Clinical trial NCT03144674
Conditions: Lymphoma
Keywords: Marginal zone lymphoma phosphatidylinositol 3-kinase (PI3K)δ inhibitor indolent (slow-growing) non-Hodgkin lymphoma B-cell lymphoma
Sponsor: Incyte Corporation
Start date: 2017-12-18; Completion date: 2024-05-29
Enrollment: 110 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of two parsaclisib treatment regimens in participants diagnosed with relapsed or refractory marginal zone lymphoma (MZL) who are naive to or were previously treated with a Bruton's tyrosine kinase (BTK) inhibitor.

Detailed description:

Arms: arm 1: Participants who have received prior ibrutinib. arm 2: Participants who have not received a prior BTK inhibitor.
Interventions: intervention 1: Parsaclisib
Intervention descriptions: intervention 1: Parsaclisib at the protocol-defined dose.

Protocol documents:
Prot_000.pdf: 
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

SAP_001.pdf: 
Official Title: 
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) 
NCT Number: 
NCT03144674 
Document Date: 
Statistical Analysis Plan Version 2: 28 January 2021 


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STATISTICAL ANALYSIS PLAN 
 
INCB 50465-204 
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) 
 
 
 
IND Number: 
121,474 
EudraCT Number: 
2017-000970-12 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Protocol Version: 
Protocol Amendment 4 dated 23 DEC 2019 
CRF Approval Date: 
20 DEC 2018 
SAP Version: 
Amendment 2 
SAP Author:  
, PhD 
 
Date of Plan: 
28 JAN 2021 
 
 
This study is being conducted in compliance with good clinical practice, 
including the archiving of essential documents. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................7 
2.1. 
Protocol and Case Report Form Version ......................................................................7 
2.2. 
Study Objectives and Endpoints ...................................................................................7 
3. 
STUDY DESIGN .........................................................................................................9 
3.1. 
Randomization ............................................................................................................10 
3.2. 
Control of Type I Error ...............................................................................................10 
3.3. 
Sample Size Considerations .......................................................................................10 
3.4. 
Schedule of Assessments ............................................................................................11 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................11 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................11 
4.1.1. 
Day 1 ...........................................................................................................................11 
4.1.2. 
Study Day ...................................................................................................................11 
4.1.3. 
Baseline Value ............................................................................................................11 
4.1.4. 
Handling of Missing and Incomplete Data .................................................................11 
4.2. 
Variable Definitions ....................................................................................................12 
4.2.1. 
Body Mass Index ........................................................................................................12 
4.2.2. 
Prior and Concomitant Medication .............................................................................13 
5. 
STATISTICAL METHODOLOGY ...........................................................................13 
5.1. 
General Methodology .................................................................................................13 
5.2. 
Treatment Groups .......................................................................................................13 
5.3. 
Analysis Populations ..................................................................................................14 
5.3.1. 
All-Screened Population .............................................................................................14 
5.3.2. 
Full Analysis Set .........................................................................................................14 
5.3.3. 
Safety Population ........................................................................................................14 
 
14 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................15 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............15 
6.1.1. 
Demographics and Baseline Characteristics ...............................................................15 
6.1.2. 
Disease History ...........................................................................................................15 


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6.1.3. 
Prior Therapy ..............................................................................................................15 
6.1.4. 
Medical History ..........................................................................................................15 
6.2. 
Disposition of Participants ..........................................................................................16 
6.3. 
Protocol Deviations ....................................................................................................16 
6.4. 
Exposure .....................................................................................................................16 
6.5. 
Study Drug Compliance .............................................................................................16 
6.6. 
Prior and Concomitant Medication .............................................................................17 
7. 
EFFICACY .................................................................................................................17 
7.1. 
Efficacy Hypotheses ...................................................................................................17 
7.2. 
Response Assessment .................................................................................................17 
7.3. 
Analysis of the Primary Efficacy Parameter ..............................................................18 
7.3.1. 
Best Overall Response and Objective Response Rate ................................................18 
7.3.2. 
Subgroup Analyses for Objective Response Rate ......................................................18 
7.4. 
Analysis of the Secondary Efficacy Parameters .........................................................19 
7.4.1. 
Duration of Response .................................................................................................19 
7.4.2. 
Complete Response Rate ............................................................................................19 
7.4.3. 
Progression-Free Survival ..........................................................................................20 
7.4.4. 
Overall Survival ..........................................................................................................21 
7.4.5. 
Best Percentage Change in Disease Burden ...............................................................21 
 
22 
 
22 
 
23 
 
24 
 
24 
 
24 
 
 
.....................................24 
 
24 
 
25 
9. 
SAFETY AND TOLERABILITY ..............................................................................25 
9.1. 
General Considerations ...............................................................................................25 
9.2. 
Adverse Events ...........................................................................................................25 
9.2.1. 
Adverse Event Definitions ..........................................................................................25 


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9.2.2. 
Adverse Events of Special Interest .............................................................................26 
9.2.3. 
Adverse Event Summaries ..........................................................................................27 
9.3. 
Clinical Laboratory Tests ...........................................................................................29 
9.3.1. 
Laboratory Value Definitions .....................................................................................29 
9.3.2. 
Laboratory Value Summaries .....................................................................................29 
9.3.3. 
Potential Hy's Law Events ..........................................................................................30 
9.3.4. 
Worsening Laboratory Events of Special Interest ......................................................30 
9.4. 
Vital Signs ..................................................................................................................30 
9.5. 
Electrocardiograms .....................................................................................................31 
10. 
INTERIM ANALYSES ..............................................................................................32 
11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................33 
11.1. 
Changes to Protocol-Defined Analyses ......................................................................33 
11.2. 
Changes to the Statistical Analysis Plan .....................................................................33 
12. 
REFERENCES ...........................................................................................................36 
APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS ........................................37 
 
LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints ...................................................................................8 
Table 2: 
Evaluation and Censoring of Progression-Free Survival ............................................20 
 
22 
Table 4: 
Normal Ranges for Vital Sign Values ........................................................................31 
Table 5: 
Normal Ranges for Electrocardiogram Values ...........................................................31 
Table 6: 
Statistical Analysis Plan Versions ..............................................................................33 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................10 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase  
BMI 
body mass index 
bpm 
beats per minute 
BTK 
Bruton's tyrosine kinase  
CI 
confidence interval 
 
 
CMV 
cytomegalovirus 
CR 
complete response 
CRF 
case report form 
CRR 
complete response rate 
CT 
computed tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EWB 
emotional well-being 
 
 
 
 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FWB 
functional well-being 
 
 
IDMC 
Independent Data Monitoring Committee  
IRC 
Independent Review Committee 
LYMS 
lymphoma subscale 
MALT 
mucosa-associated lymphoid tissue 
MedDRA 
Medical Dictionary for Regulatory Activities  
 
 
MRI 
magnetic resonance imaging 
MZL 
marginal zone lymphoma 
NCI 
National Cancer Institute  


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Abbreviation 
Term 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PJP 
Pneumocystis jirovecii pneumonia 
 
 
PO 
orally 
PR 
partial response 
PT 
preferred term 
PWB 
physical well-being 
QD 
once daily 
QW 
once weekly 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
system organ class 
SWB 
social/family well-being 
TEAE 
treatment-emergent adverse event 
 
 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This is a Phase 2, open-label study designed to evaluate the safety and efficacy of 
2 INCB050465 treatment regimens in participants diagnosed with relapsed or refractory MZL.  
The study was originally planned to enroll 2 cohorts:  Cohort 1 for participants who have 
received prior ibrutinib (n = 60) and Cohort 2 for participants who are naive to a BTK inhibitor 
(n = 60).  Per Protocol Amendment Version 3, Cohort 1 was closed to further enrollment. 
Section 1 of the Protocol provides a detailed description of the investigational product, target 
patient population, rationale for doses to be examined, and potential risks and benefits of 
treatment with INCB050465. 
The purpose of this SAP is to provide details of the statistical analyses that have been outlined in 
the Study INCB 50465-204 Protocol.  The scope of this plan includes the interim and final 
analyses that are planned and will be executed by the Department of Biostatistics or designee, 
  
 
 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS 
2.1. 
Protocol and Case Report Form Version 
This SAP is based on INCB 50465-204 Protocol Amendment 4 dated 23 DEC 2019 and CRFs 
approved 20 DEC 2018.  Unless superseded by an amendment, this SAP will be effective for all 
subsequent Protocol amendments and CRF versions. 
2.2. 
Study Objectives and Endpoints 
The primary, secondary, 
 objectives and endpoints described herein are 
applicable for both cohorts (Table 1). 


