A Phase 2, Open-Label, 2-Cohort Study of INCB050465, a PI3Kδ Inhibitor, in Subjects With Relapsed or Refractory Marginal Zone Lymphoma With or Without Prior Exposure to a BTK Inhibitor (CITADEL-204)
Phase: PHASE2
Conditions: Lymphoma
Sponsor: Incyte Corporation

Offici al Titl e:  
A P h as e 2, O p e n -L a b el, 2-C o h ort St u d y of I N C B 0 5 0 4 6 5, a PI 3 K δ I n hi bit or, i n 
S u bj ects w it h R el a ps e d or R efr act or y M ar gi n al Z o n e L y m p h o m a w it h or 
Wit h o ut Pri or E x p os ur e t o a B T K I n hi bit or ( CI T A D EL -2 0 4)  
N C T N u m b er:  
N C T 0 3 1 4 4 6 7 4  
D oc u m e nt  D at e : 
Cli nic al St u d y Pr ot oc ol  A m e n d m e nt  V ersi o n  4: 2 3 D ec e m b er 2 0 1 9 

Cli nic al St u d y Pr ot oc ol  
I N C B 5 0 4 6 5 -2 0 4  
A P h ase 2, O pe n -L a bel, 2 -C o h ort St u d y of I N C B 0 5 0 4 6 5, a PI 3 K δ 
I n hi bit or, i n S u bjects Wit h Rel a pse d or Refr act or y M ar gi n al Z o ne 
L y m p h o m a Wit h or Wit h o ut Pri or E x p os ure t o a B T K I n hi bit or 
( CI T A D E L-2 0 4)  
Pr o d uct:  
I N C B 05 0 4 6 5  
I N D N u m ber: 
1 2 1, 4 7 4  
E u dr a C T N u m ber:  
2 0 1 7 -0 0 0 9 7 0 -1 2  
P h ase of St u d y : 
2 
S p o ns or:  
I nc yte C or p or ati o n 
1 8 0 1 A u g usti ne C ut - Off 
Wil mi n gt o n, D E 1 9 8 0 3  
Ori gi n al Pr ot oc ol  ( Versi o n 
0) : 
2 2  M A R 2 0 1 7  
Pr ot oc ol ( Versi o n 0 -U K):  
2 6 S E P 2 0 1 7  
A me n d me nt ( Versi o n) 1:  
2 4  J A N 2 0 1 8  
A me n d me nt ( Versi o n) 1 -
F R A:  
2 3 F E B 2 0 1 8  
A me n d me nt ( Versi o n) 2 -
F R A:  
2 8 M A R 2 0 1 8  
A me n d me nt ( Versi o n) 2:  
1 8  J U L  2 0 1 8  
A me n d me nt ( V ersi o n) 3:  
0 7 D E C  2 0 1 8  
A me n d me nt ( Versi o n)  4:  
2 3  D E C  2 0 1 9 
T his st u d y will be perf or me d i n acc or da nce wit h et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of 
Helsi n ki a n d c o n d ucte d i n a d here nce t o t he st u d y Pr ot oc ol, G o o d Cli nical Practices as defi ne d i n Title 2 1 of t he 
U S  C o de of Fe deral Re g ulati o ns Parts 1 1, 5 0, 5 4 , 5 6, a n d 3 1 2 , as well as I C H G C P c o ns oli date d g ui deli nes ( E 6) a n d 
a p plica ble re g ulat or y re q uire me nts.  
T he i nf or mati o n i n t his d oc u me nt is c o nfi de ntial.  N o part of t his i nf or mati o n ma y be d u plicate d, refere nce d,  or 
tra ns mitte d i n a n y f or m or b y a n y mea ns (electr o nic, mec ha nical, p h ot oc o p y, rec or di n g, or ot her wise) wit h o ut t he pri or 
writte n c o nse nt of I nc yte C or p orati o n.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
Versi o n 4
Pa ge 1 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

I N V E S TI G A T O R' S AG R E E M E N T 
I ha ve rea d  the I N C B 5 0 4 6 5- 2 0 4 Pr ot oc ol A me n d me nt  4 ( Versi o n 4 d ate d 2 3  DE C  2 0 1 9) a n d 
a gree t o c o n d uct the st u d y as o ut li ne d.  I agree to mai ntai n t he co nfi de nti alit y of all i nf or mati o n 
recei ve d or de vel o ped i n c o n necti o n wit h t his P rot oc ol. 
( Pri nte d Na me of I n vesti gat or)  
( Si g nat ure of I n vesti gat or) 
( Date) 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
Versi o n 4
Pa ge 2 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

S Y N O P SI S  
N a me of I n vesti g ati o n al Pr o d uct:  I N C B 05 0 4 6 5  
Title of S t u d y:  A P hase 2, O pe n -La bel, 2- C o h ort St u d y of I N C B 0 5 0 4 6 5, a PI 3 K δ I n hi bit or, i n 
S u bjects W it h Rela pse d or Refract or y Mar gi nal Z o ne L y m p h o ma Wit h or Wit h o ut Pri or E x p os ure t o a 
B T K I n hi bit or ( CI T A DE L -2 0 4)  
Pr ot oc ol N u m ber:   I N C B 5 0 4 6 5 -2 0 4  
St u d y P h ase:   2 
I n dic ati o n:  Mar gi nal zo ne ly m p h o ma  
 
O bjecti ves  
E n d p oi nts  
Pri m ar y  
T o assess t he efficac y of I N C B 0 5 0 4 6 5 
i n ter ms of o bjecti ve res p o nse rate 
( O R R) i n s u bjects wit h mar gi nal z o ne 
l y m p h o ma ( M Z L) t hat is rela pse d or 
refract or y after at least 1 s yste mic 
treat me nt re gi me n. 
O R R defi ne d as t he perce nta ge of s u bjects wit h a c o m plete 
res p o nse ( C R) or partial res p o nse ( P R) as deter mi ne d b y 
I n de pe n de nt Re vie w C o m mittee (I R C) assess me nt of res p o nse 
acc or di n g t o c o m p ute d t o m o gra p h y ( C T) -base d res p o nse criteria f or 
l y m p h o mas. 
Sec o n d ar y  
T o assess d urati o n of res p o nse ( D O R).  
D O R defi ne d as t he ti me fr o m first d oc u me nte d e vi de nce of C R or 
P R u ntil disease pr o gressi o n or deat h fr o m a n y ca use a m o n g 
s u bjects w h o ac hie ve a n o bjecti ve res p o nse, as deter mi ne d b y 
ra di o gra p hic disease assess me nt pr o vi de d b y a n I R C. 
T o assess c o m plete res p o nse rate 
( C R R). 
C R R defi ne d as t he perce nta ge of s u bjects wit h a C R as defi ne d b y 
res p o nse criteria f or l y m p h o mas, as deter mi ne d b y a n I R C. 
T o assess pr o gressi o n -free s ur vi val 
( P F S). 
P F S defi ne d as t he ti me fr o m t he date of t he first d ose of st u d y 
treat me nt u ntil t he earliest date of disease pr o gressi o n, as 
deter mi ne d b y ra di o gra p hic disease assess me nt pr o v i de d b y a n I R C, 
or deat h fr o m a n y ca use.  
T o assess o verall s ur vi val ( O S).  
O S defi ne d as t he ti me fr o m t he date of t he first d ose of st u d y 
treat me nt u ntil deat h fr o m a n y ca use. 
T o assess t he best perce nta ge c ha n ge i n 
tar get lesi o n size. 
Best perce nta ge c h a n ge i n tar get lesi o n size fr o m baseli ne, w here 
tar get lesi o n size is meas ure d b y t he s u m of t he pr o d uct of 
dia meters of all tar get lesi o n sizes.  
T o c haracterize t he safet y a n d 
t olera bilit y of I N C B 0 5 0 4 6 5. 
Safet y meas ure d b y a d verse e ve nts ( A Es), 1 2 -lea d 
electr ocar di o gra ms ( E C Gs), c he mistr y a n d he mat ol o g y la b orat or y 
val ues, vital si g ns, a n d p h ysical e xa mi nati o ns.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

O ver all St u d y Desi g n:   T his is a P hase 2, o pe n -la bel st u d y desi g ne d t o e val uate t he safet y a n d 
efficac y of 2 I N C B 0 5 0 4 6 5 treat me nt re gi me ns i n s u bjects dia g n ose d wit h rela pse d or refract or y M Z L.  
T he st u d y was ori gi nall y pla n ne d t o e nr oll 2 c o h orts:   C o h ort 1 f or s u bjects w h o  were pre vi o usl y 
treate d wit h a Br ut o n's t yr osi ne ki nase ( B T K) i n hi bit or ( n = 6 0) a n d C o h ort 2 f or s u bjects w h o are 
nai ve  t o B T K i n hi bit or ( n = 6 0) . 
Per Pr ot oc ol A me n d me nt (Versi o n ) 3, o nl y s u bjects w h o ha ve n ot  recei ve d a pri or B T K i n hi bit or (ie, 
C o h ort  2) will c o nti n ue t o be e nr olle d.  C o h ort 1, w hic h c o m prises s u bjects w h o ha ve recei ve d pri or 
i br uti ni b, will be cl ose d t o f urt her e nr oll me nt wit h Pr ot oc ol A me n d me nt (Versi o n ) 3.  
S u bjects alrea d y e nr olle d i n C o h ort 1 will c o nti n ue t o recei ve st u d y treat me nt per t he pr ot oc ol , a n d 
t heir data will be re p orte d a n d a nal y ze d  se paratel y fr o m s u bjects i n C o h ort 2 . 
S u bjects i n C o h ort  2 ( n = 6 0) will be f urt her all ocate d t o 1 of t he 2 st u d y treat me nt re gi me ns as 
f oll o ws: 
•  Treat me nt A:  I N C B 0 5 0 4 6 5 2 0 m g o nce dail y ( Q D) f or 8 wee ks f oll o we d b y 2 0 m g o nce wee kl y. 
•  Treat me nt B:  I N C B 0 5 0 4 6 5 2 0 m g Q D  f or 8 wee ks f oll o we d b y 2. 5 m g Q D . 
S u bjects will be e val uate d f or O R R b y a n I R C  a n d f or safet y a n d will be  f oll o we d f or D O R, P F S, a n d 
O S.  S u bjects will recei ve treat me nt u ntil disease pr o gressi o n, deat h, u nacce pta ble t o xicit y, or c o nse nt 
wit h dra wal.  
A n i nteri m f utilit y a nal ysis is pla n ne d w he n t he first 3 0  s u bjects i n C o h ort 2 ha ve bee n treate d a n d 
e val uate d f or res p o nse or per ma ne ntl y disc o nti n ue d st u d y treat me nt beca use of disease pr o gressi o n, 
wit h dra wal of c o nse nt, or deat h.  C o h ort 2 will  be ter mi nate d f or f utilit y if ≤ 1 0 of t he 3 0 s u bjects ha ve 
res p o n de d (ie, C R or P R) base d o n assess me nts pr o vi de d b y t he I R C.  A ti mel y assess me nt of res p o nse 
will be perf or me d t o a v oi d t he ris k of o vere nr oll me nt.  
T o better u n dersta n d t he safet y a n d efficac y of I N C B 0 5 0 4 6 5, a n a d diti o nal 3 0 s u bjects will be e nr olle d 
i nt o o ne of t he t w o treat me nt re gi me ns ( A or B) bei n g e val uate d i n t his St u d y .  T he treat me nt re gi me n 
will be selecte d after e nr oll me nt is c o m plete d f or C o h ort 2  (ie, 6 0 s u bjects e nr olle d) a n d after 
e val uati o n of e mer gi n g safet y a n d efficac y data fr o m t his a n d ot her  m o n ot hera p y st u dies of 
I N C B 0 5 0 4 6 5 i n N H L.  O nce a treat me nt re gi me n is selecte d, t he n o n-selecte d treat me nt re gi me n will 
be cl ose d t o f urt her e nr oll me nt.  S u bjects recei vi n g t he  n o n -selecte d treat me nt re gi me n ma y s witc h t o 
t he selecte d treat me nt re gi me n or re mai n o n t heir c urre nt treat me nt re gi me n, pr o vi de d t he s u bject has 
n ot met st u d y -treat me nt wit h dra wal criteria a n d t here are n o safet y c o ncer ns f or t heir c urre nt treat me nt 
re gi me n.  There will be n o re -baseli ni n g f or s u bjects w h o s witc h treat me nt re gi me ns  a n d all s u bjects 
will c o nti n ue t o f oll o w t he sa me assess me nt sc he d ule . 
St u d y P o p ul ati o n:   S u bjects wit h hist ol o gicall y c o nfir me d M Z L, i ncl u di n g e xtra n o dal, n o dal, a n d 
s ple nic s u bt y pes, w h o pre vi o usl y recei ve d 1 or m ore li nes of s yste mic t hera p y, i ncl u di n g at least 
1 a nti-C D 2 0 a nti b o d y, wit h d oc u me nte d pr o gressi o n or d oc u me nte d fail ure t o ac hie ve C R or P R after 
t he m ost rece nt s yste mic treat me nt re gi me n. 
Ke y I ncl usi o n Criteri a:  
•  Me n a n d w o me n, a ge d 1 8 or ol der (e xce pt i n S o ut h K orea, a ge d 1 9 or ol der) . 
•  Ra di o gra p hicall y meas ura ble l y m p ha de n o pat h y or e xtra n o dal l y m p h oi d mali g na nc y ( defi ne d as t he 
prese nce of ≥ 1 lesi o n t hat meas ures >  1. 5 c m i n t he l o n gest tra ns verse dia meter  ( L Di) a n d ≥ 1. 0 c m 
i n t he l o n gest per pe n dic ular dia meter  as assesse d b y C T or ma g netic res o na nce i ma gi n g ( M RI) . 
-  S u bjects wit h s ple nic M Z L w h o d o n ot meet t he ra di o gra p hicall y meas ura ble disease criteria 
descri be d herei n are eli gi ble f or partici pati o n pr o vi de d that b o ne marr o w i nfiltrati o n of M Z L is 
hist ol o gicall y c o nfir me d . 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

T A B L E O F C O N T E N T S  
S Y N O P SI S  ...................................................................................................................................... 3 
LI S T O F A B B R E VI A TI O N S ........................................................................................................ 1 3  
1.  
I N T R O D U C TI O N ...................................................................................................... 1 5 
1. 1.  
Mar gi nal Z o ne L y m p h o ma ......................................................................................... 1 5  
1. 1. 1.  
E xtra n o dal M Z L ( M A L T)  .......................................................................................... 1 5 
1. 1. 2.  
N o dal M Z L ................................................................................................................. 1 6  
1. 1. 3.  
S ple nic M Z L  ............................................................................................................... 1 6 
1. 2.  
Treat me nt f or Mar gi nal Z o ne L y m p h o ma  .................................................................. 1 7 
1. 2. 1.  
I br uti ni b ...................................................................................................................... 1 8 
1. 3.  
I N C B 0 5 0 4 6 5 ............................................................................................................... 1 8 
1. 4.  
St u d y Rati o nale ........................................................................................................... 2 0  
1. 5.  
P ote ntial Ris ks a n d Be nefits of t he Treat me nt Re gi me n  ............................................ 2 1 
2.  
S T U D Y O BJ E C TI V E S A N D  E N D P OI N T S  .............................................................. 2 2 
3.  
S U BJ E C T E LI GI BI LI T Y  ........................................................................................... 2 3 
3. 1.  
S u bject I ncl usi o n Criteria  ........................................................................................... 2 3 
3. 2.  
S u bject E xcl usi o n Criteria .......................................................................................... 2 5  
4.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 2 7 
4. 1.  
O verall St u d y Desi g n  .................................................................................................. 2 7 
4. 2.  
Meas ures Ta ke n t o A v oi d Bias  ................................................................................... 2 9 
4. 3.  
N u m ber of S u bjects .................................................................................................... 2 9  
4. 3. 1.  
Pla n ne d N u m ber of S u bjects ...................................................................................... 2 9  
4. 3. 2.  
Re place me nt of S u bjects  ............................................................................................. 2 9 
4. 4.  
D urati o n of Treat me nt a n d S u bject Partici pati o n  ....................................................... 3 0 
4. 5.  
O verall St u d y D urati o n  ............................................................................................... 3 0 
4. 6.  
St u d y Ter mi nati o n ...................................................................................................... 3 0  
5.  
T R E A T M E N T  ............................................................................................................ 3 1 
5. 1.  
Treat me nt Assi g n me nt  ................................................................................................ 3 1 
5. 1. 1.  
S u bject N u m beri n g a n d Treat me nt Assi g n me nt ......................................................... 3 1  
5. 1. 2.  
Ra n d o mizati o n a n d Bli n di n g ...................................................................................... 3 1  
5. 2.  
I N C B 0 5 0 4 6 5 ............................................................................................................... 3 1 
5. 2. 1.  
Descri pti o n a n d A d mi nistrati o n  .................................................................................. 3 1 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

5. 2. 2.  
S u p pl y, Pac ka gi n g, a n d La beli n g ............................................................................... 3 2  
5. 2. 3.  
St ora ge ........................................................................................................................ 3 2  
5. 2. 4.  
I nstr ucti o n t o S u bjects f or Ha n dli n g I N C B 0 5 0 4 6 5 .................................................... 3 2 
5. 3.  
Treat me nt C o m plia nce  ................................................................................................ 3 3 
5. 4.  
Treat me nt I nterr u pti o ns a n d A dj ust me nts  .................................................................. 3 3 
5. 4. 1.  
Criteria a n d Pr oce d ures f or D ose I nterr u pti o ns a n d Re d ucti o ns of 
I N C B 0 5 0 4 6 5 ............................................................................................................... 3 3 
5. 4. 1. 1.  
D ose M o dificati o ns  ..................................................................................................... 3 3 
5. 4. 2.  
S u p p orti ve Care G ui deli nes f or Diarr hea/ C olitis  ....................................................... 3 5 
5. 4. 3.  
S u p p orti ve Care G ui deli nes f or Ne utr o pe nia a n d T hr o m b oc yt o pe nia ....................... 3 7  
5. 4. 4.  
Defi niti o n f or I m m u ne- Relate d A d verse E ve nts  ........................................................ 3 7 
5. 5.  
St u d y Treat me nt Disc o nti n uati o n ............................................................................... 3 8  
5. 5. 1.  
Criteria f or St u d y Treat me nt Disc o nti n uati o n  ............................................................ 3 8 
5. 5. 2.  
Pr oce d ures f or St u d y Treat me nt Disc o nti n uati o n ....................................................... 3 8  
5. 6.  
C o nc o mita nt Me dicati o ns  ........................................................................................... 3 9 
5. 6. 1.  
P ne u m ocystis Jir ovecii  P ne u m o nia Pr o p h yla xis ........................................................ 3 9 
5. 6. 2.  
Restricte d Me dicati o ns  ............................................................................................... 3 9 
5. 6. 3.  
Pr o hi bite d Me dicati o ns  ............................................................................................... 4 0 
5. 7.  
Criteria f or St u d y Disc o nti n uati o n  .............................................................................. 4 0 
5. 8.  
Treat me nt After t he E n d of t h e St u d y ......................................................................... 4 0  
6.  
S T U D Y A S S E S S M E N T S  .......................................................................................... 4 1 
6. 1.  
Scree ni n g  .................................................................................................................... 4 6 
6. 2.  
Treat me nt  .................................................................................................................... 4 7 
6. 3.  
E n d of Treat me nt ........................................................................................................ 4 7  
6. 4.  
F oll o w- U p  ................................................................................................................... 4 7 
6. 4. 1.  
Safet y F oll o w -U p  ........................................................................................................ 4 7 
6. 4. 2.  
Disease Stat us F oll o w -U p  ........................................................................................... 4 7 
6. 4. 3.  
S ur vi val F oll o w- U p  .................................................................................................... 4 8 
6. 5.  
E n d of St u d y ............................................................................................................... 4 8  
6. 6.  
U nsc he d ule d Visits ..................................................................................................... 4 8  
7.  
C O N D U C T O F S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ........................... 4 9 
7. 1.  
A d mi nistrati o n of I nf or me d C o nse nt F or m ................................................................ 4 9  
7. 2.  
I nteracti ve We b Res p o nse Tec h n ol o g y Pr oce d ure ..................................................... 4 9 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 8 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

7. 3.  
De m o gra p h y a n d Me dical Hist or y .............................................................................. 4 9  
7. 3. 1.  
De m o gra p hics a n d Ge neral Me dical Hist or y  ............................................................. 4 9 
7. 3. 2.  
Disease C haracteristics a n d Treat me nt Hist or y  .......................................................... 4 9 
7. 4.  
Pri or a n d C o nc o mita nt Me dicati o ns a n d Pr oce d ures .................................................. 4 9  
7. 5.  
Safet y Assess me nts  ..................................................................................................... 4 9 
7. 5. 1.  
A d verse E ve nts ........................................................................................................... 4 9  
7. 5. 2.  
C o m pre he nsi ve P h ysical E xa mi nati o n  ....................................................................... 5 0 
7. 5. 3.  
Disease - S pecific P h ysical E xa mi nati o n ..................................................................... 5 0 
7. 5. 4.  
Vital Si g ns  .................................................................................................................. 5 0 
7. 5. 5.  
Electr ocar di o gra ms  ..................................................................................................... 5 0 
7. 5. 5. 1.  
Ti me d Electr ocar di o gra m s .......................................................................................... 5 1 
7. 5. 6.  
E C O G Perf or ma nce Stat us  ......................................................................................... 5 1 
7. 5. 7.  
La b orat or y Assess me nts  ............................................................................................. 5 1 
7. 5. 7. 1.  
C he mistr y a n d He mat ol o g y ........................................................................................ 5 1  
7. 5. 7. 2.  
Pre g na nc y Testi n g ...................................................................................................... 5 1  
7. 5. 7. 3.  
Ser ol o g y ...................................................................................................................... 5 1  
7. 6.  
Efficac y Assess me nts  ................................................................................................. 5 2 
7. 6. 1.  
C o m p ute d T o m o gra p h y Sca n or Ma g netic Res o na nce I ma gi n g ................................ 5 2  
7. 6. 2.  
B o ne Marr o w E xa mi nati o n ......................................................................................... 5 2  
 
5 3  
7. 6. 4.  
I n de pe n de nt Re vie w C o m mittee ................................................................................. 5 3 
 
5 3  
 
5 3  
 
5 4  
 
5 4  
 
5 4  
 
. 5 4 
 
5 4  
 
5 4  
 
5 4  
 
5 5  
7. 9.  
Ot her St u d y Pr oce d ures  .............................................................................................. 5 5 
7. 9. 1.  
Distri b uti o n of S u bject  Re mi n der Car ds ..................................................................... 5 5 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 9 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

7. 9. 2.  
Data C ollecti o n f or S ur vi val F oll o w- U p  .................................................................... 5 5 
8.  
S A F E T Y M O NI T O RI N G A N D R E P O R TI N G  ......................................................... 5 5 
8. 1.  
A d verse E ve nts ........................................................................................................... 5 5  
8. 1. 1.  
Defi niti o ns  .................................................................................................................. 5 5 
8. 1. 2.  
Re p orti n g .................................................................................................................... 5 5  
8. 2.  
La b orat or y Test A b n or malities  ................................................................................... 5 7 
8. 3.  
Seri o us A d verse E ve nts  .............................................................................................. 5 7 
8. 3. 1.  
Defi niti o ns  .................................................................................................................. 5 7 
8. 3. 2.  
Re p orti n g .................................................................................................................... 5 8  
8. 4.  
E mer ge nc y U n bli n di n g of Treat me nt Assi g n me nt ..................................................... 5 9  
8. 5.  
A d verse E ve nts of S pecial I nterest  ............................................................................. 5 9 
8. 6.  
Pre g na nc y ................................................................................................................... 5 9  
8. 7.  
War ni n gs a n d Preca uti o ns .......................................................................................... 6 0  
8. 8.  
I n de pe n de nt Data M o nit ori n g C o m mittee .................................................................. 6 0 
8. 9.  
Pr o d uct C o m plai nts .................................................................................................... 6 0  
9.  
S T A TI S TI C S  .............................................................................................................. 6 1 
9. 1.  
St u d y P o p ulati o ns ....................................................................................................... 6 1  
9. 2.  
Selecti o n of Sa m ple Size  ............................................................................................ 6 1 
9. 3.  
Le vel of Si g nifica nce .................................................................................................. 6 1  
9. 4.  
Statistical A nal yses  ..................................................................................................... 6 1 
9. 4. 1.  
Efficac y A nal yses  ....................................................................................................... 6 2 
9. 4. 1. 1.  
Pri mar y Efficac y A nal yses  ......................................................................................... 6 2 
9. 4. 1. 2.  
Sec o n dar y Efficac y A nal yses  ..................................................................................... 6 2 
9. 4. 1. 3.  
Ot her Efficac y A nal yses  ............................................................................................. 6 3 
9. 4. 2.  
Safet y A nal yses  .......................................................................................................... 6 3 
9. 4. 2. 1.  
A d verse E ve nts ........................................................................................................... 6 3  
9. 4. 2. 2.  
Cli nical La b orat or y Tests  ........................................................................................... 6 3 
9. 4. 2. 3.  
Vital Si g ns  .................................................................................................................. 6 4 
9. 4. 2. 4.  
Electr ocar di o gra ms  ..................................................................................................... 6 4 
9. 4. 2. 5.  
A d verse E ve nts of S pecial I nterest  ............................................................................. 6 4 
 
6 4  
 
6 4  
9. 5.  
A nal yses f or t he Data M o nit ori n g C o m mittee ............................................................ 6 5  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 0 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

9. 6.  
I nteri m A nal ysis .......................................................................................................... 6 5 
1 0.  
E T HI C A L C O N SI D E R A TI O N S A N D A D MI NI S T R A TI V E 
P R O C E D U R E S  .......................................................................................................... 6 5 
1 0. 1.  
I n vesti gat or Res p o nsi bilities ....................................................................................... 6 5 
1 0. 2.  
Acc o u nta bilit y, Ha n dli n g, a n d Dis p osal of St u d y Dr u g ............................................. 6 7  
1 0. 3.  
Data Ma na ge me nt  ....................................................................................................... 6 7 
1 0. 4.  
Data Pri vac y a n d C o nfi de ntialit y of St u d y Rec or ds ................................................... 6 8  
1 0. 5.  
Fi na ncial Discl os ure  ................................................................................................... 6 8 
1 0. 6.  
P u blicati o n P olic y  ....................................................................................................... 6 8 
1 1.  
R E F E R E N C E S  ........................................................................................................... 7 0 
A P P E N DI X  A.  I N F O R M A TI O N R E G A R DI NG E F F E C TI V E N E S S O F 
C O N T R A C E P TI V E M E T H O D S ............................................................................... 7 3  
A P P E N DI X  B.  E A S T E R N C O O P E R A TI V E O N C O L O G Y G R O U P 
P E R F O R M A N C E S C O R E S  ....................................................................................... 7 4 
A P P E N DI X  C.  L U G A N O C L A S SI FI C A TI O N F O R R E S P O N S E A S S E S S M E N T 
( C T-B A S E D O N L Y)  .................................................................................................. 7 5 
A P P E N DI X  D.  C Y P 3 A I N HI BI T O R S A N D  I N D U C E R S ........................................................ 7 7 
A P P E N DI X  E.  P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S  ............................ 8 3 
 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 1 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

LI S T O F A B B R E VI A TI O N S 
T he f oll o wi n g a b bre viati o ns a n d s pecial ter ms are use d i n t his cli nical st u d y Pr ot oc ol. 
A b bre vi ati o n  
Defi niti o n  
A E  
ad verse eve nt  
A L T  
ala ni ne a mi n otra nsferase 
A N C  
abs ol ute ne utr o p hil c o u nt  
A S T  
as partate a mi n otra nsferase 
B T K  
Br ut o n 's t yr osi ne ki nase 
C F R  
C o de of Fe deral Re g ulati o ns  
CI  
c o nfi de nce i nter val  
 
 
C M R 
c o m plete meta b olic res p o nse  
C M V  
c yt o me gal o vir us  
C R  
c o m plete res p o nse  
C R R  
c o m plete res p o nse rate  
C S R  
Cli nical St u d y Re p ort  
C T  
c o m p ute d t o m o gra p h y  
C T C A E 
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C Y P  
c yt oc hr o me P 4 5 0  
D L B C L  
diff use lar ge B -cell l y m p h o ma  
D N A  
de o x yri b o n ucleic aci d  
D O R  
d urati o n of res p o nse  
E C G  
electr ocar di o gra m  
E C O G  
Easter n C o o perati ve O nc ol o g y Gr o u p  
e C R F 
electr o nic case re p ort f or m  
E O T  
e n d of treat me nt  
 
 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
GI  
gastr oi ntesti nal  
H Bs A g  
he patitis B s urface a nti ge n  
H B V  
he patitis B vir us  
H C V  
he patitis C vir us  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act of 1 9 9 6  
HI V  
h u ma n i m m u n o deficie nc y vir us  
 
 
I B 
I n vesti gat or's Br oc h ure 
I C F 
inf or me d co nse nt f or m  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 3 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A b bre vi ati o n  
Defi niti o n  
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
I E C 
i n de pe n de nt et hics c o m mittee 
I N 
I n vesti gat or N otificati o n 
ir A E 
i m m u ne-relate d a d verse e v e nt 
I R B 
i nstit uti o nal re vie w b oar d 
I R C 
I n de pe n de nt Re vie w C o m mittee 
I W R S 
i nteracti ve we b res p o nse s yste m  
L D i 
l o n gest tra ns verse dia meter  
M A L T  
m u c osa -ass ociate d l y m p h oi d tiss ue  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
 
 
M RI  
ma g netic res o na nce i ma gi n g  
M Z L  
mar gi nal z o ne l y m p h o ma  
N CI  
Nati o nal Ca ncer I nstit ute  
N F -κ B  
n uclear fact or -κ B  
 
 
N H L  
n o n -H o d g ki n 's l y m p h o ma 
O R R  
o bjecti ve res p o nse rate  
O S  
o verall s ur vi val  
P D  
pr o gressi ve disease  
P F S  
pr o gressi o n -free s ur vi val 
PJ P  
P ne u m ocystis jir ove cii p ne u m o nia  
 
 
 
res p o nse 
P O  
orall y  
P P  
per pr ot oc ol  
P R  
partial res p o nse  
Q D  
o nce dail y  
R N A  
ri b o n ucleic aci d 
S A E  
seri o us a d verse e ve nt 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
U L N  
u p per li mit of n or mal  
 
 
W B C 
w hite bl o o d cell  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

