A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants With Previously Treated Glioblastoma or Other Primary Central Nervous System Tumors Harboring Activating FGFR1-3 Alterations (FIGHT-209)
Phase: PHASE2
Conditions: Glioblastoma, Adult-type Diffuse Gliomas
Sponsor: Incyte Corporation

Offici al Title:  
A P hase 2, O pe n -La bel, Si n gle -Ar m, M ultice nter St u d y t o E val uate t he  
Efficac y a n d Safet y of Pe mi gati ni b i n Partici pa nts Wit h Pre vi o usl y 
Treate d Gli o blast o ma or Ot her Pri mar y Ce ntral Ner v o us S yste m T u m ors  
Har b ori n g Acti vati n g F G F R 1 -3 Alterati o ns ( FI G H T- 2 0 9) 
N C T N u m ber:  
N C T 0 5 2 6 7 1 0 6  
D oc u me nt D ate:  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3 Versi o n 4 2 6 J U L 2 0 2 4  
 
 
 

I nc yte C or p orati o n 
Pa ge 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
 
Cli nic al St u d y Pr ot oc ol  
 
TI T L E P A G E  
I N C B 5 4 8 2 8-2 0 9  
A P hase 2, O pe n -La bel, Si n gle -Ar m, M ultice nter St u d y t o E val uate t he 
Efficac y a n d Safet y of Pe mi gati ni b  i n Partici pa nts Wit h Pre vi o usl y 
Treate d Gli o blast o ma or Ot her Pri mar y Ce ntral Ner v o us S yste m T u m ors 
Har b ori n g Acti vati n g F G F R 1 -3  Alterati o ns ( FI G H T -2 0 9)  
 
Pr o d uct:  
Pe mi g ati ni b  (I N C B0 5 4 8 2 8 ) 
I N D N u m ber: 
I N D 1 5 8, 1 3 5 
E u dr a C T N u m ber:  
2 0 2 1 -0 0 4 7 4 0 -2 4  
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, Del a w are, U S A 1 9 8 0 3  
Ori gi n al Pr ot oc ol:  
2 4  S E P  2 0 2 1  
A me n d me nt 1:  
1 9  N O V 2 0 2 1  
A me n d me nt 2:  
1 9 J A N 2 0 2 3  
A me n d me nt 3:  
2 6  J U L 2 0 2 4  
 
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 ( Brazil 2 0 1 3) 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, a p plica ble G o o d Cli nical Practices, a n d 
a p plica ble la ws a n d c o u ntr y -s pecific re g ulati o ns, i ncl u di n g W M O ( Me dical Researc h I n v ol vi n g H u ma n Partici pa nts 
Act) a n d Cli nical Trials Re g ulati o n ( E U) N o. 5 3 6/ 2 0 1 4, i n w hic h t he st u d y is bei n g c o n d ucte d.  
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, refe re 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 pri or 
writte n c o nse nt.  

I nc yte C or p orati o n 
Pa ge 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
I N V E S TI G A T O R'S A G R E E M E N T  
I h a ve rea d t he I N C B 5 4 8 2 8-2 0 9 Pr ot oc ol A me n d me nt 3  ( date d 2 6  J U L 2 0 2 4) a n d a gree t o  
c o nd uct t he st u d y as o utli ne d . I a gree t o mai ntai n t he c o nfi de ntialit y of all i nf or mati o n recei ve d 
or de vel o pe d i n c o n n ecti o n wit h t his Pr ot oc ol.  
 
 
 
 
 
( Pri nte d Na me of I n vesti gat or) 
 
 
 
 
 
 
 
 
( Si g nat ure of I n v esti gat or) 
 
( Date) 

I nc yte C or p orati o n 
Pa ge 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
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  
TI T L E P A G E  ...................................................................................................................................1  
I N V E S TI G A T O R' S A G R E E M E N T ................................................................................................2  
T A B L E O F C O N T E N T S  .................................................................................................................3  
LI S T O F A B B R E VI A TI O N S  ..........................................................................................................8  
1.  
P R O T O C O L S U M M A R Y  ..........................................................................................1 1  
2.  
I N T R O D U C TI O N ......................................................................................................1 8  
2. 1.  
Bac k gr o u n d  .................................................................................................................1 8  
2. 1. 1.  
Fi br o blast Gr o wt h Fact or Rece pt or I n hi biti o n i n O nc ol o g y  .......................................1 8  
2. 1. 2.  
Gli o blast o ma a n d Ce ntral Ner v o us S yste m T u m ors  ..................................................2 0  
2. 1. 3.  
R ole of Fi br o blast Gr o wt h Fact or R ece pt ors i n Gli o blast o ma a n d Ot her 
Ce ntral Ner v o us S yste m T u m ors  ................................................................................2 1  
2. 2.  
St u d y Rati o nale  ...........................................................................................................2 2  
2. 2. 1.  
Scie ntific Rati o nale f or St u d y Desi g n  ........................................................................2 3  
2. 2. 2.  
J ustificati o n f or D ose ..................................................................................................2 3  
2. 3.  
Be nefit/ Ris k Assess me nt  ............................................................................................2 3  
3.  
O BJ E C TI V E S A N D E N D P OI N T S  ............................................................................2 4  
4.  
S T U D Y D E SI G N  .......................................................................................................2 6  
4. 1.  
O verall Desi g n  ............................................................................................................2 6  
4. 2.  
O verall St u d y D urati o n  ...............................................................................................2 7  
4. 3.  
St u d y Ter mi nati o n  ......................................................................................................2 7  
5.  
S T U D Y P O P U L A TI O N  .............................................................................................2 9  
5. 1.  
I n cl usi o n Criteria ........................................................................................................2 9  
5. 2.  
E xcl usi o n Criteria  .......................................................................................................3 1  
5. 3.  
Lifest yle C o nsi derati o ns  .............................................................................................3 3  
5. 4.  
Scree n Fail ures  ............................................................................................................3 4  
5. 5.  
Re place me nt of Partici pa nts  .......................................................................................3 4  
6.  
S T U D Y T R E A T M E N T  ..............................................................................................3 5  
6. 1.  
St u d y Treat me nt A d mi nistere d  ...................................................................................3 5  
6. 2.  
Pre parati o n, H a n dli n g, a n d Acc o u nta bilit y  ................................................................3 5  
6. 3.  
Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g  ........................................3 6  
6. 4.  
St u d y Treat me nt C o m plia nce  .....................................................................................3 6  
6. 5.  
D ose M o dificati o ns  .....................................................................................................3 6  

I nc yte C or p orati o n 
Pa ge 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
6. 5. 1.  
Criteria a n d Pr oce d ures f or D ose I nterr u pti o ns a n d A dj ust me nts of St u d y 
Dr u g  ............................................................................................................................3 6  
6. 5. 2.  
Ma na ge me nt of H y per p h os p hate mia  ..........................................................................3 8  
6. 5. 3.  
Criteria f or Per m a ne nt Disc o nti n uati o n of St u d y Dr u g  ..............................................3 9  
6. 6.  
C o nc o mita nt Me dicati o ns a n d Pr o ce d ures  .................................................................4 0  
6. 6. 1.  
Restricte d Me dicati o ns a n d Pr oce d ures  ......................................................................4 0  
6. 6. 2.  
Pr o hi bite d Me dicati o ns a n d Pr oce d ures  .....................................................................4 1  
6. 7.  
Treat me nt Aft er t he E n d of t he St u d y  .........................................................................4 1  
7.  
DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D P A R TI CI P A N T 
WI T H D R A W A L  ........................................................................................................4 2  
7. 1.  
Disc o nti n uati o n of St u d y Treat me nt  ...........................................................................4 2  
7. 1. 1.  
Reas o ns f or Disc o nti n uati o n  .......................................................................................4 2  
7. 1. 2.  
Disc o nti n uati o n Pr oce d ures  ........................................................................................4 2  
7. 2.  
Partici pa nt Wit h dra w al Fr o m t he St u d y  .....................................................................4 3  
7. 3.  
L ost t o F oll o w -U p .......................................................................................................4 3  
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ......................................................4 4  
8. 1.  
A d mi nistrati ve a n d Ge neral Pr oce d ures  .....................................................................4 4  
8. 1. 1.  
I nf or me d C o nse nt Pr ocess ..........................................................................................4 4  
8. 1. 2.  
Prescree ni n g a n d Scree ni n g Pr oce d ures  .....................................................................4 5  
8. 1. 3.  
I nteracti ve Res p o nse Tec h n ol o g y Pr oce d ure ..............................................................4 5  
8. 1. 4.  
Distri b uti o n of Re mi n der Car ds  ..................................................................................4 5  
8. 1. 5.  
C ortic oster oi d Use  ......................................................................................................4 6  
8. 1. 6.  
De m o gra p h y a n d Me dical Hist or y  ..............................................................................4 6  
8. 1. 6. 1.  
De m o gra p hics a n d Ge n eral Me dical Hist or y  .............................................................4 6  
8. 1. 6. 2.  
Disease C haracteristics a n d Treat me nt Hist or y  ..........................................................4 6  
8. 2.  
Efficac y Assess me nts  .................................................................................................4 6  
8. 2. 1.  
T u m or I m a gi n g  ...........................................................................................................4 6  
8. 2. 2.  
K ar n ofs k y Perf or ma n ce Stat us  ...................................................................................4 7  
8. 2. 4.  
Me dical Res o urce Utilizati o n a n d Healt h Ec o n o mi cs  ................................................4 7  
8. 3.  
Safet y Assess me nts  .....................................................................................................4 8  
8. 3. 1.  
A d verse E v e nts  ...........................................................................................................4 8  
8. 3. 2.  
P h ysical E xa mi nati o ns  ................................................................................................4 8  

I nc yte C or p orati o n 
Pa ge 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8. 3. 3.  
Ne ur ol o gical Ass ess me nt  ............................................................................................4 9  
8. 3. 4.  
Vital Si g ns  ..................................................................................................................4 9  
8. 3. 5.  
Electr ocar di o gra ms  .....................................................................................................4 9  
8. 3. 6.  
C o m pre he nsi ve E ye E x a mi nati o n ...............................................................................5 0  
8. 3. 7.  
La b orat or y Ass ess me nts  .............................................................................................5 0  
8. 3. 7. 1.  
Pre g na nc y T esti n g  ......................................................................................................5 2  
8. 3. 7. 2.  
Ser ol o g y  ......................................................................................................................5 2  
8. 4.  
P har mac o ki netic Assess me nts  ....................................................................................5 2  
8. 4. 1.  
Bl o o d Sa m ple C ollecti o n  ............................................................................................5 2  
8. 4. 2.  
P har mac o ki netic A n al ysis  ..........................................................................................5 3  
8. 5.  
P har mac o d y na mic a n d Tra nslati o nal Assess me nts  ....................................................5 3  
8. 5. 1.  
Bi o mar ker Assess me nt f or Eli gi bilit y  ........................................................................5 3  
8. 5. 2.  
Plas ma f or M utati o nal A nal ysis ..................................................................................5 4  
8. 5. 3.  
Plas ma f or C orrelati ve A nal ysis  .................................................................................5 4  
8. 5. 4.  
Tiss ue Bi o psies  ...........................................................................................................5 4  
8. 6.  
U nsc he d ule d Visits  .....................................................................................................5 5  
8. 7.  
E n d of Treat me nt a n d/ or Earl y Ter mi nati o n  ..............................................................5 5  
8. 8.  
F oll o w -U p  ...................................................................................................................5 5  
8. 8. 1.  
Safet y F oll o w -U p  ........................................................................................................5 5  
8. 8. 2.  
P ost -Treat me nt Diseas e F oll o w -U p  ............................................................................5 6  
8. 8. 3.  
S ur vi val F oll o w -U p  ....................................................................................................5 6  
9.  
A D V E R S E E V E N T S: D E FI NI TI O N S A N D P R O C E D U R E S F O R 
R E C O R DI N G, E V A L U A TI N G, F O L L O W -U P, A N D R E P O R TI N G  ......................5 7  
9. 1.  
Defi niti o n of A d vers e E v e nt  .......................................................................................5 7  
9. 2.  
Defi niti o n of Seri o us A d verse E ve nt  ..........................................................................5 8  
9. 3.  
Rec or di n g a n d F oll o w -U p of A d verse E ve nts a n d/ or Seri o us A d verse E ve nts  .........5 9  
9. 4.  
Re p orti n g of Seri o us A d verse E ve nts  .........................................................................6 1  
9. 5.  
E ve nts of Cli nical I nt erest  ..........................................................................................6 2  
9. 6.  
E mer ge nc y U n bli n di n g of Treat me nt Assi g n me nt  .....................................................6 3  
9. 7.  
Pre g na nc y  ...................................................................................................................6 3  
9. 8.  
War ni n gs a n d Preca uti o ns  ..........................................................................................6 3  
9. 9.  
Pr o d uct C o m plai nts  ....................................................................................................6 4  
9. 1 0.  
Treat me nt of O v er d ose  ...............................................................................................6 4  

I nc yte C or p orati o n 
Pa ge 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1 0.  
S T A TI S TI C S  ..............................................................................................................6 5  
1 0. 1.  
Sa m ple Size Deter mi nati o n  ........................................................................................6 5  
1 0. 2.  
P o p ulati o ns f or A nal ysis  .............................................................................................6 5  
1 0. 3.  
Le vel of Si g nifica nce  ..................................................................................................6 5  
1 0. 4.  
Statistical A nal yses  .....................................................................................................6 6  
1 0. 4. 1.  
Pri mar y A nal ysis  ........................................................................................................6 6  
1 0. 4. 2.  
Sec o n dar y A n al ysis  ....................................................................................................6 6  
1 0. 4. 3.  
Safet y A nal yses  ..........................................................................................................6 7  
1 0. 5 . 
I nteri m A nal ysis ..........................................................................................................6 7  
1 1.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  ..................................................................................................6 8  
1 1. 1.  
I n v esti gat or Res p o nsi bilities .......................................................................................6 8  
1 1. 1. 1.  
I d e ntificati o n of t he C o or di nati n g Pri nci pal I n v esti gat or ...........................................6 9  
1 1. 2.  
Data Ma na g e me nt  .......................................................................................................6 9  
1 1. 3.  
Data Q ualit y Ass ur a nce  ..............................................................................................7 1  
1 1. 4.  
Data Pri vac y a n d C o nfi de ntialit y of St u d y Rec or ds  ...................................................7 2  
1 1. 5.  
Fi na ncial Discl os ur e  ...................................................................................................7 2  
1 1. 6.  
P u blicati o n P olic y  .......................................................................................................7 3  
1 1. 7.  
St u d y a n d Site Cl os ure ................................................................................................7 3  
1 2.  
R E F E R E N C E S  ...........................................................................................................7 5  
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 A N D D E FI NI TI O N S  ............................................7 8  
A P P E N DI X  B.  E LI GI B L E F G F R G E N E A L T E R A TI O N S  ......................................................8 0  
A P P E N DI X  C.  I N S T R U C TI O N T O P A R TI CI P A N T S F O R H A N D LI N G S T U D Y 
D R U G ( P E MI G A TI NI B)  ...........................................................................................8 2  
A P P E N DI X  D.  C Y P 3 A 4 I N HI BI T O R S A N D I N D U C E R S  ......................................................8 3  
A P P E N DI X  E.  C O VI D -1 9 P A N D E MI C MI TI G A TI O N S T R A T E GI E S A N D 
I N S T R U C TI O N S .......................................................................................................8 6  
A P P E N DI X  F.  N A N O S C A L E  ...................................................................................................8 8  
A P P E N DI X  G.  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  ...........................9 1  
 

I nc yte C or p orati o n 
Pa ge 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
LI S T O F T A B L E S  
Ta ble  1:  
Pri mar y a n d Sec o n dar y O bjecti ves a n d E n d p oi nts  .....................................................1 1  
Ta ble  2:  
Ke y St u d y Desi g n Ele me nts  .......................................................................................1 2  
Ta ble  3:  
Sc he d ule of A cti vities  .................................................................................................1 5  
Ta ble  4:  
Sc he d ule of La b orat or y Assess me nts  .........................................................................1 7  
Ta ble  5:  
T u m ors Wit h Fre q u e nc y > 1 % f or F G F R 1 -3 M utati o ns a n d Rearra n g e me nts 
i n T he Ca ncer Ge n o me Atlas Data bas e ......................................................................1 9  
Ta ble  6:  
O bjecti ves a n d E n d p oi nts  ...........................................................................................2 4  
Ta ble  7:  
E xcl usi o nar y La b orat or y Val ues  ................................................................................3 2  
Ta ble  8:  
St u d y Treat me nt I nf or mati o n  .....................................................................................3 5  
Ta ble  9:  
G ui deli nes f or I nterr u pti o n a n d Restarti n g of St u d y Dr u g  .........................................3 7  
Ta ble  1 0:  Rec o m me n de d A p pr o ac h f or H y per p h os p hate mia Ma na ge me nt  ...............................3 9  
Ta ble  1 1:  Kar n ofs k y Perf or ma n ce Stat us Sc ores  ........................................................................4 7  
Ta ble  1 2:  Re q uire d La b orat or y A n al ytes  ....................................................................................5 1  
Ta ble  1 3:  P har mac o ki netic Bl o o d Sa m ple Ti mi n g  .....................................................................5 3  
Ta ble  1 4:  Bi o mar ker/ Tra nslati o nal Sa m ple Ti mi n g  ...................................................................5 5  
Ta ble  1 5:  P o p ulati o ns f or A nal ysis  .............................................................................................6 5  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
St u d y Desi g n Sc he ma  .................................................................................................1 4  

I nc yte C or p orati o n 
Pa ge 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o ns a n d 
S peci al Ter ms  
Defi niti o n  
A E  
a d verse e ve nt  
A L T  
ala ni ne a mi n otra nsferase  
A N C  
a bs ol ute ne utr o p hil c o u nt  
A N S M  
A ge nce Nati o nale de Séc urité d u Mé dica me nt et des Pr o d uits de Sa nté  
a P T T 
acti vate d partial t hr o m b o plasti n ti me  
A S T  
as partate a mi n otra nsferase  
B C N U  
carm usti ne  
B O R  
best o verall res p o nse  
C C N U  
l o m usti ne 
C E C  
ce ntral et hics co m mittee  
cf D N A 
cell -free de o x yri b o n ucleic aci d 
CI  
c o nfi de nce i nter val  
C L/ F  
a p pare nt oral d ose cleara nce  
C LI A  
Cli nical La b orat or y I m pr o ve me nt A me n d me nts  
C N S  
ce ntral ner v o us s yste m  
C R  
c o m plete res p o nse  
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 C R  
disease c o ntr ol rate  
D M C  
Data M o nit ori n g C o m mittee  
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 R F  
electr o nic case re p ort f or m  
E D C  
electr o nic data ca pt ure  
E G F R  
e pi der mal gr o wt h fact or rece pt or  
E O R T C Q L Q -C 3 0  
E ur o pea n Or ga nisati o n f or Researc h a n d Treat me nt of Ca ncer Q ualit y of Life 
Q uesti o n naire –  C ore 3 0  
E O T  
e n d of treat me nt  
E Q -5 D  
E ur o Q o L q uesti o n naire 5 D  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F G F  
fi br o blast gr o wt h fact or 

I nc yte C or p orati o n 
Pa ge 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A b bre vi ati o ns a n d 
S peci al Ter ms  
Defi niti o n  
F G F R  
fi br o blast gr o wt h fact or rece pt or 
F G F R 1 -3  
fi br o blast gr o wt h fact or rece pt ors 1, 2, or 3 
F G F R 1/ 3  
fi br o blast gr o wt h fact or rece pt ors 1 a n d/ or 3 
FI S H  
fl u oresce nt i n sit u h y bri dizati o n 
F MI  
F o u n dati o n Me dici ne, I nc  
F S H  
f ollicle-sti m ulati n g h or m o ne 
G B M  
gli o blast o ma  
G C P  
G o o d Cli nical Practice  
G D P R  
Ge neral Data Pr otecti o n Re g ulati o n  
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 
HI V  
h u ma n i m m u n o deficie nc y vir us  
H P  
h y per p h os p hate mia  
H R T  
h or m o ne re place me nt t hera p y  
I B 
I n vesti gat or's Br oc h ure 
I C F 
i nf or me d c o nse nt f or m  
I C H 
I nter nati o nal C o u ncil f or  Har m o ni sati o n 
I C R 
I n de pe n de nt Ce ntral Re vie w 
I D H 
is ocitrate de h y dr o ge nase  
I E C 
i n de pe n de nt et hics c o m mittee 
I H C 
i m m u n o hist oc he mistr y 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I N R 
i nter nati o nal n or malize d rati o 
I R B 
i nstit uti o nal re vie w b oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y  
J-G C P  
Ja pa nese G o o d Cli nical Practice 
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M G M T  
O( 6) -met h yl g ua ni ne -D N A met h yltra nsferase  
M H R A  
Me dici ne a n d Healt hcare Pr o d ucts Re g ulat or y A ge nc y ( U K)  
M RI  
ma g netic res o na nce i ma gi n g 
N A N O  
Ne ur ol o gic Assess me nt i n Ne ur o -O nc ol o g y  
N C C N  
Nati o nal C o m pre he nsi ve Ca ncer Net w or k  
O C T  
o ptical c o here nce t o m o gra p h y  
O C T 2  
or ga nic cati o n tra ns p orter 2  

I nc yte C or p orati o n 
Pa ge 1 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A b bre vi ati o ns a n d 
S peci al Ter ms  
Defi niti o n  
O R R  
o bjecti ve res p o nse rate  
O S  
o verall s ur vi val  
P D  
p har mac o d y na mic(s)  
P F S  
pr o gressi o n -free s ur vi val 
P K  
p har mac o ki netic (s) 
P M D A  
P har mace uticals a n d Me dical De vices A ge nc y  
P R  
partial res p o nse  
P T  
pr ot hr o m bi n ti me  
P T H  
parat h yr oi d h or m o ne  
P T T  
partial t hr o m b o plasti n ti me  
Q D  
o nce dail y  
Q Tc F  
Q T i nter val c orrecte d usi n g Fri dericia's f or m ula 
R A N O  
Res p o nse Assess me nt i n Ne ur o -O nc ol o g y  
R N A  
ri b o n ucleic aci d 
R SI  
Refere nce Safet y I nf or mati o n  
S A E  
seri o us a d verse e ve nt 
S D  
sta ble disease 
S o A  
sc he d ule of acti vities 
S O P  
sta n dar d o perati n g pr oce d ure  
S R D/ R P E D  
ser o us reti nal detac h me nt/reti nal pi g me nte d e pit heli u m detac h me nt 
T A C C  
tra nsf or mi n g aci d c oile d-c oil 
T C G A  
T he Ca ncer Ge n o me Atlas  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T M Z  
te m oz ol o mi de 
U K C A  
U K C o nf or mit y Assesse d  
U K NI  
U K N ort her n Irela n d  
U L N  
u p per li mit of n or mal  
V E G F  
vasc ular e n d ot helial gr o wt h fact or  
V E G F R  
vasc ular e n d ot helial gr o wt h fact or rece pt or  
V z/ F 
a p pare nt oral d ose v ol u me of distri b uti o n  
W B C  
w hite bl o o d cell  
W H O  
W orl d Healt h Or ga nizati o n  
W H O -C N S 5  
W H O Classificati o n of T u m o urs of t he Ce ntral Ner v o us S yste m, fift h e diti o n  
W O C B P  
w o ma n of c hil d beari n g p ote ntial  

I nc yte C or p orati o n 
Pa ge 1 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1.  
P R O T O C O L S U M M A R Y  
Pr ot oc ol Title:  
A P hase 2, O pe n -La bel, Si n gle -Ar m, M ultice nter St u d y t o E val uate t he Efficac y a n d Safet y of 
Pe mi gati ni b  i n Partici pa nts Wit h Pre vi o usl y Treate d Gli o blast o ma or Ot her Pri mar y Ce ntral 
Ner v o us S yste m T u m ors Har b ori n g A cti vati n g F G F R 1 -3  Alterati o ns  ( FI G H T-2 0 9)  
Pr ot oc ol N u m ber : I N C B 5 4 8 2 8 -2 0 9  
O bjecti ves a n d E n d p oi nts:  
Ta ble  1  pres e nts t he pri mar y a n d maj or/ k e y sec o n dar y o bjecti ves a n d e n d p oi nts.  
T a ble  1 : 
Pri m ar y a n d Sec o n d ar 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 deter mi ne t he efficac y of pe mi gati ni b  i n 
partici pa nts wit h rec urre nt G B M  wit h a n 
acti vati n g F G F R 1 -3 m utati o n or 
f usi o n/rearra n ge me nt. 
•  O R R i n C o h ort A, defi ne d as t he pr o p orti o n of 
partici pa nts i n C o h ort A w h o ac hie ve a B O R  of 
C R or P R base d o n R A N O as deter mi ne d b y a n 
I C R. 
Sec o n d ar y  
T o deter mi ne t he efficac y of  pe mi gati ni b  i n 
partici pa nts wit h rec urre nt G B M or ot her  
rec urre nt gli o ma s, circ u mscri be d astr oc ytic 
gli o mas , a n d gli o ne ur o n al a n d ne ur o nal t u m ors 
wit h a n acti vati n g F G F R 1 -3 m utati o n or 
f usi o n/rearra n ge me nt. 
•  O R R i n C o h ort B, defi ne d as t he pr o p orti o n of 
partici pa nts i n C o h ort B w h o ac hie ve a B O R of 
C R or P R base d o n R A N O as deter mi ne d b y a n 
I C R. 
•  O R R i n C o h orts A a n d B  c o m bi ne d , defi ne d as 
t he pr o p orti o n of partici pa nts i n C o h orts A a n d B 
w h o ac hie ve a B O R  of C R or P R base d o n 
R A N O as deter mi ne d b y a n I C R.  
•  D O R i n C o h orts A a n d B, res pecti vel y, defi ne d 
as t he ti me fr o m first assess me nt of C R or P R 
u ntil pr o gressi ve disease (acc or di n g t o R A N O 
a n d assesse d b y a n I C R), or deat h ( w hic he ver 
occ urs first). 
•  O R R i n eac h c o h ort as deter mi ne d b y 
i n vesti gat or assess me nt . 
•  D C R  i n C o h orts A a n d B, res pecti vel y, 
descri be d as t he pr o p orti o n of partici pa nts w h o 
ac hie ve a C R , P R , or S D  as assesse d b y a n I C R. 
•  P F S  i n C o h orts A a n d B, res pecti vel y, defi ne d as 
t he ti me fr o m first d ose u ntil pr o gressi ve disease 
(acc or di n g t o R A N O a n d assesse d b y a n I C R) or 
deat h  ( w hic he ver occ urs first). 
•  O S  i n C o h orts A a n d B, res pecti vel y, defi ne d as 
t he ti me fr o m first d ose of st u d y dr u g t o deat h 
d ue t o  ca use. 

I nc yte C or p orati o n 
Pa ge 1 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a bl e 1 : 
Pri m ar y a n d Sec o n d ar y O bjecti ves a n d E n d p oi nts  ( C o nti n ue d) 
O bjecti ves  
E n d p oi nts  
Sec o n d ar y  ( C o nti n ue d) 
T o deter mi ne t he safet y a n d t olera bilit y of 
pe mi gati ni b i n partici pa nts wit h rec urre nt G B M  
or ot her rec urre nt gli o mas , circ u mscri be d 
astr oc ytic gli o mas,  a n d gli o ne ur o n al a n d 
ne ur o nal t u m ors , wit h a n acti vati n g F G F R 1 -3 
m utati o n or f usi o n/rearra n ge me nt.  
•  Safet y a n d t olera bilit y, assesse d b y m o nit ori n g 
t he fre q ue nc y a n d se verit y of A E s b y  perf or mi n g  
p h ysical e xa mi nati o ns, e val uati n g c ha n ges i n 
vital si g ns a n d E C Gs, a n d e val uati n g cli nical 
la b orat or y bl o o d sa m ples acc or di n g t o N CI 
C T C A E v 5. 0.  
•  I m pact o n -st u d y treat me nt, assesse d b y 
m o nit ori n g t he fre q ue nc y of treat me nt 
i nterr u pti o ns, d ose re d ucti o ns, a n d wit h dra wal of 
st u d y treat me nt d ue t o A Es. 
O ver all Desi g n:  
Ta ble  2  pres e nts t he ke y st u d y desi g n ele me nts. F urt her st u d y details are prese nte d after t he 
ta ble. 
T a ble  2 : 
Ke y St u d y Desi g n Ele me nts  
St u d y P h ase  
P hase 2  
Cli nic al I n dic ati o n  
Treat me nt of a d ults wit h rec urre nt G B M  or ot her rec urre nt gli o mas , 
circ u mscri be d astr oc ytic gli o mas, a n d gli o ne ur o n al a n d ne ur o nal t u m ors , 
har b ori n g a n F G F R 1 -3  m utati o n or  f usi o n/rearra n ge me nt w h o ha ve ha d 
disease pr o gressi o n o n or after at least 1  li ne of ra diati o n a n d/ or c he m ot hera p y 
P o p ul ati o n  
P artici pa nts at least 1 8 years of a ge w h o ha ve rec urre nt G B M  or ot her 
rec urre nt gli o mas , circ u mscri be d astr oc ytic gli o mas, a n d gli o ne ur o n al a n d 
ne ur o nal t u m ors , har b ori n g a n F G F R 1 -3 m utati o n or f usi o n/ rearra n ge me nt 
w h o ha ve ha d disease pr o gressi o n o n at least 1 li ne of sta n dar d-of -care t hera p y  
(e g, c he m ot hera p y a n d/ or ra diati o n t hera p y ) 
N u m ber of 
P artici p a nts  
A p pr o xi matel y 1 6 4 partici pa nts will be e nr olle d  ( 8 2 partici pa nts i n C o h ort A 
a n d u p t o 8 2 part ici pa nts i n C o h ort B)  
St u d y Desi g n  
Si n gle -ar m, o pe n -la bel, m ultice nter 
Esti m ate d D ur ati o n 
of St u d y 
P artici p ati o n  
U p t o 2 8 da ys f or scree ni n g, i nter mitte nt treat me nt o n a 2 -wee k  o n -t hera p y a n d 
1 -wee k  off -t hera p y sc he d ule i n c o nsec uti ve 2 1-da y c ycles as l o n g as 
partici pa nts are recei vi n g be nefit a n d ha ve n ot met a n y criteria f or st u d y 
wit h dra wal, a n d 3 0 da ys f or f oll o w -u p after t he last d ose of st u d y dr u g. It is 
esti mate d t hat a n i n di vi d ual will partici pate f or a p pr o xi mate l y 3 m o nt hs.  
D M C  
N o  
C o or di n ati n g 
Pri nci p al 
I n vesti g at or 
T o be deter mi ne d  

I nc yte C or p orati o n 
Pa ge 1 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
Tre at me nt Gr o u ps a n d D ur ati o n:  
T he st u d y desi g n sc he ma is prese nte d i n Fi g ur e  1 . T his st u d y c o nsists of 2  c o h orts, C o h orts A  
a n d B, a n d will e nr oll a p pr o xi matel y 8 2 partici pa nts i nt o eac h c o h ort. Partici pa nts will recei ve 
pe mi gati ni b  1 3. 5 m g Q D o n a 2 -wee k  o n -t hera p y a n d 1 -wee k  off -t hera p y sc he d ule as l o n g as 
t he y are recei vi n g be nefit a n d ha ve n ot met a n y criteria f or tr eat me nt disc o nti n uati o n. 
Partici pa nts wit h l ocal la b orat or y test res ults (tiss ue is preferre d b ut plas m a -base d m olec ular 
assa ys ma y be acce pte d after disc ussi o n wit h t he me dical  m o nit or) d oc u m e nti n g a n acti o na ble 
F G F R 1 -3  g e ne alterati o n are eli gi ble t o e nr oll as l o n g as t he res ul ts meet t h e c o h ort criteria. 
Acti o na ble F G F R 1 -3 g e n e alterati o ns i ncl u de defi ne d m utati o ns, ge ne f usi o n/rearra n ge me nts, or 
i n-fra me d eleti o ns (see A p pe n di x  B  f or a list of eli gi ble ge ne alterati o ns a n d k n o w n F G F R 
resista nce m utati o ns). Partici pa nts will be re q uire d t o ha ve a d oc u m e nte d acti o na ble F G F R 1 -3 
ge ne alterati o n  fr o m t u m or tiss ue ( or plas ma) as d eter mi ne d b y a l ocall y q ualifie d la b orat or y 
e m pl o yi n g a m olec ular assa y ha vi n g a rele va nt m ar k of c o nf or mit y f or a n al ytical perf or ma nce 
(e g, C LI A [ U S] or U K C A, C E, C E U K NI, or ot h ers [ o utsi de of t he U S]) or a c o m mercial re p ort 
fr o m t he ce ntr al la b orator y t o be eli gi ble. C o nfir mat or y testi n g t hr o u g h t he s p o ns or -desi g nate d 
ce ntral ge n o mics l a b orat or y s h o ul d be perf or me d f or all partici pa nts  t o c o nfir m t he prese n ce of 
a n eli gi ble F G F R alterati o n ; h o we ver, res ults fr o m t he ce ntral ge n o mics l a b orat or y are not 
re q uire d b ef ore e nr oll me nt. Partici pa nts w h o ha ve a c o m merci al re p ort at scree ni n g fr o m t he 
s p o ns or-desi g nate d ce ntr al la b orat or y will n ot nee d t o ha ve  a sa m ple s e nt f or c o nfir mat or y 
testi n g. P artici pa nts will be  assi g ne d t o a desi g nat e d c o h ort as f oll o ws:  
•  C o h ort A: Partici pa nts wit h hist o pat h ol o gicall y pr o ve n, W H O Gra d e 4 , 
I DH −wil d -t y pe G B M  O R m olec ular dia g n osis of I D H -wil d -t y pe, diff use astr oc ytic 
gli o ma wit h m olec ular feat ures of Gra de 4 G B M per W H O 2 0 2 1 (ast ro c ytic gli o ma 
re q uires pr ese nce of eit her a m plificati o n of E G F R, w h ole c hr o m os o me 7 gai n a n d 
w h ole c hr o m os o me 1 0 l oss, or T E R T pr o m oter  m utati o n; L o uis et al 2 0 2 1 ) t hat is 
rec urre nt, har b ori n g F G F R 1 -3 f usi o ns /or ot her rearra n ge m e nts ( F G F R 1-3 i n -fra me 
f usi o ns, a n y F G F R 2 rearra n ge me nt, or F G F R 1/ 3 rearra n ge me nt wit h k n o w n part ner) 
o r wit h a defi ne d F G F R 1 -3  acti vati n g m utati o n  or i n-fra me deleti o n (see 
A p pe n di x  B ). O nl y partici pa nts wit h F G F R f usi o ns  or rearra n g e me nts wit h a n i ntact 
ki nase d o mai n  (see A p pe n di x  B ) are eli gi ble ( n = 8 2).  
•  C o h ort B: Partici pa nts wit h ot her hist o pat h ol o gicall y pr o ve n, per W H O criteria 
(L o uis et al 2 0 2 1 ), gli o mas  ot her t ha n G B M  (e g, I D H-m uta nt astr oc yt o ma, I D H-
m uta nt a n d 1 p / 1 9 q c o del ete d oli g o de n dr o gli o ma ), circ u mscri be d astr oc ytic gli o mas , 
a n d gli o ne ur o nal a n d n e ur o nal t u m ors  t hat are rec urre nt, har b ori n g F G F R 1 -3 
f usi o ns/or ot her rearra n g e me nts ( F G F R 1-3 i n -fra me f usi o ns, a n y F G F R 2 
rearra n ge m e nt, F G F R 1/ 3 rearra n ge m e nt wit h k n o w n part ner)  or wit h a d efi ne d 
F G F R 1 -3 acti vati n g m utati o n  o r i n-fra m e deleti o n (see A p pe n di x  B ). O nl y F G F R 
f usi o ns or rearra n g e me nts wit h a n i ntact ki nase d o mai n  (see A p pe n di x  B ) are eli gi ble 
( n =  u p  t o 8 2).  
Partici pa nts wit h k n o w n F G F R  resista nce m utati o ns are n ot eli gi ble.  
T here is n o differe n ce i n t he treat me nt re gi me n b et wee n t he c o h orts.  

I nc yte C or p orati o n 
Pa ge 1 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
Treat me nt will start o n Da y 1. Partici pa nts will u n der g o re g ul ar safet y a n d efficac y ass ess me nts 
d uri n g treat me nt. Partici pa nts ca n c o nti n ue st u d y dr u g a d mi nistrati o n i n 2 1 -da y c ycl es u ntil 
d oc u me nte d diseas e pr o gressi o n or u nacce pta bl e t o xicit y is re p orte d. F or partici pa nts e x hi biti n g  
disease pr o gressi o n base d o n l ocal ra di ol o gic re vie w, treat me nt s h o ul d n ot be disc o nti n ue d u ntil 
c o nfir mati o n  b y t he I C R u nless t he pri nci pal i n vesti gat or belie ves it is i n t he best i nterest of t he 
partici pa nt t o disc o nti n ue treat me nt bef ore recei vi n g c o nfir mati o n. A f utilit y a nal ysis  (see 
Secti o n  1 0. 5 ) is pla n ne d f or C o h ort A w he n a p pr o xi matel y 2 5 partici pa nts are e v al u a ble i n t he 
c o h ort. 
T he S o A is prese nte d i n Ta ble  3 , a n d T a ble  4  pres e nts t he sc he d ule of l a b orat or y assess me nts. 
A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A, is esse ntial 
a n d re q uir e d f or st u d y c o n d uct.  
Fi g ure  1 : 
St u d y Desi g n Sc he m a  
 
 
a O nl y F G F R f usi o ns or rearra n ge me nts wit h a n i ntact ki nase d o mai n . F G F R resista nce m utati o ns  are n ot eli gi ble. 

