A Phase I Clinical Study to Investigate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of BTK Inhibitor BGB-3111 in Chinese Patients With B-cell Lymphoma
Phase: PHASE1
Conditions: B-cell Lymphoma
Sponsor: BeiGene

B G B -3 1 1 1 C hi nese P hase I Cli nical St u d y Pr ot oc ol    B ei Ge ne （B eiji n g ）C o., Lt d     Pr ot oc ol N o.: B G B -3 1 1 1 -1 0 0 2  
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V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a  
 
B G B -3 1 1 1 Pr ot oc ol of a C hi nese P h ase I Cli nic al St u d y  
 
Pr ot oc ol Title:  
A p h ase I cli nic al st u d y t o i n vesti g ate t he s afet y, t oler a bilit y a n d 
p h ar m ac o ki netics/ p h ar m ac o d y n a mics of B T K i n hi bit or B G B -3 1 1 1 i n 
C hi nese p atie nts wit h B -cell l y m p h o m a  
 
Pr ot oc ol N o. : 
B G B -3 1 1 1 -1 0 0 2  
 
Versi o n N o.  & D ate:  
Versi o n 2. 0, Fe br u ar y 0 6, 2 0 1 7  
 
St u d y P h ase:  
P h ase  I 
 
S p o ns or:  
B ei Ge ne ( B eiji n g) C o., Lt d 
 
Pri nci p al i n vesti g at or:  
 
S p o ns or ’s M e dic al M o nit o r:  
 
 
 
 
 
 
C o nfi de ntialit y State me nt  
T his c o nfi de ntial 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 vesti 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 pe n de nt Et hics 
C o m mittee. Y o ur acce pta nce of t his d oc u me 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.

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o., Lt d              Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
 
 
 
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C o n f i d e n t i a  
S I G N A T U R E 
P R O T O C O L TI T L E:  
A p h ase I cli nic al st u d y  t o i n vesti g ate t he s afet y, t oler a bilit y a n d 
p h ar m ac o ki netics/ p h ar m a c o d y n a mics of B T K i n hi bit or B G B -
3 1 1 1 i n C hi nese p atie nts wit h B -cell l y m p h o m a  
P R O T O C O L N O:  
 
B G B -3 1 1 1 -1 0 0 2  
S P O N S O R:  
S p o ns or: Bei Ge n e ( Beiji n g) C o., Lt d  
A d dress: N o. 3 0, Scie nce Par k R oa d, Z h o n g g ua n c u n Life Sci e nce Par k, C ha n g pi n g District, Beiji n g 
Cit y; P ost C o de: 1 0 2 2 0 6  
Tel: （0 1 0 ）5 8 9 5 8 0 8 8  
H o me pa ge: w w w. bei ge n e.c o m  
 
 
 
 
Si g nat ure b y S p o ns or Re prese ntati ve  
 
Date  
 
 
 
S p o ns or Re prese ntati ve ( pri nte d na me)  
 
 
 
 
 
I n v esti gat or 
 
 
 
 
 
Si g nat ure b y Pri nci p al i n vesti gat or  
 
Date  
 
 
 
Pri nci pal i n vesti gat or ( pri nte d na me)  
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
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A M E N D M E N T ( V E R SI O N 2 . 0) (F E B . 6 T H, 2 0 1 7) 
T he o verall reas o ns f or t his re visi o n i ncl u de u p dati n g t he pr o gra m base d o n et hical a d vice a n d ne wl y o btai ne d 
i nf or mati o n fr o m t he ce nters; a n d ma ki n g mi n or c ha n ges. 
Secti o n N o.  
Descri pti o n of C h a n ge  
R ati o n ale : B ase d o n t he effecti ve ness d at a of B G B-3 1 1 1 i n gl o b al tri als, t he tre at me nt peri o d is 
e xte n de d t o t hree  ye a rs.  
Pr ot oc ol s y n o psis  
4. 1 O verall desi g n  
T a ble 3, F o ot n ote 2  
5. 5. 1 C o m pleti o n of St u d y  
6. 2 D osa ge & A d mi nistrati o n  
1 1. 2. 2  St u d y a nal ysis  
T a ble 3: St u d y Assess me nts a n d 
Pr oce d ures Sc he d ule.  
A n ne x 5: Fl o wc hart  
T he ori gi nal treat me nt peri o d is o ne year,  a n d t he re vise d tre at me nt 
peri o d is e xte n de d t o t hree years. St u d y d urati o n i ncl u des scr ee ni n g ( 2 8 
da ys); treat me nt peri o d u p t o 3 years or u ntil disease pr o gressi o n, 
u nacce pta ble t o xicit y or deat h, wit h dra wal of c o nse nt, l ost t o f oll o w -u p, 
or st u d y ter mi nati o n b y t he s p o ns or , w hic he ver occ urs first ; safet y 
f oll o w-u p ( u ntil 3 0 da ys after t he last d ose); s ur vi val f oll o w -u p u ntil 
st u d y c o m pleti o n. 
M ore o ver, I n T a ble 3, we a d de d ite ms t o be c hec ke d after o ne year a n d 
its fre q ue nc y, as well as safet y f oll o w-u p  a n d s ur vi val f oll o w -u p.  
R ati o n ale : T o a v oi d c o nf usi o n, pri nci ple i n vesti g at or w as c h a n ge d t o le a d i n vesti g at or. 
S i g nat ure pa ge 
Pr ot oc ol s y n o psis  
4. 1 o verall desi g n  
T o a v oi d c o nf usi o n, pri nci ple i n vesti gat or was c ha n ge d t o  lea di n g 
i n vesti gat or. 
R ati o n ale : T o f urt her e x pl ore t he a nti-t u m or acti vit y of B G B-3 1 1 1 i n a n i n d ole nt l y m p h o m a, w e a d d 
d ose e x p a nsi o n st u d y as P art II . T he n u m b er of p atie nts t o be e nr olle d h as bee n  i ncre ase d fr o m a b o ut 
2 0 t o a b o ut 4 0.  
Pr ot oc ol s y n o psis  
1. 6  Cli nical efficac y of B T K 
i n hi bit ors i n i n d ole nt l y m p h o ma 
2  St u d y O bj ecti ves  
3  St u d y E n d p oi nts  
4  St u d y Pla n  
5. 1  I ncl usi o n Criteria 
1 1  Statistical met h o ds a n d 
a nal ysis  
T a ble 3: St u d y Assess me nts a n d 
Pr oce d ures Sc he d ule.  
T a ble 5: P har mac o ki netic 
T he cli nical res ults of P hase I trials i n A ustralia s h o w t hat B G B -3 1 1 1 has 
a ver y g o o d efficac y i n B -cell mali g na nc y s u bj ects, es peciall y i n s u bj ects 
wit h c hr o nic l y m p h oc ytic le u ke mia, ma ntle cell l y m p h o ma, a n d 
W al de nstr o m macr o gl o b uli ne mia . W he n B G B-3 1 1 1 c o m pletes t he safet y 
assess me nt i n B l y m p h oc ytic t u m ors i n C hi nese s u bj ects a n d deter mi nes 
t he rec o m me n de d d ose f or P hase II trials, P hase II trials of m ulti ple 
i n dicati o ns will be f oll o we d. F or patie nts wit h f ollic ular l y m p h o ma a n d 
mar gi nal l y m p h o ma, B G B -3 1 1 1 als o s h o we d preli mi nar y  efficac y, b ut 
d ue t o t he li mite d n u m ber of s u bj ects c urre ntl y partici pati n g i n t he trial, 
after t he c o m pleti o n of t he P art I  f or d ose safet y assess me nt , ab o ut 2 0 
patie nts wit h rec urre nt or refract or y f ol lic ular l ym p h o ma or mar gi nal 
l y m p h o ma will be e nr olle d f or f urt her e val uati o n.  
T he n u m ber of patie nts t o be e nr olle d i n t he trial has bee n i ncrease d fr o m 
a b o ut 2 0 t o a b o ut 4 0.  
T he bac k gr o u n d k n o wle d ge of f ollic ular l y m p h o ma a n d mar gi nal 
l y m p h o ma, i ncl u di n g m or bi dit y, basic t y pi n g, a n d c urre nt cli nical 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
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Sa m pli n g i n t he P art II  
sta n dar d treat me nt, has i ncrease d. 
I n P art II , t he s u bj ect will c o nti n ue t o c ollect p har mac o ki neti c sa m ples. 
I n or der t o i ncrease t he acc urac y of t he data, t he c ollecti o n of 
p har mac o ki netic sa m ples at 6 h o urs after d osi n g i n C ycle 1 Da y 1, a n d at 
6 a n d 1 2 h o urs after d osi n g i n C ycle 2 Da y 1, has bee n a d de d. 
P har mac o d y na mic sa m ples will n ot be c ollecte d i n t he P art II  st u d y. 
R ati o n al e: Acc or di n g t o i n veti g at ors’ s u g gesti o n, t he pl atelet c o u nt re q uire me nt i n i n cl usi o n critiri a is 
m o difie d.  
S y n o psis:  
5. 1 i ncl usi o n criteria:  
A de q uate he mat ol o gical f u ncti o n, defi ne d b y ne utr o p hils ≥ 1. 0 x 1 0 9/ L, 
he m o gl o bi n ≥7 0 g/ L ; a n d platelets ≥ 5 0 x 1 0 9/ L if b o ne marr o w i n v ol ve d; 
or platelets ≥ 7 0 x 1 0 9/ L if n o b o ne marr o w i n v ol ve d.  
R ati o n ale: A d d i nf o r m ati o n o n l y m p h oc yte i ncre ase c a use d b y B T K i n hi bit ors, i n dic ati n g t h at 
l y m p h oc yt osis is a p h ar m ac o d y n a mic effect of B T K i n hi bit ors. As y m pt o m atic dr u g-rel ate d 
l y m p h oc yt osis are n ot d oc u me nte d a n d re p orte d as a d verse e ve nts. 
1. 1  P har mac ol o gical acti o n a n d 
M O A of B G B -3 1 1 1 a n d B T K 
i n hi bit or 
8. 2. 8 . 1 As y m pt o matic 
l y m p h oc yt osis i n d uce d b y st u d y 
dr u g is n ot rec or de d a n d re p orte d 
as a n a d verse e ve nt  
Descri be o ur c urre nt k n o wle d ge of re versi ble l y m p h oc yt osis a n d t he 
o bser ve d l y m p h oc ytes i ncreas e d uri n g t he treat me nt of B T K i n hi bit ors, 
i ncl u di n g B G B-3 1 1 1, a n d a d d s u p p orti ve refere nces. Base d o n t he 
cli nical trial  of i br uti ni b , it is clearly defi ne d t hat as y m pt o matic dr u g-
i n d uce d l y m p h oc yt osis are n ot d oc u me nte d a n d re p orte d as a d verse 
e ve nts.  
R ati o n ale: U p d ate t he cli nic al d at a of B G B -3 1 1 1, i ncl u di n g effic ac y a n d s afet y assess me nt.  
1. 4  Cli nical St u d y of B G B -3 1 1 1  
1. 4. 2  Preli mi nar y Efficac y of 
B G B -3 1 1 1  
1. 4. 3  Safet y Assess me nt of 
B G B -3 1 1 1  
U p date d cli nical data fr o m t he B G B -3 1 1 1 Gl o bal P hase I trial, i ncl u di n g 
dr u g safet y a n d efficac y a nal ysis.  
B ase d o n t he rec o m me n d ati o ns fr o m i n vesti g at ors a n d t he ce ntr al et hics c o m mittee, t he d ose 
i nterr u pti o ns a n d a dj ust me nts are descri be d i n det ail. 
4. 3  D ose I nterr u pti o n a n d 
M o dificati o n  
4. 3. 1 D ose Re d ucti o ns f or 
He mat ol o gic T o xicit y  
4. 3. 2  D ose Re d ucti o ns f or N o n -
he mat ol o gic T o xicit y  
It is clearl y defi ne d t hat B G B-3 1 1 1 treat me nt all o ws u p t o 2 8 da ys of 
c o nti n u o us i nterr u pti o n. If a s u bj ect, after 2 8 c o nsec uti ve da ys of 
disc o nti n uati o n, is j u d ge d b y t he i n vesti gat or t hat he/s he ca n still be nefit 
fr o m t he treat me nt of B G B-3 1 1 1, a disc uss i o n will be c o n d ucte d bet wee n 
t he i n vesti gat or a n d t he s p o ns or’s me dical m o nit or t o deci de w het her t his 
s u bj ect c o ul d c onti n ue t o recei ve treat me nt, if yes,  t he s p o ns or’s me dical 
e xa mi ner s h o ul d iss ue a writte n c o nse nt f or m . M ore o ver, t he d ose 
a dj ust me nts t hat s h o ul d be f oll o we d i n t he e ve nt of he mat ol o gical 
t o xicit y a n d n o n-he mat ol o gic t o xicit y are gi ve n i n m ore detail.  
Reti o n ale: B ase d o n t he i n vesti g at or's rec o m me n d ati o ns, t he re q uire me nt f or b o ne m arr o w 
e x a mi n ati o n d uri n g t he scre e ni n g peri o d w as rel a x e d, a n d t he b o ne m arr o w e x a mi n ati o n of t he 
s u bjects wit h W al de nstr o m M acr o gl o b uli ne mi a  w as s pe cifie d i n det ail.  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
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T a ble 3 F o ot n ote 1 0  
7. 3. 3  B o ne marr o w assess me nt  
D uri n g t he scree ni n g peri o d, all s u bj ects are re q uire d t o u n der g o b o ne 
marr o w e xa mi nati o n (i ncl u di n g s mear a n d bi o ps y). If t he b o ne marr o w 
e xa mi nati o n has bee n perf or me d wit hi n 3 0 da ys bef ore t he s cree ni n g 
peri o d, t he n d o n ot nee d t o re peat, t he test res ults ca n be use d f or 
scree ni n g peri o d. 
F or s u bj ects wit h Wal de nstr o m macr o gl o b uli ne mia , if bo ne marr o w 
lesi o ns are detecte d d uri n g t he scree ni n g peri o d, a b o ne marr o w test 
s h o ul d be perf or me d e ver y 6 m o nt hs. 
R ati o n ale:  T he he m at ol o gic al e x a mi n ati o n of W 1 D 1 is all o w e d t o perf or m wit hi n 4 8 h o urs pri or t o 
a d mi nistr ati o n , b ase d o n t he i n vesti g at or's a d vice.  
T a ble 3 F o ot n ote 1 2  
T he he mat ol o gical e xa mi nati o n of W 1 D 1 was all o we d t o be perf or me d 
wit hi n 4 8 h o urs pri or t o a d mi nistrati o n t o e ns ure t he safet y of t he s u bj ect 
d uri n g t he first a d mi nistrati o n.  
R ati o n al e: C ollect a d diti o n al s a m ple  t o e x pl ore mec h a nis m of dr u g resist a nce if s u bje ct e xperie nces  
dise ase pr o gressi o n.  
T a ble 3:  
T a ble 3 F o ot n ote 2 0  
5. 5. 2 Earl y wit h dra wl  
8. 5 Efficac y Assess me nt  
F or s u bj ect wit h disease pr o gr essi o n, bl o o d sa m ple or ot her relate d 
sa m ple ( b o ne marr o w or l y m p h n o de) s h o ul d be c ollecte d  t o a nal yze dr u g 
resista nce after  ha vi n g o btai n e d  s u bj ect’s c o nse nt.  
 
 
 
R ati o n ale: c ar a m b ol a a n d p o me g r a n ate j uice h as bee n a d de d t o t he restricte d f o o d list.  
5. 4  Restriti o ns  of S u bj ects  
T he st u d y pr o hi bits t he c o ns u m pti o n of a n y f o o d or dri n k c o ntai ni n g 
gra p efr uit j uice, cara m b ola, or p o me gra nate j uice.  
R ati o n ale: Cl arif y t he criteri a f or st u d y c o m pleti o n a n d wit h dr a w al fr o m st u d y, b ase d o n t he 
i n vesti g at or's a d vice. 
5. 5. 1  C o m pleti o n of St u d y  
5. 5. 3  Reas o ns f or Wit h dra wal  
Clarif y t he criteria f or st u d y c o m pleti o n a n d wit h dra wal fr o m st u d y.  
R ati o n ale: T he pr o hi bite d me dic ati o n is cle a rl y defi ne d t o e ns ure t he s afet y of t he s u bjects.  
7. 2  Pr o hi bite d Me dicati o n  
Pr o vi de  a li n k f or c o m plete list of Q T c dr u gs, a n d clearl y sti p ulates t hat 
d uri n g t he treat me nt, a ntic oa g ula nts or her bs s h o ul d als o be a v oi de d. If 
t here are n o s u bstit utes, please c o ns ult me dical m o nit or  a n d s h o ul d get 
a p pr o val  bef ore use.  
R ati o n ale: t he s pecific ste ps of P K & P D s a m pli n g a n d s a m ple pr ocessi n g h a ve bee n r e m o ve d  
8. 6 P har mac o ki netics  
8. 7 P har mac o d y na mics  
I n or der t o a v oi d c o nf usi o n, t he s pecific ste ps of P K & P D sa m pli n g a n d 
sa m ple pr ocessi n g ha ve bee n re m o ve d. Detaile d pr ocessi n g met h o ds ca n 
be f o u n d i n t he ce ntral la b orat or y ser v ice ma n ual.  
R ati o n ale:  Acc or di n g t o t he C D E criteri a, t he ass oci ati o n bet w ee n a d verse e ve nts a n d st u d y dr u g  h as 
bee n  m o difie d.  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
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1 0. 4 Assess me nt of Ca usalit y  
T he fi ve -cate g or y criteria is us e d t o assess t he c orrelati o n bet wee n 
a d verse e ve nts a n d st u d y dr u g: certai nl y relate d, pr o ba bl y relate d, li kel y 
relate d, p ossi bl y u nrelate d, a n d u nrelate d. 
R ati o n ale: T he tre at me nt of pre g n a nc y occ urre nce is des cri be d i n det ail.  
1 0. 8 Pre g na nc ies 
T he treat me nt of pre g na nc y oc c urre nce is descri be d i n detail.  
R ati o n ale: D ue t o t he li mit ati o ns of t he ce ntr al test, t he ite ms of cli nic al l a b or at or y e x a mi n ati o n h a ve 
bee n a me n de d.  
A p pe n di x 1: Cli nical La b orat or y 
T est  
D ue t o t he li mitati o ns of t he c e ntral test, t he ite ms of cli nical la b orat or y 
e xa mi nati o n ha ve bee n a me n de d.  
R ati o n ale: Acc or di n g t o t he l atest pr o gress, u p d ate t he e v al u ati o n criteri a f or n o n -H o d g ki n's 
l y m p h o m a. 
A p pe n di x 3:  Efficac y 
Assess me nt Criteri o n  
F or n o n -H o d g ki n's l y m p h o ma, t he L u ga n o Res p o nse criteria 2 0 1 4 is 
use d.  
R ati o n ale:  Acc or di n g t o t he l atest pr o gress o n W al de nstr o m m acr o gl o b uli ne mi a, a criteri a of ver y 
g o o d p arti al res p o nse h as bee n u p d ate d.  
A p pe n di x 3:  Efficac y 
Assess me nt Criteri o n  
F or W al de nstr o m macr o gl o b uli ne mia , a criteria of ver y g o o d partial 
res p o nse ha s bee n u p date d.  
R ati o n ale: A det aile d s pecific ati o n is gi ve n f or t he detecti o n of m olec ul ar m ar kers i n f ollic ul ar 
l y m p h o m a or m ar gi n al l y m p h o m a s u bjects. 
T a ble 3 F o ot n ote 1 9  
8. 8 M olec ular mar kers  
All s u bj ects i n P art II  st u d y m ust pr o vi de a rece nt st u d y of t u m or mar kers 
f or m olec ular mar kers. If t he s u bj ect d oes n ot ha ve a rece nt s a m ple of 
t u m or tiss ue, fres h t u m or bi o ps y m ust be perf or me d d uri n g t he scree ni n g 
peri o d. T u m or tiss ue ca n be ei t her f or mali n-fi xe d paraffi n-e m be d de d 
t u m or tiss ue wa x bl oc k or at l east 1 0 u nstai ne d sli des a n d se nt t o t he 
ce ntral la b orat or y f or a nal ysis. F or patie nts wit h f ollic ular l y m p h o ma or 
mar gi nal z o ne l y m p h o ma w h o ha ve bee n e nr olle d ( pr ot oc ol 1. 0), 
hist orical t u m or s peci me ns or sa m ples s h o ul d be pr o vi de d after v ol u ntar y 
si g nat ure of ne w i nf or me d c o nse nt. F or detaile d i nf or mati o n o n t u m or 
tiss ue c ollecti o n, please refer t o t he la b orat or y ma n ual. 
R ati o n ale: w e f o u n d s m all mist a kes  
o verall pr ot oc ol  
Mi n or c ha n ges  t o gra m mar, f or mat, or s pelli n g. 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
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S Y N O P SI S  
N a me of S p o ns or  
B ei Ge ne ( B eiji n g) C o., Lt d  
N a me of St u d y Pr o d uct  
B G B -3 1 1 1 ca ps ule  
Title of St u d y  
A 
p h ase 
I 
cli nic al 
st u d y 
t o i n vesti g ate 
t he 
s afet y, t oler a bilit y 
a n d 
p h ar m ac o ki netics / p h ar m a c o d y n a mics of B T K i n hi bit or B G B -3 1 1 1 i n C hi nese 
p atie nts wit h B -cell l y m p h o m a  
Pr ot oc ol N o . 
B G B -3 1 1 1 -1 0 0 2  
St u d y ce nters  
3 -4 st u d y ce nters  
St u d y p h ase  
I 
St u d y Pl a n  
Scree ni n g ( 2 8 da ys); dail y treat me nt u ntil disease pr o gressi o n, u nacce pta ble t o xicit y or 
deat h, wit h dra wal of c o nse nt, l ost t o f oll o w -u p, or st u d y ter mi nati o n b y t he  s p o ns or, 
treat me nt ( u p t o 3 years); safet y f oll o w-u p ( wit hi n 3 0 da ys  of last d ose ); s ur vi val 
f oll o w-u p u ntil stu d y c o m pleti o n . 
O bjecti ves  
P art I : S afet y e v al u ati o n 
Pri m ar y:  
 T o e val uate t he safet y a n d t olera bilit y of B G B -3 1 1 1 i n C hi nese patie nts wit h B -cell l y m p h o ma  a n d deter mi ne 
rec o m me n de d p hase 2 d ose ( R P 2 D).  
Sec o n d ar y:  
 T o c haracterize t he p har mac o ki netics ( P K) of si n gle- a n d m ulti ple - d ose of B G B -3 1 1 1  orall y  i n C hi nese patie nts 
wit h B -cell l y m p h o ma.  
 T o e val uate t he i n hi bit or y effe ct of B G B -3 1 1 1 o n  B T K i n peri p heral bl o o d m o n o n uclear cells ( P B M Cs).  
E x pl or at or y:  
 
 
P art II : D ose e x p a nsi o n 
Pri m ar y:  
 
T o e val uate  t he preli mi nar y a nti -t u m or acti vit y of B G B-3 1 1 1 i n s u bj ects wit h f ollic ular l y m p h o ma ( F L) or 
mar gi nal z o ne l y m p h o ma ( M Z L).  
Sec o n d ar y:  
 
T o f urt her assess t he safet y a n d t olera bilit y of B G B -3 1 1 1 i n patie nts wit h f ollic ular l y m p h o ma ( F L) or mar gi nal 
z o ne l y m p h o ma ( M Z L) . 
 
T o f urt her c haracterize t he p har mac o ki netics ( P K) of si n gle - a n d m ulti ple - d ose of B G B -3 1 1 1 orall y i n C hi nese 
patie nts wit h  B -cell l y m p h o ma . 
E x pl or at or y:  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
8  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
 
 
M et h o d ol o g y:  
T his st u d y is t o i n vesti gate t he d ose safet y, t olera bilit y, p har mac o ki netics a n d p har ma c o d y na mics of B G B-3 1 1 1 i n 
C hi nese patie nts wit h B -cell l y m p h o ma, a n d t o deter mi ne rec o m me n d p hase II d ose ( R P 2 D), base d o n t he m ulti -d ose, 
d ose escalati o n p hase I trials w hic h has c o mplete d i n A ustralia a n d Ne w Zeala n d. Ba se d o n t he res ults t hat will be 
o btai ne d , d ose e x pa nsi o n st u dies will be perf or me d after war ds i n patie nts wit h f ollic ular l y m p h o ma ( F L) a n d mar gi nal 
z o ne l y m p h o ma ( M Z L).  
T he st u d y was c o n d ucte d i n t w o sta ges, t he firs t sta ge bei n g t he safet y assess me nt of d ose, a n d t he sec o n d sta ge bei n g 
t he d ose e xpa nsi o n.  
P art I : S afet y e v al u ati o n  
Acc or di n g t o t he res ults of precli nical t o xic ol o gical trials a n d t he res ults of t he p hase I cli nical st u d y c o n d ucte d i n 
A ustralia a n d Ne w  Zeala n d, t w o re gi me ns of B G B -3 1 1 1 3 2 0 m g dail y ( 1 6 0 m g BI D, a d mi nistere d  i n t he m or ni n g a n d at  
ni g ht, or 3 2 0 m g Q D) a n d “ 3 + 3 ” desi g n  is a d o pted f or t he assess me nt. T hree eli gi ble s u bj ects will be e nr olle d f or eac h 
d ose re gi me n: first, if 1/ 3 ( 1 case) patie nts e x perie nce d ose -li miti n g t o xicit y ( D L T), a n ot her  3 s u bj ects will be e nr olle d 
f or c o nti n ue d o bser vati o n. Ac c or di n g t o t he preli mi nar y res ults of t he cli nical st u d y i n A ustralia a n d Ne w Zeala n d, t w o 
re gi me ns of B G B -3 1 1 1 3 2 0 m g d ose gr o u p are b ot h safe a n d t olera ble. If n o ne of t he first 3 e nr olle d patie nts 
e x perie nces  D L T or o nl y o ne patie nt a m o n g t he 6 patie nts (i ncl u di n g t he s u p ple me nte d 3 p atie nts) e x perie nce D L T, 
t he n it is pres u me d t hat t he d ose of B G B-3 1 1 1 ( 1 6 0 m g BI D a n d/ or 3 2 0 m g Q D) is safe a n d t olera ble. Ne xt eac h d ose 
gr o u p will recr uit n e w patie nts  u ntil  a b o ut 1 0 patie nts per gr o u p (i ncl u d i n g t he patie nts e nr olle d pre vi o usl y) t o f urt her 
assess t he safet y, t olera bilit y, p har mac o ki netics a n d preli mi nar y p har mac o d y na mics of B G B -3 1 1 1.  
If m ore t ha n t w o (i ncl usi ve) fr o m 3  s u bj ects or 6 s u bj ects (i ncl u di n g t he s u p ple me nte d 3 patie nts) e x perie nce D L T 
wit hi n t he D L T  o bser vat i o n wi n d o w ( Da y 1 -2 8), i t will be c o ncl u de d  t hat t he d ose of B G B-3 1 1 1 ( 1 6 0 m g BI D a n d/ or 
3 2 0 m g Q D) has e xcee d e d t he ma xi m u m t olerate d d ose ( M T D) a n d d ose s h o ul d be  decreaese d  t o 8 0 m g BI D or 1 6 0 m g 
Q D. T hree eli gi ble patie nts will be e nr olle d i nt o eac h ne w d ose gr o u p f or  re-assess me nt. If 8 0 m g BI D or 1 6 0 m g Q D is 
safe, t he s p o ns or a n d i n vesti gat or will  a nal yze a n d disc uss w het he r t o m o ve f or war d wit h a n i nter mediate d ose gr o u p 
( 1 2 0 m g BI D or 2 4 0 m g Q D) acc or di n g t o t he a vaila ble safet y data a n d P K data. If neit her 1 6 0 m g  Q D a n d/ or 8 0 m g 
BI D is t olera ble, t he trial will be ter mi nate d.  
D uri n g t he trial, t he s p o ns or, lea di n g i n vesti gat or a n d i n vesti gat or s will esta blis h a safet y m o nit ori n g c o m mittee ( S M C) 
f or o n g oi n g safet y assess me nt.  S M C will deci de t he d ose le vel  a n d re gi me n f or ne xt gr o u p or  if e nr oll m ore eli gi ble 
patie nts , base d o n  t he efficac y data fr o m t he f or mer d ose le vel.  
T he t o xicit y o bser vati o n peri o d of B G B -3 1 1 1 is 2 8 da ys a n d treat me nt o bser vati o n  peri o d is fr o m da y 2 9 t o t hree years. 
A s u bj ect will be c o nsi dere d e n d of st u d y if he/s he s h o ws disease pr o gressi o n, i nt oler a nce  t o t o xicit y, deat h, wit h dra wal 
fr o m t he st u d y, l ost t o f oll o w-u p, st u d y ter mi nati o n b y t he s p o ns or, or  ha vi n g c o m pl ete d all 3 year s of treat me nt, 
w hic he ver occ urs fi rst. If a s u bj ect is j u d ge d t o still ha ve cli nical be nefit b y t he i n vesti gat or at t he e n d of 3-year 
treat me nt, he/s he ma y be tra nsferre d t o t he e xte nsi o n st u d y t o c o nti n ue B G B-3 1 1 1 treat me nt u ntil disease pr o gressi o n , 
i nt olera nce, deat h, or wit h dra wal fr o m st u d y, u n der t he a p pr o val b y t he s p o ns or’s me dical m o nit or.  T he first st u d y 
a nal ysis will be c o n d ucte d after all t he s u bj ects ha ve c o m plete d D L T assess me nt, a n d t his a nal ysis will f oc us o n t he 
safet y a n d t olera bilit y of B G B-3 1 1 1. P har mac o ki netics, p har mac o d y na mics, will als o be i ncl u de d i n t his a nal ysis. 
Acc or di n g t o t he safet y data of t he P art I  an d t he res ults of t he A ustralia n P hase I cli nical trial, t he d ose of 1 6 0 m g BI D 
has bee n selecte d as t he R P 2 D.  F or s u bj ects i n part I , if t he i nitial d ose is 3 2 0 m g Q D, after t he c o m pleti o n of D L T 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
9  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
assess me nt a n d wit h pri or a p pr o val fr o m i n vesti gat or a n d s p o ns or’s me dical m o nit or, t he a d mi nistrati o n re gi me n ca n be 
c ha n ge d t o 1 6 0 m g BI D.  
P art II : D ose e x p a nsi o n  
T o f urt her e val uate t he preli mi nar y a nti -t u m or effects of B G B-3 1 1 1 i n C hi nese s u bj ects wit h f ollic ular l y m p h o ma ( F L) 
or mar gi nal z o ne l y m p h o ma ( M Z L) , a p pr o xi matel y 2 0 s u bj ects wit h rela pse d or refract or y f ollic ular l y m p h o ma ( F L) or 
mar gi nal z o ne l y m p h o ma ( M Z L) will be e nr olle d. T he rec o m me n de d P hase 2 d ose,  1 6 0 m g BI D, will be use d i n t he P art 
II. 
A ustralia n p hase I cli nical st u d y s h o w e d  g o o d efficac y  of B G B -3 1 1 1 i n patie nts wit h B cell mali g na ncies, es peciall y i n 
s u bj ects 
wit h 
c hr o nic l y m p h oc ytic le u ke mia ( C L L), 
ma nt le cell l y m p h o ma ( M C L) 
a n d 
W al de nstr ö m’s  
m acr o gl o b uli ne mia. Preli mi nar y efficac y wit h B G B -3 1 1 1 o n li mite d s u bj ects wit h f ollic ular l y m p h o ma ( F L) a n d 
mar gi nal z o ne l y m p h o ma ( M Z L) s u p p orts f urt her i n vesti gati o n i n a p pr o xi mate l y 2 0 s u bj ects wit h rela ps ed  a nd rec urre nt 
f ollic ular a n d mar gi nal z o ne l y mp h o ma after safet y e val uati o n i n P art I .  
T o e val uate t he preli mi nar y efficac y wit h o ut  har mi n g  s u bj ect’s be nefit , t he a nti-t u m or acti vit y assess me nt will be 
c o n d ucte d e ver y 1 2 wee ks (c o n d ucte d a p pr o xi mate e ver y 2 4 wee ks 1 year later) after first d ose. S u bj ects w h o d o n ot 
e x perie nce disease pr o gressi o n ma y c o nti n ue treat me nt u ntil i nt olera ble t o t o xicit y, deat h, pr o gressi o n of t he disease, 
wit h dra wal of i nf or me d c o nse nt, or disc o nti n ui n g treat me nt b y t he i n vesti gat or w he n t he ris k is greater t ha n t he be n efit.  
If a s u bj ect is j u d ge d t o still ha ve cli nical be nefit b y t he i n vesti gat or at t he e n d of 3-year treat me nt, he/s he ma y be 
tra nsferre d t o t he e xte nsi o n st u d y t o c o nti n ue B G B-3 1 1 1 treat me nt u ntil disease pr o gress, i nt olera nce, deat h, or 
wit h dra wal fr o m s t u d y. 
Pla n ne d n u m ber of cases:  
A p pr o xi matel y 4 0 s u bj ects  
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 0  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
St u d y P o p ul ati o n  
I ncl usi o n criteria: 
 
 Me n a n d w o me n wit h t he a ge of 1 8 -7 5 years, v ol u ntaril y c o nse nte d t o t he st u d y.  
 
 P art I : S u bj ects 
wit h 
B-cell l y m p h o ma ( defi ne d b y 
W H O classificati o n) 
refract or y or rela pse d f oll o wi n g at least o ne li ne of t hera p y, i ncl u di n g c hr o nic 
l y m p h oc ytic le u ke mia/ s mall l y m p h oc ytic l y m p h o ma ( C L L/ S L L), ma ntle cell 
l y m p h o ma ( M C L), 
Wal de nstr ö m's 
macr o gl o b uli ne mia/ l y m p h o plas mac ytic 
l y mp h o ma ( W M/ L P L), f ollic ular l y m p h o ma ( F L), mar gi nal z o ne l y m p h o ma 
( M Z L), hair y cell le u ke mia a n d n o n -ger mi nal ce nter diff use lar ge B cell 
l y m p h o ma ( D L B C L). P art II : S u bj ects wit h F L or M Z L w hic h is refract or y or 
rela pse d f oll o wi n g at least o ne li ne of t herap y.  S u bj ects i n P art II  m ust  pr o vi de 
rece nt arc hi ve t u m or s peci me n or perf or m t u m or bi o ps y . 
 
