Conditions: B-cell Lymphoma
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 44
Healthy volunteers: no

Brief summary:
This phase I clinical study was to investigate the safety, tolerability, and pharmacokinetics/pharmacodynamics of Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (BGB-3111) in Chinese participants with B-cell lymphoma by conducting in two stages, the first stage being the safety assessment of dose and the second stage being the dose expansion.

Part I: Safety evaluation - according to the results of preclinical toxicological trials and the results of the phase I clinical study conducted in Australia and New Zealand, two regimens of zanubrutinib 320 milligrams (mg) daily (160 mg twice daily \[BID\]), administered in the morning and at night, or 320 mg once daily \[QD\]) and "3+3" design was adopted for the assessment. The recommended dose and method of administration of the phase II clinical study was determined according to the Part I results.

Part II: Dose expansion - this stage was to further evaluate the preliminary anti-tumor effects of zanubrutinib in Chinese participants with follicular lymphoma (FL) or marginal zone lymphoma (MZL), approximately 20 participants with relapsed or refractory FL or MZL were to be enrolled. The recommended Phase 2 dose (RP2D) was used in Part II.

Detailed description:

Arms:
arm 1: Safety Evaluation: Two regimens of zanubrutinib 320 milligrams (mg) daily (160 mg twice daily \[BID\]) administered in the morning and at night, or 320 mg (once daily \[QD\]), and a "3+3" design was adopted for Part I of the study to determine recommended Phase 2 dose (RP2D). arm 2: Safety Evaluation: Two regimens of zanubrutinib 320 mg daily (160 mg BID, administered in the morning and at night, or 320 mg QD) and a "3+3" design was adopted for Part I of the study to determine RP2D. arm 3: Dose Expansion: The RP2D determined in Part I was used in Part II to further evaluate the preliminary anti-tumor effects of zanubrutinib in Chinese participants with follicular lymphoma (FL) or marginal zone lymphoma (MZL).

Interventions: intervention 1: Zanubrutinib
Intervention descriptions: intervention 1: Zanubrutinib is a white to off-white solid that is slightly hygroscopic. The drug product was formulated as 20-mg (blue, size 3) and 80-mg (white, size 0) hard gelatin, opaque oral capsules. Zanubrutinib is classified as a Biopharmaceutics Classification System Class II compound.

Protocol document:
Prot_000.pdf: 
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  
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  
 
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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C o n f i d e n t i a
 
 
 
 
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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C o n f i d e n t i a
 
 
 
 
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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V e r s i o n  2 . 0  F e b r u a r y  0 6 , 2 0 1 7  
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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   
 
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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
 
 
 
 
 
 
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  
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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  
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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  
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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  
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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  
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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  
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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  
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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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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  


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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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C o n f i d e n t i a  
 
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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C o n f i d e n t i a  
 
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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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.  
 


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  
 
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  
 


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 2  
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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  
7 3  
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C o n f i d e n t i a  
 
 
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. 
 
 
 


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)  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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C o n f i d e n t i a  
 
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). 


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 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  
 
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.  
 
 
 


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 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  
 
 
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 . 
 
 






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  
8 0  
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C o n f i d e n t i a  
 
 
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 


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  
8 1  
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C o n f i d e n t i a  
 
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  
 
 
 
 

SAP_001.pdf: 
B ei Ge ne ( B eiji n g) C o., Lt d  
   B G B -3 1 1 1 -1 0 0 2  
     ( Statistical A nal ysis Pla n) 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1  of 2 8  
C O N FI D E N TI A L  
S T A TI S TI C A L A N A L Y SI S  P L A N  
St u d y Pr ot oc ol 
N u m ber:  
B G B -3 1 1 1 -1 0 0 2  
St u d y Pr ot oc ol 
Title:  
A  p hase  I  cli nical  st u d y  t o  i n vesti gate  t he  s afet y,  t olera bilit y  a n d 
p har mac o ki netics/  p har mac o d y na mics  of  B T K  i n hi bit or  B G B -3 1 1 1  i n 
C hi nese patie nts wit h B -cell l y m ph o ma 
D ate:  
N o ve m ber  1 , 2 0 1 7  
Versi o n : 
2. 0  










 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 3  of 2 8   
C O N FI D E N TI A L  
 
T A B L E O F C O N T E N T S  
S U M M A R Y O F M AJ O R C H A N G E S F R O M P R E VI O U S V E R SI O N  
7  
1  
I N T R O D U C TI O N 
8  
2  
S T U D Y O V E R VI E W  
8  
3  
S T U D Y O BJ E C TI V E S  
1 0  
3. 1  
Part I : Safet y E val uati o n  
1 0  
3. 1. 1  
Pri mar y O bj ecti ve  
1 0  
3. 1. 2  
Sec o n dar y O bj ecti ve  
1 0  
3. 1. 3  
E x pl orat or y O bjecti ve 
1 0  
3. 2  
Part II : D ose e x pa nsi o n 
1 0  
3. 2. 1  
Pri mar y O bj ecti ve  
1 0  
3. 2. 2  
Sec o n dar y O bj ecti ve  
1 0  
3. 2. 3  
E x pl orat or y O bjecti ve 
1 0  
4  
S T U D Y E N D P OI N T S  
1 0  
4. 1  
Part I : Safet y E val uati o n  
1 0  
4. 1. 1  
Pri mar y E n d p oi nts: 
1 0  
4. 1. 2  
Sec o n dar y E n d p oi nts: 
1 1  
4. 1. 3  
E x pl orat or y E n d p oi nts: 
1 1  
4. 2  
Part II: D ose E x pa nsi o n  
1 1  
4. 2. 1  
Pri mar y E n d p oi nts: 
1 1  
4. 2. 2  
Sec o n dar y E n d p oi nts: 
1 1  
4. 2. 3  
E x pl orat or y E n d p oi nts: 
1 1  
5  
S A M P L E SI Z E C O N SI D E R A TI O N S  
1 1  
6  
S T A TI S TI C A L M E T H O D S  
1 2  
6. 1  
A nal ysis P o p ulati o ns 
1 2  
6. 2  
Data A nal ysis Ge n er al C o nsi derati o ns  
1 2  
6. 2. 1  
Defi niti o ns a n d C o m p utati o ns 
1 3  
6. 2. 2  
C o n ve nti o ns 
1 3  
6. 2. 3  
Ha n dli n g of Missi n g Dat a 
1 4  
6. 2. 4  
A dj ust me nt f or C o variates 
1 5  
6. 2. 5  
M ulti plicit y A dj ust me nt  
1 5  
6. 2. 6  
Data I nte grit y  
1 5  
6. 3  
S u bject C haracteristics  
1 5  
6. 3. 1  
S u bject Dis p ositi o n  
1 5  
6. 3. 2  
Pr ot oc ol De viati o ns 
1 5  
6. 3. 3  
De m o gra p hic a n d Ot her Baseli ne C haracteristics  
1 5  
6. 3. 4  
Pri or A nti -Ca ncer Dr u g T hera pies a n d S ur geries  
1 6  
6. 3. 5  
Pri or a n d C o nc o mita nt Me dicati o ns 
1 6  
6. 3. 6  
Me dical Hist or y  
1 6  
6. 4  
Efficac y A nal ysis  
1 7  
6. 5  
Safet y A nal yses  
1 9  
6. 5. 1  
E xte nt of E x p os ure 
1 9  


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
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C O N FI D E N TI A L  
 
6. 5. 2  
A d verse E v e nts  
2 0  
6. 5. 2. 1  
D L T A nal ysis  
2 0  
6. 5. 2. 2  
Ot her A d verse E v e nts A nal ysis  
2 0  
6. 5. 2. 3  
E x p os ure- A dj uste d I n ci d e nce Rates ( E AI R)  
2 1  
6. 5. 3  
La b orat or y V al ues  
2 2  
6. 5. 4  
Vital Si g ns  
2 3  
6. 5. 5  
P h ysical E x a mi nati o n  
2 4  
6. 5. 6  
Electr ocar di o gra ms ( E C G)  
2 4  
6. 5. 7  
Easter n C o o perati ve O nc ol o g y Gr o u p  (E C O G)  
2 4  
6. 6  
P har mac o ki netic A n al ys es  
2 4  
7  
I N T E RI M A N A L Y SI S 
2 5  
8  
C H A N G E S I N T H E P L A N N E D A N A L Y SI S  
2 6  
9  
R E F E R E N C E S  
2 6  
1 0  
A P P E N DI X  
2 7  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 5  of 2 8   
C O N FI D E N TI A L  
 
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  
Ter m  
A E  
A d verse e ve nt  
A T C  
A nat o mical T hera pe utic C he mical  
A U C  
A rea u n d er t he c o nce ntrati o n-ti me c ur ve 
BI D  
T wice a D a y 
B MI  
B o d y Mass I n d e x  
B T K  
Br ut o n t yr osi ne ki nase  
C ma x  
Ma xi m u m o bser ve d plas ma c o nce ntrati o n  
C L/ F  
Plas ma dr u g cleara nce rate  
C R F  
C ase re p ort f or m  
C R  
C o m plete res p o nse  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
C L L  
C hr o nic l y m p h oc ytic le u ke mia 
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 
D O R  
D urati o n of res p o ns e  
E C G  
Electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
F L  
F ollic ular L y m p h o ma  
H b  
H e m o gl o bi n  
H C L  
Hair y Cell Le u ke mia  
L P L  
L y m p h o plas mac yti c L y m p h o ma  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M C L  
M a ntle Cell L y m p h o ma  
M R D  
Mi ni mal Resi d ual Disease  
M Z L  
Mar gi nal Z o ne L y m p h o ma  
N CI  
Nati o nal Ca ncer I nstit ute  
O R R  
O verall  r es p o nse rate 
O S  
O verall s ur vi val  
P B M Cs  
P eri p heral bl o o d m o n o n u clear  cells  
P D  
P r o gr essi ve disease, dis ease pr o gressi o n 
P D  
P har mac o d y na mics  
P K  
P har mac o ki netic  


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
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C O N FI D E N TI A L  
 