I nc yte C or p orati o n 
Pa ge 1 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  3 : 
Sc he d ule of Acti vities  
Visit D a y ( R a n ge)  
Scree ni n g  
Tre at me nt  
E O T  
F oll o w -U p  
N otes  
D a ys  
−2 8  t o −1  
C ycle 1  
C ycles 2 +  
S afet y  
E O T  +  
3 0  D a ys  
Dise ase  
E ver y 
9  Wee ks  
±  7  D a ys  
S ur vi v al  
E ver y 
8  Wee ks  
( ± 1 4 D a ys)  
D a y 1  
D a y 8  
( ± 3 D a ys ) 
D a y 1 5  
( ± 3 D a ys ) 
D a y 1  
( ± 3 D a ys ) 
A d mi nistr ati ve pr oce d ures  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
See Secti o n  8. 1. 1 . 
C o ntact I R T  
X  
X  
X  
X  
X  
X  
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
 
 
 
 
 
 
Pri or treat me nts, pr oce d ures, 
s ur ger y f or disease 
X  
 
 
 
 
 
 
 
 
 
De m o gra p hics a n d ge neral 
a n d disease me dical hist or y  
X  
 
 
 
 
 
 
 
 
 
Pri or/c o nc o mita nt 
me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
 
 
 
C ortic oster oi d use  
X  
X  
X  
X  
X  
X  
X  
X  
 
C ortic oster oi d use d uri n g t h e st u d y m ust 
be ca pt ure d at e ver y st u d y visit a n d 
c o m pare d wit h t h e c ortic oster oi d i nta ke 
of t h e pri or visit. T he c ha n ges will be 
rec or de d as "I ncrease d," "Sta ble, " or 
"Decrease d. " 
Dis pe nse/a d mi nister 
pe mi g ati ni b  
 
X  
X *  
 
X  
 
 
 
 
* T o  be a d mi nistere d o n -site after pre d ose 
P K sa m ple . 
Distri b ute re mi n der car ds  
 
X  
X  
X  
X  
X  
X  
X  
 
 
C ollect st u d y dr u g a n d re vie w 
re mi n der car ds 
 
 
X  
X  
X  
X  
 
 
 
 
Assess c o m plia nce  
 
 
X  
X  
X  
X  
 
 
 
 
S afet y assess me nts  
Slit -la m p, vis ual ac uit y, 
f u n do sc o p y wit h di gital 
i ma gi n g (e ye), a n d O C T 
X  
 
 
 
X *  
X  
 
 
 
* O nce e ver y 3 c ycles starti n g at C ycle  3 
( ± 7  da ys), as well as w he n cli nicall y 
i n dicate d. 
A E assess m e nts  
X  
X  
X  
X  
X  
X  
X  
 
 
 
Ne ur ol o gical assess me nt 
( N A N O) 
X  
X  
 
 
X *  
X  
X  
X  
 
* M ust b e perf or me d  o n Da y 1  of  e ver y 
c ycle. 
P h ysical e xa mi n ati o n / b o d y 
wei g ht/ hei g ht  
X  
X  
X  
X  
X  
X  
X  
 
 
Hei g ht at scree ni n g o nl y. Wei g ht at 
scree ni n g a n d Da y 1 of eac h c ycle o nl y . 
Vital si g ns  
X  
X  
 
 
X  
X  
X  
 
 
 
1 2 -lea d E C G 
X  
X  
 
 
X *  
X  
X  
 
 
* O nce  e ver y 3  c ycles (starti n g at C ycle  3), 
as wel l as w he n cli nicall y i n dicate d. 

I nc yte C or p orati o n 
Pa ge 1 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  3 : 
Sc he d ule of Acti vities  ( C o nti n ue d) 
Visit D a y ( R a n ge)  
Scree ni n g  
Tre at me nt  
E O T  
F oll o w -U p  
N otes  
D a ys  
−2 8 t o −1  
C ycle 1  
C ycles 2 +  
S afet y  
E O T + 
3 0  D a ys  
Dise ase  
E ver y 
9  Wee ks 
±  7  D a ys  
S ur vi v al  
E ver y 
8  Wee ks  
( ± 1 4 D a ys)  
D a y 1  
D a y 8  
( ± 3 D a ys) 
D a y 1 5  
( ± 3 D a ys) 
D a y 1  
( ± 3 D a ys) 
Effic ac y assess me nts  
Brai n M RI  
X  
 
 
 
X *  
X †  
 
X  
 
O nce e ver y 3 c ycles starti n g at t he e n d of 
C ycle 3 ( ± 7 da ys).  
† Perf or m at E O T if n ot d o ne wit hi n 
1  m o nt h pri or t o E O T.  
Kar n ofs k y perf or ma nce stat us  
X  
X  
 
 
X  
X  
X  
X  
 
 
S ur vi val  
 
 
 
 
 
 
 
 
X  
 

I nc yte C or p orati o n 
Pa ge 1 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  4 : 
Sc he d ule of L a b or at or y Assess m e nts  
Pr oce d ure  
Scree ni n g  
Tre at me nt  
E O T  
F oll o w -U p  
N otes  
D a ys  
−2 8  t o −1 
C ycle 1  
C ycles 2 +  
S afet y  
E O T + 3 0  D a ys  
D a y 1  
D a y 8  
( ± 3 D a ys) 
D a y 1 5  
( ± 3 D a ys) 
D a y 1  
( ± 3 D a ys) 
Cli nic al l a b or at or y assess me nts 
Bl o o d c he mistries  
X  
X *  
X  
X  
X †  
X  
X  
*If scree ni n g is p erf or me d wit hi n 1 4  da ys of C ycle 1 
Da y 1, a d diti o nal sa m ple n ot re q uire d.  
† H P i n C ycle 1 re q uires Da y 8 testi n g of ser u m 
p h os p hate i n C ycles  2 +  u ntil p h os p hate is <  7  m g/ d L 
o n Da y 8 f or at least 2 c o nsec uti ve c ycles o n sta ble 
d ose of bi n d ers. 
He mat ol o g y  
X  
X *  
 
 
X  
X  
 
*If scree ni n g is p erf or me d wit hi n 1 4  da ys of C ycle 1 
Da y 1, a d diti o nal sa m ple n ot re q uire d.  
C oa g ulati o n pa nel  
X  
X *  
 
 
X  
X  
 
*If scree ni n g is p erf or me d wit hi n 1 4  da ys of C ycle 1 
Da y 1, a d diti o nal sa m ple n ot re q uire d.  
E n d ocri n e f u ncti o n 
( P T H o nl y) 
X  
 
 
 
X *  
X  
 
* E v er y 3 c ycles o n Da y 1 starti n g wit h C ycle 3.  
Ser ol o g y  
X  
 
 
 
 
 
 
 
I D H m utati o n stat us 
X  
 
 
 
 
 
 
O nl y if n ot a vaila ble pri or t o scree ni n g.  
M G M T pr o m oter 
met h ylati o n stat us  
X  
 
 
 
 
 
 
O nl y if n ot a vaila ble pri or t o scree ni n g. 
1 p/ 1 9 q c o deleti o n  
X  
 
 
 
 
 
 
T o be assesse d i n partici p a nts wit h 
oli g o de n dr o gli o mas o nl y if n ot a vaila ble pri or t o 
scree ni n g.  
Uri nal ysis  
X  
 
 
 
 
 
 
 
Pre g na nc y testi n g  
X  
X  
 
 
X  
X  
X  
Ser u m at scree ni n g , E O T , a n d safet y f oll o w -u p , uri n e 
at ot h er ti me p oi nts. 
P K a n d tr a nsl ati o n al l a b or at or y assess me nts 
Plas ma cf D N A  
 
X *  
 
 
 
X †  
 
* Pre d ose.  
† At ti me of pr o gressi o n or at E O T if treat me nt is 
e n de d f or reas o n ot her t h a n pr o gressi o n. 
Ge netic testi n g 

I nc yte C or p orati o n 
Pa ge 1 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
2.  
I N T R O D U C TI O N 
2. 1.  
B ac k gr o u n d  
T he rece nt a d v a nces i n o nc ol o g y ha ve i m pr o ve d o ur u n dersta n di n g of t he r ole of ca n cer 
bi o mar kers a n d le d t o t he de vel o p me nt of i n n o vati ve dr u gs tar geti n g t he m olec ular pr ofile of 
patie nts. Ma n y tar gete d t hera pies are n o w i n cl u de d i n treat me nt g ui deli nes a n d ha ve s hifte d 
cli nical practice t o utilize ge n o mic i nf or mati o n as a n i nte gral c o m p o ne nt of cli nical 
decisi o n -ma ki n g. M olec ular alterati o ns i n s pecific ki nases ca n res ult i n c o nstit uti ve acti vit y a n d 
dri ve i nitiati o n a n d pr o gressi o n of ca ncer. Bi o mar ker -dri ve n treat me nts wit h tar gete d t hera pies 
are n o w sta n dar d of care i n certai n c a ncers ( N C C N 2 0 2 1 ). Pe mi gati ni b  is a n i n hi bit or of t he 
F G F R fa mil y of rece pt or t yr osi ne ki nases t hat is pr o p ose d f or t he treat me nt of G B M  or ot her 
rec urre nt gli o mas a n d gli o ne ur o n al a n d n e ur o nal t u m ors  wit h a n acti vati n g F G F R m utati o n or 
f usi o n/rearra n ge me nt. A berra nt si g nali n g t hr o u g h F G F R res ulti n g fr o m ge ne m utati o ns or 
c hr o m os o mal f usi o ns/rearra n ge m e nts has bee n d e m o nstrate d i n m ulti ple t y pes of h u ma n ca ncers . 
Fi br o blast gr o wt h fact or rece pt or si g na li n g c o ntri b utes t o t he de vel o p me nt of mali g na ncies b y 
pr o m oti n g t u m or cell pr oliferati o n, s ur vi val, mi grati o n, a n d a n gi o ge nesis . I nc yte is pr o p osi n g t o 
st u d y pe mi gati ni b  f or t he treat me nt of rec urre nt G B M  or  ot her rec urre nt gli o mas , circ u mscri b e d 
astr oc yt ic gli o mas , a n d gli o ne ur o nal a n d ne ur o nal t u m o rs, har b ori n g a n acti vati n g F G F R 
m utati o n or f usi o n/rearra n ge me nt.  
2. 1. 1.  
Fi br o bl ast Gr o wt h F act or Rece pt or I n hi biti o n i n O nc ol o g y  
T he ma m malia n F G F R fa mil y is c o m p ose d of 4 hi g hl y c o nser ve d rece pt ors ( F G F R 1, F G F R 2, 
F G F R 3, a n d F G F R 4) t hat ha ve a n e xtr acell ular li ga n d -bi n di n g d o mai n, a si n gle tra ns me m bra n e 
d o mai n, a n d a n i ntracell ular t yr osi ne ki nase d o mai n . Ei g htee n F G F  li ga n ds, di vi de d i nt o 
ca n o nical a n d h or m o nal F G Fs, bi n d t o F G F Rs le a di n g t o rece pt or di meri zati o n, acti vati o n of t he 
ki nase d o mai n, a n d tra ns p h os p h or ylati o n of t he rece pt ors  (Es wara k u m ar et al 2 0 0 5 ). S u bse q ue nt 
si g nal tra ns ducti o n occ urs t hr o u g h p h os p h or ylati o n of s u bstrate pr otei ns, s uc h as F G F R s u bstrate 
2, w hic h lea ds t o acti vati o n of t he R A S -mit o ge n – acti vate d pr otei n ki nas e a n d p h os p h oi n ositi de 
3 -ki nase – pr otei n ki nas e B pat h wa ys a n d of t he p h os p h oli pase Cγ t hat acti vates t he pr otei n ki nase 
C pat h wa y . I n s o me cell ular c o nte xt, si g nal tra ns d ucer a n d acti vat or of tra nscri pti o n pr otei ns are 
als o acti vate d b y F G F Rs . Si g nali n g t hr o u g h t he F G F -F G F R pat h wa y is ti g htl y c o ntr olle d t hr o u g h 
fee d bac k re g ulati o n. Mit o ge n -acti vate d pr otei n ki nase p h os p hatases a n d S pr o ut y pr otei ns are 
u pre g ulate d u p o n F G F R sti m ulati o n a n d a nta g o nize F G F -de pe n de nt acti vati o n of  e xtracell ular 
si g nal-re g ulate d ki nases. I n ma n y cases, F G F R pat h wa y acti vati o n pr o m otes cell pr oliferati o n, 
s ur vi val, a n d mi grati o n; h o we ver, cell ular c o nte xt pla ys a n i m p orta nt r ole, a n d i n certai n tiss ues, 
F G F R si g nali n g res ults i n gr o wt h arrest a n d cell ular differe ntiati o n ( Daile y et  al 2 0 0 5 ). 
I n a d ults, F G F-F G F R si g nali n g is i n v ol ve d i n a n gi o ge nesis d uri n g w o u n d heali n g . T he h or m o nal 
F G F li ga n ds c o ntri b ute t o re g ulati o n of meta b olic pat h wa ys i n v ol vi n g li pi d, gl uc ose, p h os p hate, 
a n d vita mi n D ( It o h 2 0 1 0). Ge netic d efects i n t he F G F 2 3 -si g nali n g pat h wa y lea d t o dis or dere d 
p h os p hate meta b olis m : l oss of f u ncti o n m utati o ns i n F G F 2 3 or its si g nali n g res ults i n rete nti o n of 
p h os p hate a n d tiss ue mi neralizi n g, w hile gai n of f u ncti o n m utati o ns i n t he F G F 2 3 p at h wa y 
ma nifests as h y p o p h os p h ate mic ric kets s y n dr o m e ( Farr o w a n d W hite 2 0 1 0 ). 

I nc yte C or p orati o n 
Pa ge 1 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
Str o n g ge netic a n d f u n cti o nal e vi de nce s u p p ort  t hat d ysre g ulati o n of F G F R ca n lea d t o t he 
esta blis h me nt a n d pr o gressi o n of ca ncer . Ge n etic alterati o ns i n F G F R 1 -3 h a ve bee n descri be d i n 
ma n y t u m or t y pes ( K ni g hts a n d C o o k 2 0 1 0 , T ur ner a n d Gr ose 2 0 1 0 ). T h es e i ncl u de acti vati n g 
m utati o ns, tra nsl ocati o ns, a n d ge ne a m plificati o n res ulti n g i n li ga n d -i n de pe n de nt, c o nstit uti ve 
acti vati o n of t he rece pt ors or a berra nt li ga n d -de p e n de nt si g nali n g t hr o u g h F G F Rs.  
A s u bsta ntial b o d y of e vi de nce s u p p orts t hat a ge n eticall y acti vate d F G F R pat h wa y se nsitizes 
F G F R -altere d ca n cer cells t o k n oc k d o w n or i n hi biti o n of t hese rece pt ors ( K u nii et al 2 0 0 8 , 
La m o nt et al 2 0 1 1 , Na ka m ura et al 2 0 1 5 , Qi n g  et al 2 0 0 9 , Sia et al 2 0 1 5 , Weiss et al 2 0 1 0 ). 
A  lar ge scree n of m ore t h a n 5 0 0 t u m or cell li nes wit h a selecti ve F G F R i n hi bit or de m o nstrate d 
t hat o nl y a s mall perce nt a ge ( 5. 9 %) of all cells were  se nsiti ve t o F G F R i n hi biti o n, a n d 
gr o wt h -s u p presse d cell li nes were hi g hl y e nric he d f or F G F R alterati o ns ( G ua g na n o et al 2 0 1 2 ). 
T hese res ults de m o nstrat e t hat F G F R i n hi bit ors are acti ve i n a tar gete d m a n ner a gai nst ca ncers 
wit h acti vate d F G F R pat h wa y . A n i m plicati o n of t hese data is t hat  selecti o n base d o n m olec ular-, 
ge netic -, or pr otei n-bas e d dia g n ostic tests f or s pecific F G F R alterati o ns i n t u m ors ma y be 
i m p orta nt f or i de ntif yi n g patie nts m ost li kel y t o be nefit fr o m a n F G F R i n hi bit or. 
A s ur ve y of 4 8 5 3 s oli d t u m ors i de ntifie d F G F R 1 -3 m u tati o ns or rearra n ge m e nts i n 2. 2 5 % of all 
t u m ors teste d (Helste n et al 2 0 1 6 ). A nal ysis of F G F R 1 -3 m utati o ns a n d rearra n ge m e nts i n 
T C G A 's data base ( N CI 2 0 1 9 ), de m o nstrated  t hat F G F R alterati o ns are n ot restricte d t o 1  t u m or 
t y pe b ut rat her br oa dl y distri b ute d acr oss a di verse ra n ge of t u m ors (see T a ble  5 ). I m p orta ntl y, 
precli nical a n d cli nical d ata s u p p ort t he use of F G F R i n hi bit ors i n F G F R -altere d cell li nes a n d 
t u m ors deri ve d fr o m a v ariet y of ca n cer t y p es, i ncl u di n g bla d der ca n cer, c h ola n giocarci n o ma, 
e n d o metrial ca n cer, a n d gli o ma a n d s q ua m o us l u n g ca ncer (P orta et al 2 0 1 7 ). 
T a ble  5 : 
T u m ors Wit h Fre q ue nc y > 1 % f or F G F R 1 -3 M ut ati o ns a n d Re arr a n ge me nts 
i n The C a ncer G en o me A tl as D at a b ase 
T u m or T y pe  
F G F R 1  
F G F R 2  
F G F R 3  
T ot al 
( %) 
M ut ati o n 
( %) 
F usi o n 
( %) 
M ut ati o n 
( %) 
F usi o n 
( %) 
M ut ati o n 
( %) 
F usi o n 
( %) 
Ur ot helial carci n o ma  
0  
0  
0. 7 5  
0  
1 2. 6 4  
3. 1 5  
1 6. 5 4  
C h ola n gi ocarci n o ma  
0  
0  
0  
1 3. 9  
0  
0  
1 3. 9  
E n d o metrial carci n o ma  
0  
0  
9. 6 8  
0. 1 8  
0  
0  
9. 8 6  
Gli o blast o ma m ultif or me  
0. 4 8  
0  
0  
0  
0. 4 8  
8. 6 2  
9. 5 8  
L u n g s q ua m o us cell carci n o ma  
0. 2 1  
0. 2  
1. 4 5  
0. 2  
1. 4 5  
1. 4  
4. 9 1  
Cer vical carci n o ma  
0  
0  
0. 5 1  
0  
0  
1. 9 7  
2. 4 8  
Re n al pa pillar y cell carci n o ma  
0  
0  
0  
0  
1. 4 1  
0. 6 8  
2. 0 9  
Rectal a d e n ocarci n o ma  
0  
0  
2. 0 1  
0  
0  
0  
2. 0 1  
Hea d a n d nec k s q ua m o us cell 
carci n o ma 
0  
0  
0  
0  
1. 1 4  
0. 7 6  
1. 9  
L o w -gra d e gli o ma  
0. 1 9  
0  
0  
0  
0  
1. 7 1  
1. 9  
Uteri ne carci n osarc o ma  
0  
0  
1. 7 5  
0  
0  
0  
1. 7 5  
Es o p ha g eal a de n ocarci n o ma  
0  
0. 5 4  
0  
0  
0  
1. 0 8  
1. 6 2  
St o mac h a d e n ocarci n o ma  
0. 2 5  
0  
0. 5  
0. 4 8  
0. 2 5  
0  
1. 4 8  
Pr ostate a d e n ocarci n o ma  
0  
0  
0  
1. 2  
0  
0. 2  
1. 4  

I nc yte C or p orati o n 
Pa ge 2 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  5 : 
T u m ors Wit h Fre q ue nc y > 1 % f or F G F R 1 -3 M ut ati o ns a n d Re arr a n ge me nts 
i n T he C a ncer Ge n o m e Atl as D at a b ase ( C o nti n ue d) 
T u m or T y pe  
F G F R 1  
F G F R 2  
F G F R 3  
T ot al 
( %) 
M ut ati o n 
( %) 
F usi o n 
( %) 
M ut ati o n 
( %) 
F usi o n 
( %) 
M ut ati o n 
( %) 
F usi o n 
( %) 
Breast (i n vasi ve) carci n o ma  
0  
0. 3 6  
0. 6  
0. 3 6  
0  
0  
1. 3 2  
A dre n oc ortical carci n o ma  
0  
0  
1. 1  
0  
0  
0  
1. 1  
P he o c hr o m oc yt o ma a n d 
para g a n gli o ma  
1. 0 9  
0  
0  
0  
0  
0  
1. 0 9  
C ol orectal a de n ocarci n o ma  
0. 2 7  
0  
0. 5 4  
0  
0. 2 7  
0  
1. 0 8  
S ki n c uta ne o us mela n o ma  
0. 2 1  
0  
0. 8 4  
0  
0  
0  
1. 0 5  
Base d o n t hese o bser vati o ns, a n F G F R i n hi bit or ma y be acti ve acr oss a variet y of t u m or t y pes, 
i ncl u di n g G B M s as well as ot her rec urre nt gli o mas , circ u mscri be d astr oc ytic gli o mas, a n d 
gli o ne ur o nal a n d ne ur o nal t u m ors  wit h acti vati n g m utati o ns a n d ge ne f usi o ns of F G F R 1 -3.  
2. 1. 2.  
Gli o bl ast o m a a n d Ce ntr al Ner v o us S yste m T u m ors  
Ce ntral ner v o us s yste m  t u m ors i ncl u de a di vers e set of pat h ol o gical e ntities a n d are a m o n g t he 
m ost let hal of all t y pes of ca ncers  (Ar dizz o n e et al 2 0 2 0 , Tila k et al  2 0 2 1 ). T he y are 
disti n g uis he d base d o n t heir ori gi n, wit h a first dis ti ncti o n i n "n o n -glial t u m ors " a n d "glial 
t u m ors." T he  latter are calle d gli o mas a n d are t he m ost c o m m o n of all C N S t u m ors, re pres e nti n g 
8 1 % of mali g na nt brai n t u m ors. A m o n g t he m ost c o m m o n gli o mas are a str oc yt o mas ( ori gi nati n g 
fr o m astr oc ytic cells) i ncl udi n g G B M , oli g o de n dr o gli o mas (fr o m oli g o de n dr o glial cells), a n d 
e pe n dy m o mas (fr o m e pe n d y mal cells) . Gli o blast o ma m ultif or me is t he m ost a g gressi ve pri mar y 
brai n t u m or a n d t he m ost fre q ue ntl y occ urri n g i n a d ults ( We n  et al 2 0 2 0 ). It acc o u nts f or t h e 
maj orit y of deat hs a m o n g patie nts wit h pri mar y brai n t u m ors. Alt h o u g h t here has b ee n pr o gress 
i n u n dersta n di n g t he bi ol o g y of t hese t u m ors, it has n ot res ulte d i n si g nifica nt i m pr o ve me nts i n 
t hera pies or o utc o m es f or patie nts. M ore t ha n t w o-t hir ds of a d ults dia g n ose d wit h G B M  will die 
wit hi n 2  years of dia g n osis a n d t he 5 -year O S  is o nl y 6. 8 %. 
C he m ot hera p y ma y be us ef ul i n s o me t y pes of brai n t u m ors  (Ar dizz o n e et al 2 0 2 0 ). A m o n g t he 
dr u gs m ost c o m m o nl y use d are al k ylati n g a ge nts s uc h as T M Z a n d dr u gs bel o n gi n g t o t he 
nitr os o ureas f a mil y s uc h as C C N U a n d B C N U . T h e c o m bi nati o n of dr u g t h era p y a n d 
ra di ot hera p y h as ofte n b ee n m ore effecti ve, a n d t h e c o m bi nati o n of C C N U , pr ocarb azi ne , a n d 
vi ncristi ne wit h  ra di ot hera p y has c o ntri b ute d t o pr ol o n ge d s ur vi val i n patie nts wit h l o w -gra de 
gli o mas.  
T he c or nerst o ne of G B M  treat me nt relies o n ma xi mal s ur gical res ecti o n of t he t u m or wit h 
c o nc urre nt c he m or a diati o n wit h T M Z f oll o we d b y a dj u v a nt T M Z f or a t ot al of 6 m o nt hs 
acc or di n g t o t he la n d m ar k trial b y St u p p et al ( 2 0 0 5 ). Me dia n O S i n well-selecte d patie nts i n 
cli nical trials is a p pr o xi matel y 1 5  t o 1 8 m o nt hs a n d 5 -year s ur vi val is less t ha n 1 0 %. 
Gli o blast o ma s i n varia bl y rec ur after a me dia n i nter val of less t ha n 7 m o nt hs (We n et  al 2 0 2 0 ), 
a n d t here is n o cl ear sta n dar d -of -care sal v a ge t hera p y. O nce G B M s rec ur, me dia n O S is 
esti mate d t o be 2 4  t o 4 4 wee ks . Beca use n o n e of t he sta n dar d-of -care treat me nts f or b ot h ne wl y 
dia g n ose d a n d rec urre nt G B M s are c urati ve, t he N C C N rec o m me n ds cli ni cal trials as t he 
preferre d o pti o n f or eli gi ble patie nts. Ot her o pti o ns i ncl u de s yste mic t hera p y , s uc h as T M Z 

I nc yte C or p orati o n 
Pa ge 2 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
rec halle n g e, nitr os o ureas, be vaciz um a b, reirra diati o n, a n d t u m or -treati n g fi el ds (i n t he 
U nite d  States), n o ne of w hic h ha ve bee n s h o w n t o pr ol o n g s ur vi val i n ra n d o mize d trials i n t his 
setti n g, or palliati ve care f or patie nts wit h p o or perf or ma nce stat us (We n  et al 2 0 2 0 ). 
C e ntral ner v o us s yste m  t u m ors ha ve pr o ve d c hall e n gi n g t o treat, lar gel y o wi n g t o t he bi ol o gical 
c haracteristics of t hes e ca ncers, w hic h ofte n li mit pr o gress. I n creasi n g k n o wle d ge o f t he 
m olec ular c h aracteristics of brai n t u m ors has,  h o we ver,  e n a ble d t he d efi niti o n of m ol ec ularl y 
disti nct s u b gr o u ps  wit hi n hist ol o gicall y si milar s u bsets of t u m or s a n d esta blis he d t he pr o g n ostic 
val ue of certai n bi o mar k ers  (Al da p e et al 2 0 1 9 ). T he W H O-C N S 5 hi g hli g ht s h o w t he prese n ce or 
a bse nce of a m utati o n i n t he I D H 1/ 2 ge n e, deleti o n of c hr o m os o me ar ms 1 p a n d 1 9 q 
( 1 p/ 1 9 q c o deleti o n), a n d m utati o ns i n t he T E R T pr o m oter ai d i n esta blis hi n g a s pecific 
hist o m olec ular s u bt y pe ( L o uis et al 2 0 2 1 ). I n a d diti o n, I D H– wil d -t y pe, diff use astr oc ytic t u m ors 
i n a d ults, w hic h als o c o ntai n 1  t o 3  ge netic para meters , T E R T pr o m oter m ut ati o n, E G F R ge ne 
a m plificati o n, a n d/ or c o m bi n ati o n of gai n o f c hr o m os o me 7 a n d l oss of c hr o m os o me 1 0 
( + 7/−1 0) , is s uffi cie nt t o classif y a t u m or as G B M, W H O G ra de 4 . Fi nall y, t he pre dicti ve r ole of 
M G M T met h ylati o n i n G B M is well k n o w n a n d has bee n de m o nstr ate d i n se veral st u dies  
(Tila k  et al 2 0 2 1, We n et  al 2 0 2 0 ). 
Ge n o mic pr ofili n g c o nti n ues t o a d va nce o ur u n dersta n di n g of t he m olec ular pat h o ge nesis of 
C N S  t u m ors, a n d t he i nte grati o n of m olec ular i nf or mati o n wit h cli nical data ma y f urt her i de ntif y 
o p p ort u nities f or t he de v el o p me nt of ge n o me -dir ecte d t hera pi es f or s u bsets of patie nts . It is well 
rec o g niz e d t hat defects r elate d t o c hr o m os o mal a n d ge n o mic alterati o ns pl a y a n i m p orta nt r ole i n 
t he u nc o ntr olle d gr o wt h of brai n c ells, i n v ol vi n g m ulti ple mec ha nis ms a n d pat h wa ys, i n w hic h 
F G F Rs als o c o ntri b ute ( Ar dizz o ne et al 2 0 2 0 , Ji me nez-Pas c ual et al 2 0 1 9 ). 
2. 1. 3.  
R ole of Fi br o bl ast Gr o wt h F act or Rece pt ors i n Gli o bl ast o m a a n d Ot her C e ntr al 
N er v o us S yste m  T u m ors  
Fi br o blast gr o wt h fact or rece pt o rs c o ntr ol ma n y bi ol o gical f u ncti o ns, i ncl u di n g cell pr oliferati o n, 
s ur vi val, a n d c yt os keletal re g ulati o n (Ji me nez-Pas c ual et al 2 0 1 9 ). Fi br o blast gr o wt h fact or 
rece pt or si g nali n g is i m p orta nt d uri n g e m br y o nal de vel o p me nt of t he C N S a n d as a s ur vi v al 
mec ha nis m f or a d ult ne ur o ns a n d astr oc yt es. F urt her m ore, F G F R si g nali n g was f o u n d t o pr o m ote 
self-re n e wal a n d fate s p ecificati o n of ne ur o nal ste m cells (Ji me nez-Pas c ual et al 2 0 1 9 ). 
Ge ne -e x pressi o n pr ofili n g a n d w h ole -g e n o me se q ue nci n g data i n dicate t hat a berrati o ns i n all 
4  F G F Rs are v aria bl y pr ese nt i n gli o mas, t he m ost c o m m o n t y pes of pri mar y C N S t u m ors. 
M utati o ns of F G F R 1 ha v e bee n re p orte d i n o ptic -pat h wa y pil oc ytic astr o c yt o mas 
(Ar dizz o n e  et al 2 0 2 0, Tris oli ni et  al 2 0 1 9 ). M o derate-t o-str o n g F G F R 3 e x pressi o n has bee n 
re p orte d i n pil oc ytic astr oc yt o mas (Le hti ne n et al 2 0 1 7 ). Ge ne-e x pressi o n a nal ysis of T C G A data 
( G B M 5 4 0) s h o we d a l ar ge heter o g e neit y of F G F R 1 -4 e x pressi o n acr oss p atie nts  wit h G B M . 
E x pressi o n of F G F R 1 i n creas es wit h W H O gra de i n astr oc yt o mas, a n d i ncrease d F G F R 1 le vels 
i n G B M are n ot d ue t o a m plificati o n of t he F G F R 1 ge ne (Ji me nez-Pasc u al et al 2 0 1 9 ). I n 
c o ntrast,  F G F R 2 e x pressi o n decreases wit h gli o ma gra de. E x pressi o n of F G F R 3 a n d F G F R 4 has 
als o bee n re p orte d i n i n v asi ve G B M.  
Fi br o blast gr o wt h fact or rece pt or  m utati o ns a n d a m plificati o ns are g e n erall y ver y l o w i n G B M 
( F G F R 1: 5 1/ 3 0 6 8 sa m ples, F G F R 2: 1 2/ 2 6 6 2  sa m ples, F G F R 3: 1 6/ 2 8 8 7  sa m ples, a n d 
F G F R 4:  9/ 2 4 5 6  sa m ples; Ji me nez-Pasc u al et al 2 0 1 9 ); h o we ver , F G F R passe n ger m utati o ns (i e, 
m utati o ns n ot pr o vi di n g a s ur vi val be nefit) ha ve n ot bee n f o u n d i n G B M, li kel y i n dicati n g t hat 

I nc yte C or p orati o n 
Pa ge 2 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
t he mai nte na nce of F G F R si g nali n g is i m p orta nt f or t he de vel o p me nt a n d/ or pr o gressi o n of 
G B M.  
I m p ort a ntl y, o nc o ge nic f usi o ns i n v ol vi n g F G F R 1 a n d F G F R 3 wit h t he T A C C ge ne, i n partic ular 
T A C C 3 a n d T A C C 1 ha ve als o bee n re p orte d i n G B M. T he f usi o n bet wee n F G F R 3 a n d T A C C 3 
ge nes, re p orte d i n a p pr o xi matel y 3 % of patie nts  wit h G B M , ge nerates a n o nc o ge nic F G F R 3 
f or m, w hic h c o ntri b ute s t o carci n o g e nic e v e nts cl osel y related t o G B M pr o gressi o n 
(Ar dizz o n e  et al 2 0 2 0). 
T he lar ge v aria bilit y i n t he de gree of e x pressi o n of t he 4  F G F Rs a n d t he variet y of ge n o mic 
alterati o ns hi g hli g ht t he heter o ge n eit y of C N S t u m ors as well as t he i m p orta nce of t he F G FR 
si g nali n g pat h wa y i n disease pr o gressi o n. It is, h o we ver, still u n k n o w n w het her i n di vi d ual 
F G F Rs a n d/ or is of or ms acti vate s pecific p at h wa ys a n d differe nt bi ol o gical as pects (e g, t u m or 
i nitiati o n, i n vasi o n, t hera p y resista nce). S mall-m olec ule F G F R i n hi bit ors ha ve bee n s h o w n t o be 
effecti ve at bl oc ki n g t u m or gr o wt h i n ca n cers w h ere F G F R f usi o ns a n d/ or rearra n ge me nts ha v e 
bee n dete cte d . A P hase 2  trial of i nfi grati ni b i n a d ult partici pa nt s wit h rec urre nt hi g h-gra de 
gli o mas f oll o wi n g fail ure of i nitial t hera p y t hat har b ore d F G F R 1 -T A C C 1 or F G F R 3 -T A C C 3 
f usi o ns; acti vati n g m utati o ns i n F G F R 1, -2 , or -3; or F G F R 1, -2, -3, or -4 a m plificati o n re p orte d 
a n O R R of 7. 7 % ( 9 5 % CI : 1. 0, 2 5. 1), a me dia n P F S of 1. 7 m o nt hs ( 9 5 % CI : 1. 1 , 2. 8) , a n d a 
me dia n O S of 6. 7 m o nt hs ( 9 5 %  CI : 4. 2 , 1 1. 7 ; Lass ma n et al 2 0 1 9 ). Preli mi nar y data fr o m t he 
o n g oi n g  P hase 2 st u d y I N C B 5 4 8 2 8 -2 0 7  ( data o n file) i n sec o n d-li ne or greater tr eat me nt i n all 
t u m or t y pes ha ve s h o w n pr o misi n g efficac y si g nals ( O R R, P F S) a n d t olera ble safet y i n 
partici pa nts wit h acti vati n g F G F R alterati o ns i n G B M  a n d ot her pri mar y C N S mali g na ncies . T he 
preli mi nar y res ults fr o m I N C B 5 4 8 2 8 -2 0 7 ( data o n file) , a bas k et st u d y, e nr olle d 7 partici pa nt s 
wit h hist ol o gic dia g n osi s of G B M har b ori n g F G F R 3-T A C C 3 f usi o ns. Of t he se 7 partici p a nt s, 
1  ac hie ve d a P R a n d has bee n o n  st u d y f or 5 7 3 d a ys. T w o ot her partici p a nts  ha d a B O R or S D o n  
st u d y f or 1 2 3 a n d 1 3 9 da ys at the ti me of t he last assess me nt . A partici pa nt  wit h a diff use 
astr oc yt o ma har b ori n g a n F G F R 1 K 6 5 6 E m utati o n ac hie ve d a B O R of P R o n  st u d y f or 2 5 8 da ys 
at t he ti me of t he last ass ess me nt.  
2. 2.  
St u d y R ati o n ale  
Des pite scie ntific a d v a nces, c urre nt C N S t u m or treat me nts ha ve n ot i m pr o ve d t he s ur vi val rat es 
of p atie nts. U n dersta n di n g of t he m olec ular bi ol o g y u n derl yi n g t he de vel o p me nt a n d pr o gressi o n 
of C N S t u m ors is i m pr o vi n g, h o we ver, tar gete d t h era pies h a ve bee n s h o w n t o ha ve li mite d 
effic ac y. T heref ore, t he i de ntificati o n of ge n o mic alterati o ns a n d m olec ular pat h wa ys i n v ol ve d i n 
C N S t u m or de vel o p me nt is a critical c o m p o ne nt of t he researc h i n ne ur o -o nc ol o g y. T he r ole of 
t he F G F R si g nali n g i n t he pr o gressi o n of gli o mas s u g gests t he great i m p ort a nce t o i de ntif y ne w 
dr u gs t o c o u nteract t u m or gr o wt h. Pe mi gati ni b  is a p ote nt selecti ve i n hi bit or of F G F R 1-3 t hat 
has de m o nstrate d  a ntit u m or acti vit y i n patie nts wit h c h ola n gi ocarci n o ma h ar b ori n g F G F R 2 
f usi o ns/rearra n ge me nts a n d has gai ne d re g ulat or y a p pr o val i n t he U nite d States a n d i n E ur o pe 
(Pe maz yre ®  2 0 2 1 a, Pe ma z yre 2 0 2 1 b ). T his c o m p o u n d is pr o p ose d f or t he treat me nt of 
partici pa nts wit h rec urre nt G B M  or ot her rec urre nt gli o mas , circ u mscri be d astr oc ytic gli o mas , 
a n d gli o ne ur o nal a n d n e ur o nal t u m ors, h ar b ori n g a n acti vati n g F G F R 1 -3  m utat i o n or 
f usi o n/rearra n ge me nt. 

I nc yte C or p orati o n 
Pa ge 2 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
2. 2. 1.  
Scie ntific R ati o n ale f or St u d y Desi g n  
T his st u d y has bee n desi g ne d t o e val uate t h e efficac y a n d safet y of p e mi gati ni b  i n partici pa nts 
wit h rec urre nt gli o mas  i ncl u di n g G B M, circ u mscribe d astr oc ytic gli o mas , a n d gli o ne ur o n al a n d 
ne ur o n al t u m ors har b ori n g a n acti vati n g  F G F R 1 -3 m utati o n or f usi o n/rearra n ge me nt . B ot h 
treat me nt c o h orts i ncl u de t he F G F R 1-3 ge n o mic alterati o ns t hat are k n o w n or e x pect e d t o be 
pre dicti ve of res p o nse t o treat me nt wit h pe mi gati ni b. T he patie nt p o p ulati o n selecte d f or t his trial 
i ncl u des partici pa nts  wit h rec urre nt gli o mas  i ncl u di n g G B M; circ u mscri be d astr oc ytic gli o mas,  
a n d gli o ne ur o nal  a n d n e ur o n al t u m ors. T he F G F R ge n o mic alterati o ns selecte d i n t his trial will 
be pr os pecti vel y e val uate d  f or cli nical r ele va n ce i n partici pa nt s i n b ot h c o h orts. As scie nce a n d 
i nf or mati o n e v ol ves, t he Pr ot oc ol  ma y be a me n de d t o i ncl u d e t he detecti o n of n o vel m olec ular 
alterati o ns or differe nt v aria nts of a n e xisti n g ge n o mic alterati o n . 
T he pr o p ose d st u d y desi g n is si n gle -ar m a n d o pe n -la bel st u d y ai mi n g t o s h o w t hat pe mi gati ni b  
pr o vi des be neficial i m pr o ve me nt of o utc o me i n t he s u bset of partici p a nts  har b ori n g defi n e d 
F G F R g e n o mic alterati o ns. T he si n gle-ar m desi g n is a l o wer ris k a p pr oac h, as efficac y rates i n 
t his patie nt p o p ulati o n i n past st u dies have  bee n l ess t ha n 1 5 % o n a vera ge , a n d n o a p pr o ve d 
c o m parat or e x ists f or rec urre nt G B M  at t his p oi nt . A n i n de pe n de nt , ce ntral ra di ol o g y gr o u p will 
e val uate t u m or res p o nse t o s u p p ort t he pri mar y a n d sec o n dar y e n d p oi nts t o mi ni mize bias.  
2. 2. 2.  
J ustific ati o n f or D ose  
Pe mi gati ni b  has bee n st u die d usi n g a n i nter mitte nt d os e re gi me n ( 2 wee ks o n  treat me nt a n d 
1  wee k off  treat me nt) as well as a c o nti n u o us d os e re gi me n  ( n o treat me nt br ea k). Data fr o m 
se veral st u dies wit h pe mi gati ni b  utilizi n g b ot h treat me nt re gi me ns ha ve  s h ow n a t olera ble s afet y 
pr ofile, c o nfir m e d efficac y i n c h ola n gi ocarci n o m a wit h F G F R 2 rearra n g e me nts 
(Pe maz yre  2 0 2 1a , Pe ma z yre 2 0 2 1 b ), a n d effi cac y si g nals i n ot her t u m or t y pes t hat ha ve 
acti vati n g F G F R alterati o ns  (refer t o t he I B f or a d diti o nal details). 
T his st u d y will utilize t he i nter mitte nt d os e re gi me n ( 2 wee ks o n tr eat me nt a n d 1 wee k off 
treat me nt), w hic h was r ec o m me n de d base d o n s afet y, P K , a n d preli mi nar y si g nals of cli nical 
be nefit a n d has b ee n s h o w n t o ha ve effic ac y i n c h ola n gi ocarci n o ma. T his d os e re gi me n will 
all o w a m ore fa v ora bl e s afet y pr ofile wit h a 1 -wee k i nter val t o all o w t o xicities t o rec o ver a n d 
a v oi d c u m ulati ve t o xicities.  
2. 3.  
Be nefit/ Ris k Assess me nt  
Tar gete d t h era pies wit h a ma na gea bl e safet y pr ofil e t hat ca n pr o vi d e a d ura ble res p o nse or 
si g nifica nt disease c o ntr ol i n a m olec ularl y defi ne d p o p ulati o n w o ul d pr o vi de a mea ni n gf ul 
cli nical be nefit.  T o dat e, pe mi gati ni b has bee n a d mi nistere d t o o ver 9 0 0 patie nts acr oss 
7  I n c yte-s p o ns or e d cli nic al trials a n d c o m merciall y (Pe maz yre  2 0 2 1a , Pe m az yre 2 0 2 1 b ); it has 
a n esta blis he d cli nical b e nefit i n c h ola n gi ocarci n o ma as well as a r o b ust safet y pr ofile. I n a n 
earlier cli nical trial ( St u d y I N C B 5 4 8 2 8 -2 0 7), pe mi gati ni b was teste d i n se veral p artici pa nts wit h 
G B M a n d s h o we d a fa v ora ble ris k/ be nefit rati o f or f urt her de vel o p me nt i n t his p o p ulatio n.  
T he m ost fre q ue ntl y re p orte d T E A E s ass o ciate d wit h pe mi gati ni b use i ncl u des H P , nail t o xicit y, 
a n d h y p o p h os p hate mia. Rare b ut si g nifica nt A E s ass ociate d wit h pe mi gati ni b use i ncl u de S R D  
a n d s oft tiss ue mi neralizati o n i ncl u di n g calci n osis a n d calci p h yla xis.  

