Phase Ib/II Trial of Ibrutinib Plus Nivolumab in Patients With Previously-Treated Metastatic Renal Cell Cancer
Phase: PHASE1
Conditions: Metastatic Renal Cell Cancer, Stage IV Renal Cell Cancer
Sponsor: University of California, Davis

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 
I S T P R O T O C O L  
 
TI T L E:  
P hase I b/II trial of I br uti ni b pl us Ni v ol u ma b i n Patie nts wit h Pre vi o usl y-
treate d Metastatic Re nal Cell Ca ncer 
P R O T O C O L N U M B E R:  
U C D C C # 2 6 2  
S T U D Y D R U G S: 
I br uti ni b ( P CI- 3 2 7 6 5) a n d Ni v ol u ma b ( O p di v o) 
P ri nci p al I n vesti g at or : 
P ri m o N. L ar a, Jr. M D 
U ni versit y of Calif or nia, Da vis ( U C D)  
U C Da vis C o m pre he nsi ve Ca ncer Ce nter  
4 5 0 1 X Street, Sacra me nt o, C A 9 5 8 1 7 
 
 
 
C o -I n vesti g at or(s):  
C h o n g -xi a n  P a n, M D, P h D  
U C  Da vis C o m pre he nsi ve Ca ncer Ce nter  
4 5 0 1 X Street , Sacra me nt o, C A 9 5 8 1 7 
 
 
St atistici a n:  
L a urel B ec kett, P h. D  
U ni versit y of Calif or nia Da vis  
Me d Sci 1 - C, Da vis, C A 9 5 6 1 6 
 
  
 
 
I N D E xe m p ti o n #:  
1 3 0 4 1 3 
I N D S p o ns or: 
U ni versit y of Calif or nia Da vis C o m pre he nsi ve Ca ncer Ce nter  
D A T E FI N A L:  
1 0 A u g ust 2 0 1 5  
P r ot oc ol Versi o n N o./ D ate:  
Ori gi nal / A u g ust 1 0, 2 0 1 5  
A me n d me nt 1. 0 / Fe br uar y 3, 2 0 1 6 
A me n d me nt 2. 0 / Marc h 7, 2 0 1 6  
A me n d me nt 3. 0 / A pril 1 5, 2 0 1 6  
A me n d me nt 4. 0 / J u ne 1 5, 2 0 1 6 
A me n d me nt 5. 0 / Se pte m ber 2 6, 2 0 1 6 
A me n d me nt 6. 0 / Ma y 1 0 , 2 0 1 7 
A me n d me nt 7. 0/ J u ne 1 5, 2 0 1 7  
P artici p ati n g Ce nters:  
T B D  
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 
T A B L E O F C O N T E N T  
T A B L E O F C O N T E N T  ................................................................................................................. 2 
LI S T O F A P P E N DI C E S  ............................................................................................................... 5 
LI S T O F I N -T E X T T A B L E S  ....................................................................................................... 6 
SI T E P RI N CI P A L I N V E S TI G A T O R SI G N A T U R E P A G E  .................................................... 7 
S Y N O P SI S  ...................................................................................................................................... 8 
A B B R E VI A TI O N S  ...................................................................................................................... 1 2 
1.  B A C K G R O U N D  ................................................................................................................... 1 3 
1. 1.  
Disease/ Hist ol o g y  .............................................................................................................. 1 3 
1. 1. 1.  
Treat me nt O pti o ns  ....................................................................................................... 1 4 
1. 1. 2.  
R ole of B T K i n Disease/ Hist ol o g y  .............................................................................. 1 4 
1. 2.  
I n v esti gati o nal Pr o d uct Na me a n d D escri pti o n ................................................................. 1 5 
1. 3.  
S u m mar y of N o n cli nical Data  ........................................................................................... 1 6 
1. 3. 1.  
P har mac ol o g y  .............................................................................................................. 1 6 
1. 3. 2.  
T o xic ol o g y ................................................................................................................... 1 6  
1. 3. 2. 1.  
Carci n o ge nesis, M uta ge n esis, I m p air me nt of Fertilit y  .......................................... 1 6 
1. 4.  
S u m mar y of Cli nical Dat a  ................................................................................................. 1 7 
1. 4. 1.  
P har mac o ki netics a n d Pr o d uct Meta b olis m ................................................................. 1 7  
1. 5.  
S u m mar y of Cli nical Saf et y  ............................................................................................... 1 7 
1. 5. 1.  
Ris ks ............................................................................................................................. 1 8  
1. 5. 2.  
Blee di n g -relate d e ve nts ................................................................................................ 1 8 
1. 5. 3.  
Atrial Fi brillati o n  ......................................................................................................... 1 8 
1. 5. 4.  
C yt o pe nias .................................................................................................................... 1 9 
1. 5. 5.  
Dia rr hea........................................................................................................................ 1 9 
1. 5. 6.  
I nfecti o ns...................................................................................................................... 1 9 
1. 5. 6. 1.  
N o n -mela n o ma s ki n ca ncer .................................................................................... 1 9 
1. 5. 7.  
Ras h ..............................................................................................................................1 9  
1. 5. 8.  
T u m or L ysis S y n dr o me................................................................................................ 1 9  
1. 5. 9.  
I nterstital L u n g Disease (I L D)  ..................................................................................... 2 0 
1. 5. 1 0.  
H y p erte nsi o n  ................................................................................................................ 2 0 
1. 6.  
St u d y R ati o nale  .................................................................................................................. 2 0 
2.  S T U D Y  O B J E C TI V E  ........................................................................................................... 2 0 
2. 1.  
Pri mar y O bj ecti ve  .............................................................................................................. 2 0 
2. 2.  
S ec o n dar y O bj ecti ve(s)  ...................................................................................................... 2 0 
2. 3.  
E x pl orat or y O bjecti ve(s) .................................................................................................... 2 0  
3.  S T U D Y D E SI G N  .................................................................................................................. 2 1 
3. 1.  
O ver vie w of St u d y D esi g n ................................................................................................. 2 1  
3. 1. 1.  
St u d y Sc h e ma ............................................................................................................... 2 2 
3. 2.  
St u d y Desi g n Rati o nale...................................................................................................... 2 3  
3. 2. 1.  
St u d y P o p ulati o n A n d Tr eat me nt................................................................................. 2 3  
3. 2. 2.  
D ose Selecti o n  ............................................................................................................. 2 3 
4.  S U B J E C T S E L E C TI O N  ...................................................................................................... 2 3 
4. 1.  
I n cl usi o n Criteria ............................................................................................................... 2 4 
4. 2.  
E x cl usi o n Criteria  .............................................................................................................. 2 5 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 
5.  T R E A T M E N T O F S U B J E C T S ........................................................................................... 2 6  
5. 1.  
Treat me nt all ocati o n a n d bli n di n g (if a p pr o priate)  ............................................................ 2 6 
5. 2.  
St u d y treat me nt  .................................................................................................................. 2 6 
5. 2. 1.  
R o ute a n d sc he d ule ...................................................................................................... 2 6  
5. 3.  
St u d y M e dicati o n  ............................................................................................................... 2 7 
5. 3. 1.  
I br uti ni b........................................................................................................................ 2 7 
5. 3. 1. 1.  
F or m ulati o n/ Pac ka gi n g/ St ora ge  ............................................................................. 2 7 
5. 3. 1. 2.  
D ose a n d A d mi nistrati o n ....................................................................................... 2 7  
5. 3. 1. 3.  
O ver d ose ................................................................................................................ 2 8  
5. 3. 1. 4.  
D ose M o dificati o n f or A d verse Reacti o ns ............................................................. 2 8  
5. 3. 1. 5.  
D ose M o dificati o n f or H e patic I m paire d S u bjects ................................................ 2 9  
5. 3. 2.  
Ni v ol u ma b.................................................................................................................... 2 9  
5. 3. 2. 1.  
F or m ulati o n/ Pac ka gi n g/ St ora ge  ............................................................................. 2 9 
5. 3. 2. 2.  
D ose a n d A d mi nistrati o n ....................................................................................... 3 0  
5. 3. 3.  
Ma na ge me nt of  Ni v ol u ma b- S pecific A d v erse E ve nts  ................................................ 3 0 
5. 3. 4.  
G ui deli nes f or D osa ge M o dificati o n a n d Treat me nt I nterr u pti o n or Disc o nti n uati o n 3 1  
5. 3. 4. 1.  
Ma na ge me nt of i nf usi o n- relate d reacti o n .............................................................. 3 1 
5. 3. 4. 2.  
Gastr oi ntesti nal T o xicit y  ........................................................................................ 3 2 
5. 3. 4. 3.  
He pat ot o xicit y  ........................................................................................................ 3 3 
5. 3. 4. 4.  
Re nal T o xicit y  ........................................................................................................ 3 4 
5. 3. 4. 5.  
E n d ocri ne T o xicit y................................................................................................. 3 5  
5. 3. 4. 6.  
P ul m o nar y T o xicit y ............................................................................................... 3 6  
5. 3. 4. 7.  
Pericar dial a n d Ple ural Eff usi o ns  ........................................................................... 3 7 
6.  C O N C O MI T A N T M E DI C A TI O N S/ P R O C E D U R E S  ...................................................... 3 8 
6. 1.  
Per mitte d C o nc o mita nt Me dicati o ns  .................................................................................. 3 8 
6. 2.  
Me dicati o ns t o be Use d wit h Ca uti o n ................................................................................ 3 8  
6. 2. 1.  
C Y P 3 A - I n hi bit ors/I n d ucers ........................................................................................ 3 8 
6. 2. 2.  
Dr u gs T hat Ma y H a ve T heir Plas ma C o nce ntrati o ns Altere d b y I br uti ni b  ................. 3 8 
6. 2. 3.  
Q T Pr ol o n gi n g A ge nts ................................................................................................. 3 9  
6. 2. 4.  
A nti platelet A ge nts a n d A ntic oa g ula nts  ...................................................................... 3 9 
6. 3.  
Pr o hi bite d C o nc o mita nt Me dicati o ns  ................................................................................ 3 9 
6. 4.  
G ui deli nes f or I br uti ni b Ma na ge me nt wit h S ur geries or Pr oce d ure .................................. 3 9  
6. 4. 1.  
Mi n or S ur gical Pr oce d ur es .......................................................................................... 3 9  
6. 4. 2.  
Maj or S ur gi cal Pr oce d ur es  ........................................................................................... 4 0 
6. 4. 3.  
E mer ge nc y Pr o ce d ur es ................................................................................................. 4 0 
7.  S T U D Y E V A L U A TI O N S  .................................................................................................... 4 0 
7. 1.  
Descri pti o n of Pr oce d ures .................................................................................................. 4 0  
7. 1. 1.  
Assess me nts  ................................................................................................................. 4 0 
7. 1. 1. 1.  
I nf or me d C o nse nt F or m ......................................................................................... 4 0 
7. 1. 1. 2.  
C o nfir m Eli gi bilit y  ................................................................................................. 4 1 
7. 1. 1. 3.  
Me dical Hist or y  ..................................................................................................... 4 1 
7. 1. 1. 4.  
C o nc o mita nt Me dicati o ns ...................................................................................... 4 1  
7. 1. 1. 5.  
A d verse E v e nts  ...................................................................................................... 4 1 
7. 1. 1. 6.  
P h ysical E x a mi nati o n ............................................................................................. 4 1 
7. 1. 1. 7.  
Vital Si g ns  .............................................................................................................. 4 2 
7. 1. 1. 8.  
Perf or ma nce Stat us  ................................................................................................ 4 2 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 
7. 1. 2.  
La b orat or y  .................................................................................................................... 4 2 
7. 1. 2. 1.  
He mat ol o g y  ............................................................................................................ 4 2 
7. 1. 2. 2.  
C he mistr y ( Ser u m)  ................................................................................................. 4 2 
7. 1. 3.  
Dia g n ostics/ Pr oce d ures ................................................................................................ 4 2  
7. 1. 3. 1.  
Uri nal ysis  ............................................................................................................... 4 2 
7. 1. 3. 2.  
Pre g n a nc y T est  ....................................................................................................... 4 2 
7. 1. 3. 3.  
E C G ........................................................................................................................ 4 2 
7. 2.  
Efficac y E val uati o ns ( Hist ol o g y S pecific)  ......................................................................... 4 3 
7. 3.  
Sa m ple C ollecti o n a n d Ha n dli n g ....................................................................................... 4 3  
8.  S T U D Y P R O C E D U R E S  ...................................................................................................... 4 3 
8. 1.  
Scree ni n g P hase  ................................................................................................................. 4 3 
8. 2.  
Tre at me nt P hase  ................................................................................................................. 4 4 
8. 2. 1.  
C ycle 1, Da y 1 Visit ..................................................................................................... 4 4  
8. 2. 2.  
C ycle 1, Da y 1 5 Visit ................................................................................................... 4 4  
8. 2. 3.  
C ycle 2, Da y 1 Visit ..................................................................................................... 4 5  
8. 2. 4.  
C ycle 2, Da y 1 5 Visit ................................................................................................... 4 5  
8. 2. 5.  
C ycle 3 - 7,  Da y 1 Visit ................................................................................................ 4 5 
8. 2. 6.  
C ycle 3 - 7, Da y 1 5 Visit .............................................................................................. 4 5 
8. 2. 7.  
C ycle 8 a n d Be y o n d ..................................................................................................... 4 6  
8. 2. 8.  
E n d of Treat me nt ( E O T) Visit  ..................................................................................... 4 6 
8. 3.  
F oll o w- u p P hase................................................................................................................. 4 6  
9.  S U B J E C T C O M P L E TI O N A N D WI T H D R A W A L  ......................................................... 4 6 
9. 1.  
C o m pleti o n  ......................................................................................................................... 4 6 
9. 2.  
Wit h dra wal fr o m St u d y Treat me nt  .................................................................................... 4 6 
9. 3.  
Wit h dra wal fr o m St u d y ...................................................................................................... 4 7 
1 0.  S T A TI S TI C A L M E T H O D S A N D A N A L Y SI S  ................................................................. 4 7 
1 0. 1.  S u bject I nf or mati o n  ........................................................................................................... 4 7 
1 0. 2.  E n d p oi nts ........................................................................................................................... 4 8  
1 0. 2. 1.  
Pri m ar y E n d p oi nt ......................................................................................................... 4 8  
1 0. 2. 2.  
Sec o n dar y E n d p oi nts ................................................................................................... 4 8  
1 0. 2. 3.  
Ot her Sec o n d ar y E n d p oi nts ......................................................................................... 4 8  
1 0. 2. 4.  
E x pl orat or y E n d p oi nts ................................................................................................. 4 8  
1 0. 3.  Sa m ple Size Deter mi nati o n ................................................................................................ 4 8 
1 0. 4.  A nal ysis P o p ulati o ns .......................................................................................................... 4 8  
1 0. 4. 1.  
Safet y P o p ulati o n ......................................................................................................... 4 8  
1 0. 4. 2.  
Efficac y p o p ulati o ns .................................................................................................... 4 8  
1 0. 5.  Statistical Met h o ds  ............................................................................................................. 4 9 
1 1.  A D V E R S E E V E N T R E P O R T I N G ..................................................................................... 4 9 
1 1. 1.  Defi niti o ns .......................................................................................................................... 4 9 
1 1. 1. 1.  
A d verse E v e nts  ............................................................................................................ 4 9 
1 1. 1. 2.  
Seri o us A d verse E v e nts ............................................................................................... 5 0  
1 1. 1. 3.  
Se verit y Criteria ( Gra de 1 - 5) ....................................................................................... 5 1 
1 1. 1. 4.  
Ca usalit y ( Attri b uti o n)  ................................................................................................. 5 2 
1 1. 2.  U ne x pecte d A d verse E ve nts .............................................................................................. 5 2  
1 1. 3.  S pecial Re p orti n g Sit uati o ns  .............................................................................................. 5 2 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 
1 1. 4.  D oc u me nti n g a n d Re p orti n g of A d v erse E v e nts a n d Seri o us A d verse E v e nts b y 
I n v esti gat ors ................................................................................................................................... 5 3 
1 1. 4. 1.  
Assess me nt of A d vers e E ve nts .................................................................................... 5 3  
1 1. 4. 2.  
A d verse E ve nt R e p orti n g Peri o d  .............................................................................. 5 3 
1 1. 4. 3.  
Pre g n a nc y  ..................................................................................................................... 5 4 
1 1. 4. 4.  
Ot her Mali g na nci es  ...................................................................................................... 5 4 
1 1. 4. 5.  
E ye -Relate d A d v erse E v e nts ........................................................................................ 5 4 
1 1. 4. 6.  
A d verse E v e nts of S peci al I nt erest ( A E SI)  .................................................................. 5 4 
1 1. 4. 6. 1.  
Maj or He m orr h a ge  ................................................................................................. 5 5 
1 1. 4. 7.  
E x pe diti n g Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts ............................... 5 5  
1 2.  S T U D Y A D MI NI S T R A TI O N  A N D I N V E S TI G A T O R O B LI G A TI O N S  ...................... 5 6 
1 2. 1.  Re g ulat or y a n d Et hical C o m plia nce .................................................................................. 5 6  
1 2. 2.  I nf or me d C o nse nt............................................................................................................... 5 6 
1 2. 3.  Q ualit y C o ntr ol a n d Q u alit y Ass ura n ce ............................................................................. 5 6  
1 2. 4.  Data a n d Saf et y M o nit ori n g ............................................................................................... 5 6  
1 2. 5.  Pr otecte d S u bject Healt h I nf or mati o n A ut h orizati o n  ........................................................ 5 7 
1 2. 6.  St u d y Files a n d Rec or d Rete nti o n...................................................................................... 5 7  
1 2. 7.  Case Re p ort F or ms a n d Rec or d Mai nte na n ce  .................................................................... 5 8 
1 2. 8.  I n v esti gati o nal St u d y Dr u g A cc o unta bilit y  ....................................................................... 5 9 
1 2. 9.  Pr ot oc ol A me n d me nts ........................................................................................................ 5 9  
1 2. 1 0.  P u blicati o n of St u d y Res ults .............................................................................................. 5 9  
1 2. 1 1.  St u d y Disc o nti n uati o n  ........................................................................................................ 5 9 
1 3.  R E F E R E N C E S  ..................................................................................................................... 6 0 
1 4.  A P P E N DI C E S  ....................................................................................................................... 6 1 
 
LI S T O F A P P E N DI C E S  
A p pe n di x 1.  Sc he d ule of Assess me nts ........................................................................................ 6 2  
A p pe n di x 2.  E C O G a n d Kar n ofs k y Perf or ma n ce Stat us Sc ores 1, 2 .............................................. 6 4 
A p pe n di x 3.  I n hi bit ors a n d I n d u cers of C Y P 3 A .......................................................................... 6 5  
A p pe n di x 4.  Res p o nse Criteria .................................................................................................... 6 6  
A p pe n di x 5: Pill Diar y  .................................................................................................................. 7 0 
A p pe n di x 6: N CI C T C V ersi o n 4. 0 3 ............................................................................................ 7 1  
A p pe n di x 7:  Re gistrati o n G ui deli nes ........................................................................................... 7 2  
A p pe n di x 8: M olec ular C orrelati ve Sa m ple Ha n dli n g  ................................................................. 7 3 
A p pe n di x 9: S u b missi o n F or m ..................................................................................................... 7 5  
A p pe n di x 1 0: C hil d- P u g h Sc ore ................................................................................................... 7 6  
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 
LI S T O F I N -T E X T T A B L E S  
Ta ble 1            I br uti ni b D ose M o dificati o ns  
Ta ble 2   
D ose M o dificati o n G ui deli nes f or Gastr oi ntesti nal T o xicit y  
Ta ble 3  
D ose M o dificati o n G ui deli nes f or He pat ot o xicit y 
Ta ble 4  
D ose M o dificati o n G ui deli nes f or Re nal T o xicit y  
Ta ble 5  
D ose M o dificati o n G ui deli nes f or E n d ocri ne T o xicit y  
Ta ble 6   
D ose M o dificati o n G ui deli nes f or P ul m o nar y T o xicit y  
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 7 
 
SI T E P RI N CI P A L I N V E S TI G A T O R SI G N A T U R E P A G E  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Si g nat ure of Site Pri nci pal I n vesti gat or  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Date  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Pri nte d Na me of  Site Pri nci pal I n vesti gat or  
 
I nstit uti o n Na me: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
B y m y si g nat ure, I a gree t o pers o nall y s u per vise t he c o n d uct of t his st u d y a n d t o e ns ure its c o n d uct i n 
c o m plia nce wit h t he pr ot oc ol, i nf or me d c o nse nt, I R B/ E C pr oce d ures, i nstr ucti o ns fr o m P har mac yclics  
re prese ntati ves, t he Declarati o n of Helsi n ki, I C H G o o d Cli nical Practices g ui deli nes, a n d t he a p plica ble 
parts of t he U nite d States C o de of Fe deral Re g ulati o ns or l ocal re g ulati o ns g o ver ni n g t he c o n d uct of 
cli nical st u dies. 
 
 
 
 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 8 
S Y N O P SI S  
St u d y Title:  
A P hase I b/II tri al of I br uti ni b pl us Ni v ol u ma b i n Patie nts wit h 
Pre vi o usl y- treate d Met astatic Re nal Cell Ca ncer 
P r ot oc ol N u m ber:  
U C D C C # 2 6 2  
St u d y P h ase:  
1 b/ 2 
St u d y D ur ati o n:  
3 0 m o nt hs 
N u m ber of S u bjects:  
3 0  
I n vesti g ati o n al Pr o d uct 
a n d Ref ere nce T her a p y:  
I br uti ni b will be s u p plie d as 1 4 0 m g har d gelati n ca ps ules f or oral ( P O) 
a d mi nistrati o n.  I br uti ni b will be s u p plie d b y P har mac yclics. 
Ni v ol u ma b will be a d mi nistere d at  2 4 0 m g as a n i ntra ve n o us i nfusi o n 
o ver 6 0 mi n utes e ver y 2 wee ks.   Ni v ol u ma b is c o m merciall y a vaila ble.   
O bjecti ves:  
P ri m ar y O bjecti ve:  
T o assess i n a preli mi nar y fas hi o n t he feasi bilit y a n d efficac y of i br uti ni b 
i n c o m bi nati o n wit h ni v ol u ma b i n patie nts wit h pre vi o usl y-treate d 
metastatic re nal cell ca ncer ( m R C C).  
Sec o n d ar y O bjecti ves : 
T o e val uate t he safet y of t he c o m bi nati o n of i br uti ni b a n d ni v ol u ma b i n 
patie nts wit h pre vi o usl y treate d m R C C.  
E x pl or at or y O bjecti ves:  
Arc hi val t u m or s peci me ns will be c ollecte d f or p ote ntial B T K. E T K a n d 
P D 1 c orrelati ve st u dies . 
St u d y Desi g n:  
Pr os pecti ve, o pe n-la bel, n o n-ra n d o mi ze d, U S m ultice nter st u d y 
P o p ul ati o n: 
A d ult s u bjects wit h metastatic re nal cell carci n o ma of a n y hist ol o gic 
s u bt y pe w h o ha ve c o m plete d at least o ne li ne of pri or s yste mic t hera p y 
are p ote ntiall y eli gi ble f or t his trial. 
Ce nters:  
U C Da vis a n d o ne a d diti o nal site  ( T B D) 
I ncl usi o n Criteri a: 
Refer t o Secti o n 4. 0  f or t he 
c o m plete a n d det aile d list of 
i ncl usi o n/excl usi o n criteri a. 
Dise ase Rel ate d  
Patie nts wit h m etastatic re nal cell carci n o ma of a n y hist ol o gic 
s u bt y pe wit h meas ura ble a n d/ or e val ua bl e disease w h o ha ve 
c o m plete d at least o ne li n e of pri or s yste mic t hera p y are p ote ntiall y 
eli gi ble f or t his trial.  
L a b or at ory 
•  
A de q uate h e mat ol o gi c f u ncti o n defi ne d as :  
A bs ol ute ne utr o p hil c o u nt > 7 5 0  cells/ m m 3 ( 0. 7 5 x 1 09/ L).   
Platelet c o u nt > 5 0, 0 0 0 cells/ m m 3 ( 5 0 x 1 09/ L).    
He m o gl o bi n > 8. 0 g/ d L. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 9 
•  
A de q uate h e patic a n d re n al f u ncti o n defi ne d as : 
Ser u m as partate tra nsa mi nase ( A S T) or ala ni ne tra nsa mi nase 
( A L T) ≤ 3. 0 x u p per li mit of n or mal ( U L N). 
Esti mate d ( meas ure d or calc ulate d) Creati ni ne Cleara nce ≥3 0 
ml/ mi n ( C oc kcr oft -Ga ult)  
Bilir u bi n ≤1. 5 x U L N ( u nless bilir u bi n rise is d ue t o Gil bert’s 
s y n dr o me or of n o n- he patic ori gi n) 
•  
P T/I N R < 1. 5 x U L N a n d P T T (a P T T) < 1. 5 x U L N. 
De m o gr a p hic 
•  
Me n a n d w o me n ≥ 1 8 years of a ge. 
•  
Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) p erf or ma nce 
stat us of 0- 2 
E xcl usi o n Criteri a:  
C o nc urre nt C o n diti o ns  
•  
C yt ot o xic c he m ot hera p y ≤2 1 da ys pri or t o first a d mi nistrati o n 
of st u d y treat me nt a n d/ or m o n ocl o nal a nti b o d y ≤ 4 wee ks pri or 
t o first a d mi nistrati o n of st u d y treat me nt a n d/ or ot her R C C-
directe d s yste mic t hera p y < 2 wee ks pri or t o first 
a d mi nistrati o n of st u d y treat me nt  
•  
A n y k n o w n a d diti o nal mali g na n c y t hat is pr o gressi n g or 
re q uires acti ve treat me nt. E x cepti o ns i ncl u de basal cell 
carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of t he s ki n, or 
i n sit u cer vical ca ncer t hat has u n der g o ne p ote ntiall y c urati ve 
t hera p y. 
•  
C o nc urre nt s yste mic i m m u n os u p pressa nt t hera p y (e g, 
c ycl os p ori ne A, tacr oli m us, etc., or c hr o ni c a d mi nistrati o n of 
> 1 0 m g/ da y of pre d nis o n e) wit hi n 2 8 da ys of t he first d ose of 
st u d y dr u g.  
•  
Vacci n ate d wit h li ve, atte n uate d vacci nes wit hi n 4 wee ks of 
first d ose of st u d y dr u g. 
•  
Rece nt i nfecti o n re q uiri n g s yste mic treat me nt t hat was 
c o m plete d ≤1 4 da ys bef ore t he first d ose of st u d y dr u g. 
•  
U nres ol ve d t o xicities fr o m pri or a nti- ca n cer t hera p y, defi ne d as 
ha vi n g n ot res ol ve d t o C o m m o n Ter mi n ol o g y Criteria f or 
A d verse E v e nt ( C T C A E, versi o n 4), gra d e 0 or 1, or t o t he 
le vels dictate d i n t he i ncl usi o n/e x cl usi o n criteria wit h t he 
e x ce pti o n of al o pecia.  
•  
K n o w n blee di n g dis or ders (e g, v o n Wille bra n d’s disease) or 
he m o p hilia. 
•  
Hist or y of str o k e or i ntracra nial he m orr ha ge wit hi n 6 m o nt hs 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 0 
pri or t o e nr oll me nt.  
•  
K n o w n hist or y of h u ma n i m m u n o deficie nc y vir us ( HI V) or 
acti ve wit h he patitis C vir us ( H C V) or h e patitis B vir us ( H B V). 
S u bjects w h o are p ositi ve f or he p atitis B c ore a nti b o d y or 
he patitis B s urface a nti ge n m ust ha ve a ne gati ve p ol y merase 
c hai n reacti o n ( P C R) res ult bef ore e nr oll me nt.  T h ose w h o are 
P C R p ositi ve will b e e x cl u de d . 
•  
A n y u n c o ntr olle d acti ve s yste mic i nfecti o n. 
•  
Maj or s ur ger y wit hi n 4 wee ks of first d ose of st u d y dr u g. 
•  
A n y life -t hreate ni n g ill ness, me dical c o n diti o n, or or ga n 
s yste m d ysf u ncti o n t hat, i n t he i n vesti gat or’s o pi ni o n, c o ul d 
c o m pr o mise t he s u bject’s safet y or p ut t he st u d y o utc o mes at 
u n d ue ris k. 
•  
C urre ntl y acti ve, cli nicall y si g nifica nt car di o vas c ular disease, 
s uc h as u nc o ntr olle d arr h yt h mia or Class 3 or 4 c o n gesti ve 
heart fail ure 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 Classificat i o n; or a hist or y of m y o car di al i nfarcti o n, 
u nsta ble a n gi na, or ac ute c or o nar y s y n dr o me wit hi n 6 m o nt hs 
pri or t o e nr oll me nt. 
•  
U na ble t o s wall o w ca ps ules or 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 n cti o n, or 
resecti o n of t he st o mac h or s mall b o wel, s y m pt o m atic 
i nfla m mat or y b o wel disease or ulcerati ve c olitis, or partial or 
c o m plete b o wel o bstr ucti o n. 
•  
Lactati n g or pre g na nt. 
•  
U n willi n g or u na ble t o p artici pate i n all re q uire d st u d y 
e val uati o ns a n d pr o ce d ures. 
•  
U na ble t o u n dersta n d t h e p ur p ose a n d ris ks of t he st u d y a n d t o 
pr o vi de a si g ne d a n d d ate d i nf or me d c o nse nt f or m (I C F) a n d 
a ut h orizati o n t o use pr otecte d healt h i nf or m ati o n (i n 
acc or d a nce wit h nati o nal a n d l ocal s u bject pri v ac y re g ulati o ns) 
•  
C o nc o mita nt use of warfari n or ot her Vita mi n K a nta g o nists.  
N ote: S u bjects recei vi n g a nti platelet a ge nts i n c o nj u ncti o n wit h 
i br uti ni b s h o ul d be o bser ve d cl osel y f or a n y si g ns of blee di n g 
or br uisi n g, a n d i br uti ni b s h o ul d be wit h hel d i n t he e ve nt of 
a n y bl ee di n g e v e nts. S u p ple me nts s uc h as fis h oil a n d vita mi n 
E pre parati o ns s h o ul d be a v oi de d. 
•  
Re q uires treat me nt wit h a str o n g c yt oc hr o me P 4 5 0 ( C Y P) 
3 A 4/ 5 i n hi bit or. (see A p pe n di x 3 ) 
•  
Q T pr ol o n gati o n a n d/ or fa miliar hist or y of Q T pr ol o n gati o n 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 1 
a n d u nc o ntr olle d car diac arr h yt h mias  t hat i n t he o pi ni o n of t he 
i n vesti gat or w o ul d i nterfere wit h t he patie nt’s safet y or 
c o m plia nce o n trial. 
•  
C urre ntl y acti ve, cli nicall y si g nifica nt h e patic i m pair me nt 
C hil d -P u g h class B or C acc or di n g t o t he C hil d P u g h 
classificati o n ( A p p e n di x 1 0). 
St u d y Tre at me nt:  
I br uti ni b 4 2 0- 5 6 0 m g P O dail y 
Ni v ol u ma b 2 4 0 m g I V q 2 wee ks  
C ycles r e peate d e v er y 2 8 da ys  
C o nc o mit a nt T her a p y:  
Refer t o Secti o n 6  f or i nf or m ati o n o n c o nc o mit a nt t her a py. 
S af et y Pl a n:  
 
A d verse e ve nts a n d seri o us a d verse e ve nts ( S A Es) will be re vie we d 
b y t he D ata a n d Safet y M o nit ori n g C o m mittee o n a n o n g oi n g b asis 
t o i dentif y safet y c o ncer ns.  
St atistic al Met h o ds a n d 
D at a A n al ysis: 
Pri m ar y Effic ac y A n al ysis:  R E CI S T criteri a will be use d t o assess 
efficac y (i.e., pr o gressi o n free s ur vi val rate.)  
 