 J u d ge d b y t he i n vesti gat or as re q uiri n g treat me nt.  
 
 E C O G perf or ma nce stat us of 0 -1.  
 
 Life e x pecta nc y of at least 4 m o nt hs.  
 
 A de q uate he mat ol o gic al f u ncti o n, defi ne d b y ne utr o p hils ≥ 1. 0 x 1 09/ L, 
he m o gl o bi n ≥7 0 g/ L;  a n d platelets ≥ 5 0 x 1 0 9/ L if b o ne marr o w i n v ol ve d; or 
platelets ≥ 7 0 x 1 0 9/ L if n o b o ne marr o w i n v ol ve d. 
 
 A de q uate re nal f u ncti o n, defi ne d b y creati ni ne cleara nce of ≥ 3 0 ml/ mi n (as 
esti mate d b y t he C oc kcr oft -G a ult e q uati o n or C K D -E PI e q uati o n , or as meas ure d 
b y n uclear me dici ne sca n or 2 4 h o ur uri ne  e val uati o n). 
 
 A de q uate li ver f u ncti o n, defi ne d b y A S T a n d A L T ≤ 2. 5 x U L N, a n d bilir u bi n ≤ 
1. 5 x U L N ( u nless d oc u me nte d Gil bert’s s y n dr o me). 
 
 C oa g ulati o n f u ncti o n: I N R a n d A P T T ≤ 1. 5 x U L N.  
 
 Fe male s u bj ects of c hil d beari n g p ote ntial a n d n o n -sterile males m ust practice at 
least o ne of t he f oll o wi n g met h o ds of birt h c o ntr ol wit h part ner(s) t hr o u g h o ut t he 
st u d y a n d f or 9 0 da ys after disc o nti n ui n g st u d y dr u g: t otal a bsti ne nce fr o m 
se x ual i nterc o urse, d o u ble-barrier c o ntrace pti o n, I U D or h or m o nal c o ntrace pti ve 
i nitiate d at least 3 m o nt hs pri or t o first d ose of st u d y dr u g. 
 
 Male s u bj ects m u st n ot d o nate s per m fr o m start of st u d y dr u g a d ministrati o n, 
u ntil 9 0 da ys after  disc o nti n uati o n  of treat me nt . 
 
E xcl usi o n criteri a:  
 
 Wit h C N S i n v ol ve me nt  of t he disease.  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 1  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
 
 T he pat h ol o gical t y pe of t he disease has D isease tra nsf or mati o n. 
 
 H as u n der d o ne  all o ge neic he mat o p oietic ste m cell tra ns pla ntati o n . 
 
 H as recei ve d c ortic oster oi d a nti-ne o plastic treat me nt ( > 1 0  m g dail y pre d nis o ne 
e q ui vale nts ) wit hi n 7 da ys bef ore t he first d ose of B G B-3 1 1 1, ha s recei ve d 
ra di ot hera p y a n d c he m ot hera p y wit hi n 4 wee ks bef ore t he first d ose of B G B -
3 1 1 1 or ha s recei ve d treat me nt wit h m o n ocl o nal a nti b o d y wit hi n 4 wee ks bef ore 
t he first d ose of B G B-3 1 1 1 . 
 
 Has recei ve d B T K i n hi bit or treat me nt pri or t o e nr oll me nt.  
 
 H as recei ve d c he m ot hera p y a n d has n ot yet  rec o vere d fr o m t o xicit y ( ≤ gra d e 1 
acc or di n g t o N CI -C T C A E 4. 0 3).  
 
 Has recei ve d  C hi nese her bal me dici ne as a nti -ne o plastic t hera p y wit hi n 4 wee ks 
bef ore  starti n g st u d y treat me nt. 
 
 Hist or y of ot her mali g na ncies wit hi n 2 years bef ore st u d y e ntr y, wit h e xce pti o n 
of ( 1) a de q uatel y c ure d  i n-sit u carci n o ma of cer vi x; ( 2) l ocall y  basal  or 
s q ua m o us cell s ki n ca ncer ; ( 3) l ocal mali g na nc y w hic h has u n der g o ne ra dical 
treat me nt (s ur ger y or ot her m o dalit y). 
 
 Wit h u nc o ntr olle d s yste mic i nfecti o n  
 
 Maj or s ur ger y i n t he past 4 we e ks.  
 
 Wit h k n o w n HI V, or acti ve he p atitis B or he p atitis C vir us i nfecti o n 
 
 Wit h c ar di o vasc ular diseas e of  Ne w 
Y or k 
Heart 
Ass ociati o n ( N Y H A) 
Classificati o n ≥ 3.  
 
 Q T c > 4 5 0 msecs ( defi ne d as a Q T c F > 4 5 0 msecs base d o n t he Fre dericia’s  
f or m ula) or ot her si g nifica nt E C G a b n or malities i ncl u di n g 2 n d de gree A V bl oc k 
t y pe II, 3r d de gree A V bl o c k, or bra d ycar dia ( ve ntric ul ar rate less t ha n 5 0 
beats/ mi n).  
 
 Si g nifica nt acti ve re nal, ne ur ol o gic, ps yc hiatric, he patic or e n d ocri n ol o gic 
disease t hat i n t he i n vesti gat or’s o pi ni o n w o ul d a d versel y i m pact o n his/ her 
partici pat i o n i n t he st u d y. 
 
 I na bilit y t o c o m pl y wit h st u d y pr oce d ures. 
 
 C urre ntl y ta ki n g a ntic oa g ula nt dr u gs. 
 
 C urre ntl y ta ki n g p ote nt C Y P 3 A i n hi bit or or i n d ucer (refer t o Secti o n  7. 2  f or 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 2  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
details ). 
 
 Ha d  str o ke or cere bral he m orr ha ge wit hi n 6  m o nt hs bef ore e nr oll me nt.  
D ose stre n gt h  
B G B -3 1 1 1 2 0 m g a n d 8 0 m g ca ps ules  
Criteri a f or E v al u ati o n:  
P art I : S afet y e v al u ati o n of d ose  
Pri m ar y E n d p oi nts:  
 
Safet y a n d t olera bilit y of B G B -3 1 1 1:  T he occ urre nce of a d verse e ve nts ( A Es) a n d s eri o us a d verse e ve nts 
( S A Es) of eac h s u bj ect will be m o nit ore d acc or di n g t o N CI-C T C A E 4. 0 3 gra di n g criteria d uri n g t he w h ole 
st u d y a n d t he safet y of B G B-3 1 1 1  re gi me n will be e val uate d.  
Sec o n d ar y E n d p oi nts:  
 
P har mac o ki netic para meters:  
P K para meters f or si n gle d ose: A U C last、A U C 0 -∞、C ma x 、tma x 、t1/ 2、C L/ F 、V d/ F  
P K para meters f or stea d y stat us after m ulti ple d oses: A U C ss、C ma x,ss 、tma x,ss  
 
T he i n hi bit or y effect of B G B -3 1 1 1 o n B T K acti vit y i n peri p heral bl o o d m o n o n uclear cells will be assesse d b y 
meas uri n g t he pr o p orti o n of B T K occ u pie d i n peri p heral bl o o d m o n o n uclear cells.  
E x pl or at or y E n d p oi nts:  
P art II : D ose e x p a nsi o n  
Pri m ar y E n d p oi nts:  
 
O verall res p o nse rate ( O R R), c o m plete res p o nse rate ( C R R ), partial res p o nse rate ( P RR ), d urati o n of res p o nse 
( D O R) a n d pr o gressi o n free s ur vi val ( P F S) of B G B-3 1 1 1 i n s u bj ects wit h F L a n d M Z L . 
Sec o n d ar y E n d p oi nts:  
 
Safet y a n d  t olera bilit y of m ulti ple d ose of B G B -3 1 1 1 i n F L a n d M Z L : T he occ urre nce of a d verse e ve nts ( A Es) 
a n d seri o us a d verse e ve nts ( S A Es) of eac h s u bj ect will be m o nit ore d acc or di n g t o N CI -C T C A E 4. 0 3.  
 
P har mac o ki netic para meters:  
P K para meters f or si n gle d ose: A U C last、A U C 0 -∞、C ma x 、tma x 、t1/ 2、C L/ F 、V d/ F  
P K para meters f or stea d y stat us after m ulti ple d oses: A U C ss、C ma x,ss 、tma x,ss  a n d ot her a p plica ble para meters.  
E x pl or at or y E n d p oi nts:  
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 3  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
St atistic al M et h o ds:  
P art I  ( Safet y e val uati o n): T he fi nal sa m ple size of t he trial will de pe n d o n t he assesse d d ose le vels a n d t o xicit y 
occ urre nce of B G B -3 1 1 1. It is e x pecte d t hat a b o ut 2 0 s u bj ects will be e nr olle d i n or der t o assess t he safet y a n d 
t olera bilit y of B G B-3 1 1 1 a n d dete r mi ne R P 2 D . 
P art II  ( D ose e x pa nsi o n): A p pr o xi matel y 2 0 s u bj ects wit h rela pse d or refract or y F L a n d M Z L will be e nr olle d t o 
e val uate t he a nti -t u m or acti vities of B G B-3 1 1 1. T he sa m ple size calc ulati o n is base d pri maril y o n t he acc urac y le vel of 
t he O R R esti mate. W he n t he sa m ple size is 2 0 s u bj ects, if t he O R R is 3 5 %, t he 9 5 % c o nfi de nce i nter val w o ul d be 
( 1 5. 4 %, 5 9. 2 %). T he st u d y dat a will be s orte d a n d a nal yze d acc or di n g t o t he statistical pla n.  
All s u bj ects e x p ose d t o B G B -3 1 1 1 will be i ncl u de d i n t he s afet y  a nal ysis p o p ulati o n. All t he s u bj ects w h o ha ve recei ve d 
B G B -3 1 1 1 wit h e val ua ble p har mac o ki netic data  will be i ncl u de d i n t he p har mac o ki netics a nal ysis p o p ulati o n a n d all t he 
ot her e val ua ble para meters will be liste d i n t he statistical re p ort.   
 
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 4  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
T A B L E O F C O N T E N T S  
SI G N A T U R E  .............................................................................................................................2  
A M E N D M E N T ( V E R SI O N 2 . 0) ( F E B. 6 T H, 2 0 1 7)… … … … … … … … … … … … … … … … … … … … … ..3   
                            
