A Single Arm, Multicenter, Phase 2 Study of BGB-A317 as Monotherapy in Relapsed or Refractory Classical Hodgkin Lymphoma
Phase: PHASE2
Conditions: Classical Hodgkin Lymphoma
Sponsor: BeiGene



Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
 
C LI NI C A L S T U D Y P R O T O C O L  
 
Pr ot oc ol Title:  
A Si n gle Ar m, M ultice nter, P h ase 2 St u d y of B G B -A 3 1 7 
as M o n ot her a p y i n Rel a pse d or Refr act or y Cl assic al 
H o d g ki n L y m p h o m a  
 
Pr ot oc ol N u m ber:  
B G B -A 3 1 7 -2 0 3   
 
D ate of Pr ot oc ol:  
1 5 -J ul y -2 0 1 9  
 
Versi o n:  
6. 0  
 
St u d y P h ase:  
2  
 
S p o ns or:  
Bei Ge ne ( S h a n g h ai) C o., Lt d.  
4t h  Fl o or, B uil di n g D , 
7 8 0 C ail u n  R o a d,  
C hi n a ( S h a n g h ai) Pil ot -free Tr a de Z o ne 
S h a n g h ai, C hi n a 2 0 1 2 0 3  
 
S p o ns or Me dic al M o nit or:  
Li u di Y a n g, M D  
Bei Ge ne ( S h a n g h ai) C o., Lt d   
li u di. y a n g @ bei ge ne.c o m 
 
 
C o nfi de nti alit y St ate me nt  
T his  
 i nf or mati o n i n t his d oc u me nt is pr o vi de d t o y o u as a n I n v esti gat or or c o ns ulta nt 
f or re vie w b y y o u, y o ur staff, a n d t he a p plica ble I nstit uti o nal Re vie w B oar d/I n de p e n de nt Et hics 
C o m mittee.   Y o ur acce pta nce of t his d oc u m e nt c o nstit utes a gree me nt t hat y o u will n ot discl ose 
t he i nf or mati o n c o ntai ne d herei n t o ot hers wit h o ut writte n a ut h orizati o n fr o m t he S p o ns or. 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
SI G N A T U R E S  
 
P R O T O C O L TI T L E:  
A Si n g le Ar m, M ultice nt er, P hase 2 St u d y of B G B -A 3 1 7 as 
M o n ot hera p y i n Rela pse d or Refract or y Classical H o d g ki n 
L y m p h o ma  
 
P R O T O C O L N O:  
B G B -A 3 1 7 -2 0 3  
 
D A T E O F P R O T O C O L:  
1 5 -J ul y-2 0 1 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P P D
C CI
P P D
P P D

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
P R O T O C O L A M E N D M E N T ( V E R SI O N 6. 0)  
T he pri m ar y re as o ns f or pr ot oc ol r e visi o ns i ncl u de a d d 
 
a n d r oll -o ver st u d y .  I n a d diti o n, t hr o u g h o ut are a d mi nistr ati v e u p d ates, e dit ori al c h a n ges, 
a n d/ or st yle a n d f or m atti n g re visi o ns m a de w it h t he p ur p ose of i m pr o vi n g cl arit y a n d 
c o nsiste nc y t hr o u g h o ut t he d oc u me nt a n d wit h ot her Bei Ge ne pr ot oc ols.  
A p plic a ble secti o ns  
Descri pti o n of re visi o n  
Re as o n:  Te xt re vise d as c orrecti o n a n d f or c o nsiste nc y wit h ot her Bei Ge ne pr ot oc ols  
LI S T O F A B B R E VI A TI O N S 
A N D D E FI NI TI O N S O F 
T E R M S  
S y n o psis : Statistical Met h o ds 
Secti o n  1 0. 2  P o p ulati o ns  
Secti o n  1 0. 3  Sa m ple Siz e 
C o nsi derati o n  
C ha n ge “ P o p ulati o n” t o “ A nal ysis Set ” w he n it refers t o a 
statistical a nal ysis, c h a n ges i ncl u de d: 
•  C ha n ge “ P o p ulati o ns” t o “ A nal ysis Sets”  
•  C ha n ge “ Safet y P o p ulati o n” t o “ Safet y A nal ysis Set ” 
•  C ha n ge “ Per -pr ot oc ol P o p ulati o n ( P P)” t o “ Per -
pr ot oc ol ( P P) A nal ysis S et ” 
•  
 
Re as o n:  C orrecte d he a di n g t o kee p c o nsiste nt wit h t h at i n s y n o psis  
Secti o n  1 0. 2. 5. 3 :  
 
 
Pre vi o us pr ot oc ol:  
 
After re visi o n:  
 
Re as o n:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
Re as o n: A d de d r oll -o ver st u d y f or c o nti n u o us tre at me nt a n d m o nit ori n g.  
Secti o n  6. 1 1  E n d of St u d y  
A p pe n di x  5 .  Sc he d ule of 
Assess me nt  
Secti o n  6. 1 1  E n d of St u d y  
A d de d bel o w para gra p h:  
Patie nts still recei vi n g st u d y treat me nt w he n t he r oll -o ver 
st u d y is o pe n will tra nsfer t o t he r oll-o ver st u d y f or 
c o nti n u o us treat me nt a n d m o nit ori n g.  P atie nts alrea d y off 
st u d y treat me nt b ut n ot wit h dre w t he I C F will ha ve effi cac y 
(if d isc o nti n ue d n ot d ue t o disease pr o gressi o n) , s afet y a n d 
s ur vi val f oll o w-u p (as d efi ne d i n t his pare nt st u d y) i n t he 
r oll-o ver st u d y (see A p pe n di x  5 ). 
A p pe n di x 5 .  Sc he d ule of Assess me nt 
A d de d bel o w se nt e nce i n f o ot n ote:  
C CI
C CI
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
2 6.  S u bjects  still recei vi n g st u d y treat me nt w he n t he r oll-
o ver st u d y is o p e n will tra nsfer t o r oll -o v er st u d y f or 
c o nti n u o us treat me nt.  
Re as o n: A d de d se nte nce s t o ke e p c o nsiste nt wit h Secti o n 5. 1  a n d Secti o n 5. 2 . 
S y n o psis: I n cl usi o n Criteria  
S y n o psis: E x cl usi o n Criteria  
S y n o psis: I ncl usi o n Criteri a  
S u bjects ma y be e nr olle d o n st u d y o nl y if t he y meet all t he 
f oll o wi n g criteria:  
S y n o psis: E xcl usi o n Criteri a  
S u bjects will n ot be e nr olle d o n st u d y if t he y meet a n y of t he 
f oll o wi n g criteria: 
Re as o n: F or c o m plete ness, a d de d a b bre vi ati o ns t o T a ble 5 , A p pe n di x  6 a n d A p pe n di x 7 . 
Ta ble  5  I m m u ne-relate d 
A d verse E v e nts  
 
A p pe n di x  6  T he L u ga n o 
Classificati o n  
 
A p pe n di x  7  
 
 
 
 
 
A d de d t he f ull list of a b bre viati o ns t o ta ble s. 
T a ble 5 I m m u ne-rel ate d A d verse E ve nts  
A b bre viati o ns: A L T, ala ni ne a mi n otra nsferase; A S T, 
as partate a mi n otra nsferas e.  
A p pe n di x 6 T he L u g a n o Cl assific ati o n  
A b bre viati o ns: P E T,  P ositr o n E missi o n T o m o gra p h y;  I H C, 
I m m u n o hist oc he mistr y; P S, p oi nt scale; P P D,  p urifie d 
pr otei n deri vati ve; L D, l o n gest dia met er; S D, s h ort est 
dia meter; C T,  C o m p ute d T o m o gra p h y;  F D G, 
fl u or o de o x y gl uc ose. 
 
 
 
 
 
 
Re as o n: C orrecte d descri pti o n f or t he assess me nt of hei g ht i n Secti o n 7. 4. 2. 
Secti o n 7. 4. 2  P h ysical 
E x a mi nati o n, Vital Si g ns, 
Hei g ht, a n d Wei g ht  
Delete “ h ei g ht”  fr o m t he bel o w se nte nce beca use hei g ht o nl y 
meas ure d o n Da y 1 C ycl e 1.  
Pre vi o us pr ot oc ol:  
A c o m plete or tar gete d p h ysical e x a mi nati o n, vital si g ns 
(sitti n g bl o o d press ure, p ulse rate, b o d y te m perat ure, a n d 
res pirat or y rate), wei g ht  a n d hei g ht will be perf or me d at eac h 
st u d y visit. 
After re visi o n:  
A c o m plete or tar gete d p h ysical e x a mi nati o n, vital si g ns 
(sitti n g bl o o d press ure, p ulse rate, b o d y te m perat ure, a n d 
res pirat or y rate) a n d wei g ht will be perf or me d at eac h st u d y 
visit.  
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Re as o n: R e m o v e “f oll o wi n g refere nce d oc u me nts ” bec a use t here is o nl y o ne refere nce.  
Secti o n 9. 1. 1 3  E x pe dite d 
Re p orti n g t o Healt h 
A ut h orities, I n v esti gat ors, 
I nstit uti o nal Re vie w B oar ds 
a n d Et hics C o m mittees  
Pre vi o us pr ot oc ol:  
T o deter mi ne t he re p orti n g re q uire me nts f or i n di vi d ual 
S A Es, t he s p o ns or will assess t he e x pecte d ness of t he S A Es 
usi n g t he  f oll o wi n g refere nce d o c u me nts: 
•  Tisleliz u ma b I n v esti gat or’s Br oc h ure .  
After re visi o n:  
T o deter mi ne t he re p orti n g re q uire me nts f or i n di vi d ual 
S A Es, t he s p o ns or will assess t he e x pecte d ness of t he S A Es 
usi n g t he  T isleliz u ma b I n vesti gat or’s Br oc h ure. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
Bei Ge ne ( S ha n g hai)  C o. , Lt d . 
N a me of Fi nis he d P r o d uct:  
Tisleliz u ma b ( B G B -A 3 1 7)  
N a me of Acti ve I n gre die nt:  
Tisleliz u ma b , A N o vel A nti -P D -1 M o n ocl o nal A nti b o d y  
Title of St u d y:  
A Si n g le Ar m, M ultice nter, P hase 2 St u d y of B G B -A 3 1 7 as M o n ot hera p y i n 
Rela pse d or Refract or y Classical H o d g ki n L y m p h o ma  
P r ot oc ol N o:  
B G B -A 3 1 7 -2 0 3  
St u d y C e nters: 
A p pr o xi matel y  1 5  sites i n C hi na  
St u d y d ur ati o n:   Scree ni n g wi n d o w ( u p t o 2 8 da ys); st u d y treat me nt c o nti n ues 
u ntil disease pr o gressi o n, u nacce pta ble t o xicit y, or st u d y wit h dra wal f or ot her 
reas o n; e n d of st u d y safet y f oll o w-u p ( 3 0 da ys); s ur vi val f oll o w -u p u ntil st u d y 
ter mi nati o n 
P h ase:  2  
O bjecti ves:  
P ri m ar y:  
T o e val uate t he efficac y of tisleliz u ma b (als o k n o w n as B G B -A 3 1 7) , assesse d b y I n de pe n de nt Re vie w 
C o m mittee (I R C) , i n s u bjects wit h ce ntrall y c o nfir me d rela pse d or refract or y classical H o d g ki n 
l y m p h o ma (c H L), as meas ure d b y O verall Resp o nse Rate ( O R R) per t he L u ga n o Classificati o n 
(C hes o n et al, 2 0 1 4 ) (A p pe n di x  6 ). 
Sec o n d ar y:  
T o e val uate tisleliz u ma b wit h res pect t o:  
• 
Pr o gressi o n -free S ur vi val ( P F S) assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 
2 0 1 4 ) (A p pe n di x  6 ) 
• 
D urati o n of Res p o nse ( D O R) assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ) 
(A p pe n di x  6 ) 
• 
Rate of c o m plete res p o nse ( C R) assesse d b y I R C per t he L u ga n o Classificati o n  (C hes o n et al, 
2 0 1 4 ) (A p pe n di x  6 ) 
• 
Ti me t o Res p o nse ( T T R) assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ) 
(A p pe n di x  6 ) 
• 
Safet y a n d t olera bilit y  
 
 
 
 
 
 
 
  
 
 
 
 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Met h o d ol o g y:  
T his is a n o pe n -la bel, si n gle-ar m, m ulti -ce nter a n d m ulti -nati o nal P hase  2  st u d y. 
Pl a n ne d n u m ber of s u bjects:  
A p pr o xi matel y 6 8 wit h c o nfir me d c H L 
St u d y P o p ul ati o n  
I ncl usi o n Criteri a: 
S u bj ects ma y be e nr olle d o n st u d y o nl y if t he y meet all t he 
f oll o wi n g criteria:  
1.  ≥ 1 8 years of a ge at ti me of i nf or me d c o nse nt.  
2.  Hist ol o gicall y c o nfir me d rela pse d or refract or y c H L 
( bi o ps y fr o m dia g n osis or at a n y rela pse is acce pta ble).  
3.  S u bj ect m ust ha ve rela pse d ( disease pr o gressi o n after m ost 
rece nt t hera p y) or refract or y (fail ure t o ac hie ve 
C R/c o m plete meta b olic res p o nse [ C M R] or partial 
res p o nse [ P R] t o m ost rece nt t hera p y) c H L a n d meets 
eit her o ne of t he f oll o wi n g criteria:  
a. Has faile d t o ac hie ve a res p o nse or pr o gresse d after 
a ut ol o g o us he mat o p oietic ste m cell  tra ns pla nt 
(a ut o-S C T).  
b.  Has recei ve d at least t w o pri or s yste mic 
c he m ot hera p y re gi me ns f or c H L a n d is n ot a n a ut o -
S C T ca n di date d ue t o: c he m o -resista nt disease 
( u na ble t o ac hie ve C R or partial res p o nse [ P R] t o 
sal va ge c he m ot hera p y), a d va nce d a ge ( ≥ 6 5 years 
of a ge), fail ure t o c ollect ste m cells or u na ble t o 
perf or m ste m cell c ollecti o n as assesse d b y t he 
I n vesti gat or, or a n y si g nifica nt c o-e xisti n g me dical 
c o n diti o ns. 
4.  S u bj ect m ust ha ve meas ura ble disease defi ne d as ≥ 1 n o dal 
lesi o n t hat is > 1. 5 c m i n t he l o n gest dia meter, or ≥ 1 e xtra-
n o dal lesi o n (e. g. he patic n o d ules) t hat is > 1 c m i n t he 
l o n gest dia meter. 
5.  A vaila bilit y of arc hi val or fres h t u m or tiss ue sa m ple fr o m 
a n e val ua ble c ore or e xcisi o nal bi o ps y ( 1 0 -1 5 u nstai ne d 
f or mali n-fi xe d paraffi n e m be d de d [ F F P E] sli des).  
Ot her wise, s u bjects ma y be per mitte d t o e nr oll o n a case -
b y -case basis after disc ussi o n wit h t he S p o ns or’s me dical 
m o nit ors, pr o vi de d c H L dia g n osis ca n be c o nfir me d b y a 
ce ntral la b orat or y.  
6.  Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G)  
perf or ma nce stat us of 0 or 1.  
7.  Life e x pecta nc y ≥ 1 2 wee ks.  
8.  S u bj ect m ust ha ve a de q uate or ga n f u ncti o ns as i n dicate d b y 
t he f oll o wi n g la b orat or y val ues: 
a. A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5 x  1 0 9/ L, 
i n de pe n de nt of gr o wt h fact or s u p p ort wit hi n 7 da ys 
of first d ose. 
b.  Platelet ≥ 7 5 x 1 0 9/ L, i n de pe n de nt of gr o wt h fact or 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
s u p p ort or tra nsf usi o n wit hi n 7 da ys of first d ose. 
c. He m o gl o bi n ( H g b) ≥ 8 g/ d L or ≥ 5 m m ol/ L.  
d.  Ser u m creati ni ne ≤ 1. 5  x u p per li mit of n or mal 
( U L N).  
e. As partate a mi n otra nsferase ( A S T)/ ser u m gl uta mic -
o xal oacetic tra nsa mi nase ( S G O T) a n d ala ni ne 
a mi n otra nsferase ( A L T)/ ser u m gl uta mic -p yr u vic 
tra nsa mi nase ( S G P T) ≤ 2. 5 x u p per li mit of n or mal 
( U L N), or ≤ 5 x  U L N if li ver metastases are 
prese nt.  
f. Ser u m t otal b ilir u bi n ≤ 1. 5 x U L N (t otal bilir u bi n 
le vel < 4 x U L N f or s u bjects wit h Gil bert’s 
s y n dr o me). 
9.  I nter nati o nal n or malize d rati o (I N R) ≤ 1. 5 x U L N a n d 
acti vate d partial t hr o m b o plasti n ti me (a P T T) ≤ 1. 5 x U L N  
u nless patie nt is recei vi n g a ntic oa g ula nt t hera p y a n d 
c oa g ulati o n para meters ( pr ot hr o m bi n ti me  [ P T/I N R] a n d 
a P T T) are wit hi n i nte n de d t hera pe utic ra n ge of i nte n de d 
use of t he a ntic oa g ula nt at ti me of Scree ni n g .  Patie nts wit h 
fact or i n hi bit ors pr ol o n gi n g P T or I N R ma y be i ncl u de d 
after disc ussi o n wit h t he me dical m o nit or.   
1 0.  S u bj ect m ust ha ve n o e vi de nce of d ys p nea at rest a n d a 
p ulse o xi metr y of > 9 2 % w hile breat hi n g r o o m air.  
1 1.  S u bj ect m ust ha ve f orce d e x pirat or y v ol u me i n o ne sec o n d 
( F E V 1)/f orce d vital ca pacit y ( F V C) > 6 0 % b y p ul m o nar y 
f u ncti o n test ( P F T); car b o n m o n o xi de diff usi o n ca pacit y 
( D L C O), F E V 1 a n d F V C all > 5 0 % pre dicte d val ue; all 
P F Ts m ust be o btai ne d wit hi n 4 wee ks pri or t o t he first 
d ose of tisleliz u ma b.  
1 2.  Fe male s u bject is eli gi ble t o e nter a n d partici pate i n t he 
st u d y if s he is of:  
a. N o n -c hil d beari n g p ote ntial (i.e. p h ysi ol o gicall y 
i nca pa ble of bec o mi n g pre g na nt) i ncl u di n g a n y 
fe male w h o: 
i. Has ha d a h ysterect o m y.  
ii. Has ha d a bilateral o o p h orect o m y 
( o variect o m y). 
iii. Has ha d a bilateral t u bal li gati o n.  
i v. Is p ost-me n o pa usal (t otal cessati o n of 
me nses f or ≥ 1 year).  
b.  Fe males of c h il d beari n g p ote ntial m ust be willi n g 
t o use a hi g hl y effecti ve met h o d of birt h c o ntr ol f or 
t he d urati o n of t he st u d y, a n d f or at least 1 2 0 da ys 
after t he last d ose of tisleliz u ma b, a n d ha ve a 
ne gati ve uri ne or ser u m pre g na nc y test wit hi n 7 
da ys of t he firs t d ose of st u d y dr u g. A de q uate 
c o ntrace pti o n, w he n use d c o nsiste ntl y a n d i n 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
acc or da nce wit h b ot h t he pr o d uct la bel a n d 
i nstr ucti o ns of t he p h ysicia n, are defi ne d as: 
i. Vasect o mize d part ner w h o is sterile pri or 
t o t he fe male s u bject’s st u d y e ntr y a n d is 
t he sole se x ual part ner f or t hat fe male.  
ii. A n y i ntra uteri ne de vice wit h a d oc u me nte d 
fail ure rate of < 1 % per year. 
iii. D o u ble barrier c o ntrace pti o n defi ne d as 
c o n d o m wit h s per mici dal jell y, f oa m, 
s u p p osit or y, or fil m; O R dia p hra g m wit h 
s per mici de; O R male c o n d o m a n d 
dia p hra g m.  
1 3.  N o n -sterile males m ust be willi n g t o use a hi g hl y effecti ve 
met h o d of birt h c o ntr ol f or t he d urati o n of t he st u d y a n d f or 
at least 1 2 0 da ys after t he last d ose of tisleliz u ma b.  
1 4.  Pri or c he m ot hera p y, ra di ot hera p y, i m m u n ot hera p y or 
i n vesti gati o nal t hera p y (i ncl u di n g C hi nese her bal me dici ne 
a n d C hi nese pate nt me dici ne) use d t o c o ntr ol ca ncer 
i ncl u di n g l oc ore gi o nal treat me nt m ust ha ve bee n c o m plete d 
≥ 4 wee ks bef ore t he first d ose of tisleliz u ma b, a n d all 
treat me nt-relate d a d verse e ve nts are sta ble a n d ha ve eit her 
ret ur ne d t o baseli ne or Gra de 0/ 1 (e xce pt f or al o pecia a n d 
he m o gl o bi n ). F or he m o gl o bi n, please f oll o w i ncl usi o n 
criteria # 8c [ he m o gl o bi n]).  
1 5.  S u bj ect has v ol u ntaril y a gree d t o partici pate b y gi vi n g 
writte n i nf or me d c o nse nt. 
E xcl usi o n Criteri a:  
S u bj ects will n ot be e nr olle d o n st u d y if t he y meet a n y of t he 
f oll o wi n g criteria: 
1.  N o d ular l y m p h oc yte -pre d o mi na nt H o d g ki n l y m p h o ma or 
gra y z o ne l y m p h o ma.  
2.  Pri or all o ge neic he mat o p oietic ste m cell tra ns pla nt.  
3.  Hist or y of se vere h y perse nsiti vit y reacti o n t o m o n ocl o nal 
a nti b o dies. 
4.  Ne w Y or k Heart Ass ociati o n ( N Y H A) C lass III or I V heart 
fail ure, u nsta ble a n gi na, se vere u nc o ntr olle d ve ntric ular 
arr h yt h mia, electr ocar di o gra p hic e vi de nce of ac ute 
isc he mia, or m y ocar dial i nfarcti o n wit hin 6 m o nt hs of first 
da y of Scree ni n g.  
5.  Pri or mali g na nc y wit hi n t he past 3 years e xce pt f or 
c urati vel y treate d basal or s q ua m o us cell s ki n ca ncer, 
s u perficial bla d der ca ncer, or carci n o ma i n sit u of t he 
cer vi x or breast.  
6.  Pri or t hera p y tar geti n g P D -1 or P D -L 1 . 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
7.  S u bj ect wit h acti ve a ut oi m m u ne disease or hist or y of 
a ut oi m m u ne disease wit h hi g h ris k of rec urre nce i ncl u di n g 
b ut n ot li mite d t o hist or y of i m m u ne -relate d ne ur ol o gic 
disease, m ulti ple scler osis, a ut oi m m u ne ( de m yeli nati n g) 
ne ur o pat h y, G uillai n -Barrè s y n d r o me, m yast he nia gra vis, 
s yste mic l u p us er yt he mat os us ( S L E), c o n necti ve tiss ue 
disease, scler o der ma, i nfla m mat or y b o wel disease 
i ncl u di n g Cr o h n’s disease a n d ulcerati ve c olitis, 
a ut oi m m u ne he patitis, t o xic e pi der mal necr ol ysis ( T E N), or 
Ste ve ns -J o h ns o n s y ndr o me.  
N ote: S u bject is per mitte d t o e nr oll if he/s he has vitili g o, 
ecze ma, t y pe I dia betes mellit us, e n d ocri ne deficie ncies 
i ncl u di n g t h yr oi ditis ma na ge d wit h re place me nt h or m o ne 
a n d/ or p h ysi ol o gic c ortic oster oi d.  S u bject wit h r he u mat oi d 
art hritis a n d/ or ot her art hr o pat hies, Sj ö gre n’s s y n dr o me or 
ps oriasis c o ntr olle d wit h t o pical me dicati o n, a n d s u bject 
wit h p ositi ve ser ol o g y s uc h as p ositi ve a nti n uclear a nti b o d y 
( A N A) or a nti-t h yr oi d a nti b o d y s h o ul d be e val uate d f or 
prese nce of tar get or g a n i n v ol ve me nt a n d p ote ntial nee d f or 
s yste mic treat me nt b ut s h o ul d ot her wise be eli gi ble. 
8.  C o n diti o ns re q uiri n g s yste mic treat me nt wit h eit her 
c ortic oster oi ds ( > 1 0 m g dail y Pre d nis o ne e q ui vale nt) or 
ot her i m m u n os u p pressi ve me dicati o ns wit hi n 1 4 da ys of 
first d ose of tisleliz u ma b. 
N ote: A dre nal re place me nt d oses of ≤ 1 0 m g dail y 
Pre d nis o ne are per mitte d i n t he a bse nce of acti ve 
a ut oi m m u ne disease.  T o pical, oc ular, i ntra -artic ular, i ntra -
nasal a n d i n halati o nal c ortic oster oi d ( wit h mi ni mal 
s yste mic a bs or pti on), a brief c o urse of c ortic oster oi d f or 
pr o p h yla xis (e. g. c o ntrast d ye aller g y) or f or treat me nt of 
n o n -a ut oi m m u ne c o n diti o ns (e. g. dela ye d -t y pe 
h y perse nsiti vit y reacti o n ca use d b y c o ntact aller ge n) are 
all o we d. 
9.  Has hist or y of i nterstitial l u n g disease or  n o n -i nfecti o us 
p ne u m o nitis  or has e vi de nce of i nterstitial l u n g disease or 
n o n -i nfecti o us p ne u m o nitis c urre ntl y.   
1 0.  Q T c F i nter val > 4 8 0 msec, u nless sec o n dar y t o b u n dle 
bra nc h bl oc k.  
1 1.  Seri o us ac ute or c hr o nic i nfecti o n re q uiri n g s yste mic 
t hera p y. 
1 2.  K n o w n ce nt ral ner v o us s yste m ( C N S) l y m p h o ma. 
1 3.  U n derl yi n g me dical c o n diti o ns t hat, i n t he I n vesti gat or’s 
o pi ni o n, will re n der t he a d mi nistrati o n of st u d y dr u g 
hazar d o us or o bsc ure t he i nter pretati o n of t o xicit y or 
a d verse e ve nts. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 4.  K n o w n h u ma n i m m u n o deficie nc y vir us ( HI V), or acti ve 
he patitis B ( H B V) or he patitis C ( H C V) i nfecti o n ( detecte d 
p ositi ve b y p ol y merase c hai n reacti o n [ P C R])  
 
I ncl usi o n 
E xcl usi o n  
HI V  
A nti b o d y ( -) 
A nti b o d y ( +)  
H B V  
H Bs A g ( -) a n d H B c A b ( -) 
H Bs A g ( +)  
H Bs A g ( -)  
A N D  
H B c A b ( +)  
H B V D N A <  1 0 0 0 
I U/ ml. A fter 
e nr oll me nt, m o nt hl y 
m o nit ori n g f or H B V 
D N A or a nti -viral 
t hera p y s h o ul d be 
gi ve n t o pre ve nt 
H B V reacti vati o n  
H Bs A g ( -
)  
A N D  
H B c A b 
( +) 
H B V D N A 
≥ 1 0 0 0 
I U/ ml 
H C V  
H C V A b ( -) 
H C V A b 
( +) 
H C V R N A 
≥ 1 
(l o g1 0I U/ ml) 
H C V A b 
( +) 
H C V R N A < 1 
(l o g1 0I U/ ml) 
H Bs A g: He patitis B s urface a nti ge n; H Bc A b: He patitis B c ore a nti b o d y; 
H B V: He p atitis B vir us; H C V: He patitis C vir us; H C V A b: He patitis C 
a nti b o d y; HI V: h u ma n i m m u n o deficie nc y vir us; D N A: de o x yri b o n ucleic 
aci d; R N A: ri b o n ucleic aci d  
1 5.  A ut ol o g o us he mat o p oietic ste m cell tra ns pla nt wit hi n 1 0 0 
da ys of first d ose of tisleliz u ma b.  
1 6.  Use of a n y li ve vacci ne a gai nst i nfecti o us diseases (e. g. 
i nfl ue nza, varicella, etc.) wit hi n 4 wee ks ( 2 8 da ys) of t he 
first d ose of tisleliz u ma b, a n d a n y i nte n de d use wit hi n 6 0 
da ys after t he last d ose of tisleliz u ma b.  
1 7.  Maj or s ur ger y wit hi n 4 wee ks of t he first d ose of 
tisleliz u ma b. 
1 8.  Pre g na nt or lactati n g w o me n.  
T est pr o d uct, d ose a n d m o de of 
a d mi nistrati o n: 
Tisleliz u ma b 2 0 0 m g i ntra ve n o usl y (I V) e ver y  3  wee ks ( Q 3 W) 
Criteri a f or E v al u ati o n:  
Res p o nse will be assesse d b y c o m p ute d t o m o gra p h y ( C T) sca n per t he L u ga n o Classificati o n  
(C hes o n et al, 2 0 1 4 ) (A p pe n di x  6 ).  C o m p ute d t o m o gr a p h y sca n wit h c o ntrast will occ ur at Scree ni n g, 
W ee k 1 2, W ee k 1 8, t he n e ver y 1 2  wee ks i n t he first year, a n d e ver y 1 5 wee ks t hereafter , u ntil pr o gressi ve 
disease ( P D), ne w a nti -ca ncer t hera p y, wit h dra wal of c o nse nt, deat h, l ost t o f oll o w -u p, or e n d of st u d y 
( E O S), w hic he ver occ urs first.  T otal b o d y ma g netic res o na nce i ma gi n g ( M RI) is all o we d if C T wit h 
c o ntrast is c o ntrai n dicate d.  P ositr o n e missi o n t o m o gra p h y ( P E T)/ C T ma y be use d i n lie u of a C T wit h 
c o ntrast o nl y if t he C T of t he P E T/ C T has bee n perf or me d wit h dia g n ostic q ualit y a n d c o ntrast is 
a d mi nistere d.   
T u m or assess me nt b y P E T/ C T will als o be perf or me d at Scree ni n g, Wee k 1 2, Wee k 2 4, Wee k 4 2, 
Wee k 5 7, a n d e ver y 3 0 wee ks t hereafter.  P E T/ C T s h o ul d als o be perf or me d at P D s us pecte d cli nicall y 
or b y C T, a n d C R s us pecte d cli nicall y or b y C T.   
D uri n g treat me nt wit h i m m u ne c hec k p oi nt i n hi bit or s uc h as wit h  tisleliz u ma b, pse u d o-pr o gressi o n ma y 
occ ur d ue t o i m m u ne cell i nfiltrati o n a n d ot her mec ha nis ms as ma nifeste d b y a p pare nt i ncrease of 
e xisti n g t u m or masses or a p peara nce of ne w t u m or lesi o ns. S u bjects are all o we d t o c o nti n ue st u d y 
treat me nt if t here is s us pici o n of pse u d o-pr o gressi o n, pr o vi de d t he y are as y m pt o matic a n d ha ve 
ra di o gra p hic pr o gressi o n o nl y, u ntil a sec o n d c o nsec uti ve C T sca n de m o nstrates P D at w hic h ti me 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
st u d y treat me nt will be disc o nti n ue d per ma ne ntl y.  Patie nts s h o ul d c o nti n ue o n treat me nt t o 
pr o gressi o n re gar dless of res p o nse stat us (e. g. i n C R) .  
S u bj ects will be e val uate d f or a d verse e ve nts ( A Es) (all gra des per 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 nts, Versi o n 4. 0 3 [N CI -C T C A E v. 4. 0 3]), seri o us A Es ( S A Es), 
a n d a n y A Es re q uiri n g st u d y dr u g i nterr u pti o n or disc o nti n uati o n, starti n g fr o m i nitial d ose of st u d y 
dr u g u ntil 3 0  da ys after last d ose of st u d y dr u g.  S u bjects w h o, at t he ti me of P D, ha ve a n o n g oi n g A E 
t hat lea ds t o treat me nt disc o nti n uati o n, will be f oll o we d u ntil eit her t he e ve nt res ol ves, t he i n vesti gat or 
assesses t he e ve nt as sta ble, or t he s u bj ect is l ost t o f oll o w -u p.  If a s u bject disc o nti n ues st u d y treat me nt 
d ue t o reas o n ot her t ha n P D, t he n disease stat us assess me nt will be c a pt ure d u ntil start of ne w a nti -
ca ncer t hera p y, P D, deat h, l ost t o f oll o w -u p or s u bject wit h dra ws c o nse nt t o efficac y f oll o w -u p.  
E n d p oi nts:  
P ri m ar y E n d p oi nt:  
•  
O R R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ves a best res p o nse of C R or P R, assesse d 
b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ).   
Sec o n d ar y E n d p oi nts:  
•  
P F S is defi ne d as t he ti me fr o m t he first d ose of tisleliz u ma b t o t he date of P D or deat h, w hic he ver 
occ urs first, assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
•  
D O R is defi ne d as t he ti me fr o m t he date t hat res p o nse criteria are first met t o t he date of P D or 
deat h, w hic he ver occ urs first, assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
•  
Rate of C R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ves a best res p o nse of C R, assesse d 
b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
•  
T T R is defi ne d as t he ti me fr o m t he date of t he first d ose of tisleliz u ma b t o t he ti me t he res p o nse 
criteria are first met, assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
•  
T o e val uate t he safet y a n d t olera bilit y of tisleliz u ma b, as defi ne d b y:  
o  T he i nci de nce a n d se verit y of a d verse e ve nts acc or di n g t o N CI -C T C A E v 4. 0 3  
o  C ha n ges i n vital si g ns, p h ysical fi n di n gs, a n d cli nical la b orat or y res ults  
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
St atistic al M et h o ds: 
A n al ysis sets  
T he Safet y A nal ysis Set  i ncl u des all s u bjects w h o recei ve d a n y d ose of tisleliz u ma b.  T his will be t he 
p o p ulati o n f or t he safet y a nal yses.   
T he m o difie d Safet y A nal ysis Set  i ncl u des all s u bjects i n t he Safet y A nal ysis Set  w h o ha d c o nfir me d c H L.  
T his will be t he p o p ulati o n f or t he efficac y a nal yses. 
T he Per -pr ot oc ol ( P P) A nal ysis Set  i ncl u des s u bj ects w h o recei ve d a n y d ose of tisleliz u ma b a n d ha d n o 
maj or pr ot oc ol de viati o ns.  Criteria f or e xcl usi o n fr o m t he P P A nal ysis S et will be deter mi ne d a n d 
d oc u me nte d bef ore t he data base l oc k f or t he pri mar y a nal ysis.  T his will be t he sec o n dar y a nal ysis 
p o p ulati o n f or efficac y a nal ysis.  
 
. 
P ri m ar y Effic ac y A n al ysis  
I n rela pse d or refract or y H o d g ki n l y m p h o ma ( H L), O R R wit h si n gle a ge nt treat me nt as hist orical 
c o ntr ol is ass u me d t o be a p pr o xi matel y 3 5 % base d o n hist orical trials.  T he O R R of tisleliz u ma b i n t his 
st u d y is ass u me d as 5 5 %, w hic h is deeme d a cli nicall y mea ni n gf ul i m pr o ve me nt.  He nce, t he n ull a n d 
alter nati ve h y p ot heses are set as f oll o ws:  
H 0:  O R R = 3 5 % 
H a:  O R R > 3 5 % 
A bi n o mial e xact test will be perf or me d f or h y p ot hesis testi n g i n t he m o difie d Safet y A nal ysis Set .  If 
t he o btai ne d o ne-si de d p-val ue is ≤ 0. 0 2 5, it will be c o ncl u de d t hat t he si n gle a ge nt tisleliz u ma b 
statisticall y si g nifica ntl y i ncreases O R R c o m pare d wit h hist orical c o ntr ols.  T heref ore, t he s u peri orit y 
of si n gle a ge nt tisleliz u ma b will be de m o nstrate d.  
A t w o -si de d Cl o p per-Pears o n 9 5 % c o nfi de nce i nter val ( CI) of O R R will be c o nstr ucte d t o assess t he 
precisi o n of t he rate esti mate.  
Best o verall res p o nse ( B O R) is defi ne d as t he best res p o nse rec or de d fr o m t he first d ose of tisleliz u ma b 
u ntil data c ut or start of ne w a nti -ne o plastic treat me nt.  S u bj ects wit h n o p ost -baseli ne res p o nse 
assess me nt ( d ue t o a n y reas o n) will be c o nsi dere d n o n -res p o n ders f or B O R.  T he pr o p orti o n a n d its 
c orres p o n di n g Cl o p per -Pears o n 9 5 % CI f or eac h of t he res p o nse cate g ories will be prese nte d.  
T he pri mar y efficac y a nal ysis will be c o n d ucte d a p pr o xi matel y 8 m o nt hs after t he first d ose of t he last 
s u bj ect, a n d will be base d o n t he m o difie d Safet y A nal ysis Set . 
Sec o n d ar y Effic ac y A n al ysis  
T he distri b uti o n of pr o gressi o n -free s ur vi val will be esti mate d usi n g t he Ka pla n-Meier met h o d i n t he 
m o difie d Safet y A nal ysis Set .  Pr o gressi o n-free s ur vi val rates at selecte d ti me p oi nts will be esti mate d 
b y t he Ka pla n -Meier met h o d wit h t heir 9 5 % CIs usi n g Gree n w o o d’s f or m ula.  Pr o gressi o n -free 
s ur vi val ce ns ori n g r ule will f oll o w t he U nite d States ( U S) F o o d a n d Dr u g A d mi nistrati o n ( F D A) 
G ui da nce f or I n d ustr y Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d Bi ol o gics ( 2 0 0 7).  
D O R will be a nal yze d si milarl y as P F S.  T T R will be s u m marize d usi n g sa m ple statistics, s uc h as 
sa m ple mea n, me dia n, a n d sta n dar d de viati o n.  O nl y s u bj ects w h o ha ve ac hie ve d a n o bjecti ve res p o nse 
will be i ncl u de d i n t he a nal ysis of D O R a n d T T R.  
C o m plete Res p o nse rate will be  s u m marize d i n t he m o difie d Safet y A nal ysis Set .  Its Cl o p per-Pears o n 
9 5 % CI will be calc ulate d.  
I n de pe n de nt Re vie w C o m mittee assess me nt per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ) will be 
use d i n t he pri mar y a n d sec o n dar y efficac y a nal yses.  
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
T A B L E O F C O N T E N T S  
SI G N A T U R E S  .................................................................................................................................2  
P R O T O C O L A M E N D M E N T ( V E R SI O N 6. 0)  ..............................................................................3  
S Y N O P SI S  ......................................................................................................................................7  
T A B L E O F C O N T E N T S  ...............................................................................................................1 6  
LI S T O F T A B L E S  .........................................................................................................................2 2  
LI S T O F FI G U R E S  .......................................................................................................................2 2  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  ................................................2 3  
1.  
I N T R O D U C TI O N ......................................................................................................2 8  
1. 1.  
H o d g ki n L y m p h o ma  ...................................................................................................2 8  
1. 2.  
I m m u ne C hec k p oi nt I n hi bit ors  ...................................................................................2 9  
1. 2. 1.  
Pe m br oliz u ma b  ...........................................................................................................2 9  
1. 2. 2.  
Ni v ol u ma b  ..................................................................................................................3 0  
1. 2. 3.  
I m m u ne-relat e d A d verse E ve nts  .................................................................................3 0  
1. 3.  
Tisleliz u ma b  ...............................................................................................................3 0  
1. 3. 1.  
N o n -Cli nical Data  of Tisleliz u ma b  .............................................................................3 1  
1. 3. 2.  
Cli nical Data of Tisleliz u ma b  .....................................................................................3 2  
1. 3. 2. 1.  
Safet y  ..........................................................................................................................3 3  
1. 3. 2. 2.  
P har mac o ki netics  ........................................................................................................3 4  
1. 3. 2. 3.  
A nti -t u m or Acti vit y ...................................................................................................3 5  
1. 3. 3.  
St u d y R ati o nale  ...........................................................................................................3 5  
1. 3. 4.  
Rati o nale f or Tisleliz u ma b D osa ge  ............................................................................3 6  
2.  
O BJ E C TI V E S  .............................................................................................................3 8  
2. 1.  
Pri mar y O bj ecti ve  .......................................................................................................3 8  
2. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................3 8  
2. 3.  
3 8  
3.  
S T U D Y E N D P OI N T S  ................................................................................................3 9  
3. 1.  
Pri mar y E n d p oi nt  ........................................................................................................3 9  
3. 2.  
Sec o n da r y E n d p oi nts ..................................................................................................3 9  
3. 3.  
3 9  
4.  
S T U D Y D E SI G N  .......................................................................................................4 0  
5.  
S T U D Y P O P U L A TI O N  .............................................................................................4 2  
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
5. 1.  
I n cl usi o n Criteria ........................................................................................................4 2  
5. 2.  
E x cl usi o n Criteria  .......................................................................................................4 4  
6.  
S T U D Y T R E A T M E N T S ............................................................................................4 6  
6. 1.  
St u d y Treat me nt  ..........................................................................................................4 6  
6. 2.  
St u d y Treat me nt Pre parati o n a n d Dis pe nsati o n  .........................................................4 6  
6. 2. 1.  
Pac ka gi n g a n d La b eli n g  ..............................................................................................4 6  
6. 2. 2.  
Ha n dli n g a n d St ora ge  .................................................................................................4 6  
6. 2. 3.  
C o m plia nce a n d Acc o u nta bilit y  .................................................................................4 6  
6. 2. 4.  
Dis p osal a n d Destr ucti o n  ............................................................................................4 7  
6. 3.  
S u bject N u m beri n g a n d Treat me nt Assi g n me nt  .........................................................4 7  
6. 3. 1.  
S u bject N u m beri n g  .....................................................................................................4 7  
6. 3. 2.  
Treat me nt Assi g n me nt  ................................................................................................4 7  
6. 3. 3.  
Treat me nt Bli n di n g  .....................................................................................................4 7  
6. 4.  
D osa ge a n d A d mi nistrati o n  ........................................................................................4 7  
6. 5.  
D ose I nterr u pti o n a n d M o dificati o n  ...........................................................................4 7  
6. 5. 1.  
D ose M o dificati o n  ......................................................................................................4 7  
6. 5. 2.  
D ose I nterr u pti o n  ........................................................................................................4 8  
6. 6.  
D ose Dela y  ..................................................................................................................4 8  
6. 7.  
C o nc o mita nt Me dicati o ns a n d N o n -Dr u g T h era pies  ..................................................4 8  
6. 7. 1.  
Pr o hi bite d Me dicati o ns  ...............................................................................................4 8  
6. 7. 2.  
Per mitte d Me dicati o ns  ................................................................................................4 9  
6. 8.  
Diet/ Acti vit y/ Ot her C o nsi derati o ns  ............................................................................4 9  
6. 8. 1.  
Diet  .............................................................................................................................4 9  
6. 8. 2.  
C o ntrace pti o n  ..............................................................................................................4 9  
6. 8. 3.  
Pre g n a nc y  ...................................................................................................................5 0  
6. 8. 4.  
N ursi n g W o me n  ..........................................................................................................5 0  
6. 9.  
E n d of Treat me nt  ........................................................................................................5 1  
6. 1 0.  
F oll o w -u p P hase  .........................................................................................................5 1  
6. 1 0. 1.  
Safet y F oll o w -u p  ........................................................................................................5 1  
6. 1 0. 2.  
Efficac y F oll o w U p  .....................................................................................................5 1  
6. 1 0. 3.  
S ur vi val F oll o w U p .....................................................................................................5 2  
6. 1 1.  
E n d of St u d y  ...............................................................................................................5 2  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
7.  
S T U D Y A S S E S S M E N T S  ..........................................................................................5 3  
7. 1.  
St u d y Pr oce d ures  ........................................................................................................5 3  
7. 1. 1.  
Scree ni n g  ....................................................................................................................5 3  
7. 1. 2.  
C ycle 1 Da y 1 ( ± 3 da ys)  ............................................................................................5 4  
7. 1. 3.  
Da y 1 of C ycle 2 a n d All S u bse q ue nt C ycles ( ± 3 da ys)  ............................................5 5  
7. 1. 4.  
E n d of Treat me nt  ........................................................................................................5 5  
7. 1. 5.  
Safet y F oll o w -u p  ........................................................................................................5 6  
7. 1. 6.  
S ur vi val F oll o w -u p  .....................................................................................................5 7  
7. 2.  
T u m or Assess me nt  ......................................................................................................5 7  
7. 2. 1.  
I ma gi n g St u dies ..........................................................................................................5 7  
7. 2. 1. 1.  
C T wit h c o ntrast  .........................................................................................................5 7  
7. 2. 1. 2.  
P E T/ C T  .......................................................................................................................5 7  
7. 2. 2.  
B o ne Marr o w As pir ate a n d Bi o ps y  ............................................................................5 7  
7. 2. 3.  
Disease Pr o gressi o n wit h I m m u ne C hec k p oi nt I n hi bit ors ..........................................5 7  
7. 2. 4.  
Arc hi val Tiss ue C ollecti o n wit h Ce ntral Dia g n osis C o nfi r mati o n .............................5 8  
7. 3.  
5 8  
7. 4.  
Safet y  a n d T olera bilit y Assess me nts  ..........................................................................5 8  
7. 4. 1.  
A d verse E v e nts  ...........................................................................................................5 8  
7. 4. 2.  
P h ysical E x a mi nati o n,  Vital Si g ns, Hei g ht, a n d Wei g ht  ............................................5 8  
7. 4. 3.  
Me dical Hist or y  ..........................................................................................................5 9  
7. 4. 4.  
E C O G Perf or ma n ce Stat us  .........................................................................................5 9  
7. 4. 5.  
Electr ocar di o gra m  .......................................................................................................5 9  
7. 4. 6.  
La b orat or y E v al uati o ns  ...............................................................................................5 9  
7. 4. 6. 1.  
He mat ol o g y  .................................................................................................................6 0  
7. 4. 6. 2.  
Cli nical C he mistr y  ......................................................................................................6 0  
7. 4. 6. 3.  
C oa g ulati o n  .................................................................................................................6 0  
7. 4. 6. 4.  
Uri nal ysis  ....................................................................................................................6 0  
7. 4. 6. 5.  
He pat itis B a n d H e patitis C Testi n g ...........................................................................6 0  
7. 4. 6. 6.  
T h yr oi d F u ncti o n Test  ................................................................................................6 0  
7. 4. 6. 7.  
Pre g n a nc y T est  ............................................................................................................6 1  
8.  
D A T A H A N D LI N G A N D Q U A LI T Y A S S U R A N C E  ..............................................6 2  
8. 1.  
Data C ollecti o n  ...........................................................................................................6 2  
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
8. 2.  
Data Ma na ge me nt/ C o di n g  ..........................................................................................6 2  
8. 3.  
Q ualit y Ass ura nce  .......................................................................................................6 3  
9.  
S A F E T Y M O NI T O RI N G A N D R E P O R TI N G  .........................................................6 4  
9. 1.  
A d verse E v e nts  ...........................................................................................................6 4  
9. 1. 1.  
Defi nit i o n a n d Re p orti n g of a n A d verse E ve nt ..........................................................6 4  
9. 1. 2.  
Assess me nt of Se verit y  ...............................................................................................6 4  
9. 1. 3.  
Assess me nt of Ca usalit y  .............................................................................................6 5  
9. 1. 4.  
F oll o w -U p of A d v erse E ve nts  ....................................................................................6 6  
9. 1. 5.  
La b orat or y T est A b n or m alities  ...................................................................................6 6  
9. 1. 6.  
Defi niti o n of a Seri o us A d verse E ve nt  .......................................................................6 7  
9. 1. 7.  
Ti mi n g, Fre q ue n c y, a n d Met h o d of Ca pt uri n g A d verse E ve nts a n d Seri o us 
A d verse E v e nts  ...........................................................................................................6 8  
9. 1. 7. 1.  
A d verse E v e nt Re p orti n g Peri o d  ................................................................................6 8  
9. 1. 7. 2.  
Eliciti n g A d vers e E ve nt  ..............................................................................................6 8  
9. 1. 7. 3.  
S pecific I nstr ucti o ns f or Rec or di n g A d verse E ve nts a n d Seri o us A d verse 
E ve nts  .........................................................................................................................6 8  
9. 1. 8.  
Pr o m pt Re p orti n g of Seri o us A d verse E v e nts  ............................................................6 9  
9. 1. 8. 1.  
Ti mefra mes f or S u b mitti n g Seri o us A d verse E v e nts  .................................................6 9  
9. 1. 8. 2.  
C o m pleti o n a n d Tra ns missi o n of t he Seri o us A d verse E ve nt Re p ort  ........................7 0  
9. 1. 8. 3.  
Re g ulat or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts  .............................7 0  
9. 1. 9.  
Pre g n a nc y Re p orti n g  ..................................................................................................7 0  
9. 1. 1 0.  
P ost -st u d y A d vers e E ve nt ...........................................................................................7 1  
9. 1. 1 1.  
Assessi n g a n d R ec or di n g I m m u ne -Relate d A d verse E ve nts  ......................................7 1  
9. 1. 1 2.  
Ma na ge me nt of A Es of S pecial I nterest  .....................................................................7 1  
9. 1. 1 2. 1.  
I nf usi o n-relat e d Reacti o ns ..........................................................................................7 1  
9. 1. 1 2. 2.  
I m m u ne-Relate d A d v ers e E ve nts  ...............................................................................7 3  
9. 1. 1 2. 3.  
Re nal F u ncti o n A b n or m alities  ....................................................................................7 4  
9. 1. 1 2. 4.  
Se vere H y p erse nsiti vit y Reacti o ns a n d Fl u -Li k e S y m pt o ms  .....................................7 5  
9. 1. 1 3.  
E x pe dite d Re p orti n g t o Healt h A ut h orities, I n vesti gat ors, I nstit uti o nal 
Re vie w B o ar ds a n d Et hics C o m mittees  ......................................................................7 6  
9. 1. 1 4.  
Lac k of Efficac y  .........................................................................................................7 6  
9. 2.  
Safet y M o nit ori n g C o m mittee  ....................................................................................7 6  
1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S A N D A N A L Y TI C A L P L A N  .......................7 7  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 0. 1.  
Pri mar y, Sec o n dar y a n d 
St u d y E n d p oi nts  ..............................................7 7  
1 0. 1. 1.  
Pri mar y E n d p oi nt  ........................................................................................................7 7  
1 0. 1. 2.  
Sec o n dar y E n d p oi nts  ..................................................................................................7 7  
1 0. 1. 3.  
7 7  
1 0. 2.  
Statistical A nal ysis  ......................................................................................................7 8  
1 0. 2. 1.  
A nal ysis Sets  ...............................................................................................................7 8  
1 0. 2. 2.  
S u bj ect Dis p ositi o n .....................................................................................................7 8  
1 0. 2. 3.  
De m o gra p hic a n d Ot her Baseli ne C haracteristics  ......................................................7 8  
1 0. 2. 4.  
Pri or a n d C o nc o mita nt T hera p y  ..................................................................................7 8  
1 0. 2. 5.  
Efficac y A nal yses  .......................................................................................................7 9  
1 0. 2. 5. 1.  
Pri mar y Efficac y A nal ysis  ..........................................................................................7 9  
1 0. 2. 5. 2.  
Sec o n dar y Efficac y A nal ysis  ......................................................................................7 9  
1 0. 2. 5. 3.  
8 0  
1 0. 2. 6.  
Safet y A nal ysis  ...........................................................................................................8 0  
1 0. 2. 6. 1.  
E xte nt of E x p os ure  .....................................................................................................8 0  
1 0. 2. 6. 2.  
A d verse E v e nts  ...........................................................................................................8 0  
1 0. 2. 6. 3 . 
La b orat or y A nal yses  ...................................................................................................8 1  
1 0. 2. 6. 4.  
Vital Si g ns  ..................................................................................................................8 1  
1 0. 2. 7.  
8 1  
1 0. 2. 8.  
8 1  
1 0. 3.  
Sa m ple Siz e C o nsi derati o n  .........................................................................................8 2  
1 0. 4.  
I nteri m A nal ysis ..........................................................................................................8 2  
1 1.  
E T HI C A L C O N SI D E R A TI O N S A N D A D MI NI S T R A TI V E 
P R O C E D U R E S  ..........................................................................................................8 3  
1 1. 1.  
Re g ulat or y A ut h orit y A p pr o val  ..................................................................................8 3  
1 1. 2.  
I n v esti gat or Res p o nsi bilities .......................................................................................8 3  
1 1. 2. 1.  
G o o d Cli nical Practice  ................................................................................................8 3  
1 1. 2. 2.  
Et hical C o n d uct of t he St u d y a n d Et hics A p pr o val  ....................................................8 3  
1 1. 2. 3.  
I nf or me d C o nse nt .......................................................................................................8 4  
1 1. 2. 4.  
I n v esti gat or Re p orti n g Re q uire me nts .........................................................................8 4  
1 1. 2. 5.  
C o nfi de ntialit y  ............................................................................................................8 4  
1 1. 2. 6.  
Case Re p ort F or ms  .....................................................................................................8 4  
1 1. 2. 7.  
Dr u g Acc o u nta bilit y  ...................................................................................................8 5  
C CI
C CI
C CI
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 1. 2. 8.  
I ns p ecti o ns ..................................................................................................................8 5  
1 1. 2. 9.  
Pr ot oc ol C o m plia nce  ..................................................................................................8 5  
1 1. 3.  
S p o ns or Res p o nsi bilities  .............................................................................................8 5  
1 1. 3. 1.  
Pr ot oc ol M o dificati o ns  ...............................................................................................8 5  
1 1. 3. 2.  
St u d y R e p ort a n d P u blicati o ns ....................................................................................8 5  
1 1. 4.  
St u d y a n d St u d y Ce nt er Cl os ure  .................................................................................8 6  
1 1. 5.  
Rec or ds Rete nti o n a n d St u d y Files  .............................................................................8 7  
1 1. 5. 1.  
St u d y Files a n d Ret e nti o n of Rec or ds  ........................................................................8 7  
1 1. 6.  
Pr o visi o n of St u d y Res ults a n d I nf or mati o n t o I n v esti gat ors  .....................................8 8  
1 1. 7.  
I nf or mati o n Discl os ure a n d I n v e nti o ns ......................................................................8 8  
1 1. 8.  
J oi nt I n vesti gat or/ S p o ns or Res p o nsi bilities ................................................................8 9  
1 1. 8. 1.  
Access t o I nf or mati o n f or M o nit ori n g  ........................................................................8 9  
1 1. 8. 2.  
Access t o I nf or mati o n f or A u diti n g or I ns pecti o ns  ....................................................8 9  
1 2.  
R E F E R E N C E S  ...........................................................................................................9 0  
1 3.  
A P P E N DI C E S  ............................................................................................................9 2  
A P P E N DI X  1.  SI G N A T U R E O F I N V E S TI G A T O R  .................................................................9 2  
A P P E N DI X  2.  C LI NI C A L L A B O R A T O R Y A S S E S S M E N T ...................................................9 3  
A P P E N DI X  3.  H O D G KI N L Y M P H O M A S T A GI N G ...............................................................9 4  
A P P E N DI X  4.  I N T E R N A TI O N A L P R O G N OS TI C S C O R E  ....................................................9 5  
A P P E N DI X  5.  S C H E D U L E O F A S S E S S M E N T .......................................................................9 6  
A P P E N DI X  6.  T H E L U G A N O C L A S SI FI C A TI O N  ...............................................................1 0 1  
A P P E N DI X  7.  
 