S af et y A n al ysis: A d verse e ve nts will be e v al uate d a n d rec or de d 
usi n g C T C A E versi o n 4.  
 
I nteri m A n al ysis 
N o i nteri m a nal ysis is pla n ne d.  
S a m ple Size 
Deter mi n ati o n: 
3 0  
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 2 
A B B R E VI A TI O N S  
C R F  
case re p ort f or m  
D C F  
data clarificati o n f or m  
D M C  
Data M o nit ori n g C o m mittee  
D S M -I V 
Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders ( 4t h e diti o n)  
E C G  
E lectr ocar di o gra m 
e D C 
electr o nic data ca pt ure 
G C P  
G o o d Cli nical Practice  
H Bs A g  
he patitis B s urface a nti ge n  
HI V  
h u ma n i m m u n o deficie nc y vir us 
I A C 
I nteri m A nal ysis C o m mittee 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I R B 
I nstit uti o nal Re vie w B oar d 
I V R S 
i nteracti ve v oice res p o nse s yste m 
I W R S 
i nteracti ve we b res p o nse s yste m 
L C -M S/ M S  
li q ui d c hr o mat o gra p h y/ mass s pectr o metr y/ mass s pectr o metr y 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M R U  
me dical res o urce utilizati o n  
P D  
P har mac o d y na mic 
P K  
P har mac o ki netic  
P Q C  
Pr o d uct Q ualit y C o m plai nt 
P R O  
patie nt -re p orte d o utc o me(s) 
R C C  
Re nal cell ca rci n o ma 
T F  
Treat me nt Fail ure  
T S H  
T h yr oi d Ster oi d H or m o ne 
U S P  
U nite d States P har mac o peia  
 
 
 
 
 
 
 
 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 3 
1.  
B A C K G R O U N D 
1. 1.  
Dise ase/ Hist ol o g y  
Re nal cell carci n o ma ( R C C) is dia g n ose d i n o ver 3 3 0, 0 0 0 patie nts dia g n os e d gl o b all y a n d is 
res p o nsi ble f or o v er 1 4 0, 0 0 0 deat hs. O ne-t hir d of patie nts are t y picall y dia g n ose d wit h o vert 
metastases at i nitial prese ntati o n. A d diti o nall y, i n t h ose patie nts i ni tiall y di a g n ose d wit h or ga n-
c o nfi ne d R C C a n d w h o are s ur gicall y treate d wit h a c urati ve i nte nt, a p pr o xi matel y o n e- t hir d will 
rela pse a n d s u bse q ue ntl y s ucc u m b t o t he disease.  
M utati o n or i nacti vati o n of v o n Hi p pel- Li n da u ( V H L) t u m or s u p press or ge ne is f o u n d i n o ver 
8 0 % of clear cell R C C t u m ors. T his lea ds t o acc u m ulati o n of h y p o xia i n d uci ble fact or ( HI F) a n d 
t he u pre g ulati o n of vas c ular e n d ot helial gr o wt h fact or ( V E G F) pr o d ucti o n. T h us, a ge nts t hat 
m o d ulate or i n hi bit V E G F a n d its rece pt ors a n d cell ular pat h wa ys ha v e bee n s h o w n t o be hi g hl y 
efficaci o us i n metastatic R C C. S yste mic t hera pies directe d a gai nst a n gi o ge nesis are 
c o m merciall y a v aila ble a n d are i n wi de us e f or t he treat me nt of metastatic R C C. T hese a ge nts 
i ncl u de s u niti ni b, s orafe ni b, paz o pa ni b, a xiti ni b, a n d be vaciz u ma b. Of n ote, s u niti ni b, paz o pa ni b, 
a n d be vaciz u ma b ( pl us i nterfer o n- al p ha) were i n v esti gate d i n t he first -li ne setti n g, w hile 
s orafe ni b a n d a xiti ni b were i n vesti gate d f oll o wi n g pr o gressi o n wit h a first-li ne treat me nt. Als o 
a p pr o ve d f or t he treat me nt of m R C C are t he ma m malia n tar get of ra pa m yci n ( m T O R) i n hi bit ors 
te msir oli m us (first-li ne, p o or ris k patie nts) a n d e v er oli m us (sec o n d li ne a n d be y o n d).  
U ni versall y, t he vast maj orit y of p atie nts treate d wit h o ne or m ore of t hes e dr u gs will e x perie nce 
disease pr o gr essi o n eit her after a n i nitial res p o nse or t u m or sta bilizati o n, or at t he o utset. T he 
me dia n pr o gressi o n-free s ur vi val ti me ra n ges fr o m 8 t hr o u g h 1 1 m o nt hs f or first-li ne s u niti ni b or 
paz o pa ni b, a n d fr o m 3 t hr o u g h 5 m o nt hs wit h s orafe ni b or a xiti ni b f oll o wi n g pr o gressi o n wit h 
first-li ne s u niti ni b treat me nt. E ver oli m us i m pr o ve d pr o gressi o n-free s ur vi val c o m pare d t o 
place b o i n a p h ase 3 trial i n R C C patie nts w h o pre vi o usl y pr o gresse d o n s u niti ni b a n d/ or 
s orafe ni b. 
Mec ha nis ms of r esista nc e t o V E G F - directe d t hera p y are n ot f ull y k n o w n.  S o me e vi de nce p oi nts 
t o re vasc ularizati o n as a n esca pe m ec ha nis m. A cti vit y of ot her a nti- V E G F a ge nts after 
de vel o p me nt of r esista nce t o V E G F- R bl oc ka de s u g gests t hat c o m plet e i n de pe n de n ce fr o m 
V E G F d o es n ot de vel o p i n t he resista nt state.  I n t he case of V E G F - R T KIs, t he s u bsta ntial 
varia bilit y i n t heir tar get pr ofiles a n d bi n di n g s p ecificit y s u g gests t hat resist a nce t o a n ot h er i n -
class a ge nt is n ot i m plicit. N u mer o us trials ha ve s h o w n cli nical acti vit y of V E G F - p at h wa y a ge nts 
i n disease t hat has pr o gr esse d des pite i nitial V E G F- bl oc ka de.  Mai ntai ni n g V E G F i n hi biti o n i n 
t his setti n g ma y b e a pr o d ucti ve strate g y.  S uc h m a y b e t he case i n c ol orect al ca ncer, w h ere s o me 
e vi de nce h as s u g geste d t hat c o nti n ui n g be v aciz u ma b i n t he face of diseas e pr o gressi o n ma y b e 
ass ociate d wit h better o ut c o me. A xiti ni b was s h o w n t o ha ve a P F S be n efit w he n c o m pare d t o 
s orafe ni b i n t he A XI S trial of pre d o mi na ntl y sec o n d-li ne m R C C patie nts.  
W hile c o nti n ue d V E G F i n hi biti o n has t he oretic al rati o nale, c h a n gi n g t h era pe utic dr u g class u p o n 
pr o gressi o n is a n a p pr o ac h t hat has bee n vali dat e d i n t he case of m T O R i n hi biti o n after V E G F-

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 4 
T KI t hera p y.  E ver oli m us de m o nstrate d a P F S a d va nta ge o ver place b o aft er s u niti ni b a n d/ or 
s orafe ni b t hera p y a n d is a vali d treat me nt c h oi ce i n t his setti n g.   
1. 1. 1.  
Tre at me nt O pti o ns  
M ulti ple c o m bi nati o ns of t he ne w a ge nts are b ei n g e x pl ore d i n o n g oi n g st u dies.  Mi ni mal 
ra n d o mize d data ar e yet a vaila ble r e gar di n g relati ve effi cac y of s uc h c o m bi nati o ns. T he o pti mal 
strate g y i n ma na gi n g pr o gr essi ve R C C after resista nce t o i nitial t hera p y is i n ra pi d e v ol uti o n. 
Rece nt trials of t he P D 1 i n hi bit or Ni v ol u ma b a n d t he V E G F R/ M E T T KI Ca b oza nti ni b i n t he 
pre vi o usl y tr eate d s etti n g s h o we d efficac y be nefit f or t hese a ge nts w he n c o m pare d t o 
e ver oli m us; h o we ver, as of t his writi n g, neit her of t hese ne wer a ge nts ha ve bee n F D A-a p pr o ve d 
f or metastatic R C C.  Si nce t he a v aila bilit y of m ulti ple a ge nts, s witc hi n g dr u gs i n t he face of 
pr o gressi o n has i nstea d b ec o me a sta n d ar d p ractice. 
C hec k p oi n t i n hi bit or t hera p y is als o p artic ularl y acti ve i n R C C, partic ularl y wit h P D 1 i n hi bit ors. 
A rece nt pa per b y M otzer et al (J C O 2 0 1 4) re p ort e d t he res ults of a ra n d o mize d p hase II trial 
testi n g t he B M S P D 1 i n hi bit or Ni v ol u ma b i n m R C C. A t otal of 1 6 8 patie nts were ra n d o ml y 
assi g ne d t o t hr ee d ose l e vels of ni v ol u ma b 0. 3- ( n = 6 0), 2- ( n = 5 4), a n d 1 0- m g/ k g ( n = 5 4). 
Me dia n P F S was 2. 7, 4. 0, a n d 4. 2 m o nt hs, res pecti vel y ( P = . 9). Res pecti ve O R Rs were 2 0 %, 
2 2 %, a n d 2 0 %. Me di a n O S was 1 8. 2 m o nt hs ( 8 0 % CI, 1 6. 2 t o 2 4. 0 m o nt hs), 2 5. 5 m o nt hs ( 8 0 % 
CI, 1 9. 8 t o 2 8. 8 m o nt hs), a n d 2 4. 7 m o nt hs ( 8 0 % CI, 1 5. 3 t o 2 6. 0 m o nt hs), res pecti vel y. 
Ni v ol u ma b was als o rece ntl y re p orte d t o i m pr o ve O S c o m pare d t o e v er oli m us i n a lar ge 
ra n d o mize d p hase III trial.  
1. 1. 2.  
R ole o f B T K  i n Dise ase/ Hist ol o g y 
T he Bt k f a mil y ki nas es r e prese nt me m b ers of n o n -rece pt or t yr osi ne ki nas es, w hic h i ncl u de 
Bt k/ At k, It k/ E mt/ Ts k, B m x/ E T K, a n d Tec. Si milar t o Src -fa mil y ki nas es, Bt k fa mil y ki nases 
pla y ce ntral b ut di verse m o d ulat or y r ol es i n vari o us cell ular pr ocesses, partic ularl y i n 
tra nsf or me d or mali g n a nt cells. T here is n o w c o n vi nci n g e vi d e nce t h at Bt k fa mil y ki nas es 
( partic ularl y E T K) are o v er-e x presse d i n re nal cell ca ncer. A rece nt pa per b y Z h ua n g et al (J E x p 
Cli n Ca ncer Res 2 0 1 4) re p orte d t he res ults of precli nical st u dies i n 9 0 h u ma n R C C t u m or 
s peci me ns a n d 3 0 n or mal tiss ues. I n t his st u d y, E T K e x pressi o n b y I H C w as f o u n d t o be 
i ncreas e d i n R C C as c o m pare d t o n or mal c o ntr ols. F urt her m ore, t here was a p ositi ve c orrel ati o n 
bet wee n E T K e x pre ssi o n a n d i ncreasi n g cli nical sta ge, gra d e a n d met astasis. I n a d diti o n, E T K 
e x pressi o n a p pear e d t o ha ve pr o g n ostic rele va n ce: o verall s ur vi val a p p eare d t o be s h orter f or 
patie nts w h ose t u m ors ha d hi g her E T K e x pressi o n. I n R C C cell li ne m o dels, d o w nre g ulati o n of 
E T K res ulte d i n si g nifica nt t u m or gr o wt h i n hi biti o n as well as re d ucti o n i n mi grati o n/i n vasi o n. 
T here w as als o n ote of e n ha nce d a p o pt osis w he n E T K was d o w nre g ulate d. 
T hese earl y data s u g gest t hat E T K ma y be a reas o na ble t hera p e utic tar get i n R C C.  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 5 
1. 2.  
I n vesti g ati o n al Pr o d uct N a me a n d Descri pti o n  
I br uti ni b is a first-i n-class, p ote nt, orall y a d mi nistere d c o v ale nt l y- bi n di n g i n hi bit or of Br ut o n’s 
t yr osi ne ki nas e ( B T K).  I n hi biti o n of B T K bl oc ks d o w nstrea m B-cell rece pt or ( B C R) si g nali n g 
pat h wa ys a n d t h us pr e ve nts B-cell pr oliferati o n. I n vitr o, i br uti ni b i n hi bits p urifie d B T K a n d 
selecte d me m bers of t he ki nase fa mil y wit h 1 0-f ol d s pecificit y c o m pare d wit h n o n- B T K ki nases.  
I br uti ni b (I M B R U VI C A® ) is a p pr o v e d b y t he U. S. F o o d a n d Dr u g A d mi nistrati o n ( F D A) f or t he 
treat me nt of: 1) ma ntle cell l y m p h o ma ( M C L) i n patie nts w h o ha ve recei ve d at least o ne pri or 
t hera p y bas e d o n o ver all res p o nse r ate, 2) c hro nic l y m p h oc ytic le u k e mia ( C L L) i n cl u di n g  
patie nts wit h 1 7 p deleti o n or a T P 5 3 m utati o n 3) Wal de nstr ö m’s Macr o gl o b uli ne mia ( W M).  
I br uti ni b is c urre ntl y u n d er i n vesti gati o n i n vari o us i n dicati o ns.   
B cells are l y m p h oc ytes wit h m ulti ple f u ncti o ns i n t he i m m u ne res p o nse, i ncl u di n g a nti ge n 
prese ntati o n, a nti b o d y pr o d ucti o n, a n d c yt o ki ne release.  B- cells e x press cell s urface 
i m m u n o gl o b uli ns c o m prisi n g t he B-cell rece pt or ( B C R), w hic h is acti vate d b y bi n di n g t o 
a nti ge n.  A nti ge n bi n di n g i n d uces rece pt or a g gre gati o n a n d t he cl usteri n g a n d acti vati o n of 
m ulti ple t yr osi n e ki nases, w hic h i n t ur n acti vate f urt her d o w nstrea m si g n ali n g pat h w a ys ( Bis h o p 
2 0 0 3).  
T he pr ocess of B-cell mat urati o n, i ncl u di n g i m m u n o gl o b uli n c hai n rearra n ge m e nt a n d s o matic 
m utati o n, is ti g h tl y re g ul ate d.  It is t h o u g ht t hat B-cell l y m p h o mas a n d C L L res ult fr o m 
m utati o ns a n d tra nsl ocati o ns ac q uire d d uri n g n or mal B-cell de vel o p me nt ( S haffer 2 0 0 2).  
Se veral li nes of e vi d e nce s u g gest t hat si g nali n g t hr o u g h t he B C R is necess ar y t o s ustai n t he 
via bilit y of B -cell mali g n a ncies.   
T he r ole of B T K i n B C R si g nal tra ns d u cti o n is de m o nstrate d b y t h e h u ma n ge n etic 
i m m u n o deficie nc y diseas e X-li n ke d a ga m ma gl o b uli ne mia a n d t he m o use ge netic disease X-
li n ke d i m m u n o deficie nc y, b ot h ca use d b y a m utati o n i n t he B T K ge n e.  T h ese ge netic dis eases 
are c h ar acterize d b y r e d u ce d B C R si g nali n g a n d a fail ure t o ge n erate m at ure B -cells.  T he B T K 
pr otei n is e x presse d i n m ost he mat o p oietic cells wit h t he e x ce pti o n of T -cells a n d nat ural killer 
cells, b ut t he selecti ve eff ec t of B T K m utati o ns s u g gests t hat its pri mar y f u ncti o nal r ole is i n 
a nti ge n rece pt or si g nali n g i n B-cells ( Sattert h wait e 2 0 0 0).   
Data fr o m St u d y P C Y C - 0 4 7 5 3 de m o nstrate t hat alt h o u g h i br uti ni b is ra pi dl y eli mi nate d fr o m t he 
plas ma after oral a d mi nistrati o n,  o nce dail y d osi n g wit h i br uti ni b is a de q uate t o s ustai n ma xi mal 
p har mac o d y n a mic acti vit y f or 2 4 h o urs p ost d ose at d ose le vels ≥2. 5 m g/ k g. I n St u d y P C Y C-
0 4 7 5 3, t he B T K o cc u pa n cies f or t he 2. 5 m g/ k g/ da y t o 1 2. 5 m g/ k g/ d a y c o h orts a n d f or t he 
5 6 0 m g c o nti n u o us d osi n g c o h ort, wer e all a b o v e 9 0 % at eit her 4 or 2 4 h o urs after dr u g 
a d mi nistrati o n.  
F or t he m ost c o m pre h e nsi ve n o ncli nical a n d cli nical i nf or mati o n re gar di n g i br uti ni b bac k gr o u n d, 
safet y, efficac y, a n d i n vitr o a n d i n vi v o precli nical acti vit y a n d t o xic ol o g y of i br uti ni b, refer t o 
t he latest versi o n of t he i br uti ni b I n vesti gat or's Br oc h ure. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 6 
1. 3.  
S u m m ar y of N o ncli nic al D at a 
F or t he m ost c o m pre h e nsi ve n o ncli nical i nf or mati o n re gar di n g i br uti ni b, refer t o t he c urre nt 
versi o n of t he I n v esti gat or's Br o c h ure.  
1. 3. 1.  
P h ar m a c ol o g y  
I br uti ni b was desi g ne d as a selecti ve a n d c o val e nt i n hi bit or of t he Bt k ( Pa n 2 0 0 7).  I n vitr o, 
i br uti ni b is a p ote nt i n hi bit or of Bt k acti vit y (I C5 0 = 0. 3 9 n M).  T he irre versi ble bi n di n g of 
i br uti ni b t o c ystei ne- 4 8 1 i n t he acti ve site of Bt k res ults i n s ustai ne d i n hi biti o n of Bt k cat al ytic 
acti vit y a n d e n ha n ce d sel ecti vit y o ver ot her ki nas es t hat d o n ot c o ntai n a c ystei ne at t his p ositi o n.  
W he n a d de d directl y t o h u ma n w h ole bl o o d, i br uti ni b i n hi bits si g nal tra ns d ucti o n fr o m t he B- cell 
rece pt or a nd bl oc ks pri m ar y B- cell acti vati o n (I C 5 0 = 8 0  n M) as assa ye d b y a nti -I g M sti m ulati o n 
f oll o we d b y C D 6 9 e x pressi o n ( Her ma n 2 0 1 1)   
F or m ore d etaile d a n d c o m pre he nsi ve i nf or m ati o n re gar di n g n o n cli nical p h ar mac ol o g y, refer t o 
t he c urr e nt I n vesti gat or’s Br oc h ure.  
1. 3. 2.  
T o xic ol o g y 
I n s afet y p har mac ol o g y assess me nts, n o treat me nt-relate d effects were o bs er ve d i n t he ce ntral 
ner v o us s yst e m or res pir at or y s yst e m i n rats at a n y d ose test e d.  F urt her, n o treat me nt- relate d 
c orrecte d Q T i nter val ( Q Tc) pr ol o n gati o n effe ct was o bser v e d at a n y teste d d ose i n a 
car di o vas c ular st u d y usi n g tele m etr y- m o nit ore d d o gs.   
Base d o n d ata fr o m rat a n d d o g i ncl u di n g ge n eral t o xicit y st u dies u p t o 1 3 wee ks d urati o n, t he 
gr eatest p ote ntial f or h u ma n t o xicit y wit h i br uti ni b  is pre dicte d t o be i n l y m p h oi d tiss ues 
(l y m p h oi d de pleti o n) a n d t he gastr oi ntesti nal tract (s oft feces/ diarr h ea wit h or wit h o ut 
i nfla m mati o n).  A d diti o nal t o xicit y fi n di n gs see n i n o nl y o ne s p ecies wit h n o o bser ve d h u ma n 
c orrel ate i n cli nical st u dies t o date i ncl u de pa n creatic aci nar cell atr o p h y (rat), mi ni mall y 
decrease d tra bec ul ar a n d c ortical b o ne (rat) a n d c or neal d ystr o p h y ( d o g).   
I n vitr o a n d i n vi v o ge netic t o xicit y st u dies s h o we d t hat i br uti ni b is n ot ge n ot o xic.  I n a rat 
e m br y o -fet al t o xicit y st u d y i br uti ni b a d mi nistrati o n was ass ociat e d wit h fet al l oss a n d 
malf or mati o ns (terat o ge nicit y)  at i br uti ni b d oses t hat res ult i n a p pr o xi matel y 6 ti mes a n d 
1 4 ti mes t he e x p os ure ( A U C) i n patie nts a d mi nistere d t he d os e of 4 2 0 a n d 5 6 0 m g dail y, 
res pecti vel y.     
1. 3. 2. 1.  
C arci n o ge n esis, M ut a ge nesis, I m p air me nt of Fertilit y 
Carci n o ge nicit y st u dies h a ve n ot bee n c o n d ucte d wit h i br uti ni b. 
I br uti ni b was n ot m uta ge nic i n a bacterial m uta ge nicit y ( A mes) assa y, was n ot clast o ge ni c i n a 
c hr o m os o me a berrati o n assa y i n ma m malia n ( C H O) cells, n or w as it clast o ge ni c i n a n i n vi v o 
b o ne marr o w micr o n ucle us assa y i n mice at d oses u p t o 2 0 0 0 m g/ k g. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 7 
Fertilit y st u dies wit h i br uti ni b ha ve n ot bee n c o n d ucte d i n a ni mals. I n t he ge neral t o xic ol o g y 
st u dies c o n d ucte d i n rats a n d d o gs, orall y a d mi nistere d i br uti ni b di d n ot res ult i n a d verse effects 
o n re pr o d ucti ve or ga ns. 
1. 4.  
S u m m ar y of Cli nic al D at a 
F or t he m ost c o m pre h e nsi ve cli nical i nf or mati o n re gar di n g i br uti ni b, refer t o t he c urre nt versi o n 
of t he I n vesti gat or's Br o c h ure.  
1. 4. 1.  
P h ar m a c o ki netics a n d Pr o d uct Met a b olis m  
F oll o wi n g oral a d mi nistrati o n of i br uti ni b at d oses ra n gi n g fr o m 1. 2 5 t o 1 2. 5 m g/ k g/ da y as w ell 
as fi x e d d ose le vels of 4 2 0, 5 6 0, a n d 8 4 0 m g/ da y, e x p os ure t o i br uti ni b i ncrease d as d os es 
i ncreas e d wit h s u bsta ntial i nters u bject varia bilit y.  T he mea n half life (t1/ 2) of i br uti ni b acr oss 3 
cli nical st u dies ra n ge d fr o m 4 t o 9 h o urs, wit h a me dia n ti me t o ma xi m u m plas ma c o nce ntrati o n 
( Tma x ) of 2 h o urs.  A d mi nistrati o n of 4 2 0 m g i br uti ni b wit h a hi g h-fat brea kfast i n s u bjects wit h 
C L L  a p pr o xi matel y d o u ble d t he mea n s yste mic e x p os ure c o m pare d t o i nta k e after o ver ni g ht 
fasti n g wit h me dia n ti me t o Tma x  dela ye d fr o m 2 t o 4 h o urs.  I br uti ni b was e xte nsi vel y 
meta b olize d t o t he di h y dr o di ol meta b olite P CI - 4 5 2 2 7, a re versi ble i n hi bit or of Bt k, wit h 
a p pr o xi matel y 1 5 ti mes l o wer i n hi bit or y p ot e nc y c o m pare d t o i br uti ni b.  T he meta b olite- t o-
pare nt A U C r ati o ra n ge d fr o m 0. 7 t o 3. 4.  Stea d y-state e x p os ure of i br uti ni b a n d P CI- 4 5 2 2 7 was 
less t ha n 2-f ol d of first d ose e x p os ure. 
T he res ults of h u ma n mass bala nce st u d y of [ 1 4C] -i br uti ni b c o n d ucte d i n si x healt h y m ale 
s u bjects de m o nstrate d t h at less t ha n 1 0 % of t he t otal d ose of [ 1 4C] -i br uti ni b is re nall y e x crete d, 
w hereas a p pr o xi matel y 8 0 % is rec o vere d i n feces.  S u bjects wit h mil d a n d m o derate re nal 
i ns ufficie nc y ( creati ni ne clear a nce > 3 0 m L/ mi n) were eli gi ble t o e nr oll i n St u d y P C Y C- 1 1 0 2-
C A i n w hic h p har mac o ki netic ( P K) assess me nts w ere i ncl u de d.  N o d ose a dj ust me nt is nee de d 
f or mil d or m o derate re n al i m pair me nt ( greater t h a n 3 0 m L/ mi n creati ni ne cleara nce).  T here is 
n o data i n patie nts wit h se vere re n al i m pair me nt or patie nts o n dial ysis.  T h e st u d y of i br uti ni b i n 
he patic i m paire d s u bjects is c urre n tl y i n pr o gress. 
1. 5.  
S u m m ar y of Cli nic al S af et y  
F or m ore d etaile d i nf or m ati o n refer t o t he c urre nt versi o n of t he I B. 
P o ole d safet y data f or a t otal of 4 2 3 s u bjects treat e d wit h vari o us t hera pi es i n c o m bi nati o n wit h 
i br uti ni b fr o m 4 st u dies, w hic h i ncl u de d 1 ra n d o mi ze d-c o ntr ol st u d y, are s u m marize d bel o w.  
T hera pies us e d i n c o m bi nati o n wit h i br uti ni b i n t hese st u dies, i ncl u de d B R, F C R, ofat u m u ma b, 
a n d R- C H O P. T he me dia n d urati o n of treat me nt f or t his p o ol was 1 4. 0 m o nt hs (ra n ge: 0. 2 t o 
2 7. 1 m o nt hs).  Refer t o t he i br uti ni b I B, e diti o n 9. 0, date d 3 0 J u ne 2 0 1 5 f or a d diti o nal details 
c o ncer ni n g t hes e st u dies  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 8 
M ost fre q ue ntl y re p orte d treat me nt -e mer ge nt a d v erse e ve nts ( T E A Es) i n s u bjects recei vi n g 
i br uti ni b i n c o m bi nati o n t hera p y ( N =4 2 3 ): 
M ost fre q ue ntl y re p orte d 
T E A Es  ≥ 2 0 % a   
M ost fre q ue ntl y re p orte d Gra de 3 
or 4 T E A Es ≥ 3 % b  
M ost fre q ue ntl y re p orte d Seri o us 
T E A Es ≥ 2 % c  
Ne utr o pe nia  
Ne utr o pe nia  
P ne u m o nia  
Diarr hea  
T hr o m b oc yt o pe nia 
Fe brile ne utr o pe nia  
Na usea  
Fe brile ne utr o pe nia  
Atrial fi brillati o n  
T hr o m b oc yt o pe nia 
P ne u m o nia 
P yre xia  
Fati g ue  
Ne utr o p hil c o u nt decrease d  
Cell ulitis  
A ne mia  
A ne mia  
 
P yre xia  
Fati g ue  
 
 
H y perte nsi o n 
 
 
Diarr hea  
 
a S o urce is T a ble 1 0 of  I B ( v 1 0), b S o urce is T a ble 1 2 of I B ( v 1 0), c S o urce is T a ble 1 3 of I B ( v 1 0).  
 