1.  
I N T R O D U C TI O N 
1. 1.  
M ar gi n al Z o ne L y m p h o m a  
I n t he U nite d States, N H L is t he se ve nt h m ost c o m m o n ca ncer affecti n g a d ults.  Bet wee n 1 9 7 5 
a n d 2 0 1 3, t he i nci de nce of N H L i n t he U nite d States nearl y d o u ble d, a n d m ore t ha n 7 2, 0 0 0 ne w 
cases are e x pecte d t o be dia g n ose d i n 2 0 1 6  (L y m p h o ma Researc h F o u n dati o n 2 0 1 7a ).  I n 
E ur o pe, N H L is t he 1 1t h m ost c o m m o n ca ncer, w it h a p pr o xi matel y 9 3, 5 0 0 ne w cases dia g n ose d 
i n 2 0 1 2 ( 3 % of t he t otal).  N o n - H o d g ki n l y m p h o ma is t he 1 0t h m ost c o m m o n ca ncer w orl d wi de, 
wit h nearl y 3 8 6, 0 0 0 ne w cases dia g n ose d i n 2 0 1 2 ( 3 % of t he t otal ; Ferla y  et al 2 0 1 3).  
Mar gi nal z o ne l y m p h o mas, a gr o u p of i n d ole nt (s l o w- gr o wi n g) N H L B-cell l y m p h o mas, acc o u nt 
f or a p pr o xi matel y 1 0% of all hist ol o gicall y dia g n ose d N H L cases  i n wester n c o u ntries 
(C u ne o a n d Cast ol di 2 0 0 6 ).  T he a vera ge a ge at dia g n osis is 6 0 years, a n d it is sli g htl y m o re 
c o m m o n i n w o me n t ha n i n me n ( L y m p h o ma Researc h F o u n dati o n 2 0 1 7 b ).   
Mar gi nal z o ne l y m p h o mas ori gi nate fr o m me m or y B l y m p h oc ytes n or mall y prese nt i n a disti nct 
micr o a nat o mic c o m part me nt calle d t he " mar gi nal z o ne" of t he sec o n dar y l y m p h oi d f ollicles 
(Zi nza ni  2 0 1 2).  T he s u bt y pes of M Z L s hare a si milar i m m u n o p he n ot y pe t hat are p ositi ve f or t he 
B-cell mar kers C D 1 9, C D 2 0, a n d C D 2 2 a n d ne gati ve f or C D 5, C D 1 0, a n d us uall y C D 2 3 
(S wer dl o w et al 2 0 1 6 ). 
T he latest l y m p h o ma classificati o n i de ntifies 3 s u bt y pes of M Z L acc or di n g t o t he i n v ol ve d site 
a n d c haracteristic m olec ular fi n di n gs ( S wer dl o w et al 2 0 1 6 ): 
•  E xtra n o dal M Z L of M A L T  t y pe, 
•  N o dal M Z L, a n d 
•  S ple nic M Z L . 
1. 1. 1.  
E xtr a n o d al M Z L ( M A L T)  
E xtra n o dal M Z L is t he m ost c o m m o n f or m of M Z L acc o u nti n g f or t w o-t hir ds of all cases per 
year a n d c o m p oses  a p pr o xi matel y 5% of all N H L s (L y m p h o ma Researc h F o u n dati o n 2 0 1 7 b ).  
E xtra n o dal M Z L ( M A L T) differs fr o m s ple nic a n d n o dal M Z L d ue i n part t o its i n v ol ve me nt i n 
e pit helial tiss ues, i ncl u di n g t he st o mac h, l u n gs, sali var y gla n ds, s mall b o wel, t h yr oi d, a n d 
lac hr y mal gla n ds.  E xtra n o dal M Z L is h y p ot hesize d t o arise fr o m me m or y B cells wit h t he 
a bilit y t o differe ntiate i nt o mar gi nal z o ne cells a n d plas ma cells ( N o va k et al 2 0 1 1 ).  F o ur 
rec urre nt c hr o m os o mal tra nsl ocati o ns ha ve bee n s pecificall y ass ociate d wit h t he pat h o ge nesis of 
e xtra n o dal M Z Ls  (Bert o ni a n d Z ucca 2 0 0 6 ): 
•  t( 1 1; 1 8)( q 2 1; q 2 1), 
•  t( 1; 1 4)( p 2 2; q 3 2),  
•  t( 1 4; 1 8)( q 3 2; q 2 1), a n d 
•  t( 3; 1 4)( p 1 4. 1; q 3 2).  
T he o nc o ge nic acti vit y of t( 1 1; 1 8), t( 1 4; 1 8), a n d t( 1; 1 4) is attri b uta ble t o t he pat h o p h ysi ol o gic 
i ncreases i n t he acti vati o n of N F -κ B  t hr o u g h t he B C L1 0/ M A L T 1 si g nali n g c o m ple x, t here b y 
e n ha nci n g t he pr oliferati o n a n d s ur vi val of e xtra n o dal M Z L cells ( Sa gaert  et al 2 0 0 7 ).  T he ot her 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 5 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

k n o w n tra nsl ocati o n, t( 3; 1 4)( p 1 3; q 3 2), f uses t he F O X P 1 ge ne o n c hr o m os o me 3 t o t he I g H ge ne 
a n d res ults i n i ncrease d n uclear le vels of t he F O X P 1 tra nscri pti o n fact or  (Wl o dars ka et al 2 0 0 5 ).   
I ncreasi n g e vi de nce s u g gests t hat e xtra n o dal M Z L ma y be relate d t o c hr o nic i m m u ne reacti o ns 
ca use d b y bacterial (ie , Helic o b acter pyl ori -i n d uce d c hr o nic gastritis a n d C a m pyl o b acter 
psitt aci ), viral (ie, H C V i nfecti o n ), or a ut oi m m u ne sti m uli (ie, hist or y of Sj ö gre n's s y n dr o me) 
(A m br osetti et al 2 0 0 4 , Ra m os -Casals  et al 2 0 0 7 , Sris ka n daraja h  a n d Dear de n  2 0 1 6). 
M ost patie nts wit h e xtra n o dal M Z L prese nt wit h A n n Ar b or sta ge I E disease (i e, e xtra n o dal 
disease li mite d t o t he  site of ori gi n) wit h o ut b o ne marr o w  or peri p heral l y m p h n o de i n v ol ve me nt.  
T he cli nical fi n di n gs a n d prese nti n g s y m pt o ms of e xtra n o dal M Z L are ge nerall y relate d t o t he 
pri mar y l ocati o n.   T he st o mac h is t he m ost c o m m o n site of l ocalizati o n, acc o u nti n g f or 
a p pr o xi matel y o ne-t hir d of cases of e xtra n o dal M Z L ( Zi nza ni 2 0 1 2 ).  A d va nce d disease at 
dia g n osis is m ore c o m m o n i n patie nts wit h n o n gastric e xtra n o dal M Z L , wit h nearl y  5 0 % of t h ose 
wit h n o n- GI  l y m p h o ma prese nti n g wit h disse mi nate d disease c o m pare d wit h a p pr o xi matel y 2 5 % 
wit h gastric l y m p h o ma ( Tr oc h  et al 2 0 1 1 ).   
Patie nts wit h e xtra n o dal M Z L ha ve a fa v ora ble o utc o me wit h a n a vera ge 5 -year O S  of m ore t ha n 
8 5 % i n m ost series.  A st u d y i n a n u nselecte d p o p ulati o n of patie nts wit h M Z L s u bt y pes i ncl u de d 
i n t he S E E R data base re veale d a w orse pr o g n osis f or patie nts wit h res pirat or y a n d GI 
l y m p h o mas ( 5- year l y m p h o ma-relate d deat h of 9. 5 %- 1 4. 3 %) c o m pare d wit h t h ose wit h disease 
at oc ular a d ne xal a n d e n d ocri ne sites ( 4. 5 %- 7. 8 %; p < 0. 0 0 0 1) ( Olsze ws ki  a n d Castill o 2 0 1 3 ).   
1. 1. 2.  
N o d al M Z L 
N o dal M Z L is a pri mar y n o dal l y m p h o ma i n t he a bse nce of pre vi o us or c o nc urre nt i n v ol ve me nt 
of a n y e xtra n o dal site.  It is rare, c o m p osi n g 1 0 % of M Z L cases a n d a p pr o xi matel y 2 % of all 
N H Ls  (L y m p h o ma Researc h F o u n dati o n 2 0 1 7 b ).  T he dia g n osis of n o dal M Z L is base d o n 
e val uati o n of n o dal bi o ps y i n t he c o nte xt of t he cli nical prese ntati o n .  N o s pecific dia g n ostic 
hall mar ks of n o dal M Z L , i ncl u di n g t y pical c yt o ge netic a b n or malities, ha ve bee n re p orte d.  
M or p h ol o gicall y a n d acc or di n g t o i m m u n o p he n o t y pe, cases of n o dal M Z L ca n rese m ble eit her 
e xtra no dal ( M A L T) M Z L o r s ple nic M Z L. 
N o dal M Z Ls a p pear as a heter o ge ne o us disease wit h t u m ors h y p ot hesize d t o ori gi nate fr o m 
differe nt s u bsets of mar gi nal z o ne B cells, i ncl u di n g vir gi n B cells e x pressi n g u n m utate d V H  
ge nes, me m or y B cells s h o wi n g s o matic m utati o ns, a n d ger mi na l ce nter B cells (C o nc o ni 
et al 2 0 0 1). 
M ost patie nts wit h n o dal M Z L prese nt wit h disse mi nate d peri p heral a n d a b d o mi nal n o dal 
i n v ol ve me nt.  Less t ha n half of t he patie nts prese nt wit h b o ne marr o w  i n v ol ve me nt, a n d 
peri p heral b l o o d i n v ol ve me nt is q uite rare (Ar mita ge  a n d Weise n b ur ger 1 9 9 8, Ber ger  et al 2 0 0 0 , 
N o n - H o d g ki n's L y m p h o ma Classificati o n Pr oject 1 9 9 7). 
Patie nts wit h n o dal M Z L ha ve a n a vera ge 5 -year O S  of 6 0 % t o 7 0 % a n d a 5- year e ve nt -free 
s ur vi val of a p pr o xi matel y 3 0 %. 
1. 1. 3.  
S ple nic M Z L  
S ple nic M Z L gr o ws i n a mar gi nal z o ne patter n i n t he s plee n; h o we ver, n o cli nical o verla p occ urs 
wit h e xtra n o dal a n d n o dal M Z Ls a n d, as s uc h, is  cli nicall y disti nct.   S ple nic M Z L c o nstit utes 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 6 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

a p pr o xi matel y 2 0 % of all M Z L cases a n d < 1 % of all N H Ls  (Ar mita ge  a n d Weise n b ur ger 1 9 9 8 , 
L y m p h o ma  Researc h Or ga n izati o n 2 0 1 7 b).  
S ple nic M Z L is h y p ot hesize d t o arise fr o m a p ost– ger mi nal ce nter me m or y B cell of s ple nic t y pe  
(S wer dl o w et al 2 0 1 6 ).  Alt h o u g h t he precise m olec ular pat h o ge nesis has n ot bee n clearl y 
defi ne d, ac q uire d s o matic m utati o ns as see n wit h ot her ca ncers ma y pla y a n i m p orta nt r ole.  
O vere x pressi o n of ge nes i n v ol ve d i n B- cell rece pt or si g nali n g, t u m or necr osis si g nali n g, a n d 
N F -κ B acti vati o n ha ve bee n o bser ve d a n d warra nt m ore s yste mic st u dies of pat h o ge nesis 
(R uiz -Ballester os  et al 2 0 0 5 ).  
Si milar t o e xtra n o dal M Z L, t here is a n ass ociati o n bet wee n s ple nic M Z L a n d i nfecti o n wit h 
vir uses, s uc h as H C V a n d Ka p osi' s sarc o ma-ass ociate d her pes vir us ( Her mi ne  et al 2 0 0 2 , 
Be na ve nte et al 2 0 1 1 ).  
Patie nts wit h s ple nic M Z L t y picall y prese nt wit h s ple n o me gal y, l y m p h oc yt osis, a n d c yt o pe nias 
pri maril y  ca use d b y h y pers ple nis m a n d less fre q ue ntl y t o a ut oa nti b o dies or b o ne marr o w 
i nfiltrati o n.  U nli ke m ost ot her N H Ls, l y m p ha de n o pat h y a n d i n v ol ve me nt of e xtral y m p hatic 
or ga ns is rare ( Fra nc o  et al 2 0 0 3 ).  A p pr o xi matel y 9 0 % or m ore of cases are Sta ge I V disease at 
prese ntati o n.  
T he c o urse of s ple nic M Z L is ge nerall y e xtre mel y i n d ole nt, wit h a me dia n O S > 1 0 years; 
h o we ver, a s u bset of cases c haracterize d b y a m ore a g gressi ve disease c o urse e x hi bite d a me dia n 
s ur vi val of 1 8 m o nt hs (C hac ó n et al 2 0 0 2 ).    
1. 2.  
Tre a t me nt f or M ar gi n al Z o ne L y m p h o m a 
Treat me nt selecti o n f or patie nts wit h M Z L de pe n ds o n disease c haracteristics, i ncl u di n g t y pe, 
sta ge, a n d l ocati o n as well as ot her patie nt c haracteristics, s uc h as a ge a n d o verall healt h.  
Beca use  M Z L is m ost oft e n a sl o w - gr o wi n g disease, a "watc h -a n d-wait " a p pr oac h is a p pr o priate 
u ntil s y m pt o ms a p pear. 
H. pyl ori – p ositi ve gastric M A L T l y m p h o ma is i nitiall y treate d wit h a nti bi otics i n c o m bi nati o n 
wit h pr ot o n p u m p i n hi bit ors.  I n cases w here gastric M A L T l y m p h o ma rela pses or bec o mes 
refract or y after a nti bi otic t hera p y, treat me nt o pti o ns i ncl u de rit u xi ma b ( RI T U X A N® ) wit h or 
wit h o ut c he m ot hera p y, c hl ora m b ucil ( or ot her al k ylati n g a ge nts), ra diati o n t hera p y, a n d s ur ger y. 
I n patie nts wit h s y m pt o matic n o n- gastric M A L T l y m p h o ma, treat me nt ma y i ncl u de s ur ger y f or 
certai n sites (l u n g, breast) or  ra diati o n t hera p y, as nee de d.  M ore a d va nce d disease is us uall y 
i nitiall y treate d wit h i m m u n ot hera p y a n d c he m ot hera p y, i ncl u di n g be n da m usti ne ( T R E A N D A® ) 
pl us rit u xi ma b a n d R- C H O P (rit u xi ma b, c ycl o p h os p ha mi de, d o x or u bici n, vi ncristi ne, a n d 
pre d nis o ne).  
W he n treat me nt is necessar y i n patie nts wit h s y m pt o matic n o dal M Z L, o pti o ns i ncl u de ra diati o n 
t hera p y, c he m ot hera p y a n d/ or i m m u n ot hera p y, a n d ot her treat me nts c o m m o nl y use d i n ot her 
t y pes of sl o w- gr o wi n g l y m p h o mas, s uc h as f ollic ular l y m p h o ma.  
S o me patie nts wit h s ple nic M Z L ma y u n der g o a s ple nect o m y.  Patie nts i neli gi ble f or s ur ger y 
ma y recei ve l o w - d ose ra diati o n of t he s plee n or rit u xi ma b wit h or wit h o ut c he m ot hera p y.  
I n s o me cases, beca use of t he ass ociati o n of t his t y pe of l y m p h o ma wit h H C V, i nterfer o n wit h or 
wit h o ut a nti viral t hera p y ma y be gi ve n t o patie nts w h o s h o w e vi de nce of H C V i nfecti o n .  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

I n Ja n uar y 2 0 1 7, i br uti ni b (I M B R U VI C A® ) was gra nte d accelerate d a p pr o val fr o m t he U S F D A 
f or use as treat me nt of patie nts wit h M Z L w h o re q uire s yste mic t hera p y a n d ha ve recei ve d at 
least 1 pri or a nti -C D 2 0 – base d t hera p y  (see Secti o n  1. 2. 1 ; I m br u vica 2 0 1 7). 
Se veral ot her dr u gs a n d dr u g c o m bi nati o ns are bei n g st u die d i n cli nical trials of M Z L a n d 
i ncl u de che m o t hera p y a ge nts ( be n da m usti ne), m o n ocl o nal a nti b o dies ( bli nat u m o ma b, 
o bi n ut uz u ma b, pe m br oliz u ma b, a n d i brit u m o ma b), a nti b o d y dr u g c o nj u gate ( bre nt u xi ma b), 
s mall m olec ules (i delalisi b, c o pa nlisi b, d u velisi b, T G R - 1 2 0 2, a n d ve net ocla x), pr oteas o me 
i n hi bit or ( b ortez o mi b), i m m u n o m o d ulat ors (le nali d o mi de a n d u blit u xi ma b), a n d 
ra di oi m m u n ot hera p y strate gies (9 0Y- i brit u m o ma b ti u xeta n). 
1. 2. 1.  
I br uti ni b 
I br uti ni b, a first-i n-class, oral, o nce - dail y t hera p y t hat i n hi bits B T K, was a p pr o ve d b y t he F D A 
as treat me nt of patie nts wit h M Z L w h o re q uire s yste mic t hera p y a n d ha ve recei ve d at least 
1 pri or a nti -C D 2 0 – base d t hera p y  (I m br u vica 2 0 1 7).  T he accelerate d a p pr o val was base d o n data 
fr o m a P hase 2, o pe n-la bel, m ulti-ce nter, si n gle-ar m st u d y i n s u bjects wit h M Z L .  T he efficac y 
a nalysis i ncl u de d 6 3 s u bjec ts wit h e xtra n o dal ( M A L T ; n = 3 2), n o dal ( n = 1 7), a n d s ple nic 
( n = 1 4) M Z Ls .  T he me dia n ti me o n st u d y was 1 6. 6 m o nt hs, a n d t he me dia n durati o n of t hera p y 
was 1 1. 7 m o nt hs.   O bjecti ve res p o nse rate was 4 6 %  ( 9 5 % CI:  3 3. 4 %- 5 9. 1 %) as assesse d b y a n 
I R C usi n g a d o pte d I nter nati o nal W or ki n g Gr o u p criteria f or mali g na nt l y m p h o ma; 3. 2 % of 
s u bjects ha d a C R a n d 4 2. 9 % ha d a P R.  T he me dia n ti me t o res p o nse was 4. 5 m o nt hs 
(ra n ge:  2. 3- 1 6. 4 m o nt hs), a n d me dia n D O R  was n ot reac he d (ra n ge:  1 6. 7 m o nt hs t o n ot 
reac he d).  I n t he E U, i br uti ni b has n ot yet recei ve d C o m mittee o n H u ma n M e dici nal Pr o d ucts 
a p pr o val f or M Z L. 
T he m ost c o m m o n A E s ( A Es ≥ 2 0 %) of a n y gra de i ncl u de d t he f oll o wi n g:  fati g ue ( 4 4 %), 
diarr hea ( 4 3 %), a ne mia ( 3 5 %), na usea a n d t hr o m b oc yt o pe nia ( 2 5 % eac h), peri p heral e de ma 
( 2 4 %), c o u g h a n d art hral gia ( 2 2 % eac h), a n d d ys p nea a n d u p per res pirat or y tract i nfecti o n 
( 2 1 %).  A d verse e ve nts ≥ Gra de 3 occ urre d i n 4 0 s u bject s ( 6 3 %); m ost c o m m o n e ve nts were 
a ne mia ( 1 4 %), p ne u m o nia ( 8 %), a n d fati g ue ( 6 %).  Seri o us A Es of a n y gra de occ urre d i n 
2 8 s u bjects ( 4 4 %), wit h Gra de 3/ 4 p ne u m o nia bei n g t he m ost c o m m o n A E ( 5 s u bjects [ 8 %]).  
T hree T E A Es res ulte d i n deat h d ue t o disease pr o gressi o n, cere bra l he m orr ha ge, a n d 
parai nfl ue nza vir us i nfecti o n lea di n g t o m ulti ple or ga n fail ure.  T he m ost c o m m o n A E lea di n g t o 
treat me nt disc o nti n uati o n was diarr hea i n 2 s u bjects ( 3 %). 
1. 3.  
I N C B 0 5 0 4 6 5 
P h os p hati d yli n osit ol 3- ki nases bel o n g t o a fa mil y of li pi d- si g nali n g ki nases t hat p h os p h or ylate 
p h os p h oi n ositi des of t he i n osit ol ri n g ( Ca ntle y  2 0 0 2).  P h os p hati d yli n osit ol 3 ki nases are di vi de d 
i nt o 3 classes ( Class I, II, a n d III) acc or di n g t o t heir str uct ure, re g ulati o n, a n d s u bstrate 
s pecificit y.  Class I PI 3 Ks, w hic h i ncl u de PI 3 K α, PI 3 K β, PI 3 Kγ, a n d PI 3 K δ, are d ual-s pecificit y 
li pi d a n d pr otei n ki nases t hat catal yze t he p h os p h or ylati o n of p h os p hati d yli n osit ol- 4, 5-
bis p h os p hate, gi vi n g rise t o p h os p hati d yli n osit ol- 3, 4, 5-tris p h os p hate.  P h os p hati d yli n osit ol-
3, 4, 5- tris p h os p hate f u ncti o ns as a sec o n d messe n ger t hat c o ntr ols a n u m ber of cell ular pr ocesses, 
i ncl u di n g gr o wt h, s ur vi val, a d hesi o n, a n d mi grati o n.  T he rec o g niti o n t hat a berra nt si g nal 
tra ns d ucti o n occ urs i n mali g na nt B-l y m p h oc ytes via t he PI 3 K pat h wa ys res ulti n g i n disease 
pr o gressi o n has le d t o a f oc us o n a ge nts t hat m o d ulate t hese si g nali n g pat h wa ys.   
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 8 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

I N C B 0 5 0 4 6 5 is a p ote nt i n hi bit or of PI 3 K δ (I C5 0 val ue = 1. 1 ± 0. 5 n M), wit h a p pr o xi matel y 
2 0, 0 0 0-f ol d selecti vit y f or t he ot her PI 3 K fa mil y me m bers.  I N C B 0 5 0 4 6 5 d oes n ot si g nifica ntl y 
i n hi bit ( < 3 0 % i n hi biti o n) a br oa d pa nel of ki nases w he n teste d at a c o nce ntrati o n of 1 0 0 n M 
(refer t o t he I N C B 0 5 0 4 6 5 I n vesti gat or's Br oc h ure [I B]).  I N C B 0 5 0 4 6 5 is p ote nt (I C5 0 val ues of 
≤ 1 0 n M) i n cell-base d assa ys rele va nt t o t he pat h o ge nesis of B -cell mali g na ncies, s uc h as 
PI 3 K δ -me diate d si g nali n g a n d gr o wt h of h u ma n B- cell li nes.  T his effect is n ot d ue t o ge neral 
c yt ot o xicit y.  C o m pare d wit h i n hi biti o n of B- cell pr oliferati o n, I N C B 0 5 0 4 6 5 is si milarl y p ote nt 
i n bl oc ki n g hel per T-cell differe ntiati o n b ut is > 1 0 0 ti mes less p ote nt i n assa ys t hat meas ure 
effects o n h u ma n T -cell a n d nat ural killer cell pr oliferati o n or m o n oc yte f u ncti o n.  T hese data 
s u g gest t hat t he i m pact of I N C B 0 5 0 4 6 5 o n t he h u ma n i m m u ne s yste m will lar gel y be restricte d 
t o B-cell a n d hel per T-cell differe ntiati o n .  T he I C9 0 f or p A K T i n hi biti o n of Pfeiffer cells i n 
h u ma n w h ole bl o o d is 7 7 n M.  Precli nical t o xic ol o g y st u dies s u p p orte d e val uati o n of 
I N C B 0 5 0 4 6 5 i n h u ma n cli nical st u dies (I B). 
I N C B 0 5 0 4 6 5 is bei n g e val uate d as a m o n ot hera p y i n a P hase 1/ 2, d ose-escalati o n a n d e x pa nsi o n 
st u d y (I N C B 5 0 4 6 5- 1 0 1, N C T 0 2 0 1 8 8 6 1; P hilli ps  et al 2 0 1 6).  As of 1 8 A U G 2 0 1 7, data were 
a vaila ble f or 7 2 s u bjects w h o recei ve d I N C B 0 5 0 4 6 5 a d mi nistere d orall y at Q D d oses of 5 m g 
( n = 1), 1 0 m g ( n = 3), 1 5 m g ( n = 3), 2 0 m g ( n  = 3 4), 3 0 m g ( n = 2 7), a n d 4 5 m g ( n = 4).  T he 
me dia n d urati o n of treat me nt was 1 2 2. 5 da ys (ra n ge:  7- 6 9 0).  A d v erse e ve nts o bser ve d i n ≥ 2 0 % 
of s u bjects were na usea ( 3 6 %), diarr hea ( 3 5 %),  fati g ue a n d ras h (eac h 3 1 %), a n d c o u g h a n d 
v o miti n g ( eac h 2 4%).  Ne w or w orse ni n g ≥ Gra de 3 a ne mia, t hr o m b oc yt o pe nia, a n d ne utr o pe nia 
occ urre d i n 7 %, 1 0 %, a n d 2 0 % of s u bjects, res pecti vel y.  N o  ≥ Gra de 3 n o n he mat ol o gical 
treat me nt-relate d A Es were re p orte d i n ≥ 1 0 % of s u bjects.  Seri o us A Es t hat occ urre d i n 
≥ 2 s u bjects i ncl u de d diarr hea ( n = 5) ; p yre xia ( n = 4); c olitis, se psis, a n d h y p ote nsi o n ( n = 3 
eac h); a n d ve ntric ular tac h ycar dia, p ne u m o nia, e xf oliati ve der matiti s, res pirat or y fail ure, 
s y nc o pe, uri nar y tract i nfecti o n, br o nc hitis, a n d bactere mia ( n = 2 eac h).  F o urtee n (1 9 %) of t he 
7 2 s u bjects disc o nti n ue d st u d y treat me nt d ue t o t he f oll o wi n g 1 0 A Es:  diarr hea ( n  = 3); 
e xf oliati ve der matitis  a n d c olitis  ( n = 2 eac h); a n d p ne u m o nitis, ras h, ps oriasis, ne utr o pe nia, 
ple ural eff usi o n, c yt o me gal o vir us c olitis , a n d h y percalce mia ( n = 1 eac h).  N o li v er f u ncti o n test 
a b n or malities > Gra de 1 were re p orte d w hile s u bjects were rece i vi n g st u d y treat me nt.  N o 
d ose- li miti n g t o xicities were i de ntifie d, a n d t he ma xi m u m t olerate d d ose was n ot reac he d. 
P har mac o ki netics a nal ysis s h o we d t he t ma x  is 0. 5 t o 1 h o ur, t he ter mi nal half-life is 
a p pr o xi matel y 8 t o 1 2 h o urs, a n d e x p os ure a p peare d t o be d ose- pr o p orti o nal bet wee n 5 m g Q D 
a n d 4 5 m g Q D at stea d y state.  T he p har mac o d y na mic a nal yses de m o nstrate d r o b ust a n d 
s ustai ne d pat h wa y i n hi biti o n at all d ose le vels teste d (P hilli ps et al 2 0 1 6 ).  Refer t o t he I B f or 
f urt her details (I B). 
As of 1 8 A U G 2 0 1 7, 3 0 o bjecti ve res p o nses as re p orte d b y i n vesti gat ors were o bse r ve d i n 
5 5 e val ua ble s u bjects wit h D L B C L , f ollic ular l y m p h o ma, M Z L , a n d ma ntle cell l y m p h o ma.  
T hese res ults i ncl u de 3 C M Rs  a n d 4 P R s ( 1 P R a n d 3 P M R) a m o n g 9 e val ua ble s u bjects wit h 
M Z L.  Si x o bjecti ve res p o nse s, i ncl u di n g 2 C M Rs, occ urre d b y t he ti me of t he first disease 
assess me nt  ( 9 wee ks), a n d 1 C M R occ urre d ar o u n d t he 1 8- wee k disease assess me nt  visit .  
A m o n g t he 7 o bjecti ve res p o nses, 2 de m o nstrate d 1 0 0 % re d ucti o n i n t heir tar get lesi o ns.  T he 
l o n gest d urati o n of st u d y treat me nt a m o n g s u bjects wit h M Z L  was a p pr o xi matel y  5 7 wee ks ; all 
s u bjects ha ve disc o nti n ue d treat me nt.  Of n ote, n o ne of t he s u bjects wit h M Z L ha d recei ve d pri or 
treat me nt wit h a B T K i n hi bit or. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 1 9 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

1. 4.  
St u d y R ati o n ale  
S u bsta ntial pr o gress has bee n ma de i n defi ni n g t he eti ol o g y a n d critical cell ular a n d m olec ular 
pat h ol o gical e ve nts of M Z Ls.  H o we ver, gi ve n t he rarit y of t he disease, t here re mai ns a lac k of 
lar ge data bases or cli nical data o n t his s u bset of patie nts.  T heref ore, t he decisi o n re gar di n g 
treat me nt strate gies is less well-defi ne d , a n d a c o nti n ue d i m pr o ve me nt i n t he cli nical 
u n dersta n di n g of M Z Ls a n d de vel o p me nt of s pecific t hera pies f or M Z L is warra nte d.   
St u d y I N C B 5 0 4 6 5- 2 0 4 was i nitiall y desi g ne d t o e nr oll 2 c o h orts, of w hic h o ne w o ul d c o m prise 
s u bjects w h o ha d recei ve d pri or treat me nt wit h i br uti ni b.  T he B T K i n hi bit or, i br uti ni b, is  t he 
first-e ver a p pr o ve d treat me nt f or pa tie nts i n t he U nite d States wit h M Z L w h o re q uire s yste mic 
t hera p y a n d ha ve recei ve d at least 1 pri or a nti -C D 2 0 – base d t hera p y ; ap pr o val was base d o n 
accelerate d a p pr o val  a n d a c o nfir mat or y trial is o n g oi n g.  Se veral o bser vati o nal st u dies  ha ve 
s h o w n t hat patie nts wit h ma ntle cell l y m p h o ma a n d c hr o nic l y m p h oc ytic le u ke mia  rela pse after 
treat me nt wit h ibr uti ni b a n d t hat o verall cli nical o utc o me is p o or ( C hea h  et al 2 0 1 5, Ste ve ns a n d 
S p ur ge o n 2 0 1 5 , Marti n  et al 2 0 1 6).  Marti n  et al (2 0 1 6 ) re veale d t hat 1 1 4 patie nt s wit h a vaila ble 
s ur vi val data ha d a me dia n O S of 2. 9 m o nt hs after cessati o n of i br uti ni b.  Gi ve n t he s h ort 
s ur vi val re p orte d after treat me nt wit h i br uti ni b, de vel o pi n g treat me nt o pti o ns i n t he p ost- i br uti ni b 
setti n g is warra nte d.  T his p o p ulatio n re prese nts a n u n met me dical nee d.   Gi ve n t he li mite d 
a vaila bilit y of i br uti ni b (a p pr o ve d f or M Z L i n t he U nite d States  o nl y), o nl y ver y fe w s u bjects are 
eli gi ble f or e nr oll me nt i nt o t he pri or-i br uti ni b c o h ort.  At t he ti me of Pr ot oc ol A me n d me nt 
(Versi o n ) 3, o nl y 2 s u bjects ha ve bee n e nr olle d i nt o C o h ort 1 (s u bjects pre vi o usl y treate d wit h 
i br uti ni b) si nce t he start of t he st u d y i n J U N 2 0 1 7.  T heref ore, C o h ort 1 was cl ose d t o f urt her 
e nr oll me nt f or feasi bilit y reas o ns.  
I N C B 0 5 0 4 6 5 is a p ote nt a n d selecti ve PI 3 K δ i n hi bit or a n d preli mi nar y data has de m o nstrate d 
ra pi d a n d dee p o bjecti ve res p o nses i n s u bjects wit h rela pse d M Z L w h o were naive t o a B T K 
i n hi bit or (see Secti o n  1. 3 ).  T his st u d y is desi g ne d t o f urt her e val uate t he efficac y a n d safet y of 
I N C B 0 5 0 4 6 5 i n s u bjects wit h M Z L t hat has rela pse d after or was refract or y t o pri or s yste mic 
t hera p y.   
All s u bjects wi ll i nitiall y recei ve I N C B 0 5 0 4 6 5 a d mi nistere d orall y at a d ose of 2 0 m g Q D f or 
8 wee ks.  Base d o n a n ex viv o w h ole bl o o d assa y, t he 2 0 m g Q D d ose pr o vi des e x p os ure ra n gi n g 
fr o m a p pr o xi matel y 2-f ol d a b o ve t he I C9 0 at tr o u g h t o 1 9-f ol d a b o ve t he I C9 0 at pea k.  Data fr o m  
S E P  2 0 1 6 s h o w t hat of t he 1 1 N H L s u bjects a d mi nistere d 2 0 m g Q D, 1 0 ac hie ve d a n o bjecti ve 
res p o nse at t he ti me of first disease assess me nt ( 9 wee ks).  H o we ver, a m o n g all e val ua ble 
s u bjects wit h a n o bjecti ve res p o nse ( n = 2 0), 7 ( 3 5 %) disc o nti n ue d st u d y treat me nt d ue t o a n A E.  
C o nse q ue ntl y, after recei vi n g 2 0 m g Q D of I N C B 0 5 0 4 6 5 f or 8 wee ks, s u bjects will recei ve 
eit her 2 0 m g o nce wee kl y (referre d t o as Treat me nt A) or 2. 5 m g Q D of I N C B 0 5 0 4 6 5 (referre d 
t o as Treat me nt B). 
T he 2 0 m g o nce- wee kl y re gi me n is pr o p ose d t o mai ntai n res p o nse w hile pr o vi di n g ti me off fr o m 
pat h wa y i n hi biti o n, w hic h ma y re d uce t he fre q ue nc y of A Es lea di n g t o st u d y treat me nt 
wit h dra wal  (see Secti o n 1. 3 ).  P har mac o d y na mic data fr o m St u d y I N C B 5 0 4 6 5- 1 0 1 s h o we d t hat 
a si n gle d ose of 2 0 m g e x hi bite d ma xi mal i n hi biti o n of A K T i n a n ex viv o p har mac o d y na mic 
assa y, a n d P K m o deli n g s u g gests t hat 2 0 m g o nce wee kl y will 1) ac hie ve ma xi mal i n hi biti o n 
e q ui vale nt t o a p pr o xi matel y 1 0 × I C 9 0, 2) e xcee d t he I C9 0 f or a p pr o xi matel y 3 6 h o urs, 
a n d 3) ha ve mi ni mal t o n o i n hi biti o n f or a p pr o xi matel y half t he d osi n g i nter val.  T his 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 0 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