 ..................................................................................................1 0 6  
A P P E N DI X  8.  I M M U N E-R E L A T E D A D V E R S E E V E N T S E V A L U A TI O N  A N D 
M A N A G E M E N T  .....................................................................................................1 0 7  
 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
LI S T O F T A B L E S  
Ta ble  1:  
Treat me nt -e mer ge nt A d v erse E ve nts Ass esse d as Relate d t o Tisleliz u ma b 
Occ urri n g i n ≥ 5 % of Patie nts a n d C orres p o n di n g Relate d ≥ Gra d e 3 
I n ci de nce i n St u d y B G B-A 3 1 7 _ 0 0 1 - P hase 1 b (as of 1 3 J a n u ar y 2 0 1 7, N = 
1 8 9)  .............................................................................................................................3 4  
Ta ble  2:  
E C O G  Perf or ma n ce Stat us  .........................................................................................5 9  
Ta ble  3:  
Ti me Fra m e f or Re p orti n g Seri o us A d verse E v e nts t o t he S p o ns or or 
Desi g n ee  .....................................................................................................................6 9  
Ta ble  4:  
Treat me nt M o dificati o n f or S y m pt o ms of I nf usi o n -Relate d Reacti o ns D ue t o 
Tisleliz u ma b  ...............................................................................................................7 2  
Ta ble  5:  
I m m u ne-relat e d A d verse E ve nts .................................................................................7 4  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
Cleara nce vs B o d y Wei g ht  .........................................................................................3 5  
Fi g ure  2:  
St u d y Desi g n  ...............................................................................................................4 1  
 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  
A b bre vi ati o n  
Defi niti o n  
A B V D  
D o x or u bici n, ble o m yci n, vi n blasti ne, dacar bazi ne  
 
 
A D C C  
A nti b o d y -de pe n de nt cell ular c yt ot o xicit y 
A E  
A d verse E ve nt  
A L T  
A la ni ne a mi n otra nsferase 
A N C  
A bs ol ute N e utr o p hil C o u nt  
a P T T  
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
A s partate a mi n otra nsferase 
 
 
A ut o -S C T  
A ut ol o g o us ste m cell tra ns pla nt 
 
 
 
B E A C O P P  
Ble o m yci n, et o p osi de, d o x or u bici n, c ycl o p h os p ha mi de, vi ncristi ne, 
pr ocar bazi n e, pre d nis o ne 
B O R  
B est o verall res p o nse  
B P  
B l o o d press ure 
B U N  
B l o o d urea nitr o ge n 
C B C  
C o m plete bl o o d c o u nt  
c H L 
Classical H o d g ki n l y m p h o ma  
C D  
Cl uster of differe ntiati o n, s uc h as C D 4, C D 8 , etc. 
C D C  
C o m ple me nt -de pe n de nt c yt ot o xicit y  
CI  
C o nfi de nce i nter val  
 
 
C N S  
C e ntral n er v o us syste m  
C M R  
C o m plete meta b olic res p o nse  
C R  
C o m plete res p o nse  
C R F  
Case re p ort f or m, pa per or electr o nic  
C R O  
C o ntract researc h or ga nizati o n  
C S R  
C li nical st u d y re p ort 
C T  
C o m p ute d T o m o gra p h y  
C T C A E  
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
  
 
D O R  
D urati o n of res p o nse  
E B V  
E pstei n -Barr vir us  
E C G  
E lectr ocar di o gra m 
E C H O  
E c h ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
E lectr o nic case re p ort f or m 
C CI
C CI
C CI
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A b bre vi ati o n  
Defi niti o n  
E D C  
Electr o nic data ca pt ure  
e G F R 
esti mate d gl o mer ular filtrati o n rate  
E O S  
E n d of st u d y  
E O T  
E n d of T reat me nt 
E S R  
Er yt hr oc yte se di me ntati o n rate  
Fc  
Fra g me nt cr ystalliza ble re gi o n  
Fc R  
Ga m ma Fc rece pt or  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F D G -P E T  
[1 8F]  fl u or o de o x y gl uc ose p ositr o n e missi o n t o m o gra p h y  
F F P E  
F or mali n -fi xe d, paraffi n-e m be d de d  
FI H  
F irst i n h u ma n 
G C P  
G o o d C li nical P ractice 
G -C S F  
Gra n ul oc yte c ol o n y sti m ulati n g fact or  
G L P  
G o o d La b orat or y Practices  
G M -C S F  
Gra n ul oc yte -m o n oc yte c ol o n y sti m ulati n g fact or  
G M P  
G o o d Ma n ufact uri n g Practice  
H Bc A b  
H e patitis B c ore a nti b o d y 
H Bs A b  
H e patitis B s urface a nti b o d y  
H Bs A g  
H e patitis B s urface a nti ge n  
H B V  
H e patitis B vir us 
H C V  
H e patitis C vir us 
H C V A b  
He patitis C a nti b o d y  
H D T  
Hi g h d ose c he m ot hera p y  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H L  
H o d g ki n l y m p h o ma  
H N S C C  
hea d a n d nec k s q ua m o us cell carci n o ma  
I B 
In vesti gat or’s b r oc h ure 
I C F 
I nf or me d c o nse nt f or m 
IC H  
Inter nati o nal C o nfere nce o n Har m o nizati o n  
I E C 
In de pe n de nt E t hics C o m mittee  
I F N-α  
I nterfer o n-al p ha 
I F N- 
Interfer o n -ga m ma  
 
 
I H C 
Im m u n o hist oc he mistr y  
I L 
Interle u ki n  
I M P 
I n vesti gati o nal me dici nal pr o d uct 
I N D 
I n vesti gati o nal ne w dr u g 
I N R 
I nter nati o nal N or malize d Rati o 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A b bre vi ati o n  
Defi niti o n  
ir A E 
I m m u ne-relate d a d verse e ve nt 
I R C 
I n de pe n de nt Re vie w C o m mittee 
I V  
I ntra ve n o us 
L D C H L  
L y m p h oc yte de plete d classical H o d g ki n l y m p h o ma  
L D H  
Lactate de h y dr o ge nase  
L R C H L  
L y m p h oc yte -ric h classical H o d g ki n l y m p h o ma 
 
 
M C C H L  
Mi xe d cell ularit y classical H o d g ki n l y m p h o ma  
M C H  
Mea n c or p usc ular he m o gl o bi n  
M C H C  
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n  
M C V  
Mea n c or p usc u lar v ol u me 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m g  
M illi gra m 
m L  
M illiliter 
m m  
M illi meter 
M M R  
Me diasti nal mass rati o  
M RI  
M a g netic res o na nce i ma gi n g  
M T D  
M a xi m u m t olerate d d ose  
M U G A  
M ulti gate d ac q uisiti o n sca n  
N CI  
N ati o nal C a ncer Instit ute  
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 nts  
n g  
N a n o gra m 
N K  
Nat ural killer  
N L P H L  
N o d ular l y m p h oc yte -pre d o mi na nt H o d g ki n l y m p h o ma  
N S AI D  
N o nster oi dal a nti -i nfla m mat or y dr u gs 
N S C H L  
N o d ular scler osis classical H o d g ki n l y m p h o ma 
N S C L C  
N o n -s mall cell l u n g carci n o ma 
N Y H A  
Ne w Y or k Heart Ass ociati o n  
O R R  
O verall res p o nse rate  
O T C  
O ver -t he-c o u nter 
 
 
P B M C  
Peri p heral bl o o d m o n o n uclear cells  
P C R  
P ol y merase C hai n R eacti o n 
P D  
P r o gressi ve disease 
P D -1  
P r o gra m me d cell deat h-1  
P D -L 1  
Pr o gra m Deat h Li ga n d -1, Pr o gra me d Deat h Rece pt or Li ga n d -1, 
Pr o gra me d Deat h -1 Li ga n d -1  
P D -L 2  
Pr o gra m Deat h Li ga n d -2  
C
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A b bre vi ati o n  
Defi niti o n  
P E T  
P ositr o n E missi o n T o m o gra p h y  
P F S  
P r o gressi o n-F ree S ur vi val  
p H  
P o u v oir h y dr o ge ne  
 
 
P R  
P artial Res p o nse 
P P  
per -P r ot oc ol A nal ysis Set  
P T  
Pr ot hr o m bi n ti me  
Q D  
O nce dail y  
Q 2 W  
O nce e ver y t w o wee ks  
Q 3 W  
O nce e ver y t hree wee ks  
Q C  
q ualit y c o ntr ol  
Q T c F  
Q T i nter val c orrecte d usi n g Fri dericia’s f or m ula  
R B C  
Re d bl o o d cell  
R D W  
Re d cell distri b uti o n wi dt h  
R S  
Ree d -Ster n ber g  
S A E  
S eri o us a d verse e ve nt  
S A P  
S tatistical a nal ysis pla n 
S D  
S ta ble disease 
S G O T  
S er u m gl uta mic o xal oacetic tra nsa mi nase  
S G P T  
S er u m gl uta mic p yr u vic tra nsa mi nase  
S M C  
Safet y M o nit ori n g C o m mittee  
S O C  
S yste m or ga n class  
S O Ps  
S ta n dar d o perati n g pr oce d ures 
S P D  
S u m of t he pr o d uct of t he l o n gest dia meters  
Sta nf or d V  
D o x or u bici n, vi n blasti ne, mec hl oret ha mi ne, et o p osi de, vi ncristi ne, 
ble o m yci n, pre d nis o ne  
T 1/ 2 
h alf -life  
T C R  
T -cell rece pt or  
T E A E  
Treat me nt -e mer ge nt a d verse e ve nt  
T G F -β  
Tra nsf or mi n g gr o wt h fact or -beta  
TI L  
T u m or -i nfiltrati n g l y m p h oc ytes 
T K  
T o xic o ki netics  
T N F -α  
T u m or necr osis fact or -al p ha 
Tre g  
Re g ulat or y T  
T S H  
T h yr oi d sti m ulati n g h or m o ne  
T T R  
T i me t o res p o nse 
g  
M icr o gra m 
U L N  
U p per L i mit of N or mal  
U S  
U nite d States  
C
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A b bre vi ati o n  
Defi niti o n  
 
 
W B C  
W hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
C CI
C

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1.  
I N T R O D U C TI O N 
1. 1.  
H o d g ki n L y m p h o m a  
H o d g ki n l y m p h o ma ( H L) is a  B -cell l y m p h oi d mali g na nc y wit h a n i ncrease d i nci de nce i n y o u n g 
a d ults bet wee n 1 5 a n d 3 0 years of a ge, as well as i n patie nts 5 5 years a n d ol der.  T he W orl d 
Healt h Or ga niz ati o n ( W H O) classificati o n di vi des H L i nt o 2 mai n t y pes: classical H L (c H L) a n d 
n o d u lar l y m p h oc yt e-pre d o mi na nt H L ( N L P H L), wit h c H L f urt her s u b di vi de d i nt o n o d ular 
scler osis c H L ( N S C H L), mi x e d cell ularit y c H L ( M C C H L), l y m p h oc yte -d e plete d c H L ( L D C H L), 
a n d l y m p h oc yt e -ric h c H L ( L R C H L).  Classical H L acc o u nts f or 9 5 % a n d N L P H L acc o u nts f or 
5 %  of all H L ( We ber et al, 2 0 1 5 ).  N o d ular scler osis c H L t e n ds t o affect y o u n g a d ults m ore ofte n 
t ha n t he el derl y, a n d is m ore c o m m o n i n fe mal es t ha n males.  It is als o less fre q ue ntl y ass o ciate d 
wit h E pstei n -Barr vir us ( E B V).  C o m pare d t o ot her t y p es of c H L, me diasti nal i n v ol ve me nt is 
m ore c o m m o n f or N S C H L. I n c o ntrast t o N S C H L, M C C H L a n d L D C H L are ass ociate d wit h a 
greater pre v ale nce i n males, fre q u e nt E B V i nfecti o n of t he ne o plastic cells, a n d te n d t o e x hi bit a 
differe nt p atte r n of s pr ea d wit hi n t he i m m u ne s yst e m (Marafi oti et al, 2 0 0 0 ).  M C C H L re pres e nts 
m ost cases of c H L i n t he pe diatric p o p ulati o n, a n d is t y pi call y ass ociat e d wit h m ore a d va nce d 
sta ge of diseas e at pres e ntati o n a n d a w orse pro g n osis.  F or L D C H L, it mai nl y occ urs i n a n ol der 
patie nt p o p ulati o n a n d i n t h ose wit h ac q uire d i m m u ne deficie nc y s y n dr o me.  
Prese nce of mali g n a nt m ulti n ucleate d Ree d -Ster n ber g ( R S) cells, w hic h are of f ollic ular ce nter 
B -cell ori gi n a n d c o nstit ute less t ha n 1 % of cells i n t he affecte d l y m p h n o des, wit hi n a 
c haracteristic reacti ve cell ular bac k gr o u n d of n or mal l y m p h oc ytes, e osi n o p hils a n d histi oc yt es, is 
t he hall mar k of c H L (Mc Der m ott et al, 2 0 1 3 ). Des pite t he B -cell ori gi n, R S cells ha ve a gl o b al 
l oss of B-cell ge ne e x pressi o n a n d neit her pr o d uce i m m u n o gl o b uli n n or ha ve f u ncti o nal B -cell 
a nti ge n rece pt ors ( Marafi oti et al, 2 0 0 0 ).  A variet y of c yt o ki nes, c he m o ki n es, gr o wt h factors a n d 
t heir rece pt ors i ncl u di n g b ut n ot li mite d t o i nterle u ki ns (I L 1 t o I L 1 0), i nterfer o n (I F N), t u m or 
necr osis fact or -al p ha ( T N F-α), tra nsf or mi n g gr o wt h fact or -b eta ( T G F -β), gra n ul oc yte c ol o n y 
sti m ulati n g fact or ( G-C S F), a n d gra n ul oc yte -m o n oc yt e c ol o n y sti m ulati n g fact or ( G M-C S F) pla y 
a r ole i n creati n g t his micr oe n vir o n me nt ( Desai et al, 2 0 1 6 ; Rile y, 2 0 0 9 ).  T he T-cell i nfiltrate i n 
c H L pre d o mi na ntl y c o m prises T h 2 a n d re g ulat or y T ( Tre g) cells,  a n d ge n erall y lac ks T h 1 cells, 
C D 8 c yt ot o xic T cells a n d nat ural killer ( N K) cells, res ulti n g i n a n i n hi biti o n of c yt ot o xic a nti -
t u m or i m m u ne res p o nses (O hs hi ma et al, 2 0 0 3 ; O p di v o ®  U S Prescri bi n g I nf or mati o n ).  
Fact ors i n d eter mi ni n g t h e i nitial c h oice of t hera p y f or H L i ncl u de t he hist ol o g y of t h e disease 
(c H L or N L P H L), t he a n at o mical sta ge of disease (li mite d or a d va nce d dise ase), prese nce of 
p o or pr o g n ostic feat ures, prese nce of  c o nstit uti o nal s y m pt o ms, a n d prese n ce of b ul k y disease.  
Fl u or o de o x y gl uc os e p ositr o n e missi o n t o m o gra p h y ( F D G -P E T) sca n ni n g pla ys a r ole i n 
decisi o ns t o c o m plete t hera p y as pla n n e d, or t o a d d or o mit c o m p o ne nts of t hera p y.  I n ge neral, 
patie nts wit h earl y  sta ge disease are treate d wit h c o m bi ne d m o dalit y strate gies usi n g a b bre viate d 
c o urse of c he m ot hera p y f oll o we d b y i n v ol ve d fi el d ra diati o n, w hile t h ose wit h a d va nce d sta ge 
disease recei ve a l o n ger c o urse of c h e m ot hera p y.  Fr o nt li ne c he m ot hera p y re gi me ns f or c H L 
ma y i ncl u d e d o x or u bici n, ble o m yci n, vi n blasti ne, dacar bazi ne ( A B V D), d ose -escalate d 
ble o m yci n, et o p osi de, d o x or u bici n, c ycl o p h os p ha mi de, vi ncristi ne, pr ocar bazi ne, pre d nis o ne 
( B E A C O P P), or d o x or u bici n, vi n blasti ne, mec hl oret ha mi ne, et o p osi de, vi ncristi ne, ble o m yci n, 
pre d nis o ne  (Sta nf or d V ), wit h a d diti o n of rit u xi ma b t o c he m ot hera p y f or N L P H L (A nsell, 2 0 1 2 ).   
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  2 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Des pite a hi g h c ure rat e wit h i nitial t hera p y, a p pr o xi matel y 5 -1 0 % of H L patie nts will ha ve 
pri mar y refract or y diseas e, a n d 1 0 -3 0 % of patie nts will rela pse aft er ac hie vi n g a n i nitial C R 
(A nsell, 2 0 1 2 ).  
 
 
 
  A d diti o nal t hera pe utic o pti o ns 
i ncl ude bre nt u xi ma b ve d oti n, a C D 3 0 -directe d a nti b o d y -m o n o met h yl a urist ati n E c o nj u gate, 
w hic h is ass ociate d wit h a C R rate of 3 4 % a n d a n o verall res p o ns e rate ( O R R) of 7 5 %  
(Y o u nes et al, 2 0 1 2 a ).  I n 2 0 1 1, bre nt u xi ma b ve d oti n was a p pr o ve d b y t he U S F o o d a n d Dr u g 
A d mi nistrati o n ( F D A), a n d later i n E ur o pe, f or treat me nt of patie nts wit h rela pse d H L aft er 
fail ure of a ut o-S C T or aft er fail ure of at least t w o pri or c he m ot hera p y re gi me ns i n patie nts w h o 
are n ot tra ns pla nt ca n di d ates.  B re nt u xi ma b ve d oti n has n ot bee n a p pr o ve d i n C hi na t o date.  
Ni v ol u ma b, a f ull y h u ma n m o n ocl o nal i m m u n o gl o bi n G 4 (I g G 4) a nti b o d y directe d a gai nst 
pr o gra m me d cell deat h -1 ( P D -1), has als o b ee n a p pr o ve d f or tr eat me nt of p atie nts wit h c H L t hat 
rela pse d or pr ogress e d after H D T/a ut o -S C T a n d p ost -tra ns pla ntati o n bre nt u xi ma b ve d oti n.  
Ni v ol u ma b has n ot bee n a p pr o ve d i n C hi na.   Pa n o bi n ostat, a hist o ne deacet yl ase i n hi bit or 
(Y o u nes, 2 0 1 2 b ), as well as t he ra pt or ma m malia n tar get of rapa m yci n i n hi bit or e ver oli m us 
(J o h nst o n et al, 2 0 1 0), a n d t he i m m u n o m o d ulat or y a ge nt le nali d o mi de (Fe h ni ger et al, 2 0 1 1 ), 
ha ve als o be e n e x a mi ne d i n t he treat me nt of rela pse d/refract or y H L.  
1. 2.  
I m m u ne C hec k p oi nt I n hi bit ors 
I m m u ne c hec k p oi nt-i n hi bit or y rece pt or, P D-1, is mai nl y e x presse d i n acti vate d T -cells i ncl u di n g 
C D 8 + c yt ot o xic T -l y m p h oc yt es a n d C D 4 + T-hel p er l y m p h o c yt es ( O hs hi m a et al, 2 0 0 2 ). It is 
belie ve d t h at P D-1 pla ys a n i m p orta nt r ole i n i m m u ne m o d ulati o n of t u m or pr o gressi o n b y 
re g ulati n g t h e ke y i n hi bit or y si g nali n g i n t he T-cells w he n e n ga ge d b y its li ga n ds. T h e P D -1 
si g nali n g cas ca d e ne gati v el y re g ulates T-cell rece pt or ( T C R) a n d atte n uat e T -cell pr ol iferati o n 
a n d f u ncti o nal a cti vities, lea di n g t o T -cell e x ha usti o n. P D -1 e x pressi o n is mar ke dl y u p -re g ulate d 
i n t u m or-i nfiltrati n g l y m p h oc yt es ( TI L), w hile t he e x pressi o n of P D-1 li ga n d, P D -L 1, is 
si g nifica ntl y i ncreas e d i n t u m or cells a n d t u m or-ass ociate d i m m u ne cells i n t he prese n ce of 
sti m ulati n g c yt o ki nes s u c h as I F N- ( ga m ma) a n d I F N- (al p ha)  i n t he t u m or micr oe n vir o n me nt 
(Sir o hi et al, 2 0 0 8 ). 
1. 2. 1.  
Pe m b r oliz u m a b  
Pe m br oliz u ma b, a h u ma nize d a nti -P D -1 I g G 4 ka p pa a nti b o d y, h as be e n a p pr o ve d b y t he U S 
F D A f or t he treat me nt of patie nts wit h u nresecta bl e or metastatic mela n o m a, metastatic n o n-
s mall cell l u n g carci n o m a ( N S C L C) w h ose t u m ors e x press P D-L 1 a n d h a v e pr o gress e d o n or 
after plati n u m -c o nt ai ni n g c he m ot hera p y, a n d rec urre nt or  metastatic h ea d a n d nec k s q ua m o us 
cell carci n o ma ( H N S C C) t hat pr o gresse d o n or aft er plati n u m -c o ntai ni n g c he m ot hera p y.  
Pe m br oliz u ma b has bee n s h o w n t o be effi caci o us i n b ot h i pili m u ma b -naï ve a n d i pili m u ma b -
refract or y mel a n o ma pati e nts, wit h O R R of 3 3-3 4 %  a n d 2 1-2 5 %, res pecti vel y.  F or N S C L C t h at 
pr o gresse d after pl ati n u m -c o ntai ni n g c he m ot hera p y, O R R was 4 1 % w hile f or H N S C C, O R R was 
1 6 % wit h 5 % c o m plete res p o nses ( Ke ytr u da ®  U S Prescri bi n g I nf or m ati o n ). 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
I n a st u d y of 3 1 s u bjects wit h c H L ( 7 1 % of w h o m ha d u n der g o n e pri or a ut o-S C T) w h o recei ve d 
pe m br oliz u ma b after bre nt u xi ma b ve d oti n fail ure, O R R was 6 5 % wit h  a C R rate of 1 6 % a n d P R 
rate of 4 8 %.  M aj orit y of res p o nses ( 7 0 %) laste d l o n ger t ha n 2 4 wee ks wit h a me dia n f oll o w-u p 
of 1 7 m o nt hs.  Pr o gressi o n -free s ur vi val w as 6 9 % at 2 4 wee ks a n d 4 6 % at 5 2 wee ks.  F or t he 
s u bset of s u bjects w h o ha d  u n der g o ne a ut o -S C T ( n = 2 2), 1 4 % ac hie ve C R a n d 5 9 % ac hie ve d P R 
f or a n O R R of 7 3 % f or t h ose 2 2 s u bjects (Ar m a n d e t al, 2 0 1 6). 
1. 2. 2.  
Ni v ol u m a b  
Ni v ol u ma b, a f ull y h u ma n a nti -P D -1 I g G 4 a nti b o d y, has b ee n a p pr o ve d b y t he U S F D A f or t he 
treat me nt of b ot h pr ot o-o nc o ge ne B -Raf a n d v -Raf m uri ne sarc o ma viral o nc o ge ne h o m ol o g 
( B R A F) V 6 0 0 wil d-t y pe a n d m utati o n-p ositi ve u nresect a ble  or metastatic mela n o ma as a si n gle 
a ge nt, i n c o m bi nati o n wit h i pili m u ma b f or u nresecta ble metastatic mela n o m a, metastatic N S C L C 
t hat pr o gresse d o n or after plati n u m-base d c h e m ot hera p y, a d v a nce d re n al cell carci n o ma ( R C C) 
after pri or a nti -a n gi o ge ni c t hera p y, a n d classical H L t hat rela pse d or pr o gresse d after H D T/a ut o -
S C T a n d p ost -tra ns pla ntati o n bre nt u xi ma b ve d oti n. 
I n a st u d y of 9 5 s u bjects wit h c H L w h o ha d pre vi o usl y u n der g o n e H D T/ a ut o-S C T a n d 
bre nt u xi ma b ve d oti n treat me nts ( me dia n of 5 pri or s yste mic re g i me ns), ni v ol u ma b was 
ass ociate d wit h a n O R R of 6 5 % wit h 7 % C R a n d 5 8 % P R.  Me dia n d urati o n of res p o nse was 8. 7 
m o nt hs a n d T T R was 2. 1 m o nt hs ( O p di v o ®  U S Prescri bi n g I nf or mati o n ).  I n a n ot her st u d y of 2 3 
H L s u bjects ( 7 8 % h a d recei ve d pri or bre nt u xi ma b ve d oti n, 7 8 % ha d pre vi o usl y u n der g o n e 
H D T/a ut o -S C T), O R R was 8 7 % wit h 1 7 % C R a n d 7 0 % P R ( A nsell et al, 2 0 1 5 ). 
1. 2. 3.  
I m m u ne-rel at e d A d verse E ve nts  
I m m u ne-relat e d t o xicities ma y de vel o p d uri n g i m m u n ot hera p y treat me nt. F or ni v ol u ma b, t he 
maj orit y of i m m u ne -relat e d t o xicities occ ur wit hi n t he first 4 m o nt hs (Bra h mer et al, 2 0 1 5 ; 
Y o u nes et al 2 0 1 2a ).  Me dia n ti me t o o nset of treat me nt-relate d a d v erse e v e nts ca n var y 
de pe n di n g o n t he t y pe of t o xicit y: fr o m 5 wee ks f or s ki n A Es t o 1 5. 1 wee ks f or ki d ne y A Es. 
Base d o n t his me dia n ti m e t o o nset, i m m u ne -relate d t o xicities c o ul d be classifie d as earl y 
( me dia n ti me t o o nset < 2  m o nt hs) a n d late t o xicities ( me dia n ti me t o o nset > 2 m o nt hs). Earl y 
t o xicities ma y i ncl u de s ki n ( 5 wee ks), gastr oi ntesti nal ( 7. 3 wee ks) a n d he p atic ( 7. 7 wee ks) 
e ve nts, w hereas late t o xicities ma y i ncl u d e p ul m o nar y ( 8. 9 wee ks), e n d ocri ne ( 1 0. 4 wee ks) a n d 
re nal ( 1 5. 1 wee ks) e ve nts.  H owe ver, differe nt t o xicities ca n de v el o p at a n y ti me si nce t he 
c o nfi de nce i nter val ma y var y wi del y a m o n g or ga ns: 0. 1 – 5 7 wee ks f or s ki n; 0. 1 – 3 7. 6 wee ks f or 
gastr oi ntesti nal ( C ha m pi at et al, 2 0 1 6 ).   
1. 3.  
Tisleliz u m a b  
Tisleliz u ma b  (als o k n o w n as B G B-A 3 1 7) is a h u ma nize d I g G 4 varia nt m o n o cl o nal a nti b o d y 
a gai nst P D-1. It is bei n g de vel o pe d f or t he treat me nt of h u ma n mali g n a nci es. Tisleliz u ma b  was 
ma n ufact ur e d u n der G o o d Ma n ufact uri n g Practice ( G M P) q ualit y c o ntr ol ( Q C) s yste ms. T he 
cli nical trial dr u g pr o d uct is f or m ulate d i n a n a q ue o us b uffer wit h p H 6. 5 a n d is ot o nic 
os m olalit y. T h e s u g geste d a d mi nistrati o n r o ute is I V i nf usi o n after t he a p pr o priate dil uti o n i n 
0. 9 % s o di u m c hl ori de s ol uti o n.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1. 3. 1.  
N o n -Cli nic al D at a  of Tisleliz u m a b  
Tisleliz u ma b  bi n ds t o t he e xtracell ular d o mai n of h u ma n P D -1 wit h hi g h s pecificit y a n d affi nit y 
( KD  = 0. 1 5 n M) as de m o nstrate d b y rece pt or bi n di n g assa ys b ase d o n s urface plas m o n res o n a nce 
( S P R). It c o m petiti vel y bl oc ks t he bi n di n g of b ot h P D-L 1 a n d pr o gra m deat h li ga n d -2 ( P D -L 2) , 
i n hi biti n g P D-1 me diate d ne gati ve si g n ali n g i n T -cells. I n  i n vitr o cell-base d assa ys, t he 
h u ma nize d a nti b o d y c o nsiste ntl y a n d d ose -d e pe n d e ntl y e n h a nce d t he f u ncti o nal acti vit y of 
h u ma n T -cells a n d pre-acti vate d, pri mar y peri p h era l bl o o d m o n o n uclear cells ( P B M Cs). I n 
a d diti o n, tisleliz u ma b de m o nstrate d a nti -t u m or acti vit y i n se v eral h u ma n ca ncer all o ge neic 
x e n o graft m o dels, i ncl u di n g h u ma n ca ncer cells ( A 4 3 1) h u ma n e pi der m oi d carci n o ma, B C C O -
0 2 8 c ol o n ca ncer, a n d B C L U -0 5 4 N S C L C m o d els, w here t he P B M Cs were c o -i nject e d wit h t he 
A 4 3 1 or t he t u m or fra g me nts ( B C C O -0 2 8 a n d B C L U -0 5 4) i nt o t he i m m u n oc o m pr o mise d mice.  
T he I g G 4 varia nt a nti b o d y has v er y l o w bi n di n g affi nit y t o effect or rece pt ors i ncl u di n g Fc Rs 
a n d C 1 q b y i n vitr o assa ys a n d  wit h a l o w or n o a nti b o d y -de p e n de nt cell ular -c yt ot o xicit y 
( A D C C) a n d c o m ple me nt-de pe n de nt c yt ot o xicit y ( C D C) effect i n h u ma ns. U nli ke nat ural I g G 4 
a nti b o d y, tisleliz u ma b has n o o bser va ble Fa b -Ar m e x c ha n ge acti vit y b y t he i n vitr o assa y, 
pre dicti n g t h e a nt i b o d y w o ul d be sta ble i n viv o, u nli kel y f or mi n g bis pecific a nti b o d y. 
Tisleliz u ma b  bi n ds t o t he c y n o m ol g us m o n ke y a n d h u ma n P D -1 wit h si milar affi nit y, b ut d oes n ot 
bi n d t o m o use P D -1 d ue t o t he si g nifica nt se q u e nce di ver ge n ce fr o m h u ma n a n d m o n ke y P D -1. 
T h eref ore, c y n o m ol g us m o n ke ys w ere t h e rele va nt s pecies f or n o n cli nical safet y e v al uati o n.  
A P K st u d y of tisleliz u ma b was c o n d u cte d i n m o n ke ys at si n gle d os es of 3, 1 0, or 3 0 m g/ k g or at 
a re peat d ose of 1 0 m g/ k g w ee kl y f or 5 d os es via I V i nf usi o n. T he s yste mic e x p os ure a p peare d t o 
i ncreas e d ose-pr o p orti o nall y wit h o ut ge n der differe nce or acc u m ulati o n. After si n gl e d ose 
a d mi nistrati o n of 3, 1 0, or 3 0 m g/ k g, t he half -life ( T1/ 2) ra n ge d fr o m 7 4 t o 1 8 3 h o urs; ma xi m u m 
o bser ve d ser u m c o nce ntr ati o n ( C ma x ) ra n ge d fr o m 9 0 t o 9 9 9 µ g/ m L, a n d A U C0 -1 0 0 8 h (area u n der 
t he c o nce ntr ati o n-ti me c ur ve fr o m ti me zer o [ pre-d ose] t o last ti me of q ua ntifia ble c o nce ntrati o n) 
ra n ge d fr o m 1 2, 3 2 2 t o 1 6 3, 7 5 5 h * µ g/ m L; v ol u me of distri b uti o n ( Vd) was l o w, a n d ra n ge d fr o m 
2 2 t o 5 2 ml/ k g.   
A P K bri d gi n g st u d y f or tisleliz u ma b was c o n d uct e d i n m o n ke ys at a si n gle d ose of 1 0 m g/ k g via 
I V i nf usi o n. N o mar ke d differe n ces o n T1/ 2, Cma x , area u n d er t he c o nce ntrati o n-ti me c ur ve 
( A U C), Vd, C L a n d M R T were n ote d bet wee n t he t w o batc hes. 
T he T 1/ 2 of tisleliz u ma b i n m o n ke ys s u p p ort e d o n ce bi wee kl y d osi n g i n t he re peat -d ose 
t o xic ol o g y st u d y wit h a d e q uate s yste mic e x p os ure t o s u p p ort t o xic ol o g y e v al uati o n of 
tisleliz u ma b. Base d o n P K res ults i n m o n ke ys, t he Vd of tisleliz u ma b i n h u ma n is e x pecte d t o be 
li ke t hat i n m o n ke ys. T he T1/ 2 of tisleliz u ma b i n h u ma n is e x pecte d t o be 1 0 -2 0 da ys de pe n di n g 
o n t he act ual d ose le v els, w hic h all o ws m ulti ple -d ose treat me nt of tisleliz u ma b f or h u ma n wit h a 
d osi n g i nter val of 1 4 or 2 1 da ys t o pr o vi d e t he tar get s yste m ic e x p os ure at t he pr ojecte d 
t hera pe utic d os e of 0. 5 t o 1 0 m g/ k g wit h o ut e x cessi ve dr u g acc u m ulati o n. 
T he t o xicit y a n d s afet y pr ofile of tisleliz u ma b was c haracterize d i n si n gl e d ose t o xic ol o g y 
st u dies i n mice a n d m o n ke ys a n d i n a 1 3-wee k re p eat d ose t o xic ol o g y st u d y i n m o n ke ys. T he 
tiss ue cr oss reacti vit y w as e val uate d i n t he n or m al fr oze n tiss ues fr o m b ot h h u ma ns a n d 
m o n ke ys. T h e c yt o ki ne release assa ys were als o e val uate d usi n g fres h h u m a n w h ole bl o o d cells. 
T he pi v otal st u dies were c o n d ucte d f oll o wi n g G o o d La b orat or y Practice ( G L P) re g ulati o ns. T he 
si n gle d osi n g re gi me ns w ere s pa n ne d fr o m t he i nte n de d h u ma n d oses t o 1 0-f ol d hi g her t ha n t he 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
ma xi m u m of t he i nte n de d h u ma n d oses, a n d t he re peat d osi n g re gi me ns s p a n ne d t o 3-f ol d hi g her 
t ha n t he ma xi m u m of t he i nte n de d h u ma n d oses. C y n o m ol g us m o n ke y was t he o nl y rele va nt 
s pecies base d o n t he tar get se q ue nce h o m ol o g y a n d bi n di n g acti vit y.  
N o a p pare nt t o xicit y w as n ote d i n b ot h mice a n d m o n ke ys f oll o wi n g a si n gle d ose u p t o 1 0 0 
m g/ k g a n d i n m o n ke ys f oll o wi n g a r e peat d os e u p t o 3 0 m g/ k g bi w ee kl y f or 1 3 wee ks. T he 
t o xic o ki netics ( T K) pr ofile was c haracterize d i n m o n ke y st u dies a n d t he s yste mic e x p os ure 
a p peare d t o be d ose pr o p orti o nal wit h o ut ge n der differe n ce or acc u m ulati o n o ver t he d osi n g 
peri o d. N o a p p are nt i m m u n ot o xicit y was o bser ve d as n o a p pare nt c ha n ges i n cli nical pat h ol o g y 
or hist o pat h ol o g y were n ote d i n t hese st u dies. 
 