P F S  
P r o gr essi o n-free s ur vi val 
P T  
Preferre d Ter m  
Q 1  
2 5 % q ua ntile  
Q 3  
7 5 % q ua ntile  
Q D  
Dail y  
R P 2 D  
R ec o m me n de d P hase II d ose  
S A E  
S eri o us a d verse e ve nt  
S A P  
Stat istical A nal ysis Pla n 
S D  
S ta n dar d de viati o n 
S L L  
S ma ll L y m p h o c yti c Ly m p h o ma  
S M C  
Safet y M o nit ori n g C o m mittee  
S O C  
S yste m Or ga n Class  
T E A E  
T reat me nt-e mer ge nt a d v erse e v e nt  
t1/ 2 
Ter mi nal half -life 
tma x  
Ti me c orres p o n di n g t o m a xi m u m o bser ve d plas ma c o nce ntrati 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  
Wal de nstr ö m's macr o gl o b uli ne mia  


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
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P a ge 7  of 2 8   
C O N FI D E N TI A L  
 
S U M M A R Y O F M A J O R C H A N G E S F R O M P R E VI O U S V E R SI O N  
 
Secti o n  
Versi o n 1 . 0 
( Pre vi o us) 
Versi o n 2 . 0 ( C urre nt) 
Rati o nale  
Str uct ure  
 
 
T o c o m pl y t o 
Bei Ge n e S A P 
sta n dar d. 
1 . I ntr o d u cti o n: 
P ur p ose 
6. 2 Data A nal ysis 
Ge ner al 
C o nsi derati o ns  
T o descri be t he D ose 
Li mit T o xicit y ( D L T) 
a nal ysis of Part I 
o nl y. 
T o descri be t he fi nal 
a nal ysis of b ot h Part I 
a n d Par II.  
T o meet a nal ysis 
nee ds w he n st u d y 
pr ocee ds t o a fi nal 
sta ge. 
6. 3 S u bject 
C haracteristics  
6. 5 Safet y A nal ysis 
T o pla n c o ncise 
s u m maries ser vi n g 
t he D L T 
deter mi nati o n 
p ur p ose.  
T o pla n f ull sc o pe 
s u m maries wit h 
details, ser vi n g t h e 
fi nal a nal ysis 
p ur p ose.  
T o meet a nal ysis 
nee ds f or fi nal 
a nal ysis; t o c o m pl y t o 
Bei Ge n e S A P 
sta n dar d. 
6. 4 Efficac y A nal ysis  
N ot a vaila ble.  
T o pla n f ull sc o pe 
s u m maries wit h 
details, ser vi n g t h e 
fi nal a nal ysis 
p ur p ose.  
T o meet a nal ysis 
nee ds f or fi nal 
a nal ysis; t o c o m pl y t o 
Bei Ge n e S A P 
sta n dar d. 
6. 6 P K A nal ysis  
T o pla n c o ncise 
s u m maries ser vi n g 
t he D L T 
deter mi nati o n 
p ur p ose.  
T o pla n f ull sc o pe 
s u m maries wit h 
details, ser vi n g t h e 
fi nal a nal ysis 
p ur p ose.  
T o meet a nal ysis 
nee ds f or fi nal 
a nal ysis.  
Refere n ces, 
A p pe n dices 
T o s u p p ort c o nte nt.  
T o s u p p ort c o nte nt.  
T o s u p p ort u p date d 
c o nte nt, c o m pl y t o 
B ei Ge n e S A P 
sta n dar d, a n d reflect 
latest safet y i nterests 
f or t he pr o d uct. 
 
 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 8  of 2 8   
C O N FI D E N TI A L  
 
1  
I N T R O D U C TI O N 
T he p ur p ose of t his statistical a nal ysis pla n ( S A P) is t o descri be t he pr o ce d ures a n d t he statistical 
met h o ds t hat will be use d t o a nal yze a n d re p ort res ults f or B G B - 3 1 1 1- 1 0 0 2. T he f oc us of t his 
S A P is f or t he fi nal pla n ne d a nal ysis s pecifi e d i n t he st u d y pr ot o c ol. T his S A P is base d o n 
versi o n 2. 0 of t he pr ot oc ol, date d Fe br uar y 6, 2 0 1 7. 
T he a nal ysis details f or P har mac o ge n o mics a n d Bi o mar ker a nal yses are n ot descri be d  wit hi n t his 
S A P.  
2  
S T U D Y O V E R VI E W  
T his p hase I st u d y is t o i n vesti gate t h e d ose safet y, t olera bilit y, p har mac o ki netics ( P K ) a n d 
P har mac o d y na mics ( P D ) 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 ec o m me n de d p hase II d ose ( R P 2 D), base d o n t he m ulti- d os e, d ose escalati o n 
p hase I trials w hic h h as c o m plete d i n A ustralia a n d Ne w Zeala n d.  
T he st u d y c o nsists of t w o parts , t he first part  b ei n g t he safet y e v al uati o n  of t w o d ose sc he d ules, 
a n d t he sec o n d p art  bei n g t he d ose e x pa nsi o n. At t he ti me of t his S A P’s c o m p ositi o n, t he first 
part  was c o m plet e d a n d 1 6 0 m g BI D w as c h ose n as t he R P 2 D. Base d o n t he res ults o btai ne d, 
d ose e x pa nsi o n st u dies were  perf or m e 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 n al z o ne l y m p h o ma ( M Z L).  
P art I: S af et y e v al u ati o n   
Acc or di n g t o t he r es ults of precli nical t o xic ol o gical st u dies a n d t he res ults of t he p hase I cli nical 
st u d y c o n d u cte d i n A ustr alia a n d Ne w Zeal a 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 nister e d i n t he m or n i 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 was  
a d o pte d f or t he assess me nt. T hree eli gi ble s u bjects were  e nr olle d f or eac h d ose re gi me n: first, if 
1/ 3 ( 1 case) p atie nts e x perie nce d d os e- li miti n g t o xicit y ( D L T), a n ot her 3 s u bjects were t o  be 
e nr olle d f or c o nti n ue d o bser vati o n. Acc 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 N e 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 n e of t he first 3 e nr olle d patie nts e x perie nce d 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 D L T, t h e n it was  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 w o ul d 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 p atie nts 
e nr olle d pre vi o usl y) t o f urt her assess t he s afet y, t olera bilit y, P K  a n d preli mi nar y P D  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 bjects or 6 s u bjects (i ncl u di n g t h e s u p ple me nte d 3 
patie nts) e x perie nce d D L T wit hi n t he D L T o bs er v ati o n wi n d o w ( Da y 1- 2 8), it w o ul d be 


 
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                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
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C O N FI D E N TI A L  
 
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) h a d e x cee de d t he 
ma xi m u m t olerate d d ose ( M T D) a n d d os e w o ul d b e decreas e d  t o 8 0 m g BI D or 1 6 0 m g Q D. 
T hree eli gi ble patie nts w o ul d 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 saf e, t he s p o ns or a n d i n vesti gat or w o ul d a nal yz e a n d disc uss w het her t o 
m o ve f or war d wit h a n i nter me diate d os e 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 was  t olera ble, t h e 
trial w o ul d be ter mi nate d.  
D uri n g t h e trial, t he s p o ns or, lea di n g i n vesti gat or a n d i n vesti gat ors w o ul d 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 s afet y assess me nt. S M C w o ul d deci de t he d ose l e 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 dat a fr o m t he 
f or mer d ose l e vel. 
T he t o xicit y o bser vati o n peri o d of B G B- 3 1 1 1 was  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 bject 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 
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 hiche ver o cc urs first. 
If a s u bject 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 b e 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, d eat h, or wit h dra wal fr o m st u d y, u n d er 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 was  c o n d ucte d after all t he s u bjects ha ve c o m plet e d D L T assess me nt, 
a n d t his a nal ysis f o c us e d o n t he safet y a n d t olera bilit y of B G B- 3 1 1 1. P K a n d  P D  were  als o 
i ncl u de d i n t his a nal ysis. Acc or di n g t o t he safet y d ata of t he Part I a n 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 b ee n sel ecte d as t he R P 2 D. F or 
s u bjects i n part I, if t he i nitial d ose was  3 2 0 m g Q D, after t h e c o m pleti o n of D L T 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 
c o ul d 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 pr eli mi nar y a nti- t u m or effects of B G B- 3 1 1 1 i n Chi n ese s u bjects wit h F L 
or M Z L, a p pr o xi matel y 2 0 s u bjects wit h rela pse d or refract or y F L or M Z L will be e nr olle d. T he 
R P 2 D deter mi ne d i n Part I, i.e. 1 6 0 m g BI D, will be use d i n t he Part II.  
T o e val uate t he preli mi nar y efficac y wit h o ut har mi n g s u bject’s be n efit, t h e a nti -t u m or acti vit y 
assess me nt will be c o n d u cte 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 w ee ks 1 year 
later) after first d ose. S u bjects w h o d o n ot e x perie nce diseas e 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 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
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C O N FI D E N TI A L  
 
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 bject 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 b e 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, d eat h, or wit h dra wal fr o m st u d y. 
3  
S T U D Y O B J E C TI V E S  
3. 1  
P A R T I: S A F E T Y E V A L U A TI O N  
3. 1. 1  Pri m ar y O bjecti ve  
•  T o e val uate t he s afet y a n d t olera bilit y o f 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 d eter mi ne R P 2 D. 
3. 1. 2  Sec o n d ar y O bjecti ve  
•  T o c har acterize t he 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 effect 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).  
3. 1. 3  E x pl or at or y O bjecti ve 
•
  
3. 2  
P A R T II: D O S E E X P A N SI O N  
3. 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 bjects wit h F L or M Z L.  
3. 2. 2  Sec o n d ar y O bjecti ve  
•  T o f urt her assess t he saf et y a n d t olera bilit y of B G B- 3 1 1 1 i n patie nts wit h F L or M Z L . 
•  T o f urt her c har acterize t he 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.  
3. 2. 3  E x pl or at or y O bjecti ve 
•  
 