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Table 1: 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To assess the efficacy of INCB050465 
in terms of ORR in participants with 
MZL that is relapsed or refractory after 
at least 1 systemic treatment regimen. 
ORR defined as the percentage of participants with a CR or PR as 
determined by IRC assessment of response according to CT-based 
response criteria for lymphomas (Cheson et al 2014). 
Secondary 
To assess DOR. 
DOR defined as the time from first documented evidence of CR or PR 
until disease progression or death from any cause among participants 
who achieve an objective response, as determined by radiographic 
disease assessment provided by an IRC. 
To assess CRR. 
CRR defined as the percentage of participants with a CR as defined 
by response criteria for lymphomas (Cheson et al 2014), as 
determined by an IRC. 
To assess PFS. 
PFS defined as the time from the date of the first dose of study 
treatment until the earliest date of disease progression, as determined 
by radiographic disease assessment provided by an IRC, or death 
from any cause. 
To assess OS. 
OS defined as the time from the date of the first dose of study 
treatment until death from any cause. 
To assess the best percentage change in 
target lesion size. 
Best percentage change in target lesion size from baseline, where 
target lesion size is measured by the sum of the product of diameters 
of all target lesion sizes. 
To characterize the safety and 
tolerability of INCB050465. 
Safety measured by AEs, 12-lead ECGs, chemistry and hematology 
laboratory values, vital signs, and physical examinations. 


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3. 
STUDY DESIGN 
This is a Phase 2, open-label study designed to evaluate the safety and efficacy of 
2 INCB050465 treatment regimens in participants diagnosed with relapsed or refractory MZL 
(see Figure 1).  The study was originally planned to enroll 2 Cohorts:  Cohort 1, comprising 
60 participants who had received prior ibrutinib, and Cohort 2, comprising 60 participants who 
had not received a prior BTK inhibitor.  However, Cohort 1 was closed to further enrollment for 
feasibility reasons per Protocol Amendment (Version) 3.  Participants enrolled in Cohort 1 and 
the first 60 participants in Cohort 2 will be further allocated to 1 of 2 study treatment regimens as 
follows: 
• Treatment A:  INCB050465 20 mg QD PO for 8 weeks followed by 20 mg QW PO.  
− Participants in Cohort 1 receiving Treatment A will be referred to as Cohort 1A.  
− Participants in Cohort 2 receiving Treatment A will be referred to as Cohort 2A.  
• Treatment B:  INCB050465 20 mg QD PO for 8 weeks followed by 2.5 mg QD PO.  
− Participants in Cohort 1 receiving Treatment B will be referred to as Cohort 1B.  
− Participants in Cohort 2 receiving Treatment B will be referred to as Cohort 2B.  
An interim futility analysis is planned for Cohort 2 when 30 participants have been treated and 
evaluated for response or have permanently discontinued study treatment because of disease 
progression, withdrawal of consent, or death.  Cohort 2 will be terminated for futility if ≤ 10 of 
the 30 participants responded (ie, CR or PR) based on assessments provided by an IRC; 
otherwise the study for Cohort 2 will continue.   
An additional 30 participants will be enrolled into one of the two treatment regimens (A or B) 
being evaluated in this study to better understand the safety and efficacy of INCB050465.  The 
treatment regimen will be selected after enrollment is completed for Cohort 2 (ie, 60 participants 
enrolled) and will be selected after evaluation of emerging safety and efficacy data from this and 
other monotherapy studies of INCB050465 in non-Hodgkin's lymphoma.  Once a treatment 
regimen is selected, the non-selected treatment regimen will be closed to further enrollment.  
Participants receiving the non-selected treatment regimen may switch to the selected treatment 
regimen or remain on their current treatment regimen, provided the participant has not met 
study-treatment withdrawal criteria and there are no safety concerns for their current treatment 
regimen.  There will be no re-baselining for participants who switch treatment regimens and all 
participants will continue to follow the same assessment schedule. 
Participants will receive treatment until disease progression, death, unacceptable toxicity, or 
consent withdrawal.  Participants will be evaluated for ORR by an IRC and followed for DOR, 
PFS, OS, and safety. 


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Figure 1: 
Study Design 
 
3.1. 
Randomization 
Not applicable.  
3.2. 
Control of Type I Error 
There will not be any statistical comparison between Cohort 1 and Cohort 2.  Within each of the 
2 cohorts, there will not be any statistical comparison between the 2 treatment regimens, and 
2-sided 95% CIs will be reported for all analyses when appropriate. 
Within each cohort, no adjustment for alpha-spending is considered, as there are no plans to stop 
the study early for overwhelming efficacy.  An IDMC will be assembled to monitor safety data 
and study conduct on a regular and ongoing basis during the study.  The IDMC will also be 
charged with evaluating interim futility results.  See Section 10 for details regarding interim 
analyses conducted in this study. 
3.3. 
Sample Size Considerations 
Cohort 1 was closed to further enrollment with Protocol Amendment (Version) 3. 
The study will enroll up to 90 participants into Cohort 2.  If the true ORR is 60%, then there is 
approximately 90% or 96% probability of observing the lower bound of the 95% CI of ORR 
≥ 40% with 60 or 90 participants, respectively. 


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3.4. 
Schedule of Assessments 
See Protocol Amendment 4 dated 23 DEC 2019 for a full description of all study procedures and 
assessment schedules for this study.   
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS 
4.1. 
Scheduled Study Evaluations and Study Periods 
4.1.1. 
Day 1 
Day 1 is the date that the first dose of study drug (INCB050465) is administered to the 
participants.  
4.1.2. 
Study Day 
If a visit/reporting date is on or after Day 1, then the study day at the visit/reporting date will be 
calculated as  
Day # = (Visit/Reporting Date – Day 1 date + 1). 
If the visit/reporting date is before Day 1, then the study day at the visit/reporting date will be 
calculated as  
Day # = (Visit/Reporting Date – Day 1 date). 
A study day of -1 indicates 1 day before Day 1. 
4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of 
INCB050465, unless otherwise defined.   
When scheduled assessments and unscheduled assessments occur on the same day and time of 
the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
• If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
• If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.1.4. 
Handling of Missing and Incomplete Data  
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections.  The original reported dates collected on the 
eCRF should be used in all relevant listings.  The following rules will be used for handling 
missing or partial dates for analyses requiring dates.  


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When calculating time since initial diagnosis of cancer, partial diagnosis date will be handled in 
the calculation as follows:  
• If only the day is missing, then the first day of the month will be used.  
• If both the month and day are missing, then 01 JAN will be used.  
• Otherwise, the time since diagnosis will not be calculated.  
When the date of the last dose is used in deriving variables such as duration of treatment or 
TEAE flag, missing or partial date of last dose will be handled in the calculation as follows:  
• If only the day is missing, then the earlier date of the last day of the month or the date 
that the participant discontinued treatment will be used.  
• If both the month and day are missing, then the earlier date of 31 DEC of the year or 
the date that the participant discontinued treatment will be used. 
• Otherwise, the date that the participant discontinued treatment will be used as the date 
of the last dose.  
When calculating DOR, PFS, and OS, a partial date of death will be handled in the calculation as 
follows:  
• If mmyyyy for the last known alive date = mmyyyy for the death date, then the day 
after the last known alive date will be used.  
• If mmyyyy for the last known alive date < mmyyyy for the death date, then the first 
day of the death month will be used.  
• Otherwise, the partial death date will not be handled.  
When calculating time to onset or duration of a TEAE, a partial or missing AE onset/end date 
will be handled in the calculation as follows:  
• If only the day is missing, then the first day of the month or Day 1, whichever is later, 
will be used as the onset date; the earlier date of the last day of the month or the date 
that the participant discontinued study or died will be used as the end date. 
• If both the month and day are missing, then 01 JAN or Day 1, whichever is later, will 
be used as the onset date; the earlier date of 31 DEC or the date that the participant 
discontinued study or died will be used as the end date.  
• Otherwise, Day 1 will be used as the onset date, and the missing end date will not be 
handled.  
4.2. 
Variable Definitions 
4.2.1. 
Body Mass Index 
BMI will be calculated as follows: 
BMI (kg/m2) = [weight (kg)] / [height (m)]2. 


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4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
INCB050465. 
Concomitant medication is defined as any nonstudy medication that is started accordingly:  
• Before the date of first administration of INCB050465 and is ongoing throughout the 
study or ends on/after the date of first study drug administration. 
• On/after the date of first administration of INCB050465 and is ongoing or ends 
during the course of study. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of INCB050465.  In the listing, it will be indicated whether a 
medication is prior-only, concomitant-only, or both prior and concomitant medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 
5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS software (SAS Institute Inc, Cary, NC; Version 9 or later) will be 
used for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries for 
continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of participants in each category. 
Interim analyses are planned for this study as defined in Section 10. 
5.2. 
Treatment Groups 
This is a Phase 2, open-label study.  All analyses will be conducted independently for Cohort 1 
and Cohort 2, and there will not be multiplicity adjustment between the cohorts.  Within each 
cohort, there will not be any statistical comparison between the treatment groups. 
For the purpose of analysis, the 20 mg QW dosing period in Treatment A and the 2.5 mg QD 
dosing period in Treatment B are considered maintenance dosing periods.  Within each cohort, 
data will be presented in summary tables by actual received treatment regimen and combined, 
with an exception for participants who cross over to the selected treatment regimen after the start 
of the maintenance dosing period.   
For participants who cross over from the initially assigned treatment regimen to the selected 
treatment regimen, if the crossover happens before/on the start of the maintenance dosing period, 
then the participant will be summarized, according to the actual received treatment, in the 
selected treatment regimen; otherwise, the participant will be summarized in: 
• A separate treatment regimen (ie, Crossover) for the safety summaries during the 
maintenance dosing period (eg. summaries of TEAEs and exposure). 
• The initially assigned treatment regimen for all other summaries. 