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  ..........................................1 7  
1  
I N T R O D U C TI O N .......................................................................................................1 9  
1. 1  
P har mac ol o gical a cti o n a n d M O A of B G B -3 1 1 1 a n d B T K i n hi bit or  .............1 9  
1. 2  
Pre -cli nical P har mac o ki n etic St u d y of B G B -3 1 1 1  ..........................................2 0  
1. 3  
Pre -cli nical T o xic ol o gical St u d y of B G B -3 1 1 1  ...............................................2 0  
1. 4  
Cli nical St u d y of B G B -3 1 1 1  ............................................................................2 1  
1. 4. 1  
S u m mar y of Cli nical P har mac ol o g y of B G B -3 1 1 1  ...........................2 1  
1. 4. 2  
Preli mi nar y Efficac y of B G B -3 1 1 1  ...................................................2 2  
1. 4. 3  
Safet y Assess me nt of B G B -3 1 1 1  ......................................................2 2  
1. 5  
Cli nical D ose Selecti o n of B G B -3 1 1 1 i n C hi na  ..............................................2 2  
1. 6  
Cli nical Efficac y of B T K 3 1 1 1 i n I n d ole nt L y m p h o ma  ...................................2 2  
2  
O BJ E C TI V E S  ..............................................................................................................2 4  
2. 1  
Part I ：Safet y E val u ati o n of d ose ....................................................................2 4  
2. 1. 1  
Pri mar y O bj ecti ve  ..............................................................................2 4  
2. 1. 2  
Sec o n dar y O bj ecti ve  ..........................................................................2 4  
2. 1. 3  
E x pl orat or y O bjecti ve  .......................................................................2 4  
2. 2  
Part II ：D ose e x pa nsi o n  ..................................................................................2 4  
2. 2. 1  
Pri mar y O bj ecti ve  ..............................................................................2 4  
2. 2. 2  
Sec o n dar y O bj ecti ve  ..........................................................................2 4  
2. 2. 3  
E x pl orat or y O bjecti ve  .......................................................................2 4  
3  
E N D P OI N T S  ...............................................................................................................2 5  
3. 1  
Part I ：Safet y E val u ati o n of d ose ....................................................................2 5  
3. 1. 1  
Pri mar y E n d p oi nts:  ............................................................................2 5  
3. 1. 2  
Sec o n dar y E n d p oi nts:  ........................................................................2 5  
3. 1. 3  
E x pl orat or y E n d p oi nts:  ......................................................................2 5  
3. 2  
Part II : D ose E x pa nsi o n ...................................................................................2 5  
3. 2. 1  
Pri mar y E n d p oi nts:  ............................................................................2 5  
3. 2. 2  
Sec o n dar y E n d p oi nts:  ........................................................................2 5  
3. 2. 3  
E x pl orat or y E n d p oi nts:  ......................................................................2 5  
4  
S T U D Y D E SI G N .........................................................................................................2 6  
4. 1  
O verall Desi g n  .................................................................................................2 6  
4. 2  
D ose Li miti n g T o xicit y ( D L T)  ........................................................................2 7  
4. 3  
D ose I nterr u pti o n a n d M o dificati o n .................................................................2 8  
4. 3. 1  
D ose Re d ucti o ns f or He mat ol o gic T o xicit y  ......................................2 8  
4. 3. 2  
D ose Re d ucti o ns f or N o n -he mat ol o gi c T o xicit y  ...............................2 8  
5  
S T U D Y P O P U L A TI O N  ..............................................................................................3 5  
5. 1  
I n cl usi o n Criteria .............................................................................................3 5  
5. 2  
E x cl usi o n Criteria  ............................................................................................3 5  
5. 3  
Ot her C o nsi derati o n f or eli gi bilit y  ...................................................................3 6  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 5  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
5. 4  
Restricti o ns of S u bjects ....................................................................................3 6  
5. 5  
C o m pleti o n of St u d y a n d a n d Earl y  W it h dra wal .............................................3 7  
5. 5. 1  
C o m pleti o n of St u d y  ..........................................................................3 7  
5. 5. 2  
Earl y Wit h dra wal  ...............................................................................3 7  
5. 5. 3  
Reas o ns f or Wit h dra wal  ....................................................................3 7  
6  
S T U D Y T R E A T M E N T  ...............................................................................................3 9  
6. 1  
St u d y Dr u g  .......................................................................................................3 9  
6. 2  
D osa ge a n d A d mi nistrati o n ..............................................................................3 9  
6. 3  
S u bject N u m beri n g  ..........................................................................................3 9  
6. 4  
Pac ka gi n g a n d La b elli n g  ..................................................................................3 9  
6. 5  
Dr u g St ora ge  ....................................................................................................3 9  
6. 6  
Res p o nsi bilit y of St u d y Dr u g Ma na ge me nt  .....................................................4 0  
6. 7  
C o m plia nce Assess me nt  ..................................................................................4 0  
6. 8  
Ha n dli n g of St u d y O v er d ose  ............................................................................4 0  
6. 9  
Occ u pati o nal Ris k  ............................................................................................4 0  
7  
C O N C O MI T A N T M E DI C A TI N A N D P R O HI BI T E D M E D I C A TI O N ....................4 1  
7. 1  
C o nc o mita nt Me dicati o n  ..................................................................................4 1  
7. 2  
Pr o hi bite d Me dicati o n  ......................................................................................4 1  
7. 3  
Me dicati o n t o be use d wit h ca uti o n  .................................................................4 1  
8  
S T U D Y A S S E S S M E N T O N S A F E T Y, P H A R M A C O KI N E TI C S, 
P H A R M A C O D Y N A MI C S A N D  O T H E R P A R A M E T E R S  ......................................4 3  
8. 1  
De m or gra p h y a n d Baseli ne C haracteristics  .....................................................4 3  
8. 2  
Assess me nt d uri n g tr eat me nt  ...........................................................................4 4  
8. 2. 1  
Assess me nt at La b orat or y of St u d y Ce nter  .......................................4 4  
8. 2. 2  
P h ysical E x a mi nati o n, Vital si g ns,  B -s y m pt o ms ..............................4 4  
8. 2. 3  
E C G  ...................................................................................................4 5  
8. 2. 4  
C T Sca n  .............................................................................................4 5  
8. 2. 5  
B o ne Marr o w E x a mi nati o n  ...............................................................4 5  
8. 2. 7  
Detecti o n of Mi ni mal Resi d ual Disease ( M R D)  ...............................4 6  
8. 2. 8  
A d verse E v e nts  ..................................................................................4 6  
8. 3  
Safet y  ...............................................................................................................4 6  
8. 4  
F oll o w -u p Assess me nt  .....................................................................................4 6  
8. 5  
Efficac y Assess me nt  ........................................................................................4 6  
8. 6  
P har mac o ki netics  .............................................................................................4 7  
8. 7  
P har mac o d y na mics  ..........................................................................................4 7  
9  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ...........................................4 8  
9. 1  
St u d y M o nit ori n g  .............................................................................................4 8  
9. 2  
Data Ma na ge me nt a n d C o di n g .........................................................................4 9  
9. 3  
Q ualit y Ass ura nce  ............................................................................................5 0  
1 0  
S A F E T Y  ......................................................................................................................5 1  
1 0. 1  
A d verse E v e nt ( A E) a n d Seri o us A d verse E v e nt ( S A E)  .................................5 1  
1 0. 2  
Ti mefra me f or A d verse E ve nt  .........................................................................5 1  
1 0. 3  
D oc u me ntati o n of A d verse E ve nt  ....................................................................5 2  
1 0. 4  
Assess me nt of Ca usalit y  ..................................................................................5 5  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 6  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
1 0. 5  
A d verse E v e nts W hic h Ca n n ot be Gra d e d Acc or di n g t o C T C ........................5 6  
1 0. 6  
Ma na ge me nt of A d vers e E ve nt  ........................................................................5 6  
1 0. 6. 1  
Re p ort of A d verse E ve nt  ...................................................................5 6  
1 0. 6. 2  
Re p ort of Seri o us A d verse E ve nt  ......................................................5 6  
1 0. 7  
F oll o w -u p of A d v erse E v e nt  ............................................................................5 7  
1 0. 8  
Pre g n a ncies  ......................................................................................................5 7  
1 0. 8. 1  
Pre g n a nc y T est  ..................................................................................5 7  
1 0. 8. 2  
Ti me Peri o d t o C ollect Pre g na nc y I nf or m ati o n  .................................5 7  
1 0. 8. 3  
Ma na ge me nt t o Pre g n a nc y  ................................................................5 7  
1 1  
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  .........................5 9  
1 1. 1  
Sa m ple Siz e C o nsi derati o n  ..............................................................................5 9  
1 1. 2  
Ge neral G ui deli ne f or Data A nal ysis  ...............................................................5 9  
1 1. 2 . 1 
Data A nal ysis P o p ulati o n  ..................................................................5 9  
1 1. 2 . 2 
St u d y A nal ysis  ...................................................................................5 9  
1 1. 3  
Efficac y A nal ysis  .............................................................................................6 0  
1 1. 4  
Safet y A nal ysis  ................................................................................................6 0  
1 1. 4. 1  
A nal ysis of D osa ge  ............................................................................6 0  
1 1. 4. 2  
Electr ocar di o gra m  .............................................................................6 0  
1 1. 5  
P har mac o ki netic Assess me nt  ...........................................................................6 1  
1 1. 6  
P har mac o d y na mics Ass ess me nt  ......................................................................6 2  
1 1. 7  
Sa m ple Siz e i n Part II  ......................................................................................6 2  
1 2  
E T HI C A L C O N SI D E R A TI O N S A N D I N F O R M E D C O N S E N T  ..............................6 3  
1 2. 1  
A p pr o val fr o m Re g ulat or y A ut h orit y  ..............................................................6 3  
1 2. 2  
Et hical d oc u me nt a n d Et hical A p pr o val  ..........................................................6 3  
1 2. 3  
I nf or me d C o nse nt.............................................................................................6 3  
1 2. 4  
I n v esti gat or Re p orti n g Re q uire me nts ..............................................................6 3  
1 3  
P R O T O C O L M O DI FI C A TI O N S  ................................................................................6 4  
1 4  
R E T E N TI O N O F S T U D Y F I L E S, C R F A N D R E C O R DS  ........................................6 5  
1 4. 1  
Rete nti o n of St u d y Files a n d D oc u me nt  ..........................................................6 5  
1 4. 2  
S o urce D oc u m e nt a n d Data  .............................................................................6 5  
1 4. 3  
A u dit a n d I ns pecti o n  ........................................................................................6 5  
1 4. 4  
Case Re p ort F or m  ( C R F) .................................................................................6 5  
1 5  
U TI LI Z A TI O N A N D P U B L I C A TI O N O F R E S E A R C H D A T A  ...............................6 7  
1 5. 1  
Utiliz ati o n of St u d y Data  .................................................................................6 7  
1 5. 2  
P u blicati o n  .......................................................................................................6 7  
1 6  
R E F E R E N C E S  ............................................................................................................6 8  
1 7  
A P P E N DI X  ..................................................................................................................7 0  
A p pe n di x 1:  Cli nical La b orat or y Test  ........................................................................7 0  
A p pe n di x 2:  Sa m ple C ollecti n g V ol u me  ....................................................................7 1  
A p pe n di x 3:  Efficac y Assess me nt Criteri o n  ...............................................................7 3  
A p pe n di x 4:  St u d y Desi g n of Part I  ............................................................................7 8  
A p pe n di x 5:  Fl o w C hart ..............................................................................................7 9  
A p pe n di x 6 ：Me dicati o ns Ca use d Q T/ Q Tc Pr ol o n ge d  .............................................8 0  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 7  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
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 Es  
a d verse e ve nts  
A U C  
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve 
B MI  
B o d y mass i n de x  
B T K  
Br ut o n’s t yr osi ne ki nase  
C L/ F  
a p pare nt t otal b o d y cleara nce of t he dr u g fr o m plas ma  
C L L  
c hr o nic l y m p h oc ytic le u ke mia  
C ma x  
ma xi m u m o bser ve d plas ma c o nce ntrati o n  
C R  
c o m plete res p o nse  
C R R  
c o m plete res p o nse rate  
C T  
c o m p ute d t o m o gra p h y  
D B P  
diast olic bl o o d press ure  
D L B C L  
diff use lar ge B cell l y m p h o ma  
D L T  
D ose li miti n g t o xicit y  
e C R F  
electr o nic case re p ort f or m  
E D C  
Electr o nic data c ollecti o n  
E D T A  
et h yle ne dia mi ne tetra acetic aci d  
F L  
f ollic ular l y m p h o ma 
G C P  
G o o d Cli nical Practice  
H B V  
he p atitis B vir us  
H C L  
hair y cell le u ke mia  
HI V  
h u ma n i m m u n o deficie nc y vir us  
I B 
I n vesti gat or’s Br oc h ure 
I C5 0 
5 0 % ma xi m u m i n hi bit or y c o nce ntrati o n  
I E C 
I n de p e n de nt Et hics C o m mitte e 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 8  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
I R B 
I T K 
L P L  
I nstit uti o nal Re vie w B oar d 
i nterle u ki n-2 -i n d uci ble T cell ki nase 
l y m p h o plas mac ytic l y m p h o ma 
M C L  
ma ntle cell l y m p h o ma  
Me d D R A  
me dical Dicti o nar y f or Re g ulat or y Acti vities  
M R D  
mi ni mal resi d ual disease  
M T D  
ma xi m u m t olerate d d ose  
M Z L  
mar gi nal z o ne l y m p h o ma  
N CI C T C A E  
Nati o nal Ca ncer I nstit ute C o m m o n T o xicit y Criteria f or A d verse E ve nts  
O R R  
o verall res p o nse rate  
P B M Cs  
peri p heral bl o o d m o n o n uclear cells  
P P B  
Plas ma bi n di n g pr otei n  
R P 2 D  
Rec o m me n de d p hase 2 d ose  
S A Es  
seri o us a d verse e ve nts 
S B P  
s yst olic bl o o d press ure 
S L L  
S mall l y m p h oc ytic le u ke mia  
S M C  
Safet y m o nit or c o m mittee  
S O Ps  
sta n dar d o perati n g pr oce d ures 
t1/ 2 
T er mi nal half ti me  
tma x  
Ti me t o ma xi m u m c o nce ntrati o n i n plas ma  
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  
W M  
W al de nstr ö m's macr o gl o b uli ne mia  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
1 9  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
1  
I N T R O D U C TI O N 
1. 1  
P h ar m ac ol o gic al a cti o n a n d M O A of B G B -3 1 1 1 a n d B T K  i n hi bit or 
B cell rece pt or ( B C R) si g nal p at h wa y pla ys a critical r ole i n t he n or mal gr o wt h, de vel o p me nt, differe ntiati o n a n d 
f u ncti o n of B cells 3. It is k n o w n t hat B C R pat h wa y is a b n or mall y acti vate d  i n vari o us B cell mali g na ncies  s uc h as 
ma ntel cell l y m p h o ma ( M C L), c hr o nic l y m p h oc ytic le u ke mi a ( C L L)/s mall l y m p h oc ytic l y m p h o ma ( S L L), f ollic ular 
l y m p h o ma ( F L), W al de nstr ö m's macr o gl o b uli ne mia ( W M)/l y m p h o plas mac ytic l y m p h o ma ( L P L) a n d diff use l ar ge B 
cell l y m p h o ma ( D L B C L) . Br ut o n’s t yr osi ne ki nase ( B T K) is a n i m p orta nt si g nali n g m olec ule i n t he B C R pat h wa y . 
B T K, as a me m ber of t he n o n -rece pt or t yr osi ne ki nase of t he T E C ki nase fa mil y, is e x presse d pre d o mi na ntl y i n t he 
de vel o p me ntal sta ges of B l y m p h oc ytes.  T he acti vati o n pr ocess of t he B C R pat h wa y i ncl u des t he mi grati o n of B T K t o 
t he plas ma me m bra ne, a ut o p h os p h or ylati o n of l oc us 2 2 3 o n t yr osi ne, a n d t he s u bse q ue nt a cti vati o n of t he d o w nstrea m 
p h os p h oli pase P L Cγ 2 a n d t he release of calci u m i o ns.  T hese si g nali n g e ve nts s u bse q ue ntl y  acti vate d o w nstrea m 
si g nali n g tra ns d ucti o n pat h wa ys, i ncl u di n g N F-B, t o pr o m ote e x pressi o n of  ge nes  i n v ol ve d i n cell pr oliferati o n a n d 
s ur vi val 4.  
St u dies ha ve s h o w n t hat bl oc ki n g B T K si g nali n g ca n i n hi bit t he gr o wt h of B cell t u m or  cells, i n d uce a p o pt osis a n d 
i n hi bit cell tra nsfer a n d a d hesi o n. Dr u gs tar geti n g B-cell rec e pt or si g nali n g ha ve p har mac o d y na mic effects t hat ca use 
tra nsie nt l y m p h oc yt osis, w hic h ca uses B T K-me diate d cell h o mi n g a n d a d hesi o n t o be i n hi bite d, lea di n g t o mi gra ti o n of 
t u m or cells t o peri p heral bl o o d 2 0, 2 1. A re versi ble i ncrease i n l y m p h oc yte c o u nt was o bser ve d at t he be gi n ni n g of 
treat me nt (ie, ≥5 0 % hi g her t ha n baseli ne, or a bs ol ute c o u nts a b o ve 5 0 0 0/m m 3). T his is us uall y ass ociate d wit h 
alle viati o n of l y m p h n o de lesi o n, a n d t his sit uati o n occ urs t o m ost patie nts wit h rec urre nt or refract or y C L L /S L L d uri n g 
t he treat me nt of B T K i n hi bit ors. S o me  rec urre nt or refract or y M C L patie nts a n d ot her B cell t u m or pa tie nts s h o we d 
sa me sit uati o n d uri n g  t he treat me nt of B T K i n hi bit ors. 
I n rece nt years, B T K as a tar get f or t he treat me nt of B-cell l y m p h o ma has ma de a maj or brea kt hr o u g h. B T K i n hi bit or 
i br uti ni b5 ,6 has bee n a p pr o ve d b y t he F D A f or t he treat me nt of patie nts w h o ha ve pre vi o usl y recei ve d at least o ne li ne of 
treat me nt of M C L ( N o ve m ber 2 0 1 3) a n d C L L ( Fe br uar y 2 0 1 4) 7 -9, 1 2. Rece ntl y i br uti ni b was a p pr o ve d f or t he treat me nt 
of C L L wit h 1 7 p deleti o n (J ul y 2 0 1 4) a n d W M (J a n uar y 2 0 1 5)  1 0 ,1 1. 
B G B -3 1 1 1, a n i n de p e n de ntl y de vel o pe d B T K i n hi bit or, has a hi g her selecti vit y a n d str o n ger acti vit y t ha n i br uti ni b. 
Bi oc he mical a n d c yt ol o gical st u dies ha ve s h o w n t hat B G B -3 1 1 1 is m ore s pecific t ha n i br uti ni b f or i n hi biti o n of B T K, 
a n d i n hi bit or y acti vit y a gai nst ot her ki nases s uc h as E G F R, J A K 3, H E R 2, T E C, I T K, etc. is wea ker t ha n i br uti ni b. 
T heref ore it is e x pecte d t hat t he t o xicit y of B G B -3 1 1 1 i n cli nical trials w o ul d be l o wer t ha n t hat of i br uti ni b. I n a d diti o n, 
d ue t o t he wea k i n hi biti o n of I T K b y B G B -3 1 1 1, t he i n hi biti o n of rit u xi ma b -i n d uce d A D C C i n precli nical trials was 
si g nifica ntl y wea ker t ha n t hat of i br uti ni b 1 3 ,1 4. 
I n a d diti o n, i n vi v o B T K occ u pa nc y test s h o we d t hat t he acti vit y of B G B-3 1 1 1 was a b o ut t hree ti mes t hat of i br uti ni b. 
I n vi v o p har mac o d y na mic test res ults als o s h o we d t hat B G B-3 1 1 1 i n hi bite d t he gr o wt h of M C L or D L B C L 
s u bc uta ne o usl y i n oc ulate d i n mice i n a d ose-de pe n de nt ma n ner. At c o m para ble d oses, B G B -3 1 1 1 ha d better t u m or 
s u p pressi o n t ha n i br uti ni b. B G B-3 1 1 1 al s o s h o we d g o o d p har mac o ki netic c haracteristics i n rats a n d d o gs wit h g o o d 
bi oa vaila bilit y a n d c o ul d be q uic kl y e xcrete d fr o m b o d y.  
Acc or di n g t o t he selecti vit y a n d efficac y s h o w n i n t he precli nical st u d y of B G B -3 1 1 1, we pre dicte d t hat B G B -3 1 1 1  ca n 
effecti vel y i n hi bit t he acti vit y of B T K ki nase at a l o wer d ose t ha n i br uti ni b i n cli nical practice, a n d beca use of its 
s pecificit y f or B T K i n hi biti o n, B G B-3 1 1 1 ca n greatl y a v oi d ma n y si de effects of i br uti ni b arisi n g fr o m i n hi biti o n of 
ot her tar gets . M ore i m p orta ntl y, c o nsi deri n g t he I T K acti vit y i n hi biti o n b y B G B-3 1 1 1 is at least 1 0 ti mes wea ker  t ha n 
t hat of i br uti ni b, t he c o m bi ne d effect wit h t he cli nical first-li ne dr u g rit u xi ma b ma y be s u p eri or t o t hat of i br uti ni b. 
T heref ore, we e x pecte d t hat t he effic ac y of B G B -3 1 1 1 m o n ot hera p y a n d c o m bi nati o n t hera p y ma y be s u peri or t o t hat of 
i br uti ni b i n cli nical trials. 
* ple ase r efer t o B G B -3 1 1 1 i nvesti g at or br oc h ure f or det aile d b ack gr o u n d i nf or m ati o n.  
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 0  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
1. 2  
Pre -cli nic al P h ar m ac o ki neti c S t u d y of B G B-3 1 1 1  
B G B -3 1 1 1 s h o w e d m o derate a n d hi g h oral bi oa vaila bilit y i n S D rats a n d Bea gle d o gs, wit h hi g h a n d me di u m cleara nce 
rates, s mall v ol u me of a p pare nt distri b uti o n, s h ort half-life a n d better li near p har mac o ki netic pr ofiles. N o si g nifica nt 
acc u m ulati o n after re p eate d a d mi ni strati o n. T he dr u g e x p os ure i n fe male rats was si g nific a ntl y hi g her t ha n t hat i n male 
rats (a b o ut t wice as m uc h), b ut t here is n o si g nifica nt ge n der differe nce i n t he p har mac o ki netic para meters f or B ea gle 
d o gs.  
T he a vera ge plas ma pr otei n bi n di n g rates of B G B -3 1 1 1 i n h u ma n, c y n o m ol g us m o n ke y, B ea gle d o gs, S D rats a n d I C R 
mice were 9 4. 2 %, 9 3. 9 %, 9 3. 3 %, 9 6. 7 % a n d 9 4. 9 %, res pecti vel y. B G B -3 1 1 1 is mai nl y distri b ute d i n plas ma f or 
h u ma ns a n d Bea gle d o gs, a n d is n ot distri b ute d i n a c o nce ntrati o n -de pe n de nt ma n ner,  b ut is mai nl y distri b ute d i n 
plas ma at l o w c o nce ntrati o ns f or S D rats a n d te n ds t o be i n bl o o d cells at hi g h c o nce ntrati o ns . B G B -3 1 1 1 ca n be q uic kl y 
distri b ute d t o t he b o d y or ga ns  after oral a d mi nistrati o n , a n d eli mi nate fr o m or ga ns wit hi n 8 h o urs b y a lar ge e xte nt. 
T he cleara nce rate of B G B -3 1 1 1 i n h u ma n, c y n o m ol g us m o n ke y, Bea gle d o gs, S -D rats a n d m o use li ver micr os o mes 
was me di u m t o hi g h, wit h t he cleara nce rate i n d o gs bei n g relati vel y l o w. B G B -3 1 1 1 pr o d uces a lar ge n u m ber of 
meta b olites i n vari o us li ver mi cr os o mes a n d S D rats. A m o n g t he vari o us li ver micr os o mes, t he meta b olites of B G B-
3 1 1 1 are mai nl y me diate d b y  o xi dati ve dea mi nati o n, h y dr o x ylati o n, de h y drati o n a n d N -desal k ylati o n, B G B -3 1 1 1 
meta b olis m i n rats is mai nl y me diate d b y c ystei ne bi n di n g, acet ylati o n, gl uc ur o ni dati o n, h y dr o x ylati o n, N -desal k ylati o n 
a n d s ulfati o n. B Y P -3 1 1 1 ha s a certai n de gree of i n hi biti o n o n C Y P 2 C 8, C Y P 2 C 9 a n d C Y P 2 C 1 9 wit h I C 5 0 val ues of 
4. 0 3, 5. 6 9 a n d 7. 5 8 μ M, res pecti vel y, w hic h ha s a sli g ht i n hi bit or y effect o n C Y P 2 D 6 a n d C Y P 3 A a n d ha s n o 
si g nifica nt i n hi bit or y effect o n C Y P 1 A 2. B G B-3 1 1 1 is mai nl y meta b olize d b y C Y P 3 A. B G B -3 1 1 1 ha s n o o b vi o us 
effect o n t he acti vit y of C Y P 1 A 2 a n d C Y P 2 B 6 i n he pat oc yt es, a n d ha s a certai n i n d ucti o n effect o n C Y P 3 A 4 w he n t he 
c o nce ntrati o n is greater t ha n or e q ual t o 3 μ M.  
I n rats, after oral a d mi nistrati o n of B G B-3 1 1 1, t he e xcreti o n of pare nt dr u g via feces, uri ne a n d bile is ver y s mall. M ost 
of 1 4C -la bele d B G B-3 1 1 1 is e xcrete d b y feces, wit h t otal ra di oacti vit y rec o ver y rate u p t o 9 8 %, s u g ges ti n g t hat i n t he rat 
B G B -3 1 1 1 is mai nl y eli mi nat e d i n b o d y a n d rarel y left i n t he b o d y.  
* Ple ase r efer t o B G B -3 1 1 1 i nvesti g at or br oc h ure f or m ore i nf or m ati o n a b o ut p h ar m ac o dy n a mics  a n d A D M E.  
1. 3  
Pre -cli nic al T o xic ol o gic al S t u d y of B G B-3 1 1 1  
I n vitr o h E R G test res ults s h o we d t hat t he i n hi bit or y effect of B G B-3 1 1 1 o n h E R G p otassi u m c ha n nel was m o derate, 
t he half -i n hi biti o n c o nce ntrati o n (I C5 0) was 3. 8 μ M ( p ositi ve c o ntr ol a mitri pt yli ne: 1. 9 μ M). T he car di o vasc ular safet y 
p har mac ol o g y tele metr y test s h o we d t hat 1 0  t o 1 0 0 m g/ k g of B G B-3 1 1 1 ha d n o effect o n E C G, bl o o d press ure a n d heart 
rate. B G B-3 1 1 1 was a d mi nist ere d t o rats at a d ose of 1 0 0 m g/ k g, wit h n o si g nifica nt effect o n ce ntral ner v o us s yste m 
a n d res pirat or y f u ncti o n. I n t he si n gle a n d re p eate d a d mi nistrati on  trials i n d o gs, n o E C G a b n or malities were o bser ve d. 
N o a b n or mal cli nical ma nifest ati o ns a n d/ or hist o pat h ol o gical c ha n ges ass ociate d wit h t he car di o vasc ular s yste m, ce ntral 
ner v o us s yste m a n d res pirat or y s yste m were f o u n d i n si n gle a n d re peate d a d mi nistrati o n tri als  i n rats a n d d o gs. 
T he M T D ( ma xi m u m t olerate d d ose) of rats a n d d o gs was hi g her t ha n 1 0 0 0 m g/ k g i n a si n gle d ose ac ute t o xicit y test.  
I n t he 1 4-da y re p eate d a d mi nistrati o n e x pl orat or y st u d y, t he M T D is hi g her t ha n 2 5 0 m g/ k g/ da y f or rats a n d hi g her t ha n 
1 0 0  m g/ k g/ da y f or d o gs.  
I n t he rat 2 8-da y re p eate d a d mi nistrati o n st u d y, n o deat h ass ociate d wit h t he test pr o d uct was o bser ve d i n a ni mals. T he 
cli nical o bser vati o n a n d cli nic al test c ha n ges relate d t o t he test pr o d uct mai nl y occ urre d i n t he male a n d fe male a ni mals 
of t he 5 0 0 m g/ k g/ da y gr o u p, i ncl u di n g cr usts/s welli n g ar o u n d t he n ose, m o ut h, li ps a n d e yeli ds, sali vati o n a n d s oft 
st o ols; W B C, N E U T a n d R E T i ncrease d, R B C, H G B a n d H C T decrease d; uri nar y occ ult bl o o d/re d bl o o d cells, a n d 
p ositi ve uri ne pr otei n a n d  bilir u bi n . T he dr u g e x p os ure i ncre ase d pr o p orti o nall y wit h t he d ose wit h o ut  acc u m ulati o n 
effect, a n d t he s yste mic e x p os ure i n fe male a ni mals is a b o ut 1. 8 t o 2. 9 ti mes t he sa me d ose of male a ni mals. 
Hist o pat h ol o gical c ha n ges ass ociate d wit h t he test pr o d uc t were o bser ve d i n t he pa ncreas, s ki n ( n ose a n d li ps), s plee n, 
pr ostate, lar ge i ntesti ne a n d ut er us. Hist o pat h ol o gical c ha n ges i n t he pa ncreas a n d s ki n are c o nsi dere d t o xic ol o gical; t he 
hist o pat h ol o gical c ha n ges of ot her or ga ns or tiss ues are mil d or mil d,  a n d are c o nsi dere d t o be n or mal p h ysi ol o gical or 
stress reacti o ns a n d are n ot t o xic ol o gical. P a ncreatic c ha n ges occ urre d pre d o mi na ntl y i n male a ni mals i n all gr o u ps, 
wit h mil d t o m o derate lesi o n s, n o t d ose -relate d, a n d bei n g re versi ble d uri n g rec o ver y peri o d. C ha n ges of  s ki n ( n ose a n d 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 1  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
li ps) occ urre d mai nl y i n male a n d fe male a ni mals of 5 0 0 m g /k g /da y  gr o u p , b ut n ot o bser ve d d uri n g t he rec o ver y peri o d. 
U n der t he test c o n diti o ns, t he M T D of male a n d fe male rats was c o nsi dere d t o be 5 0 0 m g /k g /da y.  
I n t he rat 1 3-wee k re p eate d a d mi nistrati o n st u d y, t he hi g hest d ose of 3 0 0 m g/ k g di d n ot res ult i n deat h i n rats, si milar t o 
t he 2 8-da y re p eate d t o xicit y test, i ncl u di n g a sli g ht decrease i n K a n d C K. T he pat h ol o gical c ha n ges of pa ncreatic tiss ue 
are c o nsi d ere d har mless a n d n o ne w t o xicit y is f o u n d. U n der t he test c o n diti o ns, t he M T D of male a n d fe male rats was 
c o nsi dere d t o be 3 0 0 m g/ k g/ d a y.  
I n t he d o g 2 8-da y re p eate d a d mi nistrati o n st u d y, n o deat h was o bser ve d i n all d ose gr o u ps. O nl y a ni mals i n 1 0 0 
m g /k g /da y gr o u p s h o we d a tra nsie nt s oft st o ol a n d v o miti n g d uri n g t he d osi n g peri o d; t her e was n o t o xic ol o gical c ha n ge 
i n b o d y wei g ht, f o o d i nta ke, he mat ol o g y, bl o o d bi oc he mistr y, a n d uri ne test. O nl y 3 0 a n d 1 0 0 m g/ k g/ da y gr o u ps 
s h o we d a sli g ht i ncrease i n fi brin o ge n ( FI B) o n da y 2 7. T he dr u g e x p os ure i ncrease d pr o p orti o nall y wit h t he d ose, a n d 
t here was n o si g nifica nt ge n der differe nce a n d acc u m ulati o n effect. At t he e n d of t he a d mi nistrati o n peri o d , n o 
si g nifica nt macr osc o pic lesi o ns or c ha n ges of or ga n wei g ht were o bser ve d; o nl y mil d t o mil d s plee n l y m p h o pe nia was 
o bser ve d i n all a d mi nistere d a ni mals, a n d n o c ha n ges i n he mat ol o g y a n d or ga n wei g ht were o bser ve d.  T his c ha n ge was 
re versi ble d uri n g rec o ver y peri o d a n d was c o nsi dere d t o ha ve n o t o xic ol o gical si g nifica nce. U n der t h e test c o n diti o ns, 
t he M T D of male a n d fe male d o gs was c o nsi dere d t o be hi g her t ha n 1 0 0 m g /k g /da y.  
I n t he d o g 1 3-wee k re p eate d a d mi nistrati o n st u d y, t he hi g hest d ose was 1 0 0 m g / k g. The fi n di n gs  fr o m t his st u d y were 
si milar t o t he 2 8-da y re p eat a d mi nistrati o n t o xicit y st u d y, a n d n o ne w t o xicit y was f o u n d.  
B G B -3 1 1 1 d oes n ot ca use c hr o m os o me m utati o ns ( A mes test), n or d oes it ca use s c hr o m os o me brea ks ( I n Vitr o 
Ma m malia n Cells C hr o m os o me A berrati o n T est  a n d micr o n ucle us  tests i n rats). 
B ase d o n t he a b o ve fi n di n gs, it is c o nsi dere d t hat t he cli nical i n vesti gati o n is s u p p orte d b y t he g o o d safet y pr ofiles a n d 
wi de safet y wi n d o w of B G B -3 1 1 1. Dr u g -relate d cha n ges i n cl u de  mil d i ncrease of W B C, N E U T a n d FI B; mil d 
re d ucti o n of R E T, R B C, H G B a n d H C T; mil d re d ucti o n of K a n d C K; re versi ble har mless hist o pat h ol o gical c ha n ges  i n 
pa ncreas, a dre nal, l u n g, s ki n a n d B cell -ass ociate d l y m p hati c s yste m . Hist o pat h ol o gical c ha n ges i n t he pa ncreas were 
o bser ve d  i n rats, a n d t he c ha n ges i n male a ni mals were m ore si g nifica nt t ha n i n fe male a ni mals wit h n o dr u g 
relati o ns hi ps. T he s yste mic e x p os ure i ncrease d pr o p orti o nall y wit h t he d ose, a n d n o si g nifi ca nt ge n der differe nces a n d 
acc u m ulati o n effects were o bser ve d.  
* Ple ase refer t o i nvesti g at or br oc h ure f or m ore t oxic ol o gic al i nf or m ati o n of B G B -3 1 1 1.  
1. 4  
Cli nic al S t u d y of B G B-3 1 1 1  
B G B -3 1 1 1 is a n o vel, p ote nt a n d hi g hl y selecti ve B T K i n hi bit or de vel o pe d b y Bei Ge ne, w hic h o w ns t he i n de p e n de nt 
i ntellect ual pr o pert y ri g hts a n d gl o bal pate nts of t he pr o d uct a n d i nte n ds t o carr y o ut cli nic al trials si m ulta ne o usl y i n t he 
w orl d. T he first -i n-h u ma n ( FI H) st u d y of B G B -3 1 1 1 ( pr ot oc ol N o.: B G B -3 1 1 1 -A U -0 0 3) was la u nc he d i n A us tralia i n 
A u g ust 2 0 1 4. It  was a n o pe n, m ulti -d ose, d ose escalati o n P hase I cli nical st u d y de si g ne d t o assess t he safet y, t olera bilit y 
a n d p har mac o ki netic c haracteristics of B T K i n hi bit or B G B -3 1 1 1 i n s u bj ects wit h B cell l y m p h o ma.  
T he safet y, t olera bilit y, a n d p har mac o ki netics of t he f o ur d os es ( 4 0 m g, 8 0 m g, 1 6 0 m g, a n d 3 2 0 m g dail y) ha ve bee n 
assesse d f or d ose escalati o n of t he B G B-3 1 1 1 i n cli nical P hase I st u d y. Of t hese, 4 0 m g, 8 0 m g a n d 1 6 0 m g were 
a d mi nistere d o nce dail y ( Q D); 3 2 0 m g ha d t w o d osi n g re gi me ns ( 3 2 0 m g Q D a n d 1 6 0 m g BI D). At prese nt, t he cli nical 
p hase II d ose has bee n i de ntifi e d as 1 6 0 m g BI D or 3 2 0 m g Q D, a n d a n u m ber of f urt her cli nical trials of l y m p h oi d 
t u m ors ha ve bee n i nitiate d. As of J u ne 1 0, 2 0 1 6, 1 2 5 s u bj ects ha d bee n e nr olle d, a n d 1 0 9 of t he m recei ve d B G B -3 1 1 1 
d ose of 3 2 0 m g Q D or 1 6 0 m g BI D ; n o D L T occ urre d. Of t hese, 9 5 s u bj ects ha d recei ve d at least o ne assess me nt of 
dr u g  res p o nse or earl y ter mi nate d treat me nt d ue t o pr o gressi o n of t he disease. T he me dia n d urati o n of treat me nt was 1 9 7 
da ys ( 6 -6 3 3 da ys). T he p har mac o ki netics, p har mac o d y na mi cs, cli nical safet y, a n d pre li mi nar y efficac y of t he dr u g will 
be descri be d i n detail bel o w.  
1. 4. 1  
S u m m ar y of Cli nic al P h ar m ac ol o g y of B G B -3 1 1 1  
B ase d o n t he li mite d n u m ber of cases, t he i nteri m a nal ysis of p har mac o ki netic data s h o we d t hat B G B -3 1 1 1 was ra pi dl y 
a bs or be d a n d eli mi nate d after oral a d mi nistrati o n. T he ma xi mal plas ma c o nce ntrati o n ( C m a x ) a n d bl o o d e x p os ure ( A U C0 -
2 4 h) i ncrease d li nearl y i n t he ra n ge of 4 0-3 2 0 m g Q D after si n gle a d mi nistrati o n a n d at stea d y state. T he half -life of 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 2  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
B G B -3 1 1 1 is bet wee n 1 . 8 h o urs a n d 3. 7 h o urs. I n t he 3 2 0 m g Q D a n d 1 6 0 m g BI D  gr o u ps , t he hi g hest plas ma 
c o nce ntrati o n a n d bl o o d e x p os ure of B G B -3 1 1 1 were 6 4 6 n g /m L * h  a n d 2, 7 0 4 n g /m L * h at stea d y state ( C ma x  a n d 
A U Css), a n d 2 8 2 n g /m L * h  a n d 3, 0 0 6 n g /m L * h , res pecti vel y. 
I n t he P hase I trial of B G B-3 1 1 1, t he dr u g occ u pa nc y of Br ut o n T yr osi ne Ki nase ( B T K) i n peri p heral bl o o d 
m o n o n uclear cells ( P B M Cs) was e xa mi ne d t o assess t he i n hi bit or y effect of B G B -3 1 1 1 o n t he tar get. I nitial a nal ysis 
s h o we d t hat ra pi d, s ustai ne d, near-t o-c o m plete i n hi biti o n was ac hie ve d e ve n at t he i nitial d ose ( 4 0 m g) of B G B -3 1 1 1. 
T hese data s h o w t hat B G B -3 1 1 1 is a ver y effecti ve B T K i n hi bit or. I n t he d ose gr o u p of 3 2 0 m g Q D a n d 1 6 0 m g BI D, 
t he dr u g occ u pa nc y rate of B T K i n t he l y m p h n o des was also c o m plete  be f ore a d mi nistrati o n o n t hir d da y. 
1. 4. 2  
Preli mi n ar y E ffic ac y of B G B-3 1 1 1  
As of c ut -off date (J u ne 1 0, 2 0 1 6), a t otal of 1 2 5 s u bj ects were e nr olle d i n t he st u d y. E xce pt t hat t he ne wl y e nr olle d 
patie nts ha d n ot yet o btai ne d t he res ults of t he first efficac y e val uati o n a n d 2 s u bj ects wit h dre w fr o m  st u d y d ue t o 
i nt olera nce, t he re mai ni n g 9 5 s u bj ects were i ncl u de d i n t he i nitial efficac y e val uati o n. I n t he 2 8 cases of treate d C L L 
patie nts, t he t otal res p o nse rat e ( O R R) was 9 3 %, i ncl u di n g 2 6 cases ( 9 3 %) partial res p o nse ( P R) a n d 2 cases of sta ble 
dise ase ( S D); i n t he 2 4 cases of treate d W M patie nts, t he O R R was 9 3 %, wit h a maj or res p o nse rate of 8 3 %, i ncl u di n g 8 
cases ( 3 3 %) ver y g o o d partial res p o nse ( V G P R) a n d 1 2 cases ( 5 0 %) P R; i n t he 1 5 treate d M C L patie nts, t he O R R was 
8 0 %, i ncl u di n g 3 cases ( 2 0 %) c o m plete res p o nse ( C R) a n d 9 cases ( 6 0 %) P R; i n t he 1 5 cas es of treate d D L B C L patie nts, 
t he O R R was 2 5 %, a n d t he O R R reac he d 3 3 % i n patie nts of n o n-ger mi nal ce nter D L B C L. T hese preli mi nar y cli nical 
res ults s h o w t hat B G B-3 1 1 1 has a g o o d effect i n B -cell mali g na ncies, es peciall y i n C L L, M C L, W M a n d D L B C L. 
1. 4. 3  
S afet y A ssess me nt of B G B-3 1 1 1  
As of J u ne 1 0, 2 0 1 6, 1 2 5 s u bjects ha d bee n e nr olle d a n d all s u bj ects were i ncl u de d i n t he s afet y assess me nt. T he me dia n 
d urati o n of treat me nt was 1 9 7 da ys ( 6 -6 3 3 da ys), of w hic h 1 7 s u bj ects ha d bee n treate d f or m ore t ha n 1 year a n d n o 
d ose -li miti n g t o xicity ( D L T) was o bser ve d, n or di d it reac h t he ma xi m u m t olerate d d ose ( M T D). All s u bj ects were well 
t olerate d wit h B G B-3 1 1 1, a n d t he m ost c o m m o n a d verse e ve nts (re gar dless of t he ca usalit y) i ncl u de d: mil d blee di n g 
a n d br uisi n g ( 3 7 %), u p per res pirat or y tract i n fecti o n ( 2 5 %), diarr hea 2 2 %), c o u g h ( 2 0 %), ras h ( 1 9 %), l o wer res pirat or y 
tract i nfecti o n ( 1 7 %), c o nsti pati o n ( 1 6 %), ne utr o pe nia ( 1 6 %), fati g ue ( 1 3 %), na usea ( 1 2 %) a n d a ne mia ( 1 1 %).  Gra d e  ≥ 
3 a d verse reacti o ns i ncl u de d  ne utr o pe nia ( 1 6 cases), l o wer res pira t or y tract i nfecti o n ( 1 0 cases), a ne mia ( 9 cases), 
diarr hea ( 2 cases)  a n d blee di n g, c o u g h a n d na usea (eac h 1 case ). 
At prese nt t he trial is i n pr o gress, it will f urt her e val uate t he safet y of B G B -3 1 1 1.  
1. 5  
Cli nic al D ose S electi o n of B G B -3 1 1 1 i n C hi n a  
T he selec ti o n of B G B-3 1 1 1 d ose i n earl y cli nical safet y st u dies is base d o n t he pre -cli nic al de vel o p me nt g ui deli nes f or 
a nti ne o plastic a ge nts, n o n -cli nical p har mac ol o gical data, p har mac o ki netic data, a n d t o xic ol o gical data.  I n rat a n d d o g 
t o xic ol o g y st u dies, t he ST D 1 0 d ose was n ot reac he d . Acc or di n g t o t he e xtra p olati o n of a ni mal t o xic ol o gical data ( 1/ 1 0 of 
t he M T D of rat a n d d o g), t he starti n g d ose of h u ma n ca n be u p t o 5 0 0 m g per da y. 
I n t he cli nical p hase I trial i n A ustralia a n d Ne w Zeala n d, t he d ose esclati o n of t he B G B-3 1 1 1 cli nical trial has bee n 
c o m plete d. T he R P 2 D  has bee n deter mi ne d t o be 1 6 0 m g t wi ce dail y or 3 2 0 m g o nce dail y. N o d ose -li miti n g t o xicit y 
( D L T) was o bser ve d, n or di d n ot reac h t he ma xi m u m t olerat e d d ose ( M T D). U p t o n o w n o ne s u bj ects e x perie n ce d a n y 
dr u g -relate d seri o us a d verse effects. Of t he 5 5 s u bj ects c urre ntl y e nr olle d, 5 were Asia n. Base d o n t hese data, it is 
c o nsi dere d t hat B G B-3 1 1 1  at d ose of 3 2 0 m g Q D or 1 6 0 m g BI D w o ul d be safe a n d effecti ve. T he o bj ecti ves of t his 
trial is t o vali date t he safet y, t olera bilit y a n d p har mac o ki neti c / p har mac o d y na mic of B G B -3 1 1 1 at 3 2 0 m g Q D a n d 1 6 0 
m g BI D in t he C hi nese p o p ulati o n. If t his  d ose is i nt olerable t o t he  C hi nese s u bj ect s, t his d ose will be f urt her re d uce d 
u ntil a safe d ose is deter mi ne d.  
1. 6  
Cli nic al Effic ac y of B T K 3 1 1 1 i n F ollic ul ar  L y m p h o m a  a n d M ar gi n al Z o ne L y m p h o m a  
F ollic ular L y m p h o ma ( F L) is a n i n d ole nt B cell t u m or ori gi nati n g fr o m f ollic ular ger mi nal ce n ter cells. M ost F L 
patie nts ha ve bee n i n a d va nce d sta ge of disease a n d diffic ult t o  be c ure d w he n detect e d. I n Wester n c o u ntries, F L 
acc o u nts f or 2 2 % t o 3 5 % of n o n -H o d g ki n l y m p h o ma ( N H L), a n d t he i nci de nce of F L i n C hi na is relati vel y l o w, 
acc o u nti n g f or 8. 1 % t o 2 3. 5 % of N H L 1 6. A hi g h pr o p orti o n of F L is tra nsf or me d i nt o diff use lar ge B-cell l y m p h o ma ( 3 % 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 3  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
per year) 1 6. F L cells are C D 1 0 +, C D 1 9 +, C D 2 2 +, C D 2 0 + a n d C D 5-, t ( 1 4: 1 8) c hr o m os o me tra nsl ocati o n a n d hi g h 
B C L 2 e x pressi o n i n F L are all ver y c o m m o n. F or F L patie nts, t he m e dia n s ur vi val is a b o ut 1 0 years ( 1 - 2 0 years) wit h 
5 -year s ur vi val rate of 7 2 % -7 7 %.  
Mar gi nal Z o ne L y m p h o ma ( M Z L) is a B -cell l y m p h o ma ori gi nati n g fr o m t he mar gi nal z o ne, w hic h is a n i n d ole nt 
l y m p h o ma a n d di vi de d i nt o t hree s u bt y pes acc or di n g t o its ori gi n, na mel y, e xtra n o dal M Z L (als o k n o w n as m uc osa-
ass ociate d l y m p h oi d tiss ue ( M A L T) l y m p h o ma), l y m p h n o de M Z L a n d s ple nic mar gi nal z o ne M Z L. M A L T l y m p h o ma 
is t he m ost c o m m o n s u bt y pe, als o C hi na's m ost c o m m o n i n d ole nt l y m p h o ma. T he pr o g n osis of M A L T l y m p h o ma is 
better t ha n l y m p h n o de M Z L a n d s plee n M Z L 2 5. 
F L is o ne of t he mali g na ncies ver y se nsiti ve t o c he m ot hera p y a n d ra di ot hera p y. F or patie nts w h o nee d treat me nt, 
c urre ntl y ra di ot hera p y, rit u xi ma b m o n ot hera p y or c o m bi ne d t hera p y wit h ot her a ge nts s uc h as R-C V P a n d R -C H O P, has 
bee n c o nsi dere d  as a first -li ne treat me nt. I n 2 0 1 0, Rit u xi ma b was a p pr o ve d as mai nte na nce t hera p y after first -li ne 
i m m u n oc he m ot hera p y. I n 2 0 1 2 B e n da m usti n c o m bi ne d wit h rit u xi ma b has bee n s h o w n t o ac hie ve t wice  t he 
pr o gressi o n -free s ur vival of R -C H O P i n F L patie nts. B ut F L patie nts are pr o ne t o rec ur aft er i nitial c ure 1 5. 
M A L T l y m p h o ma is t he m ost c o m m o n pri mar y gastric M A L T l y m p h o ma. F or patie nts at sta ge I a n d II: H p -p ositi ve 
patie nts, a nti -H p treat me nt  is preferre d; f or patie nts refract or y t o a nti-H p treat me nt or H p -ne gati ve patie nts, l ocal 
ra di ot hera p y is preferre d; f or patie nts n ot s uita ble f or ra di ot hera p y, rit u xi ma b m o n ot hera p y c o ul d be c o nsi dere d; F or 
patie nts at sta ge III a n d I V: patie nts wit h o ut treat me nt i n dicati o ns ma y c h o ose t o kee p u n der o bser vati o n , w hile patie nts 
wit h i n dicati o ns ca n refer t o t he treat me nt pri nci ples of a d va nce d F L, a n d s ur gical treat me nt is o nl y li mite d t o blee di n g, 
perf orati o n or ot her s pecial circ u msta nces. F or l y m p h n o de M Z L patie nts, t he treat me nt pri nci ples of F L  ca n be referre d . 
F or t he s plee n M Z L, f or patie nts w h o is as y m pt o matic a n d wit h o ut pr o gressi ve bl o o d cell re d ucti o n or s ple n o me gal y, 
ca n kee p u n der o bser vati o n . For patie nts wit h s ple n o me gal y a n d p ositi ve he patitis C vir us, if t here is n o 
c o ntrai n dicati o ns f or he p atitis C  treat me nt, ca n be gi ve n A nti -he patitis C treat me nt; F or patie nts acc o m pa nie d b y 
s ple n o me gal y a n d ne gati ve he patitis C vir us, if as y m pt o mati c ,  ca n als o kee p u n der o bser vati o n ; f or s y m pt o matic 
patie nts, t he first c h oice is s pl e nect o m y or rit u xi ma b m o n ot hera p y . F or patie nts w h ose disease pr o gresse d after 
treat me nt, t he treat me nt of a d va nce d F L ca n be referre d 2 5. 
B T K i n hi bit or i br uti ni b ha ve bee n a p pr o ve d b y a n u m ber of c o u ntries, i ncl u di n g U nite d St ates, f or t he treat me nt of 
c hr o nic l y m p h oc ytic le u ke mia, ma ntle cell l y m p h o ma a n d Wal de nstr o m macr o gl o b uli ne mia . I br uti ni b has als o s h o w n 
cli nical efficac y i n rec urre nt refract or y F L a n d M Z L s u bj ects: P hase II cli nical trials ha ve s h o w n a n o verall res p o nse 
rate of 3 0 % a n d a t u m or re gressi o n rate of 6 5 % i n rela psi n g refract or y F L s u bj ects; t he i nt eri m pr o gressi o n -free s ur vi val 
was 9. 9 m o nt hs 1 7. T he o verall res p o nse rate was 4 8 % a n d t u m or re gressi o n rate was 7 9 % i n t he rela pse d refract or y 
M Z L s u bj ects
2 6. B G B-3 1 1 1, a ne w ge nerati o n of  B T K i n hi bit ors, has a hi g her selecti vit y a n d str o n ger acti vit y i n hi biti o n 
c o m pare d t o i br uti ni b, a n d is li kel y t o i n hi bit t u m or gr o wt h m ore effecti vel y i n cli nical practice. I n t his st u d y, 
a p pr o xi matel y 2 0 patie nts wit h refract or y f ollic ular l y m p h o ma or m ar gi nal l y m p h o ma will be e nr olle d  a n d t he a nti -
t u m or acti vit y of B G B-3 1 1 1 will b e  e val uate d.  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 4  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
2  
O B J E C TI V E S  
2. 1  
P art I ：S afet y E v al u ati o n  of d ose  
2. 1. 1  
Pri m ar y O bjecti ve  
 T o e val uate t he safet y a n d t olera bilit y of B G B -3 1 1 1 i n C hi nese patie nts wit h B -cell l y m p h o ma a n d deter mi ne 
rec o m me n de d p hase 2 d ose ( R P 2 D). 
2. 1. 2  
Sec o n d ar y O bjecti ve  
 T o c haracterize t he p har mac o ki netics ( P K) of si n gle - a n d m ulti ple - d ose of B G B -3 1 1 1 orall y i n C hi nese patie nts 
wit h B -cell l y m p h o ma.  
 T o e val uate t he i n hi bit or y effe ct of B G B -A 3 1 1 1 o n B T K i n pe ri p heral bl o o d m o n o n uclear cells ( P B M Cs). 
2. 1. 3  
E x pl or at or y O bjecti ve  
 
  
2. 2  
P art II ：D ose e x p a nsi o n  
2. 2. 1  
Pri m ar y O bjecti ve  
 T o e val uate t he preli mi nar y a nti -t u m or acti vit y of B G B-3 1 1 1 i n s u bj ects wit h f ollic ular l y m p h o ma ( F L) or mar gi nal 
z o ne l y m p h o ma ( M Z L).  
2. 2. 2  
Sec o n d ar y O bjecti ve  
 T o f urt her assess t he safet y a n d t olera bilit y of B G B -3 1 1 1 i n patie nts wit h f ollic ular l y m p h o ma ( F L) a n d mar gi nal 
z o ne l y m p h o ma ( M Z L). 
 T o f urt her c haracterize t he p har mac o ki netics ( P K) of si n gle - a n d m ulti ple - d ose of B G B -3 1 1 1 orall y i n C hi nese 
patie nts wit h B -cell l y m p h o ma.  
2. 2. 3  
E x pl or at or y O bjecti ve  
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 5  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
3  
E N D P OI N T S  
3. 1  
P art I ：S afet y E v al u ati o n  of d ose  
3. 1. 1  
Pri m ar y E n d p oi nts:  
 
Safet y a n d t olera bilit y of B G B -3 1 1 1:  T he occ urre nce of a d verse e ve nts ( A Es) a n d s eri o us a d verse e ve nts 
( S A Es) of eac h s u bj ect will be m o nit ore d acc or di n g t o N CI-C T C A E 4. 0 3 gra di n g criteria d uri n g t he w h ole 
st u d y a n d t he safet y of B G B-3 1 1 1 re gi me n will be e val uate d.  
3. 1. 2  
Sec o n d ar y E n d p oi nts:  
 
P har mac o ki netic para meters:  
P K para meters f or si n gle d ose: A U C last、A U C 0 -∞、C ma x 、tma x 、t1/ 2、C L/ F 、V d/ F  
P K para meters f or stea d y stat us after m ulti ple d oses: A U C ss、C ma x,ss 、tma x,ss  
 
T he i n hi bit or y effect of B G B -3 1 1 1 o n B T K acti vit y i n peri p heral bl o o d m o n o n uclear cells will be assesse d b y 
meas uri n g t he pr o p orti o n of B T K occ u pie d i n peri p heral bl o o d m o n o n uclear cells.  
3. 1. 3  
E x pl or at or y E n d p oi nts:  
 
 
 
3. 2  
P art II : D ose Ex p a nsi o n  
3. 2. 1  
Pri m ar y E n d p oi nts:  
 
O verall res p o nse rate ( O R R), c o m plete res p o nse rate ( C R R), partial res p o nse rate ( P R R), d urati o n of res p o nse 
( D O R) a n d pr o gressi o n free s ur vi val ( P F S) of B G B-3 1 1 1 i n s u bj ects wit h f ollic ular l y m p h o ma ( F L) a n d  
mar gi nal z o ne l y m p h o ma ( M Z L) . 
3. 2. 2  
Sec o n d ar y E n d p oi nts:  
 
Safet y a n d t olera bilit y of B G B -3 1 1 1 i n F L a n d M Z L: T he occ urre nce of a d verse e ve nts ( A Es) a n d seri o us 
a d verse e ve nts ( S A Es) of eac h s u bj ect will be m o nit ore d acc or di n g t o N CI -C T C A E 4. 0 3.  
 