F or m ore d etaile d i nf or m ati o n refer t o t he c urre nt versi o n of t he I B. 
1. 5. 1.  
Ris ks  
1. 5. 2.  
Blee di n g -rel ate d e ve nts  
T here h a ve bee n  re p orts of he m orr ha gi c e ve nts i n s u bjects treate d wit h i br uti ni b b ot h wit h a n d 
wit h o ut t hr o m b oc yt o pe ni a.  T hese i ncl u d e pri maril y mi n or he m orr h a gic e v e nts s uc h as 
c o nt usi o n, e pista xis, a n d petec hiae; a n d s o me maj or he m orr ha gi c e ve nts i n cl u di n g 
gastr oi ntesti nal blee di n g, i ntracra ni al he m orr ha ge a n d he mat uria. Us e of i br uti ni b i n s u bjects 
re q uiri n g ot her a ntic o a g ula nts or me dicati o ns t hat i n hi bit platelet f u ncti o n ma y i ncreas e t he ris k 
of blee di n g. S u bjects wit h c o n ge nital blee di n g diat hesis ha ve n ot bee n st u die d. 
1. 5. 3.  
Atri al Fi brill ati o n   
Atrial fi brillati o n a n d atri al fl utter ha ve b ee n re p orte d i n s u bjects treate d wit h i br uti ni b , 
partic ularl y i n s u bjects wit h car diac ris k fact ors, h y p erte nsi o n, ac ut e i nfecti o ns, a n d a pre vi o us 
hist or y of atrial fi brillati o n . S u bjects w h o de vel o p arr h yt h mic s y m pt o ms (e g, pal pitati o ns, 
li g ht hea d e d ness) or n e w o nset of d ys p n ea s h o ul d be e val uat e d cli nicall y, a n d if i n dicate d, ha ve 
a n E C G perf or me d.  F or  atrial fi brillati o n w hic h  persists,  c o nsi der t he ris ks a n d be nefits of 
i br uti ni b treat me nt a n d f oll o w t he pr ot oc ol d ose m o dificati o n g ui deli nes.  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 1 9 
1. 5. 4.  
C yt o pe ni as 
Treat me nt - e mer ge nt Gra de 3 or 4 c yt o pe nias ( ne utr o pe nia, t hr o m b oc yt o pe nia, a n d a ne mia) were 
re p orte d i n s u bjects tr eat e d wit h i br uti ni b. S u bjects s h o ul d be m o nit ore d f or fe ver, wea k ness, or 
eas y br uisi n g a n d/ or blee di n g.  
1. 5. 5.  
Di arr he a  
Diarr hea is t he m ost fre q ue ntl y r e p orte d n o n h e mat ol o gic A E wit h i br uti ni b m o n ot hera p y a n d 
c o m bi nati o n t hera p y. Ot her fr e q ue ntl y re p orte d gastr oi ntesti nal e ve nts i ncl u de na usea, v o miti n g, 
a n d c o nsti pati o n. T hese e ve nts are r ar el y s e vere . S h o ul d s y m pt o ms be se vere or pr ol o n ge d 
f oll o w t he pr ot oc ol d ose m o dificati o n g ui deli nes.   
1. 5. 6.  
I nf ecti o ns 
I nfecti o ns (i ncl u di n g se psis, bacterial, viral, or f u n gal i nfecti o ns) were o bs er ve d i n s u bjects 
treate d wit h i br uti ni b t hera p y. S o me of t hese re p orte d i nfecti o ns ha v e bee n ass ociate d wit h 
h os pitalizati o n a n d deat h. C o nsi der pr o p h yl a xis acc or di n g t o sta n d ar d of care i n s u bjects w h o are 
at i ncreas e d ris k f or o p p ort u nistic i nfecti o ns (refere nce Secti o n 6. 1 ). Alt h o u g h ca usalit y h as n ot 
bee n esta blis he d, cases of pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y ( P M L) h a ve occ urre d i n 
patie nts treate d wit h i br uti ni b. S u bjects s h o ul d be m o nit ore d f or s y m pt o ms (fe ver, c hills, 
wea k ness, c o nf usi o n) a n d a p pr o priate t h era p y s h o ul d be i nstit ute d as i n dicate d. 
1. 5. 6. 1.  
 N o n -mel a n o m a s ki n c a ncer  
N o n - mela n o ma s ki n ca ncers ha ve o cc urre d i n pati e nts treate d wit h I M B R U VI C A.  M o nit or 
patie nts f or t he a p p ear a n ce of n o n -m ela n o ma  s ki n ca ncer. 
1. 5. 7.  
R as h  
Ras h has bee n c o m m o nl y r e p orte d i n s u bjects treate d wit h eit her si n gle a ge nt i br uti ni b or i n 
c o m bi nati o n wit h c he m ot hera p y.  M ost ras h es were mil d t o m o derate i n se v erit y. Is ol ate d cases 
of se ver e c uta n e o us a d verse reacti o ns ( S C A Rs) i ncl u di n g Ste ve ns-J o h ns o n s y n dr o me ( SJ S) ha ve 
bee n re p orte d i n s u bjects treate d wit h i br uti ni b. S u bjects s h o ul d be cl osel y m o nit ore d f or si g ns 
a n d s y m pt o ms s u g gesti ve of S C A R i ncl u di n g SJ S. S u bjects recei vi n g i br uti ni b s h o ul d be 
o bser ve d cl os el y f or r as h es a n d  treate d s y m pt o maticall y, i ncl u di n g i nterr u pti o n of t he s us pecte d 
a ge nt as a p pr o priate. I n a d diti o n, h y p erse nsiti vit y- relate d e v e nts i ncl u di n g er yt h e ma, urticaria, 
a n d a n gi oe de m a ha ve b ee n re p ort e d . 
1. 5. 8.  
T u m or L ysis S y n dr o me 
T here h a ve bee n re p orts of t u m or l ys is s y n dr o me ( T L S) e ve nts i n s u bjects treate d wit h si n gle-
a ge nt i br uti ni b or i n c o m bi nati o n wit h c he m ot hera p y. S u bjects at ris k of t u m or l ysis s y n dr o me 
are t h ose wit h c o m or bi dities a n d/ or ris k fact ors s uc h as hi g h t u m or b ur de n pri or t o treat me nt, 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 0 
i ncreas e d uric aci d ( h y per urice mia), ele vat e d lactate de h y dr o ge n ase (L D H ), b ul k y diseas e at 
baseli ne, a n d pr e ‐e xisti n g ki d ne y a b n or malities . 
1. 5. 9.  
I nterstit al L u n g Dise ase (I L D) 
Cases of i nterstitial l u n g disease (I L D) ha v e bee n re p orte d i n patie nts treate d wit h i br uti ni b . 
M o nit or patie nts f or p ul m o nar y s y m pt o ms i n dicati ve of I L D. S h o ul d s y m pt o ms de vel o p f oll o w 
t he pr ot oc ol d ose m o dificati o n g ui d eli nes (see Secti o n 5. 3. 1. 4 ). 
1. 5. 1 0.  
H y perte nsi o n  
H y p erte nsi o n has b ee n c o m m o nl y re p ort e d i n s u bjects treate d wit h i br uti ni b. M o nit or s u bjects 
f or ne w o ns et of h y pert e nsi o n or h y perte nsi o n t hat is n ot a de q uatel y c o ntr olle d after starti n g 
i br uti ni b. A dj ust e xisti n g a nti-h y p erte nsi ve me di cati o ns a n d/ or i nitiate a nti -h y p erte nsi ve 
treat me nt as a p pr o priate. 
 
1. 6.  
St u d y R ati o n ale   
T he o p e n-la b el, par allel assi g n me nt C hec k Mat e- 0 2 5 trial ra n d o mize d 8 2 1 pre vi o usl y treate d 
patie nts wit h a d va nce d or metastatic clear -cell R C C t o 3 m g/ k g of I V ni v ol u ma b e ver y 2 wee ks 
or 1 0 m g of oral e v er oli m us dail y u ntil pr o gressi o n or u nacce pta ble t o xicit y. A trial c o m bi ni n g 
ni v ol u ma b wit h t he B T K/ E T K i n hi bit or i br uti ni b w o ul d be of great i nterest t o t he m R C C 
c o m m u nit y. 
2.  
S T U D Y O B J E C TI V E   
2. 1.  
Pri m ar y O bjecti ve  
T o assess i n a preli mi nar y f as hi o n t he feasi bilit y a n d efficac y o f i br uti ni b i n c o m bi nati o n wit h 
ni v ol u ma b i n patie nts wit h pre vi o usl y- treat e d metastatic re nal cell ca ncer ( m R C C).  
2. 2.  
Sec o n d ar y O bjecti ve(s)  
T o e val uate t he s afet y of t he c o m bi nati o n of i br uti ni b a n d ni v ol u ma b i n patie nts wit h pre vi o usl y 
treate d m R C C.  
2. 3.  
E x pl or at or y O bjecti ve(s)  
Arc hi val t u m or s peci me ns will be c ollecte d f or p ot e ntial B T K. E T K a n d P D 1 c orrel ati ve st u dies. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 1 
3.  
S T U D Y D E SI G N  
3. 1.  
O ver vie w of St u d y Desi g n 
T his is a pr os pecti ve P hase I b/II o pe n-la bel, n o n- ra n d o mize d, U S m ultice nter st u d y t h at is 
desi g ne d t o test t he effi cac y of t he a d diti o n of i br uti ni b t o ni v ol u ma b f or t he treat me nt of re nal 
cell ca n cer.  
 
 
 
 
 
 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 2 
3. 1. 1.  
St u d y Sc he m a   
 
 
  
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* D L T assess me nt after 1 c ycle (4 w ee ks)  
* D L T = Gr a de III  or hi g her S A E attri b ute d t o treat me nt  
* * Patie nts will ha ve t w o de- escalati o n d ose le vels f or ( -1 a n d - 2) f or all pati e nts base d o n i nteri m 
t o xicities. 
 
 
Metastatic R C C  
 
A n y n u m ber of Pri or T h era pies 
 
E C O G 0 - 2 
 
D ose le vel ∅    
I br uti ni b      5 6 0 m g  p o Da y 1- D a y 2 8  
Ni v ol u ma b  2 4 0 m g I V q 2 wee ks  
 
 
6 pts  
D L T i n 2 or m ore pts  
 + 2 4 pts  
D ose le vel -1    
I br uti ni b       4 2 0 m g  p o Da y 1- D a y 2 8  
Ni v ol u ma b   2 4 0 m g I V q 2 wee ks 
 
 
D L T i n < 2 pts  
6 pts  
+ 1 8 pts  
D L T i n 2 or 
m ore pts  
St o p  
D L T 
i n < 2 
pts 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 3 
 
3. 2.  
St u d y Desi g n R ati o n ale 
T his is a pr os pecti ve P hase I b/II o pe n-la bel, n o n- ra n d o mize d, U S m ultice nter st u d y t h at is 
desi g ne d t o test t he effi cac y of t he a d diti o n of i br uti ni b t o ni v ol u ma b f or t he treat me nt of 
pre vi o usl y- treat e d re n al cell ca ncer. T he o v erall st u d y pla n will c o nsist of a scree ni n g p eri o d, a 
st u d y treat me nt p hase, a f oll o w u p p hase, if a p plica ble, a safet y f oll o w- u p a n d a s ur vi val f oll o w-
u p.  F or safet y, all patie nts will be f oll o we d f or 3 0 da ys after t h e last d ose of st u d y treat me nt or 
u ntil all treat me nt relate d cl i nical si g nifica nt t o xicities res ol ve t o ≤ gra de 1. S ur vi val stat us ( date 
of deat h or d ate of last c o ntact) will be rec or de d.  
3. 2. 1.  
St u d y P o p ul ati o n A n d Tre at me nt  
T he st u d y will e nr oll a d ult s u bjects wit h pat h ol o gicall y d eter mi ne d re nal cell ca ncer.  T his st u d y  
will be c o n d ucte d at t he U ni versit y of Calif or nia Da vis C o m pre he nsi ve Ca ncer Ce nter a n d at 
a n ot her site t hat is yet t o be deter mi ne d.  T h ere will be a t otal of 2 U S sites.  
I br uti ni b i n c o m bi nati o n wit h ni v ol u ma b will be i n vesti gate d.  T he assi g ne d treat me nt (I br uti ni b 
i n c o m bi nati o n wit h ni v ol u ma b) will c o nti n ue i n s u bjects  f or a ma xi m u m of 1 year or u ntil 
pr o gressi o n, u nacce pta bl e or i nt olera ble t o xicit y, p h ysicia n c h oice (if i n best i nterest of patie nt), 
or patie nt wit h dra w al f or a n y reas o n.  I n t he e v ent t hat t he patie nt is u na ble ( d ue t o t o xicit y or 
t olera bilit y iss ues) or u n willi n g t o recei ve b ot h a ge nts c o nc urre ntl y after t he first t w o c ycles, t h e n 
si n gle a ge nt ni v ol u ma b ca n be a d mi nistere d at t he i n vesti gat or’s discreti o n t o c o m plete o ne year 
of t he ra p y. T reat me nt wit h i br uti ni b will c o nti n ue u ntil eit her disease pr o gressi o n O R 
p h ysicia n/ patie nt c h oice O R u nacce pt a ble or i nt ol era ble t o xicities . 
3. 2. 2.  
D ose Selecti o n  
T he select e d d ose of i br uti ni b ra n ges fr o m 4 2 0- 5 6 0 m g ( 2- 4 x 1 4 0 m g ca ps ules) o nce d ail y. 
Alt h o u g h i br uti ni b is ra pi dl y eli mi nate d fr o m t he plas ma after oral a d mi nistrati o n, o nce dail y 
d osi n g wit h i br uti ni b is a de q uate t o s ustai n ma xi mal p har mac o d y n a mic acti vit y f or 2 4 h o urs 
p ost d ose at d ose le vels ≥2. 5 m g/ k g. A d ose greater t ha n 2. 5 m g/ k g w as c o nsi dere d necessar y t o 
ac hie ve c o nsiste nt, f ull B T K occ u pa n c y, i n pre vi o us P C Y C st u dies. I n St u d y P C Y C- 0 4 7 5 3, t he 
B T K occ u pa n cies f or t he 2. 5 m g/ k g/ da y t o 1 2. 5 m g/ k g/ da y c o h orts a n d f or t he 5 6 0 m g 
c o nti n u o us d osi n g c o h ort, were all a b o ve 9 0 % at eit her 4 or 2 4 h o urs after dr u g a d mi nistrati o n.  
4.  
 S U B J E C T S E L E C TI O N 
Patie nts will be recr uite d i n t he me dical, u r ol o g y, a n d ra diati o n o nc ol o g y cli nics of t he 
U ni versit y of Calif or nia Da vis Me dical Ce nter a n d partici pati n g ce nters.  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 4 
4. 1.  
I ncl usi o n Criteri a 
T o be e nr olle d i n t he st u d y, eac h p ote ntial s u bject m ust satisf y all of t he f oll o wi n g i ncl usi o n 
criteria.  
Dise ase Rel ate d  
M etastatic r e nal cell ca n cer   patie nts ( a n y hist ol o gic  s u bt y pe) wit h meas ura ble a n d/ or e v al ua ble 
disease w h o ha v e c o m plete d at least o ne li ne of pri or s yste mic t hera p y are p ote ntiall y eli gi ble f or 
t his trial. A n y n u m ber of pri or s yste mic t h era pies are all o w e d, i ncl u di n g pri or ni v ol u ma b.  
L a b or at ory 
1.  A de q uate h e mat ol o gi c f u ncti o n defi ne d as:  
o     A bs ol ute ne utr o p hil c o u nt > 7 5 0 cells/ m m 3 ( 0. 7 5 x 1 09/ L).   
o  Platelet c o u nt > 5 0, 0 0 0 cells/ m m 3 ( 5 0 x 1 09/ L).    
o  He m o gl o bi n > 8. 0 g/ d L. 
2.  A de q uate h e patic a n d re n al f u ncti o n defi ne d as:  
o  Ser u m as partate tra nsa mi nase ( A S T) or ala ni ne tra nsa mi nase ( A L T) 
≤ 3. 0 x u p per li mit of n or mal ( U L N).  
o  Esti mate d Creati ni ne Cleara nce ≥3 0 ml/ mi n ( C oc kcr oft- G a ult)  
o  Bilir u bi n ≤1. 5 x U L N ( u nless bilir u bi n rise is d ue t o Gil bert’s s y n dr o me or of 
n o n- he patic ori gi n) 
3.  P T/I N R < 1. 5 x U L N a n d P T T (a P T T) < 1. 5 x U L N. 
De m o gr a p hic 
4.  Me n a n d w o me n ≥ 1 8 years of a ge. 
5.  Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) p erf or ma nce stat us of 0- 2. 
Et hic al/ Ot her  
6.  Fe male s u bjects w h o ar e of n o n-re pr o d ucti ve p ote ntial (ie, p ost- me n o pa usal b y hist or y - 
n o me nses f or ≥1 year; O R hist or y of h ysterect o m y; O R hist or y of bilateral t u bal li gati o n; 
O R hist or y of bilater al o o p h orect o m y). Fe male s u bjects of c hil d beari n g p ot e ntial m ust 
ha ve a n e gati ve ser u m pr e g n a nc y test u p o n st u d y e ntr y.  
7.  Male a n d f e male s u bjects w h o a gree t o use b ot h a hi g hl y effecti ve m et h o ds of birt h 
c o ntr ol (e g, i m pla nts, i njecta bles, c o m bi ne d oral c o ntrace pti ves, s o me i ntra uteri ne 
de vices [I U Ds], se x ual a bsti ne nce, or sterilize d part ner) a n d a barrier m et h o d (e g, 
c o n d o ms, cer vical ri n g, s p o n ge, etc) d uri n g t h e peri o d of t hera p y a n d f or 3 0 da ys after t h e 
last d ose of st u d y dr u g 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 5 
4. 2.  
E xcl usi o n Criteri a  
T o be e nr olle d i n t he st u d y, p ote ntial s u bjects m ust meet N O N E of t he f oll o wi n g e x cl usi o n 
criteria: 
C o nc urre nt C o n diti o ns 
1.  C yt ot o xic c he m ot hera p y ≤2 1 da ys pri or t o first a d mi nistrati o n of st u d y treat me nt a n d/ or 
m o n ocl o nal a nti b o d y ≤ 4 wee ks pri or t o first a d mi nistrati o n of st u d y treat me nt a n d/ or 
ot her R C C- directe d s yste mic t hera p y < = 2 wee ks pri or t o first a d mi nistrati o n of  st u d y 
treat me nt 
2.  A n y k n o w n a d diti o nal mali g na n c y t hat is pr o gressi n g or re q uires acti ve treat me nt. 
E x ce pti o ns i ncl u de basal cell carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of t he s ki n, 
or i n sit u cer vical ca ncer t hat has u n der g o ne p ot e ntiall y c urati ve t hera p y. 
3.  C o nc urre nt s yste mic i m m u n os u p pressa nt t hera p y (e g, c ycl os p ori ne A, tacr oli m us, etc., or 
c hr o nic a d mi nistrati o n  [ > 1 4 da ys] of > 1 0 m g/ da y of pre d nis o ne) wit hi n 2 8 da ys of t he 
first d ose of st u d y dr u g. 
4.  Vacci n ate d wit h li ve, atte n uate d vacci nes wit hi n  4 wee ks of first d ose of st u d y dr u g. 
5.  Rece nt i nfecti o n re q uiri n g s yste mic treat me nt t hat was c o m plete d ≤1 4 da ys bef ore t h e 
first d ose of st u d y dr u g. 
6.  U nres ol ve d t o xicities fr o m pri or a nti-ca n cer t hera p y, defi ne d as h a vi n g n ot res ol ve d t o 
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nt ( C T C A E, versi o n 4), gra de ≤1 , or t o 
t he le vels dictate d i n t he i ncl usi o n/e x cl usi o n criteria wit h t he e x ce pti o n of al o pecia. 
7.  K n o w n blee di n g dis or ders (e g, v o n Wille bra n d’s disease) or h e m o p hilia. 
8.  Hist or y of str o k e or i ntracra nial he m orr ha ge wit hi n 6 m o nt hs pri or t o e nr oll me nt. 
9.  K n o w n hist or y of h u ma n i m m u n o deficie nc y vir us ( HI V) or acti ve wit h he p atitis C vir us 
( H C V) or he p atitis B vir us ( H B V). S u bjects w h o are p ositive f or he p atitis B c ore 
a nti b o dy or he p atitis B s urf ace a nti ge n m ust h ave a ne g ative p oly m er ase c h ai n re acti o n 
( P C R) r es ult bef ore e nr oll me nt.  T h ose w h o are P C R p ositive will be excl u de d. 
1 0.  A n y u n c o ntr olle d acti ve s yste mic i nfecti o n. 
1 1.  Maj or s ur ger y wit hi n 4 wee ks of first d ose of st u d y dr u g. 
1 2.  A n y life -t hreate ni n g ill ness, k n o w n a ut oi m m u ne disease, me dical c o n diti o n, or or ga n 
s yste m d ysf u ncti o n t hat, i n t he i n vesti gat or’s o pi ni o n, c o ul d c o m pr o mise t he s u bject’s 
safet y or p ut t he st u d y o utc o mes at u n d ue ris k. 
1 3.  C urre ntl y acti ve, cli nicall y si g nifica nt car di o vas c ular disease, s u c h as u nc o ntr olle d 
arr h yt h mia or Class 3 or 4 c o n gesti ve heart fail ure as defi ne d b y t he Ne w Y or k Heart 
Ass ociati o n F u ncti o nal Classificati o n; or a hist or y of m y ocar dial i nfarcti o n, u nsta ble 
a n gi n a, or ac ute c or o nar y s y n dr o me wit hi n 6 m o nt hs pri or t o e nr oll me nt . 
1 4.  U na ble t o s wall o w ca ps ules or 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 n cti o n, or resecti o n of t he st o mac h or s mall b o wel, s y m pt o matic 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 6 
i nfla m mat or y b o wel disease or ulcerati ve c olitis, or partial or c o m plet e b o wel 
o bstr ucti o n. 
1 5.  Lactati n g or pr e g na nt. 
1 6.  U n willi n g or u na ble t o p artici pate i n all re q uire d st u d y e v al uati o ns a n d pr o ce d ures. 
1 7.  U na ble t o u n dersta n d t h e p ur p ose a n d ris ks of t he st u d y a n d t o pr o vi de a si g ne d a n d date d 
i nf or me d c o nse nt f or m (I C F) a n d a ut h orizati o n t o use pr otecte d h ealt h i nf or mati o n (i n 
acc or d a nce wit h nati o nal a n d l ocal s u bject pri v ac y re g ulati o ns). 
1 8.  C o nc o mita nt use of warf ari n or ot her Vita mi n K a nta g o nists. N ote: S u bjects recei vi n g 
a nti platelet a ge nts i n c o nj u ncti o n wit h i br uti ni b s h o ul d be o bser ve d cl osel y f or a n y si g ns 
of blee di n g or br uisi n g, a n d i br uti ni b s h o ul d be wit h hel d i n t he e ve nt of a n y blee di n g 
e ve nts. S u p ple me nts s uc h as fis h oil a n d vita mi n E pre parati o ns s h o ul d be a v oi de d. 
1 9.  Re q uires treat me nt wit h a str o n g c yt oc hr o me P 4 5 0 ( C Y P) 3 A 4/ 5 i n hi bit or. (see A p p e n di x 3 ) 
2 0.  Q T pr ol o n gati o n a n d/ or f a miliar hist or y of Q T pr ol o n gati o n a n d u n c o ntr olle d car di ac 
arr h yt h mias t hat i n t he o pi ni o n of t he i n vesti gat or w o ul d i nterfere wit h t he patie nt’s 
safet y or c o m plia n ce o n trial. 
2 1.  C urre ntl y  acti ve,  cli nicall y  si g nifica nt  he patic  i m pair me nt C hil d -P u g h  class  B  or  C 
acc or di n g t o t he C hil d P u g h cl assificati o n ( A p p e n di x 1 0). 
 
5.  
T R E A T M E N T O F S U B J E C T S  
5. 1.  
Tre at me nt all oc ati o n a n d bli n di n g  (if a p pr o pri ate) 
N/ A  
5. 2.  
St u d y tre at me nt  
T his will be a n o n-ra n d o mize d o pe n-la bel pr os pecti ve p hase 1 b /II st u d y of t he c o m bi nati o n of 
i br uti ni b wit h ni v ol u ma b i n m R C C . See Secti o n 3. 1. 1 St u d y Sc h e ma. 
5. 2. 1.  
R o ute a n d sc he d ule  
Re peat e ver y 2 8 da ys 
D ose Le vel  
Ni v ol u m a b d ose  
I br uti ni b d ose ( d a ys 1-2 8) *  
Le vel 0  
2 4 0  m g I V q 2 wee ks  
5 6 0 m g P O  
Le vel -1  
2 4 0  m g  I V q 2 wee ks  
4 2 0 m g P O  
*s h o ul d be ta ke n at t he s a me ti me e ver y d a y  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 7 
D ose li miti n g t o xicit y ( D L T) m ust be treat me nt -relate d ( p ossi bl y, pr o b a bl y, or defi nitel y). T o be 
e val ua ble f or D L T, t he s u bject m ust ha ve ha d o ne d ose of Ni v ol u ma b a n d at least 3 wee ks of 
I br uti ni b.  
D ose li miti n g t o xicit y ( D L T) is d efi ne d as:  
1) Gra d e 4 a bs ol ute ne utr o p hil c o u nt wit h fe ver ( > 1 0 1. 4 F) or d o c u me nte d i nfecti o n;  
2) Gra d e 4 t hr o m b oc yt o p e nia or Gr a de 3 t hr o m b o c yt o p e nia wit h blee di n g;  
3) A n y g ra d e 3 or gr eater n o n-he mat ol o gi c t o xicit y e x cl u di n g al o peci a.  
D L T will be assesse d aft er 1 c ycl e ( 4 w ee ks) .  
5. 3.  
St u d y Me dic ati o n  
5. 3. 1.  
I br uti ni b  
5. 3. 1. 1.  
F or m ul ati o n/ P ac k a gi n g/ St or a ge  
I br uti ni b ca ps ules ar e pr o vi de d as a har d gelati n ca ps ule c o ntai ni n g 1 4 0 m g of i br uti ni b.  All 
f or m ulati o n e x ci pie nts are c o m pe n dial a n d are c o m m o nl y us e d i n oral f or m ulati o ns.  Refer t o t he 
i br uti ni b I n vesti gat or's Br oc h ure f or a list of e x ci pie nts.  
T he i br uti ni b ca ps ules will be pac ka ge d i n o pa q ue hi g h- de nsit y p ol yet h yle n e plastic b ottles wit h 
la bels beari n g t he a p pr o priate la bel te xt as re q uire d b y g o ver ni n g re g ulat or y a ge ncies.  All st u d y 
dr u gs will be dis pe ns e d i n c hil d- resista nt pac k a gi n g.   
Refer t o t he p har mac y m a n ual/site i n vesti gati o nal pr o d uct ma n ual f or a d diti o nal g ui da n ce o n 
stu d y dr u g st ora ge, pr e parati o n a n d ha n dli n g. 
St u d y dr u g la bels will c o ntai n i nf or mati o n t o meet t he a p plica ble re g ulat or y re q uire me nts.  
5. 3. 1. 2.  
D ose a n d A d mi nistr ati o n   
I br uti ni b is a d mi nistere d orall y o n ce dail y. T h e ca ps ules are t o be ta k e n ar o u n d t he sa me ti me 
eac h d a y wit h 8  o u nces ( a p pr o xi matel y 2 4 0 m L) of water.  T h e ca ps ules s h o ul d be s wall o we d 
i ntact a n d s u bjects s h o ul d n ot atte m pt t o o pe n ca ps ules or diss ol ve t he m i n water. T h e use of 
str o n g C Y P 3 A i n hi bit ors/i n d ucers, a n d gra pefr uit a n d Se ville ora n ges s h o ul d be a v oi de d f or t h e 
d urati o n of t he st u d y ( A p pe n di x  3). 
If a d ose is n ot ta ke n at t he sc he d ule d t i me, it ca n be ta ke n as s o o n as p ossi ble o n t he sa me da y 
wit h a ret ur n t o t he n or m al sc he d ule t he f oll o wi n g da y.  T h e s u bject s h o ul d n ot ta ke e xtra 
ca ps ules t o ma ke u p t he misse d d ose. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 8 
T he first d ose will be deli vere d i n t he cli nic o n D a y 1, after w hi c h s u bse q ue nt d osi n g is t y picall y 
o n a n o ut patie nt basis.  I br uti ni b will be dis pe nse d t o s u bjects i n b ottles at eac h visit.  U n use d 
i br uti ni b dis pe nse d d uri n g pr e vi o us visits m ust be ret ur ne d t o t he site a n d dr u g acc o u nt a bilit y 
rec or ds ( Secti o n 1 2. 8 ) u p date d at eac h visit.  Ret ur ne d ca ps ules m ust n ot be re dis pe nse d t o 
a n y o n e.  
5. 3. 1. 3.  
O ver d ose  
A n y d os e of st u d y dr u g i n e x cess of t hat s pecifie d i n t his pr ot oc ol is c o nsi dere d t o be a n 
o ver d ose.  Si g ns a n d s y m pt o ms of a n o ver d ose t hat meet a n y Seri o us A d verse E ve nt criteri o n 
m ust be re p orte d as a Seri o us A d verse E ve nt i n t h e a p pr o pri ate ti me fra m e a n d d oc u me nte d as 
cli nical se q uelae t o a n o v er d ose.  
 