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Per Protocol Amendment (Version) 3, Cohort 1 was closed to further enrollment.  If the number 
of participants who have enrolled in Cohort 1 is relatively few, summary tables will be replaced 
with listings.   
5.3. 
Analysis Populations 
5.3.1. 
All-Screened Population 
The all-screened population includes all participants who signed the informed consent form. 
The all-screened population will be used for the summary of analysis populations. 
5.3.2. 
Full Analysis Set 
The FAS includes all participants enrolled in the study who received at least 1 dose of 
INCB050465.  
The FAS will be used for the summary of demographics, baseline characteristics, participant 
disposition, and all efficacy data. 
5.3.3. 
Safety Population 
The safety population includes all enrolled participants who received at least 1 dose of 
INCB050465.   
All safety analyses will be conducted using the safety population. 
 
 
 
 
 
 


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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Appendix A provides a list of planned tables, figures, and listings.  Sample data displays are 
included in a separate document. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographics and Baseline Characteristics 
The following demographics will be summarized and listed for the FAS:  age, sex, race, 
ethnicity, geographic region, weight, height, and BMI.  ECOG performance status at baseline 
will be summarized and listed for the FAS. 
6.1.2. 
Disease History 
Time since initial diagnosis, disease subtype, relationship of MZL to an infection, relationship of 
MZL to an H. pylori–induced infection, initial cytogenetics, current cytogenetics, initial Ann 
Arbor stage, current Ann Arbor stage, initial presence of B-symptoms, current presence of 
B-symptoms, bone marrow involvement (Yes vs No), and relapsed/refractory status to the most 
recent prior therapy will be summarized and listed for all participants in the FAS.  Date of tumor 
marker tests and test results will be listed. 
Time since diagnosis will be calculated as: 
Time since diagnosis (years) = (Day 1 date – date of diagnosis + 1) / 365.25. 
6.1.3. 
Prior Therapy 
Number of prior systemic cancer therapy regimens will be summarized for all participants in the 
FAS.  The component drugs of prior systemic therapy regimens will be coded using the WHO 
Drug Dictionary.  Number and percentage of participants with each drug will be summarized by 
WHO drug class and WHO drug PT.  Regimen name, component drugs, start and stop date, route 
of the medication, best response, reason for discontinuation, and date of relapse/progression will 
be listed. 
Number of participants who received prior radiation will be summarized for the FAS.  
Anatomical location of the administration, start and stop date, and total dose will be listed. 
Number of participants who had prior surgery or surgical procedure for the cancer treatment will 
be summarized for the FAS.  Date and description of the surgery/procedure will be listed. 
Number of participants who had hematopoietic stem cell transplant will be summarized for the 
FAS.  Date of transplant, type of transplant, source of cells, line of therapy, best response, date of 
relapse/progression, regimen name, and drug used with the transplant will be listed. 
6.1.4. 
Medical History 
Medical history will be coded to SOC and PT using MedDRA coding dictionary.  For 
participants in the FAS, medical history will be summarized by SOC and PT and listed.   


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6.2. 
Disposition of Participants 
The number and percentage of participants who were treated, who were ongoing with study 
treatment, who discontinued study treatment with a primary reason for discontinuation, who 
were still in the study, and who withdrew from the study with a primary reason for withdrawal 
will be summarized and listed for the FAS.  
The number of participants enrolled by country and site will also be provided for the FAS. 
6.3. 
Protocol Deviations  
Protocol deviations recorded on the eCRF will be summarized and listed for the FAS. 
6.4. 
Exposure 
For participants in the safety population, exposure to INCB050465 will be summarized 
descriptively as the following: 
• Duration of treatment (days):  Date of last dose – date of first dose + 1. 
• Duration of treatment during the initial QD dosing period (days):  Date of last 
dose during the initial QD dosing period – date of first dose + 1. 
• Duration of treatment during the maintenance dosing period (days):  Date of last 
dose – date of first dose during the maintenance dosing period + 1.  Crossover 
participants who switched to the selected treatment regimen after the start of the 
maintenance dosing period will be summarized in a separate group (ie, Crossover). 
• Average reported daily dose during the initial QD dosing period (mg/day):  total 
reported dose taken during the initial QD dosing period (mg) / duration of treatment 
during the initial QD dosing period (days).  
• Average reported daily dose during the maintenance dosing period (mg/day):  
total reported dose taken during the maintenance dosing period (mg) / duration of 
treatment during the maintenance dosing period (days).  Crossover participants who 
switched to the selected treatment regimen after the start of the maintenance dosing 
period will be summarized in a separate group (ie, Crossover). 
• Dose modifications:  Number of participants who had dose reduction and 
interruption will be summarized.  The number of dose reductions and the number of 
interruptions for each participant will be summarized. 
6.5. 
Study Drug Compliance 
For participants in the safety population, overall compliance (%) for INCB050465 will be 
calculated for all participants as 
compliance (%) = 100  [total dose actually taken] / [total prescribed dose]. 
The total prescribed dose is defined as the sum of the doses prescribed by the investigator 
accounting for dose modifications.   


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The total actual dose taken will be calculated based on information entered on the drug 
accountability CRF.  If there are dispensed drugs that have not been returned yet, the actual dose 
taken starting from the dispense date of the unreturned drugs will be imputed by the dose taken 
as reported on the dosing CRF.  
6.6. 
Prior and Concomitant Medication 
Prior medications and concomitant medications will be coded using the WHO Drug Dictionary.  
Number and percentage of participants in the FAS with each prior and concomitant medication 
will be summarized by WHO drug class and WHO drug PT. 
7. 
EFFICACY 
Appendix A provides a list of planned tables, figures, and listings.  Sample data displays are 
included in a separate document. 
7.1. 
Efficacy Hypotheses 
Not applicable. 
7.2. 
Response Assessment 
An objective assessment of disease status is required at baseline (screening) using the CT-based 
response criteria of the Lugano Classification (Cheson et al 2014).  Disease status will be 
subsequently assessed by CT/MRI every 8 weeks through Week 24, then every 12 weeks 
through Week 96, and then every 24 weeks thereafter until disease progression.  
Bone marrow examination is required at baseline assessment at screening except for reasons 
provided in Section 7.6.2 of the Protocol.  If disease is present in bone marrow at baseline, a 
bone marrow examination will be required to confirm CR or may be performed as clinically 
indicated.  If the bone marrow does not have lymphoma involvement at baseline, a repeat 
marrow examination is not required to confirm indication of CR on imaging.  For participants 
with splenic MZL without measurable disease (ie, only have histologically confirmed bone 
marrow infiltration), a bone marrow biopsy/examination must be performed when the number of 
lymphocytes in the blood normalize. 
Sites will use the CT-based response criteria of the Lugano Classification (Cheson et al 2014) to 
assess response to treatment locally.  At each postbaseline disease assessment, response will be 
collected in the eCRF as CR, PR, SD, PD, or NE.  
All imaging will be submitted to an IRC.  Imaging data and applicable clinical data will be 
reviewed and response assessed using the CT-based response criteria of the Lugano 
Classification (Cheson et al 2014) by independent reviewers as described in the Independent 
Review Charter.  An overall timepoint response at each postbaseline disease assessment, the best 
overall response, the date of initial response (if applicable), and the date of disease progression 
along with reason(s) of disease progression (if applicable) for each participant, considering 
radiographic data and clinical data, will be provided by the clinical reviewer.  Data as determined 
by the IRC will be used in the analyses of related efficacy endpoints for all participants and 
participants who have at least 2 prior therapies in the FAS.   