o nce- wee kl y re gi me n is si milar t o t hat of a n ot her PI 3 K i n hi bit or (c o pa nlisi b), w hic h is 
a d mi nistere d i ntra ve n o usl y o n Da ys 1, 8, a n d 1 5 of a 2 8- da y c ycle a n d w hic h ac hie ve d 
7 o bjecti ve res p o nses i n 9 s u bjects wit h N H L  (Pat nai k  et al 2 0 1 6).  A m o n g t he 5 1 s u bjects w h o 
recei ve d c o pa nlisi b , 4 disc o nti n ue d treat me nt d ue t o a n A E.  T here were 2 e ve nts of Gra de 3 
n o ni nfecti o us p ne u m o nitis, 1 e ve nt of Gra de 3 diarr hea, a n d n o e ve nts of c olitis.  
T he 2. 5 m g Q D re gi me n is pr o p ose d t o pr o vi de e n o u g h e x p os ure (esti mate d t o be a p pr o xi matel y 
1 × I C 9 0 at pea k) t o mai ntai n PI 3 K pat h wa y i n hi biti o n b ut re d uce t he fre q ue nc y of A Es t hat lea d 
t o st u d y treat me nt wit h dra wal.  T he c o nti n u o us Q D re gi me n has de m o nstrate d pr ol o n ge d 
res p o nses i n b ot h a g gressi ve a n d i n d ole nt N H L, a n d a c o nti n u o us l o wer d os e will be e val uate d i n 
t his st u d y.  O ne s u bject wit h f ollic ular l y m p h o ma w h o recei ve d a 1 0 m g Q D d ose ac hie ve d a 
C M R  a n d re mai ne d o n st u d y treat me nt f or a p pr o xi matel y 1 3 m o nt hs bef ore wit h dra wi n g d ue t o 
a n A E ( Gra de 2 ps oriasis).   
1. 5.  
P ote nti al Ris ks a n d Be nefits of t he Tre at me nt Re gi me n  
I N C B 0 5 0 4 6 5 has effects o n t he i m m u ne s yste m.  T heref ore, s u bjects i n t his st u d y will be 
m o nit ore d cl osel y f or e vi de nce of i nfecti o ns or ne w ca ncers, a n d st u d y treat me nt a d mi nistrati o n 
will be disc o nti n ue d if t here is e vi de nce of cli nicall y si g nifica nt i nfecti o n or ne w ca ncer.  
W hile PJ P has n ot bee n re p orte d wit h t he use of I N C B 0 5 0 4 6 5 eit her as m o n ot hera p y or i n 
c o m bi nati o n t hera p y, s u bjects w h o recei ve I N C B 0 5 0 4 6 5 i n t his st u d y will recei ve PJ P 
pr o p h yla xis.  S u bjects will be  as ke d t o re p ort all s ulfa dr u g aller gies an d t h ose aller gic t o 
sta n dar d PJP pr o p h yla xis wit h s ulf o na mi de a nti bi otics will recei ve eit her i n hale d pe nta mi di ne or 
at o va q u o ne f or PJ P pr o p h yla xis; t hese s u bjects will n ot be gi ve n da ps o ne. 
As prese nte d i n Secti o n  1. 3 , t he m ost c o m m o n A Es ( ≥ 2 0 %) o bser ve d  wit h I N C B 0 5 0 4 6 5 
m o n ot hera p y ha ve bee n na usea, diarr hea, fati g ue, c o u g h, ras h, a n d v o miti n g.  Seri o us A Es  
( ≥ 2 s u bjects) ha ve i ncl u de d c olitis, diarr hea, se psis, h y p ote nsi o n, ve ntric ular tac h ycar dia, 
p yre xia, res pirat or y fail ure, p ne u m o nia, br o nc hitis, e xf oliati ve der matitis, s y nc o pe, uri nar y tract 
i nfecti o n, a n d bactere mia .  D ose m o dificati o n g ui da nce a n d s u p p orti ve care g ui deli nes f or 
diarr hea/c olitis are i m ple me nte d i n t his st u d y.  
Base d o n efficac y a n d safet y data fr o m t he o n g oi n g St u d y I N C B 5 0 4 6 5- 1 0 1, w hic h e val uate d a 
c o nti n u o us 2 0 m g Q D d ose re gi me n, t he treat me nt re gi me n f or St u d y I N C B 5 0 4 6 5- 2 0 4 wi ll be 
2 0 m g Q D f or 8 wee ks, f oll o we d b y eit her 2 0 m g o nce wee kl y or 2. 5 m g Q D of I N C B 0 5 0 4 6 5.  
As detaile d i n Secti o n  1. 3 , t hese re gi me ns are pr o p ose d t o assess w het her t he fre q ue nc y of A Es 
lea di n g t o treat me nt wit h dra wal will be re d uce d w hile mai ntai ni n g PI 3 K pat h wa y i n hi biti o n a n d 
mai nte na nce  of res p o nse. 
I N C B0 5 0 4 6 5 is meta b olize d pri maril y b y C Y P3 A 4; t heref ore, use of a n y p ote nt C Y P 3 A 4 
i n hi bit ors or i n d ucers wit hi n 1 4 da ys or 5 half-li ves ( w hic he ver is l o n ger) bef ore t he first d ose of 
I N C B 0 5 0 4 6 5 will be pr o hi bite d. 
T he  effects of I N C B 0 5 0 4 6 5 o n fetal de vel o p me nt has n ot bee n e val uate d n or is it k n o w n w het her 
I N C B 0 5 0 4 6 5 passes i nt o h u ma n breast mil k; t heref ore, s u bjects w h o are pre g na nt or 
breastfee di n g are e xcl u de d fr o m partici pati o n i n t his st u d y. 
T here are n o precli nical data a vaila ble t o date o n t he p ote ntial  p h ot ot o xicit y of I N C B 0 5 0 4 6 5.  
T heref ore, s u bjects e nr olle d i n t his st u d y ta ki n g I N C B 0 5 0 4 6 5 will be i nstr ucte d b y t he site staff 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 1 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

t o ta ke preca uti o n t o pr otect t he msel ves fr o m t he s u n/ ultra vi olet li g ht.  T his i ncl u des weari n g 
l o n g slee ves, l o n g tr o users, hats, a n d s u n glasses. 
Preli mi nar y data i n st u d y I N C B 5 0 4 6 5- 1 0 1 de m o nstrate d efficac y of I N C B 0 5 0 4 6 5 m o n ot hera p y 
i n w hic h 7 of 9  ( 7 8 %) e val ua ble s u bjects wit h M Z L  ha d a n o bjecti ve res p o nse.  T he l o n gest 
d urati o n o n st u d y treat me nt f or t hese s u bjects was a p pr o x i matel y 5 7 wee ks . 
2.  
S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  
T he pri mar y, sec o n dar y, 
 o bjecti ves a n d e n d p oi nts descri be d herei n are 
a p plica ble f or b ot h c o h orts ( Ta ble  1).  See Secti o n 9  f or details o n t he a nal ysis of e n d p oi nts f or 
eac h c o h ort. 
T a ble  1: 
St u d y O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ar y  
T o assess t he effi cac y of I N C B 0 5 0 4 6 5 i n ter ms 
of O R R i n s u bjects wit h M Z L t hat is rela pse d  or 
refract or y after at least 1 s yste mic treat me nt 
re gi me n. 
O R R defi ne d as t he perce nta ge of s u bjects  wit h a 
C R or  P R  as deter mi ne d b y I R C assess me nt of 
res p o nse acc or di n g t o C T -base d res p o nse criteria 
f or l y m p h o mas (C hes o n  et al 2 0 1 4 ). 
Sec o n d ar y  
T o assess D O R . 
D O R  defi ne d as t he ti me fr o m first d oc u me nte d 
e vi de nce of C R or P R u ntil disease pr o gressi o n or 
deat h fr o m a n y ca use a m o n g s u bjects w h o ac hie ve 
a n o bjecti ve res p o nse, as deter mi ne d b y 
ra di o gra p hic disease assess me nt pr o vi de d b y a n 
I R C. 
T o assess C R R . 
C R R  defi ne d as t he perce nta ge of s u bjects wit h a 
C R as defi ne d b y res p o nse criteria f or l y m p h o mas 
(C hes o n et al 2 0 1 4 ), as deter mi ne d b y a n I R C. 
T o assess P F S . 
P F S  defi ne d as t he ti me fr o m t he date of t he first 
d ose of st u d y treat me n t u ntil t he earliest date of 
disease pr o gressi o n, as deter mi ne d b y ra di o gra p hic 
disease assess me nt pr o vi de d b y a n I R C, or deat h 
fr o m a n y ca use. 
T o assess O S . 
O S  defi ne d as t he ti me fr o m t he date of t he first 
d ose of st u d y treat me nt u ntil deat h fr o m a n y ca use . 
T o assess t he best perce nta ge c ha n ge i n tar get 
lesi o n size. 
Best perce nt a ge c ha n ge i n tar get lesi o n size fr o m 
baseli ne, w here tar get lesi o n size is meas ure d b y t he 
s u m of t he pr o d uct of dia meters of all tar get lesi o n 
sizes. 
T o c haracterize t he safet y a n d t olera bilit y of 
I N C B 0 5 0 4 6 5. 
Safet y meas ure d b y A Es, 1 2 -lea d E C Gs, c he mistr y 
a n d he mat ol o g y la b orat or y val ues,  vital si g ns, a n d 
p h ysical e xa mi nati o ns . 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 2 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

T a ble  1: 
St u d y O bjecti ves a n d E n d p oi nts ( C o nti n ue d)  
3.  
S U B J E C T E LI GI BI LI T Y  
De viati o ns fr o m eli gi bilit y criteria are n ot all o we d beca use t he y ca n p ote ntiall y je o par dize t he 
scie ntific i nte grit y of t he st u d y, re g ulat or y acce pta bilit y, a n d/ or s u bject safet y.  T heref ore, 
a d here nce t o t he criteria as s pecifie d i n t he P r ot oc ol is esse ntial. 
3. 1.  
S u bject I ncl usi o n Criteri a  
A s u bject  w h o meet s all of t he f oll o wi n g criteria ma y be i ncl u de d i n t he st u d y: 
1.  Me n a n d w o me n, a ge d 1 8 or ol der (e xce pt i n S o ut h K orea, a ge d 1 9 or ol der). 
2.  Hist ol o gicall y c o nfir me d M Z L , i ncl u di n g e xtra n o dal, n o dal, a n d s ple nic s u bt y pes. 
3.  Pre vi o usl y recei ve d 1 or m ore li nes of s yste mic t hera p y, i ncl u di n g at least 1 a nti-C D 2 0 
a nti b o d y (eit her as m o n ot hera p y or i n c o m bi nati o n as c he m oi m m u n ot hera p y), wit h 
d oc u me nte d pr o gressi o n or d oc u me n te d fail ure t o ac hie ve C R or P R after t he m ost rece nt 
s yste mic treat me nt re gime n . 
a. S u bjects i n C o h ort 1 m ust ha ve recei ve d pri or i br uti ni b ( N O T E:   C o h ort 1 will be 
cl ose d t o f urt her e nr oll me nt wit h Pr ot oc ol A me n d me nt [Versi o n ] 3). 
b.  S u bject s i n C o h ort 2 m ust n ot ha ve rec ei ve d a pri or B T K i n hi bit or ( e g, i br uti ni b). 
c. S u bjects wit h H. pyl ori -p ositi ve gastric e xtra n o dal M Z L  w h o recei ve d a n i nitial 
treat me nt wit h c urre ntl y acce pte d a nti bi otics ma y be c o nsi dere d eli gi ble if, after 
a nti bi otic re gi me n, s u bject has hist ol o gicall y c o nfir me d M Z L a n d was s u bse q ue ntl y 
treate d wit h at least 1 li ne of s yste mic t hera p y . 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 3 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

4.  Ra di o gra p hicall y meas ura ble l y m p ha de n o pat h y or e xtra n o dal l y m p h oi d mali g na nc y 
( defi ne d as t he prese nce of ≥ 1 lesi o n t hat meas ures >  1. 5 c m i n the L D i a n d ≥ 1. 0 c m i n 
t he l o n gest per pe n dic ular dia meter as assesse d b y C T or M RI per res p o nse criteria f or 
l y m p h o mas (C hes o n et al 2 0 1 4 ). 
a. S u bjects wit h s ple nic M Z L w h o d o n ot meet t he ra di o gra p hicall y meas ura ble disease 
criteria descri be d herei n are eli gi ble f or partici pati o n pr o vi de d t hat b o ne marr o w 
i nfiltrati o n of M Z L is hist ol o gicall y c o nfir me d. 
5.  S u bjects m ust be willi n g t o u n der g o a n i ncisi o nal or e xcisi o nal l y m p h n o de or tiss ue 
bi o ps y or pr o vi de a l y m p h n o de or tiss ue bi o ps y fr o m t he m ost r ece nt a vaila ble arc hi val 
tiss ue. 
a. S u bjects wit h s ple nic M Z L w h o d o n ot ha ve a t u m or t o bi o ps y or a n arc hi val t u m or 
tiss ue sa m ple are eli gi ble f or partici pati o n pr o vi de d s u bject is willi n g t o u n der g o a 
b o ne marr o w bi o ps y or pr o vi de a n arc hi val b o ne marr o w bi o ps y t hat was o btai ne d 
si nce c o m pleti o n of last t hera p y a n d wit hi n 2 years bef ore t he date of t he first d ose of 
st u d y treat me nt; b o ne marr o w sa m ple m ust s h o w hist ol o gicall y c o nfir me d i nfiltrati o n 
of M Z L.  
6.  Life e x pecta nc y >  3 m o nt hs. 
7.  E C O G  perf or ma nce stat us 0 t o 2 ( O ke n  et al 1 9 8 2; see A p pe n di x B ). 
8.  A de q uate he mat ol o gic, he patic, a n d re nal f u ncti o n ( val ues m ust n ot be ac hie ve d wit h 
gr o wt h fact ors):  
a. A N C ≥ 1. 0 × 1 09/ L. 
b.  He m o gl o bi n ≥ 8. 0 g/ d L. 
c. Platelet c o u nt ≥ 5 0 × 1 09/ L. 
d.  T otal bilir u bi n ≤ 1. 5 × U L N.  S u bjects wit h d oc u me nte d hist or y of Gil bert’s 
s y n dr o me a n d i n w h o m t otal bilir u bi n ele vati o ns are acc o m pa nie d b y ele vate d 
i n direct bilir u bi n are eli gi ble. 
e. A L T/ A S T ≤ 3. 0 U L N or ≤ 5 × U L N i n t he prese nce of li ver metastases . 
f. Calc ulate d creati ni ne cleara nce ≥ 5 0 m L/ mi n b y t he C oc kcr oft- Ga ult E q uati o n 
(C oc kcr oft a n d Ga ult 1 9 7 6 ) or t he esti mate d gl o mer ular filtrati o n rate  
≥ 5 0 m L/ mi n/ 1. 7 3 m2 usi ng t he M o dificati o n of Diet i n Re nal Disease f or m ula. 
9.  Willi n g ness t o a v oi d pre g na nc y or fat heri n g c hil dre n base d o n t he criteria bel o w: 
a. W o m a n of n o nc hil d beari n g p ote ntial ( ie, s ur gicall y sterile wit h a h ysterect o m y a n d/ or 
bilateral o o p h orect o m y O R ≥ 1 2 m o nt hs of a me n orr hea a n d at least 4 5 years of a ge) . 
b.  W o ma n of c hil d beari n g p ote ntial w h o  has a ne gati ve ser u m pre g na nc y test at 
scree ni n g a n d w h o a grees t o ta ke a p pr o priate preca uti o ns t o a v oi d pre g na nc y ( wit h at 
least 9 9 % certai nt y) fr o m scree ni n g t hr o u g h safet y f oll o w- u p.  Per mitte d met h o ds t hat 
are at least 9 9 % effecti ve i n pre ve nti n g pre g na nc y (see A p pe n di x A ) s h o ul d be 
c o m m u nicate d t o t he s u bject a n d t heir u n dersta n di n g c o nfir me d. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

c. Ma n w h o a grees t o ta ke a p pr o priate preca uti o ns t o a v oi d fat heri n g c hil dre n ( wit h at 
least 9 9 % certai nt y) fr o m scree ni n g t hr o u g h at least 9 3 da ys after t he last d ose of 
st u d y treat me nt.  Per mitte d met h o ds t hat are at least 9 9 % effecti ve i n pre ve nti n g 
pre g na nc y ( see A p pe n di x A ) s h o ul d be c o m m u nicate d t o t he s u bject a n d t heir 
u n dersta n di n g c o nfir me d. 
3. 2.  
S u bject E xcl usi o n Criteri a  
A s u bject  w h o meet s a n y of t he f oll o wi n g criteria will be e xcl ude d fr o m t he st u d y: 
1.  E vi de nce of D L B C L tra nsf or mati o n. 
a. S u bjects wit h pres u m pti ve e vi de nce of tra nsf or mati o n base d o n cli nical assess me nt of 
fact ors s uc h as, b ut n ot li mite d t o, i ncreasi n g lactate de h y dr o ge nase, ra pi dl y 
w orse ni n g disease, or fre q ue nt B -s y m pt o ms, m ust be r ule d o ut f or a tra nsf o r mati o n t o 
a m ore a g gressi ve disease , s uc h as D L B C L. 
2.  Hist or y of ce ntral ner v o us s yste m l y m p h o ma (eit her pri mar y or metastatic)  or 
le pt o me ni n geal disease.  
3.  Pri or treat me nt wit h i delalisi b, ot he r selecti ve PI 3 K δ i n hi bit ors, or a pa n- PI 3 K i n hi bit or. 
4.  All o ge neic ste m cell tra ns pla nt wit hi n t he last 6 m o nt hs, or a ut ol o g o us ste m cell 
tra ns pla nt wit hi n t he last 3 m o nt hs bef ore t he date of t he first d ose of st u d y treat me nt. 
5.  Acti ve graft vers us h ost dise ase. 
6.  Use of i m m u n os u p pressi ve t hera p y wit hi n 2 8 da ys of t he date of st u d y treat me nt 
a d mi nistrati o n.  I m m u n os u p pressi ve t hera p y i ncl u des, b ut is n ot li mite d t o, 
c ycl os p ori ne A, tacr oli m us, or hi g h- d ose c ortic oster oi ds.  S u bjects recei vi n g 
c ortic oster oi ds m ust be at a d ose le vel ≤ 1 0 m g/ da y wit hi n 7 da ys of t he st u d y treat me nt 
a d mi nistrati o n .  
7.  Recei pt of a ntica ncer me dicati o ns or i n vesti gati o nal dr u gs wit hi n t he f oll o wi n g i nter vals 
bef ore t he date of t he first d ose of st u d y treat me nt: 
a. < 1 0 wee ks fr o m c o m pl eti o n of a n y ra di o- or t o xi n -i m m u n oc o nj u gates.  
b.  < 6 wee ks f or mit o m yci n- C or nitr os o ureas. 
c. < 4 wee ks f or i m m u n ot hera p y. 
d.  < 3 wee ks f or ra di ot hera p y. 
e. < 3 da ys f or i br uti ni b ( N O T E:  C o h ort 1 [s u bjects w h o recei ve d pri or i br uti ni b] will 
be cl ose d t o f urt her e nr oll me nt wit h Pr ot oc ol A me n d me nt [Versi o n ] 3). 
f. < 2 wee ks f or a n y i n vesti gati o nal a ge nt or ot her a ntica ncer me dicati o ns. 
8.  I na de q uate rec o ver y fr o m t o xicit y a n d/ or c o m plicati o ns fr o m a maj or s ur ger y bef ore 
starti n g t hera p y. 
9.  Pri or treat me nt -relate d t o xicities ha ve n ot res ol ve d t o N CI C T C A E v 4. 0 3 (N CI  2 0 1 0) 
≤ Gra de 1 bef ore  t he date of t he first d ose of st u d y treat me nt, e xce pt for sta ble c hr o nic 
t o xicities (≤ Gra de 2) n ot e x pecte d t o res ol ve ( e g, sta ble Gra de 2 peri p heral 
ne ur ot o xicit y). 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 5 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

1 0.  C o nc urre nt a ntica ncer t hera p y ( e g, c he m ot hera p y, ra diati o n t hera p y, s ur ger y, 
i m m u n ot hera p y, bi ol o gic t hera p y, h or m o nal t hera p y, i n vesti gati o nal t hera p y, or t u m or 
e m b olizati o n).  
1 1.  Use or e x pecte d use d uri n g t he st u d y of a n y pr o hi bite d me dicati o ns, i ncl u di n g p ote nt 
C Y P 3 A 4 i n hi bit ors  or i n d ucers (see A p pe n di x D ), wit hi n 1 4 da ys or 5 half-li ves 
( w hic he ver is l o n ger) bef ore t he date of st u d y treat me nt a d mi nistrati o n. 
1 2.  Si g nifica nt c o nc urre nt, u nc o ntr olle d me dical c o n diti o n , i ncl u di n g, b ut n ot li mite d t o, 
re nal, he patic, he mat ol o gical, GI , e n d ocri ne, p ul m o nar y, ne ur ol o gical, cere bral, or 
ps yc hiatric disease.  
1 3.  C urre nt or pre vi o us ot her mali g na nc y wit hi n 3 years of st u d y e ntr y, e xce pt c ure d basal or 
s q ua m o us cell s ki n ca ncer, s u perficial bla d der ca ncer, pr ostate i ntrae pit helial ne o plas m, 
carci n o ma i n sit u of t he cer vi x, or ot her n o ni n vasi ve or i n d ole nt mali g na nc y wit h o ut 
s p o ns or a p pr o val. 
1 4.  Hist or y of str o ke or i ntracra nial he m orr ha ge wit hi n 6 m o nt hs of t he date of st u d y 
treat me nt a d mi nistrati o n. 
1 5.  C hr o nic or c urre nt acti ve i nfecti o us disease re q uiri n g s yste mic a nti bi otics, a ntif u n gal, or 
a nti viral treat me nt  or e x p os ure t o a li ve vacci ne wit hi n 3 0 da ys of d osi n g. 
1 6.  K n o w n HI V i nfecti o n or p ositi vit y o n i m m u n oassa y.  N ote:   HI V scree ni n g test is 
o pti o nal f or s u bjects e nr olle d i n t he U nite d States, b ut s u bjects wit h k n o w n HI V i nfecti o n 
i n t he U nite d States will be e xcl u de d. 
1 7.  Li ver disease:   H B V or H C V i nfecti o n: S u bjects p ositi ve f or H Bs A g or he patitis B c ore 
a nti b o d y will be eli gi ble if t he y are ne gati ve  f or H B V-D N A; t hese s u bjects s h o ul d be 
c o nsi dere d f or pr o p h ylactic a nti viral t hera p y.  S u bjects p ositi ve f or a nti - H C V a nti b o d y 
will be eli gi ble if t he y are ne gati ve f or H C V -R N A . 
1 8.  Cli nicall y si g nifica nt car diac disease, i ncl u di n g u nsta ble a n gi na, a c ute m y ocar dial 
i nfarcti o n, a n d/ or car diac c o n d ucti o n iss ues wit hi n 6 m o nt hs of t he date of st u d y 
treat me nt a d mi nistrati o n.  
1 9.  C urre nt Ne w Y or k Heart Ass ociati o n Class II t o I V c o n gesti ve heart fail ure or 
u nc o ntr olle d arr h yt h mia.  
2 0.  Prese nce of a n a b n or mal E C G t hat is cli nicall y mea ni n gf ul.  Scree ni n g Q Tc i nter val  
> 4 5 0 millisec o n ds is e xcl u de d (c orrecte d b y Fri dericia).  I n t he e ve nt t hat a si n gle Q Tc is 
> 4 5 0 millisec o n ds, t he s u bject ma y e nr oll if t he a vera ge Q Tc f or 3 E C Gs is 
< 4 5 0 millisec o n ds.  
2 1.  U na ble t o s wall o w a n d retai n oral me dicati o n, mala bs or pti o n s y n dr o me, disease 
si g nifica ntl y affecti n g GI  f u ncti o n, t otal resecti o n of t he st o mac h or s mall b o wel, 
ulcerati ve c olitis, s y m pt o matic i nfla m mat or y b o wel disease, or partial or c o m plete b o wel 
o bstr ucti o n. 
2 2.  K n o w n h y perse nsiti vit y or se vere reacti o n t o I N C B 0 5 0 4 6 5 or its e xci pie nts (see I B).   
2 3.  Hist or y of seri o us aller gic reacti o ns i ncl u di n g a na p h yla xis a n d t o xic e pi der mal 
necr ol ysis. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 6 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

2 4.  C urre ntl y pre g na nt or breastfee di n g. 
2 5.  A n y c o n diti o n t hat w o ul d, i n t he i n vesti gat or' s j u d g me nt, i nterfere wit h f ull partici pati o n 
i n t he st u d y, i ncl u di n g a d mi nistrati o n of st u d y treat me nt a n d atte n di n g re q uire d st u d y 
visits; p ose a si g nifica nt ris k t o t he s u bject; or i nterfere wit h i nter pretati o n of st u d y data.  
2 6.  I na bilit y t o c o m pre he n d or u n willi n g t o si g n the I C F . 
4.  
I N V E S TI G A TI O N A L P L A N  
4. 1.  
O ver all St u d y Desi g n  
T his is a P hase 2, o pe n -la bel st u d y desi g ne d t o e val uate t he safet y a n d efficac y of 
2 I N C B 0 5 0 4 6 5 treat me nt re gi me ns i n s u bjects dia g n ose d wit h rela pse d or refract or y M Z L (see 
Fi g ure 1 ).  A t otal of a p pr o xi matel y 9 0 s u bjects will be e nr olle d. 
S u bjects wit h M Z L t hat is rela pse d or refract or y t o at least 1 li ne of pri or s yste mic t hera p y t hat 
i ncl u de d a n a nti- C D 2 0 a nti b o d y will be scree ne d f or eli gi bilit y.  T he st u d y was ori gi nall y 
pla n ne d t o e nr oll 2 c o h orts: 
•  C o h ort 1:  S u bjects w h o ha ve recei ve d pri or i br uti ni b ( n  = 6 0) 
•  C o h ort 2:  S u bjects w h o ha ve n ot recei ve d a pri or B T K i n hi bit or ( n = 6 0) 
H o we ver, gi ve n t he li mite d a vaila bilit y of i br uti ni b (a p pr o ve d f or M Z L i n t he U nite d States  
o nl y), t he n u m ber of s u bjects wit h rela pse d or refract or y M Z L pre vi o usl y treate d wit h i br uti ni b 
is l o w.  At t he ti me of Pr ot oc ol A me n d me nt (Versi o n ) 3, o nl y 2 s u bjects ha ve bee n e nr olle d i nt o 
C o h ort 1, 1 8 m o nt hs after t he st u d y st art i n J U N 2 0 1 7.  T heref ore, C o h ort 1 was cl ose d t o f urt her 
e nr oll me nt f or feasi bilit y reas o ns.  
S u bjects alrea d y e nr olle d i nt o C o h ort 1 will c o nti n ue t o recei ve st u d y treat me nt per t he Pr ot oc ol, 
a n d t heir data will be re p orte d a n d a nal yze d se paratel y fr o m s u bjects i n C o h ort 2. 
T he first 6 0 s u bjects i n C o h ort 2 a n d a n y s u bjects e nr olle d i n C o h ort 1 w h o meet t he eli gi bilit y 
criteria will be f urt her all ocate d t o 1 of 2 st u d y treat me nt re gi me ns t hr o u g h t he I W R S (see 
Secti o n  5. 1 ): 
•  Treat me nt A:  I N C B 0 5 0 4 6 5 2 0 m g Q D  P O  f or 8 wee ks f oll o we d b y 2 0 m g o nce 
wee kl y  P O . 
− S u bjects i n C o h ort 1 recei vi n g T reat me nt A will be referre d t o as C o h ort 1 A. 
− S u bjects i n C o h ort 2 recei vi n g T reat me nt A will be referre d t o as C o h ort 2 A. 
•  Treat me nt B:  I N C B 0 5 0 4 6 5 2 0 m g Q D  P O f or 8 wee ks f oll o we d b y 2. 5 m g Q D  P O . 
− S u bjects i n C o h ort 1 recei vi n g T reat me nt B will be referre d t o as C o h ort 1 B. 
− S u bjects i n C o h ort 2 recei v i n g Treat me nt B will be referre d t o as C o h ort 2 B. 
T o better u n dersta n d t he safet y a n d efficac y of I N C B 0 5 0 4 6 5, a n a d diti o nal 3 0 s u bjects will be 
e nr olle d i nt o o ne of t he t w o treat me nt re gi me ns ( A or B)  bei n g e val uate d i n t his St u d y.  T he 
treat me nt re gi me n will be selecte d after e nr oll me nt is c o m plete d f or C o h ort 2 (ie, 6 0 s u bjects 
e nr olle d) a n d after e val uati o n of e mer gi n g safet y a n d efficac y data fr o m t his a n d ot her 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

m o n ot hera p y st u dies of I N C B 0 5 0 4 6 5 i n N H L.  O nce a treat me nt re gi me n is selecte d, t he 
n o n- selecte d treat me nt re gi me n will be cl ose d t o f urt her e nr oll me nt.  S u bjects recei vi n g t he 
n o n- selecte d treat me nt re gi me n ma y s witc h t o t he selecte d treat me nt re gi me n or re mai n o n t heir 
c urre nt treat me nt re gi me n , pr o vi de d t he s u bject has n ot met st u d y-treat me nt wit h dra wal criteria 
a n d t here are n o safet y c o ncer ns f or t heir c urre nt treat me nt re gi me n.  T here will be n o 
re-baseli ni n g f or s u bjects w h o s witc h treat me nt re gi me ns a n d all s u bjects will c o nti n ue t o f oll o w 
t he sa me assess me nt sc he d ule. 
N O T E:   T he pri mar y, sec o n dar y, 
 o bjecti ves a n d e n d p oi nts descri be d i n 
Secti o n  2  are a p plica ble f or  b ot h c o h orts; h o we ver, t he c o h orts will be a nal yze d se paratel y, w he n 
a p plica ble, as detaile d i n Secti o n  9 . 
S u bjects will recei ve treat me nt u ntil disease pr o gressi o n, deat h, u nacce pta ble t o x icit y, or c o nse nt 
wit h dra wal.  
S u bjects will be m o nit ore d f or safet y a n d efficac y peri o dicall y u ntil disease pr o gressi o n, deat h, 
u nacce pta ble t o xicit y, or wit h dra wal of i nf or me d c o nse nt.  A n I D M C will re vie w safet y data 
peri o dicall y as state d i n t he I D M C c h arter.  S u bjects w ill be e val uate d f or O R R b y a n I R C a nd 
f oll o we d f or D O R, P F S, a n d O S. 
A n i nteri m f utilit y a nal y sis is pla n ne d f or C o h ort 2 w he n 3 0 s u bjects ha ve bee n treate d a n d ha ve 
bee n e val uate d f or res p o nse or ha ve per ma ne ntl y disc o nti n ue d st u d y treat me nt beca use of 
disease pr o gressi o n, wit h dra wal of c o nse nt, or deat h.  C o h ort 2 will be ter mi nate d f or f utilit y if 
≤ 1 0 of t he 3 0 s u bjects res p o n de d (ie, C R or P R) base d o n assess me nts pr o vi de d b y t he I R C.  A 
ti mel y assess me nt of res p o nse will be perf or me d t o a v oi d t he ris k of o vere nr oll me nt. 
After treat me nt disc o nti n uati o n, s u bjects will be f oll o we d f or safet y a n d s ur vi val.  S u bjects w h o 
ha ve disc o nti n ue d st u d y treat me nt d ue t o reas o ns ot her t ha n disease pr o gressi o n will be f oll o we d 
f or eit her ra di ol o gic disease pr o gressi o n, t he start of a ne w a ntica ncer t hera p y, or deat h, 
w hic he ver c o mes first.  It is e x pecte d t hat t he fi nal a nal ysis will oc c ur n o later t ha n 2 years after 
t he first d ose of I N C B 0 5 0 4 6 5 is a d mi nistere d t o t he last s u bject treate d. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 8 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

Fi g ure  1: 
St u d y Desi g n  of I N C B 5 0 4 6 5- 2 0 4 
 
4. 2.  
Me as ures T a ke n t o A v oi d Bi as  
T his is a n o pe n -la bel st u d y; n o c o m paris o ns will be ma de bet wee n s u bjects or a gai nst hist orical 
c o ntr ols.  Meas ure me nts of safet y a n d efficac y are o bjecti ve meas ure me nts, a n d o nl y 
c o m paris o ns t o pretreat me nt c o n diti o ns will be ma de.  Safet y will be o bjecti vel y assesse d usi n g 
N CI C T C A E v 4. 0 3 ( N CI  2 0 1 0) g ui deli nes a n d re vie we d b y t he I D M C.  T u m or res p o nse will be 
assesse d b y a n I R C usi n g t he C T -base d criteria of t he L u ga n o classificati o n ( C hes o n et al 2 0 1 4 ). 
4. 3.  
N u m ber of S u bjects  
4. 3. 1.  
Pl a n ne d N u m ber of S u bjects  
T he st u d y will e nr oll a p pr o xi matel y 9 0  s u bjects at a p pr o xi matel y 1 0 0 gl o bal i n vesti gati ve sites. 
4. 3. 2.  
Re pl ace me nt of S u bjects  
N o s u bjects will be re place d at a n y ti me d uri n g t his st u d y. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 2 9 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

4. 4.  
D ur ati o n of Tre at me nt a n d S u bject P artici p ati o n  
After si g ni n g t he I C F, scree ni n g assess me nts ma y be c o m plete d o ver a peri o d of u p t o 2 8 da ys.  
Eac h s u bject e nr olle d i n t he st u d y ma y c o nti n ue t o recei ve st u d y treat me nt i n c o nti n u o us 2 8- da y 
i nter vals.  If t he s u bject disc o nti n ues st u d y treat me nt, t he treat me nt peri o d will e n d, a n d t he 
s u bject will e nter t he 3 0  t o 3 5- da y safet y f oll o w- u p peri o d, after w hic h t he s u bject will e nter t he 
s ur vi val f oll o w- u p peri o d (see Secti o n  6. 4. 3 ).  S u bject partici pati o n is e x pecte d t o a vera ge 
a p pr o xi matel y 2 5 m o nt hs. 
4. 5.  
O ver all St u d y D ur ati o n  
T he st u d y be gi ns w he n t he first s u bject si g ns t he I C F.  T he e n d of t he st u d y will occ ur w he n all  
s u bjects ha ve disc o nti n ue d fr o m t he st u d y (see Secti o n 5. 7 ) or  ha ve c o m plete d at least  2 4 m o nt hs 
of st u d y partici pati o n (starti n g fr o m t he first d ose of st u d y treat me nt).  It is esti mate d t hat t he 
st u d y will ta ke a p pr o xi matel y 2 years t o accr ue a p pr o xi matel y 9 0  s u bjects a n d t hat t he fi nal 
a nal ysis will be perf or me d n o later t ha n 2 years after t he first d ose of st u d y treat me nt is 
a d mi nistere d t o t he  last s u bject treate d.  S u bjects w h o are still o n st u d y treat me nt a n d w h o ha ve 
n o e vi de nce of pr o gressi ve disease at t he e n d of t he st u d y will ha ve t he o pti o n t o c o nti n ue o n 
m o n ot hera p y wit h I N C B 0 5 0 4 6 5 pr o vi de d wit hi n a r oll o ver Pr ot oc ol, as l ocal la w per mits (see 
Secti o n  5. 8 ). 
4. 6.  
St u d y Ter mi n ati o n  
T he i n vesti gat or retai ns t he ri g ht t o ter mi nate st u d y partici pati o n at a n y ti me, acc or di n g t o t he 
ter ms s pecifie d i n t he st u d y c o ntract.  T he in vesti gat or is t o n otif y t he i nstit uti o nal re vie w b oar d 
(I R B)/i n de pe n de nt et hics c o m mittee (I E C) i n writi n g of t he st u d y's c o m pleti o n or earl y 
ter mi nati o n, se n d a c o p y of t he n otificati o n t o t he s p o ns or or s p o ns or's desi g nee, a n d retai n 
1 c o p y f or t he site st u d y re g ulat or y file. 
T he s p o ns or ma y ter mi nate t he st u d y electi vel y, if re q uire d b y re g ulat or y decisi o n, or u p o n 
a d vice of t he ID M C .  If t he st u d y is ter mi nate d pre mat urel y, t he s p o ns or will n otif y t he 
i n vesti gat ors, t he I R Bs a n d IE C s, a n d re g ulat or y b o dies of t he decisi o n a n d reas o n f or 
ter mi nati o n of t he st u d y.  T he ID M C  will rec o m me n d ter mi nati o n of t he st u d y if warra nte d, as 
descri be d i n t he I D M C C harter (see als o Secti o n  9. 5 ). 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 0 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

