de d.  S pecific or esti mate d d ates 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 n c o mita nt me dicati o ns, a n d 
la b orat or y dat a 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.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 3  
F or fatal e ve nts, t he n arrati 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 d oc u m e nts  (i ncl u di n g me di cal rep orts ) will be 
retai ne d at t he st u d y site a n d s h o ul d n ot be s u b mitte d t o t he S p o ns or f or S A E re p orti n g 
p ur p 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/ U  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 ple te data p ossi ble wit hi n eac h F/ U .   
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.  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 x e d t o t he C R O usi n g t he pr o vi de d fa x tr a 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 m es a vaila ble, pl ease e nter 
S A Es re p orte d o n t he S A V E R F or m i nt o e C R F as s o o n as p ossi ble.  
See Secti o n  1 5. 1 0. 3  f or c o ntact i nf or mati o n f or S A E re p orti n g.  Please call t he l ocal S A E 
H otli ne (see St u d y M a n u al) 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, a n d 
Instit uti o n al R e vie w B o ar d / Et hics C o m mittee  
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/ Et hics C o m mittees 
(I R Bs/E C s), a n d re g ulat or y a ut h orities of a n y S us pecte d U n e x pecte d Seri o us A d verse 
Reacti o ns ( S U S A Rs) occ urri n g i n ot her st u d y sites or ot her st u dies of t he st u d y dr u g , as 
a p pr o priate per l ocal re p orti n g re q uire me nts.   Daiic hi Sa n k y o a n d/ or C R O  will c o m pl y 
wit h a n y a d diti o nal l ocal safet y re p orti n g re q uire me nts.  
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 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 st u d y dr u g.  
Alt h o u g h pre g na nc y is n ot tec h nicall y a n A E , all pre g na nci es m ust be f oll o we d t o 
c o ncl usi o n t o deter mi ne t heir o utc o me.  T his i nf or mati o n is i m p orta nt f or b ot h dr u g 
safet y a n d p u blic h ealt 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 n ee, 
t o re p ort a n y pre g na nc y i n a fe male s u bj ect usi n g t he E x p os ure I n Uter o ( EI U) Re p orti n g 
f orm.  Please c o ntact y o ur st u d y m o nit or t o recei v e 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 n c y.  T he In 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 n a nc y a n d c o m plete t h e EI U Re p orti n g F or m wit h c o m plete 
pre g n a nc y o ut c o me i nf or mati o n, i ncl u di n g n or mal deli ver y a n d i n d uce d a b orti o n.  T he 
a d verse pre g na n c y o utc o me, eit her seri o us or n o n -seri o us, s h o ul d be re p orte d i n 
acc or da nce wit h st u d y pr oce d ures.   If t he o utc o m e of t he pre g n a nc y meets t he criteria f or 
i m me diate classificati o n as a S A E (ie, p ost-p art u m c o m plicati o ns, s p o nta ne o us or 
i n d uce d a b orti o n, still birt h, ne o natal deat h, or c o n ge nital a n o mal y, i ncl u di n g t hat i n a n 
a b orte d fet us), t he I n 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 .  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 4  
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 ite ms will be meas ure d.  F or cli nical la b orat or y para meters, t he refere n ce 
ra n ge of t h e i nstit uti o n t hat perf or ms t he m eas ure me nts will be use d. 
I nf or mati o n will be e ntere d i n t he case re p ort f or m ( C R F) o n w het her meas ure d, date of 
meas ure me nt, a n d meas ure me nt res ults f or t h e f oll o wi n g ite ms.   
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, pl atelet 
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 yt es, 
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 B L , b l o o d 
urea nitr o ge n , Ca, Cl, ser u m creati ni ne, lactate 
de h y dr o ge nas e , K, Na, M g  
Creati ni ne cleara n ce ( m L/ mi n) will be calc ulate d usi n g t he C oc kcr oft -Ga ult e q uati o n . 
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 Secti o n  
1 7. 7  . 
 Uri nal ysis test i ncl u di n g pr otei n, gl uc ose, bl o o d, micr osc o p y assess me nts (if 
i n dicate d), a n d s p ecific gra vit y m ust be p erf or me d d uri n g t he Scree ni n g 
Peri o d.    
 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  m ust be 
perf or me d d uri n g t he Scree ni n g Peri o d.  
 Pre g n a nc y test (s er u m or uri ne) f or all fe male s u bj ects 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 t est res ult m ust be c o nfir me d i m me diat el y usi n g a s er 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 S cree ni n g Peri o d . 
 Tr o p o ni n ( prefera bl y hi g h -se nsiti ve tr o p o ni n-T) test m ust be perf or me d at t he 
visits i n dicate d i n  Ta ble  8 .3 .  Sa me assa y s h o ul d be use d f or t h e s u bject 
t hr o u g ho ut t heir st u d y partici pati o n.  
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 h e 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 m al la b orat or y v al 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 b e f oll o we d (see Secti o n  9. 5 ).  
A b n or mal la b orat or y v al ues ( N CI -C T C A E gra de 3 or 4) occ urri n g d uri n g t he cli nical 
st u d y will be f oll o we d u ntil re peat test 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.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 5  
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 t e m perat ure.  A d diti o nall y, S p O 2 will be meas ure d b ef 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 E C G para meters 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  will be 
meas ure d  usi n g i de ntical e q ui p me nt wit h sta n dar dize d pr oce d ures, b ot h of w hic h were 
pr o vi de d b y a t hir d -part y E C G ce ntral  la b orat or y.  All E C Gs m ust be e val uate d b y 
I n v esti gat or or del e gate d p h ysicia n f or t he prese nce of a b n or malities.   All E C G  data  will 
be tra ns mitte d t o t he ce ntral la b orat or y, a n d a h ar d c o p y of eac h E C G s h o ul d be pri nte d 
l ocall y a n d retai n e d at t h e site wit h t he s o urce d o c u me ntati o n. 
T he tri plicate 1 2 -lea d safet y E C Gs will be perf or me d at the ti me p oi nts s pecifie d i n 
Ta ble  9 .1  i n cl ose s uccessi o n, n o m ore t ha n a p pr o xi matel y 2 mi n a part, a n d after at least 
1 0 mi n of q uiet rest i n t he s u pi n e p ositi o n.   
N ote:  A n y st u d y pr oce d ures s uc h as bl o o d sa m pli n g are n ot all o we d d uri n g q uiet rest a n d 
pri or t o E C G meas ure m e nt.  Bef ore electr o des are re m o ve d, t he el ectr o de p ositi o n is t o 
be mar ke d o n t he s ki n wit h i n deli ble i n k a n d t he sa me electr o de p os iti o n use d f or all 
s u bse q ue nt E C Gs d uri n g c o nfi ne me nt f or eac h s u bject. 
T a ble  9 .1 :  
E C G Me as ure me nt Ti me P oi nt s 
C ycle   
D a y  
Me as ure me nt Ti me P oi nt ( Acce pt a ble R a n ge  of E C G me as ure me nt 
st art ti me) 
Scree ni n g  -  
Wit hi n 7 da ys bef ore e nr oll me nt  
C ycle 1   
Da y 0  
( wit hi n 
3 da ys 
bef ore 
Da y 0)  
1 5 mi n utes bef ore t he pla n ne d start ti me of a d mi nistrati o n  o n C ycle  1, 
Da y  1   
( ± 1 0 mi n utes) 
3 0  mi n utes after t he pla n ne d start ti me of a d mi nistrati o n o n C ycle  1, 
Da y  1  
( ± 1 0 mi n utes) 
2 h o urs after t he pla n ne d start ti me of a d mi nistrati o n  o n C ycle  1, Da y  1   
( ± 1 0 mi n utes) 
4 h o urs after t he pla n ne d start ti me of a d mi nistrati o n  o n C ycle  1, Da y  1   
( ± 1 0 mi n utes) 
7  h o urs after t he pla n ne d s tart ti me of a d mi nistrati o n o n C ycle  1, Da y  1   
( ± 1 0 mi n utes) 
Da y 1   
1 5 mi n utes BI ( ± 1 0 mi n utes)  
2 h o urs after t he start of a d mi nistrati o n ( ± 1 0 mi n utes)  
4 h o urs after t he start of a d mi nistrati o n ( ± 1 0 mi n utes)  
7 h o urs after t he start of a d mi nistrati o n ( ± 1 0 mi n utes)  
Da y 8   
7 da ys after t he start of a d mi nistrati o n ( ± 1 da y)  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 6  
C ycle   
D a y  
Me as ure me nt Ti me P oi nt ( Acce pt a ble R a n ge  of E C G me as ure me nt 
st art ti me) 
Da y 1 5  
1 4 da ys after t he start of a d mi nistrati o n ( ± 1 da y)  
C ycle 2   
Da y 1   
BI ( wit hi n 3 da ys bef ore a d mi nistrati o n ) 
C ycle 3   
Da y 1   
1 5 mi n utes BI ( ± 1 0 mi n utes)  
E OI  (wit hi n 1 5  mi n utes)  
2 h o urs after t he start of a d mi nistrati o n ( ± 1 0 mi n utes)  
4 h o urs after t he start of a d mi nistrati o n ( ± 1 0 mi n utes)  
7 h o urs after t he start of a d mi nistrati o n ( ± 1 0 mi n utes)  
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)  
After 
C ycle 4  
Da y 1   
BI ( wit hi n 3 da ys bef ore a d mi nistrati o n ) 
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).   
BI = bef ore i nf usi o n, E O T = e n d of treat me nt. 
9. 1 0. 1.   
Ce ntr al re vi e w  
I n a d diti o n t o e val uati o n b y I n v esti gat or, E C Gs at Scree ni n g, C ycle 1, C ycl e 2 a n d C ycle 
3 will be re vie we d b y a s uita bl y -q ualifie d car di ol o gist i n t he ce ntral la b orat or y.  I n t he 
re vie w, i nf or m ati o n s uc h as de m o gra p hics a n d ti me p oi nt will be bli n de d. 
T he detail pr oce d ures f or t he re vie w are i n cl u de d i n a se parate d oc u m e nt.  
9. 1 1.   
P h ysic a l E x a mi n ati o ns 
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 n eral a p peara nce; der mat ol o gi cal; 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 h atic; 
m usc ul os keletal/e xtre mities; a n d ne ur ol o gical.  W ei 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. 
9. 1 2.   
Ot her E x a mi n ati o ns  
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 ass ess 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 g at or or dele gate d p h ysici a n.  A d diti o nal safet y ass ess me nts 
s h o ul d be c o n d ucte d as n ee 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 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 7  
1 0.   
O T H E R A S S E S S M E N T S  
N ot a p plica ble.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 8  
1 1.   
S T A TI S TI C A L  M E T H O D S   
1 1. 1.   
Ge ner al St atistic al C o nsi der ati o ns  
T he data c ut off f or t h e 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 c o m plete d at least 3 c ycl es , w hic he ver c o mes first.  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 select e d de m o gra p hic, safet y, a n d P K data b y  
ti me as a p pr o priate.  Des cri 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 vi ati o ns  ( S Ds), a n d ra n ges (as well as ge o metric m ea ns a n d 
ge o m etric c o effici e nt of variat i o n f or C ma x  a n d A U C P K para meters), w hil e cate g orical 
data will be s u m marize d usi n g fre q ue n c y c o u nts a n d perce nt a ges.  Gra p hical s u m maries 
of t he data ma y b e pres e 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 h e last n o n missi n g val ue of a v aria ble ta ke n b ef ore t he first d ose of 
stu d y dr u g will be use d as t he baseli ne val ue, u nl ess ot her wise s pecifi e d.  I n ge n eral, 
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 n al ysis, u nless 
ot her wise s pecifie d.   
Safet y a nal yses will be perf or me d b ase d o n t he safet y a nal ysis  set.  E C G  anal yses  will be 
perf or me d b ase d o n t he c ar diac safet y an al ysis set.  A nal ysis of P K para met ers will be 
base d o n t he P K a n al 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 s ets.  Efficac y e n d p oi nts will be a nal yz e d base d  o n t he efficac y a nal ysis set.   
A detaile d statistical a nal ysis pla n ( S A P) des cri 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 bas e l oc k.  Statistical met h o ds 
descri be d wit hi n t his d oc u me nt ma y b e c ha n ge d b ase d o n a d va n ces i n r esearc h.  
1 1. 2.   
A n al ysis Sets  
1 1. 2. 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 
t he st u d y. 
1 1. 2. 2.   
Effic ac y A n al ysis Set  
T he effi cac y a nal ysis set will i ncl u de all s u bjects e nr olle d i n t he st u d y w h o recei v e 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 d ata. 
1 1. 2. 3.   
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 e nr olle d i n t he st u d y w h o recei ve d at least 
o ne d ose of D S -8 2 0 1 a.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 8 9  
1 1. 2. 4.   
C ar di ac S af et y A n al ysis Set  
T he car diac safet y a n al ysis set will i ncl u de all s u bjects e nr olle d i n t he st u d y w h o recei ve d 
at least o ne d ose of D S -8 2 0 1a, ha d ti me-matc h e d baseli ne  a n d p ost -treat me nt E C G data 
a n d di d n ’t recei ve Q Tc pr ol o n gati o n dr u gs . 
1 1. 2. 5.   
P h ar m a c o ki netic A n al ysis  Set  
T he P K a nal ysis set will i ncl u de all s u bjects i n t he e nr olle d a nal ysis set w h o recei v e d at 
least o ne d ose of D S-8 2 0 1a a n d ha d meas ura bl e ser u m c o nce ntrati o ns of D S -8 2 0 1a.  
1 1. 2. 6.   
Bi o m ar ker A n al ysis Set  
T he bi o mar ker a nal ysis s et 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 v e 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. 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 h e 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 s et. 
De m o gra p hic a n d baseli n e 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 n cer sta ge, best res p o ns e 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 effi cac y a nal ysis set, a n d 
safet y a n al ysis set.  If 2 a nal ysis sets 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.   
St atistic al A n al ysis  
1 1. 4. 1.   
Pri m ar y A n al yses  
T he pri mar y  e n d p oi nts i n cl u de  b aseli ne -a dj uste d Q Tc F i nter val , ser u m c o nce ntrati o n a n d 
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 a. 
1 1. 4. 1. 1.  Q Tc Pr ol o n g ati o n A n al yses  
T he Q T i nter vals will be c orrecte d f or heart rate b y Fri dericia’s f or m ula ( Q Tc F =  
Q T/[ R R] 1/ 3).  T he baseli ne Q Tc F i nter val f or eac h s u bject will be s u btracte d fr o m Q Tc F 
i nter val t o create a b aseli ne-a dj uste d Q Tc F i nter val f or eac h s u bject at eac h ti me p oi nt  
( C ycl e 1  t o 3) . T he pri mar y a nal ys is f or t he b aseli ne-a dj uste d Q Tc F will be perf or me d  
base d o n t he car diac safet y a n al ysis set . 
T he baseli ne -a dj uste d Q Tc F will be a v era ge d acr oss s u bjects at eac h ti me p oi nt a n d a 
p oi nt wise t w o -si de d 9 0 % c o nfi de nce i nter val ( CI)  will als o be calc ulate d.   If t he u p per 
li mit of t he o ne-si de 9 5 % CI fo r t he calc ulate d mea n baseli ne -adj uste d a vera ge Q Tc F 
i nter val < 1 0 ms  at eac h ti me p oi nt, t he effect o n Q Tc i nter val will be c o nsi d ere d 
cli nicall y i nsi g nifica nt.  T he s u bjects wit h A D A ’s will be i ncl u de d f or t his a nal ysis. 
T he d escri pti ve statistics will be pr o vi de d f or E C G para meters  (e g. H R, P R, Q R S a n d 
R R)  a n d c ha n ges fr o m ti me -matc he d b aseli ne  b y sc he d ule d ti me of e v al 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 p ost-treat me nt val ue.  I n a d diti o n, t he n u m ber a n d 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 0  
perce nt a ge of s u bjects wit h E C G i nter val  val ues m eeti n g t h e criteria will be ta b ulate d (e g, 
Q Tc ≤ 4 5 0 ms, > 4 5 0 t o ≤ 4 8 0 ms, > 4 8 0 m s t o ≤ 5 0 0 ms, a n d > 5 0 0 ms).    
Relati o ns hi p bet wee n dr u g c o n ce ntrati o ns  a n d Q Tc F will  als o be e x pl ore d. 
1 1. 4. 1. 2.  P h ar m a c o ki netic A n al yses  
T he pri mar y a n al ys is f or ser u m c once ntrati o n a n d 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 a, will be p erf or me d  base d o n t he P K a n al ysis set .  
Ser u m c o nce ntr ati 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 a will be liste d, pl otte d, a n d s u m marize d usi n g des cri pti ve statistics at eac h ti me 
p oi nt.  
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 a will be liste d 
a n d s u m marize d usi n g descri pti ve statistics.  
T he p o p -P K m o dels w hi c h were c o nstr uct e d usi n g P K data fr o m t he P hase 1 st u d y 
( D S 8 2 0 1-A -J 1 0 1) will be u p date d t o e val uat e t he effect of i ntri nsic a n d e xtri nsic fact ors 
o n P K  of D S -8 2 0 1a a n d M A A A -1 1 8 1 a.  After esta blis h me nt of t he p o p-P K m o del, a 
e x p os ure-res p o nse m o del will be u p date d t o e val u ate t he rel ati o ns hi p bet wee n e x p os ure 
a n d effi cac y a n d t o xicit y.   T he res ults of p o p ulati o n P K a nal ys es will be re p orte d 
se parat el y (ie, n ot i n t he Cli nical St u d y Re p ort). 
1 1. 4. 2.   
S afet y A n al yses  
Safet y e n d p oi nts will be base d o n A Es , p h ysical e x a 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, A D A , 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 3 .   
Safet y a nal yses i n ge n eral will  be descri pti ve a n d will be prese nte d i n ta b ul ar f or mat wit h 
t he a p pr o priat e s u m mar y statistics. 
1 1. 4. 2. 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 4 0 -Da y F/ U visit), ha vi n g bee n a bs e 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 h e n t h e A E is 
c o nti n u o us.  
T he n u m ber a n d p erce nta ge of s u bjects r e 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 yst e m Or ga n Class ( S O C), a n d P T .   
Si milarl y, t he n u m b er a n d perce nt a ge of s u bjects r e p orti n g treat me nt -e mer ge nt S A Es will 
be ta b ulate d, as w ell 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 bj ect A E (i n cl 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, P T , 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 n cl u di n g t h ose lea di n g t o p er ma ne nt 
disc o nti n uati o n fr o m D S -8 2 0 1a, will be liste d.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 1  
1 1. 4. 2. 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 select e d cli nical la b orat or y test res ults 
( he mat ol o g y a n d c h e mistr y) a n d c h a n ges fr o m bas eli ne b y s c 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 d e d acc or di n g t o N CI -C T C A E versi o n 4. 0 3 , 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 bas eli ne a n d t he 
w orst p ost -treat me nt val u e 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 nifi ca nce or of G ra de 3 or 4 will be liste d. 
1 1. 4. 2. 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 ul e 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. 4. 2. 4.  A nti -dr u g A nti b o dies A n al yses  
A s hift ta ble, prese nti n g t he 2 -wa y fre q u e nc y ta b ul ati 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, will be pr o vi de d f or i nci de nce of A D A . 
1 1. 4. 2. 5.  Ot her S afet y  A n al yses  
All ot her safet y e n d p oi nts (e g, 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, 
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. 4. 3.   
Effic ac y A n al yses  
Efficac y e n d p oi nts 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 d ate), C B R 
(t he pr o p orti o n of s u bjects w h o ac hie ve d a best o v erall res p o ns e of C R or P R or m ore 
t ha n 6 m o nt hs S D), D o R , d urati o n of S D, T T R, P F S, O S, a n d perce nt c ha n ge i n tar get 
lesi o n usi n g R E CI S T 1. 1. 
T he effi cac y e n d p oi nts will be liste d a n d s u m marize d.  F or O R R, D C R  a n d C B R , p oi nt 
esti mates a n d 9 5 % e x act bi n o mial CI s will be pr o vi de d.  Ti me t o e ve nt varia bles 
i ncl u di n g d urati o n of res p o nse, d urati o n of S D T T R, P F S, a n d O S will be s u m marize d 
descri pti vel y usi n g t he Ka pla n -Meier met h o d.   
D urati o n of res p o ns e is defi ne d as t he ti me fr o m t he date of t he first d oc u me ntati o n of 
o bjecti ve res p o nse ( C R or P R) t o t he date of t he first o bjecti ve d oc u me ntati o n of 
ra di o gra p hic P D.  D urati o n of res p o nse will be m eas ure d f or res p o n di n g s u bjects ( C R or 
P R) o nl y.  D urati o n of S D is defi ne d f or s u bj ects w h ose best res p o ns e is S D as t he ti me 
fr o m t he date of t h e first d ose t o t he date of t he first d oc u me ntati o n of P D.  T T R 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 date of t he firs t d oc u me ntati o n of 