4  
S T U D Y E N D P OI N T S  
4. 1  
P A R T I: S A F E T Y E V A L U A TI O N  
4. 1. 1  Pri m ar y E n d p oi nts:  
•  Safet y a n d t oler a bilit y of B G B - 3 1 1 1: T he o cc urre n ce of a d v erse 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 bjec t will be m o nit ore d acc or di n g t o N CI-C T C A E  4. 0 3 


 
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                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 1  of 2 8   
C O N FI D E N TI A L  
 
gr a di n g criteri a d uri n g t h e 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.  
4. 1. 2  Sec o n d ar y E n d p oi nts:  
•  P K  para meters  of B G B - 3 1 1 1 after a si n gle d os e a n d m ulti ple d oses 
•  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 P B M C  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 P B M C . 
4. 1. 3  E x pl or at or y E n d p oi nts: 
•  
 
 
4. 2  
P A R T II: D O S E E X P A N SI O N  
4. 2. 1  Pri m ar y E n d p oi nts:  
•  O R R, C R R, P R R, d urati o n of res p o nse ( D O R) a n d P F S of B G B- 3 1 1 1 i n s u bjects wit h F L or 
M Z L.  
4. 2. 2  Sec o n d ar y E n d p oi nts:  
•  Safet y a n d t oler a bilit y of B G B - 3 1 1 1 i n F L a n d M Z L: T he o cc urre n ce of A Es a n d S A Es of 
eac h s u bject 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 K  para meters  of B G B - 3 1 1 1 after a si n gle d os e a n d m ulti ple d oses 
4. 2. 3  E x pl or at or y E n d p oi nts: 
•  
 
 
 
5  
S A M P L E SI Z E  C O N SI D E R A TI O N S  
Part 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 os e 
le vels a n d t o xicit y o cc urr e 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 bjects will be e nr olle d 
i n or der t o assess t he s afet y a n d t oler a bilit y of B G B- 3 1 1 1 a n d d eter mi ne R P 2 D. 
Part II ( D os e 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 at t he R P 2 D le vel ( 1 6 0 m g 
BI D) . T he sa m ple size calc ulati o n is base d pri maril y o n t he acc urac y le v el of t he O R R esti mate. 
W he n t he sa m ple size is 2 0 s u bjects, if t he O R R is 3 5 %, t he 9 5 % e x act c o nfi de nce i n ter 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 L  or M Z L  
will be clearl y de m o nstr ate d.   


 
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                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 2  of 2 8   
C O N FI D E N TI A L  
 
6  
S T A TI S TI C A L M E T H O D S  
6. 1  
A N A L Y SI S P O P U L A TI O N S  
D L T E v al ua ble P o p ulati o n: I ncl u d es all s u bjects w h o recei ve d at least 7 5 % of t he pla n ne d d os es 
of treat me nt d uri n g t he D L T o bser vati o n peri o d ( Da y 2 8). T his p o p ulati o n will be use d i n t he 
D L T s u m mary. 
Safet y P o p ulati o n :  I ncl u des all s u bjects w h o recei ved at least o ne d os e of B G B - 3 1 1 1. T he s afet y 
p o p ulati o n will be use d f or all s u m maries (e x ce pt D L T  a n d P K). 
P K P o p ulati o n: I n cl u des all s u bjects w h o recei ve d at least o ne d ose of B G B - 3 1 1 1 a n d at least 
o ne p ost d ose P K c o nce ntrati o n. S u bjects w h o ha d maj or pr ot oc ol de viati o ns t hat w o ul d i m pact 
t he a bs or pti o n, distri b uti o n, meta b olis m a n d e x creti o n of B G B - 3 1 1 will be e x cl u de d. 
Per - pr ot oc ol ( P P) P o p ulati o n i ncl u des s u bjects w h o recei v e d at least o ne d ose of B G B- 3 1 1 1 a n d 
ha d n o maj or pr ot oc ol de viati o ns. Criteria f or e x cl usi o n fr o m t he P P will be deter mi ne d a n d 
d oc u me nte d bef ore t he d ata base l oc k. T his m a y b e use d as a s u p pl e me ntar y t o t he a n al ysis of t h e 
pri mar y (efficac y) e n d p oi nts of t he d ose e x pa nsi o n part if m ore t ha n 1 5 % of t he safet y 
p o p ulati o n ha ve maj or pr ot oc ol de viati o ns. 
S u m mar y of a nal ysis p o p ulati o ns will pr o vi de t he n u m ber a n d perce nt a ge of s u bjects i n eac h 
a nal ysis p o p ulati o n, o ut of all t he s u bjects i n t he Safet y P o p ulati o n. 
6. 2  
D A T A A N A L Y SI S G E N E R A L C O N SI D E R A TI O N S  
Part I of t he st u d y is c o m plete d a n d t his S A P descri bes t he fi nal a n al ysis  t o be perf or me d after 
st u d y c o m pleti o n (“ pri mar y a nal ysis” i n t he pr ot oc ol). St u d y will be c o m pl ete d if all s u bjects 
e x perie nce disease pr o gr essi o n, i nt olera nce 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 h a vi n g c o m plete d all 3- year treat m e nt. T he fi nal  a n al ysis will i ncl u d e t he safet y, 
t olera bilit y, P K, P D, a n d efficac y of b ot h re gi me ns of B G B- 3 1 1 1. T h e res ults of t hese a nal yses 
will be i ncl u de d i n t he C S R . 
E x ce pt f or t he D L T s u m mar y  w hic h  is t o be perf or me d f or Part I patie nts o nl y, all ot her 
s u m maries will be perf or me d f or Part I p atie nts o nl y, Part II patie nts o nl y, a n d all patie nts 
p o ole d. I n Part I s u m maries, patie nts will be gr o u pe d b y t h e t w o d ose le vel/sc he d ules (i.e. 1 6 0 
m g BI D a n d 3 2 0 m g Q D)  i n di vi d uall y, t he n p ossi bl y p o ole d. A s u bject will be i ncl u de d i n t he 
d ose le vel/sc he d u le gr o u p per t he first d ose h e/s he recei ve d.  T h e y will als o be gr o u pe d b y 
disease t y pe. I n Part II s u m maries, all patie nts recei ve d t he R P 2 D of 1 6 0 m g BI D, t heref ore t he y 
will be gr o u p e d b y diseas e t y p e F L, M Z L a n d t he n p o ole d. I n t he p o ole d s u m maries of b ot h Part 
I a n d Part II p atie nts, patie nts will be gr o u p e d b y disease t y pe o nl y. 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 3  of 2 8   
C O N FI D E N TI A L  
 
All ce nters will be p o ole d t o get her i n all a nal yses.  
Statistical pr o gra m mi n g a n d a nal yses will be p erf or me d usi n g S A S ® ( S A S I nstit ute, I nc., C ar y, 
N C, U S A), versi o n 9. 3. 
6. 2. 1  Defi n iti o ns a n d C o m p ut ati o ns 
St u d y treat me nt (st u d y dr u g) f or t his st u d y is B G B- 3 1 1 1. 
St u d y d a y : St u d y da y will be calc ulate d relati ve t o t he date of t he first d ose of st u d y treat me nt.  
F or ass ess me nts c o n d uct e d o n or aft er t he dat e of t he first d ose of st u d y t reat me nt, st u d y da y will 
be calc ul ate d as (assess m e nt date – date of first d ose of st u d y treat me nt + 1) .  F or assess me nts 
c o n d ucte d bef ore t h e dat e of t he first d ose of st u d y treat me nt, st u d y d a y is calc ulate d as 
(assess me nt date – d ate of first d ose of st u d y treat me nt). T here is n o st u d y da y 0.  
I n t he sit uati o n w h ere t he e ve nt date is partial or missi n g, t he date will a p p ear partial or missi n g 
i n t he listi n gs; St u d y d a y  a n d a n y c orres p o n di n g d urati o ns will be prese nte d base d o n t he 
i m p utati o ns s pecifie d in A p pe n di x A. 
Treat me nt d ur ati o n: T he treat me nt d urati o n will be calc ul ate d as ( d ate of last d ose of st u d y 
treat me nt – date of first d ose of st u d y treat me nt + 1) . 
Baseli ne: U nl ess ot her wise s pecifie d, a baseli ne v al ue is defi ne d as t he last n o n -missi n g val ue 
c ollecte d bef ore t he d ate a n d ti me of first d ose of st u d y treat me nt.   
Defi niti o ns of efficac y v aria bles are pr o vi d e d i n Secti o n 6. 4 a n d defi niti o ns of safet y varia bles 
are pr o vi d e d i n Secti o n 6. 5 . 
6. 2. 2  C o n ve nti o ns 
U nless ot her wise s pecifie d, t he f oll o wi n g c o n v e nti o ns will be a p plie d t o all a nal ys es: 
•  1 year = 3 6 5. 2 5 da ys. N u m ber of years is calc ul ate d as ( da ys/ 3 6 5. 2 5) r o u n d e d u p t o 1 
si g nifica nt di git. 
•  1 m o nt h = 3 0. 4 3 7 5 da ys. N u m ber of m o nt hs is cal c ulate d as ( d a ys/ 3 0. 4 3 7 5) r o u n de d u p 
t o 1 si g nifica nt di git. 
•  A ge will be cal c ulate d as t he i nte ger part of ( dat e of i nf or me d c o ns e nt – date of birt h + 
1)/ 3 6 5. 2 5 
•  Ti me t o a n d d urati o n of i ma ge-bas e d e ve nt e n d p oi nts (s uc h as P F S a n d D F S) will be 
base d o n t he act ual date t he ra di o gra p h was o btai n e d rat her t ha n t he ass o ciate d visit date.  
•  Missi n g effi cac y or saf et y dat a will n ot be i m p ute d u nless ot her wise s pecifie d.  
•  F or b y -visit o bser v e d dat a a nal yses, p erce nta ges will be calc ulate d b a se d o n t he n u m ber 
of patie nts wit h n o n missi n g dat a as t he de n o mi nat or, u nless ot her wise s pecifie d. 