I nc yte C or p orati o n 
Pa ge 2 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
O verall, t he effic ac y a n d safet y data fr o m t he pe mi gati ni b cli nical de vel o p me nt pr o gra m t o date 
s h o w a fa v ora ble b e nefit/ris k rati o f or pe mi gati ni b treat me nt i n patie nts wit h F G F R 2 rearra n g e d 
s oli d t u m ors. 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d  e x pecte d be n efits a n d ris ks a n d reas o n a bl y 
e x pecte d A E s of pe mi gati ni b ma y be f o u n d i n t he I B. 
3.  
O B J E C TI V E S A N D E N D P OI N T S  
Ta ble  6  pres e nts t he o bje cti ves a n d e n d p oi nts.  
T a ble  6 : 
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 deter mi ne t he efficac y of pe mi gati ni b i n 
part ici pa nts wit h rec urre nt G B M  wit h a n 
acti vati n g F G F R 1 -3 m utati o n or 
f usi o n/rearra n ge me nt. 
•  O R R i n C o h ort A, defi ne d as t he pr o p orti o n of 
partici pa nts i n C o h ort A w h o ac hie ve a B O R 
of C R or P R base d o n R A N O as deter mi ne d b y 
a n I C R. 
Sec o n d ar y  
T o deter mi ne t he efficac y of pe mi gati ni b i n 
partici pa nts wit h rec urre nt G B M  or ot her 
rec urre nt gli o mas, circ u mscri be d astr oc ytic 
gli o mas , a n d gli o ne ur o n al a n d ne ur o nal t u m ors  
w it h a n acti vati n g F G F R 1-3 m utati o n or 
f usi o n/rearra n ge me nt. 
•  O R R i n C o h ort B, defi ne d as t he pr o p orti o n of 
partici pa nts i n C o h ort B w h o ac hie ve a B O R 
of C R or P R base d o n R A N O as deter mi ne d b y 
a n I C R. 
•  O R R i n C o h orts A a n d B c o m bi ne d, defi ne d as 
t he pr o p orti o n of partici pa nts i n C o h orts A a n d 
B w h o ac hie ve a B O R of C R or P R base d o n 
R A N O as deter mi ne d b y a n I C R.  
•  D O R i n C o h orts A a n d B, res pecti vel y, 
defi ne d as t he ti me fr o m first assess me nt of 
C R or P R u ntil pr o gressi ve disease (acc or di n g 
t o R A N O a n d assesse d b y a n I C R) or deat h 
( w hic he ver occ urs first). 
•  O R R i n eac h c o h ort as deter mi n e d b y 
i n vesti gat or assess me nt. 
•  D C R i n C o h orts A a n d B, res pecti vel y, 
descri be d as t he pr o p orti o n of partici pa nts w h o 
ac hie ve a C R, P R, or S D as assesse d b y I C R. 
•  P F S i n C o h orts A a n d B, res pecti vel y, defi ne d 
as t he ti me fr o m first d ose u ntil pr o gressi ve 
dis ease (acc or di n g t o R A N O a n d assesse d b y 
a n I C R) or deat h ( w hic he ver occ urs first).  
•  O S i n C o h orts A a n d B, res pecti vel y, defi ne d 
as t he ti me fr o m first d ose of st u d y dr u g t o 
deat h d ue t o a n y ca use. 

I nc yte C or p orati o n 
Pa ge 2 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  6 : 
O bjecti ves a n d E n d p oi nts  ( C o nti n ue d) 
O bjecti ves  
E n d p oi nts  
Sec o n d ar y  ( C o nti n ue d) 
T o deter mi ne t he safet y a n d t olera bilit y of 
pe mi gati ni b i n partici pa nts wit h rec urre nt G B M  or 
ot her rec urre nt gli o mas, circ u mscri be d astr oc ytic 
gli o mas , a n d gli o ne ur o n al a n d ne ur o nal  t u m ors wit h 
a n acti vati n g F G F R 1 -3 m utati o n or 
f usi o n/rearra n ge me nt. 
•  Safet y a n d t olera bilit y i n eac h c o h ort, assesse d b y 
m o nit ori n g t he fre q ue nc y a n d se verit y of A Es b y 
perf or mi n g p h ysical e xa mi nati o ns, e val uati n g 
c ha n ges i n vital si g ns a n d E C Gs, a n d e val uati n g 
cli nical la b orat or y bl o o d sa m ples acc or di n g t o N CI 
C T C A E v 5. 0.  
•  I m pact o n -st u d y treat me nt, assesse d b y m o nit ori n g 
t he fre q ue nc y of treat me nt i nterr u pti o ns, d ose 
re d ucti o ns, a n d wit h dra wal of st u d y treat me nt d ue t o 
A Es.  
E x pl or at or y  

I nc yte C or p orati o n 
Pa ge 2 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
4.  
S T U D Y D E SI G N  
4. 1.  
O ver all Desi g n  
T his is a n o pe n -la bel, m o n ot hera p y st u d y of pe mi gati ni b  i n partici pa nts wit h rec urre nt G B M  or 
ot her gli o mas , circ u mscri be d astr oc ytic gli o mas , a n d gli o ne ur o n al a n d ne ur o nal t u m ors t hat ha ve 
rec urre d wit h a n acti vati n g F G F R 1 -3 m utati o n or f usi o n/rearra n ge me nt. T his st u d y c o n sists of 2  
c o h orts, C o h orts A a n d B, a n d will e nr oll a p pr o xi matel y 8 2  partici pa nts  i n C o h ort A a n d u p t o 8 2 
partici pa nts i n C o h ort  B . Partici pa nts will recei ve pe mi gati ni b  1 3. 5  m g  Q D  o n a 2 -wee k  o n -
t hera p y a n d 1-wee k  off -t hera p y sc h e d ule as l o n g as t he y are recei vi n g be n efit a n d ha ve n ot met 
a n y criteri a f or st u d y wit h dra wal ( s ee Secti o n 7 ). Partici pa nts wit h l ocal la b orat or y test res ults 
(tiss ue is preferre d  b ut pl as ma -base d m olec ular assa ys ma y be acce pt e d aft er disc ussi o n wit h t he 
me dical m o nit or) d oc u m e nti n g a n acti vati n g F G F R 1, F G F R 2, or F G F R 3 m utati o n or ge ne 
f usi o n/rearra n ge me nt are eli gi ble t o e nr oll as l o n g as t he res ults meet t he c o h ort criteria (see 
A p pe n di x  B  f or list of eli gi ble alterati o ns) . Partici pa nts will be re q uire d t o ha ve a d o c u me nte d 
F G F R 1 -3 re arra n ge me nt or acti o na ble m utati o n fr o m t u m or tiss ue  or plas ma  as deter mi ne d b y a 
l ocall y q ualifie d la b orat or y e m pl o yi n g a m olec ular assa y ha vi n g a rele va nt mar k of c o nf or mit y 
f or a nal ytic al perf or ma nce (e g, C LI A [ U S] or U K C A, C E, C E U K NI, or ot hers [ o utsi de of t he 
U S]) or a c o m mercial re p ort fr o m t he ce ntral la b orat or y t o be eli gi ble.  C o nfir mat or y testi n g 
t hr o u g h t he s p o ns or-desi g nate d ce ntr al ge n o mics la b orat or y will be perf or me d f or partici p a nts; 
h o we ver, res ults fr o m t he ce ntral ge n o mics l a b orat or y are n ot r e q uire d b ef ore e nr oll me nt . 
Testi n g f or I D H m utati o n stat us a n d M G M T pr o m oter met h ylati o n stat us is re q uire d f or all 
partici pa nts if n ot a vaila ble pri or t o scree ni n g. F or partici pa nt s wit h astr oc ytic gli o ma s, testi n g 
f or E G F R a m plificati o ns a n d/ or w h ole c hr o m os o me 7  gai n a n d w h ole c hr o m os o me 1 0 l oss  a n d/ or 
T E R T  p r o m oter m utati o ns s h o ul d be perf or m e d  t o esta blis h t he dia g n osis of G B M. Testi n g f or 
c hr o m os o me 1 p/ 1 9 q c o d eleti o n s h o ul d be perf or me d f or all partici p a nts wit h oli g o de n dr o gli o mas 
if n ot a vaila ble pri or t o s cree ni n g. Partici pa nt s w h o ha ve a c o m mercial re p ort at scree ni n g fr o m 
t he s p o ns or-desi g nate d ce ntral la b orat or y will n ot nee d t o ha ve  a sa m ple se nt f or c o nfir mat or y. 
P artici pa nts will  be assi g ne d t o a c o h ort  as f oll o ws : 
•  C o h ort A: Partici pa nts wit h hist o pat h ol o gicall y pr o ve n, W H O Gra d e 4, I DH −wil d -
t y pe G B M O R m olec ular dia g n osis of I D H -wil d -t y pe, diff use astr oc ytic gli o ma wit h 
m olec ular feat ures of Gra de 4 G B M per W H O 2 0 2 1 (astr oc ytic gli o m a re q uires 
prese nce of eit her a m plificati o n of E G F R, w h ole c hr o m os o me 7 gai n a n d w h ole 
c hr o m os o me 1 0 l oss, or T E R T pr o m oter m utati o n; L o uis et al 2 0 2 1 ) t hat is rec urre nt, 
har b ori n g F G F R 1 -3 f usi o ns  or ot her rearra n ge me nts ( F G F R 1-3 i n -fra me f usi o ns, a n y 
F G F R 2 rearra n g e me nt, or F G F R 1/ 3 rearra n g e me nt wit h k n o w n part ner) or wit h a 
defi ne d F G F R 1 -3 acti vati n g m utati o n or i n -fra me deleti o n (see A p pe n di x  B ). O nl y 
partici pa nts wit h F G F R f usi o ns  or rearra n ge m e nts wit h a n i ntact ki nase d o mai n ( see 
A p pe n di x  B ) are eli gi ble ( n = 8 2). 
•  C o h ort B: Partici pa nts wit h ot her hist o pat h ol o gicall y pr o ve n, per W H O criteria 
(L o uis et al 2 0 2 1 ), gli o mas  ot her t ha n G B M (e g, I D H-m uta nt astr oc yt o ma, I D H -
m uta nt a n d 1 p/ 1 9 q c o del ete d oli g o de n dr o gli o ma), circ u mscri be d astr oc ytic gli o mas , 
a n d gli o ne ur o nal a n d n e ur o nal t u m ors  t hat are rec urre nt, har b ori n g F G F R 1-3 f usi o ns  
or ot her rearra n ge me nts ( F G F R 1-3 i n -fra me f usi o ns, a n y F G F R 2 rearran ge me nt, 
F G F R 1/ 3 r earra n ge m e nt wit h k n o w n part ner) or wit h a defi ne d F G F R 1 -3 acti vati n g 

I nc yte C or p orati o n 
Pa ge 2 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
m utati o n or i n -fra me d eleti o n (see A p pe n di x  B ). O nl y F G F R f usi o ns or 
rearra n ge m e nts wit h a n i ntact ki nase d o mai n (see A p pe n di x  B ) are eli gi ble 
( n =  u p  t o 8 2).  
Partici pa nts wit h k n o w n F G F R  resistan ce m utati o ns are n ot eli gi ble.  
T here is n o differe n ce i n t he treat me nt re gi me n b et wee n t he c o h orts . 
Treat me nt will start o n Da y 1 . Partici pa nts will u n der g o re g ul ar safet y a n d efficac y ass ess me nts 
d uri n g treat me nt . Partici pa nts ca n c o nti n ue st u d y dr u g a d ministrati o n i n 2 1 -da y c ycl es u ntil 
d oc u me nte d diseas e pr o gressi o n or u nacce pta bl e t o xicit y is re p orte d  (see criteria f or st u d y dr u g 
disc o nti n uati o n i n Secti o n  7. 1 ). F or partici pa nts e x hi biti n g  disease pr o gressi o n base d o n l ocal 
ra di ol o gic re vie w, treat m e nt s h o ul d n ot be disc o nti n ue d u ntil c o nfir mati o n  b y t he I C R u nless t he 
pri nci pal i n vesti gat or belie ve s it is i n t he best i nterest of t he partici pa nt t o disc o nti n ue treat me nt 
bef ore recei vi n g c o nfir m ati o n . A f utilit y a nal ysis is pla n ne d f or C o h ort A w he n a p pr o xi matel y 
2 5  partici pa nts are e val u a ble i n t his c o h ort. C o h ort  A  ca n be cl ose d if  t he pre s pecifi e d mi ni mal 
n u m ber of res p o n d ers is n ot ac hie ve d f or t hat c o h ort. Detaile d i nf or mati o n is descri be d i n 
Secti o n  1 0. 5 . 
4. 2.  
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 partici pa nt si g ns t he st u d y I C F . 
T he st u d y will i ncl u de u p t o 2 8  da ys f or scree ni n g, 2 wee ks o n a n d 1 wee k off  treat me nt i n 
c o nsec uti ve 2 1 -d a y c y cles as l o n g as partici pa nts are recei vi n g be n efit a n d h a ve n ot met a n y 
criteria f or st u d y wit h dra wal, a n d 2 8  ( m ust be a mi ni m u m of 2 8 da ys) t o 3 0 da ys f or f oll o w -u p 
after t he l ast d ose of st u d y dr u g . It is esti mate d t hat a n i n di vi d ual will partici pate f or 
a p pr o xi matel y 3  m o nt hs.  
A partici pa nt is c o nsi dere d t o ha ve c o m plet e d t he st u d y if he/s h e has c o m plete d all parts of t he 
st u d y i ncl u di n g t he last visit. A st u d y is c o nsi dere d c o m plete d w he n t he l ast partici pa nt last visit 
has occ urre d.  
If t here h a ve b ee n ≤ 3 partici pa nts o n st u d y f or m ore t ha n 6 m o nt hs, a data base l oc k of t he st u d y 
ma y occ ur , a n d t he st u d y ma y be c o nsi dere d c o m plete d t o all o w t he a nal ysis of t he st u d y data. 
A n y re mai ni n g partici p a nts ma y c o nti n ue t o recei ve st u d y treat me nt a n d be see n b y t he 
i n vesti gat or per us ual sta n dar d of care f or t his p o p ulati o n. T he i n vesti gat or will be e x pecte d t o 
m o nit or f or a n d re p ort a n y S A Es, a n d pre g na n cies as detaile d i n Secti o n  9 . T he  re mai ni n g 
partici pa nts are c o nsi dere d t o be o n st u d y u ntil a disc o nti n uati o n criteri o n is met.  
T he e n d of t he st u d y will occ ur w h e n all partici p a nts ha ve bee n f oll o we d f or at least 1 year after 
t he i nitiati o n of st u d y treat me nt, deat h, or wit h dra wal of  c onse nt, w hi c he ver occ urs first. 
4. 3.  
St u d y Ter mi n ati o n  
T he i n vesti gat or ret ai 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 h e i n vesti gat or/ hea d of t h e st u d y site (Ja pa n) is t o n otif y 
t he I R B/IE 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 ne e, 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. 

I nc yte C or p orati o n 
Pa ge 2 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T he s p o ns or ma y ter mi nate t he st u d y electi vel y, if  nee de d . Reas o ns t ha t t he st u d y ma y be 
ter mi nate d c o ul d i ncl u de: 
•  S afet y c o ncer ns wit h pe mi gati ni b (st u d y dr u g) d uri n g t he st u d y or i n ot her o n g oi n g 
st u dies 
•  D e vel o p me nt of pe mi gati ni b is ter mi nate d  
•  S t u d y e nr oll me nt is e xtre mel y sl o w ma ki n g c o m pleti o n of t he st u d y wit hi n acce pt a ble 
ti me fra me u nli kel y 
•  C lear e vi de n ce of lac k of efficac y i n t he patie nt p o p ulati o n bei n g st u die d  
•  U p o n re q uest of c o m pete nt a ut h orities 
•  O t her u nf oresee n circ u msta nces  
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/ hea d of t he st u d y 
site (Ja pa n), t he I R Bs a n d I E Cs, 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 . F or Ja p a n, t he decisi o n fr o m t he s p o ns or will be via t he hea d of t he st u d y site(s) 
w h o will n otif y t he i n vesti gat ors a n d t he I R Bs o f 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. 

I nc yte C or p orati o n 
Pa ge 2 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
5.  
S T U D Y P O P U L A TI O N  
De viati o ns fr o m eli gi bilit y criteria are n ot all o w e d beca use t h e y ca n p ot e ntiall y je o par dize t h e 
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 partici pa nt safet y . T heref ore, 
a d here n ce t o t he criteria as s pecifie d i n t he Pr ot oc ol  is esse ntial. Pr os pecti ve a p pr o val of Pr ot oc ol  
de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n as Pr ot oc ol  wai vers or e xe m pti o ns, 
are n ot per mitte d.  
5. 1.  
I ncl usio n Criteri a  
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y:  
1.  A bilit y t o c o m pre he n d a n d willi n g ness t o si g n a writte n I C F f or t he st u d y.  A le gall y 
a ut h orize d re pres e ntati ve ca n si g n t he state me nt of i nf or me d  c o nse nt f or t he partici pa nt.  
F or  G er ma n y  a n d Fra nce : O nl y partici pa nts w h o ca n pr o vi de t heir o w n c o nse nt are a ble 
t o partici pate i n t his cli nical st u d y. 
2.  P artici pa nts a ge d 1 8 years  or ol der  at t he ti me of si g ni n g t he I C F.  
3.  Hist ol o gical , c yt ol o gical , or m ole c ular c o nfir m ati o n of rec urre nt G B M  or ot her  gli o ma s, 
circ u mscri be d a str oc ytic gli o mas , a n d gli o ne ur o nal or ne ur o nal t u m ors  t hat ha ve  
rec urre d. 
a. F or C o h ort A: Pri or , hist o pat h ol o gicall y pr o ve n, W H O Gra de 4,  I DH −wil d -t y pe 
G B M  O R m olec ular dia g n osis of I D H -wil d -t y pe, diff use astr oc ytic gli o ma wit h 
m olec ular feat ures of Gra de 4 G B M per W H O 2 0 2 1 (astr oc ytic gli o ma re q uires 
prese nce of eit her a m plificati o n of E G F R, w h ole c hr o m os o me 7 gai n a n d w h ole 
c hr o m os o me  1 0 l oss , or T E R T pr o m oter m utati o n ; L o uis et al 2 0 2 1 ) t hat has rec urre d 
or pr o gress e d o n or after treat me nt wit h at least 1  li ne of sta n dar d-of -care t hera p y . 
b.  F or C o h ort  B : Pri or , hist o pat h ol o gicall y pr o ve n, per W H O criteri a ( L o uis et al 2 0 2 1 ), 
gli o mas  ot her t ha n G B M (e g, I D H-m uta nt astr oc yt o ma, I D H -m uta nt a n d 1 p/ 1 9 q 
c o delete d oli g o de n dr o gli o ma), circ u mscri be d astr oc ytic gli o mas , a n d gli o ne ur o nal 
a n d ne ur o nal t u m ors  t hat are rec urre nt or h a ve p r o gresse d o n or after at least 1  li ne of 
sta n dar d-of -care t hera p y (eg,  ra di ot hera p y a n d/ or treat me nt wit h a n al k ylati n g 
c he m ot hera p y s u c h as T M Z , C C N U , or B C N U -c o ntai ni n g c he m ot hera p y) . 
4.  Ra di o gra p hicall y meas ura ble disease ( per  R A N O ; We n et al 2 0 1 0 ). T u m or lesi o ns 
l ocate d i n a pre vi o usl y irra diate d area, or i n a n area s u bjecte d t o ot her l o c o -re gi o nal 
t hera p y, are c o nsi dere d meas ura ble if pr o gressi o n has bee n cl earl y d e m o nstrate d i n t he 
lesi o n. 
5.  Kar n ofs k y p erf or m a nce stat us ≥ 6 0.  
6.  Life e x pecta nc y ≥ 1 2 w ee ks.  
7.  D oc u me ntati o n of a n acti o na ble F G F R 1 -3 ge n e alt erati o n (defi ne d m utati o ns, ge ne 
f usi o n/rearra n ge me nts, or i n-fra m e deleti o ns; see A p pe n di x  B ) fr o m tiss ue or cf D N A 
fr o m a q ualifie d la b orat or y s uc h as F MI or G u ar da nt Healt h  ma y be acce pt a ble after 
re vie w b y me dical m o nit or; see Secti o n  4. 1  a n d A p pe n di x  B ). Partici pa nts wit h k n o w n 
F G F R resista nce m utati o ns are n ot eli gi ble.  

I nc yte C or p orati o n 
Pa ge 3 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
a. C o h ort A : Partici pa nts wit h hist o pat h ol o gicall y pr o ve n, W H O Gra d e 4 , 
I DH −wil d -t y pe G B M O R m olec ular dia g n osis of I D H -wil d -t y pe, diff use astr oc ytic 
gli o ma wit h m olec ular feat ures of Gra de 4 G B M per W H O 2 0 2 1 (astr o c ytic gli o ma 
re q uires pr ese nce of eit her a m plificati o n of E G F R, w h ole c hr o m os o me 7 gai n a n d 
w h ole c hr o m os o me 1 0 l oss, or T E R T pr o m oter m utati o n; L o uis et al 2 0 2 1 ) t hat are 
rec urre nt, har b ori n g F G F R 1 -3 f usi o ns / or ot her rearra n ge m e nts ( F G F R 1-3 i n -fra me 
f usi o ns, a n y F G F R 2 rearra n ge me nt, or F G F R 1/ 3 rearra n ge me nt wit h k n o w n part ner) 
or wit h a defi ne d F G F R 1 -3 acti vati n g m utati o n or i n -fra me deleti o n (see 
A p pe n di x  B ). O nl y partici pa nts wit h F G F R f usi o ns  or rearra n g e me nts wit h a n i ntact 
ki nase d o mai n ( see A p pe n di x  B ) are eli gi ble. 
b.  C o h ort B : Partici pa nts wit h ot her hist o pat h ol o gicall y pr o ve n, per W H O criteria 
(L o uis et al 2 0 2 1 ), gli o mas  ot her t ha n G B M (e g, I D H-m uta nt astr oc yt o ma, I D H -
m uta nt a n d 1 p/ 1 9 q c o del ete d oli g o de n dr o gli o ma), circ u mscri be d astr oc ytic gli o mas , 
a n d gli o ne ur o nal a n d n e ur o nal t u m ors  t hat are rec urre nt, har b ori ng F G F R 1 -3 
f usi o ns/or ot her rearra n g e me nts ( F G F R 1-3 i n -fra me f usi o ns, a n y F G F R 2 
rearra n ge m e nt, F G F R 1/ 3 rearra n ge m e nt wit h k n o w n part ner) or wit h a defi ne d 
F G F R 1 -3 acti vati n g m utati o n or i n -fra m e deleti o n (see A p pe n di x  B ). O nl y F G F R 
f usi o ns or rearra n g e me nts wit h a n i ntact ki nase d o mai n (see A p pe n di x  B ) are eli gi ble. 
8.  M RI -d o c u me nte d o bje cti ve pr o gressi o n  after pri or t hera p y  a n d m ust ha ve n o t hera p y 
a vaila ble t hat is li kel y t o pr o vi de cli nical be nefit . A n i nter val of at least 1 2  wee ks after 
pri or ra di ot hera p y is re q uire d u nless t here is eit her hist o pat h ol o gical c o nfir mati o n of 
rec urre nt t u m or or ne w e n ha nce me nt o n M RI o utsi de t he ra di ot hera p y fiel d. Partici pa nts 
w h o are i nt olera nt of  or u ns uita ble f or t he a p pr o ve d t hera p y, i n t he o pi ni o n of t he 
i n vesti gat or, are eli gi ble o nl y if t he y ha ve n o t he ra p y a vaila ble t hat is li kel y t o pr o vi de 
cli nical be nefit.  
9.  M ost rece nt arc hi val t u m or s peci me n  m ust be a t u m or bl oc k or a mi ni m u m of 
1 5  u nstai ne d sli des fr o m bi o ps y or resecti o n of pri mar y t u m or or metastasis.  
1 0.  Willi n g ness t o a v oi d pre g na nc y or fat heri n g c h il dre n base d o n t h e criteria bel o w. 
a. Male partici pa nts wit h re pr o d ucti ve p ote ntial m ust a gree t o ta k e a p pr o priate 
preca uti o ns t o a v oi d f at heri n g c hil dre n fr o m scree ni n g t hr o u g h 9 0 da ys (a 
s per mat o ge nesis c y cle) after t he last d ose of st u d y dr u g a n d m ust ref rai n fr o m 
d o nati n g s per m d uri n g t his peri o d . Per mitte d met h o ds 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 parti ci pa nts a n d t heir u n dersta n di n g 
c o nfir me d.  
b.  Fe male p artici pa nts w h o are W O C B P m ust ha ve a ne gati ve ser u m pre g na n c y test at 
scree ni n g a n d a ne g ati ve uri ne pre g n a nc y test  bef ore t he first d ose o n Da y 1 a n d m ust 
a gree t o ta k e a p pr o priate preca uti o ns t o a v oi d pr e g na nc y fr o m scree ni n g t hr o u g h 
3 0  da ys ( 1  me nstr ual c y cle) after t he last d ose of st u d y pe mi gati ni b  a n d m ust refrai n 
fr o m d o nati n g o oc ytes d uri n g t his peri o d. Per mitt e d met h o ds i n pre ve nti n g pre g na nc y 
(see A p p e n di x  A ) s h o ul d be c o m m u nicate d t o t he partici pa nts a n d t heir u n d ersta n di n g 
c o nfir me d.  
c. A fe male p artici pa nt n ot c o nsi dere d t o be of c hil d beari n g p ote ntial as d efi n e d i n 
A p pe n di x  A  is eli gi ble. 

I nc yte C or p orati o n 
Pa ge 3 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
5. 2.  
E xcl usi o n Criteri a  
Partici pa nts are e xcl u d e d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
1.  Pri or recei pt of a n  F G F R i n hi bit or.  
2.  Recei pt of a ntica n cer me dicati o ns or i n vesti gati o nal dr u gs f or a n y i n dicati o n or reas o n 
wit hi n 2 8  da ys bef ore first d ose of st u d y dr u g. Partici pa nts m ust ha ve rec o v ere d 
( ≤ Gra de  1 as per C T C A E v 5. 0 or at pretr eat me nt baseli ne) fr o m A Es fr o m pre vi o usl y 
a d mi nistere d t hera pi es (e xcl u di n g al o pecia).  
3.  Partici pa nts ma y ha ve h a d treat me nt f or a n u nli mite d n u m ber of pri or rela pses b ut m ust 
n ot ha ve ha d pri or b e vaciz u ma b or ot her V E G F/ V E G F R  i n hi bit ors (e xce pti o n: pri or 
be vaciz u m a b is all o we d if it was a d mi nistere d f or t he treat me nt of ra diati o n necr osis 
rat her t ha n pr o gressi ve t u m or a n d was st o p pe d at least 1 2 wee ks pri or t o M RI s h o wi n g 
t u m or pr o gressi o n). 
4.  C o nc urre nt a ntic a ncer t h era p y (e g, c h e m ot hera p 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).  
5.  Ca n di date f or p ote ntiall y c urati ve s ur ger y . 
6.  De xa met has o n e ( or e q ui vale nt) >  4 m g dail y at t h e ti me of st u d y re gistrati o n ( hi g her d ose 
of ster o i d f or s y m pt o m c o ntr ol is all o we d d uri n g t he st u d y). 
7.  C urre nt e vi de nce of cli nicall y si g nifica nt c or n eal (i ncl u di n g b ut n ot li mite d t o 
b ull o us/ ba n d kerat o pat h y, c or neal a brasi o n, i nfla m mati o n/ ulcerati o n, a n d 
kerat oc o nj u ncti vitis) or reti nal dis or der (i ncl u d i n g b ut n ot li mite d t o mac ular/reti nal 
de ge nerati o n, dia betic reti n o pat h y, a n d reti nal detac h me nt) as c o nfir me d b y 
o p ht hal m ol o gic e xa mi nati o n.  
8.  Diff use le pt o me ni n geal disease . 
9.  Ra diati o n t hera p y a d mi nistere d wit hi n 1 2 wee ks b ef ore  e nr oll me nt/first d ose of st u d y 
dr u g . A n i nter val of at least 1 2 wee ks after pri or ra di ot hera p y is re q uire d u nless t here is 
eit her hist o pat h ol o gical c o nfir mati o n of rec urre nt t u m or or ne w e n h a nce me nt o n M RI 
o utsi de t he ra di ot hera p y fiel d . 
1 0.  K n o w n a d diti o nal mali g na nc y t hat is pr o gressi n g or re q uires acti ve s yste mic treat me nt . 
E xce pti o ns i ncl u de basal cell carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of t he s ki n, 
or i n sit u cer vical c a ncer t hat has u n der g o ne p ot e ntiall y c urati ve t hera p y.  
1 1.  Partici pa nts wit h la b orat or y val ues at scree ni n g  d efi ne d i n Ta ble  7 . 

I nc yte C or p orati o n 
Pa ge 3 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  7 : 
E xcl usi o n ar y L a b or at or y V al ues  
L a b or at or y P ar a meter  
E xcl usi o n Criteri o n  
He m at ol o g y  
a 
Platelets  
≤ 7 5 × 1 0 9/ L (tra nsf usi o n all o we d wit h a 2-wee k was h o ut peri o d)  
b  
He m o gl o bi n  
≤ 9 g/ d L (tra nsf usi o n all o we d wit h a 2 -wee k was h o ut peri o d)  
c 
A N C  
≤ 1. 5 × 1 0 9/ L 
He p atic  
d  
A L T  
≥ 3 × U L N ( > 5 × U L N f or li ver metastasis)  
e 
A S T  
≥ 3 × U L N ( > 5 × U L N f or li ver metastasis)  
f 
T otal bilir u bi n  
≥ 1. 5 × U L N ( ≥ 2. 5 × U L N if Gil bert's s y n dr o me or li ver 
metastasis)  
g  
Al kali ne p h os p hatase  
≥ 3 × U L N  
Re n al  
h  
Ser u m creati ni ne cleara nce  
≤ 3 0 m L/ mi n ute b ase d o n C oc kcr oft -Ga ult f or m ula  
C he mistr y  
i 
Ser u m p h os p hate  
>  U L N  
j 
Ser u m calci u m  
O utsi de of n or mal ra n ge or ser u m al b u mi n -c orrecte d calci u m 
o utsi de of t he n or mal ra n ge w he n ser u m al b u mi n  is o utsi de of t he 
n or mal ra n ge  
1 2.  Hist or y of calci u m a n d p h os p hate h o me ostasis dis or der or s yste mic mi neral i m bala nce 
wit h ect o pic calcificati o n of s oft tiss ues (e xce pti o n : c o m m o nl y o bser ve d cal cificati o ns i n 
s oft tiss ues s uc h as t he s ki n, ki d ne y te n d o n, or vessels d ue t o i nj ur y, disease, or a gi n g i n 
t he a bse nce of s yste mic mi neral i m bala nce). 
1 3.  Si g nifica n t gastr oi ntesti nal dis or der(s) t h at c o ul d i nterfere wit h a bs or pti o n, meta b olis m, 
or e xcreti o n of st u d y dr u g. 
1 4.  Cli nicall y si g nifica nt or u nc o ntr olle d car diac dise ase i ncl u di n g u nsta ble a n gi na, ac ute 
m y ocar dial i nfarcti o n wit hi n 6 m o nt hs bef ore Da y 1 of st u d y dr u g a d mi nistrati o n, Ne w 
Y or k Heart Ass ociati o n Class III or I V c o n gesti v e heart fail ure, a n d u nc o ntr olle d 
arr h yt h mia ( partici pa nts wit h pace ma ker or wit h atrial fi brillati o n a n d well c o ntr olle d 
heart rate are all o we d).  
1 5.  Hist or y or prese n ce of a n a b n or mal E C G t hat, i n t he i n vesti gat or 's o pi ni o n, is cli nicall y 
mea ni n gf ul . A scree ni n g Q Tc F i nter val > 4 8 0 millisec o n ds  is e xcl u de d. F or partici pa nts 
wit h a n i ntra ve ntric ular c o n d ucti o n dela y ( Q R S i nter val > 1 2 0 ms), t he J T c i nter val ma y 
be use d i n place of t he Q Tc wit h me dical m o nit or a p pr o val . T he J T c m ust be 
≤ 3 4 0  millisec o n ds  if J Tc is use d i n place of t he Q Tc. 
1 6.  Acti v e c hr o nic or c urre nt i nfecti o us disease re q uiri n g s yste mic a nti bi otic, a ntif u n gal, or 
a nti viral treat me nt wit hi n 2 wee ks bef ore e nr oll me nt ( partici pa nts wit h as y m pt o matic 
c hr o nic i nfecti o ns o n pr o p h ylactic treat me nt are all o we d).  

I nc yte C or p orati o n 
Pa ge 3 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1 7.  E vi de nce of acti ve H B V or H C V i nfecti o n ( defi ne d as partici pa nts wit h ele vate d 
tra nsa mi nases or cirr h osis). Partici pa nts wit h c hr o nic H B V/ H C V i nfecti o n wit h n o 
cirr h osis a n d n o ele v ate d tra nsa mi nases are all o we d . 
1 8.  Partici pa nts  wit h a  k n o w n  HI V i nfecti o n w h o ha v e C D 4 +  T -cell c o u nt <  3 5 0 cells/ µ L will 
be e xcl u de d.  Partici pa nts  wit h C D 4 +  T -cell ( C D 4 + ) c o u nts ≥ 3 5 0 cells/ μ L s h o ul d 
ge nerall y be eli gi ble.  
1 9.  C urre nt use of pr o hi bite d me dicati o n as descri be d i n Secti o n  6. 6. 2 . 
2 0.  Use of a n y p ote nt C Y P 3 A 4 i n hi bit ors or i n d ucers or m o derate C Y P 3 A 4 i n d ucers (see 
A p pe n di x  D ) wit hi n 1 4 d a ys or 5  half -li ves ( w hic he ver is l o n ger) bef ore t he first d ose of 
st u d y dr u g. M o derate C Y P 3 A 4 i n hi bit ors are n ot pr o hi bite d b ut s h o ul d be a v oi de d (see 
Secti o n  6. 6. 1 ). 
2 1.  K n o w n h y perse nsiti vit y or se vere reacti o n t o pe mi gati ni b  or e xci pie nts of pe mi gati ni b  
(Pe maz yre 2 0 2 1a , Pe ma z yre 2 0 2 1 b ). 
2 2.  I n a bilit y or u nli keli ness of t he partici pa nt t o c o m pl y wit h t he d ose sc he d ul e a n d st u d y 
e val uati o ns, i n t he o pi ni o n of t he i n vesti gat or.  
2 3.  I n a de q uat e 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. 
2 4.  W o me n w h o are pre g na nt or breastf ee di n g.  F or Ja pa n, w o me n w h o are breastfee di n g a n d 
wis h t o e nr oll m ust disc o nti n ue breastfee di n g at least 9 0 da ys bef ore recei vi n g st u d y 
dr u g . T he y m ust als o refrai n fr o m breastfee di n g d uri n g t he c o urse of st u d y a n d f or 
9 0  da ys after t h e last d ose of st u d y dr u 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 dr u g a n d atte n di n g re q uir e d st u d y visits; 
p os e a si g nifica nt ris k t o t he partici pa nt; or i nterfere wit h i nter pret ati o n of st u d y data.  
2 6.  Hist or y of h y p o vita mi n osis D re q uiri n g s u pra p h ysi ol o gic d oses (e g, 5 0, 0 0 0  UI/ wee kl y) t o 
re ple nis h t he defi cie nc y. Vita mi n D s u p ple me nts are all o we d.  
2 7.  T he f oll o wi n g part ici pa nts are e x cl u de d i n Fra nce : v ul nera ble p o p ulati o ns acc or di n g t o 
article L. 1 1 2 1 -6 of t he Fre nc h P u blic Healt h C o de a n d a d ults u n der le g al pr otecti o n or 
w h o are u n a ble t o e x press t heir c o nse nt per article L. 1 1 2 1 -8 of t he Fre n c h P u blic Healt h 
C o de.  
5. 3.  
Lifes t yle C o nsi der ati o ns 
Base d o n t he preli mi nar y res ults fr o m t he f o o d effect c o h ort i n St u d y I N C B 5 4 8 2 8 -1 0 1, n o 
si g nifica nt f o o d effect w as o bser ve d. Pe mi gati ni b  ma y be a d mi nistrate d wit h or wit h o ut f o o d.  
Partici pa nts s h o ul d refrai n fr o m c o ns u m pti o n of re d wi ne, Se ville ora n ges, gra pefr uit or 
gra pefr uit j uice, p o mel os, e x otic citr us fr uits, gra p efr uit h y bri ds, or fr uit j uices  t hat c o ntai n 
p ote nt C Y P 3 A 4 i n hi bit ors  fro m  1 4  da ys bef ore t he start of st u d y treat me nt u ntil after t he fi nal 
d ose , as t his ca n affect t he meta b olis m of t he st u d y dr u g.  