o bjecti ve res p o nse ( C R or P R).  Detaile d ce ns ori n g r ules f or D o R , d urati o n of S D, a n d 
T T R will be s pecifie d i n t he S A P.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 2  
P F S is defi ne d as t he ti me fr o m t he dat e 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 mentati o n of ra di o gra p hic P D or deat h d ue t o a n y ca us e.  Ce ns ori n g 
r ules f or t he P F S a n al 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 r ati 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.  
O S is defi ne d as t he ti me fr o m  t he date of t h e first d ose t o t he date of d eat h f or a n y ca use. 
If t here is n o d eat h re p ort e d f or a s u bject bef ore t h e data c ut-off f or O S a nal ysis, O S will 
be ce ns ore d at t he last c o ntact date at w hic h t he s u bject is k n o w n t o be ali ve.  
Descri pti ve statistics f or t he best perce nt c ha n ge i n t he s u m of dia meters  of meas ura ble 
t u m ors will be pr o vi de d.  A waterfall pl ot of t he b est perce nt c ha n ge fr o m s cree ni n g i n 
t he s u m of dia meters  f or eac h s u bject will be pres e nte d. 
1 1. 4. 4.   
P h ar m a c o d y n a mi c / Bi o m a r ker A n al yses  
1 1. 4. 4. 1.  P h ar m a c o d y n a mi c A n al yses  
N ot a p plica ble.  
1 1. 4. 4. 2.  Bi o m ar ker A n al yses  
E x pl orat or y  a nal ys es 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. 4. 4. 3.  P h ar m a c o ge n o mic  A n al yses  
N ot a p plica ble.  
1 1. 5.   
I nteri m A n al yses  
N o f or mal i nteri m a nal ysis is pla n ne d.  
1 1. 6.   
S a m ple Size Deter mi n ati o n  
T he sa m ple siz e of 5 0 s u bjects was c h os e n t o sec ure e n o u g h pr o b a bilit y of o bser vi n g t h e 
u p per b o u n d of t he t w o-si de d 9 0 % CI f or t he baseli ne -a dj uste d Q Tc F i nter val < 1 0  ms .  
Fr o m t h e res ults of t he T -D M 1 p hase 2 st u d y ( T D M 4 6 8 8 g), S D  of t he baseli ne -a dj uste d 
Q Tc F i nter val was esti mate d as a p pr o xi matel y 1 5  ms .  Ass u mi n g t hat t he e x pecte d 
baseli ne -a dj uste d Q Tc F i nter val is 0  ms  a n d t he S D is 1 5  ms , t he sa m ple size of 5 0 
s u bjects pr o vi des 9 9. 9 % pr o ba bilit y t hat t he u p per b o u n d of t he t w o-si de d 9 0 % CI f or t he 
baseli ne -a dj uste d Q Tc F i nter val < 1 0  ms .  T h us, t he pr o ba bilit y of o bser vi n g t he u p per 
b o u n d of t he t w o-si de d 9 0 % CI f or t he baseli ne -a dj uste d Q Tc F i nter val < 1 0  ms  f or all 
ti me p oi nts (t otal of 1 4 ti me p oi nts) is m ore t ha n 9 0 %.  
T he pr o ba bilit y v al ues f or t he sa m ple size are d eri 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. 3.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 3  
1 1. 7.   
St atistic al A n al ysis Pr ocess  
T he cli nical st u d y will be a nal yze d b y t h e s p o ns or or its a ge nt/ C R O  f oll o we d b y t his 
pr ot oc ol, a n d S A P w hic h will de m o nstrate all met h o d ol o gies a n d dis pla ys/s hells f or 
statistical a nal ys es. 
T he S A P will pr o vi de t he statistical met h o ds a n d defi niti o ns f or t he a nal ysis of t he 
efficac y a n d s afet y d ata, as wel l as des cri be t he a p pr oac hes t o b e ta ke n f or s u m marizi n g 
ot her cli nical st u d y i nf or mati o n s uc h as s u bject dis p ositi o n, de m o gra p hic a n d baseli ne 
c haracteristics, st u d y dr u g e x p os ure, a n d pri or a n d c o nc o mita nt me dicati o ns.  T he S A P 
will als o i ncl u de a descri pti o n of h o w missi n g, u n use d, a n d s p uri o us data will be 
a d dresse d.  
T o preser ve t he i nte grit y of t he statistical a nal ysis a n d cli nical st u d y c o ncl usi o ns, t he S A P 
will be fi nalize d pri or t o data base l oc k.  
All statistical a nal yses will be perf or me d usi n g S A S ®  Versi o n 9. 3  or hi g her ( S A S 
I nstit ute, Car y, N C 2 7 5 1 3). 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 4  
1 2.   
D A T A  IN 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 2. 1.   
M o nit ori n g a n d I ns pecti o ns  
T he S p o ns or , C R O m o nit or a n d re g ul at 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 h e 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 m e nts).  
 T he verificati o n  of a d h ere 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 ul ati o ns o n t he c o n d uct of cli nical 
researc h will be acc o m plis he d t hr o u g h a c o m bi nati o n of o nsite visits b y t he m o nit or a n d 
re vie w of st u d y d ata re m otel y.  T he fre q u e nc y of t he m o nit ori n g visit will var y base d o n 
t he acti vit y at eac h st u d y site .  T he m o nit or is res p o nsi ble f or i ns pecti n g t he C R Fs a n d 
e ns uri n g c o m plete ness of t he st u d y ess e ntial d oc u me nts.  T he m o nit or s h o ul d ha ve access 
t o s u bject me dical rec or ds a n d ot her st u d y-relate d rec or ds nee de d t o v erif y t he e ntries o n 
t he C R Fs.  Detaile d i nf or mati o n is pr o vi de d i n t he m o nit ori n g pla n.  
T he m o nit or will c o m m u nicate de viati o ns fr o m t h e pr ot oc ol, S O Ps, G C P a n d a p plica ble 
re g ulati o ns t o t he I n vesti gat or a n d will e ns ure t h at a p pr o priate acti o n (s) d esi g ne d t o 
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 nt e d. 
T he I n vesti gat or a grees t o c o o perat e wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms 
detecte d i n t he c o urse of t hese m o nit ori n g visits are a d dress e d  t o t he satisfacti o n of t he 
s p o ns or a n d d oc u me nt e d.  
I n acc or da n ce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y site ma y b e 
selecte d f or a u dit b y re prese ntati ves fr o m t he S p o ns or.  A u dit  of st u d y site facilities (e g, 
p har mac y, dr u g st ora ge areas, la b orat ories) a n d re vie w of st u d y relate d rec or d s will occ ur 
i n or der t o e val u ate t he st u d y c o n d u ct 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.   T he I n v esti gat or s h o ul d res p o n d t o a u dit fi n di n gs .  I n 
t he e ve nt t hat a reg ulat or y a ut h orit y i nf or ms t he I n vesti gat or t h at it i nte n ds t o c o n d uct a n 
i ns pecti o n, t he S p o ns or s hall be n otifie d i m me diatel y. 
1 2. 2.   
D at a C ollecti o n  
Daiic hi Sa n k y o  or a desi g nee will s u p pl y e C R Fs.   A n e C R F m ust be c o m pl ete d f or eac h 
s u bject w h o si g ns a n I C F a n d u n der g oes a n y scree ni n g pr oce d ure.   If a su bject is n ot 
treate d, t he reas o n m ust be rec or de d o n t he e C R F.  All data c ollecte d d uri n g t he st u d y 
will be rec or de d i n t his i n di vi d ual, s u bject -s pecifi c e C R F.  I nstr u cti o ns will be pr o vi de d 
f or t he c o m pleti o n of t he e C R F a n d a n y c orrecti o ns ma de will be a ut o maticall y 
d oc u me nte d via t he E D C s oft ware ’s “a u dit trail. ” 
C o m pleti o n of t he e C R F 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.  All i nf or mati o n a n d ot her materi al t o 
be use d b y s u bjects  a n d i n vesti gati ve staff m ust use v oca b ular y a n d la n g u a ge t h at are 
clearl y u n derst o o d.  T he 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 In v esti gat or.   T he I n v esti gat or will si g n a n d date t he i n dicate d places o n t he e C R F via 
t he E D C syste m ’s electr o nic si g nat ure.  T hes e si g n at ures will i n dicate t hat t he 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 5  
I n v esti gat or i ns pecte d or re vie we d t h e data o n t he e C R F, t he data q ueries, a n d t he site 
n otificati o ns, a n d a grees wit h t he c o nte nt.  
1 2. 3.   
Electr o nic D at a C a pt ure S yste m  
T he E D C s yst e 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. 
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 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  
1 2. 4.   
D at a M a n a ge me nt  
Eac h s u bject will be i de ntifie d i n t he data base b y a u ni q ue s u bject i de ntifier as defi ne d b y 
t he s p o ns or. 
T o e ns ure t he q ualit y of cli nical data acr oss all s u bjects a n d st u d y sites, a Cli nical Data 
Ma na ge me nt re vie w will be perf or me d o n s u bject data acc or di n g t o s pecifi cati o ns gi ve n 
t o S p o ns or or C R O.  Data will be vette d b ot h electr o nicall y a n d ma n uall y f or C R Fs a n d 
t he data will be electr o ni call y v ette d b y pr o gra m me d data r ules wit hi n t he a p plicati o n.  
Q ueries ge n erat e d b y r ul es a n d raise d b y re vie wers will be ge n erat e d wit hi n t he E D C 
a p plicati o n .  D uri n g t his re vie w, s u bject data will be c hec ke d f or c o nsiste nc y, 
c o m plete ness  a n d a n y a p pare nt discre pa nci es.  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 n ci le 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 d verse E v e nts will be c o de d usi n g Me dical Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A).  All c o n c o mita nt me dicati o ns  a n d pri or ca ncer t hera p ies w ill b e c o de d usi n g 
W orl d Healt h Or ga nizati o n Dr u g Refere nce ( W H O D R U G) List.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 6  
1 2. 5.   
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 u alifie d p ers o ns t o 
w h o m he/s he has dele gat e 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 n at ure List.  
I n v esti gat ors will mai ntai n a c o nfi de ntial scree ni n g l o g of all p ote ntial st u d y ca n di dates 
t hat i ncl u des li mite d i nf or mati o n of t he s u bjects, d ate a n d o utc o me of scree ni n g pr ocess.  
I n v esti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n 
t he st u d y i n dicati n g t heir assi g ne d st u d y n u m ber. 
I n v esti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n c o de list.  T his 
c o nfi de ntial list of na m es of all s u bjects all ocate d t o st u d y n u m bers o n e nr olli n g i n t he 
st u d y all o ws t he I n v esti gat or t o re veal t he i de ntit y of a n y s u bject w h e n necessar y.  
S o urce d oc u me nts are ori gi nal d oc u m e nts, data, a n d rec or ds fr o m w hic h t he s u bject’s 
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, di aries, micr ofi c hes, X -ra ys, a n d 
c orres p o n d e nce.  
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, dat a c orrecti o n f or ms, 
C R Fs, i n ve nt or y of st u d y dr u g, re g ulat or y d o c u me nts (e g, pr ot oc ol a n d a m e 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 Fs, I n v esti gat or’s 
A gree me nt, cli nical s u p plies recei pts, distri b uti o n a n d ret ur n rec or ds), a n d ot her s p o ns or 
c orres p o n d e nce p ertai 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 fil es at t he st u d y 
site ( Trial Master File).  S o urce d oc u me nts i ncl u d e 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 h e e val uati o n a n d 
rec o nstr ucti o n of t h e cli nical st u d y.  T hese rec or ds will be retai ne d i n a sec ure file f or t he 
peri o d re q uir e d b y t he i nstit uti o n or st u d y site p olic y.  Pri or t o tra nsfer or d estr 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 b e gi ve n t he o p p ort u nit y t o 
f urt her st ore s u c h rec or ds. 
1 2. 6.   
Rec or d Kee pi n g  
T he I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce 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 pres e 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  c o ntai ne d i n t he Trial 
Master File  i ncl u d e: 
 S u bject files c o ntai ni n g c o m plete d C R Fs, I C Fs, a n d s u p p orti n g c o pies of 
s o urce d oc u m e ntati o n (if ke pt). 
 St u d y files c o ntai ni n g t h e pr ot oc ol wit h all a me n d me nts, I B, c o pies of 
rele va nt ess e ntial d oc u m e 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 E C/I R B a n d t he S p o ns or.  
 Rec or ds rel ate d t o t he st u d y dr u g(s) i ncl u di n g ac k n o wle d g m e nt of recei pt at 
st u d y site, acc o u nta bilit y rec or ds a n d fi nal rec o nciliati o n a n d a p plica ble 
c orres p o n d e nce.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 7  
I n a d diti o n, all ori gi nal s o urce d oc u m e nts s u p p orti n g e ntries i n t he C R Fs m ust be 
mai ntai ne d a n d be rea dil y a v aila ble.  
All  st u d y relat e d esse ntial d oc u me ntati o n will be retai ne d b y t he I n v esti gat or u ntil at least 
3  years after t he l ast a p pr o val of a mar k eti n g a p plicati o n i n a n I C H  re gi o n a n d u ntil t here 
are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n a n I C H re gi o n or at least 3  
years ha v e 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 dr u g .  T h ese d oc u me nts s h o ul d be retai ne d f or a lo 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 m e 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 In vesti gat or/i nstit uti o n as t o 
w he n t hese d o c u me nts n o l o n ger nee d t o be retai n e d.  
S u bj ect's me dical files s h o ul d be retai ne d i n acc or da nce wit h a p plica ble le gislati o n a n d i n 
acc or da nce wit h t he ma xi m u m peri o d of ti me per mitte d b y t he h os pital, i nstit uti o n or 
pri vate practice.  
N o st u d y d oc u m e nt s h o ul d be destr o ye d wit h o ut pri or writte n a gre e me nt b et 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 v esti gat or wis h t o assi g n t he st u d y rec or ds t o 
a n ot her part y or m o ve t h e m t o a n ot her l ocati o n, h e/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. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 8  
1 3.   
FI N A N CI N G A N D IN 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 t he S p o ns or or a C R O .  T his a gree m e 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 h all 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.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 9 9  
1 4.   
P U B LI C A TI O N P O LI C Y  
A st u d y site ma y n ot p u blis h res ults of a st u d y u ntil after a c o or di nate d m ultice nter 
p u blicati o n has bee n s u b mitte d f or p u blicati o n or u ntil 1  year after t he st u d y has e n de d, 
w hic he ver occ urs first.  T heref ore, t he st u d y site will ha ve t he o p p ort u nit y t o p u blis h t he 
res ults of t he st u d y, pr o vi de d t hat Daiic hi Sa n k y o has ha d t he o p p ort u nit y t o re vie w a n d 
c o m me nt o n t he st u d y sit e’s pr o p ose d p u blicati o n pri or t o its bei n g s u b mitte d f or 
p u blicati o n wit h  t he a d vice of c o m p a ny pate nt c o u ncil a n d i n acc or d wit h nee ds f or  
s u bject pr otecti o n. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 0  
1 5.   
E T HI C S A N D S T U D Y  A D MI NI S T R A TI V E  IN F O R M A TI O N  
1 5. 1.   
C o m pli a nce St ate me nt, Et hics , a n d Re g ul at or y C o m pli a nce  
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I nter n ati o nal C o u ncil f or  
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 n cl 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 ul ati o ns: C o de of Fe d eral 
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 
a n d/ or; 
 J a pa nese Mi nistr y of Healt h, La b o ur a n d Welfare ( M H L W)  Or di n a nce N o. 2 8 
of 2 7 Marc h, 1 9 9 7 a n d/ or;  
 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 n erati ve a n d C ell 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 of 2 5 N o ve m ber,  2 0 1 4  a n d/ or; 
 Ot her a p plica bl e l ocal r e g ulati o ns.  
A d diti o nal i nf or mati o n f or J a pa nese st u d y s ites 
T his st u d y will be c o n d u cte d i n c o m plia nce wit h t he sta n dar ds sti p ulate d i n Article 1 4 -3 
a n d Article 8 0 -2 of t he P har mace utical a n d Me dical De vice Act a n d b y t he “ Or di na nce 
Re gar di n g G o o d Cli nical Practice” ( M H L W Or di na nce N o. 2 8, date d 2 7 Mar 1 9 9 7).  I n 
c o m plia nce wit h t he et hi cal pri nci ples of t he Decl arati o n of Helsi n ki, t he h u ma n ri g hts, 
welfare, a n d safet y of t he s u bjects will be t he first c o nsi derati o ns i n t he c o n d ucti n g of t his 
st u d y. 
1 5. 2.   
S u bject C o nfi de nti alit y  
T he I n vesti gat ors a n d t h e S p o ns or will preser ve t h e c o nfi de ntialit y of all s u bjects ta ki n g 
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 ul ati o ns.  
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 C R Fs or 
ot her d oc u me nts s u b mitte d t o t he S p o ns or or t he C R O, s u bjects s h o ul d be i de ntifie d b y a 
u ni q ue s u bject i de ntifier as desi g n ate d b y t he S p o ns or.  D oc u me nts t hat are n ot f or 
s u b missi o n t o t he S p o ns or or t he C R O (e g, si g ne d I C F) s h o ul d be ke pt i n strict 
c o nfi de nce b y t he I n v esti gat or.  
I n c o m plia nce wit h I C H G C P G ui deli nes, it is re q uire d t hat t he I n vesti gat or a n d 
i nstit uti o n per mit a ut h orize d re prese nt ati 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 R B/ E C direct access t o re vie w t he s u bject’s ori gi nal me di cal rec or ds f or 
verificati o n of st u d y -relat e 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 v e na me d 
re pres e ntati ves wit h o ut vi olati n g t he c o nfi de ntialit y of t he s u bj ect. 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 1  
1 5. 3.   
I nf or me d C o nse nt  
Bef ore a s u bj e ct’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 u ate 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 
p r ot oc ol-s pecifi c pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  S u bjects s h o ul d be 
gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d recei ve satisfact or y a ns wers t o t heir i n q uiries, 
a n d s h o ul d ha ve a d e q uat e ti me t o deci de w h et her or n ot t o partici pate i n t he st u d y.   T he 
writte n I C F s h o ul d be pre pare d i n t he l o cal la n g u a ge(s) of t he p ote ntial s u bject 
p o p ulati o n.  
I n o btai ni n g a n d d o c u me nti n g i nf or 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 E C or 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 d oc u me nte d i n t he s u bject’s me dical 
rec or ds.  T h e 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 n ce wit h i nstit uti o nal p olic y, a n d a c o p y 
of t he si g n e 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 dat e a n d ti me (if 
a p plica ble) t hat i nf or me d c o nse nt was gi ve n s h o ul d be rec or de d o n t he C R F.  
S u g geste d m o del te xt f or t he I C F f or t h e 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.) are pr o vi de d i n t he S p o ns or’s 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 st u d y site. 
1 5. 4.   
Re g ul at or y C o m pli a nce  
T he st u d y pr o t oc ol, s u bject i nf or mati o n a n d c o nse nt f or m, t he I B, a n y s u bject writte n 
i nstr ucti o ns t o be gi ve n t o t he s u bject, a vaila ble 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 v esti gat or’s q ualificati o ns s h o ul d be 
s u b mitte d t o t he E C or I R B f or et hical re vie w a n d a p pr o val acc or di n g t o l 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 
revie we d b y n a me a n d v ersi o n.  
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a n al ysis will be d oc u me nt e d i n a pr ot oc ol 
a me n d me nt a n d/ or t he S A P.  
T he S p o ns or will a p p oi nt a C o or di nati n g I n v esti gat or.   A m o n g ot her p ossi ble d uties, t he 
C o or di nati n g I n vesti gat or will be res p o nsi ble f or re vie wi n g a n d a p pr o vi n g t he Fi nal 
Cli nical St u d y Re p ort a n d testif yi n g t o t he acc urac y of t he des cri pti o n of t he st u d y 
c o n d uct.  Beca us e t he C o or di nati n g I n v esti gat or s h o ul d ha ve pers o nal k n o wle d ge of t he 
c o n d uct of t he st u d y, he or s he will n or mall y b e c h ose n fr o m a m o n g t h ose I n v esti gat ors 
w h o ha ve e nr olle d a n d tr eate d at least o ne s u bject.  H o we ver, w here a n I n v esti gat o r has 
s pecial k n o wle d ge of t he fiel d or of t he trial, t he C o or di nati n g I n v esti gat or ca n be c h ose n 
pri or t o e nr ol me nt of t he first s u bject.  I n all cas es, t he C o or di nati n g I n v esti gat or m ust  be 
ch ose n pri or t o l oc ki n g t he data bas e.     


