A Randomized, Multicenter, Open-Label, Phase 3 Study to Evaluate the Efficacy and Safety of Acalabrutinib Versus Chlorambucil Plus Rituximab in Subjects With Previously Untreated Chronic Lymphocytic Leukemia
Phase: PHASE3
Conditions: Untreated Chronic Lymphocytic Leukemia
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1
 
 
  
Cli nic al St u d y Pr ot oc ol  
 
Dr u g S u bsta nce  
Acala br uti ni b ( A C P -1 9 6)  
 
St u d y C o de  
D 8 2 2 B C 0 0 0 0 1  
 
Versi o n  
5 . 0 
 
Date  
0 3 A pr 2 0 2 4  
 
 
 
A R a n d o mize d, M ultice nter, O pe n -L a bel, P h ase  3 St u d y t o 
E v al u ate t he Effic ac y a n d S afet y of Ac al a br uti ni b vers us 
C hl or a m b ucil pl us Rit u xi m a b i n S u bjects wit h Pre vi o usl y 
U ntre ate d C hr o ni c Ly m p h oc ytic Le u ke mi a   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S p o ns or:  Astr a Ze nec a A B, 1 5 1 8 5 S ö dert älje, S we de n  
 
 
 
 
 
 
 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 3
 
Secti o n  
S u m m ar y of c h a n ge  
All  
I R C c ha n ge d t o BI C R 
All  
‘ C o n ge nital a b n or malit y’ c ha n ge d t o ‘ C o n ge nital a n o mal y’  
Secti o n 1. 1, Ta ble 
1, Ta ble 2, Ta ble 3  
Re vise f o ot n ote t o clarif y E O T visit sc he d ule, a n d u p date i n secti o n 7. 1. 1  
Secti o n 1. 2  
U p date d statistical met h o ds secti o n t o reflect st u d y desi g n u p date  
Secti o n 2. 2. 3  
U p date d acala br uti ni b cli nical st u dies res ults base d o n I B versi o n 1 1. 0  
Secti o n 2. 3. 1  
U p date d acala br uti ni b safet y pr ofile base d o n I B versi o n 1 1. 0  
Secti o n 4. 1. 1  
A d de d i nstr ucti o n f or st u d y c o n d uct miti gati o n d uri n g st u d y disr u pti o ns d ue t o cases of 
ci vil crisis, nat ural disaster, or p u blic healt h crisis  
Secti o n 5. 1  
U p date d i ncl usi o n criteria 1 0 t o c ha n ge male c o ntrace pti o n d urati o n after t he last d ose of 
rit u xi ma b or c hl ora m b ucil fr o m ‘ 1 2 m o nt hs’ t o ‘ 9 0 da ys’ t o s h orte n t he u n necessar y l o n g 
c o ntrace pti o n. 
Secti o n 6. 1. 2  
A d de d t o descri be Ar m B treat me nt  
Secti o n 6. 5. 2  
Ta ble 7  
U p date d Ta ble 7 f or ‘i nstr ucti o ns f or c oa d mi nistrati o n of mil d C Y P 3 A i n hi bit or a n d 
str o n g C Y P 3 A i n d ucer of dr u gs wit h Acala br uti ni b c oa d mi nistere d dr u g’ 
Secti o n 7. 1. 1  
U p date d descri pti o n of E O T visit sc he d ule  
Secti o n 7. 1. 2  
U p date d defi niti o n of s u bjects w h o s h o ul d e nter p ost -treat me nt disease f oll o w u p peri o d 
Secti o n 8. 2. 2  
•  
U p date d ‘ T he ner v o us s yste m e xa mi nati o n will i ncl u de atte nti o n t o ne ur ol o gic 
si g ns a n d s y m pt o ms of P M L’ 
•  
A d de d rec or di n g a n d re p orti n g re q uire me nts f or ‘c ha n ges fr o m baseli ne 
a b n or malities’ a n d ‘ ne w or w orse ne d cli nicall y si g nifica nt a b n or malities’  
Secti o n 8. 2. 3  
•  
U p date d vital si g ns c ollecti o n re q uire me nt  
•  
A d d e d rec or di n g a n d re p orti n g re q uire me nts f or ‘c ha n ges fr o m baseli ne 
a b n or malities’ a n d ‘ ne w or w orse ne d cli nicall y si g nifica nt a b n or malities’  
Secti o n 8. 3. 1 a n d 
Ta ble 1 3  
U p date d ti me peri o d a n d fre q ue nc y f or c ollecti n g A E a n d S A E i nf or mati o n f or clarit y 
a n d  c ha n ge i n re p orta bilit y f or A Es of c o ncer n p ost -3 0 da ys last d ose.  
Secti o n 8. 3. 1 0  
U p date d re q uire me nts f or A E SI re p orti n g  
Secti o n 8. 4. 2. 2  
U p date d male c o ntrace pti o n or d o nati n g or ba n ki n g s per m re q uire me nt f or n o n -sterilise d 
male s u bjects t o 9 0 da ys after t he last d ose of rit u xi ma b or c hl ora m b ucil t o reflect 
c ha n ges ma de t o secti o n 5. 1.  
Secti o n 9. 2  
U p dates t o trial desi g n as f oll o ws: e dits t o hazar d rati o, u p date t o i nteri m a n d fi nal 
a nal yses t o acc o m m o date e x pectati o n of t he hazar d rati o gi ve n latest acala br uti ni b data, 
relate d u p dates i n secti o n 9. 5. 6 a n d secti o n 9. 6. 
Secti o n 9. 3,  
Ta ble 1 6  
U p date descri pti o n of o utc o me varia ble f or efficac y data.  
Secti o n 9. 5. 6  
 
U p dates t o trial desi g n as f oll o ws: e dits t o hazar d rati o, u p date t o i nteri m a n d fi nal 
a nal yses t o acc o m m o date e x pectati o n of t he hazar d rati o gi ve n latest acala br uti ni b data  
Secti o n 9. 6  
U p dates t o trial desi g n as f oll o ws: e dits t o hazar d rati o, u p date t o i nteri m a n d fi nal 
a nal yses t o acc o m m o date e x pectati o n of t he hazar d rati o gi ve n latest acala br uti ni b data 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 6
T A B L E O F C O N T E N T S
V E R SI O N HI S T O R Y   ............................................................................................................... 2
T A B L E O F C O N T E N T S  .......................................................................................................... 6
LI S T O F T A B L E S   .................................................................................................................... 9
LI S T O F FI G U R E S  ................................................................................................................. 1 0
LI S T O F A P P E N DI C E S   ......................................................................................................... 1 0
1
P R O T O C O L S U M M A R Y .................................................................................... 1 1
Sc he d ule of ass ess me nts ( S o A)  ............................................................................ 1 1
S y n o psis ................................................................................................................ 2 7
Sc he ma  .................................................................................................................. 3 1
2
I N T R O D U C TI O N ................................................................................................ 3 3
St u d y  Rati o nale ..................................................................................................... 3 3
Bac k gr o u n d ........................................................................................................... 3 3
2. 2. 1
Fr o nt li ne treat me nt f or el derl y patie nts wit h C L L  ............................................... 3 3
2. 2. 2 
B T K i n hi biti o n i n C L L ......................................................................................... 3 4
2. 2. 3
Acala br uti ni b  ........................................................................................................ 3 5
Be nefit/ris k assess me nt  ......................................................................................... 3 7
2. 3. 1
Acala br uti ni b  ........................................................................................................ 3 7
2. 3. 1. 1
Ris k assess me nt  .................................................................................................... 3 7
2. 3. 2 
Rit u xi ma b a n d c hl ora m b ucil................................................................................. 3 9
3
O BJ E C TI V E S A N D E N D P OI N T S  ...................................................................... 4 0
4
S T U D Y  D E SI G N  ................................................................................................. 4 2
O verall desi g n  ....................................................................................................... 4 2
4. 1. 1 
St u d y C o n d uct Miti gati o n D uri n g St u d y Disr u pti o ns D ue t o Cases of Ci vil 
Crisis, Nat ural Disaster, or P u blic Healt h Crisis  .................................................. 4 3
Scie ntific rati o nale f or st u d y desi g n  ..................................................................... 4 4
J ustificati o n f or d ose ............................................................................................. 4 4
4. 3. 1  
Acala br uti ni b d ose r ati o nale ................................................................................. 4 4
4. 3. 2 
Rit u xi ma b d ose rati o nale ...................................................................................... 4 5
4. 3. 3 
C hl ora m b ucil d ose rati o n ale ................................................................................. 4 5
E n d of st u d y defi niti o n ......................................................................................... 4 5
5
S T U D Y P O P U L A TI O N  ....................................................................................... 4 7
I n cl usi o n criteria ................................................................................................... 4 7
E xcl usi o n criteria  .................................................................................................. 5 0
Lifest yle restricti o ns  ............................................................................................. 5 2
Scree n f ail ures   ...................................................................................................... 5 2
6
S T U D Y T R E A T M E N T S   ..................................................................................... 5 4
Treat me nts a d mi nistere d  ....................................................................................... 5 4

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 7
6. 1. 1
I n v esti gati o nal  pr o d ucts ........................................................................................ 5 4
6. 1. 2 
C hl ora m b ucil a n d Rit u xi ma b ................................................................................ 5 4
Pre parati o n/ ha n dli n g/st ora ge/acc o u nta bilit y ........................................................ 5 5
6. 2. 1
Acala br uti ni b  ........................................................................................................ 5 6
6. 2. 2
C hl ora m b ucil ........................................................................................................ 5 6
6. 2. 3
Rit u xi ma b   ............................................................................................................. 5 6
6. 2. 3. 1
Pre parati o n/ ha n dli n g ............................................................................................. 5 6
6. 2. 3. 2
St ora ge .................................................................................................................. 5 7
Meas ures t o mi ni mise bias: ra n d o misati o n a n d bli n di n g ..................................... 5 7
Tre at me nt c o m plia nce   .......................................................................................... 5 7
6. 4. 1
Acala br uti ni b  ........................................................................................................ 5 8
6. 4. 2
C hl ora m b ucil ........................................................................................................ 5 8
6. 4. 3
Rit u xi ma b   ............................................................................................................. 5 8
C o nc o mita nt  t hera p y ............................................................................................. 5 8
6. 5. 1
Per mitte d c o nc o mita nt t hera p y  ............................................................................. 5 9
6. 5. 2 
Pr o hi bite d c o nc o mita nt t hera p y ............................................................................ 5 9
6. 5. 3
Ot her c o nc o mita nt tr eat me nt  ................................................................................ 6 1
D ose dela y a n d m o dificati o n ................................................................................ 6 1
6. 6. 1
Acala br uti ni b  ........................................................................................................ 6 1
6. 6. 2 
Rit u xi ma b a n d c hl ora m b ucil................................................................................. 6 2
Treat me nt after t he e n d of t he st u d y  ..................................................................... 6 4
Cr oss o ver .............................................................................................................. 6 4
7
DI S C O N TI N U A TI O N O F T R E A T M E N T A N D S U BJ E C T WI T H D R A W A L  .. 6 6
Disc o nti n uati o n of st u d y treat me nt ....................................................................... 6 6
7. 1. 1 
Pr oce d ures f or disc o nti n uati o n of st u d y treat me nt ............................................... 6 6
7. 1. 2 
F oll o w- u p f or pr o gressi o n a n d s ur vi val ................................................................ 6 7
L ost t o f oll o w- u p .................................................................................................. 6 7
Wit h dra wal fr o m t he st u d y ................................................................................... 6 8
8
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S ................................................ 7 0
Efficac y assess me nts   ............................................................................................ 7 1
8. 1. 1
T u m or assess me nts  ............................................................................................... 7 1
8. 1. 2
Mi ni mal Resi d ual Disease  .................................................................................... 7 4
8. 1. 3
Cli nical la b orat or y assess me nts  ............................................................................ 7 4
8. 1. 4
B- S y m pt o ms ......................................................................................................... 7 7
8. 1. 5
 7 7
8. 1. 5. 1
 7 7
8. 1. 5. 2
 7 8
8. 1. 5. 3
 7 8
8. 1. 5. 4
 7 8
Safet y assess me nts  ................................................................................................ 7 9
8. 2. 1
Cli nical safet y la b orat or y assess me nts   ................................................................. 7 9
8. 2. 2
P h ysical e xa mi nati o n  ............................................................................................ 8 0
8. 2. 3
Vital si g ns  ............................................................................................................. 8 0
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
A cala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 8
8. 2. 4
Electr ocar di o gra ms  ............................................................................................... 8 0
8. 2. 5
E C O G perf or ma nce stat us  .................................................................................... 8 1
C ollecti o n of a d verse e ve nts ................................................................................. 8 1
8. 3. 1 
Ti me peri o d a n d fre q ue n c y f or c ollecti n g A E a n d S A E i nf or mati o n ................... 8 1
8. 3. 2 
F oll o w- u p of A Es a n d S A Es................................................................................. 8 2
8. 3. 3
Ca usalit y c ollecti o n   .............................................................................................. 8 3
8. 3. 4  
A Es base d o n si g ns a n d s y m pt o ms ....................................................................... 8 4
8. 3. 5  
A Es base d o n e x a mi nati o ns a n d tests ................................................................... 8 4
8. 3. 6
H y’s la w  ................................................................................................................ 8 4
8. 3. 7
Disease pr o gressi o n  .............................................................................................. 8 5
8. 3. 8 
Sec o n d pri mar y mali g na ncies ............................................................................... 8 5
8. 3. 9
Deat hs  ................................................................................................................... 8 6
8. 3. 1 0
A d verse E v e nt of S pecial I nterest ( A E SI)  ............................................................ 8 6
8. 3. 1 1 
Safet y Data t o be C ollecte d F oll o wi n g t he Fi n al D ata C ut off of t he St u d y ......... 8 7
Safet y re p orti n g a n d m e dical ma na ge me nt ........................................................... 8 7
8. 4. 1 
Re p orti n g of S A Es ................................................................................................ 8 7
8. 4. 2
Pre g na nc y   ............................................................................................................. 8 8
8. 4. 2. 1
Mater nal e x p os ure   ................................................................................................ 8 8
8. 4. 2. 2
Pater nal  e x p os ur e .................................................................................................. 8 8
8. 4. 3
O ver d ose ............................................................................................................... 8 9
8. 4. 4  
Me dicati o n Err or, Dr u g A b use, a n d Dr u g Mis use ................................................ 9 0
8. 4. 4. 1
Me dicati o n  Err or ................................................................................................... 9 0
8. 4. 4. 2
Dr u g  A b use ........................................................................................................... 9 0
8. 4. 4. 3
Dr u g  Mis use.......................................................................................................... 9 0
8. 4. 5  
D ose m o dificati o n ma na ge me nt of I P- relate d t o xi cities  ...................................... 9 0
P har mac o ki netics  .................................................................................................. 9 1
8. 5. 1  
Deter mi nati o n of dr u g c o nce ntrati o n .................................................................... 9 1
8. 5. 2 
St ora ge a n d destr u cti o n of p har mac o ki netic sa m pl es ........................................... 9 1
P har mac o d y na mics  ............................................................................................... 9 2
Ge netics  ................................................................................................................ 9 2
Bi o mar kers  ............................................................................................................ 9 2
Healt h ec o n o mics / me di cal res o urce utilizati o n a n d healt h ec o n o mics   .............. 9 2
9
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................. 9 2
Statistical h y p ot heses  ............................................................................................ 9 2
Sa m ple size deter mi nati o n  .................................................................................... 9 2
P o p ulati o ns f or a nal yses ....................................................................................... 9 3
O utc o me meas ur es f or a nal yses ............................................................................ 9 4
9. 4. 1
Calc ulati o n or deri vati o n of efficac y v aria bles  ..................................................... 9 4
9. 4. 1. 1 
Pr o gressi o n- fr ee s ur vi val ...................................................................................... 9 4
9. 4. 1. 2
O verall r es p o nse r ate  ............................................................................................ 9 4
9. 4. 1. 3  
D urati o n of res p o ns e ............................................................................................. 9 5
9. 4. 1. 4 
Ti me t o ne xt t hera p y ............................................................................................. 9 5
9. 4. 1. 5
O verall  s ur vi val  .................................................................................................... 9 5
9. 4. 1. 6
Mi ni m u m resi d ual disease rate  ............................................................................. 9 5

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 9
9. 4. 2 
Calc ulati o n or deri vati o n of safet y varia bles ........................................................ 9 5
9. 4. 2. 1
Ot her si g nifica nt a d v erse e ve nts  ........................................................................... 9 5
9. 4. 3
 9 6
9. 4. 3. 1
 9 6
9. 4. 3. 2
 9 6
9. 4. 3. 3
 9 6
Statistical a nal yses  ................................................................................................ 9 6
9. 5. 1
Efficac y a nal ys es  .................................................................................................. 9 7
9. 5. 1. 1 
Pr o gressi o n- fr ee s ur vi val ...................................................................................... 9 7
9. 5. 1. 2
O verall r es p o nse r ate  ............................................................................................ 9 8
9. 5. 1. 3  
D urati o n of res p o ns e ............................................................................................. 9 8
9. 5. 1. 4 
Ti me t o ne xt t hera p y ............................................................................................. 9 9
9. 5. 1. 5
O verall  s ur vi val  .................................................................................................... 9 9
9. 5. 1. 6
M R D ne gati vit y rate  ............................................................................................. 9 9
9. 5. 2
Safet y a nal yses ...................................................................................................... 9 9
9. 5. 3
 1 0 1
9. 5. 4
P K a nal yses  ......................................................................................................... 1 0 2
9. 5. 5
Ot her a nal ys es  ..................................................................................................... 1 0 2
9. 5. 6  
Met h o ds f or m ulti plicit y c o ntr ol ......................................................................... 1 0 2
I nteri m a nal yses .................................................................................................. 1 0 2
9. 6. 1
Data m o nit ori n g c o m mittee  ................................................................................ 1 0 2
1 0
R E F E R E N C E S  ................................................................................................... 1 0 3
1 1
S U P P O R TI N G  D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  .......................................................................................... 1 0 8
LI S T O F T A B L E S
Ta ble 1 
Sc he d ule of Assess me nts: Treat me nt Ar m A ( Acala br uti ni b)  .................... 1 2
Ta ble  2
Sc he d ule of Assess me nts: Treat me nt Ar m  B ( Rit u xi ma b a n d 
C hl ora m b ucil)  ............................................................................................. 1 7
Ta ble  3 
Sc he d ule of Assess me nts: Cr oss o ver .......................................................... 2 3
Ta ble  4
St u d y  O bjecti ves  ......................................................................................... 4 0
T a ble 5  
Hi g hl y Effecti ve M et h o ds of C o ntrace pti o n ............................................... 5 0
Ta ble 6
St u d y  Treat me nts  ........................................................................................ 5 4
Ta ble 7
I nstr u cti o ns f or C oa d mi nistrati o n of Dr u gs wit h A cala br uti ni b 
C oa d mi nistere d  Dr u g .................................................................................. 6 0
Ta ble  8  
Acala br uti ni b D ose M o dificati o n ................................................................ 6 2
Ta ble  9 
Rit u xi ma b a n d C hl ora m b ucil D ose M o dificati o n ....................................... 6 2
Ta ble  1 0
Res p o nse Assess me nt Criteria f or C L L ( m o difie d fr o m Halle k  2 0 1 8) – 
I W C L L Criteria ........................................................................................... 7 3
C CI
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1 0
 
Ta ble  1 1 
La b orat or y V aria bl es  ................................................................................... 7 6 
Ta ble  1 2 
E C O G Perf or ma n ce Stat us Scale  ................................................................ 8 1 
Ta ble  1 3 
G ui da nce f or Re p orti n g A d verse E v e nts ..................................................... 8 2  
Ta ble  1 4 
Ar m  A P K Sa m pli n g Sc he d ule ................................................................... 9 1 
Ta ble  1 5 
A nal ysis P o p ulati o ns ................................................................................... 9 3  
Ta ble  1 6 
A nal ysis Sets f or O utc o me Varia bles  ......................................................... 9 3 
Ta ble  1 7 
F oll o w- u p Tests f or Ass essi n g P ote ntial H y’s La w / H y’s La w .............. 1 2 6  
 
LI S T O F FI G U R E S   
Fi g ure 1  
St u d y desi g n ................................................................................................ 3 2  
 
 
 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 1
1
P R O T O C O L S U M M A R Y   
Sc he d ule of assess me nts ( S o A)    
T he sc he d ule of assess m e nts ( S o A) f or Ar m A is prese nte d i n Ta bl e 1.
T he S o A f or Ar m  B is pr ese nte d i n Ta ble  2.
T he S o A f or t he cr oss o ver ar m is prese nte d i n Ta ble  3.

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 3
 
 
Scree ni n
g  
Tre at m e nt  a a n d P ost -tre at me nt Dise ase F oll o w-u p P h ase  b 
E o T/ S F U  
Visit  c 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 3 - 7 
( 2 8-d a y 
c ycles)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d 
C ycle 1 – 2 5: 
q 1 2 w ks  
After C 2 5: 
q 2 4  w ks  d 
 
Q 2 4  wee ks
*  
 
 
 
1 
8 
1 5  
2 2  
1 
8 
1 5  
1 
 
 
 
 
 
Visit wi n d o w  
−2 8 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
C o nc o mita nt 
me dicati o ns  
X 
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =  
X 
 
6. 5  
E C O G P S  
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
8. 2. 5  
R o uti ne s afet y m e as ure m e nts  
E C G  
X 
 
 
 
 
 
 
 
 
 
 
 
 
8. 2. 4  
He patitis ser ol o g y  e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
5. 2 , 8. 1. 3  
A d verse e ve nts  f 
X 
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =  
X 
S A Es o nl y  
8. 3 , 8. 4  
Pre g na nc y test  g 
X 
X 
As cli nicall y i n dicate d  
X 
 
8. 1. 3 , 
8. 4. 2  
H B V P C R  h*  
X 
 
 
 
 
X 
 
 
Q M  
Q 3 M *  
 
 
Q 3 M *  
8. 1. 3  
H C V P C R  i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8. 1. 3  
Cli nical c he mistr y  
X 
X  j 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
8. 1. 3  
Effic ac y m e as ure m e nts  
C T sca ns  k 
X  l 
 
 
 
 
 
 
 
C ycles  4,  7 
o nl y  
 
E ver y 
2 4  wee ks after 
C ycle  7 
 
 
8. 1. 1  
O verall res p o nse 
assess me nt  
 
 
 
 
 
 
 
 
 
 
X 
 
 
3 , 9. 4. 1. 2  
B o ne marr o w 
bi o ps y a n d as pirate  
X m  
 
 
 
 
 
 
 
 
 
T o c o nfir m 
C R  n 
 
 
8. 1. 1  

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 4
 
 
Scree ni n
g  
Tre at m e nt  a a n d P ost -tre at me nt Dise ase F oll o w-u p P h ase  b 
E o T/ S F U  
Visit  c 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 3 - 7 
( 2 8-d a y 
c ycles)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d 
C ycle 1 – 2 5: 
q 1 2 w ks  
After C 2 5: 
q 2 4  w ks  d 
 
Q 2 4  wee ks
*  
 
 
 
1 
8 
1 5  
2 2  
1 
8 
1 5  
1 
 
 
 
 
 
Visit wi n d o w  
−2 8 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
M R D 
assess me nt  o*  
 
X  m 
( P B a n d 
B M)  
 
 
 
 
 
 
 
 
C ycle  9 o nl y  
( P B o nl y) 
At P R, C R,  
a n d CR i 
( P B a n d B M) 
X 
( P B a n d 
B M)  
 
8. 1. 2  
Disease -relate d 
s y m pt o ms 
X 
 
 
 
 
X 
 
 
X 
X 
X 
 
 
8. 1. 4  
He mat ol o g y  r*  
X 
X  j 
X 
X 
X 
X 
X 
X 
X 
X 
A N C, A L C, 
P L T, H g b 
( wit hi n C T 
± 7 da ys)  * 
X 
 
8. 1. 3  
S ur vi val stat us a n d 
ne w a ntica ncer 
t hera p y 
 
 
 
 
 
 
 
 
 
 
 
 
X 
7. 1. 2  
Ot her assess m e nts  
C yt o ge netics a n d 
ge netic m olec ular 
pr o g n ostic 
m olec ules *  
X 
 
 
 
 
 
 
 
 
 
 
E o T or 
S F U  s*  
  
8. 1. 3  
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 5
 
 
Scree ni n
g  
Tre at m e nt  a a n d P ost -tre at me nt Dise ase F oll o w-u p P h ase  b 
E o T/ S F U  
Visit  c 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 3 - 7 
( 2 8-d a y 
c ycles)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d 
C ycle 1 – 2 5: 
q 1 2 w ks  
After C 2 5: 
q 2 4  w ks  d 
 
Q 2 4  wee ks
*  
 
 
 
1 
8 
1 5  
2 2  
1 
8 
1 5  
1 
 
 
 
 
 
Visit wi n d o w  
−2 8 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
Ser u m 
i m m u n o gl o b uli ns, 
β 2- micr o gl o b uli n  t, 
T/ B/ N K c o u nts  t*  
 
X  j 
 
 
 
 
 
 
C ycle 7 
o nl y  
E ver y  
2 4  wee ks (e. g., 
C ycles 1 3, 
1 9)  q*  
 
 
 
8. 1. 3  
P K sa m ple 
c ollecti o n  u 
 
 
 
 
 
X 
 
 
 
 
 
 
 
8. 5  
FI S H pa nel *  
X 
 
 
 
 
 
 
 
C ycle 7 
o nl y  v 
 
 
E o T or 
S F U  s*  
 
8. 1. 3  
 
A b bre viati o ns: A L C =a bs ol ute l y m p h o c yte c o u nt; A N C =a bs ol ute n e utr o p hil c o u nt; BI D =t wice d ail y; B M = b o n e marr o w; CI R S = C u m ulati ve  Ill ness Rati n g Scale; C R =c o m plete re missi o n 
(res p o nse); C T =c o m p ute d t o m o gra p h y; E C G =electr o car di o gra m; E C O G P S = Easter n C o o p erati v e O nc ol o g y Gr o u p p erf or ma n ce stat us; E o T=e n d of treat me nt; FI S H =fl u oresce nce i n sit u 
h y bri dizati o n; H Bc = he p atitis  B c ore a nti b o d y; H Bs = h e p atitis  B s urface a nti b o d y; H Bs A g = h e p atitis  B s urface a nti g e n; H B V = h e p atitis  B vir us; H C V = he patitis  C vir us; H g b = he m o gl o bi n 
le vel; I VI G =i ntra ve n o us i m m u n o gl o b uli ns; M R D = mi ni mal resi d u al disease; P B = p eri p h eral bl o o d; P C R = p ol y merase c h ai n reacti o n; P K = p har mac o ki netics; P L T = platelet c o u nt; P O= oral; 
; Q M =e v er y m o nt h; S F U =safet y f oll o w u p. 
* As of A me n d me nt 5. 0  
a. T here is n o restricti o n o n ma xi m u m treat me nt all o we d wit h acala br uti ni b.  
b.  F or s u bjects w h o disc o nti n u e st u d y dr u g d u e t o reas o ns ot h er t h a n disease pr o gressi o n.  If disease pr o gressi o n h as n ot o cc urre d at t he ti me of t he 3 0-da y S F U visit, p ost treat me nt 
disease f oll o w -u p visits s h o ul d o cc ur a p pr o xi matel y e v er y 1 2 wee ks or 2 4 wee ks fr o m t h e d ate of last disease e v al u ati o n u ntil disease pr o gressi o n, re gar dless of w h et her t he 
s u bject recei ves a n e w a ntica n cer t h era p y.   
c. A n e n d of treat me nt visit will b e d o n e wit hi n 7 d a ys f or s u bjects w h o p er ma n e ntl y disc o nti n u e st u d y dr u g earl y f or a n y reas o n  (e xce pt f or deat h, l ost t o f oll o w-u p, or wit h dra wal of 
c o nse nt), i ncl u di n g disease pr o gressi o n. See d etail i n Secti o n  7. 1. 1 . A safet y f oll o w-u p visit is c o n d ucte d 3 0  d a ys ( + 7  d a ys) after t he last acala br uti ni b d ose, re gar dless of w het her 
t he s u bject recei v es a n e w a ntica ncer t h era p y or d e m o nstrates disease pr o gressi o n wit hi n t his ti mefra me. If t h e safet y f oll o w-u p visit is wit hi n ± 7  da ys of a re g ularl y sc he d ule d visit 
d uri n g t he p ost -treat me nt p h ase, t h e visits ma y b e c o m bi n e d i nt o a si n gle visit.  
d.  Res p o nse e val uati o ns will b e d o ne e v er y 1 2  we e ks ( ± 1 4  d a ys) wit h t h e first o n -treat me nt assess me nt o cc urri n g o n C y cle 4 Da y  1, t he sec o n d o n C ycle  7 Da y  1, a n d s o o n t hr o u g h 
C ycle  2 5.  After C y cle  2 5 res p o nse e v al u ati o ns will b e d o n e e v er y 2 4  wee ks ( ± 1 4  d a ys) t h ereafter, u ntil disease pr o gressi o n.  F or a d diti o nal details o n t he c o nfir mat or y b o ne 
marr o w bi o ps y f or s u bjects i n Ar m  A, see Mi ni mal Resi d u al Disease/ Res p o nse E v al u ati o n i n Secti o n  8. 1. 2 . 
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 6
 
e. He patitis se r ol o g y m ust i n cl u d e he p atitis B s urface a nti g e n ( H Bs A g), h e p atitis  B s urface a nti b o d y (a nti -H Bs), h e p atitis  B c ore a nti b o d y (a nti -H Bc), a n d he patitis  C ( H C V) 
a nti b o d y.  
f. After t he e n d of t h e pr ot o c ol -d efi n e d a d v erse e v e nt re p orti n g p eri o d ( Secti o n  8. 3. 1 ), o nl y seri o us a d v erse e v e nts c o nsi d ere d relate d t o st u d y dr u g(s) or st u d y pr oce d ures are 
re q uire d t o be c ollecte d.   
g.  W o me n of c hil d b eari n g p ote ntial o nl y.  A uri n e or  ser u m pre g n a n c y test is acce pta ble.  Pre g n a n c y testi n g ca n b e d o n e m ore fre q ue ntl y t ha n t he pr ot oc ol -defi ne d sc he d ule.  
h.  S u bjects w h o are a nti -H Bc p ositi v e s h o ul d h a v e a q u a ntitati v e P C R test f or H B V D N A p erf or me d d uri n g scree ni n g a n d e v er y 3 m o nt h s t hereafter. M o nit ori n g e ver y 3 m o nt hs  
s h o ul d c o nti n ue u ntil 1 2 m o nt hs after last d ose of st u d y dr u g(s).  A n y s u bject wit h a risi n g viral l o a d (a b o v e l o wer li mit of  detecti o n) s h o ul d disc o nti n ue st u d y dr u g a n d ha ve 
a nti viral t hera p y i nstit u te d a n d a c o ns ultati o n wit h a p h ysicia n wit h e x p ertise i n ma n a gi n g H B V.  As i ntra v e n o us i m m u n o gl o b uli ns (I VI G) m a y ca use false-p ositi ve he patitis 
ser ol o g y, m o nt hl y P C R testi n g is n ot re q uire d i n s u bjects w h o are c urre ntl y recei vi n g or w h o h a v e recei v e d pr o p h ylactic I VI G wit hi n 3 m o nt hs bef ore st u d y e nr oll me nt a n d ha ve a 
d oc u me nte d ne g ati v e a nti -H Bc test b ef ore t h e i nitiati o n of I VI G t h era p y.  P C R testi n g s h o ul d b e p erf or me d w h e n cli nicall y i n dicate d (e. g., i n t he sett i n g of risi n g tra nsa mi nase 
le vels). 
i. S u bj ects wit h a k n o w n hist or y of h e p atitis C or w h o are H C V a nti b o d y p ositi v e s h o ul d h a v e q u a ntitati v e P C R testi n g f or H C V R N A perf or me d d uri n g scree ni n g. N o f urt her testi n g 
is necessar y if t h e P C R res ults are n e g ati v e at scree ni n g. 
j. T he i n dicate d sa m ples at t his ti me p oi nt ( C y cle 1 Da y 1) m ust b e dra w n pre d ose. If scree ni n g assess m e nts c h e mistr y a n d h e mat ol o g y are perf or me d wit hi n 5 da ys pri or t o C ycle 1 
Da y 1, t he y d o n ot n ee d t o b e re peate d at C y cle 1 Da y 1.  
k.  C T sca n ca n be p erf or me d u p t o 7 d a ys b ef ore res p o nse e v al u ati o n.   
l. S u bjects w h o ha v e sta n d ar d of care C T/ M RI res ults ma y use t h ese res ults i n lie u of t h e Scree ni n g C T/ M RI re q uire d f or t his st u d y, pr o vi de d t he C T/ M RI was d o ne wit hi n 2 8 da ys 
of first d ose a n d was ac q uire d i n acc or d a n ce wit h t h e g ui d eli n es o utli n e d i n Secti o n  8. 1. 1 . 
m.  B o ne marr o w as pirati o n a n d bi o ps y will b e d o n e at scree ni n g or wit hi n 6 0 d a ys b ef ore t h e first d ose of st u d y dr u g p er cli nica l g ui deli nes.  B o ne marr o w bi o ps y a n d as pirate, M R D 
assess me nt ca n b e teste d o n C y cle 1 Da y 1 pre -d ose if n ot p erf or me d d uri n g scree ni n g.  
n.  If t he s u bject’s p h ysical e x a mi n ati o n fi n di n gs, la b orat or y e v al u ati o ns, a n d ra di o gra p hic e v al u ati o ns s u g g est t h at C R h as b ee n ac hie ve d, a c o nfir mat or y b o ne marr o w 
as pirate/ bi o ps y m ust b e o btai n e d t o c o nfir m t h e C R.  
o.  If t he s u bject’s p h ysical e x a mi n ati o n fi n di n gs, la b orat or y e v al u ati o ns, a n d ra di o gra p hic e v al u ati o ns s u g g est t h at P R, C R, or C Ri has bee n ac hie ve d, a peri p heral  bl o o d ( P B) a n d 
b o ne marr o w ( B M) sa m ple t o e v al u ate M R D stat us (fl o w b ase d) s h o ul d b e d o n e b et wee n 8 -1 2  wee ks fr o m t h e ti me of s u p p orti ve cli nical assess me nts, i ncl u di n g C T i ma gi n g of 
s us pecte d P R, C R, or C Ri. If M R D sa m ples are n ot ta k e n at E o T visit, t h e sa m ples ca n b e dra w n at S F U visit. After fi n al a nal ysis(F A ) a n d per A me n d me nt 5. 0, M R D tests are n ot 
ma n dat or y a n d will  b e l o call y p erf or me d p er cli nical practice.  
p.  
 
q.  After C ycle 7 Da y 1,
, ser u m i m m u n o gl o b uli ns, β 2-micr o gl o b uli n, a n d T/ B/ N K c o u nts s h o ul d b e c ollecte d e ver y 2 4 wee ks, be gi n ni n g wit h C ycle 1 3.  After F A 
a n d per A me n d me nt 5. 0,
 are n ot re q uire d,  la b orat or y assess me nts i n cl u di n g ser u m i m m u n o gl o b uli ns, β 2 -micr o gl o b uli n, a n d T/ B/ N K are n ot re q uire d a n d will  be 
l ocall y perf or me d if n ecessar y p er t h e discreti o n of i n v esti g at or. 
r. He mat ol o g y assess me nts als o c o n d u cte d as p art of safet y acti vitie s. After F A a n d p er A me n d me nt 5. 0, h e mat ol o g y testi n g will be perf or me d l ocall y.  
s. Bl o o d sa m ple f or C yt o g e n etics a n d g e n etic m olec ular pr o g n ostic m olec ules, FI S H e v al u ati o n will als o b e dra w n w h e n a s u bject h as a disease-pr o gressi o n, at t he e n d of treat me nt 
visit or a safet y f oll o w -u p visit.  After F A a n d p er A me n d me nt 5. 0 , C yt o g e n etics a n d g e n etic m olec ular pr o g n ostic m olec ules a n d FI S H  are n ot re q uire d a n d will  be l ocall y 
perf or me d per t h e discreti o n of i n v esti g at or. 
t. β 2- micr o gl o b uli n a n d T/ B/ N K t o b e a n al y ze d b y ce ntral la b orat or y.  After F A a n d p er A me n d me nt 5. 0, β 2 -micr o gl o b uli n a n d T/ B/ N K  are n ot re q uire d a n d will  be l ocall y 
perf or me d per t h e discreti o n of i n v esti g at or. 
u.  S parse P K sa m pli n g will o cc ur o n C y cle 2 Da y 1. F or s u bjects w h ere i n P K sa m pli n g c o ul d n ot b e d o n e o n C y cle 2 Da y 1 a n d ca n be d o ne o n C ycle 3 Da y 1 i nstea d.  O n t he da y 
of sa m pli n g, t he s u bject will n ot ta k e a d ose b ef ore arri v al at t h e cli nic.  T h e d ose will b e o bser v e d b y cli nic staff a n d t h e ti me of d ose will be rec or de d.  P K sa m ples will be 
c ollecte d pre d ose ( wit hi n 3 0 mi n utes b ef ore t h e m or ni n g d osi n g) a n d p ost -d ose at t h e f oll o wi n g ti me p oi nts: 1 h o ur ( ± 1 5 mi n utes) p ost -d ose, 2 h o urs ( ± 1 5 mi n utes) p ost -d ose, a n d 
4 h o urs ( ± 3 0 mi n utes) p ost -d ose.  
v.  If t hese sa m ples are d a mag e d d uri n g c ollecti o n or s hi p me nt, t h e y s h o ul d b e re dra w n at a n y s u bse q u e nt visit.  
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 7
 
 
 
T a ble 2 
Sc he d ule of Assess me nts:  Tre at me nt Ar m  B ( Rit u xi m a b a n d C hl or a m b ucil)  
 
Scree ni n g  Tre at m e nt P h ase  
P ost -tre at m e nt Dise ase 
F oll o w -u p P h ase  a 
Tre at m e nt 
a n d P ost -
tre at m e nt 
Dise ase 
F oll o w -u p 
P h ase  
E o T/  
S F U  
Visit  b 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 
3- 6 
( 2 8-d a y 
c ycles)  
C ycle  7 
( 2 8-d a y 
c ycle)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d  
C ycle 1 – 2 5: 
q 1 2 w ks  
After C 2 5: 
q 2 4 w ks  c 
 
Q 2 4  wee ks
* 
 
 
 
1 
2 
8 
1 5  
2 2  
1 
8 
1 5  
1 
1 5  
1  
Visit wi n d o w  
−2 8 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
St u d y dr u g a d mi nistr ati o n  
Ar m B  
Rit u xi ma b I V 
3 7 5  m g/ m 2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 3. 2  
Rit u xi ma b I V 
5 0 0  m g/ m 2 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
4. 3. 2  
C hl ora m b ucil 
0. 5  m g/ k g P O  
 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
4. 3. 3  
Dis pe nse/ret ur n of 
dr u g  
 
X  
 
X  
 
X  
 
X  
X  
X  
 
6. 4  
Dr u g 
acc o u nta bilit y 
 
X  
 
X  
 
X  
 
X  
X  
X  
 
6. 2 , 6. 4  
R o uti ne cli nic al pr oce d ures  
I nf or me d c o nse nt 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 1 , A 3  
C o nfir m eli gi bilit y 
a n d ra n d o miz e 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. 1 , 5 , 6. 3  

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 8
 
 
Scree ni n g  T re a t m e nt P h ase 
P ost -tre at m e nt Dise ase 
F oll o w -u p P h ase  a 
Tre at m e nt 
a n d P ost -
tre at m e nt 
Dise ase 
F oll o w -u p 
P h ase  
E o T/  
S F U  
Visit  b 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 
3- 6 
( 2 8-d a y 
c ycles)  
C ycle  7 
( 2 8-d a y 
c ycle)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d  
C ycle 1 – 2 5: 
q 1 2 w ks  
After C 2 5: 
q 2 4 w ks  c 
 
Q 2 4  wee ks
* 
 
 
 
1 
2 
8 
1 5  
2 2  
1 
8 
1 5  
1 
1 5  
1  
Visit wi n d o w  
−2 8 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
Me dical hist or y  
(i ncl. Rai sta ge) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8  
CI R S  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A p pe n di x  
F  
P h ysical e xa m  
X 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
8. 2. 2  
Vital si g ns  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
8. 2. 3  
Wei g ht  
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
8. 2. 2  
C o nc o mita nt 
me dicati o ns  
X 
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =  
X 
 
6. 5  
E C O G P S  
X 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
 
X 
 
8. 2. 5  
R o uti ne s afet y m e as ure m e nts  
E C G  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 2. 4  
He patitis ser ol o g y  d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 2 , 8 . 1. 3 
A d verse e ve nts  e 
X 
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =  
X 
S A Es o nl y  
8. 3 , 8. 4  
Pre g na nc y test f 
X 
X 
As cli nicall y i n dicate d  
X 
 
8. 1. 3 , 
8. 4. 2  
H B V P C R  g 
X 
 
 
 
 
 
X 
 
 
Q M  
 
X 
Q M  
 
 
Q M  
8. 1. 3  
H C V P C R  h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8. 1. 3  

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 9
 
 
Scree ni n g  T re at m e nt P h ase  
P ost -tre at m e nt Dise ase 
F oll o w -u p P h ase  a 
Tre at m e nt 
a n d P ost -
tre at m e nt 
Dise ase 
F oll o w -u p 
P h ase  
E o T/  
S F U  
Visit  b 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 
3- 6 
( 2 8-d a y 
c ycles)  
C ycle  7 
( 2 8-d a y 
c ycle)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d  
C ycle 1 – 2 5: 
q 1 2 w ks  
After C 2 5: 
q 2 4 w ks  c 
 
Q 2 4  wee ks
* 
 
 
 
1 
2 
8 
1 5  
2 2  
1 
8 
1 5  
1 
1 5  
1  
Visit wi n d o w  
−2 8 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
Cli nical c he mistr y  
X 
X i 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
8. 1. 3  
Effic ac y m e as ure m e nts  
C T sca ns  j 
X  k 
 
 
 
 
 
 
 
 
Cycl
e 4 
o nl y  
 
X 
 
E ver y 
2 4  wee ks 
after C ycle 7 
 
 
8. 1. 1  
O verall res p o nse 
assess me nt  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
3 , 9. 4. 1. 2  
B o ne marr o w 
bi o ps y a n d as pirate  
X l 
 