 
 
 
 
 
  
T he tiss ue cr oss reacti vit y of tisleliz u ma b was e val uate d i n n or mal h u ma n a n d c y n o m ol g us 
m o n ke y fr oze n tiss ues usi n g  t he i m m u n o hist oc he mistr y (I H C) m et h o d, wit h a p pr o priate p ositi ve 
a n d ne gati ve c o ntr ols. U n der t he st u d y c o n diti o n s, n o s pecific tiss ue cr oss reacti vit y wit h 
tisleliz u ma b was n ote d i n b ot h h u ma n a n d c y n o m ol g us m o n ke y tiss ues. Neit her he m ol ytic 
effects i n d uce d b y tisleliz u ma b i n t he ra b bit bl o o d cells n or i ncre m e nt of c yt o ki ne releas e fr o m 
h u ma n w h ole bl o o d cells after treat me nt wit h tisleliz u ma b were o bser ve d i n i n vitr o e val uati o ns.  
O verall, n o a p p are nt t o xicit y w as n ote d i n mice a n d m o n ke y t o xicit y st u dies.  N o tiss ue cr oss 
reacti vit y was f o u n d i n b ot h h u ma n a n d m o n ke y tiss ues, n or effect o n c yt o ki ne releas e was 
o bser ve d i n h u ma n w h ol e bl o o d assa y s. T o xic o ki netics pr ofile was well c h aract erize d wit h d ose 
pr o p orti o nall y i ncreas es i n s yste mic e x p os ure wit h o ut a p pare nt acc u m ulati o n or se x differe nce.  
I m m u n o ge nicit y w as o bser ve d wit h o ut a p pare nt i m m u n ot o xicit y a n d effect o n t he s yste mic 
e x p os ure.  T he N o O bser ve d A d vers e Effect Le v el ( N O A E L) of tisleliz u ma b i n  t he 1 3 -wee k 
m o n ke y t o xicit y st u d y w as c o nsi dere d t o b e  3 0 m g/ k g. T he s afet y pr ofile of tisleliz u ma b is 
c o nsi dere d a de q uat e t o s u p p ort first -i n-h u ma n ( FI H) d ose safel y a n d et hicall y.   
Refer t o t he I n v esti gat or’s Br oc h ure (I B) f or m or e detaile d i nf or mati o n o n t he bac k gr o u n d of 
tisleliz u ma b. 
1. 3. 2.  
Cli nic al D at a of Tisleliz u m a b  
St u d y B G B -A 3 1 7 _ 0 0 1 is a t w o -sta ge st u d y c o nsisti n g of a P has e 1a d ose escalati o n a n d d ose-
fi n di n g c o m p o ne nt t o est a blis h t he ma xi m u m t olerate d d ose ( M T D), if a n y, a n d rec o m me n d e d 
p hase 2 d ose(s) ( R P 2 D) (s), f oll o we d b y a P hase 1 b c o m p o ne nt t o i n vesti gate efficac y i n select 
t u m or t y pes. 
T he P hase 1a, Part 1 c o m p o ne nt is a m ulti ple -d ose, d ose escal ati o n, first -i n-h u ma n st u d y.  T he 
P hase 1a, Part 2 c o m p o n e nt e val uates t he s afet y a n d P K of t w o d osi n g sc h e d ules o nce e ver y 2 
wee ks ( Q 2 W) vers us o nce e ver y t hree wee ks ( Q 3 W) at selecte d d oses.  T h e P hase 1a, Part 3 
c o m p o ne nt e val uat es t he safet y a n d P K of tisleliz u ma b at flat d oses.  T he pri mar y o bjecti ve of 
P hase 1a is t o assess t he safet y a n d t olera bilit y of tisleliz u ma b i n s u bjects wit h a d va nce d t u m or s. 
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
T he P hase 1 b sta ge is a m ultice nter, o pe n -la bel, m ulti ple-ar m, i n dicati o n e x pa nsi o n st u d y.  T h e 
pri mar y o bjecti ve of P hase 1 b is t o assess t he a nti -t u m or acti vit y of tisleliz u ma b i n select t u m or 
t y pes. 
1. 3. 2. 1.  
S afet y  
1. 3. 2. 1. 1.  S afet y S u m m a r y of St u d y B G B -A 3 1 7 _ 0 0 1 P h ase 1 a  
I n St u d y B G B-A 3 1 7 _ 0 0 1 P hase 1a, Part 1, t he m a xi m u m a d mi nistere d d ose was 1 0 m g/ k g Q 2 W.  
T he ma xi m u m t olerate d d ose was n ot i de ntifie d.  O nl y o ne d os e -li miti n g t o xicit y ( D L T) of 
Gra de 3 c olitis occ urre d wit h 5 m g/ k g Q 2 W. Base d o n t he res ults of 1 0 3 pts i n t he d ose escalati o n 
a n d d ose e x pa nsi o n part of t he P hase 1 A st u d y, 5 m g/ k g Q 3 W was selecte d t o e x pl ore 
tisleliz u ma b acti vit y i n t he P hase 1 B. 
As of 1 3 J a n uar y 2 0 1 7, treat me nt -e mer ge nt A Es ( T E A Es) assess e d as relat e d t o tisleliz u ma b b y 
t he I n v esti gat or occ urre d i n 7 2 % of s u bjects acr oss all parts of P hase 1a.  T he m ost fre q ue ntl y 
occ urri n g e ve nts assess e d as relate d t o tisleliz u ma b i ncl u de d fati g ue ( 2 2 %), diarr h oea ( 1 4 %), 
pr urit us ( 1 3 %), ras h ( 1 3 %), a n d na us ea ( 1 0 %).  T here was n o a p pare nt c orrelati o n bet wee n d ose s 
( 2 m g/ k g, 5 m g/ k g, or 1 0 m g/ k g) a n d i nci d e nce or se verit y of T E A Es, assesse d as relat e d t o 
tisleliz u ma b. Ele ve n of t he 1 1 1 t otal s u bjects ( 1 0 %) ha d T E A Es assesse d as relate d t o 
tisleliz u ma b t hat were ≥ Gra de 3 i n se v erit y. T hes e i ncl u de d 2 e v e nts e ac h of fati g ue, dia betic 
ket oaci d osis, a n d h y p ote nsi o n.  Ta ble  1  s h o ws t he m ost fre q ue ntl y o cc urri n g T E A Es o cc urri n g i n 
≥ 5 % of s u bjects ( 6 or m ore s u bjects) assesse d as relate d t o tisleliz u ma b b y t he I n v esti gat or i n 
St u d y B G B -A 3 1 7 _ 0 0 1 P hase 1 b . 
1. 3. 2. 1. 2.  S afet y S u m m a r y of St u d y B G B -A 3 1 7 _ 0 0 1 P h ase 1 b  
Treat me nt -e mer ge nt A Es assesse d as r elate d t o tisleliz u ma b b y t he I n vesti gat or occ urr e d i n 
4 1. 8 % of s u bjects i n P hase 1 b.  T he m ost fre q u e ntl y occ urri n g e v e nts assesse d as relat e d t o 
tisleliz u ma b i ncl u de d fati g ue ( 9 %), ras h ( 5 %), na usea ( 5 %), a n d diarr h oea ( 5 %).  Te n of t h e t otal 
1 8 9 s u bjects ( 5 %) ha d T E A Es assesse d as relat e d t o tisleliz u ma b t hat were ≥ Gra de 3 i n se v erit y.  
T hese i ncl u de d 2 e ve nts eac h of p n e u m o nitis, diarr h oea, a n d c olitis.  All ot her T E A Es ass esse d 
as relate d t o tisleliz u ma b occ urre d i n si n gle s u bj ects.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
T a ble  1 : 
Tre at me nt -e mer g e nt A d verse E ve nts Assesse d as Rel ate d t o Tisleliz u m a b 
Occ urri n g i n ≥ 5 % of P atie nts a n d C orres p o n di n g Rel ate d ≥ Gr a de 3 
I nci de nce i n St u d y B G B-A 3 1 7 _ 0 0 1 - P h ase 1 b ( as of 1 3 J a n u ar y 2 0 1 7, N = 1 8 9)  
 
O ver all I nci de nce ( All 
Gr a des)  
≥ Gr a de 3  
S yste m Or g a n Cl ass  
   Preferre d Ter m  
N = 1 8 9  
n ( %)  
N = 1 8 9  
n ( %)  
Patie nts wit h at least o ne relate d T E A E  
7 9 ( 4 1. 8)  
1 0 ( 5. 3)  
S ki n a n d s u bc ut a ne o us tiss ue dis or ders  
 
 
   Ras h  
1 0 ( 5. 3)  
0 ( 0. 0)  
G astr oi ntesti n al dis or ders  
 
 
   Na usea  
1 0 ( 5. 3)  
1 ( 0. 5)  
   Diarr h oea  
9 ( 4. 8)  
2 ( 1. 1) 
Ge ner al dis or ders a n d a d mi nistr ati o n site 
c o n diti o ns 
 
 
   Fati g ue  
1 7 ( 9. 0)  
1 ( 0. 5)  
Data as of 1 3 J a n uar y 2 0 1 7; T E A E w hic h starts o n or after d osi n g date, or w orse ns i n se verit y d uri n g treat me nt 
relati ve t o t he pretreat me nt state, w he n t he A E is c o nti n u o us. All A Es are c o de d usi n g Me d D R A versi o n 1 7. 0 or 
later a n d gra de d acc or di n g t o N CI-C T C A E v 4. 0 3. A patie nt wit h m ulti ple occ urre nces of a n A E is c o u nte d o nl y 
o nce i n t he A E cate g or y. F or t he p ur p ose of t his re p orti n g, A E occ urri n g at least 9 of 1 8 9 patie nts ( n u mericall y, 
4. 8 %) is c o nsi dere d ≥5 %.  
A E = a d verse e ve nt; Me d D R A = Me dical Dicti o n ar y f or Re g ulat or y Acti vities; N = t otal patie nts treate d;  
n = n u m ber of patie nts wit hi n eac h cate g or y; 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; T E A E = treat me nt -e mer ge nt a d verse e ve nt.  
1. 3. 2. 2.  
P h ar m a c o ki netics  
I n t he FI H st u d y B G B-A 3 1 7 _ 0 0 1, preli mi nar y P K a nal ysis ( wit h a c ut -off date of 1 8 A pril 2 0 1 7 ) 
was c o n d ucte d b y n o n -c o m part me ntal a nal ysis met h o ds, usi n g ser u m c o n ce ntrati o ns fr o m 
patie nts w h o recei ve d d oses of 0. 5, 2. 0, 5. 0 a n d 1 0 m g/ k g Q 2 W a n d patie nts w h o recei v e d d oses 
of 2. 0 a n d 5. 0 m g/ k g Q 3 W ( P hase 1a Part 1 a n d P art 2).  T he C ma x a n d t he dr u g e x p os ure (t he 
area u n d er t he c o nce ntrati o n -ti me c ur ve [ A U C]) i ncreas e d i n a nearl y d ose-pr o p orti o nal ma n ner 
fr o m 0. 5 m g/ k g t o 1 0 m g/ k g, b ot h after si n gl e-d os e a d mi nistrati o n a n d at stea d y  state.  
Preli mi nar y p o p ulati o n P K a nal yses ( wit h a c ut -off date of 0 8 Oct o ber 2 0 1 6) were c o n d uct e d 
usi n g 6 4 2 ser u m sa m ples fr o m 6 9 patie nts w h o recei ve d d oses of 0. 5, 2, 5 a n d 1 0 m g/ k g Q 2 W 
a n d 2 a n d 5  m g/ k g Q 3 W. P K fr o m tisleliz u ma b is li near a n d was c har act eri ze d wit h a 2 -
c o m part me nt m o del wit h first or der eli mi nati o n.  S yste mic cleara n ce of tisleliz u ma b was 
0. 0 0 7 9 4 L/ h, v ol u me of distri b uti o n i n t he ce ntral a n d peri p heral c o m part me nt were 2. 7 5 a n d 
1. 6 5 L, res pecti vel y, a n d t he ter mi nal eli mi nati o n half -life was a p pr o xi matel y 1 7 d a ys.  Patie nts’ 
b o d y w ei g ht is n ot a si g nifica nt c o variate o n t he cl eara n ce of tisleliz u ma b (Fi g ure  1 ), w hic h 
s u p p orts flat-d osi n g.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Fi g ure  1 : 
Cle ar a nce vs B o d y Wei g ht  
 
1. 3. 2. 3.  
A nti -t u m o r Acti vit y 
As of 1 3 J a n uar y 2 0 1 7, 1 1 1 s u bjects ha d recei ve d tisleliz u ma b treat me nt i n P ha se 1a of St u d y 
B G B -A 3 1 7 _ 0 0 1. F or t he 2 2 s u bjects treate d i n P hase 1a, Part 1, t he mea n tr eat me nt d urati o n was 
1 0 9. 2 da ys (ra n ge: 1 t o 3 6 5). D urati o n of tr eat me nt was l o n ger f or t h e 8 1 s u bjects treate d i n 
P hase 1a, Part 2; mea n 1 4 2. 4 da ys i n t he 2 m g/ k g Q 2 W  a n d mea n 1 9 1. 9 da ys i n t he 5 m g/ k g 
Q 3 W ( o verall ra n ge: 1 t o 4 7 1). F or t he 8 s u bj ects treate d i n P hase 1 a, Part 3, t he mea n treat me nt 
d urati o n was 5 4. 1 da ys (ra n ge: 3 2 t o 6 7).  
F or s u bjects i n P hase 1 a, Part 1 ( n = 2 2), t here was 1 s u bject wit h a cli nical r e s p o nse (c o nfir me d 
P R) i n t he 2 m g/ k g d os e gr o u p ( 5 %). F or s u bjects i n P hase 1a, Part 2 ( n = 8 1), t here was 1 s u bject 
( 1 %) wit h a C R i n t he 2 m g/ k g Q 2 W d ose gr o u p a n d 1 5 s u bjects ( 1 9 %) wit h c o nfir me d P R 
( o verall cli nical res p o nse rate: 1 5 % [ 9 5 % c o nfi de nce i nter val [ CI]: 5. 7 1 %, 2 9. 8 4 %] f or t he Q 2 W 
re gi me n; a n d 2 4 % [ 9 5 % CI: 1 2. 3 6 %, 4 0. 3 0 %] f or t he Q 3 W re gi me n).  
T here w ere 1 5 5 e val ua bl e s u bjects a n d 6 s u bjects wit h a c o nfir me d cli nical res p o nse of P R ( 4 % 
[ 9 5 % CI: 1. 4 3 %, 8. 2 3 %]) i n P hase 1 b. 
1. 3. 3.  
St u d y R ati o n ale  
T he st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, G o o d Cli nical Practice ( G C P) 
g ui deli nes, T h e Declarati o n of Helsi n ki a n d a n y a p plica ble re g ulat or y re q uire me nts.  
Wit h t he detecti o n of P D -L 1 o v er -e x pressi o n i n H L cells w hic h ma y i m part  a ge neticall y 
deter mi ne d v ul nera bilit y of t he l y m p h o ma cells t o P D -1 bl oc ka de ( A nsell et al, 2 0 1 5 ), c o u ple d 
wit h t he data of ni v ol u ma b i n patie nts wit h rela ps e d or refract or y H L as descri be d i n Secti o n  1. 2 , 
t he effic ac y a n d safet y of tisleliz u ma b i n s u bjects wit h rela pse d or refract or y c H L will be 
i n vesti gate d.  Rati o nale f or t his st u d y is f urt her  s u p p orte d b y i n viv o t u m or gr o wt h i n hi biti o n 
st u dies w hic h de m o nstrat e d tisleliz u ma b has si g nifica ntl y hi g her a nti-t u m or acti vities t ha n 
ni v ol u ma b or pe m br oliz u ma b i n m o use m o dels carr yi n g all o ge ni c h u ma n ca ncer cells a n d 
P B M Cs ( Bei G e ne i nter nal data).  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
T he safet y of tisleliz u ma b has bee n teste d acr oss a ra n ge of d oses i n St u d y B G B -
A 3 1 7 _ St u d y _ 0 0 1 (0. 5 m g/ k g t o 1 0 m g/ k g Q 2 W [ N = 6 2]; 2 m g/ k g t o 5 m g/ k g Q 3 W  [N = 4 1]) wit h 
n o M T D defi ne d at t he hi g hest d ose e x a mi ne d .  Base d o n rec o m me n d ati o n of t he Safet y 
M o nit or i n g C o m mittee ( S M C), tisleliz u ma b at 5 m g/ k g Q 3 W was selecte d as t he d ose f or t h e 
i n dicati o n e x pa nsi o n part of St u d y B G B -A 3 1 7 _ St u d y _ 0 0 1 ( P has e 1 B).  Efficac y has als o bee n 
de m o nstrate d i n 1 5 of 9 9  e val ua ble s u bjects t o date w h o ha d bee n dia g n ose d wit h a va riet y of 
t u m or t y pes a n d were treate d wit h si n gle a ge nt tisleliz u ma b at d oses t hat ra n ge d fr o m 2 m g/ k g t o 
5 m g/ k g a d mi nistere d eit her Q 2 W or Q 3 W.  Bas e d o n t he preli mi nar y efficac y d ata, n o cl ear d ose 
de pe n de n ce i n efficac y w as o bser ve d a m o n g t he differe nt e x pa nsi o n c o h orts, i ncl u di n g 2 m g/ k g 
or 5 m g/ k g, at eit her Q 2 W or Q 3 W re gi me n.  I n li g ht of t hese preli mi nar y safet y a n d efficac y 
res ults f or m o n ot hera p y tisleliz u ma b, c o u ple d wit h t he fi n di n g t hat patie nts’ b o d y wei g ht is n ot a 
si g nifica nt c o variat e o n t he cleara nce of tisleliz u ma b ( Fi g ure  1 ), a fi x e d d ose of tisleliz u ma b at 
2 0 0 m g Q 3 W will be e x pl ore d i n t his st u d y.   
1. 3. 4.  
R ati o n ale f or Tisleliz u m a b D os a ge  
T he fi x e d d ose of 2 0 0 m g w as select e d o n t he basis of b ot h n o ncli nical st u dies a n d a vaila ble 
cli nical data as d escri be d bel o w.  
N o tiss ue cr oss reacti vit y was f o u n d i n b ot h h u ma n a n d m o n ke y tiss ues, n or effect o n c yt o ki ne 
releas e was obser ve d i n h u ma n w h ole bl o o d assa y. N o a p pare nt t o xicit y was n ote d i n b ot h mice 
a n d m o n ke ys f oll o wi n g a si n gle d ose u p t o 1 0 0 m g/ k g a n d i n m o n ke ys f oll o wi n g a re peat d ose 
u p t o 3 0 m g/ k g bi w ee kl y f or 1 3 wee ks. T he t o xic o ki netics ( T K) pr ofile was c haracteriz e d i n 
m o n ke y st u dies a n d t h e s yste mic e x p os ure a p p eare d t o be d ose pr o p orti o nal wit h o ut ge n der 
differe n ce or acc u m ulati o n o ver t he d osi n g peri o d. N o a p pare nt i m m u n ot o xicit y was o bs er ve d as 
n o a p pare nt c ha n ges i n cli nical pat h ol o g y or hist o pat h ol o g y were n o te d i n t hese st u dies.  
Acc or di n g t o t he P hase 1 A P K data i n A ustralia, s er u m c o nce ntrati o ns of tisleliz u ma b s h o we d 
li near rel ati o ns hi ps wit h d oses fr o m 0. 5 m g/ k g Q 2 W t o 1 0 m g/ k g Q 2 W. F urt her m ore, acc or di n g 
t o t he res ults of p o p ulati o n P K a nal ysis, t here was n o si g nifica nt c orrelati o n bet wee n t he wei g ht 
of s u bjects a n d t he i n viv o cleara nce rate of tisleliz u ma b. T his c o ncl usi o n s u p p orts t he h y p ot hesis 
of fi x e d d ose a d mi nistrati o n.  A 2 0 0 m g fi x e d -d os e ( b o d y  wei g ht a dj uste d d ose bet wee n 3 m g/ k g 
a n d 4 m g/ k g) a d mi nistere d e ver y 3 wee ks was e x pecte d t o res ult i n ser u m e x p os ure t hat fall 
bet wee n e x p os ures ass ociate d bet wee n 2 m g/ k g a n d 5 m g/ k g d oses.  
Rates of treat me nt -e mer ge nt, treat me nt -relate d A Es as well as treat me nt-rel ate d seri o us a d v erse 
e ve nts (S A Es ) o bser v e d i n patie nts ta ki n g 2 m g/ k g a n d 5 m g/ k g were c o m para ble s u g gesti n g n o 
clear d os e de pe n d e nce acr oss t hese d oses. C o nse q ue ntl y, patie nts r ecei vi n g 2 0 0 m g Q 3 W fi x e d 
d ose are e x pecte d t o ha v e si milar A E pr ofiles t o t h ose w h o treat e d wit h 2 m g/ k g a n d 5 m g/ k g 
Q 3 W re gi me n.  
C o nfir me d o verall res p o nse rates i n patie nts treat e d wit h 2 m g/ k g a n d 5 m g/ k g Q 2 W ra n ge d 
bet wee n 5 a n d 1 4 %, w h ereas t he y w ere b et wee n 1 7 t o 3 7 % f or pate nts d ose d 2 m g/ k g a n d 5 
m g/ k g Q 3 W. T heref ore, cli nical acti vit y of tisleliz u ma b is e x pecte d t o be mai ntai ne d i n patie nts 
recei vi n g 2 0 0 m g Q 3 W.  
I n s u m mar y, 2 0 0 m g Q 3 W was selecte d as t he rec o m me n de d d ose f or pi v otal st u dies base d o n 
t he t otalit y of e vi de n ce a vaila ble, i ncl u di n g cli nical P K, safet y, a n d efficac y 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
All a vaila ble P K, safet y, a n d eff i cac y d ata f or tisleliz u ma b will c o nti n ue t o be e val uat e d as 
descri be d a b o ve t o s u p p ort t he pr o p ose d 2 0 0 m g fi x e d d ose.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
2.  
O B J E C TI V E S  
2. 1.  
Pri m ar y O bjecti ve  
T o e val uate t he effi cac y of tisleliz u ma b , assesse d b y I n d e pe n de nt Re vie w C o m mittee (I R C), i n 
s u bjects wit h ce ntrall y c o nfir me d rela ps e d or refract or y c H L, as meas ure d b y O R R per t h e 
L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ) (A p pe n di x  6 ). 
2. 2.  
Sec o n d ar y O bjecti ves  
T o e val uate tisleliz u ma b wit h res pect t o:  
•  Pr o gressi o n -free S ur vi val ( P F S) assesse d b y I R C per t he L u ga n o Classificati o n 
(C hes o n et al, 2 0 1 4 ) (A p pe n di x  6 ) 
•  D urati o n of Res p o nse ( D O R) assesse d b y I R C per t he L u ga n o Classificati o n  
(C hes o n et al, 2 0 1 4 ) (A p pe n di x  6 ) 
•  Rate of C R assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ) 
(A p pe n di x  6 ) 
•  Ti me t o Res p o nse assess e d b y I R C p er t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ) 
(A p pe n di x  6 ) 
•  Safet y a n d t olera bilit y  
2. 3.  
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  3 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
3.  
S T U D Y E N D P OI N T S  
3. 1.  
Pri m ar y E n d p oi nt  
•  O R R  is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve s a best res p o ns e of C R or 
P R, assesse d b y I R C per t he L u ga n o Classificati o n  
(C hes o n et al, 2 0 1 4 ). 
3. 2.  
Sec o n d ar y E n d p oi nts  
•  P F S is defi ne d as t he ti me fr o m t he first d ose of tisle liz u ma b t o t he date of P D or 
deat h, w hic he v er occ urs first, assesse d b y I R C per t he L u ga n o Classificati o n (C hes o n 
et al, 2 0 1 4). 
•  D O R  is defi ne d as t he ti me fr o m t he date t h at res p o nse criteria are first met t o t he 
date t hat P D  is o bjecti vel y d oc u m e nte d or deat h, w hic he ver occ urs first, assesse d b y 
I R C per t h e L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
•  Rate of C R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ve a best r es p o nse of 
C R, assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
•  T T R is defi ne d as t he ti me fr o m t he dat e of t he first d ose of tisleliz u ma b t o t he ti me 
t he res p o nse criteria are first met, assesse d b y I R C per t he L u ga n o Classificat i o n 
(C hes o n et al, 2 0 1 4 ). 
•  T o e val uate t he s afet y a n d t olera bilit y of tisleliz u ma b, as defi ne d b y:  
− T he i nci de nce a n d se v erit y of a d v erse e ve nts a cc or di n g t o N CI -C T C A E v 4. 0 3  
− C ha n ges i n vital si g ns, p h ysical fi n di n gs, a n d cli nical la b orat or y res ults  
3. 3.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
4.  
S T U D Y D E SI G N  
T his is a n o pe n -la bel, m ulti-ce nter, si n gle -ar m P hase 2 st u d y t o e val uate tisleliz u ma b t hera p y i n 
a d ult s u bjects wit h rela ps e d or refract or y c H L. S u bjects m ust ha ve eit her faile d t o ac hie ve a 
res p o nse or pr o gresse d after a ut o-S C T, or are n ot ca n di dates f or a ut o -S C T sec o n dar y t o c he m o -
resista nt disease, a d v a nce d a ge ( ≥ 6 5 years), or c o-e xisti n g me dical c o n d iti o ns a n d ha ve recei ve d 
at least t w o pri or s yste mic c he m ot hera p y re gi me ns f or c H L.   
A p pr o xi matel y 6 8 s u bj ects will be e nr olle d o nt o st u d y t o recei ve tisleliz u ma b at a d ose of 2 0 0 
m g I V Q 3 W.  St u d y tr eat me nt will c o nti n ue u ntil P D, u nacce pt a ble t o xicit y, deat h, or st u d y 
wit h dra wal f or ot her reas o ns.  St u d y d esi g n is d e picte d i n Fi g ure  2 . 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Fi g ure  2 : 
St u d y Desi g n  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A b bre viati o ns : C R, c o m plete r es p o nse; C T, c o m p ute d t o m o gra p h y; E O S, e n d of st u d y; E O T, e n d of treat me nt; I V, 
i ntra ve n o us; P D, pr o gressi ve  disease; P E T, p ositr o n e missi o n t o m o gra p h y; Q 3 W, o nce e ver y 3 wee ks.  
 
C T assess me nt perf or me d at Scree ni n g, Wee ks 1 2, 1 8, 3 0, 4 2 i n t he first year, a n d 
e ver y 1 5 w ee ks fr o m Wee k 5 3.  P E T/ C T assess me nt at Scree ni n g, Wee k 1 2, 
Wee k  2 4, Wee k 4 2, Wee k 5 7, a n d e ver y 3 0 wee ks t hereafter.  P E T/ C T s h o ul d als o 
be perf or me d at P D s us p ecte d cli nicall y or b y C T, a n d  C R s us pecte d cli nicall y or 
b y C T  
Tre at me nt   
Tisleliz u ma b 2 0 0 m g I V Q 3 W  
Disc o nti n ue  d ue t o P D  
F oll o w -u p Visit ( 3 0 d a ys after E O T) ; 
S ur vi val f oll o w -u p e ver y 3 m o nt hs  
Scree ni n g  ( Da y-2 8 t o Da y -1)  
F oll o w -u p  Visit ( 3 0 da ys after E O T);  
C o nti n ue t u m or assess me nt u ntil P D, 
ne w a nti-ca n cer t hera p y, wit h dra wal of 
c o nse nt, deat h, l ost t o f oll o w -u p, or 
E O S, w hic he ver occ urs first ; 
S ur vi val f oll o w -u p e ver y 3 m o nt hs  
Disc o nti n ue  
d ue t o reas o n ot her t ha n P D  
E n d of Treat me nt ( E O T)  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
5.  
S T U D Y P O P U L A TI O N  
5. 1.  
I ncl usi o n Criteri a 
S u bjects ma y be e nr olle d o n st u d y o nl y if t he y meet all t he f oll o wi n g criteri a:  
1.  ≥ 1 8 years of a ge at ti me of i nf or me d c o ns e nt.  
2.  Hist ol o gicall y c o nfir m e d rela pse d or refract or y c H L ( bi o ps y fr o m dia g n osis or at a n y 
rela pse is a cce pt a ble).  
3.  S u bject m ust ha ve rela ps e d ( disease pr o gressi o n after m ost rece nt t hera p y) or refract or y 
(fail ure t o a c hie ve C R/ C M R or P R t o m ost rece nt t hera p y) c H L a n d meets eit her o ne of 
t he f oll o wi n g criteria: 
a. Has faile d t o a c hie ve a res p o nse or pr o gresse d aft er a ut o -S C T.  
b.  Has recei ve d at least t w o pri o r s yste mic c he m ot hera p y re gi me ns f or c H L a n d is n ot 
a n a ut o -S C T ca n di date d ue t o: c he m o -resista nt disease ( u na ble t o ac hi e ve C R or P R 
t o sal va ge c he m ot hera p y), a d va nce d a ge ( ≥ 6 5 years of a ge), fail ure t o c oll ect ste m 
cells or u na ble t o perf or m ste m cell c ollecti o n as assesse d b y t he I n v esti gat or, or a n y 
si g nifica nt c o-e xisti n g me dical c o n diti o ns.  
4.  S u bject m ust ha ve meas ura ble diseas e defi n e d as ≥ 1 n o dal lesi o n t hat is > 1. 5 c m i n t he 
l o n gest dia meter, or ≥ 1 e xtra-n o dal lesi o n (e. g. he patic n o d ules) t hat i s > 1 c m i n t he 
l o n gest dia meter. 
5.  A vaila bilit y of arc hi val or fres h t u m or tiss ue sa m ple fr o m a n e v al ua ble c ore or e x cisi o nal 
bi o ps y  ( 1 0-1 5 u nstai n e d f or mali n -fi x e d paraffi n e m be d de d [ F F P E] sli des).  Ot her wise, 
s u bjects ma y b e per mitte d t o e nr oll o n a cas e-b y -case basis aft er disc ussi o n wit h t he 
S p o ns or’s me dical m o nit ors, pr o vi de d c H L di a g n osis ca n be c o nfir me d b y a ce ntr al 
la b orat or y. 
6.  E C O G perf or ma nce stat us of 0 or 1.  
7.  Lif e e x pecta nc y ≥ 1 2 w ee ks.  
8.  S u bject m ust ha ve a de q u ate or ga n f u ncti o ns as i n dicate d b y t he f oll o wi n g la b orat or y 
val ues:  
a. A bs ol ute ne utr o p hil c o u nt ( A N C) ≥ 1. 5 x 1 0 9/ L, i n de pe n de nt of gr o wt h fact or s u p p ort 
wit hi n 7 da ys of first d ose.  
b.  Platelet ≥ 7 5 x 1 0 9/ L, i n d e pe n de nt of gr o wt h fact or s u p p ort wit hi n 7 da ys of first 
d ose.  
c. H g b ≥ 8 g/ d L or ≥ 5 m m ol/ L.  
d.  Ser u m creati ni ne ≤ 1. 5  x  u p per li mit of n or mal ( U L N).  
e. A S T ( S G O T) a n d A L T ( S G P T) ≤ 2. 5  x  U L N, or ≤ 5  x  U L N if li ver metast ases are 
prese nt.  
f. Ser u m t otal b ilir u bi n ≤ 1. 5 x  U L N (t otal bilir u bi n le vel < 4  x  U L N f or s u bjects wit h 
Gi l bert’s s y n dr o me). 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
9.  I nter nati o nal n or malize d rati o (I N R) ≤ 1. 5 x U L N a n d a P T T ≤ 1. 5 x U L N, u nless patie nt 
is recei vi n g a ntic o a g ula nt t hera p y a n d c o a g ulati o n para meters ( P T/I N R a n d  a P T T,) are 
wit hi n  i nte n de d t hera pe utic ra n ge of i nte n de d use of t he a ntic oa g u la nt at ti me of 
Scree ni n g.  Patie nts wit h fact or i n hi bit ors pr ol o n gi n g P T or I N R ma y b e i ncl u de d after 
disc ussi o n wit h t he me dical m o nit or.   
1 0.  S u bject m ust ha ve n o e vi de nce of d ys p n ea at rest a n d a p ulse o xi metr y of > 9 2 % w hile 
breat hi n g r o o m air.  
1 1.  S u bject m ust ha ve F E V 1/ F V C > 6 0 % b y P F T; D L C O, F E V 1 a n d F V C all > 5 0 % 
pre dicte d val u e; all P F Ts m ust be o btai ne d wit hi n 4 wee ks pri or t o t he first d ose of 
tisleliz u ma b. 
1 2.  Fe male s u bject is eli gi ble t o e nter a n d partici pate i n t he st u d y if s he is of:  
a. N o n -c hil d beari n g p ot e ntial (i.e. p h ysi ol o gicall y i n ca pa ble of bec o mi n g pre g na nt) 
i ncl u di n g a n y fe male w h o: 
i. 
Has ha d a h ysterect o m y.  
ii. 
Has ha d a bilateral o o p h orect o m y ( o variect o m y).  
iii. 
Has ha d a bilateral t u bal li gati o n.  
i v. 
Is p ost-me n o p a usal (t otal cessati o n of me nses f or ≥ 1 year).  
b.  Fe males of c hil d beari n g p ote ntial m ust be willi n g t o use a hi g hl y effecti ve met h o d of 
birt h c o ntr ol f or t he d urati o n of t he st u d y, a n d f or at least 1 2 0 da ys aft er t he last d ose 
of tisleliz u ma b, a n d ha ve a ne gati ve uri n e or ser u m pre g n a nc y test wit hi n 7 da ys of 
t he first d ose of st u d y dr u g. A de q uate c o ntrace pti o n, w he n use d c o nsiste ntl y a n d i n 
acc or da nce wit h b ot h t he pr o d uct la bel a n d i nstr ucti o ns of t he p h ysicia n, are defi ne d 
as: 
i. 
Vasect o miz e d part ner w h o is sterile pri or t o t he fe male s u bject’s st u d y 
e ntr y a n d is t he s ole se x ual part ner f or t hat fe male.  
ii. 
A n y i ntra uteri ne de vice wit h a d oc u me nte d fail ure rate of < 1 % p er year.  
iii. 
D o u ble barri er c o ntr ace pti o n defi ne d as c o n d o m wit h s per mici dal jell y, 
f oa m, s u p p osit or y, or fil m; O R dia p hra g m wit h s per mici de; O R male 
c o n d o m a n d dia p hra g m.  
1 3.  N o n -sterile males m ust b e willi n g t o use a hi g hl y effecti ve met h o d of birt h c o ntr ol f or t he 
d urati o n of t he st u d y a n d f or at least 1 2 0 da ys after t he last d ose of tisleliz u ma b.  
1 4.  Pri or c he m ot hera p y, ra di ot hera p y, i m m u n ot hera p y  or i n vesti gati o nal t hera p y (i ncl u di n g 
C hi nese her bal me dici n e a n d C hi nese pate nt me di ci ne ) use d t o c o ntr ol ca n cer i ncl u di n g 
l oc ore gi o nal treat me nt m ust ha ve bee n c o m plete d ≥ 4 wee ks bef ore t he first d ose of 
tisleliz u ma b, a n d all treat me nt-relate d a d verse e ve nts are sta ble a n d h a ve eit her ret ur n e d 
t o baseli ne or Gra de 0/ 1 ( e x ce pt f or al o pecia a n d h e m o gl o bi n). F or he m o gl o bi n, please 
f oll o w i ncl usi o n criteria # 8c ( he m o gl o bi n). 
1 5.  S u bject has v ol u ntaril y a gree d t o partici pate b y gi vi n g w ritte n i nf or m e d c o nse nt. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
5. 2.  
E xcl usi o n Criteri a  
S u bjects will n ot be e nr olle d o n st u d y if t he y meet a n y of t he f oll o wi n g criteria:  
1.  N o d ular l y m p h o c yt e -pre d o mi na nt H o d g ki n l y m p h o ma or gra y z o ne l y m p h o ma.  
2.  Pri or all o ge n eic he m at o p oietic ste m cell tra ns pla nt.  
3.  Hist o r y of s e vere h y pers e nsiti vit y reacti o n t o m o n ocl o nal a nti b o dies. 
4.  Ne w Y or k Heart Ass ociati o n ( N Y H A) C lass III or I V heart fail ure, u nsta bl e a n gi na, 
se vere u n c o ntr olle d ve ntric ular arr h yt h mia, electr o car di o gra p hic e vi de nce of ac ute 
isc he mia, or m y ocar dial i nfarcti o n wit hi n 6 m o nt hs of first da y of Scree ni n g. 
5.  Pri or mali g na n c y wit hi n t he past 3 years e x ce pt f or c urati vel y tr eate d basal or s q ua m o us 
cell s ki n ca ncer, s u perfici al bla d der ca ncer, or carci n o ma i n sit u of t he cer vi x or breast.  
6.  Pri or t hera p y tar geti n g  P D -1 or P D -L 1.  
7.  S u bject wit h acti ve a ut oi m m u ne disease or hist or y of a ut oi m m u ne disease wit h hi g h ris k 
of rec urre n ce i ncl u di n g b ut n ot li mite d t o hist or y of i m m u ne -relate d n e ur ol o gic disease, 
m ulti ple scler osis, a ut oi m m u ne ( de m yeli nati n g) ne ur o pat h y, G uill ai n-Barrè s y n dr o me, 
m yast he nia gra vis, s yste mic l u p us er yt h e mat os us ( S L E), c o n necti ve tiss ue disease, 
scler o der m a, i nfla m mat or y b o wel diseas e i ncl u di n g Cr o h n’s disease a n d ul cerati ve 
c olitis, a ut oi m m u ne he patitis, t o xic e pi der mal necr ol ysis ( T E N), or Ste ve ns -J o h ns o n 
s y n dr o me. 
N ote: S u bject is per mitte d t o e nr oll if he/s he has vitili g o, ecze ma, t y p e I dia betes 
mellit us, e n d ocri ne defici e ncies i ncl u di n g t h yr oi ditis ma na ge d wit h re place me nt h or m o ne 
a n d/ or p h ysi ol o gic c ortic oster oi d.  S u bject s wit h r he u mat oi d a rt hritis a n d/ or ot her 
art hr o pat hies, Sj ö gre n’s s y n dr o me or ps oriasis c o ntr olle d wit h t o pical me dicati o n, a n d 
s u bject wit h p ositi ve ser ol o g y s uc h as p ositi ve a nti n uclear a nti b o d y ( A N A) or a nti -
t h yr oi d a nti b o d y s h o ul d be e val uat e d f or prese n ce of tar get or gan i n v ol ve me nt a n d 
p ote ntial nee d f or s yste mic treat me nt b ut s h o ul d ot her wise be eli gi ble.  
8.  C o n diti o ns  re q uiri n g s yst e mic treat me nt wit h eit her c ortic oster oi ds ( > 1 0 m g dail y 
Pre d nis o ne e q ui vale nt) or ot her i m m u n os u p pressi ve me dicati o ns wit hi n 1 4 da ys of fir st 
d ose of tisleliz u ma b.  
N ote: A dre nal re pla ce me nt d oses of ≤ 1 0 m g dail y Pre d nis o ne e q ui vale nt are per mitte d i n 
t he a bse nce of acti ve a ut oi m m u ne disease.  T o pical, oc ular, i ntra-artic ular, i ntra -nasal a n d 
i n halati o nal c ortic oster oi d ( wit h mi ni mal s yste mic a bs or pti o n), a brief c o urse of 
c ortic oster oi d f or pr o p h yla xis (e. g. c o ntrast d ye aller g y) or f or treat me nt of n o n -
a ut oi m m u ne c o n diti o ns (e. g. d ela ye d -t y p e h y perse nsiti vit y reacti o n ca use d b y c o nt act 
aller ge n) are all o we d.  
9.  Has hist or y of i nterstitial l u n g diseas e or n o n-i nf ecti o us p ne u m o nitis or has e vi de nce of 
i nterstitial l u n g disease or n o n-i nfecti o us p ne u m o nitis. 
1 0.  Q Tc F i nter val > 4 8 0 msec, u nless sec o n d ar y t o b u n dle bra nc h bl oc k.  
1 1.  Seri o us ac ute or c hr o nic i nfecti o n re q uiri n g s yste mic t he ra p y. 
1 2.  K n o w n C N S l y m p h o ma.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 3.  U n derl yi n g me dical c o n diti o ns t hat, i n t he I n vesti gat or’s o pi ni o n, will re n der t he 
a d mi nistrati o n of st u d y dr u g h azar d o us or o bsc ure t he i nter pretati o n of t o xicit y or a d verse 
e ve nts.  
1 4.  K n o w n h u ma n i m m u n o deficie nc y vir us ( HI V) i nfect i o n, or acti ve h e patitis B ( H B V) or 
he patitis C ( H C V) i nfecti o n ( detecte d p ositi ve b y p ol y merase c h ai n reacti o n [ P C R]).  
 