P har mac o ki netic para meters:  
  
P K para meters f or si n gle d ose: A U C last、A U C 0 -∞、C ma x 、tma x 、t1/ 2、C L/ F 、V d/ F  
  
P K para meters f or stea d y stat us after m ulti ple d oses: A U C ss、C ma x,ss 、tma x,ss a n d ot her a p plica ble para meters.  
3. 2. 3  
E x pl or at or y E n d p oi nts:  
 
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 6  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
4  
S T U D Y D E SI G N  
4. 1  
O ver all D esi g n 
T his st u d y is t o i n vesti gate t he d ose safet y, t olera bilit y, p har mac o ki netics a n d p har ma c o d y na mics of B G B -3 1 1 1 i n 
C hi nese patie nts wit h B -cell l y m p h o ma, a n d t o deter mi ne t he R P 2 D, base d o n t he m ulti -d ose, d ose escalati o n p hase I 
trials w hic h has c o m plete d in A ustralia a n d Ne w Zeala n d . Base d o n t he res ults t hat will be o btai ne d, d ose e x pa nsi o n 
st u dies will be perf or me d aft er war ds i n patie nts wit h i n d ole nt l y m p h o ma, i ncl u di n g f ollic ular l y m p h o ma ( F L) a n d 
mar gi nal z o ne l y m p h o ma ( M Z L).  
T he st u d y was c o n d ucte d i n  t w o sta ges, t he first sta ge bei n g t he safet y assess me nt of d ose, a n d t he sec o n d sta ge bei n g 
t he d ose e xpa nsi o n.  
P art I : S afet y e v al u ati o n  
Acc or di n g t o t he res ults of precli nical t o xic ol o gical trials a n d t he res ults of t he p hase I cli nical st u d y c o n d ucte d  i n 
A ustralia a n d Ne w Zeala n d, t w o re gi me ns of B G B -3 1 1 1 3 2 0 m g dail y ( 1 6 0 m g BI D, a d mi nistere d i n t he m or ni n g a n d at 
ni g ht, or 3 2 0 m g Q D) a n d “ 3 + 3 ” desi g n is a d o pte d f or t he assess me nt. T hree eli gi ble s u bj ects will be e nr olle d f or eac h 
d ose re gi me n: first,  if 1/ 3 ( 1 case) patie nts e x perie nce d ose-li miti n g t o xicit y ( D L T), a n ot her 3 s u bj ects will be e nr olle d 
f or c o nti n ue d o bser vati o n. Ac c or di n g t o t he preli mi nar y res ults of t he cli nical st u d y i n A ustralia a n d Ne w Zeala n d, t w o 
re gi me ns of B G B-3 1 1 1 3 2 0 m g d ose gr o u p are b ot h safe a n d t olera ble. If n o ne of t he first 3 e nr olle d patie nts 
e x perie nces D L T or o nl y o ne patie nt a m o n g t he 6 patie nts (i ncl u di n g t he s u p ple me nte d 3 patie nts) e x perie nce D L T, 
t he n it is pres u me d t hat t he d ose of B G B-3 1 1 1 ( 1 6 0 m g BI D a n d/ or 3 2 0 m g Q D) is safe a n d t olera ble. Ne xt eac h d ose 
gr o u p will recr uit ne w patie nts u ntil a b o ut 1 0 patie nts per gr o u p (i ncl u di n g t he patie nts e nr olle d pre vi o usl y) t o f urt her 
assess t he safet y, t olera bilit y, p har mac o ki netics a n d preli mi nar y p har mac o d y na mics of B G B -3 1 1 1.  
If m ore t ha n t w o (i ncl usi ve) fr o m 3 s u bj ects or 6 s u bj ects (i ncl u di n g t he s u p ple me nte d 3 patie nts) e x perie nce D L T 
wit hi n t he D L T o bser vati o n wi n d o w ( Da y 1 -2 8), i t will be c o ncl u de d t hat t he d ose of B G B-3 1 1 1 ( 1 6 0 m g BI D a n d/ or 
3 2 0 m g Q D) has e xcee d e d t he ma xi m u m t olerate d d ose ( M T D) a n d d ose s h o ul d be ta pere d d o w n t o 8 0 m g BI D or 1 6 0 
m g Q D. T hree eli gi ble patie nts will be e nr olle d i nt o eac h ne w d ose gr o u p f or re -assess me nt. If 8 0 m g BI D or 1 6 0 m g 
Q D is safe, t he s p o ns or a n d i n vesti gat or will a nal yze  a n d disc uss w het he r t o m o ve f or war d wit h a n i nter mediate d ose 
gr o u p ( 1 2 0 m g BI D or 2 4 0 m g Q D) acc or di n g t o t he a vaila ble safet y data a n d P K data. If neit her 1 6 0 m g Q D a n d/ or 8 0 
m g BI D is t olera ble, t he trial will b e ter mi nate d.  
D uri n g t he trial, t he s p o n s or, lea di n g i nvesti gat or a n d i n vesti gat ors will esta blis h a safet y m o nit ori n g c o m mittee ( S M C) 
f or o n g oi n g safet y assess me nt. S M C will deci de t he d ose le vel a n d re gi me n f or ne xt gr o u p or if e nr oll m ore eli gi ble 
patie nts  or a d d u nsc he d ule d d ose(s) i nt o st u d y , base d o n t he efficac y data fr o m t he f or mer d ose le vel, a n d deci de t he 
R P 2 D.  
F or t he BI D gr o u p, t he s u bj ect will recei ve o nl y t he m or ni n g d ose ( half of t he dail y d ose) o n Da y 1 of t he st u d y f or t he 
2 4 -h o ur P K e val uati o n. Fr o m t he ne xt da y, a d mi nistrati o n will be s hifte d t o o nce i n t he m or ni n g a n d e ve ni n g 
res pecti vel y wit h a n i nter val of 1 2 h o urs ± 2 h o urs. It is str o n gl y rec o m me n de d t o ta ke t he me dici ne at t he sa me ti me 
e ver y da y.  
T he t o xicit y o bser vati o n peri o d of B G B -3 1 1 1 is 2 8 da ys ( D a y 1-2 8) a n d treat me nt o bser vati o n peri o d is fr o m da y 2 9 t o 
t hree years. A s u bj ect will be c o nsi dere d e n d of st u d y if he/s he s h o ws disease pr o gressi o n, i nt olera nce t o t o xicit y, deat h, 
wit h dra wal fr o m t he st u d y, l ost t o f oll o w -u p, st u d y t er mi nati o n b y t he s p o ns or, or ha vi n g c o m plete d all 3 years of 
treat me nt, w hic he ver occ urs first. If a s u bj ect is j u d ge d t o still ha ve cli nical be nefit b y t he i n vesti gat or at t he e n d of 3-
year treat me nt, he/s he ma y be tra nsferre d t o t he e xte nsi o n st u d y t o c o nti n ue B G B -3 1 1 1 treat me nt u ntil disease 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 7  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
pr o gressi o n , i nt olera nce, deat h, or wit h dra wal fr o m st u d y, u n der t he a p pr o val b y t he s p o ns or’s me dical m o nit or.  
T he first s u bj ect ( o ut p ost s u bj ects) i n eac h d ose gr o u p will be h os pitalize d a n d kee p u n der o bser vati o n f or 2 4 h o urs after 
recei vi n g t he first si ngle d ose a d mi nistrati o n a n d will  be n ot all o we d t o c o nti n ue e nr oll me nt wit hi n t his 2 4 -h o ur 
h os pitalizati o n, s o as t o a v oi d  t he occ urre nce of acci de nce or ac ute t o xicit y. Acc or di n g t o t he safet y data of t he P art I  
a n d t he res ults of t he gl o bal P has e I cli nical trial, 1 6 0 m g of BI D has bee n i de ntifie d as t he R P 2 D.  
If a s u bj ect is j u d ge d t o still ha ve cli nical be nefit b y t he i n vesti gat or at t he e n d of 3-year treat me nt, he/s he ma y be 
tra nsferre d t o t he e xte nsi o n st u d y t o c o nti n ue B G B-3 1 1 1 treat me nt u ntil disease pr o gress, i nt olera nce, deat h, or 
wit h dra wal fr o m st u d y, u n der t he a p pr o val b y t he s p o ns or’s me dical m o nit or.  
P art II : D ose e x p a nsi o n  
T o f urt her e val uate t he preli mi nar y a nti -t u m or effects of B G B-3 1 1 1  i n C hi nese s u bj ects wit h f ollic ular l y m p h o ma ( F L) 
or mar gi nal z o ne l y m p h o ma ( M Z L) , a p pr o xi matel y 2 0 s u bj ects wit h rela pse d or refract or y f ollic ular l y m p h o ma ( F L) or 
mar gi nal z o ne l y m p h o ma ( M Z L) will be e nr olle d. T he R P 2 D deter mi ne d i n P art I , i.e. 1 6 0 m g BI D, will be use d i n t he 
P art II . 
T o e val uate t he preli mi nar y efficac y wit h o ut  har mi n g s u bj ect’s be nefit , t he a nti-t u m or acti vit y assess me nt will be 
c o n d ucte d e ver y 1 2 wee ks (c o n d ucte d a p pr o xi mate e ver y 2 4 wee ks 1 year later) after first d ose. S u bj ec ts w h o d o n ot 
e x perie nce disease pr o gressi o n ma y c o nti n ue treat me nt u ntil i nt olera ble t o t o xicit y, deat h, pr o gressi o n of t he disease, 
wit h dra wal of i nf or me d c o nse nt, or disc o nti n ui n g treat me nt  b y t he i n vesti gat or w he n t he ris k i s greater t ha n t he be nefit. 
If a s u bj ect is j u d ge d t o still ha ve cli nical be nefit b y t he i n vesti gat or at t he e n d of 3-year treat me nt, he/s he ma y be 
tra nsferre d t o t he e xte nsi o n st u d y t o c o nti n ue B G B-3 1 1 1 treat me nt u ntil disease pr o gress i o n, i nt olera nce, deat h, or 
wit h dra wal fr o m st u d y.  
4. 2  
D ose Li mit i n g T o xicit y ( D L T)  
T he D L T e val uati o n peri o d i s defi ne d as fr o m t he first use of B G B-3 1 1 1 t o t he da y 2 8 after a d mi nistrati o n.  
All t o xicit y a n d a d verse e ve nts will be assesse d acc or di n g t o t he N CI C T C A E V 4. 0 3 2 gra di n g criteri a, a n d t he f oll o wi n g 
e ve nts will be  defi ne d as D L T:  
D ose Restricti o n T o xicit y ( D L T) refers t o a dr u g -relate d t o xi cit y or a d verse e ve nt t hat occ urs d uri n g t he treat me nt of t he 
D L T e val uati o n peri o d ( da ys 1 -2 8) a n d meets t he f oll o wi n g criteria a n d d oes n ot i ncl u de a n e ve nt t hat is n ot ass ociate d 
wit h B G B -3 1 1 1 : Disease pr o gressi o n, u n derl yi n g disease, c o nc urre nt disease or c o nc o mita nt treat me nt). 
- 
Gra d e 4 ne utr o pe nia s ustai ne d f or m ore t ha n 7 da ys (i n t he c o n diti o n of recei vi n g gr o wt h fact ors) or ≥ gra d e 3 
fe brile ne utr o pe nia ( ≥3 8. 3° C or c o nti n u o us fe ver of ≥3 8. 0° C lasti n g f or m ore t ha n 1 h o ur).  
- 
Gra d e 4 t hr o m b oc yt o pe nia or ≥ gra d e 3 t hr o m b oc yt o pe nia ass ociate d wit h blee di n g.  
- 
Ot her gra d e ≥2 n o n -he mat ol o gical t o xicit y w hic h nee d d os e a dj ust me nt of B G B -3 1 1 1 or a d mi nistrati o n dela y o ver 
1 wee k.   
- 
Ot her gra d e ≥3 dr u g -relate d n o n -he mat ol o gical t o xicit y (e xcl u di n g of as y m pt o matic a b n or mal la b orat or y res ults 
wit h n o cli nical si g nifica nce a n d n o n -he mat ol o gical t o xicit y w hic h ha s rec o vere d t o gra de ≤2 wit hi n 7 da ys) . 
- 
A n y de gree of t o xicit y re q uiri n g wit h dra wal fr o m st u d y as per i n vesti gat or or s p o ns or’s j u d ge me nt.  
 
W he n D L T occ urs , bl o o d sa m ple ( 4 m L) s h o ul d be c ollecte d as s o o n as p ossi ble t o a nal yz e plas ma c o nce ntrati o n of 
B G B -3 1 1 1. If D L T t o xicit y has rec o vere d t o Gra de ≤ 1 wit hi n 1 4 da ys after D L T has bee n treate d a n d treat me nt 
i nterr u pti o n or dela y is ≤ 2 8 da ys, t he B G B -3 1 1 1 treat me nt ca n be res u me d at 5 0 % of d ose . W he n ot her dr u g -
relate d seri o us a d verse reacti o ns occ ur, if t he i n vesti gat or a n d t he s p o ns or’s me dical m o nit or  c o nsi der it necessar y, 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 8  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
bl o o d sa m ple  ( 4 m L) s h o ul d be c ollecte d as s o o n as p ossi ble t o a nal yze t he mec ha nis m of t he e ve nt.  
If a s u bj ect disc o nti n ues treat me nt i n t he e val uati o n wi n d o w of t he D L T n ot d ue t o dr u g-relate d t o xicit y a n d has 
recei ve d less t ha n 7 5 % of t he defi ne d d ose, t he s u bj ect will be e xcl u de d fr o m t he D L T e val uati o n a n d s h o ul d be 
re place d b y a ne w s u bj ect. 
4. 3  
D ose I nterr u pti o n a n d M o dific ati o n  
I n t he e ve nt of he mat ol o gic t o xicit y ( 4. 3. 1) or n o n-he mat ol o gic t o xicit y ( 4. 3. 2), t he d ose re d ucti o n of B G B -3 1 1 1 as 
s pecifie d i n T a ble 2 s h o ul d be f oll o we d. 
T a ble 2  D ose Re d ucti o n of B G B -3 1 1 1 f or t o xicit y  
D ose Le v el  
B G B -3 1 1 1 D ail y D ose  
0 = starti n g d ose  
3 2 0 m g Q D  
1 6 0 m g BI D  
-1 d ose le vel  
1 6 0 m g Q D  
8 0 m g BI D  
-2 d ose le vel  
8 0 m g Q D  
8 0 m g Q D  
BI D = t wice dail y, Q D = o nce dail y  
B G B -3 1 1 1 treat me nt all o ws u p t o 2 8 da ys of c o nti n u o us i nt err u pti o n. If a s u bj ect, after 2 8 c o nsec uti ve da ys of 
disc o nti n uati o n, is j u d ge d b y t he i n vesti gat or t hat he/s he ca n still be nefit fr o m t he treat me nt of B G B -3 1 1 1, t he 
i n vesti gat or a n d t he s p o ns or's me dical m o nit or s h o ul d disc uss a n d deci de w het her t o c o nti n ue treat me nt; if yes, a writte n 
c o nse nt s hall be iss ue d b y t he s p o ns or’s me dical m o nit or.  
4. 3. 1  
D ose Re d ucti o ns f or He m at ol o gic T o xicit y  
If t he s u bj ect s h o ws t he f oll o wi n g s y m pt o ms, t he treat me nt of B G B-3 1 1 1 will be disc o nti n ue d a n d t he s u bj ect will be 
treate d acc or di n g t o t he cli nic al sit uati o n. 
 
Gra d e 4 ne utr o pe nia (s ustai ne d  > 7 da ys, disc o nti n ue treat me nt if cli nicall y necessar y ) 
 
Gra d e  4 t hr o m b oc yt o pe nia (s u stai ne d > 7 da ys, disc o nti n ue treat me nt if cli nicall y necessar y ) 
 
Gra d e ≥ 3 fe brile ne utr o pe nia 
 
Gra d e ≥ 3 t hr o m b oc yt o pe nia wit h blee di n g  
 
W he n t he t o xicit y ha s rec o ver e d t o Gra d e 1 or baseli ne, B G B -3 1 1 1 treat me nt ca n be res u me d wit h pri or d ose. If t he 
sa me t o xicit y rec urs, t he treat me nt s h o ul d be res u me d at 5 0 % d ose le vel w he n t he t o xicit y has rec o vere d t o Gra d e ≤1 or 
baseli ne. T he d ose is all o we d t o be re d uce d u p t o t wice.  
If a s u bj ect e x perie nces  Gra d e ≥3 t hr o m b oc yt o pe nia wit h si g nifica nt bleedi n g s y m pt o ms re q uiri n g treat me nt, t he s u bj ect 
nee ds t o disc o nti n ue treat me nt a n d wit h dra w fr o m st u d y. 
T he st u d y dr u g -i n d uce d l y m p h oc yt osis is a n e x pecte d e ve nt a n d ma y occ ur fre q ue ntl y. I n t his st u d y, s u bj ects wit h 
as y m pt o matic, st u d y dr u g -i n d uce d l y m p h ocyt osis , i ncl u di n g t he tri g gere d le u k oc yt osis, c o ul d c o nti n ue t o recei ve st u d y 
dr u g.  
4. 3. 2  
D ose Re d ucti o ns f or N o n -he m at ol o gic T o xicit y  
T he treat me nt of B G B -3 1 1 1 will be disc o nti n ue d if a s u bj ect e x perie nces a Gra de ≥3 dr u g -r elate d n o n-he mat ol o gic 
t o xicit y (e xce pt arr h yt h mia or oral me dicati o n c o ntr olla ble h y perte nsi o n ). T he B G B-3 1 1 1  treat me nt ca n be  res u me d 
w he n t he t o xicit y ha s rec o vere d t o  Gra de 1 , b ut it s h o ul d st art fr o m -1 d ose  le vel (i.e. re d uce b y 5 0% ). If t he sa me 
t o xicit y rec urs at Gra d e ≥3, it is necessar y t o disc o nti n ue B G B -3 1 1 1 treat me nt u ntil it has rec o vere d t o  Gra de 1 , t he n 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2   
 
2 9  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a
 
 
 
 
start fr o m -2 d ose le vel . If t he sa me t o xicit y rec urs e ve n at Gra de ≥3 at -2 d ose le vel , t his s u bj ect s h o ul d disc o nti n ue 
treat me nt p er ma ne ntl y a n d wit h dra w fr o m st u d y. If a s u bj ect e x perie nes ma na ga ble  arr h yt h mia , t he B G B-3 1 1 1 
treat me nt ma y be c o nti n ue d as ori gi nal d ose or at a d ose of 5 0 % w he n t he t o xicit y has rec o vered t o  Gra de 1 , 
de p e n di n g o n  t he decisi o n of t he i n vesti gat or. 
Ot her s pecial circ u msta nces s hall be disc usse d  a n d deci de d bet wee n i n vesti gat or a n d me di cal m o nit or . 
F or st u d y assess me nts sc he d ul e, a n d p har mac o ki netic a n d p har mac o d y na mic sa m pli n g, please r efer t o sta ble 3, ta ble 4, 
a n d ta ble 5 . 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
3 2  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a  
 
deter mi ne w het her M RI is t o be use d i nstea d of C T, or w het her P E T -C T is t o be per f or me d d uri n g scree ni n g. F or s u bj ects wit h p ositi ve P E T-C T 
d uri n g scree ni n g, it is re q uire d t o c o n d uct re -e xa mi nati o n w he n c o nfir mi n g C R. F or t he earl y ter mi nati o n visit, C T sca n is re q uire d if t he pre vi o us 
sca n was perf or me d m ore t ha n 3 m o nt hs a g o.   
1 0.  All s u bj ects nee d t o perf or m b o ne marr o w e xa mi nati o n (i ncl u di n g s mear a n d bi o ps y) d uri n g t he scree ni n g peri o d. If b o ne marr o w e xa mi nati o n was 
perf or me d 3 0 da ys bef ore scre e ni n g, it d oes n ot nee d t o re peat a n d t he res ults c o ul d be use d f or scree ni n g. F or s u bj ec ts wit h W al de nstr o m's 
macr o gl o b uli ne mia, a b o ne marr o w test s h o ul d be perf or me d e ver y 2 4 wee ks. S u bj ects w h o ha ve bee n dia g n ose d wit h b o ne marr o w l esi o ns at t he 
ti me of e nr oll me nt ma y nee d t o u n der g o f urt her b o ne marr o w as pirati o n a n d bi o ps y t o c o nfir m C R if t his case is j u d ge d t o be p ossi ble C R b y p h ysical 
e xa mi nati o n or C T sca n.  
1 1.  He mat ol o g y i ncl u des R B C c o u nt, he m o gl o bi n, he mat ocrit, retic ul oc yte c o u nt ( o pti o nal), 
W B C c o u nt, a bs ol ute differe ntial c o u nt 
( ne utr o p hils, 
e osi n o p hils, l y m p h oc ytes, m o n oc ytes, ba s o p hils, blasts) a n d platelet c o u nt. I n t he e ve nt of ne utr o pe nia (a bs ol ute ne utr o p hil c o u nt < 1 0 0 0/ m m 3) or 
t hr o m b oc yt o pe nia ( platelet c o u nt < 5 0, 0 0 0/ m m3), or Gra de ≥ 3 t o xicit y, t he test ma y ne e d t o re p eat at a n y ti me base d o n d oct or’s j u d ge me nt, u ntil 
t o xicit y res ol ves t o Gra d e ≤ 2. T he he mat ol o gical test of W 1 D 1 is all o we d t o ta ke place wit hi n 4 8 h o urs pri or t o a d mi nistratio n.  
1 2.  Cli nical c he mistr y i ncl u des p otassi u m, s o di u m, c hl ori de, calci u m, p h os p h or us, ma g nesi u m, C O 2, t otal pr otei n( T P), al b u mi n( A L B), bl o o d gl uc ose, 
urea 
nitr o ge n, 
creati ni ne, 
al kali ne 
p h os p hatase( A L P), lactic 
de h y dr o ge nase( L D H), t otal 
bilir u bi n( BI L), 
direct 
bilir u bi n, 
as pa rtate 
a mi n otra nsferase( A S T), ala ni ne a mi n otra nsferase( A L T) a n d uric aci d. I n t he e ve nt of Gra de ≥3 cli nical c he mistr y t o xi cit y, t he test ma y nee d t o re p eat 
at a n y ti me base d o n d oct or’s j u d ge me nt, u ntil t o xicit y res ol ves t o Gra de ≤ 2. T he cli nical c he mistr y test of W 1 D 1 is all o we d  t o ta ke place wit hi n 4 8 
h o urs pri or t o a d mi nistrati o n.  
1 3.  All patie nts wit h W al de nstr o m macr o gl o b uli ne mia will u n der g o a first i m m u n ofi xati o n electr o p h oresis test at t he ti me of scree ni n g. If m o n ocl o nal 
pr otei ns are f o u n d, t his test ne e d t o re peat at f oll o w -u p.  
1 4.  All w o me n of c hil d beari n g p ote ntial (i ncl u di n g t h ose w h o ha ve ha d a t u bal li gati o n) wil l ha ve a ser u m pre g na nc y test at scree ni n g. Uri ne pre g na nc y 
tests will b e perf or me d at s pecifie d s u bse q ue nt visits. If a uri ne pre g na nc y test is p ositi ve, it m ust be c o nfir me d b y a ser um pre g na nc y test.  
1 5.  T he vir us ser ol o g y i ncl u des he p atitis B s urface a nti g e n ( H Bs A g), he patitis B s urface a nti b o d y (a nti -H Bs) a n d he p atitis B c ore a nti b o d y (a nti -H B c); 
he p atitis C a nti b o d y a n d AI D S vir us.  
1 6.  If uri ne pr otei n ≥2 + i n uri nal micr osc o pic e xa mi nati o n, t he 2 4-h uri ne sa m ple s h o ul d be c ollecte d t o test t he 2 4 h t otal uri ne  pr otei n ( Refer t o Secti o n 
8. 2. 1 assess me nt at la b orat or y of st u d y ce nter f or details). 
1 7.  T he details of t he ti me p oi nts of t he c o nti n u o us p har mac o ki netics sa m pli n g detail i n T a ble 4 a n d T a ble 5.  
1 8.  T he p har mac o d y na mics bl o o d sa m pli n g  is o nl y f or s u bj ects of P art I, a n d t he ti me p oi nts f or c ollecti o n detail i n T a ble 4.  
1 9.  P atie nts wit h diff use lar ge B cell l y m p h o ma m ust  pr o vi de arc hi ve t u m or tiss ues or fres h t u m or bi o ps y t o c o nfir m D L B C L s u bt y pe. S u bj ects wit h F L 
or M Z L m ust  pr o vi de rece nt arc hi ve tiss ue f or t he bi o mar ker a nal ysis. If n o t u m or s peci me ns are a vaila ble, nee dle -bi o ps y of l y m p h n o des w hic h is 
s y m pt o matic d uri n g t he scree ni n g peri o d a n d ca n be sa m pl e d, ma y be c o nsi dere d. F or s u bj ects wit h F L or M Z L w h o ha ve bee n e nr olle d u n der t he 
pr ot oc ol versi o n 1. 0, t he arc hi ve tiss ue or fres h t u m or bi o ps y s h o ul d be c ollecte d after t he ne w I C F is si g ne d.  
2 0.  F or s u bj ect wit h disease pr o gressi o n, bl o o d sa m ple or ot her relate d sa m ple ( b o ne marr o w or l y m p h n o de) s h o ul d be c ollect e d  t o a nal yze dr u g 
resista nce after ha vi n g  o btai n e d  s u bj ect’s c o nse nt.  
2 1.  After t he fi nal visit, t he s ur vi val f oll o w -u p will be c o n d ucte d e ver y 3 m o nt hs u ntil wit h dr a wal of c o nse nt, l oss t o f oll o w -u p, deat h, or t he c ut -off dat e 
of fi nal data a nal ysis. I n vesti gat or s or t heir a ut h orize d pers o n nel will als o c o nti n ue t o c oll ect i nf or mati o n o n t he use of ne w a nti -ca ncer t hera pies gi ve n 
after t he last d ose of t he st u d y dr u g.  
 
 
 
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
3 3  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a  
 
T a ble 4  
P h ar m ac o ki netic a n d P h ar m ac o d y n a mic S a m pli n g i n t he P art I . 
Pr o ce d ure  
W 1  
D 1  
W 1 
D 2  
W 2  
D 1  
W 5  
D 1  
W 9  
D 1  
H o urs  
Pre - 
d ose  
0. 5  
1  
2  
3  
4  
8  
1 2  
2 4 1  
Pre - 
d ose  
0. 5  
1  
2  
3  
4  
8  
Pre - 
d ose  
Pre -d ose  
E C G e xa mi n ati o n  
X 5 
 
X 2 
X 3 
X 3 
X 3 
X 4 
X 4 
X 5 
X 5 
 
X 2 
X 3 
X 3 
X 3 
X 3 
X 5 
X 5 
Vital si g ns  
X 5 
X 2 
X 2 
X 3 
X 3 
X 3 
X 4 
X 4 
X 5 
X 5 
X 2 
X 2 
X 3 
X 3 
X 3 
X 3 
X 5 
X 5 
P har mac o ki netic 
bl o o d 
sa m pli n g 
X 5 
X 2 
X 2 
X 3 
X 3 
X 3 
X 4 
X 4 
X 5 
X 5 
X 2 
X 2 
X 3 
X 3 
X 3 
X 3 
X 5 
X 5 
P har mac o d y na mic 
bl o o d sa m pli n g  
X 5 
 
 
 
 
X 3 
 
 
X 5 
X 5 
 
 
 
 
 
 
 
 
N ote: It is i m p orta nt t hat t he p har mac o ki netics ( P K) a n d p har mac o d y na mics ( P D) sa m pli n g ti mes s h o ul d be c o nsiste nt wit h t heir  sc he d ule d ti me. T o ac hie ve t his, 
ot her assess me nt ite ms at t he sa me ti me are all o we d t o be a d va nce d or dela ye d s o t hat  t here is s ufficie nt ti me t o c o m plete t he P K / P D bl o o d sa m pli n g.  T h us, a n 
o perati o n or der as f oll o ws is r ec o m me n de d: 1) E C G (i n tri plicate at eac h P K bl o o d p oi ntse xce pt 0. 5 h o urs) ), 2) meas ur e me nt of vital si g ns, 3) P K / P D  bl o o d 
sa m pli n g (at t he precise sc he d ule d ti me as far as p ossi ble), 4) ot her tests / assess me nts.  
1.  O n W 1 D 2, bef ore t he m or ni n g d ose.  
2.  T he wi n d o w peri o d is ± 1 0 mi n utes.  
3.  T he wi n d o w peri o d is ± 2 0 mi n utes.  
4.  T he wi n d o w peri o d is ± 3 0 mi n utes.  
5.  Wit hi n 2 h o urs pri or t o d osi n g.  
 
 
 
 
 
 
 
 
 
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
3 4  
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C o n f i d e n t i a  
 
 
 
T a ble 5  
P h ar m ac o ki netic S a m pli n g i n t he P art II . 
Pr o ce d ure  
W 1  
D 1  
W 1  
D 2  
W 2  
D 1  
W 5  
D 1  
W 9  
D 1  
H o urs  
Pre -d ose  
0. 5  
1  
2  
3  
4  
6  
8  
1 2  
2 4 1 
Pre -d ose  
0. 5  
1  
2  
3  
4  
6  
8  
1 2  
Pre -  d ose  
Pre -d ose  
E C G 
e xa mi nati o n  
X 5 
 
 
X 
3 
 
 
 
 
 
 
X 5 
 
 
X 
3 
 
 
 
 
 
X 5 
X 5 
Vital si g ns  
X 5 
X 2 
X 
2 
X 
3 
X 
3 
X 
3 
X 
4 
X 
4 
X 4 
X 5 
X 5 
X 2 
X 
2 
X 
3 
X 
3 
X 
3 
X 
3 
X 
4 
X 4 
X 5 
X 5 
P har mac o ki netic 
bl o o d sa m pli n g  
X 5 
X 2 
X 
2 
X 
3 
X 
3 
X 
3 
X 
4 
X 
4 
X 4 
X 5 
X 5 
X 2 
X 
2 
X 
3 
X 
3 
X 
3 
X 
3 
X 
4 
X 4 
X 5 
X 5 
N ote: It is i m p orta nt t hat t he p har mac o ki netics ( P K) sa m pli n g ti mes s h o ul d be c o nsiste nt wit h t heir sc he d ule d ti me. T o ac hie ve t his, ot her assess me nt it e ms at t he 
sa me ti me are all o we d t o be a d va nce d or dela ye d s o t hat t here is s ufficie nt ti me t o c o m plete t he P K  bl o o d sa m pli n g.  T h us, a n o perati o n or der as f oll o ws is 
rec om me n de d: 1) E C G (i n tri plicate at eac h P K bl o o d p oi nts,), 2) meas ure me nt of vital si g ns, 3) P K bl o o d sa m pli n g (at t he precise  sc he d ule d ti me as far as 
p ossi ble), 4) ot her tests / assess me nts.  
1.  O n W 1 D 2, bef ore t he m or ni n g d ose.  
2.  T he wi n d o w peri o d is ± 1 0 mi n ut es.  
3.  T he wi n d o w peri o d is ± 2 0 mi n utes.  
4.  T he wi n d o w peri o d is ± 3 0 mi n utes.  
5.  Wit hi n 2 h o urs pri or t o d osi n g.  
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol            Bei Ge ne （Beiji n g ）C o. , Lt d               Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
 
 
 
3 5  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a  
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 bj ects are eli gi ble f or i ncl usi o n i n t he st u d y if t he y meet all of t he f oll o wi n g criteria:  
 
Me n a n d w o me n wit h t he a ge of 1 8 -7 5  years, v ol u ntaril y c o nse nte d t o t he st u d y.  
 
P art I : S u bj ects wit h B-cell l y m p h o ma ( defi ne d b y W H O cl assificati o n) refract or y or rela pse d f oll o wi n g at least 
o ne li ne of t hera p y, i ncl u di n g c hr o nic l y m p h oc ytic le u ke mia/ s mall l y m p h oc ytic l y m p h o ma ( C L L/ S L L), m a ntle 
cell l y m p h o ma ( M C L), W al de nstr ö m's macr o gl o b uli ne mia/ l y m p h o plas mac ytic l y m p h o ma ( W M/ L P L), f ollic ular 
l y m p h o ma ( F L), mar gi nal z o ne l y m p h o ma ( M Z L), hair y cell le u ke mia a n d n o n-ger mi nal c e nter diff use lar ge B cell 
l y m p h o ma ( D L B C L). P art II : S u bj ects wit h F L or M Z L w hi c h is refract or y or rela pse d f oll o wi n g at least o ne li ne 
of t hera p y. S u bj ects i n P art II  m ust  pr o vi de rece nt arc h i ve t u m or s peci me n or perf or m t u m or bi o ps y. 
 
J u d ge d b y t he i n vesti gat or as re q uiri n g treat me nt.  
 
E C O G perf or ma nce stat us of 0 -1.  
 
Life e x pecta nc y of at least 4 m o nt hs.  
 
A de q uate he mat ol o gical f u ncti o n, defi ne d b y ne utr o p hils ≥ 1. 0 x 1 0 9/ L, he m o gl o bi n ≥7 0 g/ L a n d platelets ≥ 5 0 x 
1 0 9/ L if b o ne marr o w i n v ol ve d; o r  platelets ≥ 7 0 x 1 0 9/ L if n o b o ne marr o w i n v ol ve d.. 
 
A de q uate re nal f u ncti o n, defi ne d b y creati ni ne cleara nce of ≥ 3 0 ml/ mi n (as esti mate d b y t he C oc kcr oft-Ga ult 
e q uati o n or C K D -E PI e q uati o n, or as meas ure d b y n uclear me dici ne sca n or 2 4 h o ur uri ne e val uati o n).  
 
A de q uate li ver f u ncti o n, defi ne d b y A S T a n d A L T ≤ 2. 5 x U L N, a n d bilir u bi n ≤ 1. 5 x U L N ( u nless d oc u me nte d 
Gil bert’s s y n dr o me).  
 
C oa g ulati o n f u ncti o n: I N R a n d A P T T ≤ 1. 5 x U L N.  
 
Fe male s u bj ects of c hil d beari n g p ote ntial a n d n o n -sterile mal es m ust practice at least o ne of t he f oll o wi n g met h o ds 
of birt h c o ntr ol wit h part ner(s) t hr o u g h o ut t he st u d y a n d f or 9 0 da ys after disc o nti n ui n g st u d y dr u g: t otal 
a bsti ne nce fr o m se x ual i nterc o urse, d o u ble -barrier c o ntrace pti o n, I U D or h or m o nal c o ntrac e pti ve i nitiate d at least 
3 m o nt hs pri or t o first d ose of st u d y dr u g.  
 
Male s u bj ec ts m ust n ot d o nate s per m fr o m start of st u d y dr u g a d mi nistrati o n, u ntil 9 0 da ys after disc o nti n uati o n of 
treat me nt. 
5. 2  
E xcl usi o n Criteri a  
S u bj ects are t o be e xcl u de d fr o m t he st u d y if t he y meet a n y of t he f oll o wi n g criteria:  
 
Wit h C N S i n v ol ve me nt of t he disea se. 
 