 
 
 
 
 
 
 
 
 
 
 
T o c o nfir m 
C R  m 
 
 
8. 1. 1  
M R D 
assess me nt  n*  
X l 
( P B a n d 
B M)  
 
 
 
 
 
 
 
 
 
 
 
C ycle 9 o nl y u 
( P B o nl y) 
At P R, C R, 
C Ri  
( P B a n d B M) 
 
 
8. 1. 2  
Disease -relate d 
s y m pt o ms 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
8. 1. 4  
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 0
 
 
Scree ni n g  T re at m e nt P h ase  
P ost -tre at m e nt Dise ase 
F oll o w -u p P h ase  a 
Tre at m e nt 
a n d P ost -
tre at m e nt 
Dise ase 
F oll o w -u p 
P h ase  
E o T/  
S F U  
Visit  b 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 
3- 6 
( 2 8-d a y 
c ycles)  
C ycle  7 
( 2 8-d a y 
c ycle)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d  
C ycle 1 – 2 5: 
q 1 2 w ks  
After C 2 5: 
q 2 4 w ks  c 
 
Q 2 4  wee ks
* 
 
 
 
1 
2 
8 
1 5  
2 2  
1 
8 
1 5  
1 
1 5  
1  
Visit wi n d o w  
−2 8 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
He mat ol o g y  q*  
X 
X  i 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
A N C, A L C, 
P L T, H g b  
( wit hi n C T ± 
7 da ys)  * 
X 
 
8. 1. 3  
S ur vi val stat us a n d 
ne w a ntica ncer 
t hera p y 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
7. 1. 2  
Ot her assess m e nts  
C yt o ge netics a n d 
ge netic m olec ular 
pr o g n ostic 
m olec ules *  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
E o T   or 
S F U r  
 
8. 1. 3  
Ser u m 
i m m u n o gl o b uli ns, 
β 2 -micr o gl o b uli n  s, 
T/ B/ N K c o u nts  s*  
 
X  i 
 
 
 
 
 
 
 
 
 
X 
E ver y 2 4  wee ks 
fr o m C ycle 7 
(e. g., 
C ycles  1 3, 
1 9)  p*  
 
 
 
8. 1. 3  
FI S H pa nel *  
X 
 
 
 
 
 
 
 
 
 
 
C ycle  7 
o nl y  t 
 
 
E o T   or 
S F U r*  
 
8. 1. 3  
A b bre viati o ns: A L C =a bs ol ute l y m p h o c yte c o u nt; A N C =a bs ol ute n e utr o p hil c o u nt; C R =c o m plete re missi o n (res p o nse); C T =c o m p ute d t o m o gra p h y; E C G =ele ctr ocar di o gra m; 
E C O G  P S = Easter n C o o p erati v e O n c ol o g y Gr o u p p erf or ma n ce stat us; E o T =e n d of treat me nt; FI S H =fl u oresc e n ce i n sit u h y bri dizati o n; H Bc = he patitis B c ore a nti b o d y; H Bs = he patitis B 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 1
 
s urface a nti b o d y; H Bs A g = h e p atitis B s urface a nti g e n; H B V = h e p atitis B vir us; H C V = h e p atitis C vir us; H g b = h e m o gl o bi n le v el; I V =i ntra ve n o us; I VI G =i ntra ve n o us i m m u n o gl o b uli ns; 
M R D = mi ni ma l resi d u al disease; P C R = p ol y merase c h ai n reacti o n; P L T = platelet c o u nt; P O = oral;
; Q M =e ver y m o nt h; S F U =safet y f oll o w u p. 
* A s  of A me n d me nt 5. 0  
a. S u bjects w h o st o p b ot h dr u gs earl y b eca use of a n a d v erse e v e nt a n d disease pr o gressi o n h as n ot o cc urre d at t h at ti me, will t h e n e nter a n P ost -treat me nt disease f oll o w u p p hase. 
P ost -treat me nt disease f oll o w-u p visits s h o ul d o cc ur a p pr o xi matel y e v er y 1 2 wee ks or 2 4 wee ks fr o m t h e d ate of last disease e val uati o n u ntil disease pr o gressi o n, re gar dless of 
w het her t he s u bject recei v es a n e w a ntica n cer t h era p y.   
b.  A n e n d of treat me nt visit will b e d o n e wit hi n 7 d a ys f or s u bjects w h o p er ma n e ntl y disc o nti n u e st u d y dr u gs earl y f or a n y reas o n (e xce pt f or deat h, l ost t o f oll o w -u p, or 
wit h dra wal of c o nse nt), i n cl u di n g disease pr o gressi o n. See d etail i n Secti o n  7. 1. 1 . A safet y f oll ow- u p visit is c o n d u cte d 3 0  da ys ( + 7  da ys) after t he last d ose of st u d y dr u g, 
re gar dless of w h et h er t h e s u bject recei v es a n e w a ntica n cer t h era p y or d e m o nstrates disease pr o gressi o n wit hi n t his ti mefra me. If t he safet y f oll o w-u p visit is wit hi n ± 7  da ys of 
a re g ularl y sc h e d ule d visit d uri n g t h e P ost-treat me nt P h ase, t h e visits ma y b e c o m bi n e d i nt o a si n gle visit.  
c. Res p o nse e v al u ati o ns will b e d o ne e v er y 1 2  wee ks ( ± 1 4  d a ys) wit h t h e first o n -treat me nt assess me nt o cc urri n g o n C y cle 4 Da y  1, t he sec o n d o n C ycle  7 Da y  1, a n d s o o n 
t hr o u g h C y cle 2 5.  After C y cle  2 5 res p o nse e v al u ati o ns will b e d o ne e v er y 2 4  wee ks ( ± 1 4  d a ys) t h ereafter, u ntil disease pr o gressi o n.  F or a d diti o nal details o n t he c o nfir mat or y 
b o ne marr o w bi o ps y f or s u bjects i n Ar m  B, see Mi ni mal Resi d u al Disease/ Res p o nse E v al u ati o n i n Secti o n  8. 1. 2 . 
d.  He patitis ser ol o g y m ust i n cl u d e he p atitis  B s urface a nti g e n ( H Bs A g H b s A g), h e p atitis B s urface a nti b o d y (a nti -H Bs),  he patitis  B c ore a nti b o d y (a nti -H Bc), a n d he patitis  C 
( H C V) a nti b o d y.   
e. After t he e n d of t h e pr ot o c ol -d efi n e d a d v erse e v e nt re p orti n g p eri o d ( Secti o n  8. 3. 1 ), o nl y seri o us a d v erse e v e nts c o nsi dere d relate d t o st u d y dr u g(s) or st u d y pr oce d ures are 
re q uire d t o b e c ollecte d.   
f. W o me n of c hil d b eari n g p ote ntial o nl y.  A uri n e or ser u m pre g n a n c y test is acce pta ble.  Pre g n a n c y testi n g ca n b e d o n e m ore fre q ue ntl y t ha n t he pr ot oc ol -defi ne d sc he d ule.  
g.  S u bjects w h o are a nti -H Bc p ositi v e s h o ul d h a v e a q u a ntitati v e P C R test f or H B V D N A p erf or me d d uri n g scree ni n g a n d e ver y m o nt h t hereafter. M o nt hl y m o nit ori n g s h o ul d 
c o nti n ue u ntil 1 2  m o nt hs after last d ose of st u d y dr u g(s).  A n y s u bject wit h a risi n g viral l o a d (a b o v e l o wer li mit of d etecti o n) s h o ul d disc o nti n ue st u d y dr u g a n d ha ve a nti viral 
t hera p y i nstit ute d a n d a c o ns ultati o n wit h a p h ysicia n wit h e x p ertise i n ma n a gi n g h e p atitis B.  As i ntra v e n o us i m m u n o gl o b uli ns (I VI G) ma y ca us e false-p ositi ve he patitis 
ser ol o g y, m o nt hl y P C R testi n g is n ot re q uire d i n s u bjects w h o are c urre ntl y recei vi n g or w h o h a v e recei v e d pr o p h ylactic I VI G wit hi n 3  m o nt hs bef ore st u d y e nr oll me nt a n d 
ha ve a d oc u me nte d n e g ati v e a nti -H Bc test b ef ore t h e i nitiati o n of I VI G t h era p y.  P C R testi n g s h o ul d b e p erf or me d w h e n cli nicall y i n dicate d (e. g., i n t he setti n g of risi n g 
tra nsa mi nase le v els).   
h.  S u bjects wit h a k n o w n hist or y of h e p atitis C or w h o are h e p atitis C a nti b o d y p ositi v e s h o ul d h a v e q ua ntitati v e P C R testi n g f or H C V R N A perf or me d d uri n g scree ni n g. N o 
f urt her testi n g is n ecessar y if t h e P C R res ults are n e g ati v e at scree ni n g. 
i. T he i n dicate d sa m ples at t his ti me p oi nt ( C y cle 1 Da y 1) m ust b e dra w n pre d ose. If scree ni n g assess m e nts c h e mistr y a n d he mat ol o g y are per f or me d wit hi n 5 da ys pri or t o C ycle 
1 Da y 1, t he y d o n ot n ee d t o b e re p eate d at C y cle 1 Da y 1.  
j. C T sca n ca n b e p erf or me d u p t o 7  d a ys b ef ore res p o nse e v al u ati o n.   
k.  S u bjects w h o h a v e sta n d ar d of care C T/ M RI res ults ma y use t h ese res ults i n lie u of t h e Scree ni n g C T/ M RI re q uire d f or t his st u d y, pr o vi de d t he C T/ M RI was d o ne wit hi n 
2 8  da ys of first d ose a n d was ac q uire d i n acc or d a n ce wit h t h e g ui deli n es o utli n e d i n Secti o n  8. 1. 1 . 
l. B o ne marr o w as pirati o n a n d bi o ps y will b e d o n e at scree ni n g or wit hi n 6 0 d a ys b ef ore t h e first d ose of st u d y dr u g p er cli nical g ui deli nes.  B o ne marr o w bi o ps y a n d as pirate, 
M R D assess m e nt ca n b e teste d o n C y cle 1 Da y 1 pre -d ose if n ot p erf or me d d ur i n g scree ni n g.  
m.  If t he s u bject’s p h ysical e x a mi n ati o n fi n di n gs, la b orat or y e v al u ati o ns, a n d ra di o gra p hic e v al u ati o ns s u g g est t h at C R h as bee n ac hie ve d, a c o nfir mat or y b o ne marr o w 
as pirate/ bi o ps y m ust b e o btai n e d t o c o nfir m t h e C R.  
n.  If t he s u bject’s p h ysical e x a mi n ati o n fi n di n gs, la b orat or y e v al u ati o ns, a n d ra di o gra p hic e v al u ati o ns s u g g est t h at P R, C R, or C Ri has bee n ac hie ve d, a peri p heral bl o o d ( P B) a n d 
b o ne marr o w ( B M) sa m ple t o e v al u ate M R D stat us (fl o w b ase d) s h o ul d b e d o n e b et wee n 8 -1 2  wee ks fr o m t h e ti me of s u p p orti ve cli nical assess me nts, i ncl u di n g C T i ma gi n g 
of s us pecte d P R, C R, or C Ri. After F A a n d p er A me n d me nt 5. 0, M R D tests are n ot ma n d at or y a n d will  b e l o call y p erf or me d per cli nical practice.  
o.  
  
C CI
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 4
 
 
Scree ni n g  
T re at m e nt P h ase  a 
Tre at m e nt a n d P ost -tre at m e nt 
dise ase f oll o w u p P h ase  b 
E o T/ S F U  
Visit  c 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 3 - 7 
( 2 8-d a y 
c ycles)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d  C ycle 
1 – 2 5: q 1 2 w ks  
After C 2 5:   
q 2 4  wee ks  d 
 
Q 2 4  wee ks
* 
 
 
 
1  
8  
1 5  
2 2  
1  
8  
1 5  
1  
 
 
 
 
 
Visit wi n d o w  
−4 2 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
E C O G P S  
X 
X 
 
 
 
X 
 
 
X 
X 
 
X 
 
8. 2. 5  
Disease -relate d 
S y m pt o ms  
X 
 
 
 
 
 
 
 
 
 
X 
 
 
8. 1. 4  
R o uti ne s afet y m e as ure m e nts  
E C G  
X 
 
 
 
 
 
 
 
 
 
 
 
 
8. 2. 4  
A d verse e ve nts  e 
X 
= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =  
X 
S A Es o nl y  
8. 3 , 8. 4  
Pre g na nc y test f 
X 
X 
As cli nicall y i n dicate d  
X 
 
8. 1. 3 , 
8. 4. 2  
He patitis ser ol o g y 
g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
5. 2 , 8. 1. 3  
H B V P C R  h*  
X 
 
 
 
 
 
 
 
Q 3 M *  
Q 3 M *  
 
 
Q 3 M *  
8. 1. 3  
H C V P C R  i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8. 1. 3  
Cli nical 
c he mistr y  
X 
X j 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
8. 1. 3  
Effic ac y m e as ure m e nts  
C T sca ns  k 
X 
 
 
 
 
 
 
 
C ycle 4, 7 
o nl y  
 
E ver y 
2 4  wee ks after 
C ycle  7 
 
 
8. 1. 1  
O verall res p o nse 
assess me nt  
 
 
 
 
 
 
 
 
 
 
X 
 
 
3 , 9. 4. 1. 2  

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 5
 
 
Scree ni n g  
T re at m e nt P h ase  a 
Tre at m e nt a n d P ost -tre at m e nt 
dise ase f oll o w u p P h ase  b 
E o T/ S F U  
Visit  c 
S ur vi v al 
F oll o w u p  
Det ails i n 
Secti o n  
D a ys  
 
C ycle  1  
( 2 8-d a y c ycle)  
C ycle  2 
( 2 8-d a y c ycle)  
C ycles 3 - 7 
( 2 8-d a y 
c ycles)  
q 1 2  wee ks 
st arti n g at 
C ycle  1 0  
(e. g., 
C ycles  1 0, 1 3, 
1 6)  
Res p o nse 
e v al u ati o n 
assesse d  C ycle 
1 – 2 5: q 1 2 w ks  
After C 2 5:   
q 2 4  wee ks  d 
 
Q 2 4  wee ks
* 
 
 
 
1  
8  
1 5  
2 2  
1  
8  
1 5  
1  
 
 
 
 
 
Visit wi n d o w  
−4 2 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 3 da ys  
± 1 4 da ys  
+ 7 da ys  
± 7 da ys  
 
B o ne marr o w 
bi o ps y a n d 
as pirate  
X l 
 
 
 
 
 
 
 
 
 
T o c o nfir m 
C R  m 
 
 
8. 1. 1  
M R D 
assess me nt  n*   
 
 
 
 
 
 
 
 
 
 
At C R, C Ri  
( P B a n d B M) * 
 
 
8. 1. 2  
He mat ol o g y  
o*  
X 
X  j 
X 
X 
X 
X 
X 
X 
X 
X 
A N C, A L C, 
P L T, H g b  
( wit hi n C T ± 7 
da ys)  * 
X 
 
8. 1. 3  
S ur vi val stat us 
a n d ne w 
a ntica ncer 
t hera p y 
 
 
 
 
 
 
 
 
 
 
 
 
X 
7. 1. 2  
A b bre viati o ns: A L C =a bs ol ute l y m p h o c yte c o u nt; A N C =a bs ol ute n e utr o p hil c o u nt; BI D =t wice d ail y; C R =c o m plete re missi o n (res p o nse); C T =c o m p ute d t o m o gra p h y; 
E C G = electr ocar di o gra m; E C O G P S = Easter n  C o o p erati v e O n c ol o g y Gr o u p p erf or ma n ce stat us; E o T =e n d of treat me nt; FI S H =fl u oresce nce i n sit u h y bri dizati o n; H Bc = he patitis B  c ore 
a nti b o d y; H Bs = he patitis B s urface a nti b o d y; H Bs A g = h e p atitis B s urface a nti g e n; H B V = h e p atitis B vir us; H C V = h e p atitis C vir us;  H g b = he m o gl o bi n le vel; I VI G =i ntra ve n o us 
i m m u n o gl o b uli ns; M R D = mi ni mal resi d u al disease; P C R = p ol y merase c h ai n reacti o n; P K = p h ar mac o ki n etics; P L T = platelet c o u nt; P O = oral; 
; Q M =e ver y 
m o nt h; S F U =safet y f oll o w u p.  
* A s  of A me n d me nt 5. 0  
a. 
T here is n o restricti o n o n ma xi m u m treat me nt all o we d wit h acala br uti ni b.  
b.  
T he P ost -treat me nt disease f oll o w u p p h ase b e gi ns w h e n t h e s u bject st o ps acala br uti ni b d u e t o reas o ns ot h er t h a n disease pr o gressi o n. Visits s h o ul d occ ur a p pr o xi matel y 
e ver y 1 2 wee ks or 2 4 wee ks fr o m t h e d ate of last disease e v al u ati o n u ntil disease pr o gressi o n, re g ar dless of w h et h er t he s u bject recei ves a ne w a ntica ncer t hera p y.   
c. 
A n e n d of treat me nt visit will b e d o n e wit hi n 7 d a ys f or s u bjects w h o p er ma n e ntl y disc o nti n u e st u d y dr u g earl y f or a n y reas o n  (e xce pt f or deat h, l ost t o f oll o w-u p, or 
wit h dra wal of c o nse nt), i n cl u di n g disease pr o gressi o n. See d etail i n Secti o n  7. 1. 1 . A safet y f oll o w-u p visit is c o n d u cte d 3 0  da ys ( + 7) after t he last acala br uti ni b d ose, 
re gar dless of w h et h er t h e s u bject recei v es a n e w a ntica n cer t h era p y or d e m o nstrates disease pr o gressi o n wit hi n t his ti mefra me.  If t he safet y f oll o w-u p visit is wit hi n ± 7  da ys 
of a re g ularl y sc h e d ule d visit d uri n g t h e P ost -treat me nt P h ase, t h e visits ma y b e c om bi n e d i nt o a si n gle visit.  
C CI

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d.  
Res p o nse e v al u ati o ns will b e d o ne e v er y 1 2  wee ks ( ± 1 4  d a ys) wit h t h e first o n -treat me nt assess me nt o cc urri n g o n C ycle 4 Da y  1, t he sec o n d o n C ycle  7 Da y  1, a n d s o o n 
t hr o u g h C y cle 2 5, a n d t h e n e v er y 2 4  wee ks ( ± 1 4  d a ys) t h ereafte r.  F or a d diti o n al d etails o n t h e c o nfir mat or y b o n e marr o w bi o ps y f or s u bjects i n Ar m C, see Mi ni mal Resi d ual 
Disease/ Res p o nse E v al u ati o n i n Secti o n  8. 1. 2 . 
e. 
After t h e e n d of t h e pr ot o c ol -d efi n e d a d v erse e v e nt re p orti n g p eri o d ( Secti o n  8. 3. 1 ), o nl y seri o us a d v erse e v e nts c o nsi dere d relate d t o st u d y dr u g(s) or st u d y pr oce d ures are 
re q uire d t o b e c ollecte d. 
f. 
W o me n of c hil d b eari n g p ote ntial o nl y.  A uri n e or ser u m pre g n a n c y test is acce pta ble.  Pre g n a n c y testi n g ca n b e d o n e m ore fre q ue ntl y t ha n t he pr ot oc ol -defi ne d sc he d ule.  
g.  
He patitis ser ol o g y m ust i n cl u d e he p atitis B s urface a nti g e n ( H Bs A g), h e p atitis B s urface a nti b o d y (a nti -H Bs), h e p atitis B c ore a nti b o d y (a nti -H Bc), a n d he patitis C ( H C V) 
a nti b o d y.   
h.  
S u bjects w h o are a nti -H Bc p ositi v e s h o ul d h a v e a q u a ntitati v e P C R test f or H B V D N A p erf or me d d uri n g scree ni n g a n d e ver y 3 m o nt h s t hereafter. M o nit ori n g e ver y 3 m o nt hs   
s h o ul d c o nti n u e u ntil 1 2 m o nt hs after last d ose of st u d y dr u g(s).  A n y s u bject wit h a risi n g viral l o a d (a b o v e l o wer li mit of detecti o n) s h o ul d disc o nti n ue st u d y dr u g a n d ha ve 
a nti viral t hera p y i nstit ute d a n d a c o ns ultati o n wit h a p h ysicia n wit h e x p ertise i n ma n a gi n g h e p atitis  B.  As i ntra v e n o us i m m u n o gl o b uli ns (I VI G) m a y ca use false p ositi ve 
he patitis ser ol o g y, m o nt hl y P C R testi n g is n ot re q uire d i n s u bjects w h o are c urre ntl y recei vi n g or recei v e d  pr o p h ylactic I VI G wit hi n 3  m o nt hs bef ore st u d y e nr oll me nt a n d 
ha ve a d oc u me nte d n e g ati v e a nti -H Bc test b ef ore t h e i nitiati o n of I VI G t h era p y. P C R testi n g s h o ul d b e p erf or me d w h e n cli nicall y i n dicate d (e. g. i n t he setti n g of risi n g 
tra nsa mi nase le v els).   
i. 
S u bject wit h a k n o w n hist or y of he p atitis C or w h o are h e p atitis C a nti b o d y p ositi v e s h o ul d h a v e q u a ntitati v e P C R testi n g f or  H C V R N A perf or me d d uri n g scree ni n g. N o 
f urt her testi n g is n ecessar y if t h e P C R res ults are n e g ati v e at scree ni n g. 
j. 
T he i n dicate d sa m ples at t his ti me p oi nt ( C y cle 1 Da y 1) m ust b e dra w n pre d ose. If scree ni n g assess m e nts c h e mistr y a n d he mat ol o g y are perf or me d wit hi n 5 da ys pri or t o 
C ycle 1 Da y 1, t h e y d o n ot n ee d t o b e re p eate d at C y cle 1 Da y 1.  
k.  
C T sca ns t h at s h o we d disease pr o gressi o n fr o m Ar m B ca n b e use d f or t h e cr oss o v er scree ni n g C T sca n, if wit hi n 6 0  da ys of cr oss o ver d osi n g C ycle  1 Da y  1.  C T sca n ca n be 
perf or me d u p t o 7  d a ys b ef ore res p o nse e v al u ati o n.  
l. 
B o ne marr o w as pirati o n a n d bi o ps y will b e d o n e at scree ni n g or wit hi n 6 0 d a y s b ef ore t h e first d ose of st u d y dr u g p er cli nical g ui deli nes.  
m.  If t he s u bject’s p h ysical e x a mi n ati o n fi n di n gs, la b orat or y e v al u ati o ns, a n d ra di o gra p hic e v al u ati o ns s u g g est t h at C R has bee n ac hie ve d, a c o nfir mat or y b o ne marr o w 
as pirate/ bi o ps y m ust b e o btai n e d t o c o nfir m t h e C R.  
n.  
If t he s u bject’s p h ysical e x a mi n ati o n fi n di n gs, la b orat or y e v al u ati o ns, a n d ra di o gra p hic e v al u ati o ns s u g g est t h at C R or C Ri has bee n ac hie ve d after cr oss o ver, a peri p heral 
bl o o d ( P B) a n d b o n e marr o w ( B M) sa m ple t o e v al u ate M R D stat us  (fl o w b ase d) s h o ul d b e d o n e b et wee n 8-1 2 wee ks fr o m t he ti me of s u p p orti ve cli nical assess m e nts, 
i ncl u di n g C T i ma gi n g of s us p ecte d C R or C Ri. After F A a n d p er A me n d me nt 5. 0, M R D tests are n ot ma n d at or y a n d will  be l ocall y perf or me d per cli nical practice.  
o.  
After F A a n d p er A me n d me nt 5. 0, h e mat ol o g y testi n g will b e p erf or me d l o call y.  
 
 

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pre vi o usl y u ntreate d C L L wit h o ut del( 1 7 p) or T P 5 3 m utati o n.  Gi ve n t he differe nt treat me nt 
a d mi nistrati o n sc he d ules a n d treat me nt d urati o ns, t his st u d y will use a n o pe n-la bel desi g n.  
Patie nts will be stratifie d acc or di n g t o t he f oll o wi n g criteria:  
•  Easter n C o o per ati ve O nc ol o g y Gr o u p perf or ma nce stat us ( E C O G- P S [ 0 - 1 vers us 2]) 
•  Rai sta ge ( 0 -II vers us III-I V) 
 
St u d y peri o d:  
Esti mate d date of first patie nt e nr olle d:  Q 1 2 0 2 0  
Esti mate d date of last patie nt c o m plete d:  Q 4 2 0 2 4 
D urati o n of st u d y: A p pr o xi matel y 5 4 m o nt hs i ncl u di n g e nr oll me nt ti me.  
N u m ber of s u bjects:  
A p pr o xi matel y 1 5 0 s u bjects will be ra n d o mize d i n a 1: 1 rati o i nt o 2 ar ms ( n = 7 5  patie nts eac h) 
t o recei ve eit her acala br uti ni b m o n ot herap y ( Ar m  A) or rit u xi ma b i n c o m bi nati o n wit h 
c hl ora m b ucil ( Ar m B).  It is pla n ne d t o ra n d o mize a p pr o xi matel y 7 5 t o 1 2 0 patie nts i n t otal 
( 5 0 % t o 8 0 % of t otal sa m ple size) fr o m C hi na.   
Tre at m e nts a n d tre at m e nt d ur ati o n:  
Treat me nt Ar m  A (acala br uti ni b m o n ot hera p y):  
•  All eli gi ble s u bjects will recei v e acala br uti ni b 1 0 0  m g BI D u ntil disease pr o gressi o n or 
a n y ot her treat me nt disc o nti n uati o n criteri o n is met.  
Treat me nt Ar m  B (rit u xi ma b i n c o m bi nati o n wit h c hl ora m b ucil):  
•  Rit u xi ma b: I V i nf usi o n o n Da y 1 of eac h c ycle  
− 
C ycle 1: 3 7 5 m g/ m 2 
− 
C ycles 2 - 6: 5 0 0 m g/ m 2 
•  C hl ora m b ucil: orall y at a d ose of 0. 5 m g/ k g b o d y wei g ht  
− 
Da y 1 a n d D a y 1 5 of eac h c ycle 
•  Treat me nt will c o nti n ue f or 6 c ycles or u ntil t here is disease pr o gressi o n or a n y ot her 
treat me nt disc o nti n uati o n criteri o n is met. 
 
Cr oss o ver: 
At i n vesti gat or discreti o n, s u bjects ra n d o mize d t o Ar m B w h o ha ve BI C R- c o nfir me d disease 
pr o gressi o n a n d meet eli gi bilit y f or cr oss o ver will recei v e treat me nt wit h si n gle -a ge nt 
acala br uti ni b at 1 0 0  m g BI D u ntil disease pr o gressi o n or u nacce pta ble t o xi cit y. After t he fi n al 

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a nal ysis a n d per A me n d me nt 5. 0, s u bjects ca n cr oss o ver wit h i n vesti gat or-assessed P D  wit h 
a gree m e nt fr o m me dical m o nit or/st u d y p h ysicia n pri or t o t he c o ncl usi o n of t he st u d y . 
D at a m o nit ori n g c o m mittee:  
A n i n de pe n de nt dat a m o nit ori n g c o m mittee (I D M C) c o m prisi n g i n de pe n de nt e x perts will be 
esta blis he d t o re vie w t he i nteri m a nal ysis res ults a n d safet y res ults peri o dicall y if nee de d (see 
Secti o n  9. 6. 1 ).  F oll o wi n g t he I D M C meeti n g, t he I D M C will re p ort t o t he s p o ns or a n d ma y 
rec o m me n d c h a n ges i n t he c o n d uct of t he st u d y. 
F ull details of t he I D M C pr oce d ur es, pr ocesses, safet y re vie w a n d i nteri m a nal yses ca n b e 
f o u n d i n t he I D M C C hart er. 
St atistic al m et h o ds:  
T he pri mar y o bjecti ve of t he st u d y is t o test t he f oll o wi n g h y p ot hesis: 
•  
H 0:  Bli n de d i n de pe n de nt ce ntral re vie w ( BI C R)-assesse d pr o gressi o n -free s ur vi val ( P F S) 
of Ar m  A is t he sa me as Ar m  B 
•  
H 1:  BI C R -assess e d P F S of Ar m  A is n ot t he sa me as Ar m  B 
 
U n der t he e x p o ne ntial  m o del ass u m pti o ns, t he st u d y is e x pecte d t o ra n d o mize a p pr o xi matel y 
7 5 s u bjects per ar m ( 1 5 0 patie nts i n t otal fr o m b ot h ar ms) wit h 1: 1 ra n d o mi zati o n rati o.  T he 
st u d y is size d t o ac hie ve m ore t ha n 9 5 % p o w er t o detect a h azar d rati o of 0. 3 3 3 i n P F S ( w hic h 
tra nslates i nt o a n i m pr o v e me nt i n me dia n P F S fr o m 3 0 m o nt hs t o 9 0 m o nt hs) at t he 2-si de d 
si g nifica nce le v el of 0. 0 5, all o wi n g f or o ne i nteri m a nal ysis c o n d ucte d at a p pr o xi matel y 7 6 % 
of t he tar get e ve nts.  T he sa m ple size calc ulati o n ass u mes a me dia n P F S of 3 0  m o nt hs i n 
Ar m  B (Mic hallet  et al 2 0 1 8).  
T he fi nal a n al ysis of BI C R -assesse d  P F S is e ve nt - dri ve n a n d will be c o n d u cte d w he n 
e nr oll me nt is c o m plete d a n d t here are a p pr o xi mat el y 5 0 BI C R -ass esse d P F S e ve nts i n t otal 
fr o m Ar m A a n d Ar m  B.  T he accr ua l p eri o d is ass u me d t o be a p pr o xi matel y 3 0 m o nt hs.   It is 
ass u me d t hat a b o ut 5 % of t he patie nts i n eac h ar m will dr o p o ut at t he ti me of fi nal P F S 
a nal ysis.  T he i nteri m a n d fi nal a nal ysis are a ntici pate d t o occ ur a p pr o xi matel y 4 0 m o nt hs a n d 
5 3 m o nt hs, re s pecti vel y, after t he first patie nt is ra n d o mize d.  
O ne i nteri m a nal ysis will  be c o n d ucte d t o assess earl y effi cac y of Ar m  A v ers us Ar m  B wit h 
res pect t o t he pri mar y efficac y e n d p oi nt, BI C R-assesse d P F S usi n g La n a n d De Mets s pe n di n g 
f u ncti o n wit h O’ Brie n- Fle mi n g b o u n dar y (La n  a n d De Mets  1 9 8 3; 
O’ Brie n  a n d Fle mi n g  1 9 7 9).  T he i nteri m a nal ysis will occ ur w he n a p pr o xi matel y 3 8 BI C R -
assesse d P F S e ve nts ( 7 6 % of tar get P F S e ve nts re q uire d f or fi n al a nal ysis) ha ve bee n o bser v e d 
i n b ot h ar ms c o m bi ne d.  T he n o mi nal al p ha le vel f or t he i nteri m a n d fi n al a nal ysis of 3 8 a n d 
5 0 BI C R-assess e d P F S e ve nts is 0. 0 2 a n d 0. 0 4 4 res pecti vel y. T he act ual n o mi nal al p ha le vel 

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will be deter mi ne d bas e d o n t he n u m ber of BI C R- assesse d P F S e ve nts o bs er ve d at t he ti me of 
eac h r es pecti ve a nal ysis.   
At D C O of 0 3Ja n 2 0 2 4 f or t he pla n ne d i nteri m a n al ysis, 4 8 P F S e ve nts were o bser ve d b y 
BI C R w hic h met t he criteria of fi n al a nal ysis(a p pr o xi matel y 5 0 e ve nts), t h eref ore t his a nal ysis 
was c o nsi der e d as fi n al a nal ysis , he nce the st u d y was u n bli n de d. 
E A S T  6. 5 was e m pl o ye d t o c o n d uct t he sa m ple si ze calc ulati o n. 
Efficac y data will be s u m marize d a n d a nal yze d usi n g t he i nte nt- t o-treat (I T T) p o p ulati o n (all 
ra n d o mize d patie nts) a n d t he treat me nt gr o u ps will be c o m pare d  o n t h e basis of ra n d o mize d 
treat me nt, re g ar dless of t he treat me nt act uall y recei ve d.  Patie nts w h o were ra n d o mize d b ut 
di d n ot s u bse q ue ntl y g o o n t o recei ve st u d y treat me nt are i ncl u de d i n t he I T T p o p ul ati o n.  
P F S will be defi ne d as ti me fr o m ra n d o mizati o n t o t he first occ urre nce of disease pr o gressi o n 
or deat h fr o m a n y ca us e ( w hic he ver o cc urs  first) acc or di n g t o t he I W C L L 2 0 1 8 criteria.  T h e 
pri mar y a nal ysis will be perf or me d i n t he I T T p o p ulati o n t o c o m pare P F S as assesse d b y t he 
BI C R usi n g a 2-si de d str atifie d l o g ra n k test, a dj usti n g f or E C O G ( 0- 1 vers us 2) a n d Rai sta g e 
( 0-II v ers us III-I V) at r a n d o mizati o n.  T he H R a n d t he 2 -si de d c orres p o n di n g CI of H R will be 
esti mate d usi n g a C o x pr o p orti o nal hazar d m o del stratifie d b y t he ra n d o mi zati o n strata.  
All patie nts w h o recei ve d at least o ne d ose of st u d y dr u g will be i ncl u de d i n t he safet y 
a nal ysis set.  Safet y data will be s u m marize d descri pti vel y a n d will n ot be f or mall y a nal yze d.  
Sc he m a   
T he ge neral st u d y desi g n is s u m marise d i n Fi g ure 1 .

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2
I N T R O D U C TI O N  
St u d y R ati o n ale 
T his st u d y will e val uate t he safet y a n d efficac y of t he s mall - m olec ule B T K i n hi bit or, 
acala br uti ni b, vers us rit u xi ma b i n c o m bi nati o n wit h c hl ora m b ucil i n s u bjects wit h pre vi o usl y 
u ntreate d C L L.  T he d esi g n a n d c o n d uct of t his st u d y are s u p p ort e d b y a n u n dersta n di n g of t he 
nat ural hist or y a n d c urre nt t hera pies f or s u bjects wit h C L L; k n o wle d ge of t he acti vit y a n d 
safet y of t he B C R i n hi bit ors (i.e., i br uti ni b) i n s u bjects wit h B-cell mali g na ncies; a n d t he 
a vaila ble n o ncli nical a n d cli nical i nf or mati o n re g ar di n g acala br uti ni b.  
Rati o nale f or t he desi g n of t his st u d y is prese nte d i n Secti o n 4. 2.   
B ac k gr o u n d   
2. 2. 1 
Fr o nt li ne tre at m e nt f or el derl y p atie nts wit h C L L   
C hr o nic l y m p h oc ytic le u ke mia ( C L L) is a mali g n a nc y of B cells t hat pre d o mi na ntl y affects 
t he ol der p o p ulati o n.  C L L has a vari a ble cli nical c o urse, w h ere ma n y patie nts d o n ot re q uire 
treat me nt f or y ears a n d h a ve s ur vi val e q u al to a ge matc he d c o ntr ols.  Ot her patie nts, h o we ver, 
e x hi bit a g gressi ve diseas e a n d ha v e a p o or pr o g n osis des pite a p pr o priate t h era p y (B yr d  2 0 0 4).  
W hile patie nts wit h earl y disease ha v e n ot bee n  s h o w n t o ha ve a s ur vi v al a d va nta ge wit h earl y 
treat me nt, m ost patie nts will e ve nt uall y re q uire t h era p y f or t heir diseas e wit h t he o nset of 
s y m pt o ms or c yt o pe nias.  Des pite t he rel ati vel y l o n g life-e x pecta nc y f or earl y sta ge disease, 
C L L re mai ns a n i nc ur a bl e disease.
T he treat me nt of C L L h as pr o gresse d si g nifica ntl y o ver t he pre vi o us deca d es.  W hile al k ylat or 
t hera p y was us e d i n t he p ast (O' Brie n  1 9 9 5), ra n d o mize d trials ha ve d e m o nstrate d a hi g her 
res p o nse r ate a n d l o n ger P F S wit h fl u dara bi ne a n d s u bse q ue ntl y wit h fl u dara bi ne- a n d 
c ycl o p h os p ha mi de- b ase d c o m bi nati o ns i n y o u n g, fit patie nts wit h C L L (J o h ns o n 1 9 9 6,
Rai  2 0 0 0, Le p orrier  2 0 0 1, Eic h h orst 2 0 0 6, Cat o vs k y 2 0 0 7, Fli n n  2 0 0 7).  At t he sa me ti me, t he 
c hi meric a nti -C D 2 0 + m o n ocl o nal a nti b o d y rit u xi ma b was i ntr o d uce d f or t he treat me nt of C L L 
(B yr d  2 0 0 1, O' Brie n  2 0 0 1).  T he efficac y of rit u xi ma b has bee n i m pr o v e d b y c o m bi ni n g it 
wit h tra diti o nal c yt ot o xic a ge nts s uc h as fl u d ara bi ne (B yr d  2 0 0 3, B yr d  2 0 0 5) or fl u dara bi ne 
pl us c ycl o p h os p ha mi de (Wier da  2 0 0 5), w hic h ha v e pr o d uce d hi g h C R rat es a n d e xte n de d P F S 
c o m pare d wit h hist orical c o ntr ols.  A lar ge ra n d o mize d cli nical trial re p ort e d b y t he Ger m a n 
C L L St u d y Gr o u p ( G C L L S G) has s h o w n t he be n efit of t he a d diti o n of rit u xi ma b t o 
fl u dara bi ne a n d c y cl o p h os p ha mi de i n P F S a n d O S i n patie nts wit h pre vi o usl y u ntreate d C L L 
(Halle k 2 0 1 0) .
W hile fl u dar a bi ne- bas e d c he m oi m m u n ot hera p y is sta n dar d f or treat me nt- n aï ve, y o u n ger/fitter 
patie nts wit h C L L, t he t hera p y f or ol der p atie nts or patie nts wit h c o -m or bi dities is less well 
defi ne d.  I n t he l ar ge P ha se 2 a n d P hase 3 trials o utli ne d pre vi o usl y, me dia n a ges were 
t y picall y i n t he earl y- 6 0s, w hile t he a vera ge a ge of patie nts dia g n ose d wit h C L L is 7 2 years, 

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w hic h calls i nt o q uesti o n w het her t hes e res ults are ge neraliza ble t o t he e ntire C L L p o p ulati o n.  
I n fact, a ra n d o mize d P hase 3 trial i n vesti gati n g pri mar y C L L t hera p y (fl u dara bi ne v ers us 
c hl ora m b ucil) de m o nstr ate d t hat i n patie nts ≥6 5  years of a ge, fl u d ara bi ne was n ot s u peri or t o 
c hl ora m b ucil (Eic h h orst 2 0 0 9 ).  T his fi n di n g was c orr o b orate d b y a lar ge retr os pecti ve st u d y 
of fr o nt -li ne trials perf or me d b y t he Allia nce f or Cli nical Trials i n O nc ol o g y, w hic h c o nfir me d 
t hat fl u dara bi ne is n ot s u peri or t o c hl ora m b u cil i n ol der patie nts a n d als o s h o we d t hat t he 
a d diti o n of rit u xi ma b t o c he m ot hera p y w as be neficial re gar dl ess of a ge (W o yac h  2 0 1 3). 
T he effi cac y of C L L treat me nts i n Asia n a n d wester n patie nts has bee n c o m para ble, i ncl u di n g 
c he m oi m m u n ot hera p y, C D 2 0 + a nti b o dies a n d B T K i n hi bit or (H ua n g 2 0 1 8 ).  C hi na C L L 
g ui deli ne has bee n u p d ate d i n 2 0 1 8 (Versi o n  2 0 1 8) a n d c hl ora m b ucil ± rit u xi ma b is 
rec o m me n de d f or first-li ne u nfit patie nts.  I br uti ni b was als o a p pr o v e d f or t he first-li ne 
treat me nt of C L L i n C hi na.  H o we v er, efficac y a n d safet y data of i br uti ni b i n C hi nese C L L 
p o p ulati o n is still ver y li mite d, es peciall y i n first-li ne setti n g. 
C urre ntl y, trial data t hat c o n vi nci n gl y de m o nstrat e s u peri orit y t o rit u xi ma b a n d c hl ora m b ucil 
are li mite d i n me dicall y u nfit patie nts, es peciall y i n C hi na.  T here e xists a nee d f or fr o ntli ne 
c he m ot hera p y -fr ee r e gi me ns t hat ca n offer i m pr o v e d o utc o mes wit h less t o xicit y. 
2. 2. 2  
B T K i n hi biti o n i n C L L  
Br ut o n t yr osi ne ki nase ( B T K) i n hi biti o n is a n esta blis he d t hera p e utic i nter ve nti o n f or t he 
treat me nt of C L L.  I br uti ni b (I M B R U VI C A® ), a c o vale nt B T K i n hi bit or, has de m o nstrate d 
i m pr o ve d P F S a n d O S i n patie nts wit h C L L as c o m pare d wit h c o n ve nti o nal t hera pies 
(I M B R U VI C A®  prescri bi n g i nf or mati o n).  Alt h o u g h it is a hi g hl y p ote nt B T K i n hi bit or, 
i br uti ni b has als o s h o w n i n vitr o acti vit y a gai nst ot her ki nases (e. g., e pi der mal gr o wt h fact or 
rece pt or [ E G F R]; H o ni g ber g et al. 2 0 1 0).  I n a d diti o n, i br uti ni b is a s u bstrate f or 
c yt oc hr o me P 4 5 0 ( C Y P) e nz y mes  3 A 4/ 5, w hic h i n creas es t he p ossi bilit y of dr u g- dr u g 
i nteracti o ns.  Fi nall y, t he i n hi biti o n of i nterle u ki n- 2 –i n d uci ble T-cell ki nase (I T K) t hat is see n 
wit h i br uti ni b has t he p ote ntial t o a br o gate n at ural killer ( N K) cell a nti b o d y -de pe n de nt cell ular 
c yt ot o xicit y (K o hrt et al. 2 0 1 4), w hic h ma kes c o m bi nati o n wit h m o n ocl o nal a nti b o dies less 
effecti ve.  
Za n u br uti ni b, als o k n o w n as B G B - 3 1 1 1, is a ne xt ge nerati o n B T K i n hi bit or c urre ntl y i n 
cli nical de vel o p me nt f or C L L a n d n o n- H o d g ki n l y m p h o ma.  Za n u br uti ni b has a m ore s pecific 
tar get bi n di n g pr ofile t ha n i br uti ni b.  Za n u br uti ni b has fe w er off-tar g et effects o n relate d 
e nz y mes, i ncl u di n g E G F R, I T K, J a n us ki nase 3 (J A K 3), h u ma n e pi d er mal gr o wt h fact o r 
rece pt or 2 ( H E R 2), a n d t yr osi ne ki nase e x presse d i n he mat o p oietic carci n o ma ( T E C).  
Preli mi nar y data fr o m r el a pse d/refract or y C L L cli nical trials s h o we d c o m p ara ble efficac y a n d 
safet y pr ofile wit h i br uti ni b (Se y m o ur et al. 2 0 1 7).  A P hase 3 st u d y c o m p ari n g t he fr o ntli ne 
use of za n u br uti ni b vers us be n da m usti ne pl us rit u xi ma b i n patie nts wit h C L L is c urre ntl y 
o n g oi n g. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 3 5
 