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 2  
T he I n vesti gat or a n d/ or S p o ns or  m ust s u b mit a n d, w here n ecess ar y, o btai n a p pr o val fr o m 
t he E C or I R B f or all s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he I C F.  T he 
I n v esti gat or s h o ul d n otif y t he E C or 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 st u d y sit e an d ot her A E re p orts recei ve d fr o m t he S p o ns or/ C R O, i n 
acc or da nce wit h l ocal pr oce d ures.  
As re q uire d b y l o cal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y Affairs gr o u p or 
re pres e ntati ve t o w h o m t his res p o nsi bilit y h as bee n dele gate d will e ns ure all le gal aspects 
are c o v ere d, a n d a p pr o val fr o m t he a p pr o priate re g ulat or y b o dies o bt ai ne d, pri or t o st u d y 
i nitiati o n.  If c h a n ges t o t he i nitial pr ot oc ol a n d ot her rel e va nt st u d y d o c u m e nts are ma de, 
t his re prese ntati ve will als o e ns ure t hat a n y re vise d d oc u me nts re quire d f or s u b missi o n 
are s u b mitte d t o re g ulat or y a ut h orities a n d i m ple me ntati o n of t hese c h a n ges ha p pe n o nl y 
after a p pr o val b y t he rele va nt re g ulat or y b o dies, as re q uire d . 
I n t he e ve nt of a n y pr o hi biti o n or restricti o n i m p ose d (e g, cli nical h ol d) b y a n a p plica ble 
Re g ulat or y  A ut h orit y( i es) i n a n y area of t he w orl d, or if t he I n vesti gat or is a ware of a n y 
ne w  i nf or mati o n w hic h mi g ht i nfl ue nce t h e e val u ati o n of t he be nefits a n d ris ks of t he 
i n vesti gati o nal dr u g , t he S p o ns or s h o ul d be i nf or me d i m me diatel y.   
I n a d diti o n, t he In 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 In vesti gat or t o pr ot ect 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 In v esti gat or 
bec o mes a ware of.  
1 5. 5.   
Pr ot oc ol De vi ati o ns  
T he I n vesti gat or s h o ul d c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y 
S p o ns or a n d, if re q uir e d, b y t he re g ulat or y a ut h orit y(ies), a n d w hi c 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 Bs/ E Cs.  
A de viati o n t o a n y pr ot oc ol pr oce d ure or wai ver t o a n y stat e d criteria will n ot be all o we d 
i n t his st u d y e x ce pt w h ere necessar y t o eli mi nate i m me diate hazar d(s) t o t h e 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 o r, or p ers o n desi g n ate d b y t he In v esti gat or, s h o ul d d oc u m e nt a n d e x plai n 
a n y d e viati o n fr o m t he a p pr o ve d pr ot oc ol.  
If a s u bject w as i neli gi ble or recei ve d t h e i nc orrect d ose or st u d y treat me nt, a n d ha d at 
least 1 a d mi nistrati o n of st u d y dr u g, dat a s h o ul d be c ollecte d f or safet y p ur p oses. 
If a p plica bl e, the I n vesti gat or s h o ul d n otif y t he I R B or 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.  
1 5. 6.   
S u p pl y of Ne w I nf or m ati o n Affecti n g t he C o n d uct of t he St u d y  
W he n ne w i nf or mati o n b ec o mes a v aila ble t hat ma y a d v ersel y affect t he safet y of s u bj ects 
or t he c o n d uct of t h e st u d y, t he S p o n s 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 h e pr ot oc ol a n d/ or s u bject i nf or mati o n.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 3  
T he I n vesti gat or s h o ul d i m me diatel y i nf or m t he s u bject w he ne v er  ne w i nf or mati o n 
bec o mes a v aila ble t hat m a y b e rel e va nt t o t he s u bj ect’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 di cal rec or ds, f or e x a m ple, a n d it s h o ul d be c o nfir me d w het her t he 
s u bject is willi n g t o re mai n i n t he st u d y.  
If t he s u bject i nf or m ati o n is re vise d, it m ust be re-a p pr o ve d b y t he I n de pe n de nt Et hics 
C o m mittee (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 v esti 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 d ate t he re vise d I C F.  
1 5. 7.   
Pr ot oc ol A me n d me nts  
A n y a me n d me nts t o t he st u d y pr ot oc ol t hat 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 Daiic hi Sa n k y o  or t he C R O .  
Als o, t he S p o ns or will e ns ure t he ti mel y s u b missi o n of a me n d me nts t o re g ul at or y 
a ut h orities. 
A gl o bal pr ot oc ol a me n d me nt will affect st u d y c o n d uct at all st u d y sites i n all re gi o ns of 
t he w orl d.  S uc h a me n d me nts will be i nc or p orate d i nt o a re vise d pr ot oc ol d oc u me nt.  
C ha n ges m a de b y s uc h a me n d me nts will 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 o c 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 m e nt will affect st u d y c o n d uct at a partic ul ar st u d y site(s) a n d/ or 
i n a partic 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 b e 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 priat e, u nless i m me diate i m ple me ntati o n of t he 
c ha n ge is ne cessar y f or s u bject safet y. 
1 5. 8.   
St u d y Ter mi n ati o n  
T he s p o ns or has t he ri g ht t o ter mi nate t he st u d y at a n y ti me a n d t he st u d y t er mi nati o n 
ma y als o be re q u este d b y (a) c o m p ete nt a ut h orit y/i es.  
1 5. 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 5. 1 0.  
A d dress List  
A list of ke y st u d y pers o n nel (i ncl u di n g p ers o n nel at t he s p o ns or, C R O, la b orat ories, a n d 
ot her ve n d ors) a n d t heir c o ntact i nf or mati o n (a d dress, tele p h o ne, fa x, e mail) will be ke pt 
o n file a n d re g ul arl y u p d ate d as necessar y. 








Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 7  
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 n ce 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  N o v ; 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 v al 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  Oct ; 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 m a 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  A pr ; 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 
gastri c ca n cer: 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  
J u n; 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 t ar get. A n n O nc ol. 2 0 0 8  Se p ; 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 p ecita bi ne i n patie nts wit h H E R 2 o vere x pressi n g metastatic pa n creatic 
ca ncer. Br J Ca ncer. 2 0 1 2  Mar 1 3 ; 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 p aris o n of i m m u n o hist oc he mistr y, fl u oresce n ce i n sit u 
h y bri dizati o n ( FI S H), d ual -I S H, a n d ge n e m utati o ns. L u n g Ca n cer. 2 0 1 4 
Se p ; 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 p las mic O vere x pressi o n of 
H E R 2: a K e y F act or i n C ol orectal C a ncer. Cli n Me d I nsi g hts O n c 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 n ce. 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 m a n a d ult a n d fet al tiss ues. O nc o ge ne. 1 9 9 0  J ul; 5( 7): 9 5 3-
6 2.  
1 1.  Herce pti n: F ull prescri bi n g i nf or m ati o n ( U nite d States). Re vise d 2 0 1 5 A pr [cite d 
2 0 1 7 A u g 1 8]. A vaila ble fr o m:   
htt p:// w w w.access dat a.f da. g o v/ dr u gs atf da _ d o cs/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 ( E ur o pe). U p date d 2 0 1 5 A pr 2 1 [ cite d 
2 0 1 7 A u g 1 8]. A vaila ble f ro m:   
htt p:// w w w.e ma.e ur o pa. e u/ d ocs/e n _ G B/ d oc u m e 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 (J a pa n). Re vise d 2 0 1 5 Dec [cite d 2 0 1 7 A u g 1 8]. 
A vaila ble fr o m:  htt p:// w w w.i nf o. p m da. g o.j p/ g o/ p ac k/ 4 2 9 1 4 0 6 D 3 0 2 1 _ 1 _ 0 2 / 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 8  
1 4.  Ka d c yla: F ull prescri bi n g i nf or mati o n ( U nite d States). Re vise d 2 0 1 4 J ul [cite d 
2 0 1 7 A u g 1 8]. A vaila ble f ro m:   
htt p:// w w w.access dat a.f da. g o v/ dr u gs atf da _ d o cs/la bel/ 2 0 1 4/ 1 2 5 4 2 7s 0 3 3l bl. p df  
1 5.  Ka dc yla: E P A R - Pr o d uct I nf or mati o n ( E ur o pe). U p date d 2 0 1 4 Dec 3 [ cite d 2 0 1 7 
A u g 1 8]. A vaila ble f ro m:   
htt p:// w w w.e ma.e ur o pa. e u/ d ocs/e n _ G B/ d oc u m e 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 k a ge I ns ert (Ja pa n). Re vise d 2 0 1 7 J a n [cite d 2 0 1 7 A u g 1 8]. 
A vai la ble fro m:  htt p:// w w w.i nf o. p m da. g o.j p/ g o / p ac k/ 4 2 9 1 4 2 6 D 1 0 2 6 _ 1 _0 4 / 
1 7.  A b o u -Alfa G K, Let o ur n ea u R, Har ker G, et al. . Ra n d o mize d p hase III st u d y of 
e x ateca n a n d ge mcita bi ne c o m pare d wit h ge mcita bi ne al o ne i n u ntreat e d 
a d va nce d pa ncreatic ca n cer. J. Cli n O nc ol . 2 0 0 6 Se p 2 0;2 4( 2 7) :4 4 4 1 -7.  
1 8.  C he vert o n P, Fr iess H, A n dras C, et al. P hase III res ults of e x ateca n ( D X-8 9 5 1f) 
vers us ge mcita bi ne ( Ge m) i n c he m ot hera p y -na ïve patie nts wit h a d va nce d 
pa ncreatic ca ncer ( A P C). J Cli n O nc ol. 2 2: 1 4s, 2 0 0 4 (a bstr 4 0 0 5).  
1 9.  De J a ger R, C he vert o n P, Ta ma n oi K, et al. D X -8 9 5 1f: s u m mar y of p hase I 
cli nical trials. A n n N Y Aca d Sci. 2 0 0 0; 9 2 2: 2 6 0 -7 3.  
2 0.  O gita ni  Y , Ai d a T , Ha gi h ara K , et al. D S-8 2 0 1a, A N o vel H E R 2 -Tar geti n g A D C 
wit h a N o vel D N A T o p ois o merase I I n hi bit or, De m o nstrates a Pr o misi n g 
A ntit u m or Efficac y wit h Differe ntiati o n fr o m T -D M 1. Cli n Ca ncer Res. 
2 0 1 6; 2 2( 2 0): 5 0 9 7 -5 1 0 8.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 0 9  
1 7.   
A P P E N DI C E S  
1 7. 1.   
C oc kcr oft -G a ult E q u ati o n  
T he esti mate d creati ni ne cleara nce ( Cr C L ; m L/ mi n) will be calc ulat e d usi n g t he 
C oc kcr oft -Ga ult e q uati o n base d o n act u al wei g ht i n kil o gra ms ( 1 kil o gra m = 2. 2 p o u n ds):  
C o n ve nti o n al –  ser u m cre ati ni ne i n m g/ d L: 
Male:  
Cr C L  ( m L/ mi n) = 
7 2
 x 
mg/ d L)
(in 
 