 T he pat h ol o gical t y pe of t he disease has D isease tra nsf or mati o n. 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
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 
Has u n der d o ne all o ge neic he mat o p oietic ste m cell tra ns pla ntati o n.  
 
Has recei ve d c ortic oster oi d a nti -ne o plastic treat me nt ( > 1 0  m g dail y pre d nis o ne e q ui vale nts) wit hi n 7 da ys bef ore 
t he first d ose of B G B-3 1 1 1, has recei ve d ra di ot hera p y a n d c he m ot hera p y wit hi n 4 wee ks b ef ore t he first d ose of 
B G B -3 1 1 1 or has recei ve d treat me nt wit h m o n ocl o nal a nti b o d y wit hi n 4 wee ks bef ore t he first d ose of B G B -3 1 1 1.  
 
Has recei ve d B T K i n hi bit or treat me nt pr i or t o e nr oll me nt. 
 
Has recei ve d c he m ot hera p y a n d has n ot yet rec o vere d fr o m t o xicit y ( ≤ gra de 1 acc or di n g t o N CI -C T C A E 4. 0 3).  
 
Has recei ve d C hi nese her bal me dici ne as a nti -ne o plastic t hera p y wit hi n 4 wee ks bef ore st arti n g st u d y treat me nt.  
 
Hist or y of ot her m ali g na ncies wit hi n 2 years bef ore  st u d y e ntr y, wit h e xce pti o n of ( 1) a de q uatel y c ure d i n -sit u 
carci n o ma of cer vi x; ( 2) l ocall y basal or s q ua m o us cell s ki n ca ncer; ( 3) l ocal mali g na nc y w hic h has u n der g o ne 
ra dical treat me nt (s ur ger y or ot her m o dalit y). 
 
Wit h u nc o ntr olle d s yste mic i nfecti o n.  
 
Maj or s ur ger y i n t he past 4 we e ks.  
 
Wit h k n o w n HI V, or acti ve he patitis B or he patitis C vir us i nfecti o n.  
 
Wit h car di o vasc ular disease of Ne w Y or k Heart Ass ociati o n ( N Y H A) Classificati o n ≥ 3.  
 
Q T c > 4 5 0 msecs ( defi ne d as a Q T c F > 4 5 0 msecs base d o n t he Fre dericia’s f or m ula) or ot her si g nifica nt E C G 
a b n or malities i ncl u di n g 2 n d d e gree A V bl oc k t y pe II, 3r d de gree A V bl oc k, or bra d ycar dia ( ve ntric ular rate less 
t ha n 5 0 beats/ mi n). 
 
Si g nifica nt acti ve re nal, ne ur ol o gic, ps yc hiatric,  he patic or e n d ocri n ol o gic disease t hat i n t he i n vesti gat or’s o pi ni o n 
w o ul d a d versel y i m pact o n his/ her partici pati o n i n t he st u d y.  
 
I na bilit y t o c o m pl y wit h st u d y pr oce d ures. 
 
C urre ntl y ta ki n g a ntic oa g ula nt dr u gs.  
 
C urre ntl y ta ki n g p ote nt C Y P 3 A i n hi bit or or i n d ucer (refer t o Secti o n 7. 2  f or details). 
 
Ha d str o ke or cere bral he m orr ha ge wit hi n 6 m o nt hs bef ore e nr oll me nt.  
5. 3  
Ot her C o nsi der ati o n f or eli gi bilit y  
A n y p ote ntial or safet y i m pact o n t he s u bj ect nee ds t o be a de q uatel y a d dresse d, a n d t he i n vesti gat or m ust refer t o t he 
I C F f or detaile d i nf or mati o n, preca uti o ns, war ni n gs, c o ntrai n dicati o ns, a d verse e ve nts, a n d i m p orta nt data fr o m t his 
st u d y or ot her st u dies w hic h use d t his pr o d uct.   
5. 4  
Restricti o ns of S u bjects  
T he f oll o wi n g restricti o ns ma y ha ve a n effect o n t he res ults of t his st u d y: 
 
Fr o m t he scree ni n g gr o u p t o t he e n d of t he st u d y, t he s u bj ect s h o ul d i nf or m t he i n vesti gat or as s o o n as p ossi ble if 
usi n g a n y dr u g.  

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 
I n t he c o urse of t he st u d y, s u bj ects s h o ul d be faste d e xce pt dri n ki n g water i n 2 h o urs bef or e a d mi nistrati o n a n d 1 
h o ur after a d mi nistrati o n; t he st u d y pr o hi bits t he c o ns u m pti o n of a n y gra pefr uit j uice, cara m b ola, or p o me gra nate 
j uice of f o o d or dri n k, ot her diet is n ot li mite d. 
5. 5  
C o m pleti o n of St u d y a n d a n d E arl y  W ith dr a w al  
5. 5. 1  
C o m pleti o n of St u d y  
S u bj ects w h o ha ve c o m plete d t he p har mac o ki netic sa m ple c ollecti o n (i ncl u di n g data f or Da y 1 Wee k 2) a n d di d n ot 
wit h dra w fr o m st u d y bef ore c o m pleti o n of t he D L T e val uati o n peri o d (fr o m B G B -3 1 1 1 first a d mi nistrati o n t o 2 8 da ys) 
w ill be dee me d t o c o m plete t he st u d y. T he S u bj ects will c o nti n ue t o recei ve st u d y dr u g u ntil c o m pleti o n of t he t hree-
year treat me nt peri o d, or u ntil disease pr o gressi o n, i nt olera ble t o xicit y or deat h, wit h dra wal of i nf or me d c o nse nt, l oss of 
f oll o w-u p or ter mi nati o n of trial b y s p o ns or, w hic he ver occ urs first. If a s u bj ect still ha ve cli nical be nefits after 
c o m pleti n g t he t hree -year treat me nt, he/s he ca n be tra nsferre d t o t he e xte nsi o n st u d y u n der a p pr o val b y t he me dical 
m o nit or. T he nee d t o st o p t he st u d y tr eat me nt will n ot ca us e t he s u bj ect t o wit h dra w fr o m t he st u d y a ut o maticall y. A 
s u bj ect s h o ul d disc o nti n ue st u d y treat me nt if a n y of t he f oll o wi n g occ urs:  
 
Si g nifica nt d isease pr o gressi o n or rela pse  
 
U nacce pta ble t o xicit y  
 
Pre g na nc y  
 
S u bj ect  ref use f urt her treat me nt 
 
Maj or pr ot oc ol d e viati o n deter mi ne d b y pri mar y i n vesti gat or or s p o ns or  
 
F or safet y reas o ns (s uc h as a d verse e ve nts), t he i n vesti gat or belie ve t hat disc o nti n ui n g treat me nt is i n li ne wit h t he 
best be nefit of t he s u bj ect  
T he reas o ns  f or treat me nt disc o nti n uati o n will be rec or de d i n s o urce d oc u me nt a n d C R F. I n vesti gat or s h o ul d tr y t o 
c o m plete safet y f oll o w u p visit at 3 0 da ys after t he last d ose.  
 
5. 5. 2  
E arl y Wit h dr a w al  
S u bj ects ma y v ol u ntaril y wit h dra w fr o m t he st u d y or be dr o p pe d fr o m it at t he discreti o n of t he i n vesti gat or at a n y ti me.  
I n vesti gat or s h o ul d e val uate f oll o wi n g ite ms wit hi n 7 da ys of st u d y ter mi nati o n: p h ysical e xa mi nati o n, vital si g ns, 1 2 
lea d E C G, E C O G perf or ma nc e, B -s y m pt o ms, E C G, la b orat or y test (c o m plete bl o o d c o u nt, blo o d bi oc he mistr y, 
uri nal ysis, a n d ser u m i m m u n o gl o b uli n), c o nc o mita nt me dicati o n a n d A E assess me nt, w hic h will be rec or de d as basic 
assess me nt b ef ore wit h dra wal. F urt her m ore, if p ossi ble, safet y f oll o w u p s h o ul d be c o n d uct e d wit hi n 3 0 ± 7 da ys after 
t he last d ose a n d t hereafter e ver y 3 m o nt hs f or s ur vi val f oll o w u p.  
S u bj ects w h o wit h dra w fr o m st u d y d ue t o a d verse e ve nt (f or defi niti o n refer t o secti o n 1 0. 1) at a n y ti me m ust b e treate d 
acc or di n g t o pr oce d ures i n secti o n 1 0. 6.  
If a D L T occ urs, 4 m L of bl o o d sa m ple s h o ul d be c ollecte d as s o o n as p ossi ble t o a nal yze t he plas ma c o nce ntrati o n of 
B G B -3 1 1 1. If dr u g relate d S A E occ urs, 4 m L of bl o o d sa m pl e s h o ul d be c ollecte d as s o o n as p ossi ble if re gar de d as 
nee de d b y i n vesti gat or a n d  s p o ns or’s me dical m o nit or. F or s u bj ect wit h disease pr o gressi o n, bl o o d sa m ple or ot her 
relate d sa m ple ( b o ne marr o w or l y m p h n o de) s h o ul d be c ollecte d  t o a nal yze dr u g resista nc e after ha vi n g  o btai n e d  
s u bj ect’s c o nse nt.  
 
A s u bj ect w h o wit h dra w fr o m t he st u d y f or a n y reas o n or wit h dra w t he i nf or me d c o nse nt f or m will n ot be re place d 
u nless he/s he is wit h dra w n d ue t o D L T(s), i n w hic h case t he s p o ns or a n d t he S M C ma y c o nsi der re place me nt.  
5. 5. 3  
Re as o ns f or Wit h dr a w al  
S u bj ects will be  wit h dra w n  fr o m st u d y f or a n y of t he f oll o wi n g: 
 
S u bj ect wit h dra w c o nse nt  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
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 
St u d y of B G B -3 1 1 1 is ter mi nate d b y s p o ns or  
 
L ost t o f oll o w -u p  
If s u bj ect l ost t o f oll o w-u p, i n vesti gat or s h o ul d tr y best t o c o ntact s u bj ect a n d c o nfir m reas o ns f or disc o nti n uati o n 
/ wit h dra wal a nd d oc u me nt t he reas o ns i n s o urce d oc u me nt a n d C R F bef ore wit h dra wal.  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
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C o n f i d e n t i a  
 
6  
S T U D Y T R E A T M E N T    
6. 1  
St u d y Dr u g  
Acc or di n g t o differe nt d oses r ecei ve d b y s u bj ects, B G B -3 1 1 1 f or m ulati o n is 2 0 m g a n d 8 0 m g ca ps ules ( 2 0 m g is bl ue 
o pa q ue 3 # ca ps ules, 8 0 m g is w hite o pa q ue 0 # ca ps ule).  
6. 2  
D os a ge a n d A d mi nistr ati o n  
T he i nitial d ose of B G B -3 1 1 1 a d mi nistrati o n is 3 2 0 m g dail y ( 3 2 0 m g Q D or 1 6 0 m g BI D). F or t he BI D re gi me n, o nl y 
1 6 0 m g m or ni n g d ose will be a d mi nistere d o n da y 1, fr o m da y 2 t o t he e n d of treat me nt, t wice dail y ( 1 6 0 m g BI D) 
( o nce i n t he m or ni n g, o nce i n t he e ve ni n g,  a n i nter val of 1 2 ± 2 h o urs is hi g hl y rec o m me n d e d ) will be a d mi nistere d. 
S wall o w t he ca ps ules wit h a glass of b oile d water. If t he e ve ni n g d ose is n ot ta ke n wit hi n 1 2 ± 2 h o urs of sc he d ule d 
ti me, t he act ual me dicati o n ti me nee ds t o be rec or de d o n t he patie nt l o g.  
S u bj ects will be a d vise d t hat if a d ose of t he st u d y dr u g is n ot ta ke n at t he sc he d ule d ti me, t he y s h o ul d ta ke t he misse d 
d ose as s o o n as t he y re me m ber a n d ret ur n t o t he n or mal sc he d ule f or t he ne xt d ose. S u bj ects s h o ul d s ki p t he misse d 
d ose if it is 4 h o urs or less t o t he ne xt sc he d ule d d ose.  
S u bj ects will c o nti n u o us ta ke st u d y dr u g u ntil i nt olera nce t o t o xicit y, disease pr o gressi o n, s u bj ect or i n vesti gat or deci des 
t o wit h dra w fr o m st u d y. If t he treat me nt has bee n i nterr u pt e d f or m ore t ha n 4 wee ks, t he s u bj ect ma y ta ke s h ort-ter m 
pr o hi bite d dr u g s pecifie d i n t he pr ot oc ol u n der a p pr o val b y t he d oct or a n d dafet y m o nit or.  
S u bj ects ca n n ot ta ke f o o d wit hi n 2 h o urs bef ore a n d 1 h o ur after dr u g a d mi nistr ati o n.  
T he D L T o bser vati o n peri o d of B G B -3 1 1 1 is 2 8 da ys ( Da y 1 -2 8) a n d s u bse q ue nt treat me nt peri o d is fr o m da y 2 9 t o 
ha vi n g bee n i n c o nti n u o us treat me nt f or 3 yeas. T he treat me nt ma y be disc o nti n ue d w he n disease pr o gressi o n, 
i nt olera ble t o t o xicit y, deat h, wit h dra wal fr o m t he st u d y, l ost t o f oll o w -u p, st u d y ter mi nati o n b y t he s p o ns or, or ha vi n g 
c o m plete d all 3 years of treat me nt, w hic he ver occ urs first. If a s u bj ect is j u d ge d t o still ha ve cli nical be nefit b y t he 
i n vesti gat or at t he e n d of 3-year trea t me nt, he/s he ma y be tra nsferre d t o t he e xte nsi o n st u d y t o c o nti n ue B G B-3 1 1 1 
treat me nt u n der t he a p pr o val b y t he s p o ns or’s me dical m o nit or. 
6. 3  
S u bject N u m b eri n g  
S u bj ects ca n o nl y be  i de ntifie d b y a s u bj ect n u m ber.  Eac h s u bj ect e nr olle d i n t his st u d y will recei ve a u ni q ue s u bj ect 
n u m ber w hic h will b e assi g ne d w he n t he s u bj ect is scree ne d or e nr olle d i n t he st u d y.  S u bj ect will be assi g ne d i n 
c hr o n ol o gical or der starti n g wit h t he l o west n u m ber.  O nce a s u bj ect n u m ber has bee n assi g ne d t o a s u bj ect, it ca n n ot b e  
reassi g ne d t o a n y ot her s u bj ect. If a s u bj ect is re place d, ne w e nr olle d s u bj ect will be assi g ne d ne xt effecti ve s u bj ect 
n u m ber.  
6. 4  
P ac k a gi n g a n d L a belli n g  
T he ca ps ule s u p plies of B G B -3 1 1 1  will be pr o vi de d i n a c hil d -resista nt hi g h de nsit y p ol yet h yle ne ( H D P E) b ottle wit h 
i n d ucti o n seal a n d b ottle la bel. T he la bel will i ncl u de: dr u g q ua ntit y, pr ot oc ol n u m ber, batc h n u m ber, directi o ns f or 
usa ge, st ora ge c o n diti o ns, e x pir y date, s pace t o e nter t he s u bj ect n u m ber a n d a b bre viati o n of na me. 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 l ocal re g ulat or y re q uire me nts. 
6. 5  
Dr u g St o r a ge  
T he st u d y dr u g will be dis patc he d t o a st u d y ce nter o nl y after recei pt of t he re q uire d d oc u me nts i n acc or da nce wit h 
a p plica ble re g ulat or y re q uire me nts a n d t he s p o ns or’s  pr oce d ures.  
St u d y dr u g m ust b e dis pe nse d or a d mi nistere d acc or di n g t o pr oce d ures descri be d i n t his pr ot oc ol. O nl y e nr olle d s u bj ects 
ca n recei ve st u d y dr u g, 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 pers o n nel ca n 

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s u ppl y or ma na ge st u d y dr u g.  All st u d y dr u gs m ust be st ore d i n a sec ure area wit h access li mite d t o t he i n vesti gat or a n d 
a ut h orize d st u d y pers o n nel , a n d st ore d u n der 1 5° C -3 0° C or u n der c o n diti o ns re q uire d b y l atest i n vesti gat or br oc h ure.  
6. 6  
Res p o nsi bilit y of S t u d y Dr u g M a n a ge me nt  
I n vesti gat or is res p o nsi ble f or usa ge, dis pe nsati o n, a n d rec or di n g of t he st u d y dr u g. Acc or di n g t o t he e xisti n g re g ulat or y 
re q uire me nts, i n vesti gat ors or desi g nate d pers o n nel of t he st u d y ce nter s hall rec or d t he acce pta nce, distri b uti o n, usa ge 
a n d rec ycli n g of t he st u d y dr u g t hr o u g h o ut t he c o urse of t he st u d y.  
After c o m pleti o n of t he st u d y, all u n use d B G B -3 1 1 1 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 he 
h os pital p har macist. T he i n ve nt orie d s u p plies will be ret ur ne d t o t he s p o ns or or destr o ye d o n site, after ha vi n g recei ve d  
writte n a p pr o val  fr o m s p o ns or.  
6. 7  
C o m pli a nce Assess me nt  
All s u bj ects will nee d t o a ns wer q uesti o ns a b o ut c o m plia nce bef ore bei n g recr uite d acr oss all st u d y ce nters.     
I n t he c o urse of st u d y, i n vesti gat ors will dis pe nse d osa ge ac c or di n g t o d ose gr o u p a n d rec or d act ual d ose e xactl y. T he 
act ual d ose s h o ul d be c o nsiste nt wit h d ose i n pr ot oc ol. C o m plia nce will be deter mi ne d acc or di n g t o n u m ber of st u d y 
dr u g dis pe nse d t o a n d ret ur n b y s u bj ects i n e ver y treat me nt c ycle a n d at t he ti me of st u d y disc o nti n uati o n.  
6. 8  
H a n dli n g of St u d y O ver d ose  
If t he s u bj ect is s us pecte d of o ver d ose, r o uti ne s u p p orti ve care s h o ul d be gi ve n, a n d s u bse q ue nt treat me nt will be 
deter mi ne d b y i n vesti gat or aft er disc ussi o n wit h me dical m o n it or, a n d a n y a d verse e ve nts d ue t o o ver d ose will be 
re p orte d t o t he me dical m o nit or. 
6. 9  
Occ u p ati o n al Ris k  
T he use a n d ma na ge me nt of st u d y dr u g u n der n or mal c o n diti o ns d oes n ot p ose a si g nifica nt occ u pati o nal safet y ris k t o 
st u d y ce nter pers o n nel. 

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7  
C O N C O MI T A N T  M E DI C A TI N A N D P R O HI BI T E D M E DI C A TI O N  
7. 1  
C o nc o mit a nt M e dic ati o n  
All c o nc o mita nt me dicati o n will be rec or de d i n s o urce d oc u me nt a n d C R F d uri n g st u d y, i ncl u di n g its i n dicati o n, d osa ge 
a n d dates of a d mi nistrati o n.  
7. 2  
Pr o hi bite d M e dic ati o n  
S u bj ect ca n n ot recei ve ot her a nti -t u m or treat me nt d uri n g st u d y, i ncl u di n g b ut n ot li mite dt o c he m ot hera p y, bi ot hera p y, 
h or m ot hera p y a n d ot her st u d y dr u g. Di p h os p h o nate c o ul d be use d if it has bee n at sta ble d ose 3 m o nt h bef ore 
e nr oll me nt.  C ortic oster oi d f or n ot m ore t ha n 2 wee ks is per mitte d if it is use d i n ot her i n dic ati o ns ( n ot ca ncer). If t here 
are n o ot her alter nati ve , t he tre at me nt s h o ul d be deci de d b y i n vesti gat or after disc ussti o n wit h  me dical m o nit or a n d a 
writte n a p pr o val s h o ul d be iss ue d firstl y b y s p o ns or’s me dic al m o n it or.  
Dr u gs k n o w n t o pr ol o n g t he Q T/ Q T c i nter val are pr o hi bite d, i n acc or da nce wit h t he 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:  E 1 4 Cli nical E val uati o n of Q T/ Q T c I nter val Pr ol o n gati o n a n d Pr oarr h yt h mic P ote ntial 
f or N o n-A ntiarr h yt h mic D r u gs. F or a c o m plete list please refer t o htt p:// w w w.azcert. or g/ me dical -pr os/ dr u g -lists/ dr u g-
lists.cf m a n d A p pe di x 6. If t he dr u g has t o be use d i n s pecial circ u msta nces, t he trea t me nt s h o ul d be deci de d b y 
i n vesti gat or after disc ussi o n wit h  me dical m o nit or , a n d a writte n a p pr o val s h o ul d be iss ue d firstl y b y s p o ns or ’s me dical 
m o nit or.   
A ntic oa g ulati o n dr u g a n d C hi nese her bal me dicati o n s h o ul d be a v oi de d d uri n g st u d y. If n o ot her alter nati ves, t he 
treat me nt s h o ul d be deci de d b y i n vesti gat or after disc ussi o n wit h  me dical m o nit or , a n d a writte n a p pr o val s h o ul d be 
iss ue d firstl y b y s p o ns or’s me dical m o nit or.  
 Res ults of i n vitr o st u d y i n dicate B G B -3 1 1 1 is n ot a str o n g i n h i bit or of h u ma n C Y P is oe nz y me. H o we ver C Y P 3 A 
i n v ol ves mai n meta b olic r o ute of B G B-3 1 1 1. Ta ble 6 lists pr o hi bite d me dicati o n i n t his st u d y (str o n g i n hi bit or a n d 
i n d ucer of C Y P 3 A), f or a m ore c o m plete d list please refer t o: htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n -ta ble/ 
T a ble 6  
Pr o hi bite d M e dic ati o ns ( C Y P 3 A I n hi bit ors a n d C Y P 3 A I n d ucers)  
Str o n g C Y P 3 A I n hi bit ors  
i n di na vir  
sa q ui na vir 
itrac o naz ole, ,  
ket oc o naz ole  
clarit hr o m yci n  
nefaz o d o ne  
rit o na vir, ,  
telit hr o m yci n 
nelfi na vir  
s u b o x o ne 
Str o n g C Y P 3 A I n d ucers  
car bi maz ole  
p he n o bar bital  
p he n yt oi n  
St. J o h n’s w ort ( h y peric u m perf orat u m ) 
rifa m pi n (rifa m pici n) 
 
7. 3  
M e dic ati o n t o be use d wit h c a uti o n  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
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C o n f i d e n t i a  
 
B G B -3 1 1 1 is a wea k i n hi bit or of h u ma n C Y P is oe nz y me C Y P 2 C 8 (I C 5 0 = 4. 0 3 M), C Y P 2 C 9 (I C
5 0 = 5. 6 9 M), a n d 
C Y P 2 C 1 9 (I C 5 0 = 7. 5 8 M).  Alt h o u g h we belie ve t hat B G B -3 1 1 1 d oes n ot cli nicall y i n hi bit t he dr u g c o nce ntrati o n of 
t hese C Y P is oz y mes, t he i n vesti gat ors s h o ul d be a ware t hat B G B-3 1 1 1  ma y ha ve a n effect o n dr u gs t hat are 
meta b olize d b y C Y P 2 C 8, C Y P 2 C 9 a n d C Y P 2 C 1 9. E xa m pl es of t hese me dicati o ns i ncl u de, b ut are n ot li mite d t o t h ose 
liste d i n T a ble 7, f or a c o m plete list please refer t o htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n -ta ble/ 
T a ble 7  
M e dic ati o ns t o be use d wit h c a uti o n ( S u bstr ates of C Y P 2 C 8, C Y P 2 C 9, a n d C Y P 2 C 1 9)  
S u bstr ates of C Y P 2 C 8  
S u bstr ates of C Y P 2 C 9  
S u bstr ates of C Y P C 1 9  
A m o dia q ui ne  
Or al  a nti -di a betes mellit us  
Pr ot o n P u m p I n hi bit ors   
ceri vastati n  
T ol b uta mi de  
la ns o praz ole1 
paclita xel  
gli pizi de  
o me praz ole 1 
Re p a gli ni de  
A n gi ote nsi n II rece pt or bl oc ker  
P a nt o pr az ole  
S orafe ni b  
L osarta n  
ra be praz ole 
t orse mi de 
ir besarta n 
A nti -e pile ptics:  
 
s ulf o n yl ure as 
Diaze p a m  
 
Gl y b uri de  
P he n yt oi n ( O)  
 
Gli be ncla mi de  
S -me p he n yt oi n 1, 2 
 
Gli pizi de  
P he n o bar bit o ne  
 
Gli me piri de  
ot hers  
 
T ol b uta mi de  
A mitri pt yli ne  
 
ot hers  
Caris o pr o d ol  
 
A mitri pt yli ne  
Cital o pra m  
 
Celec o xi b  
C hl ora m p he nic ol  
 
Fl u o xeti ne  
Nelfi na vir  
 
Fl u vastati n  
Pr o gester o ne  
 
S -warfari n  
Pr o g ua nil  
 
 
Pr o pra n ol ol  
 
 
R -warfari n  
  

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8  
S T U D Y A S S E S S M E N T O N S A F E T Y, P H A R M A C O KI N E TI C S, P H A R M A C O D Y N A MI C S A N D 
O T H E R P A R A M E T E R S  
All s u bj ects m ust si g n o n i nf or me d c o nse nt bef ore scre n ni n g. T a ble 3, St u d y Assess me nts a n d Pr oce d ures Sc he d ule, 
s h o ws s pecific st u d y e val uati o ns a n d pr oce d ures. T a ble 4 a n d T a ble 5 s h o w t he ti me p oi nts f or p har mac o ki netics a n d 
efficac y sa m pli n g . 
8. 1  
De m or g r a p h y a n d B aseli ne C h ar a cteristics  
De m or gra p h y i ncl u des date of birt h, race, hei g ht (c m), wei g ht ( k g), a n d b o d y mass i n de x ( k g/ m
2). W he n meas uri n g 
hei g ht a n d wei g ht, s u bj ects ca n n ot wear s h oes, all o wi n g t he m t o wear i n d o or da yti me cl ot hes. T his data will be e ntere d 
i nt o t he electr o nic case re p ort f or m a n d data b ase. After si g ni n g t he i nf or me d c o nse nt f or m, t he s u bj ect is re q ueste d t o 
perf or m scree ni n g acc or di n g t o t he criteria liste d i n secti o n 5 t o deter mi ne w het her t he s u bj ect is eli gi ble t o e nt er t he 
st u d y. I n a d diti o n t o t he diseas e assess me nt, a scree ni n g e val uati o n will be c o m plete d wit hi n 2 8 da ys pri or t o t he i nitial 
d ose of st u d y dr u g. As i n dicat e d i n T a ble 3, t he scree ni n g assess me nt c o m plete d wit hi n 7 2 h o urs of a d mi nistrati o n ca n 
be use d as a baseli ne assess me nt. Scree ni n g assess me nts i ncl u de:  
B aseli ne de m gra p hic data  
Me dical hist or y a n d baseli ne c haracteristics  
C ollect p hat h ol o gic i nf or mati o n, i ncl u de pre dict ors of s u bj ects wit h C L L ( del 1 7 p, del 1 1 q, del 1 3 q a n d p 5 3 m utati o n 
a n d I g V H m utati o n), C X C R 4 a n d M Y C 8 8 m utati o n of s u bj ects of W M.  
Vital si g ns (s yst oic press ure, diast olic press ure, p ulse, b o d y t e m pret ure a n d res pirat or y rate)  
B -s y m pt o ms ( b o d y wei g ht d ecrease > 1 0 % wit hi n 6 m o nt hs wit h o ut si g nifica nt ca uses, fe ver > 3 8 ° C a n d/ or ni g ht s weat)  
Ge neral p h ysical e xa mi nati o n  
E C O G perf or ma nce sc ore  
Ec h ocar di o gra m  
1 2 -lea d E C G 
C o nc o mita nt me dicati o n  
A d verse e ve nt a n d  seri o us a d verse e ve nt rec or di n g 
C T/ P E T  or C T sca n f or t u m or e val uati o n  
B o ne marr o w e xa mi nati o n  
C o m plete bl o o d c o u nt (secti o n 1 7. 0, a p pe n di x 1)  
Cli nical bi oc he mistr y (secti o n 1 7. 0, a p pe n di x 1)  
C oa g ulati o n test (secti o n 1 7. 0, a p pe n di x 1)  

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I m m u n o gl o b uli n ser u m I g A, I g G, I g M le vel a n d i m m u n ofi xati o n electr o p h oresis （secti o n 1 7. 0, a p pe n di x 1） 
Pre g na nc y test i n w o me n wit h c hil d beari n g p ote ntial  
Ser u m viral test ( H B V, H C B, HI V)  
Uri nal ysis (secti o n 1 7, a p pe n di x 1)  
T he a b o ve data will b e i ncl u d e d i n s o urce d oc u m e nt, a n d if t here is a res ult be y o n d t he n or mal ra n ge, t he i n vesti gat or 
will d eci de case -b y -case w het her or n ot t o re p eat t he assess me nt.  
8. 2  
Assess me nt d uri n g tre at me nt  
Safet y assess me nt will b e c o n d ucte d d uri n g eac h visit at st u d y ce nter a n d t hr o u g h o ut t he s t u d y. T a ble 3 lists t he 
assess me nt sc he d ule a n d pr oce d ure t o be i m ple me nte d.  
8. 2. 1  
Assess me nt at L a b or at or y of St u d y Ce nter  
B ef ore gi vi n g st u d y dr u g, la b orat or y test s h o ul d be c o n d ucte d at l ocal la b o n da y 1. If assess me nts c o m plete d d uri n g 
scree ni n g is wit hi n 7 2 h o urs bef ore t he first d ose, t here is n o nee d t o re peat tests. Assess me nts t o be perf or me d are liste d 
i n secti o n 1 7. 0 a p pe n di x 1. 
Cli nical bi oc he mistr y a nal ysis, c o m plete bl o o d c o u nt, c oa g ulati o n test, uri nal ysis, i m m u n o gl o b uli n a n d i m m u n ofi xati o n 
electr o p h oresis s h o ul d be perf or me d as sc he d ule d i n ta ble 3.  
If a s u bj ect e x perie nces  ne utr o pe nia (a bs ol ute ne utr oc yte c o u nt < 1 0 0 0/ m m 3), t hr o m b oc yt o pe nia ( platelet c o u nt < 
5 0, 0 0 0/ m m 3), or gra d e 3 of cli nical bi oc he mistr y t o xicit y, re peate d tests s h o ul d be c o nd uct e d as per p h ysicia n’s 
j u d ge me nt u ntil t o xicit y has rec o vere d t o Gra de ≤ 2. If necessar y, relate d a d diti o nal tests c o ul d be perf or me d acc or di n g 
t o g ui deli nes of h os pital. All s u bj ects w h o ha ve gra de 3 or 4 la b orat or y a b n or malities at t he ti me of wit h drawal s h o ul d 
be f oll o we d u ntil t he y ha ve res ol ve d t o gra d e 1 or 2, u nless t hese para meters ca n n ot be i m pr o ve d d ue t o t he disease 
itself. 
I n uri ne r o uti ne a nal ysis, if uri nar y pr otei n ≥ 2 +, a  q ua ntitati ve  test of  2 4 -h o ur  uri nar y t otal  pr otei n will be perf or me d. If 
t he pr otei n is > 2 g / 2 4 h o urs, t he st u d y dr u g will be disc o ntin ue d u ntil t he uri nar y pr otei n ha s res ol ve d t o ≤ 2 g / 2 4 
h o urs (f or s u bj ects wit h W al d e nstr o m's macr o gl o b uli ne mia , it s h o ul d be deter mi ne d b y t he d oct or w het her or n ot t o 
disc o nti n ue) . If t he uri ne pr otei n ≤ 2 g / 2 4 h o urs, f urt her cli nical e xa mi nati o n or re peat test s h o ul d  be c o nsi dere d  
de p e n di n g o n cli nical ma nifestati o ns . All s u bj ects wit h Wal de nstr o m's macr o gl o b uli ne mi a  s h o ul d u n der g o a first 
i m m u n ofi xati o n electr o p h oresis d uri n g scree ni n g. If m o n ocl o nal pr otei n ( M pr otei n) prese nt, re peat tests will b e 
c o n d ucte d i n t he s u bse q ue nt i m m u n o gl o b uli n tests.  
8. 2. 2  
P h ysic al E x a mi n ati o n, Vit al si g ns, B -s y m pt o ms 
A c o m plete d or tar gete d e xa mi nati o n, viatl si g ns (s yst oic press ure, diast olic press ure, p ulse, b o d y te m pret ure a n d 
res pirat or y rate) e xa mi nati o n, wei g ht a n d B -s y m pt o ms meas ure me nts s h o ul d be perf or me d acc or di n g t o sc he d ule i n 
ta ble 3, ta ble 4 a n d ta ble 5. 