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7.3. 
Analysis of the Primary Efficacy Parameter 
The primary efficacy analyses will be conducted when all participants in the FAS who have 
achieved a response (ie, CR or PR) as determined by IRC have been followed approximately 
12 months from the onset of first response. 
7.3.1. 
Best Overall Response and Objective Response Rate 
For responses as determined by IRC, the best overall response for each participant will be 
provided by the clinical reviewer.  A participant is considered an objective responder if they have 
a best overall response of CR or PR. 
The ORR is the proportion of objective responders.  Participants who do not have sufficient 
baseline or on-study response assessment information to be adequately assessed for response 
status will be included in the denominators in the calculation of ORR. 
Best overall response as determined by IRC will be summarized descriptively.  The ORR as 
determined by IRC with 95% CIs will be calculated.  Confidence intervals will be calculated 
based on the exact method for binomial distributions.  
Because participants who switched to the selected treatment regimen after starting the 
maintenance dose received a mixture of the non-selected and selected maintenance regimens and 
could confound the efficacy evaluation of the non-selected treatment regimen, a sensitivity 
analysis of ORR as determined by IRC will be provided to summarize these crossover 
participants as a separate treatment regimen.  In addition, the number of participants who 
achieved best overall response as determined by IRC after the time of crossover along with the 
best overall response data will be presented under this separate treatment regimen.  The analyses 
described above will be summarized for all participants and participants who have at least 2 prior 
therapies in the FAS. 
When applicable, sensitivity analysis of ORR as determined by an IRC may be provided 
excluding participants that do not have evaluable radiological images at baseline per the IRC.   
7.3.2. 
Subgroup Analyses for Objective Response Rate 
Subgroups will be formed based on the following participant characteristics and baseline 
variables: 
• Age:  < 65 years, ≥ 65 years 
• Gender:  male, female 
• Race:  White, Others 
• Geographic region:  Europe, North America, Rest of World 
• Disease subtype:  nodal MZL, extranodal MZL - MALT, splenic MZL 
• Number of prior systemic therapy regimens:  < 3, ≥ 3 
• Bone marrow involvement at baseline:  yes, no, unknown 


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• ECOG performance status:  0, 1, 2 
• Relapsed/refractory status to the most recent prior therapy: relapsed, refractory, 
unknown 
Subgroups may be further divided or combined based on emerging data.  The ORR as 
determined by IRC and its 95% exact binomial CIs will be provided for participants for each 
subgroup.  A forest plot will be created to summarize the variability in ORRs as determined by 
IRC for participants across subgroups.  
7.4. 
Analysis of the Secondary Efficacy Parameters 
7.4.1. 
Duration of Response 
Duration of response is defined as the time from first documented evidence of CR or PR until 
disease progression or death due to any cause among participants who achieve an objective 
response (ie, CR or PR), as determined by revised response criteria for lymphomas (Cheson 
et al 2014).  For responses assessed by IRC, the date of initial response and date of disease 
progression will be provided by the clinical reviewer for participants who have achieved best 
response of CR or PR.  Censoring of DOR will follow the same algorithm as the censoring of 
PFS (Section 7.4.3). 
The total number of responders as determined by IRC, the number of participants whose disease 
progressed as determined by IRC or who died, and the number of participants censored will be 
summarized.  The Kaplan-Meier estimate of median DOR as determined by IRC and its 95% CIs 
will be provided, with the CIs calculated using the generalization of Brookmeyer and Crowley's 
method (1982) with log-log transformation (Klein and Moeschberger 1997).  
A sensitivity analysis of DOR will be performed where response assessments after the time of 
crossover will be excluded from the determination of DOR for participants who switched to the 
selected treatment regimen after starting the maintenance dose.  Crossover participants who have 
not progressed at the time of crossover will be censored at the last valid radiologic assessment 
on/before the time of crossover.  Participants who failed to achieve a response of CR or PR 
on/before the time of crossover will not be considered as responders for this analysis. 
The analyses described above will be summarized for all participants and participants who have 
at least 2 prior therapies in the FAS.  
7.4.2. 
Complete Response Rate 
Complete response rate is the percentage of participants with a best overall response of CR as 
defined by revised response criteria for lymphomas (Cheson et al 2014).  For responses as 
determined by IRC, the best overall response for each participant will be provided by the clinical 
reviewer.  Participants who do not have sufficient baseline or on-study response assessment 
information to be adequately assessed for response status will be included in the denominators in 
the calculation of CRR.  
The CRR as determined by IRC will be estimated with 95% CIs for all participants and 
participants who have at least 2 prior therapies in the FAS.  Confidence intervals will be 
calculated based on the exact method for binomial distributions. 


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A sensitivity analysis of CRR will be provided to summarize participants who switched to the 
selected treatment regimen after starting the maintenance dose as a separate treatment regimen. 
7.4.3. 
Progression-Free Survival 
Progression-free survival is defined as the time from the date of the first dose of the study drug to 
the first documented disease progression as determined by revised response criteria for 
lymphomas (Cheson et al 2014), or death due to any cause, whichever occurs first.  For response 
assessed by IRC, date of disease progression will be provided by the clinical reviewer.  
Censoring for PFS will follow the algorithm outlined in Table 2, which is based on FDA 
Guidance for Industry:  Clinical Trial Endpoints for the Approval of Non-Small Cell Lung 
Cancer Drugs and Biologics (2015) and Guidance for Industry:  Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (2018). 
Table 2: 
Evaluation and Censoring of Progression-Free Survival 
Situation 
Outcome 
Date of Progression or Censoring 
No baseline tumor assessments 
Censored 
Day 1 
No valid postbaseline response 
assessments 
Censored 
Day 1  
Progression documented between 
scheduled response assessments 
Progressed 
Date of first overall response of PD 
No progression 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) 
Study discontinuation for 
undocumented progression 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) 
Study discontinuation for toxicity 
or other reason 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) 
New anticancer treatment started 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) on/before starting a new 
anticancer treatment 
Death before first progressive 
response assessment 
Progressed 
Date of death 
Death between adequate response 
assessments 
Progressed 
Date of death 
Death or progression after 2 or 
more missed assessments 
Censored 
Date of last valid radiologic assessment (not 
NE and not missing) before the missed 
assessments 
NE = not evaluable. 


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The total number of participants whose disease progressed as determined by IRC or who died 
and the number of participants censored will be summarized.  The Kaplan-Meier estimate of 
median PFS as determined by IRC and its 95% CIs will be provided, with the CIs calculated 
using the generalization of Brookmeyer and Crowley's method (1982) with log-log 
transformation (Klein and Moeschberger 1997).  Progression-free survival rates at Month 6, 12, 
18, 24, and 36 will also be provided with 95% CIs calculated using Greenwood's formula to 
estimate the standard error.  
A sensitivity analysis of PFS will be performed where response assessments after the time of 
crossover will be excluded from the determination of PFS for participants who switched to the 
selected treatment regimen after starting the maintenance dose.  Crossover participants who have 
not progressed at the time of crossover will be censored at the last valid radiologic assessment 
on/before the time of crossover. 
The analyses described above will be summarized for all participants and participants who have 
at least 2 prior therapies in the FAS.  
7.4.4. 
Overall Survival 
Overall survival is defined as the time from the date of the first dose of study drug to death due 
to any cause.  For participants who are still alive at the time of the analysis, OS will be censored 
on the date the participant is last known to be alive.  
The number of participants who died and the number of participants censored will be 
summarized.  The Kaplan-Meier estimate of median OS and its 95% CIs will be presented, with 
the CIs calculated using the generalization of Brookmeyer and Crowley's method (1982) with 
log-log transformation (Klein and Moeschberger 1997).  Survival rates at Month 6, 12, 18, 24, 
and 36 will also be provided with 95% CIs calculated using Greenwood's formula to estimate the 
standard error.   
The analyses described above will be summarized for all participants and participants who have 
at least 2 prior therapies in the FAS.  
7.4.5. 
Best Percentage Change in Disease Burden 
For each participant with measurable lesions at baseline, target lesion size as measured by sum of 
product of diameters of all target lesions will be used as the measure for disease burden.  For all 
participants and participants who have at least 2 prior therapies in the FAS, the best percentage 
change from baseline, defined as the largest decrease in target lesion sizes during the study, will 
be summarized, and a waterfall plot of the best percentage change will be generated using data 
from IRC.  Note that for participants who only have increases in target lesion sizes from 
baseline, the smallest increase will be considered as the best change from baseline.  For IRC, 
there will be 2 radiologic reviewers for each participant.  An adjudication will be performed per 
the Independent Review Charter when Reviewers 1 and 2 disagree on the CT/MRI best overall 
response, or when best overall response is consistent and the date of initial response and/or the 
date of PD differ between Reviewers 1 and 2.  The adjudicator will choose the read that he or she 
believes most accurately represents the adjudication parameter(s) in question.  This is considered 
the "accepted read," and data from this reviewer will be used for the analysis.  When there was 
no adjudication needed, data from Reviewer 1 will be used for the analysis.  An indicator is 
provided to identify the read that is considered to be the accepted assessment in data from IRC. 


