Clinical trial NCT03209973
Conditions: Classical Hodgkin Lymphoma
Sponsor: BeiGene
Start date: 2017-04-21; Completion date: 2020-11-02
Enrollment: 70 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of this study was to evaluate the efficacy of tislelizumab assessed by Independent Review Committee (IRC) in participants with relapsed or refractory classical Hodgkin lymphoma (cHL), as measured by Overall Response Rate (ORR) per the Lugano Classification

Detailed description:
This was an open-label, single-arm, multi-center Phase 2 study. Response was to be assessed by PET(positron emission tomography) and computed tomography (CT) scan per the Lugano Classification. CT scan with contrast and Positron emission tomography (PET)/CT was used as required by protocol, until progressive disease (PD), new anti-cancer therapy, withdrawal of consent, death, lost to follow-up, or end of study (EOS), whichever occurred first. Total body magnetic resonance imaging (MRI) was allowed if CT with contrast is contraindicated. During treatment with immune checkpoint inhibitor such as with tislelizumab, pseudo-progression may occur due to immune cell infiltration and other mechanisms as manifested by apparent increase of existing tumor masses or appearance of new tumor lesions. Participants were allowed to continue study treatment if there is suspicion of pseudo-progression, provided they are asymptomatic and have radiographic progression only, until a second consecutive CT scan demonstrates PD at which time study treatment was discontinued permanently. Participants were evaluated for Adverse Events (AEs) (all Grades per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03 \[NCI CTCAE v. 4.03\]), serious AEs (SAEs), and any AEs requiring study drug interruption or discontinuation.

Arms: arm 1: Tislelizumab 200 mg administered intravenously (IV) every-3-weeks (Q3W)
Interventions: intervention 1: Tislelizumab
Intervention descriptions: intervention 1: Administered as specified in the treatment arm

Protocol documents:
Prot_001.pdf: 


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


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 4  of 1 1 9  
 
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  
 
Pa ge:  6 5  of 1 1 9  
 
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  
B G B -A 3 1 7 -2 0 3  
 
Pa ge:  6 6  of 1 1 9  
 
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.  
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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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Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
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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B G B -A 3 1 7 -2 0 3  
 
Pa ge:  7 2  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
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 
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 3  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
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.  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
. 
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:  7 4  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
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.  
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 5  of 1 1 9  
 
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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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 6  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
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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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 7  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
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.  
 
 
 
 
 
 
 
 
 
 
 
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:  7 8  of 1 1 9  
 
Versi o n 6 . 0, 1 5-J ul y-2 0 1 9  
•  
 
 
 
 
 
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 
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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.  
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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 
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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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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.  
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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 
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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. 
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 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). 
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 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
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:  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. 
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 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.   
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 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

SAP_000.pdf: 
BGB-A317-203 (NCT03209973)
A Single Arm, Multicenter, Phase 2 Study of BGB-A317 
as Monotherapy in Relapsed or Refractory Classical 
Hodgkin Lymphoma   
Document Type: Statistical Analysis Plan 
Document Date: Jul 17, 2018