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S yste mic p h ysical e xa mi nati o n i ncl u de car di o vasc ular s yste m, res pirat or y s yste m, a b d o me n, ne ur os yste m, l y m p h 
n o de/s plee n s ki n, or o p har y n x a n d li m bs.  T ar gete d e xa mi nati o n mai nl y tar gets o n cli nical r ele va nt s yste ms (e. g. 
car di o vasc ular s yste m, res pirat or y s yste m, l y m p h n o de, li ver a n d s plee n) a n d cli nical s y m pt o m /si g n rele va nt s yste m. B -
s y m pt o ms i ncl u des u ne x plai ne d wei g ht l oss > 1 0 % o ver pre vi o us 6 m o nt hs, fe ver ( > 3 8° C), a n d/ or ni g ht s weat.  
8. 2. 3  
E C G  
A 1 2 -lea d E C G will be perf or me d i n tri plicate at scree ni n g, EO T or pre mat ure wit h dra wal. S u bj ects s h o ul d be i n t he 
se mi-rec u m be nt or s u pi ne p ositi o n i n E C G e xa mi nati o n. 
E C G s h o ul d be perf or me d acc or di n g t o sc he d ule i n ta ble 3, ta ble 4 a n d ta ble 5. It is re q uire d t o perf or m E C G i n 
tri plicate at eac h P K sa m pli n g ti me p oi nts, b ut E C G is n ot nee de d at  sa m pli n g ti me p oi nt of 0. 5 h o urs after 
a d mi nistrati o n.  
Si g nifica nt pr ol o n ge d Q T c i nter val is defi ne d as Q T c F i nter val ≥ 5 0 0 msec, or Q T c F i nter val ≥ 6 0 msec  fr o m baseli ne. 
F or b ot h cases, t w o or m ore E C G f oll o w -u p e xa mi nat i o ns s h o ul d be perf or me d a n d t he i nter val bet wee n t w o E C Gs 
s h o ul d be at least 5 mi n utes. M ore o ver, it s h o ul d be ma n uall y meas ure d b y a q ualifie d d oct or.  
If a s u bj ect  e x perie nce s si g nifi ca nt pr ol o n ge d Q T c:  
- Dela y t he a d mi nistrati o n of st u d y dr u g  
-  C o n d uct a me dical e val uati o n of t he s u bj ect, gi ve a p pr o priate treat me nt, a n d t he n perf or m at least 3 E C Gs per 
wee k u ntil t he Q T a n d Q T c i nter vals ret ur n t o wit hi n 3 0 ms of t he baseli ne le vel.  
  C o ns ult me dical m o nit or bef ore res u mi n g treat me nt.  
  C o ns ult me dical m o n it or bef ore i nitiati n g hi g her d ose . 
8. 2. 4  
C T Sc a n  
S u bj ects nee d t o u n der g o a t u m or e val uati o n at t he ti me of e nr oll me nt. If e nlar ge d li ver, s plee n, l y m p h n o des or ot her 
a b n or mal cli nical s y m pt o ms are detecte d, a c o ntrast -e n ha nc e d C T e xa mi nati o n m ust be perf or me d  wit hi n 7 da ys of t he  
e n ds of W ee k 1 2, 2 4, 3 6, 4 8, a n d wit hi n 2 wee ks of e ver y 2 4 wee ks e n d after war ds . S u bj ects wit h  hair y le u ke mia s h o ul d 
be e val uate d wit hi n 7 da ys aft er W ee k 1 2, 2 4, 3 6, 4 8, a n d f oll o w e d b y l ocal practice after o ne year. C o ntrast -e n ha nce d 
C T sca n ( oral or I V c o ntrast) ca n be use d i n t u m or assess me nt, i ncl u di n g nec k, c hest, a b d o me n a n d pel vic . In or der t o 
i m pr o ve t he res ol uti o n of C T sca n , P E T /C T sca n ca n be use d t o acc uratel y meas ure t he lesi o ns size of l y m p h n odes, 
li ver, s plee n. I n vesti gat ors ca n als o use M RI t o re place C T.  I n vesti gat or s h o ul d j u d ge if P E T-C T is re q uire d d uri n g 
scree ni n g. F or s u bj ects w h o are p ositi ve f or P E T -C T d uri n g scree ni n g, it is necessar y t o re peat e xa mi nati o n w he n  
c o nfir mi n g C R. In vesti gat ors at eac h st u d y ce nter s h o ul d perf or m a relate d i ma gi n g st u d y at eac h dise ase assess me nt . If 
a s u bj ect ter mi nates t he treat me nt pre mat urel y a n d has n ot u n der g o ne C T sca ns wit hi n 3 m o nt hs, a C T sca n is als o 
re q uire d at t he ti me of ter mi nati o n. 
8. 2. 5  
B o ne M arr o w E x a mi n ati o n  
All s u bj ects ha ve t o u n der g o b o ne marr o w e xa mi nati o n d uri n g t he scree ni n g peri o d. If t he b o ne marr o w e xa mi nati o n 
ha d bee n perf or me d 3 0 da ys b ef ore t he scree ni n g peri o d, t he res ults c o ul d be use d f or scre e ni n g wit h o ut re peate d 

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e xa mi nati o n. F or patie nts wit h W al de nstr ö m’s Macr o gl o b uli n, if t here is b o ne marr o w lesi o n, b o ne marr o w e xa mi nati o n 
is re q uire d e ver y si x m o nt hs. P atie nts w h o ha ve bee n dia g n ose d wit h b o ne marr o w lesi o ns at t he ti me of e nr oll me nt ma y 
nee d t o u n der g o f urt her b o ne marr o w as p irati o n a n d bi o ps y t o c o nfir m if t he y are s u bse q ue ntl y j u d ge d t o be p ossi ble C R 
b y a p h ysical e xa mi nati o n or C T sca n.  
8. 2. 7 Detecti o n of Mi ni m al R esi d u al Dise ase  ( M R D) 
F or C R s u bj ects, peri p heral bl o o d or peri p heral bl o o d pl us b o ne marr o w sa m ples will be e xa mi ne d b y fl o w c yt o metr y 
( F C M) at least t hree m o nt hs after st u d y dr u g disc o nti n uati o n t o detect mi ni mal resi d ual disease ( M R D).  
8. 2. 8 A d verse E ve nts  
All a d verse e ve nts a n d seri o us a d verse e ve nts, re gar dless of ca usalit y, will be c ollecte d t hr o u g h o ut t he p r ocess fr o m t he 
ti me of si g ni n g t he i nf or me d c o nse nt f or m t o 3 0 da ys of f oll o w-u p after last a d mi nistrati o n.  
8. 2. 8. 1 As y m pt o m atic l y m p h oc yt osis i n d uce d b y st u d y dr u g is n ot rec o r d e d a n d re p orte d as a n a d verse e v e nt  
I n t his pr ot oc ol, t he st u d y dr u g-i n d uce d l y m p h oc yt osis is defi ne d as l y m p h oc yte c o u nt i ncrease b y ≥ 5 0 % c o m pare d t o 
baseli ne a n d a bs ol ute c o u nt ≥ 5, 0 0 0/ μ L, wit h at least o ne disease -relate d para meter (i ncl u di n g l y m p h n o de size, s plee n 
size), he mat ol o gical para meters ( he m o gl o bi n or platelet c o u nt)  or disease -relate d s y m pt o ms ha ve i m pr o ve d si g nifica ntl y. 
I n vie w of t he k n o w n mec ha nis m of acti o n of B T K i n hi bit ors, t he st u d y dr u g-i n d uce d l y m p h oc yt osis is e x pecte d a n d 
ma y occ ur fre q ue ntl y. I n t his st u d y, as y m pt o matic st u d y dr u g -i n d uce d l y m p h oc yt osis (incl u di n g t he res ulti n g W B C 
i ncrease) w o ul d n ot b e rec or de d a n d re p orte d as a n a d verse e ve nt a n d w o ul d n ot affect t he patie nt's c o nti n ue d treat me nt 
of t he st u d y dr u g.  
8. 3  
S afet y  
Safet y assess me nt para meters  i ncl u de vital si g ns, B-s y m pt o ms, cli nical la b orat or y tests ( he mat ol o g y, cli nical 
bi oc he mical a nal ysis, c o a g ulati o n, uri ne a nal ysis, i m m u n o gl o b uli n a nal ysis, a n d i m m u n ofi xati o n electr o p h oresis), 1 2 -
lea d electr ocar di o gra m a n d p h ysical e xa mi nati o n. T hr o u g h o ut t he c o urse of t he st u d y, t he staff at t he researc h ce nter 
will f oll o w-u p  t he a d verse e ve nts a n d gra d e  t he a d verse e ve nts a n d t o xicit y acc or di n g t o N CI-C T C A E versi o n 4. 0 3.  
8. 4  
F oll o w -u p Assess me nt  
At 3 0 da ys after t he last a d mi nistrati o n, all s u bj ects s h o ul d be ret ur ne d t o t he st u d y ce nter f or fi nal assess me nt. T a ble 3 
lists t he assess me nt ite ms t o be c o n d ucte d. 
F oll o w -u p all a b n or malities t hat are i n de p e n de nt of disease pr o gressi o n u ntil t he y ha ve res ol ve d t o baseli ne le vel. 
8. 5  
Effic ac y Assess me nt  
Efficac y is n o t a pri mar y o bj ecti ve. H o we ver, t he f oll o wi n g efficac y e n d p oi nts will be assesse d:  
 
N u m ber a n d pr o p orti o n of s u bj ects w h o ha ve ac hie ve d o bj ecti ve res p o nse or sta ble disease (c o m plete res p o nse, 
partial res p o nse, a n d c o m plete res p o nse + partial res p o nse)  
 
Cleara nce rate of mi ni mal resi d ual disease  ( M R D) 

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 
Pr o gressi o n -free s ur vi val ( P F S) 
 
T he d urati o n of c o m plete res p o nse or partial re s p o nse, a n d t he d urati o n bei n g i n sta ble disease.  
T he efficac y e val uati o n will b e base d o n a p pr o priate e val uati o n criteria (I W C L L -C L L 1 5, 1 6, N CI-W G -N H L 1 7, I W W M-
W M
1 8, as s h o w n i n secti o n 1 7. 0, A p pe n di x 3) . A C T sca n ( P E T, if a p plica ble) will be perf or me d at t he e n d of W ee k 1 2、
2 4 、3 6 、4 8 、7 2 a n d 9 6 of treat me nt, a n d b o ne marr o w as pirati o n a n d/ or bi o ps y will be perf or me d at Wee k 1 2 of 
treat me nt a n d t hereafter (if t he s u bj ect has b o ne marr o w lesi o ns bef ore e nr oll me nt a n d is s us pecte d t o ac hie ve C R).  
8. 6  
P h ar m ac o ki netics  
T o u n dersta n d t he p har mac o ki netic pr ofile of B G B -3 1 1 1 a n d p ossi bl y maj or meta b olites, bl o o d sa m ples nee d t o be 
c ollecte d. T he  a m o u nt of bl o o d t o be c ollecte d at eac h ti me p oi nt is a p pr o xi matel y 4 ml f or p har mac o ki netic a nal ysis. 
T a ble 4 a n d T a ble 5 s h o w t he sa m pli n g ti me p oi nts . T he Ce nter La b orat or y Ser vice Ma n ual details o perati o n 
i nstr ucti o ns o n ha n dli n g p har mac o ki netic plas ma sa m ples, i ncl u di n g la beli n g a n d s hi p pi n g i nstr ucti o ns. As t he st u d y 
will c o nti n ue t o m o nit or t he dr u g e x p os ure, fr oze n plas ma sa m ples s h o ul d be tra ns p orte d as s o o n  as p ossi ble after 
c ollecti o n.  
I n t he e ve nt of d ose-li miti n g t o xicit y ( D L T) or ot her seri o us dr u g t o xicit y, bl o o d sa m ples ( 4 ml) nee d be c ollecte d t o 
deter mi ne t he B G B -3 1 1 1 plas ma c o nce ntrati o n, dr u g -dr u g i nteracti o n, a n d ot her p ossi ble mec ha nis ms, acc or di n g t o t he 
o pi ni o n of t he i n vesti gat or aft er disc ussi o n wit h s p o ns or’s me dical m o nit or. I n vesti gat or m ust rec or d t he ti me of bl o o d 
c ollecti o n a n d t he ti me of a d mi nistrati o n i n t he e C R F.  
If it is s us pecte d t hat B G B-3 1 1 1 i nteracts wit h a c o nc o mita nt dr u g, a f urt her bl o o d sa m ple ma y be c ollecte d f or 
p har mac o ki netic a nal ysis t o descri be t he e xte nt of dr u g i nter acti o ns.  
A p pe n di x 2 descri bes t he ma xi m u m a m o u nt of bl o o d t o be c ollecte d d uri n g t he c o urse of t he st u d y (i ncl u di n g t he safet y 
assess me nt d uri n g t he scree ni n g peri o d).  
8. 7  
P h ar m ac o d y n a mics  
T he pr o p orti o n of B T K occ u pie d i n peri p heral bl o o d m o n o n uclear cells will be e val uate d as a bi o mar ker f or t he 
i n hi biti o n of B T K. F or i nf or mati o n of sa m ple c ollecti o n, ha n dli n g, st ora ge a n d tra ns p ortati o n, please refer t o t he Ce nter 
La b orat or y Ser vice Ma n ual.  
8. 8  
M olec ul ar M ar ker s 
All s u bj ects i n P art II  s h o ul d pr o vi de a rece nt t u m or s peci me n f or m olec ular mar ker a nal ysis. If t he s u bj ect d oes n ot 
ha ve a rece nt sa m ple of t u m or tiss ue, a fres h t u m or bi o ps y m ust be perf or me d d uri n g t he scree ni n g peri o d. T he t u m or 
tiss ue ca n be eit her f or mali n-fi xe d paraffi n-e m be d de d t u m or tiss ue bl oc k or at least 1 0 u nst ai ne d sli des a n d se nt t o t he 
ce ntral la b orat or y f or a nal ysis. F or patie nts wit h f ollic ular l y m p h o ma or mar gi nal z o ne l y m p h o ma w h o ha v e bee n 
e nr olle d u n der pr ot oc ol 1. 0, hist orical t u m or s peci me ns or sa m ples nee d t o be pr o vi de d after v ol u ntar y si g nat ure of ne w 
i nf or me d c o nse nt. F or detaile d i nf or mati o n o n t u m or tiss ue c ollecti o n, please refer t o t he la b orat or y ma n ual. 

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9  
Q U A LI T Y C O N T R O L A N D  Q U A LI T Y A S S U R A N C E  
U n der t he G C P, t he s p o ns or is res p o nsi ble f or t he i m ple me nt ati o n a n d mai nte na nce of t he sta n dar d o perati n g pr oce d ures 
( S O P) s yste m f or q ualit y ass ur a nce a n d q ualit y c o ntr ol. 
Q ualit y c o ntr ol will be perf or me d at all sta ges of data pr ocessi n g.  
T o e ns ure t he acc urac y, c o nsiste nc y, c o m plete ness a n d data relia bilit y of t he st u d y, t he f oll o wi n g meas ures will be ta ke n:  
 
C o n ve ne  i n vesti gat or meeti n gs 
 
Verif y t he q ualificati o n of la b orat or y a n d c hec k u p t he E C G res ults  
 
C o n d uct i nitiati o n visi t t o st u d y ce nters 
 
First P atie nt E nr oll me nt visit  
 
Re g ular m o nit or i n g 
 
C o nti n u o us c o m m u nicati o n a n d trai ni n g of  st u d y ce nters 
 
Q ualit y c o ntr ol of data ma na ge me nt  
 
C o nt i n u o us data ac q uisiti o n a n d clea ni n g 
 
I nter nal data re vie w 
 
Q ualit y c o ntr ol c hec ks f or  cli nica l st u d y re p orts 
I n a d diti o n, t he s p o ns or a n d t he C R O’s Q ualit y Ass ura nce will re vie w t he st u d y pr ocess o n a re g ular basis, i ncl u di n g b ut 
n ot li mite d t o st u d y ce nters, ce ntral la b orat ories, s u p pliers, cli nical data b ases, a n d fi nal cli nical st u d y re p orts.  
 
9. 1  
S t u d y M o nit o ri n g 
Acc or di n g t o t he rele va nt re g ulati o ns, G C P a n d t he re q uire me nts of t he s p o ns or, t he s p o ns or’s m o nit or will c o n d uct a n  
o n -t he-site i ns pecti o n of t he st u d y ce nter bef ore e nr oll me nt pr oce d ure , a n d als o o n-t he-sit e m o nit or o n a re g ular basis 
d uri n g t he st u d y peri o d . T he p ur p ose s of t he m o nit ori n g acti vit y i ncl u de : 
 
Lear n a b o ut st u d y pr o gress.  
 
Verif y st u d y data. 
 
E ns ure of d ata tracea bilit y.  
 
Q & A f or all q uesti o ns.  
 
E ns ure t hat t he data is tr ue, ac c urate a n d c o m plete.  

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 
E ns ure t hat t he safet y a n d b e n efits of t he s u bj ect are pr otecte d.  
 
T he i n vesti gat or a grees a n d all o ws t he  m o nit or  t o ha ve direct access t o all st u d y d oc u me nts a n d t o disc uss or 
a ns wer a n y q uesti o ns relate d t o t he st u d y.  
9. 2  
D at a M a n a ge me nt a n d C o di n g  
T he data ge nerate d b y t his cli nical st u d y will be pr ocesse d acc or di n g t o t he rele va nt S O Ps of t he c o m pa n y's data 
ma na ge me nt a n d bi ostatistics de p art me nts.  
T his  st u d y will use a n electr o nic data ac q uisiti o n s yste m i n w hic h t he st u d y ce nter will tra nscri be all electr o nic case 
re p ort data i nt o a s prea ds heet. Data c ollecti o n will be perf or me d b y t he a ut h orize d st u d y c e nter staff desi g nate d b y 
i n vesti g or. Trai ni n g a nd safet y g ui da nce f or i n vesti gat ors a n d all a ut h orize d st u d y ce nter p ers o n nel s h o ul d be pr o vi de d 
pri or t o i nitiati o n of t he st u d y a n d bef ore t he s u bj ect data bei n g e ntere d i nt o s yste m.  
T he e C R F s h o ul d reflect t he l atest o bser vati o ns of t he s u bj ect. T heref o re, t he e C R F s h o ul d be c o m plete d as s o o n as t he 
s u bj ect visits or after treat me nt. I n or der t o a v oi d data discre pa ncies bet wee n o bser vers, tr y t o e ns ure t hat all safet y 
e val uati o ns are perf or me d b y t he sa me i n vesti gat or fr o m t he i nitial baseli ne assess me nt  t o f oll o w-u p. T he i n vesti gat or 
m ust verif y t he acc urac y a n d c orrect ness of all t he data e nter e d i nt o t he e C R F. If s o me of t he assess me nt ite ms are n ot 
carrie d o ut, or if certai n i nf or mati o n is n ot a vaila ble or is n ot a p plica ble or is n ot k n o w n, t he i n vest i gat or s h o ul d i n dicat e 
i n t he e C R F. After t he cli nical data is c ollecte d, t he i n vesti gat or m ust c o nfir m t he c o nte nts b y electr o nic si g nat ure. 
T he i n vesti gat or will c hec k t he e C R F t o assess its c o m plete ness a n d c o nsiste nc y. I n or der t o e ns ure t hat t here is n o 
discre p a nc y bet wee n t he ke y d ata, t he e C R F will be teste d f or tracea bilit y wit h s o urce d oc u me nts. All rec or ds, 
c orrecti o ns a n d c ha n ges t o t he e C R F are ma d e b y t he lea d i n vesti gat or or its desi g nate d pers o n(s). T he m o nit or ca n n ot 
e nter data i n e C R F. O nc e t he cli nical data of t he electr o nic case re p ort f or m has bee n se nt t o t he ce ntral ser ver, a n y data 
m o dificati o n will lea ve a c orrecti o n trail (re visi o n mar k), i.e t he reas o n f or t he c ha n ge, t he na me of t he re viser a n d t he 
ti me a n d date of t he c ha n ge. B efore t he cli nical data has bee n e ntere d i nt o t he e C R F, t he st u d y ce nter staff will be 
assi g ne d c orres p o n di n g ri g hts. If data re visi o ns are re q uire d, t he m o nit or or data ma na ger will q uesti o n t he data 
c ollecte d  t hr o u g h t he pr oce d ures, a n d a ut h orize d st u d y center staff will res p o n d t o t hese q uesti o ns.  
T he e C R F is esse ntiall y a data e ntr y f or m a n d s h o ul d n ot be treate d as a ra w ( or s o urce) me dical rec or d u nless ot her wise 
s pecifie d. T he s o urce file is defi ne d as all d oc u me nts use d b y t he i n vesti gat or or h os pital  relate d t o t he hist or y of t he 
s u bj ect, w hic h de m o nstrate t he prese nce of t he s u bj ect, verif y t he i ncl usi o n a n d e xcl usi o n criteria, a n d c o ver all t he 
rec or ds of t he s u bj ect d uri n g t he st u d y peri o d. T he s o urce fil es i ncl u de la b orat or y rec or ds, E C G res ults, me m os, dr u g 
dis pe nsati o n rec or ds, s u bj ect files, a n d s o o n.  
It is t he res p o nsi bilit y of t he i n vesti gat or t o mai ntai n t he s o ur ce d oc u me nt. At eac h m o nit ori n g acti vit y , t hese d oc u me nts 
m ust  be i n a stat us t hat all o ws t he m o nit or t o c hec k. T he i n vesti gat or m ust se n d a c o m plete d eC R F  t o eac h s u bj ect w h o 
recei ves t he st u d y dr u g, re gar dless of t he d urati o n  bei n g i n  t he st u d y. All s u p p orti n g d oc u me nts se nt wit h t he eC R F , 
s uc h as la b orat or y or h os pital rec or ds, s h o ul d ha ve a clear st u d y i de ntificati o n c o de a n d a s u bj ect i de ntificati o n c o de. I n 
or der t o pr otect t he c o nfi de nti alit y of pers o nal i nf or mati o n, pers o nal i nf or mati o n i ncl u di n g t he na me of t he s u bj ect 
s h o ul d be re mo ve d or o mitte d .  

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T he electr o nic case re p ort f or m will a ut o maticall y a d d t he u ni q ue user na me of t he creat or as pr o of of i de ntit y. T he 
i n vesti gat or ma kes a n electr o nic si g nat ure i n t he s pecifie d d oc u me nts, i n dicati n g t hat he/s he has c hec ke d t he data a n d 
c o nfir ms its acc urac y. I n vesti gat ors use t heir u ni q ue user na me a n d pass w or d f or electr o ni c si g nat ures; f or electr o nic 
si g nat ures, t he date a n d ti mest a m p will be a ut o maticall y a d de d. If a n y rec or ds i n t he e C R F nee d t o be c ha n ge d, it s h o ul d 
f oll o w t he rele va nt s oft ware fl o w. All c ha n ges will be f ull y d oc u me nte d i n t he pr otecte d a u dit trail a n d t he reas o ns f or 
t he c ha n ge will be clarifie d.  
A d verse e ve nts will be e nc o de d usi n g t he Me d D R A  1 7. 0, acc o m pa n yi n g dr u g will be e nc o de d usi n g t he W orl d Healt h 
Or ga nizati o n 's dr u g dicti o nar y ( W H O -D D ), a n d acc o m pa n y disease/ me dical hist or y will b e e nc o de d usi n g t he Me d D R A 
1 7. 0.  
9. 3  
Q u alit y Ass ur a nce  
T o e ns ure c o m plia nce 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 
perf or m q ualit y a ss ura nce a u dit(s).  Re g ulat or y a ut h orities  ma y als o c o n d uct a re g ulat or y i ns pecti 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 he 
i n vesti gat or a n d i nstit uti o n a gr ee 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 f or t he a u dit/i ns pecti o n, a n d disc uss cli nical fi n di n gs or a n y rele va nt iss ues.  

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1 0  
S A F E T Y  
1 0. 1  
A d verse E ve nt ( A E) a n d Seri o us A d verse E ve nt ( S A E)  
A n A E is defi ne d as a n y u nfa v ora ble  me dical occ urre nce  aft er patie nt or s u bj ect si g ni n g i nf or me d c o nse nt , re gar dless of 
w het her it is relate d t o t he st u d y dr u g . 
A seri o us a d verse e ve nt ( S A E)  is a n y u nt o war d me dical occ urre nce t hat res ults i n deat h, is  life-t hreate ni n g, re q uires 
h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, r es ults i n disa bilit y/i nca pacit y, is a c o n ge nital a n o mal y/ birt h 
defect, or is si g nifica nt me dic al e ve nt re q uiri n g i nter ve nti o n.  
If a n a d verse e ve nt o cc urs d uri n g t he trial, t he i n vesti gat or or t he lea d i n vesti gat or m ust gi ve pr o per treat me nt 
i m me diatel y a n d e x plai n t o t he s u bj ect. A d verse e ve nts m ust be f oll o we d u ntil t he s u bj ect has ret ur ne d  t o n or mal or t he 
i n vesti gat or c o nsi ders t hat t he f oll o w-u p is n o l o n ger nee de d. 
T a ble 7 : defi nit i o n of seri o us a d verse e ve nt 
Deat h  
A d verse e ve nt(s) ca use deat h of t he s u bj ect, e xce pt f or deat h d ue t o disease 
pr o gressi o n   
Life -t hreate ni n g 
Refers t o a n e ve nt i n w hic h t he s u bj ect was at ris k of deat h at t he ti me of t he 
e ve nt. It d oes n ot refer t o a n e ve nt, w hic h h y p ot heticall y mi g ht ha ve ca use d 
deat h, if it were m ore se vere.  
H os pitalizati o n  
A d verse e ve nt le a ds t o h os pitalizati o n, e xcl u di n g e mer ge nc y treat me nt  or 
o ut -patie nt visit . 
Pr ol o n gati o n of e xisti n g h os pitalizati o n  
A d verse e ve nt occ urs d uri n g h os pitalizati o n a n d ma ke t he h os pitalizati o n 
l o n ger t ha n e x pecte d. 
C o n ge nital a b n or malit y  
F o u n d def or mit y at birt h or aft er birt h, or a n y def or mities res ult i n a b orti o n.  
Res ult i n p er ma ne nt or si g nifi ca nt 
disa bilit y / d ysf u ncti o n  
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 dical si g nifica nce s uc h as u nc o m plicate d 
hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d acc i de ntal tra u ma (e. g., 
s prai ne d a n kle) w hic h ma y i nt erfere or pre ve nt e ver 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.  
Si g nifica nt me dical e ve nt re q uiri n g 
m e dical i nter ve nti o n  
Si g nifica nt me dical e ve nt t hat will n ot ca use i m me diate deat h or t hreat life 
or lea d t o h os pitalizati o n  at t he ti me of e ve nt , b ut it ma y j e o par dize t he 
s u bj ect or ma y re q uire me dical/s ur gical i nter ve nti o n t o prese nt o ne of t he 
o utc o mes liste d a b o ve  
1 0. 2  
Ti mefr a me f or A d verse E ve nt  

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All a d verse e ve nts a n d seri o us a d verse e ve nts will be c ollecte d fr o m si g ni n g t he i nf or me d c o nse nt u ntil 3 0 ± 7 da ys after 
treat me nt disc o nti o n, eit her re p ort b y i n vesti gat or or s p o nta ne o usl y re p ort b y s u bj ect. 
After si g ni n g t he  i nf or me d c o nse nt, seri o us a d verse e ve nts t hat occ ur pri or t o t he i nitiati o n of st u d y dr u g b ut relate t o t he 
o perati o n (e. g. bi o ps y) re q uire d b y t he pr ot oc ol s h o ul d als o be re p orte d.   
After m ore t ha n 3 0 ± 7 da ys after disc o nti n uati o n of t he st u d y treat me nt, t he i n v esti gat or s h o ul d re p ort a seri o us a d verse 
e ve nt t hat is c o nsi dere d t o be relate d wit h t he st u d y treat me nt.  
T he i n vesti gat ors s ho ul d j u d ge t he a d verse e ve nts b y as ki n g t he s u bj ects f or n o n -i n d uce d q uesti o ns. 
1 0. 3  
D oc u me nt ati o n of A d verse E ve nt  
I n vesti gat or s h o ul d use me dic al ter mi n ol o g y/ defi niti o n t o rec or d A E or S A E. Oral  a n d a b bre viati o n s s h o ul d be a v oi de d. 
All A E (i ncl u di n g S A E) s h o ul d rec or d i n s o urce d oc u me nt a n d A E pa ges  i n C R F.  
Di a g n osis, s y m pt o ms a n d si g ns  
If a dia g n osis has bee n ma d e, t he dia g n osis s h o ul d be rec or de d o n t he C R F rat her t ha n t he i n di vi d ual s y m pt o ms a n d 
si g ns (e g, li ver fail ure, n ot j a u n dice, ele vate d tra nsa mi nase, a n d fla p pi n g). H o we ver, if t he s y m pt o ms a n d si g ns ca n n ot 
be classifie d as a n i n di vi d ual dia g n osis at t he ti me of t he re p or t, eac h i n di vi d ual e ve nt s h o ul d be rec or de d o n t he C R F as 
A E or S A E. If later dia g n ose d, it s h o ul d be re p orte d as f oll o w -u p i nf or mati o n.  
A d verse e v e nt sec o n d ar y t o ot her e v e nt  
I n ge neral, pri mar y e ve nts s h o ul d be rec or de d f or a d verse e ve nts sec o n dar y t o ot her e ve nts, s uc h as t h ose ca use d b y 
ot her e ve nts or cli nical se q uel ae, u nless t he sec o n dar y e ve nt is se vere or seri o us a d verse e ve nts. H o we ver, sec o n dar y 
e ve nts wit h si g nifica n t cli nical si g nifica nce s h o ul d be rec or de d as i n de pe n de nt a d verse e ve nts i n t he s o urce d oc u me nt 
a n d C R F if t he ti me of occ urre nce of t he pri mar y e ve nt is differe nt. If t he ass ociati o n bet wee n e ve nts is u nclear, t he y  
s h o ul d be rec or de d se p aratel y b ot h i n t he s o urce d oc u me nts a n d C R F.  
Persiste nt or rec urri n g a d verse e v e nts  
P ersiste nt a d verse e ve nts refer t o a d verse e ve nts t hat persist a n d ha ve n ot bee n alle viate d bet wee n t w o ti me p oi nts of t he 
s u bj ect.  T his a d verse e ve nt s h o ul d be rec or de d o nl y o nce o n t he s o urce d oc u me nt a n d C R F. T he i nitial se verit y of t he 
e ve nt s h o ul d be rec or de d a n d u p date d w he n t he e ve nt is a g gra vate d t o rec or d t he m ost seri o us de gree of t he e ve nt.  
Rec urre nce of a d verse e ve nts refers t o t he a d verse e ve nts t hat ha ve bee n alle viate d bet wee n t w o ti me p oi nts, b ut ha ve 
occ urre d later. T he occ urre nce of t he e ve nt s h o ul d be rec or de d se paratel y i n t he s o urce d oc u me nt a n d t he C R F.  
L a b or at or y a b n or m alities or a b n or m al vit al si g ns  
N ot all la b orat or y a b n or maliti es/ vital s i g ns s h o ul d be re p orte d as A E.  O nl y l a b orat or y a b n or malities/a b n or mal vital 
si g ns t hat meet t he f oll o wi n g criteria s h o ul d be re p orte d as A E:  
 Wit h  cli nical s y m pt o ms.  

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 Lea d  t o c ha n ges i n st u d y treat me nt (e.g d ose a dj ust me nt, i nt err u pti o n  or per ma ne nt wit h dra wal, etc.).  
 Re q uires  me dic al i nter ve nti o n or c ha n ges i n c o m bi nati o n t hera p y.  
 J u d ge d b y i n vesti gat or ha ve a si g nifica nt cli nical si g nifica nc e.  
It is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all la b orat or y a b n or malities a n d a b n or mal vital si g ns a n d t o c o n d uct 
me dical j u d g me nt s w het her ea c h la b orat or y a b n or malit y or a b n or mal vital si g ns s h o ul d be re p orte d as A E.  
If la b orat or y a b n or malities or a b n or mal vital si g ns wit h cli ni cal si g nifica nce is act uall y ma nifestati o ns of a disease or 
s y n dr o me (s uc h as al kali ne p h os p hatase a n d bilir u bi n i ncrease d t o m ore t ha n 5 ti mes t he n or mal u p per li mit  ca use d b y 
c h olec ystitis), o nl y t he dia g n osis (ie, c h olec ystitis) is rec or de d o n t he s o urce d oc u me nt a n d t he A E pa ge of t he C R F . O n 
t he c o ntrar y, la b orat or y a b n or malities or a b n or mal vital si g ns s h o ul d be rec or de d o n t he s o urce d oc u me nt a n d t he A E 
pa ge of C R F , a n d i n dicate t hat t he test val ue is a b o ve or bel o w t he n or mal ra n ge (e .g it s h o ul d be rec or de d as " ele vate d 
ser u m p otassi u m" i nstea d of " A b n or mal ser u m p otassi u m"). If la b orat or y a b n or malities or vital si g ns ha ve 
c orres p o n di n g sta n dar d cli nical ter ms , t he n cli nical ter ms s h o ul d be rec or de d i n t he  s o urce d oc u me nt a n d C R F. F or 
e xa m ple, ser u m p otassi u m i ncrease d t o m ore t ha n t he n or mal u p per li mit s h o ul d be rec or de d as " h y per kale mia." 
T he sa me cli nicall y si g nifica nt la b orat or y a b n or malities or vital si g ns f o u n d i n m ulti ple f oll o w -u p visits s h o ul d n ot b e 
rec or de d as A E or S A E f or m ulti ple ti mes n o matter i n t he s o urce d oc u me nt or  C R F u nless t here is a c ha n ge i n se verit y 
or eti ol o g y.  
De at h  
All deat hs occ urri n g d uri n g t he e ntire trial, i ncl u di n g t he f oll o w -u p peri o d of 3 0 ± 7 da ys aft er t he last a d mi nistrati o n, 
w het her or n ot relate d t o t he st u d y dr u g, s h o ul d be rec or de d i n t he s o urce d oc u me nt a n d deat h re p ort f or m i n C R F a n d 
re p orte d t o t he s p o ns or i n a ti mel y ma n ner. 
I n t he e ve nt of a deat h e ve nt, if t here is a n a d verse e ve nt lea di n g t o deat h, a n i n di vi d ual me dical ter m s h o ul d be use d t o 
rec or d t he deat h e ve nt i n t he s o urce d oc u me nt a n d t he A E p a ge of C R F, a n d t his e ve nt s h o ul d be re p orte d as a n S A E i n 
Accelerate d Re p ort; if t he ca use of t he deat h is u n k n o w n at t he ti me of re p ort, it s h o ul d be rec or de d i n t he s o urce 
d oc u me nt a n d A E pa ge of C R F as " u ne x plai ne d deat h", a n d firstl y re p ort as s o i n S A E acc elerate d r e p ort, t he n f urt her 
i n vesti gate t he e xact ca use of deat h; if deat h is ca use d b y t u m or pr o gressi o n , it will n ot be rec or de d a n d re p orte d as 
A E/ S A E, b ut t he i n vesti gat or s h o ul d rec or d t he deat h i n t he deat h re p ort f or m of C R F, a n d pr o m ptl y i nf or m t he s p o ns o r. 
Pre -e xisti n g me dic al c o n diti o n  
S y m pt o ms/si g ns t hat ha ve bee n prese nt i n t he trial scree ni n g peri o d s h o ul d be rec or de d a n d re p orte d as a d verse e ve nts 
o nl y if t herer is a n i ncrease i n se verit y, fre q ue nc y, a n d nat ur e (e xce pt f or t he deteri orati o n of t he d isease c o n diti o n u n der 
st u d y). C ha n ges relati ve t o baseli ne, s uc h as "i ncrease i n he a dac he fre q ue nc y", s h o ul d be reflecte d i n t he rec or d.  
Re q uires h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n  
A n y a d verse e ve nts t hat res ult i n h os pitalizati o n  or pr ol o n gati o n of e xisti n g h os pitalizati o n s h o ul d be rec or de d a n d 
re p orte d as S A E, wit h t he f oll o wi n g e xce pti o ns: 

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 
Pla n ne d h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitali zati o n acc or di n g t o pr ot oc ole (e. g f or 
a d mi nistrati o n, efficac y assess me nt, etc .). 
 