2. 2. 3  
Ac al a br uti ni b 
Acala br uti ni b ( als o k n o w n as A C P - 1 9 6) is a selecti ve, irre versi ble s mall m olec ule i n hi bit or of 
B T K c urre ntl y u n der cli nical i n vesti gati o n.  I n Oct o ber 2 0 1 7, acala br uti ni b was gra nte d 
accelerat e d a p pr o v al i n t he U nite d States ( U S) f or t he treat me nt of a d ult patie nts wit h ma ntle 
cell l y m p h o ma ( M C L) w h o ha ve recei ve d a t least 1 pri or t hera p y. 
Acala br uti ni b s h o ws e n c o ura gi n g acti vit y a n d acce pta ble safet y i n n o ncli nical a n d cli nical 
st u dies.  I n a d diti o n, la b orat or y st u dies ha ve s h o w n t hat acala br uti ni b a n d its maj or meta b olite 
A C P - 5 8 6 2 ha ve li mite d off -tar g et ki nase acti vit y, i n hi biti n g o nl y 2 ki nases ( Er b -B 2  rece pt or 
t yr osi ne ki nase 4 [ Er b B 4] a n d b o ne marr o w t yr osi ne ki nase ge n e i n c hr o m os o me X [ B M X]) at 
cli nicall y rele va nt c o nce ntrati o ns (Barf  et al. 2 0 1 7).  T he lac k of acti vit y a gai nst ot her Tec- 
a n d Src-f a mil y ki nases, w hic h are i m p ort a nt f or t he f u ncti o n of T cells, N K cells, a n d 
platelets, a n d a gai nst E G F R, a ki nase i m p orta nt f or e pit helial cell f u ncti o ns, ma y c o ntri b ute t o 
t he safet y a n d effi cac y pr ofile of acala br uti ni b. 
As of 3 0 Oct o ber 2 0 2 1 , acala br uti ni b has bee n a d mi nistere d t o m ore t ha n 5 0 0 0 partici pa nts i n 
cli nical st u dies (wit h a p pr o xi matel y 4 6 0 0 s u bjects recei vi n g acala br uti ni b as m o n ot hera p y or 
i n c o m bi nati o n wit h ot her a ge nts), i ncl u di n g s u bjects wit h he mat ol o gic mali g na ncies, s oli d 
t u m ors, or r he u mat oi d art hritis, a n d partici pa nts w h o are healt h y s u bjects or t h ose wit h mil d-
t o-m o derate h e patic i m pair me nt.  
St u d y A C E- C L - 3 0 9 e nr olle d a n d ra n d o mize d a t otal of 3 1 0 s u bjects ( 1 5 Ja n uar y 2 0 1 9), a n d 
all b ut 3 s ubjects ( 1 i n t he acala br uti ni b ar m a n d 2 i n t he i delalisi b + rit u xi ma b [I R] / 
be n da m usti ne a n d rit u xi ma b [ B R] ar m) recei v e d st u d y treat me nt. T he me dia n ti me o n st u d y 
f or acala br uti ni b a n d I R/ B R s u bjects was 1 6. 1 m o nt hs (ra n ge: 0. 5- 2 2. 4 m o nt hs) a n d 1 5. 7 
m o nt hs (ra n ge: 0. 0- 2 2. 1 m o nt hs), res pecti vel y. A cala br uti ni b de m o nstrate d a 6 9 % re d u cti o n 
i n ris k of Bli n de d  In de p e n de nt Re vie w C o m mittee ( BI C R)-assesse d disease pr o gressi o n or 
deat h c o m par e d wit h I R/ B R ( hazar d rati o [ H R] = 0. 3 1 [ 9 5 % CI: 0. 2 0, 0. 4 9], p < 0. 0 0 0 1). T he 
me dia n esti mate d P F S f or acal a br uti ni b was n ot reac he d; t he me dia n esti mate d P F S f or I R/ B R 
was 1 6. 5 m o nt hs ( 9 5 % CI: 1 4. 0, 1 7. 1). T he K a pla n- Meier ( K M) esti mate d 1 8 - m o nt h P F S 
rates f or acala br uti ni b a n d I R/ B R were 7 9. 0 % ( 9 5 % CI: 6 9. 7, 8 5. 8) a n d 3 8. 6 % ( 9 5 % CI: 2 7. 3, 
4 9. 8), res pecti vel y. T he k e y se nsiti vit y a nal ysis of P F S wit h o ut ce ns ori n g f or s u bse q ue nt 
a ntica ncer t her a p y was c o nsiste nt wit h t he pri mar y a nal ysis a n d s h o we d si milar i m pr o ve me nt 
i n P F S f or acal a br uti ni b c o m pare d wit h I R/ B R ( H R = 0. 3 3; p < 0. 0 0 0 1). All ot her se nsiti vit y 
a nal yses were als o c o nsiste nt wit h t he pri mar y a nal ysis, c o nfir mi n g t he r o b ust ness of t he 
pri mar y a nal ysis. A nal ysis o n t he sec o n dar y e n d p oi nt of i n vesti gat or- assesse d P F S was 
c o nsiste nt wit h pri mar y a nal ysis ( H R = 0. 2 8 [ 9 5 % CI: 0. 1 8, 0. 4 5]; p < 0. 0 0 0 1). T he cli nical 
be nefit wit h acala br uti ni b was f urt her de m o nstrat e d b y a cli nicall y rele va nt i m pr o ve me nt i n 
D O R f or acala br uti ni b c o m pare d wit h I R/ B R, b ot h b y BI C R assess me nt ( H R = 0. 3 3) a n d 
i n vesti gat or-assessme nt ( H R = 0. 2 0), a n d a si g nifica nt pr ol o n gati o n of ti me t o ne xt treat me nt 
( T T N T) f or acala br uti ni b c o m pare d wit h I R/ B R ( H R = 0. 3 5; p < 0. 0 0 0 1). O R R ( C R + C Ri + 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 3 6
 
n P R + P R) f or acala br uti ni b a n d I R/ B R was si milar base d o n BI C R assess me nt ( 8 1. 3 % a n d 
7 5. 5 %, res pecti vel y) a n d i n vesti gat or assess me nt ( 7 9. 4 % a n d 8 3. 2 %, res pecti vel y). 
St u d y A C E- C L - 0 0 7 e nr olle d a n d ra n d o mize d a t otal of 5 3 5 s u bjects ( 0 8 Fe br uar y 2 0 1 9), a n d 
5 2 6 s u bjects  ( 9 8. 3 %) w er e treate d wit h at least o ne st u d y dr u g. T he me dia n ti me o n st u d y f or 
acala bruti ni b + o bi n ut uz u ma b, acal a br uti ni b m o n ot hera p y, a n d o bi n ut uz u ma b + c hl ora m b u cil 
s u bjects was 2 8. 5 m o nt hs (ra n ge: 1. 7- 4 0. 3 m o nt hs), 2 8. 4 m o nt hs (ra n ge: 0. 1- 4 0. 8 m o nt hs), 
a n d 2 8. 0 m o nt hs (ra n ge: 0. 0- 4 0. 4 m o nt hs), res pecti vel y. Acala br uti ni b + o bi n ut uz u ma b 
de m o nstrate d a statisticall y si g nifica nt i m pr o ve me nt i n BI C R -assesse d P F S c o m pare d wit h 
o bi n ut uz u ma b +c hl ora m b ucil, wit h a 9 0 % re d u cti o n i n ris k of disease pr o gressi o n or deat h 
( H R = 0. 1 0 [ 9 5 % CI: 0. 0 6, 0. 1 7]; p < 0. 0 0 0 1). Acala br uti ni b m o n ot hera p y als o de m o nstrate d a 
statisticall y si g nifica nt i m pr o ve me nt i n BI C R-ass esse d P F S c o m pare d wit h o bi n ut uz u ma b + 
c hl ora m b ucil, wit h a n 8 0 % re d ucti o n i n ris k of dis ease pr o gressi o n or deat h ( H R = 0. 2 0 [ 9 5 % 
CI: 0. 1 3, 0. 3 0]; p < 0. 0 0 0 1). T he me dia n esti mate d P F S was n ot reac he d f or acala br uti ni b + 
o bi n ut uz u ma b or acala br uti ni b m o n ot hera p y a n d was 2 2. 6 m o nt hs ( 9 5 % CI: 2 0. 2, 2 7. 6) f or 
o bi n ut uz u ma b + c hl ora m b ucil. T he K M esti mate d 2 4- m o nt h P F S rate f or acala br uti ni b + 
o bi n ut uz u ma b was 9 2. 7 % ( CI 9 5 %: 8 7. 4, 9 5. 8), acala br uti ni b m o n ot hera p y was 8 7. 3 % ( CI 
9 5 %: 8 0. 9, 9 1. 7), a n d o bi n ut uz u ma b + c hl ora m b ucil was 4 6. 7 % ( CI 9 5 %: 3 8. 5, 5 4. 6). 
T he ke y se nsi ti vit y a nal ysis of P F S wit h o ut ce ns ori n g f or s u bse q ue nt a ntica ncer t hera p y w as 
c o nsiste nt wit h t he pri mar y a nal ysis a n d s h o we d si milar i m pr o ve me nt i n P F S f or acal a br uti ni b 
+ o bi n ut uz u ma b a n d acal a br uti ni b m o n ot hera p y c o m pare d wit h o bi n ut uz u ma b +c hl ora m b u cil 
( H R = 0. 1 1 [ 9 5 % CI: 0. 0 6, 0. 1 8] a n d H R = 0. 2 0 [ 9 5 % CI: 0. 1 3, 0. 3 1], res pecti vel y). All ot her 
se nsiti vit y a nal yses were als o c o nsiste nt wit h t he pri mar y a nal ysis. T he cli nical be nefit wit h 
acala br uti ni b was f urt her de m o nstrate d b y a si g nifica nt pr ol o n gati o n of T T N T c o m pare d wit h 
o bi n ut uz u ma b +c hl ora m b ucil f or b ot h acala br uti ni b + o bi n ut uz u ma b ( H R = 0. 1 4 [ 9 5 % CI: 0. 0 8, 
0. 2 6]; p < 0. 0 0 0 1) a n d acala br uti ni b m o n ot hera p y ( H R = 0. 2 4 [ 9 5 % CI: 0. 1 5, 0. 4 0]; p < 0. 0 0 0 1). 
BI C R -assess e d O R R f or acala br uti ni b + o bi n ut uz u ma b a n d o bi n ut uz u ma b +c hl ora m b ucil w as 
9 3. 9 % ( 9 5 % CI: 8 9. 3, 9 6. 5) a n d 7 8. 5 % ( 9 5 % CI: 7 1. 9, 8 3. 9), res pecti vel y, wit h a statisticall y 
si g nifica nt differ e nce b et wee n treat me nt ar ms of 1 5. 3 % p < 0. 0 0 0 1). T h e BI C R-assesse d O R R 
i n t he acala br uti ni b m o n ot hera p y ar m was 8 5. 5 % ( 9 5 % CI: 7 9. 6, 8 9. 9) ( p = 0. 0 7 6 3 c o m pare d 
wit h t he o bi n ut uz u ma b +c hl ora m b ucil ar m). 
T he eff ecti ve n ess of acal a br uti ni b i n patie nts wit h C L L has als o b ee n c o nfir me d i n n u m ber of 
s u p p orti ve st u dies. See t he Acal a br uti ni b I n vesti gat or’s Br oc h ure f or a d diti o nal details o n 
n o ncli nical a n d cli nical st u dies.  

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 7
Be nefit/ris k assess me nt 
2. 3. 1  
Ac al a br uti ni b 
Acala br uti ni b m o n ot her a p y has de m o nstrate d effi cac y i n s u bjects wit h rela pse d/refract or y 
( ma ntle cell l y m p h o ma) M C L a n d i n s u bjects wit h treat me nt naï ve or rela pse d/refract or y 
c hr o nic l y m p h oc ytic le u k e mia ( C L L).  
Base d o n re vie w of t he a vaila ble saf et y a n d efficac y data f or acala br uti ni b as well as 
c o nsi derati o n of meas ures i m ple me nte d i n t he acal a br uti ni b cli nical de vel o p me nt pr o gra m t o 
mi ni mize p ote ntial ris ks t o s u bjects, t he o verall be nefit -ris k assess me nt pr ofile of 
acala br uti ni b f or t he i n dicati o n u n der i n vesti gati o n re mai ns fa v o ura ble f or c o nti n ui n g cli nical 
de vel o p me nt a n d is j ustifie d b y t he percei ve d be n efits t hat ma y be aff or de d t o t he patie nts.  
Preca uti o nar y s afet y meas ures, a n d re g ular m o nit ori n g of safet y b y a n i n de pe n de nt Data 
M o nit ori n g C o m mittee ( D M C) a n d t he s p o ns or e na ble earl y i de ntificati o n of safet y si g nals i n 
t he st u d y a n d mi ni mize t he ris k t o s u bjects. 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits a n d p ote ntial ris ks of 
acala br uti ni b ma y be f o u n d i n t he I n v esti gat or’ s Br oc h ure a n d De v el o p me nt Safet y U p date 
Re p ort ( D S U R).
2. 3. 1. 1
Ris k assess m e nt
C o ntr ai n dic ati o ns 
N o c o ntrai n dicati o ns are k n o w n f or acala br uti ni b. 
I m p ort a nt i de ntifie d ris ks
T he f oll o wi n g s u m marizes t he i m p orta nt i de ntifie d ris ks o bser ve d wit h acala br uti ni b i n 
he mat ol o gical ca n cer st u dies. F ull details re gar di n g t he cli nical safet y of acala br uti ni b are 
prese nte d i n t he acala br uti ni b I n vesti gat or’s Br o c h ure.
•
He m orr h a ge
Seri o us he m orr ha gic e ve nts, i ncl u di n g fatal e ve nts, ha ve occ urre d i n cli nical trials wit h 
acala bruti ni b .
T he mec ha nis m f or he m orr ha ge is n ot w ell u n derst o o d. Patie nts recei vi n g a ntit hr o m bic 
a ge nts ma y be at i ncrease d ris k of he m orr h a ge. Us e ca uti o n wit h a ntit hr o m b otic a ge nts 
a n d c o nsi der a d diti o nal m o nit ori n g f or si g ns of blee di n g w he n c o n c o mita nt use is 
me dicall y necess ar y.
C o nsi der t he be nefit-ris k of wit h h ol di n g acala br uti ni b f or at least 3 da ys pre- a n d p ost-
s ur ger y.  

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 3 8
 
S u bjects wit h he m orr ha g e s h o ul d be ma na ge d p er i nstit uti o nal g ui deli nes wit h s u p p orti ve 
care a n d dia g n ostic e v al u ati o ns as cli nicall y i n dicate d.  
•  
I nfecti o n 
Seri o us i nfecti o ns ( bact erial, viral, a n d f u n gal), i n cl u di n g fatal e ve nts, ha v e occ urre d i n 
cli nical st u dies wit h acal a br uti ni b.  T he m ost fre q ue ntl y re p orte d Gra de ≥3 i nfecti o n was 
p ne u m o nia ( preferre d ter m).  Acr oss t he acala br uti ni b cli nical de vel o p me nt pr o gra m 
(i ncl u di n g s u bjects treate d wit h acala br uti ni b i n c o m bi nati o n wit h ot her dr u gs), cases of 
he patitis  B vir us ( H B V) r eacti vati o n, as per gill osis, a n d pr o gressi ve m ultif ocal 
le u k oe nce p h al o pat h y ( P M L) ha ve occ urre d. 
C o nsi der pr o p h yla xis i n patie nts w h o are at i ncrease d ris k f or o p p ort u nistic i nfecti o ns. 
S u bjects s h o ul d be m o nit ore d f or si g ns a n d s y m pt o ms of i nfecti o n a n d treate d as 
me dicall y a p pr o pri ate.   
S u bjects wit h i nfecti o n e ve nts s h o ul d be ma na ge d acc or di n g t o i nstit uti o nal g ui deli nes 
wit h ma xi mal s u p p orti ve care a n d dia g n ostic e v al uati o ns as cli nicall y i n dicate d. 
•  
C yt o pe ni as 
Treat me nt -e mer ge nt Gra de  3 or 4 c yt o pe nias, i n cl u di n g ne utr o pe nia, a n e mia, a n d 
t hr o m b oc yt o pe nia ha ve o cc urr e d i n cli nical st u dies wit h acala br uti ni b.  M o nit or bl o o d 
c o u nts as s pecifie d i n t he sc he d ule of assess me nts a n d as me dicall y a p pr o priate.  
S u bjects wit h c yt o pe nias s h o ul d be ma na ge d acc or di n g t o i nstit uti o nal g ui deli nes wit h 
ma xi mal s u p p orti ve car e a n d dia g n ostic e val uati o ns as cli nicall y i n dicate d.  S u bjects 
s h o ul d be cl osel y m o nit ore d as a p pr o priate. 
•  
Sec o n d Pri m ar y M ali g n a ncies  
E ve nts of sec o n d pri mar y mali g na ncies, i ncl u di n g n o n- mela n o ma s ki n carci n o mas, ha ve 
bee n re p orte d i n cli nical st u dies patie nts treate d wit h acala br uti ni b.  T he m ost fre q ue ntl y 
re p orte d sec o n d pri mar y mali g na nc y was s ki n ca n cer.   
S u bjects s h o ul d be m o nit ore d f or si g ns a n d s y m pt o ms of mali g na nc y.  S u bjects w h o 
de vel o p a sec o n d pri mar y mali g na nc y s h o ul d be ma na ge d acc or di n g t o i nstit uti o nal 
g ui deli nes wit h dia g n osti c e val uati o ns as cli nicall y i n dicate d, a n d it ma y b e necessar y f or 
s u bjects t o per ma ne ntl y disc o nti n ue st u d y treat me nt.  C o nti n uati o n of acal a br uti ni b 
treat me nt s h o ul d be disc usse d wit h t he st u d y p h ysicia n. 
 
•  
Atri al Fi brill ati o n  

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 3 9
 
E ve nts of atrial fi brillati o n/fl utter ha ve occ urre d i n cli nical st u dies wit h acal a br uti ni b, 
partic ularl y i n s u bjects wit h car diac ris k fact ors, h y perte nsi o n, dia betes mellit us, ac ute 
i nfecti o ns, or a n d a pre vi o us hist or y of atrial fi brillati o n. 
M o nit or f or s y m pt o ms of atri al fi brillati o n a n d atri al fl utter (e. g., p al pitati o ns, dizzi ness, 
s y nc o pe, c hest p ai n, d ys p nea) a n d o bt ai n a n E C G as a p pr o priat e. S u bjects wit h atrial 
fi brillati o n s h o ul d be ma na ge d per i nstit uti o nal g ui deli nes or as cli nicall y i n dicate d. 
I m p ort a nt p ote nti al ris ks 
T here is o ne i m p orta nt p ote ntial ris k f or acala br uti ni b m o n ot hera p y. I nf or mati o n relate d t o 
t his i m p orta nt p ote ntial ris k is prese nte d bel o w. F ull details re gar di n g t he cli nical safet y of 
acala br uti ni b are pr ese nt e d i n t he acala br uti ni b I n vesti ga t or’s Br oc h ure.  
•  
He p at ot o xicit y 
T he mec ha nis m u n derl yi n g he pat ot o xicit y e ve nts of n o n-i nfecti o us eti ol o g y is c urre ntl y 
u n k n o w n. F oll o wi n g a c o m pre he nsi ve re vie w of h e pat ot o xicit y e ve nts i n t he 
acala br uti ni b cli nical pr o gra m, t here was i ns uffici e nt e vi de nce  t o esta blis h a n ass ociati o n 
bet wee n h e pat ot o xicit y e ve nts a n d acala br uti ni b d ue t o t he c o ntri b uti o n of c o nf o u n di n g 
fact ors, a bs e nce of cli nical s y m pt o ms, a n d q uic k rec o ver y wit h o ut treat me nt f or patie nts 
wit h tra nsa mi nase ele v ati o ns. T here is li mite d e vi d e nce re gar di n g he pat ot o xicit y of n o n-
i nfecti o us eti ol o g y fr o m literat ure f or ot her B T K i n hi bit ors. 
 
2. 3. 2  
Rit u xi m a b a n d c hl or a m b ucil 
Rit u xi ma b i n c o m bi nati o n wit h c hl ora m b ucil is o ne of t he preferre d re gi me ns per C hi nese 
C L L/ S L L Dia g n ostic a n d Treat me nt G ui deli n e (V ersi o n  2 0 1 8) f or m e dicall y u nfit C L L 
patie nts.  Ris ks ass ociate d wit h rit u xi ma b a n d c hl ora m b ucil are descri be d i n t he l ocal 
prescri bi n g i nf or mati o n (i.e., S u m mar y of Pr o d uc t C haracteristics, etc). 
O verall, t he a v aila ble cli nical data i ncl u di n g t he s afet y e x p erie n ce s u p p ort f urt her cli nical 
i n vesti gati o n of acala br uti ni b as well as rit u xi ma b i n c o m bi nati o n wit h c hl ora m b ucil i n t his 
st u d y.  Preca uti o nar y saf et y meas ures, a n d re g ul ar m o nit ori n g of safet y b y t he s p o ns or e na bl e 
earl y i de ntificati o n of s af et y si g nals i n t he st u d y a n d mi ni mize t he ris k t o s u bjects.   
I n c o ncl usi o n, it is c o nsi dere d t hat t he b e nefit ris k rati o f or t his st u d y is fa v ora ble. 
 
 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 2
4
St u d y D E SI G N   
O ver all desi g n
T his ra n d o mize d, r e gi o nal, m ultice nter, o pe n- la b el, P hase 3 st u d y will e val uate t he efficac y 
a n d safet y of acala br uti ni b m o n ot hera p y vers us c hl ora m b ucil pl us rit u xi ma b i n s u bjects wit h 
pre vi o usl y u ntreate d C L L wit h o ut del( 1 7 p) or T P 5 3 m utati o n. 
A p pr o xi matel y 1 5 0 s u bjects will be ra n d o mize d i n a 1: 1 rati o i nt o 2 treat me nt ar ms 
( n = 7 5 s u bjects eac h) t o r ecei ve eit her acala br uti ni b m o n ot hera p y ( Ar m A) or rit u xi ma b i n 
c o m bi nati o n wit h c hl ora m b ucil ( Ar m B).  It is pla n ne d t o ra n d o mize a p pr o xi matel y 7 5 t o 1 2 0 
patie nts i n t otal ( 5 0 % t o 8 0 % of t otal sa m ple size) fr o m C hi na. Ra n d o mizati o n will be 
stratifie d b y E C O G [0- 1 vers us 2] a n d Rai sta g e [ 0- II vers us III-I V].  A sc he d ule of scree ni n g 
a n d trial assess me nts is pr o vi de d i n Ta ble 1 ( Ar m A) a n d Ta bl e  2 ( Ar m B).  
At i n vesti gat or discreti o n, s u bjects ra n d o mize d t o Ar m B w h o ha ve BI C R -c o nfir me d or 
i n vesti gat or-assesse d  (aft er F A a n d per A me n d me nt 5. 0) disease pr o gressi o n a n d meet 
eli gi bilit y f or cr oss o ver are per mitte d t o recei ve acala br uti ni b m o n ot hera p y treat me nt u ntil 
disease pr o gr essi o n or u n acce pta ble t o xicit y. F or t he details, please refer t o Secti o n 6. 8.
S u bject partici pati o n will i n cl u de a scree ni n g p has e, treat me nt p has e, p ost- treat me nt diseas e 
f oll o w- u p p hase, a n d s ur vi val f oll o w- u p p hase.  T he scree ni n g p hase will last u p t o 2 8 da ys 
bef ore t h e first d ose of st u d y dr u g, d uri n g w hic h t he s u bject’s eli gi bilit y a n d baseli ne 
c haracteri stics will be det er mi ne d.  T he treat me nt p hase will last fr o m ra n d o mizati o n u ntil 
st u d y dr u g(s) disc o nti n uati o n.  Treat me nt wit h acala br uti ni b ma y be c o nti n ue d u ntil disease 
pr o gressi o n or a n y ot h er treat me nt disc o nti n uati o n criteri o n is met.  Treat me nt wi t h 
c hl ora m b ucil/rit u xi ma b is u p t o 6 c ycles, or u ntil t here is diseas e pr o gressi o n or a n y ot her 
treat me nt disc o nti n uati o n criteri o n is met.  D ose m o dificati o n pr o visi o ns are pr o vi de d i n 
Secti o n 6. 6.
Assess me nt f or t u m or res p o nse a n d pr o gressi o n will be c o n d ucte d i n acc or d a nce wit h t he 
I W C L L 2 0 1 8 criteria.  Disease assess me nts will b e d o ne acc or di n g t o S o A u ntil c o nfir mati o n 
of disease pr o gressi o n or deat h, c o nse nt wit h dra wal, or l ost t o f oll o w- u p.  S u bjects fr o m 
Ar m  B w h o ha ve BI C R-c o nfir me d or i n vesti gat or-assesse d(after F A a n d per A me n d me nt 5. 0) 
disease pr o gr essi o n ma y be eli gi ble t o cr oss o ver a n d recei v e si n gle a ge nt acala br uti ni b 
1 0 0 m g BI D at i n vesti gat or discreti o n.  A n e n d- of- treat me nt ( E o T) visit is re q uire d f or s afet y 
assess me nts f or a n y s u bj ects w h o per m a ne ntl y disc o nti n ue st u d y treat me nt f or a n y reas o n 
(e xce pt f or deat h, l ost t o f oll o w- u p, or wit h dra w al of c o nse nt), i ncl u di n g disease pr o gressi o n.  
T he E o T v isit s h o ul d be perf or me d wit hi n 7 da ys of t he last d ose of all st u d y dr u gs, if 
p ossi ble, a n d is n ot re q uire d f or s u bjects w h o disc o nti n ue fr o m st u d y treat me nt wit hi n 1 0 da ys 
of a sc he d ul e d st u d y visit, or if t he E o T visit w o ul d be perf or me d wit hi n 1 4 da ys of t he safet y 
f oll o w- u p ( S F U) visit. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 4 3
 
T he s ur vi val f oll o w- u p will be gi n after BI C R- or i n vesti gat or-c o nfir m e d pr o gressi ve diseas e.  
D uri n g t his p hase, s u bse q ue nt a ntica ncer t hera p y t o treat C L L i ncl u di n g best res p o nse, 
I W C L L i n dicati o n f or tr eat me nt i nitiati o n, a d diti o nal mali g na nc y occ urre n ce, a n d s ur vi v al 
stat us will be rec or d e d.  T he s ur vi val f oll o w- u p will c o nti n ue u ntil deat h, l ost t o f oll o w- u p, 
c o nse nt wit h dra w al, or st u d y cl os ure, w hic h e ver o cc urs first.  F or treat me nt after t he e n d of 
st u d y see Secti o n 6. 7 . 
F or a n o v er vie w of t he st u d y desi g n see  Fi g ure 1 , Secti o n 1. 3 .  F or details o n treat me nts gi ve n 
d uri n g t he st u d y, see Secti o n  6  St u d y Treat me nts.   
F or details o n w h at is i ncl u de d i n t he efficac y a n d safet y e n d p oi nts, see Secti o n  3  O bjecti ves 
a n d E n d p oi nts.   
4. 1. 1  
St u d y C o n d uct Miti g ati o n D uri n g St u d y Disr u pti o ns D ue t o C as es of 
Ci vil Crisis, N at ur al Dis aster, o r P u bli c He alt h Crisis  
T he g ui da nce gi v e n bel o w s u perse d es i nstr ucti o ns pr o vi de d else w h ere i n t his C S P a n d s h o ul d 
be i m ple me nte d o nl y d uri n g cases of ci vil crisis, nat ural disaster, or p u blic healt h crisis (e g, 
d uri n g q uara nti nes a n d res ulti n g site cl os ures, re gi o nal tra vel restricti o ns, a n d c o nsi derati o ns if 
site pers o n nel or st u d y partici pa nts bec o me i nfecte d wit h S A R S- C o V-2 or si milar pa n de mic 
i nfecti o n) w hic h w o ul d pre ve nt t he c o n d u ct of st u d y-relate d acti vities at st u d y sites, t here b y 
c o m pr o misi n g t he st u d y site staff or t he partici pa nt’s a bilit y t o c o n d uct t he st u d y. T he 
i n vesti gat or or desi g nee s h o ul d c o ntact t he st u d y S p o ns or t o disc uss w het her t he miti gati o n 
pla ns bel o w s h o ul d be i m ple me nte d.   
T o e ns ure c o nti n uit y of t he cli nical st u d y d uri n g a ci vil crisis, nat ural disaster, or p u blic healt h 
crisis, c ha n ges ma y b e i m ple me nte d t o e ns ure t h e safet y of st u d y p artici p a nts, mai ntai n 
c o m plia nce wit h G o o d Cli nical Practice, a n d mi ni mize ris ks t o st u d y  i nte grit y.  
W here all o wa ble b y l ocal healt h a ut h orities, et hics c o m mittees, healt hcare pr o vi der g ui deli nes 
(e g, h os pital p olicies) or l ocal g o ver n me nt, t hes e c ha n ges ma y i ncl u de t he f oll o wi n g o pti o ns:  
•  
Rescree ni n g: A d diti o nal rescr ee ni n g f or s cree n fail ur e a n d t o c o nfir m eli gi bilit y t o 
partici pate i n t he cli nical st u d y ca n be perf or me d i n pre vi o usl y scree ne d partici pa nts. T he 
i n vesti gat or s h o ul d c o nfir m t his wit h t he desi g nate d st u d y p h ysicia n.  
•  
H o me or Re m ote visit: Perf or me d b y a site q ualifi e d Healt h Ca re Pr ofessi o nal ( H C P) or 
H C P pr o vi de d b y a t hir d- part y ve n d or ( T P V). 
•  
Tele me dici ne visit: Re m ote c o ntact wit h t he  partici pa nts  usi n g telec o m m u nicati o ns 
tec h n ol o g y i ncl u di n g p h o ne calls, virt ual or vi de o visits, a n d m o bile healt h de vices. H o me 
deli ver y of A cala br uti ni b b y a desi g nate d c o urier. If a site visit is n ot p ossi ble, 
Acala br uti ni b ma y be d eli vere d t o t he partici pa nt's h o me b y a desi g nate d c o urier if 
feasi ble. T he o pti o n of h o me deli ver y e ns ures a p artici pa nt’s safet y i n cas es of a 
pa n de mic w here part ici p a nts ma y be at i ncrease d ris k b y tra velli n g t o t he site/cli nic. T his 
will als o mi ni mize i nterr u pti o n of Acala br uti ni b a d mi nistrati o n d uri n g ot her st u d y 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 4
disr u pti o ns, e g, site cl os ures d ue t o nat ural disaster. 
•
At - h o me I n vesti gati o nal Pr o d uct (I P) a d mi nistrati o n: Perf or me d b y a site q ualifie d H C P, 
or b y t he partici pa nts or t he partici pa nt’s care gi ver, if p ossi ble. A d diti o nal i nf or mati o n 
relate d t o t he visit ca n be o btai ne d via tele me dici n e. 
•
H o me deli ver y of Acal a br uti ni b b y a desi g nate d c o urier: If a site visit is n ot p ossi ble, 
Acala br uti ni b ma y be d eli vere d t o t he partici pa nt's h o me b y a desi g nate d c o urier if 
feasi ble. T he o pti o n of h o me deli ver y e ns ures a p artici pa nt’s safet y i n cas es of a 
pa n de mic w here partici p a nts ma y be at i ncrease d ris k b y tra velli n g t o t he site/cli nic. T his 
will als o mi ni mize i nterr u pti o n of Acala br uti ni b a d mi nistrati o n d uri n g ot her st u d y 
disr u pti o ns, e g, site cl os ures d ue t o nat ural disaster. 
F or f urt her det ails o n st u d y c o n d uct d uri n g ci vil crisis, nat ural disaster, or p u blic hea lt h crisis, 
refer t o A p pe n di x J.   
Scie ntific r ati o n ale f or st u d y desi g n   
T his is a P hase  3, ra n d o mize d, c o ntr olle d st u d y t o assess t he be nefit/ris k pr ofile of 
acala br uti ni b m o n ot hera p y vers us rit u xi ma b i n c o m bi nati o n wit h c hl ora m b ucil.  Gi ve n t he 
dif fere nt tr eat me nt a d mi nistrati o n sc he d ules a n d treat me nt d urati o ns, t his st u d y will use a n 
o pe n-la bel desi g n.
T his st u d y is tar geti n g t he me dicall y u nfit C L L s u bjects, a n d rit u xi ma b i n c o m bi nati o n wit h 
c hl ora m b ucil was sel ecte d as t he c o m parat or per C hi nese C L L/ S L L Dia g n ostic a n d Treat me nt 
G ui deli ne (Versi o n  2 0 1 8) as o ne of t he preferre d re gi me ns.  N C C N G ui deli nes 
(Versi o n  5 2 0 1 9) als o rec o m me n d c hl ora m b ucil pl us a nti- C D 2 0 m o n ocl o nal a nti b o d y f or frail 
patie nts wit h si g nifica nt c o m or bi dit y ( n ot a ble t o t olerate p uri n e a nal o gs), p atie nts a ge d 
≥6 5  years, a n d y o u n g er p atie nts wit h si g nifica nt c o m or bi dities.  C urre ntl y, rit u xi ma b is t he 
o nl y N C C N- rec o m me n d e d a nti- C D 2 0 a nti b o d y a p pr o ve d i n C hi na. 
F or C L L patie nts w h o ar e el derl y a n d/ or ha ve c o m or bi dities t hat ma ke t he m i neli gi ble f or 
fl u dara bi ne- base d tr eat m e nt, c hl ora m b ucil pl us rit u xi ma b is a n a p pr o priate t hera pe utic o pti o n.  
I n t he P h ase 2 Nati o nal Ca ncer Res earc h I nstit ute St u d y C L L 2 0 8, a t otal of 1 0 0 patie nts were 
treate d wit h rit u xi ma b-c hl ora m b ucil, wit h a me dia n f oll o w - u p of 3 0 m o nt hs (Hill me n  G et al. 
2 0 1 4) .  Me dia n a g e of patie nts was 7 0 years (ra n g e 4 3 t o 8 6 years), wit h patie nts ha vi n g a 
me dia n of 7 c o m or bi dities.  O verall res p o ns e rat es i n t he C L L 2 0 8 st u d y were 8 4 %, wit h C R 
ac hie ve d i n 1 0 % of patie nts.  Me dia n P F S was 2 3. 5 m o nt hs.  He mat ol o gic t o xicities 
acc o u nte d f or m ost Gra d e 3- 4 A Es re p orte d, wit h ne utr o pe nia a n d l y m p h o p e nia b ot h 
occ urri n g i n 4 1 % of patie nts a n d le u k o pe nia occ urri n g i n 2 3 % of patie nts.  
J ustific ati o n f or d ose
4. 3. 1  
Ac al a br uti ni b d ose r ati o n ale    
T he rec o m me n de d d ose of acal a br uti ni b is 1 0 0 m g BI D b ase d o n t he f oll o wi n g data:  

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 4 5
I n t he P h ase 1/ 2 st u d y i n s u bjects wit h C L L/ S L L (A C E- C L - 0 0 1), s u bjects recei ve d 
acalabr uti ni b at d osa ges fr o m 1 0 0 t o 4 0 0 m g Q D or 1 0 0 t o 2 0 0 m g BI D.  N o d ose- li miti n g 
t o xicities ( D L Ts) wer e i d e ntifie d at d osa ges of ≤4 0 0 m g Q D or at d osa ges of 1 0 0 t o 2 0 0 m g 
BI D.  Wit h a me dia n f oll o w u p of 1 5. 5 m o nt hs i n e val ua ble s u bjects ( n = 1 2 8), t he best o verall 
res p o nse r ate, i ncl u di n g partial res p o nse a n d parti al res p o nse wit h l y m p h oc yt osis ( P R L), was 
9 6. 9 %.   
P har mac o d y na mics r es ults fr o m A C E- C L - 0 0 1 s u g gest B T K re-s y nt hesis occ urs i n mali g na nt 
B cells wit hi n 2 4  h o urs.  W hile all d osa ges e v al uate d s h o w f ull B T K occ u p a nc y 4 h o urs after 
d osi n g, t he 1 0 0 m g BI D c o h ort s h o ws f ull tar get c o vera ge o v er 2 4 h o urs ( ≥9 7 % B T K 
occ u pa n c y at 4 a n d 2 4 h o urs).  Base d o n p har mac o ki netics ( P K)/ p har mac o d y na mics a n d 
efficac y r es ults of t he P hase  1/ 2 st u d y, acal a br uti ni b 1 0 0 m g BI D is select e d as t he 
rec o m me n de d d os e.  
I n a n o n g oi n g Ja pa n ese P hase 1 st u d y (
), preli mi nar y data fr o m Part  1 (t he 
d ose-c o nfir m ati o n p hase) s h o we d acce pta ble s afet y a n d t olera bilit y.  N o D L T was o bser v e d 
a m o n g t he 6 e val ua bl e s u bjects.  N o cli nicall y rele va nt P K et h nic differe nce was o bser ve d 
bet wee n Ja p a nes e a n d Wester n s u bjects.
4. 3. 2  
Rit u xi m a b d ose r ati o n ale 
T he lice nse d d ose of rit u xi ma b f or use i n C L L will be use d. 
4. 3. 3  
C hl or a m b ucil d ose r ati o n ale 
T he rati o nale f or t he c hl ora m b ucil d osi n g is base d o n t he fi n di n gs fr o m t he Ger ma n C L L 
St u d y Gr o u p ( G C L L S G) C L L 5 trial ( Eic h h orst et al, 2 0 0 9).  T he trial dat a i n dicate d t hat 
me dia n a d mi nistere d d os e f or c hl or a m b ucil was 0. 5 m g/ k g a n d me dia n d urati o n of treat me nt 
was 6. 5 m o nt hs, t h o u g h c hl ora m b ucil was sc he d ul e d at 0. 4 m g/ k g i nitial l y wit h a s u bse q ue nt 
i ncreas e t o a ma xi m u m of 0. 8 m g/ k g if well t olerate d a n d o n a 1 4-d a y c ycl e f or a m a xi m u m of 
2 4 c ycles i n t he pr ot oc ol.  T he C L L 5 st u d y s u g geste d t hat t he treat me nt sc h e d ule of 0. 5 m g/ k g 
f or 6 c ycl es i n t otal is a relati vel y l o w d ose b u t n o ni nferi or t o fl u dara bi ne i n el derl y patie nts 
wit h C L L.  T he sa me treat me nt sc he d ule w as a d o pte d i n t he C L - 1 1 st u d y, w hic h de m o nstrate d 
c o nsiste nt res p o nse a n d s afet y pr ofile i n t he m e dicall y u nfit C L L patie nts (G oe de et al,  2 0 1 4).
E n d of st u d y defi niti o n
T he fi nal a n al ysis was c o n d ucte d  a p pr o xi matel y 4 5 m o nt hs after t he first p atie nt wa s 
ra n d o mize d i nt o t his st u d y.  Wit h A me n d me nt 5. 0, t he e n d of st u d y is t o occ ur a p pr o xi mat el y 
5 4 m o nt hs after t he first s u bject is ra n d o mize d i nt o t his st u d y.
A s u bject is c o nsi dere d t o ha ve c o m plete d t h e st u d y w he n he/s he h as c o m plete d his/ her last 
sc he d ule d visit/c o ntact.  S u bject ca n wit h dra w fr o m treat me nt b ut ma y still c o m plete t he st u d y
b y atte n di n g all re q uire d visits as s h o w n i n t he S o A.
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 4 6
 
See Secti o n  6. 7  f or det aile d i nf or mati o n f or treat m e nt after t h e e n d of st u d y. See 
A p pe n di x  A 6  f or g ui deli nes f or t he disse mi nati o n of st u d y res ults. 
 