T here is n o s pecific e x perie nce i n t he ma n a ge me nt of i br uti ni b o ver d ose i n patie nts. N o 
ma xi m u m t olerate d d ose ( M T D) was reac he d i n t h e P hase 1 st u d y i n w hi c h s u bjects recei ve d u p 
t o 1 2. 5 m g/ k g/ d a y ( 1 4 0 0 m g/ da y). Healt h y s u bjects were e x p ose d u p t o si n gle d ose of 1 6 8 0 m g. 
O ne healt h y s u bject e x perie nce d re versi ble Gra d e 4 he patic e nz y m e i ncreas es ( A S T a n d A L T) 
after a d ose of 1 6 8 0 m g. S u bjects w h o i n geste d m ore t ha n t he rec o m me n d e d d osa ge s h o ul d be 
cl osel y m o nit ore d a n d gi ve n a p pr o pri ate s u p p orti ve treat me nt. 
Refer t o Secti o n 1 1. 3 f or f urt her i nf or m ati o n re gar di n g s peci al re p orti n g sit uati o ns as a res ult of 
o ver d ose.  
5. 3. 1. 4.  
D ose M o dific ati o n f or A d verse R e acti o ns  
T he d ose of st u d y dr u g s h o ul d be m o difie d acc or di n g t o t he d ose m o dificati o n g ui deli nes i n 
Ta ble  1 if a n y of t h e f oll o wi n g t o xicities occ ur: 
• 
Gra de 4 A N C ( < 5 0 0/ µ L) f or m ore t ha n 7 d a ys or fi br o ne utr o pe nia.  
• 
Gra de 3 t hr o m b o c yt o p e nia ( < 5 0, 0 0 0/ µ L) i n t he prese nce of cli nicall y si g nifica nt blee di n g 
e ve nts. 
• 
Gra de 4 t hr o m b o c yt o p e nia ( < 2 5, 0 0 0/ µ L). 
• 
Gra de 3 or 4 na usea, v o miti n g, or diarr h ea if p ersiste nt, des pite o pt i mal a nti-e metic 
a n d/ or a nti-diarr heal t her a p y.  
• 
A n y ot her Gr a de 4 or u n ma na gea bl e Gra d e 3 t o xicit y. 
F or Gr a de 3 or 4 atrial fi brillati o n or persiste nt atrial fi brillati o n of a n y gra de, c o nsi der t he ris ks 
a n d be nefits of i br uti ni b treat me nt. If cli nicall y i n dicate d, t he use of a ntic oa g ula nts or a nti platelet 
a ge nts ma y be c o nsi d ere d f or t he t hr o m b o pr o p h yl a xis of atrial fi brillati o n ( Secti o n 6. 2. 4). 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 2 9 
N ote: After a d ose re d ucti o n, d ose esc al ati o n of i br uti ni b t o a previ o us hi g her d ose is N O T 
all o we d.  
Ta ble 1. I br uti ni b D ose M o dificati o ns  
Occ urre nce  Acti o n t o be T a ke n   
First  
Wit h h ol d st u d y dr u g 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 
Sec o n d  
Wit h h ol d st u d y dr u g u ntil rec o ver y t o Gra de ≤1 or baseli ne; ma y restart at 1 d ose le vel 
l o wer (ie, 2 8 0 m g/ da y f or 4 2 0 m g/ da y d ose; 4 2 0  m g / da y f or 5 6 0 m g / da y d ose ) 
T hir d  
Wit h h ol d st u d y dr u g u ntil rec o ver y t o Gra de ≤1 or baseli ne; ma y restart at 1 d ose le vel 
l o wer (ie, 1 4 0 m g/ da y f or 4 2 0 m g/ da y d ose; 2 8 0 m g / da y f or 5 6 0 m g / da y d ose ) 
F o urt h 
Disc o nti n ue st u d y dr u g 
 
5. 3. 1. 5.  
D ose M o dific ati o n f or He p atic I m p aire d S u bjects  
I br uti ni b is meta b olize d i n t he li ver a n d t heref ore s u bjects wit h cli nicall y si g nifica nt c hr o nic 
he patic i m pair me nt at t he ti me of scree ni n g ( C hil d - P u g h cl ass B or C) are e x cl u de d fr o m st u d y 
partici pati o n. F or s u bjects wit h e xisti n g c hr o nic mil d he patic i m pair me nt ( C hil d -P u g h class A) at 
e nr oll me nt, t he starti n g d ose has t o be a dj uste d t o a le vel of 2 8 0 m g dail y (t w o ca ps ules). F or 
s u bjects w h o de vel o p mil d li ver i m pairme nt w hile o n st u d y ( C hil d - P u g h class A), t he 
rec o m me n de d d os e re d u cti o n f or i br uti ni b is t o a le vel of 2 8 0 m g dail y (t w o ca ps ules) u nless 
l o wer d oses ha d alrea d y bee n i m ple me nte d. F or s u bjects w h o de vel o p m o derate li ver i m pair me nt 
w hile o n st u d y ( C hil d- P u g h cl ass B), t h e rec o m me n de d d ose re d u cti o n is t o a le vel of 1 4 0 m g 
dail y ( o n e ca ps ul e). S u bjects w h o de vel o p s e vere he patic i m pair me nt ( C hil d- P u g h cl ass C) m ust 
h ol d st u d y dr u g u ntil res ol ve d t o m o derate i m pair me nt ( C hil d- P u g h class B) or b etter. M o nit or 
s u bjects f or si g ns of t o xicit y a n d f oll o w d ose m o dificati o n g ui da n ce as nee de d ( Refer t o 
A p pe n di x 1 0 a n d Secti o n 5. 3. 1. 4 ).  
5. 3. 2.  
Ni v ol u m a b 
5. 3. 2. 1.  
F or m ul ati o n/ P ac k a gi n g/ St or a ge  
Ni v ol u ma b (als o ref err e d t o as B M S - 9 3 6 5 5 8 or M D X- 1 1 0 6) 4 0 a n d/ or 1 0 0 m g vials ( 1 0 m g/ m L) 
wi ll be s u p plie d usi n g c o m mercial s u p pl y.  Ni v ol u ma b is a pr o gra m me d d eat h rece pt or- 1 ( P D -1) 
bl oc ki n g a nti b o d y. Ni v ol u ma b vials m ust be st ore d i n t he refri gerat or at 2- 8 o C, pr otecte d fr o m 
li g ht a n d fr eezi n g. If st or e d i n a glass fr o nt refri gerat or, vials s h o ul d be st ore d i n t he cart o n. T h e 
pr o d uct d oes n ot c o ntai n a preser vati ve, a n d as s uc h after pre parati o n, ni v ol u ma b i nf usi o ns 
s h o ul d be st ore d at r o o m te m perat ur e f or n o m ore t ha n 4 h o urs fr o m ti me of pre parati o n. T his 
i ncl u des r o o m te m perat ure st ora ge of inf usi o n i n I V c o ntai ner a n d ti me f or a d mi nistrati o n of 
i nf usi o n. Alter nati vel y, ni v ol u ma b i nf usi o n ca n be st ore d u n der refri gerati o n at 2 t o 8 de grees C 
( 3 6- 4 6oF) f or n o m ore t h a n 2 4 h o urs fr o m t he ti m e of i nf usi o n pre p arati o n. T he i nf usi o n s h o ul d 
n ot be fr oze n. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 0 
Rec o m me n de d saf et y meas ures f or pre p arati o n a n d ha n dli n g of ni v ol u ma b i ncl u de la b orat or y 
c oats a n d gl o ves. F or c o m plete details o n dr u g pre parati o n, a d mi nistrati o n, st ora ge c o n diti o ns, 
cli nical p har mac ol o g y, p har mac o ki netics, a n d k n o w n preca uti o ns a n d a d v erse reacti o ns please 
refer t o t he Ni v ol u ma b p ac ka ge i nsert. 
5. 3. 2. 2.  
D ose a n d A d mi nistr ati o n  
T he dr u g pr o d u ct s ol uti o n s h o ul d be vis uall y i ns p ecte d f or partic ulat e matter a n d disc ol orati o n 
pri or t o a d mi nistrati o n. Ni v ol u ma b is a clear t o o p alesce nt, c ol orless t o pale- yell o w s ol uti o n. 
Discar d t he vial if t he s ol uti o n is cl o u d, is disc ol ore d, or c o ntai ns e xtra ne o us partic ulate matter 
ot her t ha n a f e w tra nsl u ce nt -t o- w hite, pr otei nace o us particles. D o n ot s ha k e t he vial. 
T he re q uir e d v ol u me of ni v ol u ma b s h o ul d be wit h dra w n a n d tra nsferre d i nt o a n i ntra ve n o us 
c o ntai ner. Ni v ol u ma b s h o ul d be t he n be dil ute d wit h eit her 0. 9 % s o di u m c hl ori de i njecti o n, U S P 
or 5 % de xtr ose i njecti o n, U S P, t o pre pare a n i nf usi o n wit h a fi nal c o nce ntrati o n ra n gi n g fr o m 1 
m g/ m L t o 1 0 m g/ m L. Dil ute d s ol uti o n s h o ul d be mi x e d b y ge ntle i n v ersi o n, b ut s h o ul d n ot be 
s ha ke n. Partiall y use d or e m pt y vials of ni v ol u ma b s h o ul d be discar de d. 
Patie nts s h o ul d be a d mi nistere d ni v ol u ma b 2 4 0 m g as a n i n i ntra ve n o us i nf usi o n o ver 6 0 mi n utes 
e ver y 2 w ee ks. F or t he first i nf usi o n, t he patie nt’s vital si g ns ( heart rate, res pirat or y rate, bl o o d 
press ures, a n d te m per at ure) s h o ul d be d eter mi ne d wit hi n 6 0 mi n utes bef ore, d uri n g (e ver y 1 5 
[ ± 5] mi n utes), a n d 3 0 ( ± 1 0) mi n utes after t he i nf usi o n. F or s u bse q ue nt i nf usi o ns, vital si g ns will 
be c ollecte d wit hi n 6 0 mi n utes bef ore i nf usi o n.  Patie nts will be i nf or me d a b o ut t he p ossi bilit y of 
dela ye d p ost-i nf usi o n s y m pt o ms a n d i nstr ucte d t o c o ntact t heir st u d y p h ysicia n if t he y de v el o p 
ac ute s y m pt o ms. 
A d mi nister t he i nf usi o n o ver 6 0 mi n utes t hr o u g h a n i ntra ve n o us li ne c o nt ai ni n g a sterile, 
n o n p yr o ge nic, l o w pr otei n bi n di n g i n- li ne filter ( p ore size of 0. 2 micr o meter t o 1. 2 micr o meter).  
D o n ot c oa d mi nister ot her dr u gs t hr o u g h t he sa me i ntra ve n o us li ne.  
Fl us h t he i ntra ve n o us li n e at e n d of i nf usi o n. 
5. 3. 3.  
M a n a ge me nt of  Ni v ol u m a b- S pecific A d verse E ve nts  
T o xicities ass ociate d or p ossi bl y ass ociate d wit h ni v ol u ma b treat me nt s h o ul d be ma na ge d 
acc or di n g t o sta n d ar d me dical practice.  A d diti o nal tests, s uc h as a ut oi m m u ne ser ol o g y or 
bi o psies, ma y be us e d t o deter mi ne a p ossi ble i m m u n o ge nic eti ol o g y. 
 
Alt h o u g h m ost i m m u ne-r elate d a d v erse e ve nts o bs er ve d wit h i m m u n o m o d ulat or y a ge nts ha v e 
bee n mil d a n d self-li miti n g, s uc h e ve nts s h o ul d b e rec o g nize d earl y a n d treate d pr o m ptl y t o 
a v oi d p ote ntial maj or c o m plicati o ns.  Disc o nti n uati o n of ni v ol u ma b ma y n ot ha ve a n i m me diate 
t hera pe utic eff ect a n d i n se vere cases, i m m u ne-rel ate d t o xicities ma y re q uire ac ute m a na ge me nt 
wit h t o pical c ortic oster oi ds, s yste mic c ortic o ster oi ds, m yc o p h e n olate, or T N F- α i n hi bit ors. 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 1 
T he pri mar y a p pr oac h t o Gra de 1- 2 i m m u ne-rel ate d a d verse e ve nts is s u p p orti ve a n d 
s y m pt o matic care wit h c o nti n ue d treat me nt wit h ni v ol u ma b; f or hi g her gra de i m m u ne-relate d 
a d verse e ve nts, ni v ol u ma b s h o ul d be h el d a n d oral/ pare ntal ster oi ds a d mi nistere d.  Rec urre nt 
Gra de 2 i m m u ne-relate d a d verse e ve nts ma y als o ma n date h ol di n g ni v ol u ma b or t he use of 
ster oi ds.  C o nsi derati o n f or be nefit/ris k bala n ce s h o ul d be ma de b y t he i n vesti gat or, wit h 
c o nsi derati o n of t he t otalit y of i nf or mati o n as it pertai ns t o t he nat ure of t h e t o xicit y a n d t he 
de gree of cli nical be n efit a gi v e n patie nt ma y be e x perie nci n g pri or t o f urt h er a d mi nistrati o n of 
ni v ol u ma b.  Ni v ol u ma b s h o ul d be per ma ne ntl y dis c o nti n ue d i n patie nts wit h life- t hreat e ni n g 
ir A Es. 
 
See Prescri bi n g I nf or mati o n f or f ull details.  
5. 3. 4.  
G ui deli nes f or D os a ge M o dific ati o n a n d Tre at me nt I nterr u pti o n or 
Disc o nti n u ati o n 
Ni v ol u ma b treat me nt will be gi ve n f or u p t o o ne year.  
 
Patie nts ma y te m p or aril y s us pe n d st u d y treat me nt f or u p t o 4 2 da ys fr o m t h e last d ose if t he y 
e x perie nce t o xicit y t hat is c o nsi dere d r elate d t o t h e st u d y dr u g a n d re q uires a d ose t o be hel d.  If 
ni v ol u ma b is hel d beca us e of a d verse e v e nts f or > 4 2 da ys b e y o n d t he last d ose, t he n t he patie nt 
will be disc o nti n ue d fr o m ni v ol u ma b. 
 
If a patie nt m ust be ta p er e d off ster oi ds use d t o treat a d vers e e ve nts, ni v ol u ma b ma y b e hel d f or 
a d diti o nal ti me be y o n d 4 2 da ys fr o m t he last d ose u ntil ster oi ds are disc o nti n ue d or re d u ce d t o 
pre d nis o ne d ose ( or d ose e q ui vale nt) ≤1 0 m g/ da y.  T he acce pta ble l e n gt h of i nterr u pti o n will 
de pe n d o n a n a gree me nt bet wee n t he i n v esti gat or a n d t he Pri nci pal I n vesti gat or. 
 
D ose i nterr u pti o ns f or reas o n(s) ot her t h a n t o xicit y, s uc h as s ur gical pr oce d ures, ma y be all o we d 
wit h Pri nci pal I n v esti gat or a p pr o val.  T h e acce pta ble le n gt h of i nterr u pti o n will de pe n d o n 
a gree m e nt bet wee n t he i n vesti gat or a n d t he Pri nci pal I n v esti gat or. 
 
A n y t o xicities ass ociate d or p ossi bl y ass oci ate d wit h ni v ol u ma b treat me nt s h o ul d be ma na ge d 
acc or di n g t o sta n d ar d me dical pra ctice.  A d diti o nal tests, s uc h as a ut oi m m u ne ser ol o g y or 
bi o psies, ma y be us e d t o deter mi ne a p ossi ble i m m u n o ge nic eti ol o g y.   
 
Patie nts s h o ul d be assesse d cli nicall y (i ncl u di n g re vie w of la b orat or y val u es) f or t o xicit y pri or t o, 
d uri n g, a n d after eac h i nf usi o n.  If u n m a na gea ble t o xicit y d ue t o ni v ol u ma b occ urs at a n y ti me 
d uri n g t he st u d y, treat me nt wit h ni v ol u ma b s h o ul d be disc o nti n ue d. 
 
Ma na ge me nt of p ot e ntial i m m u ne relate d A Es are descri be d i n t he f oll o wi n g secti o ns. 
5. 3. 4. 1.  
M a n a ge me nt of i nf usi o n- rel ate d re acti o n  
N o pre me dicati o n will be all o we d f or t he first d ose of ni v ol u ma b.  Pre me di cati o n ma y be 
a d mi nistere d f or 2 d oses or great er at t he discreti o n of t he treati n g p h ysicia n.  Patie nts w h o 
e x perie nce i nf usi o n -ass ociate d s y m pt o ms ma y b e treate d s y m pt o maticall y wit h a nti p yretics 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 2 
(i b u pr ofe n pr eferre d), di p he n h y dra mi ne, a n d/ or ci meti di ne or a n ot her H 2 rece pt or a nta g o nist, as 
per sta n dar d practice.  
 
T he ma na ge m e nt of i nf usi o n- relate d r eacti o ns will be acc or di n g t o s e verit y as per i nstit uti o nal 
g ui deli nes. 
 
5. 3. 4. 2.  
G astr oi nt esti n al T o xicit y 
I m m u ne-me diate d c olitis has bee n ass o ciate d wit h t he a d mi nistrati o n of ni v ol u ma b. Diarr hea or 
c olitis was re p orte d i n 2 1 % of patie nts i n t w o trials of ni v ol u ma b. I m m u ne- me diate d c olitis 
occ urr e d i n 2. 2 % of p atie nts i n o ne trial- of t hese o ne patie nt ha d Gra de 2 c olitis, a n d fi ve ha d 
Gra de 3 c olitis. I n t he ot h er trial, Gr a de 3 i m m u ne- me diate d c olitis occ urre d i n 0. 9 % of patie nts. 
 
Patie nts s h o ul d be a d vise d t o i nf or m t he i n vesti gat or if a n y diarr hea o cc urs, e ve n if it is mil d. 
Ra n ge f or ti me t o o nset of s y m pt o ms of c olitis has bee n 1- 6 m o nt hs. 
 
If t he e v e nt is of si g nifica nt d urati o n or ma g nit u d e or is ass ociate d wit h si g ns of s yste mic 
i nfla m mati o n or ac ute p h ase reacta nts (e. g. i ncreas e d C R P or platelet c o u nt or ba n de mia), it is 
rec o m me n de d t h at si g m oi d osc o p y ( or c ol o n osc o p y, if a p pr o priate) wit h c ol o nic bi o ps y wit h 
t hree t o fi ve s peci me ns f or sta n dar d paraffi n bl oc k be perf or me d.   
 
Treat me nt ma y be restarte d f oll o wi n g t he res ol uti o n of c olitis.  I n a d diti o n, if t he patie nt is bei n g 
ma na ge d wit h c ortic ost er oi ds, treat me nt s h o ul d n ot be restarte d u ntil t he ster oi ds ha ve bee n 
ta pere d d o w n t o a pre d nis o ne d ose ≤ 1 0 m g/ d a y.  Patie nts w h o res u me treat me nt s h o ul d be 
m o nit ore d cl osel y f or si g ns of re ne we d diarr hea. 
 
Ta ble 2 pr o vi des a s u m m ar y of d ose m o dificati o n g ui deli nes f or gastr oi ntesti nal t o xicities.  
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 3 
T a ble 2 D ose M o dific ati o n G ui deli nes f or G astr oi ntesti n al T o xicit y 
 
S y m pt o ms  
M a n a ge me nt  
F oll o w -u p  
Gra de 1 diarr hea: < 4 st o ols per da y 
o ver baseli ne  
Gra de 1 c olitis: as y m pt o matic c olitis  
C o nti n ue ni v ol u ma b  
A d mi nister s y m pt o matic 
treat me nt 
 
‐ Cl ose m o nit ori n g f or w orse ni n g 
s y m pt o ms 
‐ E d ucate patie nts t o re p ort w orse ni n g 
i m me diatel y 
Gra de 2 diarr hea: 4 -6 st o ols per da y 
o ver baseli ne  
‐ I V fl ui ds i n dicate d < 2 4 hrs 
‐ N ot i nterferi n g wit h A D L  
Gra de 2 C olitis: a b d o mi nal pai n, 
bl o o d i n st o ol  
Wit h h ol d ni v ol u ma b  
A d mi nister s y m pt o matic 
treat me nt 
If s y m pt o ms persist > 5 da ys or 
rec ur: 0. 5 t o 1 m g/ k g/ da y 
pre d nis o ne e q ui vale nts  
If i m pr o ve d: 
‐ res u me ni v ol u ma b 
‐ if ster oi ds ha ve bee n a d mi nist ere d, 
ta per ster oi ds o ver at least 1 m o nt h 
bef ore res u mi n g ni v ol u ma b  
If s y m pt o ms w orse n or persist > 3-5 da ys 
wit h oral ster oi ds:  
‐ treat as Gra de 3 or 4  
Gra de 3 or 4  
Gra de 3 diarr hea: > 7 st o ols per da y 
o ver baseli ne, i nc o nti ne nce  
‐ I V fl ui ds > 2 4 hs  
‐ I nterferes wit h A D Ls 
C olitis Gra de 3: se vere a b d o mi nal 
pai n, me dical i nter ve nti o n i n di cate d, 
perit o neal si g ns prese nt  
 
C olitis Gra de 4: life t hreate ni n g  
s y m pt o ms, perf orati o n 
Gra de 3: wit h h ol d ni v ol u ma b 
u ntil s y m pt o ms are Gra de 1  
Gra de 3 persists or w orse ns, or 
Gra de 4: per ma ne ntl y 
disc o nti n ue ni v ol u ma b  
 
A d mi nister 1 -2 m g/ k g/ da y 
pre d nis o ne e q ui vale nts  
 
C o nsi der l o wer -GI e n d osc o p y  
If i m pr o ve d fr o m Gra de 3: 
‐ w he n at Gra de 1, ta per ster oi ds o ver 1 
m o nt h bef ore res u mi n g ni v ol u ma b  
If i m pr o ve d fr o m persiste nt Gra de 3 or 
Gra de 4  
‐ c o nti n ue ster oi ds u ntil Gra de 1, t he n 
ta per o ver at least 1 m o nt h 
If s y m pt o ms persist > 3-5 da ys, or rec ur 
after i m pr o ve me nt  
‐ a d d n o n-c ortic oster oi d 
i m m u n os u p pressi ve me dicati o n 
 
5. 3. 4. 3.  
He p at ot o xicit y 
I m m u ne- me diate d h e patitis has occ urr e d wit h t he a d mi nistrati o n of ni v ol u ma b. 
 
Patie nts s h o ul d be m o nit ore d f or a b n or mal li ver t ests pri or t o a n d peri o dicall y d uri n g treat me nt. 
W hile o n t his st u d y, pati e nts prese nti n g wit h ri g ht u p per- q ua dra nt a b d o mi n al pai n a n d/ or 
u ne x plai ne d na usea or v o miti n g s h o ul d ha ve L F Ts perf or me d i m me diat el y a n d L F Ts s h o ul d be 
re vie we d b ef or e a d mi nistrati o n of t he ne xt d ose of st u d y dr u g. 
 
If L F Ts i n crease, ne o plastic, c o nc urr e nt me dicati o ns, viral he patitis, a n d t o xic eti ol o gies s h o ul d 
be c o nsi der e d a n d a d dresse d, as a p pr o priate.  I ma gi n g of t he li ver, gall bla d der, a n d biliar y tree 
s h o ul d be perf or m e d t o r ule o ut ne o plastic or ot her ca uses f or t he i ncreas e d L F Ts.  A nti- n ucl ear 
a nti b o d y, peri n uclear a nti- ne utr o p hil c yt o pl as mic a nti b o d y, a nti- li ver-ki d ne y micr os o mal 
a nti b o dies, a n d a nti-s m o ot h m uscle a nti b o d y tests s h o ul d be perf or m e d i n a n a ut oi m m u ne 
eti ol o g y is c o nsi der e d. 
  
Patie nts wit h L F T a b n or malities s h o ul d be ma na ge d acc or di n g t o t he g ui deli nes i n Ta ble 3. 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 4 
 
T a ble 3  
 D ose M o dific ati o n G ui deli nes f or He p at ot o xicit y 
 
S y m pt o ms  
M a n a ge me nt  
F oll o w -u p  
Gra de 1:  
A S T or A L T > U L N t o 
3 x U L N a n d/ or T Bili 
> U L N t o 1. 5 x U L N  
C o nti n ue ni v ol u ma b  
Re g ularl y m o nit or L F Ts  
C o nti n ue m o nit ori n g L F Ts  
Gra de 2:  
A S T or A L T > 3 t o < 5 x 
U L N a n d/ or T Bili > 1. 5 
t o < 3 U L N  
‐ Wit h h ol d ni v ol u ma b  
‐ I ncrease fre q ue nc y of m o nit ori n g 
t o e ver y 3 da ys 
‐ 1 t o 2 m g/ k g/ da y pre d nis o ne 
e q ui vale nts  
If i m pr o ve d t o Gra de 1 or baseli ne, res u me 
ni v ol u ma b.  
If ster oi ds ha ve bee n a d mi nist ere d, ta per ster oi ds 
o ver at least 1 m o nt h bef ore res u mi n g 
ni v ol u ma b.  
Res u me r o uti ne L F T m o nit ori n g  
Gra de 3 or 4:  
A S T or A L T > 5 x U L N 
a n d/ or T Bili > 3 x U L N  
‐ P er ma ne ntl y disc o nti n ue 
ni v ol u ma b  
‐ I ncrease fre q ue nc y of m o nit ori n g 
t o e ver y 1 -2 da ys  
‐ Gastr oe nter ol o g y c o ns ult  
‐ Treat wit h 1 -2 m g/ k g/ da y 
pre d nis o ne e q ui vale nt  
If i m pr o ve d t o < Gra de 2, ta per ster oi ds o ver at 
least 1 m o nt h 
If la bs persist > 3-5 da ys, w ors e n or re b o u n d: a d d 
n o n -c ortic oster oi d i m m u n os u p pressi ve 
me dicati o n  
I V =  i ntra ve n o us; L F T =  li ver f u ncti o n test; U L N =  u p per li mit of n or mal.  
 
5. 3. 4. 4.  
Re n al T o xicit y 
I m m u ne- me diate d n e p hritis or re nal d ysf u ncti o n o cc urre d wit h ni v ol u ma b treat me nt. Patie nts 
s h o ul d be m o nit ore d f or ele vate d ser u m creati ni ne pri or t o a n d peri o dicall y d uri n g treat me nt a n d 
cli nicall y m o nit ore d f or s y m pt o ms of decreas e d v ol u me of uri nati o n, he mat uria, peri p heral 
e de ma, a n d l oss of a p petite. 
 
I n o n e trial, t here was i ncrease d i n ci de nce of ele v ate d creati ni ne i n t he ni v ol u ma b -treat e d gr o u p 
as c o m par e d t o c he m ot hera p y ( 1 3 % v 9 %). Gra de 2 or 3 i m m u ne- me diate d ne p hritis or re nal 
d ysf u n cti o n occ urre d i n 0. 7 % ( 2/ 2 6 8) of patie nts. I n a n ot her trial, t he i n ci de nce of ele vat e d 
creati ni ne w as 2 2 %, wit h Gra de 2 i m m u ne- m e diat e d re nal d ysf u ncti o n occ urri n g i n 0. 9 % ( 1/ 1 1 7) 
patie nts.  
 
Re nal t o xicit y s h o ul d be ma na ge d acc or di n g t o t h e g ui d eli nes i n Ta ble 4.  
 
 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 5 
T a ble 4 
D ose M o dific ati o n G ui deli nes f or Re n al T o xicit y  
 
T o xicit y, Gr a de  
M a n a ge me nt  
F oll o w -u p  
Gra de 1  
‐ Creati ni ne > U L N a n d > baseli ne 
b ut < 1. 5 x baseli ne  
C o nti n ue ni v ol u ma b  
‐ M o nit or creati ni ne wee kl y  
If i m pr o ve d t o baseli ne, res u me 
r o uti ne creati ni ne m o nit ori n g. 
Gra de 2 or 3  
‐ Creati ni ne > 1. 5 t o < 6 x U L N or 
> 1. 5 x baseli ne  
Wit h h ol d ni v ol u ma b  
‐ M o nit or creati ni ne e ver y 2 -3 
da ys  
‐ Treat wit h 0. 5 t o 1 m g/ k g/ da y 
pre d nis o ne e q ui vale nts  
‐ C o nsi der re nal bi o ps y  
If i m pr o ve d t o Gra de 1, ta per 
ster oi ds o ver at least 1 m o nt h bef ore 
res u mi n g ni v ol u ma b wit h r o uti ne 
creati ni ne m o nit ori n g.  
 
If ele vati o ns persist > 7 da ys or 
w orse n, treat as Gra de 4  
Gra de 4  
‐ Creati ni ne > 6 x U L N  
P er ma ne ntl y disc o nti n ue ni v ol u ma b  
‐ M o nit or creati ni ne dail y  
‐ Ne p hr ol o g y c o ns ult  
‐ Treat wit h 1 -2 m g/ k g/ da y 
pre d nis o ne e q ui vale nts  
‐ C o nsi der re nal bi o ps y  
If i m pr o ve d t o Gra de 1, ta per 
ster oi ds o ver at least 1 m o nt h 
 
5. 3. 4. 5.  
E n d ocri ne T o xicit y  
I m m u ne- me diate d h y p ot h yr oi dis m a n d h y pert h yr oi dis m has bee n ass ociat e d wit h t he 
a d mi nistrati o n of ni v ol u ma b. I n o ne trial, Gra de 1 or 2 h y p ot h yr oi dis m occ urre d i n 8 % ( 2 1/ 2 6 8) 
of patie nts recei vi n g ni v ol u ma b. Gra de 1 or 2 h y pert h yr oi dis m occ urre d i n 3 % ( 8/ 2 6 8) of 
patie nts o n ni v ol u ma b o n t hat trial, a n d i n 1 % ( 1/ 1 0 2) patie nts recei vi n g c h e m ot hera p y. I n 
a n ot her trial, h y p ot h yr oi dis m occ urre d i n 4. 3 % ( 5/ 1 1 7) of patie nts. H y pert h yr oi dis m occ urre d i n 
1. 7 % ( 2/ 1 1 7) of patie nts. O ne patie nt e x perie nce d Gra de 2 h y p ert h yr oi dis m. 
 
Patie nts wit h u ne x plai ne d s y m pt o ms s uc h as fati g ue, hea d ac hes, m yal gias, i m p ote nce, me ntal 
stat us c ha n ges, or c o nsti pati o n s h o ul d be i n vesti gate d f or t he prese nce of t h yr oi d, pit uitar y, or 
a dre nal e n d ocri n o p at hies, as well as f or h y p o n atre mia or h y p er kal e mia.  A n e n d ocri n ol o gist 
s h o ul d be c o ns ulte d if a n e n d ocri n o pat h y is s us pecte d.  T S H a n d free T 4 l e vels s h o ul d be 
o btai ne d t o deter mi ne if t h yr oi d a b n or malities are prese nt.  T S H, pr olacti n, a n d a m or ni n g 
c ortis ol le vel will hel p t o differe ntiat e pri mar y a dre nal i ns ufficie n c y fr o m pri mar y pit uitar y 
i ns ufficie nc y. 
 
H y p ot h yr oi dis m s h o ul d be ma na ge d acc or di n g t o t he g ui d eli nes i n Ta ble 5. 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 6 
T a ble 5  
D ose M o dific ati o n G ui deli nes f or E n d ocri ne T o xicit y  
 
T o xicit y Gr a de  
M a n a ge me nt  
F oll o w -u p  
As y m pt o matic e n d ocri n o pat h y 
(e. g h y p ot h yr oi dis m or 
h y pert h yr oi dis m)  
‐ C o nti n ue ni v ol u ma b  
‐ If T S H < 0. 5 x L L N or T S H > 2 x U L N, or 
c o nsiste ntl y o ut of ra n ge i n 2 s u bse q ue nt 
meas ure me nts, i ncl u de free T 4 at 
s u bse q ue nt c ycles as cli nicall y i n dicate d 
‐ C o nsi der e n d ocri n ol o g y c o ns ult  
 
C o nti n ue sta n dar d 
m o nit ori n g  
S y m pt o matic e n d ocri n o pat h y –  
eit her h y p ot h yr oi dis m or 
h y pert h yr oi dis m  
‐ c o nti n ue ni v ol u ma b f or h y p ot h yr oi dis m 
or h y pert h yr oi dis m  
‐ wit h h ol d ni v ol u ma b  f or ot her 
e n d ocri n o pat hies wit h a b n or mal 
la b/ pit uitar y sca n 
‐ e val uate e n d ocri ne f u ncti o n  
‐ c o nsi der pit uitar y sca n  
‐ re peat la bs i n 1-3 wee ks  
‐ re peat M RI i n 1 m o nt h if s y m pt o ms 
persist b ut n or mal la b/ pit uitar y sca n  
‐ c o nsi der e n d ocri n ol o g y c o ns ult  
If i m pr o ve d ( wit h or wit h o ut 
h or m o ne re place me nt) - 
res u me ni v ol u ma b 
 
C o nti n ue sta n dar d 
m o nit ori n g  
 
P atie nts wit h a dre nal 
i ns ufficie nc y ma y nee d t o 
c o nti n ue ster oi ds wit h 
mi neral oc ortic oi d c o m p o ne nt  
S us pici o n of a dre nal crisis:  
‐ se vere de h y drati o n 
‐ h y p ote nsi o n  
‐ s h oc k o ut of pr o p orti o n t o 
c urre nt ill ness  
‐ wit h h ol d ni v ol u ma b  
‐ r ule o ut se psis 
‐ c o ns ult e n d ocri n ol o g y  
‐ stress-d ose I V ster oi ds wit h 
mi neral oc ortic oi d acti vit y ( ma y be 
s witc he d t o a n e q ui vale nt d ose of oral 
c ortic oster oi ds at start of ta peri n g or 
earlier, o nce s ustai ne d cli nical 
i m pr o ve me nt o bser ve d) 
‐ a d mi nister I V fl ui ds  
W he n a dre nal crisis r ule d 
o ut, treat as s y m pt o matic 
e n d ocri n o pat h y 
T S H  =  t h yr oi d-sti m ulati n g h or m o ne. 
 
5. 3. 4. 6.  
P ul m o n ar y T o xicit y 
Se vere p ne u m o nitis or i nterstitial l u n g disease, i ncl u di n g fatal cases, h a ve o cc urre d wit h 
ni v ol u ma b treat me nt. As s uc h, patie nts m ust be m o nit ore d f or si g ns a n d s y m pt o ms of 
p ne u m o nitis. Acr oss cli nical trial e x perie nce i n 6 9 1 patie nts wit h s oli d t u m ors, f atal i m m u ne 
me diate d p ne u m o nitis occ urre d i n 0. 7 % ( 5/ 6 9 1) of patie nts recei vi n g ni v ol u ma b. I n o ne trial 
2. 2 % ( 6/ 2 6 8) of patie nts recei vi n g ni v ol u ma b de v el o pe d i m m u ne- me diate d p ne u m o nitis, o ne 
wit h Gra de 3 a n d wit h Gra de 2 cases. I n a n ot her trial, i m m u ne- me diate d p ne u m o nitis occ urre d i n 
6 % ( 7/ 1 1 7) of patie nts r ecei vi n g ni v ol u ma b i ncl u di n g fi ve Gra d e 3 a n d t w o Gra de 2 cases. 
 