H os pitalizati o n f or electi ve tre at 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 aseli ne, s uc h as 
electi ve s ur ger y/treat me nt sc he d ule d bef ore partici pati o n i n t he st u d y. H o we ver, if t he pre -e xisti n g disease has 
bee n deteri orate d i n t he st u d y (e. g re q uires s ur ger y/treat me nt earlier t ha n ori gi nall y pla n ne d ), electi ve 
s ur ger y/treat me nt t hat is re q uire d d ue t o t he deteri orati o n of t he disease will be c o nsi dere d a n a d verse e ve nt. 
 
H os pitalizati o n d ue t o r o uti ne or s ocial reas o ns or h os pitaliz a ti o n b y reas o ns ot her t ha n a d verse e ve nts, is n ot 
c o nsi dere d a n a d verse e ve nt.  
Pre g n a nc y  
If a fe male s u bj ect b ec o me pre g na nt d uri n g st u d y, st u d y dr u g s h o ul d be disc o nti n ue d i m me diatel y a n d i n vesti gat or 
s h o ul d be i nf or me d pr o m ptl y. I n vesti gat or s h o ul d re p or t t o s p o ns or wit hi n 2 4 h o urs. T he i n vesti gat or s h o ul d disc uss 
wit h t he s u bj ect t he ris k of c o nti n ui n g pre g na nc y a n d t he p ossi ble i m pact o n fet us. T he m o nit ori n g of t he  s u bj ect s h o ul d 
c o nti n ue u ntil e n d of pre g na nc y. Pre g na nc y wit hi n 3 0 ± 7 da ys of t he last  d ose s h o ul d be re p orte d t o i n vesti gat or.  
W het her i n d uce d a b orti o n or s p o nta ne o us a b orti o n, it s h o ul d be rec or de d a n d re p orte d as S A E. A ba b y b or n t o a fe male 
s u bj ect w h o has ta ke n st u d y dr u g or t he fe male part ner of a male s u bj ect s h o ul d be rec or de d a n d r e p orte d as S A E if a n y 
c o n ge nital a b n or malit y/ birt h d efects e xists.  
M e dic ati o n err or, o ver d ose, a b use a n d mis use  
If me dicati o n err or, o ver d ose, a b use a n d mis use of st u d y dr u g e x perie nce d b y s u bj ects, it s h o ul d be re p orte d t o s p o ns or 
wit hi n 2 4 h o urs of i n vesti gat or’s k n o wle d ge. If a b o ve sit uati o ns lea d t o S A E, i n vesti gat or s h o ul d re p ort t he S A E, a n d 
sit uati o ns s uc h as me dicati o n err or nee d n ot t o be re p orte d  i n a se parate re p ort.  
Li ver f u ncti o n a b n or m al  
A L T or A S T i ncrease t o m ore t ha n 3 ti mes t he baseli ne val ue wit h t otal bilir u bi n i ncrease t o m ore t ha n 2 ti mes t he 
n or mal u p per li mit a n d r ule d o ut cli nical j a u n dice i n d uce d b y c h olestasis or ot her ca use is c o nsi dere d a si g n of se vere 
li ver i nj ur y. T heref ore,  i n vesti gat or m ust re p ort f oll o wi n g cases as a d verse e ve nts: 
 
 
D uri n g treat me nt A L T or A S T i ncrease t o  m ore t ha n 3 ti mes t he baseli ne  wit h t otal bilir u bi n i ncrease t o 
m ore t ha n 2 ti mes t he n or mal u p per li mit ( 3 5 % of t he direct bilir u bi n).  
 
D uri n g treat me nt A L T or A S T i ncrease t o  m ore t ha n 3 ti mes t he baseli ne  wit h cli nical j a u n dice.  
T he m ost a p pr o priate dia g n osis , or la b orat or y o utliers w he n t he dia g n osis is n ot esta blis he d s h o ul d be rec or de d i n 
s o urce d oc u me nt a n d t he A E pa ge of C R F , a n d re p ort to s p o ns or wit hi n 2 4 h o urs after k n o wle d ge of  t he e ve nt, w het her 
or n ot it is seri o us A d verse e v e nts.  
Dise ase pr o gressi o n  

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T he disease st u die d i n t his st u d y, or t he e x pecte d disease pr o gressi o n, or t he s y m pt o ms or si g ns i n d uce d b y disease 
pr o gressi o n, will n ot b e re p orte d as a n a d verse e ve n t u nless it is m ore se vere t ha n e x pecte d. 
L ac k of effic ac y  
W he n t he disease treate d b y t he st u d y dr u g is deteri orati n g, it ma y n ot be p ossi ble t o deter mi ne w het her it is a lac k of 
efficac y or a n a d verse e ve nt. I n t his case, u nless t he i n vesti gat or j u d ges t hat t he deteri orati o n of t he disease is relate d 
wit h t he st u d y dr u g, or s uc h c ha n ge is c o nsi dere d lac k of efficac y rat her t ha n a d verse e ve nts.  
1 0. 4  
Assess me nt of C a us alit y  
T he relati o ns hi p bet wee n t he st u d y dr u g a n d a d verse e ve nt(s) or t he r ole of st u d y dr u g i n a d verse e ve nt(s) ca n be j u d ge d 
b y t he f oll o wi n g classificati o n a n d criteria:  
1)  Defi nitel y rel ate d  
T he refere nce criteria are as f oll o ws: t here is a reas o na ble te m p oral relati o ns hi p bet wee n a d verse e ve nts a n d dr u g 
a d mi nistrati o n; e ve nts ca n n ot be e x plai ne d b y u n derl yi n g disease or ot her dr u gs; de -c halle n ge reacti o n is 
c o nfir me d p ositi ve; a d verse e ve nts  are c o nsiste nt wit h t he p har mac ol o gical pr o perties of t he dr u g a n d, if necessar y, 
pl us p ositi ve re-c halle n ge.  
2)  Pr o b a bl y rel ate d  
T his cate g or y a p plies t o t h ose a d verse e ve nts t hat are hi g hl y deter mi ne d t o be  relate d wit h t he st u d y dr u g. T he 
a d verse e ve nt w o ul d be c o nsi d ere d t o be rele va nt if t he f oll o wi n g t hree or m ore are met:  
a) Has reas o na ble te m p oral relati o ns hi p.  
b)  Ca n n ot b e reas o na bl y e x plai ne d b y t he k n o w n cli nical s y m pt o ms a n d si g ns of t he s u bj ect, t he e n vir o n me ntal 
or t o xic fact ors, or ot her treat me nt r ecei ve d b y t he s u bj ect.  
c) A d verse e ve nt disa p pears or alle viates after disc o nti n uati o n or re d ucti o n of d ose.  
d)  B e c o nsiste nt wit h k n o w n t o xi cit y of s us pect dr u g.  
e) A d verse e ve nts rec ur after re -c halle n ge.  
3)  P ossi bl y rel ate d  
T his cate g or y a p plies t o a d verse e ve nts t hat has u ncertai n b ut n ot p ositi vel y e xcl u de d relati o ns hi p wit h t he st u d y 
dr u g. If t he f oll o wi n g 2 or m ore are met, it is c o nsi dere d t hat t he a d verse e ve nt is li kel y t o be rele va nt:  
a)  Has reas o na ble te m p oral relati o ns hi p  
b)  Ma y be ca use d b y t he disease,  e n vir o n me ntal or t o xic fact ors of t he s u bj ect or ot her treat me nt recei ve d b y t he 
s u bj ect. 
c) B e c o nsiste nt wit h k n o w n t o xi cit y of s us pect dr u g.  

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4)  P ossi bl y u nrel ate d  
Us uall y t his cate g or y a p plies t o a d verse e ve nts meeti n g t w o or m ore of t he f oll o wi n g criteri a: 
a) U nreas o na ble te m p oral relati o ns hi p. 
b)  A d verse e ve nt is o b vi o usl y ca use d b y s u bj ect’s disease, e n vir o n me nt or t o xic fact ors or ot her treat me nt 
recei ve d b y s u bj ects . 
c) I nc o nsiste nt wit h t o xicit y of s us pect dr u g  
d)  N o rec urre nce or a g gra vati o n of a d verse e ve nt af ter rec halle n ge. 
5)  U nrel ate d  
T his cate g or y a p plies t o a d verse e ve nts o b vi o usl y ca use d b y ot her fact ors s uc h as disease or e n vir o n me nt . A n d it is 
i nc o nsiste nt wit h all a b o ve crit eria .  
1 0. 5  
A d verse E ve nt s W hic h C a n n ot be Gr a de d Acc or di n g t o C T C  
W he n c o m pleti n g t he A E F or m i n e C R F, t he i n vesti gat or s h o ul d refer t o t he fi ve -gra de sc ale de vel o pe d fr o m N CI 
C T C -A E versi o n 4. 0 3. F or a d verse e ve nts t hat ca n n ot be cl assifie d acc or di n g t o C T C, t he se verit y of eac h a d verse 
e ve nt will be gra d e d b y t he cli n ical descri pti o n, as f oll o ws: 
 
Gra d e 1: Mil d; as y m pt o matic or wit h sli g ht si g n s; o nl y wit h cli nical or dia g n ostic o bser vati o ns ; n o 
me dical i nter ve nti o n nee de d.  
 
Gra d e 2: M o derate; re q uires mi ni mal, l ocal or n o n -i n vasi ve treat me nt, a ge-a p pr o priate dail y life f u ncti o ns 
(e. g. c o o ki n g, s h o p pi n g, usi n g p h o ne, fi na ncial, etc) are li mite d. 
 
Gra d e 3: seri o us or  cli nicall y si g nifica nt b ut n ot i m me diatel y life-t hreate ni n g; h os pitalizati o n or pr ol o n ge d 
e xisti n g h os pitalizati o n; disa ble d, dail y self -care (e. g. bat h i n g, weari n g cl ot hes, eati n g, t oil et, me dicati o n) 
li mite d, b ut n ot b e d -ri d de n.  
 
Gra d e 4: lea d i n g t o life-t hreate ni n g c o nse q ue nces; e mer ge nt treat me nt is re q uire d.  
 
Gra d e 5: a d verse e ve nt relate d t o deat h .  
1 0. 6  
M a n a ge me nt of A d verse E ve nt  
1 0. 6. 1  
Re p ort of A d verse E ve nt  
T he i n vesti gat or nee ds t o e val uate a n d rec or d a n y of t he a d verse e ve nts i n detail, i ncl u di n g t he o nset date, s y m pt o ms, 
se verit y, d urati o n a n d o utc o me, t he relati o ns hi p bet wee n t he a d verse e ve nt a n d t he st u d y dr u g, dia g n osis a n d t he 
meas ures ta ke n. T he i n vesti g at or s h o ul d pr o vi de ot her e x pla nati o ns f or seri o us a d verse e ve nts t hat p ossi bl y u nrelate d or 
u nrelate d t o t he st u d y dr u g.  
1 0. 6. 2  
Re p ort of Seri o us A d verse E ve nt  

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F or seri o us a d verse e ve nts ( or pre g na ncies) t hat occ ur d uri n g t he st u d y peri o d u p t o 3 0 ± 7 da ys afte r t he last 
a d mi nistrati o n, t he i n vesti gat ors m ust re p ort it t o t he s p o ns or wit hi n 2 4 h o urs of k n o wle d ge me nt, re gar dless of w het her 
t he s u bj ect has recei ve d treat me nt. T he i n vesti gat or s hall s u b mit t he e ve nt re p ort t o t he re g ulat or y a ut h orities or t he 
et hics c o m mittee i n acc or da nce wit h rele va nt re g ulati o ns. Seri o us a d verse e ve nts occ urri n g o utsi de t he a b o ve -me nti o ne d 
peri o d, if c o nsi dere d t o be relate d wit h t he st u d y dr u g, s h o ul d als o be re p orte d t o t he s p o ns or.  
1 0. 7  
F oll o w -u p of A d verse E ve nt  
A d verse e ve nts rel ate d wit h t he st u d y dr u g s h o ul d be f oll o we d u p u ntil t he e ve nt ret ur ns t o baseli ne or bei n g sta ble. If 
a d verse e ve nts ca n n ot b e res ol ve d t o t he baseli ne le vel or bei n g sta ble, a reas o na ble e x pla nati o n s h o ul d be rec or de d i n 
t he s o urce d oc u me nt a n d C R F. Re gar dless of w het her t he e ve nt is relate d t o t he st u d y dr u g, all seri o us a d verse e ve nts 
nee d t o be ha n dle d pr o perl y u ntil t he lea d i n vesti gat or or i n vesti gat or deter mi nes t hat t he e ve nt is c hr o nic or sta ble, or 
t hat t he e ve nt is fi nall y deter mi ne d t o be u nrelate d t o t he st u d y dr u g or rele va nt pr oce d ures. T he rec o ver y a n d date of 
A E or S A E s h o ul d be rec or de d i n s o urce d oc u me nt a n d C R F.  
1 0. 8  
Pre g n a ncies  
1 0. 8. 1  
Pre g n a nc y Test  
F or w o me n wit h c hil d beari n g p ote ntial, ser u m pre g na nc y test will be perf or me d d uri n g t he scree ni n g peri o d, a n d t he 
uri ne pre g na nc y test will be perf or me d  acc or di n g t o t he ti me p oi nts s pecifie d i n T a ble 3. Pre g na nt fe male s u bj ects are 
n ot all o we d t o partici pate i n t his st u d y. If t he pre g na nc y test is p ositi ve at a n y ti me d uri n g t he st u d y peri o d, t he fe male 
s u bj ect s h o ul d i m me diatel y wit h dra w fr o m t he st u d y.  
T he res ults of t he pre g na nc y t est nee d t o be e ntere d i nt o t he data b ase.  
1 0. 8. 2  
Ti me  Peri o d  t o C ollect Pre g n a nc y I nf o r m ati o n  
T he ti me peri o d f or c ollecti n g t he pre g na nc y i nf or mati o n is fr o m t he scree ni n g peri o d u ntil f oll o w -u p of 3 0 ± 7 da ys 
after t he last d ose. It is n ot nec essar y t o re p ort t he pre g na nc y i nf or mati o n c o nfir me d bef ore t he start me dicati o n t o t he 
s po ns or.  
1 0. 8. 3  
M a n a ge me nt t o Pre g n a nc y  
After recei vi n g t he st u d y dr u g, if t he s u bj ect's pre g na nc y test is p ositi ve at a n y ti me, t he s u bj ect s h o ul d be i m me diatel y 
wit h dra w n fr o m t he st u d y. W he n t he st u d y is disc o nti n ue d, all rele va nt test res ults s h o ul d be c ollecte d as baseli ne 
assess me nt.  
T he i n vesti gat or or his a ut h orize d pers o n nel is res p o nsi ble f or c ollecti n g pre g na nc y i nf or mati o n a b o ut fe male part ners 
w h o are pre g na nt or male s u bj ect’s fe male part ner w h o are pre g na nt d uri n g t he st u d y. T he i n vesti gat or or his a ut h orize d 
pers o n nel s h o ul d pr o perl y rec or d t he pre g na nc y i nf or mati o n a n d c o m plete t he pre g na nc y r e p ort f or m wit hi n 2 4 h o urs of 
k n o wle d ge me nt a n d s u b mit it t o t he s p o ns or, a n d f oll o w u p t he pre g na nc y t o c ollect t he o utc o me. Re p ort t o t he s p o ns or 
of a n y earl y ter mi nati o n of pre g na nc y or m ot her a n d c hil d st at us i nf or mati o n. I n ge neral, t he f oll o w -u p peri o d d oes n ot 
e xcee d 6 t o 8 wee ks after t he e x pecte d date of deli ver y.  
Alt h o u g h t he occ urre nce of pre g na nc y is n ot c o nsi dere d a n A E or S A E, b ut t he pre g n a nc y c o m plicati o ns or n o n -ur ge nt 
pre g na nc y ter mi nati o n f or me dical reas o ns will be rec or de d as a n A E or S A E a n d will be f oll o we d.  

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 S p o nta ne o us  a b orti o n is c o nsi dere d a S A E a n d will be re p orte d. I n a d diti o n, f or seri o us a d verse e ve nts t hat occ ur as a 
res ult of pre g na nc y after wit h dra wal fr o m t he st u d y, t he i n vesti gat or s h o ul d reas o na bl y c o nsi der t he e ve nt t o be relate d 
t o t he st u d y dr u g a n d re p ort t he e ve nt t o t he s p o ns or. Alt h o u g h t he i n vesti gat or has n o res p o nsi bilit y t o acti vel y c ollect 
i nf or mati o n a b o ut s p o nta ne o us a b orti o n i n pre vi o us s u bj ects, he/s he ma y be i nf or me d of s eri o us a d verse e ve nts t hr o u g h 
s p o nta ne o us re p orti n g. 

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1 1  
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  
1 1. 1  S a m ple Size C o nsi der ati o n  
P art I  ( d ose safet y assess me nt): T he fi nal sa m ple size will de pe n d o n t he a m o u nt of d ose le vel t o be e val uate d a n d D L T 
of eac h d ose gr o u p. It is esti mate d t hat 2 0 s u bj ects will be e nr olle d t o c o m plete t he d ose s electi o n of B G B -3 1 1 1 
m o n ot hera p y i n C hi nese s u bj ects  wit h B cell mali g na nt l y m p h o ma. St u d y data will be s orte d a n d a nal yze d acc or di n g t o 
statistical pla n. 
P art II  ( d ose e xpa nsi o n): a p pr o xi matel y 2 0 s u bj ects wit h rel a pse d a n d refract or y f ollic ular l y m p h o ma or mar gi nal z o ne 
l y m p h o ma will be e nr olle d t o assess a nti-t u m or acti vit y of B G B-3 1 1 1. St u d y data will be  s orte d a n d a nal yze d acc or di n g 
t o statistical pla n. 
1 1. 2  Ge ne r al G ui deli ne f or  D at a A n al ysis  
All statistical a nal yzes will be perf or me d usi n g S A S ® Versi o n 9. 2 hi g her ( Statistical A nal ysis S yste m, S A S I nstit ute, 
I nc., Car y, N ort h Car oli na), u nless ot her wise i n dicate d. 
1 1. 2. 1 D at a A n al ysis P o p ul ati o n  
T he Safet y P o p ulati o n i ncl u des all s u bj ects w h o recei ve d B G B -3 1 1 1. T he P K p o p ulati o n i ncl u des all treate d s u bj ects 
wit h e val ua ble B G B -3 1 1 1 P K para meters.  Ot her e val ua ble  para meters will be liste d i n statistics re p ort .  
Detaile d statistics met h o d will be ill ustrate d i n statistics pla n.  
1 1. 2. 2 St u d y A n al ysis  
T w o a nal yses will be c o n d uct e d acc or di n g t o st u d y sc he d ul e. T he first a nal ysis will be c o n d ucte d after all e nr olle d 
s u bj ects ha ve c o m plete d a d ose-li miti n g t o xicity ( D L T) assess me nt, a n d t his a nal ysis will f oc us o n assessi n g t he safet y 
a n d t olera bilit y of B G B -3 1 1 1. P har mac o ki netic a n d p har ma c o d y na mics a nal ysis will be i ncl u de d i n t his a nal ysis if data 
is a vaila ble. R P 2 D will be bas e d o n t he res ults of t he first a nal ysis. St u d y will be c o m plete d if all s u bj ects e x perie nce 
disease pr o gressi o n, i nt olera n ce  t o t o xicit y, deat h, wit h dra w n fr o m st u d y, ter mi nati o n  b y s p o ns or or ha vi n g c o m plete d 
all 3 -year treat me nt. T he pri mar y a nal ysis will be c o n d ucte d after t he e n d of st u d y, i ncl u di n g t he safet y, t olera bilit y, 
p har mac o ki netics, p har mac o d y na mics, a n d efficac y of b ot h re gi me ns of B G B -3 1 1 1. T he res ults of t hese a nal yzes  will 
be i ncl u de d i n t he cli nical trial re p ort.  

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1 1. 3  Effic ac y A n al ysis  
Efficac y is n ot t he pri mar y o bj ecti ve of t he P art I  p orti o n of t his st u d y. T he efficac y e val uati o n will be base d o n 
a p pr o priate e val uati o n criteria (I W C L L -C L L 1 5, 1 6, N CI-W G -N H L 1 7, I W W M-W M
1 8, as des cri be d i n A p pe n di x 3, Secti o n 
1 7. 0). Data base a n d classifie d s y n o psis will b e pr o vi de d if data vali dati o n nee de d.  
T he pr o gr essi o n -free s ur vi val ( P F S) ( defi ne d as t he ti me fr o m t he starti n g date of B G B-3 1 1 1 t o t he date of first 
d oc u me ntati o n of disea se pr o gressi o n or deat h, w hic he ver occ urs first) w o ul d be esti mate d usi n g t he Ka pla n-Meier 
met h o d , wit h a me dia n a n d 9 5 % c o nfi de nce I nter val. 
T he o bj ecti ve res p o nse rate ( O R R), t he c o m plete res p o nse rate ( C R R), will be assesse d wit h 9 5 %  c o nfi de nce i nter val. 
T he d urati o n of res p o nse ( D o R) will be esti mate d usi n g t he Ka pla n -Meier met h o d.  
Detaile d statistical met h o ds will be descri be d i n detail i n t he statistical pla n.  
1 1. 4  S afet y A n al ysis  
A n y s u bj ects w h o ha ve recei ve d at least o ne d ose of B G B -3 1 1 1 will be i ncl u de d i n t he safet y a nal ysis (ie, t he safet y 
assess me nt p o p ulati o n). T he safet y is e val uate d b y a s u m mar y of c ha n ges i n a d verse e ve nts, c ha n ges i n la b orat or y 
fi n di n gs, a n d c ha n ges i n vital si g ns. A d verse e ve nts o b vi o usl y ca use d b y disease pr o gressi o n were n ot i ncl u de d i n t he 
dr u g -relate d t o xicit y assess me nt. 
A d verse e ve nts of s pecial i nterests (s uc h as blee di n g) will b e defi ne d i n t he statistical pla n.  
A d verse e ve nts will be c o u nte d o n i n di vi d ual s u bj ect a n d treat me nt gr o u p. All a d verse e ve nts will be gra de d acc or di n g 
t o N CI C T C A E ( versi o n 4. 0 3). T he a d verse e ve nts will be c o de d usi n g t he I nter nati o nal Me dical Dicti o nar y ( Me d D R A 
1 7. 0 or hi g her ). Acc or di n g t o t he S yste m O r ga n Classificati o n a nd t he c orres p o n di n g Preferre d T er m t o s u m u p t h e 
n u m ber a n d fre q ue nc y of a d verse e ve nts. All S A E (i ncl u di n g deat h), D L T, a d verse e ve nts l ea di n g t o wit h dra wal will be 
c o u nte d.  
T he safet y data will b e s u m marize d acc or di n g t o t he d ose at w hic h t he s u bj ect is ra n d o ml y assi g ne d at t he ti me of 
e nr oll me nt. F or s u bj ects wit h a d ose i ncrease or decrease, t he a d verse e ve nts t hat occ urre d will still be c o u nte d 
acc or di n g t o t he assi g ne d i niti al d ose le vel gr o u p.  
F or l a b or at or y p ar a meters,  he m at ol o g y , bl o o d bi oc he mistr y, c o a g ul ati o n, uri ne r o uti ne a n al ysis will be liste d 
o ne b y o ne a n d i n dic ate i ncre ase or decre ase c o m p are d wit h t he n or m al r a n ge. T he l a b or at or y res ults bef ore a n d 
after a d mi nistr ati o n will be c o m p are d a n d a n al yze t he re as o n f or t he i ncre ase or decre ase, if a p pr o pri ate  
1 1. 4. 1 A n al ysis  of D os a ge  
T he  d osa ge a nal ysis will b e a p pli e d  t o all s u bj ects treate d wit h B G B-3 1 1 1, a n d all d os es will be a nal yze d acc or di n g t o 
me dicati o n  stat us, wit h dra wal , d ose a dj ust me nt, etc.  
1 1. 4. 2 Electr o c a r di o gr a m  
E C G a nal ysis of all s u bj ects, i ncl u di n g Q T i nter val ( Q T c) a n d  c ha n ges relati ve t o baseli ne le vels, will be a nal yze d case -
b y -case a n d i n dicate c orres p o n di n g d osa ge le vel a n d assess me nt ti me. T o e x pl ore t he relati o ns hi p bet wee n Q T c i nter val 
a n d d ose le vel, Q T i nter val will be calc ulate d usi n g Q T c F f or m ula. T he c ha n ges  i n Q T c F ( baseli ne c orrecte d Q T c F) f or 

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eac h s u bj ect a n d t he B G B -3 1 1 1 bl o o d e x p os ure at t he sa me ti me p oi nt will be a nal yze d se p aratel y f or t he Da y 1  W ee k 1 
a n d Da y 1 W ee k 2 , a n d if p ossi ble, a gra p hical or statistical a p pr oac h will be use d t o i n vesti gate the p ote ntial c orrelati o n.  
1 1. 5  P h ar m ac o ki netic Assess me nt  
T he ti me p oi nt of t he p har mac o ki netic sa m pli n g ca n be deter mi ne d acc or di n g t o t he pre -test. T he bl o o d sa m ple will be 
c ollecte d after si n gle d ose of Da y 1 a n d Da y 2 of W ee k 1, after m ulti ple d oses o n Da y 1 W ee k 2, Da y 1 W ee k 5, a n d 
Da y 1 W ee k 9 (refer t o T a ble 4 a n d T a ble 5).  
P har mac o ki netic para meters of B G B -3 1 1 1 will be a nal yze d as liste d  bel o w : 
A U C 0 -∞ 
A rea u n der t he plas ma c o nce ntrati o n-ti me c ur ve f or 0-∞ 
A U C last a n d A U C ss 
A rea u n der t he plas ma c o nce ntrati o n-ti me c ur ve f or 0 -fi nal s a m pli n g ti me 
p oi nt a n d f or stea d y state 
C ma x  a n d C ma x,ss  
Ma xi m u m plas ma c o nce ntr ati o n a n d c o nce ntrati o n at  stea d y state 
tma x  a n d t ma x,ss  
Ti me t o ma xi m u m plas ma c o nce ntrati o n a n d ti me t o stea d y plas ma 
c o nce ntrati o n  
λz  
E li mi nati o n rate c o nsta nt 
t1/ 2 
Half life  
C L/ F  
A p pare nt plas ma cleara nce  
V d/ F  
T er mi nal a p pare nt distri b uti o n v ol u me  
R A U C  
A U C  acc u m ulati o n ( A U C of Da y 1 Wee k 2/ A U C of Da y 1 W ee k 1 ) 
R C ma x  
Acc u m ulati o n of m a xi m u m pl as ma c o nce ntrati o n  (C ma x  of D a y 1 W ee k 
2/ C ma x  of Da y 1 W ee k 1 ) 
If p ossi ble, t he f oll o wi n g p har mac o ki netic para meters will b e calc ulate d usi n g t he list i nste a d of descri pti ve 
statistics 
I nter val 
I nter val ( h o urs)  t o deter mi ne t he λ z l o garit h m li near re gressi o n 
n  
N u m ber of data p oi nts t o deter mi ne λ z l o garit h m li near re gressi o n ( at least 
3 p oi nts)  
Rs q  
Calc ulate t he s q uare of t he λz c orrelati o n c oefficie nt, a n d if t he s q uare of 
t he c orrelati o n c oefficie nt is less t ha n 0. 8 0 0, t he n λz a n d t he rele va nt 
para meters will n ot be re p orte d.  
% A U Ce x  
T he perce nta ge of A U C is cal c ulate d usi n g e xtra p olati o n, a n d if m ore t ha n 

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2 0 %, A U C a n d relate d para meters will n ot be re p orte d  
Ot her p har mac o ki netic para meters t hat nee d t o be esti mate d.  
 
T he B G B -3 1 1 1 plas ma c o nce ntrati o n -ti me data will be s u m marize d b y fi g ures a n d ta bles, a n d will be a nal yze d base d o n 
n o n -c o m part me ntal m o del a n d/ or c o m part me ntal m o del.  
T he p har mac o ki netic para met ers  A U C last、A U C 0 -∞、C ma x 、tma x 、t1/ 2、C L/ F 、V d/ F  f or si n gle d ose a n d A U C ss、C ma x,ss 、
tma x,ss  f or m ulti ple d oses at ste a d y state will be e val uate d. T he varia bles o btai ne d at differe nt ti me p oi nts will be 
statisticall y descri be d b y d ose gr o u p. If t he data is s ufficie nt, t he para meter val ues ( mea n, sta n dar d de viati o n, me dia n, 
mi ni m u m, ma xi m u m, sta n dar d de viati o n a n d l o garit h m of ge o metric mea n) f or all treat me nt gr o u ps a n d eac h d ose 
gr o u p will be descri be d se p aratel y i n t he s u m mar y re p ort.  
T he d ose  pr o p orti o nalit y of A U C ss、C ma x 、 a n d C ma x,ss   of B G B -3 1 1 1 will be e val uate d usi n g a p o wer m o del i n a n 
e x plicit c hart f or m. T he statistical a nal ysis of t he relati o ns hi p bet wee n t he de pe n de nt varia bles (l o garit h m of P K 
para meters A U C, C ma x , a n d A U Clast) a n d t he i n de pe n de nt varia bles (l o garit h m of d ose) will be perf or me d i n a li near 
re gressi o n m o del (l o g [ P K] = α + β * l o g [ D ose]), t h us t he m o del para meters [ β] [ α] will be esti mate d usi n g least 
s q uares re gressi o n a nal ysis. D ose pr o p orti o nalit y wit h t w o -si de d 9 5 % c o nfi de nce i nter val of re gressi o n c oefficie nt will 
be esti mate d wit h p o wer f u ncti o n m o del of at least 3 cases wit h effecti ve p har mac o ki netic para meters.  
1 1. 6  P h ar m ac o d y n a mics  Assess me nt  
P har mac o d y na mics is n ot t he pri mar y o bj ecti ve  of t his st u d y. B T K occ u pa nc y pr o p orti o n i n peri p heral m o n o n uclear cell 
wit h b y a nal yze d wit h sa m ples  c ollecte d at sc he d ule d ti me p oi nts s pecifie d i n T a ble 3 a n d T a ble 4 .  
1 1. 7  S a m ple Size i n P art II  
 2 0 s u bj ects wit h rela pse d a n d refract or y f ollic ular l y m p h o ma or mar gi nal z o ne l y m p h o ma will be e nr olle d i n P art II  of 
d ose escalati o n st u d y. T he sa m ple size calc ulati o n is pri maril y base d o n t he acc urac y le vel of t he o verall res p o nse rate 
esti mate. If t he o verall res p o nse rate is 3 5 %, t he 9 5 % e xact c o nfi de nce i nter val w o ul d be ( 1 5. 4 %,  5 9. 2 %), t h us t he a nti -
t u m or acti vit y of B G B-3 1 1 1 i n refract or y f ollicle L y m p h o ma or mar gi nal z o ne l y m p h o ma will be clearl y de m o nstrate d.  

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E T HI C A L C O N SI D E R A TI O N S A N D I N F O R M E D C O N S E N T  
1 2. 1  
A p pr o v al fr o m Re g ul at or y A ut h orit y  
T he s p o ns or s h o ul d o btai n a cli nical t rial a p pr o val fr o m C F D A acc or di n g t o rele va nt re g ulati o ns bef ore t he st u d y is 
i nitiate d at a st u d y ce nter.  
1 2. 2  
Et hic al d oc u me nt a n d Et hic al  A p pr o v al  
T his st u d y will be c o n d ucte d i n acc or da nce wit h G C P a n d all a p plica ble re g ulat or y re q uire me nts, i ncl u di n g, w he re 
a p plica ble, c urre nt versi o n of t he Declarati o n of Helsi n ki , t o best pr otect s u bj ects.  
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  a n d a me n d me nts , 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 will be prese nte d t o p ote ntial s u bj ects (e . g a d vertise me nts f or recr uit me nt) 
as well as ot her necessar y d oc u me nts  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 he i n vesti 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 oc u me nts. T he s p o ns or will pr o vi de t he i n vesti gat or wit h rele va nt 
d oc u me nt(s)/ data t hat are nee de 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.  T he a p pr o val of t he I E C/I R B m ust b e 
o btai ne d bef ore t he st u d y starts a n d t he c o m mittee's meeti n g a n d a p pr o val date s h o ul d be i n dicate d i n t he a p pr o val letter 
t o i n vesti gat ors. 
A n y re visi o n of t he pr ot oc ol m ust b e f or mall y a p pr o ve d or file d b y t he I E C/ R B.  
D uri n g t he st u d y, if a n y pr ot oc ol vi olati o n ma y i ncrease t he ris k of t he s u bj ect, i n vesti g at ors s h o ul d re p ort t o t he 
I E C/I R B pr o m ptl y. 
1 2. 3  
I nf o r me d C o nse nt 
S u bj ects m ust si g n i nf or me d c o nse nt bef ore e nr oll me nt, a n d t he pr ocess of si g ni n g i nf or me d c o nse nt will f oll o w t he 
rele va nt re g ulati o ns. 
1 2. 4  
I n vesti g at or Re p orti n g Re q uire me nts 
As descri be d i n Secti o n 1 0. 6, t he i n vesti gat or or s p o ns or s h o ul d re p ort all seri o us a d verse e ve nts t o rele va nt et hics 
c o m mittee a n d re g ulat or y a ut h orities  i n acc or da nce wit h rele va nt re g ulati o ns. I n a d diti o n, i n vesti gat ors nee d t o re p ort 
u p date d safet y re p orts a n d ce nter cl os u re n otificati o ns t o t he I E C/I R B o n a re g ular basis d uri n g t he c o urse of t he st u d y, 
a n d t he res p o nsi bilit y of s uc h peri o dic all y re p orti n g rests o n  t he i n vesti gat or i nstea d of t he s p o ns or.  