 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
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5
S T U D Y P O P U L A TI O N
Pr os pecti ve a p pr o v al of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e x e m pti o ns, is n ot per mitte d. 
Eac h s u bject s h o ul d meet all of t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria f or t his 
st u d y i n or der t o assi g ne d/ra n d o mise d t o a st u d y i nter ve nti o n. U n der n o circ u msta nces ca n 
t here be e xce pti o ns t o t his r ule.  S u bjects w h o d o n ot meet t he e ntr y re q uire me nts are 
c o nsi dere d scree n fail ur es. Scree n f ail ure s u bjects ma y be res cree ne d o ne a d diti o nal ti me.  
(ref er t o Secti o n 5. 4) . 
I n t his pr ot oc ol, “e nr olle d” s u bjects are defi n e d as t h ose w h o si g n i nf or me d c o nse nt a n d 
recei v e a n e nr oll me nt n u m ber.  “ Ra n d o mize d ” s u bjects are d efi ne d as t h ose w h o u n der g o 
ra n d o mizati o n a n d r ecei ve a ra n d o mizati o n n u m ber. 
W here a s u bject d o es n ot meet all t he eli gi bilit y criteria b ut is treate d i n err or, or i nc orrectl y 
starte d o n treat me nt, t he i n vesti gat or s h o ul d i nf or m t he Astra Ze neca st u d y p h ysicia n 
i m me diatel y, a n d a disc ussi o n s h o ul d occ ur bet wee n t he Astra Z e neca st u d y p h ysicia n a n d t he 
i n vesti gat or re gar di n g w het her t o c o nti n ue or disc o nti n ue t he patie nt fr o m treat me nt.  T he 
Astra Ze neca st u d y p h ysi cia n m ust e ns ure all decisi o ns are a p pr o priatel y d oc u me nte d.  F or 
pr oce d ur es f or wit h dra w al of i nc orr ectl y e nr olle d s u bjects see Secti o n 7. 3.
I ncl usi o n criteri a
S u bjects are eli gi ble t o b e i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g i ncl usi o n criteria 
a n d n o ne of t he e xcl usi o n criteria a p pl y: 
I nf or m e d c o nse nt
1 
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt w hic h i ncl u des c o m plia nce wit h t he 
re q uire me nts a n d restricti o ns liste d i n t he i nf or me d c o nse nt f or m (I C F) a n d i n t his 
pr ot oc ol 
2 
Pr o visi o n of si g ne d a n d date d, writte n i nf or me d c o nse nt f or m pri or t o a n y ma n dat or y 
st u d y s pecific pr oce d ures, sa m pli n g, a n d a nal yses  
T he I C F pr o cess is descri be d  i n A p pe n di x A 3 .
A ge
3  
Me n a n d w o me n:  
(a) ≥6 5 years of a ge O R

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( b) > 1 8 a n d < 6 5 y ears of a ge, pr o vi de d t hat t he y meet at least o ne of t he f oll o wi n g 
criteria:  
(i) Creati ni ne cleara n ce 3 0 t o 6 9  m L/ mi n usi n g t he C oc kcr oft- Ga ult e q uati o n 
(i w C L L g ui deli nes) 
(ii) A sc ore hi g her t ha n 6 o n t he C u m ulati ve Ill ness R ati n g Sc ore- G eriatric ( CI R S -
G) (A p pe n di x F )  
 
T y pe of s u bject a n d dise ase c h ar acteristics  
4  
E C O G perf or ma nce stat us of 0, 1, or 2 
5  
Dia g n osis of C L L t hat meets p u blis he d dia g n ostic criteria (Halle k  2 0 1 8): 
(a) M o n ocl o nal B-c ells (eit h er ka p pa or la m b da li g ht c hai n restrict e d) t hat are cl o nall y 
c o- e x pressi n g B- cell mar ker ( C D 1 9, C D 2 0, a n d C D 2 3) a n d C D 5 
( b) Pr ol y m p h oc ytes ma y c o m prise < 5 5 % of bl o o d l y m p h oc ytes 
(c) Prese nce of ≥5 × 1 0 9 B l y m p h oc ytes/ L ( 5 0 0 0/ μ L) i n t he peri p heral bl o o d (at a n y p oi nt 
si nce t he i nitial dia g n osis) 
6  
Acti ve disease p er I W C L L 2 0 1 8 criteria t hat re q uires treat me nt, at least 1 of t he f oll o wi n g 
criteria s h o ul d be met:  
(a) E vi de nce of pr o gressi ve marr o w fail ure as ma nifeste d b y t he de vel o p me nt of, or 
w orse ni n g of, a n e mia ( he m o gl o bi n < 1 0 g/ d L) a n d/ or t hr o m b oc yt o pe nia ( platelets 
< 1 0 0, 0 0 0/ μ L)  
( b) Massi ve (i.e., ≥6  c m bel o w t he left c ostal mar gi n), pr o gressi ve, or s y m pt o m atic 
s ple n o me gal y 
(c) Massi ve n o des (i.e., ≥1 0  c m i n t he l o n gest dia meter), pr o gressi ve, or s y m pt o matic 
l y m p ha de n o pat h y  
( d) Pr o gressi ve l y m p h oc yt osis wit h a n i ncrease of > 5 0 % o ver a 2- m o nt h peri o d or a 
l y m p h oc yte d o u bli n g ti me ( L D T) of < 6 m o nt hs.  L D T ma y be o btai ne d b y li near 
re gressi o n e xtra p olati o n of a bs ol ute l y m p h oc yte c o u nt ( A L C) o btai ne d at i nter vals of 
2 wee ks o ver a n o bser vati o n peri o d of 2 t o 3 m o nt hs.  I n s u bjects wit h i nitial bl o o d 
l y m p h oc yte c o u nts of < 3 0 × 1 09/ L ( 3 0, 0 0 0/ μ L), L D T s h o ul d n ot be use d as a si n gle 
para meter t o defi ne i n dicati o n f or treat me nt.  I n a d diti o n, fact ors c o ntri b uti n g t o 
l y m p h oc yt osis or l y m p ha de n o pat h y ot her t ha n C L L (e. g., i nfecti o ns) s h o ul d be 
e xcl u de d. 
(e) A ut oi m m u ne a ne mia a n d/ or t hr o m b oc yt o pe nia t hat is p o orl y res p o nsi ve t o sta n dar d 
t hera p y 
(f) S y m pt o matic or f u ncti o nal e xtra n o dal i n v ol ve me nt (e. g., s ki n, ki d ne y, l u n g, s pi ne). 

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( g) B-s y m pt o ms d oc u me nte d i n t he s u bject’s c hart wit h s u p p orti ve o bjecti ve meas ures, 
as a p pr o priat e, defi n e d as ≥1 of t he f oll o wi n g disease -relate d s y m pt o ms or si g ns: 
(i) U ni nte nti o nal wei g ht l oss ≥1 0 % wit hi n t he pre vi o us 6  m o nt hs bef ore Scree ni n g 
(ii) Si g nifica nt fati g ue ( E C O G perf or m a nce st at us  2 or hi g her; i na bilit y t o w or k or 
perf or m us ual acti vities)  
(iii) Fe vers hi g her t ha n 1 0 0. 5° F or 3 8. 0° C f or ≥2  w ee ks bef ore Scree ni n g wit h o ut 
e vi de nce of i nfecti o n  
(i v) Ni g ht s weats f or ≥1  m o nt h bef ore Scree ni n g wit h o ut e vi de nce of i nfecti o n 
7  
Meet t he f oll o wi n g la b or at or y para meters: 
(a) A de q uate b o n e marr o w f u ncti o n i n de pe n de nt of gr o wt h fact or or tra nsf usi o n s u p p ort 
1 wee k bef ore assess me nt, as f oll o ws:  
(i) A bs ol ute ne utr o p hil c o u nt ( A N C) ≥7 5 0  cells/ μ L ( 0. 7 5 × 1 0 9/ L); A N C 
≥5 0 0  cells/ μ L ( 0. 5 0 × 1 0 9/ L) i n s u bjects wit h d oc u me nte d b o ne marr o w 
i n v ol ve me nt of C L L 
(ii) Platelet c o u nt ≥5 0, 0 0 0  cells/ μ L ( 5 0 × 1 0 9/ L); platelet c o u nt ≥3 0, 0 0 0 cells/ μ L 
( 3 0 × 1 09/ L) i n s u bjects wit h d oc u me nte d b o ne marr o w i n v ol ve me nt of C L L 
( b) Ser u m as partate a mi n otra nsferas e ( A S T) a n d ala ni ne a mi n otra nsferase ( A L T) ≤2. 5 × 
u p per li mit of n or mal ( U L N)  
(c) T otal bilir u bi n ≤2. 0 × U L N, u nless directl y attri b ut a ble t o Gil bert’s s y n dr o me  
( d) Esti mate d creati ni ne cleara nce of ≥3 0  m L/ mi n usi n g t he C oc kcr oft- Ga ult e q uati o n 
(A p pe n di x E ) 
 
Re pr o d ucti o n  
8  
Ne gati ve pr e g na nc y t est ( uri ne or ser u m) f or fe male s u bjects of c hil d beari n g p ote ntial 
pri or t o e nr oll me nt 
9  
Pri or t o t he pla n ne d date of ra n d o mizati o n f or fe m ale s u bjects, at least 1 of t he f oll o wi n g 
criteria s h o ul d be met:  
(a) ≥ 1  year p ost- me n o p a usal  
( b) p er ma ne ntl y sterilize d ( h ysterect o m y, bilateral o o p h orect o m y, or bilateral 
sal pi n gect o m y) 
(c) or usi n g hi g hl y effecti ve met h o ds of c o ntrace pti o n ( hi g hl y effecti ve met h o ds of 
c o ntrace pti o n are d efi ne d i n Ta ble  5) f or t h e d urati o n of t he st u d y (fr o m t he ti me t he y 
si g n c o nse nt) a n d f or 2 d a ys after t h e last d ose of acala br uti ni b or 1 2  m o nt hs after t he 
last d ose of rit u xi ma b or c hl ora m b ucil, w hic he v er is l o n ger, t o pre ve nt pre g na nc y.  
1 0  F or rit u xi ma b a n d c hl ora m b ucil: male s u bjects w h o are se x u all y acti ve m ust a gree t o use 
hi g hl y effecti ve m et h o ds of c o ntrace pti o n wit h t he a d diti o n of a barrier met h o d (c o n d o m) 
d uri n g t he st u d y (fr o m t he ti me t he y si g n c o nse nt) a n d f or 9 0 da ys after t he last d ose of 

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rit u xi ma b or c hl ora m b ucil, w hic he ver is later, t o pre ve nt pre g na nc y i n a part ner.  Male 
s u bjects m ust a gree t o r efrai n fr o m s per m d o n ati o n d uri n g t his sa me ti me peri o d. 
T a ble 5
Hi g hl y Effecti ve Met h o ds of C o ntr ace pti o n
Hi g hl y effecti ve met h o ds of c o ntrace pti o n (t o be use d d uri n g heter ose x ual acti vit y) are defi ne d as met h o ds t hat ca n 
ac hie ve a fail ure rate of < 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y. S uc h met h o ds i ncl u de:
• C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n, 
w hic h ma y be oral, i ntra va gi nal, or tra ns der mal
• Pr o gest o ge n-o nl y h or m o nal c o ntrace pti o n a ss ociate d wit h i n hi biti o n of o v ulati o n, w hic h ma y be oral, i njecta ble, 
or i m pla nta ble
• I ntra uteri ne de vice (I U D) or i ntra uteri ne h or m o ne-releasi n g s yste m (I U S)
• Bilateral t u bal occl usi o n
• Vasect o m y of a fe male s u bject’s male part ner ( wit h me dical assess me nt a n d c o nfir mati o n of vasect o m y s ur gical 
s uccess)
• Se x ual a bsti ne nce ( o nl y if refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h 
t he st u d y treat me nts)
A bsti ne nce (relati ve t o heter ose x ual acti vit y) ca n o nl y be use d as t he s ole met h o d of c o ntrace pti o n if it is 
c o nsiste ntl y e m pl o ye d d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts as t he s u bject’s 
preferre d a n d us ual lifest yle a n d if acce pta ble t o l ocal re g ulat or y a ge ncies a n d I n de pe n de nt Et hics 
C o m mittees/I nstit uti o nal Re vi e w B oar ds.  
Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt o -t her mal, a n d p ost-o v ulati o n met h o ds) a n d wit h dra wal (c oit us 
i nterr u pt us), s per mici des o nl y, a n d lactati o nal a me n orr h oea met h o d ( L A M) are n ot acce pta ble met h o ds of 
c o ntrace pti o n. Fe male c o n d o m a n d male c o n d o m s h o ul d n ot be use d t o get her as a n effecti ve met h o d of 
c o ntrace pti o n.
E xcl usi o n criteri a 
Me dic al c o n diti o ns
1  
K n o w n detect e d del( 1 7 p) or T P 5 3 m utati o n ( N ote: test res ults s h o ul d be o btai ne d fr o m 
ce ntral la b d uri n g scree ni n g) 
2 
Tra nsf or mati o n of C L L t o a g gressi ve n o n- H o d g ki n l y m p h o ma ( N H L) (e. g., Ric hter’s 
tra nsf or mati o n, P L L, or diff use lar g e B-cell l y m p h o ma [ D L B C L]), or ce ntral ner v o us 
s ystem ( C N S) i n v ol ve me nt b y le u ke mia 
3  
Hist or y of c o nfir me d pr o gressi ve m ultif ocal le u k o e nce p h al o pat h y ( P M L) 
4  
Hist or y of pri or mali g na nc y t hat c o ul d affect c o m plia nce wit h t he pr ot oc ol, or 
i nter pretati o n of r es ults, e xce pt f or t he f oll o wi n g: 
(a) C urati vel y treate d b asal cell carci n o ma or s q ua m o us cell carci n o ma of t he s ki n or 
carci n o ma i n sit u of t he cer vi x at a n y ti me pri or t o st u d y 
( b) Ot her ca n cers n ot s pecifi e d a b o ve w hi c h ha ve b ee n c urati vel y treate d b y s ur ger y 
a n d/ or ra diati o n t her a p y fr o m w hic h s u bject is disease- free f or ≥3 years wit h o ut 
f urt her tr eat me nt
5 
Si g nifica nt car di o vasc ul ar disease s uc h as u nc o ntr olle d or u ntreate d s y m pt o matic 
arr h yt h mias, c o n gesti ve heart f ail ure, or m y ocar di al i nfarcti o n wit hi n 6 m o nt hs of 

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Scree ni n g, or a n y Class 3 or 4 car di ac diseas e as d efi ne d b y t he N e w Y or k Heart 
Ass ociati o n F u ncti o nal Classificati o n at Scree ni n g.  E xce pti o n: s u bjects wit h c o ntr olle d, 
as y m pt o matic atrial fi brillati o n d uri n g Scree ni n g are all o we d t o e nr oll o n st u d y. 
6  
Mala bs or pti o n s y n dr o me, disease si g nifica ntl y affecti n g gastr oi ntesti nal f u ncti o n, or 
resecti o n of t he st o mac h, or e xte nsi ve s mall b o wel resecti o n t hat is li kel y t o affect 
a bs or pti o n, s y m pt o matic i nfla m mat or y b o wel disease, or partial or c o m plet e b o wel 
o bstr ucti o n, or gastric r estricti o ns a n d bariatric s ur ger y, s uc h as g astric b y p ass 
7  
K n o w n hist or y of i nfecti o n wit h h u ma n i m m u n o deficie nc y vir us ( HI V) 
8  
Ser ol o gic stat us reflecti n g acti ve he p atitis  B or C i nfecti o n 
(a) S u bjects w h o are h e patitis  B c ore a nti b o d y (a nti- H Bc) p ositi ve a n d w h o are 
he patitis  B s urface a nti ge n ( H Bs A g) ne gati ve will nee d t o ha ve a ne g ati ve 
p ol y merase c h ai n reacti o n ( P C R) res ult bef ore ra n d o mizati o n a n d m ust be willi n g t o 
u n der g o D N A P C R testi n g d uri n g t he st u d y.  T h ose w h o are H bs A g- p ositi ve or 
he patitis  B P C R - p ositi ve will be e xcl u de d. 
( b) S u bjects w h o are h e patitis  C a nti b o d y p ositi ve will nee d t o ha ve a ne gati ve P C R 
res ult bef or e ra n d o mizati o n.  T h ose w h o are he p atitis C P C R -p ositi ve will be 
e xcl u de d. 
9  
A n y acti ve s yste mic i nfecti o n (e. g., bact erial, viral, or f u n gal i nfecti o n) re q uiri n g 
s yste mic treat me nt 
1 0  U nc o ntr olle d a ut oi m m u ne he m ol ytic a ne mia or i di o pat hic t hr o m b oc yt o pe ni c p ur p ura 
defi ne d as d ecli ni n g he m o gl o bi n or platelet c o u nt sec o n dar y t o a ut oi m m u ne destr ucti o n 
wit hi n t he Scree ni n g peri o d 
1 1  Hist or y of blee di n g diat h esis (e. g., he m o p hilia, v o n Wille bra n d diseas e)  
1 2  Hist or y of str o ke or i ntracra nial he m orr ha g e wit hi n 6 m o nt hs bef ore first d ose of st u d y 
dr u g 
1 3  Maj or s ur gical pr o ce d ur e wit hi n 3 0 da ys of first d ose of st u d y dr u g.  N ote: If a s u bject 
ha d maj or s ur ger y, t he y m ust ha ve rec o v ere d a de q uatel y fr o m a n y t o xicit y a n d/ or 
c o m plicati o ns fr o m t he i nter ve nti o n bef ore t he first d ose of st u d y dr u g. 
 
Pri or/c o nc o mit a nt t her a p y  
1 4  A n y pri or C L L-s pecific t hera pies ( N ote: pri or l ocalize d ra di ot hera p y is all o we d) 
1 5  C ortic oster oi d use > 2 0 m g/ da y wit hi n 1 wee k bef ore first d ose of st u d y dr u g, e xce pt as 
i n dicate d f or ot her me dical c o n diti o ns s uc h as i n hale d ster oi d f or ast h ma, t o pical ster oi d 
use, or as pr e me dicati o n f or a d mi nistrati o n of st u d y dr u g.  F or e xa m ple, s u bjects 
re q uiri n g ster oi ds at dail y d oses > 2 0 m g pre d nis o ne e q ui vale nt s yste mic e x p os ure dail y, 
or t h ose w h o ar e a d mi nistere d ster oi ds f or le u ke mia c o ntr ol or w hite bl o o d cell c o u nt 
l o weri n g ar e e xcl u d e d. 
1 6  Re q uires or recei vi n g a ntic oa g ulati o n wit h warfari n or e q ui vale nt vita mi n K a nta g o nists 

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1 7 Re q uires treat me nt wit h a str o n g C Y P 3 A i n hi bit or.  T he use of str o n g or m o derate 
C Y P 3 A i n hi bit ors or i n d ucers wit hi n 7 da ys of t h e first d ose of st u d y dr u g is pr o hi bite d. 
1 8 Recei ve d a n y i n v esti gati o nal dr u g wit hi n 3 0 da ys bef ore first d ose of st u d y dr u g 
1 9
Recei ve d a  li ve vir us vacci nati o n wit hi n 2 8 da ys of first d ose of st u d y dr u g 
2 0  Hist or y of k n o w n h y pers e nsiti vit y or a na p h ylactic reacti o ns t o st u d y dr u gs or e xci pie nts 
Pri or/c o nc urre nt cli nic al st u d y e x perie nce
2 1 C o nc urre nt partici pati o n i n a n ot her t hera pe utic cli nical trial
Ot her e xcl usi o ns
2 2 F or w o me n o nl y: br eastf ee di n g or pre g na nt 
2 3 I n v ol ve m e nt i n t he pla n ni n g a n d/ or c o n d uct of t he st u d y (a p plies t o b ot h s p o ns or staff 
a n d/ or staff at t he st u d y site) 
2 4 J u d g me nt b y t he i n vesti gat or t hat t he s u bject s h o ul d n ot partici pate i n t he st u d y if t he 
s u bject is u nli kel y t o c o m pl y wit h st u d y pr oce d ures, restricti o ns a n d re q uire me nts 
Lifest yle restricti o ns
T his secti o n is n ot a p plica ble as n o r estricti o ns are re q uire d. 
Scree n f ail ures
Scree n f ail ures are defi ne d as s u bjects w h o si g ne d t he i nf or me d c o nse nt f or m t o partici pate i n 
t he cli nical st u d y b ut are n ot s u bse q ue ntl y ra n d o mize d i n t he st u d y.  A mi ni mal set of scree n 
fail ure i nf or m ati o n is re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure s u bjects t o 
meet t he C o ns oli d ate d Sta n dar ds of Re p orti n g Trials ( C O N S O R T) p u blis hi n g re q uire me nts 
a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities.  Mi ni mal i nf or mati o n i ncl u des 
de m o gra p h y, scree n fail ure details, eli gi bilit y criteria, a n d a n y s eri o us a d verse e ve nt ( S A E). 
T hese s u bjects s h o ul d ha ve t he reas o n f or st u d y wit h dra wal rec or de d i n t he e C R F (i.e., s u bject 
d oes n ot meet t he re q uir e d i ncl usi o n/e xcl usi o n criteria) a n d re gister i n I R T/ R T S M as scree n 
fail ure.
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t his st u d y (scree n fail ure) ma y b e 
re-scree n e d, w hic h r e q uir es si g ni n g t he I C F a gai n a n d re peati n g scree ni n g pr oce d ures. O nl y 1-
ti me rescree ni n g is all o w e d i n t he st u d y. Rescree n e d partici pa nts s h o ul d be assi g ne d t he sa me 
partici pa nt n u m ber ( E- c o de) as f or t he i nitial scree ni n g. T he i n vesti gat or s h o ul d disc uss eac h 
i n di vi d ual case wit h st u d y p h ysicia n bef ore a n y p atie nt is rescree ne d. T h e b o ne marr o w 
bi o ps y a n d as pirate, C T s ca n d o n ot nee d t o b e re p eate d if still wit hi n ti mefra me pri or t o t he 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 5 3
 
first d ose as re q uire d i n pr ot oc ol; c yt o ge netics, ge netic m olec ular pr o g n ostic m olec ules, FI S H 
pa nel, a n d M R D d o n ot n ee d t o be re peat e d after c o nfir mati o n wit h st u d y p h ysicia n.   
 
 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 4
6
S T U D Y T R E A T M E N T S
St u d y treat me nt is defi ne d as a n y i n vesti gati o nal pr o d uct(s) (I Ps [i n cl u di n g mar kete d pr o d u ct 
c o m parat or a n d place b o]) or me dical d e vice(s) i nte n de d t o be a d mi nistere d t o a st u d y 
partici pa nt acc or di n g t o t he st u d y pr ot oc ol.  St u d y treat me nt i n t his st u d y refers t o 
acala br uti ni b or rit u xi ma b a n d c hl ora m b ucil. 
Tre at me nts a d mi nistere d
6. 1. 1
I n vesti g ati o n al pr o d u cts
T he I P acala br uti ni b ca ps ules f or oral a d mi nistrati o n is s u p plie d as 1 0 0 m g bl ue a n d yell o w 
o pa q ue, har d gelati n o us ca ps ules a n d is pr o vi de d i n w hite, hi g h- de nsit y p ol yet h yle ne b ottles.  
La bels will be pre p are d i n acc or d a nce wit h G o o d Cli nical Practice ( G C P) Or di na nce.  T he 
dr u g pr o d uct is ma n ufact ure d b y Astra Z e neca A B.  All f or m ulati o n e xci pie nts are c o m pe n di al 
a n d are c o m m o nl y use d i n oral f or m ulati o ns 
6. 1. 2  
C hl or a m b ucil a n d Rit u xi m a b 
Rit u xi ma b will be a d mi nistere d as des cr i be d i n Ta ble 6, o n Da ys of C ycles 1 t hr o u g h 6. 
L ocall y a p pr o v e d la belli n g ma y be c o nsi dere d f or a d mi nistrati o n of rit u xi ma b.   
C hl ora m b ucil will be orall y a d mi nistere d at a d ose of 0. 5 m g/ k g of b o d y wei g ht o n Da ys 1 
a n d 1 5 of C ycles 1 t hr o u g h 6. C hl ora m b ucil s h o ul d n ot be d ose d s o o ner t ha n 1 4 da ys fr o m t he 
last d ose of c hl ora m b u cil. O n da ys w he n c hl ora m b ucil a n d rit u xi ma b are b ot h a d mi nistere d, 
t he or der of st u d y tr eat m e nt a d mi nistrati o n will be c hl ora m b ucil f oll o w e d b y rit u xi ma b.
T he s u bject’s b o d y w ei g ht at scree ni n g a n d b o d y s urface area ( B S A) calc ulate d at scree ni n g 
s h o ul d be use d t o calc ulate t he d ose of c hl ora m b u cil, rit u xi ma b t hr o u g h o ut t he st u d y u nless 
t he s u bject’s wei g ht i ncr eases or d ecreases b y ≥1 0 % fr o m scree ni n g.  
T a ble 6
St u d y Tre at m e nts
Ar m A
Ar m B
St u d y tre at m e nt 
n a m e:
Acala br uti ni b ( A C P -1 9 6) 
C hl ora m b ucil
Rit u xi ma b
D os a ge 
f or m ul ati o n:
1 0 0 m g ca ps ule f or oral 
a d mi nistrati o n
As s o urce d l ocall y
1 0 m L ( 1 0 0 m g) a n d 5 0 m L 
( 5 0 0 m g) vial s ol uti o n f or 
i nf usi o n after dil uti o n, 
1 0 m g/ m L
R o ute of 
a d mi nistr ati o n: 
Oral
Oral
I V i nf usi o n

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 5
T a ble 6
St u d y Tre at m e nts
Ar m A
Ar m B
D osi n g 
i nstr ucti o ns: 
O ne Ca ps ule of 1 0 0 m g t wice 
dail y orall y wit h a p pr o xi matel y 
2 4 0 m L of water.  It ma y be 
ta ke n wit h or wit h o ut f o o d.  T he 
ca ps ule s h o ul d be s wall o we d 
i ntact a n d s h o ul d n ot be o pe ne d 
or diss ol ve d i n li q ui d.  D oses 
s h o ul d be a d mi nistrate d 
a p pr o xi matel y 1 2 h o u rs a part 
(rec o m me n de d t o be ta ke n as 
cl ose as t he sc he d ule ti me as 
p ossi ble prefera bl y wit hi n 
± 1 h o ur).  If a d ose is misse d, it 
ca n be ta ke n u p t o 3 h o urs after 
t he sc he d ule d ti me wit h a ret ur n 
t o t he n or mal sc he d ule wit h t he 
f oll o wi n g d ose.  If it has 
be e n > 3 h o urs, t he d ose s h o ul d 
n ot be ta ke n.  T he misse d d ose 
will n ot be ma de u p a n d m ust be 
ret ur ne d t o t he site at t he ne xt 
sc he d ule ti me. 
0. 5 m g/ k g b o d y wei g ht 
orall y o n Da y 1 a n d 
Da y 1 5 of all treat me nt 
c ycles ( C ycles 1-6) 
C hl ora m b ucil s h o ul d n ot 
be d ose d s o o ner t ha n 
1 4 da ys fr o m t he last d ose 
of c hl ora m b ucil.
O n da ys w he n 
c hl ora m b ucil a n d 
rit u xi ma b are b ot h 
a d mi nistere d, t he or der of 
st u d y treat me nt 
a d mi nistrati o n will be 
c hl ora m b ucil f oll o we d b y 
rit u xi ma b.
3 7 5 m g/ m 2 of rit u xi ma b I V 
i nf usi o n o n Da y 1 of t he first 
treat me nt c ycle ( C ycle 1).  a  
5 0 0 m g/ m 2 I V i nf usi o n o n 
Da y 1 f or eac h of 
s u bse q ue nt c ycles ( C ycles 2-
6).
Pre me dicate bef ore eac h 
i nf usi o n wit h aceta mi n o p he n 
a n d a n a nti hista mi ne i n 
acc or da nce wit h l ocal 
prescri bi n g i nf or mati o n.
P ac k a gi n g a n d 
l a belli n g
St u d y treat me nt will be pr o vi de d 
i n w hite, hi g h-de nsit y 
p ol yet h yle ne b ottles.  Eac h b ottle 
will be la belle d i n acc or da nce 
wit h G o o d Ma n ufact uri n g 
Practice ( G M P) A n ne x 1 3 a n d 
per c o u ntr y re g ulat or y 
re q uire me nt.
T his st u d y will use 
c o m merciall y a vaila ble 
c hl ora m b ucil.  
Refer t o t he a p pr o ve d 
la bel of c hl ora m b ucil f or 
f urt her detail b
T his st u d y will use 
c o m merciall y a vaila ble 
rit u xi ma b. 
Refer t o t he a p pr o ve d la bel 
of rit u xi ma b f or f urt her 
detail  b
Pr o vi der
Astra Ze neca A B
S o urce d l ocall y b y site  b
S o urce d l ocall y b y site  b  
a
T he i nitial d ose o n Da y 1 ma y be di vi de d f or a d mi nistrati o n t o ma na ge I R Rs acc or di n g t o l ocal practice.
b
C hl ora m b ucil a n d rit u xi ma b are s o urce d l ocall y b y site, u n der certai n circ u msta nces w he n l ocal s o urci n g is n ot 
feasi ble a sta n dar d of care treat me nt ma y be s u p plie d ce ntrall y t hr o u g h t he s p o ns or, a cli nical la bel will be 
pre pare d b y t he s p o ns or i n s uc h circ u msta nce.
Pre p ar ati o n/ h a n dli n g/st or a ge/ acc o u nt a bilit y
All st u d y dr u gs s h o ul d be ke pt i n a sec ure place u n der a p pr o priate st ora g e c o n diti o ns.  A 
descri pti o n of t he a p pr o priate st ora ge c o n diti o ns is s pecifie d i n t he la bels.  T he i n vesti gat or or 
desi g nee m ust c o nfir m a p pr o priate te m perat ure c o n diti o ns ha ve bee n mai ntai ne d d uri n g 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 5 6
 
tra nsit f or all st u d y treat me nt recei v e d a n d a n y discre pa n cies are re p orte d a n d res ol ve d b ef ore 
use of t he st u d y treat me nt. 
O nl y s u bjects e nr olle d i n t he st u d y ma y recei ve st u d y treat me nt a n d o nl y a ut h orise d site staff 
ma y s u p pl y or a d mi n ister st u d y treat me nt.  All st u d y treat me nts m ust be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n u al or a ut o mate d) area i n acc or da n ce wit h t he 
la belle d st ora ge c o n diti o ns wit h access li mite d t o t he i n vesti gat or a n d a ut h orise d site staff. 
T he i n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w here a p plica ble) is 
res p o nsi ble f or st u d y treat me nt acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na nce (i.e., 
recei pt, rec o n ciliati o n, a n d fi nal dis p ositi o n rec or ds). 
F urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y treat me nt are 
pr o vi de d i n t he Cli nical St u d y A gree me nt. 
6. 2. 1  
Ac al a br uti ni b 
N o a d diti o nal pre parati o n a n d ha n dli n g are re q uire d f or acala br uti ni b. 
6. 2. 2  
C hl or a m b ucil 
N o a d diti o nal pre parati o n a n d ha n dli n g are re q uire d f or c hl ora m b ucil.  
C hl ora m b ucil will be o btai ne d b y t he i n vesti gati o nal sites a n d la belle d l ocall y if re q uire d.  See 
l ocal prescri bi n g i nf or mati o n f or f urt her i nstr ucti o ns re gar di n g rec o m me n d e d st ora ge 
c o n diti o ns a n d pac ka gi n g c o nfi g urati o n. 
6. 2. 3  
Rit u xi m a b 
6. 2. 3. 1  
Pre p ar ati o n/ h a n dli n g  
T he a nti b o d y is f or m ulat e d f or i ntra v e n o us i njecti o n as a sterile pr o d u ct i n a s ol uti o n of 
s o di u m c hl ori de ( p H 6. 5) c o ntai ni n g p ol ys or bate 8 0 a n d s o di u m citrate.  Rit u xi ma b is 
pac ka g e d i n 1 0 m L ( 1 0 0 m g) a n d 5 0 m L ( 5 0 0 m g) p har mace utical -gra de gl ass vials at a 
c o nce ntr ati o n of 1 0 m g pr otei n per m L. 
Rit u xi ma b s h o ul d be st ore d i n a sec ure refri gerat or at 2°- 8° Celsi us ( 3 6°- 4 6° Fa hre n heit).  D o 
n ot freeze or st or e at r o o m te m perat ure.  T h e pr o d uct is a pr otei n – H A N D L E G E N T L Y A N D 
A V OI D F O A MI N G, as t his ma y lea d t o t he de - n at uri n g of t he pr o d uct pr ot ei ns. 
All tra nsfer pr oce d ures r e q uire strict a d h ere n ce t o ase ptic tec h ni q ues, prefera bl y i n a la mi nar 
fl o w h o o d.  Pre par e rit u xi ma b s ol uti o n as f oll o ws: 
•  
Refri ger ate ( 2° -8° C [ 3 6° -4 6° F]) a ll materials a n d s ol uti o ns pri or t o use. 
•  
Use sterile, n o n - p yr o ge ni c dis p osa ble c o ntai ners, s yri n ges, nee dles, st o pc o c ks, a n d 
tra nsfer t u bi n g et c. 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 7
•
Tra nsfer of rit u xi ma b fr o m t he glass vial s h o ul d be ma de b y usi n g a s uita bl e sterile 
gra d uate d s yri n g e a n d lar ge ga u ge n ee dle.
•
Tra nsfer t he a p pr o priate a m o u nt of rit u xi ma b fr o m t he gra d uate d s yri n g e i nt o a partiall y 
file d I V pac k c o ntai ni n g sterile p yr o ge n-free 0. 9 % s o di u m c hl ori de s ol uti o n (sali ne 
s ol uti o n).  Mi x b y i n verti n g t he ba g ge ntl y.  D O N O T U S E A V A C U U M A P P A R A T U S 
t o tra nsfer t he pr o d uct fr o m s yri n ge t o t he plastic ba g. 
•
Place a n I V a d mi nistrati o n i nt o t he o utfl o w p ort of t he ba g c o ntai ni n g t he i nf usi o n 
s ol uti o n 
•
N O T E: D O N O T U S E e vac uate d gl ass c o ntai ners w hic h re q uire ve nte d a d mi nistrati o n 
sets beca use t his ca uses f oa mi n g as air b u b bles pass t hr o u g h t he s ol uti o n. 
•
T he a d mi nistrati o n of rit u xi ma b will be acc o m plis he d b y sl o w I V i nf usi o n.  C A U TI O N: 
D O N O T A D MI NI S T E R A S A N I V P U S H O R B O L U S.
•
D o n ot i nf use c o nc o mita ntl y wit h a n ot her I V s ol uti o n or I V m e dicati o ns. 
6. 2. 3. 2 
St or a ge 
Rit u xi ma b s h o ul d be st ore d i n a sec ure refri gerat or at 2- 8° C ( 3 6 -4 6° F).  Refer t o l ocal la b el 
f or f urt her i nstr ucti o n re g ar di n g rec o m me n de d st ora ge c o n diti o n.  
Me as ures t o mi ni mise bi as: r a n d o mis ati o n a n d bli n di n g
All s u bjects will be ce ntr all y/re gi o nal/l ocal assi g n e d t o ra n d o mise d st u d y treat me nt usi n g a n 
I nteracti ve Res p o nse Tec h n ol o g y/ Ra n d o misati o n a n d Trial S u p pl y Ma na ge me nt 
(I R T/ R T S M).  Bef ore t he st u d y is i nitiate d, t he tele p h o ne n u m ber a n d call-i n directi o ns f or t he 
I R T a n d/ or t he l o g-i n i nf or mati o n a n d directi o ns f or t he R T S M will be pr o vi de d t o eac h site. 
If a s u bject wit h dr a ws fr o m t he st u d y, t he n his/ her e nr oll me nt/ra n d o misati o n c o de ca n n ot be 
re use d.  Wit h dr a w n s u bjects will n ot be re place d. 
T his is a n o pe n-la bel st u d y.  T o mai ntai n t he i nte grit y of t he st u d y, Astra Z e neca pers o n n el 
directl y i n v ol ve d i n t he st u d y c o n d uct will refrai n fr o m accessi n g treat me nt rec or ds w he ne v er 
p ossi ble, a n d u n der n o circ u msta nces will t he y vie w data a g gre gate d b y treat me nt ar m d uri n g 
t he c o urse of t h e st u d y.  T he site will c o ntact t he I R T/ R T S M pri or t o t he start of st u d y 
treat me nt a d mi nistrati o n f or eac h s u bject.  T h e site will rec or d t h e treat me nt assi g n me nt o n t he 
a p plica ble case r e p ort f or m, if re q uire d.  P ote ntial bias will be re d uce d b y ce nt ral 
ra n d o mizati o n.  O ne ra n d o mizati o n list will be pr o d uce d f or eac h of t he ra n d o mizati o n strata.  
A bl oc ke d ra n d o mizati o n will be ge nerat e d, a n d all ce nters will use t he sa m e list i n or der t o 
mi ni mize a n y i m bala nce i n t he n u m ber of patie nts assi g ne d t o eac h treat me nt gr o u p. 
Tre at me nt c o m pli a nce
T he i n vesti gati o nal pr o d uct s h o ul d o nl y be use d as directe d i n t his pr ot oc ol.  Details of 
treat me nt wit h i n vesti gati o nal pr o d uct i ncl u di n g: c ha n ge fr o m t he d osi n g sc he d ule, d oes 
i nterr u pti o ns, d ose re d ucti o ns, d ose disc o nti n uati o ns s h o ul d be rec or d e d i n e C R F. 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 8
T he i n vesti gati o nal pr o d uct
will n ot be distri b ute d t o t he st u d y site u ntil t he c o ntract is 
c o ncl u de d bet w ee n t he st u d y site a n d t he s p o ns or.  T he i n vesti gat or or desi g nee is res p o nsi ble 
f or ma na gi n g t he I M P fr o m ti me of recei pt b y t he st u d y site u ntil t he destr ucti o n of all u n use d 
I M P at t hat site.  T he i n v esti gat or(s) is res p o nsi ble f or e ns uri n g t hat all u n use d I M P is ret ur ne d 
t o t he site b y t he s u bject(s). 
6. 4. 1  
Ac al a br uti ni b 
F or acala br uti ni b ta ke n i n t he cli nic, s u bjects s h o ul d ta ke t he d ose fr o m t h e dr u g dis pe nse d t o 
t he m f or t hat partic ular ti me peri o d.  S u bjects will recei v e a dr u g di ar y t o rec or d t he s pecific 
ti me eac h d ose w as ta ke n a n d t o rec or d reas o ns f or a n y misse d d oses.  
S u bject c o m plia nce will be assess e d at eac h st u d y visit.  T he s u bject will be i nstr ucte d t o bri n g 
t he diar y a n d a n y re mai ni n g ca ps ules t o t he cli nic at t heir ne xt visit.  T he st u d y staff will 
re vie w t he diar y a n d as k t he s u bject if all of t he ca ps ules were a d mi nistere d.  A n y re mai ni n g 
or ret ur ne d ca ps ules will be c o u nte d a n d rec or de d i n acc o u nta bilit y rec or ds.  Ret ur ne d 
ca ps ules m ust n ot be re- dis pe nse d t o a n ot her s u bject. 
6. 4. 2  
C hl or a m b ucil 
Acc o u nta bilit y a n d s u bject c o m plia nce will be ass esse d b y mai ntai ni n g a de q uate “ dr u g 
dis pe nsi n g” a n d ret u r n rec or ds.
S u bjects will be as ke d t o ret ur n all use d a n d u n us e d c hl ora m b ucil c o ntai ners at t he e n d of t he 
treat me nt as a meas ure of c o m plia nce.
A Dr u g Dis pe nsi n g L o g m ust be ke pt c urre nt a n d s h o ul d c o ntai n t he f oll o wi n g i nf or mati o n: 
•
I d e ntificati o n of t he s u bj ect t o w h o m t he st u d y me dicati o n was dis pe nse d 
•
Date(s) a n d q ua ntit y of t he st u d y me dicati o n dis pe nse d t o s u bject 
•
Date(s) a n d q ua ntit y of c hl ora m b ucil ret ur ne d b y t he s u bject 
6. 4. 3  
Rit u xi m a b 
S u bject ca n o nl y ret ur n t o site f or I V i nf usi o n of rit u xi ma b.  Trea t me nt c o m plia nce will be 
ass ure d b y r ec o nciliati o n of site dr u g acc o u nta bilit y l o gs. 
C o nc o mit a nt t her a p y
A n y me dicati o n or vacci ne i ncl u di n g o ver-t he-c o u nter or pres cri pti o n me dici nes, vita mi ns, 
a n d/ or her b al s u p ple me nts t hat t he s u bject is recei vi n g at t h e ti me of 4 wee ks pri or t o starti n g 
st u d y treat me nt a n d all c o nc o mita nt treat me nts d uri n g t he st u d y t hr o u g h 3 0 da ys after t h e last 
d ose of all st u d y dr u gs m ust be rec or d e d i n t he electr o nic Case Re p ort F or m (e C R F) al o n g 
wit h:

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 5 9
 
•  
Reas o n f or use (i n dicati o n) 
•  
Da tes of a d mi nistrati o n i ncl u di n g start a n d e n d dates 
•  
D osa ge i nf or m ati o n i ncl u di n g d ose, fre q u e nc y a n d r o ute 
 
After a s u bject disc o nti n ues st u d y treat me nt, recei pt of all s u bse q ue nt a ntica ncer t h era pi es t o 
treat C L L will be c ollect e d i n s ur vi val f oll o w- u p. 
6. 5. 1  
Per mitte d c o nc o mit a nt t her a p y 
A ntie metics are p er mitte d if cli nicall y i n dicate d.  Sta n dar d s u p p orti ve care me dicati o ns are 
per mitte d as per i nstit uti o nal sta n dar ds.  Use of h e mat o p oietic gr o wt h fact ors is per mitte d per 
C o nse ns us of C hi nese E x perts (Versi o n  2 0 1 5).  Pri mar y pr o p h ylactic us e of m yel oi d gr o wt h 
fact ors ( e. g., gra n ul oc yte c ol o n y-sti m ulati n g fact or [G- C S F ]) is n ot all o we d acc or di n g t o t he 
g ui deli ne. 
F or s u bjects c o nsi dere d at ris k f or t u m or l ysis s y n dr o me: a d mi nister a p pr o priate h y drati o n a n d 
all o p uri n ol or ras b uricase per i nstit uti o nal sta n dar ds bef ore i nitiati n g treat m e nt. 
F or s u bjects at ris k f or i nfecti o ns: bacterial/ viral/f u n gal pr o p h yla xis is all o we d per 
i nstit uti o nal sta n dar ds.  
S h ort c o urse use of ster oi ds ( ≤2  wee ks) > 2 0  m g/ da y is per mitte d f or pre me dicati o n use, or t o 
ma na ge i nf usi o n- r elate d reacti o ns or t o ma n a ge ot her i nfla m mat or y reacti o ns, s uc h as ast h ma 
e xacer bati o n.  D uri n g st u d y partici pati o n, s u bjects ma y als o recei ve s yste mic or e nteri c 
c ortic oster oi ds at  a n y re q uire d d osa ge as nee d e d f or treat me nt -e mer ge nt c o m or bi d c o n diti o ns. 
6. 5. 2  
Pr o hi bite d c o nc o mit a nt t her a p y 
A n y c o nc urre nt c h e m ot hera p y ( e. g., be n d a m usti ne, c ycl o p h os p ha mi de, p e nt ostati n, or 
fl u dara bi ne), a ntica n cer i m m u n ot hera p y (e. g., o bi n ut uz u ma b, ale mt uz u ma b, or ofat u m u ma b), 
c ortic oster oi ds (at d os a ges e q ui vale nt t o pre d nis o n e > 2 0 m g/ da y), ki nas e i n hi bit ors (e. g., 
i br uti ni b, za n u br uti ni b, a n d i delalisi b), b o ne marr o w tra ns pla nt, e x peri me ntal t hera p y, a n d 
ra di ot hera p y f or treati n g C L L are pr o hi bite d.  L o calize d, s h ort c o urs es of ra di ot hera p y are 
all o we d f or t he tr eat me nt of lesi o ns u nrelate d t o t h e disease u n d er st u d y, if a p pr o ve d b y t he 
st u d y p h ysicia n. S h o ul d a s u bject de vel o p a sec o n d pri mar y mali g na nc y w hile o n trial, t he 
s u bject s h o ul d be ma na g e d acc or di n g t o i nstit uti o nal g ui deli nes wit h dia g n ostic e val uati o ns as 
cli nicall y i n dicate d, a n d it ma y be necessar y f or s u bjects t o per ma ne ntl y dis c o nti n ue st u d y 
treat me nt.  C o nti n uati o n of acal a br uti ni b treat me nt s h o ul d be disc usse d wit h t he st u d y 
p h ysicia n . 
 