I ncl usi o n 
E xcl usi o n  
HI V  
A nti b o d y ( -) 
A nti b o d y ( +)  
H B V  
H Bs A g ( -) a n d H Bc A b ( -) 
H Bs A g ( +)  
H Bs A g ( -) A N D 
H Bc A b ( +)  
H B V D N A <  1 0 0 0 I U/ ml.  
After e nr oll me nt, m o nt hl y 
m o nit ori n g f or H B V D N A or 
a nti -viral t hera p y s h o ul d be 
gi ve n t o pre ve nt H B V 
reacti vati o n 
H Bs A g ( -) 
A N D  
H Bc A b ( +)  
H B V D N A 
≥ 1 0 0 0  I U/ ml 
H C V  
H C V A b ( -) 
H C V A b ( +)  
H C V R N A ≥ 1 
(l o g1 0 I U/ ml) 
H C V A b ( +)  
H C V R N A < 1 (l o g1 0 I U/ ml) 
H Bs A g: He p atitis B s urface a nti ge n; H Bc A b: He patitis B c ore a nti b o d y; H B V: He p atitis B vir us; H C V: 
He p atitis C vir us; H C V A b: H e p atitis C a nti b o d y; HI V: h u ma n i m m u n o deficie nc y vir us; D N A: 
de o x yri b o n ucleic aci d; R N A: ri b o n ucleic aci d  
1 5.  A ut ol o g o us  he mat o p oieti c ste m cell tra ns pla nt wit hi n 1 0 0 da ys of first d ose of 
tisleliz u ma b. 
1 6.  Use of a n y li ve v acci n e a gai nst i nfecti o us diseases (e. g. i nfl ue nza, vari cella, etc.) wit hi n 4 
wee ks ( 2 8 d a ys) of t he first d ose of tisleliz u ma b, a n d a n y i nte n de d use wit hi n 6 0 da ys 
after t he l ast d ose of tisleliz u ma b.  
1 7.  Maj or s ur ger y wit hi n 4 wee ks of t he first d ose of tisleliz u ma b.  
1 8.  Pre g n a nt or lact ati n g w o me n.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
6.  
S T U D Y T R E A T M E N T S  
6. 1.  
St u d y Tre at me nt  
S u bjects will recei ve tisleliz u ma b at 2 0 0 m g I V Q 3 W.  O ne c ycle is 2 1 da y s.  All patie nts s h o ul d 
n ot recei ve pre me dicati o n t o pre ve nt i nf usi o n reacti o n bef ore t he first i nf usi o n of tisleliz u ma b, i n 
or der t o deter mi ne if pre me dicati o n is necessar y.  If a patie nt e x perie nces a n i nf usi o n reacti o n, 
he/s he ma y recei ve pre m e dicati o n s o n s u bse q ue nt d osi n g da ys.  T h e pre me dicati o n s s h o ul d be 
c h ose n per i nstit uti o nal sta n dar d of care, at t he dis creti o n of t he treati n g p h ysicia n.  
6. 2.  
St u d y Tre at me nt  Pre p ar ati o n a n d Dis pe ns ati o n  
6. 2. 1.  
P ac k a gi n g a n d L a beli n g  
Tisleliz u ma b is a m o n ocl o nal a nti b o d y f or m ulate d f or I V i njecti o n i n a si n gle -use vial ( 2 0 R 
glass, U S P t y p e I), c o ntai ni n g a t otal of 1 0 0 m g a nti b o d y i n 1 0 m L of is ot o nic s ol uti o n.  
Tisleliz u ma b has bee n  as e pticall y fille d i n si n gle -use vials wit h a Fl ur otec -c oate d b ut yl r u b ber 
st o p per a n d a n al u mi n u m ca p.  O ne vi al is pac ka ge d i n a si n gle cart o n b o x.   
T he la bel will i ncl u de , at mi ni m u m, dr u g na me, d ose stre n gt h, c o nte nts, s p o ns or, pr ot oc ol 
n u m ber, l ot n u m ber, directi o ns f or use, st ora ge c o n diti o ns a n d ca uti o n state me nts.  T he c o nte nts 
of t he la bel will be i n acc or da nce wit h all a p plica ble re g ulat or y re q uire m e nts.  
6. 2. 2.  
H a n dli n g a n d St or a ge  
Tisleliz u ma b (i n vesti gati o nal pr o d uct) will be dis patc he d t o a st u d y ce nter o nl y aft er recei pt of 
t he re q uire d d o c u me nts i n acc or da nce wit h a p plica ble re g ulat or y re q uir e m e nts a n d t he S p o ns or’s 
pr oce d ures.  
I n v esti gati o nal pr o d uct m ust be dis pe nse d or a d mi nistere d per pr o ce d ures descri be d herei n. O nl y 
s u bjects e nr olle d i n t he st u d y ma y recei ve i n vesti gati o nal pr o d uct, i n acc or da nce wit h all 
a p plica ble re g ulat or y re q uire me nts.  O nl y a ut h orize d st u d y ce nter p ers o n nel ma y s u p pl y or 
a d mi nister i n vesti gati o nal pr o d uct.  All i n vesti gati o nal pr o d ucts m ust be st ore d i n a sec ure area 
wit h access li mite d t o t he I n v esti gat or a n d a ut h orize d st u d y ce nter pers o n nel a n d u n der p h ysic al 
c o n diti o ns t hat are c o nsiste nt wit h i n vesti gati o nal pr o d uct s pecific re q uir e me nts.  T he 
in vesti gati o nal pr o d u ct m ust be ke pt at 2° C t o 8° C ( 3 6° F t o 4 6° F) a n d pr ot ecte d fr o m li g ht.  
Refer t o t he P har m ac y M a n ual  f or d etails re gar di n g a d mi nistrati o n, acc o u nt a bilit y, a n d dis p osal. 
6. 2. 3.  
C o m pli a nce a n d Acc o u nt a bilit y  
C o m plia nce will be assesse d b y t h e I n vesti gat or a n d/ or st u d y pers o n nel at eac h visit a n d 
i nf or mati o n pr o vi de d b y t he s u bject a n d/ or care gi ver will be ca pt ure d i n t h e Dr u g Acc o u nta bilit y 
F or m.  T his i nf or mati o n m ust be ca pt ure d i n t he s o urce d oc u m e nt at eac h s u bject visit.  
T he I n vesti gat or is r es p o nsi ble f or st u d y dr u g acc o u nta bilit y, rec o n ciliati o n, a n d r ec or d 
mai nte na nce.  I n acc or da nce wit h all a p plica ble re g ulat or y re q uire m e nts, t he I n vesti gat or or 
desi g nat e d st u d y ce nter pers o n nel m ust mai ntai n st u d y dr u g acc o u nta bilit y rec or ds t hr o u g h o ut 
t he c o urse of t h e st u d y.  T his pers o n will d oc u me nt t he a m o u nt of st u d y dr u g recei v e d fr o m t he 
s p o ns or, t he a m o u nt s u p plie d, a n d/ or a d mi nistere d t o a n d ret ur ne d b y s u bjects, if a p plica ble.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
6. 2. 4.  
Dis p os al a n d Destr ucti o n  
After c o m pleti o n of t he st u d y, all u n use d tisleliz u ma b will be i n ve nt orie d a n d pac ka ge d f or 
ret ur n s hi p me nt b y t h e h os pital u nit p har macist or ot her desi g nate d st u d y ce nter pers o n nel.  T he 
i n ve nt orie d s u p plies will be ret ur n e d t o t he s p o ns or or destr o ye d o n site or de p ot, after recei vi n g 
writte n s p o ns or a p pr o val.  
6. 3.  
S u bject N u m beri n g a n d Tre at me nt Assi g n me nt  
6. 3. 1.  
S u b ject N u m beri n g 
S u bjects will be i de ntifie d b y a s u bj ect n u m ber.  Eac h s u bject e nr olle d i n t his st u d y will recei v e a 
u ni q ue s u bject n u m ber w hic h will be assi g n e d w he n t he s u bject is scree ne d or e nr olle d i n t he 
st u d y.  S u bject n u m bers  will be assi g ne d i n c hr o n ol o gical or d er starti n g wit h t he l o west n u m ber.  
O nce a s u bject n u m ber has bee n assi g n e d t o a s u bject, it ca n n ot be reassi g n e d t o a n y ot her 
s u bject. 
6. 3. 2.  
Tre at me nt Assi g n me nt  
All s u bjects i n t he st u d y will recei ve tisleliz u ma b.  
6. 3. 3.  
Tre at me nt Bli n di n g  
T his is a n o pe n -la bel st u d y. 
6. 4.  
D os a ge a n d A d mi nistr ati o n  
Tisleliz u ma b  at 2 0 0 m g will be a d mi nistere d b y  I V i nf usi o n usi n g a v ol u m etric p u m p  t hr o u g h a n 
I V li ne c o ntai ni n g a steril e, n o n-p yr o ge ni c, l o w -pr otei n bi n di n g < 0. 2 2  micr o n  i n-li ne or a d d-o n 
filter.  S pecific i ns tr ucti o ns f or pr o d uct pr e parati o n a n d a d mi nistrati o n are pr o vi de d i n t he 
P har mac y Ma n u al.  
As a r o uti ne preca uti o n, s u bjects w h o recei ve t he first a n d sec o n d i nf usi o n of tisleliz u ma b m ust 
be o bser ve d f or 2 h o urs after i nf usi o n, a n d t hat res uscitati o n e q ui p m e nt a n d e mer ge n c y a ge nts 
nee d t o be a v aila ble.  
F or m ore d etaile d i nf or m ati o n re gar di n g a d mi nistrati o n, refer t o t he P har mac y M a n ual  a n d 
I n v esti gat or’s Br oc h ure. 
T he i nitial i nf usi o n will be deli vere d o v er 9 0 mi n; if well -t olerate d, s ec o n d i nf usi o n a n d eac h 
s u bse q ue nt i nf usi o n ma y be a d mi nistere d o ver 6 0 mi n, o ver 3 0 mi n if 6 0 mi n i nf usi o n t olerate d.  
D o n ot c o -a d mi nister ot h er dr u gs t hr o u g h t he s a me i nf usi o n li ne.  
6. 5.  
D ose I nterr u pti o n a n d M o dific ati o n  
6. 5. 1.  
D ose M o dific ati o n  
T here is n o d ose re d ucti o n or d ose escala ti o n of tisleliz u ma b. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
6. 5. 2.  
D ose I nterr u pti o n  
I m m u ne-relat e d a d verse e ve nt (ir A E), as des cri be d i n Secti o n  1. 2. 3 ., ma y occ ur d uri n g tr eat me nt 
wit h c hec k p oi nt i n hi bit ors s uc h as tisleliz u ma b.  Ke y p oi nts i n t he e v e nt of a n ir A E:  
•  Cl ose m o nit ori n g  
•  A m b ulat or y v ers us i n pati e nt care  
•  S y m pt o matic treat me nt  
•  Im m u n ot hera p y s us pe nsi o n or ter mi nati o n  
•  C ortic oster oi d t hera p y a n d ass ociate d meas ures  
•  O t her i m m u n os u p pressi ve dr u gs 
•  P atie nt i nf or mati o n o n h o w t o self -m o nit or cli nical ele me nts  
Refer t o Secti o n  9. 1. 1 2. 2  a n d A p pe n di x  8  f or i nf or mati o n re gar di n g t he m a na ge me nt of ir A Es. 
6. 6.  
D ose Del a y  
D ose dela y criteria a p pl y f or all dr u g -relate d A Es. T he s u bjects s h o ul d res u me tisleliz u ma b 
treat me nt as s o o n as p ossi ble after t he A Es rec o ver t o n or mal or Gra de 1 wit hi n 1 2 wee ks after 
last d ose of st u d y tr eat me nt.  I n case a s u bject is be nefiti n g fr o m t he st u d y tr eat me nt w hile 
meeti n g t he disc o nti n uati o n criteria, disc ussi o n bet wee n S p o ns or a n d I n vesti gat or will be 
c o n d ucte d t o ma ke a decisi o n t hat will be i n t he best i nterest of t he s u bject.  
S u bjects wit h i nf usi o n dela y > 6 wee ks  fr o m pla n n e d d osi n g d ate f or reas o n(s) ot her t ha n 
treat me nt-relate d t o xicit y s h o ul d n or mall y disc o nti n ue treat me nt a n d e nter t he F oll o w-u p Peri o d 
e x ce pt f or dela ys r elate d t o pr o p h yla ctic vacci nati o ns or after s pecific c o ns ultati o n a n d 
a gree m e nt bet wee n t he I n vesti gat or a n d S p o ns or me dical m o nit or i n setti n gs w h ere b e nefit/ris k 
ma y j ustif y c o nti n ue d st u d y t hera p y (e. g. s u bject  d eri vi n g cli nical be nefit w h o re q uires 
pr ol o n ge d ster oi d ta per f or ma na ge me nt of ir A Es).  
If t he ti mi n g of a pr ot oc ol-ma n date d st u d y visit c oi nci des wit h a h oli da y, wee ke n d, or ot h er 
e ve nt, t he visit s h o ul d be sc he d ule d o n t he nearest feasi ble dat e (refer t o t he visit wi n d o w i n 
A p pe n di x  5 ), wit h s u bse q ue nt visits c o n d ucte d acc or di n g t o t he pl a n ne d sc he d ule Q 3 W fr o m 
C ycle 1 D a y 1.  
6. 7.  
C o nc o mit a nt Me dic ati o ns a n d N o n -Dr u g T her a pies  
6. 7. 1.  
Pr o hi bite d Me dic ati o ns  
T he f oll o wi n g m e dicati o ns are pr o hi bite d d uri n g Scree ni n g a n d St u d y Treat me nt Peri o ds:  
•  I m m u n os u p pr essi ve a ge nts (e x ce pt t o treat a dr u g-relate d A E) 
•  S yste mic c ortic oster oi d > 1 0 m g dail y Pre d nis o ne e q ui vale nt (e x ce pt t o treat a dr u g -
relate d a d v erse e ve nt). 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  4 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
•  A n y c o nc urre nt a nti ne o pl astic t hera p y (i. e. c he m ot hera p y, h or m o n al t hera p y, 
i m m u n ot hera p y, e xte nsi ve ra diati o n t hera p y, sta n d ar d or i n vesti gati o nal a ge nts f or 
treat me nt of ca ncer). 
•  Li ve v acci n es wit hi n 2 8 da ys pri or t o t he first d os e of st u d y t h era p y a n d w hile 
partici pati n g i n st u d y.  E x a m ples of li ve vacci nes i ncl u de b ut are n ot li mite d t o: 
measles, m u m ps, r u bella, c hic ke n p o x, yell o w fe v er, seas o n al fl u, H 1 N 1 fl u, ra bies, 
B C G, a n d  t y p h oi d vacci n e.  I nacti vat e d i nfl ue nza vacci ne is all o we d. 
•  C hi nese her bal me dici n e a n d C hi nese pate nt me di ci ne  f or tr eat me nt of ca n cer. 
6. 7. 2.  
Per mitte d Me dic ati o ns  
I n ge neral, c o nc o mita nt me dicati o ns a n d t hera pies dee me d necessar y f or s u p p orti ve care (e. g. 
a nti-e metics, a nti -diarr heals) a n d safet y of t he pati e nt are all o we d.  All treat me nts t hat t he 
I n v esti gat or c o nsi ders n ecessar y f or a p atie nt’s welfare ma y b e a d mi nistere d at t he discreti o n of 
t he I n v esti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of me dical care.  All c o nc o mita nt 
me dicati o n will be rec or de d o n t he ele ctr o nic cas e re p ort f or m (e C R F) i ncl u di n g all pres cri pti o n 
a n d o ver-t h e-c o u nter ( O T C) me dicati o ns, her bal s u p ple me nts, a n d I V me dicati o ns a n d fl ui ds. If 
c ha n ges occ ur d uri n g t he st u d y peri o d, d o c u me ntati o n of dr u g d os a ge, fre q ue nc y, r o ute, a n d date 
will als o be i ncl u de d o n t he e C R F.  All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da ys bef ore 
t he first d ose of st u d y me diati o n a n d 3 0 da ys after t he last i nf usi o n of st u d y me dicati o n s h o ul d be 
rec or de d. 
S yste mic c ortic oster oi ds re q uire d f or t he c o ntr ol of ir A Es m ust be ta pere d o ver at least 1 m o nt h 
a n d be at n o n -i m m u n os u p pressi ve d oses ( ≤ 1 0 m g/ da y of Pre d nis o ne or e q ui vale nt) bef ore t he 
ne xt st u d y dr u g a d mi nistrati o n. T he use of ster oi ds as  pr o p h yl actic tr eat me nt f or s u bjects wit h 
c o ntrast aller gies t o dia g n ostic i ma gi n g c o ntr ast d yes will be per mitte d.  
S u bjects ma y c o nti n ue t o recei v e h or m o ne re place me nt if i nitiate d pri or t o e nr oll me nt . 
6. 8.  
Diet/ Acti vit y/ Ot her C o nsi der ati o ns  
6. 8. 1.  
Diet  
S u bjects s h o u l d mai ntai n a n or mal diet u nless m o dificati o ns are re q uire d t o ma na ge a n A E s uc h 
as diarr hea, na us ea or v o miti n g.  
6. 8. 2.  
C o ntr ace pti o n  
Tisleliz u ma b ma y h a ve a d verse effects o n a fet us i n uter o.  F urt her m ore, it is n ot k n o w n if 
tisleliz u ma b has tra nsie nt a d verse effects o n t he c o m p ositi o n of s per m.  N o n-pre g na nt, n o n -
breast -fee di n g w o me n m a y b e e nr olle d if t he y are c o nsi dere d hi g hl y u nli kel y t o c o ncei ve or of 
n o n -c hil d beari n g p ote nti al (i.e. p h ysi ol o gicall y i n ca pa ble of bec o mi n g pre g na nt).  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Hi g hl y u nli kel y t o c o ncei ve or of n o n -c hil d beari n g p ote ntial (i.e. p h ysi ol o gi call y i n ca pa ble of 
bec o mi n g pre g na nt) is defi ne d as 1) has h a d a h yst erect o m y, or 2) has ha d a bilateral 
o o p h orect o m y ( o variect o m y), or 3) has ha d a bilat eral t u bal li gati o n, or 4) is p ost me n o pa usal  
(t otal cessati o n of me nses f or ≥ 1 year). 1 ) or 4) n ot heter ose x uall y acti ve f or t he d urati o n of t he 
st u d y, or 5) heter os e x uall y acti ve a n d willi n g t o use t w o met h o ds of birt h c o ntr ol ( w hic h is als o 
rec o m me n de d f or t he fe male part ners of male p atie nts).  
S u bjects m ust a gree t o us e a de q u ate c o ntr ace pti o n  w hile o n st u d y treat me nt, defi ne d as 
vasect o miz e d part ner w h o is sterile pri or t o t he fe male s u bject’s st u d y e ntr y a n d is t he s ole 
se x ual part ner f or t hat fe male, a n y i ntra uteri ne de vice wit h a d oc u me nt e d fail ure rat e of < 1 % per 
year, or d o u bl e barrier c o ntrace pti o n defi ne d as t w o birt h c o ntr ol met h o ds, e. g. t w o b arri er 
met h o ds or a barrier met h o d pl us a h or m o nal met h o d t o pre ve nt pre g n a nc y, use d t hr o u g h o ut t he 
st u d y starti n g wit h Visit 1 t hr o u g h 1 2 0  d a ys after t he last d ose of st u d y m e dicati o n. Male pati e nts 
e nr olle d i n t his st u d y m ust als o a gree t o use a n a d e q uate met h o d of c o ntrace pti o n starti n g wit h 
Visit 1 t hr o u g h 1 2 0  da ys after t he l ast d ose of st u d y dr u g.  
T he f oll o wi n g are c o nsi d ere d a d e q uate barri er met h o ds of c o ntrace pti o n: dia p hra g m, c o n d o m ( b y 
the part ner), c o p per i ntra uteri ne de vic e, s p o n ge, or s per mici de.  A p pr o priat e h or m o nal 
c o ntrace pti ves will i ncl u de a n y re gistere d a n d m ar kete d c o ntr ace pti ve a ge nt t hat c o ntai ns a n 
estr o ge n a n d/ or a pr o gest ati o nal a ge nt (i ncl u di n g oral, s u bc uta ne o us, i ntr a ut eri ne, or 
i ntra m usc ular a ge nts).  
Patie nts s h o ul d be i nf or me d t hat ta ki n g t he st u d y me dicati o n ma y i n v ol ve u n k n o w n ris ks t o t he 
fet us ( u n b or n ba b y) if pre g n a nc y w ere t o o cc ur d uri n g t he st u d y.  T o partici pate i n t he st u d y, 
t he y m ust a d here t o t he c o ntrace pti o n re q uire me nt ( descri be d a b o ve) f or t h e d urati o n of t he st u d y 
a n d f oll o w-u p peri o d.  If t here is a n y q uesti o n t hat a patie nt will n ot relia bl y c o m pl y wit h t he 
re q uire me nts f or c o ntr ace pti o n, t hat patie nt s h o ul d n ot e nter t he st u d y. 
6. 8. 3.  
Pre g n a nc y  
Tisleliz u ma b ma y h a ve a d verse effects o n a fet us; t heref ore, w o me n wit h a p ositi ve pre g n a nc y 
test at Scree ni n g will n ot be eli gi ble f or e nr oll me nt.  If a patie nt i na d v erte ntl y bec o mes pre g na nt 
w hile o n treat me nt wit h tisleliz u ma b, t he patie nt will i m me diatel y b e re m o ve d fr o m t he st u d y.  
T he site will c o ntact t he patie nt at least m o nt hl y a n d d oc u me nt t he patie nt’s stat us u ntil t he 
pre g na nc y h as bee n c o m plete d or ter mi nate d.  T h e o utc o me of t he pre g na n c y will be re p ort e d t o 
t he s p o ns or wit h o ut dela y a n d wit hi n 2 4 h o urs if t he o utc o me is a seri o us a d verse e x perie n ce 
(e. g. deat h, a b orti o n, c o n ge nital a n o mal y, or ot her disa bli n g or life-t hreat e ni n g c o m plicati o n t o 
t he m ot her or ne w b or n).  If a male p atie nt’s part n er bec o mes pre g na nt o n st u d y t he pre g na n c y 
m ust be re p orte d t o t he s p o ns or.  T he st u d y I n vesti gat or will ma ke e ver y eff ort t o o btai n 
per missi o n t o f oll o w t he o utc o me of t he pre g na nc y a n d re p ort t he c o n diti o n of t he fet us or 
ne w b or n t o t he s p o ns or a n d f oll o we d as des cri be d a b o ve.  
6. 8. 4.  
N ursi n g W o me n  
It is u n k n o w n w h et her tisleliz u ma b is e x crete d i n h u ma n mil k.  Si nce ma n y dr u gs are e x crete d i n 
h u ma n mil k, a n d beca use of t he p ote ntial f or seri o us a d verse reacti o ns i n t he n ursi n g i nfa nt, 
patie nts w h o are breast -fee di n g are n ot eli gi ble f or e nr oll me nt. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
6. 9.  
E n d of Tre at me nt  
All s u b jects, re gar dl ess of reas o n f or disc o nti n uati o n of st u d y tr eat me nt, will u n der g o a n E n d of 
Treat me nt ( E O T) visit wit hi n 7 da ys of st o p pi n g st u d y dr u g.  T h e reas o n f or disc o nti n uati o n 
fr o m treat me nt will be rec or de d o n e C R F.  Refer t o Secti o n  7. 1. 4  f or re q uir e d assess me nts at t he 
E O T visit.  
S u bjects ma y disc o nti n ue st u d y dr u g f or a n y of t h e f oll o wi n g reas o ns:  
•  Disease pr o gressi o n  
•  A d verse e ve nt(s)  
•  S u bject wit h dre w c o nse nt  
•  I n v esti gat or decisi o n 
•  Ot her  
S u bjects ma y v ol u ntaril y wit h dra w c o nse nt fr o m st u d y at a n y ti me.  A s u bj ect ma y c o nti n ue t o 
partici pate i n t he f oll o w u p p hase if t he s u bject wit h dra ws c o nse nt fr o m t he treat me nt p hase.  
6. 1 0.  
F oll o w -u p P h ase  
6. 1 0. 1.  
S afet y F oll o w -u p  
S u bjects w h o disc o nti n ue treat me nt f or a n y reas o n will be as ke d t o ret ur n t o t he cli nic f or a 
safet y f oll o w-u p visit (t o occ ur wit hi n 3 0 da ys [ ± 7 da ys]) after t he last st u d y treat me nt.  I n 
a d diti o n, tele p h o ne c o nta cts wit h s u bjec ts s h o ul d be c o n d ucte d t o assess A Es a n d c o nc o mita nt 
me dicati o ns (if a p pr o priate, i.e. ass ociate d wit h a n A E or is a ne w a nti -ca n cer t hera p y) at 6 0 a n d 
9 0 da ys ( ± 1 4 da ys) after t he last d ose of tisleliz u ma b.  All A Es a n d S A Es are c ollecte d u p t o 9 0 
da ys af ter t h e last d ose of st u d y dr u g.  Be y o n d 9 0 da ys, i n v esti gat ors s h o ul d c o nti n ue t o re p ort 
a n y S A Es t hat are b elie v e d t o be relat e d t o st u d y dr u g if t h e y bec o m e a ware of t he m.  
T he  E O T  visit at w hic h a res p o nse ass ess me nt s h o we d pr o gressi ve disease, res ulti n g i n s u bject 
disc o nti n uati o n, ma y be use d as t he safet y f oll o w -u p visit , pr o vi de d t hat it occ urre d 3 0 da ys ( ± 7 
da ys) after t he last st u d y treat me nt.  S u bjects w h o disc o nti n ue st u d y treat me nt pri or t o disease 
pr o gressi o n will ha ve t heir t u m ors assesse d as o utli ne d i n Secti o n  7. 2 . 
See t he st u d y s c he d ule pr o vi de d i n A p pe n di x  5  f or assess me nts t o be perf or me d at t he safet y 
f oll o w-u p visit.   
6. 1 0. 2.  
Effic ac y F oll o w U p  
Disease stat us f or s u bj ects w h o disc o nti n ue fr o m st u d y dr u g f or a n y reas o n ot he r t ha n P D (e. g. 
A E) will be assesse d ra di o gra p hicall y b y t he sa m e i ma gi n g m o dalit y as t he Treat me nt Peri o d.  
T u m or i ma gi n g will be p erf or me d p er pr ot o c ol (refer t o Secti o n  3 , Fi g ure  2  St u d y Desi g n ) u ntil 
P D, ne w a nti -ca ncer t hera p y, wit h dra wal of c o nse nt, deat h, l ost t o f o ll o w-u p, or e n d of st u d y 
( E O S), w hic he v er occ urs first. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
6. 1 0. 3.  
S ur vi v al F oll o w U p  
S u bjects will be f oll o we d f or s ur vi val after safet y f oll o w -u p visit or efficac y f oll o w -u p via p h o ne 
c o ntact ( wit h t he s u bject’s g uar dia n, if a p plica ble) a p pr o xi matel y e ver y 3  m o nt hs.  T he 
I n v esti gat or or his/ her desi g nee will als o c o nti n ue t o c ollect i nf ormati o n o n ne w a nti -ca ncer 
t hera p y gi ve n after t he l ast d ose of st u d y dr u g. 
6. 1 1.  
E n d of St u d y  
Patie nts still recei vi n g st u d y treat me nt w he n t he r oll -o ver st u d y is o pe n will tra nsfer t o t he r oll -
o ver st u d y f or c o nti n u o us treat me nt a n d m o nit ori n g .  Patie nts alrea dy off st u d y treat me nt b ut n ot 
wit h dre w t he I C F will ha ve effi cac y (if disc o nti n uati o n n ot d ue t o disease pr o gressi o n), safet y 
a n d s ur vi val f oll o w -u p (as defi ne d i n t his pare nt st u d y) i n t he r oll -o ver st u d y  (see A p pe n di x  5 ). 
Pre mat ure disc o nti n uati o n fr o m t he st u d y (i ncl u di n g all f oll o w -u p visits) will occ ur u n der t he 
f oll o wi n g cir c u msta nces: 
•  Maj or pr ot oc ol vi olati o n  
•  S u bject wit h dre w c o nse nt  
•  L ost t o f oll o w-u p  
•  Deat h  
•  St u d y t er mi nati o n b y s p o ns or  
•  I n v esti gat or’s discreti o n 
S u bject ma y v ol u ntaril y wit h dra w c o nse nt fr o m t he st u d y at a n y ti me.  
S u bjects l ost t o f oll o w -u p s h o ul d be rec or de d as s uc h o n t he e C R F.  F or s u bjects w h o are l ost t o 
f oll o w-u p, t he I n vesti gat or s h o ul d d oc u me nt i n t he s o urce d o c u me nts ste ps ta ke n t o c o ntact t he 
s u bject, e. g. dates of t ele p h o ne calls, re gistere d letters, etc. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
7.  
S T U D Y A S S E S S M E N T S  
7. 1.  
St u d y Pr oce d ures  
7. 1. 1.  
Scree ni n g  
A si g ne d, writte n i nf or m e d c o nse nt f or m (I C F) m ust be o btai ne d fr o m t he s u bject pri or t o a n y 
st u d y-s pecific pr oce d ures or assess me nts.  Re-scree ni n g of patie nts will n ot be all o we d, b ut 
la b orat or y para meters w hic h d o n ot meet t he i ncl usi o n criteria ma y be re-t este d wit hi n t he 
scree ni n g wi n d o w ( Da y -2 8 t o Da y -1).  
Pr oce d ur es a n d assess me nts t o be perf or me d d uri n g t he Scree ni n g wi n d o w ( Da y -2 8 t o D a y -1):  
•  I nf or me d c o ns e nt 
•  De m o gra p hic  
•  Me dical hist or y i n cl u di n g dat e of c H L dia g n osis, date of last rec urre nce, d ate of last 
ca ncer treat me nt, c H L s u bt y pe, sta ge of diseas e at dia g n osis ( A p pe n di x  3 ) I P S at 
dia g n osis ( A p p e n di x  4 ), a n d bi o ps y d etails 
•  I n cl usi o n/ E x cl usi o n Criteria 
•  C o nc o mita nt me dicati o ns wit hi n 2 8 da ys pri or t o first d ose of tisleliz u ma b  
•  Pri or t y pe a n d dates of tr eat me nts f or  c H L i ncl u di n g c h e m ot hera p y, ra diati o n, a n d 
s ur ger y 
•  C T wit h c o ntrast a n d P E T/ C T of nec k, c h est, a b d o me n, a n d pel vis.  P E T/ C T ma y be 
use d i n lie u of a C T wit h c o ntrast o nl y if t h e C T of t he P E T/ C T has bee n perf or me d 
wit h dia g n ostic q ualit y a n d c o ntrast is a d mi nistere d.  T otal b o d y M RI is all o we d if 
c o ntrai n dicate d t o C T wit h c o ntrast.   
•  E C O G perf or ma nce stat us  
•  Vital si g ns i ncl u di n g t e m perat ur e, bl o o d press ur e, p ulse, res pirat or y rate, a n d p ulse 
o xi metr y  
•  P h ysical e x a mi nati o n  
•  P ul m o nar y f u ncti o n test  
•  A d verse e ve nts  
•  1 2 -lea d ele ctr ocar di o gra m ( E C G) 
•  Ec h ocar di o gra m ( E C H O) or M ulti gate d Ac q uisiti o n Sca n ( M U G A), if n ot perf or me d 
wit hi n 9 0 da ys of first da y of Scree ni n g  
•  C o m plete bl o o d c o u nt ( C B C) wit h differe ntial, mea n c or p usc ul ar v ol u me ( M C V), 
mea n c or p us c u lar he m o gl o bi n ( M C H), mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 
( M C H C), re d cell distri b uti o n wi dt h ( R D W) 
•  C o m pre he nsi ve ser u m c h e mistr y pa n el ( Refer t o A p pe n di x  2 ) 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
•  H Bs A g, H Bs A b, H Bc A b, H C V A b, a n d f urt h er testi n g b y P C R t o assess H B V D N A 
or , H C V R N A le vel ma y be perf or me d f or deter mi nati o n of st u d y eli gi bilit y as per 
I n cl usi o n/ E x cl usi o n Criteria. 
•  C oa g ulati o n para meters ( P T, a P T T, I N R)  
•  Ser u m pre g na n c y test ( o nl y i n w o me n of c hil d beari n g p ote ntial), m ust be perf or me d 
wit hi n 3 da ys of t he first d ose of tisleliz u ma b  
•  Arc hi val t u m or tiss ue a n d/ or a fres h t u m or bi o ps y ( 1 0 t o 1 5 u nstai ne d f or m ali n -fi x e d, 
paraffi n -e m bed d e d [ F F P E] sli des)  
•  B o ne marr o w as pirate a n d bi o ps y, if n ot perf or me d wit hi n 6 0 da ys of first d ose of 
st u d y dr u g 
•  Refer t o t he Sc he d ul e of Assess me nt ( A p pe n di x  5 ) f or a d diti o nal details. 
•  T he f oll o wi n g e C R Fs m ust be c o m plete d f or scree n -fail patie nts: 
•  Scree ni n g P hase Dis p ositi o n pa ge (i ncl u di n g reas o n f or n ot bei n g starte d o n 
treat me nt) 
•  I nf or me d c o ns e nt 
•  De m o gra p h y  
•  A d verse E v e nt s ( o nl y if a n S A E occ urs) 
•  I n cl usi o n/ E x cl usi o n criteria 
7. 1. 2.  
C ycle 1 D a y 1 ( ± 3 d a ys)  
Pr oce d ures a n d assess me nts t o be perf or me d o n Da y 1 of C ycle 1 ( ± 3 d a ys):  
•  E C O G perf or ma nce stat us  
•  Vital si g ns i ncl u di n g t e m perat ur e, bl o o d press ur e, p ulse, res pirat or y rate, a n d p ulse 
o xi metr y  
•  Hei g ht a n d wei g ht  
•  P h ysical e x a mi nati o n  
•  A d verse e ve nts  
•  C o nc o mita nt me dicati o ns  
•  C B C wit h differe ntial, M C V, M C H, M C H C, R D W  
•  C o m pre he nsi ve ser u m c h e mistr y pa n el ( Refer t o A p pe n di x  2 ) 
•  Er yt hr o c yte se di me nt ati o n rate ( E S R)  
•  Uri nal ysis  
•  T h yr oi d f u ncti o n test (t h yr oi d sti m ulati n g h or m o n e [ T S H], free  T 4, free T 3)  
•  St u d y dr u g a d mi nistrati o n  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
•  
 
 
Refer t o t he Sc he d ul e of Assess me nt ( A p pe n di x  5 ) f or f urt her det ails. 
7. 1. 3.  
D a y 1 of C ycle 2 a n d All S u bse q ue nt C ycles ( ± 3 d a ys)  
Pr oce d ures a n d assess me nts t o be perf or me d o n Da y 1 of C ycle 2 a n d all s u bse q ue nt c ycles ( ± 3 
da ys):  
•  E C O G perf or ma nce stat us  
•  Vital si g ns i ncl u di n g t e m perat ur e, bl o o d press ur e, p ulse, res pirat or y rate, a n d p ulse 
o xi metr y  
•  Wei g ht  
•  P h ysical e x a mi nati o n  
•  A d verse e ve nts  
•  C o nc o mita nt me dicati o ns  
•  C B C wit h differe ntial, M C V, M C H, M C H C, R D W  
•  C o m pre he nsi ve ser u m c h e mistr y pa n el ( Refer t o A p pe n di x  2 ) 
•  Uri nal ysis (st art at C 7 D 1 a n d re peat e ver y 6 c ycl es)  
•  St u d y dr u g a d mi nistrati o n  
•  
 
 
Refer t o t he Sc he d ul e of Assess me nt ( A p pe n di x  5 ) f or f urt her det ails. 
7. 1. 4.  
E n d of Tre at me nt  
Pr oce d ures a n d assess me nts t o be perf or me d wit hi n 7 da ys of st o p pi n g tisleliz u ma b at E O T:  
•  E C O G perf or ma nce stat us  
•  Vital si g ns i ncl u di n g t e m perat ur e, bl o o d press ur e, p ulse, res pirat or y rate, a n d p ulse 
o xi metr y  P h ysical e x a mi nati o n  
•  A d verse e ve nts  
•  C o nc o mita nt me dicati o ns  
•  C B C wit h differe ntial ( R efer t o A p pe n di x  2 ) 
•  C o m pre he nsi ve ser u m c h e mistr y pa n el ( Refer t o A p pe n di x  2 ) 
•  T h yr oi d f u ncti o n test ( T S H, free T 4, free T 3)  
•  Uri nal ysis  
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
•  C T wit h c o ntrast of nec k, c hest, a b d o me n, a n d p el vis.   P E T/ C T ma y b e use d i n lie u of 
a C T wit h c o ntrast o nl y if t he C T of t he P E T/ C T has bee n perf or m e d wit h dia g n ostic 
q ualit y a n d c o ntrast is a d mi nistere d.  T u m or i ma gi n g f or E O T d oes n ot h a v e t o be 
perf or me d if t he m ost rece nt t u m or i ma gi n g was p erf or me d wit hi n t he pre vi o us 6 
wee ks.  
•  Uri ne pre g n a nc y test  
•  B o ne marr o w as pirate a n d bi o ps y will be re q uir e d f or c o nfir m ati o n of C R if baseli ne 
b o ne marr o w was p ositi ve f or c H L i n v ol ve me nt.   
•  P E T/ C T f or c o nfir mati o n of P D, if P D is reas o n f or disc o nti n uati o n of treat me nt.  
Refer t o t he Sc he d ul e of Assess me nt ( A p pe n d i x 5 ) f or f urt her det ails. 
7. 1. 5.  
S afet y F oll o w -u p  
Pr oce d ures a n d assess me nts t o be perf or me d at t he Safet y F oll o w -u p Visit ( 3 0 da ys ± 7 da ys 
after last d ose of tisleliz u ma b):  
•  Vital si g ns i ncl u di n g t e m perat ur e, bl o o d press ur e, p ulse, res pirat or y rate, a n d p ulse 
o xi metr y  
•  P h ysical e x a mi nati o n  
•  E C O G perf or ma nce stat us  
•  1 2 -lead E C G  
•  A d verse e ve nts  
•  C o nc o mita nt me dicati o ns  
•  C B C wit h differe ntial, M C V, M C H, M C H C, R D W  
•  C o m pre he nsi ve ser u m c h e mistr y pa n el ( Refer t o A p pe n di x  2 ) 
•  Uri na l ysis 
•  T h yr oi d f u ncti o n test ( T S H, free T 4, free T 3)  
•  
 
I n a d diti o n, tele p h o ne c o ntacts wit h s u bjects s h o ul d be c o n d ucte d t o ass ess A Es a n d c o nc o mita nt 
me dicati o ns (if a p pr o priate, i.e. ass ociate d wit h a n A E or is a ne w a nti -ca n cer t hera p y) at 6 0 a n d 
9 0  da ys ( ± 1 4 da ys) after t he last d ose of tisleliz u ma b.  All A Es a n d S A Es are c ollecte d u p t o 
9 0  da ys after t h e last d ose of st u d y dr u g.  Be y o n d 9 0 da ys, i n v esti gat ors s h o ul d c o nti n ue t o 
re p ort a n y S A Es t hat are belie ved t o be relate d t o st u d y dr u g if t he y b ec o m e a ware of t h e m.  
Refer t o t he Sc he d ul e of Assess me nt ( A p pe n di x  5 ) f or f urt her det ails. 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
7. 1. 6.  
S ur vi v al F oll o w -u p  
F oll o wi n g c o m pleti o n of t he treat me nt a n d Safet y F oll o w -u p p hases of t he st u d y, e v er y eff ort 
s h o ul d be ma de t o f oll o w s u bjects a p pr o xi matel y e ver y 3  m o nt hs  f or s u bse q ue nt a ntit u m or 
treat me nt after t he e n d of st u d y treat me nt a n d s ur vi val u ntil s u bject deat h or st u d y ter mi nati o n b y 
t he S p o ns or. 
7. 2.  
T u m or Assess me nt  
7. 2. 1.  
I m a gi n g St u dies 
Res p o nse assess me nt f or O R R will be b y c o ntrast C T a n d P E T/ C T se paratel y a n d cate g orize d as 
per t he L u ga n o Classificati o n ( A p pe n di x  6 ). 
7. 2. 1. 1.  
C T wit h c o ntr ast  
T u m or assess me nt b y C T wit h c o ntrast of nec k, c h est, a b d o me n, a n d pel vis will be perf or me d a t 
pr ot oc ol s pecifie d ti me  p oi nts ( Refer t o A p pe n di x  5 ).  T otal b o d y M RI is all o we d if C T wit h 
c o ntrast is c o ntrai n dicate d.  P E T/ C T ma y be use d i n lie u of a C T wit h c o ntr ast o nl y if t he C T of 
t he P E T/ C T has bee n perf orme d wit h dia g n ostic q ualit y a n d c o ntrast is a d mi nistere d.   
C T sca n slice t hic k ness s h o ul d n ot e x cee d 8 m m c uts usi n g a c o nti g u o us rec o nstr ucti o n 
al g orit h m. Cli nical s us pici o n of disease pr o gressi o n at a n y ti me will re q uir e a p h ysical 
e x a mi nati o n a n d ra di o l o gical c o nfir mati o n t o be perf or me d pr o m ptl y, rat her t ha n waiti n g f or t he 
ne xt sc he d ule d t u m or assess me nt.  I n cas e of a n u nsc he d ule d or d ela ye d t u m or assess me nt f or 
a n y reas o n, s u bs e q ue nt t u m or assess me nts m ust be perf or me d per t he ori gi nall y pla n ne d 
sc he d ule fr o m b aseli ne.  
7. 2. 1. 2.  
P E T/ C T  
T u m or assess me nt b y P E T/ C T will be perf or me d at pr ot oc ol s pecifie d ti me  p oi nts ( Refer t o 
A p pe n di x  5 ).  P E T/ C T ma y b e use d i n lie u of a C T wit h c o ntrast o nl y if t h e C T of t he P E T/ C T 
has bee n perf or m e d wit h dia g n ostic q ualit y a n d c o ntrast is a d mi nistere d.   
7. 2. 2.  
B o ne M arr o w As pir ate a n d Bi o ps y  
B o ne marr o w as pirate a n d bi o ps y will be re q uir e d at Scree ni n g .  I m m u n o hist oc he mistr y s h o ul d 
be perf or me d.  Re peat b o ne marr o w as pirate a n d bi o ps y is re q uir e d at t he ti me of C R f or 
c o nfir mati o n of res p o nse if baseli ne marr o w e x a mi nati o n was p ositi ve f or c H L i n v ol ve me nt.  
7. 2. 3.  
Dise ase Pr o g ressi o n wit h I m m u ne C hec k p oi nt I n hi bit ors  
D uri n g tr eat me nt wit h i m m u ne c hec k p oi nt i n hi bit ors s uc h as wit h tisleliz u ma b, pse u d o -
pr o gressi o n ma y occ ur d ue t o i m m u ne cell i nfiltrati o n a n d ot her mec ha nis ms as ma nifeste d b y 
a p pare nt i ncrease of e xisti n g t u m or masses or a p peara nce of ne w t u m or le si o ns.  S u bjects are 
all o we d t o c o nti n ue st u d y treat me nt if t here is s us pici o n of pse u d o -pr o gressi o n, pr o vi de d t he y 
are as y m pt o matic a n d ha ve ra di o gra p hic pr o gressi o n o nl y, u ntil a sec o n d c o nsec uti ve C T sca n 
de m o nstrates P D at w hic h ti me st u d y treat me nt wi ll be disc o nti n ue d per ma ne ntl y.  Patie nts 
s h o ul d c o nti n ue o n treat me nt t o pr o gressi o n re gar dless of res p o ns e stat us (e. g. i n C R).  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
7. 2. 4.  
Arc hi v al Tiss ue C ollecti o n wit h Ce ntr al Di a g n osis C o nfir m ati o n  
Arc hi val tiss ue ( 1 0 -1 5 u nstai ne d F F P E sli des) will be c ollecte d  at Scree ni n g.  Ce ntr al re vie w of 
t he tiss ue will be perf or m e d t o c o nfir m dia g n osis of c H L (ce ntr al c o nfir mati o n of c H L dia g n osis 
n ot re q uire d f or st u d y e ntr y).  E nr oll me nt ma y be i ncreas e d base d o n ce ntr al re vie w.  
7. 3.  
 
 
 
  
 
 
 
 
  
7. 4.  
S afet y  a n d T oler a bilit y Assess me nts  
Safet y assess me nts s h o ul d be perf or me d at all visits b y t he I n v esti gat or t hr o u g h o ut t he st u d y.  
Safet y assess me nts will c o nsist of m o nit ori n g all A Es a n d seri o us a d v erse e ve nts ( S A Es),  re g ular 
m o nit ori n g of bl o o d tests, uri ne tests, vital si g ns, wei g ht,  a n d perf or ma nce stat us, a n d b y re g ular 
p h ysical e x a mi nati o ns ( P Es).  F or s c he d ule of st u d y visits, refer t o t he Sc he d ule of Assess me n t 
(A p pe n di x  5 ). 
7. 4. 1.  
A d verse E ve nts  
All a d verse e ve nts, i ncl u di n g S A Es, will be c ollecte d as descri b e d i n Secti o n  9 .  At t he e n d of 
treat me nt, o n g oi n g a d verse e ve nts c o nsi dere d relate d t o st u d y treat me nt will be f oll o we d u ntil 
t he e ve nt has res ol ve d t o baseli ne, t he e v e nt is assesse d b y t he i n vesti gat or as sta ble, t he s u bject 
is l ost t o f oll o w-u p, t he s u bject wit h dra ws c o ns e nt, or it has bee n det er mi ne d t hat st u d y treat me nt 
or partici pati o n is n ot t he ca use of t h e a d verse e v e nt.  
Atte nti o n s h o ul d be f oc use d o n i de ntif yi n g p o te ntial ir A Es a n d ma na gi n g t hese ir A Es 
effecti vel y. T he A d mi nistrati ve Bi n der c o ntai ns a c o m pre he nsi ve g ui d eli ne f or t he assess me nt 
a n d ma na ge m e nt of ir A Es t o e ns ure t hat p ote ntial i m m u ne relate d e v e nts are i de ntifie d i n ti mel y 
ma n ner. M ost ir A Es e x pecte d fr o m i m m u n ot hera pies, i ncl u di n g tisleliz u ma b, are m a na gea ble 
a n d re versi ble w he n d ete cte d a n d ma n a ge d earl y.  
7. 4. 2.  
P h ysic al E x a mi n ati o n,  Vit al Si g ns, Hei g ht, a n d Wei g ht  
P h ysical e x a mi nati o ns will i ncl u de a n e x a mi nati o n of ge neral a p peara n ce, s ki n, nec k (i ncl u di n g 
t h yr oi d), e yes, ears, n ose, t hr oat, l u n gs, heart, a b d o me n, bac k, l y m p h n o des, e xtre mities, a n d a 
basic ner v o us s yste m e v al uati o n.   A c o m plete or tar gete d p h ysical e x a mi nati o n, vital si g ns 
(sitti n g bl o o d press ure, p ulse rate, b o d y te m perat ure, a n d res pirat or y rate) a n d wei g ht will be 
perf or me d at eac h st u d y visit.  T o t he e xte nt feasi ble, bl o o d press ure will b e ta ke n o n t he sa m e 
ar m t hr o u g h o ut t he st u d y. A lar ge c uff s h o ul d be use d f or o bes e patie nts.  Patie nts m ust be 
resti n g i n a sitti n g p ositi o n f or 1 0 mi n utes pri or t o o btai ni n g vital si g ns.  If bl o o d press ure is 
> 1 5 0/ 1 0 0 m m H g i n a p atie nt wit h o ut a hist or y of h y perte nsi o n, or i ncrease d > 2 0 m m H g 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  5 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
( diast olic) fr o m bas eli ne meas ure me nt i n a patie nt wit h a pre vi o us hist or y of h y p erte nsi o n, t he 
assess me nt s h o ul d be re p eate d i n 1 0 mi n utes f or c o nfir mati o n. Hei g ht i n ce nt i meters (c m) a n d 
b o d y w ei g ht (t o t he nearest 0. 1 kil o gra m [ k g] i n i n d o or cl ot hi n g, b ut wit h o ut s h oes) will be 
meas ure d.  H ei g ht will be meas ur e d o n Da y 1 of C ycle 1 o nl y.   Wei g ht will be meas ure d o n Da y 
1 of eac h treat me nt c ycle.  
Si g nifica nt ne w fi n di n gs t hat be gi n or w orse n after i nf or me d c o ns e nt m ust be rec or de d o n t he 
A d verse E v e nt pa ge of t he patie nt’s e C R F.  
7. 4. 3.  
Me dic al Hist or y  
T he I n vesti gat or will o bt ai n t he patie nt's me dical hist or y at t he Scree ni n g Visit.  Me dical hist or y 
will i ncl u de all acti ve c o n diti o ns, a n d a n y c o n diti o ns dia g n ose d wit hi n t he pri or 1 0 years t h at are 
c o nsi dere d t o be cli nicall y si g nifica nt b y t he I n vesti ga t or.  Si g nifica nt fi n di n gs t hat w ere prese nt 
pri or t o t he si g ni n g of i nf or me d c o nse nt m ust be i ncl u de d i n t he rele va nt me dical hist or y/ c urre nt 
me dical c o n diti o ns pa ge o n t he patie nt’s e C R F.   
7. 4. 4.  
E C O G Perf or m a nce St at us  
Easter n C o o perati ve O nc ol o g y Gr o u p p erf o r ma nce stat us (Ta ble  2 ) will be assesse d at t he 
Scree ni n g Visit, Da y 1 of eac h tr eat me nt c ycl e, E n d of Treat me nt Visit, a n d at t he Safet y 
F oll o w -u p Vi sit.  If t he S cree ni n g la b orat or y assess me nt is perf or me d ≤ 3 d a ys pri or t o t he first 
a d mi nistrati o n of tisleliz u ma b, t he y d o n ot h a ve t o be re peate d o n Da y 1 of C ycl e 1 a n d will be 
use d as Baseli ne.   
T a ble  2 : 
E C O G  Perf or m a nce St at us  
Gr a de  
P erf or m a nce  
0  
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n  
1  
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure, e. g. li g ht h o use w or k, office w or k  
2  
A m b ulat or y a n d ca pa ble of all selfcare b ut u na ble t o carr y o ut a n y w or k acti vities; u p a n d 
a b o ut m ore t ha n 5 0 % of wa ki n g h o urs  
3  
Ca pa ble of o nl y li mite d selfcare; c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs  
4  
C o m pletel y disa ble d; ca n n ot carr y o n a n y selfcare; t otall y c o nfi ne d t o be d or c hair  
5  
Dea d  
7. 4. 5.  
Electr oc a r di o gr a m  
E lectr ocar di o gra m ( E C G) assess me nts are t o be perf or me d wit h t he s u bject i n se mi -rec u m be nt 
s u pi ne p ositi o n a n d reste d f or 5 mi n utes.  
7. 4. 6.  
L a b or at or y E v al u ati o ns  
La b orat or y tests will be  c ollecte d a n d a n al yze d  as s pecifie d i n A p pe n di x  5 . Scree ni n g bl o o d tests 
perf or me d wit hi n 3 da ys of t he first st u d y dr u g a d mi nistrati o n d o n ot nee d t o be re peate d o n 
C ycle 1 Da y 1.  A b n or m al la b orat or y v al ues will c o nstit ute A Es o nl y if t he y are ass o ciate d wit h  
cli nical si g ns or s y m pt o ms t hat are cli nicall y si g nifica nt a n d/ or re q uire t h era p y, a n d s h o ul d  b e 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  6 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
rec or de d o n t he A Es e C R F.  I n a d diti o n, is olate d a b n or mal la b orat or y v al ues t hat are c o nsi dere d 
cli nicall y si g nifica nt (e. g. ca use st u d y disc o nti n uati o n or c o nstit utes i n a n d of itself a S A E) 
s h o ul d be rec or de d o n t h e A Es e C R F.  L o cal la b orat or y assess me nts o n ser u m c he mistr y, 
he mat ol o g y, c oa g ulati o n, a n d uri nal ysis will be c o n d ucte d, of w hic h cert ai n ele me nts will be 
c ollecte d as s p ecifie d i n A p pe n di x  2 . 
7. 4. 6. 1.  
He m at ol o g y  
He mat ol o g y l a b orat or y st u dies i ncl u de w hite bl o o d cell ( W B C) c o u nt wit h differe ntial 
( ne utr o p hil, l y m p h oc yt e, m o n oc yte, e osi n o p hil, bas o p hil), H g b, he m at ocrit, platelet c o u nt, a n d 
R B C i n dices. I n t he e v e nt of ≥ Gra de 3 n e utr o pe ni a or t hr o m b oc yt o pe nia t h at de vel o pe d o n st u d y 
treat me nt, fre q ue nc y of C B C m o nit ori n g will be c o n d ucte d as ofte n as cli nicall y i n dicat e d, at 
I n v esti gat or’s me dical j u d g me nt, t o e ns ure s u bject safet y, a n d cl ose m o nit ori n g s h o ul d occ ur 
u ntil t o xicit y res ol ves t o ≤ Gra de  2 . 
7. 4. 6. 2.  
Cli nic al C he mistr y  
Cli nical c he mistr y i ncl u d es s o di u m, p otassi u m, c hl ori de, bicar b o nate, bl o o d urea nitr o ge n 
( B U N), creati ni ne, gl uc ose, calci u m, ma g nesi u m, p h os p h or us, al b u mi n, A S T, A L T, t otal 
bilir u bi n, c o nj u gate d bilir u bi n, al kali ne p h os p hatase, lacta te de h y dr o ge n ase ( L D H), t otal pr otei n, 
uric aci d, creati ne ki nase, creati ne ki n ase -car diac m uscle is oe nz y me. I n t he e ve nt t hat creati ne 
ki nase -car diac m us cle is oe nz y me fracti o nati o n is n ot a vaila ble, pleas e assess tr o p o ni n I a n d/ or 
tr o p o ni n T i nstea d.  I n t he e ve nt of ≥ Gra de 3 cli nical c he mistr y t o xicit y t h at de vel o pe d o n st u d y 
treat me nt, fre q ue nc y of cli nical c he mistr y m o nit ori n g will be c o n d u cte d as ofte n as cli nicall y 
i n dicate d, at I n vesti gat or’s me dical j u d g me nt, t o e ns ure s u bject safet y, a n d cl ose m o nit ori n g 
s h o ul d occ ur u ntil t o xicit y res ol ves t o ≤ Gra d e  2.  
7. 4. 6. 3.  
C o a g ul ati o n  
C oa g ulati o n pr ofile i n cl u des P T, I N R, a n d a P T T will be perf or me d at Scree ni n g.  Re p eat testi n g 
ma y als o be perf or me d as cli nicall y i n dicat e d d uri n g t he treat me nt peri o d i ncl u di n g f or t h ose 
s u bjects recei vi n g a ntic o a g ul ati o n t hera p y at st u d y e ntr y.   
7. 4. 6. 4.  
Uri n al ysis  
Uri nal ysis will be ass ess e d usi n g uri n e di pstic k.  Uri ne micr osc o p y will be perf or me d if uri ne 
di pstic k is a b n or mal.  Uri nal ysis i ncl u des p H, gl uc ose, pr otei n, ket o nes, bilir u bi n, b l o o d, a n d 
s pecific gra vit y. 
7. 4. 6. 5.  
He p atitis B a n d He p atitis C Testi n g  
Testi n g will be perf or me d at Scree ni n g a n d i n cl u des H Bs A g, H Bc A b, H Bs A b, H C V A b, H B V 
D N A P C R, H C V R N A P C R.  S u bjects w h o are HI V A b or H Bs A g p ositi ve will be e x cl u de d 
fr o m st u d y e ntr y.  S u bjects w h o are H Bs A g ne gati ve b ut H Bc A b p ositi ve, H B V D N A m ust be 
<  1 0 0 0  I U/ ml t o be eli gi ble f or st u d y e ntr y.  S u bjects w h o are H C V A b p ositi ve, H C V R N A 
m ust be < 1 (l o g 1 0I U/ ml) t o be eli gi ble f or st u d y e ntr y. 
7. 4. 6. 6.  
T h yr oi d F u ncti o n Test  
Free T 3, Free T 4, a n d T S H will be perf or me d.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  6 1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
7. 4. 6. 7.  
Pre g n a nc y Test  
A ser u m pre g n a nc y test will be perf or me d at Scree ni n g a n d E n d of Treat m e nt i n w o me n of 
c hil d beari n g p ote ntial.  A n y fe male s u bject w h o is pre g na nt will n ot be eli gi ble f or t he st u d y.  
S u bjects m ust ha ve a ne gati ve ser u m pre g n a nc y test at Scree ni n g ( wit hi n 3 da ys b ef ore t he first 
i n vesti gati o nal pr o d u ct a d mi nistrati o n).  S u bse q ue nt tests ma y b e uri ne tests, a n d s h o ul d be 
perf or me d as cli nicall y i n dicate d. A s u bject w h o has a p ositi ve pre g na n c y test res ult at a n y ti me  
after t he st u d y dr u g a d mi nistrati o n will be i m me diatel y wit h dra w n fr o m partici pati o n i n t he 
st u d y.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  6 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
8.  
D A T A H A N D LI N G A N D Q U A LI T Y A S S U R A N C E  
T his st u d y will be or ga ni ze d, perf or me d, a n d re p orte d i n c o m plia nce wit h t he pr ot oc ol, sta n dar d 
o perati n g pr oce d ures ( S O Ps), w or ki n g practice d oc u me nts, a n d a p plica bl e re g ulati o ns a n d 
g ui deli nes.  Site a u dits will be ma de peri o dicall y b y t he S p o ns or’s or t he C o ntract Researc h 
Or ga niz ati o n’s ( C R O’s) q ualifie d c o m plia nce a u diti n g tea m, w hic h is a n i n de pe n de nt f u n cti o n 
fr o m the st u d y te a m res p o nsi ble f or c o n d uct of t h e st u d y.  
8. 1.  
D at a C ollecti o n  
A n electr o nic d ata ca pt ur e ( E D C) s yste m will be use d f or t his st u d y, mea ni n g t hat all e C R F d ata 
will be e ntere d i n el ectr o nic f or ms at t he st u d y ce nter.  Data c ollecti o n will be c o m plete d b y 
a ut h orize d st u d y ce nter p ers o n nel desi g nate d b y t h e i n vesti gat or.  A p pr o pri ate trai ni n g a n d 
sec urit y meas ur es will be c o m plete d wit h t he i n vesti gat or a n d all a ut h orize d st u d y ce nter 
pers o n nel pri or t o t he st u d y bei n g i nitiate d a n d a n y dat a bei n g e ntere d  i nt o t he s yste m f or a n y 
s u bjects. 
Data re q uire d b y t he pr ot oc ol will be c ollecte d o n t he eC R Fs a n d e ntere d i nt o a vali date d data 
ma na ge me nt s yste m t hat is c o m plia nt wit h all re g ulat or y re q uire m e nts.  As defi ne d b y 
I nter nati o nal C o nfere nce of Har m o nisati o n (I C H) g ui deli nes, t he case re p ort f or m ( C R F) is a 
pri nte d, o ptical, or ele ctr o nic d oc u me nt desi g ne d t o rec or d all t he pr ot oc ol -re q uire d i nf or mati o n 
t o be re p orte d t o t he s p o ns or o n eac h st u d y s u bject. 
Data c ollecti o n o n t he eC R F m ust f oll o w t he i nstr ucti o ns descri be d i n t he eC R F C o m pleti o n 
G ui deli nes.  T he i n vesti gat or has ulti mate res p o nsi bilit y f or t he c ollecti o n a n d re p orti n g of all 
cli nical data e ntere d o n t he eC R F.  T he i n vesti gat or or desi g nee m ust si g n t he c o m plete d C R F t o 
attest t o its acc urac y, a u t he nticit y, a n d c o m plete ness. 
C o m plete d, eC R Fs are t h e s ole pr o pert y of Bei Ge ne a n d s h o ul d n ot be ma de a vaila ble i n a n y 
f or m t o t hir d parties wit h o ut writte n per missi o n fr o m Bei Ge n e, e x ce pt f or a ut h orize d 
re pres e ntati ves of Bei G e ne or a p pr o priate re g ulat ory a ut h orities.  
8. 2.  
D at a M a n a ge me nt/ C o di n g  
Data ge n erate d wit hi n t his cli nical st u d y will be ha n dle d per t he rele va nt S O Ps of t he data 
ma na ge me nt a n d bi ostatistics de part me nts.  
T he e C R Fs s h o ul d al wa ys reflect t he l atest o bser v ati o ns o n t he s u bjects partici pati n g i n t he 
st u d y.  T heref ore, t he e C R Fs are t o b e c o m plete d as s o o n as p ossi ble d uri n g or after t h e s u bject’s 
visit.  T o a v oi d i nter -o bser ver varia bilit y, e ver y eff ort s h o ul d be ma de t o e ns ure t hat t he sa me 
i n di vi d ual w h o ma de t he i nitial baseli ne deter mi nati o ns c o m pletes all safet y e val uati o ns.  T he 
i n vesti gat or m ust verif y t hat all data e ntries i n t he e C R Fs are acc urate a n d c orrect.  If s o me 
assess me nts are n ot d o n e, or if cert ai n i nf or mati o n is n ot a vaila ble or n ot a p plica ble or u n k n o w n, 
t he i n vesti gat or sh o ul d i n dicate t his i n t he e C R F.  T he i n vesti gat or will be re q uire d t o 
electr o nicall y si g n off o n t he cli nical data.   
T he m o nit or will re vie w t he e C R Fs a n d e v al uate t he m f or c o m plete ness a n d c o nsiste nc y.  T he 
e C R F will be c o m pare d wit h t he s o urce d oc u m e nt s t o e ns ure t hat t here are n o discre pa n cies 
bet wee n critical data.  All e ntries, c orrecti o ns, a n d alterati o ns are t o be ma d e b y t h e res p o nsi ble 
i n vesti gat or or his/ her desi g nee.  T he m o nit or ca n n ot e nter data i n t he e C R Fs.  O nce cli nical data 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  6 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
of t he e C R F h a v e bee n s u b mitte d t o t he ce ntral ser ver, c orrecti o ns t o t he data fiel ds will be a u dit 
traile d, mea ni n g t hat t he reas o n f or c ha n ge, t he na me of t he pers o n w h o perf or me d t he c h a n ge, 
t o get her wit h ti me a n d date will be l o g ge d.  R oles a n d ri g hts of t he st u d y ce nter pers o n nel 
res p o nsi ble f or e nteri n g t he cli nical data i nt o t he e C R F will be deter mi ne d i n a d va nce.  If 
a d diti o nal c orrecti o ns are nee de d, t he res p o nsi ble m o nit or or data ma na ger will raise a q uer y i n 
t he E D C a p plicati o n.  T h e a p pr o pri ate st u d y ce nter pers o n nel will a ns wer q ueries se nt t o t he 
i n vesti gat or. 
T he e C R F is esse ntiall y c o nsi dere d a d ata e ntr y f or m a n d s h o ul d n ot c o nstit ute t he ori gi n al ( or 
s o urce) me di cal r ec or ds u nless ot her wise s pecifie d.  S o urce d oc u me nts are all d oc u me nts use d 
b y t he i n v esti gat or or h os pital t hat relate t o t he s u bject’s me dical hist or y, t h at verif y t he e xiste nce 
of t he s u bject, t he i ncl usi o n a n d e x cl usi o n criteria a n d all rec or ds c o veri n g t he s u bject’s 
partici pati o n i n t he st u d y.  T he y i n cl u de la b orat or y n otes, E C G res ult s, me m ora n da, p har mac y 
dis pe nsi n g rec or ds, s u bject files, etc.  
T he I n vesti gat or is r es p o nsi ble f or mai ntai ni n g s o urce d oc u m e nts.  T hese will be ma de a vaila ble 
f or i ns pecti o n b y t he st u d y m o nit or at eac h m o nit ori n g visit.  T he i n vesti gat or m ust s u b mit a 
c o mplete d e C R F f or eac h s u bject w h o recei ves tisleliz u ma b, re gar dless of t he d urati o n.  All 
s u p p orti ve d oc u me ntati o n s u b mitte d wit h t he e C R F, s uc h as la b orat or y or h os pital rec or ds, 
s h o ul d be clearl y i de ntifi e d wit h t he st u d y a n d s u bject n u m ber.  A n y pers o nal  i nf or mati o n, 
i ncl u di n g s u bject na m e, s h o ul d be re m o ve d or re n dere d ille gi ble t o pres er ve i n di vi d ual 
c o nfi de ntialit y.  
Electr o nic C R F rec or ds will be a ut o maticall y a p p e n de d wit h t he i de ntificati o n of t he creat or, b y 
mea ns of t heir u ni q ue Us er I D.  S pe cifie d  rec or ds will be electr o nicall y si g ne d b y t h e 
i n vesti gat or t o d oc u m e nt his/ her re vie w of t he data a n d ac k n o wl e d ge me nt t hat t he data are 
acc urate.  T his will be facilitate d b y mea ns of t he i n vesti gat or’s u ni q u e User I D a n d p ass w or d; 
date a n d ti me sta m ps wil l be a d de d a ut o maticall y at t he ti me of t he electr o ni c si g nat ure.  If a n 
e ntr y o n a n e C R F re q uires c ha n ge, t he c orrecti o n s h o ul d be ma de i n acc or da nce wit h t he rele va nt 
s oft ware pr oce d ures.  All c ha n ges will be f ull y rec or de d i n a pr otecte d a u dit trail, a n d a reas o n 
f or t he c h a n ge will be re q uire d. 
A d verse e ve nts will be c o de d usi n g t he M e dical Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A® ) Versi o n 19 . 1 or hi g h er.  C o nc o mita nt me dicati o ns will be c o de d usi n g t he W orl d 
Healt h Or ga niz ati o n Dr u g Dicti o nar y ( W H O -D D).  C o nc o mita nt diseases/ me dical hist or y will be 
c o de d usi n g t he Me d D R A Versi o n 1 9 . 1 or hi g her. 
8. 3.  
Q u alit y Ass ur a nce  
T o e ns ure c o m plia n ce wit h G o o d Cli nical Practice ( G C P) a n d all a p plica ble re g ulat or y 
re q uire me nts, t he s p o ns or ma y c o n d uct a q ualit y ass ura nce a u dit.  Re g ul at or y a ge nci es ma y als o 
c o n d uct a re g ulat or y i ns p ecti o n of t his st u d y.  S uc h a u dits/i ns pecti o ns ca n occ ur at a n y ti me 
d uri n g or after c o m pleti o n of t he st u d y.  If a n a u dit or i ns pecti o n occ urs, t h e i n vesti gat or a n d 
i nstit uti o n a gree t o all o w t he a u dit or/i ns pect or direct access t o all rele va nt d oc u me nts a n d t o 
all ocate his/ her ti me a n d t he ti me of his/ her pers o n nel t o t he a u dit or/i ns pect or t o disc uss fi n di n gs 
a n d a n y rel e va nt iss ues.  
C CI