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For splenic MZL participants who have splenomegaly only at baseline, the spleen size as 
measured by the enlarged portion of the splenic length (ie, splenic length in excess of the 13 cm 
normal threshold) will be used as the measure for disease burden.  The best percentage change 
from baseline, defined as the largest decrease in spleen size during the study, will be 
summarized, and the best percentage change using data from IRC will be included in the 
waterfall plot as described above.  Note that for participants who only have increases in spleen 
size from baseline, the smallest increase will be considered as the best change from baseline. 
Best change in disease burden as reported by the investigator will also be summarized as 
described above for all participants in the FAS.  Target lesions considered "too small to measure" 
will be assigned a default value of 5 mm × 5 mm for purposes of this analysis.  Likewise, target 
lesions identified as "not present" at postbaseline assessments will be assigned 0 mm × 0 mm for 
this analysis.  In the event a target lesion is unaccounted for in a particular postbaseline timepoint 
(ie, assessment missing or NE), then the overall sum of product of diameters for target lesions 
will not be evaluable for that postbaseline timepoint. 


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9. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of planned tables, figures, and listings.  Sample data displays are 
included in a separate document. 
9.1. 
General Considerations 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique PTs reported on relatively 
few participants. 
9.2. 
Adverse Events 
9.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug and within 30 days of the last administration of study drug regardless of 
starting new anti-lymphoma therapy.  Analysis of AEs (as discussed below) will be limited to 
TEAEs, but data listings will include all AEs regardless of their timing in relation to study drug 
administration.  For purposes of analysis, all AEs will be considered TEAEs unless the AE can 
unequivocally be defined as not treatment-emergent. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE version 4.03.  The CTCAE reporting guidelines and grading details are 
available on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to study drug will be considered to 
be treatment-related AEs.  If the investigator does not specify the relationship of the AE to study 
drug, the AE will be considered to be treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated.  In addition, serious TEAEs will also be tabulated. 


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9.2.2. 
Adverse Events of Special Interest  
The number of participants who experienced any TEAEs of special interest listed below will be 
tabulated by maximum severity.   
• Colitis 
• Diarrhea  
• Exfoliative dermatitis 
• Febrile neutropenia 
• Intestinal perforation 
• Rash  
• Pneumonitis 
• Pneumonia 
• PJP infection 
• CMV infection 
• Herpes simplex  
• Varicella zoster virus infection 
The time to onset of a TEAE is defined as the interval between the date of first dose of study 
drug and the date of the first occurrence of a TEAE.  Participants who have not experienced a 
TEAE at the time of analysis will be right-censored at the earlier of 30 days after the last dose 
date and date of last study visit through the end of safety follow-up.  If participants have missing 
or partial last dose dates of study drug or onset date of a TEAE, the partial or missing dates will 
be handled using the rules explained in Section 4.1.4.   
Summaries of time to onset of new or worsening Grade 3 or higher AEs will be provided using 
descriptive statistics and the life-table method for rash, colitis, diarrhea, febrile neutropenia, 
pneumonia, herpes simplex, and varicella zoster virus infection.  In addition, summaries of time 
to onset of new or worsening AEs of any grade will be provided using descriptive statistics and 
the life-table method for colitis, diarrhea, exfoliative dermatitis, intestinal perforation, 
pneumonia, pneumonitis, PJP infection, CMV infection, herpes simplex, and varicella zoster 
virus infection.  Kaplan-Meier plots of time to onset of new or worsening Grade 3 or higher AEs 
will be provided for rash, colitis, and diarrhea.  In addition, Kaplan-Meier plots of time to onset 
of new or worsening AEs of any grade will be provided for colitis and diarrhea. 
Descriptive statistics of time to onset of these TEAEs of special interest are based on all 
participants who have experienced a TEAE at the time of analysis.  To summarize these TEAEs 
of special interest using the life-table method, the effective sample size is defined as the number 
of participants at the beginning of interval minus half the participants censored in the interval.  
The conditional proportion is calculated as the number of first events divided by the effective 
sample size in the interval.   


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The longest duration of a TEAE of any grade is defined as the longest interval between the date 
of occurrence of a TEAE and the date of resolution.  The longest duration of a Grade 3 or higher 
TEAE is defined as the longest interval between the date of occurrence of a Grade 3 or higher 
TEAE and the date of improvement to Grade 2 or lower.  If participants have missing or partial 
onset/end date of a TEAE, the partial or missing dates will be handled using the rules explained 
in Section 4.1.4.  Participants who have missing end date of a TEAE at the time of analysis will 
be right-censored using the following algorithm: 
• If the TEAE is serious, then the participant will be censored at the earlier date of data 
cutoff, study discontinuation, and death.  
• If the TEAE is not serious,  
− 
If the participant is ongoing with study treatment, then the participant will be 
censored at the data cutoff date, OR  
− If the participant discontinued treatment, then the participant will be censored at 
date of safety follow-up visit, or 35 days after the end of treatment visit (or after 
the last dose if the end of treatment visit was not performed), whichever is later; 
the censored date will be truncated by the earlier date of data cutoff, study 
discontinuation, and death if beyond. 
Longest duration of new or worsening Grade 3 or higher colitis, diarrhea, rash, and febrile 
neutropenia will be summarized.  In addition, longest duration of new or worsening AEs of any 
grade will be summarized for colitis, diarrhea, and rash.  
The total number of participants whose TEAE of any grade resolved or whose Grade 3 or higher 
TEAE improved to Grade 2 or lower and the number of participants censored will be 
summarized.  The Kaplan-Meier estimate of median time to resolution/improvement and its 
95% CIs will be provided, with the CIs calculated using the generalization of Brookmeyer and 
Crowley's method (1982) with log-log transformation (Klein and Moeschberger 1997).  
Resolution/improvement rates at selected timepoints will also be provided with 95% CIs 
calculated using Greenwood's formula to estimate the standard error. 
TEAEs of special interest to be summarized may be adjusted based on emerging data. 
9.2.3. 
Adverse Event Summaries 
Overall summaries of TEAEs by treatment regimen will be provided during the INCB050465 
initial QD dosing period, maintenance dosing period, and overall period (ie. all TEAEs 
regardless of the timing of occurrence).  These summaries will include the following: 
• Number (%) of participants reporting any TEAEs 
• Number (%) of participants reporting any Grade 3 or higher TEAEs 
• Number (%) of participants reporting any serious TEAEs 
• Number (%) of participants reporting any TEAEs related to INCB050465 
• Number (%) of participants reporting any Grade 3 or higher TEAEs related to 
INCB050465 
• Number (%) of participants reporting any serious TEAEs related to INCB050465 


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• Number (%) of participants who had TEAE with fatal outcome 
• Number (%) of participants with INCB050465 dose reductions because of TEAEs  
• Number (%) of participants who temporarily interrupted INCB050465 because of 
TEAEs 
• Number (%) of participants who permanently discontinued INCB050465 because of 
TEAEs 
The following summaries will be produced for TEAEs during the overall period by MedDRA 
term (if 10 or fewer participants appear in a table, a listing may be appropriate): 
• Summary of TEAEs by SOC and PT 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of TEAEs by SOC, PT, and maximum severity 
• Summary of TEAEs by PT and maximum severity in decreasing order of frequency 
• Summary of Grade 3 or higher TEAEs by SOC and PT 
• Summary of Grade 3 or higher TEAEs by PT in decreasing order of frequency 
• Summary of serious TEAEs by SOC and PT 
• Summary of serious TEAEs by PT in descending order of frequency 
• Summary of INCB050465 treatment-related TEAEs by SOC and PT 
• Summary of INCB050465 treatment-related TEAEs by PT in decreasing order of 
frequency 
• Summary of INCB050465 treatment-related TEAEs by SOC, PT, and maximum 
severity 
• Summary of Grade 3 or higher INCB050465 treatment-related TEAEs by SOC and 
PT 
• Summary of INCB050465 treatment-related serious TEAEs by SOC and PT 
• Summary of TEAEs with a fatal outcome by SOC and PT 
• Summary of TEAEs leading to INCB050465 dose reduction by SOC and PT 
• Summary of TEAEs leading to INCB050465 dose interruption by SOC and PT 
• Summary of TEAEs leading to discontinuation of INCB050465 by SOC and PT 
• Summary of selected TEAEs of special interest by maximum severity 