creatinine
 
ser u m
k g)
(in 
 x weight 
years)]
(in 
 
a ge
 - 
[ 1 4 0
 
Fe male:  
Cr C L  ( m L/ mi n) = 
7 2
 x 
mg/ d L)
(in 
 
creatinine
 
ser u m
k g)
(in 
 x weight 
years)]
(in 
 
a ge
 - 
[ 1 4 0
  0. 8 5  
 
I nter n ati o n al S yste m of U nits ( SI) –  ser u m cre ati ni ne i n μ m ol/ L: 
Male:  
Cr C L  ( m L/ mi n) = 
0. 0 1 1 3
 x 
7 2
 x 
mol/ L)
(in 
 
creatinine
 
ser u m
k g)
(in 
 x weight 
years)]
(in 
 
a ge
 - 
[ 1 4 0

 
 
Fe male:  
Cr C L  ( m L/ mi n) = 
0. 0 1 1 3
 x 
7 2
 x 
mol/ L)
(in 
 
creatinine
 
ser u m
k g)
(in 
 x weight 
years)]
(in 
 
a ge
 - 
[ 1 4 0

 
 0. 8 5  
 
S o urce: C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m ser u m 
creati ni ne. Ne p hr o n 1 9 7 6; 1 6 ( 1): 3 1-4 1.  
 