5.  
T R E A T M E N T  
5. 1.  
Tre at me nt Assi g n me nt  
5. 1. 1.  
S u bject N u m beri n g a n d Tre at me nt Assi g n me nt  
St u d y sites will e nter s u bject de m o gra p hic a n d baseli ne data i nt o t he I W R S i n or der t o recei ve a 
s u bject n u m ber a n d treat me nt all ocati o n. 
All s u bject n u m bers will be 6 di gits; t he first 3 di gits will be t he site n u m ber , a n d t he last 3 di gits 
will be t he s u bject 's n u m ber.  T his s u bject n u m ber will be mai ntai ne d t hr o u g h o ut t he st u d y a n d 
will n ot be reassi g ne d.  S u bjects w h o wit h dra w c o nse nt or disc o nti n ue fr o m t he st u d y after bei n g 
assi g ne d a s u bject n u m ber will retai n t heir i nitial n u m ber.  
Site staff will c o ntact t he I W R S t o all ocate t he s u bject t o treat me nt assi g n me nt a n d o btai n t he 
i nitial st u d y treat me nt assi g n me nt.  T he i n vesti gat or or desi g nee will select t he assi g ne d  b ottles 
of st u d y treat me nt fr o m t heir st oc k t hat c orres p o n d t o t he n u m ber pr o vi de d b y t he I WR S a n d 
dis pe nse t he st u d y treat me nt t o t he s u bject.  All s u bse q ue nt dis pe nsi n g of st u d y treat me nt s h o ul d 
f oll ow t his pr ocess.  Refer t o t he I WR S M a n ual f or detaile d i nf or mati o n. 
If a s u bject is mista kenl y gi ve n a b ottle of st u d y treat me nt t hat is n ot t he b ottle assi g ne d b y t he 
I WR S, t he I WR S hel p des k m ust be n otifie d i m me diatel y.  T he reas o n f or t he misall ocati o n  of 
t he st u d y treat me nt m ust be d oc u me nte d b y t he st u d y site a n d re p orte d t o t he I R B/I E C . 
F or s u bjects w h o si g ne d a n I C F b ut are n ot all ocate d st u d y treat me nt a n d f or s u bjects w h o are 
all ocate d st u d y treat me nt b ut were n ot treate d, refer t o t he e C R F C o m pleti o n G ui deli nes f or 
i nstr ucti o n o n w hic h e C R Fs t o c o m plete. 
5. 1. 2.  
R a n d o mi z ati o n a n d Bli n di n g  
N ot a p plica ble. 
5. 2.  
I N C B 0 5 0 4 6 5 
5. 2. 1.  
Descri pti o n a n d A d mi nistr ati o n  
Details of I N C B 0 5 0 4 6 5 are s h o w n i n Ta ble  2. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 1 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

•  T o ma ke e ver y eff ort t o ta ke d oses o n sc he d ule.  
•  T o re p ort a n y misse d d oses.  
•  T o kee p I N C B 0 5 0 4 6 5 i n a safe place a n d o ut of reac h of c hil dre n. 
•  T o bri n g all use d a n d u n use d st u d y treat me nt kits t o t he site at eac h visit.  
5. 3.  
Tre at me nt C o m pli a nce  
C o m plia nce wit h all st u d y -relate d treat me nts s h o ul d be e m p hasize d t o t he s u bject b y t he site 
pers o n nel, a n d a p pr o priate ste ps s h o ul d be ta ke n t o o pti mize c o m plia nce d uri n g t he st u d y.  
C o m plia nce wit h st u d y treat me nt will be calc ulate d b y t he s p o ns or base d o n t he dr u g 
acc o u nta bilit y d oc u me nte d b y t he site staff a n d m o nit ore d b y t he s p o ns or/ desi g nee (ta blet 
c o u nts).  S u bjects will be i nstr ucte d t o bri n g all st u d y  treat me nts wit h t he m t o t he st u d y visits i n 
or der f or site pers o n nel t o c o n d uct ta blet c o u nts t o assess st u d y treat me nt acc o u nta bilit y.  T he 
dr u g acc o u nta bilit y d oc u me ntati o n will be use d b y t he s p o ns or t o calc ulate treat me nt 
c o m plia nce.  
5. 4.  
Tre at me nt I nterr u pti o ns a n d A dj ust me nts 
5. 4. 1.  
Criteri a a n d Pr oce d ures f or D ose I nterr u pti o ns a n d Re d ucti o ns of I N C B 0 5 0 4 6 5 
Treat me nt wit h I N C B 0 5 0 4 6 5 ma y be i nterr u pte d f or u p t o 1 4 da ys t o all o w f or res ol uti o n of 
t o xicit y.  S u bjects ma y res u me treat me nt if n o me dical c o n diti o n or ot her circ u msta nce e xists 
t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d ma ke t he s u bject u ns uita ble f or f urt her 
partici pati o n i n t he st u d y.  T he treati n g i n vesti gat or s h o ul d c o ntact t he s p o ns or t o disc uss t he 
case of a n y s u bject w h ose treat me nt has bee n i nterr u pte d f or m ore t ha n 1 4 da ys bef ore restarti n g 
treat me nt wit h I N C B 0 5 0 4 6 5. 
5. 4. 1. 1.  
D ose  M o dific ati o ns 
D ose m o dificati o n g ui da nce f or A Es t hat ha ve bee n pre vi o usl y o bser ve d i n s u bjects recei vi n g 
I N C B 0 5 0 4 6 5 or are p ote ntial class-effect A Es are pr o vi de d (see Ta ble  3 a n d Ta ble  5).  T he 
starti n g d ose a n d d ose re d ucti o n le vels of I N C B 0 5 0 4 6 5 are pr o vi de d (see Ta ble  4).  I n di vi d ual 
decisi o ns re gar di n g d ose i nterr u pti o n a n d re d ucti o n s h o ul d be ma de usi n g cli nical j u d g me nt a n d 
i n c o ns ultati o n wit h t he s p o ns or's me dical m o nit or, ta ki n g i nt o acc o u nt relate d ness of t he A E t o 
t he st u d y treat me nt a n d t he s u bject's u n derl yi n g c o n diti o n.  A d verse e ve nts t hat ha ve a clear 
alter nati ve e x pla nati o n or tra nsie nt ( ≤ 7 2 h o urs) a b n or mal la b orat or y val ues wit h o ut ass ociate d 
cli nicall y si g nifica nt si g ns or s y m pt o m s ma y be e xe m pt fr o m d ose re d ucti o n g ui deli nes. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 3 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

T a ble  3: 
G ui deli nes f or I nterr u pti o n a n d Rest arti n g I N CB 0 5 0 4 6 5 
A D V E R S E E V E N T  
A C TI O N T A K E N  
C he mistr y  
•  Gra de 3 A S T a n d/ or A L T ( >  5. 0  × U L N).  
N ote:   I n s u bjects wit h li ver 
metastasis −relate d ele vati o ns at baseli ne, 
c o ntact s p o ns or t o disc uss cli nical 
ma na ge me nt a n d p ossi ble d ose re d ucti o ns.  
Ste p 1:   I nterr u pt I N C B 0 5 0 4 6 5 a n d m o nit or wee kl y u ntil t he 
t o xicit y has res ol ve d t o ≤ Gra de  1.  
Ste p 2:   Restart  I N C B 0 5 0 4 6 5 at ne xt l o wer d ose wit h me dical 
m o nit or a p pr o val.  M o nit or as cli nicall y i n dicate d.  
He m at ol o g y  
•  Gra de 3 A N C ( < 1. 0  × 1 0 9/L).  
•  Gra de 2 platelet c o u nt ( 5 0 t o 
< 7 5  × 1 0 9/ L) f or s u bjects w h o e nr olle d 
wit h platelets >  1 0 0  × 1 0 9/ L. 
•  Gra de 3 platelet c o u nt ( < 5 0  × 1 0 9/ L) f or 
s u bjects w h o e nr olle d wit h platelets 
≤ 1 0 0  × 1 0 9/ L. 
Ste p 1:   I nterr u pt I N C B 0 5 0 4 6 5 u p t o 1 4 da ys u ntil t he t o xicit y 
has res ol ve d t o ≤ Gra de 1 or pret hera p y baseli ne.  F or Gra de 3 
A N C, m o nit or at least wee kl y.  
Ste p 2:   Restart I N C B 0 5 0 4 6 5 at sa me d ose; m o nit or as cli nicall y 
i n dicate d. 
•  Gra de 4 A N C ( < 0. 5  × 1 0 9/L).  
•  Gra de  3 or Gra de 4 fe brile ne utr o pe nia. 
•  Platelet c o u nt is Gra de 4 ( <  2 5  × 1 0 9/ L). 
Ste p 1:   I nterr u pt I N C B 0 5 0 4 6 5 u p t o 1 4 da ys u ntil t he t o xicit y 
has res ol ve d ≤ Gra de 2.   ( Mo nit or at least wee kl y.)  
Ste p 2:   Restart  I N C B 0 5 0 4 6 5 at sa me d ose.  M o nit or as cli nicall y 
i n dicate d.  If re occ urs, restart at ne xt l o wer d ose. 
Ot her t o xicities  
•  Diarr hea/c olitis.  
See Ta ble  5. 
•  P ne u m o nitis ( Gra de 1) . 
Ste p 1:  I nterr u pt I N C B 0 5 0 4 6 5 u ntil t he t o xicit y has res ol ve d.   
Ste p 2:   Restart I N C B 0 5 0 4 6 5 at ne xt l o wer d ose.  M o nit or as 
cli nicall y i n dicate d.  
•  P ne u m o nitis  ( Gra de ≥ 2) . 
Per ma ne ntl y disc o nti n ue I N C B 0 5 0 4 6 5.  
•  S ki n t o xicit y ( e g, ras h, pr urit us , u nless 
ot her wise s pecifie d ; Gra de 2 a n d 3) . 
Ste p 1:  I nterr u pt I N C B 0 5 0 4 6 5 u ntil t he t o xicit y has res ol ve d 
t o ≤ Gra de 1.  
Ste p 2:   Restart I N C B 0 5 0 4 6 5 at sa me d ose.  If assesse d as  relate d 
t o I N C B 0 5 0 4 6 5, restart at ne xt l o wer d ose. 
•  E xf oliati ve der matitis ( Gra de 1) . 
Ste p 1:  I nterr u pt I N C B 0 5 0 4 6 5 u ntil t he t o xicit y has res ol ve d. 
Ste p 2:   Restart I N C B 0 5 0 4 6 5 at ne xt l o wer d ose.  M o nit or as 
cli nicall y i n dicate d.  
•  E xf oliati ve  der matitis ( ≥ Gra de  2) . 
Per ma ne ntl y disc o nti n ue I N C B 0 5 0 4 6 5.  
•  I ntesti nal perf orati o n (a n y gra de). 
Per ma ne ntl y disc o nti n ue I N C B 0 5 0 4 6 5.  
•  PJ P i nfecti o n. 
I nterr u pt I N C B 0 5 0 4 6 5.  Per ma ne ntl y disc o nti n ue I N C B 0 5 0 4 6 5 if 
PJ P i nfecti o n is c o nfir me d. 
•  C M V i nfecti o n . 
S u bjects wit h C M V vire mia wit h o ut ass ociate d cli nical si g ns of 
C M V i nfecti o n s h o ul d be caref ull y m o nit ore d.  C o nsi der 
i nterr u pti n g I N C B 0 5 0 4 6 5 f or s u bjects wit h C M V vire mia a n d 
cli nical si g ns of i nfecti o n u ntil t he i nfecti o n has res ol ve d.  Restart 
I N C B 0 5 0 4 65 re d uce d b y 1 d ose le vel if a p pr o ve d b y t he me dical 
m o nit or.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

T a ble  3: 
G ui deli nes f or I nterr u pti o n a n d Rest arti n g I N C B 0 5 0 4 6 5  ( C o nti n ue d) 
A D V E R S E E V E N T  
A C TI O N T A K E N  
•  Varicella z oster i nfecti o n . 
I nterr u pt I N C B 0 5 0 4 6 5.  Restart I N C B 0 5 0 4 6 5 o nl y b y a p pr o val 
of t he me dical m o nit or.  
•  A n y Gra de 1 or Gra de 2 t o xicit y u nless 
ot her wise s pecifie d.  
C o nti n ue I N C B 0 5 0 4 6 5 a n d treat t he t o xicit y; m o nit or as 
cli nicall y i n dicate d.  
•  A n y Gra de 3 t o xicit y, if cli nicall y 
si g nifica nt a n d n ot ma na gea ble b y 
s u p p orti ve care u nless ot her wise 
s pecifie d. 
Ste p 1:   I nterr u pt I N C B 0 5 0 4 6 5 u p t o 1 4 da ys u ntil t he t o xicit y 
has res ol ve d t o ≤ Gra de 1.  
Ste p 2:   Restart I N C B 0 5 0 4 6 5 at sa me d ose.  If assesse d as relate d 
t o I N C B 0 5 0 4 6 5, restart at ne xt l o wer d ose.  If i nterr u pte d f or 
> 1 4  da ys, c o ntact t he me dical m o nit or f or a p pr o val t o restart 
I N C B 0 5 0 4 6 5.  M o nit or as cli nicall y i n dicate d. 
•  A n y rec urre nt Gra de 3 t o xicit y after 
2 d ose re d ucti o ns.  
Disc o nti n ue I N C B 0 5 0 4 6 5 a d mi nistrati o n a n d f oll o w -u p per 
Pr ot oc ol.  E x ce pti o ns re q uire a p pr o val of s p o ns or.  
•  A n y ot her Gra de 4 t o xicit y.  
Disc o nti n ue I N C B 0 5 0 4 6 5 a d mi nistrati o n a n d f oll o w -u p per 
Pr ot oc ol.  E xce pti o ns re q uire a p pr o val of s p o ns or.  
A L T = ala ni ne a mi n otra nsferase; A S T = as partate a mi n otra nsferase; C M V = c y t o me gal o vir us; I V = i ntra ve n o us; U L N = u p per 
li mit of n or mal. 
T a ble  4: 
D ose Le vels a n d Re d ucti o ns f or I N CB 0 5 0 4 6 5 
Ti me p oi nt  
Tre at me nt A  
Tre at me nt B  
Starti n g d ose  
2 0 m g Q D  f or 8 wee ks 
( Da y 1 t hr o u g h Da y 5 6) 
2 0 m g Q D  f or 8 wee ks 
( Da y 1 t hr o u g h Da y 5 6) 
First d ose re d ucti o n  
1 0 m g Q D  
1 0 m g Q D  
Sec o n d d ose re d ucti o n  
5 m g Q D  
5 m g Q D  
Wee k 9 ( Da y 5 7)  o n war d  
2 0 m g o nce wee kl y a 
2. 5 m g Q D b 
First d ose re d ucti o n  
1 0 m g  o nce wee kl y  
1 m g Q D c 
Sec o n d d ose re d ucti o n  
5 m g  o nce wee kl y  
N A  
a All s u bjects will recei ve 2 0 m g o nce wee kl y at W ee k 9 ( Da y 5 7) re gar dless of pri or d ose le vel , u nless a d ose 
m o dificati o n of a s witc h t o a Q W sc he d ule bef ore W ee k 9 is re q uire d f or diarr hea/c olitis  ma na ge me nt (s ee 
Ta ble  5). 
b All s u bjects will recei ve 2. 5 m g Q D at Wee k 9 ( Da y 5 7) re gar dless of pri or d ose le vel , u nless a d ose m o dificati o n 
of a s witc h t o a Q W sc he d ule is re q uire d f or diarr hea /c olitis ma na g e me nt (s ee Ta ble  5). 
c F urt her  d ose m o dificati o n d ue t o diarr hea or c olitis f or s u bjects o n 1 m g Q D is per mitte d  (see Ta ble  5). 
5. 4. 2.  
S u p p orti ve C are G ui deli nes f or Di arr he a/ C olitis  
S u bjects s h o ul d be i nf or me d t o i m me diatel y re p ort t o t he i n vesti gat or a n y e ve nt of diarr hea.  
Treat me nt wit h I N C B 0 5 0 4 6 5 ma y be i nterr u pte d or m o difie d acc or di n g t o t he g ui deli nes i n 
Ta ble  5 t o all o w f or res ol uti o n of diarr hea/c olitis . 
S u bjects s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y b y t he 
i n vesti gat or.  F or a n y ≥ Gra de 1 diarr hea, s u bjects s h o ul d be a d vise d t o dri n k li beral q ua ntities of 
clear fl ui ds.  If s ufficie nt oral fl ui d i nta ke is  n ot feasi ble, fl ui d a n d electr ol ytes s h o ul d be 
s u bstit ute d via I V i nf usi o n.  S u bjects s h o ul d tr y t o eat 5 t o 6 s mall meals per da y; l o w-fat, 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 5 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

hi g h- pr otei n f o o ds; a n d c o o ke d i nstea d of ra w ve geta bles.  S u bjects ma y s u p ple me nt t heir diet 
wit h ba na nas, rice, a p plesa uce, a n d t oast t o re d uce t he n u m ber of b o wel m o ve me nts a n d ma y 
als o tr y crac kers, gelati n, n o o dles, or oat meal.  S u bjects s h o ul d a v oi d frie d, fatt y, greas y, or s pic y 
f o o ds; mil k, mil k pr o d ucts, a n d aci dic dri n ks; hi g h-fi ber f o o ds a n d f o o ds t hat ca use gas; a n d 
alc o h ol, caffei ne, a n d her bal s u p ple me nts ( C o utré et al 2 0 1 5). 
F or eac h occ urre nce, atte m pts s h o ul d be ma de t o r ule o ut ot her ca uses, s uc h as metastatic disease 
or bacterial or viral i nfecti o n (i ncl u di n g C M V), w hic h mi g ht re q uire a d diti o nal s u p p orti ve care. 
It ma y be necessar y t o perf or m c o n diti o nal pr oce d ures s uc h as c ol o n osc o p y wit h bi o ps y as part 
of e val uati o n of t he e ve nt.  N ote t hat se veral c o urses of ster oi d ta peri n g ma y be necessar y as 
s y m pt o ms ma y w orse n w he n t he ster oi d d ose is decrease d. 
S u bjects s h o ul d be caref ull y m o nit ore d f or si g ns a n d s y m pt o ms of e nter oc olitis (s uc h as diarr hea, 
a b d o mi nal pai n or cra m pi n g, bl o o d or m uc us i n st o ol, wit h or wit h o ut fe ver) a n d of b o wel 
perf orati o n (s uc h as perit o neal si g ns a n d ile us). 
T a ble  5: 
G ui deli nes f or D ose M o dific ati o n of I N C B 0 5 0 4 6 5 f or Di arr he a/ C olitis  
A D V E R S E E V E N T  
A C TI O N T A K E N  
•  Diarr hea ( Gra de 1).  
Ste p 1:   Treat wit h a nti m otilit y a ge nts (e g, 4 m g l o pera mi de  f oll o we d b y 2 
m g e ver y 4 h o urs or after e ver y u nf or me d st o ol) a n d i nitiate s u p p orti ve care 
(see Secti o n  5. 4. 2 ).  M o nit or a p pr o xi matel y e ver y 4 8 h o urs u ntil res ol ve d.  
If n ot i m pr o ve d after 4 8 h o urs, treat per g ui da nce f or Gra de 2.  
•  Diarr hea ( Gra de 2).  
Ste p 1:   I nterr u pt I N C B 0 5 0 4 6 5.  Perf or m w or k-u p f or i nfecti o n (i ncl u di n g 
C M V, C. difficile , etc) i m me diatel y.  I nitiate or c o nti n ue s u p p orti ve care 
(see Secti o n  5. 4. 2 ).  M o nit or a p pr o xi matel y e ver y 4 8 h o urs u ntil res ol uti o n . 
Ste p 2:   If i m pr o ve d wit hi n 4 8 h o urs a n d/ or i nfecti o n* is c o nfir me d , restart 
I N C B 0 5 0 4 6 5 at t he s a me sc he d ule a n d d ose after res ol ve d t o ≤ Gra de 1 
a n d c o nti n ue t o m o nit or.  
* F or i nfecti o us  diarr hea/ c olitis, f oll o w i nstit uti o nal sta n dar d-of -care 
g ui deli nes a n d restart I N C B 0 5 0 4 6 5 acc or di n g t o cli nical j u d ge me nt after 
res ol ve d t o ≤ Gra de 1.  C o ns ult wit h me dical m o nit or if nee de d . 
Ste p 3:   If n ot i m pr o ve d wit hi n 4 8 h o urs a n d i nfecti o n is r ule d o ut, start oral 
ster oi ds, or c o nsi der I V ster oi ds if partici pa nt  is bei n g gi ve n I V fl ui ds.  If n o 
i m pr o ve me nt wit h oral ster oi ds, s witc h t o I V ster oi ds. 
Ste p 4:   W he n diarr hea res ol ves t o ≤ Gra de 1, c o nti n ue s u p p orti ve care a n d 
ta per ster oi ds acc or di n g t o i nstit uti o nal sta n dar d of care .  W he n ta per is 
c o m plete (e g, n o ster oi d or ≤ 1 0 m g/ da y pre d nis o ne or e q ui vale nt ) a n d 
diarr hea is ≤ Gra de 1, restart I N C B 0 5 0 4 6 5 at t he ne xt l o wer d ose wit h 
a p pr o val of t he me dical m o nit or  (see Ta ble  4 f or d ose le vels). 
Ste p 5:   If Gra de 2 diarr hea re occ urs, treat per g ui da nce f or diarr hea 
( ≥ Gra de  3)/ n o ni nfecti o us c olitis . 
Ste p 6:   If ≥ Gra de 2 diarr hea re occ urs a t hir d ti me, per ma ne ntl y 
disc o nti n ue I N C B 0 5 0 4 6 5.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 6 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

T a ble  5: 
G ui deli nes f or D ose M o dific ati o n of I N C B 0 5 0 4 6 5 f or Di arr he a/ C olitis 
( C o nti n ue d) 
A D V E R S E E V E N T  
A C TI O N T A K E N  
•  Diarr hea ( ≥ Gra de 3) . 
•  N o ni nfecti o us colitis (a n y 
gra de; c o nfir me d or s us pecte d) . 
Ste p 1:   I nterr u pt I N C B 0 5 0 4 6 5.  Perf or m w or k-u p f or i nfecti o n (i ncl u di n g 
C M V, C. difficile , etc) i m me diatel y.  Initiate or c o nti n ue s u p p orti ve care 
(see Secti o n  5. 4. 2 ).  C o nsi der c ol o n osc o p y wit h bi o ps y f or diarr hea 
≥ Gra de  3 a n d/ or if s y m pt o msa s u g gesti ve of c olitis.  M o nit or e ver y 
4 8  h o urs u ntil res ol uti o n.  
Ste p  2:   If i nfecti o n* is r ule d o ut, start oral ster oi ds, or c o nsi der I V ster oi ds 
if partici pa nt is bei n g gi ve n I V fl ui ds.  If n o i m pr o ve me nt wit h oral ster oi ds 
wit hi n 4 8 h o urs, s witc h t o I V ster oi ds. 
* F or i nfecti o us diarr hea/c olitis, f oll o w i nstit uti o nal sta n dar d of care 
g ui deli nes a n d restart parsaclisi b acc or di n g t o cli nical j u d ge me nt after 
res ol ve d t o ≤ Gra de  1.   Co ns ult wit h me dical m o nit or if nee de d . 
Ste p 3:   W he n diarr hea/c olitis  res ol ves t o ≤ Gra de 1, c o nti n ue s u p p orti ve 
care a n d ta per ster oi ds acc or di n g t o i nstit uti o nal sta n dar d of care .  W he n 
ta per is c o m plete (e g, n o ster oi d or ≤ 1 0 m g/ da y pre d nis o ne or e q ui vale nt ) 
a n d diarr hea /c olitis is ≤ Gra de 1, restart I N C B 0 5 0 4 6 5 as descri be d herei n 
a n d wit h a p pr o val of t he me dical m o nit or .  C o nti n ue t o m o nit or.  
I N C B 0 5 0 4 6 5 C urre nt D ose 
D ose M o dific ati o n  
A n y d ose wit h  Q D d osi n g  
2 0 m g Q W re gar dless of 
Treat me nt  A or B assi g n me nt  
2 0 or 1 0 m g Q W  
Restart ne xt l o wer d ose  
5 m g Q W  
Per ma ne ntl y disc o nti n ue  
Ste p 4:   If ≥ Gra de 3 diarr hea/c olitis (a n y gra de) re occ urs, per ma ne ntl y 
disc o nti n ue I N C B 0 5 0 4 6 5. 
a Diarr hea acc o m pa nie d b y a b d o mi nal pai n a n d/ or m uc us or bl o o d i n st o ol . 
5. 4. 3.  
S u p p orti ve C are G ui deli nes f or Ne utr o pe ni a a n d T hr o m b oc yt o pe ni a  
Ne utr o pe nia a n d t hr o m b oc yt o pe nia a p pear t o be PI 3 K δ class -effect t o xicities.  I n vesti gat ors 
s h o ul d e ns ure t hat s u bjects u n dersta n d t he nee d t o see k me dical care w he n t he y ha ve c o n diti o ns 
t hat c o ul d bec o me life-t hreate ni n g i n t he prese nce of c yt o pe nias (e g, ne utr o pe nic fe ver or 
blee di n g wit h l o w platelets).  S u bjects s h o ul d be i nstr ucte d t o re p ort i m me diatel y a n y si g ns of 
i nfecti o n, u ne x pecte d blee di n g, or s u d de n, e xtre mel y pai nf ul hea dac hes. 
5. 4. 4.  
Defi niti o n f or I m m u ne -Rel ate d A d verse E ve nts  
A d verse e ve nts of a p ote ntial i m m u n ol o gic eti ol o g y, or ir A Es, ma y be defi ne d as a n A E 
c o nsiste nt wit h a n i m m u ne p he n o me n o n ass ociate d wit h st u d y treat me nt e x p os ure after all ot her 
eti ol o gies ha ve bee n eli mi nate d.  I m m u ne-relate d A Es ma y be e x pecte d base d o n pre vi o us 
e x perie nce  wit h I N C B 0 5 0 4 6 5.  S pecial atte nti o n s h o ul d be pai d t o A Es t hat ma y be s u g gesti ve of 
p ote ntial ir A Es.  Base d o n e mer gi n g data fr o m t he o n g oi n g St u d y I N C B 5 0 4 6 5- 1 0 1, m ost ir A Es 
occ ur after t he first 9 wee ks of st u d y treat me nt a d mi nistrati o n.  H o we ver, a n ir A E c o ul d occ ur at 
a n y ti me.  S us pecte d ir A Es s h o ul d be disc usse d wit h t he me dical m o nit or w he n p ossi ble. 
S u bjects s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y b y t he 
treati n g i n vesti gat or.  S u g geste d s u p p orti ve care meas ures f or t he ma na ge me nt of dr u g-relate d 
A Es wit h p ote ntial i m m u n ol o gic eti ol o g y are o utli ne d i n Ta ble  3 a n d Secti o n  5. 4. 1 .  F or eac h 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A E, atte m pts s h o ul d be ma de t o r ule o ut ot her ca uses, i ncl u di n g b ut n ot li mite d t o metastatic 
disease or bacterial or viral i nfecti o n, w hic h mi g ht re q uire s pecific s u p p orti ve c are. 
5. 5.  
St u d y Tre at me nt  Disc o nti n u ati o n  
T he decisi o n t o disc o nti n ue st u d y treat me nt will n ot c o nstit ute st u d y c o m pleti o n.  I n t he e ve nt 
t hat st u d y treat me nt is disc o nti n ue d, t he treat me nt peri o d will be c o nsi dere d c o m plete, a n d t he 
f oll o w- u p peri o ds will be gi n.  
5. 5. 1.  
Criteri a  f or St u d y Tre at me nt Disc o nti n u ati o n 
S u bjects m ust  be wit h dra w n fr o m st u d y treat me nt f or a n y 1 of f oll o wi n g reas o ns: 
•  T he s u bject has e x perie nce d a n u nacce pta ble t o xicit y defi ne d as f oll o ws:  
− Occ urre nce of a n A E t hat is relate d t o st u d y treat me nt t hat, i n t he j u d g me nt of t he 
i n vesti gat or or t he s p o ns or's me dical m o nit or, c o m pr o mises t he s u bject's a bilit y t o 
c o nti n ue st u d y -s pecific pr oce d ures or is c o nsi dere d t o n ot be i n t he s u bject's best 
i nterest. 
− Persiste nt A E re q uiri n g a dela y of t her a p y f or m ore t ha n 2 wee ks ( 1 4 da ys) u nless 
a greater dela y has bee n a p pr o ve d b y t he s p o ns or.  
•  T he s u bject is u na ble t o t olerate st u d y treat me nt.  
•  T he s u bject has a n o bjecti ve ra di o gra p hic t u m or res p o nse of P D. 
•  F urt her partici pati o n w o ul d be i nj uri o us t o t he s u bject's healt h or well- bei n g, i n t he 
i n vesti gat or's me dical j u d g me nt. 
•  T he s u bject bec o mes pre g na nt. 
•  I nf or me d c o nse nt is wit h dra w n.   
N ote:   C o nse nt wit h dra w n mea ns t hat t he s u bject ca n n o l o n ger be f oll o we d.  
S u bjects ma y c h o ose t o disc o nti n ue st u d y treat me nt a n d re mai n i n t he st u d y t o be 
f oll o we d f or disease pr o gressi o n a n d s ur vi val per t he sc he d ule of assess me nts. 
•  T he st u d y is ter mi nate d b y t he s p o ns or. 
•  T he st u d y is ter mi nate d b y t he l ocal healt h a ut h orit y, I R B, or I E C. 
A s u bject m a y  be disc o nti n ue d fr o m st u d y treat me nt i n t he f oll o wi n g sit uati o ns:  
•  If a s u bject is n o nc o m plia nt wit h st u d y pr oce d ures or st u d y treat me nt a d mi nistrati o n 
i n t he i n vesti gat or's o pi ni o n, t he n t he s p o ns or s h o ul d be c o ns ulte d f or i nstr ucti o n o n 
ha n dli n g t he s u bject.  
5. 5. 2.  
Pr oce d ures  f or St u d y Tre at me nt Disc o nti n u ati o n  
Reas o na ble eff orts s h o ul d be ma de t o ha ve t he s u bject ret ur n f or a f oll o w- u p visit.   T hese visits 
are descri be d i n Secti o n  6. 4 .  T he last date of t he last d ose of st u d y treat me nt a n d t he reas o n f or 
s u bject wit h dra wal will be rec or de d i n t he e C R F. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 8 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