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• Summary of time to onset of selected TEAEs of special interest 
• Summary of time to onset of selected TEAEs of special interest: life-table method 
• Summary of longest duration of selected TEAEs of special interest 
The following supporting summaries will be produced for TEAEs during the INCB050465 initial 
QD dosing period and the maintenance dosing period by MedDRA term.  For the supporting 
summaries during the maintenance dosing period, participants who cross over to the selected 
treatment regimen after the start of the maintenance dosing period will be summarized in a 
separate group (ie, Crossover). 
• Summary of TEAEs by PT in decreasing order of frequency 
• Summary of TEAEs by PT and maximum severity in decreasing order of frequency 
• Summary of Grade 3 or higher TEAEs by PT in decreasing order of frequency  
• Summary of serious TEAEs by PT in descending order of frequency 
• Summary of TEAEs with a fatal outcome by SOC and PT  
• Summary of TEAEs leading to discontinuation of INCB050465 by SOC and PT 
9.3. 
Clinical Laboratory Tests 
9.3.1. 
Laboratory Value Definitions 
Laboratory values and change from baseline values will be summarized descriptively by visit.  
Baseline will be determined according to Section 4.1.3.  If there are multiple values that meet the 
criteria for baseline, the value from the central laboratory has priority over the value from the 
local laboratory.  Thereafter, additional rules may be provided after consultation with the 
medical monitor to delineate which value will be defined as baseline. 
Laboratory test values will be assessed for severity (grade) based on the numerical component of 
CTCAE v4.03. 
9.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from central laboratories will be reported in SI 
units.  Any laboratory test results and associated normal ranges from local laboratories will be 
converted to SI units.   
When there are multiple laboratory nonmissing values for a participant's particular test at a 
scheduled visit, central laboratory values have higher priority over local laboratory values.  If a 
tie still exists, the laboratory value with the smallest laboratory sequence number will be used in 
by-visit summaries. 
Numeric laboratory values will be summarized descriptively in SI units, and non-numeric test 
values will be tabulated when necessary.  In addition, line graphs will be provided for ALT, 
AST, hemoglobin, platelet counts, leukocytes, neutrophils, and lymphocytes. 
Shift tables will be presented showing change in CTCAE grade from baseline to worst grade 
postbaseline.  Separate summaries for abnormally high and abnormally low laboratory values 


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will be provided when the laboratory parameter has both high and low grading criteria.  The 
denominator for the percentage calculation will be the number of participants in the baseline 
category.  The number of participants who experienced worsening of laboratory abnormalities 
will be summarized by maximum postbaseline severity. 
9.3.3. 
Potential Hy's Law Events 
Participants with elevated ALT or AST > 3 × ULN range and alkaline phosphatase < 2 × ULN 
range accompanied by total bilirubin > 2 × ULN range at the same visit will be listed by 
treatment group. 
9.3.4. 
Worsening Laboratory Events of Special Interest 
Laboratory events of special interest are listed below.  
• ALT increased 
• AST increased 
• Absolute neutrophil count decreased 
The time to onset of a worsening laboratory event is defined as the interval between the date of 
first dose of study drug and the date of the first occurrence of CTC grade worse than baseline for 
the laboratory event.  Participants who have not experienced a worsening laboratory event at the 
time of analysis will be right-censored at the last postbaseline study visit with nonmissing CTC 
grade of the laboratory event. 
Time to onset of worsening Grade 3 or 4 laboratory events of special interest will be summarized 
using descriptive statistics and the life-table method as described in Section 9.2.2, and the 
Kaplan-Meier plot of time to onset of worsening Grade 3 or 4 absolute neutrophil count 
decreased will be provided.  Laboratory events of special interest to be summarized may be 
adjusted based on emerging data. 
9.4. 
Vital Signs 
Values at each scheduled visit, change, and percent change from baseline for vital signs, 
including systolic blood pressure, diastolic blood pressure, pulse, body temperature, respiratory 
rate, and weight will be summarized descriptively.   
Normal ranges for vital sign values are defined in Table 4.  The abnormal values for participants 
exhibiting vital sign abnormalities will be listed along with their assigned treatment regimen.  
Alert vital signs are defined as an absolute value outside the defined range and percentage 
change greater than 25%.  Note that the definition of alert vital signs does not apply for body 
temperature and weight.  The abnormal values for participants exhibiting alert vital sign 
abnormalities will be listed. 


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Table 4: 
Normal Ranges for Vital Sign Values 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
≤ 155 mmHg 
≥ 85 mmHg 
Diastolic blood pressure 
≤ 100 mmHg 
≥ 40 mmHg 
Pulse 
≤ 100 bpm 
≥ 45 bpm 
Temperature 
≤ 38ºC 
≥ 35ºC 
Respiratory rate 
≤ 24 breaths/min 
≥ 12 breaths/min 
9.5. 
Electrocardiograms 
Twelve-lead ECGs including PR, QRS, QT, QTcB, QTcF, and RR intervals will be obtained for 
each participant during the study.  Values at each scheduled visit, change, and percent change 
from baseline will be summarized for each ECG parameter.  Baseline will be determined as the 
average of all nonmissing values before the first administration of INCB050465. 
Normal ranges for ECG values are defined in Table 5.  Electrocardiogram values will also be 
considered abnormal if the absolute percentage change from baseline is more than 25% (30% for 
QRS interval).  Participants exhibiting ECG abnormalities will be listed with study visit and 
assigned treatment regimen.  Abnormal values for participants with alert ECG values, defined as 
both the absolute value and the percentage change from baseline being outside normal ranges, 
will be identified and listed.  Outliers of QT, QTcB, and QTcF values, defined as absolute values 
> 450 milliseconds or change from baseline > 30 milliseconds, will be summarized. 
Table 5: 
Normal Ranges for Electrocardiogram Values 
Parameter  
High Threshold  
Low Threshold  
PR  
≤ 220 msec 
≥ 75 msec 
QRS  
≤ 120 msec 
≥ 50 msec 
QT  
≤ 500 msec 
≥ 300 msec 
QTcF, QTcB  
≤ 450 msec 
≥ 295 msec 
RR  
≤ 1330 msec 
≥ 600 msec 
QTcF = Fridericia's correction; QTcB = Bazett's correction. 


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10. 
INTERIM ANALYSES 
An interim futility analysis is planned for Cohort 2 when 30 participants have been treated and 
evaluated for response or have permanently discontinued study treatment because of disease 
progression, withdrawal of consent, or death.   
Cohort 2 will be terminated for futility if ≤ 10 of the 30 participants responded (ie, CR or PR) 
based on assessments provided by IRC; otherwise, the study for Cohort 2 will continue.  The 
probability of stopping at interim for futility is 0.29 when the true response rate is 40%, 0.05 
when the true response rate is 50%, or 0.003 when the true response rate is 60%. 
An IDMC will be charged with evaluating interim futility results.  The IDMC will consist of 
clinicians and an independent statistician.  The IDMC will make recommendations to the sponsor 
at the planned interim futility analysis for Cohort 2.  The process by which the IDMC will make 
recommendations and decisions will be documented in the IDMC Charter.  Additional 
operational details of the interim analyses, including tables, figures, and listings provided to the 
IDMC, will be provided in the IDMC Charter.   


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11. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN 
All versions of the SAP are listed in Table 6. 
Table 6: 
Statistical Analysis Plan Versions 
SAP Version 
Date 
Original 
21 FEB 2019 
Amendment 1 
27 AUG 2020 
Amendment 2 
28 JAN 2021 
11.1. 
Changes to Protocol-Defined Analyses 
Not applicable. 
11.2. 
Changes to the Statistical Analysis Plan 
Amendment 2 (28 JAN 2021) 
Overall Rationale for the Amendment:  The primary purpose of this amendment is to comply 
with responses to comments provided by FDA regarding the Statistical Analysis Plan 
Amendment 1.  
• Section 6.4 was updated to include the summary for the number of dose reductions and 
the number of dose interruptions of each participant. 
• Section 7.3 was updated to include the timing of primary efficacy analysis. 
• Section 7.3.1 was updated to include a sensitivity analysis of ORR that summarizes 
participants who switched to the selected dose after starting the maintenance dose in a 
separate treatment regimen and to include an additional analysis on the number of 
participants who achieved best overall response after the time of crossover along with the 
best overall response data for this separate treatment regimen. 
• Section 7.4.1 and Section 7.4.3 were updated to included sensitivity analyses where 
response assessments after the time of crossover will be excluded from the determination 
of DOR and PFS for participants who switched to the selected treatment regimen after 
starting the maintenance dose. 
• Section 7.4.2 was updated to include a sensitivity analysis of CRR by summarizing 
participants who switched to the selected dose after starting the maintenance dose in a 
separate treatment regimen. 
• Section 9.2.1 was modified to clarify how AEs that occur after new anti-lymphoma 
therapy will be assessed. 
• Incorporation of minor changes.  Other minor changes have been incorporated 
throughout the SAP and are noted in the redline version of the amendment. 