1 7. 2.   
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  
N or mal acti vit y .  F ull y acti ve, a ble t o carr y o n all pre -disease 
perf or ma nce wit h o ut restricti o n  
1  
S y m pt o ms, b ut a m b ulat or y.   Restricte d i n p h ysicall y stre n u o us 
acti vit y, b ut a m b ulat or y a n d a ble t o carr y o ut  w or k of a li g ht or 
se de ntar y nat ure, e g, li g ht h o use w or k, office w or k  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 0  
G R A D E  
D E S C RI P TI O N  
2  
I n be d < 5 0 % of t he ti me.  A m b ulat or y a n d ca pa ble of all self -care, 
b ut u na ble t o carr y o ut a n y w or k acti vities,  u p a n d a b o ut m ore t ha n 
5 0 % of wa ki n g h o urs  
3  
I n be d > 5 0 % of t he ti me.  Ca pa ble of o nl y li mite d self -care, 
c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of  wa ki n g h o urs  
4  
1 0 0 % be dri d de n.   C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -
care.  T otall y c o nfi ne d t o be d or  c hair 
5   
Dea d  
                       S o urce: O ke n M M, Creec h R H, T or me y D C, et al. T o xicit y a n d res p o nse criteria of t he 
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.  
1 7. 3.   
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. 3. 1.   
Me as ur a bilit y of T u m or at B aseli ne  
1 7. 3. 1. 1.  Defi niti o ns  
At baseli ne, t u m or lesi o ns/l y m p h n o d es will be cat e g orize d meas ura bl e or n o n -
meas ura ble as f oll o ws:  
1 7. 3. 1. 1. 1.  Me as ur a ble  
 T u m or lesi o ns: M ust be acc urat el y m eas ure d i n at least 1 di me nsi o n (l o n gest 
dia meter i n t he pla ne of meas ure 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 s ca n slice t hic k ness n o gre ater t ha n 5 m m)  
 1 0 m m cali per meas ure m e 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 m ali g n a nt l y m p h n o des: T o be c o nsi dere d pat h ol o gicall y e nlar ge d 
a n d meas ura ble, a l y m p h n o 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 h e 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 o c u me ntati o n of tar get a n d 
n o n -tar get lesi o ns” f or i nf or mati o n o n l y m p h n o de meas ure me nt. 
1 7. 3. 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 no n -meas ura ble lesi o ns.  
Lesi o ns c o nsi dere d tr ul y n o n -meas ura bl e 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 diseas e, l y m p ha n gitic i n v ol ve me nt of s ki n or 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 1  
l u n g, a n d a b d o mi nal masses/a b d o mi nal or ga n o me gal y i de ntifie d b y p h ysi cal e xa m 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. 3. 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. 3. 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) s ca n or plai n fil ms are n ot 
c o nsi dere d a de q uat e i ma gi n g tec h ni q u es 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 n ce or disa p p eara nce of b o ne 
lesi o ns. 
 L ytic b o ne l esi o n s or mi xe d l ytic-bl astic lesi o ns, wit h i de ntifia ble s oft tiss ue 
c o m p o ne nts, t hat ca n be e val uate d b y cr oss -secti o nal i ma gi n g tec h ni q ues s uc h 
as C T or M RI ca n b e c o nsi dere d as meas ura ble l esi o ns if t he s oft tiss ue 
c o m p o ne nt meets t he defi niti o n of meas ura bi lit y d escri be d a b o ve. 
 Blastic b o ne lesi o ns are n o n -meas ura bl e.  
1 7. 3. 1. 1. 3. 2.  C ystic Lesi o ns  
 Lesi o ns t hat meet t he crit eria f or ra di o gra p hicall y defi ne d si m ple c ysts s h o ul d 
n ot be c o nsi dere d as mali g na nt lesi o ns ( neit her meas ura ble n or n o n -
meas ura ble) si nce t he y are, b y d efi niti o n, si m ple c ysts.  
 “ C ystic lesi o ns” t h o u g ht t o re prese nt c ystic metast ases ca n b e c o nsi dere d as 
meas ura ble l esi o ns, if t he y meet t he defi niti o n of meas ura bilit y d escri be d 
a b o ve.  H o we ver, if n o n c ystic lesi o ns are pres e nt i n t he sa me s u bject, t hese 
are preferre d f or sel ecti o n as tar get lesi o ns. 
1 7. 3. 1. 1. 3. 3.  Lesi o ns wit h Pri or L oc al Tre at me nt  
 T u m or lesi o ns sit uate d i n a pre vi o usl y irra di ate d area, or i n a n area s u bjecte d 
t o ot her l oc o-re gi o n al t hera p y, are n ot c o nsi dere d meas ura ble u nl ess t here has 
bee n de m o nstra t e d pr o gressi o n i n t he lesi o n. 
1 7. 3. 1. 2.  S pecific ati o ns b y Met h o ds of Me as ure me nts  
1 7. 3. 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 v al uati o ns s h o ul d be perf or me d as cl ose as p ossi bl e 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. 3. 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 haract erize 
eac h i de ntifie d a n d re p orte d lesi o n at baseli ne a n d d uri n g F/ U.  I ma gi n g base d e val uati o n 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 2  
s h o ul d al wa ys b e perf or me d rat her t h a n cli nical e x a 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 v aila 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 ns e ass ess me nt.  T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n 
C T sca n base d o n t 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 h a 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 bl e i n certai n sit uati o ns (e g, f or 
b o d y sca ns).  
1 7. 3. 2.   
T u m or Res p o nse E v al u ati o n  
1 7. 3. 2. 1.  Assess me nt of O ver all T u m or B ur de n  a n d Me as ur a ble Dise ase  
T o assess o bjecti ve res p o nse or f ut ure pr o gressi o n, it is necessar y t o esti mat e t he o verall 
t u m or b ur de n at 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.   
1 7. 3. 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 b aseli ne (t his mea ns i n i nstances 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 b asis 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 n s, b ut i n a d diti o n s h o ul d be t h ose t hat 
le n d t he msel ves t o re pr o d uci ble re peate d meas ure me nts.  It ma y b e t he case t hat, o n 
occasi o n, t he lar gest lesi o n d oes n ot le n d itself t o re pr o d uci ble m eas 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 b e 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 peci al 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 b e visi ble b y i ma gi n g e v e 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 bl e a n d ma y b e i de ntifie d as tar get lesi o ns m ust meet 
t he criteri o n of a s h ort a xis of ≥ 1 5 m m b y C T sca n.  O nl y t 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 si ze 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 h e a xial pla ne; f or M RI t he pla n e of ac q uisiti o n ma y b e a xial, sa gittal, or 
c or o nal).  T h e s maller of t hese meas ures is t he s h ort a xis.  F or e x a m ple, a n a b d o mi nal 
n o de w hic h is re p orte d as bei n g 2 0 m m × 3 0 m m h as a s h ort a xis of 2 0 m m a n d q ualifies 
as a mali g n a nt, meas ura ble n o de.  I n t his e x a m ple, 2 0 m m s h o ul d be rec or de d as t he n o de 
meas u re 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 h at 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 gi cal 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 h e baseli ne s u m dia meters.  If l y m p h 
n o des are t o b e 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 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 3  
t he s um.  T he baseli ne s u m dia meters will be use d as refere n ce t o f urt her c haract erise 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 p at h ol o gical l y m p h n o des s h o ul d be 
i de ntifie d as no n -tar get lesi o ns a n d s h o ul d als o be rec or de d at baseli ne.  M eas ure m e nts 
are n ot r e q uire d a n d t h es e lesi o ns s h o ul d be f oll o we d as “ prese nt,” “a bs e nt,” or i n rare 
cases “ u n e 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 p el vic l y m p h n o des” or “ m ulti ple li ver m etastases”).  
1 7. 3. 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. 3. 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. 
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 n ce 
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 n ce 
t he s mallest s u m o n st u d y (t his i ncl u des t he b aseli 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 ncreas e of 2 0 %, t he s u m m ust als o de m o nstrate a n a bs ol ute 
i ncreas e of at least 5 m m.  ( N ote: t he a p 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 n t i ncreas e t o q ualif y f or 
P D, ta ki n g as refere n ce t he s mallest s u m dia meters w hile o n st u d y.  
1 7. 3. 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 h a v e t he act u al 
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 n e as t he baseli ne 
e x a mi nati o n), e ve n if t he n o des re gress t o bel o w 1 0 m m o n st u d y.  T his mea ns t hat w he n 
l y m p h n o des are i ncl u de d as tar get lesi o ns, t he “s u m” of lesi o ns ma y n ot b e zer o e ve n if 
C R criteria are met, s i nce a n or mal l y m p h n o d e is defi ne d as h a vi n g a s h ort a xis of < 1 0 
m m.  F or P R, S D, a n d P D, t he act ual s h ort a xis meas ure m e 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 m e nts rec or de d at 
eac h s u bse q ue nt e val u ati o n, e ve n w he n v er y s mall (e g, 2 m m).  H o we v er, 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 t ar 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 x act meas ure a n d 
ma y re p ort t he m as b ei n g “t o o s mall t o meas ure.”  W he n t his occ urs, it is i m p orta nt t hat a 
val ue be rec or de d o n t he e C R F.  If it is t he o pi ni o n of t he ra di ol o gist t hat t he lesi o n has 
li kel y disa p peare d, t h e meas ure m e nt s h o ul d be rec or de d as 0 m m.  If t he l esi 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 d efa ult val ue of 5 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
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Pa ge 1 1 4  
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 u e ntl y s urr o u n de d b y 
fat s uc h as i n t he retr o perit o ne u m; h o we ver, if a l y m p h n o de is belie ve d t o be prese nt a n d 
is fai ntl y see n b ut t oo s m all t o meas ure, a d efa 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 d eri 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 f alse res p o ns es or pr o gressi o ns bas e d u p o n meas ure me nt err or.  T o reiterat e, 
h o we ver, if t h e 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 h e 
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 h er t o calc ulate t he 
tar get lesi o n s u m.  Si milarl y, as l esi 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 l esi o ns ha ve tr ul y c oal esce d s uc h t hat t he y are n o l o n ger 
se para bl e, 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 maxi mal 
l o n gest dia meter f or t h e “c oalesce d lesi o n.” 
1 7. 3. 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 h e 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 v el 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. 3. 2. 3. 4.  S peci al N otes o n Assess me nt of Pr o g ressi o n of N o n -t ar get Dise ase 
T he c o nce pt of pr o gressi o n of n o n -tar get disease re q uires a d diti o nal e x pla nati o n as 
f oll o ws: 
W he n t he s u bject als o h as m e 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 v erall le vel of 
s u bsta ntial w orse ni n g i n n o n-tar get diseas e s uc h t hat, e ve n i n pres e nce of S D or P R i n 
tar get disease, t h e overall 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 n e q ui v ocal pr o gressi o n stat us.  T he 
desi g nati o n of o v erall pr o gre ssi 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 t ar get diseas e 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 s a me ge n eral c o nce pts a p pl y 
here as n ot e d a b o ve, h o we ver, i n t his i nsta nce t here is n o meas ura ble dis eas e assess me nt 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 5  
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 bl e 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 b l e) a usef ul test t hat ca n be a p plie d w he n ass essi 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-m eas ura ble diseas e is c o m para ble i n ma g nit u de t o t he i ncreas e t hat 
w o ul d be re q uir e d t o decl are P D f or meas ura ble disease (ie, a n i ncrease i n t u m or b ur de n 
re pres e nti n g a n a d diti o nal 7 3 % i ncreas e i n ‘ v ol u me’ [ w hic h is e q ui vale nt t o a 2 0 % 
i ncreas e 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 ncreas e m ust be s u bsta ntial.  
1 7. 3. 2. 3. 5.  Ne w Lesi o ns  
T he a p peara n ce of ne w mali g na nt lesi o ns de n otes disease pr o gressi o n; t heref ore, s o me 
c o m me nts o n detecti o n of ne w lesi o ns are i m p orta nt.  T here are n o s pecific criteria f or 
t he i de ntificati o n of ne w ra di o gra p hic l esi 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 pres e nt s o met hi n g ot her t ha n t u m or (f or 
e x a m ple, s o me “ ne w” b o ne lesi o ns ma y b e si m pl y heali n g or flare of pree x isti n g lesi o ns).  
T his is partic ularl y i m p orta nt w he n t he s u bject’s b aseli ne lesi o ns s h o w P R or C R.  F or 
e x a m ple, necr osis of a li ver lesi o n ma y be re p 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 n at o mical l ocati o n t hat was n ot sca n ne d at 
baseli ne is c o nsi dere d a n e w lesi o n a n d will i n dicate disease pr o gressi o n.  A n e x a m ple of 
t his is t he s u bject w h o has visceral diseas e at baseli ne a n d w hile o n st u d y h as a C T or 
M RI brai n or dere d w hic h re vea ls met astases.  T he s u bject’s brai n metastas es are 
c o nsi dere d t o be e vi de nce of P D e ve n if he/s he di d n ot ha ve brai n i ma gi n g at baseli ne.   
If a ne w lesi o n is e q ui v ocal, f or e x a m ple beca use of its s mall size, c o nti n ue d t hera p y a n d 
F/ U e val u ati o n will clari f y if it re prese nts tr ul y ne w disease.  If re p eat sca ns c o nfir m t here 
is defi nitel y a n e 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 dat e of t he i nitial 
sca n.   
1 7. 3. 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 r ec 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 n ce of ne w 
lesi o ns. 
1 7. 3. 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 pecifi e d ti me p oi nt, a res p o nse ass ess 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 diseas e at baseli ne.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
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Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 6  
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.  
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. 3. 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 m e 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 ns e.  T his w o ul d be m ost li kel y t o ha p pe n 
i n t he case of P D.  F or e x a m ple, if a s u bject h a 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 l esi o ns were assesse d, b ut t h ose ga v e 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.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 7  
1 7. 3. 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 ns e 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 ns e 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 m e nt, a n d P D o n last 
assess me nt has a b est o verall res p o ns e 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 h e s u bse q ue nt assess me nts. 
1 7. 3. 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 m e 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 ncreas e i n size of t he n o des.  As n ote d 
earlier, t his mea ns t h at s u bject s 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 det eri o rati o n.”  E ver y eff ort s h o ul d be ma de t o d oc u me nt o bj ecti 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 st a t us of s uc h s u bjects is t o be deter mi ne d b y e v al uati o n of tar get a n d 
n o n -tar get diseas e. 
F or e q ui v o cal fi n di n gs of pr o gressi o n (e g, v er y s m all 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 n e 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 h e earlier date w he n pr o gressi o n was s us pecte d.  
1 7. 3. 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 uct e 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 v er 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 dise ase, wit h dra wal of c o nse nt, deat h, or l oss t o F/ U.  S ca n dates 
s h o ul d n ot be a dj uste d or resc he d ul e d d ue t o dose 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 d e t o e ns ure c o nsiste nc y b et wee n t he baseli ne meas ure me nts a n d 
all s u bse q ue nt meas 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 v al 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 s cree ni n g p eri 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 m a de t o use t he sa m e 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 met astasis at t he ti me 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 8  
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 les i o ns i n t he res pecti ve or ga n(s) a n d s h o ul d c o nf or m t o t he i ma ge 
ac q uisiti o n g ui deli nes acc or di n g t o i nstit uti o nal sta n dar ds.  
All tar get a n d n o n -tar get sites are e v al uate d at eac h ti me p oi nt of t u m or assess me nt.  
1 7. 4.   
Ne w Y or k He art Ass oci ati o n F u ncti o n al Cl assi fic ati o n 
F u ncti o n al C a p acit y  
O bjecti ve Assess me nt  
Cl ass I.  
Patie nts wit h car diac disease b ut wit h o ut res ulti n g 
li mitati o n of p h ysical acti vit y.  Or di nar y p h ysical 
acti vit y d oes n ot ca use u n d ue fati g ue, pal pitati o n, 
d ys p nea, or a n gi nal pai n . 
A.  
N o o bj ecti ve e vi de nce of 
car di o vasc ular disease.  
Cl ass II.  
Patie nts wit h car diac disease res ulti n g i n sli g ht 
li mitati o n of p h ysical acti vit y.  T he y are 
c o mf orta ble at rest. Or di nar y p h ysical acti vit y 
res ults i n fati g ue, pal pitati o n, d ys p nea, or a n gi nal 
pai n . 
B.  
O bjecti ve e vi de nce of 
mi ni mal car di o vasc ular 
disease.  
Cl ass III.  
Patie nts wit h car diac disease res ulti n g i n mar ke d 
li mitati o n of p h ysical acti vit y.  T he y are 
c o mf orta ble at rest.  Less t ha n or di nar y acti vit y 
ca uses fati g ue, pal pitati o n, d ys p nea, or  a n gi nal 
pai n.  
C.  
O bjecti ve e vi de nce of 
m o deratel y se vere 
car di o vasc ular disease.  
Cl ass I V.  
Patie nts wit h car diac disease res ulti n g i n i na bilit y 
t o carr y o n a n y p h ysical acti vit y wit h o ut 
disc o mf ort.  S y m pt o ms of heart fail ure or t he 
a n gi nal s y n dr o me ma y  be prese nt e ve n at rest.  If 
a n y p h ysical acti vit y is u n derta ke n, disc o mf ort is 
i ncrease d. 
D.  
O bjecti ve e vi de nce of 
se vere car di o vasc ular 
disease.  
S o urce: A merica n Heart Ass ociati o n, I nc. Classificati o n of F u ncti o nal Ca pacit y a n d 
O bj ecti ve Assess me nt. A vaila ble fr o m: 
htt p:// m y.a merica n heart. or g/ pr ofessi o nal/ State me nts G ui deli nes/ B y P u blicati o n Date/ Pre vi o us
Years/ Classificati o n -of -F u ncti o nal -Ca pacit y -a n d -O bj ecti ve -
Assess me nt _ U C M _ 4 2 3 8 1 1 _ Article.js p  
1 7. 5.   
S u p ple me nt List  
S u p ple me nts are pre p are d se parat el y fr o m pr o t oc ol, a n d t heir versi o ns are i n de pe n de nt 
fr o m pr ot oc ol. 
S u p ple me nt 6  is a J a pa n-s pecific d oc u m e nt.  T his  will be pre pare d i n J a pa nese la n g ua ge 
a n d o nl y s u b mitte d f or Ja pa nese site’s I R B.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 1 9  
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: 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 3: T he list of Q T pr ol o n gati o n dr u gs  
 S u p ple me nt 4 : T he list of C Y P 3 A 4 str o n g i n hi bit ors a n d O A T P i n hi bit ors  
 S u p ple me nt 5 : N ot a p plica bl e 
 S u p ple me nt 6: A d diti o nal i nf or mati o n  
 