P ul m o nar y t o xicit y s h o ul d be ma na ge d acc or di n g t o t he g ui deli nes i n Ta ble 6. 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 7 
T a ble 6  
D ose M o dific ati o n G ui deli nes f or P ul m o n ar y T o xicit y 
 
Descri pti o n  
M a n a ge me nt  
F oll o w -u p  
Gra de I - ra di o gra p hic 
c ha n ges o nl y 
‐ C o nsi der wit h h ol di n g ni v ol u ma b.  
‐ M o nit or e ver y 2 -3 da ys  
‐ c o nsi der p ul m o nar y a n d i nfecti o us 
disease c o ns ults.  
‐ Reassess at least e ver y 3 wee ks  
‐ If i m pr o ve d, res u me ni v ol u ma b (if 
it has bee n disc o nti n ue d) w he n 
s y m pt o ms sta bilize d 
‐ If w orse ns, treat as Gra de 2 or 
a b o ve 
Gra de 2:  
‐ mil d t o m o derate 
s y m pt o ms 
‐ ra di o gra p hic c ha n ges 
‐ wit h h ol d ni v ol u ma b  
‐ m o nit or dail y  
‐ c o ns ult P ul m o nar y a n d I nfecti o us 
diseases  
‐ treat me nt wit h 1 m g/ k g/ da y pr e d nis o ne 
or e q ui v  
‐ c o nsi der br o nc h osc o p y/l u n g bi o ps y  
If i m pr o ve d t o baseli ne: 
‐ ta per ster oi ds o ver at least 1 
m o nt h bef ore res u mi n g ni v ol u ma b  
 
If n ot im pr o vi n g after 2 wee ks or 
w orse ni n g:  
‐ treat as Gra de 3 or 4 
Gra de 3 or 4:  
‐ se vere s y m pt o ms 
‐ ne w/ w orse ni n g h y p o xia  
‐ life-t hreate ni n g s y m pt o ms 
‐ H os pitalize patie nt  
‐ P er ma ne ntl y disc o nti n ue ni v ol u ma b  
‐ M o nit or dail y  
‐ O btai n P ul m o nar y a n d I nfecti o us 
Disease c o ns ults  
‐ Treat wit h 1 -2 m g/ k g/ da y pre d nis o ne or 
e q ui vale nt  
‐ C o nsi der br o nc h osc o p y, l u n g bi o ps y  
If i m pr o ve d t o baseli ne: 
‐ ta per ster oi ds o ver at least 1 
m o nt h  
 
If persists or w orse ns after 2 da ys 
‐ a d d n o n-c ortic oster oi d 
i m m u n os u p pressi ve me dicati o n 
 
 
 
5. 3. 4. 7.  
Peric ar di al a n d Ple ur al Eff usi o ns  
Pericar dial a n d ple ural i n v ol ve me nt wit h ass ociate d eff usi o ns is c o m m o n i n patie nts wit h 
N S C L C a n d ha v e t he t he oretical p ote ntial t o be e x acer b ate d b y i nfla m mati o n ass ociate d wit h 
a ntit u m or i m m u nit y f oll o wi n g P D - L 1 bl oc k a de.  P atie nts prese nti n g wit h d ys p nea, c hest p ai n, or 
u ne x plai ne d tac h ycar di a s h o ul d be e val uate d f or t he prese n ce of a pericar dial eff usi o n.  Patie nts 
wit h pree xisti n g pericar dial eff usi o n s h o ul d be f oll o we d cl osel y f or p ericar dial fl ui d v ol u me 
meas ure me nts a n d i m pact o n car diac f u ncti o n.  W he n i nter ve nti o n is re q uire d f or pericar dial or 
ple ural eff usi o ns, a p pr o priate w or k u p i ncl u d es c yt ol o g y, L D H, gl u c ose, c h olester ol, pr otei n 
c o nce ntr ati o ns ( wit h ple ural eff usi o ns), a n d cell c o u nt.  F or patie nts wit h a pericar dial eff usi o n 
ca usi n g e n d -diast olic ri g ht ve ntric ular c olla ps e, treat me nt ma y be restarte d f oll o wi n g t he 
place me nt of a pericar dial wi n d o w, de m o nstrati o ns of he m o d y n a mic sta bilit y, a n d res ol uti o n of 
ri g ht ve ntri c ular d ysf u n cti o n. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 8 
6.  
C O N C O MI T A N T M E DI C A TI O N S/ P R O C E D U R E S 
6. 1.  
Per mitte d C o n c o mit a nt  Me d ic ati o ns 
S u p p orti ve me dicati o ns i n acc or d a nce wit h sta n dar d practice (s uc h as f or e mesis, diarr hea, etc.) 
are per mitte d.  Use of n e utr o p hil gr o wt h fact ors (fil grasti m a n d pe gfil grasti m)  or re d bl o o d cell 
gr o wt h fact ors (er yt hr o p oieti n)  is per mitte d per i nstit uti o nal p olic y a n d i n acc or da n ce wit h t he 
A S C O g ui deli nes ( S mit h 2 0 0 6).  Tra nsf usi o ns ma y be gi v e n i n acc or da n ce wit h i nstit uti o nal 
p olic y.  
S h ort c o urses ( ≤1 4 da ys) of ster oi d treat me nt f or n o n- ca ncer relate d me di cal reas o ns (e g, j oi nt 
i nfla m mati o n, ast h ma e xacer b ati o n, ras h, a ntie m etic use a n d i nf usi o n reacti o ns) at d oses t hat d o 
n ot e x cee d 1 0 0 m g p er da y of pre d nis o ne or e q ui vale nt are per mitte d. 
6. 2.  
Me d ic ati o ns t o be Use d wit h C a uti o n 
6. 2. 1.  
C Y P 3 A - I n hi bit ors/I n d ucers 
I br uti ni b is meta b olize d pri maril y b y C Y P 3 A. A v oi d c o-a d mi nistrati o n wit h str o n g C Y P 3 A 
i n hi bit or (e g, k et oc o naz ole, i n di na vir, nelfi na vir, rit o na vir, sa q ui na vir, clarit hr o m yci n, 
telit hr o m yci n, itrac o n az ole, c o bicistat, p osac o n az ole, a n d nefaza d o ne) or m o derate C Y P 3 A 
i n hi bit ors a n d c o nsi der alter nati ve a ge nts wit h less C Y P 3 A i n hi biti o n. If a str o n g C Y P 3 A 
i n hi bit or m ust be use d, eit her re d u ce i br uti ni b  d ose t o 1 4 0 m g or wit h h ol d treat me nt te m p oraril y 
(f or 7 da ys or less). S u bjects s h o ul d be m o nit ore d f or si g ns of i br uti ni b t o xicit y. If a m o derate 
C Y P 3 A i n hi bit or (e g. Fl uc o naz ole, v oric o naz ole, er yt hr o m yci n, a m pre n a vir, a pre pita nt, 
ataza na vir, ci pr ofl o x aci n, criz oti ni b, diltiaze m, f osa m pre na vir, i mati ni b, vera pa mil, a mi o dar o ne, 
a n d dr o ne dar o ne) m ust b e use d, re d u ce i br uti ni b t o 1 4 0 m g f or t h e d urati o n of t he i n hi bit or use. 
N o d ose a dj ust me nt is re q uire d i n c o m bi nati o n wit h mil d i n hi bit ors. A v oi d gra pefr uit a n d Se ville 
ora n ges d uri n g i br uti ni b treat me nt, as t hes e c o ntai n m o derate i n hi bit ors of C Y P 3 A (see Secti o n 
5. 3. 1. 2 ). 
A v oi d c o nc o mita nt use of str o n g C Y P 3 A i n d ucers (e g, car ba maze pi ne, rifa m pi n, p he n yt oi n, a n d 
St. J o h n’s W ort). C o nsi der alter n ati ve a ge nts wit h less C Y P 3 A i n d ucti o n.  
A list of c o m m o n C Y P 3 A i n hi bit ors a n d i n d ucers is pr o vi de d i n A p pe n di x 3.  A c o m pre h e nsi ve 
list of i n hi bit ors, i n d ucers, a n d s u bstrates ma y be f o u n d at 
htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ mai n -ta ble/    
T his we bsite is c o nti n uall y re vis e d a n d s h o ul d be c hec k e d fre q ue ntl y f or u p dates. 
6. 2. 2.  
Dr u gs T h at M a y H a ve T heir Pl as m a C o nce ntr ati o ns Altere d b y I br uti ni b 
I n vitr o st u dies i n dicat e d t hat i br uti ni b is n ot a s u bstrate of P-gl yc o pr otei n ( P - g p), b ut is a mil d 
i n hi bit or ( wit h a n I C5 0 of 2. 1 5 μ g/ m L).  I br uti ni b is n ot e x pecte d t o ha ve s yste mic dr u g-dr u g 
i nteracti o ns wit h P-g p s u bstrates. H o we v er, it ca n n ot be e x cl u de d t hat i br uti ni b c o ul d i n hi bit 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 3 9 
i ntesti nal P-g p after a t hera pe utic d ose. T h ere is n o cli nical data a v aila ble; t heref ore , t o a v oi d a 
p ote ntial i nteracti o n i n t he GI tract, narr o w t hera p e utic ra n ge P - g p s u bstrates s uc h as di g o xi n, 
s h o ul d be ta ke n at least 6 h o urs bef or e or after i br uti ni b. 
6. 2. 3.  
Q T Pr ol o n gi n g A ge nts 
A n y me di cati o ns k n o w n t o ca use Q T pr ol o n gati o n s h o ul d be use d wit h ca uti o n; peri o dic E C G 
a n d electr ol yte m o nit ori n g s h o ul d be c o nsi dere d.  
6. 2. 4.  
A nti pl atelet  A ge nts  a n d A ntic o a g ul a nts 
Warfari n or vita mi n K a nta g o nists s h o ul d n ot be a d mi nistere d c o nc o mita ntl y wit h i br uti ni b.  I n 
a n i n vitr o platelet f u ncti o n st u d y, i n hi bit or y effects of i br uti ni b o n c olla ge n- i n d uce d platelet 
a g gre gati o n w ere o bs er v e d. S u p ple me nts s uc h as fis h oil a n d vita mi n E pre parati o ns s h o ul d be 
a v oi de d.  Use i br uti ni b wit h ca uti o n i n s u bjects re q uiri n g ot her a ntic oa g ula nts or me dicati o ns 
t hat i n hi bit platelet f u ncti o n. Blee di n g e v e nts of a n y gra de, i ncl u di n g br uisi n g a n d p etec hi ae, 
occ urr e d i n s u bjecte d tr eate d wit h i br uti ni b. S u bjects wit h c o n ge nital blee di n g diat hesis ha v e n ot 
bee n st u die d.  F or g ui da n ce o n i br uti ni b a n d t he us e of a ntic oa g ul a nts d uri n g 
pr oce d ur es/s ur geri es see Secti o n 6. 4. 
S u bjects re q uiri n g t h e i nitiati o n of t hera pe utic a nti c oa g ulati o n t hera p y (e g, atrial fi brillati o n), 
c o nsi der t he ris ks a n d b e nefits of c o nti n ui n g i br uti ni b treat me nt.  If t hera pe utic a ntic oa g ulati o n is 
cli nicall y i n dicat e d, treat me nt wit h i br uti ni b s h o ul d be hel d a n d n ot be restarte d u ntil t he s u bject 
is cli nicall y sta ble a n d h as n o si g ns of blee di n g.  S u bjects s h o ul d be o bser v e d cl osel y f or si g ns 
a n d s y m pt o ms of blee di n g.  N o d os e re d u cti o n is re q uire d w he n st u d y dr u g is restarte d. 
6. 3.  
Pr o hi bite d C o nc o mit a nt Me dic ati o ns  
A n y c he m ot her a p y, e x peri me ntal t hera p y, or ra di ot hera p y are pr o hi bite d w hile t he s u bject is 
recei vi n g st u d y treat me nt.   
C ortic oster oi ds f or t he tr eat me nt of t he u n derl yi n g diseas e is pr o hi bite d e x ce pt w he n re q uire d t o 
treat Ni v ol u ma b t o xicit y.  C ortic oster oi ds f or t he treat me nt of n o n-ca n cer relate d reas o ns f or 
l o n ger t h a n 1 4 da ys a n d/ or at d oses > 1 0 0 m g of pre d nis o ne or its e q ui vale nt are pr o hi bite d.   
6. 4.  
G ui deli nes f or I br uti ni b M a n a ge me nt wit h S ur geries o r Pr o ce d ure  
I br uti ni b ma y i ncreas e ris k of blee di n g wit h i n vasi ve pr oce d ures or s ur ger y. T he f oll o wi n g 
g ui da n ce s h o ul d be a p pli e d t o t he use of i br uti ni b i n t he peri o perati ve peri o d f or s u bjects w h o 
re q uire s ur gi cal i nter ve nti o n or a n i n vasi ve pr oce d ure w hile recei vi n g i br uti ni b.   
6. 4. 1.  
Mi n or S ur gic al Pr o ce d ures  
F or mi n or pr o ce d ur es (s u c h as a ce ntral li ne place me nt, nee dle bi o ps y, t h orace ntesis, or 
parace ntesis) i br uti ni b s h o ul d be hel d f or at least 3 da ys pri or t o t he pr oce d ure a n d s h o ul d n ot be 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 0 
restarte d f or at least 3 da ys after t he pr oce d ure. F or b o ne marr o w bi o psies t hat are perf or m e d 
w hile t he s u bject is o n i br uti ni b, it is n ot necessar y t o h ol d i br uti ni b f or t hese pr oce d ures.   
6. 4. 2.  
M aj or S ur gic al Pr o ce d ures  
F or a n y s ur ger y or i n vasi ve pr oce d ure re q uiri n g s ut ures or sta ples f or cl os ure, i br uti ni b s h o ul d be 
hel d at least 7 da ys pri or t o t he i nter ve nti o n a n d s h o ul d be hel d at least 7 da ys after t he pr oce d ure 
a n d restart e d at t he discr eti o n of t he i n vesti gat or w he n t he s ur gical site is reas o na bl y heale d 
wit h o ut ser osa n g ui ne o us drai na ge or t he nee d f or drai na ge t u bes.   
6. 4. 3.  
E mer ge nc y Pr oce d ures  
F or e mer ge n c y pr oce d ur es, i br uti ni b s h o ul d be hel d after t he pr o ce d ure u ntil t he s ur gical site is 
reas o na bl y h eale d, f or at least 7 da ys after t he ur ge nt s ur gi cal pr oce d ure. 
7.  
S T U D Y E V A L U A TI O N S   
7. 1.  
Descri pti o n  of Pr o ce d ures  
A c ycle h as a d ur ati o n of 2 8 da ys t hr o u g h o ut t his st u d y. 
All scree ni n g cli nical a n d la b orat or y ass ess me nts m ust be perf or me d wit hi n 2 8 da ys of St u d y 
Da y 1 a n d pri or t o t he first d ose of st u d y treat me nt. 
All st u d y tests a n d pr oce d ures s h o ul d be e v al uate d at t he st u d y c e nter at w hic h t he s u bject was 
e nr olle d. 
7. 1. 1.  
Assess me nts   
7. 1. 1. 1.  
I nf or me d C o nse nt F or m 
T he s u bject m ust rea d, u n dersta n d, a n d si g n t he I nstit uti o nal Re vie w B oar d/ Researc h Et hics 
B oar d/I n de pe n d e nt Et hics C o m mittee (I R B/ R E B/I E C) a p pr o ve d i nf or me d c o nse nt f or m (I C F) 
c onfir mi n g his or h er willi n g ness t o partici pat e i n t his st u d y b ef ore a n y st u d y -s p ecific s cree ni n g 
pr oce d ur es ar e perf or me d. 
S u bjects m ust als o gra nt per missi o n t o use pr otect e d healt h i nf or mati o n per t he Healt h I ns ura nce 
P orta bilit y a n d Acc o u nta bilit y A ct ( HI P A A). I n a d diti o n, s u bjects m ust si g n all a p pr o ve d I C F 
a me n d me nts per t he site I R B/ R E B/I E C g ui deli nes d uri n g t he c o urse of t he st u d y. 
T he s u bject ma y be e nr olle d i n t he st u d y o nl y aft er si g ni n g t he I C F a n d bei n g dee me d eli gi ble 
f or e ntr y bas e d o n scr ee nin g pr oce d ur es a n d hist or y re vie w. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 1 
7. 1. 1. 2.  
C o nfir m Eli gi bilit y  
All necessar y s cree ni n g pr oce d ur es a n d e v al uati o ns, al o n g wit h re vie w of me dical hist or y, m ust 
be perf or me d t o d oc u me nt t hat t he s u bject meets all of t he i ncl usi o n criteri a a n d n o ne of t h e 
e x cl usi o n criteria ( Secti o n 4). I n a d diti o n t o t he re vie w of scree ni n g pr o ce d ures a n d res ults, 
d oc u me ntati o n of pat h ol o gic c o nfir mati o n of eli gi ble disease ( Secti o n 4) is re q uire d f or 
c o nfir mati o n of eli gi bilit y pri or t o e nr oll me nt.  
7. 1. 1. 3.  
Me dic al Hist or y  
T he s u bject’s c o m plet e hist or y t hr o u g h re vie w of me dical rec or ds a n d b y i nter vie w will be 
c ollecte d a n d rec or de d. C o nc urre nt me di cal si g ns a n d s y m pt o ms d uri n g scree ni n g a n d pri or t o 
first d ose of st u d y treat m e nt m ust be d oc u me nte d t o esta blis h baseli ne se verities. A disease 
hist or y, i ncl u di n g t he dat e of i nitial dia g n osis a n d a list of all pri or a ntica ncer treat me nts, dates 
a d mi nistere d, res p o nse, a n d d urati o n of res p o ns e t o t hese treat me nts is re q uire d t o be clearl y 
d oc u me nte d i n t he s u bject’s me dical rec or d. 
7. 1. 1. 4.  
C o nc o mit a nt Me d ic ati o ns 
All me dicati o ns fr o m t he si g ni n g of I C F t hr o u g h 3 0 da ys after t h e last d ose of st u d y dr u g will be 
d oc u me nte d i n t he s u bject’s me dical rec or d.  
7. 1. 1. 5.  
A d verse E ve nts  
T he acce pte d re g ulat or y defi niti o n f or a n a d v erse e ve nt is pr o vi de d i n Secti o n 1 1. 1. All me dical 
occ urr e nces t hat meet t he a d verse e ve nt defi niti o n will be d oc u me nte d i n t he s o urce d o c u me nts 
fr o m t he ti me of first d os e of st u d y treat me nt u ntil 3 0 da ys f oll o wi n g t he l ast d ose of st u d y dr u gs. 
S A Es will be re p orte d t o t he P har mac yclics a n d t h e st u d y s p o ns or fr o m t he ti me of first d ose of 
st u d y treat me nt. 
B ot h seri o us a n d n o n-seri o us A Es will be rec or d e d i n t he C R F fr o m t he first d ose of st u d y dr u g 
u ntil 3 0 da ys aft er t he last d ose of st u d y dr u g(s). 
A d diti o nal i m p orta nt re q uire me nts f or a d v ers e e v e nt a n d seri o us a d v erse e ve nt re p orti n g are 
e x plai ne d i n Secti o n 1 1. 
7. 1. 1. 6.  
P h ysic al E x a mi n ati o n 
T he Scree ni n g a n d E n d- of -Treat me nt p h ysi cal e x a mi nati o n will i ncl u de, at a mi ni m u m, t he 
ge n eral a p peara n ce of t h e s u bject, hei g ht (scree ni n g o nl y) a n d wei g ht  ( o n Ni v ol u ma b d osi n g 
da ys) , a n d e x a mi nati o n of t he s ki n, e yes, ears, n os e, t hr oat, l u n gs, h eart, a b d o me n, e xtre mities, 
m usc ul os keletal s yste m, ner v o us s yst e m, a n d l y m p hatic s yste m. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 2 
7. 1. 1. 7.  
Vit al Si g ns  
Vital si g ns will i ncl u de bl o o d press ure, heart rate, res pirat or y rate, a n d b o d y te m perat ure a n d will 
be assesse d after t h e s u bject has bee n resti n g i n t he sitti n g p ositi o n f or at least 3 mi n utes.  
7. 1. 1. 8.  
Perf or m a nce St at us  
T his assess me nt m ust be perf or me d d uri n g t he scree ni n g assess me nts as w ell as t he da y of t he 
first st u d y treat me nt a n d pri or t o t he first d ose. S u bse q ue nt assess me nts will be perf or m e d as per 
t he Sc he d ule of Ass ess me nts ( A p pe n di x 1). 
T he E C O G a n d K P S perf or ma nce i n dices are pr o vi de d i n A p pe n di x 2. 
7. 1. 2.  
L a b or at or y 
7. 1. 2. 1.  
He m at ol o g y 
He mat ol o g y p ara m eters will i ncl u de a c o m ple te bl o o d c o u nt i ncl u di n g plat elets a n d differe ntial. 
7. 1. 2. 2.  
C he mistr y ( Ser u m)  
Ser u m c he mistr y p ar a meters will i ncl u de s o di u m, p otassi u m, c hl ori de, bl o o d urea nitr o ge n 
( B U N), cr eati ni ne, gl uc ose, calci u m, t otal pr otei n, al b u mi n, A S T, A L T, al k ali ne p h os p hatase, 
t otal bilir u bi n, lactate de h y dr o ge nase ( L D H), p h os p hate, uric aci d, ma g nesi u m a n d bicar b o nate. 
Baseli ne T S H will als o be re q uir e d.  If T S H is a b n or mal, f urt her e val uati o n of ser u m T 3, T 4 will 
be at i n vesti gat or’s discr eti o n.   
7. 1. 3.  
Di a g n ostics/ Pr o ce d ures   
7. 1. 3. 1.  
Uri n al y sis 
Uri nal ysis i ncl u des p H, k et o nes, s pecific gra vit y, bilir u bi n, pr otei n, bl o o d, a n d gl u c ose. 
7. 1. 3. 2.  
Pre g n a nc y Test  
Ser u m or uri ne pr e g na nc y test will be re q uire d at Scree ni n g b y l ocal la b orat or y o nl y f or w o me n 
of c hil d beari n g p ote ntial. A ser u m or uri ne pre g n a nc y t est will als o be perf or me d o n Da y 1 pri or 
t o first d ose. If p ositi ve, pre g na nc y m ust be r ule d o ut b y ultras o u n d t o be eli gi ble. 
7. 1. 3. 3.  
E C G  
E C Gs s h o ul d be perf or m e d at scr ee ni n g a n d s u bse q ue ntl y at t he i n v esti gat or’s discreti o n, 
partic ularl y i n s u bjects  wit h arr h yt h mic s y m pt o ms (e g, pal pitati o ns, li g ht hea de d ness) or ne w 
o nset d ys p nea. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 3 
S u bjects s h o ul d be i n s u pi ne p ositi o n a n d resti n g f or at least 1 0 mi n utes bef ore st u d y- rel ate d 
E C Gs. D uri n g visits i n w hic h b ot h E C Gs a n d bl o o d dra ws are perf or me d, E C Gs s h o ul d be 
perf or me d first. A b n or m alities n ote d at Scree ni n g s h o ul d be i ncl u de d i n t he me dical hist or y. 
7. 2.  
Effic ac y E v al u ati o ns ( Hist ol o g y S pecific) 
Arc hi val s peci me ns  will be o btai ne d at scree ni n g wit hi n 2 8 da ys bef ore t he first d ose of i br uti ni b 
a n d ni v ol u ma b. 
7. 3.  
S a m ple C ollecti o n a n d H a n dli n g  
T he act ual d ates a n d ti mes of sa m ple c ollecti o n m ust be rec or d e d i n s o urce d oc u me nts f or 
tra nscri pti o n t o t he C R F or la b orat or y re q uisiti o n f or m. Refer t o t he Sc h e d ule of Assess me nts 
( A p pe n di x 1) f or t he ti mi n g a n d fre q u e nc y of all sa m ple c ollecti o ns.  
8.  
S T U D Y P R O C E D U R E S  
8. 1.  
Scree ni n g P h ase  
Scree ni n g pr o ce d ur es will be perf or m e d u p t o 2 8 da ys pri or t o t he first d ose of st u d y treat me nt, 
u nless ot her wise s pecifie d. O btai n writte n i nf or me d c o nse nt as i n dicate d b y s u bject’s si g n at ure 
o n t he I R B a p pr o ve d I C F. 
• 
I nf or me d C o nse nt 
• 
Me dical hist or y  
• 
Re vie w of eli gi bilit y crit eria  
• 
Re vie w a n d r ec or di n g of all c urre nt, o n g oi n g me di cati o ns a n d a n y me dicati o ns ta ke n 
wit hi n 3 0 da ys pri or t o st art of st u d y me dicati o n (i ncl u di n g o ver-t he-c o u nter dr u gs, 
vita mi ns a n d her bs) 
• 
C o m plete p h ysical e x a m i ncl u di n g hei g ht a n d w ei g ht 
• 
Vitals si g ns (i ncl u di n g bl o o d press ure, h eart rate, res pirat or y rate, a n d b o d y te m perat ure) 
• 
Perf or ma nce Stat us  
• 
C T/ M RI sca n  
• 
1 2- lea d E C G. S u bjects s h o ul d be i n a s u pi ne p ositi o n a n d resti n g f or at least 1 0 mi n utes 
bef ore o bt ai ni n g t he E C G. 
• 
Arc hi val  s peci me n 
• 
Uri ne test  
• 
Pre g n a nc y T est  
• 
Bl o o d f or tr a nslati o nal st u dies 
• 
Uri ne f or tr a nslati o nal st u dies  
• 
Creati ni ne Cleara nce ( meas ure d or calc ulat e d)  
• 
La b orat or y tests f or:  
o  He mat ol o g y i n cl u di n g differe ntial  
o  Ser u m c he mistries  (i ncl u di n g T S H) 
o  Ser u m pre g na n c y test (f or w o me n of c hil d beari n g p ote ntial o nl y) 
o  P T/I N R a n d P T T  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 4 
o  He patitis ser ol o gi es  
• 
C o nfir m eli gi bilit y – c o m plete e nr oll me nt c hec klist pri or t o e nr oll me nt  
8. 2.  
Tre at me nt P h ase  
Treat me nt wit h i br uti ni b i n c o m bi nati o n wit h ni v ol u ma b will c o nti n ue f or a ma xi m u m of o ne 
year o r u ntil 1) t u m or pr o gr essi o n; 2) u nacce pta ble or i nt olera ble t o xicit y; 3) patie nt wit h dra w al 
f or a n y r eas o n; 4) p h ysici a n c h oice if i n t he b est i nterest of t he patie nt. Treat me nt wi t h I br uti ni b 
will c o nti n ue u ntil eit her disease pr o gr essi o n, or p h ysicia n c h oice, or patie nt c h oice, or 
u nacce pta ble or i nt oler a ble t o xicities.  I n v esti gat or discreti o n as t o c o nti n ui n g si n gle a ge nt 
ni v ol u ma b f or a ma xi m u m of o ne year will be all o we d f or p atie nts w h o are u na ble t o recei ve t h e 
d o u blet d ue t o t o xicit y or patie nt pref ere n ce.  
8. 2. 1.  
C ycle 1, D a y 1 Visit 
F oll o wi n g c o m pleti o n of t he Scree ni n g Visit a n d o nce eli gi bilit y has bee n c o nfir me d, s u bjects 
are e nr olle d. E nr oll me nt s h o ul d occ ur as cl ose t o t he t i me of t he e x pecte d first d ose as p ossi ble. 
• 
C o nfir m  eli gi bilit y criteri a 
• 
Re vie w of c urre nt me dicati o ns a n d a n y ne w me di cati o ns si nce scree ni n g visit  
• 
Re vie w of c urre nt si g ns/s y m pt o ms i ncl u di n g a n y n e w u nt o war d e ve nts si nce scree ni n g 
• 
C o m plete p h ysical e x a m a n d wei g ht 
• 
Vital si g ns  
• 
Perf or ma nce  stat us 
• 
Pre g n a nc y T est  
• 
La b orat or y tests f or:  
o  He mat ol o g y i n cl u di n g differe ntial  
o  Ser u m c he mistr y  
• 
D ose a d mi nistrati o n – i br uti ni b 
• 
D ose a d mi nistrati o n – ni v ol u ma b 
• 
Pr o vi de dr u g di ar y a n d d osi n g i nstr ucti o ns t o s u bject 
• 
Dis pe nse st u d y dr u gs 
8. 2. 2.  
C ycle 1, D a y 1 5 Visit  
• 
Re vie w of c o n c o mita nt me dicati o ns  
• 
Re vie w of a d v erse e ve nts  
• 
Re vie w ret ur n e d s u bject d osi n g diar y 
• 
P h ysical e x a m  
• 
Vital si g ns  
• 
Perf or ma nce Stat us   
• 
Bl o o d f or tr a nslati o nal st u dies 
• 
Uri ne f or tr a nslati o nal st u dies  
• 
La b s a m ple c ollecti o n f or 
o  He mat ol o g y  
o  Ser u m c he mistr y  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 5 
 
8. 2. 3.  
C ycle 2, D a y 1 Visit  
• 
Re vie w of c o n c o mita nt me dicati o ns  
• 
Re vie w of a d v erse e ve nts  
• 
Re vie w ret ur n e d s u bject d osi n g diar y a n d dis pe ns e ne w diar y 
• 
P h ysical e x a m  
• 
Vital si g ns  
• 
Perf or ma nce Stat us   
• 
La b s a m ple c ollecti o n f or  
o  He mat ol o g y  
o  Ser u m c he mistr y  
 
8. 2. 4.  
C ycle 2, D a y 1 5 Visit  
• 
Re vie w of c o n c o mita nt me dicati o ns  
• 
Re vie w of a d v erse e ve nts  
• 
Re vie w ret ur n e d s u bject d osi n g diar y 
• 
P h ysical e x a m  
• 
Vital si g ns  
• 
Perf or ma nce Stat us   
• 
La b s a m ple c ollecti o n f or  
o  He mat ol o g y i n cl u di n g differe ntial  
 