 
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                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 4  of 2 8   
C O N FI D E N TI A L  
 
•  F or c o nti n u o us e n d p oi nts, s u m mar y statistics will i ncl u de n, mea n, sta n dar d de viati o n 
( S D), me dia n, Q 1, Q 3 a n d ra n ge ( mi ni m u m a n d m a xi m u m). T he mi ni m u m a n d ma xi m u m 
will be re p orte d t o t he sa me n u m ber of deci mal places as t h e ra w d ata rec or de d i n t he 
data base. T h e mea n, m e dia n, Q 1 a n d Q 3 will be re p orte d t o o ne m ore d eci mal place t ha n 
t he ra w dat a rec or de d i n t he data bas e.  T he S D will be re p orte d t o t w o m ore deci mal 
places t ha n t he ra w d ata r ec or de d i n t he d ata bas e. I n ge n eral, t he m a xi m u m n u m ber of 
deci mal places re p ort e d s hall be f o ur f or a n y s u m mar y st atistic.  
•  F or discr ete e n d p oi nts, s u m mar y statistics will i ncl u de fre q ue nci es a n d perce nta ges. 
Perce nta ges wi ll be pres e nte d t o o ne deci mal place. Perce nta ges will n ot be prese nte d f or 
zer o c o u nts. 
•  U nless s pecifie d ot her wise, t he visit wi n d o w i n t he ta ble 2 of pr ot o c ol will be use d i n 
a nal ysis. All ass ess me nt o ut of t he visit wi n d o w will be c o nsi dere d as u nsc he d u le d 
assess me nt a n d n ot i ncl u de d i n b y visit a nal ysis. F or b y visit a nal ysis, if m ulti ple 
assess me nts ha p pe n e d i n t he sa me visit wi n d o w, t he cl osest assess me nt t o t he pla n 
date/ti me (if c ollecte d) will be use d i n a nal ysis. If m ore t ha n o ne rec or ds h a ve sa me  
dista nce t o t he pla n date/ti me or m ulti ple assess me nts o n t he pla n ne d date/ti me, t he last 
n o n- missi n g o ne will be use d. 
6. 2. 3  H a n dli n g of M issi n g D at a  
Missi n g data will n ot be i m p ute d u nless ot her wise s pecifie d. Missi n g d ates or partiall y missi n g 
dates will be i m p ute d c o nser vati vel y f or a d vers e e ve nts a n d pri or/c o n c o mita nt 
me dicati o ns/ pr oce d ur es as pr o vi de d i n A p pe n di x A. 
W he n s u m marizi n g cate g orical vari a bles, s u bjects wit h missi n g data are ge n erall y i ncl u de d i n 
t he de n o mi nat or t o calc ul ate per ce nta ges u nless ot her wise s pecifie d. W he n nee de d, t he cate g or y 
of “ Missi n g” is create d a n d t he n u m ber of patie nts wit h missi n g data is pres e nte d. 
W he n s u m marizi n g c o nti n u o us varia bles, s u bjects wit h missi n g data are n ot i ncl u de d i n 
calc ulati o ns. N o i m p utati o ns are ma d e.  
B y - visit e n d p oi nts will be a nal yz e d usi n g o bs er ve d data, u nless ot her wise s pecifie d. F or 
o bser ve d dat a a nal yses, missi n g data will n ot be i m p ute d a n d o nl y t he o bs er ve d rec or ds will be 
i ncl u de d.  
If t he start da y of a s u bse q ue nt a nti-ca n cer t hera p y is missi n g , it will be ass u me d t o be t he first 
da y of t he m o nt h. 
If o nl y t h e da y of d eat h d ate is missi n g, t he deat h will be ass u me d t o be o n t he first da y of t he 
m o nt h if t he last k n o w n ali ve data is earlier. If t he last k n o w n ali ve date is l ater t ha n t he first da y  
of t he m o nt h, t he n t he deat h date will be ass u me d t o be t he last k n o w n ali ve date pl us 1 da y. 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 5  of 2 8   
C O N FI D E N TI A L  
 
N o i m p utati o n of A E gr a des will be perf or me d. T E A Es wit h missi n g C T C A E gra de will o nl y be 
s u m marize d i n t he all- gr a des c ol u m n. 
If t he assess me nt of t he r elati o nshi p of a n A E t o st u d y treat me nts is missi n g, t he n t he A E is 
ass u me d t o be relat e d t o t he st u d y tr eat me nts i n t he safet y a nal ysis, b ut n o i m p utati o n s h o ul d be 
d o ne at t he data le vel.   
6. 2. 4  A dj ust me nt  f or C o v ari ates 
N o a dj ust me nts f or c o variates are pl a n ne d. Base li n e fact ors ma y be use d i n t he m o del as 
c o variates as s u p p orti ve a nal ys es f or e n d p oi nts.  
6. 2. 5  M ulti plicit y  A dj ust me nt  
N ot a p plica ble.   
6. 2. 6  D at a I nte grit y  
Bef ore pr e -s pecifie d statistical a nal ysis be gi ns, t he i nte grit y of t he d ata s h o ul d be re vie w e d t o 
ass ure fit -for - p ur p os e.  T he data set f or a nal ysis s h o ul d be a n acc urat e a n d c o m plete 
re pres e ntati o n of t he s u bj ects' rele v a nt o utc o mes fr o m t he cli nical data bas e.  All data s h o ul d be 
c o m plete a n d r e vie we d u p t o a pre-s pecifie d c ut off date.  C o nsiste nc y c h ec ks a n d a p p r o pri ate 
s o urce dat a verifi cati o n s h o ul d be c o m plete. 
6. 3  
S U B J E C T C H A R A C T E RI S TI C S  
6. 3. 1  S u bject Dis p ositi o n  
T he n u m ber ( p erce nta ge) of s u bjects scree ne d, treate d, disc o nti n ue d fr o m st u d y dr u g a n d 
disc o nti n ue d fr o m t he D L T p h ase a n d  t he e ntire st u d y will be s u m marized. T he pri mar y reas o n 
f or e n d of tr eat me nt (st u d y dr u g disc o nti n uati o n) a n d e n d of st u d y will be s u m marize d b y 
cate g ories. If dat a c ut - off date is bef or e st u d y c o m pleti o n, t he n u m ber ( perce nta ge) of s u bjects 
o n g oi n g i n t he treat me nt peri o d a n d i n t he st u d y at c ut-off will als o be s u m marize d.   
6. 3. 2  Pr ot oc ol D e vi ati o ns 
Maj or pr ot oc ol de viati o n criteria will be est a blis he d a n d s u bjects wit h maj or pr ot oc ol de viati o ns 
will be i de ntifie d a n d d oc u me nte d bef ore t he dat a b ase l oc k. Maj or pr ot oc ol de viati o ns will be 
s u m marize d b y cate g or y . T he y will als o be liste d b y eac h cate g or y. 
6. 3. 3  De m o gr a p hic a n d Ot her B aseli ne C h ar acteristics  
De m o gra p hic a n d ot her b aseli ne c haracteristics will be s u m marize d usi n g descri pti ve statistics.   
C o nti n u o us varia bles i ncl u de a ge, h ei g ht , w ei g ht,  b o d y mass i n de x ( B MI), vital si g ns; 
cate g orical varia bl es i ncl u de se x, a ge gr o u p ( < 6 5, ≥6 5), E aster n C o o perati ve O nc ol o g y Gr o u p 
( E C O G) perf or ma n ce sc ore,  ser u m vir ol o g y a n d ec h ocar di o gra m.  


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 6  of 2 8   
C O N FI D E N TI A L  
 
T he n u m ber ( p erce nta ge) of s u bjects re p orti n g a hist or y of disease a n d c haracteristic, as rec or de d 
o n t he C R F, will be s u m marize d. Disease c h aract eristic s ma y i n cl u de B- C ell L y m p h oi d 
Mali g na n cies t y pe, sta ge of disease  at i nitial dia g n osis a n d at st u d y e ntr y, ge n ot y p e stat us f or 
W M ( M Y D 8 8, C X C R 4), C L L ( d el( 1 7 p), del( 1 1 q), del( 1 3 q), p 5 3 deleti o n, I g V H m utati o n ), 
prese nce or a bs e nce of disease -relate d c o nstit uti o nal s y m pt o ms, l y m p ha d e n o pat h y, 
he pat o me gal y, s ple n o me gal y, ti me ( years) fr o m first dia g n osis of B-Cell L y m p h oi d 
Mali g na n cies t o first d os e date, ti me ( years) si nce m ost rece nt of pr o gressi o n rela pse t o first d ose 
date , baseli ne b o n e marr o w cell ularit y  a n d bas eli ne b o ne marr o w t u m or cell i nfiltrati o n . A listi n g 
of disease hist or y will be pr o vi de d. 
6. 3. 4  Pri o r A nti -C a ncer D r u g T her a pies a n d S ur geries  
T he n u m ber ( p erce nta ge) of s u bjects wit h pri or a nti- B- cell l y m p h o ma dr u g t hera pies, pri or a nti - 
B- cell l y m p h o ma r a di ot hera p y a n d pri or a nti- B-cell l y m p h o ma s ur geries will be s u m marize d, as 
well as t he n u m ber of t h ese pri or t her a pies. T he t h era pies a n d s ur geri es wit h t he sa me 
se q ue nce/re gi me n n u m ber are c o u nte d as o n e pri or t hera p y/s ur ger y.  
6. 3. 5  Pri o r a n d C o nc o mit a nt Me dic ati o ns  
Pri or a n d c o nc o mita nt m e dicati o ns will be c o de d usi n g t he W orl d Healt h Or ga nizati o n Dr u g 
Dicti o nar y ( W H O D D) dr u g c o des versi o n Se pte m ber 2 0 1 6, a n d will be f urt her classifie d t o t he 
a p pr o priate A nat o mical T hera p e utic C he mical ( A T C) c o de.  
T he n u m ber ( p erce nta ge) of s u bjects re p orti n g pri or a n d c o nc o mita nt me di cati o ns will be 
s u m marize d b y A T C me dicati o n class a n d W H O D D preferre d ter m i n t he safet y p o p ulati o n. 
Pri or me dicati o ns are d efi ne d as me dicati o ns t hat starte d bef ore t he first d ose date. C o nc o mita nt 
me dicati o ns will be defi n e d as me dicati o ns t hat ( 1)  starte d bef ore t he first d ose of st u d y 
treat me nt a n d w ere c o nti n ui n g at t he ti me of t he first d ose of st u d y treat me nt, or ( 2) starte d o n or 
after t he d ate of t he first d ose of st u d y treat me nt u p  t o 3 0 da ys after t he s u bject’s last d ose or 
i nitiati o n of a ne w a nti-ca ncer t h era p y. A listi n g of pri or a n d c o nc o mita nt me dicati o ns will be 
pr o vi de d.  
6. 3. 6  Me dic al Hist or y  
Me dical Hist or y will be c o de d usi n g Me d D R A ( versi o n 1 9. 1). T he n u m ber ( perce nta ge) of 
s ubjects re p orti n g a hist or y of a n y me dical c o n diti o n, as rec or de d o n t he C R F, will be 
s u m marize d b y S yste m Or ga n Class ( S O C) a n d Preferre d Ter m ( P T)  i n t he safet y p o p ulati o n. A 
listi n g of me dical hist or y will be pr o vi de d.  