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Amendment 1 (27 AUG 2020) 
• Section 4.1.4 was updated to include details of rules for handling partial/missing onset or 
end date of TEAEs in the calculation of time to onset or duration of a TEAE.  Rules for 
partial/missing date of last dose were updated to include details of handling situations 
where both month and day are missing. 
• Section 5.2 was modified to provide details regarding how crossover participants will be 
summarized.  
• Section 5.3 was updated to remove the efficacy evaluable analysis set and use the FAS 
for all analyses on efficacy data.  This change is to comply with comments from FDA 
that any participants who received at least 1 dose should be included in the efficacy 
analyses for a single-arm trial.  The all-screened population was added for the summary 
of analysis populations. 
• Section 6.1.2 was modified to remove summaries of tumor markers but only keep 
listings.  Relapsed/refractory status to the most recent prior therapy was added to the 
summary table of disease history because the response to last regimen before entering the 
study may be a prognostic factor for clinical outcomes.   
• Section 6.2 was modified to add summaries of participants who are ongoing with 
treatment or still in the study. 
• Section 6.4 was modified to change the calculations of duration of treatment and average 
dose during the maintenance dosing period because Group B with 2.5 mg QD was 
selected as the maintenance dose. 
• Section 7.3 and Section 7.4 were modified to add efficacy analyses for participants in the 
FAS who have at least 2 prior therapies to support an indolent NHL indication in the 
same line of therapy as with follicular lymphoma in Study INCB 50465-203. 
• Section 7.3.1 was modified to replace the efficacy evaluable analysis set with the FAS.  
This change is to align with Protocol Amendment 4 dated 23 DEC 2019 and include all 
treated participants in the efficacy analyses to comply with comments from FDA.  
• Section 7.3.2 was modified to add "unknown" as a category for bone marrow 
involvement at baseline.  Relapsed/refractory status to the most recent prior therapy was 
added to the subgroup analysis because the response to last regimen before entering the 
study may be a prognostic factor for clinical outcomes.   
• Section 7.4.3 was modified to update references of censoring for PFS. 
• Section 9.2.2 was updated to include details of analyses on time to onset of selected 
TEAEs of special interest.  Summaries of longest duration of selected TEAEs of special 
interest were added to have a better understanding of the safety profile in terms of 
duration of class-effect AEs as well as AEs influenced by treatment regimens.  "Grade 2 
or higher" was changed to "Grade 3 or higher" for time to onset summary of rash.  This 
change was made to be consistent with other PI3K inhibitors, which highlighted more 
severe cutaneous reactions graded as Grade 3 or higher in the labeling.  "Herpes simplex 
virus infection" was changed to "herpes simplex" based on MedDRA coding dictionary 


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as a broader term.  Exfoliative dermatitis was added to the list of TEAEs of special 
interest. 
• Section 9.2.3 was updated to include summary of TEAEs by PT and maximum severity 
in decreasing order of frequency, summary of longest duration of selected TEAEs of 
special interest, and additional supporting summaries during the INCB050465 initial QD 
dosing period and the maintenance dosing period, which will provide supportive data of 
the safety profile of the maintenance dose.  Summary of nonserious of TEAEs by SOC 
and PT was removed because it will not be used for the clinical study report but will be 
provided for result disclosure.  
• Section 9.3.2 was modified to include ALT and AST in the line graphs as additional 
supportive analyses for laboratory events of special interest. 
• Section 9.3.3 was added to identify potential Hy's law events to better monitor liver 
toxicity. 
• Section 9.3.4 was updated to align with the analysis plan for adverse events of special 
interest.  Summary of worsening of laboratory events of special interest was removed 
because this is covered by the summary of worsening of laboratory abnormalities. 
• Section 9.5 was updated to change the high threshold of QTcF and QTcB interval from 
460 to 450 milliseconds for purpose of analysis.  This change is to comply with the 
categories outlined in FDA Guidance for Industry (E14 Clinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs) used 
to characterize outliers in QTc values. 


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12. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 
1982;38:29-41. 
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin 
Oncol 2014;32:3059-3068. 
Klein JP, Moeschberger ML. Survival Analysis: Techniques for Censored and Truncated Data. 
2nd ed. New York: Springer-Verlag; 1997. 


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APPENDIX A. PLANNED TABLES, FIGURES, AND LISTINGS 
This appendix provides a list of the planned tables, figures, and listings for the Clinical Study 
Report for Cohort 1 and Cohort 2.  Outputs from Cohort 1 will have ".1" at the end of the 
numbering.  Outputs from Cohort 2 will have ".2" at the end of the numbering.  Shells are 
provided in a separate document for tables that are not in the Standard Safety Tables version 1.9. 
The lists of tables, figures, and listings and the shells are to be used as guidelines.  Modifications 
of the list that do not otherwise affect the nature of the analysis will not warrant an amendment to 
the SAP. 
Tables 
Table No. 
Title 
Population 
Standard 
Baseline and Demographic Characteristics 
1.1.1 
Analysis Populations 
All-Screened 
X 
1.1.2 
Summary of Participant Disposition 
FAS 
X 
1.1.3 
Summary of Number of Participants Enrolled by Country and Site 
FAS 
X 
1.1.4 
Summary of Protocol Deviations 
FAS 
X 
1.2.1 
Summary of Demographics and Baseline Characteristics 
FAS 
X 
1.3.1 
Summary of Baseline Disease Characteristics 
FAS 
X 
1.3.2 
Summary of Prior Cancer Therapy 
FAS 
 
1.3.3 
Summary of Prior Systematic Cancer Therapy by WHO Drug Class 
and Preferred Term 
FAS 
 
1.4.1 
Summary of Prior Medications 
FAS 
X 
1.4.2 
Summary of Concomitant Medications 
FAS 
X 
1.5.1 
Summary of General Medical History 
FAS 
X 
Efficacy 
2.1.1 
Summary of Best Overall Response and Objective/Complete Response 
Rate as Determined by Independent Review Committee 
FAS 
 
2.1.2 
Summary of Best Overall Response and Objective/Complete Response 
Rate as Reported by Investigator 
FAS 
 
2.1.3 
Summary of Best Overall Response and Objective Response Rate as 
Determined by Independent Review Committee by Subgroup 
FAS 
 
2.2.1 
Summary of Duration of Response as Determined by Independent 
Review Committee 
FAS 
 
2.2.2 
Summary of Duration of Response as Reported by Investigator 
FAS 
 
2.2.3 
Summary of Progression-Free Survival as Determined by Independent 
Review Committee 
FAS 
 
2.2.4 
Summary of Progression-Free Survival as Reported by Investigator 
FAS 
 
2.2.5 
Summary of Overall Survival  
FAS 
 
2.2.6 
Summary of Best Change in Target Lesion Size as Determined by 
Independent Review Committee 
FAS 
 
2.2.7 
Summary of Best Change in Target Lesion Size as Reported by 
Investigator 
FAS 
 
2.2.8 
Summary of Best Change in Spleen Size as Determined by 
Independent Review Committee 
FAS 
 
2.2.9 
Summary of Best Change in Spleen Size as Reported by Investigator 
FAS 
 


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Table No. 
Title 
Population 
Standard 
2.4.1 
Summary of Best Overall Response and Objective/Complete Response 
Rate as Determined by Independent Review Committee – Crossover as 
a Separate Treatment Group 
FAS 
 
2.4.2 
Summary of Best Overall Response and Objective/Complete Response 
Rate as Reported by Investigator – Crossover as a Separate Treatment 
Group 
FAS 
 
2.4.3 
Summary of Best Overall Response as Determined by Independent 
Review Committee for Crossover Participants 
FAS 
 
2.4.4 
Summary of Best Overall Response as Reported by Investigator for 
Crossover Participants 
FAS 
 
2.4.5 
Summary of Duration of Response as Determined by Independent 
Review Committee – Censoring Crossover Participants 
FAS 
 
2.4.6 
Summary of Duration of Response as Reported by Investigator – 
Censoring Crossover Participants 
FAS 
 
2.4.7 
Summary of Progression-Free Survival as Determined by Independent 
Review Committee – Censoring Crossover Participants 
FAS 
 
2.4.8 
Summary of Progression-Free Survival as Reported by Investigator – 
Censoring Crossover Participants 
FAS 
 
Safety 
3.1.1 
Summary of Exposure and Compliance 
Safety 
 
3.1.2 
Summary of Exposure and Average Daily Dose During Initial QD 
Dosing Period 
Safety 
 
3.1.3 
Summary of Exposure and Average Daily Dose During Maintenance 
Dosing Period 
Safety 
 
3.2.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety 
X 
3.2.2 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Safety 
X 
3.2.3 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.4 
Summary of Treatment-Emergent Adverse Events by MedDRA 
System Organ Class, Preferred Term, and Maximum Severity 
Safety 
X 
3.2.6 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.7 
Summary of Grade 3 or Higher Treatment-Emergent Adverse Events 
by Preferred Term in Decreasing Order of Frequency 
Safety 
X 
3.2.8 
Summary of Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.9 
Summary of Treatment-Emergent Serious Adverse Events by Preferred 
Term in Decreasing Order of Frequency 
Safety 
X 
3.2.10 
Summary of INCB050465 Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.11 
Summary of INCB050465 Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA Preferred Term in Decreasing Order of 
Frequency 
Safety 
X 
3.2.12 
Summary of INCB050465 Treatment-Related Treatment-Emergent 
Adverse Events by MedDRA System Organ Class, Preferred Term, 
and Maximum Severity 
Safety 
X 