If a s u bject per m a ne ntl y disc o nti n ues st u d y tre at me nt, t he n t he f oll o win g s h o ul d occ ur:  
•  T he reas o n(s) f or disc o nti n uati o n m ust be d oc u me nte d i n t he s u bject' s me dical rec or d 
a n d i n t he eC R F.  
•  T he E O T  visit s h o ul d be perf or me d. 
− If t he E O T visit c oi nci des wit h a re g ular st u d y visit, t he n t he E O T e val uati o ns 
will s u perse de t h ose of t hat sc he d ule d visit, a n d t he data will be e ntere d i n t he 
E O T visit i n t he e C R F.  
•  T he date of t he E O T visit s h o ul d be rec or de d i n t he I WR S.  
•  S u bjects m ust be f oll o we d f or safet y f or n o less t ha n 3 0 da ys after t he E O T visit or 
u ntil st u d y dr u g –relate d t o xicities res ol ve, ret ur n t o baseli ne, or are dee me d 
irre versi ble, w hic he ver is l o n gest. 
If t he s u bject disc o nti n ues st u d y treat me nt a n d acti vel y wit h dra ws c o nse nt f or c ollecti o n of 
f oll o w- u p data (safet y f oll o w- u p or disease assess me nt), t he n n o a d diti o nal data will be 
c ollecte d.  Ho we ver, s u bjects ma y wit h dra w c o nse nt f or st u d y treat me nt b ut c o nti n ue t o be 
assesse d f or disease pr o gressi o n a n d s ur vi val per t he sc he d ule of assess me nts.  
5. 6.  
C o nc o mit a nt Me dic ati o ns  
All c o nc o mita nt me dicati o ns a n d treat me nts m ust be rec or de d i n t he e C R F.  A n y pri or 
me dicati o n recei ve d u p t o 3 0 da ys bef ore t he date of st u d y treat me nt a d mi nistrati o n ( Da y 1) will 
be rec or de d i n t he e C R F.  C o nc o mita nt treat me nts a n d/ or pr oce d ures t hat are  re q uire d t o ma na ge 
a s u bject 's me dical c o n diti o n d uri n g t he st u d y will als o be rec or de d i n t he e C R F.   
5. 6. 1.  
P ne u m ocystis Jir oveci i P ne u m o ni a Pr o p h yl a xis  
All s u bjects are re q uire d t o recei ve a sta n dar d PJ P pr o p h yla xis re gi me n deter mi ne d b y t he 
i n vesti gat or (see Secti o n 5. 2. 2 ).  E xa m ples of sta n dar d PJ P pr o p h yla xis t hera pies f or t his 
p o p ulati o n i ncl u de tri met h o pri m-s ulfa met h o xaz ole, at o va q u o ne, da ps o ne wit h or wit h o ut 
p yri met ha mi ne, a n d pe nta mi di ne ( N C C N  2 0 1 7).  D ue t o re p orts of cr oss-se nsiti vit y bet wee n 
s ulf o na mi des a n d da ps o ne, all s u bjects w h o ha ve a k n o w n or s us pecte d aller g y t o s ulf o na mi des 
m ust recei ve eit her i n hale d pe nta mi di ne or at o va q u o ne f or PJ P pr o p h yla xis.  Pr o p h yla xis s h o ul d 
be gi ve n w hile s u bjects are recei vi n g st u d y treat me nt a n d s h o ul d c o nti n ue f or at least 2 t o 
6 m o nt hs after t he last d ose of st u d y treat me nt.  
5. 6. 2.  
Restricte d Me dic ati o ns  
•  Use of s yste mic c ortic oster oi d d oses ≤ 1 0 m g/ da y pre d nis o ne ( or e q ui vale nt) is 
per mitte d b ut disc o ura ge d fr o m t he scree ni n g visit t hr o u g h E O T.  
•  S h ort c o urses of s yste mi c c ortic oster oi d d oses > 1 0 m g/ da y pre d nis ol o ne or 
e q ui vale nt are per mitte d o nl y i n t he case of se vere or life -t hreate ni n g c o m plicati o ns, 
w hic h ca n n ot be c o ntr olle d wit h ot her dr u gs, b ut are ot her wise disc o ura ge d fr o m t he 
scree ni ng visit t hr o u g h E O T. 
•  Use of wea k or m o derate i n d ucers or i n hi bit ors of C Y P 3 A 4 ( see A p pe n di x D ) is 
disc o ura ge d, a n d i n vesti gat ors s h o ul d see k ot her o pti o ns w here p ossi ble. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 3 9 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

•  Use of  P- gl yc o pr otei n s u bstrates of cli nical rele va nce s h o ul d be use d wit h ca uti o n 
(ie, alis kire n, a m brise nta n, c o lc hici ne, da bi gatra n ete xilate, di g o xi n, e ver oli m us, 
fe x ofe na di ne, i mati ni b, la pati ni b, mara vir oc, nil oti ni b, p osac o naz ole, ra n olazi ne, 
sa xa gli pti n, sir oli m us, sita gli pti n, tali n ol ol, t ol va pta n, t o p oteca n) fr o m t he scree ni n g 
visit t hr o u g h t he E O T visit . 
•  L o calize d ra di ot hera p y will be per mitte d if a d mi nistere d as treat me nt f or pai n or 
i m pe n di n g c o m pressi o n fract ures a n d wit h pri or a p pr o val of t he me dical m o nit or. 
5. 6. 3.  
Pr o hi bite d Me dic ati o ns  
•  Use of p ote nt i n d ucers a n d i n hi bit ors of C Y P 3 A 4 is pr o hi bite d (see A p pe n di x D ).  
Base d o n t he l o w o verall bi oa vaila bilit y of t o pical ket oc o naz ole, t here are n o 
restricti o ns o n t o pical ket oc o naz ole.  
•  A part fr o m t he st u d y t reat me nts, t he use of a n y a ntica ncer me dicati o ns as descri be d 
(see Secti o n  3. 2 ) t hr o u g h t he 3 0- da y f oll o w-u p is pr o hi bite d.  
•  E x p os ure t o a li ve vacci ne wit hi n 3 0 da ys of st u d y treat me nt t hr o u g h 3 m o nt hs after 
t he last d ose of I N C B 0 5 0 4 6 5. 
5. 7.  
Criteri a f or St u d y Disc o nti n u ati o n  
A s u bject will be disc o nti n ue d fr o m t he st u d y f or a n y 1 of t he f oll o wi n g reas o ns: 
•  T he s u bject has die d. 
•  T he s u bject is c o nsi der e d l ost-t o-f oll o w- u p w he n he/s he re peate dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site (e g, after 3 tele p h o ne 
calls a n d/ or a certifie d letter or l ocal e q ui vale nt).  
•  I nf or me d c o nse nt is wit h dra w n. 
•  T he st u d y is ter mi n ate d b y t he s p o ns or. 
•  T he st u d y is ter mi nate d b y t he l ocal healt h a ut h orit y , I R B or I E C. 
5. 8.  
Tre at me nt After t he E n d of t he St u d y  
At t he e n d of t he st u d y as defi ne d i n S ecti o n 6. 5 , s u bjects w h o ha ve c o m plete d at least 2 4 m o nt hs 
of st u d y partici pati o n (starti n g fr o m t he first d ose of st u d y treat me nt), w h o re mai n o n acti ve 
st u d y treat me nt, a n d w h o ha ve n o e vi de nce of pr o gressi ve disease will ha ve  t he o pti o n t o 
c o nti n ue o n m o n ot hera p y wit h I N C B 0 5 0 4 6 5 pr o vi de d wit hi n a r oll o ver Pr ot oc ol, as l ocal la w 
per mits . 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 0 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

6.  
S T U D Y A S S E S S M E N T S  
All st u d y assess me nts will be perf or me d as i n dicate d  i n t he sc he d ule of assess me nts (Ta ble  6), 
a n d all la b orat or y assess me nts will be perf or me d as i n dicate d i n  Ta ble  7.  All assess me nts 
ma n date d t hr o u g h o ut t he st u d y m ust be perf or me d o n a cale n dar sc he d ule; dela ys i n treat me nt 
a d mi nistrati o n will n ot del a y perf or ma nce of assess me nts.   B y c o n ve nti o n, Wee k 4, Wee k 8, 
Wee k 1 2, etc, mea ns t he c o m pleti o n of 4, 8, or 1 2 wee ks , res pecti vel y.  Ta ble  8 prese nts a 
s u m mar y of cli nical la b orat or y a nal ytes t o be assesse d.  T he or der of assess me nts is s u g geste d b y 
t he or der of me nti o n wit hi n t he sc he d ule of assess me nts .  See Secti o n  7  f or i nstr ucti o ns o n eac h 
assess me nt . 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 1 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

T a ble  6: 
Sc he d ule of Assess me nts  
Pr oce d ure  
Secti o n  
Scree ni n
g  
Tre at me nt  
E O T  
F oll o w -U p  
D a ys  
-2 8 t o -1  
D a y 1 a 
E ver y 4  Wee ks 
T hr o u g h Wee k 4 8  
( ± 3 D a ys)  
E ver y 1 2 
Wee ks Fr o m 
Wee k 4 8  
( ± 1 Wee k) 
S afet y  
Dise ase  
S ur vi v al  
E O T +  
3 0 -3 5 
D a ys  
 
E ver y 
1 2  Wee ks 
( ± 1  Wee k)  
I nf or me d c o nse nt 
7. 1  
X  
 
 
 
 
 
 
 
C o ntact I W R S  
7. 2  
X  
X  
X  
X  
X  
 
 
 
I ncl usi o n a n d e xcl usi o n criteria 
3  
X  
X  
 
 
 
 
 
 
De m o gra p h y a n d me dical 
hist or y  
7. 3  
X 
 
 
 
 
 
 
 
Pri or/c o nc o mita nt me dicati o ns  
7. 4  
X  
X  
X  
X  
X  
X  
 
 
A E assess me nt d 
8. 1  
X  
X  
X  
X  
X  
X  
 
 
C o m pre he nsi ve p h ysical e xa m  
7. 5. 2  
X e 
 
 
 
X  
 
 
 
Disease -s pecific p h ysical e xa m 
7. 5. 3  
 
X  
X  
X  
 
X  
 
 
Vital si g ns  
7. 5. 4  
X  
X  
X  
X  
X  
X  
 
 
1 2 -lea d E C G 
7. 5. 5  
X  
X f 
X f 
X  
X  
X  
 
 
E C O G perf or ma nce stat us  
7. 5. 6  
X  
X  
X  
X  
X  
X  
 
 
C T/ M RI sca n  
7. 6. 1  
X 
 
E ver y 8  wee ks t hr o u g h Wee k  2 4 
( ± 1 wee k) , t he n 
e ver y 1 2 wee ks t hr o u g h Wee k 9 6, a n d 
t he n e ver y 2 4 wee ks t hereafter u ntil 
P D  
 
 
X c 
 
B o ne marr o w e xa m  
7. 6. 2  
X g 
 
X h 
 
 
X h 
 
Pr o p h ylactic treat me nt f or PJ P  
5. 6. 1  
 
X i 
 
 
 
St u d y treat me nt dis pe nsi n g  
5. 1. 1  
 
X  
X  
X  
 
 
 
 
St u d y treat me nt c o m plia nce  
5. 3  
 
X  
X  
X  
X  
 
 
 
I N C B 0 5 0 4 6 5 a d mi nistrati o n 
5. 2. 1  
 
X  
X  
X  
 
 
 
 
Disease f oll o w -u p  
6. 4. 2  
 
 
 
 
 
 
X c 
 
S ur vi val f oll o w -u p  
6. 4. 3  
 
 
 
 
 
 
 
X j 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 2 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

a All pr oce d ures are t o be perf or me d bef ore a d mi nistrati o n of st u d y treat me nt o n Da y 1 . 
 
 
 
 
d A d verse e ve nts will be m o nit ore d fr o m t he ti me t he s u bject si g ns t he I C F u ntil at least 3 0 da ys after t he last d ose of st u d y treat me nt.  Seri o us A Es occ urri n g m ore t ha n 3 0 da ys 
after t he last d ose of st u d y treat me nt s h o ul d be re p orte d t o t he s p o ns or or its desi g nee if t he i n vesti gat or s us pects a ca usal relati o ns hi p t o t he st u d y treat me nt.  O nce detecte d, A Es 
s h o ul d be f oll o we d u ntil res ol ve d or j ud ge d t o be per ma ne nt.  
e Hei g ht re q uire d at scree ni n g o nl y . 
f Ti me d tri plicate E C G s will be o btai ne d d uri n g t he Da y 1 visit ( pre d ose) a n d Wee k 4 visit ( pre d ose a n d 1. 5 h o urs [± 1 5 mi n utes ] after recei vi n g st u d y treat me nt).   
g Re q uire d at baseli ne e xce pt f or reas o ns pr o vi de d i n Secti o n  7. 6. 2 .   
h If disease is prese nt i n b o ne marr o w at baseli ne, a b o ne marr o w bi o ps y will be re q uire d t o c o nfir m C R or ma y be perf or me d as cli nicall y i n dicate d.  F or s u bjects wit h s ple nic 
M Z L wit h o ut meas ura ble disease (ie, o nl y ha ve hist ol o gicall y c o nfir me d b o ne marr o w i nfiltrati o n), a b o ne marr o w bi o ps y/e xa mi nati o n m ust be perf or me d w he n t he n u m ber of 
l y m p h oc ytes i n t he bl o o d n or malize. 
i P ne u m ocystis jir ovecii  p ne u m o nia pr o p h yla xis s h o ul d be gi ve n w hile s u bjects are recei vi n g st u d y treat me nt a n d c o nti n ue f or at least 2 t o 6 m o nt hs after t he last d ose of st u d y 
treat me nt. 
j Ma y be c o n d ucte d b y cli nic visit, tele p h o ne, o r e mail. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 3 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

T a ble  7: 
Sc he d ule of L a b or at or y Assess me nts  
L a b or at or y Tests a 
Secti o n  
Scree ni n g  
Tre at me nt  
E O T  
S afet y 
F oll o w -U p  
D a y  
-2 8 t o -1  
D a y 1 b  
E ver y 4  Wee ks 
T hr o u g h Wee k 4 8  
( ± 3 D a ys) 
E ver y 1 2 Wee ks 
F r o m Wee k 4 8 
( ± 1 Wee k) 
Ot her  
E O T +  
3 0 -3 5 D a ys  
Ser u m c he mistries  
7. 5. 7. 1  
X  
X c 
X  
X  
 
X  
X  
He mat ol o g y d 
7. 5. 7. 1  
X  
X c 
X  
X  
X e 
X  
X  
Ser ol o g y  
7. 5. 7. 3  
X  
 
X f 
X f 
 
 
 
HI V testi n g  
7. 5. 7. 3. 1  
X g 
 
 
 
 
 
 
Ser u m pre g na nc y  
7. 5. 7. 2  
X h 
 
 
 
 
X  
 
Uri ne pre g na nc y  
7. 5. 7. 2  
 
 
 
 
X i 
 
 
T u m or / b o ne marr o w 
bi o ps y  
7. 8. 5  
X m  
 
 
 
X n 
 
 
a All la b orat or y assess me nts m ust be perf or me d at a ce ntral la b orat or y, u nless ot her wise s pecifie d (see Secti o n  7. 5. 7 ). 
b All la b orat or y assess me nts are t o be perf or me d bef ore a d mi nistrati o n of st u d y treat me nt o n Da y 1, u nless ot her wise s pecifie d.  
c If c he mistr y a n d/ or he mat ol o g y la b orat or y assess me nts occ urre d i n t he prece di n g 7 da ys, Da y 1 assess me nts ma y be o mitte d. 
d He mat ol o g y will be c ollecte d e ver y 2 wee ks f or t he first 8 wee ks.  
e Wee k 2 ( Da y 1 5) a n d Wee k 6 ( Da y 4 3) ± 3 da ys.  
f Sa m ples f or C M V D N A a nal ysis o nl y.  
g O pti o nal f or s u bjects e nr olle d i n t he U nite d States.  
h O nl y f or fe males of c hil d beari n g p ote ntial; ne gati ve ser u m pre g na nc y test m ust be o btai ne d wit hi n 1 4 da ys bef ore a d mi nistrati o n of st u d y treat me nt.  Scree ni n g test ma y be 
perf or me d ce ntrall y or  at t he i n vesti gati ve site la b orat or y.  
i O nl y f or fe males of c hil d beari n g p ote ntial; if a uri ne pre g na nc y test is p ositi ve, t he n a ser u m pre g na nc y test s h o ul d be perf or me d.  Uri ne pre g na nc y m ust  be c ollecte d e ver y 
4 wee ks u ntil last d ose of st u d y treat me nt.  
 
 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

T a ble  8: 
L a b o r at or y Tests:  Re q uire d A n al ytes  
Ser u m C he mistries  
He m at ol o g y  
Ser ol o g y  
Al b u mi n  
Al kali ne p h os p hatase  
A L T 
A S T  
Bicar b o nate  
Bl o o d urea nitr o ge n  
C- reacti ve pr otei n 
Calci u m  
C hl ori de  
Creati ni ne  
Gl uc ose  
Lactate de h y dr o ge nase  
P h os p hate  
P otassi u m  
S o di u m  
T otal bilir u bi n  
Direct bilir u bi n (if t otal bilir u bi n is 
> U L N)  
T otal pr otei n  
Uric aci d  
C o m plete bl o o d c o u nt, 
i ncl u di n g: 
He m o gl o bi n  
He mat ocrit  
Platelet c o u nt (a bs ol ute)  
Re d bl o o d cell c o u nt  
W hite bl o o d cell c o u nt  
 
Differe ntial c o u nt, i ncl u di n g:  
Bas o p hils  
E osi n o p h ils 
L y m p h oc ytes  
M o n oc ytes  
Ne utr o p hils  
 
A bs ol ute val ues m ust be 
pr o vi de d f or:  
W B C differe ntial la b orat or y 
res ults: 
L y m p h oc ytes  
Ne utr o p hils  
He patitis B s urface a nti ge n  
He patitis B s urface a nti ge n a nti b o d y  
He patitis B c ore a nti b o d y  
H B V -D N A  
H C V a nti b o d y  
H C V -R N A  
C M V D N A  
HI V a nti b o d y (i m m u n oassa y) a 
Pre g n a nc y Testi n g  
O nl y f or fe male s u bjects of 
c hil d beari n g p ote ntial  
Pre g na nc y tests (ser u m or uri ne) 
s h o ul d be re peate d if re q uire d b y 
l ocal re g ulati o ns. 
N ote:  A d diti o nal tests ma y be re q uire d, as a gree d b y i n vesti gat or a n d s p o ns or, base d o n e mer gi n g safet y data.  
a O pti o nal f or s u bjects e nr olle d i n t he U nite d States . 
6. 1.  
Scree ni n g  
Scree ni n g is t he i nter val bet wee n si g ni n g t he I C F a n d t he date of first d ose of st u d y treat me nt 
( Da y 1).  Scree ni n g ma y n ot e xcee d 2 8 da ys.  Assess me nts t hat are re q uire d t o de m o nstrate 
eli gi bilit y ma y be perf or me d o ver t he c o urse of 1 or m ore da ys d uri n g t he scree ni n g pr ocess.  
Ce ntral la b orat or y res ults f or ser u m c he mistr y, he mat ol o g y, a n d ser ol o g y will be use d t o 
deter mi ne eli gi bilit y.  Ser u m pre g na nc y tests ma y be perf or me d ce ntrall y or at t he i n vesti gati ve 
site la b orat or y. 
Pr oce d ures c o n d ucte d as part of t he s u bject 's r o uti ne cli nical ma na ge me nt (e g, i ma gi n g st u d y) 
a n d o btai ne d bef ore si g ni n g of i nf or me d c o nse nt ma y be use d f or scree ni n g or baseli ne p ur p oses, 
pr o vi de d t hat t he pr oce d ure meets t he Pr ot oc ol- defi ne d criteria a n d has bee n perf or me d i n t he 
scree ni n g i nter val.  All i nf or mati o n ass ociate d wit h eli gi bilit y re q uire me nts m ust be e ntere d i nt o 
t he a p pr o priate e C R F pa ges. 
Res ults fr o m t he scree ni n g visit e val uati o ns will be re vie we d b y t he i n vesti gat or t o c o nfir m 
s u bject eli gi bilit y bef ore e nr oll me nt or t he a d mi nistrati o n of st u d y dr u g.  Tests wit h res ults t hat 
fail eli gi bilit y re q uire me nts ma y be re peate d d uri n g scree ni n g if t he i n vesti gat or belie ves t he 
res ults t o be i n err or.  F or scree ni n g assess me nts t hat are re peate d, t he m ost rece nt a vaila ble 
res ult bef ore a d mi nistrati o n of st u d y dr u g will be use d t o deter mi ne s u bject eli gi bilit y.  
A d diti o nall y, a s u bject w h o fails scree ni n g ma y re peat t he scree ni n g pr ocess 1 ti me if t he 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 6 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

i n vesti gat or belie ves t here has bee n a c ha n ge i n eli gi bilit y stat us (e g, after rec o ver y fr o m a n 
i nfecti o n).  S uc h s u bjects will be assi g ne d a ne w s u bject I D n u m ber. 
6. 2.  
Tre at me nt  
T he treat me nt peri o d be gi ns o n t he date of first d ose of st u d y treat me nt ( Da y 1).  Da y 1 m ust be 
n o m ore t ha n 2 8 da ys after t he s u bject has si g ne d t he I C F.  Dates f or s u bse q ue nt st u d y visits will 
be deter mi ne d base d o n t h is date a n d s h o ul d occ ur wit hi n t he visit wi n d o ws o utli ne d i n t he 
sc he d ule of assess me nts (see Ta ble  6) u nless dela ye d f or safet y reas o ns.  At Da y 1, res ults fr o m 
scree ni n g visit e val uati o ns s h o ul d be re vie we d b y t he i n vesti gat or t o deter mi ne w het her t he 
s u bject c o nti n ues t o meet t he eli gi bilit y re q uire me nts, as s pecifie d i n t he P r ot oc ol.  S u bjects ma y 
recei ve treat me nt u ntil disease pr o gressi o n, deat h, u nacce pta ble t o xicit y, or c o nse nt wit h dra wal. 
6. 3.  
E n d of Tre at me nt  
T here is n o defi ne d date of E O T.  W he n  t he s u bject per ma ne ntl y disc o nti n ues st u d y treat me nt, 
t he n t he E O T visit s h o ul d be c o n d ucte d.  If t he E O T  visit c oi nci des wit h a re g ular st u d y visit, t he 
E O T  e val uati o ns will s u perse de t h ose of t hat sc he d ule d visit, a n d t he data s h o ul d be e ntere d i n 
t he E O T  visit i n t he eC R F .  T he s u bject s h o ul d be e nc o ura ge d t o ret ur n f or t he safet y f oll o w- u p 
v isit. 
6. 4.  
F oll o w -U p  
6. 4. 1.  
S afet y F oll o w- U p  
T he safet y f oll o w- u p peri o d is t he i nter val bet wee n t he E O T visit a n d t he sc he d ule d f oll o w- u p 
visit, w hic h s h o ul d occ ur 3 0 t o 3 5 da ys after t he E O T visit ( or after t he last d ose of st u d y 
treat me nt if t he E O T visit was n ot perf or me d).  Ad verse e ve nts  a n d S A Es m ust be re p orte d u p 
u ntil at least 3 0 da ys after t he last d ose of st u d y treat me nt, t he date of t he f oll o w- u p visit, or u ntil 
t o xicities res ol ve, ret ur n t o baseli ne, or are dee me d irre versi ble, whic he ver is l o n ger.  Reas o na ble 
eff orts s h o ul d be ma de t o ha ve t he s u bject ret ur n f or t he f oll o w - u p visit a n d re p ort a n y A Es t hat 
ma y occ ur d uri n g t his peri o d.   
If a s u bject is sc he d ule d t o be gi n a ne w a ntica ncer t hera p y bef ore t he e n d of t he safet y f oll ow- u p 
peri o d, t he n t he  safet y f oll o w- u p visit s h o ul d be perf or me d bef ore ne w a ntica ncer t hera p y is 
starte d.  O nce ne w a ntica ncer t hera p y has bee n i nitiate d, t he s u bject will m o ve i nt o t he s ur vi val 
f oll o w- u p peri o d. 
6. 4. 2.  
Dise ase St at us  F oll o w-U p  
S u bjects w h o disc o nti n ue st u d y treat me nt f or a reas o n ot her t ha n disease pr o gressi o n will 
c o nti n ue t o be f oll o we d f or disease assess me nts  b y ra di ol o gic i ma gi n g per t he sc he d ule of 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

assess me nts (see Ta ble  6).  E ver y eff ort s h o ul d be ma de t o c ollect i nf or mati o n re gar di n g disease 
stat us u ntil 1 of t he f oll o wi n g occ urs: 
•  T he start of ne w a nti ne o plastic t hera p y.  
•  Disease pr o gressi o n . 
•  Deat h . 
•  T he e n d of t he st u d y. 
6. 4. 3.  
S ur vi v al F oll o w- U p  
O nce a s u bject has recei ve d t he last d os e of st u d y treat me nt, c o nfir me d disease pr o gressi o n , or 
starts a ne w a ntica ncer t hera p y, t he s u bject m o ves i nt o t he s ur vi val f oll o w- u p peri o d a n d s h o ul d 
be f oll o we d u p e ver y 1 2 wee ks  b y a cli nic visit, tele p h o ne, or e- mail .  T he site will use 
c o nti n ui n g s u bject rec or ds t o s u p pl y data o n s u bse q ue nt treat me nt re gi me ns, t u m or assess me nts 
(if disc o nti n ue d treat me nt f or a reas o n ot her t ha n pr o gressi o n), a n d O S i n t he e C R F. 
F or s u bjects w h o d o n ot i nte n d t o ret ur n t o t he st u d y i n vesti gat or f or t heir o n g oi n g care, 
f oll o w- u p s h o ul d be mai ntai ne d t o assess f or s ur vi val stat us u ntil deat h, wit h dra wal of c o nse nt, 
or t he e n d of t he st u d y, w hic he ver occ urs first. 
6. 5.  
E n d of St u d y  
T he e n d of t he st u d y will be w he n a ll s u bjects ha ve met a n y of t he st u d y disc o nti n uati o n criteria 
i n Secti o n  5. 7  or  ha ve c o m plete d at least 2 4 m o nt hs of st u d y partici pati o n (starti n g fr o m first 
d ose of I N C B 0 5 0 4 6 5). 
At t he e n d of t he st u d y, s u bjects w h o ha ve c o m plete d at least 2 4 m o nt hs of st u d y partici pati o n, 
w h o re mai n o n acti ve st u d y treat me nt, a n d w h o ha ve n o e vi de nce of pr o gressi ve disease will 
ha ve t he o pti o n t o c o nti n ue o n m o n ot h era p y wit h I N C B 0 5 0 4 6 5 pr o vi de d wit hi n a r oll o ver 
Pr ot oc ol, as l ocal la w per mits.  
6. 6.  
U nsc he d ule d Visits  
U nsc he d ule d visits ma y be hel d at a n y ti me at t he i n vesti gat or's discreti o n a n d a p pr o priate 
cli nical a n d la b orat or y meas ure me nts perf or me d base d o n A Es or o t her fi n di n gs. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 8 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

7.  
C O N D U C T O F S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
7. 1.  
A d mi nistr ati o n of I nf or me d C o nse nt F or m  
Vali d i nf or me d c o nse nt m ust be o btai ne d fr o m t he st u d y s u bject bef ore  c o n d ucti n g a n y 
st u d y-s pecific pr oce d ures usi n g a n I C F a p pr o ve d b y t he l ocal I R B/I E C t hat c o ntai ns all ele me nts 
re q uire d b y I C H E 6 a n d descri bes t he nat ure, sc o pe, a n d p ossi ble c o nse q ue nces of t he st u d y i n a 
f or m u n dersta n da ble t o t he st u d y s u bject.  L ocal a n d i nstit uti o nal g ui deli nes f or I C F c o nte nt a n d 
a d mi nistrati o n m ust be f oll o we d; t he ori gi nal si g ne d I C F m ust be retai ne d b y t he i n vesti gat or, 
a n d a c o p y of t he si g ne d I C F m ust be pr o vi de d t o t he st u d y s u bject.  T he i nf or me d c o nse nt 
pr ocess f or eac h s u bject m ust be d oc u me nte d i n writi n g wit hi n t he s u bject s o urce d oc u me ntati o n. 
7. 2.  
I nter acti ve We b Res p o nse Tec h n ol o g y  Pr oce d ure  
T he I WR S  will be c o ntacte d t o o btai n a s u bject I D n u m ber w he n a s u bject e nters scree ni n g.  
U p o n deter mi ni n g t hat t he s u bject is eli gi ble f or st u d y e ntr y, t he I WR S  will be c o ntacte d t o 
o btai n t he treat me nt assi gn me nt.   A d diti o nall y, t he I WR S  will be c o ntacte d at eac h re g ular st u d y 
v isit t o u p date t he st u d y treat me nt s u p pl y (see Secti o n  5. 1. 1  a n d Ta ble  6). 
7. 3.  
De m o gr a p h y a n d Me dic al Hist or y  
7. 3. 1.  
De m o gr a p hics a n d Ge ner al Me dic al Hist or y  
De m o gra p hic data a n d a ge neral me dical hist or y  will be c ollecte d at scree ni n g. 
7. 3. 2.  
Dise ase C h ar acteristics a n d Tre at me nt Hist or y  
A disease -tar gete d me dical a n d me dicati o n hist or y, i ncl u di n g date of dia g n osis of M Z L, 
hist ol o g y, c urre nt sta gi n g, gra de, sites of disease, pri or a nti ne o plastic t hera p y, s ur ger y, ra diati o n, 
a n d ot her details relate d t o t he disease u n der  st u d y, will be c ollecte d at scree ni n g.  
7. 4.  
Pri or  a n d C o nc o mit a nt Me dic ati o ns  a n d Pr oce d ures  
Pri or  a n d c o nc o mita nt me dicati o ns a n d pr oce d ures will be re vie we d t o deter mi ne s u bject 
eli gi bilit y.  All pri or a n d c o nc o mita nt me dicati o ns a n d meas ures m ust be rec or de d i n t he e C R F, 
a n d a n y me dicati o n recei ve d  or pr oce d ure perf or me d wit hi n 3 0 da ys bef ore e nr oll me nt a n d u p t o 
t he e n d of st u d y treat me nt will be rec or de d i n t he eC R F.  T he me dicati o n rec or d will be 
mai ntai ne d  after si g ni n g t he I C F t o d oc u me nt c o nc o mita nt me dicati o ns, i ncl u di n g a n y c ha n ges t o 
t he d ose or re gi me n.  C o nc o mita nt me dicati o ns i ncl u de a n y prescri pti o n, o ver-t he-c o u nter, or 
nat ural/ her bal pre parati o ns ta ke n or a d mi nistere d d uri n g t he st u d y peri o d.  C o nc o mita nt 
treat me nts a n d/ or pr oce d ures t hat are re q uire d t o ma na ge a s u bject's me dical c o n diti o n d uri n g t he 
st u d y will als o be rec or de d i n t he eC R F.  
7. 5.  
S afet y Assess me nts  
7. 5. 1.  
A d verse E ve nts  
A d verse e ve nts will be m o nit ore d fr o m t he ti me t he s u bject si g ns t he I C F.  S u bjects will be 
i nstr ucte d t o re p ort all A Es d uri n g t he st u d y a n d will be assesse d f or t he occ urre nce of A Es 
t hr o u g h o ut t he st u d y.  I n or der t o a v oi d bias i n eliciti n g A Es, s u bjects will be as ke d ge neral, 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 4 9 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

n o nlea di n g q uesti o ns  s uc h as " H o w are y o u feeli n g?"  All A Es (seri o us a n d n o nseri o us) m ust be 
rec or de d o n t he s o urce d oc u me nts a n d eC R Fs  re gar dless of t he ass u m pti o n of a ca usal 
relati o ns hi p wit h t he st u d y dr u g.  T he defi niti o n, re p orti n g, a n d rec or di n g re q uire me nts f or A Es 
are descri be d i n Secti o n  8 . 
7. 5. 2.  
C o m pre he nsi ve P h ysic al  E x a mi n ati o n  
Cli nicall y n ota ble a b n or malities t hat are c o nsi dere d cli nicall y si g nifica nt i n t he j u d g me nt of t he 
i n vesti gat or are t o be re p orte d as A Es. 
P h ysical e xa mi nati o ns m ust be perf or me d b y a me dicall y q ualifie d i n di vi d ual s uc h as a lice nse d 
p h ysicia n, p h ysicia n' s assista nt, or a n a d va nce d re gistere d n urse practiti o ner, as l ocal la w 
per mits.  
T he c o m pre he nsi ve p h ysical e xa mi nati o n will i ncl u de hei g ht (at scree ni n g  o nl y), b o d y wei g ht 
( wit hi n 1 l b or 0. 5 k g), a n d assess me nt(s) of t he f oll o wi n g or ga n or b o d y s yste ms:  s ki n; hea d, 
e yes, ear s, n ose, a n d t hr oat; t h yr oi d; l u n gs; car di o vasc ular s yste m; a b d o me n (li ver, s plee n); 
e xtre mities; a n d l y m p h n o des; as well as a brief ne ur ol o gical e xa m i nati o n (e g, refle xes, stre n gt h, 
R o m ber g 's t est, vi brati o n se nse, a n d gr oss se ns or y perce pti o n). 
7. 5. 3.  
Dise ase -S pecific  P h ysic al  E x a mi n ati o n  
A disease -s pecific p h ysical e xa mi nati o n will be a s y m pt o m- directe d e val uati o n a n d will i ncl u de 
assess me nt(s) of t he b o d y s yste ms or or ga ns, as i n dicate d b y s u bject disease a n d s y m pt o ms, A Es, 
or ot her fi n di n gs as deter mi ne d b y t he i n vesti gat or or desi g nee.  A disease- s pecific p h ysical 
e xa mi nati o n m ust i ncl u de a meas ure me nt of t he s u bject 's b o d y wei g ht ( wit hi n 1 l b or 0. 5 k g), 
a n d a n e val uati o n of a n y A Es or s y m pt o ms t hat t he s u bject has pre vi o usl y re p orte d. 
7. 5. 4.  
Vit al Si g ns  
Vital si g n meas ure me nts i ncl u de bl o o d press ure, p ulse, res pirat or y rate, a n d b o d y te m perat ure.  
Bl o o d press ure a n d p ulse will be ta ke n wit h t he s u bject i n t he rec u m be nt, se mirec u m be nt , or 
sitti n g p ositi o n after 5 mi n utes of rest.   Cli nicall y n ota ble a b n or m alities t hat are c o nsi dere d 
cli nicall y si g nifica nt i n t he j u d g me nt of t he i n vesti gat or are t o be re p orte d as A Es. 
7. 5. 5.  
Electr oc ar di o gr a ms  
All 1 2 -lea d E C Gs will be perf or me d wit h t he s u bject i n a rec u m be nt or se mirec u m be nt p ositi o n 
after 5 mi n utes of rest.   T he 1 2- lea d E C Gs will be perf or me d l ocall y a n d be  i nter prete d b y t he 
i n vesti gat or at t he site a n d use d f or i m me diate s u bject ma na ge me nt.  Baseli ne E C Gs o btai ne d 
d uri n g scree ni n g ca n be perf or me d usi n g a si n gle meas ure me nt; h o we ver,  E C Gs  ma y  be 
perf or me d i n triplicate if t he si n gle Q Tc meas ure me nt is >  4 5 0 millisec o n ds (c orrecte d b y 
Fri dericia; see Secti o n  3. 2 ).  T he decisi o n t o i ncl u de or e xcl u de a s u bject or disc o nti n ue a 
s u bject's partici pati o n i n t he st u d y base d o n a n E C G fla g ge d as " A b n or mal, Cli nicall y 
Si g nifica nt" is t he res p o nsi bilit y of t he i n vesti gat or, i n c o ns ultati o n wit h t he s p o ns or' s me dical 
m o nit or, as a p pr o priate.  If a si n gle meas ure me nt de m o nstrates a Q Tc i nter val 
> 5 0 0 millisec o n ds, 2 m ore E C Gs s h o ul d be o btai ne d o ver a brief peri o d, a n d t he a vera ge d Q Tc 
i nter vals s h o ul d be use d t o deter mi ne w het her t he st u d y treat me nt s h o ul d be i nterr u pte d (see 
Secti o n  5. 4. 1 ). 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 5 0 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