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 7  of 2 8   
C O N FI D E N TI A L  
 
6. 4  
E F FI C A C Y  A N A L Y SI S  
T his secti o n des cri bes t h e effi cac y a nal ysis of b ot h t he e x pl orat or y e n d p oi nts of Part I a n d t he 
pri mar y e n d p oi nts of part II t o be perf or me d at st u d y c o m pleti o n .  
Res p o nse a n d pr o gr essi o n stat us will be deter mi ne d b y t h e i n vesti gat or usi n g t he e val uati o n 
criteria (I W C L L-C L L, L u ga n o criteri a f or N H L, I W W M - W M) detaile d i n pr ot oc ol A p pe n di x 3. 
A patie nt’s best o ver all r es p o nse is t he best c o nfir me d res p o nse rec or de d pri or t o t he date of 
pr o gressi ve disease, data c ut, or start of ne w a nti- ca ncer treat me nt, w hic h e v er is t he ea rliest. 
Se nsiti vit y a n al ys es will be perf or me d f or all t he efficac y e n d p oi nts i n t he P P p o p ulati o n , if m ore 
t ha n 1 5 % of t he safet y p o p ulati o n ha ve maj or pr ot oc ol de viati o ns. 
Pri mar y e fficac y e n d p oi nts of part II will be s u m m arize d i n F L a n d M Z L p atie nts res pecti vel y. 
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)  
‘O ver all Res p o nse’ i n O R R is defi ne d as a s u bject’s best o verall res p o ns e bei n g c o m plete 
res p o nse ( C R) or p artial r es p o nse ( P R) f or t he N H L s u bjects; C R, C Ri , n P R, P R, or partial 
res p o nse wit h l y m p h o c yt osis ( P R-L)  f or t he C L L s u bjects; a n d C R, ver y g o o d partial res p o nse 
( V G P R), P R, or mi n or res p o nse ( M R) f or t he W M s u bjects. O R R is defi ne d as t he pr o p orti o n of 
s u bjects w h o ac hie v e t he ‘ o verall r es p o nse’. C R R i s defi ne d as t he pr o p orti o n of s u bjects w h o 
ac hie ve t h e C R as t he best o verall res p o nse.  P R R is defi ne d as t he pr o p orti o n of s u bjects w h o 
ac hie ve t h e P R or hi g her ( or P R a n d V G P R f or W M s u bjects) as t he best o verall res p o ns e.  
T he n u m ber a n d pr o p orti o n of s u bjects w h o ac hie ve eac h best o verall res p o nse i n t he e val uati o n 
criteria a n d w h o ac hie ve  ‘o verall r es p o nse’ as defi ne d a b o ve will be s u m marize d.  Patie nts 
wit h o ut p ost baseli ne t u m or assess me nt will be c o nsi dere d as n o n-res p o n ders. T he 2 -si de d 9 5 % 
e x act bi no mial c o nfi de nce i nter val of O R R , C R R, P R R a n d ot her pr o p orti o ns will be deter mi ne d 
usi n g t he Cl o p per- Pears o n met h o d.  
Pr o gr essi o n Fr ee S ur vi val ( P F S) 
P F S is defi ne d as t he ti me  (i n m o nt hs) fr o m t he date of first st u d y treat me nt t o disease 
pr o gressi o n or d eat h ( d ue t o a n y ca use), w hic he v er occ urs first. F or p ur p os es of calc ulati n g P F S, 
t he start date of pr o gressi ve disease is t he dat e at w hic h pr o gressi o n w as first o bser ve d.  
T he d urati o n of P F S will be ri g ht-ce ns ore d f or pati e nts w h o met 1 of t he f oll o wi n g c o n diti o ns: 1) 
n o baseli ne disease assess me nts; 2) starti n g a n e w a nti -ca ncer t hera p y bef ore d oc u me ntati o n of 
disease pr o gr essi o n or deat h; 3) deat h or disease pr o gressi o n i m me diatel y after m ore t ha n 1 
c o nsec uti vel y misse d disease ass ess me nt visit; a n d 4)  ali ve wit h o ut d oc u me ntati o n of disease 
pr o gressi o n bef ore t he d ata c ut off dat e. F or s u c h p atie nts, t he pri mar y a n al ysis of P F S will be 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 8  of 2 8   
C O N FI D E N TI A L  
 
ri g ht- ce ns or e d acc or di n g t o t he c o n ve nti o n descri b e d i n Ta ble 1. T hes e c o n ve nti o ns are bas e d o n 
2 0 1 2 国家食品药品监督管理局《抗肿瘤药物临床试验终点技术指导原则》. 
T a ble 1: D ate of Pr o gressi o n or Ce ns ori n g f or Pr o g ressi o n- free S ur vi v al 
Sit u ati o n  
D ate of Pr o gressi o n or Ce ns ori n g  
O utc o me  
N o baseli ne diseas e assess me nts  
Date of first d os e 
Ce ns ore d  
Ne w a nti -ca ncer treat me nt starte d 
bef ore d o c u me ntati o n of P D or deat h 
Date of last diseas e assess me nt pri or 
t o start of a ne w a nti-ca n cer treat me nt  
Ce ns ore d  
Deat h or P D i m me diatel y after m or e 
t ha n 1 c o nsec uti vel y misse d disease 
assess me nt visit *  
Date of last diseas e assess me nt visit 
wit h o ut d o c u me ntati o n of P D t hat is 
bef ore t h e first misse d visit  
Ce ns ore d  
Ali ve a n d wit h o ut P D d oc u me ntati o n  
Date of last diseas e assess me nt  
Ce ns ore d  
Deat h or P D bet w ee n pla n ne d disease 
assess me nts  
Date of deat h or first disease 
assess me nt s h o wi n g P D, w hic he ver 
o cc urs first  
Pr o gresse d  
Deat h bef ore first disease assess me nt  
Date of deat h  
Pr o gresse d  
* t he fre q ue nc y of disease ass ess me nts is e ver y 1 2 wee ks i n t he first 4 8 wee ks a n d e ver y 2 4 wee ks t hereafter.  
T he distri b uti o n of P F S, i ncl u di n g me dia n P F S a n d P F S ra te at selecte d ti me p oi nts s uc h as 1 2 
a n d 2 4 wee ks , will be s u m marize d descri pti vel y usi n g t he K a pla n- Meier m et h o d. T he 9 5 % 
c o nfi de nce i nter val f or m e dia n a n d ot her q u artiles of P F S will be ge nerate d b y usi n g 
Br o o k me yer met h o d ( Br o o k me yer a n d Cr o wle y 1 9 8 2), w hereas t he 9 5 % c o nfi de nce i nter val f or 
P F S rate at selecte d ti me p oi nts will be ge nerate d b y usi n g Gree n w o o d f or m ula ( Gree n w o o d 
1 9 2 6). D urati o n of f oll o w- u p f or P F S will be esti mate d b y re verse K a pla n -Meier met h o d 
( Sc he m per a n d S mit h 1 9 9 6). Ka pla n -M eier c ur ves will be c o nstr ucte d t o pr o vi de a vis ual 
descri pti o n of t he P F S c h a n ge wit h ti me.  
D urati o n of Res p o nse ( D O R) 
D urati o n of res p o ns e f or res p o n ders (t h ose w h o ac hie ve o verall res p o nse P R or a b o ve) is defi ne d 
as t he ti me i nter val  (i n n u m ber of da ys) b et w ee n t he date of t he earliest q ualif yi n g res p o nse a n d 
t he date of P D or d eat h f or a n y ca us e (w hi c he ver occ urs earlier ). D urati o n of res p o nse a nal ysis 
will o nl y i n cl u de res p o n d ers. Ce ns ori n g r ule f or D O R will f oll o w P F S ce ns ori n g r ul e. 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 1 9  of 2 8   
C O N FI D E N TI A L  
 