8. 2. 5.  
C ycle 3 - 7,  D a y 1 Visit 
• 
Re vie w of c o n c o mita nt me dicati o ns  
• 
Re vie w of a d v erse e ve nts  
• 
Re vie w ret ur n e d s u bject d osi n g diar y a n d dis pe ns e ne w diar y 
• 
P h ysical e x a m  
• 
Vital si g ns  
• 
Perf or ma nce Stat us   
• 
Disease ass ess me nt  
• 
La b s a m ple c ollecti o n f or  
o  He mat ol o g y i n cl u di n g differe ntial  
o  Ser u m c he mistr y   
8. 2. 6.  
C ycle 3 - 7, D a y 1 5 Visit 
• 
Re vie w of c o n c o mita nt me dicati o ns  
• 
Re vie w of a d v erse e ve nts  
• 
Vital si g ns  
• 
La b s a m ple c ollecti o n f or  
o  He mat ol o g y i n cl u di n g differe ntial  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 6 
8. 2. 7.  
C ycle 8 a n d Be y o n d 
• 
Re vie w of c o n c o mita nt me dicati o ns  
• 
Re vie w of a d v erse e ve nts  
• 
Re vie w ret ur n e d s u bject d osi n g diar y a n d dis pe ns e ne w diar y 
• 
Disease ass ess me nt  
• 
La b s a m ple c ollecti o n f or  
o  He mat ol o g y i n cl u di n g differe ntial  
o  Ser u m c he mistr y   
8. 2. 8.  
E n d of Tre at me nt ( E O T) Visit  
• 
Re vie w of c o n c o mita nt me dicati o ns  
• 
Re vie w of a d v erse e ve nts  
• 
Bl o o d f or tr a nslati o nal st u dies 
• 
Uri ne f or tr a nslati o nal st u dies  
• 
La b s a m ple c ollecti o n f or  
o  He mat ol o g y i n cl u di n g differe ntial  
o  Ser u m c he mistr y  
8. 3.  
F oll o w- u p P h ase  
O nce a s u bject has c o m pl ete d t he E n d - of-Treat me nt Visit t he y will e nter t h e F oll o w - u p P hase. 
O nce s u bjects e x perie nce T F, rel a pse, or start use of alter nati ve a ntica ncer t hera p y (f or s u bjects 
w h o ha ve n ot wit h dra w n c o nse nt), t he y will be c o ntacte d a p pr o xi matel y e v er y 3 m o nt hs ( ± 1 4 
da ys) b y cli nic visit or tele p h o ne u ntil deat h, s u bject wit h dra wal, l ost t o f oll o w- u p, st u d y 
ter mi nati o n b y t he st u d y s p o ns or, or u p t o 6 m o nt hs w hic he ver o cc urs first. 
• 
S ur vi val stat us, i ncl u di n g ot her mali g n a ncies 
• 
S u bse q ue nt a ntica ncer t h era p y  
9.  
S U B J E C T C O M P L E TI O N A N D WI T H D R A W A L 
9. 1.  
C o m pleti o n  
A s u bject will be c o nsi dere d t o ha ve c o m plete d t h e st u d y if h e or s he h as die d bef ore t he e n d of 
t he st u d y, has n ot bee n l ost t o f oll o w u p, or has wit h dra w n c o nse nt b ef ore t he e n d of st u d y. 
9. 2.  
Wit h dr a w al f r o m St u d y Tre at me nt 
St u d y treat me nt will be disc o nti n ue d i n t he e ve nt of a n y of t he f oll o wi n g e ve nts: 
1.  U nacce pta ble t o xicit y  
2.  Treat me nt f ail ure or n o e vi de nce of cli nical be nefit per i n vesti gat or assess me nt  
3.  A n i nterc urr e nt ill ness or a d verse e ve nt t hat pre ve nts f urt her i br uti ni b a d mi nistrati o n. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 7 
4.  Wit h dra wal of c o nse nt f or treat me nt b y s u bject  
5.  I n v esti gat or decisi o n (s u c h as c hr o ni c n o nc o m plia nce, si g nifica nt pr ot oc ol de viati o n, or 
best i nterest of t he s u bject)  
6.  St u d y t er mi nati o n b y P har mac yclics or st u d y s p o ns or 
7.  S u bject bec o mes pr e g na nt  
8.  Ni v ol u ma b is hel d f or gr eater t ha n 4 2 d a ys (t he s u bject ca n sta y o n st u d y wit h I br uti ni b 
o nl y) 
9.  I br uti ni b is hel d f or greater t ha n 4 wee ks. If l br uti ni b t hera p y is hel d f or greater t ha n 4 
wee ks, t he n t he s u bject m ust disc o nti n ue fr o m t he ni v ol u ma b as well 
All s u bjects, re gar dl ess of reas o n f or disc o nti n uati o n of st u d y treat me nt will u n der g o a n E n d of 
Treat me nt Visit a n d be f oll o we d f or treat me nt fail ure a n d s ur vi val. 
9. 3.  
Wit h dr a w al f r o m St u d y  
Wit h dra wal fr o m st u d y (i ncl u di n g all f oll o w - u p) will occ ur u n der t h e f oll o wi n g circ u msta nces: 
1.  Wit h dra wal of c o nse nt f or f oll o w- u p o bser v ati o n b y t he s u bject 
2.  L ost t o f oll o w- u p 
3.  St u d y t er mi nati o n b y P har mac yclics or st u d y s p o ns or 
4.  Deat h  
 
If a s u bject is l ost t o f oll o w- u p, e ver y reas o na ble eff ort s h o ul d be ma de b y t he st u d y site 
pers o n nel t o c o ntact t he s u bject. T he meas ures ta k e n t o f oll o w u p s h o ul d be d oc u me nte d. 
W he n a s u bject wit h dra ws bef ore c o m pleti n g t he st u d y, t he f oll o wi n g i nf or mati o n s h o ul d be 
d oc u me nte d i n t he s o urce d oc u me nts:  
1.  Reas o n f or wit h dr a wal 
2.  W het her t he s u bject wit h dra ws f ull c o nse nt (i.e. wit h dra ws c o nse nt t o treat me nt a n d all 
f urt her c o nt act) or p artial c o nse nt (i.e. wit h dra ws c o nse nt t o treat me nt b ut a grees t o 
partici pate i n f oll o w -u p visits)  
1 0.  S T A TI S TI C A L M E T H O D S A N D A N A L Y SI S 
1 0. 1.  S u bject I nf or m ati o n  
All patie nts recei vi n g at l east o ne c ycl e of t hera p y a n d are e val ua bl e f or  res p o nse will be 
assessa ble f or t he pri mar y e n d p oi nt of pr o gressi o n free s ur vi val (e v al ua ble p o p ulati o n). 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 8 
1 0. 2.  E n d p oi nts   
1 0. 2. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y a n al yti c o bjecti ve of t his P hase I B/II st u d y is pr o vi de a preli mi nar y assess me nt of 
t he efficac y of t his treat me nt c o m bi nati o n, as meas ure d b y Pr o gressi o n-Free S ur vi val ( P F S).  
1 0. 2. 2.  
Sec o n d ar y E n d p oi nts  
Sec o n dar y a n al yti c o bjecti ves are t o pr o vi de preli mi nar y assess me nts of t h e R E CI S T Res p o nse 
Rate , O ver all S ur vi val, a n d Safet y  of t his treat me nt c o m bi nati o n.  
1 0. 2. 3.  
Ot her Sec o n d ar y E n d p oi nts  
N/ A  
1 0. 2. 4.  
E x pl or at or y E n d p oi nts 
N/ A  
1 0. 3.  S a m ple Size D eter mi n ati o n  
I n t he R E C O R D- 1 trial, P F S at 6 m o nt hs was a p pr o xi matel y 4 0 %. Ass u mi n g t hat t he i br uti ni b 
pl us ni v ol u ma b c o m bi nati o n will i ncrease t he P F S rate fr o m 4 0 t o 7 0 % at t he 6 m o nt h ti me p oi nt, 
a sa m ple size of 2 5 patie nts will pr o vi de 9 0 % p o wer a n d o n e- si de d le v el 0. 0 3 4 t o detect t his 
differe n ce , wit h a critical val ue of 1 5 or m ore pati e nts o ut of 2 5 e x perie nci n g P F S at 6 m o nt hs. 
T o acc o u nt f or dr o p o uts, a t otal of 3 0 patie nts will be accr ue d. Efficac y a n al ysis will be 
perf or me d o n all patie nts e nr olle d i n t he st u d y re gar dless of d ose l e vel assi g n me nt; i.e., patie nts 
fr o m eac h of t he c o m plet e d d ose le vels will be p o ole d as descri b e d i n t he st u d y sc he m a.  
1 0. 4.  A n al ysis P o p ul ati o ns 
1 0. 4. 1.  
S af et y P o p ul ati o n   
T he safet y p o p ulati o n will i ncl u de all patie nts w h o recei v e at least o ne d ose of eit her st u d y dr u g. 
A baseli ne meas ure me nt a n d at least o ne la b orat or y, vital si g n, or ot her s afet y -relate d 
meas ure me nt o btai n e d after at least o ne d os e of st u d y me di cati o n ma y be re q uire d f or i n cl usi o n 
i n a nal ys es of a s p ecific s afet y para meter. 
1 0. 4. 2.  
Effic ac y p o p ul ati o ns 
E val ua ble p o p ulati o n:  
T he e val ua bl e p o p ulati o n will be t he basis f or t he pri mar y a nal ysis of efficac y ( pr o gressi o n- free 
s ur vi val). T his p o p ulati o n will incl u de all patie nts w h o c o m plete at least o ne c ycle of t hera p y at 
eit her of t he t w o pla n n e d d ose le vels a n d are e v al ua ble f or t he pri mar y res p o nse ( pr o gressi o n -

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 4 9 
free s ur vi val). Sec o n d ar y a nal ys es ma y re q uire i nstea d t hat patie nts be e v al ua ble f or sec o n dar y 
efficac y a n al ys es ( R E CI S T res p o nse, o verall s ur vi val.)  
Per - pr ot oc ol p o p ulati o n: 
A s u p p orti ve a nal ysis ma y be carrie d o ut usi n g t h e per- pr ot oc ol p o p ulati o n, defi ne d as a s u bset 
of t he e val ua bl e p o p ulati o n t hat f urt her e x cl u des p atie nts w h o e x perie nce d de viati o ns fr o m 
pr ot oc ol t hat ma y aff ect pri mar y or sec o n dar y o ut c o mes.  
1 0. 5.   St atistic al Met h o ds  
Pri mar y e n d p oi nt: Pr o gr essi o n-free s ur vi val ( P F S) as t he n u m ber of m o nt hs fr o m baseli ne t o 
deat h or pr o gr essi o n, defi ne d i n A p pe n di x 4. T he d urati o n of P F S will be s u m marize d 
descri pti vel y usi n g K a pla n- Meier s ur vi v al pl ots a n d life ta bles. T he n u m ber a n d pr o p orti o n wit h 
P F S of 6 m o nt hs or m ore will be re p orte d, a dj usti n g f or ce ns ori n g usi n g t h e life- ta ble a p pr oac h. 
If t he n u m ber wit h P F S at least si x m o nt hs is 1 5 or m ore o ut of 2 5 e val u a ble patie nts, t his will 
c o nstit ute e vi de nce s u p p orti n g a n i m pr o v e me nt o ver hist oric P F S rates. 
Sec o n dar y e n d p oi nts: R E CI S T res p o ns e will be calc ulate d as i n A p pe n di x 4, a n d will be 
s u m marize d b y t he n u m b er a n d perce nta ge of p atie nts, acc o m pa ni e d b y 2-si de d e x act 9 5 % 
c o nfi de nce i nter vals. O v erall s ur vi val will be s u m marize d descri pti vel y b y Ka pla n- Mei er c ur ves 
a n d life ta ble esti mates, as f or P F S. N u m ber a n d t y pe of a d verse e v e nts will be s u m marize d 
descri pti vel y b y s yst e m or ga n class affe cte d a n d b y gra de of e ve nt, o verall a n d b y d os e.  Vital 
si g ns a n d la b orat or y test res ults will be s u m marize d descri pti vel y ( mea n, S D, ra n ge) o verall a n d 
b y d ose.  
1 1.  
A D V E R S E E V E N T R E P O R TI N G 
Ti mel y, acc ur ate, a n d c o m plete re p orti n g a n d a nal ysis of safet y i nf or mati o n fr o m cli nical st u dies 
are cr ucial f or t he pr otecti o n of s u bjects, i n vesti gat ors, a n d t he s p o ns or, a n d are ma n d ate d b y 
re g ulat or y a ge ncies w orl d wi de.  
1 1. 1.  Defi niti o ns  
1 1. 1. 1.  
A d verse E ve nts  
A n A E is a n y u nt o war d me dical occ urre n ce i n a s u bject  a d mi nistere d a p h ar mace utical pr o d uct 
a n d w hic h d oes n ot necessaril y h a ve a ca usal relati o ns hi p wit h t his treat me nt.  A n A E ca n 
t heref or e be a n y u nfa v or a ble a n d u ni nte n de d si g n (i ncl u di n g a cli nicall y si g nifica nt a b n or mal 
la b orat or y fi n di n g, f or e x a m ple), s y m pt o m, or disease te m p orall y ass o ciate d wit h t he use of a n 
i n vesti gati o nal st u d y dr u g, w h et her or n ot c o nsi dere d rel ate d t o t he st u d y dr u g (I C H- E 2 A, 1 9 9 5). 
F or t he p ur p os es of t his cli nical st u d y, A Es i ncl u d e e ve nts w h ic h are eit her ne w or re pres e nt 
detecta ble e x acer b ati o ns of pre - e xisti n g c o n diti o ns. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 0 
T he ter m “ disease pr o gressi o n” s h o ul d n ot be re p orte d as a n a d vers e e ve nt t er m.  As a n e x a m ple, 
" w ors e ni n g of u n derl yi n g diseas e" or t he cli nical dia g n osis t hat is ass ocia t e d wit h disease 
pr o gressi o n s h o ul d be re p orte d. 
A d verse e ve nts ma y i ncl u de, b ut are n ot li mite d t o: 
•  
S u bjecti ve or o bjecti ve s y m pt o ms pr o vi de d b y t h e s u bject a n d/ or o bser ve d b y t he 
I n v esti gat or or st u d y staff i ncl u di n g la b orat or y a b n or malities. 
•  
A n y A Es e x perie nce d b y t he s u bject  t hr o u g h t he c o m pleti o n of fi nal st u d y pr oce d ures. 
•  
A Es n ot pre vi o usl y o bs er ve d i n t he s u bject t hat e mer ge d uri n g t he pr ot o c ol-s pecifie d A E 
re p orti n g peri o d, i ncl u di n g si g ns or s y m pt o ms ass ociate d wit h t he u n derl yi n g disease t hat 
were n ot pr ese nt bef ore t he A E re p orti n g p eri o d  
•  
C o m plicati o ns t hat occ ur as a res ult of pr ot oc ol- m a n date d i nter v e nti o ns (e g, i n vasi ve 
pr oce d ur es s uc h as bi o psies). 
T he f oll o wi n g are N O T c o nsi dere d A Es: 
•  
Pre - e xisti n g c o n diti o n:  A pre - e xisti n g c o n diti o n is n ot c o nsi dere d a n A E u nless t he 
se verit y, fr e q ue nc y, or c h aract er of t he e ve nt w orse ns d uri n g t h e st u d y p eri o d. 
•  
Pre -pl a n ne d or electi v e h os pit aliz ati o n:   A h os pitalizati o n pla n ne d bef ore si g ni n g t he 
i nf or me d c o nse nt f or m is n ot c o nsi dere d a n S A E, b ut rat her a t h era p e utic i nter ve nti o n.  
H o we ver, if d uri n g t he pr e- pla n ne d h os pitalizati o n a n e ve nt occ urs, w hic h pr ol o n gs t he 
h os pitalizati o n or meets a n y ot h er S A E criteria, t he e ve nt will be c o nsi dere d a n S A E.  
S ur geries or i nter v e nti o ns t hat were u n d er c o nsi derati o n, b ut n ot perf or me d bef ore 
e nr oll me nt i n t he st u d y, will n ot be c o nsi dere d seri o us if t he y are p erf or me d after e nr oll me nt 
i n t he st u d y f or a c o n diti o n t hat has n ot c ha n ge d fr o m its baseli ne le vel.  Electi ve 
h os pitalizati o ns f or s ocial reas o ns, s olel y f or t he a d mi nistrati o n of c he m ot hera p y, or d u e t o 
l o n g tra v el dista nces are als o n ot S A Es. 
•  
Di a g n ostic Testi n g a n d Pr o ce d ures:   Testi n g a n d pr oce d ures s h o ul d n ot t o be re p ort e d as 
A Es or S A Es, b ut rat her t he ca use f or t he test or pr oce d ure s h o ul d b e re p orte d. 
1 1. 1. 2.  
Seri o us A d verse E ve nts  
A seri o us a d verse e v e nt base d o n I C H a n d E U G ui deli nes o n P har mac o vi gila nce f or M e dici nal 
Pr o d ucts f or H u ma n Us e is a n y u nt o w ar d me dical occ urre nce t hat at a n y d ose: 
•  
Res ults i n deat h (ie, t he A E act uall y ca uses or lea ds t o deat h).  
•  
Is life-t hreate ni n g.  Life-t hreate ni n g is defi n e d as a n A E i n w hic h t he s u bject was at ris k of 
deat h at t he ti me of t he e ve nt.  It d o es n ot refer t o a n e ve nt w hic h h y p ot h eticall y mi g ht ha v e 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 1 
ca use d deat h if it wer e m ore se vere.  If eit her t h e I n vest i gat or or t he I N D S p o ns or belie ves 
t hat a n A E meets t he d efi niti o n of life-t hreate ni n g, it will be c o nsi dere d life-t hreate ni n g. 
•  
Re q uires i n - patie nt h os pitalizati o n > 2 4 h o urs or pr ol o n gati o n of e xisti n g h os pitalizati o n. 
•  
Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y (ie, t he A E res ults i n s u bsta ntial 
disr u pti o n of t he s u bject’s a bilit y t o c o n d uct n or m al life f u ncti o ns). 
•  
Is a c o n ge nital a n o mal y/ birt h defect. 
•  
Is a n i m p orta nt me dical e ve nt t hat ma y n ot res ult i n deat h, be i m me diatel y life-t hreate ni ng 
or re q uire h os pitalizati o n, b ut ma y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate 
me dical j u d g m e nt, t he e v e nt ma y j e o par dize t he s u bject  or s u bject ma y re q uire i nter ve nti o n 
t o pre ve nt o ne of t h e ot her o utc o mes liste d i n t his defi niti o n.  E x a m ples of s uc h e ve nts are 
i nte nsi ve treat me nt i n a n e mer ge n c y de part me nt or at h o me f or aller gic br o n c h os pas m, 
bl o o d d yscr asias, or c o n v ulsi o n t hat d oes n ot res ult i n h os pitalizati o n; or de vel o p me nt of 
dr u g d e pe n de nc y or dr u g a b use. 
1 1. 1. 3.  
Se verit y Criteri a ( Gr a de 1 - 5) 
Def i niti o ns f o u n d i n t he C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts versi o n 4. 0 3 
( C T C A E v 4. 0 3) will be use d f or gr a di n g t h e se verit y (i nte nsit y) of n o n h e m at ol o gic  A Es.   T he 
C T C A E v 4. 0 3 will be use d f or t he gr a di n g of he m at ol o gic A Es w he n a p pli ca ble.  T he  C T C A E 
v 4. 0 3 dis pla ys Gr a des 1 t hr o u g h 5 wit h u ni q ue cli nical descri pti o ns of se v erit y f or eac h 
refere nce d A E.  S h o ul d a s u bject e x perie nce a n y A E n ot liste d i n t he C T C A E v 4. 0 3, t he 
f oll o wi n g gr a di n g s yste m s h o ul d be use d t o assess se verit y: 
•  
Gra de 1 ( Mil d A E) – e x perie nces w hic h are us uall y tra nsi e nt, re q uiri n g n o s pecial treat me nt, 
a n d n ot i nterferi n g wit h t he s u bject’s dail y acti vities  
•  
Gra de 2 ( M o der ate A E) – e x perie nces w hic h i ntr o d uce s o me le vel of i nc o n ve nie nce or 
c o ncer n t o t he s u bj ect, a n d w hic h ma y i nterfere wit h dail y acti vities, b ut are us uall y 
a meli orate d b y si m ple t hera pe utic m eas ures  
•  
Gra de 3 ( Se ver e A E) – e x perie nces w hic h are u nacce pta bl e or i nt olera ble, si g nifica ntl y 
i nterr u pt t he s u bject’s us ual dail y acti vit y, a n d re q uire s yste mic dr u g t hera p y or ot her 
treat me nt 
•  
Gra de 4 ( Life -t hreat e ni n g or disa bli n g A E) – e x perie nces w hic h ca use t he s u bject  t o be i n 
i m mi ne nt da n ger of deat h 
•  
Gra de 5 ( Deat h relate d t o A E) – e x perie nces w hic h res ult i n s u bject deat h  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 2 
1 1. 1. 4.  
C a us alit y ( Attri b uti o n)  
T he I n vesti gat or is t o ass ess t he ca usal relati o n (ie, w het her t here is a reas o na ble p ossi bilit y t h at 
t he st u d y dr u g ca use d t he e ve nt) usi n g t he f oll o wi n g defi niti o ns: 
N ot Rel at e d  ( u nrel ate d): A n ot her ca us e of t he A E is m ore pla usi ble; a te m p oral se q ue n ce 
ca n n ot be esta blis he d wit h t he o nset of t he A E a n d a d mi nistrati o n of 
t he i n vesti gati o nal pr o d u ct; or, a ca us al relati o ns hi p is c o nsi dere d 
bi ol o gicall y i m pla usi ble.  
U nli kel y:  
T he c urr e nt k n o wle d ge or i nf or mati o n a b o ut t he A E i n dicates t hat a 
relati o ns hi p t o t he i n vesti gati o nal pr o d u ct is u nli kel y. 
P ossi bl y Rel ate d:  
T here is a cli nicall y pl a usi ble ti me se q ue nce b et w ee n o nset of t he 
A E a n d a d mi nistrati o n of t he i n vesti gati o nal pr o d u ct, b ut t he A E 
c o ul d als o be attri b ute d t o c o nc urre nt or u n derl yi n g diseas e, or t he 
use of ot her dr u gs or pr o ce d ures.  P ossi bl y relate d s h o ul d be use d 
w he n t he i n vesti gati o nal pr o d uct is o ne of se v eral bi ol o gicall y 
pla usi ble A E ca uses.  
Rel ate d:  
T he A E is clearl y relat e d t o use of t he i n vesti gati o nal pr o d uct.  
1 1. 2.  U ne x pecte d A d verse E v e nts  
A n “ u ne x pecte d” A E is a n A E t hat is n ot liste d i n t he I n v esti gat or's Br oc h ure/ pac k a ge i nsert or is 
n ot liste d at t he s pecificit y or s e verit y t hat has b ee n o bser ve d.  F or e x a m ple, he patic necr osis 
w o ul d be “ u ne x pecte d ” ( b y virt ue of greater se v erit y) if t he I n v e sti gat or's Br oc h ure referre d o nl y 
t o ele vate d he p atic e nz y mes or he patitis.  Si milarl y, cere bral t hr o m b oe m b olis m a n d cere bral 
vasc ulitis w o ul d be “ u ne x pecte d” ( b y virt ue of greater s p ecificit y) if t he I n vesti gat or's 
Br oc h ure/ pac ka ge i ns ert liste d o nl y cere bral vasc ular acci de nts.  " U ne x pect e d" als o refers t o A Es 
t hat are me nti o ne d i n t he I n v esti gat or's Br oc h ure as occ urri n g wit h a class of dr u gs or as 
a ntici pate d fr o m t he p h ar mac ol o gi cal pr o perties of t he dr u g, b ut are n ot s pecificall y me nti o ne d 
as occ urri n g wit h t he st u d y dr u g u n d er i n vesti gati o n. 
1 1. 3.  S peci al Re p orti n g Sit u ati o ns  
S pecial re p orti n g sit uati o n o n a S p o ns or st u d y ma y re q uire e x pe dite d re p orti n g a n d/ or safet y 
e val uati o n i ncl u de, b ut ar e n ot li mite d t o: 
•  
O ver d ose of a n y st u d y dr u g 
•  
S us pecte d a b use/ mis u se of a st u d y dr u g 
•  
I n a d vert e nt or acci de ntal e x p os ure t o a st u d y dr u g 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 3 
•  
Me dicati o n err or i n v ol vi n g a pr o d uct ( wit h or wit h o ut s u bject e x p os ure t o t he st u d y dr u g, 
e. g., n a me c o nf usi o n) 
If a n y s pecial re p orti n g sit uati o ns meet t he criteria of a n A E, it s h o ul d be re p orte d o n t he Seri o us 
A d verse E v e nt Re p ort F or m. T he Seri o us A d verse E ve nt F or m s h o ul d be se nt via e mail or fa x t o 
P har mac yclics Dr u g Safet y or desi g n ee wit hi n 1 5 da ys of a w are n ess.  
 
1 1. 4.  D oc u me nti n g a n d Re p orti n g of A d verse E ve nts a n d Seri o us A d verse E ve nts b y 
I n vesti g at ors 
1 1. 4. 1.  
Assess me nt of A d verse E ve nts  
I n v esti gat ors will assess t he occ urre n ce of a d vers e e ve nts a n d seri o us a d vers e e ve nts at all 
s u bject e val uati o n ti me p oi nts d uri n g t he st u d y. All a d verse e ve nts a n d seri o us a d verse e ve nts 
w het her v ol u nteere d b y t he s u bject, disc o vere d b y st u d y pers o n n el d uri n g q uesti o ni n g, detecte d 
t hr o u g h p h ysical e x a mi nati o n, all a b n or mal  la b orat or y v al ues , or ot her mea ns, will be rec or de d.  
Eac h r ec or d e d a d verse e ve nt or seri o us a d v erse e ve nt will be descri be d b y its d u rati o n (ie, start 
a n d e n d dates), se verit y, re g ulat or y seri o us ness criteria (if a p plica ble), s us p ecte d relati o ns hi p t o 
t he i n vesti gati o nal pr o d u ct, a n d a n y acti o ns ta ke n. 
1 1. 4. 2.  A d verse E ve nt R e p orti n g Peri o d  
All A Es w het her seri o us or n o n-seri o us, will be ca pt ure d fr o m t he ti me si g n e d a n d date d I C F is 
o btai ne d u ntil 3 0 da ys f oll o wi n g t he last d ose of st u d y dr u g.  
Seri o us a d verse e ve nts r e p orte d after 3 0 da ys f oll o wi n g t he last d ose of st u d y dr u g s h o ul d als o b e 
re p orte d if c o nsi dere d rel ate d t o st u d y dr u g. Res ol uti o n i nf or mati o n after 3 0 da ys s h o ul d be 
pr o vi de d.  
Pr o gr essi ve disease s h o ul d N O T be r e p orte d as a n e ve nt ter m, b ut i nstea d s y m pt o ms/cli nical 
si g ns of diseas e pr o gr essi o n ma y b e re p orte d. ( See Secti o n 1 1. 1. 1) 
All a d verse e ve nts, re gar dless of seri o us ness, se v erit y, or pres u me d relati o ns hi p t o st u d y dr u g, 
m ust be rec or d e d usi n g me dical ter mi n ol o g y i n t he s o urce d o c u me nt. All rec or ds will nee d t o 
ca pt ure t he d etails of t he d urati o n a n d t he se v erit y of eac h e pis o de, t he acti o n ta ke n wit h res pect 
t o t he st u d y dr u g, i n vesti gat or’s e val u ati o n of its relati o ns hi p t o t he st u d y dr u g, a n d t he e v e nt 
o utc o me. W he ne ver p ossi ble, dia g n oses s h o ul d be gi ve n w h e n si g ns a n d s y m pt o ms are d ue t o a 
c o m m o n eti ol o g y (e g, c o u g h, r u n n y n os e, s neezi n g, s ore t hr oat, a n d h ea d c o n gesti o n s h o ul d be 
re p orte d as " u p p er r es pir at or y i nfecti o n").  
All deat hs s h o ul d be re p orte d wit h t he pri mar y ca use of deat h as t he A E ter m, as deat h is 
t y picall y t he o utc o me of t he e ve nt, n ot t he e v e nt itself.  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 4 
If a deat h occ urs wit hi n 3 0 da ys after t h e last d ose of st u d y dr u g, t h e deat h m ust be re p orte d as a 
seri o us a d vers e e v e nt.  
1 1. 4. 3.  
Pre g n a nc y  
Bef ore st u d y e nr oll me nt, s u bjects m ust a gree t o ta ke a p pr o pri ate meas ures t o a v oi d pre g na nc y. 
H o we ver, s h o ul d a pre g n a nc y occ ur i n a fe male st u d y s u bject, c o nse nt t o pr o vi de f oll o w- u p 
i nf or mati o n re gar di n g t h e o utc o me of t he pre g na n c y a n d t he healt h of t he i nfa nt u ntil 3 0 da ys ol d 
will be re q ueste d.  
A fe male s u bject m ust i m me diatel y i nf or m t he I n vesti gat or if s h e bec o mes pre g na nt fr o m t he 
ti me of c o nse nt t o 3 0 da ys after t he last d ose of st u d y dr u g. A male s u bject m ust i m me diatel y 
i nf or m t he I n vesti gat or if his part ner bec o mes pre g na nt fr o m t he ti me of c o nse nt t o 3 m o nt hs 
after t he l ast d ose of st u d y dr u g. A n y fe mal e s u bjects recei vi n g st u d y dr u g(s) w h o bec o me 
pre g na nt m ust i m me diatel y disc o nti n ue st u d y dr u g. T he I n vesti gat or s h o ul d c o u nsel t he s u bject, 
disc ussi n g a n y ris ks of c o nti n ui n g t he pre g n a nc y a n d a n y p ossi ble effects o n t he fet us.   
Alt h o u g h pr e g na nc y itself is n ot re gar d e d as a n a d verse e v e nt, t he o utc o me will nee d t o be 
d oc u me nte d. A n y pr e g na nc y o cc urri n g i n a s u bject or s u bject’s part ner fr o m t he ti me of c o nse nt 
t o 3 0 da ys after t he l ast d ose of st u d y dr u g m ust be re p ort e d. A n y occ urre n ce of pre g na n c y m ust 
be re p ort e d t o P har mac yclics Dr u g Safet y, or desi g nee, per S A E re p orti n g ti meli nes. All 
pre g na nci es will be f oll o we d f or o utc o m e, w hic h is defi ne d as electi ve ter mi nati o n of t he 
pre g na nc y, miscarri a ge, or deli ver y of t he fet us. Pre g na nci es wit h a n o utc o me of li ve birt h, t he 
ne w b or n i nfa nt will be f oll o we d u ntil 3 0 da ys ol d a n d t his m ust be re p orte d t o P har mac yclics 
Dr u g Safet y, or d esi g n ee, per S A E re p orti n g ti meli nes. A n y c o n ge nital a n o mal y/ birt h defect 
n ote d i n t he i nfa nt m ust be re p ort e d as a s eri o us a d verse e v e nt. 
1 1. 4. 4.  
Ot her M ali g n a ncies  
All ne w mali g n a nt t u m ors i ncl u di n g s oli d t u m ors, s ki n mali g na ncies a n d he mat ol o gic 
mali g na n cies will be re p orte d f or t he d urati o n of st u d y treat me nt a n d d uri n g a n y pr ot oc ol-
s pecifie d f oll o w- u p p eri o ds i ncl u di n g p ost- pr o gressi o n f oll o w- u p f or o verall s ur vi val. 
1 1. 4. 5.  
E ye- Rel ate d A d verse E ve nt s 
Ne w or w orse ni n g e ye -r elate d s y m pt o ms t hat are Gra de 2 or hi g h er, or a s y m pt o m t hat was 
Gra de 2 or hi g h er at baseli ne w orse ns, s h o ul d be e val uate d b y a n o p ht hal m ol o gist. 
1 1. 4. 6.  
A d verse E ve nts of S peci al I nterest ( A E SI)  
S pecific a d verse e v e nts, or gr o u ps of a d v erse e ve nts, will be f oll o we d as part of sta n dar d saf et y 
m o nit ori n g acti vities  b y t he S p o ns or. T hese e v e nts (re gar dless of seri o us ness) will be re p orte d o n 
t he Seri o us A d verse E ve nt Re p ort F or m a n d se nt via e mail or fa x t o P har mac yclics Dr u g Safet y 
or desi g n ee  wit hi n 1 5 da ys of a ware ness.   