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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
9.  
S A F E T Y M O NI T O RI N G A N D R E P O R TI N G  
T he i n vesti gat or is res p o nsi ble f or t he m o nit ori n g a n d d oc u me ntati o n of e v e nts t hat meet t he 
criteria a n d defi niti o n of a n A E or S A E as pr o vi de d i n t his pr ot oc ol.  
9. 1.  
A d verse E ve nts  
9. 1. 1.  
Defi niti o n a n d Re p orti n g of a n A d verse E ve nt  
A n A E is defi ne d as a n y u nfa v ora bl e a n d u ni nte n d e d si g n (i n cl u di n g a n a b n or mal la b orat or y 
fi n di n g), s y m pt o m, or dis ease ( ne w or e x acer bate d) te m p orall y ass ociat e d wit h t he use of a st u d y 
dr u g, w het her c o nsi dere d relate d t o st u d y dr u g or n ot.  
E x a m ples of a n A E i ncl u de:  
•  W orse ni n g of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g a n i ncreas e i n 
se verit y, fre q ue nc y, d urati o n, a n d/ or has a n ass o ciati o n wit h a si g nifica ntl y w orse 
o utc o me.    
•  Ne w c o n diti o ns detect e d or dia g n os e d after st u d y dr u g a d mi nistrati o n e ve n t h o u g h it 
ma y h a ve bee n pres e nt b ef ore t h e start of t he st u d y.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d i nteracti o n.  
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y dr u g 
or a c o nc urre nt me di cati o n ( o ver d ose p er se s h o ul d n ot be re p orte d as a n A E or S A E).  
W he n a n A E or S A E occ urs, it is t he res p o nsi bilit y of t he i n v esti gat or t o re vie w al l 
d oc u me ntati o n (e. g., h os pital pr o gress n otes, la b orat or y res ults a n d dia g n ostics re p orts) relati ve 
t o t he A E or S A E. T he i n vesti gat or will t he n rec or d all rele va nt i nf or m ati o n re gar di n g a n A E or 
S A E i n t he e C R F. H o we ver, t here ma y be i nsta nces w he n c o pie s of me dical rec or ds f or certai n 
cases are re q ueste d b y t h e s p o ns or.  I n t his i nsta nce, all s u bject i de ntifiers will be bli n de d o n t he 
c o pies of t he me dic al rec or ds pri or t o s u b missi o n t o t he s p o ns or.  
9. 1. 2.  
Assess me nt of Se verit y  
T he i n vesti gat or will ma ke a n a ssess me nt of se verit y f or eac h A E a n d S A E re p orte d d uri n g t h e 
st u d y. A Es a n d S A Es s h o ul d be assesse d a n d gra de d base d u p o n t he N CI-C T C A E v 4. 0 3.  
T o xicities t hat are n ot s pecifie d i n t he N CI -C T C A E will be defi ne d as f oll o ws:  
•  Gra de 1: Mil d; as y m pt o matic or mi l d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d  
•  Gra de 2: M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate i nstr u me ntal acti vities of dail y li vi n g ( A D L)  
•  Gra de 3: Se vere or me dic all y  si g nifica nt b ut n ot i m me diatel y life-t hreate ni n g; 
h os pitaliz ati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self -
care A D L  
•  Gra de 4: Lif e -t hreate ni n g c o nse q ue nces; ur ge nt i nt er ve nti o n i n dicate d  
•  Gra de 5: D eat h r elate d t o A E  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
N O T E: T he ter ms “s e vere” a n d “seri o us” are n ot s y n o n y m o us. Se verit y is a meas ure of i nte nsit y 
(f or e x a m ple, gra d e of a s pecific A E, mil d [ Gra de 1], m o derate [ Gra de 2], se vere [ Gra de 3], or 
life-t hreat e ni n g [ Gra de 4]), w hereas s eri o us ness is classifie d b y t he criteria base d o n t he 
re g ulat or y defi niti o ns. Seri o us ness ser ves as t he g ui de f or defi ni n g re g ulat or y re p orti n g 
o bli gati o ns fr o m t he S p o ns or t o a p plica ble re g ulat or y a ut h orities as descri b e d i n Secti o n  9. 1. 8. 1 . 
9. 1. 3.  
Assess me nt of C a us alit y  
T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n t he st u d y dr u g a n d t h e occ urre n ce 
of eac h A E or S A E.  T he i n vesti gat or will use cli nical j u d g me nt t o deter m i ne t he relati o ns hi p. 
Alter nati ve ca uses, s uc h as nat ural hist or y of t he u n derl yi n g dise ases, c o n c o mita nt t hera p y, ot h er 
ris k fact ors, a n d t he te m p oral relati o ns hi p of t he A E or S A E t o t he st u d y dr u g will be c o nsi dere d 
a n d i n vesti gat e d.  T he i n vesti gat or w ill als o c o ns ult t he I B a n d/ or Pr o d u ct I nf or mati o n, f or 
mar kete d pr o d u cts, i n t he deter mi nati o n of his/ her assess me nt.  
T here ma y b e sit uati o ns w he n a n S A E has o cc urre d, a n d t he i n vesti gat or h as mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort t o t he s po ns or.  H o we ver, it is ver y i m p orta nt t hat t he 
i n vesti gat or al wa ys ma kes assess me nt of ca us alit y f or e ver y S A E pri or t o tra ns missi o n of t he 
S A E re p ort/e C R F t o t he s p o ns or si nce t he ca usalit y ass ess me nt is o ne of t h e criteri a use d w he n 
deter mi ni n g re g ulat or y re p orti n g re q uire me nts.  T h e i n vesti gat or ma y c h a n ge his/ her o pi ni o n of 
ca usalit y i n li g ht of t he f oll o w-u p i nf or mati o n, a me n di n g t he S A E re p ort/ e C R F acc or di n gl y.  
I n v esti gat ors m ust  als o sy ste maticall y assess t he ca usal  relati o ns hi p o f A Es  t o i n v esti g ati o n al 
m e di ci n al pr o d u ct (s) ( I M P [s])/st u d y treat me nt (i ncl u di ng  a n y  ot her  n o n -IM Ps,  ra di ati on 
t hera py , et c. ) usi n g t he f oll o wi ng d efi niti o ns:  
•  Defi nitel y relate d: T h ere is clear e vi d e nce t o s u g gest a ca us al relati o ns hi p t hat t here is 
reas o na bl e te m p oral r elati o ns hi p; t he p ositi ve of de-c halle n ge res ult ( w he n necessar y 
t he p ositi ve of re-c halle n ge res ult); t he occ urre nce of A E t hat c o ul d be attri b ute d t o 
t he p har mac ol o gic al effect of st u d y tr eat me nt 
•  Pr o ba bl y relate d: T his ca usalit y assess me nt will  b e a p plie d f or A E t hat is re gar de d b y 
t he i n vesti gat or as hi g hl y p ositi ve relate d t o t he st u d y treat me nt t hat: T here is a 
reas o na bl e te m p oral r elati o ns hi p; t he occ urre n ce of A E c o ul d n ot be e x plai ne d b y t h e 
s u bject’s me dical hist or y, c o nc urre nt me dical c on diti o n, or ot her t he s u bject’s si g ns 
or s y m pt o ms; t he p ositi ve of de -c halle n ge res ult; t he p ositi ve of re -c halle n ge res ult.  
•  P ossi bl y relate d: T here is s o me e vi de nce t o s u g gest a ca usal r elati o ns hi p (e. g., t he A E 
occ urre d wit hi n a reas o n a ble ti me after a d m i nistrati o n of t he st u d y dr u g).  H o we ver, 
t he i nfl ue nce of ot her fact ors ma y h a ve c o ntri b ute d t o t he A E (e. g., t he s u bject’s 
cli nical c o n diti o n, ot her c o nc o mita nt A Es).  
•  U nli kel y relate d: T here is little e vi de nce t o s u g gest t here is a ca us al relati o ns hi p. 
T here is a n ot her reas o na ble e x pla nati o n f or t he A E.  
•  U nrelate d: A n A E will be c o nsi dere d “ n ot rel ate d” t o t he use of t he pr o d u ct if a n y of 
t he f oll o wi n g tests are m et: 
− A n u nreas o n a ble te m p or al relati o ns hi p bet wee n a d mi nistrati o n of t he pr o d uct a n d 
t he o nset o n t he A E (e. g., t he A E occ urre d eit her bef ore, or t o o l o n g after 
a d mi nistrati o n of t he pr o d uct f or it t o be c o nsi dere d pr o d uct -relate d); 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
− A ca usal r elati o ns hi p bet wee n t he pr o d uct a n d t he A E is bi ol o gicall y i m pla usi ble 
(e. g., deat h as a pass e n ger i n a n a ut o m o bile acci de nt);  
− A clearl y m or e li kel y alter nati ve e x pla nati o n f or t h e A E is prese nt (e. g., t y pical 
a d verse reacti o n t o a c o n c o mita nt dr u g a n d/ or t y pical disease -rel ate d A E). 
9. 1. 4.  
F oll o w -U p of A d verse E ve nts  
After t he i nitial A E or S A E re p ort, t he i n ves ti gat or is re q uire d t o pr o acti v el y f oll o w eac h s u bj ect 
a n d pr o vi de f urt her i nf or mati o n t o t he s p o ns or o n t he s u bject’s c o n diti o n.  
All A Es a n d S A Es d oc u me nte d at a pre vi o us visit/c o ntact a n d desi g nate d as o n g oi n g will be 
re vie we d at s u bse q ue nt visits/c o ntacts. 
All A Es a n d S A Es will be f oll o we d u ntil res ol uti o n, t he c o n diti o n sta bilizes or is c o nsi dere d 
c hr o nic, t he A E or S A E is ot her wise e x plai ne d, t he s u bject is l ost t o f oll o w -u p or t he s u bject 
wit h dra ws c o nse nt. O n ce res ol ve d, t he a p pr o priate A E or S A E e C R F pa ge(s) will be u p date d. 
T he i n vesti gat or will e ns ure t hat f oll o w -u p i ncl u d es a n y s u p ple me ntal i n vesti gati o ns as ma y be 
i n dicate d t o el uci date t he nat ure a n d/ or ca usalit y of t he A E or S A E.  T his m a y i n cl u de a d diti o nal 
la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gi cal e xa mi nati o ns, or c o ns ultati o n wit h ot her 
healt h care pr ofessi o nals.  
T he s p o ns or ma y re q uest t hat t he i n vesti gat or p erf or m or arra n ge f or t he c o n d uct of s u p ple me ntal 
meas ure me nts a n d/ or e val uati o ns t o el uci date as f ull y as p ossi ble t he nat ure a n d/ or ca us alit y of 
t he A E or S A E. T he i n vesti gat or is o bli gate d t o assist.  If a s u bj ect dies d uri n g partici p ati o n i n 
t he st u d y or d uri n g a rec o g niz e d f oll o w-u p peri o d, t he s p o ns or will be pr o vi de d wit h a c o p y of 
a n y p ost -m orte m fi n di n gs, i ncl u di n g hi st o pat h ol o g y. 
Ne w or u p d ate d i nf or mati o n will be rec or de d o n t he ori gi n all y c o m plete d S A E re p ort/e C R F, 
wit h all c ha n ges si g ne d a n d date d b y t he i n vesti gat or. T he u p date d S A E re p ort/e C R F s h o ul d be 
rese nt t o t he s p o ns or wit hi n t he ti me fra mes o utli ne d i n Sec ti o n 9. 1. 8. 1 . 
9. 1. 5.  
L a b or at or y Test A b n or m alities  
A b n or mal la b orat or y fi n di n gs (e. g., cli nical c he mistr y, C B C, c o a g ulati o n, or uri nal ysis) or ot her 
a b n or mal assess me nts ( e. g., E C Gs, X -ra ys, or vital si g ns) t hat are j u d ge d b y t he i n vesti gat or as 
cli nicall y si g nifica nt will be rec or de d as A Es or S A Es if t he y meet t he defi niti o n of a n A E (as 
defi ne d i n Secti o n  9. 1. 1 ) or a n S A E (as i n Secti o n  9. 1. 6 ). Cli nicall y si g nifica nt a b n or mal 
la b orat or y fi n di n gs or ot her a b n or m al assess me nts t hat are det ecte d d uri n g t he st u d y or are 
prese nt at bas eli ne a n d si g nifica ntl y w orse n f oll o wi n g t he start of t he st u d y will be re p orte d as 
A Es or S A Es. H o we v er, cli nicall y si g nifica nt a b n or mal la b orat or y f i n di n gs or ot her a b n or mal 
assess me nts t hat are ass o ciate d wit h t he diseas e bei n g st u die d, u nless j u d ge d b y t he i n vesti gat or 
as m ore se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n, or t hat are pres e nt or detecte d at t he 
start of t he st u d y a n d d o n ot w orsen, will n ot be re p orte d as A Es or S A Es. T he y s h o ul d b e 
re p orte d as A Es or S A Es if t he y i n d uc e cli nical si g ns or s y m pt o ms, nee d acti ve i nter ve nti o n, 
nee d d ose i nterr u pti o n or disc o nti n uati o n or are cli nicall y si g nifica nt i n t he o pi ni o n of t he 
i n vesti gat or. 
T he i n vesti gat or will e x ercise his/ her me dical a n d scie ntific j u d g m e nt i n deci di n g w het her a n 
a b n or mal la b orat or y fi n di n g or ot her a b n or mal assess me nt is cli nicall y si g nifica nt.  
C CI

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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
9. 1. 6.  
Defi niti o n of a Seri o us A d verse E ve nt  
A n S A E is a n y u nt o w ar d me dical occ urre n ce t hat, at a n y d ose:  
•  Res ults i n deat h.  
•  Is life-t hreate ni n g.  
N O T E: T he ter m “life -t hreate ni n g” i n t he d efi niti o n of “seri o us” refers t o a n A E 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 A E. It d oes n ot refer t o a n 
A E, w hic h h y p ot hetica ll y mi g ht ha ve ca use d d eat h, if it were m ore s e vere.  
•  Re q uires h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n.  
N O T E: I n ge n eral, h os pitalizati o n si g nifies t hat t he s u bject was a d mitte d ( us uall y 
i n v ol vi n g at least a n o v er ni g ht sta y) t o t he h ospital or e mer ge nc y war d f or 
o bser vati o n a n d/ or tr eat me nt t hat w o ul d n ot ha ve bee n a p pr o priate i n t he p h ysicia n’s 
office or o ut p atie nt setti n g.  C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es.  
If a c o m plic ati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot h er seri o us criteri a, t he A E 
is seri o us.  W he n i n d o u bt as t o w het her “ h os pitali zati o n” occ urre d or was necessar y, 
t he A E s h o ul d be c o nsi dere d seri o us.  
− H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot 
w orse n fr o m b ase li ne is n ot c o nsi dere d a n S A E. 
− H os pitalizati o n f or s ocial/c o n ve nie nce c o nsi derati o ns is n ot c o nsi dere d a n S A E.  
− Sc he d ule d t hera p y f or t h e tar get disease of t he st u d y, i ncl u di n g a d missi o ns f or 
tra nsf usi o n s u p p ort or c o n ve nie nce, is n ot c o nsi dere d a n S A E.  
•  R es ults i n disa bilit y/i nca pacit y.  
N O T E: T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o 
c o n d uct n or mal life f u ncti o ns.  T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces 
of relati vel y mi n or me dic al si g nifica nce, s u c h as u nc o m plicate d hea dac h e, na usea, 
v o miti n g, diarr hea, i nfl ue nza, a n d acci d e ntal tra u m a (e. g., s prai ne d a n kle), w hic h ma y 
i nterfere or pre ve nt e v er y da y life f u ncti o ns, b ut d o n ot c o nstit ute a s u bsta ntial 
disr u pti o n.  
•  Is a c o n ge nital a n o mal y/ birt h defect.  
•  Is c o nsi dere d a si g nifica nt me dical A E b y t he i n vesti gat or bas e d o n me dical 
j u d ge me nt (e. g., ma y je o par dize t he s u bject or ma y re q uire me di cal/s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve). 
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9. 1. 7.  
Ti mi n g, Fre q ue nc y, a n d Met h o d of C a pt uri n g A d ver se E ve nts a n d Seri o us 
A d verse E ve nts  
9. 1. 7. 1.  
A d verse E ve nt Re p orti n g Peri o d  
After t he i nf or me d c o nse nt has bee n si g ne d b ut pri or t o t he a d mi nistrati o n of t he st u d y dr u g, o nl y 
S A Es s h o ul d be re p orte d.  
After i nitiati o n of st u d y dr u g, all A Es a n d S A Es, re gar dless of relati o ns hi p t o st u d y dr u g, will be 
re p orte d u ntil 9 0 da ys after t he last st u d y treat me nt of tisleliz u ma b.  After t his peri o d, t he 
i n vesti gat or s h o ul d r e p ort a n y S A Es t hat are belie ve d t o be relat e d t o pri or st u d y dr u g tr eat me nt. 
9. 1. 7. 2.  
Eliciti n g A d verse E ve nt  
T h e I n vesti gat or or d esi g nee will as k a b o ut A Es b y as ki n g t he f oll o wi n g st a n dar d q uesti o ns:  
•  H o w are y o u feeli n g?  
•  Ha ve y o u ha d a n y me dical pr o ble ms si nce y o ur last visit?  
•  Ha ve y o u ta k e n a n y ne w me dici nes si nce y o ur last visit?  
9. 1. 7. 3.  
S pecific I nstr ucti o ns f or Re c o r di n g A d verse E ve nts a n d Seri o us A d verse E ve nts  
9. 1. 7. 3. 1.  Di a g n osis vers us Si g ns a n d S y m pt o ms  
If a dia g n osis is k n o w n at t he ti me of re p orti n g, t his s h o ul d be rec or de d i n t he e C R F (a n d S A E 
re p ort, as a p plica ble), rat her t ha n t he i n di vi d ual si g ns a n d s y m pt o ms (e. g., rec or d o nl y h e patitis 
rat her t ha n ele vate d tra ns a mi nases, bilir u bi n or ja u n dice).  H o we ver, if a c o nstellati o n of si g ns 
a n d/ or s y m pt o ms ca n n ot be me dicall y c haracterize d as a si n gl e dia g n osis or s y n dr o me at t he ti me 
of re p orti n g, eac h i n di vi d ual A E s h o u l d be rec or de d as a n S A E or A E o n t h e e C R F (a n d S A E 
re p ort, if a p plica ble).  If a dia g n osis is s u bse q ue ntl y esta blis he d, it s h o ul d re place t h e i n di vi d ual 
si g ns a n d/ or s y m pt o ms as t he A E ter m o n t he e C R F (a n d S A E re p ort, if a p plica ble), u nless t he 
si g ns/s y mpt o ms are cli nicall y si g nifica nt.  
9. 1. 7. 3. 2.  A d verse E ve nts Occ urri n g Sec o n d ar y t o Ot her E ve nts  
I n ge neral, A Es occ urri n g sec o n dar y t o ot her A Es (e. g., cli nical se q u elae or a cas ca d e of A Es) 
s h o ul d be i de ntifie d b y t h eir pri mar y ca use. F or e x a m ple, if se vere v o miti n g  is k n o w n t o res ult i n 
de h y drati o n, it is s ufficie nt t o rec or d o nl y v o miti n g as t he S A E or A E o n t h e e C R F (a n d S A E 
re p ort, if a p plica ble). H o we ver, if a s u bject i nitiall y has a n o n-seri o us A E, a n d it s u bse q ue ntl y 
bec o mes a n S A E, b ot h A Es s h o ul d be re p orte d  s e paratel y o n t he e C R F. T h e o nset date of t h e 
n o n -seri o us A E s h o ul d b e rec or de d as t he start dat e of t he n o n-s eri o us A E.  T he o nset date of t h e 
S A E s h o ul d be rec or de d as t he start date w he n t he n o n -seri o us A E bec o mes a n S A E.   
9. 1. 7. 3. 3.  Persiste nt or Rec u rri n g A d ve rse E ve nts  
A persiste nt A E is o ne t h at e xte n ds c o nti n u o usl y, wit h o ut res ol uti o n, bet wee n s u bject e val u ati o n 
ti me p oi nts.  S uc h A Es s h o ul d o nl y be rec or de d o nce o n t he A E e C R F (a n d S A E re p ort, if 
a p plica ble). If a p ersiste nt A E w orse ns i n gra d e, it s h o ul d b e rec or de d as a n e w A E o n t he e C R F 
(a n d a st o p date s h o ul d b e rec or de d i n t he pre vi o us A E).  
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A rec urre nt A E is o n e t hat occ urs a n d res ol ves b et wee n s u bject e val uati o n ti me p oi nts, a n d 
s u bse q ue ntl y rec urs.  All rec urre nt A Es s h o ul d be rec or de d se paratel y o n  t h e e C R F (a n d S A E 
re p ort, if a p plica ble).  
9. 1. 7. 3. 4.  Dise ase Pr o g ressi o n  
Disease pr o gressi o n is meas ure d as a n efficac y e n d p oi nt a n d n ot c o nsi dere d t o be a n A E.  
H o we ver, if t here are se p arate i de ntifia bl e cli nical se q uelae t hat res ult fr o m disease pr o gressi o n, 
t hose se q uelae are re p ort a ble as A Es.  F or i nsta nce, a s u bject wit h ple ural eff usi o n prese nts wit h 
s h ort ness of breat h.  T he ca use of t h e s h ort ness of breat h is a ple ural eff usi o n res ulti n g fr o m 
disease pr o gressi o n.  T he A E ter m s h o ul d be re p orte d as “ ple ura l eff usi o n” i nstea d of disease 
pr o gressi o n or metastasis t o l u n gs.  If a s u bject has a seiz ure t hat is deter mi ne d t o be ass ociat e d 
wit h a brai n metastasis, t he ter m “seiz ure” s h o ul d be rec or de d as t he A E i nstea d of diseas e 
pr o gressi o n or brai n metastasis.  If a s u bject e x perie nce d m ulti-or ga n fail ure d ue t o diseas e 
pr o gressi o n, t he ter m “ m ulti -or ga n fail ure” s h o ul d be re p ort e d as t he A E i nstea d of diseas e 
pr o gressi o n.  Deat hs t hat are ass esse d b y t he i n vesti gat or as s olel y d u e t o disease pr o gressi o n 
s h o ul d be rec or de d o n St u d y C o m pleti o n or Earl y Disc o nti n uati o n e C R F as efficac y dat a.  T he y 
s h o ul d n ot be re p orte d as a n S A E.  If deat hs are assesse d b y t he i n vesti gat or as n ot s olel y d u e t o 
disease pr o gressi o n, w het her t he y are assess e d as relate d or n ot r elate d t o t he st u d y dr u g, t h e y 
s h o ul d be re p orte d as a n S A E i m me diatel y.  
If t here is a n y u ncertai nt y re gar di n g w het her a n A E is d ue t o disease pr o gressi o n, it s h o ul d be 
re p orte d as a n A E. 
9. 1. 7. 3. 5.  De at h  
W he n rec or di n g a d eat h as a n S A E, t he A E t hat ca use d or c o ntri b ute d t o fatal o utc o me s h o ul d be 
rec or de d as t he si n gle me dical c o nce pt.  If t he ca us e of deat h is u n k n o w n a n d ca n n ot be 
ascert ai ne d at t he ti me of re p orti n g, rec or d “ u n e x plai ne d deat h”.  
9. 1. 8.  
Pr o m pt Re p orti n g of Seri o us A d verse E ve nts  
9. 1. 8. 1.  
Ti mefr a mes f or S u b m itti n g Seri o us A d verse E ve nts  
Seri o us a d verse e ve nts will be re p orte d pr o m ptl y t o t he s p o ns or or desi g nee as descri be d i n 
Ta ble  3 , once t h e i n vesti ga t or d eter mi nes t hat t he A E meets t he pr ot oc ol defi niti o n of a n S A E. 
T a ble  3 : 
Ti me  Fr a me f or R e p orti n g Seri o us A d verse E ve nts t o t he S p o ns or or 
Desi g nee  
T y pe of S A E  
I niti al Re p ort 
D oc u me nt  
F oll o w -u p S A E  
D oc u me nt  
All S A Es  
Wit hi n 2 4 h o urs of 
first k n o wle d ge of 
t he S A E  
S A E f or m  
As e x pe diti o usl y as 
p ossi ble  
U p date d S A E 
f or m 
 
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9. 1. 8. 2.  
C o m pleti o n a n d Tr a ns missi o n of t he Seri o us A d verse E ve nt Re p ort  
O nce a n i n v esti gat or bec o mes a ware t hat a n S A E has occ urre d i n a s u bject, he/s he will re p ort t he 
i nf or mati o n t o t he s p o ns or wit hi n 2 4 h o urs as o utli ne d i n Secti o n  9. 1. 8. 1 . T he S A E re p ort f or m 
will al wa ys b e c o m plete d as t h or o u g hl y as p ossi ble wit h all a vaila ble det ails of t he S A E, si g ne d 
b y t he i n vesti gat or a n d f or war de d t o t he s p o ns or wit hi n t he desi g nate d ti me fra mes. If t he 
i n vesti gat or d o es n ot hav e all t he i nf or mati o n re gar di n g a n S A E h e/s he will n ot wait t o recei ve 
a d diti o nal i nf or mati o n bef ore n otif yi n g t he s p o ns or of t he S A E/ A E  of s peci al i nterest  a n d 
c o m pleti n g t he f or m. T he f or m will be u p date d w h e n a d diti o nal i nf or mati o n is recei ve d. T h e 
i n vesti gat or will al w a ys pr o vi de a n ass ess me nt of ca usalit y at t he ti me of t he i nitial re p ort as 
descri be d i n Secti o n  9. 1. 8. 1 .  
E -mail tra ns missi o n of t he S A E re p ort f or m is t he preferre d m et h o d t o tra ns mit t his i nf or mati o n 
t o t he pr oject c o ntact f or S A E recei pt. Facsi mile tr a ns missi o n is t he bac k-u p met h o d f or S A E 
re p orti n g.   
T he s p o ns or will pr o vi de a list of pr oject c o ntacts f or S A E recei pt, fa x n u m bers, tele p h o ne 
n u m bers, a n d maili n g a d dresses.  
9. 1. 8. 3.  
Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts  
T he i n vesti gat or will pr o m ptl y re p ort all S A Es t o t he s p o n s or i n acc or da nce wit h t he pr oce d ures 
detaile d i n Secti o n  9. 1. 8 . T he s p o ns or has a l e gal r es p o nsi bilit y t o n otif y, as a p pr o priate, b ot h t he 
l ocal re g ulat or y a ut h orit y a n d ot her re g ulat or y a ge ncies a b o ut t he safet y of a pr o d uct u n der 
cli nical i n vesti gati o n.  Pr o m pt n otificati o n of S A Es b y t he i n vesti gat or t o t h e a p pr o pri ate pr oject 
c o ntact f or S A E recei pt is esse ntial s o t hat le gal o bli gati o ns a n d et hical res p o nsi bilities t o war ds 
t he safet y of ot her s u bjects are met.  
T he i n vesti gat or, or res p o nsi ble pers o n acc or di n g t o l ocal re q uire m e nts, will c o m pl y wit h t he 
a p plica ble l ocal re g ulat or y re q uire me nts relate d t o t he re p orti n g of S A Es t o re g ulat or y a ut h orities 
a n d t he I nstit uti o nal Re vie w B o ar d (I R B)/I n d e pe n de nt Et hics C o m mittee (I E C).  
E x pe dite d i n vesti gat or safet y re p orts are pre pare d acc or di n g t o t he s p o ns or’s p olic y a n d are 
f or war de d t o i n vesti gat ors as necess ar y.  T he p ur p ose of t he re p ort is to f ulfill s pecific re g ulat or y 
a n d G C P re q uire me nts r e gar di n g t h e pr o d uct u n d er i n vesti gati o n.  
W he n a st u d y ce nter recei ves a n i nitial or f oll o w -u p re p ort or ot her safet y i nf or mati o n (e. g., 
re vise d I B) fr o m t he s p o ns or, t he res p o nsi ble pers o n acc or di n g t o local re q uire me nts is re q uire d 
t o pr o m ptl y n otif y his/ her I R B or I E C. 
9. 1. 9.  
Pre g n a nc y Re p orti n g  
If a fe male s u bject or t he part ner of a male s u bject bec o mes pre g na nt w hile recei vi n g 
i n vesti gati o nal t hera p y or wit hi n 1 2 0 da ys after t he last d ose of tisleliz u ma b, a pre g na n c y re p ort 
f or m s h o ul d be c o m plete d a n d e x pe diti o usl y s u b mitte d t o t he s p o ns or t o facilitate o utc o me 
f oll o w-u p. I nf or m ati o n o n t he stat us of t he m ot her a n d c hil d will be f or war de d t o t he s p o ns or. 
Ge nerall y, f oll o w -u p will be n o l o n ger t ha n 6 t o 8 we e ks f oll o wi n g t he esti mate d deli ver y dat e. 
A n y pre mat ure ter mi nati o n of t he pre g n a nc y will be re p ort e d.  
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W hile pre g na n c y itself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y c o m plicati o n or 
electi ve ter mi nati o n of a pre g na nc y f or me dical reas o ns will be rec or de d as a n A E or S A E.  
Pre g n a nc y s h o ul d be rec or de d o n Pre g na nt F or m i n e C R F.  
A n a b orti o n, w het her acci de ntal, t hera pe utic, or s p o nta ne o us s h o ul d be al w a ys  re p orte d as a n 
S A E.  Si milarl y, a n y c o n ge nital a n o mal y/ birt h d efect i n a c hil d b or n t o a s u bj ect e x p ose d t o t he 
st u d y dr u g s h o ul d be rec or de d a n d re p orte d as a n S A E.  
9. 1. 1 0.  
P ost -st u d y A d verse E ve nt 
A p ost -st u d y A E or S A E is defi ne d as a n y A E t hat occ urs o utsi de of t he A E/ S A E re p orti n g 
peri o d, defi ne d i n Secti o n  9. 1. 7. 1 . 
I n v esti gat ors are n ot o bli gat e d t o acti vel y see k A Es or S A Es i n f or mer s u bj ects. H o we v er, if t he 
i n vesti gat or lear ns of a n y S A E, i ncl u di n g a deat h at a n y ti me after a s u bj ect has bee n disc h ar ge d 
fr o m t he st u d y, a n d he/s h e c o nsi ders t he S A E relat e d t o t he st u d y dr u g, t h e i n vesti gat or will 
n otif y t he s p o ns or.  
9. 1. 1 1.  
Assessi n g a n d Rec or di n g I m m u ne -Rel at e d A d verse E ve nts  
Si nce treat me nt wit h a nti -P D -1 t hera p y ca n ca use a ut oi m m u ne dis or ders, A Es c o nsi dere d b y t he 
i n vesti gat or i m m u ne-relate d (see Secti o n  9. 1. 1 2. 2 ) s h o ul d be classifie d as ir A Es a n d i de ntifie d as 
s uc h i n t he e C R F A E pa ge u ntil Da y 9 0, after treat me nt disc o nti n uati o n.  
I n v esti gat ors s h o ul d c o ns ult t he g ui da nce o n dia g n ostic e val uati o n a n d ma n a ge me nt of ir A Es, 
w hic h are c o m m o nl y s ee n wit h i m m u ne c hec k p oi nt i n hi bit ors, i n A p pe n di x  8 . 
A n e xte nsi ve list of p ote ntial ir A Es a p pears i n Secti o n  9. 1. 1 2. 2 , Ta ble  5 .  All c o n diti o ns si milar 
t o t h ose liste d s h o ul d be e val uate d t o deter mi ne w het her t he y are ir A Es, base d o n a si milar 
dia g n ostic pr o cess t o t h ose reacti o ns t hat are pres e nte d i n m ore  detail i n A p pe n di x  8 . 
9. 1. 1 2.  
M a n a ge me nt of A Es of S peci al I nterest  
As a r o uti ne preca uti o n, after i nf usi o n of tisleliz u ma b o n Da y 1 of C ycle 1 a n d C ycl e 2, patie nts 
m ust be m o nit ore d f or at least 1 h o ur after war ds i n a n area wit h res us citati o n e q ui p me nt a n d 
e mer ge n c y a ge nts.  Fr o m C ycle 3 o n war d, a mi ni m u m of a 3 0 -mi n ute m o nit ori n g peri o d is 
re q uire d i n a n area wit h r es uscitati o n e q ui p me nt a n d e mer ge n c y a ge nts.  
T he ma na ge m e nt f or i nf usi o n -relate d reacti o ns, se vere h y perse nsiti vit y reacti o ns a n d ir A Es 
acc or di n g t o t he N CI-C T C A E criteria are o utli ne d bel o w . 
9. 1. 1 2. 1.  I nf usi o n-rel ate d Re acti o ns  
T he s y m pt o ms of i nf usi o n -relate d reacti o ns i ncl u de fe ver, c hills/ri g or, na us ea, pr urit us, 
a n gi o e de ma, h y p ote nsi o n, hea dac he, br o nc h os pas m, urt icaria, ras h, v o miti n g, m yal gia, dizzi ness 
or h y p erte nsi o n. Se vere reacti o ns ma y i ncl u de ac ute res pirat or y distress s y n dr o me, m y o car di al 
i nfarcti o n, ve ntric ul ar fi brillati o n, a n d car di o ge nic s h oc k.  S u bjects s h o ul d be cl osel y m o nit ore d 
f or s uc h reacti o ns. I m me diate access t o a n I nte nsi ve Care U nit (I C U) or e q ui vale nt e n vir o n me nt 
a n d a p pr o pri ate me dic al t hera p y (i n cl u di n g e pi ne p hri ne, c ortic oster oi ds, I V a nti hista mi nes, 
br o nc h o dilat ors, a n d o x y ge n) m ust be a vaila bl e t o treat i nf usi o n -rel ate d reacti o ns. 
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Treat me nt m o dificati o n f or s y m pt o ms of i nf usi o n -relate d reacti o ns d ue t o tisleliz u ma b is 
prese nte d i n Ta bl e  4 .  
T a ble  4 : 
Tre at me nt M o dific ati o n f or S y m pt o ms of I nf usi o n -Rel ate d Re acti o ns D ue t o 
Tisleliz u m a b  
N CI -C T C A E Gr a de  
Tre at me nt M o dific ati o n f or Tisleliz u m a b  
Gr a de 1 or 2  
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.  
Tisleliz u ma b i nf usi o n rate is decrease d b y 5 0 % 
a n d a n y w orse ni n g is cl osel y m o nit ore d.  Me dical 
ma na ge me nt as nee de d.   
S u bse q ue nt i nf usi o ns s h o ul d be gi ve n after 
pre me dicati o n a n d at t he re d uce d i nf usi o n rate.  
Gr a de 2  
T hera p y or i nf usi o n i nterr u pti o n i n dicate d b ut 
res p o n ds pr o m ptl y t o s y m pt o matic treat me nt (e. g., 
a nti hista mi nes, N S AI Ds, narc otics, I V fl ui ds); 
pr o p h ylactic me dicati o ns i n dicate d f or ≤2 4 h o urs.  
Tisleliz u ma b i nf usi o n is disc o nti n ue d. I nf usi o n is 
res u me d at 5 0 % of pre vi o us rate o nce 
i nf usi o n-relate d reacti o ns has res ol ve d or 
decrease d t o at least Gra de 1 i n se verit y a n d a n y 
w orse ni n g is cl osel y m o nit ore d. Pr o per me dical 
ma na ge me nt s h o ul d be i nstit ute d as descri be d 
bel o w.  
S u bse q ue nt i nf usi o ns s h o ul d be gi ve n after 
pre me dicati o n a n d at t he re d uce d i nf usi o n rate.  
Gr a de 3 : se vere 
Pr ol o n ge d (e. g., n ot ra pi dl y res p o nsi ve t o 
s y m pt o matic me dicati o n a n d/ or brief i nterr u pti o n 
of i nf usi o n); rec urre nce of s y m pt o ms f oll o wi n g 
i nitial i m pr o ve me nt; h os pitalizati o n i n dicate d f or 
cli nical se q uelae.  
Tisleliz u ma b i nf usi o n is i m me diatel y 
disc o nti n ue d a n d i nf usi o n t u bi n g w o ul d be 
disc o n necte d fr o m t he s u bject.  Pr o per me dical 
ma na ge me nt s h o ul d be i nstit ute d as descri be d 
bel o w.  
T he patie nt s h o ul d be wit h dra w n fr o m 
tisleliz u ma b treat me nt. 
Gr a de 4: life t hre ate ni n g  
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. 
Patie nts ha ve t o be wit h dra w n i m me diatel y fr o m 
tisleliz u ma b treat me nt a n d m ust n ot recei ve 
tisleliz u ma b treat me nt a n y m ore. Pr o per me dical 
ma na ge me nt s h o ul d be i nstit ute d as descri be d 
bel o w.  
H os pitalizati o n is rec o m me n de d.  
I V = i ntra ve n o us, 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 Criteri a f or A d verse E ve nt, 
N S AI Ds = n o nster oi dal a nti -i nfla m mat or y dr u gs.  
O nce t he tisleliz u ma b i nf usi o n rate has bee n decrease d b y 5 0 % or s us p e n de d d ue t o a n i nf usi o n-
relate d reacti o n, it m ust re mai n decreas e d f or all s u bse q ue nt i nf usi o ns wit h pre me dicati o n . If t he 
patie nt  has a sec o n d i nf usi o n -relate d reacti o n ( Gra de ≥2) o n t he sl o wer i nf usi o n rate , i nf usi o n 
s h o ul d be disc o nti n ue d a n d t he s u bject s h o ul d be wit h dra w n fr o m tisleliz u ma b treat me nt.  
C T C A E Gr a de 1 o r 2 i nf usi o n re acti o n : Pr o per me dical ma na ge m e nt s h o ul d be i nstit ute d, as 
i n dicate d per t y pe of t he reacti o n. T his i ncl u des b ut is n ot li mite d t o a n a ntihista mi ne (e. g., 
di p he n h y dra mi ne or e q ui vale nt), a nti -p yretic (e. g., paraceta m ol or e q ui val e nt), a n d if c o nsi dere d 
i n dicate d oral or I V gl uc oc ortic oi ds, e pi ne p hri ne, br oc h o dilat ors, a n d o x y g e n.  I n t he ne xt c ycle, 
patie nts s h o ul d recei ve oral pre me di cati o n  wit h a n a nti hista mi ne (e. g., di p he n h y dra mi ne or 
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e q ui vale nt) a n d a n a nti -p yreti c (e. g., p araceta m ol or e q ui vale nt), a n d t he y s h o ul d be cl osel y 
m o nit ore d f or cli nical si g ns a n d s y m pt o ms of a n i nf usi o n reacti o n.  
C T C A E Gr a de 3 o r 4 i nf usi o n re acti o n : I m me diatel y st o p t he i nf usi o n.  Pr o per me dical 
ma na ge me nt s h o ul d be i nstit ute d i m me diatel y, as i n dicate d per t y pe a n d se verit y of t he reacti o n.  
T his i ncl u des b ut is n ot li mite d t o oral or I V a nti -hista mi ne, a nti -p yretic, gl uc oc ortic oi ds, 
e pi ne p hri ne, br o n c h o dilat ors, a n d o x y ge n.  
If a s u bject e x perie nces a Gra de 3 or 4 i nf usi o n-rel ate d reacti o n at a n y ti me, tisleliz u ma b m ust be 
disc o nti n ue d.  
9. 1. 1 2. 2.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
. 
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T a ble  5 : 
I m m u ne-rel at e d A d verse E ve nts  
B o d y S yste m Affecte d  
E ve nts  
S ki n ( mil d -c o m m o n)  
pr urit us or mac ul o pa p ular ras h; vitili g o  
S ki n ( m o derate)  
f ollic ular or urticarial der matitis; er yt he mat o us/lic he n oi d ras h; S weet’s 
s y n dr o me 
S ki n (se vere -rare) 
f ull-t hic k ness necr ol ysis/ Ste ve ns-J o h ns o n s y n dr o me 
Gastr oi ntesti nal  
c olitis (i ncl u des diarr hea wit h a b d o mi nal pai n or e n d osc o pic/ra di o gra p hic 
e vi de nce of i nfla m mati o n); pa ncreatitis; he patitis; a mi n otra nsferase 
( A L T/ A S T) ele vati o n; b o wel perf orati o n 
E n d ocri ne  
t h yr oi ditis, h y p ot h yr oi dis m, h y pert h yr oi dis m; h y p o p h ysitis wit h feat ures of 
h y p o pit uitaris m, e .g . fati g ue, wea k ness, wei g ht gai n; i ns uli n-de pe n de nt 
dia betes mellit us; dia betic ket oaci d osis, a dre nal i ns ufficie nc y  
Res pirat or y  
p ne u m o nitis/ diff use al ve olitis  
E ye  
e piscler itis; c o nj u ncti vitis; iritis/ u veitis 
Ne ur o m usc ular  
art hritis; art hral gia; m yal gi a; ne ur o pat h y; G uillai n -Barre s y n dr o me; ase ptic 
me ni n gitis; m yast he nic s y n dr o me/ m yast he nia gra vis, me ni n g oe nce p halitis; 
m y ositis  
Bl o o d  
a ne mia; le u k o pe nia; t hr o m b oc yt o pe nia  
R e nal 
i nterstitial ne p hritis; gl o mer ul o ne p hritis; ac ute re nal fail ure 
Car diac  
pericar ditis; m y ocar ditis; heart fail ure  
A b bre viati o ns: A L T , ala ni ne a mi n otra nsferase; A S T , as partate a mi n otra nsferase.  
D ose m o dificati o n a n d m a na ge me nt f or ir A Es are detaile d i n A p pe n di x  8 . 
If a t o xicit y d oes n ot res ol ve t o ≤ Gra de 1 wit hi n  1 2 wee ks, st u d y dr u g(s) s h o ul d be disc o nti n ue d 
after c o ns ultati o n wit h t he S p o ns or.  Patie nts w h o e x perie nce a rec urre nce of a n y e ve nt at t he 
sa me or hi g her s e verit y gra de wit h r ec halle n ge s h o ul d per ma ne ntl y disc o nti n ue treat me nt.  
9. 1. 1 2. 3.  Re n al F u ncti o n A b n or m ali ties 
Patie nts wit h m o derate re nal d ysf u n cti o n (esti mate d gl o mer ular filtrati o n rat e  [e G F R] > 3 0 
m L/ mi n a n d <  6 0  m L/ mi n b y C hr o nic Ki d n e y Dis ease E pi de mi ol o g y C olla b orati o n e q uati o n) 
ma y b e e nr olle d i nt o t he st u d y.  T he f oll o wi n g al g orit h m is pr o p ose d f or t he use of ster oi d 
treat me nt i n t he ma na ge me nt of ir A Es: 
•  If t he ser u m creati ni ne is n or mal at baseli ne, pleas e see Secti o n  9. 1. 1 2. 2  a n d refer t o 
A p pe n di x  8  f or dia g n osis a n d ma na ge m e nt of pati e nts wit h a b n or mal re n al la b orat or y 
val ues.  
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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
•  If t he ser u m creati ni ne is Gra de 1 at baseli ne a n d i ncreas e i n ser u m creati ni ne meets 
criteria f or ser u m creati ni ne i ncrease ≥ Gra de 2 aft er starti n g treat me nt wit h 
tisleliz u ma b, refer t o A p pe n di x  8  f or dia g n osis a n d ma na ge me nt of p atie nts wit h 
a b n or mal re n al la b orat or y val u es.  C hec k t he eG F R usi n g A p pe n di x  8  a n d t he e G F R 
calc ulat or li n k.  I n t he s etti n g of a Gra d e 2 ser u m creati ni ne i ncrease o nl y, st u d y 
treat me nt ca n c o nti n ue u nless t he ser u m creati ni ne i ncreases b y at least 5 0 % fr o m t he 
baseli ne val ue or  t he e G F R falls bel o w 2 0 m L/ mi n. 
•  If t he ser u m creati ni ne is Gra de 2 at baseli ne a n d i ncreas e i n ser u m creati ni ne meets 
criteria f or ser u m creati ni ne i ncrease ≥ Gra de 3 aft er starti n g treat me nt wit h 
tisleliz u ma b, refer t o A p pe n di x  8  f or dia g n osis a n d ma na ge me nt of p atie nts wit h 
a b n or mal re n al la b orat or y val u es.  I n t he setti n g of a Gra de 3 ser u m creati ni ne 
i ncreas e o nl y, st u d y tr eat me nt will be hel d u ntil ser u m creati ni ne i m pr o ves t o baseli ne 
a n d treat me nt ma y res u m e o nl y after disc ussi o n wit h t he s p o ns or me dical m o nit or.  
9. 1. 1 2. 4.  Se vere H y pers e nsiti vit y Re acti o ns a n d Fl u -Li ke S y m pt o ms  
If h y pers e nsiti vit y reacti o n occ urs, t he p atie nt m ust be treate d acc or di n g t o t he best a vaila ble 
me dical p ractice as d escri be d i n t he c o m plete g ui deli ne f or e m er ge n c y treat me nt of a na p h ylactic 
reacti o ns acc or di n g t o t h e W or ki n g Gr o u p of t he Res uscitati o n C o u ncil (U K ) (S oar et al, 2 0 0 8 ).  
Patie nts s h o ul d be i nstr ucte d t o re p ort a n y dela ye d reacti o ns t o t he i n vesti gat or i m me diat el y.  
I n t he e ve nt of a s yste mic a na p h yla ctic/a na p h ylact oi d reacti o n (t y picall y m a nifeste d wit hi n 
mi n utes f oll o wi n g a d mi nistrati o n of t he dr u g/a nti ge n, a n d c h aracterize d b y: re s pirat or y distress; 
lar y n geal e d e ma; a n d/ or i nte nse br o nc h os p as m; a n d ofte n f oll o we d b y vas c ular c olla pse or s h oc k 
wit h o ut a ntece de nt r es pir at or y diffic ult y; c uta ne o us ma nifestati o ns s uc h as pr urit us a n d urticari a 
wit h/ wit h o ut e de ma; a n d gastr oi ntesti nal m a nif estati o ns s uc h as na usea, v o miti n g, cra m p y 
a b d o mi nal pai n, a n d diarr hea), t h e i nf usi o n m ust be i m me diatel y st o p pe d a n d t he patie nt 
disc o nti n ue d fr o m t he st u d y.  
T he patie nts will be a d mi nistere d e pi ne p hri n e i njecti o n a n d de x a met has o ne i nf usi o n if  a 
h y pe rse nsiti vit y reacti o n is o bser ve d a n d t he n t he patie nt s h o ul d be place d o n m o nit or 
i m me diatel y a n d I C U s h o ul d be alerte d f or p ossi ble tra nsfer if nee d e d. 
F or pr o p h yla xis of fl u -li ke s y m pt o ms, a d ose of 2 5 m g i n d o met haci n or a c o m para ble d ose of 
n o nster oi da l a nti-i nfla m mat or y dr u gs (i.e. 6 0 0 m g i b u pr ofe n, 5 0 0 m g na pr o x e n s o di u m) ma y b e 
a d mi nistere d 2 h o urs bef ore a n d 8 h o urs after t he start of eac h d ose of st u d y dr u gs(s) i nf usi o n.  
Alter nati ve treat me nts f or fe ver ( i.e. p araceta m ol) ma y b e gi ve n t o patie nts at t he discreti o n of 
t he i n vesti gat or. 
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9. 1. 1 3.  
E x pe dite d Re p orti n g t o He alt h A ut h orities, I n vesti g at ors, I nstit uti o n al Re vie w 
B o ar ds a n d Et hics C o m mittees  
T he s p o ns or will pr o m ptl y ass ess all S A Es a gai nst c u m ulati ve st u d y dr u g e x perie nce t o i de ntif y 
a n d e x pe diti o u sl y c o m m u nicate ne w s afet y fi n di n gs t o re g ul at or y a ut h oriti es, i n vesti gat ors, I R Bs 
a n d I E Cs base d o n a p plica ble le gislati o n.  
T o deter mi ne t he re p orti n g re q uire me nts f or i n di vi d ual S A Es, t he s p o ns or will assess t he 
e x pecte d ness of t he S A Es usi n g t he  Tisleliz u ma b I n v esti gat or’s Br oc h ure .  
9. 1. 1 4.  
L ac k of Effic ac y  
“ Lac k of efficac y” will n ot be re p orte d as a n A E.  T he si g ns a n d s y m pt o ms or cli nical se q uelae 
res ulti n g fr o m lac k of efficac y will be re p orte d if t he y f ulfill t he A E or S A E defi niti o n (i ncl u di n g 
clarificati o ns).   
9. 2.  
S afet y M o nit ori n g C o m mittee  
Re g ular safet y m o nit ori n g (at least e v er y 6 m o nt hs) a n d efficac y m o nit ori n g will be perf or me d 
b y a n i nter nal Safet y M o nit ori n g C o m mittee ( S M C).  
T he first S M C safet y re vi e w will occ ur after at least 2 0 patie nts ha ve bee n o n treat me nt f or at 
least o ne m o nt h i n or der t o deter mi ne if t he pr o p ose d d osi n g sc h e d ule of tisleliz u ma b is safe a n d 
t olera ble.  T he S M C ma y rec o m me n d st u d y m o dificati o n i ncl u di n g ter mi nati o n of t he st u d y d ue 
t o safet y a n d/ or effic ac y c o ncer ns.  T h e f u ncti o n a n d me m bers hi p of t he S M C will be descri be d 
i n t he S M C C harter.  
I n a d diti o n t o t he pla n ne d S M C re vie w(s), a d h o c re vie ws ma y ta ke place base d o n ne w 
i nf or mati o n.  
F oll o wi n g S M C re vie w a n d disc ussi o n, t he S p o ns or will ma ke all fi nal decisi o ns re gar di n g a n y 
c ha n ge i n st u d y c o n d uct.  Plea se see t he details i n t he S M C C harter.  
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1 0.  
S T A TI S TI C A L C O N SI D E R A TI O N S A N D A N A L Y TI C A L P L A N  
All statistical a nal yses will be perf or me d b y t h e S p o ns or or desi g nee after t he st u d y is c o m plete d 
a n d t he data b ase is l oc ke d a n d rele ase d.  Data will be liste d a n d s u m m arize d usi n g S A S ®  Versi o n 
9. 3 or hi g h er ( S A S I nstit ute, I n c., Car y, N ort h Car oli na) per S p o ns or a gree d re p orti n g sta n dar ds, 
w here a p plica ble.  Details of t he statistical a nal yses will be i ncl u de d i n a se parate Statistical 
A nal ysis Pla n ( S A P).  
1 0. 1.  
Pri m ar y, Sec o n d ar y a n d 
St u d y E n d p oi nts  
1 0. 1. 1.  
Pri m ar y E n d p oi nt  
•  O R R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ves a best res p o ns e of C R or 
P R, assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
1 0. 1. 2.  
Sec o n d ar y E n d p o i nts 
•  P F S is defi ne d as t he ti me fr o m t he first d ose of tisleliz u ma b t o t he date of P D or 
deat h, w hic he v er occ urs first, assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n 
et al, 2 0 1 4). 
•  D O R is defi ne d as t he ti me fr o m t he date t h at res p o nse criteria are first met t o t he 
date t hat P D is o bjecti vel y d oc u m e nte d or deat h, w hic he ver occ urs first, assesse d b y 
I R C per t h e  L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
•  Rate o f C R is defi ne d as t he pr o p orti o n of s u bjects w h o ac hie ves a best r es p o nse of 
C R, assesse d b y I R C per t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ). 
•  T T R is defi ne d as t he ti me fr o m t he dat e of t he first d ose of tisleliz u ma b t o t he ti me 
t he res p o nse criteria are first met, assesse d b y I R C per t he L u ga n o Classificati o n 
(C hes o n et al, 2 0 1 4 ). 
•  T o e val uate t he s afet y a n d t olera bilit y of tisleliz u ma b, as defi ne d b y:  
− T he i nci de nce a n d se v erit y of a d v ers e e ve nts a cc or di n g t o N CI -C T C A E v 4. 0 3  
− C ha n ges i n vital si g ns, p h ysical fi n di n gs, a n d cli nical la b orat or y res ults  
1 0. 1. 3.  
 