T he distri b uti o n of D O R will be s u m marize d descri pti vel y usi n g t he Ka pl a n - Meier met h o d. 
Me dia n f oll o w- u p f or D O R will be esti mate d acc or di n g t o t he K a pla n -Mei er esti mate of 
p ote ntial f oll o w -u p als o ter me d “re verse K a pla n - Meier” ( Sc h e m per a n d S mit h 1 9 9 6).  
Mi ni mal Resi d ual Disea se ( M R D) 
M R D is meas ure d i n patie nts wit h C R o nl y. M R D cleara nce rate  is defi ne d as t he pr o p orti o n of 
patie nts wit h ne gati ve M R D stat us a m o n g all C R  patie nts, a n d will be esti mate d wit h 9 5 % e x act 
bi n o mial c o nfi de nce i nter val. T he s u m mar y will b e pr o vi de d s e p aratel y f or t he assess me nt of 
M R D i n t he b o ne marr o w a n d i n t he peri p heral bl o o d. 
6. 5  
S A F E T Y A N A L Y S E S  
T he i nci de nce of t reat me nt-emer ge nt ad vers e eve nts ( T E A Es ) will be s u m marize d. La b orat or y 
test res ults, vital si g ns, p h ysical e x a ms a n d E C G meas ure me nts a n d t h eir c ha n ges fr o m b aseli ne 
will be s u m marize d usi n g des cri pti ve statistics  (e. g., n, mea n, sta n dar d d e viati o n, me dia n, Q 1, 
Q 3, mi ni m u m, ma xi m u m f or c o nti n u o us varia bl es; n [ %] f or cate g orical v aria bles.  
6. 5. 1  E xte nt of E x p os ure 
T he f oll o wi n g m eas ur es of o vera ll e xte nt of st u d y dr u g e x p os ure will be s u m marize d.  
•  D urati o n of B G B - 3 1 1 1 tr eat me nt ( wee ks), defi ne d as ( date of l ast d ose – date of first 
d ose + 1) di vi de d b y 7 
•  N u m ber ( %) of patie nt s d ose d wit h B G B - 3 1 1 1 b y ti me i nter vals, w here a p atie nt will be 
c o nsi dere d t o ha v e bee n d ose d i n a n i nter val if t he patie nt  recei ves at least o ne d ose of 
st u d y dr u g i n t hat i nter val 
•  C u m ulati ve d ose of B G B- 3 1 1 1 ( m g) a d mi nistere d  
•  A vera ge dail y d ose ( d os e i nte nsit y) of B G B -3 1 1 1 ( m g / da y) a d mi nistere d, d efi ne d as t he 
c u m ulati ve d ose ( m g) di vi de d b y t he d urati o n of B G B- 3 1 1 1 treat me nt ( da ys) a n d 
calc ulate d b ase d o n met h o ds w hic h acc o u nt f or treat me nt dela ys o n t he calc ulate d d ose 
i nte nsit y res ults ( Hr y ni u k 1 9 9 0, L o n g o 1 9 9 0) 
•  Relati ve d ose i nte nsit y of B G B- 3 1 1 1 ( %, act u al vs pla n ne d), defi ne d as t he rati o of t he 
c u m ulati ve a d mi nistere d d ose t o t he prescri be d starti n g dail y d ose ti mes t he d urati o n of 
B G B - 3 1 1 1 treat me nt ( da ys)  
•  N u m ber ( %) of patie nt s wit h B G B- 3 1 1 1 per m a ne ntl y disc o nti n ue d 
•  Reas o ns f or per ma ne nt disc o nti n uati o n of B G B- 3 1 1 1  
•  N u m ber ( %) of patie nt s wit h d ose i nterr u pti o n f or B G B- 3 1 1 1 a n d n u m ber of d ose 
i nterr u pti o ns  
•  N u m ber ( %) of patie nt s wit h d ose re d ucti o ns f or B G B- 3 1 1 1 a n d n u m b er of d ose 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 2 0  of 2 8   
C O N FI D E N TI A L  
 
re d ucti o ns 
6. 5. 2  A d verse E ve nts  
A Es will be gra de d b y t h e i n vesti gat ors usi n g C T C A E v 4. 0 3. T he A E ver b ati m descri pti o ns 
(i n vesti gat or t er ms fr o m t he C R F) will be classifie d i nt o sta n dar dize d me dical ter mi n ol o g y usi n g 
t he Me dical Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A). A d v erse e ve nts will be c o de d t o 
t he Me d D R A ( V ersi o n 1 9. 1) l o wer le v el ter m cl osest t o t he ver bati m ter m.  T he li n ke d Me d D R A 
preferre d t er m ( P T) a n d pri mar y s yst e m or ga n cl ass ( S O C) are als o ca pt ure d i n t he data base.  
6. 5. 2. 1  D L T A n al ysis  
D ose -li miti n g t o xicit y ( D L T) i n t he t o xicit y o bser vati o n peri o d is defi ne d i n pr ot oc ol Secti o n 4. 2 
a n d wer e  e val u ate d  b y t h e Safet y M o nit ori n g C o m mittee ( S M C) a n d use d t o deter mi ne t he 
R P 2 D.  N o D L T w as o bs er ve d i n Part I of t his st u d y a n d n o s u m mar y or listi n g will be ge nerate d. 
6. 5. 2. 2  Ot her A d verse E v e nts A n al ysis  
A treat me nt e mer ge nt a d verse e v e nt ( T E A E) is defi ne d as a n A E t hat ha d a n o nset date o n or 
after t he d ate of t he first d ose of st u d y treat me nt t hr o u g h 3 0 d a ys aft er t he last d ose ( per ma n e nt 
disc o nti n uati o n of st u d y treat me nt) or i nitiati o n of ne w a nti- ca ncer t hera p y, w hic he ver is earlier. 
O nl y t h os e A Es t h at wer e treat me nt e m er ge nt will be i ncl u de d i n s u m mar y ta bles.  All A Es, 
treat me nt e mer ge nt or ot her wise, will be prese nte d i n s u bject data listi n gs. 
A n o ver vie w t a ble, i ncl u di n g t he i nci de n ce of a n d t he n u m ber of s u bjects wit h T E A Es, 
treat me nt-e mer ge nt seri o us a d verse e ve nts ( S A Es), treat me nt -relate d T E A Es, T E A Es wit h gra de 
3 or a b o ve, tr eat me nt-r el ate d T E A Es wit h gra d e 3 or a b o ve, treat me nt-relat e d S A Es, T E A Es t hat 
le d t o deat h, treat me nt-relate d T E A Es t hat le d t o d eat h,  a n d T E A Es t h at le d t o treat me nt 
disc o nti n uati o n, or d ose i nterr u pti o n will be pr o vi de d. Treat me nt- relat e d A Es i ncl u de t h ose 
e ve nts c o nsi der e d b y t he i n vesti gat or t o be d efi nitel y relate d, p ossi bl y or pr o ba bl y relate d t o 
st u d y treat me nt or wit h missi n g assess me nt of t h e ca usal relati o ns hi p.   
T he i nci de nce of T E A Es will be re p orte d as t he n u m ber ( perce nta ge) of s u bjects wit h T E A Es b y 
S O C a n d P T (i n decreasi n g fre q ue n c y of t he p o ol e d gr o u p).  A s u bject will be c o u nte d o nl y o nce 
b y t he hi g hest se v erit y gr a de acc or di n g t o C T C A E v. 4. 0 3  wit hi n a n S O C a n d P T, e ve n if t he 
s u bject e x perie nce d m or e t ha n 1 T E A E wit hi n a s p ecific S O C a n d P T.  
T he f oll o wi n g T E A E cate g ories will be s u m marize d b y S O C a n d P T:  
•  all T E A Es  
•  treat me nt-e mer ge nt S A Es  
•  treat me nt-r elate d T E A Es 


 
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                     B G B -3 1 1 1 -1 0 0 2  
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C O N FI D E N TI A L  
 
•  T E A Es wit h gra de 3 or a b o ve 
•  treat me nt-r elate d T E A Es wit h gra de 3 or a b o ve 
•  treat me nt-r elate d S A Es 
•  T E A Es t hat le d t o deat h  
•  T E A Es t hat le d t o treat m e nt disc o nti n uati o n, or d ose i nterr u pti o n  
T he f oll o wi n g T E A E cate g ories will be s u m marize d b y P T i n des ce n di n g or der of i nci d e nces:  
•  all T E A Es  
•  treat me nt-r elate d T E A Es  
•  T E A Es wit h gra de 3 or a b o ve  
T he f oll o wi n g T E A E cate g ories will be s u m marize d b y S O C, P T, a n d ma xi m u m se verit y:  
•  all T E A Es  
•  treat me nt-r elate d T E A Es. 
I n ci de nce of T E A Es of i nterest, T E A Es of i nterest  wi t h gra d e 3 or a b o v e, treat me nt-relate d 
T E A Es of i nterest  will be s u m marize d b y cate g or y a n d P T. T E A Es of i nterest will als o be 
s u m marize d b y cate g or y, P T, a n d ma xi m u m se verit y. T E A Es of i nterest are defi ne d i n A p p e n di x 
B.  
S u bject data listi n gs of all A Es,  S A Es, treat me nt -relate d A Es, gra de 3 or a b o ve A Es, A Es t hat 
le d t o deat h a n d A Es t hat le d t o treat me nt disc o nti n uati o n will be pr o vi de d. 
All deat hs a n d ca us es of deat h will be s u m marize d, i ncl u di n g t h ose occ urre d d uri n g t he st u d y 
treat me nt peri o d a n d t h ose re p ort e d d uri n g t he s ur vi val f oll o w- u p peri o d after treat me nt 
c o m pleti o n/ disc o nti n uati o n. 
6. 5. 2. 3  E x p os ure- A dj uste d I nci de nce R ates  ( E AI R) 
Gi ve n t he l o n g B G B- 3 1 1 1 treat me nt d urati o n, a n e x p os ure a dj uste d a nal ysis is als o pla n ne d t o 
a nal yze A EIs ( T E A E of i nterest). T he a nal ysis restricts o n t he occ urre n ce of t he first e ve nt per 
patie nt a n d i g n ores t he e xiste nce of later ( m ulti ple) e ve nts as t hese ca n n ot be ass u me d t o occ ur 
i n de pe n de nt of pr e vi o us e ve nts. 
T he i nci de nce rate f or a patie nt is deri ve d fr o m t h e d urati o n of treat me nt e x p os ure of t hat patie nt. 
A patie nt’s d urati o n of e x p os ure is gi ve n eit her 1) b y t he ti me w h e n t he e v e nt has occ urre d ( n o n-
ce ns ore d d ata), or 2) b y t he t otal d urati o n of treat me nt i n case t he patie nt d oes n ot s h o w t he 
a d verse e ve nt of i nterest (ce ns or e d data). De p e n di n g o n w h et her a patie nt h as a n a d verse e v e nt or 
n ot, t he d urati o n of e x p os ure e nters t h e de n o mi nat or i n its n o n-ce ns ore d or ce ns ore d f or m, 
res pecti vel y. 