T he c o nc o mita nt use of str o n g i n hi bit ors/i n d ucers of C Y P 3 A wit h acala br uti ni b s h o ul d be 
a v oi de d w he n p ossi ble (s ee  A p pe n di x H ).  If a s u bject re q uires s h ort-ter m treat me nt wit h a 
str o n g C Y P 3 A i n hi bit or (s uc h as a nti-i nfecti ves f or u p t o 7 da ys), i nterr u pt acala br uti ni b 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 6 0
 
treat me nt.  Refer t o Ta bl e 7  f or d ose m o dificati o ns d ue t o re q uire d s h ort-ter m use of m o derate 
C Y P 3 A i n hi bit ors. 
Warf ari n or e q ui vale nt vita mi n  K a nta g o nists (e. g., p he n pr oc o u m o n ) are pr o hi bite d.  
A d mi nistrati o n of her bal me dicati o n d uri n g st u d y treat me nt peri o d is n ot rec o m me n de d, 
u nless it is prescri be d b y t he i n ve sti gat or f or treat me nt of s pecific cli nical e ve nts.  Use of 
pr ot o n- p u m p i n hi bit ors, H 2 rece pt or a nta g o nists, or a ntaci ds w hile ta ki n g acala br uti ni b has t he 
p ote ntial t o decrease acal a br uti ni b e x p os ure.  If treat me nt wit h a gastric aci d re d uci n g a g e nt is 
req uire d, c o nsi der usi n g a H 2-r ece pt or a nta g o nist ( 2 h o urs after acala br uti ni b) or a ntaci d ( 2 
h o urs bef or e or 2 h o urs after acala br uti ni b).  A v oi d c oa d mi nistrati o n wit h pr ot o n- p u m p 
i n hi bit ors. 
T a ble 7  
I nstr ucti o ns f or C o a d mi nistr ati o n o f Dr u gs wit h Ac al a br uti ni b 
C o a d mi nistere d Dr u g  
I nstr ucti o ns f or C o a d mi nistr ati o n of 
Dr u gs wit h Ac al a br uti ni b 
C o a d mi nistere d Dr u g  
Ac al a br uti ni b  
Str o n g C Y P 3 A i n hi bit or  
A v oi d c o nc o mita nt use wit h acala br uti ni b.  If t he i n hi bit or will be 
use d s h ort -ter m (s uc h as a nti-i nfecti ves f or u p t o 7 da ys), i nterr u pt 
acala br uti ni b. 
M o derate C Y P 3 A i n hi bit or  
N o d ose a dj ust me nt. M o nit or patie nts cl osel y f or a d verse reacti o ns 
if ta ki n g m o derate C Y P 3 A i n hi bit ors. 
Mil d C Y P 3 A i n hi bit or  
N o c ha n ge 
Str o n g C Y P 3 A i n d ucer  
A v oi d c o nc o mita nt use.  If a s u bject re q uires treat me nt wit h a 
str o n g C Y P 3 A i n d ucer, i ncrease t he acala br uti ni b d ose t o 2 0 0 m g 
BI D d uri n g c o nc o mita nt a d mi nistrati o n wit h t he str o n g i n d ucer a n d 
ret ur n t o rec o m me n de d d ose of 1 0 0 m g BI D after st o p pi n g t he 
str o n g C Y P 3 A i n d ucer.  
M o derate C Y P 3 A i n d ucer  
N o c ha n ge  
P- g p i n hi bit or  
N o c ha n ge  
B C R P i n hi bit or  
N o c ha n ge  
Narr o w t hera pe utic i n de x P -g p 
s u bstrate 
N o c ha n ge  
Bile aci d se q uestra nts  
N o c ha n ge  
Stati n ( O A T P s u bstrate)  
N o c ha n ge  
Pr ot o n p u m p i n hi bit ors  
A v oi d c o nc o mita nt use.  
H 2 -rece pt or a nta g o nists 
Ta ke acala br uti ni b 2 h o urs bef ore ta ki n g a H 2 -rece pt or a nta g o nist. 
A ntaci ds  
Se parate d osi n g b y at least 2 h o urs.  
 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 1
6. 5. 3  
Ot her c o nc o mit a nt tr e at m e nt 
Ot her me dicati o n ot her t ha n t hat descri b e d a b o ve, w hic h is c o nsi dere d n ecessar y f or t he 
s u bject’s safet y a n d well bei n g, ma y be gi ve n at t h e discreti o n of t he i n vesti gat or a n d rec or d e d 
i n t he a p pr o priate s ecti o ns of t he e C R F. 
D os e del a y a n d m o dific ati o n
6. 6. 1  
Ac al a br uti ni b 
T he acti o ns i n Ta ble  8 s h o ul d be ta ke n f or t h e f oll o wi n g t o xicities (acc or di n g t o C T C A E 
criteria v ersi o n  5. 0): 
•
Gra de  4 n e utr o pe nia ( A N C < 5 0 0/ μ L) f or > 7 da ys ( m yel oi d gr o wt h fact ors are per mitte d 
per C o nse ns us of C hi nes e E x perts [ V ersi o n 2 0 1 5] a n d use m ust be rec or de d o n t he e C R F) 
•
Gra de 3 plat elets decreas e d i n t he prese n ce of cli nicall y si g nifica nt blee di n g
•
Gra de 4 plat elets decreas e d
•
Gra de  3 or 4 na usea, v o miti n g, or diarr hea, if p ersiste nt des pite o pti mal a ntie metic a n d/ or 
a nti-diarr heal t hera p y
•
A n y ot her Gr a de 4 t o xicit y or u n ma na gea bl e Gra d e 3 t o xicit y
If t he t o xicit y res ol ves or re verts t o C T C A E Gra de 1 or baseli ne wit hi n 2 8 d a ys of o nset a n d 
t he s u bject is s h o wi n g cli nical be nefit, treat me nt wit h acala br uti ni b ma y be restarte d usi n g t he 
r ules bel o w f or d os e m o dificati o ns (see T a ble  8 ).  Whe ne v er p ossi ble, a n y d ose a dj ust me nt of 
acala br uti ni b s h o ul d be disc usse d bet wee n t he i n vesti gat or a n d t he s p o ns or bef ore 
i m ple me ntati o n.  T he a p pr o priate cli nic staff s h o ul d dis pe nse t he st u d y dr u g f or t he ne w d os e 
le vel a n d i nstr uct t he s u bject/car e gi ver a b o ut t he c ha n ge i n d ose le vel.  A n y c ha n ges t o t he 
d osi n g re gi me n m ust be r ec or de d i n t he a p pr o pri ate e C R F. 
O nce de -escalati o n has o cc urr e d, t he d ose s h o ul d n ot restart at ori gi nal d os e le vel. 
Treat me nt wit h acala br uti ni b s h o ul d be hel d f or a n y u n ma na gea bl e, p ote ntiall y st u d y dr u g-
relate d t o xicit y t hat is Gr a de ≥3 i n se verit y.  A n y ot her cli nicall y i m p orta nt e ve nts w here d ose 
dela ys ma y be c o nsi d ere d a p pr o priate b y t h e i n vesti gat or m ust be disc usse d wit h t he s p o ns or. 
St u d y dr u g ma y be hel d f or a ma xi m u m of 2 8 c o nsec uti ve da ys fr o m e x pecte d d ose.  St u d y 
treat me nt s h o ul d be disc o nti n ue d i n t he e ve nt of a t o xicit y re q uiri n g t he p ost p o ne me nt of 
d osi n g lasti n g > 2 8 da ys, u nless re vie w e d a n d a p pr o ve d b y t he s p o ns or. 
N ote: Te m p or ar y wit h h ol di n g of st u d y dr u g f or as little as 7  d a ys c a n c a use a tr a nsie nt 
w orse ni n g of dise ase a n d/ or of c o nstit uti o n al s y m pt o ms.  Refer t o Secti o n 7. 1 f or m ore 
i nf or mati o n o n assessi n g disease pr o gressi o n u n der t hese circ u msta nces. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 6 2
 
T a ble  8  
Ac al a br uti ni b D ose M o dific ati o n  
Occ urre nce  
Acti o n  
1 st- 2n d 
H ol d acala br uti ni b u ntil rec o ver y t o Gra de  1 or baseli ne; ma y restart at ori gi nal d ose le vel 
( 1 0 0 m g BI D)  
3 r d 
H ol d acala br uti ni b u ntil rec o ver y t o Gra de  1 or baseli ne; restart at o ne d ose le vel l o wer 
( 1 0 0 m g Q D)  
4t h  
Disc o nti n ue acala br uti ni b.  
A b bre viati o ns:  BI D =t wice dail y; Q D = o nce per da y.  
 
6. 6. 2  
Rit u xi m a b a n d c hl or a m b ucil  
If a patie nt e x perie n ces a n y ≥ Gra de 2 n o n - he mat ol o gical t o xicit y, c hl ora m b ucil a n d/ or 
rit u xi ma b s h o ul d be h ol d u ntil t he n o n- he mat ol o gical t o xicit y ret ur ns t o Gra de 1 or bas eli ne. If 
treat me nt is dela ye d f or m ore t ha n 4 wee ks d ue t o st u d y dr u g-relate d t o xi cit y, c hl ora m b ucil 
a n d/ or rit u xi ma b s h o ul d be disc o nti n ue d. 
If a patie nt e x perie n ces Gra de 3 or 4 c yt o pe nia, t he g ui deli nes f or d ose d ela y (c hl ora m b u cil or 
rit u xi ma b) a n d d ose r e d u cti o n (c hl ora m b ucil o nl y) are o utli ne d i n Ta ble  9.   
T a ble  9  
Rit u xi m a b a n d C hl or a m b ucil D ose M o dific ati o n  
 
C hl or a m b ucil  
Rit u xi m a b  
Gra de  3 or 4 
c yt o pe nia 
Dela y d osi n g f or a ma xi m u m of 4  wee ks.  
A d mi nister G -C S F f or ne utr o pe nia or platelets 
or re d bl o o d cells as re q uire d.  
1 st e pis o de: If i m pr o ve me nt t o Gra de ≤2 ( or 
baseli ne), decrease Cl b d ose t o 7 5 % of i nitial 
d ose f or s u bse q ue nt c ycles  
2 n d e pis o de: If i m pr o ve me nt t o Gra de ≤2 ( or 
baseli ne), decrease Cl b d ose t o 5 0 % of i nitial 
d ose f or s u bse q ue nt c ycles 
3 r d e pis o de: Disc o nti n ue Cl b 
If i m pr o ve me nt t o Gra de ≤2 ( or 
baseli ne), a d mi nister f ull d ose.  
If Cl b is disc o nti n ue d, rit u xi ma b ma y 
c o nti n ue at t he i n vesti gat or's 
discreti o n.  
Gra de  1 or 2 
c yt o pe nia 
N o d ose re d ucti o n or dela y  
N o d ose re d ucti o n or dela y  
A b bre viati o ns: Cl b =c hl ora m b ucil; G -C S F = gra n ul oc yte c ol o n y -sti m ulati n g fact or. 
 
N o re d ucti o n i n t he d ose of rit u xi ma b is all o we d.  Se vere, i ncl u di n g fatal, i nf usi o n reacti o ns 
ca n occ ur wit h rit u xi ma b.  Disc o nti n ue rit u xi ma b i nf usi o n a n d pr o vi de me dical treat me nt f or 
Gra de  3 or 4 i nf usi o n reacti o ns.  F or less se v ere i nf usi o n reacti o ns ( gra de 1 or 2), i nterr u pt t he 
i nf usi o n or sl o w t he i nf usi o n rate.  Rit u xi ma b ma y c o nti n ue at t he discreti o n of t he 
i n vesti gat or w he n t he t o xicit y has i m pr o ve d ( Gra d e ≤2 f or he mat ol o gical t o xicit y a n d Gra de  1 
or baseli ne f or n o n- he mat ol o gical t o xicit y).  If rit u xi ma b is disc o nti n ue d, t he patie nt is 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 6 3
 
wit h dra w n fr o m st u d y treat me nt. Refer t o t he rit u xi ma b l ocal prescri bi n g i nf or mati o n f or d ose 
wit h h ol di n g or disc o nti n uati o n i n res p o nse t o s pecific t o xicities ass ociate d wit h rit u xi ma b.  
C hl ora m b ucil d ose re d ucti o ns are descri be d i n Ta ble 9.  O nce re d uce d, t he d ose of 
c hl ora m b ucil s h o ul d n ot be escal ate d.  A del a y of u p t o 4 wee ks is per mitte d f or c hl ora m b u cil 
t o all o w rec o ver y of he m at ol o gic t o xicities t o Gra de ≤2 or n o n - he mat ol o gi c t o xicities t o 
Gra de  1 or baseli ne le v el.  If t he treat me nt is dela ye d f or m ore t h a n 4  wee ks d ue t o t o xicit y, 
c hl ora m b ucil s h o ul d be disc o nti n ue d.   
If a Gra de 3 or 4 c yt o pe nia pre ve nts treat me nt o n Da y 1 5 ( of a n y c ycl e f or Ar m B), t he Da y 
1 5 c hl ora m b ucil d ose will be s ki p pe d i n or der t o k ee p t he a nti b o d y o n sc h e d ule.  Rit u xi ma b + 
c hl ora m b ucil a d mi nistrati o n o n Da y 1 of t he f oll o wi n g c ycle will be gi ve n if t he c yt o pe nia has 
res ol ve d t o Gr a de ≤2.  C hl ora m b ucil will be gi ve n at a re d u ce d d ose.  If t h e c yt o pe nia p er sists, 
rit u xi ma b + c hl ora m b ucil a d mi nistrati o n will be dela ye d u ntil t he c yt o pe nia has i m pr o ve d t o 
Gra de  ≤2  
C hl ora m b ucil has bee n r e p orte d t o e xacer bate or preci pitate a ut oi m m u ne h e m ol ytic a ne mia 
a n d patie nts s h o ul d be m o nit ore d caref ull y f or t his c o n diti o n.  If a ra pi d d ecreas e of 
he m o gl o bi n occ urs d uri n g t hera p y, t he p ossi bilit y of c hl ora m b ucil- or a ut oa nti b o d y-i n d uce d 
he m ol ysis s h o ul d be c o nsi dere d a n d a p pr o priat e dia g n ostic tests ( L D H, bilir u bi n, ha pt o gl o bi n, 
retic ul oc ytes, C o o m bs test) s h o ul d be perf or m e d.  If he m ol ysis is s us pecte d, a C o o m bs test 
s h o ul d be perf or m e d. If, i n t he j u d g me nt of t he treati n g p h ysicia n, t here is e vi de nce of 
cli nicall y si g nifica nt he m ol ytic a ne mia sec o n d ar y t o c hl ora m b ucil, st u d y treat me nt s h o ul d be 
pr o m ptl y wit h dra w n.  F ull details of t he he m ol ytic a ne mia s h o ul d be rec or d e d o n t he a d verse 
e ve nt pa ges of t he e C R F.  
As ma n y of t hese p atie nts ha ve m ulti ple c o m or bi dities, treat me nt ma y be d ela ye d l o n ger t h a n 
4 wee ks (f or b ot h treat me nts) t o e na ble res ol uti o n of u nrelate d A Es, c o nc u rre nt diseas es, or 
rec o ver y fr o m s ur gi cal pr oce d ures.  T his is at t he i n vesti gat ors discreti o n b ut s h o ul d be 
disc usse d i n a d va nce wit h t he s p o ns or.  
A patie nt s h o ul d disc o nti n ue st u d y treat me nt wit h c hl ora m b ucil/rit u xi ma b if a n y of t he 
f oll o wi n g occ ur: 
•  
Gra d e 4 i nf usi o n r elate d s y m pt o m ( patie nt s h o ul d be wit h dra w n i m me diatel y) 
•  
Gra de  3 i nf usi o n r elate d s y m pt o m at re-c halle n g e  
•  
Gra de  3 or 4 c yt o pe nia t h at has n ot res ol ve d t o Gra de ≤2 a n d del a ys treat m e nt b y 4  wee ks  
•  
Gra de  ≥2 n o n -c yt o pe nic t o xicit y t hat d oes n ot res ol ve t o Gra de 1/ bas eli ne a n d dela ys 
treat me nt b y 4 wee ks  
 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 4
Tre at me nt after t he e n d of t he st u d y
N o i nter ve nti o n f or patie nts is pla n ne d after t he e n d of t he st u d y. H o we ver, pr o visi o ns will be 
i n place f or p atie nts still e nr olle d at t he e n d of t he trial t o c o nti n ue t o recei v e st u d y 
i nter ve nti o n if, i n t he o pi ni o n of t he i n vesti gat or, t he y are c o nti n ui n g t o recei ve be nefit fr o m 
treat me nt.
I n t he e ve nt t hat a r oll- o v er or safet y e xte nsi o n st u d y is a vaila ble at t he ti me of t he data b ase 
cl os ure, patie nts c urre ntl y recei vi n g treat me nt wit h st u d y i nter ve nti o n ma y be tra nsiti o ne d t o 
s uc h a st u d y, a n d t he c urr e nt st u d y w o ul d reac h its e n d. Patie nts i n Ar m B will still be all o we d 
t o cr oss o ver t o r ecei ve acala br uti ni b as s pecifie d i n secti o n 6. 7. T he r oll-o ver or safet y 
e xte nsi o n st u d y w o ul d e ns ure treat me nt c o nti n uati o n wit h visits a n d assess me nts per its 
pr ot oc ol. A n y patie nt w h o w o ul d be pr o p ose d t o m o ve t o s uc h a st u d y w o ul d be as ke d t o si g n 
a ne w I C F.  
S uc h s u bjects w h o ar e still recei vi n g or will cr oss o ver t o recei ve acala br uti ni b will c o nti n ue 
t o be m o nit ore d f or all A Es u p t o 3 0 ( + 7) da ys aft er t he last d ose of i n v esti gati o nal pr o d uct.  
F or s u bjects w h o d o c o nti n ue t o recei v e treat me nt be y o n d t he cl os ure of t he data base, 
i n vesti gat ors will c o nti n ue t o re p ort all S A Es t o t he s p o ns or Patie nt Safet y u ntil 3 0 da ys after 
I P is disc o nti n ue d, i n acc or da nce wit h Secti o n 8. 4. 1( Re p orti n g of S A Es).  
Cr oss o ver
At i n vesti gat or discreti o n, s u bjects ra n d o mize d t o Ar m B w h o ha ve BI C R -c o nfir me d disease 
pr o gressi o n a n d meet eli gi bilit y f or cr oss o ver ma y ha ve t he o pti o n t o recei ve acala br uti ni b 
m o n ot hera p y as cr oss o ver treat me nt pr o vi de d t h e i nf or me d c o ns e nt of t he cr oss o ver treat me nt 
is si g ne d. After t he fi nal a nal ysis a n d per A me n d me nt 5. 0, s u bjects ca n cr oss o ver wit h 
i n vesti gat or-assesse d P D wit h a gree me nt fr o m me dical m o nit or/st u d y p h ysicia n pri or t o t he 
c o ncl usi o n of t he st u d y. Scree ni n g assess me nts f or cr oss o ver liste d i n Ta ble  3 s h o ul d be 
perf or me d wit hi n t he scr ee ni n g ti me wi n d o w of 4 2 da ys (as t he E o T/ S F U visit or its 
c orres p o n di n g tests i n ter ms of sc he d ule ma y o verla p wit h t he cr oss o ver s cree ni n g visit or its 
c orres p o n di n g tests, t he E o T/ S F U visit a n d its c orres p o n di n g tests ca n be wai ve d i n s uc h case, 
e. g. t he tests or assess me nts are sc he d ul e d b ot h i n E o T/ S F U wi n d o w a n d cr oss o ver scree ni n g 
wi n d o w. C T sca ns t hat s h o we d disease pr o gressi o n fr o m Ar m B ca n b e use d f or t he cr oss o v er 
scree ni n g C T sca n, if wit hi n 6 0 da ys of cr oss o ver d osi n g C ycle 1 Da y 1).  Eli gi bilit y f or 
cr oss o ver i ncl u d es t he f oll o wi n g criteria: 
•
Cr oss o ver ca n di d ates  m ust have BI C R -c o nfir m e d or i n vesti gat or-assess e d disease 
pr o gressi o n. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 6 5
 
•  E C O G perf or ma nce stat us a n d t he la b orat or y p ara meters as o utli ne d i n t he i ncl usi o n 
criteria # 4 a n d # 7, a n d e x cl usi o n criteria # 8 s h o ul d be met. See Secti o n  5. 1  a n d Secti o n 
5. 2 . 
•  T here are n o c o ncer ns b y t he i n vesti gat or j u d ge me nt i ncl u di n g b ut n ot li mite d t o safet y 
ris ks, c o m plia nce, r estricti o ns a n d st u d y pr ocess re q uire me nts. 
Cr oss o ver ca n di d ates ma y n ot recei ve a n y ot her a ntica ncer t h era p y t o treat C L L, i ncl u di n g 
acala br uti ni b o utsi de t he st u d y, fr o m t he last d ose of Ar m B treat me nt t o t h e i nitiati o n of 
cr oss o ver t hera p y wit h acala br uti ni b. S h o ul d a s u bject de vel o p a s ec o n d pri mar y mali g na nc y 
w hile o n trial, cr oss o ver o pti o n after c urati ve treat me nt of t he sec o n d pri mar y mali g na nc y 
ma y be c o nsi der e d aft er disc ussi o n wit h t he st u d y p h ysicia n. Cr oss o ver s u bjects will be 
treate d wit h acala br uti ni b u ntil disease pr o gressi o n base d o n i n vesti gat or ass ess me nt or 
u nacce pta ble t o xicit y. BI C R assess me nt is n ot re q uire d f or cr oss o ver s u bjects.  
F or  cr oss o ver s u bjects, A Es will be c ollecte d fr o m ti me of si g nat ure of i nf or me d c o nse nt of 
cr oss o ver tr eat me nt t hr o u g h o ut t he treat me nt peri o d a n d i ncl u di n g t he f oll o w- u p peri o d. T h e 
f oll o w- u p peri o d is defi n e d as 3 0 da ys after t he l ast d ose of cr oss o ver treat me nt. T he ot her 
re q uire me nts f or A E c oll ecti o n a n d re p orti n g are pr o vi de d i n Secti o n 8 . 
 
 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 6
7
Disc o nti n u ati o n O F T R E A T M E N T A N D S U B J E C T Wit h dr a w al   
Disc o nti n u ati o n of st u d y tre at me nt 
S u bjects ma y be disc o nti n ue d fr o m I P i n t he f oll o wi n g sit uati o ns ( n ote t hat disc o nti n uati o n 
fr o m st u d y treat me nt is N O T t he sa me t hi n g as a c o m plete wit h dra w al fr o m t he st u d y): 
•
A n y s u bject w h o has o bj ecti ve e vi de n ce of diseas e pr o gressi o n w hile recei vi n g pr ot oc ol 
re q uire d st u d y dr u g s h o ul d be disc o nti n ue d fr o m t he st u d y treat me nt.  If t h ere is 
u ncertai nt y r e gar di n g w h et her t here is disease pr o gressi o n, t he s u bject ma y c o nti n ue 
st u d y treat me nt a n d re m ai n u n der disease e val uati o n u ntil c o nfir mati o n of disease 
pr o gressi o n.  I n partic ular, tra nsie nt w ors e ni n g of disease d uri n g te m p orar y i nterr u pti o n 
of st u d y t hera p y ( e. g., f or dr u g-relat e d t o xicit y, s ur ger y, or i nterc urre nt ill ness) ma y n ot 
i n dicate disease pr o gressi o n.  I n s u c h circ u msta nces, a n d if me dicall y a p pr o priate, 
s u bjects ma y res u me t her a p y a n d rel e va nt cli nical, la b orat or y, a n d/ or ra di o gra p hic 
assess me nts s h o ul d be d o ne t o d oc u me nt w het her t u m or c o ntr ol ca n b e mai ntai ne d or 
w het her act ual diseas e pr o gressi o n has occ urre d. 
•
A n y A E t hat pres e nts a s u bsta ntial cli nical ris k t o t he s u bject wit h c o nti n ue d st u d y 
treat me nt d osi n g.
•
S u bject decisi o n.  T he s u bject is at a n y ti me free t o disc o nti n ue treat me nt, wit h o ut 
prej u dic e t o f urt h er treat me nt.
•
Pre g na nc y i n a s u bject, i nte n d t o bec o me pre g na nt or be gi n breast fee di n g.  
•
Se vere n o n - c o m plia nce wit h t he cli nical st u d y pr ot oc ol. 
•
Start of alter nati ve a nti - C L L t hera p y. 
•
St u d y ter mi nate d b y s p o ns or.  
See t he S o A f or dat a t o be c o llecte d at t he ti me of treat me nt disc o nti n uati o n a n d f oll o w- u p 
a n d f or a n y f urt her e val u ati o ns t hat nee d t o be c o m plete d.  S u bjects t hat disc o nti n ue st u d y 
treat me nt will c o nti n ue wit h st u d y f oll o w- u p visits u ntil deat h, wit h dra wal of c o nse nt, l ost t o 
f oll ow- u p, or st u d y ter mi nati o n, w hic he ver o cc urs first. 
7. 1. 1 
Pr oce d ures f or dis c o nti n u ati o n of st u d y tre at m e nt 
T he i n vesti gat or s h o ul d i nstr uct t he s u bject t o c o ntact t he site bef ore or at t he ti me if st u d y 
treat me nt is st o p pe d.  A s u bject t hat deci des t o dis c o nti nue st u d y treat me nt will al wa ys be 
as ke d a b o ut t he r eas o n(s) a n d t he pres e nce of a n y A Es.  T he date of last i nta ke of st u d y 
treat me nt s h o ul d be d oc u me nte d i n t he e C R F.  All st u d y treat me nt s h o ul d be ret ur n e d b y t he 
s u bject at t heir ne xt o n-site st u d y visit or u nsc he d ule d visit.  S u bjects per ma ne ntl y 
disc o nti n ui n g st u d y treat me nt s h o ul d be gi ve n l ocall y a vaila ble sta n dar d of care t h era p y, at t he 
discreti o n of t he i n vesti g at or. 
Disc o nti n uati o n of st u d y treat me nt, f or a n y reas o n, d oes n ot i m pact o n t he s u bject’ s 
partici pati o n i n t he st u d y.  T he s u bject s h o ul d c o nti n ue atte n di n g s u bse q ue nt st u d y visits a n d 
data c ollecti o n s h o ul d c o nti n ue acc or di n g t o t he st u d y pr ot oc ol.  Patie nts w h o ha ve 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 7
per ma ne ntl y disc o nti n ue d fr o m f urt her recei pt of I P will nee d t o be dis c o nti n ue d fr o m t he 
I R T/ R T S M. 
A n E o T visit is re q uire d f or saf et y assess me nts f or a n y s u bjects w h o p er ma ne ntl y disc o nti n ue 
st u d y treat me nt f or a n y r eas o n (e x ce pt f or deat h, l ost t o f oll o w- u p, or wit h dra wal of c o nse nt), 
i ncl u di n g disease pr o gr essi o n. T he e n d of treat me nt visit is n ot re q uire d f or s u bjects w h o 
disc o nti n ue fr o m st u d y treat me nt wit hi n 1 0 da ys of a sc he d ul e d st u d y visit or if t he E o T visit 
w o ul d be perf or me d wit hi n 1 4 da ys of t he safet y f oll o w- u p visit. If t he S F U visit is wit hi n ± 
7 da ys of a r e g ularl y sc h e d ule d visit d uri n g t he p ost- treat me nt p hase, t h e visits ma y be 
c o m bi ne d i nt o a si n gle visit. 
I n a d diti o n t o t he E o T visit, a n S F U visit s h o ul d be c o n d ucte d at 3 0 ( + 7) da ys after his or h er 
last d ose of all st u d y dr u gs t o m o nit or f or res ol uti o n or pr o gressi o n of A Es a n d t o d oc u me nt 
t he occ urre nce of a n y n e w e ve nts, re g ar dless of w het her t he s u bject recei ves a ne w a ntica ncer 
t hera p y or d e m o nstrates disease pr o gressi o n wit hi n t his ti me fra me.  Refer t o Ta bles 1- 3, f or 
t he assess me nts re q uir e d f or t he E o T a n d S F U visits. 
If t he s u bject d oes n ot a gree t o c o nti n ue i n- p ers o n st u d y visits, a m o difie d f oll o w- u p m ust be 
arra n g e d t o e ns ur e t he c ollecti o n of e n d p oi nts a n d safet y i nf or mati o n.  T his c o ul d be a 
tele p h o ne c o ntact wit h t he s u bject at e n d of treat me nt f oll o w u p visit, a c o ntact wit h a rel ati ve 
or treati n g p h ysicia n, or i nf or mati o n fr o m me dical rec or ds.  T h e a p pr oac h t a ke n s h o ul d be 
rec or d e d i n t he me dical r ec or ds.  A s u bject t hat a grees t o m o difie d f oll o w- u p is n ot c o nsi dere d 
t o ha ve wit h dra w n c o nse nt or t o ha ve wit h dra w n fr o m t he st u d y. 
7. 1. 2 
F oll o w- u p f or pr o gressi o n a n d s ur vi v al 
P ost -tre at m e nt Dise ase F oll o w u p: All s u bjects e nr olle d w h o c o m plete t he st u d y treat me nt 
( Ar m B) or disc o nti n ue fr o m st u d y treat me nt d ue t o reas o ns ot her t ha n disease pr o gressi o n 
will be f oll o we d f or disease e val u ati o n a p pr o xi matel y e ver y 1 2 w ee ks or 2 4  wee ks  fr o m t he 
latest date of diseas e e v al uati o n bef ore st u d y treat me nt disc o nti n uati o n u ntil disease 
pr o gressi o n, re g ar dless of w het her t h e s u bject recei ves a ne w a nti -C L L t hera p y. 
S ur vi v al F oll o w u p : All s u bjects w h o ha ve diseas e pr o gressi o n a n d h a ve n ot wit h dra w n 
c o nse nt will be c o ntact e d a p pr o xi matel y e very 2 4 wee ks b y cli nical visit or tele p h o ne, t o 
assess s ur vi val a n d t he us e of alter n ati ve a nti -C L L t hera p y a n d o cc urre nce of a n y sec o n d ar y 
mali g na ncies u ntil deat h or l ost t o f oll o w u p.  At t he ti me of t he pla n ne d fi nal a nal ysis, a 
s ur vi val s wee p ma y b e c o n d ucte d.  All s u bjects w h o are o n st u d y a n d n ot k n o w n t o ha ve die d 
bef ore t h e s ur vi val s wee p ma y be c o ntacte d at t hat ti me.
L ost t o f oll o w -u p
A s u bject will be c o nsi dere d p ote ntiall y l ost t o f oll o w - u p if he or s h e fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site.   

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br ut i ni b ( A C P-1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 8
T he f oll o wi n g acti o ns m ust be ta ke n if a s u bject fails t o ret ur n t o t he cli n ic f or a re q uire d 
st u d y visit: 
•
T he site m ust atte m pt t o c o ntact t he s u bject a n d resc he d ule t he misse d visit as s o o n as 
p ossi ble a n d c o u nsel t he s u bject o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit 
sc he d ule.
•
Bef ore a s u bj ect is dee m e d l ost t o f oll o w- u p, t he i n vesti gat or or desi g nee m ust ma ke 
e ver y eff ort t o r e gai n c o ntact wit h t he s u bject or t hr o u g h t heir fa mil y, or b y c o ntact wit h 
s u bject’s c urr e nt p h ysicia n, e. g., b y re p eat tele p h o ne calls, certifie d letter t o t he s u bject´s 
last k n o w n maili n g a d dress, or l ocal e q ui vale nt met h o ds.  If a p u blic deat h re gistr y is 
a vaila ble, deat h i nf or mati o n (i.e., date of d eat h) s h o ul d be c ollecte d w h ere all o we d b y 
re g ulat or y a n d E C r e q uir e me nts.  
•
All atte m pts t o c o ntact t he s u bject s h o ul d be ma de r o uti nel y a n d rec or de d i n e C R F o n t he 
s ur vi val stat us m o d ule.  T he site s h o ul d re p ort t he atte m pte d date of c o ntact a n d t he last 
date k n o w n t o be ali ve.  
•
If c o ntact or re gistr y/ p u blic s o urce is u ns uccessf ul ( or n o clear stat us ca n b e o btai ne d), list 
s u bject’s stat us as “ u n k n o w n” a n d c o nti n ue t h e c o ntact atte m pts u ntil e n d of t he st u d y 
( u ntil fi nal a nal ysis). 
•
Patie nts s h o ul d n ot be mar ke d as l ost t o f oll o w- u p o n t he Ter mi nati o n ( D S) m o d ule u ntil 
t he e n d of t he st u d y (at fi nal a nal ysis) w he n all atte m pts t o c ollect s ur vi val f oll o w- u p ha ve 
bee n e x h a uste d.
•
At t he ti me of fi nal a nal yses, all e nr olle d s u bjects’ s ur vi val stat us i n t he safet y a nal ysis set 
s h o ul d be re-c hec k e d, i ncl u di n g t h ose s u bjects w h o ha ve wit h dra w n c o nse nt or are 
classifie d as “l ost t o f oll o w - u p.” 
−
S u bjects w h o ha ve wit h dra w n c o ns e nt:  I n t he e ve nt t hat t he s u bject has acti vel y 
wit h dra w n c o nse nt t o t he pr ocessi n g of t heir p ers o nal data, t he s ur vi val stat us of t he 
s u bject ca n be o bt ai ne d b y site pers o n nel fr o m p u blicl y a vaila ble deat h re gistries (if 
a vaila ble) w h er e it is p ossi ble t o d o s o u n der a p plica ble l ocal la ws, t o o btai n a c urre nt 
s ur vi val stat us i n t he 7 da ys f oll o wi n g data c ut-off.  ( T he a p plica ble C R F m o d ules 
will be u p date d.) 
−
S u bjects classifie d as l ost t o f oll o w - u p:  Site pers o n nel s h o ul d c hec k h os pit al rec or ds, 
t he s u bject’s c urre nt p h ysicia n, a n d a p u blicl y a v aila ble deat h re gistr y (if a vaila ble) t o 
o btai n a c urr e nt s ur vi val stat us i n t he 7 da ys f oll o wi n g data c ut-off.  ( T he S U R VI V E 
m o d ule will be u p date d.) 
Wit h dr a w al fr o m t he st u d y
A s u bject ma y wit h dra w fr o m t he st u d y (e. g., wit h dra w c o ns e nt), at a n y ti m e (i n vesti gati o nal 
pr o d uct a n d  assess me nts) at his/ her o w n re q uest, wit h o ut prej u dice t o f urt her treat me nt.  
If t he s u bject wit h dr a ws c o nse nt f or discl os ure of f ut ure i nf or mati o n, t he s p o ns or ma y retai n 
a n d c o nti n ue t o use a n y d ata c ollecte d b ef ore s uc h a wit h dra wal of c o nse nt. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 6 9
 
If a s ubject wit h dr a ws fr o m t he st u d y, he/s he ma y re q uest destr u cti o n of a n y sa m ples ta ke n, 
a n d t he i n vesti gat or m ust d oc u me nt t his i n t he site st u d y rec or ds.  If sa m ples alrea d y h a ve 
bee n a n al yze d at t he ti me of t he re q u est, t he s p o ns or will n ot be o bli ge d t o destr o y t he res ults 
of t his resear c h.   
S uc h s u bjects will al wa ys be as ke d a b o ut t he reas o n(s) a n d t he prese n ce of a n y A Es.  T he 
i n vesti gat or will f oll o w u p s u bjects as me dicall y i n dicate d.  T he s u bject will ret ur n electr o ni c 
e P R O de vice(s).  
T he s p o ns or or i ts dele gate will re q uest i n vesti gat ors t o c ollect i nf or mati o n o n s u bjects’ vital 
stat us ( dea d or ali ve; date of deat h w he n a p plica bl e) at t he dat a c ut- off f or st u d y a nal yses fr o m 
p u blicl y a vaila ble s o urces, i n acc or d a nce wit h l ocal re g ulati o ns.  K n o wle d ge of t he vital stat us 
at data c ut - off f or st u d y a nal yses i n all s u bjects is cr ucial f or t he i nte grit y of t he st u d y.  
See t he S o As (Ta ble 1 , T a ble  2, a n d Ta bl e  3) f or d ata t o be c ollect e d at t he ti me of st u d y 
disc o nti n uati o n a n d f oll o w- u p a n d f or a n y f urt her e val uati o ns t hat nee d t o b e c o m plete d. A n y 
re mai ni n g st u d y treat me nt(s) s h o ul d be ret ur n e d b y all s u bjects. 
 