I nc yte C or p orati o n 
Pa ge 3 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
5. 4.  
Scree n F ail ures  
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y  e ntere d i n t he st u d y . 
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t his st u d y (scree n fail ure) ma y  b e 
rescree ne d n o m ore t ha n 1 ti me. 
Tests wit h res ults t hat fail eli gi bilit y re q uire me nts ma y be re p eate d o nce d uri n g scree ni n g if t h e 
i n vesti gat or belie ves t he res ult t o be i n err or. A d diti o nall y, a partici pa nt w h o fails scree ni n g ma y 
re peat t he s cree ni n g pr ocess 1 ti me if t he i n vesti gat or belie ves t hat t here has bee n a c ha n ge i n 
eli gi bilit y stat us . Partici pa nts w h o rescree n m ust r ec o nse nt a n d b e assi g ne d a ne w partici pa nt 
n u m ber.  
5. 5.  
Re pl ace me nt of P artici p a nts  
N o partici pa nts 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 
Pa ge 3 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
6.  
S T U D Y T R E A T M E N T  
6. 1.  
St u d y Tre at me nt A d mi nistere d  
Ta ble  8  pres e nt s t he st u d y treat me nt i nf or mati o n. T he starti n g d ose of pe mi gati ni b  f or all 
partici pa nts is 1 3. 5 m g Q D.  
T a ble  8 : 
St u d y Tre at me nt I nf or m ati o n  
St u d y tre at me nt n a me:  
Pe mi gati ni b /I N C B 0 5 4 8 2 8 
Mec h a nis m of acti o n:  
Tar gete d i n hi bit or o f F G F R 1 -3  
D os a ge f or m ul ati o n:  
Ta blet  
U nit d ose stre n gt h(s)/ d os a ge le vel(s):  
1 3. 5 m g, 9 m g, a n d 4. 5 m g  
R o ute of a d mi nistr ati o n:  
Oral  
A d mi nistr ati o n i nstr ucti o ns:  
O ne ta blet ta ke n e ver y m or ni n g ( u nless ot her wise 
directe d)  f or 2 wee ks a n d t he n 1 wee k off  
P ac k a gi n g a n d l a beli n g:  
Pe mi gati ni b  will be pr o vi de d i n b ottles; eac h b ottle 
will be la bele d as re q uire d per c o u ntr y 
re q uire me nt. 
St or a ge:  
R o o m te m perat ure ( 1 5 °C -3 0 °C)  
St at us of tre at me nt i n p artici p ati n g c o u ntries:  
I n vesti gati o nal 
6. 2.  
Pre p ar ati o n, H a n dli n g, a n d Acc o u nt a bilit y  
T he i n vesti gat or or desi g nee, or i n vesti gati o nal dr u g st ora ge ma na g er (f or J a pa n), m ust c o nfir m 
a p pr o priate t e m perat ur e c o n diti o ns ha ve bee n mai ntai n e d d uri n g tra nsit f or all st u d y treat me nts 
recei v e d a n d a n y dis cre p a ncies are re p orte d a n d res ol ve d bef ore use of t he st u d y treat me nt. 
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e st u d y treat me nt, a n d o nl y a ut h orize d site 
staff ma y s u p pl y or a d mi nister st u d y treat me nt. All st u d y treat me nt s m ust be st ore d i n a sec ure, 
e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n u al or a ut o mate d) area i n acc or da n ce wit h t he 
la bele d st ora g e c o n diti o ns wit h access li mite d t o t he i n vesti gat or, i n vesti gati o nal dr u g st orage 
ma na ger (f or Ja p a n), a n d a ut h orize d site staff.  
T he i n vesti gat or, i n vesti gati o nal dr u g st ora ge ma na ger (f or Ja p a n), or d esi g nee is res p o nsi ble f or 
st u d y treat me nt acc o u nta bilit y, rec o nciliati o n, a n d rec or d m ai nte na nce (ie, recei pt, rec o n ciliati o n, 
a n d fi nal dis p ositi o n rec or ds). 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 bl e f or i ns p ecti 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, i n vesti gati o nal dr u g st ora ge ma na g er (f or 
Ja pa n) or d esi g nee m ust mai ntai n rec or ds t hat d o c u me nt t he f oll o wi n g: 
•  Deli ver y of st u d y dr u g t o t he st u d y site.  
•  I n v e nt or y of st u d y dr u g at t he site. 
•  Partici pa nt use of t he st u d y dr u g, i ncl u di n g pill c o u nts fr o m eac h s u p pl y dis pe ns e d.  
•  Ret ur n of st u d y dr u g t o t he i n vesti gat or, i n vesti gati o nal dr u g st ora ge ma na ger (f or 
Ja pa n), or desi g nee b y p artici pa nts.  

I nc yte C or p orati o n 
Pa ge 3 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
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  (see A p pe n di x  C ). 
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 partici pa nts were 
pr o vi de d t he s pecifi e 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 seri al n u m bers or u ni q ue c o d e 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 partici pa nts.  
C o m plete d acc o u nta bilit y rec or ds will be arc hi v e d b y t he site . T he i n vesti gat or, i n vesti gati o nal 
dr u g st ora ge ma n a ger (f or Ja pa n), or desi g ne e 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 h e s p o ns or) . At t he c o n cl usi o n of t he st u d y, t he i n vesti gat or, 
i n vesti gati o nal dr u g st ora ge ma na ger (f or Ja pa n), 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 d estr ucti o n acc or di n g t o i nstit uti o nal 
S O Ps . If l ocal pr oce d ures ma n date o n-site destr u cti o n of t he i n vesti gati o nal s u p pl y, t he site 
s h o ul d ( w here l o cal pr oce d ures all o w) m ai 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 pects t he acc o u nta bilit y rec or ds i n or d er t o e v al 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 site s 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. 
F urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d st u d y treat me nts are 
pr o vi de d i n t he P har mac y Ma n ual.  
6. 3.  
Me as ures t o Mi ni mize Bi as : R a n d o miz ati o n a n d Bli n di n g  
T his is a n o pe n -la bel, n o nra n d o mize d st u d y . 
6. 4.  
St u d y Tre at me nt C o m pli a nce  
C o m plia nce wit h all st u d y -relate d tr eat me nts s h o ul d be e m p hasize d t o t he p artici pa nt b y t he site 
pers o n nel, a n d a p pr o priat e 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 pe mi gati ni b  will be calc ulate d b y t he s p o ns or base d o n t h e dr u g acc o u nta bilit y 
(ie, ta blet c o u nts) d oc u m e 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. 
Partici pa nts will be i nstr ucte d t o bri n g all u n use d st u d y dr u g wit h t he m t o t he st u d y visits i n 
or der f or site pers o n n el t o c o n d uct ta blet c o u nts t o assess st u d y dr u g acc o u nta bilit y . 
6. 5.  
D ose M o dific ati o ns  
I n di vi d ual de cisi o n re gar di n g d ose m o dificati o ns of pe mi gati ni b  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 r elate d ness 
of t he A E t o t he st u d y dr u g  a n d t he partici pa nt 's u n derl yi n g c o n diti o n. A d verse e v e 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 v al ues wit h o ut 
ass ociate d cli nicall y si g nifica nt si g ns or s y m pt o ms ma y be e xe m pt fr o m d ose  re d ucti o n r ules. 
6. 5. 1.  
Criteri a a n d Pr oce d ures f or D ose I nterr u pti o ns a n d A dj ust me nts of St u d y Dr u g  
Safet y c o ncer ns s h o ul d b e disc usse d wit h t he s p o ns or i m me diatel y u p o n occ urre n ce or a ware n ess 
t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue st u d y treat me nt. 
A d verse e ve nts ass oci ate d wit h pe mi gati ni b ca n ofte n be ma na g e d wit h c o nc o mita nt 
me dicati o ns, s u p p orti ve care, a n d/ or d ose m o dificati o ns as per Ta bl e  9 . Eac h treat me nt 
i nter ve nti o n s h o ul d be cl earl y d oc u me nt e d i n t he e C R F. 

I nc yte C or p orati o n 
Pa ge 3 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
Treat me nt wit h pe mi gati ni b  ma y be dela ye d u p t o 2 wee ks ( 1 4 da ys) t o all o w f or res ol uti o n of 
t o xicit y. Partici pa nts ma y res u me treat me nt if n o me dical c o n diti o n or ot her cir c 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 partici pa nt u ns uita ble f or f urt h er 
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 h e case 
of a n y partici p a nt w h ose treat me nt has bee n dela ye d f or m ore t h a n 1 4 da ys bef ore restarti n g 
treat me nt wit h pe mi gati ni b . 
T a ble  9 : 
G ui deli nes f or I nterr u pti o n a n d Rest arti n g of St u d y Dr u g  
A d verse E ve nt  
Acti o n T a k e n 
C he mistr y  
•  A S T a n d/ or A L T is > 5. 0 × U L N.  
Ste p 1 : I nterr u pt st u d y dr u g u p t o 2 wee ks ( 1 4  da ys) u ntil 
t he t o xicit y has res ol ve d t o ≤ Gra de 1  or baseli ne  e xce pt b y 
a p pr o val of t he me dical m o nit or.  
Ste p 2 : Restart st u d y dr u g at sa me d ose . If assesse d as 
relate d t o st u d y dr u g, restart st u d y dr u g at ne xt l o wer d ose; 
m o nit or as cli nicall y i n dicate d.  
Ot her t o xicities  
•  A n y Gra de 1 or Gra de 2 t o xicit y.  
C o nti n ue st u d y dr u g treat me nt 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  
Ste p 1 : I nterr u pt st u d y dr u g u p t o 2 wee ks ( 1 4  da ys)  u ntil 
t o xicit y res ol ves t o ≤ Gra de 1 or baseli ne . 
Ste p 2 : Restart st u d y dr u g at sa me d ose. If assesse d as 
relate d t o st u d y dr u g, restart st u d y dr u g at ne xt l o wer d ose; 
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 st u d y dr u g 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 n y ot her Gra de 4 t o xicit y.  
•  Q T/ Q Tc t o > 5 0 0 ms or t o >  6 0 ms 
o ver baseli ne a. 
Disc o nti n ue st u d y dr u g a d mi nistrati o n a n d f oll o w -u p per 
Pr ot oc ol . 
a F or ele v ati o ns of t he J Tc i nter val, c o ns ultati o n wit h a car di ol o gist is rec o m me n de d. A decisi o n re gar di n g d ose 
m o dificati o n or disc o nti n uati o n of pe mi gati ni b s h o ul d be ma de i n c o ns ultati o n wit h t he s p o ns or's me dical m o nit or.  
Pe mi gati ni b will be self -a d mi nistere d as a Q D oral treat me nt o n a 2 1 -d a y c ycle. Partici pa nts  will 
ta ke st u d y dr u g f or 2 w ee ks ( 1 4 da ys) c o nti n u o usl y f oll o we d b y a 1 -wee k ( 7 -da y) brea k. T h e 
starti n g d ose will be 1 3. 5 m g. Base d o n preli mi nar y res ults fr o m t he f o o d effect c o h ort i n 
St u d y  I N C B 5 4 8 2 8-1 0 1, pe mi gati ni b ma y be a d mi nistere d wit h or wit h o ut f o o d.  
F or d ose a dj ust me nts , a ma xi m u m of 2 d ose le vel re d ucti o ns are rec o m me n de d  as f oll o ws : 
partici pa nts a d mi nistere d 1 3. 5 m g ca n decreas e t o 9 m g, a n d if a n a d diti o nal d ose re d ucti o n is 
re q uire d, p artici pa nts  ca n decrease t o 4. 5  m g. D os e re d ucti o ns bel o w 4. 5  m g are n ot all o we d. 
T he fre q u e nc y of a d mi nistrati o n  will  re mai n t he sa me (Q D ) as w ell as t he sc he d ule ( 2 wee ks o n 
treat me nt f oll o we d b y 1 wee k off treat me nt). 

I nc yte C or p orati o n 
Pa ge 3 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
F or partici pa nts w h o pres e nt wit h p ossi ble or c o nfir me d S R D/ R P E D base d o n O C T , t he 
g ui deli nes i n Ta ble  9  s h o ul d be f oll o we d. It is rec o m me n de d t o discuss t he fi n di n gs wit h t he 
s p o ns or's m e dical m o nit or bef ore ma ki n g c ha n g es t o t he partici pa nt 's treat m e nt. 
Per C T C A E v 5. 0, reti nal detac h me nt is gra d e d as 3 ( mac ular s p ari n g) a n d 4 ( mac ula‐ off), b ut 
t his refers t o r h e g mat o ge n o us reti nal detac h m e nt ( w he n a h ole occ urs i n t he reti na). T here is n o 
gra di n g f or S R D/ R P E D ( n o h ole i n t he mac ula, j ust fl ui d acc u m ulati o n) . T heref ore, gra di n g 
s h o ul d be base d o n t he C T C A E v 5. 0 ter m of reti n o pat h y. 
6. 5. 2.  
M a n a ge me nt of H y per p h os p h ate mi a  
H y per p h os p hate mia is a n e x pecte d o n -tar g et p har mac ol o gic effect of F G F R i n hi biti o n. 
H y per p h os p hate mia s h o ul d be ma na ge d wit h diet m o dificati o ns, p h os p hate bi n ders a n d di uretics, 
or a d ose re d ucti o n per t h e  rec o m me n d ati o ns i n Ta ble  1 0 . 
T he use of diet m o dificati o ns al o ne i ncl u de f o o d e xc ha n ges fr o m hi g h -p h os p hate f o o ds t o 
l o w-p h os p hate f o o ds a n d ca n be i m p le me nte d o nce ser u m p h os p hate le v els are a b o v e t he U L N 
b ut d o n ot e xcee d 7. 0 m g/ d L . Diet m o dificati o n s h o ul d c o nti n ue wit h t he i ncl usi o n of p h os p hate 
bi n ders o nce s er u m p h os p hate le vels e x cee d 7. 0 m g/ d L . E xa m ples of p h os p hate bi n ders are 
se vela mer H Cl (e xam ples of bra n d na m es : Re ne g el ®  a n d Re n vela ® ) or la nt ha n u m H Cl. 
A d mi nistrati o n of p h os p hate bi n ders s h o ul d be 3 ti mes per da y (e g, wit h eac h meal) t o re d uce 
a bs or pti o n of p h os p hate . D oses a n d fre q ue n c y of d oses s h o ul d be base d o n t he partici pa nt 's 
t olera nce f or t he bi n der a n d t he c o ntr ol of ser u m p h os p hate. If bi n ders are use d t o ma na ge H P  
d uri n g treat me nt, it is rec o m me n de d t o st o p bi n ders at t he sa me ti me pe mi gati ni b  is st o p pe d t o 
re d uce t h e ris k of h y p o p h os p hate mia. 
F or gra di n g of H P , n ote t hat C T C A E v 5. 0 n o w has a cate g or y f or H P . 
F or Ja p a n, t he s p o ns or will pr o vi de t he p h os p hate bi n der la nt ha n u m car b o nate h y drate f or t he 
treat me nt of H P  w he n re q uire d (see Ta ble  1 0 ). 

I nc yte C or p orati o n 
Pa ge 3 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  1 0 : 
Rec o m me n de d A p pr o ac h f or H y per p h os p h ate mi a M a n a ge me nt  
Ser u m P h os p h ate 
Le v el  
S u p p orti ve C are  
G ui d a nce f or 
I nterr u pti o n/ Disc o nti n u ati o n 
of Pe mi g ati ni b  
G ui d a nce f or Rest arti n g 
Pe mi g ati ni b  
> 5. 5 m g/ d L a n d 
≤ 7 m g/ d L  
I nitiate a l o w-p h os p hate diet.  N o acti o n.  
N ot a p plica ble.  
>  7 m g/ d L a n d 
≤ 1 0  m g/ d L  
I nitiate/c o nti n ue a 
l o w-p h os p hate diet a n d 
i nitiate p h os p hate-bi n di n g 
t hera p y. M o nit or ser u m 
p h os p hate a p pr o xi matel y 
t wice a wee k a n d a dj ust t he 
d ose of bi n ders as nee de d; 
c o nti n ue t o m o nit or ser u m 
p h os p hate at least t wice a 
wee k u ntil le vel ret ur ns t o 
≤ 7  m g/ d L.  
If ser u m p h os p hate le vel 
c o nti n ues t o be > 7 m g/ d L a n d 
≤ 1 0 m g/ d L wit h c o nc o mita nt 
p h os p hate -bi n di n g t hera p y f or 
2  we e ks, or if t here is 
rec urre nce of ser u m p h os p hate 
le vel i n t his ra n ge, i nterr u pt 
pe mi gati ni b  f or u p t o 2 wee ks.  
Restart at t he sa me d ose 
w he n ser u m p h os p hate is 
<  7  m g/ d L . If ser u m 
p h os p hate le vel rec urs at 
>  7  m g/ d L, restart 
pe mi gati ni b  wit h d ose 
re d ucti on.  
> 1 0 m g/ d L  
C o nti n ue t o mai ntai n a 
l o w-p h os p hate diet, a dj ust 
p h os p hate -bi n di n g t hera p y, 
a n d start/c o nti n ue 
p h os p hat uric a g e nt . 
C o nti n ue t o m o nit or ser u m 
p h os p hate a p pr o xi matel y 
t wice a wee k u ntil le vel 
ret ur ns t o ≤ 7  m g/ d L.  
If ser u m p h os p hate le vel is 
>  1 0  m g/ d L f or 1 wee k 
f oll o wi n g p h os p hate-bi n di n g 
t hera p y a n d l o w-p h os p hate diet, 
i nterr u pt pe mi gati ni b . If t here is 
rec urre nce of ser u m p h os p hate 
le vel i n t his ra n ge f oll o wi n g 
2  d ose re d ucti o ns, per ma ne ntl y 
disc o nti n ue  pe mi gati ni b . 
Restart pe mi gati ni b  at 
re d uce d d ose wit h 
p h os p hate bi n ders w he n 
ser u m p h os p hate is 
<  7  m g/ d L.  
6. 5. 3.  
Criteri a f or Per m a ne nt Disc o nti n u ati o n of St u d y Dr u g  
T he occ urre n ce of u nacce pta ble t o xicit y n ot ca use d b y t he u n derl yi n g disease will re q uire t hat 
t he st u d y dr u g be per ma n e ntl y disc o nti n ue d . U nacce pta ble t o xicit y is defi n e d as f oll o ws:  
•  T he occ urre n ce of a n A E t hat is relate d t o st u d y dr u g 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 partici pa nt'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 partici pa nt's best 
i nterest. 
•  A n A E re q uiri n g m ore t ha n 2 d ose re d u cti o ns.  
•  A persiste nt A E re q uiri n g a dela y of t hera p y f or m ore t ha n 2 wee ks ( 1 4  d a ys) u nless a 
greater dela y h as bee n a p pr o ve d b y t he s p o ns or.  
•  A n i ncreas e i n Q T/ Q Tc t o >  5 0 0 millisec o n ds or t o >  6 0 millisec o n ds o ver baseli ne . 
I n t he cas e of a Q Tc >  5 0 0 millisec o n ds, t he partici pa nt m ust be h os pitalize d , a n d 
c o nti n u o us E C G m o nit ori n g m ust be set u p u ntil t he meas ure of t he Q Tc i nter val 
decreases bel o w 5 0 0  millisec o n ds a n d is acce pta bl e i n t he o pi ni o n of t he l ocal 
car di ol o gist.  F or el e vati o ns of t he J Tc i nter val, c o ns ultati o n wit h a car di ol o gist is 
rec o m men de d. A decisi o n re gar di n g d os e m o dificati o n or disc o nti n uati o n of 
pe mi gati ni b s h o ul d be ma de i n c o ns ultati o n wit h t he sp o ns or 's me dical m o nit or.  
See Secti o n  7  f or disc o nti n uati o n pr oce d ures. 

I nc yte C or p orati o n 
Pa ge 4 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
6. 6.  
C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures  
All c o nc o mita nt me dicati o ns a n d treat me nts (i ncl u di n g o ver -t he-c o u nter or prescri pti o n 
me dici nes, vita mi ns, vacci nes, a n d/ or her bal s u p ple 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 2 8  da ys bef ore t he first d ose of st u d y dr u g t hr o u g h 3 0 da ys after 
t he last d ose of st u d y dr u g, or u ntil t he partici pa nt be gi ns a ne w a ntica ncer t hera p y, w hic h e ver 
occ urs first,  will be rec or de d i n t he e C R F . A n y a d diti o n , deleti o n, or c ha n g e i n t he d ose of t hese 
me dicati o ns will als o be rec or de d . C o nc o mita nt me dicati o ns a d mi nistere d f or treat me nt of S A Es 
(as defi ne d i n Secti o n 9. 2 ) s h o ul d be rec or de d e ve n if t he S A E is re p orte d b e y o n d 3 0 da ys aft er 
t he last d ose of st u d y dr u g. C o nc o mita nt treat me nts/ pr oce d ures t h at are re q uire d t o ma na ge a 
partici pa nt '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. T he me dical 
m o nit or s h o ul d be c o ntacte d if t here are a n y q uesti o ns re gar di n g c o nc o mita nt or pri or t hera p y.  
6. 6. 1.  
Restricte d Me dic ati o ns a n d Pr oce d ures  
Pe mi gati ni b  is pre d o mi na ntl y meta b olize d b y C Y P 3 A 4. T here is a n e x pect e d 5 0 % i ncrease i n 
e x p os ure i n part ici pa nts w h o c o nc o mita ntl y use C Y P 3 A 4 m o derate i n hi bit ors. H o we ver, as 
d oses a b o ve t he rec o m m e n de d P hase 2 d ose of 1 3. 5  m g Q D ha ve bee n test e d ( 2 0 m g Q D is 
t olera ble), t here is a s ufficie nt safet y mar gi n. T he use of m o derat e C Y P 3 A 4 i n hi bit ors (see 
A p pe n di x  D ) s h o ul d be a v oi de d; h o we ver, if u n a v oi da ble, t he pe mi gati ni b d ose  s h o ul d be 
re d uce d fr o m 1 3. 5 m g t o 9 m g or fr o m 9 m g t o 4. 5 m g. If c o nc o mita nt use of a m o derate C Y P 3 A 
i n hi bit or is disc o nti n ue d, t he pe mi gati ni b d ose ca n be i ncrease d (after 3 pl as ma half-li ves of t he 
C Y P 3 A i n hi bit or) t o t he d ose t hat was a d mi nistere d bef ore starti n g t he m o derate i n hi bit or. T he 
use of p ote nt C Y P 3 A 4 i n hi bit ors a n d i n d ucers a re pr o hi bite d (see Secti o n  6. 6. 2 ). 
I n cert ai n i nsta nces, palli ati ve s ur ger y or ra di ot hera p y t o s pecific lesi o ns is per mitte d if 
c o nsi dere d of be nefit a n d me dicall y necess ar y b y t he i n vesti gat or. T he s p o ns or m ust be n otifie d 
if palliati ve s ur ger y or ra di ot hera p y is starte d; f or a n y palliati ve ra di ot hera p y or 
n o n – disease -relate d s ur g eries, t he me dical m o nit or s h o ul d be c o ns ulte d o n w he n t o restart 
pe mi gati ni b . T he  lesi o ns treate d wit h palliati ve s ur ger y or ra di ot hera p y ca n n o l o n ger  be ass esse d 
as tar get lesi o ns.  
I n g e neral, i n vesti gat ors s h o ul d ma na ge a partici p a nt 's care wit h s u p p orti ve t hera pies as 
cli nicall y i n dicate d, per l ocal sta n dar d practice. H o we ver, care s h o ul d be ta ke n t o assess a n y 
c o nc o mita nt me dicati o n f or t he p ote ntial t o ha ve a d verse dr u g -dr u g i nteracti o ns wit h st u d y 
treat me nt, i ncl u di n g p ote ntiall y i m pactin g C Y P 3 A 4 meta b olis m.  
Caref ul m o nit ori n g is re q uire d w he n pe mi gati ni b  is c o nc o mita ntl y a d mi nistere d wit h O C T 2 
s u bstrates s uc h as d of etili de a n d metf or mi n, mil d or m o derate C Y P 3 A 4 i n hi bit ors or i n d ucers, 
a n d pr ot o n p u m p i n hi bit ors.  
Calci u m -base d p h os p hat e -b i n di n g me dicati o ns s h o ul d n ot be use d d ue t o a c o ncer n f or s oft 
tiss ue mi neralizati o n. R efer t o t he I B f or f urt her details. 

I nc yte C or p orati o n 
Pa ge 4 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
6. 6. 2.  
Pr o hi bite d Me dic ati o ns a n d Pr oce d ures  
T he f oll o wi n g me dicati o ns a n d meas ur es are pr o hi bite d:  
•  T he c o nc o mita nt a d mi nistrati o n of p ote nt C Y P 3 A 4 i n hi bit ors a n d i n d ucers a n d 
m o derate C Y P 3 A 4 i n d ucers (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 ol e, t here are n o restricti o ns o n t o pical 
ket oc o naz ol e.  
•  A n y c o nc o mita nt use of a n  F G F R i n hi bit or ( ot her t ha n pe mi gati ni b ). 
•  A n y ot her i n vesti gati o nal  st u d y dr u g f or a n y i n dicati o n. 
•  Pri or use of re g orafe ni b.  
•  Use of a n y a nt ica ncer me dicati o ns ot her t ha n t he st u d y me dicati o n bei n g teste d i n t his 
Pr ot oc ol . 
6. 7.  
Tre at me nt After t he E n d of t he St u d y  
Partici pa nts w h o ha ve n ot ha d eit her a R A N O -det er mi ne d or cli nicall y det er mi ne d  disease 
pr o gressi o n at t he e n d of t he st u d y will be offe re d c o nti n ue d access t o st u d y dr u g b ut o utsi de t h is 
st u d y i n acc or da n ce wit h t he l ocal re g ulati o ns or vi a t he s p o ns or. 

I nc yte C or p orati o n 
Pa ge 4 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
7.  
DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D 
P A R TI CI P A N T WI T H D R A W A L  
7. 1.  
Disc o nti n u ati o n of St u d y Tre at me nt  
7. 1. 1.  
Re as o ns f or Disc o nti n u ati o n  
Partici pa nts m ust  be disc o nti n ue d fr o m st u d y treat me nt f or t he f oll o wi n g reas o ns:  
•  T he partici pa nt bec o mes pre g na nt . 
•  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 partici p a nt has e x plicitl y i n dicate d t hat 
he/s he d oes n ot wa nt t o b e f oll o we d a n y l o n ger; i n t his case n o f urt her data, e xce pt 
data i n p u blic d o mai n, ma y be s olicite d fr o m or c ollecte d o n t he partici p a nt . 
Partici pa nts 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 pr o gressi o n a n d s ur vi val.  
•  F urt her partici pati o n w o ul d be i nj uri o us t o t he partici pa nt 's healt h or well-b ei n g, i n 
t he i n vesti gat or's me dical j u d g me nt. 
•  U nacce pta ble t o xicit y as n ote d i n Secti o n  6. 5 . 
•  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.  
•  Disease pr o gressi o n has bee n re p orte d b y a n I C R . 
•  Ot her a nti ne o plastic tr eat me nt is i nitiate d, n ot i ncl u di n g pa lliati ve ra diati o n. 
A partici pa nt  m a y be disc o nti n ue d fr o m st u d y treat me nt as f oll o ws:  
•  If, d uri n g t he c o urse of t h e st u d y, a partici pa nt is f o u n d n ot t o ha ve met eli gi bilit y 
criteria, t he me di cal m o nit or, i n c olla b orati o n wit h t he i n vesti gat or, will deter m i ne 
w het her t he p artici pa nt s h o ul d be disc o nti n ue d  fr o m st u d y treat me nt. 
•  If a partici pa nt is n o nc o m plia nt wit h st u d y pr oce d ures or st u d y dr u g a d mi nistrati o n i n 
t he i n vesti gat or's o pi ni o 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 partici pa nt. 
7. 1. 2.  
Disc o nti n u ati o n Pr oce d ures  
I n t he e ve nt t hat t he d ecisi o n is ma de t o per ma ne ntl y disc o nti n ue t he st u d y treat me nt, t he E O T 
visit s h o ul d be c o n d ucte d . Reas o na ble eff orts s h o ul d be ma de t o ha ve t h e partici pa nt ret ur n f or a 
f oll o w-u p visit . T hese visi ts are descri be d i n Ta ble  3  a n d Ta ble  4 . T h e last date of t he last d ose of 
st u d y dr u g a n d t he reas o n f or disc o nti n uatio n of st u d y dr u g will be rec or de d i n t he e C R F.  

I nc yte C or p orati o n 
Pa ge 4 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
If a p artici p a nt is disc o nti n ue d fr o m st u d y tre at me nt: 
•  T he st u d y m o nit or or s p o ns or m ust be n otifie d.  
•  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 partici pa nt 's me dical 
rec or d a n d t he pri mar y reas o n f or disc o nti n uati o n m ust be i ncl u de d i n t he e C R F.  
•  T he E O T visit s h o ul d be perf or me d a n d date rec or de d.  
•  T he stat us of t he partici p a nt s h o ul d be u p date d t o E O T i n t he I R T.  
•  Partici pa nts m ust be f oll o we d f or s afet y u ntil t he ti me of t he f oll o w -u p visit or  u ntil 
st u d y dr u g– relate d t o xicities res ol ve, ret ur n t o b as eli ne, or are dee me d irre versi ble, 
w hic he ver is l o n gest.  
If t he partici p a nt 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 (s afet y f oll o w -u p or disease assess me nt), t he n n o a d diti o nal data c ollecti o n 
s h o ul d occ ur; h o we v er, partici pa nts will ha ve t he o pti o n of wit h dra wi n g c o nse nt f or st u d y 
treat me nt b ut c o nti n ui n g i n t he f oll o w-u p peri o d of t he st u d y f or safet y/effi cac y assess me nts . 
7. 2.  
P artici p a nt Wit h dr a w al Fr o m t he St u d y  
A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest, or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he i n vesti gat or f or safet y, be ha vi oral, c o m plia nce, or 
a d mi nistrati ve reas o ns.  
If a partici pa nt wit h dra ws fr o m t he st u d y, he/s he ma y re q uest destr u cti o n of a n y sa m ples ta ke n 
a n d n ot teste d, a n d t he i n vesti gat or m ust d oc u me nt t his i n t he site st u d y rec or ds . If t he partici pa nt 
wit h dra ws c o nse nt f or discl os ure of f ut ur e i nf or m ati o n, t he s p o ns or ma y retai n a n d c o nti n ue t o 
use a n y data c ollecte d b ef ore s uc h a wit h dra wal of c o nse nt.  
See Ta ble  3  a n d Ta ble  4  f or data t o be c ollecte d at t he ti me of st u d y wit h dra wal a n d f oll o w-u p 
a n d f or a n y f urt her e val u ati o ns t hat nee d t o be c o m plete d.  
7. 3.  
L ost t o F oll o w -U p  
A partici pa nt  will be c o nsi dere d l ost t o f ol l o w-u p if he/s he re p eate 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. 
T he f oll o wi n g acti o ns m ust be ta ke n if a p artici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit: 
•  T he site m ust atte m pt t o c o ntac t t he partici pa nt a n d resc he d ul e t he misse d visit as 
s o o n as p ossi ble a n d c o u nsel t he partici pa nt o n t h e i m p orta nce of mai ntai ni n g t he 
assi g ne d visit sc he d ule a n d ascert ai n w het her or n ot t he partici pa nt wis hes t o a n d/ or 
s h o ul d c o nti n ue i n t he st u d y. 
•  Bef or e a p artici pa nt is dee me d l ost t o f oll o w -u p, t he i n vesti gat or or desi g n ee m ust 
ma ke e ver y eff ort t o re g ai n c o ntact wit h t he partici pa nt ( w here p ossi ble, 3 tele p h o ne 
calls a n d, if necessar y, a certifie d letter t o t he parti ci pa nt 's last k n o w n maili n g a d dress 
or l ocal e q ui vale nt met h o ds) . T hese c o nt act atte m pts s h o ul d be d oc u me nte d i n t he 
partici pa nt 's me dical r ec or d. 
•  S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve 
wit h dra w n fr o m t he st u d y.  

I nc yte C or p orati o n 
Pa ge 4 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
8. 1.  
A d mi nistr ati ve a n d Ge ner al Pr oce d ures  
8. 1. 1.  
I nf or me d C o nse nt Pr ocess 
•  T he i n vesti gat or or his/ her re prese nt ati ve will e x plai n t he nat ure of t h e st u d y t o t he 
partici pa nt or his/ her le g all y a ut h orize d re pres e nt ati ve a n d a ns w er all q uesti o ns 
re gar di n g t he st u d y. 
− I nfor me d c o ns e 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 o c ol.  
− I nf or me d c o ns e 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 partici pa nt. 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 wl e 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 ne e a n d re g ul at or y a ut h oriti es ha ve 
direct access t o partici pa nt rec or ds.  
− T he I C F m ust c o ntai n all re q uire d ele me nts a n d d escri be t he nat ure, s c 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 
partici pa nt.  
•  Partici pa nts m ust be i nf or me d t hat t heir partici p ati o n is v ol u ntar y . Partici pa nts or 
t heir le gall y a ut h orize d re prese nt ati ve will be re q uire d t o si g n a state me nt of i nf or me d 
c o nse nt t hat meets t he a p plica ble re q uir e me nts a n d re g ulati o ns f or t he c o u ntries i n 
w hic h t he st u d y is bei n g c o n d ucte d as w ell as t he I R B/I E C or st u d y ce nt er.  
•  T he partici pa nt m ust be i nf or me d t hat his/ her pers o nal st u d y -relate d d ata will be use d 
b y t he s p o ns or i n acc or da nce wit h l ocal dat a pr otecti o n la ws . T he le vel of discl os ure 
m ust als o be e x plai ne d t o t he partici pa nt.  
•  T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e xa mi ne d b y 
Cli nical Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he 
s p o ns or, b y a p pr o priat e I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y 
a ut horities.  
•  T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was 
o btai ne d bef ore t he partici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n 
c o nse nt was o btai ne d . T h e a ut h orize d p ers o n o btai ni n g t he i nf or me d c o nse nt m ust 
als o s i g n t he I C F. 
•  Partici pa nts m ust pr o vi de c o nse nt t o t he m ost c urre nt versi o n of t he I C F d uri n g t heir 
partici pati o n i n t he st u d y.  
•  A c o p y of t he I C F(s) m ust be pr o vi de d t o t he partici pa nt or t he partici pa nt 's le gall y 
a ut h orize d re pres e ntati ve.  
Partici pa nts w h o  are rescree ne d are re q uir e d t o si g n a ne w I C F  a n d will recei ve a ne w 
partici pa nt 's n u m ber. 

I nc yte C or p orati o n 
Pa ge 4 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8. 1. 2.  
Prescree ni n g a n d Scree ni n g Pr oce d ures  
Prescree ni n g is all o we d i n cases i n w hic h t he site ma y nee d t o c o ns ult wit h t he s p o ns or o n t he 
eli gi bilit y of a p ote ntial part ici pa nt's ge n o mic alterati o n. T his is n ot re q uire d f or all partici pa nts; 
it a p plies o nl y t o t h ose w h ose ge n o mic alterati o ns nee d t o be re vie we d f or eli gi bilit y. If 
prescree ni n g is nee d e d , t he partici pa nt m ust si g n a prescree ni n g c o nse nt f or m i n a d diti o n t o t he 
I C F. 
Scree ni n g is t he i nter val bet wee n si g ni n g t he st u d y I C F ( n ot t he prescree ni n g c o nse nt f or m) a n d 
t he da y t he partici p a nt is e nr olle d i n t he st u d y ( C ycle 1 Da y  1) . S cree 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 d a ys d uri n g t he scree ni n g pr ocess.  
Pr oce d ures c o n d ucte d as part of t he partici pa nt 's r o uti ne cli nical ma na ge m e nt (e g, bl o o d c o u nt, 
i ma gi n g st u d y) a n d o btai ne d bef ore si g ni n g of t he I C F m a y be us e d f or scree ni n g or bas eli ne 
p ur p oses pr o vi de d t he pr oce d ure m eets t he Pr ot oc ol -defi ne d criteria a n d has bee n perf or me d i n 
t he ti mefra me of t h e st u d y (ie, wit hi n 2 8  da ys bef ore C ycle 1 Da y 1) . F or partici pa nts w h o are 
e nr olle d i n t he st u d y, i nf or ma ti 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 priat e 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 ors t o c o nfir m 
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 p eate d o nce d uri n g scree ni n g if t h e 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 tr eat me nt be gi ns will be use d t o deter mi ne eli gi bilit y . Treat me nt s h o ul d start as s o o n as 
p ossi ble, b ut wit hi n 3 da ys after t he d ate of e nr oll me nt.  
See Secti o ns  5. 4  a n d 5. 5  f or i nf or mati o n re g ar di n g scree n fail ures a n d re pl ace me nt of 
partici pa nts, res p ecti vel y.  
8. 1. 3.  
I nter acti ve Res p o nse Tec h n ol o g y Pr oce d ure 
Eac h par tici pa nt will be i de ntifie d i n t he st u d y b y a partici pa nt I D n u m ber, w hic h is a 
c o m bi nati o n of t he c o u ntr y's a b bre vi ati o n, site I D, a n d partici pa nt n u m ber . Site staff s h o ul d 
c o ntact t he I R T t o o btai n t he partici pa nt I D n u m b er d uri n g pres cree ni n g (if a p plic a ble) or 
scree ni n g. U p o n d eter mi ni n g t hat t he partici pa nt is eli gi ble f or st u d y e ntr y, t he I R T will be 
c o ntacte d t o o btai n t he treat me nt assi g n me nt . A d diti o nall y, t he I R T will be c o ntacte d at eac h 
re g ular st u d y visit t o u p date t he st u d y dr u g s u p pl y. A d diti o nal details are pr o vi de d i n t he I R T 
Ma n ual.  
8. 1. 4.  
Distri b uti o n of Re mi n der C ar ds  
Partici pa nts will be pr o vi de d wit h a re mi n der car d at eac h visit . T he re mi n der car d will i n dicate 
t he date/ti me of t he ne xt visit a n d will als o re mi n d t he partici pa nt t hat t he y s h oul d n ot ta ke t heir 
m or ni n g d ose of st u d y dr u g o n C ycle 1 D a y 8, as t he y will ta ke it after bl o o d dra ws f or safet y 
e val uati o n ha ve b ee n c o m plete d . 