 
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                     B G B -3 1 1 1 -1 0 0 2  
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C O N FI D E N TI A L  
 
T he a vera ge E AI R per A EI c o nsi ders t he first e ve nt per patie nt per A EI o nl y, a n d t he 
c orres p o n di n g e x p os ure ti me i n t he de n o mi nat or: 
𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐴𝐴𝐴𝐴𝐴𝐴= ∑
𝑇𝑇𝐸𝐸𝐸𝐸𝐸𝐸𝐴𝐴𝐴𝐴𝐴𝐴,𝑖𝑖
𝑛𝑛
𝑖𝑖= 1
∑
𝑡𝑡𝐴𝐴𝐴𝐴𝐴𝐴,𝑖𝑖
𝑛𝑛
𝑖𝑖= 1
 
W here b y T E A E
A EI,i  re pr ese nts t he first T E A E a m o n g all A EI T E A Es of p atie nt i a n d ti as ti me 
w he n t he T E A E o cc urs ( n o n-ce ns or e d data) or t otal d urati o n of treat me nt if n o e ve nt occ ur s 
(ce ns or e d data).     
6. 5. 3  L a b or at or y V al ues 
L a b orat or y s afet y tests will be e val uate d f or select e d  he mat ol o g y, c he mistr y , c o a g ulati o n, 
i m m u n ol o g y a n d uri nal ysis para meters d escri be d  i n Ta ble 2. 
Descri pti ve s u m mar y statistics f or la b orat or y p ara meters a n d t hei r c ha n ges fr o m baseli ne will be 
s u m marize d b y visit. T he a nal ysis visit will be deri ve d base d o n t he r ul es defi ne d i n secti o n 
6. 2. 2. La b orat or y res ults will be sta n dar dize d a n d s u m marize d usi n g Sta n dar d  I nter n ati o nal ( SI) 
u nits, as a p pr o priate. 
La b orat or y p ara m eters ( A L P, A L T, A S T, t otal bilir u bi n, al b u mi n, creati ni ne, calci u m, gl uc ose, 
uric aci d, s o di u m, p h os p h or us, p otassi u m, ma g nesi u m, he m o gl o bi n, platelet c o u nts, W B C c o u nt, 
ne utr o p hil, l y m p h oc yte , A P T T a n d I N R) t hat are gra de d i n N CI C T C A E ( v. 4. 0 3) will be 
s u m marize d b y s hifts fr o m baseli ne C T C A E gra d es t o ma xi m u m p ost-baseli ne gra des. I n t he 
s u m mar y of la b orat or y p ara meters b y C T C A E gra de, para m eters wit h C T C A E gra di n g i n b ot h 
hi g h a n d l o w dir ecti o ns will be s u m marize d se paratel y. N u m ber ( perce nta ge) of s u bjects wit h 
a b n or mal p ost baseli ne la b orat or y val ues (t h ose o utsi de t he n or mal ra n ge) a n d wit h gra de 3 or 
a b o ve t o xicit y will be s u m marize d  b y visit a n d acr oss all p ost-baseli ne visits . 
S u bject data listi n gs of selecte d he mat ol o g y a n d s er u m c he mistr y p ar a meters, i m m u n ol o g y, 
uri nal ysis a n d c oa g ulati o n will be pr o vi de d. 
T a ble 2 L a b or at or y Tests  
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  ( A L P) 
He m o gl o bi n ( H g b) Pr ot hr o m bi n T i me 
( P T) 
p H val ue  
I g A 
Ala ni ne  
a mi n otra nsferase  
( A L T) 
Retic ul oc yte c o u nt  
( o pti o nal test) 
Acti vate d Partial 
T hr o m b o plasti n 
Ti me  ( A P T T) 
S pecific gra vit y  
I g G 


 
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C O N FI D E N TI A L  
 
As partate 
ami n otra nsferase  
( A S T) 
Platelet c o u nts  
I nter nati o nal 
N or malize d Rati o  
(I N R) 
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 n2 
T otal a n d direct 
b ilir 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  
( B U 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 3 
Ba n d s ( o pti o nal 
test) 
 
 
 
C hl ori n e 
 
 
 
 
Creati ni ne  
 
 
 
 
Gl uc ose  
 
 
 
 
Lactate  
de h y dr o ge nase 
( L D H) 
 
 
 
 
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.  All 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 det ecte d.  
3.  
F or h y p ocalce mia a n d h y perc alce mia, ser u m calci u m will be c orrecte d usi n g t he f or m ula: C orrecte d calci u m = 
Ser u m calci u m + 0. 8 * ( 4 – ser u m al b u mi n) w here ser u m cal ci u m is rec or de d i n m g/ d L a n d ser u m al b u mi n is 
rec or de d i n g/ d L. 
6. 5. 4  Vit al Si g ns  
Descri p ti ve statistics f or vital si g n para meters (s yst olic a n d diast olic bl o o d press ure [ B P ], p ulse 
rate, te m perat ure, wei g ht a n d res pirat or y rate) a n d c ha n ges fr o m baseli ne will be prese nte d b y 
visit.  T he a nal ysis visit will be deri ve d base d o n t h e r ules defi n e d  i n secti o n 6. 2. 2. I f t he vital 


 
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C O N FI D E N TI A L  
 
si g ns assess me nt dat e is t he sa me as t he P K s a m ple ta ke n dat e, t he pre-d ose vital si g ns will be 
use d i n s u m mar y.  
Bl o o d press ur e will als o be s u m marize d b y s hifts fr o m baseli ne C T C A E gra des t o ma xi m u m 
p ost- baseli ne gra d es.  
All vital si g ns i ncl u di n g t he p ost- d ose assess me nt at t he P K sa m ple date, re peat assess me nts a n d 
u nsc he d ule d ass ess me nts will be liste d  b y s u bjects a n d visits. 
6. 5. 5  P h ysic al E x a mi n ati o n 
P h ysical e x a mi nati o n res ults will be liste d wit h o ut s u m mar y.    
6. 5. 6  Electr oc a r di o gr a ms  ( E C G) 
Descri pti ve statistics f or E C G  H R a n d  i nter vals (P R, R R, Q R S, Q T, Q T c, Q Tc -Bazzett [ Q Tc B],  
a n d Q Tc -Fri d ericia  [ Q Tc F]) a n d c ha n ges fr o m b aseli ne will be prese nt e d b y visit. T he a n al ysis 
visit will be deri ve d base d o n t he r ules defi ne d i n secti o n 6. 2. 2. If m ulti ple rea di n gs are rec or d e d, 
the a ver a ge of t h e rea di n gs at eac h visit  will be use d f or t he s u m mar y. If t h ere are b ot h pre- d ose 
a n d p ost-d ose rea di n gs o n t he sa me date, pre -d os e rea di n gs will be use d i n calc ulati n g c ha n ge 
fr o m baseli ne. N u m ber a n d perce nt a ge of p atie nts wit h at least o ne p ost baseli ne Q Tc F of > 4 5 0 
msec, > 4 8 0 msec, or > 5 0 0 msec, a n d wit h t he lar gest i ncreas e fr o m bas eli ne i n t he ≤ 3 0 msec, > 
3 0 a n d ≤ 6 0 msec, a n d > 6 0 msec will be s u m marize d. T he i nter pretati o n of t he E C G will be 
liste d wit h o ut s u m mar y. A n y cli nicall y si g nifica nt a b n or malities t hat are c h a n ges fr o m bas eli ne 
will be descri be d i n t he C S R. 
6. 5. 7  E aster n C o o per ati ve O nc ol o g y Gr o u p  (E C O G ) 
E C O G sc ores will be s u m marize d b y visit. A s hift ta ble fr o m baseli ne t o w orst p ost- baseli ne i n 
E C O G perf or ma nce sc or e will be s u m marize d.  
6. 6  
P H A R M A C O KI N E TI C A N A L Y S E S  
T he a nal ysis p o p ulati o n f or s u bjects wit h P K sa m ples will c o ntai n all s u bjects w h o ha ve at least 
o ne P K sa m ple c ollecte d acc or di n g t o t he pr ot oc ol a n d la b orat or y m a n ual. N o mi nal ti me ma y be 
use d f or t he i nteri m P K a nal ysis a n d act ual c ollecti o n ti mes will be use d i n t he fi nal a nal ysis a n d 
re p orti n g. F or i nte nsi ve P K pr ofile, p har mac o ki netic para met ers will be deri ve d usi n g sta n d ar d 
n o n-c o m part me ntal met h o ds.  I n a d diti o n, P K d ata fr o m t his st u d y, al o n g wit h data fr o m ot her 
trials will be i ncl u de d i n t he p o p ulati o n P K a nal ysis a n d will be re p orte d s e paratel y. 
F or i nte nsi ve P K pr ofile o n Da y 1 a n d D a y 2 of Wee k 1 a n d Da y 1 of Wee k 2 , plas ma B G B-
3 1 1 1 c o nce ntr ati o n- ti me data will be s u m marize d a n d dis pla ye d i n b ot h ta b ular a n d gra p hical 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
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C O N FI D E N TI A L  
 