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 5 
1 1. 4. 6. 1.  
M aj or He m orr h a ge 
Maj or he m orr h a ge is defi ne d as a n y of t h e f oll o wi n g: 
•  A n y tr eat me nt-e mer ge nt he m orr ha gic a d vers e e v e nt s of Gra de 3 or hi g h er *. A n y 
treat me nt-e mer ge nt seri o us a d verse e ve nts of blee di n g of a n y gra d e 
•  A n y tr eat me nt- e mer ge nt ce ntral ner v o us s yste m he m orr ha ge/ he mat o ma of a n y gra de 
* All he m orr ha gic e ve nts re q uiri n g tra nsf usi o n of re d bl o o d cells s h o ul d be re p orte d as gra d e 3 or 
hi g her A E per C T C A E v 4. 0 3. 
E ve nts meeti n g t h e defi niti o n of maj or he m orr ha ge will b e ca pt ure d as a n e ve nt of s pecial 
i nterest acc or di n g t o Secti o n 1 1. 3. 6 a b o ve. 
1 1. 4. 7.  
E x pe diti n g Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts  
All seri o us a d vers e e ve nts a n d A E SIs as per Secti o n 1 1. 3. 6 (i nitial a n d f oll o w- u p i nf or mati o n) 
will  be re p orte d o n F DA Me d watc h a n d se nt via e mail (A Ei nta ke C T @ pc yc.c o m ) or fa x (( 4 0 8) 
2 1 5- 3 5 0 0) t o P har mac yclics Dr u g Safet y, or d esi g nee, wit hi n 1 5 da ys of t h e e ve nt. 
P har mac yclics ma y re q u est f oll o w - u p a n d ot her a d diti o nal i nf or mati o n fr o m t he S p o ns or 
I n v esti gat or.  
All ser i o us a d vers e e ve nts t hat ha ve n ot res ol ve d b y t he e n d of t he st u d y, or t hat ha ve n ot 
res ol ve d u p o n disc o nti n uati o n of t he s u bject's partici pati o n i n t he st u d y, m ust be f oll o we d u ntil 
a n y of t he f oll o wi n g occ urs: 
•  
T he e ve nt r es ol ves  
•  
T he e ve nt sta bilizes  
•  
T he e ve nt r et ur ns t o baseli ne, if a baseli ne v al ue/stat us is a vaila ble  
•  
T he e ve nt ca n be attri b ute d t o a ge nts ot her t ha n t h e st u d y dr u g or t o fact ors u nrelate d t o                                   
st u d y c o n d u ct 
•  
It bec o mes u nli kel y t hat a n y a d diti o nal i nf or mati o n ca n be o btai n e d (s u bject or healt h care 
practiti o ner r ef usal t o pr o vi de a d diti o nal i nf or mati o n, l ost t o f oll o w u p after de m o nstrati o n 
of d ue dili ge n ce wit h f oll o w- u p eff orts) 
It is t he r es p o nsi bilit y of t he I n v esti gat or a n d t he researc h tea m t o e ns ure t h at seri o us a d verse 
e ve nts ar e re p orte d acc or di n g t o t he C o de of Fe d eral Re g ulati o ns, G o o d Cli nical P ractices 
( G C P), t he pr ot oc ol g ui deli nes, t he s p o ns or’s g ui d eli nes, a n d I nstit uti o nal Re vie w B o ar d p olic y. 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 6 
1 2.  S T U D Y A D MI NI S T R A TI O N  A N D I N V E S TI G A T O R O B LI G A TI O N S   
1 2. 1.  Re g ul at or y a n d Et hic al C o m pli a nce 
T his cli nical st u d y was d esi g ne d a n d will be i m ple me nte d i n acc o r da n ce wit h t he pr ot oc ol, t he 
I C H H ar m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practices, wit h a p plica ble l ocal 
re g ulati o ns  i ncl u di n g U S C o de of Fe deral Re g ul ati o ns [ C F R] Title 2 1 a n d wit h t he et hical 
pri nci ples lai d d o w n i n t he Decl arati o n of H elsi n ki. 
1 2. 2.  I nf or me d C o nse nt 
After t he st u d y has b ee n f ull y e x plai ne d, writte n i nf or me d c o ns e nt will be o btai ne d fr o m eit her 
t he patie nt or his/ her g uar dia n or le gal re prese ntati ve pri or t o st u d y partici p ati o n.  T he met h o d of 
o btai ni n g a n d d o c u me nti n g t he i nf or me d c o nse nt a n d t he c o nte nts of t he c o nse nt will c o m pl y 
wit h I C H -G C P a n d all a p plica ble re g ulat or y re q uire me nt(s).  I n acc or da nce wit h U C D O C R 
p olic y a n ori gi n al si g n e d a n d date d partici pa nt I nf or me d C o nse nt d oc u me nt will resi de i n a 
sec ure d l o cati o n wit hi n t he U C D O C R . Partici pati n g sites will st ore ori gi nal si g ne d a n d d ate d 
i nf or me d c o nse nt per its p olicies.  C o pies of t he si g ne d a n d date d I nf or me d C o nse nt d oc u me nt 
will be pr o vi de d t o t he st u d y partici pa nt a n d U C D Healt h S yste m I nf or mati o n Ma na ge me nt f or 
i ncl usi o n i n t he partici pa nt’s U C D Healt h S yste m Me dical Rec or d or per p artici pati n g site’s 
p olicies.  
1 2. 3.  Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce 
Q ua lit y ass ura nce a u dits of select patie nts a n d s o urce d oc u m e nts ma y be c o n d ucte d b y t he U C 
Da vis Ca ncer C e nter Q u alit y Ass ur a nce C o m mittee as o utli ne d i n t he U C Da vis Ca ncer C e nter 
Data a n d Saf et y M o nit ori n g pla n. 
Q ualit y c o ntr ol will be m ai ntai ne d b y t he O C R Q u alit y Ass ura nce tea m acc or di n g t o O C R 
p olic y. 
Q ualit y ass ura nce a u dits ma y b e acc o m plis he d i n o ne of t w o wa ys: ( 1) s o urce d oc u m e nts a n d 
researc h r ec or ds f or selecte d patie nts are m aile d/se nt b y fr o m p artici pati n g sites t o t he 
C o or di nati n g Ce nter f or a u dit, or ( 2) selecte d pati e nt rec or ds ma y be a u dit e d o n- site at 
partici pati n g sites.  
1 2. 4.  D at a a n d S af et y M o nit ori n g 
I n a d diti o n t o t he re q uire me nts f or a d verse e v e nt re p orti n g as o utli ne d i n Secti o n 1 1, t his 
pr ot oc ol is als o s u bject t o t he U C Da vis Ca ncer Ce nter’s ( U C D C C) Dat a a n d Safet y M o nit ori n g 
Pla n. T he U C D C C is c o m mitte d t o p urs ui n g hi g h- q ualit y patie nt- orie nte d cli nical researc h a n d 
has esta blis he d mec h a nis ms t o e ns ure b ot h scie ntific ri g or a n d p atie nt safet y i n t he c o n d u ct of 
cli nical researc h st u dies. T he U C D C C relies o n a m ulti -tiere d c o m mittee s yste m t hat re vie ws a n d 
m o nit ors all ca ncer cli nical trials a n d e ns ures t he s afet y of its partici p a nts, i n c o m plia nce wit h 
i nstit uti o nal a n d fe deral re q uire me nts o n a d v erse e ve nt ( A E) re p orti n g, verificati o n of data 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 7 
acc ur ac y, a n d a d here n ce t o pr ot oc ol eli gi bilit y re q uire me nts, treat me nt g ui deli nes, a n d rel ate d 
matters. T he Scie ntific R e vie w C o m mittee ( S R C) ass u mes o verall o versi g ht of ca ncer st u dies, 
wi t h assista nce a n d i n p ut fr o m t w o i n de pe n de nt, b ut i nteracti n g, c o m mittees: t he Q ualit y 
Ass ura nce C o m mittee a n d t he Data Safet y M o nit ori n g C o m mittee. A m ulti -le vel re vie w s yste m 
stre n gt h e ns t he a bilit y of t he U C D C C t o f ulfill its missi o n i n c o n d ucti n g hi g h q ualit y cli nical 
ca ncer r esearc h.  
As per U ni versit y of Calif or nia Da vis Ca n cer Ce nt er ( U C D C C) Office of Cli nical Researc h  
(O C R ) S O P A M 5 0 6: Pr ot oc ol S pecific Meeti n gs, t he pri nci pal i n vesti gat or ( PI) a n d cli nical 
researc h c o or di nat or ( C R C) meet at least m ont hl y f or o n g oi n g st u d y i nf or mati o n, t o disc uss 
patie nt data a n d a d vers e e ve nts a n d t o deter mi ne if d ose escalati o n is warra nte d, w he n 
a p plica ble.   
Acc or di n g t o t he U C D C C Data a n d Safet y M o nit ori n g Pla n ( D S M P), a n y ne w seri o us a d v erse 
e ve nts relat e d t o t h e dr u gs bei n g use d o n t his trial are re vie w e d m o nt hl y b y t he U C D C C Data 
a n d Safet y M o nit ori n g C o m mittee ( D S M C) a n d a n y a p plica ble c h a n ges t o t he st u d y are 
rec o m me n de d t o t he PI, if necess ar y. 
T he U C D C C Scie ntific Re vie w C o m mittee ( S R C) deter mi nes if a U C D C C Data a n d Safet y 
M o nit ori n g B o ar d ( D S M B) is re q uire d.  If re q uire d, t he D S M C will a p p oi nt a D S M B. T he 
D S M B is res p o nsi ble f or re vie wi n g st u d y accr ual l o gs, a d v erse e ve nt i nf or mati o n a n d d ose 
escalati o n meeti n g mi n utes ( w here a p plica ble) t o e ns ure s u bject s afet y a n d c o m plia nce wit h 
pr ot oc ol defi ne d g ui deli n es. 
1 2. 5.  Pr otecte d S u bject He alt h I nf or m ati o n A ut h oriz ati o n  
I n or der t o mai ntai n patie nt pri vac y, all st u d y re p orts a n d c o m m u nicati o ns will i de ntif y t he 
patie nt b y i nitials a n d t he assi g ne d p atie nt n u m ber.  Da ta ca pt ure rec or ds a n d dr u g acc o u nt a bilit y 
rec or ds will be st ore d i n sec ure ca bi nets i n t he U C D O C R  or at t he partici p ati n g i nstit uti o n (s).  
Me dical rec or ds of p atie nts will be mai ntai ne d i n strict c o nfi de nce acc o r di n g t o le gal 
re q uire me nts.  T h e patie nt’s  c o nfi de ntialit y will be mai ntai ne d a n d will n ot be ma de p u blicl y 
a vaila ble t o t he e xte nt per mitte d b y t he a p plica ble la ws a n d re g ul ati o ns.  
1 2. 6.  St u d y Files a n d Rec or d Rete nti o n  
T he i n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H -G C P a n d a p plica ble re g ulat or y 
re q uire me nt(s).   
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 8 
1 2. 7.  C ase Re p ort F or ms a n d Rec or d M ai nte n a nce  
All data will be c ollecte d usi n g U C Da vis data c ollecti o n f or ms. T he c ollecti o n f or ms are p df e dita ble 
f or ms t hat ca n be fa xe d/e maile d t o U C D. C o pies of t he c o m plete d f or ms will be s u b mitte d t o U C Da vis 
data c o or di nati n g ce nter f or data e ntr y a n d st ora ge i n a sec ure l ocati o n. T he ori gi nal data c ollecti o n f or ms 
will resi de i n sec ure l ocati o n.  
 
 
 S U B MI T WI T HI N 2 4 H O U R S O F R E GI S T R A TI O N:  
Pat ie nt Re gistrati o n F or m  
 
 S U B MI T WI T HI N 1 4 D A Y S O F R E GI S T R A TI O N:  
Pre ‐St u d y E val uati o n F or m (I H ‐1 0 2)  
 
 S U B MI T WI T HI N 7 D A Y S O F S C R E E NI N G F AI L U R E:  
Patie nt Scree n Fail ure F or m  
 
 S U B MI T WI T H 1 4 D A Y S O F C Y C L E C O M P L E TI O N:  
A d verse E ve nt/ Dr u g Relati o ns hi p F or m  
 
 
 S U B MI T WI T HI N 1 4 D A Y S O F E N D O F E A C H T R E A T M E N T C Y C L E:  
Treat me nt C ycle F or m - Oral   
Treat me nt C ycle F or m - I nf usi o n 
 
 S U B MI T WI T HI N 1 4 D A Y S O F E A C H R E S P O N S E A S S E S S M E N T:  
T u m or Meas ure me nt L o g  
 
 S U B MI T WI T HI N 1 4 D A Y S O F O F F T R E A T M E N T:  
Off Treat me nt/I n F oll o w- u p/ Off St u d y/ E x pirati o n F or m (I H‐3 0 1)  
 
 S U B MI T WI T HI N 1 4 D A Y S O F K N O W L E D G E O F D E A T H I F P A TI E N T I S S TI L L O N 
S T U D Y O R 3 0 – D A Y S I F O F F S T U D Y:  
Off Treat me nt/I n F oll o w - u p/ Off St u d y/ E x pirati o n F or m (I H‐3 0 1)  
 
 S U B MI T WI T HI N 2 D A Y S O F K N O W L E D G E O F P R O T O C O L D E VI A TI O N:  
N otice of Pr ot oc ol De viati o n  
 
 S U B MI T WI T HI N 1 4 D A Y S O F E A C H R E Q UI R E D F O L L O W ‐U P E N C O U N T E R:  
F oll o w ‐U p F or m (I H ‐3 0 2)  
 
 A L L S E RI O U S A D V E R S E E V E N T S M U S T B E R E P O R T E D A S O U T LI N E D I N T H E 
P R O T O C O L  
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 5 9 
1 2. 8.  I n vesti g ati o n al St u d y Dr u g Acc o u nt a bilit y 
I br uti ni b will be s u p plie d b y P har m ac yclics.  I br uti ni b m ust be ke pt i n a l oc ke d li mite d access 
r o o m. T he st u d y dr u g m ust n ot be use d o utsi de t he c o nte xt of t he pr ot oc ol. U n der n o 
circ u msta nces s h o ul d t he I n v esti gat or or ot her site pers o n nel s u p pl y i br uti ni b t o ot her 
I n v esti gat ors, s u bjects, or cli nics or all o w s u p plies t o be use d ot her t ha n as directe d b y t his 
pr ot oc ol wit h o ut pri or a ut h orizati o n fr o m P har mac yclics. 
A n I n vesti gati o nal Dr u g Acc o u nta bilit y L o g m ust be use d f or dr u g acc o u nt a bilit y. F or acc urat e 
acc o u nta bilit y, t he f oll o wi n g i nf or m ati o n m ust be n ote d w he n dr u g s u p plies are us e d d uri n g t he 
st u d y: 
1. St u d y i d e ntificati o n n u m ber 
2. S u bject i de ntificati o n n u m ber 
3. L ot n u m ber(s) of i br uti ni b or c o m parat or dis pe nse d f or t hat s u bject 
4. Date a n d q u a ntit y of dr u g dis pe ns e d 
5. A n y u n us e d dr u g r et ur ne d b y t h e s u bject 
1 2. 9.  Pr ot oc ol A me n d me nts  
Per t he I S T A gree me nt , an y a m e n d me nt s t o t he Pr ot oc ol or I nf or me d C o ns e nt F or m pr ot oc ol 
m ust be se nt t o P har mac yclics f or r e vie w a n d a p pr o val pri or t o s u b missi o n t o t he I R B.  Writte n 
verificati o n of I R B a p pr o val will be o btai ne d bef ore a n y a m e n d me nt is i m ple me nte d. 
1 2. 1 0.  P u blic ati o n of St u d y Res ults  
Per t he I S T A gree me nt , t he I n vesti gat or is re q uire d t o s ub mit t o P har mac yclics a c o p y of a 
pla n ne d p u blicati o n (a bstract, p oster, oral pres e ntati o n or ma n uscri pt) pri or t o t he s u b missi o n 
t here of f or p u blicati o n or discl os ure.  P har mac yclics  ma y pr o vi de scie ntifi c c o m me nts a n d 
s u g gesti o ns u n derst a n di n g t hat t he I n v esti gat or has s ole e dit orial res p o nsi bilit y, a n d ret ai ns t he 
a ut h orit y t o ma ke t h e fi n al deter mi nati o n o n w het her or n ot t o i nc or p orate P har mac yclics  
c o m me nts or re q uests f or a d diti o nal i nf or mati o n. 
1 2. 1 1.  St u d y Disc o nti n u ati o n  
Per t he I S T C o ntract, t he I n v estigat or res er ves t he ri g ht t o ter mi nate t he st u d y at a n y ti me.  
S h o ul d t his be necessar y, b ot h t he I n v esti gat or will arra n ge disc o nti n uati o n pr oce d ures i n 
part ners hi p wit h P har mac yclics.  I n ter mi nati n g t he st u d y, t he I n vesti gat or will ass ure t hat 
a de q uate co nsi der ati o n is gi ve n t o t he pr ot ecti o n of t he s u bjects’ i nterest s.  P har mac yclics ma y 
ter mi nate t he st u d y f or r eas o ns i ncl u di n g, b ut n ot li mite d t o: e vi de nce t hat t he PI or a n i n v ol ve d 
i n vesti gat or is u n q ualifie d t o c o n d uct researc h or f ulfill s p o ns or res p o nsi bilities (e. g., is liste d o n 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 0 
a de bar m e nt or i neli gi ble i n vesti gat or list); fail ure t o meet ti meli nes o r ac hi e ve a gree d u p o n 
milest o nes; a k n o w n or percei v e d ris k t o patie nt w ell- bei n g is i de ntifie d; or breac h of c o ntract. 
A d diti o nal gr o u n ds f or ter mi nati o n are o utli ne d i n t he I S T A gree m e nt . 
 
1 3.  
R E F E R E N C E S 
Bis h o p G A, Ha x hi nast o S A, St u nz L L, et al. A nti ge n-s pe cifi c B-l y m p h o c yte acti vati o n.  Crit 
Re v I m m u n ol 2 0 0 3; 2 3: 1 6 5 – 1 9 7.   
C ha n g B Y, Fra n cesc o M, De R o oij M F, et al. E gress of C D 1 9 + C D 5 + cells i nt o peri p heral bl o o d 
f oll o wi n g treat me nt wit h t he Br ut o n t yr osi ne ki nas e i n hi bit or i br uti ni b i n ma ntle cell l y m p h o ma 
patie nts. Bl o o d. 2 0 1 3a; 1 2 2: 2 4 1 2- 2 4.  
C ha n g B Y, Fra n cesc o M, Ste g ger d a S, et al. I br uti ni b I n hi bits Mali g n a nt Cell A d hesi o n a n d 
Mi grati o n a n d Re d u ces T u m or B ur d e n i n L y m p h N o de a n d B o ne Marr o w i n a M uri ne M o del of 
Ma ntle Cell Disse mi nati o n a n d Pr o gressi o n. 2 0 1 3 b A A C R: A bstract 9 2 3.  
Her ma n S E, G or d o n A L, Hertlei n E, et al. Br ut o n t yr osi ne ki nas e re prese nts a pr o misi n g 
t hera pe utic tar get f or treat me nt of c hr o nic l y m p h o c ytic l e u ke mia a n d is effecti vel y tar get e d b y 
P CI - 3 2 7 6 5. Bl o o d. 2 0 1 1; 1 1 7: 6 2 8 7- 9 6. 
M otzer, et al. Ni v ol u ma b f or Metastatic Re n al Cell Carci n o ma: Res ults of a Ra n d o mize d P hase 
II Trial 2 0 1 4. 
Pa n Z, Sc h eer e ns H, Li SJ, et al. Disc o ver y of selecti ve irre v ersi ble i n hi bit ors f or Br ut o n's 
t yr osi ne ki nas e. C he m Me d C he m 2 0 0 7; 2: 5 8- 6 1. 
Sattert h waite A B, Witte  O N. T he r ole of Br ut o n's t yr osi ne ki nas e i n B cell de vel o p me nt a n d 
f u ncti o n: a ge netic p ers p ecti ve. I m m u n ol Re v 2 0 0 0; 1 7 5: 1 2 0- 1 2 7. 
S haffer A L, R ose n wal d A, Sta u dt L M. L y m p h oi d mali g na n cies: T he dar k si de of B- cell 
differe ntiati o n.  N at Re v I m m u n ol 2 0 0 2; 2: 9 2 0 – 9 3 2.   
S mit h TJ, K hatc heressia n J, L y ma n G H, et al. 2 0 0 6 u p date of rec o m me n d ati o ns f or t he use of 
w hite bl o o d cell gr o wt h f act ors: A n e vi de n ce- b ase d cli nical practice g ui deli ne. J Cli n O nc ol 
2 0 0 6; 2 4: 3 1 8 7- 2 0 5.  
Ste ve ns o n F K, Kr ys o v S, Da vies AJ, et al. B- cell rece pt or si g nali n g i n c hr o nic l y m p h oc ytic 
le u ke mia. Bl o o d 2 0 1 1; 1 1 8: 4 3 1 3- 4 3 2 0. Z h u a n g, et al. T he e x pressi o n a n d r ole of t yr osi ne ki nase 
E T K/ B M X i n r e nal cell carci n o ma. E x pt Cli n Ca ncer Res 2 0 1 4.  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 1 
1 4.  A P P E N DI C E S 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 2 
A p pe n di x 1.  Sc he d ule of Assess me nts   
St u d y Visits  
Scree ni n g 
P h as e  
Tre at me nt P h ase ( 1 c y cle = 2 8 d a ys) 
S us pecte d 
P D  
E n d -of -Tr e at me nt a 
F U b 
C y cle 1  
C y cle 2  
C y cles 3 – 7 
C y cles 8  a n d 
be y o n d  
D 1 ( b aseli ne)  
D 1 5  
D 1  
D 1 5  
D 1  
D 1 5  
D 1  
A n y ti me  
3 0 d a ys  after tre at me nt d/c  
q 3  m os
 
St u d y Visit Wi n d o ws  
-2 8 d a ys  
± 3 d a ys  
A n y ti me  
+ 7  da ys  
± 7 da ys  
I nf or me d c o nse nt 
x  
 
 
 
 
 
 
 
 
 
 
C o nfir m eli gi bilit y  
x  
x  
 
 
 
 
 
 
 
 
 
Me dical hist or y  
x  
 
 
 
 
 
 
 
 
 
 
Re vie w c o nc o mita nt me dicati o ns  
x  
x  
x  
x  
x  
x  
x  
x  
 
x  
 
Re vie w a d verse e v e nts c 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
St u d y dr u g c o m plia n ce re vie w d  
 
x  
x  
x  
x  
x  
 
x  
 
 
 
Hei g ht  
x  
 
 
 
 
 
 
 
 
 
 
P h ysical e xa m, vital si g ns, wei g ht, E C O G  
x  
x  
x  
x  
x  
x  
 
x  
x  
x  
x  
Disease assess me nt †: 
 
 
 
 
 
 
 
 
 
 
 
C T/ M RI sca n  
x  
 
 
 
 
x  
 
x  
x  
 
x  
O verall res p o nse assess me nt  
 
 
 
 
 
x  
 
x  
x  
 
x  
He mat ol o g y  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
Ser u m c he mistr y *  
x  
x  
x  
x  
 
x  
 
x  
x  
x  
 
T S H f 
x  
x  
 
 
 
x  
 
x  
 
x  
 
Creati ni ne cleara nce ( C o c kcr oft -Ga ult)  
x  
 
 
 
 
 
 
 
 
x  
 
P T/I N R a n d P T T  
x  
 
 
 
 
 
 
 
 
 
 
He patitis ser ol o gies  
x  
 
 
 
 
 
 
 
 
 
 
Pre g na nc y test  
x  
x  
 
 
 
 
 
 
 
 
 
1 2 lea d E C G  
x  
As cli nicall y i n dicate d ¥ 
 
 
 
Uri ne test  
x  
 
 
 
 
 
 
 
 
 
 
Arc hi val S peci me n  
x  
 
 
 
 
 
 
 
 
 
 
Bl o o d f or Tra nslati o n al St u dies e 
x  
  
x  
 
 
 
 
 
 
x  
 
Uri ne f or Tra nslati o n al St u dies  
x  
 
x  
 
 
 
 
 
 
x  
 
A n y ne w a ntica ncer t h era p y  
 
 
 
 
 
 
 
 
 
 
x  
St u d y Dr u g A d mi nistr ati o n  
 
 
 
 
 
 
 
 
 
 
 
Ni v ol u ma b i nf usi o n  
 
E ver y 2 wee ks  
 
 
 
I br uti ni b (c o nti n u o us) 
 
x  
x  
x  
x  
x  
x  
x  
x  
 
 
 
A b bre viati o ns: D = d a y; d/c = disc o nti n u ati o n; P D = pr o gressi ve disease; F U = f oll o w-u p , T S H = t h yr oi d sti m ulati n g h or m o ne.  
Ni v ol u ma b: 2 4 0 m g I V e ver y 2 wee ks 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 3 
 
†Disease assess me nt t o b e p erf or me d e ver y 8 wee ks  
* La b orat or y testi n g pri or t o Ni v ol u ma b  treat me nt ( will b e d o n e b ef ore e ver y 2 d oses of Ni v ol u ma b treat me nt, e ver y 4 wee ks).  
¥ E C G’s ma y be p erf or me d at t h e i n vesti gat or’s discreti o n, p artic ularl y i n s u bjects wit h arr h yt h mic s y m pt o ms (e g, p al pitati o ns,  li g ht hea de d ness) or ne w o nset d ys p nea 
a. A n E O T visit will o cc ur 3 0 ± 7 d a ys fr o m t h e last d ose of st u d y dr u g or pri or t o t h e start of a n e w a ntica n cer treat me nt . 
b.  O nce s u bjects e x p erie n ce T F, rela pse, or start use of alter n ati ve a ntica n cer t h era p y (f or s u bjects w h o h a ve n ot wit h dra w n c o n se nt), t he y will be c o ntacte d a p pr o xi mat el y e ver y 3 
m o nt hs ( ± 1 4 d a ys) b y cli nic visit or tele p h o n e u ntil d eat h, s u bject wit h dra wal, l ost t o f oll o w -u p, st u d y ter mi n ati o n b y t he st u d y s p o ns or, or u p t o 6 m o nt hs w hic he ver occ urs 
first. 
c. A Es are re p orte d fr o m t h e t i me t h e p atie nt si g ns t h e I nf or me d C o nse nt F or m u ntil 3 0 d a ys f oll o wi n g last d ose of st u d y dr u g.  
d.  I ncl u des patie nt i nstr u cti o n a n d r o uti n e re vie w of st u d y dr u g diar y a n d e val u ati o n of c o nte nts of st u d y dr u g c o ntai n ers fr o m h o me a d mi nistrati o n  
e. See A p p e n di x 8 f or c ollecti o n a n d pr o cessi n g i nstr u cti o ns  
f. T S H will be meas ure d at scree ni n g, e ver y ot h er c ycle starti n g at C ycle 1, a n d at t h e e n d of treat me nt visit. 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 4 
A p pe n di x 2.  E C O G  a n d K ar n ofs k y Perf or m a nce St at us Sc ores 1, 2  
 
 
E C O G P E R F O R M A N C E S T A T U S  
K A R N O F S K Y P E R F O R M A N C E S T A T U S  
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 0 0 — N or mal, n o c o m plai nts; n o e vi de nce of disease  
 9 0 — A ble t o carr y o n n or mal acti vit y; mi n or si g ns or 
s y m pt o ms of disease 
1 — Restricte d i n p h ysicall y str e 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  
 8 0 — N or mal acti vit y wit h eff ort, s o me si g ns or 
s y m pt o ms of disease 
 7 0 — Cares f or self b ut u na ble t o carr y o n n or mal 
acti vit y or t o d o acti ve w or k  
2 — A m b ulat or y a n d ca pa ble of all selfcare  b ut 
u na ble t o carr y o ut a n y w or k a cti 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  
 6 0 — Re q uires occasi o nal assista nce b ut is a ble t o care 
f or m ost of pers o nal nee ds 
 5 0 — Re q uires c o nsi dera ble assista nce a n d fre q ue nt 
me dical care  
3 — Ca pa ble of o nl y li m ite d selfcare; c o nfi ne d t o 
be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs  
 4 0 — Disa ble d; re q uires s pecial care a n d assista nce  
 3 0 — Se verel y disa ble d; h os pitalizati o n is i n dicate d 
alt h o u g h deat h n ot i m mi ne nt  
4 — C o m pletel y disa ble d; ca n n ot carr y o n a n y 
selfcare; totall y c o nfi ne d t o be d or c hair  
 2 0 — Ver y ill; h os pitalizati o n a n d acti ve s u p p orti ve 
care necessar y 
 1 0 — M ori b u n d  
5 — Dea d  
  0 — Dea d  
1.  Kar n ofs k y D, B urc he nal  J, T he cli nical e val uati o n of c he m ot hera pe utic a ge nts i n ca ncer. I n: Mac Le o d C, e d. 
E val uati o n of C he m ot hera pe utic A ge nts. Ne w Y or k, N Y: C ol u m bia U ni versit y Press; 1 9 4 9: 1 9 1 – 2 0 5.  
2.  Z u br o d C, et al. A p praisal of met h o ds f or t he st u d y of c he m ot hera p y i n ma n: C o m parati ve t hera pe utic trial of 
nitr o ge n m ustar d a n d t hi o p h os p h ora mi de. J o ur nal of C hr o nic Diseases; 1 9 6 0: 1 1: 7 -3 3.  
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 5 
A p pe n di x 3.  I n hi bit ors a n d I n d ucers of C Y P 3 A 
I n hi bit ors of C Y P 3 A are defi ne d as f oll o ws. A c o m pre he nsi ve list of i n hi bit ors ca n be f o u n d at t he 
f oll o wi n g we bsite: htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ta ble.as p x  . T he ge neral cate g orizati o n i nt o 
str o n g, m o derate, a n d wea k i n hi bit ors acc or di n g t o t he we bsite is dis pla ye d bel o w. Refer t o S ecti o n 6. 2. 1  
o n i nstr ucti o ns f or c o nc o mita nt use o f C Y P 3 A i n hi bit ors a n d i n d ucers wit h i br uti ni b. 
I n hi bit ors of C Y P 3 A 
I n d ucers of C Y P 3 A 
Str o n g i n hi bit ors  ( S H O U L D A V OI D): 
Car ba maze pi ne  
I N DI N A VI R 
Efa vire nz  
N E L FI N A VI R  
Ne vira pi ne  
RI T O N A VI R  
B ar bit urates  
C L A RI T H R O M Y CI N  
Gl uc oc ortic oi ds  
I T R A C O N A Z O L E 
M o dafi nil  
K E T O C O N A Z O L E  
O xcar barze pi ne  
N E F A Z O D O N E  
P he n o bar bital  
S A Q UI N A VI R  
P he n yt oi n  
S U B O X O N E  
Pi o glitaz o ne  
T E LI T H R O M Y CI N  
Rifa b uti n  
M o der ate i n hi bit ors:  
Rifa m pi n  
A pre pita nt  
St. J o h n’s W ort  
Er yt hr o m yci n  
Tr o glitaz o ne  
diltiaze m  
 
Fl uc o naz ole  
 
gra pefr uit j uice  
 
Se ville ora n ge j uice  
 
Vera pa mil  
 
We a k i n hi bit ors:  
 
Ci meti di ne  
 
All ot her i n hi bit ors:  
 
A mi o dar o ne  
 
N O T azit hr o m yci n  
 
C hl ora m p he nic ol  
 
B oce pre vir  
 
Ci pr ofl o xaci n  
 
Dela viri di ne  
 
diet h yl -dit hi ocar ba mate  
 
Fl u v o xa mi ne  
 
Gest o de ne  
 
I mati ni b 
 
Mi befra dil  
 
Mife prist o ne  
 
N orfl o xaci n  
 
N orfl u o xeti ne  
 
star fr uit 
 
T ela pre vir  
 
Tr olea n d o m yci n  
 
V oric o naz ole  
 
S o urce:  htt p:// me dici ne.i u p ui.e d u/cli n p har m/ d dis/ta ble.as p x.  
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 6 
A p pe n di x 4.  Res p o nse  Criteri a  
Res p o nse a n d pr o gr essi o n will be e val uate d i n t his st u d y usi n g t h e ne w i nt er nati o nal criteria 
pr o p ose d b y t he r e vise d Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) g ui deli ne 
( versi o n 1. 1) ( 2 5). C ha n ges i n t he lar gest dia meter ( u ni di me nsi o nal meas ure me nt) of t he t u m or 
lesi o ns a n d t he s h ortest dia meter i n t he case of mali g na nt l y m p h n o d es are use d i n t he R E CI S T 
criteria.  
 