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Table No. 
Title 
Population 
Standard 
3.2.14 
Summary of Grade 3 or Higher INCB050465 Treatment-Related 
Treatment-Emergent Adverse Events by MedDRA System Organ 
Class and Preferred Term 
Safety 
X 
3.2.15 
Summary of INCB050465 Treatment-Related Serious Treatment-
Emergent Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.16 
Summary of Treatment-Emergent Adverse Events With a Fatal 
Outcome by MedDRA System Organ Class and Preferred Term 
Safety 
X 
3.2.18 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB050465 Dose Reduction by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.19 
Summary of Treatment-Emergent Adverse Events Leading to 
INCB050465 Dose Interruption by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.20 
Summary of Treatment-Emergent Adverse Events Leading to 
Discontinuation of INCB050465 by MedDRA System Organ Class and 
Preferred Term 
Safety 
X 
3.2.25 
Summary of Treatment-Emergent Adverse Events by MedDRA 
Preferred Term and Maximum Severity in Decreasing Order of 
Frequency 
Safety 
 
3.2.26 
Summary of Selected Treatment-Emergent Adverse Events of Special 
Interest by Maximum Severity 
Safety 
 
3.2.27 
Summary of Time to Onset of Selected Treatment-Emergent Adverse 
Events of Special Interest 
Safety 
 
3.2.28 
Summary of Time to Onset of Selected Treatment-Emergent Adverse 
Events of Special Interest : Life-Table Method 
Safety 
 
3.2.29 
Summary of Longest Duration of Selected Treatment-Emergent 
Adverse Events of Special Interest 
Safety 
 
3.3.1.1 
Summary of Laboratory Values - Hematology 
Safety 
X 
3.3.1.2 
Summary of Laboratory Values - Chemistry 
Safety 
X 
3.3.3.1  
Shift Summary of Hematology Laboratory Values in CTC Grade - To 
the Worst Abnormal Value  
Safety 
X 
3.3.3.2 
Shift Summary of Chemistry Laboratory Values in CTC Grade - To 
the Worst Abnormal Value 
Safety 
X 
3.3.3.4 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Hematology 
Safety 
X 
3.3.3.5 
Treatment-Emergent Worsening of Laboratory Abnormalities - 
Chemistry 
Safety 
X 
3.3.6 
Time to Onset of Treatment-Emergent Worsening of Laboratory 
Events of Special Interest 
Safety 
 
3.3.7 
Time to Onset of Treatment-Emergent Worsening of Laboratory 
Events of Special Interest: Life-Table Method 
Safety 
 
3.4.1 
Summary of Systolic Blood Pressure 
Safety 
X 
3.4.2 
Summary of Diastolic Blood Pressure  
Safety 
X 
3.4.3 
Summary of Pulse  
Safety 
X 
3.4.4 
Summary of Respiratory Rate 
Safety 
X 
3.4.5 
Summary of Body Temperature 
Safety 
X 
3.4.6 
Summary of Weight 
Safety 
X 
3.5.1 
Summary of PR Interval (msec) From 12-Lead ECG 
Safety 
X 
3.5.2 
Summary of QRS Interval (msec) From 12-Lead ECG 
Safety 
X 
3.5.3 
Summary of QT Interval (msec) From 12-Lead ECG 
Safety 
X 
3.5.4 
Summary of QTcB Interval (msec) From 12-Lead ECG 
Safety 
X 


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Table No. 
Title 
Population 
Standard 
3.5.5 
Summary of QTcF Interval (msec) From 12-Lead ECG 
Safety 
X 
3.5.6 
Summary of RR Interval (msec) From 12-Lead ECG 
Safety 
X 
3.5.8 
Summary of Outliers of QT, QTcB, and QTcF Interval Values From 
12-Lead ECG 
Safety 
X 
3.5.9 
Summary of Clinically Significant ECG Abnormality 
Safety 
X 
Figures 
Figure No. 
Title 
4.1.1 
Forest Plot of Objective Response Rate as Determined by Independent Review Committee 
4.2.1 
Kaplan-Meier Estimates of Duration of Response as Determined by Independent Review 
Committee 
4.2.2 
Kaplan-Meier Estimates of Duration of Response as Reported by Investigator 
4.2.3 
Kaplan-Meier Estimates of Progression-Free Survival as Determined by Independent Review 
Committee 
4.2.4 
Kaplan-Meier Estimates of Progression-Free Survival as Reported by Investigator 
4.2.5 
Kaplan-Meier Estimates of Overall Survival  
4.2.6 
Waterfall Plot of Best Percentage Change in Disease Burden as Determined by Independent 
Review Committee 
4.2.7 
Waterfall Plot of Best Percentage Change in Disease Burden as Reported by Investigator 
4.3.1 
Kaplan-Meier Estimates of Duration of Response as Determined by Independent Review 
Committee – Censoring Crossover Participants 
4.3.2 
Kaplan-Meier Estimates of Duration of Response as Reported by Investigator  – Censoring 
Crossover Participants 
4.3.3 
Kaplan-Meier Estimates of Progression-Free Survival as Determined by Independent Review 
Committee – Censoring Crossover Participants 
4.3.4 
Kaplan-Meier Estimates of Progression-Free Survival as Reported by Investigator – Censoring 
Crossover Participants 
4.5.1 
Kaplan-Meier Estimates of Time to Onset of Selected TEAEs of Special Interest 
4.5.2 
Kaplan-Meier Estimates of Longest Duration of Selected TEAEs of Special Interest  
4.6.1 
Line Graph of Mean Values Over Time for Selected Laboratory Values (Hemoglobin, Platelet 
Counts, Leukocytes, Neutrophils, and Lymphocytes) 
4.6.2 
Kaplan-Meier Estimates of Time to Onset of Selected Worsening Laboratory Events of Special 
Interest 
Listings 
Listing No. 
Title 
2.1.1 
Participant Enrollment and Disposition Status 
2.1.2 
Participant Inclusion and Exclusion Criteria Violations 
2.2 
Protocol Deviations  
2.3 
Analysis Population 
2.4.1 
Demographic and Baseline Characteristics 
2.4.2 
Disease History 
2.4.3 
Prior Systemic Therapy 
2.4.4 
Prior Radiation Treatment 
2.4.5 
Prior Surgery or Surgical Procedure 
2.4.6 
Prior Stem Cell Transplant 
2.4.7 
Medical History 
2.4.8 
Prior and Concomitant Medication 
2.4.9 
Tumor Markers 
2.5.1 
Study Drug Compliance 


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28 JAN 2021 
VV-CLIN-000139 
CONFIDENTIAL 
Listing No. 
Title 
2.5.2 
Study Drug Administration 
2.6.1 
Best Overall Response, Duration of Response, and Progression-Free Survival per Independent 
Review Committee 
2.6.2 
Best Overall Response, Duration of Response, and Progression-Free Survival per Investigator 
2.6.3 
Overall Response Assessment by Visit per Independent Review Committee 
2.6.4 
Independent Review Committee Response Assessment:  Target Lesions  
2.6.5 
Independent Review Committee Response Assessment:  Non-Target Lesions  
2.6.6 
Independent Review Committee Response Assessment:  New Lesions  
2.6.7 
Overall Response Assessment by Visit per Investigator 
2.6.8 
Investigator Response Assessment:  Target Lesions  
2.6.9 
Investigator Response Assessment:  Non-Target Lesions  
2.6.10 
Investigator Response Assessment:  New Lesions  
2.6.11 
Deaths and Overall Survival 
2.6.12 
Bone Marrow Examination 
 
 
2.6.14 
Best Overall Response, Duration of Response, and Progression-Free Survival per Independent 
Review Committee – Censoring Crossover Participants 
2.6.15 
Best Overall Response, Duration of Response, and Progression-Free Survival per Investigator – 
Censoring Crossover Participants 
2.7.1 
Adverse Events 
2.7.2 
Serious Adverse Events 
2.7.3 
Grade 3 and Higher Adverse Events 
2.7.4 
Treatment-Related Adverse Events 
2.7.5 
Fatal Adverse Events 
2.7.6 
Adverse Events Leading to Interruption, Reduction or Discontinuation of INCB050465 
2.8.1 
Clinical Laboratory Values - Hematology 
2.8.2 
Clinical Laboratory Values - Chemistry 
2.8.3 
Abnormal Clinical Laboratory Values - Hematology 
2.8.4 
Abnormal Clinical Laboratory Values - Chemistry 
2.8.5 
Potential Hy's Law Events 
2.9.1 
Vital Signs 
2.9.2 
Abnormal Vital Sign Values 
2.9.3 
Alert Vital Sign Values 
2.10.1 
12-Lead ECG Values 
2.10.2 
Abnormal 12-Lead ECG Values 
2.10.3 
Alert 12-Lead ECG Values