 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 7 0
 
8  
St u d y  Assess me nts  A N D P R O C E D U R E S  
St u d y pr oce d ures a n d t heir ti mi n g are s u m marise d i n t he S o A ( Secti o n  1. 1 ).  Descri pti o ns of 
t he sc he d ule d e v al uati o ns are o utli ne d i n t he s u bs ecti o ns bel o w.  Bef ore st u d y e ntr y, 
t hr o u g h o ut t he st u d y, a n d at t he f oll o w- u p e v al uati o n, vari o us cli nical a n d dia g n ostic 
la b orat or y e v al uati o ns ar e o utli ne d.  T he p ur p ose of o btai ni n g t hese detaile d meas ure me nts is 
t o e ns ure a d e q uate safet y a n d effi cac y assess me nts.  Cli nical e val uati o ns a n d la b orat or y 
st u dies ma y be re peate d m ore fre q u e ntl y if cli nicall y i n dicate d.  S uc h u nsc he d ule d 
assess me nts will be ca pt ure d i n t he pr ot oc ol- s p ecific data bas e as a p pr o priate. 
T he i n vesti gat or will e ns ure t hat data are rec or de d o n t he e C R Fs.  A we b -b ase d data ca pt ure 
( W B D C) s yste m will be use d f or data c ollecti o n a n d q uer y ha n dli n g.   
T he i n vesti gat or e ns ur es t he acc urac y a n d c o m plet e ness of e C R Fs a n d ti meli ness of t he data 
rec or d e d, a n d of t h e pr o visi o n of a ns wers t o data q ueries acc or di n g t o t he Cli nical St u d y 
A gree me nt.  T h e i n vesti gat or will electr o nicall y si g n t he c o m plete d e C R Fs.  A c o p y of t he 
c o m plete d e C R Fs will be arc hi ve d at t he st u d y site.  
I m me diat e saf et y c o ncer ns s h o ul d be disc usse d wit h t he s p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness t o det er mi ne if t he s u bject s h o ul d c o nti n ue or disc o nti n ue st u d y treat me nt. 
A d here n ce  t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is esse ntial 
a n d re q uir e d f or st u d y c o n d uct. 
All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial s u bjects 
meet all eli gi bilit y criteria.  T he i n vesti gat or will mai ntai n a scree ni n g l o g t o rec or d d etails of 
all s u bjects scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or scree ni n g fail ure, as 
a p plica ble.   
Me dical hist or y m ust be c ollecte d a n d rec or de d i n cl u di n g c o nc urre nt me dical si g ns a n d 
s y m pt o ms, alc o h ol use a n d, if a s m o ker, ci garette use.  Disease hist or y, i ncl u di n g t he date of 
i nitial dia g n osis, Rai sta gi n g wit hi n 2 8 da ys of first d ose wit h st u d y dr u g, a n d hist or y of 
a ut oi m m u ne C L L c o m plicati o ns a n d t heir treat me nt will als o be rec or d e d b ase d u p o n 
a vaila ble d oc u me nts a n d s u bject hist or y. 
Pr oce d ures c o n d ucte d as part of t he s u bject’s r o uti ne cli nical ma na g e me nt (e. g., bl o o d c o u nt) 
a n d o btai ne d bef ore si g ni n g of t he I C F ma y b e utilise d f or scree ni n g or b aseli ne p ur p oses, 
pr o vi de d t he pr oce d ures met t he pr ot oc ol- s pecifie d criteria a n d were perf or me d wit hi n t he 
ti mefra me defi ne d i n t he S o A. 
Re peat or u nsc h e d ule d sa m ples ma y be ta ke n f or s afet y reas o ns or f or tec h nical iss ues wit h 
t he sa m ples. 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
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C O N FI D E N TI A L A N D P R O P RI E T A R Y  
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Effic ac y assess me nts 
8. 1. 1 
T u m or assess m e nts 
O verall r es p o nse assess m e nts will be base d u p o n e val uati o n of p h ysical e x a ms, rec or di n g of 
s y m pt o ms, ra di ol o gic e val uati o ns, he mat ol o gic e val uati o ns, a n d b o ne marr o w e xa ms per t he 
S o A.   
B aseli ne:
F or bas eli ne, a C T sca n wit h c o ntrast ( or M RI if C T is c o ntrai n dicate d) is re q uire d wit hi n 
2 8 da ys bef or e t he first d ose of st u d y dr u g a n d m ust i ncl u de t he nec k, c h est, a b d o me n, a n d 
pel vis a n d a n y ot her disease sites (e. g., brai n).  S plee n a n d li ver size s h o ul d be rec or de d i n C T 
meas ure me nt.  A d diti o nall y, b o ne marr o w as pirati o n a n d bi o ps y are re q uire d wit hi n 6 0 da ys 
bef ore first d ose of st u d y dr u g.  P h ysical e xa m (es peciall y l y m p h n o de a n d or ga n o me gal y), 
B-s y m pt o ms, bl o o d c o u nts wit h differe ntial, a n d ot her cli nical i nf or mati o n at baseli ne s h o ul d 
be rec or de d i n t h e e C R F. 
U p t o 6 meas ura ble disease sites ( o nl y n o dal lesi o ns ≥1. 5 c m i n t he l o n gest dia meter, clearl y 
meas ura ble i n 2  p er pe n di c ular di me nsi o ns), will be f oll o we d as tar get lesi o ns f or eac h s u bject.  
Meas ura ble sites of disease s h o ul d be c h ose n s uc h t hat t h e y are re prese ntati ve of t he s u bject’s 
disease.  I n a d diti o n, selecti o n of tar get lesi o ns s h o ul d be fr o m as dis parate re gi o ns of t he 
b o d y as p ossi ble w he n t h ese ar eas are si g nifica ntl y i n v ol ve d.  Tar get l y m p h n o des s h o ul d n ot 
be selecte d fr o m pr e vi o usl y ir ra diate d areas.  If t h e s ole meas ura ble lesi o n lies wit hi n t he fiel d 
of pri or ra di ot hera p y, t here m ust be e vi de n ce of disease pr o gressi o n i n t hat lesi o n t hat has n ot 
bee n pre vi o usl y irr a diate d.  If a d diti o nal lesi o ns are prese nt b ut are n ot i ncl u de d i n t he tar get 
lesi o n assess me nt, t he y ca n be a d d e d as n o n-tar get lesi o ns f oll o we d t hr o u g h o ut t he st u d y.  T he 
cra nial -ca u d al meas ure m e nt of t he s plee n a n d l o n gest dia meter of t he li ver will be assesse d at 
scree ni n g a n d all s u bse q ue nt res p o nse e val uati o ns. 
F oll o w- u p:
Ra di ol o gic t u m or assess me nt will be perf or me d acc or di n g t o S o A.  I n vesti gat ors will assess 
res p o nse a n d pr o gressi o n base d o n cli nical/la b orat or y si g ns a n d s y m pt o ms.  Ra di ol o g y re p orts 
fr o m a C T sca n will be use d t o s u p p ort t he e val uati o n of c o m plete a n d partial res p o nse. 
S u bjects w h o ha ve si g ns a n d s y m pt o ms of disease pr o gressi o n o utsi de of t h e sc he d ule d st u d y 
visits a n d assess me nts s h o ul d be e val uate d b y t h e i n vesti gat or wit h p h ysical e xa m a n d bl o o d 
c o u nts wit h differe ntial t o deter mi ne if diseas e pr o gressi o n is prese nt.  T he bl o o d sa m ples f or 
res p o nse or disease pr o gr essi o n deter mi nati o n s h o ul d be c o nfir me d b y a ce ntral la b orat or y 
(sa m ples fr o m l ocal la b orat ories ca n be use d if ce ntral testi n g is u na vaila ble).  Wit h 
A me n d me nt 5. 0, t he bl o o d sa m ples f or res p o nse or disease pr o gressi o n will be teste d i n l ocal 
la b orat ories. A n y s us p ect e d case of diseas e pr o gressi o n (i n t he a bse nce of la b orat or y or 

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hist o pat h ol o gic c ha n ges meeti n g t he criteria f or P D) s h o ul d be c o nfir m e d wit h a C T sca n a n d 
s h o ul d be re p orte d t o t he s p o ns or or desi g nee. S u bjects ma y c o nti n ue st u d y treat me nt u ntil 
pr o gressi o n is c o nfir me d b y a serial e x a m.  I n a d diti o n, w he n cli nicall y a p pr o priate, base d o n 
i n vesti gat or-per cei ve d ris k -be nefit ass ess me nt, a s u bject ma y c o nti n ue treat me nt  a n d re mai n 
u n der cl ose o bs er vati o n u ntil pr o gressi o n is c o nfir me d. Ne w a nti- C L L t hera p y s h o ul d be 
wit h hel d if cli nicall y a p pr o priate i n t he a bs e nce of c o nfir me d pr o gressi ve disease.  
If t he s u bject’s p h ysical e xa mi nati o n fi n di n gs, la b orat or y e v al uati o ns ( wit h he mat ol o g y pr ofile 
i ncl u di n g a bs ol ute l y m p h oc yte c o u nt, A N C, platel et c o u nt, a n d H g b), a n d ra di o gra p hic 
e val uati o ns s u g gest t hat C R/ C Ri has bee n ac hie v e d i n all res p o nse para meters, a b o ne marr o w 
as pirate a n d bi o ps y m ust be o btai ne d t o c o nfir m t h e C R a n d peri p heral bl o o d a n d b o ne 
marr o w sa m ple m ust be o btai ne d t o e val uate mi ni mal resi d ual disease ( M R D).  T he b o ne 
marr o w as pir ate a n d bi o ps y m ust be d o ne bet wee n  8- 1 2 wee ks of t he C T i ma gi n g t hat 
s u p p orte d t he assess me nt of C R/ C Ri. S u bjects w h o are ot her wise i n a c o m plete re missi o n b ut 
ha ve b o ne marr o w n o d ul es t hat ca n be i d e ntifie d hist ol o gicall y, s h o ul d be c o nsi dere d t o ha v e 
“ n o d ular P R.” I m m u n o hist oc he mistr y s h o ul d be perf or me d t o d efi ne w h et h er t hese n o d ules 
are c o m p os e d of pri maril y T cells, l y m p h oc ytes ot her t ha n C L L cells, or C L L cells. If t he 
n o d ules are n ot c o m p ose d of C L L cells, a C R ca n be d oc u me nte d pr o vi d e d all ot her criteri a 
are met. I n cases w her e c yt o pe nic pr o gressi o n is s us pecte d, a b o n e marr o w as pirate or bi o ps y 
m ust be perf or me d t o disti n g uis h a ut oi m m u ne a n d dr u g- relat e d c yt o pe nias.  I n cases w here 
Ric hter’s tra nsf or mati o n is s us pecte d (e. g., ra pi dl y pr o gressi ve B-s y m pt o ms; b ul k y 
l y m p ha de n o pat h y; or ga n o me gal y; a ne mia; a l o w platelet c o u nt; a n d ele v ate d ser u m L D H, 
calci u m, a n d β 2 micr o gl o b ul i n le vels), dia g n osis s h o ul d be c o nfir me d b y bi o ps y of l y m p h 
n o des, b o ne marr o w, or i n v ol ve d or ga ns.  Pat h ol o g y a nal yses will be d o ne f or c o nfir m ati o n of 
Ric hter’s tra nsf or mati o n.  Bi o ps y of t he affecte d site is dia g n ostic a n d s ufficie nt f or 
c o nfir mati o n.  If a n a ncillar y w h ole- b o d y P E T- C T sca n ( n ot re q uire d f or st u d y) is perf or m e d 
per l ocal sta n d ar d of car e or at i n vesti gat or discreti o n, t he res ults of t his sca n s h o ul d be 
ca pt ure d i n t he e C R F as a n u nsc he d ule d visit. 
A ce ntral i ma gi n g ser vice will be use d t o pr o vi de i n de pe n de nt ra di ol o gic assess me nts f or t he 
p ur p oses of t he pri mar y e n d p oi nt.  All i ma gi n g assess me nts (i ncl u di n g u nsc he d ule d visit sca n) 
will be se nt t o t he s p o ns or a p p oi nte d ce ntral rea der o n a n o n g oi n g basis.  Assess me nt of sca ns 
b y BI C R will be tri g gere d o nl y u p o n i n vesti gat or-assesse d pr o gressi o n f or b ot h ar ms a n d t he 
BI C R c o nfir mati o n will be re p ort e d bac k t o sites. If t he BI C R d oes n ot c o nfir m disease 
pr o gressi o n, t u m or assess me nts s h o ul d be c o nti n ue d i n li ne wit h t he sc he d ule of assess me nts. 
Si nce t he pri mar y a n al ysis of t he st u d y is base d o n BI C R, it is i m p orta nt t hat st u d y treat me nt 
a n d sc he d ule d i ma gi n g assess me nts c o nti n ue u ntil pr o gressi o n c o nfir m e d b y BI C R. After t h e 
fi nal a nal ysis a n d per A me n d me nt 5. 0, disease pr o gressi o n ca n b e ass esse d b y i n vesti gat or.  

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If at t he ti me of pri mar y P F S a nal ysis it is i de ntifie d t hat a patie nt has disease pr o gressi o n b y 
BI C R t hat has n ot bee n i de ntifie d b y t he i n vesti gat or, t he s p o ns or will c o ntact t he i n vesti gat or 
t o disc uss w het her c o nti n ue d treat me nt wit h st u d y me dicati o n is a p pr o priate.  
T he i n vesti gat or m ust e v al uate t he r es p o nse of t he s u bject per I W C L L criteria (see  Ta ble  1 0). 
T a ble  1 0  
Res p o nse Assess me nt Criteri a f o r C L L ( m o difie d fr o m  H alle k  2 0 1 8 ) –  
I W C L L Criteri a 
Gr o u p  
P ar a m eter  
C R  a 
P R  b 
P D  
S D  
A  
L y m p h n o des  
N o ne ≥1. 5  c m 
Decrease 
≥5 0 % (fr o m 
baseli ne)  c  
I ncrease ≥5 0 % 
fr o m baseli ne or 
fr o m res p o nse 
C ha n ge of -4 9 %  
t o + 4 9 % 
Li ver a n d/ or 
s plee n size d 
S plee n size 
< 1 3  c m; li ver 
size n or mal 
Decrease 
≥5 0 % (fr o m 
baseli ne)  
I ncrease ≥5 0 % 
fr o m baseli ne or 
fr o m res p o nse 
C ha n ge of -4 9 %  
t o + 4 9 % 
C o nstit uti o nal 
s y m pt o ms 
N o ne  
A n y  
A n y  
A n y  
Circ ulati n g 
l y m p h oc yte 
c o u nt 
N or mal  
Decrease 
≥5 0 % fr o m 
baseli ne  
I ncrease ≥5 0 % o ver 
na dir wit h a bs ol ute 
c o u nt ≥ 5× 1 0 9/ L 
C ha n ge of -4 9 %  
t o + 4 9 % 
B  
Platelet c o u nt  
≥1 0 0, 0 0 0/ µ L  
≥1 0 0, 0 0 0/ µ L 
or i ncrease 
≥5 0 % o ver 
baseli ne  
Decrease of ≥5 0 % 
fr o m baseli ne 
sec o n dar y t o C L L 
C ha n ge of -4 9 %  
t o + 4 9 % 
He m o gl o bi n  
≥1 1. 0  g/ d L 
( u ntra nsf use d 
a n d wit h o ut 
er yt hr o p oieti n) 
≥1 1  g/ d L or 
i ncrease ≥5 0 % 
o ver baseli ne  
Decrease of 
≥2  g/ d L fr o m 
baseli ne sec o n dar y 
t o C L L 
I ncrease 
< 1 1. 0  g/ d L or 
< 5 0 % o ver 
baseli ne, or 
decrease > 2  g/ d L  
 
Marr o w  
N or m ocell ular, 
n o C L L cells, n o 
B- l y m p h oi d 
n o d ules  
Prese nce of 
C L L cells, or 
of B -l y m p h oi d 
n o d ules, or n ot 
d o ne  
I ncrease of C L L 
cells b y ≥5 0 % o n 
s uccessi ve bi o psies 
N o c ha n ge i n 
marr o w i nfiltrate  
A b bre viati o ns:  C L L =c hr o nic l y m p h o c ytic le u k e mia; C R =c o m plete res p o nse; C T =c o m p ute d t o m o gra p h y; 
P D = pr o gressi v e disease; P R = p artial res p o nse; S D =sta ble disease.  
N ote: C R, c o m plete re missi o n:  all of t h e criteria h a v e t o b e met; P R, p artial res p o nse: f or a P R at least 2 of t h e 
para meters of gr o u p A a n d 1 p ara meter of gr o u p B n ee d t o i m pr o v e if pre vi o usl y a b n or mal.  If o nl y o n e p ara meter 
of b ot h gr o u ps A a n d B is a b n or mal pri or t o t h era p y, o nl y 1 n ee ds t o i m pr o v e.  P D, pr o gressi v e disease: at least o n e 
of t he a b o ve criteria of gr o u p A or gr o u p B h as t o b e met; S D, sta ble disease:  all of t h e a b o v e criteria h a v e t o b e 
met.  C o nstit uti o n al s y m pt o ms al o n e d o n ot d efi n e P D.  
a      C Ri ( C R wit h i n c o m plete b o n e marr o w rec o v er y) refers t o s u bjects w h o f ulfill all t h e criteria f or a C R (i n cl u di n g t he 
b o ne marr o w e x a mi n ati o ns), b ut h a v e a p ersiste nt a n e mia, t hr o m b o c yt o p e nia, or n e utr o p e nia a p p are ntl y u nrelate d t o 
C L L, b ut relate d t o dr u g t o xicit y. S u bjects w h o are ot h er wise i n a c o m plete re missi o n, b ut b o n e marr o w n o d ules ca n be 
i de ntifie d hist ol o gicall y, s h o ul d be c o nsi d ere d t o h a v e “ n o d ular P R.” I m m u n o hist o c h e mistr y s h o ul d b e p erf or me d t o 
defi ne w h et h er t h ese n o d ules are c o m p ose d of pri maril y T cells, l y m p h o c ytes ot h er t h a n C L L cells, or C L L cells. If t he 
n o d ules are n ot c o m p ose d of C L L cells, a C R ca n b e d o c u me nte d pr o vi d e d all ot h er criteria are met.  

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b      P R L ( partial res p o nse wit h l y m p h o c yt osis): prese n ce of l y m p h o c yt osis, pl us ≥ 5 0 % re d u cti o n i n l y m p h a d e n o p at h y 
a n d/ or i n s plee n or li v er e nlar g e me nt, pl us o n e of t h e P R criteria f or platelets or h e m o gl o bi n h a v e t o be met.  
c 
S u m of t h e pr o d u cts of 6 or less l y m p h n o d es (as e v al u ate d b y C T sca ns a n d p h ysical e x a mi n ati o n i n cli nical trials, or 
b y p h ysical e x a mi n ati o n i n  g e n eral practice).  
d 
S plee n size is c o nsi d ere d n or mal if < 1 3  c m.  T h ere is n ot fir ml y esta blis h e d, i nter n ati o n al c o nse ns us of t h e size of a 
n or mal li v er; t h eref ore, li v er size s h o ul d b e e v al u ate d b y i ma gi n g a n d ma n u al p al p ati o n i n cli nical trials a n d b e rec or de d 
acc or di n g t o t h e d efi niti o n use d i n a st u d y pr ot o c ol.  
F or a d etaile d des cri pti o n of t he res p o nse p ara meters see  H alle k  2 0 1 8. 
I n p artic ular, gi v e n t he k n o w n mec ha nis m of acti o n of B C R -i n hi biti n g a ge nts i ncl u di n g 
acala br uti ni b, treat me nt -r elate d l y m p h oc yt osis is a n e x pecte d a n d fre q ue nt p he n o me n o n 
o bser ve d wit h i nitiati o n ( or re-i nitiati o n) of B T K i n hi bit ors.  A n i ncrease i n bl o o d l y m p h oc yte 
c o u nt b y itself d oes n ot u nif or ml y i n dicate a n i ncrease d t u m or b ur d e n b ut ma y reflect 
re distri b uti o n of le u ke mia cells fr o m l y m p h oi d tiss ues t o t he bl o o d.  I n s u c h cases, i ncreas e d 
l y m p h oc yt osis al o ne is n ot a si g n of treat me nt fail ure or P D. T he i n v esti gat or ma y use t heir 
cli nical j u d g me nt w he n assi g ni n g t he o verall res p o nse wit h bl o o d l y m p h oc yte c o u nt, as 
necessar y.  
8. 1. 2  
Mi ni m al Resi d u al Dis e ase 
If t he s u bject’s p h ysical e xa mi nati o n fi n di n gs, la b orat or y e v al uati o ns, a n d ra di o gra p hic 
e val uati o ns s u g gest t hat P R, C R, or C Ri has bee n ac hie ve d, a peri p h eral bl o o d a n d b o ne 
marr o w sa m ple t o e v al uate M R D b y fl o w c yt o metr y s h o ul d be d o ne bet w ee n 8- 1 2 wee ks fr o m 
t he ti me of s u p p orti ve cli nical assess me nts i ncl u di n g C T i ma gi n g of s us pecte d P R, C R, or 
C Ri.  
A peri p her al bl o o d a n d b o ne marr o w s a m ple testi n g f or mi n i mal resi d ual disease ( M R D) will 
be d o ne at ti me p oi nts s pecifie d i n t he S O A.  If M R D sa m ples are n ot ta k e n at t he E o T visit, 
t he n it ca n be dr a w n at S F U visit. 
Sa m ples f or t he M R D tests will be se nt t o t he ce ntral la b orat or y f or a n al ysis as per 
i nstr ucti o ns i n t he la b orat or y ma n ual. After F A a n d per A me n d me nt 5. 0, M R D tests are n ot 
ma n dat or y a n d will  be l o call y perf or me d per cli nical practice .  
8. 1. 3  
Cli nic al l a b or at o r y assess m e nts 
See  Ta ble  1 1 f or t he list of cli nical la b orat or y tests t o be perf or m e d a n d t o t he S o A f or t he 
ti mi n g a n d fre q ue nc y.  All pr ot oc ol-re q uire d l a b orat or y assess me nts, as d efi ne d i n t he ta ble, 
m ust be c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he S o A. 
T he i n vesti gat or s h o ul d ma ke a n ass ess me nt of t he a vaila ble res ults wit h re gar d t o cli nicall y 
rele va nt a b n or malities.  T he la b orat or y res ults s h o ul d be si g ne d a n d date d a n d retai ne d at 
ce ntre as s o urce data f or la b orat or y varia bles.  

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A d diti o nal la b orat or y sa m ples ma y be c ollecte d if cli nicall y i n dicate d at t h e discreti o n of t he 
i n vesti gat or.  T he date, ti me of c ollecti o n a n d res ults ( val ues, u nits a n d refere nce ra n g es) will 
be rec or de d o n t he a p pr o priate e C R F.  
T he cli nical c h e mistr y, pre g na nc y t est, he patitis ser ol o g y a n d ser u m i m m u n o gl o b uli n le vels 
a nal yses will be perf or m e d l ocall y at t he visits as i n dicate d i n t he S o A (see  Ta ble 1 , Ta ble  2, 
a n d Ta ble  3), t h eref ore s a m ple v ol u mes ma y var y acc or di n g t o l ocal h os pital practice.  If 
scree ni n g assess me nt cli nical c he mistr y a n d h e mat ol o g y are perf or m e d wit hi n 5 da ys pri or t o 
t he baseli ne visit (i.e., first d ose da y), t he y d o n ot nee d t o be re peat e d at t he baseli ne visit.  All 
sa m ples will be use d u p or dis p ose d of aft er a n al yses.  
Pre g na nc y tests are r e q uire d o nl y f or w o m e n wit h c hil d beari n g p ote ntial. A uri ne or ser u m 
pre g na nc y t est is acce pta ble. Pre g na nc y tests will be perf or me d at Scree ni n g, o n C yc le 1 Da y 
1, a n d at t he saf et y -f oll o w- u p visit, a n d ma y be p erf or me d m ore fre q ue ntl y if re q uire d b y l ocal 
re g ulat or y a ut h orities 
He mat ol o g y testi n g will be e val uat e d at t he ce ntral la b orat or y  a n d will i ncl u de a c o m plete 
bl o o d c o u nt ( C B C) wit h W B C differe ntial i ncl u di n g, b ut n ot li mite d t o w hite bl o o d cell c o u nt, 
he m o gl o bi n, he mat ocrit, platelet c o u nt, A N C, a n d A L C.  A n y missi n g ce ntral la b orat or y 
bl o o d sa m ples s h o ul d be re dra w n as s o o n as p ossi ble.  I n t h e e ve nt t hat t he missi n g ce ntral 
la b orat or y sa m ple is u nr ec o vera bl e, l ocal la b orat or y res ults will be c ollecte d, if a vaila ble, a n d 
e ntere d i n t he cli nical dat a base f or res p o ns e or pr o gressi o n c o nfir mati o n. After F A a n d per 
A me n d me nt 5. 0, he mat ol o g y testi n g will be perf or me d l ocall y . 
β 2 - micr o gl o b uli n: peri p heral bl o o d sa m ples will be c ollecte d a n d se nt t o t he ce ntral la b orat or y 
f or β 2-micr o gl o b uli n test.  After F A a n d p er A me n d me nt 5. 0, t he testi n g is n ot re q uire d a n d 
will be l ocall y perf or m e d per  t he discreti o n of i n vesti gat or. 
T/ B/ N K cell c o u nt (i.e., C D 3, C D 4, C D 8, C D 1 9, C D 1 6/ 5 6) will be perf or me d at t he ce ntr al 
la b orat or y. Aft er F A a n d per A me n d me nt 5. 0, t he t esti n g is n ot re q uire d a n d will be l ocall y 
perf or me d p er t he discreti o n of i n vesti gat or. 
C yt o ge netics a n d FI S H P a nel: scree ni n g peri p heral bl o o d will be se nt t o a ce ntral la b orat or y 
t o be teste d f or 1 7 p del, 1 3 q del, tris o m y 1 2, 1 1 q del b y FI S H a n d sti m ulate d kar y ot y pi n g, t he 
stat us of 1 7 p del is ma n dat or y t o be teste d b y ce ntral la b d uri n g scree ni n g p eri o d.  A bl o o d 
sa m ple f or FI S H e val u ati o n will also be dra w n at C ycle 7, a n d w he n a s u bject has diseas e 
pr o gressi o n ( wit h P D c o nfir mati o n fr o m BI C R , c yt o ge netic a n d ge n etic m olec ular pr o g n ostic 
m olec ules a n d FI S H e val uati o n nee d t o be perf or me d after si g ni n g cr oss o ver I C F), at t he E o T 
or S F U visits. If t h ese sa m ples are da m a ge d d uri n g c ollecti o n or s hi p me nt, t he y s h o ul d be 
re dra w n at t he ne xt s u bse q ue nt visit. After F A a n d per A me n d me nt 5. 0, t he testi n g is n ot 
re q uire d a n d will be l ocall y perf or me d p er t he discreti o n  of i n vesti gat or. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 7 6
 
Ge netic m olec ular pr o g n ostic m olec ules: scree ni n g peri p heral sa m ple will be se nt t o ce ntr al 
la b orat or y f or se q ue n ci n g of i m m u n o gl o b uli n hea v y-c hai n varia ble (I G H V) a n d p 5 3 
m utati o nal stat us.  A bl o o d sa m ple will als o be dra w n w he n a s u bject has disease pr o gressi o n 
(wit h  P D c o nfir mati o n fr o m BI C R, c yt o ge netic a n d ge netic m olec ular pr o g n ostic m olec ules 
a n d FI S H e val uati o n nee d t o be perf or m e d aft er si g ni n g cr oss o ver I C F), at t he E o T or S F U 
visits. After F A a n d p er A me n d me nt 5. 0, t he testi n g is n ot re q uire d a n d will b e l ocall y 
perf or me d p er t he discreti o n of i n vesti gat or. 
T a ble  1 1  
L a b or at or y V ari a bles  
Cli nic al C he mistr y a 
 
Calci u m  
Urea or bl o o d urea nitr o ge n  
C hl ori de  
Uric aci d  
Ma g nesi u m  
Creati ni ne  
P h os p hate/ P h os p h or us  
T otal bilir u bi n  
P otassi u m  
Gl uc ose  
S o di u m  
Al b u mi n  
A S T  
T otal pr otei n  
A L T  
Tri gl yceri des  
Al kali ne p h os p hatase ( A L P)  
C h olester ol  
Ga m ma gl uta m yl tra nsferase ( G G T)  
Lact ate de h y dr o ge nase ( L D H)  
He m at ol o g y b  
 
W hite bl o o d cell ( W B C) c o u nt wit h differe ntial  
Platelet c o u nt  
Re d bl o o d cell ( R B C) c o u nt  
A bs ol ute ne utr o p hil c o u nt ( A N C)  
He mat ocrit  
A bs ol ute l y m p h oc yte c o u nt ( A L C)  
He m o gl o bi n  
 
Pre g n a nc y Test (fe m ales of c hil d be ari n g p ote nti al o nl y)  
Uri ne h u ma n c h ori o nic g o na d otr o pi n ( h C G) or Ser u m 
β h C G  
 
He p atitis B a n d C Testi n g c 
 
H Bs A g  
He patitis B s urface a nti b o d y ( H Bs A b)  
A nti -H Bc  
He patitis C ( he patitis C vir us [ H C V]) a nti b o d y  
He patitis B P C R (cli nicall y i n dicate d)  
He patitis C P C R (cli nicall y i n dicate d)  
Ot her Tests  
 
T/ B/ N K Cell C o u nt b 
Ser u m i m m u n o gl o b uli n le vels  
β 2 -micr o gl o b uli n b 
 
C yt o ge netics a n d FI S H Pa nel b, d 
Ge netic m olec ular pr o g n ostic m olec ules b, e 
a       I n case a s u bject s h o ws a n A S T or A L T ≥3 × U L N t o g et h er wit h t otal bilir u bi n ≥2 × U L N please refer t o  A p pe n di x  D 
‘ Acti o ns re q uire d i n cases of i n creases i n li v er bi o c h e mistr y a n d e val u ati o n of H y’s La w,’ f or f urt h er i nstr u cti o ns. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 7 7
 
b      T hese tests will b e p erf or me d at t h e ce ntral la b orat or y.  
c       He patitis ser ol o g y testi n g m ust i n cl u d e H Bs A g, H Bs A b, a nti -H Bc a n d  h e p atitis C ( H C V) a nti b o d y.  I n a d diti o n, a n y 
s u bjects testi n g p ositi v e f or a nti-H Bc m ust h a v e q u a ntitati v e P C R testi n g f or H B V D N A d uri n g scree ni n g a n d e v er y 3 
m o nt hs  t h ereafter.  M o nit ori n g e ver y 3 m o nt hs s h o ul d c o nti n u e u ntil 1 2 m o nt hs after last d ose of st u d y dr u g(s)  f or Ar m 
A a n d Ar m C s u bjects . F or Ar m B s u bjects, m o nt hl y m o nit ori n g s h o ul d c o nti n u e u ntil 1 2 m o nt hs after last d ose of Ar m 
B treat me nts.  ( See Ta ble 1 , Ta ble  2, a n d Ta ble  3, a n d e x cl usi o n criteria # 8).  A n y s u bject wit h a risi n g viral l oa d 
(a b o ve l o wer li mit of d etecti o n) s h o ul d disc o nti n u e st u d y dr u g a n d h a v e a nti viral t h era p y i nstit ute d a n d a c o ns ultati o n 
wit h a p h ysicia n wit h e x p ertise i n ma n a gi n g h e p atitis B.  Si n ce I VI G m a y ca use false p ositi v e h e p atitis ser ol o g y, 
m o nt hl y P C R testi n g is n ot re q uire d i n s u bjects w h o are c urre ntl y recei vi n g or recei v e d pr o p h ylactic I VI G wit hi n 3 
m o nt hs b ef ore st u d y e nr oll me nt a n d h a v e a d o c u me nte d n e g ati v e a nti -H Bc test b ef ore t h e i nitiati o n of I VI G t h era p y.  
P C R testi n g s h o ul d b e p erf or me d w h e n cli nicall y i n dicate d (e. g., i n t h e setti n g of risi n g tra nsa mi n ase le v els).  Refer 
t o ,Ta ble 1  , Ta ble  2a n d  Ta ble  3 re g ar di n g m o nit ori n g of s u bjects w h o are a nti-H Bc p ositi v e or w h o h a v e a k n o w n 
hist or y of H B V.  S u bjects wit h a k n o w n hist or y of h e p atitis  C or w h o are h e p atitis  C-a nti b o d y p ositi v e s h o ul d h a ve 
q ua ntitati v e P C R testi n g f or H C V R N A p erf or me d d uri n g scree ni n g.  N o f urt h er testi n g is n ecessar y if t h e P C R res ults 
are ne g ati v e at scree ni n g. 
d      C yt o ge n etics a n d FI S H Pa n el i n cl u d e 1 7 p d el, 1 3 q d el, tris o m y 1 2, 1 1 q d el b y FI S H a n d sti m ulate d k ar y ot y pi n g.  
e 
Ge netic m olec ular pr o g n ostic m olec ules p a n el i n cl u d e, b ut is n ot li mite d t o, se q u e n ci n g of p 5 3 m utati o ns, 
i m m u n o gl o b uli n h ea v y-c h ai n v aria ble (I G H V) m utati o n al stat us.  
 
8. 1. 4  
B- S y m pt o ms 
B-s y m pt o ms are c o nstit uti o nal s y m pt o ms defi ne d as a n y o ne or m ore of t he f oll o wi n g disease 
relate d s y m pt oms or si g ns: 
•  
U ni nte nti o nal wei g ht l oss of 1 0 % or m ore wit hi n t he pre vi o us 6 m o nt hs 
•  
Si g nifica nt fati g ue (i.e., E C O G perf or ma nce stat us 2 or w orse; i na bilit y t o w or k or 
perf or m us ual acti vities)  
•  
Fe vers > 1 0 0. 5° F or 3 8. 0° C f or ≥2  wee ks wit h o ut ot her e vi de nce of i nfecti o n 
•  
Ni g ht s weats f or > 1 m o nt h wit h o ut e vi de nce of i nfecti o n 
 
B-s y m pt o ms is part of t u m or res p o nse ass ess me nt f or C L L s u bjects per  Halle k 2 0 1 8 . 
B-s y m pt o ms s h o ul d n ot be re p ort e d as A Es. W orse ni n g is ge nerall y c o nsi dere d a s y m pt o m 
( b ut n ot a n o bjecti ve criteri o n) of pr o gressi o n. 
8. 1. 5  
 
 
 
 
 
 
8. 1. 5. 1  
 
 
 
 
C CI
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 7 8
 
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 7 9
S afet y assess me nts 
Pla n ne d ti me p oi nts f or all safet y assess me nts are pr o vi de d i n t he S o A. 
8. 2. 1  
Cli nic al s afet y l a b or at or y assess m e nts 
Cli nical safet y la b orat or y assess me nt s  are i ncl u de d i n Ta ble  1 1 a n d s pecifie d i n t he S o A f or 
t he ti mi n g a n d fre q ue n c y.  
F or i nf or m ati o n o n h o w A Es base d o n la b orat or y tests s h o ul d be rec or d e d a n d re p ort e d, see 
Secti o n 8. 3. 5.
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 8 0
 
A d diti o nal safet y sa m ples ma y be c ollecte d if cli nicall y i n dicate d at t he dis creti o n of t he 
i n vesti gat or.  T he date, ti me of c ollecti o n a n d res ults ( val ues, u nits a n d refere nce ra n g es) will 
be r ec or de d o n t he a p pr o priate C R F. 
8. 2. 2  
P h ysic al e x a mi n ati o n 
A p h ysical e xa mi nati o n will be perf or me d a n d i n cl u de a n ass ess me nt of t he f oll o wi n g: hei g ht 
(scree ni n g o nl y) a n d w ei g ht, a n d e xa mi nati o n of t he s ki n, e yes, ears, n ose, t hr oat, l u n gs, heart, 
a b d o me n, e xtre mities, m usc ul os keletal, ner v o us, l y m p hatic s yste m, a n d ge neral a p p eara nce.  
T he ner v o us s yste m e x a mi nati o n will i ncl u de atte nti o n t o ne ur ol o gic si g ns a n d s y m pt o ms of 
P M L. T he l y m p hatic s yste m e xa mi nati o n will i ncl u de e xa mi nati o n of pal p a ble l y m p h n o des 
a n d s plee n a n d li ver bel o w t he c ostal mar gi n o n t h e res pecti ve si de.  O nl y p h ysicia ns s h o ul d 
perf or m t he l y m p hatic s yste m e xa mi nati o n.  As m uc h as p ossi ble, t he sa me pers o n s h o ul d 
perf or m all t he l y m p hatic e xa ms f or a gi v e n s u bject. C ha n ges fr o m baseli ne a b n or malities 
s h o ul d be rec or de d i n me dical n ote. Ne w or w ors e ne d cli nicall y si g nifica nt a b n or malities 
s h o ul d be rec or de d as A Es o n t he A d verse E ve nt e C R F. 
P h ysical e xa mi nati o n will be perf or m e d at ti meli nes as s pecifi e d i n t he S o A, i n vesti gat ors 
s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us seri o us ill nesses, ne w or 
w orse ni n g a b n or m alities ma y q ualif y as a d v erse e ve nts, see Secti o n  8. 3. 5  f or details. 
8. 2. 3  
Vit al si g ns 
B o d y te m perat ure, p ulse rate, r es pirat or y rate a n d bl o o d press ure will be assesse d after t he 
s u bject has reste d i n t he sitti n g p ositi o n. 
Bl o o d press ure a n d p ulse meas ure me nts will be assesse d wit h a c o m pletel y a ut o mate d de vice.  
Ma n ual tec h ni q ues will b e use d o nl y if a n a ut o mat e d de vice is n ot a v aila ble. 
C ha n ges fr o m bas eli ne a b n or malities s h o ul d be rec or de d i n s u bject n otes. Ne w or w orse ne d 
cli nicall y si g nifica nt a b n or malities s h o ul d be rec or de d as A Es o n t he A d verse E ve nt e C R F. 
 
8. 2. 4  
Electr oc ar di o gr a ms 
Si n gle 1 2-lea d E C G will be o btai ne d as o utli ne d i n t he S o A (see Secti o n  1. 1 ) usi n g a n E C G 
mac hi ne t hat a ut o maticall y calc ulates t he h eart rat e a n d meas ures P R, Q R S, Q T, a n d Q Tc 
i nter vals. St u d y -relate d E C G s h o ul d be d o ne i n s u pi ne p ositi o n after t he s u bject has bee n 
resti n g f or at least 1 0 mi n utes.  A d diti o nal E C G testi n g c o ul d be sc he d ule d as cli nicall y 
i n dicate d, a sta n dar dize d E C G mac hi ne s h o ul d be use d, a n d t he s u bject s h o ul d be e xa mi ne d 
usi n g t he sa me mac hi ne t hr o u g h o ut t he st u d y if p ossi ble. 
After pa p er E C Gs ha v e b ee n rec or d e d, t he i n vesti gat or or desi g nate d p h ysi cia n will re vie w 
eac h of t h e E C Gs a n d ma y refer t o a l ocal car di ol o gist if a p p r o priate.  A p a per c o p y s h o ul d be 
file d i n t he patie nt’s me dical rec or ds. 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 8 1
If a n a b n or mal E C G fi n di n g at scree ni n g or b aseli ne is c o nsi dere d t o be cli nicall y si g nifica nt 
b y t he i n vesti gat or, it s h o ul d be re p orte d as a c o n c urre nt c o n diti o n.  F or all E C Gs det ails of 
r h yt h m, E C G i nter vals a n d a n o verall e v al uati o n will be rec or d e d. 
8. 2. 5 
E C O G pe rf or m a nce st at us 
E C O G perf or ma nce stat us will be assesse d at scree ni n g, pri or t o t he first d ose of st u d y 
treat me nt a n d per S o A t hereafter acc or di n g t o E C O G criteri a as s h o w n in Ta ble  1 2 . 
T a ble 1 2
E C O G Perf or m a nce St at us Sc ale
Gr a de
E C O G 
0 
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n
1 
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure, e. g., li g ht h o use w or k, office w or k
2 
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut a n y w or k acti vities.   U p a n d 
a b o ut m ore t ha n 5 0 % of wa ki n g h o urs
3 
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs
4 
C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -care.  T otall y c o nfi ne d t o be d or c hair
5 
Dea d
C ollecti o n of a d verse e ve nts
T he pri nci pal i n vesti gat or is res p o nsi ble f or e ns uri n g t hat all staff i n v ol ve d i n t he st u d y are 
fa miliar wit h t he c o nte nt of t his secti o n
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x B.
A E will be re p orte d b y t h e s u bject ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or t he 
s u bject's le gall y a ut h orize d re pr ese ntati ve).  
T he i n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, rec or di n g, a n d 
re p orti n g e ve nts t hat meet t he defi niti o n of a n A E.  
8. 3. 1 
Ti m e peri o d a n d fre q ue nc y f or c ollecti n g A E a n d S A E i nf or m ati o n  
A Es a n d S A Es will be c ollecte d b y t he site fr o m t he ti me of si g nat ure of i nf or me d c o nse nt 
f or m t hr o u g h o ut t he treat me nt peri o d a n d i ncl u di n g t he f oll o w- u p peri o d. After t he si g ni n g of 
t he I C F a n d pri or t o t he first d ose of st u d y treat me nt all S A Es, re gar dless of ca usalit y, m ust be 
re p orte d t o t he s p o ns or. C ollecti o n a n d re p orti n g of A Es a n d S A Es aft er t h e fi nal D C O is 
descri be d i n Secti o n 8. 3. 1 1.
All A Es a n d S A Es will be re p ort e d fr o m first d ose of st u d y treat me nt u ntil 3 0 da ys after t h e 
last d ose of st u d y treat me nt or t he start of ne w a ntica ncer t hera p y ( w hic h e v er c o mes first). 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 8 2
 
After t his peri o d, i n vesti gat ors s h o ul d re p ort S A Es t hat are belie v e d t o be relate d t o t he st u d y 
treat me nt or a n y A Es of c o ncer n ( dee me d b y t he s p o ns or or i n vesti gat or), re gar dless of 
causalit y t o t he st u d y treat me nt as rele va nt.  
All S A Es t hat occ ur d uri n g t he re p orti n g peri o d s h o ul d be f oll o we d t o res ol uti o n or u ntil t he 
i n vesti gat or assesses t he s u bject as sta ble, or u ntil t he s u bject is l ost t o f oll o w u p or wit h dra ws 
c o nse nt. Res ol uti o n/sta ble mea ns t he s u bject has ret ur ne d t o baseli ne stat e of healt h or t he 
i n vesti gat or d oes n ot e x p ect a n y f urt her i m pr o ve m e nt or w orse ni n g of t h e e ve nt.  
T a ble  1 3  
G ui d a nce f or R e p orti n g A d verse E ve nts  
 
A Es  
S A Es  
A E SIs  
A Es of c o ncer n  
Si g ni n g of I C F – 
First d ose of st u d y 
treat me nt  
 
N ot re p orte d 
(rec or de d as 
me dical hist or y)  
 
Relate d (t o st u d y 
pr oce d ure)  
 
U nrelate d  
N ot re p orte d 
(rec or de d as 
me dical hist or y)  
 
N ot re p orte d 
(rec or de d as 
me dical hist or y)  
 
First d ose of st u d y 
treat me nt – 3 0 da ys 
after last d ose of 
st u d y treat me nt  
Relate d  
 
U nrelate d  
Relate d  
 
U nrelate d  
Relate d  
 
U nrelate d  
Relate d  
 
U nrelate d  
P ost -3 0 da ys after 
last d ose of st u d y 
treat me nt  
N ot re p orte d  
Relate d  
N ot re p orte d  
 
Relate d  
 
U nrelate d  
 
All S A Es/ A E SIs will be rec o r de d a n d re p orte d t o t he s p o ns or or desi g nee wit hi n 2 4 
h o urs.  T he i n vesti gat or will s u b mit a n y u p date d S A E/ A E SI dat a t o t he s p o ns or wit hi n 2 4 
h o urs of it bei n g a vaila bl e. 
I n v esti gat ors ar e n ot o bli gate d t o acti vel y see k A E or S A E data i n f or mer st u d y s u bjects. 
H o we ver, if at a n y ti me after a s u bject’s last visit t he  i n vesti gat or lear ns of a n y S A E, 
i ncl u di n g a deat h, t hat is c o nsi dere d t o be reas o n a bl y relate d t o t he st u d y treat me nt or st u d y 
partici pati o n, t he i n vesti gat or ma y n otif y t he s p o ns or. 
 
8. 3. 2  
F oll o w- u p of A Es a n d S A Es 
A n y A Es t hat ar e u nres ol ve d at t he s u bject’s last A E assess me nt visit i n t he st u d y are f oll o w e d 
u p b y t he i n vesti gat or f or as l o n g as me dicall y i n dicate d, b ut wit h o ut f urt her rec or di n g i n t he 
e C R F.  T he s p o ns or r etai ns t he ri g ht t o re q uest a d diti o nal i nf or mati o n f or a n y s u bject wit h 
o n g oi n g A E(s)/ S A E(s) at t he e n d of t he st u d y, if j u d ge d necessar y. 

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A d verse e v e nt v ari a bles 
T he f oll o wi n g varia bles will be c ollecte d f or eac h A E:  
•  
A E ( ver b ati m)  
•  
T he date w h e n t he A E st arte d a n d st o p pe d 
•  
C T C A E gra de/ ma x C T C A E gra de/ c ha n ges i n C T C A E gra de 
•  
W het her t he A E is ser i o us or n ot (A p pe n di x B ). 
•  
I n v esti gat or ca us alit y rati n g a gai nst t he I P(s) ( y es or n o) 
•  
Acti o n ta ke n wit h re g ar d t o I P(s) 
•  
A E ca use d p artici pa nt’s wit h dra wal fr o m st u d y ( yes or n o). 
•  
A d mi nistrati o n of treat me nt f or t he A E.  
•  
O utc o me 
 
I n a d diti o n, t he f oll o wi n g varia bles will be c ollecte d f or S A Es: 
•  
Date A E met criteria f or S A E  
•  
Date i n vesti gat or beca me a war e of S A E  
•  
Seri o us ness criteria  
•  
Date of h os pitalisati o n  
•  
Date of disc h ar ge  
•  
Pr o ba ble ca us e of deat h  
•  
Date of deat h  
•  
A ut o ps y perf or me d 
•  
Ca usalit y assess me nt i n relati o n t o st u d y pr oce d ure(s) 
•  
Ca usalit y assess me nt t o ot her me dicati o n  
•  
Descri pti o n of t he S A E 
T he gra di n g scales f o u n d i n t he Nati o nal Ca ncer I nstit ute C T C A E will be utilise d f or all 
e ve nts wit h a n assi g ne d C T C A E gra di n g. F or t h ose e ve nts wit h o ut assi g ne d C T C A E gra des, 
t he rec o m me n d ati o n i n t he C T C A E criteria t h at c o n verts mil d, m o derate, a n d se vere e ve nts 
i nt o C T C A E gra des s h o ul d be use d. A c o p y of t h e C T C A E ca n be d o w nl oa de d fr o m t he 
Ca ncer T h era p y E v al uati o n Pr o gra m we bsite ( htt p://cte p.ca ncer. g o v). 
 