I nc yte C or p orati o n 
Pa ge 4 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8. 1. 5.  
C ortic ost er oi d Use  
C ortic oster oi d use d uri n g t he st u d y m ust be rec or de d as i n dicate d i n t he S o A (see T a ble  3 ) a n d 
c o m pare d wit h t he c ortic oster oi d i nta ke of t he pri or visit. T he c ha n ges will be rec or de d as 
"I n crease d," "Sta ble, " or "Decrease d. " 
8. 1. 6.  
De m o gr a p h y a n d Me dic al Hist or y  
8. 1. 6. 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 d ata a n d g e neral me di cal hist or y will be c ollecte d at scree ni n g b y t he i n vesti gat or 
or q ualifie d desi g ne e a n d will i ncl u de year of birt h/a ge, me dical a n d s ur gical hist or y, a n d c urre nt 
ill nesses. Me dical hist or y will i ncl u de rele va nt me dical or s ur gical treat me nt wit hi n t he last 
1 0  years t hat are c o nsi d ere d t o be cli nicall y si g nifica nt b y t he i n vesti gat or.  
8. 1. 6. 2.  
Dise ase C h ar acteristi cs a n d Tre at me nt Hist or y  
A disease -tar gete d m e dic al a n d treat me nt hist or y will be c ollecte d at scree ni n g. Details re gar di n g 
t he partici pa nt 's mali g na nc y u n der st u d y, i ncl u di n g date of dia g n osis, i nitial a n d c urre nt ca n cer 
sta ge, t u m or hist ol o g y, rele va nt disease c haracteristics, a n d pri or treat me nts, i ncl u di n g s yste mic 
treat me nts, ra diati o n, a n d s ur gical pr oce d ures will be rec or de d.  
8. 2.  
Effic ac y Assess me nts  
8. 2. 1.  
T u m or I m a gi n g  
O bjecti ve assess me nt of t u m or stat us is re q uire d usi n g a p pr o priate disease -s pecific tec h ni q ues, 
a n d a ce ntral r a di ol o gic facilit y will be use d t o deter mi ne res p o ns es , w hic h will be l o g ge d i nt o 
t he e C R F. Res p o nse Ass ess me nt i n Ne ur o -O nc ol o g y ( R A N O) criteria will be use d t o assess 
t u m or res p o nse a n d pr o gressi o n. T u m or assess me nt will c o nsist of a brai n M RI (alter nati ve 
m o dalities [e g, C T sca n ] s h o ul d n ot be s u bstit ute d f or a n M RI). F urt her details ca n be f o u n d i n 
t he i ma gi n g ma n ual. 
T he sc he d ule f or M RI assess me nts will be  d uri n g  scree ni n g (t his will be c o nsi dere d t he bas eli ne 
sca n), e v er y 9 wee ks ( e v er y 3 c ycl es), a n d t he n at E O T (if a p plica ble). E v er y eff ort s h o ul d be 
u n derta ke n t o e ns ure t he sca n is d o ne wit hi n 7 da ys of C ycle 1 D a y 1, es peciall y i n cases of ra pi d 
pr o gressi o n, t o e ns ure t h at a tr ue bas eli ne is ca pt ure d ( Elli n gs o n et al 2 0 2 2 ). I ma gi n g s h o ul d 
c o nti n ue i n 9 -wee k i nter vals re gar dl ess of de la ys i n c ycle starts. F or partici pa nts s h o wi n g a 
res p o nse, a c o nfir mat or y sca n ma y be p erf or me d a mi ni m u m of 4 wee ks fr o m t he pre vi o us sca n 
( per R A N O; We n et al 2 0 1 0 ). F or partici pa nts s h o wi n g a pr o gressi o n bas e d o n l ocal r a di ol o gic 
re vie w, tr eat me nt s h o ul d n ot be disc o nti n ue d u ntil pr o gressi o n of diseas e has bee n deter mi ne d b y 
t he I C R u nless t he pri n ci pal i n vesti gat or belie ves it is i n t he best i nterest of t he partici pa nt t o 
disc o nti n ue treat me nt bef ore recei vi n g c o nfir mati o n.  
F or partici pa nts w h o disc o nti n ue treat me nt f or reas o ns ot her t ha n disease pr o gressi o n, e ver y 
eff ort s h o ul d be ma d e t o c o nti n ue m o nit ori n g t heir disease stat us b y ra di o gr a p hic i ma gi n g u ntil 
t he start of ne w a ntica ncer t hera p y, d o c u me nte d disease pr o gressi o n b y I C R , deat h, or t he e n d of 
st u d y, w hic he ver occ urs first. 

I nc yte C or p orati o n 
Pa ge 4 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8. 2. 2.  
K ar n ofs k y Perf or m a nce St at us  
Kar n ofs k y p erf or m a nce stat us is a sta n dar d wa y of meas uri n g t he a bilit y of  patie nts wit h ca ncer  
t o perf or m or di nar y tas ks. T he sc ores ra n ge fr o m 0 t o 1 0 0 (see Ta ble  1 1 ) a n d will be assesse d at 
t he visits s pecifie d i n t he S o A (see Ta bl e  3 ). It is rec o m me n de d, w hen  p ossi ble, t hat a 
partici pa nt 's perf or ma nce stat us be assesse d b y t he sa me pers o n t hr o u g h o ut t he st u d y . 
T a ble  1 1 : 
K ar n ofs k y Perf or m a nce St at us  Sc ores  
Sc ore  
Perf or m a nce St at us  
1 0 0  
N or mal, n o c o m plai nts; n o e vi de nce of disease . 
9 0  
A ble t o carr y o n n or mal acti vit y, mi n or  si g ns or s y m pt o ms of disease.  
8 0  
N or mal acti vit y wit h eff ort , s o me s y m pt o ms or si g ns of disease . 
7 0  
C ares f or self; u na ble t o carr y o n  n or mal acti vit y or t o d o acti ve w or k.  
6 0  
Re q uiri n g occasi o nal assista nce , ca n ta ke care of m ost pers o nal re q uire me nts. 
5 0  
Re q uires c o nsi dera ble assista nce , re q uires fre q ue nt me dical care. 
4 0  
Disa ble d, re q ui res s pecial care a n d assista nce. 
3 0  
Se verel y disa ble d, h os pital a d missi o n i n dicate d b ut n o ris k of deat h.  
2 0  
Ver y ill, ur ge ntl y re q uiri n g h os pital a d missi o n, re q uires s u p p orti ve meas ures or treat me nt.  
1 0  
M ori b u n d; fatal pr ocesses pr o gressi n g ra pi dl y.  
0  
Dea d . 
S o urce : Terret et al 2 0 1 1 . 
8. 2. 4.  
Me dic al Res o urce Utiliz ati o n a n d He alt h Ec o n o mics  
Me dical res o urce utilizati o n a n d healt h ec o n o mics data, ass ociat e d wit h me dical e nc o u nters, ma y 
be assesse d usi n g dat a alr ea d y ca pt ure d i n t he e C R F f or all partici pa nts i n t his st u d y (e g, A Es, 
c o nc o mita nt me dicati o ns, pr oce d ures).  
T he data c ollecte d ma y b e use d t o c o n d uct e x pl orat or y ec o n o mic a n al yses a n d ma y i ncl u de:  
•  N u m ber a n d d urati o n of me dical care e n c o u nters, i ncl u di n g s ur geries, a n d ot her 
selecte d pr o ce d ures (i n patie nt a n d o ut patie nt). 
•  D urati o n of h os pitalizati o n (t otal da ys or le n gt h of sta y, i ncl u di n g d urati o n b y war ds 
[e g, i nte nsi ve care u nit). 
•  N u m ber a n d t y pe of dia g n ostic a n d t hera p e utic tests a n d pr oce d ures.  
•  O ut patie nt me dical e nc o u nters a n d treat me nts (i ncl u di n g p h ysicia n or e mer ge nc y 
r o o m visits, tests a n d pr oce d ures, a n d me dicati o ns).  

I nc yte C or p orati o n 
Pa ge 4 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8. 3.  
S afet y Assess me nts  
See Secti o n  6. 5  f or g ui deli nes re gar di n g t he ma n a ge me nt of rel e va nt la b orat or y or ot her s afet y 
assess me nt a b n or mali ties. 
8. 3. 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 partici pa nt si g ns t he I C F u ntil at least 
3 0  da ys after t h e last d ose of st u d y dr u g or u ntil t he start of ne w a ntica n cer t hera p y . A d verse 
e ve nts f or e nr olle d partici pa nts t hat be gi n or w ors e n after i nf or me d c o nse nt s h o ul d be rec or de d 
o n t he A d verse E ve nts F or m i n t he e C R F re g ar dless of t he ass u m pti o n of a ca usal r elati o ns hi p 
wit h t he st u d y dr u g . C o n diti o ns t hat were alrea d y prese nt at t he ti me of i nf or me d c o nse nt s h o ul d 
be rec or de d o n t h e M e dic al Hist or y F or m i n t he e C R F . A d verse e ve nts (i n cl u di n g la b orat or y 
a b n or malities t hat c o nstit ute A Es) s h o ul d be des cri be d usi n g a 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. 
A d verse e ve nts will be re p orte d b y t he partici p a nt ( or, w he n a p pr o priat e, b y a care gi ver, 
s urr o gate, or t h e partici p a nt's le gall y a ut h orize d re prese nt ati ve). T he i n v esti gat or a n d a n y 
q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d rec or di n g e ve nts t hat meet 
t he defi niti on of a n A E or S A E a n d re m ai n res p o nsi ble f or f oll o wi n g -u p o n A Es t hat are s eri o us, 
c o nsi dere d relate d t o t he st u d y dr u g/ pr oce d ures, or t hat ca use d t h e partici p a nt t o disc o nti n ue t he 
st u d y dr u g. Care will be t a ke n n ot t o i ntr o d uce bias w he n detecti n g A Es a n d/ or S A Es . 
O pe n -e n d e d a n d n o nle a di n g ver bal q uesti o ni n g of t he partici pa nt, s uc h as "H o w are y o u 
feeli n g?" is t he preferre d met h o d t o i n q uire a b o ut A E occ urre nces . A d verse e ve nts ma y als o be 
detecte d w h e n t he y are v ol u nteere d b y t he p artici pa nt  d uri n g t he scree ni n g pr ocess or b et wee n 
visits or t hr o u g h p h ysical e xa mi nati o ns, la b orat or y tests, or ot her assess me nts . 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  9 . 
All S A Es will 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 . T he i n vesti gat or will 
s u b mit a n y u p date d S A E data t o t he s p o ns or wit hi n 2 4 h o urs of it bei n g a vaila ble. 
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts . All S A Es will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt 
is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w-u p (as defi ne d i n Secti o n 7. 3 ). 
F or Ja p a n, t he relati o ns hi p of t he a d verse e v e nt t o p h os p hate bi n der(s) s h o ul d als o be c ollecte d 
o n t he A d verse E ve nts F or m i n t he e C R F. 
8. 3. 2.  
P h ysic al E x a mi n ati o ns  
P h ysical e xa mi nati o ns m ust be perf or m e 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 n ce d re gistere d n urse practiti o ner, as l ocal la w 
per mits . A b n or malities i de ntifie d after  t he first d ose of st u d y treat me nt c o nstit ute a n A E if t he y 
are c o nsi d ere 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 g es i n st u d y dr u g. I n v esti gat ors s h o ul d pa y s pecial atte nti o n t o cli nical 
si g ns relate d t o pre vi o us seri o us ill nesses. 
At t he scree ni n g visit, a c o m pre he nsi ve p h ysical e xa mi nati o n s h o ul d be c o n d ucte d . T he 
c o m pre he nsi ve p h ysic al e xa mi nati o n will i ncl u de hei g ht a n d b o d y wei g ht, 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, ears, n os e, a n d t hr o at; t h yr oi d; l u n gs; 

I nc yte C or p orati o n 
Pa ge 4 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
car di o vas c 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 x a mi nati o n.  
Wei g ht will als o be assesse d at t he be gi n ni n g of eac h c y cle . 
D uri n g t he st u d y, partici pa nts will be assesse d b y t he i n vesti gat or or me dicall y q ualifie d 
desi g nee per i nstit uti o nal sta n dar d of care . T hese assess me nts s h o ul d be a n e val uati o n as 
i n dicate d b y partici pa nt s y m pt o ms, A Es, or ot her fi n di n gs a n d d oc u me nte d o n t he A E e C R F. 
8. 3. 3.  
Ne ur ol o gic al Assess me nt  
Ne ur ol o gical ass ess me nts 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 ysi cia n's assista nt, or a n a d v a nce d re gistere d n urse practiti o ner, as l ocal 
la w per mits. A ne ur ol o gi cal assess me nt usi n g t he N A N O sc ore m ust be perf or me d as i n dicat e d 
i n t he S o A (see Ta ble  3 ). 
8. 3. 4.  
Vit al Si g ns  
A b n or mal vital si g n res ults i de ntifie d after t he first  d ose of st u d y dr u g c o nstit ute a n A E if t he y 
are c o nsi d ere 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 g es i n st u d y dr u g. 
Vital si g n meas ure me nts (t o be ta ke n bef ore bl o o d c ollecti o n f or la b orat or y  tests), 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 . If vital si g ns ca n n ot be ta ke n bef ore 
bl o o d c ollecti o n f or la b orat or y tests, t here m ust be a mi ni m u m of 3 0 mi n utes fr o m t he 
c o m pleti o n of t he bl o o d c ollecti o n pr oce d ures t o t he  be gi n ni n g of t he vital si g ns c ollecti o n . 
Bl o o d press ure a n d p ulse will be ta ke n wit h t he partici pa nt  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 . 
8. 3. 5.  
Electr oc a r di o gr a ms  
Si n gle 1 2 -lea d E C Gs will be o btai ne d as o utli ne d i n t he S o A (see Ta ble  3 ) usi n g a n E C G 
mac hi ne t hat a ut o maticall y calc ulates t he h eart rat e a n d meas ures P R, Q R S, Q T, a n d Q Tc 
i nter vals. All 1 2 -lea d E C Gs will be perf or m e d wit h t he partici pa nt 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 i nter pret e d b y t he i n vesti gat or at t he site t o be use d f or i m me diate 
partici p a nt ma na g e me nt . A d diti o nal 1 2 -lea d E C Gs ma y be perf or me d as cli nicall y i n dicate d t o 
ma na ge partici pa nt  safet y. T he decisi o n t o i ncl u d e or e xcl u d e a partici pa nt or disc o nti n ue st u d y 
treat me nt base d o n a n E C G fla g ge d as "A b n or m al, 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. 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 . I n t he e vent t hat a si n gl e Q Tc is >  4 8 0  millisec o n ds at scree ni n g, t he 
partici pa nt  ma y e nr oll if t he a vera ge Q Tc f or t he 3 E C Gs is ≤ 4 8 0  millisec o n ds or wit h a p pr o val 
fr o m t he me dical m o nit or. F or p artici pa nt s wit h a n i ntra ve ntric ular c o n d ucti o n dela y ( Q R S 
i nter val >  1 2 0  millisec o n ds) at scree ni n g, t he J Tc i nter val ma y be us e d i n place of t h e Q Tc wit h 
me dical m o nit or a p pr o val . I n a d diti o n, t he J Tc i nt er val s h o ul d be use d f or all s u bse q ue nt 
assess me nts.  

I nc yte C or p orati o n 
Pa ge 5 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8. 3. 6.  
C o m pre he nsi ve E ye E x a mi n ati o n  
A c o m pre he nsi v e e ye e x a mi nati o n s h o ul d be perf or me d b y a q ualifie d o p ht hal m ol o gist at 
scree ni n g, o n ce e v er y 3 c ycles ( ± 7 da ys, starti n g at C ycle 3), at E O T, a n d as cli nicall y i n dicate d . 
T he e ye e xa mi nati o n s h o ul d i ncl u de a vis ual ac uit y test, slit -la m p e xa mi nati o n, f u n do sc o p y wit h 
di gital i ma gi n g, a n d O C T . E ver y eff ort s h o ul d be ma de t o e ns ure t h at all s u bse q ue nt 
e xa mi nati o ns are p erf or me d b y t he sa me o p ht hal m ol o gist.  
Per C T C A E v 5. 0, reti nal detac h me nt is gra d e d as 3 ( mac ular s p ari n g) a n d 4 ( mac ula‐ off), b ut 
t his refers t o r h e g mat o ge n o us reti nal detac h m e nt ( w he n a h ole occ urs i n t he reti na). T here is n o 
gra di n g f or S R D/ R P E D ( n o h ole i n t he mac ula, j ust fl ui d acc u m ulati o n). T heref ore, gra di n g 
s h o ul d be base d o n t he C T C A E v 5. 0 ter m of reti n o pat h y. 
8. 3. 7.  
L a b or at or y Assess m e nts  
See Ta ble  1 2  f or t he list of cli nical la b orat or y tests t o be perf or m e d a n d Ta ble  4  f or t he ti mi n g 
a n d fre q u e nc y . A certifi e d la b orat or y l ocal t o t he i n vesti gati ve site will perf or m all cli nical 
la b orat or y ass ess me nts f or safet y (i e, bl o o d c he mistries, he mat ol o g y assess me nts, c oa g ulati o n 
tests, e n d ocri ne f u ncti o n, a n d uri nal ysis). T he i n vesti gati ve site will e nter t he la b orat or y res ults 
a n d la b orat or y n or mal ra n ges i nt o t he e C R F . A d diti o nal testi n g ma y be re q uire d b y t he s p o ns or 
base d o n e mer gi n g safet y data . A d diti o nal tests ma y als o be perf or me d if cli nicall y i n dicate d . 
A ce ntral la b orat or y will a nal yze all P K a n d tra nsl ati o nal sa m ples . I nf or mati o n re gar di n g 
c ollecti o n, pr ocessi n g, a n d s hi p pi n g of la b orat or y assess me nts is pr o vi de d i n t he La b orat or y 
Ma n ual.  
Ser u m p h os p hate testi n g is re q uire d o n Da y 8 i n C ycl es 2 + if a p artici pa nt d e vel o ps H P  d uri n g 
C ycle 1 . Parat h yr oi d h or m o ne (e n d ocri ne) testi n g is re q uire d at bas eli ne a n d Da y 1 of e v er y t hir d 
c ycle (starti n g wit h C ycle 3) as parat h yr oi d h or m o ne pla ys a r ole i n calci u m a n d p h os p hate 
he m ostasis ( K h u n d miri et al 2 0 1 6 ). 
Cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs are t h ose t hat are n ot ass ociate d wit h t he 
u n derl yi n g disease, u nless j u d ge d b y t he i n vesti gat or t o be m ore se v ere t h a n e x pecte d f or t he 
partici pa nt 's c o n diti o n. All  la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntl y 
a b n or mal d uri n g partici p ati o n i n t he st u d y or wit hi n 3 0 da ys after t he l ast d ose of st u d y treat me nt 
s h o ul d be re peate d u ntil t he val ues ret ur n t o n or mal or baseli ne or are n o l o n ger c o nsi dere d 
cli nicall y si g nifica nt b y t he i n vesti gat or or me dical m o nit or.  
Scree ni n g la b orat or y ass ess me nts f or he mat ol o g y, c he mistr y, a n d c o a g ulati o n m ust be perf or me d 
wit hi n 1 4 da ys bef ore C y cle 1 Da y 1 . If perf or me d m ore t ha n 1 4 da ys bef ore C ycle 1 Da y 1, t he n 
t he tests m ust be re peat e d a n d eli gi bilit y c o nfir me d bef ore st u d y tr eat me nt a d mi nistrati o n o n 
C ycle 1 Da y 1 . 
La b orat or y s a m ple c ollecti o n o n C ycle 1 Da y 1 m ust be perf or m e d bef ore st u d y treat me nt 
a d mi nistrati o n . After C ycle  1, pre d os e la b orat or y pr o ce d ures ca n b e c o n d u cte d u p t o 7 2  h o urs 
bef ore st u d y tr eat me nt a d mi nistrati o n ( wit hi n t he 3 -da y st u d y wi n d o w), a n d res ults s h o ul d be 
re vie we d b y t h e i n vesti gat or or q ualifie d d esi g nee a n d f o u n d t o be acce pt a ble bef ore a ne w c ycl e 
of treat me nt is i nitiate d.  

I nc yte C or p orati o n 
Pa ge 5 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  1 2 : 
Re q uire d L a b or at or y A n al ytes  
Bl o o d C he mistries  
He m at ol o g y  
Uri n al ysis Wit h 
Micr osc o pic E x a mi n ati o n  
S er ol o g y 
C o a g ul ati o n  
Al b u mi n  
Al kali ne p h os p hatase  
A L T  
A S T  
A m ylase  
Bicar b o nate or C O 2  (n ot 
a p plica ble i n Ja p a n ) 
Bl o o d urea nitr o ge n or urea  
Calci u m  
C hl ori de  
Creati ni ne  
Gl uc ose  
Lactate de h y dr o ge nase  
Li pase  
Ma g nesi u m  
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 ele v ate d a b o ve U L N) 
T otal pr otei n  
Uric aci d  
Vita mi n D ( 2 5 -h y dr o x y vita mi n D 
a n d 1, 2 5 -di hi dr o x y vita mi n D) a 
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 m at ocrit  
•  Platelet c o u nt  
•  Re d bl o o d cell c o u nt  
•  W B C 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 hils  
•  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 
C ol or a n d a p peara nce  
p H a n d s pecific gra vit y  
Bilir u bi n  
Gl uc ose  
Ket o nes  
Le u k oc ytes  
Nitrite  
Occ ult bl o o d  
Pr otei n  
H Bs A g  
H Bs A g a nti b o d y  
He p atitis B c ore a nti b o d y  
H C V a nti b o d y  
N O T E : If a n y of t he a b o ve 
are p ositi ve, H B V -D N A, 
H C V -R N A ma y be d o ne t o 
assess ris k of reacti vati o n, if 
i n dicate d (e g, n o hist or y of 
i m m u nizati o n) 
P T  
P T T or a P T T  
I N R 
E n d ocri ne F u ncti o n  
Pre g n a nc y Testi n g  
P T H a 
h C G (ser u m a n d uri ne)  
N ote: A d diti o nal tests ma y be re q uire d, as a gree d u p o n b y t he i n vesti g at or a n d s p o ns or, base d o n e mer gi n g safet y data or t o r ule o ut a dia g n osis.  
a Res ults n ot re q uire d pri or t o d ose a d mi nistrati o n.  
 

I nc yte C or p orati o n 
Pa ge 5 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8. 3. 7. 1.  
Pre g n a nc y Testi n g  
A ser u m pre g n a nc y test will be re q uire d f or all W O C B P  d uri n g scree ni n g a n d at t he E O T  a n d 
safet y f oll o w-u p  visit s; partici pa nts g oi n g i nt o h os pice are n ot re q uir e d t o ha ve a n  E O T 
pre g na nc y t est . Uri ne pre g na nc y tests will be perf or me d l ocall y o n Da y 1 of eac h c ycle, as 
o utli ne d i n Ta ble  4 , as me dicall y i n dicate d (e g, i n case of l oss of m e nstr ual c ycle, w h e n 
pre g na nc y is s us pecte d), or per c o u ntr y -s pecific re q uire me nt ( n ote t hat c o u ntr y-re q uir e d uri ne 
pre g na nc y t esti n g will be o utli ne d a n d c o m m u nicate d t o i n vesti gati o nal sites u n der se parate 
c o ver). If a uri ne pre g na n c 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 t est.  
If t he ser u m pre g na n c y test is ne gati ve after a uri n e test was p ositi ve, the i n vesti gat or will assess 
t he p ote ntial be nefit/ris k t o t he partici pa nt a n d det er mi ne w het her it is i n t he partici pa nt's best 
i nterest t o res u me st u d y dr u g a n d c o nti n ue partici pati o n i n t he st u d y.  
If a pre g na nc y is c o nfir m e d b y a ser u m pre g na n c y test, see Secti o n 9. 7  f or re p orti n g 
re q uire me nts. 
8. 3. 7. 2.  
Ser ol o g y  
Ser ol o g y  assess me nts will be perf or m e d at t he scree ni n g visit t o r ule o ut he patitis i nfecti o n; 
re q uire d a nal ytes are s h o w n i n Ta ble  1 2 . Ge n erall y, he patitis tests s h o ul d be perf or me d earl y i n 
t he scree ni n g pr ocess d u e t o t he le n gt h of ti me nee de d t o o btai n t he res ults. A d diti o nal tests ma y 
be perf or me d if cli nicall y i n dicate d.  
8. 4.  
P h ar m ac o ki netic Assess me nts  
Plas ma  sa m ples will be c ollecte d f or t he m eas ure me nt of plas ma  c o nce ntr ati o ns of pe mi gati ni b  
as s pecifie d i n T a ble  4  a n d Ta ble  1 3 . A ma xi m u m of 8  sa m ples ma y be c oll ecte d at a d diti o nal 
ti me p oi nts d uri n g t he st u d y if warra nte d a n d a gree d u p o n bet wee n t he i n v esti gat or a n d t he 
s p o ns or. Sa m ples c ollect e d f or a n al y ses of p e mi gati ni b  plas ma  c o nce ntr ati o ns ma y als o be use d 
t o e val uate safet y or effic ac y as pects relat e d t o c o ncer ns arisi n g d uri n g or after t he st u d y. T he 
act ual date a n d ti me ( 2 4 -h o ur cl oc k ti me) of eac h sa m ple will be rec or de d . I nstr u cti o ns f or t he 
c ollecti o n a n d ha n dli n g of bi ol o gical sa m ples will be pr o vi de d i n t he La b orat or y Ma n ual.  
8. 4. 1.  
Bl o o d S a m ple C ollecti o n  
P har mac o ki netic sa m ples will be o btai ne d at t he visits i n dicate d i n Ta ble  4 . T he e xact date a n d 
ti me of t he P K bl o o d dra ws will be rec or de d i n t he e C R F al o n g wit h t he date a n d ti me of t he last 
d ose of st u d y dr u g prece di n g t he bl o o d dra w a n d t he ti me of t he m ost rece nt meal. I nstr u cti o ns 
f or sa m ple pre parati o n a n d s hi p pi n g will be pr o vi de d i n t he La b orat or y Ma n ual. Partici pa nt s will 
recei v e re mi n der car ds pri or t o  t he st u d y visit pr o vi di n g i nstr ucti o n t o h ol d t he d ose of st u d y 
dr u g o n t he da y of t he visit . D uri n g C ycle 1, P K sa m ples will be o btai n e d o n Da y 8. T he 
partici pa nt m ust refrai n fr o m eati n g 8 h o urs bef ore arri vi n g at t he site. A tr o u g h ( pre d ose) P K 
sa m ple will be dra w n earl y i n t he st u d y visit; t he sa m ple m ust be dra w n a p pr o xi matel y 1 h o ur 
bef ore st u d y dr u g a d mi nistrati o n. A 5 -mi n ute wi n d o w ca n be a p plie d t o P K sa m ple c ollecti o n  at 
1  a n d 2 h o urs p ost d ose . Partici pa nts t he n nee d t o f ast f or 1 a d diti o nal h o ur after ta ki n g st u d y 
me dicati o n. O nce t h e partici pa nt  ta kes t he st u d y dr u g, a n y s u bse q ue nt ti me d sa m ples will be 
ta ke n as per Ta ble  1 3 . 

I nc yte C or p orati o n 
Pa ge 5 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  1 3 : 
P h ar m ac o ki netic Bl o o d S a m ple Ti mi n g  
St u d y Visit  
Ti mi n g of S a m ple  
C ycle 1 Da y 8  
•  Pre d ose  
•  1  h o ur p ost d ose  
•  2  h o urs p ost d ose  
•  4 -1 2  h o urs p ost d ose  
8. 4. 2.  
P h ar m ac o ki netic  A n al ysis  
T he data will be a n al yze d b y sta n dar d p o p ulati o n P K met h o ds usi n g a p pr o priate s oft ware 
(e g, N O N M E M ® ). A n atte m pt will be ma de t o e val uate t he effect of d e m o gra p hic a n d b aseli ne 
c haract eristics ( e g, a ge, wei g ht, se x, race, re nal f u ncti o n,  a n d F G F/ F G F R alterati o n stat us) o n t he 
p o p ulati o n P K pr ofile. A d diti o nall y, e x p os ure -res p o nse a nal yses f or ke y efficac y a n d safet y 
para meters will als o be c o nsi dere d if t here are s ufficie nt data a v aila ble. 
8. 5.  
P h ar m ac o d y n a mic a n d Tr a nsl ati o n al Assess me nts  
8. 5. 1.  
Bi o m ar ker  Assess m e nt  f or Eli gi bilit y 
Partici pa nts will be re q uire d t o ha ve a d oc u me nte d acti o na ble F G F R 1 -3 g e ne alterati o n 
(i ncl u di n g defi ne d m utati o ns, ge ne f usi o n/rearra n g e me nts, or i n-fra me deleti o ns; see 
A p pe n di x  B ) fr o m t u m or tiss ue (or plas ma ) as d eter mi ne d b y a l ocall y q ualifie d la b orat or y 
e m pl o yi n g a m olec ular assa y ha vi n g a rele va nt m ar k of c o nf or mit y f or a n al ytical perf or ma nce 
(e g, C LI A [ U S] or U K C A, C E, C E U K NI , or ot h ers [ o utsi de of t he U S ]) or a c o m mercial re p ort 
fr o m t he ce ntr al la b orat or y t o be eli gi ble.  A p pe n di x  B  c o ntai ns a list of eli gi ble ge ne alterati o ns 
a n d k n o w n F G F R resista nce m utati o ns . A p pe n di x  B  is n ot all-i ncl usi ve, s o e xtre mel y rare or 
n o vel acti vati n g alterati o ns ma y n ot be i n t he list . 
Partici pa nts ma y be e nr olle d  a n d ca n recei ve  treat me nt base d o n a l ocal ge n o mics re p ort 
( n o n-F MI a n d c o m merci al F MI re p orts) or fr o m t he ce ntr al ge n o mics la b orat or y  ( F MI). F or 
p artici pa nts e nr olle d b ase d o n a l ocal ge n o mics re p ort f or tu m or tiss ue or bl o o d cf D N A  
( G uar da nt Healt h or c o m mercial F MI f or li q ui d bi o psies), t he y will be re q uire d t o pr o vi de a 
re dact e d ge n o mics la b orat or y res ult d oc u me nti n g t he eli gi ble alterati o n f or s p o ns or re vie w after 
si g ni n g t he I C F. A d diti o nall y, f or partici pa nts e nr olle d wit h a l ocal ge n o mic re p ort, t u m or tiss ue 
sa m ple (eit her arc hi val or fres h bi o ps y) s h o ul d be se nt t o t he s p o ns or's ce ntral ge n o mics 
la b orat or y ( F MI) f or retr os pecti ve c o nfir m ati o n of eli gi ble F G F R 1 -3 ge ne alterati o ns  (res ults 
fr o m ce ntr al re vie w are n ot re q uire d bef ore t h e first d ose). 
Arc hi val tiss ue , or fres h bi o ps y if arc hi val tiss ue is n ot a vaila ble, is e x pecte d at scree ni n g for 
co nfir mati o n testi n g of F G F R 1 -3 m utati o n or rearra n ge me nt at ce ntral g e n o mic la b orat or y usi n g 
F 1 C D x assa y . Partici p a nts w h o ha ve a c o m merci al re p ort fr o m t he ce ntr al la b orat or y ( F MI ) at 
scree ni n g will n ot nee d t o se n d a sa m ple f or c o nfir mat or y testi n g. Deta ils re gar di n g sa m ple 
c ollecti o n, pr ocessi n g, a n d s hi p pi n g will be pr o vi de d i n t he La b orat or y Ma n ual.  
I n a d diti o n t o c o nfir mati o n of t he F G F R alterati o n, baseli ne t u m or tiss ue ma y be use d f or I H C, 
ge ne -e x pressi o n pr ofili n g, t u m or m utati o n b ur de n, a n d i m m u ne -cell pr ofili n g i n or der t o st u d y 

I nc yte C or p orati o n 
Pa ge 5 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
baseli ne c haracteristics of t he t u m or a n d t u m or micr oe n vir o n me nt f o r p ote ntial c orrelati o ns wit h 
res p o nse, resista nce, or t o xicit y t o pe mi gati ni b . 
8. 5. 2.  
Pl as m a f or M ut ati o n al A n al ysis  
Bl o o d f or m utati o nal a nal ysis of cf D N A will be c ollecte d pre d os e o n C ycle 1 Da y  1 ( baseli ne) 
a n d at disease pr o gressi o n  or E O T  (see Ta ble  4  a n d Ta ble  1 4 ). A nal ysis of t u m or m utati o nal  
stat us will be c o n d ucte d b y t he s p o ns or or its desi g nee, a n d ot her assa ys rele va nt t o t he 
o bjecti ves of t he st u d y ma y be perf or me d base d u p o n e mer gi n g data . Details re gar di n g sa m ple 
c ollecti o n, pr ocessi n g, a n d s hi p pi n g will be pr o vi de d i n t he La b orat or y M a n ual.  
8. 5. 3.  
Pl as m a f or C orrel ati ve A n al ysis  
Bl o o d f or plas ma bi o mar ker a nal ysis will be dra w n f or all partici pa nts at pr e d ose o n C ycle 1 
Da y  1  a n d a n y ti me o n  C ycle 1 Da y 8  a n d C ycle 4 Da y 1 (see Ta ble  4  a n d Ta ble  1 4 ). A d diti o nal 
assess me nts ma y be c ollecte d i n or der t o c orrelate p ote ntial bi o mar kers wit h A Es, res p o nse, or 
resista nce t o treat me nt. T he a nal yses ma y i n cl u de assess me nt of mar k ers of i m m u ne a n d 
i nfla m mati o n stat us, i ncl u di n g c yt o ki nes a n d s ol u ble rece pt ors, as w ell as e xa mi nati o n of 
mar kers ass o ciate d wit h t u m or meta b olis m . Ot her assa ys rele va nt t o t he o bjecti ves of t he st u d y 
ma y be perf or me d bas e d u p o n e mer gi n g data . Det ails re gar di n g sa m ple collecti o n, pr ocessi n g , 
a n d s hi p pi n g will be pr o vi de d i n t he La b orat or y M a n ual.  
8. 5. 4.  
Tiss ue Bi o psies  
T u m or bi o psies will be c ollecte d  at t he ti me p oi nts i n dicate d i n Ta ble  4  a n d Ta ble  1 4  as f oll o ws: 
•  Scree ni n g : T u m or tiss ue ma y be c ollecte d d uri n g scree ni n g. Arc hi val f or mali n -fi xe d 
paraffi n -e m be d d e d tiss ue sa m ple is e x pecte d or a fres h bi o ps y ma y be perf or me d if 
arc hi val tiss ue is n ot a vaila ble.   
N ote : Fres h t u m or bi o psi es s h o ul d be ta ke n fr o m n o ntar get lesi o ns w he n p ossi ble.  
•  E n d of Tre at me nt : A bi o ps y at E O T/t he ti me of pr o gressi o n is re q ues t e d b ut n ot 
re q uire d fr o m all partici p a nts. A nal ysis of t he t u m or tiss ue will assist i n 
u n dersta n di n g t he c h a n ges t hat occ ur i n ge n o mic alterati o ns after treat me nt wit h 
pe mi gati ni b. If E O T occ urs less t ha n 6 wee ks after t he o n-treat me nt bi o ps y was 
perf or me d, a n E O T bi o ps y s h o ul d n ot be perf or me d.  

I nc yte C or p orati o n 
Pa ge 5 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble  1 4 : 
Bi o m ar ker/ Tr a nsl ati o n al S a m ple Ti mi n g  
Bi o m ar ker Assess me nt  
St u d y Visit  
Ti mi n g of S a m ple  
A n yti me  
Pre d ose  
Plas ma c orrelati ve sa m ple  
C ycle 1 Da y 1  
 
X  
C ycle 1 Da y 8  
X  
 
C ycle 4 Da y 1  
X  
 
Plas ma cf D N A  
C ycle  1 Da y 1  
 
X  
E O T  
X  
 
T u m or tiss ue 
Scree ni n g  
X  
 
E O T  
X  
 
8. 6.  
U nsc he d ule d Visits  
U nsc he d ule d visits ma y occ ur as cli nicall y i n dicate d . T he y ca n b e use d f or visits t hat occ ur 
o utsi de of visit wi n d o ws a n d s h o ul d be n ote d i n t he e C R F as a n u nsc he d ule d visit. 
8. 7.  
E n d of Tre at me nt a n d/ or E arl y Ter mi n ati o n  
W he n t he partici pa nt per ma ne ntl y disc o nti n ues st u d y dr u g w het her t h e partici pa nt is ter mi nati n g 
t he st u d y earl y or t he p artici pa nt has c o m plete d t h e st u d y, t he EO 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 u ati 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 nt ere d i n t he E O T visit i n t he e C R F. T he partici pa nt 
s h o ul d be e nc o ura ge d t o ret ur n f or t h e f oll o w-u p visit.  
8. 8.  
F oll o w -U p  
8. 8. 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 da ys  after t h e E O T visit ( or after t he l ast d ose of st u d y dr u g if t he 
E O T visi t was n ot perf or me d). A d vers e e v e nts a n d S A Es m ust be re p orte d u p u ntil 1)  at least 
3 0  da ys after t h e last d ose of st u d y dr u g  or t he start of a ne w a ntica n cer t hera p y  or 2) u ntil 
t o xicities res ol ve, ret ur n t o baseli ne, or are dee me d irre versi ble, w hic he v er is l o n ger. Reas o na ble  
eff orts s h o ul d be ma d e t o ha ve t he partici pa nt 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 t he p artici pa nt ca n n ot ret ur n t o t he site f or t he safet y f oll o w-
u p visit (e g, li ves far a w a y), t he partici pa nt s h o ul d be c o ntact e d b y tele p h o n e f or ass ess me nt of 
A Es a n d S A Es . Sites s h o ul d be i nstr ucte d t o d oc u me nt t his c o ntact i n t he s o urce.  
If a partici pa nt is sc he d ul e d t o be gi n a ne w a ntica n cer t hera p y bef ore t h e e n d of t he 3 0-da y s afet y 
foll o w -u p peri o d, t he safet y f oll o w -u p visit s h o ul d be perf or me d bef ore t h e ne w a ntica ncer 
t hera p y is starte d. O n ce a ne w a ntica n cer t h era p y has bee n i nitiate d, t he partici pa nt will m o ve 
i nt o t he s ur vi val f oll o w-u p peri o d.  