 
 
 
 
 
 
 
 
 
 
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•  
 
 
 
 
 
1 0. 2.  
St atistic al A n al ysis  
1 0. 2. 1.  
A n al ysis Sets  
T he Safet y A n al ysis Set  i ncl u des all s u bjects w h o recei v e d a n y d ose of tisleliz u ma b.  T his will 
be t he p o p ulati o n f or t he safet y a n al ys es.   
T he m o difie d Safet y A n al ysis Set  i ncl u des all s u bjects i n t he Safet y A nal ysis Se t w h o ha d 
c o nfir me d c H L. T his will be t he p o p ulati o n f or t he efficac y a n al ys es.  
T he Per -Pr ot oc ol ( P P) A nal ysis Set  i ncl u des s u bj ects w h o recei ve d a n y d ose tisleliz u ma b a n d 
ha d n o maj or pr ot oc ol de viati o ns.  Criteria f or e x cl usi o n fr o m t he P P  A nal ysis S et w ill be 
deter mi ne d a n d d o c u me nte d bef ore t he data base l o c k f or t he pri mar y a n al ysis.  T his will be t he 
sec o n dar y a nal ysis p o p ulati o n f or efficac y a nal ysis. 
 
 
1 0. 2. 2.  
S u bject Dis p ositi o n  
T he n u m ber of s u bjects e nr olle d, treate d, pre mat urel y disc o nti n ue d fr o m st u d y dr u g ( defi n e d as 
t h ose w h o disc o nti n ue d st u d y dr u g d u e t o a n y reas o n e x ce pt f or P D) a n d t h ose wit h maj or 
pr ot o c ol de viati o ns will be c o u nte d.  T he pri mar y reas o n f or st u d y dr u g disc o nti n ue d will be 
s u m marize d acc or di n g t o t he cate g ori es i n t he e C R F.  T he e n d of st u d y stat us (ali ve, deat h, 
wit h dre w c o nse nt or l ost t o f oll o w -u p) at t he data c ut off date will be s u m ma rize d usi n g t he data 
fr o m t he e C R F. 
Maj or pr ot oc ol de viati o ns will be s u m marize d a n d liste d b y eac h cate g or y.  
1 0. 2. 3.  
De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics  
De m o gra p hic a n d ot her b aseli ne c haracteristics will be s u m marize d i n t he m o difie d Safet y 
A nal ysis S et usi n g descri pti ve statistics.  C o nti n u o us varia bles i ncl u de a ge, wei g ht, vital si g ns, 
ti me si nce i nitial c H L dia g n osis, n u m ber of pri or li ne of t hera p y f or c H L; cate g ori cal varia bles 
i ncl u de ge n der, E C O G, s yste mic s y m pt o ms ( B s y m pt o ms), I nter n ati o nal Pro g n ostic Sc ore (I P S) 
at dia g n osis, b ul k y diseas e defi ne d as me diasti nal mass rati o ( M M R) of 0. 3 3 or size of a n y si n gle 
n o de/ n o dal mass is ≥ 1 0 c m i n dia meter, a n d E S R.  
1 0. 2. 4.  
Pri o r a n d C o nc o mit a nt T her a p y  
C o nc o mita nt me dicati o ns will be assi g ne d a n 1 1 -di git c o de usi n g t he W H O Dr u g Dicti o nar y 
dr u g c o des.  C o nc o mita nt me dicati o ns will be f urt her c o de d t o t he a p pr o pri ate A nat o mical 
T hera p e utic C he mical ( A T C) c o de i n dicati n g t hera pe utic classificati o n.  Pri or a n d c o nc o mita nt 
me dicati o ns will be s u m marize d a n d liste d b y dr u g a n d dr u g class i n t he Cli nical St u d y Re p ort 
( C S R) f or t his pr ot oc ol.  Pri or me dicati o ns will be defi ne d as me di cati o ns t hat st o p pe d bef ore t he 
C CI
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first d ose of st u d y dr u g.  C o nc o mita nt me dicati o ns will be defi ne d as me di cati o ns t hat ( 1) starte d 
bef ore t h e first d ose of st u d y dr u g a n d were c o nti n ui n g at t he ti me of t he first d ose of st u d y dr u g, 
or ( 2) starte d o n or after t he date of t he first d ose of st u d y dr u g u p t o 3 0 d a ys after t he s u bject’s 
last d ose. A listi n g of pri or a n d c o nc o mita nt me di cati o ns wi ll be i ncl u de d i n t he C S R of t his 
pr ot oc ol.  
1 0. 2. 5.  
Effic ac y A n al yses  
1 0. 2. 5. 1.  Pri m ar y Effic ac y A n al ysis  
I n rela pse d or refract or y H L, O R R wit h si n gle a ge nt treat me nt as hist orical c o ntr ol is ass u me d t o 
be a p pr o xi matel y 3 5 % b ase d o n hist orical trials.  T he O R R of tisleliz u ma b i n t his st u d y is 
ass u me d as 5 5 %, w hic h is dee me d a cli nicall y m ea ni n gf ul i m pr o ve me nt.  He nce, t h e n ull a n d 
alter nati ve h y p ot hes es are set as f oll o ws:  
H 0:  O R R = 3 5 % 
H a:  O R R > 3 5 % 
A bi n o mial e x act test will be perf or m e d f or h y p ot hesis testi n g i n t he m o difie d Safet y A nal ysis 
Set .  If t h e o btai ne d o ne-si de d p-val ue is ≤ 0. 0 2 5, it will be c o ncl u de d t hat t he si n gle a ge nt 
tisleliz u ma b statisticall y si g nifica ntl y i ncreas es O R R c o m pare d wit h hist orical c o ntr ols.  
T heref ore, t he s u p eri orit y of si n gle a ge nt tisleliz u ma b will be de m o nstrate d.  
A t w o -si de d Cl o p per-Pears o n 9 5 % CI of O R R will be c o nstr ucte d t o ass ess t he precisi o n of t he 
rate esti mate. 
Best O verall Res p o nse ( B O R) is defi n e d as t he  b est res p o nse rec or de d fr o m t he first d ose of 
tisleliz u ma b u ntil data c ut or start of ne w a nti-ne o plastic treat me nt.  S u bjects wit h n o p ost -
baseli ne res p o ns e assess me nt ( d ue t o a n y reas o n) will be c o nsi dere d n o n -res p o n ders f or B O R.  
T he pr o p orti o n a n d its  c orres p o n di n g Cl o p per -Pears o n 9 5 % CI f or eac h of t he res p o nse 
cate g ories will be prese nt e d.  
T he pri mar y effic ac y a n al ysis will be c o n d ucte d a p pr o xi matel y 8 m o nt hs after t he first d ose of 
t he last s u bject, a n d will be base d o n t he m o difie d Safet y A nal ysis Set .  T he I R C ass ess me nt per 
t he L u ga n o Classificati o n (C hes o n et al, 2 0 1 4 ) will be use d i n t he pri mar y efficac y a n al ysis. 
1 0. 2. 5. 2.  Sec o n d ar y Effic ac y A n al ysis  
T he distri b uti o n of pr o gressi o n -free s ur vi val ( P F S) will be esti mate d usi n g t he Ka pla n-M eier 
met h o d i n t he m o difie d Safet y A nal ysis Set .  Pr o gressi o n-free s ur vi val at selecte d ti me p oi nts 
will be esti mate d wit h its 9 5 % CI usi n g Gree n w o o d’s f or m ula.  Pr o gre ssi o n-free s ur vi val 
ce ns ori n g r ule will f oll o w  t he U S F D A G ui da nce f or I n d ustr y Cli nical Tri al E n d p oi nts f or t he 
A p pr o val of Ca n cer Dr u gs a n d Bi ol o gics ( 2 0 0 7).  
Ot her ti me t o e ve nt varia bles  (e. g. D O R ), will be a nal yze d si milarl y as P F S.  T T R will be 
a nal yz e d usi n g sa m ple st atistics s uc h as mea n, me dia n a n d sta n dar d de viati o n.  O nl y s u bjects 
w h o ha ve ac hie ve d a n o bjecti ve res p o nse will be i ncl u de d i n t he a nal ysis of D O R a n d T T R.  
C o m plete Res p o nse ( C R) rate will be s u m marize d i n t he m o difie d Safet y A nal ysis S et.  Its 
Cl o p per -Pears o n 9 5 % CI will be calc ulate d. T h e I R C assess me nt per t he L u ga n o Classificati o n 
(C hes o n et al, 2 0 1 4 ) will be use d i n t he sec o n d ar y efficac y a n al ysis.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 0. 2. 5. 3.  
 
 
 
 
 
 
 
 
  
1 0. 2. 6.  
S afet y A n al ysis  
Safet y will be assesse d b y m o nit ori n g a n d rec or di n g of all A Es gra d e d b y N CI -C T C A E v 4. 0 3. 
La b orat or y v al ues (e. g. h e mat ol o g y, cli nical c he mistr y, uri nal ysis), vi tal si g ns, a n d P Es, will als o 
be use d i n deter mi ni n g safet y.  Descri pti ve statistics will be use d t o a nal yze all safet y data i n t he 
Safet y A nal ysis Set . 
1 0. 2. 6. 1.  E xte nt of E x p os ure  
E xte nt of e x p os ure t o st u d y dr u g will be s u m marize d descri pti vel y as t he n u m ber of c ycl es 
recei v e d ( n u m ber a n d perce nta ge of s u bjects), d urati o n of e x p os ure ( da ys), c u m ulati ve t otal d ose 
recei v e d per s u bject ( m g), d ose i nte nsit y ( m g/ da y) a n d relati ve d os e i nte nsit y. 
T he n u m ber ( perce nta ge) of s u bjects re q uiri n g d os e i nterr u pti o n, d ose dela y, a n d dr u g 
disc o nti n uati o n d ue t o A Es will be s u m marize d.  T he c ycle i n w hi c h t he first d ose i nterr u pti o n 
occ urre d will be s u m mariz e d usi n g descri pti ve statistics.  Fre q ue nc y of d ose i nterr u pti o ns will be 
s u m marize d b y cate g ories.  
S u bject dat a listi n gs will be pr o vi de d f or all d osi n g rec or ds a n d f or calc ulat e d s u m mar y statistics.  
1 0. 2. 6. 2.  A d verse E ve nts  
T he A E ver bati m descri pti o ns (i n vesti gat or ter ms fr o m t he  eC R F ) will be classifie d i nt o 
sta n dar dize d me dical ter mi n ol o g y usi n g Me di cal Dicti o nar y f or Re g ul at or y Acti vities 
( Me d D R A® ).  A d verse e ve nts will be c o de d t o M e d D R A ( Versi o n 2 0. 0  or hi g her) l o wer l e vel 
ter m cl osest t o t he ver bati m ter m.  T he li n ke d Me d D R A preferre d ter m ( P T) a n d pri mar y s yste m 
or ga n class ( S O C) are als o ca pt ure d i n t he d ata bas e.  
A  treat me nt-e mer ge nt a d verse e v e nt ( T E A E) is defi ne d as a n A E t hat ha d a n o nset date or a 
w orse ni n g i n se verit y fr o m baseli ne ( pre -treat me nt) o n or after t he first d os e of st u d y dr u g u p t o 
9 0  da ys f oll o wi n g st u d y dr u g disc o nti n uati o n, re gar dless of w h et her or n ot t he s u bject starts a 
ne w a nti -ca ncer t hera p y.  O nl y t h ose A Es t h at were treat me nt e m er ge nt will be i ncl u de d i n 
s u m mar y ta bl es.  All A Es, treat me nt e mer ge nt or ot her wise, will be pres e nte d i n s u bject data 
listi n gs. 
T he i nci de nce of T E A Es will be re p o rte d as t he n u m ber ( perce nta ge) of s u bjects wit h T E A Es b y 
S yste m Or ga n Class ( S O C) a n d Preferre d Ter m.  A s u bject will be c o u nte d o nl y o nce b y t he 
hi g hest se v erit y gra d e per N CI -C T C A E v. 4. 0 3 wit hi n a n S O C a n d Preferre d Ter m, e ve n if t h e 
C
C
I
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s u bject e x perie nce d m or e t ha n 1 T E A E wit hi n a s p ecific S O C a n d Preferre d Ter m.  T he n u m ber 
( perce nta ge) of s u bjects wit h T E A Es will als o be s u m marize d b y rel ati o ns hi p t o t he st u d y dr u g.  
Treat me nt -relate d A Es i ncl u de t h ose e ve nts c o nsi dere d b y t he I n vesti gat or t o be defi nitel y, 
p ossi bl y, or pr o ba bl y relate d t o st u d y treat me nt or wit h missi n g assess me nt of t he ca us al 
relati o ns hi p.  S A E s, deat hs, T E A Es wit h Gra de 3 or a b o ve, relate d T E A E s a n d T E A Es t hat le d t o 
treat me nt disc o nti n uati o n or d ose i nterr u pti o n will be s u m marize d. 
1 0. 2. 6. 3.  L a b or at or y A n al yses  
Cli nical la b orat or y (e. g. he mat ol o g y, ser u m c he mistr y, uri nal ysis) val u es will be e val uate d f or 
eac h la b orat or y p ara met er as a p pr o priate.  A b n or mal la b orat or y val u es will be fla g ge d a n d 
i de ntifie d as t h ose o utsi de (a b o ve or bel o w) t he n or mal ra n ge.  Refere nce ( n or mal) ra n ges f or 
la b orat or y para meters will be i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R) f or t his pr ot oc ol.  
Descri pti ve s u m mar y statistics (e. g. n, mea n, sta n d ar d de viati o n, me dia n, mi ni m u m, ma xi m u m 
f or c o nti n u o us varia bl es; n[%] f or cate g orical v ari a bles) f or l a b orat or y p ara meters a n d t heir 
c ha n ges fr o m baseli ne will be calc ulate d.  La b orat or y v al ues will be s u m marize d b y visit a n d b y 
w orst p ost baseli ne visit.  
La b orat or y p ara m eters t h at are gra de d i n C T C A E v. 4. 0 3 will be s u m mar ize d b y C T C A E gra de.  
I n t he s u m mar y of la b orat or y para met ers b y C T C A E gra de, p ara m eters wit h C T C A E gra di n g i n 
b ot h hi g h a n d l o w directi o ns (e. g. cal ci u m, gl uc os e, ma g nesi u m, p otassi u m, s o di u m) will be 
s u m marize d se paratel y. 
1 0. 2. 6. 4.  Vit al Si g ns  
Descri pti ve statist ics f or vital si g n para meters (s yst olic a n d diast olic bl o o d press ure [ B P], heart 
rate, res pirat or y rate, te m perat ur e, wei g ht, p ulse o xi metr y) a n d c h a n ges fr o m baseli ne will be 
prese nte d b y visit f or all visits.  Vital si g ns will be liste d b y s u bject a n d vi sit. 
1 0. 2. 7.  
 
 
 
 
  
 
1 0. 2. 8.  
 
 
 
 
 
 
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C CI
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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 0. 3.  
S a m ple Size C o nsi der ati o n  
T he sa m ple siz e calc ulati o n is base d o n t he p o wer of t he c o m paris o n t o t he hist orical c o ntr ol 
rate, a n d ass u me d a n O R R of 5 5 % i n t he st u d y as c o m pare d t o 3 5 % i n t he hist orical c o ntr ol.  
Usi n g a bi n o mial e x act test, t he p o wer is 0. 9 1 2 wit h 6 8 s u bjects i n t he m o difie d Safet y A nal ysis 
Set  t o de m o nstrate statistical si g nifica nce at a 1-si de d al p ha of 0. 0 2 5.  T h e 9 5 % e xact CI w o ul d 
be ( 0. 4 2 5, 0. 6 7 1)  wit h a s a m ple siz e of 6 8 s u bjects, w he n t he o bser ve d O R R is 0. 5 5.  
1 0. 4.  
I nteri m A n al ysis 
N o i nteri m a nal ysis is pla n ne d f or t his st u d y.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 1.  
E T HI C A L C O N SI D E R A TI O N S A N D A D MI NI S T R A TI V E 
P R O C E D U R E S  
1 1. 1.  
Re g ul at or y A ut h orit y A p pr o v al  
T he S p o ns or will o btai n a p pr o val t o c o n d uct t he st u d y fr o m t he a p pr o pri ate re g ulat or y a ge n c y i n 
acc or da nce wit h a n y a p plica ble c o u ntr y -s p ecific re g ulat or y re q uire m e nts bef ore t he st u d y is 
i nitiate d at a st u d y ce nter i n t hat c o u ntr y. 
1 1. 2.  
I n vesti g at or Res p o nsi bilities 
1 1. 2. 1.  
G o o d Cli nic al Pr a ctice  
T he I n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n acc or da n ce wit h t he pri nci ples of t he 
“ Decl arati o n of H elsi n ki” I C H g ui deli nes, a n d t hat t he basic pri nci ples of “ G o o d Cli nical 
Practice,” as o utli ne d i n 2 1 C o de of Fe d eral Re g u lati o ns ( C F R) 3 1 2, S u b part D, “ Res p o nsi bilities 
of S p o ns ors a n d I n vesti gat ors,” 2 1 C F R, Part 5 0, a n d 2 1 C F R, Part 5 6, are a d here d t o.  
I n v esti gat ors a n d all s u b-i n vesti gat ors m ust pr o vi d e d oc u me ntati o n of t heir fi na ncial i nterest or 
arra n ge me nts wit h Bei Ge ne, or pr o priet ar y i nterests i n t he dr u g b ei n g st u die d. T his 
d oc u me ntati o n m ust be pr o vi de d bef ore partici pati o n of t he i n vesti gat or a n d a n y s u b -
i n vesti gat or. T h e I n vesti gat or a n d s u b-i n vesti gat or(s) a gree t o n otif y Bei G e ne of a n y c ha n ge i n 
re p orta ble i nterests d uri n g t he st u d y a n d f or 1 year f oll o wi n g c o m pleti o n of t he st u d y. St u d y 
c o m pleti o n is defi ne d as t he date t hat t he last s u bject has c o m plete d t h e pr ot oc ol defi ne d 
acti vities. 
1 1. 2. 2.  
Et hic al C o n d uct of t he St u d y a n d Et hics A p pr o v al  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h G C P a n d all a p plica ble re g ul at or y re q uir e me nts, 
i ncl u di n g, w here a p plica ble, c urre nt versi o n of t h e Decl arati o n of Helsi n ki. 
T he I n vesti gat or ( or S p o ns or, w here a p plica ble) is res p o nsi ble f or e ns uri n g t hat t his pr ot oc ol, t he 
st ud y ce nt er’s i nf or me d c o nse nt f or m, a n d a n y ot h er i nf or mati o n t hat will be prese nt e d t o 
p ote ntial s u bjects (e. g. a d vertise me nts or i nf or mati o n t hat s u p p orts or s u p ple me nts t he i nf or me d 
c o nse nt) are re vie we d a n d a p pr o ve d b y t he a p pr o priate I E C/I R B.  T h e I n ve sti gat or a grees t o 
all o w t he I E C/I R B direct access t o all rele va nt d o c u me nts.  T he I E C/I R B m ust be c o nstit ute d i n 
acc or da nce wit h all a p plica ble re g ulat or y re q uire me nts.  T he S p o ns or will pr o vi de t he 
I n v esti gat or wit h rele v a nt d oc u me nt(s)/ data t hat are need e d f or I E C/I R B re vie w a n d a p pr o val of 
t he st u d y.  Bef ore t he st u d y dr u g(s) ca n be s hi p pe d t o t he st u d y ce nt er, t he s p o ns or m ust recei ve 
c o pies of t he I E C/I R B a p pr o val, t he a p pr o ve d i nf or me d c o nse nt f or m, a n d a n y ot her i nf or mati o n 
t hat t he I E C/I R B has a p pro ve d f or prese ntati o n t o p ote ntial s u bjects.  
If t he pr ot oc ol, t he i nf or me d c o nse nt f or m, or a n y ot her i nf or mati o n t hat t he I E C/I R B has 
a p pr o ve d f or pres e ntati o n t o p ote ntial s u bjects is a me n de d d uri n g t he st u d y, t he I n v esti gat or is 
res p o nsi ble f or e ns uri n g t he I E C/I R B re vie ws a n d a p pr o ves, w h ere a p plica ble, t hese a me n de d 
d oc u me nts.  T he I n vesti gat or m ust f oll o w all a p plica ble re g ulat or y re q uire me nts pertai ni n g t o t he 
use of a n a m e n de d i nf or me d c o nse nt f or m i ncl u di n g o btai ni n g I E C/I R B a p pr o val of t he a m e n de d  
f or m bef ore a n e w s u bject c o nse nts t o ta ke part i n t he st u d y usi n g t his versi o n of t he f or m.  
C o pies of t he I E C/I R B a p pr o val of t he a m e n de d i nf or me d c o ns e nt f or m/ ot her i nf or mati o n a n d 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
t he a p pr o ve d a me n de d i nf or me d c o nse nt f or m/ ot her i nf or mati o n m ust be f or war de d t o t he 
s p o ns or pr o m ptl y. 
1 1. 2. 3.  
I nf or me d C o nse nt 
T he I n vesti gat or is r es p o nsi ble f or o btai ni n g writte n i nf or me d c o ns e nt fr o m e ver y o ne 
partici pati n g i n t his st u d y after a de q uat e e x pla nati o n of t he ai ms, met h o ds, o bjecti ves, a n d 
p ote ntial hazar ds of t he st u d y a n d b ef ore u n derta ki n g a n y st u d y -relate d pr oce d ures. T h e 
I n v esti gat or m ust utilize a n I R B/I E C-a p pr o ve d c o nse nt f or m f or d o c u me nti n g writte n i nf or me d 
c o nse nt. Eac h i nf or me d c o nse nt will be a p pr o priat el y si g ne d a n d date d b y t he s u bject or t he 
s u bject’s legall y a ut h orize d re prese ntati ve a n d t he pers o n o btai ni n g c o nse nt.  
I nf or me d c o ns e nt will be o btai ne d bef ore t he s u bj ect ca n p artici pate i n t he st u d y.  T he c o nte nts 
a n d pr ocess of o btai ni n g i nf or me d c o nse nt will be i n acc or da nce wit h all a p plica ble re g ulat or y 
re q uire me nts. 
1 1. 2. 4.  
I n vesti g at or Re p orti n g Re q uire me nts 
T he I n vesti gat or ( or S p o ns or, w here a p plica ble) is res p o nsi ble f or re p orti n g S A Es t o t he 
I E C/I R B, i n acc or da n ce wit h all a p plica ble re g ul ati o ns.  F urt her m ore, t h e i n vesti gat or m a y be 
re q uire d t o pr o vi de peri o dic safet y u p dat es o n t he c o n d uct of t he st u d y at his/ her st u d y ce nter a n d 
n otificati o n of st u d y cl os ure t o t he I E C/I R B.  S uc h peri o dic safet y u p d ates a n d n otificati o ns are 
t he res p o nsi bilit y of t he i n vesti gat or a n d n ot of t he s p o ns or. 
1 1. 2. 5.  
C o nfi de nti alit y  
T he I n vesti gat or m ust ass ure t hat s u bjects’ a n o n y mit y will be strictl y mai ntai ne d a n d t hat t heir 
i de ntities are pr otecte d fr o m u na ut h orize d parties.  O nl y s u bject i nitials, date of birt h, a n d a n 
i de ntificati o n c o de (i.e. n ot na mes) s h o ul d be rec or de d o n a ny f or m or bi ol o gical sa m ple 
s u b mitte d t o t he s p o ns or, I R B, or la b orat or y.  T he i n vesti gat or m ust kee p a scree ni n g l o g 
s h o wi n g c o d es, na mes, a n d a d dresses f or all s u bjects scree n e d a n d f or all s u bjects e nr olle d i n t he 
trial. 
T he i n vesti gat or a grees t hat all  i nf or mati o n recei v e d fr o m Bei Ge n e, i ncl u di n g b ut n ot li mite d t o 
t he I B, t his pr ot oc ol, C R Fs, t he i n vesti gati o nal ne w dr u g, a n d a n y ot h er st u d y i nf or m ati o n, 
re mai n t he s ole a n d e x cl usi ve pr o pert y of Bei G e ne d uri n g t he c o n d uct of t h e st u d y a n d 
t hereafter.  T his i nf or mati o n is n ot t o be discl ose d t o a n y t hir d part y (e x ce pt e m pl o yees or a ge nts 
directl y i n v ol ve d i n t he c o n d uct of t he st u d y or as re q uire d b y la w) wit h o ut pri or writte n c o nse nt 
fr o m Bei Ge ne.  T h e I n vesti gat or f urt her a grees t o ta ke all reas o na ble preca uti o ns t o pre ve nt t he 
discl os ure b y a n y e m pl o yee or a ge nt of t he st u d y site t o a n y t hir d part y or ot her wise i nt o t he 
p u blic d o mai n.  
1 1. 2. 6.  
C ase Re p ort F or ms  
F or eac h s u bject e nr olle d, a C R F m ust be c o m plete d a n d si g ne d b y t he pri n ci pal i n vesti gat or or 
s u b-i n vesti gat or wit hi n a reas o na bl e ti me fra me aft er data c ollecti o n.  T his als o a p plies t o rec or ds 
f or t h ose s u bjects w h o f ail t o c o m plete t he st u d y (e ve n d uri n g a pre-ra n d o mizati o n scree ni n g 
peri o d if a C R F w as i nitiate d).  If a s u bject wit h dr a ws fr o m t he st u d y, t he reas o n m ust be n ote d 
o n t he C R F.  If a s u bject is wit h dra w n fr o m t he st u d y beca use of a tr eat me nt -li miti n g A E, 
t h or o u g h eff orts s h o ul d b e ma de t o clearl y d oc u m e nt t he o utc o me. 
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Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  8 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 1. 2. 7.  
Dr u g Acc o u nt a bilit y  
T he I n vesti gat or or d esi g nee ( i.e. p h ar macist) is res p o nsi ble f or e ns uri n g a d e q uate acc o u nta bilit y 
of all use d a n d u n use d st u d y dr u g.  T his i ncl u des ac k n o wle d g me nt of recei pt of eac h s hi p me nt of 
st u d y pr o d uct ( q ua ntit y a n d c o n diti o n), s u bject dis pe nsi n g rec or ds a n d ret ur ne d or destr o ye d 
st u d y pr o d uct.  Dis p e nsi n g rec or ds will d oc u me nt q ua ntities recei ve d fr o m Bei Ge n e a n d 
q ua ntities dis pe nse d t o s u bjects, i ncl u di n g l ot n u m ber, date dis pe nse d, s u bject i de ntifier n u m ber, 
s u bject i nitials, a n d t he i nitials of t he pers o n dis pe nsi n g t he me di cati o n.  
At st u d y i nitiati o n, t he m o nit or will e val uate t he site’s sta n dar d o perati n g pr oce d ure f or st u d y 
dr u g dis p osal/ destr u cti o n i n or der t o e ns ure t hat it c o m plies wit h Bei Ge n e re q uire me nts.  At t he 
e n d of t he st u d y, f oll o wi n g fi nal dr u g i n ve nt or y rec o nc iliati o n b y t he m o nit or, t he st u d y site will 
dis p ose of a n d/ or destr o y all u n use d st u d y dr u g s u p plies, i ncl u di n g e m pt y c o ntai ners, acc or di n g 
t o t hese pr oce d ures.  If t he site ca n n ot meet Bei G e ne’s re q uir e me nts f or dis p osal, arra n ge me nts 
will be ma de bet wee n t he site a n d Bei G e ne or its r e prese nt ati ve f or d estr ucti o n or ret ur n of 
u n use d st u d y dr u g s u p pli es.  
All dr u g s u p plies a n d ass ociate d d oc u me nt ati o n will be peri o dicall y re vie we d a n d verifie d b y t he 
st u d y m o nit or o ver t he c o urse of t he st u d y. 
1 1. 2. 8.  
I ns pecti o ns 
T he I n vesti gat or s h o ul d u n dersta n d t hat s o urce d oc u me nts f or t his trial s h o ul d be ma de a v aila ble 
t o a p pr o priatel y q ualifie d pers o n nel fr o m Bei G e ne or its re prese ntati ves, t o I R Bs/I E Cs, or t o 
re g ulat or y a ut h orit y or healt h a ut h orit y i ns p ect ors. 
1 1. 2. 9.  
Pr ot oc ol C o m p li a nce 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he st u d y is c o n d u cte d i n acc or da nce wit h t he 
pr oce d ures a n d e v al uati o ns descri be d i n t his pr ot oc ol.  
1 1. 3.  
S p o ns or Res p o nsi bilities  
1 1. 3. 1.  
Pr ot oc ol M o dific ati o ns  
Pr ot oc ol m o dificati o ns, e x ce pt t h ose i nte n de d t o re d uce  i m me diate ris k t o st u d y s u bjects, ma y b e 
ma de o nl y b y Bei G e ne. All pr ot oc ol m o dificati o ns m ust be s u b mitte d t o t he I R B/I E C  i n 
acc or da nce wit h l ocal re q uire me nts. A p pr o val m ust be o btai ne d bef ore c h a n ges ca n b e 
i m ple me nte d. 
1 1. 3. 2.  
St u d y Re p ort a n d P u blic ati o ns  
A cli nical st u d y re p ort will be pre pare d a n d pr o vi d e d t o t he re g ulat or y a ge n c y(i es).  Bei G e ne will 
e ns ure t hat t he re p ort meets t he sta n dar ds set o ut i n t he I C H G ui deli ne f or Str uct ure a n d C o nte nt 
of Cli nical St u d y Re p orts (I C H E 3).  N ote t h at a n a b bre viate d  re p ort ma y b e pre pare d i n certai n 
cases.  
F or m ulti -ce nter st u dies, t he first p u blicati o n or discl os ure of st u d y res ults s hall be a c o m plete, 
j oi nt m ulti-ce nter p u blicati o n or discl os ure c o or di nate d b y t he s p o ns or.  T h ereafter, a n y 
sec o n dar y p u blicati o ns will refere n ce t he ori gi n al p u blicati o n(s). 
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Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  8 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
After c o n cl usi o n of t he st u d y a n d wit h o ut pri or writte n a p pr o val fr o m Bei G e ne, I n vesti gat ors i n 
t his st u d y ma y c o m m u nicate, orall y prese nt, or p u blis h i n scie ntific j o ur nals or ot her sc h olarl y 
me dia o nl y after t h e  f oll o wi n g c o n diti o ns ha ve b ee n met: 
•  T he res ults of t he st u d y i n t heir e ntiret y ha v e bee n p u blicl y discl ose d b y or wit h t he 
c o nse nt of Bei Ge n e i n a n a bstract, ma n uscri pt, or prese ntati o n f or m; or  
•  T he st u d y h as bee n c o m plete d at all st u d y sites f or at least  2 years.  
N o s uc h c o m m u nicati o n, prese ntati o n, or p u blicati o n will i ncl u de Bei Ge n e’s  
 