8. 3. 3  
C a us alit y c ollecti o n 
T he i n vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n I n v esti gati o nal Pr o d uct a n d eac h 
A d verse E v e nt, a n d a ns w er ‘ yes’  or ‘ n o’ t o t he q uesti o n: ‘ D o y o u c o nsi der t h at t here is a 
re as o n a ble p ossi bility t h at t he eve nt m a y h ave b ee n c a use d by t h e i nvesti g ati o n al pr o d uct ?’ 
F or S A Es, ca usal rel ati o ns hi p s h o ul d als o be assesse d f or ot her m e dicati o n a n d st u d y 
pr oce d ur es.  N ote t hat f or S A Es t hat c o ul d be ass ociate d wit h a n y st u d y pr oce d ure t h e ca us al 
relati o ns hi p is i m plie d as ‘ yes.’ 

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A g ui de t o t he i nter pret ati o n of t he ca usalit y q uesti o n is f o u n d i n  A p pe n di x B .  
8. 3. 4  
A Es b ase d o n si g ns a n d s y m pt o ms 
All A Es s p o nta ne o usl y r e p orte d b y a s u bject or care pr o vi d er,  or re p orte d i n res p o nse t o t he 
o pe n q uesti o n fr o m t he st u d y site staff: ‘ H ave y o u h a d a ny he alt h pr o ble ms si nce t he previ o us 
visit/y o u were l ast aske d ?’  or re v eale d b y o bs er vati o n, will be c ollecte d a n d rec or d e d i n t he 
e C R F.  W he n c ollecti n g A Es, t he rec or di n g of dia g n oses is preferre d ( w he n p ossi ble) o ver 
rec or di n g a list of si g ns a n d s y m pt o ms.  H o we ver, if a dia g n osis is k n o w n a n d t here are ot her 
si g ns or s y m pt o ms t hat are n ot ge nerall y part of t h e dia g n osis, t he dia g n osis a n d eac h si g n or 
s y m pt o m will be rec or de d se parat el y. 
8. 3. 5  
A Es b ase d o n e x a mi n ati o ns a n d tests 
T he res ults fr o m t he Cli nical St u d y Pr ot oc ol- ma n date d la b orat or y tests, vital si g ns p h ysical 
e xa mi nati o ns, a n d E C Gs will be s u m marise d i n t he cli nical st u d y re p ort ( C S R).   
Deteri or ati o n as c o m par e d t o baseli ne i n pr ot oc ol- ma n date d la b orat or y val u es, vital si g ns, 
E C G, or ot her saf et y assess me nt s h o ul d t heref ore o nl y be re p orte d as A Es if t he y f ulfil a n y of 
t he S A E criteria, are t h e r eas o n f or disc o nti n uati o n of treat me nt wit h t he I P or are c o nsi dere d 
t o be cli nicall y rele v a nt as j u d ge d b y t he i n vesti gat or ( w hic h ma y i ncl u d e b ut n ot li mite d t o 
c o nsi derati o n as t o w het h er treat me nt or n o n- pla n n e d visits were re q uire d or ot her acti o n was 
ta ke n wit h t he st u d y treat me nt, e. g., d ose a dj ust me nt or dr u g i nterr u pti o n). 
If deteri orati o n i n a la b or at or y val ue/ vital si g n/ E C G or ot her safet y assess m e nt is ass ociate d 
wit h cli nical si g ns a n d s y m pt o ms, t he si g n or s y m pt o m will be re p orte d as a n A E a n d t he 
ass ociate d la b or at or y r es ult/ vital si g n/ E C G or ot her safet y asse ss me nt will be c o nsi dere d as 
a d diti o nal i nf or mati o n.  W here v er p ossi ble, t he re p orti n g i n vesti gat or s h o ul d use cli nical 
rat her t ha n l a b orat or y t er ms (e. g., ‘a nae mia’ v ers us ‘l o w hae m o gl o bi n val u e’).  I n t he a bse n ce 
of cli nical si g ns or s y m pt o ms, cli nicall y  rele va nt d eteri orati o ns i n n o n-ma n date d para meters 
s h o ul d be re p orte d as A E(s). 
Deteri or ati o n of a la b or at or y val ue t hat is u ne q ui v ocall y d ue t o disease pr o gressi o n s h o ul d n ot 
be re p ort e d as a n A E/ S A E.  
A n y ne w or a g gra v ate d cli nicall y rele va nt, a b n or mal me dical fi n di n g at a p h ysical 
e xa mi nati o n as c o m pare d wit h t he baseli ne assess me nt will be re p orte d as a n A E u nless 
u ne q ui v ocall y relat e d t o t he disease u n d er st u d y.  
8. 3. 6  
H y’s l a w 
Cases w her e a s u bject s h o ws ele vati o n i n li ver bi o c he mistr y ma y re q uire f urt her e v al uati o n, 
a n d occ urre n ces of A S T or A L T ≥3 × U L N, t o get h er wit h t otal bilir u bi n ≥2 × U L N, ma y n ee d t o 

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be re p ort e d as S A Es.  Please refer t o  A p p e n di x D  f or f urt her i nstr u cti o n o n cases of i ncreases 
i n li ver bi oc he mistr y a n d e val uati o n of H y’s L a w. 
8. 3. 7  
Dise ase pr o gressi o n  
Disease pr o gressi o n ca n be c o nsi der e d as a w orse ni n g of a s u bject’s c o n diti o n attri b uta ble t o 
t he disease f or w hic h t he I P is bei n g st u die d.  It m a y be a n i ncreas e i n t he s e verit y of t he 
disease u n der st u d y a n d/ or i ncreases i n t he s y m pt o ms of t he disease.  T he de vel o p me nt of 
ne w, or pr o gressi o n of e xisti n g metastasis t o t he pri mar y ca ncer u n d er st u d y s h o ul d be 
c o nsi dere d as disease pr o gressi o n a n d n ot a n A E.  E ve nts t h at are u ne q ui v oc all y d ue t o 
dise ase pr o gressi o n s h o ul d n ot be re p orte d as A Es d uri n g t he st u d y.  
H os pitalizati o n d ue s olel y t o t he pr o gressi o n of u n derl yi n g mali g na nc y s h o ul d N O T be 
re p orte d as a n S A E.  Cli nical s y m pt o ms of pr o gressi o n ma y be re p orte d as A Es if t he 
s y m pt o ms ca n n ot be deter mi ne d as e xcl usi vel y d u e t o t he pr o gressi o n of t h e u n derl yi n g 
mali g na nc y, or if t he y d o n ot fit t he e x pecte d p atter n of pr o gressi o n f or t he disease u n der 
st u d y. 
S y m pt o matic deteri orati o n ma y occ ur i n s o me s u bjects.  S y m pt o matic deteri orati o n is w he n 
pr o gressi o n is e vi de nt i n t he s u bject’s cli nical s y m pt o ms a n d t he i n vesti gat or ma y elect n ot t o 
perf or m f urt her disease assess me nts.  If t here is a n y u ncertai nt y a b o ut a n A E bei n g d ue o nl y t o 
t he disease u n der st u d y, it s h o ul d be re p orte d as a n A E or S A E. 
8. 3. 8  
Sec o n d p ri m ar y m ali g n a ncies  
 A Es f or mali g na nt t u m ors re p orte d d uri n g a st u d y s h o ul d ge nerall y be assesse d as S A Es.  If 
n o ot her seri o us ness criteria a p pl y, t he “I m p orta nt Me dical E ve nt” criteri o n s h o ul d be 
use d.  I n certai n sit uati o ns, h o we ver, me di cal j u d g me nt o n a n i n di vi d ual e ve nt basis s h o ul d be 
a p plie d t o clarif y t hat t he mali g na nt t u m or e ve nt s h o ul d be assesse d a n d re p orte d as a 
n o nseri o us A E.  F or e xa m ple, if t he t u m or is i ncl u de d as me dical hist or y a n d pr o gressi o n 
occ urs d uri n g t he st u d y b ut t he pr o gressi o n d oes n ot c ha n ge treat me nt a n d/ or pr o g n osis of t he 
mali g na nt t u m or, t he A E ma y n ot f ulfil t he attri b utes f or bei n g ass esse d as s eri o us, alt h o u g h 
re p orti n g of t he pr o gressi o n of t he mali g na nt t u m or as a n A E is vali d a n d s h o ul d occ ur.  Als o, 
s o me t y pes of mali g na nt t u m ors, w hic h d o n ot s prea d re m otel y after a r o uti ne treat me nt t hat 
d oes n ot re q uire h os pitali zati o n, ma y be ass esse d as n o nseri o us; e xa m ples i n a d ults i ncl u de 
Sta ge 1 basal cell carci n o ma a n d Sta ge 1 A 1 cer vical ca ncer re m o ve d via c o ne bi o ps y.  
T he a b o ve i nstr ucti o n a p plies o nl y w he n t he mali g na nt t u m or e ve nt i n q uesti o n is a ne w 
mali g na nt t u m or (i.e., it is n ot t he t u m or f or w hic h e ntr y i nt o t he st u d y is a criteri o n a n d t hat is 
bei n g treate d b y t he i n v esti gati o nal pr o d uct u n der st u d y a n d is n ot t he de vel o p me nt of ne w or 
pr o gressi o n of e xisti n g metastasis t o t he t u m or u n der st u d y).  Mali g na nt t u m ors t hat — as part 
of n or mal, if rare, pr o gressi o n — u n der g o tra nsf or mati o n (e. g., Ric hter's tra nsf or mati o n of B-

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cell c hr o nic l y m p h oc ytic le u ke mia i nt o diff use lar ge B-cell l y m p h o ma) s h o ul d n ot be 
c o nsi dere d a ne w mali g n a nt t u m or. 
8. 3. 9  
De at hs 
All deat hs t hat occ ur d uri n g t he st u d y, or wit hi n t he f oll o w- u p peri o d after t h e a d mi nistrati o n 
of t he last d ose of I P, m ust be re p orte d as f oll o ws: 
•  
Deat h, w hic h is u ne q ui v o call y d ue t o disease pr o gressi o n, s h o ul d be c o m m u nicate d t o t he 
st u d y m o nit or at t he ne xt m o nit ori n g visit a n d s h o ul d be d oc u me nte d i n t he e C R F 
m o d ule, b ut s h o ul d n ot be re p ort e d as a S A E d uri n g t he st u d y. 
•  
W here d eat h is n ot d ue ( or n ot clearl y d u e) t o disease pr o gressi o n of t he disease u n der 
st u d y, t he A E ca usi n g t he deat h s h o ul d be re p orte d t o t he st u d y m o nit or as a n S A E wit hi n 
2 4 h o urs.  It s h o ul d als o be d oc u me nte d i n t he State me nt of Deat h p a ge i n t he e C R F. T he 
re p ort s h o ul d c o ntai n a c o m me nt re gar di n g t he c o-i n v ol ve me nt of pr o gressi o n of disease, 
if a p pr o priate, a n d s h o ul d assi g n t he mai n a n d c o ntri b ut or y ca uses of d eat h.  
   • Deat h wit h a n u n k n o w n ca use s h o ul d al w a ys be re p ort e d as a n S A E a n d d oc u me nte d 
i n t he State me nt of Deat h pa ge i n t he e C R F, b ut e v er y eff ort s h o ul d be ma d e t o deter mi ne 
a ca use of deat h.  A p ost- m orte m ma y be hel pf ul i n t he assess me nt of t he ca use of deat h 
a n d, if perf or me d, a c o p y of t he p ost- m orte m res ults ( wit h tra nslati o n of i m p orta nt parts 
i nt o E n glis h) s h o ul d be re p orte d i n a n e x p e dite d fas hi o n t o a s p o ns or re prese ntati ve 
wit hi n t he us ual ti mefra mes.  
Deat hs occ urri n g after t h e pr ot oc ol- defi ne d f oll o w- u p peri o d aft er t he a d mi nistrati o n of t he 
last d ose of st u d y i nter ve nti o n s h o ul d be d oc u me nte d i n t he State me nt of D eat h pa ge. If t he 
deat h occ urre d as a r es ult of a n e ve nt t hat starte d after t he defi ne d f oll o w- u p peri o d a n d t he 
e ve nt is c o nsi dere d t o b e d ue t o a late- o ns et t o xicit y t o  st u d y i nter ve nti o n, t he n it s h o ul d als o 
be re p ort e d as a n S A E.  
8. 3. 1 0  
A d verse E ve nt of S pe ci al I nterest ( A E SI) 
A E SIs are e ve nts of sci e ntific a n d me dical i nterest s pecific t o t he f urt h er u n dersta n di n g of t he 
i n vesti gati o nal pr o d uct safet y pr ofile a n d re q uire cl ose m o nit ori n g a n d ra pi d c o m m u nicati o n 
b y t he i n vesti gat or t o t he s p o ns or.   
T he f oll o wi n g e ve nts are A E SIs f or s u bjects recei vi n g acala br uti ni b treat me nt ar m a n d m ust 
be re p ort e d t o t he s p o ns ors e x pe diti o usl y, irres pecti ve of re g ulat or y s eri o us ness criteri a or 
ca usalit y:  
• 
Ve ntric ular arr h yt h mias ( e. g., ve ntric ular e xtras yst oles, ve ntric ular tac h ycar dia, ve ntric ular 
arr h yt h mia, ve ntric ul ar fi brillati o n, etc.) 

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8. 3. 1 1 
S afet y D at a t o be C oll ecte d F oll o wi n g t he Fi n al D at a C ut off of t he 
St u d y
F or partici pa nts c o nti n ui n g t o recei ve acala br uti ni b after t he fi nal D C O, A Es a n d S A Es will be 
c ollecte d, b ut o nl y S A Es will be re p orte d. I n a d diti o n, it is rec o m me n de d t h at i n vesti gat ors 
m o nit or t he partici pa nt’s safet y la b orat or y res ults peri o dicall y d uri n g treat me nt wit h 
acala br ut i ni b i n or der t o ma na ge A Es, c o nsiste nt wit h t he d ose m o dificati o n g ui deli nes f or 
ma na ge me nt of st u d y i nt er ve nti o n- relate d t o xicities (see Secti o n 6. 6). All data after t he fi nal 
D C O a n d data b ase cl os ur e will be rec or de d i n t he partici pa nt n otes b ut, wit h t he e xce pti o n of 
S A Es, will n ot ot her wise be re p ort e d f or t he p ur p oses of t his st u d y. 
All S A Es t hat occ ur i n partici pa nts still recei vi n g acala br uti ni b after t he fi nal D C O m ust be 
re p orte d as detaile d i n Secti o n 8. 4. 1.
S afet y re p orti n g a n d me dic al m a n a ge me n t 
8. 4. 1  
Re p orti n g of S A Es  
All S A Es ha ve t o be re p orte d, w het her or n ot c o nsi dere d ca usall y relat e d t o t he I P or t o t he 
st u d y pr oce d ur e(s).  All S A Es will be rec or d e d i n t he e C R F. 
If a n y S A Es occ ur i n t he c o urse of t he st u d y, t he n i n vesti gat ors or ot her site pers o n nel s h o ul d 
i nf or m t he a p pr o pri ate s p o ns or re prese ntati ves wit hi n 1 da y, i.e., i m me diatel y b ut n o l ater 
t h a n 2 4 h o urs  of w he n he or s he bec o mes a ware of it. 
T he desi g nate d s p o ns or r e prese nt ati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all t he 
necessar y i nf or mati o n is pr o vi de d t o t he s p o ns or Patie nt Safet y data e ntr y site wit hi n 
1 c ale n d ar d a y of i nitial recei pt f or fat al a n d life -t hreate ni n g e v e nts a n d wit h i n 5 c ale n d ar
d a ys of i nitial recei pt f or all ot her S A Es.
F or f atal or life -t hreate ni n g A Es w here i m p orta nt or rele v a nt i nf or mati o n is missi n g, acti ve 
f oll o w- u p is u n derta ke n i m me diatel y.  I n v esti gat ors or ot her site pers o n nel i nf or m s p o ns or 
re pres e ntati ves of a n y f oll o w- u p i nf or mati o n o n a pre vi o usl y re p orte d S A E wit hi n 1 cale n dar 
da y, i.e., i m me diatel y b ut n o l ater t h a n 2 4 h o urs of w he n he or s he bec o m es a ware of t he 
i nf or mati o n. 
O nce t he i n vesti gat ors or ot her site pers o n nel i n di cate a n A E is seri o us i n t he E D C s yste m, a n 
a ut o mate d e mail alert is se nt t o t he desi g nate d s p o ns or re prese ntati ve.
If t he E D C s yste m is n ot a vaila ble, t he n t he i n vesti gat or or ot her st u d y site staff re p orts a n 
S A E t o t he a p pr o priate s p o ns or re prese ntati ve b y s u b mitti n g a pa per S A E re p ort as bac k - u p. 
F or f urt her g ui da n ce o n t he defi niti o n of a S A E, s ee A p pe n di x B.    

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8. 4. 2  
Pre g n a nc y 
All pre g na ncies a n d o utc o mes of pre g n a nc y wit h c o nce pti o n dates f o ll o wi n g t he first date of 
st u d y i nter ve nti o n, i ncl u di n g pre g na nc y i n t he p art ner of male p artici pa nts, s h o ul d be re p orte d 
t o t he s p o ns or. 
If a pr e g na nc y is r e p orte d, t he i n vesti gat or s h o ul d i nf or m t he s p o ns or wit hi n 2 4 h o urs of 
lear ni n g of t he pr e g na n c y. 
A b n or mal pre g n a nc y o ut c o mes (e. g., s p o nta n e o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g n a nc y) are c o nsi dere d S A Es.  
8. 4. 2. 1  
M ater n al e x p os ure  
If a s u bject b ec o mes pr e g na nt d uri n g t he c o urse of t he st u d y, t he I P s h o ul d be disc o nti n ue d 
i m me diatel y. 
Pre g na nc y itself is n ot re gar de d as a n A E u nless t here is a s us pici o n t hat t h e I P u n der st u d y 
ma y ha ve i nterfer e d wit h t he eff ecti ve ness of a c o ntrace pti ve me di cati o n.  C o n ge nital 
a n o malies/ birt h defects a n d s p o nta ne o us miscarria ges s h o ul d be re p ort e d a n d ha n dle d as 
S A Es.  Electi ve a b orti o ns wit h o ut c o m plicati o ns s h o ul d n ot be ha n dle d as A Es.  T he o utc o me 
of all pre g na n cies (s p o nt a ne o us miscarria ge, electi ve ter mi nati o n, ect o pic pre g na nc y, n or mal 
birt h, or c o n ge nital a n o m al y) s h o ul d be f oll o we d u p a n d d oc u me nte d e ve n if t he s u bject was 
disc o nti n ue d fr o m t he st u d y. 
If a n y pr e g na nc y occ urs i n a s u bject d uri n g e x p os ure t o i n vesti gati o nal pr o d uct  a n d u ntil 
2 da ys after t h e last d ose of acal a br uti ni b or 1 2 m o nt hs after t he last d ose of rit u x i ma b or 
c hl ora m b ucil, w hic he v er is l o n ger, t he n t he i n vesti gat or or ot her site p ers o n nel i nf or ms t he 
a p pr o priate s p o ns or re prese ntati ves wit hi n 1 da y, i.e., i m me diatel y b ut n o l ater t h a n 2 4 h o urs 
of w he n he or s he bec o m es a ware of it. 
T he desi g nate d s p o ns o r r e prese nt ati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all rele v a nt 
i nf or mati o n is pr o vi de d t o t he s p o ns or Patie nt Safet y data e ntr y site wit hi n 1 or 5  cale n d ar 
da ys f or S A Es (see Secti o n  8. 4. 1 ), a n d wit hi n 3 0 da ys f or all ot her pre g na ncies. 
T he sa me ti meli nes a p pl y w he n o utc o me i nf or m ati o n is a vaila ble. 
T he e C R F - P R E G R E P m o d ule is use d t o re p ort a pre g na nc y; t he e C R F-P R E G O U T m o d ule is 
use d t o re p ort t he o utc o m e of a pr e g na n c y. 
8. 4. 2. 2  
P ater n al e x p os ure  
N o n -sterilise d male s u bjects w h o i nte n d t o be se x u all y acti ve wit h a fe male part ner of 
c hil d beari n g p ote ntial s h o ul d refrai n fr o m fat h eri n g a c hil d or s per m d o nati o n f or t he d urati o n 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 8 9
 
of t he st u d y (fr o m t he ti me of scree nin g) a n d f or 9 0 da ys after t h e last d ose of rit u xi ma b or 
c hl ora m b ucil, w hic he v er is later.  
Pre g na nc y of t h e partici p a nt’s part ner is n ot c o nsi dere d t o be a n A E. H o w e ver, t he o utc o me of 
all pre g na nci es (s p o nta ne o us miscarria ge, electi ve ter mi nati o n, ect o pic pre g na nc y, n or mal 
birt h, or c o n ge nital a n o m al y) occ urri n g fr o m t he d ate of t he first d ose of st u d y i nter ve nti o n 
u ntil  2 da ys after t he last d ose of acala br uti ni b or 9 0 da ys after t h e last d ose of rit u xi ma b or 
c hl ora m b ucil, w hic he v er is l o n ger , s h o ul d be f oll o we d u p a n d d oc u m e nte d i n t he me dical 
rec or d a n d pr o vi de d t o t h e s p o ns or Patie nt Safet y data e ntr y site. C o nse nt fr o m t he part ner 
m ust be o btai ne d bef or e t he i nf or mati o n is c ollecte d a n d re p ort e d t o Astra Z e neca. 
W here a r e p ort of pr e g na nc y is recei ve d, pri or t o o btai ni n g i nf or mati o n a b o ut t he pre g na nc y, 
t he i n vesti gat or m ust o btai n t he c o nse nt of t he p artici pa nt’s part ner. T h e l o cal st u d y tea m 
s h o ul d a d o pt t he Master Pre g na nt Part ner F or m i n li ne wit h l ocal pr oce d ures/re q uire me nts a n d 
s u b mit it t o t he rele va nt Re g ulat or y A ut h orit y/I R Bs/I E Cs pri or t o use. 
8. 4. 3  
O ver d ose 
F or t his st u d y, a n y d ose of acal a br uti ni b great er t ha n t he d ose bei n g st u die d will be c o nsi dere d 
a n o ver d ose. 
•  
A n o ver d ose wit h ass o ciate d A Es is rec or de d as t he A E dia g n osis/s y m pt o ms o n t he 
rele va nt A E m o d ules i n t he e C R F a n d o n t he O ver d ose e C R F m o d ule. 
•  
A n o ver d ose wit h o ut ass ociate d s y m pt o ms is o nl y re p orte d o n t he O ver d os e e C R F 
m o d ule. 
 
If a n o ver d ose o n a acala br uti ni b occ urs i n t he c o urse of t he st u d y, t he n t he i n vesti gat or or 
ot her site pers o n nel i nf or m a p pr o priate s p o ns or re prese ntati ves i m me diatel y, or n o l ater t h a n 
2 4 h o urs  of w he n he or s he bec o mes a ware of t he o ver d ose. 
T he desi g nate d s p o ns or r e prese nt ati ve w or ks wit h t he  i n vesti gat or t o e ns ure t hat all rele v a nt 
i nf or mati o n is pr o vi de d t o t he s p o ns or Patie nt Safet y data e ntr y site wit hi n 1 or 5 cale n d ar 
da ys f or o ver d oses ass oci ate d wit h a S A E (see Secti o n  8. 4. 1 ) a n d wit hi n 3 0 da ys f or all ot her 
o ver d oses. 
F or partici pa nts recei vi n g S o C (rit u xi ma b a n d c hl ora m b ucil), refer t o t he l ocal Prescri bi n g 
I nf or mati o n f or tr eat me nt of cases of o ver d os e. If a n y o ver d ose is ass ociate d wit h a n A E or 
S A E, t he A E/ S A E dia g n osis or s y m pt o ms are rec or de d i n t he rel e va nt A E m o d ules a n d S A Es 
are r e p orte d t o t he s p o ns or Patie nt Safet y data e ntr y site f or e ntr y i nt o t he s afet y data b ase (s ee 
Secti o n  8. 4. 1 ).  
 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 9 0
 
8. 4. 4  
Me dic ati o n Err or, Dr u g A b us e, a n d Dr u g Mis use  
If a n e v e nt of me dicati o n err or, dr u g a b use, o r  dr u g mis use occ urs d uri n g t he st u d y, t he n t he 
i n vesti gat or or ot her site pers o n nel i nf or ms t he a p pr o priate Astra Ze neca re prese ntati ves wit hi n 
1 c ale n d ar d a y  i.e., i m me diatel y b ut n o l ater t h a n 2 4 h o urs  of w he n t he y bec o me a ware of 
it. 
T he desi g nate d Astr a Ze n eca r e pr ese ntati ve w or ks wit h t he i n vesti gat or t o e ns ure t hat all 
rele va nt i nf or m ati o n is c o m plete d wit hi n 1  (i nitial fatal/life-t hreate ni n g or f oll o w u p fatal/life-
t hreate ni n g e v e nts) or 5  ( ot her seri o us i nitial a n d f oll o w u p e ve nts) c ale n d ar d a ys  if t here is 
a n S A E ass ociate d wit h t he e ve nt of me di cati o n err or, dr u g a b us e, or mis use (see Secti o n 
8. 4. 1) a n d  wit hi n 3 0 d a ys f or all ot her e v e nts. 
8. 4. 4. 1  
Me dic ati o n Err or  
F or t he p ur p os es of t his cli nical st u d y a me dicati o n err or is a n u ni nte n de d  fail ure or mista ke 
i n t he treat me nt pr ocess f or a n I M P or Astra Ze neca N o n I n vesti gati o nal Me dici nal Pr o d uct 
( NI MP) t hat eit her ca uses har m t o t he partici pa nt or has t he p ote ntial t o ca use har m t o t he 
partici pa nt.  
T he f ull defi niti o n a n d e x a m ples of me dicati o n err or ca n be f o u n d i n A p pe n di x B 8. 
8. 4. 4. 2  
Dr u g A b use  
Dr u g a b use is t he p ersiste nt or s p ora dic i nte nti o n al, n o n-t hera pe utic e xcessi ve use of I M P or 
Astra Ze neca NI M P f or a percei v e d re war d or desire d n o n -t hera pe utic effect. 
T he f ull defi niti o n a n d e x a m ples of dr u g a b us e ca n be f o u n d i n A p pe n di x B 8. 
8. 4. 4. 3  
Dr u g Mis use  
Dr u g mis use is t he i nte nti o n al a n d i na p pr o priate use ( b y a st u d y partici p a nt) of I M P or 
Astra Ze neca NI M P f or me dici nal p ur p oses o utsi de of t he a ut h orise d pr o d uct i nf or mati o n, or 
f or u na ut h orise d I M Ps or Astra Ze neca NI M Ps, o utsi de t he i nte n de d use as s pecifie d i n t he 
pr ot oc ol a n d i ncl u des deli berate a d mi nistrati o n of t he pr o d uct b y t he wr o n g r o ute. 
T he f ull defi niti o n a n d e x a m ples of dr u g mis use ca n be f o u n d i n A p pe n di x B 8. 
 
8. 4. 5  
D ose m o dific ati o n m a n a ge m e nt of I P-rel ate d t o xicities 
D ose m o dificati o n ma na ge me nt of I P-relate d t o xi cities ca n be f o u n d i n Secti o n  6. 6 . 
 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9 1
P h ar m ac o ki netics
S parse P K sa m ples will be c ollecte d fr o m all s u bjects ra n d o mize d t o Ar m  A, t o i n vesti gate t he 
p har mac o ki netics of acal a br uti ni b a n d A C P- 5 8 6 2 (acal a br uti ni b’s meta b olite).  Bl o o d sa m ples 
f or P K will be c ollecte d fr o m eac h Ar m  A s u bject accor di n g t o t he ti me p oi nts s h o w n i n 
Ta ble  1 4.
T a ble 1 4
Ar m A P K S a m pli n g Sc he d ule
Visit
Ti m e P oi nt
S a m ple T y pe a n d A n al yte
C ycle 2 Da y  1 
Pre d ose ( wit hi n 3 0  mi n utes bef ore d osi n g) 
Plas ma f or acala br uti ni b 
Plas ma f or A C P -5 8 6 2
1 h o ur ( ± 1 5 mi n utes) after d osi n g
Plas ma f or acala br uti ni b
Plas ma f or A C P -5 8 6 2
2 h o urs ( ± 1 5 mi n utes) after d osi n g
Plas ma f or acala br uti ni b
Plas ma f or A C P -5 8 6 2
4 h o urs ( ± 3 0 mi n utes) after d osi n g
Plas ma f or acala br uti ni b
Plas ma f or A C P -5 8 6 2
O n t he da y of sa m pli n g, t he s u bject will n ot ta ke a d ose of a n y st u d y dr u g b ef ore arri v al at t he 
cli nic.  T he s u bject will bri n g a meal ( prefera bl y t h e first meal of t he d a y) t o t he cli nic, a n d t he 
m or ni n g d ose of acala br uti ni b will be ta ke n wit hi n 3 0 mi n utes after eati n g t he meal.  T he 
st u d y dr u g a d mi nistrati o n will be o bser ve d b y cli nic staff.  T he act ual ti me of t he o bser v e d 
d ose a n d t he bl o o d dra ws f or P K sa m ples m ust be acc uratel y rec or d e d, t o t he mi n ute, i n t he 
e C R F.  P K sa m ples m ust be pr ocess e d acc or di n g t o t he i nstr ucti o ns i n t he la b ma n ual. 
At eac h ti me p oi nt, P K sa m ples s h o ul d be c ollect e d a n d pr ocesse d acc or di n g t o t he 
i nstr ucti o ns i n t he la b orat or y ma n ual.  Sa m ples will be s hi p pe d t o a ce ntral la b orat or y. T h e 
ce ntral la b orat or y will s hi p t he sa m ples t o t he bi oa nal ytical la b orat or y as directe d.  
Dr u g c o nce ntrati o n i nf or mati o n t hat ma y u n bli n d t he st u d y will n ot be re p orte d t o bli n de d 
pers o n nel u ntil t he st u d y has bee n u n bli n de d. 
8. 5. 1  
Deter mi n ati o n of dr u g c o nce ntr ati o n 
Sa m ples f or deter mi nati o n of acal a br uti ni b a n d A C P - 5 8 6 2 c o nce ntrati o ns i n plas ma will be 
a nal yse d b y a n al ytical test sites o n be half of t he s p o ns or, usi n g vali date d bi oa nal ytical 
met h o ds.  F ull details of t he a nal ytical met h o d use d will be descri be d i n a s e parat e 
bi oa nal ytical re p ort.
8. 5. 2 
St or a ge a n d dest r ucti o n of p h ar m ac o ki neti c s a m ples 
P K sa m ples will be st ore d a n d dis p ose d of acc or di n g t o l ocal la ws a n d re g ulati o ns.  T he 
resi d ual P K sa m ples will be dis p ose d of aft er t he C S R fi nalizati o n.  

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9 2
P h ar m ac o d y n a mics
P har mac o d y na mic p ara m eters ar e n ot e val u ate d i n t his st u d y.
Ge netics
Ge netic testi n g is n ot e val uate d i n t his st u d y. 
Bi o m ar kers
Bi o mar kers ar e n ot e val u ate d i n t his st u d y. 
He alt h ec o n o mics / me dic al res o urce utiliz ati o n a n d he alt h 
ec o n o mics
Healt h ec o n o mics/ me dical res o urce utilizati o n a n d healt h ec o n o mics para meters are n ot 
e val uate d i n t his st u d y. 
9
St atistic al  C O N SI D E R A TI O N S 
St atistic al h y p ot heses
T he pri mar y o bjecti ve of t he st u d y is t o test t he f oll o wi n g h y p ot hesis: 
H 0: BI C R -assess e d P F S of Ar m  A is t he sa me as Ar m  B 
H 1: BI C R -assess e d P F S of Ar m A is n ot t he sa me as Ar m  B 
T he st u d y will be c o nsi dere d p ositi ve (a s u ccess) if t he pri mar y P F S a nal ysis res ult f or Ar m A 
vers us Ar m B is statisticall y si g nifica nt. 
S a m ple size deter mi n ati o n 
U n der t he e x p o ne ntial m o del ass u m pti o ns, t his st u d y is e x pecte d t o ra n d o mize a p pr o xi matel y 
7 5 patie nts per ar m ( 1 5 0 patie nts i n t otal fr o m b ot h ar ms) wit h 1: 1 ra n d o mi zati o n rati o.  It is 
pla n ne d t o ra n d o mize a p pr o xi matel y 7 5 t o 1 2 0 patie nts i n t otal fr o m b ot h ar ms ( 5 0 % t o 8 0 % 
of t otal sa m ple size) fr o m C hi na.  T he st u d y is size d t o ac hi e ve m ore t h a n 9 5% p o wer t o 
detect a h azar d rati o of 0. 3 3 3 i n P F S ( w hic h tra nsl ates i nt o a n i m pr o ve me nt i n me dia n P F S 
fr o m 3 0 m o nt hs t o 9 0 m o nt hs) at t he 2-si de d si g nifica nce l e vel of 0.0 5, all o wi n g f or o ne 
i nteri m a nal ysis c o n d ucte d at a p pr o xi matel y 7 6 % of t he target e ve nts.  T he sa m ple size 
calc ulati o n ass u mes a m e dia n P F S of 3 0  m o nt hs i n Ar m B (Mic hallet et al  2 0 1 8).  
T he fi nal a n al ysis of BI C R -assesse d P F S is e ve nt - dri ve n a n d will be c o n d u cte d w he n 
e nr oll me nt is c o m plete d a n d t here are a p pr o xi mat el y 5 0 BI C R -ass esse d P F S e ve nts i n t otal 
fr o m Ar m A a n d Ar m  B.  T he accr ual p eri o d is ass u me d t o be a p pr o xi matel y 3 0 m o nt hs. It is 
ass u me d t hat a b o ut 5 % of t he patie nts i n eac h ar m will dr o p o ut at t he ti me of fi nal P F S 

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9 3
a nal ysis.  T he i nteri m a n d fi nal a nal ysis are a ntici pate d t o occ ur a p pr o xi matel y 4 0 m o nt hs a n d 
5 3 m o nt hs , res pecti vel y, after t he first patie nt is ra n d o mize d. 
O ne i nteri m a nal ysis will be c o n d ucte d t o assess earl y effi cac y of Ar m  A v ers u s Ar m B wit h 
res pect t o t he pri mar y efficac y e n d p oi nt, BI C R-assesse d P F S usi n g La n a n d De Mets s pe n di n g 
f u ncti o n wit h O’ Brie n- Fle mi n g b o u n dar y (La n a n d  De Mets  1 9 8 3;
O’ Brie n a n d Fle mi n g  1 9 7 9).  T he i nteri m a nal ysis will occ ur w he n a p pr o xi matel y 3 8 BI C R -
assesse d P F S e ve nts ( 7 6 % of tar get P F S e ve nts re q uire d f or fi n al a nal ysis) ha ve bee n o bser v e d 
i n b ot h ar ms c o m bi ne d.  T he n o mi nal al p ha le vel f or t he i nteri m a n d fi n al a nal ysis of 3 8 a n d 
5 0 BI C R-assess e d P F S e ve nts is 0. 0 2 a n d 0. 0 4 4 res pecti vel y. T he act ual n o mi nal al p ha le vel 
will be deter mi ne d bas e d o n t he n u m ber of BI C R -assesse d P F S e ve nts o bs er ve d at t he ti me of 
eac h r es pecti ve a nal ysis . 
E A S T  6. 5 was e m pl o ye d t o c o n d uct t he sa m ple si ze calc ulati o n.  
P o p ul ati o ns f or a n al yses
P o p ulati o ns of t he f ull a nal ysis set, safet y a nal ysis set, a n d P K a nal ysis set are defi ne d i n 
Ta ble  1 5.  T he p o p ulati o n sets a n d c orres p o n di n g o utc o me varia bles are s h o w n i n Ta ble  1 6.  
T a ble 1 5
A n al ysis P o p ul ati o ns
P o p ul ati o n
Descri pti o n
F ull a nal ysis set
All ra n d o mize d patie nts (I T T p o p ulati o n) 
Safet y a nal ysis set
All s u bjects w h o ha ve recei ve d at least 1 d ose of i n vesti gati o nal pr o d uct.  
Err o ne o usl y treate d s u bjects (e. g., t h ose ra n d o mise d t o Ar m A b ut act uall y 
gi ve n Ar m B treat me nt) are acc o u nte d f or i n t he treat me nt gr o u p of t he 
treat me nt t he y act uall y recei ve d.
P K a nal ysis set
All ra n d o mize d patie nts t hat ha ve at least 1 p ost -d ose e val ua ble c o nce ntrati o n -
ti me data f or P K a nal ysis.
T a ble 1 6
A n al ysis Sets f or O utc o me V ari a bles
O utc o m e v ari a ble
P o p ul ati o n
Efficac y Data ( BI C R - a n d I N V-assesse d)
P F S 
F ull a nal ysis set (I T T p o p ulati o n)
O R R, D O R, T T N T, O S, M R D rate, 
De m o gra p h y
Safet y Data
E x p os ure
Safet y a nal ysis set
A Es
La b orat or y meas ure me nts
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9 4
T a ble 1 6
A n al ysis Sets f or O utc o me V ari a bles
O utc o m e v ari a ble
P o p ul ati o n
Vital si g ns
E C Gs
P K Data
P K a nal ysis set
O utc o me me as ures f or a n al yses
9. 4. 1  
C alc ul ati o n or d eri v ati o n of effic ac y v ari a bl es 
9. 4. 1. 1
Pr o gressi o n -f ree s ur vi v al 
P F S is defi ne d as t he ti me fr o m t he dat e of ra n d o mizati o n u ntil pr o gressi o n (assesse d b y t he 
BI C R per I W C L L  2 0 1 8 criteria) or d eat h fr o m a n y ca use, w hic h e ver occ urs first.  S u bjects 
w h o wit h dra w fr o m t he st u d y or are c o nsi dere d l ost t o f oll o w- u p wit h o ut pri or d oc u me ntati o n 
of disease pr o gressi o n will be ce ns ore d o n t h e date of t he last a de q u ate disease assess me nt.  
S u bjects w h o start ne w a ntica ncer t h era p y b ef ore d oc u me ntati o n of disease pr o gressi o n will 
be ce ns or e d o n t he dat e of t he last a de q u ate diseas e assess me nt t hat is o n or bef ore t h e start 
date of t he ne w a ntica n cer t hera p y.  F or s u bjects wit h o ut a n a de q uate p ost- b aseli ne disease 
assess me nt, P F S will be ce ns ore d o n t h e date of ra n d o mizati o n u nless t he y die wit hi n 2 visits 
of baseli ne.   
P F S will als o  be o btai ne d usi n g t he sa me deri vati o n r ule descri b e d a b o ve b ase d o n 
i n vesti gat or assess me nt.  
9. 4. 1. 2
O ver all res p o nse r ate 
O R R is defi ne d as t he pr o p orti o n of patie nts w h o ha ve a C R, C Ri, n P R or P R assesse d b y 
BI C R per I W C L L 2 0 1 8 criteria at or b ef ore i nitiati o n of s u bse q ue nt a ntica n cer t hera p y.  C Ri 
refers t o s u bjects w h o f ulfill all t he criteria f or a C R (i ncl u di n g t he b o ne marr o w 
e xa mi nati o ns), b ut ha ve a persiste nt a ne mia, t hr o m b oc yt o pe nia, or ne utr o pe nia a p pare ntl y 
u nrelate d t o C L L, b ut rel ate d t o dr u g t o xi cit y. n P R refers t o patie nts w h o f ulfil all t he criteria 
f or a C R b ut wit h t he prese nce of B-l y m p h oi d n o d ules i n t he b o ne marr o w w hic h refl ect 
resi d ual disease.
Best o verall res p o nse ( B O R) is t he best res p o nse a patie nt has ha d f oll o wi n g ra n d o mizati o n 
date , b ut pri or t o starti n g a n y s u bse q ue nt a ntica ncer t hera p y, u p t o a n d i n cl u di n g pr o gressi o n 
or t he last e val ua bl e assess me nt i n t he a bse nce of pr o gressi o n. 
O R R a n d B O R will als o be o btai ne d usi n g t he sa me deri vati o n r ule d escri be d a b o ve b ase d o n 
i n vesti gat or assess me nt.