I nc yte C or p orati o n 
Pa ge 5 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
8. 8. 2.  
P ost -Tre at me nt Dise as e F oll o w -U p  
P artici pa nts w h o disc o nti n ue st u d y dr u g f or a reas o n ot her t ha n disease pr o gressi o n will m o ve 
i nt o t he disease stat us f oll o w-u p peri o d a n d s h o ul d be assesse d e ver y 9 wee ks ± 7 da ys b y 
ra di ol o gic i ma gi n g t o m o nit or disease stat us. E ver y eff ort s h o ul d be ma d e  t o c ollect i ma gi n g 
i nf or mati o n re gar di n g disease stat us u ntil: 
•  T he start of ne w a ntica n cer t hera p y: t he start of t h e ne w treat me nt s h o ul d be ca pt ur e d, 
b ut t he partici pa nt s h o ul d c o nti n ue t o ha ve diseas e assess me nts u ntil pr o gressi ve 
disease (see bel o w)  
•  Di sease pro gressi o n (c o nfir me d b y a n I C R)  
•  Deat h  
•  T he e n d of st u d y  
8. 8. 3.  
S ur vi v al F oll o w -U p  
O nce a p artici pa nt has recei ve d t he last d ose of st u d y dr u g, has c o nfir m e d disease pr o gressi o n, or 
starts a ne w a ntica ncer t h era p y, t he p artici pa nt 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 c o ntacte d b y tele p h o ne, e mail, or visit at least e very 8  wee ks  (±  1 4 da ys)  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.  
F or partici pa nts ha vi n g e ntere d t he s ur vi val f oll o w -u p peri o d of t h e st u d y, t he site will use 
c o nti n ui n g partici pa nt re c or ds t o s u p pl y data o n s u bse q ue nt treat me nt r e 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 partici pa nts 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 b y p h o ne c o ntact, partici pa nt  rec or ds, a n d p u blic 
rec or ds/ dat a bases at i nter vals of n o l o n ger t ha n 8  wee ks.  

I nc yte C or p orati o n 
Pa ge 5 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
9.  
A D V E R S E E V E N T S: D E FI NI TI O N S A N D P R O C E D U R E S F O R 
R E C O R DI N G, E V A L U A TI N G, F O L L O W -U P, A N D R E P O R TI N G  
9. 1.  
Defi niti o n of A d verse E ve nt  
A d verse E ve nt Defi niti o n  
•  A n A E is a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g i n h u ma ns, w het her or 
n ot it is c o nsi dere d dr u g -relate d. 
•  A n A E ca n t heref ore be a n y u nfa v ora ble or u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y 
fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y ass ociate d wit h t he use of st u d y dr u g. 
A d diti o n al G ui d a nce f or E ve nts Meeti n g t he A d verse E ve nt Defi niti o n  
•  A n y safet y assess me nts (e g, E C G, vital si g ns meas ure me nts), i ncl u di n g t h ose t hat w orse n fr o m 
baseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he me dical a n d scie ntific j u d g me nt of t he i n vesti gat or 
(ie, n ot relate d t o pr o gressi o n of u n derl yi n g disease) are t o be re p orte d as a n A E. 
•  A b n or mal la b orat or y test res ults are  t o be re p orte d as a n A E if t he y are 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. W he ne ver p ossi ble, a dia g n osis (e g, a ne mia, t hr o m b oc yt o pe nia) s h o ul d be rec or de d i n 
t he e C R F rat her t ha n t he a b n or mal la b orat or y test res ult (e g, l o w he m o gl o bi n, platelet c o u nt 
decrease d).  
•  E xacer bati o n of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n/ disease, i ncl u di n g eit her a n i ncrease 
i n t he fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n, is t o be re p orte d as a n A E. 
•  Ne w c o n diti o ns detecte d or dia g n ose d after t he start of st u d y dr u g a d mi nistrati o n are t o be re p orte d 
as a n A E. 
•  Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n are t o be re p orte d as 
a n A E. 
•  Si g ns a n d/ or s y m pt o ms fr o m d ose a d mi nistrati o n  err ors of a st u d y dr u g (e g, o ver d ose) or a 
c o nc o mita nt me dicati o n are t o be re p orte d as a n A E.  
•  "Lac k of efficac y, " "disease pr o gressi o n, " or "fail ure of e x pecte d p har mac ol o gical acti o n" will n ot be 
re p orte d as a n A E or S A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y assess me nts.  
•  A c o n diti o n t hat lea ds t o a me dical or s ur gical pr oce d ure (e g, e n d osc o p y, a p pe n dect o m y) will be 
re p orte d as a n A E if it occ urs after o btai ni n g i nf or me d c o nse nt. T he pr oce d ure s h o ul d als o be 
d oc u me nte d i n t he e C R F. If t he c o n diti o n is prese nt bef ore e nteri n g t he st u d y ( pri or t o si g ni n g t he 
I C F), t he n it s h o ul d be ca pt ure d as me dical hist or y. 
•  Pre -e xisti n g diseases or c o n diti o ns wit h e x pecte d fl uct uati o ns i n si g ns or s y m pt o ms s h o ul d be 
re p orted as a n A E o nl y if t he i n vesti gat or j u d ges t he fl uct uati o n t o ha ve w orse ne d m ore t ha n 
e x pecte d d uri n g st u d y partici pati o n.  

I nc yte C or p orati o n 
Pa ge 5 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
9. 2.  
Defi niti o n of Seri o us A d verse E ve nt  
If a n e v e nt is n ot a n A E per t he defi niti o n a b o ve, t he n it ca n n ot be a n S A E e ve n if seri o us 
c o n diti o ns are met (e g, h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n der st u d y, deat h d ue 
t o pr o gressi o n of diseas e). 
A seri o us a d verse e ve nt is defi ne d as a n y u nt o w ar d me dic al occ urre nce t h at, at a n y d ose:  
a.  Res ults i n de at h  
b.  Is life-t hre ate ni n g 
T he ter m "life-t hreate ni n g" i n t he defi niti o n of "seri o us" refers t o a n a d verse dr u g e x perie nce t hat 
places t he partici pa nt, i n t he o pi ni o n of t he i nitial re p orter, at i m me diate ris k of deat h fr o m t he a d verse 
e x perie nce as it occ urs . T his d oes n ot i ncl u de a n a d verse dr u g e x perie nce t hat, ha d it occ urre d i n a 
m ore se vere f or m, mi g ht ha ve ca use d deat h . 
c. Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n  
I n ge neral, h os pitalizati o n si g nifies t hat t he partici pa nt has bee n detai ne d (i n v ol vi n g at least a n 
o ver ni g ht sta y) at t he h os pital  or e mer ge nc y war d f or o bser vati o n a n d/ or treat me nt t hat w o ul d n ot ha ve 
bee n a p pr o priate i n t he p h ysicia n 's office or o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g 
h os pitalizat i o n are A Es. If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, 
t he e ve nt is seri o us. W he n i n d o u bt as t o w het her h os pitalizati o n occ urre d or was necessar y, t he A E 
s h o ul d be c o nsi dere d seri o us. 
H os pitalizati o n f or electi ve t reat me nt or pla n ne d s ur ger y (e g, ste nt re place me nt, hi p s ur ger y) is n ot 
c o nsi dere d a n S A E.  
H os pitalizati o n f or me dical i nter ve nti o ns i n w hic h n o u nfa v ora ble me dical occ urre nce occ urre d 
(ie, electi ve pr oce d ures or r o uti ne me dical visits) are n ot c o nsi dere d S A Es.  
d.  Res ults i n persiste nt or si g nific a nt dis a bilit y/i nc a p acit y  
•  T he ter m "disa bilit y " mea ns a s u bsta ntial disr u pti o n of a pers o n 's a bilit y t o c o n d uct n or mal life 
f u ncti o ns. T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce, s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d acci de ntal 
tra u ma (e g, s prai ne d a n kle), t hat ma y i nterfere wit h or pre ve nt e ver y da y life f u ncti o ns b ut d o n ot 
c o nstit ute a s u bsta ntial disr u pti o n.  
e. Is a c o n ge nit al a n o m al y/ birt h defect 
f. Is a n i m p ort a nt me dic al e ve nt 
A n i m p orta nt me dical e ve nt is a n 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 partici pa nt a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt 
o ne of t he o utc o mes liste d i n t he a b o ve defi niti o n . E xa m ples of s uc h e ve nts i ncl u de ne w i n vasi ve or 
mali g na nt ca ncers (e xcl u di n g t he disease[s] u n der st u d y), i nte nsi ve treat me nt i n a n e mer ge nc y 
de part me nt or at h o me f or aller gic br o nc h os pas m, bl o o d d yscrasias, or c o n v ulsi o ns t hat d o n ot res ult i n 
h os pitalizati o n, or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use . Sec o n dar y mali g na ncies s h o ul d 
al wa ys be c o nsi dere d S A Es.  
F or Ja pa n, an e ve nt t hat ma y lea d t o disa bilit y is als o c o nsi dere d a n i m p orta nt me dical e ve nt. It 
i ncl u des a case t hat is e x p ose d t o a ris k of d ysf u ncti o n t o a n e xte nt t hat i nterferes wit h dail y life w he n 
t he a d verse dr u g reacti o n occ urs. It d oes n ot i ncl u de a n a d verse dr u g reacti o n t hat, ha d t he reacti o n 
bee n m ore se vere, ma y ha ve ca use d disa bilit y . 

I nc yte C or p orati o n 
Pa ge 5 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
9. 3.  
Rec or di n g a n d F oll o w -U p of A d verse E ve nts a n d/ or Seri o us A d verse 
E ve nts  
A d verse E ve nt a n d Seri o us A d verse E ve nt Rec or di n g  
•  A n A E/ S A E t hat be gi ns or w orse ns after i nf or me d c o nse nt is si g ne d s h o ul d be rec or de d o n t he 
A d verse E ve nt F or m i n t he e C R F . A Es/ S A Es s h o ul d be re p orte d f or e nr olle d partici pa nts, b ut o nl y 
S A Es nee d t o be re p orte d f or scree n fail ure partici pa nts . F or e nr olle d partici pa nts , c o n diti o ns t hat 
were prese nt at t he ti me i nf or me d c o nse nt was gi ve n s h o ul d be rec or de d o n t he Me dical Hist or y 
e C R F. F or detaile d i nf or mati o n refer t o t he e C R F g ui deli nes.  
•  W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he i n vesti gat or t o re vie w all d oc u me ntati o n 
(e g, h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostic re p orts) relate d t o t he e ve nt.  
•  T he i n vesti gat or ( or dele gate) will t he n rec or d all rele va nt A E/ S A E i nf or mati o n i n t he e C R F.  
•  It is n ot  acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he partici pa nt 's me dical rec or ds 
i n lie u of c o m pleti n g t he A d verse E ve nt F or m i n t he e C R F. 
•  T here ma y be rare i nsta nces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d . I n t his 
case, all partici pa nt i de ntifiers, wit h t he e xce pti o n  of t he partici pa nt n u m ber, will be re dacte d b y t he 
site staff o n t he c o pies of t he me dical rec or ds bef ore s u b missi o n . T hese rec or ds ca n be s u b mitte d t o 
I nc yte P har mac o vi gila nce b y e mail/fa x per t he c o ntact i nf or mati o n liste d i n t he St u d y Refere nce 
Ma n ual or as per S A E c o m pleti n g g ui deli nes . 
•  T he i n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, s y m pt o ms, a n d/ or 
ot her cli nical i nf or mati o n . W he ne ver p ossi ble, t he dia g n osis ( n ot t he i n di vi d ual si g ns/s y m pt o ms) will 
be d oc u me nte d as  t he A E/ S A E. 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/ S A E. 
T o t he e xte nt p ossi ble, eac h A E/ S A E s h o ul d be e val uate d t o deter mi ne t he f oll o wi n g:  
•  T he se verit y gra de ( C T C A E v 5. 0 Gra de 1 t o 5) . See be l o w f or f urt her i nstr ucti o ns o n t he assess me nt 
of i nte nsit y.  
•  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 dr u g : s us pecte d 
( yes) or n ot s us pecte d ( n o). See bel o w f or f urt her i nstr ucti o ns o n t he assess me nt of ca usalit y. 
•  T he start a n d e n d dates, u nless u nres ol ve d at t he fi nal safet y f oll o w -u p visit.  
•  T he acti o n ta ke n wit h re gar d t o st u d y dr u g as a res ult of t he A E/ S A E(s).  
•  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 ved wit h se q uelae, fatal, u n k n o w n ). 
•  T he seri o us ness, as per t he S A E defi niti o n pr o vi de d i n Secti o n  9. 2 . 
•  T he acti o n ta ke n wit h re gar d t o t he e ve nt. N ote : If a n A E is treate d wit h a c o 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 t he A d verse E ve nt F or m , a n d t he treat me nt 
s h o ul d be s pecifie d o n t he a p pr o priate e C R F (e g, Pri or/ C o nc o mita nt Me dicati o ns, Pr o ce d ures a n d 
N o n -Dr u g T hera p y).  

I nc yte C or p orati o n 
Pa ge 6 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
Assess me nt of I nte nsit y  
T he se verit y of A Es will be assesse d usi n g C T C A E v 5. 0 Gra des 1 t hr o u g h 5 . 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.  
T he i n vesti gat or will ma ke a n assess me nt of i nte nsit y f or eac h A E a n d S A E re p orte d d uri n g t he st u d y 
a n d assi g n it t o 1 of t he f oll o wi n g cate g ories:  
•  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 va ti o ns o nl y; treat me nt 
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 treat me nt 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 dicall 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 treat me nt i n dicate d. 
•  Gr a de 5 : Fatal.  
Assess me nt of C a us alit y  
•  T he i n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y dr u g a n d eac h occ urre nce of 
eac h A E/ S A E . 
•  A "reas o na ble p ossi bilit y" of a relati o ns hi p c o n ve ys t hat t here are me dical facts, e vi de nce, a n d/ or 
ar g u me nts t o s u g gest a ca usal relati o ns hi p, rat her t ha n t hat a relati o ns hi p c a n n ot be r ule d o ut. 
•  T he i n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he p ossi bilit y of a relati o ns hi p.  
•  T he i n vesti gat or will als o c o ns ult t he R SI i n t he I B i n ma ki n g his/ her assess me nt.  
•  Alter nati ve ca uses, s uc h as u n derl yi n g or c o nc urre nt disease( s), c o nc o mita nt t hera p y, a n d ot her ris k 
fact ors, as well as t he te m p oral relati o ns hi p of t he e ve nt t o st u d y dr u g a d mi nistrati o n, will be 
c o nsi dere d a n d i n vesti gate d.  
•  F or eac h A E/ S A E, t he i n vesti gat or m ust  d oc u me nt i n t he me dical n otes t hat he/s he has re vie we d t he 
A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y.  
•  Wit h re gar d t o assessi n g ca usalit y of S A Es:  
− T here ma y be sit uati o ns i n w hic h a n S A E has occ urre d a n d t he i n vesti gat or has mi ni mal 
i nf or mati o n t o i ncl u de i n t he i nitial re p ort. H o we ver, t he ca usali t y assess me nt is o ne of t he criteria 
use d w he n deter mi ni n g re g ulat or y re p orti n g re q uire me nts . T heref ore, it is ver y i m p ort a nt t h at 
t he i n vesti g at or al w a ys m a ke a n assess me nt of c a us alit y b ase d o n t he a v ail a ble i nf or m ati o n 
f or e ver y e ve nt bef ore t he i niti al tr a ns missi o n of t he S A E. 
− T he i n vesti gat or ma y c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w -u p i nf or mati o n a n d 
s u b mit t he u p date d ca usalit y assess me nt. 

I nc yte C or p orati o n 
Pa ge 6 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
F oll o w -U p of A d verse E ve nts a n d Seri o us A d verse E ve nts  
•  T he i n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal meas ure me nts 
a n d/ or e val uati o ns as me dicall y i n dicate d or as re q ueste d b y t he s p o ns or t o el uci date t he nat ure 
a n d/ or ca usalit y of t he A E or S A E as f ull y as p ossi ble . T his ma y i ncl u de a d diti o na l la b orat or y tests 
or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n wit h ot her healt h care 
pr ofessi o nals.  
•  O nce a n A E is detecte d, it s h o ul d be f oll o we d i n t he A E e C R Fs u ntil it has res ol ve d or u ntil it 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.  
•  If a partici pa nt dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w-u p peri o d, t he 
i n vesti gat or will pr o vi de t he s p o ns or wit h a c o p y of a n y p ost m orte m fi n di n gs, i ncl u di n g 
hist o pat h ol o g y . 
•  U p date d S A E i nf or mati o n will be rec or de d i n t he ori gi nall y c o m plete d e C R F a n d re p orte d t o I nc yte 
P har mac o vi gila nce (i n t he S A E E D C C R F) u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise 
e x plai ne d, or t he  partici pa nt is l ost t o f oll o w -u p.  
•  A n y u p date d S A E data (i ncl u di n g S A Es bei n g d o w n gra de d t o n o nseri o us) will be s u b mitte d t o t he 
s p o ns or ( or desi g nee) wit hi n 2 4 h o urs of recei pt of t he i nf or mati o n.  
9. 4.  
Re p orti n g of Seri o us A d verse E ve nts  
Re gar dless of s us pect e d ca usalit y (e g, relati o ns hi p t o st u d y dr u g or st u d y pr oce d ure[s]), all S A Es 
occ urri n g after t h e partici pa nt has si g ne d t he I C F t hr o u g h 3 0  da ys aft er t he last d ose of st u d y 
dr u g or  u ntil t he partici pa nt  starts a ne w a ntica ncer t hera p y, w hi c he ver occ urs earlier, m ust be 
re p orte d t o t he s p o ns or ( or desi g nee) i m me diat el y, wit h o ut u n d ue dela y b ut n ot later t ha n wit hi n 
2 4  h o urs  of o btai ni n g k n o wle d ge of its occ urre n ce u nless ot her wise s p ecifie d b y t he Pr ot oc ol . 
T he i n vesti gat or will s u b mit a n y u p date d S A E data t o t he s p o ns or ( or desi g nee) i m me diatel y, 
wit h o ut u n d ue dela y b ut n ot later t ha n wit hi n 2 4 h o urs of it bei n g a vaila ble. F or Ja p a n, t his 
i nf or mati o n m ust als o be re p orte d i m me diatel y t o t he hea d of t h e st u d y site. 
I n v esti gat ors are n ot o bli gate d t o acti vel y see k S A E i nf or mati o n after 3 0  d a ys after t he last d ose 
of st u d y dr u g . If t he i n vesti gat or lear ns of a n y S A E, i ncl u di n g deat h, at a n y ti me d uri n g t he 
s ur vi val peri o d a n d he/s h e c o nsi ders t he e ve nt t o b e reas o n a bl y relat e d t o t he st u d y dr u g or st u d y 
partici pati o n, t he n t he i n vesti gat or m ust n otif y 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 a ware of t h e e ve nt . 
After t he i nitial A E/ S A E re p ort, t he i n vesti gat or is re q uire d t o pr o acti vel y f oll o w eac h partici pa nt 
at s u bse q ue nt visits/c o ntacts . All S A Es  will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt 
is ot her wise e x plai ne d, or t he partici pa nt is l ost t o f oll o w-u p (as defi ne d i n Secti o n  7. 3 ). 
Pr o m pt n otificati o n b y t he i n vesti gat or t o t he s p o ns or re gar di n g a n S A E is esse ntial s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war d t he safet y of partici pa nts a n d t he safet y o f a st u d y 
dr u g u n der cli nic al i n vesti gati o n are met.  
If t he S A E is n ot d oc u me nte d i n t he R SI of t he I B f or t he st u d y dr u g ( n e w occ urre nce) a n d is 
t h o u g ht t o be relate d t o t he st u d y dr u g, t he s p o ns or or its desi g nee ma y ur g e ntl y re q uire f urt her 

I nc yte C or p orati o n 
Pa ge 6 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
i nf or mati o n fr o m t he i n v esti gat or f or e x p e dite d re p orti n g t o healt h a ut 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 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 ort e d . S us pecte d u ne x pecte d s eri o us 
a d verse reacti o ns 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 rele va 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 r e g ulat or y re q uire m e nts 
i n partici pati n g c o u ntries. 
F or Ja p a n, t he s p o ns or will re p ort s us pecte d e x p ecte d deat hs a n d life -t hreate ni n g e ve nts t o t he 
P M D A as per l ocal re g ul at or y re q uir e me nts.  
T he s p o ns or has a l e gal r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a g e ncies a b o ut t he safet y of a st u d y dr u g u n der cli nical i n vesti gati o n . T he s p o ns or 
will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g t o t he 
re g ulat or y a ut h orit y, I R B/I E C, a n d i n vesti gat ors. 
I n v esti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x p ecte d s eri o us a d verse reacti o ns 
acc or di n g t o l ocal re g ulat or y re q uire m e nts a n d s p o ns or p olic y a n d f or war de d t o i n vesti gat ors as 
necessar y.  
A n i n vesti gat or w h o recei ves a n i n vesti gat or safet y re p ort descri bi n g a n S A E or ot her s pecific 
safet y i nf or mati o n ( e g, s u m mar y or listi n g of S A Es) fr o m t he s p o ns or will re vie w a n d t h e n file it 
al o n g wit h t he I B a n d will n otif y t he I R B/I E C, if a p pr o priate, acc or di n g t o l ocal re q uir e me nts.  
Seri o us A d verse E ve nt Re p orti n 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 i n t he e C R F. 
•  T he i n vesti gat or m ust re p ort wit hi n 2 4 h o urs of lear ni n g of its occ urre nce a n y S A E via t he E D C 
s yste m ( pri mar y met h o d) or b y c o m pleti n g t he Seri o us A d verse E ve nt Re p ort F or m i n E n glis h ( o nl y 
if t he E D C s yste m is n ot a vaila ble. T he c o ntact i nf or mati o n f or I nc yte P har mac o vi gila nce b y 
e mail/fa x is liste d i n t he St u d y Refere nce Ma n ual or as per 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 o r m). 
•  I n circ u msta nces w here t he E D C s yste m is n ot accessi ble f or re p orti n g S A E i nf or mati o n (i nitial 
a n d/ or f oll o w-u p S A E i nf or mati o n) t o t he s p o ns or wit hi n 2 4 h o urs, 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 Re p ort F or m . O nce t he E D C s yste m is f u ncti o nal, t he 
S A E re p ort s h o ul d be retr os pecti vel y a d de d t o t he E D C s yste m a n d f oll o w -u p s h o ul d be c o m plete d 
t hr o u g h t he E D C. T he ori gi nal c o p y of t he Seri o us A d verse E ve nt Re p ort F or m a n d t he e mail or 
facsi mile c o nfir mati o n s heet m ust be ke pt at t he st u d y site (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 Re p ort F or m or St u d y Refere nce Ma n ual f or details a n d f or t he 
e mail a d dress or fa x n u m ber).  
•  F oll o w -u p i nf or mati o n is als o rec or de d i n t he e C R F a n d tra ns m itte d t o I nc yte P har mac o vi gila nce via 
t he E D C s yste m. 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 pre vi o usl y, 
s uc h as t he o utc o me of t he e ve nt, 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 partici pa nt 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 . 
9. 5.  
E ve nts of Cli nic al I nterest  
N ot a p plica ble.  

I nc yte C or p orati o n 
Pa ge 6 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
9. 6.  
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.  
9. 7.  
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 t he 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 di cati o n or met h o d . W he n a 
pre g na nc y h as bee n c o nfir me d i n a partici p a nt d uri n g mater nal or p ater 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 safet y:  
•  T he st u d y dr u g  m ust be i n terr u pte d i m me diatel y (fe male partici pa nts o nl y). 
•  If t he fe m ale partici pa nt is n o l o n ger pre g n a nt a n d meets t he treat me nt c o nti n uati o n 
criteria wit hi n 2 8 da ys of t he sc he d ule d start of a c ycle, st u d y treat me nt ma y be 
res u me d aft er a p pr o val h as bee n recei ved fr o m t h e s p o ns or me dical m o nit or . 
•  T he i n vesti gat or m ust c o m plete a n d s u b mit t he I n c yte Cli nical Trial Pre g n a 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 n c y.  
Data o n fet al o utc o me are c ollecte d f or re g ulat or y re p orti n g  a n d dr u g s afet 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 n c 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 n ce or a bse n ce of a n y birt h defects, 
c o n ge nital a b n or malities, or mater na l 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 ded 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 n c 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 ul ati o ns, w hic he ver is lat er. Refer t o t he I n c yte 
Refere n ce G ui d e f or C o m pleti n g t he Cli nical Trial Pre g na nc y F or m or St u d y Refere n ce M a n ual.  
A n y S A E occ urri n g d uri n g pre g n a nc y of a st u d y p artici p a nt m ust be rec or de d o n t he 
Seri o us A d verse E ve nt Re p ort F or m a n d s u b mitte d t o t he s p o ns or or its desi g nee.  
A b n or mal pre g n a nc y o ut c o mes (e g, s p o nta n e o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, or ect o pic pre g na nc y) are c o nsi dere d S A Es (if occ urri n g i n t he st u d y partici pa nt) a n d 
m ust be re p orte d as d escri be d i n Secti o n  9. 4 . If a n a b n or mal pre g n a nc y o utc o me is re p orte d i n a 
st u d y partici pa nt's part ner, t he e ve nt s h o ul d be re p orte d t o t he s p o ns or o n t he Cli nical Trial 
Pre g na nc y F or m.  
9. 8.  
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 s afet 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 nt e 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 d ates will be c o m m u nicate d i n t he f or m of I n vesti gat or N otificati o 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 partici pa nt 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 h e y will be a d de d t o t he I C F. 

I nc yte C or p orati o n 
Pa ge 6 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
9. 9.  
Pr o d uct C o m pl ai nts  
T he s p o ns or c oll ects 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 s afet 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.  
All pr o d uct c o m plai nts ass ociate d wit h material  p ac ka g e d, la bele d, a n d rel ease 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 o ciate 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 ne e is r es p o nsi ble f or re p orti n g a c o m plet e 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 ur er as n ot e d i n t he pac ka gi n g i nf or mati o n . A n y A E ass ociat e d wit h a pr o d uct 
c o m plai nt s h o ul d be rec or de d as des cri be d i n Secti o n 9. 3 . 
If t he i n vesti gat or is as ke d t o ret ur n t he pr o d uct f or i n vesti gati o n, he/s he will ret ur n a c o p y of t h e 
pr o d uct  c o m plai nt c o m m u nicati o n wit h t he pr o d uct.  
F or Ja p a n : C o m plai nts ass ociate d wit h u na p pr o ve d me dical de vices will be re p orte d t o t he 
s p o ns or wit h a Me dical De vice D efect Re p ort F or m, a n d t he s p o ns or will re p ort me dical de vice 
defects t o t he P M D A as per l oca l r e g ulat or y re q uire me nts. 
9. 1 0.  
Tre at me nt of O ver d ose  
T here h as bee n n o cli nical e x perie nce wit h o ver d ose of pe mi gati ni b. Treat me nt of o ver d ose 
s h o ul d c o nsist of ge neral s u p p orti ve meas ures. 

I nc yte C or p orati o n 
Pa ge 6 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1 0.  
S T A TI S TI C S  
1 0. 1.  
S a m ple Size Deter mi n ati o n  
T he patie nt p o p ulati o n selecte d f or t his trial i ncl u d es partici pa nt s wit h rec urre nt G B M  or ot her 
gli o mas , circ u mscri be d astr oc ytic gli o mas, a n d gli o ne ur o n al a n d n e ur o nal t u m ors  wit h a n 
acti vati n g F G F R 1 -3 m utati o n or f usi o n/rearra n g e me nt . F or t hese p artici pa nt s, t here is n o defi ne d 
sta n dar d of care. Sec o n d s ur ger y or reirra diati o n are o pti o ns f or select parti ci pa nt s. Al k ylati n g 
c he m ot hera p y s u c h as nitr os o ureas or T M Z  rec halle n ge, as well as t h e V E G F a nti b o d y 
be vaciz u m a b  are alter nati ve o pti o ns. Res p o nse rates re p orte d i n ra n d o mize d trials wit h 
c he m ot hera p y i n rec urre nt G B M  ha ve bee n less t ha n 2 0 % ( Se ysta hl  et al 2 0 1 6 ). A p pr o xi matel y 
8 2 partici pa nts  eac h are pla n ne d f or t he fi nal a nal ysis of t he pri mar y e n d p oi nt of O R R i n 
C o h ort  A. C o h ort assi g n me nt is base d o n ce ntr al ge n o mic la b orat or y res ults. Wit h t he ass u me d 
rate of 2 8 % f or pe mi gati ni b , a sa m ple size of a p pr o xi matel y 8 2 partici pa nts w o ul d pr o vi de a b o ut 
8 0 % pr o ba bilit y t o ha ve a 9 5 % CI  wit h l o wer li mit of >  1 5 %. U p t o 8 2  partici pa nts will be 
e nr olle d i n C o h ort B, w hic h will pr o vi de a n a p pr o xi matel y 8 0 %  c ha nce of o bser vi n g at least 
2 0  res p o n ders i n t his c o h ort if the u n derl yi n g O R R is 2 8 %.  
1 0. 2.  
P o p ul ati o ns f or A n al ysis  
T he p o p ulati o ns f or a n al ysis are pr o vi de d i n Ta bl e  1 5 . 
T a ble  1 5 : 
P o p ul ati o ns f or A n al ysis  
P o p ul ati o n  
Descri pti o n  
F ull a nal ysis set 
T he f ull a nal ysis set i ncl u des all e nr olle d partici pa nts  w h o recei ve d at least 1 d ose 
of pe mi gati ni b  i n C o h orts A  a n d B . 
T he f ull a nal ysis set will be use d f or t he s u m mar y of de m o gra p hics, baseli ne 
c haracteristics,  partici pa nt  dis p ositi o n, a n d a nal yses of all efficac y data.  
Safet y  
T he safet y p o p ulati o n i ncl u des all e nr olle d partici pa nts  w h o recei ve d at least 1  d ose 
of pe mi gati ni b . 
All safet y a nal yses will be c o n d ucte d usi n g t he safet y p o p ulati o n . 
Per pr ot oc ol  
Partici pa nts  i n t he f ull a nal ysis set w h o are c o nsi dere d t o be s ufficie ntl y c o m plia nt 
wit h t he Pr ot oc ol c o m p o se t he per pr ot oc ol p o p ulati o n. 
R A N O 
e val ua ble 
T he R A N O e val ua ble p o p ulati o n i ncl u des all  partici pa nts  i n t he f ull a nal ysis set 
w h o ha ve at least 2 p ost baseli ne o bjecti ve t u m or res p o nse assess me nts per I C R or 
w h o wit h dra w  fr o m t he st u d y or disc o nti n ue  fr o m treat me nt wit h o ut p ost-treat me nt 
t u m or assess me nts. 
T he R A N O e val ua ble p o p ulati o n will be use d f or O R R a nal ysis i n t he i nteri m  
a nal ysis . 
1 0. 3.  
Le vel of Si g nific a nce  
C o nfi de nce i nter vals will be pr o vi de d at a 9 5 % CI . 

I nc yte C or p orati o n 
Pa ge 6 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1 0. 4.  
St atistic al A n al yses  
Partici pa nts will be s u m marize d b y c o h orts, a n d c o h ort deter mi nati o n will be base d o n 
F G F/ F G F R stat us fr o m c e ntralize d g e n o mic testi n g res ults as s pec ifie d i n S ecti o n  4. 1 . 
1 0. 4. 1.  
Pri m ar y A n al ysis  
T he pri mar y e n d p oi nt of t he st u d y is O R R i n C o h ort A . O bjecti ve res p o nse rate  is defi ne d as t he 
pr o p orti o n of partici pa nts w h o ac hie v e a B O R  of C R or P R , base d o n R A N O  (We n et al 2 0 1 0 ), 
as assesse d b y a n I C R. T his pri mar y a nal ysis of O R R will be base d o n t he f ull a nal ysis set . 
Partici pa nts w h o d o n ot ha ve s uffici e nt baseli ne or o n -st u d y res p o nse ass ess me nt i nf or mati o n t o 
be a de q u atel y assesse d f or res p o nse stat us will be i ncl u de d i n t he de n o mi nat ors i n t he calc ul ati o n 
of O R R. T he 9 5 % CI  f or t he O R R will be esti mate d usi n g t he Clo p per -Pears o n met h o d.  
T he O R R  will als o be a n al yze d bas e d o n t he per  pr ot oc ol p o p ulati o n as se nsiti vit y a nal ysis . 
1 0. 4. 2.  
Sec o n d ar y A n al ysis  
Sec o n dar y effic ac y a n al ysis will be c o n d ucte d f or t he f ull a nal ysis set.  
T he O R R i n C o h ort B is defi ne d as t he pr o p orti o n o f partici pa nts i n C o h ort B w h o ac hie ve a 
B O R of C R or P R, base d o n R A N O  (We n et al 2 0 1 0 ), as assesse d b y a n I C R. It will be esti mate d 
wit h its 9 5 % CI usi n g t he Cl o p per -Pears o n met h o d.  
T he O R R i n C o h ort s A a n d B c o m bi ne d is defi ne d as t he pr o p orti o n of partici pa nts i n C o h orts  A 
a n d B w h o ac hie v e a B O R  of C R or P R , base d o n R A N O  (We n et al 2 0 1 0 ), as assesse d b y a n 
I C R. It will be esti mate d wit h its 9 5 % CI  usi n g t he Cl o p per -Pears o n met h o d.  
T he O R R i n eac h c o h ort , base d o n R A N O  (We n et al 2 0 1 0 ), as assesse d b y t he i n vesti gat or will 
als o be esti mate d wit h its 9 5 % CI  usi n g t he Cl o p p er -Pears o n met h o d.  
Disease c o ntr ol rate is defi ne d as t he pr o p orti o n of partici pa nts w h o ac hie ve a B O R  of C R, P R, 
or S D , per R A N O  (We n et al 2 0 1 0 ), as ass esse d b y a n I C R. T he D C R a n d its e xact 9 5 % CI will 
be calc ul ate d f or b ot h  C o h orts A a n d B.  
P r 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 pe mi gati ni b  t o t he 
date of t he first d o c u me nte d pr o gressi ve dise ase or deat h d ue t o a n y ca us e, w hic he ver is first . 
Pr o gressi ve disease will be e val uat e d acc or di n g t o R A N O  (We n et al 2 0 1 0 ) a n d assess e d b y a n 
I C R. Partici pa nts w h o are ali ve wit h o ut pr o gressi o n bef ore  t h e a nal ysis c ut off date will be 
ce ns ore d . Ce ns ori n g f or P F S will f oll o w t he al g orit h m base d o n F D A g ui d a nce ( F D A 2 0 0 7 ). 
P r o gressi o n-free s ur vi val data will be a nal y ze d b y t he Ka pla n -M eier met h o d i n C o h orts A a n d B, 
res pecti vel y. 
F or o bjecti ve res p o n ders, D O R is defi ne d as t he ti me fr o m t he date t h at a partici pa nt first 
ac hie ves C R or P R, u ntil t he date of first d o c u me nte d pr o gressi ve dise ase or deat h, w hic he ver is 
first. Res p o nses a n d pr o gressi ve diseas e will be e v al uate d base d o n R A N O (We n et al 2 0 1 0 ) b y 
a n I C R. Partici pa nts w h o are ali ve wit h o ut pr o gressi o n bef ore t he a nal ysis c ut off  date will be 
ce ns ore d . Ce ns ori n g of D O R will f oll o w t he sa me al g orit h m as t he ce ns ori n g of P F S . D urati o n 
of res p o nse  d ata will be a nal yze d b y t he Ka pla n -M eier met h o d i n C o h orts A a n d  B, res pecti vel y.  
O verall s ur vi val  is defi n e d as t he ti me fr o m t he dat e of first d ose of p e mi gati ni b  t o t he date of 
deat h d ue t o a n y ca use. P artici pa nts wit h o ut deat h o bser ve d at t he ti me of t h e a nal ysis will be 

I nc yte C or p orati o n 
Pa ge 6 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
ce ns ore d at last date k n o w n t o be ali ve . O ve rall s ur vi val will be a nal yze d b y t he Ka pla n -M eier 
met h o d i n C o h orts A a n d B, res pecti vel y.  
1 0. 4. 3.  
S afet y A n al yses  
Safet y a nal yses will be c o n d ucte d f or t he s afet y p o p ulati o n . A d verse e v e nts will be c o de d b y t he 
Me d D R A dicti o nar y, a n d T E A E s (ie, A Es re p orte d f or t he first ti me or w orse ni n g of a 
pre -e xisti n g e ve nt after first d ose of pe mi gati ni b  a n d wit hi n 3 0 da ys of last d ose of pe mi gati ni b ) 
will be ta b ulate d b y preferre d ter m a n d s yste m or g a n class f or all e ve nts, r elate d e ve nts, e v e nts of 
Gra de 3 or hi g her acc or di n g t o N CI C T C A E v 5. 0 , a n d e ve nts lea di n g t o d ose i nterr u pti o n, d ose 
re d ucti o n, a n d st u d y treat me nt disc o nti n uati o n . Q ua ntitati ve safet y varia bles  (la b orat or y, vital 
si g ns, etc) a n d t heir c ha n ges fr o m baseli ne will be s u m marize d wit h descri pti ve statistic s. 
Cli nicall y n ota ble a b n or mal val ues will be fla g ge d a n d ta b ulate d bas e d o n pre defi n e d criteria.  
T he cli nical la b orat or y d ata will be a nal yze d usi n g s u m mar y statistics; n o f or mal c o h ort 
c o m paris o ns are pla n ne d . I n a d diti o n, distri b uti o ns of ke y la b orat or y para m eters ma y be pl otte d 
o ver ti me; t hese val ues will als o be classifie d i nt o C T C A E v 5. 0 t o xicit y gra des, a n d ta b ulate d.  
Descri pti ve statistics a n d mea n c ha n g e fr o m b aseli ne will be deter mi ne d f or vital si g ns 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.  
Descri pti ve statistics a n d mea n c ha n g e fr o m b aseli 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 r es ults will be re vie we d f or cli nicall y n ota ble 
a b n or malities . Partici pa nts  e x hi biti n g cli nicall y n ota ble E C G a b n or malities will be liste d.  
Meas ures of e x p os ur e of pe mi gati ni b  will be s u m marize d b y mea ns of s u m mar y statistics.  
1 0. 5.  
I nteri m A n al ysis 
As li mite d efficac y d ata are a v aila ble f or pe mi gati ni b  i n G B M, a f utilit y a nal ysis will be 
perf or me d  f or C o h ort A w he n a p pr o xi matel y 2 5 p artici pa nts are e nr olle d i nt o t his c o h ort a n d 
ha ve at least 2 p ost baseli ne o bjecti ve t u m or res p o nse assess me nts per I C R or are wit h dra w n  fr o m 
t he st u d y or disc o nti n ue d fr o m treat me nt wit h o ut p ost-treat me nt t u m or ass ess me nts. C o h ort A 
ca n be cl ose d f or f utilit y if ≤ 4 res p o n ders are o bs er ve d i n t he R A N O e val u a ble p o p ulati o n, f or 
w hic h t here is < 5 % pr o ba bilit y of clai mi n g O R R >  1 5 % at fi nal a nal ysis . Gi ve n t he s mall 
sa m ple size at t he i nteri m a nal ysis a n d t he p ossi ble c o nf o u n di n g fact ors, t his r ule is f or i nter nal 
g ui da nce a n d  is n o n bi n di n g. T he t otalit y of data c ollecte d, i ncl u di n g res p o n ders as w ell as 
partici pa nts wit h S D , will be ta ke n i nt o acc o u nt i n t he decisi o n t o c o nti n ue or ter minate 
C o h ort  A . 