i nf or mati o n.  
T he I n vesti gat or will s u b mit a n y pr o p ose d p u blicati o n or prese ntati o n al o n g wit h t he res pecti ve 
scie ntific j o ur nal or prese ntati o n f or u m at least 3 0 da ys b ef ore s u b missi o n of t he p u blicati o n or 
prese ntati o n.  T he I n vesti gat or will c o m pl y wit h Bei Ge ne’s re q uest t o del ete refere n ces t o its 
 i nf or mati o n ( ot her t ha n t he st u d y res ults) i n a n y pa p er or prese ntati o n a n d a grees t o 
wit h h ol d p u b licati o n or prese ntati o n f or a n a d diti o nal 6 0 da ys i n or der t o o btai n pate nt pr otecti o n 
if dee me d necessar y. 
If a writte n c o ntract f or t he c o n d uct of t he st u d y, w hic h i ncl u des p u blicati o n pr o visi o ns 
i nc o nsiste nt wit h t his state me nt is e x ec ute d, t hat c o ntract’s p u blicati o n pr o visi o ns s hall a p pl y 
rat her t ha n t his state me nt.  
1 1. 4.  
St u d y a n d St u d y Ce nter Cl os ure  
U p o n c o m pleti o n of t he st u d y, t he m o nit or will c o n d uct t he f oll o wi n g acti vities i n c o nj u ncti o n 
wit h t he i n vesti gat or or st u d y ce nter p ers o n nel, as a p pr o pria te: 
•  Ret ur n of all st u d y d ata t o t he s p o ns or.  
•  Data q ueri es.  
•  Acc o u nta bilit y, rec o n ciliati o n, a n d arra n ge me nts f or u n use d st u d y dr u g(s).  
•  Re vie w of st u d y rec or ds f or c o m plete ness.  
•  Ret ur n of treat me nt c o des t o t he s p o ns or.  
•  
. 
I n a d diti o n, t he S p o ns or reser ves t he ri g ht t o s us pe n d or pre mat urel y dis c o nti n ue t his st u d y eit her 
at a si n gle st u d y ce nter or at all st u d y ce nters at a n y ti me f or reas o ns i ncl u di n g, b ut n ot li mite d 
t o, safet y or et hical iss ues or se vere n o n-c o m plia nce.  If t h e S p o ns or deter mi nes s uc h acti o n is 
nee de d, t he S p o ns or will disc uss t his wit h t he i n vesti gat or (i ncl u di n g t he reas o ns f or ta ki n g s uc h 
acti o n) at t hat ti me.  W he n feasi ble, t he S p o ns or will pr o vi de a d va nce n otifi cati o n t o t he 
i n vesti gat or of t h e i m pe n di n g acti o n pri or t o it ta ki n g effect. 
T he S p o ns or will pr o m ptl y i nf or m all ot her I n vesti gat ors a n d/ or i nstit uti o ns c o n d ucti n g t h e st u d y 
if t he st u d y is s us pe n de d or ter mi nate d f or safet y reas o ns, a n d will als o i nf or m t he re g ulat or y 
a ut h oriti es of t he s us pe nsi o n or ter mi nati o n of t he st u d y a n d t he reas o n(s) f or t he acti o n.  If 
re q uire d b y a p plica ble re g ulati o ns, t he i n vesti gat or m ust i nf or m t he I E C/I R B pr o m ptl y a n d 
pr o vi de t he reas o n f or t h e s us pe nsi o n or ter mi nati o n.  
C CI
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C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  8 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
If t he st u d y is pre mat urel y disc o nti n ue d, all st u d y data m ust be ret ur n e d t o t he s p o ns or.  I n 
a d diti o n, arra n ge me nts will be ma de f or all u n use d st u d y dr u g(s) i n acc or da nce wit h t he 
a p plica ble s p o ns or pr oce d ures f or t he st u d y.  
Fi na ncial c o m pe nsati o n t o i n vesti gat ors a n d/ or i nstit uti o ns will be i n acc or da nce wit h t he 
a gree m e nt esta blis he d bet wee n t he i n vesti gat or a n d t he s p o ns or.  
1 1. 5.  
Rec or ds Rete nti o n a n d St u d y Files  
1 1. 5. 1.  
St u d y Files a n d Rete nti o n of Rec or ds  
T he I n vesti gat or m ust mai ntai n a de q uate a n d acc urate rec or ds t o e n a ble t h e c o n d uct of t he st u d y 
t o be f ull y d oc u m e nte d a n d t he st u d y data t o b e s u bse q ue ntl y v erifie d.  T h ese d oc u me nts s h o ul d 
be classifie d i nt o at least t he f oll o wi n g 2 cate g ori es: ( 1) I n vesti gat or’s st u d y file, a n d ( 2) s u bject 
cli nical s o urce d o c u me nts.  
T he I n vesti gat or’s  st u d y file will c o ntai n t he pr ot oc ol/a me n d me nts, C R F a n d q uer y f or ms, 
I R B/I E C, a n d g o ver n me ntal a p pr o val wit h c orres p o n de nce, i nf or me d c o ns e nt, dr u g rec or ds, staff 
c urric ul u m vitae a n d a ut h orizati o n f or ms, a n d ot her a p pr o priate d oc u m e nts a n d c orres p o n de n c e.  
S u bject cli nical s o urce d oc u me nts ( us uall y d efi ne d b y t he pr oject i n a d va n ce t o rec or d ke y 
effic ac y/safet y para meters i n de pe n de nt of t he C R Fs) w o ul d i ncl u de (alt h o u g h n ot be li mite d t o) 
t he f oll o wi n g: s u bject h os pital/cli nic rec or ds, p h ysicia n’s a n d n urs e’s n otes, a p p oi nt me nt b o o k, 
ori gi nal la b orat or y re p orts, E C G, electr oe n ce p h al o gra m, x -ra y, p at h ol o g y a n d s pecial assess me nt 
re p orts, c o ns ulta nt letters, scree ni n g a n d e nr oll me nt l o g, etc.  
F oll o wi n g cl os ure of t he st u d y, t he i n vesti gat or m ust mai ntai n al l st u d y rec or ds i n a safe a n d 
sec ure l o cati o n.  T he rec or ds m ust be mai ntai ne d t o all o w eas y a n d ti mel y retrie val, w h e n nee de d 
(e. g., a u dit or i ns pecti o n), a n d, w he ne v er feasi ble, t o all o w a n y s u bs e q ue nt r e vie w of dat a i n 
c o nj u ncti o n wit h assess me nt of t he  facilit y, s u p p orti n g s yst e ms, a n d pers o n nel.  W here per mitte d 
b y l oc al la ws/re g ulati o ns or i nstit uti o nal p olic y, s o me or all of t hese rec or ds ca n be mai ntai ne d i n 
a f or mat ot her t h a n har d c o p y (e. g. micr ofic he, s ca n ne d, electr o nic); h o we ver, ca uti o n nee ds  t o 
be e x ercise d bef ore s u c h acti o n is ta ke n.  T he i n vesti gat or m ust ass ure t h at all re pr o d ucti o ns are 
le gi ble, are a tr ue a n d acc urate c o p y of t he ori gi nal, a n d meet accessi bilit y a n d retrie val 
sta n dar ds, i ncl u di n g re-ge nerati n g a h ar d c o p y, if re q uire d.  F urt her m ore, t he i n vesti gat or m ust 
e ns ure t here is a n acce pta ble bac k u p of t hes e re pr o d ucti o ns a n d t hat a n acce pta ble q ualit y 
c o ntr ol pr ocess e xists f or ma ki n g t hese re pr o d ucti o ns.  
T he S p o ns or will i nf or m t he I n v esti gat or of t he ti me peri o d f or retai ni n g  t hese rec or ds t o c o m pl y 
wit h all a p plica ble re g ul at or y re q uire me nts.  T h e mi ni m u m rete nti o n ti me will meet t he strictest 
sta n dar d a p plica ble t o t hat st u d y ce nter f or t he st u d y, as dict ate d b y a n y i nstit uti o nal 
re q uire me nts or l o cal la ws or re g ulati o ns, or t he s p o ns or’s sta n dar ds/ pr o ce d ures; ot her wise, t he 
rete nti o n peri o d will defa ult t o 1 5 years. 
T he I n vesti gat or m ust n otif y t he s p o ns or of a n y c h a n ges i n t he arc hi val arra n ge m e nts, i ncl u di n g, 
b ut n ot li mite d t o, t he f oll o wi n g: arc hi val at a n off -site facilit y, tra nsfer of o w ners hi p of t he 
rec or ds i n t he e ve nt t he i n vesti gat or l ea ves t he st u d y ce nter. 
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Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  8 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
If t he I n vesti gat or ca n n ot g uara nte e t his arc hi vi n g re q uire me nt at t he st u d y site f or a n y or all t he 
d oc u me nts, s pecial arra n ge m e nts m ust be ma de b et wee n t he I n vesti gat or a n d Bei Ge ne t o st ore 
t hese i n seale d c o ntai ners o utsi de of t he site s o t hat t he y ca n be ret ur n e d seal e d t o t he 
i n vesti gat or i n case of a re g ul at or y a u dit. W he n s o urce d oc u m e nts are re q uire d f or t he c o nti n ue d 
care of t he s u bject, a p pr o priate c o p ies s h o ul d be m a de f or st or a ge o utsi de of t he site. 
Bi ol o gic al sa m ples at t he c o ncl usi o n of t his st u d y ma y b e retai n e d i n st ora ge b y t h e S p o ns or f or 
a peri o d u p t o 1 year f or p ur p oses of t his st u d y.  
1 1. 6.  
Pr o visi o n of St u d y Res ults a n d I nf or m ati o n t o I n vesti g at o rs 
W he n t he cli nical st u d y re p ort ( C S R) is c o m plete d, t he S p o ns or will pr o vi de t he maj or fi n di n gs 
of t he st u d y t o t he i n vesti gat or.  
I n a d diti o n, details of t he st u d y dr u g assi g n me nt will be pr o vi de d t o t he I n v esti gat or t o e na ble 
hi m/ her t o re vie w t he d ata  t o deter mi ne t he o utc o me of t he st u d y f or his/ her s u bject(s). 
T he S p o ns or will n ot r o uti nel y i nf or m t he I n v esti gat or or s u bject t he test res ults, beca use t he 
i nf or mati o n ge nerate d fr o m t his st u d y will be preli mi nar y i n nat ure, a n d t h e si g nifica nce a n d 
scie ntific vali dit y of t h e res ults will be u n deter mi ne d at s uc h a n earl y sta ge of researc h.   
1 1. 7.  
I nf or m ati o n Discl os ure a n d I n ve nti o ns 
All i nf or mati o n pr o vi de d b y t he S p o ns or a n d all data a n d i nf or m ati o n ge nerate d b y t he st u d y 
ce nter as part of t h e st u d y ( ot her t ha n a s u bject’s me dical rec or ds) is t he s ole pr o pert y of t he 
S p o ns or.  
All ri g hts, title, a n d i nterests i n a n y i n ve nti o ns, k n o w -h o w or ot her i ntellect ual or i n d ustrial 
pr o pert y ri g hts w hic h are c o ncei ve d or re d u ce d t o practice b y t h e st u d y ce nt er pers o n nel  d uri n g 
t he c o urse of or as a res ult of t he st u d y are t he s ole pr o pert y of t he S p o ns or, a n d are h ere b y 
assi g ne d t o t he S p o ns or.  
If a writte n c o ntract f or t he c o n d uct of t he st u d y w hic h i ncl u des o w ners hi p pr o visi o ns 
i nc o nsiste nt wit h t his state me nt is e x ec ute d bet wee n t he s p o ns or a n d t he st u d y ce nter, t hat 
c o ntract’s o w ners hi p pr o visi o ns s hall a p pl y rat her t ha n t his state me nt.  
All i nf or mati o n pr o vi de d b y t he s p o ns or a n d all data a n d i nf or mati o n ge n erate d b y t he st u d y 
ce nter as part of t h e st u d y ( ot her t ha n a  s u bject’s me dical rec or ds) will be ke pt b y t he 
i n vesti gat or a n d ot her st u d y ce nter p ers o n nel.  T his i nf or mati o n a n d data will n ot be use d b y t he 
I n v esti gat or or ot her st u d y ce nter p ers o n nel f or a n y p ur p os e ot her t ha n c o n d ucti n g t he st u d y.   
T hese restri cti o ns d o n ot a p pl y t o: 
•  I nf or mati o n w hic h bec o mes p u blicl y a v aila ble t hr o u g h n o fa ult of t he i n vesti gat or or 
st u d y ce nt er pers o n nel. 
•  I nf or mati o n w hic h is necessar y t o discl ose i n c o nfi de nce t o a n I E C/I R B s olel y f or t he 
e val uati o n of t he st u d y.  
•  I nf or mati o n w hic h is necessar y t o discl ose i n or der t o pr o vi de a p pr o priate me dical 
care t o a s u bject.  
•  St u d y res ults w hic h ma y be p u blis he d.   
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Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  8 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
If a writte n c o ntract f or t he c o n d uct of t he st u d y w hic h i ncl u des pr o visi o ns i nc o nsiste nt wit h t his 
state me nt is e x ec uted, t hat c o ntract’s pr o visi o ns s hall a p pl y rat her t h a n t his state me nt.  
1 1. 8.  
J oi nt I n vesti g at or/ S p o ns or Res p o nsi bilities  
1 1. 8. 1.  
Access t o I nf or m ati o n f or M o nit ori n g  
I n acc or da n ce wit h I C H G C P g ui deli nes, t he st u d y m o nit or m ust ha ve direct access t o t he 
I n v esti gat or’s s ource d oc u me ntati o n i n or der t o verif y t h e data rec or de d i n t he C R Fs f or 
c o nsiste nc y.  
T he m o nit or is res p o nsi ble f or r o uti ne re vie w of t he C R Fs at re g ular i nter vals t hr o u g h o ut t he 
st u d y t o verif y a d here nce t o t he pr ot oc ol a n d t he c o m plete ness, c o nsiste nc y, a n d acc urac y of t he 
data bei n g e ntere d o n t he m.  T he m o nit or s h o ul d ha ve access t o a n y s u bject rec or ds nee de d t o 
verif y t he e ntri es o n t he C R Fs.  T he I n vesti gat or a grees t o c o o perate wit h t he m o nit or t o e ns ure 
t hat a n y pr o ble ms detecte d d uri n g t hese m o nit ori n g visits are res ol ve d. 
1 1. 8. 2.  
Access t o I nf or m ati o n f or A u diti n g or I ns pecti o ns  
Re prese ntati ves of re g ulat or y a ut h orities or of Bei Ge ne ma y c o n d uct i ns pecti o ns or a u dits of t he 
cli nical st u d y.  If t he I n v esti gat or is n otifie d of a n i ns pecti o n b y a re g ulat or y a ut h orit y t he 
i n vesti gat or a grees t o n otif y t he s p o ns or or its desi g nee i m me diatel y.  T he I n vesti gat or a grees t o 
pr o vi de t o re prese ntati ves of a re g ulat or y a ge n c y or Bei G e ne access t o rec or ds, facilities, a n d 
pers o n nel f or t h e effecti v e c o n d uct of a n y i ns pe cti o n or a u dit.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 2.  
R E F E R E N C E S  
A nsell S M, Les o k hi n A M, B orrell o I, et al.  P D -1 bl oc ka de wit h ni v ol u ma b i n rela pse d or 
refract or y H o d g ki n’s l y m p h o ma.  N E n gl J Me d 2 0 1 5; 3 7 2( 4): 3 1 1-9.  
A nsell S M.  H o d g ki n L y m p h o ma: 2 0 1 2 u p date o n dia g n osis, ris k-str atificati o n, a n d 
ma na ge me nt.  A m J He mat ol 2 0 1 2; 8 7( 1 2): 1 0 9 7 -1 0 3.  
Ar ma n d P, S hi p p M A, Ri bra g V, et al.  Pr o gra m me d deat h -1 bl oc k ade wit h pe m br oliz u ma b i n 
patie nts wit h classical H o d g ki n l y m p h o m a after bre nt u xi ma b ve d oti n fail ure.  J Cli n O nc ol 
2 0 1 6 ;3 4( 3 1): 3 7 3 3 -3 9.  
Bra h m er J R, Ha m mer H, Li ps o n EJ.  Ni v ol u ma b: tar geti n g P D -1 t o b olster a ntit u m or i m m u nit y.  
F ut ure O n c ol 2 0 1 5; 1 1( 9): 1 3 0 7 -2 6.  
C ha m piat S, La m b otte O, Barrea u E, et al. Ma n a ge me nt of i m m u ne c hec k p oi nt bl oc ka de 
d ysi m m u ne t o xicities: a c olla b o rati ve p ositi o n pa per. A n n O nc ol 2 0 1 6; 2 7( 4): 5 5 9-7 4.  
 
 
 
C hes o n B D, Fis her RI, Barri n gt o n S F, et al.  Re c o m me n dati o ns f or i nitial e val uati o n, sta gi n g, 
a n d res p o nse assess me nt of H o d g ki n a n d n o n -H o d g ki n l y m p h o m a: T he L u ga n o Classificati o n.  J 
Cli n O nc ol 2 0 1 4; 3 2( 2 7): 3 0 5 9 -6 7.  
Desai J, Mar k ma n B, Sa n d h u S K, et al.  A p hase I d ose -escalati o n st u d y of B G B -A 3 1 7, a n a nti -
pr o gra m me d deat h -1 ( P D -1) m A b i n patie nts wit h a d va nce d s oli d t u m ors.  J Cli n O nc ol 
2 0 1 6; 3 4(s u p pl):a bstr 3 0 6 6.  
Fe h ni ger T A, Lars o n S, Tri n ka us K, et al.  A p h ase 2 m ultice nter st u d y of le nali d o mi de i n 
rela pse d or refract or y classical H o d g ki n l y m p h o m a.  Bl o o d 2 0 1 1; 1 1 8( 1 9): 5 1 1 9-2 5.  
Haa ne n J B A G, C ar b o n nel F, R o bert C, et al.  Ma n a ge me nt of t o xicities fr o m i m m u n ot hera p y: 
E S M O Cli nical Practice G ui deli nes f or dia g n o sis, treat me nt, a n d f oll o w-u p.  A n n O nc ol. 
2 0 1 7: 2 8 (s u p ple me nt 4):i v 1 1 9 -4 2.  
J o h nst o n P B, I n war ds DJ, C ol ga n J P, et al.  A p hase II trial of t he oral m T O R i n hi bit or 
e ver oli m us i n rela pse d H o d g ki n l y m p h o m a.  A m J He mat ol 2 0 1 0; 8 5( 5): 3 2 0 -4.  
Ke ytr u da ®  U nite d St ates Prescri bi n g I nf or m ati o n.  
htt p:// w w w. merc k.c o m/ pr o d uct/ usa/ pi _circ ulars/ k/ ke ytr u d a/ ke ytr u d a _ pi. p df  
 
 
 
 
Mc Der m ott M F, At ki ns M B.  P D -1 as a p ot e ntial tar get i n ca n cer t hera p y.  Ca nce r Me d 
2 0 1 3; 2( 5): 6 6 2 -7 3.  
O hs hi ma K, Kar u be K, Ha masa ki M, et al.  I m bal a nces of c h e m o ki nes, c he m o ki ne rece pt ors a n d 
c yt o ki nes i n H o d g ki n l y m p h o ma: classical H o d g ki n l y m p h o m a vs. H o d g ki n -li ke A T L L.  I nt J 
Ca ncer 2 0 0 3; 1 0 6( 5): 7 0 6 -1 2.  
C CI
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
O hs hi ma K, T uti ya T, Ya ma g u c hi T, et al.  I nfiltrati o n of T h 1 a n d T h 2 l y m p h oc yt es ar o u n d 
H o d g ki n a n d R ee d -Ster n ber g ( H & R S) cells i n H o d g ki n diseas e: Relati o n wit h e x pressi o n of 
C X C a n d C C c he m o ki nes o n H & R S cells.  I nt J Ca ncer 2 0 0 2; 9 8( 4): 5 6 7 -7 2.  
O p di v o ®  ( ni v ol u ma b) I m m u ne Me diate d A d verse Reacti o ns Ma na ge m e nt G ui de. 
htt p:// w w w. o p di v o hc p.c o m/ser vlet/ser vlet. File D o w nl oa d?file = 0 0 Pi 0 0 0 0 0 0ijs 1 v E A A.  
O p di v o ®  U nite d States Prescri bi n g I nf or mati o n.  
htt p:// pac ka gei ns erts. b ms.c o m/ pi/ pi _ o p di v o. p df.  
Res uscitati o n C o u ncil ( U K).  E mer ge n c y treat m e nt of a na p h ylactic reacti o ns: G ui deli nes f or 
healt hcare pr o vi ders.  htt ps:// w w w.res us. or g. u k/ p a ges/reacti o n. p df.  
 
Sir o hi B, C u n ni n g ha m D, P o wles R, et al.  L o n g -t er m o utc o me of a ut ol o g o us ste m -cell 
tra ns pla ntati o n rela ps e d or refract or y H o d g ki n’s l y m p h o ma.  A n n O nc ol 2 0 0 8; 1 9( 7): 1 3 1 2-1 9.  
S oar J, P u m p hre y R, Ca nt A, et al.  E mer ge n c y treat me nt of a na p h ylactic reacti o ns --g ui deli nes 
f or healt hcare pr o vi ders.  Res uscitati o n. 2 0 0 8; 7 7( 2): 1 5 7-6 9.  
Stat his A, Y o u nes A.  T he ne w t hera pe utic s ce nari o of H o d g ki n l y m p h o ma.  A n n O nc ol 
2 0 1 5; 2 6: 2 0 2 6 -3 3.  
We ber J S, D’ A n gel o S P, Mi n or D, et al. Ni v ol u ma b vers us c he m ot hera p y i n patie nts wit h 
a d va nce d mela n o ma w h o pr o gresse d after a nti -C T L A -4 treat me nt  ( C hec k M ate-0 3 7): a 
ra n d o mise d, c o ntr olle d, o pe n-la bel, p has e 3 trial.  La n cet O n c ol 2 0 1 5; 1 6( 4): 3 7 5-8 4.  
Y o u nes A, G o pal A K, S mit h S E, et al.  Res ults of a pi v otal p hase II st u d y of bre nt u xi ma b 
ve d oti n f or patie nts wit h rela pse d or refract or y H o d g ki n’s l y m p h o ma. J Cli n O nc ol 
2 0 1 2a; 3 0( 1 8): 2 1 8 3 -2 1 8 9.  
Y o u nes A, S ure da A, Be n -Ye h u da D, et al.  Pa n o bi n ostat i n patie nts wit h rela pse d/refract or y 
H o d g ki n’s l y m p h o ma after a ut ol o g o us ste m -cell tra ns pla ntati o n: res ults of a p hase II st u d y.  J 
Cli n O nc ol 2 0 1 2 b; 3 0( 1 8): 2 1 9 7 -2 0 3.  
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 3.  
A P P E N DI C E S  
A P P E N DI X  1.  SI G N A T U R E O F I N V E S TI G A T O R  
 
P R O T O C O L TI T L E:  
A Si n gle Ar m, M ulti -Ce nter, P hase 2 St u d y of B G B -A 3 1 7 as 
M o n ot hera p y i n Rela pse d or Refract or y Classical H o d g ki n 
L y m p h o ma  
P R O T O C O L N O:  
 
B G B -A 3 1 7 -2 0 3  
 
T his pr ot oc ol is a  
 c o m m u nicati o n of Bei Ge n e ( S ha n g h ai) C o., Lt d.  I c o nfir m t hat I 
ha ve rea d t his pr ot oc ol, I u n dersta n d it, a n d I will w or k i n acc or da n ce wit h t his pr ot oc ol.  I will 
als o w or k c o nsiste ntl y wit h t he et hical pri nci ples t hat ha ve t heir ori gi n i n t h e Decl arati o n  of 
Helsi n ki a n d t hat are c o nsiste nt wit h g o o d cli nical practices a n d t he a p plica ble la ws a n d 
re g ulati o ns.  Acce pta nce of t his d oc u me nt c o nstit utes m y a gree m e nt t hat n o u n p u blis he d 
i nf or mati o n c o ntai ne d herei n will be p u blis he d or discl ose d wit h o ut pri or writte n a p pr o val fr o m 
Bei Ge n e ( S ha n g h ai) C o., Lt d.  
 
I h a ve rea d t his pr ot oc ol i n its e ntiret y a n d a gree t o c o n d uct t he st u d y acc or di n gl y: 
 
 
Si g nat ure of I n vesti gat or:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   Date:  _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Pri nte d Na me:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
I n v esti gat or Title: 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Na me/ A d dress of Ce nter:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A P P E N DI X  2.  C LI NI C A L L A B O R A T O R Y A S S E S S M E N T  
Ser u m  C he mistr y  
C B C wit h Differe nti al  
C o a g ul ati o n  
Uri n al ysis  
S o di u m  
R B C  
P T  
p H  
P otassi u m  
He mat ocrit  
a P T T 
S pecific gra vit y  
C hl ori de  
He m o gl o bi n  
I N R 
Gl uc ose  
Bicar b o nate  
M C H  
 
Pr otei n  
B U N  
M C H C  
 
Ket o nes  
Creati ni ne  
M C V  
 
Bl o o d  
L D H  
R D W  
 
 
Gl uc ose  
Platelet  
 
 
Calci u m  
W B C wit h differe ntial  
 
 
A S T ( S G O T)  
     Ne utr o p hil  
 
 
A L T ( S G P T)  
     L y m p h oc yte  
 
 
T otal bilir u bi n  
     M o n oc yte  
 
 
C o nj u gate d bilir u bi n  
     E osi n o p hil  
 
 
Al kali ne p h os p hatase  
     Bas o p hil  
 
 
T otal pr otei n  
 
 
 
Ma g nesi u m  
 
 
 
P h os p h or us  
 
 
 
Uric aci d  
 
 
 
Al b u mi n  
 
 
 
Creati ne ki nase ( C K)  
 
 
 
Creati ne ki nase -car diac 
m uscle is oe nz y me 
( C K-M B) *  
 
 
 
A S T: as partate a mi n otra nsferase; A L T: ala ni ne a mi n otra nsferase; S G O T: ser u m gl uta mic -o xal oacetic tra nsa mi nase; 
S G P T: ser u m gl uta mic -p yr u vi c tra nsa mi nase; M C H: mea n c or p usc ular he m o gl o bi n; M C H C: mea n c or p usc ular 
he m o gl o bi n c o nce ntrati o n; M C V: mea n c or p usc ul ar v ol u me; R D W: re d cell distri b uti o n wi dt h; W B C: w hite bl o o d 
cell c o u nt; R B C: re d bl o o d cell c o u nt; P T: pr ot hr o m bi n ti me; a P T T: acti vate d partial t hr o m b o plasti n ti me; I N R: 
i nter nati o nal n or malize d rati o; L D H: lactate de h y dr o ge nase; B U N: bl o o d urea nitr o gen; p H: p o u v oir h y dr o ge ne  
* I n t he e ve nt t hat C K -M B fra cti o nati o n is n ot a vaila ble, please assess tr o p o ni n I a n d/ or tr o p o ni n T  i nstea d. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A P P E N DI X  3.  H O D G KI N L Y M P H O M A S T A GI N G  
St a ge  
I n v ol ve me nt 
I 
I n v ol ve me nt of a si n gle l y m p h n o de re gi o n (I) or l ocalize d i n v ol ve me nt of a si n gle e xtra-
l y m p hatic or ga n or site (IE ) 
II 
I n v ol ve me nt of t w o or m ore l y m p h n o de re gi o ns o n t he sa me si de of t he dia p hra g m (II) or 
l ocalize d i n v ol ve me nt of a si n gle ass ociate d e xtra-l y m p hatic or ga n or site a n d its re gi o nal 
l y m p h n o de(s), wit h or wit h o ut i n v ol ve me nt of ot her l y m p h n o de re gi o ns o n t he sa me si de 
of t he dia p hra g m (II E ) 
III 
I n v ol ve me nt of l y m p h n o de re gi o ns o n b ot h si des of t he dia p hra g m (III), w hic h ma y als o 
be acc o m pa nie d b y l ocalize d i n v ol ve me nt of a n ass ociate d e xtra -l y mp hatic or ga n or site 
(IIIE ), or b y i n v ol ve me nt of t he s plee n (IIIS ), or b y b ot h (IIIE + S ) 
I V 
Disse mi nate d ( m ultif ocal) i n v ol ve me nt of o ne or m ore e xtra -l y m p hatic or ga ns, wit h or 
wit h o ut ass ociate d l y m p h n o de i n v ol ve me nt, or is olate d e xtra -l y m p hatic or ga n 
in v ol ve me nt wit h dista nt ( n o n -re gi o nal) n o dal i n v ol ve me nt 
A: N o s yste mic s y m pt o ms prese nt  
B: U ne x plai ne d fe vers > 3 8 oC; dre nc hi n g ni g ht s weats; or wei g ht l oss > 1 0 % of b o d y wei g ht wit hi n 6 m o nt hs pri or 
t o dia g n osis 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A P P E N DI X  4.  I N T E R N A TI O N A L P R O G N OS TI C S C O R E  
•  Male se x  
•  A ge ≥ 4 5 years  
•  Sta ge I V  
•  He m o gl o bi n < 1 0. 5 g/ d L  
•  W B C ≥ 1 5 x 1 0
9/ L 
•  L y m p h oc yte c o u nt < 0. 6 x 1 0 9/ L or < 8 % of differe ntial 
•  Al b u mi n < 4 g/ d L  
 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A P P E N DI X  5.  S C H E D U L E O F A S S E S S M E N T  
 
Scree ni n g 1 
Tre at me nt P eri o d  
S af et y 
F oll o w -u p 2 
S af et y/ S ur vi v al/ Effic ac y 
F oll o w -u p 3 
C ycle 1  
( 2 1 D a ys) 2 2 
C ycle 2 a n d 
a d diti o n al 
c ycles  
(e ver y 2 1 
d a ys)  
E O T 1 9 
 
 
D a ys  
-2 8 t o -1  
1 ± 3  
1 ± 3  
 
3 0 ± 7  
( after l ast 
d ose)  
 
I nf or me d c o nse nt 4 
x  
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
x  
 
 
 
 
 
De m o gra p hic/ Me dical 
hist or y/ Pri or me dicati o ns 5 
x  
 
 
 
 
 
Vital si g ns 8 
x  
x  
x  
x  
x  
 
Hei g ht a n d wei g ht 2 1 
 
x  
x  
x  
 
 
P h ysical e xa mi nati o n  
x  
x  
x  
x  
x  
 
E C O G perf or ma nce stat us  
x  
x  
x  
x  
x  
 
1 2 -lea d E C G 1 0 
x  
 
 
 
x  
 
P ul m o nar y f u ncti o n test  
x  
 
 
 
 
 
Re vie w a d verse e ve nts 9 
x  
x  
x  
x  
x  
x  
Re vie w c o nc o mita nt 
me dicati o ns 1 2 
x  
x  
x  
x  
x  
x  
C B C wit h differe ntial 1 3 
x  
x  
X 2 5 
x  
x  
 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
 
Scree ni n g 1 
Tre at me nt P eri o d  
S af et y 
F oll o w -u p 2 
S af et y/ S ur vi v al/ Effic ac y 
F oll o w -u p 3 
C ycle 1  
( 2 1 D a ys) 2 2 
C ycle 2 a n d 
a d diti o n al 
c ycles  
(e ver y 2 1 
d a ys)  
E O T 1 9 
 
 
D a ys  
-2 8 t o -1  
1 ± 3  
1 ± 3  
 
3 0 ± 7  
( after l ast 
d ose)  
 
Ser u m c he mistr y pa nel 1 3 
x  
x  
X 2 5 
x  
x  
 
C oa g ulati o n para meters 1 4 
x  
 
 
 
 
 
He patitis B a n d C a n d HI V 1 5 
x  
 
 
 
 
 
E S R  
 
X 2 5 
 
 
 
 
Uri nal ysis  
 
X 2 5 
x 2 5 
( Start at C 7 D 1, 
re peat e ver y 6 
c ycles) 
x  
x  
 
Pre g na nc y test 1 7 
x  
 
 
x  
 
 
T h yr oi d f u ncti o n test 1 6 
 
X 2 5 
X 2 5  
(after C 2/ D 1, 
re peat e ver y 2 
c ycles)  
x  
x  
 
T u m or tiss ue 6 
x  
 
 
 
 
 
T u m or i ma gi n g 7, 2 0 
x  
Wee k 1 2, Wee k 1 8, t he n e ver y 
1 2 wee ks i n t he first year, a n d 
e ver y 1 5 wee ks t hereafter, ± 7 
da ys  
x 2 0 
 
x 2 0 
E C H O or M U G A 1 1 
x  
 
 
 
 
 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
 
Scree ni n g 1 
Tre at me nt P eri o d  
S af et y 
F oll o w -u p 2 
S af et y/ S ur vi v al/ Effic ac y 
F oll o w -u p 3 
C ycle 1  
( 2 1 D a ys) 2 2 
C ycle 2 a n d 
a d diti o n al 
c ycles  
(e ver y 2 1 
d a ys)  
E O T 1 9 
 
 
D a ys  
-2 8 t o -1  
1 ± 3  
1 ± 3  
 
3 0 ± 7  
( after l ast 
d ose)  
 
B o ne marr o w 
as pirate/ bi o ps y 2 3 
x  
 
 
 
 
 
 
 
 
 
 
 
 
St u d y dr u g a d mi nistrati o n 2 6 
 
x  
x  
 
 
 
  
 
 
 
 
 
 
A nti -dr u g a nti b o d y 2 4 
 
x  
x  
 
x  
 
A b bre viati o ns: A E, a d verse e ve nt; a P T T, acti vate d partial t hr o m b o plasti n ti me; C, c ycle; C B C, c o m plete bl o o d c o u nt; c H L, clas sical H o d g ki n l y m p h o ma; C R, 
c o m plete res p o nse; C R F, case re p ort f or m ; C T, c o m p ute d t o m o gra p h y; D, d a y; E C G, electr ocar di o gra m; E C H O, ec h ocar di o gra m; E C O G, Easter n C o o perati ve 
O nc ol o g y Gr o u p; E O S, e n d of st u d y; E O T, e n d of treat me nt; E S R, er yt hr oc yte se di me ntati o n rate; F F P E, f or mali n fi xe d paraffi n -e m be d de d; H C V, he p atitis C 
vir us; HI V, h u ma n i m m u n o defi cie nc y vir us; H L, H o d g ki n l y m p h o ma; I C F, i nf or me d c o nse nt f or m; I N R, i nter nati o nal n or malize d rati o; M RI, ma g netic 
res o na nce i ma gi n g; ir A E, i m m u ne-relate d a d verse e ve nt; M U G A, m ulti gate d ac q uisiti o n sca 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 o l o g y 
Criteria f or A d verse E ve nts; P C R, p ol y merase c hai n reacti o n; P D, pr o gressi ve disease; P E T, p ositr o n e missi o n t o m o gra p h y; 
; P T, 
pr ot hr o m bi n ti me; S A E, seri o us a d verse e ve nt; T S H, t h yr oi d sti m ulati n g h or m o ne.  
1.  All assess me nts ma n date d t hr o u g h o ut t he st u d y m ust be perf or me d o n a cale n dar sc he d ule.  Scree ni n g pr oce d ures ma y b e  perf or me d u p t o 2 8 da ys pri or t o  
first d ose of treat me nt.  Scree ni n g pr oce d ures t hat ha ve a differe nt visit wi n d o w are i n dicat e d i n pare nt heses . 
2.  T he ma n dat or y Safet y F oll o w -u p Visit s h o ul d be c o n d ucte d after i nitiati o n of st u d y dr u g, a n d all A Es a n d S A Es, re gar dless of relati o ns hi p t o st u d y dr u g, 
will b e re p orte d u ntil 9 0 da ys after last d ose of st u d y treat me nt.  S u bj ects wit h a n o n g oi n g A E t hat lea ds t o treat me nt dis c o nti n uati o n will be f oll o we d u ntil 
eit her t he e ve nt res ol ves, t he i n vesti gat or assesses t he e ve nt as sta ble, or t he s u bj ect is l ost t o f oll o w u p, w hic he ver c o me s first.   
3.  
 
 
 
  
C CI
C
C CI
C CI
C
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  9 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
4.  Writte n c o nse nt m ust b e o btai ne d pri or t o perf or mi n g a n y pr ot oc ol s pecific pr oce d ure. Res ults of a test perf or me d as part of r o uti ne cli nical ma na ge me nt are 
acce pta ble i n lie u  of a scree ni n g test if perf or me d wit hi n t he s pecifie d ti mefra me (e. g. wit hi n 2 8 da ys pri or t o C ycle 1 Da y 1). Assi g n baseli ne  n u m ber w he n 
t he st u d y i nf or me d c o nse nt is si g ne d. 
5.  I ncl u des hist or y f or t he pri mar y dia g n osis ( date of H L dia g n osis a n d last rec urre nce, H L s u bt y pe, sta ge, I nter nati o nal Pr o g n ostic Sc ore [I P S], a n d bi o ps y 
details), treat me nt of H L i ncl u di n g pri or s yste mic, ra diati o n a n d s ur gical treat me nt. Date of last pri or ca ncer treat me nt m us t b e d oc u me nte d. Ra di o gra p hic 
st u dies perf or me d pri or t o st u d y e ntr y ma y be c ollecte d f or re vie w b y t he I n vesti gat or. Re p ort c o m plete me dicati o n hist or y f or 2 8 da ys pri or t o t he Scree ni n g 
Visit ( Visit 1).  
6.  
 
  
7.  T u m or i ma gi n g ( C T wit h c o ntrast of nec k, c hest, a b d o me n a n d pel vis, a n d P E T/ C T) will b e perf or me d wit hi n 2 8 da ys pri or t o t he  first d ose of st u d y dr u g 
treat me nt. A n y q ualifie d i ma gi n g assess me nts alrea d y c o m plete d d uri n g t he re g ular w or k-u p of t he patie nt are acce pte d wit hi n 2 8 da ys pri or t o start of 
treat me nt, i ncl u di n g bef ore si g ni n g t he mai n st u d y I C F, a n d ca n be c o nsi dere d as t he Scree ni n g/ baseli ne i ma ge f or t his st u d y. I ma gi n g ti mi n g s h o ul d f oll o w 
cale n dar da ys a n d s h o ul d n ot b e a dj uste d f or treat me nt dela ys. T u m or assess me nts b y C T wit h c o ntrast s h o ul d be perf or me d at Scree ni n g, W ee k 1 2, W ee k 
1 8, t he n e ver y 1 2  wee ks i n t he first year, a n d e ver y 1 5 wee ks t hereafter  ( ± 7  da ys ), u ntil P D or treat me nt disc o nti n uati o n, w hic he ver is earlier. T ar get a n d 
n o n -tar get lesi o ns m ust b e i de ntifie d at t he ti me of Scree ni n g a n d t he sa me lesi o n(s) m ust be re -assesse d b y I n vesti gat or at eac h ti me p oi nt i n a c o nsist e nt 
ma n ner i n acc or da nce wit h t he L u ga n o Classificati o n ( C hes o n et al, 2 0 1 4 ).  T he sa me dia g n ostic m o dalit y m ust b e use d t hr o u g h o ut t he st u d y.  P E T/ C T ca n 
be perf or me d i n lie u of a C T wit h c o ntrast o nl y if t he C T is perf or me d wit h dia g n ostic q ualit y a n d c o ntrast is a d mi nistere d.  T otal b o d y M RI ma y be 
s u bstit ute d f or C T if C T wit h c o ntrast is c o ntrai n dicate d.  P E T/ C T s h o ul d be perf or me d, i n a d diti o n t o d uri n g Scree ni n g P eri o d, at W ee ks 1 2, 2 4, 4 2, 5 7, a n d 
e ver y 3 0 wee ks t hereafter.  P E T/ C T s h o ul d als o be perf or me d at P D s us pecte d cli nicall y or b y C T, a n d C R s us pecte d cli nicall y or b y C T.   
8.  Vital si g ns t o i ncl u de te m perat ure, bl o o d press ure, p ulse, res pirat or y rate, a n d p ulse o xi metr y.   
9.  A d verse e x perie nces a n d la b orat or y safet y meas ure me nts will be gra de d per N CI -C T C A E versi o n 4. 0 3.  All a d verse e x p erie nces, w het her gra d a ble b y  
C T C A E or n ot, will als o be e v al uate d f or seri o us ness.  
1 0.  At eac h ti me p oi nt liste d, a si n gle 1 2 -lea d E C G will be perf or me d b y q ualifie d site pers o n nel after t he s u bj ect has reste d i n a se mi-rec u m be nt or s u pi ne 
p ositi o n f or at least 5 mi n utes. T w o c o pies of t he E C G traci n g s h o ul d be o btai ne d at t he ti me of t he E C G; t he first c o p y will b e ke pt i n t he s u bj ect’s me dical 
c hart a n d t he sec o n d c o p y will be ke pt i n t he st u d y file f or retr os pecti ve c ollecti o n b y t he S p o ns or if necessar y. T he Scree n i n g E C G ma y be perf or me d o n 
Da y 1 bef ore t he first d ose.  
1 1.  Ec h ocar di o gra p h y ( E C H O) or M ulti gate d Ac q uisiti o n Sca n ( M U G A) is re q uire d at Scree ni n g u nless perf or me d wit hi n 9 0 da ys of fir st d a y of Scree ni n g 
( Visit 1). 
1 2.  All C o nc o mita nt Me dicati o ns wit hi n 2 8 da ys pri or t o  first st u d y treat me nt a n d u ntil 3 0 da ys after t he last d ose of st u d y tr eat me nt s h o ul d be rec or de d i n t he 
C R Fs.  A n y ne w a nti -ca ncer t hera p y, if ta ke n after treat me nt disc o nti n uati o n, will als o be rec or de d.  
1 3.  If scree ni n g la b assess me nt f or eli gi bilit y is c o m plete d wit hi n 3 da ys of st u d y dr u g a d mi nistrati o n, t he y d o n ot nee d t o be perf or me d a gai n f or C 1 D 1.  
Re -scree ni n g of patie nts will n ot b e all o we d, b ut la b orat or y p ara meters w hic h d o n ot meet t he i ncl usi o n criteria ma y be re -teste d wit hi n t he Scree ni n g 
wi n d o w ( Da y -2 8 t o Da y -1).  F or C 2 D 1 a n d all s u bse q ue nt c ycles, he mat ol o g y a n d ser u m c he mistr y (i ncl u di n g l i ver f u ncti o n tests) s h o ul d be perf or me d 
wit hi n 4 8  h o urs bef ore st u d y dr u g a d mi nistrati o n.  F or ser u m c he mistr y pa nel, a fasti n g bl o o d sa m ple is ta ke n w he n p ossi ble, u nless it is ur ge nt.  
1 4.  C oa g ulati o n para meters ( P T, I N R, a P T T) s h o ul d be deter mi ne d at S cree ni n g a n d d uri n g st u d y treat me nt as cli nicall y i n dicate d.  
1 5. T esti n g will be perf or me d at Scree ni n g a n d i ncl u des He p atitis C vir us ( H C V) a nti b o d y, He p atitis B s urface a nti ge n ( H Bs A g) , He p atitis B s urface a nti b o d y 
( H Bs A b), He p atitis B c ore a nti b o d y ( H Bc A b),  a n d HI V testi n g . S u bj ects w h o are H B c A b p ositi ve or H C V a nti b o d y p ositi ve at Scree ni n g m ust n ot b e 
e nr olle d u ntil f urt her testi n g b y P C R t o assess He p atitis B or H C V viral l oa d f or deter mi nati o n of st u d y eli gi bilit y as per I ncl usi o n/ E xcl usi o n Criteri a (s ee 
Secti o n  5  f or a d diti o nal i nf or mati o n). 
1 6.  T S H, free T 4, a n d free T 3 will be perf or me d.  
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
1 7.  O nl y i n w o me n of c hil d beari n g p ote ntial. S u bj ect s m ust ha ve a ne gati ve ser u m pre g na nc y test at scree ni n g ( wit hi n 7 2 h o urs bef ore t he first i n vesti gati o nal 
pr o d uct a d mi nistrati o n). S u bs e q ue nt tests ma y be uri ne tests, a n d s h o ul d be perf or me d as cli nicall y i n dicate d.  
1 8.  
 
 
 
 
1 9.  W he n s u bj ects g o off treat me nt, t he y will nee d t o u n der g o E O T visit wit hi n 7 da ys of last d ose of tisleliz u ma b.  
2 0.  T u m or i ma gi n g f or E O T d oes n ot ha ve t o be perf or me d if t he m ost rece nt t u m or i ma gi n g was perf or me d wit hi n t he pre vi o us 6 wee k s.  F or s u bj ects w h o 
disc o nti n ue st u d y treat me nt f or reas o n ot her t ha n P D, t u m or i ma gi n g will be perf or me d e ver y 1 2 wee ks ( ± 7 da ys) u ntil P D, ne w a nti-ca ncer t hera p y, 
wit h dra wal of c o nse nt, deat h, l ost t o f oll o w -u p, or E O S, w hi c he ver occ urs first.  
2 1.  Hei g ht o nl y nee ds t o be meas ure d o n Da y 1 of C ycle 1.  
2 2.  C B C a n d c o m pre he nsi ve ser u m c he mistr y pa nel, if o btai ne d ≤ 3 da ys pri or t o Da y 1 of C ycle 1 as part of Scree ni n g, ma y be use d  as B aseli ne a n d re -t esti n g 
o n Da y 1 of C ycle 1 is n ot re q uire d.  
2 3.  
 
   
2 4.  
 
 
 
 
 
2 5.  T hese tests s h o ul d be c o m plet e d wit hi n 3 da ys bef ore t he start of ne xt c ycle. 
2 6.  S u bj ects  still recei vi n g st u d y treat me nt w he n t he r oll-o ver st u d y is o pe n will tra nsfer t o r oll -o ver st u d y f or c o nti n u o us tre at me nt.  
 
C CI
C CI
C CI
C CI

Bei Ge ne (S ha n g hai ), C o., Lt d.  
B G B -A 3 1 7 -2 0 3  
 
P a ge: 1 0 1  of  1 1 9  
 
Versi o n 5 . 0, 1 3 -J ul y-2 0 1 8  
A P P E N DI X  6.  T H E L U G A N O C L A S SI FI C A TI O N  
Res p o nse a n d Site  
P E T -C T -B ase d Res p o nse  
C T -B ase d Res p o ns e 
C o m plete  
      
 
C o m plete meta b olic res p o nse  
 
C o m plete ra di ol o gic res p o nse (all of t he f oll o wi n g):  
T ar get n o des/ n o dal masses m ust re gress t o ≤ 1. 5 c m i n L Di  
N o e xtra -l y m p hatic sites of disease 
 
     L y m p h n o des a n d  
     e xtra-l y m p hatic sites 
 
Sc ore 1, 2, 3 * wit h or wit h o ut a resi d ual mass o n 
5 P S  
It is rec o g nize d t hat i n Wal de yer’s ri n g or e xtra-
n o dal sites wit h p h ysi ol o gic u pta ke or wit h 
acti vati o n wit hi n s plee n or marr o w (e. g., wit h 
c he m ot hera p y or m yel oi d c ol o n y -sti m ulati n g 
fact ors), u pta ke ma y be greater t ha n n or mal 
me diasti n u m a n d/ or li ver.  I n t his circ u msta nce, 
c o m plete meta b olic res p o nse ma y be i nferre d if 
u pta ke at sites of i nitial i n v ol ve me nt is n o greater 
t ha n s urr o u n di n g n or mal tiss ue e ve n if t he tiss ue has 
hi g h p h ysi ol o gic u pta ke  
 
     N o n -meas ure d  
     lesi o n 
 
N ot a p plica ble  
A bse nt  
 
     Or ga n e nlar ge me nt  
N ot a p plica ble  
Re gress t o n or mal  
 
     Ne w lesi o ns  
N o ne  
N o ne  
 
     B o ne marr o w  
N o e vi de nce of F D G -a vi d disease i n marr o w 
N or mal b y m or p h ol o g y, if i n deter mi nate, I H C ne gati ve  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Res p o nse a n d Site  
P E T -C T -B ase d Res p o nse  
C T -B ase d Res p o ns e 
Partial  
      
 
Partial meta b olic res p o nse  
 
Partial re missi o n (all of t he f oll o wi n g):  
≥ 5 0 % decrease i n S P D of u p t o 6 tar get meas ura ble n o des 
a n d e xtra -n o dal sites  
W he n a lesi o n is t o o s mall t o meas ure o n C T, assi g n 5 m m 
x 5 m m as t he defa ult val ue  
W he n n o l o n ger visi ble, 0 x 0 m m  
F or a n o de > 5 m m x 5 m m, b ut s maller t ha n n or mal, use 
act ual meas ure me nt f or calc ulati o n  
 
     L y m p h n o des a n d  
     e xtra-l y m p hatic sites 
 
Sc ore 4 or 5  wit h re d uce d u pta ke c o m pare d  wit h 
baseli ne a n d resi d ual mass(es) of a n y size  
At i nteri m, t hese fi n di n gs s u g gest res p o n di n g 
disease  
At e n d of treat me nt, t hese fi n di n gs i n dicate resi d ual 
disease  
 
 
     N o n -meas ure d  
     lesi o ns 
 
N ot a p plica ble  
A bse nt/ n or mal, re gresse d, b ut n o i ncrease  
 
     Or ga n e nlar ge me nt  
N ot a p plica ble  
S plee n m ust ha ve re gresse d b y > 5 0 % i n le n gt h be y o n d 
n or mal  
 
     Ne w lesi o ns  
N o ne  
N o ne  
 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Res p o nse a n d Site  
P E T -C T -B ase d Res p o nse  
C T -B ase d Res p o ns e 
     B o ne marr o w  
Resi d ual u pta ke hi g her t ha n u pta ke i n n or mal 
marr o w b ut re d uce d c o m pare d wit h baseli ne 
( diff use u pta ke c o m pati ble wit h reacti ve c ha n ges 
fr o m c he m ot hera p y all o we d).  If t here are persiste nt 
f ocal c ha n ges i n t he marr o w i n t he c o nte xt of a 
n o dal res p o nse, c o nsi derati o n s h o ul d be gi ve n t o 
f urt her e val uati o n wit h M RI or bi o ps y or a n i nter val 
sca n 
N ot a p pl ica ble 
N o res p o nse or sta ble 
disease  
      
 
N o meta b olic res p o nse  
 
Sta ble disease  
< 5 0 % decrease fr o m baseli ne i n S P D of u p t o 6 d o mi na nt, 
meas ura ble n o des a n d e xtra -n o dal sites; n o criteria f or 
pr o gressi ve disease are met  
 
     Tar get n o des/ n o dal  
     masses, e xtra -n o dal  
     lesi o ns 
 
Sc ore 4 or 5  wit h n o si g nifica nt c ha n ge i n F D G 
u pta ke fr o m baseli ne at i nteri m or e n d of treat me nt  
 
 
 
     N o n -meas ure d  
     lesi o ns 
 
N ot a p plica ble  
N o i ncrease c o nsiste nt wit h pr o gressi o n  
 
     Or ga n e nlar ge me nt  
N ot a p plica ble  
N o i ncrease c o nsiste nt wit h pr o gressi o n  
 
     Ne w lesi o ns  
N o ne  
N o ne  
 
     B o ne marr o w  
N o c ha n ge fr o m baseli ne  
N ot a p plica ble  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Res p o nse a n d Site  
P E T -C T -B ase d Res p o nse  
C T -B ase d Res p o ns e 
Pr o gressi ve disease  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr o gressi ve meta b olic disease  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr o gressi ve disease re q uires at least 1 of t he f oll o wi n g P P D 
pr o gressi o n:  
 
A n i n di vi d ual n o de/lesi o n m ust be a b n or mal wit h:  
L Di > 1. 5 c m a n d  
I ncrease b y ≥ 5 0 % fr o m P P D na dir a n d 
A n i ncrease i n L Di or S Di fr o m na dir  
0. 5 c m f or lesi o ns ≤ 2 c m  
1. 0 c m f or lesi o ns > 2 c m  
I n t he setti n g of s ple n o me gal y, t he s ple nic le n gt h m ust 
i ncrease b y > 5 0 % of t he e xte nt of its pri or i ncrease be y o n d 
baseli ne (e. g. a 1 5 -c m s plee n m ust i ncrease t o > 1 6 c m).  If 
n o pri or s ple n o me gal y, m ust i ncrease b y at least 2 c m fr o m 
baseli ne  
Ne w or rec urre nt s ple n o me gal y  
     I n di vi d ual tar get  
     n o des/ n o dal masses  
 
Sc ore 4 or 5  wit h a n i ncrease i n i nte nsit y of u pta ke 
fr o m baseli ne a n d/ or ne w F D G-a vi d f oci c o nsiste nt 
wit h l y m p h o ma at i nteri m or e n d of treat me nt 
assess me nt 
 
 
     N o n -meas ure d  
     lesi o ns 
 
N o ne  
Ne w or clear pr o gressi o n of pre -e xisti n g n o n -meas ure d 
lesi o ns 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Res p o nse a n d Site  
P E T -C T -B ase d Res p o nse  
C T -B ase d Res p o ns e 
     Ne w lesi o ns  
Ne w F D G -a vi d f oci c o nsiste nt wit h l y m p h o ma 
rat her t ha n a n ot her eti ol o g y (e. g., i nfecti o n, 
i nfla m mati o n).  If u ncertai n re gar di n g eti ol o g y of 
ne w lesi o ns, bi o ps y or i nter val sca n ma y be 
c o nsi dere d 
Re gr o wt h of pre vi o usl y res ol ve d lesi o ns  
A ne w n o de > 1. 5 c m i n a n y a xis  
A ne w e xtra -n o dal site > 1. 0 c m i n a n y a xis; if < 1. 0 c m i n 
a n y a xis, its prese nce m ust be u ne q ui v ocal a n d m ust be 
attri b uta ble t o l y m p h o ma 
Assessa ble disease of a n y size u ne q ui v ocall y attri b uta ble t o 
l y m p h o ma 
     B o ne marr o w  
Ne w or rec urre nt F D G -a vi d f oci 
Ne w or rec urre nt i n v ol ve me nt  
C hes o n B D, Fis her RJ, B arri n gt o n S F, et al.  J Cli n O nc ol 2 0 1 4; 3 2( 2 7): 3 0 5 9 -6 7 . 
A b bre viati o n s: P E T,  P ositr o n E missi o n T o m o gra p h y ; 
; P S , p oi nt scale; P P D , p urifie d pr otei n deri vati ve ; L D , l o n gest dia meter; S D , 
s h ortest dia meter ; C T,  C o m p ute d T o m o gra p h y ; F D G , fl u or o de o x y gl uc ose. 
* A sc ore 3 i n ma n y patie nts i n dicates a g o o d pr o g n osis wit h sta n dar d treat me nt, es peciall y if at t he ti me of a n i nteri m sca n.   H o we ver, i n trials i n v ol vi n g P E T 
w here de -escalati o n is i n vesti gate d, it ma y be prefera ble t o c o nsi der a sc o re of 3 as i na de q uate res p o nse (t o a v oi d u n der treat me nt).  Meas ure d d o mi na nt lesi o ns: 
U p t o si x of t he lar gest d o mi na nt n o des, n o dal masses, a n d e xtra -n o dal lesi o ns selecte d t o be clearl y meas ura ble i n t w o dia meters.  N o des s h o ul d prefer a bl y be 
fr o m dis parate re gi o ns of t he b o d y a n d s h o ul d i ncl u de, w here a p plica ble, me diasti nal a n d retr o perit o neal areas.  N o n -n o dal lesi o ns i ncl u de t h ose i n s oli d or ga ns 
(e. g. li ver, s plee n, ki d ne ys, l u n gs), gastr oi ntesti nal ( GI) i n v ol ve me nt, c uta ne o us lesi o ns, or t h ose n ote d o n pal pati o n.  N o n -meas ure d lesi o ns: A n y dis ease n ot 
selecte d as meas ure d, d o mi na nt disease a n d tr ul y assessa ble disease s h o ul d be c o nsi dere d n ot meas ure d.  T hese sites i ncl u de a n y n o des, n o dal masses, a n d e xtra -
n o dal sites n ot selecte d as d o mi na nt or me as ura ble or t hat d o n ot meet t he re q uire me nts f or meas ura bilit y b ut are still c o nsi dere d a b n or mal, as well as tr ul y 
assessa ble disease, w hic h is a n y site of s us pecte d disease t hat w o ul d be diffic ult t o f oll o w q ua ntitati vel y wit h meas ure me nt,  i ncl u di n g ple ural eff usi o ns, ascites, 
b o ne lesi o ns, le pt o me ni n geal disease, a b d o mi nal masses, a n d ot her lesi o ns t hat ca n n ot be c o nfir me d a n d f oll o we d b y i ma gi n g.  I n W al de yer’s ri n g or i n e xtra-
n o dal sites (e. g., GI tract, li ver, b o ne marr o w), F D G u pta ke ma y be greater t ha n i n t he me diasti n u m wit h c o m plete meta b olic res p o nse, b ut s h o ul d be n o hi g her 
t ha n s urr o u n di n g n or mal p h ysi ol o gic u pta ke (e. g., wit h marr o w acti vati o n as a res ult of c he m ot hera p y or m yel oi d gr o wt h fact ors). 
 