f or m.  I n di vi d ual a n d mea n plas ma c o nce ntrati o n vers us ti me data will be t a b ulate d a n d pl otte d 
b y d ose l e vel. T he P K para meter will be esti mate d base d o n n o nc o m part me ntal met h o ds a n d will 
be c o m p ute d i n Wi n N o nli n ® E nter prise v. 5. 2 or hi g her.  
T he P K para m eter esti mates f or a si n gle d ose pr ofile i ncl u de: 
A U C 0 -∞ 
Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m zer o t o i nfi nit y 
A U C last  
Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m zer o t o t he last 
meas ura ble c o nce ntrati o n  
C ma x  
Ma xi m u m plas ma c o nce ntrati o n  
tma x   
Ti me t o ma xi m u m plas ma c o nce ntrati o n   
t1/ 2 
Half life  
C L/ F  
A p pare nt plas ma cleara n ce  
V d/ F  
A p pare nt v ol u me  of distri b uti o n  
T he P K para m eter esti mates f oll o wi n g m ulti ple d oses  i ncl u de: 
A U C 0 -τ 
Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve at eac h d osi n g i nter v al  
A U C last  
Area u n d er t he pla s ma c o nce ntrati o n-ti me c ur ve fr o m zer o t o t he last 
meas ura ble c o nce ntrati o n  
C ma x  
Ma xi m u m plas ma c o nce ntrati o n  
tma x   
Ti me t o ma xi m u m plas ma c o nce ntrati o n   
C mi n  
Mi ni ma dr u g c o n ce ntr ati o n (tr o u g h) d uri n g a n y d osi n g i nter val at stea d y st ate  
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 Wee k 1)  
R C ma x  
Acc u m ulati o n of ma xi m u m plas ma c o nce ntrati o n ( C ma x  of Da y 1 Wee k 2/ Cma x  
of Da y 1 Wee k 1)  
A d diti o nal P K para meters ma y be calc ul ate d if dee me d a p pr o priate. Esti mates f or t hes e 
para meters will be ta b ulate d a n d s u m marize d b y t he d ose le vel, sc h e d ule a n d c ollecti o n da y (i.e., 
n, Mea n, Sta n dar d d e viati o n, C V %, Me dia n, Mi n, a n d Ma x, Ge o Mea n a n d Ge o C V %).  
Si nce o nl y 2 d ose s c he d ules ( 1 6 0 m g BI D a n d 3 2 0 m g Q D, e q ui vale nt dail y d ose) were st u die d, 
t he d ose pr o p orti o nalit y a nal ysis will n ot be perf or me d . 
7  
I N T E RI M A N A L Y SI S 
N o f or mal i nteri m a nal ys es are pl a n ne d f or t his st u d y. D ata fr o m Part I of t he st u d y w ere  
re vie we d b y t h e S M C  at t he e n d of t he D L T o bs er vati o n peri o d. S u m maries a n d a nal yses of 
s u bsets of t he st u d y d ata will be  perf or me d o n a p eri o dic basis f or s u b missi o n t o pr ofessi o nal 
meeti n gs a n d f or i nter n al decisi o n -ma ki n g.    


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
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C O N FI D E N TI A L  
 
8  
C H A N G E S I N T H E P L A N N E D A N A L Y SI S  
 N o ne. 
9  
R E F E R E N C E S  
Br o o k me yer B a n d Cr o wle y J. A c o nfi de n ce i nter val f or t he me dia n s ur vi val ti me. Bi o metrics, 
3 8: 2 9- 4 1, 1 9 8 2 
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts, Versi o n 4. 0 3. Ca ncer T hera p y E v al uati o n 
Pr o gr a m. 1 4 J u ne 2 0 1 0. 
Hr y ni u k W a n d G o o d year M.  T he cal c ulati o n of recei ve d d os e i nte nsit y.  J o ur nal of Cli nical 
O nc ol o g y 8: 1 9 3 5 – 1 9 3 7, 1 9 9 0  
L o n g o D, D uff e y P, De Vita V, Wesle y M, H u b b ar d S, a n d Y o u n g R.  T he calc ulati o n of act u al 
or recei ve d d ose i nte nsit y:  A c o m p aris o n of p u blis he d met h o ds.  J o ur nal of Cli nical O nc ol o g y 
9: 2 0 4 2 – 2 0 5 1, 1 9 9 1  
Sc he m per M, S mit h T L.  A n ote o n q ua ntif yi n g f oll o w- u p i n st u dies of fail ure ti me. C o ntr olle d 
Cli nical Trials 1 7: 3 4 3 – 3 4 6, 1 9 9 6 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 2 7  of 2 8   
C O N FI D E N TI A L  
 
1 0  A P P E N DI X 
A p pe n di x A: Missi n g D at a I m p ut ati o n R ule  
I n ge ner al, missi n g or partial dates will n ot be i m p ute d at data le vel. T h e f oll o wi n g r ules will be 
a p plie d t o t he s pecific a n al ysis a n d s u m mar y d escri be d bel o w.   
A. 1 Pri or/ C o nc o mit a nt Me dic ati o ns/ Pr o ce d ures  
W he n t he start date or e n d date of a me di cati o n is partiall y missi n g, t h e dat e will be i m p ute d t o 
deter mi ne w het h er t he m e dicati o n is pri or or c o n c o mita nt. T he f oll o wi n g r ules will be a p plie d t o 
i m p ute partial dates f or me dicati o ns: 
If start date of a me dicati o n is partiall y missi n g, i m p ute as f oll o ws: 
•  If b ot h m o nt h a n d da y ar e missi n g, t he n set t o J a n uar y 0 1 
•  If o nl y d a y is missi n g, t h e n set t o t he first of t he m o nt h 
If e n d dat e of a me di cati o n is partiall y missi n g, i m p ute as f oll o ws:  
•  If b ot h m o nt h a n d da y ar e missi n g, t he n set t o Dece m ber 3 1 
•  If o nl y d a y is missi n g, t h e n set t o last da y of t he m o nt h 
If start date or e n d dat e of a me dicati o n is c o m plet el y missi n g, d o n ot i m p ut e. 
A. 2 A d verse E ve nts  
T he i m p utati o n r ule f or t he safet y a nal yses will be use d t o a d dress t he iss ues wit h partial dates. 
W he n t he start date or e n d date of a n a d vers e e ve nt is partiall y missi n g, t he date will be i m p ute d 
t o deter mi ne w het her t he a d verse e ve nt is treat me nt-e mer ge nt. W he n i n d o u bt, t he a d verse e ve nt 
will be c o nsi dere d tr eat m e nt e mer ge nt b y d efa ult. T he f oll o wi n g r ules will be a p plie d t o i m p ute 
partial dates f or a d verse e ve nts:  
If start date of a n a d v erse e ve nt is partiall y missi n g, i m p ute as f oll ows:  
•  If b ot h m o nt h a n d da y ar e missi n g a n d year = year of treat me nt start date, t he n set t o 
treat me nt start date 
•  If b ot h m o nt h a n d da y ar e missi n g a n d year ≠ year of treat me nt start date, t he n set t o 
J a n uar y 0 1 
•  If da y is missi n g a n d m o nt h a n d year = m o nt h an d year of treat me nt start date, t he n set t o 
treat me nt start date 
•  If da y is missi n g a n d m o nt h a n d year ≠ m o nt h a n d year of treat me nt start date, t he n set t o 
first da y of t he m o nt h 


 
B ei Ge ne ( B eiji n g) C o., Lt d  
                     B G B -3 1 1 1 -1 0 0 2  
              ( Statistical A nal ysis Pla n) 
 
 
Versi o n 2. 0 :  1 1/ 0 1/ 2 01 7  
P a ge 2 8  of 2 8   
C O N FI D E N TI A L  
 
•  If start date is c o m plet el y missi n g, set t o treat me nt start date as l o n g as a d verse e ve nt e n d 
date is n ot bef ore treat me nt start date  
If e n d dat e of a n a d vers e e ve nt is partiall y missi n g, i m p ute as f oll o ws: 
•  If b ot h m o nt h a n d da y ar e missi n g, t he n set t o Dece m ber 3 1 
•  If o nl y d a y is missi n g, t h e n set t o last da y of t he m o nt h 
If e n d dat e is c o m pletel y missi n g, d o n ot i m p ute . 
A. 3  De at hs  
I n case o nl y t he d a y of a deat h date is missi n g, t he deat h will be ass u me d t o be o n t he 1st date of 
t he m o nt h if t he last date of s u bject k n o w n t o be ali ve is earlier t hat t he 1st date of t he m o nt h, 
ot her wise t he deat h date will be ass u me d t o be o n 1 da y after t he last date of s u bject k n o w n t o be 
ali ve. 
A p pe n di x B: E ve nts of I nterest ( E OI)  
 
E OI N a me  
Se arc h Criteri a  
1  
He m orr ha ge  
Hae m orr h a ge ter ms (e x cl la b orat or y ter ms) S M Q N  
2  
Maj or he m orr h a ge - 
defi ne d  as C T C A E 
v 4. 0 3 Gra de ≥ 3 
blee di n g of a n y site, or 
ce ntral ner v o us s yste m 
( C N S) blee di n g of a n y 
gr a de.  
Hae m orr h a ge ter ms (e x cl la b orat or y ter ms) S M Q N: Select P Ts 
of a n y S O C ot her t ha n t h e Ner v o us s yste m dis or d ers S O C t hat 
are Gra de ≥ 3 a n d P Ts of t he Ner v o us s yste m dis or d ers S O C 
t hat are of a n y gra d e. 
3  
Atrial fi brillati o n  
Atrial fi brillati o n P T, Atrial fl utter P T  
4  
H y p erte nsi o n  
H y p erte nsi o n S M Q N  
5  
Sec o n d pri mar y 
mali g na n cies  
Mali g na nt T u m o urs S M Q N  
6  
Diarr hea  
Diarr h oea P T, Diarr h oea i nfecti o us P T, Cl ostri di u m difficile  
c olitis P T, Diarr h oea hae m orr ha gic P T  
7  
T u m or l ysis s y n dr o me  
T u m o ur l ysis s y n dr o me S M Q N  
8  
I nfecti o n 
I nfecti o ns a n d I nfestati o ns S O C 
9  
Ne utr o pe nia  
Ne utr o pe nia P T, N e utr o p hil c o u nt decrease d P T, Fe brile 
ne utr o pe nia P T, A gra n ul oc yt osis P T, Ne utr o p e nic i nfecti o n P T, 
Ne utr o pe nic s e psis P T  
1 0  
T hr o m b oc yt o p e nia  
T hr o m b oc yt o p e nia P T, Platelet c o u nt decreas e d P T  
1 1  
A ne mia  
A nae mia P T, Hae m o gl o bi n decrease d P T  
S M Q N: Sta n dar d Me d D R A Q uer y Narr o w; P T: Preferre d Ter m; H L G T: Hi g h Le vel Gr o u p T er m; S O C: S yste m 
Or ga n Class