I nc yte C or p orati o n 
Pa ge 6 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1 1.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  
1 1. 1.  
I n vesti g at or Res p o nsi bilities 
•  T he Pr ot oc ol, Pr ot oc ol A me n d me nts , I C F, I B, a n d ot her rele va nt d oc u me nts 
(e g, a d vertise me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he i n vesti gat or a n d 
re vie we d a n d a p pr o ve d b y t he I R B/I E C a n d h ealt h a ut h orities , bef ore t he st u d y is 
i nitiate d. 
•  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 r e p orts pr o vi de d b y t he 
s p o ns or are re vie we d a nd pr ocesse d i n acc or da nce wit h re g ulat or y re q uire m e nts, 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 n d i nstit uti o nal re q uire me nts.  
•  A n y a me n d me nts t o t he Pr ot oc ol will re q uire a p pr o val fr o m b ot h healt h a ut h orities 
a n d I R B/I E C bef ore i m pl e me ntat i o n of c ha n g es m a de t o t he st u d y desi g n, e xce pt f or 
c ha n ges necessar y  t o eli mi nate a n i m me diate hazar d t o st u d y partici pa nts. 
•  T he i n vesti gat or will be res p o nsi ble f or t he f oll o wi n g:  
− Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n u all y or 
m ore fre q u e ntl y i n acc or da nce wit h t he re q uire m e nts, p olicies, a n d pr oce d ures 
esta blis he d b y t he I R B/I E C.  
− N otif yi n g t he I R B/I E C of S A Es or ot her si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures. 
− Pr o vi di n g o versi g ht of t he c o n d uct of t h e st u d y at t he site a n d a d here nce t o G C P, 
I R B/I E C re q uir e me nts, i nstit uti o nal re q uire me nts, a n d a p plica ble la ws a n d 
c o u ntr y-s pecific re g ul ati o ns. 
•  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 greei 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, s ec o n d, b y t he 
I R B/I E C. Eac h i n v esti gat or is res p o nsi ble f or e nr olli n g partici pa nts w h o ha ve met t he 
s pecifie d eli gi bilit y criteria. 
•  Retai ni 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 aft er t he last m ar 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 p e n di n g or c o nt e 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 aft er 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 ul at or y a ut h orit y t o re vie w.  
− T he i n vesti ga t 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 d uri n g t he 
rete nti o n peri o d 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 d e 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.  

I nc yte C or p orati o n 
Pa ge 6 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
− All e C 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 
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 r e 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.  
•  F or J a p a n : T he rec or d retai ner ( d ele gate d b y t h e hea d of t he st u d y site) will retai n 
t he J-G C P – defi ne d esse ntial d oc u me ntati o n at t his site u ntil t he re g ulat or y a p pr o val 
of t he st u d y dr u g or at least 3 years after t he dis c o nti n uati o n or c o m pleti o n of t he 
st u d y c o n d uct, w hic he ver is later. If t he s po ns or re q uires ret e nti o n of t hese d oc u me nts 
f or a l o n ger p eri o d of ti m e, t he d urati o n a n d met h o d of rete nti o n will be deci de d u p o n 
t hr o u g h disc ussi o n bet wee n t he s p o ns or a n d t he st u d y site. It is t he res p o nsi bilit y of 
t he s p o ns or t o i nf or m t he hea d of t he st u d y site as t o w he n t he d oc u me nts n o l o n ger 
nee d t o be retai ne d.  
1 1. 1. 1.  
I de ntific ati o n of t he C o or di n ati n g Pri nci p al I n vesti g at or  
A c o or di nati n g pri nci pal i n vesti gat or will be a p p oi nte d b y t he s p o ns or bef ore t he e n d of t he 
st u d y. As part of t heir res p o nsi bilities, t he c o or di nati n g pri nci pal i n vesti gat or will re vie w t he 
fi nal C S R. A gree me nt wit h t he fi nal C S R will be d oc u me nte d b y t he dat e d si g nat ure of t he 
c o or di nati n g pri nci pal i n vesti gat or.  
1 1. 2.  
D at a M a n a ge me nt  
Data ma na g e me nt will be perf or me d i n a vali dat e d E D C s yste m . 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 b e c o m plete d f or eac h p artici pa nt.  
T he site will be pr o vi de d wit h e C R F c o m pleti o n g ui deli nes f or i nstr ucti o ns o n data e ntr y i n t he 
e C R F. T he st u d y m o nit or will refere nce t h e 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. Ot her data o utsi de t h e E D C s yste m re q uire d i n t he st u d y c o n d uct of 
t he Pr ot oc ol , s uc h as d oc u me nts or res ults tra ns mitte d t o t he s p o ns or via a ce ntral la b orat or y or 
s pecialize d te c h nical v e n d ors a n d, as desi g nat e d b y t he s p o ns or, will ha ve t heir o w n data fl o w 
ma na ge me nt pla ns, st u d y c harters, or bi o mar ker pl a ns, as a p plica bl e . 
T he s p o ns or ( or desi g nee) will be res p o nsi ble f or  t he f oll o wi n g: 
•  Ma na gi n g t he i nte grit y of t he data a n d t h e q ualit y of t he c o n d uct of t h e st u d y, s uc h as 
e ns uri n g t hat st u d y m o nit ors perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat 
data e ntere d i nt o t he e C R F b y a ut h orize d site pers o n nel are acc urate, c o m plete, a n d 
verifia ble fr o m s o urce d o c u me nts; t hat t he safet y a n d ri g hts of partici pa nts are bei n g 
pr otecte d; a n d t hat t he st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y 
a p pr o ve d  Pr ot oc ol a n d a n y ot her st u d y a gree me nts, I C H G C P, a n d all a p plica ble 
re g ulat or y re q uire me nts. 
•  Ma na gi n g a n d rec o ncili n g t he data ge n erate d  a n d/ or c ollecte d , i ncl u di n g d o c u me nts 
a n d res ults s uc h as la b orat or y or i ma gi n g data a n al yze d ce ntrall y b y a desi g nat e d 
ve n d or of t he s p o ns or.  

I nc yte C or p orati o n 
Pa ge 7 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T he i n vesti gat or will be res p o nsi ble f or  t he f oll o wi n g: 
•  Rec or di n g, or e ns uri n g t he rec or di n g of, all rele va nt data relati n g t o t he st u d y i n t he 
e C R F. 
•  Deli veri n g, or e ns uri n g t he deli ver y of, all ot her res ults, d oc u me nts, data, k n o w -h o w, 
or f or m ulas rel ati n g t o t he st u d y t o t he s p o ns or or desi g nee electr o nicall y a n d/ or 
ce ntrall y (e g, la b orat or y data, i ma gi n g data, bi o mar ker data, p h ot o gra p hs, diar y data) 
or as ot her wise s p ecifie d i n t he Pr ot oc ol.  
•  Mai ntai ni n g a de q uate a n d acc urate s o urce d oc u m e nts a n d trial rec or ds t hat i ncl u de all 
perti ne nt o bser vati o ns o n eac h of t h e site 's trial partici pa nts. S o urce data s h o ul d be 
attri b uta ble, le gi ble, c o nt e m p ora ne o us, ori gi nal, acc urat e, a n d c o m plet e . C ha n ges t o 
s o urce dat a s h o ul d be tracea ble, sh o ul d n ot o bsc ure t he ori gi nal e ntr y, a n d s h o ul d be 
e x plai ne d if necessar y (e g,  via a n a u dit trail) . S o urce dat a are , i n ge neral, all 
i nf or mati o n i n ori gi nal rec or ds a n d certifie d c o pies of ori gi nal rec or ds of cli nical 
fi n di n gs, o bser vati o ns, or ot her activities i n a cli nical trial necessar y f or t he 
rec o nstr ucti o n a n d e val u ati o n of t he trial. S o urce data are c o ntai ne d i n s o urce 
d oc u me nts ( ori gi nal rec or ds or certifie d c o pies).  
•  Verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or electr o nica ll y 
si g ni n g t he e C R F. 
•  Mai ntai ni n g acc urate d oc u me ntati o n (s o urce d ata) t hat s u p p orts t he i nf or mati o n 
e ntere d i n t he e C R F, se nt t o a ce ntral v e n d or desi g nate d b y t he s p o ns or, or as 
descri be d i n ot her st u d y a n d data fl o w ma n uals.  
− S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste n ce of t he p artici pa nt a n d 
s u bsta ntiate t he i nte grit y of t he data c ollecte d. S o urce d oc u m e nts are file d a n d 
a vaila ble at t he i n vesti gat or 's site. E xa m ples of s o urce d oc u m e nts are ori gi nal 
d oc u me nts, data, a n d rec or ds (e g,  h os pital rec or ds ; electr o nic h os pital rec or ds ; 
cli nical a n d office c h arts ; la b orat or y n otes; me m ora n da ; partici pa nts ' diaries or 
e val uati o n c hec klists ; p har mac y dis pe nsi n g rec or ds ; rec or de d d ata fr o m 
a ut o mate d i nstr u me nts ; c o pies or tra nscri pti o ns certifie d after verificati o n as 
bei n g acc urate c o pies ; micr ofic hes ; p h ot o gra p hic ne gati ves ; micr ofil m or 
ma g netic me dia ; x -ra ys; partici pa nts ' files; a n d e -rec or ds/rec or ds ke pt at t he 
p har mac y, at t he la b orat ories , a n d at me dic o -tec h nical de part me nts i n v ol ve d i n 
t he cli nical trial). 
− Data e ntere d i n t he e C R F t hat are tr a nscri be d fr o m s o urce d oc u m e nts m ust be 
c o nsiste nt wit h t he s o urce d oc u me nts or t he discre pa ncies m ust be e x plai n e d . T he 
i n vesti gat or ma y nee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds, 
de pe n di n g o n t he st u d y . C urre nt a p plica ble m e dical rec or ds m ust be a vaila ble.  

I nc yte C or p orati o n 
Pa ge 7 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
•  Se n di n g partici pa nts ' dat a, eit her as u ni q u e sa m ples, or c o pies, or p h ot o gra p hs, t o be 
e val uate d ce ntrall y or a n al yze d ce ntrall y, or b ot h, b y a q ualifie d ve n d or desi g nate d b y 
t he s p o ns or. 
− As re q uire d b y pri vac y a n d data pr otecti o n re g ulati o ns a n d I n c yte 's pri vac y 
p olicies, if a n y p h ot o gra p hs of partici pa nts are t o b e ta ke n, t he p h ot o gra p hs m ust 
be li mite d t o t he area of t he face or t he b o d y t h at is  strictl y necessar y a n d t he 
p h ot o gra p hs s h o ul d be mas ke d (ie, i de ntif yi n g feat ures s uc h as e yes, m o ut h, scars, 
tatt o os, or u ni q ue mar ki n gs or feat ur es s h o ul d be eit her o bsc ure d wit h a blac k bar 
or di gitall y pi xelate d s o as t o n ot per mit t he rei de ntificati o n of t he partici pa nts a n d 
preser ve t heir c o nfi de ntialit y) b y a s peciall y desi g nate d p h ot o gra p h y ve n d or pri or 
t o se n di n g t he p h ot o gra p hs t o I nc yt e or a n y ot her t hir d-part y ve n d ors f or a nal ysis 
or f urt her pr ocessi n g.  
•  Per 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 ni cal st u d y 
d oc u me nts.  
− M o nit ori n g : Q ualifie d re prese ntati ves of t h e 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 materi als a n d 
partici pa nt rec or ds at e ac 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 uat e 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 pa rtici pa nts. 
− 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 m e 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 pect e d t o c o o perat e wit h t he i ns pe ct ors 
a n d all o w access t o all s o urce d oc u m e 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 m e 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 nta cte 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 u cti n g a n 
i ns pecti o n. 
1 1. 3.  
D at a Q u alit y Ass ur a nce  
•  T he s p o ns or ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals (e g, 
c o ntract r esearc h or ga niz ati o ns). T he s p o ns or or d esi g nee is res p o nsi ble f or t he data 
ma na ge me nt of t his st u d y, i ncl u di n g q ualit y c hec ki n g of t he data. F urt her, m o nit ori n g 
de tails descri bi n g strate g y, i ncl u di n g defi niti o n of st u d y-critical data ite ms a n d 
pr ocesses (e g, ris k -b ase d i nitiati ves i n o perati o ns a n d q ualit y s uc h as ris k 
ma na ge me nt a n d miti gati o n strate gies a n d a n al ytical ris k -base d m o nit ori n g), 
met h o ds, res p o nsi bilit ies, a n d re q uir e me nts, i ncl u di n g ha n dli n g of n o nc o m plia nce 
iss ues, P r ot oc ol de viati o ns, a n d m o nit ori n g tec h ni q ues (e g, ce ntral, r e m ote, or o n -site 
m o nit ori n g)  are pr o vi de d i n t he Cli nical O perati o ns Pla n a n d t he Pr ot oc ol De viati o ns 
Ma na ge me nt Pla n . 

I nc yte C or p orati o n 
Pa ge 7 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
•  Q ualit y  t olera nce li mits will be pre defi n e d i n t he I nte grate d Pr oject Ma na g e me nt Pla n 
t o i de ntif y s yste matic iss ues t hat ca n i m pact p artici pa nts' safet y, efficac y res ults a n d 
a nal ysis,  a n d/ or relia bilit y of st u d y res ults. T hese pre defi n e d para meters will  be 
m o nit ore d d uri n g t he st u d y a n d ca n b e a dj uste d d uri n g t he st u d y u p o n data re vie w. 
Im p ort a nt de viati o ns fr o m t he q ualit y t olera nce li mit s a n d re me dial acti o ns ta ke n, 
i ncl u di n g re p ortin g t o I R Bs/ I E Cs a n d healt h a ut h orities if a p plica ble, will b e 
s u m marize d in t he C S R.  
1 1. 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 ve sti 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 m ati 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 n d t he s p o ns or o perates 
c o m pre he nsi ve d ata pri v ac y a n d d ata sec urit y pr o gra ms t hat are a p plica ble t o t his st u d y . 
A p pr o priate n otic e, or n otice a n d c o nse nt (as ma y be re q uir e d b y eac h a p pli ca ble j uris dicti o n), 
f or c ollecti o n, use, 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 l a ws.  A p pr o pri ate  data pr otecti o n ter ms t hat 
c o m pl y wit h a p plica ble la ws will be i ncl u de d i n rele va nt st u d y a gree me nts.  
T o e ns ure c o nfi de ntialit y of rec or ds a n d pr ot ect pers o nal data, p artici pa nt n a 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 partici pa nt n u m ber will be rec or de d i n t he 
e C R F; if t he partici pa nt 's na me a p pears o n a n y ot h er 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 n t 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 priat e 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.  
I n t he e ve nt of a data breac h i n v ol vi n g partici pa nt data, t he s p o ns or or its d esi g nee will f oll o w 
t he s p o ns or's i nci de nt res p o nse pr oce d ures. T h e precise defi niti o n of a data breac h v aries i n 
acc or da nce wit h a p plica ble la w b ut ma y ge nerall y be u n derst o o d as a breac h of sec urit y lea di n g 
t o t he acci dental or u nla wf ul destr ucti o n, l oss, alterati o n, u na ut h orize d discl os ure of, or access t o, 
pers o nal data. I n acc or da nce wit h its i nci de nt res p o nse pr oce d ures, t he s p o ns or will assess t he 
breac h t o c o nsi der its n otificati o n a n d re me diati o n o bli gati o ns u n der a p plica ble la w.  
1 1. 5.  
Fi n a nci al Discl os ure  
Bef ore st u d y i nitiati o n, all 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 F R Part 5 4 –  Fi na ncial Dis cl 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 n vesti gat or Fi na nci al Discl os ure F or 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 partici pa nts, 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 uir e 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 Cli nical I n vesti gat or Fi na nci al Discl os ure F or m. D uri n g a c o v ere 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 nical 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, 

I nc yte C or p orati o n 
Pa ge 7 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
t he cli nical i n vesti gat ors will be re mi n de d of t heir o bli gati o ns . I n t he e v e nt t hat t he cli nical 
i n vesti gat or is n ot re mi n de d, t he y ne vert heless 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 h a 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 h a n ges 
i n t heir fi na ncial i nf or mati o n f or a peri o d of 1 y ear after c o m pleti o n of t he c o vere d cli nical st u d y.  
1 1. 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 i n vesti gat or a n d t heir 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 n c yte C or p orati o n  (I n c 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 n ce wit h a p plica bl e 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 ualificati 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 
are c o nt ai ne d 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 h e s p o ns or or its desi g nee.  
T he res ults of t his st u d y ma y be p u blis he d or pres e nte d at scie ntific meeti n gs . If t his is f oresee n, 
t he i n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he s p o ns or bef ore s u b missi o n. 
T his  all o ws t he s p o ns or t o pr otect pr o priet ar y i nf or mati o n a n d t o pr o vi de c o m me nts.  
T he s p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults . I n acc or da nce 
wit h sta n dar d e dit orial a n d et hical practice, t he s p o ns or will ge nerall y s u p p ort p u blicati o n of 
m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site data . I n t his case, a 
c o or di nati n g i n vesti gat or will be desi g nate d b y m ut ual a gree m e nt.  
A ut h ors hi p will be deter mi ne d i n li ne wit h I nter n ati o nal C o m mittee of Me dical J o ur na l E dit ors 
a ut h ors hi p re q uire m e nts.  
1 1. 7.  
St u d y a n d Site Cl os ure  
T he s p o ns or or desi g ne e reser ves t he ri g ht t o cl ose t he st u d y site or ter mi nate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti o n of t he s p o ns or. Reas o ns t hat t he st u d y ma y be 
ter mi nate d co ul d i ncl u de:  
•  S afet y c o ncer ns wit h pe mi gati ni b (st u d y dr u g) d uri n g t he st u d y or i n ot her o n g oi n g 
st u dies 
•  D e vel o p me nt of pe mi gati ni b is ter mi nate d  
•  S t u d y e nr oll me nt is e xtre mel y sl o w ma ki n g c o m pleti o n of t he st u d y wit hi n acce pta ble 
ti mefra me u nli kel y 
•  C lear e vi de n ce of lac k of efficac y i n t he patie nt p o p ulati o n bei n g st u die d  
•  U p o n re q uest of c o m pete nt a ut h orities 
•  O t her u nf oresee n circ u msta nces  
St u d y sites will be cl ose d u p o n st u d y c o m pleti o n . A st u d y site is c o nsi dere d cl ose d w he n all 
re q uire d d o c u me nts an d st u d y s u p plies ha ve bee n c ollecte d a n d a st u d y -site cl os ure visit has 
bee n perf or me d.  

I nc yte C or p orati o n 
Pa ge 7 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
F or J a p a n : W he n t he tri al is c o m plete d, t he i n vesti gat or s h o ul d i nf or m t he hea d of t he st u d y site 
of t he c o m pleti o n i n writi n g a n d s u b mit a writte n s u m mar y of t he tria l's o ut c o me, t he n t he hea d 
of t he st u d y site s h o ul d pr o m ptl y i nf or m t he I R B a n d s p o ns or or desi g nee of t he c o m pleti o n i n 
writi n g.  
T he i n vesti gat or ma y i nitiate st u d y -site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nt e n de d ter mi nati o n.  
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he s p o ns or or i n vesti gat or ma y i ncl u de b ut are 
n ot li mite d t o:  
•  Fail ure of t he i n vesti gat or t o c o m pl y wit h t he Pr ot oc ol, t he re q uir e me nts of t he 
I R B/I E C or l ocal h ealt h a ut h orities, t he s p o ns or's pr oce d ures, or G C P g ui deli nes. 
•  I n a de q uat e recr uit me nt of partici pa nts b y t he i n vesti gat or. 
•  Disc o nti n uati o n of f urt her st u d y treat me nt de vel o p me nt.  

I nc yte C or p orati o n 
Pa ge 7 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1 2.  
R E F E R E N C E S  
Al da pe  K, Bri n dle K M, C hesler L, et al. C halle n g es t o c uri n g pri mar y brai n t u m o urs. Nat Re v 
Cli n O nc ol 2 0 1 9; 1 6: 5 0 9 -5 2 0.  
Ar dizz o ne  A, Sc u deri S A, Gi uffri da D, et al. R ole of fi br o blast gr o wt h fact ors rece pt ors ( F G F Rs) 
i n brai n t u m ors, f oc us o n astr oc yt o ma a n d gli o blast o ma. Ca ncers ( Bas el) 2 0 2 0; 1 2: 3 8 2 5. 
B yr ne  K, Waller J, Pierc y J, S ha w J, Dasta ni H. P 1 8. 1 0 I m p act of gli o blast o ma m ultif or me 
( G B M) o n patie nts' q ualit y of life ( Q o L). Ne ur o O nc ol 2 0 1 7; 1 9( S u p pl 3):iii 1 2 3.  
Cli nical Trials Facilitati o n a n d C o or di nati o n Gr o u p. Rec o m me n dati o ns relate d t o c o ntrace pti o n  
a n d pre g na n c y testi n g i n cli nical trials. 2 0 2 0 . 
Daile y L, A m br osetti D, Ma ns u k ha ni A, Basilic o C. Mec ha nis ms u n derl yi n g differe ntial 
res p o nses t o F G F si g nali n g. C yt o ki ne Gr o wt h Fact or Re v 2 0 0 5; 1 6: 2 3 3-2 4 7.  
Elli n gs o n B M, Gerst ner E R, Lass ma n A B, et al. H y p o t hetical ge neralize d fra me w or k f or a ne w 
i ma gi n g e n d p oi nt of t hera pe utic acti vit y i n earl y p hase cli nical trials i n brai n t u m ors. 
Ne ur o  O n c ol  2 0 2 2; 2 4 :1 2 1 9 -1 2 2 9 . 
Es wara k u mar V P, La x I, Sc hlessi n ger J. Cell ular si g nali n g b y fi br o blast gr o wt h fact or rece pt ors . 
C yt o ki ne Gr o wt h Fact or Re v 2 0 0 5; 1 6: 1 3 9 -1 4 9.  
E ur o pea n Me dici nes A ge nc y. G ui da nce o n t he Ma na ge me nt of Cli nical Tri als D uri n g t he 
C O VI D -1 9 ( C or o n a vir us) Pa n de mic. 2 0 2 0.  
E ur o Q ol Gr o u p. E ur o Q ol --a ne w facilit y f or t he meas ure m e nt of healt h -relate d q ualit y of life. 
Healt h P olic y 1 9 9 0; 1 6: 1 9 9 -2 0 8.  
Farr o w E G, W hite K E. R ece nt a d v a nces i n re nal p h os p hate ha n dli n g. Nat R e v Ne p hr ol 
2 0 1 0; 6: 2 0 7 -2 1 7.  
F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y: Cli nical Trial E n d p oi nts f or t he A p pr o val 
of Ca ncer Dr u gs a n d Bi ol o gics. 2 0 0 7.  
G ua g na n o V, Ka uff m a n n A, W ö hrle S, et al. F G F R ge netic alterati o ns pre dict f or se nsiti vit y t o 
N V P -B GJ 3 9 8, a selecti v e pa n -F G F R i n hi bit or. Ca ncer Disc o v 2 0 1 2; 2: 1 1 1 8 -1 1 3 3.  
Helste n T, El ki n S, Art h ur E, T o ms o n B N, Carter J, K urzr oc k R. T he F G F R lan dsca pe i n ca ncer: 
a nal ysis of 4, 8 5 3 t u m ors b y ne xt -ge nerati o n se q ue nci n g. Cli n Ca ncer Res 2 0 1 6; 2 2: 2 5 9 -2 6 7.  
It o h N. H or m o ne-li ke (e n d ocri ne) F G F s: t heir e v ol uti o nar y hist or y a n d r oles i n de vel o p me nt, 
meta b olis m, a n d disease. Cell Tiss ue Res 2 0 1 0; 3 4 2: 1 -1 1.  
Ji me nez-Pasc u al  A, Sie bze h nr u bl F A. Fi br o bl ast gr o wt h fact or rece pt or f u ncti o ns i n 
gli o blast o ma. Cells 2 0 1 9; 8: 7 1 5.  
K h u n d miri SJ, M urra y R D, Le derer E. P T H a n d vita mi n D. C o m pr P h ysi ol 2 0 1 6; 6: 5 6 1 -6 0 1.  
K ni g hts V, C o o k SJ. De -re g ulate d F G F rece pt ors as t hera p e utic tar gets i n ca ncer. P har mac ol 
T her 2 0 1 0; 1 2 5: 1 0 5 -1 1 7.  
K u nii K, Da vis L, G ore nstei n J, et al. F G F R 2 -a m plifie d gastric ca n cer cell li nes re q uire F G F R 2 
a n d Er b b 3 si g nali n g f or gr o wt h a n d s ur vi val. Ca ncer Res 2 0 0 8; 6 8: 2 3 4 0 -2 3 4 8.  

I nc yte C or p orati o n 
Pa ge 7 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
La m o nt F R, T o mli ns o n D C, C o o per P A, S h n y der S D, C hester J D, K n o wles M A. S mall m olec ule 
F G F rece pt or i n hi bit ors bl oc k F G F R -de pe n d e nt ur ot helial carci n o ma gr o wt h i n vitr o a n d i n vi v o. 
Br J Ca ncer 2 0 1 1; 1 0 4: 7 5 -8 2.  
Lass ma n A B, Se p úl v e da-Sá nc hez J M, Cl o u g hes y T, et al. O S 1 0. 6 I nfi grati ni b ( B GJ 3 9 8) i n 
patie nts wit h rec urre nt gli o mas wit h fi br o blast gr o wt h fact or rece pt or ( F G F R) alterati o ns: a 
m ultice nter p hase II st u d y. Ne ur o O n c ol 2 0 1 9; 2 1(s u p pl 3):iii 2 1 -iii 2 2. 
Le hti ne n  B, Raita A, Kess eli J, et al. Cli nical ass ociati o n a nal ysis of e pe n d y m o mas a n d pil oc ytic 
astr oc yt o mas re v eals ele vate d F G F R 3 a n d F G F R 1 e x pressi o n i n a g gressi ve e pe n d y m o mas. B M C 
Ca ncer 2 0 1 7; 1 7: 3 1 0.  
L o uis D N, Perr y A, Wesseli n g P, et al. T he 2 0 2 1 W H O Classificati o n of T u m or s of t he Ce ntral 
Ner v o us S yste m: a s u m mar y. Ne ur o O nc ol 2 0 2 1; 2 3: 1 2 3 1 -1 2 5 1.  
Na ka m ura H, Arai Y, T ot o ki Y, et al. Ge n o mic s p ectra of biliar y tract ca ncer. Nat G e net 
2 0 1 5; 4 7: 1 0 0 3 -1 0 1 0.  
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: 
Ce ntral Ner v o us S yste m Ca ncers Versi o n 2. 2 0 2 1. 2 0 2 1.  
Nati o nal Ca ncer I nstit ute. Ge n o mic Data C o m m o ns Data P ortal. 2 0 1 9 . 
Pe maz yre ( pe mi gati ni b) [ prescri bi n g i nf or mati o n]. I n c yte C or p orati o n; Fe br uar y, 2 0 2 1 a. 
Pe maz yre ( pe mi gati ni b) [s u m mar y of pr o d uct c haracteristics]. I n c yte Bi osci e nces Distri b uti o n 
B V; Marc h, 2 0 2 1 b.  
Pe mi gati ni b I n vesti gat or 's Br oc h ure. Wil mi n gt o n, D E: I n c yte C or p orati o n. 
P orta R, B orea R, C oel h o A, et al. F G F R a pr o misi n g dr u g ga ble tar get i n ca ncer: m olec ular 
bi ol o g y a n d ne w dr u gs. Crit Re v O nc ol He mat ol 2 0 1 7; 1 1 3: 2 5 6 -2 6 7.  
Qi n g J, D u X, C he n Y, et al. A nti b o d y -base d tar g eti n g of F G F R 3 i n bla d der carci n o ma a n d 
t( 4; 1 4)-p ositi ve m ulti ple m yel o ma i n mice. J Cli n  I n v est 2 0 0 9; 1 1 9: 1 2 1 6-1 2 2 9.  
Sia D, L osic B, M oei ni A, et al. Massi ve parallel se q ue nci n g u nc o vers acti o na ble 
F G F R 2 -P P H L N 1 f usi o n a n d A R A F m utati o ns i n i ntra he patic c h ola n gi ocarci n o ma. Nat C o m m u n 
2 0 1 5; 2 2: 6 0 8 7.  
Se ysta hl K, Wic k W, Weller M. T hera p e utic o pti o ns i n rec urre nt gli o blast o ma --A n u p dat e. Crit 
Re v O nc ol He mat ol. 2 0 1 6; 9 9: 3 8 9 -4 0 8.  
St u p p R, Mas o n W P, va n de n Be nt MJ, et al. Ra di ot hera p y pl us c o nc o mita nt a n d a dj u va nt 
te m oz ol o mi de f or gli o blast o ma. N E n gl J Me d 2 0 0 5; 3 5 2: 9 8 7-9 9 6.  
Terret C, Al bra n d G, M o nce ni x G, Dr o z J P. Kar n ofs k y Perf or ma nce Scale ( K P S) or P h ysical 
Perf or ma nce Test ( P P T)? T hat is t he q uesti o n. Crit Re v O nc ol He mat ol 2 0 1 1; 7 7: 1 4 2 -1 4 7.  
Tila k M, H ol b or n J, Ne w L A, Lal o n de J, J o nes N. Rece pt or t yr osi ne ki nas e si g nali n g a n d 
tar geti n g i n gli o blast o ma m ultif or me. I nt J M ol Sci 2 0 2 1; 2 2: 1 8 3 1. 
Tris oli ni E, War di g hi D E, Gir y M, et al. Acti o na bl e F G F R 1 a n d B R A F m ut ati o ns i n a d ult 
circ u mscri be d gli o mas. J Ne ur o o nc ol 2 0 1 9; 1 4 5: 2 4 1 -2 4 5.  

I nc yte C or p orati o n 
Pa ge 7 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T ur ner  N, Gr ose R. Fi br o blast gr o wt h fact or si g nalli n g: fr o m de vel o p me nt t o ca ncer. Nat Re v 
Ca ncer 2 0 1 0; 1 0: 1 1 6 -1 2 9.  
Weiss J, S os M L, Sei del D, et al. Fre q ue nt a n d f ocal F G F R 1 a m plificati o n ass ociates wit h 
t hera pe uticall y tracta ble F G F R 1 d e pe n de n c y i n s q ua m o us cell l u n g ca ncer. Sci Tra nsl Me d 
2 0 1 0; 2: 6 2ra 9 3.  
We n P Y, Mac d o n al d D R, Rear d o n D A, et al. U p date d res p o nse assess me nt criteria f or hi g h -
gra de gli o mas: Res p o nse Assess me nt i n Ne ur o -O nc ol o g y W or ki n g Gr o u p. J Cli n O nc ol 
2 0 1 0; 2 8: 1 9 6 3 -1 9 7 2.  
We n P Y, Weller M, Lee E Q, et al. Gli o blast o ma i n a d ults: a S ociet y f or Ne ur o -O nc ol o g y ( S N O) 
a n d E ur o pea n S ociet y of Ne ur o -O n c ol o g y ( E A N O) c o nse ns us r e vie w o n c urre nt ma na g e me nt 
a n d f ut ure dir ecti o ns. Ne ur o O nc ol 2 0 2 0; 2 2: 1 0 7 3 -1 1 1 3.  

I nc yte C or p orati o n 
Pa ge 7 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
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 A N D D E FI NI TI O N S  
Defi niti o ns  
W O C B P : A w o ma n w h o is c o nsi dere d fertile f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma n e ntl y sterile (see bel o w)  
W o me n i n t he f oll o wi n g cate g ories are n ot c o nsi dere d W O C B P:  
•  Pre me n arc h al  
•  Pre me n o pa usal wit h 1 of t he f oll o wi n g: a 
− D oc u me nte d h ysterect o m y  
− D oc u me nte d bilateral sal pi n gect o m y  
− D oc u me nte d bilateral o o p h orect o m y  
•  P ost me n o pa usal  
− A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use.  
o  A hi g h F S H le vel i n t he p ost me n o pa usal ra n ge ma y be use d t o c o nfir m a p ost me n o pa usal state i n 
w o me n n ot usi n g h or m o nal c o ntrace pti o n or H R T . H o we v er, i n t he a bse nce of 1 2 m o nt hs of 
a me n orr hea, c o nfir mati o n wit h 2 F S H meas ure me nts i n t he p ost me n o pa usal ra n ge is re q uire d . 
− Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use 1 of t he n o n h or m o nal, 
hi g hl y effecti ve c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue t heir H R T d uri n g t he st u d y . Ot h er wise, 
t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n of p ost me n o pa usal stat us bef ore st u d y e nr oll me nt. 
F or m ale p artici p a nts of re pr o d ucti ve p ote nti al b 
T he f oll o wi n g met h o ds d uri n g t he Pr ot oc ol -defi ne d t i mefra me i n Secti o n 5. 1  are hi g hl y effecti ve:  
•  Use of a male c o n d o m pl us part ner use of a n a d diti o nal c o ntrace pti ve met h o d w he n ha vi n g pe nile -va gi nal 
i nterc o urse wit h a w o ma n of c hil d beari n g p ote ntial w h o is n ot c urre ntl y pre g na nt. 
•  Vasect o m y wit h me dical assess me nt of t he s ur gical s uccess ( verifie d b y site pers o n nel 's re vie w of t he 
partici pa nt 's me dical rec or ds). 
•  Se x ual a bsti ne n ce c (se x ual a bsti ne n ce is n ot all o we d i n Ja pa n). 
− A bsti ne n ce fr o m pe nile -va gi nal i nterc o urse  
T he f oll o wi n g are n ot  acce pta ble met h o ds of c o ntrace pti o n:  
•  Peri o dic a bsti ne n ce (cale n dar, s y m pt ot her mal, p os to v ulati o n  met h o ds), wit h dra wal (c oit us i nterr u pt us), 
s per mici des o nl y, a n d lactati o nal a me n orr h oea met h o d. 
•  Male c o n d o m wit h ca p, dia p hra g m, or s p o n ge wit h s per mici de.  
•  Male a n d fe male c o n d o m use d t o get her.  
N ote : Me n wit h a pre g na nt or breastfee di n g part ner  m ust a gree t o re mai n a bsti ne nt fr o m pe nile -va gi nal 
i nterc o urse or use a male c o n d o m d uri n g eac h e pis o de of pe nile pe netrati o n. Se x ual a bsti ne nce is n ot all o we d i n 
Ja p a n.  

I nc yte C or p orati o n 
Pa ge 7 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
F or fe m ale p artici p a nts w h o are W O C B P  
T he f oll o wi n g met h o ds d uri n g t he Pr ot oc ol -defi ne d ti mefra me i n Secti o n  5. 1  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 met h o ds: 
•  C o m bi ne d (estr o ge n a n d pr o gest o ge n c o nta i 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 d 
− oral  
− i ntra v a gi nal (a d mi nistrati o n r o ute is n ot a p pr o ve d i n Ja pa n) 
− tra ns der mal (a d mi nistrati o n r o ute is n ot a p pr o ve d i n Ja pa n) 
•  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 d (pr o gester o ne -o nl y 
h or m o nal c o ntrace pti o n is n ot a p pr o ve d i n Ja pa n, s o t his b ullet a n d its s u b -b ullets will n ot a p pl y f or Ja p a n ) 
− oral  
− i njecta ble 
− i m pla nta blee 
•  I ntra uteri ne de vicee 
•  I ntra uteri ne h or m o ne-releasi n g s yste me 
•  Bilateral t u bal occl usi o n e 
•  Vasect o mize d part ner e,f 
•  Se x ual a bsti ne n ce c (se x ual a bsti ne n ce is n ot a p pr o ve d i n Ja pa n). 
a D oc u me ntati o n ca n c o me fr o m t he site p ers o n nel 's re vie w of t he partici p a nt's me dical rec or ds, me dical e xa mi n ati o n, or me dical 
hist or y i nter vie w.  
b If t h e male partici p a nt has a part ner wit h c hil dbeari n g  p ote ntial t he part n er s h o ul d als o use c o ntrace pti ves.  
c I n t h e c o nte xt of t his g ui d a 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 h e relia bilit y of se x ual 
a bsti ne nce nee ds t o be e val u ate d i n relati o n t o t h e d urati o n of t h e cli nical  st u d y a n d t he preferre d a n d us ual lifest yle of t h e 
partici p a nt . 
d 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 h e I M P, w hic h ma y re d uce t h e efficac y of t he c o ntrace pti o n 
met h o d . I n t his case, 2 met h o ds of c o ntrace pti o n s h o ul d be use d. 
e C o ntrace pti o n met h o ds t h at i n t he c o nte xt of t his g ui d a nce are c o nsi d ere d t o ha ve l o w user de pe n de nc y.  
f Vasect o mize d part n er 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 d e d t h at part n er is t he s ole se x ual part n er of t he 
W O C B P st u d y partici p a nt a n d t hat t h e vasect o mize d part ner has recei v e d me dical assess m e nt of t he  s ur gical s uccess. 
S o urce : Cli nical Trials Facilitati o n a n d C o or di nati o n Gr o u p 2 0 2 0 . 