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C O N FI D E N TI A L A N D P R O P RI E T A R Y   
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9. 4. 1. 3  
D ur ati o n of res p o nse  
D O R (assesse d b y BI C R per I W C L L  2 0 1 8 criteria) is defi ne d as t he ti me fr o m t he date of first 
d oc u me nte d res p o ns e u ntil date of d oc u me nte d pr o gressi o n or deat h i n t he a bse nce of diseas e 
pr o gressi o n.  S u bjects w h o wit h dra w fr o m t he st u d y or are c o nsi dere d l ost t o f oll o w- u p 
wit h o ut pri or d oc u me ntati o n of disease pr o gressi o n will be ce ns ore d o n t h e date of t he last 
a de q uate disease assess me nt.  S u bjects w h o start ne w a ntica n cer t h era p y b ef ore 
d oc u me ntati o n of disease pr o gressi o n will be ce ns ore d o n t he date of t he last a de q uate disease 
assess me nt t hat is o n or bef ore t h e start date of t he ne w a ntica n cer t h era p y.  
D O R will als o be o btai ne d usi n g t he sa me deri vati o n r ule descri b e d a b o ve base d o n 
i n vesti gat or assess me nt. 
9. 4. 1. 4  
Ti m e t o ne xt t her a p y  
Ti me t o ne xt t hera p y ( T T N T) is defi ne d as ti me fr o m ra n d o mizati o n u ntil i nstit uti o n of n o n-
pr ot oc ol s pecifie d tr eatm e nt f or C L L or deat h d ue t o a n y ca use, w hic he ver c o mes first.  As f or 
t he detaile d ce ns ori n g r ul es, please refer t o t he statistical a nal ysis pla n ( S A P). 
9. 4. 1. 5  
O ver all s ur vi v al 
O verall s ur vi val is t he le n gt h of ti me fr o m ra n d o mizati o n u ntil t he date of deat h d ue t o a n y 
ca use.  A n y p atie nt n ot k n o w n t o ha ve die d at t he ti me of a nal ysis will be ce ns ore d bas e d o n 
t he last rec or d e d date o n w hic h t he patie nt was k n o w n t o be ali ve.  
9. 4. 1. 6  
Mi ni m u m resi d u al dise a se r ate  
M R D ne gati ve rate is d efi ne d as t he pr o p orti o n of s u bjects wit h M R D- ne gati vit y ( defi ne d as 
< 1  C L L cell per 1 0, 0 0 0 l e u k oc ytes).  
9. 4. 2  
C alc ul ati o n or d eri v ati o n of s afet y v ari a bles 
Safet y a n d t oler a bilit y will be assesse d i n ter ms of A Es (i ncl u di n g S A Es) , la b orat or y data, 
vital si g ns, E C Gs, a n d e x p os ure.  T hese will be c ollecte d f or all s u bjects.  ‘ O n treat me nt’ will 
be defi ne d as assess me nts bet wee n dat e of first d ose a n d 3 0  da ys f oll o wi n g disc o nti n uati o n.  
A p pr o priate s u m mari es of t hese data will be pre se nte d as descri b e d i n Secti o n 9. 5. 2 .  
9. 4. 2. 1  
Ot her si g nific a nt a d verse e ve nts  
D uri n g t he e val uati o n of t he A E data, a s p o ns or me dicall y q ualifie d e x p ert will re vie w t he list 
of A Es t hat wer e n ot re p orte d as S A Es a n d A Es l ea di n g t o disc o nti n uati o n of I P.  Base d o n t he 
e x pert’s j u d ge me nt, a d verse e ve nts of p artic ular cli nical i m p orta nce ma y, after c o ns ultati o n 
wit h t he Gl o bal Safet y  P h ysicia n, be c o nsi dere d as ot her si g nifica nt a d vers e e ve nts ( O A Es) 
a n d re p ort e d as s uc h i n t he C S R.  A si milar re vie w of la b orat or y val ues, vital si g ns, E C Gs, 
a n d ot her saf et y assess m e nts will be perf or me d f or i de ntificati o n of O A Es. 

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C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 9 6
St atistic al a n al yses
A nal yses will be perf or m e d b y t he s p o ns or or its re prese nt ati ves.  A c o m pre he nsi ve sta tistical 
a nal ysis pla n will be de v el o pe d a n d fi nalise d b ef ore data b ase l oc k a n d will descri be t he 
s u bject p o p ulati o ns t o be i ncl u de d i n t he a nal yses, a n d pr oce d ures f or acc o u nti n g f or missi n g, 
u n use d, a n d s p uri o us dat a. T his secti o n is a s u m mar y of t he pla n n e d statistical a nal yses of t he 
pri mar y a n d sec o n dar y e n d p oi nts.  A n y  de viati o ns fr o m t his pla n will  be re p orte d i n t he C S R . 
Descri pti ve statistics will be use d f or all varia bles, as a p pr o priat e, a n d will be prese nt e d b y 
treat me nt gr o u p. U nless ot her wise state d, c o nti n u o us varia bles will be s u m marize d b y t he 
C CI

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C O N FI D E N TI A L A N D P R O P RI E T A R Y   
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n u m ber of o bser v ati o ns, mea n, sta n dar d d e viati o n, me dia n, mi ni m u m, a n d ma xi m u m; 
cate g orical varia bl es will be s u m marize d b y fre q u e nc y c o u nts a n d p erce nta ges f or eac h 
cate g or y.  U nl ess ot her wise state d,  perce nta g es will be calc ulate d o ut of t he p o p ulati o n t otal 
f or t he c orres p o n di n g treat me nt ar m.  
I n g e ner al, t he baseli ne v al ue f or statistical a n al ysis is t he last n o n- missi n g val ue pri or t o 
a d mi nistrati o n of t he first d ose of I P , e xce pt f or efficac y varia bles. F or efficac y vari a bles, 
baseli ne is defi ne d as t he last assess me nt pri or t o ra n d o mizati o n. 
All data c ollecte d will be liste d. Efficac y a n d  
 data will be s u m marize d a n d a nal yze d 
base d o n t he F A S.  Safet y data will be s u m marize d o n t he safet y a n al ysis set. P K data will be 
s u m marize d o n t he P K a nal ysis set. 
T he effi cac y a n d saf et y i n C hi na s u b gr o u p ma y be a nal yze d t o facilitate a be nefit- ris k 
assess me nt f or r e g ulat or y s u b missi o n i n C hi na. Details of t his a nal ysis will be s pecifie d i n t he 
S A P.  
9. 5. 1  
Effic ac y a n al yses 
9. 5. 1. 1  
Pr o gressi o n -f ree s ur vi v al  
T he pri mar y a n al ysis will be perf or m e d i n t he I T T p o p ulati o n t o c o m pare P F S as assesse d b y 
t he BI C R usi n g a 2-si de d stratifie d l o g ra n k test, a dj usti n g f or E C O G ( 0- 1 vers us 2) a n d Rai 
sta ge ( Sta ge 0-II vers us III-I V) at r a n d o mizati o n. T he esti mate of t he H R a n d its 
c orres p o n di n g 9 5 % CI will be c o m p ute d usi n g a C o x pr o p orti o nal hazar ds m o del stratifie d b y 
t he ra n d o mizati o n strata. 
Ka pla n - Mei er pl ots of P F S will be prese nte d b y treat me nt ar m. S u m maries of t he n u m ber a n d 
perce nt a ge of p atie nts e x perie nci n g a P F S e ve nt a n d t he t y pe of e ve nt ( pr o gressi o n or deat h) 
will be pr o vi de d al o n g wit h me dia n P F S f or eac h treat me nt.  
T he f oll o wi n g se nsiti vit y a nal yses will be perf or m e d:  
•  
U nstratifie d l o g ra n k test a n d u nstratifie d C o x m o del.  
•  
Ascertai n me nt bias will be assesse d b y a nal yzi n g i n vesti gat or data.  T he stratifie d l o g-
ra n k test use d f or t he pri mar y P F S a nal ysis will be re peate d.  
•  
O ne se nsiti vit y a nal ysis will be perf or me d b y re p eati n g t he pri mar y a nal ysis, e xce pt t hat 
act ual P F S e ve n t ti mes after s u bse q ue nt t hera p y will be use d rat her t ha n ce ns ore d ti mes.  
 
S u b gr o u p a nal yses will be c o n d ucte d c o m pari n g P F S bet wee n Ar m A vers us Ar m  B i n t he 
f oll o wi n g s u b gr o u ps ( b ut n ot li mite d t o): 
•  
A ge at ra n d o mizati o n ( < 6 5 vers us ≥6 5)  
•  
Se x ( male vers us  fe male) 
C CI

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C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 9 8
 
•  
E C O G ( 0 - 1 vers us 2) 
•  
I G H V m utati o n stat us ( m utate d vers us n o n-m utate d)  
•  
C o u ntr y ( C hi na vers us ot her) 
•  
Rai sta ge at scr ee ni n g ( Sta ge 0 -II vers us III-I V) 
•  
β 2 -micr o gl o b uli n at baseli ne ( ≤3. 5  m g/ L vers us > 3. 5 m g/ L)  
•  
B ul k y disease (l o n gest dia meter of l y m p h n o de < 5 c m vers us ≥5  c m at bas eli ne) 
 
T he H R a n d c orres p o n di n g 9 5 % CI f or eac h s u b gr o u p will be calc ulat e d b ase d o n a n 
u nstratifie d C o x re gr essi o n m o del a n d prese nt e d i n a f orest pl ot as a p pr o priate.  
Ot her baseli ne v aria bles ma y als o be assess e d if t here is cli nical j ustificati o n or a n i m bala nce 
is o bser ve d bet w ee n t he treat me nt gr o u ps.  T h e p ur p ose of t he s u b gr o u p a n al yses is t o assess 
t he c o nsiste nc y of tr eat m e nt eff ect acr oss e x pecte d pr o g n ostic a n d/ or pre di cti ve fact ors.  
U nless t here is a mar ke d  differe n ce b et wee n t h e res ults of t he statistical a nal yses of t he P F S 
fr o m t he BI C R data a n d t hat of t he site i n vesti gat or t u m or data, t hese s u b gr o u p a nal yses will 
o nl y be perf or m e d o n t he P F S e n d p oi nt usi n g t he BI C R data.  
N o a dj ust me nt t o t he si g nifica n ce l e vel f or t esti n g of t he s u b gr o u p a n d se nsiti vit y a nal yses 
will be ma de si nce all t hese a nal yses will be c o nsi dere d s u p p orti ve of t he a nal ysis of P F S.  
F urt her d etails will be pr o vi de d i n t he S A P.  
9. 5. 1. 2  
O ver all res p o nse r ate  
O R R (assesse d b y BI C R per I W C L L  20 1 8 criteria) will be c o m pare d bet wee n treat me nt ar ms 
( Ar m A vers us Ar m  B) usi n g t he C oc hra n-Ma ntel -Hae ns zel ( C M H) c hi -s q uare test, a dj uste d 
f or ra n d o mizati o n stratificati o n fact ors. 
N u m ber a n d p erce nta ge of patie nts wit h a t u m or res p o nse ( C R, C Ri, n P R, or P R) will be 
prese nte d b y tr eat me nt ar m.  F or eac h treat me nt ar m, best o verall res p o nse ( B O R) will be 
s u m marize d b y n ( %) of eac h cate g or y ( C R, C Ri, n P R, P R, S D, P D, N E).  N o f or mal 
statistical a nal ysis is pla n ne d f or B O R. 
O R R a n d B O R assesse d b y i n vesti ga t or will be a n al yze d i n t he sa me fas hi o n as t hat f or BI C R-
assesse d O R R a n d B O R.  
9. 5. 1. 3  
D ur ati o n of res p o nse  
D o R assesse d b y BI C R or i n vesti gat or per I W C L L 2 0 1 8 criteria will be a n al yze d i n t he sa me 
fas hi o n as t hat f or pri mar y efficac y e n d p oi nt P F S as descri be d i n Secti o n 9. 5. 1. 1 .  

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9. 5. 1. 4  
Ti m e t o ne xt t her a p y  
T T N T will be a nal yse d i n t he sa me fas hi o n as t h at f or pri mar y efficac y e n d p oi nt P F S as 
descri be d i n Secti o n  9. 5. 1. 1 .  
9. 5. 1. 5  
O ver all s ur vi v al 
O S will be a nal yse d i n t he sa me f as hi o n as t hat f or pri mar y efficac y e n d p oi nt P F S as 
descri be d i n Secti o n  9. 5. 1. 1 .  
A se nsiti vit y a nal ysis will be perf or m e d.  Patie nts w h o recei ve cr oss o ver t h era p y will be 
ce ns ore d at t he date b ef ore first d ose d ate of t he cr oss o ver t hera p y.  
9. 5. 1. 6  
M R D ne g ati vit y r ate 
Peri p heral bl o o d M R D n e gati vit y rate at t he start of C ycle 9 will be c o m par e d bet wee n 
treat me nt ar ms ( Ar m A v ers us Ar m  B) usi n g t he C M H c hi-s q uare test, a dj uste d f or 
ra n d o mizati o n stratificati o n fact ors. 
9. 5. 2  
S afet y a n al yses 
Safet y a nal yses will be perf or me d usi n g t he s afet y a nal ysis set.  U nless n ote d else wise, 
s u m maries will be based o n safet y data c ollecte d i n t he i nitial treat me nt peri o d (i.e., f or 
patie nts w h o cr oss o ver t o Ar m A, t he safet y data o n or after recei vi n g first d ose of cr oss- o v er 
t hera p y will be e x cl u de d).  Safet y data o n or after recei vi n g first d ose of cr oss- o ver t hera p y 
mi g ht be s u m marize d se paratel y, pr o vi d e d t hat t here are a s ufficie nt n u m b er of patie nts t o 
warr a nt t his.  
All safet y data will be liste d.  
A d verse E ve nts  
A d verse e ve nts will be c o de d usi n g t he m ost rece nt versi o n of t he Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A) t hat will ha ve b ee n rel ease d f or e x ec uti o n at t he 
s p o ns or/ desi g nee.  
Safet y data will be pr ese nte d usi n g descri pti ve statistics u nless ot her wise s pecifie d.  
A Es will be prese nte d f or eac h tr eat me nt gr o u p b y S O C  a n d/ or P T c o veri n g n u m ber a n d 
perce nt a ge of s u bjects re p orti n g at least o ne e v e nt a n d n u m ber of e ve nts w here a p pr o priate. 
A Es occ urri n g pri or t o start of I P, treat me nt e mer ge nt A Es, a n d p ost- treat me nt A Es will be 
prese nte d se p ar atel y.   
A n o ver vie w of A Es will be prese nt e d f or eac h treat me nt gr o u p t he n u m ber a n d perce nta ge of 
s u bjects wit h a n y A E, A Es wit h o utc o me of deat h, seri o us A Es, a n d A Es lea di n g t o 
disc o nti n uati o n of I P, as well as A Es lea di n g t o I P d ose dela ys, A Es lea di n g t o I P d ose 
re d ucti o n as w ell as t he n u m ber of i n di vi d ual occ urre nces i n t h ose cat e g ories. 

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Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1 0 0  of 1 4 8  
 
Se parate A E ta bles will be pr o vi de d ta ke n i nt o c o nsi derati o n relati o ns hi p as assesse d b y t he 
i n vesti gat or, C T C A E gra di n g, seri o us ness, deat h a n d e ve nts lea di n g t o disc o nti n uati o n of I P 
as well as ot her acti o n ta ke n relate d t o I P, e ve nts of s pecial i nterest, Ot her si g nifica nt a d vers e 
e ve nts. 
A n a d diti o nal ta ble will prese nt n u m ber a n d perce nta ge of s u bjects wit h m ost c o m m o n A Es 
(fre q u e nc y of > 5 %). 
Ke y s u bject i nf or mati o n will be prese nte d f or s u bjects wit h A Es wit h o utc o me of deat h, 
seri o us A Es, a n d A Es lea di n g t o disc o nti n uati o n of I P. 
A n A E listi n g f or t he saf et y a nal ysis set will c o ver details f or eac h i n di vi d ual A E.  
F ull details of A E a n al yses will be pr o vi de d i n t he S A P. 
Tre at m e nt E m er ge nt  
T he f oll o wi n g e ve nts are c o nsi dere d treat me nt e m er ge nt:  
•  A d verse e ve nts wit h a n o nset date o n or after first d ose of I P, a n d wit hi n 3 0 da ys after 
last d ose of I P 
•  W orse ni n g of pr e- e xisti n g e ve nts o n or after first d ose of I P, a n d wit hi n 3 0 da ys after 
last d ose of I P 
 
Cli nic al L a b or at or y Tests 
D at a S u m m ar y Met h o ds 
F or gr a da ble p ara met ers, a s u m mar y of w orst p ost- baseli ne t o xicit y gra de will be pr o vi de d i n 
t he “ o n-treat me nt” peri o d b y treat me nt ar m.  A p pr o priate s u m maries of la b orat or y data o v er 
ti me a n d c ha n ge fr o m baseli ne will be pr o vi de d b y treat me nt ar m.  
A n al ysis of L y m p h oc yt osis  
F or all s u bjects wit h bas eli ne a n d a n y p ost- baseli n e A L C meas ure me nts, A L C at pea k 
s u m mar y will be pr o vi de d b y treat me nt ar m. 
L y m p h oc yt osis is defi ne d as a n A L C > 5 0 0 0 cells/ µ L a n d a n i ncrease a b o v e baseli ne.  T h e 
n u m ber of s u bjects wit h at least o ne occ urre nce of l y m p h oc yt osis will be s u m marize d.  F or 
s u bjects wit h l y m p h oc yt osis, res ol uti o n of l y m p h oc yt osis is defi ne d as 1) a decreas e of A L C 
val ue t o t he baseli ne le v el or l o wer, or 2) a n ac hie ve me nt of A L C val ue t hat is bel o w 
5, 0 0 0 cells/ μ L, w hic he ver occ urs first.  T he f oll o wi n g a nal yses will be c o n d ucte d f or s u bjects 
wit h l y m p h oc yt osis b y treat me nt ar m:  A L C at pea k a n d ti me t o pea k A L C f or s u bjects w h o 
ha ve l y m p h oc yt osis.  T he data will be s u m marize d b y descri pti ve statistics. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1 0 1
 
D urati o n of l y m p h oc yt osis is defi ne d as t he d urati o n of ti me fr o m t he earliest date o n w hic h 
t he A L C val ue met t he l y m p h oc yt osis criteria at a p ost-baseli ne assess me nt t o t he earliest date 
o n w hic h a s u bse q ue nt A L C val ue met t he res ol uti o n criteria. 
A n al ysis of Se r u m I m m u n o gl o b uli ns 
Ser u m i m m u n o gl o b uli ns (I g A, I g G, a n d I g M) are c ollecte d as s c he d ule d i n t he S o A.  F or eac h 
varia ble, des cri pti ve statistics will be prese nte d at eac h sc h e d ule d p ost -bas eli ne assess me nt b y 
treat me nt ar m.  S u bjects w h o recei ve d I VI G o n t h e st u d y will be e xcl u de d fr o m t he s u m mar y 
f or I g G. 
E C O G Perf or m a nce St at us  
T he E C O G perf or ma n ce stat us will be c ollecte d as sc he d ule d i n t he S o A.  T he E C O G 
perf or ma n ce stat us gr a de ra n ges fr o m 0 – 5.  Descri pti ve statistics a n d c ha n g e fr o m baseli ne 
will be p r o vi de d f or eac h visit o ver ti me. 
Wei g ht 
Descri pti ve statistics a n d c ha n ge fr o m baseli ne will be pr o vi de d o ver ti me. 
Vit al si g ns  
Vital si g n para meters will be prese nte d f or eac h treat me nt gr o u p.  S u m mar y statistics f or 
c o nti n u o us varia bles c o v er n, mea n, S D, Mi n, Q 1, me dia n, Q 3, a n d Ma x.  Fre q u e nc y ta bles 
c o ver n u m ber a n d perce nta ge of s u bjects i n t he res pecti ve cate g or y. 
F or eac h sc h e d ule d p ost- baseli ne visit, descri pti ve statistics f or all vital si g n para meters will 
be prese nt e d f or o bs er ve d val ues a n d c h a n ge fr o m baseli ne.  
Details of vital si g ns a nal yses will be pr o vi de d i n t he S A P. 
9. 5. 3  
 
 
 
  
 
 
 
   
C CI

Cli nical St u d y Pr ot oc ol – 5 . 0
Astra Ze neca
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 0 2
9. 5. 4 
P K a n al yses 
Plas ma c o nce ntr ati o ns of acala br uti ni b a n d A C P - 5 8 6 2 will be ta b ulate d f or eac h s u bject i n 
Ar m A b y visit a n d ti me p oi nt.  S u m mar y statistics (i ncl u di n g b ut n ot li mite d t o: ge o metric 
mea n, c oefficie nt of v ari ati o n, ge o metric mea n ± ge o metric sta n dar d deri v ati o n, arit h metic 
mea n, sta n dar d d eri vati o n, mi ni m u m, me dia n, ma xi m u m, a n d n u m ber of o bser vati o ns) will be 
prese nte d as a p pr o priate. 
9. 5. 5  
Ot her a n al yses  
A d diti o nal a nal yses ma y be c o n d ucte d b y c o m bi n g P K data acr oss st u dies.  P ote ntial 
c orrel ati o ns of e x p os ure wit h safet y a n d efficac y o utc o mes or P D e n d p oi nts ma y be e x pl ore d 
as warra nte d b y t he d ata.  T hese a n al yses ma y be re p orte d se p aratel y fr o m t he C S R.  
9. 5. 6  
Met h o ds f or m ulti plicit y c o ntr ol 
T o c o ntr ol t he o ver all t y pe I err or at 0. 0 5 le v el, t he La n- De m ets al p ha s pe n di n g f u ncti o n base d 
o n t he O’ Brie n- Fle mi n g b o u n dar y is use d t o s plit al p ha f or t he i nteri m a n d fi nal a nal yses of 
P F S.  If e xactl y 7 6 % of P F S e ve nts at fi nal is a v aila ble at t he ti me of t he i nt eri m a nal ysis, t hat 
is 3 8/ 5 0 P F S e ve nts base d o n BI C R ha ve o cc urre d, t he 2-si de d al p ha le v el t o be a p plie d f or 
t he i nteri m a n d t he fi nal a nal ysis will be 0. 0 2 a n d 0. 0 4 4, res pecti vel y.  T h e n o mi nal al p ha 
le vels f or t he i nteri m a n d fi nal a nal yses will be det er mi ne d base d o n act ual n u m ber of P F S 
e ve nts o bser v e d at t he ti me of t he a nal ys es.
I nteri m a n al yses 
T his pr ot oc ol i ncl u des o ne i nteri m a nal ysis a n d a fi nal a nal ysis.  T he Statistical A nal ysis Pla n 
will descri be t he pla n n e d i nteri m a nal yses i n greater detail.
T he i nteri m a nal ysis will be perf or me d t o test f or s u peri orit y of Ar m A relati ve t o Ar m  B.  
T his a nal ysis will be perf or me d w he n a p pr o xi matel y 3 8 P F S e ve nts base d o n BI C R ha ve b ee n 
o bser ve d i n t he st u d y ( 2 5. 3 % mat urit y or 7 6 % i nf or mati o n fracti o n). It is ass u me d t hat a b o ut 
5 % of t he patie nts i n eac h ar m will dr o p o ut at t he ti me of fi nal P F S a nal ysis .  T he i nteri m 
a nal ysis is a ntici pate d t o occ ur a p pr o xi matel y 4 0 m o nt hs after t he first pati e nt is ra n d o mize d.  
9. 6. 1  
D at a m o nit ori n g c o m mittee  
A n i n de pe n de nt dat a m o nit ori n g c o m mittee (I D M C) will be utilize d f or t his st u d y.  
A p pe n di x A 5 pr o vi des m ore details o n t he rati o n ale f or a n d t he re mit of t h e c o m mittee.
T he I D M C will e val uate efficac y f or t he i nteri m a nal ysis. A d diti o nal I D M C safet y re vie w will 
be c o n d ucte d wit h first safet y data re vie w will be perf or me d b y t h e I D M C after a p pr o xi matel y 
5 0 s u bjects ha ve bee n ra n d o mize d.  T hereafter, t h e I D M C will meet a p pr o xi matel y e ver y 6 
m o nt hs or at a fre q u e nc y deter mi ne d b y t he I D M C a n d t he s p o ns or acc or di n g t o t he e mer gi n g 
safet y pr ofile.  M e m bers of t he I D M C will be e xter nal t o t he s p o ns or.  A n I D M C c harter will 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1 0 3
 
be de vel o pe d w hic h will s pecif y t he C o m mittee’s res p o nsi bilities, a ut h orities, a n d pr oce d ures 
al o n g wit h details of t he a nal ysis pla n ni n g, d ecisi o n- ma ki n g g ui da nce, a n d disse mi nati o n of 
t he res ults as well as t he rec o m me n dati o ns a n d d ecisi o ns after t he a nal ysis.  
F ull details of t he I D M C pr oce d ur es, pr ocesses, safet y re vie w a n d i nteri m a nal ysis ca n be 
f o u n d i n t he I D M C c harter.  
1 0  
R E F E R E N C E S  
B arf 2 0 1 7 
Barf T, C o ve y T, Iz u mi R, Kar B V D, G ulraj a ni M, Lit h B V et al. Acala br uti ni b ( A C P- 1 9 6): A 
c o vale nt Br ut o n t yr osi ne ki nase ( B T K) i n hi bit or wit h a differe ntiat e d selecti vit y a n d i n vi v o 
p ote nc y pr ofile. J o ur n al of P har mac ol o g y a n d E x peri me ntal T hera pe utics 2 0 1 7: 1 - 4 0. 
B yr d 2 0 0 1 
B yr d J C, M ur p h y T, H o war d R S, et al. Rit u xi ma b usi n g a t hrice wee kl y d osi n g sc he d ule i n B-
cell c hr o nic l y m p h oc ytic le u ke mia a n d s mall l y m p h oc ytic l y m p h o ma de m o nstrates cli nical 
acti vit y a n d acce pta ble t o xicit y. J Cli n O nc ol 2 0 0 1 A pr 1 5; 9( 8): 2 1 5 3- 2 1 6 4. 
B yr d 2 0 0 3 
B yr d J C, Peters o n B L, M orris o n V A, et al. Ra n d o mize d p hase 2 st u d y of fl u dara bi ne wit h 
c o nc urr e nt vers us se q u e ntial treat me nt wit h rit u xi ma b i n s y m pt o matic, u ntreate d p atie nts wit h 
B-cell c hr o nic l y m p h oc ytic le u ke mia: res ults fr o m Ca ncer a n d Le u ke mia Gr o u p B 9 7 1 2 
( C A L G B 9 7 1 2). Bl o o d 2 0 0 3 Ja n 1; 1 0 1( 1): 6- 1 4. 
B yr d 2 0 0 4 
B yr d J C, Stil ge n ba uer S, Fli n n I W. C hr o nic l y m p h oc ytic le u ke mia. H e mat ol o g y A m S oc 
He mat ol E d uc Pr o gra m. 2 0 0 4: 1 6 3- 8 3. 
B yr d 2 0 0 5 
B yr d J C, Rai K, Peters o n B L, et al. A d diti o n of rit u xi ma b t o fl u dara bi ne m a y pr ol o n g 
pr o gressi o n-free s ur vi val a n d o verall s ur vi val i n p atie nts wit h pre vi o usl y u ntreate d c hr o nic 
l y m p h oc ytic le u ke mia: a n u p date d retr os p ecti ve c o m parati ve a n al ysis of C A L G B 9 7 1 2 a n d 
C A L G B 9 0 1 1. Bl o o d 2 0 0 5 Ja n 1; 1 0 5( 1): 4 9- 5 3. 
B yr d 2 0 1 6 
B yr d J C, Harri n gt o n B, O' Brie n S, J o nes J S, Sc h u h A, De vere u x S, et al. A cala br uti ni b ( A C P-
1 9 6) i n rela pse d c hr o nic l y m p h oc ytic le u ke mia. T he Ne w E n gla n d J o ur nal of Me dici ne 
2 0 1 6; 3 7 4: 3 2 3- 3 2. 
C at o vs k y 2 0 0 7 
Cat o vs k y D, Ric har ds S, Mat utes E, Oscier D, D y er M, Bezares R F, et al. Assess me nt of 
fl u dara bi ne pl us c y cl o p h os p ha mi de f or patie nts wit h c hr o nic l y m p h oc ytic le u kae mia (t h e L R F 
C L L 4 Trial): a ra n d o mis e d c o ntr olle d trial. La n cet. 2 0 0 7 J ul 2 1; 3 7 0( 9 5 8 3): 2 3 0- 2 3 9. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1 0 4
 
Cell a 2 0 0 2 
Cella D, Lai J S, C ha n g C H, Peter ma n A, Sla vi n M. Fati g ue i n ca ncer patie nts c o m pare d wit h 
fati g ue i n t he ge neral U nite d States p o p ulati o n. Ca ncer 2 0 0 2; 9 4: 5 2 8- 5 3 8. 
C hes o n 2 0 1 2 
C hes o n B D, B yr d J C, Rai K R, Ka y N E, O' Brie n S M, Fli n n I W, et al. N o v el tar gete d a g e nts 
a n d t he nee d t o r efi ne cli nical e n d p oi nts i n c hr o ni c l y m p h oc ytic le u ke mia. J Cli n O nc ol. 
2 0 1 2; 3 0: 2 8 2 0- 2. 
C hi nese C L L/ S L L Di a g n ostic a n d Tre at me nt G ui deli ne ( Versi o n 2 0 1 8)  
Jia n y o n g L, L u g ui Q. He mat ol o g y C o m mittee of C hi nese Me dical Ass ociati o n, He mat ol o gical 
O nc ol o g y C o m mittee of C hi na A nti- Ca ncer Ass o ciati o n, C hi nese W or ki n g Gr o u p f or C hr o nic 
L y m p h oc ytic Le u ke mia. T he g ui deli nes f or 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/s mall l y m p h oc ytic l y m p h o ma i n C hi na. Chi n J He mat ol . 2 0 1 8 ; 3 9 ( 5).  
C o nse ns us of C hi nese E x perts Versi o n 2 0 1 5 
T he C hi nese e x perts’ c o nse ns us o n t he a p plicati o n of t he rec o m bi na nt h u ma n gra n ul oc yte 
c ol o n y sti m ulati n g fact or (r h G- C S F) i n t u m or c h e m ot hera p y. Natl Me d J C hi na. 2 0 1 5; 9 5: 3 7. 
Eic h h orst 2 0 0 6 
Eic h h orst B F, B usc h R, H o pfi n ger G, Pas ol d R, He nsel M, Stei n brec h er C, et al. Fl u dara bi ne 
pl us c ycl o p h os p ha mi de v ers us fl u dara bi ne al o ne i n first-li ne t hera p y of y o u n ger patie nts wit h 
c hr o nic l y m p h oc ytic le u k e mia. Bl o o d. 2 0 0 6 Fe b 1; 1 0 7( 3): 8 8 5- 9 1. 
Eic h h orst 2 0 0 9 
Eic h h orst B F, B usc h R, Stil ge n ba uer S, Sta uc h M, Ber g ma n n M A, Rit ge n M, et al. First -li ne 
t hera p y wit h fl u dar a bi ne c o m pare d wit h c hl ora m b ucil d oes n ot res ult i n a maj or be nefit f or 
el derl y patie nts wit h a d v a nce d c hr o nic l y m p h oc ytic le u ke mia. Bl o o d. 2 0 0 9; 1 1 4( 1 6): 3 3 8 2- 9 1. 
E ur o Q ol Gr o u p 1 9 9 0 
E ur o Q ol Gr o u p. E ur o Q ol — a ne w f acilit y f or t he meas ure me nt of h ealt h -relate d q ualit y of life. 
Healt h P olic y 1 9 9 0; 1 6: 1 9 9- 2 0 8. 
F a yers 2 0 0 1 
Fa yers P M, Aar o ns o n N K, Bj or dal K, et al., o n b e half of t he E O R T C Q ualit y of Life Gr o u p. 
T he E O R T C Q L Q - C 3 0 Sc ori n g Ma n ual ( 3r d E diti o n). P u blis he d b y: E ur o pea n Or g a nisati o n 
f or Researc h a n d Treat me nt of Ca ncer, Br ussels 2 0 0 1. 
Fli n n 2 0 0 7 
Fli n n I W, N e u ber g D S, Gre ver M R, De wal d G W, Be n nett J M, Paietta E M, et al. P hase III 
trial of fl u dar a bi ne pl us c ycl o p h os p ha mi de c o m pare d wit h fl u dara bi ne f or patie nts wit h 
pre vi o usl y u ntreate d c hr o nic l y m p h oc ytic le u ke mia: U S I nt er gr o u p Trial E 2 9 9 7. J Cli n O nc ol. 
2 0 0 7 Mar 1; 2 5( 7): 7 9 3- 8. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1 0 5
 
G oe de 2 0 1 4 
G oe de V, Fisc her K, B usc h R, E n gel ke A, Eic h h orst B, We n dt ner C M, et al. O bi n ut uz u ma b 
pl us c hl ora m b ucil i n patie nts wit h C L L a n d c oe xisti n g c o n diti o ns. N E n gl J Me d. 2 0 1 4 Mar 
2 0; 3 7 0( 1 2): 1 1 0 1- 1 0. 
H alle k 2 0 0 8 
Halle k M, C hes o n B D, Cat o vs k y D, Cali garis- Ca p pi o F, Bi g hier o G, D o h ner H, 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 dei nes. Bl o o d 2 0 0 8; 1 1 1: 5 4 4 6- 5 6. 
H alle k 2 0 1 0 
Halle k M, Fisc h er K, Fi n gerle - R o ws o n G, Fi n k A M, B usc h R, Ma yer J, et al. A d diti o n of 
rit u xi ma b t o fl u dara bi ne a n d c ycl o p h os p ha mi de i n patie nts wit h c hr o nic l y m p h oc ytic 
le u kae mia: a r a n d o mise d, o pe n-la bel, p has e 3 trial. La ncet. 2 0 1 0 O ct 2; 3 7 6( 9 7 4 7): 1 1 6 4- 7 4. 
H alle k 2 0 1 8 
Halle k M, C hes o n B D, Cat o vs k y D, Cali garis- Ca p pi o F, Di g hier o G, D o h n er H, et al. i w C L L 
g ui deli nes f or dia g n osis, i n dicati o ns f or treat me nt, res p o nse ass ess me nt, a n d s u p p orti ve 
ma na ge me nt of C L L. Bl o o d 2 0 1 8; 1 3 1( 2 5): 2 7 4 5- 7 6 1. 
Her d m a n 2 0 1 1 
Her d ma n M, G u d e x C, Ll o y d A, et al. De vel o p me nt a n d preli mi nar y testi n g of t he ne w fi v e-
le vel versi o n of E Q-5 D ( E Q - 5 D- 5 L). Q ualit y of Life Researc h 2 0 1 1; 2 0: 1 7 2 7- 3 6. 
Hill m e n G 2 0 1 4  
Hill me n P, Gri b be n J G, F oll o ws G A, Milli ga n D, Sa yala H A, M oret o n P, et al. Rit u xi ma b 
pl us c hl ora m b ucil as first- li ne treat me nt f or c hr o ni c l y m p h oc ytic le u ke mia: fi nal a nal ysis of 
a n o pe n-la b el p hase II st u d y. J Cli n O nc ol. 2 0 1 4; 3 2( 1 2): 1 2 3 6- 1 2 4 1.  
H o ni g ber g 2 0 1 0 
H o ni g ber g L, S mit h A, Sirisa wa d M, Ver ner E, L o ur y D, C ha n g B et al. T he Br ut o n t yr osi ne 
ki nase i n hi bit or P CI- 3 2 7 6 5 bl oc ks B-cell acti vati o n a n d is efficaci o us i n m o dels of 
a ut oi m m u ne disease a n d B-cell mali g na nc y. P N A S 2 0 1 0; 1 0 7( 2 9): 1 3 0 7 5- 1 3 0 8. 
H u a n g 2 0 1 8 
H ua n g X, Qi u L, Ji n J, Z h o u D, C he n X, H o u M, et al. I br uti ni b vers us rit u xi ma b i n rela pse d 
or refract or y c hr o nic l y m p h oc ytic le u ke mia or s m all l y m p h oc ytic l y m p h o ma: a ra n d o mize d, 
o pe n-la bel p has e 3 st u d y. Ca ncer Me di ci ne 2 0 1 8; 7( 4): 1 0 4 3- 1 0 5. 
I M B R U VI C A pres cri bi n g i nf or m ati o n 
I M B R U VI C A®  [ pac ka g e i nsert]. H ors ha m, P A: Ja nsse n Bi otec h, I nc; 2 0 1 5. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1 0 6
 
J o h ns o n 1 9 9 6 
J o h ns o n S, S mit h A G, L öffler H, Os b y E, J uli uss o n G, E m meric h B, et al. M ultice ntre 
pr os pecti ve r a n d o mise d trial of fl u dara bi ne vers us c ycl o p h os p ha mi de, d o x or u bici n, a n d 
pre d nis o ne ( C A P) f or treat me nt of a d va n ce d-sta g e c hr o nic l y m p h oc ytic le u kae mia. T he 
Fre n c h C o o per ati ve Gr o u p o n C L L. La ncet. 1 9 9 6 Ma y 2 5; 3 4 7( 9 0 1 3): 1 4 3 2- 8. 
K o hrt 2 0 1 4 
K o hrt H E, Sa gi v- Barfi I, Rafi q S, et al. I br uti ni b a nta g o nizes rit u xi ma b- de p e n de nt N K cell-
me diate d c yt ot o xicit y. Bl o o d 2 0 1 4 Mar 2 0; 1 2 3( 1 2): 1 9 5 7- 1 9 6 0. 
L a n a n d De Mets 1 9 8 3 
La n G a n d D e Mets D L. Discrete se q u e ntial b o u n daries f or cli nical trials. Bi o metri ka 
1 9 8 3; 7 0: 6 5 9- 6 3. 
Le p orrier 2 0 0 1  
Le p orrier M, C he vret S, Cazi n B, et al. Ra n d o mize d c o m paris o n of fl u dara bi ne, C A P, a n d 
C h O P i n 9 3 8  pre vi o usl y u ntreate d sta g e B a n d C c hr o nic l y m p h oc ytic le u k e mia patie nts. 
Bl o o d 2 0 0 1 Oct 1 5; 9 8( 8): 2 3 1 9- 2 3 2 5. 
Mic h allet 2 0 1 8 
Mic hallet A S, et al. 4 9 7 P hase II, m ultice nter tri al, e x pl ori n g “c he m o- s pari n g” strate g y 
ass ociati n g o bi n ut uz u ma b +i br uti ni b f oll o we d b y a M R D- dri ve n strat e g y, i n pre vi o usl y 
u ntreate d s y m pt o matic me dicall y fit c hr o nic l y m p h oc ytic le u ke mia patie nts ( C L L): 
preli mi nar y res ults of t he i n d ucti o n p hase of t he Icll- 0 7 Fil o St u d y. Oral a n d P oster A bst racts. 
Sessi o n: 6 4 2. C L L: T hera p y, e xcl u di n g Tra ns pla ntati o n: Tar geti n g M R D Ne gati ve C L L wit h 
C o m bi nati o ns of N o vel A ge nts a n d C he m oi m m u n ot hera p y Re gi me ns, Ne w Treat me nts. 2 0 1 7 
Dece m b er  1 0. 
Mic h allet 2 0 1 8 
Mic hallet A S, et al. Rit u xi ma b pl us be n da m usti ne or c hl ora m b ucil f or c hr o nic l y m p h oc ytic 
le u ke mia: pri mar y a n al ysis of t he ra n d o mize d, o p e n-la bel M A B L E st u d y. H ae mat ol o gica. 
2 0 1 8; 1 0 3( 4): 6 9 8- 7 0 6. 
N C C N G ui deli nes Versi o n 5 2 0 1 9  
Nati o nal C o m pre he nsi ve Ca ncer N et w or k. C hr o ni c L y m p h oc ytic Le u k e mia/ S mall 
L y m p h oc ytic Le u ke mia ( Versi o n  5. 2 0 1 9). htt p:// w w w. ncc n. or g. Accesse d Ma y 2 3, 2 0 1 9. 
O’ Brie n a n d Fle mi n g 1 9 7 9 
O' Brie n P C, Fle mi n g T R. A M ulti ple Testi n g Pr oce d ure f or Cli nical Trials. Bi o metrics 
1 9 7 9; 3 5( 3): 5 4 9- 5 6. 
O' Brie n 1 9 9 5 
O' Brie n S, del Gi gli o A, Keati n g M. A d va n ces i n t he bi ol o g y a n d treat me nt of B- cell c hr o nic 
l y m p h oc ytic le u ke mia. Bl o o d. 1 9 9 5 Ja n 1 5; 8 5( 2): 3 0 7- 1 8. 

Cli nical St u d y Pr ot oc ol – 5 . 0 
Astra Ze neca  
Acala br uti ni b ( A C P -1 9 6)  - D 8 2 2 B C 0 0 0 0 1  
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y   
 1 0 7
 
O' Brie n 2 0 0 1 
O' Brie n S M, Ka ntarjia n H, T h o mas D A, et al. Rit u xi ma b d ose- escalati o n trial i n c hr o nic 
l y m p h oc ytic le u ke mia. J Cli n O nc ol 2 0 0 1 A pr 1 5; 1 9( 8): 2 1 6 5- 7 0. 
R ai 2 0 0 0 
Rai K R, Peters o n B L, A p pel ba u m F R, et al. Fl u dara bi ne c o m pare d wit h c hl ora m b ucil as 
pri mar y t hera p y f or c hr o nic l y m p h oc ytic le u ke mia. N EJ M 2 0 0 0 Dec 1 4; 3 4 3( 2 4): 1 7 5 0- 1 7 5 7. 
Se y m o ur 2 0 1 7 
Se y m o ur J F, O pat S, C ull G, Tr ot ma n, G ottlie b D, Si m ps o n D, et al. Hi g h o verall res p o ns e 
rate wit h t he B T K i n hi bit or B G B- 3 1 1 1 i n patie nts wit h 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: a n u p date o n safet y a n d acti vit y. He mat ol o gical O nc ol o g y. 
2 0 1 7; 3 5( S 2): 2 3 4- 5. 
Wier d a 2 0 0 5 
Wier da W, O' Brie n S, We n S, et al. C he m oi m m u n ot hera p y wit h fl u dara bi n e, 
c ycl o p h os p ha mi de, a n d rit u xi ma b f or rela pse d a n d refract or y c hr o nic l y m p h oc ytic le u ke mia. J 
Cli n O nc ol 2 0 0 5 J u n 2 0; 2 3( 1 8): 4 0 7 0- 4 0 7 8. 
W o y ac h 2 0 1 3 
W o yac h J A, R u p pert A S, Rai K R, et al. I m p act of A ge o n O utc o mes F oll o wi n g I nitial 
T hera p y wit h C he m ot her a p y a n d Differe nt C he m oi m m u n ot hera p y Re gi me ns i n Patie nts wit h 
C hr o nic L y m p h oc ytic Le u ke mia ( C L L): Res ults of Se q ue ntial C A L G B St u dies 
C he m oi m m u n ot hera p y Re gi me ns i n Patie nts wit h C hr o nic L y m p h oc ytic Le u k e mia ( C L L): 
Res ults of Se q ue ntial C A L G B St u dies. J Cli n O nc ol 2 0 1 3 Fe b 1; 3 1( 4): 4 4 0- 4 4 7. 
Yelle n 1 9 9 7 
Yelle n S B, Cella D F, We bster K, et al. Meas uri n g fati g ue a n d ot her a ne mia- relate d s y m pt o ms 
wit h t he F u ncti o nal Assess me nt of Ca ncer T h era p y ( F A C T) meas ure m e nt s yste m. J Pai n 
S y m pt o m Ma na ge. 1 9 9 7; 1 3( 2): 6 3 – 7 4.