7. 5. 5. 1.  
Ti me d Electr oc ar di o gr a ms  
Ti me d tri plicate E C G s will be o btai ne d d uri n g t he Da y 1 visit ( pre dose) a n d at Wee k 4 ( pre d ose 
a n d 1. 5 h o urs [ ± 1 5 mi n utes] after recei vi n g st u d y treat me nt ).  Whe n tri plicate E C Gs are bei n g 
o btai ne d, i n di vi d ual meas ure me nts s h o ul d be perf or me d 5 mi n utes ( ± 3 mi n utes) a part.  
7. 5. 6.  
E C O G Perf or m a nce St at us  
Easter n C o o perati ve O nc ol o g y Gr o u p perf or ma nce stat us ( O ke n  et al 1 9 8 2; see A p pe n di x B ) will 
be assesse d.  Perf or ma nce stat us m ust be assesse d b y a me dicall y q ualifie d i n di vi d ual a n d 
rec or de d i n t he e C R F. 
7. 5. 7.  
L a b or at or y Assess me nts  
Bl o o d dra ws f or la b orat or y assess me nts will occ ur at st u d y v isits i n dicate d i n t he sc he d ule of 
la b orat or y assess me nts (see Ta ble  7).  S pecific la b orat or y assess me nts are pr o vi de d i n Ta ble  8.   
All la b orat or y assess me nts , i ncl u di n g t h ose c o n d ucte d d uri n g u nsc he d ule d visits, will be 
perf or me d at a ce ntral la b orat or y , wit h t he e xce pti o n of t he f oll o wi n g, i n w hic h case t he 
i n vesti gati ve site la b orat or y or a n accre dite d l ocal la b orat or y ma y be use d:  
•  Ser u m pre g na nc y testi n g perf or me d at scree ni n g (see Secti o n  7. 5. 7. 2 ) 
N ote:   A l ocal la b orat or y assess me nt  (i ncl u di n g refere nce ra n ges) will  be rec or de d 
i nt o t he s u bject's e C R F o nl y if t here is n o acc o m pa n yi n g ce ntral la b orat or y 
assess me nt a n d t he l ocal la b orat or y assess me nt ca use d a c ha n ge i n s u bject  
ma na ge me nt (e g, a d ose i nterr u pti o n or re d ucti o n) or was a n A E or S A E. 
7. 5. 7. 1.  
C he mistr y  a n d He m at ol o g y 
All c he mistr y a n d he mat ol o g y assess me nts (see Ta ble  7 a n d Ta ble  8) will be perf or me d fr o m 
bl o o d sa m ples c ollecte d usi n g i nstit uti o nal best practices.  
7. 5. 7. 2.  
Pre g n a nc y Testi n g  
A ser u m pre g na nc y test at scree ni n g will be re q uire d f or all w o me n of c hil d beari n g p ote nt ial (see 
Secti o n  3. 1 ) as s h o w n (Ta ble  7) a nd ca n be perf or me d eit her at t he ce ntral or l ocal la b orat or y .   
Uri ne pre g na nc y tests wil l be c o n d ucte d as s h o w n (Ta ble  7).  If a uri ne pre g na nc y test is 
p ositi ve, t he res ults s h o ul d be c o nfir me d wit h a ser u m pre g na nc y test.  If t he ser u m pre g na nc y 
test is ne gati ve after a p ositi ve uri ne test, t he i n vesti gat or will assess t he p ote ntial be nefit/ris k t o 
t he s u bject a n d deter mi ne w het her it is i n t he s u bject's best i nterest t o res u me st u d y treat me nt a n d 
c o nti n ue partici pati o n i n t he st u d y. 
7. 5. 7. 3.  
Ser ol o g y 
Ser ol o g y assess me nts will be perf or me d at a ce ntral la b orat or y (see Ta ble  7 a n d Ta ble  8). 
7. 5. 7. 3. 1.  HI V Testi n g  
S u bjects e nr o lle d o utsi de of t he U nite d States m ust ha ve a n HI V i m m u n oassa y test at scree ni n g 
t o e ns ure ne gati ve HI V stat us (see Secti o n 3. 2 ).  HI V testi n g is o pti o nal f or s u bjects e nr olle d i n 
t he U nite d States. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 5 1 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

7. 8. 5.  
T u m or  o r B o ne M arr o w  
S u bjects m ust ha ve a n a vaila ble arc hi val t u m or bi o ps y sa m ple ( prefera bl y o btai ne d si nce 
c o m pleti o n of last t hera p y) or be willi n g t o u n der g o a pretreat me nt t u m or bi o ps y at baseli ne.  
S u bjects wit h s ple nic M Z L u na ble t o pr o vi de a t u m or bi o ps y sa m ple m ust ha ve a n arc hi val b o ne 
marr o w bi o ps y t hat was o btai ne d si nce c o m pleti o n of last t hera p y a n d wit hi n 2 years bef ore t he 
date of t he first d ose of st u d y treat me nt or be willi n g t o u n der g o a b o ne marr o w bi o ps y at 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 5 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

dia g n osis w he ne ver p ossi ble rat her t ha n b y i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.  W he n a 
clear dia g n osis ca n n ot be i de ntifie d, eac h si g n or s y m pt o m s h o ul d be re p orte d as a se parate A E . 
T he ter m "disease pr o gressi o n " s h o ul d be rec or de d as a n A E/ S A E o nl y if t here are n o other 
i de ntifia ble A Es/ S A Es ass ociate d wit h t he disease pr o gressi o n at t he ti me of re p orti n g.   F or 
e ve nts ass ociate d wit h disease pr o gressi o n , t he rele va nt si g ns a n d s y m pt o ms s h o ul d be re p orte d 
usi n g a dia g n osis w he ne ver p ossi ble rat her t ha n i n di vi d ual u n derl yi n g si g ns a n d s y m pt o ms.  
W he n a clear dia g n osis ca n n ot be i de ntifie d, eac h si g n or s y m pt o m s h o ul d be re p orte d as a 
se parate A E.  If t he e ve nts res ulti n g fr o m disease pr o gressi o n meet t he criteria f or a n S A E 
(e g, res ulte d i n h os pitalizati o n, a life-t hreate ni n g e ve nt, or deat h), t he s pecific e ve nt(s) s h o ul d be 
re p orte d as a n S A E(s)  as descri be d i n Secti o n  8. 3. 2 .  I n b ot h cases ( ie, A Es or S A Es relate d t o 
disease pr o gressi o n), it s h o ul d be i n dicate d t hat eac h e ve nt  (re p orte d as a dia g n osis or as si g ns 
a n d s y m pt o ms) is relate d t o disease pr o gressi o n o n t he A d verse E ve nts f or m of t he e C R F. 
T he se verit y of A Es  will be assesse d usi n g C T C A E v 4. 0 3 Gra des 1 t hr o u g h 5 ( N CI  2 0 1 0).  If a n 
e ve nt is n ot classifie d b y C T C A E, t he se verit y of t he A E will be gra de d acc or di n g t o t he scale 
bel o w t o esti mate t he gra de of se verit y: 
Gr a de  1 
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n n ot i n dicate d. 
Gr a de 2  
M o derate; mi ni mal, l ocal, or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate acti vities of dail y li vi n g. 
Gr a de 3  
Se vere or me dical l y si g nifica nt b ut n ot i m me diatel y life-t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
self-care acti vities of dail y li vi n g . 
Gr a de 4  
Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d. 
Gr a de 5  
Deat h d ue t o A E  
T he occ urre nce of A Es  s h o ul d be s o u g ht b y n o n directi ve q uesti o ni n g of t he s u bject d uri n g t he 
scree ni n g pr ocess after si g ni n g t he I C F a n d at eac h visit d uri n g t he st u d y.  Ad verse e ve nts ma y  
als o be detecte d w he n t he y are v ol u nteere d b y t he s u bject d uri n g t he scree ni n g pr ocess or 
bet wee n visits, or t hr o u g h p h ysical e xa mi nati o n, la b orat or y test, or ot her assess me nts.  T o t he 
e xte nt p ossi ble, eac h A E  s h o ul d be e val uate d t o deter mi ne: 
•  T he s e verit y gra de ( C T C A E Gra de 1 t o 5). 
•  W het her t here is at least a reas o na ble p ossi bilit y t hat t he A E is relate d t o t he st u d y 
treat me nt:  s us pecte d ( yes) or n ot s us pecte d ( n o). 
•  T he s tart a n d e n d dates, u nless u nres ol ve d at fi nal f oll o w- u p. 
•  T he a cti o n ta ke n wit h re gar d t o st u d y dr u g. 
•  T he e ve nt o utc o me (e. g., n ot rec o vere d/ n ot res ol ve d, rec o vere d/res ol ve d, 
rec o veri n g/res ol vi n g, rec o vere d/res ol ve d wit h se q uelae, fatal, u n k n o w n). 
•  T he s eri o usness , as per seri o us a d verse e ve nt (S A E ) defi niti o n pr o vi de d i n 
Secti o n  8. 3. 1 . 
U nli ke r o uti ne safet y assess me nts, S A Es are m o nit ore d c o nti n u o usl y a n d ha ve s pecial re p orti n g 
re q uire me nts (see Secti o n 8. 3. 2 ). 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 5 6 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

All A Es  s h o ul d be treate d a p pr o priatel y.  If a n A E is treate d wit h a co nc o mita nt me dicati o n or 
n o n- dr u g t hera p y, t his acti o n s h o ul d be rec or de d o n A d verse E ve nt f or m a n d t he treat me nt 
s h o uld be s pecifie d o n  t he Pri or/ C o nc o mita nt Me dicati o ns or Pr oce d ures a n d N o n- Dr u g T hera p y 
f or m i n t he eC R F . 
O nce a n A E  is detecte d, it s h o ul d be f oll o we d u ntil it has res ol ve d or u ntil i t is j u d ge d t o be 
per ma ne nt; assess me nt s h o ul d be ma de at  eac h visit ( or m ore fre q ue ntl y  if necessar y) of a n y 
c ha n ges i n se verit y, t he s us pecte d relati o ns hi p t o t he st u d y dr u g , t he i nter ve nti o ns re q uire d t o 
treat t he e ve nt, a n d t he o utc o me. 
W he n t he se verit y of a n A E  c ha n ges o ver ti me f or a re p orti n g peri o d (e. g., bet wee n visits), eac h 
c ha n ge i n se verit y will be re p orte d as a  se parate A E  u ntil t he e ve nt res ol ves.  F or e xa m ple, 
2 se parate A Es  will be re p orte d if a s u bject ha s Gra de 1 diarr hea, meeti n g t he defi niti o n of a n 
A E, t hat lasts f or 3 da ys bef ore w orse ni n g t o a Gra de 3 se verit y.  T he Gra de 1 e ve nt will be 
re p orte d as a n A E  wit h a start date e q ual t o t he da y t he e ve nt met t he Gra de  1 A E  defi niti o n a n d 
a st o p date e q ual t o t he da y t hat t he e ve nt i ncrease d i n se verit y fr o m Gra de 1 t o Gra de 3.  T he 
Gra de  3 e ve nt will als o be re p orte d as a n A E , wit h t he start date e q ual t o t he da y t he e ve nt 
c ha n ge d i n i nte nsit y fr o m Gra de 1 t o Gra de 3 a n d a st o p date e q ual t o t he da y t hat t he e ve nt 
eit her c ha n ge d se verit y a gai n or res ol ve d. 
8. 2.  
L a b or at or y Test A b n or m alities  
La b orat or y a b n or malities t hat c o nstit ute a n A E  i n t heir o w n ri g ht (c o nsi dere d cli nicall y 
mea ni n gf ul, i n d uce cli nical si g ns or s y m pt o ms, re q uire c o nc o mita nt t hera p y, or re q uire c ha n ges 
i n st u d y dr u g ) s h o ul d be rec or de d on t he A d verse E ve nt f or m i n t he eC R F.   W he ne ver p ossi ble, a 
dia g n osis rat her t ha n a s y m pt o m s h o ul d be pr o vi de d (e. g., "a ne mia" i nstea d of "l o w 
he m o gl o bi n").  La b orat or y a b n or malities t hat meet t he criteria f or A Es  s h o ul d be f oll o we d u ntil 
t he y ha ve ret ur ne d t o n or mal or a n a de q uate e x pla nati o n of t he a b n or malit y is f o u n d.  W he n a n 
a b n or mal la b orat or y test res ult c orres p o n ds t o a si g n or s y m pt o m of a pre vi o usl y re p orte d A E , it 
is n ot necessar y t o se paratel y rec or d t he la borat or y  test res ult as a n a d diti o nal e ve nt. 
La b orat or y a b n or malities  t hat d o n ot meet t he defi niti o n of a n A E  s h o ul d n ot be re p orte d as A Es .  
A Gra de 3 or 4 A E  d oes n ot a ut o maticall y i n dicate a n S A E u nless it meets t he defi niti o n of 
seri o us, as defi ne d i n Secti o n 8. 3. 1 .  A d ose m o dificati o n  f or t he la b orat or y a b n or malit y ma y be 
re q uire d (see Secti o n  5. 4 ) a n d s h o ul d n ot c o ntri b ute t o t he desi g nati o n of a la borat or y test  
a b n or malit y as a n S A E . 
8. 3.  
Seri o us A d verse E ve nts  
8. 3. 1.  
Defi niti o ns  
A n S A E is defi ne d as a n e ve nt t hat meets at least 1 of t he f oll o wi n g criteria: 
•  Is fatal or life-t hreate ni n g. 
•  Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, u nless 
h os pitalizati o n is a res ult of: 
− A r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n n ot ass ociate d wit h 
a n y deteri orati o n i n c o n diti o n  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 5 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

− A n electi ve s ur ger y or pre pla n ne d treat me nt f or a pre -e xisti n g c o n diti o n t hat is 
u nrelate d t o t he i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he 
I C F. 
− A treat me nt o n a n e mer ge nc y o ut patie nt basis f or a n e ve nt n ot f ulfilli n g a n y of t he 
defi niti o ns of a S A E a n d n ot res ulti n g i n h os pital a d missi o n. 
− A n y s ocial reas o ns a n d res pite care, i n t he a bse nce of a n y deteri orati o n i n t he 
s u bject's ge neral c o n diti o n. 
•  Res ults i n persiste nt or si g nifica nt disa bilit y , i nca pacit y, or a s u bsta ntial disr u pti o n of 
a pers o n 's a bilit y t o c o n d uct n or mal life f u ncti o ns. 
•  C o nstit utes a c o n ge nital a n o mal y  or birt h defect . 
•  Is co nsi dere d t o be a n i m p orta nt me dical e ve nt or a me dicall y si g nifica nt 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 n g, or re q uire h os pitalizati o n b ut 
ma y be c o nsi dere d seri o us w he n, base d o n a p pr o priate me dical j u d g me nt, t he e ve nt 
ma y je o par dize t he s u bject or ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
1 of t he o utc o mes liste d a b o ve. 
8. 3. 2.  
Re p o rti n g 
E ver y S A E, re gar dless of s us pecte d ca usalit y (e g , relati o ns hi p t o st u d y dr u g(s) or st u d y 
pr oce d ure or disease pr o gressi o n), occ urri n g after t he s u bject has si g ne d t he I C F t hr o u g h t he last 
st u d y visit ( or 3 0 da ys after t he last d ose of st u d y treat me nt , w hic he ver is later) m ust be re p orte d 
t o t he s p o ns or ( or desi g nee) wit hi n 2 4  h o urs  of lear ni n g of its occ urre nce, u nless ot her wise 
s pecifie d b y t he Pr ot oc ol.  A n y S A Es occ urri n g m ore t ha n 3 0 da ys after t he last d ose of st u d y 
treat me nt s h o ul d be re p orte d t o t he s p o ns or or its desi g nee o nl y if t he i n vesti gat or s us pects a 
ca usal relati o ns hi p t o t he st u d y dr u g.   
I nf or mati o n a b o ut all S A Es is c ollecte d a n d rec or de d o n t he A d verse E ve nt f or m of t he e C R F .  
T he i n vesti gat or m ust assess a n d re c or d t he ca usal relati o ns hi p of eac h S A E t o t he st u d y 
treat me nt.   
T he i n vesti gat or m ust als o c o m plete t he I nc yte Seri o us A d verse E ve nt Re p ort F or m, i n E n glis h, 
a n d se n d t he c o m plete d a n d si g ne d f or m t o t he s p o ns or or desi g nee wit hi n 2 4 h o urs of bec o mi n g 
aware of t he S A E.  T he i n vesti gat or m ust pr o vi de a ca usalit y assess me nt, t hat is, assess w het her 
t here is at least a reas o na ble p ossi bilit y t hat t he S A E is relate d t o t he st u d y treat me nt:  s us pecte d 
( yes) or n ot s us pecte d ( n o).  Refer t o t he I nc yte Refere nce G ui de f or C o m pleti n g t he Seri o us 
A d verse E ve nt Re p ort F or m. 
T he c o ntact i nf or mati o n of t he s p o ns or' s st u d y-s pecific re prese ntati ves is liste d i n t he 
i n vesti gat or ma n ual pr o vi de d t o eac h site.  T he ori gi nal c o p y of t he S A E Re p ort F or m a n d t he 
c o nfir mati o n  s heet m ust be ke pt at t he st u d y site. 
I n vesti gati o nal site pers o n nel m ust re p ort a n y ne w i nf or mati o n re gar di n g t he S A E wit hi n 
2 4 h o urs of bec o mi n g a ware of t he i nf or mati o n i n t he sa me ma n ner t hat t he i nitial S A E Re p ort 
F or m was se nt.  F oll o w- u p i nf or mati o n is rec or de d o n a n a me n de d or ne w S A E Re p ort F or m, 
wit h a n i n dicati o n t hat it is f oll o w - u p t o t he pre vi o usl y re p orte d S A E a n d t he date of t he ori gi nal 
re p ort.  T he f oll o w- u p re p ort s h o ul d i ncl u de i nf or mati o n t hat was n ot pr o vi de d o n t he pre vi o us 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 5 8 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

S A E Re p or t F or m, s uc h as t he o utc o me of t he e ve nt (e. g., res ol ve d or o n g oi n g), treat me nt 
pr o vi de d, acti o n ta ke n wit h st u d y dr u g beca use of t he S A E (e. g., d ose re d uce d, i nterr u pte d, or 
disc o nti n ue d), or s u bject dis p ositi o n ( e. g., c o nti n ue d or wit h dre w fr o m st u d y partici pati o n).  
Eac h rec urre nce, c o m plicati o n, or pr o gressi o n of t he ori gi nal e ve nt s h o ul d be re p orte d as 
f oll o w-u p t o t hat e ve nt, re gar dless of w he n it occ urs.  
If t he S A E is n ot d oc u me nte d of t he I B f or t he st u d y dr u g ( ne w occ urre nce) a n d is t h o u g ht t o be 
relate d t o t he s p o ns or's st u d y dr u g, t he s p o ns or or its desi g nee ma y ur ge ntl y re q uire f urt her 
i nf or mati o n fr o m t he in vesti gat or f or re p orti n g  t o healt h aut h orities .  T he s p o ns or or its desi g nee 
ma y nee d t o iss ue a n  I n vesti gat or N otificati o n (I N) t o i nf or m all i n vesti gat ors i n v ol ve d i n a n y 
st u d y wit h t he sa me dr u g t hat t his S A E has bee n re p orte d.  S us pecte d U ne x pecte d Seri o us 
A d verse Reacti o ns ( S U S A Rs) will be c ollecte d a n d re p orte d t o t he c o m pete nt a ut h orities a n d 
releva nt et hics c o m mittees i n acc or da nce wit h Directi ve 2 0 0 1/ 2 0/ E C , or as per nati o nal 
re g ulat or y re q uire me nts i n partici pati n g c o u ntries. 
8. 4.  
E mer ge nc y U n bli n di n g of Tre at me nt Assi g n me nt  
N ot a p plica ble. 
8. 5.  
A d verse E ve nts of S peci al I nterest  
S pecific A E s, or gr o u ps of A E s, will be f oll o we d as part of sta n dar d safet y m o nit ori n g acti vities.   
•  A L T ≥ 5 × U L N  
•  A S T ≥ 5 × U L N  
•  C olitis  
•  Diarr hea ≥ Gra de 2 
•  I ntesti nal perf orati o n 
•  Ras h ≥ Gra de 2  
•  E xf oliati ve der matitis  
•  P ne u m o nitis 
•  PJ P  i nfecti o n 
•  C M V i nfecti o n  
•  Her pes si m ple x vir us i nfecti o n 
•  Varicella z oster vir us i nfecti o n  
8. 6.  
Pre g n a nc y 
Pre g na nc y, i n a n d of itself, is n ot re gar de d as a n A E  u nless t here is s us pici o n t hat st u d y dr u g ma y 
ha ve i nterfere d wit h t he effecti ve ness of a c o ntrace pti ve me dicati o n or met h o d.  W he n a 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 5 9 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

p re g na nc y has bee n c o nfir me d i n a s u bject d uri n g mater nal or pater nal e x p os ure t o st u d y dr u g, 
t he f oll o wi n g pr oce d ures s h o ul d be f oll o we d i n or der t o e ns ure s u bject safet y: 
•  T he s t u d y dr u g m ust be disc o nti n ue d i m me diatel y (fe male s u bjects o nl y; see 
Secti o n  5. 4. 1  f or t he ma xi m u m per mitte d d urati o n of st u d y dr u g i nterr u pti o n). 
•  T he i n vesti gat or m ust c o m plete a n d s u b mit t he I nc yte Cli nical Trial Pre g na nc y f or m 
t o t he s p o ns or or its desi g nee wit hi n 2 4 h o urs  of lear ni n g of t he pre g na nc y. 
Data o n fetal o utc o me a n d breastfee di n g are c ollecte d f or re g ulat or y re p orti n g a n d dr u g safet y 
e val uati o n.  F oll o w- u p s h o ul d be c o n d ucte d f or eac h pre g na nc y t o deter mi ne o utc o me, i ncl u di n g 
s p o nta ne o us or v ol u ntar y ter mi nati o n, details of t he birt h, a n d t he prese nce or a bse nce of a n y 
birt h defects, c o n ge nital a b n or malities, or mater nal a n d/ or ne w b or n c o m plicati o ns, b y f oll o wi n g 
u ntil t he first well -ba b y visit.  Pre g na nc y s h o ul d be rec or de d o n a Cli nical Trial Pre g na nc y f or m 
a n d re p orte d b y t he i n vesti gat or t o t he s p o ns or or its desi g nee .  Pre g na nc y f oll o w- u p i nf or mati o n 
s h o ul d be rec or de d o n t he sa me f or m a n d s h o ul d i ncl u de a n assess me nt of t he p ossi ble ca usal 
relati o ns hi p t o t he s p o ns or's st u d y dr u g t o a n y pre g na nc y o utc o me, as well as f oll o w- u p t o t he 
first well- ba b y visit or t he d urati o n s pecifie d i n l ocal re g ulati o ns, w hic he ver is later.  Refer t o t he 
I nc yte Refere nce G ui de f or C o m pleti n g t he Cli nical Trial Pre g na nc y F or m. 
A n y S A E occ urri n g  d uri n g pre g n a nc y m ust be re c or de d o n t he S A E re p ort for m a n d 
s u b mitte d t o t he s p o ns or or desi g nee. 
8. 7.  
W ar ni n gs a n d Prec a uti o ns  
S pecial war ni n gs or preca uti o ns f or t he st u d y dr u g, deri ve d fr o m safet y i nf or mati o n c ollecte d b y 
t he s p o ns or or its desi g nee, are prese nte d i n t he I B.  A d diti o nal safet y i nf or mati o n c ollecte d 
bet wee n I B u p dates will be c o m m u nicate d i n t he f or m of I Ns.  A n y i m p orta nt ne w safet y 
i nf or mati o n s h o ul d be disc usse d wit h t he s u bject d uri n g t he st u d y, as necessar y .  If ne w 
si g nifica nt ris ks are i de ntifie d, t he y will be a d de d t o t he I C F. 
8. 8.  
I n de pe n de nt D at a M o nit ori n g C o m mittee  
A n ID M C will be f or me d  a n d will c o nsist of q ualifie d i n di vi d uals w h o are n ot i n v ol ve d wit h t he 
c o n d uct of t he st u d y.  T h e esta blis h me nt, c o m p ositi o n, r oles, d uties, a n d res p o nsi bilities of t he 
ID M C are a d dresse d i n t he a p pr o ve d ID M C c harter.  
8. 9.  
Pr o d uct C o m pl ai nts  
T he s p o ns or c ollects pr o d uct c o m plai nts o n st u d y dr u gs a n d dr u g deli ver y s yste ms use d i n 
cli nical st u dies i n or der t o e ns ure t he safet y of st u d y partici pa nts, m o nit or q ualit y, a n d facilitate 
pr ocess a n d pr o d uct i m pr o ve me nts.  
A ll pr o d uct c o m plai nts ass ociate d wit h material pac ka ge d, la bele d, a n d release d b y t he s p o ns or 
or its desi g nee  will be re p orte d  t o t he s p o ns or.  All pr o d uct c o m plai nts ass ociate d wit h ot her 
st u d y material will be re p orte d directl y t o t he res pecti ve ma n ufact urer. 
T he i n vesti gat or or his/ her desi g nee is res p o nsi ble f or re p orti n g a c o m plete descri pti o n of t he 
pr o d uct c o m plai nt via e mail or ot her writte n c o m m u nicati o n t o t he s p o ns or c o ntact or res pecti ve 
ma n ufact urer as n ote d i n t he pac ka gi n g i nf or mati o n.  A n y A E ass ociate d wit h a pr o d uct 
c o m plai nt s h o ul d be re p orte d as descri be d i n Secti o n  8. 1. 2  of t his Pr ot oc ol. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 6 0 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

9. 4. 1.  
Effic ac y A n al yses 
9. 4. 1. 1.  
Pri m ar y Effic ac y A n al yses 
O bjecti ve res p o nse rate is defi ne d as t he perce nta ge of s u bjects wit h a C R or P R as deter mi ne d 
b y re vise d res p o nse criteria f or l y m p h o mas ( C hes o n et al 2 0 1 4 ). 
T he O R R as deter mi ne d b y t he I R C a n d its 9 5 % e xact bi n o mial CIs will be calc ulate d.  T his is 
c o nsi dere d t he pri mar y efficac y a nal ysis f or eac h of t he 2 c o h orts.  
T he O R R as re p orte d b y t he i n vesti gat or a n d its 9 5 % e xact bi n o mial CIs will als o be calc ulate d.  
Res p o nse data will be a nal yze d w he n all s u bjects i n t he f ull a nal ysis set of t he res pecti ve c o h ort 
ha ve reac he d at least 1 p ost baseli ne disease assess me nt or ha ve pr o gresse d , wit h dra w n fr o m t he 
st u d y, or die d. 
9. 4. 1. 2.  
Sec o n d ar y Effic ac y A n al yses 
D urati o n of res p o nse is defi ne d as t he ti me fr o m first d oc u me nte d e vi de nce of C R or P R u ntil 
disease pr o gressi o n or deat h d ue t o a n y ca use a m o n g s u bjects w h o ac hie ve a n o verall res p o nse 
(ie, C R or P R) as deter mi ne d b y re vise d res p o nse criteria f or l y m p h o mas ( C hes o n et al 2 0 1 4 ).  
F or s u bjects w h o ha ve n ot pr o gresse d a n d are still ali ve at t he ti me of t he a nal ysis, D O R will be 
ce ns ore d o n t he da y of last e val ua ble disease assess me nt.  F or s u bjects w h o ha ve disc o nti n ue d 
st u d y or ha ve starte d ot her a ntica ncer treat me nt, D O R will be ce ns ore d o n t he da y of last 
e val ua ble disease assess me nt d oc u me nti n g a bse nce of P D bef ore t he disc o nti n uati o n or t he start 
of t he ne w a nti ca ncer treat me nt.  
Pr o gressi o n-free s ur vi val is defi ne d as t he ti me fr o m t he date of first d ose of t he st u d y dr u g t o t he 
first d oc u me nte d disease pr o gressi o n as deter mi ne d b y re vise d res p o nse criteria f or l y m p h o mas 
(C hes o n et al 2 0 1 4 ), or deat h d ue t o a n y ca use, w hic he ver occ urs first.  F or s u bjects w h o ha ve 
n ot pr o gresse d a n d are still ali ve at t he ti me of t he a nal ysis, P F S will be ce ns ore d o n t he da y of 
last e val ua ble disease assess me nt.  F or s u bjects w h o ha ve disc o nti n ue d st u d y or ha ve starte d 
ot her a ntica ncer treat me nt, P F S will be ce ns ore d o n t he da y of last e val ua ble disease assess me nt 
d oc u me nti n g a bse nce of P D bef ore t he disc o nti n uati o n or t he start of t he ne w a ntica ncer 
treat me nt.  F or s u bjects w h o ha ve n o baseli ne or n o p ostbaseli ne disease assess me nt, P F S will be 
ce ns ore d wit h ce ns ore d d urati o n of 1 da y. 
T he Ka pla n -Meier esti mati o n of me dia n D O R a n d P F S as deter mi ne d b y t he I R C a n d its 
9 5 % CIs will be pr o vi de d. 
C o m plete res p o nse rate is defi ne d as t he perce nta ge of s u bjects wit h a C R as deter mi ne d b y 
re vise d res p o nse criteria f or l y m p h o mas (C hes o n et al 2 0 1 4 ). 
T he C R R as deter mi ne d b y t he I R C a n d its 9 5 % e xact bi n o mial CIs will be calc ulate d.   
O verall s ur vi val is defi ne d as t he ti me fr o m t he date of  first d ose of st u d y dr u g t o deat h d ue t o 
a n y ca use.  F or s u bjects w h o are still ali ve at t he ti me of t he a nal ysis, O S will be ce ns ore d o n t he 
date t he s u bjects is last k n o w n t o be ali ve.  T he Ka pla n -Meier esti mati o n of me dia n O S a n d its 
9 5 % CIs will be pr o vi de d. 
Tar get lesi o n size is meas ure d b y t he s u m of t he pr o d uct of dia meters of all tar get lesi o n sizes.  
Best perce nta ge c ha n ge i n tar get lesi o n size fr o m baseli ne will be s u m marize d descri pti vel y.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 6 2 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

9. 4. 2. 3.  
Vit al Si g ns  
Descri pti ve statistics a n d mea n c ha n ge fr o m baseli ne will be deter mi ne d f or vital si g ns ( bl o o d 
press ure, p ulse , res pirat or y rate, a n d b o d y te m perat ure) at eac h assess me nt ti me.  Vital si g n 
res ults will be re vie we d f or cli nicall y n ota ble a b n or malities (see Ta ble  1 0), a n d s u bjects 
e x hi biti n g cli nicall y n ota ble vital si g n a b n or malities will be liste d.  A val ue will be c o nsi dere d a n 
"alert" val ue if it is o utsi de t he esta blis he d ra n ge a n d s h o ws a > 2 5 % c ha n ge fr o m baseli ne.   T he 
a b n or mal val ues f or s u bjects e x hi biti n g alert vital si g n a b n or malities will be liste d. 
T a ble  1 0: 
Criteri a f or Cli nic all y N ot a ble Vit al Si g n A b n or m alities  
P ar a meter  
Hi g h T hres h ol d  
L o w T hres h ol d  
S yst olic bl o o d press ure  
> 1 5 5 m m H g  
< 8 5 m m H g  
Diast olic bl o o d press ure  
> 1 0 0 m m H g  
< 4 0 m m H g  
P ulse  
> 1 0 0 b p m  
< 4 5  b p m  
Te m perat ure  
> 3 8º C  
< 3 5º C  
Res pirat or y rate 
> 2 4  breat hs / mi n 
< 1 2  breat hs / mi n 
9. 4. 2. 4.  
Electr oc ar di o gr a ms  
Descri pti ve statistics a n d mea n c ha n ge fr o m baseli ne will be deter mi ne d f or eac h E C G para meter 
at eac h assess me nt ti me.  Electr ocar di o gra m res ults will be re vie we d f or cli nicall y n ota ble 
a b n or malities acc or di n g t o pre defi ne d criteria ( Ta ble  1 1).  S u bjects e x hi biti n g cli nicall y n ota ble 
E C G  a b n or malities will be liste d.  
T a ble  1 1: 
Criteri a f or Cli nic all y N ot a ble Electr oc ar di o gr a m A b n or m alities  
P ar a meter  
Hi g h T hres h ol d  
L o w T hres h ol d  
Q Tc F  
> 4 5 0 ms ec  
< 2 9 5 ms ec  
P R  
> 2 2 0 ms ec  
< 7 5 ms ec 
Q R S  
> 1 2 0 ms ec  
< 5 0 ms ec 
Q T  
> 5 0 0 ms ec  
< 3 0 0 ms ec  
R R  
> 1 3 3 0 ms ec 
< 6 0 0 ms ec  
Q Tc F = Fri dericia c orrecti o n.  
9. 4. 2. 5.  
A d verse E ve nts of S peci al I nterest  
A d verse e ve nts of s pecial i nterest (see Secti o n  8. 5 ) will be s u m marize d as detaile d i n t he 
Statistical A nal ysis Pla n.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 6 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