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P R O T O C O L M O DI FI C A TI O N S  
All pr ot oc ol m o dificati o ns m ust b e 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 b e 
o btai ne d bef ore c ha n ges ca n b e i m ple me nte d, u nless t his m o dificati o n is i nte n de d t o re d uce i m me diate ris k t o s u bj ects, 
or o nl y i n v ol ve wit h a d mi nistr ati ve i nf or mati o n c ha n ge (s uc h as te le p h o ne n u m ber c ha n ge). 

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R E T E N TI O N O F S T U D Y F I L E S, C R F A N D R E C O R DS  
1 4. 1  
Rete nti o n of St u d y Files a n d D oc u me nt  
T he i n vesti gat or m ust mai ntai n a d e q uate a n d acc urate rec or ds t o e na ble t he c o n d uct of t he st u d y t o be f ull y d oc u me nte d 
a n d t he st u d y data t o be s u bse q ue ntl y verifie d.  T hese 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 ories: ( 1) i n vesti gat or’s st u d y file, a n d ( 2) s u bj ect cli nic al s o urce d oc u me nts.  
T he i n vesti gat or’s st u d y file i ncl u des 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 re g ulat or y 
a p pr o val wit h c orres p o n de nce, sa m ple of i nf or me d c o nse nt, dr u g i n ve nt or y f or m, 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 me nts a n d c orres p o n de nce.  
S u bj ec t’s s o urce d oc u me nts ( us uall y defi ne d i n a d va nce t o re c or d ke y efficac y/safet y para meters)   i ncl u de s u bj ect 
h os pital/cli nic rec or ds, p h ysici a n’s a n d n urse’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, C T , X-ra y, 
P E T re p ort, pat h ol o g y a n d s pe cial assess me nt re p orts, si g ne d I C F, c o ns ulta nt rec or ds, scree ni n g a n d e nr oll me nt l o g, etc.  
I n vesti gat ors nee d t o reser ve t he d oc u me nts f or 5 years after c o m pleti o n or ter mi nati o n of st u d y . D oc u me nts c o ul d be 
destr o ye d i n acc or da nce wit h t he la ws a n d re g u lati o ns fi ve years after st u d y c o m pleti o n. S p o ns or s h o ul d be n otifie d 
bef ore d oc u me nts destr o ye d.  
T he i n vesti gat or m ust n otif y t he s p o ns or of a n y c ha n ges i n t he arc hi val arra n ge me nts.  
If t he i n vesti gat or ca n n ot g uara ntee t his arc hi vi n g re q uire me nt at t he st u d y ce nter  f or a n y or all of t he d oc u me nts, 
s pecial arra n ge me nts m ust b e ma d e bet 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 ne d seale d t o t he i n vesti gat or i n case of a re g ulat or y a u dit. W he n s o urce d oc u me nts are 
re q uire d f or t he c o nti n ue d care of t he s u bj ect, a p pr o priate c o pies s h o ul d be ma de f or st ora ge o utsi de of t he site.  
1 4. 2  
S o urce D oc u me nt a n d D at a  
If t he C R F is am bi g u o us or a n err or occ urs i n t he data tra nsfer, i n vesti gat or s h o ul d pr o vi de t he ori gi nal data i n t he st u d y 
d oc u me nt or t he me dical rec or d at t he re q uest of s p o ns or. If t here is a s pecial q uesti o n, q uer y fr o m re g ulat or y a ut h orities 
a n d/ or re q uest d uri n g i ns pecti o n, co m plete  st u d y rec or ds s h o ul d be pr o vi de d  wit h pr otecti o n of s u bj ect ’s pri vac y.  
1 4. 3  
A u dit a n d I ns pecti o n  
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 vaila ble t o a p pr o priatel y 
q ualifie d pers o n nel fr o m s p o ns or 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 pect ors. 
1 4. 4  
C ase Re p ort F or m  ( C R F) 
F or eac h s u bj ect e nr olle d, a C R F m ust b e c o m plete d a n d si g ne d b y t he pri nci pal i n vesti gat or or desi g nate d pers o n nel  
wit hi n a rea s o na ble ti me peri o d after data c ollecti o n.  T his als o a p plies t o rec or ds f or t h ose s u bj ects w h o fail 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 was i nitiate d).  If a s u bj ect wit h dra ws fr o m t he 
st u d y, t he reas o n m ust b e n ote d o n t he C R F.  If a s u bj ect is wit h dra w n fr o m t he st u d y d ue t o D L T , e ver y e n dea v or  
s h o ul d be ma d e t o clearl y d oc u me nt t he o utc o me.  

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All C R F m ust b e writte n wit h ball p oi nt p e n w h ic h is n ot eas y t o fa de. W he n ma ki n g a n y necessar y c orrecti o ns, dra w a 
li ne o n t he  i nc orrect rec or ds rat her t ha n s mear, a n d write d o w n t he c orrect c o nte nt, t he a b bre viate d si g nat ure a n d date of 
t he i n vesti gat or or desi g nee.  

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U TI LI Z A TI O N A N D P U B LI C A TI O N O F R E S E A R C H D A T A  
1 5. 1  
Utiliz ati o n of St u d y  D at a  
All data of B G B -3 1 1 1, s uc h as pate nt a p plicati o n, d osa ge f or m, ma n ufact uri n g pr ocess, basic researc h data, etc. is 
re gar de d as c o nfi de ntial i nf or mati o n as l o n g as it has n ot bee n p u blis he d.  
Data o btai ne d fr o m st u d y is re gar de d as c o nfi de ntial i nf or mal as w ell. Bei Ge ne will p u blis h data t o ot her cli nical 
researc hers, t he state f o o d a n d dr u g a d mi nistrati o n, or ot her g o ver n me nt a ge nc y w he n a p pr o priate. T o e ns ure t he 
i nte grit y of t he cli nical data a nal ysis, t he i n vesti gat ors ha ve a n o bli gati o n t o offer c o m plete test res ults a n d data t o 
s p o ns or.  
I n vesti gat ors m ust e ns ure t hat t he pri vac y of t he s u bj ects is n ot discl ose d t o a n y u na ut h oriz e d t hir d part y. T he na mes of 
t he s u bj ects s h o ul d n ot b e i ncl u de d i n s u b mitte d C R F a n d ot her file d oes, b ut o nl y i de ntifi e d wit h  a c o de . I n vesti gat or 
c o ul d retai n e nr oll me nt f or m w hic h i ncl u des i de ntif y  c o de, na me a n d a d dress of s u bj ects. I nf or me d c o nse nt f or m a n d 
ot her d oc u me nts s h o ul d be strictl y c o nfi de ntial, a n d n ot be s u b mitte d t o s p o ns or . 
1 5. 2  
P u blic ati o n  
T he res ults of t his st u d y  ca n b e p u blis he d i n c ore j o ur nals. I n vesti gat or w h o pr o vi des maj or c o ntri b uti o n t o t he 
i m ple me ntati o n a n d ma na ge me nt of t he st u d y, a n d e m pl o yee w h o pr o vi des maj or c o ntri b uti o n t o t he st u d y desi g n, 
e x pla nati o n or a nal ysis ca n be si g ne d.  
B ei Ge ne pr o mises t o  s u b mit pa p er t o i n vesti gat or f or re vie w bef ore p u blicati o n of a n y st u d y d ata. I n vesti gat ors m ust 
o btai n  a p pr o val fr o m s p o ns or bef ore p osti n g t he aca de mic p a per or a bstract. I n vesti gat or has t he ri g ht t o p u blis h  t he 
res ults of t his st u d y b ut s h o ul d c o m pl y  wit h t he pr otecti o n of c o nfi de ntial  i nf or mati o n.  
C o nfi de ntial i nf or mati o n of t he i ntellect ual pr o pert y ri g hts bel o n g t o Bei Ge ne. Wit h o ut writte n c o nse nt fr o m B ei Ge ne, 
c o nfi de ntial i nf or mati o n s hall n ot b e discl ose d t o ot hers or use d f or i nterti o ns e xce pt f or t his st u d y.  

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1 6  
R E F E R E N C E S  
1.  I n vesti gat or’s Br oc h ure, B G B-3 1 1 1.  E diti o n 1, d oc u me nt n u m ber B G B -3 1 1 1 -0 4 2 0 1 4: 0 1, A pril 2 0 1 4.  
2.  C o m m o n T o xicit y Criteria Versi o n 4. 0 3. Ca ncer T hera p y E val uati o n Pr o gra m. 1 4  J u ne 2 0 1 0.  
3.  Ric kert R C.  Ne w i nsi g hts i nt o pre -B C R a n d B C R si g nali n g wit h rele va nce t o B cell mali g na ncies.  Nat Re v 
I m m u n ol 2 0 1 3.  1 3( 8): 5 7 8-9 1  
4.  Wiest ner A. T he r ole of B -cell rece pt or i n hi bit ors i n t he treat me nt of patie nts wit h c hr o nic l y m p h oc yctic le u ke mia. 
Hae mat ol o gica 2 0 1 5. 1 0 ( 1 2): 1 4 9 5 -1 5 0 7.  
5.  A d va ni R H, et al.  Br ut o n t yr osi ne ki nase i n hi bit or i br uti ni b (( P CI -3 2 7 6 5) has si g nifica nt acti vit y i n patie nts wit h 
rela pse d/refract or y B-cell mali g na ncies.  J Cli n O nc ol 2 0 1 3. 3 1( 1): 8 8-9 4.  
6.  Br o w n J R. P CI -3 2 7 6 5, t he First B T K ( Br ut o n’s T yr osi ne Ki nase) I n h i bit or i n Cli nical Trials. C urr. He mat ol. Mali g. 
Re p. 2 0 1 3. 8( 1): 1 -6.  
7.  B yr d J C, et al.  T ar geti n g B T K wit h i br uti ni b i n rela pse d c hr o nic l y m p h oc ytic le u ke mia.  N E n gl J Me d 2 0 1 3. 
3 6 9( 1): 3 2 -4 2  
8.  W a n g M L, et al., T ar geti n g B T K wit h i br uti ni b i n rela pse d or ref ract or y ma ntle-cell l y m p h o ma. N E n gl J Me d 2 0 1 3. 
3 6 9( 6): 5 0 7 -1 6  
9.  Clar o R, et al. F D A A p pr o val: I br uti ni b f or P atie nts wit h Pre vi o usl y Treate d Ma ntle Cell L y m p h o ma a n d 
Pre vi o usl y Treate d C hr o nic L y m p h oc ytic Le u ke mia. Cli n. Ca ncer Res. 2 0 1 5. 2 1 ( 1 6): 3 5 8 6 -3 5 9 0.  
1 0.   O’ Brie n S, et al. I br uti ni b as i nitial t hera p y f or el derl y patie nts wit h c hr o nic l y m p h oc ytic l e u ke mia or s mall 
l y m p h oc ytic l y m p h o ma: a n o pe n-la bel, m ultice nter, p hase 1 b/ 2 trial. La ncet O nc ol. 2 0 1 4. 1 5: 4 8 -5 8.  
1 1.  Tre o n S P, et al. I br uti ni b i n Pre vi o usl y Treate d Wal de nstr ö m’s m’s Macr o gl o b uli ne mia. N. E n gl. J. Me d. 2 0 1 5. 3 7 2 
( 1 5): 1 4 3 0-1 4 4 0.  
1 2.  W a n g M L, et al. T ar geti n g B T K wit h i br uti ni b i n rela pse d or refract or y ma ntle -cell l y m p h o ma. N E n gl J Me d. 2 0 1 3. 
3 6 9( 6): 5 0 7 -1 6.  
1 3.  K o hrt H E et al. I br uti ni b a nta g o nizes ri t u xi ma b-de pe n de nt N K cell -me diate d c yt ot o xicit y. Bl o o d. 2 0 1 4. 
1 2 3( 1 2): 1 9 5 7 -6 0.  
1 4.  R oit F D et al. I br uti ni b i nterferes wit h t he cell -me diate d a nti -t u m or acti vit y of t hera pe utic C D 2 0 a nti b o dies: 
i m plicati o ns f or c o m bi nati o n t hera p y. Hae mat ol o gica. 2 0 1 5. 1 0 0( 1): 7 7 -8 6.  
1 5.   Halle k M, et al. G ui deli nes f or t he dia g n osis a n d treat me nt of c hr o nic l y m p h oc ytic le u ke mia: a re p ort fr o m t he 
I nter nati o nal W or ks h o p o n C hr o nic L y m p h oc ytic Le u ke mia u p dati n g t he Nati o nal Ca ncer I nstit ute -W or ki n g Gr o u p 
1 9 9 6 g ui deli nes. Bl o o d. 2 0 0 8.  1 1 1( 1 2): 5 4 4 6 -5 4 5 6.  
1 6.  B ai B, et al. I n di vi d ualize d ma na ge me nt of f ollic ular l y m p h o ma. C hi n Cli n O nc ol. 2 0 1 5: 4( 1): 7.  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
6 9  
V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
C o n f i d e n t i a  
 
1 7.  B artlett N, et al. I br uti ni b m o n ot hera p y i n rela pse d/refract or y f ollic ular l y m p h o ma ( F L): preli mi nar y res ults of a 
P hase 2 C o ns orti u m ( P 2 C) T rial. Bl o o d. 2 0 1 4. 1 2 4: 8 0 0.  
1 8.  I nter nati o nal W or ks h o p Gr o u p o n C L L (I W C L L) res p o nse criteria f or C L L. 2 0 1 5 
1 9.  C hes o n, B D et al. Rec 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 ma: T he L u ga n o Classificati o n. J Cli n O nc ol. 2 0 1 4. 3 2: 3 0 5 9 – 3 0 6 8.  
2 0.  O we n R G, et al. Res p o nse assess me nt i n Wal de nstr ö m’s¨ m macr o gl o b uli nae mia: u p date fr o m t he VIt h 
I nter nati o nal W or ks h o p. Br. J. Hae mat ol. 2 0 1 3. 1 6 0( 2): 1 7 1-1 7 6.  
2 1.  I nter nati o nal C o nfere nce o n H ar m o nizati o n N ote f or G ui da nce o n G o o d Cli nical Practice ( C P M P/I C H/ 1 3 5/ 9 5).  
J ul y 1 9 9 6. 
2 2.  C he n S S, et al. B T K i n hi biti o n res ults i n i m paire d C X C R 4 c he m o ki ne rece pt or s urface e x pressi o n, si g nali n g a n d 
f u ncti o n i n c hr o nic l y m p h oc ytic le u ke mia. Le u ke mia 2 0 1 6. 3 0 ( 4): 8 3 3 -4 3.  
2 3.  B ur ger J A, et al . I br uti ni b as I nitial T hera p y f or P atie nts wit h C hr o nic L y m p h oc ytic le u ke mia. N. E n gl. J. Me d. 
2 0 1 5. 3 7 3 ( 2 5): 2 4 2 5 -3 7  
2 4.  N C C N G ui deli nes, L y m p h o plas mac ytic L y m p h o ma/ W al de nstr ö m’s m’s Macr o gl o b uli ne mi a 2 0 1 5: V 2.  
2 5.  中国恶性淋巴瘤诊疗规范（2 0 1 5 年版） 
2 6.  P hase II P C Y C -1 1 2 1 Trial: I br uti ni b M o n ot hera p y Acti ve i n R/ R Mar gi nal Z o ne L y m p h o ma. A S H 2 0 1 6  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
7 0  
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C o n f i d e n t i a  
 
1 7  
A P P E N DI X  
A p pe n di x 1:  Cli nic al L a b or at or y Test  
Cli nic al bi oc he mistr y  
He m at ol o g y  
C o a g ul ati o n  
Uri n al ysis  
I m m u n o gl o b uli n 
a n al ysis a n d 
i m m u n ofi x ati o n  
Al kali ne p h os p hatase  
He m o gl o bi n  
Pr ot hr o m bi n ti me  
p H val ue  
I g A  
Ala ni ne 
a mi n otra nsferase  
Retic ul oc yte c o u nt  
O pti o nal test  
Acti vate d P artial 
t hr o m b o plasti n Ti me 
S pecific gra vit y  
I g G 
As partate 
a mi n otra nsferase  
Platelet c o u nts  
I nter nati o nal 
N or malize d Rati o  
Gl uc ose  
I g M 
 
Al b u mi n  
W B C c o u nt wit h 
differe ntial  
 
Pr otei n  
i m m u n ofi xati o n 2 
T otal a n d direct 
bilir u bi n  
Ne utr o p hil c o u nt  
 
Ket o nes  
 
C O 2（Car b o n 
di o xi de ） 
E osi n o p hil c o u nt  
 
he mat uria  
 
Bl o o d urea nitr o ge n  
L y m p h oc yte c o u nt  
 
2 4 -h o ur pr otei n 1 
Ra n d o m uri ne pr otei n  
 
Calci u m  
B a n ds  
O pti o nal test  
 
 
 
C hl ori ne  
 
 
 
 
Creati ni ne  
 
 
 
 
Gl uc ose  
 
 
 
 
Lactate de h y dr o ge nase  
 
 
 
 
P h os p hate  
O pti o nal test  
 
 
 
 
T otal pr otei n  
 
 
 
 
P otassi u m  
 
 
 
 
S o di u m  
 
 
 
 
Ma g nesi u m  
 
 
 
 
P h os p h or us  
 
 
 
 
Uric Aci d  
 
 
 
 
creati ni ne cleara nce  
 
 
 
 
 
1.  If uri ne pr otei n is ≥2 + i n uri nal ysis, a 2 4 -h o ur uri ne pr otei n  will be detecte d wit h calc ulati o n of ra n d o m uri ne 
pr otei n t o creati ni ne rati o.  
2.  Al l s u bj ects wit h W M will recei ve t he first i m m u n ofi xati o n. If m o n ocl o nal pr otei n e xists, all i m m u n o gl o b uli n will 
be detecte d.  
3.  It is n ot c o nsi dere d as a pr ot oc ol d e viati o n  i n case t hat a site ca n n ot pr o vi de all e xa mi nati o n res ults b ut it has n o 
i m pact o n dr u g safet y assess me nt a n d wit h a p pr o val fr o m me dical m o nit or.  
 

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C o n f i d e n t i a  
 
A p pe n di x 2:  S a m ple C ollecti n g V ol u me  
Ti me  
P ar a meters t o be assesse d 
Bl o o d c ollect i o n 
v ol u me ( m L) i n 
P art I  
Bl o o d c ollecti o n 
v ol u me ( m L) i n 
P art II  
Scree ni n g  
 
 
 
Bi oc he mistr y  
5  
5  
 
Hea met ol o g y  
2. 5  
2. 5  
 
C oa g ulati o n test  
3  
3  
 
I g A, I g G, I g M le vel a n d 
i m m u n ofi xati o n electr o p h oresis  
5  
5  
 
Ser u m vir us detecti o n  
5  
5  
 
T otal v ol u me  
2 0. 5  
2 0. 5  
Wee k 1  
 
 
 
Da y 1  
 
 
 
 
Bi oc he mistr y  
5  
5  
 
Hea met ol o g y  
2. 5  
2. 5  
 
C oa g ulati o n test  
3  
3  
 
P har mac o ki netics 1  
P har mac o d y na mics  
3 2 2  
1 6 2 
3 6 2  
 
 
T otal v ol u me  
5 8. 5  
4 6. 5  
Da y 2  
 
 
 
 
P har mac o ki netics  1  
P har mac o d y na mics  
4 2  
8 2 
4 2  
 
 
T otal v ol u me  
1 2  
4  
Wee k 2  
Da y 1  
 
 
Bi oc he mistr y  
Hea met ol o g y  
P har mac o ki netics 1  
P har mac o d y na mics  
 
 
5  
2. 5  
2 8 2 
8 2 
 
 
5  
2. 5  
3 6 2 
 
 
 
 
 
 
T otal v ol u me  
4 3. 5  
4 3. 5  
Wee k 3  
 
 
 
Da y 1  
 
 
 
 
Bi oc he mistr y  
5  
5  
 
Hea met ol o g y  
2. 5  
2. 5  
 
T otal v ol u me  
7. 5  
7. 5  
Wee k 5  
 
 
 
Da y 1  
 
 
 
 
Bi oc he mistr y  
5  
5  
 
Hea met ol o g y  
2. 5  
2. 5  
 
C oa g ulati o n test  
3  
3  
 
I g A, I g G, I g M le vel a n d 
i m m u n ofi xati o n electr o p h oresis  
5  
5  
P har mac o ki netics 1 
4  
4  
 
T otal v ol u me  
1 9. 5  
1 9. 5  
Wee k 7  
 
 
 
Da y 1  
 
 
 
 
Bi oc he mistr y  
5  
5  
 
Hea met ol o g y  
2. 5  
2. 5  
 
T otal v ol u me  
7. 5  
7. 5  
Wee k 9 -5 3  
 
 
Bi oc he mistr y  
 
 
5  
 
 
5  
E ver y 4 wee ks  
 

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C o n f i d e n t i a  
 
 
Hea met ol o g y  
C oa g ulati o n test  
I g A, I g G, I g M le vel a n d 
i m m u n ofi xati o n electr o p h oresis  
P har mac o ki netics 1 
2. 5  
3  
5  
 
4  
2. 5  
3  
5  
 
4  
 
 
 
T otal v ol u me  
1 9. 5  
1 9. 5  
Wee k 5 3 +  
E ver y 8 wee ks  
 
 
Bi oc he mistr y  
 
 
5  
 
 
5  
Hea met ol o g y  
2. 5  
2. 5  
C oa g ulati o n test  
3  
3  
I g A, I g G, I g M le vel a n d 
i m m u n ofi xati o n electr o p h oresis  
5  
5  
 
T otal v ol u me  
1 5. 5  
1 5. 5  
Tre at me nt 
disc o nti n u ati o n 
or pre m at ure 
wit h dr a w al  
 
 
 
 
Bi oc he mistr y  
5  
5  
 
Hea met ol o g y  
2. 5  
2. 5  
 
C oa g ulati o n test  
3  
3  
 
I g A, I g G, I g M le vel a n d 
i m m u n ofi xati o n electr o p h oresis  
5  
5  
 
T otal v ol u me  
1 5. 5  
1 5. 5  
1 W he n a safet y e ve nt nee ds t o be assesse d f or a relati o ns hi p wit h dr u g e x p os ure, t he p har mac o ki netic sa m ple will be 
c ollecte d at a n y ti me wit h o ut pri or pla n ni n g.  
2 I ntra ve n o us i n d welli n g nee dle ma y be preset f or c ollecti n g p har mac o ki netic a n d p har mac o d y na mics sa m ples. 
Sa m ples will be c ollecte d t hr o u g h t he i ntrave n o us i n d welli n g nee dle at ti me p oi nts s pecifi e d i n ta ble 4. Discar d 1  ml 
of bl o o d sa m ple  b ef ore eac h s a m pli n g .   
3 O nl y p har mac o ki netic bl o o d sa m ple will be c olllecte d  o n Da y 1 W ee k 9 . 
 
 

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
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A p pe n di x 3:  Effic ac y Assess me nt Criteri o n  
A)  C hr o nic l y m p h oc ytic le u ke mi a 1 5 ,1 8   
P ara meters  
C R *  
P R  
P D  
Gr o u p A  
 
     
 
l y m p ha d e n o pat h y N o ne > 1. 5 c m  
Decrease b y ≥5 0 % a n d n o ne w 
l y m p ha de n o pat h y（> 1. 5 
c m） 
I ncrease b y ≥5 0 % or ne w 
l y m p h n o de lesi o n 
he p at o me gal y  
N o ne  
Decrease  b y  ≥5 0 % if li ver 
e nlar ge d at baseli ne  
I ncrease b y ≥5 0 %  
s ple n o me gal y 
N o ne  
Decrease b y ≥5 0 % if s plee n 
e nlar ge d at baseli ne  
I ncrease b y ≥5 0 %  
Bl o o d 
l y m p h oc ytes 
< 4 0 0 0/ μl  
Decreasse b y ≥5 0 % fr o m 
baseli ne  
I ncrease b y ≥5 0 % * * fr o m 
baseli ne  
Marr o w  
N o cl o nal C L L cell i nfiltrati o n, 
n o n o d ular l y m p h oc ytes 
a g gre gate  
 
 
Gr o u p B  
  
 
 
B P C  
> 1 0 0 0 0 0/ μl  
> 1 0 0 0 0 0/ μ l or i ncrease b y 
≥5 0 % fr o m baseli ne  
Decreasse b y ≥5 0 % fr o m 
baseli ne  
H b  
> 1 1. 0 g/ d L  
> 1 1. 0 g/ d L or i ncrease b y 
≥5 0 % fr o m baseli ne  
Decreasse b y > 2 g/ d L fr o m 
baseli ne  
A N C  
> 1 5 0 0/ μl  
> 1 5 0 0/ μ l or i ncrease b y 
≥5 0 % fr o m baseli ne  
 
Criteria i n Gr o u p A defi ne t he t u m or l oa d;  Criteria i n Gr o u p B defi n e t he f u nc tio n of he mat o p oietic s yste m ( or marr o w) . 
C R  ( C o m plete rea p o nse): c o m plies wit h all criteria a n d wit h n o disease -relate d s yste mic s y m pt o ms. 
P R  (P artial re s p o nse): ≥ 1  criteria i n Gr o u p A pl us  ≥ 1 criteria i n Gr o u p B .  P ersiste nt  l y m p h oc yt osis d oes n ot affect t he 
dia g n osis  of P R, w hic h ca n be la belle d P R -L . 
S D  (Sta ble disease ): d o n ot meet t he criteria f or partial res p o nse or pr o gressi ve disease . 
P D  (Pr o gressi ve disease ): ≥ 1 criteria i n Gr o u p A or  ≥ 1 criteria i n Gr o u p B.  
* C Ri: C o m plia nce wit h all C R criteria, b ut t here ma y be persiste nt ne utr o pe nia, a ne mia or t hr o m b oc yt o pe nia t hat ma y 
be ass oci ate d wit h dr u g t o xicit y i nstea d of disease.  
* *  I n t he c o nte xt of re d uce d l y m p h n o de v ol u me, miti gate d or ga n e nlar ge me nt, or i m pr o ve d he m o gl o bi n/ platelet c o u nt, 
is olate d pr o gressi ve l y m p h oc yt osis will n ot b e c o nsi dere d pr o gressi ve disease. 
 
 
 

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B)  L u ga n o criteria f or N o n H o d g ki n L y m p h o ma res p o nse assess me nt ( P E T s h o ul d be c o m plete d wit h dia g n ostic 
c o ntrast e n ha nce d C T at t he sa me ti me or pr ocee d wit h differ e nt pr o gra ms. 1 7 
Res p o nse  
Site  
Pet -C T ( met a b olic 
res p o nse) 
C T ( R a di ol o gic re s p o nse)d  
C o m plete  res p o nse 
L y m p h n o des a n d 
e xtral y m p hatic sites  
Sc ore of 1, 2, or 3 a o n 5 -p oi nt 
scale, wit h or wit h o ut a 
resi d ual mass b, c 
All of t he f oll o wi n g:  
T ar get n o des/ n o dal mass 
m ust re gress t o ≤ 1. 5 c m i n 
L Di  
N o e xtral y m p hatic sites of 
disease  
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 i n m or p h ol o g y; if 
i n deter mi nate, I H C ne gati ve 
P artial res p o nse  
L y m p h n o des a n d 
e xtral 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  
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  
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  
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 
is 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 plica ble  
N o res p o nse or sta ble 
disease  
T ar 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 
< 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  

B G B -3 1 1 1 C hi n ese P hase I Cli nical St u d y Pr ot o c ol          Bei Ge ne （Beiji n g ）C o. , Ltd                         Pr ot o c ol N o.:  B G B -3 1 1 1 -1 0 0 2  
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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  
Pr o gressi ve disease  
I n di vi d ual tar get 
n o des/ n o dal masses  
E xtra n o dal lesi o ns  
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 
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/le si 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 
u n meas ura ble  lesi o ns 
N o ne  
Clear pr o gressi o n of ne w or 
pre -e xisti n g u n meas ura ble  
lesi o ns 
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 ot her eti ol o g y 
(e g, i nfecti o n, 
i nfla m mati o n). If t he 
eti ol o g y of ne w lesi o ns is 
u ncertai n, 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 
 
 
a A sc ore of 3 i n ma n y patie nts i n dicates a g o o d pr o g n osis, es peciall y if at 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 ore of 3 as i na de q uate res p o nse (t o a v oi d 
u n der -treat me nt). 

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b Refer t o P E T 5 P S ( 5 -P S)  
c Ge nerall y , t he u pta ke i n W al de yer’s ri n g or sites of hi g h ps ysi ol o gical u pta ke or s plee n/ b o ne marr o w acti vati o n (e. g., 
b y c he m ot hera p y or m yel oi d c ol o n y sti m ulati n g fact or) ma y be greater t ha n t hat of n or mal me diasti n u m a n d/ or li ver. I n 
t his case, if t he u pta ke of i niti all y i n v ol ve d site is n ot greater t ha n t he s urr o u n di n g n or mal tiss ue, e ve n if t his site is of 
hi g h p h ysi ol o gical u pta ke, it c a n als o be j u d ge d as c o m plete m olec ular res p o nse ( C M R).  
d It is p ossi ble t o o bser ve false p ositi ve P E T sca n res ults ass ociate d wit h i nfecti o us or i nfla m mat or y c o n diti o ns. Bi o ps y 
i n t he affecte d area is still t he g ol d sta n dar d f or c o nfir mi n g ne w or persiste nt lesi o ns.  
 
 
P E T 5 -p oi nt scale  (5 -P S ): 
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.  
 
 
 

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C)  W al de nstr ö m’s macr o gl o b uli ne mia
 1 8 ，2 4 
 C o m plete res p o nse ( C R): A bs e nce of ser u m m o n ocl o nal I g M pr otei n b y i m m u n ofi xati o n, N or mal ser u m I g M le vel, 
C o m plete res p o nse of e xtra me d ullar y disease, N o  s ple n o me gal y or l y m p ha de n o pat h y if prese nt at baseli ne, 
M or p h ol o gicall y  n or mal i n b o ne marr o w as pirate a n d bi o ps y , No s y m pt o ms a n d si g ns ca us e d b y macr o gl o b uli n mia.  
 Ver y g o o d partial re missi o n ( V G P R): M o n ocl o nal I g M pr otei n is detecta ble , > 9 0 %  re d ucti o n i n ser u m I g M le vel 
fr o m baseli ne, C o m plete re s p o nse of e xtra me d ullar y disease , N o s ple n o me gal y or l y m p ha d e n o pat h y  if prese nt at 
baseli ne, N o ne w si g ns or s y m pt o ms of acti ve disease . 
 P artial re s p o nse ( P R): M o n ocl o nal I g M pr otei n is detecta ble, > 5 0 % b ut < 9 0 % re d ucti o n i n ser u m I g M le vel fr o m 
baseli ne , Re d ucti o n i n l y m p ha de n o pat h y/s ple n o me gal y if prese nt at baseli ne, N o ne w si g ns or s y m pt o ms of acti ve 
disease . 
 Mi n or  res p o nse  ( M R): M o n ocl o nal I g M pr otei n is detecta ble , ≥2 5 % b ut < 5 0 % re d ucti o n i n ser u m I g M le vel fr o m 
baseli ne , N o ne w si g ns or s y m pt o ms of acti ve disease .  
 Sta ble disease ( S D): M o n ocl o nal I g M pr otei n is detecta ble,  wit h < 2 5 % re d ucti o n b ut i ncr ease als o < 2 5 % i n ser u m 
I g M le vel fr o m baseli ne, N o pr o gressi o n i n l y m p ha de n o pat h y/s ple n o me gal y , N o ne w si g ns or s y m pt o ms of acti ve 
disease.  
 Pr o gressi ve disease  ( P D): > 2 5 % i ncrease i n ser u m I g M le vel fr o m na dir a n d/ or pr o gressi o n i n cli nical ma nifestati o n s 
attri b uta ble t o disease . 
 
 

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A p pe n di x 6 : M e dic ati o ns C a use d Q T/ Q Tc Pr ol o n ge d  
A nti arr h yt h mics  
a mi o dar o ne  
dis o p yra mi de  
d ofetili de  
flecai ni de 
i b utili de 
pr ocai na mi de  
q ui ni di ne  
s otal ol 
A ntic a ncer  
arse nic tri o xi de  
va n deta ni b  
A nti hist a mi nes  
aste miz ole  
terfe na di ne 
A nti bi otics  
azit hr o m yci n  
clarit hr o m yci n  
er yt hr o m yci n  
m o xifl o xaci n  
s parfl o xaci n 
A nti a n gi n al  
be pri dil  
A nti m al ari al  
c hl or o q ui ne  
hal ofa ntri ne  
A nti ps yc h otics  
c hl or pr o mazi ne  
hal o peri d ol  
mes ori dazi ne  
pi m ozi de  
t hi ori dazi ne 
A nti n a use a  
d o m peri d o ne  
dr o peri d ol  
d olasetr o n (i ntra ve n o us a n d  oral)  
A nti -i nfecti ve 
pe nta mi di ne  
A ntili pe mic  
pr o b uc ol  
A nti d press a nts  
cital o pra m 

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O pi ate a g o nists  
le v o met ha d yl 
met ha d o ne  
GI sti m ul a nt  
cisa pri de