1 7. 6.   
I nstr ucti o ns rel ate d t o Se vere Ac ute Res pir at or y S y n dr o me 
C or o n a vir us 2 ( S A R S -C o V -2)  
D ue t o t he p ote ntial i m pact of S A R S -C o V -2, ie C O VI D -1 9, o n s u bject safet y, t he 
S p o ns or rec o m me n ds t he f oll o wi n g d ose m o dificati o n a n d ma na ge me nt pla n f or s u bjects 
wit h c o nfir me d or s us pecte d S A R S -C o V -2 w hile bei n g treate d wi t h D S-8 2 0 1a. D o se 
m o dificati o ns will be base d o n t he w orst C T C A E gra de. All d ose m o dificati o ns 
( disc o nti n uati o n, i nterr u pti o ns or re d ucti o ns) m ust be rec or de d o n t he A E a n d dr u g 
a d mi nistrati o n e C R Fs.  
 
1 7. 6. 1.   
D ose m o dific ati o n criteri a f or s us pecte d or c o nfir me d C O VI D -1 9  
If S A R S-C o V -2 i nfecti o n is s us pecte d, i nterr u pt D S -8 2 0 1a a n d r ule o ut S A R S -C o V -2 per 
l ocal g ui d a nce. 
 If S A R S-C o V -2 is c o nfir me d or is still s us pecte d afte r e val uati o n f oll o w d ose 
m o dificati o n as o utli ne d i n Ta ble  1 7 .3  bel o w a n d ma na ge S A R S -C o V -2 per 
l ocal g ui d a nce u ntil rec o ver y of S A R S-C o V -2. S A R S -C o V -2 re c o v er y is 
defi ne d as n o si g ns/s y m pt o ms of S A R S -C o V -2, at least 1  ne gati ve real -ti m e 
re verse tra nscri pti o n p ol y merase c hai n reacti o n ( R T-P C R) test res ult, a n d 
nearl y or c o m pletel y res ol ve d c hest C T fi n di n gs.  
 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 0  
T a ble  1 7 .3 : 
S A R S -C o V -2 D ose M o dific ati o n Criteri a  
S A R S -C o V -2 W orst T o xicit y N CI -C T C A E 
Versi o n 5. 0 Gr a de ( u nless ot her wise s pecifie d)  
Sc he d ule M o dific ati o n  f or D S-8 2 0 1 a  
Gra de 1  
Res u me st u d y dr u g at t he sa me d ose a 
Gra de 2  
Res u me st u d y dr u g at t he sa me d ose if c hest C T 
fi n di n gs are c o m pletel y res ol ve da 
Re d uce b y 1 d ose le vel if c hest C T fi n di n gs are 
nearl y res ol ve d  
Gra de 3  
Re d uce b y 1 d ose le vel if c hest C T fi n di n gs are 
c o m pletel y res ol ve d  
Disc o nti n ue st u d y dr u g if c hest C T fi n di n gs are 
n ot  c o m pletel y res ol ve d  
Gra de 4  
Disc o nti n ue st u d y dr u g  
S A R S -C o V -2 = se vere ac ute r es pirat or y s y n dr o me c or o na vir us 2 ( S A R S -C o V -2); C T = c o m p ute d 
t o m o gra p h y 
a Cl osel y m o nit or si g ns/s y m pt o ms after res u mi n g D S -8 2 0 1a, i nitiall y wit h a p h o ne call e ver y 3 da ys f or t he 
first wee k, a n d t he n wit h a we e kl y p h o ne call t hereafter, f or a t otal of 6 wee ks. 
I n a d diti o n t o t he rec o m me n dati o ns o utli ne d i n Ta ble  1 7 .3 , in vesti gat ors ma y c o nsi der 
d ose m o dificati o ns of t he st u d y dr u g acc or di n g t o t he s u bject’s c o n diti o n a n d after 
disc ussi o n wit h t he st u d y Me dical M o nit or or desi g nee.  
If a n e v e nt is s us pecte d t o be dr u g-relate d I L D/ p n e u m o nitis, ma na ge p er pr ot oc ol 
I L D/ p n e u m o nitis ma na ge me nt g ui d eli ne (Ta ble  5 .2 ). 
 
1 7. 6. 2.   
Pri o r a n d C o nc o mit a nt Me dic ati o ns  
 C hl or o q ui ne or h y dr o x yc hl or o q ui ne;  
 C o nc o mita nt treat me nt is n ot all o we d d uri n g t h e st u d y treat me nt ( Secti o n  
5. 6. 1 ). 
 If treat me nt is a bs ol utel y re q uire d f or S A R S-C o V -2 , D S -8 2 0 1a m ust be 
i nterr u pte d. 
 If a d mi nistere d, t he n a was h o ut peri o d of n o less t ha n 1 4 da ys is re q uire d 
bef ore res u m pti o n of D S -8 2 0 1a.  
 
1 7. 6. 3.   
P K Assess me nt(s) if C hl or o q ui ne or H y dr o x yc hl or o q ui ne is A d mi nistere d  
A d diti o nal P K ser u m sa m ples s h o ul d be c ollecte d, if c hl or o q ui ne or h y dr o x yc hl or o q ui ne 
is a d mi nistere d f or S A R S-C o V -2 i nfecti o n, at t he ti me p oi nts s pecifie d i n  Ta ble  8 .2 . 
T he c hl or o q ui ne or h y dr o x yc hl or o q ui ne a d mi nistrati o n ti me a n d t he e x act ti me of bl o o d 
sa m ple c ollecti o n f or P K a nal ysis m ust be rec or de d o n t he e C R F.  
 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 1  
1 7. 6. 4.   
S A R S -C o V -2 Assess m e nt(s) 
All c o nfir me d or s us pecte d S A R S -C o V -2 i nfecti o n e ve nts m ust be rec or de d i n t he e C R F. 
If a s u bject prese nts t o t h e cli nic wit h s y m pt o ms s u g gesti ve of S A R S-C o V -2, b ut t he 
real-ti me R T-P C R test is n ot a vaila ble at t he site, a sa m ple kit will be pr o vi de d f or 
sa m ple c ollecti o n t o be teste d at a ce ntral la b orat or y.  
Ser u m sa m ples will be use d f or S A R S -C o V -2 testi n g fr o m eac h s u bject w h o pr o vi des 
c o nse nt.  Sa m ples will be c ollecte d pri or t o t he st u d y dr u g i nf usi o n, s hi p pe d t o a ce ntral 
la b orat or y, a n d st ored t here u ntil t he tests bec o me a vaila ble.  
If s u bjects c o ns e nt, t he re mai ni n g ser u m sa m ples will als o be st ore d f or f ut ure a nal ysis. 
 