9. 5.  
A n al ys es f or t he D at a M o nit ori n g C o m mittee 
Pre pla n ne d a nal yses of safet y will be pr o vi de d t o t he I D M C as s pecifie d i n t he I D M C c harter.  I n 
a d diti o n, t he I D M C will ma ke rec o m me n dati o ns t o t he s p o ns or at t he pla n ne d i nteri m f utilit y 
a nal yses (see Secti o n  9. 6 ).  T he pr ocess b y w hic h t he I D M C will ma ke rec o m me n dati o ns a n d 
decisi o ns will be d oc u me nte d i n t he I D M C C harter. 
9. 6.  
I nteri m A n al ysis 
A n i nteri m f utilit y a nal ysis is pla n ne d f or C o h ort 2 w he n 3 0 s u bjects ha ve bee n treate d a n d 
e val uate d f or res p o nse or ha ve per ma ne ntl y disc o nti n ue d st u d y treat me nt beca use of disease 
pr o gressi o n, wit h dra wal of c o nse nt, or deat h.  C o h ort 2 will be ter mi nate d f or f util it y if ≤ 1 0 of 
t he 3 0 s u bjects res p o n de d (ie, C R or P R) base d o n assess me nts pr o vi de d b y t he I R C. 
1 0.  
E T HI C A L C O N SI D E R A TI O N S A N D A D MI NI S T R A TI V E 
P R O C E D U R E S  
1 0. 1.  
I n vesti g at or Res p o nsi bilities 
T his st u d y will be perf or me d i n acc or da nce wit h et hical pri nci ples t hat ori gi nate  i n t he 
Declarati o n of Helsi n ki a n d c o n d ucte d i n a d here nce t o t he st u d y Pr ot oc ol; G C Ps as defi ne d i n 
Title  2 1 of t he U S C F R Parts 1 1, 5 0, 5 4, 5 6, a n d 3 1 2; I C H E 6 G C P c o ns oli date d g ui deli nes; a n d 
l ocal re g ulat or y re q uire me nts as a p plica ble t o t he st u d y l ocati o ns. 
T he i n vesti gat or will be res p o nsi ble f or:  
•  P er mitti n g st u d y-relate d m o nit ori n g, s p o ns or a u dits, I R B/I E C re vie w, a n d re g ulat or y 
i ns pecti o ns b y pr o vi di n g direct access t o s o urce data a n d ot her rele va nt cli nical st u d y 
d oc u me nts. 
− M o nit ori n g:  Q ualifie d re prese ntati ves of t he s p o ns or or its desi g nee, st u d y 
m o nit ors, will m o nit or t he st u d y acc or di n g t o a pre deter mi ne d pla n.  T he 
i n vesti gat or m ust all o w t he st u d y m o nit ors t o re vie w a n y st u d y materials a n d 
s u bject rec or ds at eac h m o nit ori n g visit . 
− A u diti n g:  Q ualifie d re prese ntati ves of t he s p o ns or or its desi g nee ma y a u dit t he 
cli nical st u d y site a n d st u d y data t o e val uate c o m plia nce wit h t he Pr ot oc ol, 
a p plica ble l ocal cli nical st u d y re g ulati o ns, a n d o verall st u d y c o n d uct.  T he 
i n vesti gat or m ust all o w t he a u dit ors t o re vie w ori gi nal s o urce rec or ds a n d st u d y 
d oc u me ntati o n f or all s u bjects.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 6 5 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

− Re g ulat or y i ns pecti o n:  Re g ulat or y a ut h orities ma y c o n d uct a n i ns pecti o n of t he 
st u d y a n d t he site at a n y ti me d uri n g t he de vel o p me nt of a n i n vesti gati o nal 
pr o d uct.  T he i n vesti gat or a n d staff are e x pecte d t o c o o perate wit h t he i ns pect o rs 
a n d all o w access t o all s o urce d oc u me nts s u p p orti n g t he e C R Fs a n d ot her 
st u d y-relate d d oc u me nts.  T he i n vesti gat or m ust i m me diatel y n otif y t he s p o ns or 
w he n c o ntacte d b y a n y re g ulat or y a ut h orit y f or t he p ur p oses of c o n d ucti n g a n 
i ns pecti o n. 
•  O btai ni n g i nf or me d c o nse nt a n d e ns uri n g t hat t he st u d y s u bjects' q uesti o ns ha ve bee n 
a ns were d a n d t he s u bject s f ull y u n dersta n d st u d y pr oce d ures: 
− I nf or me d c o nse nt m ust be o btai ne d bef ore  a n y st u d y-relate d pr oce d ures are 
c o n d ucte d , u nless ot her wise s pecifie d b y t he Pr ot oc ol. 
− I nf or me d c o nse nt m ust be o btai ne d usi n g t he I R B/I E C-a p pr o ve d versi o n i n a 
la n g ua ge t hat is nati ve a n d u n dersta n da ble t o t he s u bject.  A te m plate will be 
pr o vi de d b y t he s p o ns or or its desi g nee.  T he s p o ns or or its desi g nee m ust re vie w 
a n d ac k n o wle d ge t he site-s pecific c ha n ges t o t he I C F te m plate.  T he I C F m ust 
i ncl u de a state me nt t hat t he s p o ns or or its desi g nee a n d re g ulat or y a ut h orities ha ve 
direct access t o s u bject rec or ds.  
•  O btai ni n g a p pr o val fr o m t he I R B/I E C bef ore t he start of t he st u d y a n d f or a n y 
c ha n ges t o t he cli nical st u d y Pr ot oc ol, i m p orta nt Pr ot oc ol de viati o ns, r o uti ne u p dates, 
a n d safet y i nf or mati o n i n acc or da nce wit h i nstit uti o nal re q uire me nts a n d l ocal la w. 
− T he  i n vesti gat or is res p o nsi ble f or e ns uri n g t hat t he safet y re p orts pr o vi de d b y t he 
s p o ns or are re vie we d a n d pr ocesse d i n acc or da nce wit h re g ulat or y re q uire me nts 
a n d wit h t he p olicies a n d pr oce d ures esta blis he d b y t he I R B /I E C. 
•  A d heri n g t o t he Pr ot oc ol as descri be d i n t his d oc u me nt a n d a gree i n g t hat c ha n ges t o 
t he Pr ot oc ol pr oce d ures, wit h t he e xce pti o n of me dical e mer ge ncies, m ust be 
disc usse d a n d a p pr o ve d , first, b y t he s p o ns or or its desi g nee a n d, sec o n d, b y t he 
I R B/IE C.  Eac h i n vesti gat or is res p o nsi ble f or e nr olli n g s u bjects w h o ha ve met t he 
s pecifie d eli gi bilit y criteria. 
•  Retai n i n g rec or ds i n acc or da nce wit h all l ocal, nati o nal, a n d re g ulat or y la ws, b ut f or a 
mi ni m u m peri o d of at least 2 years after t he last mar keti n g a p plicati o n a p pr o val i n a n 
I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o ns i n 
a n I C H re gi o n, or if n ot a p pr o ve d, 2 years after t he ter mi nati o n of t he test article f or 
i n vesti gati o n t o e ns ure t he a vaila bilit y of st u d y d oc u me ntati o n s h o ul d it bec o me 
necessar y f or t he s p o ns or or a re g ulat or y a ut h orit y t o re vie w. 
− T he i n vesti gat or m ust n ot destr o y a n y rec or ds ass ociate d wit h t he st u d y wit h o ut 
recei vi n g a p pr o val fr o m t he s p o ns or.  T he i n vesti gat or m ust n otif y t he s p o ns or or 
its desi g nee i n t he e ve nt of acci de ntal l oss or destr ucti o n of a n y st u d y rec or ds.  If 
t he i n vesti gat or lea ves t he i nstit uti o n w here t he st u d y was c o n d ucte d, t he s p o ns or 
or its desi g nee m ust be c o ntacte d t o arra n ge alter nati ve rec or d st ora ge o pti o ns.  
− All eC R F data e ntere d b y t he site (i ncl u di n g a u dit trail), as well as c o m p uter 
har d ware a n d s oft ware (f or accessi n g t he data), will be mai ntai ne d or ma de 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 6 6 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

a vaila ble at t he site i n c o m plia nce wit h a p plica ble rec or d rete nti o n re g ulati o ns.  
T he s p o ns or will retai n t he ori gi nal e C R F data a n d a u dit trail.  
1 0. 2.  
Acc o u nt a bilit y, H a n dli n g, a n d Dis p os al of St u d y Dr u g  
T he i n vesti gat or is res p o nsi ble f or dr u g acc o u nta bilit y at t he st u d y site; h o we ver, s o me of t he 
dr u g acc o u nta bilit y d uties ma y be assi g ne d t o a n a p pr o priate p har macist or ot her desi g nee.  
I n ve nt or y a n d acc o u nta bilit y rec or ds m ust be mai ntai ne d a n d rea dil y a vaila ble f or i ns pecti o n b y 
t he st u d y m o nit or a n d are o pe n t o i ns pecti o n at a n y ti me b y a n y a p plica ble re g ulat or y a ut h orities.  
T he i n vesti gat or or desi g nee m ust mai ntai n rec or ds t hat d oc u me nt:  
•  Deli ver y of st u d y dr u g t o t he st u d y site. 
•  I n ve nt or y of st u d y dr u g at t he site. 
•  S u bject use of t he st u d y dr u g i ncl u di n g pill or u nit c o u nts fr o m eac h s u p pl y 
dis pe nse d. 
•  Ret ur n of st u d y dr u g t o t he i n vesti gat or or desi g nee b y s u bjects. 
T he i n vesti gati o nal pr o d uct m ust be use d o nl y i n acc or da nce wit h t he Pr ot oc ol.  T he i n vesti gat or 
will  als o mai ntai n rec or ds a de q uatel y d oc u me nti n g t hat t he s u bjects were pr o vi de d t he s pecifie d 
st u d y dr u g.  T hese rec or ds s h o ul d i ncl u de dates, q ua ntities, a n d a n y a vaila ble batc h or serial 
n u m bers or u ni q ue c o de n u m bers assi g ne d t o t he i n vesti gati o nal pr o d uct a n d st u d y s u bjects. 
C o m plete d acc o u nta bilit y rec or ds will be arc hi ve d b y t he site.  T he i n vesti gat or or desi g nee will 
be e x pecte d t o c ollect a n d retai n all use d, u n use d, a n d partiall y use d c o ntai ners of st u d y dr u g 
u ntil verifie d b y  t he st u d y m o nit or ( u nless ot her wise a gree d t o b y t he s p o ns or).  At t he 
c o ncl usi o n of t he st u d y, t he i n vesti gat or or desi g nee will o versee s hi p me nt of a n y re mai ni n g 
st u d y dr u g bac k t o t he s p o ns or or its desi g nee f or destr ucti o n acc or di n g t o i nstit uti o nal sta n dar d 
o perati n g pr oce d ures.  If l ocal pr oce d ures ma n date o n-site destr ucti o n of i n vesti gati o nal s u p pl y, 
t he site s h o ul d ( w here l ocal pr oce d ures all o w) mai ntai n t he i n vesti gati o nal s u p pl y u ntil t he st u d y 
m o nit or i ns pect s t he acc o u nta bilit y rec or ds i n or der t o e val uate c o m plia nce a n d acc urac y of 
acc o u nta bilit y b y t he i n vesti gati ve site.   At sites w here t he st u d y dr u g is destr o ye d bef ore 
m o nit or i ns pecti o n, t he m o nit ors rel y o n d oc u me ntati o n of destr ucti o n per t he site S O P. 
1 0. 3.  
D at a M a n a ge me nt  
Data ma na ge me nt will be perf or me d i n a vali date d data base via a n Electr o nic Data Ca pt ure 
( E D C) s yste m.  All data e ntr y, verificati o n, a n d vali dati o n will be perf or me d i n acc or da nce wit h 
t he c urre nt sta n dar d o perati n g pr oce d ures of t he Data Ma na ge me nt De part me nt  at t he s p o ns or or 
its desi g nee.  T he data base will be a ut h orize d f or l oc k o nce all defi ne d pr oce d ures are c o m plete d. 
T he i n vesti gat or will be pr o vi de d wit h access t o a n E D C s yste m s o t hat a n e C R F ca n be 
c o m plete d f or eac h s u bject.  E ntries ma de i n t he e C R F m ust be verifia ble a gai nst s o urce 
d oc u me nts; if u p dates t o t he data base are n ot p ossi ble, a n y discre pa ncies s h o ul d be e x plai ne d 
a n d d oc u me nte d.  T he i n vesti gat or will be res p o nsi ble f or re vie wi n g all data a n d e C R F e ntries, 
a n d will si g n a n d date t he desi g nate d f or ms i n eac h s u bject's e C R F, verif yi n g t hat t he 
i nf or mati o n is tr ue a n d c orrect.  T he i n vesti gat or is res p o nsi ble f or t he re vie w a n d a p pr o val of all 
q uer y res p o nses. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 6 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

Pr ot oc ol de viati o ns will be i de ntifie d a n d rec or de d i n t he Pr ot oc ol De viati o n f or m of t he e C R F.  
T he st u d y m o nit or will refere nce t he M o nit ori n g Pla n i n or der t o e ns ure t hat eac h iss ue i de ntifie d 
is a p pr o priatel y d oc u me nte d, re p orte d, a n d res ol ve d i n a ti mel y ma n ner i n acc or da nce wit h t he 
pla n' s re q uire me nts. 
1 0. 4.  
D at a  Pri v ac y a n d C o nfi de nti alit y  of St u d y Rec or ds  
T he i n vesti gat or a n d t he s p o ns or or its desi g nee m ust a d here t o a p plica ble data pr otecti o n  la ws 
a n d re g ulati o ns.  T he i n vesti gat or a n d t he s p o ns or or its desi g nee are res p o nsi ble f or e ns uri n g 
t hat se nsiti ve pers o nal i nf or mati o n is ha n dle d i n acc or da nce wit h l ocal data pr otecti o n la ws  
(i ncl u di n g b ut n ot li mite d t o HI P A A  a n d G D P R) as a p plica ble .  A p pr o priate c o nse nt f or 
c ollecti o n, use , a n d discl os ure a n d/ or tra nsfer (if a p plica ble) of pers o nal i nf or mati o n m ust be 
o btai ne d i n acc or da nce wit h l ocal data pr otecti o n la ws. 
S u bject na mes will n ot be s u p plie d t o t he s p o ns or or its desi g nee.  O nl y t he s u bject n u m ber will 
be rec or de d i n t he e C R F; if t he s u bject's na me a p pears o n a n y ot her d oc u me nt (e g, la b orat or y 
re p ort), it m ust be o bliterate d o n t he c o p y of t he d oc u me nt t o be s u p plie d t o t he s p o ns or or its 
desi g nee.  St u d y fi n di n gs st ore d o n a c o m p uter will be st ore d i n acc or da nce wit h a p pr o priate 
tec h nical a n d or ga nizati o nal meas ures as re q uire d b y l ocal data pr otecti o n la ws.   
1 0. 5.  
Fi n a nci al Discl os ure  
Bef ore st u d y i nitiati o n, a ll cli nical i n vesti gat ors partici pati n g i n cli nical st u dies s u bject t o F D A 
Re g ulati o n Title 2 1 C o de of Fe deral Re g ulati o ns ( C F R) Part 5 4 – Fi na ncial Discl os ure b y 
Cli nical I n vesti gat ors (ie, "c o vere d st u dies ") are re q uire d t o s u b mit a c o m plete d Cli nical 
I nvesti gat or Fi na ncial Discl os ure for m t hat s ufficie ntl y details a n y fi na ncial i nterests a n d 
arra n ge me nts t hat a p pl y.  F or t he p ur p ose of t his re g ulati o n, " cli nical i n vesti gat or " is defi ne d as 
a n y i n vesti gat or or s u bi n vesti gat or w h o is directl y i n v ol ve d i n t he treat me nt or e val uati o n of 
researc h s u bjects, i ncl u di n g t he s p o use a n d eac h de pe n de nt c hil d of t he cli nical i n vesti gat or or 
s u bi n vesti gat or.  T hese re q uire me nts a p pl y t o b ot h U S a n d f orei g n cli nical i n vesti gat ors 
c o n d ucti n g c o vere d cli nical st u dies.  
A n y  ne w cli nical i n vesti gat ors a d de d t o t he c o vere d cli nical st u d y d uri n g its c o n d uct m ust als o 
s u b mit a c o m plete d I n vesti gat or Fi na ncial Discl os ure F or m.  D uri n g a c o vere d cli nical st u d y, 
a n y c ha n ges t o t he fi na ncial i nf or mati o n pre vi o usl y re p orte d b y a cli n ical i n vesti gat or m ust be 
re p orte d t o t he s p o ns or or its desi g nee.  At t he c o ncl usi o n of t he c o vere d cli nical st u d y, t he 
cli nical i n vesti gat ors will be re mi n de d of t heir o bli gati o n s.  I n t he e ve nt t hat t he cli nical 
i n vesti gat or is n ot re mi n de d, t he y ne vertheless  will  re mai n o bli gate d t o re p ort t o t he s p o ns or or 
its desi g nee a n y c ha n ges t o t he fi na ncial i nf or mati o n pre vi o usl y re p orte d , as well as a n y c ha n ges 
i n t heir fi na ncial i nf or mati o n f or a peri o d of 1 year after c o m pleti o n of t he c o vere d cli nical st u d y. 
1 0. 6.  
P u blic ati o n P olic y  
B y si g ni n g t he st u d y Pr ot oc ol , t he in vesti gat or a n d his or her i nstit uti o n a gree t hat t he res ults of 
t he st u d y ma y be use d b y t he s p o ns or, I nc yte C or p orati o n (I nc yte), f or t he p ur p oses of nati o nal 
a n d i nter nati o nal re gistrati o n, p u blicati o n, a n d i nf or mati o n f or me dical a n d p har mace utical 
pr ofessi o nals.  St u d y res ults will be p u blis he d i n acc or da nce wit h a p plica ble l ocal a n d nati o nal 
re g ulati o ns.  If necessar y, t he a ut h orities will be n otifie d of t he i n vesti gat or's na me, a d dress, 
q ualific ati o ns, a n d e xte nt of i n v ol ve me nt.  T he ter ms re gar di n g t he p u blicati o n of st u d y res ults 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 6 8 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

are c o ntai ned i n t he a gree me nt si g ne d wit h t he s p o ns or or its desi g nee.  A si g ne d a gree me nt will 
be retai ne d b y t he s p o ns or or its desi g nee. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 6 9 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

1 1.  
R E F E R E N C E S  
A m br osetti A, Z a n otti R, Pattar o C, et al. M ost cases of pri mar y sali var y m uc osa -ass ociate d 
l y m p h oi d tiss ue l y m p h o ma are ass ociate d eit her wit h Sj oe gre n s y n dr o me or he patitis C vir us 
i nfecti o n. Br J of Hae mat ol 2 0 0 4; 1 2 6: 4 3- 4 9. 
Ar mita ge J O, Weise n b ur ger D D. Ne w a p pr oac h t o c lassif yi n g n o n- H o d g ki n' s ly m p h o mas: 
cli nical feat ures of t he m aj or hist ol o gic s u bt y pes. J Cli n O nc ol 1 9 9 8; 1 6: 2 7 8 0- 2 7 9 5. 
Be na ve nte Y, M bisa G, La b o N, et al. A nti b o dies a gai nst l ytic a n d late nt Ka p osi' s 
sarc o ma-ass ociate d her pes vir us a nti ge ns an d l y m p h o ma i n t he E ur o pea n E pi L y m p h case-c o ntr ol 
st u d y. Br J of Ca ncer 2 0 1 1; 1 0 5: 1 7 6 8- 1 7 7 1. 
Ber ger F, Fel ma n P, T hi e ble m o nt C, et al. N o n- M A L T mar gi nal z o ne B -cell l y m p h o mas: a 
descri pti o n of cli nical prese ntati o n a n d o utc o me i n 1 2 4 patie nts. Bl o o d 2 0 0 0; 9 5: 1 9 5 0- 1 9 5 6. 
Bert o ni F, Z ucca  Z.  Del vi n g dee per i nt o M A L T l y m p h o ma bi ol o g y. J Cli n I n vest 
2 0 0 6; 1 1 6: 2 2- 2 6. 
Ca ntle y L C.  T he p h os p h oi n ositi de 3- ki nase pat h wa y. Scie nce 2 0 0 2; 2 9 6: 1 6 5 5- 1 6 5 7. 
C hac ó n JI, M ollej o M, M uñ oz E, et al. S ple nic mar gi nal z o ne l y m p h o ma: cl i nical c haracteristics 
a n d pr o g n ostic fact ors i n a series of 6 0 patie nts. Bl o o d 2 0 0 2; 1 0 0 : 1 6 4 8- 1 6 5 4. 
C hea h C Y, C hi hara D, R o ma g uera J E, et al. Patie nts wit h ma ntle cell l y m p h o ma faili n g i br uti ni b 
are u nli kel y t o res p o n d t o sal va ge c he m ot hera p y a n d ha ve p o or o utc o mes. A n n O nc ol 
2 0 1 5; 2 6: 1 1 7 5- 1 1 7 9. 
C hes o n B D, Fis her RI, Barri n gt o n S F, et al. Rec o m me n dati o ns f or i nitial e val uati o n, sta gi n g, a n d 
res p o nse assess me nt of H o d g ki n a n d n o n- H o d g ki n l y m p h o ma: t he L u ga n o Classificati o n. J Cli n 
O nc ol 2 0 1 4; 3 2: 3 0 5 9- 3 0 6 8. 
Cli nical Trial Facilitati o n Gr o u p ( C T F G). Rec o m me n dati o ns relate d t o c o ntrace pti o n a n d 
pre g na nc y testi n g i n cli nical trials. Se pte m ber 1 5, 2 0 1 4. htt p:// w w w. h ma.e u/ctf g. ht ml . Accesse d 
Oct o ber 8, 2 0 1 5. 
C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m ser u m creati ni ne. Ne p hr o n 
1 9 7 6; 1 6: 3 1- 4 1. 
C o nc o ni A, Bert o ni F, Pe dri nis E, et al. N o dal mar gi nal z o ne B- cell l y m p h o mas ma y arise fr o m  
differe nt s u bsets of mar gi nal z o ne B l y m p h oc ytes. Bl o o d 2 0 0 1; 9 8: 7 8 1- 7 8 6. 
C o utré S E, Barrie nt os J C, Br o w n J R, et al . Ma na ge me nt of a d verse e ve nts ass ociate d wit h 
i delalisi b treat me nt: e x pert pa nel o pi ni o n. Le u k L y m p h o ma 2 0 1 5; 5 6: 2 7 7 9- 2 7 8 6. 
C u ne o A, Cast ol di G. Mar gi nal z o ne B- cell l y m p h o ma. Atlas Ge net C yt o ge net O nc ol Hae mat ol 
2 0 0 6; 1 0: 1 8 0- 1 8 3. 
Ferla y J, S oerj o matara m I,  Er vi k M, et al. G L O B O C A N 2 0 1 2 v 1. 0, Ca ncer I nci de nce a n d 
M ortalit y W orl d wi de: I A R C  Ca ncer Base N o. 1 1 [I nter net]. L y o n, Fra nce: I nter nati o nal A ge nc y 
f or Researc h o n Ca ncer. 2 0 1 3. htt p:// gl o b oca n.iarc.fr. Accesse d Fe br uar y 1 3, 2 0 1 7. 
Fra nc o V, Fl ore na A M, Ia n nitt o E. S ple nic mar gi nal z o ne l y m p h o ma. Bl o o d 
2 0 0 3; 1 0 1: 2 4 6 4- 2 4 7 2. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 7 0 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

Her mi ne  O, Lefrère, Br o n o wic ki J P, et al. Re gressi o n of s ple nic l y m p h o ma wit h vill o us 
l y m p h oc ytes after treat me nt of he pa ptitis C vir us i nfecti o n. N E n gl J Me d 2 0 0 2; 3 4 7: 8 9- 9 4. 
I m br u vica [ pac ka ge i nsert]. S u n n y vale, C A: P har mac yclics L L C; 2 0 1 7. 
I N C B 05 0 4 6 5 I n vesti gat or's Br oc h ure (I B). Wil mi n gt o n, D E: I nc yte C or p orati o n. 
L y m p h o ma Researc h F o u n dati o n. Getti n g t he Facts. N o n- H o d g ki n l y m p h o ma (l y m p h oi d 
ne o plas ms). 2 0 1 7a. htt p:// w w w.l y m p h o ma. o r g/atf/cf/ % 7 Baaf 3 b 4e 5- 2c 4 3- 4 0 4c-afe 5-
f d 9 0 3c 8 7 b 2 5 4 % 7 D/ L R F _ F A C T S H E E T _ N O N _ H O D G KI N _ L Y M P H O M A. P D F. Accesse d 
Fe br uar y 1 3, 2 0 1 7. 
L y m p h o ma Researc h F o u n dati o n. Getti n g t he Facts. Mar gi nal z o ne l y m p h o ma. 2 0 1 7 b. 
htt p:// w w w.l y m p h o ma. or g/atf/cf/ % 7 Baaf 3 b 4e 5- 2c 4 3- 4 0 4c- afe 5-
f d 9 0 3c 8 7 b 2 5 4 % 7 D/ L R F _ F A C T S H E E T _ N O N _ H O D G KI N _ L Y M P H O M A. P D F. Accesse d 
Fe br uar y 1 3, 2 0 1 7. 
Marti n P, Ma d d oc ks K, Le o nar d J P, et al. P osti br uti ni b o utc o mes i n patie nts wit h ma ntle cell 
l y m p h o ma. Bl o o d 2 0 1 6; 1 2 7: 1 5 5 9- 1 5 6 3. 
Nati o nal C o m pre he nsi ve Ca ncer Net w or k ( N C C N). Cli nical Practice G ui deli nes i n O nc ol o g y: 
B-cell l y m p h o mas Versi o n 1. 2 0 1 7. htt ps:// w w w. ncc n. or g/ pr ofessi o nals/ p h ysicia n _ gls/ p df/ b-
cell. p df. Accesse d Fe br uar y 1, 2 0 1 7. 
Nati o nal Ca ncer I nstit ute ( N CI). C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts Versi o n 
4. 0 3. 2 0 1 0. htt p://e vs. nci. ni h. g o v/ft p 1/ C T C A E/ C T C A E _ 4. 0 3 _ 2 0 1 0- 0 6-
1 4 _ Q uic k Refere nce _ 5 x 7. p df. Accesse d Fe br uar y 1, 2 0 1 7.  
N o n- H o d g ki n's L y m p h o ma Classificati o n Pr oject . A c li nical e val uati o n of t he I nter nati o nal 
L y m p h o ma  St u d y Gr o u p classificati o n of n o n- H o d g ki n's ly m p h o ma. Bl o o d 1 9 9 7; 8 9: 3 9 0 9- 3 9 1 8.  
N o va k U, Bass o K, Pas q ual ucci L,  Dalla -Fa vera R, B ha gat G . Ge n o mic a nal ysis of n o n-s ple nic 
mar gi nal z o ne l y m p h o mas ( M Z L) i n dicates si milarities bet wee n n o dal a n d e xtra n o dal M Z L a n d 
s u p p orts t heir deri vati on fr o m m e m or y B-cells. Br J Hea mat ol 2 0 1 1; 1 5 5: 3 6 2- 3 6 5. 
O ke n M M, Creec h R H, T or me y D C, et al. T o xicit y a n d res p o nse criteria of t he Easter n 
C o o perati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol 1 9 8 2; 5: 6 4 9- 6 5 5. 
Olsze ws ki AJ , Castill o  JJ. S ur vi val of patie nts wit h mar gi nal z o ne l y m p h o ma. Ca ncer 
2 0 1 3; 1 1 9: 6 2 9- 6 3 8. 
Pat nai k A, A p ple ma n LJ, T olc her A W, et al. First- i n- h u ma n p hase I st u d y of c o pa nlisi b ( B A Y 
8 0- 6 9 4 6), a n i ntra ve n o us pa n-class I p h os p hati d yli n osit ol 3- ki nase i n hi bit or, i n patie nts wit h 
a d va nce d s oli d t u m ors a n d n o n- H o d g ki n's l y m p h o mas. A n n O nc ol 2 0 1 6; 2 7: 1 9 2 8- 1 9 4 0. 
P hilli ps TJ, Ra mc ha n dre n R, Wert hei m M S, et al. A n o n g oi n g o pe n- la bel P hase 1/ 2 st u d y of 
I N C B 0 5 0 4 6 5, a selecti ve PI 3 K δ I n hi bit or, i n patie nts wit h pre vi o usl y treate d B-cell 
m ali g na ncies. Prese nte d at: 5 8t h A merica n S ociet y of He mat ol o g y A n n ual Meeti n g a n d 
E x p ositi o n; Dece m ber 3 - 6, 2 0 1 6; Sa n Die g o, C A. 
Ra m os -Casals  M, la Ci vita L, d e Vita S, et al. C haracterizati o n of B cell l y m p h o ma i n patie nts 
wit h Sj ö gre n 's s y n dr o me a n d he patitis C vir us i nfecti o n. Art hritis R he u m 2 0 0 7; 5 7: 1 6 1- 1 7 0. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 7 1 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A P P E N DI X  A.  I N F O R M A TI O N R E G A R DI N G E F F E C TI V E N E S S O F 
C O N T R A C E P TI V E M E T H O D S 
F or S u bjects P artici p ati n g i n t he St u d y:  
T he f oll o wi n g met h o ds t hat ca n ac hie ve a fail ure rate of less t ha n 1 % per year w he n use d 
c o nsiste ntl y a n d c orrectl y are c o nsi dere d as hi g hl y effecti ve birt h c o ntr ol m et h o ds.  
S uc h met h o ds i ncl u de: 
•  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n 1 
− oral 
− i ntra va gi nal 
− tra ns der mal 
•  Pr o gest o ge n- o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 1 
− oral 
− i njecta ble 
− i m pla nta ble2 
•  I ntra uteri ne de vice (I U D)2 
•  I ntra uteri ne h or m o ne-releasi n g s yste m (I U S)2 
•  Bilateral t u bal occl usi o n 2 
•  Vasect o mise d part ner 2, 3 
•  Se x ual a bsti ne nce 4 
F or M ale S u bjects P artici p ati n g i n t he St u d y  
I n a d diti o n t o t he af ore me nti o ne d c o ntrace pti ve met h o ds, male s u bjects m ust als o use a c o n d o m 
d uri n g i nterc o urse fr o m t he ti me of first d ose of st u d y treat me nt a n d t hr o u g h at least 9 3 da ys 
after last d ose of st u d y treat me nt.   Males w h o ha ve ha d a vasect o m y q ualif y as ha vi n g met t he 
re q uire me nt f or a hi g hl y effecti ve birt h c o ntr ol met h o d. 
1  H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t he I M P, w hic h ma y re d uce t he efficac y of t he 
c o ntrace pti o n met h o d.  
2  C o ntrace pti o n met h o ds t hat i n t he c o nte xt of t his g ui da nce are c o nsi dere d t o ha ve l o w user de pe n de nc y.  
3  Vasect o mise d part ner is a hi g hl y effecti ve met h o d of a v oi di n g pre g na nc y  pr o vi de d t hat part ner is t he s ole se x ual 
part ner of t he W O C B P trial partici pa nt a n d t hat t he vasect o mise d part ner has recei ve d me dical assess me nt of t he 
s ur gical s uccess.  
4  I n t he c o nte xt of t his g ui da nce, se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as 
refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y treat me nts.  T he 
relia bilit y of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he d urati o n of t he cli nical trial a n d t he 
preferre d a n d us ual lifest yle of t he s u bject.  
S o urce:  C T F G  2 0 1 4 . 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 7 3 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A P P E N DI X  B.  E A S T E R N C O O P E R A TI V E O N C O L O G Y G R O U P 
P E R F O R M A N C E S C O R E S  
Gr a de  
Perf or m a nce St at us  
0 
F ull y acti ve, a ble t o carr y o n all pre disease perf or ma nce wit h o ut restricti o n . 
1 
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a 
li g ht or se de ntar y nat ure, e g, li g ht h o use w or k, office w or k. 
2 
A m b ulat or y a n d ca pa ble of all self -care b ut u na ble t o carr y o ut a n y w or k acti vities.  U p 
a n d a b o ut m ore t ha n 5 0 % of wa ki n g h o urs . 
3 
Ca pa ble of o nl y li mite d self -care, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g 
h o urs . 
4 
C o m pletel y disa ble d.  Ca n n ot carr y o n a n y self -care.  T otall y c o nfi ne d t o be d or c hair . 
5 
Dea d . 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 7 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