I nc yte C or p orati o n 
Pa ge 8 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A P P E N DI X  B.  E LI GI B L E F G F R G E N E A L T E R A TI O N S  
T a ble B 1 . 
Eli gi ble F G F R Ge ne Alter ati o ns  
Ge ne  
V ari a nt Cl ass  
Eli gi bilit y  R ules  
F G F R 1 
( N M _0 2 3 1 1 0 , 
P 1 1 3 6 2 ) 
 
F G F R 2  
( N M _ 0 0 0 1 4 1, 
P 2 1 8 0 2 )  
 
F G F R 3  
( N M _ 0 0 0 1 4 2, 
P 2 2 6 0 7 ) 
S h ort n ucle oti de 
varia nts  
•  
A n y of t he m utati o ns liste d i n A p pe n di x Ta ble A 2  
•  
I n dels: F G F R 2 I n-fra me d eleti o ns (s pa n ni n g wit hi n pr otei n 
se q ue nce 1 6 7-1 7 6, 2 5 6 -2 7 3, 2 8 0 -3 1 2)  
Rearra n ge me nts  
•  
A n y rearra n ge me nt wit h a literat ure-deri ve d k n o w n part ner 
ge ne liste d i n A p pe n di x Ta ble A 3 re gar dless of stra n d or 
fra me 
•  
A n y rearra n ge me nt wit h a n o vel part ner ge ne t hat is i n -
fra me a n d i n t he sa me 5' t o 3' orie ntati o n  
•  
A n y rearra n ge me nt wit h 1  brea k p oi nt i n t he h ots p ot re gi o n 
(i ntr o n 1 7 t o e x o n 1 8) a n d t he ot her brea k p oi nt i n a n 
i nter ge nic re gi o n or wit hi n a n ot her ge ne. T his r ule e xcl u des 
3 'd u plicati o ns of e x o n 1 8  
•  
A n y intra ge nic d u plicati o n of re gi o n c o ntai ni n g t he ki nase  
d o mai n (e x o ns 1 1 -1 7)  
C o p y n u m ber  
N ot i ncl u de d  
 
 
I neli gi bilit y R ules 
 
 
F G F R rearra n ge me nts or s h ort varia nts  are i neli gi ble if  
•  
T here is a pe mi gati ni b resista nce m utati o n, liste d i n 
A p pe n di x  Ta ble  A 4  
•  
T he ki nase d o mai n is n ot i ntact . F or rearra n ge me nts, t he 
ki nase d o mai n is c o nsi dere d i ntact if t he F G F R brea k p oi nt is 
n ot l ocate d bet wee n e x o ns 1 1 a n d 1 7  
T a ble B 2 . 
Eli gi ble F G F R 1 -3 M ut ati o ns f or I ncl usi o n  
Ge ne  
P ositi o n  
Alter ati o n  
Ge ne  
P ositi o n  
Alter ati o n  
Ge ne  
P ositi o n  
Alter ati o n  
F G F R 1  
6 5 6  
K 6 5 6( E, M, N, T)  F G F R 2  
2 5 2  
S 2 5 2 W  
F G F R 3  
2 4 8  
R 2 4 8 C  
 
 
 
F G F R 2  
2 5 3  
P 2 5 3 R  
F G F R 3  
2 4 9  
S 2 4 9 C  
 
 
 
F G F R 2  
2 5 3  
P 2 5 3 F  
F G F R 3  
3 7 0  
G 3 7 0 C  
 
 
 
F G F R 2  
2 9 0  
W 2 9 0 C  
F G F R 3  
3 7 1  
S 3 7 1 C  
 
 
 
F G F R 2  
3 7 2  
S 3 7 2 C  
F G F R 3  
3 7 3  
Y 3 7 3 C  
 
 
 
F G F R 2  
3 7 5  
Y 3 7 5 C  
F G F R 3  
3 7 5  
G 3 7 5 C  
 
 
 
F G F R 2  
3 8 2  
C 3 8 2 R  
F G F R 3  
3 8 0  
G 3 8 0 R  
 
 
 
F G F R 2  
3 9 5  
V 3 9 5 D  
F G F R 3  
6 5 0  
K 6 5 0( E, M, N, T)  
 
 
 
F G F R 2  
6 5 9  
K 6 5 9( E, M, N, T)  
 
 
 
N ote: P ositi o ns refer t o ca n o nical se q ue nces f or F G F R 1 ( P 1 1 3 6 2 ), F G F R 2 (P 2 1 8 0 2 ), a n d F G F R 3 ( P 2 2 6 0 7 ). 

I nc yte C or p orati o n 
Pa ge 8 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
T a ble B 3 . 
K n o w n F G F R F usi o n P art ner Ge nes  
Ge ne  
K n o w n F usi o n P art ners  
F G F R 1  
Z N F 7 0 3, T A C C 1, F G F R 1 O P A C V R 1, Z M Y M 2, T RI M 2 4, B C R, C N T R L, B A G 4, E R LI N 2  
F G F R 2  
BI C C 1, A F F 3, C A S P 7, C C D C 6, KI A A 1 9 6 7, O F D 1, S L C 4 5 A 3, KI A A 1 5 9 8, A H C Y L 1, 
B F S P 2, CI T, M G E A 5, N O L 4, P A R K 2, S H 3 G L B 1, T A C C 1, T A C C 2, T A C C 3  
F G F R 3  
E T V 6, T A C C 3, B AI A P 2 L 1  
T a ble B 4 . 
Pe mi g ati ni b  Resist a nce  M ut ati o ns f or E xcl usi o n  
Ge ne  
Resist a nce M ut ati o ns  
F G F R 1  
V 5 6 1( L, M,I, F)  
F G F R 2  
N 5 4 9( K, H, D, T), V 5 6 4( L, M,I, F), M 5 3 7I, E 5 6 5 A, K 5 6 9 M, L 6 1 7 V, K 6 4 1 R  
F G F R 3  
N 5 4 0( K, H, D, T), V 5 5 5( L, M,I, F), M 5 2 8I  

I nc yte C or p orati o n 
Pa ge 8 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A P P E N DI X  C.  I N S T R U C TI O N T O P A R TI CI P A N T S F O R H A N D LI N G 
S T U D Y D R U G ( P E MI G A TI NI B ) 
T he partici pa nt m ust be i nstr ucte d i n t he ha n dli n g of st u d y dr u g as f oll o ws:  
•  St ore t he st u d y dr u g at r o o m te m perat ure.  
•  O nl y re m o ve t he n u m ber of ta blets nee d e d at t he ti me of a d mi nistrati o n.  
•  D o n ot  re m o ve d oses i n a d va nce of t h e ne xt sc h e d ule d a d mi nistrati o n. 
•  Ma ke e ver y eff ort t o ta ke d oses o n sc he d ule.  
•  Re p ort a n y misse d d oses/l ost ta blets/ca ps ules.  
•  T a ke st u d y dr u g wit h a f ull glass of water.  
•  If v o miti n g occ urs  aft er t a ki n g st u d y dr u g, d o  n ot ta ke a n ot her d os e.  
•  K ee p st u d y dr u g i n a s afe place a n d o ut of reac h of c hil dre n.  
•  B ri n g all use d a n d u n use d st u d y dr u g b ottles/ kits t o t he site at eac h visit. 
•  If a d ose of pe mi gati ni b  is misse d b y m ore t ha n 4 h o urs, t hat d ose s h o ul d be s ki p pe d 
a n d t he ne xt sc he d u l e d d ose s h o ul d be a d mi nistere d at t he us ual ti me. 

I nc yte C or p orati o n 
Pa ge 8 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A P P E N DI X  D.  C Y P 3 A 4 I N HI BI T O R S A N D I N D U C E R S  
C Y P 3 A I n d ucers  
I n d ucers 
T her a pe utic cl ass  
P ote nt C Y P 3 A I n d ucers  
Rifa m pi n  
A nti bi otics  
Mit ota ne  
Ot her a nti ne o plastics  
A vasi mi be  
Ot her a ntili pe mics  
Rifa pe nti ne  
A nti bi otics  
A pal uta mi de  
A ntia n dr o ge ns  
P he n yt oi n  
A ntic o n v ulsa nts  
Car ba maze pi ne  
A ntic o n v ulsa nts  
E nzal uta mi de  
A ntia n dr o ge ns  
St J o h n 's W ort e xtract 
Her bal me dicati o ns  
L u macaft or  
C ystic fi br osis treat me nts  
Rifa b uti n  
A nti bi otics  
P he n o bar bital  
A ntic o n v ulsa nts  
M o der ate C Y P 3 A I n d ucers  
Rit o na vir a n d St J o h n 's W ort  
N o ne  
Se ma gacestat  
Alz hei mer 's treat me nts 
Efa vire nz  
N N R TIs  
Ti pra na vir a n d rit o na vir  
Pr otease i n hi bit ors  
Da brafe ni b  
Ki nase i n hi bit ors  
Lesi n ura d  
A nti g o ut a n d uric os uric a ge nts  
B ose nta n  
E n d ot heli n rece pt or a nta g o nists  
Ge nistei n  
F o o d pr o d ucts  
T hi ori dazi ne  
A nti ps yc h otics  
Nafcilli n  
A nti bi otics  
Tal virali ne  
N N R TIs  
L o pi na vir  
Pr otease i n hi bit ors  
M o dafi nil  
Ps yc h osti m ula nts  
Pf -0 6 2 8 2 9 9 9  
M yel o per o xi dase i nacti vat ors  
Etra viri ne  
N N R TIs  
Lersi viri ne  
N N R TIs  
Tel otristat et h yl  
A nti diarr heals  

I nc yte C or p orati o n 
Pa ge 8 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
C Y P 3 A I n hi bit ors  
I n hi bit or 
T her a pe utic  Cl ass  
P ote nt C Y P 3 A I n hi bit ors  
VI E KI R A P A K  
A nti virals  
I n di na vir/ RI T 
Pr otease i n hi bit ors  
Ti pra na vir/ RI T  
Pr otease i n hi bit ors  
Rit o na vir  
Pr otease i n hi bit ors  
C o bicistat ( G S -9 3 5 0)  
N o ne  
Ket oc o naz ole  
A ntif u n gals  
I n di na vir 
Pr otease i n hi bit ors  
Tr olea n d o m yci n  
A nti bi otics  
Tela pre vir  
A nti virals  
Da n o pre vir/ RI T  
A nti virals  
El vite gra vir/ RI T  
Treat me nts of AI D S  
Sa q ui na vir/ RI T  
Pr otease i n hi bit ors  
L o pi na vir/ RI T  
Pr otease i n hi bit ors  
Itrac o naz ole 
A ntif u n gals  
V oric o naz ole  
A ntif u n gals  
Mi befra dil  
Calci u m c ha n nel bl oc kers  
L C L 1 6 1  
Ca ncer treat me nts  
Clarit hr o m yci n  
A nti bi otics  
P osac o naz ole  
A ntif u n gals  
Telit hr o m yci n  
A nti bi otics  
Gra pefr uit j uice  
F o o d pr o d ucts  
C o ni va pta n  
Di uretics  
Nefaz o d o ne  
A nti de pressa nts  
Nelfi na vir  
Pr otease i n hi bit ors  
Sa q ui na vir  
Pr otease i n hi bit ors  
Ri b ocicli b  
Ki nase i n hi bit ors  
I delalisi b 
Ki nase i n hi bit ors  
B oce pre vir  
A nti virals  

I nc yte C or p orati o n 
Pa ge 8 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
C Y P 3 A I n hi bit or s ( C o nti n ue d) 
I n hi bit or 
T her a pe utic  Cl ass  
M o der ate C Y P 3 A I n hi bit ors  
Er yt hr o m yci n  
A nti bi otics  
Fl uc o naz ole  
A ntif u n gals  
Ataza na vir/ RI T  
Pr otease i n hi bit ors  
Dar u na vir  
Pr otease i n hi bit ors 
Diltiaze m  
Calci u m c ha n nel bl oc kers  
Dar u na vir/ RI T  
Pr otease i n hi bit ors  
Dr o ne dar o ne  
A ntiarr h yt h mics  
Criz oti ni b  
Ki nase i n hi bit ors  
Ataza na vir  
Pr otease i n hi bit ors  
Leter m o vir  
A nti virals  
G S K 2 6 4 7 5 4 4  
Alz hei mer 's disease & de me ntia treat me nts 
A pre pita nt  
A ntie metics  
Cas o pita nt  
A ntie metics  
A m pre na vir  
Pr otease i n hi bit ors  
Fal da pre vir  
A nti virals  
I mati ni b 
A nti ne o plastic a ge nts  
Vera pa mil  
Calci u m c ha n nel bl oc kers  
Net u pita nt  
A ntie metics  
Nil oti ni b  
Ki nase i n hi bit ors  
Gra pefr uit j uice  
F o o d pr o d ucts  
T ofis o pa m  
Be nz o diaze pi nes  
C ycl os p ori ne  
I m m u n os u p pressa nts 
A C T -1 7 8 8 8 2  
Re ni n i n hi bit ors  
Ci pr ofl o xaci n  
A nti bi otics  
Ma g n olia vi ne ( Sc hisa n dra s p he na nt hera)  
Her bal me dicati o ns  
Isa v uc o naz ole 
A ntif u n gals  
Ci meti di ne  
H -2 rece pt or a nta g o nists 
F K 1 7 0 6  
Ce ntral ner v o us s yste m a ge nts  

I nc yte C or p orati o n 
Pa ge 8 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A P P E N DI X  E.  C O VI D -1 9 P A N D E MI C MI TI G A TI O N S T R A T E GI E S A N D 
I N S T R U C TI O N S 
T he C O VI D -1 9 gl o b al pa n de mic pres e nts n u mer o us c halle n ges t o t he o n g oi n g c o n d uct of 
cli nical trials . I n li ne wit h t he E ur o pea n M e dici nes A ge nc y's G ui da n ce o n t he Ma na ge m e nt of 
Cli nical Trials D uri n g t he C O VI D -1 9 ( C or o na vir us) Pa n de mic ( 2 0 2 0 ), t he s p o ns or has iss ue d t he 
f oll o wi n g Pr ot oc ol c o nsi derati o ns t o e ns ure p artici pa nt safet y is mai ntai ne d a n d a de q u ate 
be nefit/ ris k a nal yses are a p plie d relati ve t o t he c o m pleti o n of st u d y pr oce d ures a n d mai ntai ni n g 
t he i n vesti gati o nal pr o d uct s u p pl y c hai n. 
Rec o g nizi n g t he fle xi bilit y re q uire d t o ma n a ge t he i m pact of t he pa n de mic o n t his cli nical trial, 
a d diti o nal details will be a d de d t o res p ecti ve st u d y ma n uals a n d pr oject pla n d oc u me nts a n d 
c o m m u nicate d t o t he i n vesti gati ve sites as nee d e d.  
St u d y Site Visits  
If l ocal tra v el restricti o ns, is olati o n re q uire me nts, or t he i n vesti gat or's be nefit/ris k assess me nt 
deter mi nes it t o be u n safe f or partici pa nts t o atte n d st u d y visits at t he i n vesti gati o nal site, t he site 
staff ma y ele ct t o p urs ue t he f oll o wi n g: 
•  I n or der t o mi ni mize partici pa nt ris k, st u d y visits ma y be c o n d uct e d via tel e me dici ne 
m o dalities ( p h o ne or vi de o) . At a mi ni m u m, a r e vie w of A Es, c o n c o mita nt 
me dicati o ns, a n d st u d y dr u g c o m plia nce m ust be c o m plete d . Peri o dic o n -site visits 
s h o ul d be c o n d ucte d w h e ne ver feasi ble. 
•  I n or der t o s u p p ort i n vesti gat or o versi g ht of partici pa nt safet y a n d disease 
ma na ge me nt, t he p artici p a nt ma y be as ke d t o u n d er g o s o me la b orat or y t ests or st u d y 
pr oce d ures (e g,  e ye e xa mi nati o n) at a l ocal ( pr o xi mate) h os pital la b orat or y or facilit y 
cl oser t o t he partici p a nt 's resi de nce rat her t ha n at t he i n vesti gati o nal site. I n t his case, 
t he st u d y p h ysicia n will pr o vi de t he partici p a nt wit h t he list of para meters t o be 
c hec k e d . T hese t ests s h o ul d be perf or m e d i n certifie d la b orat ori es.  
•  Assess me nts t hat are misse d s h o ul d be n ote d as de viati o ns t o t he Pr ot oc ol a n d s h o ul d 
be d oc u me nte d acc or di n gl y.  
I n vesti g ati o n al Me dici n al Pr o d uct Dis pe ns ati o n a n d Distri b uti o n 
I n or der t o e ns ure t he c o nti n uit y of pr o vi di n g t heir partici pa nt' cli nical s u p plies wit hi n t he 
c o nstrai nts i m parte d b y t he pa n de mic, t he site staff ca n deci de t o s u p pl y I M P t o partici pa nts as 
f oll o ws: 
•  W here p ossi ble, w he n t h e partici pa nt atte n ds a visit at t he st u d y site, t he i n vesti gat or 
ca n dis pe nse a n a d diti o nal a m o u nt of pe mi gati ni b  ta blets t o c o ver a l o n g er i nter val 
bet wee n o n -site st u d y visits t ha n sti p ulate d i n t he S o A (see Ta bl e  3 ). 
•  Alter nati vel y, if t he partici pa nt ca n n ot atte n d a visit at t he st u d y site, a de q uate 
s u p plies of I M P t o c o v er 1 or m ore c y cles ca n b e s hi p pe d t o t he partici pa nt b y t he 
i n vesti gat or or a p pr o pri atel y dele gate d staff (e g, t h e st u d y p har mac y staff) usi n g a 
t hir d-part y ser vice if d ul y a ut h orize d b y t he partici pa nt . T he st u d y site ma y use t heir 
o w n preferre d c o urier, pr o vi de d t he c o urier a d heres t o certai n sta n dar ds (e g, use of 
pers o nal pr otecti o n e q ui p me nt, mai nte na nce of te m perat ure -c o ntr olle d tr a nsit 
e n vir o n me nt), or o ne ce ntrall y c o ntracte d b y t he s p o ns or.  

I nc yte C or p orati o n 
Pa ge 8 7  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
Cli nic al Tri al M o nit ori n g  
St u d y m o nit ori n g visits c o ul d be p ost p o ne d; h o we ver, t he site m o nit or will c o nti n ue t o e m pl o y 
off -site m o nit ori n g practi ces s uc h as r o uti ne c o m m u nicati o n met h o ds (e g, p h o ne calls, e mails, 
vi de o visits) wit h t he sites t o get i nf or mati o n o n trial pr o gress, partici pa nt stat us, a n d i nf or mati o n 
o n iss ue res ol uti o n . T he st u d y m o nit or ma y re m otel y re vie w data e ntere d i nt o t he E D C f or 
acc urac y a n d c o m plete n ess . Re m ote s o urce data verificati o n ma y be i m ple me nte d wit h 
a gree m e nt of t he pri nci p al i n vesti gat or a n d i nstit uti o n, as a p plica ble.  
If t he st u d y site m o nit or ca n n ot be o n-site t o perf or m t he fi nal dr u g acc o u nt a bilit y f or 
rec onciliati o n p ur p oses, a n d t he o perati o n ca n n ot be p ost p o ne d, it ma y be perf or me d b y a 
p har macist fr o m t he h os pital p har mac y or b y t h e st u d y c o or di nat or/ data m a na ger wit h s uita ble 
trai ni n g. T he I M P ca n b e ret ur ne d t o t he s p o ns or b y t he h os pital p har mac y dire ctl y or destr o y e d 
i n acc or da nce wit h l ocal practices, if a p plica ble, a n d wit h s p o ns or a p pr o val. 
Direct C o ntr acts Wit h T hir d P arties/ S peci alize d Ser vice C o m p a nies  
If necessar y, dir ect c o ntracts ca n b e esta blis he d wit h t hir d-part y l ocal p h ysicia ns t o c o n d uct  
acti vities relate d t o t he cli nical ma na ge me nt of p artici pa nts f or w h o m t he i n vesti gat or is 
res p o nsi ble a n d mai ntai ns o versi g ht. I n s u c h sit uati o ns, t he i n vesti gat or is re q uire d t o pr o vi de t he 
l ocal p h ysicia n wit h a del e gati o n letter listi n g all dele gate d acti vities. T he s p o ns or, t hr o u g h t he 
st u d y i n vesti gat or or i nstit uti o n, will rei m b urse t he l ocal p h ysicia n f or t he t est/ pr oce d ures 
c o n d ucte d o utsi de of t he sta n dar d of care.  
Rei m b urse me nt of E xtr a or di n ar y E x pe nses  
T he s p o ns or will arra n ge t o rei m b urse part ici p a nts f or a n y e xtr a or di nar y e x p e nses, kee pi n g 
a p pr o priate d o c u me ntati o n as e vi de nce (e g, tr a vel e x pe nses f or t he l ocal la b orat or y visit[s], t he 
c osts of l ocal [ pr o xi mate] la b orat or y tests).  

I nc yte C or p orati o n 
Pa ge 8 8  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A P P E N DI X  F.  N A N O S C A L E  
 

I nc yte C or p orati o n 
Pa ge 8 9  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
 

I nc yte C or p orati o n 
Pa ge 9 0  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
 

I nc yte C or p orati o n 
Pa ge 9 1  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A P P E N DI X  G.  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 me n d me nt 1  
1 9  N O V 2 0 2 1  
A me n d me nt 2  
1 9 J A N 2 0 2 3  
A me n d me nt 3  
2 6  J U L 2 0 2 4 
A me n d me nt 3 ( 2 6  J U L 2 0 2 4)  
O verall Rati o nale f or t he A me n d me nt:  
T he mai n p ur p ose of t his a me n d me nt is t o i n dicate t hat at t he e n d of t h e st u d y, partici pa nts w h o 
c o nti n ue t o recei ve t he st u d y dr u g will ha ve c o nti n u e d access t o it i n acc or da nce wit h  l ocal 
re g ulati o ns or via I n c yte. 
1.  Secti o n 1, Pr ot oc ol S u m m ar y ( T a ble 3: Sc he d ule of Acti vities); Secti o n 8. 8. 3, 
S ur vi v al F oll o w -U p  
Descri pti o n of c h a n ge:  A d de d a wi n d o w of ± 1 4 da ys f or s ur vi val f oll o w u p visits. 
R ati o n ale f or c h a n ge:  T he wi n d o w was i na d v erte ntl y o mitte d i n pre vi o us versi o ns of t he 
pr ot oc ol.  
2.  Secti o n 4. 2 , O ver all St u d y D ur ati o n  
Descri pti o n of c h a n ge:  U p date d t o i n dicate  w he n  t he e n d of st u d y will occ ur . 
Rati o nale f or c h a n ge:  T o c larify  e n d of st u d y . 
3.  Secti o n 5. 1, I ncl usi o n Criteri a (I ncl usi o n Criteri o n 1)  
Descri pti o n of c h a n ge:  I ncl usi o n criteri o n 1 has b ee n u p date d t o i n dicate t hat a le gall y 
a ut h orize d re pres e ntati ve ma y si g n t he state me nt of i nf or me d c o ns e nt f or a partici pa nt . 
A d d e d Fra nce t o Ger m a n y s pecificati o n  t hat re q uires partici pa nts t o pr o vi d e t heir o w n 
c o nse nt.  
R ati o n ale f or c h a n ge:  U p date was t o ali g n wit h Secti o n  8. 1. 1 , a n d t he a d diti o n of Fra n ce 
was fee d bac k fr o m Fre n c h A N S M . 
4.  Secti o n 6. 7 , Tre at me nt After t he E n d of St u d y  
Descri pti o n of c h a n ge:  U p date d partici p a nt  access t o st u d y dr u g after e n d of st u d y.  
R ati o n ale f or c h a n ge:  T o c larify  t hat at t he e n d of st u d y if partici pa nts  are still recei vi n g 
be nefit, t he y will be offere d c o nti n u o us access t o st u d y dr u g i n acc or da nce wit h  l ocal 
re g ulati o ns or via s p o ns or (I nc yte). 
5.  I nc or p or ati o n of a d mi nistr ati ve c h a n ges. Ot her re g ulat or y g ui da nce a n d a d mi nistrati ve 
c ha n ges ha v e 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 m e nt.  

I nc yte C or p orati o n 
Pa ge 9 2  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A me n d me nt 2 ( 1 9 J A N 2 0 2 3 ) 
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 os e of t his a me n d me nt is t o i nc or p orate p artici pa nts fr o m C o h ort C wit h 
acti vati n g m utati o ns i nt o C o h orts A a n d B . A d diti o nal cha n ges are s u m marize d bel o w.  
1.  Secti o n 1, Pr ot oc ol S u m m ar y; Secti o n 4. 1, O ver all Desi g n; Secti o n 8. 6. 1, Bi o m ar ker 
Assess m e nt f or Eli gi bilit y  
Descri pti o n of c h a n ge: Clarifie d t hat m olec ular assa ys t o deter mi ne F G F R alterati o ns 
ha ve t he rele va nt mar k of c o nf or mit y i n t he U K.  
R ati o n ale f or c h a n ge:  Fee d bac k fr o m M H R A.  
2.  Secti o n 1, Pr ot oc ol S u m m ar y ( T a ble 1 : Pri m ar y a n d Sec o n d ar y O bjecti ves a n d 
E n d p oi nts ); Secti o n  3, O bjecti ves a n d E n d p oi nts ( T a ble 6: O bjecti ves a n d 
E n d p oi nts)  
Descri pti o n of c h a n ge : U p date d t he des cri pti o ns of t he t u m ors base d o n t h e ne west 
classificati o n of W H O criteria.  
R ati o n ale f or c h a n g e: Fee d bac k fr o m t he Scie ntific Steeri n g C o m mittee  a n d ne wl y 
p u blis he d i nf or mati o n.  
3.  Secti o n 1, Pr ot oc ol S u m m ar y ( T a ble 1: Pri m ar y a n d Sec o n d ar y O bjecti ves a n d 
E n d p oi nts; T a ble 2: Ke y St u d y Desi g n Ele me nts ; Fi g ure 1: St u d y Desi g n Sc he m a); 
Secti o n 3, O bjecti ves a n d E n d p oi nts ( T a ble 6: O bjecti ves a n d E n d p oi nts); 
Secti o n  4. 1, O ver all Desi g n; Secti o n 5. 1, I ncl us i o n Criteri a ( Criteri a 3 a n d 7) 
Descri pti o n of c h a n ge: Delete d C o h ort C a n d i nc or p orate d t he p o p ul ati o n i nt o 
C o h orts  A a n d B.  
R ati o n ale f or c h a n ge:  N e w p u blicati o ns a n d e mer gi n g data ha ve s h o w n t hat o nc o ge nic 
m utati o ns d o be nefit fr o m tar gete d t hera pies. T heref ore, t he e x pl or at or y c o h ort was 
re m o ve d a n d t he m utati o ns were i nc or p orat e d i nt o C o h orts A a n d B. 
4.  Secti o n 1, Pr ot oc ol S u m m ar y ( T a ble 1:  Pri m ar y a n d Sec o n d ar y O bjecti ves a n d 
E n d p oi nts; T a ble 2: Ke y St u d y Desi g n Ele me nt s; Fi g ure 1: St u d y Desi g n Sc he m a ); 
Secti o n 2, I ntr o d ucti o n; Secti o n 3, O bjecti ves a n d E n d p oi nts ( T a ble 6: O bjecti ves 
a n d E n d p oi nts); Secti o n  4. 1, O ver all Desi g n ; Secti o n 1 0. 1, S a m ple Size 
Deter mi n ati o n  
Descri pti o n of c h a n ge:  Re place d "ot her pri mar y C N S t u m ors " wit h  "ot her gli o mas , 
circ u mscri be d astr oc ytic gli o mas , a n d gli o ne ur o nal a n d ne ur o nal t u m ors ." 
R ati o n ale f or c h a n ge:  T o mat ch u p date d W H O criteria . 
5.  Secti o n 1, Pr ot oc ol S u m m ar y ( T a ble 2: Ke y St u d y Desi g n Ele me nts)  
Descri pti o n of c h a n ge:  Re vise d t he n u m ber of partici pa nts t o 1 6 4 (a p pr o xi matel y 
8 2  partici pa nts i n eac h c o h ort).  
R ati o n ale f or c h a n ge:  R e m o val of C o h ort C.  

I nc yte C or p orati o n 
Pa ge 9 3  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
6.  Secti o n 1, Pr ot oc ol S u m m ar y ; Secti o n  4. 1, O ver all Desi g n;  Secti o n 5. 1, I ncl usi o n 
Criteri a ( Crit eri o n 7); Secti o n 8. 6. 1, Bi o m ar ker Assess m e nt f or Eli gi bilit y  
Descri pti o n of c h a n ge: Clarifie d t he alterati o ns t hat are eli gi ble f or t he st u d y. 
R ati o n ale f or c h a n ge:  Fee d bac k  fr o m sites. 
7.  Secti o n 1, Pr ot oc ol S u m m ar y ; Secti o n  4. 1, O ver all Desi g n;  Secti o n 8. 6. 1, Bi o m ar ker 
Assess m e nt f or Eli gi bilit y  
Descri pti o n of c h a n ge: A d de d te xt t hat partici pa nts will be re q uire d t o ha ve a 
d oc u me nte d acti o na ble F G F R 1 -3 ge n e alterati o n fr o m t u m or tiss ue ( or plas ma) as 
deter mi n e d b y a l oc all y q ualifie d la b orat or y e m pl o yi n g a m olec ular ass a y h a vi n g a 
rele va nt mar k of c o nf or mit y a nal ytical perf or m a nce (e g, C LI A [ U S] or U K C A, C E, C E 
U K NI, or ot hers [ o utsi de of t he U S]) or a c o m mercial re p ort fr o m t he ce ntr al la b orat or y 
t o be eli gi ble. 
R ati o n ale f or c h a n ge:  Fee d bac k fr o m M H R A.  
8.  Secti o n 1, Pr ot oc ol S u m m ar y ; Secti o n  4. 1, O ver all Desi g n;  Secti o n 5. 1, I ncl usi o n 
Criteri a ( Crit eri o n 9); Secti o n 8. 6. 1, Bi o m ar ker Assess m e nt f or Eli gi bilit y; 
Secti o n  8. 6. 4, Tiss ue Bi o psies  
Descri pti o n of c h a n ge : Re m o ve d t he re q uir e me nt f or testi n g t o c o nfir m t he prese n ce of 
a n eli gi ble F G F R alterati o n t o be perf or me d wit hi n 2 4 m o nt hs of scree ni n g a n d t he 
re q uire me nt of a bi o ps y f or ot her testi n g. 
R ati o n ale f or c h a n ge:  Fee d bac k fr o m sites.  
9.  Secti o n 1, Pr ot oc ol S u m m ar y ; Secti o n  4. 1, O ver all Desi g n;  Secti o n 5. 1, I ncl usi o n 
Criteri a ( Crit eri o n 7)  
Descri pti o n of c h a n ge: A d de d te xt t hat partici pa nts wit h k n o w n F G F R resista nce 
m utati o ns are n ot eli gi ble.  
R ati o n ale f or c h a n ge : It has bee n s h o w n t hat t here is u nli kel y be nefit wit h F G F R 
resista nt m utati o ns. 
1 0.  Secti o n 4. 3, St u d y Ter mi n ati o n; Secti o n 1 1. 6, St u d y a n d Site Cl os ure  
Descri pti o n of c h a n ge:  A d de d s pecifi c p ossi ble reas o ns f or st u d y or site cl os ure.  
R ati o n ale f or c h a n ge : F ee d bac k fr o m G er ma n C E C.  
1 1.  Secti o n 5. 1, I ncl usi o n Criteri a ( Criteri a  1  a n d 3 a ) 
Descri pti o n of c h a n ge:  A d de d  la n g ua g e f or Ger ma n y t o Criteri o n 1 t hat o nl y 
partici pa nts w h o ca n pr o vi de t heir o w n c o nse nt are a ble t o partici p ate i n t he st u d y , a n d 
re m o ve d ra di ot hera p y fr o m Criteri o n 3a t o clarif y t hat partici pa nts ca n n ot e nter t he st u d y 
after o nl y ha vi n g r ecei ve d ra di ot hera p y . 
R ati o n ale f or c h a n ge:  F ee d bac k fr o m G er ma n C E C a n d Fre nc h A N S M.  

I nc yte C or p orati o n 
Pa ge 9 4  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1 2.  Secti o n 5. 1, I ncl usi o n Criteri a ( Criteri o n 1 ) 
Descri pti o n of c h a n ge:  R e m o ve d la n g ua ge f or Ja pa n t hat partici pa nts a g e d 2 0 years or 
ol der ca n pr o vi de c o nse nt  at t he ti me of si g ni n g t he I C F.  
R ati o n ale f or c h a n ge: P M D A re q uir e me nt.  
1 3.  Secti o n 5. 1, I ncl usi o n Criteri a ( Criteri o n 8)  
Descri pti o n of c h a n ge:  C ha n ge d w or di n g t o i n dicate partici pa nts w h o are u ns uita ble f or 
t he a p pr o ve d t hera p y. 
R ati o n ale f or c h a n ge:  F ee d bac k fr o m Fre n c h A N S M . 
1 4.  Secti o n 5. 2, E xcl usi o n Criteri a ( Crit eri o n 1) ; Secti o n 6. 6. 2, Pr o hi bite d Me dic ati o ns 
a n d Pr oce d ures  
Descri pti o n of c h a n ge:  C ha n ge d w or di n g s o t hat pri or recei pt of a n F G F R i n hi bit or  a n d 
pri or recei pt of re g orafe ni b is pr o hi bite d.  
R ati o n ale f or c h a n ge:  S u g geste d b y Scie ntific Steeri n g c o m mittee as it has a n i m pact o n 
resista nce me c ha nis m t o selecti ve F G F R i n hi bit ors. 
1 5.  Secti o n 5. 3, Lifest yle C o nsi der ati o ns  
Descri pti o n of c h a n ge:  Clarifie d t he t y pe of fr uit j uices t hat s h o ul d be a v oi de d  a n d t he 
ass ociate d ti mi n g . 
R ati o n ale f or c h a n ge:  Fee d bac k  fr o m sites. 
1 6.  Secti o n 6. 5. 1, Criteri a a n d Pr oce d ures f or D os e I nterr u pti o ns a n d A dj ust me nts of  
St u d y Dr u g ( T a ble 9: G ui deli nes f or I nterr u pti o n a n d Rest arti n g of St u d y Dr u g); 
Secti o n 6. 5. 3, Criteri a f or Per m a ne nt Disc o nti n u ati o n of St u d y Dr u g  
Descri pti o n of c h a n ge:  U p date d g ui deli ne f or ele vati o ns of t he J Tc i nter val a n d r e m o ve d 
t he n ote relate d t o li ver metastasis. 
R ati o n ale f or c h a n ge:  F ee d bac k fr o m G er ma n C E C a n d Fre nc h A N S M.  
1 7.  Secti o n 8. 3. 1, T u m or I m a gi n g  
Descri pti o n of c h a n ge:  A d de d te xt re q u esti n g t hat baseli ne M RI sca ns are d o ne wit hi n 7 
da ys of  C ycle 1 Da y 1 . 
R ati o n ale f or c h a n ge:  A d vice fr o m t he Scie ntific Steeri n g C o m mittee. 
1 8.  Secti o n 8. 6. 4, Tiss ue Bi o psies  
Descri pti o n of c h a n ge:  A d de d clarificati o n t hat E O T bi o psies will  i ncl u de a nal ysis of 
t he t u m or tiss ue t o assist i n u n dersta n di n g c ha n g es t hat occ ur i n ge n o mic alterati o ns after 
treat me nt wit h pe mi gati ni b. 
R ati o n ale f or c h a n ge:  F ee d bac k fr o m G er ma n C E C.  

I nc yte C or p orati o n 
Pa ge 9 5  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
1 9.  Secti o n 1 0. 1, S a m ple Size Deter mi n ati o n  ( T a ble 1 5: P o p ul ati o ns f or A n al ysis); 
Secti o n 1 0. 3. 1, Pri m ar y A n al ysis; Secti o n 1 0. 3. 2, Sec o n d ar y A n al ysis; Secti o n 1 0. 4, 
I nteri m A n al ysis 
Descri pti o n of c h a n ge:  Re m o ve d C o h ort C fr o m statistical a nal ysis a n d m o ve d O R R i n 
C o h ort B t o sec o n dar y a n al ysis.  
R ati o n ale f or c h a n ge:  A d vice fr o m t he Scie ntific Steeri n g C o m mittee a n d ne wl y 
p u blis he d data.  
2 0.  A p pe n di x B, Eli gi ble F G F R Ge ne Alter ati o ns  
Descri pti o n of c h a n ge:  U p date d ta bles wit h eli gi bilit y r ules, m utati o ns eli gi ble f or 
i ncl usi o n, k n o w n fusi o n part ner ge nes, a n d p e mi gati ni b -resista nt m utati o ns f or e xcl usi o n. 
R at i o n ale f or c h a n ge: I n res p o nse t o a d vice fr o m t he Scie ntific Steeri n g C o m mittee, site 
q uesti o ns a n d ne wl y p u blis he d i nf or mati o n.  
2 1.  I nc or p or ati o n of a d mi nistr ati ve ch a n ges.  Ot her re g ulat or y g ui da nce a n d a d mi nistrati ve 
c ha n ges ha v e 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 m e nt.  

I nc yte C or p orati o n 
Pa ge 9 6  of 9 6  
Pr ot oc ol I N C B 5 4 8 2 8 -2 0 9 A m 3  
Versi o n 4  
2 6  J U L 2 0 2 4  
V V -C LI N -0 1 6 6 5 4  
C O N FI D E N TI A L  
A me n d me nt 1 ( 1 9  N O V 2 0 2 1)  
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 nc or p orate u p d ates bas e d o n F D A re vie w of t h e Pr ot oc ol . A d diti o nal c ha n ges are s u m marize d 
bel o w.  
1.  Secti o n 1, Pr ot oc ol S u m m ar y ( T a ble 2: Ke y St u d y Desi g n Ele me nts ; Fi g ure 1: St u d y 
Desi g n Sc he m a ; T a ble 3: Sc he d ule of Acti vities); Secti o n 2. 2. 2, J ustific ati o n f or 
D ose; Secti o n 4. 1, O ver all St u d y Desi g n; Secti o n 4. 2, O ver all St u d y D ur ati o n ; 
Secti o n 6. 1, St u d y Tre at me nt I nf or m ati o n  (T a ble 8 : St u d y Tre at me nt I nf or m ati o n ); 
Secti o n 6. 5. 1, Criteri a a n d Pr oce d ures f or D os e I nterr u pti o ns a n d A dj ust me nts of 
St u d y Dr u g  
Descri pti o n of c h a n ge:  Treat me nt a d mi nistrati o n  c ha n ge d fr o m c o nti n u o us d osi n g t o 
i nter mitte nt d osi n g. 
R ati o n ale f or c h a n ge:  Fee d bac k fr o m F D A . 
2.  Secti o n 5. 2, E xcl usi o n Criteri a  ( Crit eri o n 2 0); Secti o n 6. 6. 1, Restri cte d Me dic ati o ns 
a n d Pr oce d ures  
Descri pti o n of c h a n ge:  U p date d wit h la n g ua g e re gar di n g t he c o n c o mit a nt use of 
m o derate C Y P 3 A 4 i n hi bit ors . 
R ati o n ale f or c h a n ge:  Fee d bac k fr o m F D A . 
3.  Secti o n 6. 5. 1, Criteri a a n d Pr oce d ures f or D os e I nterr u pti o ns a n d A dj ust me nts of 
St u d y Dr u g ( T a ble 9: G ui deli nes f or I nterr u pti o n a n d Rest arti n g of St u d y Dr u g)  
Descri pti o n of c h a n ge:  U p date d g ui deli nes f or i nterr u pti o ns a n d d ose a dj ust me nts.  
R ati o n ale f or c h a n ge:  Fee d bac k fr o m F D A.  
4.  Secti o n 6. 7, Tre at me nt After t he E n d of t he St u d y  
Descri pti o n of c h a n ge:  A d de d te xt t o i n dicate t h at partici pa nts ca n e nter t he I N C B 
5 4 8 2 8 -8 0 1 st u d y if t he y c o nti n ue t o recei ve cli nical be nefit fr o m p e mi gati ni b o nce t his 
st u d y is c o m plete d. 
R ati o n ale f or c h a n ge:  A d mi nistrati ve err or.  
5.  Secti o n 8. 5. 1, Bl o o d S a m ple C ollecti o n ( T a ble 1 3: P h ar m ac o ki netic Bl o o d S a m ple 
Ti mi n g)  
Descri pti o n of c h a n ge:  Re m o ve d C ycle 1 Da y 1 fr o m P K sa m ple ti mi n g.  
R ati o n ale f or c h a n ge:  A d mi nistrati ve err or.  
6.  Secti o n 1 0. 5 , I nteri m A n al ysis 
Descri pti o n of c h a n ge:  A d de d detail a b o ut c o h ort c o nti n uati o n a n d ter mi nati o n.  
R ati o n ale f or c h a n ge:  P er F D A fee d bac k.  
7.  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.  

Signature Page for VV-CLIN-016654 v5.0
Signature Page for VV-CLIN-016654 v5.0
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