Dise ase P ar a met ers  
 
Meas ura ble  Diseas e 
T he  prese n ce  of  at least o ne meas ur a ble  lesi o n. If t he meas ura ble  diseas e  is restricte d t o a 
s olitar y lesi o n, its ne o plastic  nat ure  s h o ul d be  c o nfir me d  b y  c yt ol o g y/ hist ol o g y.   
 
Meas ura ble  Lesi o ns 
Lesi o ns t hat ca n be acc ur atel y m eas ur e d  i n at least o ne di me nsi o n wit h l o n gest dia meter  2 0 m m  
usi n g  c o n v e nti o nal  tec h ni q ues or  1 0 m m  wit h  s piral C T  sca n.  
 
N o n - Meas ur a ble Lesi o ns 
All  ot her  lesi o ns, i ncl u di n g s mall lesi o ns (l o n gest dia meter  < 2 0  m m  wit h  c o n ve nti o nal  
tec h ni q ues or  < 1 0  m m  wit h  s piral C T  sca n), i.e., b o ne  lesi o ns, le pt o me ni n geal disease,  ascites, 
ple ural/ pericar dial  eff usi o n,  i nfla m mat or y breast  disease,  l y m p h a n gitis c utis/ p ul m o nis,  c ystic 
lesi o ns, a n d als o a b d o mi nal  masses  t hat are n ot  c o nfir me d  a n d f oll o we d b y  i ma gi n g tec h ni q u es. 
  
All  meas ure me nts  s h o ul d be  ta ke n a n d rec or de d i n metric  n otati o n,  usi n g  a r uler or  cali pers.  All  
baseli ne  e val u ati o ns  s h o ul d be  perf or m e d  as cl osel y as p ossi ble  t o t he be gi n ni n g  of  treat me nt a n d 
ne ver  m or e  t ha n 4  wee ks  bef ore  t h e be gi n ni n g  of  t he treat me nt.  
 
 T he  sa me met h o d  of  assess me nt  a n d t he sa me tec h ni q ue s h o ul d be  use d  t o c haracterize eac h 
i de ntifie d a n d re p orte d lesi o n at baseli ne  a n d d uri n g  f oll o w u p.   
 
Cli nical  lesi o ns will  o nl y  be  c o nsi der e d  meas ura bl e  w he n  t he y are s u p erfici al (e. g., s ki n n o d ules  
a n d pal pa ble  l y m p h n o des).  F or  t he case of  s ki n lesi o ns, d oc u me ntati o n  b y  c ol or p h ot o gra p h y,  
i ncl u di n g a r ul er t o esti mate t he size of  t he lesi o n, is rec o m me n de d.  
 
Met h o ds  of Me as ure me nt  
 
C T a n d M RI are t he b est c urre ntl y a v aila ble a n d re pr o d uci ble met h o ds t o meas ure t ar get lesi o ns 
selecte d f or res p o ns e ass ess me nt. C o n ve nti o nal C T a n d M RI s h o ul d b e perf or me d wit h c uts of 
1 0 m m or less i n slice t hic k ne ss c o nti g u o usl y. S piral C T s h o ul d be perf or me d usi n g a 5 m m 
c o nti g u o us r ec o nstr ucti o n al g orit h m. T his a p plies t o t u m ors of t he c hest, a b d o me n a n d pel vis. 
Hea d a n d n ec k t u m ors a n d t h ose of e xtre mities us uall y re q uire s pecific pr ot oc ols.  
Lesi o ns o n c hest X- r a y are acce pta bl e as meas ura ble lesi o ns w he n t he y are clearl y defi ne d a n d 
s urr o u n de d b y aerat e d l u n g. H o w e ver, C T is prefera ble.  
  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 7 
W he n t he pri mar y e n d p oi nt of t he st u d y is o bjecti ve res p o nse e val uati o n, ultras o u n d ( U S) s h o ul d 
n ot be use d t o meas ure t u m o r lesi o ns. It is, h o we v er, a p ossi ble alter nati ve t o cli nical 
meas ure me nts of s u p erfi cial pal pa ble l y m p h n o des, s u bc uta ne o us lesi o ns a n d t h yr oi d n o d ules. 
U S mi g ht als o be usef ul t o c o nfir m t he c o m plete disa p peara nce of s u perfici al lesi o ns us uall y 
assesse d b y cli nical e x a mi nati o n.  
 
T he  utilizati o n  of  e n d osc o p y a n d l a par os c o p y f or o bjecti ve  t u m or e val uati o n has  n ot  yet  b ee n  
f ull y a n d wi del y  v ali date d.  T heir  uses  i n t his s pecific c o nte xt re q uire s o p histicate d e q ui p me nt  
a n d a hi g h  le vel of  e x pertise t hat ma y  o nl y  be  a vaila ble i n s o me ce nters. T h eref ore,  t he 
utilizati o n  of  s uc h tec h ni q ues f or o bjecti ve  t u m or res p o nse s h o ul d be  restri cte d t o vali dati o n  
p ur p oses  i n s pecialize d ce nters. H o w e ver,  s u c h tec h ni q ues ca n b e  usef ul  i n c o nfir mi n g c o m plete 
pat h ol o gical  res p o nse w h e n  bi o psies  are o btai n e d.   
 
C yt ol o g y  a n d hist ol o g y  ca n be  use d  t o differe ntiat e  bet wee n  P R  a n d C R  i n rare cases (e. g., after 
treat me nt t o differ e ntiate  bet wee n  r esi d ual be ni g n  lesi o ns a n d resi d ual mali g na nt  lesi o ns i n t u m or 
t y pes s uc h as ger m  cell t u m ors).  
  
B aseli ne  Doc u me nt ati o n  of “ T ar get ” a n d “ N o n-T ar get ”  Lesi o ns  
 
As per R E CI S T 1. 1: W h e n m ore t ha n o ne m eas ura ble lesi o n is prese nt at b aseli ne all lesi o ns u p 
t o a ma xi m u m of fi ve lesi o ns t otal (a n d a ma xi m u m of t w o lesi o ns per or ga n) re prese ntati ve of 
all i n v ol ve d or ga ns s h o ul d be i de ntifie d as tar get lesi o ns a n d will be rec or d e d a n d meas ure d at 
baseli ne  (t his mea ns i n i nsta nces w here patie nts h a ve o nl y o n e or t w o or ga n sites i n v ol ve d a 
ma xi m u m of t w o a n d f o ur lesi o ns res pecti vel y will be rec or de d).  
 
Tar get lesi o ns s h o ul d be selecte d o n t he b asis of t heir size (lesi o ns wit h t he l o n gest dia meter), be 
re pres e ntati ve of all i n v ol ve d or ga ns, b ut i n a d diti o n s h o ul d be t h ose t hat le n d t he msel ves t o 
re pr o d uci ble re peate d meas ure me nts. It ma y b e t he case t h at, o n occasi o n, t he lar gest lesi o n d oes 
n ot le n d itself t o re pr o d u ci ble meas ur e me nt i n w hic h circ u msta nce t he ne xt lar gest lesi o n w hic h 
ca n be meas ure d re pr o d u ci bl y s h o ul d be sel ecte d.   
 
L y m p h n o des merit s peci al me nti o n si nce t he y are n or ma l a nat o mical str uct ures w hic h ma y b e 
visi ble b y i ma gi n g e ve n if n ot i n v ol ve d b y t u m or. As n ote d i n Secti o n 3, pat h ol o gical n o des 
w hic h are d efi ne d as meas ura ble a n d ma y b e i de ntifie d as tar get lesi o ns m ust meet t he criteri o n 
of a s h ort a xis of > 1 5 m m b y C T sca n. O nl y t he s h ort a xis of t hese n o des will c o ntri b ute t o t he 
baseli ne s u m.   
 
A  s u m of  t he l o n gest dia meter  ( L D) f or all tar get lesi o ns will  be  calc ulate d  a n d re p ort e d as t he 
baseli ne  s u m L D.  T he  b aseli ne  s u m L D  will  be  use d  as refere nce b y  w hic h  t o c haracterize t he 
o bjecti ve  t u m or.  
  
All  ot her  lesi o ns ( or sites of  disease)  s h o ul d b e  i de ntifie d as n o n -tar get lesi o ns a n d s h o ul d als o be  
rec or d e d at bas eli ne.  Meas ure me nts  of  t hes e lesi o ns are n ot  re q uire d, b ut  t he prese n ce  or  a bse n ce 
of  eac h s h o ul d b e  n ote d  t hr o u g h o ut f oll o w-u p.   
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 8 
Res p o nse  Criteri a   
  
E val uati o n of T ar get Lesi o ns  
•  C o m plete  R es p o nse  ( C R): Disa p p eara nce  of  all tar get lesi o ns  
•  P arti al  Res p o nse  ( P R):  At  least a 3 0 % decrease  i n t he s u m of t he L D  of  t ar get lesi o ns, 
ta ki n g as ref ere n ce t he b aseli ne  s u m L D   
•  Pr o g ressi ve  Dise ase  ( P D): At  least a 2 0 % i ncrease i n t he s u m of t he L D  of  tar get 
lesi o ns, ta ki n g as r efere n ce t he s mallest s u m L D  rec or de d si n ce t he treat me nt starte d or 
t he a p peara nce of o n e or m ore  ne w  lesi o ns  
•  St a ble Dise ase ( S D): N eit her s ufficie nt s hri n ka ge t o q ualif y f or P R n or s ufficie nt 
i ncreas e t o q ualif y f or P D, ta ki n g as refere nce t h e s mallest s u m L D si nce t he treat me nt 
starte d  
  
E val uati o n of N o n- T ar get Lesi o ns  
 
•  C o m plete R es p o nse ( C R ): Disa p peara nce of all n o n-tar get lesio ns a n d n or malizati o n of 
t u m or mar ker le v el  
•  I nc o m plet e Res p o nse/ St a ble Dise ase ( S D): Persiste nce of o ne or m ore n o n- tar get 
lesi o n(s) or/a n d mai nte na nce of t u m or mar k er le v el a b o ve t he n or mal li mits  
•  Pr o g ressi ve Dise ase ( P D): A p peara nce of o ne or m ore ne w  l esi o ns a n d/ or u ne q ui v ocal 
pr o gressi o n of e xisti n g n o n- tar get lesi o ns 
  
Alt h o u g h a clear pr o gressi o n of “ n o n tar get” l esi o ns o nl y is e x ce pti o nal, i n s uc h circ u msta nces, 
t he o pi ni o n of t he treati n g p h ysicia n s h o ul d pre vail a n d t he pr o gressi o n stat us s h o ul d be 
c o nfir me d later o n b y t he re vie w pa n el ( or st u d y c hair).  
  
E v al u ati o n of  Best Over all  Res p o nse   
 
T he best o ver all res p o nse is t he best res p o nse rec or de d fr o m t he start of t he treat me nt u ntil 
disease pr o gr essi o n/rec urre nce (ta ki n g as refere n ce f or P D t he s mallest meas ure me nts rec or d e d 
si nce t he treat me nt starte d). I n ge neral, t he patie nt's best res p o nse assi g n me nt will de pe n d o n t he 
ac hie ve m e nt of b ot h meas ure me nt a n d c o nfir mati o n criteria.  
 
T a ble 3. Best O ver all Res p o nse E v al u ati o n 
T ar get Lesi o n  
N o n -T ar get Lesi o n  
Ne w Lesi o n  
O ver all Res p o nse  
C R  
C R  
N o  
C R  
C R  
I n c o m plete Res p o nse/ S D 
N o  
P R  
P R  
N o n -P D  
N o  
P R  
S D  
N o n -P D  
N o  
S D  
P D  
A n y  
Yes or N o  
P D  
A n y  
P D  
Yes or N o  
P D  
A n y  
A n y  
Yes  
P D  
  
Patie nts  wit h  a gl o bal  det eri orati o n  of  healt h  stat us re q uiri n g disc o nti n uati o n  of  treat me nt 
wit h o ut  o bjecti ve  e vi de n ce of  disease  pr o gressi o n  at t hat ti me s h o ul d be  classifie d as ha vi n g  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 6 9 
“s y m pt o matic det eri orati o n”.  E ver y  eff ort s h o ul d be  ma de  t o d oc u me nt  t he o bjecti ve  pr o gressi o n  
e ve n aft er disc o nti n uati o n  of  treat me nt.  
 
I n s o me circ u msta n ces  it ma y  b e  diffic ult  t o disti n g uis h  resi d u al disease  fr o m n or mal  tiss ue.  
W he n  t he e val uati o n  of  c o m plete res p o nse de p e n ds  o n  t his deter mi nati o n,  it is rec o m me n de d t hat 
t he resi d ual lesi o n be i n v esti gate d  (fi ne n ee dle  as pirate/ bi o ps y)  t o c o nfir m  t he c o m plete res p o nse 
stat us.  

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 7 0 
A p pe n di x 5: Pill Di ar y  
P R O T O C O L N U M B E R:  U C D C C # 2 6 2 
P A TI E N T N A M E:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _      
M E DI C A L R E C O R D N U M B E R:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
I N V E S TI G A TI O N A L A G E N T: Or al i br uti ni b  
 
C Y C L E # : _ _ _ _ _ _ _ _ _  
S T A R T D A T E:  _ _ _ _ _ _ _ _ _ _ _ _ _                         D O S E:  
 
 
I nstr ucti o ns: I br uti ni b is a n oral a ge nt t hat s h o ul d be ta ke n o nce dail y e v er y da y o n  a 2 8-d a y  c ycle.  It s h o ul d be t ake n ar o u n d t he 
s a me ti me e ac h d ay. Please i n dicate i n t he c orres p o n di n g b o x usi n g a c h ec k mar k t he da ys t hat y o u t o o k i br uti ni b. If y o u miss a d ose, 
d o n ot d o u ble u p t he ne xt d ose. J ust lea ve t he c orres p o n di n g b o x f or t he misse d d ose bla n k.  
 
 
P A TI E N T SI G N A T U R E: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Da y of 
C ycle  
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  
1 1  
1 2  
1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
2 0  
2 1  
2 2  
2 3  
2 4  
2 5  
2 6  
2 7  
2 8  
Please 
i nitial 
i n eac h 
b o x t o 
i n dicate 
y o u 
t o o k 
d ose  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 7 1 
A p pe n di x 6 : N CI C T C Versi o n 4. 0 3 
 
T o xicit y will be sc or e d usi n g N CI C T C Versi o n 4. 0 3 f or t o xicit y a n d a d verse e ve nt re p orti n g.  A 
c o p y of t he N CI C T C Versi o n 4. 0 3 ca n be d o w nl o a de d fr o m t he C T E P h o me pa ge: 
(htt p://cte p.i nf o. ni h. g o v ).  All a p pr o priate treat me nt areas h a ve access t o a c o p y of t he C T C 
Versi o n. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 7 2 
A p pe n di x 7:  Re gistr ati o n G ui deli nes  
A.  Bef ore r e gistrati o n, t he site st u d y c o or di nat or s h o ul d c hec k t o ma ke s ure t hat t he 
c orres p o n di n g I n v esti gati o nal Dr u g Ser vice or e q ui vale nt has st u d y dr u g i n st oc k. 
B.  Re gistrati o ns f or t his P hase I pr ot oc ol m ust be ma de t hr o u g h t he Office of Cli nical 
Researc h of t he U ni versit y of Calif or nia, Da vis C o m pre he nsi ve Ca ncer Ce nter bet wee n 
t he h o urs of 9a m a n d 3 p m ( Pacific Ti me), M o n da y t hr o u g h Fri da y (e x ce pt h oli da ys).  
D oc u me ntati o n of c urre nt I R B a p pr o v al of t his pr ot oc ol b y n o n- U C Da vis i nstit uti o ns 
m ust be o n file pri or t o re gistrati o n of patie nts at t hese i nstit uti o ns.  
C.  Pre -st u d y l a b orat or y tests, sca ns, a n d x-ra ys, m ust be c o m plete d pri or t o re gistrati o n, 
wit hi n t he ti me fra me s pecifie d i n t he pr ot oc ol.  T h e eli gi bilit y c hec klist m ust be 
c o m plete d.  Patie nts m ust si g n a n i nf or me d c o nse nt pri or t o re gistrati o n.  
D.  Patie nts ma y be re gister e d u p t o 7 2 h o urs pri or t o treat me nt i nitiati o n. All pa ges of t he 
si g ne d c o nse nt, c o m plete d c hec klist a n d re p orts fr o m all pre-st u d y l a b orat or y tests, sca ns 
a n d x-ra ys m ust be fa x e d t o U C Da vis O C R
 or e m aile d t o U C D i n or der 
t o re gister t he patie nt. T h ese d oc u ments are t o be re dacte d a n d “ p atie nt i nitials” or “a 
partici pati n g site s u bject i de ntifier” will be writte n o n t he d oc u me nts u ntil t he St u d y 
S u bject I D is iss ue d.  T he U C Da vis St u d y C o or di nat or will re vie w t hese d oc u me nts a n d 
fa x/e mail a re gistrati o n c o nfir mati o n wit hi n 2 4 h o urs. 
Re mi n der: C o nfir m eli gi bilit y f or a n cillar y st u dies a n d willi n g ness t o parti ci pate at t he 
sa me ti me as eli gi bilit y f or t he treat me nt st u d y. 
E.  If t he patie nt is t o be r e gistere d t he sa me d a y as t h e pr o p ose d treat me nt start date, t he UC 
Da vis St u d y C o or di nat or m ust be n otifie d b y fa x 2 4 h o urs pri or t o pr o p ose d treat me nt 
start date t hat t he site has a patie nt t o re gister.   
F.  T he St u d y C o or di nat or will verif y t hat t he p atie nt is eli gi ble, t hat pre -st u d y tests ha ve bee n 
c o m plete d, a n d t hat t he f or ms are c o m plet e.  T he St u d y C o or di n at or will t he n re gister t he 
patie nt a n d assi g n a patie nt accessi o n n u m ber.  T h e St u d y C o or di nat or will fa x or e mail a 
re gistrati o n c o nfir mati o n i ncl u di n g t he patie nt accessi o n n u m ber wit hi n 2 4 h o urs. 
G.  A patie nt faili n g t o meet all pr ot oc ol re q uire m e nts ma y n ot be re gistere d.  If y o u h a ve a n y 
q uesti o ns re gar di n g eli gi bilit y, c o ntact t he c o or di nati n g site PI or St u d y C o or di nat or.   
N O T E: A d mi nistr ati o n of st u d y me dic ati o n m a y n ot be i niti ate d u ntil t he re gistr ati o n 
c o nfir m ati o n h as bee n recei ve d.  
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 7 3 
A p pe n di x 8 : M olec ul ar C orrel ati v e S a m ple H a n dli n g  
 
S peci me n S u b missi o n f or C orrel ati ve St u dies :  
Wit h t he patie nt's c o nse nt, tiss ue a n d bl o o d s peci me ns will be s u b mitte d as o utli ne d bel o w.  
 
S peci me n C ollecti o n, St or a ge, S hi p pi n g a n d S u b missi o n Re q uire me nts  
 
• Arc hi v al t u m o r s peci me ns : If a vaila bl e, 1 - 2 paraffi n -e m be d d e d tiss ue bl oc ks c o ntai ni n g 
f or mali n-fi x e d t u m or or nee dle as pirate fr o m ti me of dia g n osis ( or s u bse q u e nt, b ut pri or t o 
t hera p y) s h o ul d be s u b mitte d f or e val u ati o n of e x pressi o n of or m utati o ns i n rele va nt m olec ul ar 
pat h wa ys. Paraffi n bl oc ks ma y be pr ocesse d acc or di n g t o sta n dar d i nstit uti o nal pr ot oc ols. If 
bl oc ks are u n a vaila ble, 1 6 u nstai ne d sli des are acce pta ble alter n ati ves. If s u b mitti n g sli des, 
please i ncl u de a si n gl e H & E stai ne d sli de t hat has bee n re vi e we d b y a pat h ol o gist f or 
a de q uac y. A c o p y of t he c orres p o n di n g Pat h ol o g y Re p o rt s h o ul d be s u b mitte d wit h all t u m or 
s peci me ns. 
 
• Bl o o d s peci me ns : Bl o o d  will be c ollecte d fr o m eac h p atie nt pri or t o i nitiati n g treat me nt  
( baseli ne), pri or t o treat m e nt o n C ycle 1 Da y 1 5, a n d w he n t he patie nt is re m o ve d fr o m st u d y 
treat me nt.  Eac h bl o o d dr a w will c o nsist of 3 x 1 0 ml, p ur ple t o p K 2 E D T A t u bes  
  Pl as m a & B uff y C o at: 
•  
Bl o o d c ollecte d i nt o o ne of t he 1 0 ml K 2 E D T A t u bes s h o ul d be i n verte d s e veral ti mes, 
a n d place d o n wet ice u ntil ce ntrif u gati o n. T he t u b es s h o ul d be ce ntrif u ge d as s o o n as 
p ossi ble at a p pr o xi matel y 8 0 0 x g f or 1 0 mi n utes. Plas ma s h o ul d be re m o ve d a n d 
tra nsferre d t o a 1 5 ml c o nical tu be.  T his t u be will ce ntrif u ge d a sec o n d ti m e t o pellet 
a n y re mai ni n g cell ular de bris.  T he sec o n d ce ntrif u gati o n s h o ul d be d o ne at 8 0 0 – 1 5 0 0 
( pref err e d) x g f or 1 0 mi n utes.  Res ulti n g plas ma is t o be tra nsferre d i n 5 0 0 µl ali q u ots 
i n la bele d cr y ot u bes. B uff y c oat cells s h o ul d be se paratel y re m o ve d a n d pl ace d i n 
la bele d cr y ot u b es. All s peci me ns m ust be l a bele d wit h pr ot oc ol n u m ber, p atie nt 
re gistr ati o n n u m ber, a n d d ate of s peci me n c ollecti o n. All t u bes are t he n t o be fr oze n 
a n d st ore d at or b el o w - 7 0° C.  
  P B M C Is ol ati o n: 
•  Bl o o d c ollecte d i nt o t he r e mai ni n g t w o 1 0 m L K 2 E D T A t u bes s h o ul d be pr ocesse d f or 
via ble P B M Cs acc or di n g t o t he M olec ular P har mac ol o g y S hare d Res o urce ( M P S R) 
S O P f or P B M C Is olati o n fr o m W h ole Bl o o d.  Bri efl y, bl o o d will be dil ute d wit h R P MI 
or P B S, la yer e d o ver Fic oll, a n d s p u n at 4 0 0 x g f or 3 0 mi n utes wit h n o bra ke t o 
se parat e P B M Cs fr o m R B Cs.  T he P B M Cs will be caref ull y c ollect e d a n d was he d i n 
P B S 2 x a n d res us pe n de d i n R P MI f or cell c o u nti n g ( usi n g a Sce pter a ut o mate d 
c o u nter).  Cells will be ste p wise fr oze n at a b o ut 1. 0 e 7 i n F B S/ D M S O ( 1 0 % fi nal 
c o nce ntr ati o n of D M S O) usi n g a Mr. Fr ost y freezi n g c o nt ai ner.  Fr oze n cells m ust be 
s hi p pe d t o U C Da vis wit hi n o ne wee k of c ollecti o ns s o t hat t he y ca n be tra nsferre d t o 
li q ui d Nitr o ge n f or l on g -ter m st ora ge.  S O P will be e maile d t o partici p ati n g sites u p o n 
re q uest - see c o ntact i nf or mati o n i n A p pe n di x 9 ( S peci me n S u b missi o n F or m). 
 
•  If p artici p ati n g sites are u n a ble t o pr ocess bl o o d f or P B M Cs, w h ole bl o o d s h o ul d be 
s hi p pe d directl y t o U C Da vis C o m pre he nsi ve Ca n cer Ce nter via o ver ni g ht c o urier f or 
pr ocessi n g.  Bl o o d s h o ul d be c ollecte d a n d s hi p pe d M- T h O N L Y a n d n otifi cati o n of 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 7 4 
s hi p me nt m ust be se nt t o pr ocessi n g la b. See A p pe n di x 9 ( S peci me n S u b missi o n 
F or m) f or s hi p pi n g a n d c o nt act i nf or m ati o n.   
 
•  Uri ne S peci me n:   Uri n e will be c ollecte d fr o m eac h patie nt pri or t o i nitiati n g treat me nt 
( baseli ne), pri or t o treat m e nt o n C ycle 1 Da y 1 5, a n d w he n t he patie nt is re m o ve d fr o m st u d y 
treat me nt.  A p pr o xi matel y 1 0 m L of s a m ple wit h be tra nsferre d t o a 1 5 m L c o nical a n d 
ce ntrif u ge d at 3 0 0 0 x g f or 5- 1 0 mi n utes.  I m m e diatel y after ce ntrif u gati o n, tra nsfer 1. 5 m L of 
uri ne t o eac h cr y o vial, m a xi m u m of 5 cr y o vials.  Cr y o vials m ust be la bel e d as a b o ve a n d 
st ore d at or bel o w - 7 0°C.  
 
•  S hi p pi n g I nstr ucti o ns: All arc hi val paraffi n bl oc k or sli de s peci me ns s h o ul d be se nt at 
a m bient te m perat ur e. Fr o ze n s peci me ns s h o ul d be s hi p pe d o n dr y ice . T hes e s h o ul d be s hi p pe d 
b y o ver ni g ht c o urier M o n da y t hr o u g h We d nes da y o nl y, acc or di n g t o t he i nstr ucti o ns i n 
A p pe n di x 9 . 
 
•  A S peci me n S u b missi o n F or m m ust be s u b mitte d wit h e ac h s peci me n . I nstit uti o ns s h o ul d 
n otif y t he r eci pie nt b y eit her p h o ne or fa x pri or t o s hi p pi n g s peci me ns. T his will all o w t he 
reci pie nt t o trac k t h e pac ka ge i n t he e v e nt t hat t here are a n y pr o bl e ms i n deli ver y.  
 
 
 
 
T he Fe der al G ui deli nes f or S hi p me nt are as f oll o ws (t hese peri o dic all y c h a n ge, ple ase 
c hec k f or t he m ost c urre nt g ui deli nes):  
1. T he s peci me n m ust be wra p pe d i n a n a bs or b a ble material  
2. T he s peci me n m ust t he n be place d i n a n AI R TI G H T c o ntai ner (reseala bl e ba g) 
3. Pac k t he res eala ble b a g a n d s p eci me n i n a  st yr of oa m s hi p pi n g c o nt ai ner  
4. Pac k t he st yr of oa m s hi p pi n g c o ntai n er i n a car d b oar d b o x 
5. T he car d b oar d b o x s h o ul d be la bele d “ U N 3 3 7 3 Bi ol o gical S u bsta nce, Cate g or y B”  
“ BI O H A Z A R D ”  
 
 
 
 
 
 
 
 
 
 
 

I br uti ni b ( P CI- 3 2 7 6 5) 
U C D C C # 2 6 2  
J u ne 1 5, 2 0 1 7 
Fi nal  
P har mac yclics L L C.  V 7. 0 J u ne 1 5, 2 0 1 7 
C M R C - 0 1 0 4 0 0 5/ 1 5 
P r o priet ar y  a n d  C o nfi de nti al  
Pa ge 7 6 
A p pe n di x 1 0 : C hil d -P u g h Sc ore  
 
Me as ure  
1 p oi nt  
2 p oi nts  
3 p oi nts  
T otal bilir u bi n, μ m ol/ L ( m g/ dL) 
< 3 4 ( < 2) 
3 4- 5 0 ( 2- 3) 
> 5 0 ( > 3) 
Ser u m al b u mi n, g/ L ( g/ d L)  
> 3 5 ( > 3. 5) 
2 8- 3 5 ( 2. 8- 3. 5) 
< 2 8 ( < 2. 8) 
P T I N R  
< 1. 7 
1. 7 1- 2. 3 0 
> 2. 3 0 
Ascites  
N o ne 
Mil d  
M o derate t o Se vere  
He patic e nce p hal o pat h y  
N o ne 
Gra de I -II ( or s u p presse d 
wit h me dicati o n) 
Gra de III -I V  
( or refract or y) 
 
P oi nts  
Cl ass  
5 -6  
A  
7- 9 
B 
1 0- 1 5 
C 
 
S o urce:  
1.  C hil d C G, T urc otte J G . “ S ur ger y a n d p ortal h y perte nsi o n”. I n C hil d C G. T he liver a n d p ort al hy perte nsi o n. 
P hila del p hia: Sa u n ders. 1 9 6 4 . p p. 5 0 -6 4.   
2.  P u g h R N, M urra y -L y o n I M, Da ws o n L, Pietr o ni M C, Willi a ms R . “ Tra nsecti o n of te oes o p ha g us f or 
blee di n g oes o p ha geal varices”.  T he Britis h j o ur n al of s ur gery , 1 9 7 3; 6 0 : 6 4 6-9.