g ol d e ns e al  
H er b al M e dic ati o ns  
cl otri m az ol e 
A ntif u n g als  
t acr oli m us 
I m m u n os u p pr ess a nts 
p al b ocicli b  
Ki n as e I n hi bit ors  
cil ost az ol 
A nti pl at el ets  
tic a gr el or 
A nti pl at el ets 
p e p p er mi nt oil  
F o o d Pr o d ucts  
i v ac aft or 
C ystic fi br osis tr e at m e nts  
G S K 2 2 4 8 7 6 1  
Tr a nscri pt as e I n hi bit ors  
G u a n M ai Ni n g  
H er b al M e dic ati o ns  
osil o dr ost at  
A dr e n al St er oi d o g e n esis I n hi bit ors  
A Z D 2 3 2 7  
D e pr essi o n Tr e at m e nts  
pi p eri n e  
F o o d Pr o d ucts  
r es v er atr ol 
F o o d Pr o d ucts  
r o xit hr o m yci n 
A nti bi otics  
s u v or e x a nt 
H y p n otics - S e d ati v es  
pr o pi v eri n e  
A ntic h oli n er gics  
is o ni azi d 
A nti bi otics  
b er b eri n e  
H er b al M e dic ati o ns  
or al c o ntr ac e pti v es  
Or al c o ntr ac e pti v es  
d el a vir di n e  
N N R TIs  
d acl at as vir  
A nti vir als 
si m e pr e vir 
Pr ot e as e I n hi bit ors  
at or v ast ati n  
H M G C o A R e d uct as e I n hi bit ors ( St ati ns)  
t ol v a pt a n 
V as o pr essi n A nt a g o nists  
al m or e x a nt  
H y p n otics - S e d ati v es 
G S K 1 2 9 2 2 6 3  
Ot h er A ntili p e mics  
e v ac etr a pi d  
C E T P i n hi bit ors  
li n a gli pti n 
Di p e pti d yl P e pti d as e 4 I n hi bit ors  
gr az o pr e vir  (i n gr e di e nt of Z e p ati er)  
A nti vir als 
l aci di pi n e 
C alci u m C h a n n el Bl oc k ers  
cr a n b err y j uic e 
F o o d Pr o d ucts  
p az o p a ni b  
Ki n as e I n hi bit ors  
f ost a m ati ni b 
Ot h er  
e v er oli m us  
I m m u n os u p pr ess a nts 
bl u e b err y j uic e  
F o o d Pr o d ucts  
fli b a ns eri n 
C e ntr al N er v o us S yst e m A g e nts  
l a p ati ni b 
Ki n as e I n hi bit ors  
br o d al u m a b  
I m m u n o m o d ul at ors Bi ol o gics 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 7 9 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

ticl o pi di n e 
A ntic o a g ul a nts a n d A nti pl at el ets  
is a v uc o n az ol e 
A ntif u n g als  
bri v ar ac et a m  
A ntic o n v uls a nts  
Stri bil d  
Tr e at m e nts of AI D S  
pi o glit az o n e  
T hi az oli di n e di o n es  
VI E KI R A P A K  
A nti vir als  
d e x a m et h as o n e  
C ortic ost er oi ds  
t er bi n afi n e 
A ntif u n g als  
q u erc eti n  
F o o d Pr o d ucts  
gl yc yrr hizi n  
H er b al M e dic ati o ns  
a pr e pit a nt  
N e ur o ki ni n -1 R ec e pt or A nt a g o nists  
pr et o m a ni b ( P A -8 2 4)  
A nti bi otics  
s afi n a mi d e 
M A O -B I n hi bit ors  
orit a v a nci n  
A nti bi otics  
A Z D 7 3 2 5  
A nxi ol ytics  
m et h yl pr e d nis ol o n e  
C ortic ost er oi ds  
t o pir a m at e 
A ntic o n v uls a nts  
 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 8 2 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A P P E N DI X  E.  P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S  
D oc u me nt  
D ate  
A d mi nistrati ve C ha n ge 1 : 
1 6 A U G 2 0 1 7  
A d mi nistrati ve C ha n ge 2 ( Versi o n 0- U K):  
2 6 S E P 2 0 1 7  
A me n d me nt ( Versi o n) 1:  
2 4  J A N 2 0 1 8 
A me n d me nt ( Versi o n) 1 -F R A:  
2 3 F E B 2 0 1 8  
A me n d me nt ( Versi o n) 2 -F R A:  
2 8 M A R 2 0 1 8  
A me n d me nt ( Versi o n) 2:  
1 8 J U L 2 0 1 8  
A me n d me nt ( Versi o n) 3:  
0 7  D E C  2 0 1 8  
A me n d me nt ( Versi o n) 4:  
2 3  D E C  2 0 1 9 
A me n d me nt  4 (2 3  DE C  2 0 1 9) 
O ver all R ati o n ale  f or the  Ame n d me nt:   T he pri mar y p ur p ose of this a me n d me nt is to pr o vi de 
a d diti o nal g ui da nce o n d ose m o dificati o n i n t he e ve nt of di arr hea an d c olitis a n d t o defi ne the 
e n d of the st u d y, i ncl u di n g t he o pt i o n t o recei ve c o nti n ued treat me nt w it h I N C B 0 5 0 4 6 5 i n a 
r oll o ver pr ot oc ol. 
1.
Secti o n  5. 4. 1. 1, D ose M o dific ati o ns ( T a ble 3:  G ui deli nes f or I nterr u pti o n a n d
Rest arti n g I N C B 0 5 0 4 6 5; T a ble 4:  D ose Le vels a n d Re d ucti o ns f or I N C B 0 5 0 4 6 5);
Secti o n 5. 4. 2 , S u p p orti ve C are G ui deli nes f or Di arr he a/ C olitis (T a ble 5:  G ui deli nes
f or D ose M o dific ati o n of I N C B 0 0 5 0 4 6 5 f or Di arr he a/ C olitis )
Descri pti o n of c h a n ge:   Re visi o n t o te xt pertai ni n g t o i nterr u pti o ns a n d restarti n g
I N C B 0 5 0 4 6 5 f or a d verse e ve nts of diarr hea a n d c olitis.
R ati o n ale f or c h a n ge:   T o pr o vi de a d diti o nal d ose m o dificati o ns of I N C B 0 5 0 4 6 5 f or
diarr hea a n d c olitis.
2.
S y n o psis; Secti o n 4. 5, O ver all St u d y D ur ati o n; Secti o n 5. 8 , Tre at me nt After t he E n d
of t he St u d y; Secti o n 6. 5, E n d of St u d y
Descri pti o n of c h a n ge:   Te xt  a n d ne w secti o n a d de d t o descri be t hat s u bjects w h o are
recei vi n g acti ve st u d y treat me nt a n d ha ve n o e vi de nce of pr o gressi ve disease  at t he e n d of
t he st u d y will ha ve t he o pti o n t o c o nti n ue o n I N C B 0 5 0 4 6 5 pr o vi de d wit hi n a r oll o ver
Pr ot oc ol.
R ati o n al f or c h a n ge:   To clarif y w hat treat me nt o pti o ns are a vaila ble at t he e n d of t he
st u d y.
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
Versi o n 4
Pa ge 8 3 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

3.
S y n o psis  ( Esti m ate d D ur ati o n of P artici p ati o n); Secti o n 4. 4, D ur ati o n of Tre at me nt
a n d S u bject P artici p ati o n; Secti o n 4. 5, O ver all St u d y D ur ati o n; Secti o n 5. 7, Criteri a
f or St u d y Disc o nti n u ati o n; Secti o n 6. 5, E n d of St u d y
Descri pti o n of c h a n ge:   Te xt a n d ne w secti o n a d de d t o defi ne t he f oll o wi n g:  a) criteria
f or a s u bject t o be disc o nti n ue d fr o m t he st u d y a n d b) t he e n d of st u d y.
R ati o n al f or c h a n ge:   T o clarif y w he n a s u bject will be disc o nti n ue d fr o m t he st u d y a n d
w he n t he st u d y will e n d.
4.
Secti o n 6, St u d y Assess me nts  ( T a ble 6:  Sc he d ule of Assess me nts)
Descri pti o n of c h a n ge:   C ha n ge d fre q ue nc y of st u d y treat me nt dis pe nsati o n a n d
assess me nt of c o m plia nce fr o m e ver y 4 wee ks t o e ver y 1 2 wee ks starti n g at Wee k 4 8.
R ati o n ale f or c h a n ge:   T o ali g n wit h t he fre q ue nc y of cli nic visits after Wee k 4 8
w here b y re d uci n g t he b ur de n of e xtra cli nic visits f or t he s u bjects.
5.
Secti o n 9. 1, St u d y P o p ul ati o ns
Descri pti o n of c h a n ge:   Re m o ve d t he P P p o p ulati o n.
R ati o n ale f or c h a n ge:   F or a si n gle-ar m, o pe n-la bel st u d y, t he deter mi nati o n of s u bjects
t o be e xcl u de d fr o m t he P P p o p ulati o n is p ost- h oc a n d ma y n ot be d o ne o bjecti vel y; t h us,
a nal ysis base d o n t his p o p ulati o n ma y n ot be mea ni n gf ul.
6.
Secti o n 9. 1, St u d y P o p ul ati o ns; Secti o n 9. 4. 1. 1, Pri m ar y Effic ac y A n al ysis
Descri pti o n of c h a n ge:   T he efficac y e val ua ble a nal ysis set was re place d wit h t he f ull
a nal ysis set.
R ati o n ale f or c h a n ge:   T o i ncl u de all treate d s u bjects i n t he efficac y a nal yses.
7.
Secti o n 9. 4. 2. 4, Electr oc ar di o gr a ms ( T a ble 1 1:  Criteri a f or Cli nic all y N ot a ble
Electr oc ar di o gr a m  A b n or m alities)
Descri pti o n of c h a n ge:   C ha n ge d hi g h t hres h ol d of Q Tc F i nter val fr o m > 4 6 0 msec t o
> 4 5 0 msec f or a nal ysis p ur p oses.
R ati o n ale f or c h a n ge:   T o c o m pl y wit h t he cate g ories o utli ne d i n F D A G ui da nce f or 
I n d ustr y ( E 1 4 Cli nical E val uati o n of Q T/ Q Tc I nter val Pr ol o n gati o n a n d Pr oarr h yt h mic 
P ote ntial f or N o n- A ntiarr h yt h mic Dr u gs) use d t o c haracterize o utliers i n Q Tc val ues.  
8.
I nc or p or ati o n of a d mi nistr ati ve c h a n ges.  Ot her mi n or, a d mi nistrati ve c ha n ges ha ve
bee n i nc or p orate d t hr o u g h o ut t he Pr ot oc ol a n d are n ote d i n t he re dli ne versi o n of t he
a me n d me nt.
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
Versi o n 4
Pa ge 8 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A me n d me nt 3 ( 0 7 D E C  2 0 1 8) 
O ver all R ati o n ale f or t he A me n d me nt:  T he pri mar y p ur p ose of t h is a me n d me nt is to cl ose 
e nr oll me nt i n C o h ort 1 a n d t o i ncrease t he n u m ber of s u bjects e nr olle d i n C o h ort 2 t o better 
u n dersta n d t he safet y a n d efficac y of I N C B 0 5 0 4 6 5 a d mi nistere d at o ne of t he 2 treat me nt 
re gi me ns. 
1.
S y n o psis; Secti o n 1. 2. 1, I br uti ni b; Secti o n 1. 4, St u d y R ati o n ale; Secti o n 3. 1, S u bject
I ncl usi o n Criteri a; Secti o n 3. 2, S u bject E xcl usi o n Criteri a; Secti o n 4. 1, O ver all
St u d y Desi g n  ( Fi g ure 1, St u d y Desi g n of I N C B 5 0 4 6 5- 2 0 4); Secti o n 4. 3. 1, Pl a n ne d
N u m ber of S u bjects; Secti o n 4. 5, O ver all St u d y D ur ati o n; Secti o n 9. 2, Selecti o n of
S a m ple Size; Secti o n 9. 4. 1. 1, Pri m ar y Effic ac y A n al ys es; Secti o n 9. 6, I nteri m
A n al ysis
Descri pti o n of c h a n ge:  Te xt has bee n a d de d t o descri be t he f oll o wi n g:  a) C o h ort 1 will
be cl ose d t o f urt her e nr oll me nt , b) a n a d diti o nal 3 0 s u bjects will be e nr olle d i nt o C o h ort 2
a n d recei ve t he selecte d treat me nt re gi me n , a n d c) s u bjects ma y s witc h o ver t o t he
selecte d treat me nt re gi me n.
R ati o n ale f or c h a n ge:   D ue t o t he li mite d a vaila bilit y of i br uti ni b (a p pr o ve d i n t he
U nite d States  o nl y) a n d t he s u bse q ue nt l o w n u m ber of s u bjects e nr olle d t o date,
e nr oll me nt i nt o C o h ort 1 will be cl ose d.  A d diti o nal s u bjects will be e nr olle d i n C o h ort 2
t o better u n dersta n d t he safet y a n d efficac y of I N C B 0 5 0 4 6 5 a d mi nistere d at t he selecte d
treat me nt re gi me n.  T o all o w all s u bjects t o recei ve t he selecte d treat me nt re gi me n,
s u bjects i nitiall y all ocate d t o t he n o n-selecte d treat me nt re gi me n ma y s witc h o ver t o t he
selecte d treat me nt re gi me n.
2.
Secti o n 9. 1, St u d y P o p ul ati o ns
Descri pti o n of c h a n ge:  De fi ne d t he efficac y e val ua ble a nal ysis set t hat will be use d f or
t he efficac y a nal yses i n place of t he f ull a nal ysis set.
R ati o n ale f or c h a n ge:   T he efficac y e val ua ble a nal ysis set was a d de d t o clarif y t he
p o p ulati o n t hat will be i ncl u de d i n t he efficac y a n al yses.
3.
Secti o n 1 0. 4, D at a Pri v ac y a n d C o nfi de nti alit y of St u d y Rec or ds
Descri pti o n of c h a n ge:   Re visi o n t o la n g ua ge pertai ni n g t o t he pr otecti o n of pers o nal
data.
R ati o n ale f or c h a n ge:   T o c o m pl y wit h t he Ge neral Data Pr otecti o n Re g ulati o n
2 0 1 6/ 6 7 9.
4.
Secti o n 3. 2, S u bject E xcl usi o n Criteri a;  Secti o n 5. 6. 2, Restricte d Me dic ati o ns;
Secti o n 5. 6. 3, Pr o hi bite d Me dic ati o ns; A p pe n di x D, C Y P 3 A I n hi bit ors a n d I n d ucers
Descri pti o n of c h a n ge:  A d de d ta bles of C Y P 3 A i n hi bit ors a n d i n d ucers i n A p pe n di x D.
T hese ta bles were u p date d a n d m o difie d c o m pare d wit h  t he pre vi o us versi o ns, w hic h ha d
bee n re m o ve d fr o m Pr ot oc ol Versi o n 2 a n d place d i n t he P har mac y Ma n ual.
R ati o n ale f or c h a n ge:   T hese ta bles were ret ur ne d t o t he Pr ot oc ol b y t he re q uest of t he
Ger ma n Re g ulat or y A ut h orit y, Bf Ar M.
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
Versi o n 4
Pa ge 8 6 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

5.  I nc or p or ati o n of a d mi nistr ati ve c h a n ges.  Ot her mi n or, a d mi nistrati ve c ha n ges ha ve 
bee n i nc or p orate d t hr o u g h o ut t he Pr ot oc ol a n d are n ote d i n t he re dli ne versi o n of t he 
a me n d me nt.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 8 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A me n d me nt 2 ( 1 8 J U L  2 0 1 8) 
O ver all R ati o n ale f or t he A me n d m e nt:  T he pri mar y p ur p ose of t his a me n d me nt is t o m o dif y 
t he d ose re d ucti o n sc he d ules. 
1.  Secti o n 3. 1, S u bject I ncl usi o n Criteri a  
Descri pti o n of c h a n ge:  Criteri o n 8 d was re vise d t o all o w s u bjects w h ose t otal bilir u bi n 
val ues are > 1. 5 × U L N t o e nr oll if t he ele vati o n is d ue t o Gil bert’s s y n dr o me. 
R ati o n ale f or c h a n ge:   Gil bert’s s y n dr o me is a here ditar y c o n diti o n c haracterize d b y 
i nter mitte nt, u nc o nj u gate d h y per bilir u bi ne mia i n t he a bse nce of he pat ocell ular da ma ge 
a n d he m ol ysis.  C o nsiste nt wit h ot her PI 3 K δ i n hi bit ors, ele vate d bilir u bi n d ue t o 
Gil bert’s s y n dr o me is n ot e x pecte d t o alter t he ris k/ be nefit pr ofile f or s u bjects ta ki n g 
I N C B 0 5 0 4 6 5. 
2.  Secti o n 3. 2, S u bject E xcl usi o n Criteri a; Secti o n 5. 6. 2, Restricte d Me dic ati o ns; 
Secti o n 5. 6. 3, Pr o hi bite d Me dic ati o ns;  A p pe n di x B, C yt oc hr o me P 4 5 0 3 A I n hi bit ors 
a n d I n d ucers  
Descri pti o n of c h a n ge:  Delete d a p pe n di x a n d c orres p o n di n g cr oss- refere nces. 
R ati o n ale f or c h a n ge:   M o ve d i nf or mati o n t o t he P har mac y Ma n ual. 
3.  Secti o n 5. 4, Tre at me nt I nterr u pti o n a n d A dj ust me nts ( T a ble  3: G ui deli nes f or 
I nterr u pti o n a n d Rest arti n g I N C B 0 5 0 4 6 5) 
Descri pti o n of c h a n ge:  Re defi ne d “ Gra de 3 or Gra de 4 A N C wit h a n oral te m perat ure 
of at least 3 8. 5° C O R wit h ≥ Gra de 3 i nfecti o n” as Gra de 3 or Gra de 4 fe brile 
ne utr o pe nia.  All o wa nce is ma de t o restart I N C B 0 5 0 4 6 5 at t he sa me d ose after Gra de 4 
A N C, Gra de 4 platelet c o u nt, or Gra de 3 or Gra de 4 fe brile ne utr o pe nia res ol ve t o 
≤ Gra de  2, rat her t ha n Gra de 1, re gar dless of attri b uti o n. 
R ati o n ale f or c h a n ge:  A restart at t he sa me d ose le vel re gar dless  of attri b uti o n is 
all o we d t o pr o vi de i n vesti gat ors fle xi bilit y i n s u bject ma na ge me nt.  St u d y dr u g 
a d mi nistrati o n is all o we d t o be gi n at ≤ Gra de 2 t o be c o nsiste nt wit h eli gi bilit y criteria, 
w hic h start at Gra de 2 f or ne utr o p hil a n d platelet c o u nts. 
4.  Secti o n 5. 4, Tre at me nt I nterr u pti o ns a n d A dj ust me nts ( T a ble 4: D ose Le vels f or 
I N C B 0 5 0 4 6 5) 
Descri pti o n of c h a n ge:   M o difie d t he d ose re d ucti o n sc he d ules.  
R ati o n ale f or c h a n ge:   T he ne w sc he d ules are bei n g i m ple me nte d t o e ns ure t hat all 
s u bjects will re mai n o n a Q D d osi n g sc he d ule f or t he first 8 wee ks ( Da ys 1- 5 6) a n d t o 
pr o vi de c o nsiste nc y bet wee n Treat me nts A a n d B.  
5.  Secti o n 6, St u d y Assess me nts ( T a ble 6: Sc he d ule of L a b or at or y Assess me nts, 
f o ot n ote a); Secti o n 7. 5. 7, L a b or at or y Assess me nts 
Descri pti o n of c h a n ge:   Clarifie d t he sce nari os i n w hic h a l ocal la b orat or y assess me nt 
ma y be perf or me d a n d i n w hic h cases l ocal la b orat or y val ues w o ul d be e ntere d i nt o t he 
e C R F.  
R ati o n ale f or c h a n ge:   Clarificati o n.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 8 8 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A me n d me nt 2 - F R A ( 2 8 M A R 2 0 1 8) 
O ver all R ati o n ale f or t he A me n d me nt:   
T he pri mar y p ur p ose of t his a me n d me nt is t o re vise t he e xcl usi o n criteri o n f or li ver disease a n d 
i nc or p orate ot her re visi o ns re q ueste d b y healt h a ut h orities i n or der t o ali g n wit h gl o bal Pr ot oc ol 
A me n d me nt 1. 
1.  Secti o n 5. 4. 3, S u p p orti ve C are G ui deli nes f or Ne utr o pe ni a a n d T hr o m b oc yt o pe ni a  
Descri pti o n of c h a n ge:  Pr o vi de d i nstr ucti o ns t o i n vesti gat ors t o re mi n d s u bject t o re p ort 
si g ns or s y m pt o ms of i nfecti o n, blee di n g, or s u d de n, e xtre mel y pai nf ul hea dac hes. 
R ati o n ale f or c h a n ge:  Re q ueste d b y t he U S F D A. 
2.  S y n o psis; Secti o n 3. 2, S u bj ect E xcl usi o n Criteri a  
Descri pti o n of c h a n ge:  Criteri o n 1 7  was re vise d  t o all o w f or s u bjects w h o are p ositi ve 
f or H Bs A g or he patitis B c ore a nti b o d y t o e nr oll if t he y are ne gati ve f or H B V-D N A a n d 
t o re m o ve ris k of reacti vati o n as e xcl usi o nar y. 
R ati o n ale f or c h a n ge:   As t here ha ve bee n n o re p orte d H B V or H C V reacti vati o ns i n 
I N C B 5 0 4 6 5- 1 0 1, t he e xcl usi o n criteri o n was a me n de d t o ali g n wit h t h ose of a p pr o ve d 
PI 3 K i n hi bit ors. 
3.  Secti o n 1. 3, I N C B 0 5 0 4 6 5; Secti o n 1. 5, P ote nti al Ris ks a n d Be nefits of t he Tre at me nt 
Re gi me n  
Descri pti o n of c h a n ge:  U p date d safet y a n d efficac y data fr o m P hase 1/ 2 st u d y 
I N C B 5 0 4 6 5- 1 0 1. 
Re as o n f or c h a n ge:   Re q ueste d b y Ger ma n re g ulat or y a ut h orit y. 
4.  Secti o n 5. 2. 2, S u p pl y, P ac k a gi n g, a n d L a beli n g 
Descri pti o n of c h a n ge:  Clarifie d la n g ua ge o n  h o w PJ P pr o p h ylactic a ge nts will be 
s u p plie d. 
R ati o n ale f or c h a n ge:  I nc yte will n ot pr o vi de PJ P pr o p h ylactic a ge nts, b ut rat her sites 
will be res p o nsi ble f or s o urci n g fr o m c o m mercial s u p pl y a n d I nc yte will rei m b urse.  
5.  Secti o n 5. 5. 1, Criteri a f or St u d y Tre at me nt Disc o nti n u ati o n  
Descri pti o n of c h a n ge:   T he f oll o wi n g b ullet has bee n delete d fr o m Secti o n 5. 5. 1:  If a 
s u bject is f o u n d n ot t o ha ve met eli gi bilit y criteria, t he n t he me dical m o nit or a n d 
i n vesti gat or will c olla b orate t o deter mi ne w het her t he s u bject s h o ul d be wit h dra w n fr o m 
t he st u d y. 
R ati o n a le f or c h a n ge:  Re q ueste d b y U S a n d Ca na dia n re g ulat or y a ut h orities d uri n g 
re vie w of ot her I nc yte pr ot oc ols. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 9 0 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A me n d me nt 1 - F R A ( 2 3 F E B 2 0 1 8) 
O ver all R ati o n ale f or t he A me n d me nt:  
T he pri mar y p ur p ose of t his a me n d me nt is t o i nstit ute he mat ol o g y testi n g e ver y 2 wee ks f or t he 
first 8 wee ks of I N C B 0 5 0 4 6 5 d osi n g. 
1.  S y n o psis; Secti o n 6, St u d y Assess me nts ( T a ble 6, Sc he d ule of L a b or at or y 
Assess me nts  
Descri pti o n of c h a n ge:  St u d y visits were a d de d at Wee k 2 a n d Wee k 6 f or he mat ol o g y 
testi n g. 
R ati o n ale f or c h a n ge:   Re q ueste d b y t he Fre nc h Nati o nal A ge nc y f or Me dici nes a n d Healt h 
Pr o d ucts Safet y. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 9 2 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A me n d me nt 1 ( 2 4 J A N 2 0 1 8) 
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteria set f ort h i n Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n. 
O ver all R ati o n ale f or t he A me n d me nt:   
T he pri mar y p ur p ose of t his a me n d me nt is t o i nstit ute he mat ol o g y testi n g e ver y 2 wee ks f or t he 
first 8 wee ks of d osi n g a n d re vise t he e xcl usi o n criteri o n f or li ver disease. 
T he c ha n ges i nc or p orate d i n t he I N C B 5 0 4 6 5- 2 0 4 Pr ot oc ol A me n d me nt 1 (Versi o n 1 date d 
2 4 J A N 2 0 18 ) are s u m marize d bel o w. 
1.  S y n o psis; Secti o n 6, St u d y Assess me nts ( T a ble 6, Sc he d ule of Assess me nts)  
Descri pti o n of c h a n ge:   St u d y visits were a d de d at Wee k 2 a n d Wee k 6 f or he mat ol o g y 
testi n g. 
R ati o n ale f or c h a n ge:   Re q ueste d b y t he U S F D A. 
2.  Secti o n 5. 4. 3, S u p p orti ve C are G ui deli nes  f or Ne utr o pe ni a a n d T hr o m b oc yt o pe ni a 
Descri pti o n of c h a n ge:  Pr o vi de d i nstr ucti o ns t o i n vesti gat ors t o re mi n d s u bject t o re p ort 
si g ns or s y m pt o ms of i nfecti o n, blee di n g, or s u d de n, e xtre mel y pai nf ul hea dac hes. 
R ati o n ale f or c h a n ge:  Re q ueste d b y t he U S F D A.  
3.  S y n o psis; Secti o n 3. 2, S u bject E xcl usi o n Criteri a  
Descri pti o n of c h a n ge:  Criteri o n 1 7  was re vise d  t o all o w f or s u bjects w h o are p ositi ve 
f or H Bs A g or he patitis B c ore a nti b o d y t o e nr oll if t he y are ne gati ve f or H B V-D N A a n d 
t o re m o ve ris k of reacti vati on as e xcl usi o nar y. 
R ati o n ale f or c h a n ge:   As t here ha ve bee n n o re p orte d H B V or H C V reacti vati o ns i n 
I N C B 5 0 4 6 5- 1 0 1, t he e xcl usi o n criteri o n was a me n de d t o ali g n wit h t h ose of a p pr o ve d 
PI 3 K i n hi bit ors. 
4.  Secti o n 1. 3, I N C B 0 5 0 4 6 5; Secti o n 1. 5, P ote nti al Ris ks a n d Be nefits of t he Tre at me nt 
Re gi me n  
Descri pti o n of c h a n ge:  U p date d safet y a n d efficac y data fr o m P hase 1/ 2 st u d y 
I N C B 5 0 4 6 5- 1 0 1. 
Re as o n f or c h a n ge:   Re q ueste d b y Ger ma n re g ulat or y a ut h orit y. 
5.  Secti o n 5. 2. 2, S u p pl y, P ac k a gi n g, a n d L a beli n g 
Descri pti o n of c h a n ge:  Clarifie d la n g ua ge o n h o w PJ P pr o p h ylactic a ge nts will be 
s u p plie d. 
R ati o n ale f or c h a n ge:  I nc yte will n ot pr o vi de PJ P pr o p h ylactic a ge nts, b ut rat her sites 
will be res p o nsi ble f or s o urci n g fr o m c o m mercial s u p pl y a n d I nc yte will rei m b urse.  
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 9 3 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

6.  Secti o n 5. 5. 1, Criteri a f or St u d y Tre at me nt Disc o nti n u ati o n  
Descri pti o n of c h a n ge:   T he f oll o wi n g b ullet has bee n delete d fr o m Secti o n 5. 5. 1:  If a 
s u bject is f o u n d n ot t o ha ve met eli gi bilit y criteria, t he n t he me dical m o nit or a n d 
i n vesti gat or will c olla b orate t o deter mi ne w het her t he s u bject s h o ul d be wit h dra w n fr o m 
t he st u d y. 
R ati o n ale f or c h a n ge:   Re q ueste d b y U S a n d Ca na dia n re g ulat or y a ut h orities d uri n g 
re vie w of ot her I nc yte pr ot oc ols. 
7.  Secti o n 5. 6. 2, Restricte d Me dic ati o ns; Secti o n 5. 6. 3, Pr o hi bite d Me dic ati o ns  
Descri pti o n of c h a n ge:  Ra diati o n t hera p y was re m o ve d fr o m Secti o n 5. 6. 3 as it was 
re d u n da nt wit h Secti o n 3. 2 ( E xcl usi o n Criteri o n 1 0), w hic h lists e xcl u de d, c o nc urre nt 
a ntica ncer t hera pies.  A descri pti o n of per mitte d ra di ot hera p y w as a d de d t o Secti o n 5. 6. 2. 
R ati o n ale f or c h a n ge:  A d mi nistrati o n of l ocalize d ra di ot hera p y i n cases of pai n or 
i m pe n di n g c o m pressi o n fract ures ma y be per mitte d t o all o w s u bjects w h o are ot her wise 
be nefitti n g t o c o nti n ue st u d y treat me nt.   
9.  S y n o psis; Secti o n 3. 1, S u bject I ncl usi o n Criteri a; Secti o n 6, St u d y Assess me nt 
( T a ble 5, Sc he d ule of Assess me nts); Secti o n 7. 8. 5, T u m or 
Descri pti o n of c h a n ge:  La n g ua ge was a d de d t o all o w s u bjects  wit h s ple nic M Z L t o 
partici pate if a b o ne marr o w bi o ps y is pr o vi de d at baseli ne. 
R ati o n ale f or c h a n ge:  S u bjects wit h s ple nic M Z L ma y n ot ha ve a t u m or lesi o n t o 
bi o ps y or a n arc hi val t u m or tiss ue t o pr o vi de.  T heref ore, a b o ne marr o w sa m ple 
hist ol o gicall y c o nfir mi n g i nfiltrati o n of M Z L is all o we d.  
1 0.  A p pe n di x A, I nf or m ati o n Re g ar di n g Effecti ve ness of C o ntr ace pti ve Met h o ds  
Descri pti o n of c h a n ge:  Pr o vi de d i nf or mati o n f or male c o ntrace pti o n met h o ds. 
R ati o n ale f or c h a n ge:  I nf or mati o nal. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 9 4 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A d mi nistr ati ve C h a n ge 2 ( 2 6 S E P 2 0 1 7) 
O ver all R ati o n ale f or t he A d mi nistr ati ve C h a n ge:  
T he pri mar y p ur p ose of t his a d mi nistrati ve c ha n ge is t o a d dress c ha n ges re q ueste d b y t he 
Me dici nes a n d Healt hcare Pr o d ucts Re g ulat or y A ge nc y ( M H R A) i n t he U nite d Ki n g d o m.  
T he c ha n ges t o t he Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 Versi o n 0 ( 2 2 M A R 2 0 1 7) are s u m marize d bel o w.  
1.  A p pe n di x A, I nf or m ati o n Re g ar di n g Effecti ve ness of C o ntr ace pti ve Met h o ds  
Descri pti o n of c h a n ge:   A state me nt was a d de d n oti n g t hat male s u bjects partici pati n g i n 
t he st u d y m ust als o use a c o n d o m d uri n g i nterc o urse fr o m t he ti me of first d ose of st u d y 
treat me nt a n d t hr o u g h at least 9 3 da ys after last d ose of st u d y treat me nt.  
R ati o n ale f or c h a n ge:  R e q ueste d b y M H R A.  
2.  Secti o n 5. 6. 3, Pr o hi bite d Me dic ati o ns  
Descri pti o n of c h a n ge:   A state me nt was a d de d n oti n g t hat e x p os ure t o a li ve vacci ne is 
pr o hi bite d wit hi n 3 0 da ys of st u d y treat me nt t hr o u g h 3 m o nt hs after t he last d ose of 
I N C B 0 5 0 4 6 5. 
R ati o n ale f or c h a n ge:  Re q ueste d b y M H R A.  
3.  A p pe n di x F, Pr ot oc ol A me n d me nt S u m m ar y of C h a n ges  
Descri pti o n of c h a n ge:   T his a p pe n di x was a d de d t o pr o vi de a descri pti o n of t he 
a d mi nistrati ve c ha n ges t o t he Pr ot oc ol t o date a n d t he rati o nale f or c ha n ges. 
R ati o n ale f or c h a n ge:   T o e ns ure c o m plia nce wit h I nc yte's ne w sta n dar d Pr ot oc ol 
te m plate. 
4.  Title P a ge; he a der of all p a ges i n t he Pr ot oc ol; P a ge 2, I n vesti g at or A gree me nt 
Descri pti o n of c h a n ge:   Re vise d versi o n n u m ber ( Versi o n 0- U K).  
R ati o n ale f or c h a n ge:   T o de n ote t he a d mi nistrati ve c ha n ges ma de t o t his Pr ot oc ol a p pl y 
t o all partici pati n g i n vesti gati ve sites i n t he U nite d Ki n g d o m. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 9 6 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L

A d mi nistr ati ve C h a n ge 1 ( 1 6 A U G 2 0 1 7) 
O ver all R ati o n ale f or t he A d mi nistr ati ve C h a n ge:  
T he pri mar y p ur p ose of t his a d mi nistrati ve c ha n ge is t o de n o te a versi o n n u m ber ass ociate d wit h 
t he pr ot oc ol i n res p o nse t o a re q uest fr o m t he Nati o nal Researc h Et hics Ser vice ( N R E S) i n t he 
U nite d Ki n g d o m. 
T his a me n d me nt i ncl u des t he c ha n ges t o t he Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 ( 2 2 M A R 2 0 1 7) 
s u m marize d bel o w.   
1.  C o ver P a g e a n d he a der of all p a ges i n t he Pr ot oc ol 
Descri pti o n of c h a n ge:   T he ta ble o n t he c o ver pa ge a n d hea der were re vise d t o a d d a 
versi o n n u m ber.  T his ori gi nal pr ot oc ol will be Versi o n 0. 
I nc yte C or p orati o n 
Pr ot oc ol I N C B 5 0 4 6 5- 2 0 4 A m 4
 
Versi o n 4
Pa ge 9 7 of 9 7 
2 3 D E C 2 0 1 9
C O N FI D E N TI A L