S ple n o me gal y defi ne d as vertical s plee n le n gt h > 1 3 c m.   
 
P E T 5 -p oi nt scale ( Dea u ville Criteria):  
•  
1: n o u pta ke a b o ve bac k gr o u n d  
•  
2. u pta ke ≤ me diasti n u m  
•  
3. u pta ke > me diasti n u m b ut ≤ li ver  
•  
4. u pta ke m o deratel y > li ver  
•  
5. u pta ke mar ke dl y hi g her t ha n li ver a n d/ or ne w lesi o ns  
•  
X. ne w areas of u pta ke u nli kel y t o be relate d t o l y m p h o ma  
 
C CI
C CI

Bei Ge ne (S ha n g hai ), C o., Lt d.  
B G B -A 3 1 7 -2 0 3  
 
P a ge: 1 0 6  of  1 1 9  
 
Versi o n 5 . 0, 1 3 -J ul y-2 0 1 8  
A P P E N DI X  7.  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A P P E N DI X  8.  I M M U N E-R E L A T E D A D V E R S E E V E N T S E V A L U A TI O N  
A N D M A N A G E M E N T  
T he rec o m me n dati o ns bel o w f or t he dia g n osis a n d ma na ge me nt of a n y ir A E are i nte n d e d as a 
g ui da n ce.  T his d oc u me nt s h o ul d be use d i n c o nj u ncti o n wit h e x pert cli nical j u d ge me nt ( b y 
s pecialist p h ysicia ns e x perie nce d i n t he treat me nt of ca ncer usi n g i m m u n o l o gical a ge nts), a n d 
i n di vi d ual i nstit uti o nal g ui deli nes or p olicies. 
Criteria use d t o dia g n ose ir A Es i ncl u de bl o o d tests, dia g n ostic i ma gi n g, hist o pat h ol o g y, a n d 
micr o bi ol o g y assess me nts t o e x cl u de alter nati ve ca uses s uc h as i nf ecti o n, disease pr o gressi o n , 
a n d a d vers e effects of c o nc o mita nt dr u gs.  I n a d diti o n t o t he res ults of t hese tests, t he f oll o wi n g 
fact ors s h o ul d be c o nsi dere d w he n ma ki n g a n ir A E dia g n osis: 
•  W hat was t he te m p oral r elati o ns hi p bet wee n i nitiati o n of tisleliz u ma b a n d t he a d verse 
e ve nt?  
•  H o w di d t he patie nt res p o n d t o wit h dra wal of tisleliz u ma b?  
•  Di d t he e ve nt rec ur w h e n tisleliz u ma b was rei ntr o d uce d?  
•  Was t here a cli nical res p o nse t o c ortic oster oi ds?  
•  Is t he e ve nt a n a ut oi m m u ne e n d ocri n o p at h y? 
•  Is disease pr o gressi o n or a n alter nati ve di a g n osis a m ore li kel y e x pla nati o n? 
W he n alter nati ve e x pla nati o ns t o a ut oi m m u ne t o xicit y ha v e bee n e x cl u de d, t he ir A E fiel d, 
ass ociate d wit h t he A E i n t he e C R F s h o ul d be c hec ke d.  
Rec o m me n de d Di a g n ostic Tests i n t he M a n a ge me nt of  
P ossi ble I m m u ne -rel ate d A d verse E ve nts  
I m m u ne-rel ate d T o xicit y 
Di a g n ostic E v al u ati o n G ui deli ne  
T h yr oi d Dis or ders  
Sc he d ule d a n d re peat t h yr oi d f u ncti o n tests ( T S H a n d T 4).  
H y p o p h ysitis  
C hec k vis ual fiel ds a n d c o nsi der pit uitar y e n d ocri ne a xis bl o o d pr ofile.  
Perf or m pit uitar y a n d w h ole brai n M RI i n patie nts wit h hea dac he, vis ual 
dist ur ba nce, u ne x plai ne d fati g ue, ast he nia, wei g ht l oss a n d u ne x plai ne d 
c o nstit uti o nal s y m pt o ms.  
C o nsi der c o ns ultati o n wit h a n e n d ocri n ol o gist if a n a b n or malit y is 
detecte d.  
P ne u m o nitis  
All patie nts prese nti n g wit h ne w or w orse ne d p ul m o nar y s y m pt o ms or 
si g ns, s uc h as a n u p per res pirat or y i nfecti o n, ne w c o u g h, s h ort ness of 
breat h or h y p o xia s h o ul d be assesse d b y hi g h -res ol uti o n C T.  C o nsi der 
p ul m o nar y f u ncti o n test i ncl u di n g D L C O .  
Ra di o gra p hic a p peara nce is ofte n n o ns pecific.  De pe n di n g o n t he 
l ocati o n of t he a b n or malit y, br o nc h osc o p y a n d br o nc h oal ve olar la va ge 
or l u n g bi o ps y ma y be c o nsi dere d.  C o ns ult wit h a res pirat or y me dici ne 
p h ysicia n f or cases of u ncertai n ca use.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
Rec o m me n de d Di a g n ostic Tests i n t he M a n a ge me nt of  
P ossi ble I m m u ne -rel ate d A d verse E ve nts  
I m m u ne-rel ate d T o xicit y 
Di a g n ostic E v al u ati o n G ui deli ne  
Ne ur ol o gic al T o xicit y 
Perf or m a c o m pre he nsi ve ne ur ol o gical e xa mi nati o n a n d brai n M RI f or 
all C N S s y m pt o ms; re vie w alc o h ol hist or y a n d ot her me dicati o ns.  
C o n d uct a dia betic scree n, a n d assess bl o o d B 1 2/f olate, HI V stat us, 
T F Ts, a n d c o nsi der a ut oi m m u ne ser ol o g y.  C o n si der t he nee d f or 
brai n/s pi ne M RI/ M R A a n d ner ve c o n d ucti o n st u d y f or peri p heral 
ne ur o pat h y.  C o ns ult wit h a ne ur ol o gist if t here are a b n or mal fi n di n gs.  
C olitis  
Re vie w dietar y i nta ke a n d e xcl u de steat orr hea.  C o nsi der c o m pre he nsi ve 
testi n g, i ncl u di n g t he f oll o wi n g: F B C, U E C, L F Ts, C R P, T F Ts, st o ol 
micr osc o p y a n d c ult ure, viral P C R, Cl ostri di u m difficile  t o xi n, 
cr y pt os p ori dia ( dr u g -resista nt or ga nis m).  
I n case of a b d o mi nal disc o mf ort, c o nsi der i ma gi n g, e g, X-ra y, C T sca n.  
If a patie nt e x perie nces blee di n g, pai n or diste nsi o n, c o nsi der 
c ol o n osc o p y wit h bi o ps y a n d s ur gical i nter ve nti o n, as a p pr o priate.  
E ye Dis or ders  
If patie nts e x perie nce ac ute, ne w o nset, or w orse ni n g of e ye 
i nfla m mati o n, bl urre d visi o n, or ot her vis ual dist ur ba nces, refer t he 
patie nt ur g e ntl y t o a n o p ht hal m ol o gist f or e val uati o n a n d ma na ge me nt.   
He patitis  
C hec k A L T/ A S T/t otal bilir u bi n, I N R/al b u mi n; t he fre q ue nc y will 
de pe n d o n se verit y of t he A E (e g, dail y if Gra de 3 -4; e ver y 2 -3 da ys if 
Gra de 2, u ntil rec o veri n g).  Re vie w me dicati o ns ( e g, stati ns, a nti bi otics) 
a n d alc o h ol hist or y.  Perf or m li ver scree n i ncl u di n g He patitis A/ B/ C 
ser ol o g y, He patitis E P C R a n d assess a nti-
A N A/ S M A/ L K M/ S L A/ L P/ L CI, ir o n st u dies.  C o nsi der i ma gi n g, e g, 
ultras o u n d sca n f or metastases or t hr o m b oe m b olis m.  C o ns ul t wit h a 
he pat ol o gist a n d c o nsi der li ver bi o ps y.  
Re nal t o xicit y  
Re vie w h y drati o n stat us, a n d me dicati o n hist or y.  T est a n d c ult ure uri ne.  
C o nsi der re nal ultras o u n d sca n, pr otei n assess me nt ( di pstic k/ 2 4 -h o ur 
uri ne c ollecti o n), or p hase -c o ntrast micr osc o p y.  Refer t o ne p hr ol o g y f or 
f urt her ma na ge me nt assista nce.  
Der mat ol o g y  
C o nsi der ot her ca uses b y c o n d ucti n g a p h ysical e xa mi nati o n, c o nsi der 
der mat ol o g y referral f or s ki n bi o ps y  
J oi nt or m uscle 
i nfla m mati o n 
C o n d uct m usc ul os keletal hist o r y a n d perf or m c o m plete m usc ul os keletal 
e xa mi nati o n. C o nsi der j oi nt X -ra y a n d ot her i ma gi n g as re q uire d t o 
e xcl u de metastatic disease. Perf or m a ut oi m m u ne ser ol o g y a n d refer t o 
r he u mat ol o g y f or f urt her ma na ge me nt assista nce. 
F or s us pecte d m y ositis/r ha b d o m y o l ysis/ m yast he nia i ncl u de: C K, E S R, 
C R P, tr o p o ni n, a n d c o nsi der a m uscle bi o ps y.  
M y ocar ditis  
Perf or m E C G, ec h ocar di o gra m, C K/ C K -M B, tr o p o ni n (I a n d/ or T), a n d 
refer t o a car di ol o gist. 
A b bre viati o ns: A E, a d verse e ve nt; A L T, ala ni ne a mi n otra nsferase; A N A, a nti n uclear a nti b o d y; A S T, as partate 
a mi n otra nsferase; C K, creati ne ki nase; C K -M B, creati ne ki nase car diac is oe nz y me; C N S, ce ntral ner v o us s yste m; 
C R P, C -reacti ve pr otei n; C T, c o m p ute d t o m o gra p h y; D L C O, diff usi n g ca pacit y f or car b o n m o n o xi de; E C G, 
electr oca r di o gra m; E S R, er yt hr oc yte se di me ntati o n rate; F B C, f ull bl o o d c o u nt; HI V, h u ma n i m m u n o deficie nc y 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 0 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
vir us; I N R, i nter nati o nal n or malize d rati o; L CI, li ver c yst oli c a nti ge n ; L F T, li ver f u ncti o n test; L K M, li ver ki d ne y 
micr os o mal a nti b o d y; L P, li ver pa ncreas a nti ge n; M R A, ma g netic res o na nce a n gi o gra m; M RI, ma g netic res o na nce 
i ma gi n g; P C R, p ol y merase c hai n reacti o n; S L A, s ol u ble li ver a nti ge n; S M A, s m o ot h m uscle a nti b o d y; T 4, 
t h yr o xi ne; T F T, t h yr oi d f u ncti o n tests; T S H, t h yr oi d-sti m ulati n g h or m o ne; U E C,  urea electr ol ytes a n d creati ni ne.  
Tre at me nt of I m m u ne -rel ate d A d ve rse E ve nts  
•  I m m u ne-relat e d A Es ca n escalate q ui c kl y; st u d y tr eat me nt i nterr u pti o n, cl ose 
m o nit ori n g, ti mel y dia g n ostic w or k -u p a n d tr eat m e nt i nter ve nti o n, as a p pr o priate, 
wit h patie nts is re q uire d 
•  I m m u ne-relat e d A Es s h o ul d i m pr o ve pr o m ptl y aft er i ntr o d ucti o n of 
i m m u n os u p pressi ve t hera p y.  If t his d oes n ot occ ur, re vie w t h e dia g n osis, see k f urt her 
s pecialist a d vice a n d c o ntact t he st u d y me di cal m o nit or 
•  F or s o me Gra de 3 t o xicities t hat res ol v e q uic kl y, rec halle n ge wit h st u d y dr u g ma y b e 
c o nsi dere d if t here is e vi de nce of a cli nical r es p o nse t o st u d y treat me nt, aft er 
c o ns ultati o n wit h t he st u d y me dical m o nit or  
•  Ster oi d d osa ges i n t he ta ble bel o w are f or oral or i ntra ve n o us ( met h yl) pre d nis ol o ne.  
E q ui vale nt d osa ges of ot her c ortic oster oi ds ca n b e s u bstit ute d.  F or ster oi d -refract or y 
ir A Es, c o nsi der use of ster oi d-s pari n g a ge nts (e g, m yc o p h e n olate m ofetil [ M M F]) 
•  C o nsi der pr o p h yl actic a nti bi otics f or o p p ort u nistic i nfecti o ns if t he patie nt is 
recei vi n g l o n g-ter m i m m u n os u p pressi ve t hera p y 
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
T h yr oi d 
Dis or ders  
1 -2  
As y m pt o matic T F T 
a b n or malit y or mil d 
s y m pt o ms 
 
Re place t h yr o xi ne if h y p ot h yr oi d, 
u ntil T S H/ T 4 le vels ret ur n t o n or mal 
ra n ge. 
T h yr ot o xic patie nts s h o ul d be 
referre d t o a n e n d ocri n ol o gist.  I n 
cases wit h s yste mic s y m pt o ms: 
wit h h ol d st u d y treat me nt, treat wit h 
a beta bl oc ker a n d c o nsi der oral 
pre d nis ol o ne 0. 5  m g/ k g/ da y f or 
t h yr oi d pai n.  T a per c ortic oster oi ds 
o ver 2 -4 wee ks. M o nit or t h yr oi d 
f u ncti o n re gar di n g t he nee d f or 
h or m o ne re place me nt.  
C o nti n ue st u d y 
treat me nt or 
wit h h ol d 
treat me nt i n cases 
wit h s yste mic 
s y m pt o ms. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 0  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
3 -4  
Se vere s y m pt o ms, 
h os pitalizati o n 
re q uire d 
Refer patie nt t o a n e n d ocri n ol o gist.   
If h y p ot h yr oi d, re place wit h 
t h yr o xi ne 0. 5-1. 6  µ g/ k g/ da y (f or t he 
el derl y or t h ose wit h c o -m or bi dities, 
t he s u g geste d starti n g d ose is 
0. 5  µ g/ k g/ da y).  A d d oral 
pre d nis ol o ne 0. 5  m g/ k g/ da y f or 
t h yr oi d pai n.  T h yr ot o xic patie nts 
re q uire treat me nt wit h a beta bl oc ker 
a n d ma y re q uire car bi maz ole u ntil 
t h yr oi ditis res ol ves. 
H ol d st u d y 
treat me nt; res u me 
w he n 
res ol ve d/i m pr o ve d 
t o Gra de 0-1.  
H y p o p h ysitis  
1 -2  
Mil d s y m pt o ms  
Refer patie nt t o a n e n d ocri n ol o gist 
f or h or m o ne re place me nt.  A d d oral 
pre d nis ol o ne 0. 5 -1  m g/ k g/ da y f or 
patie nts wit h pit uitar y i nfla m mati o n. 
T a per c ortic oster oi ds o ver at least 
1  m o nt h.  If t here is n o i m pr o ve me nt 
i n 4 8 h o urs, treat as Gra de 3 -4.  
T a per c ortic oster oi ds o ver at least 1 
m o nt h.  
C o nti n ue s t u d y 
treat me nt. 
3 -4  
M o derate -se vere 
s y m pt o ms 
Refer patie nt t o a n e n d ocri n ol o gist 
f or assess me nt a n d treat me nt.  
I nitiate p ulse I V met h yl pre d nis ol o ne 
1 m g/ k g f or patie nts wit h 
hea dac he/ vis ual dist ur ba nce d ue t o 
pit uitar y i nfla m mati o n.  C o n vert t o 
oral pre d nis ol o ne a n d ta per o ver at 
least 1 m o nt h.  Mai ntai n h or m o ne 
re place me nt acc or di n g t o 
e n d ocri n ol o g y a d vice. Mai ntai n 
h or m o ne re place me nt acc or di n g t o 
e n d ocri n ol o g y a d vice.  
H ol d st u d y 
treat me nt f or 
patie nts wit h 
hea dac he/ vis ual 
dist ur ba nce d ue t o 
pit uita r y 
i nfla m mati o n u ntil 
res ol ve d/i m pr o ve d 
t o Gra de 2 or less. 
Disc o nti n uati o n is 
us uall y n ot 
necessar y.  
P ne u m o nitis  
1  
Ra di o gra p hic c ha n ges 
o nl y  
M o nit or s y m pt o ms e ver y 2 -3 da ys.  
If a p peara nce w orse ns, treat as 
Gra de 2.  
C o nsi der h ol di n g 
st u d y treat me nt 
u ntil a p peara nce 
i m pr o ves a n d 
ca use is 
deter mi ne d.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 1  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
2  
S y m pt o matic: 
e xerti o nal 
breat hless ness  
C o m me nce a nti bi otics if i nfecti o n 
s us pecte d.  A d d oral pre d nis ol o ne 1 
m g/ k g/ da y if s y m pt o ms/a p peara nce 
persist f or 4 8 h o urs or w orse n.  
C o nsi der P ne u m oc ystis i nfecti o n 
pr o p h yla xis.  Ta per c ortic oster oi ds 
o ver at least 6  wee ks.  
C o nsi der pr o p h yla xis f or a d verse 
ster oi d effects: e g, bl o o d gl uc ose 
m o nit ori n g, vita mi n D/calci u m 
s u p ple me nt. 
H ol d st u d y 
treat me nt. 
Retreat me nt is 
acce pta ble if 
s y m pt o ms res ol ve 
c o m pletel y or are 
c o ntr olle d o n 
pre d nis ol o ne 
≤ 1 0  m g/ da y.  
Disc o nti n ue st u d y 
treat me nt if 
s y m pt o ms persist 
wit h 
c ortic oster oi d 
treat me nt. 
3 -4  
Se vere or 
life-t hreate ni n g 
s y m pt o ms 
Breat hless at rest  
A d mit t o a h os pital a n d i nitiate 
treat me nt wit h I V 
me t h yl pre d nis ol o ne 2-4  m g/ k g/ da y.  
If t here is n o i m pr o ve me nt, or 
w orse ni n g after 4 8 h o urs, a d d 
i nfli xi ma b 5 m g/ k g (if n o he patic 
i n v ol ve me nt).  C o n vert t o oral 
pre d nis ol o ne a n d ta per o ver at least 
2 m o nt hs.  C o ver wit h e m piric 
a nti bi otics a n d c o nsi der pr o p h yla xis 
f or P ne u m oc ystis i nfecti o n a n d ot her 
a d verse ster oi d effects, e g, bl o o d 
gl uc ose m o nit ori n g, vita mi n 
D/calci u m s u p ple me nt.  
Disc o nti n ue st u d y 
treat me nt. 
Ne ur ol o gic al 
T o xicit y  
1  
Mil d s y m pt o ms  
 
C o nti n ue st u d y 
treat me nt. 
2  
M o derate s y m pt o ms  
Treat wit h oral pre d nis ol o ne 0. 5 -1 
m g/ k g/ da y.  T a per o ver at least 4 
wee ks. O btai n ne ur ol o g y 
c o ns ultati o n. 
H ol d st u d y 
treat me nt; res u me 
w he n 
res ol ve d/i m pr o ve d 
t o Gra de 0-1.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
3 -4  
Se vere/life -t hreate ni n g 
I nitiate treat me nt wit h oral 
pre d nis ol o ne or I V 
met h yl pre d nis ol o ne 1 -2 m g/ k g/ da y, 
de pe n di n g o n s y m pt o ms.  Ta per 
c ortic oster oi ds o ver at least 4 wee ks.  
C o nsi der azat hi o pri ne, M M F, 
c ycl os p ori ne if n o res p o nse  wit hi n 
7 2 -9 6 h o urs.  
Disc o nti n ue st u d y 
treat me nt. 
C olitis/  
Di arr he a  
1  
Mil d s y m pt o ms: 
<  3  li q ui d st o ol per 
da y o ver baseli ne a n d 
feeli n g well 
S y m pt o matic ma na ge me nt: fl ui ds, 
l o pera mi de, a v oi d hi g h fi ber/lact ose 
diet.  
If Gra de 1 persists f or > 1 4 da ys 
ma na ge as a Gra de 2 e ve nt  
C o nti n ue st u d y 
treat me nt. 
2  
M o derate s y m pt o ms: 
4 -6 li q ui d st o ols per 
da y o ver baseli ne, or 
a b d o mi nal pai n, or 
bl o o d i n st o ol, or 
na usea, or n oct ur nal 
e pis o des 
Oral pre d nis ol o ne 0. 5 m g/ k g/ da y 
( n o n-e nteric c oate d). 
D o n ot wait f or a n y dia g n ostic tests 
t o start treat me nt.  T a per ster oi ds 
o ver 2 -4 wee ks,  c o nsi der e n d osc o p y 
if s y m pt o ms are rec urri n g. 
H ol d st u d y 
treat me nt; res u me 
w he n 
res ol ve d/i m pr o ve d 
t o baseli ne gra de. 
3  
Se vere s y m pt o ms: 
>  6  li q ui d st o ols per 
da y o ver baseli ne, or 
if e pis o dic wit hi n 
1  h o ur of eati n g 
I nitiate I V met h yl pre d nis ol o ne 1-
2 m g/ k g/ da y.  
C o n vert t o oral pre d nis ol o ne a n d 
ta per o ver at least 4 wee ks.  
C o nsi der pr o p h yla xis f or a d verse 
ster oi d effects, e g, bl o o d gl uc ose 
m o nit ori n g, vita mi n D/calci u m 
s u p ple me nt. 
If n o i m pr o ve me nt i n 7 2 h o urs or 
s y m pt o ms w orse n, c o nsi der 
i nfli xi ma b 5 m g/ k g if n o perf orati o n, 
se psis, T B, he patitis, N Y H A gra de 
III/I V C H F or ot her 
i m m u n os u p pressi ve treat me nt: 
M M F or tacr oli m us.  
C o ns ult gastr oe nter ol o gist t o 
c o n d uct c ol o n osc o p y/ 
si g m oi d osc o p y. 
H ol d st u d y 
treat me nt; 
retreat me nt ma y 
be c o nsi dere d 
w he n 
res ol ve d/i m pr o ve d 
t o baseli ne gra de 
a n d after 
disc ussi o n wit h 
t he st u d y me dical 
m o nit or.  
4  
Life -t hreate ni n g 
s y m pt o ms 
Disc o nti n ue st u d y 
treat me nt. 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
S ki n re acti o ns  
1  
S ki n ras h, wit h or 
wit h o ut s y m pt o ms, 
<  1 0 % B S A  
A v oi d s ki n irrita nts a n d s u n 
e x p os ure; t o pical e m ollie nts 
rec o m me n de d. 
 
C o nti n ue st u d y 
treat me nt. 
2  
Ras h c o vers 1 0 % -3 0 % 
of B S A  
A v oi d s ki n irrita nts a n d s u n 
e x p os ure; t o pical e m ollie nts 
rec o m me n de d. 
T o pical ster oi ds ( m o derate stre n gt h 
crea m o nce a da y or p ote nt crea m 
t wice a da y) ± oral or t o pical 
a nti hista mi nes f or itc h. C o nsi der a 
s h ort c o urse of oral ster oi ds. 
C o nti n ue st u d y 
treat me nt. 
3  
Ras h c o vers >  3 0 % 
B S A or Gra de 2 wit h 
s u bsta ntial s y m pt o ms 
A v oi d s ki n irrita nts a n d s u n 
e x p os ure; t o pical e m ollie nts 
rec o m me n de d. 
I nitiate ster oi ds as f oll o ws base d o n 
cli nical j u d ge me nt:  
•  
F or m o derate s y m pt o ms: oral 
pre d nis ol o ne 0. 5 -1 m g/ k g/ da y 
f or 3 da ys t he n ta per o ver 
2 -4  wee ks.  
•  
F or se vere s y m pt o ms: I V 
met h yl pre d nis ol o ne 0. 5 -1 
m g/ k g/ da y; c o n vert t o oral 
pre d nis ol o ne a n d ta per o ver at 
least 4 wee ks. 
H ol d st u d y 
treat me nt. 
Re -treat w he n A E 
is res ol ve d or 
i m pr o ve d t o mil d 
ras h ( Gra de 1-2) 
after disc ussi o n 
wit h t he st u d y 
me dical m o nit or.  
 
 
4  
S ki n sl o u g hi n g >  3 0 % 
B S A wit h ass ociate d 
s y m pt o ms (e g, 
er yt he ma, p ur p ura, 
e pi der mal 
detac h me nt)  
I nitiate I V met h yl pre d nis ol o ne 1-2 
m g/ k g/ da y. C o n vert t o oral 
pre d nis ol o ne a n d ta per o ver at least 
4 wee ks.  
A d mit t o a h os pital a n d see k ur ge nt 
der mat ol o g y c o ns ultati o n.  
Disc o nti n ue st u d y 
treat me nt. 
 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
He p atitis  
1  
A L T or A S T >  U L N 
t o 3 X U L N 
C hec k L F Ts wit hi n 1 wee k a n d 
bef ore t he ne xt d ose c hec k L F Ts t o 
verif y t hat t here has bee n n o 
w orse ni n g.  
If L F Ts are w orse ni n g, rec hec k 
e ver y 4 8 -7 2 h o urs u ntil 
i m pr o ve me nt is see n. 
C o nti n ue st u d y 
treat me nt if L F Ts 
are u nc ha n ge d or 
i m pr o vi n g. H ol d 
st u d y treat me nt if 
L F Ts are 
w orse ni n g u ntil 
i m pr o ve me nt is 
see n. 
 
2  
A L T or A S T 3 -5 X 
U L N  
Rec hec k L F Ts e ver y 4 8 -7 2 h o urs:   
F or persiste nt A L T/ A S T ele vati o n: 
c o nsi der oral pre d nis ol o ne 0. 5 -1 
m g/ k g/ da y f or 3 da ys t he n ta per o ver 
2 -4 wee ks.  
F or risi n g A L T/ A S T: start oral 
pre d nis ol o ne 1  m g/ k g/ da y a n d ta per 
o ver 2 -4 wee ks; re -escalate d ose if 
L F Ts w orse n, de pe n di n g o n cli nical 
j u d ge me nt.  
H ol d st u d y 
treat me nt; 
treat me nt ma y be 
res u me d w he n 
res ol ve d/i m pr o ve d 
t o baseli ne gra de 
a n d pre d nis ol o ne 
ta pere d t o ≤ 1 0 
m g.  
3  
A L T or A S T 5 -2 0 X 
U L N  
A L T/ A S T < 4 0 0 I U/ L a n d n or mal 
bilir u bi n/I N R/al b u mi n: I nitiate oral 
pre d nis ol o ne 1  m g/ k g a n d ta per o ver 
at least 4 wee ks.  
A L T/ A S T > 4 0 0 I U/ L or raise d 
bilir u bi n/I N R/l o w al b u mi n: I nitiate 
I V ( met h yl) pre d nis ol o ne 
2  m g/ k g/ da y.  W he n L F Ts i m pr o ve 
t o Gra de 2 or l o wer, c o n vert t o oral 
pre d nis ol o ne a n d ta per o ver at least 
4 wee ks.  
H ol d st u d y 
treat me nt u ntil 
i m pr o ve d t o 
baseli ne gra de; 
rei ntr o d uce o nl y 
after disc ussi o n 
wit h t he st u d y 
me dical m o nit or.  
4  
A L T or A S T >  2 0 X 
U L N  
I nitiate I V met h yl pre d nis ol o ne 2 
m g/ k g/ da y. C o n vert t o oral 
pre d nis ol o ne a n d ta per o ver at least 
6 wee ks.  
Disc o nti n ue st u d y 
treat me nt. 
W orse ni n g L F Ts des pite ster oi ds : 
•  
If o n oral pre d nis ol o ne c ha n ge t o p ulse d I V met h yl pre d nis ol o ne  
•  
If o n I V a d d m yc o p he n olate m ofetil ( M M F) 5 0 0-1 0 0 0 m g t wice a da y  
•  
If w orse ns o n M M F, c o nsi der a d diti o n of tacr oli m us 
D urati o n a n d d ose of ster oi d re q uire d will de pe n d o n se verit y of e ve nt  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 5  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
Ne p hritis  
1  
Creati ni ne 1. 5 X 
baseli ne  
or > U L N t o 1. 5 X 
U L N  
Re peat creati ni ne wee kl y.  
If s y m pt o ms w orse n, ma na ge as per 
criteria bel o w. 
C o nti n ue st u d y 
treat me nt. 
 
2  
Creati ni ne >  1. 5 -3 X 
baseli ne or >  1. 5 -3 X 
U L N  
E ns ure h y drati o n a n d re vie w 
creati ni ne i n 4 8 -7 2 h o urs; if n ot 
i m pr o vi n g, c o nsi der creati ni ne 
cleara nce meas ure me nt b y 2 4 -h o ur 
uri ne c ollecti o n.  Disc uss wit h 
ne p hr ol o gist t he nee d f or ki d ne y 
bi o ps y.  
If attri b ute d t o st u d y dr u g, i nitiate 
oral pre d nis ol o ne 0. 5 -1 m g/ k g a n d 
ta per o ver at least 2 wee ks. 
Re peat creati ni ne/ U & E e ver y 4 8 -7 2 
h o ur s. 
H ol d st u d y 
treat me nt. 
If n ot attri b ute d t o 
dr u g t o xicit y, 
restart treat me nt. 
If attri b ute d t o 
st u d y dr u g a n d 
res ol ve d/i m pr o ve d 
t o baseli ne gra de: 
Restart st u d y dr u g 
if ta pere d t o < 1 0 
m g pre d nis ol o ne.  
3  
Creati ni ne > 3 X 
baseli ne or > 3 -6 X 
U L N  
H os pitalize patie nt f or m o nit ori n g 
a n d fl ui d bala nce; re peat creati ni ne 
e ver y 2 4 h o urs; refer t o a 
ne p hr ol o gist a n d disc uss nee d f or 
bi o ps y.  If w orse ni n g, i nitiate I V 
( met h yl) pre d nis ol o ne 1-2  m g/ k g. 
T a per c ortic oster oi ds o ver at least 4 
wee ks.  
H ol d st u d y 
treat me nt u ntil t he 
ca use is 
i n vesti gate d.  
If st u d y dr u g 
s us pecte d: 
Disc o nti n ue st u d y 
treat me nt. 
4  
Creati ni ne >  6 X  U L N  
As per Gra de 3, patie nt s h o ul d be 
ma na ge d i n a h os pital w here re nal 
re place me nt t hera p y is a vaila ble. 
Disc o nti n ue st u d y 
treat me nt. 
Di a betes/  
H y per gl yce mi a  
 
1  
Fasti n g gl uc ose val ue 
U L N t o 1 6 0 m g/ d L; 
U L N t o 8. 9 m m ol/ L  
M o nit or cl osel y a n d treat acc or di n g 
t o l ocal g ui deli ne. C hec k f or C-
pe pti de a n d a nti b o dies a gai nst 
gl uta mic aci d decar b o x ylase a n d 
islet cells are rec o m me n de d 
C o nti n ue St u d y 
Treat me nt.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
 
 
2  
Fasti n g gl uc ose val ue 
1 6 0 - 2 5 0 m g/ d L; 8. 9 - 
1 3. 9 m m ol/ L  
O btai n a re peat bl o o d gl uc ose le vel 
at least e ver y wee k. Ma na ge 
acc or di n g t o l ocal g ui deli ne.  
C o nti n ue St u d y 
Treat me nt or h ol d 
treat me nt if 
h y per gl yce mia is 
w orse ni n g. 
Res u me treat me nt 
w he n bl o o d 
gl uc ose is 
sta bilize d at 
baseli ne or Gra de 
0 -1.  
3  
Fasti n g gl uc ose val ue 
2 5 0 - 5 0 0 m g/ d L; 
1 3. 9  - 2 7. 8 m m ol/ L  
A d mit patie nt t o h os pital a n d refer t o 
a dia bet ol o gist f or h y per gl yce mia 
ma na ge me nt. C ortic oster oi ds ma y 
e xacer bate h y per gl yce mia a n d 
s h o ul d be a v oi de d. 
 
H ol d st u d y 
treat me nt u ntil 
patie nt is 
h y per gl yce mia 
s y m pt o m-free, 
a n d bl o o d gl uc ose 
has bee n 
sta bilize d at 
baseli ne or Gra de 
0 -1.  
4  
Fasti n g gl uc ose val ue 
> 5 0 0 m g/ d L; > 2 7. 8 
m m ol/ L  
A d mit patie nt t o h os pital a n d 
i nstit ute l ocal e mer ge nc y dia betes 
ma na ge me nt. Refer t he patie nt t o a 
dia bet ol o gist f or i ns uli n 
mai nte na nce a n d m o nit ori n g.  
Oc ul ar T o xicit y  
 
 
 
1  
As y m pt o matic e ye 
e xa m/test a b n or malit y  
C o nsi der alter nati ve ca uses a n d 
prescri b e t o pical treat me nt as 
re q uire d. 
C o nti n ue St u d y 
Treat me nt.  
2  
A nteri or u veitis or 
mil d s y m pt o ms  
Refer patie nt t o a n o p ht hal m ol o gist 
f or assess me nt a n d t o pical 
c ortic oster oi d treat me nt. C o nsi der a 
c o urse of oral ster oi ds.  
C o nti n ue St u d y 
Treat me nt or h ol d 
treat me nt if 
s y m pt o ms w orse n 
or if t here are 
s y m pt o ms of 
vis ual dist ur ba nce.  
3  
P osteri or u veitis/ 
pa n u veitis or 
si g nifica nt s y m pt o ms 
Refer patie nt ur ge ntl y t o a n 
o p ht hal m ol o gist. I nitiate oral 
pre d nis ol o ne 1 -2  m g/ k g a n d ta per 
o ver at least 4 wee ks.  
H ol d st u d y 
treat me nt u ntil 
i m pr o ve d t o 
Gra de 0 -1; 
rei ntr o d uce o nl y 
after disc ussi o n 
wit h t he st u d y 
me dical m o nit or.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
4  
Bli n d ness (at least 
2 0/ 2 0 0) i n t he affecte d 
e yes  
I nitiate I V ( met h yl) pre d nis ol o ne 
2  m g/ k g/ da y. C o n vert t o oral 
pre d nis ol o ne a n d ta per o ver at least 
4  wee ks.  
Disc o nti n ue st u d y 
treat me nt. 
P a ncre atitis  
 
 
2  
As y m pt o matic, bl o o d 
test a b n or malities 
M o nit or pa ncreatic e nz y mes.  
C o nti n ue st u d y 
treat me nt.  
3  
A b d o mi nal pai n, 
na usea a n d v o miti n g  
A d mit t o h os pital f or ur ge nt 
ma na ge me nt. I nitiate I V 
( met h yl) pre d nis ol o ne 1-
2  m g/ k g/ da y. C o n vert t o oral 
pre d nis ol o ne w he n a m ylase/li pase 
i m pr o ve d t o Gra de 2, a n d ta per o ver 
at least 4  wee ks.  
H ol d st u d y 
treat me nt; 
rei ntr o d uce o nl y 
after disc ussi o n 
wit h t he st u d y 
me dical m o nit or . 
4  
Ac ute a b d o mi nal pai n, 
s ur gical e mer ge nc y 
A d mit t o h os pital f or e mer ge nc y 
ma na ge me nt a n d a p pr o priate 
referral.  
Disc o nti n ue st u d y 
treat me nt. 
Art hritis  
 
 
1  
Mil d pai n wit h 
i nfla m mati o n, 
s welli n g 
Ma na ge me nt per l ocal g ui deli ne.  
C o nti n ue st u d y 
treat me nt. 
2  
M o derate pai n wit h 
i nfla m mati o n, 
s welli n g, li mite d 
i nstr u me ntal (fi ne 
m ot or) acti vities  
Ma na ge me nt as per l ocal g ui deli ne.  
C o nsi der referri n g patie nt t o a 
r he u mat ol o gist. If s y m pt o ms w orse n 
o n treat me nt ma na ge as a Gra de 3 
e ve nt. 
C o nti n ue 
treat me nt or, if 
s y m pt o ms 
c o nti n ue w orse ns, 
h ol d st u d y 
treat me nt u ntil 
s y m pt o ms 
i m pr o ve t o 
baseli ne or Gra de 
0 -1  
3  
Se vere pai n wit h 
i nfla m mati o n or 
per ma ne nt j oi nt 
da ma ge, dail y li vi n g 
acti vit y li mi te d 
Refer patie nt ur ge ntl y t o a 
r he u mat ol o gist f or assess me nt a n d 
ma na ge me nt. I nitiate oral 
pre d nis ol o ne 0. 5 -1 m g/ k g a n d ta per 
o ver at least 4 wee ks.  
H ol d st u d y 
treat me nt u nless 
i m pr o ve d t o 
Gra de 0 -1; 
rei ntr o d uce o nl y 
after disc ussi o n 
wit h t he st u d y 
me dical m o nit or.  
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
M uc ositis/  
st o m atitis 
 
 
 
1  
T est fi n di n gs o nl y or 
mi ni mal s y m pt o ms  
C o nsi der t o pical treat me nt or 
a nal gesia as per l ocal g ui deli ne  
C o nti n ue st u d y 
treat me nt. 
2  
M o derate pai n, 
re d uce d oral i nta ke, 
li mite d i nstr u me ntal 
acti vities 
As per l ocal g ui deli nes, treat wit h 
a nal gesics, t o pical treat me nts a n d 
oral h y gie ne care. E ns ure a de q uate 
h y drati o n. If s y m pt o ms w orse n or 
t here is se psis or blee di n g, ma na ge 
as a Gra de 3 e ve nt.  
C o nti n ue st u d y 
treat me nt. 
3  
Se vere pai n, li mite d 
f o o d a n d fl ui d i nta ke, 
dail y li vi n g acti vit y 
li mite d  
A d mit t o h os pital f or a p pr o priate 
ma na ge me nt. I nitiate I V 
( met h yl) pre d nis ol o ne 1-
2  m g/ k g/ da y. C o n vert t o oral 
pre d nis ol o ne w he n s y m pt o ms 
i m pr o ve d t o Gra de 2 a n d ta per o ver 
at least 4  wee ks  
H ol d st u d y 
treat me nt u ntil 
i m pr o ve d t o 
Gra de 0 -1.  
4  
Life -t hreate ni n g 
c o m plicati o ns or 
de h y drati o n  
A d mit t o h os pital f or e mer ge nc y 
care. C o nsi der I V c ortic oster oi ds if 
n ot c o ntrai n dicate d b y i nfecti o n  
Disc o nti n ue st u d y 
treat me nt. 
M y ositis/  
R h a b d o m y ol ysis  
1  
Mil d wea k ness 
wit h/ wit h o ut pai n  
Prescri be a nal gesics.  
If C K is si g nifica ntl y ele vate d a n d 
patie nt has s y m pt o ms, c o nsi der oral 
ster oi ds a n d treat as Gra de 2  
C o nti n ue st u d y 
treat me nt. 
2  
M o derate wea k ness 
wit h/ wit h o ut pai n  
If C K is 3 X U L N or w orse, i nitiate 
oral pre d nis ol o ne 0. 5 -1 m g/ k g a n d 
ta per o ver at least 4 wee ks 
H ol d st u d y 
treat me nt u ntil 
i m pr o ve d t o gra de 
0 -1  
3 -4  
Se vere wea k ness, 
li miti n g self-care 
A d mit t o h os pital a n d i nitiate oral 
pre d nis ol o ne 1 m g/ k g. C o nsi der 
b ol us I V ( met h yl) pre d nis ol o ne a n d 
1 -2  m g/ k g/ da y mai nte na nce f or 
se vere acti vit y restricti o n or 
d ys p ha gia.  If s y m pt o ms d o n ot 
i m pr o ve a d d i m m u n os u p pressa nt 
t hera p y. Ta per oral ster oi ds o ver at 
least 4 wee ks 
H ol d st u d y 
treat me nt u ntil 
i m pr o ve d t o gra de 
0 -1.  Disc o nti n ue 
if a n y e vi de nce of 
m y ocar dial 
i n v ol ve me nt 
C CI

Bei Ge ne ( S ha n g hai) C o., Lt d  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  1 1 9  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
A ut oi m m u ne 
T o xicit y  
Gr a de  
Tre at me nt G ui deli nes ( S u bject t o 
Cli nic al J u d ge me nt)  
St u d y Dr u g 
M a n a ge me nt  
M y oc ar ditis  
< 2  
As y m pt o matic b ut 
si g nifica ntl y i ncrease d 
C K -M B or i ncrease d 
tr o p o ni n O R cli nicall y 
si g nifica nt 
i ntra ve ntric ular 
c o n d ucti o n dela y  
I nitiate car diac e val uati o n u n der 
cl ose m o nit ori n g wit h re peat ser u m 
testi n g; c o nsi der referral t o a 
car di ol o gist. 
If dia g n osis of m y ocar ditis is 
c o nfir me d, treat as Gra de 2  
H ol d st u d y 
treat me nt. 
If a dia g n osis of 
m y ocar ditis is 
c o nfir me d, 
per ma ne ntl y 
disc o nti n ue st u d y 
treat me nt i n 
patie nts wit h 
m o derate or 
se vere s y m pt o ms. 
Patie nts wit h n o 
s y m pt o ms or mil d 
s y m pt o ms ma y 
n ot restart 
tisleliz u ma b 
u nless car diac 
para meters ha ve 
ret ur ne d t o 
baseli ne a n d after 
disc ussi o n wit h 
t he st u d y me dical 
m o nit or.  
2  
S y m pt o ms o n 
mil d -m o derate 
e xerti o n 
A d mit t o h os pital a n d i nitiate oral 
pre d nis ol o ne or I V 
( met h yl) pre d nis ol o ne at 1-2 
m g/ k g/ da y.  C o ns ult wit h a 
car di ol o gist a n d ma na ge s y m pt o ms 
of car diac fail ure acc or di n g t o l ocal 
g ui deli nes.  
If n o i m me diate res p o nse c ha n ge t o 
p ulse d d oses of 
( met h yl) pre d nis ol o ne 1 g/ da y a n d 
a d d M M F, i nfli xi ma b or a nti -
t h y m oc yte gl o b uli n 
3  
Se vere s y m pt o ms wit h 
mil d e xerti o n  
4  
Life -t hreate ni n g 
A b bre viati o ns: A E, a d verse e ve nt; A L T, ala ni ne a mi n otra nsferase; A S T, as partate a mi n otra nsferase; B S A, b o d y 
s urface area; C H F, c hr o nic he art fail ure; C K, creati ne ki nas e; C K -M B, creati ne ki nase -car diac m uscle is oe nz y me ; 
I N R, i nter nati o nal n or malize d rati o; I V, i ntra ve n o us; L F T, li ver f u ncti o n test; M M F, m yc o p he n olate m ofetil;  
N Y H A, Ne w Y or k Heart Ass ociati o n; T 4, t h yr o xi ne; T B, t u berc ul osis; T F T, t h yr oi d f u ncti o n test; T S H, 
t h yr oi d-sti m ulati n g h or m o ne; U & E, urea a n d electr ol ytes; U L N, u p per li mit of n or mal.  
C CI