1 7. 6. 5.   
St atistic al A n al ysis - Assess me nt of t he I m p act of S A R S -C o V -2  
If dee m e d a p pr o priate, a nal yses will be perf or me d t o e x pl ore t he i m pact of S A R S-C o V -2 
o n safet y, efficac y, a n d a n y ot her e n d p oi nts, as a p pr o priate, re p orte d f or t he st u d y. 
As a res ult of t he i m pact of S A R S -C o V -2 o n st u d y c o n d u ct, a dj ust me nts t o t he statistical 
a nal ysis a n d i nter pretati o n will be ma de, if re q uire d. T hese will be descri be d i n t he 
statistical a nal ysis pla n 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 2  
1 7. 7.   
Sc he d ule of E ve nts  
 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 3  
T a ble  1 7 .4 : 
Sc he d ule of E ve nts  
  
S  
C  
R  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4  
a n d 
s u bse q ue nt 
c ycles 
C ycle 5  
a n d 
s u bse q ue nt 
c ycles 
E O T a 
4 0 D  
F/ U b 
N C T 
a n d 
S U 
F/ U  
D a y  
[ All o w a nce 
(± )] 
0   
1   
2   
4   
8  
[1 ] 
1 5  
[1 ] 
( 2 2) 
[ 2] 
1  
[ 2] 
8  
[ 2] 
1 5  
[ 2] 
2 2  
[ 2] 
1  
[ 2] 
2   
4   
8  
[1 ] 
1 5  
[1 ] 
( 2 2) 
[ 2] 
1  
[ 2] 
1  
[ 2] 
  
  
 
BI   
E OI   
  
  
  
  
  
BI   
E OI   
  
  
  
BI   
E OI   
  
  
  
  
  
BI   
E OI   
BI   
E OI   
  
  
 
I nf or m e d 
c o nse nt 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
De m o gra p hic 
i nf or mati o n 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
I ncl usi o n/ 
E xl usi o n 
Criteria  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Uri nal ysis test   
X d  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
HI V a nti b o d y 
test 
X c 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Pre g na nc y test   
X d 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X   
X  
 
I H C/ FI S H 
(t u m or sa m ple) 
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
A d mi nister  
D S -8 2 0 1a  
  
  
X   
  
  
  
  
  
X   
  
  
  
X   
  
  
  
  
  
X  
X   
  
 
 
Hei g ht  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
Wei g ht , 
E C O G P S  
X d  
  
X e 
  
  
  
  
  
  
X e  
  
  
  
  
X e  
  
  
  
  
  
  
X e  
  
X e  
  
X   
X  
 
Vital si g n   
X d  
  
X e  
X   
X   
X   
X   
X   
  
X e  
X   
X   
X   
  
X e  
X   
X   
X   
X   
X   
  
X e  
  
X e  
  
X   
X  
 
P h ysical 
e xa mi nati o n 
X d  
  
X e  
  
  
  
  
  
  
X e  
  
  
  
  
X e  
  
  
  
  
  
  
X e  
  
X e  
  
X   
X  
 
S p O 2 
  
  
X e  
  
  
  
  
  
  
X e  
  
  
  
  
X e  
  
  
  
  
  
  
X e  
  
X e  
  
X   
X  
 


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 4  
 
S  
C  
R  
C ycle 1  
C ycle 2  
C ycle 3  
C ycle 4  
a n d 
s u bse q ue nt 
c ycles 
C ycle 5  
a n d 
s u bse q ue nt 
c ycles 
E O T a 
4 0 D  
F/ U b 
N C T 
a n d 
S U 
F/ U  
D a y  
[ All o w a nce 
(± )] 
0   
1   
2   
4   
8  
[1 ] 
1 5  
[1 ] 
( 2 2) 
[ 2] 
1  
[ 2] 
8  
[ 2] 
1 5  
[ 2] 
2 2  
[ 2] 
1  
[ 2] 
2   
4   
8  
[1 ] 
1 5  
[1 ] 
( 2 2) 
[ 2] 
1  
[ 2] 
1  
[ 2] 
  
  
 
BI   
E OI   
  
  
  
  
  
BI   
E OI   
  
  
  
BI   
E OI   
  
  
  
  
  
BI   
E OI   
BI   
E OI   
  
  
 
O p ht hal m ol o gi
c assess me nts 
X f 
  
  
  
  
  
  
  
  
X e  
  
  
  
  
  
  
  
  
  
  
 
 
X   
 
 
T u m or 
assess me nt 
X f 
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   
 
 
La b orat or y 
tests 
X d  
  
X e  
  
X   
  
X   
X   
  
X e  
  
X   
X   
  
X e  
  
X   
  
X   
X   
  
X e  
  
X e  
  
X   
X  
 
pr ot hr o m bi n 
ti me, acti vate d 
partial 
t hr o m b o plasti n 
ti me 
X d  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
A D A  
  
  
X h 
  
  
  
X   
  
  
X h  
  
  
  
  
  
  
  
  
  
  
  
X hi 
  
  
  
X   
X  
(X ) j 
Tr o p o ni n   
X d  
  
  
X k  
  
  
  
  
  
  
X k  
  
  
  
  
X k  
  
  
  
  
  
  
  
  
  
X   
  
 
1 2 -lea d E C G 
i n tri plicate 
X d 
X
l 
X m  
X n 
  
  
X   
X   
  
X e  
  
  
  
  
X  m   
X o  
  
  
X   
X   
  
X e  
  
X e  
  
X   
 
 
P K  
  
  
X p 
X q 
X r 
X r  
X p  
X p  
( X)s 
X h  
X t 
  
  
( X) s   X p  
X u  
X r  
X r  
X p  
X p  
( X) s   X h v 
X  t v  
 
(X ) 
sy 
  
 
 
E C H O or 
M U G A  
X f  
  
  
  
  
  
  
  
  
X e  
  
  
  
  
X e  
  
  
  
  
  
  
  
  
X e w  
  
X   
 
 
A Es  
X z 
 
C o nc o mita nt 
me dicati o ns  
X  
 
Ne w ca ncer 
treat me nt a n d 
S ur vi val  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X x 
S C R: scree ni n g, 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, 4 0 D F/ U: 4 0 -Da y f oll o w -u p , N C T: ne w ca ncer treat me nt, S U: s ur vi val 
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 4 0  da ys (  +  7 da ys) after t he last st u d y dr u g a d mi nistrati o n or bef ore starti n g ne w a ntica ncer treat me nt, w hic he ver c o mes first.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 5  
c Latest data wit hi n 9 0 da ys bef ore e nr oll me nt . 
d Latest data wit hi n 7 da ys bef ore e nr oll me nt .   
e Latest data wit hi n 3 da ys bef ore a d mi nistrati o n.  
f Latest data wit hi n 2 8 da ys bef ore e nr oll me nt . 
h Wit hi n 8 h o urs BI.  
i E ver y 2 c ycles u ntil t he E O T (e g, C ycle 4, 6, 8, 1 0, 1 2...) . A p orti o n of A D A bl o o d sa m ple will be use d f or f ut ure ce ntral la b a nal ysis f or S A R S -C o V -2 testi n g o nce 
pr ot oc ol versi o n 7 . 0 is a p plie d f or a s u bj ect. S A R S-C o V -2 testi n g will be c o n d ucte d e ver y 4 c ycles fr o m C ycle 4 ( C ycle 4, C ycle 8 etc.).  
j F or s u bj ects wit h p ositi ve A D A  at 4 0 D 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 l ast 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.  
k C ollect bl o o d sa m ples f or tr o p o ni n ( prefera bl y hi g h -se nsiti vit y tr o p o ni n-T) 2 -3 h o urs after E OI.  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 h o u r) a n d 1 2 h o urs ( ±  1 h o u r) 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 h o u r) 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 perf or m E C G testi n g , re peat tr o p o ni n testi n g at 6 h o urs ( ±  1 h o u r) 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 h o u r) 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 o car 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 t est if t he tr o p o ni n le vel is n ot Gra de 3.  
l 1 5 mi n utes bef ore t he pla n ne d start ti me of a d mi nistrati o n o n C ycle 1, Da y 1 ( ± 1 0 mi n ut es), a n d 3 0 mi n utes, 2, 4 a n d 7 h o urs after t he pla n ne d start ti me of 
a d ministrati o n o n C ycle 1, Da y 1 ( ± 1 0 mi n utes) . 
m  1 5 mi n utes BI ( Acce pta ble ra n ge of E C G meas ure me nt start ti me: ± 1 0 mi n utes). 
n 2, 4 a n d 7 h o urs after t he start of a d mi nistrati o n ( Acce pta ble ra n ge of E C G meas ure me nt st art ti me: ± 1 0 mi n utes). 
o E OI  ( Wit hi n 1 5  mi n utes) a n d 2, 4 a n d 7 h o urs after t he start of a d mi nistrati o n ( Acce pta ble ra n ge of E C G meas ure me nt st art ti me: ± 1 0 mi n utes). 
p Wit hi n 1 0 mi n utes after c o m pl eti n g E C G meas ure me nt.  
q Wit hi n 1 0 mi n utes after E OI, a n d 2, 4 a n d 7 h o urs after t he start of a d mi nistrati o n ( Wit hi n 1 0 mi n utes after c o m pleti n g E C G meas ure me nt).  
r 2 4 a n d 7 2 h o urs after t he start of a d mi nistrati o n ( ± 2 h o urs).  
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 bj ect 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.  
t Wit hi n 3 0 mi n utes after E OI.  
u E OI a n d 2, 4 a n d 7 h o urs after t he start of a d mi nistrati o n ( Wit hi n 1 0 mi n utes after c o m pleti n g E C G meas ure me nt).  
v E ver y 2 c ycles u ntil C ycle 8 ( e g, C ycle 4, 6,  8).   E ve n if bl o o d sa m ple is c ollecte d o n Da y 2 2 of C ycle 3, 5 a n d/ or 7, 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, 6 a n d/ or 8 if p ossi ble.  
w  E ver y 2 c ycles u ntil t he E O T (e g, C ycle 5, 7, 9, 1 1, 1 3...).  
x  S u bj ects will be assesse d e ver y  3 m o nt hs ( ± 1 4 da ys), fr o m t he date of 4 0 -Da y F/ U visit, f or s ur vi val a n d s u bse q ue nt a ntica ncer t hera p y u ntil deat h, wit h dra wal of 
c o nse nt, l ost t o F/ U or st u d y cl os ure, w hic he ver occ urs first.  
y  C ycle 5 , Da y 2 2 a n d C ycle 7 , Da y 2 2 o nl y.  


Pr ot oc ol  D S 8 2 0 1 -A -J 1 0 2 
 Versi o n 7 . 0, 0 3  J ul 2 0 2 0  
Pr o prietar y a n d C o nfi de ntial  
Pa ge 1 2 6  
z 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  (infecti o us d isease c o ns ultati o n as cli nicall y i n dicate d) 
•  b l o o d c ult ure a n d C B C. Ot her bl o o d  tests c o ul d be c o nsi dere d as nee de d 
•  co nsi der br o nc h osc o p y a n d br o nc h oal ve olar la va ge if cli nic all y i n dicate d a n d feasi ble  
•  p ul m o nar y f u ncti o n tests a n d p ulse o xi metr y ( S p O 2)  
•  arterial bl o o d gases if cli nicall y i n dicate d  
•  o ne bl o o d sa m ple c ollect i o n f or P K 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.